Phenotypic	O
analysis	O
demonstrates	O
that	O
trio	B-GENE
and	O
Abl	B-GENE
cooperate	O
in	O
regulating	O
axon	O
outgrowth	O
in	O
the	O
embryonic	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
.	O

In	O
the	O
cervical	O
enlargement	O
they	O
were	O
located	O
in	O
the	O
middle	O
part	O
of	O
lamina	O
VII	O
and	O
in	O
lamina	O
VIII	O
,	O
accounting	O
for	O
about	O
25	O
%	O
of	O
the	O
total	O
labeled	O
neurons	O
.	O

We	O
measured	O
electromyograms	O
(	O
EMG	O
)	O
of	O
the	O
alae	O
nasi	O
to	O
determine	O
the	O
relationship	O
between	O
their	O
activity	O
and	O
timing	O
to	O
contraction	O
of	O
the	O
rib	O
cage	O
muscles	O
and	O
diaphragm	O
during	O
obstructive	O
apnea	O
in	O
nine	O
patients	O
.	O

A	O
case	O
control	O
study	O
(	O
1	O
:	O
2	O
)	O
of	O
182	O
pairs	O
of	O
Hepatitis	O
A	O
was	O
carried	O
out	O
in	O
Weng	O
-	O
ling	O
Zhe	O
-	O
jiang	O
during	O
April	O
1988	O
.	O

In	O
the	O
absence	O
of	O
shock	O
,	O
sepsis	O
,	O
or	O
other	O
identifiable	O
causes	O
of	O
lactic	O
acidosis	O
,	O
the	O
severe	O
anemia	O
(	O
hemoglobin	B-GENE
1	O
.	O
2	O
g	O
/	O
dl	O
)	O
appeared	O
to	O
be	O
the	O
primary	O
etiologic	O
factor	O
.	O

However	O
the	O
precise	O
function	O
of	O
DNA	B-GENE
-	I-GENE
PK	I-GENE
in	O
DNA	O
double	O
-	O
strand	O
break	O
repair	O
is	O
not	O
known	O
.	O

The	O
COR	B-GENE
biosynthetic	O
gene	O
cluster	O
in	O
P	O
.	O
syringae	O
pv	O
.	O
glycinea	O
PG4180	O
is	O
encoded	O
by	O
a	O
32	O
-	O
kb	O
region	O
which	O
contains	O
both	O
the	O
structural	O
and	O
regulatory	O
genes	O
needed	O
for	O
COR	B-GENE
synthesis	O
.	O

Substitution	O
of	O
cholinergic	O
drugs	O
in	O
the	O
treatment	O
of	O
Alzheimer	O
type	O
dementia	O
(	O
AD	O
/	O
SDAT	O
)	O
has	O
hitherto	O
not	O
been	O
very	O
successful	O
.	O

FEurea	O
was	O
also	O
measured	O
during	O
stable	O
graft	O
function	O
,	O
7	O
-	O
14	O
days	O
prior	O
to	O
allograft	O
dysfunction	O
.	O

The	O
findings	O
are	O
discussed	O
with	O
reference	O
to	O
possible	O
mechanisms	O
by	O
which	O
parasite	O
development	O
might	O
be	O
controlled	O
.	O

Interestingly	O
,	O
basal	O
MAPK	B-GENE
,	O
but	O
not	O
Raf	B-GENE
-	I-GENE
1	I-GENE
,	O
activity	O
was	O
constitutively	O
enhanced	O
in	O
Jak1	B-GENE
-	O
deficient	O
HeLa	O
cells	O
.	O

On	O
the	O
other	O
hand	O
hypokalemia	O
,	O
induced	O
by	O
diuretics	O
,	O
may	O
also	O
be	O
accompanied	O
by	O
a	O
significant	O
depletion	O
of	O
total	O
body	O
K	O
,	O
bringing	O
about	O
more	O
general	O
consequences	O
.	O

We	O
present	O
here	O
the	O
complete	O
primary	O
structure	O
of	O
human	B-GENE
gp330	I-GENE
,	O
the	O
human	O
variant	O
of	O
the	O
principal	O
kidney	O
autoantigen	O
causing	O
Heymann	O
membranous	O
glomerulonephritis	O
in	O
rats	O
.	O

A	O
series	O
of	O
deletion	O
mutants	O
was	O
expressed	O
transiently	O
in	O
two	O
human	O
hepatocytes	O
,	O
HepG2	O
and	O
PLC	O
.	O

Biol	O
.	O

Copyright	O
2000	O
Academic	O
Press	O
.	O

No	O
patient	O
demonstrated	O
a	O
decrease	O
in	O
bone	O
marrow	O
fibrosis	O
as	O
determined	O
by	O
serial	O
procollagen	B-GENE
(	O
PC	B-GENE
III	I-GENE
)	O
serum	O
level	O
analysis	O
.	O

In	O
four	O
calves	O
given	O
Haemonchus	O
contortus	O
larvae	O
,	O
the	O
serum	B-GENE
pepsinogen	I-GENE
concentration	O
rose	O
quickly	O
to	O
reach	O
a	O
mean	O
of	O
3	O
.	O
5	O
iu	O
tyrosine	O
on	O
day	O
14	O
after	O
infection	O
.	O

The	O
P	B-GENE
-	I-GENE
ITIM	I-GENE
-	I-GENE
compelled	I-GENE
multi	I-GENE
-	I-GENE
phosphoprotein	I-GENE
complex	I-GENE
binds	O
to	O
and	O
activates	O
SHP	B-GENE
-	I-GENE
2	I-GENE
,	O
which	O
in	O
turn	O
dephosphorylates	O
SHIP	B-GENE
and	O
Shc	B-GENE
and	O
probably	O
other	O
substrates	O
.	O

Paradoxically	O
,	O
loop	O
3i	O
from	O
the	O
M1Ach	B-GENE
-	I-GENE
muscarinic	I-GENE
receptor	I-GENE
also	O
maximally	O
inhibited	O
GnRH	B-GENE
agonist	O
-	O
stimulated	O
cAMP	O
accumulation	O
and	O
PRL	B-GENE
release	O
by	O
40	O
%	O
(	O
both	O
effects	O
mediated	O
through	O
activation	O
of	O
the	O
Gs	B-GENE
protein	I-GENE
)	O
.	O

Electrophoretic	O
mobility	O
-	O
shift	O
assays	O
with	O
nuclear	O
extracts	O
from	O
COS	O
-	O
1	O
cells	O
transfected	O
with	O
expression	O
vectors	O
for	O
SMADs	B-GENE
1	I-GENE
-	I-GENE
5	I-GENE
indicate	O
that	O
SMAD3	B-GENE
forms	O
a	O
complex	O
with	O
a	O
migration	O
similar	O
to	O
that	O
of	O
the	O
endogenous	B-GENE
TGF	I-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
specific	I-GENE
complex	I-GENE
observed	O
in	O
fibroblast	O
extracts	O
.	O

Oligomers	O
corresponding	O
to	O
the	O
region	O
of	O
the	O
mlc	B-GENE
-	I-GENE
1	I-GENE
/	I-GENE
3	I-GENE
enhancer	I-GENE
,	O
which	O
encompasses	O
this	O
conserved	O
sequence	O
,	O
bound	O
MEF	B-GENE
-	I-GENE
2	I-GENE
and	O
competed	O
for	O
its	O
binding	O
to	O
the	O
mck	B-GENE
enhancer	O
.	O

cDNA	O
cloning	O
and	O
transcriptional	O
properties	O
of	O
a	O
novel	O
GC	B-GENE
box	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
,	O
BTEB2	B-GENE
.	O

N0	O
disease	O
is	O
more	O
favorable	O
than	O
N1	O
or	O
N2	O
disease	O
.	O

Elimination	O
of	O
brush	O
border	O
as	O
well	O
as	O
of	O
glomerular	O
marker	O
proteins	O
was	O
significantly	O
lower	O
after	O
intravenous	O
injection	O
of	O
low	O
-	O
osmolar	O
CM	O
iopamidol	O
370	O
(	O
832	O
mOsm	O
/	O
kg	O
)	O
than	O
after	O
meglumine	O
diatrizoate	O
76	O
(	O
2100	O
mOsm	O
/	O
kg	O
)	O
.	O

Overall	O
graft	O
and	O
patient	O
survival	O
after	O
HAT	O
were	O
33	O
.	O
3	O
%	O
and	O
75	O
%	O
,	O
respectively	O
.	O

Of	O
81	O
girls	O
cured	O
from	O
the	O
bacteriuria	O
24	O
recurred	O
,	O
5	O
with	O
a	O
symptomatic	O
pyelonephritis	O
and	O
3	O
with	O
cystitis	O
.	O

Partial	O
hepatectomy	O
in	O
metastatic	O
Wilms	O
'	O
tumor	O
.	O

MRS	O
allowed	O
the	O
differentiation	O
of	O
the	O
following	O
metabolites	O
in	O
5	O
patients	O
:	O
N	O
-	O
acetyl	O
-	O
aspartate	O
(	O
NAA	O
)	O
,	O
creatine	O
and	O
phosphocreatine	O
,	O
phosphorylcholine	O
and	O
glycerophosphorylcholine	O
,	O
beta	O
-	O
and	O
gamma	O
-	O
glutamate	O
(	O
GLU	O
)	O
.	O

Plasma	O
prolactin	B-GENE
in	O
patients	O
with	O
colorectal	O
cancer	O
.	O

Studies	O
of	O
fetal	O
maturity	O

A	O
comparison	O
of	O
the	O
rate	O
of	O
recovery	O
and	O
time	O
for	O
detection	O
of	O
mycobacteria	O
from	O
clinical	O
specimens	O
of	O
the	O
newly	O
developed	O
Mycobacteria	O
Growth	O
Indicator	O
Tube	O
(	O
MGIT	O
)	O
,	O
the	O
biphasic	O
Septi	O
-	O
Chek	O
,	O
and	O
the	O
egg	O
-	O
based	O
Ogawa	O
medium	O
was	O
made	O
.	O

E2A	B-GENE
-	O
HLF	B-GENE
-	O
mediated	O
cell	O
transformation	O
requires	O
both	O
the	O
trans	O
-	O
activation	O
domains	O
of	O
E2A	B-GENE
and	O
the	O
leucine	O
zipper	O
dimerization	O
domain	O
of	O
HLF	B-GENE
.	O

In	O
transient	O
transfections	O
using	O
luciferase	B-GENE
reporter	I-GENE
genes	I-GENE
driven	O
by	O
1	O
kb	O
of	O
the	O
5	O
'	O
flanking	O
DNA	O
of	O
the	O
three	O
CALM	B-GENE
genes	I-GENE
,	O
the	O
promoter	O
activity	O
correlated	O
with	O
the	O
endogenous	B-GENE
CALM	I-GENE
transcriptional	O
activity	O
,	O
but	O
only	O
when	O
the	O
5	O
'	O
untranslated	O
regions	O
were	O
included	O
in	O
the	O
constructs	O
.	O

In	O
this	O
report	O
,	O
several	O
health	O
behaviors	O
were	O
investigated	O
in	O
relation	O
to	O
maintaining	O
mobility	O
during	O
4	O
years	O
of	O
follow	O
-	O
up	O
among	O
6	O
,	O
981	O
men	O
and	O
women	O
aged	O
65	O
years	O
and	O
older	O
with	O
intact	O
mobility	O
at	O
baseline	O
between	O
1981	O
and	O
1983	O
who	O
lived	O
in	O
one	O
of	O
three	O
communities	O
:	O
East	O
Boston	O
,	O
Massachusetts	O
;	O
Iowa	O
and	O
Washington	O
counties	O
,	O
Iowa	O
;	O
and	O
New	O
Haven	O
,	O
Connecticut	O
.	O

Binding	O
of	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
to	O
phospho	O
-	O
TAMs	O
is	O
notable	O
for	O
the	O
high	O
level	O
of	O
cooperativity	O
between	O
the	O
two	O
SH2	B-GENE
domains	I-GENE
,	O
which	O
individually	O
demonstrate	O
low	O
affinity	O
interaction	O
with	O
the	O
ligand	O
.	O

A	O
clinical	O
study	O
.	O

Two	O
-	O
dimensional	O
echocardiographic	O
parasternal	O
long	O
-	O
and	O
short	O
-	O
axis	O
views	O
were	O
obtained	O
during	O
graded	O
bleeding	O
by	O
rapid	O
withdrawal	O
of	O
blood	O
from	O
an	O
arterial	O
cannula	O
,	O
with	O
increments	O
of	O
5	O
%	O
each	O
up	O
to	O
30	O
%	O
of	O
calculated	O
blood	O
volume	O
.	O

Comparative	O
analyses	O
indicate	O
that	O
the	O
5	O
'	O
-	O
peripheral	O
domain	O
exhibits	O
a	O
75	O
-	O
bp	O
length	O
polymorphism	O
near	O
sequences	O
associated	O
with	O
the	O
termination	O
of	O
the	O
H	O
-	O
strand	O
replication	O
.	O

Thirty	O
-	O
five	O
pts	O
were	O
transplanted	O
for	O
constitutional	O
disease	O
:	O
Fanconi	O
anemia	O
(	O
FA	O
)	O
(	O
26	O
pts	O
)	O
,	O
Dyskeratosis	O
congenita	O
(	O
2	O
pts	O
)	O
,	O
Blackfan	O
-	O
Diamond	O
erythroblastopenia	O
(	O
2	O
pts	O
)	O
,	O
Glanzmann	O
thrombasthenia	O
(	O
1	O
pt	O
)	O
,	O
osteopetrosis	O
(	O
1	O
pt	O
)	O
and	O
Gaucher	O
'	O
s	O
disease	O
(	O
1	O
pt	O
)	O
.	O

One	O
patient	O
exhibited	O
a	O
non	O
-	O
sense	O
mutation	O
(	O
codon	O
388	O
)	O
,	O
which	O
changed	O
a	O
glutamine	O
codon	O
(	O
CAG	O
)	O
to	O
a	O
stop	O
codon	O
(	O
TAG	O
)	O
.	O

Using	O
the	O
same	O
approach	O
we	O
have	O
shown	O
that	O
hFIRE	B-GENE
binds	O
the	O
stimulatory	O
proteins	O
Sp1	B-GENE
and	O
Sp3	B-GENE
in	O
addition	O
to	O
CBF	B-GENE
.	O

Cellular	O
fractionation	O
and	O
Percoll	O
gradient	O
centrifugation	O
combined	O
with	O
immunoblotting	O
show	O
that	O
p67	B-GENE
cofractionates	O
with	O
nuclei	O
and	O
is	O
enriched	O
in	O
resistant	O
structure	O
that	O
is	O
insoluble	O
in	O
2	O
M	O
NaCl	O
,	O
25	O
mM	O
lithium	O
3	O
,	O
5	O
'	O
-	O
diiodosalicylate	O
,	O
and	O
1	O
%	O
Triton	O
but	O
is	O
soluble	O
in	O
8	O
M	O
urea	O
.	O

Gene	O
expression	O
is	O
in	O
part	O
controlled	O
by	O
chromatin	O
remodeling	O
factors	O
and	O
the	O
acetylation	O
state	O
of	O
nucleosomal	B-GENE
histones	I-GENE
.	O

Corticosteroid	O
treatment	O
before	O
,	O
during	O
,	O
or	O
after	O
fludarabine	O
treatment	O
in	O
patients	O
with	O
alkylator	O
-	O
resistant	O
,	O
low	O
-	O
grade	O
lymphoid	O
malignancies	O
who	O
have	O
not	O
received	O
PCP	O
prophylaxis	O
is	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
opportunistic	O
pulmonary	O
infections	O
.	O

Here	O
we	O
demonstrate	O
that	O
several	O
genes	O
associated	O
with	O
NHEJ	O
perform	O
essential	O
functions	O
in	O
the	O
repair	O
of	O
endonuclease	O
-	O
induced	O
DSBs	O
in	O
vivo	O
.	O

The	O
primary	O
structure	O
of	O
cholesterol	B-GENE
esterase	I-GENE
displayed	O
no	O
significant	O
homology	O
with	O
other	O
lipases	B-GENE
,	O
although	O
the	O
putative	O
lipid	O
interfacial	O
recognition	O
site	O
of	O
G	O
-	O
X	O
-	O
S	O
-	O
X	O
-	O
G	O
is	O
present	O
in	O
the	O
cholesterol	B-GENE
esterase	I-GENE
sequence	I-GENE
.	O

Subtype	O
-	O
and	O
response	O
element	O
-	O
dependent	O
differences	O
in	O
transactivation	O
by	O
peroxisome	B-GENE
proliferator	I-GENE
-	I-GENE
activated	I-GENE
receptors	I-GENE
alpha	I-GENE
and	I-GENE
gamma	I-GENE
.	O

Monoclonal	O
antibodies	O
to	O
the	O
hapten	O
phenyloxazolone	O
were	O
raised	O
7	O
days	O
after	O
immunization	O
in	O
mice	O
of	O
six	O
strains	O
(	O
BALB	O
/	O
c	O
,	O
C57BL	O
-	O
Igha	O
,	O
DBA2	O
,	O
RF	O
,	O
A	O
/	O
J	O
,	O
and	O
CE	O
)	O
.	O

PMA	O
produced	O
similar	O
results	O
,	O
but	O
the	O
induction	O
of	O
the	O
WT	B-GENE
AP1	I-GENE
c	B-GENE
-	I-GENE
jun	I-GENE
promoter	O
-	O
CAT	O
plasmid	O
was	O
smaller	O
.	O

Although	O
the	O
QT	O
duration	O
was	O
higher	O
(	O
p	O
=	O
0	O
.	O
0001	O
)	O
at	O
night	O
,	O
the	O
beat	O
-	O
to	O
-	O
beat	O
variability	O
of	O
this	O
interval	O
was	O
lower	O
:	O
in	O
the	O
time	O
domain	O
(	O
decreased	O
standard	O
deviation	O
,	O
p	O
=	O
0	O
.	O
0005	O
)	O
,	O
in	O
the	O
frequency	O
domain	O
(	O
decreased	O
low	O
-	O
frequency	O
power	O
of	O
the	O
spectra	O
,	O
p	O
=	O
0	O
.	O
004	O
)	O
,	O
and	O
the	O
chaotic	O
domain	O
(	O
tighter	O
clustering	O
of	O
the	O
points	O
in	O
the	O
Poincare	O
plots	O
)	O
.	O

J	O
.	O

Student	O
health	O

In	O
both	O
study	O
stages	O
.	O
post	O
-	O
exposure	O
treatment	O
consisted	O
of	O
five	O
injections	O
of	O
vaccine	O
[	O
(	O
D	O
)	O
ays	O
0	O
,	O
3	O
,	O
7	O
,	O
14	O
,	O
28	O
]	O
,	O
together	O
with	O
a	O
dose	O
of	O
rabies	B-GENE
immunoglobulin	I-GENE
(	O
RIG	B-GENE
)	O
of	O
equine	O
or	O
human	O
origin	O
on	O
D0	O
.	O

Essential	O
fatty	O
acid	O
deficiency	O
in	O
childhood	O

We	O
have	O
earlier	O
proposed	O
that	O
CG	O
rich	O
sequences	O
resembling	O
CpG	O
islands	O
,	O
which	O
are	O
associated	O
with	O
many	O
imprinted	O
genes	O
and	O
often	O
subject	O
to	O
parental	O
-	O
specific	O
methylation	O
,	O
could	O
act	O
as	O
a	O
common	O
imprinting	O
element	O
.	O

Electrophoretic	O
mobility	O
-	O
shift	O
assays	O
showed	O
a	O
rapid	O
induction	O
of	O
nuclear	O
proteins	O
that	O
bound	O
to	O
the	O
consensus	B-GENE
kappa	I-GENE
B	I-GENE
motif	I-GENE
.	O

The	O
thalamic	O
SD	O
was	O
regularly	O
triggered	O
by	O
short	O
(	O
0	O
.	O
02	O
-	O
0	O
.	O
05	O
s	O
)	O
high	O
-	O
frequency	O
(	O
200	O
-	O
500	O
Hz	O
)	O
ES	O
of	O
the	O
parietal	O
cortical	O
surface	O
.	O

As	O
in	O
IncP	O
alpha	O
plasmids	O
,	O
these	O
operons	O
are	O
transcribed	O
from	O
a	O
bidirectional	O
promoter	O
region	O
consisting	O
of	O
trfAp	B-GENE
for	O
the	O
trfA	B-GENE
operon	I-GENE
and	O
trbAp	B-GENE
and	O
trbBp	B-GENE
for	O
the	O
trb	B-GENE
operon	I-GENE
.	O

Comparison	O
of	O
the	O
encoded	O
ERCC3Dm	B-GENE
protein	I-GENE
with	O
the	O
homologous	O
proteins	O
of	O
mouse	O
and	O
man	O
shows	O
a	O
strong	O
amino	O
acid	O
conservation	O
(	O
71	O
%	O
identity	O
)	O
,	O
especially	O
in	O
the	O
postulated	O
DNA	O
binding	O
region	O
and	O
seven	O
'	B-GENE
helicase	I-GENE
'	I-GENE
domains	I-GENE
.	O

Genetic	O
analysis	O
places	O
CWH43	B-GENE
upstream	O
of	O
the	O
BCK2	B-GENE
branch	O
of	O
the	O
PKC1	B-GENE
signalling	O
pathway	O
,	O
since	O
cwh43	B-GENE
mutations	O
were	O
synthetic	O
lethal	O
with	O
pkc1	B-GENE
deletion	O
,	O
whereas	O
the	O
cwh43	B-GENE
defects	O
could	O
be	O
rescued	O
by	O
overexpression	O
of	O
BCK2	B-GENE
and	O
not	O
by	O
high	O
-	O
copy	O
-	O
number	O
expression	O
of	O
genes	O
encoding	O
downstream	O
proteins	O
of	O
the	O
PKC1	B-GENE
pathway	O
However	O
,	O
unlike	O
BCK2	B-GENE
,	O
whose	O
disruption	O
in	O
a	O
cln3	B-GENE
mutant	I-GENE
resulted	O
in	O
growth	O
arrest	O
in	O
G	O
(	O
1	O
)	O
,	O
no	O
growth	O
defect	O
was	O
observed	O
in	O
a	O
double	O
cwh43	B-GENE
cln3	B-GENE
mutants	I-GENE
.	O

Expression	O
of	O
the	O
E2	B-GENE
protein	I-GENE
resulted	O
in	O
rapid	O
repression	O
of	O
HPV	B-GENE
E6	I-GENE
and	O
E7	B-GENE
expression	O
,	O
followed	O
approximately	O
12	O
h	O
later	O
by	O
profound	O
inhibition	O
of	O
cellular	O
DNA	O
synthesis	O
.	O

Peak	O
reactive	O
hyperemia	O
(	O
mL	O
.	O
min	O
-	O
1	O
.	O
100	O
mL	O
-	O
1	O
)	O
was	O
determined	O
in	O
the	O
calf	O
and	O
forearm	O
immediately	O
before	O
and	O
after	O
12	O
weeks	O
of	O
training	O
.	O

The	O
hematopoietic	O
form	O
of	O
PTPN6	B-GENE
transcript	I-GENE
is	O
initiated	O
at	O
a	O
downstream	O
promoter	O
separated	O
by	O
7	O
kb	O
from	O
the	O
first	O
.	O

Reversal	O
of	O
biliary	O
sphincter	O
spasm	O
with	O
low	O
dose	O
glucagon	B-GENE
during	O
operative	O
cholangiography	O
.	O

In	O
ten	O
other	O
endotoxin	O
-	O
albumin	B-GENE
-	O
treated	O
pigs	O
PGE1	O
infusion	O
(	O
0	O
.	O
25	O
micrograms	O
X	O
kg	O
-	O
1	O
X	O
min	O
-	O
1	O
)	O
was	O
begun	O
after	O
established	O
pulmonary	O
and	O
cardiovascular	O
dysfunction	O
,	O
for	O
closer	O
mimicking	O
of	O
clinical	O
use	O
.	O

In	O
particular	O
,	O
MF	O
males	O
receiving	O
either	O
a	O
5	O
.	O
0	O
-	O
mg	O
/	O
kg	O
CDP	O
dose	O
or	O
a	O
3	O
.	O
0	O
-	O
mg	O
/	O
kg	O
RO	O
dose	O
explored	O
the	O
object	O
more	O
often	O
than	O
MM	O
males	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

A	O
single	O
HD	O
session	O
using	O
cellulose	O
triacetate	O
or	O
polysulfone	O
membrane	O
significantly	O
increased	O
water	O
content	O
both	O
at	O
forearm	O
and	O
lower	O
leg	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

In	O
the	O
yeast	O
two	O
-	O
hybrid	O
assays	O
,	O
PNRC	B-GENE
interacted	O
with	O
the	O
orphan	O
receptors	O
SF1	B-GENE
and	O
ERRalpha1	B-GENE
in	O
a	O
ligand	O
-	O
independent	O
manner	O
.	O

Further	O
,	O
we	O
will	O
review	O
our	O
evaluation	O
of	O
the	O
survival	O
rate	O
and	O
prognostic	O
factors	O
for	O
9	O
,	O
262	O
patients	O
from	O
1981	O
to	O
1996	O
.	O

Kaposi	O
'	O
s	O
eruptive	O
disease	O
.	O

The	O
results	O
were	O
subjected	O
to	O
analysis	O
of	O
23	O
autopsies	O
carried	O
out	O
in	O
children	O
dying	O
of	O
intoxication	O
with	O
Amanita	O
phalloides	O
.	O

Microscopic	O
examination	O
of	O
these	O
colonies	O
showed	O
a	O
high	O
percentage	O
of	O
histiocytes	O
identical	O
to	O
those	O
seen	O
in	O
the	O
patient	O
'	O
s	O
bone	O
marrow	O
.	O

Diffusion	O
epidemic	O
models	O
with	O
incubation	O
and	O
crisscross	O
dynamics	O
.	O

Additional	O
genetic	O
analyses	O
described	O
herein	O
suggest	O
that	O
Skb1	B-GENE
is	O
a	O
component	O
of	O
the	O
morphology	O
control	O
branch	O
of	O
the	O
Ras	B-GENE
signaling	O
cascade	O
in	O
S	O
.	O
pombe	O
and	O
that	O
it	O
positively	O
modulates	O
Shk1	B-GENE
function	O
.	O

Transient	O
transfection	O
assays	O
indicated	O
that	O
the	O
(	O
-	O
4551	O
)	O
UCP1	B-GENE
-	O
CAT	B-GENE
construct	O
,	O
containing	O
the	O
5	O
'	O
-	O
regulatory	O
region	O
of	O
the	O
rat	B-GENE
ucp	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
,	O
was	O
activated	O
by	O
PPARalpha	B-GENE
co	O
-	O
transfection	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
and	O
this	O
activation	O
was	O
potentiated	O
by	O
Wy	O
14	O
,	O
643	O
and	O
retinoid	B-GENE
X	I-GENE
receptor	I-GENE
alpha	I-GENE
.	O

CRKL	B-GENE
,	O
an	O
SH2	B-GENE
-	O
SH3	B-GENE
-	O
SH3	B-GENE
adapter	O
protein	O
,	O
is	O
one	O
of	O
the	O
major	O
tyrosine	B-GENE
phosphoproteins	I-GENE
detected	O
in	O
primary	O
leukemic	O
neutrophils	O
from	O
patients	O
with	O
CML	O
.	O

Idealized	O
versus	O
realized	O
overall	O
treatment	O
times	O
.	O

Serum	B-GENE
C3	I-GENE
was	O
measured	O
in	O
1	O
,	O
282	O
school	O
children	O
with	O
abnormal	O
urinary	O
findings	O
between	O
1980	O
and	O
1997	O
.	O

Tc	O
-	O
99m	O
HMPAO	O
brain	O
SPECT	O
compared	O
to	O
CT	O
and	O
EEG	O
after	O
seizures	O
in	O
childhood	O
.	O

The	O
adenovirus	B-GENE
E1B	I-GENE
19	I-GENE
,	I-GENE
000	I-GENE
-	I-GENE
molecular	I-GENE
-	I-GENE
weight	I-GENE
(	I-GENE
19K	I-GENE
)	I-GENE
protein	I-GENE
is	O
a	O
potent	O
inhibitor	O
of	O
apoptosis	O
and	O
cooperates	O
with	O
E1A	B-GENE
to	O
transform	O
primary	O
rodent	O
cells	O
.	O

Subclones	O
of	O
R15	O
which	O
reverted	O
to	O
kappa	B-GENE
light	I-GENE
chain	I-GENE
production	O
contained	O
genomic	O
deletions	O
of	O
R15ns	O
and	O
/	O
or	O
the	O
surrounding	O
intron	O
.	O

Previous	O
data	O
suggested	O
a	O
subtle	O
increase	O
in	O
serum	O
P	O
at	O
the	O
time	O
of	O
hCG	B-GENE
injection	O
without	O
LH	B-GENE
surge	O
reduces	O
the	O
PR	O
of	O
women	O
having	O
oocyte	O
retrievals	O
for	O
IVF	O
;	O
this	O
study	O
compared	O
PRs	O
of	O
recipients	O
in	O
a	O
shared	O
oocyte	O
program	O
according	O
to	O
the	O
donors	O
'	O
pre	B-GENE
-	I-GENE
hCG	I-GENE
P	O
level	O
.	O

Scleraxis	B-GENE
overexpression	O
enhanced	O
expression	O
of	O
the	O
aggrecan	B-GENE
gene	I-GENE
,	O
which	O
is	O
not	O
normally	O
expressed	O
at	O
high	O
levels	O
in	O
these	O
osteoblastic	O
cells	O
.	O

Region	O
-	O
specific	O
enhancers	O
near	O
two	O
mammalian	B-GENE
homeo	I-GENE
box	I-GENE
genes	I-GENE
define	O
adjacent	O
rostrocaudal	O
domains	O
in	O
the	O
central	O
nervous	O
system	O
.	O

Cells	O
were	O
cotransfected	O
with	O
this	O
plasmid	O
,	O
and	O
the	O
appropriate	O
responder	O
plasmids	O
and	O
clonies	O
were	O
selected	O
on	O
the	O
basis	O
of	O
their	O
resistance	O
to	O
Geneticin	O
(	O
via	O
the	O
neomycin	B-GENE
aminoglycoside	I-GENE
phosphotransferase	I-GENE
gene	I-GENE
)	O
.	O

To	O
clone	O
cDNAs	O
for	O
the	O
beta	O
subunit	O
of	O
rabbit	B-GENE
eIF	I-GENE
-	I-GENE
2B	I-GENE
,	O
amino	O
acid	O
sequence	O
data	O
was	O
first	O
obtained	O
and	O
used	O
to	O
design	O
redundant	O
oligonucleotide	O
primers	O
for	O
use	O
in	O
PCR	O
.	O

Deletion	O
analysis	O
of	O
the	O
3	O
.	O
5kb	O
DNA	O
fragment	O
revealed	O
that	O
the	O
region	O
between	O
-	O
125	O
to	O
+	O
1	O
,	O
containing	O
a	O
single	O
Sp1	B-GENE
binding	I-GENE
site	I-GENE
,	O
is	O
essential	O
for	O
transcription	O
of	O
the	O
embigin	B-GENE
gene	I-GENE
.	O

A	O
29	O
.	O
425	O
kb	O
segment	O
on	O
the	O
left	O
arm	O
of	O
yeast	O
chromosome	O
XV	O
contains	O
more	O
than	O
twice	O
as	O
many	O
unknown	O
as	O
known	O
open	O
reading	O
frames	O
.	O

By	O
applying	O
a	O
sufficiently	O
strong	O
crusher	O
gradient	O
in	O
the	O
EPI	O
pulse	O
sequence	O
,	O
the	O
temporal	O
variation	O
induced	O
by	O
SSFP	O
disturbance	O
can	O
be	O
suppressed	O
due	O
to	O
diffusion	O
.	O

The	O
cdc42W97R	B-GENE
temperature	I-GENE
-	I-GENE
sensitive	I-GENE
allele	I-GENE
in	O
S	O
.	O
cerevisiae	O
displayed	O
the	O
same	O
cell	O
-	O
division	O
-	O
cycle	O
arrest	O
phenotype	O
(	O
large	O
,	O
round	O
unbudded	O
cells	O
)	O
as	O
the	O
cdc42	B-GENE
-	I-GENE
1ts	I-GENE
mutant	I-GENE
.	O

Wolf	O
-	O
Hirschhorn	O
syndrome	O
(	O
WHS	O
)	O
is	O
a	O
malformation	O
syndrome	O
associated	O
with	O
a	O
hemizygous	O
deletion	O
of	O
the	O
distal	O
short	O
arm	O
of	O
chromosome	O
4	O
(	O
4p16	O
.	O
3	O
)	O
.	O

To	O
address	O
this	O
question	O
with	O
respect	O
to	O
skeletal	O
muscle	O
,	O
we	O
have	O
examined	O
the	O
effects	O
of	O
the	O
Providence	O
mutation	O
in	O
cultured	O
muscle	O
cells	O
,	O
after	O
adoptive	O
gene	O
transfer	O
to	O
adult	O
mice	O
,	O
and	O
in	O
two	O
infants	O
homozygous	O
for	O
spectrin	B-GENE
Providence	I-GENE
.	O

Adenovirus	O
-	O
mediated	O
gene	O
transfer	O
of	O
MMAC1	B-GENE
/	O
PTEN	B-GENE
to	O
glioblastoma	O
cells	O
inhibits	O
S	O
phase	O
entry	O
by	O
the	O
recruitment	O
of	O
p27Kip1	B-GENE
into	O
cyclin	B-GENE
E	I-GENE
/	O
CDK2	B-GENE
complexes	O
.	O

Increasing	O
insulin	B-GENE
sensitivity	O
in	O
type	O
I	O
diabetic	O
patients	O
should	O
alert	O
clinicians	O
to	O
the	O
possibility	O
of	O
glucocorticoid	O
deficiency	O
.	O

Experiment	O
B	O
:	O
Clinical	O
,	O
biochemical	O
,	O
and	O
histological	O
variables	O
were	O
measured	O
over	O
a	O
12	O
-	O
day	O
period	O
after	O
the	O
zymosan	O
had	O
been	O
given	O
.	O

Lesions	O
of	O
this	O
kind	O
resemble	O
those	O
in	O
vitamin	O
A	O
-	O
deficient	O
chickens	O
and	O
are	O
the	O
first	O
to	O
be	O
induced	O
by	O
excess	O
vitamin	O
E	O
.	O

Immunoblotting	O
using	O
a	O
phosphospecific	B-GENE
anti	I-GENE
-	I-GENE
Src	I-GENE
(	I-GENE
416Y	I-GENE
)	I-GENE
antibody	I-GENE
showed	O
a	O
ceramide	O
-	O
induced	O
increase	O
in	O
pp60	B-GENE
(	O
src	B-GENE
)	O
tyrosine	O
phosphorylation	O
.	O

Spinophilin	B-GENE
,	O
a	O
novel	O
protein	B-GENE
phosphatase	I-GENE
1	I-GENE
binding	I-GENE
protein	I-GENE
localized	O
to	O
dendritic	O
spines	O
.	O

The	O
Htf9	B-GENE
-	I-GENE
a	I-GENE
gene	I-GENE
encodes	O
the	O
RanBP1	B-GENE
protein	I-GENE
,	O
a	O
major	O
partner	O
of	O
the	O
Ran	B-GENE
GTPase	I-GENE
.	O

Membrane	O
extraction	O
has	O
been	O
interfaced	O
with	O
gas	O
chromatography	O
and	O
mass	O
spectroscopy	O
for	O
the	O
analysis	O
of	O
volatile	O
organics	O
in	O
water	O
.	O

We	O
have	O
produced	O
the	O
Ure2	B-GENE
protein	I-GENE
to	O
high	O
yield	O
in	O
Escherichia	O
coli	O
from	O
a	O
synthetic	O
gene	O
.	O

Triethylene	O
glycol	O
.	O

The	O
SM	O
-	O
specific	O
selection	O
of	O
exon	O
2	O
results	O
from	O
the	O
inhibition	O
of	O
exon	O
3	O
.	O

Ultimobranchial	O
body	O
and	O
parathyroid	O
glands	O
of	O
the	O
freshwater	O
snake	O
Natrix	O
piscator	O
in	O
response	O
to	O
vitamin	O
D3	O
administration	O
.	O

In	O
contrast	O
to	O
the	O
p16	B-GENE
-	O
mediated	O
G1	O
block	O
,	O
G1	O
arrest	O
mediated	O
by	O
the	O
cdk	B-GENE
inhibitors	O
p21Cip1	B-GENE
or	O
p27Kip1	B-GENE
cannot	O
be	O
bypassed	O
either	O
by	O
inactivation	O
of	O
pRb	B-GENE
or	O
overexpression	O
of	O
E2F	B-GENE
family	I-GENE
members	I-GENE
.	O

More	O
than	O
80	O
%	O
appropriate	O
lever	O
responding	O
was	O
established	O
after	O
27	O
,	O
38	O
and	O
44	O
daily	O
training	O
sessions	O
with	O
DN	O
-	O
2327	O
,	O
diazepam	O
and	O
PTZ	O
,	O
respectively	O
,	O
as	O
the	O
training	O
drug	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
have	O
investigated	O
the	O
effects	O
of	O
SDZ	O
ENA	O
713	O
on	O
spatial	O
learning	O
deficits	O
in	O
aged	O
rats	O
.	O

A	O
retrospective	O
analysis	O
of	O
data	O
accumulated	O
over	O
a	O
21	O
-	O
month	O
period	O
,	O
from	O
December	O
1989	O
to	O
September	O
1991	O
,	O
regarding	O
investigational	O
use	O
of	O
a	O
308	O
nanometer	O
Xenon	O
Chloride	O
Excimer	O
Laser	O
Coronary	O
Angioplasty	O
(	O
ELCA	O
)	O
system	O
(	O
Advanced	O
Interventional	O
Systems	O
,	O
Inc	O
.	O
,	O
Irvine	O
,	O
CA	O
)	O
was	O
performed	O
.	O

Upon	O
increasing	O
the	O
Marangoni	O
number	O
beyond	O
this	O
threshold	O
,	O
the	O
initially	O
stationary	O
flow	O
becomes	O
quickly	O
time	O
dependent	O
.	O

Investigation	O
on	O
the	O
asymmetrical	O
induced	O
yields	O
in	O
90Sr	O
-	O
90Y	O
-	O
beta	O
-	O
irradiated	O
D	O
-	O
and	O
L	O
-	O
alanines	O
.	O

One	O
of	O
the	O
major	O
transcripts	O
encodes	O
MEQ	B-GENE
,	O
a	O
339	O
-	O
amino	O
-	O
acid	O
bZIP	B-GENE
protein	I-GENE
which	O
is	O
homologous	O
to	O
the	O
Jun	B-GENE
/	O
Fos	B-GENE
family	O
of	O
transcription	O
factors	O
.	O

Given	O
a	O
rapid	O
induction	O
of	O
Egr	B-GENE
-	I-GENE
1	I-GENE
on	O
stimulation	O
with	O
growth	O
factors	O
or	O
injury	O
,	O
these	O
findings	O
may	O
represent	O
at	O
least	O
one	O
of	O
the	O
molecular	O
mechanisms	O
underlying	O
phenotypic	O
modulation	O
of	O
smooth	O
muscles	O
after	O
vascular	O
injury	O
.	O

An	O
identical	O
polypeptide	O
was	O
detected	O
by	O
Western	O
blot	O
analysis	O
of	O
K1F	O
virions	O
.	O

The	O
predictive	O
value	O
of	O
the	O
remotely	O
sensed	O
map	O
based	O
on	O
NDVI	O
data	O
appears	O
to	O
be	O
better	O
than	O
that	O
from	O
forecast	O
indices	O
based	O
only	O
on	O
climatic	O
data	O
.	O

The	O
concentration	O
of	O
vitamin	O
B1	O
,	O
B2	O
and	O
B6	O
are	O
found	O
to	O
be	O
9	O
.	O
96	O
,	O
9	O
.	O
92	O
and	O
3	O
.	O
01	O
mg	O
,	O
respectively	O
in	O
240	O
mg	O
of	O
capsule	O
powder	O
of	O
a	O
standard	O
company	O
(	O
name	O
has	O
not	O
been	O
disclosed	O
due	O
to	O
secrecy	O
purpose	O
)	O
.	O

We	O
have	O
shown	O
that	O
the	O
human	O
cell	O
MRC	O
closely	O
resembles	O
the	O
murine	O
cell	O
MRC	O
,	O
in	O
both	O
its	O
protein	O
composition	O
and	O
its	O
fractionation	O
and	O
chromatographic	O
profile	O
.	O

Red	O
blood	O
cell	O
binding	O
of	O
99mTc	O
-	O
EC	O
and	O
131I	O
-	O
OIH	O
was	O
6	O
.	O
1	O
%	O
and	O
20	O
%	O
,	O
respectively	O
.	O

Identification	O
of	O
a	O
68	B-GENE
-	I-GENE
kilodalton	I-GENE
nuclear	I-GENE
ATP	I-GENE
-	I-GENE
binding	I-GENE
phosphoprotein	I-GENE
encoded	O
by	O
bovine	O
papillomavirus	O
type	O
1	O
.	O

To	O
identify	O
the	O
GRK6	B-GENE
homologue	I-GENE
on	O
chromsome	O
13	O
,	O
several	O
sets	O
of	O
closely	O
-	O
spaced	O
primers	O
were	O
designed	O
based	O
on	O
the	O
GRK6	B-GENE
cDNA	I-GENE
sequence	I-GENE
and	O
then	O
used	O
to	O
amplify	O
human	O
genomic	O
DNA	O
by	O
PCR	O
.	O

During	O
the	O
burst	O
period	O
(	O
approximately	O
5	O
-	O
10	O
min	O
)	O
,	O
local	O
blood	O
H2O2	O
concentrations	O
and	O
xanthine	B-GENE
oxidase	I-GENE
activities	O
were	O
highly	O
correlated	O
(	O
r	O
=	O
0	O
.	O
999	O
)	O
.	O

This	O
mutant	O
also	O
functions	O
in	O
vivo	O
as	O
a	O
trans	O
-	O
acting	O
dominant	O
negative	O
regulator	O
:	O
the	O
transcriptional	O
inducibility	O
of	O
the	O
HIV	B-GENE
long	I-GENE
terminal	I-GENE
repeat	I-GENE
(	O
which	O
contains	O
two	O
potential	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
binding	I-GENE
sites	I-GENE
)	O
by	O
phorbol	O
ester	O
(	O
PMA	O
)	O
is	O
inhibited	O
when	O
it	O
is	O
co	O
-	O
transfected	O
into	O
CD4	B-GENE
+	I-GENE
T	O
cells	O
with	O
the	O
delta	O
SP	O
mutant	O
.	O

We	O
demonstrate	O
that	O
the	O
WRM	B-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
binds	O
to	O
LIT	B-GENE
-	I-GENE
1	I-GENE
in	O
vivo	O
and	O
that	O
WRM	B-GENE
-	I-GENE
1	I-GENE
can	O
activate	O
the	O
LIT	B-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
kinase	I-GENE
when	O
coexpressed	O
in	O
vertebrate	O
tissue	O
culture	O
cells	O
.	O

To	O
assess	O
the	O
safety	O
of	O
the	O
angiotensin	B-GENE
converting	I-GENE
enzyme	I-GENE
inhibitor	O
enalapril	O
a	O
multicenter	O
,	O
open	O
,	O
randomized	O
,	O
prazosin	O
-	O
controlled	O
trial	O
was	O
designed	O
comparing	O
the	O
incidence	O
and	O
severity	O
of	O
symptomatic	O
hypotension	O
on	O
the	O
first	O
day	O
of	O
treatment	O
.	O

Mutating	O
bases	O
-	O
142	O
to	O
-	O
151	O
abolishes	O
formation	O
of	O
complex	O
VII	O
and	O
partially	O
inhibits	O
complex	O
IV	O
,	O
suggesting	O
that	O
the	O
proteins	O
forming	O
these	O
complexes	O
bind	O
neighboring	O
segments	O
of	O
DNA	O
.	O

In	O
this	O
study	O
,	O
we	O
report	O
the	O
cloning	O
and	O
sequencing	O
of	O
several	O
overlapping	O
cDNAs	O
encoding	O
approximately	O
4	O
.	O
1	O
kb	O
of	O
the	O
human	B-GENE
homologue	I-GENE
of	I-GENE
Wnt	I-GENE
-	I-GENE
5A	I-GENE
.	O

We	O
provided	O
evidence	O
that	O
CaM	B-GENE
kinase	I-GENE
II	I-GENE
played	O
a	O
role	O
in	O
regulating	O
neurite	O
outgrowth	O
and	O
growth	O
cone	O
motility	O
in	O
these	O
cells	O
,	O
and	O
that	O
the	O
autophosphorylation	O
is	O
essential	O
for	O
the	O
kinase	O
to	O
sufficiently	O
exert	O
its	O
cellular	O
function	O
in	O
vivo	O
[	O
Y	O
.	O

We	O
propose	O
that	O
GCD7	B-GENE
and	O
GCD2	B-GENE
play	O
important	O
roles	O
in	O
the	O
regulatory	O
interaction	O
between	O
eIF	B-GENE
-	I-GENE
2	I-GENE
and	O
eIF	B-GENE
-	I-GENE
2B	I-GENE
and	O
that	O
the	O
suppressor	O
mutations	O
we	O
isolated	O
in	O
these	O
genes	O
decrease	O
the	O
susceptibility	O
of	O
eIF	B-GENE
-	I-GENE
2B	I-GENE
to	O
the	O
inhibitory	O
effects	O
of	O
phosphorylated	O
eIF	B-GENE
-	I-GENE
2	I-GENE
without	O
impairing	O
the	O
essential	O
catalytic	O
function	O
of	O
eIF	B-GENE
-	I-GENE
2B	I-GENE
in	O
translation	O
initiation	O
.	O

Furthermore	O
,	O
we	O
demonstrate	O
that	O
in	O
myeloid	O
and	O
B	O
cell	O
extracts	O
,	O
PU	B-GENE
.	I-GENE
1	I-GENE
forms	O
a	O
novel	O
,	O
specific	O
,	O
more	O
slowly	O
migrating	O
complex	O
(	O
PU	B-GENE
-	I-GENE
SF	I-GENE
)	O
when	O
binding	O
the	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
receptor	I-GENE
alpha	I-GENE
promoter	O
PU	B-GENE
.	I-GENE
1	I-GENE
site	O
.	O

The	O
antiserum	O
used	O
for	O
immunoblotting	O
specifically	O
supershifts	O
uteroglobin	B-GENE
promoter	I-GENE
-	I-GENE
protein	I-GENE
complexes	I-GENE
in	O
gel	O
shift	O
experiments	O
.	O

Plasma	B-GENE
LH	I-GENE
and	O
progesterone	O
levels	O
after	O
single	O
or	O
multiple	O
injections	O
of	O
synthetic	O
LH	B-GENE
-	O
RH	B-GENE
in	O
anoestrous	O
ewes	O
and	O
comparison	O
with	O
levels	O
during	O
the	O
oestrous	O
cycle	O
.	O

Soluble	O
recombinant	O
RI	B-GENE
and	O
soluble	O
recombinant	O
C	B-GENE
alpha	I-GENE
can	O
associate	O
in	O
vitro	O
and	O
be	O
activated	O
by	O
cyclic	O
AMP	O
.	O

We	O
have	O
isolated	O
and	O
structurally	O
characterized	O
genomic	O
DNA	O
and	O
cDNA	O
sequences	O
encoding	O
ribulose	B-GENE
-	I-GENE
1	I-GENE
,	I-GENE
5	I-GENE
-	I-GENE
bisphosphate	I-GENE
carboxylase	I-GENE
/	I-GENE
oxygenase	I-GENE
(	I-GENE
Rbu	I-GENE
-	I-GENE
P2	I-GENE
carboxylase	I-GENE
)	I-GENE
activase	I-GENE
from	O
barley	O
(	O
Hordeum	O
vulgare	O
L	O
.	O
)	O
.	O

Cytokine	O
inducibility	O
of	O
VCAM1	B-GENE
in	O
endothelial	O
cells	O
utilizes	O
the	O
interaction	O
of	O
heterodimeric	O
p50	B-GENE
/	O
p65	B-GENE
proteins	O
with	O
IRF	B-GENE
-	I-GENE
1	I-GENE
.	O

The	O
cases	O
with	O
terminal	O
forces	O
of	O
left	O
ventricular	O
activation	O
in	O
the	O
same	O
direction	O
as	O
the	O
delta	O
wave	O
,	O
superiorly	O
and	O
to	O
the	O
left	O
at	O
-	O
60	O
degrees	O
or	O
inferiorly	O
and	O
to	O
the	O
right	O
at	O
+	O
120	O
degrees	O
,	O
forming	O
a	O
single	O
deflection	O
of	O
over	O
0	O
,	O
12	O
seconds	O
'	O
duration	O
,	O
are	O
the	O
result	O
of	O
delayed	O
activation	O
of	O
the	O
anterior	O
or	O
posterior	O
fascicle	O
of	O
the	O
left	O
bundle	O
after	O
a	O
long	O
delay	O
.	O

From	O
a	O
chromosomal	O
cosmid	O
library	O
of	O
Streptomyces	O
argillaceus	O
,	O
a	O
Mtm	B-GENE
producer	O
,	O
a	O
clone	O
(	O
cosAR7	O
)	O
was	O
isolated	O
by	O
homology	O
to	O
the	O
actI	B-GENE
/	I-GENE
III	I-GENE
region	I-GENE
of	O
S	O
.	O
coelicolor	O
and	O
the	O
strDEM	B-GENE
genes	I-GENE
of	O
S	O
.	O
griseus	O
.	O

A	O
31	O
-	O
year	O
-	O
old	O
man	O
with	O
primary	O
myelofibrosis	O
initially	O
received	O
low	O
dose	O
Ara	O
C	O
.	O

The	O
factors	O
defective	O
in	O
groups	O
A	O
(	O
CIITA	B-GENE
)	O
,	O
C	O
(	O
RFX5	B-GENE
)	O
and	O
D	O
(	O
RFXAP	B-GENE
)	O
have	O
been	O
identified	O
.	O

Manifestation	O
of	O
superfluidity	O
in	O
an	O
evolving	O
bose	O
-	O
einstein	O
condensed	O
Gas	O
We	O
study	O
the	O
generation	O
of	O
excitations	O
due	O
to	O
an	O
"	O
impurity	O
"	O
(	O
static	O
perturbation	O
)	O
placed	O
into	O
an	O
oscillating	O
Bose	O
-	O
Einstein	O
condensed	O
gas	O
in	O
the	O
time	O
-	O
dependent	O
trapping	O
field	O
.	O

By	O
sequencing	O
of	O
exonuclease	B-GENE
III	I-GENE
deletion	O
clones	O
an	O
open	O
reading	O
frame	O
of	O
405	O
nucleotides	O
was	O
found	O
coding	O
for	O
a	O
protein	O
of	O
135	O
amino	O
acids	O
with	O
a	O
molecular	O
mass	O
of	O
15	O
kDa	O
.	O

The	O
c	B-GENE
-	I-GENE
raf	I-GENE
-	I-GENE
1	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
is	O
the	O
cellular	B-GENE
homologue	I-GENE
of	I-GENE
v	I-GENE
-	I-GENE
raf	I-GENE
,	O
the	O
oncogene	O
of	O
the	O
acutely	O
transforming	O
retrovirus	O
3611	O
-	O
MSV	O
.	O

We	O
report	O
the	O
genomic	O
organization	O
of	O
the	O
mouse	O
orphan	B-GENE
receptor	I-GENE
related	I-GENE
to	I-GENE
tyrosine	I-GENE
kinases	I-GENE
(	O
Ryk	B-GENE
)	O
,	O
a	O
structurally	O
unclassified	O
member	O
of	O
the	O
growth	B-GENE
factor	I-GENE
receptor	I-GENE
family	O
.	O

Electrophoretic	O
mobility	O
-	O
shift	O
assays	O
between	O
viral	O
RNA	O
and	O
BMV	B-GENE
CP	I-GENE
peptides	I-GENE
with	O
either	O
proline	O
or	O
alanine	O
substitutions	O
revealed	O
that	O
the	O
interaction	O
is	O
nonspecific	O
.	O

Furthermore	O
,	O
we	O
detect	O
hCoch	B-GENE
-	I-GENE
5B2	I-GENE
on	O
three	O
overlapping	O
YACs	O
,	O
two	O
of	O
which	O
also	O
contain	O
one	O
of	O
the	O
markers	O
linked	O
to	O
DFNA9	B-GENE
.	O
mCoch	B-GENE
-	I-GENE
5B2	I-GENE
was	O
genetically	O
mapped	O
in	O
the	O
mouse	O
to	O
chromosome	O
12	O
,	O
in	O
a	O
region	O
of	O
homologous	O
synteny	O
with	O
human	O
14q11	O
.	O
2	O
-	O
q13	O
,	O
which	O
contains	O
the	O
asp1	B-GENE
(	O
audiogenic	B-GENE
seizure	I-GENE
prone	I-GENE
)	O
locus	O
in	O
the	O
mouse	O
.	O

Reasons	O
are	O
given	O
for	O
suggesting	O
that	O
tiapamil	O
warrants	O
further	O
clinical	O
evaluation	O
,	O
after	O
which	O
it	O
may	O
join	O
the	O
more	O
established	O
calcium	O
antagonists	O
as	O
a	O
valuable	O
therapeutic	O
agent	O
.	O

Histopathologic	O
studies	O
displaying	O
spongiform	O
changes	O
in	O
the	O
gray	O
matter	O
,	O
neuronal	O
loss	O
,	O
and	O
atrogliosis	O
confirmed	O
the	O
clinical	O
diagnosis	O
of	O
Creutzfeldt	O
-	O
Jakob	O
disease	O
.	O

Current	O
body	O
size	O
(	O
wt	O
/	O
ht2	O
)	O
was	O
significantly	O
associated	O
with	O
life	O
-	O
time	O
weight	O
dissatisfaction	O
in	O
both	O
sexes	O
(	O
P	O
less	O
than	O
0	O
.	O
0005	O
)	O
.	O

Our	O
results	O
are	O
consistent	O
with	O
TCOF1	B-GENE
mutations	I-GENE
leading	O
to	O
the	O
Treacher	O
Collins	O
syndrome	O
phenotype	O
.	O

Mannich	O
bases	O
of	O
vanillin	O
oxime	O
.	O

Its	O
activity	O
was	O
twice	O
that	O
of	O
a	O
construct	O
where	O
the	O
CAT	B-GENE
gene	I-GENE
was	O
driven	O
by	O
the	O
H	B-GENE
-	I-GENE
2Kb	I-GENE
5	I-GENE
'	I-GENE
enhancer	I-GENE
region	I-GENE
(	O
H2TF1	B-GENE
/	O
KBF1	B-GENE
site	O
)	O
and	O
comparable	O
to	O
that	O
of	O
pRSVCAT	O
construct	B-GENE
carrying	I-GENE
the	I-GENE
strong	I-GENE
Rous	I-GENE
sarcoma	I-GENE
virus	I-GENE
LTR	I-GENE
enhancer	I-GENE
.	O

CONCLUSIONS	O
:	O
These	O
findings	O
imply	O
that	O
the	O
spinal	O
cord	O
is	O
not	O
a	O
simple	O
command	O
-	O
carrying	O
medium	O
from	O
the	O
brain	O
to	O
the	O
limbs	O
,	O
and	O
implies	O
that	O
some	O
computational	O
activities	O
take	O
place	O
at	O
the	O
spinal	O
cord	O
level	O
.	O

The	O
dipper	O
(	O
RONF	O
of	O
BP	O
(	O
or	O
HR	O
)	O
>	O
or	O
=	O
10	O
%	O
2	O
.	O

I	O
.	O

Acute	O
spontaneous	O
subdural	O
haematoma	O
.	O

Nonsuicidal	O
mortality	O
in	O
late	O
-	O
life	O
depression	O
.	O

DSS4	B-GENE
-	I-GENE
1	I-GENE
is	O
a	O
dominant	O
suppressor	O
of	O
sec4	B-GENE
-	I-GENE
8	I-GENE
that	O
encodes	O
a	O
nucleotide	O
exchange	O
protein	O
that	O
aids	O
Sec4p	B-GENE
function	O
.	O

A	O
study	O
of	O
characteristics	O
in	O
adult	O
asthmatics	O
who	O
are	O
sensitized	O
by	O
cats	O
and	O
dogs	O
allergens	O

The	O
failure	O
suggests	O
that	O
these	O
assembly	O
competent	O
but	O
complementation	O
-	O
negative	O
alpha	O
mutants	O
lack	O
an	O
as	O
yet	O
unidentified	O
function	O
(	O
s	O
)	O
.	O

Ciprofloxacin	O
levels	O
in	O
serum	O
and	O
blister	O
fluid	O
at	O
the	O
end	O
of	O
the	O
dosing	O
interval	O
(	O
8	O
h	O
)	O
were	O
superior	O
or	O
almost	O
superior	O
to	O
MICs	O
for	O
sensitive	O
organisms	O
including	O
Pseudomonas	O
aeruginosa	O
.	O

However	O
,	O
both	O
peptides	O
1	O
-	O
49	O
and	O
63	O
-	O
87	O
bound	O
to	O
PDE	B-GENE
alpha	I-GENE
/	I-GENE
beta	I-GENE
in	O
a	O
solid	O
-	O
phase	O
binding	O
assay	O
.	O

SETTING	O
:	O
A	O
private	O
office	O
-	O
based	O
fertility	O
program	O
.	O

Our	O
results	O
showed	O
that	O
direct	O
enantiomeric	O
separation	O
of	O
mephenytoin	O
was	O
obtained	O
by	O
using	O
a	O
chiral	O
capillary	O
column	O
,	O
the	O
retention	O
times	O
for	O
S	O
-	O
and	O
R	O
-	O
mephenytoin	O
were	O
25	O
.	O
5	O
and	O
26	O
.	O
2	O
min	O
respectively	O
,	O
with	O
a	O
detection	O
limit	O
less	O
than	O
50	O
ng	O
/	O
ml	O
of	O
mephenytoin	O
.	O

The	O
consensus	O
mammalian	O
ER	O
stress	O
response	O
element	O
(	O
ERSE	O
)	O
conserved	O
among	O
grp	B-GENE
promoters	I-GENE
consists	O
of	O
a	O
tripartite	O
structure	O
CCAAT	O
(	O
N9	O
)	O
CCACG	O
,	O
with	O
N	O
being	O
a	O
strikingly	O
GC	O
-	O
rich	O
region	O
of	O
9	O
bp	O
.	O

Further	O
,	O
we	O
find	O
that	O
the	O
BMI1	B-GENE
protein	I-GENE
can	O
also	O
interact	O
with	O
itself	O
.	O

These	O
data	O
suggest	O
that	O
certain	O
of	O
the	O
nuclear	O
protein	O
import	O
functions	O
of	O
NTF2	B-GENE
and	O
Ran	B-GENE
/	O
TC4	B-GENE
are	O
closely	O
linked	O
and	O
that	O
NTF2	B-GENE
may	O
serve	O
to	O
modulate	O
a	O
transport	O
step	O
involving	O
Ran	B-GENE
/	O
TC4	B-GENE
.	O

Our	O
analysis	O
indicates	O
that	O
a	O
gene	O
correction	O
mechanism	O
has	O
been	O
operating	O
on	O
the	O
Hbbs	B-GENE
chromosome	O
to	O
keep	O
beta	B-GENE
s	I-GENE
and	O
beta	B-GENE
t	I-GENE
evolving	O
in	O
concert	O
,	O
whereas	O
on	O
the	O
Hbbd	B-GENE
chromosome	O
,	O
beta	B-GENE
dmin	I-GENE
has	O
diverged	O
considerably	O
from	O
beta	B-GENE
dmaj	I-GENE
.	O

The	O
prosomal	B-GENE
RNA	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
p27K	I-GENE
is	O
a	O
member	O
of	O
the	O
alpha	B-GENE
-	I-GENE
type	I-GENE
human	I-GENE
prosomal	I-GENE
gene	I-GENE
family	I-GENE
.	O

Because	O
controlled	O
-	O
release	O
niacin	O
seems	O
to	O
be	O
more	O
potent	O
than	O
crystalline	O
niacin	O
,	O
product	O
substitution	O
without	O
dose	O
adjustment	O
should	O
be	O
avoided	O
.	O

Expression	O
of	O
the	O
gene	O
encoding	O
transcription	B-GENE
factor	I-GENE
cyclic	I-GENE
adenosine	I-GENE
3	I-GENE
'	I-GENE
,	I-GENE
5	I-GENE
'	I-GENE
-	I-GENE
monophosphate	I-GENE
(	I-GENE
cAMP	I-GENE
)	I-GENE
response	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CREB	B-GENE
)	O
:	O
regulation	O
by	O
follicle	B-GENE
-	I-GENE
stimulating	I-GENE
hormone	I-GENE
-	O
induced	O
cAMP	O
signaling	O
in	O
primary	O
rat	O
Sertoli	O
cells	O
.	O

Comparison	O
of	O
the	O
therapeutic	O
effectiveness	O
of	O
membrane	O
and	O
centrifugation	O
plasmapheresis	O

Number	O
of	O
warm	O
-	O
units	O
with	O
higher	O
rates	O
of	O
firing	O
and	O
greater	O
thermal	O
coefficients	O
,	O
comparable	O
to	O
those	O
of	O
warm	O
-	O
units	O
in	O
the	O
adult	O
,	O
gradually	O
increased	O
with	O
growth	O
.	O

To	O
investigate	O
the	O
effect	O
of	O
hyperthyroidism	O
on	O
the	O
pattern	O
and	O
time	O
course	O
of	O
O2	O
uptake	O
(	O
VO2	O
)	O
following	O
the	O
transition	O
from	O
rest	O
to	O
exercise	O
,	O
six	O
patients	O
and	O
six	O
healthy	O
subjects	O
performed	O
cycle	O
exercise	O
at	O
an	O
average	O
work	O
rate	O
(	O
WR	O
)	O
of	O
18	O
and	O
20	O
W	O
respectively	O
.	O

88	O
,	O
3739	O
-	O
3743	O
)	O
)	O
.	O

CHIEF	O
OUTCOME	O
MEASURES	O
:	O
Endoluminal	O
release	O
of	O
prostacyclin	O
(	O
6	O
-	O
Keto	O
-	O
PGF1	O
alpha	O
)	O
and	O
thromboxane	O
B2	O
(	O
TxB2	O
)	O
,	O
patency	O
,	O
EC	O
coverage	O
and	O
cell	O
identity	O
.	O

Elevated	O
systolic	O
blood	O
pressure	O
and	O
high	O
postglucose	O
serum	B-GENE
insulin	I-GENE
levels	O
showed	O
an	O
independent	O
,	O
significant	O
association	O
with	O
left	O
ventricular	O
mass	O
in	O
female	O
diabetic	O
subjects	O
.	O

Seasonal	O
variation	O
of	O
the	O
cadmium	O
content	O
of	O
Murex	O
trunculus	O
in	O
a	O
non	O
-	O
cadmium	O
polluted	O
environment	O
.	O

The	O
total	O
area	O
under	O
the	O
blood	O
glucose	O
curve	O
over	O
the	O
initial	O
value	O
was	O
not	O
altered	O
2	O
h	O
after	O
treatment	O
with	O
SH	O
B	O
209	O
AB	O
or	O
Neogynon	O
.	O

Serum	B-GENE
IgM	I-GENE
levels	O
showed	O
a	O
highly	O
significant	O
increase	O
in	O
all	O
types	O
of	O
brain	O
tumour	O
when	O
compared	O
to	O
controls	O
.	O

Here	O
we	O
describe	O
the	O
characterization	O
of	O
cDNAs	O
encoding	O
two	O
unusual	O
E2Fs	B-GENE
,	O
E2F	B-GENE
-	I-GENE
4	I-GENE
and	O
E2F	B-GENE
-	I-GENE
5	I-GENE
,	O
each	O
identified	O
by	O
the	O
ability	O
of	O
their	O
gene	O
product	O
to	O
interact	O
with	O
p130	B-GENE
in	O
a	O
yeast	O
two	O
-	O
hybrid	O
system	O
.	O

Ultra	O
-	O
energy	O
(	O
UHE	O
)	O
imaging	O
is	O
usually	O
performed	O
in	O
simultaneous	O
F	O
-	O
18	O
FDG	O
/	O
Tc	O
-	O
99m	O
MIBI	O
studies	O
.	O

However	O
,	O
electron	O
microscopy	O
revealed	O
that	O
while	O
sec4	B-GENE
mutant	I-GENE
cells	O
accumulate	O
secretory	O
vesicles	O
,	O
ypt31	B-GENE
/	I-GENE
32	I-GENE
mutant	I-GENE
cells	O
accumulate	O
aberrant	O
Golgi	O
structures	O
.	O

Furthermore	O
,	O
Grap	B-GENE
is	O
associated	O
with	O
a	O
Ras	B-GENE
guanine	I-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
mSos1	B-GENE
,	O
primarily	O
through	O
its	O
N	B-GENE
-	I-GENE
terminal	I-GENE
SH3	I-GENE
domain	I-GENE
.	O

Correlation	O
of	O
nitrogen	O
,	O
carbohydrate	O
and	O
lipid	O
metabolic	O
indices	O
in	O
rats	O
cooled	O
under	O
conditions	O
of	O
an	O
altered	O
gaseous	O
environment	O

Transfer	O
of	O
F	O
-	O
like	O
plasmids	O
is	O
regulated	O
by	O
the	O
FinOP	B-GENE
system	O
,	O
which	O
controls	O
the	O
expression	O
of	O
traJ	B-GENE
,	O
a	O
positive	O
regulator	O
of	O
the	O
transfer	O
operon	O
.	O

This	O
regimen	O
may	O
be	O
considered	O
front	O
-	O
line	O
therapy	O
when	O
autologous	O
stem	O
cell	O
transplantation	O
is	O
not	O
feasible	O
and	O
when	O
a	O
rapid	O
response	O
is	O
particularly	O
important	O
.	O

To	O
investigate	O
this	O
issue	O
,	O
we	O
used	O
a	O
recognition	O
task	O
in	O
which	O
two	O
strings	O
of	O
letters	O
are	O
presented	O
sequentially	O
.	O

Comparison	O
to	O
the	O
murine	O
homologues	O
of	O
these	O
molecules	O
reveals	O
a	O
high	O
degree	O
of	O
conservation	O
between	O
the	O
products	O
of	O
one	O
of	O
these	O
genes	O
,	O
Fc	B-GENE
gamma	I-GENE
RIIb	I-GENE
,	O
and	O
the	O
murine	B-GENE
beta	I-GENE
gene	I-GENE
in	O
primary	O
sequence	O
,	O
splicing	O
pattern	O
,	O
and	O
tissue	O
distribution	O
.	O

A	O
rabbit	O
antiserum	O
raised	O
against	O
a	O
unique	O
(	O
V3	O
domain	O
)	O
bacterially	O
expressed	O
PKC	B-GENE
theta	I-GENE
fragment	I-GENE
immunoprecipitated	O
specifically	O
an	O
82	O
-	O
kDa	O
protein	O
from	O
Jurkat	O
cell	O
lysates	O
.	O

These	O
changes	O
persisted	O
during	O
the	O
first	O
week	O
.	O

Hematological	O
parameters	O
(	O
leukocyte	O
,	O
neutrophil	O
and	O
platelet	O
counts	O
)	O
and	O
liver	O
function	O
tests	O
were	O
determined	O
by	O
standard	O
procedures	O
.	O

(	O
1993	O
)	O
8	O
,	O
94	O
-	O
99	O
)	O
.	O

The	O
effect	O
of	O
betamethasone	O
on	O
duodenal	O
calcium	O
absorption	O
and	O
1	O
,	O
25	O
-	O
dihydroxy	O
vitamin	O
D3	O
production	O
in	O
the	O
chick	O
.	O

Phosphate	O
compounds	O
in	O
isolated	O
,	O
perfused	O
hearts	O
during	O
pH	O
variation	O
due	O
to	O
changes	O
in	O
extracellular	O
PCO2	O
and	O
bicarbonate	O

We	O
report	O
on	O
a	O
case	O
discovered	O
in	O
a	O
13	O
year	O
-	O
old	O
girl	O
presenting	O
with	O
anaemia	O
.	O

Although	O
analysis	O
of	O
the	O
similarity	O
between	O
the	O
44	O
-	O
kDa	O
protein	O
and	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
RecA	I-GENE
protein	I-GENE
did	O
not	O
show	O
any	O
significant	O
homology	O
between	O
them	O
,	O
it	O
revealed	O
their	O
identity	O
by	O
five	O
amino	O
-	O
acid	O
residues	O
involved	O
in	O
the	O
formation	O
of	O
the	O
epitope	O
that	O
recognized	O
the	O
paratope	O
of	O
the	O
RecA	B-GENE
protein	I-GENE
antibody	I-GENE
for	O
subsequent	O
epitope	O
-	O
paratope	O
binding	O
of	O
these	O
proteins	O
.	O

It	O
would	O
seem	O
that	O
caution	O
should	O
be	O
exercised	O
in	O
using	O
HPL	B-GENE
values	O
as	O
an	O
index	O
of	O
placental	O
function	O
in	O
anaemic	O
women	O
.	O

No	O
IORT	O
related	O
mortality	O
has	O
been	O
observed	O
.	O

Characterization	O
of	O
a	O
tonB	B-GENE
-	O
phoA	B-GENE
gene	O
fusion	O
suggests	O
that	O
the	O
amino	O
-	O
terminal	O
41	O
amino	O
acids	O
of	O
TonB	B-GENE
are	O
sufficient	O
to	O
promote	O
export	O
of	O
the	O
fusion	O
protein	O
and	O
presumably	O
TonB	B-GENE
as	O
well	O
.	O

Characterization	O
of	O
a	O
unique	O
protein	O
component	O
of	O
yeast	B-GENE
RNase	I-GENE
MRP	I-GENE
:	O
an	O
RNA	O
-	O
binding	O
protein	O
with	O
a	O
zinc	O
-	O
cluster	O
domain	O
.	O

This	O
raises	O
the	O
possibility	O
that	O
recombination	O
occurred	O
between	O
corresponding	O
LTR	O
and	O
vif	B-GENE
loci	I-GENE
of	O
the	O
quasi	O
-	O
species	O
present	O
in	O
the	O
isolates	O
described	O
here	O
.	O

2	O
.	O

The	O
antihypertensive	O
action	O
corresponds	O
to	O
those	O
of	O
established	O
diuretics	O
.	O

These	O
results	O
are	O
discussed	O
in	O
relation	O
to	O
predicted	O
isoform	O
L	O
diversity	O
across	O
human	O
tissues	O
and	O
cells	O
.	O

In	O
the	O
healing	O
tendons	O
,	O
the	O
rate	O
of	O
collagen	B-GENE
synthesis	O
decreased	O
and	O
the	O
rate	O
of	O
noncollagen	O
protein	O
synthesis	O
remained	O
unchanged	O
.	O

The	O
aromatic	B-GENE
hydrocarbon	I-GENE
receptor	I-GENE
(	O
AHR	B-GENE
)	O
is	O
a	O
ligand	O
-	O
activated	O
transcription	O
factor	O
that	O
regulates	O
the	O
expression	O
of	O
several	O
drug	O
-	O
metabolizing	O
enzymes	O
and	O
has	O
been	O
implicated	O
in	O
immunosuppression	O
,	O
teratogenesis	O
,	O
cell	O
-	O
specific	O
hyperplasia	O
,	O
and	O
certain	O
types	O
of	O
malignancies	O
and	O
toxicities	O
.	O

Fluctuations	O
of	O
the	O
measured	O
ECF	O
energy	O
-	O
related	O
substances	O
corresponded	O
to	O
various	O
clinical	O
events	O
presumably	O
involving	O
hypoxia	O
/	O
ischemia	O
.	O

After	O
3	O
months	O
of	O
intervention	O
,	O
sustained	O
physical	O
training	O
was	O
associated	O
with	O
the	O
decrease	O
of	O
FVII	B-GENE
and	O
PAI	B-GENE
-	I-GENE
1	I-GENE
levels	O
.	O

The	O
metalloproteinase	B-GENE
mediating	O
Met	B-GENE
cleavage	O
was	O
specifically	O
inhibited	O
by	O
the	O
tissue	B-GENE
inhibitor	I-GENE
of	I-GENE
metalloproteinases	I-GENE
(	I-GENE
TIMP	I-GENE
)	I-GENE
-	I-GENE
3	I-GENE
,	O
but	O
not	O
by	O
TIMP	B-GENE
-	I-GENE
1	I-GENE
or	O
TIMP	B-GENE
-	I-GENE
2	I-GENE
.	O

This	O
constant	O
expression	O
profile	O
,	O
coupled	O
with	O
the	O
observation	O
that	O
over	O
-	O
expression	O
of	O
mSin3A	B-GENE
does	O
not	O
augment	O
the	O
anti	B-GENE
-	I-GENE
Myc	I-GENE
activity	O
of	O
Mxi1	B-GENE
-	O
SR	O
in	O
the	O
rat	O
embryo	O
fibroblast	O
(	O
REF	O
)	O
transformation	O
assay	O
,	O
suggests	O
that	O
mSin3A	B-GENE
is	O
not	O
a	O
limiting	O
factor	O
in	O
the	O
regulation	O
of	O
Myc	B-GENE
superfamily	I-GENE
function	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
The	O
effect	O
of	O
prolonged	O
nitrate	O
therapy	O
between	O
2	O
days	O
and	O
6	O
weeks	O
during	O
healing	O
after	O
infarction	O
on	O
serial	O
parameters	O
of	O
ventricular	O
remodeling	O
(	O
scar	O
expansion	O
,	O
scar	O
thinning	O
,	O
ventricular	O
dilation	O
,	O
and	O
hypertrophy	O
)	O
and	O
function	O
(	O
asynergy	O
or	O
akinesis	O
plus	O
dyskinesis	O
and	O
ejection	O
fraction	O
)	O
by	O
serial	O
two	O
-	O
dimensional	O
echocardiography	O
,	O
hemodynamics	O
,	O
postmortem	O
topography	O
(	O
computerized	O
planimetry	O
,	O
geometric	O
maps	O
,	O
and	O
radiographs	O
)	O
,	O
and	O
collagen	B-GENE
content	O
(	O
hydroxyproline	O
)	O
was	O
studied	O
in	O
64	O
instrumented	O
dogs	O
randomized	O
2	O
days	O
after	O
left	O
anterior	O
descending	O
coronary	O
artery	O
ligation	O
to	O
various	O
nitrate	O
regimens	O
(	O
n	O
=	O
32	O
)	O
over	O
the	O
first	O
2	O
weeks	O
(	O
subgroup	O
1	O
:	O
2	O
%	O
transdermal	O
nitroglycerin	O
at	O
8	O
AM	O
and	O
4	O
PM	O
,	O
n	O
=	O
6	O
;	O
subgroup	O
2	O
:	O
2	O
%	O
transdermal	O
nitroglycerin	O
plus	O
2	O
.	O
6	O
mg	O
of	O
sustained	O
-	O
release	O
oral	O
nitroglycerin	O
at	O
8	O
AM	O
,	O
3	O
PM	O
,	O
and	O
10	O
PM	O
,	O
n	O
=	O
5	O
;	O
subgroup	O
3	O
:	O
oral	O
isosorbide	O
dinitrate	O
,	O
30	O
mg	O
at	O
8	O
AM	O
and	O
4	O
PM	O
,	O
n	O
=	O
11	O
)	O
or	O
6	O
weeks	O
(	O
subgroup	O
4	O
:	O
isosorbide	O
dinitrate	O
,	O
n	O
=	O
10	O
)	O
and	O
in	O
matching	O
controls	O
(	O
n	O
=	O
32	O
)	O
.	O

A	O
nationwide	O
survey	O
uncovered	O
a	O
tenfold	O
variation	O
between	O
counties	O
in	O
the	O
prescribing	O
of	O
IFNB	B-GENE
.	O

We	O
have	O
demonstrated	O
that	O
a	O
putative	O
HOX	B-GENE
cofactor	I-GENE
,	O
PBX1A	B-GENE
,	O
participates	O
in	O
cooperative	O
DNA	O
binding	O
with	O
HOXA	B-GENE
-	I-GENE
1	I-GENE
and	O
the	O
Deformed	B-GENE
group	O
protein	O
HOXD	B-GENE
-	I-GENE
4	I-GENE
.	O

RESULTS	O
-	O
-	O
261	O
patients	O
were	O
enrolled	O
into	O
this	O
study	O
;	O
of	O
these	O
,	O
138	O
(	O
53	O
%	O
)	O
patients	O
attended	O
for	O
repeat	O
colposcopy	O
and	O
cytology	O
at	O
one	O
year	O
.	O

We	O
have	O
found	O
that	O
pro	B-GENE
-	I-GENE
IGF	I-GENE
-	I-GENE
2	I-GENE
can	O
initially	O
form	O
two	O
disulfide	O
isomers	O
that	O
undergo	O
rearrangement	O
to	O
a	O
single	O
conformation	O
in	O
vivo	O
.	O

Thus	O
,	O
primate	O
vs	O
.	O
rodent	O
promoter	O
selectivity	O
mediated	O
by	O
the	O
TBP	B-GENE
-	O
TAFI	B-GENE
complex	O
is	O
likely	O
to	O
be	O
the	O
result	O
of	O
cumulative	O
subtle	O
differences	O
between	O
individual	O
subunits	O
that	O
lead	O
to	O
species	O
-	O
specific	O
properties	O
of	O
RNA	B-GENE
polymerase	I-GENE
I	I-GENE
transcription	O
.	O

Anti	B-GENE
-	I-GENE
Jo	I-GENE
-	I-GENE
1	I-GENE
antibody	I-GENE
was	O
not	O
present	O
.	O

The	O
structure	O
and	O
expression	O
of	O
the	O
murine	B-GENE
gene	I-GENE
encoding	I-GENE
granulocyte	I-GENE
-	I-GENE
macrophage	I-GENE
colony	I-GENE
stimulating	I-GENE
factor	I-GENE
:	O
evidence	O
for	O
utilisation	O
of	O
alternative	O
promoters	O
.	O

Cotransfection	O
of	O
pINV	O
-	O
2473	O
,	O
a	O
construct	O
containing	O
2473	O
base	O
pairs	O
of	O
hINV	B-GENE
upstream	I-GENE
sequence	I-GENE
linked	O
to	O
luciferase	B-GENE
,	O
with	O
POU	B-GENE
homeodomain	I-GENE
transcription	I-GENE
factors	I-GENE
Oct1	B-GENE
,	O
Oct2	B-GENE
,	O
Brn4	B-GENE
,	O
SCIP	B-GENE
,	O
Skn1a	B-GENE
or	O
Skn1i	B-GENE
,	O
results	O
in	O
a	O
strong	O
suppression	O
of	O
basal	O
promoter	O
activity	O
.	O

Central	O
treatment	O
unit	O
saves	O
nurses	O
,	O
adds	O
income	O
,	O
improves	O
care	O
.	O

The	O
Grb2	B-GENE
SH3	B-GENE
(	I-GENE
C	I-GENE
)	I-GENE
binding	I-GENE
region	I-GENE
of	O
Gab1	B-GENE
has	O
significant	O
homology	O
to	O
a	O
region	O
of	O
the	O
adapter	B-GENE
protein	I-GENE
SLP	I-GENE
-	I-GENE
76	I-GENE
.	O

The	O
QCS	O
appears	O
comparable	O
with	O
the	O
MMSE	O
and	O
is	O
quicker	O
to	O
administer	O
.	O

A	O
positive	O
FTA	B-GENE
-	I-GENE
ABS	I-GENE
-	I-GENE
19S	I-GENE
-	I-GENE
IgM	I-GENE
test	O
indicates	O
the	O
necessity	O
of	O
treatment	O
.	O

A	O
DNA	O
binding	O
protein	O
was	O
identified	O
which	O
binds	O
to	O
two	O
novel	O
target	O
-	O
like	O
sequences	O
:	O
(	O
i	O
)	O
at	O
the	O
5	O
'	O
flanking	O
site	O
of	O
the	O
breakpoint	O
junction	O
of	O
chromosome	O
8	O
in	O
a	O
patient	O
with	O
T	O
-	O
acute	O
lymphoblastic	O
leukemia	O
(	O
ALL	O
)	O
carrying	O
the	O
t	O
(	O
8	O
;	O
14	O
)	O
(	O
q24	O
;	O
q11	O
)	O
rearrangement	O
and	O
(	O
ii	O
)	O
on	O
chromosome	O
1	O
in	O
three	O
of	O
five	O
T	O
-	O
ALL	O
patients	O
with	O
the	O
t	O
(	O
1	O
;	O
14	O
)	O
(	O
p32	O
;	O
q11	O
)	O
rearrangement	O
.	O

1988	O
)	O
.	O

The	O
effect	O
of	O
iron	O
on	O
the	O
toxigenicity	O
of	O
Vibrio	O
cholerae	O
.	O

The	O
rest	O
of	O
the	O
3	O
'	O
untranslated	O
sequences	O
were	O
common	O
to	O
both	O
cDNA	O
clones	O
.	O

The	O
anesthesiologist	O
and	O
the	O
cardiac	O
surgeon	O
.	O

The	O
three	O
proteins	O
copurified	O
through	O
several	O
biochemical	O
fractionation	O
steps	O
and	O
could	O
be	O
coimmunoprecipitated	O
by	O
using	O
antibodies	O
against	O
GCD1	B-GENE
or	O
GCD2	B-GENE
.	O

From	O
1998	O
to	O
1999	O
,	O
a	O
large	O
number	O
of	O
community	O
-	O
acquired	O
respiratory	O
tract	O
isolates	O
of	O
Streptococcus	O
pneumoniae	O
(	O
n	O
=	O
566	O
)	O
,	O
Haemophilus	O
influenzae	O
(	O
n	O
=	O
513	O
)	O
and	O
Moraxella	O
catarrhalis	O
(	O
n	O
=	O
228	O
)	O
were	O
collected	O
from	O
15	O
centres	O
in	O
Australia	O
,	O
Hong	O
Kong	O
,	O
Japan	O
,	O
China	O
,	O
the	O
Philippines	O
,	O
Singapore	O
,	O
South	O
Africa	O
and	O
Taiwan	O
through	O
the	O
SENTRY	O
Antimicrobial	O
Surveillance	O
Program	O
.	O

Rats	O
on	O
the	O
multiple	O
oral	O
dosage	O
regimen	O
were	O
given	O
unlabelled	O
HMCF	O
in	O
their	O
drinking	O
water	O
for	O
13	O
days	O
before	O
the	O
administration	O
of	O
a	O
bolus	O
dose	O
of	O
[	O
14C	O
]	O
HMCF	O
on	O
day	O
14	O
.	O

In	O
order	O
to	O
search	O
for	O
mutations	O
in	O
the	O
multicopy	B-GENE
RBM	I-GENE
genes	I-GENE
that	O
might	O
be	O
associated	O
with	O
male	O
infertility	O
,	O
we	O
have	O
used	O
sequence	O
data	O
from	O
the	O
reported	O
cDNA	O
clone	O
to	O
determine	O
the	O
intron	O
exon	O
boundaries	O
of	O
the	O
YRRM	B-GENE
1	I-GENE
gene	I-GENE
.	O

Uterine	O
contractions	O
began	O
with	O
a	O
mean	O
latency	O
of	O
62	O
min	O
in	O
the	O
PGF2	O
alpha	O
infused	O
women	O
,	O
in	O
controls	O
uterine	O
activity	O
remained	O
unchanged	O
.	O

The	O
implication	O
of	O
Rac	B-GENE
and	O
Cdc42	B-GENE
was	O
analyzed	O
in	O
transient	O
transfection	O
experiments	O
using	O
either	O
constitutively	O
active	O
(	O
V12	O
)	O
or	O
dominant	O
-	O
interfering	O
(	O
N17	O
)	O
mutants	O
.	O

The	O
evolutionary	O
significance	O
of	O
the	O
similarities	O
of	O
intron	O
secondary	O
structures	O
and	O
open	O
reading	O
frames	O
of	O
the	O
ND3	B-GENE
,	I-GENE
4	I-GENE
and	I-GENE
ATPase	I-GENE
6	I-GENE
genes	I-GENE
is	O
discussed	O
,	O
including	O
the	O
possible	O
separate	O
evolution	O
of	O
structural	O
and	O
coding	O
sequences	O
.	O

Although	O
there	O
is	O
evidence	O
that	O
cone	O
ratios	O
do	O
determine	O
colour	O
appearance	O
under	O
many	O
conditions	O
,	O
the	O
site	O
or	O
sites	O
of	O
their	O
computation	O
is	O
unknown	O
.	O

Procedures	O
with	O
perfected	O
method	O

In	O
an	O
effort	O
to	O
identify	O
factors	O
involved	O
in	O
the	O
expression	O
of	O
this	O
important	O
erythroid	O
-	O
specific	O
regulatory	O
protein	O
,	O
we	O
have	O
isolated	O
the	O
mouse	B-GENE
EKLF	I-GENE
gene	I-GENE
and	O
systematically	O
analyzed	O
the	O
promoter	O
region	O
.	O

Accordingly	O
,	O
superpeptide	O
antigenic	O
material	O
was	O
readily	O
detected	O
by	O
immunoblotting	O
cell	O
extracts	O
and	O
enriched	O
in	O
vacuolar	O
preparations	O
of	O
PrA	B-GENE
deficient	O
mutant	O
cells	O
.	O

RESULTS	O
:	O
All	O
primary	O
tumors	O
were	O
positive	O
for	O
CAM5	B-GENE
.	I-GENE
2	I-GENE
.	O

However	O
massive	O
necrosis	O
of	O
the	O
renal	O
tubules	O
had	O
been	O
found	O
with	O
more	O
than	O
15mg	O
of	O
DSM	O
administration	O
.	O

A	O
case	O
of	O
functioning	O
parathyroid	O
carcinoma	O
with	O
hypereninemic	O
hypertension	O
.	O

Together	O
with	O
a	O
number	O
of	O
phase	O
II	O
trials	O
,	O
phase	O
I	O
trials	O
utilizing	O
escalating	O
doses	O
of	O
carboplatin	O
and	O
paclitaxel	O
with	O
growth	O
factor	O
or	O
growth	O
factor	O
and	O
blood	O
stem	O
-	O
cell	O
support	O
have	O
shown	O
that	O
substantial	O
increases	O
in	O
dose	O
intensity	O
can	O
be	O
achieved	O
.	O

The	O
study	O
was	O
performed	O
in	O
a	O
class	O
100	O
laminar	O
flow	O
clean	O
bench	O
in	O
order	O
to	O
minimize	O
particulate	O
contamination	O
from	O
extraneous	O
sources	O
.	O

Moreover	O
,	O
since	O
the	O
integrated	O
transforming	O
DNA	O
was	O
not	O
altered	O
or	O
lost	O
expression	O
of	O
the	O
RbcS2	B-GENE
:	O
:	O
aadA	B-GENE
:	O
:	O
RbcS2	B-GENE
gene	I-GENE
(	I-GENE
s	I-GENE
)	I-GENE
appears	O
to	O
be	O
repressed	O
.	O

In	O
contrast	O
,	O
the	O
holo	B-GENE
-	I-GENE
dTFIIA	I-GENE
(	O
L	O
/	O
S	O
)	O
binds	O
TBP	B-GENE
with	O
high	O
affinity	O
.	O

In	O
one	O
trial	O
,	O
116	O
subjects	O
with	O
transfusion	O
-	O
related	O
chronic	O
hepatitis	O
C	O
were	O
treated	O
with	O
lymphoblastoid	B-GENE
interferon	I-GENE
(	O
5	O
MU	O
/	O
m2	O
three	O
times	O
a	O
week	O
for	O
2	O
mo	O
,	O
then	O
3	O
MU	O
/	O
m2	O
three	O
times	O
a	O
week	O
for	O
4	O
or	O
10	O
mo	O
)	O
.	O

These	O
results	O
demonstrate	O
the	O
preferential	O
endometrial	O
cell	O
-	O
type	O
expression	O
of	O
BTEB	B-GENE
and	O
suggest	O
its	O
regulatory	O
role	O
in	O
pregnancy	O
-	O
associated	O
endometrial	O
epithelial	O
gene	O
expression	O
.	O

The	O
sequence	O
of	O
LZ321	B-GENE
matched	O
that	O
of	O
RREB1	B-GENE
,	O
a	O
transcription	O
factor	O
that	O
bound	O
to	O
a	O
Ras	B-GENE
responsive	I-GENE
element	I-GENE
(	O
RRE	B-GENE
)	O
very	O
different	O
from	O
the	O
sequence	O
with	O
which	O
we	O
isolated	O
LZ321	B-GENE
.	O

Phosphorylation	O
at	O
Ser	O
(	O
670	O
)	O
impairs	O
the	O
ability	O
of	O
GRK2	B-GENE
to	O
phosphorylate	O
both	O
soluble	O
and	O
membrane	O
-	O
incorporated	O
receptor	O
substrates	O
and	O
dramatically	O
attenuates	O
Gbetagamma	B-GENE
-	O
mediated	O
activation	O
of	O
this	O
enzyme	O
.	O

However	O
,	O
the	O
sequence	O
of	O
mRAR	B-GENE
-	I-GENE
beta	I-GENE
3	I-GENE
region	I-GENE
A	I-GENE
differs	O
from	O
that	O
of	O
mRAR	B-GENE
-	I-GENE
beta	I-GENE
1	I-GENE
by	O
an	O
additional	O
27	O
C	O
-	O
terminal	O
amino	O
acids	O
encoded	O
in	O
an	O
81	O
nucleotide	O
-	O
long	O
putative	O
exon	O
which	O
is	O
spliced	O
in	O
between	O
the	O
exons	O
encoding	O
the	O
A	B-GENE
and	I-GENE
B	I-GENE
regions	I-GENE
of	I-GENE
mRAR	I-GENE
-	I-GENE
beta	I-GENE
1	I-GENE
.	O

Rad18	B-GENE
is	O
required	O
for	O
DNA	O
repair	O
and	O
checkpoint	O
responses	O
in	O
fission	O
yeast	O
.	O

The	O
longest	O
S1	O
-	O
S2	O
interval	O
at	O
which	O
S2	O
failed	O
to	O
capture	O
(	O
effective	O
refractory	O
period	O
)	O
was	O
longer	O
by	O
5	O
.	O
5	O
+	O
/	O
-	O
8	O
.	O
2	O
msec	O
at	O
twice	O
threshold	O
(	O
0	O
.	O
05	O
less	O
than	O
p	O
less	O
than	O
0	O
.	O
10	O
)	O
and	O
5	O
.	O
5	O
+	O
/	O
-	O
3	O
.	O
5	O
msec	O
at	O
5	O
times	O
threshold	O
stimulation	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
when	O
the	O
basic	O
drive	O
and	O
extrastimuli	O
were	O
delivered	O
to	O
separate	O
sites	O
.	O

Using	O
lasers	O
,	O
PRK	O
involves	O
reshaping	O
the	O
cornea	O
so	O
that	O
its	O
refractive	O
power	O
is	O
increased	O
.	O

Using	O
in	O
vivo	O
screening	O
,	O
we	O
first	O
identified	O
a	O
gene	O
that	O
appeared	O
to	O
interfere	O
with	O
the	O
His	O
-	O
Asp	O
phosphorelay	O
between	O
the	O
HPt	O
domain	O
and	O
the	O
receiver	O
domain	O
of	O
OmpR	B-GENE
,	O
provided	O
that	O
the	O
gene	O
product	O
was	O
expressed	O
through	O
a	O
multicopy	O
plasmid	O
.	O

In	O
addition	O
,	O
six	O
other	O
landmarks	O
favored	O
the	O
xeroradiograph	O
but	O
not	O
to	O
the	O
degree	O
of	O
statistical	O
significance	O
.	O

Coronary	O
vasoconstriction	O
caused	O
by	O
endothelin	B-GENE
-	I-GENE
1	I-GENE
is	O
enhanced	O
by	O
ischemia	O
-	O
reperfusion	O
and	O
by	O
norepinephrine	O
present	O
in	O
concentrations	O
typically	O
observed	O
after	O
neonatal	O
cardiopulmonary	O
bypass	O
.	O

Inhibition	O
of	O
Raf	B-GENE
-	I-GENE
1	I-GENE
signaling	O
by	O
a	O
monoclonal	O
antibody	O
,	O
which	O
interferes	O
with	O
Raf	B-GENE
-	I-GENE
1	I-GENE
activation	O
and	O
with	O
Mek	B-GENE
substrate	O
binding	O
.	O

Laparoscopic	O
examination	O
1	O
year	O
after	O
surgery	O
revealed	O
an	O
enlarged	O
,	O
thin	O
-	O
walled	O
,	O
and	O
fluid	O
-	O
filled	O
uterine	O
segment	O
cranial	O
to	O
the	O
midcornus	O
occlusion	O
sites	O
in	O
all	O
animals	O
.	O

NBSII	O
is	O
essential	O
for	O
ribosome	O
-	O
stimulated	O
activity	O
.	O

Gel	O
shift	O
and	O
southwestern	O
experiments	O
revealed	O
nuclear	O
proteins	O
of	O
43	O
kDa	O
and	O
30	O
kDa	O
in	O
GC	O
and	O
fish	O
cells	O
,	O
respectively	O
,	O
that	O
bind	O
specifically	O
to	O
the	O
tGH	B-GENE
CRE	O
,	O
suggesting	O
the	O
involvement	O
of	O
CRE	B-GENE
-	I-GENE
binding	I-GENE
-	I-GENE
protein	I-GENE
/	O
activating	B-GENE
-	I-GENE
transcription	I-GENE
-	I-GENE
factor	I-GENE
-	I-GENE
l	I-GENE
-	O
related	O
peptides	O
in	O
cAMP	O
response	O
.	O

Moreover	O
,	O
such	O
mutations	O
lead	O
to	O
a	O
dramatic	O
transition	O
in	O
chromatin	O
structure	O
:	O
the	O
DNase	B-GENE
I	I-GENE
hypersensitive	I-GENE
region	I-GENE
is	O
replaced	O
by	O
two	O
stable	O
,	O
sequence	O
-	O
positioned	O
nucleosomes	O
.	O

Two	O
measures	O
of	O
sensory	O
inhibition	O
were	O
employed	O
,	O
S2	O
/	O
S1	O
x	O
100	O
amplitude	O
ratio	O
and	O
S1	O
-	O
S2	O
amplitude	O
difference	O
.	O

The	O
transcriptional	O
start	O
site	O
,	O
identified	O
by	O
primer	O
extension	O
and	O
S1	B-GENE
nuclease	I-GENE
assay	O
,	O
is	O
34	O
nt	O
upstream	O
of	O
the	O
translation	O
initiation	O
codon	O
.	O

The	O
clinical	O
effects	O
of	O
valproate	O
and	O
ethosuximide	O
can	O
be	O
related	O
to	O
this	O
differential	O
modulation	O
of	O
thalamocortical	O
excitability	O
.	O

Central	O
projections	O
of	O
gastric	O
afferent	O
vagal	O
inputs	O
.	O

Our	O
results	O
suggest	O
a	O
biological	O
role	O
for	O
Elf	B-GENE
-	I-GENE
1	I-GENE
in	O
the	O
regulation	O
of	O
IgH	B-GENE
gene	I-GENE
expression	O
,	O
attribute	O
a	O
functional	O
role	O
for	O
receptor	O
-	O
induced	O
AP	B-GENE
-	I-GENE
1	I-GENE
proteins	I-GENE
in	O
B	O
lymphocytes	O
and	O
provide	O
evidence	O
for	O
a	O
direct	O
link	O
between	O
IgM	B-GENE
receptor	I-GENE
-	O
mediated	O
signalling	O
and	O
3	O
'	O
enhancer	O
activation	O
.	O

Like	O
Mdm2	B-GENE
,	O
MdmX	B-GENE
is	O
able	O
to	O
bind	O
p53	B-GENE
and	O
inhibit	O
p53	B-GENE
transactivation	O
;	O
however	O
,	O
the	O
ability	O
of	O
MdmX	B-GENE
to	O
degrade	O
p53	B-GENE
has	O
yet	O
to	O
be	O
examined	O
.	O

The	O
structure	O
of	O
the	O
mAR	B-GENE
ORF	O
was	O
confirmed	O
by	O
sequence	O
analysis	O
of	O
mAR	B-GENE
cDNA	O
fragments	O
,	O
which	O
were	O
obtained	O
by	O
PCR	O
amplification	O
of	O
mouse	O
testis	O
cDNA	O
,	O
using	O
mAR	B-GENE
specific	O
primers	O
.	O

Transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta	I-GENE
(	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
)	O
inhibits	O
cell	O
cycle	O
progression	O
,	O
in	O
part	O
through	O
up	O
-	O
regulation	O
of	O
gene	O
expression	O
of	O
the	O
p21	B-GENE
(	O
WAF1	B-GENE
/	O
Cip1	B-GENE
)	O
(	O
p21	B-GENE
)	O
cell	O
cycle	O
inhibitor	O
.	O

Decreased	O
plasma	O
level	O
of	O
antithrombin	B-GENE
III	I-GENE
was	O
assumed	O
to	O
be	O
one	O
of	O
the	O
major	O
factors	O
underlying	O
hypercoagulable	O
state	O
in	O
nephrotic	O
syndrome	O
.	O

In	O
both	O
RAW	O
cells	O
and	O
the	O
microglia	O
cell	O
line	O
EOC20	O
,	O
two	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
-	O
activated	O
transcription	O
factors	O
,	O
STAT	B-GENE
-	I-GENE
1alpha	I-GENE
and	O
IRF	B-GENE
-	I-GENE
1	I-GENE
,	O
bind	O
the	O
GAS	B-GENE
and	O
IRF	B-GENE
elements	I-GENE
,	O
respectively	O
.	O

All	O
patients	O
received	O
marrow	O
from	O
HLA	B-GENE
-	O
identical	O
sibling	O
donors	O
,	O
underwent	O
similar	O
myeloablative	O
regimens	O
,	O
and	O
had	O
similar	O
pretreatment	O
characteristics	O
.	O

In	O
Types	O
I	O
and	O
II	O
,	O
capillary	O
walls	O
became	O
thinner	O
and	O
more	O
capillary	O
lumens	O
were	O
visiable	O
.	O

Immunoblot	O
analyses	O
revealed	O
that	O
the	O
loss	O
of	O
activator	O
function	O
coincides	O
with	O
selective	O
removal	O
of	O
the	O
C	B-GENE
-	I-GENE
terminal	I-GENE
domain	I-GENE
(	I-GENE
CTD	I-GENE
)	I-GENE
-	I-GENE
hyperphosphorylated	I-GENE
RNAP	I-GENE
IIO	I-GENE
along	O
with	O
NC2	B-GENE
.	O

In	O
bell	O
pepper	O
,	O
a	O
gene	O
encoding	O
a	O
major	O
plastid	O
-	O
lipid	O
associated	O
protein	O
is	O
expressed	O
as	O
both	O
partially	O
and	O
totally	O
spliced	O
transcripts	O
(	O
respectively	O
PAP2	B-GENE
and	O
PAP1	B-GENE
)	O
.	O

Aggregation	O
in	O
washed	O
platelets	O
from	O
rats	O
with	O
diabetes	O
was	O
enhanced	O
.	O

Instead	O
,	O
the	O
large	O
difference	O
in	O
ssDNA	O
-	O
binding	O
affinities	O
reflects	O
the	O
loss	O
of	O
hexamerization	O
ability	O
by	O
uvsY	B-GENE
,	O
suggesting	O
that	O
a	O
form	O
of	O
intrahexamer	O
synergism	O
or	O
cooperativity	O
between	O
binding	O
sites	O
within	O
the	O
uvsY	B-GENE
hexamer	I-GENE
leads	O
to	O
its	O
high	O
observed	O
affinity	O
for	O
ssDNA	O
.	O

The	O
authors	O
investigate	O
in	O
a	O
group	O
of	O
211	O
children	O
aged	O
2	O
-	O
6	O
years	O
,	O
incl	O
.	O
in	O
particular	O
a	O
group	O
of	O
33	O
2	O
-	O
year	O
-	O
old	O
ones	O
,	O
in	O
1990	O
and	O
checked	O
in	O
1991	O
at	O
two	O
sites	O
in	O
Bratislava	O
-	O
-	O
a	O
town	O
with	O
a	O
varying	O
concentration	O
of	O
NOX	O
,	O
SO2	O
,	O
dustiness	O
and	O
dust	O
fallout	O
-	O
-	O
their	O
influence	O
on	O
the	O
incidence	O
,	O
type	O
and	O
course	O
of	O
relapsing	O
respiratory	O
disease	O
.	O

Such	O
results	O
suggest	O
that	O
there	O
are	O
no	O
differences	O
in	O
the	O
BMR	O
of	O
age	O
-	O
and	O
weight	O
-	O
matched	O
Asian	O
Indian	O
males	O
,	O
other	O
tropical	O
populations	O
and	O
Americans	O
.	O

CONCLUSION	O
:	O
DaunoXome	O
has	O
an	O
improved	O
pharmacokinetic	O
profile	O
compared	O
with	O
free	O
daunorubicin	O
,	O
and	O
is	O
well	O
tolerated	O
.	O

Furthermore	O
,	O
the	O
zincon	O
-	O
loaded	O
resin	O
was	O
applied	O
to	O
the	O
selective	O
concentration	O
of	O
trace	O
amounts	O
of	O
chalcophile	O
elements	O
in	O
natural	O
water	O
samples	O
prior	O
to	O
neutron	O
activation	O
analysis	O
.	O

Analyses	O
focused	O
on	O
two	O
platyrrhine	O
(	O
New	O
World	O
monkey	O
)	O
species	O
:	O
the	O
common	O
marmoset	O
(	O
Callithrix	O
jacchus	O
)	O
and	O
the	O
brown	O
capuchin	O
monkey	O
(	O
Cebus	O
apella	O
)	O
,	O
each	O
of	O
which	O
has	O
paired	O
,	O
non	O
-	O
allelic	O
gamma	O
loci	O
(	O
5	O
'	O
-	O
gamma	O
1	O
-	O
gamma	O
2	O
-	O
3	O
'	O
)	O
.	O

Over	O
half	O
of	O
the	O
children	O
initially	O
unresponsive	O
to	O
H	O
.	O
influenzae	O
type	O
b	O
meningitis	O
subsequently	O
developed	O
specific	O
antibodies	O
.	O

The	O
electron	O
spin	O
resonance	O
study	O
also	O
demonstrated	O
that	O
the	O
formation	O
of	O
superoxide	O
-	O
DMPO	O
spin	O
adduct	O
was	O
strongly	O
inhibited	O
by	O
a	O
selective	O
cyclooxygenase	B-GENE
-	I-GENE
2	I-GENE
inhibitor	O
,	O
etodolac	O
,	O
in	O
a	O
concentration	O
-	O
dependent	O
manner	O
.	O

Sox8	B-GENE
maps	O
to	O
the	O
t	B-GENE
complex	I-GENE
on	O
mouse	O
chromosome	O
17	O
and	O
to	O
human	O
chromosome	O
16p13	O
.	O
3	O
,	O
a	O
region	O
associated	O
with	O
the	O
microphthalmia	O
-	O
cataract	O
syndrome	O
CATM	O
and	O
the	O
alpha	O
-	O
thalassemia	O
/	O
mental	O
retardation	O
syndrome	O
ATR	O
-	O
16	O
.	O

If	O
vascular	O
induction	O
between	O
a	O
vascular	O
carrier	O
and	O
the	O
selected	O
jejunal	O
segment	O
is	O
done	O
as	O
a	O
kind	O
of	O
flap	O
prefabrication	O
,	O
the	O
jejunal	O
interposition	O
flap	O
can	O
be	O
used	O
without	O
the	O
need	O
for	O
complex	O
microsurgery	O
.	O

There	O
was	O
no	O
difference	O
in	O
the	O
day	O
-	O
42	O
cure	O
rates	O
between	O
the	O
QC7	O
(	O
n	O
=	O
65	O
)	O
and	O
A7	O
(	O
n	O
=	O
64	O
)	O
regimens	O
with	O
an	O
efficacy	O
of	O
100	O
%	O
in	O
both	O
,	O
confirmed	O
by	O
parasite	O
genotyping	O
.	O

Acetyl	B-GENE
-	I-GENE
CoA	I-GENE
carboxylase	I-GENE
from	O
yeast	O
is	O
an	O
essential	O
enzyme	O
and	O
is	O
regulated	O
by	O
factors	O
that	O
control	O
phospholipid	O
metabolism	O
.	O

The	O
NH	O
(	O
2	O
)	O
-	O
terminus	O
of	O
all	O
three	O
proteins	O
contains	O
a	O
POZ	O
domain	O
,	O
a	O
conserved	O
120	O
amino	O
acid	O
motif	O
involved	O
in	O
transcriptional	O
repression	O
and	O
protein	O
dimerization	O
.	O

Recognition	O
of	O
DNA	O
by	O
single	O
-	O
chain	O
derivatives	O
of	O
the	O
phage	O
434	O
repressor	O
:	O
high	O
affinity	O
binding	O
depends	O
on	O
both	O
the	O
contacted	O
and	O
non	O
-	O
contacted	O
base	O
pairs	O
.	O

In	O
the	O
absence	O
of	O
Mg2	O
+	O
,	O
the	O
extent	O
of	O
destabilization	O
of	O
tRNAPhe	B-GENE
is	O
greater	O
but	O
appears	O
to	O
be	O
confined	O
to	O
internal	O
regions	O
of	O
the	O
acceptor	O
and	O
T	O
psi	O
C	O
helices	O
,	O
as	O
evidenced	O
by	O
the	O
selectively	O
enhanced	O
exchange	O
rates	O
for	O
imino	O
protons	O
associated	O
with	O
these	O
base	O
pairs	O
.	O

This	O
gene	O
is	O
named	O
PKNOX1	B-GENE
by	O
the	O
Human	O
Nomenclature	O
Committee	O
.	O

The	O
carboxyl	O
-	O
terminal	O
75	O
amino	O
acids	O
of	O
the	O
two	O
proteins	O
contain	O
the	O
bHLH	O
motif	O
and	O
differ	O
from	O
each	O
other	O
by	O
only	O
three	O
conservative	O
amino	O
acid	O
changes	O
,	O
while	O
the	O
amino	O
-	O
terminal	O
portions	O
are	O
markedly	O
divergent	O
from	O
each	O
other	O
.	O

A	O
Drosophila	O
subobscura	O
genomic	O
fragment	O
containing	O
all	O
the	O
exons	O
and	O
the	O
late	O
and	O
early	O
promotors	O
in	O
the	O
Sxl	B-GENE
gene	I-GENE
of	I-GENE
D	I-GENE
.	I-GENE
melanogaster	I-GENE
was	O
isolated	O
.	O

The	O
data	O
from	O
animal	O
experiments	O
indicate	O
that	O
the	O
incidence	O
of	O
solid	O
tumors	O
in	O
marrow	O
transplant	O
patients	O
may	O
still	O
rise	O
in	O
the	O
coming	O
decades	O
.	O

The	O
results	O
of	O
the	O
transient	O
-	O
transfection	O
assay	O
showed	O
that	O
the	O
Sp1	B-GENE
binding	I-GENE
element	I-GENE
located	O
in	O
the	O
core	O
region	O
(	O
positions	O
-	O
-	O
64	O
to	O
+	O
1	O
)	O
of	O
the	O
alpha2	B-GENE
-	I-GENE
integrin	I-GENE
promoter	I-GENE
plays	O
an	O
essential	O
role	O
in	O
the	O
alpha2	B-GENE
-	I-GENE
integrin	I-GENE
promoter	I-GENE
activity	O
and	O
its	O
downregulation	O
by	O
Erb	B-GENE
-	O
B2	B-GENE
.	O

These	O
observations	O
suggest	O
that	O
the	O
AF	O
-	O
1	O
region	O
of	O
PPARalpha	B-GENE
is	O
partially	O
silenced	O
by	O
corepressor	O
proteins	O
,	O
which	O
might	O
interact	O
in	O
a	O
phosphorylation	O
-	O
dependent	O
manner	O
.	O

Evaluation	O
of	O
the	O
effects	O
of	O
chelation	O
therapy	O
with	O
time	O
following	O
strontium	O
exposure	O
to	O
mice	O
.	O

Insertion	O
of	O
alternatively	O
spliced	O
exon	O
W	O
into	O
CREB	B-GENE
mRNA	I-GENE
during	O
spermatogenesis	O
results	O
in	O
a	O
polycistronic	O
RNA	O
that	O
encodes	O
two	O
novel	O
internally	O
translated	O
CREB	B-GENE
repressor	I-GENE
isoforms	I-GENE
called	O
I	B-GENE
-	I-GENE
CREBs	I-GENE
,	O
consisting	O
of	O
the	O
carboxy	O
-	O
terminal	O
DNA	O
-	O
binding	O
domain	O
devoid	O
of	O
the	O
transactivation	O
domains	O
.	O

The	O
human	B-GENE
BRCA1	I-GENE
promoter	I-GENE
also	O
contains	O
a	O
conserved	O
E2F	B-GENE
site	I-GENE
and	O
is	O
similarly	O
regulated	O
by	O
E2F1	B-GENE
and	O
Rb	B-GENE
.	O

In	O
the	O
studies	O
described	O
in	O
this	O
report	O
,	O
we	O
have	O
identified	O
two	O
potential	O
Ets	B-GENE
binding	O
sites	O
,	O
EBS1	B-GENE
and	O
EBS2	B-GENE
,	O
which	O
are	O
conserved	O
in	O
both	O
the	O
human	O
and	O
murine	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
enhancers	O
.	O

An	O
enhancement	O
of	O
benign	O
liver	O
tumors	O
(	O
tumorigenic	O
effect	O
)	O
was	O
observed	O
only	O
in	O
CF1	O
male	O
mice	O
(	O
17	O
/	O
56	O
at	O
the	O
only	O
tested	O
dose	O
:	O
400	O
ppm	O
vs	O
.	O

Stamps	O
in	O
cardiology	O
:	O
de	O
Musset	O
sign	O
.	O

Here	O
,	O
we	O
analyzed	O
the	O
interaction	O
of	O
CYT	B-GENE
-	I-GENE
18	I-GENE
with	O
a	O
small	O
RNA	O
(	O
P4	B-GENE
-	I-GENE
P6	I-GENE
RNA	I-GENE
)	O
corresponding	O
to	O
the	O
isolated	O
P4	B-GENE
-	I-GENE
P6	I-GENE
domain	I-GENE
of	O
the	O
N	B-GENE
.	I-GENE
crassa	I-GENE
mitochondrial	I-GENE
large	I-GENE
subunit	I-GENE
ribosomal	I-GENE
RNA	I-GENE
intron	I-GENE
.	O

268	O
,	O
6858	O
-	O
6861	O
)	O
.	O

Polyglutamine	O
-	O
containing	O
protein	O
fragments	O
have	O
been	O
shown	O
to	O
accumulate	O
as	O
aggregates	O
in	O
the	O
nucleus	O
and	O
in	O
the	O
cytoplasm	O
,	O
and	O
to	O
induce	O
cell	O
death	O
when	O
expressed	O
in	O
cultured	O
cells	O
,	O
leading	O
to	O
the	O
proposal	O
that	O
polyglutamine	O
aggregation	O
is	O
an	O
important	O
step	O
in	O
the	O
pathogenesis	O
.	O

We	O
have	O
previously	O
shown	O
that	O
the	O
transcriptional	O
activator	O
CREM	B-GENE
is	O
highly	O
expressed	O
in	O
postmeiotic	O
cells	O
.	O

For	O
more	O
detailed	O
mapping	O
,	O
we	O
constructed	O
mouse	O
A9	O
cells	O
containing	O
STFs	O
derived	O
from	O
human	O
chromosome	O
2	O
tagged	O
with	O
pSTneo	O
at	O
different	O
regions	O
in	O
2q31	O
-	O
qter	O
.	O

We	O
therefore	O
propose	O
that	O
PRR2	B-GENE
,	O
and	O
not	O
PVR	B-GENE
,	O
is	O
the	O
true	O
human	O
homolog	O
of	O
MPH	B-GENE
.	O

We	O
have	O
analyzed	O
herein	O
the	O
roles	O
that	O
four	O
different	O
PIAS	B-GENE
proteins	I-GENE
(	O
ARIP3	B-GENE
/	O
PIASx	B-GENE
alpha	I-GENE
,	O
Miz1	B-GENE
/	O
PIASx	B-GENE
beta	I-GENE
,	O
GBP	B-GENE
/	O
PIAS1	B-GENE
,	O
and	O
PIAS3	B-GENE
)	O
play	O
in	O
the	O
regulation	O
of	O
steroid	B-GENE
receptor	I-GENE
-	O
or	O
STAT	B-GENE
-	O
mediated	O
transcriptional	O
activation	O
.	O

Yet	O
testosterone	O
was	O
predominant	O
in	O
the	O
plasma	O
of	O
the	O
Type	O
II	O
male	O
morph	O
which	O
neither	O
courts	O
females	O
nor	O
nests	O
,	O
but	O
instead	O
parasitizes	O
Type	O
I	O
males	O
with	O
sneak	O
or	O
satellite	O
spawning	O
tactics	O
.	O

To	O
better	O
understand	O
the	O
relationship	O
between	O
expression	O
of	O
an	O
oncogene	O
and	O
genetic	O
instability	O
,	O
we	O
have	O
studied	O
a	O
cell	O
line	O
expressing	O
an	O
activated	B-GENE
human	I-GENE
Ha	I-GENE
-	I-GENE
ras	I-GENE
under	O
the	O
control	O
of	O
bacterial	B-GENE
lactose	I-GENE
operon	I-GENE
regulatory	I-GENE
elements	I-GENE
for	O
changes	O
in	O
methotrexate	O
resistance	O
and	O
dihydrofolate	B-GENE
reductase	I-GENE
(	O
dhfr	B-GENE
)	O
gene	O
amplification	O
following	O
mutant	B-GENE
Ha	I-GENE
-	I-GENE
ras	I-GENE
induction	O
.	O

Cbl	B-GENE
is	O
a	O
signaling	O
molecule	O
with	O
multiple	O
functional	O
domains	O
:	O
an	O
SH2	B-GENE
domain	I-GENE
which	O
binds	O
phosphotyrosine	O
residues	O
,	O
a	O
RING	O
finger	O
domain	O
which	O
acts	O
as	O
a	O
ubiquitin	B-GENE
ligase	I-GENE
,	O
a	O
proline	O
-	O
rich	O
region	O
which	O
serves	O
as	O
a	O
docking	O
site	O
for	O
SH3	B-GENE
-	I-GENE
containing	I-GENE
proteins	I-GENE
,	O
phosphotyrosine	O
residues	O
which	O
serve	O
as	O
docking	O
sites	O
for	O
SH2	B-GENE
-	I-GENE
containing	I-GENE
proteins	I-GENE
such	O
a	O
CrkL	B-GENE
and	O
the	O
p85	B-GENE
subunit	I-GENE
of	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
,	O
and	O
a	O
nuclear	O
localization	O
signal	O
.	O

No	O
interaction	O
with	O
epidural	O
anesthesia	O
was	O
observed	O
.	O

Region	O
I	O
includes	O
the	O
two	O
cysteine	O
-	O
cysteine	O
zinc	O
fingers	O
that	O
comprise	O
a	O
DNA	O
-	O
binding	O
domain	O
which	O
typifies	O
all	O
members	O
of	O
the	O
superfamily	O
.	O

Leukocytoclasic	O
vasculitis	O
during	O
treatment	O
with	O
low	O
-	O
dose	O
captopril	O

In	O
contrast	O
to	O
Phase	O
III	O
,	O
which	O
has	O
a	O
single	O
study	O
design	O
-	O
-	O
the	O
controlled	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
study	O
-	O
-	O
Phase	O
IV	O
requires	O
different	O
designs	O
for	O
each	O
of	O
the	O
many	O
different	O
questions	O
.	O

The	O
results	O
suggest	O
that	O
both	O
superficial	O
and	O
deep	O
cortical	O
venous	O
drainage	O
of	O
the	O
cat	O
kidney	O
should	O
be	O
considered	O
when	O
measuring	O
renal	B-GENE
renin	I-GENE
release	O
.	O

The	O
aim	O
of	O
this	O
work	O
was	O
to	O
organize	O
chemical	O
data	O
in	O
a	O
client	O
-	O
server	O
environment	O
using	O
Database	O
Management	O
System	O
and	O
Web	O
fashion	O
for	O
the	O
client	O
interface	O
.	O

This	O
bound	O
[	O
3H	O
]	O
iloprost	O
with	O
high	O
affinity	O
and	O
stimulated	O
cAMP	O
production	O
when	O
exposed	O
to	O
agonist	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
exhibits	O
95	O
.	O
3	O
and	O
76	O
.	O
1	O
%	O
identity	O
with	O
the	O
CAD	B-GENE
sequences	I-GENE
of	I-GENE
hamster	I-GENE
and	I-GENE
Squalus	I-GENE
acanthias	I-GENE
.	O

Juvenile	O
idiopathic	O
inflammatory	O
myopathies	O
:	O
the	O
value	O
of	O
magnetic	O
resonance	O
imaging	O
in	O
the	O
detection	O
of	O
muscle	O
involvement	O
.	O

The	O
methods	O
used	O
were	O
the	O
AOAC	O
method	O
of	O
dilution	O
and	O
heating	O
;	O
the	O
addition	O
of	O
mercuric	O
chloride	O
,	O
charcoal	O
,	O
and	O
Carrez	O
reagents	O
at	O
2	O
different	O
pH	O
values	O
;	O
and	O
direct	O
analysis	O
of	O
sample	O
supernatants	O
with	O
no	O
treatment	O
(	O
control	O
)	O
.	O

In	O
src	B-GENE
-	O
transformed	O
cells	O
GAP	B-GENE
forms	O
heteromeric	O
complexes	O
,	O
notably	O
with	O
a	O
highly	O
tyrosine	O
phosphorylated	O
62	B-GENE
-	I-GENE
kDa	I-GENE
protein	I-GENE
(	I-GENE
p62	I-GENE
)	I-GENE
.	O

Genomic	O
Southern	O
analysis	O
reveals	O
10	O
to	O
15	O
hybridising	O
fragments	O
,	O
suggesting	O
that	O
maize	O
contains	O
a	O
small	O
gene	O
family	O
.	O

The	O
signal	O
-	O
to	O
-	O
noise	O
ratio	O
(	O
SNR	O
)	O
was	O
calculated	O
in	O
the	O
T2	O
-	O
weighted	O
sequence	O
.	O

The	O
MIC90	O
of	O
ABK	O
against	O
coagulase	B-GENE
type	I-GENE
IV	I-GENE
strains	O
was	O
rather	O
high	O
,	O
12	O
.	O
5	O
micrograms	O
/	O
ml	O
.	O

A	O
review	O
of	O
156	O
patients	O
younger	O
than	O
40	O
treated	O
at	O
our	O
Department	O
between	O
1960	O
and	O
1991	O
with	O
transitional	O
cell	O
carcinoma	O
of	O
the	O
bladder	O
revealed	O
that	O
89	O
.	O
1	O
%	O
had	O
superficial	O
(	O
Ta	O
/	O
T1	O
)	O
disease	O
and	O
the	O
remaining	O
10	O
.	O
9	O
%	O
presented	O
with	O
invasive	O
disease	O
.	O

Expression	O
of	O
the	O
Asp	O
but	O
not	O
the	O
Ala	O
gB	B-GENE
mutation	O
resulted	O
in	O
an	O
increase	O
in	O
the	O
steady	O
-	O
state	O
expression	O
of	O
gB	B-GENE
at	O
the	O
plasma	O
membrane	O
(	O
PM	O
)	O
in	O
U373	O
cells	O
.	O

Large	O
volumes	O
of	O
bone	O
marrow	O
may	O
be	O
required	O
for	O
certain	O
types	O
of	O
autologous	O
bone	O
marrow	O
transplants	O
.	O

These	O
results	O
suggest	O
that	O
dauricine	O
and	O
verapamil	O
have	O
a	O
salutary	O
effect	O
in	O
extracorporeal	O
circulation	O
.	O

Central	O
-	O
venous	O
-	O
catheter	O
-	O
related	O
infection	O
is	O
readily	O
diagnosed	O
by	O
comparing	O
simultaneous	O
quantitative	O
cultures	O
of	O
blood	O
samples	O
obtained	O
via	O
the	O
catheter	O
and	O
a	O
peripheral	O
vein	O
.	O

For	O
evaluation	O
of	O
the	O
model	O
,	O
simulations	O
of	O
physiological	O
excitation	O
and	O
of	O
pathologies	O
(	O
Wolff	O
-	O
Parkinson	O
-	O
White	O
syndrome	O
,	O
complete	O
AV	O
-	O
block	O
,	O
inferior	O
wall	O
ischaemia	O
)	O
were	O
examined	O
.	O

For	O
rotating	O
stimuli	O
presented	O
to	O
the	O
dominant	O
eye	O
,	O
this	O
class	O
of	O
neurons	O
responded	O
best	O
to	O
rotation	O
of	O
the	O
visual	O
world	O
about	O
an	O
axis	O
oriented	O
near	O
the	O
horizontal	O
plane	O
and	O
approximately	O
45	O
degrees	O
azimuth	O
.	O

Protein	B-GENE
kinase	I-GENE
C	I-GENE
transiently	O
activated	O
heteromeric	B-GENE
N	I-GENE
-	I-GENE
methyl	I-GENE
-	I-GENE
D	I-GENE
-	I-GENE
aspartate	I-GENE
receptor	I-GENE
channels	I-GENE
independent	O
of	O
the	O
phosphorylatable	O
C	O
-	O
terminal	O
splice	O
domain	O
and	O
of	O
consensus	O
phosphorylation	O
sites	O
.	O

The	O
incidence	O
of	O
the	O
variability	O
of	O
the	O
free	O
PSA	B-GENE
/	O
total	O
PSA	B-GENE
ratio	O
on	O
the	O
early	O
diagnosis	O
of	O
prostate	O
cancer	O

Moreover	O
,	O
we	O
show	O
that	O
ectopic	O
expression	O
of	O
the	O
E2A	B-GENE
protein	I-GENE
E12	B-GENE
in	O
this	O
macrophage	O
line	O
results	O
in	O
the	O
induction	O
of	O
many	O
B	O
lineage	O
genes	O
,	O
including	O
EBF	B-GENE
,	O
IL7Ralpha	B-GENE
,	O
lambda5	B-GENE
,	O
and	O
Rag	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
the	O
ability	O
to	O
induce	O
kappa	B-GENE
light	I-GENE
chain	I-GENE
in	O
response	O
to	O
mitogen	O
.	O

A	O
TAAATA	O
sequence	O
is	O
present	O
26	O
nt	O
upstream	O
from	O
the	O
major	O
CAP	O
site	O
,	O
and	O
within	O
the	O
5	O
'	O
-	O
flanking	O
region	O
there	O
are	O
several	O
putative	O
transcription	O
factor	O
binding	O
sites	O
.	O

OBJECTIVES	O
:	O
The	O
present	O
study	O
tested	O
the	O
hypothesis	O
that	O
stimulating	O
the	O
central	O
noradrenergic	O
system	O
using	O
the	O
new	O
noradrenaline	O
re	O
-	O
uptake	O
inhibitor	O
reboxetine	O
would	O
result	O
in	O
a	O
dose	O
-	O
dependent	O
enhancement	O
of	O
memory	O
for	O
emotional	O
material	O
in	O
man	O
.	O

Iris	O
binding	O
and	O
bioavailability	O
.	O

The	O
dopamine	B-GENE
D1	I-GENE
dopamine	I-GENE
receptor	I-GENE
antagonist	O
SCH	O
23390	O
dose	O
dependently	O
(	O
7	O
.	O
5	O
-	O
30	O
micrograms	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
antagonized	O
the	O
stimulant	O
locomotor	O
effect	O
on	O
both	O
drugs	O
but	O
did	O
not	O
prevent	O
their	O
antiimmobility	O
effect	O
on	O
the	O
behavioral	O
despair	O
test	O
.	O

Neither	O
symptoms	O
,	O
virions	O
,	O
nor	O
viral	O
RNA	O
was	O
detectable	O
in	O
plants	O
inoculated	O
with	O
this	O
mutant	O
or	O
a	O
mutant	O
with	O
a	O
frameshift	O
mutation	O
in	O
the	O
coat	B-GENE
gene	I-GENE
.	O

Chromaffin	O
cells	O
transfected	O
with	O
a	O
plasmid	O
with	O
the	O
entire	O
coding	O
sequence	O
of	O
c	B-GENE
-	I-GENE
Rabphilin3a	I-GENE
inserted	O
in	O
the	O
antisense	O
orientation	O
inhibited	O
secretion	O
of	O
co	O
-	O
expressed	O
GH	B-GENE
by	O
approximately	O
30	O
%	O
.	O

A	O
sequence	O
-	O
ready	O
3	O
-	O
Mb	O
PAC	O
contig	O
covering	O
16	O
breakpoints	O
of	O
the	O
Wilms	B-GENE
tumor	I-GENE
/	I-GENE
anirida	I-GENE
region	I-GENE
of	O
human	O
chromosome	O
11p13	O
.	O

Compression	O
of	O
pulmonary	O
artery	O
and	O
right	O
ventricular	O
outflow	O
tract	O
by	O
aneurysm	O
of	O
ascending	O
aorta	O
.	O

The	O
sulfur	O
species	O
could	O
be	O
separated	O
within	O
less	O
than	O
4	O
min	O
by	O
CZE	O
with	O
a	O
pyromellitic	O
acid	O
electrolyte	O
at	O
pH	O
3	O
.	O
5	O
to	O
5	O
.	O
0	O
.	O

High	O
expression	O
of	O
p51A	B-GENE
(	O
TAp63gamma	B-GENE
)	O
in	O
the	O
skeletal	O
muscle	O
tissue	O
drove	O
us	O
to	O
investigate	O
a	O
differentiation	O
-	O
inducible	O
myoblastic	O
cell	O
line	O
which	O
showed	O
increased	O
p51A	B-GENE
expression	O
after	O
differentiation	O
induction	O
.	O

Nosographic	O
problems	O

Since	O
UmuD	B-GENE
protein	I-GENE
is	O
proteolytically	O
processed	O
to	O
an	O
active	O
form	O
(	O
UmuD	B-GENE
*	I-GENE
)	O
in	O
a	O
RecA	B-GENE
*	O
-	O
dependent	O
fashion	O
,	O
and	O
MucA	B-GENE
shares	O
extensive	O
amino	O
acid	O
homology	O
with	O
UmuD	B-GENE
,	O
we	O
examined	O
whether	O
MucA	B-GENE
is	O
similarly	O
processed	O
in	O
the	O
cell	O
,	O
using	O
antiserum	O
against	O
a	O
LacZ	B-GENE
'	I-GENE
-	O
'	B-GENE
MucA	I-GENE
fusion	O
protein	O
.	O

Changes	O
in	O
BHR	O
were	O
found	O
to	O
correlate	O
significantly	O
with	O
changes	O
in	O
the	O
levels	O
of	O
24	O
h	O
mean	O
SO2	O
,	O
NO2	O
and	O
smoke	O
;	O
48	O
h	O
mean	O
NO2	O
and	O
smoke	O
;	O
24	O
h	O
lag	O
NO2	O
;	O
although	O
the	O
effect	O
was	O
only	O
small	O
,	O
accounting	O
for	O
approximately	O
10	O
%	O
of	O
the	O
variability	O
in	O
within	O
-	O
subject	O
BHR	O
between	O
visits	O
.	O

50	O
-	O
nucleotide	O
)	O
intron	O
to	O
AA	O
.	O

Foamy	O
viruses	O
(	O
FVs	O
)	O
express	O
the	O
Gag	B-GENE
protein	I-GENE
as	O
a	O
precursor	O
with	O
a	O
molecular	O
mass	O
of	O
74	O
kDa	O
(	O
pr74	B-GENE
)	O
from	O
which	O
a	O
70	O
-	O
kDa	O
protein	O
(	O
p70	B-GENE
)	O
is	O
cleaved	O
by	O
the	O
viral	O
protease	O
.	O

Identification	O
of	O
domains	O
mediating	O
transcription	O
activation	O
,	O
repression	O
,	O
and	O
inhibition	O
in	O
the	O
paired	B-GENE
-	I-GENE
related	I-GENE
homeobox	I-GENE
protein	I-GENE
,	O
Prx2	B-GENE
(	O
S8	B-GENE
)	O
.	O

Because	O
of	O
the	O
structural	O
similarities	O
the	O
new	O
gene	O
will	O
be	O
termed	O
scERV2	B-GENE
from	O
now	O
on	O
.	O

Where	O
the	O
resonator	O
has	O
two	O
holes	O
,	O
these	O
terms	O
should	O
be	O
somewhat	O
modified	O
:	O
A	O
is	O
the	O
combined	O
area	O
of	O
the	O
two	O
holes	O
,	O
L	O
is	O
16	O
/	O
3pi	O
r	O
(	O
~	O
1	O
.	O
7r	O
)	O
for	O
a	O
simple	O
hole	O
in	O
a	O
thin	O
-	O
walled	O
vessel	O
and	O
r	O
is	O
the	O
radius	O
of	O
one	O
hole	O
(	O
Seto	O
,	O
1971	O
)	O
.	O

The	O
most	O
distal	O
active	O
site	O
in	O
TIGA	B-GENE
is	O
created	O
by	O
excision	O
of	O
a	O
66	O
-	O
bp	O
intron	O
.	O

GeneCalling	O
analysis	O
was	O
successful	O
in	O
detecting	O
members	O
of	O
complex	O
metabolic	O
pathways	O
and	O
uncovering	O
novel	O
genes	O
that	O
were	O
either	O
coincidentally	O
regulated	O
or	O
directly	O
involved	O
in	O
such	O
pathways	O
.	O

Cerebellar	O
functional	O
compensation	O
after	O
its	O
complete	O
destruction	O
by	O
a	O
neoplasm	O

Analysis	O
of	O
the	O
DNA	O
sequence	O
upstream	O
of	O
the	O
narQ	B-GENE
gene	I-GENE
,	O
which	O
encodes	O
the	O
second	O
nitrate	O
-	O
responsive	O
sensor	O
-	O
transmitter	O
protein	O
in	O
Escherichia	O
coli	O
,	O
revealed	O
an	O
open	O
reading	O
frame	O
(	O
ORF	O
)	O
whose	O
product	O
shows	O
a	O
high	O
degree	O
of	O
similarity	O
to	O
a	O
number	O
of	O
iron	B-GENE
-	I-GENE
sulfur	I-GENE
proteins	I-GENE
as	O
well	O
as	O
to	O
the	O
beta	O
subunit	O
of	O
glutamate	B-GENE
synthase	I-GENE
(	O
gltD	B-GENE
)	O
of	O
E	O
.	O
coli	O
.	O

Thus	O
,	O
the	O
antibody	O
class	O
switch	O
appears	O
to	O
be	O
directed	O
by	O
induction	O
of	O
accessibility	O
,	O
as	O
assayed	O
by	O
transcription	O
of	O
germ	O
line	O
CH	B-GENE
genes	O
.	O

With	O
repetitive	O
intermittent	O
exercise	O
,	O
gradual	O
increases	O
in	O
blood	O
lactate	O
concentration	O
[	O
(	O
LA	O
]	O
b	O
)	O
occurred	O
,	O
whereas	O
its	O
rate	O
of	O
accumulation	O
(	O
delta	O
[	O
LA	O
]	O
b	O
)	O
decreased	O
.	O

Wingless	B-GENE
/	O
Wnt	B-GENE
signaling	O
directs	O
cell	O
-	O
fate	O
choices	O
during	O
embryonic	O
development	O
.	O

In	O
CYP7A1	B-GENE
transgenic	O
mice	O
,	O
livers	O
contained	O
approximately	O
3	O
-	O
fold	O
more	O
sterol	B-GENE
response	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
-	I-GENE
2	I-GENE
mRNA	I-GENE
.	O

Patients	O
with	O
the	O
chronic	O
photosensitivity	O
dermatitis	O
with	O
actinic	O
reticuloid	O
syndrome	O
have	O
high	O
total	O
serum	O
IgE	B-GENE
concentrations	O
.	O

Furthermore	O
,	O
the	O
cognate	O
binding	O
protein	O
is	O
present	O
in	O
both	O
rat	O
and	O
human	O
(	O
HeLa	O
)	O
cell	O
nuclear	O
extracts	O
.	O

The	O
effect	O
of	O
stimulation	O
of	O
the	O
entopeduncular	O
nucleus	O
(	O
EP	O
)	O
on	O
the	O
jaw	O
-	O
opening	O
reflex	O
(	O
JOR	O
)	O
was	O
studied	O
in	O
the	O
cat	O
anesthetized	O
with	O
sodium	O
pentobarbital	O
.	O

We	O
cloned	O
the	O
BamHI	B-GENE
-	I-GENE
F	I-GENE
fragment	I-GENE
from	O
the	O
left	O
end	O
of	O
Ad4	O
in	O
pUC13	O
-	O
1	O
between	O
the	O
SalI	B-GENE
and	O
BamHI	B-GENE
sites	I-GENE
in	O
order	O
to	O
carry	O
out	O
the	O
structural	O
analysis	O
of	O
the	O
E1A	B-GENE
region	I-GENE
of	I-GENE
Ad4	I-GENE
.	O

Results	O
of	O
this	O
study	O
indicate	O
that	O
when	O
amniotic	O
fluid	O
samples	O
are	O
stored	O
frozen	O
and	O
strict	O
quality	O
control	O
is	O
maintained	O
in	O
analytic	O
procedures	O
,	O
only	O
minimal	O
changes	O
occur	O
in	O
phospholipid	O
concentrations	O
over	O
12	O
months	O
.	O

The	O
objective	O
of	O
this	O
research	O
was	O
to	O
determine	O
if	O
ergotamine	O
,	O
an	O
ergopeptine	O
alkaloid	O
isolated	O
from	O
Neotyphodium	O
-	O
infected	O
grasses	O
and	O
associated	O
with	O
toxicoses	O
in	O
livestock	O
,	O
altered	O
plasma	O
concentrations	O
of	O
reproductive	O
hormones	O
in	O
follicular	O
phase	O
heifers	O
and	O
in	O
cows	O
given	O
a	O
progestin	O
implant	O
.	O

The	O
following	O
parameters	O
were	O
measured	O
:	O
onset	O
time	O
(	O
time	O
interval	O
from	O
injection	O
to	O
maximal	O
or	O
total	O
block	O
)	O
,	O
T125	O
/	O
75	O
(	O
time	O
for	O
T1	O
to	O
reach	O
25	O
%	O
or	O
75	O
%	O
of	O
control	O
)	O
,	O
TOF70	O
(	O
time	O
for	O
TOF	O
ratio	O
to	O
reach	O
70	O
%	O
of	O
control	O
)	O
,	O
heart	O
rate	O
and	O
blood	O
pressure	O
.	O

Ectopic	O
Xbra	B-GENE
can	O
induce	O
Xegr	B-GENE
-	I-GENE
1	I-GENE
transcription	O
by	O
an	O
indirect	O
mechanism	O
that	O
appears	O
to	O
operate	O
via	O
primary	O
activation	O
of	O
fibroblast	B-GENE
growth	I-GENE
factor	I-GENE
secretion	O
.	O

A	O
total	O
of	O
10	O
,	O
763	O
men	O
and	O
3	O
,	O
118	O
women	O
has	O
been	O
studied	O
,	O
of	O
whom	O
97	O
%	O
and	O
89	O
%	O
,	O
respectively	O
,	O
have	O
been	O
traced	O
and	O
36	O
%	O
and	O
16	O
%	O
have	O
died	O
.	O

The	O
association	O
of	O
I	B-GENE
-	I-GENE
92	I-GENE
with	O
p92	B-GENE
,	O
p84	B-GENE
,	O
p75	B-GENE
,	O
p73	B-GENE
,	O
p69	B-GENE
,	O
and	O
p57	B-GENE
was	O
completely	O
reversible	O
after	O
treatment	O
with	O
the	O
detergent	O
deoxycholate	O
(	O
DOC	O
)	O
.	O

Although	O
the	O
elevated	O
signalling	O
is	O
eliminated	O
by	O
deletion	O
of	O
Ste20p	B-GENE
(	O
or	O
components	O
downstream	O
of	O
Ste20p	B-GENE
)	O
,	O
the	O
growth	O
and	O
morphological	O
abnormalities	O
of	O
cells	O
lacking	O
Akr1p	B-GENE
are	O
not	O
rescued	O
by	O
deletion	O
of	O
any	O
of	O
the	O
known	O
pheromone	O
response	O
pathway	O
components	O
.	O

2	O
)	O
Depending	O
on	O
the	O
structure	O
,	O
certain	O
compounds	O
are	O
sequestered	O
in	O
the	O
cornea	O
(	O
presumably	O
the	O
stroma	O
)	O
and	O
form	O
a	O
release	O
system	O
into	O
the	O
anterior	O
aqueous	O
.	O

To	O
gain	O
further	O
insights	O
into	O
these	O
events	O
,	O
the	O
porcine	B-GENE
G	I-GENE
alpha	I-GENE
i	I-GENE
-	I-GENE
3	I-GENE
gene	I-GENE
minimal	I-GENE
promoter	I-GENE
was	O
characterized	O
and	O
found	O
67	O
base	O
pairs	O
upstream	O
from	O
the	O
major	O
transcription	O
start	O
site	O
.	O

Two	O
authors	O
,	O
two	O
journal	O
titles	O
,	O
two	O
drug	O
names	O
,	O
and	O
two	O
topics	O
of	O
a	O
general	O
medical	O
nature	O
were	O
retrieved	O
under	O
identical	O
circumstances	O
and	O
conditions	O
on	O
the	O
hosts	O
DATA	O
-	O
STAR	O
,	O
DIALOG	O
,	O
DIMDI	O
,	O
and	O
STN	O
.	O

For	O
example	O
,	O
the	O
presence	O
of	O
two	O
related	O
genes	O
,	O
b	B-GENE
and	O
b	B-GENE
'	I-GENE
,	O
in	O
the	O
cyanobacterium	O
suggests	O
that	O
its	O
ATP	B-GENE
synthase	I-GENE
is	O
a	O
complex	O
of	O
nine	O
polypeptides	O
,	O
and	O
that	O
it	O
may	O
have	O
single	O
copies	O
of	O
related	O
b	B-GENE
and	O
b	B-GENE
'	I-GENE
proteins	I-GENE
rather	O
than	O
two	O
copies	O
of	O
identical	O
b	B-GENE
subunits	I-GENE
as	O
found	O
in	O
the	O
E	O
.	O
coli	O
enzyme	O
.	O
4	O
+	O
off	O

DDD	O
(	O
R	O
)	O
pacing	O
with	O
automatic	O
mode	O
switch	O
in	O
patients	O
with	O
paroxysmal	O
atrial	O
fibrillation	O
following	O
AV	O
nodal	O
ablation	O
.	O

These	O
events	O
were	O
only	O
weakly	O
stimulated	O
by	O
the	O
activated	B-GENE
PDGF	I-GENE
alpha	I-GENE
-	I-GENE
receptor	I-GENE
.	O

These	O
results	O
establish	O
that	O
the	O
DNA	O
fragment	O
we	O
have	O
isolated	O
contains	O
the	O
human	B-GENE
gp130	I-GENE
promoter	I-GENE
and	O
that	O
interleukin	B-GENE
-	I-GENE
6	I-GENE
type	I-GENE
cytokines	I-GENE
may	O
influence	O
the	O
activity	O
of	O
this	O
promoter	O
via	O
activated	O
STATs	B-GENE
.	O

Only	O
53	O
%	O
of	O
all	O
injuries	O
and	O
12	O
.	O
5	O
%	O
of	O
serious	O
injuries	O
involved	O
children	O
,	O
and	O
in	O
contrast	O
to	O
the	O
1950s	O
and	O
early	O
1960s	O
,	O
young	O
adults	O
appear	O
at	O
greatest	O
risk	O
in	O
the	O
1980s	O
.	O

Three	O
simple	O
methods	O
of	O
detecting	O
malnutrition	O
on	O
medical	O
wards	O
.	O

We	O
also	O
show	O
that	O
an	O
internal	O
fragment	O
of	O
U24	B-GENE
methylation	I-GENE
guide	I-GENE
snoRNA	I-GENE
,	O
encompassing	O
the	O
upstream	O
antisense	O
element	O
and	O
the	O
D	O
'	O
and	O
C	O
'	O
box	O
motifs	O
,	O
can	O
support	O
the	O
site	O
-	O
specific	O
methylation	O
of	O
rRNA	O
.	O

The	O
gap	B-GENE
protein	O
knirps	B-GENE
mediates	O
both	O
quenching	O
and	O
direct	O
repression	O
in	O
the	O
Drosophila	O
embryo	O
.	O

One	O
of	O
them	O
is	O
its	O
limited	O
sensitivity	O
to	O
weak	O
interactions	O
,	O
which	O
are	O
common	O
in	O
the	O
mammalian	O
cerebral	O
cortex	O
.	O

An	O
infant	O
of	O
8	O
months	O
with	O
congenital	O
glaucoma	O
and	O
hemophilia	O
A	O
lost	O
one	O
eye	O
due	O
to	O
haemorrhages	O
after	O
trabeculotomy	O
in	O
an	O
eye	O
hospital	O
.	O

Encapsulation	O
of	O
sodium	O
fluorescein	O
for	O
dye	O
release	O
studies	O
.	O

Ethanol	O
preference	O
in	O
strains	O
of	O
rats	O
selectively	O
bred	O
for	O
behavioral	O
characteristics	O
.	O

VAV	B-GENE
and	O
SOCS1	B-GENE
form	O
a	O
protein	O
complex	O
through	O
interactions	O
between	O
the	O
VAV	B-GENE
NH	I-GENE
(	I-GENE
2	I-GENE
)	I-GENE
-	I-GENE
terminal	I-GENE
regulatory	I-GENE
region	I-GENE
and	O
the	O
SH2	B-GENE
domain	I-GENE
of	O
SOCS1	B-GENE
in	O
a	O
phosphotyrosine	O
-	O
independent	O
manner	O
.	O

Incubation	O
of	O
HeLa	O
cell	O
cytoplasmic	O
extracts	O
with	O
a	O
purified	O
recombinant	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
-	O
raf	B-GENE
fusion	O
protein	O
in	O
the	O
presence	O
of	O
ATP	O
released	O
active	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
that	O
could	O
be	O
detected	O
by	O
electrophoretic	O
gel	O
mobility	O
shift	O
assay	O
.	O

Cefminox	O
shows	O
greater	O
in	O
vivo	O
activity	O
than	O
that	O
expected	O
for	O
the	O
MICs	O
,	O
excellent	O
efficacy	O
and	O
safety	O
.	O

Both	O
the	O
p38	B-GENE
kinase	I-GENE
inhibitor	O
SB205380	O
(	O
SB	O
)	O
and	O
cotransfection	O
of	O
a	O
dominant	O
-	O
negative	O
mutant	O
of	O
p38	B-GENE
kinase	I-GENE
reduced	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
stimulation	O
of	O
the	O
hBNP	B-GENE
promoter	I-GENE
.	O

Recent	O
geological	O
studies	O
focusing	O
on	O
the	O
Davie	O
Fracture	O
Zone	O
of	O
the	O
Mozambique	O
Channel	O
offer	O
a	O
resolution	O
to	O
this	O
situation	O
,	O
by	O
suggesting	O
the	O
presence	O
of	O
a	O
land	O
-	O
bridge	O
from	O
the	O
mid	O
-	O
Eocene	O
to	O
the	O
early	O
Miocene	O
,	O
an	O
interval	O
that	O
matches	O
the	O
ages	O
of	O
Madagascar	O
'	O
s	O
mammalian	O
groups	O
.	O

We	O
have	O
previously	O
demonstrated	O
that	O
pyrene	O
in	O
diesel	O
-	O
exhaust	O
particles	O
(	O
DEP	O
)	O
has	O
an	O
adjuvant	O
activity	O
on	O
immunoglobulin	B-GENE
E	I-GENE
(	O
IgE	B-GENE
)	O
antibody	O
production	O
in	O
mice	O
immunized	O
with	O
Japanese	O
cedar	O
pollen	O
allergen	O
(	O
JCPA	O
)	O
or	O
ovalbumin	B-GENE
(	O
OA	B-GENE
)	O
intraperitoneally	O
.	O

On	O
the	O
basis	O
of	O
8	O
cases	O
,	O
the	O
authors	O
report	O
different	O
clinical	O
pictures	O
all	O
caused	O
by	O
cardiac	O
toxicity	O
of	O
5FU	O
.	O

The	O
immunoprofile	O
of	O
60	O
adult	O
patients	O
of	O
pulmonary	O
tuberculosis	O
was	O
studied	O
and	O
compared	O
with	O
22	O
normal	O
controls	O
.	O

Effects	O
of	O
long	O
-	O
term	O
use	O
of	O
raloxifene	O
,	O
a	O
selective	O
estrogen	B-GENE
receptor	I-GENE
modulator	O
,	O
on	O
thyroid	O
function	O
test	O
profiles	O
.	O

Module	O
2	O
of	O
RifA	B-GENE
lacks	O
a	O
beta	B-GENE
-	I-GENE
ketoacyl	I-GENE
:	I-GENE
acyl	I-GENE
carrier	I-GENE
protein	I-GENE
reductase	I-GENE
(	O
KR	B-GENE
)	O
domain	O
and	O
the	O
one	O
in	O
module	O
3	O
has	O
an	O
apparently	O
inactive	O
NADPH	B-GENE
binding	I-GENE
motif	I-GENE
,	O
similar	O
to	O
one	O
found	O
in	O
the	O
Er	B-GENE
PKS	I-GENE
,	O
while	O
the	O
other	O
eight	O
KR	B-GENE
domains	I-GENE
of	O
the	O
Rf	B-GENE
PKS	I-GENE
should	O
be	O
functional	O
.	O

Synergy	O
between	O
interferon	B-GENE
-	I-GENE
gamma	I-GENE
and	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
in	O
transcriptional	O
activation	O
is	O
mediated	O
by	O
cooperation	O
between	O
signal	B-GENE
transducer	I-GENE
and	I-GENE
activator	I-GENE
of	I-GENE
transcription	I-GENE
1	I-GENE
and	O
nuclear	B-GENE
factor	I-GENE
kappaB	I-GENE
.	O

The	O
corresponding	O
tetrapeptide	O
sequences	O
SSPD	O
and	O
SATD	O
for	O
human	B-GENE
and	I-GENE
mouse	I-GENE
PKC	I-GENE
-	I-GENE
epsilon	I-GENE
,	O
respectively	O
,	O
are	O
unusual	O
for	O
caspase	B-GENE
-	I-GENE
3	I-GENE
.	O

The	O
effect	O
of	O
pneumoperitoneum	O
on	O
dissemination	O
and	O
scar	O
implantation	O
of	O
intra	O
-	O
abdominal	O
tumor	O
cells	O
.	O

CONCLUSIONS	O
:	O
In	O
the	O
results	O
of	O
this	O
study	O
,	O
SDB	O
,	O
even	O
snoring	O
,	O
was	O
independently	O
associated	O
with	O
hypertension	O
in	O
both	O
men	O
and	O
women	O
.	O

A	O
poly	O
(	O
ortho	O
ester	O
)	O
designed	O
for	O
combined	O
ocular	O
delivery	O
of	O
dexamethasone	O
sodium	O
phosphate	O
and	O
5	O
-	O
fluorouracil	O
:	O
subconjunctival	O
tolerance	O
and	O
in	O
vitro	O
release	O
.	O

Subclones	O
stably	O
expressing	O
alpha1A	B-GENE
-	O
,	O
alpha1B	B-GENE
-	O
,	O
and	O
alpha1D	B-GENE
-	O
ARs	O
under	O
control	O
of	O
an	O
inducible	O
promoter	O
,	O
or	O
at	O
high	O
and	O
low	O
receptor	O
density	O
,	O
were	O
isolated	O
and	O
characterized	O
.	O

Transfection	O
of	O
both	O
Calu	O
-	O
6	O
and	O
JEG	O
-	O
3	O
cells	O
with	O
a	O
PKA	B-GENE
expression	O
vector	O
resulted	O
in	O
a	O
10	O
-	O
fold	O
induction	O
of	O
human	B-GENE
renin	I-GENE
transcriptional	O
activity	O
in	O
constructs	O
containing	O
the	O
native	O
or	O
consensus	O
CRE	O
and	O
5	O
-	O
fold	O
activation	O
in	O
a	O
construct	O
containing	O
a	O
nonfunctional	O
CRE	O
.	O

In	O
renal	O
vein	O
thrombosis	O
,	O
similar	O
pattern	O
to	O
acute	O
tubular	O
necrosis	O
was	O
found	O
but	O
RI	O
venography	O
was	O
helpful	O
.	O

Restricted	O
expression	O
of	O
a	O
novel	O
murine	B-GENE
atonal	I-GENE
-	I-GENE
related	I-GENE
bHLH	I-GENE
protein	I-GENE
in	O
undifferentiated	O
neural	O
precursors	O
.	O

Oligo	O
-	O
[	O
alpha	O
]	O
-	O
deoxynucleotides	O
can	O
be	O
derived	O
by	O
stabilizing	O
(	O
intercalating	O
)	O
agents	O
or	O
reactive	O
groups	O
(	O
cleaving	O
reagents	O
,	O
cross	O
-	O
linkers	O
.	O
.	O
.	O
)	O
.	O

Electronic	O
structure	O
of	O
Si	O
(	O
111	O
)	O
-	O
NiSi2	O
(	O
111	O
)	O
A	O
-	O
type	O
and	O
B	O
-	O
type	O
interfaces	O
.	O

In	O
addition	O
,	O
two	O
cis	O
-	O
acting	O
elements	O
direct	O
the	O
first	O
zygotic	O
expression	O
of	O
Kr	B-GENE
in	O
a	O
striped	O
subpattern	O
within	O
the	O
central	O
region	O
of	O
the	O
blastoderm	O
embryo	O
.	O

Embryonal	O
mortality	O

Regardless	O
of	O
muscle	O
tensioning	O
or	O
marination	O
treatments	O
,	O
aging	O
of	O
the	O
carcass	O
for	O
24	O
h	O
(	O
T1	O
,	O
T2	O
,	O
and	O
T3	O
)	O
produced	O
meats	O
with	O
lower	O
shear	O
values	O
than	O
those	O
from	O
hot	O
-	O
boned	O
carcasses	O
(	O
T4	O
and	O
T5	O
)	O
.	O

This	O
effect	O
was	O
stronger	O
after	O
multiple	O
predoses	O
of	O
sertraline	O
,	O
when	O
imipramine	O
Cmax	O
and	O
AUC	O
(	O
0	O
-	O
infinity	O
)	O
were	O
increased	O
by	O
39	O
%	O
and	O
68	O
%	O
,	O
respectively	O
.	O

For	O
capsules	O
containing	O
only	O
the	O
drug	O
,	O
the	O
value	O
of	O
T50	O
increased	O
as	O
the	O
particle	O
size	O
of	O
the	O
drug	O
decreased	O
.	O

Its	O
prognostic	O
impact	O
is	O
superior	O
to	O
the	O
T1	O
/	O
2	O
one	O
(	O
RR	O
=	O
2	O
.	O
9	O
;	O
p	O
=	O
0	O
.	O
0010	O
)	O
.	O

We	O
also	O
show	O
that	O
in	O
fusions	O
with	O
the	O
DNA	O
binding	O
domain	O
of	O
GAL4	B-GENE
,	O
full	O
activity	O
requires	O
the	O
entire	O
BHV	B-GENE
-	I-GENE
alpha	I-GENE
TIF	I-GENE
,	O
although	O
both	O
amino	O
and	O
carboxyl	O
termini	O
display	O
some	O
activity	O
on	O
their	O
own	O
.	O

As	O
well	O
,	O
variation	O
in	O
capillary	O
size	O
and	O
density	O
was	O
apparent	O
between	O
ventricles	O
in	O
the	O
fetal	O
and	O
neonatal	O
periods	O
.	O

Previous	O
studies	O
have	O
demonstrated	O
that	O
the	O
21	O
-	O
or	O
the	O
72	O
-	O
bp	O
repeat	O
transcriptional	O
control	O
elements	O
enhance	O
the	O
efficiency	O
of	O
SV40	O
DNA	O
replication	O
in	O
vivo	O
,	O
provided	O
either	O
of	O
these	O
repeats	O
is	O
located	O
near	O
the	O
end	O
of	O
the	O
core	O
replication	O
origin	O
containing	O
the	O
17	O
-	O
bp	O
A	O
+	O
T	O
-	O
containing	O
sequence	O
.	O

It	O
is	O
pathogenetically	O
proved	O
to	O
use	O
antithrombin	B-GENE
III	I-GENE
concentrate	O
preparations	O
with	O
anti	O
-	O
and	O
dysaggregatory	O
properties	O
,	O
fibronectin	B-GENE
preparations	O
,	O
trasylol	O
or	O
its	O
analogs	O
during	O
complex	O
preoperative	O
preparation	O
of	O
patients	O
.	O

ER	O
and	O
DR	O
were	O
significantly	O
correlated	O
with	O
MIB	B-GENE
-	I-GENE
1	I-GENE
LI	O
(	O
P	O
<	O
0	O
.	O
01	O
and	O
P	O
<	O
0	O
.	O
05	O
,	O
respectively	O
)	O
,	O
but	O
RI	O
and	O
Td	O
/	O
Te	O
were	O
not	O
.	O

D	O
.	O
,	O
and	O
Long	O
,	O
C	O
.	O

A	O
lead	O
phthalocyanin	O
method	O
for	O
the	O
demonstration	O
of	O
acid	B-GENE
hydrolases	I-GENE
in	O
plant	O
and	O
animal	O
tissues	O
.	O

On	O
the	O
sixth	O
postirradiation	O
day	O
the	O
absorption	O
of	O
phenobarbitone	O
,	O
sulphafurazole	O
and	O
mecamylamine	O
had	O
returned	O
to	O
the	O
control	O
level	O
,	O
but	O
the	O
absorption	O
of	O
quinidine	O
and	O
isoniazid	O
was	O
still	O
retarded	O
.	O

Here	O
,	O
we	O
describe	O
the	O
three	O
-	O
dimensional	O
structure	O
of	O
the	O
enzyme	O
from	O
Escherichia	O
colidetermined	O
and	O
refined	O
to	O
2	O
.	O
0	O
A	O
resolution	O
.	O

cDNA	O
cloning	O
,	O
sequencing	O
and	O
chromosome	O
mapping	O
of	O
a	O
non	B-GENE
-	I-GENE
erythroid	I-GENE
spectrin	I-GENE
,	O
human	B-GENE
alpha	I-GENE
-	I-GENE
fodrin	I-GENE
.	O

In	O
serial	O
recall	O
from	O
short	O
-	O
term	O
memory	O
,	O
repeated	O
items	O
are	O
recalled	O
well	O
when	O
close	O
together	O
(	O
repetition	O
facilitation	O
)	O
,	O
but	O
not	O
when	O
far	O
apart	O
(	O
repetition	O
inhibition	O
;	O
the	O
Ranschburg	O
effect	O
)	O
.	O

Posterior	O
osteophytes	O
around	O
the	O
posterior	O
edges	O
of	O
vertebral	O
body	O
resulted	O
in	O
intervertebral	O
insufficiency	O
,	O
and	O
corresponded	O
to	O
hypertrophic	O
spur	O
in	O
osteochondrosis	O
.	O

LV	O
compliance	O
was	O
determined	O
from	O
the	O
slope	O
of	O
the	O
LV	O
end	O
-	O
diastolic	O
pressure	O
(	O
LVEDP	O
)	O
vs	O
.	O

Biol	O
.	O

There	O
was	O
no	O
significant	O
correlation	O
between	O
serum	O
amiodarone	O
or	O
desethylamiodarone	O
levels	O
and	O
dosage	O
of	O
amiodarone	O
.	O

Nuclear	O
extracts	O
from	O
Sertoli	O
cells	O
were	O
found	O
to	O
cause	O
an	O
E	O
-	O
box	O
gel	O
shift	O
when	O
the	O
cells	O
were	O
stimulated	O
to	O
differentiate	O
in	O
culture	O
,	O
but	O
not	O
under	O
basal	O
conditions	O
.	O

The	O
combination	O
of	O
ICP47	B-GENE
and	O
US11	B-GENE
rendered	O
fibroblasts	O
negative	O
for	O
surface	B-GENE
class	I-GENE
I	I-GENE
MHC	I-GENE
and	O
allowed	O
a	O
class	B-GENE
I	I-GENE
MHC	I-GENE
-	O
low	O
population	O
of	O
T	O
cells	O
to	O
be	O
sorted	O
by	O
flow	O
cytometry	O
.	O

The	O
recovery	O
of	O
adults	O
schistosomes	O
by	O
extracorporeal	O
filtration	O
.	O

Biochemical	O
studies	O
and	O
studies	O
of	O
cells	O
expressing	O
mutant	O
IL	B-GENE
-	I-GENE
2	I-GENE
receptors	I-GENE
indicate	O
that	O
IL	B-GENE
-	I-GENE
2	I-GENE
-	O
induced	O
tyrosine	B-GENE
kinase	I-GENE
activation	O
initiates	O
a	O
complex	O
signaling	O
cascade	O
.	O

Serum	O
levels	O
of	O
angiotensin	B-GENE
converting	I-GENE
enzyme	I-GENE
were	O
well	O
maintained	O
.	O

We	O
tested	O
the	O
effects	O
of	O
antifungal	O
drugs	O
on	O
adherence	O
of	O
Candida	O
albicans	O
in	O
vitro	O
.	O

The	O
sections	O
were	O
stained	O
with	O
anti	O
-	O
polymorphonuclear	O
leukocyte	O
antibody	O
,	O
the	O
endothelial	O
marker	O
factor	B-GENE
VIII	I-GENE
-	I-GENE
related	I-GENE
antigen	I-GENE
,	O
and	O
with	O
hematoxylin	O
and	O
eosin	O
.	O

Portions	O
of	O
the	O
3	O
'	O
-	O
coding	O
and	O
3	O
'	O
-	O
untranslated	O
regions	O
were	O
found	O
to	O
be	O
missing	O
from	O
the	O
7	B-GENE
.	I-GENE
2	I-GENE
-	I-GENE
and	I-GENE
4	I-GENE
.	I-GENE
8	I-GENE
-	I-GENE
kb	I-GENE
topo	I-GENE
II	I-GENE
alpha	I-GENE
mRNAs	I-GENE
by	O
Northern	O
blot	O
analysis	O
.	O

The	O
combined	O
in	O
vitro	O
effects	O
of	O
ethanol	O
wih	O
methaqualone	O
,	O
phenobarbital	O
,	O
pyrazole	O
or	O
disulfiram	O
were	O
studied	O
using	O
rat	B-GENE
brain	I-GENE
microsomal	I-GENE
NA	I-GENE
-	I-GENE
K	I-GENE
-	I-GENE
ATPase	I-GENE
.	O

An	O
analogue	O
of	O
calcium	O
,	O
strontium	O
chloride	O
Sr	O
89	O
is	O
rapidly	O
cleared	O
from	O
the	O
blood	O
after	O
i	O
.	O
v	O
.	O
injection	O
.	O

These	O
mutants	O
,	O
assayed	O
by	O
injection	O
into	O
Xenopus	O
oocyte	O
nuclei	O
,	O
delimit	O
the	O
promoter	O
to	O
36	O
bp	O
of	O
DNA	O
upstream	O
of	O
the	O
cap	O
site	O
and	O
73	O
bp	O
of	O
the	O
untranslated	O
mRNA	O
leader	O
.	O

The	O
ARE	O
is	O
loosely	O
defined	O
as	O
the	O
five	O
-	O
nucleotide	O
sequence	O
AUUUA	O
embedded	O
in	O
a	O
uracil	O
-	O
rich	O
region	O
.	O

The	O
essential	O
oil	O
composition	O
of	O
three	O
Zingiberaceae	O
widely	O
used	O
as	O
medicinal	O
aromatic	O
plants	O
from	O
S	O
.	O

(	O
3	O
)	O
With	O
the	O
exception	O
of	O
the	O
anteroposterior	O
direction	O
of	O
layers	O
II	O
-	O
-	O
III	O
and	O
the	O
mediolateral	O
direction	O
of	O
layer	O
IV	O
,	O
the	O
vertical	O
conductivity	O
of	O
the	O
cortex	O
was	O
always	O
greater	O
than	O
either	O
of	O
the	O
horizontal	O
conductivities	O
.	O

Acad	O
.	O

To	O
obtain	O
information	O
on	O
the	O
functional	O
role	O
of	O
the	O
Rac1	B-GENE
/	O
p38	B-GENE
/	O
MAPKAPK	B-GENE
-	I-GENE
2	I-GENE
pathway	O
in	O
RA	O
signaling	O
,	O
the	O
effects	O
of	O
pharmacological	O
inhibition	O
of	O
p38	B-GENE
on	O
RA	O
-	O
induced	O
gene	O
transcription	O
and	O
cell	O
differentiation	O
were	O
determined	O
.	O

A	O
regulatory	O
element	O
of	O
the	O
empty	B-GENE
spiracles	I-GENE
homeobox	O
gene	O
is	O
composed	O
of	O
three	O
distinct	O
conserved	O
regions	O
that	O
bind	O
regulatory	O
proteins	O
.	O

CONCLUSIONS	O
:	O
The	O
MC	O
/	O
UA	O
ratio	O
improves	O
the	O
sensitivity	O
for	O
the	O
prediction	O
of	O
poor	O
perinatal	O
outcome	O
when	O
it	O
is	O
combined	O
with	O
the	O
NST	O
.	O

Together	O
with	O
previous	O
work	O
our	O
results	O
suggest	O
that	O
C	B-GENE
/	I-GENE
EBP	I-GENE
may	O
be	O
a	O
general	O
cooperation	O
partner	O
for	O
v	B-GENE
-	I-GENE
Myb	I-GENE
in	O
myelomonocytic	O
cells	O
.	O

Evolution	O
of	O
cytomegalovirus	O
antibodies	O
of	O
maternal	O
origin	O
and	O
acquired	O
,	O
throughout	O
the	O
first	O
year	O
of	O
life	O

IENF	O
density	O
at	O
the	O
calf	O
was	O
lower	O
than	O
that	O
obtained	O
from	O
skin	O
at	O
more	O
proximal	O
sites	O
,	O
indicating	O
the	O
length	O
dependency	O
of	O
small	O
-	O
fiber	O
loss	O
in	O
these	O
neuropathies	O
.	O

The	O
sequence	O
contained	O
five	O
repeats	O
of	O
the	O
hypothetical	O
leucine	O
zipper	O
motif	O
:	O
one	O
is	O
in	O
the	O
N	O
-	O
terminal	O
globular	O
domain	O
,	O
and	O
four	O
are	O
in	O
the	O
central	O
alpha	O
-	O
helical	O
stalk	O
.	O

This	O
paper	O
reports	O
estimates	O
of	O
the	O
prevalence	O
of	O
mental	O
retardation	O
and	O
associated	O
factors	O
based	O
on	O
a	O
population	O
survey	O
of	O
2	O
-	O
to	O
9	O
-	O
year	O
-	O
old	O
children	O
in	O
Greater	O
Karachi	O
,	O
Pakistan	O
.	O

Zta	B-GENE
stimulated	O
the	O
HAT	B-GENE
activity	O
of	O
CBP	B-GENE
that	O
had	O
been	O
partially	O
purified	O
or	O
immunoprecipitated	O
from	O
mammalian	O
cells	O
as	O
well	O
as	O
from	O
affinity	O
-	O
purified	O
,	O
baculovirus	O
expressed	O
CBP	B-GENE
.	O

Previous	O
studies	O
using	O
partial	O
sequences	O
have	O
suggested	O
the	O
potential	O
of	O
26S	B-GENE
or	O
large	B-GENE
-	I-GENE
subunit	I-GENE
(	O
LSU	B-GENE
)	O
rDNA	O
for	O
phylogeny	O
retrieval	O
at	O
taxonomic	O
levels	O
comparable	O
to	O
those	O
investigated	O
with	O
18S	B-GENE
rDNA	I-GENE
.	O

P53	B-GENE
mutations	I-GENE
also	O
offer	O
new	O
approaches	O
to	O
the	O
study	O
of	O
the	O
origins	O
of	O
mutations	O
in	O
human	O
cancer	O
.	O

Due	O
to	O
significant	O
homology	O
to	O
the	O
C	O
-	O
terminus	O
of	O
the	O
Mutator	B-GENE
transposase	I-GENE
this	O
alternative	O
gene	O
product	O
was	O
named	O
Trap	B-GENE
(	O
transposon	B-GENE
-	I-GENE
associated	I-GENE
protein	I-GENE
)	O
.	O

RT	O
-	O
PCR	O
analysis	O
of	O
FGFR	B-GENE
-	I-GENE
3	I-GENE
mRNA	I-GENE
showed	O
the	O
presence	O
of	O
a	O
splice	O
variant	O
in	O
which	O
exons	O
7	O
and	O
8	O
are	O
deleted	O
.	O

A	O
novel	O
serine	B-GENE
kinase	I-GENE
activated	O
by	O
rac1	B-GENE
/	O
CDC42Hs	B-GENE
-	O
dependent	O
autophosphorylation	O
is	O
related	O
to	O
PAK65	B-GENE
and	O
STE20	B-GENE
.	O

CYP51P1	B-GENE
is	O
96	O
.	O
5	O
%	O
identical	O
to	O
the	O
human	B-GENE
CYP51	I-GENE
coding	O
sequence	O
and	O
is	O
not	O
interrupted	O
with	O
introns	O
but	O
has	O
six	O
in	O
-	O
frame	O
stop	O
codons	O
resulting	O
from	O
point	O
mutations	O
.	O

Patients	O
with	O
risk	O
factors	O
were	O
compared	O
with	O
those	O
without	O
risk	O
factors	O
.	O

Mutations	O
in	O
glnB	B-GENE
,	O
nifR1	B-GENE
(	O
ntrC	B-GENE
)	O
,	O
and	O
NifR4	B-GENE
(	O
ntrA	B-GENE
encoding	O
sigma	B-GENE
54	I-GENE
)	O
had	O
no	O
influence	O
on	O
put	B-GENE
gene	I-GENE
expression	O
.	O

This	O
bud	O
morphology	O
results	O
at	O
least	O
in	O
part	O
from	O
a	O
cell	O
cycle	O
delay	O
imposed	O
by	O
the	O
Cdc28p	B-GENE
-	O
inhibitory	O
kinase	O
Swe1p	B-GENE
.	O

IgE	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
of	O
Psocoptera	O
were	O
determined	O
by	O
immunoblotting	O
experiments	O
.	O

174	O
,	O
233	O
-	O
247	O
)	O
and	O
Serrate	O
(	O
Serrate1	O
and	O
2	O
;	O
Myat	O
,	O
A	O
.	O
,	O
Henrique	O
,	O
D	O
.	O
,	O
Ish	O
-	O
Horowicz	O
,	O
D	O
.	O
and	O
Lewis	O
,	O
J	O
.	O
,	O
1996	O
.	O

A	O
new	O
technique	O
for	O
the	O
identification	O
of	O
phases	O
contained	O
within	O
a	O
polymer	O
blend	O
is	O
described	O
in	O
this	O
paper	O
.	O

Nonlethal	O
sec71	B-GENE
-	I-GENE
1	I-GENE
and	O
sec72	B-GENE
-	I-GENE
1	I-GENE
mutations	I-GENE
eliminate	O
proteins	O
associated	O
with	O
the	O
Sec63p	B-GENE
-	O
BiP	B-GENE
complex	O
from	O
S	O
.	O
cerevisiae	O
.	O

Our	O
studies	O
indicate	O
no	O
single	O
trans	O
-	O
acting	O
factor	O
is	O
absolutely	O
essential	O
for	O
enhancer	O
activity	O
,	O
and	O
that	O
the	O
enhancer	O
activity	O
of	O
MerI	B-GENE
is	O
mediated	O
via	O
a	O
combinatorial	O
and	O
additive	O
mechanism	O
.	O

We	O
recently	O
reported	O
the	O
cloning	O
and	O
sequencing	O
of	O
the	O
alpha	B-GENE
7	I-GENE
integrin	I-GENE
chain	I-GENE
and	O
its	O
regulated	O
expression	O
during	O
the	O
development	O
of	O
skeletal	O
muscle	O
(	O
Song	O
et	O
al	O
.	O

Analytical	O
scanning	O
isoelectrofocusing	O
.	O

A	O
structural	O
model	O
for	O
Vpu	B-GENE
is	O
proposed	O
in	O
which	O
the	O
membrane	O
anchor	O
precedes	O
a	O
region	O
comprising	O
two	O
amphipathic	O
alpha	O
-	O
helices	O
of	O
opposed	O
polarity	O
,	O
joined	O
by	O
a	O
strongly	O
acidic	O
turn	O
that	O
protrudes	O
into	O
the	O
cytoplasm	O
and	O
contains	O
the	O
CK	B-GENE
-	I-GENE
2	I-GENE
phosphorylation	I-GENE
sites	I-GENE
.	O

Primer	O
extension	O
analysis	O
and	O
subcloning	O
of	O
the	O
virJ	B-GENE
-	O
phoA	B-GENE
fusion	O
indicate	O
that	O
the	O
acetosyringone	O
-	O
inducible	O
promoter	O
lies	O
directly	O
upstream	O
of	O
the	O
virJ	B-GENE
structural	I-GENE
gene	I-GENE
.	O

This	O
novel	O
TRPC7	B-GENE
gene	I-GENE
could	O
be	O
a	O
candidate	O
gene	O
for	O
genetic	O
disorders	O
such	O
as	O
bipolar	O
affective	O
disorder	O
,	O
nonsyndromic	O
hereditary	O
deafness	O
,	O
Knobloch	O
syndrome	O
,	O
and	O
holoprosencephaly	O
,	O
which	O
were	O
mapped	O
to	O
this	O
region	O
.	O

In	O
the	O
future	O
,	O
transoesophageal	O
echocardiography	O
may	O
be	O
used	O
to	O
measure	O
variations	O
in	O
wall	O
thickness	O
which	O
change	O
the	O
global	O
loading	O
conditions	O
in	O
the	O
basal	O
midwall	O
compartments	O
of	O
the	O
left	O
ventricle	O
.	O

METHODS	O
:	O
A	O
discriminant	O
function	O
predicting	O
surgery	O
outcome	O
(	O
seizure	O
-	O
free	O
vs	O
.	O
non	O
-	O
seizure	O
-	O
free	O
)	O
was	O
computed	O
separately	O
for	O
samples	O
of	O
patients	O
with	O
left	O
(	O
n	O
=	O
79	O
)	O
and	O
right	O
(	O
n	O
=	O
62	O
)	O
temporal	O
lobectomy	O
(	O
LATL	O
,	O
RATL	O
)	O
.	O

A	O
porcine	O
model	O
of	O
diffuse	O
axonal	O
injury	O
,	O
developed	O
with	O
information	O
from	O
these	O
physical	O
models	O
and	O
earlier	O
in	O
vitro	O
tissue	O
modeling	O
studies	O
,	O
is	O
used	O
to	O
correlate	O
histologic	O
and	O
radiologic	O
evidence	O
of	O
axonal	O
injury	O
to	O
predicted	O
regions	O
of	O
injury	O
from	O
the	O
experimental	O
and	O
theoretical	O
analysis	O
.	O

Control	O
of	O
ovulation	O
in	O
mares	O
in	O
the	O
early	O
breeding	O
season	O
with	O
ovarian	O
steroids	O
and	O
prostaglandin	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
response	O
properties	O
of	O
the	O
human	O
visual	O
cortex	O
to	O
chromatic	O
stimuli	O
using	O
magnetoencephalography	O
(	O
MEG	O
)	O
.	O

By	O
subtractive	O
and	O
differential	O
screening	O
,	O
we	O
have	O
cloned	O
12	O
of	O
these	O
sequences	O
,	O
2	O
of	O
which	O
were	O
c	B-GENE
-	I-GENE
fos	I-GENE
and	O
krox	B-GENE
-	I-GENE
24	I-GENE
.	O

Basal	O
level	O
expression	O
was	O
reduced	O
to	O
20	O
and	O
50	O
%	O
when	O
the	O
UGA	O
stop	O
codon	O
was	O
replaced	O
by	O
UAG	O
or	O
UAA	O
,	O
respectively	O
,	O
consistent	O
with	O
the	O
finding	O
that	O
in	O
E	O
.	O
coli	O
translation	O
terminates	O
more	O
efficiently	O
at	O
UAG	O
and	O
UAA	O
than	O
at	O
UGA	O
.	O

3	O
.	O

The	O
root	O
-	O
mean	O
-	O
square	O
deviation	O
of	O
bond	O
lengths	O
from	O
the	O
ideal	O
values	O
is	O
0	O
.	O
02	O
A	O
.	O

Sugar	O
analysis	O
was	O
performed	O
on	O
alpha	B-GENE
-	I-GENE
TM	I-GENE
to	O
investigate	O
a	O
possible	O
biosynthetic	O
mechanism	O
for	O
part	O
-	O
time	O
PGs	O
.	O

To	O
our	O
knowledge	O
no	O
transcription	O
factors	O
have	O
previously	O
been	O
identified	O
that	O
exhibit	O
androgen	O
-	O
dependent	O
expression	O
in	O
the	O
epididymis	O
.	O

4	O
.	O

Proceedings	O
:	O
Influence	O
of	O
halothane	O
on	O
mortality	O
from	O
murine	O
hepatitis	O
virus	O
(	O
MHV3	O
)	O
.	O

Prevalence	O
of	O
rheumatic	O
diseases	O
in	O
a	O
rural	O
population	O
in	O
western	O
India	O
:	O
a	O
WHO	O
-	O
ILAR	O
COPCORD	O
Study	O
.	O

Finally	O
,	O
in	O
samples	O
obtained	O
from	O
two	O
patients	O
with	O
drug	O
refractory	O
ALL	O
,	O
BAC	O
-	O
derived	O
probes	O
applied	O
to	O
archived	O
marrow	O
cells	O
demonstrated	O
that	O
a	O
breakpoint	O
occurred	O
between	O
MDR1	B-GENE
and	O
sequences	O
500	O
-	O
1000	O
KB	O
telomeric	O
to	O
MDR1	B-GENE
,	O
consistent	O
with	O
a	O
random	O
chromosomal	O
rearrangement	O
.	O

We	O
conclude	O
that	O
clonidine	O
3	O
micrograms	O
/	O
kg	O
produces	O
sedation	O
comparable	O
to	O
diazepam	O
0	O
.	O
2	O
mg	O
/	O
kg	O
and	O
also	O
attenuates	O
the	O
intubation	O
response	O
without	O
increasing	O
the	O
incidence	O
of	O
complications	O
.	O

The	O
other	O
regions	O
include	O
potential	O
binding	O
sites	O
for	O
transcription	O
factors	O
ATF	B-GENE
,	O
NF1	B-GENE
,	O
and	O
a	O
CCAAT	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
.	O

The	O
analysis	O
predicted	O
that	O
progressive	O
increases	O
in	O
serum	O
creatinine	O
or	O
aspartate	B-GENE
transaminase	I-GENE
activity	O
will	O
result	O
in	O
only	O
a	O
50	O
%	O
reduction	O
of	O
clearance	O
.	O

5	O
Intravenous	O
prizidilol	O
hydrochloride	O
decreases	O
resting	O
blood	O
pressure	O
and	O
left	O
ventricular	O
area	O
,	O
increases	O
pulse	O
rate	O
and	O
has	O
virtually	O
no	O
effect	O
on	O
left	O
ventricular	O
ejection	O
fraction	O
.	O

The	O
Saccharomyces	O
cerevisiae	O
targets	O
of	O
rapamycin	O
,	O
TOR1	B-GENE
and	O
TOR2	B-GENE
,	O
signal	O
activation	O
of	O
cell	O
growth	O
in	O
response	O
to	O
nutrient	O
availability	O
.	O

This	O
50	O
-	O
kDa	O
protein	O
contains	O
two	O
SH2	B-GENE
domains	I-GENE
and	O
an	O
inter	B-GENE
-	I-GENE
SH2	I-GENE
domain	I-GENE
of	O
p85alpha	B-GENE
,	O
but	O
the	O
SH3	B-GENE
and	O
bcr	B-GENE
homology	I-GENE
domains	I-GENE
of	O
p85alpha	B-GENE
were	O
replaced	O
by	O
a	O
unique	O
6	O
-	O
amino	O
acid	O
sequence	O
.	O

Gene	O
structure	O
and	O
precursor	O
processing	O
.	O

This	O
effect	O
is	O
independent	O
of	O
the	O
Gal4	B-GENE
protein	I-GENE
,	O
as	O
it	O
operates	O
in	O
a	O
gal4	B-GENE
mutant	I-GENE
background	O
as	O
well	O
.	O

Thus	O
,	O
d	O
-	O
delta3	O
-	O
carene	O
was	O
about	O
four	O
times	O
more	O
potent	O
as	O
a	O
sensory	O
irritant	O
than	O
I	O
-	O
beta	O
-	O
pinene	O
,	O
whereas	O
the	O
difference	O
with	O
I	O
-	O
alpha	O
-	O
pinene	O
was	O
more	O
marked	O
;	O
as	O
a	O
sensory	O
irritant	O
,	O
I	O
-	O
alpha	O
-	O
pinene	O
is	O
almost	O
inactive	O
.	O

Blood	O
and	O
whole	O
-	O
brain	O
mercury	O
concentrations	O
were	O
determined	O
in	O
pups	O
on	O
PN	O
0	O
(	O
birth	O
)	O
and	O
PN	O
21	O
(	O
weaning	O
)	O
.	O

Multiple	O
copies	O
of	O
this	O
binding	O
site	O
are	O
found	O
in	O
the	O
viral	O
genomes	O
.	O

Tubular	O
dysfunction	O
in	O
renal	O
lithiasis	O
:	O
cause	O
or	O
consequence	O
?	O
]	O
To	O
investigate	O
whether	O
overall	O
tubular	O
dysfunction	O
is	O
encountered	O
in	O
a	O
particular	O
subgroup	O
of	O
patients	O
with	O
urolithiasis	O
,	O
the	O
following	O
parameters	O
of	O
renal	O
tubular	O
function	O
have	O
been	O
measured	O
in	O
fasting	O
morning	O
urine	O
in	O
124	O
male	O
stone	O
formers	O
:	O
excretion	O
of	O
lysozyme	B-GENE
and	O
gamma	B-GENE
-	I-GENE
glutamyl	I-GENE
transpeptidase	I-GENE
(	O
gamma	B-GENE
-	I-GENE
GT	I-GENE
)	O
,	O
fractional	O
excretion	O
(	O
FE	O
)	O
or	O
glucose	O
,	O
insulin	B-GENE
,	O
bicarbonate	O
after	O
an	O
alkali	O
load	O
,	O
and	O
theoretical	O
phosphate	O
threshold	O
(	O
TmP	O
/	O
GFR	O
)	O
.	O

The	O
blood	O
pressures	O
in	O
43	O
subjects	O
were	O
compared	O
during	O
rapid	O
weight	O
loss	O
and	O
at	O
identical	O
weights	O
during	O
post	O
-	O
fast	O
weight	O
gain	O
(	O
Study	O
A	O
)	O
.	O

Mol	O
.	O

Arg	O
-	O
130	O
,	O
Gly	O
-	O
132	O
and	O
Lys	O
-	O
167	O
are	O
conserved	O
in	O
all	O
members	O
of	O
the	O
type	B-GENE
IB	I-GENE
topoisomerase	I-GENE
family	I-GENE
.	O

The	O
maximal	O
rise	O
in	O
plasma	O
adrenaline	O
was	O
of	O
similar	O
magnitude	O
in	O
all	O
three	O
groups	O
but	O
a	O
lower	O
plasma	O
glucose	O
was	O
required	O
to	O
stimulate	O
this	O
hormonal	O
response	O
in	O
the	O
'	O
unaware	O
'	O
patients	O
,	O
in	O
whom	O
the	O
plasma	O
adrenaline	O
concentration	O
was	O
lower	O
at	O
the	O
time	O
of	O
the	O
reaction	O
.	O

PATIENTS	O
-	O
-	O
125	O
women	O
consulting	O
the	O
general	O
practitioner	O
for	O
symptomatic	O
bacterial	O
vaginosis	O
.	O

Patients	O
with	O
advanced	O
ovarian	O
carcinoma	O
,	O
Stage	O
III	O
or	O
IV	O
(	O
International	O
Federation	O
of	O
Gynaecology	O
and	O
Obstetrics	O
)	O
,	O
were	O
randomized	O
to	O
primary	O
chemotherapy	O
with	O
doxorubicin	O
(	O
Adriamycin	O
)	O
and	O
cisplatin	O
plus	O
or	O
minus	O
hexamethylmelamine	O
,	O
and	O
cyclophosphamide	O
(	O
CHAP	O
)	O
.	O

Promoter	O
activity	O
of	O
the	O
proliferating	B-GENE
-	I-GENE
cell	I-GENE
nuclear	I-GENE
antigen	I-GENE
gene	I-GENE
is	O
associated	O
with	O
inducible	O
CRE	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
in	O
interleukin	B-GENE
2	I-GENE
-	O
stimulated	O
T	O
lymphocytes	O
.	O

Sequence	O
analysis	O
revealed	O
100	O
%	O
homology	O
of	O
all	O
RA	O
-	O
derived	O
PTEN	B-GENE
fragments	I-GENE
to	O
those	O
from	O
normal	O
SF	O
as	O
well	O
as	O
to	O
the	O
published	O
GenBank	O
sequence	O
(	O
accession	O
number	O
U93051	B-GENE
)	O
.	O

The	O
mutation	O
also	O
preferentially	O
limits	O
(	O
compared	O
with	O
total	O
protein	O
synthesis	O
)	O
translation	O
of	O
an	O
induced	O
gene	O
that	O
depends	O
on	O
five	O
AGA	O
codons	O
,	O
i	O
.	O
e	O
.	O
,	O
the	O
lambda	B-GENE
cI	I-GENE
repressor	I-GENE
gene	I-GENE
.	O

The	O
influence	O
of	O
a	O
high	O
n	O
-	O
3	O
PUFA	O
intake	O
on	O
measures	O
of	O
lipid	O
peroxidation	O
has	O
been	O
equivocal	O
.	O

In	O
contrast	O
,	O
inhibition	O
of	O
MAPK	B-GENE
activity	O
by	O
MAPK	B-GENE
kinase	I-GENE
inhibitor	O
(	O
PD	O
98059	O
)	O
or	O
by	O
overexpression	O
of	O
kinase	O
-	O
deficient	O
MAPKs	B-GENE
activated	O
basal	O
and	O
GnRH	B-GENE
-	I-GENE
A	I-GENE
-	O
stimulated	O
GnRHR	B-GENE
-	O
Luc	B-GENE
activity	O
.	O

For	O
the	O
first	O
,	O
short	O
-	O
term	O
(	O
concurrent	O
)	O
TAL	O
,	O
two	O
different	O
-	O
flavored	O
stimuli	O
were	O
presented	O
at	O
the	O
same	O
time	O
,	O
one	O
associated	O
with	O
simultaneous	O
intragastric	O
administration	O
of	O
an	O
aversive	O
product	O
,	O
hypertonic	O
NaCl	O
,	O
and	O
the	O
other	O
with	O
saline	O
.	O

CONCLUSIONS	O
:	O
LHB	O
is	O
simple	O
,	O
easy	O
and	O
safe	O
to	O
implement	O
,	O
and	O
is	O
the	O
only	O
technique	O
capable	O
of	O
maintaining	O
independent	O
upper	O
and	O
lower	O
body	O
perfusion	O
pressure	O
.	O

Heterodimerization	B-GENE
mutant	I-GENE
RXR	I-GENE
failed	O
to	O
alter	O
GFP	B-GENE
-	O
VDR	B-GENE
and	O
nlsGFP	B-GENE
-	O
VDR	B-GENE
distribution	O
or	O
activity	O
.	O

New	O
TB	O
respirator	O
standards	O
mean	O
more	O
choices	O
at	O
less	O
cost	O
.	O

After	O
first	O
strand	O
cDNA	O
synthesis	O
from	O
fetal	O
brain	O
mRNAs	O
,	O
short	O
fragment	O
cDNAs	O
(	O
sf	O
-	O
cDNAs	O
)	O
were	O
synthesized	O
with	O
a	O
two	O
-	O
step	O
amplification	O
system	O
by	O
use	O
of	O
our	O
modified	O
Degenerate	O
Oligonucleotide	O
Primed	O
Shuttle	O
Polymerase	O
Chain	O
Reaction	O
(	O
DOP	O
-	O
Shuttle	O
-	O
PCR	O
)	O
method	O
.	O

Fulminant	O
hepatic	O
failure	O
in	O
these	O
cases	O
could	O
be	O
characterized	O
by	O
:	O
(	O
1	O
)	O
rapid	O
decrease	O
in	O
serum	B-GENE
alanine	I-GENE
transaminase	I-GENE
(	O
ALT	B-GENE
)	O
level	O
after	O
discontinuation	O
of	O
ecarazine	O
,	O
(	O
2	O
)	O
prolonged	O
jaundice	O
despite	O
discontinuation	O
of	O
ecarazine	O
,	O
(	O
3	O
)	O
high	O
incidence	O
of	O
anti	B-GENE
-	I-GENE
nuclear	I-GENE
antibody	I-GENE
(	O
ANA	B-GENE
)	O
(	O
57	O
%	O
)	O
,	O
and	O
(	O
4	O
)	O
histological	O
findings	O
of	O
extensive	O
hepatocellular	O
necrosis	O
ranging	O
from	O
bridging	O
necrosis	O
to	O
massive	O
necrosis	O
.	O

Smectic	O
-	O
A	O
ordering	O
at	O
a	O
liquid	O
-	O
vapor	O
interface	O
.	O

Simulation	O
results	O
based	O
on	O
the	O
presented	O
model	O
are	O
compared	O
with	O
the	O
experimental	O
data	O
for	O
two	O
types	O
of	O
cMUTs	O
reported	O
in	O
the	O
recent	O
literature	O
.	O

These	O
results	O
demonstrate	O
that	O
the	O
entire	O
E3L	B-GENE
gene	I-GENE
is	O
required	O
for	O
pathogenesis	O
in	O
the	O
mouse	O
model	O
.	O

Parelaphostrongylus	O
odocoilei	O
is	O
redescribed	O
from	O
worms	O
collected	O
from	O
the	O
type	O
host	O
(	O
Odocoileus	O
hemionus	O
columbianus	O
)	O
in	O
California	O
,	O
as	O
well	O
as	O
material	O
from	O
experimentally	O
infected	O
mule	O
deer	O
(	O
O	O
.	O
h	O
.	O
heminus	O
)	O
in	O
Alberta	O
.	O

Sodium	O
dodecylsulfate	O
polyacrylamide	O
gel	O
electrophoresis	O
(	O
SDS	O
-	O
PAGE	O
)	O
showed	O
two	O
bands	O
of	O
about	O
the	O
same	O
intensity	O
with	O
apparent	O
molecular	O
masses	O
of	O
24	O
.	O
5	O
and	O
22	O
.	O
5	O
kDa	O
.	O

Particle	O
bombardment	O
of	O
barley	O
aleurone	O
with	O
a	O
B22EL8	B-GENE
promoter	I-GENE
-	O
GUS	B-GENE
(	O
beta	B-GENE
-	I-GENE
glucuronidase	I-GENE
)	O
construct	O
demonstrates	O
that	O
the	O
promoter	O
(	O
3	O
kb	O
)	O
is	O
active	O
in	O
developing	O
barley	O
grains	O
.	O

The	O
cloning	O
of	O
CWH43	B-GENE
showed	O
that	O
it	O
corresponds	O
to	O
YCR017c	B-GENE
and	O
encodes	O
a	O
protein	O
with	O
14	O
-	O
16	O
transmembrane	O
segments	O
containing	O
several	O
putative	O
phosphorylation	O
and	O
glycosylation	O
sites	O
.	O

They	O
elicit	O
similar	O
regional	O
cerebral	O
blood	O
flow	O
(	O
rCBF	O
)	O
patterns	O
,	O
even	O
though	O
sign	O
language	O
is	O
dependent	O
on	O
spatial	O
information	O
.	O

However	O
,	O
at	O
the	O
time	O
of	O
salvage	O
treatment	O
,	O
the	O
mean	O
serum	B-GENE
PSA	I-GENE
levels	O
were	O
9	O
.	O
1	O
and	O
1	O
.	O
1	O
ng	O
/	O
mL	O
for	O
the	O
salvage	O
RP	O
and	O
salvage	O
RT	O
groups	O
,	O
respectively	O
(	O
P	O
=	O
0	O
.	O
0001	O
)	O
.	O

First	O
,	O
a	O
GATA	B-GENE
-	I-GENE
1	I-GENE
motif	I-GENE
was	O
found	O
to	O
bind	O
nuclear	O
factor	O
(	O
s	O
)	O
,	O
presumably	O
the	O
GATA	B-GENE
-	I-GENE
1	I-GENE
factor	I-GENE
,	O
present	O
in	O
K	O
-	O
562	O
cell	O
extracts	O
and	O
in	O
living	O
K	O
-	O
562	O
cells	O
.	O

There	O
was	O
a	O
direct	O
proportional	O
relationship	O
between	O
the	O
spiral	O
artery	O
flow	O
and	O
the	O
pressure	O
difference	O
between	O
the	O
spiral	O
artery	O
and	O
the	O
amniotic	O
fluid	O
;	O
the	O
pressure	O
difference	O
per	O
flow	O
(	O
the	O
resistance	O
of	O
the	O
cotyledonary	O
unit	O
)	O
was	O
found	O
to	O
be	O
1	O
-	O
-	O
3	O
mm	O
Hg	O
.	O
ml	O
-	O
1	O
.	O
min	O
(	O
8	O
-	O
-	O
24kPa	O
.	O
ml	O
-	O
1	O
.	O
s	O
)	O
.	O

Truncations	O
from	O
Hip	B-GENE
'	O
s	O
N	O
terminus	O
resulted	O
in	O
an	O
apparent	O
loss	O
of	O
Hip	B-GENE
homo	O
-	O
oligomerization	O
,	O
but	O
these	O
mutants	O
retained	O
association	O
with	O
hsp70	B-GENE
and	O
were	O
recovered	O
in	O
receptor	O
complexes	O
.	O

An	O
oligomer	O
synthesized	O
to	O
this	O
region	O
of	O
homology	O
produced	O
two	O
DNA	O
-	O
protein	O
complexes	O
with	O
oviduct	O
nuclear	O
proteins	O
.	O

The	O
myeloid	B-GENE
zinc	I-GENE
finger	I-GENE
gene	I-GENE
1	I-GENE
(	O
MZF1	B-GENE
)	O
encodes	O
a	O
C	B-GENE
(	I-GENE
2	I-GENE
)	I-GENE
H	I-GENE
(	I-GENE
2	I-GENE
)	I-GENE
zinc	I-GENE
finger	I-GENE
transcription	I-GENE
factor	I-GENE
that	O
regulates	O
granulopoiesis	O
and	O
may	O
have	O
a	O
regulatory	O
role	O
in	O
cellular	O
proliferation	O
and	O
oncogenesis	O
.	O

3	O
.	O

The	O
rate	O
of	O
collagen	B-GENE
synthesis	O
in	O
normal	O
scar	O
was	O
approximately	O
constant	O
between	O
6	O
months	O
and	O
20	O
years	O
after	O
the	O
initial	O
wounding	O
,	O
but	O
in	O
both	O
hypertrophic	O
scar	O
and	O
keloid	O
the	O
rate	O
was	O
initially	O
approximately	O
twice	O
that	O
in	O
normal	O
scar	O
,	O
and	O
2	O
-	O
3	O
years	O
after	O
wounding	O
it	O
fell	O
to	O
approximately	O
the	O
same	O
level	O
as	O
in	O
normal	O
scar	O
.	O

When	O
phentermine	O
was	O
mixed	O
with	O
other	O
unlabeled	O
reversible	O
MAO	B-GENE
inhibitors	O
(	O
e	O
.	O
g	O
.	O
pseudoephedrine	O
,	O
ephedrine	O
,	O
norephedrine	O
;	O
estradiol	O
benzoate	O
)	O
,	O
the	O
degree	O
of	O
MAO	B-GENE
inhibition	O
was	O
additive	O
.	O

W	O
.	O
,	O
and	O
Touster	O
,	O
O	O
.	O

There	O
was	O
a	O
57	O
%	O
reduction	O
in	O
IGF	B-GENE
IR	I-GENE
mRNA	I-GENE
levels	O
in	O
clone	O
CA9	O
after	O
confluence	O
compared	O
with	O
clone	O
ME10	O
.	O

Uncoupling	O
gene	O
activity	O
from	O
chromatin	O
structure	O
:	O
promoter	O
mutations	O
can	O
inactivate	O
transcription	O
of	O
the	O
yeast	B-GENE
HSP82	I-GENE
gene	I-GENE
without	O
eliminating	O
nucleosome	O
-	O
free	O
regions	O
.	O

Heating	O
had	O
no	O
effect	O
upon	O
either	O
force	O
decline	O
or	O
slowing	O
of	O
relaxation	O
during	O
fatiguing	O
contractions	O
.	O

Uncertainty	O
exists	O
about	O
the	O
function	O
of	O
these	O
potential	O
isoforms	O
of	O
the	O
Cbfa1	B-GENE
gene	I-GENE
.	O

The	O
RTI40	B-GENE
gene	I-GENE
spans	O
35	O
kilobase	O
pairs	O
;	O
it	O
contains	O
6	O
exons	O
and	O
at	O
least	O
6	O
rat	O
Identifier	O
repetitive	O
elements	O
.	O

The	O
characteristics	O
of	O
a	O
simple	O
apparatus	O
for	O
clinical	O
use	O
to	O
measure	O
DEOAEs	O
are	O
described	O
together	O
with	O
typical	O
examples	O
of	O
emissions	O
.	O

Anatomical	O
considerations	O
in	O
transsphenoidal	O
hypophysectomy	O
.	O

It	O
has	O
been	O
confirmed	O
in	O
animal	O
experiments	O
that	O
the	O
number	O
of	O
microspheres	O
in	O
a	O
myocardial	O
sample	O
approximately	O
follows	O
a	O
Poisson	O
distribution	O
,	O
under	O
adequate	O
experimental	O
conditions	O
.	O

Maximal	O
exercise	O
duration	O
and	O
peak	O
oxygen	O
consumption	O
were	O
not	O
changed	O
.	O

Hard	O
methacrylic	O
polymers	O
.	O

Validity	O
of	O
the	O
short	O
-	O
form	O
QIF	O
was	O
assessed	O
by	O
correlation	O
with	O
motor	O
scores	O
and	O
using	O
analysis	O
of	O
variance	O
by	O
motor	O
levels	O
and	O
motor	O
score	O
groupings	O
.	O

An	O
81	O
-	O
nt	O
tandem	O
duplication	O
of	O
the	O
C	O
-	O
terminal	O
coding	O
region	O
is	O
located	O
adjacent	O
to	O
the	O
termination	O
codon	O
of	O
the	O
CyIIIb	B-GENE
gene	I-GENE
,	O
a	O
potential	O
relic	O
of	O
a	O
slipped	O
mispairing	O
and	O
replication	O
event	O
.	O

During	O
seed	O
maturation	O
,	O
the	O
transcriptional	O
activity	O
of	O
napin	B-GENE
genes	I-GENE
is	O
regulated	O
by	O
developmental	O
signals	O
involving	O
the	O
transcriptional	B-GENE
activator	I-GENE
ABI3	I-GENE
and	O
abscisic	O
acid	O
(	O
ABA	O
)	O
.	O

Here	O
we	O
report	O
the	O
cloning	O
,	O
by	O
either	O
peptide	O
sequencing	O
or	O
by	O
sequence	O
similarity	O
to	O
the	O
human	O
cDNAs	O
,	O
of	O
the	O
S	O
.	O
cerevisiae	O
genes	O
RFC1	B-GENE
,	O
RFC2	B-GENE
,	O
RFC3	B-GENE
,	O
RFC4	B-GENE
,	O
and	O
RFC5	B-GENE
.	O

On	O
the	O
other	O
hand	O
,	O
V3	O
"	O
values	O
were	O
not	O
significantly	O
correlated	O
with	O
the	O
degree	O
of	O
tremor	O
,	O
seborrhea	O
,	O
and	O
duration	O
of	O
the	O
illness	O
.	O

The	O
isomerization	O
of	O
the	O
pre	O
-	O
existing	O
closed	O
complex	O
to	O
an	O
open	O
promoter	O
form	O
,	O
as	O
judged	O
by	O
the	O
local	O
denaturation	O
of	O
promoter	O
DNA	O
which	O
rendered	O
sequences	O
from	O
+	O
5	O
to	O
-	O
10	O
reactive	O
towards	O
KMnO4	O
,	O
was	O
shown	O
to	O
be	O
fully	O
dependent	O
on	O
NifA	B-GENE
.	O

Mouse	B-GENE
macrophage	I-GENE
beta	I-GENE
subunit	I-GENE
(	I-GENE
CD11b	I-GENE
)	I-GENE
cDNA	I-GENE
for	O
the	O
CR3	B-GENE
complement	I-GENE
receptor	I-GENE
/	O
Mac	B-GENE
-	I-GENE
1	I-GENE
antigen	I-GENE
.	O

The	O
predicted	O
product	O
exhibits	O
91	O
%	O
amino	O
acid	O
identity	O
to	O
the	O
murine	B-GENE
voltage	I-GENE
-	I-GENE
gated	I-GENE
potassium	I-GENE
channel	I-GENE
protein	I-GENE
Kv1	I-GENE
.	I-GENE
7	I-GENE
(	O
Kcna7	B-GENE
)	O
,	O
which	O
plays	O
an	O
important	O
role	O
in	O
the	O
repolarization	O
of	O
cell	O
membranes	O
.	O

Elective	O
replacement	O
of	O
the	O
aortic	O
root	O
in	O
Marfan	O
'	O
s	O
syndrome	O
.	O

Principles	O
of	O
thyroid	O
hormone	O
treatment	O

Their	O
main	O
representatives	O
are	O
the	O
American	O
diagnostic	O
and	O
statistical	O
manual	O
of	O
mental	O
disorders	O
,	O
DSM	O
-	O
III	O
,	O
its	O
revised	O
version	O
DSM	O
-	O
III	O
-	O
R	O
and	O
the	O
new	O
international	O
classification	O
of	O
mental	O
disorders	O
iCD	O
-	O
10	O
.	O

Each	O
received	O
20	O
mL	O
of	O
one	O
of	O
three	O
test	O
solutions	O
:	O
levobupivacaine	O
control	O
,	O
levobupivacaine	O
and	O
fentanyl	O
2	O
microg	O
/	O
mL	O
,	O
or	O
levobupivacaine	O
and	O
fentanyl	O
3	O
microg	O
/	O
mL	O
.	O

Time	O
for	O
action	O
on	O
hepatitis	O
B	O
immunisation	O
.	O

Kramer	O
Hamburg	O
1988	O
,	O
ISBN	O
:	O
3	O
926952	O
07	O
5	O
)	O
,	O
the	O
syndromatic	O
day	O
-	O
to	O
-	O
day	O
shifting	O
of	O
the	O
psychopathological	O
features	O
with	O
manic	O
,	O
depressive	O
and	O
several	O
mixed	O
states	O
has	O
a	O
well	O
-	O
defined	O
time	O
structure	O
,	O
as	O
in	O
25	O
patients	O
studied	O
and	O
reported	O
on	O
in	O
this	O
paper	O
.	O

Internal	O
controls	O
over	O
the	O
volume	O
of	O
milk	O
suckled	O
do	O
not	O
appear	O
until	O
infant	O
rats	O
are	O
about	O
2	O
weeks	O
of	O
age	O
at	O
which	O
time	O
gastric	O
distension	O
,	O
milk	O
,	O
systemic	O
dehydration	O
,	O
and	O
intestinal	B-GENE
hormone	I-GENE
cholecystokinin	I-GENE
suppress	O
milk	O
intake	O
derived	O
through	O
suckling	O
.	O

In	O
the	O
HIV	B-GENE
LTR	I-GENE
,	O
this	O
region	O
has	O
been	O
demonstrated	O
to	O
have	O
both	O
positive	O
and	O
negative	O
regulatory	O
effects	O
on	O
HIV	O
gene	O
expression	O
.	O

Analysis	O
of	O
rat	O
brain	O
,	O
heart	O
,	O
lung	O
,	O
liver	O
,	O
kidney	O
and	O
skeletal	O
muscle	O
revealed	O
psi	B-GENE
PKC	I-GENE
zeta	I-GENE
mRNA	I-GENE
only	O
in	O
brain	O
.	O

To	O
identify	O
and	O
determine	O
the	O
function	O
of	O
Ino2p	B-GENE
in	O
yeast	O
cells	O
,	O
we	O
raised	O
antibodies	O
to	O
a	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
/	O
Ino2	B-GENE
fusion	O
protein	O
.	O

In	O
addition	O
,	O
WR	O
-	O
3689	O
,	O
WR	O
-	O
109342	O
,	O
and	O
WR	O
-	O
168643	O
were	O
used	O
with	O
per	O
os	O
administration	O
to	O
determine	O
hematopoietic	O
lethality	O
.	O

Isolation	O
and	O
characterization	O
of	O
human	O
orthologs	O
of	O
yeast	O
CCR4	B-GENE
-	O
NOT	B-GENE
complex	O
subunits	O
.	O

Serum	O
AFP	B-GENE
is	O
a	O
useful	O
tumor	O
marker	O
for	O
monitoring	O
the	O
results	O
of	O
therapy	O
.	O

The	O
paper	O
calls	O
for	O
standardized	O
question	O
formats	O
and	O
a	O
centralized	O
body	O
to	O
monitor	O
changes	O
in	O
these	O
parameters	O
of	O
sexual	O
behaviour	O
.	O

A	O
heterologous	O
promoter	O
construct	O
containing	O
three	O
repeats	O
of	O
a	O
consensus	O
Sp1	B-GENE
site	I-GENE
,	O
cloned	O
upstream	O
of	O
a	O
single	O
copy	O
of	O
the	O
ZII	B-GENE
(	O
CREB	B-GENE
/	O
AP1	B-GENE
)	O
element	O
from	O
the	O
BZLF1	B-GENE
promoter	I-GENE
linked	O
to	O
the	O
beta	B-GENE
-	I-GENE
globin	I-GENE
TATA	O
box	O
,	O
exhibited	O
phorbol	O
ester	O
inducibility	O
.	O

A	O
long	O
-	O
term	O
follow	O
-	O
up	O
study	O
of	O
a	O
children	O
'	O
s	O
psychiatric	O
day	O
treatment	O
center	O
.	O

Risk	O
factors	O
for	O
atherosclerosis	O
related	O
to	O
nutrition	O
are	O
hypercholesterolemia	O
,	O
hyperglycemia	O
-	O
diabetes	O
,	O
and	O
for	O
hypertension	O
,	O
obesity	O
,	O
high	O
salt	O
intake	O
,	O
and	O
excessive	O
use	O
of	O
alcohol	O
.	O

We	O
demonstrate	O
that	O
the	O
recently	O
proposed	O
synthetic	O
imaging	O
technique	O
[	O
J	O
.	O

We	O
compared	O
the	O
quantities	O
collected	O
with	O
both	O
pollen	O
traps	O
during	O
February	O
,	O
March	O
and	O
April	O
1988	O
and	O
1989	O
.	O

Of	O
the	O
CSF	O
tested	O
,	O
24	O
stimulated	O
oxygen	O
consumption	O
above	O
our	O
cut	O
off	O
,	O
and	O
8	O
did	O
not	O
(	O
0	O
.	O
84	O
+	O
/	O
-	O
0	O
.	O
34	O
,	O
n	O
=	O
24	O
compared	O
with	O
the	O
rate	O
of	O
0	O
.	O
27	O
+	O
/	O
-	O
0	O
.	O
1	O
mumol	O
/	O
min	O
/	O
g	O
dry	O
wt	O
,	O
respectively	O
;	O
SD	O
n	O
=	O
8	O
)	O
at	O
180	O
minutes	O
.	O

These	O
psoralens	O
are	O
being	O
used	O
in	O
research	O
projects	O
sponsored	O
by	O
the	O
National	O
Toxicology	O
Program	O
.	O

Four	O
of	O
15	O
patients	O
with	O
R2	B-GENE
had	O
rheumatoid	O
arthritis	O
and	O
in	O
two	O
of	O
these	O
four	O
cases	O
the	O
antibody	O
was	O
of	O
the	O
IgA	B-GENE
class	O
.	O

Seventy	O
-	O
nine	O
percent	O
of	O
the	O
children	O
screened	O
and	O
91	O
.	O
0	O
%	O
of	O
the	O
children	O
with	O
PbB	O
at	O
least	O
10	O
micrograms	O
/	O
dL	O
were	O
Hispanic	O
.	O

We	O
report	O
here	O
on	O
an	O
eight	O
-	O
year	O
-	O
old	O
boy	O
who	O
first	O
developed	O
acute	O
intravascular	O
hemolysis	O
following	O
therapy	O
with	O
amphotericin	O
B	O
(	O
AmB	O
)	O
and	O
subsequently	O
a	O
delayed	O
hemolytic	O
transfusion	O
reaction	O
due	O
to	O
alloantibodies	O
.	O

However	O
,	O
no	O
significant	O
difference	O
in	O
either	O
the	O
Valsalva	O
ratio	O
or	O
delta	O
SBP	O
was	O
found	O
between	O
diabetic	O
patients	O
and	O
controls	O
.	O

The	O
PDSS	O
identified	O
17	O
(	O
94	O
%	O
)	O
of	O
the	O
women	O
diagnosed	O
with	O
major	O
postpartum	O
depression	O
,	O
the	O
EPDS	O
identified	O
14	O
of	O
these	O
women	O
(	O
78	O
%	O
)	O
,	O
and	O
the	O
BDI	O
-	O
II	O
identified	O
10	O
of	O
the	O
18	O
women	O
(	O
56	O
%	O
)	O
.	O

One	O
ORF	O
extends	O
from	O
nucleotides	O
415	O
to	O
1620	O
,	O
encodes	O
402	O
amino	O
acids	O
,	O
and	O
is	O
preceded	O
by	O
a	O
ribosome	O
-	O
binding	O
site	O
.	O

Blood	B-GENE
coagulation	I-GENE
Factor	I-GENE
X	I-GENE
and	O
its	O
activated	O
form	O
Factor	B-GENE
Xa	I-GENE
play	O
an	O
essential	O
role	O
in	O
the	O
midphase	O
of	O
the	O
clotting	O
cascade	O
.	O

The	O
Ras	B-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
-	I-GENE
protein	I-GENE
-	I-GENE
related	I-GENE
human	I-GENE
protein	I-GENE
IQGAP2	B-GENE
harbors	O
a	O
potential	O
actin	B-GENE
binding	I-GENE
domain	I-GENE
and	O
interacts	O
with	O
calmodulin	B-GENE
and	O
Rho	B-GENE
family	I-GENE
GTPases	I-GENE
.	O

On	O
a	O
national	O
level	O
,	O
undiscounted	O
costs	O
are	O
expected	O
to	O
increase	O
up	O
to	O
approximately	O
DF1	O
42	O
million	O
annually	O
during	O
the	O
first	O
40	O
years	O
after	O
introduction	O
of	O
the	O
preventative	O
strategy	O
.	O

Reduction	O
of	O
p53	B-GENE
protein	I-GENE
was	O
detected	O
after	O
1	O
day	O
of	O
OM	B-GENE
treatment	O
and	O
reached	O
maximal	O
suppression	O
of	O
10	O
-	O
20	O
%	O
of	O
control	O
after	O
3	O
days	O
in	O
H3922	O
and	O
40	O
%	O
of	O
control	O
after	O
4	O
days	O
in	O
MCF	O
-	O
7	O
cells	O
.	O

This	O
seems	O
to	O
take	O
place	O
in	O
the	O
same	O
nuclear	O
compartment	O
as	O
normal	O
cis	O
splicing	O
and	O
proceeds	O
through	O
Y	O
-	O
branched	O
intermediates	O
analogous	O
to	O
the	O
lariats	O
formed	O
in	O
cis	O
splicing	O
.	O

Production	O
of	O
a	O
chicken	O
meat	O
infusion	O
broth	O
suitable	O
for	O
the	O
mass	O
production	O
of	O
a	O
Haemophilus	O
gallinarum	O
bacterin	O
.	O

The	O
maternal	B-GENE
par	I-GENE
genes	I-GENE
and	O
the	O
segregation	O
of	O
cell	O
fate	O
specification	O
activities	O
in	O
early	O
Caenorhabditis	O
elegans	O
embryos	O
.	O

These	O
results	O
suggest	O
that	O
E6010	B-GENE
may	O
be	O
of	O
clinical	O
value	O
in	O
the	O
treatment	O
of	O
coronary	O
occlusion	O
.	O

Real	O
-	O
time	O
two	O
-	O
dimensional	O
echocardiographic	O
studies	O
of	O
the	O
mitral	O
valve	O
in	O
short	O
-	O
axis	O
view	O
were	O
obtained	O
from	O
10	O
normal	O
subjects	O
.	O

We	O
determined	O
their	O
N	O
-	O
terminal	O
amino	O
acid	O
sequence	O
and	O
found	O
that	O
these	O
polypeptides	O
were	O
CotT	B-GENE
,	O
YeeK	B-GENE
,	O
YxeE	B-GENE
,	O
CotF	B-GENE
,	O
YrbA	B-GENE
(	O
31	O
and	O
45	O
kDa	O
)	O
,	O
and	O
SpoIVA	B-GENE
,	O
respectively	O
.	O

The	O
determination	O
of	O
diacetyl	O
,	O
2	O
,	O
3	O
-	O
pentanedione	O
and	O
acetoin	O
was	O
performed	O
in	O
two	O
steps	O
.	O

The	O
same	O
pattern	O
of	O
firing	O
was	O
seen	O
with	O
saccades	O
in	O
light	O
and	O
in	O
complete	O
darkness	O
.	O

The	O
critical	O
obstacle	O
in	O
modeling	O
psychiatric	O
disorders	O
has	O
been	O
limited	O
information	O
about	O
their	O
origin	O
and	O
underlying	O
neural	O
mechanisms	O
.	O

These	O
results	O
suggest	O
that	O
both	O
the	O
distinct	O
DNA	O
binding	O
properties	O
of	O
PMLRAR	B-GENE
homodimers	I-GENE
and	O
the	O
sequestration	O
of	O
RXR	B-GENE
by	O
PMLRARs	B-GENE
may	O
contribute	O
to	O
the	O
molecular	O
mechanisms	O
which	O
underlie	O
the	O
pathogenesis	O
of	O
APL	O
.	O

CONCLUSIONS	O
:	O
Patients	O
'	O
attainment	O
of	O
TGB	O
monotherapy	O
was	O
associated	O
with	O
their	O
achievement	O
of	O
positive	O
changes	O
of	O
varying	O
degree	O
on	O
psychological	O
tests	O
.	O

In	O
alfalfa	O
,	O
the	O
insecticides	O
caused	O
significant	O
mortality	O
to	O
most	O
of	O
the	O
insects	O
evaluated	O
.	O

Sixtieth	O
anniversary	O
of	O
Angiotensin	B-GENE
.	O

In	O
addition	O
,	O
we	O
found	O
that	O
the	O
transactivation	O
mediated	O
by	O
the	O
p68c	B-GENE
-	I-GENE
ets	I-GENE
-	I-GENE
1	I-GENE
pr	I-GENE
p55erg	B-GENE
through	O
the	O
Polyomavirus	B-GENE
enhancer	I-GENE
sequence	I-GENE
is	O
specifically	O
inhibited	O
by	O
the	O
p46kDaPax	B-GENE
-	I-GENE
QNR	I-GENE
in	O
transient	O
transfection	O
assay	O
.	O

SCAN	B-GENE
boxes	O
are	O
found	O
in	O
eight	O
other	O
genes	O
in	O
the	O
GenBank	O
database	O
,	O
five	O
of	O
which	O
are	O
also	O
in	O
the	O
Kruppel	B-GENE
family	I-GENE
of	O
zinc	B-GENE
finger	I-GENE
proteins	I-GENE
lacking	O
KRAB	B-GENE
A	I-GENE
and	I-GENE
B	I-GENE
domains	O
and	O
thereby	O
define	O
a	O
new	O
subclass	O
of	O
zinc	B-GENE
finger	I-GENE
proteins	I-GENE
.	O

The	O
in	O
-	O
plane	O
orientational	O
anisotropy	O
of	O
the	O
8CB	O
films	O
grown	O
on	O
unidirectionally	O
photopolymerized	O
PVCN	O
substrates	O
is	O
considerably	O
lower	O
than	O
the	O
intrinsic	O
surface	O
orientational	O
anisotropy	O
of	O
these	O
substrates	O
,	O
which	O
can	O
explain	O
the	O
generally	O
found	O
weak	O
surface	O
anchoring	O
of	O
liquid	O
crystals	O
on	O
PVCN	O
alignment	O
layers	O
.	O

The	O
introduction	O
of	O
FWD1	B-GENE
into	O
cells	O
significantly	O
promotes	O
ubiquitination	O
and	O
degradation	O
of	O
IkappaBalpha	B-GENE
in	O
concert	O
with	O
IkappaB	B-GENE
kinases	I-GENE
,	O
resulting	O
in	O
nuclear	O
translocation	O
of	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
.	O

Since	O
blood	O
serotonin	O
is	O
primarily	O
produced	O
peripherally	O
,	O
these	O
results	O
suggest	O
that	O
some	O
aspect	O
of	O
peripheral	O
serotonin	O
metabolism	O
is	O
abnormal	O
in	O
major	O
depression	O
.	O

She	O
had	O
been	O
diagnosed	O
with	O
severe	O
aplastic	O
anemia	O
1	O
year	O
previously	O
and	O
,	O
while	O
hospitalized	O
,	O
had	O
received	O
methyl	O
prednisolone	O
pulse	O
therapy	O
,	O
which	O
was	O
not	O
successful	O
.	O

We	O
next	O
developed	O
a	O
rapid	O
purification	O
method	O
for	O
bacterial	B-GENE
recombinant	I-GENE
MyoD	I-GENE
-	I-GENE
bHLH	I-GENE
domain	I-GENE
by	O
affinity	O
chromatography	O
using	O
a	O
calmodulin	B-GENE
-	O
Sepharose	O
column	O
and	O
investigated	O
the	O
phosphorylation	O
of	O
that	O
peptide	O
by	O
PKC	B-GENE
and	O
its	O
interactions	O
with	O
calmodulin	B-GENE
and	O
S100a	B-GENE
.	O

The	O
22	O
-	O
d	O
orbital	O
flight	O
of	O
rats	O
onboard	O
the	O
Cosmos	O
-	O
605	O
biosatellite	O
was	O
followed	O
by	O
inhibition	O
of	O
erythroblastosis	O
,	O
alteration	O
in	O
the	O
morphology	O
of	O
megakaryocytes	O
,	O
and	O
stimulation	O
of	O
myelopoiesis	O
.	O

Partial	O
albinism	O
and	O
immunodeficiency	O
:	O
ultrastructural	O
study	O
of	O
haemophagocytosis	O
and	O
bone	O
marrow	O
erythroblasts	O
in	O
one	O
case	O
.	O

Optical	O
rotation	O
of	O
the	O
second	O
harmonic	O
radiation	O
from	O
retinal	O
in	O
bacteriorhodopsin	B-GENE
monomers	I-GENE
in	O
Langmuir	O
-	O
Blodgett	O
film	O
:	O
evidence	O
for	O
nonplanar	O
retinal	O
structure	O
.	O

RESULTS	O
:	O
Twenty	O
-	O
two	O
patients	O
(	O
30	O
%	O
)	O
showed	O
ST	O
-	O
segment	O
depression	O
during	O
AEM	O
and	O
34	O
(	O
49	O
%	O
)	O
on	O
ExT	O
.	O

Enhanced	O
quantum	O
correlations	O
in	O
bound	O
higher	O
-	O
order	O
solitons	O
Quantum	O
effects	O
in	O
N	O
-	O
bound	O
solitons	O
can	O
be	O
drastically	O
enhanced	O
compared	O
to	O
the	O
fundamental	O
soliton	O
.	O

Acute	O
intoxication	O
with	O
cypermethrin	O
(	O
NRDC	O
149	O
)	O
.	O

Anesthesia	O
in	O
the	O
radical	O
surgery	O
of	O
arteriosclerotic	O
coronary	O
disease	O

Whereas	O
the	O
sequence	O
of	O
alpha	B-GENE
-	I-GENE
actinin	I-GENE
(	O
Noegel	O
,	O
A	O
.	O
,	O
W	O
.	O

Overall	O
,	O
it	O
appears	O
that	O
prenatal	O
exposure	O
to	O
androgen	O
-	O
based	O
synthetic	O
progestin	O
exerted	O
a	O
masculinizing	O
and	O
/	O
or	O
defeminizing	O
influence	O
on	O
human	O
behavioral	O
development	O
,	O
whereas	O
prenatal	O
exposure	O
to	O
natural	O
progesterone	O
and	O
progesterone	O
-	O
based	O
synthetic	O
progestin	O
had	O
a	O
feminizing	O
and	O
/	O
or	O
demasculinizing	O
influence	O
,	O
particularly	O
among	O
female	O
subjects	O
.	O

CONCLUSION	O
:	O
In	O
an	O
acute	O
canine	O
model	O
of	O
progressive	O
LCX	O
coronary	O
stenosis	O
,	O
CFR	O
was	O
impaired	O
in	O
both	O
ischemic	O
and	O
remote	O
nonischemic	O
regions	O
in	O
association	O
with	O
mild	O
to	O
moderate	O
ischemic	O
-	O
induced	O
regional	O
myocardial	O
dysfunction	O
.	O

Parathyroid	B-GENE
hormone	I-GENE
responses	O
of	O
cyclic	O
AMP	O
-	O
,	O
serum	O
-	O
and	O
phorbol	O
ester	O
-	O
responsive	O
reporter	O
genes	O
in	O
osteoblast	O
-	O
like	O
UMR	O
-	O
106	O
cells	O
.	O

Genome	O
timeline	O
.	O

The	O
"	O
Ulm	O
Zucker	O
Uhr	O
System	O
"	O
comprises	O
a	O
microdialysis	O
probe	O
,	O
a	O
biosensor	O
(	O
Glucosensor	O
Unitec	O
Ulm	O
s	O
.	O
c	O
.	O
)	O
,	O
a	O
sender	O
transferring	O
telemetrically	O
the	O
glucose	O
concentrations	O
,	O
and	O
a	O
receiving	O
indicator	O
.	O

Previous	O
work	O
has	O
shown	O
that	O
glucose	O
repression	O
of	O
PRB1	B-GENE
transcription	O
is	O
not	O
mediated	O
by	O
HXK2	B-GENE
or	O
by	O
the	O
SNF1	B-GENE
,	O
SNF4	B-GENE
,	O
and	O
SNF6	B-GENE
genes	I-GENE
(	O
C	O
.	O

The	O
cumulative	O
experience	O
in	O
liver	O
transplantation	O
since	O
the	O
introduction	O
of	O
cyclosporine	O
A	O
has	O
confirmed	O
its	O
efficacy	O
in	O
the	O
treatment	O
of	O
diverse	O
liver	O
diseases	O
in	O
children	O
and	O
adults	O
.	O

Our	O
objective	O
was	O
to	O
find	O
possible	O
predictors	O
for	O
the	O
expression	O
and	O
progression	O
of	O
LJM	O
and	O
to	O
evaluate	O
the	O
relationship	O
between	O
LJM	O
and	O
other	O
long	O
-	O
term	O
complications	O
of	O
insulin	B-GENE
-	O
dependent	O
diabetes	O
mellitus	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
we	O
developed	O
a	O
system	O
of	O
transient	O
transfection	O
of	O
rat	O
adipocytes	O
with	O
constructs	O
containing	O
glyceraldehyde	B-GENE
-	I-GENE
3	I-GENE
-	I-GENE
phosphate	I-GENE
dehydrogenase	I-GENE
(	O
GAPDH	B-GENE
)	O
and	O
fatty	B-GENE
acid	I-GENE
synthetase	I-GENE
(	O
FAS	B-GENE
)	O
promoters	O
fused	O
to	O
gene	B-GENE
reporter	I-GENE
CAT	I-GENE
.	O

Comparison	O
of	O
this	O
gene	O
with	O
the	O
available	O
databases	O
reveals	O
very	O
significant	O
homology	O
to	O
the	O
ETS	B-GENE
factor	I-GENE
PE	B-GENE
-	I-GENE
1	I-GENE
and	O
probable	O
near	O
-	O
identity	O
with	O
the	O
recently	O
cloned	O
factor	O
ERF	B-GENE
.	O

Eight	O
of	O
these	O
suppressors	O
for	O
into	O
two	O
complementation	O
groups	O
,	O
designated	O
KCS1	B-GENE
and	O
KCS2	B-GENE
.	O

Also	O
,	O
the	O
absence	O
of	O
PdNi	O
between	O
the	O
segments	O
reduces	O
the	O
heat	O
production	O
of	O
the	O
seed	O
.	O

Further	O
analysis	O
of	O
the	O
CAP59	B-GENE
locus	I-GENE
of	I-GENE
Cryptococcus	I-GENE
neoformans	I-GENE
:	O
structure	O
defined	O
by	O
forced	O
expression	O
and	O
description	O
of	O
a	O
new	O
ribosomal	B-GENE
protein	I-GENE
-	I-GENE
encoding	I-GENE
gene	I-GENE
.	O

The	O
results	O
showed	O
a	O
significant	O
group	O
effect	O
only	O
on	O
the	O
active	O
task	O
.	O

Localization	O
of	O
the	O
porcine	O
enzyme	O
in	O
the	O
endoplasmic	O
reticulum	O
is	O
consistent	O
with	O
immuno	O
-	O
electron	O
-	O
microscopic	O
studies	O
using	O
pig	O
hepatocytes	O
.	O

These	O
larger	O
sizes	O
,	O
however	O
,	O
are	O
consistent	O
with	O
predictions	O
from	O
the	O
DNA	O
sequence	O
of	O
the	O
pol	B-GENE
gene	I-GENE
.	O

More	O
important	O
,	O
ligand	O
-	O
activated	O
insulin	B-GENE
and	O
IGF	B-GENE
-	I-GENE
I	I-GENE
receptors	I-GENE
phosphorylate	O
SHC	B-GENE
proteins	I-GENE
in	O
vitro	O
,	O
indicating	O
that	O
SHC	B-GENE
proteins	I-GENE
could	O
be	O
direct	O
substrates	O
for	O
insulin	B-GENE
and	O
IGF	B-GENE
-	I-GENE
I	I-GENE
receptors	I-GENE
.	O

International	O
efforts	O
are	O
now	O
being	O
made	O
to	O
standardize	O
haemolytic	O
test	O
conditions	O
and	O
the	O
present	O
study	O
is	O
meant	O
as	O
a	O
contribution	O
to	O
this	O
.	O

The	O
DFA	O
slide	O
prepared	O
from	O
the	O
ThinPrep	O
Test	O
and	O
the	O
conventional	O
DFA	O
sample	O
prepared	O
from	O
the	O
endocervical	O
swab	O
were	O
evaluated	O
independently	O
.	O

We	O
suggest	O
that	O
the	O
responses	O
to	O
types	B-GENE
I	I-GENE
and	I-GENE
II	I-GENE
collagen	I-GENE
were	O
caused	O
by	O
a	O
cross	O
-	O
reaction	O
with	O
type	B-GENE
III	I-GENE
collagen	I-GENE
peptides	O
.	O

The	O
nucleotide	O
sequence	O
of	O
the	O
estrogen	B-GENE
receptor	I-GENE
gene	I-GENE
of	I-GENE
Oreochromis	I-GENE
aureus	I-GENE
(	O
OaER	B-GENE
)	O
indicates	O
that	O
the	O
hormone	O
-	O
binding	O
E	O
domain	O
is	O
composed	O
of	O
4	O
exons	O
interspersed	O
by	O
short	O
introns	O
of	O
only	O
0	O
.	O
18	O
-	O
1	O
.	O
3	O
kb	O
each	O
.	O

To	O
test	O
for	O
progesterone	B-GENE
receptor	I-GENE
-	O
mediated	O
activation	O
of	O
transcription	O
in	O
yeast	O
,	O
reporter	O
plasmids	O
were	O
constructed	O
to	O
transform	O
yeast	O
cells	O
expressing	O
PRB	B-GENE
or	O
C1C2	B-GENE
receptors	I-GENE
.	O

Beyond	O
the	O
first	O
year	O
post	O
-	O
renal	O
transplantation	O
there	O
was	O
no	O
difference	O
in	O
C	O
(	O
IO	O
)	O
between	O
LRD	O
and	O
CAD	O
allografts	O
.	O

TAF	B-GENE
-	I-GENE
1	I-GENE
activates	O
transcription	O
constitutively	O
and	O
was	O
mapped	O
to	O
the	O
first	O
32	O
amino	O
acids	O
of	O
the	O
A	O
-	O
region	O
.	O

The	O
ventricular	O
demand	O
pacemaker	O
(	O
VVI	O
)	O
was	O
implanted	O
three	O
years	O
ago	O
and	O
because	O
of	O
further	O
impairment	O
of	O
cardiac	O
performance	O
an	O
av	O
-	O
sequential	O
pacemaker	O
(	O
DDD	O
)	O
was	O
used	O
to	O
restore	O
atrio	O
-	O
ventricular	O
synchronisation	O
.	O

In	O
the	O
present	O
study	O
we	O
found	O
that	O
CD34	B-GENE
downregulation	O
during	O
hematopoiesis	O
occured	O
at	O
the	O
level	O
of	O
transcriptional	O
initiation	O
.	O

Following	O
replicate	O
control	O
measurements	O
,	O
test	O
ramps	O
were	O
repeated	O
in	O
the	O
presence	O
of	O
sodium	O
nitroprusside	O
(	O
1	O
microM	O
)	O
and	O
phentolamine	O
(	O
1	O
microM	O
)	O
to	O
eliminate	O
potential	O
smooth	O
muscle	O
and	O
alpha	B-GENE
1	I-GENE
-	I-GENE
adrenoceptor	I-GENE
effects	O
,	O
respectively	O
.	O

Individual	O
and	O
combined	O
effects	O
of	O
fumonisin	B-GENE
B1	I-GENE
present	O
in	O
Fusarium	O
moniliforme	O
culture	O
material	O
and	O
diacetoxyscirpenol	O
or	O
ochratoxin	O
A	O
in	O
turkey	O
poults	O
.	O

This	O
C	O
-	O
terminal	O
domain	O
contains	O
several	O
YxxI	O
/	O
L	O
motifs	O
reminiscent	O
of	O
LMP2A	B-GENE
and	O
a	O
putative	O
TRAF	B-GENE
binding	I-GENE
site	I-GENE
as	O
in	O
LMP1	B-GENE
.	O

Possibilities	O
and	O
limints	O
of	O
immunofluorescence	O
in	O
the	O
laboratory	O
diagnosis	O
of	O
rabies	O

The	O
4	O
-	O
nt	O
sequence	O
of	O
the	O
rotavirus	O
3	O
'	O
TE	O
represents	O
by	O
far	O
the	O
shortest	O
of	O
any	O
of	O
the	O
sequence	O
enhancers	O
known	O
to	O
stimulate	O
translation	O
.	O

Muscle	O
and	O
liver	O
biopsies	O
demonstrated	O
the	O
same	O
anomalies	O
,	O
again	O
without	O
branching	B-GENE
enzyme	I-GENE
deficiency	O
in	O
the	O
liver	O
.	O

The	O
1031	B-GENE
-	I-GENE
bp	I-GENE
wild	I-GENE
-	I-GENE
type	I-GENE
HIT1	I-GENE
DNA	I-GENE
which	O
contained	O
an	O
open	O
reading	O
frame	O
encoding	O
a	O
protein	O
of	O
164	O
amino	O
acids	O
and	O
the	O
AGG	B-GENE
arginine	I-GENE
tRNA	I-GENE
gene	I-GENE
complemented	O
all	O
hit1	B-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
phenotypes	I-GENE
,	O
indicating	O
that	O
the	O
mutant	O
phenotypes	O
were	O
caused	O
by	O
the	O
deletion	O
of	O
these	O
genes	O
.	O

The	O
chicken	O
genome	O
contains	O
two	O
functional	O
nonallelic	O
beta1	B-GENE
,	I-GENE
4	I-GENE
-	I-GENE
galactosyltransferase	I-GENE
genes	I-GENE
.	O

Human	B-GENE
CR2	I-GENE
has	O
a	O
restricted	O
cellular	O
distribution	O
,	O
being	O
expressed	O
on	O
B	O
lymphocytes	O
,	O
dendritic	O
cells	O
of	O
the	O
spleen	O
,	O
pharyngeal	O
epithelial	O
cells	O
,	O
and	O
at	O
low	O
levels	O
on	O
some	O
T	O
lymphocytes	O
.	O

Heterotrimeric	O
guanine	B-GENE
nucleotide	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
(	O
G	B-GENE
-	I-GENE
proteins	I-GENE
)	O
function	O
as	O
signal	O
transducers	O
for	O
a	O
variety	O
of	O
hormone	O
-	O
coupled	O
enzyme	O
and	O
ion	O
transport	O
systems	O
in	O
eukaryotic	O
cells	O
.	O

The	O
enzyme	B-GENE
ACC	I-GENE
oxidase	I-GENE
catalyses	O
the	O
last	O
step	O
of	O
ethylene	O
biosynthesis	O
in	O
plants	O
,	O
converting	O
1	O
-	O
aminocyclopropane	O
-	O
1	O
-	O
carboxylic	O
acid	O
(	O
ACC	O
)	O
to	O
ethylene	O
.	O

Virol	O
.	O

Mibefradil	O
(	O
Ro	O
40	O
-	O
5967	O
)	O
is	O
a	O
novel	O
nondihydropyridine	O
calcium	O
antagonist	O
.	O

We	O
have	O
used	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
reporter	O
gene	O
system	O
to	O
study	O
the	O
effect	O
of	O
T	B-GENE
on	O
the	O
long	O
terminal	O
repeats	O
(	O
LTRs	O
)	O
of	O
a	O
large	O
family	O
of	O
human	O
endogenous	O
retrovirus	O
-	O
like	O
sequences	O
,	O
RTVL	O
-	O
H	O
.	O

They	O
contain	O
a	O
large	O
(	O
0	O
.	O
9	O
X	O
10	O
(	O
3	O
)	O
to	O
1	O
.	O
88	O
X	O
10	O
(	O
3	O
)	O
base	O
-	O
pairs	O
)	O
intron	O
in	O
the	O
middle	O
of	O
the	O
gene	O
and	O
are	O
further	O
interrupted	O
close	O
to	O
the	O
5	O
'	O
end	O
of	O
the	O
gene	O
.	O

The	O
recombinant	O
containing	O
the	O
full	O
-	O
length	O
polyhedrin	B-GENE
leader	O
sequence	O
gave	O
levels	O
of	O
N	B-GENE
mRNA	I-GENE
comparable	O
to	O
those	O
of	O
AcNPV	B-GENE
polyhedrin	I-GENE
mRNA	I-GENE
.	O

Long	O
-	O
term	O
results	O
and	O
curative	O
mechanisms	O
of	O
vesicoureteral	O
reflux	O
by	O
endoscopic	O
injection	O
of	O
blood	O
.	O

Primer	O
extension	O
experiments	O
using	O
dbcAMP	O
-	O
differentiated	O
U937	O
RNA	O
indicated	O
a	O
single	O
transcriptional	O
initiation	O
site	O
.	O

Sequences	O
within	O
and	O
flanking	O
hypersensitive	O
sites	O
3	O
and	O
2	O
of	O
the	O
beta	B-GENE
-	I-GENE
globin	I-GENE
locus	O
control	O
region	O
required	O
for	O
synergistic	O
versus	O
additive	O
interaction	O
with	O
the	O
epsilon	B-GENE
-	I-GENE
globin	I-GENE
gene	I-GENE
promoter	I-GENE
.	O

Four	O
of	O
12	O
patients	O
(	O
33	O
%	O
)	O
were	O
initially	O
diagnosed	O
as	O
having	O
a	O
benign	O
disease	O
(	O
false	O
-	O
negatives	O
)	O
.	O

The	O
mean	O
was	O
66	O
cells	O
/	O
mm2	O
in	O
the	O
laser	O
group	O
and	O
63	O
.	O
7	O
cells	O
/	O
mm2	O
in	O
the	O
control	O
group	O
.	O

Using	O
reporter	O
gene	O
constructs	O
driven	O
by	O
the	O
CD4	B-GENE
promoter	I-GENE
,	O
we	O
report	O
that	O
HHV	O
-	O
6	O
can	O
efficiently	O
transactivate	O
such	O
genetic	O
elements	O
.	O

Through	O
genomic	O
library	O
screening	O
and	O
PCR	O
-	O
based	O
genomic	O
walking	O
we	O
have	O
now	O
cloned	O
the	O
mouse	B-GENE
E	I-GENE
-	I-GENE
Tmod	I-GENE
gene	I-GENE
,	O
whose	O
coding	O
region	O
spans	O
approximately	O
60kb	O
containing	O
nine	O
exons	O
and	O
eight	O
introns	O
.	O

On	O
a	O
variety	O
of	O
fronts	O
,	O
chronic	O
bacterial	O
infection	O
is	O
being	O
found	O
to	O
be	O
significantly	O
associated	O
with	O
the	O
development	O
of	O
atherosclerosis	O
and	O
the	O
clinical	O
complications	O
of	O
unstable	O
angina	O
,	O
myocardial	O
infarction	O
,	O
and	O
stroke	O
.	O

Cost	O
analysis	O
and	O
the	O
HSA	O
:	O
a	O
framework	O
.	O

Removal	O
of	O
ink4a	B-GENE
dramatically	O
reduces	O
the	O
lymphoid	O
and	O
neurological	O
defects	O
seen	O
in	O
bmi	B-GENE
-	I-GENE
1	I-GENE
-	O
deficient	O
mice	O
,	O
indicating	O
that	O
ink4a	B-GENE
is	O
a	O
critical	O
in	O
vivo	O
target	O
for	O
Bmi	B-GENE
-	I-GENE
1	I-GENE
.	O

In	O
fifty	O
non	O
selected	O
ductal	O
carcinomas	O
of	O
the	O
breast	O
we	O
found	O
that	O
a	O
marked	O
tumoral	O
inflammatory	O
infiltrate	O
(	O
P	O
less	O
than	O
0	O
.	O
025	O
)	O
,	O
perinodal	O
tumoral	O
infiltrate	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
sinus	O
catarrh	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
follicular	O
hyperplasia	O
(	O
P	O
less	O
than	O
0	O
.	O
025	O
)	O
,	O
mixed	O
pattern	O
in	O
lymph	O
nodes	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
and	O
with	O
54	O
years	O
of	O
age	O
or	O
younger	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
correlated	O
significantly	O
with	O
lymph	O
node	O
metastases	O
and	O
/	O
or	O
high	O
histologic	O
grade	O
.	O

The	O
herpesvirus	B-GENE
entry	I-GENE
mediator	I-GENE
C	I-GENE
(	O
HveC	B-GENE
)	O
,	O
previously	O
known	O
as	O
poliovirus	B-GENE
receptor	I-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
1	I-GENE
(	O
PRR1	B-GENE
)	O
,	O
and	O
the	O
herpesvirus	B-GENE
Ig	I-GENE
-	I-GENE
like	I-GENE
receptor	I-GENE
(	O
HIgR	B-GENE
)	O
are	O
the	O
bona	O
fide	O
receptors	O
employed	O
by	O
herpes	O
simplex	O
virus	O
-	O
1	O
and	O
-	O
2	O
(	O
HSV	O
-	O
1	O
and	O
-	O
2	O
)	O
for	O
entry	O
into	O
the	O
human	O
cell	O
lines	O
most	O
frequently	O
used	O
in	O
HSV	O
studies	O
.	O

Spinal	O
injuries	O
in	O
a	O
multiple	O
trauma	O
patient	O
.	O

Creatinine	O
and	O
creatine	B-GENE
phosphokinase	I-GENE
(	O
CPK	B-GENE
)	O
.	O

The	O
glyoxysomal	O
and	O
plastid	O
molecular	O
chaperones	O
(	O
70	B-GENE
-	I-GENE
kDa	I-GENE
heat	I-GENE
shock	I-GENE
protein	I-GENE
)	O
of	O
watermelon	O
cotyledons	O
are	O
encoded	O
by	O
a	O
single	O
gene	O
.	O

Thus	O
,	O
cross	O
-	O
resistance	O
between	O
fluoroquinolones	O
was	O
shown	O
for	O
both	O
enterococci	O
and	O
MRSA	O
.	O

Furthermore	O
we	O
elucidate	O
the	O
subtle	O
highly	O
anisotropic	O
interchain	O
correlations	O
and	O
reveal	O
the	O
detailed	O
atomic	O
structure	O
of	O
the	O
low	O
-	O
temperature	O
(	O
8x2	O
)	O
phase	O
.	O

025	O
)	O
.	O

With	O
stimulation	O
beyond	O
the	O
theta	O
-	O
range	O
three	O
phenomena	O
occurred	O
:	O
shift	O
of	O
the	O
burst	O
frequencies	O
to	O
higher	O
or	O
lower	O
harmonics	O
of	O
stimulation	O
frequencies	O
;	O
complex	O
interactions	O
of	O
basic	O
background	O
frequency	O
with	O
rhythm	O
of	O
stimulation	O
(	O
"	O
beating	O
"	O
)	O
;	O
return	O
to	O
background	O
theta	O
-	O
burst	O
frequency	O
in	O
spite	O
of	O
continuing	O
stimulation	O
(	O
"	O
escape	O
"	O
)	O
.	O

Incorporation	O
of	O
this	O
information	O
in	O
the	O
data	O
brought	O
about	O
a	O
revised	O
five	O
-	O
year	O
survival	O
estimate	O
of	O
55	O
percent	O
.	O

Using	O
a	O
dominant	O
negative	O
form	O
of	O
Sp3	B-GENE
and	O
transcriptional	O
activation	O
assays	O
in	O
Schneider	O
SL	O
-	O
2	O
insect	O
cells	O
,	O
it	O
was	O
confirmed	O
that	O
ERalpha	B-GENE
-	O
Sp3	B-GENE
interactions	O
define	O
a	O
pathway	O
for	O
E2	B-GENE
-	O
mediated	O
inhibition	O
of	O
gene	O
expression	O
,	O
and	O
this	O
represents	O
a	O
new	O
mechanism	O
for	O
decreased	O
gene	O
expression	O
by	O
E2	B-GENE
.	O

While	O
these	O
could	O
be	O
unusual	O
cases	O
of	O
chronic	O
non	O
-	O
A	O
,	O
non	O
-	O
B	O
hepatitis	O
,	O
this	O
can	O
be	O
only	O
speculation	O
until	O
a	O
serologic	O
test	O
for	O
non	O
-	O
A	O
,	O
non	O
-	O
B	O
hepatitis	O
becomes	O
available	O
.	O

Our	O
previous	O
studies	O
demonstrated	O
that	O
the	O
promyelocytic	O
leukemia	O
gene	O
,	O
PML	B-GENE
which	O
involved	O
in	O
the	O
15	O
;	O
17	O
translocation	O
in	O
acute	O
promyelocytic	O
leukemia	O
(	O
APL	O
)	O
is	O
a	O
growth	O
and	O
transformation	O
suppressor	O
.	O

These	O
characteristics	O
add	O
to	O
the	O
suitability	O
of	O
NM441	O
as	O
an	O
effective	O
prodrug	O
of	O
NM394	O
.	O

Sequence	O
analysis	O
of	O
cDNA	O
clones	O
encoding	O
human	O
gamma	O
revealed	O
an	O
open	O
reading	O
frame	O
predicting	O
a	O
protein	O
of	O
299	O
amino	O
acids	O
(	O
approximately	O
32	O
kDa	O
)	O
,	O
half	O
the	O
size	O
of	O
the	O
bovine	O
gamma	O
subunit	O
.	O

DISCUSSION	O
:	O
The	O
higher	O
absolute	O
knee	O
extension	O
strength	O
measures	O
of	O
leg	O
and	O
the	O
similar	O
extension	O
strength	O
of	O
the	O
trunk	O
in	O
the	O
obese	O
sample	O
compared	O
to	O
the	O
lean	O
might	O
be	O
explained	O
by	O
the	O
training	O
effect	O
of	O
weight	O
bearing	O
and	O
support	O
of	O
a	O
larger	O
body	O
mass	O
.	O

Measuring	O
the	O
dim	O
light	O
melatonin	O
onset	O
(	O
DLMO	O
)	O
is	O
a	O
useful	O
and	O
practical	O
way	O
to	O
assess	O
circadian	O
phase	O
position	O
in	O
humans	O
.	O

Although	O
the	O
energy	O
-	O
based	O
DFT	O
was	O
not	O
affected	O
by	O
isoproterenol	O
(	O
from	O
6	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
5	O
to	O
6	O
.	O
0	O
+	O
/	O
-	O
1	O
.	O
7	O
J	O
)	O
,	O
it	O
was	O
decreased	O
to	O
3	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
6	O
J	O
in	O
the	O
third	O
stage	O
by	O
infusion	O
of	O
E4031	O
and	O
isoproterenol	O
(	O
p	O
<	O
0	O
.	O
01	O
vs	O
.	O
baseline	O
and	O
vs	O
.	O
isoproterenol	O
)	O
.	O

This	O
communication	O
presents	O
two	O
patients	O
with	O
clinically	O
massive	O
PE	O
of	O
recent	O
onset	O
(	O
confirmed	O
by	O
lung	O
perfusion	O
scans	O
)	O
who	O
were	O
successfully	O
treated	O
with	O
a	O
single	O
i	O
.	O
v	O
.	O
dose	O
of	O
30	O
mg	O
of	O
anisoylated	B-GENE
lys	I-GENE
-	I-GENE
plasminogen	I-GENE
streptokinase	I-GENE
activator	I-GENE
complex	I-GENE
(	O
APSAC	B-GENE
,	O
comparable	O
to	O
1	O
,	O
500	O
,	O
000	O
U	O
of	O
streptokinase	B-GENE
)	O
followed	O
by	O
systemic	O
heparinization	O
for	O
7	O
days	O
.	O

Capillary	O
tortuosity	O
was	O
a	O
function	O
of	O
sarcomere	O
length	O
in	O
all	O
animals	O
and	O
this	O
relationship	O
was	O
not	O
changed	O
by	O
hypoxia	O
.	O

A	O
survey	O
of	O
children	O
with	O
HBsAg	B-GENE
markers	I-GENE
related	O
to	O
their	O
parents	O
HBV	O
markers	O
.	O

In	O
cases	O
of	O
intracapsular	O
prostatic	O
cancer	O
the	O
level	O
of	O
prostatic	B-GENE
acid	I-GENE
phosphatase	I-GENE
(	O
PAP	B-GENE
)	O
measured	O
by	O
radioimmunoassay	O
was	O
1	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
8	O
micrograms	O
/	O
l	O
.	O

Rv	O
was	O
7	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
4	O
mmHg	O
.	O
ml	O
-	O
1	O
.	O
min	O
.	O
100	O
g	O
-	O
1	O
and	O
Cv	O
was	O
0	O
.	O
59	O
+	O
/	O
-	O
0	O
.	O
25	O
ml	O
/	O
mmHg	O
,	O
tau	O
v	O
calculated	O
from	O
the	O
product	O
of	O
Rv	O
and	O
Cv	O
was	O
4	O
.	O
20	O
+	O
/	O
-	O
1	O
.	O
58	O
s	O
and	O
from	O
the	O
ratio	O
of	O
delta	O
V	O
to	O
delta	O
Q	O
was	O
4	O
.	O
95	O
+	O
/	O
-	O
1	O
.	O
53	O
s	O
(	O
P	O
=	O
NS	O
)	O
at	O
a	O
mean	O
Pel	O
of	O
17	O
.	O
6	O
+	O
/	O
-	O
3	O
.	O
7	O
mmHg	O
.	O
delta	O
V	O
was	O
also	O
produced	O
by	O
changing	O
Pv	O
;	O
the	O
average	O
tau	O
v	O
(	O
1	O
.	O
95	O
+	O
/	O
-	O
0	O
.	O
37	O
s	O
)	O
,	O
was	O
shorter	O
than	O
that	O
with	O
changes	O
in	O
flow	O
.	O

Peripheral	O
neuropathy	O
in	O
the	O
cherry	O
-	O
red	O
spot	O
-	O
myoclonus	O
syndrome	O
(	O
sialidosis	O
type	O
I	O
)	O
.	O

The	O
meaning	O
of	O
hope	O
in	O
health	O
and	O
illness	O
.	O

For	O
O3	O
,	O
the	O
correlation	O
between	O
personal	O
exposures	O
and	O
ambient	O
levels	O
was	O
weakest	O
in	O
the	O
winter	O
for	O
residential	O
microenvironments	O
(	O
rs	O
=	O
0	O
.	O
05	O
,	O
p	O
>	O
0	O
.	O
05	O
)	O
,	O
and	O
was	O
strongest	O
in	O
the	O
summer	O
for	O
outdoor	O
near	O
-	O
roadway	O
microenvironments	O
(	O
rs	O
=	O
0	O
.	O
91	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
myb	B-GENE
proto	I-GENE
oncogene	I-GENE
product	I-GENE
(	O
c	B-GENE
-	I-GENE
Myb	I-GENE
)	O
is	O
a	O
transcriptional	O
regulator	O
and	O
its	O
expression	O
and	O
function	O
are	O
tightly	O
linked	O
to	O
the	O
cellular	O
entry	O
into	O
S	O
phase	O
and	O
DNA	O
synthesis	O
.	O

However	O
,	O
and	O
in	O
contrast	O
to	O
other	O
MMP	B-GENE
genes	I-GENE
,	O
no	O
significative	O
synergistic	O
effect	O
on	O
CAT	B-GENE
activity	O
between	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
and	O
PEA	B-GENE
-	I-GENE
3	I-GENE
elements	I-GENE
found	O
in	O
the	O
collagenase	B-GENE
-	I-GENE
3	I-GENE
gene	I-GENE
promoter	I-GENE
was	O
found	O
.	O

CONCLUSIONS	O
:	O
The	O
number	O
of	O
Spanish	O
articles	O
published	O
in	O
Anesthesiology	O
,	O
BJA	O
,	O
and	O
Anesth	O
Analg	O
is	O
low	O
,	O
although	O
the	O
comparison	O
of	O
our	O
productivity	O
with	O
that	O
of	O
other	O
EU	O
countries	O
in	O
function	O
of	O
GNPpc	O
places	O
us	O
in	O
an	O
intermediate	O
position	O
.	O

This	O
fragment	O
contains	O
two	O
complete	O
endo	B-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
1	I-GENE
,	I-GENE
4	I-GENE
-	I-GENE
glucanase	I-GENE
-	I-GENE
encoding	I-GENE
genes	I-GENE
,	O
designated	O
celCCC	B-GENE
and	O
celCCG	B-GENE
.	O

The	O
"	O
Gregg	O
phenomenon	O
"	O
implies	O
that	O
myocardial	O
function	O
and	O
oxygen	O
consumption	O
(	O
MVO2	O
)	O
increase	O
when	O
coronary	O
perfusion	O
is	O
enhanced	O
within	O
or	O
above	O
the	O
autoregulatory	O
range	O
.	O

Pollinosis	O
in	O
the	O
U	O
.	O
A	O
.	O
R	O
.	O

The	O
use	O
of	O
sigma	B-GENE
54	I-GENE
promoters	I-GENE
,	O
known	O
to	O
require	O
cognate	O
binding	O
proteins	O
,	O
could	O
allow	O
the	O
fine	O
-	O
tuning	O
that	O
provides	O
the	O
temporal	O
ordering	O
of	O
flagellar	O
gene	O
transcription	O
.	O

Over	O
a	O
period	O
of	O
five	O
training	O
sessions	O
(	O
2	O
.	O
5	O
days	O
)	O
,	O
the	O
animals	O
learned	O
not	O
to	O
breathe	O
,	O
and	O
the	O
number	O
of	O
stimuli	O
received	O
in	O
the	O
fifth	O
session	O
was	O
significantly	O
lower	O
than	O
in	O
the	O
first	O
session	O
.	O

The	O
genes	O
on	O
each	O
chromosome	O
involved	O
in	O
this	O
translocation	O
have	O
been	O
identified	O
as	O
the	O
transcription	O
factor	O
-	O
encoding	O
genes	O
PAX3	B-GENE
and	O
FKHR	B-GENE
.	O

We	O
found	O
that	O
the	O
PRP20	B-GENE
gene	I-GENE
is	O
identical	O
to	O
the	O
yeast	B-GENE
SRM1	I-GENE
gene	I-GENE
(	O
Clark	O
and	O
Sprague	O
1989	O
)	O
.	O

Transcriptional	O
activation	O
of	O
the	O
proopiomelanocortin	B-GENE
gene	I-GENE
by	O
cyclic	B-GENE
AMP	I-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
binding	I-GENE
protein	I-GENE
.	O

Recombinant	B-GENE
Human	I-GENE
Erythropoietin	I-GENE
and	O
Platinum	O
-	O
Based	O
Chemotherapy	O
In	O
Advanced	O
Ovarian	O
Cancer	O

After	O
discharge	O
,	O
he	O
was	O
finally	O
given	O
a	O
diagnosis	O
of	O
PCH	O
because	O
a	O
Donath	O
-	O
Landsteiner	O
test	O
was	O
positive	O
.	O

Human	O
forearm	O
was	O
used	O
as	O
a	O
dummy	O
ear	O
and	O
the	O
electrode	O
HN	O
-	O
5	O
was	O
fixed	O
thereon	O
,	O
and	O
a	O
sound	O
stimulus	O
of	O
90dBnHL	O
was	O
delivered	O
by	O
the	O
earphone	O
(	O
NC	O
-	O
3	O
)	O
.	O

Neonatal	O
hyperthyroidism	O

We	O
found	O
that	O
the	O
frequency	O
spectrum	O
of	O
physiologic	O
chest	O
sounds	O
is	O
contained	O
entirely	O
within	O
that	O
of	O
jet	O
rotocraft	O
noise	O
.	O

However	O
,	O
their	O
stability	O
was	O
low	O
as	O
already	O
reported	O
for	O
the	O
ARS	O
in	O
S	O
.	O
occidentalis	O
.	O

When	O
gene	O
conversion	O
is	O
initiated	O
by	O
a	O
double	O
-	O
strand	O
break	O
(	O
DSB	O
)	O
,	O
any	O
nonhomologous	O
DNA	O
that	O
may	O
be	O
present	O
at	O
the	O
ends	O
must	O
be	O
removed	O
before	O
new	O
DNA	O
synthesis	O
can	O
be	O
initiated	O
.	O

MRI	O
visualization	O
of	O
proteoglycan	O
depletion	O
in	O
articular	O
cartilage	O
via	O
intravenous	O
administration	O
of	O
Gd	O
-	O
DTPA	O
.	O

Furthermore	O
,	O
the	O
GC	O
-	O
rich	O
sequences	O
could	O
confer	O
Sp1	B-GENE
-	O
dependent	O
transactivation	O
to	O
a	O
heterologous	O
prolactin	B-GENE
minimal	I-GENE
promoter	I-GENE
.	O

Neuronal	O
activity	O
of	O
58	O
dopaminergic	O
(	O
DA	O
)	O
and	O
200	O
non	O
-	O
dopaminergic	O
(	O
non	O
-	O
DA	O
)	O
neurons	O
in	O
the	O
ventral	O
tegmental	O
area	O
(	O
VTA	O
)	O
of	O
female	O
monkeys	O
was	O
recorded	O
,	O
and	O
correlation	O
to	O
bar	O
press	O
feeding	O
,	O
sensory	O
stimulation	O
and	O
change	O
in	O
motivation	O
was	O
investigated	O
.	O

Serum	O
prolactin	B-GENE
rapidly	O
decreased	O
after	O
institution	O
of	O
treatment	O
,	O
with	O
actual	O
normalization	O
(	O
less	O
than	O
20	O
ng	O
/	O
ml	O
)	O
by	O
the	O
3rd	O
month	O
.	O

It	O
is	O
required	O
for	O
correct	O
expression	O
of	O
both	O
genes	O
.	O

Cloning	O
the	O
cDNA	O
for	O
a	O
new	O
human	B-GENE
zinc	I-GENE
finger	I-GENE
protein	I-GENE
defines	O
a	O
group	O
of	O
closely	O
related	O
Kruppel	B-GENE
-	I-GENE
like	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

Recently	O
,	O
we	O
and	O
other	O
laboratories	O
have	O
identified	O
a	O
family	O
of	O
caveolin	B-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
;	O
caveolin	B-GENE
has	O
been	O
re	O
-	O
termed	O
caveolin	B-GENE
-	I-GENE
1	I-GENE
.	O

Six	O
cDNAs	O
represent	O
human	O
homologs	O
of	O
genes	O
known	O
in	O
other	O
species	O
,	O
namely	O
,	O
mouse	B-GENE
HSPE71	I-GENE
,	O
Rat	B-GENE
RhoGAP	I-GENE
protein	I-GENE
,	O
S	B-GENE
cerevisiae	I-GENE
leucyl	I-GENE
tRNA	I-GENE
synthetase	I-GENE
and	O
S	B-GENE
cerevisiae	I-GENE
chromosome	I-GENE
II	I-GENE
ORF	I-GENE
YBLO44W	I-GENE
.	O

Three	O
high	O
-	O
amylose	O
rice	O
varieties	O
,	O
IR42	O
,	O
IR36	O
,	O
and	O
IR62	O
,	O
with	O
similar	O
chemical	O
composition	O
including	O
amylose	O
content	O
(	O
26	O
.	O
7	O
-	O
27	O
.	O
0	O
%	O
)	O
,	O
were	O
cooked	O
under	O
the	O
same	O
conditions	O
and	O
tested	O
for	O
in	O
vitro	O
digestibility	O
as	O
well	O
as	O
blood	O
glucose	O
and	O
insulin	B-GENE
responses	O
in	O
healthy	O
human	O
volunteers	O
.	O

The	O
hepatic	O
isoform	O
of	O
6	B-GENE
-	I-GENE
phosphofructo	I-GENE
-	I-GENE
2	I-GENE
-	I-GENE
kinase	I-GENE
/	O
fructose	B-GENE
-	I-GENE
2	I-GENE
,	I-GENE
6	I-GENE
-	I-GENE
bisphosphatase	I-GENE
(	O
PF2K	B-GENE
/	O
Fru	B-GENE
-	I-GENE
2	I-GENE
,	I-GENE
6	I-GENE
-	I-GENE
BPase	I-GENE
)	O
is	O
transcriptionally	O
stimulated	O
by	O
glucocorticoids	O
,	O
whereas	O
insulin	B-GENE
blocks	O
this	O
stimulatory	O
effect	O
.	O

I	O
.	O

Such	O
simple	O
injuries	O
may	O
however	O
be	O
accompanied	O
by	O
far	O
reaching	O
consequences	O
.	O

The	O
132	B-GENE
-	I-GENE
bp	I-GENE
PHO8p	I-GENE
fragment	I-GENE
,	O
connected	O
at	O
position	O
-	O
281	O
of	O
the	O
5	O
'	O
upstream	O
region	O
of	O
a	O
HIS5	B-GENE
'	I-GENE
-	O
'	B-GENE
lacZ	I-GENE
fused	O
gene	O
,	O
could	O
sense	O
Pi	O
signals	O
in	O
vivo	O
,	O
but	O
a	O
20	O
-	O
bp	O
synthetic	O
oligonucleotide	O
having	O
the	O
same	O
sequence	O
from	O
-	O
544	O
to	O
-	O
525	O
of	O
the	O
PHO8p	B-GENE
DNA	I-GENE
could	O
not	O
.	O

Antibiotic	O
prophylaxis	O
in	O
a	O
surgical	O
setting	O

In	O
resume	O
response	O
to	O
treatment	O
with	O
usual	O
regimens	O
,	O
doxycycline	O
plus	O
streptomycin	O
of	O
doxycycline	O
rifampicin	O
is	O
good	O
,	O
being	O
however	O
time	O
elapsed	O
until	O
pain	O
ceases	O
of	O
mean	O
length	O
in	O
hospital	O
stay	O
shorter	O
in	O
the	O
group	O
receiving	O
doxycycline	O
plus	O
streptomycin	O
.	O

This	O
indicates	O
changes	O
in	O
postvaccination	O
allergy	O
to	O
BCG	O
.	O

Having	O
demonstrated	O
proper	O
localization	O
of	O
GFP	B-GENE
-	O
calmodulin	B-GENE
in	O
budding	O
yeast	O
,	O
we	O
examined	O
the	O
localization	O
of	O
a	O
fusion	O
between	O
GFP	B-GENE
and	O
calmodulin	B-GENE
(	O
GFP	B-GENE
-	I-GENE
Camlp	I-GENE
)	O
in	O
fission	O
yeast	O
,	O
where	O
calmodulin	B-GENE
had	O
not	O
been	O
localized	O
by	O
any	O
method	O
.	O

The	O
most	O
common	O
hosts	O
were	O
equines	O
(	O
31	O
%	O
)	O
,	O
bovines	O
(	O
25	O
%	O
)	O
and	O
raccoons	O
(	O
19	O
%	O
)	O
.	O

Between	O
the	O
RNA	O
initiation	O
site	O
and	O
the	O
coding	O
region	O
is	O
a	O
GC	O
-	O
rich	O
hairpin	O
structure	O
followed	O
by	O
8	O
T	O
residues	O
that	O
looks	O
like	O
a	O
rho	B-GENE
-	I-GENE
independent	I-GENE
transcription	I-GENE
terminator	I-GENE
.	O

In	O
the	O
conscious	O
animals	O
the	O
increase	O
reached	O
statistical	O
significance	O
when	O
the	O
animals	O
were	O
exposed	O
to	O
12	O
%	O
oxygen	O
in	O
nitrogen	O
,	O
which	O
produced	O
a	O
fall	O
in	O
arterial	O
PaO2	O
of	O
44	O
.	O
7	O
+	O
/	O
-	O
5	O
.	O
0	O
%	O
.	O

Fourteen	O
eyes	O
(	O
38	O
.	O
9	O
%	O
)	O
developed	O
DLK	O
after	O
an	O
epithelial	O
defect	O
,	O
representing	O
an	O
odds	O
ratio	O
of	O
13	O
times	O
.	O

Each	O
subject	O
was	O
injected	O
in	O
the	O
antecubital	O
vein	O
with	O
7	O
mg	O
/	O
kg	O
of	O
sodium	O
fluorescein	O
(	O
25	O
%	O
solution	O
)	O
and	O
measurements	O
were	O
taken	O
1	O
hr	O
postinjection	O
at	O
4	O
.	O
5	O
mm	O
and	O
7	O
.	O
5	O
mm	O
from	O
the	O
retina	O
.	O

Such	O
tetranucleotides	O
are	O
common	O
in	O
promoter	O
regions	O
,	O
particularly	O
in	O
activating	B-GENE
transcription	I-GENE
factor	I-GENE
/	O
cyclic	B-GENE
AMP	I-GENE
response	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
ATF	B-GENE
/	O
CREB	B-GENE
)	O
and	O
E	O
-	O
box	O
motifs	O
,	O
suggesting	O
that	O
PIF	B-GENE
may	O
modulate	O
the	O
transcription	O
of	O
many	O
genes	O
.	O

The	O
long	O
terminal	O
repeat	O
is	O
590	O
bp	O
in	O
length	O
,	O
with	O
the	O
U3	O
region	O
containing	O
consensus	O
sequences	O
likely	O
to	O
be	O
involved	O
in	O
viral	O
gene	O
expression	O
.	O

A	O
pathogenetic	O
relation	O
with	O
the	O
Eisenmenger	O
'	O
s	O
syndrome	O
is	O
discussed	O
.	O

Twenty	O
-	O
six	O
calves	O
were	O
subjected	O
to	O
a	O
technique	O
of	O
cryoablation	O
in	O
order	O
to	O
establish	O
an	O
animal	O
model	O
of	O
complete	O
cardiac	O
denervation	O
.	O

The	O
PHO5	B-GENE
gene	I-GENE
is	O
activated	O
by	O
the	O
Pho4p	B-GENE
transcription	I-GENE
factor	I-GENE
,	O
which	O
itself	O
is	O
negatively	O
regulated	O
through	O
phosphorylation	O
by	O
the	O
products	O
of	O
PHO80	B-GENE
and	O
PHO85	B-GENE
.	O

CNS	O
preventive	O
treatment	O
without	O
cranial	O
irradiation	O
was	O
effective	O
in	O
all	O
the	O
groups	O
of	O
ALL	O
patients	O
.	O

This	O
deletion	O
disrupts	O
the	O
PU	B-GENE
.	I-GENE
1	I-GENE
Ets	B-GENE
domain	I-GENE
.	O

Basal	O
urinary	O
17	O
-	O
hydroxycorticoid	O
(	O
17	O
-	O
OHCS	O
)	O
values	O
were	O
elevated	O
in	O
9	O
/	O
12	O
patients	O
and	O
low	O
dose	O
dexamethasone	O
suppression	O
test	O
favoured	O
Cushing	O
'	O
s	O
syndrome	O
in	O
8	O
/	O
9	O
patients	O
.	O

In	O
this	O
cross	O
-	O
over	O
controlled	O
study	O
,	O
five	O
male	O
volunteers	O
donated	O
one	O
unit	O
of	O
red	O
cells	O
by	O
MCS	O
and	O
one	O
unit	O
of	O
whole	O
blood	O
by	O
the	O
conventional	O
manual	O
method	O
,	O
3	O
months	O
apart	O
.	O

The	O
derepressed	O
expression	O
of	O
fixN	B-GENE
was	O
not	O
observed	O
in	O
a	O
purH	B-GENE
mutant	I-GENE
.	O

The	O
lipopolysaccharide	O
-	O
binding	O
protein	O
is	O
a	O
secretory	B-GENE
class	I-GENE
1	I-GENE
acute	I-GENE
-	I-GENE
phase	I-GENE
protein	I-GENE
whose	O
gene	O
is	O
transcriptionally	O
activated	O
by	O
APRF	B-GENE
/	O
STAT	B-GENE
/	I-GENE
3	I-GENE
and	O
other	O
cytokine	O
-	O
inducible	O
nuclear	O
proteins	O
.	O

D	O
.	O

Acute	O
renal	O
vein	O
thrombosis	O
in	O
renal	O
allografts	O
:	O
detection	O
with	O
duplex	O
Doppler	O
US	O
.	O

Thus	O
,	O
Shp2	B-GENE
regulates	O
phosphotyrosine	O
-	O
signalling	O
events	O
during	O
the	O
complex	O
ectodermal	O
-	O
mesenchymal	O
interactions	O
that	O
regulate	O
mammalian	O
budding	O
morphogenesis	O
.	O

1	O
.	O

In	O
conclusion	O
,	O
in	O
coronary	O
artery	O
disease	O
patients	O
,	O
exercise	O
-	O
redistribution	O
201Thallium	O
cardiac	O
imaging	O
with	O
reinjection	O
at	O
rest	O
can	O
identify	O
severely	O
ischemic	O
but	O
still	O
viable	O
myocardium	O
and	O
may	O
be	O
particularly	O
useful	O
in	O
the	O
prognosis	O
of	O
such	O
patients	O
.	O

To	O
this	O
effect	O
,	O
the	O
present	O
survey	O
puts	O
in	O
evidence	O
that	O
the	O
maximum	O
delay	O
of	O
stream	O
that	O
guarantees	O
the	O
good	O
dimensional	O
stability	O
of	O
these	O
class	O
A	O
alginates	O
is	O
of	O
45	O
minutes	O
in	O
the	O
hot	O
and	O
humid	O
climatic	O
tropical	O
country	O
conditions	O
.	O

1995	O
.	O

The	O
term	O
Kartagener	O
syndrome	O
applies	O
to	O
this	O
syndrome	O
when	O
accompanied	O
by	O
infertility	O
and	O
dextrocardia	O
or	O
situs	O
inversus	O
.	O

Although	O
immunoglobulin	B-GENE
and	O
CRP	B-GENE
concentration	O
increased	O
,	O
anemia	O
obviously	O
improved	O
with	O
hemoglobin	B-GENE
levels	O
increasing	O
from	O
4	O
.	O
8	O
g	O
/	O
dl	O
to	O
8	O
.	O
5	O
g	O
/	O
dl	O
without	O
any	O
side	O
effects	O
.	O

These	O
data	O
also	O
demonstrate	O
that	O
insulin	B-GENE
and	O
TPA	O
activate	O
MBP	B-GENE
/	O
MAP2	B-GENE
kinase	O
activity	O
by	O
de	O
novo	O
phosphorylation	O
of	O
threonine	O
and	O
tyrosine	O
residues	O
via	O
a	O
very	O
similar	O
pathway	O
.	O

100	O
and	O
51	O
p	O
.	O

As	O
regards	O
the	O
short	O
stature	O
,	O
they	O
have	O
proved	O
that	O
the	O
syndrome	O
is	O
related	O
to	O
low	O
levels	O
of	O
somatomedin	B-GENE
C	I-GENE
(	O
SmC	B-GENE
)	O
.	O

The	O
results	O
obtained	O
with	O
[	B-GENE
F304	I-GENE
]	I-GENE
R2	I-GENE
indicate	O
that	O
structural	O
changes	O
in	O
E	B-GENE
.	I-GENE
coli	I-GENE
R2	I-GENE
in	O
the	O
vicinity	O
of	O
this	O
helix	O
distortion	O
can	O
influence	O
the	O
catalytic	O
activity	O
of	O
the	O
holoenzyme	O
.	O

This	O
result	O
is	O
consistent	O
with	O
the	O
previous	O
observation	O
that	O
expression	O
of	O
the	O
hsp70	B-GENE
genes	I-GENE
in	I-GENE
T	I-GENE
.	I-GENE
brucei	I-GENE
is	O
mainly	O
controlled	O
at	O
the	O
posttranscriptional	O
level	O
.	O

The	O
cloned	O
rRNA	O
operon	O
was	O
transcribed	O
in	O
vitro	O
by	O
using	O
purified	B-GENE
RNA	I-GENE
polymerase	I-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
.	O

To	O
test	O
whether	O
Cd	O
exposure	O
would	O
increase	O
Ca	O
release	O
from	O
bone	O
during	O
pregnancy	O
and	O
lactation	O
in	O
relation	O
to	O
the	O
etiological	O
mechanism	O
of	O
Itai	O
-	O
Itai	O
disease	O
,	O
virgin	O
female	O
mice	O
with	O
45Ca	O
prelabeled	O
skeletons	O
(	O
15	O
microCi	O
/	O
mouse	O
)	O
were	O
subjected	O
to	O
one	O
round	O
of	O
pregnancy	O
/	O
lactation	O
and	O
were	O
exposed	O
to	O
a	O
Ca	O
-	O
deficient	O
diet	O
containing	O
0	O
,	O
5	O
,	O
or	O
25	O
ppm	O
Cd	O
or	O
25	O
ppm	O
Pb	O
for	O
32	O
days	O
,	O
from	O
conception	O
until	O
Lactation	O
Day	O
14	O
.	O

G	B-GENE
-	I-GENE
box	I-GENE
binding	I-GENE
factors	I-GENE
(	O
GBFs	B-GENE
)	O
constitute	O
a	O
family	O
of	O
plant	O
DNA	O
-	O
binding	O
proteins	O
that	O
bind	O
to	O
the	O
G	O
-	O
box	O
motif	O
,	O
a	O
regulatory	O
cis	O
element	O
present	O
in	O
many	O
plant	O
genes	O
with	O
a	O
palindromic	O
DNA	O
motif	O
of	O
CACGTG	O
.	O

The	O
ferric	B-GENE
uptake	I-GENE
regulation	I-GENE
(	O
fur	B-GENE
)	O
gene	O
product	O
participates	O
in	O
regulating	O
expression	O
of	O
the	O
manganese	O
-	O
and	O
iron	O
-	O
containing	O
superoxide	B-GENE
dismutase	I-GENE
genes	I-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
.	O

This	O
was	O
further	O
suggested	O
by	O
transactivation	O
assays	O
in	O
which	O
mouse	O
fibroblasts	O
were	O
transiently	O
transfected	O
with	O
a	O
human	B-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
reporter	I-GENE
gene	I-GENE
in	O
the	O
absence	O
and	O
presence	O
of	O
an	O
LKLF	B-GENE
cDNA	I-GENE
construct	I-GENE
.	O

On	O
average	O
these	O
maximum	O
potency	O
estimates	O
were	O
within	O
one	O
order	O
of	O
magnitude	O
of	O
the	O
inverse	O
maximum	O
dose	O
tested	O
.	O

Anovulatory	O
cycles	O
with	O
an	O
apparently	O
normal	O
level	O
of	O
blood	O
prolactin	B-GENE
.	O

Furthermore	O
,	O
CL100	B-GENE
suppresses	O
the	O
[	O
val12	O
]	O
ras	B-GENE
-	O
induced	O
activation	O
of	O
MAP	B-GENE
kinase	I-GENE
in	O
a	O
cell	O
-	O
free	O
system	O
from	O
Xenopus	O
oocytes	O
.	O

The	O
maximum	O
levels	O
of	O
reporter	O
proteins	O
attained	O
in	O
transformed	O
cells	O
after	O
prolonged	O
induction	O
represented	O
from	O
1	O
%	O
to	O
7	O
%	O
of	O
total	O
cellular	O
protein	O
.	O

Cardiovascular	O
drug	O
use	O
and	O
hospitalizations	O
attributable	O
to	O
type	O
2	O
diabetes	O
.	O

The	O
PK	O
domain	O
showed	O
pairwise	O
in	O
vitro	O
binding	O
interactions	O
with	O
the	O
pseudokinase	O
,	O
HisRS	B-GENE
,	O
and	O
C	O
-	O
term	O
domains	O
;	O
additionally	O
,	O
the	O
HisRS	B-GENE
domain	I-GENE
interacted	O
with	O
the	O
C	O
-	O
term	O
region	O
.	O

Renal	O
cell	O
carcinoma	O
induced	O
Coombs	O
negative	O
autoimmune	O
hemolytic	O
anemia	O
and	O
severe	O
thrombocytopenia	O
responsive	O
to	O
nephrectomy	O
.	O

The	O
c	B-GENE
-	I-GENE
Jun	I-GENE
delta	I-GENE
-	I-GENE
domain	I-GENE
inhibits	O
neuroendocrine	O
promoter	O
activity	O
in	O
a	O
DNA	O
sequence	O
-	O
and	O
pituitary	O
-	O
specific	O
manner	O
.	O

Finally	O
,	O
antisense	O
mediated	O
reduction	O
of	O
Elk	B-GENE
-	I-GENE
1	I-GENE
in	O
GH4	O
cells	O
decreased	O
insulin	B-GENE
-	O
increased	O
prolactin	B-GENE
gene	I-GENE
expression	O
and	O
confirmed	O
the	O
requirement	O
for	O
Elk	B-GENE
-	I-GENE
1	I-GENE
for	O
insulin	B-GENE
-	O
increased	O
prolactin	B-GENE
gene	I-GENE
expression	O
.	O

Smooth	O
pursuit	O
gain	O
and	O
the	O
percentage	O
of	O
total	O
eye	O
movement	O
due	O
to	O
various	O
saccadic	O
subtypes	O
were	O
computed	O
using	O
infrared	O
oculography	O
and	O
computerized	O
pattern	O
recognition	O
software	O
.	O

This	O
is	O
similar	O
to	O
previous	O
reports	O
of	O
muscle	B-GENE
creatine	I-GENE
phosphokinase	I-GENE
release	O
in	O
psychiatric	O
patients	O
.	O

The	O
TaqI	B-GENE
and	O
HaeIII	B-GENE
RFLPs	O
will	O
provide	O
tools	O
for	O
the	O
genetic	O
analysis	O
of	O
CR2	B-GENE
.	O

A	O
transient	O
induction	O
of	O
both	O
c	B-GENE
-	I-GENE
fos	I-GENE
and	O
c	B-GENE
-	I-GENE
jun	I-GENE
mRNAs	I-GENE
by	O
TPA	O
was	O
observed	O
in	O
both	O
cell	O
populations	O
,	O
together	O
with	O
an	O
associated	O
suppression	O
of	O
BSP	B-GENE
mRNA	I-GENE
in	O
the	O
fetal	O
rat	O
calvarial	O
cells	O
.	O

Mitoxantrone	O
plus	O
ara	O
-	O
C	O
is	O
an	O
active	O
combination	O
with	O
great	O
promise	O
for	O
the	O
therapy	O
of	O
previously	O
untreated	O
patients	O
with	O
AML	O
.	O

During	O
an	O
observation	O
period	O
of	O
12	O
weeks	O
after	O
halving	O
atenolol	O
from	O
a	O
mean	O
dose	O
of	O
82	O
mg	O
to	O
41	O
mg	O
,	O
no	O
significant	O
changes	O
in	O
systolic	O
and	O
diastolic	O
blood	O
pressure	O
or	O
in	O
response	O
rate	O
(	O
defined	O
as	O
a	O
diastolic	O
blood	O
pressure	O
of	O
95	O
mm	O
Hg	O
or	O
less	O
)	O
were	O
observed	O
.	O

Diet	O
imbalances	O
and	O
aflatoxicosis	O

WBC	O
differential	O
(	O
SEG	O
,	O
BAND	O
,	O
LYMPH	O
,	O
MONO	O
,	O
EOSINO	O
,	O
BASO	O
)	O
usually	O
showed	O
log	O
-	O
normal	O
distribution	O
.	O

The	O
majority	O
of	O
the	O
respondents	O
(	O
83	O
.	O
4	O
%	O
)	O
considered	O
that	O
coitus	O
should	O
not	O
be	O
stopped	O
during	O
pregnancy	O
.	O

Genetic	O
analyses	O
indicate	O
that	O
most	O
of	O
the	O
dominant	O
mutants	O
are	O
cis	O
-	O
acting	O
and	O
that	O
the	O
recessive	O
mutants	O
define	O
a	O
minimum	O
of	O
three	O
complementation	O
groups	O
,	O
indicating	O
that	O
defects	O
in	O
several	O
different	O
genes	O
can	O
restore	O
higher	O
levels	O
of	O
HIS4C	B-GENE
expression	O
.	O

During	O
normoxic	O
exercise	O
,	O
at	O
a	O
mean	O
O2	O
uptake	O
(	O
VO2	O
)	O
of	O
4	O
.	O
0	O
l	O
/	O
min	O
,	O
almitrine	O
increased	O
arterial	O
PO2	O
(	O
PaO2	O
)	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
SaO2	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
VE	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
and	O
decreased	O
arterial	O
PCO2	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
,	O
without	O
affecting	O
pulmonary	O
hemodynamics	O
or	O
ventilation	O
-	O
perfusion	O
distributions	O
.	O

Recombinant	O
protein	O
encoded	O
by	O
ESX	B-GENE
(	O
for	O
epithelial	B-GENE
-	I-GENE
restricted	I-GENE
with	I-GENE
serine	I-GENE
box	I-GENE
)	O
exhibits	O
Ets	B-GENE
-	I-GENE
like	I-GENE
DNA	O
binding	O
specificity	O
in	O
electrophoretic	O
mobility	O
shift	O
assays	O
and	O
,	O
in	O
transient	O
transfection	O
assays	O
,	O
transactivates	O
Ets	B-GENE
-	I-GENE
responsive	I-GENE
promoter	I-GENE
elements	I-GENE
including	O
that	O
found	O
in	O
the	O
HER2	B-GENE
/	O
neu	B-GENE
oncogene	O
.	O

Static	O
and	O
dynamic	O
MRI	O
of	O
the	O
normal	O
and	O
pathological	O
female	O
pelvic	O
floor	O

Crystals	O
of	O
the	O
triple	O
mutant	O
A42D	B-GENE
/	O
D47P	B-GENE
/	O
A63L	B-GENE
,	O
which	O
are	O
stable	O
for	O
days	O
in	O
its	O
oxidized	O
form	O
,	O
were	O
grown	O
from	O
ammonium	O
sulfate	O
,	O
with	O
the	O
cell	O
constants	O
a	O
=	O
b	O
=	O
34	O
.	O
3	O
A	O
and	O
c	O
=	O
111	O
.	O
8	O
A	O
belonging	O
to	O
space	O
group	O
P3	O
(	O
2	O
)	O
21	O
.	O

Two	O
adjacent	O
,	O
highly	O
homologous	B-GENE
endoglucanase	I-GENE
genes	I-GENE
,	O
celD	B-GENE
and	O
celE	B-GENE
from	O
Fibrobacter	O
succinogenes	O
S85	O
,	O
which	O
were	O
separated	O
by	O
an	O
AT	O
-	O
rich	O
223	O
-	O
nucleotide	O
intergenic	O
region	O
were	O
characterized	O
.	O

Sequence	O
analysis	O
of	O
this	O
region	O
showed	O
it	O
contained	O
five	O
potential	O
copies	O
of	O
the	O
sterol	O
regulatory	O
element	O
(	O
SRE	O
-	O
1	O
)	O
(	O
Smith	O
,	O
J	O
.	O
R	O
.	O
,	O
Osborne	O
,	O
T	O
.	O
F	O
.	O
,	O
Brown	O
,	O
M	O
.	O
S	O
.	O
,	O
Goldstein	O
,	O
J	O
.	O
L	O
.	O
,	O
and	O
Gil	O
,	O
G	O
.	O

Toxicity	O
of	O
benzoyl	O
chloride	O
(	O
2	O
,	O
4	O
,	O
6	O
-	O
trichlorophenyl	O
)	O
hydrazone	O
(	O
Banamite	O
)	O
and	O
potential	O
metabolites	O
to	O
twospotted	O
spider	O
mites	O
and	O
potency	O
as	O
inhibitors	O
of	O
rat	B-GENE
liver	I-GENE
monoamine	I-GENE
oxidase	I-GENE
.	O

Fetal	O
PaO2	O
fell	O
somewhat	O
during	O
the	O
recovery	O
stages	O
in	O
both	O
NIT	O
and	O
control	O
groups	O
.	O

It	O
also	O
showed	O
which	O
amino	O
acid	O
residues	O
would	O
contact	O
an	O
extended	O
TATA	O
box	O
with	O
a	O
B	B-GENE
recognition	I-GENE
element	I-GENE
,	O
and	O
evolutionary	O
conservation	O
of	O
the	O
TBP	B-GENE
-	O
TFB	B-GENE
-	O
DNA	O
complex	O
orientation	O
between	O
two	O
archaeal	O
organisms	O
with	O
widely	O
different	O
optimal	O
temperature	O
for	O
growth	O
(	O
37	O
and	O
100	O
degrees	O
C	O
)	O
.	O

The	O
average	O
progression	O
was	O
11	O
.	O
6	O
(	O
SD	O
9	O
.	O
0	O
)	O
.	O

14	O
.	O
9	O
x	O
109	O
L	O
-	O
1	O
)	O
was	O
equal	O
for	O
both	O
groups	O
,	O
but	O
CCI	O
values	O
were	O
significantly	O
higher	O
for	O
the	O
bedside	O
filtered	O
PC	O
(	O
14	O
.	O
1	O
+	O
/	O
-	O
9	O
.	O
5	O
vs	O
.	O

Result	O
were	O
as	O
followed	O
:	O
1	O
)	O
Early	O
cancer	O
-	O
like	O
advanced	O
cancers	O
were	O
consisted	O
of	O
133	O
lesions	O
,	O
of	O
which	O
128	O
lesions	O
(	O
96	O
.	O
2	O
%	O
)	O
had	O
peptic	O
ulcer	O
in	O
cancerous	O
lesion	O
(	O
73	O
lesions	O
were	O
active	O
stage	O
and	O
55	O
lesions	O
were	O
scarring	O
stage	O
)	O
.	O

The	O
median	O
cumulative	O
incidence	O
rates	O
were	O
found	O
to	O
be	O
341	O
per	O
million	O
for	O
males	O
and	O
296	O
per	O
million	O
for	O
females	O
.	O

The	O
unexpected	O
prevalence	O
of	O
c	B-GENE
-	I-GENE
myc	I-GENE
and	O
alpha	B-GENE
-	I-GENE
tubulin	I-GENE
in	O
the	O
S	O
-	O
phase	O
library	O
is	O
supported	O
by	O
Northern	O
analysis	O
of	O
RNA	O
from	O
phase	O
-	O
synchronous	O
cells	O
.	O

A	O
spectrophotometric	O
method	O
for	O
the	O
microdetermination	O
of	O
periodate	O
.	O

Satisfactory	O
correlation	O
was	O
also	O
obtained	O
between	O
the	O
in	O
vivo	O
and	O
the	O
in	O
vitro	O
results	O
.	O

Eleven	O
of	O
the	O
12	O
exons	O
have	O
complete	O
sequence	O
homology	O
with	O
the	O
RBM	B-GENE
-	I-GENE
1	I-GENE
sequence	I-GENE
.	O

Polyoma	O
virus	O
in	O
urine	O
during	O
pregnancy	O
.	O

Using	O
probes	O
from	O
these	O
regions	O
,	O
rearrangements	O
have	O
been	O
identified	O
in	O
each	O
of	O
nine	O
cases	O
of	O
t	O
(	O
8	O
;	O
21	O
)	O
AML	O
examined	O
.	O

The	O
delta	O
G	O
values	O
of	O
these	O
regions	O
were	O
higher	O
,	O
i	O
.	O
e	O
.	O
potential	O
secondary	O
structural	O
elements	O
were	O
fewer	O
,	O
than	O
in	O
TIR	O
of	O
genes	O
from	O
E	O
.	O
coli	O
.	O

In	O
each	O
patient	O
,	O
MBF	O
was	O
quantified	O
in	O
the	O
three	O
major	O
vascular	O
territories	O
:	O
the	O
left	O
anterior	O
descending	O
and	O
left	O
circumflex	O
coronary	O
artery	O
territories	O
and	O
the	O
right	O
coronary	O
artery	O
(	O
control	O
region	O
)	O
territory	O
.	O

Effects	O
of	O
shosaikoto	O
,	O
an	O
oriental	O
herbal	O
medicinal	O
mixture	O
,	O
on	O
restraint	O
-	O
stressed	O
mice	O
.	O

We	O
conclude	O
that	O
99mTc	O
-	O
HL91	O
is	O
a	O
potent	O
marker	O
of	O
myocardial	O
viability	O
when	O
used	O
during	O
the	O
early	O
acute	O
phase	O
after	O
reperfusion	O
.	O

Glucose	O
may	O
reduce	O
slightly	O
the	O
pool	O
of	O
amino	O
nitrogen	O
available	O
for	O
albumin	B-GENE
and	O
urea	O
synthesis	O
by	O
diverting	O
some	O
of	O
the	O
infused	O
amino	O
acids	O
from	O
protein	O
synthesis	O
by	O
the	O
liver	O
to	O
muscle	O
.	O

The	O
community	O
-	O
acquired	O
bacteremia	O
was	O
mainly	O
due	O
to	O
E	O
.	O
coli	O
.	O

The	O
benzo	O
-	O
pyrone	O
drug	O
Venalot	O
had	O
a	O
considerable	O
effect	O
in	O
reducing	O
the	O
protein	O
concentration	O
in	O
the	O
air	O
spaces	O
and	O
the	O
interstitial	O
tissue	O
,	O
and	O
of	O
the	O
oedema	O
in	O
the	O
latter	O
.	O

The	O
brains	O
were	O
bisected	O
and	O
T1	O
and	O
T2	O
relaxation	O
times	O
were	O
determined	O
for	O
the	O
right	O
and	O
left	O
hemispheres	O
by	O
MR	O
spectroscopy	O
immediately	O
after	O
dissection	O
.	O

The	O
exact	O
function	O
of	O
IP	B-GENE
-	I-GENE
30	I-GENE
is	O
not	O
yet	O
known	O
,	O
but	O
it	O
may	O
play	O
a	O
role	O
in	O
gamma	B-GENE
-	I-GENE
interferon	I-GENE
mediated	O
immune	O
reactions	O
.	O

Indeed	O
,	O
ectopic	O
expression	O
of	O
MOX4	B-GENE
in	O
aerobic	O
cells	O
resulted	O
in	O
partially	O
constitutive	O
expression	O
of	O
DAN1	B-GENE
.	O

Finally	O
,	O
gel	O
shift	O
assays	O
showed	O
that	O
ORF2	O
was	O
able	O
to	O
bind	O
to	O
promoter	O
fragment	O
566	O
-	O
888	O
.	O

Mutation	O
of	O
K14	O
in	O
H3	B-GENE
,	O
which	O
serves	O
as	O
the	O
major	O
target	O
of	O
recombinant	B-GENE
Gcn5p	I-GENE
acetylation	O
in	O
vitro	O
,	O
confers	O
a	O
strong	O
,	O
synthetic	O
growth	O
defect	O
in	O
gcn5	B-GENE
cells	O
.	O

Histological	O
examination	O
revealed	O
variable	O
loss	O
of	O
motor	O
neurons	O
limited	O
to	O
the	O
injection	O
site	O
.	O

In	O
normal	O
B	O
cells	O
stimulated	O
by	O
LPS	O
or	O
IL	B-GENE
-	I-GENE
4	I-GENE
,	O
new	O
complexes	O
appear	O
that	O
bind	O
to	O
C	B-GENE
/	I-GENE
EBP	I-GENE
and	O
NF	B-GENE
-	I-GENE
IL	I-GENE
-	I-GENE
4	I-GENE
elements	I-GENE
,	O
respectively	O
,	O
located	O
within	O
the	O
-	O
125	O
/	O
-	O
101	O
region	O
.	O

Phylogenetic	O
analysis	O
using	O
a	O
neighbor	O
-	O
joining	O
algorithm	O
showed	O
closest	O
similarity	O
of	O
the	O
horse	B-GENE
mu	I-GENE
chain	I-GENE
-	I-GENE
encoding	I-GENE
constant	I-GENE
region	I-GENE
gene	I-GENE
to	O
human	O
and	O
dog	O
sequences	O
.	O

Progressive	O
immunodeficiency	O
in	O
a	O
patient	O
with	O
IgA	B-GENE
deficiency	O

Mouse	O
embryo	O
cells	O
(	O
C57BL	O
/	O
6	O
,	O
H	O
-	O
2b	O
)	O
transformed	O
by	O
the	O
E1A	B-GENE
and	O
E1B	B-GENE
genes	O
of	O
adenovirus	O
type	O
5	O
(	O
Ad5E1	O
MEC	O
)	O
are	O
highly	O
immunogenic	O
.	O

We	O
hypothesized	O
that	O
subjects	O
would	O
demonstrate	O
PKAR	O
during	O
both	O
hopping	O
and	O
stepping	O
,	O
adding	O
support	O
to	O
the	O
hypothesis	O
that	O
PKAR	O
is	O
a	O
centrally	O
mediated	O
adaptation	O
of	O
general	O
locomotor	O
trajectory	O
that	O
is	O
not	O
specific	O
to	O
the	O
form	O
of	O
locomotion	O
used	O
while	O
on	O
the	O
rotating	O
disk	O
.	O

The	O
major	O
open	O
reading	O
frame	O
of	O
the	O
cDNA	O
predicts	O
a	O
protein	O
of	O
59	O
kD	O
,	O
with	O
a	O
leucine	O
zipper	O
situated	O
adjacent	O
to	O
an	O
myc	B-GENE
-	I-GENE
related	I-GENE
motif	I-GENE
that	O
has	O
been	O
proposed	O
to	O
assume	O
a	O
helix	O
-	O
loop	O
-	O
helix	O
structure	O
.	O

Medical	O
management	O
of	O
early	O
-	O
stage	O
breast	O
cancer	O
.	O

Other	O
Fischer	O
-	O
344	O
rats	O
were	O
also	O
exposed	O
for	O
1	O
hr	O
to	O
0	O
.	O
0	O
or	O
to	O
0	O
.	O
6	O
ppm	O
O3	O
.	O

Evidence	O
from	O
four	O
areas	O
-	O
-	O
sensory	O
deprivation	O
,	O
enriched	O
environments	O
,	O
nervous	O
system	O
plasticity	O
,	O
and	O
sensitive	O
periods	O
of	O
neurodevelopment	O
-	O
-	O
suggests	O
that	O
sensory	O
stimulation	O
programs	O
are	O
potentially	O
beneficial	O
for	O
STR	O
patients	O
.	O

The	O
limb	O
defects	O
,	O
oligodactyly	O
and	O
syndactyly	O
,	O
have	O
been	O
traced	O
to	O
improper	O
differentiation	O
of	O
the	O
apical	O
ectodermal	O
ridge	O
(	O
AER	O
)	O
and	O
shortening	O
of	O
the	O
anteroposterior	O
limb	O
axis	O
.	O

Action	O
against	O
Vibrio	O
cholerae	O
O1	O
Tox	B-GENE
+	I-GENE
of	O
chemical	O
products	O
used	O
in	O
the	O
lemon	O
production	O
.	O

Sera	O
collected	O
in	O
1973	O
-	O
1975	O
from	O
3053	O
residents	O
of	O
12	O
selected	O
Alaskan	O
Eskimo	O
villages	O
were	O
tested	O
for	O
evidence	O
of	O
hepatitis	O
B	O
virus	O
infection	O
.	O

Donehower	O
and	O
H	O
.	O

We	O
have	O
studied	O
some	O
of	O
the	O
parameters	O
governing	O
the	O
expression	O
of	O
a	O
foreign	O
promoter	O
-	O
reporter	O
gene	O
construct	O
incorporated	O
into	O
herpes	O
simplex	O
virus	O
(	O
HSV	O
)	O
type	O
1	O
.	O

cDNA	O
cloning	O
reveals	O
two	O
mouse	B-GENE
beta5	I-GENE
integrin	I-GENE
transcripts	I-GENE
distinct	O
in	O
cytoplasmic	O
domains	O
as	O
a	O
result	O
of	O
alternative	O
splicing	O
.	O

Children	O
with	O
repeated	O
proteinuria	O
during	O
follow	O
-	O
up	O
tend	O
to	O
have	O
a	O
higher	O
incidence	O
of	O
pathologic	O
findings	O
on	O
the	O
i	O
.	O
v	O
.	O
-	O
pyelogram	O
.	O

From	O
the	O
Centers	O
for	O
Disease	O
Control	O
and	O
Prevention	O
.	O

The	O
translated	O
sequence	O
of	O
the	O
FLI	B-GENE
LRR	I-GENE
associated	I-GENE
protein	I-GENE
(	O
FLAP	B-GENE
)	O
encodes	O
a	O
novel	O
protein	O
not	O
represented	O
in	O
the	O
data	O
base	O
.	O

The	O
analysis	O
of	O
the	O
effects	O
of	O
eight	O
signaling	O
molecules	O
in	O
the	O
TGFbeta	B-GENE
,	O
FGF	B-GENE
,	O
Hh	B-GENE
,	O
Wnt	B-GENE
,	O
and	O
EGF	B-GENE
families	I-GENE
in	O
tooth	O
explant	O
cultures	O
revealed	O
that	O
the	O
expression	O
of	O
edar	B-GENE
was	O
induced	O
by	O
activinbetaA	B-GENE
,	O
whereas	O
Wnt6	B-GENE
induced	O
ectodysplasin	B-GENE
expression	O
.	O

In	O
two	O
separate	O
studies	O
,	O
specimens	O
of	O
saliva	O
from	O
57	O
individuals	O
over	O
the	O
age	O
of	O
65	O
years	O
(	O
mean	O
age	O
,	O
76	O
.	O
7	O
years	O
)	O
and	O
37	O
persons	O
under	O
the	O
age	O
of	O
40	O
years	O
(	O
mean	O
age	O
,	O
28	O
.	O
8	O
years	O
)	O
were	O
examined	O
for	O
concentrations	O
of	O
IgA	B-GENE
as	O
functions	O
of	O
volume	O
,	O
total	O
protein	O
,	O
and	O
electrolyte	O
conductivity	O
;	O
some	O
were	O
also	O
tested	O
for	O
IgG	B-GENE
and	O
IgM	B-GENE
content	O
.	O

In	O
the	O
plant	B-GENE
malate	I-GENE
synthases	I-GENE
,	O
the	O
extension	O
is	O
probably	O
involved	O
in	O
routing	O
to	O
the	O
microbodies	O
,	O
since	O
it	O
contains	O
the	O
potential	O
peroxisomal	O
targeting	O
signal	O
,	O
Ser	O
-	O
Arg	O
/	O
Lys	O
-	O
Leu	O
,	O
at	O
the	O
carboxy	O
terminus	O
.	O

These	O
motifs	O
,	O
and	O
their	O
cognate	O
transcription	O
factors	O
,	O
appear	O
to	O
act	O
in	O
concert	O
,	O
with	O
partial	O
redundancy	O
,	O
so	O
that	O
discrete	O
mutations	O
were	O
only	O
partially	O
effective	O
in	O
reducing	O
transcriptional	O
activity	O
.	O

Upon	O
incubation	O
of	O
the	O
most	O
highly	O
purified	O
fractions	O
with	O
Mn	O
-	O
ATP	O
or	O
Mg	O
-	O
ATP	O
,	O
p40	B-GENE
was	O
the	O
only	O
protein	O
phosphorylated	O
on	O
tyrosine	O
.	O

CLINICAL	O
FEATURES	O
:	O
This	O
30	O
-	O
yr	O
-	O
old	O
gravida	O
V	O
para	O
0	O
woman	O
presented	O
to	O
the	O
anaesthesia	O
consultation	O
clinic	O
at	O
37	O
-	O
wk	O
gestation	O
to	O
discuss	O
pain	O
relief	O
options	O
for	O
labour	O
and	O
delivery	O
.	O

Judge	O
Christian	O
Byk	O
renders	O
service	O
to	O
the	O
Steering	O
Committee	O
on	O
Bioethics	O
of	O
the	O
Council	O
of	O
Europe	O
(	O
CDBI	O
)	O
by	O
proposing	O
a	O
draft	O
of	O
the	O
protocol	O
destined	O
to	O
fill	O
in	O
a	O
gap	O
in	O
international	O
law	O
on	O
the	O
status	O
of	O
the	O
human	O
embryo	O
.	O

In	O
agreement	O
with	O
this	O
model	O
,	O
elimination	O
of	O
the	O
ADAM13	B-GENE
cytoplasmic	I-GENE
domain	I-GENE
increased	O
developmental	O
alterations	O
attributable	O
to	O
ADAM13	B-GENE
proteolytic	O
activity	O
.	O

Studies	O
in	O
B	O
.	O
glabrata	O
,	O
B	O
.	O
straminea	O
and	O
B	O
.	O
tenagophila	O
under	O
outdoor	O
conditions	O
.	O

E	O
.	O
R	O
.	O
C	O
.	O
P	O
.	O
is	O
an	O
important	O
advance	O
in	O
diagnosis	O
.	O

It	O
also	O
appears	O
that	O
in	O
patients	O
with	O
laboratory	O
diagnosis	O
of	O
prerenal	O
acute	O
renal	O
failure	O
(	O
i	O
.	O
e	O
.	O
,	O
a	O
RFT	O
less	O
than	O
1	O
.	O
0	O
)	O
,	O
the	O
response	O
to	O
treatment	O
is	O
unpredictable	O
and	O
in	O
fact	O
may	O
have	O
a	O
worse	O
prognosis	O
than	O
in	O
those	O
with	O
a	O
RFI	O
greater	O
than	O
1	O
.	O
0	O
(	O
5	O
/	O
7	O
deaths	O
vs	O
10	O
/	O
48	O
deaths	O
)	O
.	O

The	O
strangulated	O
intestinal	O
pathologies	O
of	O
horses	O
are	O
accompanied	O
by	O
a	O
local	O
activation	O
of	O
the	O
neutrophils	O
,	O
that	O
can	O
be	O
revealed	O
by	O
measuring	O
the	O
tissular	O
enzymatic	O
activity	O
of	O
the	O
granulocytic	O
enzyme	O
myeloperoxidase	B-GENE
(	O
MPO	B-GENE
)	O
.	O

The	O
human	O
protein	O
is	O
encoded	O
by	O
a	O
900	O
-	O
base	O
pair	O
-	O
long	O
mRNA	O
that	O
is	O
expressed	O
in	O
the	O
glandular	O
epithelial	O
cells	O
of	O
the	O
endometrium	O
in	O
a	O
cyclic	O
manner	O
;	O
in	O
addition	O
,	O
it	O
is	O
found	O
in	O
the	O
mucosal	O
epithelial	O
cells	O
of	O
the	O
fallopian	O
tubes	O
.	O

The	O
80	O
kb	O
preceding	O
the	O
expression	O
site	O
has	O
few	O
,	O
if	O
any	O
,	O
functional	O
ORFs	O
,	O
but	O
contains	O
50	O
bp	O
repeats	O
,	O
INGI	B-GENE
retrotransposon	I-GENE
-	I-GENE
like	I-GENE
elements	I-GENE
,	O
and	O
novel	O
4	O
-	O
12	O
kb	O
repeats	O
found	O
near	O
other	O
telomeres	O
.	O

Rather	O
than	O
seeking	O
a	O
blanket	O
characterization	O
of	O
an	O
essentially	O
heterogeneous	O
group	O
,	O
it	O
may	O
be	O
more	O
useful	O
to	O
consider	O
idiom	O
comprehension	O
a	O
secondary	O
manifestation	O
of	O
semantic	O
and	O
/	O
or	O
pragmatic	O
difficulties	O
.	O

The	O
two	O
redox	O
centers	O
in	O
the	O
protein	O
,	O
FAD	O
and	O
a	O
[	O
4Fe4S	O
]	O
+	O
2	O
,	O
+	O
1	O
cluster	O
,	O
are	O
present	O
in	O
a	O
64	O
-	O
kDa	O
monomer	O
.	O

The	O
BDU	O
neurons	O
and	O
the	O
ALM	O
touch	O
neurons	O
are	O
lineal	O
sister	O
cells	O
in	O
the	O
AB	O
.	O
a	O
lineage	O
and	O
the	O
VA	O
and	O
VB	O
motor	O
neurons	O
are	O
lineal	O
sister	O
cells	O
in	O
the	O
AB	O
.	O
p	O
lineage	O
.	O

We	O
conclude	O
that	O
a	O
0	O
.	O
25	O
mg	O
dose	O
of	O
triazolam	O
does	O
not	O
effectively	O
counteract	O
a	O
posture	O
-	O
induced	O
sleep	O
disturbance	O
,	O
but	O
induces	O
changes	O
in	O
the	O
EEG	O
spectra	O
which	O
are	O
typical	O
for	O
benzodiazepine	B-GENE
receptor	I-GENE
agonists	O
.	O

The	O
biological	O
actions	O
of	O
VHR	B-GENE
in	O
oocytes	O
clearly	O
distinguish	O
it	O
from	O
other	O
dual	O
specificity	O
phosphatases	O
,	O
which	O
have	O
shown	O
inhibitory	O
effects	O
when	O
tested	O
in	O
oocytes	O
.	O

Discriminant	O
function	O
analysis	O
suggests	O
that	O
AUDIT	O
scores	O
can	O
successfully	O
identify	O
SAT	O
-	O
positive	O
and	O
SAT	O
-	O
negative	O
patients	O
;	O
the	O
analysis	O
accounted	O
for	O
42	O
.	O
5	O
%	O
of	O
the	O
variance	O
and	O
correctly	O
classified	O
84	O
.	O
6	O
%	O
of	O
the	O
sample	O
.	O

Failure	O
to	O
demonstrate	O
a	O
major	O
anti	O
-	O
inflammatory	O
effect	O
with	O
alpha	O
tocopherol	O
supplementation	O
(	O
400	O
IU	O
/	O
day	O
)	O
in	O
normal	O
subjects	O
.	O

The	O
flanking	O
open	O
reading	O
frames	O
in	O
pARGC2	O
showed	O
no	O
homologies	O
to	O
arginine	O
biosynthetic	O
genes	O
.	O

Estrogen	O
pretreated	O
castrated	O
males	O
also	O
showed	O
no	O
change	O
in	O
myocardial	O
blood	O
flow	O
after	O
17	O
beta	O
-	O
estradiol	O
,	O
but	O
coronary	O
flow	O
velocity	O
decreased	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
compared	O
with	O
baseline	O
1	O
h	O
after	O
the	O
200	O
ng	O
/	O
kg	O
dose	O
(	O
from	O
1	O
.	O
69	O
+	O
/	O
-	O
0	O
.	O
61	O
to	O
1	O
.	O
41	O
+	O
/	O
-	O
0	O
.	O
42	O
kHz	O
)	O
and	O
diastolic	O
coronary	O
resistance	O
increased	O
significantly	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
compared	O
with	O
control	O
at	O
this	O
time	O
(	O
51	O
+	O
/	O
-	O
15	O
compared	O
with	O
39	O
+	O
/	O
-	O
14	O
mmHg	O
/	O
mkHz	O
)	O
.	O

The	O
studies	O
permit	O
considering	O
the	O
detected	O
shifts	O
in	O
the	O
immunity	O
system	O
an	O
important	O
component	O
of	O
the	O
pathogenesis	O
of	O
chronic	O
nontumorous	O
diseases	O
of	O
the	O
parotid	O
glands	O
.	O

The	O
interaction	O
of	O
different	O
protein	O
systems	O
with	O
microtubules	O
is	O
a	O
critical	O
step	O
in	O
the	O
cellular	O
function	O
of	O
these	O
organelles	O
.	O

Northern	O
blot	O
analysis	O
of	O
liver	O
,	O
muscle	O
,	O
fat	O
,	O
and	O
pituitary	O
RNA	O
from	O
normal	O
(	O
DwDw	O
)	O
chickens	O
shows	O
a	O
major	O
transcript	O
of	O
4	O
.	O
3	O
kilobases	O
(	O
kb	O
)	O
and	O
three	O
minor	O
transcripts	O
(	O
0	O
.	O
8	O
,	O
1	O
.	O
7	O
,	O
and	O
3	O
.	O
2	O
kb	O
)	O
,	O
which	O
correspond	O
to	O
the	O
cGHR	B-GENE
.	O

SHBG	B-GENE
concentrations	O
in	O
women	O
were	O
also	O
significantly	O
higher	O
at	O
T	O
-	O
2	O
and	O
T	O
-	O
3	O
when	O
compared	O
to	O
T	O
-	O
1	O
values	O
.	O

Chromosome	O
-	O
specific	O
STSs	O
for	O
27	O
telomeres	O
were	O
identified	O
from	O
the	O
196	O
TYACs	O
.	O

The	O
patient	O
groups	O
consisted	O
of	O
31	O
with	O
dilated	O
cardiomyopathy	O
,	O
22	O
with	O
hypertrophic	O
cardiomyopathy	O
,	O
38	O
with	O
myocardial	O
infarction	O
,	O
15	O
with	O
angina	O
pectoris	O
and	O
26	O
with	O
rheumatic	O
valvular	O
disease	O
.	O

The	O
two	O
yeast	B-GENE
pheromone	I-GENE
receptors	I-GENE
,	O
the	O
a	B-GENE
and	I-GENE
alpha	I-GENE
-	I-GENE
factor	I-GENE
receptors	I-GENE
,	O
share	O
many	O
functional	O
similarities	O
:	O
both	O
G	B-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
receptors	I-GENE
couple	O
to	O
the	O
same	O
downstream	O
signal	O
transduction	O
pathway	O
,	O
and	O
both	O
receptors	O
undergo	O
feedback	O
regulation	O
involving	O
increased	O
phosphorylation	O
on	O
their	O
C	O
-	O
terminal	O
domains	O
in	O
response	O
to	O
ligand	O
challenge	O
.	O

Heart	O
rate	O
and	O
oxygen	O
consumption	O
increased	O
75	O
+	O
/	O
-	O
4	O
bpm	O
and	O
26	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
4	O
ml	O
O2	O
/	O
kg	O
x	O
min	O
(	O
-	O
1	O
)	O
from	O
supine	O
resting	O
values	O
,	O
respectively	O
.	O

It	O
also	O
produces	O
an	O
NH2	O
terminus	O
that	O
corresponds	O
to	O
an	O
equivalent	O
NH2	O
terminus	O
on	O
the	O
processed	O
matrix	O
form	O
of	O
the	O
similar	O
alpha1	B-GENE
(	I-GENE
XI	I-GENE
)	I-GENE
chain	I-GENE
,	O
thus	O
suggesting	O
physiological	O
significance	O
.	O

To	O
determine	O
the	O
transactivation	O
potential	O
of	O
each	O
of	O
the	O
four	O
Ahr	B-GENE
Sp1	B-GENE
sites	I-GENE
,	O
we	O
fused	O
the	O
Ahr	B-GENE
promoter	I-GENE
to	O
a	O
luciferase	B-GENE
(	O
LUC	B-GENE
)	O
reporter	O
gene	O
and	O
transfected	O
the	O
construct	O
into	O
the	O
Drosophila	O
cell	O
line	O
Schneider	O
-	O
2	O
,	O
which	O
contains	O
no	O
Sp1	B-GENE
or	O
Sp1	B-GENE
-	I-GENE
like	I-GENE
factors	I-GENE
.	O

Based	O
on	O
the	O
results	O
of	O
this	O
analysis	O
,	O
we	O
also	O
predict	O
that	O
the	O
budding	B-GENE
yeast	I-GENE
arsenate	I-GENE
resistance	I-GENE
protein	I-GENE
Acr2	B-GENE
and	O
the	O
ORF	B-GENE
Ygr203w	I-GENE
encode	O
protein	O
phosphatases	O
with	O
catalytic	O
properties	O
similar	O
to	O
that	O
of	O
the	O
Cdc25	B-GENE
family	I-GENE
.	O

However	O
,	O
in	O
7	O
patients	O
with	O
normal	O
CT	O
results	O
the	O
latter	O
method	O
showed	O
areas	O
of	O
cerebral	O
activity	O
anatomically	O
correlated	O
with	O
neurological	O
signs	O
or	O
vascular	O
lesions	O
.	O

Signal	O
transduction	O
in	O
fibroblasts	O
stably	O
transformed	O
by	O
[	O
Val12	O
]	O
Ras	O
-	O
-	O
the	O
activities	O
of	O
extracellular	B-GENE
-	I-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
and	O
Jun	B-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
are	O
only	O
moderately	O
increased	O
,	O
and	O
the	O
activity	O
of	O
the	O
delta	O
-	O
inhibitor	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
is	O
not	O
alleviated	O
.	O

Avian	B-GENE
EMILIN	I-GENE
was	O
extracted	O
from	O
19	O
-	O
day	O
-	O
old	O
embryonic	O
chick	O
aortas	O
and	O
associated	O
blood	O
vessels	O
and	O
purified	O
by	O
ion	O
-	O
exchange	O
chromatography	O
and	O
gel	O
filtration	O
.	O

Asymptomatic	O
ischaemia	O
during	O
daily	O
life	O
in	O
stable	O
coronary	O
artery	O
disease	O
:	O
relevant	O
or	O
redundant	O
?	O

Individual	O
intolerance	O
to	O
betaxolol	O
will	O
continue	O
to	O
occur	O
and	O
care	O
is	O
always	O
required	O
when	O
patients	O
with	O
cardiac	O
or	O
respiratory	O
dysfunction	O
are	O
exposed	O
to	O
any	O
beta	O
-	O
antagonist	O
.	O

DESIGN	O
:	O
Prospective	O
case	O
study	O
(	O
Canadian	O
Task	O
Force	O
classification	O
II	O
-	O
2	O
)	O
.	O

The	O
highest	O
incidence	O
was	O
observed	O
for	O
V	O
.	O
alginolyticus	O
(	O
92	O
-	O
100	O
%	O
)	O
,	O
followed	O
by	O
V	O
.	O
parahaemolyticus	O
(	O
67	O
-	O
92	O
%	O
)	O
,	O
V	O
.	O
fluvialis	O
(	O
34	O
-	O
67	O
%	O
)	O
,	O
V	O
.	O
vulnificus	O
(	O
8	O
-	O
17	O
%	O
)	O
,	O
V	O
.	O
furnissii	O
(	O
0	O
-	O
17	O
%	O
)	O
,	O
V	O
.	O
mimicus	O
(	O
0	O
-	O
17	O
%	O
)	O
and	O
V	O
.	O
cholerae	O
non	O
-	O
O1	O
(	O
0	O
-	O
8	O
%	O
)	O
.	O

Self	O
-	O
consistent	O
calculation	O
of	O
the	O
surface	O
electronic	O
structure	O
of	O
the	O
(	O
1	O
x	O
2	O
)	O
reconstructed	O
Au	O
(	O
110	O
)	O
surface	O
.	O

In	O
contrast	O
,	O
polypropylene	O
glycol	O
,	O
PG	O
-	O
C	O
,	O
and	O
corn	O
oil	O
all	O
removed	O
68	O
-	O
86	O
%	O
of	O
the	O
MDI	O
in	O
the	O
first	O
h	O
,	O
74	O
-	O
79	O
%	O
at	O
4	O
h	O
,	O
and	O
72	O
-	O
86	O
%	O
at	O
8	O
h	O
.	O

Peak	O
insulin	B-GENE
response	O
to	O
glucose	O
infusion	O
declined	O
from	O
Groups	O
1	O
to	O
3	O
(	O
51	O
+	O
/	O
-	O
14	O
,	O
42	O
.	O
4	O
+	O
/	O
-	O
31	O
,	O
20	O
.	O
4	O
+	O
/	O
-	O
6	O
.	O
8	O
microU	O
/	O
ml	O
,	O
respectively	O
)	O
with	O
Group	O
3	O
exhibiting	O
a	O
significantly	O
decreased	O
mean	O
peak	O
level	O
compared	O
to	O
the	O
other	O
groups	O
.	O

Chemical	O
structure	O
of	O
antibiotic	O
SF	O
-	O
837	O
.	O

Reexamination	O
of	O
the	O
cdc4	B-GENE
-	I-GENE
1	I-GENE
mutant	I-GENE
revealed	O
that	O
,	O
in	O
addition	O
to	O
being	O
defective	O
in	O
the	O
onset	O
of	O
S	O
phase	O
,	O
it	O
is	O
also	O
defective	O
in	O
G	O
(	O
2	O
)	O
/	O
M	O
transition	O
when	O
released	O
from	O
hydroxyurea	O
-	O
induced	O
S	O
-	O
phase	O
arrest	O
.	O

Structure	O
and	O
regulation	O
of	O
the	O
luteinizing	B-GENE
hormone	I-GENE
receptor	I-GENE
gene	I-GENE
.	O

The	O
procedure	O
was	O
technically	O
successful	O
in	O
12	O
of	O
14	O
(	O
86	O
%	O
)	O
stenoses	O
in	O
the	O
fibromuscular	O
dysplasia	O
subgroup	O
but	O
in	O
only	O
one	O
of	O
five	O
(	O
20	O
%	O
)	O
lesions	O
in	O
the	O
neurofibromatosis	O
subgroup	O
.	O

Amplitude	O
of	O
late	O
surface	O
(	O
P2	O
and	O
N2	O
)	O
and	O
depth	O
(	O
B	O
and	O
C	O
)	O
components	O
significantly	O
decreased	O
when	O
patients	O
shifted	O
from	O
SWS	O
IV	O
to	O
PS	O
and	O
increased	O
from	O
PS	O
to	O
W2	O
.	O

Unconventional	O
mRNA	O
processing	O
in	O
the	O
expression	O
of	O
two	O
calcineurin	B-GENE
B	I-GENE
isoforms	I-GENE
in	O
Dictyostelium	O
.	O

T1	O
and	O
T2	O
values	O
were	O
calculated	O
from	O
guinea	O
pig	O
brain	O
in	O
vivo	O
at	O
0	O
.	O
5	O
T	O
.	O

A	O
chest	O
-	O
X	O
ray	O
film	O
showed	O
infiltrative	O
shadows	O
in	O
the	O
right	O
middle	O
and	O
lower	O
lung	O
fields	O
,	O
but	O
a	O
chest	O
CT	O
scan	O
showed	O
an	O
abnormal	O
lung	O
density	O
in	O
the	O
right	O
lower	O
lobe	O
.	O

Transcription	O
of	O
the	O
inserted	O
gene	O
into	O
the	O
predicted	O
subgenomic	O
polyadenylated	O
mRNA	O
was	O
demonstrated	O
by	O
Northern	O
(	O
RNA	O
)	O
blot	O
hybridization	O
analysis	O
,	O
and	O
the	O
encoded	O
protein	O
was	O
detected	O
by	O
enzyme	O
assay	O
and	O
by	O
radioimmunoprecipitation	O
.	O

We	O
then	O
supplemented	O
these	O
spliceosomes	O
with	O
purified	O
proteins	O
or	O
yeast	O
extract	O
fractions	O
as	O
a	O
functional	O
assay	O
for	O
second	O
-	O
step	O
splicing	O
factors	O
.	O

The	O
severity	O
of	O
the	O
psychomotor	O
retardation	O
varied	O
from	O
mild	O
to	O
severe	O
.	O

Plasma	B-GENE
insulin	I-GENE
responses	O
to	O
glucose	O
in	O
femoral	O
,	O
hepatic	O
,	O
and	O
pancreatic	O
veins	O
in	O
dogs	O
.	O

The	O
reading	O
achievement	O
of	O
students	O
with	O
learning	O
disabilities	O
who	O
received	O
reading	O
instruction	O
through	O
the	O
DISTAR	O
program	O
was	O
compared	O
to	O
that	O
of	O
similar	O
students	O
using	O
basal	O
reader	O
materials	O
.	O

We	O
discuss	O
the	O
possibility	O
that	O
DNA	O
-	O
protein	O
interactions	O
at	O
homologous	O
nucleotide	O
sequences	O
like	O
those	O
identified	O
in	O
PII	O
are	O
part	O
of	O
a	O
regulatory	O
gene	O
cascade	O
that	O
participates	O
in	O
timing	O
fla	B-GENE
gene	I-GENE
expression	O
in	O
the	O
C	O
.	O
crescentus	O
cell	O
cycle	O
.	O

Here	O
we	O
demonstrate	O
that	O
a	O
region	O
of	O
high	O
homology	O
between	O
the	O
members	O
of	O
this	O
class	O
of	O
proteins	O
contains	O
a	O
type	O
A	O
nucleotide	O
binding	O
site	O
consensus	O
sequence	O
which	O
has	O
ATPase	B-GENE
activity	O
and	O
is	O
sufficient	O
to	O
bind	O
DNA	O
containing	O
specific	O
mismatched	O
residues	O
.	O

The	O
detergent	O
-	O
solubilized	O
complex	O
oxidizes	O
caldariella	O
quinol	O
at	O
high	O
rates	O
and	O
is	O
completely	O
inhibited	O
by	O
cyanide	O
and	O
by	O
quinolone	O
analogs	O
,	O
potent	O
inhibitors	O
of	O
quinol	B-GENE
oxidases	I-GENE
.	O

Significantly	O
,	O
the	O
murine	B-GENE
P	I-GENE
-	I-GENE
selectin	I-GENE
gene	I-GENE
had	O
several	O
features	O
not	O
found	O
in	O
the	O
human	O
gene	O
.	O

Consistently	O
,	O
we	O
show	O
that	O
phosphorylation	O
by	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
inhibits	O
Sfl1	B-GENE
DNA	O
binding	O
in	O
vitro	O
,	O
and	O
that	O
a	O
tpk2Delta	B-GENE
mutation	O
increases	O
the	O
levels	O
of	O
Sfl1	B-GENE
protein	I-GENE
associated	O
with	O
specific	O
promoter	O
elements	O
in	O
vivo	O
.	O

This	O
region	O
was	O
unfavourable	O
,	O
due	O
to	O
malaria	O
in	O
the	O
past	O
.	O

SM	B-GENE
binds	O
RNA	O
in	O
vitro	O
,	O
suggesting	O
that	O
sequence	O
-	O
or	O
structure	O
-	O
specific	O
mRNA	O
interactions	O
might	O
mediate	O
SM	B-GENE
specificity	O
.	O

Stress	O
-	O
induced	O
suppression	O
of	O
the	O
prolactin	B-GENE
afternoon	O
surge	O
in	O
ovariectomized	O
,	O
estrogen	O
-	O
treated	O
rats	O
and	O
the	O
nocturnal	O
surge	O
in	O
pseudopregnant	O
rats	O
are	O
accompanied	O
by	O
an	O
increase	O
in	O
median	O
eminence	O
dihydroxyphenylacetic	O
acid	O
concentrations	O
.	O

In	O
vitro	O
kinase	O
assays	O
on	O
isolated	O
microvilli	O
and	O
microvillar	O
fractions	O
enriched	O
in	O
the	O
putative	O
signal	O
transduction	O
particle	O
showed	O
a	O
high	O
specific	O
activity	O
of	O
tyrosine	B-GENE
kinase	I-GENE
activity	O
compared	O
to	O
that	O
of	O
membranes	O
from	O
EGF	B-GENE
receptor	I-GENE
-	O
overexpressing	O
A431	O
cells	O
maximally	O
activated	O
by	O
EGF	B-GENE
.	O

Among	O
these	O
,	O
four	O
patients	O
had	O
the	O
AIDS	O
syndrome	O
,	O
while	O
42	O
individuals	O
were	O
HIV	O
carriers	O
.	O

Carcinogenic	O
action	O
of	O
groundnut	O
meal	O
containing	O
aflatoxin	O
in	O
rats	O
.	O

The	O
UASB	O
reactors	O
treated	O
a	O
VFA	O
mixture	O
(	O
with	O
an	O
acetate	O
:	O
propionate	O
:	O
butyrate	O
ratio	O
of	O
5	O
:	O
3	O
:	O
2	O
on	O
COD	O
basis	O
)	O
or	O
acetate	O
as	O
the	O
sole	O
substrate	O
at	O
different	O
COD	O
:	O
sulfate	O
ratios	O
.	O

Lack	O
of	O
changes	O
in	O
milk	O
production	O
and	O
milk	O
composition	O
suggest	O
that	O
acute	O
increases	O
in	O
somatotropin	B-GENE
with	O
concomitant	O
increases	O
in	O
insulin	B-GENE
are	O
not	O
sufficient	O
to	O
stimulate	O
synthesis	O
of	O
milk	O
and	O
milk	O
components	O
by	O
cows	O
during	O
established	O
lactation	O
.	O

The	O
initial	O
oral	O
administration	O
of	O
the	O
1	O
and	O
2	O
mg	O
/	O
kg	O
doses	O
of	O
enoximone	O
improved	O
central	O
hemodynamic	O
parameters	O
with	O
apparent	O
preferential	O
reduction	O
of	O
limb	O
vascular	O
resistance	O
and	O
augmentation	O
of	O
blood	O
flow	O
to	O
the	O
limb	O
region	O
(	O
peripheral	O
musculoskeletal	O
system	O
)	O
.	O

Genomic	O
clones	O
containing	O
the	O
C	O
.	O
briggsae	O
gene	O
are	O
able	O
to	O
completely	O
rescue	O
the	O
unc	B-GENE
-	I-GENE
119	I-GENE
phenotype	I-GENE
in	O
transgenic	O
C	O
.	O
elegans	O
mutants	O
.	O

Copyright	O
1999	O
Academic	O
Press	O
.	O

The	O
role	O
of	O
phosphorylation	O
on	O
receptor	O
desensitization	O
was	O
assessed	O
using	O
receptor	O
mutants	O
expressed	O
in	O
COS	O
cells	O
or	O
Chinese	O
hamster	O
lung	O
fibroblasts	O
.	O

For	O
il8ra	B-GENE
,	O
it	O
is	O
formed	O
from	O
two	O
exons	O
,	O
whereas	O
for	O
il8rb	B-GENE
,	O
seven	O
distinct	O
neutrophil	O
mRNAs	O
are	O
formed	O
by	O
alternative	O
splicing	O
of	O
11	O
exons	O
.	O

The	O
coding	O
sequence	O
of	O
rat	B-GENE
MEK	I-GENE
kinase	I-GENE
1	I-GENE
(	O
MEKK1	B-GENE
)	O
has	O
been	O
determined	O
from	O
multiple	O
,	O
independent	O
cDNA	O
clones	O
.	O

By	O
deletion	O
analysis	O
,	O
we	O
identified	O
the	O
regions	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
encoding	O
transformation	O
and	O
transactivation	O
functions	O
.	O

Several	O
waveforms	O
of	O
both	O
the	O
somatosensory	O
(	O
N20	O
,	O
P	O
/	O
N	O
30	O
,	O
and	O
P200	O
)	O
and	O
the	O
brainstem	O
auditory	O
-	O
evoked	O
response	O
(	O
I	O
,	O
III	O
,	O
IV	O
,	O
and	O
V	O
)	O
demonstrated	O
shorter	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
latencies	O
in	O
growth	O
-	O
retarded	O
fetuses	O
relative	O
to	O
normal	O
-	O
sized	O
fetuses	O
.	O

The	O
response	O
to	O
nitroglycerin	O
,	O
however	O
,	O
remained	O
intact	O
regardless	O
of	O
initial	O
reperfusion	O
pressure	O
.	O

Interactions	O
were	O
also	O
detected	O
between	O
full	O
-	O
length	O
HSF1	B-GENE
and	O
the	O
small	O
subunit	O
(	O
gamma	O
)	O
of	O
TFIIA	B-GENE
.	O

Pyknotic	O
osteocytes	O
increased	O
at	O
12	O
h	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
and	O
2	O
days	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
of	O
ischemia	O
.	O

Northern	O
blot	O
analysis	O
indicated	O
that	O
both	O
human	O
and	O
murine	O
genes	O
encode	O
approximately	O
6	O
-	O
kb	O
transcripts	O
.	O

ALT	B-GENE
(	O
alanine	B-GENE
aminotransferase	I-GENE
)	O
and	O
Hb	B-GENE
(	O
hemoglobin	B-GENE
)	O
appeared	O
to	O
be	O
predictive	O
for	O
efficacy	O
.	O

Maternal	O
behavior	O
was	O
assessed	O
using	O
observational	O
techniques	O
.	O

Effects	O
of	O
timepidium	O
bromide	O
(	O
TB	O
;	O
anticholinergic	O
agent	O
)	O
,	O
acetylcholine	O
(	O
ACh	O
)	O
and	O
neostigmine	O
(	O
Neost	O
)	O
on	O
gastric	O
and	O
duodenal	O
blood	O
flow	O
distribution	O
were	O
studied	O
by	O
the	O
use	O
of	O
131I	O
-	O
labeled	O
macroaggregated	O
human	O
serum	O
albumin	O
(	O
MAA	B-GENE
)	O
in	O
rabbits	O
.	O

Nucleotide	O
sequence	O
of	O
the	O
gag	B-GENE
gene	I-GENE
and	O
gag	B-GENE
-	O
pol	B-GENE
junction	O
of	O
feline	O
leukemia	O
virus	O
.	O

When	O
using	O
the	O
high	O
-	O
impedance	O
testing	O
device	O
,	O
the	O
post	O
shock	O
rhythm	O
was	O
initially	O
displayed	O
as	O
'	O
no	O
signal	O
'	O
(	O
Hewlett	O
Packard	O
XL	O
)	O
or	O
'	O
asystole	O
'	O
(	O
Physio	O
-	O
Control	O
LIFEPAK	O
9	O
)	O
.	O

The	O
plasma	O
steroid	O
levels	O
in	O
the	O
CAPD	O
patients	O
after	O
each	O
infusion	O
rate	O
were	O
equal	O
to	O
or	O
greater	O
than	O
the	O
levels	O
in	O
normal	O
subjects	O
.	O

Nramp2	B-GENE
contains	O
a	O
classical	O
iron	O
responsive	O
element	O
in	O
the	O
3	O
'	O
untranslated	O
region	O
that	O
confers	O
iron	O
dependent	O
mRNA	O
stabilization	O
.	O

In	O
addition	O
,	O
reduced	O
metabolism	O
to	O
cotinine	O
from	O
the	O
proliposomes	O
and	O
MP	O
was	O
apparently	O
responsible	O
for	O
the	O
sustained	O
plasma	O
nicotine	O
levels	O
.	O

D	O
.	O

BCR	B-GENE
-	O
ABL	B-GENE
expression	O
confers	O
cross	O
-	O
resistance	O
to	O
multiple	O
genotoxic	O
anticancer	O
drugs	O
by	O
inhibition	O
of	O
the	O
apoptotic	O
response	O
to	O
DNA	O
damage	O
in	O
association	O
with	O
cell	O
cycle	O
arrest	O
at	O
the	O
G2	O
-	O
M	O
restriction	O
point	O
.	O

When	O
a	O
longer	O
-	O
714	O
to	O
+	O
78	O
fragment	O
of	O
the	O
PBGD	B-GENE
promoter	I-GENE
is	O
used	O
,	O
the	O
-	O
70	O
GATA	O
mutant	O
still	O
displays	O
erythroid	O
-	O
specific	O
activity	O
and	O
is	O
cis	O
-	O
activated	O
by	O
the	O
5	B-GENE
'	I-GENE
HS	I-GENE
-	I-GENE
2	I-GENE
enhancer	I-GENE
,	O
while	O
the	O
-	O
100	O
CCACC	O
mutant	O
is	O
completely	O
inactive	O
in	O
the	O
absence	O
or	O
in	O
the	O
presence	O
of	O
the	O
5	B-GENE
'	I-GENE
HS	I-GENE
-	I-GENE
2	I-GENE
enhancer	I-GENE
.	O

Deletion	O
analysis	O
revealed	O
that	O
only	O
the	O
TM	O
domain	O
of	O
E2	B-GENE
was	O
required	O
for	O
Golgi	O
targeting	O
.	O

In	O
area	O
CA1	O
of	O
the	O
hippocampus	O
,	O
numbers	O
of	O
normal	O
neurons	O
were	O
increased	O
11	O
-	O
to	O
14	O
-	O
fold	O
by	O
MK	O
-	O
801	O
treatment	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Considering	O
these	O
two	O
facts	O
together	O
,	O
we	O
propose	O
that	O
vasectomy	O
may	O
lead	O
to	O
decrease	O
in	O
the	O
incidence	O
of	O
prostatic	O
tumors	O
-	O
a	O
disease	O
that	O
claims	O
nearly	O
22	O
,	O
000	O
lives	O
each	O
year	O
in	O
the	O
United	O
States	O
alone	O
.	O

Further	O
studies	O
aim	O
at	O
characterizing	O
the	O
trans	O
-	O
acting	O
factors	O
that	O
mediate	O
the	O
spatial	O
and	O
temporal	O
expression	O
of	O
Hox	B-GENE
genes	I-GENE
in	O
the	O
developing	O
embryo	O
.	O

The	O
protein	O
was	O
overexpressed	O
in	O
Escherichia	O
coli	O
and	O
purified	O
to	O
homogeneity	O
.	O

At	O
least	O
one	O
such	O
complex	O
is	O
eliminated	O
by	O
preincubating	O
the	O
nuclear	O
extract	O
with	O
an	O
antibody	O
with	O
broad	O
cross	O
-	O
reactivity	O
with	O
Ets	B-GENE
-	I-GENE
1	I-GENE
and	O
Ets	B-GENE
-	I-GENE
2	I-GENE
proteins	I-GENE
,	O
thus	O
confirming	O
that	O
an	O
ETS	B-GENE
transcription	I-GENE
factor	I-GENE
(	I-GENE
s	I-GENE
)	I-GENE
recognizes	O
the	O
-	O
12	O
motif	O
.	O

Paraplegia	O
associated	O
with	O
intraaortic	O
balloon	O
pump	O
counterpulsation	O
.	O

Gas	O
exchange	O
was	O
measured	O
breath	O
by	O
breath	O
.	O

BACKGROUND	O
:	O
Peripheral	O
kappa	B-GENE
receptor	I-GENE
agonists	O
may	O
provide	O
a	O
new	O
therapeutic	O
approach	O
for	O
the	O
treatment	O
of	O
functional	O
dyspepsia	O
.	O

Checking	O
for	O
patient	O
compliance	O
,	O
samples	O
(	O
n	O
=	O
10	O
)	O
with	O
a	O
FK	O
I	O
concentration	O
of	O
0	O
ng	O
/	O
mL	O
were	O
re	O
-	O
analyzed	O
.	O

The	O
Robert	O
Wood	O
Johnson	O
Foundation	O
:	O
billion	O
dollar	O
force	O
for	O
health	O
-	O
care	O
change	O
.	O

These	O
results	O
support	O
an	O
in	O
vivo	O
interaction	O
between	O
Nck	B-GENE
and	O
CKI	B-GENE
-	I-GENE
gamma2	I-GENE
and	O
suggest	O
that	O
CKI	B-GENE
-	I-GENE
gamma2	I-GENE
could	O
be	O
involved	O
in	O
signaling	O
pathways	O
downstream	O
of	O
RTKs	B-GENE
.	O

4	O
-	O
Hydroxyproline	O
assays	O
were	O
performed	O
to	O
determine	O
collagen	B-GENE
content	O
.	O

The	O
biological	O
basis	O
for	O
the	O
changes	O
in	O
CNAPs	O
produced	O
by	O
CS2	O
is	O
under	O
investigation	O
.	O

Non	O
-	O
suppressed	O
thyroidal	O
radioactive	O
iodine	O
uptake	O
(	O
RAIU	O
)	O
in	O
thyrotoxic	O
phase	O
in	O
a	O
case	O
of	O
subacute	O
thyroiditis	O
with	O
thyroid	O
-	O
stimulating	O
antibodies	O
(	O
TSAb	O
)	O
.	O

Blotting	O
analysis	O
of	O
intestinal	O
RNA	O
and	O
hybridization	O
of	O
the	O
blots	O
with	O
carboxy	O
apoB	B-GENE
cDNA	O
probes	O
produced	O
a	O
single	O
15	O
-	O
kb	O
hybridization	O
band	O
whereas	O
hybridization	O
with	O
amino	O
terminal	O
probes	O
produced	O
two	O
hybridization	O
bands	O
of	O
15	O
and	O
8	O
kb	O
.	O

The	O
temporal	O
expression	O
of	O
CRAlBP	B-GENE
is	O
similar	O
to	O
IRBP	B-GENE
while	O
bFGF	B-GENE
is	O
not	O
expressed	O
until	O
after	O
photoreceptor	O
differentiation	O
is	O
complete	O
.	O

Several	O
components	O
in	O
cytokine	O
signaling	O
remain	O
unidentified	O
.	O

Virgin	O
,	O
P	O
.	O

The	O
present	O
report	O
shows	O
that	O
a	O
cis	O
-	O
acting	O
element	O
between	O
-	O
189	O
and	O
-	O
175	O
bp	O
,	O
which	O
binds	O
thyroid	B-GENE
transcription	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
TTF	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
is	O
involved	O
in	O
both	O
activities	O
.	O

No	O
universally	O
accepted	O
standardized	O
classification	O
system	O
for	O
acne	O
vulgaris	O
exists	O
,	O
although	O
there	O
is	O
a	O
strong	O
need	O
for	O
it	O
.	O

Constant	O
slowing	O
of	O
median	O
MNCV	O
and	O
SNCV	O
and	O
ulnar	O
SNCV	O
without	O
changes	O
in	O
morphology	O
,	O
amplitude	O
and	O
duration	O
of	O
MAP	O
and	O
SAP	O
have	O
been	O
observed	O
in	O
92	O
patients	O
,	O
with	O
persistent	O
abnormalities	O
in	O
64	O
cases	O
after	O
six	O
months	O
.	O

Kudzu	O
extract	O
shows	O
potential	O
for	O
moderating	O
alcohol	O
abuse	O
.	O

Serum	O
IgG	B-GENE
and	O
IgA	B-GENE
level	O
were	O
decreased	O
.	O

A	O
novel	O
zinc	O
finger	O
-	O
containing	O
RNA	O
-	O
binding	O
protein	O
conserved	O
from	O
fruitflies	O
to	O
humans	O
.	O

High	O
-	O
affinity	O
binding	O
was	O
also	O
observed	O
with	O
recombinant	B-GENE
SH2	I-GENE
domains	I-GENE
from	O
v	B-GENE
-	I-GENE
src	I-GENE
and	O
v	B-GENE
-	I-GENE
fps	I-GENE
,	O
raising	O
the	O
possibility	O
of	O
protein	O
-	O
protein	O
interactions	O
between	O
various	O
members	O
of	O
the	O
cytoplasmic	B-GENE
PTK	I-GENE
family	I-GENE
.	O

The	O
M	O
-	O
phase	O
induction	O
activity	O
of	O
Cdc2	B-GENE
-	O
Cdc13	B-GENE
is	O
inhibited	O
by	O
Wee1	B-GENE
tyrosine	I-GENE
kinase	I-GENE
,	O
which	O
phosphorylates	O
Cdc2	B-GENE
on	O
tyrosine	O
-	O
15	O
.	O

Youssoufian	O
,	O
A	O
.	O

Since	O
1988	O
Modulit	O
-	O
SZ	O
-	O
20	O
has	O
been	O
tested	O
for	O
localization	O
of	O
nephroliths	O
and	O
ureteroliths	O
.	O

Lactate	O
,	O
pyruvate	O
and	O
actual	O
pH	O
values	O
in	O
the	O
venous	O
blood	O
of	O
newborn	O
calves	O

The	O
steady	O
-	O
state	O
levels	O
of	O
Cdk2	B-GENE
,	O
Cdk4	B-GENE
and	O
Cyclin	B-GENE
A	I-GENE
proteins	I-GENE
were	O
unaffected	O
by	O
HPR	O
,	O
while	O
those	O
of	O
Cyclin	B-GENE
D1	I-GENE
were	O
significantly	O
reduced	O
in	O
all	O
three	O
cell	O
lines	O
.	O

The	O
dermatoglyphic	O
pattern	O
demostrates	O
a	O
distal	O
triradius	O
and	O
small	O
whorl	O
abnormalities	O
.	O

The	O
experimental	O
results	O
suggest	O
equilibrium	O
complex	O
formation	O
between	O
OTC	O
and	O
PVP	O
,	O
it	O
being	O
mainly	O
the	O
complex	O
which	O
is	O
i	O
.	O
v	O
.	O
injected	O
when	O
both	O
products	O
are	O
combined	O
in	O
an	O
injection	O
formulation	O
.	O

The	O
MI	O
site	O
is	O
predictive	O
of	O
hemodynamic	O
left	O
ventricular	O
dysfunction	O
both	O
at	O
rest	O
and	O
during	O
exercise	O
:	O
anterior	O
MIs	O
are	O
more	O
impaired	O
than	O
inferior	O
MIs	O
.	O

The	O
median	O
survival	O
time	O
was	O
18	O
months	O
.	O

Studies	O
with	O
and	O
without	O
attenuating	O
media	O
were	O
performed	O
,	O
and	O
myocardium	O
-	O
to	O
-	O
defect	O
count	O
ratios	O
and	O
defect	O
sizes	O
from	O
dual	O
-	O
isotope	O
SPECT	O
images	O
were	O
compared	O
to	O
myocardium	O
-	O
to	O
-	O
defect	O
count	O
ratios	O
and	O
defect	O
sizes	O
from	O
single	O
-	O
isotope	O
(	O
201Tl	O
and	O
99mTc	O
)	O
SPECT	O
images	O
.	O

Biology	O
of	O
Anopheles	O
quadrimaculatus	O
under	O
field	O
conditions	O
in	O
central	O
Florida	O
.	O

This	O
transformation	O
suppression	O
by	O
Rb	B-GENE
was	O
further	O
shown	O
to	O
be	O
due	O
to	O
transcriptional	O
repression	O
of	O
neu	B-GENE
using	O
Rb	B-GENE
expressing	O
effector	O
plasmid	O
and	O
neu	B-GENE
promoter	O
-	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	O
gene	O
.	O

Collectively	O
,	O
a	O
unique	O
mechanism	O
involving	O
NF	B-GENE
-	I-GENE
ATp	I-GENE
appears	O
to	O
regulate	O
the	O
cell	O
type	O
-	O
specific	O
and	O
activation	O
-	O
dependent	O
expression	O
of	O
the	O
SCM	B-GENE
-	I-GENE
1	I-GENE
genes	I-GENE
.	O

In	O
seven	O
patients	O
(	O
7	O
.	O
8	O
%	O
)	O
with	O
new	O
Q	O
-	O
waves	O
and	O
a	O
pathologic	O
CK	B-GENE
-	I-GENE
MB	I-GENE
profile	O
(	O
group	O
II	O
)	O
troponin	B-GENE
T	I-GENE
reached	O
median	O
levels	O
of	O
10	O
.	O
47	O
micrograms	O
/	O
l	O
(	O
quartile	O
6	O
.	O
34	O
-	O
12	O
.	O
50	O
micrograms	O
/	O
l	O
)	O
(	O
P	O
<	O
0	O
.	O
001	O
I	O
vs	O
II	O
)	O
.	O

EMG	O
-	O
based	O
measures	O
of	O
fatigue	O
during	O
a	O
repetitive	O
squat	O
exercise	O
.	O

CONCLUSIONS	O
:	O
The	O
results	O
show	O
that	O
intranasal	O
challenge	O
with	O
FLU	O
induces	O
changes	O
in	O
leukocyte	O
histamine	O
release	O
,	O
but	O
not	O
other	O
systemic	O
immune	O
and	O
inflammatory	O
responses	O
.	O

Southern	O
blot	O
analysis	O
revealed	O
that	O
CCaMK	B-GENE
is	O
encoded	O
by	O
a	O
single	O
gene	O
.	O

The	O
gamma	B-GENE
-	I-GENE
GCS	I-GENE
gene	I-GENE
is	O
expressed	O
ubiquitously	O
and	O
induced	O
coordinately	O
with	O
NAD	B-GENE
(	I-GENE
P	I-GENE
)	I-GENE
H	I-GENE
:	I-GENE
quinone	I-GENE
oxidoreductase	I-GENE
(	I-GENE
1	I-GENE
)	I-GENE
(	O
NQO1	B-GENE
)	O
and	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
Ya	I-GENE
(	O
GST	B-GENE
Ya	I-GENE
)	O
in	O
response	O
to	O
xenobiotics	O
and	O
antioxidants	O
.	O

A	O
fine	O
-	O
structure	O
radiation	O
hybrid	O
map	O
for	O
the	O
region	O
that	O
extends	O
from	O
D8S520	B-GENE
(	O
distal	O
)	O
to	O
D8S1759	B-GENE
(	O
proximal	O
)	O
was	O
prepared	O
,	O
followed	O
by	O
construction	O
of	O
a	O
single	O
,	O
integrated	O
YAC	O
/	O
BAC	O
contig	O
for	O
the	O
interval	O
.	O

The	O
N1	O
-	O
P2	O
amplitudes	O
of	O
the	O
AEP	O
decreased	O
with	O
increasing	O
strength	O
of	O
muscular	O
innervation	O
.	O

Measurements	O
in	O
rats	O
given	O
a	O
dose	O
of	O
propranolol	O
that	O
partially	O
inhibited	O
the	O
NA	O
-	O
induced	O
increase	O
in	O
Q	O
to	O
IBAT	O
indicated	O
that	O
the	O
decline	O
in	O
ENAIBAT	O
was	O
attributable	O
primarily	O
to	O
the	O
increase	O
in	O
Q	O
rather	O
than	O
to	O
increasing	O
saturation	O
of	O
uptake	O
mechanisms	O
.	O

Messenger	O
RNA	O
for	O
the	O
Ad2	B-GENE
DNA	I-GENE
binding	I-GENE
protein	I-GENE
:	O
DNA	O
sequences	O
encoding	O
the	O
first	O
leader	O
and	O
heterogenity	O
at	O
the	O
mRNA	O
5	O
'	O
end	O
.	O

All	O
rights	O
reserved	O
.	O

These	O
results	O
were	O
not	O
obtained	O
using	O
either	O
preimmune	O
sera	O
or	O
antiserum	O
specific	O
for	O
the	O
luminal	O
portion	O
of	O
the	O
glycoprotein	O
precursor	O
.	O

The	O
yeast	O
genome	O
contains	O
a	O
single	O
ORD1	B-GENE
gene	I-GENE
that	O
resides	O
on	O
chromosome	O
XI	O
.	O

HNF4alpha7	B-GENE
mRNA	I-GENE
is	O
also	O
found	O
in	O
totipotent	O
embryonic	O
stem	O
cells	O
.	O

Northern	O
(	O
RNA	O
)	O
blot	O
hybridization	O
analysis	O
with	O
the	O
p68c	B-GENE
-	I-GENE
ets	I-GENE
-	I-GENE
1	I-GENE
-	O
specific	O
sequence	O
and	O
RNase	B-GENE
protection	O
experiments	O
showed	O
that	O
the	O
corresponding	O
mRNA	O
was	O
expressed	O
in	O
normal	O
chicken	O
spleen	O
and	O
not	O
in	O
normal	O
chicken	O
thymus	O
or	O
in	O
various	O
T	O
lymphoid	O
cell	O
lines	O
.	O

The	O
fz	B-GENE
-	I-GENE
1	I-GENE
and	O
fz	B-GENE
-	I-GENE
2	I-GENE
genes	I-GENE
are	O
widely	O
expressed	O
in	O
rat	O
tissues	O
with	O
the	O
highest	O
steady	O
-	O
state	O
levels	O
of	O
mRNA	O
in	O
kidney	O
,	O
liver	O
,	O
heart	O
,	O
uterus	O
,	O
and	O
ovary	O
.	O
fz	B-GENE
-	I-GENE
1	I-GENE
and	I-GENE
-	I-GENE
2	I-GENE
mRNA	I-GENE
levels	O
were	O
greater	O
in	O
neonatal	O
than	O
in	O
corresponding	O
adult	O
tissues	O
.	O

We	O
carried	O
out	O
two	O
experiments	O
to	O
investigate	O
this	O
problem	O
.	O

Mean	O
concentration	O
of	O
insulin	B-GENE
in	O
maternal	O
plasma	O
across	O
all	O
sampling	O
times	O
was	O
higher	O
in	O
ethanol	O
treated	O
animals	O
.	O

Steady	O
-	O
state	O
levels	O
of	O
murine	B-GENE
MMR	I-GENE
mRNA	I-GENE
were	O
measured	O
in	O
the	O
macrophage	O
cell	O
line	O
J774E	O
,	O
which	O
is	O
known	O
to	O
express	O
the	O
protein	O
at	O
the	O
cell	O
surface	O
.	O

In	O
this	O
work	O
,	O
we	O
have	O
used	O
Xenopus	O
oocyte	O
maturation	O
as	O
a	O
read	O
-	O
out	O
for	O
examining	O
the	O
ability	O
of	O
the	O
neu	B-GENE
tyrosine	B-GENE
kinase	I-GENE
(	O
p185neu	B-GENE
)	O
to	O
participate	O
with	O
the	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
(	I-GENE
EGF	I-GENE
)	I-GENE
receptor	I-GENE
in	O
a	O
common	O
signal	O
transduction	O
pathway	O
.	O

Triaxiality	O
in	O
the	O
proton	O
-	O
neutron	O
interacting	O
boson	O
model	O
:	O
Perturbed	O
O	O
(	O
6	O
)	O
symmetry	O
with	O
application	O
to	O
the	O
mass	O
A	O

Role	O
of	O
distinct	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
pathways	O
and	O
cooperation	O
between	O
Ets	B-GENE
-	I-GENE
2	I-GENE
,	O
ATF	B-GENE
-	I-GENE
2	I-GENE
,	O
and	O
Jun	B-GENE
family	I-GENE
members	I-GENE
in	O
human	B-GENE
urokinase	I-GENE
-	I-GENE
type	I-GENE
plasminogen	I-GENE
activator	I-GENE
gene	I-GENE
induction	O
by	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
and	O
tetradecanoyl	O
phorbol	O
acetate	O
.	O

Comparative	O
volumetric	O
analysis	O
is	O
defined	O
as	O
the	O
difference	O
between	O
mean	O
corpuscular	O
erythrocyte	O
volume	O
in	O
peripheral	O
blood	O
(	O
MCVB	O
)	O
diluted	O
in	O
urine	O
supernatant	O
after	O
centrifugation	O
and	O
mean	O
corpuscular	O
volume	O
of	O
urinary	O
erythrocytes	O
(	O
MCVU	O
)	O
.	O

To	O
assess	O
whether	O
thallium	O
-	O
201	O
thallous	O
chloride	O
(	O
Tl	O
)	O
can	O
detect	O
childhood	O
tumors	O
and	O
whether	O
diagnostic	O
effectiveness	O
improves	O
with	O
combined	O
blood	O
flow	O
imaging	O
,	O
28	O
children	O
(	O
1	O
.	O
0	O
-	O
18	O
.	O
6	O
years	O
)	O
were	O
studied	O
using	O
single	O
photon	O
emission	O
computed	O
tomography	O
(	O
SPECT	O
)	O
:	O
Tl	O
(	O
1	O
.	O
3	O
-	O
1	O
.	O
8	O
mCi	O
intravenously	O
)	O
,	O
followed	O
in	O
13	O
of	O
the	O
patients	O
by	O
technetium	O
-	O
99m	O
-	O
hexamethylpropyleneamine	O
oxime	O
(	O
99mTc	O
-	O
HMPAO	O
;	O
8	O
-	O
18	O
mCi	O
intravenously	O
)	O
.	O

The	O
role	O
of	O
NUT1	B-GENE
and	O
regulation	O
of	O
nitrogen	O
metabolism	O
in	O
the	O
disease	O
process	O
was	O
evaluated	O
by	O
pathogenicity	O
assays	O
.	O

Analysis	O
of	O
tobacco	O
mRNA	O
using	O
the	O
ACBF	B-GENE
cDNA	I-GENE
as	O
probe	O
showed	O
that	O
while	O
ACBF	B-GENE
mRNA	I-GENE
was	O
present	O
in	O
all	O
tissues	O
examined	O
,	O
the	O
highest	O
transcript	O
accumulation	O
occurred	O
in	O
stem	O
tissues	O
.	O

When	O
PCR	O
was	O
used	O
to	O
amplify	O
agar	O
cultures	O
which	O
do	O
not	O
express	O
the	O
fimbriae	O
,	O
the	O
switch	O
region	O
was	O
OFF	O
only	O
.	O

We	O
therefore	O
investigated	O
whether	O
the	O
promoter	O
activity	O
of	O
the	O
mouse	B-GENE
TRH	I-GENE
gene	I-GENE
is	O
directly	O
regulated	O
by	O
RA	O
using	O
a	O
transient	O
transfection	O
assay	O
into	O
CV	O
-	O
1	O
cells	O
.	O

This	O
study	O
tests	O
the	O
hypothesis	O
that	O
O2	O
is	O
a	O
critical	O
component	O
in	O
myocardial	O
protection	O
afforded	O
by	O
BCP	O
.	O

Sin4	B-GENE
and	O
Srb10	B-GENE
,	O
components	O
of	O
specific	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
sub	I-GENE
-	I-GENE
complexes	I-GENE
that	O
are	O
required	O
for	O
Ssn6	B-GENE
-	O
Tup1	B-GENE
repression	O
activity	O
,	O
are	O
found	O
to	O
be	O
required	O
for	O
Sfl1	B-GENE
repression	O
function	O
.	O

Functional	O
PET	O
scanning	O
in	O
the	O
preoperative	O
assessment	O
of	O
cerebral	O
arteriovenous	O
malformations	O
.	O

The	O
MEE	O
was	O
significantly	O
greater	O
than	O
the	O
BEE	O
and	O
significantly	O
less	O
than	O
the	O
calculated	O
energy	O
expenditure	O
.	O

Differences	O
were	O
not	O
found	O
in	O
colons	O
by	O
SEM	O
.	O

Consistent	O
with	O
this	O
,	O
rh5	B-GENE
expression	O
in	O
R8	B-GENE
disappears	O
when	O
R7	O
cells	O
are	O
absent	O
(	O
in	O
sevenless	B-GENE
mutant	I-GENE
)	O
.	O

The	O
human	O
RIL	B-GENE
gene	I-GENE
:	O
mapping	O
to	O
human	O
chromosome	O
5q31	O
.	O
1	O
,	O
genomic	O
organization	O
and	O
alternative	O
transcripts	O
.	O

These	O
findings	O
indicated	O
that	O
p35	B-GENE
is	O
a	O
trans	O
-	O
dominant	O
factor	O
that	O
facilitates	O
AcMNPV	O
growth	O
in	O
a	O
cell	O
line	O
-	O
specific	O
manner	O
.	O

We	O
found	O
remarkable	O
differences	O
in	O
the	O
expression	O
patterns	O
of	O
MTB	B-GENE
-	I-GENE
Zf	I-GENE
mRNA	I-GENE
and	O
two	O
other	O
hybridizable	O
mRNAs	O
of	O
5kb	O
and	O
8	O
.	O
5	O
kb	O
when	O
human	O
brain	O
and	O
primary	O
brain	O
tumors	O
were	O
compared	O
.	O

We	O
have	O
recently	O
shown	O
that	O
induced	O
expression	O
of	O
a	O
CDK	B-GENE
target	O
site	O
-	O
deficient	O
mutant	O
,	O
Op18	B-GENE
-	O
S25A	O
,	O
S38A	O
,	O
blocks	O
human	O
cell	O
lines	O
during	O
G2	O
/	O
M	O
transition	O
.	O

ATF6	B-GENE
,	O
a	O
basic	B-GENE
-	I-GENE
leucine	I-GENE
zipper	I-GENE
protein	I-GENE
,	O
was	O
isolated	O
by	O
binding	O
to	O
SRF	B-GENE
and	O
in	O
particular	O
to	O
its	O
transcriptional	O
activation	O
domain	O
.	O

An	O
ICU	O
length	O
of	O
stay	O
shorter	O
than	O
24	O
h	O
was	O
not	O
related	O
to	O
the	O
frequency	O
of	O
group	O
C	O
errors	O
.	O

Primers	O
were	O
developed	O
for	O
specific	O
amplification	O
of	O
9804	B-GENE
gene	I-GENE
fragments	I-GENE
.	O

These	O
results	O
demonstrate	O
that	O
GGTase	B-GENE
-	I-GENE
I	I-GENE
inhibitors	O
arrest	O
cells	O
in	O
G0	O
/	O
G1	O
and	O
induce	O
accumulation	O
of	O
p21WAF	B-GENE
in	O
a	O
p53	B-GENE
-	O
independent	O
manner	O
and	O
that	O
FTase	B-GENE
inhibitors	O
can	O
interfere	O
with	O
cell	O
cycle	O
events	O
by	O
a	O
mechanism	O
that	O
involves	O
neither	O
p21WAF	B-GENE
nor	O
p27KIP	B-GENE
.	O

These	O
results	O
provide	O
strong	O
evidence	O
that	O
conserved	O
interhelical	O
packing	O
interactions	O
in	O
the	O
gp41	B-GENE
core	I-GENE
are	O
important	O
determinants	O
of	O
HIV	O
-	O
1	O
entry	O
and	O
its	O
inhibition	O
.	O

Thus	O
,	O
CR2	B-GENE
possesses	O
an	O
essential	O
function	O
besides	O
pRb	B-GENE
-	O
binding	O
.	O

Injection	O
of	O
horseradish	B-GENE
peroxidase	I-GENE
(	O
HRP	B-GENE
)	O
into	O
the	O
cerebellar	O
flocculus	O
of	O
the	O
rat	O
was	O
employed	O
to	O
identify	O
neurons	O
in	O
the	O
abducens	O
nucleus	O
that	O
project	O
to	O
the	O
flocculus	O
.	O

Natl	O
.	O

In	O
contrast	O
,	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
activation	O
was	O
observed	O
in	O
these	O
cells	O
after	O
PMA	O
stimulation	O
.	O

From	O
our	O
own	O
investigations	O
on	O
phantoms	O
,	O
the	O
smallest	O
signal	O
-	O
to	O
-	O
noise	O
ratio	O
(	O
delta	O
S	O
min	O
/	O
delta	O
R	O
)	O
was	O
obtained	O
which	O
determines	O
the	O
minimal	O
contrast	O
,	O
given	O
the	O
film	O
properties	O
(	O
film	O
response	O
S	O
,	O
film	O
gradient	O
gamma	O
)	O
and	O
the	O
amount	O
of	O
scatter	O
.	O

It	O
encodes	O
a	O
sequence	O
-	O
specific	O
transcription	O
factor	O
that	O
controls	O
,	O
in	O
concert	O
with	O
other	O
gene	O
products	O
,	O
differentiative	O
pathways	O
of	O
tissues	O
in	O
which	O
Scr	B-GENE
is	O
expressed	O
.	O

We	O
functionally	O
characterised	O
AtXPO1	B-GENE
by	O
its	O
interaction	O
with	O
NESs	O
of	O
animal	O
and	O
plant	O
proteins	O
,	O
which	O
is	O
inhibited	O
by	O
the	O
cytotoxin	O
leptomycin	O
B	O
(	O
LMB	O
)	O
,	O
and	O
also	O
by	O
its	O
interaction	O
with	O
the	O
small	B-GENE
GTPase	I-GENE
Ran1	B-GENE
in	O
the	O
yeast	O
two	O
-	O
hybrid	O
system	O
.	O

The	O
use	O
of	O
self	O
-	O
measured	O
blood	O
pressure	O
determinations	O
in	O
assessing	O
dynamics	O
of	O
drug	O
compliance	O
in	O
a	O
study	O
with	O
amlodipine	O
once	O
a	O
day	O
,	O
morning	O
versus	O
evening	O
.	O

The	O
enzyme	O
encoded	O
by	O
the	O
cloned	O
fragment	O
is	O
equally	O
active	O
on	O
pyruvate	O
and	O
hydroxypyruvate	O
,	O
indicating	O
that	O
the	O
enzyme	O
has	O
both	O
D	B-GENE
-	I-GENE
lactate	I-GENE
and	I-GENE
D	I-GENE
-	I-GENE
glycerate	I-GENE
dehydrogenase	I-GENE
activities	O
.	O

We	O
propose	O
that	O
unc	B-GENE
-	I-GENE
37	I-GENE
may	O
be	O
regulated	O
by	O
unc	B-GENE
-	I-GENE
4	I-GENE
.	O

The	O
gag	B-GENE
-	O
myc	B-GENE
proteins	O
encoded	O
by	O
these	O
variants	O
efficiently	O
localized	O
to	O
the	O
cell	O
nucleus	O
.	O

From	O
the	O
supposition	O
that	O
there	O
exists	O
a	O
possible	O
connection	O
between	O
certain	O
psychopathological	O
symptoms	O
,	O
and	O
/	O
or	O
syndromes	O
(	O
e	O
.	O
g	O
.	O
,	O
hallucinations	O
)	O
and	O
regional	O
cerebral	O
dysfunction	O
,	O
patients	O
suffering	O
from	O
auditory	O
and	O
tactile	O
hallucinations	O
were	O
investigated	O
,	O
in	O
a	O
symptom	O
-	O
oriented	O
study	O
,	O
using	O
the	O
method	O
of	O
technetium	O
-	O
99m	O
-	O
Hexamethyl	O
-	O
propylenamine	O
Oxime	O
(	O
99m	O
-	O
Tc	O
-	O
HMPAO	O
)	O
-	O
Single	O
Photon	O
Emission	O
Computed	O
Tomography	O
(	O
SPECT	O
)	O
and	O
compared	O
with	O
normal	O
controls	O
.	O

The	O
encoded	O
260	B-GENE
-	I-GENE
amino	I-GENE
-	I-GENE
acid	I-GENE
(	I-GENE
aa	I-GENE
)	I-GENE
(	I-GENE
H1	I-GENE
-	I-GENE
I	I-GENE
)	I-GENE
and	O
240	B-GENE
-	I-GENE
aa	I-GENE
(	I-GENE
H1	I-GENE
-	I-GENE
II	I-GENE
)	I-GENE
polypeptides	I-GENE
possess	O
the	O
typical	O
tripartite	O
organization	O
of	O
animal	B-GENE
H1	I-GENE
histones	I-GENE
,	O
with	O
variable	O
N	O
-	O
and	O
C	O
-	O
terminal	O
domains	O
flanking	O
a	O
conserved	O
'	O
globular	O
'	O
DNA	O
-	O
binding	O
domain	O
.	O

The	O
best	O
-	O
studied	O
neurotrophin	O
,	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
(	O
NGF	B-GENE
)	O
,	O
is	O
a	O
major	O
survival	O
factor	O
in	O
sympathetic	O
and	O
sensory	O
neurons	O
and	O
promotes	O
differentiation	O
in	O
a	O
well	O
-	O
studied	O
model	O
system	O
,	O
PC12	O
cells	O
.	O

In	O
a	O
subsequent	O
phase	O
-	O
II	O
clinical	O
trial	O
safety	O
and	O
efficacy	O
of	O
transrectal	O
HIFU	O
as	O
a	O
novel	O
minimally	O
invasive	O
treatment	O
modality	O
for	O
patients	O
with	O
symptomatic	O
benign	O
prostatic	O
hyperplasia	O
(	O
BPH	O
;	O
n	O
=	O
102	O
)	O
was	O
determined	O
.	O

A	O
novel	O
alternative	O
spliced	O
variant	O
of	O
the	O
transcription	O
factor	O
AP2alpha	B-GENE
is	O
expressed	O
in	O
the	O
murine	O
ocular	O
lens	O
.	O

CONCLUSION	O
:	O
high	O
resolution	O
MF	O
-	O
ERG	O
seems	O
more	O
sensitive	O
than	O
low	O
resolution	O
MF	O
-	O
ERG	O
.	O

The	O
residual	O
small	O
rRNAs	O
in	O
[	O
poky	O
]	O
appear	O
to	O
be	O
synthesized	O
via	O
the	O
upstream	O
promoter	O
(	O
s	O
)	O
,	O
but	O
are	O
missing	O
37	O
-	O
44	O
nucleotides	O
from	O
their	O
5	O
'	O
ends	O
,	O
indicating	O
either	O
that	O
pre	O
-	O
rRNAs	O
are	O
processed	O
abnormally	O
or	O
that	O
abnormal	O
5	O
'	O
RNA	O
ends	O
are	O
unstable	O
.	O

Homology	O
is	O
much	O
higher	O
(	O
64	O
%	O
)	O
between	O
the	O
28	O
-	O
kDa	O
protein	O
and	O
regions	O
that	O
are	O
strongly	O
conserved	O
among	O
the	O
members	O
of	O
the	O
serine	B-GENE
protease	I-GENE
family	I-GENE
.	O

In	O
contrast	O
,	O
inactivation	O
of	O
the	O
Sir4p	B-GENE
-	I-GENE
interacting	I-GENE
protein	I-GENE
Rap1p	I-GENE
reduces	O
partitioning	O
by	O
a	O
LexA	B-GENE
-	O
Sir4p	B-GENE
fusion	O
.	O

Childbirth	O
and	O
authoritative	O
knowledge	O
.	O

Thus	O
,	O
the	O
end	O
of	O
a	O
linearized	O
DNA	O
fragment	O
can	O
initiate	O
new	O
DNA	O
synthesis	O
by	O
BIR	O
in	O
which	O
the	O
newly	O
synthesized	O
DNA	O
is	O
displaced	O
and	O
subsequently	O
forms	O
circles	O
by	O
NHEJ	O
.	O

The	O
relationship	O
between	O
polymorphonuclear	O
granulocytes	O
and	O
cartilage	O
destruction	O
in	O
rheumatoid	O
arthritis	O
.	O

From	O
the	O
deduced	O
amino	O
acid	O
sequence	O
,	O
a	O
molecular	O
weight	O
of	O
38	O
,	O
549	O
was	O
calculated	O
for	O
the	O
ADH	B-GENE
subunit	I-GENE
.	O

Nine	O
months	O
after	O
the	O
end	O
of	O
the	O
vaccination	O
anti	B-GENE
-	I-GENE
HBsAg	I-GENE
levels	O
had	O
dropped	O
to	O
9	O
+	O
/	O
-	O
4	O
IU	O
/	O
1	O
(	O
M	O
+	O
/	O
-	O
SE	O
)	O
,	O
with	O
a	O
geometric	O
mean	O
of	O
5	O
IU	O
/	O
1	O
,	O
in	O
the	O
nine	O
remaining	O
evaluable	O
patients	O
.	O

The	O
point	O
mutation	O
Asp	O
-	O
316	O
-	O
-	O
>	O
Asn	O
in	O
the	O
C	O
-	O
terminus	O
of	O
p38	B-GENE
,	O
analogous	O
to	O
the	O
ERK2	B-GENE
(	O
extracellular	B-GENE
-	I-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
2	I-GENE
)	O
sevenmaker	B-GENE
mutation	O
,	O
dramatically	O
decreases	O
its	O
binding	O
to	O
MKP	B-GENE
-	I-GENE
1	I-GENE
and	O
substantially	O
compromises	O
its	O
stimulatory	O
effect	O
on	O
the	O
catalytic	O
activity	O
of	O
this	O
phosphatase	O
.	O

Cortical	O
somatosensory	O
evoked	O
potentials	O
to	O
median	O
nerve	O
stimulation	O
revealed	O
significantly	O
delayed	O
peak	O
latencies	O
of	O
N20	O
,	O
P20	O
,	O
P25	O
,	O
and	O
N26	O
,	O
although	O
N16	O
latency	O
was	O
normal	O
.	O

Catalase	B-GENE
plays	O
a	O
key	O
role	O
as	O
an	O
antioxidant	O
,	O
protecting	O
aerobic	O
organisms	O
from	O
the	O
toxic	O
effects	O
of	O
hydrogen	O
peroxide	O
,	O
and	O
in	O
some	O
cases	O
has	O
been	O
postulated	O
to	O
be	O
a	O
virulence	O
factor	O
.	O

Prazosin	O
in	O
the	O
treatment	O
of	O
high	O
blood	O
pressure	O

The	O
results	O
suggest	O
that	O
proenzyme	O
processing	O
is	O
not	O
essential	O
for	O
secretion	O
of	O
PC2	B-GENE
,	O
but	O
peptides	O
containing	O
mutations	O
that	O
affect	O
the	O
ability	O
of	O
the	O
propeptide	O
(	O
and	O
cleavage	O
sites	O
)	O
to	O
fold	O
within	O
the	O
catalytic	O
pocket	O
are	O
not	O
transferred	O
beyond	O
the	O
early	O
stages	O
of	O
the	O
secretory	O
pathway	O
.	O

Cloning	O
,	O
sequence	O
analysis	O
,	O
and	O
expression	O
of	O
the	O
gene	B-GENE
encoding	I-GENE
formaldehyde	I-GENE
dismutase	I-GENE
from	I-GENE
Pseudomonas	I-GENE
putida	I-GENE
F61	I-GENE
.	O

Taking	O
into	O
account	O
certain	O
well	O
defined	O
conditions	O
(	O
frequent	O
feedings	O
,	O
no	O
supplementary	O
feeding	O
before	O
4	O
-	O
6	O
months	O
,	O
method	O
only	O
to	O
be	O
used	O
in	O
the	O
absence	O
of	O
menstruation	O
)	O
,	O
LAM	O
can	O
be	O
relied	O
on	O
for	O
contraceptive	O
protection	O
for	O
up	O
to	O
1	O
year	O
post	O
partum	O
.	O

The	O
bioconversion	O
of	O
penicillin	O
G	O
,	O
an	O
inexpensive	O
substrate	O
,	O
to	O
the	O
valuable	O
intermediate	O
for	O
semisynthetic	O
cephalosporin	O
production	O
,	O
deacetoxycephalosporin	O
G	O
(	O
DAOG	O
)	O
,	O
had	O
been	O
recently	O
shown	O
to	O
be	O
increased	O
by	O
eliminating	O
agitation	O
and	O
adding	O
decane	O
.	O

Doctors	O
given	O
intrathecal	O
methotrexate	O
had	O
headache	O
when	O
20	O
gauge	O
standard	O
needle	O
was	O
used	O
.	O

The	O
IGFBP	B-GENE
-	I-GENE
1	I-GENE
IRS	B-GENE
and	O
PEPCK	B-GENE
IRS	B-GENE
both	O
bind	O
the	O
alpha	O
and	O
beta	O
forms	O
of	O
hepatic	B-GENE
nuclear	I-GENE
factor	I-GENE
3	I-GENE
(	O
HNF	B-GENE
-	I-GENE
3	I-GENE
)	O
,	O
although	O
the	O
latter	O
does	O
so	O
with	O
a	O
sixfold	O
-	O
lower	O
relative	O
affinity	O
.	O

Free	O
protein	B-GENE
S	I-GENE
deficiency	O
in	O
acute	O
ischemic	O
stroke	O
.	O

Low	O
-	O
affinity	O
E2	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
mediates	O
downmodulation	O
of	O
E2	B-GENE
transactivation	O
of	O
the	O
human	B-GENE
papillomavirus	I-GENE
type	I-GENE
8	I-GENE
late	I-GENE
promoter	I-GENE
.	O

This	O
domain	O
encompasses	O
the	O
region	O
of	O
ARP	B-GENE
-	I-GENE
1	I-GENE
/	O
COUP	B-GENE
-	I-GENE
TFII	I-GENE
corresponding	O
to	O
helices	O
3	O
to	O
12	O
in	O
the	O
recently	O
published	O
crystal	O
structure	O
of	O
other	O
members	O
of	O
the	O
nuclear	B-GENE
receptor	I-GENE
superfamily	I-GENE
.	O

Our	O
data	O
suggest	O
that	O
the	O
ZF	B-GENE
-	I-GENE
HD	I-GENE
class	O
of	O
homeodomain	B-GENE
proteins	I-GENE
may	O
be	O
involved	O
in	O
the	O
establishment	O
of	O
the	O
characteristic	O
expression	O
pattern	O
of	O
the	O
C4	B-GENE
PEPCase	I-GENE
gene	I-GENE
.	O

When	O
medical	O
aid	O
was	O
sought	O
a	O
false	O
history	O
was	O
given	O
and	O
the	O
true	O
nature	O
of	O
the	O
child	O
'	O
s	O
illness	O
,	O
heat	O
stroke	O
,	O
was	O
not	O
determined	O
until	O
after	O
death	O
.	O

BACKGROUND	O
.	O

To	O
test	O
the	O
role	O
of	O
myb	B-GENE
family	I-GENE
members	I-GENE
in	O
progression	O
through	O
the	O
cell	O
cycle	O
,	O
we	O
comicroinjected	O
c	B-GENE
-	I-GENE
myc	I-GENE
and	O
myb	B-GENE
expression	O
vectors	O
into	O
serum	O
-	O
deprived	O
quiescent	O
SMCs	O
.	O

Previous	O
studies	O
have	O
shown	O
that	O
the	O
IME1	B-GENE
gene	I-GENE
is	O
required	O
for	O
sporulation	O
and	O
the	O
expression	O
of	O
meiosis	O
specific	O
genes	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

Cytogenetic	O
structures	O
showed	O
a	O
mixte	O
karyotype	O
:	O
mosaicim	O
46	O
XX	O
/	O
46	O
XY	O
with	O
a	O
ratio	O
of	O
a	O
80	O
/	O
20	O
.	O

CONCLUSION	O
:	O
Ultrasound	O
biomicroscopy	O
is	O
a	O
useful	O
tool	O
for	O
the	O
evaluation	O
of	O
APVR	O
,	O
which	O
is	O
difficult	O
by	O
ordinary	O
methods	O
.	O

Morphological	O
-	O
functional	O
status	O
of	O
the	O
edentulous	O
mandible	O
and	O
selection	O
of	O
the	O
most	O
effective	O
method	O
for	O
functional	O
impression	O
-	O
taking	O

Eight	O
of	O
the	O
17	O
seropositive	O
patients	O
failed	O
to	O
develop	O
detectable	O
hepatitis	B-GENE
B	I-GENE
surface	I-GENE
antibody	I-GENE
within	O
three	O
months	O
of	O
the	O
third	O
injection	O
compared	O
with	O
only	O
one	O
of	O
the	O
18	O
seronegative	O
patients	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Like	O
the	O
human	O
gene	O
,	O
the	O
Drosophila	O
gene	O
encodes	O
at	O
least	O
three	O
isoforms	O
of	O
full	B-GENE
length	I-GENE
dystrophin	I-GENE
-	I-GENE
like	I-GENE
proteins	I-GENE
(	O
dmDLP1	B-GENE
,	O
dmDLP2	B-GENE
and	O
dmDLP3	B-GENE
,	O
)	O
,	O
regulated	O
by	O
different	O
promoters	O
located	O
at	O
the	O
5	O
'	O
end	O
of	O
the	O
gene	O
,	O
and	O
a	O
smaller	O
product	O
regulated	O
by	O
an	O
internal	O
promoter	O
(	O
dmDp186	B-GENE
)	O
.	O

In	O
this	O
study	O
,	O
the	O
case	O
of	O
a	O
patient	O
presenting	O
a	O
second	O
hepatocellular	O
carcinoma	O
13	O
years	O
after	O
resection	O
of	O
a	O
first	O
tumor	O
of	O
the	O
same	O
type	O
is	O
reported	O
.	O

The	O
equation	O
for	O
mean	O
trabecular	O
number	O
passed	O
the	O
test	O
,	O
whereas	O
the	O
validity	O
of	O
the	O
equations	O
for	O
mean	O
trabecular	O
separation	O
and	O
Tb	O
.	O
Wi	O
appeared	O
limited	O
.	O

Although	O
the	O
only	O
authoritative	O
way	O
to	O
determine	O
the	O
effect	O
of	O
diet	O
on	O
urinary	O
pH	O
is	O
a	O
feeding	O
trial	O
,	O
there	O
is	O
no	O
universally	O
accepted	O
protocol	O
for	O
measuring	O
urinary	O
pH	O
.	O

The	O
performances	O
of	O
two	O
tests	O
,	O
the	O
ProstAsure	O
index	O
and	O
the	O
percent	O
free	O
PSA	B-GENE
test	O
,	O
were	O
evaluated	O
in	O
detecting	O
cancer	O
.	O

But	O
if	O
one	O
equalizes	O
the	O
upper	O
limits	O
of	O
normal	O
for	O
both	O
markers	O
to	O
a	O
common	O
95	O
%	O
specificity	O
,	O
the	O
tumour	O
-	O
indicating	O
sensitivity	O
of	O
CA	B-GENE
19	I-GENE
-	I-GENE
9	I-GENE
clearly	O
surpasses	O
that	O
of	O
CA	B-GENE
50	I-GENE
.	O

For	O
economical	O
reasons	O
,	O
we	O
could	O
not	O
send	O
a	O
questionnaire	O
to	O
all	O
the	O
35	O
,	O
779	O
individuals	O
,	O
but	O
based	O
the	O
investigation	O
on	O
a	O
SRS	O
of	O
4	O
,	O
000	O
men	O
,	O
post	O
-	O
stratified	O
in	O
a	O
high	O
-	O
risk	O
and	O
a	O
low	O
-	O
risk	O
group	O
.	O

Thus	O
,	O
over	O
a	O
wide	O
range	O
of	O
arterial	O
dimensions	O
,	O
results	O
obtained	O
with	O
caliper	O
estimates	O
of	O
luminal	O
area	O
and	O
diameter	O
are	O
comparable	O
to	O
those	O
obtained	O
with	O
videodensitometry	O
using	O
the	O
XR	O
-	O
70	O
system	O
.	O

Oncogenic	O
activation	O
of	O
RET	B-GENE
is	O
detected	O
in	O
human	O
papillary	O
thyroid	O
tumours	O
and	O
in	O
multiple	O
endocrine	O
neoplasia	O
type	O
2	O
syndromes	O
.	O

Evasion	O
of	O
host	O
immunity	O
by	O
Toxocara	O
canis	O
infective	O
larvae	O
is	O
mediated	O
by	O
the	O
nematode	O
surface	O
coat	O
,	O
which	O
is	O
shed	O
in	O
response	O
to	O
binding	O
by	O
host	O
antibody	O
molecules	O
or	O
effector	O
cells	O
.	O

These	O
data	O
show	O
that	O
the	O
processing	O
of	O
specific	O
target	O
transcripts	O
,	O
such	O
as	O
the	O
P	B-GENE
-	I-GENE
element	I-GENE
mRNA	I-GENE
,	O
is	O
regulated	O
by	O
a	O
functional	O
PSI	B-GENE
-	O
U1	B-GENE
snRNP	O
interaction	O
in	O
Drosophila	O
.	O

The	O
predicted	O
proteins	O
show	O
strong	O
homology	O
to	O
an	O
ABA	B-GENE
-	I-GENE
inducible	I-GENE
glycine	I-GENE
-	I-GENE
rich	I-GENE
protein	I-GENE
from	O
maize	O
embryos	O
and	O
to	O
the	O
mammalian	B-GENE
RNA	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
A1	I-GENE
of	O
the	O
heterogeneous	O
nuclear	O
ribonucleoprotein	O
complex	O
involved	O
in	O
pre	O
-	O
mRNA	O
splicing	O
.	O

Ptx1	B-GENE
belongs	O
to	O
an	O
expanding	O
family	O
of	O
bicoid	B-GENE
-	I-GENE
related	I-GENE
vertebrate	O
homeobox	O
genes	O
.	O

Reactive	O
mesothelial	O
cells	O
,	O
usually	O
seen	O
as	O
exfoliated	O
cells	O
,	O
were	O
consistently	O
strongly	O
positive	O
for	O
alpha	B-GENE
1	I-GENE
-	I-GENE
antichymotrypsin	I-GENE
and	O
more	O
variably	O
for	O
alpha	B-GENE
1	I-GENE
-	I-GENE
antitrypsin	I-GENE
and	O
lysozyme	B-GENE
.	O

However	O
,	O
all	O
pathophysiologic	O
assessments	O
reported	O
to	O
date	O
have	O
been	O
carried	O
out	O
during	O
or	O
immediately	O
after	O
IVOX	O
utilization	O
.	O

The	O
wet	O
and	O
dry	O
methods	O
of	O
the	O
HA	O
synthesis	O
are	O
considered	O
.	O

In	O
agreement	O
with	O
other	O
authors	O
,	O
we	O
recommend	O
the	O
procedure	O
as	O
a	O
safe	O
one	O
,	O
providing	O
satisfactory	O
results	O
.	O

In	O
several	O
steps	O
we	O
converted	O
the	O
retinoid	O
specific	O
response	O
element	O
of	O
the	O
human	B-GENE
retinoic	I-GENE
acid	I-GENE
receptor	I-GENE
beta	I-GENE
promoter	I-GENE
into	O
the	O
vitamin	O
D	O
/	O
retinoic	O
acid	O
response	O
element	O
of	O
the	O
human	B-GENE
osteocalcin	I-GENE
promoter	I-GENE
.	O

Our	O
data	O
define	O
Ile	O
(	O
16	O
)	O
,	O
Val	O
(	O
18	O
)	O
,	O
Val	O
(	O
31	O
)	O
,	O
and	O
Ile	O
(	O
33	O
)	O
as	O
crucial	O
for	O
protein	B-GENE
S	I-GENE
binding	O
,	O
with	O
secondary	O
effects	O
from	O
Leu	O
(	O
38	O
)	O
and	O
Val	O
(	O
39	O
)	O
.	O

Synthesis	O
of	O
22	O
-	O
oxavitamin	O
D3	O
analogues	O
.	O

The	O
plasmid	O
was	O
found	O
to	O
confer	O
drug	O
resistance	O
specifically	O
to	O
LMB	O
.	O

Our	O
results	O
suggest	O
that	O
at	O
least	O
some	O
chloroplast	B-GENE
-	I-GENE
like	I-GENE
tRNA	I-GENE
genes	I-GENE
in	O
wheat	O
mtDNA	O
are	O
transcribed	O
,	O
with	O
transcripts	O
undergoing	O
processing	O
,	O
post	O
-	O
transcriptional	O
modification	O
and	O
3	O
'	O
-	O
CCA	O
addition	O
,	O
to	O
produce	O
mature	O
tRNAs	O
that	O
may	O
participate	O
in	O
mitochondrial	O
protein	O
synthesis	O
.	O

Previously	O
identified	O
mutations	O
in	O
this	O
variant	O
have	O
been	O
within	O
or	O
close	O
to	O
the	O
coding	O
region	O
of	O
exon	O
1	O
of	O
the	O
HMBS	B-GENE
gene	I-GENE
,	O
the	O
only	O
exon	O
that	O
is	O
expressed	O
solely	O
in	O
the	O
ubiquitous	O
isoform	O
.	O

Immunologic	O
tolerance	O
in	O
rats	O
during	O
13	O
weeks	O
of	O
inhalation	O
exposure	O
to	O
trimellitic	O
anhydride	O
.	O

In	O
stage	O
I	O
,	O
histochemistry	O
for	O
copper	O
was	O
positive	O
in	O
11	O
out	O
of	O
21	O
cases	O
:	O
6	O
cases	O
were	O
T	O
+	O
;	O
1	O
case	O
R	O
+	O
and	O
2	O
cases	O
O	O
+	O
;	O
2	O
cases	O
were	O
T	O
+	O
,	O
R	O
+	O
,	O
O	O
+	O
.	O

Rat	B-GENE
cholesterol	I-GENE
side	I-GENE
-	I-GENE
chain	I-GENE
cleavage	I-GENE
cytochrome	I-GENE
P	I-GENE
-	I-GENE
450	I-GENE
(	O
P	B-GENE
-	I-GENE
450scc	I-GENE
)	O
gene	O
.	O

Almost	O
every	O
image	O
that	O
appears	O
during	O
a	O
therapy	O
session	O
reveals	O
a	O
symbolic	O
nature	O
,	O
but	O
the	O
very	O
concept	O
of	O
symbol	O
is	O
not	O
free	O
from	O
ambiguity	O
some	O
positions	O
originated	O
in	O
different	O
areas	O
of	O
investigation	O
are	O
mentioned	O
,	O
ending	O
with	O
a	O
description	O
of	O
the	O
traits	O
that	O
,	O
according	O
to	O
the	O
writer	O
,	O
bestow	O
a	O
symbolic	O
character	O
to	O
images	O
.	O

We	O
have	O
mapped	O
the	O
specific	O
domains	O
within	O
each	O
of	O
the	O
proteins	O
responsible	O
for	O
this	O
interaction	O
.	O

A	O
trend	O
was	O
observed	O
toward	O
increased	O
graft	O
half	O
-	O
life	O
in	O
era	O
2	O
(	O
p	O
=	O
NS	O
)	O
.	O

After	O
15	O
min	O
of	O
hemorrhage	O
the	O
cardiovascular	O
parameters	O
were	O
the	O
same	O
in	O
fed	O
and	O
starved	O
animals	O
,	O
but	O
at	O
45	O
min	O
striking	O
differences	O
were	O
observed	O
.	O

A	O
24	O
-	O
year	O
-	O
old	O
pregnant	O
woman	O
started	O
to	O
have	O
hyperemesis	O
gravidarum	O
6	O
weeks	O
before	O
admission	O
.	O

The	O
nucleoporin	B-GENE
98	I-GENE
gene	I-GENE
(	O
NUP98	B-GENE
)	O
,	O
which	O
is	O
rearranged	O
in	O
several	O
acute	O
myeloid	O
leukemia	O
translocations	O
,	O
is	O
located	O
within	O
this	O
region	O
.	O

Human	B-GENE
CD38	I-GENE
,	O
a	O
leukocyte	O
receptor	O
and	O
ectoenzyme	O
,	O
is	O
a	O
member	O
of	O
a	O
novel	O
eukaryotic	O
gene	O
family	O
of	O
nicotinamide	B-GENE
adenine	I-GENE
dinucleotide	I-GENE
+	I-GENE
-	I-GENE
converting	I-GENE
enzymes	I-GENE
:	O
extensive	O
structural	O
homology	O
with	O
the	O
genes	O
for	O
murine	B-GENE
bone	I-GENE
marrow	I-GENE
stromal	I-GENE
cell	I-GENE
antigen	I-GENE
1	I-GENE
and	O
aplysian	B-GENE
ADP	I-GENE
-	I-GENE
ribosyl	I-GENE
cyclase	I-GENE
.	O

Juvenile	O
angiofibromas	O
.	O

Mutation	O
of	O
the	O
HNF3	B-GENE
element	I-GENE
significantly	O
reduced	O
promoter	O
activity	O
in	O
HepG2	O
cells	O
,	O
whereas	O
this	O
element	O
in	O
isolation	O
conferred	O
HNF3beta	B-GENE
responsiveness	O
to	O
a	O
heterologous	O
promoter	O
.	O

CONCLUSION	O
:	O
Detection	O
of	O
recurrent	O
head	O
and	O
neck	O
cancer	O
is	O
feasible	O
with	O
FDG	O
PET	O
.	O

The	O
role	O
of	O
haptoglobin	B-GENE
in	O
asphyxia	O
mechanism	O
(	O
II	O
)	O
-	O
-	O
Acute	O
drowning	O
and	O
hanging	O

Patients	O
adopt	O
new	O
sets	O
based	O
partly	O
on	O
the	O
original	O
topic	O
and	O
partly	O
on	O
their	O
own	O
personal	O
idiosyncratic	O
concerns	O
.	O

RESULTS	O
:	O
PET	O
revealed	O
wide	O
variations	O
in	O
CBF	O
between	O
regions	O
during	O
isoflurane	O
anaesthesia	O
,	O
particularly	O
in	O
comparison	O
with	O
propofol	O
anaesthesia	O
,	O
while	O
rCMRO2	O
decreased	O
globally	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
during	O
both	O
isoflurane	O
and	O
propofol	O
anaesthesia	O
.	O

Long	O
chain	O
acyl	O
-	O
CoA	O
esters	O
are	O
important	O
intermediates	O
in	O
degradation	O
and	O
synthesis	O
of	O
fatty	O
acids	O
,	O
as	O
well	O
as	O
having	O
important	O
functions	O
in	O
regulation	O
of	O
intermediary	O
metabolism	O
and	O
gene	O
expression	O
.	O

The	O
results	O
of	O
this	O
study	O
indicate	O
that	O
the	O
Improved	O
Crest	O
Complete	O
with	O
longer	O
rippled	O
outer	O
bristles	O
provided	O
significantly	O
superior	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
interproximal	O
penetration	O
overall	O
and	O
at	O
the	O
gumline	O
than	O
the	O
Colgate	O
Total	O
and	O
Oral	O
-	O
B	O
Advantage	O
brushes	O
.	O

Buchstein	O
,	O
L	O
.	O
-	O
L	O
.	O

The	O
model	O
of	O
the	O
complex	O
provides	O
a	O
rationale	O
for	O
conserved	O
ITAM	B-GENE
residues	O
,	O
substrate	O
specificity	O
,	O
and	O
suggests	O
that	O
substrate	O
binds	O
only	O
the	O
active	O
conformation	O
of	O
the	O
Src	B-GENE
family	I-GENE
tyrosine	I-GENE
kinase	I-GENE
,	O
unlike	O
the	O
ATP	O
cofactor	O
,	O
which	O
can	O
bind	O
the	O
inactive	O
form	O
.	O

Sucrose	O
-	O
specific	O
signalling	O
represses	O
translation	O
of	O
the	O
Arabidopsis	B-GENE
ATB2	I-GENE
bZIP	I-GENE
transcription	I-GENE
factor	I-GENE
gene	I-GENE
.	O

This	O
is	O
probably	O
because	O
,	O
in	O
vivo	O
,	O
some	O
bacteria	O
(	O
perhaps	O
dormant	O
forms	O
)	O
are	O
not	O
entirely	O
dependent	O
upon	O
urease	B-GENE
for	O
survival	O
.	O

Our	O
aim	O
was	O
to	O
evaluate	O
this	O
technique	O
by	O
cross	O
-	O
calibrating	O
the	O
DXA	O
method	O
with	O
the	O
carcass	O
chemical	O
analysis	O
in	O
a	O
heterogeneous	O
population	O
of	O
nondiabetic	O
Wistar	O
and	O
diabetic	O
GK	O
rats	O
(	O
21	O
animals	O
were	O
used	O
for	O
precision	O
error	O
and	O
reproducibility	O
determinations	O
and	O
26	O
were	O
used	O
for	O
accuracy	O
studies	O
)	O
.	O

Biopsy	O
of	O
the	O
lesion	O
revealed	O
granulomatous	O
inflammation	O
and	O
numerous	O
septate	O
hyphae	O
.	O

There	O
was	O
a	O
highly	O
significant	O
decrease	O
in	O
serum	B-GENE
eosinophil	I-GENE
cationic	I-GENE
protein	I-GENE
in	O
patients	O
with	O
elevated	O
AGA	B-GENE
.	O

The	O
prototype	O
now	O
structures	O
oncology	O
-	O
related	O
information	O
available	O
on	O
the	O
Internet	O
and	O
also	O
places	O
resources	O
maintained	O
locally	O
at	O
users	O
'	O
disposal	O
.	O

Ischaemia	O
and	O
reperfusion	O
injury	O
in	O
the	O
kidney	O
:	O
current	O
status	O
and	O
future	O
direction	O
.	O

No	O
viral	O
RNA	O
replication	O
could	O
be	O
detected	O
in	O
cells	O
transfected	O
with	O
mutant	O
RNAs	O
.	O

As	O
to	O
the	O
side	O
effects	O
of	O
SISO	O
,	O
cylindruria	O
with	O
aggravation	O
of	O
microscopic	O
hematuria	O
and	O
elevations	O
of	O
GOT	B-GENE
,	O
GPT	B-GENE
and	O
A1	B-GENE
-	I-GENE
P	I-GENE
were	O
observed	O
each	O
one	O
of	O
them	O
,	O
respectively	O
.	O

However	O
,	O
to	O
date	O
,	O
no	O
viable	O
in	O
vitro	O
-	O
generated	O
deletion	O
mutant	O
of	O
PSTVd	O
has	O
been	O
reported	O
.	O

Reduced	O
cell	O
numbers	O
72	O
h	O
after	O
insonation	O
were	O
recorded	O
when	O
the	O
cells	O
were	O
insonated	O
at	O
an	O
antinode	O
but	O
not	O
when	O
they	O
were	O
at	O
a	O
node	O
.	O

We	O
have	O
now	O
isolated	O
cDNA	O
for	O
an	O
invertebrate	B-GENE
Pax	I-GENE
-	I-GENE
6	I-GENE
protein	I-GENE
from	I-GENE
sea	I-GENE
urchin	I-GENE
embryos	I-GENE
.	O

Mating	O
response	O
,	O
ovulation	O
rate	O
,	O
follicle	O
and	O
corpus	O
luteum	O
size	O
,	O
gestation	O
length	O
,	O
pregnancy	O
rate	O
,	O
lambing	O
rate	O
,	O
and	O
lamb	O
birth	O
weight	O
were	O
recorded	O
.	O

From	O
1981	O
to	O
1989	O
,	O
a	O
total	O
of	O
26	O
women	O
with	O
locally	O
or	O
regionally	O
advanced	O
carcinoma	O
of	O
the	O
uterine	O
cervix	O
were	O
treated	O
with	O
radiotherapy	O
(	O
RT	O
)	O
and	O
pelvic	O
regional	O
hyperthermia	O
(	O
HT	O
)	O
,	O
in	O
the	O
Divisions	O
of	O
Radiation	O
Oncology	O
at	O
the	O
University	O
of	O
Utah	O
Medical	O
Center	O
(	O
UU	O
)	O
and	O
the	O
Kenneth	O
Norris	O
Jr	O
Cancer	O
Hospital	O
of	O
the	O
University	O
of	O
Southern	O
California	O
(	O
USC	O
)	O
.	O

These	O
proteins	O
were	O
detected	O
by	O
an	O
antibody	O
which	O
recognizes	O
the	O
N	O
-	O
terminus	O
of	O
SRK3	B-GENE
and	O
,	O
in	O
an	O
F2	O
progeny	O
segregating	O
for	O
the	O
S3	B-GENE
haplotype	I-GENE
,	O
were	O
only	O
expressed	O
in	O
plants	O
possessing	O
the	O
S3	B-GENE
haplotype	I-GENE
.	O

For	O
all	O
samples	O
,	O
the	O
sensitivity	O
of	O
the	O
blast	O
flag	O
on	O
the	O
CD3500	O
was	O
85	O
%	O
with	O
a	O
specificity	O
of	O
91	O
%	O
(	O
STKS	O
:	O
sensitivity	O
,	O
75	O
%	O
;	O
specificity	O
,	O
85	O
%	O
)	O
;	O
the	O
sensitivity	O
of	O
the	O
CD3500	O
IG	O
flag	O
was	O
72	O
%	O
with	O
a	O
specificity	O
of	O
76	O
%	O
(	O
STKS	O
:	O
sensitivity	O
,	O
75	O
%	O
:	O
specificity	O
,	O
73	O
%	O
)	O
;	O
and	O
the	O
sensitivity	O
of	O
the	O
NRBC	O
flag	O
was	O
43	O
%	O
with	O
a	O
specificity	O
of	O
94	O
%	O
(	O
STKS	O
sensitivity	O
,	O
37	O
%	O
;	O
specificity	O
,	O
88	O
%	O
)	O
.	O

Like	O
other	O
IAPs	B-GENE
,	O
ch	B-GENE
-	I-GENE
IAP1	I-GENE
contains	O
the	O
N	B-GENE
-	I-GENE
terminal	I-GENE
baculovirus	I-GENE
IAP	I-GENE
repeats	I-GENE
and	O
C	O
-	O
terminal	O
RING	O
finger	O
motifs	O
.	O

As	O
in	O
the	O
case	O
of	O
the	O
chicken	O
homologue	O
,	O
there	O
are	O
two	O
hPR	B-GENE
forms	O
,	O
A	O
and	O
B	O
,	O
which	O
originate	O
from	O
translational	O
initiation	O
at	O
AUG2	O
(	O
codon	O
165	O
)	O
and	O
AUG1	O
,	O
respectively	O
.	O

A	O
biopsy	O
specimen	O
taken	O
from	O
the	O
frontal	O
branch	O
of	O
the	O
right	O
superficial	O
artery	O
revealed	O
segmental	O
intimal	O
thickening	O
consistent	O
with	O
intimal	O
fibroplasia	O
type	O
FMD	O
upon	O
histological	O
examination	O
.	O

Serum	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
and	O
creatine	B-GENE
kinase	I-GENE
activities	O
were	O
significantly	O
increased	O
in	O
the	O
A	O
praelongus	O
-	O
fed	O
pigs	O
and	O
significantly	O
decreased	O
in	O
Na2SeO4	O
-	O
fed	O
pigs	O
.	O

The	O
activity	O
of	O
gamma	B-GENE
-	I-GENE
glutamyl	I-GENE
transpeptidase	I-GENE
in	O
the	O
serum	O
of	O
problem	O
drinkers	O
.	O

The	O
content	O
of	O
monoamine	O
metabolites	O
,	O
5	O
-	O
hydroxyindoleacetic	O
acid	O
,	O
5	O
-	O
HIAA	O
,	O
and	O
homovanillic	O
acid	O
(	O
HVA	O
)	O
,	O
and	O
-	O
-	O
for	O
17	O
patients	O
-	O
-	O
tryptophan	O
,	O
in	O
the	O
cerebrospinal	O
fluid	O
was	O
determined	O
.	O

Reduced	O
risk	O
of	O
upper	O
gastrointestinal	O
ulcer	O
complications	O
with	O
celecoxib	O
,	O
a	O
novel	O
COX	B-GENE
-	I-GENE
2	I-GENE
inhibitor	O
.	O

Mutations	O
in	O
Saccharomyces	O
cerevisiae	O
that	O
block	O
meiotic	O
prophase	O
chromosome	O
metabolism	O
and	O
confer	O
cell	O
cycle	O
arrest	O
at	O
pachytene	O
identify	O
two	O
new	O
meiosis	B-GENE
-	I-GENE
specific	I-GENE
genes	I-GENE
SAE1	I-GENE
and	O
SAE3	B-GENE
.	O

The	O
transfer	O
by	O
conjugation	O
to	O
E	O
.	O
coli	O
K12	O
of	O
ampicillin	O
and	O
carbenicillin	O
resistance	O
was	O
obtained	O
with	O
14	O
strains	O
:	O
(	O
E	O
.	O
coli	O
:	O
9	O
,	O
C	O
.	O
freundii	O
:	O
1	O
,	O
K	O
.	O
pneumoniae	O
:	O
1	O
,	O
E	O
.	O
cloacae	O
:	O
2	O
,	O
P	O
.	O
stuartii	O
:	O
1	O
)	O
.	O

Over	O
9	O
kb	O
of	O
DNA	O
sequence	O
was	O
obtained	O
for	O
one	O
clone	O
(	O
A1	O
)	O
with	O
a	O
total	O
IGS	O
length	O
of	O
approximately	O
12	O
.	O
4	O
kb	O
.	O

Following	O
EGF	B-GENE
or	O
NGF	B-GENE
stimulation	O
of	O
the	O
v	O
-	O
CrkPC12	O
cells	O
,	O
the	O
v	B-GENE
-	I-GENE
Crk	I-GENE
protein	O
itself	O
became	O
tyrosine	O
phosphorylated	O
within	O
1	O
min	O
.	O

After	O
nine	O
months	O
GFR	O
improved	O
spontaneously	O
to	O
32	O
ml	O
/	O
min	O
/	O
1	O
.	O
73	O
m2	O
despite	O
no	O
improvement	O
in	O
his	O
hypertension	O
.	O

Insulin	B-GENE
-	O
stimulated	O
autophosphorylation	O
at	O
specific	O
sites	O
in	O
the	O
tyrosine	B-GENE
kinase	I-GENE
domain	I-GENE
of	O
the	O
receptor	O
'	O
s	O
beta	O
-	O
subunit	O
is	O
correlated	O
kinetically	O
with	O
activation	O
of	O
kinase	O
-	O
catalyzed	O
phosphorylation	O
of	O
a	O
model	O
substrate	O
(	O
reduced	O
and	O
carboxyamidomethylated	O
lysozyme	B-GENE
;	O
RCAM	B-GENE
-	I-GENE
lysozyme	I-GENE
)	O
.	O

Likewise	O
,	O
the	O
consensus	O
signal	O
believed	O
to	O
be	O
involved	O
in	O
terminating	O
VV	B-GENE
early	I-GENE
gene	I-GENE
transcription	O
,	O
TTTTTNT	O
,	O
was	O
evident	O
at	O
the	O
3	O
'	O
-	O
boundary	O
of	O
both	O
the	O
N2	O
and	O
M1	O
ORFs	O
suggesting	O
that	O
these	O
genes	O
may	O
be	O
VV	B-GENE
early	I-GENE
genes	I-GENE
.	O

Enzymatic	O
and	O
chemical	O
structure	O
probing	O
revealed	O
mainly	O
the	O
conserved	O
terminal	O
part	O
(	O
termed	O
3	O
'	O
C	O
)	O
of	O
the	O
DI9c	O
3	O
'	O
UTR	O
containing	O
distinctive	O
RNA	O
motifs	O
,	O
i	O
.	O
e	O
.	O
,	O
a	O
stable	O
stem	O
-	O
loop	O
,	O
SL	O
I	O
,	O
near	O
the	O
RNA	O
3	O
'	O
terminus	O
and	O
a	O
considerably	O
less	O
stable	O
stem	O
-	O
loop	O
,	O
SL	O
II	O
,	O
that	O
forms	O
the	O
5	O
'	O
portion	O
of	O
3	O
'	O
C	O
.	O

Attention	O
is	O
devoted	O
in	O
particular	O
to	O
the	O
action	O
of	O
thermoregulating	O
nervous	O
and	O
hormonal	O
mechanisms	O
.	O

ES	O
cells	O
in	O
which	O
the	O
gene	O
for	O
the	O
erythroid	O
transcription	O
factor	O
GATA	B-GENE
-	I-GENE
1	I-GENE
has	O
been	O
disrupted	O
fail	O
to	O
produce	O
mature	O
erythroid	O
cells	O
either	O
in	O
vivo	O
or	O
in	O
vitro	O
.	O

Acidic	O
carboxyl	O
-	O
terminal	O
domain	O
of	O
gene	B-GENE
2	I-GENE
.	I-GENE
5	I-GENE
protein	I-GENE
of	I-GENE
bacteriophage	I-GENE
T7	I-GENE
is	O
essential	O
for	O
protein	O
-	O
protein	O
interactions	O
.	O

They	O
encode	O
proteins	O
whose	O
core	O
regions	O
display	O
great	O
similarity	O
to	O
Aspergillus	B-GENE
HAPB	I-GENE
,	O
HAPC	B-GENE
and	O
HAPE	B-GENE
and	O
to	O
known	O
HAP	B-GENE
homologs	I-GENE
from	O
other	O
organisms	O
.	O

Three	O
of	O
these	O
positions	O
are	O
novel	O
in	O
that	O
they	O
had	O
not	O
been	O
identified	O
to	O
be	O
important	O
for	O
binding	O
PC	O
by	O
previous	O
crystallographic	O
analysis	O
.	O

Three	O
transcriptional	O
control	O
elements	O
within	O
300	O
base	O
pairs	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
rat	B-GENE
glucagon	I-GENE
gene	I-GENE
interact	O
with	O
regulatory	O
cellular	O
proteins	O
and	O
direct	O
transcription	O
only	O
in	O
glucagon	B-GENE
-	O
producing	O
islet	O
cells	O
.	O

Fusion	O
proteins	O
were	O
isolated	O
by	O
affinity	O
chromatography	O
on	O
APTG	O
-	O
Sepharose	O
.	O

(	O
99m	O
)	O
Tc	O
Ethyl	O
Cysteinate	O
Dimer	O
stable	O
during	O
6h	O
has	O
contributed	O
to	O
develop	O
ictal	O
studies	O
to	O
evaluate	O
the	O
location	O
of	O
partial	O
seizure	O
.	O

The	O
results	O
of	O
a	O
study	O
to	O
investigate	O
the	O
effectiveness	O
of	O
a	O
propolis	O
-	O
containing	O
mouthrinse	O
in	O
the	O
inhibition	O
of	O
de	O
novo	O
plaque	O
formation	O
are	O
presented	O
.	O

We	O
suggest	O
that	O
this	O
effect	O
of	O
Myc	B-GENE
is	O
mediated	O
by	O
its	O
action	O
upstream	O
of	O
cyclin	B-GENE
E	I-GENE
-	O
CDK2	B-GENE
,	O
and	O
occurs	O
via	O
the	O
neutralization	O
of	O
p27	B-GENE
(	O
Kip1	B-GENE
)	O
family	O
proteins	O
,	O
rather	O
than	O
induction	O
of	O
Cdc25A	B-GENE
.	O

A	O
less	O
common	O
and	O
much	O
more	O
perplexing	O
circumstance	O
occurs	O
when	O
evaluating	O
patients	O
with	O
sarcoidosis	O
established	O
for	O
several	O
years	O
present	O
with	O
evidence	O
of	O
progressive	O
or	O
chronic	O
pulmonary	O
involvement	O
and	O
dyspnea	O
.	O

The	O
training	O
programs	O
had	O
a	O
duration	O
of	O
30	O
days	O
,	O
5	O
days	O
/	O
week	O
,	O
and	O
was	O
performed	O
on	O
a	O
motor	O
-	O
driven	O
treadmill	O
.	O

(	O
1992	O
)	O
J	O
.	O

The	O
avian	O
carcinoma	O
virus	O
MH2	O
contains	O
a	O
hybrid	O
gene	O
delta	B-GENE
gag	I-GENE
-	O
mht	B-GENE
with	O
a	O
contiguous	O
open	O
reading	O
frame	O
of	O
2682	O
base	O
pairs	O
as	O
well	O
as	O
v	B-GENE
-	I-GENE
myc	I-GENE
and	O
avian	O
helper	O
virus	O
-	O
related	O
sequences	O
.	O
delta	B-GENE
gag	I-GENE
is	O
a	O
partial	O
retroviral	B-GENE
core	I-GENE
protein	I-GENE
gene	I-GENE
while	O
v	B-GENE
-	I-GENE
mht	I-GENE
and	O
v	B-GENE
-	I-GENE
myc	I-GENE
are	O
cell	O
-	O
drived	O
sequences	O
.	O

The	O
DW	O
directions	O
uniformly	O
sampled	O
the	O
diffusion	O
ellipsoid	O
surface	O
.	O

The	O
recent	O
concept	O
of	O
a	O
bioartificial	O
organ	O
is	O
an	O
attempt	O
to	O
avoid	O
such	O
disadvantages	O
.	O

The	O
pressure	O
measurements	O
under	O
steady	O
flow	O
conditions	O
showed	O
that	O
the	O
hemodynamic	O
performance	O
(	O
including	O
pressure	O
gradient	O
and	O
effective	O
orifice	O
area	O
)	O
of	O
SPAB	O
is	O
superior	O
to	O
that	O
of	O
its	O
stented	O
counterpart	O
,	O
especially	O
in	O
the	O
smaller	O
sizes	O
.	O

Recent	O
,	O
highly	O
visible	O
reviews	O
on	O
the	O
subject	O
have	O
clearly	O
pointed	O
out	O
that	O
little	O
is	O
known	O
about	O
the	O
cellular	O
mechanisms	O
through	O
which	O
inhaled	O
asbestos	O
fibers	O
cause	O
the	O
well	O
known	O
,	O
debilitating	O
lung	O
disease	O
-	O
asbestosis	O
(	O
i	O
.	O
e	O
.	O
interstitial	O
pulmonary	O
fibrosis	O
)	O
.	O

During	O
chronic	O
treatment	O
with	O
salmon	B-GENE
calcitonin	I-GENE
,	O
alkaline	B-GENE
phosphatase	I-GENE
activity	O
and	O
urinary	O
hydroxyproline	O
excretion	O
decrease	O
on	O
an	O
average	O
of	O
50	O
%	O
in	O
patients	O
with	O
Paget	O
'	O
s	O
disease	O
.	O

Cerebral	O
blood	O
flow	O
was	O
measured	O
using	O
the	O
iv	O
method	O
of	O
133	O
-	O
Xe	O
CBF	O
determination	O
and	O
AVDO2	O
was	O
measured	O
using	O
systemic	O
arterial	O
-	O
jugular	O
venous	O
oxygen	O
content	O
differences	O
.	O

Expression	O
of	O
FNCAT	B-GENE
increased	O
on	O
serum	O
treatment	O
indicating	O
that	O
the	O
region	O
of	O
the	O
FN	B-GENE
gene	I-GENE
between	O
positions	O
+	O
69	O
and	O
-	O
510	O
bp	O
mediated	O
serum	O
responsiveness	O
.	O

Gallstone	O
-	O
formation	O
has	O
traditionally	O
been	O
attributed	O
to	O
supersaturation	O
of	O
bile	O
with	O
cholesterol	O
.	O

Possible	O
consequences	O
of	O
such	O
binder	O
distribution	O
through	O
powder	O
aggregates	O
are	O
discussed	O
.	O

Bile	O
salts	O
,	O
hormonal	O
control	O
,	O
and	O
the	O
male	O
disadvantage	O
.	O

The	O
fusion	O
gene	O
cassette	O
was	O
placed	O
under	O
the	O
control	O
of	O
a	O
vaccinia	B-GENE
virus	I-GENE
early	I-GENE
promoter	I-GENE
and	O
cloned	O
in	O
a	O
host	O
-	O
restricted	O
fowlpox	O
viral	O
vector	O
.	O

We	O
describe	O
a	O
novel	O
stat	B-GENE
-	I-GENE
related	I-GENE
factor	I-GENE
,	O
p93	B-GENE
,	O
that	O
is	O
found	O
in	O
EGF	B-GENE
-	O
treated	O
A431	O
cell	O
extracts	O
but	O
appears	O
to	O
be	O
absent	O
in	O
bovine	B-GENE
fibroblast	I-GENE
growth	I-GENE
factor	I-GENE
(	O
bFGF	B-GENE
)	O
,	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
,	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
(	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
)	O
,	O
and	O
untreated	O
cells	O
.	O
p93	B-GENE
appears	O
to	O
be	O
antigenically	O
related	O
to	O
stat91	B-GENE
.	O
p185c	B-GENE
-	O
neu	B-GENE
+	O
,	O
EGFr	B-GENE
+	I-GENE
(	O
M1	B-GENE
)	O
,	O
and	O
p185c	B-GENE
-	O
neu	B-GENE
-	O
kinase	O
inactive	O
,	O
EGFr	B-GENE
+	I-GENE
(	O
NEN757	B-GENE
)	O
expressing	O
cells	O
undergo	O
different	O
mitotic	O
responses	O
to	O
EGF	B-GENE
.	O

MRI	O
measurements	O
of	O
the	O
brain	O
.	O

Phosphorylation	O
by	O
Cdc28	B-GENE
activates	O
the	O
Cdc20	B-GENE
-	O
dependent	O
activity	O
of	O
the	O
anaphase	O
-	O
promoting	O
complex	O
.	O

Phosphorylated	O
tyrosine	O
residues	O
were	O
subsequently	O
identified	O
by	O
sequencing	O
the	O
separated	O
phosphopeptides	O
by	O
matrix	O
assisted	O
laser	O
desorption	O
ionization	O
mass	O
spectrometry	O
(	O
MALDI	O
-	O
MS	O
)	O
and	O
Edman	O
degradation	O
.	O

Superovulation	O
with	O
intrauterine	O
insemination	O
(	O
SO	O
-	O
IUI	O
)	O
has	O
been	O
suggested	O
as	O
an	O
alternative	O
to	O
gamete	O
intrafallopian	O
transfer	O
(	O
GIFT	O
)	O
,	O
despite	O
the	O
absence	O
of	O
controlled	O
or	O
comparative	O
trials	O
.	O

One	O
of	O
these	O
elements	O
resembles	O
the	O
binding	O
site	O
of	O
a	O
previously	O
identified	O
cellular	O
"	O
transcription	O
"	O
factor	O
.	O

The	O
Rep78	B-GENE
protein	I-GENE
of	O
adeno	O
-	O
associated	O
virus	O
(	O
AAV	O
)	O
contains	O
amino	O
acid	O
sequence	O
motifs	O
common	O
to	O
rolling	B-GENE
-	I-GENE
circle	I-GENE
replication	I-GENE
(	I-GENE
RCR	I-GENE
)	I-GENE
initiator	I-GENE
proteins	I-GENE
.	O

METHODS	O
:	O
CD4	B-GENE
cell	O
counts	O
and	O
interview	O
data	O
were	O
recorded	O
in	O
a	O
survey	O
of	O
136	O
adult	O
patients	O
attending	O
a	O
community	O
hospital	O
-	O
based	O
HIV	O
outpatient	O
clinic	O
.	O

Based	O
on	O
29	O
determinations	O
of	O
the	O
glucose	O
from	O
sinigrin	O
,	O
analyzed	O
under	O
different	O
conditions	O
,	O
accuracy	O
of	O
the	O
total	O
glucosinolate	O
determination	O
was	O
94	O
.	O
8	O
+	O
/	O
-	O
7	O
.	O
3	O
%	O
.	O

Transcriptional	O
analysis	O
of	O
this	O
gene	O
cluster	O
was	O
performed	O
by	O
detecting	O
the	O
presence	O
of	O
mRNAs	O
spanning	O
adjacent	O
genes	O
as	O
well	O
as	O
by	O
using	O
a	O
promoterless	O
lacZ	B-GENE
reporter	I-GENE
gene	I-GENE
fused	O
to	O
each	O
of	O
the	O
seven	O
genes	O
contained	O
in	O
the	O
tol	B-GENE
-	O
oprL	B-GENE
locus	O
.	O

The	O
regions	O
encoding	O
the	O
mature	O
proteinases	O
were	O
cloned	O
into	O
an	O
expression	O
vector	O
and	O
recombinant	O
protein	O
produced	O
in	O
Escherichia	O
coli	O
.	O

H	O
.	O

Rhinovirus	B-GENE
2A	I-GENE
protease	I-GENE
and	O
foot	B-GENE
-	I-GENE
and	I-GENE
-	I-GENE
mouth	I-GENE
-	I-GENE
disease	I-GENE
virus	I-GENE
L	I-GENE
protease	I-GENE
were	O
used	O
to	O
analyze	O
the	O
association	O
of	O
eIF4G	B-GENE
with	O
eIF4A	B-GENE
,	O
eIF4E	B-GENE
,	O
and	O
eIF3	B-GENE
.	O

METHODS	O
:	O
Two	O
patients	O
developed	O
cervical	O
myelopathy	O
or	O
radiculopathy	O
after	O
spinal	O
manipulation	O
therapy	O
,	O
and	O
magnetic	O
resonance	O
imaging	O
showed	O
herniated	O
cervical	O
discs	O
at	O
C4	O
-	O
C5	O
and	O
C6	O
-	O
C7	O
,	O
respectively	O
.	O

This	O
increased	O
frequency	O
of	O
infection	O
has	O
been	O
accompanied	O
by	O
significant	O
excess	O
mortality	O
.	O

One	O
of	O
the	O
repeating	O
domains	O
(	O
Yheb1	B-GENE
)	O
,	O
consisting	O
of	O
67	O
amino	O
acids	O
,	O
was	O
cloned	O
from	O
the	O
E	O
.	O
coli	O
chromosome	O
and	O
purified	O
by	O
metal	O
chelating	O
chromatography	O
.	O

Assessment	O
of	O
two	O
anion	O
-	O
exchange	O
resins	O
for	O
direct	O
use	O
in	O
the	O
screening	O
method	O
for	O
urinary	O
porphobilinogen	O
.	O

These	O
studies	O
define	O
a	O
class	O
of	O
DNA	O
elements	O
with	O
a	O
mode	O
of	O
action	O
that	O
has	O
not	O
been	O
heretofore	O
described	O
.	O

Using	O
lacZ	B-GENE
-	O
inducible	O
T	O
cells	O
as	O
a	O
probe	O
,	O
we	O
screened	O
a	O
splenic	O
cDNA	O
library	O
in	O
transiently	O
transfected	O
antigen	O
-	O
presenting	O
cells	O
(	O
APCs	O
)	O
and	O
isolated	O
a	O
cDNA	O
clone	O
that	O
allowed	O
expression	O
of	O
the	O
appropriate	O
peptide	B-GENE
/	I-GENE
Kb	I-GENE
MHC	I-GENE
complex	I-GENE
in	O
APC	O
.	O

This	O
results	O
in	O
a	O
decreased	O
secretion	O
of	O
immunoglobulin	B-GENE
A	I-GENE
,	O
and	O
,	O
consequently	O
,	O
a	O
decreased	O
resistance	O
against	O
infections	O
.	O

A	O
previously	O
developed	O
kinetic	O
model	O
was	O
used	O
to	O
identify	O
major	O
chemical	O
reaction	O
pathways	O
involving	O
PAH	O
in	O
the	O
afterburner	O
.	O

Regulation	O
of	O
the	O
p21	B-GENE
-	I-GENE
activated	I-GENE
kinase	I-GENE
(	O
PAK	B-GENE
)	O
by	O
a	O
human	B-GENE
Gbeta	I-GENE
-	I-GENE
like	I-GENE
WD	O
-	O
repeat	O
protein	O
,	O
hPIP1	B-GENE
.	O

Activation	O
of	O
HIV	O
-	O
1	O
requires	O
the	O
binding	O
of	O
host	O
cell	O
transcription	O
factors	O
to	O
cis	O
elements	O
in	O
the	O
proviral	O
long	O
terminal	O
repeat	O
(	O
LTR	O
)	O
.	O

Based	O
on	O
the	O
ratios	O
of	O
the	O
areas	O
under	O
the	O
concentration	O
-	O
time	O
curves	O
in	O
CSF	O
and	O
serum	O
,	O
the	O
overall	O
penetration	O
of	O
rifampicin	O
into	O
CSF	O
was	O
0	O
.	O
13	O
-	O
0	O
.	O
42	O
(	O
median	O
=	O
0	O
.	O
22	O
)	O
.	O

Adaptability	O
of	O
Nippostrongylus	O
brasiliensis	O
(	O
Travassos	O
,	O
1914	O
)	O
to	O
lead	O
contamination	O

In	O
early	O
midgestation	O
embryos	O
it	O
is	O
expressed	O
in	O
telencephalic	O
,	O
diencephalic	O
and	O
mesencephalic	O
regions	O
but	O
from	O
day	O
11	O
.	O
75	O
of	O
gestation	O
its	O
expression	O
disappears	O
from	O
dorsal	O
telencephalon	O
and	O
is	O
confined	O
to	O
diencephalic	O
and	O
mesencephalic	O
regions	O
.	O

A	O
child	O
presumed	O
to	O
have	O
the	O
21	B-GENE
-	I-GENE
hydroxylase	I-GENE
deficiency	O
form	O
of	O
congenital	O
adrenal	O
hyperplasia	O
was	O
studied	O
extensively	O
as	O
an	O
infant	O
.	O

The	O
size	O
and	O
the	O
predicted	O
N	O
-	O
terminal	O
sequence	O
of	O
the	O
mouse	O
protein	O
were	O
confirmed	O
experimentally	O
.	O

It	O
was	O
found	O
that	O
Nopp140	B-GENE
binds	O
primarily	O
to	O
the	O
CK2	B-GENE
regulatory	I-GENE
subunit	I-GENE
,	I-GENE
beta	I-GENE
.	O

Further	O
,	O
more	O
recent	O
communications	O
suggest	O
that	O
liver	O
disease	O
led	O
to	O
a	O
differential	O
alteration	O
of	O
the	O
cytochrome	B-GENE
P	I-GENE
-	I-GENE
450s	I-GENE
with	O
regard	O
to	O
protein	O
content	O
and	O
activity	O
.	O

A	O
constructed	O
phylogenetic	O
tree	O
suggests	O
that	O
the	O
UbcP1	B-GENE
protein	I-GENE
may	O
represent	O
a	O
member	O
of	O
a	O
distinct	O
subfamily	O
of	O
E2s	B-GENE
.	O

Isolates	O
of	O
B	O
.	O
burgdorferi	O
from	O
humans	O
,	O
rodents	O
,	O
and	O
I	O
.	O
dammini	O
are	O
usually	O
indistinguishable	O
,	O
but	O
strains	O
of	O
B	O
.	O
burgdorferi	O
with	O
different	O
major	O
proteins	O
have	O
been	O
identified	O
.	O

Alignment	O
of	O
the	O
rat	B-GENE
and	I-GENE
human	I-GENE
WIN	I-GENE
cDNAs	I-GENE
and	O
their	O
comparison	O
with	O
mouse	O
genomic	O
sequence	O
revealed	O
that	O
the	O
WIN	B-GENE
DNA	I-GENE
binding	I-GENE
domain	I-GENE
is	O
encoded	O
by	O
four	O
exons	O
,	O
two	O
of	O
which	O
(	O
exons	O
4	O
and	O
6	O
)	O
are	O
alternatively	O
spliced	O
to	O
generate	O
at	O
least	O
three	O
classes	O
of	O
mRNA	O
transcripts	O
.	O

25	O
patients	O
received	O
20	O
mgs	O
of	O
hyoscine	O
N	O
-	O
butyl	O
bromide	O
and	O
the	O
rest	O
5	O
mgs	O
propinoxate	O
,	O
i	O
.	O
v	O
.	O
plus	O
diazepam	O
.	O

The	O
activity	O
of	O
plasminogen	B-GENE
activator	I-GENE
has	O
been	O
measured	O
in	O
tissue	O
sections	O
with	O
the	O
aid	O
of	O
a	O
modified	O
Todd	O
technique	O
.	O

These	O
sequences	O
were	O
further	O
tested	O
for	O
the	O
presence	O
of	O
an	O
enhancer	O
element	O
,	O
by	O
their	O
ability	O
to	O
activate	O
a	O
fusion	O
reporter	O
gene	O
consisting	O
of	O
the	O
CAT	B-GENE
gene	I-GENE
linked	O
to	O
the	O
gamma	B-GENE
-	I-GENE
globin	I-GENE
gene	I-GENE
promoter	I-GENE
,	O
in	O
erythroid	O
(	O
K562	O
)	O
and	O
non	O
-	O
erythroid	O
(	O
HeLa	O
)	O
cells	O
.	O

Here	O
we	O
demonstrate	O
that	O
CD40	B-GENE
or	O
IgM	B-GENE
receptor	I-GENE
stimulation	O
of	O
primary	O
B	O
cells	O
results	O
in	O
transactivation	O
of	O
this	O
enhancer	O
.	O

DESIGN	O
,	O
SETTING	O
AND	O
SUBJECTS	O
:	O
The	O
analysis	O
is	O
based	O
on	O
data	O
collected	O
in	O
the	O
first	O
two	O
rounds	O
of	O
the	O
nationally	O
representative	O
Ghana	O
Living	O
Standards	O
Survey	O
,	O
held	O
in	O
1987	O
/	O
88	O
(	O
GLSS	O
-	O
I	O
)	O
and	O
1988	O
/	O
89	O
(	O
GLSS	O
-	O
II	O
)	O
,	O
with	O
both	O
surveys	O
covering	O
approximately	O
3000	O
households	O
.	O

Genetic	O
and	O
physiological	O
experiments	O
suggest	O
a	O
close	O
relationship	O
between	O
cdc27	B-GENE
+	I-GENE
and	O
the	O
cdc2	B-GENE
+	I-GENE
gene	I-GENE
,	O
a	O
key	O
regulator	O
of	O
mitosis	O
in	O
yeast	O
and	O
also	O
in	O
higher	O
eukaryotic	O
cells	O
.	O

Association	O
of	O
Syk	B-GENE
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
(	O
PTK	B-GENE
)	O
with	O
LMP2A	B-GENE
occurs	O
at	O
the	O
two	O
tyrosines	O
of	O
the	O
LMP2A	B-GENE
immunoreceptor	I-GENE
tyrosine	O
-	O
based	O
activation	O
motif	O
,	O
and	O
it	O
is	O
hypothesized	O
that	O
Lyn	B-GENE
PTK	B-GENE
associates	O
with	O
the	O
YEEA	O
amino	O
acid	O
motif	O
at	O
LMP2A	B-GENE
tyrosine	O
112	O
(	O
Y112	O
)	O
.	O

Theoretical	O
mechanisms	O
of	O
hyperuricemia	O
.	O

As	O
a	O
result	O
,	O
relative	O
biological	O
effects	O
(	O
RBE	O
)	O
of	O
2	O
.	O
3	O
-	O
2	O
.	O
7	O
was	O
obtained	O
from	O
the	O
straight	O
line	O
that	O
was	O
given	O
by	O
modifying	O
by	O
the	O
method	O
of	O
least	O
squares	O
the	O
curves	O
of	O
the	O
frequency	O
of	O
anomalous	O
fetuses	O
in	O
total	O
implants	O
and	O
survived	O
embryos	O
irradiated	O
from	O
20	O
to	O
120	O
rad	O
by	O
Cf	O
-	O
252	O
and	O
from	O
80	O
to	O
220	O
rad	O
by	O
Co	O
-	O
60	O
on	O
day	O
8	O
of	O
pregnancy	O
.	O

Moclobemide	O
is	O
a	O
well	O
-	O
tolerated	O
alternative	O
antidepressant	O
,	O
but	O
there	O
is	O
a	O
need	O
for	O
prospective	O
controlled	O
trials	O
to	O
evaluate	O
its	O
long	O
-	O
term	O
efficacy	O
.	O

In	O
a	O
pilot	O
study	O
in	O
which	O
two	O
dogs	O
were	O
given	O
parenteral	O
rifampin	O
before	O
and	O
after	O
operation	O
and	O
grafts	O
were	O
preclotted	O
with	O
blood	O
that	O
contained	O
rifampin	O
,	O
it	O
was	O
suggested	O
that	O
there	O
was	O
a	O
slight	O
increase	O
in	O
inhibition	O
at	O
24	O
hours	O
(	O
93	O
%	O
)	O
.	O

Northern	O
blot	O
analyses	O
were	O
used	O
to	O
examine	O
the	O
regulated	O
expression	O
of	O
the	O
cys	B-GENE
-	I-GENE
14	I-GENE
+	I-GENE
gene	I-GENE
.	O

The	O
mouse	B-GENE
tapasin	I-GENE
gene	I-GENE
was	O
mapped	O
about	O
70	O
kilobases	O
from	O
H2	B-GENE
-	I-GENE
K	I-GENE
at	O
the	O
centromeric	O
end	O
of	O
the	O
mouse	B-GENE
MHC	I-GENE
.	O

Conversion	O
of	O
glucose	O
phosphate	O
-	O
14C	O
to	O
glucose	O
-	O
14C	O
in	O
passage	O
through	O
human	O
brain	O
in	O
vivo	O
.	O

New	O
,	O
selective	O
catechol	B-GENE
-	I-GENE
O	I-GENE
-	I-GENE
methyltransferase	I-GENE
inhibitors	O
as	O
therapeutic	O
agents	O
in	O
Parkinson	O
'	O
s	O
disease	O
.	O

The	O
sequence	O
of	O
the	O
gene	O
upstream	O
to	O
the	O
cap	O
site	O
contains	O
characteristic	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
promoter	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
:	O
a	O
putative	O
TATA	O
box	O
at	O
position	O
-	O
29	O
and	O
a	O
Sp	B-GENE
1	I-GENE
binding	I-GENE
site	I-GENE
(	O
GGGGCGGAGA	O
)	O
at	O
position	O
-	O
48	O
.	O

We	O
propose	O
that	O
,	O
while	O
Y	O
.	O
lipolytica	O
CEN	O
DNA	O
is	O
essential	O
for	O
plasmid	O
maintenance	O
,	O
this	O
function	O
can	O
be	O
supplied	O
by	O
several	O
sub	O
-	O
fragments	O
which	O
,	O
together	O
,	O
form	O
the	O
active	O
chromosomal	O
centromere	O
.	O

These	O
three	O
groups	O
were	O
further	O
examined	O
with	O
regard	O
to	O
the	O
modulation	O
of	O
discharge	O
rate	O
i	O
)	O
during	O
motor	O
activity	O
in	O
W	O
,	O
ii	O
)	O
at	O
the	O
transitional	O
phase	O
from	O
SS	O
to	O
paradoxical	O
sleep	O
(	O
PS	O
)	O
,	O
iii	O
)	O
during	O
rapid	O
eye	O
movements	O
(	O
REMs	O
)	O
in	O
PS	O
,	O
and	O
iv	O
)	O
following	O
electrical	O
stimulation	O
of	O
the	O
midbrain	O
reticular	O
formation	O
(	O
MRF	O
)	O
.	O

Benzyl	O
alcohol	O
administration	O
in	O
neonates	O
.	O

Id	B-GENE
-	I-GENE
1H	I-GENE
and	O
Id	B-GENE
-	I-GENE
2H	I-GENE
seem	O
to	O
be	O
human	O
homologues	O
of	O
mouse	B-GENE
Id	I-GENE
-	I-GENE
1	I-GENE
and	O
Id	B-GENE
-	I-GENE
2	I-GENE
,	O
respectively	O
,	O
and	O
have	O
potential	O
to	O
encode	O
154	O
and	O
135	O
amino	O
acid	O
proteins	O
.	O

Normal	O
dogs	O
were	O
exposed	O
to	O
either	O
10	O
,	O
15	O
,	O
or	O
30	O
Gy	O
of	O
X	O
rays	O
to	O
a	O
single	O
hemisphere	O
and	O
the	O
gross	O
and	O
histopathologic	O
changes	O
were	O
evaluated	O
qualitatively	O
.	O

The	O
characterization	O
of	O
fly	O
receptors	O
with	O
features	O
similar	O
to	O
mammalian	B-GENE
glycoprotein	I-GENE
hormone	I-GENE
receptors	I-GENE
allows	O
a	O
better	O
understanding	O
of	O
the	O
evolution	O
of	O
this	O
unique	O
group	O
of	O
GPCRs	B-GENE
and	O
future	O
elucidation	O
of	O
their	O
ligand	O
signaling	O
mechanisms	O
.	O

To	O
study	O
the	O
mechanisms	O
and	O
the	O
signaling	O
pathways	O
involved	O
,	O
IGF	B-GENE
-	I-GENE
1R	I-GENE
promoter	I-GENE
reporter	I-GENE
constructs	I-GENE
were	O
transiently	O
transfected	O
in	O
CHO	O
-	O
AT1	O
cells	O
that	O
overexpress	O
angiotensin	B-GENE
AT1	I-GENE
receptors	I-GENE
.	O

Importin	B-GENE
beta	I-GENE
mediates	O
nuclear	O
translocation	O
of	O
Smad	B-GENE
3	I-GENE
.	O

In	O
summary	O
,	O
the	O
only	O
treatment	O
-	O
related	O
effect	O
noted	O
in	O
this	O
study	O
was	O
hydrocarbon	O
nephropathy	O
in	O
male	O
rats	O
,	O
which	O
is	O
not	O
considered	O
relevant	O
for	O
human	O
health	O
.	O

Characterization	O
of	O
an	O
unusual	O
tRNA	O
-	O
like	O
sequence	O
found	O
inserted	O
in	O
a	O
Neurospora	O
retroplasmid	O
.	O

Gel	O
shift	O
analysis	O
of	O
protein	O
binding	O
from	O
nuclear	O
extracts	O
to	O
these	O
caveolin	B-GENE
promoter	I-GENE
DNA	I-GENE
sequences	I-GENE
,	O
together	O
with	O
DNase	B-GENE
I	I-GENE
footprinting	O
,	O
confirmed	O
nucleoprotein	O
binding	O
to	O
the	O
SRE	O
-	O
like	O
elements	O
as	O
part	O
of	O
the	O
transcriptional	O
response	O
to	O
LDL	B-GENE
-	I-GENE
FC	I-GENE
.	O

The	O
Ca2	O
+	O
concentration	O
in	O
rats	O
serum	O
after	O
intragastrically	O
fenarimol	O
administration	O
(	O
doses	O
1	O
/	O
40	O
,	O
1	O
/	O
20	O
and	O
1	O
/	O
10	O
LD50	O
)	O
during	O
5	O
days	O
was	O
investigated	O
.	O

Furthermore	O
,	O
deletion	O
of	O
two	O
potential	O
Ste11	B-GENE
recognition	I-GENE
sites	I-GENE
in	O
the	O
fus1	B-GENE
promoter	I-GENE
region	O
abolished	O
transcription	O
,	O
and	O
expression	O
could	O
be	O
restored	O
when	O
we	O
inserted	O
a	O
different	O
Ste11	B-GENE
site	I-GENE
from	O
the	O
mat1	B-GENE
-	I-GENE
P	I-GENE
promoter	I-GENE
.	O

J	O
.	O
,	O
&	O
Olefsky	O
,	O
J	O
.	O

Early	O
attempts	O
for	O
modifying	O
growth	O
functions	O
to	O
annual	O
variations	O
dating	O
back	O
up	O
to	O
2	O
decades	O
are	O
recalled	O
together	O
with	O
examples	O
for	O
their	O
application	O
showing	O
rather	O
different	O
degrees	O
of	O
approximation	O
.	O

PRIP	B-GENE
contains	O
two	O
LXXLL	O
signature	O
motifs	O
.	O

BPN	O
can	O
be	O
experimentally	O
produced	O
by	O
intratracheal	O
inoculation	O
of	O
microorganisms	O
in	O
high	O
concentrations	O
and	O
ventilator	O
-	O
associated	O
BPN	O
by	O
ventilating	O
baboons	O
with	O
oleic	O
-	O
acid	O
lung	O
injury	O
.	O

Coexpression	O
of	O
a	O
dominant	B-GENE
negative	I-GENE
c	I-GENE
-	I-GENE
jun	I-GENE
antagonized	O
the	O
ras	B-GENE
-	O
dependent	O
stimulation	O
of	O
the	O
92	B-GENE
-	I-GENE
kDa	I-GENE
gelatinase	I-GENE
B	I-GENE
promoter	O
-	O
driven	O
CAT	B-GENE
reporter	I-GENE
.	O

However	O
,	O
the	O
safety	O
of	O
design	O
4	O
was	O
assured	O
as	O
long	O
as	O
all	O
patients	O
received	O
three	O
courses	O
of	O
chemotherapy	O
,	O
which	O
is	O
unusual	O
in	O
phase	O
I	O
studies	O
in	O
Japan	O
.	O

The	O
plants	O
were	O
then	O
brought	O
to	O
our	O
Houston	O
laboratory	O
where	O
they	O
were	O
measured	O
and	O
analyzed	O
for	O
lignin	O
and	O
protein	O
content	O
and	O
for	O
phenylalanine	B-GENE
ammonia	I-GENE
-	I-GENE
lyase	I-GENE
(	O
PAL	B-GENE
)	O
and	O
peroxidase	B-GENE
activities	O
.	O

The	O
nucleotide	O
sequence	O
of	O
a	O
PCR	O
-	O
amplified	O
SMT3A	B-GENE
genomic	O
DNA	O
fragment	O
was	O
found	O
to	O
be	O
identical	O
to	O
that	O
of	O
SMT3A	B-GENE
cDNA	I-GENE
,	O
indicating	O
the	O
absence	O
of	O
intron	O
(	O
s	O
)	O
in	O
its	O
protein	O
coding	O
region	O
.	O

Activation	O
of	O
tyrosine	B-GENE
kinase	I-GENE
-	I-GENE
containing	I-GENE
receptors	I-GENE
,	O
heterotrimeric	B-GENE
G	I-GENE
proteins	I-GENE
,	O
and	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
enhanced	O
the	O
activities	O
of	O
both	O
MEK	B-GENE
isoforms	I-GENE
in	O
293	O
and	O
PC12	O
cells	O
.	O

CONCLUSIONS	O
:	O
Transpulmonary	O
stable	O
air	O
microbubbles	O
bound	O
to	O
a	O
galactose	O
carrier	O
represent	O
a	O
useful	O
and	O
safe	O
contrast	O
agent	O
in	O
case	O
of	O
an	O
insufficient	O
native	O
signal	O
in	O
transcranial	O
Doppler	O
investigation	O
.	O

DP	B-GENE
-	I-GENE
1	I-GENE
and	O
DP	B-GENE
-	I-GENE
2	I-GENE
encode	O
maternally	O
stored	O
transcripts	O
that	O
are	O
expressed	O
during	O
early	O
development	O
.	O

Human	B-GENE
recombinant	I-GENE
erythropoietin	I-GENE
(	O
r	B-GENE
-	I-GENE
HuEPO	I-GENE
,	O
EprexR	B-GENE
)	O
was	O
administered	O
to	O
8	O
children	O
with	O
chronic	O
renal	O
failure	O
and	O
high	O
transfusion	O
requirement	O
.	O

Specifically	O
,	O
we	O
engineered	O
two	O
chimeras	O
in	O
which	O
the	O
N	O
-	O
terminal	O
lobe	O
of	O
the	O
SH1	B-GENE
domain	I-GENE
of	O
c	B-GENE
-	I-GENE
Abl	I-GENE
was	O
swapped	O
with	O
that	O
of	O
v	B-GENE
-	I-GENE
Src	I-GENE
.	O

Indications	O
for	O
therapy	O
using	O
MAO	B-GENE
inhibitors	O

Although	O
IL	B-GENE
-	I-GENE
6	I-GENE
can	O
activate	O
ERK	B-GENE
-	I-GENE
1	I-GENE
in	O
HepG2	O
cells	O
,	O
STAT3	B-GENE
transactivation	O
and	O
Ser	O
(	O
727	O
)	O
phosphorylation	O
were	O
not	O
reduced	O
by	O
using	O
the	O
MAP	B-GENE
kinase	I-GENE
/	O
ERK	B-GENE
kinase	I-GENE
(	O
MEK	B-GENE
)	O
inhibitor	O
PD98059	O
or	O
by	O
overexpression	O
of	O
dominant	O
-	O
negative	O
Raf	B-GENE
.	O

Mean	O
disposition	O
constants	O
(	O
+	O
/	O
-	O
SD	O
)	O
were	O
obtained	O
from	O
individualized	O
fits	O
(	O
V1	O
:	O
0	O
.	O
398	O
+	O
/	O
-	O
0	O
.	O
336	O
LITER	O
/	O
KG	O
,	O
Vdarea	O
:	O
2	O
.	O
53	O
+	O
/	O
-	O
0	O
.	O
72	O
liter	O
/	O
kg	O
,	O
alpha	O
:	O
0	O
.	O
316	O
+	O
/	O
-	O
0	O
.	O
294	O
min	O
-	O
1	O
,	O
beta	O
:	O
0	O
.	O
00204	O
+	O
/	O
-	O
0	O
.	O
00262	O
min	O
-	O
1	O
,	O
k2	O
:	O
0	O
.	O
0305	O
+	O
/	O
-	O
0	O
.	O
0101	O
min	O
-	O
1	O
)	O
.	O

Clinical	O
trials	O
bring	O
informations	O
for	O
pharmacology	O
and	O
epidemiology	O
.	O

We	O
have	O
compared	O
the	O
ability	O
of	O
GST	B-GENE
-	O
Bem3	B-GENE
to	O
serve	O
as	O
a	O
GAP	B-GENE
for	O
Cdc42Hs	B-GENE
relative	O
to	O
other	O
members	O
of	O
the	O
rho	B-GENE
-	O
GAP	B-GENE
subfamily	O
and	O
found	O
the	O
following	O
order	O
of	O
potency	O
:	O
human	B-GENE
platelet	I-GENE
Cdc42Hs	I-GENE
GAP	I-GENE
>	O
p190	B-GENE
>	O
Bem3	B-GENE
>	O
break	B-GENE
point	I-GENE
cluster	I-GENE
region	I-GENE
protein	I-GENE
,	O
whereas	O
p85	B-GENE
,	O
like	O
Bem2	B-GENE
,	O
shows	O
no	O
GAP	B-GENE
activity	O
or	O
any	O
ability	O
to	O
bind	O
to	O
the	O
GTP	O
-	O
bound	O
form	O
of	O
Cdc42Hs	B-GENE
.	O

Through	O
effective	O
use	O
of	O
laboratory	O
testing	O
database	O
,	O
it	O
will	O
be	O
possible	O
to	O
shift	O
away	O
our	O
vague	O
management	O
of	O
pre	O
-	O
analytic	O
phase	O
of	O
quality	O
control	O
so	O
far	O
to	O
its	O
established	O
system	O
based	O
on	O
objective	O
evaluation	O
.	O

Nonlinearities	O
in	O
cochlear	O
hydrodynamics	O
.	O

The	O
peptides	O
are	O
generated	O
in	O
the	O
cytosol	O
,	O
then	O
translocated	O
across	O
the	O
membrane	O
of	O
the	O
endoplasmic	O
reticulum	O
by	O
the	O
transporter	B-GENE
associated	I-GENE
with	I-GENE
antigen	I-GENE
processing	I-GENE
(	O
TAP	B-GENE
)	O
.	O

An	O
in	O
vitro	O
'	O
glass	O
stomach	O
'	O
(	O
containing	O
various	O
volumes	O
of	O
hydrochloric	O
acid	O
[	O
HCl	O
]	O
and	O
ammonium	O
chloride	O
[	O
NH4Cl	O
]	O
)	O
was	O
used	O
to	O
evaluate	O
the	O
means	O
of	O
increasing	O
'	O
gastric	O
'	O
pH	O
to	O
that	O
of	O
the	O
NH4	O
+	O
-	O
-	O
>	O
NH3	O
transition	O
that	O
occurs	O
significantly	O
at	O
pH	O
9	O
.	O
24	O
.	O

Moreover	O
,	O
a	O
hybrid	O
protein	O
composed	O
of	O
a	O
PvALF	B-GENE
activation	I-GENE
domain	I-GENE
and	O
the	O
DNA	O
binding	O
and	O
dimerization	O
domain	O
of	O
ROM2	B-GENE
activated	O
gene	O
expression	O
,	O
indicating	O
that	O
ROM2	B-GENE
recognizes	O
the	O
DLEC2	B-GENE
enhancer	I-GENE
in	O
vivo	O
;	O
consequently	O
,	O
ROM2	B-GENE
functions	O
as	O
a	O
DNA	O
binding	O
site	O
-	O
dependent	O
repressor	O
.	O

Northern	O
analyses	O
further	O
confirm	O
that	O
the	O
expression	O
of	O
endogenous	O
alpha	B-GENE
-	I-GENE
ENaC	I-GENE
gene	I-GENE
in	O
salivary	O
Pa	O
-	O
4	O
cells	O
is	O
suppressed	O
by	O
an	O
ectopic	O
HMGI	B-GENE
-	I-GENE
C	I-GENE
overexpression	O
.	O

Finally	O
,	O
we	O
demonstrated	O
that	O
although	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
c	B-GENE
-	I-GENE
myb	I-GENE
is	O
required	O
for	O
both	O
the	O
differentiation	O
block	O
and	O
the	O
shift	O
in	O
cell	O
cycle	O
after	O
PMA	O
treatment	O
,	O
phosphorylation	O
by	O
casein	B-GENE
kinase	I-GENE
II	I-GENE
and	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
at	O
positions	O
11	O
and	O
12	O
or	O
532	O
of	O
c	B-GENE
-	I-GENE
myb	I-GENE
,	O
respectively	O
,	O
are	O
not	O
.	O

We	O
found	O
that	O
RXR	B-GENE
and	O
VDR	B-GENE
transactivated	O
selectively	O
from	O
VDRE	O
-	O
linked	O
templates	O
exclusively	O
as	O
a	O
heterodimeric	O
complex	O
,	O
since	O
neither	O
receptor	O
alone	O
enhanced	O
transcription	O
in	O
vitro	O
.	O

We	O
found	O
a	O
significant	O
increase	O
of	O
thromboxane	O
as	O
evidenced	O
by	O
the	O
major	O
urinary	O
metabolite	O
2	O
,	O
3	O
-	O
dinorthromboxane	O
B2	O
in	O
the	O
oestrogen	O
group	O
as	O
compared	O
to	O
the	O
orchidectomy	O
group	O
.	O

Assays	O
of	O
APRE	O
-	O
luciferase	B-GENE
reporter	O
plasmids	O
transfected	O
into	O
HepG2	O
cells	O
show	O
that	O
a	O
mutated	O
APRE	O
that	O
binds	O
only	O
BPi	B-GENE
functions	O
as	O
an	O
IL	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
inducible	O
enhancer	O
,	O
whereas	O
a	O
mutated	O
APRE	O
that	O
binds	O
only	O
BPc	B-GENE
does	O
not	O
.	O

Compared	O
with	O
controls	O
,	O
patients	O
in	O
the	O
unmedicated	O
state	O
had	O
low	O
smooth	O
pursuit	O
gain	O
,	O
had	O
a	O
higher	O
rate	O
of	O
corrective	O
catch	O
-	O
up	O
saccades	O
,	O
and	O
tended	O
to	O
spend	O
less	O
time	O
engaged	O
in	O
the	O
tracking	O
task	O
.	O

Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
nuclear	I-GENE
antigen	I-GENE
2	I-GENE
exerts	O
its	O
transactivating	O
function	O
through	O
interaction	O
with	O
recombination	B-GENE
signal	I-GENE
binding	I-GENE
protein	I-GENE
RBP	I-GENE
-	I-GENE
J	I-GENE
kappa	I-GENE
,	O
the	O
homologue	O
of	O
Drosophila	B-GENE
Suppressor	I-GENE
of	I-GENE
Hairless	I-GENE
.	O

A	B-GENE
.	I-GENE
thaliana	I-GENE
cystathionine	I-GENE
beta	I-GENE
-	I-GENE
lyase	I-GENE
exhibits	O
22	O
%	O
sequence	O
identity	O
with	O
the	O
E	O
.	O
coli	O
corresponding	O
enzyme	O
and	O
contains	O
a	O
70	O
amino	O
acid	O
N	O
-	O
terminal	O
additional	O
sequence	O
compared	O
with	O
the	O
bacterial	O
protein	O
.	O

The	O
three	O
-	O
dimensional	O
structure	O
of	O
the	O
E	O
.	O
coli	O
CR	O
domain	O
indicates	O
that	O
this	O
sequence	O
conservation	O
is	O
likely	O
to	O
result	O
in	O
a	O
conserved	O
structural	O
motif	O
.	O

Co	O
-	O
expression	O
of	O
PLD1	B-GENE
in	O
COS	O
-	O
7	O
cells	O
with	O
the	O
two	O
recombinant	B-GENE
CK2	I-GENE
subunits	I-GENE
,	O
alpha	O
or	O
beta	O
,	O
suggests	O
that	O
the	O
association	O
of	O
PLD1	B-GENE
with	O
the	O
kinase	O
is	O
through	O
the	O
beta	O
subunit	O
.	O

Despite	O
this	O
dependency	O
,	O
however	O
,	O
a	O
B	B-GENE
.	I-GENE
japonicum	I-GENE
fixK	I-GENE
mutant	I-GENE
did	O
not	O
have	O
the	O
phenotypic	O
characteristics	O
of	O
B	B-GENE
.	I-GENE
japonicum	I-GENE
fixL	I-GENE
and	O
fixJ	B-GENE
mutants	I-GENE
:	O
the	O
fixK	B-GENE
mutant	I-GENE
was	O
neither	O
Fix	O
-	O
in	O
symbiosis	O
with	O
soybean	O
plants	O
nor	O
defective	O
in	O
anaerobic	O
respiration	O
with	O
nitrate	O
as	O
the	O
terminal	O
electron	O
acceptor	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
of	O
Pst1p	B-GENE
possessed	O
high	O
sequence	O
homology	O
with	O
the	O
Sin3	B-GENE
family	I-GENE
of	O
proteins	O
,	O
known	O
for	O
their	O
interaction	O
with	O
histone	B-GENE
deacetylases	I-GENE
.	O

This	O
selective	O
squelching	O
activity	O
suggests	O
that	O
GRIM	B-GENE
can	O
interact	O
with	O
an	O
essential	O
component	O
of	O
the	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
transcription	O
machinery	O
.	O

A	O
third	O
group	O
(	O
n	O
=	O
10	O
)	O
was	O
assigned	O
to	O
receive	O
the	O
canalith	O
repositioning	O
maneuver	O
without	O
mastoid	O
vibration	O
.	O

With	O
the	O
help	O
of	O
partially	O
overlapping	O
parenchymatous	O
sutures	O
,	O
different	O
renal	O
segments	O
were	O
devitalized	O
.	O

The	O
S	B-GENE
.	I-GENE
typhimurium	I-GENE
aspartyl	I-GENE
/	I-GENE
asparaginyl	I-GENE
beta	I-GENE
-	I-GENE
hydroxylase	I-GENE
homologue	I-GENE
(	O
designated	O
lpxO	B-GENE
)	O
was	O
cloned	O
into	O
pBluescriptSK	O
and	O
expressed	O
in	O
Escherichia	O
coli	O
K	O
-	O
12	O
,	O
which	O
does	O
not	O
contain	O
lpxO	B-GENE
.	O

Cardiac	O
NE	O
spillover	O
was	O
higher	O
(	O
P	O
<	O
.	O
05	O
)	O
at	O
baseline	O
in	O
the	O
patient	O
group	O
than	O
in	O
healthy	O
subjects	O
,	O
whereas	O
renal	O
and	O
whole	O
-	O
body	O
NE	O
spillovers	O
were	O
similar	O
between	O
the	O
study	O
groups	O
.	O

Translation	O
of	O
mok	B-GENE
is	O
tightly	O
regulated	O
by	O
Sok	B-GENE
RNA	I-GENE
,	O
and	O
Sok	B-GENE
RNA	I-GENE
thus	O
regulates	O
hok	B-GENE
translation	O
indirectly	O
through	O
mok	B-GENE
.	O

In	O
this	O
work	O
,	O
we	O
determined	O
the	O
sequences	O
of	O
eight	O
VirF	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
from	O
four	O
different	O
genes	O
,	O
by	O
DNase	B-GENE
I	I-GENE
or	O
hydroxyl	O
radical	O
footprinting	O
.	O

Treatment	O
with	O
ACE	B-GENE
inhibitors	O
after	O
acute	O
myocardial	O
infarction	O

One	O
-	O
hour	O
O3	O
,	O
NO2	O
,	O
and	O
SO2	O
personal	O
exposures	O
were	O
measured	O
using	O
samplers	O
developed	O
in	O
our	O
laboratory	O
,	O
while	O
short	O
-	O
term	O
PM2	O
.	O
5	O
,	O
CO	O
,	O
and	O
VOCs	O
exposures	O
were	O
measured	O
using	O
currently	O
available	O
monitors	O
.	O

Recombinant	B-GENE
MsERK1	I-GENE
(	O
rMsERK1	B-GENE
)	O
,	O
when	O
overexpressed	O
in	O
Escherichia	O
coli	O
,	O
is	O
recognized	O
by	O
antibodies	O
raised	O
against	O
MAP	B-GENE
kinases	I-GENE
from	I-GENE
rat	I-GENE
,	I-GENE
Xenopus	I-GENE
,	I-GENE
and	I-GENE
sea	I-GENE
star	I-GENE
and	O
by	O
anti	B-GENE
-	I-GENE
phosphotyrosine	I-GENE
antibodies	I-GENE
.	O

However	O
,	O
UV	O
resistance	O
is	O
only	O
minimally	O
restored	O
,	O
and	O
mutant	O
cells	O
remain	O
sensitive	O
to	O
gamma	O
radiation	O
.	O

The	O
melanoma	B-GENE
growth	I-GENE
stimulatory	I-GENE
activity	I-GENE
/	I-GENE
growth	I-GENE
-	I-GENE
regulated	I-GENE
protein	I-GENE
,	O
CXCL1	B-GENE
,	O
is	O
constitutively	O
expressed	O
at	O
high	O
levels	O
during	O
inflammation	O
and	O
progression	O
of	O
melanocytes	O
into	O
malignant	O
melanoma	O
.	O

The	O
activated	O
glucocorticoid	B-GENE
receptor	I-GENE
forms	O
a	O
complex	O
with	O
Stat5	B-GENE
and	O
enhances	O
Stat5	B-GENE
-	O
mediated	O
transcriptional	O
induction	O
.	O

A	O
simple	O
procedure	O
for	O
accurate	O
quantitation	O
of	O
factor	B-GENE
VIII	I-GENE
inhibitors	O
.	O

Diagnostic	O
importance	O
of	O
determining	O
leucine	B-GENE
aminotransferase	I-GENE
activity	O
in	O
acute	O
pancreatitis	O

In	O
contrast	O
,	O
T229E	B-GENE
-	I-GENE
p70s6k	I-GENE
migrated	O
more	O
slowly	O
in	O
SDS	O
-	O
polyacrylamide	O
gels	O
,	O
but	O
demonstrated	O
partial	O
kinase	O
activity	O
(	O
approximately	O
20	O
%	O
compared	O
with	O
the	O
wild	O
type	O
)	O
.	O

Transcription	B-GENE
factor	I-GENE
IIIC	I-GENE
(	O
TFIIIC	B-GENE
)	O
is	O
required	O
for	O
the	O
assembly	O
of	O
a	O
preinitiation	O
complex	O
on	O
5S	B-GENE
RNA	I-GENE
,	O
tRNA	O
,	O
and	O
adenovirus	B-GENE
VA	I-GENE
RNA	O
genes	O
and	O
contains	O
two	O
separable	O
components	O
,	O
TFIIIC1	B-GENE
and	O
TFIIIC2	B-GENE
.	O

Synchronous	O
multicentric	O
giant	O
cell	O
tumour	O
:	O
a	O
case	O
report	O
with	O
review	O
of	O
literature	O
.	O

Lysates	O
of	O
COS	O
cells	O
transfected	O
with	O
modified	B-GENE
hGrzB	I-GENE
cDNA	I-GENE
were	O
able	O
to	O
hydrolyze	O
tert	O
-	O
butyloxycarbonyl	O
-	O
Ala	O
-	O
Ala	O
-	O
Asp	O
-	O
thiobenzyl	O
ester	O
(	O
Boc	O
-	O
Ala	O
-	O
Ala	O
-	O
Asp	O
-	O
SBzl	O
)	O
,	O
whereas	O
lysates	O
transfected	O
with	O
unmodified	B-GENE
hGrzB	I-GENE
cDNA	I-GENE
were	O
inactive	O
.	O

Mutant	B-GENE
M	I-GENE
proteins	I-GENE
were	O
tested	O
for	O
their	O
ability	O
to	O
complement	O
growth	O
of	O
the	O
temperature	O
-	O
sensitive	O
M	B-GENE
protein	I-GENE
mutant	I-GENE
virus	O
tsO23	O
at	O
the	O
nonpermissive	O
temperature	O
.	O

The	O
POU	B-GENE
-	O
specific	O
domain	O
of	O
Pit	B-GENE
-	I-GENE
1	I-GENE
is	O
essential	O
for	O
sequence	O
-	O
specific	O
,	O
high	O
affinity	O
DNA	O
binding	O
and	O
DNA	O
-	O
dependent	O
Pit	B-GENE
-	I-GENE
1	I-GENE
-	O
Pit	B-GENE
-	I-GENE
1	I-GENE
interactions	O
.	O

It	O
competes	O
with	O
the	O
calcium	O
ion	O
which	O
brings	O
about	O
inhibition	O
of	O
myosine	B-GENE
kinase	I-GENE
,	O
and	O
therefore	O
a	O
drop	O
in	O
phosphorylated	O
myosine	O
.	O

It	O
appears	O
to	O
be	O
useful	O
in	O
untreated	O
patients	O
with	O
stage	O
I	O
or	O
II	O
NHL	O
but	O
no	O
definite	O
radiographic	O
abnormalities	O
,	O
or	O
with	O
abnormal	O
radiographs	O
but	O
no	O
extrathoracic	O
spread	O
,	O
and	O
in	O
treated	O
patients	O
with	O
questionable	O
radiographs	O
.	O

We	O
conclude	O
that	O
LGCS	O
is	O
successful	O
in	O
treating	O
esophageal	O
varices	O
in	O
the	O
setting	O
of	O
hyperdynamic	O
portal	O
circulation	O
with	O
acceptable	O
liver	O
function	O
.	O

3	O
)	O
The	O
progress	O
of	O
fibrinolysis	O
was	O
observed	O
by	O
serial	O
collection	O
of	O
middle	O
ear	O
fluid	O
in	O
the	O
same	O
side	O
ear	O
of	O
5	O
cases	O
out	O
of	O
17	O
cases	O
having	O
much	O
activity	O
for	O
fibrin	B-GENE
degradation	O
,	O
and	O
lowering	O
of	O
fibrinolytic	O
activity	O
was	O
revealed	O
in	O
4	O
out	O
of	O
these	O
5	O
cases	O
as	O
the	O
result	O
.	O

In	O
lyzozyme	B-GENE
activity	O
there	O
was	O
periodicity	O
in	O
three	O
groups	O
but	O
not	O
in	O
the	O
youngest	O
foals	O
.	O

Alternative	O
roles	O
of	O
these	O
DNA	O
motifs	O
as	O
activators	O
of	O
early	O
mRNA	O
transcription	O
and	O
as	O
an	O
initiator	O
element	O
for	O
late	O
mRNA	O
transcription	O
help	O
explain	O
how	O
polyomavirus	O
gene	O
expression	O
is	O
regulated	O
during	O
lytic	O
growth	O
and	O
provides	O
a	O
model	O
for	O
cellular	O
transcription	O
during	O
development	O
.	O

The	O
median	O
levels	O
of	O
t	B-GENE
-	I-GENE
PA	I-GENE
Ag	I-GENE
and	O
PAI	B-GENE
in	O
plasma	O
were	O
respectively	O
10	O
.	O
7	O
ng	O
/	O
ml	O
(	O
interquartile	O
range	O
8	O
.	O
6	O
ng	O
/	O
ml	O
)	O
and	O
15	O
.	O
7	O
IU	O
/	O
ml	O
(	O
interquartile	O
range	O
12	O
.	O
2	O
IU	O
/	O
ml	O
)	O
.	O

The	O
Mer1	B-GENE
protein	I-GENE
contains	O
the	O
KH	O
motif	O
found	O
in	O
some	O
RNA	O
-	O
binding	O
proteins	O
,	O
and	O
RNA	O
gel	O
mobility	O
shift	O
assays	O
demonstrate	O
that	O
Mer1	B-GENE
binds	O
specifically	O
to	O
MER2	B-GENE
RNA	I-GENE
.	O

Collectively	O
,	O
these	O
studies	O
suggest	O
that	O
the	O
major	O
EGF	B-GENE
-	O
stimulated	O
mitotic	O
growth	O
pathways	O
may	O
not	O
be	O
absolutely	O
linked	O
to	O
the	O
stat91	B-GENE
signaling	O
pathways	O
and	O
that	O
such	O
transcription	O
complexes	O
are	O
more	O
complex	O
than	O
previously	O
reported	O
.	O

A	O
procaryotic	O
regulatory	O
factor	O
with	O
a	O
histone	B-GENE
H1	I-GENE
-	I-GENE
like	I-GENE
carboxy	I-GENE
-	I-GENE
terminal	I-GENE
domain	I-GENE
:	O
clonal	O
variation	O
of	O
repeats	O
within	O
algP	B-GENE
,	O
a	O
gene	O
involved	O
in	O
regulation	O
of	O
mucoidy	O
in	O
Pseudomonas	O
aeruginosa	O
.	O

Innervation	O
of	O
reticular	O
papillae	O
in	O
sheep	O
and	O
goats	O
.	O

The	O
monkeys	O
had	O
been	O
administered	O
a	O
common	O
lead	O
isotope	O
"	O
mix	O
"	O
at	O
the	O
rate	O
of	O
about	O
1300	O
micrograms	O
Pb	O
/	O
kg	O
body	O
wt	O
/	O
day	O
from	O
age	O
10	O
months	O
until	O
the	O
start	O
of	O
the	O
study	O
.	O

Previous	O
studies	O
showed	O
that	O
a	O
palindromic	O
sequence	O
located	O
at	O
-	O
159	O
base	O
pairs	O
is	O
essential	O
for	O
induction	O
of	O
cutinase	B-GENE
gene	I-GENE
in	O
Fusarium	O
solani	O
f	O
.	O
sp	O
.	O
pisi	O
(	O
Nectria	O
haematococca	O
mating	O
type	O
VI	O
)	O
by	O
the	O
hydroxy	O
fatty	O
acids	O
from	O
plant	O
cutin	O
and	O
that	O
a	O
50	O
-	O
kDa	O
nuclear	O
protein	O
binds	O
to	O
a	O
promoter	O
that	O
contains	O
this	O
element	O
.	O

In	O
cells	O
co	O
-	O
expressing	O
high	O
levels	O
of	O
the	O
p38	B-GENE
(	O
MAPK	B-GENE
)	O
kinase	O
(	O
MKK3	B-GENE
)	O
together	O
with	O
the	O
p38	B-GENE
(	O
MAPK	B-GENE
)	O
,	O
a	O
significant	O
inhibition	O
of	O
mitogen	O
-	O
induced	O
cyclin	B-GENE
D1	I-GENE
expression	O
was	O
observed	O
.	O

ANL	O
-	O
7535	O
.	O

Pig	O
uPA	B-GENE
promoter	O
-	O
CAT	B-GENE
constructs	O
were	O
more	O
active	O
than	O
mouse	O
constructs	O
in	O
this	O
assay	O
.	O

Thermal	O
changes	O
of	O
the	O
bovine	O
uterus	O
following	O
administration	O
of	O
estradiol	O
-	O
17beta	O
.	O

Elements	O
regulating	O
cell	O
-	O
and	O
stage	O
-	O
specific	O
expression	O
of	O
the	O
C	O
.	O
elegans	O
MyoD	B-GENE
family	O
homolog	O
hlh	B-GENE
-	I-GENE
1	I-GENE
.	O

Restriction	O
analysis	O
of	O
the	O
isolated	O
genomic	O
clones	O
indicated	O
that	O
the	O
endogenous	O
sequences	O
abutting	O
the	O
3	O
'	O
ends	O
of	O
the	O
94	O
-	O
A	O
and	O
94	O
-	O
K	O
transgenes	O
are	O
separated	O
by	O
less	O
than	O
20	O
kb	O
,	O
providing	O
strong	O
support	O
for	O
the	O
single	O
integration	O
model	O
.	O

The	O
sensitivity	O
for	O
ergometry	O
and	O
treadmill	O
testing	O
was	O
75	O
and	O
62	O
%	O
respectively	O
.	O

All	O
these	O
abnormalities	O
returned	O
to	O
normal	O
after	O
removal	O
of	O
the	O
tumor	O
.	O

The	O
STS	B-GENE
sequence	I-GENE
WI	I-GENE
-	I-GENE
14920	I-GENE
is	O
in	O
fact	O
derived	O
from	O
the	O
3	O
'	O
-	O
untranslated	O
region	O
of	O
the	O
human	B-GENE
PUNC	I-GENE
gene	I-GENE
.	O

Four	O
antifungal	O
agents	O
were	O
compared	O
:	O
amphotericin	O
B	O
,	O
flucytosine	O
,	O
miconazole	O
,	O
and	O
ketoconazole	O
.	O

Phylogenetic	O
analysis	O
of	O
yeast	O
,	O
invertebrate	O
,	O
and	O
multiple	O
mammalian	O
isoforms	O
of	O
SNF4	B-GENE
shows	O
that	O
the	O
gene	O
duplication	O
likely	O
occurred	O
early	O
in	O
the	O
metazoan	O
lineage	O
,	O
as	O
the	O
protein	O
products	O
of	O
the	O
different	O
loci	O
are	O
relatively	O
divergent	O
.	O

Blood	O
samples	O
(	O
30	O
ml	O
)	O
were	O
collected	O
via	O
an	O
indwelling	O
arm	O
catheter	O
at	O
rest	O
,	O
and	O
at	O
minutes	O
13	O
and	O
28	O
of	O
exercise	O
for	O
determinations	O
of	O
plasma	O
EPI	O
,	O
serum	O
free	O
fatty	O
acid	O
(	O
FFA	O
)	O
,	O
serum	O
glycerol	O
(	O
GLY	O
)	O
,	O
blood	O
glucose	O
(	O
GLU	O
)	O
,	O
and	O
blood	O
lactate	O
(	O
LA	O
)	O
concentrations	O
.	O

The	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
precursor	O
p100	B-GENE
(	O
lyt	B-GENE
-	I-GENE
10	I-GENE
,	O
p97	B-GENE
,	O
p98	B-GENE
)	O
generates	O
after	O
proteolytic	O
processing	O
a	O
52	O
kDa	O
subunit	O
,	O
which	O
can	O
bind	O
to	O
kappa	B-GENE
B	I-GENE
-	I-GENE
motifs	I-GENE
.	O

The	O
delta	O
mean	O
VAF	O
and	O
delta	O
mean	O
SABP	O
indicated	O
varied	O
mean	O
values	O
of	O
VAF	O
and	O
SABP	O
,	O
respectively	O
.	O

Gel	O
mobility	O
shift	O
analyses	O
reveal	O
that	O
FRTL	O
-	O
5	O
thyroid	O
cell	O
nuclear	O
extracts	O
form	O
a	O
specific	O
protein	O
/	O
DNA	O
complex	O
with	O
this	O
region	O
,	O
which	O
is	O
prevented	O
by	O
the	O
TTF	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
element	I-GENE
from	O
the	O
TG	B-GENE
promoter	I-GENE
;	O
FRT	O
and	O
BRL	O
cell	O
nuclear	O
extracts	O
do	O
not	O
have	O
TTF	B-GENE
-	I-GENE
1	I-GENE
and	O
do	O
not	O
form	O
this	O
complex	O
.	O

The	O
rice	O
gene	O
consists	O
of	O
four	O
exons	O
.	O

Thallium	O
-	O
201	O
scintigraphy	O
after	O
dipyridamole	O
infusion	O
with	O
low	O
level	O
exercise	O
.	O

Dominant	O
-	O
negative	O
upf1	B-GENE
mutations	O
were	O
isolated	O
following	O
in	O
vitro	O
mutagenesis	O
of	O
a	O
plasmid	O
containing	O
the	O
UPF1	B-GENE
gene	I-GENE
.	O

One	O
of	O
the	O
ORFs	O
in	O
the	O
Methanococcus	O
jannaschii	O
genome	O
possesses	O
high	O
similarity	O
to	O
the	O
M	B-GENE
.	I-GENE
aeolicus	I-GENE
ilvB	I-GENE
,	O
indicating	O
that	O
it	O
is	O
an	O
authentic	O
AHAS	B-GENE
.	O

It	O
differed	O
from	O
cued	O
recall	O
only	O
in	O
the	O
instructions	O
,	O
which	O
directed	O
subjects	O
away	O
from	O
the	O
memory	O
aspects	O
of	O
the	O
test	O
and	O
asked	O
them	O
to	O
complete	O
each	O
three	O
-	O
letter	O
cue	O
with	O
the	O
first	O
word	O
that	O
came	O
to	O
mind	O
.	O

Such	O
saturation	O
often	O
occurs	O
for	O
several	O
recording	O
sweeps	O
after	O
large	O
amplitude	O
signals	O
such	O
as	O
eye	O
blinks	O
are	O
rejected	O
.	O

To	O
define	O
the	O
molecular	O
mechanism	O
regulating	O
FGFR	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
expression	O
in	O
proliferating	O
myoblasts	O
and	O
post	O
-	O
mitotic	O
muscle	O
fibers	O
,	O
we	O
have	O
isolated	O
and	O
partially	O
characterized	O
the	O
avian	O
FGFR	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
promoter	O
.	O

Samarium	O
-	O
153	O
for	O
intravascular	O
irradiation	O
therapy	O
with	O
liquid	O
-	O
filled	O
balloons	O
to	O
prevent	O
restenosis	O
:	O
acute	O
and	O
long	O
-	O
term	O
results	O
in	O
a	O
hypercholesterolemic	O
rabbit	O
restenosis	O
model	O
.	O

This	O
element	O
was	O
required	O
for	O
both	O
basal	O
and	O
activated	O
expression	O
and	O
almost	O
certainly	O
functions	O
as	O
a	O
TATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
interaction	O
site	O
.	O

This	O
report	O
establishes	O
that	O
the	O
effect	O
of	O
homozygous	O
sickle	O
cell	O
disease	O
on	O
growth	O
patterns	O
in	O
childhood	O
is	O
apparent	O
before	O
the	O
age	O
of	O
6	O
years	O
.	O

But	O
it	O
is	O
possible	O
that	O
the	O
two	O
hemispheres	O
differ	O
in	O
the	O
manner	O
in	O
which	O
they	O
make	O
use	O
of	O
semantic	O
structures	O
:	O
the	O
left	O
hemisphere	O
in	O
a	O
selective	O
manner	O
,	O
appropriate	O
for	O
the	O
solution	O
of	O
a	O
specific	O
task	O
,	O
and	O
the	O
right	O
hemisphere	O
in	O
a	O
more	O
diffuse	O
and	O
global	O
manner	O
.	O

The	O
results	O
reveal	O
preferences	O
for	O
particular	O
initiating	O
nucleotides	O
(	O
ATP	O
>	O
or	O
=	O
GTP	O
>	O
UTP	O
>	O
>	O
CTP	O
)	O
and	O
for	O
starting	O
positions	O
downstream	O
of	O
the	O
Pribnow	O
box	O
(	O
7	O
>	O
>	O
6	O
and	O
8	O
>	O
9	O
>	O
10	O
)	O
.	O

We	O
determined	O
that	O
Hop	B-GENE
(	I-GENE
T42	I-GENE
)	I-GENE
contains	O
a	O
glutamic	O
acid	O
-	O
to	O
-	O
lysine	O
substitution	O
at	O
amino	O
acid	O
residue	O
695	O
(	O
E695K	O
)	O
.	O

Androgen	O
ablation	O
-	O
-	O
50	O
years	O
later	O
.	O

It	O
is	O
suggested	O
that	O
on	O
presentation	O
of	O
tail	O
tip	O
necrosis	O
in	O
kittens	O
a	O
diagnosis	O
of	O
neonatal	O
isoerythrolysis	O
or	O
isoagglutination	O
should	O
be	O
considered	O
.	O

Men	O
and	O
women	O
entering	O
psychotherapy	O
more	O
often	O
had	O
negative	O
Wish	O
elements	O
than	O
others	O
.	O

This	O
clone	O
will	O
be	O
useful	O
for	O
identifying	O
the	O
genetic	O
determinants	O
of	O
FIV	O
-	O
Oma	O
'	O
s	O
biological	O
activities	O
.	O

Serum	B-GENE
prolactin	I-GENE
and	O
oestradiol	O
levels	O
at	O
different	O
stages	O
of	O
puberty	O
.	O

The	O
sequence	O
of	O
three	O
of	O
them	O
revealed	O
pure	O
CAG	O
stretches	O
.	O

Total	O
body	O
BMD	O
(	O
r	O
=	O
0	O
.	O
30	O
;	O
P	O
=	O
0	O
.	O
02	O
)	O
and	O
femoral	O
neck	O
BMD	O
(	O
r	O
=	O
0	O
.	O
39	O
;	O
P	O
=	O
0	O
.	O
002	O
)	O
were	O
positively	O
correlated	O
with	O
weight	O
-	O
bearing	O
activity	O
but	O
not	O
with	O
non	O
-	O
weight	O
-	O
bearing	O
activity	O
.	O

PCC	O
6803	O
mutant	O
impaired	O
in	O
cytochrome	B-GENE
c	I-GENE
maturation	O
.	O

Ureases	B-GENE
were	O
purified	O
from	O
the	O
recombinant	O
cells	O
and	O
shown	O
to	O
be	O
identical	O
to	O
control	O
enzyme	O
when	O
analyzed	O
by	O
gel	O
filtration	O
chromatography	O
and	O
sodium	O
dodecyl	O
sulfate	O
-	O
polyacrylamide	O
gel	O
electrophoresis	O
;	O
however	O
,	O
in	O
every	O
case	O
the	O
activity	O
levels	O
correlated	O
to	O
nickel	O
contents	O
as	O
analyzed	O
by	O
atomic	O
absorption	O
analysis	O
.	O

Sequence	O
analysis	O
of	O
the	O
catfish	O
JH	B-GENE
-	O
CH	B-GENE
intron	O
suggests	O
that	O
several	O
sequences	O
are	O
present	O
which	O
appear	O
similar	O
to	O
important	O
transcriptional	O
regulatory	O
elements	O
found	O
within	O
JH	B-GENE
-	O
CH	B-GENE
introns	O
of	O
higher	O
vertebrates	O
.	O

Seroconversion	O
after	O
hepatitis	O
B	O
vaccination	O
.	O

On	O
day	O
1	O
at	O
3500	O
m	O
,	O
RI	O
showed	O
a	O
significant	O
fall	O
in	O
body	O
weight	O
(	O
BW	O
)	O
with	O
respect	O
to	O
SL	O
but	O
AI	O
maintained	O
it	O
.	O

Expression	O
of	O
CBP	B-GENE
/	O
p300	B-GENE
potentiated	O
HS2	O
-	O
mediated	O
transactivation	O
.	O

The	O
perforated	O
splint	O
gives	O
superior	O
results	O
by	O
virtue	O
of	O
the	O
fact	O
that	O
it	O
does	O
not	O
require	O
to	O
be	O
removed	O
for	O
purposes	O
of	O
hygiene	O
and	O
can	O
thus	O
produce	O
a	O
satisfactory	O
result	O
even	O
in	O
those	O
patients	O
who	O
fail	O
to	O
grasp	O
the	O
technique	O
of	O
removal	O
and	O
replacement	O
of	O
the	O
splint	O
.	O

Using	O
lasers	O
in	O
diabetic	O
wound	O
healing	O
.	O

Protein	O
metabolism	O
disorders	O
in	O
burns	O

In	O
contrast	O
,	O
MAPK	B-GENE
activation	O
stimulated	O
by	O
the	O
Gq	B-GENE
-	O
coupled	O
alpha	O
1B	O
AR	O
or	O
M1	B-GENE
muscarinic	B-GENE
cholinergic	I-GENE
receptor	I-GENE
is	O
unaffected	O
by	O
expression	O
of	O
beta	B-GENE
ARKct	I-GENE
or	O
RasN17	B-GENE
expression	O
or	O
by	O
PTK	B-GENE
inhibitors	O
,	O
but	O
is	O
blocked	O
by	O
expression	O
of	O
N	B-GENE
delta	I-GENE
Raf	I-GENE
or	O
by	O
PKC	B-GENE
depletion	O
.	O

RNA	O
unwinding	O
in	O
U4	B-GENE
/	O
U6	B-GENE
snRNPs	O
requires	O
ATP	O
hydrolysis	O
and	O
the	O
DEIH	O
-	O
box	O
splicing	O
factor	O
Brr2	B-GENE
.	O

Extra	O
dose	O
due	O
to	O
extravehicular	O
activity	O
during	O
the	O
NASA4	O
mission	O
measured	O
by	O
an	O
on	O
-	O
board	O
TLD	O
system	O
.	O

Preface	O
and	O
acknowledgements	O
.	O

G	B-GENE
-	I-GENE
CSF	I-GENE
(	O
10	O
microg	O
/	O
kg	O
)	O
was	O
started	O
on	O
day	O
+	O
1	O
and	O
all	O
patients	O
engrafted	O
within	O
a	O
median	O
day	O
number	O
of	O
12	O
(	O
range	O
,	O
10	O
-	O
22	O
)	O
until	O
leukocytes	O
>	O
1	O
.	O
0	O
x	O
10	O
(	O
9	O
)	O
/	O
l	O
and	O
a	O
median	O
day	O
number	O
of	O
56	O
(	O
range	O
,	O
10	O
-	O
180	O
)	O
until	O
platelets	O
>	O
20	O
.	O
0	O
x	O
10	O
(	O
9	O
)	O
/	O
l	O
(	O
ie	O
platelet	O
transfusion	O
independence	O
)	O
.	O

The	O
present	O
study	O
indicates	O
that	O
the	O
high	O
-	O
dose	O
5	O
-	O
fluorouracil	O
regimen	O
shows	O
weak	O
activity	O
in	O
advanced	O
pancreatic	O
cancer	O
which	O
seems	O
comparable	O
to	O
gemcitabine	O
.	O

At	O
D28	O
,	O
149	O
of	O
386	O
patients	O
(	O
49	O
%	O
)	O
had	O
had	O
episodes	O
of	O
automatic	O
mode	O
switch	O
prompted	O
by	O
atrial	O
arrhythmias	O
.	O

Thus	O
,	O
the	O
rates	O
of	O
a	B-GENE
-	I-GENE
factor	I-GENE
receptor	I-GENE
endocytosis	O
and	O
consequent	O
vacuolar	O
turnover	O
depend	O
on	O
the	O
available	O
level	O
of	O
ubiquitin	B-GENE
in	O
the	O
cell	O
.	O

Early	O
diagnosis	O
and	O
early	O
surgical	O
division	O
of	O
the	O
biliary	O
tract	O
and	O
pancreatic	O
duct	O
is	O
recommended	O
for	O
children	O
with	O
AAPBD	O
.	O

This	O
approach	O
allowed	O
examination	O
of	O
baseline	O
factors	O
as	O
well	O
as	O
the	O
effect	O
of	O
change	O
in	O
mileage	O
,	O
the	O
occurrence	O
of	O
a	O
musculoskeletal	O
problem	O
,	O
or	O
the	O
occurrence	O
of	O
another	O
health	O
problem	O
on	O
the	O
rate	O
of	O
dropout	O
.	O

Increased	O
gliadin	B-GENE
antibody	I-GENE
levels	O
were	O
found	O
more	O
frequently	O
in	O
patients	O
with	O
subtotal	O
villous	O
atrophy	O
(	O
9	O
out	O
of	O
17	O
patients	O
,	O
or	O
53	O
%	O
;	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
than	O
in	O
patients	O
with	O
partial	O
villous	O
atrophy	O
(	O
2	O
out	O
of	O
13	O
patients	O
,	O
or	O
15	O
%	O
)	O
or	O
normal	O
villous	O
appearance	O
(	O
2	O
out	O
of	O
10	O
patients	O
,	O
or	O
20	O
%	O
)	O
.	O

The	O
effects	O
of	O
cefazolin	O
,	O
given	O
into	O
the	O
III	O
cerebral	O
ventricle	O
at	O
different	O
doses	O
were	O
studied	O
on	O
GABA	O
content	O
,	O
GAD	O
and	O
GABA	O
-	O
T	O
in	O
the	O
brain	O
-	O
stem	O
of	O
young	O
chickens	O
(	O
Gallus	O
domesticus	O
)	O
.	O

This	O
sequence	O
was	O
sufficient	O
to	O
confer	O
p53	B-GENE
-	O
dependent	O
activation	O
to	O
a	O
heterologous	O
promoter	O
and	O
p53	B-GENE
was	O
capable	O
of	O
binding	O
to	O
this	O
sequence	O
as	O
assessed	O
by	O
gel	O
shift	O
analysis	O
.	O

CAT	B-GENE
assays	O
demonstrated	O
that	O
overexpression	O
of	O
RXRalpha	B-GENE
conferred	O
the	O
best	O
RA	O
response	O
,	O
consistent	O
with	O
our	O
previous	O
observation	O
that	O
9	O
-	O
cis	O
-	O
RA	O
is	O
more	O
potent	O
than	O
all	O
-	O
trans	O
-	O
RA	O
for	O
inducing	O
the	O
expression	O
of	O
the	O
AFP	B-GENE
gene	I-GENE
.	O

In	O
addition	O
,	O
the	O
results	O
suggest	O
that	O
N	O
region	O
diversity	O
at	O
V	B-GENE
(	O
D	B-GENE
)	O
J	B-GENE
junctions	O
within	O
rearranged	O
immunoglobulin	B-GENE
and	O
T	B-GENE
cell	I-GENE
receptor	I-GENE
gene	I-GENE
loci	I-GENE
can	O
only	O
be	O
introduced	O
after	O
the	O
generation	O
of	O
RAG	B-GENE
-	O
catalyzed	O
DNA	O
double	O
-	O
strand	O
breaks	O
,	O
i	O
.	O
e	O
.	O
during	O
the	O
DNA	O
end	O
joining	O
phase	O
of	O
the	O
V	B-GENE
(	O
D	B-GENE
)	O
J	B-GENE
recombination	O
reaction	O
.	O

The	O
pra2	B-GENE
gene	I-GENE
encodes	O
a	O
pea	B-GENE
(	I-GENE
Pisum	I-GENE
sativum	I-GENE
)	I-GENE
small	I-GENE
GTPase	I-GENE
belonging	O
to	O
the	O
YPT	B-GENE
/	O
rab	B-GENE
family	O
,	O
and	O
its	O
expression	O
is	O
down	O
-	O
regulated	O
by	O
light	O
,	O
mediated	O
by	O
phytochrome	B-GENE
.	O

To	O
directly	O
address	O
this	O
issue	O
,	O
we	O
used	O
a	O
tetracycline	O
-	O
regulated	O
system	O
in	O
human	O
U2OS	O
osteosarcoma	O
cells	O
and	O
thus	O
found	O
that	O
BCL6	B-GENE
mediates	O
growth	O
suppression	O
associated	O
with	O
impaired	O
S	O
phase	O
progression	O
and	O
apoptosis	O
.	O

Changes	O
in	O
water	O
and	O
electrolyte	O
content	O
of	O
the	O
brain	O
and	O
edema	O
formation	O
after	O
acute	O
,	O
drug	O
-	O
induced	O
hypertension	O
were	O
studied	O
in	O
albino	O
rabbits	O
.	O

The	O
amino	B-GENE
-	I-GENE
terminal	I-GENE
gag	I-GENE
-	I-GENE
encoded	I-GENE
region	I-GENE
of	O
P140gag	B-GENE
-	O
fps	B-GENE
contains	O
a	O
phosphotyrosine	O
residue	O
in	O
addition	O
to	O
normal	O
gag	B-GENE
phosphorylation	O
sites	O
.	O

To	O
explore	O
the	O
effect	O
of	O
persistent	O
cardiomegaly	O
on	O
cardiovascular	O
function	O
,	O
groups	O
of	O
newborn	O
rats	O
inhaled	O
up	O
to	O
500	O
ppm	O
CO	O
for	O
33	O
days	O
,	O
after	O
which	O
development	O
continued	O
in	O
ambient	O
air	O
.	O

The	O
subjects	O
'	O
lungs	O
were	O
ventilated	O
with	O
N2O	O
in	O
O2	O
(	O
FIO2	O
0	O
.	O
3	O
)	O
to	O
the	O
end	O
-	O
tidal	O
CO2	O
present	O
before	O
anesthesia	O
,	O
and	O
then	O
CBF	O
was	O
measured	O
using	O
intravenous	O
133Xe	O
and	O
ten	O
scintillation	O
counters	O
,	O
five	O
over	O
each	O
cerebral	O
hemisphere	O
.	O

Cutaneous	O
melanoma	O
and	O
bilateral	O
retinoblastoma	O
.	O

This	O
complex	O
was	O
eliminated	O
by	O
mutation	O
of	O
either	O
half	O
-	O
site	O
,	O
and	O
it	O
was	O
supershifted	O
by	O
antibodies	O
against	O
chicken	B-GENE
ovalbumin	I-GENE
upstream	I-GENE
promoter	I-GENE
-	I-GENE
transcription	I-GENE
factor	I-GENE
(	O
COUP	B-GENE
-	I-GENE
TF	I-GENE
)	O
.	O

Polymorphisms	O
in	O
the	O
CCR5	B-GENE
genes	I-GENE
of	O
African	O
green	O
monkeys	O
and	O
mice	O
implicate	O
specific	O
amino	O
acids	O
in	O
infections	O
by	O
simian	O
and	O
human	O
immunodeficiency	O
viruses	O
.	O

The	O
transcription	O
start	O
site	O
was	O
localized	O
224	O
bp	O
upstream	O
the	O
ATG	O
codon	O
by	O
RNase	B-GENE
protection	O
and	O
primer	O
extension	O
mapping	O
.	O

Statistical	O
aspects	O
of	O
the	O
relation	O
of	O
the	O
radioprotective	O
action	O
of	O
mercaptoethylamine	O
derivatives	O
and	O
analogs	O
to	O
their	O
electron	O
parameters	O

Six	O
patients	O
(	O
24	O
%	O
)	O
developed	O
sepsis	O
and	O
only	O
one	O
survived	O
.	O

The	O
material	O
then	O
was	O
cut	O
with	O
a	O
diamond	O
saw	O
into	O
sheets	O
of	O
8	O
x	O
10	O
x	O
3	O
mm	O
,	O
and	O
the	O
upper	O
surface	O
was	O
polished	O
by	O
colloidal	O
SiO2	O
and	O
/	O
or	O
covered	O
with	O
a	O
carbon	O
-	O
titanium	O
(	O
C	O
:	O
Ti	O
)	O
layer	O
(	O
3	O
.	O
3	O
microm	O
)	O
using	O
the	O
plasma	O
-	O
enhanced	O
physical	O
vapor	O
deposition	O
method	O
.	O

We	O
present	O
here	O
a	O
statistical	O
technique	O
we	O
developed	O
to	O
identify	O
the	O
sequence	O
elements	O
that	O
may	O
be	O
responsible	O
for	O
this	O
cell	O
cycle	O
regulation	O
.	O

Diabetic	O
osteopenia	O
,	O
a	O
known	O
chronic	O
complication	O
of	O
diabetes	O
,	O
has	O
been	O
demonstrated	O
with	O
alterations	O
in	O
the	O
calcium	O
-	O
vitamin	O
D	O
endocrine	O
system	O
.	O

From	O
the	O
comparison	O
of	O
the	O
nod	B-GENE
box	I-GENE
sequences	I-GENE
of	O
(	O
brady	O
)	O
rhizobia	O
with	O
a	O
more	O
divergent	O
nod	B-GENE
box	I-GENE
from	O
Azorhizobium	O
caulinodans	O
,	O
we	O
now	O
propose	O
a	O
modular	O
build	O
-	O
up	O
of	O
the	O
nod	B-GENE
box	I-GENE
with	O
the	O
sequence	O
A	O
-	O
T	O
-	O
C	O
-	O
N9	O
-	O
G	O
-	O
A	O
-	O
T	O
as	O
the	O
binding	O
target	O
of	O
the	O
NodD	B-GENE
protein	I-GENE
(	O
the	O
NodD	B-GENE
box	I-GENE
)	O
.	O

This	O
dip	O
also	O
occurred	O
during	O
prednisone	O
and	O
vitamin	O
D	O
treatment	O
,	O
but	O
did	O
not	O
occur	O
when	O
calcium	O
was	O
added	O
to	O
prednisone	O
,	O
although	O
the	O
baseline	O
value	O
was	O
lower	O
at	O
the	O
start	O
of	O
combined	O
treatment	O
with	O
prednisone	O
and	O
calcium	O
.	O

Highly	O
conserved	O
regions	O
called	O
src	B-GENE
homology	I-GENE
2	I-GENE
and	O
3	O
(	O
SH2	B-GENE
and	O
SH3	B-GENE
)	O
,	O
comprising	O
amino	O
acid	O
residues	O
88	O
to	O
250	O
,	O
are	O
believed	O
to	O
modulate	O
the	O
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
kinase	I-GENE
activity	O
present	O
in	O
the	O
carboxy	O
-	O
terminal	O
halves	O
of	O
the	O
src	B-GENE
proteins	I-GENE
.	O

The	O
addition	O
of	O
novel	O
techniques	O
,	O
such	O
as	O
histopathologic	O
ultrastaging	O
,	O
immunohistochemistry	O
staining	O
,	O
and	O
reverse	B-GENE
transcriptase	I-GENE
polymerase	O
chain	O
reaction	O
assays	O
,	O
will	O
help	O
increase	O
the	O
accuracy	O
and	O
rate	O
of	O
detection	O
of	O
disease	O
.	O

Acanthamoeba	B-GENE
myosin	I-GENE
I	I-GENE
heavy	I-GENE
chain	I-GENE
kinase	I-GENE
(	O
MIHCK	B-GENE
)	O
phosphorylates	O
the	O
heavy	O
chains	O
of	O
amoeba	B-GENE
myosins	I-GENE
I	I-GENE
,	O
increasing	O
their	O
actin	B-GENE
-	O
activated	O
ATPase	B-GENE
activities	O
.	O

Two	O
different	O
genes	O
(	O
polA	B-GENE
and	O
polB	B-GENE
)	O
encoding	O
family	B-GENE
B	I-GENE
DNA	I-GENE
polymerases	I-GENE
were	O
cloned	O
from	O
the	O
organism	O
by	O
PCR	O
using	O
degenerated	O
primers	O
based	O
on	O
the	O
two	O
conserved	O
motifs	O
(	O
motif	O
A	O
and	O
B	O
)	O
.	O

In	O
this	O
reconstituted	O
system	O
,	O
RNAP	B-GENE
IIA	I-GENE
,	O
but	O
not	O
RNAP	B-GENE
IIB	I-GENE
,	O
can	O
transcribe	O
from	O
the	O
DHFR	B-GENE
promoter	I-GENE
.	O

Furthermore	O
,	O
the	O
data	O
suggest	O
an	O
immunological	O
non	O
-	O
responsiveness	O
to	O
enterotoxin	B-GENE
A	I-GENE
in	O
a	O
considerable	O
portion	O
of	O
the	O
patients	O
.	O

The	O
polypeptide	O
encoded	O
by	O
the	O
cDNA	O
contained	O
450	O
amino	O
acids	O
with	O
a	O
calculated	O
M	O
(	O
r	O
)	O
of	O
52	O
,	O
057	O
,	O
and	O
showed	O
significant	O
homology	O
with	O
human	O
and	O
mouse	B-GENE
CAD	I-GENE
(	O
22	O
%	O
identity	O
)	O
.	O

Focal	O
or	O
regional	O
8	O
-	O
to	O
20	O
-	O
Hz	O
low	O
-	O
voltage	O
epileptiform	O
paroxysms	O
in	O
either	O
hippocampus	O
(	O
10	O
patients	O
)	O
,	O
amygdala	O
(	O
1	O
patient	O
)	O
,	O
or	O
both	O
(	O
1	O
patient	O
)	O
preceded	O
initial	O
motionless	O
staring	O
.	O

Cytokine	O
-	O
mediated	O
I	B-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
reappearance	O
was	O
completely	O
blocked	O
by	O
the	O
protein	O
synthesis	O
inhibitor	O
cycloheximide	O
.	O

In	O
addition	O
,	O
the	O
authors	O
found	O
one	O
an3	B-GENE
allele	I-GENE
(	O
an3	B-GENE
-	I-GENE
W138A	I-GENE
)	O
in	O
which	O
a	O
dTph1	B-GENE
element	I-GENE
had	O
inserted	O
30	O
bp	O
upstream	O
the	O
translation	O
start	O
,	O
without	O
inactivating	O
the	O
gene	O
.	O

The	O
right	O
cornea	O
of	O
rats	O
was	O
cauterized	O
by	O
drops	O
of	O
1	O
.	O
5	O
N	O
HC1	O
over	O
30	O
s	O
;	O
the	O
left	O
one	O
served	O
as	O
a	O
control	O
.	O

The	O
difference	O
between	O
the	O
effects	O
of	O
the	O
two	O
dose	O
levels	O
of	O
Z	O
.	O

The	O
purpose	O
of	O
this	O
presentation	O
is	O
to	O
review	O
the	O
current	O
state	O
of	O
knowledge	O
regarding	O
5	O
,	O
8	O
,	O
11	O
,	O
14	O
-	O
eicosatetraynoic	O
acid	O
(	O
ETYA	O
,	O
Ro	O
3	O
-	O
1428	O
)	O
and	O
its	O
effects	O
on	O
lipid	O
metabolism	O
.	O

Pathophysiologic	O
mechanisms	O
underlying	O
spatial	O
disorientation	O
in	O
patients	O
with	O
Alzheimer	O
'	O
s	O
disease	O
.	O

Secretion	O
of	O
cuticle	O
over	O
and	O
between	O
the	O
domed	O
apical	O
surfaces	O
of	O
these	O
cells	O
leads	O
to	O
a	O
honeycomb	O
-	O
like	O
structure	O
and	O
gives	O
the	O
superficial	O
wart	O
-	O
like	O
phenotype	O
of	O
mitotic	O
clones	O
on	O
the	O
adult	O
.	O

The	O
sequences	O
of	O
two	O
previously	O
known	O
tail	B-GENE
genes	I-GENE
,	O
R	B-GENE
and	O
S	B-GENE
,	O
of	O
the	O
temperate	O
bacteriophage	O
P2	O
and	O
the	O
sequence	O
of	O
an	O
additional	O
open	O
reading	O
frame	O
(	O
orf	O
-	O
30	O
)	O
located	O
between	O
S	B-GENE
and	O
V	B-GENE
,	O
were	O
determined	O
.	O

NGF	B-GENE
also	O
induced	O
a	O
synthetic	O
promoter	O
with	O
repeated	O
Sp1	B-GENE
sites	I-GENE
linked	O
to	O
a	O
core	O
promoter	O
,	O
and	O
a	O
plasmid	O
regulated	O
by	O
a	O
chimeric	O
transactivator	O
in	O
which	O
the	O
Gal4	B-GENE
DNA	I-GENE
binding	I-GENE
domain	I-GENE
is	O
fused	O
to	O
the	O
Sp1	B-GENE
transactivation	I-GENE
domain	I-GENE
,	O
indicating	O
that	O
this	O
transactivation	O
domain	O
is	O
regulated	O
by	O
NGF	B-GENE
.	O

Nuclear	O
transcription	O
assays	O
confirmed	O
that	O
cys	B-GENE
-	I-GENE
3	I-GENE
+	I-GENE
was	O
under	O
sulfur	O
-	O
regulated	O
transcriptional	O
control	O
and	O
that	O
cys	B-GENE
-	I-GENE
3	I-GENE
+	I-GENE
transcription	O
was	O
constitutive	O
in	O
sulfur	B-GENE
controller	I-GENE
(	O
scon	B-GENE
)	O
-	O
negative	O
regulator	O
mutants	O
.	O

These	O
results	O
suggest	O
that	O
UvrA	B-GENE
is	O
involved	O
in	O
triplet	O
repeat	O
instability	O
in	O
cells	O
.	O

We	O
conclude	O
,	O
therefore	O
,	O
that	O
in	O
the	O
absence	O
of	O
E1A	B-GENE
,	O
E4orf4	B-GENE
is	O
sufficient	O
by	O
itself	O
to	O
trigger	O
a	O
p53	B-GENE
-	O
independent	O
apoptosis	O
pathway	O
that	O
may	O
operate	O
independently	O
of	O
the	O
known	O
zVAD	O
-	O
inhibitable	O
caspases	B-GENE
,	O
and	O
that	O
may	O
involve	O
an	O
as	O
yet	O
uncharacterized	O
mechanism	O
.	O

CONCLUSIONS	O
:	O
The	O
system	O
developed	O
in	O
this	O
study	O
can	O
be	O
used	O
as	O
a	O
method	O
to	O
detect	O
air	O
-	O
trapping	O
during	O
TGI	O
.	O

The	O
nucleotide	O
sequence	O
of	O
the	O
gene	O
encoding	O
this	O
product	O
was	O
determined	O
and	O
the	O
amino	O
acid	O
sequence	O
deduced	O
.	O

After	O
a	O
shift	O
to	O
37	O
degrees	O
C	O
,	O
the	O
mutant	O
Rat7	B-GENE
-	I-GENE
1p	I-GENE
/	O
Nup159	B-GENE
-	I-GENE
1p	I-GENE
is	O
lost	O
from	O
the	O
nuclear	O
rim	O
of	O
rat7	O
-	O
1	O
cells	O
and	O
NPCs	O
,	O
which	O
are	O
clustered	O
together	O
in	O
these	O
cells	O
grown	O
under	O
permissive	O
conditions	O
become	O
substantially	O
less	O
clustered	O
.	O

Evidence	O
for	O
Gcr1p	B-GENE
/	O
Gcr2p	B-GENE
interaction	O
has	O
been	O
presented	O
earlier	O
and	O
is	O
now	O
supported	O
by	O
the	O
isolation	O
of	O
mutations	O
in	O
Gcr1p	B-GENE
suppressing	O
gcr2	B-GENE
,	O
as	O
assessed	O
by	O
growth	O
and	O
enzyme	O
assay	O
.	O

Renal	O
function	O
was	O
evaluated	O
in	O
a	O
group	O
of	O
24	O
patients	O
(	O
21	O
men	O
and	O
3	O
women	O
,	O
mean	O
age	O
47	O
years	O
)	O
who	O
had	O
survived	O
the	O
malignant	O
phase	O
of	O
hypertension	O
during	O
the	O
period	O
of	O
1969	O
-	O
1979	O
.	O

Mammalian	O
ribonucleotide	B-GENE
reductase	I-GENE
shows	O
S	O
-	O
phase	O
specific	O
expression	O
and	O
consists	O
of	O
two	O
non	O
-	O
identical	O
subunits	O
,	O
proteins	B-GENE
R1	I-GENE
(	O
large	O
subunit	O
)	O
and	O
R2	B-GENE
(	O
small	O
subunit	O
)	O
.	O

Azoospermia	O
was	O
graded	O
in	O
the	O
following	O
way	O
:	O
adequate	O
spermatozoa	O
(	O
A1	O
)	O
,	O
low	O
,	O
scanty	O
or	O
rare	O
spermatozoa	O
(	O
A2	O
)	O
,	O
spermatid	O
arrest	O
(	O
B1	O
)	O
,	O
spermatocyte	O
arrest	O
(	O
B2	O
)	O
,	O
Sertoli	O
cell	O
-	O
only	O
pattern	O
(	O
C	O
)	O
and	O
sclerosis	O
(	O
D	O
)	O
.	O

This	O
paper	O
describes	O
a	O
course	O
of	O
therapy	O
with	O
an	O
agoraphobic	O
female	O
patient	O
.	O

Plasmids	O
bearing	O
the	O
P	B-GENE
.	I-GENE
stipitis	I-GENE
URA3	I-GENE
gene	I-GENE
and	O
ARS2	O
element	O
produced	O
more	O
than	O
30	O
,	O
000	O
transformants	O
per	O
micrograms	O
of	O
plasmid	O
DNA	O
.	O

The	O
activation	O
of	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	O
dependent	O
reporter	O
gene	O
transcription	O
by	O
E1A	B-GENE
was	O
potently	O
suppressed	O
upon	O
coexpression	O
of	O
the	O
E1B	B-GENE
19	I-GENE
-	I-GENE
kDa	I-GENE
protein	I-GENE
(	I-GENE
19K	I-GENE
)	I-GENE
.	O

We	O
analyzed	O
the	O
effects	O
of	O
light	O
on	O
tubulin	B-GENE
mRNA	I-GENE
abundance	O
in	O
Arabidopsis	O
seedlings	O
using	O
RNA	O
gel	O
blot	O
hybridizations	O
and	O
gene	O
-	O
specific	O
probes	O
.	O

We	O
conclude	O
that	O
transcription	O
of	O
both	O
SCD1	B-GENE
and	O
SCD2	B-GENE
genes	I-GENE
is	O
responsive	O
to	O
cellular	O
sterol	O
levels	O
and	O
to	O
the	O
levels	O
of	O
nuclear	O
SREBP	B-GENE
/	O
ADD1	B-GENE
and	O
that	O
transcriptional	O
induction	O
requires	O
three	O
spatially	O
conserved	O
cis	O
elements	O
,	O
that	O
bind	O
SREBP	B-GENE
and	O
NF	B-GENE
-	I-GENE
Y	I-GENE
.	O

BACKGROUND	O
:	O
Recent	O
iterative	O
methods	O
for	O
sequence	O
alignment	O
have	O
indicated	O
that	O
the	O
380	O
kDa	O
motor	O
unit	O
of	O
dynein	B-GENE
belongs	O
to	O
the	O
AAA	B-GENE
class	I-GENE
of	O
chaperone	B-GENE
-	I-GENE
like	I-GENE
ATPases	I-GENE
.	O

It	O
is	O
suggested	O
that	O
death	O
of	O
S	O
.	O
mansoni	O
cercariae	O
during	O
penetration	O
of	O
mammalian	O
host	O
skin	O
is	O
probably	O
due	O
to	O
exhaustion	O
of	O
their	O
energy	O
reserves	O
.	O

In	O
particular	O
,	O
lacZ	B-GENE
transcripts	I-GENE
synthesised	O
this	O
way	O
are	O
highly	O
unstable	O
and	O
yield	O
little	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
.	O

Recent	O
research	O
on	O
lipolysis	O
.	O

Instead	O
,	O
HBx	B-GENE
is	O
shown	O
to	O
activate	O
the	O
cyclin	B-GENE
A	I-GENE
promoter	I-GENE
,	O
induce	O
cyclin	B-GENE
A	I-GENE
-	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
2	I-GENE
complexes	O
,	O
and	O
promote	O
cycling	O
of	O
growth	O
-	O
arrested	O
cells	O
into	O
G1	O
through	O
a	O
pathway	O
involving	O
activation	O
of	O
Src	B-GENE
tyrosine	I-GENE
kinases	I-GENE
.	O

Fifty	O
-	O
seven	O
per	O
cent	O
of	O
the	O
primary	O
patients	O
reporting	O
mild	O
symptoms	O
had	O
abnormal	O
levels	O
of	O
leucocytes	O
in	O
their	O
CSF	O
.	O

The	O
vertebrate	B-GENE
transcription	I-GENE
factors	I-GENE
TCF	I-GENE
(	O
T	B-GENE
cell	I-GENE
factor	I-GENE
)	O
and	O
LEF	B-GENE
(	O
lymphocyte	B-GENE
enhancer	I-GENE
binding	I-GENE
factor	I-GENE
)	O
interact	O
with	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
and	O
are	O
hypothesized	O
to	O
mediate	O
Wingless	B-GENE
/	O
Wnt	B-GENE
signaling	O
.	O

DESIGN	O
:	O
Activating	B-GENE
protein	I-GENE
-	I-GENE
1	I-GENE
(	O
AP	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
Tat	B-GENE
-	O
induced	O
transcription	O
were	O
assessed	O
using	O
Jun	B-GENE
and	O
hybrid	O
Tat	B-GENE
/	O
Jun	B-GENE
-	O
expression	O
plasmids	O
and	O
reporter	O
gene	O
constructs	O
which	O
contained	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
sites	I-GENE
upstream	O
of	O
the	O
rat	B-GENE
prolactin	I-GENE
TATAA	I-GENE
element	I-GENE
or	O
an	O
HIV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
construct	I-GENE
in	O
which	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
sites	I-GENE
replaced	O
the	O
TAR	O
element	O
.	O

The	O
PRP4	B-GENE
protein	I-GENE
of	I-GENE
Saccharomyces	I-GENE
cerevisiae	I-GENE
is	O
an	O
essential	O
part	O
of	O
the	O
U4	B-GENE
/	O
U6	B-GENE
snRNP	O
,	O
a	O
component	O
of	O
the	O
mRNA	O
splicing	O
apparatus	O
.	O

According	O
to	O
the	O
penetration	O
of	O
Ca	O
-	O
45	O
,	O
the	O
microleakage	O
level	O
was	O
scored	O
for	O
each	O
section	O
.	O

Endothelial	O
purine	O
content	O
.	O

Binding	O
of	O
transformed	O
Ah	B-GENE
receptor	I-GENE
complex	I-GENE
to	O
a	O
dioxin	O
responsive	O
transcriptional	O
enhancer	O
:	O
evidence	O
for	O
two	O
distinct	O
heteromeric	O
DNA	O
-	O
binding	O
forms	O
.	O

KatA	B-GENE
,	O
AhpCF	B-GENE
,	O
heme	O
biosynthesis	O
enzymes	O
,	O
and	O
MrgA	B-GENE
are	O
also	O
induced	O
upon	O
entry	O
into	O
stationary	O
phase	O
under	O
conditions	O
of	O
iron	O
and	O
manganese	O
limitation	O
.	O

Characterization	O
of	O
the	O
chromosome	O
19	O
breakpoint	O
region	O
revealed	O
that	O
the	O
transcription	B-GENE
factor	I-GENE
-	I-GENE
encoding	I-GENE
USF2	I-GENE
gene	I-GENE
is	O
affected	O
.	O

Analysis	O
of	O
pseudo	B-GENE
VH	I-GENE
gene	I-GENE
segment	I-GENE
recombination	I-GENE
products	I-GENE
reveals	O
no	O
bias	O
in	O
D	B-GENE
gene	I-GENE
segment	I-GENE
reading	O
frame	O
utilization	O
.	O

It	O
is	O
dangerous	O
to	O
label	O
such	O
conditions	O
as	O
'	O
inappropriate	O
'	O
secretion	O
of	O
ADH	B-GENE
since	O
the	O
maintenance	O
of	O
circulating	O
volume	O
is	O
at	O
least	O
as	O
important	O
a	O
physiological	O
requirement	O
as	O
the	O
defence	O
of	O
tonicity	O
.	O

The	O
in	O
vitro	O
activity	O
of	O
KP	O
-	O
103	O
,	O
a	O
novel	O
triazole	O
derivative	O
,	O
against	O
pathogenic	O
fungi	O
that	O
cause	O
dermatomycoses	O
and	O
its	O
therapeutic	O
efficacy	O
against	O
plantar	O
tinea	O
pedis	O
and	O
cutaneous	O
candidiasis	O
in	O
guinea	O
pigs	O
were	O
investigated	O
.	O

Using	O
a	O
simulated	O
cough	O
machine	O
,	O
we	O
analyzed	O
the	O
effect	O
of	O
adding	O
tensio	O
-	O
active	O
liquids	O
as	O
sol	O
phase	O
simulant	O
on	O
the	O
clearance	O
of	O
gel	O
mucus	O
simulant	O
by	O
cough	O
.	O

The	O
effects	O
of	O
4	O
weeks	O
of	O
cyclosporin	O
A	O
(	O
7	O
mg	O
/	O
kg	O
per	O
day	O
)	O
(	O
CyA	O
)	O
on	O
the	O
survival	O
of	O
vascularized	O
osteochondral	O
grafts	O
between	O
rat	O
strains	O
[	O
DA	O
(	O
donor	O
)	O
and	O
Lewis	O
(	O
recipient	O
)	O
]	O
and	O
the	O
presence	O
and	O
significance	O
of	O
host	O
immune	O
tolerance	O
and	O
graft	O
antigen	O
modulation	O
after	O
cessation	O
of	O
immunosuppression	O
have	O
been	O
examined	O
.	O

Insulin	B-GENE
binding	O
to	O
the	O
alpha	O
-	O
subunit	O
of	O
its	O
receptor	O
stimulates	O
the	O
receptor	B-GENE
tyrosine	I-GENE
kinase	I-GENE
to	O
phosphorylate	O
the	O
beta	O
-	O
subunit	O
and	O
several	O
endogenous	O
protein	O
substrates	O
,	O
including	O
pp120	B-GENE
/	O
HA4	B-GENE
,	O
a	O
liver	O
-	O
specific	O
plasma	O
membrane	O
glycoprotein	O
of	O
M	O
(	O
r	O
)	O
20	O
,	O
000	O
.	O

The	O
second	O
intron	O
is	O
the	O
smallest	O
of	O
all	O
the	O
introns	O
(	O
116	O
bp	O
)	O
.	O

Moreover	O
,	O
our	O
recent	O
findings	O
on	O
the	O
Tc52	B-GENE
encoding	I-GENE
gene	I-GENE
underline	O
the	O
interest	O
of	O
genetic	O
manipulation	O
of	O
T	O
.	O
cruzi	O
,	O
not	O
only	O
making	O
it	O
possible	O
to	O
use	O
more	O
closely	O
an	O
in	O
vitro	O
approach	O
to	O
find	O
out	O
how	O
genes	O
function	O
,	O
but	O
also	O
to	O
obtain	O
'	O
attenuated	O
'	O
strains	O
that	O
could	O
be	O
used	O
in	O
the	O
development	O
of	O
vaccinal	O
strategies	O
.	O

Pretreatment	O
of	O
rats	O
with	O
different	O
dose	O
levels	O
of	O
CCl4	O
resulted	O
in	O
a	O
prolongation	O
of	O
TMO	O
half	O
-	O
life	O
,	O
and	O
increase	O
of	O
the	O
area	O
under	O
the	O
curve	O
(	O
AUC	O
)	O
,	O
and	O
a	O
decrease	O
of	O
clearance	O
,	O
but	O
the	O
apparent	O
volume	O
of	O
distribution	O
(	O
Vd	O
)	O
was	O
not	O
significantly	O
decreased	O
.	O

Healthy	O
preterm	O
infants	O
of	O
gestational	O
age	O
26	O
-	O
29	O
weeks	O
showed	O
a	O
'	O
mature	O
'	O
pattern	O
of	O
permeability	O
at	O
birth	O
,	O
followed	O
by	O
a	O
temporary	O
period	O
of	O
enhanced	O
permeability	O
after	O
3	O
-	O
4	O
weeks	O
of	O
life	O
.	O

The	O
promoter	O
for	O
HMG	B-GENE
-	I-GENE
CoA	I-GENE
synthase	I-GENE
contains	O
two	O
binding	O
sites	O
for	O
the	O
sterol	B-GENE
regulatory	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
(	O
SREBPs	B-GENE
)	O
.	O

Using	O
the	O
same	O
electrical	O
analog	O
,	O
we	O
present	O
an	O
analysis	O
that	O
allows	O
calculation	O
of	O
these	O
parameters	O
,	O
as	O
well	O
as	O
the	O
corner	O
frequency	O
of	O
the	O
network	O
(	O
f1	O
)	O
,	O
without	O
need	O
for	O
similar	O
assumptions	O
.	O

These	O
results	O
suggest	O
that	O
transcription	O
influences	O
aspects	O
of	O
gene	O
conversion	O
after	O
initiation	O
,	O
such	O
as	O
strand	O
invasion	O
and	O
/	O
or	O
mismatch	O
repair	O
(	O
MMR	O
)	O
.	O

In	O
contrast	O
,	O
a	O
similar	O
fusion	O
protein	O
(	O
hGH	B-GENE
-	O
LDLR	B-GENE
-	O
DAF17	B-GENE
,	O
abbreviated	O
HLD	B-GENE
)	O
containing	O
a	O
fragment	O
of	O
the	O
serine	O
/	O
threonine	O
-	O
rich	O
domain	O
of	O
the	O
LDL	B-GENE
receptor	I-GENE
(	O
LDLR	B-GENE
)	O
in	O
place	O
of	O
the	O
DAF	B-GENE
-	I-GENE
derived	I-GENE
serine	I-GENE
/	I-GENE
threonine	I-GENE
-	I-GENE
rich	I-GENE
sequences	I-GENE
,	O
does	O
not	O
become	O
GPI	O
anchored	O
.	O

Ocular	O
injuries	O
during	O
general	O
anesthesia	O
.	O

Of	O
concern	O
is	O
the	O
high	O
,	O
unexplained	O
prevalence	O
of	O
BV	O
among	O
African	O
-	O
American	O
women	O
,	O
who	O
are	O
also	O
at	O
extremely	O
high	O
risk	O
for	O
preterm	O
birth	O
.	O

The	O
RAG	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
encodes	O
a	O
component	O
of	O
the	O
V	B-GENE
(	I-GENE
D	I-GENE
)	I-GENE
J	I-GENE
recombinase	I-GENE
which	O
is	O
essential	O
for	O
the	O
assembly	O
of	O
antigen	O
receptor	O
genes	O
in	O
B	O
and	O
T	O
lymphocytes	O
.	O

The	O
LAB	O
in	O
the	O
cecum	O
(	O
mean	O
9	O
.	O
4	O
log	O
CFU	O
/	O
g	O
)	O
increased	O
slightly	O
with	O
increasing	O
abattoir	O
holding	O
time	O
.	O

Reproduction	O
and	O
maternal	O
response	O
of	O
the	O
rat	O
when	O
thiamine	O
intake	O
is	O
limited	O
.	O

Activated	B-GENE
Ki	I-GENE
-	I-GENE
Ras	I-GENE
suppresses	O
12	O
-	O
O	O
-	O
tetradecanoylphorbol	O
-	O
13	O
-	O
acetate	O
-	O
induced	O
activation	O
of	O
the	O
c	B-GENE
-	I-GENE
Jun	I-GENE
NH2	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
pathway	I-GENE
in	O
human	O
colon	O
cancer	O
cells	O
.	O

11	O
:	O
5801	O
-	O
5812	O
,	O
1991	O
)	O
present	O
evidence	O
that	O
the	O
Vps18	B-GENE
/	O
Pep3	B-GENE
protein	O
colocalizes	O
with	O
the	O
Vps11	B-GENE
/	O
Pep5	B-GENE
protein	O
to	O
the	O
cytosolic	O
face	O
of	O
the	O
vacuolar	O
membrane	O
.	O

Cell	O
-	O
free	O
extracts	O
of	O
E	O
.	O
coli	O
(	O
fpg	B-GENE
mutY	B-GENE
)	O
harboring	O
pYSB10	O
possess	O
an	O
enzymatic	O
activity	O
that	O
cleaves	O
a	O
34	O
-	O
mer	O
oligonucleotide	O
containing	O
a	O
single	O
8	O
-	O
oxoG	O
opposite	O
a	O
cytosine	O
(	O
8	O
-	O
OxoG	O
/	O
C	O
)	O
.	O

The	O
authors	O
discussed	O
their	O
experience	O
in	O
investigating	O
20	O
patients	O
with	O
maxillary	O
malignant	O
tumors	O
using	O
routine	O
x	O
-	O
ray	O
studies	O
and	O
MR	O
-	O
tomography	O
,	O
and	O
13	O
patients	O
,	O
investigated	O
in	O
the	O
same	O
way	O
plus	O
CT	O
.	O

Magnification	O
-	O
corrected	O
planimetry	O
of	O
the	O
parapapillary	O
region	O
was	O
performed	O
according	O
to	O
Littmann	O
'	O
s	O
method	O
in	O
312	O
unselected	O
eyes	O
with	O
chronic	O
primary	O
open	O
-	O
angle	O
glaucoma	O
and	O
in	O
125	O
normal	O
eyes	O
of	O
an	O
age	O
-	O
and	O
refraction	O
-	O
matched	O
control	O
group	O
using	O
optic	O
disk	O
photographs	O
.	O

Both	O
merR	B-GENE
genes	I-GENE
consist	O
of	O
a	O
408	O
bp	O
ORF	O
coding	O
for	O
135	O
amino	O
acids	O
.	O

The	O
1	O
.	O
3	O
-	O
kb	O
DNA	O
,	O
when	O
placed	O
upstream	O
of	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
gene	I-GENE
,	O
was	O
shown	O
to	O
be	O
functionally	O
active	O
.	O

We	O
show	O
that	O
Fos	B-GENE
down	O
regulates	O
several	O
immediate	B-GENE
-	I-GENE
early	I-GENE
genes	I-GENE
(	O
c	B-GENE
-	I-GENE
fos	I-GENE
,	O
Egr	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
Egr	B-GENE
-	I-GENE
2	I-GENE
)	O
after	O
mitogenic	O
stimulation	O
.	O

Polar	O
effects	O
of	O
transposon	O
insertions	O
demonstrated	O
that	O
all	O
of	O
these	O
mRNAs	O
arose	O
from	O
a	O
single	O
promoter	O
region	O
,	O
where	O
transcription	O
initiated	O
80	O
bp	O
5	O
'	O
to	O
nifH	B-GENE
.	O

Heart	O
disease	O
.	O

A	O
definitive	O
answer	O
to	O
the	O
question	O
must	O
come	O
from	O
large	O
scale	O
mortality	O
studies	O
of	O
patients	O
in	O
whom	O
the	O
risk	O
/	O
benefit	O
ratio	O
of	O
thrombolysis	O
is	O
not	O
unacceptably	O
high	O
,	O
in	O
whom	O
electrocardiographic	O
criteria	O
of	O
infarction	O
are	O
unequivocal	O
,	O
and	O
in	O
whom	O
treatment	O
can	O
be	O
initiated	O
early	O
after	O
the	O
onset	O
of	O
symptoms	O
with	O
regimens	O
that	O
will	O
induce	O
not	O
only	O
early	O
recanalization	O
,	O
but	O
also	O
sustained	O
patency	O
in	O
infarct	O
-	O
related	O
arteries	O
.	O

Sonography	O
depicted	O
the	O
true	O
morphology	O
of	O
these	O
cystic	O
lesions	O
more	O
clearly	O
than	O
CT	O
,	O
and	O
the	O
sonographic	O
findings	O
virtually	O
excluded	O
uncomplicated	O
hepatic	O
cyst	O
as	O
a	O
diagnosis	O
.	O

The	O
formation	O
of	O
tumorlike	O
lesions	O
in	O
the	O
cockroach	O
leucophaea	O
maderae	O
after	O
anal	O
blockage	O
.	O

Here	O
,	O
we	O
identify	O
the	O
analytical	O
form	O
of	O
the	O
PDF	O
of	O
one	O
such	O
measure	O
,	O
the	O
order	O
parameter	O
in	O
the	O
low	O
temperature	O
phase	O
of	O
the	O
2D	O
XY	O
model	O
.	O

The	O
determination	O
of	O
antithrombin	B-GENE
III	I-GENE
(	O
AT	B-GENE
III	I-GENE
)	O
and	O
its	O
clinical	O
significance	O

In	O
each	O
of	O
the	O
studied	O
HPV	O
types	O
,	O
the	O
two	O
CDP	B-GENE
/	O
Cut	B-GENE
binding	O
sites	O
of	O
PSM	B-GENE
overlap	O
with	O
the	O
known	O
or	O
presumed	O
binding	O
sites	O
of	O
the	O
replication	B-GENE
initiator	I-GENE
protein	I-GENE
E1	I-GENE
.	O

With	O
this	O
study	O
,	O
a	O
total	O
of	O
13	O
operators	O
for	O
the	O
glp	B-GENE
regulon	I-GENE
have	O
been	O
characterized	O
.	O

Located	O
between	O
the	O
3	O
'	O
trans	O
-	O
spliced	O
leader	O
acceptor	O
site	O
and	O
the	O
translational	O
initiation	O
codon	O
of	O
the	O
GP63	B-GENE
gene	I-GENE
is	O
an	O
area	O
of	O
conserved	O
hexanucleotide	O
direct	O
repeats	O
(	O
CTCGCC	O
)	O
which	O
vary	O
in	O
number	O
according	O
to	O
species	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
the	O
impact	O
of	O
the	O
ESRD	O
treatment	O
modality	O
on	O
the	O
quality	O
of	O
life	O
in	O
patients	O
with	O
Type	O
I	O
(	O
insulin	B-GENE
-	O
dependent	O
)	O
diabetes	O
mellitus	O
.	O

MDA	O
-	O
MB	O
-	O
468	O
cells	O
were	O
stably	O
transfected	O
with	O
either	O
a	O
plasmid	O
having	O
a	O
CMV	B-GENE
promoter	I-GENE
-	O
driven	O
rabbit	B-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
gene	I-GENE
or	O
plasmids	O
having	O
a	O
CMV	B-GENE
promoter	I-GENE
-	O
driven	O
chimeric	O
gadd45	B-GENE
5	O
"	O
-	O
UTR	O
-	O
rabbit	B-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
gene	O
,	O
where	O
the	O
entire	B-GENE
gadd45	I-GENE
5	I-GENE
"	I-GENE
-	I-GENE
UTR	I-GENE
(	I-GENE
from	I-GENE
+	I-GENE
1	I-GENE
to	I-GENE
+	I-GENE
298	I-GENE
)	I-GENE
or	O
a	O
45	O
bp	O
subfragment	O
of	O
the	O
gadd45	B-GENE
5	I-GENE
"	I-GENE
-	I-GENE
UTR	I-GENE
(	I-GENE
from	I-GENE
+	I-GENE
10	I-GENE
to	I-GENE
+	I-GENE
55	I-GENE
)	I-GENE
was	O
positioned	O
at	O
the	O
5	O
"	O
-	O
end	O
of	O
the	O
rabbit	B-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
gene	I-GENE
.	O

RESULTS	O
:	O
BMK	B-GENE
-	I-GENE
1	I-GENE
and	O
other	O
19	O
contents	O
significantly	O
decreased	O
depolarization	O
parameters	O
Vmax	O
,	O
APA	O
,	O
OS	O
,	O
and	O
MDP	O
,	O
which	O
was	O
similar	O
to	O
that	O
of	O
TTX	B-GENE
and	O
different	O
from	O
that	O
of	O
Nim	O
and	O
BaCl2	O
.	O

Fourteen	O
samples	O
,	O
seven	O
each	O
of	O
IR64	O
and	O
IR66	O
were	O
studied	O
with	O
regard	O
to	O
moisture	O
content	O
,	O
germination	O
test	O
,	O
abnormal	O
seedlings	O
,	O
speed	O
of	O
germination	O
,	O
conductance	O
of	O
leachates	O
,	O
total	O
dehydrogenase	O
activity	O
,	O
total	O
free	O
amino	O
acids	O
,	O
total	O
soluble	O
sugar	O
,	O
fat	O
acidity	O
,	O
gelatinization	O
temperature	O
,	O
gel	O
consistency	O
,	O
amylose	O
content	O
,	O
translucency	O
,	O
and	O
per	O
cent	O
whiteness	O
.	O

Southern	O
zoo	O
blot	O
analysis	O
indicated	O
that	O
ZNF236	B-GENE
is	O
conserved	O
in	O
the	O
genomes	O
of	O
all	O
mammalian	O
species	O
tested	O
,	O
but	O
not	O
in	O
yeast	O
.	O

3	O
.	O

This	O
alternative	O
splice	O
acceptor	O
site	O
is	O
also	O
used	O
by	O
a	O
biologically	O
active	O
provirus	O
with	O
an	O
efficiency	O
of	O
approximately	O
5	O
%	O
compared	O
with	O
the	O
upstream	O
site	O
.	O

In	O
addition	O
to	O
loss	O
of	O
digit	O
identity	O
and	O
varying	O
degrees	O
of	O
polydactyly	O
,	O
proximal	O
skeletal	O
elements	O
are	O
severely	O
shortened	O
in	O
Xt	B-GENE
;	O
ld	B-GENE
double	O
homozygous	O
limbs	O
.	O

In	O
turn	O
,	O
production	O
of	O
sufficient	O
amounts	O
of	O
TraR	B-GENE
apparently	O
is	O
sensitive	O
to	O
a	O
cellular	O
function	O
requiring	O
RNase	B-GENE
D	I-GENE
.	O

In	O
this	O
study	O
,	O
the	O
effect	O
of	O
the	O
antibiotic	O
lasalocid	O
on	O
the	O
rumen	O
anaerobic	O
fungus	O
Neocallimastix	O
frontalis	O
RK	O
21	O
was	O
examined	O
.	O

4	O
382	O
new	O
mothers	O
were	O
examined	O
retrospectively	O
with	O
the	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
(	O
ELISA	O
)	O
for	O
IgG	B-GENE
activity	O
to	O
cytomegalovirus	O
(	O
CMV	O
)	O
during	O
pregnancy	O
.	O

Promoter	O
,	O
spliced	O
leader	O
,	O
and	O
coding	O
sequence	O
for	O
BICP4	B-GENE
,	O
the	O
largest	O
of	O
the	O
immediate	B-GENE
-	I-GENE
early	I-GENE
proteins	I-GENE
of	I-GENE
bovine	I-GENE
herpesvirus	I-GENE
1	I-GENE
.	O

ER	B-GENE
beta	I-GENE
was	O
less	O
potent	O
than	O
ER	B-GENE
alpha	I-GENE
in	O
activating	O
E2	O
-	O
stimulated	O
ERELuc	B-GENE
activity	O
(	O
4	O
-	O
vs	O
.	O

Our	O
results	O
suggest	O
a	O
dose	O
-	O
dependent	O
activity	O
of	O
lysine	B-GENE
vasopressin	I-GENE
on	O
the	O
EEG	O
,	O
which	O
might	O
be	O
similar	O
to	O
that	O
observed	O
in	O
animal	O
and	O
man	O
after	O
administration	O
of	O
nicotine	O
.	O

However	O
,	O
elimination	O
of	O
the	O
kinase	O
activity	O
of	O
DCAMKL1	B-GENE
has	O
no	O
detectable	O
effect	O
on	O
its	O
microtubule	O
polymerization	O
activity	O
.	O

Sequencing	O
and	O
restriction	O
enzyme	O
analysis	O
demonstrated	O
that	O
this	O
single	O
-	O
copy	O
gene	O
contains	O
11	O
exons	O
and	O
spans	O
9596	O
base	O
pairs	O
.	O

Effects	O
of	O
prolonged	O
inhibition	O
of	O
labour	O
pains	O
with	O
Th	O
1165a	O
and	O
Isoptin	O
on	O
the	O
heart	O
,	O
circulation	O
,	O
organ	O
-	O
and	O
metabolic	O
parameters	O
of	O
the	O
mother	O

The	O
anaesthetic	O
management	O
of	O
41	O
patients	O
who	O
underwent	O
cardiac	O
transplantation	O
during	O
a	O
40	O
month	O
period	O
at	O
Clinica	O
Puerta	O
de	O
Hierro	O
is	O
reviewed	O
.	O

In	O
uraemic	O
patients	O
,	O
similar	O
maximum	O
serum	O
concentrations	O
were	O
found	O
after	O
a	O
single	O
7	O
.	O
5	O
mg	O
/	O
kg	O
iv	O
dose	O
.	O

In	O
the	O
unit	O
housing	O
of	O
a	O
compact	O
cyclotron	O
and	O
positron	O
emission	O
CT	O
(	O
PET	O
)	O
,	O
positron	O
emitting	O
gas	O
such	O
as	O
15O	O
,	O
11C	O
,	O
C15O2	O
,	O
C15O	O
etc	O
.	O
is	O
supplied	O
from	O
a	O
cyclotron	O
to	O
a	O
PET	O
room	O
through	O
a	O
transportation	O
pipe	O
with	O
an	O
appropriate	O
shield	O
to	O
reduce	O
positron	O
annihilation	O
radiation	O
.	O

Although	O
CB	O
-	O
4	O
isolates	O
were	O
less	O
resistant	O
to	O
chlorine	O
than	O
CB	O
-	O
5	O
isolates	O
,	O
after	O
1	O
,	O
000	O
min	O
of	O
contact	O
0	O
.	O
01	O
%	O
of	O
the	O
input	O
virus	O
was	O
still	O
infectious	O
.	O

Here	O
we	O
describe	O
the	O
cloning	O
and	O
initial	O
characterization	O
of	O
IPP	B-GENE
,	O
a	O
novel	O
human	O
gene	O
that	O
predicts	O
a	O
kelch	B-GENE
family	I-GENE
protein	I-GENE
homologous	O
to	O
the	O
mouse	B-GENE
Ipp	I-GENE
gene	I-GENE
,	O
a	O
previously	O
described	O
kelch	B-GENE
family	I-GENE
member	I-GENE
.	O

Sequence	O
analysis	O
identifies	O
a	O
ras	B-GENE
-	I-GENE
associating	I-GENE
(	O
RA	B-GENE
)	O
-	O
like	O
domain	O
in	O
the	O
N	O
-	O
termini	O
of	O
band	B-GENE
4	I-GENE
.	I-GENE
1	I-GENE
/	I-GENE
JEF	I-GENE
domains	I-GENE
and	O
in	O
the	O
Grb7	B-GENE
/	I-GENE
10	I-GENE
/	I-GENE
14	I-GENE
adapter	I-GENE
family	I-GENE
.	O

Sleeping	O
position	O
and	O
sudden	O
infant	O
death	O
syndrome	O
(	O
SIDS	O
)	O
:	O
effect	O
of	O
an	O
intervention	O
programme	O
to	O
avoid	O
prone	O
sleeping	O
.	O

Statistical	O
conservation	O
laws	O
in	O
turbulent	O
transport	O
.	O

Characterization	O
and	O
targeted	O
disruption	O
of	O
murine	B-GENE
Nup50	I-GENE
,	O
a	O
p27	B-GENE
(	O
Kip1	B-GENE
)	O
-	O
interacting	O
component	O
of	O
the	O
nuclear	O
pore	O
complex	O
.	O
p27	B-GENE
(	O
Kip1	B-GENE
)	O
is	O
a	O
member	O
of	O
the	O
Cip	B-GENE
-	O
Kip	B-GENE
family	O
of	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
(	O
Cdk	B-GENE
)	O
inhibitors	O
that	O
binds	O
to	O
cyclin	B-GENE
-	O
Cdk	B-GENE
complexes	O
and	O
inhibits	O
their	O
catalytic	O
activity	O
in	O
response	O
to	O
antiproliferative	O
stimuli	O
.	O
p27	B-GENE
(	O
Kip1	B-GENE
)	O
is	O
regulated	O
by	O
several	O
posttranscriptional	O
mechanisms	O
,	O
including	O
subcellular	O
localization	O
.	O

Further	O
studies	O
are	O
warranted	O
to	O
determine	O
whether	O
these	O
findings	O
are	O
idiosyncratic	O
,	O
coincidental	O
,	O
or	O
a	O
more	O
general	O
phenomenon	O
.	O

We	O
have	O
identified	O
the	O
gene	O
encoding	O
sigma	B-GENE
E	I-GENE
using	O
a	O
genetic	O
screen	O
designed	O
to	O
isolate	O
trans	O
-	O
acting	O
mutations	O
that	O
abolish	O
expression	O
from	O
either	O
htrA	B-GENE
or	O
rpoHP3	B-GENE
,	O
two	O
promoters	O
recognized	O
uniquely	O
by	O
sigma	B-GENE
E	I-GENE
-	O
containing	O
RNA	B-GENE
polymerase	I-GENE
.	O

METHODOLOGY	O
:	O
A	O
case	O
control	O
study	O
of	O
survivors	O
with	O
gestational	O
age	O
(	O
GA	O
)	O
<	O
28	O
weeks	O
or	O
birthweight	O
(	O
BW	O
)	O
<	O
1000	O
g	O
using	O
data	O
collected	O
prospectively	O
in	O
our	O
Neonatal	O
Intensive	O
Care	O
Unit	O
database	O
.	O

Based	O
on	O
these	O
results	O
,	O
it	O
has	O
been	O
concluded	O
that	O
an	O
IPFSA	O
can	O
promote	O
the	O
healing	O
process	O
in	O
the	O
avascular	O
zone	O
of	O
a	O
torn	O
meniscus	O
in	O
rabbits	O
and	O
that	O
systemic	O
vascularity	O
to	O
the	O
synovium	O
or	O
the	O
meniscus	O
is	O
not	O
essential	O
for	O
healing	O
to	O
occur	O
.	O

Biomass	O
growth	O
monitoring	O
using	O
pressure	O
drop	O
in	O
a	O
cocurrent	O
biofilter	O

Mutant	O
p53	B-GENE
DNA	I-GENE
clones	O
from	O
human	O
colon	O
carcinomas	O
cooperate	O
with	O
ras	B-GENE
in	O
transforming	O
primary	O
rat	O
cells	O
:	O
a	O
comparison	O
of	O
the	O
"	O
hot	O
spot	O
"	O
mutant	O
phenotypes	O
.	O

The	O
RHO1	B-GENE
gene	I-GENE
encodes	O
a	O
homolog	O
of	O
the	O
mammalian	O
RhoA	B-GENE
small	I-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
in	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
.	O

Inspection	O
of	O
X	B-GENE
.	I-GENE
tropicalis	I-GENE
,	I-GENE
mouse	I-GENE
and	I-GENE
human	I-GENE
U6	I-GENE
DNA	I-GENE
upstream	I-GENE
sequences	I-GENE
revealed	O
the	O
presence	O
of	O
a	O
TATA	O
box	O
as	O
well	O
as	O
of	O
the	O
proximal	O
and	O
enhancer	O
(	O
octamer	O
motif	O
)	O
elements	O
contained	O
in	O
snRNA	O
genes	O
transcribed	O
by	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
.	O

RESULTS	O
:	O
In	O
men	O
,	O
weight	O
/	O
height2	O
met	O
the	O
criteria	O
for	O
a	O
satisfactory	O
index	O
in	O
that	O
there	O
was	O
a	O
very	O
strong	O
correlation	O
with	O
triceps	O
skinfold	O
,	O
and	O
a	O
negligible	O
correlation	O
with	O
height	O
.	O

When	O
expressed	O
in	O
thymidine	B-GENE
kinase	I-GENE
-	O
deficient	O
L	O
cells	O
or	O
3T3	O
cells	O
,	O
C	B-GENE
/	I-GENE
EBPalpha	I-GENE
is	O
detected	O
in	O
a	O
protein	O
complex	O
which	O
binds	O
to	O
the	O
E2F	B-GENE
binding	I-GENE
sites	I-GENE
found	O
in	O
the	O
promoters	O
of	O
the	O
genes	O
for	O
E2F	B-GENE
-	I-GENE
1	I-GENE
and	O
dihydrofolate	B-GENE
reductase	I-GENE
(	O
DHFR	B-GENE
)	O
.	O

Phenylalanine	O
and	O
tyrosine	O
levels	O
were	O
higher	O
in	O
those	O
who	O
received	O
Vamin	O
9	O
glucose	O
but	O
55	O
%	O
of	O
infants	O
given	O
Vamin	O
Infant	O
had	O
tyrosine	O
levels	O
below	O
the	O
lower	O
limit	O
of	O
the	O
target	O
range	O
.	O

Identification	O
of	O
an	O
osteocalcin	B-GENE
gene	I-GENE
promoter	I-GENE
sequence	I-GENE
that	O
binds	O
AP1	B-GENE
.	O

CONCLUSIONS	O
:	O
Neurodevelopmental	O
assessment	O
at	O
1	O
year	O
is	O
predictive	O
of	O
school	O
performance	O
and	O
outcome	O
in	O
the	O
adolescent	O
period	O
.	O

Phenotypic	O
responses	O
of	O
additional	O
mutants	O
,	O
including	O
exo1	B-GENE
,	O
srs2	B-GENE
,	O
rad5	B-GENE
,	O
and	O
rdh54	B-GENE
strains	O
,	O
suggest	O
roles	O
in	O
recombinational	O
repair	O
,	O
but	O
not	O
in	O
NHEJ	O
.	O

Although	O
hSSTR5	B-GENE
displays	O
approximately	O
75	O
%	O
sequence	O
identity	O
with	O
rat	B-GENE
SSTR5	I-GENE
,	O
the	O
two	O
receptors	O
display	O
significantly	O
different	O
pharmacological	O
profiles	O
,	O
especially	O
with	O
respect	O
to	O
their	O
binding	O
affinities	O
for	O
the	O
SST	B-GENE
analogue	O
SMS	O
201	O
-	O
995	O
.	O

These	O
findings	O
suggest	O
that	O
IL	B-GENE
-	I-GENE
1	I-GENE
-	O
stimulated	O
,	O
Rho	B-GENE
-	O
dependent	O
cytoskeletal	O
reorganization	O
may	O
cluster	O
signaling	O
molecules	O
in	O
specific	O
architectures	O
that	O
are	O
necessary	O
for	O
persistent	O
cell	O
activation	O
in	O
chronic	O
inflammatory	O
disease	O
.	O

Deletion	O
mutants	O
of	O
the	O
human	B-GENE
CHOP	I-GENE
promoter	I-GENE
identify	O
a	O
region	O
comprising	O
nucleotides	O
-	O
75	O
to	O
-	O
104	O
required	O
for	O
both	O
constitutive	O
and	O
ER	O
-	O
stress	O
-	O
inducible	O
expression	O
.	O

Anderson	O
Hospital	O
and	O
Tumor	O
Institute	O
at	O
Houston	O
during	O
a	O
30	O
-	O
year	O
interval	O
(	O
1944	O
to	O
1974	O
)	O
,	O
with	O
a	O
minimum	O
of	O
ten	O
years	O
of	O
follow	O
-	O
up	O
,	O
we	O
determined	O
that	O
the	O
major	O
prognostic	O
factor	O
of	O
survival	O
was	O
the	O
number	O
of	O
positive	O
nodes	O
.	O

It	O
is	O
concluded	O
that	O
the	O
atherogenic	O
process	O
includes	O
stimulation	O
of	O
collagen	B-GENE
and	O
elastin	B-GENE
synthesis	O
.	O

We	O
report	O
nine	O
consecutive	O
cases	O
of	O
ACB	O
,	O
which	O
occurred	O
in	O
five	O
males	O
and	O
four	O
females	O
and	O
were	O
detected	O
in	O
11	O
,	O
159	O
routine	O
spiral	O
CT	O
examinations	O
of	O
the	O
chest	O
,	O
performed	O
between	O
1994	O
and	O
1998	O
.	O

The	O
absolute	O
CD4	B-GENE
count	O
of	O
patients	O
with	O
de	O
novo	O
IBD	O
was	O
210	O
-	O
700	O
cells	O
/	O
ml	O
at	O
the	O
time	O
of	O
IBD	O
.	O

Four	O
of	O
these	O
fibroblast	O
clones	O
were	O
infected	O
with	O
a	O
retrovirus	O
containing	O
the	O
cDNA	B-GENE
encoding	I-GENE
myoD	I-GENE
and	O
a	O
puromycin	O
selection	O
marker	O
.	O

Sexual	O
adventurism	O
,	O
high	O
-	O
risk	O
behavior	O
,	O
and	O
human	O
immunodeficiency	O
virus	O
-	O
1	O
seroconversion	O
among	O
the	O
Chicago	O
MACS	O
-	O
CCS	O
cohort	O
,	O
1984	O
to	O
1992	O
.	O

As	O
already	O
available	O
for	O
the	O
other	O
known	O
mammalian	O
members	O
of	O
this	O
enzyme	O
family	O
,	O
we	O
here	O
define	O
structural	O
and	O
functional	O
features	O
of	O
human	B-GENE
lymphoma	I-GENE
proprotein	I-GENE
convertase	I-GENE
(	O
LPC	B-GENE
)	O
.	O

This	O
study	O
demonstrates	O
the	O
feasibility	O
and	O
potential	O
usefulness	O
of	O
syngeneic	O
BM	O
Txp	O
in	O
myeloma	O
.	O

It	O
is	O
important	O
to	O
understand	O
the	O
etiology	O
of	O
HITT	O
because	O
of	O
its	O
devastating	O
clinical	O
consequences	O
.	O

Results	O
obtained	O
from	O
the	O
tritium	O
test	O
and	O
direct	O
chemical	O
analysis	O
were	O
compared	O
.	O

Relation	O
between	O
clinical	O
and	O
roentgenological	O
scores	O
and	O
measures	O
of	O
lung	O
function	O
in	O
cystic	O
fibrosis	O
,	O
with	O
special	O
reference	O
to	O
pulmonary	O
Xenon133	O
elimination	O
.	O

Phytohemagglutinin	B-GENE
(	O
PHA	B-GENE
)	O
,	O
the	O
seed	B-GENE
lectin	I-GENE
of	O
the	O
common	O
bean	O
,	O
accumulates	O
in	O
protein	O
storage	O
vacuoles	O
of	O
storage	O
parenchyma	O
cells	O
in	O
cotyledons	O
.	O

New	O
concepts	O
of	O
condyloma	O
acuminata	O
in	O
children	O
.	O

When	O
recombinant	B-GENE
gE	I-GENE
produced	O
in	O
HeLa	O
cells	O
was	O
probed	O
with	O
the	O
same	O
antiphosphotyrosine	O
antibody	O
,	O
a	O
dimeric	B-GENE
gE	I-GENE
form	O
at	O
130	O
kDa	O
was	O
detected	O
on	O
the	O
cell	O
surface	O
.	O

The	O
levels	O
of	O
soluble	O
L	B-GENE
-	I-GENE
selectin	I-GENE
and	O
ICAM	B-GENE
-	I-GENE
1	I-GENE
in	O
the	O
serum	O
were	O
determined	O
by	O
the	O
ELISA	O
method	O
.	O

The	O
effect	O
of	O
lung	O
edema	O
on	O
pulmonary	O
vasoactivity	O
of	O
furosemide	O
.	O

Within	O
the	O
last	O
few	O
years	O
,	O
the	O
WWW	O
has	O
grown	O
enormously	O
.	O

Characterization	O
of	O
insertion	O
mutations	O
in	O
the	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
MSH1	I-GENE
and	O
MSH2	B-GENE
genes	I-GENE
:	O
evidence	O
for	O
separate	O
mitochondrial	O
and	O
nuclear	O
functions	O
.	O

These	O
cells	O
also	O
showed	O
an	O
increase	O
in	O
cyclin	B-GENE
A	I-GENE
and	O
cyclin	B-GENE
A	I-GENE
-	I-GENE
and	I-GENE
E	I-GENE
-	I-GENE
associated	I-GENE
kinase	I-GENE
activities	O
characteristic	O
of	O
S	O
phase	O
induction	O
.	O

Anisotropy	O
of	O
Hc2	O
and	O
the	O
breadth	O
of	O
the	O
resistive	O
transition	O
of	O
polycrystalline	O
YBa2Cu	O

TGF	B-GENE
-	I-GENE
beta1	I-GENE
induced	O
phosphorylation	O
of	O
Smad2	B-GENE
and	O
Smad3	B-GENE
in	O
Mv1Lu	O
mink	O
lung	O
epithelial	O
cells	O
.	O

Changes	O
in	O
the	O
frequency	O
of	O
X	O
-	O
chromatin	O
in	O
women	O
under	O
Prednisone	O
therapy	O

Obtaining	O
kidney	O
cells	O
from	O
a	O
beagle	O
puppy	O
(	O
RPB	O
-	O
1	O
)	O
and	O
the	O
establishment	O
of	O
a	O
cryopreservation	O
bank	O

Microscopically	O
,	O
cartilage	O
showed	O
markedly	O
stunted	O
and	O
disorganized	O
endochondral	O
ossification	O
.	O

When	O
incubated	O
with	O
infective	O
larvae	O
which	O
had	O
penetrated	O
mouse	O
skin	O
,	O
both	O
normal	O
and	O
immune	O
cells	O
attached	O
to	O
larvae	O
in	O
the	O
absence	O
of	O
serum	O
.	O

During	O
each	O
step	O
of	O
the	O
pulse	O
infusion	O
the	O
osteocalcin	B-GENE
responses	O
to	O
changes	O
in	O
CaI	O
in	O
general	O
were	O
parallel	O
to	O
the	O
changes	O
in	O
PTH	B-GENE
(	O
r	O
=	O
0	O
.	O
462	O
;	O
P	O
=	O
0	O
.	O
02	O
)	O
and	O
were	O
inversely	O
correlated	O
to	O
CaI	O
(	O
r	O
=	O
-	O
0	O
.	O
562	O
;	O
P	O
=	O
0	O
.	O
003	O
)	O
.	O

GH	B-GENE
signals	O
by	O
interacting	O
with	O
GH	B-GENE
receptor	I-GENE
(	O
GHR	B-GENE
)	O
.	O

These	O
data	O
suggest	O
that	O
overexpression	O
of	O
MT	B-GENE
potentiates	O
the	O
growth	O
of	O
MCF7	O
cells	O
,	O
whereas	O
downregulation	O
of	O
MT	B-GENE
elicits	O
antiproliferative	O
effects	O
.	O

The	O
induction	O
by	O
dexamethasone	O
of	O
rat	B-GENE
liver	I-GENE
CYP3A1	I-GENE
differs	O
from	O
classical	O
glucocorticoid	O
gene	O
regulation	O
in	O
part	O
because	O
both	O
glucocorticoids	O
and	O
antiglucocorticoids	O
such	O
as	O
pregnenolone	O
16	O
alpha	O
-	O
carbonitrile	O
(	O
PCN	O
)	O
induce	O
CYP3A1	B-GENE
through	O
transcriptional	O
gene	O
activation	O
.	O

A	O
pharmacokinetic	O
interaction	O
between	O
LY354740	O
and	O
diazepam	O
,	O
leading	O
to	O
the	O
lowering	O
of	O
the	O
plasma	O
level	O
of	O
free	O
diazepam	O
,	O
was	O
also	O
demonstrated	O
.	O

Also	O
,	O
in	O
patients	O
with	O
MYD	O
,	O
there	O
was	O
a	O
significant	O
decrease	O
in	O
arterial	O
PO2	O
from	O
the	O
seated	O
posture	O
to	O
the	O
supine	O
posture	O
,	O
without	O
a	O
significant	O
change	O
in	O
the	O
arterial	O
PCO2	O
.	O

The	O
animals	O
were	O
followed	O
over	O
a	O
1	O
-	O
to	O
6	O
-	O
h	O
posttraumatic	O
course	O
,	O
and	O
processed	O
for	O
the	O
LM	O
and	O
TEM	O
visualization	O
of	O
HRP	B-GENE
.	O

Glucose	O
consumption	O
of	O
the	O
human	O
brain	O
under	O
the	O
influence	O
of	O
intravenous	O
infusions	O
of	O
glucose	O
,	O
glucagon	B-GENE
and	O
glucose	O
-	O
insulin	B-GENE

The	O
signs	O
of	O
enterocolitis	O
,	O
pathological	O
microbial	O
flora	O
in	O
the	O
stool	O
and	O
changes	O
in	O
the	O
colon	O
mucosa	O
were	O
absent	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
evaluate	O
the	O
physical	O
and	O
biological	O
characteristics	O
of	O
nebulized	O
interleukin	B-GENE
2	I-GENE
liposomes	O
.	O

Although	O
mutant	B-GENE
pex5delta	I-GENE
cells	O
expressing	O
a	O
yeast	B-GENE
/	I-GENE
tobacco	I-GENE
Pex5p	I-GENE
chimaera	I-GENE
failed	O
to	O
import	O
a	O
GFP	B-GENE
-	O
Eci1p	B-GENE
reporter	O
protein	O
,	O
they	O
were	O
able	O
to	O
grow	O
on	O
oleic	O
acid	O
.	O

Two	O
human	B-GENE
beta	I-GENE
-	I-GENE
1	I-GENE
,	I-GENE
6	I-GENE
-	I-GENE
N	I-GENE
-	I-GENE
acetylglucosaminyltransferases	I-GENE
forming	O
the	O
core	O
2	O
O	O
-	O
glycan	O
branch	O
,	O
C2GnT	O
and	O
the	O
I	B-GENE
antigen	I-GENE
,	O
IGnT	B-GENE
,	O
are	O
homologous	O
to	O
each	O
other	O
in	O
three	O
regions	O
of	O
the	O
catalytic	O
domain	O
(	O
A	O
,	O
B	O
,	O
C	O
)	O
and	O
their	O
genes	O
reside	O
at	O
the	O
same	O
locus	O
,	O
chromosome	O
9	O
,	O
band	O
q21	O
(	O
Bierhuizen	O
,	O
M	O
.	O
F	O
.	O
A	O
.	O
,	O
Mattei	O
,	O
M	O
.	O
-	O
G	O
.	O
and	O
Fukuda	O
,	O
M	O
.	O
,	O
Genes	O
Dev	O
.	O
,	O
7	O
,	O
468	O
-	O
478	O
,	O
1993	O
)	O
.	O

Previously	O
,	O
we	O
had	O
shown	O
that	O
interleukin	B-GENE
8	I-GENE
(	O
IL	B-GENE
-	I-GENE
8	I-GENE
)	O
is	O
constitutively	O
expressed	O
in	O
HTLV	O
-	O
I	O
-	O
infected	O
cells	O
and	O
in	O
cells	O
transiently	O
expressing	O
Tax	B-GENE
.	O

We	O
undertook	O
this	O
study	O
to	O
examine	O
the	O
relationship	O
between	O
systemic	O
oxygen	O
delivery	O
(	O
DO2	O
)	O
and	O
tissue	O
oxygen	O
tension	O
(	O
TPO2	O
)	O
in	O
hypovolemic	O
shock	O
.	O

The	O
lowest	O
PaCO2	O
values	O
were	O
significantly	O
lower	O
in	O
MCE	O
than	O
in	O
the	O
F	O
,	O
W	O
,	O
and	O
D	O
(	O
F	O
+	O
W	O
+	O
D	O
)	O
group	O
or	O
controls	O
.	O

The	O
psychosomatic	O
approach	O
to	O
temporomandibular	O
arthrosis	O

Detection	O
of	O
sinusoidal	O
gratings	O
by	O
pattern	O
-	O
specific	O
detectors	O
:	O
further	O
evidence	O
for	O
the	O
correlation	O
principle	O
in	O
human	O
vision	O
.	O

The	O
transcriptional	O
start	O
site	O
(	O
s	O
)	O
of	O
the	O
IA	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
was	O
mapped	O
by	O
5	O
'	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
to	O
97	O
bp	O
upstream	O
of	O
the	O
translational	O
start	O
site	O
.	O

Function	O
was	O
retained	O
when	O
one	O
copy	O
of	O
the	O
sequence	O
was	O
present	O
,	O
suggesting	O
that	O
this	O
sequence	O
represents	O
an	O
essential	O
element	O
.	O

The	O
data	O
also	O
suggest	O
that	O
gamma	B-GENE
CACCC	I-GENE
box	I-GENE
binding	I-GENE
factors	I-GENE
mediate	O
LCR	B-GENE
-	I-GENE
gamma	I-GENE
interactions	O
which	O
normally	O
enhance	O
gamma	B-GENE
-	I-GENE
globin	I-GENE
and	O
suppress	O
beta	B-GENE
-	I-GENE
globin	I-GENE
gene	I-GENE
expression	O
in	O
fetal	O
erythroid	O
cells	O
.	O

Left	O
ventricle	O
to	O
coronary	O
sinus	O
fistula	O
.	O

No	O
other	O
transcripts	O
of	O
different	O
length	O
could	O
be	O
detected	O
after	O
prolonged	O
exposure	O
.	O

We	O
have	O
isolated	O
and	O
sequenced	O
cDNA	O
sequences	O
corresponding	O
to	O
two	O
novel	O
genes	O
that	O
map	O
to	O
Xq28	O
.	O

The	O
vaccinia	O
virus	O
D6R	B-GENE
open	O
reading	O
frame	O
encodes	O
the	O
small	O
subunit	O
of	O
the	O
heterodimeric	O
vaccinia	B-GENE
virus	I-GENE
early	I-GENE
transcription	I-GENE
factor	I-GENE
(	O
VETF	B-GENE
)	O
that	O
activates	O
transcription	O
of	O
early	B-GENE
genes	I-GENE
in	O
vitro	O
.	O

We	O
have	O
used	O
nuclear	O
magnetic	O
resonance	O
(	O
NMR	O
)	O
to	O
obtain	O
the	O
structure	O
of	O
an	O
RNA	O
"	O
kissing	O
"	O
hairpin	O
complex	O
formed	O
between	O
the	O
HIV	O
-	O
2	O
TAR	O
hairpin	O
loop	O
and	O
a	O
hairpin	O
with	O
a	O
complementary	O
loop	O
sequence	O
.	O

Xnr3	B-GENE
is	O
transcriptionally	O
activated	O
by	O
wnt	B-GENE
signaling	O
during	O
gastrulation	O
in	O
the	O
Xenopus	O
embryo	O
.	O

In	O
this	O
report	O
,	O
we	O
identify	O
Tyr319	O
as	O
a	O
functionally	O
important	O
phosphorylation	O
site	O
in	O
the	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
interdomain	I-GENE
B	I-GENE
region	I-GENE
.	O

Renal	O
dysplasia	O
with	O
multisystem	O
malformation	O
-	O
-	O
a	O
study	O
of	O
9	O
cases	O
.	O

Brome	B-GENE
mosaic	I-GENE
virus	I-GENE
polymerase	I-GENE
-	O
like	O
protein	B-GENE
2a	I-GENE
is	O
directed	O
to	O
the	O
endoplasmic	O
reticulum	O
by	O
helicase	B-GENE
-	O
like	O
viral	B-GENE
protein	I-GENE
1a	I-GENE
.	O

Mutations	O
abolishing	O
MalK	B-GENE
function	O
not	O
only	O
result	O
in	O
inability	O
to	O
transport	O
maltose	O
but	O
also	O
cause	O
constitutive	O
expression	O
of	O
the	O
maltose	B-GENE
regulon	I-GENE
.	O

The	O
D	O
.	O
discoideum	O
proteins	O
were	O
entirely	O
conserved	O
over	O
the	O
four	O
regions	O
known	O
to	O
be	O
important	O
for	O
GTP	O
binding	O
and	O
all	O
contained	O
the	O
C	O
-	O
terminal	O
CAAX	O
aa	O
motifs	O
shared	O
by	O
other	O
Rho	B-GENE
proteins	I-GENE
.	O

The	O
lack	O
of	O
chronically	O
depressed	O
LCBF	O
(	O
after	O
1	O
day	O
)	O
may	O
be	O
related	O
to	O
the	O
quick	O
structural	O
repair	O
of	O
endothelium	O
.	O

Functional	O
uncoupling	O
of	O
the	O
Janus	B-GENE
kinase	I-GENE
3	I-GENE
-	O
Stat5	B-GENE
pathway	O
in	O
malignant	O
growth	O
of	O
human	O
T	O
cell	O
leukemia	O
virus	O
type	O
1	O
-	O
transformed	O
human	O
T	O
cells	O
.	O

An	O
environmental	O
investigation	O
found	O
evidence	O
of	O
suboptimal	O
food	O
storage	O
and	O
cooking	O
temperatures	O
at	O
Restaurant	O
A	O
;	O
cross	O
contamination	O
of	O
foods	O
may	O
have	O
contributed	O
to	O
the	O
low	O
attributable	O
risk	O
identified	O
for	O
chile	O
rellenos	O
.	O

We	O
used	O
event	O
-	O
related	O
functional	O
magnetic	O
resonance	O
imaging	O
(	O
fMRI	O
)	O
during	O
a	O
cued	O
spatial	O
-	O
attention	O
task	O
to	O
dissociate	O
brain	O
activity	O
related	O
to	O
attentional	O
control	O
from	O
that	O
related	O
to	O
selective	O
processing	O
of	O
target	O
stimuli	O
.	O

However	O
,	O
microinjection	O
of	O
reconstituted	O
mRNPs	O
into	O
Xenopus	O
oocytes	O
demonstrates	O
that	O
although	O
translational	O
repression	O
occurs	O
in	O
the	O
absence	O
of	O
consensus	O
RNA	O
binding	O
sequences	O
for	O
FRGY2	B-GENE
,	O
the	O
presence	O
of	O
FRGY2	B-GENE
recognition	I-GENE
elements	I-GENE
within	O
mRNA	O
potentiates	O
translational	O
repression	O
.	O

Results	O
of	O
the	O
study	O
suggest	O
that	O
Chinese	O
medicine	O
use	O
among	O
this	O
population	O
depends	O
on	O
health	O
conditions	O
,	O
and	O
that	O
having	O
a	O
regular	O
source	O
of	O
care	O
for	O
Chinese	O
medicine	O
as	O
well	O
as	O
a	O
preference	O
for	O
Chinese	O
medicine	O
are	O
two	O
predictors	O
for	O
its	O
use	O
.	O

A	O
V1	B-GENE
mutant	I-GENE
generated	O
in	O
vivo	O
with	O
11	O
of	O
the	O
14	O
N	O
-	O
terminal	O
amino	O
acids	O
altered	O
,	O
was	O
viable	O
and	O
produced	O
symptoms	O
typical	O
of	O
a	O
wild	O
-	O
type	O
infection	O
.	O

These	O
observations	O
suggest	O
that	O
clr4	B-GENE
+	I-GENE
and	O
rik1	B-GENE
+	I-GENE
must	O
play	O
a	O
role	O
in	O
the	O
assembly	O
of	O
Swi6p	B-GENE
into	O
a	O
transcriptionally	O
silent	O
,	O
inaccessible	O
chromatin	O
structure	O
at	O
fission	O
yeast	O
centromeres	O
which	O
is	O
required	O
to	O
facilitate	O
interactions	O
with	O
spindle	O
microtubules	O
and	O
to	O
ensure	O
normal	O
chromosome	O
segregation	O
.	O

The	O
gene	O
sequence	O
predicts	O
a	O
150	O
,	O
825	O
mol	O
wt	O
apoprotein	O
of	O
1363	O
amino	O
acids	O
having	O
an	O
N	O
-	O
terminal	O
hydrophobic	O
signal	O
sequence	O
of	O
17	O
amino	O
acids	O
,	O
19	O
potential	O
N	O
-	O
linked	O
glycosylation	O
sites	O
,	O
a	O
hydrophobic	O
anchor	O
sequence	O
of	O
approximately	O
17	O
amino	O
acids	O
near	O
the	O
C	O
terminus	O
,	O
and	O
a	O
hydrophilic	O
cysteine	O
-	O
rich	O
C	O
terminus	O
of	O
35	O
amino	O
acids	O
.	O

Likewise	O
,	O
epidural	O
morphine	O
does	O
not	O
modify	O
the	O
intraoperative	O
metabolic	O
and	O
hormonal	O
responses	O
.	O

Only	O
the	O
native	O
structure	O
of	O
phosphorylated	O
ERK	B-GENE
was	O
recognized	O
by	O
VHR	B-GENE
and	O
was	O
inactivated	O
with	O
a	O
second	O
-	O
order	O
rate	O
constant	O
of	O
40	O
,	O
000	O
M	O
-	O
1	O
s	O
-	O
1	O
.	O

Omitting	O
part	O
of	O
the	O
experimental	O
NOE	O
-	O
derived	O
distances	O
results	O
in	O
reduced	O
restraint	O
violations	O
and	O
lower	O
R	O
factors	O
but	O
impairs	O
structural	O
convergence	O
in	O
the	O
rMD	O
refinement	O
.	O

The	O
region	O
immediately	O
following	O
the	O
promoter	O
and	O
5	O
'	O
to	O
ORF1	O
has	O
a	O
potential	O
transcription	O
terminator	O
sequence	O
.	O

Cell	O
cycle	O
regulatory	O
components	O
have	O
been	O
largely	O
conserved	O
in	O
eukaryotes	O
;	O
however	O
,	O
orthologs	O
of	O
neither	O
CAK1	B-GENE
nor	O
csk1	B-GENE
have	O
been	O
identified	O
in	O
other	O
species	O
to	O
date	O
.	O

Within	O
any	O
cell	O
line	O
,	O
several	O
Tcfs	B-GENE
and	O
TLEs	B-GENE
are	O
co	O
-	O
expressed	O
.	O

In	O
marked	O
contrast	O
to	O
the	O
previously	O
published	O
human	B-GENE
CD6	I-GENE
sequence	I-GENE
,	O
the	O
mouse	O
sequence	O
predicts	O
a	O
long	O
cytoplasmic	O
tail	O
that	O
is	O
not	O
closely	O
related	O
to	O
other	O
proteins	O
and	O
possesses	O
two	O
proline	O
-	O
rich	O
motifs	O
containing	O
the	O
SH3	B-GENE
-	I-GENE
domain	I-GENE
binding	I-GENE
consensus	I-GENE
sequence	I-GENE
,	O
three	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
phosphorylation	I-GENE
site	I-GENE
motifs	I-GENE
,	O
nine	O
casein	B-GENE
kinase	I-GENE
-	I-GENE
2	I-GENE
phosphorylation	I-GENE
site	I-GENE
motifs	I-GENE
,	O
and	O
a	O
serine	O
-	O
threonine	O
-	O
rich	O
motif	O
repeated	O
three	O
times	O
.	O

The	O
Xenopus	B-GENE
homeobox	I-GENE
gene	I-GENE
twin	I-GENE
mediates	O
Wnt	B-GENE
induction	O
of	O
goosecoid	B-GENE
in	O
establishment	O
of	O
Spemann	O
'	O
s	O
organizer	O
.	O

Quinethazone	O

Divergent	O
regions	O
of	O
the	O
posterior	O
left	O
hemisphere	O
used	O
for	O
decoding	O
and	O
storage	O
of	O
information	O
emerged	O
in	O
each	O
working	O
memory	O
versus	O
control	O
task	O
comparison	O
.	O

Among	O
the	O
different	O
epithelial	O
cell	O
lines	O
tested	O
,	O
only	O
RTS3b	O
cells	O
allowed	O
an	O
expression	O
pattern	O
similar	O
to	O
that	O
observed	O
in	O
naturally	O
infected	O
benign	O
condylomas	O
.	O

These	O
involve	O
(	O
1	O
)	O
subcloning	O
a	O
promoterless	O
sucCD	B-GENE
fragment	I-GENE
downstream	O
of	O
the	O
lac	B-GENE
promoter	I-GENE
in	O
M13mp10	O
,	O
and	O
(	O
2	O
)	O
precise	O
splicing	O
of	O
the	O
suc	B-GENE
coding	I-GENE
regions	I-GENE
with	O
the	O
efficient	O
atpE	B-GENE
ribosome	I-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
and	O
expression	O
from	O
the	O
thermoinducible	O
lambda	O
promoters	O
in	O
the	O
pJLA503	O
vector	O
.	O

Increase	O
in	O
[	O
Ca	O
+	O
+	O
]	O
counteracted	O
the	O
effects	O
of	O
verapamil	O
on	O
RAD	O
.	O

Evidence	O
for	O
involvement	O
of	O
proteins	O
HU	B-GENE
and	O
RpoS	B-GENE
in	O
transcription	O
of	O
the	O
osmoresponsive	O
proU	B-GENE
operon	I-GENE
in	O
Escherichia	O
coli	O
.	O

In	O
comparison	O
to	O
a	O
silent	O
baseline	O
,	O
CBF	O
increases	O
were	O
observed	O
in	O
auditory	O
cortex	O
bilaterally	O
and	O
in	O
the	O
right	O
superior	O
parietal	O
,	O
right	O
dorsolateral	O
frontal	O
,	O
and	O
right	O
premotor	O
regions	O
,	O
with	O
no	O
modulation	O
as	O
a	O
function	O
of	O
attentional	O
condition	O
.	O

Detonation	O
-	O
traumatic	O
load	O
during	O
military	O
service	O

Deletion	O
of	O
CDC5	B-GENE
was	O
lethal	O
and	O
resulted	O
in	O
a	O
dumbbell	O
-	O
shaped	O
terminal	O
morphology	O
,	O
with	O
the	O
nuclei	O
almost	O
divided	O
but	O
still	O
connected	O
.	O

Thus	O
,	O
the	O
pathway	O
to	O
Fc	B-GENE
epsilonRI	I-GENE
-	O
mediated	O
MEK	B-GENE
/	O
ERK	B-GENE
and	O
ERK	B-GENE
activation	O
can	O
apparently	O
bypass	O
Ras	B-GENE
and	O
Raf	B-GENE
-	I-GENE
1	I-GENE
.	O

Bovine	O
anaplasmosis	O
:	O
susceptibility	O
of	O
seronegative	O
cows	O
from	O
an	O
infected	O
herd	O
to	O
experimental	O
infection	O
with	O
Anaplasma	O
marginale	O
.	O

The	O
starting	O
dose	O
was	O
8	O
mg	O
/	O
m2	O
administered	O
intravenously	O
(	O
IV	O
)	O
as	O
a	O
short	O
infusion	O
daily	O
for	O
5	O
days	O
,	O
repeated	O
every	O
3	O
weeks	O
with	O
dose	O
adjustments	O
depending	O
on	O
patient	O
tolerance	O
.	O

The	O
related	O
adhesion	B-GENE
focal	I-GENE
tyrosine	I-GENE
kinase	I-GENE
is	O
tyrosine	O
-	O
phosphorylated	O
after	O
beta1	B-GENE
-	I-GENE
integrin	I-GENE
stimulation	O
in	O
B	O
cells	O
and	O
binds	O
to	O
p130cas	B-GENE
.	O

The	O
cerebellar	O
cortical	O
vessels	O
:	O
they	O
are	O
compared	O
to	O
the	O
cerebral	O
vessels	O
.	O

Plasma	B-GENE
prolactin	I-GENE
concentrations	O
in	O
pinealectomized	O
ewes	O
receiving	O
melatonin	O
treatment	O
and	O
in	O
pineal	O
intact	O
ewes	O
maintained	O
under	O
a	O
non	O
-	O
24	O
-	O
hour	O
photoperiod	O
.	O

After	O
5	O
days	O
stimulation	O
with	O
G	B-GENE
-	I-GENE
CSF	I-GENE
(	O
10	O
micrograms	O
/	O
kg	O
)	O
1l	O
of	O
blood	O
was	O
drawn	O
,	O
kept	O
unprocessed	O
for	O
3	O
days	O
and	O
reinfused	O
24	O
h	O
after	O
completion	O
of	O
chemotherapy	O
.	O

The	O
species	O
composition	O
and	O
abundance	O
upon	O
treatment	O
of	O
manure	O
with	O
polyethylene	O
,	O
polystyrene	O
and	O
glass	O
particles	O
was	O
similar	O
to	O
that	O
of	O
the	O
treatment	O
control	O
,	O
i	O
.	O
e	O
.	O
natural	O
and	O
inert	O
sand	O
.	O

We	O
present	O
the	O
case	O
of	O
a	O
patient	O
who	O
presented	O
an	O
unusually	O
large	O
mucoid	O
cyst	O
measuring	O
38	O
x	O
25	O
mm	O
in	O
an	O
uncommon	O
localization	O
,	O
the	O
right	O
maxillary	O
.	O

Twenty	O
male	O
volunteers	O
were	O
studied	O
during	O
almokalant	O
infusion	O
aiming	O
at	O
plasma	O
concentrations	O
(	O
Cpl	O
)	O
of	O
20	O
,	O
50	O
,	O
100	O
,	O
and	O
150	O
nmol	O
/	O
l	O
.	O

Previous	O
studies	O
have	O
shown	O
that	O
TGFbeta1	B-GENE
expression	O
is	O
upregulated	O
in	O
mouse	O
keratinocytes	O
infected	O
with	O
a	O
v	B-GENE
-	I-GENE
rasHa	I-GENE
retrovirus	O
,	O
although	O
the	O
functional	O
significance	O
of	O
this	O
has	O
not	O
been	O
clear	O
.	O

A	O
significant	O
difference	O
in	O
the	O
distribution	O
of	O
antibodies	O
to	O
thyroglobulin	B-GENE
and	O
thyroid	B-GENE
peroxidase	I-GENE
was	O
found	O
in	O
subgroup	O
2	O
.	O

Protein	B-GENE
kinase	I-GENE
C	I-GENE
(	O
PKC	B-GENE
)	O
activation	O
after	O
treatment	O
of	O
human	O
neuroblastoma	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
C	O
cells	O
with	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
(	O
PMA	O
)	O
was	O
found	O
to	O
enhance	O
transcription	O
of	O
the	O
human	O
dopamine	B-GENE
beta	I-GENE
-	I-GENE
hydroxylase	I-GENE
(	O
DBH	B-GENE
)	O
in	O
those	O
cells	O
.	O

Radiographic	O
spatial	O
frequencies	O
essential	O
to	O
the	O
diagnosis	O
of	O
incipient	O
interproximal	O
lesions	O
.	O

The	O
originally	O
embryonic	B-GENE
gamma	I-GENE
-	I-GENE
globin	I-GENE
locus	I-GENE
duplicated	O
and	O
acquired	O
a	O
novel	O
(	O
fetal	O
)	O
pattern	O
of	O
expression	O
in	O
a	O
defined	O
time	O
period	O
(	O
55	O
-	O
40	O
million	O
years	O
ago	O
)	O
during	O
primate	O
phylogeny	O
.	O

The	O
pcaR	B-GENE
regulatory	I-GENE
locus	I-GENE
has	O
been	O
found	O
to	O
be	O
required	O
for	O
both	O
induction	O
of	O
all	O
of	O
the	O
genes	O
within	O
the	O
pca	B-GENE
regulon	I-GENE
(	O
pcaBDC	B-GENE
,	O
pcaIJ	B-GENE
,	O
and	O
pcaF	B-GENE
)	O
and	O
the	O
chemotactic	O
response	O
of	O
the	O
bacteria	O
to	O
aromatic	O
compounds	O
.	O

Thus	O
,	O
the	O
i	B-GENE
-	I-GENE
leader	I-GENE
protein	I-GENE
is	O
a	O
viral	O
gene	O
product	O
of	O
unknown	O
function	O
and	O
high	O
stability	O
that	O
is	O
made	O
in	O
large	O
quantities	O
at	O
intermediate	O
times	O
of	O
productive	O
infection	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Consequently	O
,	O
during	O
the	O
evolution	O
of	O
mammals	O
,	O
it	O
is	O
the	O
CKbeta4GT	B-GENE
-	I-GENE
I	I-GENE
gene	I-GENE
lineage	O
that	O
has	O
been	O
recruited	O
for	O
the	O
biosynthesis	O
of	O
lactose	O
.	O

The	O
Pi	O
signals	O
are	O
conveyed	O
to	O
PHO8	B-GENE
by	O
binding	O
of	O
PHO4	B-GENE
protein	I-GENE
,	O
a	O
positive	O
regulatory	O
factor	O
,	O
to	O
a	O
promoter	O
region	O
of	O
PHO8	B-GENE
(	O
PHO8p	B-GENE
)	O
under	O
the	O
influence	O
of	O
the	O
PHO	B-GENE
regulatory	O
circuit	O
.	O

Direct	O
saturation	O
analysis	O

The	O
results	O
of	O
the	O
neural	O
network	O
were	O
compared	O
with	O
those	O
of	O
a	O
density	O
mask	O
(	O
thresholds	O
,	O
-	O
750	O
/	O
-	O
300	O
H	O
)	O
,	O
with	O
a	O
radiologist	O
serving	O
as	O
the	O
gold	O
standard	O
.	O

Mutational	O
analysis	O
of	O
the	O
IME2	B-GENE
UAS	I-GENE
reveals	O
two	O
critical	O
sequence	O
elements	O
:	O
a	O
G	O
+	O
C	O
-	O
rich	O
sequence	O
(	O
called	O
URS1	O
)	O
,	O
previously	O
identified	O
at	O
many	O
meiotic	O
genes	O
,	O
and	O
a	O
newly	O
described	O
element	O
,	O
the	O
T4C	O
site	O
,	O
that	O
we	O
found	O
at	O
a	O
subset	O
of	O
meiotic	O
genes	O
.	O

We	O
analyzed	O
right	O
ventricular	O
size	O
and	O
function	O
and	O
201Tl	O
uptake	O
to	O
determine	O
if	O
there	O
was	O
a	O
relationship	O
between	O
201Tl	O
uptake	O
and	O
systolic	O
function	O
in	O
19	O
patients	O
with	O
pulmonary	O
artery	O
hypertension	O
who	O
were	O
being	O
evaluated	O
for	O
heart	O
-	O
lung	O
transplantation	O
.	O

Clinical	O
findings	O
plaque	O
index	O
,	O
PI	O
;	O
gingival	O
index	O
,	O
GI	O
;	O
bleeding	O
on	O
probing	O
,	O
BOP	O
;	O
pus	O
discharge	O
,	O
pus	O
;	O
and	O
probing	O
depth	O
,	O
PD	O
at	O
both	O
PT	O
-	O
01	O
and	O
control	O
sites	O
were	O
measured	O
at	O
every	O
visit	O
for	O
4	O
weeks	O
.	O

Therefore	O
the	O
effect	O
of	O
GAL11	B-GENE
on	O
PGK	B-GENE
transcription	O
must	O
be	O
mediated	O
at	O
the	O
PGK	B-GENE
UAS	I-GENE
,	O
presumably	O
as	O
part	O
of	O
the	O
activation	O
complex	O
.	O

The	O
authors	O
recommend	O
in	O
cases	O
with	O
an	O
elevated	O
transaminase	O
serum	O
activity	O
more	O
frequent	O
check	O
-	O
up	O
examinations	O
to	O
avoid	O
missing	O
of	O
a	O
relapse	O
,	O
and	O
to	O
examine	O
repeatedly	O
IgM	B-GENE
anti	B-GENE
-	I-GENE
HAV	I-GENE
as	O
in	O
protracted	O
forms	O
of	O
hepatitis	O
IgM	B-GENE
anti	B-GENE
-	I-GENE
HAV	I-GENE
may	O
persist	O
even	O
when	O
the	O
transaminase	O
activity	O
is	O
normal	O
.	O

Effects	O
were	O
studied	O
of	O
extremely	O
high	O
-	O
frequency	O
electromagnetic	O
radiation	O
(	O
EHF	O
EMR	O
)	O
on	O
indices	O
for	O
the	O
immune	O
and	O
endocrine	O
systems	O
in	O
a	O
series	O
of	O
48	O
patients	O
presenting	O
with	O
hyperplastic	O
processes	O
in	O
endometrium	O
.	O

Management	O
of	O
patients	O
with	O
Ewing	O
'	O
s	O
sarcoma	O
has	O
been	O
discussed	O
with	O
reference	O
to	O
the	O
need	O
to	O
achieve	O
an	O
excellent	O
local	O
result	O
from	O
radiation	O
therapy	O
now	O
that	O
patients	O
are	O
experiencing	O
long	O
-	O
term	O
survival	O
.	O

Effect	O
of	O
hyperaemia	O
on	O
thallium	O
-	O
201	O
redistribution	O
in	O
normal	O
canine	O
myocardium	O
.	O

After	O
dialysis	O
online	O
,	O
lactate	O
was	O
converted	O
by	O
means	O
of	O
lactate	B-GENE
oxidase	I-GENE
immobilized	O
to	O
porous	O
glass	O
,	O
and	O
the	O
depletion	O
of	O
oxygen	O
was	O
registered	O
by	O
means	O
of	O
a	O
Clark	O
electrode	O
.	O

These	O
data	O
show	O
that	O
both	O
Sp1	B-GENE
and	O
Sp3	B-GENE
transcription	I-GENE
factors	I-GENE
upregulate	O
HGF	B-GENE
promoter	I-GENE
activity	O
by	O
binding	O
to	O
the	O
Sp1	B-GENE
binding	I-GENE
site	I-GENE
at	O
position	O
-	O
318	O
to	O
-	O
303	O
bp	O
in	O
the	O
HGF	B-GENE
gene	I-GENE
promoter	I-GENE
.	O

As	O
a	O
member	O
of	O
the	O
uncoupling	B-GENE
protein	I-GENE
family	I-GENE
,	O
UCP2	B-GENE
is	O
ubiquitously	O
expressed	O
in	O
rodents	O
and	O
humans	O
,	O
implicating	O
a	O
major	O
role	O
in	O
thermogenesis	O
.	O

99Tcm	O
-	O
labelled	O
albumin	B-GENE
colloid	O
,	O
albures	O
(	O
radius	O
250	O
nm	O
)	O
or	O
nanocoll	O
(	O
radius	O
25	O
nm	O
)	O
,	O
or	O
both	O
were	O
used	O
as	O
test	O
substances	O
to	O
study	O
the	O
kinetics	O
of	O
vascular	O
clearance	O
after	O
RES	O
stimulation	O
.	O

Hepatitis	O
B	O
markers	O
in	O
Lancashire	O
police	O
officers	O
.	O

Xa4	B-GENE
is	O
a	O
dominantly	O
inherited	O
rice	O
gene	O
that	O
confers	O
resistance	O
to	O
Philippine	O
race	O
1	O
of	O
the	O
bacterial	O
blight	O
pathogen	O
Xanthomonas	O
oryzae	O
pv	O
.	O
oryzae	O
in	O
rice	O
.	O

Screening	O
of	O
human	O
cDNA	O
libraries	O
has	O
identified	O
two	O
different	O
5	O
'	O
-	O
termini	O
and	O
alternatively	O
spliced	O
forms	O
of	O
the	O
human	B-GENE
Fli	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
(	O
Fli	B-GENE
-	I-GENE
1b	I-GENE
)	O
,	O
suggesting	O
the	O
possible	O
existence	O
of	O
two	O
independent	O
promoters	O
.	O

We	O
were	O
unable	O
to	O
construct	O
chvI	B-GENE
or	O
chvG	B-GENE
insertion	I-GENE
mutants	I-GENE
of	O
R	O
.	O
meliloti	O
,	O
whereas	O
mutants	O
carrying	O
insertions	O
outside	O
of	O
these	O
genes	O
were	O
readily	O
obtained	O
.	O

Consistent	O
with	O
an	O
effect	O
on	O
transcription	O
,	O
p21	B-GENE
was	O
localized	O
in	O
nuclei	O
of	O
transfected	O
cells	O
.	O

When	O
yeast	O
cells	O
reach	O
a	O
critical	O
size	O
in	O
late	O
G1	O
they	O
simultaneously	O
start	O
budding	O
,	O
initiate	O
DNA	O
synthesis	O
,	O
and	O
activate	O
transcription	O
of	O
a	O
set	O
of	O
genes	O
that	O
includes	O
G1	B-GENE
cyclins	I-GENE
CLN1	B-GENE
,	O
CLN2	B-GENE
,	O
and	O
many	O
DNA	O
synthesis	O
genes	O
.	O

After	O
a	O
1	O
-	O
h	O
rest	O
(	O
for	O
T2	O
return	O
to	O
baseline	O
)	O
,	O
subjects	O
repeated	O
the	O
5	O
-	O
min	O
protocol	O
,	O
followed	O
by	O
a	O
final	O
MRI	O
/	O
MRS	O
.	O

Use	O
of	O
ELISAs	O
for	O
the	O
diagnosis	O
of	O
canine	O
atopy	O
.	O

In	O
situ	O
localization	O
of	O
PCP	B-GENE
-	I-GENE
A1	I-GENE
transcripts	I-GENE
revealed	O
that	O
they	O
accumulate	O
specifically	O
in	O
pollen	O
at	O
the	O
late	O
binucleate	O
/	O
trinucleate	O
stage	O
of	O
development	O
rather	O
than	O
in	O
the	O
tapetum	O
,	O
which	O
previously	O
was	O
taken	O
to	O
be	O
the	O
principal	O
source	O
of	O
the	O
pollen	O
coat	O
.	O

A	O
single	O
dose	O
of	O
Cef	O
was	O
administered	O
intravenously	O
to	O
11	O
patients	O
with	O
autoimmune	O
diseases	O
and	O
varying	O
degrees	O
of	O
renal	O
impairment	O
(	O
Group	O
I	O
CLCR	O
less	O
than	O
50	O
ml	O
/	O
min	O
,	O
Group	O
II	O
CLCR	O
greater	O
than	O
50	O
ml	O
/	O
min	O
)	O
.	O

Postheparin	O
lipoprotein	B-GENE
lipase	I-GENE
,	O
measured	O
using	O
fat	O
emulsion	O
as	O
substrate	O
,	O
also	O
was	O
significantly	O
greater	O
in	O
female	O
rats	O
compared	O
with	O
males	O
.	O

RESULTS	O
:	O
Here	O
,	O
we	O
report	O
the	O
identification	O
of	O
two	O
major	O
and	O
novel	O
Shc	B-GENE
tyrosine	O
phosphorylation	O
sites	O
,	O
Y239	O
and	O
Y240	O
.	O

The	O
results	O
obtained	O
demonstrate	O
the	O
applicability	O
of	O
countercurrent	O
chromatography	O
to	O
the	O
determination	O
of	O
ultratrace	O
elements	O
.	O

Based	O
on	O
our	O
sequence	O
data	O
,	O
ORF2	O
from	O
most	O
isolates	O
excluding	O
G1	O
encode	O
truncated	O
49	O
aa	O
(	O
pORF2a	O
)	O
because	O
of	O
an	O
in	O
-	O
frame	O
stop	O
codon	O
,	O
although	O
ORF2s	O
from	O
most	O
G1	O
isolates	O
encode	O
202	O
aa	O
(	O
pORF2ab	O
)	O
.	O

Fusions	O
between	O
the	O
GAL	B-GENE
DNA	I-GENE
binding	I-GENE
domain	I-GENE
and	O
full	B-GENE
-	I-GENE
length	I-GENE
mSin3	I-GENE
were	O
also	O
capable	O
of	O
repression	O
.	O

Clinical	O
evidence	O
provides	O
tentative	O
suggestions	O
on	O
(	O
a	O
)	O
possible	O
additional	O
risk	O
of	O
cigarette	O
smoking	O
(	O
b	O
)	O
avoidance	O
of	O
venography	O
(	O
c	O
)	O
avoidance	O
of	O
varicose	O
vein	O
surgery	O
.	O

We	O
examined	O
the	O
contribution	O
of	O
a	O
cryptic	O
plasmid	O
,	O
pRmeGR4b	O
,	O
to	O
the	O
nodulation	O
of	O
Medicago	O
sativa	O
by	O
strain	O
GR4	O
of	O
Rhizobium	O
meliloti	O
.	O

It	O
is	O
concluded	O
that	O
the	O
predominant	O
action	O
of	O
LSD	O
on	O
the	O
female	O
copulatory	O
response	O
is	O
not	O
mediated	O
by	O
increased	O
dopamine	B-GENE
receptor	I-GENE
activity	O
but	O
that	O
the	O
LSD	O
effect	O
might	O
be	O
modulated	O
by	O
decreased	O
dopaminergic	O
activity	O
.	O

The	O
frequency	O
of	O
severe	O
congestive	O
heart	O
failure	O
(	O
Killip	O
class	O
III	O
or	O
IV	O
)	O
at	O
admission	O
was	O
significantly	O
higher	O
in	O
patients	O
with	O
early	O
presentation	O
,	O
than	O
with	O
late	O
presentation	O
(	O
30	O
.	O
7	O
%	O
vs	O
7	O
.	O
6	O
%	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

These	O
findings	O
also	O
demonstrate	O
that	O
unless	O
excluded	O
by	O
other	O
factors	O
,	O
the	O
C	B-GENE
proteins	I-GENE
are	O
likely	O
to	O
be	O
located	O
along	O
the	O
length	O
of	O
nascent	O
transcripts	O
.	O

ADR1	B-GENE
in	O
extracts	O
made	O
from	O
glucose	O
-	O
repressed	O
and	O
-	O
derepressed	O
cells	O
bound	O
UAS1	O
DNA	O
with	O
similar	O
affinities	O
despite	O
having	O
greatly	O
different	O
abilities	O
to	O
activate	O
ADH2	B-GENE
gene	I-GENE
expression	O
in	O
vivo	O
.	O

Comparing	O
the	O
outcome	O
of	O
the	O
group	O
having	O
histologically	O
normal	O
biopsies	O
with	O
the	O
group	O
having	O
nonspecifically	O
abnormal	O
ones	O
it	O
is	O
concluded	O
that	O
frontal	O
biopsy	O
is	O
not	O
of	O
such	O
high	O
prognostic	O
value	O
as	O
has	O
been	O
claimed	O
in	O
previous	O
reports	O
.	O

However	O
,	O
using	O
wet	O
weight	O
/	O
dry	O
weight	O
methodology	O
,	O
we	O
found	O
that	O
administration	O
of	O
U74006F	O
significantly	O
reduced	O
water	O
content	O
in	O
the	O
right	O
hippocampus	O
(	O
contralateral	O
to	O
the	O
site	O
of	O
injury	O
)	O
compared	O
to	O
saline	O
-	O
treated	O
animals	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

A	O
ready	O
-	O
made	O
prosthesis	O
is	O
placed	O
on	O
the	O
external	O
side	O
of	O
the	O
ribs	O
vertically	O
bridging	O
the	O
flailed	O
chest	O
segment	O
,	O
and	O
fixed	O
to	O
the	O
first	O
upper	O
and	O
first	O
lower	O
intact	O
rib	O
as	O
well	O
as	O
to	O
the	O
mobile	O
segments	O
of	O
the	O
affected	O
ribs	O
.	O

The	O
authors	O
suggest	O
that	O
alprazolam	O
may	O
have	O
enhanced	O
specificity	O
for	O
a	O
subpopulation	O
of	O
benzodiazepine	B-GENE
receptors	I-GENE
.	O

They	O
showed	O
moderate	O
in	O
vitro	O
antifungal	O
activity	O
against	O
a	O
wide	O
variety	O
of	O
fungi	O
and	O
yeasts	O
including	O
clinically	O
important	O
pathogens	O
,	O
and	O
were	O
highly	O
effective	O
in	O
systemic	O
infection	O
with	O
Candida	O
albicans	O
in	O
mice	O
after	O
iv	O
and	O
im	O
administrations	O
.	O

Central	O
(	O
heart	O
rate	O
,	O
VE	O
,	O
VO2	O
)	O
or	O
local	O
(	O
muscle	O
and	O
blood	O
lactate	O
,	O
adenosine	O
triphosphate	O
,	O
creatine	B-GENE
phosphokinase	I-GENE
,	O
glycogen	O
)	O
cues	O
highlighted	O
in	O
these	O
studies	O
demonstrate	O
both	O
the	O
complexity	O
of	O
effort	O
perception	O
,	O
and	O
the	O
need	O
for	O
better	O
understanding	O
of	O
the	O
physiological	O
components	O
upon	O
which	O
it	O
is	O
based	O
.	O

The	O
method	O
was	O
tested	O
on	O
7	O
rats	O
with	O
48	O
-	O
hr	O
-	O
old	O
myocardial	O
infarction	O
and	O
4	O
sham	O
-	O
operated	O
controls	O
.	O

Disruption	O
and	O
reconstruction	O
:	O
narrative	O
insights	O
into	O
the	O
experience	O
of	O
family	O
members	O
caring	O
for	O
a	O
relative	O
diagnosed	O
with	O
serious	O
mental	O
illness	O
.	O

Transcription	O
start	O
sites	O
of	O
sal	B-GENE
and	O
salR	B-GENE
genes	I-GENE
were	O
determined	O
to	O
lie	O
30	O
-	O
and	O
24	O
-	O
bp	O
upstream	O
of	O
the	O
respective	O
initiation	O
codons	O
and	O
separated	O
from	O
each	O
other	O
by	O
78	O
nucleotides	O
.	O

Co	O
-	O
operativity	O
of	O
functional	O
domains	O
in	O
the	O
muscle	B-GENE
-	I-GENE
specific	I-GENE
transcription	I-GENE
factor	I-GENE
Myf	I-GENE
-	I-GENE
5	I-GENE
.	O

Henry	O
Quastler	O
brought	O
experience	O
from	O
an	O
actual	O
x	O
-	O
ray	O
treatment	O
,	O
and	O
Dr	O
.	O

Hybridization	O
was	O
detected	O
between	O
polyadenylated	B-GENE
H	I-GENE
chain	I-GENE
mRNA	I-GENE
,	O
isolated	O
from	O
the	O
majority	O
of	O
the	O
hybridomas	O
,	O
and	O
the	O
VH	B-GENE
probe	O
.	O

The	O
general	O
concept	O
of	O
RARE	B-GENE
-	O
cleavage	O
mapping	O
as	O
well	O
as	O
its	O
applications	O
and	O
limitations	O
are	O
discussed	O
.	O

(	O
4	O
)	O
Expression	O
in	O
different	O
sites	O
in	O
the	O
central	O
nervous	O
system	O
is	O
driven	O
by	O
separable	O
elements	O
widely	O
dispersed	O
throughout	O
8	O
kb	O
3	O
'	O
of	O
the	O
gene	O
.	O

Thus	O
,	O
an	O
increase	O
in	O
lactate	O
concentration	O
of	O
the	O
magnitude	O
observed	O
during	O
alkali	O
therapy	O
need	O
not	O
indicate	O
a	O
worsening	O
of	O
the	O
metabolic	O
picture	O
in	O
lactic	O
acidosis	O
.	O

The	O
virus	O
must	O
progress	O
past	O
the	O
immediate	O
-	O
early	O
phase	O
and	O
express	O
an	O
early	B-GENE
gene	I-GENE
product	I-GENE
(	I-GENE
s	I-GENE
)	I-GENE
for	O
activation	O
of	O
cyclin	B-GENE
E	I-GENE
expression	O
.	O

The	O
software	O
is	O
in	O
BASIC	O
adapted	O
for	O
the	O
Hewlett	O
-	O
Packard	O
calculators	O
HP	O
-	O
9845B	O
and	O
HP	O
-	O
85A	O
.	O

Genealogical	O
analysis	O
suggested	O
mainly	O
a	O
mother	O
-	O
to	O
-	O
offspring	O
transmission	O
of	O
this	O
STLV	O
-	O
1	O
.	O

The	O
deduced	O
amino	O
-	O
acid	O
sequence	O
of	O
the	O
mature	O
enzyme	O
showed	O
very	O
low	O
homology	O
(	O
<	O
20	O
.	O
4	O
%	O
identity	O
)	O
to	O
those	O
of	O
known	O
pectinolytic	O
enzymes	O
in	O
the	O
large	O
pectate	B-GENE
lyase	I-GENE
superfamily	I-GENE
(	O
the	O
polysaccharide	B-GENE
lyase	I-GENE
family	I-GENE
1	I-GENE
)	O
.	O

The	O
pineal	O
hormone	O
melatonin	O
(	O
MLT	O
)	O
is	O
able	O
to	O
exert	O
an	O
oncostatic	O
action	O
.	O

Patients	O
commonly	O
considered	O
the	O
external	O
frame	O
cumbersome	O
.	O

A	O
wound	O
model	O
for	O
decubitus	O
and	O
leg	O
ulcers	O
consisting	O
of	O
human	O
dermal	O
fibroblasts	O
in	O
type	B-GENE
I	I-GENE
collagen	I-GENE
dermal	O
"	O
equivalent	O
"	O
matrix	O
(	O
DEM	O
)	O
was	O
exposed	O
in	O
vitro	O
to	O
electric	O
fields	O
similar	O
to	O
postulated	O
endogenous	O
fields	O
in	O
wounds	O
.	O

In	O
contrast	O
to	O
the	O
effect	O
on	O
DNA	O
replication	O
,	O
the	O
L13V	O
substitution	O
in	O
large	B-GENE
T	I-GENE
antigen	I-GENE
did	O
not	O
prevent	O
complex	O
formation	O
with	O
Hsc70	B-GENE
and	O
the	O
Rb	B-GENE
protein	I-GENE
.	O

In	O
contrast	O
,	O
the	O
tail	O
deviated	O
ipsilaterally	O
in	O
cats	O
with	O
a	O
hemisection	O
,	O
and	O
the	O
tail	O
was	O
ventroflexed	O
in	O
cats	O
with	O
a	O
transection	O
.	O

Lastly	O
,	O
several	O
restriction	O
length	O
polymorphisms	O
were	O
identified	O
and	O
mapped	O
within	O
a	O
1	O
kb	O
region	O
located	O
immediately	O
upstream	O
from	O
the	O
JH	B-GENE
cluster	I-GENE
.	O

Peak	O
plasma	O
ACTH	B-GENE
responses	O
were	O
not	O
significantly	O
different	O
between	O
control	O
and	O
patient	O
groups	O
.	O

We	O
demonstrate	O
inhibition	O
of	O
2	O
-	O
deoxyglucose	O
uptake	O
in	O
isolated	O
primary	O
rat	O
adipocytes	O
and	O
3T3	O
-	O
L1	O
adipocytes	O
pretreated	O
with	O
U73122	O
.	O

It	O
is	O
likely	O
that	O
these	O
recordings	O
are	O
incomplete	O
;	O
the	O
actual	O
number	O
of	O
activated	O
neurons	O
is	O
estimated	O
to	O
be	O
about	O
300	O
in	O
the	O
acutely	O
sensitized	O
preparation	O
.	O

In	O
this	O
report	O
we	O
describe	O
the	O
structure	O
and	O
DNA	O
sequence	O
of	O
transcriptional	O
control	O
regions	O
from	O
both	O
human	B-GENE
and	I-GENE
Wistar	I-GENE
-	I-GENE
rat	I-GENE
single	I-GENE
copy	I-GENE
EGF	I-GENE
genes	I-GENE
and	O
their	O
functional	O
analysis	O
in	O
epithelial	O
cell	O
cultures	O
.	O

Along	O
with	O
these	O
species	O
,	O
F	O
.	O
graminearum	O
group	O
2	O
(	O
ZON	O
,	O
DON	O
and	O
/	O
or	O
3AcDON	O
or	O
15AcDON	O
)	O
;	O
F	O
.	O
chlamydosporum	O
;	O
F	O
.	O
acuminatum	O
(	O
type	O
-	O
A	O
trichothecene	O
derivatives	O
)	O
;	O
and	O
F	O
.	O
semitectum	O
were	O
often	O
found	O
to	O
be	O
associated	O
.	O

C	O
.	O
glabrata	O
cells	O
containing	O
the	O
CBF1	B-GENE
gene	I-GENE
under	O
the	O
influence	O
of	O
a	O
shutdown	O
promoter	O
(	O
tetO	O
-	O
ScHOP	O
)	O
arrested	O
their	O
growth	O
after	O
5	O
h	O
of	O
cultivation	O
in	O
the	O
presence	O
of	O
the	O
reactive	O
drug	O
doxycycline	O
.	O

It	O
was	O
observed	O
that	O
muscle	O
infarction	O
in	O
the	O
IPC	O
(	O
24	O
+	O
/	O
-	O
2	O
%	O
)	O
and	O
preischemic	O
LMK	O
(	O
21	O
+	O
/	O
-	O
2	O
%	O
)	O
groups	O
were	O
smaller	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
than	O
that	O
in	O
the	O
control	O
(	O
42	O
+	O
/	O
-	O
2	O
%	O
)	O
.	O

A	O
characteristic	O
feature	O
is	O
their	O
tendency	O
to	O
form	O
homo	O
-	O
and	O
/	O
or	O
heterodimeric	O
complexes	O
.	O

Copyright	O
1999	O
Academic	O
Press	O
.	O

A	O
female	O
infant	O
with	O
isolated	O
noncompaction	O
of	O
ventricular	O
myocardium	O
who	O
developed	O
ventricular	O
tachyarrhythmia	O
is	O
described	O
.	O

Methodological	O
considerations	O
limiting	O
causal	O
assertions	O
permissible	O
with	O
nonexperimental	O
data	O
are	O
discussed	O
.	O

Skytthe	O
,	O
and	O
K	O
.	O

Y1	B-GENE
,	O
Y2	B-GENE
,	O
and	O
Y4	B-GENE
/	O
PP1	B-GENE
.	O

S	O
-	O
phase	O
-	O
promoting	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
(	O
Cdks	B-GENE
)	O
and	O
the	O
kinase	O
Dbf4	B-GENE
-	O
Cdc7	B-GENE
then	O
act	O
to	O
initiate	O
replication	O
.	O

The	O
cleft	O
walls	O
are	O
lined	O
with	O
highly	O
conserved	O
residues	O
and	O
NADP	O
is	O
bound	O
along	O
one	O
wall	O
.	O

The	O
primary	O
conditions	O
for	O
acceptable	O
hospital	O
use	O
were	O
that	O
exhaled	O
-	O
volume	O
monitoring	O
be	O
performed	O
for	O
all	O
patients	O
and	O
that	O
O2	O
monitoring	O
be	O
performed	O
both	O
when	O
setting	O
FIO2	O
and	O
continuously	O
when	O
FIO2	O
levels	O
are	O
critical	O
.	O

Genetic	O
mutation	O
or	O
loss	O
of	O
activin	B-GENE
/	O
transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta	I-GENE
(	I-GENE
TGFbeta	I-GENE
)	I-GENE
receptor	I-GENE
function	O
has	O
been	O
shown	O
in	O
human	O
lymphoid	O
,	O
breast	O
,	O
and	O
colorectal	O
tumors	O
as	O
well	O
as	O
Hep2B	O
and	O
Mv1Lu	O
cell	O
lines	O
.	O

Non	O
-	O
specific	O
immunological	O
abnormalities	O
were	O
detected	O
in	O
8	O
of	O
the	O
13	O
patients	O
in	O
whom	O
they	O
were	O
looked	O
for	O
.	O

No	O
cleavage	O
of	O
gp	B-GENE
130	I-GENE
was	O
observed	O
in	O
analogous	O
pulse	O
-	O
chase	O
radiolabelling	O
of	O
Ad	O
-	O
gB	B-GENE
-	O
infected	O
human	O
fibroblasts	O
,	O
even	O
though	O
these	O
cells	O
are	O
permissive	O
for	O
HCMV	O
replication	O
and	O
can	O
process	O
the	O
native	B-GENE
gB	I-GENE
molecule	I-GENE
.	O

Because	O
levels	O
of	O
Vo2DIR	O
and	O
Vo2INDIR	O
were	O
similar	O
in	O
both	O
groups	O
,	O
we	O
pooled	O
data	O
from	O
septic	O
and	O
control	O
animals	O
.	O

A	O
case	O
comparison	O
of	O
acquired	O
immune	O
deficiency	O
syndrome	O
(	O
AIDS	O
)	O
in	O
homosexual	O
males	O
with	O
spindle	O
-	O
endothelial	O
cell	O
abnormalities	O
and	O
with	O
recrudescent	O
melioidosis	O
.	O

OBJECTIVE	O
:	O
To	O
assess	O
laboratory	O
practice	O
in	O
the	O
examination	O
of	O
blood	O
films	O
for	O
malarial	O
parasites	O
.	O

Little	O
honoured	O
in	O
his	O
own	O
country	O
:	O
statues	O
in	O
recognition	O
of	O
Edward	O
Jenner	O
MD	O
FRS	O
.	O

We	O
conclude	O
that	O
GRF1	B-GENE
and	O
GRF2	B-GENE
can	O
form	O
homo	O
-	O
and	O
hetero	O
-	O
oligomers	O
via	O
their	O
DH	B-GENE
domains	I-GENE
,	O
that	O
mutational	O
inactivation	O
of	O
oligomer	O
formation	O
by	O
GRF1	B-GENE
is	O
associated	O
with	O
impaired	O
biological	O
and	O
signaling	O
activities	O
,	O
and	O
that	O
in	O
293T	O
cells	O
GRF1	B-GENE
mediates	O
at	O
least	O
two	O
pathways	O
for	O
Raf	B-GENE
activation	O
:	O
one	O
a	O
constitutive	O
signal	O
that	O
is	O
mainly	O
Ras	B-GENE
-	O
dependent	O
,	O
and	O
one	O
an	O
ionomycin	O
-	O
induced	O
signal	O
that	O
cooperates	O
with	O
the	O
constitutive	O
signal	O
without	O
further	O
augmenting	O
the	O
level	O
of	O
GTP	B-GENE
-	I-GENE
Ras	I-GENE
.	O

The	O
significance	O
of	O
these	O
changes	O
in	O
relation	O
to	O
the	O
control	O
of	O
phosphorus	O
balance	O
in	O
ruminants	O
is	O
discussed	O
.	O

These	O
results	O
extend	O
our	O
knowledge	O
of	O
this	O
SNF2	B-GENE
-	I-GENE
like	I-GENE
family	I-GENE
member	I-GENE
and	O
suggest	O
a	O
role	O
for	O
PASG	B-GENE
in	O
leukemogenesis	O
.	O

In	O
the	O
absence	O
of	O
c	B-GENE
-	I-GENE
fos	I-GENE
gene	I-GENE
expression	O
,	O
c	B-GENE
-	I-GENE
Fos	I-GENE
protein	I-GENE
appears	O
to	O
be	O
replaced	O
by	O
proteins	O
of	O
Fos	B-GENE
family	I-GENE
(	O
Fra	B-GENE
-	I-GENE
1	I-GENE
)	O
and	O
ATF	B-GENE
family	I-GENE
(	O
ATF	B-GENE
-	I-GENE
2	I-GENE
and	O
ATFa	B-GENE
)	O
.	O

The	O
interaction	O
obtained	O
with	O
DBM	O
scores	O
was	O
further	O
qualified	O
by	O
a	O
three	O
-	O
way	O
interaction	O
that	O
limited	O
this	O
pattern	O
to	O
participants	O
scoring	O
higher	O
on	O
self	O
-	O
deception	O
.	O

To	O
elucidate	O
the	O
molecular	O
mechanism	O
by	O
which	O
the	O
Ras	B-GENE
signaling	O
pathway	O
activates	O
a	O
cell	O
-	O
type	O
-	O
specific	O
gene	O
,	O
we	O
have	O
used	O
the	O
pituitary	B-GENE
-	I-GENE
specific	I-GENE
rat	I-GENE
prolactin	I-GENE
(	O
rPRL	B-GENE
)	O
promoter	O
as	O
a	O
target	O
of	O
oncogenic	B-GENE
Ras	I-GENE
and	O
Raf	B-GENE
in	O
GH4	O
rat	O
pituitary	O
cells	O
.	O

The	O
results	O
indicate	O
that	O
expression	O
of	O
proU	B-GENE
in	O
E	O
.	O
coli	O
is	O
directed	O
from	O
two	O
promoters	O
,	O
one	O
(	O
P2	O
)	O
characterized	O
earlier	O
by	O
other	O
workers	O
with	O
the	O
start	O
site	O
of	O
transcription	O
60	O
nucleotides	O
upstream	O
of	O
the	O
initiation	O
codon	O
of	O
the	O
first	O
structural	O
gene	O
(	O
proV	B-GENE
)	O
,	O
and	O
the	O
other	O
(	O
P1	O
)	O
situated	O
250	O
nucleotides	O
upstream	O
of	O
proV	B-GENE
.	O

Coexpression	O
of	O
CREB	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CBP	B-GENE
)	O
/	O
p300	B-GENE
with	O
TReP	B-GENE
-	I-GENE
132	I-GENE
has	O
an	O
additive	O
effect	O
on	O
promoter	O
activity	O
,	O
and	O
the	O
proteins	O
were	O
demonstrated	O
to	O
interact	O
physically	O
.	O

Thirty	O
minutes	O
after	O
reperfusion	O
,	O
lung	O
lymph	O
flow	O
(	O
QL	O
)	O
increased	O
from	O
4	O
.	O
3	O
to	O
8	O
.	O
3	O
ml	O
/	O
30	O
minutes	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
lymph	O
/	O
plasma	O
protein	O
ratio	O
was	O
unchanged	O
from	O
0	O
.	O
6	O
,	O
and	O
the	O
lymph	O
protein	O
clearance	O
increased	O
from	O
2	O
.	O
6	O
to	O
4	O
.	O
6	O
ml	O
/	O
30	O
minutes	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
data	O
consistent	O
with	O
increased	O
microvascular	O
permeability	O
.	O

The	O
shift	O
from	O
complex	O
I	O
to	O
complex	O
II	O
seen	O
only	O
in	O
SCM	B-GENE
-	I-GENE
1	I-GENE
-	O
producer	O
T	O
cell	O
lines	O
upon	O
activation	O
was	O
completely	O
suppressed	O
by	O
cyclosporin	O
A	O
.	O

Database	O
searches	O
revealed	O
a	O
50	O
-	O
63	O
%	O
similarity	O
and	O
34	O
-	O
42	O
%	O
identity	O
with	O
several	O
families	O
of	O
serine	B-GENE
proteases	I-GENE
,	O
in	O
particular	O
the	O
trypsin	B-GENE
-	I-GENE
like	I-GENE
proteases	I-GENE
,	O
members	O
of	O
the	O
glandular	B-GENE
kallikrein	I-GENE
family	I-GENE
(	O
including	O
prostate	B-GENE
-	I-GENE
specific	I-GENE
antigen	I-GENE
,	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
gamma	I-GENE
,	O
and	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
)	O
and	O
the	O
activators	O
for	O
the	O
kringle	B-GENE
family	I-GENE
proteins	I-GENE
(	O
including	O
the	O
human	B-GENE
tissue	I-GENE
plasminogen	I-GENE
activator	I-GENE
and	O
human	B-GENE
hepatocyte	I-GENE
growth	I-GENE
factor	I-GENE
activator	I-GENE
)	O
.	O

UPR	O
elements	O
present	O
in	O
other	O
ER	O
chaperone	O
genes	O
,	O
such	O
as	O
yeast	B-GENE
KAR2	I-GENE
(	O
BiP	B-GENE
)	O
,	O
mammalian	B-GENE
GRP78	I-GENE
(	O
BiP	B-GENE
)	O
,	O
and	O
GRP94	B-GENE
,	O
function	O
in	O
an	O
analogous	O
manner	O
to	O
that	O
in	O
FKB2	B-GENE
.	O

No	O
bafilomycin	O
-	O
sensitive	O
ATPase	B-GENE
is	O
detected	O
in	O
a	O
vacuolar	O
fraction	O
.	O

The	O
kinase	O
domains	O
encoded	O
in	O
the	O
COOH	O
-	O
terminal	O
moiety	O
are	O
94	O
%	O
conserved	O
;	O
the	O
NH2	O
-	O
terminal	O
moieties	O
are	O
approximately	O
65	O
%	O
homologous	O
,	O
suggesting	O
this	O
region	O
may	O
encode	O
sequences	O
conferring	O
differential	O
regulation	O
of	O
the	O
two	O
kinases	O
.	O

From	O
this	O
asymmetry	O
,	O
we	O
suggested	O
previously	O
that	O
GCN4	B-GENE
interacts	O
with	O
nonequivalent	O
and	O
possibly	O
overlapping	O
half	O
-	O
sites	O
(	O
ATGAC	O
and	O
ATGAG	O
)	O
that	O
have	O
different	O
affinities	O
.	O

The	O
essential	O
questions	O
about	O
hepatitis	O
C	O

DRAP27	B-GENE
is	O
recognized	O
by	O
CD9	B-GENE
antibodies	I-GENE
.	O

YACs	O
selected	O
from	O
our	O
contig	O
will	O
be	O
the	O
starting	O
point	O
for	O
the	O
cloning	O
of	O
the	O
LGMD2B	B-GENE
gene	I-GENE
and	O
thereby	O
establish	O
the	O
biological	O
basis	O
for	O
this	O
form	O
of	O
muscular	O
dystrophy	O
and	O
its	O
relationship	O
with	O
the	O
other	O
limb	O
-	O
girdle	O
muscular	O
dystrophies	O
.	O

Acceptability	O
of	O
home	O
monitoring	O
as	O
an	O
aid	O
to	O
conception	O
.	O

Starches	O
had	O
no	O
effect	O
.	O

The	O
dominant	O
inhibitory	O
biological	O
activity	O
of	O
the	O
N	O
terminus	O
correlated	O
with	O
its	O
ability	O
to	O
impair	O
EGF	B-GENE
-	O
dependent	O
activation	O
of	O
GTP	B-GENE
-	I-GENE
Ras	I-GENE
and	O
of	O
MAP	B-GENE
kinase	I-GENE
,	O
as	O
well	O
with	O
the	O
ability	O
of	O
endogenous	O
Sos	B-GENE
to	O
form	O
a	O
stable	O
complex	O
with	O
activated	O
EGF	B-GENE
receptors	I-GENE
.	O

The	O
tensile	O
strengths	O
of	O
an	O
adhesive	O
luting	O
resin	O
'	O
Panavia	O
EX	O
'	O
to	O
the	O
bovine	O
dentin	O
decreased	O
significantly	O
by	O
the	O
zinc	O
iontophoresis	O
.	O

The	O
Giessener	O
Tumordokumentationssystem	O
(	O
GTDS	O
)	O
is	O
such	O
a	O
disease	O
specific	O
system	O
.	O

In	O
addition	O
,	O
renal	O
sympathetic	O
activity	O
was	O
measured	O
in	O
a	O
separate	O
group	O
of	O
rats	O
.	O

A	O
4	O
.	O
0	O
-	O
kb	O
Nlk	B-GENE
message	I-GENE
is	O
also	O
present	O
during	O
embryogenesis	O
,	O
detectable	O
at	O
day	O
E10	O
.	O

The	O
5	B-GENE
-	I-GENE
HT3	I-GENE
antagonist	O
ondansetron	O
reduced	O
alcohol	O
intake	O
in	O
both	O
the	O
medium	O
and	O
high	O
alcohol	O
preferring	O
rats	O
at	O
doses	O
between	O
0	O
.	O
01	O
and	O
0	O
.	O
16	O
mg	O
/	O
kg	O
.	O

In	O
humans	O
,	O
there	O
was	O
a	O
statistically	O
significant	O
decrease	O
of	O
TEWL	O
on	O
both	O
forearm	O
and	O
thigh	O
in	O
CS	O
-	O
treated	O
patients	O
compared	O
to	O
non	O
-	O
CS	O
-	O
treated	O
patients	O
and	O
controls	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Southern	O
hybridization	O
of	O
genomic	O
DNA	O
from	O
WT	O
and	O
Lp	B-GENE
/	O
Lp	B-GENE
embryos	O
failed	O
to	O
identify	O
specific	O
rearrangements	O
at	O
or	O
near	O
the	O
Nhlh1	B-GENE
locus	I-GENE
,	O
and	O
Northern	O
RNA	O
blotting	O
and	O
RT	O
-	O
PCR	O
evaluation	O
of	O
Nhlh1	B-GENE
mRNA	I-GENE
expression	O
indicated	O
that	O
both	O
the	O
levels	O
and	O
types	O
of	O
Nhlh1	B-GENE
mRNAs	I-GENE
produced	O
in	O
WT	O
and	O
Lp	B-GENE
/	O
Lp	B-GENE
embryos	O
were	O
indistinguishable	O
.	O

Mutations	O
of	O
the	O
human	B-GENE
PTEN	I-GENE
gene	I-GENE
.	O

Heart	O
rate	O
during	O
the	O
behavioral	O
avoidance	O
test	O
was	O
shown	O
to	O
be	O
as	O
susceptible	O
to	O
experimental	O
demand	O
as	O
other	O
studies	O
have	O
shown	O
approach	O
behaviors	O
to	O
be	O
influenced	O
.	O

In	O
addition	O
,	O
we	O
mapped	O
a	O
putative	O
hnRNP	B-GENE
A1	I-GENE
binding	I-GENE
site	I-GENE
in	O
U5	B-GENE
RNA	I-GENE
and	O
demonstrated	O
that	O
p40CRS	B-GENE
(	O
hnRNP	B-GENE
A1	I-GENE
)	O
binding	O
to	O
that	O
site	O
correlates	O
with	O
CRS	B-GENE
function	O
.	O

Biochemical	O
experiments	O
and	O
genome	O
sequencing	O
have	O
shown	O
that	O
,	O
despite	O
the	O
prokaryotic	O
cell	O
and	O
genome	O
organization	O
,	O
basal	O
transcriptional	O
elements	O
of	O
members	O
of	O
the	O
domain	O
Archaea	O
(	O
i	O
.	O
e	O
.	O
,	O
TATA	O
box	O
-	O
like	O
sequences	O
,	O
RNA	B-GENE
polymerase	I-GENE
,	O
and	O
transcription	O
factors	O
TBP	B-GENE
,	O
TFIIB	B-GENE
,	O
and	O
TFIIS	B-GENE
)	O
are	O
of	O
the	O
eukaryotic	O
type	O
.	O

MGF	B-GENE
is	O
a	O
novel	O
member	O
of	O
the	O
cytokine	B-GENE
-	I-GENE
regulated	I-GENE
transcription	I-GENE
factor	I-GENE
gene	I-GENE
family	I-GENE
.	O

One	O
month	O
after	O
administration	O
of	O
131I	O
,	O
the	O
29	O
cats	O
evaluated	O
were	O
clinically	O
improved	O
,	O
and	O
24	O
(	O
83	O
%	O
)	O
of	O
the	O
29	O
cats	O
evaluated	O
had	O
normal	O
serum	O
T4	O
concentrations	O
,	O
3	O
cats	O
(	O
10	O
%	O
)	O
remained	O
hyperthyroxinemic	O
,	O
and	O
2	O
cats	O
(	O
7	O
%	O
)	O
were	O
hypothyroxinemic	O
.	O

Csk	B-GENE
(	O
C	B-GENE
-	I-GENE
terminal	I-GENE
Src	I-GENE
kinase	I-GENE
)	O
is	O
a	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
that	O
phosphorylates	O
Src	B-GENE
family	I-GENE
member	I-GENE
C	I-GENE
-	I-GENE
terminal	I-GENE
tails	I-GENE
,	O
resulting	O
in	O
downregulation	O
of	O
Src	B-GENE
family	O
members	O
.	O

Northern	O
blot	O
analysis	O
of	O
enoyl	B-GENE
-	I-GENE
ACP	I-GENE
reductase	I-GENE
mRNA	I-GENE
steady	O
-	O
state	O
levels	O
during	O
seed	O
development	O
suggests	O
that	O
the	O
increase	O
in	O
enzyme	O
activity	O
during	O
the	O
phase	O
of	O
storage	O
lipid	O
accumulation	O
is	O
regulated	O
at	O
the	O
level	O
of	O
gene	O
expression	O
.	O

Lung	O
transplantation	O
is	O
warranted	O
for	O
stable	O
,	O
ventilator	O
-	O
dependent	O
recipients	O
.	O

A	O
new	O
myocyte	B-GENE
-	I-GENE
specific	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
that	O
recognizes	O
a	O
conserved	O
element	O
associated	O
with	O
multiple	O
muscle	O
-	O
specific	O
genes	O
.	O

The	O
magnesium	O
content	O
in	O
leukocytes	O
could	O
not	O
be	O
estimated	O
because	O
of	O
interaction	O
between	O
the	O
ion	O
and	O
the	O
Percoll	O
(	O
R	O
)	O
media	O
.	O

The	O
need	O
for	O
such	O
guidelines	O
is	O
clear	O
on	O
both	O
clinical	O
and	O
scientific	O
grounds	O
.	O

This	O
activity	O
creates	O
a	O
4	O
-	O
bp	O
staggered	O
cut	O
with	O
3	O
'	O
OH	O
overhangs	O
within	O
a	O
specific	O
sequence	O
of	O
the	O
21S	B-GENE
rRNA	I-GENE
gene	I-GENE
of	O
omega	O
-	O
strains	O
.	O

Herewith	O
C	O
.	O
psittaci	O
could	O
be	O
diagnosed	O
in	O
all	O
positive	O
samples	O
.	O

Chem	O
.	O

The	O
gene	O
responsible	O
for	O
multiple	O
endocrine	O
neoplasia	O
type	O
1	O
(	O
MEN1	B-GENE
)	O
,	O
a	O
heritable	O
predisposition	O
to	O
endocrine	O
tumours	O
in	O
man	O
,	O
has	O
recently	O
been	O
identified	O
.	O

Is	O
it	O
time	O
for	O
a	O
wine	O
trial	O
?	O

We	O
previously	O
identified	O
a	O
highly	O
conserved	O
L	O
-	O
X	O
-	O
X	O
-	O
L	O
-	O
F	O
sequence	O
near	O
the	O
C	O
terminus	O
of	O
the	O
p6	B-GENE
domain	I-GENE
of	O
the	O
Gag	B-GENE
precursor	I-GENE
as	O
the	O
major	O
virion	O
association	O
motif	O
for	O
HIV	B-GENE
-	I-GENE
1	I-GENE
Vpr	I-GENE
.	O

Three	O
patients	O
treated	O
with	O
amphotericin	O
B	O
,	O
single	O
course	O
as	O
well	O
as	O
multiple	O
courses	O
,	O
and	O
other	O
antifungal	O
agents	O
(	O
hydroxystilbamidine	O
and	O
miconazole	O
)	O
have	O
all	O
relapsed	O
.	O

The	O
site	O
of	O
acetylation	O
of	O
Tat	B-GENE
was	O
mapped	O
to	O
the	O
double	O
-	O
lysine	O
motif	O
in	O
a	O
highly	O
conserved	O
region	O
,	O
(	O
49	O
)	O
RKKRRQ	O
(	O
54	O
)	O
,	O
of	O
the	O
basic	O
RNA	O
-	O
binding	O
motif	O
of	O
Tat	B-GENE
.	O

In	O
contrast	O
to	O
Torpedo	O
,	O
where	O
only	O
a	O
single	O
transcript	O
is	O
seen	O
,	O
the	O
mouse	O
expresses	O
several	O
mRNAs	O
encoding	O
different	O
isoforms	O
.	O

trans	O
-	O
activation	O
of	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
by	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
Tat	I-GENE
and	O
HTLV	B-GENE
-	I-GENE
I	I-GENE
Tax	I-GENE
proteins	I-GENE
is	O
mediated	O
by	O
different	O
cis	O
-	O
acting	O
sequences	O
.	O

NSD1	B-GENE
contains	O
a	O
SET	B-GENE
domain	I-GENE
and	O
multiple	O
PHD	O
fingers	O
.	O

After	O
1	O
day	O
,	O
none	O
of	O
the	O
labeled	O
erythrocytes	O
were	O
detected	O
.	O

Latex	O
products	O
(	O
gloves	O
,	O
balloons	O
,	O
and	O
condoms	O
)	O
directly	O
bound	O
IgE	B-GENE
from	O
all	O
four	O
patients	O
.	O

The	O
results	O
indicate	O
that	O
the	O
RNA	O
in	O
T7	B-GENE
RNA	I-GENE
polymerase	I-GENE
is	O
not	O
free	O
of	O
steric	O
interactions	O
in	O
the	O
ternary	O
complex	O
and	O
not	O
available	O
for	O
structure	O
formation	O
until	O
it	O
is	O
at	O
least	O
10	O
bases	O
away	O
from	O
the	O
site	O
of	O
polymerization	O
.	O

Effect	O
of	O
infantile	O
undernutrition	O
on	O
adult	O
sucrose	O
solution	O
consumption	O
in	O
the	O
rat	O
.	O

The	O
transcriptional	O
activity	O
of	O
P	B-GENE
-	I-GENE
450	I-GENE
(	I-GENE
11	I-GENE
beta	I-GENE
)	I-GENE
gene	I-GENE
was	O
studied	O
with	O
an	O
in	O
vitro	O
transcription	O
system	O
using	O
nuclear	O
extracts	O
prepared	O
from	O
bovine	O
adrenal	O
cortex	O
.	O

The	O
analysis	O
showed	O
that	O
the	O
morning	O
active	O
(	O
MA	O
)	O
individuals	O
rose	O
earlier	O
and	O
went	O
to	O
bed	O
earlier	O
than	O
the	O
evening	O
active	O
(	O
EA	O
)	O
individuals	O
,	O
and	O
the	O
former	O
had	O
a	O
longer	O
sleep	O
length	O
than	O
the	O
latter	O
during	O
days	O
with	O
a	O
morning	O
shift	O
,	O
while	O
the	O
opposite	O
was	O
true	O
for	O
afternoon	O
and	O
night	O
shifts	O
.	O

Appl	O
.	O

The	O
CHED	B-GENE
protein	I-GENE
includes	O
the	O
consensus	O
ATP	O
binding	O
and	O
phosphorylation	O
domains	O
characteristic	O
of	O
kinases	O
,	O
displays	O
34	O
-	O
42	O
%	O
identically	O
aligned	O
amino	O
acid	O
residues	O
with	O
other	O
cdc2	B-GENE
-	I-GENE
related	I-GENE
kinases	I-GENE
,	O
and	O
is	O
considerably	O
longer	O
at	O
its	O
amino	O
and	O
carboxyl	O
termini	O
.	O

These	O
include	O
urinalysis	O
,	O
chest	O
X	O
-	O
P	O
,	O
ECG	O
,	O
hematological	O
examinations	O
(	O
RBC	O
,	O
WBC	O
,	O
Ht	O
,	O
Hb	B-GENE
,	O
PLT	O
and	O
ESR	O
)	O
and	O
biochemical	O
tests	O
(	O
AST	B-GENE
,	O
ALT	B-GENE
,	O
ALP	B-GENE
,	O
gamma	B-GENE
GTP	I-GENE
,	O
LDH	B-GENE
,	O
CPK	B-GENE
,	O
Chol	O
,	O
T	O
-	O
Bil	O
,	O
TP	O
,	O
Alb	B-GENE
,	O
TG	O
,	O
BUN	O
,	O
Cr	O
,	O
Glu	O
,	O
Na	O
,	O
K	O
,	O
Ca	O
,	O
P	O
and	O
CRP	B-GENE
)	O
.	O

We	O
challenge	O
each	O
of	O
55	O
consecutive	O
ragweed	O
(	O
RW	O
)	O
-	O
allergic	O
patients	O
with	O
hay	O
fever	O
and	O
with	O
graded	O
increasing	O
doses	O
of	O
ragweed	O
extract	O
to	O
investigate	O
the	O
frequency	O
and	O
relationship	O
between	O
the	O
early	O
(	O
ER	O
)	O
,	O
late	O
(	O
LPR	O
)	O
,	O
and	O
rechallenge	O
reactions	O
(	O
RCRs	O
)	O
to	O
nasal	O
challenge	O
.	O

Vasodilator	O
and	O
hypotensive	O
effects	O
of	O
the	O
optical	O
isomers	O
of	O
nicardipine	O
(	O
YC	O
-	O
93	O
)	O
,	O
a	O
new	O
Ca2	O
+	O
-	O
antagonist	O
.	O

The	O
encoded	O
protein	O
contains	O
an	O
amino	O
terminal	O
PDZ	B-GENE
domain	O
,	O
followed	O
by	O
a	O
predicted	O
coiled	O
-	O
coil	O
region	O
,	O
a	O
PEST	O
domain	O
,	O
and	O
a	O
carboxy	O
-	O
terminal	O
SAM	O
domain	O
.	O

The	O
5	O
'	O
ends	O
of	O
the	O
P	B-GENE
and	O
O	B-GENE
gene	I-GENE
mRNAs	I-GENE
are	O
separated	O
by	O
109	O
nucleotide	O
pairs	O
in	O
the	O
DNA	O
template	O
.	O

Those	O
diagnosed	O
as	O
having	O
affective	O
disorder	O
(	O
n	O
=	O
96	O
)	O
,	O
according	O
to	O
DSM	O
-	O
IIIR	O
criteria	O
,	O
were	O
compared	O
with	O
the	O
other	O
non	O
-	O
affective	O
suicide	O
attempters	O
(	O
n	O
=	O
161	O
)	O
.	O

The	O
leukotriene	B-GENE
receptor	I-GENE
antagonist	O
zafirlukast	O
inhibits	O
sulfur	O
dioxide	O
-	O
induced	O
bronchoconstriction	O
in	O
patients	O
with	O
asthma	O
.	O

The	O
p63	B-GENE
sequence	I-GENE
also	O
features	O
an	O
acidic	O
domain	O
characteristic	O
of	O
transcriptional	O
activation	O
factors	O
,	O
as	O
well	O
as	O
sequence	O
blocks	O
displaying	O
limited	O
similarity	O
to	O
positionally	O
equivalent	O
regions	O
in	O
sigma	B-GENE
factors	I-GENE
from	O
eubacteria	O
related	O
to	O
mitochondria	O
.	O

We	O
have	O
thus	O
cloned	O
two	O
yeast	O
homologs	O
of	O
mammalian	B-GENE
p220	I-GENE
.	O

A	O
phase	O
II	O
clinical	O
trial	O
on	O
MDS	O
was	O
conducted	O
in	O
a	O
cooperative	O
study	O
with	O
orally	O
administrable	O
ara	O
-	O
C	O
analogue	O
,	O
PLAC	O
,	O
which	O
is	O
resistant	O
to	O
cytidine	B-GENE
deaminase	I-GENE
and	O
had	O
shown	O
an	O
anti	O
-	O
tumor	O
activity	O
on	O
various	O
experimental	O
tumors	O
by	O
oral	O
route	O
.	O

The	O
arrangement	O
of	O
amino	O
acids	O
in	O
the	O
helix	O
1	O
and	O
helix	O
2	O
regions	O
is	O
quite	O
similar	O
to	O
those	O
of	O
Mxi	B-GENE
and	O
Mad	B-GENE
,	O
but	O
different	O
from	O
those	O
of	O
E2F	B-GENE
-	I-GENE
1	I-GENE
and	O
DP	B-GENE
-	I-GENE
1	I-GENE
.	O

Platelets	O
and	O
RBCs	O
from	O
each	O
animal	O
were	O
labeled	O
with	O
51Cr	O
and	O
99mTc	O
,	O
respectively	O
,	O
and	O
were	O
rapidly	O
injected	O
into	O
the	O
right	O
atrium	O
while	O
blood	O
was	O
sampled	O
from	O
the	O
ascending	O
aorta	O
.	O

PDGF	B-GENE
stimulated	O
CDK2	B-GENE
activity	O
in	O
mesangial	O
cells	O
and	O
decreased	O
the	O
level	O
of	O
p27	B-GENE
(	O
kip1	B-GENE
)	O
cyclin	O
kinase	O
inhibitor	O
protein	O
.	O

Furthermore	O
,	O
the	O
induction	O
of	O
cytochrome	B-GENE
P	I-GENE
-	I-GENE
450	I-GENE
1A1	I-GENE
observed	O
in	O
the	O
cormorant	O
indicates	O
that	O
the	O
Ah	B-GENE
receptor	I-GENE
-	O
mediated	O
process	O
,	O
by	O
which	O
TCDD	O
and	O
related	O
chemicals	O
exert	O
many	O
of	O
their	O
toxicities	O
,	O
has	O
been	O
activated	O
.	O

In	O
gel	O
mobility	O
shift	O
assays	O
,	O
high	O
binding	O
activities	O
of	O
ATPC	B-GENE
-	I-GENE
2	I-GENE
and	O
low	O
binding	O
activities	O
of	O
CBF	B-GENE
were	O
observed	O
with	O
nuclear	O
extracts	O
from	O
tissue	O
with	O
low	O
AtpC	B-GENE
expression	O
levels	O
,	O
and	O
the	O
opposite	O
was	O
observed	O
with	O
extracts	O
from	O
tissues	O
with	O
high	O
AtpC	B-GENE
expression	O
levels	O
.	O

A	O
case	O
of	O
bilateral	O
testicular	O
germ	O
cell	O
tumors	O
in	O
a	O
23	O
-	O
year	O
-	O
old	O
male	O
is	O
reported	O
.	O

Using	O
green	B-GENE
fluorescent	I-GENE
protein	I-GENE
fusions	O
we	O
demonstrate	O
that	O
the	O
SYT	B-GENE
,	O
SSX	B-GENE
and	O
the	O
SYT	B-GENE
-	O
SSX	B-GENE
proteins	O
are	O
nuclear	O
proteins	O
.	O

Thus	O
,	O
the	O
mutants	O
are	O
deficient	O
in	O
production	O
of	O
the	O
O	B-GENE
-	I-GENE
antigen	I-GENE
polymerase	I-GENE
and	O
were	O
termed	O
rfc	B-GENE
mutants	I-GENE
.	O

The	O
program	O
for	O
myogenic	O
differentiation	O
is	O
subject	O
to	O
negative	O
control	O
by	O
several	O
peptide	O
growth	O
factors	O
and	O
by	O
the	O
products	O
of	O
mutationally	O
activated	O
ras	B-GENE
oncogenes	I-GENE
,	O
which	O
persistently	O
activate	O
intracellular	O
cascades	O
normally	O
triggered	O
by	O
specific	O
growth	O
factors	O
.	O

The	O
p58	B-GENE
(	O
PITSLRE	B-GENE
beta	I-GENE
1	I-GENE
)	O
protein	O
kinase	O
(	O
PK	O
)	O
is	O
a	O
member	O
of	O
a	O
large	O
supergene	O
family	O
related	O
to	O
the	O
master	B-GENE
mitotic	I-GENE
protein	I-GENE
kinase	I-GENE
,	O
p34cdc2	B-GENE
.	O

By	O
a	O
combination	O
of	O
alternative	O
promoter	O
usage	O
and	O
exon	O
splicing	O
,	O
each	O
ROR	B-GENE
gene	I-GENE
generates	O
several	O
isoforms	O
that	O
differ	O
only	O
in	O
their	O
amino	O
terminus	O
.	O

The	O
expression	O
pattern	O
of	O
LjEmx	B-GENE
changed	O
dramatically	O
during	O
embryogenesis	O
;	O
expression	O
was	O
seen	O
initially	O
in	O
the	O
entire	O
neural	O
tube	O
and	O
mesoderm	O
,	O
which	O
were	O
secondarily	O
downregulated	O
,	O
and	O
secondarily	O
in	O
cranial	O
nerve	O
ganglia	O
and	O
in	O
the	O
craniofacial	O
mesenchyme	O
.	O

Similarly	O
,	O
antisense	B-GENE
TGF	I-GENE
-	I-GENE
beta	I-GENE
type	I-GENE
II	I-GENE
receptor	I-GENE
oligodeoxynucleotides	I-GENE
(	I-GENE
40	I-GENE
microM	I-GENE
)	I-GENE
resulted	O
in	O
a	O
58	O
%	O
increase	O
in	O
branching	O
,	O
compared	O
to	O
scrambled	O
and	O
mismatched	O
sequence	O
controls	O
,	O
while	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
,	I-GENE
type	I-GENE
II	I-GENE
receptor	I-GENE
mRNA	I-GENE
and	O
its	O
protein	O
expression	O
levels	O
were	O
suppressed	O
by	O
95	O
and	O
84	O
%	O
,	O
respectively	O
.	O

Despite	O
this	O
loss	O
,	O
YEpFAS1	B-GENE
is	O
still	O
able	O
to	O
complement	O
a	O
fas1	B-GENE
mutation	O
at	O
the	O
enoyl	B-GENE
reductase	I-GENE
domain	O
.	O

In	O
this	O
study	O
,	O
a	O
site	O
of	O
PDGF	B-GENE
-	O
induced	O
tyrosine	O
phosphorylation	O
was	O
mapped	O
to	O
Tyr	O
138	O
in	O
the	O
SH3	B-GENE
domain	I-GENE
;	O
Tyr	O
138	O
is	O
exposed	O
on	O
the	O
SH3	B-GENE
peptide	I-GENE
binding	I-GENE
surface	I-GENE
.	O

Our	O
results	O
showed	O
that	O
the	O
5	O
-	O
hydroxytryptamine	O
(	O
5	O
-	O
HT	O
)	O
content	O
in	O
platelets	O
was	O
:	O
(	O
1	O
)	O
increased	O
in	O
the	O
subgroup	O
of	O
anti	O
-	O
social	O
alcoholics	O
;	O
(	O
2	O
)	O
transiently	O
and	O
differently	O
altered	O
in	O
alcoholics	O
compared	O
to	O
opiate	O
addicts	O
;	O
and	O
(	O
3	O
)	O
lowered	O
in	O
drinking	O
alcoholics	O
and	O
normal	O
in	O
alcoholics	O
who	O
were	O
drinking	O
as	O
well	O
as	O
smoking	O
(	O
that	O
may	O
occur	O
via	O
MAO	B-GENE
-	I-GENE
B	I-GENE
inhibition	O
by	O
smoke	O
)	O
.	O

Recently	O
,	O
we	O
reported	O
that	O
SMRT	B-GENE
also	O
directly	O
associates	O
with	O
LAZ3	B-GENE
(	O
BCL	B-GENE
-	I-GENE
6	I-GENE
)	O
,	O
a	O
POZ	O
/	O
Zn	O
finger	O
transcriptional	O
repressor	O
involvedin	O
the	O
pathogenesis	O
of	O
non	O
-	O
Hodgkin	O
lymphomas	O
.	O

Regulation	O
of	O
activating	B-GENE
transcription	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
and	O
the	O
cAMP	B-GENE
response	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
by	O
Ca2	B-GENE
+	I-GENE
/	I-GENE
calmodulin	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinases	I-GENE
type	I-GENE
I	I-GENE
,	I-GENE
II	I-GENE
,	I-GENE
and	I-GENE
IV	I-GENE
.	O

Accordingly	O
,	O
constitutive	O
downregulation	O
of	O
expression	O
of	O
accessory	O
molecules	O
of	O
the	O
MHC	B-GENE
class	I-GENE
I	I-GENE
pathway	I-GENE
can	O
reveal	O
differences	O
between	O
H2	B-GENE
class	I-GENE
I	I-GENE
alleles	I-GENE
in	O
antigen	O
presentation	O
not	O
encountered	O
when	O
the	O
expression	O
levels	O
are	O
augmented	O
.	O

Cross	O
-	O
sectional	O
studies	O
continue	O
to	O
dominate	O
.	O

G6620	B-GENE
is	O
the	O
3	O
'	O
end	O
of	O
the	O
MOL1	B-GENE
gene	I-GENE
coding	O
for	O
a	O
polypeptide	O
similar	O
to	O
stress	O
-	O
inducible	O
proteins	O
from	O
Fusarium	O
;	O
G6630	B-GENE
is	O
the	O
NAT2	B-GENE
gene	I-GENE
which	O
encodes	O
a	O
methionine	B-GENE
N	I-GENE
-	I-GENE
acetyltransferase	I-GENE
;	O
G6635	B-GENE
is	O
the	O
RPL30B	B-GENE
gene	I-GENE
coding	O
for	O
the	O
ribosomal	B-GENE
protein	I-GENE
L30	I-GENE
;	O
G6658	B-GENE
is	O
RSR1	B-GENE
encoding	O
a	O
ras	B-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
;	O
G6667	B-GENE
is	O
CYS4	B-GENE
,	O
the	O
gene	O
for	O
cystathionine	B-GENE
beta	I-GENE
-	I-GENE
synthase	I-GENE
;	O
G6670	B-GENE
is	O
identical	O
to	O
ORF2	O
located	O
close	O
to	O
CYS4	B-GENE
;	O
G6673	B-GENE
is	O
PEM1	B-GENE
/	O
CHO2	B-GENE
encoding	O
a	O
phosphatidylethanolamine	B-GENE
methyltransferase	I-GENE
;	O
G7001	B-GENE
is	O
the	O
NSR1	B-GENE
gene	I-GENE
coding	O
for	O
a	O
nuclear	O
signal	O
recognition	O
protein	O
.	O

The	O
tau	O
v	O
at	O
rest	O
was	O
4	O
.	O
06	O
+	O
/	O
-	O
2	O
.	O
16	O
s	O
and	O
decreased	O
to	O
2	O
.	O
44	O
+	O
/	O
-	O
1	O
.	O
07	O
s	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
at	O
1	O
Hz	O
and	O
to	O
1	O
.	O
81	O
+	O
/	O
-	O
0	O
.	O
4	O
s	O
at	O
5	O
Hz	O
.	O

This	O
action	O
could	O
be	O
antagonized	O
by	O
aminophylline	O
,	O
a	O
competitive	O
antagonist	O
on	O
P1	B-GENE
purinoceptors	I-GENE
.	O

In	O
the	O
predicted	O
amino	O
acid	O
sequence	O
of	O
NPS1	B-GENE
,	O
sequences	O
homologous	O
to	O
the	O
catalytic	O
domain	O
of	O
protein	O
kinases	O
were	O
found	O
.	O

The	O
cDNA	O
contains	O
a	O
reading	O
frame	O
for	O
a	O
145	O
-	O
amino	O
-	O
acid	O
protein	O
and	O
it	O
lacks	O
the	O
UGA	O
codons	O
,	O
which	O
have	O
been	O
found	O
in	O
the	O
reading	O
frame	O
of	O
the	O
mouse	B-GENE
MCS	I-GENE
cDNA	I-GENE
and	O
have	O
been	O
presumed	O
to	O
encode	O
the	O
selenocysteine	O
in	O
the	O
amino	O
terminal	O
of	O
the	O
deduced	O
mouse	O
amino	O
acid	O
sequence	O
.	O

It	O
differed	O
significantly	O
by	O
country	O
(	O
from	O
2	O
.	O
4	O
%	O
in	O
the	O
United	O
Kingdom	O
to	O
24	O
.	O
7	O
%	O
in	O
Portugal	O
)	O
and	O
by	O
transmission	O
category	O
(	O
2	O
.	O
7	O
%	O
among	O
homo	O
/	O
bisexuals	O
,	O
5	O
.	O
8	O
%	O
among	O
injecting	O
drug	O
users	O
,	O
13	O
.	O
6	O
%	O
among	O
heterosexual	O
subgroup	O
1	O
)	O
.	O

A	O
definition	O
of	O
bias	O
founded	O
on	O
the	O
concept	O
of	O
the	O
study	O
base	O
.	O

The	O
results	O
showed	O
differential	O
activation	O
of	O
each	O
parahippocampal	O
region	O
during	O
verbal	O
memory	O
tasks	O
in	O
which	O
the	O
side	O
activated	O
shifted	O
depending	O
on	O
the	O
nature	O
of	O
the	O
task	O
employed	O
;	O
an	O
increase	O
in	O
rCBF	O
in	O
the	O
left	O
parahippocampal	O
gyrus	O
was	O
associated	O
with	O
retrieval	O
strategy	O
of	O
non	O
-	O
matching	O
,	O
and	O
an	O
increase	O
in	O
rCBF	O
in	O
the	O
right	O
parahippocampal	O
gyrus	O
was	O
associated	O
with	O
retrieval	O
strategy	O
of	O
matching	O
.	O

Cells	O
were	O
co	O
-	O
infected	O
simultaneously	O
with	O
IBV	O
,	O
the	O
recombinant	O
FPV	O
(	O
rFPV	O
)	O
containing	O
the	O
D	O
-	O
RNA	O
sequence	O
and	O
a	O
second	O
rFPV	O
expressing	O
T7	B-GENE
RNA	I-GENE
polymerase	I-GENE
for	O
the	O
initial	O
expression	O
of	O
the	O
D	O
-	O
RNA	O
transcript	O
,	O
subsequently	O
rescued	O
by	O
helper	O
IBV	O
.	O

Antigen	O
dose	O
-	O
response	O
curves	O
were	O
drawn	O
,	O
and	O
the	O
cumulative	O
dose	O
required	O
for	O
a	O
35	O
%	O
reduction	O
in	O
specific	O
airway	O
conductance	O
was	O
calculated	O
and	O
designated	O
Provocation	O
Dose	O
(	O
PD35	O
)	O
.	O

The	O
use	O
of	O
the	O
two	O
pharmacokinetic	O
parameters	O
,	O
t1	O
/	O
2	O
and	O
Cltp	O
,	O
as	O
indices	O
of	O
drug	O
elimination	O
ability	O
are	O
discussed	O
.	O

The	O
rapid	O
decrease	O
of	O
plasma	O
potassium	O
during	O
the	O
first	O
two	O
hours	O
of	O
standard	O
HD	O
causes	O
a	O
membrane	O
hyperpolarization	O
.	O

The	O
more	O
sustained	O
effect	O
of	O
cyclofenil	O
on	O
prolactin	B-GENE
secretion	O
with	O
a	O
reduced	O
frequency	O
of	O
relapse	O
,	O
and	O
the	O
lower	O
oestradiol	O
level	O
,	O
which	O
might	O
indicate	O
a	O
reduced	O
risk	O
of	O
thromboembolism	O
,	O
suggest	O
that	O
this	O
drug	O
has	O
some	O
advantage	O
over	O
bromocriptine	O
in	O
the	O
inhibition	O
of	O
postpartum	O
lactation	O
.	O

Therefore	O
prostaglandin	O
E2	O
is	O
characterized	O
in	O
relation	O
to	O
prostaglandin	O
F2	O
-	O
alpha	O
not	O
only	O
by	O
a	O
stronger	O
uterine	O
effectiveness	O
,	O
but	O
also	O
at	O
the	O
same	O
time	O
a	O
pronounced	O
influence	O
on	O
the	O
cardiovascular	O
system	O
.	O

Epithelial	O
cell	O
-	O
specific	O
activation	O
is	O
achieved	O
by	O
the	O
cooperative	O
interaction	O
of	O
apparently	O
ubiquitous	O
transcriptional	O
factors	O
.	O

This	O
set	O
of	O
genetic	O
and	O
physical	O
interactions	O
suggests	O
a	O
role	O
for	O
yeast	O
RNA	O
-	O
binding	O
proteins	O
in	O
transcriptional	O
regulation	O
.	O

In	O
group	O
1	O
,	O
mean	O
z	O
-	O
score	O
for	O
GFR	O
was	O
-	O
0	O
.	O
27	O
(	O
94	O
.	O
6	O
%	O
of	O
normal	O
)	O
and	O
in	O
group	O
2	O
mean	O
z	O
-	O
score	O
was	O
-	O
1	O
.	O
51	O
(	O
72	O
.	O
7	O
%	O
of	O
normal	O
for	O
two	O
kidneys	O
)	O
(	O
P	O
=	O
0	O
.	O
022	O
,	O
Mann	O
-	O
Whitney	O
U	O
-	O
test	O
)	O
.	O

A	O
new	O
B	O
-	O
cell	O
-	O
specific	O
enhancer	O
element	O
has	O
been	O
identified	O
3	O
'	O
of	O
E4	B-GENE
and	O
the	O
octamerlike	O
motifs	O
in	O
the	O
human	B-GENE
immunoglobulin	I-GENE
heavy	I-GENE
-	I-GENE
chain	I-GENE
gene	I-GENE
enhancer	I-GENE
.	O

The	O
mutants	O
retained	O
the	O
parental	O
ability	O
to	O
participate	O
in	O
intergeneric	O
coaggregation	O
with	O
human	O
oral	O
actinomyces	O
,	O
indicating	O
the	O
specificity	O
of	O
the	O
mutation	O
in	O
altering	O
intrageneric	O
coaggregations	O
.	O

Electrically	O
induced	O
undulations	O
and	O
their	O
competition	O
with	O
electrically	O
induced	O
convection	O
in	O
cholesteric	O
liquid	O
crystals	O
.	O

Critical	O
review	O
of	O
general	O
results	O

A	O
visibly	O
distinct	O
muscular	O
hypertrophy	O
(	O
mh	O
)	O
,	O
commonly	O
known	O
as	O
double	O
muscling	O
,	O
occurs	O
with	O
high	O
frequency	O
in	O
the	O
Belgian	O
Blue	O
and	O
Piedmontese	O
cattle	O
breeds	O
.	O

The	O
LS	B-GENE
gene	I-GENE
promoter	I-GENE
sequence	I-GENE
has	O
homology	O
with	O
Escherichia	O
coli	O
promoter	O
sequences	O
;	O
its	O
terminator	O
sequence	O
is	O
capable	O
of	O
forming	O
a	O
stem	O
-	O
and	O
-	O
loop	O
structure	O
.	O

The	O
apparent	O
binding	O
constant	O
of	O
6	O
to	O
calf	O
thymus	O
DNA	O
is	O
1	O
.	O
68	O
X	O
10	O
(	O
5	O
)	O
M	O
-	O
1	O
whereas	O
netropsin	B-GENE
under	O
similar	O
conditions	O
gives	O
a	O
value	O
of	O
1	O
.	O
85	O
X	O
10	O
(	O
7	O
)	O
M	O
-	O
1	O
.	O

Computed	O
tomographic	O
(	O
CT	O
)	O
findings	O
of	O
pancreatic	O
ductal	O
adenocarcinoma	O
were	O
studied	O
with	O
the	O
combined	O
method	O
of	O
early	O
enhancement	O
CT	O
and	O
high	O
dose	O
enhancement	O
CT	O
in	O
72	O
carcinomas	O
.	O

Southern	O
hybridization	O
analysis	O
of	O
BenR	B-GENE
and	O
BenS	B-GENE
transformants	I-GENE
suggested	O
that	O
plasmid	O
integration	O
occurred	O
most	O
frequently	O
at	O
the	O
chromosomal	O
bens	B-GENE
locus	I-GENE
,	O
however	O
evidence	O
for	O
gene	O
conversion	O
and	O
heterologous	O
recombination	O
was	O
also	O
observed	O
.	O

Recombinant	B-GENE
mouse	I-GENE
GSTT1	I-GENE
-	I-GENE
1	I-GENE
was	O
catalytically	O
active	O
towards	O
1	O
,	O
2	O
-	O
epoxy	O
-	O
3	O
-	O
(	O
p	O
-	O
nitrophenoxy	O
)	O
propane	O
,	O
4	O
-	O
nitrobenzyl	O
chloride	O
and	O
dichloromethane	O
.	O

The	O
amount	O
of	O
overlap	O
in	O
VFI	O
,	O
EF	O
,	O
and	O
RVF	O
values	O
among	O
the	O
clinical	O
groups	O
was	O
considerable	O
.	O

In	O
pituitary	O
GH3	O
cells	O
,	O
vitamin	O
D	O
increases	O
the	O
levels	O
of	O
PRL	B-GENE
transcripts	I-GENE
and	O
stimulates	O
the	O
PRL	B-GENE
promoter	I-GENE
.	O

Neonatal	O
masculinization	O
affects	O
maternal	O
behavior	O
sensitivity	O
in	O
female	O
rats	O
.	O

The	O
Thrombolysis	O
in	O
Myocardial	O
Infarction	O
(	O
TIMI	O
)	O
Phase	O
II	O
Trial	O
randomized	O
3	O
,	O
339	O
patients	O
to	O
either	O
an	O
invasive	O
(	O
INV	O
,	O
n	O
=	O
1	O
,	O
681	O
)	O
or	O
a	O
conservative	O
(	O
CON	O
,	O
n	O
=	O
1	O
,	O
658	O
)	O
strategy	O
after	O
intravenous	O
recombinant	B-GENE
tissue	I-GENE
-	I-GENE
type	I-GENE
plasminogen	I-GENE
activator	I-GENE
(	O
rt	B-GENE
-	I-GENE
PA	I-GENE
)	O
for	O
acute	O
myocardial	O
infarction	O
.	O

Present	O
investigation	O
was	O
undertaken	O
to	O
elucidate	O
what	O
pharmacokinetic	O
parameters	O
in	O
animal	O
experiment	O
could	O
be	O
of	O
more	O
predictable	O
for	O
human	O
clinical	O
trial	O
of	O
beta	O
-	O
blocking	O
agents	O
.	O

Association	O
of	O
Smads	B-GENE
with	O
lymphoid	B-GENE
enhancer	I-GENE
binding	I-GENE
factor	I-GENE
1	I-GENE
/	O
T	B-GENE
cell	I-GENE
-	I-GENE
specific	I-GENE
factor	I-GENE
mediates	O
cooperative	O
signaling	O
by	O
the	O
transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta	I-GENE
and	O
wnt	B-GENE
pathways	O
.	O

In	O
the	O
univariate	O
models	O
of	O
either	O
fixed	O
or	O
time	O
dependent	O
covariates	O
,	O
many	O
variables	O
were	O
significantly	O
associated	O
with	O
risk	O
of	O
progression	O
to	O
AIDS	O
(	O
T4	O
cell	O
count	O
,	O
T4	O
/	O
T8	O
ratio	O
,	O
blastogenic	O
responses	O
to	O
phytohemagglutinin	B-GENE
,	O
concanavalin	B-GENE
A	I-GENE
,	O
and	O
pokeweed	B-GENE
mitogen	I-GENE
,	O
serum	B-GENE
IgA	I-GENE
,	O
appearance	O
of	O
p24	B-GENE
antigen	I-GENE
,	O
and	O
the	O
development	O
of	O
oral	O
hairy	O
leukoplakia	O
,	O
thrush	O
,	O
or	O
herpes	O
zoster	O
)	O
.	O

But	O
,	O
when	O
mated	O
males	O
built	O
nests	O
in	O
the	O
absence	O
of	O
young	O
,	O
T	O
levels	O
were	O
higher	O
than	O
in	O
all	O
other	O
conditions	O
,	O
though	O
only	O
for	O
early	O
broods	O
.	O

RESULTS	O
:	O
At	O
short	O
dwell	O
times	O
,	O
uncorrected	O
(	O
whole	O
plasma	O
)	O
D	O
/	O
P	O
and	O
Cp	O
of	O
urea	O
values	O
were	O
higher	O
than	O
the	O
corrected	O
(	O
plasma	O
water	O
)	O
values	O
by	O
5	O
.	O
7	O
%	O
-	O
5	O
.	O
9	O
%	O
.	O

However	O
,	O
there	O
are	O
some	O
cows	O
that	O
fail	O
to	O
produce	O
adequate	O
1	O
,	O
25	O
-	O
dihydroxyvitamin	O
D	O
at	O
the	O
onset	O
of	O
lactation	O
.	O

The	O
AmyI	B-GENE
specific	O
3	O
'	O
-	O
UTR	O
is	O
characterized	O
by	O
the	O
absence	O
of	O
IR	O
sequences	O
and	O
the	O
presence	O
of	O
a	O
putative	O
'	O
AATAAA	O
'	O
polyadenylation	O
signal	O
.	O

Off	O
-	O
shell	O
effect	O
in	O
Rydberg	O
-	O
atom	O
-	O
alkali	O
-	O
metal	O
-	O
atom	O
scattering	O
.	O

We	O
examined	O
the	O
mechanisms	O
by	O
which	O
two	O
different	O
types	O
of	O
photonic	O
radiation	O
,	O
short	O
wavelength	O
UV	O
(	O
UV	O
-	O
C	O
)	O
and	O
gamma	O
radiation	O
,	O
activate	O
transcription	O
factor	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
.	O

To	O
examine	O
the	O
biochemical	O
mechanism	O
of	O
Tax1	B-GENE
transactivation	O
,	O
we	O
have	O
developed	O
an	O
in	O
vitro	O
transactivation	O
assay	O
in	O
which	O
wild	O
-	O
type	O
Tax1	B-GENE
is	O
able	O
to	O
specifically	O
transactivate	O
a	O
polymerase	B-GENE
II	I-GENE
promoter	O
through	O
upstream	O
Tax1	B-GENE
-	I-GENE
responsive	I-GENE
elements	I-GENE
.	O

The	O
atf1	B-GENE
+	I-GENE
gene	I-GENE
of	I-GENE
Schizosaccharomyces	I-GENE
pombe	I-GENE
encodes	O
a	O
bZIP	B-GENE
transcription	I-GENE
factor	I-GENE
with	O
strong	O
homology	O
to	O
the	O
mammalian	B-GENE
factor	I-GENE
ATF	I-GENE
-	I-GENE
2	I-GENE
.	O

Cotransfection	O
experiments	O
revealed	O
that	O
both	O
hGATA	B-GENE
-	I-GENE
4	I-GENE
and	O
PMA	O
/	O
A23187	O
stimulation	O
are	O
necessary	O
for	O
the	O
IL	B-GENE
-	I-GENE
5	I-GENE
promoter	I-GENE
activation	O
.	O

(	O
5	O
)	O
.	O

Prenatal	O
diagnosis	O
of	O
genetic	O
diseases	O
.	O

1	O
.	O

Mortality	O
rates	O
were	O
not	O
different	O
(	O
chi2	O
:	O
0	O
.	O
0298	O
,	O
p	O
>	O
0	O
.	O
5	O
)	O
.	O

M	O
.	O
,	O
Apps	O
,	O
D	O
.	O

Cox	O
proportional	O
hazard	O
analysis	O
identified	O
dialysis	O
modality	O
and	O
pre	O
-	O
dialysis	O
UV	O
of	O
less	O
than	O
1	O
,	O
000	O
ml	O
/	O
m2	O
per	O
24	O
h	O
as	O
the	O
only	O
significant	O
risk	O
factors	O
for	O
UV	O
survival	O
.	O

The	O
sequence	O
of	O
the	O
25	O
-	O
kDa	O
chain	O
of	O
the	O
alpha	O
subunit	O
was	O
found	O
in	O
a	O
cDNA	O
clone	O
,	O
and	O
the	O
amino	O
acid	O
sequence	O
deduced	O
from	O
the	O
cDNA	O
establishes	O
the	O
complete	O
amino	O
acid	O
sequence	O
of	O
the	O
25	O
-	O
kDa	O
chain	O
.	O

The	O
Gastrointestinal	O
Tumor	O
Study	O
Group	O
(	O
GITSG	O
)	O
protocol	O
GI	O
-	O
7175	O
randomized	O
227	O
patients	O
between	O
1975	O
and	O
1980	O
following	O
complete	O
surgical	O
resection	O
of	O
stages	O
B2	O
and	O
C	O
rectal	O
adenocarcinoma	O
to	O
four	O
treatment	O
arms	O
:	O
(	O
1	O
)	O
no	O
adjuvant	O
therapy	O
,	O
(	O
2	O
)	O
chemotherapy	O
only	O
,	O
(	O
3	O
)	O
radiotherapy	O
only	O
,	O
and	O
(	O
4	O
)	O
radiotherapy	O
and	O
chemotherapy	O
(	O
combined	O
modality	O
)	O
.	O

Samples	O
(	O
1	O
g	O
)	O
were	O
extracted	O
with	O
0	O
.	O
5	O
%	O
potassium	O
chloride	O
(	O
KCl	O
)	O
in	O
70	O
%	O
methanol	O
(	O
5	O
ml	O
)	O
and	O
diluted	O
subsequently	O
to	O
give	O
two	O
-	O
fold	O
to	O
ten	O
-	O
fold	O
step	O
-	O
wise	O
dilutions	O
in	O
phosphate	O
-	O
buffered	O
saline	O
containing	O
0	O
.	O
05	O
%	O
Tween	O
20	O
and	O
0	O
.	O
2	O
%	O
bovine	B-GENE
serum	I-GENE
albumin	I-GENE
(	O
PBS	O
-	O
T	O
BSA	B-GENE
)	O
.	O

A	O
total	O
of	O
4	O
,	O
916	O
children	O
were	O
examined	O
and	O
the	O
questionnaire	O
satisfactorily	O
completed	O
by	O
a	O
relative	O
or	O
guardian	O
(	O
usually	O
the	O
mother	O
)	O
of	O
4	O
,	O
651	O
.	O

Using	O
community	O
development	O
approaches	O
.	O

Cell	O
lines	O
expressing	O
single	O
amino	O
acid	O
substitutions	O
of	O
the	O
carboxyl	O
-	O
terminal	O
asparagine	O
of	O
CD2	B-GENE
are	O
incapable	O
of	O
avidity	O
regulation	O
by	O
TCR	B-GENE
signaling	O
,	O
PMA	O
treatment	O
,	O
or	O
elevation	O
of	O
intracellular	O
cAMP	O
levels	O
,	O
demonstrating	O
that	O
each	O
of	O
these	O
stimuli	O
utilizes	O
a	O
common	O
structural	O
element	O
for	O
regulating	O
CD2	B-GENE
avidity	O
.	O

Iomazenil	O
-	O
SPECT	O
revealed	O
a	O
highly	O
significant	O
increase	O
in	O
the	O
benzodiazepine	B-GENE
receptor	I-GENE
uptake	O
in	O
all	O
studied	O
cortical	O
regions	O
except	O
temporal	O
cortices	O
.	O

These	O
findings	O
suggest	O
that	O
PGE1	O
is	O
effective	O
in	O
increasing	O
PVF	O
in	O
the	O
liver	O
transplanted	O
condition	O
;	O
however	O
,	O
the	O
hepatic	O
circulatory	O
improvement	O
attributed	O
to	O
this	O
agent	O
would	O
be	O
limited	O
to	O
the	O
first	O
few	O
days	O
following	O
transplantation	O
.	O

However	O
,	O
in	O
a	O
variation	O
of	O
this	O
assay	O
in	O
which	O
the	O
protease	O
is	O
omitted	O
,	O
the	O
mutant	O
enzymes	O
exhibited	O
substantial	O
levels	O
of	O
prolyl	B-GENE
isomerase	I-GENE
activity	O
(	O
5	O
-	O
20	O
%	O
of	O
wild	O
-	O
type	O
)	O
,	O
revealing	O
that	O
these	O
mutations	O
confer	O
sensitivity	O
to	O
protease	O
digestion	O
and	O
that	O
the	O
classic	O
in	O
vitro	O
assay	O
for	O
prolyl	B-GENE
isomerase	I-GENE
activity	O
may	O
be	O
misleading	O
.	O

The	O
WEB2	B-GENE
gene	I-GENE
encodes	O
a	O
1	O
,	O
522	O
-	O
amino	O
-	O
acid	O
protein	O
with	O
homology	O
to	O
nucleic	B-GENE
acid	I-GENE
-	I-GENE
dependent	I-GENE
ATPases	I-GENE
.	O

V	B-GENE
-	I-GENE
ErbB	I-GENE
-	I-GENE
mediated	I-GENE
complex	I-GENE
formation	O
and	O
transformation	O
have	O
been	O
shown	O
to	O
occur	O
independently	O
of	O
Ras	B-GENE
activation	O
.	O

The	O
three	O
OAS	B-GENE
genes	I-GENE
are	O
flanked	O
by	O
markers	B-GENE
WI	I-GENE
-	I-GENE
10614	I-GENE
(	O
cen	B-GENE
)	O
and	O
D12S2293	B-GENE
(	O
tel	B-GENE
)	O
and	O
are	O
contained	O
within	O
three	O
sets	O
of	O
overlapping	O
cosmid	O
clones	O
.	O

5	O
'	O
-	O
Deletion	O
of	O
the	O
Stat	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
abolished	O
all	O
promoter	O
-	O
reporter	O
activity	O
in	O
response	O
to	O
PRL	B-GENE
.	O

Increasing	O
the	O
height	O
of	O
the	O
agar	O
column	O
overlying	O
the	O
SN	O
fabric	O
diminished	O
the	O
inhibitory	O
effect	O
of	O
SN	O
on	O
microbial	O
growth	O
.	O

However	O
,	O
differential	O
utilization	O
of	O
these	O
determinants	O
mediate	O
RAR	B-GENE
-	O
RXR	B-GENE
heterodimer	O
binding	O
to	O
DR	O
-	O
2	O
and	O
DR	O
-	O
5	O
RAREs	O
.	O

Biochem	O
.	O

Conversely	O
,	O
as	O
a	O
GAL	B-GENE
-	I-GENE
4	I-GENE
chimera	I-GENE
,	O
the	O
isolated	O
LAZ3	B-GENE
/	O
BCL6	B-GENE
BTB	B-GENE
/	O
POZ	O
domain	O
appears	O
nearly	O
as	O
efficient	O
as	O
the	O
entire	O
protein	O
at	O
inducing	O
transcriptional	O
repression	O
.	O

When	O
expressed	O
in	O
Escherichia	O
coli	O
,	O
SH	B-GENE
-	I-GENE
PTP2	I-GENE
displays	O
tyrosine	B-GENE
-	I-GENE
specific	I-GENE
phosphatase	I-GENE
activity	O
.	O

It	O
is	O
hypothesized	O
this	O
occurs	O
through	O
antagonism	O
of	O
PML	B-GENE
/	O
RAR	B-GENE
alpha	I-GENE
actions	O
in	O
these	O
leukemic	O
cells	O
.	O

The	O
main	O
new	O
features	O
of	O
this	O
version	O
are	O
that	O
end	O
-	O
tidal	O
PO2	O
instead	O
of	O
inspiratory	O
PO2	O
can	O
be	O
kept	O
constant	O
,	O
and	O
that	O
the	O
correcting	O
activity	O
of	O
both	O
controllers	O
(	O
capnostat	O
and	O
oxystat	O
)	O
is	O
proportional	O
to	O
the	O
magnitude	O
of	O
the	O
difference	O
between	O
the	O
actual	O
and	O
the	O
adjusted	O
end	O
-	O
tidal	O
PCO2	O
or	O
PO2	O
.	O

Fli	B-GENE
-	I-GENE
1	I-GENE
is	O
a	O
proto	O
-	O
oncogene	O
which	O
is	O
rearranged	O
in	O
tumors	O
induced	O
by	O
three	O
different	O
retroviruses	O
,	O
Cas	O
-	O
Br	O
-	O
E	O
,	O
F	O
-	O
MuLV	O
,	O
and	O
10A1	O
.	O

Routine	O
imaging	O
modalities	O
revealed	O
a	O
total	O
of	O
79	O
metastases	O
.	O

Cervical	O
CT	O
revealed	O
an	O
irregular	O
low	O
density	O
at	O
the	O
periphery	O
of	O
the	O
cervical	O
vertebra	O
from	O
the	O
C2	O
to	O
C4	O
level	O
.	O

Human	B-GENE
myotonic	I-GENE
dystrophy	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
DMPK	B-GENE
)	O
is	O
a	O
member	O
of	O
a	O
novel	O
class	O
of	O
multidomain	O
protein	O
kinases	O
that	O
regulate	O
cell	O
size	O
and	O
shape	O
in	O
a	O
variety	O
of	O
organisms	O
.	O

The	O
MAP	B-GENE
kinase	I-GENE
kinase	I-GENE
kinase	I-GENE
MLK2	B-GENE
co	O
-	O
localizes	O
with	O
activated	O
JNK	B-GENE
along	O
microtubules	O
and	O
associates	O
with	O
kinesin	B-GENE
superfamily	I-GENE
motor	O
KIF3	B-GENE
.	O

Sequential	O
immunoprecipitation	O
showed	O
all	O
detectable	O
p53	B-GENE
to	O
be	O
of	O
the	O
PAb246	B-GENE
+	I-GENE
class	O
in	O
each	O
LPV	O
-	O
transformed	O
cell	O
line	O
,	O
suggesting	O
that	O
the	O
stable	O
p53	B-GENE
was	O
indeed	O
wild	O
type	O
.	O

In	O
this	O
study	O
,	O
transcriptional	O
fusions	O
were	O
constructed	O
between	O
the	O
xcpP	B-GENE
and	O
xcpR	B-GENE
genes	I-GENE
and	O
the	O
lacZ	B-GENE
reporter	I-GENE
.	O

Increased	O
platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
production	O
and	O
intimal	O
thickening	O
during	O
healing	O
of	O
Dacron	O
grafts	O
in	O
a	O
canine	O
model	O
.	O

Interestingly	O
,	O
the	O
NES	B-GENE
mutant	I-GENE
proteins	I-GENE
appeared	O
to	O
have	O
altered	O
interactions	O
with	O
the	O
splicing	O
complex	O
,	O
binding	O
more	O
tightly	O
to	O
SC35	B-GENE
in	O
co	O
-	O
immunoprecipitation	O
assays	O
.	O

The	O
results	O
of	O
these	O
studies	O
indicate	O
that	O
EHV	B-GENE
-	I-GENE
1	I-GENE
gp13	I-GENE
is	O
the	O
structural	O
homolog	O
of	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
glycoprotein	I-GENE
C	I-GENE
and	O
further	O
suggest	O
that	O
the	O
epitope	O
-	O
containing	O
N	O
-	O
terminal	O
amino	O
acid	O
sequences	O
of	O
the	O
herpesvirus	B-GENE
gC	I-GENE
-	I-GENE
like	I-GENE
glycoproteins	I-GENE
have	O
undergone	O
more	O
extensive	O
evolutionary	O
divergence	O
than	O
the	O
C	O
-	O
terminal	O
sequences	O
.	O

Previously	O
,	O
a	O
cDNA	O
(	O
GT2	B-GENE
)	O
encoding	O
this	O
protein	O
was	O
isolated	O
from	O
a	O
mouse	O
3T3	O
-	O
L1	O
adipocyte	O
library	O
and	O
was	O
sequenced	O
.	O

By	O
RT	O
-	O
PCR	O
,	O
different	O
levels	O
of	O
E75	B-GENE
expression	O
can	O
be	O
detected	O
in	O
the	O
epidermis	O
,	O
nerve	O
cord	O
and	O
the	O
eyestalk	O
of	O
early	O
pre	O
-	O
molt	O
shrimp	O
.	O

PATIENTS	O
:	O
33	O
HIV	O
-	O
infected	O
,	O
zidovudine	O
-	O
experienced	O
patients	O
with	O
serum	O
HIV	O
RNA	O
levels	O
of	O
at	O
least	O
20	O
,	O
000	O
copies	O
/	O
mL	O
and	O
CD4	B-GENE
counts	O
ranging	O
from	O
50	O
to	O
400	O
cells	O
/	O
mm3	O
.	O

The	O
potential	O
biological	O
significance	O
of	O
the	O
identified	O
structural	O
motif	O
shared	O
by	O
the	O
human	B-GENE
CCR5	I-GENE
,	O
CCR3	B-GENE
,	O
CCR2B	B-GENE
and	O
other	O
GPCRs	B-GENE
is	O
discussed	O
.	O

Materials	O
are	O
presented	O
of	O
a	O
comparative	O
study	O
of	O
morphological	O
and	O
cultural	O
properties	O
and	O
virulence	O
of	O
liophylized	O
cultures	O
of	O
Leishmania	O
tropica	O
major	O
after	O
their	O
rehydration	O
or	O
after	O
a	O
long	O
passage	O
on	O
the	O
NNN	O
medium	O
.	O

The	O
chromosomal	O
location	O
of	O
these	O
YACs	O
was	O
verified	O
using	O
FISH	O
,	O
which	O
also	O
demonstrated	O
their	O
nonchimeric	O
nature	O
.	O

There	O
is	O
no	O
indication	O
from	O
these	O
experiments	O
that	O
linker	B-GENE
histones	I-GENE
bind	O
fundamentally	O
differently	O
to	O
5	B-GENE
S	I-GENE
and	O
bulk	O
nucleosomes	O
.	O

Gas	O
chromatographic	O
analysis	O
of	O
headspace	O
samples	O
of	O
alkalinized	O
vaginal	O
discharges	O
indicated	O
the	O
presence	O
of	O
trimethylamine	O
in	O
all	O
11	O
samples	O
with	O
the	O
fishy	O
odor	O
but	O
not	O
in	O
the	O
other	O
samples	O
.	O

To	O
investigate	O
the	O
step	O
of	O
spliceosome	O
assembly	O
at	O
which	O
Snu17p	B-GENE
acts	O
,	O
we	O
have	O
used	O
nondenaturing	O
gel	O
electrophoresis	O
.	O

The	O
transcription	O
start	O
site	O
was	O
identified	O
by	O
primer	O
extension	O
analysis	O
and	O
over	O
800	O
bp	O
of	O
5	O
'	O
flanking	O
DNA	O
was	O
sequenced	O
.	O

PURPOSE	O
:	O
To	O
evaluate	O
the	O
effect	O
of	O
adding	O
a	O
pulsating	O
bristle	O
action	O
to	O
the	O
established	O
oscillating	O
/	O
rotating	O
action	O
of	O
the	O
Braun	O
Oral	O
-	O
B	O
Ultra	O
Plaque	O
Remover	O
(	O
D9	O
)	O
on	O
plaque	O
removal	O
.	O

In	O
contrast	O
,	O
postmitotic	O
neurons	O
possessed	O
extremely	O
low	O
levels	O
of	O
E2F1	B-GENE
protein	I-GENE
as	O
assessed	O
by	O
the	O
electrophoretic	O
mobility	O
shift	O
assay	O
and	O
Western	O
blotting	O
.	O

The	O
high	O
degree	O
of	O
sequence	O
conservation	O
together	O
with	O
the	O
ability	O
to	O
direct	O
nucleolar	O
protein	O
transport	O
supports	O
the	O
hypothesis	O
that	O
MAK16	B-GENE
proteins	I-GENE
play	O
a	O
key	O
role	O
in	O
the	O
biogenesis	O
of	O
60S	B-GENE
subunits	I-GENE
.	O

NO2	O
pollution	O
on	O
major	O
trunk	O
roads	O
frequently	O
exceeded	O
British	O
and	O
European	O
Union	O
air	O
quality	O
standards	O
,	O
while	O
particle	O
pollution	O
was	O
lower	O
.	O

The	O
human	O
RFC	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
differs	O
from	O
the	O
mouse	O
and	O
hamster	O
genes	O
both	O
in	O
terms	O
of	O
the	O
total	O
number	O
of	O
exons	O
and	O
in	O
regard	O
to	O
alternatives	O
of	O
exon	O
1	O
which	O
encode	O
5	O
'	O
end	O
heterogeneity	O
.	O

Computer	O
analysis	O
,	O
simple	O
correlation	O
hypothesis	O
,	O
and	O
distribution	O
method	O
with	O
1	O
degree	O
of	O
freedom	O
revealed	O
significant	O
correlation	O
between	O
vertical	O
root	O
fracture	O
and	O
the	O
technique	O
of	O
instrumentation	O
and	O
obturation	O
of	O
the	O
canal	O
(	O
p	O
=	O
0	O
.	O
025	O
)	O
,	O
the	O
length	O
of	O
the	O
post	O
(	O
p	O
=	O
0	O
.	O
05	O
)	O
,	O
and	O
the	O
existence	O
of	O
the	O
post	O
(	O
p	O
=	O
0	O
.	O
05	O
)	O
.	O

CrkII	B-GENE
and	O
CrkL	B-GENE
constitutively	O
formed	O
complex	O
with	O
the	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
C3G	B-GENE
,	O
in	O
unstimulated	O
as	O
well	O
as	O
PDGF	B-GENE
-	O
stimulated	O
cells	O
.	O

Plasmid	O
subclones	O
of	O
recombinant	O
phage	O
lambda	O
Asm152	O
were	O
able	O
to	O
complement	O
both	O
Escherichia	B-GENE
coli	I-GENE
gltB	I-GENE
and	O
A	O
.	O
sesbaniae	O
Asm	O
-	O
Vi	O
mutants	O
;	O
NADPH	B-GENE
-	I-GENE
glutamate	I-GENE
synthase	I-GENE
activity	O
was	O
detected	O
in	O
all	O
such	O
strains	O
complemented	O
to	O
Asm	O
+	O
.	O

Any	O
respectative	O
material	O
(	O
class	O
0	O
)	O
was	O
not	O
obtained	O
from	O
334	O
patients	O
(	O
4	O
.	O
2	O
%	O
)	O
,	O
class	O
I	O
-	O
II	O
findings	O
belonged	O
to	O
6m141	O
patients	O
(	O
76	O
.	O
7	O
%	O
)	O
,	O
950	O
patients	O
(	O
11	O
.	O
9	O
%	O
)	O
were	O
classified	O
as	O
class	O
HII	O
and	O
IV	O
,	O
578	O
patients	O
(	O
7	O
.	O
2	O
%	O
)	O
as	O
class	O
V	O
.	O

DSIP	O
was	O
found	O
to	O
significantly	O
increase	O
slow	O
-	O
waves	O
(	O
delta	O
sleep	O
)	O
in	O
the	O
sleep	O
EEG	O
.	O

YDL003w	B-GENE
(	O
also	O
termed	O
MCD1	B-GENE
)	O
is	O
a	O
homologue	O
of	O
Schizosaccharomyces	B-GENE
pombe	I-GENE
rad21	I-GENE
,	O
an	O
essential	O
gene	O
implicated	O
in	O
DNA	O
double	O
-	O
strand	O
break	O
repair	O
and	O
nuclear	O
organization	O
in	O
fission	O
yeast	O
.	O

The	O
oral	O
movements	O
which	O
did	O
occur	O
in	O
the	O
HAL	O
-	O
treated	O
rats	O
were	O
slower	O
than	O
normal	O
.	O

The	O
recombinant	B-GENE
L	I-GENE
/	I-GENE
F	I-GENE
-	I-GENE
transferase	I-GENE
is	O
as	O
active	O
as	O
the	O
previously	O
purified	O
wild	O
type	O
enzyme	O
and	O
contains	O
no	O
detectable	O
RNA	O
component	O
.	O

AST	B-GENE
activity	O
in	O
PMNs	O
was	O
significantly	O
low	O
,	O
approximately	O
2	O
%	O
of	O
that	O
observed	O
in	O
HPLFs	O
.	O

Two	O
courses	O
of	O
chemotherapy	O
(	O
CBCDA	O
+	O
VDS	O
)	O
failed	O
to	O
gain	O
any	O
improvement	O
,	O
and	O
the	O
pain	O
resulting	O
from	O
recurrent	O
bone	O
metastases	O
was	O
managed	O
mainly	O
by	O
the	O
administration	O
of	O
the	O
best	O
supportive	O
care	O
.	O

Intraspinal	O
and	O
mediastinal	O
foregut	O
cyst	O
compressing	O
the	O
spinal	O
cord	O
.	O

The	O
H5	B-GENE
mutants	I-GENE
were	O
:	O
DH5	B-GENE
(	O
all	O
amino	O
acids	O
in	O
D	O
configuration	O
)	O
and	O
H5F	B-GENE
(	O
where	O
all	O
His	O
are	O
replaced	O
by	O
Phe	O
at	O
positions	O
3	O
,	O
7	O
,	O
8	O
,	O
15	O
,	O
18	O
,	O
19	O
,	O
21	O
)	O
.	O

Accordingly	O
,	O
infection	O
of	O
IFN	B-GENE
-	O
pretreated	O
HeLa	O
S3	O
cells	O
with	O
an	O
E3L	O
-	O
deficient	O
VV	O
(	O
VVDeltaE3L	O
)	O
resulted	O
in	O
increased	O
phosphorylation	O
levels	O
of	O
both	O
PKR	B-GENE
and	O
eIF2alpha	B-GENE
.	O

The	O
human	O
sequence	O
contains	O
the	O
element	O
TGACTCT	O
that	O
also	O
is	O
found	O
in	O
a	O
murine	B-GENE
ras	I-GENE
-	I-GENE
responsive	I-GENE
enhancer	I-GENE
.	O

GAGA	B-GENE
factor	I-GENE
is	O
known	O
to	O
remodel	O
the	O
chromatin	O
structure	O
in	O
concert	O
with	O
nucleosome	B-GENE
-	I-GENE
remodeling	I-GENE
factor	I-GENE
NURF	B-GENE
in	O
a	O
Drosophila	O
embryonic	O
S150	O
extract	O
.	O

We	O
report	O
the	O
complete	O
nucleotide	O
sequence	O
of	O
the	O
camC	B-GENE
gene	I-GENE
along	O
with	O
155	O
base	O
pairs	O
of	O
5	O
'	O
and	O
175	O
base	O
pairs	O
of	O
3	O
'	O
flanking	O
sequence	O
.	O

After	O
30	O
weeks	O
of	O
amifostine	O
therapy	O
,	O
the	O
morphology	O
of	O
the	O
MDS	O
switched	O
to	O
a	O
chronic	O
myelomonocytic	O
leukemia	O
(	O
CMML	O
)	O
-	O
like	O
appearance	O
,	O
with	O
continuously	O
increasing	O
leukocytes	O
,	O
so	O
that	O
we	O
discontinued	O
amifostine	O
therapy	O
for	O
1	O
month	O
to	O
exclude	O
a	O
possible	O
side	O
effect	O
of	O
amifostine	O
.	O

A	O
gene	O
with	O
a	O
high	O
degree	O
of	O
sequence	O
identity	O
with	O
mammalian	B-GENE
ADP	I-GENE
-	I-GENE
ribosylation	I-GENE
factors	I-GENE
(	O
ARFs	B-GENE
)	O
,	O
believed	O
to	O
be	O
important	O
in	O
vesicular	O
transport	O
,	O
was	O
identified	O
.	O

Theophylline	O
QID	O
,	O
TID	O
,	O
BID	O
and	O
now	O
QD	O
?	O
A	O
report	O
on	O
24	O
-	O
hour	O
dosing	O
with	O
slow	O
-	O
release	O
theophylline	O
formulations	O
with	O
emphasis	O
on	O
analyses	O
of	O
data	O
used	O
to	O
obtain	O
Food	O
and	O
Drug	O
Administration	O
approval	O
for	O
Theo	O
-	O
24	O
.	O

We	O
anticipated	O
SNS	O
function	O
after	O
CVA	O
to	O
be	O
asymmetric	O
and	O
selected	O
null	O
hypotheses	O
of	O
bilaterally	O
symmetric	O
SSR	O
latencies	O
and	O
amplitudes	O
irrespective	O
of	O
side	O
of	O
stimulation	O
and	O
/	O
or	O
recording	O
.	O

Taken	O
together	O
,	O
these	O
results	O
demonstrate	O
that	O
the	O
BSMV	B-GENE
coat	I-GENE
protein	I-GENE
is	O
the	O
sole	O
translation	O
product	O
of	O
the	O
genomic	B-GENE
RNA	I-GENE
beta	I-GENE
,	O
whereas	O
sgRNA	B-GENE
beta	I-GENE
1	I-GENE
serves	O
as	O
a	O
messenger	O
for	O
translation	O
of	O
the	O
beta	B-GENE
b	I-GENE
protein	I-GENE
,	O
and	O
sgRNA	B-GENE
beta	I-GENE
2	I-GENE
functions	O
as	O
a	O
messenger	O
for	O
translation	O
of	O
beta	B-GENE
c	I-GENE
and	O
beta	B-GENE
d	I-GENE
and	O
the	O
newly	O
discovered	O
beta	B-GENE
d	I-GENE
'	I-GENE
protein	I-GENE
.	O

Without	O
a	O
team	O
,	O
there	O
is	O
little	O
hope	O
for	O
fetal	O
survival	O
;	O
mortality	O
will	O
be	O
80	O
-	O
100	O
%	O
.	O

Thus	O
,	O
the	O
search	O
for	O
genetic	O
and	O
acquired	O
susceptibility	O
to	O
nontuberculous	O
mycobacteria	O
is	O
also	O
a	O
search	O
for	O
susceptibility	O
factors	O
for	O
MTB	O
as	O
well	O
as	O
an	O
opportunity	O
to	O
recognize	O
endogenous	O
pathways	O
that	O
can	O
be	O
exploited	O
therapeutically	O
.	O

This	O
gene	O
is	O
divided	O
into	O
six	O
exons	O
spanning	O
about	O
3kb	O
,	O
and	O
encodes	O
a	O
175	O
amino	O
acid	O
protein	O
with	O
40	O
-	O
52	O
%	O
identity	O
with	O
the	O
other	O
five	O
mouse	B-GENE
Reg	I-GENE
(	O
regenerating	B-GENE
gene	I-GENE
product	I-GENE
)	O
proteins	O
.	O

The	O
RNA	O
,	O
whether	O
antisense	O
,	O
ribozyme	O
,	O
or	O
RNA	O
aptamer	O
,	O
must	O
be	O
efficiently	O
transcribed	O
,	O
stabilized	O
against	O
rapid	O
degradation	O
,	O
folded	O
correctly	O
,	O
and	O
directed	O
to	O
the	O
part	O
of	O
the	O
cell	O
where	O
it	O
can	O
be	O
most	O
effective	O
.	O

Interconversions	O
between	O
haloperidol	O
and	O
reduced	O
haloperidol	O
in	O
schizophrenic	O
patients	O
and	O
guinea	O
pigs	O
:	O
a	O
steady	O
-	O
state	O
study	O
.	O

PEAP	O
was	O
significantly	O
higher	O
in	O
IDC	O
patients	O
compared	O
to	O
controls	O
(	O
48	O
.	O
7	O
+	O
/	O
-	O
32	O
.	O
6	O
vs	O
.	O

Recurrent	O
infections	O
,	O
episodic	O
lymphopenia	O
and	O
impaired	O
cellular	O
immunity	O
.	O

Bilirubin	O
and	O
red	O
cell	O
metabolism	O
in	O
relation	O
to	O
neonatal	O
jaundice	O
.	O

In	O
this	O
report	O
,	O
we	O
describe	O
a	O
patient	O
with	O
renal	O
cell	O
carcinoma	O
who	O
experienced	O
ventricular	O
tachycardia	O
while	O
undergoing	O
treatment	O
with	O
high	O
-	O
dose	O
bolus	O
IL	B-GENE
-	I-GENE
2	I-GENE
.	O

We	O
report	O
the	O
cloning	O
of	O
the	O
ade1	B-GENE
gene	I-GENE
on	O
a	O
4	B-GENE
.	I-GENE
4	I-GENE
kb	I-GENE
Sau3A	I-GENE
insert	I-GENE
in	O
the	O
yeast	O
shuttle	O
vector	O
pWH5	O
.	O

We	O
found	O
that	O
secretion	O
of	O
chitinolytic	O
enzymes	O
by	O
cultured	O
L	O
.	O
major	O
parasites	O
is	O
inhibited	O
by	O
blood	O
or	O
hemoglobin	B-GENE
,	O
and	O
hence	O
these	O
enzymes	O
are	O
apparently	O
absent	O
from	O
the	O
blood	O
-	O
fed	O
infected	O
flies	O
,	O
where	O
the	O
cardiac	O
valve	O
appears	O
undamaged	O
.	O

Oral	O
hypoglycemic	O
agents	O

Identification	O
and	O
characterization	O
of	O
a	O
yeast	O
gene	O
encoding	O
the	O
U2	B-GENE
small	I-GENE
nuclear	I-GENE
ribonucleoprotein	I-GENE
particle	I-GENE
B	I-GENE
"	I-GENE
protein	I-GENE
.	O

The	O
false	O
positive	O
fraction	O
(	O
FPF	O
)	O
decreased	O
significantly	O
if	O
the	O
count	O
density	O
increased	O
;	O
no	O
difference	O
in	O
FPF	O
was	O
found	O
for	O
a	O
change	O
in	O
lesion	O
tracer	O
concentration	O
.	O

Members	O
of	O
the	O
CRE	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CREB	B-GENE
)	O
/	O
activating	B-GENE
transcription	I-GENE
factor	I-GENE
transcription	O
family	O
as	O
well	O
as	O
members	O
of	O
the	O
Jun	B-GENE
/	O
Fos	B-GENE
family	O
have	O
been	O
shown	O
to	O
bind	O
to	O
this	O
sequence	O
.	O

Nature	O
of	O
the	O
thermopower	O
in	O
bipolar	O
semiconductors	O
.	O

Overexpression	O
of	O
SNURF	B-GENE
in	O
cultured	O
mammalian	O
cells	O
enhanced	O
not	O
only	O
androgen	O
,	O
glucocorticoid	O
,	O
and	O
progesterone	B-GENE
receptor	I-GENE
-	O
dependent	O
transactivation	O
but	O
also	O
basal	O
transcription	O
from	O
steroid	O
-	O
regulated	O
promoters	O
.	O

Long	O
-	O
range	O
mapping	O
by	O
pulse	O
-	O
field	O
gel	O
electrophoresis	O
indicated	O
that	O
the	O
three	O
mdr	B-GENE
genes	I-GENE
are	O
closely	O
linked	O
on	O
a	O
genomic	O
DNA	O
segment	O
of	O
approximately	O
625	O
kilobases	O
.	O

Oral	O
basal	O
body	O
temperature	O
(	O
BBT	O
)	O
recordings	O
of	O
46	O
women	O
that	O
conceived	O
by	O
donor	O
insemination	O
and	O
who	O
had	O
midcycle	O
monitoring	O
of	O
luteinising	B-GENE
hormone	I-GENE
(	O
LH	B-GENE
)	O
were	O
analysed	O
to	O
establish	O
features	O
associated	O
with	O
an	O
optimal	O
cycle	O
.	O

At	O
the	O
start	O
of	O
the	O
performance	O
ride	O
,	O
plasma	O
glucose	O
averaged	O
4	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
2	O
,	O
5	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
1	O
,	O
and	O
5	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
2	O
mmol	O
.	O
l	O
-	O
1	O
in	O
CON	O
,	O
CHO	O
-	O
7	O
,	O
and	O
CHO	O
-	O
0	O
/	O
21	O
,	O
respectively	O
(	O
all	O
different	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Adhesion	O
was	O
inhibited	O
by	O
mAbs	O
against	O
the	O
COOH	O
-	O
terminus	O
and	O
central	O
cell	O
binding	O
domains	O
of	O
fibronectin	B-GENE
,	O
as	O
well	O
as	O
by	O
the	O
corresponding	O
CS1	B-GENE
and	O
RGD	B-GENE
peptides	I-GENE
.	O

Usher	O
syndrome	O
1C	O
(	O
USH1C	O
)	O
is	O
a	O
congenital	O
condition	O
manifesting	O
profound	O
hearing	O
loss	O
,	O
the	O
absence	O
of	O
vestibular	O
function	O
,	O
and	O
eventual	O
retinal	O
degeneration	O
.	O

We	O
have	O
determined	O
the	O
complete	O
cDNA	O
sequence	O
of	O
rat	B-GENE
plectin	I-GENE
from	O
a	O
number	O
of	O
well	O
-	O
characterized	O
overlapping	O
lambda	O
gt11	O
clones	O
.	O

Minute	B-GENE
virus	I-GENE
of	I-GENE
mice	I-GENE
NS1	I-GENE
,	O
an	O
83	O
-	O
kDa	O
mainly	O
nuclear	O
phosphoprotein	O
,	O
is	O
the	O
only	O
viral	O
nonstructural	O
protein	O
required	O
in	O
all	O
cell	O
types	O
and	O
it	O
is	O
involved	O
in	O
multiple	O
processes	O
necessary	O
for	O
virus	O
propagation	O
.	O

On	O
the	O
basis	O
of	O
these	O
findings	O
we	O
suggest	O
that	O
the	O
acceptor	O
peptide	O
binds	O
the	O
transferase	O
in	O
a	O
beta	O
-	O
like	O
conformation	O
and	O
that	O
penultimate	O
residue	O
side	O
chain	O
steric	O
interactions	O
may	O
play	O
a	O
role	O
in	O
determining	O
extent	O
that	O
a	O
given	O
Ser	O
or	O
Thr	O
is	O
glycosylated	O
.	O

A	O
higher	O
median	O
proportion	O
of	O
spirochaetes	O
was	O
observed	O
in	O
sites	O
after	O
diagnosis	O
of	O
loss	O
of	O
attachment	O
.	O

Conventional	O
and	O
digital	O
radiography	O
of	O
the	O
heart	O
,	O
aorta	O
,	O
and	O
pulmonary	O
vascularity	O
.	O

Copyright	O
1998	O
Academic	O
Press	O
.	O

Although	O
cDNA	O
encoding	O
a	O
human	B-GENE
phagocyte	I-GENE
formyl	I-GENE
peptide	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
has	O
been	O
reported	O
recently	O
(	O
Boulay	O
,	O
F	O
.	O
,	O
Tardif	O
,	O
M	O
.	O
,	O
Brouchon	O
,	O
L	O
.	O
,	O
and	O
Vignais	O
,	O
P	O
.	O

These	O
results	O
suggest	O
that	O
the	O
PVB	O
therapy	O
is	O
not	O
sufficient	O
to	O
cure	O
the	O
cases	O
with	O
choriocarcinoma	O
element	O
or	O
bulky	O
metastasis	O
.	O

METHODS	O
:	O
A	O
spatial	O
counting	O
approach	O
in	O
which	O
the	O
location	O
of	O
each	O
and	O
every	O
PN	O
and	O
NP	O
in	O
the	O
stratum	O
pyramidale	O
of	O
sectors	O
CA1	O
-	O
4	O
was	O
applied	O
to	O
11	O
normal	O
control	O
(	O
CONs	O
)	O
and	O
10	O
SZs	O
matched	O
for	O
age	O
and	O
postmortem	O
interval	O
,	O
as	O
well	O
as	O
4	O
manic	O
depressive	O
(	O
MD	O
)	O
subjects	O
matched	O
for	O
age	O
.	O

No	O
effect	O
of	O
4	O
beta	O
-	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
was	O
observed	O
on	O
the	O
expression	O
of	O
hnRNP	B-GENE
H	I-GENE
.	O

For	O
large	O
breasts	O
(	O
>	O
70	O
mm	O
)	O
the	O
use	O
of	O
X	O
-	O
ray	O
sets	O
such	O
as	O
the	O
IGE	O
DMR	O
,	O
which	O
automatically	O
select	O
the	O
beam	O
quality	O
for	O
each	O
breast	O
,	O
resulted	O
in	O
lower	O
doses	O
compared	O
with	O
sets	O
using	O
manual	O
tube	O
potential	O
selection	O
.	O

First	O
,	O
ste12Delta	B-GENE
cells	O
differ	O
from	O
cells	O
with	O
disruptions	O
of	O
the	O
upstream	O
signaling	O
elements	O
(	O
e	O
.	O
g	O
.	O
,	O
ste4Delta	B-GENE
,	O
ste20Delta	B-GENE
,	O
ste5Delta	B-GENE
,	O
ste11Delta	B-GENE
,	O
ste7Delta	B-GENE
,	O
or	O
fus3Delta	B-GENE
kss1Delta	B-GENE
cells	O
)	O
in	O
that	O
they	O
clearly	O
retain	O
some	O
capacity	O
for	O
inducing	O
Ste3p	B-GENE
phosphorylation	O
.	O

The	O
Valpha	B-GENE
and	O
Vbeta	B-GENE
domains	I-GENE
have	O
the	O
canonical	O
features	O
of	O
known	O
teleost	B-GENE
and	I-GENE
mammalian	I-GENE
TCR	I-GENE
V	I-GENE
domains	I-GENE
,	O
including	O
conserved	O
residues	O
in	O
the	O
beginning	O
of	O
FR2	B-GENE
and	O
at	O
the	O
end	O
of	O
FR3	B-GENE
.	O

Asthma	O
diagnoses	O
were	O
made	O
according	O
to	O
recommended	O
National	O
Asthma	O
Expert	O
Panel	O
Guidelines	O
.	O

The	O
atpA	B-GENE
reading	O
frame	O
ends	O
with	O
four	O
tandem	O
UGA	O
codons	O
which	O
overlap	O
four	O
tandem	O
AUG	O
codons	O
initiating	O
an	O
unidentified	O
reading	O
frame	O
,	O
orf214	O
.	O

Deletion	O
mutagenesis	O
of	O
the	O
promoter	O
indicated	O
that	O
a	O
positive	O
regulatory	O
element	O
(	O
PRE	O
)	O
was	O
likely	O
to	O
exist	O
downstream	O
of	O
the	O
UL94	B-GENE
mRNA	I-GENE
start	I-GENE
site	I-GENE
,	O
while	O
a	O
negative	O
regulatory	O
element	O
(	O
NRE	O
)	O
was	O
present	O
upstream	O
of	O
the	O
TATA	O
box	O
.	O

An	O
ERp60	B-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
from	O
the	O
filarial	O
parasite	O
Dirofilaria	O
immitis	O
has	O
both	O
transglutaminase	O
and	O
protein	O
disulfide	O
isomerase	O
activity	O
.	O

Fos	B-GENE
/	O
Jun	B-GENE
bound	O
to	O
an	O
unacetylated	O
nucleosome	O
with	O
only	O
a	O
4	O
-	O
to	O
5	O
-	O
fold	O
reduction	O
in	O
DNA	O
binding	O
affinity	O
compared	O
with	O
naked	O
DNA	O
.	O

Pediatric	O
patients	O
-	O
-	O
handle	O
with	O
care	O
.	O

K	O
.	O

The	O
extent	O
of	O
myocardial	O
ischemia	O
in	O
the	O
coronary	O
sinus	O
study	O
was	O
significantly	O
correlated	O
to	O
the	O
coronary	O
diameters	O
of	O
the	O
proximal	O
and	O
middle	O
segments	O
of	O
the	O
Ramus	O
interventricularis	O
anterior	O
and	O
the	O
middle	O
segment	O
of	O
the	O
Ramus	O
circumflexus	O
(	O
r	O
=	O
0	O
.	O
87	O
,	O
p	O
<	O
0	O
.	O
02	O
)	O
.	O

S1	B-GENE
nuclease	I-GENE
analysis	O
of	O
the	O
RNA	O
from	O
a	O
number	O
of	O
QT6	O
-	O
LD	O
clones	O
gave	O
similar	O
results	O
,	O
indicating	O
that	O
the	O
LD	O
population	O
was	O
composed	O
of	O
viruses	O
with	O
similar	O
but	O
not	O
identical	O
deletion	O
endpoints	O
.	O

The	O
prevalence	O
of	O
ocular	O
/	O
adnexal	O
SCC	O
was	O
significantly	O
greater	O
for	O
all	O
hair	O
colors	O
when	O
compared	O
with	O
bay	O
,	O
brown	O
,	O
or	O
black	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

ZNS	O
,	O
in	O
the	O
mmolar	O
range	O
,	O
scavenged	O
hydroxyl	O
and	O
nitric	O
oxide	O
radicals	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

Murine	B-GENE
ELAM	I-GENE
-	I-GENE
1	I-GENE
is	O
encoded	O
by	O
a	O
single	O
-	O
copy	O
gene	O
,	O
spanning	O
about	O
13	O
kb	O
,	O
which	O
is	O
structurally	O
organized	O
into	O
14	O
exons	O
and	O
13	O
introns	O
;	O
very	O
similar	O
to	O
that	O
of	O
its	O
human	O
counterpart	O
.	O

The	O
three	O
more	O
slower	O
migrating	O
Stat5B	B-GENE
bands	O
observed	O
in	O
response	O
to	O
GH	B-GENE
contain	O
phosphorylated	O
tyrosyl	O
residues	O
.	O

Protection	O
levels	O
of	O
33	O
.	O
3	O
%	O
,	O
36	O
.	O
6	O
%	O
and	O
37	O
.	O
0	O
%	O
were	O
achieved	O
in	O
groups	O
which	O
had	O
received	O
,	O
respectively	O
,	O
1000	O
20	O
-	O
krad	O
cercariae	O
,	O
1000	O
10	O
-	O
krad	O
cercariae	O
,	O
2000	O
40	O
-	O
krad	O
cercariae	O
and	O
2000	O
60	O
-	O
krad	O
cercariae	O
.	O

During	O
the	O
1st	O
week	O
of	O
treatment	O
all	O
subjects	O
received	O
either	O
mianserin	O
30	O
mg	O
or	O
clomipramine	O
75	O
mg	O
once	O
daily	O
.	O

EMBO	O
(	O
Eur	O
.	O

When	O
stratifying	O
FLM	O
values	O
<	O
34	O
and	O
>	O
34	O
wks	O
'	O
gestation	O
,	O
again	O
no	O
difference	O
was	O
found	O
in	O
mean	O
difference	O
of	O
L	O
/	O
S	O
and	O
LB	O
before	O
and	O
after	O
34	O
wks	O
.	O

Are	O
there	O
any	O
lessons	O
to	O
be	O
learnt	O
?	O

The	O
other	O
five	O
from	O
within	O
the	O
SRO	O
may	O
provide	O
an	O
entrance	O
point	O
for	O
the	O
cloning	O
of	O
candidate	O
genes	O
for	O
neuroblastoma	O
.	O

Three	O
distinct	O
human	B-GENE
HDACs	I-GENE
are	O
homologous	O
to	O
RPD3	B-GENE
,	O
a	O
yeast	O
transcriptional	O
regulator	O
.	O

The	O
longest	O
cDNA	O
insert	O
identified	O
was	O
2	O
.	O
2	O
kb	O
and	O
encoded	O
the	O
entire	O
462	O
-	O
amino	O
acid	O
open	O
reading	O
frame	O
of	O
rat	B-GENE
CgA	I-GENE
including	O
an	O
18	O
-	O
amino	O
acid	O
hydrophobic	O
signal	O
peptide	O
.	O

The	O
vaccine	O
was	O
at	O
least	O
80	O
%	O
efficacious	O
against	O
Chlamydia	O
and	O
Campylobacter	O
spp	O
and	O
appeared	O
to	O
be	O
protective	O
.	O

The	O
RPC31	B-GENE
gene	I-GENE
encoding	O
the	O
C31	B-GENE
subunit	I-GENE
of	I-GENE
Saccharomyces	I-GENE
cerevisiae	I-GENE
RNA	I-GENE
polymerase	I-GENE
C	I-GENE
(	I-GENE
III	I-GENE
)	I-GENE
has	O
been	O
isolated	O
,	O
starting	O
from	O
a	O
C	O
-	O
terminal	O
fragment	O
cloned	O
on	O
a	O
lambda	O
gt11	O
library	O
.	O

Slowly	O
adapting	O
type	O
I	O
mechanoreceptor	O
discharge	O
as	O
a	O
function	O
of	O
dynamic	O
force	O
versus	O
dynamic	O
displacement	O
of	O
glabrous	O
skin	O
of	O
raccoon	O
and	O
squirrel	O
monkey	O
hand	O
.	O

The	O
goal	O
of	O
this	O
investigation	O
was	O
to	O
determine	O
whether	O
BMIPP	O
uptake	O
can	O
be	O
used	O
to	O
differentiate	O
viable	O
myocardium	O
from	O
scar	O
tissue	O
soon	O
after	O
coronary	O
thrombolysis	O
for	O
acute	O
myocardial	O
infarction	O
.	O

The	O
same	O
slice	O
was	O
imaged	O
three	O
times	O
each	O
with	O
sequences	O
using	O
spatial	O
presaturation	O
or	O
not	O
.	O

IRIS	B-GENE
/	O
GAS	B-GENE
DNA	O
also	O
formed	O
a	O
number	O
of	O
specific	O
complexes	O
with	O
constitutively	O
expressed	O
factors	O
,	O
none	O
of	O
which	O
were	O
affected	O
by	O
the	O
above	O
Abs	O
.	O

Making	O
sense	O
out	O
of	O
oxygen	O
sensor	O
.	O

Recovery	O
rates	O
of	O
energy	O
level	O
and	O
intracellular	O
pH	O
during	O
stimulation	O
at	O
100Hz	O
were	O
greater	O
than	O
those	O
observed	O
during	O
stimulation	O
at	O
30Hz	O
.	O

The	O
Zn	B-GENE
-	I-GENE
15	I-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
domain	I-GENE
comprises	O
three	O
zinc	O
fingers	O
separated	O
by	O
unusually	O
long	O
linker	O
sequences	O
that	O
would	O
be	O
expected	O
to	O
interrupt	O
specific	O
DNA	O
site	O
recognition	O
.	O

The	O
data	O
obtained	O
included	O
1	O
)	O
the	O
mean	O
frequency	O
of	O
abnormal	O
teased	O
myelinated	O
fibers	O
and	O
its	O
upper	O
limit	O
value	O
of	O
95	O
%	O
confidence	O
interval	O
,	O
and	O
2	O
)	O
the	O
mean	O
densities	O
of	O
total	O
,	O
large	O
and	O
small	O
myelinated	O
fibers	O
and	O
of	O
unmyelinated	O
fibers	O
and	O
their	O
lower	O
limit	O
value	O
of	O
95	O
%	O
confidence	O
interval	O
for	O
each	O
decade	O
.	O

The	O
yield	O
of	O
endocervical	O
cells	O
and	O
the	O
incidence	O
of	O
dysplasia	O
was	O
determined	O
for	O
both	O
the	O
prenatal	O
and	O
the	O
postpartum	O
Pap	O
smears	O
performed	O
for	O
this	O
group	O
of	O
patients	O
.	O

Others	O
as	O
for	O
example	O
C	O
-	O
11	O
labeled	O
short	O
chain	O
fatty	O
acids	O
are	O
on	O
the	O
horizon	O
.	O

We	O
conclude	O
that	O
the	O
BR	B-GENE
-	I-GENE
C	I-GENE
early	I-GENE
gene	I-GENE
directly	O
activates	O
late	B-GENE
gene	I-GENE
transcription	O
by	O
interacting	O
with	O
late	B-GENE
gene	I-GENE
cis	O
-	O
acting	O
regulatory	O
elements	O
and	O
that	O
this	O
interaction	O
is	O
responsible	O
for	O
the	O
temporal	O
linkage	O
of	O
early	O
and	O
late	O
ecdysone	O
-	O
induced	O
gene	O
expression	O
.	O

Exogenous	O
heart	O
stress	O
raised	O
log	O
circulating	O
NE	O
concentration	O
in	O
proportion	O
to	O
the	O
rise	O
in	O
heart	O
rate	O
at	O
a	O
given	O
work	O
load	O
so	O
that	O
the	O
usual	O
relationship	O
between	O
these	O
variables	O
,	O
previously	O
observed	O
during	O
other	O
stresses	O
,	O
was	O
preserved	O
.	O

We	O
tested	O
the	O
hypothesis	O
that	O
PEH	O
is	O
associated	O
with	O
reductions	O
in	O
TPR	O
and	O
sympathetic	O
nerve	O
activity	O
(	O
SNA	O
)	O
.	O

A	O
short	O
conserved	O
motif	O
is	O
required	O
for	O
repressor	O
domain	O
function	O
in	O
the	O
myeloid	O
-	O
specific	O
transcription	O
factor	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
epsilon	I-GENE
.	O

Purified	O
fER	B-GENE
exhibited	O
a	O
distribution	O
constant	O
(	O
KD	O
)	O
for	O
17	O
beta	O
-	O
estradiol	O
of	O
0	O
.	O
45	O
nM	O
.	O

However	O
,	O
strains	O
in	O
which	O
both	O
of	O
the	O
two	O
most	O
highly	O
related	O
genes	O
,	O
DdPIK1	B-GENE
and	O
DdPIK2	B-GENE
,	O
were	O
disrupted	O
showed	O
both	O
growth	O
and	O
developmental	O
defects	O
,	O
while	O
double	O
knockouts	O
of	O
DdPIK1	B-GENE
and	O
DdPIK3	B-GENE
and	O
DdPIK2	B-GENE
and	O
DdPIK3	B-GENE
appear	O
to	O
be	O
lethal	O
.	O

The	O
exon	O
sequences	O
determined	O
from	O
genomic	O
DNA	O
sequencing	O
showed	O
some	O
differences	O
when	O
compared	O
to	O
the	O
published	O
rat	B-GENE
GLUT2	I-GENE
cDNA	I-GENE
.	O

48	O
.	O
35	O
+	O
/	O
-	O
5	O
.	O
07	O
mg	O
/	O
l	O
in	O
R3	O
;	O
p	O
<	O
0	O
.	O
05	O
)	O
and	O
in	O
the	O
AUC	O
(	O
0	O
.	O
50	O
h	O
)	O
(	O
1429	O
.	O
92	O
+	O
/	O
-	O
284	O
.	O
23	O
in	O
PR	O
vs	O
.	O

This	O
integration	O
results	O
in	O
the	O
production	O
of	O
MMTV	B-GENE
/	I-GENE
mdr3	I-GENE
fusion	I-GENE
transcripts	I-GENE
that	O
originate	O
from	O
the	O
antisense	O
5	B-GENE
'	I-GENE
LTR	I-GENE
of	O
the	O
provirus	O
.	O

This	O
surface	O
in	O
specimens	O
from	O
unfertilized	O
eggs	O
is	O
almost	O
flat	O
.	O

Following	O
40	O
min	O
"	O
ischemia	O
"	O
,	O
preparations	O
treated	O
with	O
PC	O
recovered	O
from	O
transmural	O
conduction	O
block	O
more	O
rapidly	O
(	O
PC1	O
group	O
,	O
4	O
min	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
;	O
PC2	O
group	O
,	O
23	O
min	O
,	O
ns	O
)	O
,	O
compared	O
to	O
control	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

These	O
results	O
are	O
discussed	O
in	O
the	O
context	O
of	O
a	O
model	O
of	O
the	O
myogenic	O
lineage	O
that	O
is	O
based	O
on	O
the	O
expression	O
of	O
desmin	B-GENE
.	O

Characterization	O
of	O
a	O
DEAD	B-GENE
box	I-GENE
ATPase	I-GENE
/	O
RNA	B-GENE
helicase	I-GENE
protein	O
of	O
Arabidopsis	O
thaliana	O
.	O

The	O
host	O
range	O
(	O
HR	O
)	O
of	O
poliovirus	O
is	O
thought	O
to	O
be	O
primarily	O
determined	O
by	O
a	O
cell	O
surface	O
molecule	O
that	O
functions	O
as	O
poliovirus	B-GENE
receptor	I-GENE
(	O
PVR	B-GENE
)	O
,	O
since	O
it	O
has	O
been	O
shown	O
that	O
transgenic	O
mice	O
are	O
made	O
poliovirus	O
sensitive	O
by	O
introducing	O
the	O
human	B-GENE
PVR	I-GENE
gene	I-GENE
into	O
the	O
genome	O
.	O

In	O
this	O
paper	O
,	O
the	O
authors	O
used	O
measured	O
weight	O
for	O
1	O
,	O
259	O
white	O
women	O
aged	O
65	O
-	O
74	O
years	O
from	O
the	O
Epidemiologic	O
Follow	O
-	O
up	O
Study	O
of	O
the	O
First	O
National	O
Health	O
and	O
Nutrition	O
Examination	O
Survey	O
to	O
examine	O
the	O
effect	O
of	O
overweight	O
on	O
coronary	O
heart	O
disease	O
incidence	O
(	O
mean	O
length	O
of	O
follow	O
-	O
up	O
,	O
14	O
years	O
)	O
.	O

In	O
contrast	O
to	O
the	O
reciprocal	O
effects	O
of	O
Gab1	B-GENE
and	O
Gab2	B-GENE
in	O
mediating	O
Elk	B-GENE
-	I-GENE
1	I-GENE
induction	O
,	O
these	O
two	O
molecules	O
have	O
a	O
similar	O
function	O
in	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
activation	O
induced	O
by	O
either	O
oncogenic	O
Ras	B-GENE
or	O
growth	O
factor	O
stimulation	O
.	O

We	O
were	O
able	O
to	O
demonstrate	O
a	O
significant	O
statistical	O
interaction	O
effect	O
between	O
gender	O
and	O
globulin	B-GENE
protein	I-GENE
concentration	O
on	O
Vu	O
(	O
p	O
=	O
0	O
.	O
022	O
)	O
.	O

The	O
NS	B-GENE
-	I-GENE
2	I-GENE
isoforms	I-GENE
were	O
resolved	O
at	O
a	O
pI	O
value	O
close	O
to	O
5	O
.	O
5	O
as	O
three	O
groups	O
of	O
unevenly	O
phosphorylated	O
polypeptides	O
,	O
each	O
composed	O
of	O
at	O
least	O
two	O
protein	O
species	O
.	O

Effect	O
of	O
isobarin	O
on	O
electrocardiographic	O
indices	O
in	O
hypertensive	O
disease	O

The	O
column	O
densities	O
of	O
frozen	O
molecular	O
hydrogen	O
and	O
methanol	O
are	O
inferred	O
to	O
be	O
about	O
2	O
.	O
5	O
x	O
10	O
(	O
18	O
)	O
and	O
3	O
.	O
0	O
x	O
10	O
(	O
19	O
)	O
,	O
respectively	O
.	O

TAAG	O
sites	O
that	O
serve	O
as	O
functional	O
late	O
promoters	O
in	O
OpMNPV	O
were	O
found	O
to	O
mediate	O
transcription	O
initiation	O
at	O
only	O
basal	O
levels	O
in	O
the	O
context	O
of	O
the	O
AcMNPV	O
genome	O
,	O
suggesting	O
that	O
late	O
promoter	O
activation	O
may	O
be	O
virus	O
specific	O
within	O
the	O
family	O
Baculoviridae	O
.	O

The	O
carboxyl	O
globular	O
domain	O
was	O
found	O
to	O
be	O
encoded	O
by	O
six	O
exons	O
which	O
appear	O
to	O
delineate	O
its	O
structural	O
subdomains	O
.	O

In	O
3	O
of	O
the	O
5	O
patients	O
with	O
AVNRT	O
and	O
AJR	O
,	O
junctional	O
beats	O
served	O
as	O
a	O
trigger	O
for	O
reentry	O
.	O

Fus3p	B-GENE
and	O
Kss1p	B-GENE
together	O
increase	O
the	O
expression	O
of	O
CLN3	B-GENE
and	O
PCL2	B-GENE
genes	I-GENE
that	O
promote	O
budding	O
,	O
and	O
Kss1p	B-GENE
inhibits	O
the	O
MAP	B-GENE
kinase	I-GENE
cascade	O
.	O

Measurement	O
of	O
the	O
spectral	O
sensitivity	O
and	O
the	O
ERG	O
can	O
thus	O
help	O
in	O
the	O
diagnosis	O
of	O
these	O
three	O
hereditary	O
diseases	O
.	O

On	O
both	O
indocyanine	O
green	O
video	O
and	O
fluorescein	O
angiography	O
,	O
hypofluorescent	O
lesions	O
were	O
almost	O
the	O
same	O
size	O
as	O
the	O
light	O
yellow	O
area	O
and	O
the	O
dark	O
yellow	O
center	O
of	O
a	O
placoid	O
lesion	O
.	O

Other	O
similar	O
patients	O
must	O
be	O
found	O
before	O
it	O
is	O
established	O
that	O
the	O
colloid	O
cyst	O
is	O
part	O
of	O
the	O
nevoid	O
basal	O
cell	O
carcinoma	O
syndrome	O
.	O

Coexpression	O
of	O
C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
altered	O
the	O
cell	O
specificity	O
.	O

Dominant	O
-	O
negative	O
mutations	O
in	O
the	O
G	B-GENE
-	I-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
alpha	I-GENE
-	I-GENE
factor	I-GENE
receptor	I-GENE
map	O
to	O
the	O
extracellular	O
ends	O
of	O
the	O
transmembrane	O
segments	O
.	O

Possibility	O
of	O
using	O
gynecologic	O
nurses	O
in	O
the	O
independently	O
administered	O
health	O
centers	O

Platelet	O
count	O
and	O
plasma	O
volume	O
were	O
significantly	O
higher	O
in	O
group	O
A	O
than	O
in	O
group	O
B	O
throughout	O
pregnancy	O
.	O

The	O
complexity	O
of	O
some	O
of	O
the	O
reports	O
of	O
VACURG	O
studies	O
has	O
led	O
some	O
to	O
believe	O
that	O
this	O
group	O
was	O
opposed	O
to	O
estrogens	O
,	O
but	O
that	O
is	O
not	O
true	O
.	O

This	O
increase	O
is	O
not	O
the	O
result	O
of	O
alterations	O
in	O
the	O
deposition	O
of	O
inhaled	O
particles	O
of	O
capsaicin	O
brought	O
about	O
by	O
volume	O
restriction	O
.	O

Mycobacterium	O
tuberculosis	O
inhibits	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
transcriptional	O
responses	O
without	O
inhibiting	O
activation	O
of	O
STAT1	B-GENE
.	O

Pituitary	O
thyrotropic	O
adenoma	O
associated	O
with	O
congenital	O
hypothyroidism	O
.	O

Upstream	O
of	O
the	O
afa	B-GENE
-	I-GENE
3	I-GENE
gene	I-GENE
cluster	I-GENE
,	O
a	O
1	O
.	O
2	O
-	O
kb	O
region	O
was	O
found	O
to	O
be	O
96	O
%	O
identical	O
to	O
the	O
RepFIB	B-GENE
sequence	I-GENE
of	O
one	O
of	O
the	O
enterotoxigenic	O
E	O
.	O
coli	O
plasmids	O
(	O
P307	O
)	O
,	O
suggesting	O
a	O
common	O
ancestor	O
plasmid	O
.	O

Maintenance	O
metabolizable	O
-	O
energy	O
(	O
ME	O
)	O
requirement	O
averaged	O
31	O
.	O
0	O
kcal	O
/	O
kg	O
body	O
wt	O
.	O

Interferon	B-GENE
-	I-GENE
alpha	I-GENE
inducibility	O
of	O
IFI16	B-GENE
may	O
be	O
regulated	O
by	O
an	O
interferon	B-GENE
-	I-GENE
alpha	I-GENE
/	I-GENE
beta	I-GENE
-	O
stimulated	O
response	O
consensus	O
element	O
in	O
the	O
5	O
'	O
UT	O
exon	O
,	O
as	O
a	O
similar	O
motif	O
is	O
conserved	O
in	O
the	O
corresponding	O
position	O
in	O
the	O
related	O
myeloid	B-GENE
cell	I-GENE
nuclear	I-GENE
differentiation	I-GENE
antigen	I-GENE
gene	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

The	O
secondary	O
end	O
points	O
included	O
creatine	B-GENE
kinase	I-GENE
peak	O
,	O
ventricular	O
fibrillation	O
/	O
tachycardia	O
within	O
the	O
first	O
24	O
hours	O
,	O
death	O
and	O
congestive	O
heart	O
failure	O
within	O
the	O
30	O
-	O
day	O
follow	O
-	O
up	O
,	O
and	O
30	O
-	O
day	O
left	O
ventricular	O
ejection	O
fraction	O
.	O

For	O
the	O
population	O
of	O
patients	O
with	O
melanoma	O
levels	O
III	O
and	O
IV	O
significant	O
differences	O
in	O
survival	O
rate	O
were	O
associated	O
with	O
thickness	O
(	O
less	O
than	O
2	O
mm	O
or	O
greater	O
than	O
or	O
equal	O
to	O
2	O
mm	O
;	O
p	O
less	O
than	O
0	O
,	O
001	O
)	O
,	O
though	O
not	O
with	O
level	O
.	O

Here	O
we	O
show	O
that	O
the	O
sck1	B-GENE
gene	I-GENE
,	O
cloned	O
as	O
a	O
high	O
copy	O
number	O
suppressor	O
of	O
a	O
mutation	O
in	O
git3	B-GENE
,	O
is	O
able	O
to	O
suppress	O
the	O
defects	O
conferred	O
by	O
a	O
mutation	O
in	O
any	O
of	O
these	O
git	B-GENE
genes	I-GENE
.	O

The	O
contribution	O
of	O
reviewers	O
and	O
editors	O
to	O
the	O
scientific	O
work	O
of	O
the	O
authors	O

Comparisons	O
of	O
defective	O
HTLV	O
-	O
I	O
proviruses	O
predict	O
the	O
mode	O
of	O
origin	O
and	O
coding	O
potential	O
of	O
internally	O
deleted	O
genomes	O
.	O

When	O
proper	O
controls	O
were	O
used	O
,	O
the	O
psychophysical	O
data	O
and	O
computer	O
simulation	O
gave	O
remarkably	O
comparable	O
results	O
.	O

Results	O
of	O
these	O
in	O
vitro	O
studies	O
may	O
be	O
relevant	O
to	O
the	O
pathogenesis	O
of	O
alveolitis	O
in	O
organic	O
dust	O
-	O
induced	O
lung	O
diseases	O
.	O

However	O
,	O
the	O
in	O
vivo	O
attachment	O
strength	O
of	O
the	O
CSTi	O
-	O
2	O
coating	O
was	O
comparable	O
both	O
to	O
CSTi	O
-	O
1	O
and	O
to	O
an	O
HA	O
-	O
coated	O
control	O
after	O
8	O
weeks	O
.	O

The	O
phosphoprotein	B-GENE
pUL69	I-GENE
of	O
human	O
cytomegalovirus	O
(	O
HCMV	O
)	O
,	O
which	O
is	O
a	O
herpesvirus	O
of	O
considerable	O
medical	O
importance	O
in	O
immunosuppressed	O
patients	O
and	O
newborns	O
,	O
has	O
previously	O
been	O
identified	O
as	O
an	O
early	B-GENE
-	I-GENE
late	I-GENE
viral	I-GENE
protein	I-GENE
that	O
can	O
stimulate	O
several	O
viral	O
and	O
cellular	O
promoters	O
and	O
thus	O
exerts	O
a	O
rather	O
broad	O
activation	O
pattern	O
.	O

Effects	O
of	O
acute	O
exposure	O
to	O
cold	O
on	O
pulmonary	O
arterial	O
blood	O
pressure	O
in	O
awake	O
rats	O
.	O

RNase	B-GENE
protection	O
analysis	O
reveals	O
a	O
10	O
-	O
fold	O
increase	O
in	O
the	O
expression	O
of	O
SCD2	B-GENE
mRNA	I-GENE
during	O
3T3	O
-	O
L1	O
preadipocyte	O
differentiation	O
.	O

Spontaneous	O
fracture	O
of	O
the	O
tarsal	O
bone	O
in	O
2	O
cases	O
of	O
leprosy	O

CERIP	B-GENE
interaction	O
.	O

The	O
response	O
sequences	O
were	O
localized	O
between	O
-	O
67	O
and	O
+	O
30	O
in	O
the	O
simian	O
cytomegalovirus	O
IE94	B-GENE
promoter	I-GENE
and	O
upstream	O
of	O
position	O
+	O
9	O
in	O
the	O
HCMV	B-GENE
IE68	I-GENE
promoter	I-GENE
.	O

The	O
expression	O
of	O
Scmh1	B-GENE
and	O
rae28	B-GENE
/	O
mph1	B-GENE
is	O
well	O
correlated	O
in	O
most	O
tissues	O
of	O
embryos	O
.	O

Our	O
results	O
suggest	O
that	O
it	O
might	O
be	O
possible	O
to	O
augment	O
IN	B-GENE
function	O
in	O
vivo	O
through	O
a	O
heterologous	O
domain	O
.	O

Retinoic	O
acid	O
,	O
which	O
inhibits	O
the	O
progression	O
of	O
certain	O
cancers	O
,	O
repressed	O
v	B-GENE
-	I-GENE
src	I-GENE
-	O
induced	O
MMP	B-GENE
-	I-GENE
1	I-GENE
transcription	O
.	O

Untransformed	O
3T3	O
cells	O
carry	O
abundant	O
1	O
.	O
9	O
kb	O
Hox	B-GENE
1	I-GENE
.	I-GENE
3	I-GENE
RNA	O
,	O
whereas	O
the	O
methylcholanthrene	O
-	O
transformed	O
MB66	O
and	O
LTK	O
-	O
cells	O
or	O
3T3	O
cells	O
transformed	O
by	O
the	O
oncogenes	O
src	B-GENE
,	O
fos	B-GENE
or	O
SV40	B-GENE
T	I-GENE
antigen	I-GENE
express	O
only	O
low	O
levels	O
.	O

Furthermore	O
,	O
it	O
is	O
also	O
established	O
that	O
serine	O
phosphorylation	O
of	O
STAT5a	B-GENE
transactivation	O
domain	O
,	O
via	O
the	O
MAPK	B-GENE
pathway	O
,	O
is	O
a	O
means	O
of	O
modifying	O
GH	B-GENE
-	O
induced	O
transcriptional	O
activation	O
.	O

Prevention	O
of	O
gravid	O
Rhesus	O
isoimmunization	O

Expression	O
of	O
medical	O
efficiency	O
by	O
integration	O
indicators	O
with	O
the	O
rational	O
utilization	O
of	O
budgeted	O
funds	O

We	O
infer	O
that	O
RecA	B-GENE
-	O
mediated	O
cleavage	O
of	O
UmuD	B-GENE
is	O
another	O
role	O
for	O
RecA	B-GENE
in	O
SOS	O
mutagenesis	O
,	O
probably	O
activating	O
UmuD	B-GENE
for	O
its	O
mutagenic	O
function	O
.	O

Blood	O
pressure	O
was	O
controlled	O
long	O
term	O
(	O
with	O
/	O
without	O
diuretics	O
/	O
beta	B-GENE
-	I-GENE
adrenoreceptor	I-GENE
blocking	O
drugs	O
)	O
in	O
sixteen	O
out	O
of	O
nineteen	O
patients	O
with	O
mild	O
-	O
moderate	O
hypertension	O
.	O

METHODS	O
:	O
Autocapture	O
devices	O
(	O
Pacesetter	O
Microny	O
SR	O
+	O
/	O
-	O
and	O
Regency	O
SR	O
+	O
/	O
-	O
;	O
Pacesetter	O
,	O
Solna	O
,	O
Sweden	O
)	O
and	O
steroid	O
-	O
eluting	O
epicardial	O
pacing	O
leads	O
(	O
Medtronic	O
CapSure	O
Epi	O
10366	O
;	O
Medtronic	O
,	O
Inc	O
,	O
Minneapolis	O
,	O
MN	O
)	O
were	O
implanted	O
in	O
14	O
children	O
.	O

This	O
may	O
be	O
another	O
example	O
of	O
the	O
principle	O
-	O
-	O
less	O
is	O
more	O
.	O

The	O
predicted	O
amino	O
-	O
acid	O
sequence	O
includes	O
an	O
N	O
-	O
terminal	O
signal	O
sequence	O
of	O
27	O
amino	O
acids	O
,	O
a	O
27	O
amino	O
-	O
acid	O
pro	O
-	O
region	O
,	O
a	O
251	O
amino	O
-	O
acid	O
catalytic	O
domain	O
typical	O
of	O
a	O
serine	B-GENE
protease	I-GENE
with	O
trypsin	B-GENE
-	O
like	O
specificity	O
,	O
and	O
a	O
C	O
-	O
terminal	O
hydrophobic	O
extension	O
which	O
is	O
predicted	O
to	O
function	O
as	O
a	O
membrane	O
anchor	O
.	O

Effects	O
of	O
negative	O
pi	O
mesons	O
on	O
mouse	O
bone	O
marrow	O
cells	O
.	O

Phenotypic	O
and	O
molecular	O
analyses	O
of	O
patients	O
with	O
partial	O
chromosome	O
21	O
monosomy	O
enabled	O
us	O
to	O
define	O
a	O
region	O
,	O
spanning	O
2	O
.	O
4	O
Mb	O
between	O
D21S190	B-GENE
and	O
D21S226	B-GENE
,	O
associated	O
with	O
arthrogryposis	O
,	O
mental	O
retardation	O
,	O
hypertonia	O
,	O
and	O
several	O
facial	O
anomalies	O
.	O

Relation	O
between	O
circulating	O
immune	O
complexes	O
and	O
serum	B-GENE
ferritin	I-GENE
in	O
hemosiderosis	O
of	O
different	O
etiologies	O

The	O
zinc	B-GENE
finger	I-GENE
protein	I-GENE
A20	I-GENE
is	O
a	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
(	O
TNF	B-GENE
)	O
-	O
and	O
interleukin	B-GENE
1	I-GENE
(	O
IL	B-GENE
-	I-GENE
1	I-GENE
)	O
-	O
inducible	O
protein	O
that	O
negatively	O
regulates	O
nuclear	B-GENE
factor	I-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
(	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
)	O
-	O
dependent	O
gene	O
expression	O
.	O

The	O
determination	O
of	O
antithrombin	B-GENE
III	I-GENE
(	O
AT	B-GENE
III	I-GENE
)	O
and	O
its	O
clinical	O
significance	O

Treatments	O
were	O
two	O
adrenocorticotrophin	B-GENE
(	O
ACTH	B-GENE
)	O
preparations	O
given	O
intramuscularly	O
at	O
2	O
.	O
2	O
U	O
/	O
kg	O
,	O
one	O
of	O
the	O
ACTH	B-GENE
preparations	O
given	O
intramuscularly	O
at	O
1	O
U	O
/	O
kg	O
and	O
a	O
synthetic	O
polypeptide	O
with	O
ACTH	B-GENE
-	I-GENE
like	I-GENE
activity	O
(	O
tetracosactrin	O
,	O
cosyntropin	O
)	O
given	O
intravenously	O
at	O
5	O
micrograms	O
/	O
kg	O
.	O

The	O
deviation	O
site	O
is	O
equivalent	O
to	O
the	O
exon	O
1	O
/	O
exon	O
2	O
splice	O
site	O
of	O
the	O
mouse	O
C	O
-	O
subunit	O
.	O

The	O
liver	O
-	O
specific	O
sequence	O
contains	O
unique	O
consensus	O
sites	O
for	O
phosphorylation	O
by	O
cyclic	B-GENE
AMP	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
and	O
by	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
.	O

Seizure	O
recurrence	O
(	O
HR	O
1	O
.	O
30	O
;	O
95	O
%	O
CI	O
=	O
0	O
.	O
84	O
,	O
2	O
.	O
01	O
)	O
and	O
antiepileptic	O
drug	O
treatment	O
(	O
HR	O
0	O
.	O
97	O
;	O
95	O
%	O
CI	O
=	O
0	O
.	O
67	O
,	O
1	O
.	O
38	O
)	O
did	O
not	O
influence	O
mortality	O
rate	O
.	O

All	O
patients	O
whose	O
PSA	B-GENE
levels	O
reached	O
0	O
.	O
1	O
ng	O
.	O
/	O
ml	O
.	O

The	O
(	O
0	O
0	O
2	O
)	O
diffraction	O
of	O
the	O
synthesized	O
HAp	O
crystals	O
on	O
a	O
Col	O
fiber	O
showed	O
an	O
around	O
60	O
arching	O
angle	O
,	O
while	O
that	O
on	O
a	O
ChS	O
fiber	O
showed	O
just	O
around	O
10	O
degrees	O
.	O

Fas	B-GENE
(	O
APO	B-GENE
-	I-GENE
1	I-GENE
/	O
CD95	B-GENE
)	O
,	O
which	O
is	O
a	O
member	O
of	O
the	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
receptor	I-GENE
superfamily	I-GENE
,	O
is	O
a	O
cell	O
surface	O
receptor	O
that	O
induces	O
apoptosis	O
.	O

Soft	O
independent	O
modelling	O
of	O
class	O
analogy	O
(	O
SIMCA	O
)	O
is	O
applied	O
to	O
identify	O
near	O
-	O
infrared	O
(	O
NIR	O
)	O
spectra	O
of	O
ten	O
excipients	O
used	O
in	O
the	O
pharmaceutical	O
industry	O
.	O

Mutations	O
of	O
SIN4	B-GENE
,	O
ROX3	B-GENE
,	O
SRB8	B-GENE
,	O
SRB9	B-GENE
,	O
SRB10	B-GENE
,	O
SRB11	B-GENE
,	O
and	O
two	O
novel	O
genes	O
,	O
NUT1	B-GENE
and	O
NUT2	B-GENE
,	O
relieve	O
the	O
requirement	O
of	O
Swi4p	B-GENE
for	O
expression	O
of	O
this	O
reporter	O
.	O

The	O
IB2	B-GENE
gene	I-GENE
(	O
HGMW	O
-	O
approved	O
symbol	O
MAPK8IP2	B-GENE
)	O
maps	O
to	O
human	O
chromosome	O
22q13	O
and	O
contains	O
10	O
coding	O
exons	O
.	O

Implantation	O
is	O
contraindicated	O
for	O
severe	O
dysplasia	O
of	O
the	O
cochlea	O
and	O
for	O
the	O
recently	O
described	O
variety	O
of	O
x	O
-	O
linked	O
deafness	O
with	O
deficient	O
bone	O
at	O
the	O
fundus	O
of	O
the	O
internal	O
auditory	O
meatus	O
.	O

The	O
RsmA	B-GENE
-	I-GENE
mutant	I-GENE
,	O
like	O
its	O
parent	O
,	O
produces	O
N	O
-	O
(	O
3	O
-	O
oxohexanoyl	O
)	O
-	O
L	O
-	O
homoserine	O
lactone	O
(	O
HSL	O
)	O
,	O
a	O
starvation	O
/	O
cell	O
density	O
-	O
sensing	O
signal	O
required	O
for	O
extracellular	O
enzyme	O
production	O
.	O

The	O
101st	O
annual	O
meeting	O
of	O
the	O
Japanese	O
Ophthalmological	O
Society	O
.	O

The	O
other	O
end	O
of	O
this	O
cluster	O
contained	O
the	O
human	B-GENE
type	I-GENE
I	I-GENE
cytokeratin	I-GENE
K20	B-GENE
and	O
K12	B-GENE
gene	I-GENE
loci	O
.	O

In	O
patients	O
in	O
which	O
these	O
criteria	O
were	O
not	O
met	O
only	O
the	O
reproducibility	O
of	O
the	O
VO2	O
obtained	O
in	O
both	O
the	O
P	O
-	O
MET	O
and	O
the	O
C	O
-	O
MET	O
indicated	O
that	O
the	O
maximal	O
VO2	O
for	O
these	O
4	O
patients	O
had	O
been	O
reached	O
.	O

In	O
the	O
case	O
of	O
the	O
pT181	O
plasmid	O
,	O
inactivation	O
of	O
the	O
initiator	B-GENE
RepC	I-GENE
protein	I-GENE
occurs	O
by	O
the	O
attachment	O
of	O
an	O
oligonucleotide	O
to	O
its	O
active	O
tyrosine	O
residue	O
.	O

We	O
found	O
multiple	O
transcription	O
start	O
sites	O
located	O
within	O
a	O
15	O
-	O
base	O
pair	O
region	O
,	O
205	O
base	O
pairs	O
upstream	O
of	O
the	O
translation	O
start	O
codon	O
.	O

Overexpression	O
of	O
either	O
Sp1	B-GENE
or	O
phosphorylated	B-GENE
CREB	I-GENE
transactivated	O
the	O
mCgA	B-GENE
promoter	I-GENE
dose	O
dependently	O
,	O
while	O
coexpression	O
of	O
both	O
transcription	O
factors	O
resulted	O
in	O
an	O
additive	O
mCgA	B-GENE
promoter	I-GENE
response	O
.	O
mCgA	B-GENE
-	O
92	O
to	O
-	O
64	O
bp	O
,	O
comprising	O
the	O
Sp1	B-GENE
/	O
Egr	B-GENE
-	I-GENE
1	I-GENE
site	O
and	O
the	O
CRE	O
motif	O
,	O
conferred	O
gastrin	B-GENE
responsiveness	O
to	O
a	O
heterologous	B-GENE
thymidine	I-GENE
kinase	I-GENE
promoter	I-GENE
system	O
,	O
and	O
therefore	O
functions	O
as	O
a	O
"	O
true	O
"	O
enhancer	O
element	O
.	O

Alfalfa	O
phosphorus	O
release	O
kinetics	O
showed	O
high	O
bacterial	O
phosphorus	O
contamination	O
.	O

In	O
conclusion	O
,	O
ORCA3	B-GENE
regulates	O
jasmonate	O
-	O
responsive	O
expression	O
of	O
the	O
Str	B-GENE
gene	I-GENE
via	O
direct	O
interaction	O
with	O
the	O
JERE	O
.	O

PC12	O
cultures	O
that	O
had	O
been	O
"	O
primed	O
"	O
in	O
this	O
way	O
showed	O
an	O
accelerated	O
and	O
augmented	O
differentiation	O
response	O
to	O
nerve	B-GENE
growth	I-GENE
factor	I-GENE
.	O

Pseudotumor	O
form	O
of	O
pulmonary	O
nocardia	O
infection	O
(	O
Nocardia	O
nova	O
)	O
in	O
a	O
renal	O
transplant	O
patient	O

Deoxyuridine	O
-	O
suppression	O
test	O
and	O
bone	O
marrow	O
culture	O
for	O
the	O
diagnosis	O
of	O
macrocytic	O
refractory	O
anaemias	O
.	O

A	O
computerized	O
database	O
of	O
veterans	O
discharged	O
from	O
the	O
military	O
after	O
1967	O
was	O
selected	O
as	O
the	O
source	O
because	O
it	O
contains	O
about	O
50	O
%	O
of	O
the	O
total	O
Vietnam	O
era	O
veteran	O
population	O
,	O
is	O
reasonably	O
unbiased	O
,	O
and	O
provides	O
a	O
feasible	O
method	O
for	O
identifying	O
twins	O
.	O

We	O
report	O
that	O
Nim1	B-GENE
possesses	O
intrinsic	O
serine	B-GENE
-	I-GENE
kinase	I-GENE
,	O
threonine	B-GENE
-	I-GENE
kinase	I-GENE
and	O
tyrosine	B-GENE
-	I-GENE
kinase	I-GENE
activities	O
.	O

This	O
mutation	O
was	O
associated	O
with	O
reduced	O
or	O
absent	O
expression	O
of	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
RI	I-GENE
protein	I-GENE
and	O
p53	B-GENE
protein	I-GENE
in	O
tumor	O
tissues	O
.	O

Keys	O
can	O
be	O
used	O
for	O
identifying	O
species	O
from	O
the	O
European	O
part	O
of	O
the	O
USSR	O
and	O
north	O
-	O
eastern	O
Kazakhstan	O
.	O

Time	O
between	O
tests	O
(	O
usually	O
less	O
than	O
one	O
year	O
)	O
did	O
not	O
affect	O
the	O
correlations	O
,	O
but	O
MMPI	O
response	O
-	O
set	O
variables	O
(	O
L	O
,	O
F	O
,	O
K	O
,	O
F	O
-	O
K	O
)	O
did	O
.	O

Cloning	O
and	O
sequence	O
analysis	O
of	O
a	O
chymotrypsinlike	B-GENE
protease	I-GENE
from	I-GENE
Treponema	I-GENE
denticola	O
.	O

To	O
initiate	O
our	O
analysis	O
of	O
factors	O
required	O
for	O
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
expression	O
,	O
selected	O
a	O
CAP	O
-	O
proximal	O
element	O
shown	O
by	O
in	O
vivo	O
methylation	O
protection	O
analysis	O
to	O
bind	O
a	O
potential	O
regulatory	O
factor	O
.	O

The	O
isoproterenol	O
infusion	O
was	O
adjusted	O
so	O
that	O
heart	O
rate	O
(	O
HR	O
)	O
was	O
at	O
least	O
30	O
beats	O
/	O
min	O
greater	O
than	O
baseline	O
.	O

The	O
effect	O
of	O
monaural	O
middle	O
ear	O
destruction	O
on	O
postnatal	O
development	O
of	O
mouse	O
inferior	O
colliculus	O
.	O

The	O
specificity	O
and	O
sensitivity	O
of	O
this	O
method	O
(	O
limit	O
of	O
detection	O
in	O
plasma	O
0	O
.	O
025	O
micrograms	O
/	O
mL	O
and	O
<	O
or	O
=	O
0	O
.	O
0125	O
micrograms	O
/	O
mL	O
for	O
febantel	O
and	O
its	O
metabolites	O
,	O
respectively	O
)	O
were	O
sufficiently	O
high	O
to	O
enable	O
us	O
to	O
characterize	O
the	O
time	O
course	O
of	O
the	O
drug	O
in	O
the	O
plasma	O
after	O
oral	O
administration	O
of	O
therapeutic	O
doses	O
to	O
sheep	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
A	O
seven	O
-	O
wavelength	O
frequency	O
-	O
domain	O
photon	O
migration	O
probe	O
was	O
used	O
to	O
perform	O
noninvasive	O
NIR	O
measurements	O
in	O
the	O
breasts	O
of	O
28	O
healthy	O
women	O
,	O
both	O
pre	O
-	O
and	O
postmenopausal	O
,	O
aged	O
18	O
-	O
64	O
years	O
.	O

Drug	O
therapy	O
of	O
AAPMC	O
is	O
directed	O
at	O
reducing	O
the	O
amount	O
of	O
Cl	O
.	O
difficile	O
in	O
the	O
colon	O
and	O
promoting	O
normalization	O
of	O
intestinal	O
flora	O
.	O

The	O
results	O
of	O
this	O
study	O
demonstrate	O
that	O
release	O
of	O
a	O
single	O
pulley	O
after	O
repair	O
of	O
the	O
tendons	O
in	O
this	O
area	O
improved	O
gliding	O
excursions	O
of	O
the	O
tendons	O
and	O
reduced	O
resistance	O
to	O
motion	O
of	O
the	O
repaired	O
tendons	O
,	O
and	O
provide	O
support	O
for	O
partial	O
A2	O
pulley	O
incision	O
after	O
repair	O
of	O
the	O
tendons	O
in	O
the	O
area	O
of	O
the	O
pulley	O
.	O

The	O
Ick	B-GENE
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
is	O
not	O
involved	O
in	O
antibody	O
-	O
mediated	O
CD4	B-GENE
(	O
CDR3	B-GENE
-	I-GENE
loop	I-GENE
)	O
signal	O
transduction	O
that	O
inhibits	O
HIV	O
-	O
1	O
transcription	O
.	O

It	O
is	O
targeted	O
to	O
peroxisomes	O
when	O
expressed	O
in	O
mammalian	O
cells	O
and	O
yeast	O
.	O

Whether	O
or	O
not	O
these	O
novel	O
repeated	O
sequences	O
throughout	O
the	O
SMA	B-GENE
region	I-GENE
are	O
involved	O
in	O
the	O
disease	O
remains	O
to	O
be	O
determined	O
.	O

All	O
except	O
the	O
last	O
two	O
interventions	O
are	O
physical	O
treatments	O
that	O
create	O
a	O
wound	O
-	O
tissue	O
environment	O
conducive	O
to	O
healing	O
.	O

Consistent	O
with	O
our	O
observation	O
that	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	O
does	O
not	O
contribute	O
to	O
c	B-GENE
-	I-GENE
Jun	I-GENE
coactivation	O
is	O
the	O
observation	O
that	O
the	O
activation	O
of	O
PU	B-GENE
.	I-GENE
1	I-GENE
by	O
c	B-GENE
-	I-GENE
Jun	I-GENE
is	O
blocked	O
by	O
overexpression	O
of	O
c	B-GENE
-	I-GENE
Fos	I-GENE
.	O

In	O
a	O
series	O
of	O
papers	O
,	O
the	O
staging	O
system	O
for	O
melanoma	O
was	O
critically	O
analyzed	O
,	O
and	O
many	O
shortcomings	O
were	O
identified	O
.	O

The	O
transcriptional	O
initiation	O
site	O
of	O
RAG1	B-GENE
was	O
localized	O
at	O
A	O
,	O
26	O
bp	O
upstream	O
of	O
the	O
putative	O
translational	O
initiation	O
codon	O
,	O
ATG	O
,	O
by	O
the	O
primer	O
extension	O
assay	O
.	O

The	O
levels	O
of	O
products	O
expressed	O
from	O
these	O
chimeric	O
cDNAs	O
in	O
COS	O
cells	O
were	O
assessed	O
by	O
activity	O
assay	O
and	O
by	O
metabolic	O
labeling	O
of	O
the	O
proteins	O
followed	O
by	O
immunoprecipitation	O
and	O
SDS	O
-	O
PAGE	O
.	O

The	O
leucine	O
zipper	O
region	O
of	O
ATF	B-GENE
proteins	I-GENE
is	O
also	O
similar	O
to	O
that	O
of	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
/	O
c	B-GENE
-	I-GENE
jun	I-GENE
family	O
of	O
transcription	O
factors	O
,	O
whose	O
DNA	O
-	O
binding	O
site	O
differs	O
from	O
the	O
ATF	B-GENE
-	O
binding	O
site	O
at	O
a	O
single	O
position	O
.	O

Immunoblotting	O
with	O
antiphosphotyrosine	O
antibody	O
showed	O
that	O
many	O
yeast	O
proteins	O
,	O
including	O
the	O
p34CDC28	B-GENE
kinase	I-GENE
,	O
became	O
phosphorylated	O
at	O
tyrosine	O
in	O
cells	O
expressing	O
v	B-GENE
-	I-GENE
src	I-GENE
.	O

22	O
-	O
Veneto	O
Region	O
)	O

Differential	O
transcription	O
of	O
plastome	O
-	O
encoded	O
genes	O
in	O
the	O
mesophyll	O
and	O
bundle	O
-	O
sheath	O
chloroplasts	O
of	O
the	O
monocotyledonous	O
NADP	O
-	O
malic	B-GENE
enzyme	I-GENE
-	O
type	O
C4	O
plants	O
maize	O
and	O
Sorghum	O
.	O

AIMS	O
:	O
We	O
postulated	O
that	O
perhexiline	O
,	O
a	O
novel	O
anti	O
-	O
ischaemic	O
agent	O
with	O
an	O
oxygen	O
-	O
sparing	O
metabolic	O
effect	O
in	O
the	O
myocardium	O
(	O
via	O
inhibition	O
of	O
carnitine	B-GENE
palmitoyltransferase	I-GENE
-	I-GENE
1	I-GENE
)	O
and	O
no	O
adverse	O
haemodynamic	O
effects	O
,	O
may	O
improve	O
symptomatic	O
status	O
in	O
elderly	O
patients	O
with	O
severe	O
aortic	O
stenosis	O
.	O

Developmentally	O
-	O
regulated	O
interaction	O
of	O
a	O
transcription	O
factor	O
complex	O
containing	O
CDP	B-GENE
/	O
cut	B-GENE
with	O
the	O
early	B-GENE
histone	I-GENE
H3	I-GENE
gene	I-GENE
promoter	I-GENE
of	I-GENE
the	I-GENE
sea	I-GENE
urchin	I-GENE
Tetrapygus	I-GENE
niger	I-GENE
is	O
associated	O
with	O
changes	O
in	O
chromatin	O
structure	O
and	O
gene	O
expression	O
.	O

In	O
this	O
group	O
of	O
patients	O
,	O
the	O
mean	O
LH	B-GENE
(	O
9	O
.	O
3	O
+	O
/	O
-	O
5	O
.	O
9	O
IU	O
/	O
l	O
)	O
and	O
sex	B-GENE
-	I-GENE
hormone	I-GENE
binding	I-GENE
globulin	I-GENE
(	O
SHBG	B-GENE
)	O
(	O
54	O
.	O
5	O
+	O
/	O
-	O
22	O
.	O
9	O
nmol	O
/	O
l	O
)	O
concentrations	O
were	O
significantly	O
greater	O
than	O
those	O
of	O
five	O
normal	O
control	O
subjects	O
(	O
4	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
11	O
IU	O
/	O
l	O
and	O
26	O
.	O
0	O
+	O
/	O
-	O
7	O
.	O
0	O
nmol	O
/	O
l	O
respectively	O
)	O
.	O

IRA2	B-GENE
,	O
a	O
second	O
gene	O
of	O
Saccharomyces	O
cerevisiae	O
that	O
encodes	O
a	O
protein	O
with	O
a	O
domain	O
homologous	O
to	O
mammalian	O
ras	B-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
.	O

Gastrin	B-GENE
stimulates	O
transcription	O
of	O
the	O
human	B-GENE
histidine	I-GENE
decarboxylase	I-GENE
(	O
HDC	B-GENE
)	O
gene	O
through	O
binding	O
to	O
the	O
G	B-GENE
-	I-GENE
protein	I-GENE
-	O
coupled	O
cholecystokinin	B-GENE
-	I-GENE
B	I-GENE
/	O
gastrin	B-GENE
receptor	I-GENE
.	O

RESULTS	O
-	O
-	O
The	O
maximal	O
early	O
asthmatic	O
response	O
after	O
allergen	O
with	O
placebo	O
treatment	O
was	O
18	O
.	O
4	O
%	O
(	O
SE	O
4	O
.	O
4	O
%	O
)	O
and	O
with	O
WEB	O
2086	O
18	O
.	O
9	O
%	O
(	O
4	O
.	O
4	O
%	O
)	O
.	O

The	O
3	O
'	O
region	O
of	O
the	O
transcript	O
contained	O
a	O
fully	O
conserved	O
,	O
correctly	O
spliced	O
TCR	B-GENE
alpha	I-GENE
C	I-GENE
region	I-GENE
which	O
was	O
polyadenylated	O
at	O
the	O
3	O
'	O
end	O
.	O

Structural	O
organization	O
of	O
the	O
human	B-GENE
Elk1	I-GENE
gene	I-GENE
and	O
its	O
processed	O
pseudogene	B-GENE
Elk2	I-GENE
.	O

Results	O
:	O
hepatic	O
hydatidosis	O
:	O
177	O
patients	O
.	O

Prematurely	O
inactivating	O
p42	B-GENE
MAPK	I-GENE
in	O
egg	O
extracts	O
resulted	O
in	O
a	O
corresponding	O
hastening	O
of	O
the	O
first	O
mitosis	O
.	O

Anxiogenic	O
effects	O
of	O
pentagastrin	O
in	O
patients	O
with	O
social	O
phobia	O
and	O
healthy	O
controls	O
.	O

Dynamic	O
expression	O
of	O
broad	B-GENE
-	I-GENE
complex	I-GENE
isoforms	I-GENE
mediates	O
temporal	O
control	O
of	O
an	O
ecdysteroid	O
target	O
gene	O
at	O
the	O
onset	O
of	O
Drosophila	O
metamorphosis	O
.	O

Identification	O
of	O
a	O
putative	O
chromosomal	O
replication	O
origin	O
from	O
Helicobacter	O
pylori	O
and	O
its	O
interaction	O
with	O
the	O
initiator	B-GENE
protein	I-GENE
DnaA	I-GENE
.	O

There	O
was	O
91	O
%	O
concordance	O
between	O
ST	O
-	O
RD	O
/	O
RI	O
/	O
LRD	O
201Tl	O
and	O
R	O
-	O
ST	O
/	O
N	O
+	O
Inf	O
99Tcm	O
-	O
tetrofosmin	O
imaging	O
regarding	O
reversibility	O
.	O

Sub	O
-	O
inhibitory	O
and	O
post	O
-	O
antibiotic	O
effects	O
of	O
spiramycin	O
and	O
erythromycin	O
on	O
Staphylococcus	O
aureus	O
.	O

There	O
remains	O
the	O
physiological	O
problem	O
-	O
-	O
one	O
which	O
has	O
always	O
been	O
foremost	O
in	O
Moruzzi	O
'	O
s	O
thinking	O
about	O
the	O
intrinsic	O
regulation	O
of	O
brain	O
activity	O
-	O
-	O
of	O
how	O
the	O
separate	O
actions	O
of	O
the	O
different	O
arousal	O
systems	O
are	O
brought	O
together	O
into	O
a	O
functional	O
whole	O
.	O

Because	O
the	O
variation	O
in	O
the	O
carbohydrate	O
content	O
of	O
human	O
milk	O
is	O
very	O
small	O
,	O
a	O
more	O
simple	O
alternative	O
approach	O
would	O
be	O
to	O
include	O
only	O
an	O
average	O
carbohydrate	O
value	O
for	O
an	O
estimate	O
of	O
energy	O
content	O
.	O

It	O
is	O
suggested	O
that	O
biliary	O
secretion	O
of	O
both	O
TBZ	O
and	O
FBZ	O
and	O
their	O
metabolites	O
may	O
contribute	O
to	O
this	O
recycling	O
.	O

Hyperlipemia	O
has	O
been	O
recently	O
described	O
in	O
children	O
with	O
migraine	O
,	O
being	O
suggested	O
that	O
this	O
alteration	O
is	O
in	O
the	O
base	O
of	O
the	O
disease	O
.	O

BACKGROUND	O
:	O
A	O
thorough	O
understanding	O
of	O
malignant	O
fibrous	O
histiocytoma	O
(	O
MFH	O
)	O
,	O
the	O
most	O
common	O
subtype	O
of	O
soft	O
tissue	O
sarcoma	O
,	O
will	O
lead	O
to	O
improved	O
histologic	O
-	O
specific	O
protocols	O
.	O

The	O
proteins	O
encoded	O
by	O
these	O
genes	O
,	O
called	O
GF14	B-GENE
proteins	I-GENE
,	O
participate	O
in	O
protein	O
/	O
DNA	O
complexes	O
and	O
show	O
more	O
than	O
60	O
%	O
identity	O
with	O
a	O
highly	O
conserved	O
,	O
widely	O
distributed	O
protein	O
family	O
,	O
collectively	O
referred	O
to	O
as	O
14	B-GENE
-	I-GENE
3	I-GENE
-	I-GENE
3	I-GENE
proteins	O
.	O

A	O
total	O
of	O
64	O
uncomplicated	O
Type	O
-	O
2	O
diabetic	O
individuals	O
of	O
higher	O
middle	O
class	O
to	O
rich	O
socio	O
-	O
economic	O
status	O
were	O
studied	O
.	O

Using	O
yeast	O
two	O
-	O
hybrid	O
screening	O
,	O
we	O
isolated	O
histone	B-GENE
H3	I-GENE
as	O
an	O
interacting	O
factor	O
of	O
CIA	B-GENE
.	O

Elevated	O
total	O
serum	O
calcium	O
to	O
a	O
level	O
of	O
11	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
2	O
mg	O
/	O
dl	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
compared	O
to	O
control	O
group	O
)	O
developed	O
in	O
the	O
gentamicin	O
/	O
1	O
,	O
25	O
(	O
OH	O
)	O
2	O
vitamin	O
D3	O
group	O
on	O
day	O
4	O
,	O
2	O
days	O
prior	O
to	O
pronounced	O
structural	O
damage	O
,	O
and	O
continued	O
to	O
be	O
elevated	O
through	O
day	O
7	O
.	O

To	O
investigate	O
the	O
role	O
of	O
this	O
domain	O
in	O
the	O
incorporation	O
of	O
the	O
SIV	B-GENE
Env	I-GENE
into	O
virions	O
,	O
we	O
generated	O
a	O
series	O
of	O
SIV	B-GENE
Env	I-GENE
mutants	I-GENE
carrying	O
small	O
in	O
-	O
frame	O
deletions	O
within	O
the	O
cytoplasmic	O
domain	O
.	O

Ozone	O
uptake	O
was	O
assessed	O
in	O
awake	O
,	O
spontaneously	O
breathing	O
Fischer	O
-	O
344	O
Sprague	O
-	O
Dawley	O
,	O
and	O
Long	O
-	O
Evans	O
rats	O
and	O
Hartley	O
guinea	O
pigs	O
to	O
provide	O
data	O
on	O
the	O
dosimetry	O
of	O
O3	O
in	O
small	O
laboratory	O
animals	O
.	O

Treatment	O
of	O
steroid	O
resistant	O
rejection	O
following	O
renal	O
transplantation	O
:	O
benefits	O
and	O
risks	O
of	O
OKT3	B-GENE
therapy	O
.	O

SETTING	O
:	O
University	O
research	O
laboratory	O
.	O

On	O
the	O
3rd	O
day	O
after	O
ischemia	O
of	O
the	O
remained	O
kidney	O
for	O
30	O
min	O
,	O
structural	O
components	O
of	O
the	O
walls	O
of	O
the	O
glomerular	O
arterioles	O
and	O
those	O
of	O
the	O
filtration	O
-	O
reabsorption	O
barrier	O
undergo	O
certain	O
ultrastructural	O
changes	O
,	O
that	O
with	O
time	O
elapsed	O
(	O
7	O
,	O
14	O
days	O
)	O
gradually	O
pass	O
away	O
,	O
and	O
amount	O
of	O
cells	O
with	O
hypertrophic	O
processes	O
increases	O
.	O

Non	O
-	O
finger	O
-	O
coding	O
modules	O
conserved	O
among	O
members	O
of	O
subfamilies	O
of	O
zinc	B-GENE
finger	I-GENE
genes	I-GENE
have	O
been	O
described	O
in	O
the	O
murine	O
genome	O
(	O
finger	O
-	O
associated	O
boxes	O
,	O
or	O
FAX	O
domain	O
)	O
and	O
the	O
human	O
genome	O
(	O
Kruppel	B-GENE
-	I-GENE
associated	I-GENE
boxes	I-GENE
,	O
or	O
KRAB	B-GENE
domain	I-GENE
)	O
.	O

Binding	O
of	O
C	B-GENE
/	I-GENE
EBPs	I-GENE
to	O
all	O
three	O
spi	B-GENE
2	I-GENE
.	I-GENE
3	I-GENE
3	I-GENE
'	I-GENE
UTR	I-GENE
repressor	I-GENE
sites	I-GENE
,	O
although	O
rather	O
weak	O
,	O
was	O
confirmed	O
by	O
electrophoretic	O
mobility	O
shift	O
assays	O
that	O
otherwise	O
failed	O
to	O
reveal	O
specific	O
interactions	O
with	O
other	O
liver	O
nuclear	O
proteins	O
in	O
vitro	O
.	O

The	O
newly	O
identified	O
NF	B-GENE
kappa	I-GENE
B	I-GENE
enhancer	I-GENE
(	O
TGGAAATTCC	O
)	O
is	O
bound	O
by	O
a	O
TNF	B-GENE
alpha	I-GENE
-	O
induced	O
nuclear	O
protein	O
and	O
appears	O
to	O
be	O
the	O
key	O
element	O
in	O
rapid	O
transcription	O
induction	O
by	O
TNF	B-GENE
alpha	I-GENE
(	O
and	O
TPA	O
)	O
,	O
while	O
transactivation	O
of	O
this	O
element	O
is	O
repressed	O
by	O
the	O
ligand	O
-	O
bound	O
glucocorticoid	B-GENE
receptor	I-GENE
.	O

Despite	O
the	O
fact	O
that	O
biochemical	O
estimates	O
of	O
bone	O
turnover	O
indicate	O
that	O
(	O
short	O
-	O
term	O
)	O
administration	O
of	O
rhGH	B-GENE
and	O
IGF	B-GENE
-	I-GENE
I	I-GENE
stimulates	O
bone	O
metabolism	O
in	O
non	O
-	O
osteoporotic	O
older	O
people	O
,	O
no	O
significant	O
changes	O
have	O
been	O
observed	O
in	O
bone	O
mineral	O
density	O
at	O
the	O
proximal	O
femur	O
.	O

Parental	O
and	O
vector	O
-	O
transfected	O
MCF7	O
cells	O
,	O
which	O
were	O
sensitive	O
to	O
the	O
growth	O
-	O
inhibitory	O
effects	O
of	O
atRA	O
,	O
exhibited	O
atRA	O
-	O
dependent	O
retinoic	B-GENE
acid	I-GENE
receptor	I-GENE
(	O
RAR	B-GENE
)	O
transactivation	O
and	O
transrepression	O
of	O
12	O
-	O
O	O
-	O
tetradecanoylphorbol	O
-	O
13	O
-	O
acetate	O
-	O
induced	O
AP	B-GENE
-	I-GENE
1	I-GENE
activity	O
.	O

Chemiluminescence	O
induced	O
by	O
opsonized	O
zymosan	O
increased	O
significantly	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
after	O
treatment	O
with	O
bacterial	O
extracts	O
,	O
whereas	O
no	O
significant	O
changes	O
were	O
observed	O
in	O
the	O
fMLP	O
-	O
stimulated	O
PMNs	O
.	O

Using	O
the	O
two	O
-	O
hybrid	O
screening	O
method	O
,	O
we	O
have	O
identified	O
an	O
additional	O
component	O
of	O
the	O
CCAAT	B-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
.	O

Our	O
studies	O
suggest	O
that	O
the	O
helicase	B-GENE
assembly	O
protein	O
is	O
responsible	O
for	O
loading	O
T4	B-GENE
gene	I-GENE
41	I-GENE
helicase	I-GENE
specifically	O
at	O
replication	O
forks	O
,	O
and	O
that	O
its	O
binding	O
sites	O
for	O
each	O
arm	O
must	O
hold	O
more	O
than	O
six	O
,	O
but	O
not	O
more	O
than	O
12	O
nucleotides	O
.	O

These	O
results	O
strongly	O
suggest	O
that	O
HSV	O
-	O
1	O
infection	O
inhibits	O
host	O
cell	O
splicing	O
through	O
the	O
action	O
of	O
ICP27	B-GENE
.	O

Sci	O
.	O

In	O
our	O
initial	O
studies	O
,	O
we	O
treated	O
MCF	O
-	O
7	O
cells	O
with	O
paclitaxel	O
,	O
which	O
results	O
in	O
the	O
arrest	O
of	O
cells	O
in	O
G1	O
with	O
4n	O
DNA	O
content	O
(	O
pseudo	O
G1	O
)	O
.	O

A	O
GTP	O
/	O
GDP	O
exchange	O
assay	O
was	O
used	O
to	O
assess	O
the	O
potential	O
role	O
of	O
Ras	B-GENE
in	O
the	O
pathway	O
leading	O
to	O
ERK	B-GENE
phosphorylation	O
;	O
DADLE	O
failed	O
to	O
stimulate	O
GTP	O
/	O
GDP	O
exchange	O
in	O
comparison	O
to	O
PMA	O
.	O

The	O
primary	O
structures	O
of	O
the	O
human	B-GENE
KB	I-GENE
cell	I-GENE
(	I-GENE
FR	I-GENE
-	I-GENE
KB1	I-GENE
)	I-GENE
folate	I-GENE
receptor	I-GENE
(	O
FR	B-GENE
)	O
and	O
of	O
a	O
human	B-GENE
placental	I-GENE
(	I-GENE
FR	I-GENE
-	I-GENE
P2	I-GENE
)	I-GENE
FR	I-GENE
,	O
proteins	O
important	O
in	O
cellular	O
accumulation	O
of	O
folates	O
,	O
have	O
been	O
deduced	O
from	O
cDNA	O
sequences	O
.	O

Copyright	O
1999	O
Academic	O
Press	O
.	O

Possible	O
or	O
definite	O
neglect	O
or	O
abuse	O
before	O
36	O
months	O
of	O
age	O
was	O
correlated	O
with	O
low	O
DBH	B-GENE
activity	O
.	O

The	O
remaining	O
77	O
nucleotides	O
at	O
the	O
3	O
'	O
end	O
of	O
domain	O
II	O
and	O
all	O
of	O
domains	O
III	O
(	O
655	O
nucleotides	O
)	O
and	O
IV	O
(	O
770	O
nucleotides	O
)	O
are	O
not	O
present	O
in	O
DIssE	B-GENE
RNA	I-GENE
.	O

Changes	O
in	O
tension	O
were	O
monitored	O
isometrically	O
on	O
spiral	O
strips	O
of	O
freshly	O
obtained	O
bovine	O
basilar	O
arteries	O
.	O

The	O
preparative	O
regimen	O
consisted	O
of	O
fractionated	O
total	O
body	O
irradiation	O
(	O
TBI	O
)	O
and	O
cyclophosphamide	O
(	O
CY	O
)	O
.	O

The	O
dynamics	O
of	O
protozoa	O
were	O
studied	O
in	O
two	O
groups	O
of	O
rumen	O
-	O
fistulated	O
cattle	O
fed	O
on	O
a	O
basal	O
diet	O
of	O
molasses	O
ad	O
lib	O
.	O
,	O
with	O
oaten	O
chaff	O
given	O
at	O
6	O
or	O
18	O
g	O
/	O
kg	O
live	O
weight	O
.	O

Consistent	O
with	O
the	O
large	O
pocket	O
of	O
Rb	B-GENE
binding	O
to	O
TAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
250	I-GENE
,	O
the	O
large	O
pocket	O
domains	O
of	O
both	O
p107	B-GENE
and	O
p130	B-GENE
are	O
able	O
to	O
bind	O
to	O
TAF	B-GENE
(	I-GENE
II	I-GENE
)	I-GENE
250	I-GENE
in	O
vivo	O
.	O

Patients	O
with	O
Eales	O
'	O
disease	O
,	O
chorioretinitis	O
,	O
central	O
serous	O
retinopathy	O
,	O
or	O
malignant	O
choroidal	O
melanoma	O
were	O
tested	O
for	O
HLA	B-GENE
antigen	O
deviation	O
.	O

Comparison	O
of	O
the	O
derived	O
amino	O
acid	O
sequence	O
with	O
that	O
of	O
the	O
HCMV	B-GENE
UL99	I-GENE
gene	I-GENE
product	I-GENE
reveals	O
34	O
.	O
8	O
%	O
identity	O
in	O
an	O
overlap	O
of	O
66	O
amino	O
acids	O
.	O

White	O
female	O
cases	O
were	O
more	O
likely	O
to	O
have	O
worked	O
as	O
registered	O
nurses	O
than	O
were	O
the	O
controls	O
(	O
OR	O
=	O
1	O
.	O
9	O
,	O
95	O
%	O
CI	O
=	O
1	O
.	O
0	O
-	O
3	O
.	O
5	O
)	O
.	O

Fentanyl	O
citrate	O
(	O
0	O
.	O
1	O
mL	O
)	O
and	O
2H5	O
-	O
fentanyl	O
(	O
internal	O
standard	O
,	O
0	O
.	O
05	O
mL	O
,	O
100	O
mg	O
/	O
L	O
)	O
were	O
extracted	O
with	O
Toxi	O
-	O
A	O
tubes	O
(	O
Toxi	O
-	O
Lab	O
,	O
Irvine	O
,	O
CA	O
)	O
and	O
analyzed	O
by	O
gas	O
chromatography	O
-	O
mass	O
spectrometry	O
.	O

O5257	B-GENE
shows	O
homology	O
with	O
the	O
SAS2	B-GENE
protein	I-GENE
and	O
another	O
hypothetical	O
protein	O
from	O
yeast	O
.	O

Cotransfection	O
of	O
expression	O
plasmids	O
encoding	O
the	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
inhibitor	O
,	O
or	O
an	O
inactive	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
(	O
PKA	B-GENE
)	O
catalytic	O
beta	O
subunit	O
,	O
inhibited	O
both	O
forskolin	O
and	O
PACAP	B-GENE
activation	O
of	O
chromogranin	B-GENE
A	I-GENE
transcription	O
,	O
revealing	O
that	O
PACAP	B-GENE
-	O
induced	O
trans	O
-	O
activation	O
is	O
highly	O
dependent	O
on	O
PKA	B-GENE
.	O

Of	O
all	O
YASR	O
syndromes	O
,	O
the	O
highest	O
stability	O
was	O
for	O
the	O
Anxious	O
/	O
Depressed	O
scale	O
.	O

There	O
was	O
no	O
difference	O
in	O
serum	B-GENE
albumin	I-GENE
and	O
transferrin	B-GENE
levels	O
,	O
but	O
serum	B-GENE
prealbumin	I-GENE
levels	O
in	O
the	O
group	O
fed	O
early	O
were	O
more	O
desirable	O
than	O
those	O
of	O
the	O
control	O
group	O
(	O
from	O
15	O
.	O
8	O
+	O
/	O
-	O
2	O
.	O
5	O
mg	O
/	O
dl	O
to	O
28	O
.	O
9	O
+	O
/	O
-	O
3	O
.	O
8	O
mg	O
/	O
dl	O
vs	O
from	O
18	O
.	O
0	O
+	O
/	O
-	O
2	O
.	O
0	O
mg	O
/	O
dl	O
to	O
25	O
.	O
9	O
+	O
/	O
-	O
3	O
.	O
9	O
mg	O
/	O
dl	O
)	O
.	O

The	O
introduction	O
gives	O
also	O
the	O
history	O
of	O
Research	O
Programme	O
MZ	O
-	O
XVII	O
and	O
its	O
implementation	O
in	O
several	O
regions	O
of	O
Poland	O
.	O

The	O
uap100	B-GENE
cis	O
-	O
acting	O
,	O
up	O
-	O
promoter	O
,	O
constitutive	O
mutation	O
is	O
a	O
duplication	O
that	O
comprises	O
two	O
GATA	O
sites	O
and	O
suppresses	O
weakly	O
the	O
AREA	B-GENE
zinc	I-GENE
finger	I-GENE
mutation	I-GENE
but	O
does	O
not	O
alleviate	O
the	O
need	O
for	O
functional	O
UAY	B-GENE
and	O
AREA	B-GENE
proteins	I-GENE
.	O

Significant	O
differences	O
were	O
observed	O
in	O
the	O
composition	O
of	O
nuclear	O
transcription	O
factors	O
bound	O
to	O
cis	O
-	O
elements	O
within	O
the	O
LDH	B-GENE
/	I-GENE
C	I-GENE
proximal	I-GENE
promoter	I-GENE
region	I-GENE
in	O
somatic	O
versus	O
germ	O
cells	O
.	O

We	O
conclude	O
that	O
although	O
the	O
G3	O
sequence	O
contains	O
two	O
protein	O
-	O
binding	O
motifs	O
,	O
the	O
organization	O
of	O
the	O
G3	O
enhancer	O
-	O
like	O
element	O
is	O
not	O
bipartite	O
.	O

With	O
BCPP	O
protocol	O
,	O
12	O
achieved	O
a	O
complete	O
response	O
,	O
11	O
evidenced	O
a	O
75	O
%	O
response	O
,	O
and	O
7	O
displayed	O
a	O
50	O
%	O
response	O
.	O

The	O
effects	O
of	O
tilmicosin	O
administration	O
in	O
the	O
feed	O
at	O
400	O
mg	O
/	O
kg	O
and	O
an	O
injection	O
therapy	O
of	O
clinically	O
diseased	O
pigs	O
with	O
long	O
-	O
acting	O
oxytetracycline	O
(	O
Terramycine	O
LA	O
)	O
at	O
20	O
mg	O
/	O
kg	O
bodyweight	O
were	O
compared	O
.	O

In	O
7	O
men	O
and	O
1	O
woman	O
who	O
died	O
suddenly	O
the	O
functionally	O
important	O
areas	O
of	O
myocardium	O
in	O
the	O
sino	O
-	O
auricular	O
area	O
and	O
the	O
subendocardial	O
layers	O
of	O
left	O
ventricle	O
were	O
obtained	O
by	O
necropsy	O
no	O
more	O
than	O
3	O
h	O
after	O
death	O
,	O
and	O
then	O
prepared	O
for	O
study	O
by	O
electron	O
microscopy	O
.	O

Importantly	O
,	O
a	O
single	O
base	O
change	O
in	O
the	O
fifth	O
position	O
of	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
sequence	I-GENE
(	O
GGTCTnnnAGACC	O
to	O
GGTCA	O
/	O
GnnnAGACC	O
)	O
produced	O
an	O
element	O
that	O
bound	O
the	O
estrogen	B-GENE
receptor	I-GENE
and	O
conferred	O
estrogen	O
-	O
dependent	O
transcriptional	O
activation	O
of	O
a	O
reporter	O
gene	O
.	O

A	O
preterm	O
formula	O
with	O
a	O
traditional	O
corn	O
oil	O
/	O
MCT	O
blend	O
containing	O
38	O
%	O
MCTs	O
(	O
MCT	O
group	O
)	O
was	O
compared	O
to	O
a	O
new	O
fat	O
blend	O
,	O
designed	O
to	O
resemble	O
human	O
milk	O
more	O
,	O
containing	O
6	O
%	O
MCTs	O
(	O
LCT	O
group	O
)	O
.	O

The	O
existence	O
of	O
a	O
TFIIIB	B-GENE
assembly	O
pathway	O
leading	O
to	O
the	O
faithful	O
transcription	O
of	O
natural	O
eukaryotic	O
tRNA	O
genes	O
in	O
the	O
absence	O
of	O
TFIIIC	B-GENE
provides	O
novel	O
insights	O
into	O
the	O
functional	O
flexibility	O
of	O
the	O
eukaryotic	O
tRNA	O
gene	O
transcription	O
machinery	O
and	O
on	O
its	O
evolution	O
from	O
an	O
ancestral	O
RNA	B-GENE
polymerase	I-GENE
III	I-GENE
system	O
relying	O
on	O
upstream	O
,	O
TATA	O
-	O
centered	O
control	O
elements	O
.	O

Overexpression	O
of	O
N	O
-	O
terminal	O
mutations	O
disturbs	O
mitosis	O
and	O
produces	O
elongated	O
cells	O
,	O
Using	O
a	O
PCR	O
approach	O
,	O
we	O
isolated	O
a	O
putative	O
homologue	O
of	O
Prp4	B-GENE
from	O
human	O
and	O
mouse	O
cells	O
.	O

Successive	O
5	O
'	O
deletions	O
of	O
the	O
[	O
-	O
326	O
;	O
+	O
20	O
]	O
type	B-GENE
II	I-GENE
sPLA2	I-GENE
promoter	I-GENE
indicated	O
that	O
the	O
region	O
upstream	O
of	O
position	O
-	O
195	O
inhibits	O
the	O
transcription	O
activity	O
sixfold	O
in	O
HepG2	O
cells	O
but	O
not	O
in	O
HeLa	O
cells	O
.	O

Pyridostigmine	O
pretreatment	O
was	O
supplemented	O
by	O
therapy	O
with	O
two	O
doses	O
of	O
an	O
antidotal	O
combination	O
(	O
A	O
,	O
TM	O
,	O
B	O
)	O
consisting	O
of	O
0	O
.	O
05	O
mg	O
/	O
kg	O
atropine	O
,	O
2	O
.	O
24	O
mg	O
/	O
kg	O
TMB	O
-	O
4	O
,	O
and	O
0	O
.	O
4	O
mg	O
/	O
kg	O
benactyzine	O
which	O
assured	O
survival	O
in	O
five	O
of	O
six	O
animals	O
following	O
three	O
separate	O
exposures	O
to	O
10	O
LD50	O
soman	O
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
and	O
DNase	B-GENE
I	I-GENE
protection	O
analyses	O
revealed	O
that	O
FP	B-GENE
I	I-GENE
was	O
bound	O
by	O
the	O
transcription	O
factor	O
PU	B-GENE
.	I-GENE
1	I-GENE
/	O
Spi	B-GENE
-	I-GENE
1	I-GENE
.	O

Moreover	O
,	O
the	O
noncoordinate	O
effects	O
of	O
FSK	B-GENE
on	O
PMA	O
-	O
stimulated	O
MKK	B-GENE
and	O
MAPK	B-GENE
activities	O
indicates	O
the	O
presence	O
of	O
a	O
additional	O
distal	O
cAMP	O
-	O
dependent	O
inhibitory	O
mechanisms	O
.	O

Motilin	B-GENE
serum	O
levels	O
were	O
measured	O
for	O
one	O
hour	O
.	O

Parameters	O
of	O
sperm	O
quality	O
were	O
evaluated	O
before	O
and	O
after	O
freezing	O
/	O
thawing	O
.	O

Comment	O
on	O
"	O
Critical	O
behavior	O
of	O
a	O
binary	O
mixture	O
of	O
protein	O
and	O
salt	O
water	O
"	O

Site	O
-	O
directed	O
mutagenesis	O
was	O
conducted	O
to	O
investigate	O
the	O
functional	O
significance	O
of	O
this	O
element	O
and	O
the	O
3	O
'	O
minus	O
-	O
strand	O
terminal	O
sequence	O
"	O
3	O
'	O
-	O
OH	O
-	O
CCCUAU	O
,	O
"	O
which	O
contains	O
the	O
minus	O
-	O
strand	O
3	O
'	O
-	O
end	O
sequence	O
"	O
3	O
'	O
-	O
OH	O
-	O
CC	O
(	O
1	O
-	O
2	O
)	O
(	O
A	O
/	O
U	O
)	O
(	O
A	O
/	O
U	O
)	O
(	O
A	O
/	O
U	O
)	O
"	O
found	O
in	O
all	O
carmovirus	O
RNAs	O
.	O

Characterization	O
of	O
a	O
nuclear	B-GENE
deformed	I-GENE
epidermal	I-GENE
autoregulatory	I-GENE
factor	I-GENE
-	I-GENE
1	I-GENE
(	O
DEAF	B-GENE
-	I-GENE
1	I-GENE
)	O
-	O
related	O
(	O
NUDR	B-GENE
)	O
transcriptional	O
regulator	O
protein	O
.	O

Cardiac	O
lesion	O
in	O
exotoxic	O
shock	O

Effect	O
of	O
family	O
visits	O
on	O
the	O
blood	O
pressure	O
and	O
heart	O
rate	O
of	O
patients	O
in	O
the	O
coronary	O
-	O
care	O
unit	O
.	O

Prospects	O
of	O
chemosterilant	O
and	O
genetic	O
control	O
of	O
rodents	O
.	O

Neurological	O
toxicity	O
occurred	O
in	O
8	O
/	O
219	O
patients	O
treated	O
with	O
fludarabine	O
(	O
FAMP	O
)	O
,	O
30	O
mg	O
/	O
m2	O
per	O
day	O
and	O
cytosine	O
arabinoside	O
(	O
Ara	O
-	O
C	O
)	O
,	O
0	O
.	O
5	O
g	O
/	O
m2	O
per	O
hour	O
for	O
2	O
-	O
6	O
hours	O
for	O
5	O
days	O
,	O
for	O
new	O
or	O
relapsed	O
acute	O
leukemia	O
or	O
myelodysplasia	O
.	O

Ondansetron	O
is	O
thus	O
an	O
effective	O
first	O
-	O
line	O
antiemetic	O
in	O
children	O
undergoing	O
chemotherapy	O
,	O
radiotherapy	O
and	O
surgery	O
.	O

Paclitaxel	O
caused	O
a	O
rapid	O
and	O
transient	O
increase	O
in	O
c	B-GENE
-	I-GENE
Jun	I-GENE
NH2	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
)	O
activity	O
,	O
a	O
proposed	O
mediator	O
of	O
stress	O
activation	O
pathways	O
.	O

Aspirin	O
therapy	O
in	O
the	O
rheumatic	O
diseases	O
.	O

High	O
-	O
level	O
expression	O
of	O
sccypB	B-GENE
as	O
well	O
as	O
of	O
sccypA	B-GENE
cloned	O
into	O
the	O
expression	O
vector	O
pIJ702	O
did	O
not	O
produce	O
detectable	O
changes	O
in	O
growth	O
and	O
morphology	O
of	O
S	O
.	O
chrysomallus	O
and	O
S	O
.	O
lividans	O
.	O

Reasons	O
are	O
presented	O
to	O
support	O
the	O
contention	O
that	O
this	O
increase	O
is	O
in	O
part	O
real	O
.	O

Expression	O
of	O
the	O
Hox	B-GENE
genes	I-GENE
egl	B-GENE
-	I-GENE
5	I-GENE
and	O
mab	B-GENE
-	I-GENE
5	I-GENE
is	O
reduced	O
in	O
lin	B-GENE
-	I-GENE
49	I-GENE
and	O
lin	B-GENE
-	I-GENE
59	I-GENE
mutants	I-GENE
,	O
suggesting	O
lin	B-GENE
-	I-GENE
49	I-GENE
and	O
lin	B-GENE
-	I-GENE
59	I-GENE
regulate	O
HOM	B-GENE
-	I-GENE
C	I-GENE
gene	I-GENE
expression	O
in	O
C	O
.	O
elegans	O
as	O
the	O
trx	B-GENE
-	I-GENE
G	I-GENE
genes	I-GENE
do	O
in	O
Drosophila	O
.	O
lin	B-GENE
-	I-GENE
49	I-GENE
and	O
lin	B-GENE
-	I-GENE
59	I-GENE
transgenes	I-GENE
are	O
expressed	O
widely	O
throughout	O
C	O
.	O
elegans	O
animals	O
.	O

In	O
cotransfection	O
assays	O
,	O
a	O
small	O
fragment	O
of	O
Sin	B-GENE
retaining	O
the	O
Src	B-GENE
-	O
SH3	B-GENE
-	O
binding	O
site	O
and	O
one	O
tyrosine	O
-	O
containing	O
motif	O
induced	O
c	B-GENE
-	I-GENE
Src	I-GENE
activation	O
as	O
measured	O
by	O
a	O
transcriptional	O
reporter	O
.	O

TFIIB	B-GENE
and	O
VDR	B-GENE
can	O
also	O
interact	O
directly	O
,	O
and	O
these	O
factors	O
synergize	O
to	O
mediate	O
transactivation	O
.	O

In	O
addition	O
,	O
269	O
mice	O
from	O
a	O
(	O
Mus	O
spretus	O
x	O
C57BL	O
/	O
6J	O
)	O
F1	O
x	O
C57BL	O
/	O
6J	O
interspecific	O
backcross	O
were	O
also	O
used	O
to	O
order	O
marker	O
loci	O
and	O
calculate	O
intergene	O
distances	O
for	O
this	O
region	O
.	O

Our	O
findings	O
suggest	O
that	O
AIF	O
may	O
be	O
a	O
morphologic	O
correlate	O
of	O
tumor	O
regression	O
following	O
preoperative	O
cytotoxic	O
chemotherapy	O
.	O

Hypocalcemia	O
is	O
usually	O
due	O
to	O
either	O
a	O
disturbance	O
in	O
the	O
parathyroid	B-GENE
hormone	I-GENE
-	O
adenylate	B-GENE
cyclase	I-GENE
system	O
or	O
a	O
disturbance	O
in	O
vitamin	O
D	O
metabolism	O
.	O

The	O
system	O
consists	O
of	O
a	O
TV	O
unit	O
compatible	O
to	O
IBM	O
PC	O
/	O
AT	O
and	O
software	O
.	O

Newly	O
hatched	O
F1	O
nymphs	O
of	O
Aiolopus	O
thalassinus	O
(	O
Fabr	O
.	O
)	O
were	O
fed	O
on	O
food	O
treated	O
with	O
various	O
concentrations	O
of	O
HgCl2	O
,	O
CdCl2	O
,	O
and	O
PbCl2	O
until	O
the	O
end	O
of	O
adult	O
life	O
.	O

Reduced	O
concentrations	O
of	O
antithrombin	B-GENE
III	I-GENE
,	O
plasminogen	B-GENE
,	O
(	O
free	O
)	O
protein	B-GENE
S	I-GENE
,	O
and	O
protein	B-GENE
C	I-GENE
were	O
found	O
in	O
some	O
patients	O
but	O
were	O
not	O
associated	O
with	O
either	O
thrombosis	O
or	O
lupus	O
anticoagulant	O
.	O

UICC	O
criteria	O
)	O
for	O
VM	O
and	O
35	O
%	O
for	O
VE	O
(	O
not	O
significant	O
)	O
.	O

Simvastatin	O
decreased	O
levels	O
of	O
total	O
cholesterol	O
by	O
20	O
.	O
8	O
%	O
,	O
LDL	B-GENE
cholesterol	I-GENE
by	O
29	O
.	O
7	O
%	O
,	O
triglycerides	O
by	O
13	O
.	O
6	O
%	O
,	O
apolipoprotein	B-GENE
B	I-GENE
by	O
22	O
.	O
4	O
%	O
,	O
alpha	O
-	O
tocopherol	O
by	O
16	O
.	O
2	O
%	O
,	O
beta	O
-	O
carotene	O
by	O
19	O
.	O
5	O
%	O
,	O
and	O
ubiquinol	O
-	O
10	O
by	O
22	O
.	O
0	O
%	O
(	O
P	O
<	O
.	O
001	O
for	O
all	O
)	O
and	O
increased	O
levels	O
of	O
HDL	B-GENE
cholesterol	I-GENE
by	O
7	O
.	O
0	O
%	O
(	O
P	O
<	O
.	O
001	O
)	O
and	O
serum	B-GENE
insulin	I-GENE
by	O
13	O
.	O
2	O
%	O
(	O
P	O
=	O
.	O
005	O
)	O
.	O

Ultrasonography	O
is	O
a	O
diagnostic	O
alternative	O
which	O
may	O
replace	O
arthrography	O
.	O

Northern	O
blot	O
analysis	O
with	O
GPR37	B-GENE
probes	O
revealed	O
a	O
main	O
3	O
.	O
8	O
-	O
kb	O
mRNA	O
and	O
a	O
less	O
abundant	O
8	O
-	O
kb	O
mRNA	O
,	O
both	O
expressed	O
in	O
human	O
brain	O
tissues	O
,	O
particularly	O
in	O
corpus	O
callosum	O
,	O
medulla	O
,	O
putamen	O
,	O
and	O
caudate	O
nucleus	O
.	O

TNF	B-GENE
-	I-GENE
alpha	I-GENE
effect	O
was	O
eliminated	O
by	O
a	O
2	O
-	O
bp	O
substitution	O
mutation	O
in	O
the	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B1	I-GENE
binding	I-GENE
half	I-GENE
site	I-GENE
of	O
the	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
cis	I-GENE
element	I-GENE
.	O

Three	O
RasV12	B-GENE
mutants	I-GENE
(	O
S35	B-GENE
,	O
G37	B-GENE
,	O
and	O
C40	B-GENE
)	O
which	O
differ	O
by	O
their	O
ability	O
to	O
bind	O
to	O
Ras	B-GENE
effectors	I-GENE
(	O
Raf	B-GENE
,	O
Ral	B-GENE
-	I-GENE
GEFs	I-GENE
,	O
and	O
the	O
p110	B-GENE
subunit	I-GENE
of	I-GENE
PI	I-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
,	O
respectively	O
)	O
were	O
able	O
to	O
induce	O
sustained	O
NR	O
cell	O
proliferation	O
,	O
although	O
none	O
of	O
these	O
mutants	O
was	O
reported	O
to	O
transform	O
NIH	O
3T3	O
cells	O
.	O

A	O
possible	O
correlation	O
between	O
mandibular	O
growth	O
retardation	O
and	O
palatal	O
clefting	O
is	O
discussed	O
.	O

Total	O
cross	O
sections	O
for	O
electron	O
scattering	O
by	O
CO2	O
molecules	O
in	O
the	O
energy	O
range	O
400	O
-	O
5000	O
eV	O
.	O

However	O
,	O
depending	O
upon	O
the	O
promoter	O
context	O
,	O
we	O
observed	O
cooperative	O
interactions	O
between	O
the	O
two	O
domains	O
to	O
confer	O
high	O
DNA	O
-	O
binding	O
affinity	O
and	O
specificity	O
.	O

RESEARCH	O
DESIGN	O
AND	O
METHODS	O
:	O
A	O
total	O
of	O
26	O
IDDM	O
patients	O
with	O
normoalbuminuria	O
were	O
randomized	O
into	O
two	O
groups	O
,	O
with	O
one	O
group	O
receiving	O
placebo	O
(	O
n	O
=	O
13	O
,	O
age	O
36	O
+	O
/	O
-	O
3	O
years	O
,	O
BMI	O
24	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
1	O
kg	O
/	O
m2	O
)	O
and	O
the	O
other	O
group	O
receiving	O
an	O
average	O
of	O
15	O
mg	O
lisinopril	O
daily	O
(	O
n	O
=	O
13	O
,	O
age	O
34	O
+	O
/	O
-	O
2	O
years	O
,	O
BMI	O
24	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
9	O
kg	O
/	O
m2	O
)	O
.	O

This	O
experience	O
would	O
recommend	O
consideration	O
of	O
home	O
nutritional	O
support	O
in	O
patients	O
with	O
systemic	O
scleroderma	O
when	O
the	O
disease	O
is	O
relatively	O
stable	O
and	O
no	O
major	O
organ	O
failure	O
is	O
present	O
.	O

Adult	O
-	O
onset	O
parkinsonism	O
has	O
appeared	O
in	O
several	O
previously	O
unaffected	O
members	O
in	O
families	O
with	O
DRD	O
suggesting	O
that	O
this	O
may	O
be	O
an	O
additional	O
phenotypical	O
expression	O
of	O
the	O
disease	O
.	O

Production	O
of	O
VT	O
was	O
also	O
examined	O
retrospectively	O
in	O
32	O
E	O
.	O
coli	O
strains	O
of	O
serotype	O
O26	O
:	O
H11	O
isolated	O
from	O
children	O
with	O
diarrhoea	O
;	O
eight	O
(	O
25	O
%	O
)	O
of	O
them	O
produced	O
moderate	O
to	O
high	O
levels	O
of	O
verotoxin	B-GENE
1	I-GENE
despite	O
several	O
years	O
storage	O
in	O
vitro	O
.	O

The	O
present	O
study	O
deals	O
with	O
the	O
screening	O
of	O
11	O
of	O
these	O
plants	O
against	O
the	O
opportunistic	O
pathogen	O
fungus	O
Candida	O
albicans	O
.	O

The	O
tam	B-GENE
A	I-GENE
gene	I-GENE
of	I-GENE
Aspergillus	I-GENE
nidulans	I-GENE
encodes	O
a	O
739	O
-	O
amino	O
acid	O
protein	O
with	O
similarity	O
to	O
Uga35p	B-GENE
/	O
Dal81p	B-GENE
/	O
DurLp	B-GENE
of	O
Saccharomyces	O
cerevisiae	O
.	O

The	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
gene	O
,	O
approximately	O
1	O
.	O
1	O
kbp	O
long	O
,	O
had	O
no	O
known	O
regulatory	O
elements	O
for	O
transcription	O
such	O
as	O
TATA	O
,	O
GC	O
,	O
and	O
CCAAT	O
boxes	O
.	O

The	O
Molteno	O
implant	O
is	O
an	O
effective	O
procedure	O
in	O
the	O
treatment	O
of	O
complicated	O
and	O
refractory	O
cases	O
of	O
glaucoma	O
in	O
high	O
-	O
risk	O
eyes	O
.	O

Two	O
of	O
the	O
three	O
groups	O
were	O
submitted	O
to	O
two	O
different	O
levels	O
of	O
hypoxia	O
(	O
FiO2	O
=	O
0	O
.	O
05	O
,	O
group	O
F5	O
and	O
FiO2	O
=	O
0	O
.	O
1	O
,	O
group	O
F10	O
)	O
and	O
the	O
third	O
to	O
normoxia	O
(	O
FiO2	O
=	O
0	O
.	O
21	O
,	O
group	O
F21	O
)	O
in	O
a	O
thermoneutral	O
and	O
controlled	O
environment	O
.	O

Glutathione	B-GENE
reductase	I-GENE
(	O
GR	B-GENE
)	O
was	O
purified	O
from	O
the	O
cyanobacterium	O
Anabaena	O
PCC	O
7120	O
.	O

Genotype	O
-	O
phenotype	O
correlations	O
in	O
male	O
patients	O
with	O
a	O
partial	O
nullisomy	O
of	O
the	O
X	O
chromosome	O
have	O
suggested	O
that	O
at	O
least	O
one	O
locus	O
involved	O
in	O
MRX	O
is	O
on	O
Xp22	O
.	O
3	O
.	O

On	O
the	O
other	O
hand	O
,	O
NE	O
transport	O
and	O
antagonist	O
(	O
[	O
125I	O
]	O
RTI	O
-	O
55	O
)	O
binding	O
assays	O
on	O
whole	O
LLC	O
-	O
NET	O
cells	O
treated	O
with	O
tunicamycin	O
reveal	O
a	O
pronounced	O
reduction	O
in	O
NE	O
transport	O
activity	O
and	O
hNET	B-GENE
membrane	O
density	O
paralleled	O
by	O
an	O
inability	O
of	O
NET	B-GENE
proteins	I-GENE
to	O
replenish	O
the	O
higher	O
M	O
(	O
r	O
)	O
hNET	B-GENE
pool	O
.	O

We	O
have	O
now	O
completed	O
the	O
primary	O
structure	O
of	O
fibrillin	B-GENE
,	O
elucidated	O
the	O
exon	O
/	O
intron	O
organization	O
of	O
the	O
gene	O
and	O
derived	O
a	O
physical	O
map	O
of	O
the	O
genetic	O
locus	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
of	O
PutR	B-GENE
(	O
154	O
amino	O
acid	O
residues	O
)	O
showed	O
homology	O
to	O
the	O
small	O
regulatory	O
proteins	O
Lrp	B-GENE
,	O
BkdR	B-GENE
,	O
and	O
AsnC	B-GENE
.	O

NF	B-GENE
-	I-GENE
kappaB	I-GENE
only	O
partially	O
mediates	O
Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
latent	I-GENE
membrane	I-GENE
protein	I-GENE
1	I-GENE
activation	O
of	O
B	O
cells	O
.	O

In	O
contrast	O
,	O
stem	O
-	O
loop	O
structures	O
2	O
,	O
3	O
,	O
and	O
4	O
of	O
the	O
3	O
'	O
domain	O
showed	O
great	O
variations	O
in	O
size	O
,	O
sequence	O
,	O
and	O
structure	O
.	O

Whereas	O
Sprague	O
-	O
Dawleys	O
displayed	O
lights	O
-	O
off	O
and	O
lights	O
-	O
on	O
peaks	O
of	O
ingestive	O
activity	O
,	O
only	O
a	O
minority	O
of	O
Fisher	O
-	O
344s	O
displayed	O
a	O
consistent	O
lights	O
-	O
on	O
peak	O
of	O
ingestive	O
activity	O
.	O

The	O
mammalian	O
UPR	O
is	O
mediated	O
by	O
the	O
cis	O
-	O
acting	O
ER	O
stress	O
response	O
element	O
consisting	O
of	O
19	O
nt	O
(	O
CCAATN	O
(	O
9	O
)	O
CCACG	O
)	O
,	O
the	O
CCACG	O
part	O
of	O
which	O
is	O
considered	O
to	O
provide	O
specificity	O
.	O

Effects	O
of	O
dietary	O
lipids	O
on	O
whole	O
-	O
body	O
retention	O
and	O
organ	O
distribution	O
of	O
organic	O
and	O
inorganic	O
mercury	O
in	O
mice	O
.	O

This	O
region	O
shows	O
46	O
%	O
identity	O
with	O
the	O
calmodulin	B-GENE
-	I-GENE
binding	I-GENE
region	I-GENE
of	O
rat	B-GENE
brain	I-GENE
Ca2	I-GENE
+	I-GENE
/	I-GENE
calmodulin	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
II	I-GENE
and	O
32	O
%	O
identity	O
with	O
the	O
equivalent	O
region	O
of	O
chicken	B-GENE
smooth	I-GENE
muscle	I-GENE
myosin	I-GENE
light	I-GENE
chain	I-GENE
kinase	I-GENE
.	O

1H	O
and	O
15N	O
magnetic	O
resonance	O
assignments	O
,	O
secondary	O
structure	O
,	O
and	O
tertiary	O
fold	O
of	O
Escherichia	B-GENE
coli	I-GENE
DnaJ	I-GENE
(	I-GENE
1	I-GENE
-	I-GENE
78	I-GENE
)	I-GENE
.	O

The	O
effects	O
of	O
inoculum	O
size	O
,	O
medium	O
,	O
temperature	O
,	O
and	O
duration	O
of	O
growth	O
on	O
the	O
in	O
vitro	O
susceptibility	O
testing	O
of	O
Aspergillus	O
fumigatus	O
were	O
investigated	O
using	O
broth	O
micro	O
-	O
and	O
macro	O
-	O
dilution	O
techniques	O
.	O

Copyright	O
1998	O
Academic	O
Press	O
.	O

This	O
dynamic	O
nature	O
may	O
be	O
relevant	O
to	O
the	O
ability	O
of	O
E47	B-GENE
both	O
to	O
homodimerize	O
and	O
to	O
heterodimerize	O
with	O
MyoD	B-GENE
,	O
Id	B-GENE
,	O
and	O
Tal1	B-GENE
.	O

We	O
identified	O
clones	O
of	O
Chlamydomonas	O
genomic	O
DNA	O
that	O
rescued	O
the	O
Ca	O
(	O
2	O
+	O
)	O
-	O
dependent	O
axonemal	O
microtubule	O
severing	O
defect	O
of	O
fa1	B-GENE
mutants	I-GENE
.	O

STUDY	O
SELECTION	O
:	O
Not	O
applicable	O
.	O

Sequence	O
and	O
deletion	O
analysis	O
of	O
the	O
recombination	B-GENE
enhancement	I-GENE
gene	I-GENE
(	O
ref	B-GENE
)	O
of	O
bacteriophage	O
P1	O
:	O
evidence	O
for	O
promoter	O
-	O
operator	O
and	O
attenuator	O
-	O
antiterminator	O
control	O
.	O

Viral	B-GENE
protein	I-GENE
U	I-GENE
(	O
Vpu	B-GENE
)	O
is	O
a	O
protein	O
encoded	O
by	O
human	O
immunodeficiency	O
virus	O
type	O
1	O
(	O
HIV	O
-	O
1	O
)	O
that	O
promotes	O
the	O
degradation	O
of	O
the	O
virus	O
receptor	O
,	O
CD4	B-GENE
,	O
and	O
enhances	O
the	O
release	O
of	O
virus	O
particles	O
from	O
cells	O
.	O

There	O
also	O
may	O
be	O
osmotic	O
challenges	O
to	O
mucosal	O
cell	O
function	O
as	O
evidenced	O
by	O
the	O
different	O
reaction	O
rates	O
with	O
hyper	O
-	O
and	O
hypotonic	O
saline	O
.	O

The	O
overall	O
objective	O
response	O
rate	O
(	O
RR	O
)	O
was	O
50	O
%	O
[	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
=	O
29	O
-	O
71	O
%	O
]	O
including	O
four	O
complete	O
responses	O
and	O
eight	O
partial	O
responses	O
.	O

In	O
spite	O
of	O
the	O
variability	O
of	O
DD95	O
with	O
regard	O
to	O
body	O
weight	O
,	O
the	O
recovery	O
of	O
neuromuscular	O
transmission	O
in	O
the	O
patients	O
of	O
the	O
three	O
groups	O
is	O
comparable	O
.	O

SH3A	B-GENE
competes	O
with	O
the	O
SH3	B-GENE
domains	I-GENE
of	O
Grb2	B-GENE
in	O
binding	O
to	O
mSos1	B-GENE
,	O
and	O
the	O
intersectin	B-GENE
-	O
mSos1	B-GENE
complex	O
can	O
be	O
separated	O
from	O
Grb2	B-GENE
by	O
sucrose	O
gradient	O
centrifugation	O
.	O

Both	O
oligonucleotide	O
cross	O
-	O
competition	O
and	O
antibody	O
supershift	O
experiments	O
established	O
that	O
the	O
double	O
-	O
strand	O
binding	O
protein	O
is	O
equivalent	O
to	O
Sp1	B-GENE
.	O

The	O
major	O
transcription	O
start	O
site	O
,	O
designated	O
as	O
+	O
1	O
,	O
was	O
determined	O
by	O
RACE	O
(	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
)	O
analysis	O
of	O
human	O
liver	O
cDNA	O
and	O
was	O
found	O
to	O
be	O
located	O
50	O
bp	O
upstream	O
from	O
the	O
translation	O
start	O
site	O
.	O

Kerstin	O
takes	O
the	O
abbreviated	O
medical	O
education	O
.	O

Epithelial	O
cells	O
had	O
abnormal	O
and	O
accelerated	O
exfoliation	O
which	O
resulted	O
in	O
multifocal	O
epithelial	O
defects	O
.	O

Influenza	O
virus	O
-	O
induced	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	I-GENE
dependent	I-GENE
gene	I-GENE
expression	O
is	O
mediated	O
by	O
overexpression	O
of	O
viral	O
proteins	O
and	O
involves	O
oxidative	O
radicals	O
and	O
activation	O
of	O
IkappaB	B-GENE
kinase	I-GENE
.	O

The	O
Xenopus	B-GENE
annexin	I-GENE
II	I-GENE
heavy	I-GENE
chain	I-GENE
lacks	O
the	O
highly	O
conserved	O
tyrosine	O
at	O
position	O
23	O
which	O
is	O
the	O
site	O
of	O
src	B-GENE
oncogene	I-GENE
tyrosine	B-GENE
kinase	I-GENE
phosphorylation	O
in	O
the	O
murine	O
protein	O
.	O

This	O
demonstrates	O
a	O
relative	O
independence	O
of	O
the	O
given	O
synchronizer	O
of	O
rhythmicity	O
at	O
a	O
tissue	O
level	O
from	O
any	O
influence	O
of	O
the	O
higher	O
regulatory	O
center	O
.	O

Two	O
of	O
the	O
proteins	O
UPRF	B-GENE
-	I-GENE
1	I-GENE
and	O
UPRF	B-GENE
-	I-GENE
2	I-GENE
(	O
which	O
is	O
apparently	O
a	O
proteolytic	O
degradation	O
product	O
of	O
UPRF	B-GENE
-	I-GENE
1	I-GENE
)	O
bind	O
inefficiently	O
to	O
mutant	O
versions	O
of	O
the	O
UPR	O
that	O
are	O
unable	O
to	O
confer	O
responsiveness	O
to	O
unfolded	O
proteins	O
to	O
the	O
(	O
CYC1	B-GENE
)	O
promoter	O
.	O

Since	O
nearly	O
all	O
transformants	O
involving	O
homeologous	O
DNAs	O
carried	O
a	O
single	O
recombinant	O
plasmid	O
in	O
both	O
Pms	B-GENE
+	I-GENE
and	O
Pms	B-GENE
-	I-GENE
strains	O
,	O
stable	O
heteroduplex	O
DNA	O
appears	O
less	O
likely	O
than	O
for	O
homologous	O
DNAs	O
.	O

Western	O
and	O
immunocytochemical	O
analysis	O
implied	O
that	O
PREB	B-GENE
accumulates	O
specifically	O
in	O
GH3	O
cell	O
nuclei	O
.	O

Coronary	O
arteries	O
were	O
found	O
in	O
the	O
biopsy	O
tissue	O
of	O
30	O
(	O
76	O
%	O
)	O
of	O
the	O
39	O
patients	O
who	O
formed	O
the	O
study	O
group	O
.	O

Cotransfection	O
of	O
a	O
junB	B-GENE
stimulated	O
the	O
basal	O
activity	O
of	O
the	O
alpha	B-GENE
2	I-GENE
(	I-GENE
I	I-GENE
)	I-GENE
collagen	I-GENE
promoter	I-GENE
93	O
-	O
fold	O
,	O
respectively	O
.	O

The	O
extraordinary	O
high	O
substrate	O
specificity	O
of	O
rPulA	B-GENE
together	O
with	O
its	O
thermal	O
stability	O
makes	O
this	O
enzyme	O
a	O
good	O
candidate	O
for	O
biotechnological	O
applications	O
in	O
the	O
starch	O
-	O
processing	O
industry	O
.	O

An	O
atypical	O
form	O
of	O
juvenile	O
myasthenia	O
gravis	O
associated	O
with	O
severe	O
emaciation	O
,	O
muscle	O
atrophy	O
,	O
ophthalmoplegia	O
,	O
bulbar	O
signs	O
and	O
joint	O
contracture	O

Anesthesia	O
was	O
induced	O
by	O
droperidol	O
0	O
.	O
2	O
mg	O
.	O
kg	O
-	O
1	O
,	O
fentanyl	O
50	O
micrograms	O
,	O
thiamylal	O
150	O
-	O
250	O
mg	O
,	O
and	O
succinylcholine	O
1	O
mg	O
.	O
kg	O
-	O
1	O
,	O
and	O
maintained	O
with	O
nitrous	O
oxide	O
and	O
O2	O
(	O
67	O
:	O
33	O
)	O
supplemented	O
with	O
repeated	O
i	O
.	O
v	O
.	O
doses	O
of	O
fentanyl	O
(	O
within	O
15	O
micrograms	O
.	O
kg	O
-	O
1	O
)	O
.	O

In	O
this	O
system	O
,	O
enhancers	O
act	O
primarily	O
to	O
increase	O
the	O
probability	O
of	O
rapid	O
and	O
efficient	O
transcription	O
complex	O
formation	O
and	O
initiation	O
.	O

(	O
i	O
)	O
p60	B-GENE
bound	O
fast	O
-	O
migrating	O
,	O
underprocessed	O
wild	B-GENE
-	I-GENE
type	I-GENE
ICP22	I-GENE
and	O
ICP22	B-GENE
lacking	O
the	O
carboxyl	O
-	O
terminal	O
24	O
amino	O
acids	O
but	O
not	O
ICP22	B-GENE
lacking	O
the	O
carboxyl	O
-	O
terminal	O
40	O
amino	O
acids	O
,	O
whereas	O
the	O
previously	O
identified	O
cellular	B-GENE
protein	I-GENE
p78	I-GENE
(	O
R	O
.	O

Hetero	O
-	O
oligomerization	O
of	O
Smad4	B-GENE
with	O
the	O
pathway	O
-	O
restricted	O
SMAD	B-GENE
proteins	I-GENE
is	O
essential	O
for	O
Smad4	B-GENE
-	O
mediated	O
transcription	O
.	O

This	O
group	O
showed	O
the	O
presence	O
of	O
bacteria	O
infiltrated	O
at	O
the	O
dentinal	O
tubules	O
coronally	O
and	O
into	O
the	O
root	O
canals	O
.	O

Hydroxyl	O
radical	O
footprinting	O
of	O
DNA	O
complexes	O
of	O
the	O
ets	B-GENE
domain	I-GENE
of	O
PU	B-GENE
.	I-GENE
1	I-GENE
and	O
its	O
comparison	O
to	O
the	O
crystal	O
structure	O
.	O

Autophosphorylation	O
on	O
the	O
major	O
phosphorylation	O
site	O
Y1235	O
upregulates	O
the	O
kinase	O
activity	O
of	O
the	O
receptor	O
,	O
increasing	O
the	O
Vmax	O
of	O
the	O
phosphotransfer	O
reaction	O
.	O

The	O
generation	O
of	O
dorso	O
-	O
ventral	O
polarity	O
during	O
Drosophila	O
embryogenesis	O
is	O
regulated	O
by	O
the	O
action	O
of	O
12	O
maternally	O
expressed	O
gene	O
products	O
,	O
the	O
dorsal	B-GENE
group	I-GENE
.	O

Immunoblot	O
analysis	O
of	O
purified	O
and	O
protease	O
-	O
digested	O
intracellular	O
mature	O
virus	O
(	O
IMV	O
)	O
and	O
extracellular	O
enveloped	O
virus	O
(	O
EEV	O
)	O
showed	O
that	O
the	O
A36R	B-GENE
proteins	I-GENE
were	O
present	O
on	O
the	O
surface	O
of	O
EEV	O
with	O
type	O
II	O
membrane	O
topology	O
,	O
but	O
were	O
absent	O
from	O
IMV	O
.	O

To	O
prevent	O
section	O
wrinkles	O
usually	O
encountered	O
with	O
the	O
use	O
of	O
coated	O
single	O
-	O
hole	O
grids	O
,	O
a	O
simple	O
method	O
was	O
developed	O
.	O

An	O
alternative	O
approach	O
to	O
random	O
integration	O
of	O
large	O
DNA	O
fragments	O
into	O
plants	O
is	O
to	O
utilize	O
one	O
of	O
several	O
site	O
-	O
specific	O
recombination	O
(	O
SSR	O
)	O
systems	O
,	O
such	O
as	O
Cre	B-GENE
/	O
lox	B-GENE
.	O

Both	O
v	B-GENE
-	I-GENE
Myb	I-GENE
and	O
c	B-GENE
-	I-GENE
Myb	I-GENE
bind	O
specifically	O
to	O
delta	B-GENE
E3	I-GENE
.	O

After	O
at	O
least	O
one	O
year	O
follow	O
-	O
up	O
,	O
argon	O
laser	O
showed	O
a	O
statistically	O
significant	O
effect	O
(	O
p	O
less	O
of	O
0	O
,	O
01	O
;	O
Kolmogorow	O
-	O
Smirnov	O
test	O
)	O
on	O
the	O
stabilization	O
or	O
the	O
amelioration	O
of	O
visual	O
acuity	O
compared	O
with	O
the	O
non	O
treated	O
group	O
.	O

As	O
part	O
of	O
a	O
large	O
Dutch	O
prospective	O
multicenter	O
study	O
(	O
Netherlands	O
Cooperative	O
Study	O
on	O
the	O
Adequacy	O
of	O
Dialysis	O
-	O
2	O
)	O
,	O
we	O
consecutively	O
included	O
all	O
new	O
patients	O
with	O
end	O
-	O
stage	O
renal	O
disease	O
for	O
whom	O
residual	O
renal	O
function	O
could	O
be	O
obtained	O
0	O
to	O
4	O
weeks	O
before	O
the	O
start	O
of	O
dialysis	O
therapy	O
.	O

Relationship	O
between	O
age	O
-	O
associated	O
endocrine	O
deficiencies	O
and	O
muscle	O
function	O
in	O
elderly	O
women	O
:	O
a	O
cross	O
-	O
sectional	O
study	O
.	O

Intensity	O
variations	O
from	O
the	O
variable	O
TR	O
were	O
removed	O
,	O
and	O
the	O
data	O
were	O
evaluated	O
for	O
correlation	O
with	O
the	O
lateralized	O
stimulus	O
.	O

Improvement	O
of	O
some	O
pharmaceutical	O
properties	O
of	O
clofibrate	O
by	O
cyclodextrin	O
complexation	O
.	O

We	O
assessed	O
cardiovascular	O
variables	O
and	O
blood	O
O2	O
contents	O
in	O
order	O
to	O
characterize	O
O2	O
transport	O
in	O
ponies	O
during	O
treadmill	O
exercise	O
.	O

Somatic	O
and	O
visceral	O
inputs	O
to	O
the	O
thoracic	O
spinal	O
cord	O
of	O
the	O
cat	O
:	O
effects	O
of	O
noxious	O
stimulation	O
of	O
the	O
biliary	O
system	O
.	O

Some	O
of	O
these	O
DNA	O
:	O
protein	O
complexes	O
were	O
also	O
present	O
,	O
but	O
at	O
lower	O
levels	O
,	O
in	O
nuclear	O
extracts	O
from	O
untransformed	O
rat	O
cells	O
suggesting	O
the	O
possible	O
involvement	O
of	O
cellular	O
factors	O
in	O
the	O
mechanism	O
of	O
down	O
-	O
regulation	O
mediated	O
by	O
Ad12	B-GENE
E1A	I-GENE
.	O

We	O
suggest	O
that	O
the	O
induction	O
of	O
IFNA	B-GENE
promoter	I-GENE
region	I-GENE
requires	O
cooperation	O
between	O
alpha	B-GENE
F1	I-GENE
binding	I-GENE
proteins	I-GENE
and	O
IRF	B-GENE
-	I-GENE
1	I-GENE
.	O

Two	O
pharmacokinetic	O
models	O
were	O
compared	O
.	O

Morphine	O
administration	O
acutely	O
reduced	O
plasma	O
clearance	O
of	O
sulfobromophthalein	O
(	O
BSP	O
)	O
in	O
mice	O
and	O
increased	O
hepatic	O
retention	O
of	O
this	O
dye	O
.	O

A	O
Buddhist	O
view	O
of	O
abortion	O
.	O

Cryoglobulinaemia	O
among	O
maintenance	O
haemodialysis	O
patients	O
and	O
its	O
relation	O
to	O
hepatitis	O
C	O
infection	O
.	O

In	O
HepG2	O
cells	O
,	O
SREBP	B-GENE
-	I-GENE
1c	I-GENE
mRNA	I-GENE
and	O
precursor	O
protein	O
levels	O
were	O
induced	O
by	O
treatment	O
with	O
22	O
(	O
R	O
)	O
-	O
hydroxycholesterol	O
and	O
9	O
-	O
cis	O
-	O
retinoic	O
acid	O
,	O
confirming	O
that	O
endogenous	O
LXR	B-GENE
-	O
RXR	B-GENE
activation	O
can	O
induce	O
endogenous	B-GENE
SREBP	I-GENE
-	I-GENE
1c	I-GENE
expression	O
.	O

The	O
T	O
(	O
CCO2	O
)	O
was	O
related	O
to	O
the	O
PCO2	O
by	O
a	O
Pearson	O
product	O
coefficient	O
of	O
0	O
.	O
79	O
(	O
p	O
<	O
.	O
0005	O
)	O
,	O
with	O
a	O
mean	O
difference	O
of	O
1	O
.	O
94	O
(	O
T	O
(	O
CCO2	O
)	O
>	O
P	O
(	O
CO2	O
)	O
and	O
95	O
%	O
confidence	O
interval	O
of	O
-	O
0	O
.	O
12	O
to	O
4	O
.	O
07	O
.	O

Comparison	O
of	O
the	O
footprint	O
patterns	O
of	O
the	O
mouse	B-GENE
and	I-GENE
human	I-GENE
HPRT	I-GENE
genes	I-GENE
demonstrated	O
that	O
the	O
in	O
vivo	O
binding	O
of	O
regulatory	O
proteins	O
between	O
these	O
species	O
is	O
generally	O
conserved	O
but	O
not	O
identical	O
.	O

In	O
this	O
study	O
,	O
we	O
sought	O
to	O
determine	O
the	O
specific	O
effect	O
of	O
HIV	B-GENE
protease	I-GENE
inhibitors	O
on	O
patient	O
weight	O
.	O

The	O
cats	O
with	O
stage	O
-	O
2	O
lymphomas	O
that	O
were	O
FeLV	O
-	O
test	O
negative	O
had	O
the	O
best	O
response	O
to	O
treatment	O
.	O

E1	B-GENE
recognition	O
sequences	O
in	O
the	O
bovine	O
papillomavirus	O
type	O
1	O
origin	O
of	O
DNA	O
replication	O
:	O
interaction	O
between	O
half	O
sites	O
of	O
the	O
inverted	O
repeats	O
.	O

Phase	O
I	O
study	O
of	O
5	O
-	O
fluorouracil	O
and	O
leucovorin	O
by	O
a	O
14	O
-	O
day	O
circadian	O
infusion	O
in	O
metastatic	O
adenocarcinoma	O
patients	O
.	O

Although	O
polyubiquitin	B-GENE
chains	I-GENE
linked	O
through	O
Lys	O
(	O
29	O
)	O
of	O
ubiquitin	B-GENE
have	O
been	O
implicated	O
in	O
the	O
targeting	O
of	O
certain	O
substrates	O
to	O
proteasomes	O
,	O
the	O
signaling	O
properties	O
of	O
these	O
chains	O
are	O
poorly	O
understood	O
.	O

B	B-GENE
and	O
C1	B-GENE
fusions	I-GENE
with	O
yeast	B-GENE
GAL4	I-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
and	I-GENE
transcriptional	I-GENE
activation	I-GENE
domains	I-GENE
were	O
also	O
found	O
to	O
interact	O
when	O
synthesized	O
and	O
assayed	O
in	O
yeast	O
.	O

Deletion	O
analysis	O
of	O
the	O
7	B-GENE
.	I-GENE
3	I-GENE
-	I-GENE
kb	I-GENE
GATA	I-GENE
-	I-GENE
2	I-GENE
promoter	I-GENE
region	I-GENE
revealed	O
that	O
a	O
1	O
.	O
1	O
-	O
kb	O
DNA	O
sequence	O
is	O
critical	O
for	O
expression	O
of	O
GATA	B-GENE
-	I-GENE
2	I-GENE
in	O
neurons	O
.	O

In	O
this	O
study	O
,	O
we	O
verified	O
that	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
associates	O
with	O
the	O
CD4	B-GENE
:	O
p56lck	B-GENE
complex	I-GENE
as	O
judged	O
by	O
the	O
presence	O
of	O
PI	O
3	O
-	O
phosphate	O
generated	O
from	O
anti	B-GENE
-	I-GENE
CD4	I-GENE
immunoprecipitates	O
and	O
detected	O
by	O
high	O
-	O
pressure	O
liquid	O
chromatographic	O
analysis	O
.	O

Reality	O
and	O
clinical	O
application	O
of	O
immunoglobulin	B-GENE
preparations	O

This	O
evidence	O
,	O
together	O
with	O
the	O
ability	O
of	O
a	O
carboxyl	O
-	O
terminal	O
coding	O
sequence	O
starting	O
from	O
the	O
BamHI	B-GENE
site	I-GENE
to	O
complement	O
a	O
shy1	B-GENE
mutant	I-GENE
,	O
suggests	O
that	O
the	O
Shy1p	B-GENE
contains	O
two	O
domains	O
that	O
can	O
be	O
separately	O
expressed	O
to	O
form	O
a	O
functional	O
protein	O
.	O

We	O
have	O
previously	O
shown	O
that	O
UNC	B-GENE
-	I-GENE
4	I-GENE
expression	O
in	O
the	O
VA	O
motor	O
neurons	O
specifies	O
the	O
wild	O
-	O
type	O
pattern	O
of	O
presynaptic	O
input	O
.	O

However	O
,	O
technical	O
advances	O
have	O
shown	O
the	O
limitations	O
of	O
these	O
tests	O
as	O
tests	O
for	O
IgM	B-GENE
can	O
be	O
positive	O
because	O
of	O
residual	O
specific	O
IgM	B-GENE
or	O
even	O
in	O
subjects	O
free	O
of	O
acute	O
infection	O
due	O
to	O
the	O
existence	O
of	O
natural	O
interfering	O
IgM	B-GENE
.	O

Transesophageal	O
echocardiography	O
risk	O
factors	O
for	O
stroke	O
in	O
nonvalvular	O
atrial	O
fibrillation	O
.	O

Therefore	O
,	O
in	O
VDR	B-GENE
-	O
mediated	O
transcriptional	O
activation	O
,	O
1	O
,	O
25	O
(	O
OH	O
)	O
2D3	O
binding	O
to	O
VDR	B-GENE
alters	O
the	O
conformation	O
of	O
the	O
ligand	O
binding	O
domain	O
such	O
that	O
it	O
:	O
(	O
i	O
)	O
engages	O
in	O
strong	O
heterodimerization	O
with	O
RXR	B-GENE
to	O
facilitate	O
VDRE	O
binding	O
,	O
(	O
ii	O
)	O
influences	O
the	O
RXR	B-GENE
ligand	I-GENE
binding	I-GENE
domain	I-GENE
such	O
that	O
it	O
is	O
resistant	O
to	O
the	O
binding	O
of	O
9	O
-	O
cis	O
RA	O
but	O
active	O
in	O
recruiting	O
coactivator	O
to	O
its	O
AF	O
-	O
2	O
and	O
(	O
iii	O
)	O
presents	O
the	O
AF	O
-	O
2	O
region	O
in	O
VDR	B-GENE
for	O
coactivator	O
association	O
.	O

Our	O
case	O
,	O
however	O
,	O
had	O
no	O
histologic	O
evidence	O
of	O
malignancy	O
,	O
no	O
serum	B-GENE
alpha	I-GENE
fetoprotein	I-GENE
at	O
7	O
months	O
of	O
age	O
,	O
and	O
no	O
recurrence	O
at	O
1	O
years	O
.	O

Second	O
,	O
overexpression	O
of	O
RIM11	B-GENE
can	O
suppress	O
an	O
ime1	B-GENE
missense	O
mutation	O
(	O
ime1	B-GENE
-	I-GENE
L321F	I-GENE
)	O
but	O
not	O
an	O
ime1	B-GENE
deletion	O
.	O

It	O
is	O
always	O
present	O
and	O
has	O
a	O
discrete	O
origin	O
and	O
insertion	O
.	O

We	O
evaluated	O
99mTc	O
-	O
ECD	O
SPECT	O
comparing	O
with	O
rCBF	O
images	O
obtained	O
by	O
PET	O
in	O
12	O
patients	O
with	O
spinocerebellar	O
degeneration	O
(	O
SCD	O
)	O
.	O

Nimodipine	O
(	O
5	O
micrograms	O
/	O
kg	O
)	O
followed	O
by	O
infusion	O
of	O
0	O
.	O
75	O
microgram	O
/	O
kg	O
/	O
min	O
lowered	O
the	O
blood	O
pressure	O
by	O
10	O
%	O
in	O
both	O
normotensive	O
and	O
hypertensive	O
rats	O
;	O
the	O
same	O
dose	O
schedule	O
of	O
nifedipine	O
did	O
not	O
lower	O
MAP	O
.	O

When	O
severe	O
hypoxia	O
was	O
acutely	O
produced	O
by	O
ventilation	O
with	O
low	O
-	O
oxygen	O
mixtures	O
in	O
experimental	O
(	O
PaO2	O
,	O
23	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
7	O
torr	O
)	O
and	O
control	O
animals	O
(	O
PaO2	O
,	O
26	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
0	O
torr	O
)	O
,	O
plasma	B-GENE
insulin	I-GENE
responses	O
were	O
markedly	O
inhibited	O
in	O
both	O
.	O

We	O
have	O
raised	O
antibodies	O
against	O
a	O
peptide	O
specific	O
to	O
the	O
predicted	O
protein	O
product	O
of	O
this	O
second	O
mRNA	O
.	O

Using	O
unidirectional	O
PCR	O
we	O
isolated	O
a	O
361	O
-	O
bp	O
5	O
'	O
promoter	O
region	O
and	O
delineated	O
the	O
intronic	O
/	O
exonic	O
boundaries	O
which	O
include	O
a	O
non	O
-	O
coding	O
exon	O
1	O
,	O
a	O
single	O
intron	O
,	O
and	O
a	O
coding	O
exon	O
2	O
,	O
a	O
structure	O
that	O
is	O
typical	O
of	O
genes	O
of	O
the	O
RNase	B-GENE
A	I-GENE
superfamily	I-GENE
.	O

Results	O
of	O
these	O
studies	O
indicate	O
that	O
binding	O
of	O
biotin	O
to	O
the	O
protein	O
results	O
in	O
protection	O
of	O
regions	O
of	O
the	O
central	O
domain	O
in	O
the	O
vicinity	O
of	O
the	O
active	O
site	O
and	O
the	O
C	O
-	O
terminal	O
domain	O
from	O
chemical	O
cleavage	O
.	O

The	O
family	O
histories	O
were	O
obtained	O
from	O
the	O
parents	O
.	O

Absence	O
of	O
nitroso	O
formation	O
from	O
(	O
14C	O
)	O
methomyl	O
and	O
sodium	O
nitrite	O
under	O
simulated	O
stomach	O
conditions	O
.	O

The	O
structure	O
of	O
the	O
murine	B-GENE
Dtk	I-GENE
gene	I-GENE
has	O
been	O
determined	O
.	O

Outlook	O
in	O
oral	O
and	O
cutaneous	O
Kaposi	O
'	O
s	O
sarcoma	O
.	O

These	O
data	O
demonstrate	O
that	O
oleosin	B-GENE
gene	I-GENE
transcription	O
is	O
regulated	O
in	O
a	O
tissue	O
-	O
specific	O
and	O
temporally	O
regulated	O
manner	O
and	O
clearly	O
indicate	O
that	O
oleosin	B-GENE
protein	I-GENE
expression	O
is	O
co	O
-	O
ordinated	O
primarily	O
at	O
the	O
transcriptional	O
level	O
.	O

Allergic	O
field	O
:	O
how	O
to	O
detect	O
it	O
?	O

The	O
actual	O
placement	O
of	O
the	O
lesions	O
was	O
determined	O
after	O
mapping	O
of	O
the	O
GPi	O
by	O
microrecording	O
,	O
using	O
stimulation	O
to	O
identify	O
the	O
sensorimotor	O
region	O
and	O
its	O
somatotopic	O
organization	O
.	O

The	O
0	O
.	O
018	O
-	O
inch	O
FloWire	O
provides	O
a	O
high	O
-	O
fidelity	O
continuous	O
Doppler	O
signal	O
.	O

Other	O
recommendations	O
for	O
enhancing	O
the	O
safety	O
of	O
potent	O
antiplatelet	O
agents	O
in	O
a	O
variety	O
of	O
clinical	O
situations	O
are	O
provided	O
.	O

The	O
concepts	O
were	O
developed	O
by	O
Mines	O
and	O
Garrey	O
during	O
the	O
next	O
10	O
years	O
.	O

A	O
new	O
simple	O
identification	O
of	O
rheumatoid	B-GENE
factor	I-GENE
on	O
nitrocellulose	O
was	O
developed	O
that	O
allows	O
quantitative	O
detection	O
.	O

Maximum	O
overexpression	O
of	O
holoenzyme	O
activity	O
was	O
achieved	O
by	O
the	O
inclusion	O
in	O
such	O
plasmids	O
of	O
Salmonella	O
typhimurium	O
cysG	O
,	O
which	O
encodes	O
a	O
uroporphyrinogen	B-GENE
III	I-GENE
methyltransferase	I-GENE
required	O
for	O
the	O
synthesis	O
of	O
siroheme	O
,	O
a	O
cofactor	O
for	O
the	O
hemoprotein	O
.	O

Determination	O
of	O
the	O
LD	O
50	O
(	O
30	O
)	O
during	O
infant	O
period	O
and	O
growth	O
period	O

Mutational	O
analysis	O
of	O
yeast	B-GENE
CEG1	I-GENE
demonstrated	O
that	O
four	O
of	O
the	O
five	O
conserved	O
motifs	O
are	O
essential	O
for	O
capping	B-GENE
enzyme	I-GENE
function	O
in	O
vivo	O
.	O

Purified	O
phosphorylated	O
PhoP	B-GENE
(	O
PhoPP	B-GENE
)	O
had	O
a	O
half	O
-	O
life	O
of	O
approximately	O
2	O
.	O
5	O
h	O
,	O
which	O
was	O
reduced	O
to	O
about	O
15	O
min	O
by	O
addition	O
of	O
the	O
same	O
molar	O
amount	O
of	O
*	B-GENE
PhoR	I-GENE
(	O
the	O
cytoplasmic	O
region	O
of	O
PhoR	B-GENE
)	O
.	O

We	O
conclude	O
that	O
exercise	O
-	O
induced	O
ST	O
-	O
segment	O
elevation	O
in	O
patients	O
without	O
a	O
history	O
of	O
myocardial	O
infarction	O
or	O
left	O
ventricular	O
aneurysm	O
is	O
caused	O
by	O
coronary	O
spasm	O
of	O
a	O
major	O
coronary	O
vessel	O
.	O

It	O
spans	O
20	O
kilobases	O
,	O
consists	O
of	O
7	O
exons	O
and	O
6	O
introns	O
,	O
and	O
contains	O
a	O
TATA	O
motif	O
24	O
nucleotides	O
upstream	O
of	O
the	O
transcriptional	O
start	O
site	O
.	O

Metastatic	O
tumours	O
of	O
bone	O
in	O
Nigerians	O
.	O

A	O
survey	O
of	O
274	O
late	O
detected	O
cases	O
of	O
CDH	O
born	O
in	O
the	O
years	O
1970	O
-	O
-	O
74	O
is	O
presented	O
.	O

This	O
distinct	O
biochemical	O
difference	O
between	O
STAT5A	B-GENE
and	O
STAT5B	B-GENE
was	O
confirmed	O
with	O
purified	O
activated	O
STAT5	B-GENE
recombinant	I-GENE
proteins	I-GENE
.	O

Enoxacin	O
has	O
been	O
shown	O
to	O
be	O
an	O
effective	O
well	O
tolerated	O
and	O
convenient	O
treatment	O
for	O
gonorrhoea	O
.	O

METHODS	O
:	O
Precision	O
and	O
accuracy	O
were	O
measured	O
using	O
controls	O
and	O
method	O
comparison	O
studies	O
.	O

Important	O
prognostic	O
factors	O
for	O
the	O
results	O
of	O
physiotherapeutic	O
exercises	O
in	O
intermittent	O
claudication	O

Thus	O
,	O
Tax1	B-GENE
activates	O
CArG	O
-	O
mediated	O
transcription	O
without	O
mitogenic	O
signals	O
through	O
interaction	O
with	O
a	O
CArG	B-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
,	O
p67SRF	B-GENE
.	O

In	O
5	O
cases	O
,	O
combined	O
sensitization	O
to	O
mercury	O
and	O
other	O
metal	O
salts	O
,	O
particularly	O
gold	O
sodium	O
thiosulfate	O
(	O
GST	O
)	O
and	O
palladium	O
chloride	O
(	O
PDC	O
)	O
,	O
was	O
observed	O
.	O

Amongst	O
53	O
"	O
inoperable	O
"	O
(	O
T4	O
,	O
N0	O
,	O
N1	O
,	O
T	O
.	O
,	O
N2	O
,	O
N3	O
)	O
cases	O
,	O
5	O
(	O
10	O
%	O
)	O
had	O
a	O
positive	O
scan	O
and	O
5	O
a	O
doubtful	O
scan	O
.	O

Acyclovir	O
(	O
3	O
%	O
ointment	O
)	O
used	O
topically	O
one	O
to	O
five	O
times	O
a	O
day	O
on	O
acute	O
ocular	O
HSV	O
infection	O
gave	O
beneficial	O
results	O
as	O
measured	O
by	O
a	O
reduction	O
in	O
corneal	O
involvement	O
,	O
conjunctivitis	O
,	O
iritis	O
,	O
and	O
corneal	O
clouding	O
.	O

The	O
efficiency	O
of	O
transfections	O
was	O
normalized	O
relative	O
to	O
the	O
net	O
amount	O
of	O
CAT	B-GENE
plasmid	O
actually	O
transfected	O
into	O
recipient	O
cells	O
,	O
determined	O
by	O
a	O
modified	O
Southern	O
hybridization	O
procedure	O
.	O

Initial	O
computer	O
based	O
similarity	O
searches	O
identified	O
human	B-GENE
retinoblastoma	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
(	O
RBP	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
Drosophila	B-GENE
melanogaster	I-GENE
male	I-GENE
specific	I-GENE
lethal	I-GENE
-	I-GENE
3	I-GENE
(	O
Msl	B-GENE
-	I-GENE
3	I-GENE
)	O
,	O
S	B-GENE
.	I-GENE
pombe	I-GENE
altered	I-GENE
polarity	I-GENE
-	I-GENE
13	I-GENE
(	O
Alp13	B-GENE
)	O
and	O
S	B-GENE
.	I-GENE
cerevisiae	I-GENE
Eaf3p	I-GENE
,	O
a	O
component	O
of	O
the	O
yeast	B-GENE
NuA4	I-GENE
HAT	B-GENE
complex	O
(	O
Galarneau	O
et	O
al	O
.	O
,	O
2000	O
.	O

These	O
aa	O
residues	O
correspond	O
to	O
codons	O
59	O
and	O
108	O
in	O
the	O
P	B-GENE
.	I-GENE
falciparum	I-GENE
DHFR	I-GENE
active	I-GENE
site	I-GENE
in	O
which	O
similar	O
aa	O
substitutions	O
(	O
Cys	O
Arg	O
-	O
59	O
and	O
Ser	O
Asn	O
-	O
108	O
)	O
are	O
associated	O
with	O
pyrimethamine	O
resistance	O
.	O

Efficacy	O
was	O
evaluated	O
in	O
24	O
patients	O
,	O
of	O
whom	O
eight	O
received	O
RD	O
and	O
16	O
SD	O
.	O

Short	O
-	O
term	O
growth	O
:	O
rhythms	O
,	O
chaos	O
,	O
or	O
noise	O
?	O

Sequences	O
homologous	O
to	O
the	O
consensus	O
TUF	B-GENE
-	I-GENE
binding	I-GENE
UAS	I-GENE
boxes	I-GENE
are	O
present	O
in	O
the	O
5	O
'	O
flanking	O
regions	O
of	O
both	O
genes	O
.	O

Residues	O
crucial	O
for	O
Ras	B-GENE
interaction	O
with	O
GDP	B-GENE
-	I-GENE
GTP	I-GENE
exchangers	I-GENE
.	O

The	O
gene	B-GENE
atp6	I-GENE
,	O
encoding	O
subunit	O
6	O
of	O
the	O
mitochondrial	O
F0	B-GENE
-	O
ATPase	B-GENE
complex	O
,	O
has	O
been	O
characterized	O
from	O
both	O
the	O
normal	O
(	O
fertile	O
)	O
and	O
Ogura	O
(	O
male	O
-	O
sterile	O
)	O
radish	O
cytoplasms	O
in	O
order	O
to	O
determine	O
if	O
previously	O
identified	O
atp6	B-GENE
transcriptional	O
differences	O
could	O
play	O
a	O
role	O
in	O
cytoplasmic	O
male	O
sterility	O
.	O

To	O
determine	O
whether	O
the	O
transcript	O
encodes	O
an	O
active	O
enzyme	O
,	O
we	O
developed	O
a	O
novel	O
transient	O
embryonic	O
excision	O
assay	O
in	O
which	O
zebrafish	O
fertilized	O
eggs	O
were	O
co	O
-	O
injected	O
with	O
RNA	O
transcribed	O
in	O
vitro	O
using	O
the	O
Tol2	B-GENE
cDNA	I-GENE
as	O
a	O
template	O
and	O
a	O
plasmid	O
DNA	O
harboring	O
a	O
nonautonomous	O
Tol2	B-GENE
element	I-GENE
,	O
which	O
has	O
a	O
deletion	O
in	O
the	O
transposase	B-GENE
coding	I-GENE
region	I-GENE
.	O

The	O
expression	O
of	O
CAPL	B-GENE
,	O
a	O
second	O
protein	O
involved	O
in	O
calcium	O
metabolism	O
,	O
was	O
only	O
moderately	O
elevated	O
in	O
the	O
doxorubicin	O
-	O
resistant	O
cells	O
.	O

The	O
reconstituted	O
enzyme	O
binds	O
DNA	O
with	O
an	O
affinity	O
that	O
is	O
approximately	O
20	O
-	O
fold	O
lower	O
than	O
that	O
of	O
the	O
intact	O
topo70	B-GENE
.	O

In	O
late	O
October	O
,	O
1974	O
,	O
Staphylococcus	O
aureus	O
postoperative	O
wound	O
infection	O
was	O
recorded	O
in	O
a	O
nonhuman	O
primate	O
(	O
Macaca	O
mulatta	O
)	O
which	O
had	O
recently	O
undergone	O
surgical	O
operation	O
.	O

Thus	O
,	O
the	O
in	O
vivo	O
function	O
of	O
Gle2p	B-GENE
is	O
strictly	O
coupled	O
to	O
the	O
short	O
GLEBS	B-GENE
within	O
Nup116p	B-GENE
which	O
links	O
this	O
putative	O
mRNA	O
transport	O
factor	O
to	O
the	O
nuclear	O
pores	O
.	O

Seminal	O
prolactin	B-GENE
levels	O
were	O
significantly	O
elevated	O
in	O
all	O
infertile	O
males	O
.	O

The	O
recruitment	O
of	O
constitutively	O
phosphorylated	O
p185	B-GENE
(	O
neu	B-GENE
)	O
and	O
the	O
activated	O
mitogenic	O
pathway	O
proteins	O
to	O
this	O
membrane	O
-	O
microfilament	O
interaction	O
site	O
provides	O
a	O
physical	O
model	O
for	O
integrating	O
the	O
assembly	O
of	O
the	O
mitogenic	O
pathway	O
with	O
the	O
transmission	O
of	O
growth	O
factor	O
signal	O
to	O
the	O
cytoskeleton	O
.	O

The	O
pattern	O
of	O
net	B-GENE
RNA	I-GENE
expression	O
in	O
adult	O
mouse	O
tissues	O
is	O
different	O
.	O

Effect	O
of	O
capsaicin	O
on	O
hexobarbital	O
-	O
anesthetized	O
rats	O

Expression	O
of	O
human	B-GENE
complement	I-GENE
receptor	I-GENE
type	I-GENE
2	I-GENE
(	O
CR2	B-GENE
/	O
CD21	B-GENE
)	O
is	O
primarily	O
restricted	O
to	O
mature	O
B	O
cells	O
and	O
follicular	O
dendritic	O
cells	O
.	O

A	O
physical	O
and	O
genetic	O
map	O
covering	O
the	O
entire	O
RP12	B-GENE
candidate	I-GENE
gene	I-GENE
region	I-GENE
was	O
constructed	O
.	O

We	O
found	O
that	O
in	O
premature	O
infants	O
plasminogen	B-GENE
levels	O
are	O
low	O
;	O
thus	O
,	O
defense	O
against	O
intra	O
-	O
alveolar	O
fibrin	B-GENE
deposition	O
during	O
birth	O
trauma	O
is	O
reduced	O
.	O

Progestins	O
:	O
present	O
and	O
future	O
.	O

Indeed	O
,	O
DEX	O
also	O
enhanced	O
the	O
RA	O
-	O
dependent	O
increase	O
in	O
RARbeta	B-GENE
mRNA	I-GENE
in	O
a	O
cycloheximide	O
-	O
sensitive	O
manner	O
.	O

In	O
both	O
immortalized	O
and	O
normal	O
diploid	O
human	O
cells	O
,	O
wt	O
AAV	O
targeted	O
integration	O
to	O
ch	O
-	O
19	O
.	O

It	O
was	O
found	O
that	O
both	O
versions	O
of	O
the	O
brief	O
SL	O
&	O
amp	O
;	O
shy	O
;	O
ASIA	O
had	O
similar	O
correlations	O
to	O
the	O
target	O
variables	O
as	O
the	O
full	O
scale	O
SL	O
&	O
amp	O
;	O
shy	O
;	O
ASIA	O
.	O

These	O
operons	O
encode	O
subunits	O
of	O
photosystems	B-GENE
I	I-GENE
(	O
psa	B-GENE
)	O
and	O
II	O
(	O
psb	B-GENE
)	O
,	O
the	O
cytochrome	B-GENE
bGf	I-GENE
complex	I-GENE
(	O
pet	B-GENE
)	O
,	O
the	O
plastid	O
NAD	B-GENE
(	I-GENE
P	I-GENE
)	I-GENE
H	I-GENE
dehydrogenase	I-GENE
(	O
ndh	B-GENE
)	O
,	O
and	O
the	O
unidentified	O
open	O
reading	O
frame	O
ycf9	B-GENE
.	O

In	O
contrast	O
,	O
dominant	B-GENE
negative	I-GENE
Rac	I-GENE
(	O
N17Rac1	B-GENE
)	O
inhibited	O
JNK	B-GENE
activation	O
by	O
Galpha12	B-GENE
in	O
HEK293	O
cells	O
as	O
well	O
as	O
three	O
other	O
cell	O
lines	O
.	O

A	O
major	O
feature	O
of	O
this	O
genomic	O
sequence	O
is	O
the	O
presence	O
of	O
a	O
first	O
intron	O
(	O
Il	O
)	O
,	O
215	O
bp	O
long	O
,	O
located	O
48	O
bp	O
downstream	O
of	O
the	O
translation	O
start	O
ATG	O
codon	O
.	O

We	O
reviewed	O
the	O
different	O
published	O
cases	O
of	O
acute	O
high	O
dose	O
methotrexate	O
neurotoxicity	O
and	O
the	O
different	O
underlying	O
mechanisms	O
.	O

The	O
expected	O
products	O
of	O
the	O
cloned	O
bph	B-GENE
genes	I-GENE
,	O
except	O
bphA3	B-GENE
,	O
were	O
observed	O
in	O
E	O
.	O
coli	O
in	O
an	O
in	O
vitro	O
transcription	O
-	O
translation	O
system	O
.	O

The	O
immunoreactive	O
antithrombin	B-GENE
III	I-GENE
increased	O
significantly	O
while	O
the	O
increase	O
in	O
antithrombin	B-GENE
III	I-GENE
activity	O
was	O
insignificant	O
in	O
20	O
male	O
Caucasian	O
Danes	O
upon	O
3	O
weeks	O
supplementation	O
of	O
the	O
diet	O
with	O
10	O
ml	O
daily	O
of	O
a	O
cod	O
liver	O
oil	O
concentrate	O
.	O

Only	O
the	O
27	O
-	O
kDa	O
protein	O
was	O
detected	O
after	O
N	B-GENE
-	I-GENE
glycosidase	I-GENE
treatment	O
,	O
indicating	O
that	O
PLP	B-GENE
-	I-GENE
H	I-GENE
is	O
a	O
glycoprotein	O
.	O

These	O
observed	O
changes	O
were	O
not	O
found	O
when	O
assessing	O
NPY	B-GENE
level	O
in	O
plasma	O
fluid	O
.	O

In	O
three	O
other	O
patients	O
the	O
electrophysiologic	O
characteristics	O
of	O
atrioventricular	O
conduction	O
prevented	O
a	O
demonstration	O
of	O
these	O
differences	O
.	O

These	O
sequence	O
differences	O
are	O
reflected	O
in	O
differences	O
in	O
gene	O
expression	O
in	O
three	O
cell	O
lines	O
.	O

The	O
10	O
eyes	O
injected	O
with	O
human	O
RPE	O
cells	O
showed	O
STAGE	O
2	O
or	O
less	O
in	O
4	O
weeks	O
.	O

The	O
cumulative	O
dose	O
to	O
nursing	O
staff	O
for	O
the	O
week	O
after	O
treatment	O
was	O
dependent	O
on	O
patient	O
mobility	O
and	O
was	O
estimated	O
at	O
0	O
.	O
08	O
mSv	O
for	O
a	O
self	O
-	O
caring	O
patient	O
to	O
6	O
.	O
3	O
mSv	O
for	O
a	O
totally	O
helpless	O
patient	O
(	O
1840	O
MBq	O
/	O
group	O
A	O
)	O
.	O

The	O
analysis	O
consisted	O
of	O
1	O
)	O
fitting	O
first	O
-	O
and	O
second	O
-	O
order	O
autoregressive	O
models	O
(	O
AR1	O
and	O
AR2	O
)	O
and	O
2	O
)	O
obtaining	O
the	O
power	O
spectra	O
of	O
the	O
data	O
by	O
fast	O
-	O
Fourier	O
transform	O
.	O

Of	O
921	O
specimens	O
,	O
95	O
yielded	O
non	O
-	O
albicans	O
species	O
,	O
mainly	O
from	O
patients	O
with	O
low	O
CD4	B-GENE
lymphocyte	O
counts	O
and	O
extensive	O
previous	O
azole	O
exposure	O
.	O

Sequence	O
analysis	O
and	O
electrophoretic	O
mobility	O
shift	O
experiments	O
suggest	O
that	O
GnSE	B-GENE
response	I-GENE
elements	I-GENE
interact	O
,	O
in	O
these	O
two	O
regions	O
,	O
with	O
GATA	B-GENE
-	I-GENE
and	I-GENE
LIM	I-GENE
-	I-GENE
related	I-GENE
factors	I-GENE
,	O
respectively	O
.	O

The	O
NrfC	B-GENE
polypeptide	I-GENE
,	O
M	B-GENE
(	I-GENE
r	I-GENE
)	I-GENE
24	I-GENE
,	I-GENE
567	I-GENE
,	O
contains	O
16	O
cysteine	O
residues	O
arranged	O
in	O
four	O
clusters	O
typical	O
of	O
the	O
CooF	B-GENE
super	I-GENE
-	I-GENE
family	I-GENE
of	O
non	O
-	O
haem	O
iron	O
-	O
sulphur	O
proteins	O
.	O

Hamdija	O
Karamehmedovic	O
;	O
Ibn	O
al	O
-	O
Nefis	O
,	O
"	O
Mudzez	O
al	O
-	O
Kanum	O
"	O
,	O
Republicki	O
zavod	O
za	O
zdravstvenu	O
zastitu	O
Sarajevo	O
,	O
1961	O
,	O
1	O
-	O
219	O
;	O
Mr	O
ph	O
Samuel	O
Elazar	O
,	O
Ajnija	O
Omanic	O
:	O
"	O
Bibliografija	O
medicinskih	O
djela	O
u	O
SR	O
BiH	O
do	O
1895	O
.	O
"	O
Medicinska	O
knjiga	O
Beograd	O
-	O
Zagreb	O
1984	O
;	O
Besides	O
,	O
the	O
great	O
contribution	O
in	O
bibliography	O
was	O
given	O
by	O
dr	O
Lujo	O
Taler	O
,	O
prof	O
.	O
dr	O
.	O

Patients	O
randomized	O
into	O
the	O
active	O
treatment	O
groups	O
A30	O
(	O
n	O
=	O
49	O
)	O
and	O
A60	O
(	O
n	O
=	O
48	O
)	O
received	O
topical	O
treatment	O
with	O
3	O
.	O
0	O
%	O
diclofenac	O
in	O
2	O
.	O
5	O
%	O
hyaluronan	O
gel	O
0	O
.	O
5	O
g	O
twice	O
daily	O
for	O
30	O
or	O
60	O
days	O
,	O
respectively	O
.	O

Southern	O
blot	O
analysis	O
performed	O
on	O
genomic	O
DNA	O
demonstrated	O
altered	O
CpG	O
methylation	O
within	O
intron	O
1	O
in	O
DNA	O
from	O
all	O
BCC	O
compared	O
to	O
normal	O
,	O
mortal	O
human	O
mammary	O
epithelial	O
cells	O
(	O
HMEC	O
)	O
.	O

In	O
addition	O
,	O
both	O
inhibitors	O
blocked	O
phosphatidylcholine	O
hydrolysis	O
and	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
translocation	O
.	O

Human	B-GENE
PDNP3	I-GENE
is	O
expressed	O
in	O
glioma	O
cells	O
,	O
prostate	O
,	O
and	O
uterus	O
,	O
but	O
not	O
in	O
the	O
alimentary	O
tract	O
.	O

13	O
:	O
961	O
-	O
969	O
,	O
1993	O
)	O
suggested	O
that	O
T	B-GENE
antigen	I-GENE
could	O
mediate	O
transcriptional	O
activation	O
through	O
interaction	O
with	O
the	O
TATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
,	O
as	O
well	O
as	O
upstream	O
bound	O
transcription	O
factors	O
.	O

Identification	O
of	O
a	O
putative	O
infC	B-GENE
-	O
rpmI	B-GENE
-	O
rplT	B-GENE
operon	O
flanked	O
by	O
long	O
inverted	O
repeats	O
in	O
Mycoplasma	O
fermentans	O
(	O
incognitus	O
strain	O
)	O
.	O

IgE	B-GENE
antibody	I-GENE
to	O
twelve	O
common	O
food	O
and	O
inhalant	O
allergens	O
was	O
measured	O
by	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
(	O
ELISA	O
)	O
in	O
the	O
sera	O
of	O
thirteen	O
atopic	O
patients	O
with	O
one	O
or	O
more	O
allergic	O
disorders	O
(	O
asthma	O
occurring	O
in	O
eleven	O
;	O
rhinitis	O
in	O
ten	O
;	O
eczema	O
in	O
six	O
;	O
urticaria	O
in	O
four	O
;	O
mouth	O
and	O
gastro	O
-	O
intestinal	O
symptoms	O
in	O
six	O
)	O
,	O
of	O
twelve	O
non	O
-	O
atopic	O
patients	O
with	O
various	O
clinical	O
symptoms	O
(	O
asthma	O
in	O
four	O
;	O
rhinitis	O
in	O
four	O
;	O
eczema	O
in	O
one	O
;	O
urticaria	O
in	O
two	O
;	O
mouth	O
and	O
gastro	O
-	O
intestinal	O
symptoms	O
in	O
four	O
)	O
and	O
sixteen	O
cord	O
blood	O
sera	O
.	O

Analysis	O
of	O
1	O
Mb	O
of	O
published	O
sequence	O
from	O
the	O
region	O
of	O
conserved	O
synteny	O
on	O
human	O
chromosome	O
5q31	O
-	O
q33	O
identified	O
45	O
gene	O
candidates	O
,	O
including	O
35	O
expressed	O
genes	O
in	O
the	O
human	B-GENE
IL	I-GENE
-	I-GENE
4	I-GENE
cytokine	I-GENE
gene	I-GENE
cluster	O
.	O

These	O
p21	B-GENE
-	O
E2F	B-GENE
complexes	O
,	O
while	O
present	O
in	O
young	O
G1	O
cells	O
at	O
very	O
low	O
levels	O
,	O
were	O
elevated	O
in	O
senescent	O
cells	O
.	O

The	O
delta	O
Mo	O
+	O
SV	O
tumor	O
DNAs	O
from	O
B	O
-	O
lineage	O
tumors	O
were	O
typically	O
rearranged	O
at	O
the	O
immunoglobulin	B-GENE
gene	I-GENE
loci	I-GENE
and	O
contained	O
germ	O
line	O
configurations	O
of	O
the	O
T	B-GENE
-	I-GENE
cell	I-GENE
receptor	I-GENE
beta	I-GENE
gene	I-GENE
.	O

An	O
increased	O
incidence	O
of	O
ATN	O
has	O
been	O
reported	O
since	O
the	O
introduction	O
of	O
cyclosporin	O
A	O
.	O

Earlier	O
reports	O
have	O
localized	O
mutations	O
which	O
affect	O
the	O
processing	O
and	O
transport	O
of	O
herpes	O
simplex	O
virus	O
1	O
glycoproteins	O
to	O
a	O
region	O
located	O
between	O
the	O
genes	O
specifying	O
glycoprotein	B-GENE
B	I-GENE
and	O
the	O
major	O
viral	O
DNA	O
-	O
binding	O
protein	O
(	O
beta	B-GENE
8	I-GENE
)	O
.	O

Magnetic	O
force	O
and	O
torque	O
at	O
1	O
.	O
5	O
T	O
did	O
not	O
dislodge	O
the	O
GF	O
or	O
result	O
in	O
perforation	O
of	O
canine	O
IVC	O
by	O
the	O
GF	O
.	O

The	O
rec8	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
,	O
rec10	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
,	O
and	O
rec11	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
genes	I-GENE
of	I-GENE
the	I-GENE
fission	I-GENE
yeast	I-GENE
Schizosaccharomyces	I-GENE
pombe	I-GENE
exhibit	O
similar	O
specificities	O
for	O
meiotic	O
recombination	O
and	O
rec8	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
is	O
required	O
for	O
sister	O
chromatid	O
cohesion	O
and	O
homolog	O
pairing	O
.	O

Synergistic	O
induction	O
of	O
apoptosis	O
in	O
human	O
leukemia	O
cells	O
(	O
U937	O
)	O
exposed	O
to	O
bryostatin	O
1	O
and	O
the	O
proteasome	O
inhibitor	O
lactacystin	O
involves	O
dysregulation	O
of	O
the	O
PKC	B-GENE
/	O
MAPK	B-GENE
cascade	O
.	O

The	O
formation	O
of	O
a	O
D	O
-	O
loop	O
is	O
an	O
essential	O
step	O
in	O
DNA	O
double	O
-	O
strand	O
break	O
repair	O
through	O
recombination	O
.	O

Using	O
a	O
set	O
of	O
sera	O
for	O
which	O
full	O
chlamydial	O
micro	O
-	O
immunofluorescence	O
results	O
suggested	O
a	O
clear	O
diagnosis	O
,	O
we	O
have	O
evaluated	O
the	O
Chlamydia	O
Spot	O
-	O
IF	O
test	O
(	O
bioMerieux	O
)	O
,	O
which	O
allows	O
a	O
comparison	O
of	O
titres	O
to	O
Chlamydia	B-GENE
trachomatis	I-GENE
and	I-GENE
C	I-GENE
.	I-GENE
psittaci	I-GENE
antigens	I-GENE
.	O

ET	B-GENE
-	I-GENE
1	I-GENE
limited	O
the	O
electrocardiographic	O
evidence	O
of	O
subendocardial	O
ischemia	O
and	O
attenuated	O
contractile	O
dysfunction	O
compared	O
with	O
mechanical	O
stenosis	O
at	O
the	O
same	O
coronary	O
flows	O
,	O
even	O
though	O
lactate	O
flux	O
was	O
similar	O
.	O

The	O
AtNMT1	B-GENE
expression	O
profile	O
indicated	O
ubiquity	O
in	O
roots	O
,	O
stem	O
,	O
leaves	O
,	O
flowers	O
,	O
and	O
siliques	O
(	O
approximately	O
1	O
.	O
7	O
kb	O
transcript	O
and	O
approximately	O
50	O
kDa	O
immunoreactive	O
polypeptide	O
)	O
but	O
a	O
greater	O
level	O
in	O
the	O
younger	O
tissue	O
,	O
which	O
are	O
developmentally	O
very	O
active	O
.	O

CONCLUSION	O
:	O
DMIPP	O
detects	O
regionally	O
hypoperfused	O
myocardium	O
,	O
in	O
which	O
agreement	O
between	O
MBF	O
and	O
fatty	O
acid	O
uptake	O
deteriorates	O
.	O

The	O
majority	O
of	O
putative	O
TSC2	B-GENE
mutations	I-GENE
were	O
found	O
in	O
sporadic	O
rather	O
than	O
TSC2	B-GENE
-	O
linked	O
families	O
.	O

Thirty	O
-	O
three	O
small	O
glottic	O
carcinomas	O
(	O
T1	O
and	O
small	O
T2	O
;	O
UICC	O
,	O
1978	O
)	O
were	O
examined	O
by	O
malignancy	O
grading	O
using	O
the	O
8	O
-	O
factor	O
system	O
proposed	O
by	O
Jakobsson	O
et	O
al	O
.	O

None	O
of	O
the	O
10	O
sequences	O
has	O
hitherto	O
been	O
recognized	O
as	O
part	O
of	O
the	O
p53	B-GENE
signaling	O
pathway	O
.	O

Studies	O
in	O
26	O
patients	O
.	O

Transfection	O
of	O
H	B-GENE
chain	I-GENE
loss	I-GENE
variant	I-GENE
myeloma	O
with	O
the	O
complete	O
12	O
kb	O
construct	O
,	O
termed	O
238H	B-GENE
-	I-GENE
Cmicro	I-GENE
,	O
resulted	O
in	O
secretion	O
of	O
intact	O
Ig	O
pairing	O
238H	B-GENE
-	I-GENE
Cmicro	I-GENE
,	O
with	O
a	O
lambda	B-GENE
L	I-GENE
chain	I-GENE
;	O
however	O
,	O
transfectant	B-GENE
Ig	I-GENE
lacked	O
autoreactivity	O
and	O
pathogenicity	O
.	O

Comparison	O
of	O
the	O
genes	O
coding	O
for	O
mouse	O
and	O
human	O
p36	B-GENE
(	O
annexin	B-GENE
II	I-GENE
)	O
and	O
mouse	O
,	O
rat	O
and	O
human	O
p35	B-GENE
(	O
annexin	B-GENE
I	I-GENE
)	O
and	O
pigeon	O
cp35	B-GENE
(	O
an	O
annexin	B-GENE
I	I-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
)	O
shows	O
strong	O
genomic	O
structural	O
conservation	O
supporting	O
the	O
hypothesis	O
that	O
these	O
genes	O
had	O
a	O
common	O
ancestor	O
.	O

Now	O
:	O
pleasure	O
in	O
work	O

Cerumen	O
management	O
in	O
hearing	O
conservation	O
:	O
the	O
Dallas	O
(	O
Texas	O
)	O
Independent	O
School	O
District	O
program	O
.	O

Mammalian	O
homologues	O
of	O
the	O
Polycomb	B-GENE
-	I-GENE
group	I-GENE
gene	I-GENE
Enhancer	B-GENE
of	I-GENE
zeste	I-GENE
mediate	O
gene	O
silencing	O
in	O
Drosophila	O
heterochromatin	O
and	O
at	O
S	O
.	O
cerevisiae	O
telomeres	O
.	O

Xanthoepocin	O
,	O
a	O
new	O
antibiotic	O
from	O
Penicillium	O
simplicissimum	O
IFO5762	O
.	O

Additionally	O
,	O
VAHS	O
is	O
often	O
associated	O
with	O
fatal	O
infectious	O
mononucleosis	O
(	O
IM	O
)	O
.	O

In	O
addition	O
,	O
mutations	O
within	O
the	O
Ubx	B-GENE
unit	I-GENE
exons	I-GENE
are	O
known	O
and	O
most	O
of	O
these	O
behave	O
as	O
null	O
alleles	O
.	O

273	O
,	O
27420	O
-	O
27429	O
)	O
a	O
putative	O
peroxisome	O
proliferator	O
-	O
activated	O
receptor	O
response	O
element	O
(	O
PPRE	O
)	O
is	O
present	O
from	O
-	O
458	O
to	O
-	O
474	O
.	O

In	O
T	O
cells	O
these	O
two	O
signal	O
pathways	O
are	O
critical	O
for	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
production	O
.	O

These	O
results	O
induce	O
that	O
the	O
putative	O
TATA	O
box	O
and	O
initiator	O
are	O
not	O
involved	O
in	O
the	O
promoter	O
activity	O
,	O
and	O
that	O
the	O
vitronectin	B-GENE
promoter	I-GENE
lacks	O
the	O
TATA	O
box	O
,	O
initiator	O
and	O
GC	O
box	O
.	O

Both	O
residues	O
are	O
conserved	O
in	O
the	O
three	O
phosphorylated	O
paralogs	O
but	O
are	O
absent	O
in	O
the	O
ones	O
that	O
were	O
not	O
substrates	O
of	O
RsbT	B-GENE
:	O
YetI	B-GENE
and	O
YezB	B-GENE
,	O
each	O
of	O
which	O
bears	O
only	O
one	O
of	O
the	O
conserved	O
residues	O
;	O
and	O
YtvA	B-GENE
,	O
which	O
lacks	O
both	O
residues	O
and	O
instead	O
possesses	O
an	O
N	O
-	O
terminal	O
PAS	B-GENE
domain	O
.	O

The	O
role	O
of	O
PORT	O
in	O
the	O
treatment	O
of	O
N2	O
tumours	O
is	O
not	O
clear	O
and	O
may	O
justify	O
further	O
research	O
.	O

The	O
TDx	O
assay	O
for	O
cyclosporine	O
and	O
its	O
metabolites	O
in	O
blood	O
samples	O
compared	O
with	O
HPLC	O
and	O
RIA	O
methods	O
.	O

This	O
is	O
consistent	O
with	O
the	O
need	O
for	O
a	O
nuclear	O
retinoid	B-GENE
receptor	I-GENE
function	O
in	O
RA	O
-	O
induced	O
ERK2	B-GENE
activation	O
.	O

It	O
was	O
previously	O
shown	O
that	O
Vi	B-GENE
antigen	I-GENE
expression	O
was	O
regulated	O
by	O
a	O
system	O
similar	O
to	O
the	O
rcs	B-GENE
regulatory	O
system	O
involved	O
in	O
colanic	O
acid	O
synthesis	O
in	O
Escherichia	O
coli	O
.	O

However	O
,	O
the	O
molecular	O
mechanisms	O
by	O
which	O
specific	O
cis	O
-	O
and	O
trans	O
-	O
acting	O
factors	O
control	O
activity	O
of	O
the	O
prodynorphin	B-GENE
promoter	I-GENE
are	O
not	O
as	O
clearly	O
defined	O
.	O

The	O
gene	O
set	O
in	O
this	O
mitochondrial	O
genome	O
is	O
a	O
subset	O
of	O
that	O
of	O
Reclinomonas	O
americana	O
,	O
an	O
amoeboid	O
protozoan	O
.	O

The	O
library	O
will	O
thus	O
be	O
useful	O
for	O
the	O
selection	O
of	O
cosmid	O
clones	O
which	O
carry	O
CDC	B-GENE
genes	I-GENE
from	I-GENE
yeast	I-GENE
by	O
complementing	O
first	O
,	O
with	O
the	O
vectorial	O
yeast	B-GENE
gene	I-GENE
URA1	I-GENE
,	O
the	O
pyrimidine	O
auxotrophy	O
of	O
most	O
cdc	B-GENE
-	O
strains	O
and	O
then	O
,	O
with	O
the	O
respective	O
CDC	B-GENE
wild	I-GENE
-	I-GENE
type	I-GENE
genes	I-GENE
,	O
of	O
the	O
temperature	O
-	O
sensitive	O
mutant	O
alleles	O
.	O

A	O
plasma	O
cell	O
-	O
rich	O
infiltrate	O
was	O
present	O
in	O
the	O
connective	O
tissue	O
cores	O
of	O
the	O
papillae	O
.	O

Peptide	O
competition	O
studies	O
have	O
localized	O
a	O
cyclin	B-GENE
A	I-GENE
interaction	I-GENE
site	I-GENE
to	O
a	O
Lys381Lys382Leu383Met384Phe385	O
sequence	O
within	O
C	O
-	O
terminal	O
negative	O
regulatory	O
domain	O
of	O
human	B-GENE
p53	I-GENE
.	O

A	O
phase	O
II	O
study	O
was	O
initiated	O
to	O
evaluate	O
the	O
effect	O
of	O
a	O
combination	O
of	O
the	O
pure	O
L	O
-	O
isomer	O
of	O
LV	O
and	O
5	O
-	O
FU	O
along	O
with	O
epirubicin	O
in	O
patients	O
with	O
advanced	O
pancreatic	O
cancer	O
.	O

Attenuated	O
serum	O
cortisol	O
responses	O
were	O
found	O
in	O
six	O
of	O
the	O
patients	O
despite	O
a	O
normal	O
ACTH	B-GENE
test	O
.	O

While	O
some	O
still	O
automatically	O
refuse	O
all	O
patients	O
with	O
positive	O
mediastinoscopy	O
,	O
most	O
authors	O
still	O
remain	O
very	O
interventionistic	O
for	O
N2	O
patients	O
selected	O
on	O
very	O
accurate	O
criteria	O
that	O
are	O
analyzed	O
above	O
.	O

Inability	O
of	O
niacin	O
to	O
protect	O
from	O
in	O
vivo	O
hyperoxia	O
or	O
in	O
vitro	O
microsomal	O
lipid	O
peroxidation	O
.	O

Sesame	O
seed	O
should	O
also	O
be	O
considered	O
a	O
cause	O
of	O
allergic	O
reactions	O
to	O
drug	O
products	O
and	O
cosmetics	O
.	O

In	O
absence	O
of	O
i	O
.	O
m	O
.	O
medication	O
,	O
levels	O
over	O
1	O
,	O
000	O
U	O
must	O
be	O
carefully	O
screened	O
in	O
order	O
to	O
rule	O
out	O
SNM	O
or	O
organic	O
pathology	O
associated	O
.	O

A	O
yeast	O
mitochondrial	O
translation	O
initiation	O
codon	O
mutation	O
affecting	O
the	O
gene	O
for	O
cytochrome	B-GENE
oxidase	I-GENE
subunit	I-GENE
III	I-GENE
(	O
COX3	B-GENE
)	O
was	O
partially	O
suppressed	O
by	O
a	O
spontaneous	O
nuclear	O
mutation	O
.	O

Patients	O
with	O
endocarditis	O
or	O
vascular	O
infection	O
were	O
more	O
frequently	O
immunocompromised	O
and	O
older	O
than	O
those	O
with	O
acute	O
Q	O
fever	O
.	O

This	O
latter	O
complex	O
reacts	O
with	O
an	O
antibody	O
to	O
serum	B-GENE
response	I-GENE
factor	I-GENE
(	O
SRF	B-GENE
)	O
and	O
exhibits	O
the	O
same	O
binding	O
characteristics	O
as	O
purified	O
SRF	B-GENE
.	O

MEASURES	O
:	O
SF	O
-	O
36	O
questionnaires	O
were	O
completed	O
by	O
patients	O
at	O
both	O
initial	O
and	O
discharge	O
examinations	O
.	O

Hormonal	O
replacement	O
therapy	O
for	O
women	O
with	O
a	O
personal	O
history	O
of	O
breast	O
cancer	O
?	O

The	O
human	B-GENE
SHBG	I-GENE
proximal	I-GENE
promoter	I-GENE
was	O
analyzed	O
by	O
DNase	B-GENE
I	I-GENE
footprinting	O
,	O
and	O
the	O
functional	O
significance	O
of	O
6	O
footprinted	O
regions	O
(	O
FP1	O
-	O
FP6	O
)	O
within	O
the	O
proximal	O
promoter	O
was	O
studied	O
in	O
human	O
HepG2	O
hepatoblastoma	O
cells	O
.	O

Endodontic	O
treatment	O
of	O
deciduous	O
teeth	O
using	O
the	O
formocresol	O
amputation	O
method	O

The	O
analysis	O
of	O
results	O
suggests	O
that	O
seroprevalence	O
of	O
Lyme	O
borreliosis	O
in	O
dogs	O
of	O
the	O
Kosice	O
region	O
is	O
not	O
negligible	O
.	O

Mutant	O
beta2	B-GENE
-	I-GENE
adrenergic	I-GENE
receptors	I-GENE
with	O
a	O
Tyr	O
-	O
to	O
-	O
Phe	O
substitution	O
at	O
Tyr	O
-	O
350	O
do	O
not	O
display	O
agonist	O
-	O
induced	O
desensitization	O
,	O
Src	B-GENE
recruitment	O
,	O
or	O
Src	B-GENE
activation	O
.	O

The	O
feasibility	O
of	O
creating	O
CR1	B-GENE
/	O
Ig	B-GENE
chimeras	O
makes	O
possible	O
a	O
new	O
strategy	O
of	O
targeting	O
complement	O
inhibition	O
by	O
the	O
use	O
of	O
Ig	B-GENE
fusion	I-GENE
partners	I-GENE
having	O
particular	O
antigenic	O
specificities	O
.	O

Otosclerosis	O
in	O
monozygotic	O
twins	O
:	O
clinical	O
and	O
genetical	O
analysis	O

The	O
results	O
show	O
that	O
in	O
uninfected	O
NIH	O
-	O
3T3	O
cells	O
Avarol	O
(	O
i	O
)	O
causes	O
a	O
50	O
%	O
reduction	O
of	O
the	O
growth	O
rate	O
only	O
at	O
the	O
high	O
concentration	O
of	O
29	O
.	O
6	O
microM	O
and	O
(	O
ii	O
)	O
is	O
accumulated	O
in	O
the	O
cytoplasm	O
close	O
to	O
the	O
nucleus	O
.	O

Furthermore	O
,	O
disruption	O
of	O
pcr1	B-GENE
reduced	O
expression	O
of	O
fbp1	B-GENE
,	O
a	O
glucose	O
-	O
repressible	O
gene	O
negatively	O
regulated	O
by	O
PKA	B-GENE
.	O

This	O
B	O
-	O
box	O
is	O
not	O
present	O
in	O
ETS1	B-GENE
,	O
ETS2	B-GENE
,	O
PEA3	B-GENE
or	O
PU	B-GENE
.	I-GENE
1	I-GENE
and	O
these	O
proteins	O
were	O
unable	O
to	O
form	O
ternary	O
complexes	O
with	O
SRF	B-GENE
and	O
Egrl	B-GENE
-	O
SREs	O
or	O
c	B-GENE
-	I-GENE
fos	I-GENE
SRE	O
.	O

Excretion	O
of	O
radiopharmaceuticals	O
into	O
breast	O
milk	O
.	O

It	O
is	O
concluded	O
that	O
the	O
drinking	O
ampules	O
of	O
VP	O
-	O
16	O
-	O
213	O
can	O
be	O
replaced	O
with	O
the	O
new	O
oral	O
capsules	O
with	O
a	O
recommended	O
initial	O
dose	O
of	O
100	O
-	O
130	O
mg	O
/	O
m2	O
given	O
in	O
5	O
-	O
day	O
courses	O
every	O
21	O
-	O
28	O
days	O
.	O

Deletion	O
of	O
the	O
region	O
from	O
amino	O
acid	O
residues	O
2	O
-	O
67	O
in	O
E1A	B-GENE
,	O
which	O
has	O
been	O
postulated	O
to	O
interact	O
with	O
p300	B-GENE
/	O
CBP	B-GENE
,	O
also	O
abolished	O
the	O
inhibitory	O
effect	O
of	O
E1A	B-GENE
,	O
whereas	O
deletion	O
of	O
the	O
region	O
from	O
residues	O
120	O
to	O
140	O
had	O
no	O
effect	O
.	O

It	O
was	O
found	O
that	O
on	O
the	O
14th	O
and	O
21st	O
day	O
after	O
cimetidine	O
administration	O
serum	B-GENE
gastrin	I-GENE
levels	O
were	O
significantly	O
elevated	O
.	O

Both	O
PMP20	B-GENE
gene	I-GENE
products	I-GENE
contain	O
the	O
carboxyl	O
-	O
terminal	O
sequence	O
AKL	O
,	O
similar	O
to	O
the	O
putative	O
SKL	O
peroxisomal	O
sorting	O
sequence	O
(	O
Gould	O
,	O
S	O
.	O

After	O
cumulative	O
occlusions	O
of	O
15	O
,	O
30	O
,	O
45	O
,	O
and	O
90	O
min	O
,	O
transmural	O
needle	O
biopsies	O
were	O
taken	O
from	O
the	O
ischemic	O
area	O
to	O
be	O
analyzed	O
for	O
adenine	O
nucleotides	O
,	O
nucleosides	O
,	O
creatine	O
phosphate	O
,	O
and	O
ultrastructural	O
changes	O
.	O

We	O
found	O
both	O
the	O
v	B-GENE
-	I-GENE
Ras	I-GENE
-	O
and	O
PC	B-GENE
-	I-GENE
PLC	I-GENE
-	O
transformed	O
cells	O
to	O
be	O
insensitive	O
to	O
stimulation	O
with	O
platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
(	O
PDGF	B-GENE
)	O
.	O

Although	O
indomethacin	O
is	O
useful	O
for	O
examining	O
the	O
role	O
of	O
cyclooxygenase	B-GENE
products	I-GENE
in	O
asthmatic	O
responses	O
,	O
it	O
should	O
not	O
be	O
considered	O
in	O
the	O
treatment	O
of	O
asthma	O
.	O

Furthermore	O
,	O
it	O
was	O
found	O
that	O
the	O
Shb	B-GENE
-	O
overexpressing	O
cells	O
extended	O
neurites	O
in	O
response	O
to	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
.	O

Tre	O
during	O
exercise	O
at	O
35	O
W	O
at	O
23	O
degrees	O
C	O
correlated	O
r	O
=	O
-	O
70	O
with	O
Vo2max	O
and	O
r	O
=	O
0	O
.	O
80	O
with	O
Tre	O
during	O
exercise	O
in	O
heat	O
.	O

Therapeutic	O
iodine	O
125	O
for	O
hyperthyroidism	O
:	O
evidence	O
for	O
a	O
special	O
radiobiological	O
effect	O
on	O
the	O
follicular	O
cell	O
.	O

The	O
biological	O
activity	O
of	O
these	O
mutants	O
was	O
tested	O
by	O
determining	O
their	O
capacity	O
to	O
(	O
i	O
)	O
reconstitute	O
RNA	B-GENE
polymerase	I-GENE
activity	O
in	O
vivo	O
by	O
cotransfection	O
with	O
proteins	O
NP	B-GENE
,	O
PB1	B-GENE
,	O
and	O
PA	B-GENE
and	O
a	O
virion	O
-	O
like	O
RNA	O
encoding	O
the	O
cat	B-GENE
gene	O
into	O
vaccinia	O
virus	O
T7	O
-	O
infected	O
COS	O
-	O
1	O
cells	O
and	O
(	O
ii	O
)	O
complete	O
with	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
PB2	I-GENE
activity	O
.	O

Should	O
we	O
use	O
thiazide	O
diuretics	O
in	O
hypertensive	O
patients	O
with	O
non	O
-	O
insulin	B-GENE
-	O
dependent	O
diabetes	O
mellitus	O
?	O

It	O
appears	O
that	O
the	O
K	O
-	O
ABC	O
is	O
a	O
relatively	O
nonbiased	O
test	O
suitable	O
for	O
the	O
evaluation	O
of	O
both	O
gifted	O
and	O
nongifted	O
children	O
regardless	O
of	O
race	O
or	O
gender	O
.	O

The	O
University	O
of	O
North	O
Carolina	O
caries	O
risk	O
assessment	O
was	O
conducted	O
between	O
1986	O
and	O
1989	O
with	O
5000	O
children	O
initially	O
in	O
grades	O
1	O
and	O
5	O
from	O
low	O
fluoride	O
sites	O
in	O
South	O
Carolina	O
and	O
Maine	O
.	O

Treatment	O
of	O
cells	O
for	O
10	O
min	O
with	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
resulted	O
in	O
activation	O
of	O
p44	B-GENE
/	I-GENE
42	I-GENE
MAPK	O
,	O
p38	B-GENE
,	O
and	O
JNK	B-GENE
.	O

The	O
coding	O
region	O
of	O
nifA	B-GENE
was	O
determined	O
using	O
a	O
translational	O
lacZ	B-GENE
fusion	I-GENE
and	O
by	O
site	O
-	O
directed	O
mutagenesis	O
to	O
identify	O
which	O
of	O
four	O
in	O
frame	O
AUG	O
codons	O
was	O
used	O
.	O

In	O
phase	O
II	O
studies	O
,	O
MDL	O
72	O
,	O
974A	O
is	O
proving	O
to	O
be	O
a	O
useful	O
adjunct	O
to	O
conventional	O
therapy	O
.	O

A	O
derived	O
RA	O
-	O
resistant	O
line	O
,	O
NT2	O
/	O
D1	O
-	O
R1	O
,	O
is	O
deficient	O
in	O
this	O
activity	O
and	O
is	O
co	O
-	O
resistant	O
to	O
cisplatin	O
.	O

These	O
studies	O
reveal	O
that	O
CREM	B-GENE
,	O
a	O
tissue	O
-	O
specific	O
factor	O
,	O
is	O
expressed	O
and	O
regulated	O
by	O
gonadotropins	B-GENE
in	O
the	O
ovary	O
,	O
that	O
the	O
predominant	O
CREM	B-GENE
transcripts	O
encode	O
the	O
repressor	B-GENE
protein	I-GENE
ICER	I-GENE
,	O
and	O
that	O
ICER	B-GENE
is	O
capable	O
of	O
inhibiting	O
cAMP	O
-	O
induced	O
expression	O
of	O
the	O
inhibin	B-GENE
alpha	I-GENE
-	I-GENE
subunit	I-GENE
gene	I-GENE
.	O

A	O
small	O
molecule	O
ILK	B-GENE
inhibitor	O
suppresses	O
the	O
phosphorylation	O
of	O
PKB	B-GENE
at	O
the	O
Ser	O
-	O
473	O
but	O
not	O
the	O
Thr	O
-	O
308	O
site	O
in	O
the	O
PTEN	B-GENE
mutant	O
cells	O
.	O

Menstrual	O
and	O
lunar	O
cycles	O
.	O

Phenacetin	O
nephritis	O

Both	O
claR	B-GENE
and	O
car	B-GENE
are	O
expressed	O
as	O
monocistronic	O
transcripts	O
;	O
the	O
level	O
of	O
transcript	O
declined	O
rapidly	O
after	O
48h	O
in	O
complex	O
media	O
,	O
but	O
low	O
sustained	O
levels	O
of	O
both	O
transcripts	O
were	O
observed	O
in	O
defined	O
GSPG	O
medium	O
until	O
96h	O
.	O
claR	B-GENE
and	O
car	B-GENE
were	O
not	O
significantly	O
expressed	O
in	O
mutants	O
disrupted	O
in	O
the	O
ccaR	B-GENE
gene	I-GENE
,	O
a	O
regulatory	O
gene	O
that	O
controls	O
positively	O
clavulanic	O
acid	O
and	O
cephamycin	O
biosynthesis	O
.	O

Viral	O
complementary	O
15	B-GENE
S	I-GENE
mRNA	I-GENE
that	O
directs	O
the	O
synthesis	O
of	O
N	B-GENE
protein	I-GENE
and	O
hybridizes	O
to	O
the	O
predicted	O
N	B-GENE
gene	I-GENE
DNA	O
has	O
been	O
identified	O
in	O
infected	O
cell	O
extracts	O
.	O

Experiments	O
were	O
performed	O
without	O
polarization	O
or	O
with	O
cathodic	O
and	O
anodic	O
polarization	O
of	O
the	O
adsorbent	O
.	O

Our	O
results	O
suggest	O
that	O
Sp1	B-GENE
binding	I-GENE
site	I-GENE
can	O
function	O
as	O
a	O
distinct	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
responsive	I-GENE
element	I-GENE
for	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
mediated	O
promoter	O
expression	O
and	O
Sp1	B-GENE
per	O
se	O
can	O
mediate	O
this	O
response	O
.	O

A	O
positive	O
correlation	O
was	O
also	O
established	O
between	O
the	O
level	O
of	O
FP9C	B-GENE
binding	O
and	O
the	O
degree	O
of	O
cell	O
differentiation	O
in	O
vitro	O
.	O

In	O
another	O
patient	O
,	O
IRPF	O
recurred	O
in	O
the	O
ureter	O
of	O
a	O
living	O
related	O
renal	O
graft	O
6	O
months	O
after	O
transplantation	O
.	O

Similar	O
to	O
the	O
D	B-GENE
,	O
B	B-GENE
/	O
B	B-GENE
'	I-GENE
and	O
E	B-GENE
proteins	I-GENE
,	O
the	O
F	B-GENE
and	O
G	B-GENE
proteins	I-GENE
do	O
not	O
possess	O
any	O
of	O
the	O
known	O
RNA	O
binding	O
motifs	O
,	O
suggesting	O
that	O
other	O
types	O
of	O
RNA	O
-	O
protein	O
interactions	O
occur	O
in	O
the	O
snRNP	O
core	O
.	O

Ultrasound	O
-	O
guided	O
fine	O
-	O
needle	O
aspiration	O
biopsy	O
(	O
US	O
-	O
FNAB	O
)	O
revealed	O
normal	O
-	O
looking	O
squamous	O
cells	O
.	O

HC	B-GENE
-	I-GENE
toxin	I-GENE
exerts	O
a	O
potent	O
cytostatic	O
effect	O
on	O
plant	O
and	O
animal	O
cells	O
by	O
inhibiting	O
histone	B-GENE
deacetylase	I-GENE
.	O

In	O
EGF	B-GENE
receptor	I-GENE
-	O
mediated	O
signaling	O
,	O
the	O
protein	B-GENE
kinase	I-GENE
PKB	I-GENE
/	O
Akt	B-GENE
and	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
c	I-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
,	O
but	O
not	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
2	I-GENE
,	O
function	O
downstream	O
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
(	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
)	O
.	O

Blockade	O
of	O
T	O
cell	O
activation	O
using	O
a	O
surface	O
-	O
linked	O
single	O
-	O
chain	O
antibody	O
to	O
CTLA	B-GENE
-	I-GENE
4	I-GENE
(	O
CD152	B-GENE
)	O
.	O

On	O
the	O
basis	O
of	O
this	O
homology	O
,	O
we	O
examined	O
the	O
potential	O
role	O
of	O
c	B-GENE
-	I-GENE
Rel	I-GENE
in	O
controlling	O
IL	B-GENE
-	I-GENE
2R	I-GENE
alpha	I-GENE
transcription	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
shows	O
that	O
sites	O
throughout	O
the	O
IRE	B-GENE
alter	O
negative	O
control	O
and	O
IRE	B-GENE
-	I-GENE
BP	I-GENE
binding	O
reflecting	O
the	O
fact	O
that	O
the	O
footprint	O
of	O
the	O
IRE	B-GENE
-	I-GENE
BP	I-GENE
is	O
over	O
the	O
entire	O
IRE	B-GENE
.	O

However	O
,	O
LXRalpha	B-GENE
inhibited	O
binding	O
of	O
PPARalpha	B-GENE
/	O
RXRalpha	B-GENE
heterodimers	O
to	O
PPREs	O
,	O
and	O
coexpression	O
of	O
LXRalpha	B-GENE
in	O
mammalian	O
cells	O
antagonized	O
peroxisome	O
proliferator	O
signaling	O
mediated	O
by	O
PPARalpha	B-GENE
/	O
RXRalpha	B-GENE
in	O
vivo	O
.	O

In	O
clinical	O
stroke	O
cardiovascular	O
abnormalities	O
are	O
frequently	O
neglected	O
although	O
they	O
occur	O
more	O
often	O
than	O
it	O
is	O
generally	O
assumed	O
.	O

Complementary	O
DNA	O
libraries	O
from	O
liver	O
and	O
ovary	O
of	O
an	O
immature	O
female	O
channel	O
catfish	O
were	O
screened	O
with	O
a	O
homologous	B-GENE
ERalpha	I-GENE
cDNA	I-GENE
probe	O
.	O

Examination	O
of	O
the	O
Coomassie	O
-	O
stained	O
gels	O
revealed	O
that	O
the	O
capsid	O
-	O
like	O
particles	O
composed	O
of	O
the	O
N11	B-GENE
-	I-GENE
VP1	I-GENE
protein	O
did	O
not	O
contain	O
any	O
host	O
-	O
derived	O
histones	B-GENE
.	O

Here	O
we	O
show	O
that	O
one	O
nudF	B-GENE
suppressor	I-GENE
also	O
suppresses	O
hs	O
-	O
mutations	O
in	O
nudA	B-GENE
,	O
nudC	B-GENE
,	O
and	O
nudG	B-GENE
and	O
deletions	O
in	O
nudA	B-GENE
and	O
nudF	B-GENE
.	O

Thus	O
,	O
the	O
potential	O
induction	O
of	O
this	O
gene	O
rearrangement	O
by	O
E1A	B-GENE
gene	I-GENE
therapy	O
is	O
unlikely	O
to	O
be	O
clinically	O
significant	O
in	O
the	O
treatment	O
of	O
advanced	O
malignant	O
disease	O
.	O

Our	O
results	O
suggest	O
that	O
Bry1	B-GENE
/	O
Skn7	B-GENE
can	O
influence	O
the	O
expression	O
of	O
MCB	O
-	O
and	O
SCB	O
-	O
driven	O
gene	O
expression	O
in	O
budding	O
yeast	O
,	O
perhaps	O
including	O
genes	O
involved	O
in	O
cell	O
wall	O
metabolism	O
,	O
via	O
a	O
two	O
-	O
component	O
signal	O
transduction	O
pathway	O
which	O
activates	O
Bry1	B-GENE
/	O
Skn7	B-GENE
in	O
response	O
to	O
an	O
unidentified	O
signal	O
.	O

Buspirone	O
therapy	O
for	O
Type	O
A	O
behavior	O
,	O
hostility	O
,	O
and	O
perceived	O
stress	O
in	O
cardiac	O
patients	O
.	O

When	O
furA	B-GENE
alone	O
was	O
introduced	O
into	O
the	O
Delta	O
(	O
furA	B-GENE
-	O
katG	B-GENE
)	O
mutant	O
,	O
survival	O
in	O
mouse	O
lungs	O
was	O
moderately	O
increased	O
,	O
suggesting	O
that	O
FurA	B-GENE
could	O
regulate	O
genes	O
,	O
other	O
than	O
katG	B-GENE
,	O
that	O
are	O
involved	O
in	O
pathogenesis	O
.	O

The	O
resulting	O
threshold	O
elevation	O
curves	O
fell	O
into	O
a	O
small	O
number	O
of	O
distinct	O
groups	O
,	O
suggesting	O
the	O
existence	O
of	O
discrete	O
spatial	O
frequency	O
mechanisms	O
in	O
human	O
central	O
vision	O
.	O

Through	O
interactions	O
with	O
the	O
pre	O
-	O
mRNA	O
and	O
the	O
CTD	O
domain	O
of	O
the	O
Polymerase	B-GENE
II	I-GENE
,	O
SR	B-GENE
proteins	I-GENE
have	O
been	O
shown	O
to	O
regulate	O
alternative	O
splicing	O
.	O

The	O
screen	O
identifies	O
mutants	O
whose	O
growth	O
depends	O
on	O
high	O
levels	O
of	O
expression	O
of	O
that	O
gene	O
.	O

Electrophoretic	O
mobility	O
shift	O
analysis	O
of	O
protein	O
-	O
DNA	O
complexes	O
formed	O
with	O
nuclear	O
proteins	O
isolated	O
from	O
I3C	O
-	O
treated	O
and	O
-	O
untreated	O
cells	O
,	O
in	O
combination	O
with	O
supershift	O
assays	O
using	O
Sp1	B-GENE
antibodies	I-GENE
,	O
demonstrated	O
that	O
the	O
Sp1	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
in	O
the	O
CDK6	B-GENE
promoter	I-GENE
forms	O
a	O
specific	O
I3C	O
-	O
responsive	O
DNA	O
-	O
protein	O
complex	O
that	O
contains	O
the	O
Sp1	B-GENE
transcription	I-GENE
factor	I-GENE
.	O

It	O
is	O
suggested	O
that	O
the	O
mechanism	O
of	O
intestinal	O
absorption	O
of	O
vitamin	O
D	O
and	O
25	O
-	O
hydroxy	O
-	O
vitamin	O
D	O
may	O
differ	O
in	O
man	O
,	O
the	O
absorption	O
of	O
25	O
-	O
hydroxy	O
-	O
vitamin	O
D	O
possibly	O
being	O
less	O
dependent	O
on	O
bile	O
acids	O
.	O

In	O
a	O
study	O
in	O
Singapore	O
,	O
Chinese	O
,	O
Malay	O
and	O
Indian	O
patients	O
with	O
pulmonary	O
tuberculosis	O
received	O
2	O
months	O
of	O
daily	O
treatment	O
with	O
streptomycin	O
,	O
isoniazid	O
,	O
rifampicin	O
,	O
and	O
pyrazinamide	O
followed	O
by	O
daily	O
isoniazid	O
,	O
and	O
rifampicin	O
either	O
with	O
pyrazinamide	O
(	O
SHRZ	O
/	O
HRZ	O
)	O
or	O
without	O
it	O
(	O
SHRZ	O
/	O
HR	O
)	O
,	O
allocated	O
at	O
random	O
.	O

However	O
,	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
stimulated	O
transcription	O
primarily	O
through	O
the	O
cAMP	O
-	O
responsive	O
element	O
(	O
CRE	O
)	O
,	O
which	O
maps	O
between	O
positions	O
-	O
77	O
to	O
-	O
94	O
,	O
but	O
not	O
at	O
the	O
more	O
5	O
'	O
-	O
binding	O
sites	O
.	O

Helenalin	O
triggers	O
a	O
CD95	B-GENE
death	I-GENE
receptor	I-GENE
-	O
independent	O
apoptosis	O
that	O
is	O
not	O
affected	O
by	O
overexpression	O
of	O
Bcl	B-GENE
-	I-GENE
x	I-GENE
(	I-GENE
L	I-GENE
)	I-GENE
or	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
.	O

The	O
observed	O
alterations	O
in	O
lung	O
functions	O
in	O
these	O
subjects	O
indicate	O
that	O
individuals	O
performing	O
heavy	O
continuous	O
exercise	O
are	O
more	O
likely	O
to	O
be	O
affected	O
by	O
lower	O
O3	O
levels	O
.	O

Shields	O
needed	O
for	O
pacemakers	O
.	O

A	O
nationwide	O
record	O
linkage	O
of	O
the	O
Finnish	O
Twin	O
Cohort	O
Study	O
(	O
FTCS	O
)	O
with	O
the	O
Hospital	O
Discharge	O
Registry	O
and	O
the	O
Registry	O
of	O
Rights	O
for	O
Free	O
medication	O
is	O
presented	O
.	O

Results	O
demonstrated	O
that	O
for	O
both	O
S	O
.	O
europaea	O
and	O
A	O
.	O
prostrata	O
,	O
the	O
total	O
number	O
of	O
seeds	O
that	O
germinated	O
decreased	O
throughout	O
the	O
growing	O
season	O
.	O

A	O
personal	O
view	O
of	O
future	O
trends	O
in	O
the	O
field	O
of	O
immunoassay	O
concludes	O
this	O
review	O
.	O

Our	O
results	O
admit	O
that	O
a	O
ribosome	O
scanning	O
mechanism	O
of	O
the	O
MP	B-GENE
gene	I-GENE
expression	O
from	O
I	O
(	O
2	O
)	O
sgRNA	O
operates	O
concurrently	O
.	O

This	O
study	O
demonstrates	O
that	O
Fluosol	O
significantly	O
attenuates	O
neutrophil	O
adherence	O
,	O
cytotoxicity	O
,	O
and	O
enzyme	O
release	O
in	O
an	O
in	O
vitro	O
model	O
of	O
microvascular	O
injury	O
.	O

22	O
.	O
6	O
%	O
of	O
patients	O
were	O
found	O
to	O
be	O
positive	O
at	O
histology	O
in	O
the	O
corpus	O
mucosa	O
;	O
all	O
but	O
one	O
of	O
these	O
patients	O
had	O
elevated	O
circulating	O
IgG	B-GENE
to	O
H	O
.	O
pylori	O
(	O
Group	O
C	O
)	O
.	O

Concerning	O
the	O
practical	O
approach	O
in	O
a	O
clinical	O
setting	O
,	O
it	O
has	O
to	O
be	O
pointed	O
out	O
that	O
with	O
these	O
diseases	O
a	O
hepatitis	O
C	O
infection	O
has	O
to	O
be	O
considered	O
and	O
testing	O
for	O
hepatitis	B-GENE
C	I-GENE
antibodies	I-GENE
and	O
,	O
if	O
positive	O
,	O
hepatitis	B-GENE
C	I-GENE
-	I-GENE
RNA	I-GENE
is	O
indicated	O
.	O

In	O
order	O
to	O
investigate	O
the	O
effect	O
of	O
the	O
local	O
direct	O
action	O
of	O
danazol	O
upon	O
endometriosis	O
,	O
intravaginal	O
and	O
intrauterine	O
application	O
were	O
tried	O
.	O

Western	O
blot	O
experiments	O
detected	O
SMBP	B-GENE
as	O
a	O
70	O
kDa	O
protein	O
that	O
may	O
be	O
further	O
cleaved	O
into	O
an	O
active	O
34	O
kDa	O
N	O
-	O
terminal	O
polypeptide	O
.	O

80	O
bp	O
)	O
surrounding	O
the	O
site	O
of	O
transcription	O
initiation	O
.	O

A	O
backward	O
look	O
at	O
urinary	O
tract	O
infections	O
.	O

All	O
the	O
cognate	O
gene	O
clones	O
were	O
constructed	O
,	O
using	O
either	O
PCR	O
products	O
amplified	O
from	O
genomic	O
DNA	O
,	O
or	O
gap	O
-	O
repair	O
.	O

On	O
Western	O
blots	O
,	O
the	O
same	O
antibodies	O
recognized	O
the	O
recombinant	O
protein	O
migrating	O
slightly	O
slower	O
on	O
SDS	O
/	O
PAGE	O
than	O
chicken	B-GENE
axonin	I-GENE
-	I-GENE
1	I-GENE
.	O

BCR	B-GENE
-	O
ABL	B-GENE
elicits	O
transformation	O
of	O
both	O
fibroblast	O
and	O
hematopoietic	O
cells	O
and	O
blocks	O
apoptosis	O
following	O
cytokine	O
deprivation	O
in	O
various	O
factor	O
-	O
dependent	O
cells	O
.	O

The	O
transcriptional	B-GENE
transactivator	I-GENE
(	O
Tas	B-GENE
)	O
of	O
simian	O
foamy	O
virus	O
type	O
1	O
strongly	O
augments	O
gene	O
expression	O
directed	O
by	O
both	O
the	O
promoter	O
in	O
the	O
viral	O
long	O
terminal	O
repeat	O
and	O
the	O
newly	O
discovered	O
internal	O
promoter	O
located	O
within	O
the	O
env	B-GENE
gene	I-GENE
.	O

Analysis	O
of	O
nt	O
sequence	O
was	O
carried	O
out	O
on	O
three	O
out	O
of	O
the	O
more	O
than	O
15	O
of	O
these	O
regions	O
present	O
in	O
the	O
mouse	O
genome	O
.	O

Moreover	O
,	O
site	O
-	O
specific	O
integration	O
of	O
the	O
ITR	O
-	O
flanked	O
DNA	O
was	O
also	O
detected	O
by	O
PCR	O
amplification	O
of	O
the	O
ITR	B-GENE
-	I-GENE
aavs1	I-GENE
junction	I-GENE
in	O
transduced	O
human	O
fibroblasts	O
.	O

Finally	O
,	O
we	O
demonstrate	O
that	O
animals	O
carrying	O
a	O
snf	B-GENE
mutation	O
that	O
converts	O
SNF	B-GENE
from	O
a	O
bifunctional	O
protein	O
to	O
a	O
U1	B-GENE
snRNP	I-GENE
-	I-GENE
specific	I-GENE
protein	I-GENE
are	O
viable	O
.	O

For	O
this	O
interaction	O
,	O
the	O
C	O
-	O
terminal	O
part	O
of	O
Sp1	B-GENE
and	O
the	O
N	O
terminus	O
of	O
E2F1	B-GENE
,	O
a	O
domain	O
also	O
present	O
in	O
E2F2	B-GENE
and	O
E2F3	B-GENE
but	O
absent	O
in	O
E2F4	B-GENE
and	O
E2F5	B-GENE
,	O
were	O
essential	O
.	O

To	O
gain	O
additional	O
insights	O
into	O
this	O
novel	O
apoptotic	O
checkpoint	O
,	O
we	O
have	O
now	O
characterized	O
the	O
mouse	B-GENE
survivin	I-GENE
locus	I-GENE
.	O

Since	O
RIP140	B-GENE
generally	O
down	O
-	O
regulates	O
receptor	O
activity	O
in	O
mammalian	O
cells	O
and	O
specifically	O
down	O
-	O
regulates	O
coactivation	O
mediated	O
by	O
SRC	B-GENE
-	I-GENE
1	I-GENE
,	O
we	O
propose	O
a	O
model	O
in	O
which	O
RIP140	B-GENE
indirectly	O
regulates	O
nuclear	B-GENE
receptor	I-GENE
AF	I-GENE
-	I-GENE
2	I-GENE
activity	O
by	O
competition	O
for	O
coactivators	O
such	O
as	O
SRC	B-GENE
-	I-GENE
1	I-GENE
.	O

We	O
constructed	O
a	O
stable	O
,	O
doubly	O
transfected	O
cell	O
line	O
(	O
TIS	O
-	O
10	O
)	O
carrying	O
a	O
chromosomally	O
integrated	O
ptetO7	B-GENE
-	I-GENE
CMV	I-GENE
-	I-GENE
L	I-GENE
reporter	O
construct	O
and	O
expressing	O
the	O
TetR	B-GENE
-	O
KRAB	B-GENE
protein	O
.	O

Value	O
of	O
bone	O
scintigraphy	O
with	O
Tc99MDP	O
in	O
the	O
early	O
diagnosis	O
of	O
mobilization	O
of	O
the	O
total	O
hip	O
prosthesis	O

Coimmunoprecipitation	O
analysis	O
suggests	O
that	O
these	O
residues	O
likely	O
contribute	O
to	O
the	O
multimerization	O
function	O
required	O
for	O
homomeric	O
complex	O
formation	O
or	O
heteromeric	O
complex	O
formation	O
with	O
p50	B-GENE
in	O
that	O
no	O
association	O
of	O
p65	B-GENE
delta	I-GENE
with	O
itself	O
or	O
with	O
p50	B-GENE
was	O
evident	O
.	O

The	O
isolation	O
of	O
crt5	B-GENE
-	I-GENE
262	I-GENE
,	O
an	O
additional	O
cdc	B-GENE
allele	I-GENE
of	O
POL1	B-GENE
/	O
CDC17	B-GENE
,	O
suggests	O
for	O
the	O
first	O
time	O
that	O
directly	O
blocking	O
DNA	O
replication	O
can	O
provide	O
a	O
signal	O
to	O
induce	O
the	O
DNA	O
damage	O
response	O
.	O
crt2	B-GENE
mutants	I-GENE
show	O
a	O
defect	O
in	O
basal	O
level	O
expression	O
of	O
RNR1	B-GENE
-	O
lacZ	B-GENE
reporter	O
constructs	O
.	O

Denaturing	O
gradient	O
gel	O
electrophoresis	O
(	O
DGGE	O
)	O
with	O
sequence	O
analysis	O
showed	O
that	O
PGCL4	B-GENE
is	O
a	O
major	O
member	O
in	O
the	O
female	O
mammary	O
gland	O
,	O
and	O
in	O
the	O
submaxillary	O
and	O
lachrymal	O
glands	O
of	O
both	O
sexes	O
,	O
while	O
the	O
counterpart	O
in	O
male	O
liver	O
and	O
the	O
coagulate	O
glands	O
was	O
found	O
to	O
be	O
PGCL1	B-GENE
.	O

Five	O
sequence	O
variants	O
were	O
identified	O
.	O

If	O
failure	O
to	O
solve	O
invisible	O
displacements	O
was	O
due	O
to	O
increased	O
memory	O
requirements	O
,	O
then	O
the	O
primates	O
should	O
perform	O
at	O
chance	O
level	O
on	O
all	O
3	O
problems	O
.	O

Mouse	B-GENE
GRK6	I-GENE
-	I-GENE
C	I-GENE
displays	O
none	O
of	O
these	O
motifs	O
.	O

The	O
cumulative	O
length	O
of	O
the	O
RGSV	O
genome	O
,	O
including	O
RNAs	O
5	O
and	O
6	O
,	O
was	O
25142	O
nt	O
.	O

CTDK1	B-GENE
and	O
CTDK2	B-GENE
also	O
differ	O
in	O
their	O
protein	O
substrate	O
specificity	O
.	O

ATF	O
is	O
formulated	O
from	O
the	O
prothrombin	B-GENE
time	O
(	O
PT	O
)	O
,	O
fibrinogen	B-GENE
transformation	O
rate	O
(	O
FTR	O
)	O
(	O
a	O
representation	O
of	O
thrombin	B-GENE
activity	O
)	O
,	O
and	O
a	O
consideration	O
of	O
the	O
fibrinogen	B-GENE
(	O
FBG	B-GENE
)	O
content	O
of	O
blood	O
plasma	O
.	O

Protease	O
digestion	O
and	O
alkaline	O
extraction	O
of	O
microsomes	O
containing	O
labeled	O
mutant	O
proteins	O
further	O
showed	O
that	O
segment	O
3	O
was	O
sufficient	O
for	O
stable	O
membrane	O
anchoring	O
of	O
the	O
glycoproteins	O
,	O
indicating	O
that	O
this	O
segment	O
may	O
specify	O
the	O
transmembrane	O
domain	O
of	O
the	O
gB	B-GENE
glycoprotein	I-GENE
.	O

Peripheral	O
visual	O
acuity	O
with	O
monovision	O
and	O
other	O
contact	O
lens	O
corrections	O
for	O
presbyopia	O
.	O

ORF3	O
appears	O
to	O
encode	O
the	O
homologue	O
of	O
the	O
well	O
-	O
conserved	O
proteasomal	B-GENE
26S	I-GENE
regulatory	I-GENE
subunit	I-GENE
.	O

87	O
,	O
7270	O
-	O
7274	O
)	O
.	O

Protein	O
binding	O
to	O
UAS1MLS1	B-GENE
was	O
observed	O
with	O
extracts	O
from	O
derepressed	O
but	O
not	O
from	O
repressed	O
cells	O
,	O
and	O
could	O
be	O
competed	O
for	O
by	O
an	O
excess	O
of	O
the	O
unlabelled	O
CSRE	O
(	O
ICL1	B-GENE
)	O
sequence	O
.	O

This	O
inhibition	O
was	O
due	O
to	O
competition	O
from	O
the	O
EMC	O
virus	O
IRES	O
present	O
in	O
pEP	B-GENE
-	I-GENE
2A	I-GENE
transcripts	I-GENE
,	O
as	O
well	O
as	O
the	O
expression	O
of	O
proteolytically	O
active	O
2Apro	B-GENE
.	O

These	O
properties	O
prompted	O
us	O
to	O
investigate	O
Ets	B-GENE
-	I-GENE
1	I-GENE
expression	O
in	O
32	O
human	O
astroglial	O
tumors	O
of	O
WHO	O
grades	O
I	O
-	O
IV	O
and	O
to	O
correlate	O
the	O
data	O
with	O
the	O
expression	O
pattern	O
of	O
VEGF	B-GENE
,	O
Flt	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
KDR	B-GENE
.	O

The	O
CydDC	B-GENE
system	I-GENE
appears	O
to	O
be	O
the	O
first	O
prokaryotic	O
example	O
of	O
a	O
heterodimeric	B-GENE
ABC	I-GENE
transport	I-GENE
system	I-GENE
in	O
which	O
each	O
polypeptide	O
contains	O
both	O
hydrophobic	O
and	O
ATP	O
-	O
binding	O
domains	O
.	O

Ionic	O
composition	O
(	O
Na	O
+	O
,	O
K	O
+	O
,	O
Ca	O
+	O
2	O
,	O
and	O
Mg2	O
+	O
)	O
of	O
cerebrospinal	O
fluid	O
and	O
feeding	O
behavior	O
in	O
sheep	O
.	O

Recently	O
we	O
have	O
performed	O
a	O
detailed	O
analysis	O
of	O
specific	O
neuronal	O
populations	O
affected	O
by	O
the	O
mutation	O
which	O
shed	O
new	O
light	O
on	O
the	O
role	O
of	O
Krox	B-GENE
-	I-GENE
20	I-GENE
in	O
the	O
segmentation	O
and	O
on	O
the	O
physiological	O
consequences	O
of	O
its	O
inactivation	O
.	O

Comparison	O
of	O
the	O
sequences	O
of	O
the	O
alpha	B-GENE
-	I-GENE
like	I-GENE
DNA	I-GENE
polymerases	I-GENE
including	O
E	B-GENE
.	I-GENE
coli	I-GENE
DNA	I-GENE
polymerase	I-GENE
II	I-GENE
showed	O
that	O
there	O
were	O
nine	O
highly	O
conserved	O
regions	O
,	O
and	O
we	O
constructed	O
an	O
unrooted	O
phylogenetic	O
tree	O
of	O
the	O
DNA	B-GENE
polymerases	I-GENE
based	O
on	O
the	O
differences	O
in	O
these	O
conserved	O
regions	O
.	O

Guanylyl	B-GENE
cyclase	I-GENE
C	I-GENE
,	O
the	O
apparent	O
guanylin	B-GENE
receptor	I-GENE
,	O
was	O
found	O
in	O
abundant	O
amounts	O
in	O
the	O
intestine	O
by	O
Northern	O
analysis	O
,	O
and	O
by	O
the	O
polymerase	O
chain	O
reaction	O
or	O
cDNA	O
cloning	O
it	O
was	O
also	O
found	O
in	O
adrenal	O
gland	O
,	O
airway	O
epithelial	O
cells	O
,	O
brain	O
,	O
and	O
olfactory	O
and	O
tracheal	O
mucosa	O
.	O

Older	O
females	O
had	O
lumbar	O
(	O
0	O
.	O
6	O
+	O
/	O
-	O
1	O
.	O
3	O
)	O
and	O
TB	O
(	O
1	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
1	O
)	O
BMD	O
Z	O
scores	O
greater	O
than	O
0	O
(	O
both	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Mutation	O
of	O
the	O
distal	O
E2F	B-GENE
binding	I-GENE
site	I-GENE
in	O
the	O
cdc25A	B-GENE
promoter	I-GENE
abolished	O
E2	B-GENE
-	O
induced	O
repression	O
,	O
whereas	O
mutation	O
of	O
the	O
proximal	O
E2F	B-GENE
site	I-GENE
or	O
the	O
E2	B-GENE
site	I-GENE
had	O
no	O
effect	O
.	O

Psychopathological	O
,	O
vegetative	O
,	O
and	O
vital	O
parameters	O
were	O
assessed	O
every	O
hour	O
.	O

A	O
new	O
family	O
of	O
rate	O
-	O
adaptive	O
pacemakers	O
accomplishes	O
this	O
circadian	O
rate	O
variation	O
by	O
modeling	O
the	O
patient	O
'	O
s	O
sleep	O
-	O
wake	O
cycle	O
using	O
a	O
time	O
-	O
of	O
-	O
day	O
clock	O
inside	O
the	O
device	O
.	O

New	O
strategies	O
are	O
needed	O
to	O
prevent	O
coronary	O
rethrombosis	O
in	O
patients	O
with	O
minimal	O
atherosclerosis	O
after	O
thrombolytic	O
therapy	O
for	O
acute	O
myocardial	O
infarction	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
With	O
an	O
array	O
of	O
112	O
unipole	O
,	O
epicardial	O
maps	O
of	O
electrically	O
induced	O
AF	O
in	O
6	O
dogs	O
(	O
acute	O
group	O
)	O
,	O
self	O
-	O
sustained	O
AF	O
in	O
6	O
dogs	O
(	O
chronic	O
group	O
)	O
,	O
and	O
sinus	O
rhythm	O
and	O
atrial	O
pacing	O
in	O
3	O
dogs	O
(	O
control	O
group	O
)	O
were	O
analyzed	O
before	O
and	O
after	O
creating	O
linear	O
radiofrequency	O
ablation	O
lesions	O
in	O
both	O
atria	O
that	O
eliminated	O
the	O
AF	O
.	O

The	O
mitochondrial	B-GENE
tyrosyl	I-GENE
-	I-GENE
tRNA	I-GENE
synthetase	I-GENE
of	O
Podospora	O
anserina	O
is	O
a	O
bifunctional	O
enzyme	O
active	O
in	O
protein	O
synthesis	O
and	O
RNA	O
splicing	O
.	O

We	O
found	O
that	O
the	O
central	O
nonconserved	O
region	O
of	O
the	O
large	O
subunit	O
is	O
not	O
essential	O
for	O
function	O
and	O
likely	O
acts	O
as	O
a	O
spacer	O
between	O
the	O
conserved	O
N	O
-	O
and	O
C	O
-	O
terminal	O
regions	O
.	O

Further	O
comparative	O
analysis	O
identified	O
an	O
ADNP	B-GENE
paralog	O
(	O
33	O
%	O
identity	O
and	O
46	O
%	O
similarity	O
)	O
,	O
indicating	O
that	O
these	O
genes	O
belong	O
to	O
a	O
novel	O
protein	O
family	O
with	O
a	O
nine	O
-	O
zinc	O
finger	O
motif	O
followed	O
by	O
a	O
homeobox	O
domain	O
.	O

Surprisingly	O
,	O
apo	B-GENE
-	I-GENE
iso	I-GENE
-	I-GENE
1	I-GENE
-	I-GENE
cytochrome	I-GENE
c	I-GENE
is	O
absent	O
in	O
cyc3	B-GENE
-	I-GENE
strains	O
,	O
although	O
apo	B-GENE
-	I-GENE
iso	I-GENE
-	I-GENE
2	I-GENE
-	I-GENE
cytochrome	I-GENE
c	I-GENE
is	O
present	O
at	O
approximately	O
the	O
same	O
level	O
at	O
which	O
holo	B-GENE
-	I-GENE
iso	I-GENE
-	I-GENE
2	I-GENE
-	I-GENE
cytochrome	I-GENE
c	I-GENE
is	O
found	O
in	O
CYC3	B-GENE
+	I-GENE
strains	O
.	O

A	O
role	O
for	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
in	O
the	O
regulation	O
of	O
beta	B-GENE
1	I-GENE
integrin	I-GENE
activity	O
by	O
the	O
CD2	B-GENE
antigen	O
.	O

The	O
cluster	O
was	O
mapped	O
to	O
nucleotides	O
-	O
464	O
to	O
-	O
434	O
(	O
relative	O
to	O
nucleotide	O
A	O
in	O
the	O
initiation	O
codon	O
)	O
in	O
genomic	O
DNA	O
.	O

All	O
the	O
previously	O
mapped	O
structural	O
protein	O
-	O
encoding	O
genes	O
of	O
phage	O
LL	O
-	O
H	O
were	O
included	O
in	O
the	O
sequence	O
.	O

An	O
exception	O
is	O
the	O
Bcl	B-GENE
-	I-GENE
6	I-GENE
gene	I-GENE
,	O
encoding	O
a	O
transcription	O
factor	O
,	O
which	O
was	O
found	O
to	O
be	O
mutated	O
in	O
normal	O
human	O
memory	O
B	O
cells	O
.	O

Nature	O
and	O
incidence	O
of	O
conditioned	O
responses	O
in	O
a	O
methadone	O
population	O
:	O
a	O
comparison	O
of	O
laboratory	O
,	O
clinic	O
,	O
and	O
naturalistic	O
settings	O
.	O

Serum	O
PRL	B-GENE
concentrations	O
significantly	O
increased	O
after	O
MCP	O
administration	O
in	O
normal	O
women	O
,	O
hyperprolactinemic	O
patients	O
with	O
normal	O
sella	O
and	O
patients	O
with	O
microadenoma	O
,	O
but	O
not	O
in	O
macroadenoma	O
patients	O
with	O
and	O
without	O
suprasellar	O
expansion	O
(	O
SSE	O
)	O
.	O

Fourteen	O
Centers	O
participated	O
in	O
this	O
trial	O
.	O

In	O
cells	O
stably	O
transfected	O
with	O
G	B-GENE
alpha	I-GENE
i	I-GENE
-	I-GENE
2	I-GENE
or	O
G	B-GENE
alpha	I-GENE
i	I-GENE
-	I-GENE
3	I-GENE
gene	I-GENE
5	O
'	O
-	O
flanking	O
sequences	O
fused	O
to	O
firefly	O
luciferase	B-GENE
cDNA	O
reporter	O
,	O
temporal	O
10	O
-	O
15	O
-	O
fold	O
transcriptional	O
activation	O
of	O
both	O
genes	O
occurred	O
before	O
cellular	O
polarization	O
.	O

A	O
gene	O
(	O
FMR	B-GENE
-	I-GENE
1	I-GENE
)	O
was	O
identified	O
within	O
a	O
four	O
cosmid	O
contig	O
of	O
YAC	O
DNA	O
that	O
expresses	O
a	O
4	O
.	O
8	O
kb	O
message	O
in	O
human	O
brain	O
.	O

These	O
include	O
not	O
only	O
antioxidants	O
,	O
N	B-GENE
-	I-GENE
methyl	I-GENE
-	I-GENE
D	I-GENE
-	I-GENE
aspartate	I-GENE
receptor	I-GENE
antagonists	O
,	O
inhibitors	O
of	O
glutamate	O
release	O
,	O
calcium	O
channel	O
blockers	O
,	O
polyamine	O
antagonists	O
,	O
and	O
nitric	B-GENE
oxide	I-GENE
synthase	I-GENE
inhibitors	O
,	O
but	O
cannabinoids	O
,	O
aspirin	O
,	O
melatonin	O
,	O
and	O
vitamin	O
B	O
-	O
12	O
.	O

In	O
conclusion	O
,	O
ANH	O
had	O
no	O
negative	O
effects	O
on	O
the	O
endocrine	O
stress	O
response	O
during	O
orthopedic	O
surgery	O
under	O
epidural	O
anesthesia	O
.	O

Both	O
genes	B-GENE
ARO3	I-GENE
and	O
ARO4	B-GENE
are	O
strongly	O
regulated	O
under	O
the	O
general	O
control	O
regulatory	O
system	O
.	O

Calculation	O
of	O
energy	O
levels	O
,	O
E1	O
transition	O
amplitudes	O
,	O
and	O
parity	O
violation	O
in	O
francium	O
.	O

A	O
homologue	O
of	O
the	O
MAP	B-GENE
/	O
ERK	B-GENE
family	O
of	O
protein	O
kinase	O
genes	O
is	O
expressed	O
in	O
vegetative	O
and	O
in	O
female	O
reproductive	O
organs	O
of	O
Petunia	O
hybrida	O
.	O

Significance	O
of	O
esophagocardiac	O
reflexes	O
for	O
inducing	O
thoracic	O
pain	O

Northern	O
blot	O
analysis	O
confirmed	O
that	O
ADAMTS	B-GENE
-	I-GENE
1	I-GENE
was	O
up	O
-	O
regulated	O
in	O
both	O
metaphyseal	O
(	O
14	O
-	O
to	O
35	O
-	O
fold	O
)	O
and	O
diaphyseal	O
(	O
4	O
.	O
2	O
-	O
fold	O
)	O
bone	O
1	O
h	O
after	O
PTH	B-GENE
-	I-GENE
(	I-GENE
1	I-GENE
-	I-GENE
38	I-GENE
)	I-GENE
injection	O
and	O
returned	O
to	O
control	O
levels	O
by	O
24	O
h	O
.	O

The	O
findings	O
in	O
the	O
human	O
multiple	O
myeloma	O
cell	O
lines	O
represent	O
the	O
first	O
examples	O
of	O
B	O
cells	O
with	O
downregulated	O
PU	B-GENE
.	I-GENE
1	I-GENE
expression	O
and	O
apparently	O
contradict	O
observations	O
in	O
the	O
murine	O
system	O
in	O
which	O
PU	B-GENE
.	I-GENE
1	I-GENE
is	O
expressed	O
and	O
active	O
in	O
plasmacytoma	O
cell	O
lines	O
.	O

Northern	O
blot	O
analysis	O
identified	O
retina	O
-	O
specific	O
transcripts	O
of	O
3	O
.	O
0	O
kb	O
for	O
rod	B-GENE
G	I-GENE
alpha	I-GENE
t	I-GENE
and	O
2	O
.	O
6	O
kb	O
for	O
cone	B-GENE
G	I-GENE
alpha	I-GENE
t	I-GENE
.	O

The	O
STP1	B-GENE
locus	I-GENE
is	O
located	O
on	O
chromosome	O
IV	O
close	O
to	O
at	O
least	O
two	O
other	O
genes	O
involved	O
in	O
RNA	O
splicing	O
:	O
PRP3	B-GENE
and	O
SPP41	B-GENE
.	O

Both	O
sequence	O
analysis	O
and	O
restriction	O
fragment	O
length	O
polymorphism	O
analysis	O
revealed	O
a	O
high	O
degree	O
of	O
sequence	O
(	O
97	O
%	O
homology	O
)	O
and	O
structural	O
similarity	O
among	O
members	O
of	O
the	O
ART	B-GENE
-	O
CH	B-GENE
family	O
,	O
indicating	O
their	O
common	O
origin	O
and	O
recent	O
penetration	O
into	O
chicken	O
DNA	O
.	O

This	O
interesting	O
exon	O
junction	O
resulted	O
in	O
novel	O
deduced	O
amino	O
terminal	O
open	O
reading	O
frames	O
,	O
which	O
are	O
completely	O
in	O
-	O
frame	O
with	O
sequences	O
located	O
further	O
downstream	O
.	O

We	O
investigated	O
the	O
pattern	O
of	O
evolution	O
of	O
bronchial	O
albumin	B-GENE
,	O
IgA	B-GENE
,	O
and	O
IgG	B-GENE
levels	O
in	O
ventilated	O
ICU	O
patients	O
in	O
relation	O
to	O
nosocomial	O
pneumonia	O
.	O

The	O
presence	O
of	O
highly	O
correlated	O
frequencies	O
provided	O
strong	O
evidence	O
of	O
a	O
medium	O
-	O
frequency	O
pattern	O
generator	O
which	O
may	O
remain	O
operative	O
beyond	O
the	O
neonatal	O
period	O
.	O

Pancreatic	O
expression	O
of	O
the	O
glucagon	B-GENE
gene	I-GENE
depends	O
on	O
multiple	O
transcription	O
factors	O
interacting	O
with	O
at	O
least	O
three	O
DNA	O
control	O
elements	O
:	O
G1	O
,	O
the	O
upstream	O
promoter	O
element	O
,	O
and	O
G2	O
and	O
G3	O
,	O
two	O
enhancer	O
-	O
like	O
sequences	O
.	O

Before	O
and	O
6	O
and	O
12	O
months	O
after	O
H	O
.	O
pylori	O
eradication	O
the	O
patients	O
were	O
evaluated	O
for	O
fasting	O
gastrinemia	O
and	O
pepsinogen	B-GENE
I	I-GENE
,	O
basal	O
and	O
peak	O
acid	O
output	O
,	O
and	O
detailed	O
histological	O
assessment	O
including	O
the	O
ECL	O
cell	O
proliferative	O
patterns	O
.	O

Thus	O
,	O
CARP	B-GENE
is	O
a	O
YB	B-GENE
-	I-GENE
1	I-GENE
associated	I-GENE
factor	I-GENE
and	O
represents	O
the	O
first	O
identified	O
cardiac	O
-	O
restricted	O
downstream	O
regulatory	O
gene	O
in	O
the	O
homeobox	O
gene	O
Nkx2	B-GENE
-	I-GENE
5	I-GENE
pathway	O
and	O
may	O
serve	O
as	O
a	O
negative	O
regulator	O
of	O
HF	B-GENE
-	I-GENE
1	I-GENE
-	O
dependent	O
pathways	O
for	O
ventricular	O
muscle	O
gene	O
expression	O
.	O

Barium	O
mucosal	O
coating	O
was	O
judged	O
to	O
be	O
better	O
in	O
the	O
members	O
to	O
whom	O
magnesium	O
sulphate	O
was	O
administered	O
(	O
p	O
=	O
0	O
.	O
0007	O
)	O
.	O

Structure	O
and	O
chromosomal	O
localization	O
of	O
the	O
human	O
gene	O
of	O
the	O
phosphotyrosyl	B-GENE
phosphatase	I-GENE
activator	I-GENE
(	O
PTPA	B-GENE
)	O
of	O
protein	B-GENE
phosphatase	I-GENE
2A	I-GENE
.	O

This	O
article	O
expands	O
the	O
analysis	O
of	O
a	O
numeric	O
example	O
included	O
in	O
the	O
SAS	O
GLM	O
procedure	O
to	O
cover	O
several	O
crucial	O
statistical	O
aspects	O
relevant	O
to	O
ANCOVA	O
,	O
and	O
to	O
highlight	O
the	O
meaning	O
of	O
the	O
statistical	O
results	O
obtained	O
.	O

The	O
PEP4	B-GENE
gene	I-GENE
was	O
isolated	O
from	O
a	O
genomic	O
DNA	O
library	O
by	O
complementation	O
of	O
the	O
pep4	B-GENE
-	I-GENE
3	I-GENE
mutation	O
.	O

These	O
results	O
suggest	O
that	O
panretinal	O
photocoagulation	O
offers	O
a	O
highly	O
effective	O
means	O
of	O
dealing	O
with	O
early	O
and	O
moderately	O
advanced	O
cases	O
of	O
angle	O
neovascularization	O
.	O

Bilateral	O
renal	O
oncocytoma	O
in	O
a	O
Greyhound	O
dog	O
.	O

Membrane	O
depolarization	O
is	O
a	O
critical	O
element	O
of	O
neuronal	O
signaling	O
.	O

The	O
E	O
.	O
multilocularis	O
/	O
Mongolian	O
gerbil	O
system	O
can	O
replace	O
the	O
natural	O
canid	O
hosts	O
as	O
a	O
new	O
way	O
to	O
obtain	O
infective	O
eggs	O
and	O
to	O
analyze	O
host	O
-	O
parasite	O
interactions	O
.	O

The	O
Fugu	O
rubripes	O
(	O
Fugu	O
)	O
gene	O
fragment	O
was	O
used	O
to	O
isolate	O
the	O
GH	B-GENE
gene	I-GENE
from	O
a	O
Fugu	O
genomic	O
library	O
.	O

For	O
the	O
first	O
time	O
also	O
a	O
genomic	O
sequence	O
for	O
a	O
red	B-GENE
algal	I-GENE
lhc	I-GENE
gene	I-GENE
is	O
presented	O
.	O

All	O
such	O
polypeptides	O
containing	O
263	O
or	O
more	O
residues	O
derived	O
from	O
the	O
C	O
-	O
terminus	O
of	O
P130gag	B-GENE
-	O
fps	B-GENE
(	O
i	O
.	O
e	O
.	O
residues	O
920	O
-	O
1182	O
)	O
were	O
enzymatically	O
active	O
as	O
tyrosine	B-GENE
kinases	I-GENE
.	O

Were	O
this	O
hypothesis	O
correct	O
,	O
the	O
requirement	O
for	O
elF4A	B-GENE
should	O
correlate	O
with	O
the	O
degree	O
of	O
mRNA	O
secondary	O
structure	O
.	O

Comparison	O
with	O
the	O
data	O
of	O
clinical	O
development	O
and	O
hemodynamic	O
results	O

Localized	O
Bicaudal	B-GENE
-	I-GENE
C	I-GENE
RNA	I-GENE
encodes	O
a	O
protein	O
containing	O
a	O
KH	O
domain	O
,	O
the	O
RNA	O
binding	O
motif	O
of	O
FMR1	B-GENE
.	O

Despite	O
a	O
lowering	O
of	O
her	O
plasma	O
ACTH	B-GENE
concentration	O
during	O
therapy	O
with	O
valproic	O
acid	O
,	O
the	O
patient	O
'	O
s	O
tumour	O
showed	O
no	O
evidence	O
of	O
regression	O
while	O
she	O
was	O
taking	O
the	O
drug	O
.	O

This	O
is	O
the	O
first	O
report	O
which	O
clearly	O
proved	O
CEA	B-GENE
synthesis	O
in	O
the	O
cells	O
of	O
HCC	O
.	O

NASA	O
CR	O
-	O
1223	O
.	O

2	O
.	O

The	O
classic	O
sterol	O
regulatory	O
cis	O
element	O
(	O
sre	O
-	O
1	O
)	O
in	O
the	O
LDL	B-GENE
receptor	I-GENE
promoter	O
mediates	O
sterol	B-GENE
regulatory	I-GENE
element	I-GENE
binding	I-GENE
protein	I-GENE
(	O
SREBP	B-GENE
)	O
-	O
binding	O
and	O
the	O
effects	O
of	O
insulin	B-GENE
and	O
platelet	B-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
(	O
PDGF	B-GENE
)	O
.	O

The	O
D443N	B-GENE
substitution	I-GENE
is	O
an	O
activating	O
mutation	O
that	O
increases	O
the	O
activity	O
of	O
SCAP	B-GENE
and	O
renders	O
it	O
resistant	O
to	O
inhibition	O
by	O
25	O
-	O
hydroxycholesterol	O
.	O

Transcriptional	O
modulation	O
of	O
the	O
anti	B-GENE
-	I-GENE
apoptotic	I-GENE
protein	I-GENE
BCL	I-GENE
-	I-GENE
XL	I-GENE
by	O
the	O
paired	B-GENE
box	I-GENE
transcription	I-GENE
factors	I-GENE
PAX3	B-GENE
and	O
PAX3	B-GENE
/	O
FKHR	B-GENE
.	O

5	O
.	O
3	O
+	O
/	O
-	O
6	O
.	O
6	O
for	O
risperidone	O
(	O
P	O
=	O
0	O
.	O
09	O
)	O
.	O

CONCLUSIONS	O
:	O
This	O
study	O
shows	O
that	O
the	O
annual	O
rate	O
of	O
de	O
novo	O
aneurysm	O
formation	O
is	O
relatively	O
high	O
(	O
0	O
.	O
89	O
%	O
)	O
and	O
that	O
the	O
cumulative	O
risk	O
becomes	O
significant	O
after	O
9	O
years	O
.	O

In	O
this	O
case	O
myogenic	O
factors	O
are	O
not	O
initially	O
expressed	O
and	O
these	O
migratory	O
cells	O
are	O
characterized	O
by	O
the	O
expression	O
of	O
the	O
paired	B-GENE
-	O
box	O
gene	O
Pax3	B-GENE
.	O

In	O
those	O
patients	O
who	O
before	O
transplantation	O
were	O
serological	O
negative	O
for	O
CMV	O
but	O
had	O
received	O
organs	O
from	O
CMV	B-GENE
-	I-GENE
IgG	I-GENE
positive	O
donors	O
,	O
the	O
incidence	O
of	O
the	O
disease	O
was	O
highest	O
.	O

The	O
fecal	O
excretion	O
is	O
found	O
to	O
be	O
only	O
one	O
third	O
of	O
that	O
measured	O
in	O
urine	O
.	O

This	O
ERD	O
is	O
recorded	O
over	O
the	O
contralateral	O
central	O
region	O
.	O

We	O
report	O
the	O
sequence	O
of	O
a	O
7941	O
bp	O
DNA	O
fragment	O
from	O
the	O
left	O
arm	O
of	O
chromosome	O
VII	O
of	O
Saccharomyces	O
cerevisiae	O
which	O
contains	O
four	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
of	O
greater	O
than	O
100	O
amino	O
acid	O
residues	O
.	O

Tax	B-GENE
was	O
demonstrated	O
to	O
interact	O
directly	O
with	O
CREB1	B-GENE
but	O
not	O
with	O
other	O
bZIP	B-GENE
proteins	I-GENE
,	O
including	O
CREB2	B-GENE
and	O
Jun	B-GENE
.	O

Forty	O
-	O
five	O
per	O
cent	O
of	O
the	O
dose	O
was	O
excreted	O
as	O
methyldopa	O
as	O
opposed	O
to	O
18	O
%	O
normally	O
seen	O
after	O
oral	O
methyldopa	O
dosages	O
.	O

Standing	O
values	O
:	O
placebo	O
114	O
/	O
79	O
;	O
BHT	O
-	O
933	O
92	O
/	O
67	O
.	O

Zoonotic	O
areas	O
in	O
which	O
HIV	O
co	O
-	O
infection	O
is	O
common	O
could	O
also	O
be	O
at	O
risk	O
as	O
sandflies	O
can	O
become	O
infected	O
from	O
co	O
-	O
infected	O
individuals	O
.	O

In	O
cases	O
in	O
which	O
it	O
was	O
identified	O
,	O
insulitis	O
affected	O
23	O
%	O
of	O
islets	O
containing	O
insulin	B-GENE
,	O
but	O
affected	O
only	O
1	O
%	O
of	O
islets	O
which	O
were	O
insulin	B-GENE
deficient	O
,	O
thus	O
supporting	O
the	O
concept	O
that	O
insulitis	O
represents	O
an	O
immunologically	O
mediated	O
destruction	O
of	O
insulin	B-GENE
secreting	O
B	O
cells	O
.	O

Each	O
fusion	O
leads	O
,	O
in	O
principle	O
,	O
to	O
the	O
same	O
effect	O
:	O
The	O
ret	B-GENE
tyrosine	I-GENE
kinase	I-GENE
is	O
uncoupled	O
from	O
its	O
stringent	O
physiological	O
regulation	O
by	O
replacement	O
of	O
its	O
5	O
'	O
end	O
and	O
is	O
aberrantly	O
activated	O
by	O
the	O
5	O
'	O
parts	O
of	O
fused	O
genes	O
in	O
thyrocytes	O
that	O
do	O
not	O
normally	O
express	O
ret	B-GENE
tyrosine	I-GENE
kinase	I-GENE
.	O

Proteins	O
PBP	B-GENE
-	I-GENE
1	I-GENE
and	O
PBP	B-GENE
-	I-GENE
2	I-GENE
bind	O
to	O
two	O
of	O
the	O
three	O
promoter	O
elements	O
in	O
the	O
trypanosomatid	O
Leptomonas	O
seymouri	O
.	O

Induction	O
of	O
interferon	B-GENE
-	I-GENE
alpha	I-GENE
(	O
IFNalpha	B-GENE
)	O
gene	O
expression	O
in	O
virus	O
-	O
infected	O
cells	O
requires	O
phosphorylation	O
-	O
induced	O
activation	O
of	O
the	O
transcription	O
factors	O
IRF3	B-GENE
and	O
IRF7	B-GENE
.	O

The	O
differences	O
of	O
percentages	O
for	O
HIV	O
-	O
1	O
infection	O
in	O
intravenous	O
drug	O
users	O
(	O
IVDU	O
)	O
were	O
67	O
.	O
7	O
%	O
and	O
in	O
non	O
IVDU	O
were	O
3	O
.	O
8	O
%	O
with	O
a	O
significant	O
statistical	O
difference	O
(	O
chi	O
2	O
=	O
557	O
.	O
5	O
;	O
p	O
<	O
0	O
.	O
0001	O
)	O
.	O

Humoral	O
immunity	O
is	O
altered	O
with	O
the	O
drop	O
in	O
IgG	B-GENE
levels	O
.	O

The	O
vicinity	O
of	O
large	O
industrial	O
emissions	O
of	O
lead	O
,	O
where	O
mean	O
Pb	O
-	O
B	O
concentrations	O
were	O
usually	O
twice	O
as	O
high	O
as	O
in	O
rural	O
areas	O
of	O
the	O
Katowice	O
voivodship	O
.	O

(	O
control	O
hearts	O
)	O
.	O

Thus	O
,	O
BCR	B-GENE
ligation	O
initiates	O
a	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
/	O
Akt	B-GENE
/	O
GSK	B-GENE
-	I-GENE
3	I-GENE
signaling	O
pathway	O
.	O

Effect	O
of	O
a	O
new	O
positive	O
inotropic	O
agent	O
(	O
OPC	O
-	O
8212	O
)	O
on	O
intracellular	O
potential	O
of	O
isolated	O
canine	O
ventricular	O
papillary	O
muscle	O

Although	O
several	O
other	O
signal	O
transduction	O
molecules	O
also	O
contain	O
tandemly	O
occurring	O
SH3	B-GENE
and	O
SH2	B-GENE
domains	I-GENE
,	O
the	O
function	O
of	O
these	O
closely	O
spaced	O
domains	O
is	O
not	O
well	O
understood	O
.	O

At	O
the	O
same	O
acoustic	O
power	O
,	O
the	O
rate	O
of	O
chloride	O
formation	O
with	O
20	O
kHz	O
ultrasound	O
was	O
greater	O
when	O
a	O
probe	O
with	O
a	O
larger	O
tip	O
area	O
was	O
used	O
,	O
but	O
significantly	O
less	O
than	O
the	O
rate	O
with	O
900	O
kHz	O
.	O

This	O
is	O
the	O
first	O
report	O
demonstrating	O
specificity	O
at	O
the	O
level	O
of	O
the	O
energy	O
coupling	O
proteins	O
of	O
the	O
PTS	O
.	O

The	O
R260A	O
mutant	O
,	O
as	O
expected	O
,	O
was	O
unable	O
to	O
support	O
mRNA	O
synthesis	O
in	O
vitro	O
in	O
a	O
transcription	O
reconstitution	O
reaction	O
as	O
well	O
as	O
transcription	O
in	O
vivo	O
of	O
a	O
minigenome	O
using	O
a	O
reverse	O
genetic	O
approach	O
.	O

As	O
expected	O
,	O
the	O
QOLS	O
-	O
N	O
had	O
a	O
lower	O
correlation	O
with	O
physical	O
health	O
(	O
r	O
=	O
0	O
.	O
24	O
,	O
p	O
<	O
0	O
.	O
000	O
)	O
and	O
self	O
-	O
reported	O
symptoms	O
(	O
r	O
=	O
-	O
0	O
.	O
20	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
and	O
a	O
higher	O
correlation	O
with	O
mental	O
health	O
(	O
r	O
=	O
0	O
.	O
52	O
,	O
p	O
<	O
0	O
.	O
000	O
)	O
.	O

Human	B-GENE
epidermal	I-GENE
growth	I-GENE
factor	I-GENE
(	O
EGF	B-GENE
)	O
,	O
a	O
naturally	O
occurring	O
protein	O
,	O
has	O
been	O
implicated	O
in	O
the	O
protection	O
of	O
gastrointestinal	O
mucosal	O
integrity	O
.	O

Elevated	O
potassium	O
stimulation	O
of	O
GAL	B-GENE
mRNA	I-GENE
was	O
completely	O
blocked	O
,	O
but	O
pituitary	O
adenylyl	B-GENE
cyclase	I-GENE
-	I-GENE
activating	I-GENE
polypeptide	I-GENE
and	O
histamine	O
stimulations	O
were	O
only	O
partially	O
blocked	O
,	O
by	O
cycloheximide	O
.	O

DNA	O
elements	O
recognizing	O
NF	B-GENE
-	I-GENE
Y	I-GENE
and	O
Sp1	B-GENE
regulate	O
the	O
human	B-GENE
multidrug	I-GENE
-	I-GENE
resistance	I-GENE
gene	I-GENE
promoter	I-GENE
.	O

We	O
constructed	O
a	O
series	O
of	O
chimeric	O
genes	O
containing	O
part	O
of	O
the	O
first	O
exon	O
and	O
increasingly	O
longer	O
5	O
'	O
flanking	O
sequences	O
of	O
the	O
ODC	B-GENE
gene	I-GENE
fused	O
to	O
either	O
bacterial	B-GENE
chloramphenicol	I-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
or	O
luciferase	B-GENE
reporter	I-GENE
genes	I-GENE
.	O

To	O
investigate	O
this	O
possibility	O
,	O
we	O
conducted	O
split	O
-	O
visual	O
-	O
field	O
studies	O
in	O
which	O
we	O
manipulated	O
stimulus	O
sets	O
,	O
recognition	O
task	O
,	O
and	O
exposure	O
duration	O
.	O

Like	O
pimethixene	O
and	O
cyproheptadine	O
,	O
WA	O
335	O
has	O
no	O
distinct	O
antagonistic	O
qualities	O
against	O
bradykinin	B-GENE
.	O

To	O
explore	O
the	O
mechanism	O
of	O
insulin	B-GENE
receptor	I-GENE
phosphorylation	O
we	O
have	O
used	O
NIH3T3	O
cells	O
transfected	O
with	O
two	O
receptor	O
constructs	O
:	O
one	O
encoding	O
a	O
chimeric	O
receptor	O
composed	O
of	O
the	O
extracellular	O
domain	O
of	O
the	O
human	B-GENE
EGF	I-GENE
receptor	I-GENE
and	O
the	O
cytosolic	O
domain	O
of	O
the	O
human	B-GENE
insulin	I-GENE
receptor	I-GENE
beta	I-GENE
-	I-GENE
subunit	I-GENE
,	O
and	O
a	O
second	O
construct	O
encoding	O
a	O
kinase	O
-	O
defiecient	O
human	B-GENE
insulin	I-GENE
receptor	I-GENE
.	O

Additional	O
simulations	O
account	O
for	O
interactions	O
of	O
spatial	O
frequency	O
with	O
stimulus	O
duration	O
,	O
effects	O
of	O
adaptation	O
,	O
and	O
properties	O
of	O
residual	O
traces	O
,	O
as	O
opposed	O
to	O
visual	O
persistence	O
.	O

A	O
DNA	O
fragment	O
that	O
complements	O
the	O
uvs	B-GENE
-	I-GENE
2	I-GENE
mutation	O
was	O
subcloned	O
by	O
monitoring	O
its	O
ability	O
to	O
transform	O
the	O
uvs	B-GENE
-	I-GENE
2	I-GENE
mutant	I-GENE
to	O
MMS	O
resistance	O
.	O

This	O
cell	O
line	O
expresses	O
productively	O
rearranged	O
immunoglobulin	B-GENE
genes	I-GENE
as	O
well	O
as	O
the	O
Oct	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
at	O
high	O
levels	O
which	O
are	O
comparable	O
to	O
those	O
observed	O
in	O
activated	O
murine	O
splenic	O
B	O
cells	O
.	O

Back	O
-	O
ground	O
factors	O
which	O
affect	O
the	O
outcome	O
of	O
steroid	O
withdrawal	O
therapy	O
in	O
patients	O
with	O
chronic	O
type	O
B	O
hepatitis	O
-	O
-	O
statistical	O
evaluation	O
of	O
the	O
importance	O
of	O
the	O
mode	O
of	O
HBV	O
transmission	O

Effect	O
of	O
food	O
on	O
hemodynamics	O
.	O

PTP1	B-GENE
-	O
lacZ	B-GENE
studies	O
indicate	O
that	O
PTP1	B-GENE
is	O
spatially	O
localized	O
to	O
prestalk	O
and	O
anterior	O
-	O
like	O
cell	O
types	O
.	O

Morphologic	O
evidence	O
that	O
rhe	O
renal	O
calyx	O
and	O
pelvis	O
control	O
ureteric	O
activity	O
in	O
the	O
rabbit	O
.	O

Human	B-GENE
alcohol	I-GENE
dehydrogenase	I-GENE
(	O
ADH	B-GENE
)	O
exists	O
as	O
a	O
heterogeneous	O
group	O
of	O
isozymes	O
capable	O
of	O
oxidizing	O
a	O
wide	O
variety	O
of	O
aliphatic	O
and	O
aromatic	O
alcohols	O
.	O

We	O
reviewed	O
81	O
patients	O
with	O
dementia	O
and	O
autopsy	O
findings	O
of	O
Alzheimer	O
'	O
s	O
disease	O
(	O
AD	O
)	O
to	O
identify	O
patients	O
with	O
seizures	O
or	O
myoclonus	O
after	O
onset	O
of	O
dementia	O
.	O

The	O
second	O
system	O
(	O
VacFix	O
)	O
uses	O
a	O
0	O
.	O
15	O
mm	O
thick	O
plastic	O
bag	O
loosely	O
filled	O
with	O
1	O
mm	O
polysterol	O
spheres	O
.	O

Expression	O
in	O
all	O
lines	O
was	O
decreased	O
by	O
the	O
inclusion	O
of	O
regions	O
further	O
upstream	O
,	O
and	O
extinguished	O
by	O
the	O
inclusion	O
of	O
the	O
first	O
intron	O
.	O

These	O
results	O
indicate	O
that	O
the	O
changes	O
in	O
the	O
patient	O
'	O
s	O
thyroid	O
scan	O
and	O
RAIU	O
were	O
attributable	O
to	O
the	O
presence	O
of	O
TSAb	O
.	O

U	O
.	O

A	O
Laboratory	O
Manual	O
,	O
2nd	O
ed	O
.	O

In	O
the	O
case	O
of	O
a	O
moderate	O
buccal	O
Class	O
II	O
tendency	O
,	O
55	O
%	O
of	O
the	O
molars	O
were	O
in	O
a	O
Class	O
I	O
relationship	O
when	O
evaluated	O
from	O
the	O
lingual	O
side	O
,	O
whereas	O
45	O
%	O
belonged	O
to	O
mild	O
(	O
1st	O
degrees	O
)	O
Class	O
II	O
with	O
molar	O
rotations	O
present	O
in	O
81	O
%	O
of	O
the	O
cases	O
.	O

The	O
resulting	O
score	O
,	O
which	O
allowed	O
the	O
disease	O
to	O
be	O
expressed	O
as	O
a	O
continuous	O
variable	O
,	O
was	O
effectively	O
utilized	O
to	O
see	O
the	O
correlations	O
between	O
the	O
severity	O
of	O
coronary	O
arterial	O
disease	O
(	O
CAD	O
)	O
and	O
individual	O
risk	O
factors	O
/	O
risk	O
markers	O
.	O

The	O
gene	O
encoding	O
the	O
cellulase	B-GENE
(	O
Avicelase	B-GENE
)	O
Cel1	B-GENE
from	O
Streptomyces	O
reticuli	O
and	O
analysis	O
of	O
protein	O
domains	O
.	O

A	O
protein	O
which	O
promotes	O
DNA	O
strand	O
transfer	O
between	O
linear	O
double	O
-	O
stranded	O
M13mp19	O
DNA	O
and	O
single	O
-	O
stranded	O
viral	O
M13mp19	O
DNA	O
has	O
been	O
isolated	O
from	O
recA	B-GENE
-	I-GENE
E	O
.	O
coli	O
.	O

We	O
speculate	O
that	O
the	O
enhancing	O
effect	O
of	O
glucose	O
and	O
galactose	O
on	O
fructose	O
absorption	O
may	O
be	O
due	O
to	O
activation	O
of	O
the	O
fructose	B-GENE
carrier	I-GENE
.	O

The	O
nutraceuticals	O
of	O
specific	O
vitamins	O
,	O
minerals	O
,	O
phytoestrogens	O
,	O
and	O
essential	O
fatty	O
acid	O
supplementations	O
are	O
a	O
vital	O
component	O
of	O
the	O
risk	O
reduction	O
health	O
program	O
.	O

Thus	O
,	O
in	O
V	O
.	O
furnissii	O
,	O
the	O
E	B-GENE
.	I-GENE
coli	I-GENE
manX	I-GENE
equivalent	I-GENE
comprises	O
two	O
genes	O
,	O
which	O
are	O
separated	O
in	O
the	O
genome	O
by	O
two	O
other	O
genes	O
of	O
the	O
ptsM	B-GENE
complex	I-GENE
.	O

An	O
scrR	B-GENE
promoter	I-GENE
fragment	I-GENE
,	O
which	O
dose	O
not	O
contain	O
a	O
sequence	O
resembling	O
OB	B-GENE
,	O
was	O
not	O
shifted	O
by	O
the	O
fusion	O
protein	O
.	O

Ectopic	O
expression	O
of	O
cyclin	B-GENE
D1	I-GENE
in	O
progestin	O
-	O
inhibited	O
cells	O
led	O
to	O
the	O
reappearance	O
of	O
the	O
120	O
-	O
kDa	O
active	O
form	O
of	O
cyclin	B-GENE
E	I-GENE
-	O
Cdk2	B-GENE
preceding	O
the	O
resumption	O
of	O
cell	O
cycle	O
progression	O
.	O

We	O
screened	O
an	O
A	O
.	O
thaliana	O
cDNA	O
library	O
,	O
whose	O
inserts	O
are	O
under	O
the	O
control	O
of	O
the	O
galactose	O
-	O
inducible	O
GAL10	B-GENE
promoter	I-GENE
,	O
for	O
cDNAs	O
which	O
enabled	O
YDH8	O
cells	O
to	O
grow	O
at	O
the	O
restrictive	O
temperature	O
.	O

The	O
mouse	B-GENE
alpha	I-GENE
A	I-GENE
-	I-GENE
CRYBP1	I-GENE
gene	I-GENE
specifies	O
a	O
2	O
,	O
688	O
-	O
amino	O
acid	O
protein	O
with	O
72	O
%	O
amino	O
acid	O
identity	O
to	O
its	O
human	O
homologue	O
,	O
PRDII	B-GENE
-	I-GENE
BF1	I-GENE
.	O

Sequence	O
analysis	O
revealed	O
that	O
Hv	B-GENE
-	I-GENE
p68	I-GENE
belongs	O
to	O
the	O
large	O
family	O
of	O
FAD	B-GENE
-	I-GENE
dependent	I-GENE
glucose	I-GENE
methanol	I-GENE
choline	I-GENE
oxidoreductases	I-GENE
and	O
that	O
it	O
shares	O
significant	O
sequence	O
identity	O
(	O
>	O
67	O
%	O
)	O
with	O
the	O
alcohol	B-GENE
oxidases	I-GENE
of	O
the	O
methylotrophic	O
yeasts	O
.	O

Therefore	O
,	O
we	O
have	O
reevaluated	O
the	O
age	O
-	O
related	O
changes	O
in	O
serum	B-GENE
leptin	I-GENE
levels	O
and	O
their	O
relationship	O
with	O
adiposity	O
and	O
androgen	O
levels	O
in	O
a	O
large	O
group	O
of	O
community	O
dwelling	O
men	O
.	O

The	O
1	O
-	O
year	O
and	O
2	O
-	O
year	O
survival	O
rates	O
for	O
the	O
patients	O
with	O
N0	O
-	O
3	O
significantly	O
exceeded	O
those	O
of	O
N4	O
patients	O
.	O

While	O
reviewing	O
gastric	O
specimens	O
from	O
215	O
baboons	O
,	O
we	O
found	O
diffuse	O
giant	O
mucosal	O
folds	O
in	O
2	O
specimens	O
and	O
multiple	O
giant	O
mucosal	O
nodules	O
in	O
another	O
3	O
.	O

Morphologically	O
,	O
corrugation	O
of	O
the	O
internal	O
elastic	O
lamina	O
of	O
vessels	O
was	O
often	O
observed	O
in	O
the	O
vehicle	O
-	O
treated	O
group	O
,	O
but	O
was	O
not	O
prominent	O
in	O
the	O
GLNVA	O
-	O
treated	O
groups	O
or	O
healthy	O
controls	O
.	O

Transcripts	O
initiating	O
at	O
the	O
CAGT	O
motif	O
(	O
proximal	O
transcripts	O
)	O
were	O
abolished	O
by	O
deletion	O
of	O
the	O
proximal	O
TATA	O
box	O
located	O
at	O
-	O
29	O
relative	O
to	O
CAGT	O
.	O

The	O
phenomena	O
of	O
nursing	O
are	O
deeply	O
rooted	O
in	O
the	O
human	O
condition	O
.	O

Coronatine	B-GENE
(	O
COR	B-GENE
)	O
is	O
a	O
plasmid	O
-	O
encoded	O
phytotoxin	O
synthesized	O
by	O
several	O
pathovars	O
of	O
phytopathogenic	O
Pseudomonas	O
syringae	O
.	O

It	O
has	O
become	O
clear	O
that	O
there	O
is	O
not	O
one	O
mediator	O
responsible	O
for	O
ALI	O
,	O
but	O
rather	O
a	O
complex	O
interplay	O
exists	O
between	O
diverse	O
proinflammatory	O
(	O
e	O
.	O
g	O
.	O
,	O
lipopolysaccharide	O
,	O
complement	O
products	O
,	O
cytocains	O
,	O
chemocains	O
,	O
reactive	O
oxygen	O
species	O
and	O
arachidonic	O
acid	O
products	O
)	O
and	O
anti	O
-	O
inflammatory	O
(	O
IL	B-GENE
-	I-GENE
10	I-GENE
,	O
IL	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
RA	I-GENE
,	O
PGI2	O
)	O
mediators	O
.	O

Not	O
only	O
will	O
it	O
substantially	O
reduce	O
incident	O
cases	O
of	O
hepatitis	O
B	O
for	O
the	O
next	O
decade	O
,	O
it	O
will	O
also	O
provide	O
a	O
framework	O
for	O
the	O
successful	O
introduction	O
of	O
future	O
adolescent	O
vaccine	O
initiatives	O
in	O
Australia	O
.	O

Radioactively	O
labeled	O
microspheres	O
were	O
used	O
to	O
determine	O
and	O
compare	O
the	O
hemodynamic	O
effects	O
of	O
sodium	O
nitroprusside	O
(	O
SNP	O
)	O
,	O
nitroglycerin	O
(	O
NTG	O
)	O
,	O
and	O
deep	O
enflurane	O
anesthesia	O
on	O
oral	O
tissues	O
during	O
controlled	O
hypotension	O
when	O
compared	O
with	O
controls	O
.	O

We	O
conclude	O
that	O
the	O
MMF	O
lesion	O
is	O
secondary	O
to	O
intramuscular	O
injection	O
of	O
aluminium	O
hydroxide	O
-	O
containing	O
vaccines	O
,	O
shows	O
both	O
long	O
-	O
term	O
persistence	O
of	O
aluminium	O
hydroxide	O
and	O
an	O
ongoing	O
local	O
immune	O
reaction	O
,	O
and	O
is	O
detected	O
in	O
patients	O
with	O
systemic	O
symptoms	O
which	O
appeared	O
subsequently	O
to	O
vaccination	O
.	O

Advisory	O
Committee	O
report	O
recommends	O
that	O
US	O
make	O
amends	O
for	O
human	O
radiation	O
experiments	O
.	O

An	O
evaluation	O
of	O
a	O
positive	O
control	O
for	O
platelet	O
neutralization	O
procedure	O
testing	O
with	O
seven	O
commercial	O
activated	O
partial	O
thromboplastin	B-GENE
time	O
reagents	O
.	O

Transmission	O
of	O
mutans	O
streptococci	O
to	O
infants	O
following	O
short	O
term	O
application	O
of	O
an	O
iodine	O
-	O
NaF	O
solution	O
to	O
mothers	O
'	O
dentition	O
.	O

Glycoprotein	O
biosynthesis	O
in	O
Saccharomyces	O
cerevisiae	O
:	O
ngd29	B-GENE
,	O
an	O
N	O
-	O
glycosylation	O
mutant	O
allelic	O
to	O
och1	B-GENE
having	O
a	O
defect	O
in	O
the	O
initiation	O
of	O
outer	O
chain	O
formation	O
.	O

However	O
,	O
no	O
consensus	O
on	O
indications	O
exists	O
and	O
,	O
according	O
to	O
the	O
literature	O
,	O
results	O
are	O
contradictory	O
.	O

The	O
effects	O
of	O
erythrosine	O
(	O
Red	O
3	O
)	O
,	O
rose	O
bengal	O
B	O
(	O
Red	O
105	O
)	O
and	O
thyroidectomy	O
on	O
the	O
development	O
of	O
thyroid	O
tumor	O
were	O
examined	O
in	O
male	O
Wistar	O
rats	O
treated	O
with	O
N	O
-	O
bis	O
(	O
2	O
-	O
hydroxypropyl	O
)	O
nitrosamine	O
(	O
DHPN	O
)	O
.	O

The	O
region	O
surrounding	O
the	O
ZNF35	B-GENE
zinc	I-GENE
finger	I-GENE
protein	I-GENE
gene	I-GENE
on	O
3p21	O
is	O
of	O
particular	O
interest	O
,	O
as	O
this	O
region	O
of	O
chromosome	O
3	O
is	O
frequently	O
involved	O
in	O
rearrangements	O
and	O
/	O
or	O
deletions	O
associated	O
with	O
various	O
human	O
tumors	O
including	O
lung	O
and	O
renal	O
carcinoma	O
.	O

In	O
contrast	O
,	O
no	O
change	O
in	O
the	O
level	O
of	O
either	O
p53	B-GENE
or	O
activation	O
of	O
mdm2	B-GENE
protein	I-GENE
by	O
p53	B-GENE
was	O
observed	O
in	O
hamster	O
UV61	O
cells	O
after	O
UV	O
exposure	O
.	O

Complete	O
activation	O
of	O
signal	B-GENE
transducer	I-GENE
and	I-GENE
activator	I-GENE
of	I-GENE
transcription	I-GENE
1	I-GENE
(	O
STAT1	B-GENE
)	O
requires	O
phosphorylation	O
at	O
both	O
Y701	O
and	O
a	O
conserved	O
PMS	O
(	O
727	O
)	O
P	O
sequence	O
.	O

It	O
is	O
believed	O
that	O
the	O
operation	O
is	O
effective	O
because	O
it	O
cuts	O
the	O
spinothalamic	O
tract	O
(	O
STT	O
)	O
,	O
a	O
primary	O
pathway	O
carrying	O
nociceptive	O
information	O
from	O
the	O
spinal	O
cord	O
to	O
the	O
brain	O
in	O
humans	O
.	O

On	O
the	O
basis	O
of	O
experiments	O
with	O
mutant	O
virus	O
and	O
transfection	O
with	O
isolated	O
genes	O
,	O
the	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
immediate	I-GENE
-	I-GENE
early	I-GENE
gene	I-GENE
product	O
ICP4	B-GENE
is	O
known	O
to	O
positively	O
regulate	O
the	O
transcription	O
of	O
viral	B-GENE
early	I-GENE
and	I-GENE
late	I-GENE
genes	I-GENE
and	O
negatively	O
regulate	O
expression	O
from	O
its	O
own	O
promoter	O
.	O

Alcohol	O
abuse	O
and	O
treatment	O
resistance	O
in	O
skin	O
disease	O
.	O

These	O
data	O
suggest	O
that	O
reduction	O
in	O
PRA	O
may	O
have	O
contributed	O
to	O
the	O
hemodynamic	O
effects	O
of	O
this	O
peak	B-GENE
III	I-GENE
PDE	I-GENE
inhibitor	O
.	O

However	O
,	O
studies	O
using	O
the	O
A20	B-GENE
promoter	I-GENE
demonstrated	O
that	O
LMP1	B-GENE
transcriptionally	O
activates	O
the	O
A20	B-GENE
gene	I-GENE
through	O
cis	O
-	O
acting	O
kappa	B-GENE
B	I-GENE
sites	I-GENE
.	O

The	O
first	O
270	O
bp	O
of	O
the	O
promoter	O
region	O
were	O
sequenced	O
and	O
found	O
to	O
contain	O
a	O
CATAA	O
box	O
rather	O
than	O
a	O
TATAA	O
box	O
and	O
several	O
DNA	O
motifs	O
found	O
in	O
activation	O
genes	O
.	O

This	O
study	O
investigated	O
if	O
signal	O
-	O
averaged	O
low	O
amplitude	O
atrial	O
potentials	O
predict	O
atrial	O
fibrillation	O
or	O
flutter	O
(	O
AFF	O
)	O
.	O

The	O
reduced	O
expression	O
caused	O
by	O
multimerization	O
of	O
UAS2	O
in	O
the	O
native	O
promoter	O
was	O
observed	O
only	O
in	O
the	O
presence	O
of	O
ADR1	B-GENE
.	O

Finally	O
,	O
we	O
tested	O
whether	O
activation	O
by	O
either	O
of	O
these	O
factors	O
is	O
dependent	O
on	O
components	O
of	O
the	O
SAGA	B-GENE
complex	I-GENE
.	O

One	O
child	O
,	O
recently	O
fed	O
,	O
vomited	O
a	O
small	O
amount	O
of	O
breast	O
milk	O
after	O
a	O
short	O
period	O
of	O
crying	O
and	O
apparently	O
had	O
a	O
laryngospasm	O
,	O
shown	O
by	O
a	O
sudden	O
drop	O
in	O
the	O
PtcO2	O
level	O
without	O
any	O
other	O
signs	O
of	O
discomfort	O
.	O

The	O
central	O
venous	O
O2	O
saturation	O
test	O
in	O
acute	O
pulmonary	O
fat	O
embolism	O
.	O

Such	O
unique	O
recognition	O
capabilities	O
are	O
generated	O
with	O
minimal	O
alterations	O
in	O
the	O
CDR3	B-GENE
loops	O
of	O
the	O
TCR	B-GENE
.	O

Sequence	O
comparisons	O
reveal	O
that	O
the	O
P	B-GENE
.	I-GENE
woesei	I-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
is	O
strikingly	O
related	O
in	O
sequence	O
to	O
eubacterial	B-GENE
FtsZ	I-GENE
and	O
is	O
marginally	O
more	O
similar	O
to	O
eukaryotic	B-GENE
tubulins	I-GENE
than	O
are	O
bacterial	B-GENE
FtsZ	I-GENE
proteins	I-GENE
.	O

Additional	O
transection	O
of	O
both	O
ADN	O
eliminated	O
the	O
remaining	O
sigmoidal	O
correlation	O
between	O
MAP	O
and	O
RSNA	O
with	O
further	O
increases	O
in	O
resting	O
MAP	O
and	O
RSNA	O
.	O

Cross	O
-	O
talk	O
between	O
transcription	O
factors	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
and	O
C	B-GENE
/	I-GENE
EBP	I-GENE
in	O
the	O
transcriptional	O
regulation	O
of	O
genes	O
.	O

FDP	O
-	O
1	O
(	O
200	O
micrograms	O
.	O
kg	O
-	O
1	O
)	O
of	O
intracoronary	O
injection	O
increased	O
collateral	O
flow	O
,	O
reduced	O
systemic	O
artery	O
resistance	O
,	O
and	O
coronary	O
systolic	O
pressure	O
in	O
infarcted	O
region	O
and	O
the	O
area	O
of	O
infarction	O
decreased	O
from	O
28	O
.	O
9	O
+	O
/	O
-	O
1	O
.	O
3	O
%	O
to	O
15	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
2	O
%	O
(	O
P	O
<	O
0	O
.	O
01	O
,	O
n	O
=	O
6	O
)	O
.	O

The	O
results	O
of	O
these	O
experiments	O
indicated	O
that	O
charcoal	O
,	O
imbiber	O
beads	O
,	O
and	O
the	O
anion	O
exchanges	O
resins	O
,	O
Dowex	O
XFS	O
-	O
4022	O
and	O
Dowex	O
SBR	O
-	O
C1	O
,	O
would	O
not	O
be	O
useful	O
agents	O
for	O
increasing	O
the	O
amount	O
of	O
dieldrin	O
eliminated	O
via	O
feces	O
(	O
droppings	O
)	O
of	O
chickens	O
.	O

Neither	O
raw	O
nor	O
retrograded	O
resistant	O
starch	O
lowers	O
fasting	O
serum	O
cholesterol	O
concentrations	O
in	O
healthy	O
normolipidemic	O
subjects	O
.	O

A	O
regression	O
analysis	O
showed	O
that	O
86	O
%	O
of	O
the	O
variance	O
in	O
weight	O
gain	O
was	O
predicted	O
by	O
two	O
leading	O
indicators	O
in	O
the	O
middle	O
phase	O
of	O
treatment	O
.	O

Heterologous	O
hybridization	O
with	O
a	O
rps12	B-GENE
gene	I-GENE
specific	O
probe	O
from	O
Euglena	O
has	O
revealed	O
the	O
presence	O
of	O
rps12	B-GENE
homologous	I-GENE
sequences	I-GENE
within	O
the	O
inverted	O
repeat	O
of	O
Spirodela	O
chloroplast	O
DNA	O
on	O
the	O
fragment	B-GENE
BamHI	I-GENE
-	I-GENE
V	I-GENE
.	O

In	O
6	O
patients	O
(	O
9	O
kidneys	O
)	O
irrigation	O
with	O
Solution	O
G	O
in	O
the	O
renal	O
pelvis	O
was	O
performed	O
for	O
the	O
dissolution	O
of	O
their	O
infectious	O
stones	O
.	O

Derepression	O
of	O
RAR	B-GENE
signaling	O
by	O
expressing	O
a	O
dominant	O
-	O
negative	O
corepressor	O
resulted	O
in	O
embryos	O
that	O
exhibited	O
phenotypes	O
similar	O
to	O
those	O
treated	O
by	O
RA	O
.	O

Flux	O
of	O
the	O
paramyxovirus	O
hemagglutinin	B-GENE
-	O
neuraminidase	B-GENE
glycoprotein	O
through	O
the	O
endoplasmic	O
reticulum	O
activates	O
transcription	O
of	O
the	O
GRP78	B-GENE
-	O
BiP	B-GENE
gene	O
.	O

Within	O
the	O
final	O
11	O
amino	O
acids	O
there	O
are	O
5	O
aromatic	O
,	O
2	O
basic	O
,	O
and	O
no	O
acidic	O
residues	O
and	O
it	O
has	O
been	O
proposed	O
that	O
these	O
residues	O
stack	O
with	O
and	O
electrostatically	O
interact	O
with	O
the	O
kinked	O
DNA	O
at	O
the	O
site	O
of	O
a	O
pyrimidine	O
dimer	O
.	O

The	O
influence	O
of	O
different	O
temperatures	O
between	O
13	O
degrees	O
C	O
and	O
45	O
degrees	O
C	O
on	O
coagulation	O
factors	O
in	O
vitro	O
was	O
studied	O
by	O
measuring	O
clotting	O
time	O
with	O
the	O
recalcification	O
time	O
,	O
partial	O
thromboplastin	B-GENE
time	O
(	O
PTT	O
)	O
,	O
and	O
thromboplastin	B-GENE
time	O
test	O
.	O

Recombinant	O
propeptides	O
containing	O
mutations	O
of	O
one	O
of	O
the	O
three	O
tryptophan	O
residues	O
were	O
three	O
orders	O
of	O
magnitude	O
less	O
effective	O
as	O
inhibitors	O
of	O
mature	B-GENE
cathepsin	I-GENE
S	I-GENE
than	O
the	O
wild	O
-	O
type	O
propeptide	O
.	O

Molecular	O
cloning	O
of	O
cDNAs	O
encoding	O
alpha	O
-	O
subunits	O
of	O
guanine	B-GENE
nucleotide	I-GENE
-	I-GENE
binding	I-GENE
regulatory	I-GENE
proteins	I-GENE
(	O
G	B-GENE
-	I-GENE
proteins	I-GENE
)	O
has	O
revealed	O
the	O
existence	O
of	O
nine	O
species	O
of	O
alpha	O
-	O
subunits	O
.	O

In	O
all	O
cases	O
,	O
a	O
large	O
fraction	O
of	O
soluble	O
Al	O
became	O
insoluble	O
in	O
the	O
stomach	O
after	O
ingestion	O
.	O

The	O
free	O
fraction	O
of	O
amitriptyline	O
(	O
AT	O
)	O
,	O
measured	O
by	O
equilibrium	O
dialysis	O
in	O
plasma	O
from	O
29	O
AT	O
-	O
treated	O
depressed	O
patients	O
,	O
was	O
5	O
.	O
4	O
-	O
9	O
.	O
8	O
%	O
(	O
mean	O
7	O
.	O
7	O
%	O
)	O
,	O
which	O
was	O
the	O
same	O
as	O
the	O
values	O
in	O
26	O
healthy	O
controls	O
(	O
4	O
.	O
9	O
-	O
9	O
.	O
6	O
%	O
,	O
mean	O
7	O
.	O
6	O
%	O
)	O
.	O

The	O
prominent	O
fracture	O
of	O
women	O
older	O
than	O
75	O
years	O
is	O
the	O
hip	O
fracture	O
(	O
type	O
II	O
osteoporosis	O
)	O
.	O

AU	O
-	O
rich	O
elements	O
in	O
the	O
3	O
'	O
-	O
untranslated	O
region	O
of	O
a	O
new	O
mucin	B-GENE
-	I-GENE
type	I-GENE
gene	I-GENE
family	O
of	O
Trypanosoma	O
cruzi	O
confers	O
mRNA	O
instability	O
and	O
modulates	O
translation	O
efficiency	O
.	O

Under	O
anaerobic	O
conditions	O
(	O
a	O
50	O
-	O
day	O
experiment	O
)	O
these	O
organisms	O
degraded	O
15	O
-	O
18	O
%	O
of	O
the	O
TEM	O
,	O
20	O
-	O
25	O
%	O
of	O
some	O
alkanes	O
,	O
and	O
15	O
-	O
18	O
%	O
of	O
selected	O
polycyclic	O
aromatic	O
hydrocarbons	O
.	O

They	O
cause	O
temporary	O
disability	O
,	O
invalidity	O
and	O
mortality	O
of	O
a	O
great	O
part	O
of	O
the	O
productive	O
population	O
,	O
significantly	O
damaging	O
the	O
economic	O
status	O
of	O
the	O
country	O
.	O

We	O
then	O
isolated	O
the	O
full	O
-	O
length	O
coding	O
region	O
of	O
the	O
human	B-GENE
BACH1	I-GENE
gene	I-GENE
using	O
expressed	O
sequence	O
tags	O
,	O
reverse	O
transcription	O
-	O
polymerase	O
chain	O
reaction	O
and	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
.	O

In	O
addition	O
,	O
wild	O
-	O
type	O
and	O
mutated	O
DNA	O
templates	O
were	O
used	O
as	O
probes	O
in	O
DNase	B-GENE
I	I-GENE
protection	O
experiments	O
to	O
determine	O
sites	O
of	O
protein	O
-	O
DNA	O
interaction	O
.	O

CONCLUSIONS	O
-	O
-	O
Postlumbar	O
puncture	O
headache	O
may	O
be	O
mediated	O
by	O
the	O
release	O
of	O
substance	B-GENE
P	I-GENE
triggered	O
by	O
lumbar	O
puncture	O
,	O
in	O
patients	O
predisposed	O
to	O
headache	O
by	O
a	O
hypersensitivity	O
to	O
substance	B-GENE
P	I-GENE
.	O

The	O
repeats	O
are	O
highly	O
conserved	O
both	O
within	O
a	O
given	O
element	O
as	O
well	O
as	O
between	O
different	O
members	O
of	O
the	O
family	O
(	O
less	O
than	O
10	O
%	O
divergence	O
)	O
.	O

They	O
are	O
found	O
to	O
have	O
several	O
advantages	O
over	O
the	O
conventional	O
indices	O
of	O
skewness	O
and	O
kurtosis	O
(	O
square	O
root	O
of	O
b1	O
and	O
b2	O
)	O
and	O
no	O
serious	O
drawbacks	O
.	O

Second	O
,	O
CGGA	O
-	O
containing	O
sequences	O
placed	O
at	O
-	O
88	O
in	O
the	O
delta	B-GENE
MTV	I-GENE
-	I-GENE
CAT	I-GENE
reporter	I-GENE
plasmid	O
conferred	O
insulin	B-GENE
responsiveness	O
to	O
the	O
mammary	B-GENE
tumor	I-GENE
virus	I-GENE
promoter	I-GENE
.	O

Hemorrheological	O
evaluation	O
and	O
proposed	O
pharmacological	O
uses	O
.	O

Stimulation	O
of	O
the	O
endosteal	O
bone	O
formation	O
rate	O
was	O
mainly	O
impaired	O
in	O
D	O
-	O
depleted	O
rats	O
,	O
resulting	O
in	O
trabecular	O
bone	O
loss	O
,	O
which	O
,	O
in	O
-	O
D	O
mother	O
rats	O
,	O
was	O
associated	O
with	O
decreased	O
bone	O
ash	O
and	O
total	O
bone	O
calcium	O
.	O

Biochemical	O
status	O
was	O
examined	O
using	O
erythrocyte	O
enzyme	O
function	O
and	O
blood	O
vitamin	O
levels	O
.	O

The	O
Polycomb	B-GENE
group	I-GENE
proteins	I-GENE
are	O
involved	O
in	O
maintenance	O
of	O
the	O
silenced	O
state	O
of	O
several	O
developmentally	O
regulated	O
genes	O
.	O

Repeated	O
interferon	B-GENE
-	I-GENE
beta	I-GENE
(	O
IFN	B-GENE
-	I-GENE
beta	I-GENE
)	O
silencer	O
B	O
motifs	O
and	O
a	O
lysozyme	B-GENE
silencer	I-GENE
1	I-GENE
motif	I-GENE
have	O
been	O
found	O
in	O
the	O
CD95	B-GENE
gene	I-GENE
at	O
approximately	O
-	O
1	O
,	O
600	O
and	O
-	O
1	O
,	O
100	O
,	O
respectively	O
.	O

We	O
find	O
that	O
Fus3p	B-GENE
and	O
Kss1p	B-GENE
both	O
control	O
G1	O
arrest	O
through	O
multiple	O
functions	O
that	O
operate	O
in	O
parallel	O
with	O
Far1p	B-GENE
.	O

The	O
Id4	B-GENE
protein	I-GENE
contains	O
a	O
HLH	O
domain	O
highly	O
conserved	O
among	O
the	O
dnHLH	B-GENE
proteins	I-GENE
from	O
mouse	O
and	O
drosophila	O
.	O

The	O
proliferative	O
potential	O
of	O
the	O
pilocytic	O
astrocytoma	O
:	O
the	O
relation	O
between	O
MIB	B-GENE
-	I-GENE
1	I-GENE
labeling	O
and	O
clinical	O
and	O
neuro	O
-	O
radiological	O
follow	O
-	O
up	O
.	O

Desensitization	O
of	O
the	O
growth	B-GENE
hormone	I-GENE
-	O
induced	O
Janus	B-GENE
kinase	I-GENE
2	I-GENE
(	O
Jak	B-GENE
2	I-GENE
)	O
/	O
signal	B-GENE
transducer	I-GENE
and	I-GENE
activator	I-GENE
of	I-GENE
transcription	I-GENE
5	I-GENE
(	O
Stat5	B-GENE
)	O
-	O
signaling	O
pathway	O
requires	O
protein	O
synthesis	O
and	O
phospholipase	B-GENE
C	I-GENE
.	O

The	O
aim	O
of	O
our	O
study	O
was	O
to	O
determine	O
whether	O
exercise	O
training	O
can	O
augment	O
left	O
ventricular	O
diastolic	O
filling	O
at	O
rest	O
and	O
during	O
exercise	O
in	O
patients	O
with	O
ischemic	O
cardiomyopathy	O
and	O
whether	O
any	O
correlation	O
exists	O
between	O
changes	O
in	O
diastolic	O
filling	O
and	O
changes	O
in	O
exercise	O
tolerance	O
.	O

Alterations	O
in	O
TCR	B-GENE
-	O
MHC	B-GENE
contacts	O
subsequent	O
to	O
cross	O
-	O
recognition	O
of	O
class	B-GENE
I	I-GENE
MHC	I-GENE
and	O
singly	O
substituted	O
peptide	O
variants	O
.	O

Scalp	O
blood	O
flow	O
was	O
recorded	O
by	O
a	O
laser	O
Doppler	O
flow	O
sensor	O
that	O
was	O
incorporated	O
in	O
the	O
transcutaneous	O
PO2	O
electrode	O
.	O

There	O
is	O
an	O
overall	O
functional	O
similarity	O
between	O
IL	B-GENE
-	I-GENE
6	I-GENE
and	O
c	B-GENE
-	I-GENE
fos	I-GENE
promoters	I-GENE
,	O
since	O
transfection	O
of	O
excess	O
amounts	O
of	O
either	O
promoter	O
DNA	O
into	O
intact	O
HeLa	O
cells	O
modulates	O
the	O
function	O
of	O
the	O
heterologous	O
promoter	O
construct	O
.	O

Detailed	O
comparison	O
of	O
the	O
sequences	O
of	O
cp35	B-GENE
and	O
human	B-GENE
calpactin	I-GENE
II	I-GENE
shows	O
that	O
the	O
only	O
substantial	O
sequence	O
dissimilarity	O
is	O
a	O
domain	O
encoding	O
amino	O
acids	O
between	O
residues	O
20	O
and	O
40	O
which	O
includes	O
a	O
tyrosine	O
phosphorylation	O
site	O
in	O
the	O
human	O
molecule	O
,	O
along	O
with	O
other	O
residues	O
of	O
possible	O
physiological	O
significance	O
.	O

Power	O
deposition	O
by	O
inverse	O
-	O
bremsstrahlung	O
is	O
modeled	O
with	O
a	O
scheme	O
based	O
on	O
Gaussian	O
quadrature	O
to	O
accommodate	O
a	O
deposition	O
rate	O
whose	O
spatial	O
variation	O
is	O
highly	O
nonuniform	O
.	O

However	O
,	O
the	O
malaria	O
vectors	O
Anopheles	O
funestus	O
and	O
An	O
.	O
gambiae	O
have	O
both	O
become	O
more	O
abundant	O
during	O
the	O
1970s	O
and	O
1980s	O
and	O
sporozoite	O
-	O
positive	O
specimens	O
of	O
both	O
have	O
been	O
found	O
.	O

Greer	O
,	O
and	O
L	O
.	O
A	O
.	O

Expression	O
of	O
Msx	B-GENE
-	I-GENE
1	I-GENE
and	O
Msx	B-GENE
-	I-GENE
2	I-GENE
has	O
been	O
studied	O
during	O
development	O
of	O
the	O
osteoblast	O
phenotype	O
,	O
but	O
the	O
role	O
of	O
Dlx	B-GENE
in	O
this	O
context	O
and	O
in	O
the	O
regulation	O
of	O
bone	O
-	O
expressed	O
genes	O
is	O
unknown	O
.	O

The	O
salt	O
sensitivity	O
of	O
the	O
interaction	O
indicated	O
that	O
two	O
ion	O
pairs	O
are	O
involved	O
in	O
the	O
association	O
of	O
Zn2	O
+	O
(	O
NC	O
-	O
F1	O
)	O
with	O
polynucleotide	O
,	O
whereas	O
one	O
ion	O
pair	O
is	O
found	O
in	O
the	O
metal	O
-	O
free	O
peptide	O
-	O
nucleic	O
acid	O
complex	O
.	O

Histopathologically	O
,	O
(	O
mice	O
killed	O
with	O
high	O
doses	O
of	O
GMC	O
-	O
II	O
,	O
given	O
orally	O
)	O
there	O
were	O
diffuse	O
hyperemia	O
of	O
the	O
liver	O
,	O
parenchymal	O
degeneration	O
of	O
the	O
kidney	O
tubuli	O
epithelium	O
,	O
and	O
edema	O
and	O
emphysema	O
of	O
the	O
lungs	O
.	O

Cytochemical	O
and	O
ultrastructural	O
observations	O
on	O
the	O
tegument	O
of	O
the	O
trematode	O
Megalodiscus	O
temperatus	O
.	O

The	O
overall	O
rate	O
of	O
biohydrogenation	O
of	O
C18	O
:	O
2	O
was	O
14	O
.	O
3	O
%	O
/	O
h	O
,	O
but	O
declined	O
1	O
.	O
2	O
%	O
/	O
h	O
for	O
each	O
percentage	O
unit	O
increase	O
in	O
C18	O
:	O
2	O
added	O
to	O
the	O
substrate	O
.	O

Transient	O
thyrotoxicosis	O
in	O
primary	O
anti	O
-	O
phospholipid	O
syndrome	O
.	O

The	O
highest	O
TTX	B-GENE
content	O
is	O
10	O
.	O
0	O
microg	O
/	O
g	O
in	O
N	O
.	O
livescens	O
.	O

The	O
BUR	O
was	O
set	O
at	O
20	O
/	O
min	O
and	O
the	O
IT	O
at	O
.	O
5	O
seconds	O
.	O

In	O
this	O
study	O
,	O
to	O
elucidate	O
the	O
possible	O
mechanism	O
of	O
action	O
of	O
EM	O
,	O
we	O
examined	O
the	O
effect	O
of	O
the	O
drug	O
on	O
the	O
expression	O
of	O
neutrophil	O
adhesion	O
molecules	O
such	O
as	O
L	B-GENE
-	I-GENE
selectin	I-GENE
and	O
Mac	B-GENE
-	I-GENE
1	I-GENE
.	O

It	O
contains	O
31	O
exons	O
and	O
a	O
high	O
proportion	O
of	O
class	O
0	O
introns	O
,	O
alternative	O
splicing	O
of	O
which	O
results	O
in	O
significant	O
levels	O
of	O
variant	O
transcripts	O
that	O
maintain	O
the	O
original	O
open	O
reading	O
frame	O
of	O
MRP	B-GENE
mRNA	I-GENE
.	O

This	O
nuclear	O
/	O
organellar	O
gene	O
transfer	O
event	O
is	O
strikingly	O
similar	O
to	O
the	O
experimentally	O
accessible	O
process	O
of	O
nuclear	O
integration	O
of	O
introduced	O
heterologous	O
DNA	O
.	O

Under	O
control	O
conditions	O
,	O
pretreatment	O
with	O
lithium	O
during	O
7	O
days	O
did	O
not	O
modify	O
the	O
hyperlocomotion	O
produced	O
by	O
d	O
-	O
amphetamine	O
.	O

We	O
also	O
show	O
that	O
the	O
products	O
of	O
both	O
the	O
GIY	B-GENE
-	I-GENE
YIG	I-GENE
ORF	O
and	O
the	O
non	O
-	O
canonical	O
LAGLI	B-GENE
-	I-GENE
DADG	I-GENE
-	I-GENE
GIY	I-GENE
-	I-GENE
YIG	I-GENE
ORF	O
,	O
which	O
is	O
generated	O
by	O
its	O
integration	O
,	O
have	O
endonuclease	O
activities	O
which	O
recognize	O
and	O
cut	O
the	O
insertion	O
site	O
of	O
the	O
optional	O
sequence	O
.	O

This	O
article	O
describes	O
a	O
program	O
that	O
resulted	O
in	O
a	O
75	O
-	O
percent	O
reduction	O
of	O
inventory	O
over	O
a	O
five	O
-	O
year	O
interval	O
.	O

Risk	O
ratios	O
decreased	O
with	O
increasing	O
age	O
and	O
increased	O
with	O
number	O
of	O
breast	O
biopsies	O
,	O
family	O
history	O
of	O
breast	O
cancer	O
,	O
estrogen	O
use	O
,	O
time	O
between	O
screenings	O
,	O
no	O
comparison	O
with	O
previous	O
mammograms	O
,	O
and	O
the	O
radiologist	O
'	O
s	O
tendency	O
to	O
call	O
mammograms	O
abnormal	O
.	O

The	O
pharmacokinetics	O
were	O
best	O
described	O
by	O
a	O
two	O
-	O
compartment	O
open	O
model	O
giving	O
distribution	O
half	O
-	O
lives	O
of	O
0	O
.	O
31	O
h	O
and	O
1	O
.	O
53	O
h	O
,	O
and	O
elimination	O
half	O
-	O
lives	O
of	O
69	O
.	O
7	O
h	O
and	O
60	O
.	O
3	O
h	O
for	O
oxolinic	O
acid	O
and	O
oxytetracycline	O
,	O
respectively	O
.	O

However	O
,	O
the	O
relative	O
substrate	O
specificity	O
of	O
RSK3	B-GENE
differed	O
from	O
that	O
reported	O
for	O
other	O
isoforms	O
.	O

This	O
study	O
demonstrates	O
a	O
novel	O
link	O
between	O
alterations	O
in	O
platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
(	O
PDGF	B-GENE
)	O
regulation	O
of	O
ornithine	B-GENE
decarboxylase	I-GENE
(	O
ODC	B-GENE
)	O
expression	O
during	O
malignant	O
conversion	O
.	O

Fosinopril	O
decreased	O
blood	O
pressure	O
from	O
174	O
/	O
101	O
mm	O
Hg	O
to	O
149	O
/	O
88	O
mm	O
Hg	O
in	O
patients	O
with	O
diastolic	O
hypertension	O
and	O
from	O
182	O
/	O
86	O
mm	O
Hg	O
to	O
151	O
/	O
80	O
mm	O
Hg	O
in	O
patients	O
with	O
ISH	O
.	O

187	O
-	O
200	O
.	O

Loss	O
of	O
pRb	B-GENE
or	O
p107	B-GENE
binding	O
results	O
in	O
the	O
loss	O
of	O
transforming	O
activity	O
.	O

Influence	O
of	O
huanglian	O
used	O
in	O
combination	O
with	O
huangqin	O
and	O
gancao	O
on	O
the	O
erythrocytic	O
osmotic	O
fragilitas	O
of	O
experimental	O
glucose	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
phosphate	I-GENE
dehydrogenase	I-GENE
deficiency	O
in	O
rats	O
]	O
OBJECTIVE	O
:	O
To	O
study	O
the	O
influence	O
of	O
common	O
combination	O
of	O
Huanglian	O
(	O
Coptis	O
chinensis	O
)	O
on	O
the	O
erythrocytic	O
osmotic	O
fragilitas	O
of	O
glucose	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
phosphate	I-GENE
dehydrogenase	I-GENE
(	O
G6PD	B-GENE
)	O
deficiency	O
in	O
rats	O
.	O

Inhibitory	O
receptors	O
are	O
characterized	O
by	O
the	O
presence	O
of	O
a	O
characteristic	O
sequence	O
known	O
as	O
an	O
immunoreceptor	O
tyrosine	O
-	O
based	O
inhibitory	O
motif	O
(	O
ITIM	O
)	O
in	O
their	O
cytoplasmic	O
tail	O
.	O

Comparison	O
of	O
Healon	O
and	O
Amvisc	O
.	O

2	O
,	O
4	O
-	O
and	O
2	O
,	O
6	O
-	O
toluenediamine	O
in	O
hydrolysed	O
plasma	O
and	O
urine	O
after	O
test	O
-	O
chamber	O
exposure	O
of	O
humans	O
to	O
2	O
,	O
4	O
-	O
and	O
2	O
,	O
6	O
-	O
toluene	O
diisocyanate	O
.	O

The	O
role	O
of	O
the	O
medical	O
facilities	O
in	O
the	O
prognosis	O
of	O
the	O
patient	O
with	O
tetanus	O
specially	O
the	O
importance	O
of	O
considering	O
at	O
the	O
same	O
time	O
the	O
severity	O
of	O
the	O
disease	O
and	O
the	O
characteristics	O
of	O
the	O
therapy	O
deserve	O
further	O
study	O
in	O
order	O
to	O
contribute	O
to	O
the	O
development	O
of	O
the	O
medical	O
assistance	O
to	O
the	O
patients	O
with	O
tetanus	O
.	O

Interaction	O
between	O
the	O
tobacco	O
DNA	O
-	O
binding	O
activity	O
CBF	B-GENE
and	O
the	O
cyt	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
element	I-GENE
of	O
the	O
Agrobacterium	O
tumefaciens	O
T	O
-	O
DNA	O
gene	O
T	B-GENE
-	I-GENE
CYT	I-GENE
correlates	O
with	O
cyt	B-GENE
-	I-GENE
1	I-GENE
directed	O
gene	O
expression	O
in	O
multiple	O
tobacco	O
tissue	O
types	O
.	O

These	O
results	O
suggest	O
that	O
repetitive	O
GAA	O
sequences	O
enhance	O
splicing	O
by	O
binding	O
a	O
protein	O
complex	O
containing	O
a	O
sequence	O
-	O
specific	O
RNA	O
binding	O
protein	O
and	O
a	O
general	O
splicing	O
activator	O
that	O
,	O
in	O
turn	O
,	O
recruit	O
additional	O
SR	B-GENE
proteins	I-GENE
.	O

Organization	O
of	O
exons	O
suggests	O
that	O
,	O
similar	O
to	O
the	O
human	B-GENE
VEGF	I-GENE
gene	I-GENE
,	O
alternative	O
splicing	O
generates	O
the	O
120	O
-	O
,	O
164	O
-	O
,	O
and	O
188	O
-	O
amino	O
acid	O
isoforms	O
,	O
but	O
does	O
not	O
predict	O
a	O
fourth	O
VEGF	B-GENE
isoform	I-GENE
corresponding	O
to	O
human	B-GENE
VEGF206	I-GENE
.	O

The	O
papers	O
provide	O
a	O
broad	O
perspective	O
of	O
MPAs	O
and	O
include	O
social	O
,	O
economic	O
,	O
cultural	O
,	O
biological	O
and	O
statistical	O
components	O
.	O

The	O
great	O
cardiac	O
vein	O
flow	O
became	O
zero	O
due	O
to	O
the	O
cardiac	O
arrest	O
and	O
remained	O
at	O
zero	O
for	O
a	O
moment	O
(	O
dead	O
time	O
)	O
after	O
the	O
initiation	O
of	O
reperfusion	O
.	O

CONCLUSIONS	O
:	O
These	O
results	O
suggest	O
that	O
histamine	B-GENE
-	I-GENE
2	I-GENE
receptor	I-GENE
activation	O
mechanisms	O
may	O
not	O
be	O
involved	O
in	O
postoperative	O
IL	B-GENE
-	I-GENE
6	I-GENE
synthesis	O
.	O

Issues	O
discussed	O
include	O
the	O
validity	O
of	O
the	O
MMPI	O
Mf	O
scale	O
,	O
questions	O
of	O
sample	O
representativeness	O
,	O
whether	O
"	O
straights	O
"	O
can	O
do	O
adequate	O
research	O
on	O
homosexuality	O
,	O
differences	O
in	O
heterosexual	O
and	O
homosexual	O
sexuality	O
,	O
the	O
role	O
of	O
subculture	O
acculturation	O
in	O
homosexual	O
psychological	O
adjustment	O
,	O
and	O
the	O
use	O
of	O
cluster	O
-	O
analysis	O
to	O
generate	O
typologies	O
of	O
homosexualities	O
.	O

Our	O
data	O
suggest	O
that	O
some	O
defects	O
observed	O
in	O
BS	O
,	O
WS	O
or	O
RTS	O
are	O
the	O
consequence	O
of	O
unrestrained	O
recombination	O
.	O

LAC9	B-GENE
is	O
a	O
DNA	O
-	O
binding	O
protein	O
that	O
regulates	O
transcription	O
of	O
the	O
lactose	B-GENE
-	I-GENE
galactose	I-GENE
regulon	I-GENE
in	O
Kluyveromyces	O
lactis	O
.	O

Some	O
cells	O
were	O
excited	O
,	O
others	O
inhibited	O
by	O
,	O
and	O
only	O
some	O
were	O
directionally	O
sensitive	O
to	O
the	O
optomotor	O
stimulus	O
.	O

We	O
have	O
cloned	O
the	O
cDNA	O
for	O
the	O
SLBP	B-GENE
from	O
humans	O
,	O
mice	O
,	O
and	O
frogs	O
,	O
using	O
the	O
recently	O
developed	O
yeast	O
three	O
-	O
hybrid	O
system	O
.	O

The	O
molecular	O
event	O
(	O
s	O
)	O
underlying	O
the	O
functional	O
specificities	O
of	O
these	O
receptors	O
(	O
in	O
regulating	O
the	O
expression	O
of	O
their	O
native	O
target	O
genes	O
)	O
is	O
a	O
very	O
important	O
issue	O
that	O
remains	O
poorly	O
understood	O
.	O

Alternative	O
splicing	O
of	O
the	O
human	B-GENE
serotonin	I-GENE
transporter	I-GENE
gene	I-GENE
.	O

Nuclear	O
proteins	O
bound	O
the	O
cad	B-GENE
+	I-GENE
55	I-GENE
/	I-GENE
+	I-GENE
75	I-GENE
element	I-GENE
in	O
a	O
cell	O
cycle	O
-	O
dependent	O
manner	O
in	O
electromobility	O
shift	O
assays	O
;	O
antibodies	O
specific	O
to	O
USF	B-GENE
and	O
Max	B-GENE
blocked	O
the	O
DNA	O
-	O
binding	O
activity	O
of	O
different	O
growth	O
-	O
regulated	O
protein	O
-	O
DNA	O
complexes	O
.	O

For	O
Thermus	O
strain	O
ZO5	B-GENE
dihydroorotase	I-GENE
(	O
DHOase	B-GENE
;	O
encoded	O
by	O
pyrC	B-GENE
)	O
,	O
the	O
highest	O
similarity	O
scores	O
(	O
about	O
40	O
%	O
identity	O
)	O
were	O
obtained	O
with	O
DHOases	B-GENE
from	O
B	O
.	O
caldolyticus	O
and	O
Bacillus	O
subtilis	O
.	O

This	O
difference	O
between	O
SP	B-GENE
-	I-GENE
1	I-GENE
and	O
SP	B-GENE
-	I-GENE
2	I-GENE
peptides	I-GENE
was	O
not	O
due	O
to	O
their	O
differential	O
uptake	O
by	O
cell	O
,	O
since	O
approximately	O
100	O
times	O
more	O
SP	B-GENE
-	I-GENE
2	I-GENE
peptide	I-GENE
could	O
be	O
found	O
in	O
cytoplasmic	O
extracts	O
than	O
SP	B-GENE
-	I-GENE
1	I-GENE
peptide	I-GENE
in	O
experiments	O
using	O
radiolabeled	O
peptides	O
.	O

The	O
product	O
of	O
one	O
gene	O
,	O
Bv80	B-GENE
,	O
has	O
a	O
single	O
divergent	O
copy	O
of	O
a	O
sequence	O
of	O
149	O
amino	O
acids	O
(	O
approx	O
.	O

The	O
carboxy	O
-	O
proximal	O
regions	O
of	O
the	O
VP1	B-GENE
,	O
which	O
contain	O
very	O
low	O
amino	O
acid	O
homology	O
,	O
displayed	O
evidence	O
of	O
conservation	O
in	O
structural	O
features	O
such	O
as	O
a	O
hydrophilic	O
,	O
highly	O
basic	O
domain	O
.	O

The	O
sequences	O
at	O
-	O
10	O
and	O
-	O
35	O
relative	O
to	O
the	O
transcriptional	O
starting	O
site	O
showed	O
55	O
%	O
homology	O
with	O
the	O
consensus	O
sequences	O
of	O
the	O
Escherichia	B-GENE
coli	I-GENE
sigma	I-GENE
70	I-GENE
-	I-GENE
type	I-GENE
promoter	I-GENE
.	O

The	O
two	O
ORFs	O
had	O
significant	O
similarity	O
with	O
the	O
putative	O
replication	O
protein	O
from	O
plasmid	O
pTiK12	O
of	O
Thiobacillus	O
intermedius	O
and	O
other	O
CoIE2	O
-	O
related	O
plasmids	O
.	O

A	O
clinical	O
double	O
-	O
blind	O
trial	O
of	O
topical	O
miconazole	O
and	O
clotrimazole	O
against	O
superficial	O
fungal	O
infections	O
and	O
erythrasma	O
.	O

Lumbar	O
spine	O
bone	O
mineral	O
density	O
(	O
BMD	O
)	O
by	O
dual	O
-	O
energy	O
X	O
-	O
ray	O
absorptiometry	O
(	O
DXA	O
)	O
increased	O
by	O
0	O
.	O
6	O
%	O
,	O
3	O
.	O
6	O
%	O
and	O
8	O
.	O
1	O
%	O
after	O
48	O
weeks	O
in	O
groups	O
L	O
,	O
M	O
and	O
H	O
respectively	O
,	O
responses	O
in	O
groups	O
M	O
and	O
H	O
being	O
significantly	O
higher	O
than	O
in	O
L	O
(	O
p	O
<	O
0	O
.	O
05	O
,	O
Mann	O
-	O
Whitney	O
U	O
-	O
test	O
)	O
.	O

A	O
genomic	O
clone	O
representing	O
the	O
5	O
'	O
part	O
of	O
the	O
message	O
was	O
also	O
isolated	O
.	O

This	O
unusual	O
behaviour	O
may	O
be	O
explained	O
by	O
the	O
18	B-GENE
amino	I-GENE
acid	I-GENE
-	I-GENE
long	I-GENE
CDR	I-GENE
-	I-GENE
H3	I-GENE
and	O
could	O
be	O
of	O
value	O
in	O
the	O
design	O
of	O
'	O
single	O
domain	O
'	O
antibodies	O
.	O

Bleeding	O
was	O
successfully	O
prevented	O
in	O
28	O
patients	O
with	O
the	O
use	O
of	O
a	O
combined	O
treatment	O
incorporating	O
IV	O
desmopressin	O
,	O
an	O
antifibrinolytic	O
agent	O
(	O
tranexamic	O
acid	O
)	O
,	O
and	O
local	O
methods	O
(	O
surgical	O
glue	O
and	O
compression	O
techniques	O
)	O
.	O

Northern	O
blot	O
analysis	O
demonstrated	O
that	O
the	O
genes	O
are	O
transcribed	O
separately	O
.	O

CONCLUSIONS	O
:	O
Systemic	O
factors	O
that	O
increase	O
bone	O
mineral	O
density	O
appear	O
to	O
be	O
involved	O
in	O
the	O
pathogenesis	O
of	O
ossification	O
of	O
the	O
posterior	O
longitudinal	O
ligament	O
,	O
and	O
these	O
factors	O
may	O
be	O
activated	O
after	O
middle	O
age	O
.	O

FdsR	B-GENE
purified	O
to	O
homogeneity	O
after	O
overexpression	O
of	O
fdsR	B-GENE
in	O
E	O
.	O
coli	O
is	O
a	O
130	O
kDa	O
homotetramer	O
binding	O
to	O
the	O
fds	B-GENE
control	O
region	O
located	O
between	O
the	O
fdsR	B-GENE
and	O
fdsG	B-GENE
genes	I-GENE
.	O

Surgical	O
methods	O
in	O
the	O
treatment	O
of	O
rhinophyma	O
.	O

The	O
adeno	O
-	O
associated	O
virus	O
type	O
2	O
(	O
AAV	O
-	O
2	O
)	O
Rep78	B-GENE
/	O
Rep68	B-GENE
regulatory	O
proteins	O
are	O
pleiotropic	O
effectors	O
of	O
viral	O
and	O
cellular	O
DNA	O
replication	O
,	O
of	O
cellular	O
transformation	O
by	O
viral	O
and	O
cellular	O
oncogenes	O
,	O
and	O
of	O
homologous	O
and	O
heterologous	O
gene	O
expression	O
.	O

We	O
show	O
here	O
that	O
Spb1p	B-GENE
is	O
able	O
to	O
bind	O
[	O
(	O
3	O
)	O
H	O
]	O
AdoMet	O
in	O
vitro	O
,	O
suggesting	O
that	O
it	O
is	O
a	O
novel	O
methylase	O
,	O
whose	O
possible	O
substrates	O
will	O
be	O
discussed	O
.	O

Low	O
temperature	O
(	O
8	O
degrees	O
C	O
)	O
impairs	O
secretory	O
activity	O
,	O
again	O
independently	O
of	O
the	O
photoperiod	O
selected	O
.	O

These	O
data	O
suggest	O
that	O
weight	O
gain	O
or	O
increased	O
caloric	O
intake	O
,	O
in	O
contrast	O
to	O
its	O
large	O
effect	O
on	O
peripheral	O
thyroid	O
function	O
,	O
has	O
relatively	O
little	O
effect	O
on	O
CNS	B-GENE
TRH	I-GENE
activity	O
.	O

Hematopoietic	B-GENE
progenitor	I-GENE
kinase	I-GENE
1	I-GENE
(	O
HPK1	B-GENE
)	O
is	O
a	O
member	O
of	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
kinase	I-GENE
kinase	I-GENE
kinase	I-GENE
(	O
MAP4K	B-GENE
)	O
family	O
and	O
an	O
upstream	O
activator	O
of	O
the	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
)	O
signaling	O
cascade	O
.	O

We	O
conclude	O
that	O
the	O
outcome	O
of	O
patients	O
with	O
uterine	O
MMMT	O
is	O
mainly	O
influenced	O
by	O
the	O
initial	O
stage	O
and	O
the	O
type	O
of	O
epithelial	O
component	O
.	O

Increased	O
susceptibility	O
of	O
aphasics	O
to	O
a	O
distractor	O
task	O
in	O
the	O
recall	O
of	O
verbal	O
commands	O
.	O

Here	O
we	O
show	O
that	O
inhibition	O
occurs	O
with	O
a	O
NS1	B-GENE
-	O
Rev	B-GENE
chimera	O
in	O
which	O
the	O
78	O
amino	O
-	O
terminal	O
amino	O
acids	O
of	O
the	O
NS1A	B-GENE
protein	I-GENE
comprising	O
its	O
entire	O
RNA	O
-	O
binding	O
domain	O
is	O
deleted	O
,	O
thereby	O
establishing	O
that	O
this	O
carboxyl	O
portion	O
of	O
the	O
NS1A	B-GENE
protein	I-GENE
can	O
function	O
as	O
an	O
independent	O
effector	O
domain	O
.	O

We	O
hypothesized	O
that	O
conjugated	O
estrogens	O
,	O
which	O
contain	O
several	O
vasoactive	O
estrogenic	O
compounds	O
,	O
may	O
favorably	O
influence	O
the	O
vasomotor	O
response	O
to	O
acetylcholine	O
in	O
men	O
.	O

Calcium	O
bilirubinate	O
crystals	O
were	O
seen	O
in	O
gallbladder	O
bile	O
or	O
wall	O
scrapings	O
of	O
7	O
of	O
8	O
TPN	O
animals	O
but	O
in	O
none	O
of	O
the	O
controls	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Because	O
c	B-GENE
-	I-GENE
myb	I-GENE
encodes	O
a	O
transcriptional	O
activator	O
that	O
functions	O
via	O
DNA	O
binding	O
,	O
it	O
is	O
likely	O
that	O
c	B-GENE
-	I-GENE
myb	I-GENE
exerts	O
its	O
biological	O
activity	O
by	O
regulating	O
the	O
transcription	O
of	O
genes	O
required	O
for	O
DNA	O
synthesis	O
and	O
cell	O
cycle	O
progression	O
.	O

Alcohol	O
and	O
stomach	O
diseases	O

Thus	O
integration	B-GENE
host	I-GENE
factor	I-GENE
is	O
required	O
for	O
normal	O
type	B-GENE
1	I-GENE
fimbriae	I-GENE
phase	O
variation	O
in	O
E	O
.	O
coli	O
.	O

Multiple	O
attempts	O
aimed	O
at	O
disruption	O
of	O
the	O
chromosomal	B-GENE
fabG	I-GENE
gene	I-GENE
were	O
unsuccessful	O
.	O

In	O
our	O
case	O
the	O
development	O
of	O
the	O
tumor	O
at	O
the	O
posterior	O
side	O
of	O
the	O
prostate	O
,	O
the	O
lack	O
of	O
PSA	B-GENE
immunoreactivity	O
and	O
the	O
presence	O
of	O
mucinous	O
glands	O
,	O
sometimes	O
"	O
endocervical	O
-	O
like	O
"	O
,	O
could	O
suggest	O
an	O
origin	O
from	O
embryonic	O
mullerian	O
remnants	O
in	O
the	O
prostatic	O
utricle	O
rather	O
than	O
urogenital	O
sinus	O
.	O

Analysis	O
of	O
the	O
DNA	O
-	O
binding	O
and	O
transcriptional	O
activation	O
functions	O
of	O
human	B-GENE
Fli	I-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
.	O

The	O
second	O
patient	O
was	O
successfully	O
treated	O
with	O
intravenous	O
prostaglandin	O
F2	O
alpha	O
(	O
PGF2	O
alpha	O
)	O
.	O

Salts	O
of	O
these	O
four	O
metal	O
ions	O
may	O
be	O
added	O
to	O
the	O
growth	O
medium	O
to	O
facilitate	O
selective	O
isolation	O
of	O
Acinetobacter	O
.	O

DESIGN	O
-	O
-	O
A	O
randomised	O
double	O
blind	O
placebo	O
controlled	O
parallel	O
arm	O
trial	O
.	O

Base	O
substitutions	O
within	O
this	O
NFIL	B-GENE
-	I-GENE
6	I-GENE
site	I-GENE
resulted	O
in	O
virtual	O
elimination	O
of	O
LPS	O
-	O
induced	O
IL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
gene	I-GENE
transcription	O
.	O

Different	O
clinical	O
variants	O
of	O
the	O
empty	O
sella	O
turcica	O
syndrome	O
are	O
demonstrated	O
,	O
including	O
variants	O
resultant	O
from	O
substitution	O
therapy	O
of	O
thyroid	O
hypofunction	O
,	O
from	O
dopamine	O
agonist	O
therapy	O
for	O
hyperprolactinemic	O
hypogonadism	O
,	O
from	O
radiotherapy	O
of	O
hypophyseal	O
adenoma	O
.	O

Repeated	O
time	O
course	O
studies	O
in	O
the	O
same	O
patient	O
were	O
reproducible	O
although	O
the	O
absolute	O
concentrations	O
showed	O
some	O
variation	O
.	O

Our	O
data	O
suggest	O
that	O
association	O
of	O
TBP	B-GENE
with	O
the	O
TATA	O
box	O
may	O
be	O
regulated	O
,	O
directly	O
or	O
indirectly	O
,	O
by	O
a	O
substrate	O
of	O
Snf1	B-GENE
.	O

Site	O
-	O
directed	O
mutagenesis	O
of	O
the	O
T4	B-GENE
endonuclease	I-GENE
V	I-GENE
gene	I-GENE
:	O
role	O
of	O
lysine	O
-	O
130	O
.	O

Simulations	O
of	O
velocities	O
,	O
vorticity	O
,	O
pressure	O
and	O
certain	O
stress	O
values	O
were	O
developed	O
by	O
a	O
computer	O
and	O
displayed	O
for	O
man	O
-	O
machine	O
interaction	O
.	O

Together	O
,	O
these	O
results	O
implicate	O
Fal1p	B-GENE
in	O
the	O
18S	B-GENE
rRNA	I-GENE
maturation	O
pathway	O
rather	O
than	O
in	O
translation	O
initiation	O
.	O

TRAF2	B-GENE
has	O
previously	O
been	O
demonstrated	O
to	O
activate	O
both	O
transcription	O
factor	O
nuclear	B-GENE
factor	I-GENE
kappaB	I-GENE
(	O
NFkappaB	B-GENE
)	O
and	O
the	O
c	B-GENE
-	I-GENE
Jun	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
/	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
/	O
SAPK	B-GENE
)	O
pathway	O
,	O
which	O
in	O
turn	O
stimulates	O
transcription	B-GENE
factor	I-GENE
activating	I-GENE
protein	I-GENE
1	I-GENE
(	O
AP1	B-GENE
)	O
mainly	O
via	O
phosphorylation	O
of	O
the	O
c	B-GENE
-	I-GENE
Jun	I-GENE
component	O
.	O

Electrophysiology	O
and	O
pharmacology	O
of	O
epicardial	O
,	O
endocardial	O
,	O
and	O
M	O
cells	O
.	O

The	O
data	O
suggest	O
that	O
compromised	O
fibrinolytic	O
capacity	O
may	O
be	O
a	O
contributing	O
factor	O
in	O
the	O
development	O
of	O
thrombosis	O
in	O
patients	O
with	O
the	O
lupus	O
anticoagulant	O
.	O

Human	O
psychophysical	O
analysis	O
of	O
receptive	O
field	O
-	O
like	O
properties	O
-	O
-	O
II	O
.	O

Furthermore	O
,	O
agonist	O
action	O
at	O
a	O
5	B-GENE
-	I-GENE
HT1	I-GENE
receptor	I-GENE
and	O
antagonist	O
action	O
at	O
5	B-GENE
-	I-GENE
HT2	I-GENE
receptors	I-GENE
both	O
appear	O
to	O
contribute	O
to	O
antidepressant	O
-	O
like	O
activity	O
on	O
the	O
DRL	O
72	O
-	O
s	O
schedule	O
.	O

Heliox	O
improves	O
pulsus	O
paradoxus	O
and	O
peak	O
expiratory	O
flow	O
in	O
nonintubated	O
patients	O
with	O
severe	O
asthma	O
.	O

Response	O
surface	O
methodology	O
was	O
employed	O
to	O
describe	O
the	O
relationship	O
between	O
soman	O
-	O
induced	O
incapacitation	O
and	O
the	O
ATR	O
/	O
DZ	O
or	O
ATR	O
/	O
SCP	O
dosages	O
.	O

Both	O
DMP2	B-GENE
and	O
DMP3	B-GENE
are	O
closely	O
localized	O
on	O
mouse	O
chromosome	O
5q21	O
,	O
corresponding	O
to	O
human	O
chromosome	O
4q21	O
.	O

A	O
kinetic	O
model	O
for	O
99mTc	O
-	O
DMSA	O
in	O
the	O
rat	O
.	O

Together	O
with	O
the	O
up	O
-	O
regulation	O
of	O
the	O
cAMP	B-GENE
response	I-GENE
element	I-GENE
modulator	I-GENE
protein	I-GENE
(	O
CREM	B-GENE
)	O
mRNA	O
and	O
protein	O
levels	O
demonstrated	O
previously	O
in	O
CREB	B-GENE
mutant	I-GENE
mice	O
,	O
we	O
suggest	O
that	O
the	O
up	O
-	O
regulation	O
of	O
CREB	B-GENE
beta	I-GENE
may	O
also	O
contribute	O
to	O
compensation	O
within	O
the	O
CREB	B-GENE
/	O
ATF	B-GENE
family	O
of	O
transcription	O
factors	O
,	O
when	O
CREB	B-GENE
delta	I-GENE
and	O
CREB	B-GENE
alpha	I-GENE
are	O
absent	O
.	O

To	O
examine	O
the	O
effect	O
of	O
the	O
cAMP	O
signal	O
transduction	O
pathway	O
on	O
transcription	O
of	O
the	O
gene	O
encoding	O
the	O
catalytic	O
subunit	O
of	O
glucose	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
phosphatase	I-GENE
(	O
G6Pase	B-GENE
)	O
,	O
G6Pase	B-GENE
-	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
fusion	O
genes	O
were	O
transiently	O
transfected	O
into	O
either	O
the	O
liver	O
-	O
derived	O
HepG2	O
or	O
kidney	O
-	O
derived	O
LLC	O
-	O
PK	O
cell	O
line	O
.	O

The	O
structural	O
intestinal	O
defects	O
are	O
presumed	O
to	O
be	O
the	O
result	O
of	O
defective	O
collagen	B-GENE
synthesis	O
in	O
these	O
hereditary	O
connective	O
tissue	O
disorders	O
.	O

Letter	O
:	O
Dehydrated	O
test	O
strip	O
for	O
the	O
detection	O
of	O
yeasts	O
.	O

Galactorrhoea	O
is	O
a	O
rare	O
presentation	O
of	O
an	O
empty	O
sella	O
syndrome	O
.	O

The	O
transition	O
from	O
expression	O
of	O
early	O
meiotic	O
genes	O
to	O
expression	O
of	O
middle	O
sporulation	O
-	O
specific	O
genes	O
occurs	O
at	O
about	O
the	O
time	O
that	O
cells	O
exit	O
from	O
pachytene	O
and	O
form	O
the	O
meiosis	O
I	O
spindle	O
.	O

Mutations	O
away	O
from	O
splice	O
site	O
recognition	O
sequences	O
might	O
cis	O
-	O
modulate	O
alternative	O
splicing	O
of	O
goat	O
alpha	B-GENE
s1	I-GENE
-	I-GENE
casein	I-GENE
transcripts	I-GENE
.	O

These	O
Tlr	B-GENE
family	I-GENE
members	I-GENE
,	O
unlike	O
others	O
reported	O
to	O
date	O
,	O
were	O
identified	O
within	O
a	O
genomic	O
database	O
.	O

Fig1p	B-GENE
and	O
Fig2p	B-GENE
are	O
likely	O
to	O
act	O
at	O
the	O
cell	O
surface	O
as	O
Fig1	B-GENE
:	O
:	O
beta	B-GENE
-	I-GENE
gal	I-GENE
and	O
Fig2	B-GENE
:	O
:	O
beta	B-GENE
-	I-GENE
gal	I-GENE
fusion	I-GENE
proteins	I-GENE
localize	O
to	O
the	O
periphery	O
of	O
mating	O
cells	O
.	O

There	O
is	O
little	O
supportive	O
evidence	O
that	O
ACE	B-GENE
inhibitors	O
(	O
captopril	O
or	O
enalapril	O
)	O
are	O
teratogenic	O
.	O

These	O
results	O
suggest	O
that	O
the	O
PVB	O
therapy	O
is	O
not	O
sufficient	O
to	O
cure	O
the	O
cases	O
with	O
choriocarcinoma	O
element	O
or	O
bulky	O
metastasis	O
.	O

Evaluation	O
of	O
gamma	B-GENE
-	I-GENE
glutamyl	I-GENE
transpeptidase	I-GENE
in	O
myocardial	O
infarction	O
.	O

The	O
yjr041c	B-GENE
delta	I-GENE
haploid	O
cells	O
gave	O
rise	O
to	O
microcolonies	O
comprising	O
about	O
20	O
to	O
50	O
cells	O
.	O

Mean	O
latency	O
periods	O
were	O
29	O
.	O
6	O
among	O
insulators	O
,	O
35	O
.	O
4	O
among	O
dock	O
workers	O
,	O
43	O
.	O
7	O
in	O
a	O
heterogeneous	O
group	O
defined	O
as	O
various	O
,	O
46	O
.	O
4	O
in	O
non	O
-	O
shipbuilding	O
industry	O
workers	O
,	O
49	O
.	O
4	O
in	O
shipyard	O
workers	O
,	O
51	O
.	O
7	O
among	O
women	O
with	O
a	O
history	O
of	O
domestic	O
exposure	O
to	O
asbestos	O
,	O
and	O
56	O
.	O
2	O
in	O
people	O
employed	O
in	O
maritime	O
trades	O
.	O

Influence	O
of	O
dietary	O
supplementation	O
with	O
Streptococcus	O
faecium	O
M	O
-	O
74	O
on	O
broiler	O
body	O
weight	O
,	O
feed	O
conversion	O
,	O
carcass	O
characteristics	O
,	O
and	O
intestinal	O
microbial	O
colonization	O
.	O

Two	O
plasmids	O
,	O
one	O
containing	O
the	O
amino	O
terminus	O
of	O
P	O
fused	O
to	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
the	O
yeast	O
transactivator	O
,	O
GAL4	B-GENE
,	O
and	O
the	O
other	O
containing	O
the	O
amino	O
terminus	O
of	O
NP	B-GENE
fused	O
to	O
the	O
herpesvirus	O
transactivator	O
,	O
VP16	B-GENE
,	O
were	O
transfected	O
in	O
COS	O
-	O
1	O
cells	O
along	O
with	O
a	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
reporter	O
plasmid	O
containing	O
GAL4	B-GENE
DNA	O
-	O
binding	O
sites	O
.	O

7	O
-	O
Nitroindazole	O
(	O
7NI	O
)	O
,	O
a	O
relatively	O
selective	O
neuronal	O
nitric	B-GENE
oxide	I-GENE
synthase	I-GENE
(	O
nNOS	B-GENE
)	O
inhibitor	O
.	O
was	O
intraperitoneally	O
administered	O
to	O
the	O
guinea	O
pigs	O
30	O
minutes	O
before	O
the	O
onset	O
of	O
local	O
anoxia	O
.	O

New	O
protein	O
-	O
free	O
products	O
for	O
diet	O
therapy	O
in	O
chronic	O
renal	O
insufficiency	O

Impact	O
of	O
cytokine	O
gene	O
polymorphisms	O
on	O
outcomes	O
of	O
coronary	O
artery	O
bypass	O
graft	O
surgery	O
.	O

The	O
human	O
protein	O
binds	O
most	O
strongly	O
to	O
the	O
SH3	B-GENE
domain	I-GENE
from	O
the	O
abl	B-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
.	O

Adequacy	O
of	O
the	O
Haldane	O
transformation	O
in	O
the	O
computation	O
of	O
exercise	O
V	O
O2	O
in	O
man	O
.	O

Covariates	O
were	O
lower	O
extremity	O
range	O
of	O
motion	O
and	O
sensory	O
status	O
.	O

Like	O
troponin	B-GENE
Cs	I-GENE
and	O
calmodulins	B-GENE
,	O
PfCPK	B-GENE
also	O
contains	O
four	O
EF	O
hand	O
calcium	O
-	O
binding	O
motifs	O
.	O

Roller	O
pumps	O
,	O
coronary	O
suction	O
and	O
an	O
open	O
cardiotomy	O
reservoir	O
were	O
used	O
.	O

Akt	B-GENE
-	O
dependent	O
antiapoptotic	O
action	O
of	O
insulin	B-GENE
is	O
sensitive	O
to	O
farnesyltransferase	O
inhibitor	O
.	O

LT	B-GENE
-	I-GENE
beta	I-GENE
transcription	O
is	O
maximal	O
in	O
the	O
thymic	O
medulla	O
and	O
in	O
splenic	O
white	O
pulp	O
.	O

Ultrastructure	O
and	O
toxin	O
formation	O
of	O
Cor	O
.	O
diphtheriae	O
PW	O
-	O
8	O
cultured	O
in	O
the	O
presence	O
of	O
penicillin	O

Our	O
data	O
indicate	O
that	O
the	O
various	O
subunits	O
of	O
the	O
human	O
P	B-GENE
-	I-GENE
TEFb	I-GENE
complex	O
may	O
play	O
distinct	O
roles	O
at	O
multiple	O
stages	O
to	O
mediate	O
Tat	B-GENE
activation	O
of	O
HIV	O
-	O
1	O
transcription	O
elongation	O
.	O

The	O
organelles	O
synthesize	O
their	O
own	O
set	O
of	O
Fe	B-GENE
/	I-GENE
S	I-GENE
proteins	I-GENE
,	O
and	O
they	O
initiate	O
the	O
generation	O
of	O
extramitochondrial	B-GENE
Fe	I-GENE
/	I-GENE
S	I-GENE
proteins	I-GENE
.	O

Ras	B-GENE
involvement	O
in	O
signal	O
transduction	O
by	O
the	O
serotonin	B-GENE
5	I-GENE
-	I-GENE
HT2B	I-GENE
receptor	I-GENE
.	O

Engineering	O
temperature	O
-	O
sensitive	O
SH3	B-GENE
domains	I-GENE
.	O

Orlistat	O
is	O
a	O
specific	O
lipase	B-GENE
inhibitor	O
that	O
impairs	O
fat	O
absorption	O
,	O
thereby	O
reducing	O
fat	O
uptake	O
.	O

We	O
identify	O
YY1	B-GENE
recognition	O
sequences	O
within	O
the	O
vitamin	O
D	O
response	O
element	O
(	O
VDRE	O
)	O
of	O
the	O
osteocalcin	B-GENE
gene	I-GENE
that	O
are	O
critical	O
for	O
YY1	B-GENE
-	O
dependent	O
repression	O
of	O
vitamin	O
D	O
-	O
enhanced	O
promoter	O
activity	O
.	O

The	O
nine	O
subjects	O
were	O
treated	O
in	O
random	O
sequence	O
with	O
cimetidine	O
0	O
-	O
8	O
-	O
1	O
-	O
0	O
g	O
on	O
one	O
day	O
and	O
placebo	O
capsules	O
on	O
the	O
other	O
.	O

ORF3	O
encodes	O
a	O
putative	O
periplasmic	B-GENE
c	I-GENE
-	I-GENE
type	I-GENE
cytochrome	I-GENE
with	O
a	O
molecular	O
mass	O
of	O
94	O
,	O
000	O
Da	O
and	O
contains	O
seven	O
c	O
-	O
heme	O
-	O
binding	O
motifs	O
but	O
shows	O
no	O
sequence	O
homology	O
to	O
occ	B-GENE
or	O
ORF1	O
.	O

The	O
mutant	O
strain	O
carries	O
three	O
tandem	O
copies	O
of	O
the	O
18	O
bp	O
sequence	O
that	O
is	O
duplicated	O
in	O
the	O
amdI66	B-GENE
mutation	O
.	O

The	O
rat	O
anococcygeus	O
muscle	O
was	O
used	O
in	O
postsynaptic	O
studies	O
.	O

The	O
HPV	O
E1	B-GENE
and	O
E2	B-GENE
proteins	O
along	O
with	O
cellular	O
factors	O
,	O
are	O
required	O
for	O
replication	O
of	O
the	O
viral	O
genome	O
.	O

Multiple	O
organ	O
failure	O
(	O
MOF	O
)	O
following	O
major	O
trauma	O
occurs	O
in	O
response	O
to	O
perfusion	O
deficits	O
,	O
a	O
persistent	O
inflammatory	O
focus	O
,	O
or	O
a	O
persistent	O
focus	O
of	O
dead	O
and	O
/	O
or	O
injured	O
tissue	O
.	O

(	O
i	O
)	O
Several	O
ribosomal	O
proteins	O
were	O
synthesized	O
in	O
substantial	O
excess	O
.	O

These	O
results	O
suggest	O
that	O
camptothecin	O
resistance	O
in	O
CEM	O
/	O
DOX	O
cells	O
is	O
due	O
to	O
different	O
mechanism	O
(	O
s	O
)	O
than	O
topoisomerase	B-GENE
-	O
or	O
P	B-GENE
-	I-GENE
glycoprotein	I-GENE
-	O
associated	O
multidrug	O
resistance	O
.	O

The	O
detection	O
limits	O
obtained	O
by	O
using	O
the	O
mixed	O
eluent	O
were	O
0	O
.	O
05	O
-	O
0	O
.	O
13	O
mg	O
/	O
L	O
,	O
several	O
times	O
lower	O
than	O
those	O
obtained	O
by	O
using	O
single	O
KHPh	O
eluent	O
.	O

Here	O
we	O
report	O
the	O
fabrication	O
of	O
single	O
-	O
molecule	O
transistors	O
based	O
on	O
individual	O
C60	O
molecules	O
connected	O
to	O
gold	O
electrodes	O
.	O

Because	O
of	O
gut	O
fermentation	O
,	O
a	O
substantial	O
portion	O
(	O
16	O
-	O
80	O
%	O
)	O
of	O
N	O
is	O
absorbed	O
as	O
ammonia	O
N	O
(	O
NH3N	O
)	O
.	O

At	O
1	O
min	O
postalfentanil	O
,	O
N2O	O
caused	O
significantly	O
more	O
rigidity	O
than	O
100	O
%	O
O2	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

By	O
contrast	O
,	O
CIS	B-GENE
failed	O
to	O
affect	O
the	O
IL	B-GENE
-	I-GENE
9	I-GENE
response	O
.	O

Interestingly	O
,	O
PMA	O
-	O
,	O
PDGF	B-GENE
-	O
,	O
and	O
serum	O
-	O
induced	O
GHR	B-GENE
proteolysis	O
was	O
associated	O
with	O
substantial	O
decreases	O
in	O
GH	B-GENE
-	O
induced	O
activation	O
of	O
Janus	B-GENE
kinase	I-GENE
-	I-GENE
2	I-GENE
,	O
which	O
were	O
also	O
prevented	O
by	O
IC3	O
.	O

The	O
centromeric	O
dodeca	O
-	O
satellite	O
of	O
Drosophila	O
forms	O
altered	O
DNA	O
structures	O
in	O
vitro	O
in	O
which	O
its	O
purine	O
-	O
rich	O
strand	O
(	O
G	O
-	O
strand	O
)	O
forms	O
stable	O
fold	O
-	O
back	O
structures	O
,	O
while	O
the	O
complementary	O
C	O
-	O
strand	O
remains	O
unstructured	O
.	O

The	O
Aspergillus	B-GENE
uvsH	I-GENE
gene	I-GENE
encodes	O
a	O
product	O
homologous	O
to	O
yeast	B-GENE
RAD18	I-GENE
and	O
Neurospora	B-GENE
UVS	I-GENE
-	I-GENE
2	I-GENE
.	O

These	O
data	O
also	O
suggest	O
the	O
existence	O
of	O
a	O
mechanism	O
by	O
which	O
regulatory	O
subunits	O
modulate	O
the	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
-	O
mediated	O
signals	O
,	O
independent	O
of	O
the	O
kinase	O
activity	O
,	O
possibly	O
through	O
subcellular	O
localization	O
of	O
the	O
catalytic	O
subunit	O
or	O
interaction	O
with	O
additional	O
signaling	O
molecules	O
.	O

A	O
continuous	O
-	O
flow	O
BIPAP	O
system	O
consists	O
of	O
a	O
high	O
-	O
flow	O
CPAP	O
system	O
,	O
a	O
reservoir	O
bag	O
,	O
and	O
a	O
pneumatically	O
controlled	O
membrane	O
valve	O
in	O
the	O
expiratory	O
limb	O
.	O

This	O
study	O
demonstrates	O
that	O
the	O
exposure	O
to	O
sulphur	O
mustard	O
results	O
in	O
very	O
low	O
androgen	O
levels	O
and	O
hypo	O
-	O
responsiveness	O
to	O
GnRH	B-GENE
in	O
the	O
first	O
five	O
weeks	O
and	O
normalization	O
by	O
the	O
twelfth	O
week	O
after	O
injury	O
.	O

The	O
A3B3	O
domain	O
had	O
a	O
mass	O
of	O
34	O
,	O
462	O
,	O
with	O
a	O
glycosylation	O
mass	O
of	O
14	O
,	O
900	O
,	O
in	O
good	O
agreement	O
with	O
seven	O
N	O
-	O
linked	O
glycosylation	O
sites	O
of	O
average	O
mass	O
2100	O
.	O

In	O
the	O
present	O
study	O
we	O
prospectively	O
compared	O
side	O
effects	O
occurring	O
in	O
12	O
patients	O
after	O
the	O
first	O
administration	O
of	O
low	O
-	O
dose	O
OKT3	O
(	O
0	O
.	O
5	O
mg	O
twice	O
daily	O
)	O
induction	O
therapy	O
with	O
those	O
in	O
10	O
patients	O
who	O
were	O
treated	O
with	O
a	O
conventional	O
dose	O
of	O
OKT3	O
(	O
5	O
mg	O
daily	O
)	O
for	O
acute	O
rejection	O
.	O

Plasma	B-GENE
prolactin	I-GENE
concentrations	O
during	O
incubation	O
,	O
25	O
.	O
8	O
+	O
/	O
-	O
2	O
.	O
3	O
ng	O
/	O
ml	O
,	O
decreased	O
to	O
baseline	O
levels	O
,	O
10	O
.	O
8	O
+	O
/	O
-	O
1	O
.	O
9	O
ng	O
/	O
ml	O
,	O
within	O
24	O
hr	O
after	O
nestbox	O
removal	O
.	O

Our	O
findings	O
suggest	O
that	O
resting	O
Tl	O
-	O
201	O
scintigraphy	O
has	O
limited	O
value	O
in	O
the	O
detection	O
of	O
coronary	O
artery	O
disease	O
in	O
patients	O
with	O
Hurler	O
syndrome	O
.	O

Exit	O
from	O
mitosis	O
in	O
Drosophila	O
syncytial	O
embryos	O
requires	O
proteolysis	O
and	O
cyclin	B-GENE
degradation	O
,	O
and	O
is	O
associated	O
with	O
localized	O
dephosphorylation	O
.	O

Also	O
,	O
residues	O
273	O
to	O
287	O
,	O
which	O
are	O
identical	O
in	O
sequence	O
to	O
a	O
15	O
-	O
amino	O
-	O
acid	O
segment	O
near	O
the	O
carboxy	O
terminus	O
of	O
the	O
simian	B-GENE
foamy	I-GENE
virus	I-GENE
transcriptional	I-GENE
activator	I-GENE
Taf	I-GENE
,	O
can	O
independently	O
enhance	O
the	O
activity	O
of	O
the	O
minimal	O
activator	O
region	O
.	O

The	O
effect	O
of	O
buthionine	O
sulfoximine	O
(	O
BSO	O
)	O
and	O
disulfiram	O
(	O
DSF	O
)	O
on	O
the	O
urotoxicity	O
induced	O
by	O
cyclophosphamide	O
(	O
CPA	O
)	O
was	O
examined	O
in	O
mice	O
.	O

METHOD	O
:	O
Six	O
instruments	O
were	O
reviewed	O
:	O
the	O
Berg	O
Balance	O
Scale	O
(	O
Berg	O
)	O
,	O
the	O
Clinical	O
Test	O
of	O
Sensory	O
Interaction	O
and	O
Balance	O
(	O
CTSIB	O
)	O
,	O
the	O
Functional	O
Reach	O
Test	O
,	O
the	O
Tinetti	O
Balance	O
Test	O
of	O
the	O
Performance	O
-	O
Oriented	O
Assessment	O
of	O
Mobility	O
Problems	O
(	O
Tinetti	O
)	O
,	O
the	O
Timed	O
"	O
Up	O
and	O
Go	O
"	O
Test	O
(	O
TU	O
&	O
GT	O
)	O
,	O
and	O
the	O
Physical	O
Performance	O
Test	O
(	O
PPT	O
)	O
.	O

The	O
side	O
effect	O
of	O
pulmonary	O
fibrosis	O
occurs	O
in	O
20	O
to	O
30	O
percent	O
of	O
patients	O
receiving	O
this	O
drug	O
.	O

Of	O
the	O
47	O
women	O
with	O
AGCUS	O
,	O
16	O
had	O
intraepithelial	O
or	O
invasive	O
neoplasms	O
(	O
34	O
%	O
;	O
95	O
%	O
confidence	O
interval	O
,	O
21	O
-	O
49	O
%	O
)	O
,	O
including	O
9	O
low	O
or	O
high	O
grade	O
squamous	O
intraepithelial	O
lesions	O
,	O
1	O
adenocarcinoma	O
in	O
situ	O
of	O
the	O
cervix	O
,	O
3	O
adenocarcinomas	O
of	O
the	O
cervix	O
,	O
2	O
adenocarcinomas	O
of	O
the	O
endometrium	O
and	O
1	O
adenoid	O
basal	O
cell	O
carcinoma	O
of	O
the	O
cervix	O
.	O

Interestingly	O
,	O
these	O
"	O
activation	O
-	O
defective	O
"	O
mutants	O
segregated	O
into	O
two	O
classes	O
:	O
1	O
)	O
those	O
that	O
were	O
unable	O
to	O
form	O
dimers	O
but	O
that	O
could	O
still	O
form	O
higher	O
order	O
oligomers	O
and	O
transform	O
cells	O
,	O
and	O
2	O
)	O
those	O
that	O
were	O
defective	O
for	O
PDGF	B-GENE
-	I-GENE
R	I-GENE
binding	O
and	O
were	O
transformation	O
-	O
incompetent	O
.	O

Thus	O
in	O
this	O
study	O
we	O
used	O
in	O
vitro	O
methods	O
to	O
directly	O
evaluate	O
whether	O
isolated	O
human	O
saphenous	O
vein	O
segments	O
respond	O
to	O
vasoconstrictor	O
agents	O
at	O
arterial	O
pressure	O
levels	O
.	O

Genomic	O
Southern	O
blot	O
analysis	O
suggests	O
that	O
the	O
human	O
haploid	O
genome	O
contains	O
a	O
single	O
Gs	B-GENE
alpha	I-GENE
gene	I-GENE
.	O

Four	O
cDNAs	O
(	O
Kox4	B-GENE
,	O
Kox7	B-GENE
,	O
Kox12	B-GENE
,	O
and	O
Kox15	B-GENE
)	O
were	O
identified	O
that	O
match	O
one	O
or	O
more	O
genomic	O
clones	O
;	O
these	O
matches	O
were	O
confirmed	O
by	O
nucleotide	O
sequence	O
analysis	O
.	O

The	O
facilitation	O
started	O
preceding	O
the	O
onset	O
of	O
electromyographic	O
activity	O
of	O
the	O
masseter	O
muscle	O
.	O

Reactivation	O
of	O
hepatitis	O
B	O
virus	O
replication	O
is	O
a	O
rare	O
event	O
during	O
the	O
natural	O
history	O
of	O
chronic	O
hepatitis	O
B	O
.	O

SETTING	O
-	O
-	O
Hospital	O
laboratories	O
in	O
the	O
United	O
States	O
submitting	O
pneumococcal	O
isolates	O
to	O
the	O
CDC	O
between	O
October	O
1	O
,	O
1991	O
,	O
and	O
September	O
30	O
,	O
1992	O
.	O

To	O
determine	O
whether	O
transcription	O
of	O
orfX	O
and	O
vfr	B-GENE
are	O
controlled	O
by	O
the	O
same	O
mechanisms	O
that	O
control	O
transcription	O
of	O
the	O
region	O
of	O
the	O
divergent	O
ORF	O
(	O
dorf	O
)	O
and	O
of	O
crp	B-GENE
,	O
we	O
compared	O
the	O
vfr	B-GENE
-	O
orfX	O
and	O
crp	B-GENE
-	O
dorf	O
intergenic	O
regions	O
.	O

Cotransfection	O
with	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
and	O
GATA	B-GENE
-	I-GENE
1	I-GENE
expression	O
vectors	O
produced	O
a	O
5	O
-	O
fold	O
increase	O
compared	O
with	O
cotransfection	O
with	O
the	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
or	O
GATA	B-GENE
-	I-GENE
1	I-GENE
expression	O
vectors	O
individually	O
.	O

One	O
of	O
these	O
clones	O
encodes	O
Xenopus	B-GENE
N	I-GENE
-	I-GENE
ras	I-GENE
.	O

Eighteen	O
patients	O
with	O
advanced	O
epidermoid	O
carcinoma	O
of	O
the	O
head	O
and	O
neck	O
were	O
entered	O
into	O
a	O
phase	O
II	O
trial	O
of	O
N	O
-	O
Methylformamide	O
(	O
NMF	O
)	O
,	O
800	O
mg	O
/	O
M2	O
IV	O
daily	O
for	O
5	O
days	O
every	O
4	O
weeks	O
.	O

Total	O
body	O
water	O
and	O
distribution	O
space	O
of	O
Na24	O
in	O
women	O
with	O
various	O
body	O
weight	O

Transient	O
cotransfection	O
analyses	O
indicate	O
that	O
the	O
cooperative	O
association	O
of	O
NF	B-GENE
-	I-GENE
IL	I-GENE
-	I-GENE
6	I-GENE
and	O
RelA	B-GENE
with	O
the	O
IL	B-GENE
-	I-GENE
8	I-GENE
promoter	I-GENE
results	O
in	O
synergistic	O
transcriptional	O
activation	O
.	O

Sera	O
from	O
33	O
newborn	O
infants	O
with	O
gestational	O
ages	O
ranging	O
from	O
27	O
to	O
41	O
weeks	O
were	O
tested	O
by	O
radioimmunoassay	O
for	O
IgG	B-GENE
antibodies	O
to	O
surface	O
antigens	O
of	O
group	O
B	O
streptococci	O
(	O
GBS	O
)	O
types	O
Ia	O
,	O
Ib	O
,	O
II	O
and	O
III	O
.	O

On	O
average	O
,	O
rCMRglc	O
values	O
were	O
23	O
%	O
below	O
control	O
values	O
for	O
all	O
regions	O
studied	O
,	O
with	O
the	O
greatest	O
differences	O
in	O
posterior	O
brain	O
regions	O
(	O
visual	O
association	O
cortex	O
,	O
primary	O
visual	O
cortex	O
,	O
and	O
parietal	O
cortex	O
)	O
and	O
thalamus	O
.	O

The	O
NF1	B-GENE
family	I-GENE
members	O
and	O
HNF4	B-GENE
interacted	O
with	O
overlapping	O
sequences	O
of	O
the	O
L	O
-	O
II	O
element	O
,	O
wherein	O
the	O
5	O
'	O
half	O
-	O
site	O
was	O
more	O
critical	O
for	O
NF1	B-GENE
binding	O
,	O
and	O
the	O
3	O
'	O
site	O
was	O
more	O
important	O
for	O
HNF4	B-GENE
binding	O
.	O

The	O
shear	O
bond	O
strength	O
recorded	O
for	O
the	O
Novabond	O
system	O
was	O
significantly	O
lower	O
(	O
17	O
MPa	O
)	O
.	O

The	O
IR4	O
ORF	O
exhibits	O
significant	O
homology	O
to	O
the	O
immediate	B-GENE
-	I-GENE
early	I-GENE
gene	I-GENE
US1	B-GENE
(	O
ICP22	B-GENE
)	O
of	O
herpes	O
simplex	O
virus	O
type	O
1	O
and	O
to	O
the	O
ICP22	B-GENE
homologs	O
of	O
varicella	O
-	O
zoster	O
virus	O
(	O
ORF63	B-GENE
)	O
,	O
pseudorabies	O
virus	O
(	O
RSp40	B-GENE
)	O
,	O
and	O
equine	O
herpesvirus	O
4	O
(	O
ORF4	O
)	O
.	O

Psoriasis	O
on	O
tumor	O
.	O

VP4	B-GENE
differentially	O
regulates	O
TRAF2	B-GENE
signaling	O
,	O
disengaging	O
JNK	B-GENE
activation	O
while	O
directing	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
to	O
effect	O
rotavirus	O
-	O
specific	O
cellular	O
responses	O
.	O

From	O
the	O
autopsy	O
findings	O
,	O
in	O
5	O
out	O
of	O
the	O
remaining	O
23	O
expired	O
patients	O
,	O
Legionella	O
pneumonia	O
seemed	O
to	O
be	O
successfully	O
treated	O
,	O
but	O
other	O
disease	O
or	O
other	O
bacterial	O
pneumonia	O
put	O
an	O
end	O
to	O
the	O
patients	O
.	O

We	O
found	O
a	O
prevalence	O
of	O
eating	O
disorders	O
of	O
5	O
.	O
9	O
%	O
(	O
lifetime	O
prevalence	O
of	O
10	O
%	O
)	O
,	O
irrespective	O
of	O
gender	O
and	O
type	O
of	O
diabetes	O
;	O
4	O
.	O
1	O
%	O
of	O
the	O
whole	O
sample	O
reported	O
intentional	O
insulin	B-GENE
undertreatment	O
or	O
omission	O
.	O

NER	O
was	O
also	O
measured	O
by	O
a	O
plasmid	O
host	O
cell	O
re	O
-	O
activation	O
assay	O
using	O
a	O
vector	O
containing	O
a	O
luciferase	B-GENE
reporter	I-GENE
gene	I-GENE
.	O

Also	O
,	O
like	O
TUB	B-GENE
,	O
it	O
has	O
a	O
wider	O
pattern	O
of	O
tissue	O
expression	O
than	O
either	O
TULP1	B-GENE
or	O
TULP2	B-GENE
.	O

Accuracy	O
and	O
predictive	O
value	O
of	O
ultrasound	O
in	O
acute	O
rejection	O
.	O

Moist	O
healing	O
versus	O
wet	O
-	O
to	O
-	O
dry	O
.	O

Flicker	O
thresholds	O
were	O
measured	O
from	O
1	O
to	O
40	O
Hz	O
with	O
a	O
vertical	O
-	O
line	O
target	O
used	O
for	O
the	O
asynchrony	O
thresholds	O
.	O

Despite	O
the	O
same	O
decreases	O
or	O
increases	O
in	O
MAP	O
,	O
RSNA	O
was	O
attenuated	O
after	O
15	O
and	O
30	O
min	O
of	O
propofol	O
infusion	O
in	O
both	O
groups	O
compared	O
with	O
control	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Ganglia	O
are	O
cysts	O
which	O
frequently	O
occur	O
in	O
the	O
proximity	O
of	O
joints	O
.	O

Fractional	O
Ca	O
retention	O
was	O
measured	O
from	O
the	O
72	O
-	O
h	O
postdose	O
WBR	O
divided	O
by	O
WBR	O
at	O
time	O
0	O
.	O

Activity	O
was	O
reconstituted	O
,	O
however	O
,	O
by	O
combining	O
fractions	O
that	O
were	O
enriched	O
in	O
the	O
two	O
components	O
.	O

Acute	O
morphine	O
treatment	O
did	O
not	O
increase	O
the	O
locomotor	O
activity	O
of	O
mice	O
withdrawn	O
for	O
1	O
day	O
,	O
after	O
withdrawal	O
for	O
3	O
days	O
the	O
increase	O
was	O
similar	O
to	O
that	O
in	O
controls	O
,	O
and	O
after	O
5	O
days	O
the	O
increase	O
was	O
clearly	O
larger	O
than	O
in	O
controls	O
.	O

A	O
significant	O
and	O
specific	O
reduction	O
in	O
binaural	O
peak	O
amplitude	O
and	O
area	O
of	O
the	O
echo	O
-	O
evoked	O
middle	O
-	O
latency	O
component	O
Pa	O
was	O
observed	O
.	O

Non	O
-	O
dialyzable	O
transfer	B-GENE
factor	I-GENE

Gene	B-GENE
1	I-GENE
of	I-GENE
the	I-GENE
murine	I-GENE
coronavirus	I-GENE
,	I-GENE
MHV	I-GENE
-	I-GENE
A59	I-GENE
,	O
encodes	O
approximately	O
800	O
kDa	O
of	O
protein	O
products	O
within	O
two	O
overlapping	O
open	O
reading	O
frames	O
(	O
ORFs	O
1a	O
and	O
1b	O
)	O
.	O

Stress	O
thallium	O
-	O
201	O
myocardial	O
imaging	O
was	O
used	O
in	O
two	O
angina	O
-	O
free	O
patients	O
with	O
severe	O
congestive	O
heart	O
failure	O
to	O
identify	O
clinically	O
silent	O
areas	O
of	O
ischemic	O
myocardium	O
and	O
to	O
distinguish	O
between	O
scar	O
and	O
reversibly	O
ischemic	O
myocardium	O
as	O
a	O
cause	O
for	O
akinesia	O
of	O
left	O
ventricular	O
wall	O
segments	O
.	O

To	O
understand	O
this	O
dramatic	O
effect	O
,	O
we	O
examined	O
the	O
localization	O
of	O
SR	B-GENE
proteins	I-GENE
and	O
found	O
that	O
SC35	B-GENE
was	O
shifted	O
to	O
the	O
cytoplasm	O
in	O
sky1Delta	B-GENE
yeast	O
,	O
although	O
this	O
phenomenon	O
was	O
not	O
obvious	O
with	O
ASF	B-GENE
/	O
SF2	B-GENE
,	O
indicating	O
that	O
nuclear	O
import	O
of	O
SR	B-GENE
proteins	I-GENE
may	O
be	O
differentially	O
regulated	O
by	O
phosphorylation	O
.	O

GH	B-GENE
stimulated	O
the	O
activity	O
of	O
promoter	O
fragments	O
with	O
5	O
'	O
-	O
ends	O
between	O
nucleotide	O
(	O
nt	O
)	O
-	O
2001	O
and	O
nt	O
-	O
653	O
by	O
1	O
.	O
9	O
-	O
to	O
2	O
.	O
7	O
-	O
fold	O
.	O

The	O
6	O
.	O
5	O
-	O
kb	O
genomic	O
fragment	O
contains	O
the	O
complete	O
coding	O
region	O
of	O
MyoD	B-GENE
,	O
distributed	O
over	O
three	O
exons	O
,	O
plus	O
2	O
.	O
3	O
kb	O
of	O
5	O
'	O
-	O
noncoding	O
sequence	O
and	O
1	O
.	O
4	O
kb	O
of	O
3	O
'	O
-	O
noncoding	O
sequence	O
.	O

These	O
observations	O
demonstrate	O
that	O
KSR	B-GENE
is	O
capable	O
of	O
uncoupling	O
the	O
MAP	B-GENE
kinase	I-GENE
activation	O
from	O
its	O
target	O
phosphorylation	O
,	O
and	O
thus	O
provide	O
a	O
novel	O
mechanism	O
for	O
modulating	O
the	O
Ras	B-GENE
-	O
MAP	B-GENE
kinase	I-GENE
signaling	O
pathway	O
.	O

Since	O
1985	O
the	O
combination	O
of	O
chlorambucil	O
(	O
10	O
mg	O
daily	O
,	O
initially	O
for	O
six	O
weeks	O
,	O
then	O
alternating	O
fortnights	O
for	O
12	O
weeks	O
)	O
and	O
interferon	B-GENE
-	I-GENE
alpha	I-GENE
2b	I-GENE
(	O
Schering	O
-	O
Plough	O
;	O
2	O
x	O
10	O
(	O
6	O
)	O
U	O
/	O
m2	O
three	O
times	O
weekly	O
by	O
subcutaneous	O
injection	O
for	O
18	O
weeks	O
)	O
has	O
been	O
compared	O
in	O
a	O
randomised	O
trial	O
with	O
chlorambucil	O
alone	O
in	O
previously	O
untreated	O
patients	O
with	O
stage	O
III	O
or	O
IV	O
follicular	O
lymphoma	O
.	O

Correlation	O
of	O
alpha	O
activity	O
between	O
the	O
frontal	O
and	O
occipital	O
cortex	O
.	O

Nonetheless	O
,	O
the	O
majority	O
were	O
located	O
within	O
three	O
short	O
sequences	O
at	O
the	O
N	O
terminus	O
,	O
middle	O
,	O
and	O
C	O
terminus	O
that	O
are	O
phylogenetically	O
conserved	O
among	O
all	O
known	O
eubacterial	O
and	O
chloroplast	O
versions	O
of	O
this	O
protein	O
.	O

All	O
other	O
cysts	O
showed	O
a	O
unilocular	O
,	O
purely	O
cystic	O
pattern	O
,	O
with	O
homogeneous	O
fluids	O
,	O
although	O
the	O
T2	O
relaxation	O
times	O
of	O
four	O
lesions	O
overlapped	O
those	O
of	O
odontogenic	O
keratocysts	O
.	O

Processing	O
MES	O
data	O
requires	O
large	O
bit	O
manipulations	O
and	O
heavy	O
memory	O
storage	O
requirements	O
.	O

Recombinant	B-GENE
caspases	I-GENE
are	O
typically	O
produced	O
in	O
Escherichia	O
coli	O
expression	O
systems	O
with	O
the	O
attendant	O
problems	O
of	O
solubilization	O
,	O
re	O
-	O
folding	O
and	O
activation	O
of	O
the	O
protease	O
.	O

Nuclear	O
runoff	O
assays	O
show	O
that	O
complementation	O
by	O
HPV16	B-GENE
E7	I-GENE
restores	O
the	O
ability	O
of	O
the	O
E1A	B-GENE
mutants	I-GENE
to	O
stimulate	O
early	B-GENE
gene	I-GENE
expression	O
at	O
the	O
level	O
of	O
transcription	O
.	O

The	O
effect	O
of	O
deferoxamine	O
B	O
on	O
the	O
blood	O
sugar	O
behavior	O
in	O
intravenous	O
glucose	O
loading	O
in	O
healthy	O
persons	O

Constructs	O
containing	O
fragments	O
of	O
the	O
upstream	O
region	O
of	O
the	O
cytotactin	B-GENE
gene	I-GENE
fused	O
to	O
a	O
promoterless	O
gene	O
for	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
were	O
transiently	O
transfected	O
into	O
chicken	O
embryo	O
fibroblasts	O
to	O
define	O
functional	O
promoter	O
sequences	O
.	O

Like	O
the	O
human	B-GENE
erythrocyte	I-GENE
P4	I-GENE
.	I-GENE
2	I-GENE
,	O
mouse	B-GENE
erythrocyte	I-GENE
P4	I-GENE
.	I-GENE
2	I-GENE
contains	O
regions	O
strikingly	O
homologous	O
with	O
the	O
transglutaminase	O
(	O
TGase	O
)	O
proteins	O
although	O
it	O
too	O
most	O
likely	O
lacks	O
TGase	O
crosslinking	O
activity	O
.	O

The	O
rate	O
for	O
Arm	O
III	O
(	O
CAF	O
therapy	O
)	O
was	O
61	O
.	O
5	O
%	O
(	O
32	O
/	O
52	O
)	O
,	O
a	O
little	O
higher	O
than	O
that	O
for	O
the	O
other	O
two	O
.	O

The	O
CHL	B-GENE
1	I-GENE
(	O
CTF	B-GENE
1	I-GENE
)	O
gene	O
product	O
of	O
Saccharomyces	O
cerevisiae	O
is	O
important	O
for	O
chromosome	O
transmission	O
and	O
normal	O
cell	O
cycle	O
progression	O
in	O
G2	O
/	O
M	O
.	O

We	O
have	O
analyzed	O
the	O
function	O
of	O
these	O
putative	O
SL	O
structures	O
in	O
RNA	O
translation	O
by	O
constructing	O
chimeric	B-GENE
chloramphenicol	I-GENE
acetyltransferase	I-GENE
(	B-GENE
CAT	I-GENE
)	I-GENE
RNAs	I-GENE
,	O
flanked	O
either	O
by	O
both	O
5	O
'	O
-	O
and	O
3	O
'	O
-	O
terminal	O
sequence	O
domains	O
from	O
the	O
RV	O
genome	O
or	O
several	O
deletion	O
derivatives	O
of	O
the	O
same	O
sequences	O
.	O

Mutating	O
this	O
sequence	O
eliminated	O
complex	O
formation	O
and	O
markedly	O
reduced	O
basal	O
and	O
cAMP	O
-	O
dependent	O
promoter	O
activity	O
of	O
transfected	O
reporter	O
genes	O
.	O

The	O
average	O
cumulative	O
UVA	O
dose	O
was	O
65	O
J	O
/	O
cm2	O
;	O
40	O
patients	O
had	O
received	O
more	O
than	O
200	O
J	O
/	O
cm2	O
.	O

The	O
induction	O
of	O
the	O
composite	O
H	B-GENE
-	I-GENE
PK	I-GENE
/	O
Tag	B-GENE
and	O
SV	B-GENE
-	I-GENE
PK	I-GENE
/	O
Tag	B-GENE
transgenes	O
by	O
a	O
carbohydrate	O
-	O
rich	O
diet	O
in	O
the	O
liver	O
was	O
similar	O
to	O
that	O
of	O
the	O
endogenous	B-GENE
L	I-GENE
-	I-GENE
PK	I-GENE
gene	I-GENE
.	O

For	O
routine	O
medical	O
applications	O
,	O
no	O
sophisticated	O
adjustment	O
of	O
the	O
CHESS	O
pulse	O
is	O
needed	O
,	O
as	O
reported	O
in	O
previous	O
methods	O
.	O

Here	O
we	O
report	O
the	O
cloning	O
of	O
the	O
hemF	B-GENE
gene	I-GENE
,	O
encoding	O
the	O
aerobic	O
coproporphyrinogen	B-GENE
III	I-GENE
oxidase	I-GENE
from	I-GENE
Escherichia	I-GENE
coli	I-GENE
,	O
by	O
functional	O
complementation	O
of	O
a	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
HEM13	I-GENE
mutant	I-GENE
.	O

Efficacy	O
of	O
probiotic	O
feed	O
additives	O
:	O
guidelines	O
for	O
the	O
evaluation	O
of	O
the	O
efficiency	O
of	O
microorganisms	O
in	O
dogs	O
,	O
cats	O
,	O
and	O
horses	O
]	O
Probiotic	O
microorganisms	O
are	O
frequently	O
in	O
use	O
as	O
feed	O
additives	O
for	O
farm	O
and	O
pet	O
animals	O
.	O

We	O
analyzed	O
the	O
contribution	O
of	O
the	O
three	O
different	O
types	O
of	O
UV	O
-	O
inducible	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinases	I-GENE
(	O
ERK	B-GENE
,	O
JNK	B-GENE
/	O
SAPK	B-GENE
,	O
and	O
p38	B-GENE
)	O
to	O
the	O
activation	O
of	O
the	O
murine	O
uPA	B-GENE
promoter	O
by	O
UV	O
.	O

The	O
largest	O
age	O
adjusted	O
differences	O
between	O
men	O
with	O
low	O
and	O
normal	O
mood	O
were	O
for	O
the	O
AH4	O
(	O
3	O
points	O
,	O
t	O
=	O
5	O
.	O
6	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
and	O
the	O
CAMCOG	O
(	O
2	O
points	O
,	O
t	O
=	O
5	O
.	O
8	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
.	O

Nucleotide	O
sequencing	O
revealed	O
a	O
2076	O
-	O
base	O
pair	O
open	O
reading	O
frame	O
encoding	O
a	O
692	O
-	O
amino	O
acid	O
protein	O
.	O

HrpE	B-GENE
is	O
similar	O
to	O
YscL	B-GENE
of	O
Yersinia	O
spp	O
.	O

Mean	O
total	O
homocysteine	O
(	O
tHcy	O
)	O
was	O
21	O
.	O
1	O
+	O
/	O
-	O
9	O
.	O
5	O
micromol	O
/	O
L	O
and	O
median	O
concentration	O
was	O
19	O
micromol	O
/	O
L	O
.	O

To	O
facilitate	O
the	O
characterization	O
of	O
NF	B-GENE
-	I-GENE
E2	I-GENE
functions	O
in	O
human	O
cells	O
,	O
we	O
isolated	O
cDNAs	O
encoding	O
two	O
members	O
of	O
the	O
small	B-GENE
Maf	I-GENE
family	I-GENE
,	O
MafK	B-GENE
and	O
MafG	B-GENE
.	O

The	O
immediate	O
5	O
'	O
-	O
flanking	O
region	O
was	O
GC	O
-	O
rich	O
with	O
3	O
SP	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
like	I-GENE
and	O
2	O
AP	B-GENE
-	I-GENE
2	I-GENE
sites	I-GENE
identified	O
in	O
close	O
proximity	O
to	O
the	O
transcription	O
start	O
site	O
.	O

The	O
ZAG1	B-GENE
protein	I-GENE
from	O
in	O
vitro	O
translations	O
binds	O
to	O
a	O
consensus	O
target	O
site	O
that	O
is	O
recognized	O
by	O
the	O
AG	B-GENE
protein	I-GENE
.	O

Bone	O
scintigraphy	O
is	O
an	O
excellent	O
screening	O
test	O
for	O
bone	O
lesions	O
and	O
Ga	O
-	O
67	O
scintigraphy	O
is	O
a	O
useful	O
tool	O
for	O
detecting	O
inflammatory	O
lesions	O
.	O

In	O
this	O
first	O
-	O
person	O
account	O
,	O
the	O
author	O
chronicles	O
her	O
experience	O
of	O
being	O
mentally	O
ill	O
and	O
homeless	O
in	O
New	O
York	O
and	O
New	O
Jersey	O
in	O
the	O
early	O
1980s	O
.	O

Pharmacokinetics	O
of	O
skin	O
penetration	O
.	O

Dmyd	B-GENE
clone	O
encodes	O
a	O
polypeptide	O
of	O
332	O
amino	O
acids	O
with	O
82	O
%	O
identity	O
to	O
MyoD	B-GENE
in	O
the	O
41	O
amino	O
acids	O
of	O
the	O
putative	O
helix	O
-	O
loop	O
-	O
helix	O
region	O
and	O
100	O
%	O
identity	O
in	O
the	O
13	O
amino	O
acids	O
of	O
the	O
basic	O
domain	O
proposed	O
to	O
contain	O
the	O
essential	O
recognition	O
code	O
for	O
muscle	O
-	O
specific	O
gene	O
activation	O
.	O

Enterotoxin	O
production	O
by	O
staphylococci	O
isolated	O
from	O
foods	O
in	O
France	O
.	O

Binding	O
sites	O
were	O
mapped	O
for	O
each	O
factor	O
.	O

The	O
majority	O
of	O
these	O
cells	O
were	O
also	O
OKT4	B-GENE
positive	O
(	O
helper	O
/	O
inducer	O
T	O
lymphocytes	O
)	O
,	O
while	O
the	O
minority	O
were	O
OKT8	B-GENE
positive	O
(	O
suppressor	O
/	O
cytotoxic	O
T	O
lymphocytes	O
)	O
.	O

Toxicological	O
effects	O
of	O
dietary	O
Maillard	O
reaction	O
products	O
in	O
the	O
rat	O
.	O

All	O
relapses	O
occurred	O
within	O
the	O
first	O
year	O
and	O
were	O
confined	O
to	O
patients	O
with	O
PS	O
II	O
disease	O
and	O
four	O
or	O
more	O
sites	O
of	O
involvement	O
.	O

These	O
patients	O
developed	O
severe	O
diabetic	O
symptoms	O
including	O
glucose	O
intolerance	O
,	O
weight	O
loss	O
,	O
impaired	O
energy	O
utilization	O
,	O
and	O
nerve	O
and	O
brain	O
disorders	O
that	O
were	O
refractory	O
to	O
insulin	B-GENE
.	O

Buserelin	O
offers	O
an	O
effective	O
alternative	O
medical	O
treatment	O
of	O
carcinoma	O
of	O
the	O
prostate	O
and	O
,	O
apart	O
from	O
impotence	O
,	O
does	O
not	O
have	O
the	O
side	O
effects	O
of	O
oestrogens	O
.	O

BCV	B-GENE
mRNAs	I-GENE
5	I-GENE
and	I-GENE
5	I-GENE
-	I-GENE
1	I-GENE
appear	O
to	O
be	O
used	O
for	O
the	O
synthesis	O
of	O
the	O
12	O
.	O
7	O
-	O
and	O
9	O
.	O
5	O
-	O
kDa	O
proteins	O
,	O
respectively	O
,	O
which	O
demonstrates	O
a	O
pattern	O
of	O
expression	O
strikingly	O
different	O
from	O
that	O
utilized	O
by	O
MHV	O
.	O

Consistent	O
with	O
this	O
observation	O
,	O
introduction	O
of	O
Smad	B-GENE
sites	I-GENE
into	O
a	O
TGFbeta	B-GENE
-	O
insensitive	O
LEF1	B-GENE
/	O
TCF	B-GENE
target	O
gene	O
confers	O
cooperative	O
TGFbeta	B-GENE
and	O
Wnt	B-GENE
responsiveness	O
to	O
the	O
promoter	O
.	O

Recombinant	O
vaccinia	O
viruses	O
that	O
express	O
the	O
bacteriophage	B-GENE
T3	I-GENE
RNA	I-GENE
polymerase	I-GENE
(	O
VV	B-GENE
-	I-GENE
T3pol	I-GENE
)	O
or	O
the	O
Escherichia	B-GENE
coli	I-GENE
lac	I-GENE
repressor	I-GENE
(	O
VV	B-GENE
-	I-GENE
lacI	I-GENE
)	O
under	O
control	O
of	O
the	O
early	B-GENE
-	I-GENE
late	I-GENE
vaccinia	I-GENE
promoter	I-GENE
P7	I-GENE
.	I-GENE
5	I-GENE
were	O
constructed	O
.	O

Tritiated	O
1	O
,	O
24	O
,	O
25	O
-	O
trihydroxyvitamin	O
D3	O
was	O
synthesized	O
biologically	O
and	O
used	O
as	O
tracer	O
to	O
monitor	O
the	O
recovery	O
of	O
endogenous	O
metabolite	O
during	O
isolation	O
from	O
serum	O
.	O

In	O
this	O
report	O
,	O
we	O
have	O
examined	O
whether	O
PTP1B	B-GENE
effects	O
transformation	O
induced	O
by	O
p210	B-GENE
bcr	B-GENE
-	O
abl	B-GENE
.	O

This	O
study	O
examines	O
LEIBNIZ	O
'	O
idea	O
of	O
Veterinary	O
medicine	O
in	O
a	O
biographical	O
context	O
.	O

Internalization	O
of	O
prolactin	B-GENE
receptor	I-GENE
and	O
prolactin	B-GENE
in	O
transfected	O
cells	O
does	O
not	O
involve	O
nuclear	O
translocation	O
.	O

Using	O
the	O
conflict	O
drinking	O
test	O
as	O
a	O
model	O
,	O
we	O
studied	O
in	O
rats	O
the	O
effect	O
of	O
the	O
nonselective	O
beta	B-GENE
-	I-GENE
adrenoceptor	I-GENE
blockers	O
pindolol	O
and	O
cyanopindolol	O
which	O
bind	O
to	O
5	B-GENE
-	I-GENE
HT1A	I-GENE
and	I-GENE
5	I-GENE
-	I-GENE
HT1B	I-GENE
receptors	I-GENE
,	O
and	O
of	O
the	O
selective	O
beta	B-GENE
1	I-GENE
-	I-GENE
and	I-GENE
beta	I-GENE
2	I-GENE
-	I-GENE
adrenoceptor	I-GENE
antagonists	O
betaxolol	O
and	O
ICI	O
118	O
,	O
551	O
,	O
respectively	O
,	O
which	O
have	O
a	O
negligible	O
affinity	O
for	O
5	B-GENE
-	I-GENE
HT	I-GENE
receptors	I-GENE
.	O

Rewarding	O
properties	O
of	O
methylphenidate	O
:	O
sensitization	O
by	O
prior	O
exposure	O
to	O
the	O
drug	O
and	O
effects	O
of	O
dopamine	B-GENE
D1	I-GENE
-	I-GENE
and	I-GENE
D2	I-GENE
-	I-GENE
receptor	I-GENE
antagonists	O
.	O

Recently	O
,	O
we	O
have	O
demonstrated	O
that	O
mouse	O
microglial	O
cells	O
,	O
the	O
brain	O
macrophages	O
,	O
express	O
both	O
IL	B-GENE
-	I-GENE
15	I-GENE
and	O
IL	B-GENE
-	I-GENE
15	I-GENE
/	I-GENE
IL	I-GENE
-	I-GENE
2	I-GENE
receptors	I-GENE
.	O

METHODS	O
:	O
Children	O
with	O
attention	O
-	O
deficit	O
/	O
hyperactivity	O
disorder	O
(	O
ADHD	O
;	O
n	O
=	O
282	O
)	O
,	O
all	O
subtypes	O
,	O
ages	O
6	O
to	O
12	O
years	O
,	O
were	O
randomized	O
to	O
placebo	O
(	O
n	O
=	O
90	O
)	O
,	O
immediate	O
-	O
release	O
methylphenidate	O
(	O
IR	O
MPH	O
)	O
3	O
times	O
a	O
day	O
(	O
tid	O
;	O
dosed	O
every	O
4	O
hours	O
;	O
n	O
=	O
97	O
)	O
,	O
or	O
OROS	O
MPH	O
once	O
a	O
day	O
(	O
qd	O
;	O
n	O
=	O
95	O
)	O
in	O
a	O
double	O
-	O
blind	O
,	O
28	O
-	O
day	O
trial	O
.	O

Cell	O
sloughing	O
with	O
proparacaine	O
.	O

The	O
possibility	O
to	O
use	O
this	O
method	O
for	O
common	O
diagnostic	O
problems	O
is	O
indicated	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
of	O
this	O
open	O
reading	O
frame	O
is	O
significantly	O
homologous	O
to	O
the	O
HSV	B-GENE
1	I-GENE
UL49	I-GENE
.	I-GENE
5	I-GENE
gene	I-GENE
product	I-GENE
,	O
and	O
as	O
with	O
UL49	B-GENE
.	I-GENE
5	I-GENE
,	O
it	O
contains	O
a	O
potential	O
signal	O
sequence	O
and	O
transmembrane	O
domain	O
characteristic	O
of	O
membrane	O
-	O
associated	O
proteins	O
.	O

Female	O
Wistar	O
rats	O
receiving	O
alcohol	O
(	O
5	O
%	O
)	O
in	O
drinking	O
water	O
during	O
lactation	O
(	O
N	O
=	O
7	O
)	O
were	O
compared	O
to	O
normal	O
controls	O
fed	O
ad	O
libitum	O
(	O
N	O
=	O
6	O
)	O
.	O

Suspected	O
pelvic	O
endometriosis	O
was	O
prospectively	O
evaluated	O
in	O
31	O
women	O
with	O
T1	O
-	O
and	O
T2	O
-	O
weighted	O
conventional	O
spin	O
-	O
echo	O
(	O
CSE	O
)	O
magnetic	O
resonance	O
imaging	O
alone	O
and	O
in	O
combination	O
with	O
T1	O
-	O
weighted	O
fat	O
-	O
suppressed	O
(	O
T1FS	O
)	O
and	O
gadolinium	O
-	O
enhanced	O
T1FS	O
(	O
Gd	O
-	O
T1FS	O
)	O
spin	O
-	O
echo	O
techniques	O
.	O

Eph	B-GENE
receptors	I-GENE
and	O
their	O
membrane	O
-	O
associated	O
ephrin	B-GENE
ligands	I-GENE
regulate	O
cell	O
-	O
cell	O
interactions	O
during	O
development	O
.	O

A	O
group	O
of	O
factors	O
known	O
as	O
activating	B-GENE
transcription	I-GENE
factors	I-GENE
(	O
ATF	B-GENE
)	O
have	O
been	O
found	O
to	O
bind	O
to	O
the	O
latter	O
and	O
related	O
sequences	O
found	O
upstream	O
of	O
early	O
adenovirus	O
promoters	O
induced	O
by	O
E1A	B-GENE
,	O
and	O
these	O
factors	O
are	O
highly	O
homologous	O
to	O
the	O
CREB	B-GENE
protein	I-GENE
.	O

Vk8	B-GENE
/	O
Jk2	B-GENE
and	O
Vk1	B-GENE
/	O
Jk5	B-GENE
rearrangements	O
encoded	O
the	O
respective	O
L	B-GENE
chain	I-GENE
V	I-GENE
-	I-GENE
regions	I-GENE
.	O

An	O
analysis	O
of	O
the	O
c	B-GENE
-	I-GENE
kit	I-GENE
5	I-GENE
'	I-GENE
flanking	I-GENE
region	I-GENE
using	O
the	O
bacterial	B-GENE
chloramphenicol	I-GENE
acetyltransferase	I-GENE
gene	I-GENE
(	O
CAT	B-GENE
assay	O
)	O
in	O
human	O
erythroleukemia	O
HEL	O
cells	O
,	O
which	O
express	O
the	O
endogenous	O
c	B-GENE
-	I-GENE
kit	I-GENE
mRNA	I-GENE
at	O
high	O
levels	O
,	O
showed	O
that	O
a	O
region	O
from	O
-	O
180	O
to	O
-	O
22	O
is	O
important	O
for	O
the	O
expression	O
of	O
the	O
c	B-GENE
-	I-GENE
kit	I-GENE
gene	I-GENE
.	O

The	O
quantitative	O
analysis	O
of	O
1	O
-	O
alpha	O
-	O
acetylmethadol	O
and	O
its	O
principal	O
metabolites	O
in	O
biological	O
specimens	O
by	O
gas	O
chromatography	O
-	O
chemical	O
ionization	O
-	O
multiple	O
ion	O
monitoring	O
mass	O
spectrometry	O
.	O

Following	O
immunization	O
of	O
transgenic	O
mice	O
,	O
hybrid	O
molecules	O
were	O
isolated	O
from	O
B	O
cell	O
DNA	O
which	O
contained	O
the	O
transgene	O
recombined	O
with	O
the	O
endogenous	B-GENE
IgH	I-GENE
locus	I-GENE
.	O

(	O
LH	B-GENE
P	O
<	O
0	O
.	O
05	O
,	O
LH	B-GENE
/	O
FSH	B-GENE
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Here	O
we	O
show	O
that	O
expression	O
of	O
KRAB	B-GENE
domain	I-GENE
suppresses	O
in	O
vivo	O
the	O
activating	O
function	O
of	O
various	O
defined	O
activating	B-GENE
transcription	I-GENE
factors	I-GENE
,	O
and	O
we	O
demonstrate	O
that	O
the	O
KRAB	B-GENE
domain	I-GENE
specifically	O
silences	O
the	O
activity	O
of	O
promoters	O
whose	O
initiation	O
is	O
dependent	O
on	O
the	O
presence	O
of	O
a	O
TATA	O
box	O
.	O

In	O
the	O
renal	O
cortex	O
,	O
spleen	O
,	O
distal	O
colon	O
,	O
ileum	O
,	O
gallbladder	O
,	O
and	O
stomach	O
body	O
,	O
regional	O
O2	O
delivery	O
was	O
significantly	O
decreased	O
with	O
hemodilution	O
to	O
20	O
%	O
in	O
both	O
groups	O
.	O

None	O
of	O
the	O
19	O
women	O
with	O
probable	O
RA	O
and	O
100	O
of	O
the	O
116	O
women	O
with	O
definite	O
RA	O
met	O
the	O
1987	O
criteria	O
.	O

In	O
response	O
to	O
the	O
need	O
for	O
better	O
quantitative	O
estimates	O
of	O
the	O
regional	O
distribution	O
of	O
the	O
active	O
bone	O
marrow	O
organ	O
in	O
infants	O
and	O
children	O
,	O
a	O
method	O
using	O
various	O
anatomical	O
data	O
has	O
been	O
developed	O
.	O

Thus	O
the	O
Hi	O
-	O
RARE	O
represents	O
a	O
new	O
type	O
of	O
RA	O
response	O
element	O
with	O
a	O
role	O
in	O
the	O
modulation	O
of	O
the	O
expression	O
of	O
MHC	B-GENE
class	I-GENE
1	I-GENE
family	O
genes	O
.	O

RESULTS	O
:	O
Considering	O
an	O
inulin	O
clearance	O
of	O
less	O
than	O
80	O
ml	O
/	O
min	O
/	O
1	O
.	O
73	O
m2	O
,	O
the	O
cut	O
-	O
off	O
value	O
for	O
serum	O
creatinine	O
was	O
11	O
.	O
5	O
mumol	O
/	O
liter	O
for	O
men	O
and	O
90	O
mumol	O
/	O
liter	O
for	O
women	O
.	O

Our	O
results	O
strongly	O
suggest	O
that	O
activation	O
of	O
the	O
beta	O
origin	O
by	O
a	O
distant	O
replication	O
enhancer	O
element	O
requires	O
a	O
small	O
target	O
sequence	O
essential	O
for	O
initiator	O
protein	O
-	O
mediated	O
DNA	O
looping	O
.	O

Three	O
experiments	O
using	O
20	O
microM	O
2	O
-	O
(	O
hydroxyamino	O
)	O
-	O
1	O
-	O
methyl	O
-	O
6	O
-	O
phenylimidazo	O
[	O
4	O
,	O
5	O
-	O
b	O
]	O
pyridine	O
(	O
N	O
-	O
OH	O
-	O
PhIP	O
)	O
were	O
performed	O
to	O
induce	O
mutations	O
in	O
the	O
dihydrofolate	B-GENE
reductase	I-GENE
(	O
DHFR	B-GENE
)	O
gene	O
of	O
a	O
hemizygous	O
Chinese	O
hamster	O
ovary	O
(	O
CHO	O
)	O
cell	O
line	O
(	O
UA21	O
)	O
.	O

The	O
UL3	B-GENE
ORF	I-GENE
of	O
204	O
amino	O
acids	O
shows	O
significant	O
homology	O
to	O
UL3	B-GENE
(	O
nuclear	O
phosphoprotein	O
)	O
of	O
HSV	O
-	O
1	O
(	O
62	O
%	O
)	O
and	O
PRV	O
(	O
53	O
%	O
)	O
.	O

Immunogenicity	O
tested	O
in	O
experiments	O
on	O
guinea	O
pigs	O
and	O
rabbits	O
was	O
not	O
reduced	O
and	O
corresponded	O
to	O
that	O
of	O
the	O
reference	O
STI	O
-	O
1	O
vaccine	O
.	O

In	O
addition	O
,	O
we	O
show	O
that	O
expression	O
of	O
antisense	O
mRNA	O
for	O
p130CAS	B-GENE
resulted	O
in	O
reversion	O
of	O
the	O
transformed	O
phenotype	O
of	O
all	O
these	O
cell	O
lines	O
.	O

One	O
hundred	O
cDNA	O
clones	O
were	O
sequenced	O
and	O
8	O
RTKs	B-GENE
were	O
identified	O
,	O
as	O
well	O
as	O
12	O
non	O
-	O
RTKs	B-GENE
and	O
2	O
serine	B-GENE
/	I-GENE
threonine	I-GENE
kinases	I-GENE
.	O

Supportive	O
therapy	O
with	O
xenogenous	O
peptides	O
in	O
patients	O
with	O
metastatic	O
breast	O
cancer	O
undergoing	O
aggressive	O
chemotherapy	O
(	O
modified	O
AC	O
-	O
protocol	O
)	O
:	O
a	O
prospective	O
,	O
randomized	O
double	O
-	O
blind	O
study	O

The	O
inactive	O
X	O
allele	O
,	O
however	O
,	O
is	O
hypermethylated	O
in	O
leukocytes	O
,	O
presumably	O
reflecting	O
early	O
X	O
inactivation	O
events	O
that	O
become	O
important	O
for	O
gene	O
dosage	O
in	O
expressing	O
lineages	O
.	O

Development	O
of	O
neural	O
control	O
of	O
alimentary	O
motor	O
function	O
in	O
the	O
vertebrates	O
.	O

Studies	O
on	O
nitrogen	O
-	O
containing	O
heterocyclic	O
compounds	O
.	O

Cell	O
rounding	O
was	O
abrogated	O
by	O
expression	O
of	O
either	O
kinase	O
-	O
dead	O
forms	O
of	O
US3	B-GENE
PK	I-GENE
or	O
a	O
mutant	O
protein	O
lacking	O
the	O
acidic	O
cluster	O
in	O
the	O
kinase	O
regulatory	O
domain	O
.	O

The	O
psychosocial	O
features	O
of	O
people	O
using	O
self	O
-	O
ignition	O
as	O
a	O
method	O
of	O
suicide	O
are	O
consistent	O
with	O
those	O
of	O
suicide	O
in	O
general	O
.	O

The	O
genes	O
expressed	O
during	O
the	O
embryonic	O
(	O
zeta	B-GENE
)	O
or	O
fetal	O
and	O
adult	O
stage	O
(	O
alpha	B-GENE
2	I-GENE
and	O
alpha	B-GENE
1	I-GENE
)	O
can	O
be	O
modified	O
by	O
point	O
mutations	O
which	O
affect	O
either	O
the	O
processing	O
-	O
translation	O
of	O
mRNA	O
or	O
make	O
the	O
polypeptide	O
chains	O
extremely	O
unstable	O
.	O

Acoustic	O
-	O
property	O
measurements	O
of	O
the	O
oxide	O
superconductor	O
BaPb1	O
-	O
xBixO3	O
by	O
the	O
sphere	O
-	O
resonance	O
method	O
.	O

The	O
fusion	O
of	O
AML1	B-GENE
to	O
MDS1	B-GENE
is	O
in	O
frame	O
,	O
and	O
adds	O
127	O
codons	O
to	O
the	O
interrupted	O
AML1	B-GENE
.	O

The	O
ends	O
of	O
the	O
barrel	O
are	O
capped	O
by	O
short	O
helices	O
.	O

Rabbit	B-GENE
KCC1	I-GENE
(	O
rbKCC1	B-GENE
)	O
and	O
rat	B-GENE
KCC1	I-GENE
(	O
rtKCC1	B-GENE
)	O
were	O
cloned	O
by	O
screening	O
rabbit	O
kidney	O
and	O
rat	O
brain	O
cDNA	O
libraries	O
using	O
homologous	O
cDNA	O
probes	O
.	O

Taken	O
together	O
,	O
these	O
findings	O
demonstrate	O
that	O
ZNF76	B-GENE
and	O
ZNF143	B-GENE
are	O
two	O
members	O
of	O
a	O
same	O
family	O
of	O
transactivator	O
proteins	O
.	O

This	O
model	O
system	O
exploits	O
the	O
polyomavirus	O
late	O
transcription	O
termination	O
and	O
polyadenylation	O
signals	O
,	O
which	O
are	O
sufficiently	O
weak	O
to	O
allow	O
the	O
production	O
of	O
many	O
multigenome	O
-	O
length	O
primary	O
transcripts	O
with	O
repeating	O
introns	O
,	O
exons	O
,	O
and	O
poly	O
(	O
A	O
)	O
sites	O
.	O

The	O
disorders	O
are	O
accompanied	O
by	O
consistent	O
,	O
but	O
similarly	O
reversible	O
,	O
electroencephalographic	O
changes	O
.	O

Electronic	O
structure	O
and	O
optical	O
properties	O
of	O
the	O
B12O2	O
crystal	O
.	O

A	O
model	O
for	O
oligomerization	O
-	O
dependent	O
subunit	O
folding	O
.	O

The	O
reporter	O
gene	O
with	O
two	O
copies	O
of	O
the	O
wild	O
-	O
type	O
Repeat	O
2	O
+	O
3	O
sequence	O
was	O
transcribed	O
actively	O
in	O
sterol	O
-	O
deprived	O
cells	O
and	O
was	O
repressed	O
by	O
more	O
than	O
80	O
%	O
when	O
sterols	O
were	O
present	O
.	O

Basic	B-GENE
helix	I-GENE
-	I-GENE
loop	I-GENE
-	I-GENE
helix	I-GENE
proteins	I-GENE
can	O
act	O
at	O
the	O
E	O
-	O
box	O
within	O
the	O
serum	O
response	O
element	O
of	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
promoter	I-GENE
to	O
influence	O
hormone	O
-	O
induced	O
promoter	O
activation	O
in	O
Sertoli	O
cells	O
.	O

Preventive	O
health	O
counseling	O
tailored	O
to	O
the	O
needs	O
of	O
this	O
group	O
may	O
be	O
most	O
beneficial	O
.	O

Western	O
blot	O
analyses	O
reveals	O
that	O
cJun	B-GENE
and	O
the	O
C	B-GENE
/	I-GENE
EBP	I-GENE
family	I-GENE
member	I-GENE
C	B-GENE
/	I-GENE
EBP	I-GENE
-	I-GENE
beta	I-GENE
are	O
physiologically	O
relevant	O
transcription	O
factors	O
whose	O
expression	O
corresponds	O
with	O
mda	B-GENE
-	I-GENE
7	I-GENE
mRNA	I-GENE
expression	O
.	O

Recent	O
developments	O
in	O
the	O
study	O
of	O
growth	O
factors	O
:	O
GRF	B-GENE
and	O
somatomedins	B-GENE
.	O

Phenotypic	O
screening	O
of	O
mutations	O
in	O
Pmr1	B-GENE
,	O
the	O
yeast	B-GENE
secretory	I-GENE
pathway	I-GENE
Ca2	I-GENE
+	I-GENE
/	I-GENE
Mn2	I-GENE
+	I-GENE
-	I-GENE
ATPase	I-GENE
,	O
reveals	O
residues	O
critical	O
for	O
ion	O
selectivity	O
and	O
transport	O
.	O

IV	O
.	O

Routine	O
and	O
default	O
retrieval	O
home	O
visits	O
were	O
given	O
to	O
ensure	O
maximal	O
drug	O
compliance	O
.	O

This	O
review	O
chronicles	O
the	O
characteristics	O
of	O
deliberate	O
and	O
accidental	O
mass	O
poisonings	O
that	O
occurred	O
in	O
World	O
Wars	O
I	O
and	O
II	O
,	O
in	O
Bhopal	O
,	O
and	O
in	O
other	O
historical	O
cases	O
up	O
to	O
and	O
including	O
modern	O
wars	O
.	O

Thus	O
,	O
an	O
unmodified	O
threonine	O
at	O
position	O
169	O
in	O
Cdc28	B-GENE
is	O
important	O
for	O
interaction	O
with	O
G1	B-GENE
cyclins	I-GENE
.	O

These	O
alterations	O
occurred	O
at	O
both	O
the	O
mRNA	O
and	O
protein	O
levels	O
but	O
did	O
not	O
significantly	O
affect	O
the	O
subcellular	O
distribution	O
of	O
any	O
of	O
the	O
four	O
isoforms	O
.	O

Periarteritis	O
nodosa	O
with	O
ruptures	O
of	O
the	O
renal	O
vessels	O
and	O
the	O
persistence	O
of	O
the	O
hepatitis	O
B	O
and	O
C	O
viruses	O
in	O
the	O
blood	O

SETTING	O
:	O
Participants	O
in	O
the	O
Physicians	O
'	O
Health	O
Study	O
,	O
a	O
randomized	O
trial	O
of	O
aspirin	O
and	O
beta	O
-	O
carotene	O
among	O
U	O
.	O
S	O
.	O
male	O
physicians	O
.	O

Treatment	O
of	O
chronic	O
hepatitis	O
B	O
with	O
interferon	B-GENE
:	O
experience	O
in	O
western	O
countries	O
.	O

Similar	O
to	O
what	O
was	O
observed	O
for	O
P	O
.	O
putida	O
,	O
a	O
psrA	B-GENE
null	O
mutant	O
of	O
P	O
.	O
aeruginosa	O
also	O
showed	O
a	O
90	O
%	O
reduction	O
in	O
rpoS	B-GENE
promoter	I-GENE
activity	O
;	O
both	O
mutants	O
could	O
be	O
complemented	O
for	O
rpoS	B-GENE
promoter	I-GENE
activity	O
when	O
the	O
psrA	B-GENE
gene	I-GENE
was	O
provided	O
in	O
trans	O
.	O
psrA	B-GENE
mutants	I-GENE
of	O
both	O
Pseudomonas	O
species	O
lost	O
the	O
ability	O
to	O
induce	O
rpoS	B-GENE
expression	O
at	O
stationary	O
phase	O
,	O
but	O
they	O
retained	O
the	O
ability	O
to	O
produce	O
quorum	O
-	O
sensing	O
autoinducer	O
molecules	O
.	O

The	O
increments	O
in	O
median	O
plasma	B-GENE
secretin	I-GENE
concentration	O
were	O
1	O
.	O
6	O
,	O
3	O
.	O
0	O
,	O
and	O
6	O
.	O
4	O
pmol	O
x	O
1	O
(	O
-	O
1	O
)	O
after	O
secretin	B-GENE
,	O
125	O
,	O
250	O
and	O
500	O
fmol	O
x	O
kg	O
-	O
1	O
,	O
and	O
the	O
corresponding	O
15	O
-	O
min	O
bicarbonate	O
output	O
283	O
,	O
442	O
,	O
and	O
1435	O
micromol	O
,	O
respectively	O
.	O

The	O
composition	O
of	O
renal	O
stones	O
analysed	O
by	O
infrared	O
spectroscopy	O
.	O

Programmed	O
peritoneal	O
lavage	O
in	O
suppurative	O
complications	O
of	O
perforated	O
ulcer	O
of	O
the	O
stomach	O

Vibrio	O
cholerae	O
iron	O
transport	O
:	O
haem	O
transport	O
genes	O
are	O
linked	O
to	O
one	O
of	O
two	O
sets	O
of	O
tonB	B-GENE
,	O
exbB	B-GENE
,	O
exbD	B-GENE
genes	I-GENE
.	O

Zonography	O
in	O
urology	O
(	O
author	O
'	O
s	O
transl	O
)	O

Phenazopyridine	O
-	O
induced	O
hemolytic	O
anemia	O
in	O
a	O
patient	O
with	O
G6PD	B-GENE
deficiency	O
.	O

The	O
novel	O
gene	O
spans	O
16	O
.	O
7	O
kb	O
of	O
genomic	O
sequence	O
and	O
it	O
is	O
formed	O
of	O
11	O
exons	O
and	O
10	O
intervening	O
introns	O
.	O

Overexpression	O
of	O
a	O
HIF	B-GENE
-	I-GENE
1alpha	I-GENE
construct	O
with	O
deletions	O
of	O
the	O
basic	O
domain	O
and	O
carboxy	O
terminus	O
blocked	O
reporter	O
gene	O
activation	O
by	O
endogenous	O
HIF	B-GENE
-	I-GENE
1	I-GENE
in	O
hypoxic	O
cells	O
.	O

A	O
preformed	O
SREBP	B-GENE
-	I-GENE
1a	I-GENE
:	I-GENE
[	I-GENE
32P	I-GENE
]	I-GENE
DNA	I-GENE
complex	I-GENE
bound	O
specifically	O
to	O
membrane	O
-	O
immobilized	O
GST	B-GENE
-	O
CBP	B-GENE
fusion	O
proteins	O
that	O
contained	O
amino	O
-	O
terminal	O
portions	O
of	O
CBP	B-GENE
.	O

Extracellular	B-GENE
protein	I-GENE
kinase	I-GENE
A	I-GENE
as	O
a	O
cancer	O
biomarker	O
:	O
its	O
expression	O
by	O
tumor	O
cells	O
and	O
reversal	O
by	O
a	O
myristate	O
-	O
lacking	O
Calpha	O
and	O
RIIbeta	O
subunit	O
overexpression	O
.	O

By	O
incorporating	O
a	O
stent	O
with	O
posts	O
that	O
pivot	O
about	O
their	O
base	O
,	O
such	O
that	O
a	O
10	O
%	O
expansion	O
at	O
the	O
commissures	O
is	O
realized	O
,	O
we	O
were	O
able	O
to	O
reduce	O
the	O
compressive	O
commissural	O
stressing	O
from	O
250	O
to	O
150	O
kPa	O
.	O

With	O
rats	O
fed	O
on	O
the	O
Zn	O
-	O
sufficient	O
diet	O
,	O
NaFe3	O
+	O
EDTA	O
and	O
Na2EDTA	O
similarly	O
increased	O
the	O
absorption	O
,	O
urinary	O
excretion	O
and	O
retention	O
of	O
Zn	O
but	O
to	O
a	O
lesser	O
extent	O
.	O

The	O
requirement	O
for	O
an	O
essential	O
interaction	O
between	O
NPH	B-GENE
I	I-GENE
and	O
H4L	B-GENE
provides	O
an	O
explanation	O
for	O
the	O
observed	O
restriction	O
of	O
transcription	O
termination	O
to	O
early	O
viral	O
genes	O
.	O

Other	O
clinicopathological	O
features	O
have	O
no	O
definite	O
influence	O
in	O
survival	O
expectancy	O
.	O

Births	O
,	O
marriages	O
,	O
divorces	O
,	O
and	O
deaths	O
for	O
July	O
1997	O
.	O

One	O
day	O
postoperatively	O
,	O
the	O
mononuclear	O
leukocyte	O
beta	B-GENE
2	I-GENE
-	I-GENE
receptor	I-GENE
density	O
decreased	O
maximally	O
by	O
45	O
+	O
/	O
-	O
11	O
%	O
in	O
the	O
enflurane	O
patients	O
,	O
and	O
by	O
53	O
+	O
/	O
-	O
6	O
%	O
in	O
the	O
neurolept	O
patients	O
.	O

A	O
direct	O
statistically	O
reliable	O
correction	O
of	O
decrease	O
of	O
the	O
enzymes	O
with	O
the	O
initial	O
state	O
of	O
the	O
patients	O
has	O
been	O
established	O
in	O
an	O
analysis	O
of	O
25	O
patients	O
aged	O
from	O
18	O
to	O
60	O
years	O
in	O
prosthesis	O
of	O
+	O
the	O
mitral	O
valve	O
(	O
n	O
-	O
9	O
)	O
and	O
closed	O
mitral	O
commissurotomy	O
(	O
n	O
-	O
16	O
)	O
.	O

However	O
,	O
it	O
was	O
observed	O
that	O
storage	O
time	O
affected	O
significantly	O
the	O
biochemical	O
changes	O
occurring	O
in	O
the	O
constituents	O
of	O
carrots	O
exposed	O
to	O
gamma	O
-	O
irradiation	O
.	O

Partial	O
proteolysis	O
of	O
cell	O
surface	O
-	O
iodinated	O
B	B-GENE
-	I-GENE
G	I-GENE
molecules	I-GENE
generates	O
extremely	O
similar	O
patterns	O
of	O
spots	O
,	O
both	O
within	O
and	O
between	O
haplotypes	O
.	O

Here	O
we	O
demonstrate	O
the	O
ability	O
of	O
oligonucleotides	O
containing	O
the	O
C4T	O
sequence	O
to	O
confer	O
heat	O
shock	O
inducibility	O
on	O
the	O
reporter	O
gene	O
and	O
show	O
that	O
the	O
presence	O
of	O
two	O
such	O
elements	O
produces	O
more	O
than	O
additive	O
effects	O
on	O
induction	O
.	O

In	O
the	O
other	O
two	O
groups	O
(	O
NAAR	O
and	O
PLA	O
)	O
,	O
no	O
variation	O
in	O
this	O
serum	O
protease	O
was	O
observed	O
.	O

The	O
KEMAR	O
measurements	O
show	O
that	O
the	O
two	O
models	O
give	O
an	O
improvement	O
of	O
the	O
signal	O
-	O
to	O
-	O
noise	O
ratio	O
of	O
approximately	O
7	O
.	O
5	O
dB	O
in	O
a	O
diffuse	O
sound	O
field	O
.	O

Providing	O
appropriate	O
care	O
to	O
both	O
sexes	O
.	O

An	O
X	O
-	O
linked	O
zinc	B-GENE
finger	I-GENE
gene	I-GENE
mapping	O
to	O
Xq21	O
.	O
1	O
-	O
q21	O
.	O
3	O
closely	O
related	O
to	O
ZFX	B-GENE
and	O
ZFY	B-GENE
:	O
possible	O
origins	O
from	O
a	O
common	O
ancestral	O
gene	O
.	O

Mutations	O
that	O
extend	O
the	O
specificity	O
of	O
the	O
endonuclease	O
activity	O
of	O
lambda	B-GENE
terminase	I-GENE
.	O

Promoter	O
activity	O
was	O
assayed	O
by	O
transient	O
transfection	O
of	O
luciferase	B-GENE
reporter	I-GENE
constructs	I-GENE
containing	O
nested	O
deletions	O
of	O
the	O
upstream	O
sequence	O
in	O
the	O
human	O
RPE	O
cell	O
lines	O
ARPE19	O
and	O
D407	O
,	O
as	O
well	O
as	O
in	O
the	O
SK	O
-	O
Mel	O
-	O
28	O
and	O
HeLa	O
cell	O
lines	O
.	O

These	O
results	O
suggest	O
an	O
essential	O
role	O
of	O
the	O
binding	O
of	O
HNF	B-GENE
-	I-GENE
4	I-GENE
and	O
/	O
or	O
HNF	B-GENE
-	I-GENE
4	I-GENE
-	I-GENE
related	I-GENE
nuclear	I-GENE
factors	I-GENE
to	O
the	O
6	O
beta	O
A	O
-	O
A	O
site	O
on	O
the	O
basal	O
transcriptional	O
activation	O
of	O
the	O
CYP3A2	B-GENE
gene	I-GENE
in	O
liver	O
cells	O
.	O

A	O
vascular	O
component	O
to	O
impotence	O
was	O
shown	O
to	O
be	O
common	O
in	O
those	O
with	O
neurological	O
impairment	O
,	O
and	O
may	O
alter	O
management	O
.	O

Bandwidth	O
of	O
auditory	O
units	O
in	O
the	O
chick	O
forebrain	O
(	O
field	O
L	O
/	O
Hv	O
complex	O
)	O
was	O
measured	O
with	O
isointensity	O
tone	O
stimuli	O
.	O

Two	O
cases	O
of	O
Paraquat	O
poisoning	O
of	O
anticonservative	O
origin	O
are	O
described	O
.	O

The	O
promoter	O
of	O
this	O
methyltransferase	O
gene	O
lacks	O
an	O
identifiable	O
TATA	O
box	O
but	O
is	O
characterized	O
by	O
a	O
CpG	O
island	O
which	O
begins	O
approximately	O
723	O
nucleotides	O
upstream	O
of	O
the	O
major	O
transcriptional	O
start	O
site	O
and	O
extends	O
through	O
exon	O
1	O
and	O
into	O
the	O
first	O
intron	O
.	O

It	O
also	O
describes	O
the	O
preliminary	O
results	O
of	O
a	O
Phase	O
II	O
trial	O
going	O
on	O
at	O
the	O
Central	O
Institute	O
for	O
Tumors	O
in	O
Zagreb	O
,	O
using	O
a	O
combination	O
of	O
cis	O
-	O
DDP	O
,	O
5	O
-	O
fluorouracil	O
and	O
vincristine	O
.	O

Three	O
patients	O
with	O
Mirizzi	O
type	O
II	O
syndrome	O
and	O
two	O
patients	O
with	O
Mirizzi	O
type	O
I	O
syndrome	O
were	O
treated	O
laparoscopically	O
.	O

The	O
pregnancies	O
were	O
terminated	O
at	O
19	O
and	O
12	O
weeks	O
of	O
gestation	O
,	O
respectively	O
.	O

The	O
treatment	O
with	O
glucocorticoids	O
and	O
immunosuppressants	O
resulted	O
in	O
a	O
more	O
noticeable	O
decrease	O
in	O
the	O
levels	O
of	O
T3	O
and	O
E	B-GENE
-	I-GENE
RCF	I-GENE
.	O

It	O
is	O
concluded	O
that	O
the	O
new	O
class	O
of	O
competitive	O
NMDA	B-GENE
receptor	I-GENE
antagonists	O
,	O
exemplified	O
by	O
CGP	O
37849	O
,	O
is	O
the	O
most	O
promising	O
candidate	O
for	O
clinical	O
trials	O
in	O
anxiety	O
disorders	O
.	O

Rapid	O
,	O
sensitive	O
gas	O
chromatographic	O
analysis	O
of	O
8	O
-	O
methoxypsoralen	O
in	O
human	O
plasma	O
.	O

RESULTS	O
:	O
Sixty	O
-	O
one	O
percent	O
of	O
the	O
patients	O
had	O
damage	O
within	O
7	O
years	O
of	O
onset	O
(	O
mean	O
3	O
.	O
8	O
yrs	O
)	O
.	O

In	O
the	O
fungus	O
Neurospora	O
crassa	O
,	O
nit	B-GENE
-	I-GENE
2	I-GENE
,	O
the	O
major	O
nitrogen	O
regulatory	O
gene	O
,	O
activates	O
the	O
expression	O
of	O
unlinked	O
structural	O
genes	O
that	O
specify	O
nitrogen	O
-	O
catabolic	O
enzymes	O
during	O
conditions	O
of	O
nitrogen	O
limitation	O
.	O

We	O
concluded	O
that	O
HFV	O
can	O
achieve	O
values	O
of	O
CO2	O
elimination	O
close	O
to	O
the	O
estimated	O
metabolic	O
CO2	O
production	O
in	O
normal	O
unintubated	O
subjects	O
over	O
short	O
periods	O
of	O
time	O
.	O

Tetrazepam	O
:	O
a	O
benzodiazepine	O
which	O
dissociates	O
sedation	O
from	O
other	O
benzodiazepine	O
activities	O
.	O

Transcripts	O
appear	O
to	O
be	O
initiated	O
from	O
an	O
upstream	O
promoter	O
,	O
P1	O
,	O
located	O
in	O
front	O
of	O
the	O
tRNA	B-GENE
(	I-GENE
met1	I-GENE
)	I-GENE
gene	I-GENE
and	O
from	O
three	O
internal	O
promoters	O
:	O
P2	O
is	O
located	O
immediately	O
in	O
front	O
of	O
the	O
tRNA	B-GENE
(	I-GENE
met2	I-GENE
)	I-GENE
gene	I-GENE
;	O
PL10	O
is	O
near	O
the	O
beginning	O
of	O
the	O
L1	B-GENE
-	O
L10	B-GENE
intergenic	O
space	O
,	O
and	O
PL12	O
is	O
at	O
the	O
end	O
of	O
the	O
L10	B-GENE
gene	I-GENE
sequence	I-GENE
.	O

Nearly	O
1	O
.	O
5	O
million	O
American	O
men	O
age	O
65	O
and	O
older	O
have	O
osteoporosis	O
,	O
and	O
another	O
3	O
.	O
5	O
million	O
are	O
at	O
risk	O
.	O

We	O
have	O
characterized	O
21	O
mutations	O
in	O
the	O
type	B-GENE
VII	I-GENE
collagen	I-GENE
gene	I-GENE
(	O
COL7A1	B-GENE
)	O
encoding	O
the	O
anchoring	O
fibrils	O
,	O
18	O
of	O
which	O
were	O
not	O
previously	O
reported	O
,	O
in	O
patients	O
from	O
15	O
unrelated	O
families	O
with	O
recessive	O
dystrophic	O
epidermolysis	O
bullosa	O
(	O
RDEB	O
)	O
.	O

A	O
case	O
of	O
heterotopic	O
gastric	O
mucosa	O
(	O
pyloric	O
gland	O
)	O
in	O
the	O
wall	O
of	O
the	O
gallbladder	O
was	O
reported	O
.	O

Ribosome	O
association	O
of	O
GCN2	B-GENE
protein	I-GENE
kinase	I-GENE
,	O
a	O
translational	O
activator	O
of	O
the	O
GCN4	B-GENE
gene	I-GENE
of	O
Saccharomyces	O
cerevisiae	O
.	O

We	O
further	O
examined	O
the	O
interaction	O
of	O
JAK2	B-GENE
with	O
the	O
GHR	B-GENE
cytoplasmic	O
domain	O
by	O
two	O
lines	O
of	O
investigation	O
.	O

These	O
segments	O
may	O
represent	O
pseudogenes	O
.	O

Corresponding	O
oligonucleotides	O
were	O
used	O
to	O
screen	O
a	O
rat	O
liver	O
cDNA	O
library	O
constructed	O
in	O
the	O
plasmid	O
cloning	O
vector	O
,	O
pcDV	O
.	O

A	O
.	O

Extracellular	B-GENE
regulated	I-GENE
kinases	I-GENE
(	I-GENE
ERK	I-GENE
)	I-GENE
1	I-GENE
and	O
ERK2	B-GENE
are	O
authentic	O
substrates	O
for	O
the	O
dual	B-GENE
-	I-GENE
specificity	I-GENE
protein	I-GENE
-	I-GENE
tyrosine	I-GENE
phosphatase	I-GENE
VHR	I-GENE
.	O

The	O
model	O
therefore	O
predicts	O
that	O
1	O
)	O
on	O
-	O
line	O
calculation	O
of	O
airway	O
dead	O
space	O
and	O
end	O
-	O
expired	O
lung	O
volume	O
can	O
be	O
made	O
by	O
the	O
addition	O
of	O
an	O
oxygen	O
sine	O
-	O
wave	O
perturbation	O
component	O
to	O
the	O
mean	O
FIO2	O
;	O
and	O
(	O
2	O
)	O
QS	O
/	O
QT	O
can	O
be	O
measured	O
from	O
the	O
resultant	O
oxygen	O
perturbation	O
sine	O
-	O
wave	O
amplitudes	O
in	O
the	O
expired	O
gas	O
and	O
in	O
arterial	O
and	O
mixed	O
-	O
venous	O
blood	O
and	O
is	O
independent	O
of	O
the	O
mean	O
blood	O
oxygen	O
partial	O
pressure	O
and	O
oxyhemoglobin	B-GENE
saturation	O
values	O
.	O

An	O
anoerxiant	O
,	O
mazindol	O
suppresses	O
food	O
intake	O
by	O
1	O
)	O
stimulating	O
beta	B-GENE
-	I-GENE
adrenergic	I-GENE
receptors	I-GENE
,	O
2	O
)	O
inhibiting	O
the	O
feeding	O
center	O
and	O
,	O
3	O
)	O
stimulating	O
the	O
satiety	O
center	O
in	O
the	O
hypothalamus	O
.	O

When	O
patients	O
were	O
admitted	O
within	O
one	O
week	O
of	O
the	O
onset	O
of	O
dark	O
urine	O
,	O
45	O
%	O
were	O
found	O
to	O
be	O
shedding	O
HAV	O
,	O
whereas	O
only	O
11	O
%	O
of	O
specimens	O
obtained	O
from	O
patients	O
admitted	O
during	O
the	O
second	O
week	O
contained	O
virus	O
.	O

Positive	O
effects	O
of	O
radioactive	O
therapy	O
in	O
Guarapari	O

Nevertheless	O
,	O
lower	O
doses	O
which	O
alone	O
were	O
lacking	O
in	O
activity	O
(	O
100	O
-	O
250	O
mg	O
/	O
kg	O
B1	O
and	O
B6	O
,	O
1	O
-	O
2	O
.	O
5	O
mg	O
/	O
kg	O
B12	O
p	O
.	O
o	O
.	O
)	O
dose	O
-	O
dependently	O
potentiated	O
the	O
antinociceptive	O
of	O
diclofenac	O
.	O

Escherichia	O
coli	O
strains	O
carrying	O
recA730	B-GENE
(	O
or	O
other	O
recA	B-GENE
*	I-GENE
alleles	I-GENE
)	O
exhibit	O
dramatic	O
increases	O
in	O
SOS	O
-	O
dependent	O
spontaneous	O
mutator	O
activity	O
.	O

On	O
the	O
contrary	O
i	O
.	O
v	O
.	O
administration	O
of	O
calcitonin	B-GENE
increased	O
intrapyloric	O
pressure	O
via	O
vagal	O
nerves	O
in	O
atropinized	O
or	O
gallaminized	O
animals	O
.	O

An	O
hcr1	B-GENE
null	O
mutant	O
was	O
viable	O
,	O
but	O
showed	O
slight	O
reduction	O
of	O
growth	O
when	O
compared	O
with	O
the	O
wild	O
-	O
type	O
strain	O
.	O

Overall	O
,	O
free	O
-	O
chlorine	O
treatments	O
(	O
0	O
.	O
3	O
or	O
1	O
.	O
0	O
mg	O
/	O
L	O
)	O
showed	O
significantly	O
lower	O
heterotrophic	O
plate	O
numbers	O
than	O
those	O
without	O
free	O
chlorine	O
.	O

This	O
evaluation	O
examines	O
several	O
analytical	O
and	O
cost	O
parameters	O
for	O
five	O
representative	O
assays	O
:	O
IgG	B-GENE
,	O
IgA	B-GENE
,	O
IgM	B-GENE
,	O
phenytoin	O
,	O
and	O
phenobarbital	O
.	O

We	O
have	O
previously	O
identified	O
LIT1	B-GENE
,	O
a	O
paternally	O
expressed	O
antisense	O
RNA	O
within	O
the	O
KvLQT1	B-GENE
locus	I-GENE
through	O
a	O
positional	O
screening	O
approach	O
using	O
human	O
monochromosomal	O
hybrids	O
.	O

Here	O
RFX	B-GENE
/	O
X2BP	B-GENE
/	O
DNA	O
complexes	O
were	O
formed	O
on	O
all	O
class	O
II	O
isotypes	O
regardless	O
of	O
the	O
ability	O
of	O
the	O
X	O
box	O
region	O
to	O
bind	O
either	O
factor	O
individually	O
.	O

Developmental	O
slot	O
blots	O
demonstrate	O
that	O
mRNAs	O
corresponding	O
to	O
the	O
three	O
LHM	B-GENE
cDNAs	I-GENE
are	O
transcribed	O
from	O
prophase	O
of	O
meiosis	O
I	O
to	O
the	O
uninucleate	O
microspore	O
stage	O
,	O
while	O
Northern	O
analysis	O
reveals	O
these	O
tapetally	O
expressed	O
cDNAs	O
to	O
correspond	O
with	O
transcripts	O
of	O
some	O
500	O
bp	O
.	O

The	O
curse	O
of	O
the	O
Pharaohs	O
.	O

The	O
women	O
in	O
the	O
intermediate	O
calcium	O
group	O
had	O
approximately	O
the	O
same	O
mean	O
BMD	O
values	O
as	O
those	O
in	O
the	O
low	O
calcium	O
group	O
.	O

The	O
enigma	O
of	O
aging	O
bone	O
loss	O
.	O

RESULTS	O
:	O
After	O
lavage	O
,	O
a	O
rapid	O
decrease	O
in	O
arterial	O
pH	O
and	O
PaO2	O
,	O
and	O
an	O
increase	O
in	O
PaCO2	O
and	O
PIP	O
were	O
observed	O
in	O
all	O
animals	O
.	O

In	O
both	O
cell	O
types	O
,	O
insulin	B-GENE
led	O
to	O
a	O
dose	O
-	O
dependent	O
increase	O
in	O
the	O
association	O
of	O
tyrosine	B-GENE
phosphorylated	I-GENE
IRS	I-GENE
-	I-GENE
1	I-GENE
with	O
the	O
SH2	B-GENE
domain	I-GENE
of	O
the	O
p85	B-GENE
regulatory	I-GENE
subunit	I-GENE
of	O
PI	B-GENE
-	I-GENE
3	I-GENE
kinase	I-GENE
,	O
and	O
also	O
increased	O
the	O
amount	O
of	O
PI	B-GENE
kinase	I-GENE
activity	O
detected	O
in	O
anti	B-GENE
-	I-GENE
IRS	I-GENE
-	I-GENE
1	I-GENE
immunoprecipitates	O
.	O

Twelve	O
(	O
92	O
%	O
)	O
showed	O
cognitive	O
dysfunction	O
including	O
impairments	O
in	O
memory	O
,	O
attention	O
,	O
and	O
affective	O
disturbances	O
(	O
anxiety	O
,	O
depression	O
,	O
irritability	O
,	O
and	O
poor	O
frustration	O
tolerance	O
)	O
.	O

These	O
effects	O
were	O
antagonized	O
by	O
prior	O
administration	O
of	O
1	O
-	O
(	O
2	O
-	O
methoxyphenyl	O
)	O
-	O
4	O
-	O
[	O
-	O
(	O
2	O
-	O
phthalimido	O
)	O
butyl	O
]	O
piperazine	O
)	O
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
.	O

Transcription	O
initiation	O
from	O
this	O
region	O
was	O
also	O
detected	O
in	O
vivo	O
,	O
when	O
the	O
cloned	O
rRNA	O
gene	O
cluster	O
was	O
present	O
on	O
a	O
multi	O
-	O
copy	O
plasmid	O
.	O

The	O
human	B-GENE
parvalbumin	I-GENE
mRNA	I-GENE
contains	O
the	O
putative	O
polyadenylation	O
signal	O
AATAAA	O
13	O
nucleotides	O
upstream	O
from	O
the	O
polyadenylation	O
site	O
.	O

The	O
effects	O
of	O
dopamine	O
and	O
of	O
dopamine	B-GENE
D2	I-GENE
receptor	I-GENE
blocker	O
haloperidol	O
on	O
the	O
activity	O
of	O
carotid	O
chemoreceptors	O
were	O
studied	O
in	O
24	O
anesthetized	O
,	O
paralyzed	O
and	O
artificially	O
ventilated	O
newborn	O
kittens	O
aged	O
0	O
-	O
17	O
days	O
.	O

DNMT2	B-GENE
binds	O
AdoHcy	O
in	O
the	O
same	O
conformation	O
as	O
confirmed	O
m	B-GENE
(	I-GENE
5	I-GENE
)	I-GENE
C	I-GENE
MTases	I-GENE
and	O
,	O
while	O
DNMT2	B-GENE
shares	O
all	O
sequence	O
and	O
structural	O
features	O
with	O
m	B-GENE
(	I-GENE
5	I-GENE
)	I-GENE
C	I-GENE
MTases	I-GENE
,	O
it	O
has	O
failed	O
to	O
demonstrate	O
detectable	O
transmethylase	O
activity	O
.	O

Serum	B-GENE
amyloid	I-GENE
A	I-GENE
(	O
SAA	B-GENE
)	O
is	O
a	O
plasma	O
protein	O
which	O
has	O
been	O
associated	O
with	O
several	O
diseases	O
,	O
including	O
amyloidosis	O
,	O
arthritis	O
,	O
and	O
atherosclerosis	O
,	O
and	O
its	O
abnormal	O
expression	O
,	O
particularly	O
in	O
nonhepatic	O
cells	O
,	O
is	O
implicated	O
in	O
the	O
pathogenesis	O
of	O
these	O
diseases	O
.	O

The	O
standardized	O
incidence	O
in	O
Europeans	O
has	O
risen	O
significantly	O
to	O
4	O
.	O
7	O
/	O
10	O
(	O
5	O
)	O
/	O
year	O
from	O
3	O
.	O
4	O
/	O
10	O
(	O
5	O
)	O
/	O
year	O
in	O
the	O
1970s	O
(	O
chi	O
2	O
=	O
8	O
.	O
1	O
,	O
p	O
less	O
than	O
0	O
.	O
005	O
)	O
.	O

Physical	O
mapping	O
220	O
kb	O
centromeric	O
of	O
the	O
human	B-GENE
MHC	I-GENE
and	O
DNA	O
sequence	O
analysis	O
of	O
the	O
43	O
-	O
kb	O
segment	O
including	O
the	O
RING1	B-GENE
,	O
HKE6	B-GENE
,	O
and	O
HKE4	B-GENE
genes	I-GENE
.	O

The	O
cells	O
arrest	O
in	O
the	O
G1	O
phase	O
of	O
the	O
cell	O
cycle	O
and	O
grow	O
a	O
projection	O
towards	O
one	O
another	O
forming	O
a	O
shmoo	O
projection	O
.	O

Multiple	O
aortic	O
thrombi	O
associated	O
with	O
protein	B-GENE
C	I-GENE
and	O
S	B-GENE
deficiency	O
.	O

However	O
,	O
the	O
optimum	O
compressive	O
strength	O
reached	O
values	O
up	O
to	O
40	O
%	O
higher	O
than	O
CC	O
-	O
free	O
samples	O
.	O

POPULATION	O
AND	O
METHODS	O
:	O
105	O
patients	O
were	O
followed	O
prospectively	O
(	O
male	O
:	O
87	O
%	O
;	O
age	O
:	O
56	O
+	O
/	O
-	O
10	O
)	O
;	O
clinical	O
evaluation	O
was	O
performed	O
in	O
the	O
1st	O
,	O
3rd	O
and	O
6th	O
month	O
,	O
SEKG	O
in	O
the	O
4th	O
month	O
and	O
recatheterization	O
for	O
angiographic	O
control	O
in	O
the	O
6th	O
month	O
.	O

The	O
practice	O
of	O
measuring	O
of	O
AChE	B-GENE
levels	O
in	O
acute	O
poisoning	O
is	O
limited	O
.	O

M	O
.	O
,	O
Adrich	O
,	O
Z	O
.	O
,	O
Fournet	O
,	O
B	O
.	O
,	O
Capon	O
,	O
C	O
.	O
,	O
Bonicel	O
,	O
J	O
.	O

Confocal	O
fluorescent	O
microscopy	O
analysis	O
demonstrated	O
that	O
WT	O
,	O
VaI	O
,	O
and	O
VaII	O
all	O
distribute	O
equally	O
to	O
the	O
cell	O
surface	O
while	O
,	O
as	O
expected	O
,	O
a	O
WT	O
mutant	O
lacking	O
the	O
two	O
C	O
-	O
terminal	O
valine	O
residues	O
does	O
not	O
.	O

The	O
amount	O
of	O
ERCC1	B-GENE
detectable	O
by	O
immunoblotting	O
is	O
reduced	O
in	O
group	O
1	O
,	O
group	O
4	O
and	O
XP	O
-	O
F	O
extracts	O
.	O

Letter	O
:	O
Ballistocardiography	O
.	O

Metabolic	O
studies	O
of	O
tetrabenazine	O
,	O
a	O
psychotropic	O
drug	O
in	O
animals	O
and	O
man	O
.	O

From	O
the	O
frozen	O
specimen	O
,	O
a	O
large	O
number	O
of	O
sections	O
with	O
good	O
morphologic	O
characteristics	O
may	O
be	O
produced	O
.	O

Gene	O
transcripts	O
are	O
detected	O
on	O
tissues	O
such	O
as	O
bovine	O
liver	O
,	O
kidney	O
,	O
lung	O
,	O
and	O
brain	O
.	O

Plasma	B-GENE
enteroglucagon	I-GENE
was	O
measured	O
before	O
and	O
during	O
three	O
hours	O
after	O
a	O
standard	O
meal	O
in	O
21	O
untreated	O
adult	O
patients	O
with	O
suspected	O
coeliac	O
disease	O
who	O
all	O
had	O
villous	O
atrophy	O
of	O
the	O
small	O
intestinal	O
mucosa	O
and	O
malabsorption	O
,	O
and	O
in	O
nine	O
control	O
subjects	O
.	O

In	O
this	O
report	O
,	O
we	O
establish	O
that	O
the	O
heteromeric	O
CCAAT	B-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
CBF	B-GENE
is	O
the	O
major	O
component	O
of	O
the	O
C1	B-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
(	O
C1F	B-GENE
)	O
in	O
human	O
cells	O
.	O

This	O
growth	O
-	O
inhibitory	O
effect	O
was	O
suppressed	O
by	O
the	O
mpk1	B-GENE
delta	I-GENE
mutation	O
,	O
suggesting	O
that	O
hyperactivation	O
of	O
the	O
Mpk1	B-GENE
pathway	O
is	O
toxic	O
to	O
cells	O
.	O

The	O
human	B-GENE
PAX8	I-GENE
gene	I-GENE
generates	O
at	O
least	O
five	O
different	O
alternatively	O
spliced	O
transcripts	O
encoding	O
different	O
PAX8	B-GENE
isoforms	I-GENE
.	O

The	O
use	O
of	O
specific	O
somatic	O
cell	O
hybrids	O
have	O
allowed	O
us	O
to	O
locate	O
the	O
YAC	O
contig	O
telomeric	O
to	O
the	O
D3F15S2	B-GENE
locus	I-GENE
,	O
in	O
a	O
region	O
which	O
is	O
frequently	O
deleted	O
in	O
lung	O
carcinomas	O
.	O

A	O
close	O
homologue	O
of	O
the	O
APK2a	B-GENE
gene	I-GENE
,	O
named	O
APK2b	B-GENE
,	O
was	O
also	O
isolated	O
from	O
the	O
Arabidopsis	O
cDNA	O
library	O
.	O

Characterization	O
of	O
Chlamydomonas	O
reinhardtii	O
zygote	O
-	O
specific	O
cDNAs	O
that	O
encode	O
novel	O
proteins	O
containing	O
ankyrin	B-GENE
repeats	O
and	O
WW	O
domains	O
.	O

Subsequent	O
analysis	O
revealed	O
that	O
MyD88	B-GENE
possesses	O
a	O
unique	O
modular	O
structure	O
,	O
which	O
consists	O
of	O
an	O
N	O
-	O
terminal	O
"	O
death	O
domain	O
,	O
"	O
similar	O
to	O
the	O
intracellular	O
segments	O
of	O
TNF	B-GENE
receptor	I-GENE
1	I-GENE
and	O
Fas	B-GENE
,	O
and	O
a	O
C	O
-	O
terminal	O
region	O
related	O
to	O
the	O
cytoplasmic	O
domains	O
of	O
the	O
Drosophila	B-GENE
morphogen	I-GENE
Toll	I-GENE
and	O
vertebrate	O
interleukin	B-GENE
-	I-GENE
1	I-GENE
receptors	I-GENE
.	O

A	O
.	O
nidulans	O
transformants	O
secreted	O
high	O
amounts	O
of	O
PGI	B-GENE
and	O
PGII	B-GENE
in	O
comparison	O
to	O
the	O
previously	O
characterized	O
A	O
.	O
niger	O
transformants	O
and	O
a	O
novel	O
polygalacturonase	B-GENE
(	O
PGC	B-GENE
)	O
was	O
produced	O
at	O
high	O
levels	O
by	O
A	O
.	O
nidulans	O
transformed	O
with	O
the	O
subcloned	O
pgaC	B-GENE
gene	I-GENE
.	O

Role	O
of	O
zinc	B-GENE
-	I-GENE
finger	I-GENE
proteins	I-GENE
Sp1	I-GENE
and	O
zif268	B-GENE
/	O
egr	B-GENE
-	I-GENE
1	I-GENE
in	O
transcriptional	O
regulation	O
of	O
the	O
human	B-GENE
synaptobrevin	I-GENE
II	I-GENE
gene	I-GENE
.	O

However	O
,	O
the	O
recovery	O
curve	O
of	O
the	O
R2	O
component	O
of	O
the	O
blink	O
reflex	O
diminished	O
in	O
patients	O
with	O
tension	O
-	O
type	O
headache	O
compared	O
with	O
the	O
other	O
groups	O
.	O

The	O
GvpE	B-GENE
protein	I-GENE
involved	O
in	O
the	O
regulation	O
of	O
gas	O
vesicles	O
synthesis	O
in	O
halophilic	O
archaea	O
has	O
been	O
identified	O
as	O
the	O
transcriptional	O
activator	O
for	O
the	O
promoter	O
located	O
upstream	O
of	O
the	O
gvpA	B-GENE
gene	I-GENE
encoding	O
the	O
major	O
gas	O
vesicle	O
structural	O
protein	O
GvpA	B-GENE
.	O

TFIIIB	B-GENE
assembles	O
autonomously	O
on	O
the	O
upstream	O
promoter	O
of	O
the	O
yeast	B-GENE
U6	I-GENE
snRNA	I-GENE
(	O
SNR6	B-GENE
)	O
gene	O
in	O
vitro	O
,	O
through	O
the	O
interaction	O
of	O
its	O
TBP	B-GENE
subunit	I-GENE
with	O
a	O
consensus	O
TATA	O
box	O
located	O
at	O
base	O
pair	O
-	O
30	O
.	O

Effect	O
of	O
bromocriptine	O
and	O
metoclopramide	O
on	O
serum	B-GENE
prolactin	I-GENE
levels	O
in	O
patients	O
with	O
amyotrophic	O
lateral	O
sclerosis	O
.	O

Experience	O
in	O
using	O
the	O
Romashka	O
-	O
1	O
laser	O
surgical	O
unit	O
in	O
treating	O
suppurative	O
wounds	O

At	O
a	O
cutoff	O
point	O
for	O
KISA	O
%	O
of	O
100	O
,	O
280	O
of	O
281	O
participants	O
(	O
99	O
.	O
6	O
%	O
)	O
were	O
correctly	O
classified	O
.	O

To	O
evaluate	O
the	O
effect	O
of	O
selective	O
thromboxane	O
A2	O
blockade	O
on	O
clinical	O
findings	O
and	O
platelet	O
reactivity	O
in	O
refractory	O
unstable	O
angina	O
,	O
OKY	O
-	O
046	O
(	O
600	O
mg	O
/	O
day	O
,	O
p	O
.	O
o	O
.	O
)	O
was	O
administered	O
to	O
another	O
14	O
patients	O
with	O
refractory	O
unstable	O
angina	O
in	O
addition	O
to	O
the	O
conventional	O
therapy	O
.	O

The	O
AP	B-GENE
-	I-GENE
1	I-GENE
recruited	O
by	O
ARF1	B-GENE
.	I-GENE
GTP	I-GENE
is	O
released	O
from	O
the	O
Golgi	O
membrane	O
by	O
treatment	O
with	O
1	O
M	O
Tris	O
-	O
HCl	O
(	O
pH	O
7	O
)	O
or	O
upon	O
reincubation	O
at	O
37	O
degreesC	O
,	O
whereas	O
AP	B-GENE
-	I-GENE
1	I-GENE
recruited	O
with	O
GTPgammaS	O
or	O
by	O
a	O
constitutively	O
active	O
point	O
mutant	O
,	O
ARF1	B-GENE
(	I-GENE
Q71L	I-GENE
)	I-GENE
,	O
remains	O
membrane	O
bound	O
after	O
either	O
treatment	O
.	O

In	O
K562	O
cells	O
,	O
using	O
the	O
bicistronic	O
vector	O
,	O
selection	O
with	O
colchicine	O
led	O
to	O
at	O
least	O
20	O
-	O
fold	O
higher	O
expression	O
of	O
the	O
MDR1	B-GENE
gene	I-GENE
product	I-GENE
than	O
did	O
selection	O
with	O
G418	O
,	O
suggesting	O
that	O
the	O
stringent	O
MDR1	B-GENE
selection	O
system	O
is	O
very	O
efficient	O
for	O
obtaining	O
overexpression	O
of	O
foreign	O
genes	O
.	O

A	O
surge	O
in	O
the	O
rate	O
of	O
ascorbyl	O
radical	O
production	O
,	O
directly	O
correlated	O
with	O
oxyradical	O
stress	O
and	O
an	O
abrupt	O
fall	O
in	O
superoxide	B-GENE
dismutase	I-GENE
activity	O
in	O
the	O
granuloma	O
,	O
indicates	O
'	O
switching	O
on	O
'	O
of	O
a	O
free	O
radical	O
-	O
dependent	O
machinery	O
for	O
the	O
formation	O
of	O
granuloma	O
after	O
vasectomy	O
.	O

The	O
vaccine	O
was	O
highly	O
immunogenic	O
,	O
since	O
111	O
of	O
113	O
patients	O
(	O
98	O
%	O
)	O
produced	O
anti	B-GENE
-	I-GENE
HBs	I-GENE
(	O
10	O
mIU	O
/	O
ml	O
or	O
more	O
)	O
.	O

Papillomavirus	O
type	O
16	O
oncogenes	O
downregulate	O
expression	O
of	O
interferon	B-GENE
-	O
responsive	O
genes	O
and	O
upregulate	O
proliferation	O
-	O
associated	O
and	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	O
responsive	O
genes	O
in	O
cervical	O
keratinocytes	O
.	O

A	O
model	O
for	O
the	O
SMase	B-GENE
-	O
sphingomyelin	O
complex	O
structure	O
was	O
built	O
to	O
investigate	O
how	O
the	O
SMase	B-GENE
specifically	O
recognizes	O
its	O
substrate	O
.	O

MADS	B-GENE
-	I-GENE
box	I-GENE
genes	I-GENE
in	O
plants	O
are	O
a	O
diverse	O
class	O
of	O
transcription	O
factors	O
that	O
are	O
involved	O
in	O
regulating	O
developmental	O
processes	O
,	O
particularly	O
meristem	O
and	O
organ	O
identity	O
during	O
floral	O
development	O
.	O

RESULTS	O
:	O
In	O
the	O
test	O
data	O
set	O
,	O
the	O
single	O
-	O
sample	O
model	O
was	O
confirmed	O
to	O
give	O
excellent	O
estimation	O
of	O
the	O
AUC	O
:	O
AUC	O
(	O
mg	O
/	O
ml	O
x	O
min	O
)	O
=	O
0	O
.	O
93	O
x	O
C3h	O
+	O
0	O
.	O
47	O
(	O
MPE	O
%	O
=	O
4	O
.	O
4	O
%	O
,	O
RMSE	O
%	O
=	O
8	O
.	O
9	O
%	O
)	O
.	O

Our	O
results	O
show	O
that	O
a	O
combination	O
of	O
Pfu	B-GENE
exo	I-GENE
(	I-GENE
-	I-GENE
)	I-GENE
at	O
the	O
primer	O
extension	O
step	O
and	O
Taq	B-GENE
at	O
the	O
PCR	O
amplification	O
step	O
is	O
ideal	O
for	O
in	O
vivo	O
DNA	O
analysis	O
and	O
DNA	O
damage	O
mapping	O
using	O
LMPCR	O
.	O

KU	O
-	O
1257	O
also	O
significantly	O
accelerated	O
the	O
healing	O
of	O
acetic	O
acid	O
-	O
induced	O
duodenal	O
ulcers	O
as	O
well	O
as	O
famotidine	O
and	O
roxatidine	O
acetate	O
.	O

Prolongation	O
of	O
prothrombin	B-GENE
time	O
was	O
not	O
due	O
to	O
depletion	O
of	O
vitamin	O
K	O
-	O
dependent	O
coagulation	O
factors	O
or	O
manifest	O
fibrinolysis	O
,	O
but	O
due	O
to	O
the	O
presence	O
of	O
circulating	O
fibrinogen	B-GENE
fibrinmonomer	I-GENE
-	O
FDP	O
complexes	O
.	O

Clostridium	O
botulinum	O
in	O
marine	O
sediment	O

Upstream	B-GENE
stimulatory	I-GENE
factor	I-GENE
USF	B-GENE
is	O
a	O
human	O
transcriptional	O
activation	O
factor	O
,	O
which	O
uses	O
a	O
basic	O
/	O
helix	O
-	O
loop	O
-	O
helix	O
/	O
leucin	O
zipper	O
(	O
b	O
/	O
HLH	O
/	O
Z	O
)	O
motif	O
to	O
homodimerize	O
and	O
recognize	O
specific	O
sequences	O
in	O
the	O
promoter	O
region	O
of	O
both	O
nuclear	O
and	O
viral	O
genes	O
transcribed	O
by	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
.	O

Fusion	O
of	O
mouse	B-GENE
CD8	I-GENE
+	I-GENE
class	B-GENE
I	I-GENE
MHC	I-GENE
-	O
restricted	O
T	O
cells	O
with	O
the	O
BW5147	O
thymoma	O
invariably	O
yields	O
CD8	B-GENE
-	I-GENE
hybridomas	O
in	O
which	O
RNA	O
transcribed	O
from	O
the	O
CD8	B-GENE
alpha	I-GENE
(	O
Lyt	B-GENE
-	I-GENE
2	I-GENE
)	O
gene	O
is	O
undetectable	O
.	O

Consistent	O
with	O
this	O
hypothesis	O
,	O
alpha1	B-GENE
-	I-GENE
PDX	I-GENE
prevents	O
cleavage	O
of	O
BMP	B-GENE
-	I-GENE
4	I-GENE
in	O
an	O
oocyte	O
translation	O
assay	O
.	O

Convergence	O
of	O
trigeminal	O
input	O
with	O
visceral	O
and	O
phrenic	O
inputs	O
on	O
primate	O
C1	O
-	O
C2	O
spinothalamic	O
tract	O
neurons	O
.	O

In	O
this	O
study	O
we	O
cloned	O
the	O
cDNA	O
of	O
AD1	B-GENE
Ag	I-GENE
from	O
a	O
rat	O
basophilic	O
leukemia	O
2H3	O
cDNA	O
library	O
.	O

Several	O
sequences	O
resembling	O
binding	O
sites	O
for	O
liver	O
-	O
and	O
fat	O
body	O
-	O
specific	O
transcription	O
factors	O
were	O
identified	O
within	O
1	O
kb	O
upstream	O
and	O
downstream	O
of	O
the	O
gene	O
.	O

Root	O
surface	O
caries	O
incidence	O
in	O
the	O
groups	O
inoculated	O
with	O
A	O
.	O
viscosus	O
and	O
A	O
.	O
viscosus	O
plus	O
S	O
.	O
sobrinus	O
did	O
not	O
differ	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
The	O
QTd	O
and	O
JTd	O
intervals	O
in	O
39	O
children	O
with	O
long	O
QT	O
syndrome	O
were	O
compared	O
to	O
those	O
of	O
50	O
normal	O
age	O
-	O
matched	O
children	O
.	O

The	O
prgX	B-GENE
gene	I-GENE
is	O
adjacent	O
to	O
prgQ	B-GENE
which	O
provides	O
the	O
promoter	O
for	O
prgB	B-GENE
expression	O
.	O

A	O
Frank	O
vectorcardiogram	O
was	O
recorded	O
before	O
and	O
every	O
15	O
-	O
30	O
minutes	O
for	O
10	O
hours	O
after	O
the	O
occlusion	O
.	O

The	O
treatment	O
of	O
Sudeck	O
'	O
s	O
atrophy	O
in	O
the	O
upper	O
limb	O
by	O
sympathetic	O
blockade	O
.	O

Frequency	O
of	O
recurrence	O
of	O
fibroids	O
after	O
myomectomy	O
has	O
been	O
evaluated	O
in	O
145	O
women	O
(	O
median	O
age	O
38	O
years	O
,	O
range	O
21	O
-	O
52	O
)	O
who	O
underwent	O
myomectomy	O
.	O

There	O
is	O
a	O
good	O
correlation	O
between	O
the	O
occurrence	O
in	O
any	O
particular	O
vascular	O
segment	O
of	O
the	O
transient	O
contractile	O
response	O
and	O
intrinsic	O
tone	O
as	O
assessed	O
by	O
relaxation	O
to	O
papaverine	O
(	O
10	O
(	O
-	O
6	O
)	O
M	O
)	O
.	O

The	O
antimicrobial	O
of	O
choice	O
for	O
initial	O
prophylactic	O
therapy	O
among	O
asymptomatic	O
pregnant	O
women	O
exposed	O
to	O
Bacillus	O
anthracis	O
is	O
ciprofloxacin	O
,	O
500	O
mg	O
twice	O
a	O
day	O
for	O
60	O
days	O
.	O

Spontaneous	O
coronary	O
artery	O
spasm	O
during	O
coronary	O
angiography	O
in	O
a	O
patient	O
with	O
exercise	O
-	O
induced	O
ST	O
segment	O
elevation	O
.	O

Nickel	O
release	O
from	O
tools	O
on	O
the	O
Swedish	O
market	O
.	O

There	O
was	O
no	O
correlation	O
between	O
starting	O
platelet	O
-	O
associated	O
IgG	B-GENE
levels	O
or	O
changes	O
in	O
platelet	O
-	O
associated	O
IgG	B-GENE
levels	O
with	O
therapy	O
and	O
the	O
increment	O
in	O
the	O
patient	O
'	O
s	O
platelet	O
count	O
.	O

The	O
receptor	O
for	O
CSF	B-GENE
-	I-GENE
1	I-GENE
,	O
c	B-GENE
-	I-GENE
Fms	I-GENE
,	O
is	O
expressed	O
in	O
osteoclasts	O
,	O
possesses	O
intrinsic	O
tyrosine	B-GENE
-	I-GENE
kinase	I-GENE
activity	O
,	O
and	O
signals	O
via	O
rapid	O
phosphorylation	O
of	O
selected	O
proteins	O
.	O

In	O
a	O
rat	O
model	O
of	O
SAH	O
,	O
we	O
assessed	O
BBB	O
changes	O
by	O
means	O
of	O
the	O
quantitative	O
[	O
14C	O
]	O
-	O
alpha	O
-	O
aminoisobutyric	O
acid	O
technique	O
.	O

BAG	B-GENE
-	I-GENE
1	I-GENE
also	O
prevented	O
growth	O
arrest	O
following	O
UV	O
-	O
irradiation	O
-	O
induced	O
genotoxic	O
injury	O
without	O
interfering	O
with	O
accumulation	O
of	O
p53	B-GENE
protein	I-GENE
or	O
p21	B-GENE
(	O
waf	B-GENE
-	I-GENE
1	I-GENE
)	O
expression	O
.	O

During	O
the	O
last	O
three	O
days	O
of	O
the	O
study	O
,	O
mean	O
urine	O
osmolality	O
(	O
Uosm	O
)	O
and	O
free	O
water	O
reabsorption	O
(	O
TCH2O	O
)	O
increased	O
significantly	O
:	O
[	O
formula	O
:	O
see	O
text	O
]	O
.	O

[	O
(	O
OP	O
)	O
2Cu	O
]	O
+	O
also	O
detected	O
protections	O
in	O
the	O
C	O
alpha	O
-	O
helix	O
,	O
the	O
interdomain	O
hinge	O
,	O
and	O
beta	O
-	O
strands	O
2	O
-	O
7	O
.	O

When	O
O	O
-	O
2A	O
/	O
c	B-GENE
-	I-GENE
myc	I-GENE
cells	O
underwent	O
terminal	O
differentiation	O
APprog	B-GENE
complexes	I-GENE
were	O
lost	O
and	O
conventional	O
AP	B-GENE
-	I-GENE
1	I-GENE
DNA	O
-	O
binding	O
activity	O
became	O
evident	O
,	O
particularly	O
in	O
astrocytes	O
.	O

The	O
gene	O
,	O
from	O
the	O
initiator	O
methionine	O
to	O
the	O
polyadenylation	O
site	O
,	O
is	O
contained	O
within	O
13	O
244	O
basepairs	O
and	O
contains	O
19	O
exons	O
.	O

To	O
study	O
structural	O
diversity	O
of	O
the	O
three	O
homologous	O
loci	O
encoding	O
a	O
KN1	B-GENE
-	I-GENE
like	I-GENE
homeobox	I-GENE
protein	I-GENE
in	O
the	O
hexaploid	O
wheat	O
genome	O
,	O
we	O
isolated	O
clones	O
from	O
a	O
cDNA	O
library	O
of	O
young	O
spikes	O
of	O
Japanese	O
common	O
wheat	O
cultivar	O
'	O
Norin	O
26	O
'	O
.	O

Treatment	O
is	O
based	O
on	O
antifungal	O
drugs	O
,	O
most	O
frequently	O
nystatin	O
,	O
amphotericin	O
B	O
and	O
ketoconazole	O
.	O

Controversy	O
exists	O
regarding	O
both	O
the	O
natural	O
life	O
cycle	O
for	O
this	O
parasite	O
as	O
well	O
as	O
the	O
species	O
identity	O
of	O
opossum	O
Sarcocystis	O
.	O

Here	O
we	O
report	O
that	O
components	O
of	O
the	O
Ras	B-GENE
/	O
Raf	B-GENE
/	O
MAPK	B-GENE
pathway	O
are	O
constitutively	O
activated	O
in	O
these	O
lck	B-GENE
-	O
transformed	O
immature	O
thymoblasts	O
.	O
p56	B-GENE
(	O
lck	B-GENE
)	O
utilizes	O
Shc	B-GENE
and	O
Grb2	B-GENE
adaptors	I-GENE
to	O
mediate	O
activation	O
of	O
p21	B-GENE
(	O
ras	B-GENE
)	O
in	O
the	O
thymoblast	O
lines	O
by	O
promoting	O
tyrosine	O
phosphorylation	O
of	O
the	O
Shc	B-GENE
protein	I-GENE
and	O
constitutive	O
interaction	O
between	O
Shc	B-GENE
and	O
Grb2	B-GENE
.	O

Unfractionated	O
heparin	O
(	O
UFH	O
)	O
given	O
at	O
a	O
dose	O
of	O
0	O
.	O
3	O
mg	O
x	O
kg	O
-	O
1	O
bolus	O
+	O
0	O
.	O
3	O
mg	O
x	O
kg	O
-	O
1	O
x	O
h	O
-	O
1	O
infusion	O
did	O
not	O
improve	O
the	O
incidence	O
of	O
reperfusion	O
or	O
lower	O
the	O
incidence	O
of	O
reocclusion	O
.	O

The	O
quantification	O
limit	O
was	O
50	O
ng	O
/	O
ml	O
for	O
each	O
of	O
PHT	O
,	O
m	O
-	O
HPPH	O
and	O
p	O
-	O
HPPH	O
.	O

Plasma	B-GENE
hemopexin	I-GENE
homeostasis	O
during	O
the	O
acute	O
phase	O
response	O
.	O

Our	O
aim	O
was	O
to	O
check	O
whether	O
,	O
during	O
PG	O
-	O
DS	O
administration	O
,	O
serum	O
lipase	B-GENE
activity	O
changes	O
simultaneously	O
with	O
serum	O
amylase	B-GENE
activity	O
,	O
and	O
,	O
if	O
so	O
,	O
what	O
the	O
reason	O
is	O
for	O
the	O
detected	O
change	O
.	O

(	O
i	O
)	O
The	O
chimeric	O
gene	O
consisting	O
of	O
the	O
coding	O
and	O
5	O
'	O
nontranslated	O
leader	O
regions	O
of	O
the	O
TK	B-GENE
gene	I-GENE
fused	O
to	O
portions	O
of	O
the	O
domain	O
of	O
alpha	B-GENE
gene	I-GENE
0	I-GENE
extending	O
largely	O
upstream	O
from	O
the	O
site	O
of	O
initiation	O
of	O
transcription	O
of	O
alpha	B-GENE
gene	I-GENE
0	I-GENE
was	O
regulated	O
in	O
the	O
same	O
fashion	O
as	O
the	O
alpha	B-GENE
4	I-GENE
-	I-GENE
and	I-GENE
alpha	I-GENE
27	I-GENE
-	I-GENE
TK	I-GENE
chimeras	O
.	O

Cytokines	O
and	O
steroid	O
hormones	O
use	O
different	O
sets	O
of	O
signal	O
transduction	O
pathways	O
,	O
which	O
seem	O
to	O
be	O
unrelated	O
.	O

This	O
is	O
the	O
most	O
northern	O
and	O
,	O
at	O
the	O
same	O
time	O
largest	O
,	O
Q	O
fever	O
epidemic	O
recorded	O
in	O
Germany	O
over	O
the	O
last	O
28	O
years	O
.	O

Genetic	O
analysis	O
of	O
the	O
role	O
of	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
glycoprotein	I-GENE
K	I-GENE
in	O
infectious	O
virus	O
production	O
and	O
egress	O
.	O

The	O
5	O
'	O
half	O
of	O
the	O
EWS	B-GENE
gene	I-GENE
has	O
recently	O
been	O
described	O
to	O
be	O
fused	O
to	O
the	O
3	O
'	O
regions	O
of	O
genes	O
encoding	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
several	O
transcriptional	O
regulators	O
,	O
including	O
ATF1	B-GENE
,	O
FLI	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
ERG	B-GENE
,	O
in	O
several	O
human	O
tumors	O
.	O

We	O
used	O
high	O
-	O
resolution	O
ultrasound	O
to	O
characterize	O
postprandial	O
antral	O
excursion	O
characteristics	O
in	O
15	O
healthy	O
volunteers	O
.	O

Multivariable	O
logistic	O
regression	O
showed	O
that	O
mean	O
blood	O
glucose	O
level	O
for	O
the	O
first	O
2	O
days	O
(	O
p	O
=	O
0	O
.	O
002	O
)	O
,	O
obesity	O
(	O
p	O
<	O
0	O
.	O
002	O
)	O
,	O
and	O
use	O
of	O
the	O
internal	O
mammary	O
artery	O
(	O
p	O
<	O
0	O
.	O
02	O
)	O
were	O
all	O
independent	O
predictors	O
of	O
deep	O
wound	O
infection	O
.	O

Fine	O
tangled	O
pili	O
expressed	O
by	O
Haemophilus	O
ducreyi	O
are	O
a	O
novel	O
class	O
of	O
pili	O
.	O

CONCLUSIONS	O
:	O
The	O
RRM	O
is	O
one	O
of	O
the	O
most	O
common	O
and	O
best	O
characterized	O
RNA	O
-	O
binding	O
motifs	O
.	O

Torsion	O
of	O
the	O
contralateral	O
testis	O
5	O
years	O
after	O
orchiopexy	O
.	O

Serum	O
levels	O
of	O
total	O
and	O
specific	B-GENE
immunoglobulin	I-GENE
E	I-GENE
(	O
IgE	B-GENE
)	O
have	O
been	O
determined	O
by	O
radioimmunoassays	O
in	O
sixty	O
-	O
nine	O
allergic	O
subjects	O
.	O

The	O
largest	O
one	O
probably	O
corresponds	O
to	O
the	O
precursor	O
form	O
of	O
PS2	B-GENE
in	O
E	O
.	O
coli	O
.	O

Transcriptional	O
analysis	O
indicates	O
that	O
human	B-GENE
TBP	I-GENE
functions	O
poorly	O
at	O
promoters	O
recognized	O
by	O
RNA	B-GENE
polymerases	I-GENE
I	I-GENE
and	I-GENE
III	I-GENE
and	O
at	O
RNA	B-GENE
Pol	I-GENE
II	I-GENE
promoters	I-GENE
lacking	O
a	O
conventional	O
TATA	O
element	O
.	O

Elements	O
of	O
the	O
hAT	B-GENE
transposon	I-GENE
family	I-GENE
,	O
such	O
as	O
the	O
maize	B-GENE
activator	I-GENE
(	O
Ac	B-GENE
)	O
,	O
have	O
been	O
discovered	O
in	O
a	O
large	O
number	O
of	O
eukaryotic	O
species	O
.	O

The	O
identification	O
of	O
SRP54sc	B-GENE
and	O
SRP54sp	B-GENE
provides	O
the	O
first	O
evidence	O
for	O
SRP	B-GENE
related	O
proteins	O
in	O
yeast	O
.	O

We	O
have	O
isolated	O
two	O
H19	B-GENE
cDNAs	I-GENE
(	O
AP	B-GENE
and	O
ES	B-GENE
)	O
that	O
contain	O
this	O
ORF4	O
and	O
correspond	O
to	O
incomplete	O
copies	O
of	O
the	O
unique	O
2	B-GENE
.	I-GENE
3	I-GENE
kb	I-GENE
H19	I-GENE
RNA	I-GENE
.	O

Urease	B-GENE
activity	O
,	O
judged	O
as	O
the	O
amount	O
of	O
ammonia	O
production	O
from	O
urea	O
,	O
could	O
be	O
measured	O
at	O
25	O
ng	O
per	O
tube	O
(	O
S	O
/	O
N	O
=	O
1	O
.	O
5	O
)	O
with	O
Jack	B-GENE
bean	I-GENE
meal	I-GENE
urease	I-GENE
.	O

Radioimmunoassay	O
of	O
plasma	B-GENE
gonadotropins	I-GENE
;	O
problems	O
of	O
specificity	O

Tissue	O
expansion	O
was	O
used	O
successfully	O
to	O
prepare	O
adequate	O
soft	O
tissue	O
for	O
closure	O
following	O
a	O
difficult	O
clubfoot	O
correction	O
.	O

Legionella	B-GENE
antibodies	I-GENE
in	O
domestic	O
animals	O

In	O
a	O
previous	O
study	O
of	O
transforming	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
beta1	I-GENE
-	O
mediated	O
inhibition	O
of	O
the	O
cyclin	B-GENE
A	I-GENE
promoter	I-GENE
,	O
we	O
mapped	O
the	O
inhibitory	O
effect	O
to	O
the	O
ATF	B-GENE
site	I-GENE
;	O
in	O
the	O
present	O
study	O
of	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
treatment	O
,	O
functional	O
analysis	O
by	O
transient	O
transfection	O
showed	O
that	O
inhibition	O
of	O
the	O
cyclin	B-GENE
A	I-GENE
promoter	I-GENE
persisted	O
despite	O
mutation	O
of	O
the	O
ATF	B-GENE
,	O
NF	B-GENE
-	I-GENE
Y	I-GENE
,	O
or	O
CDE	O
elements	O
.	O

No	O
significant	O
difference	O
was	O
seen	O
found	O
between	O
the	O
two	O
groups	O
in	O
the	O
degree	O
of	O
postoperative	O
deterioration	O
in	O
cardiopulmonary	O
function	O
or	O
in	O
interleukin	B-GENE
-	I-GENE
6	I-GENE
levels	O
.	O

We	O
show	O
that	O
GCNF	B-GENE
binds	O
to	O
one	O
of	O
the	O
two	O
DRO	O
sequences	O
in	O
the	O
Prm1	B-GENE
promoter	I-GENE
,	O
and	O
to	O
the	O
DRO	O
sequence	O
in	O
the	O
Prm2	B-GENE
promoter	I-GENE
in	O
a	O
specific	O
manner	O
.	O

The	O
strategy	O
uses	O
RNA	B-GENE
ligase	I-GENE
to	O
add	O
DNA	O
oligonucleotide	O
priming	O
sites	O
to	O
the	O
RNA	O
for	O
subsequent	O
reverse	O
transcription	O
and	O
PCR	O
(	O
RNA	B-GENE
ligase	I-GENE
,	O
reverse	O
transcription	O
-	O
PCR	O
,	O
or	O
RL	O
/	O
RT	O
/	O
PCR	O
)	O
.	O

From	O
1977	O
to	O
1985	O
,	O
42	O
patients	O
with	O
squamous	O
cell	O
carcinoma	O
of	O
the	O
anal	O
canal	O
were	O
treated	O
with	O
mitomycin	O
C	O
(	O
15	O
mg	O
/	O
m2	O
)	O
and	O
5	O
-	O
fluorouracil	O
(	O
750	O
mg	O
/	O
m2	O
)	O
on	O
day	O
1	O
,	O
5	O
-	O
FU	O
(	O
750	O
mg	O
/	O
m2	O
/	O
d	O
)	O
alone	O
on	O
days	O
2	O
to	O
5	O
,	O
and	O
radiation	O
therapy	O
(	O
3000	O
cGy	O
)	O
on	O
days	O
7	O
to	O
28	O
.	O

Effect	O
of	O
choline	O
magnesium	O
trisalicylate	O
on	O
prostacyclin	O
production	O
by	O
isolated	O
vascular	O
tissue	O
of	O
the	O
rat	O
.	O

The	O
magnitude	O
of	O
all	O
four	O
parameters	O
increased	O
in	O
an	O
exponential	O
fashion	O
with	O
increasing	O
sperm	O
number	O
up	O
to	O
400	O
x	O
10	O
(	O
6	O
)	O
per	O
ejaculate	O
.	O

A	O
sharp	O
transition	O
from	O
a	O
random	O
chaotic	O
state	O
to	O
a	O
correlated	O
turbulent	O
state	O
of	O
finite	O
coherence	O
time	O
is	O
found	O
when	O
the	O
Rayleigh	O
number	O
becomes	O
larger	O
than	O
a	O
critical	O
value	O
Ra	O
(	O
c	O
)	O
approximately	O
equal	O
to	O
5	O
x	O
10	O
(	O
7	O
)	O
.	O

In	O
HMEC	O
stably	O
transfected	O
with	O
an	O
ER	B-GENE
mutant	I-GENE
containing	O
a	O
deletion	O
in	O
the	O
second	O
zinc	O
finger	O
of	O
the	O
DNA	O
-	O
binding	O
domain	O
,	O
E	O
and	O
HT	O
had	O
different	O
effects	O
on	O
EBBP	B-GENE
gene	I-GENE
expression	O
;	O
EBBP	B-GENE
regulation	O
by	O
E	O
was	O
dramatically	O
reduced	O
while	O
the	O
effects	O
of	O
HT	O
were	O
augmented	O
.	O

6	O
h	O
after	O
ingestion	O
of	O
aspirin	O
on	O
day	O
1	O
to	O
day	O
14	O
,	O
both	O
TX	O
and	O
PGI2	O
levels	O
also	O
significantly	O
decreased	O
(	O
p	O
<	O
0	O
.	O
0001	O
)	O
.	O

When	O
transfected	O
into	O
HepG2	O
cells	O
,	O
which	O
lack	O
C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
,	O
the	O
mouse	B-GENE
ob	I-GENE
promoter	I-GENE
was	O
only	O
weakly	O
active	O
.	O

Desarrollo	O
de	O
un	O
modelo	O
matematico	O
general	O
para	O
los	O
procesos	O
fermentativos	O
,	O
Cinetica	O
de	O
la	O
degradacion	O
anaerobia	O
,	O
Ph	O
.	O
D	O
.	O

NF	B-GENE
-	I-GENE
kappaB	I-GENE
DNA	O
-	O
protein	O
binding	O
and	O
ICAM	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
activity	O
were	O
enhanced	O
by	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
and	O
these	O
effects	O
were	O
inhibited	O
by	O
tyrphostin	O
23	O
,	O
but	O
not	O
by	O
PD	O
98059	O
or	O
SB	O
203580	O
.	O

In	O
murine	O
cells	O
,	O
FPGS	B-GENE
expression	O
is	O
controlled	O
by	O
two	O
promoters	O
that	O
,	O
as	O
we	O
show	O
here	O
,	O
vary	O
substantially	O
in	O
their	O
efficiency	O
,	O
at	O
least	O
in	O
the	O
context	O
of	O
a	O
reporter	O
gene	O
assay	O
.	O

Quantitative	O
measurement	O
of	O
antigamma	B-GENE
globulin	I-GENE
factors	I-GENE
(	O
rheumatoid	B-GENE
factors	I-GENE
)	O
using	O
laser	O
-	O
nephelometry	O
in	O
comparison	O
with	O
the	O
latex	O
agglutination	O
test	O
and	O
the	O
Waaler	O
-	O
Rose	O
test	O

Disruption	O
of	O
INP53	B-GENE
,	O
but	O
not	O
the	O
related	O
INP51	B-GENE
and	O
INP52	B-GENE
genes	I-GENE
,	O
resulted	O
in	O
alpha	B-GENE
-	I-GENE
factor	I-GENE
maturation	O
defects	O
and	O
exacerbated	O
alpha	B-GENE
-	I-GENE
factor	I-GENE
maturation	O
defects	O
when	O
combined	O
with	O
chc1	B-GENE
-	I-GENE
521	I-GENE
.	O

The	O
complete	O
nucleotide	O
sequence	O
of	O
odontoglossum	O
ringspot	O
virus	O
(	O
Cy	O
-	O
1	O
strain	O
)	O
genomic	O
RNA	O
.	O

Paradoxically	O
there	O
is	O
a	O
decrease	O
in	O
the	O
level	O
of	O
soluble	B-GENE
A	I-GENE
beta	I-GENE
secreted	O
from	O
the	O
cells	O
.	O

When	O
translated	O
in	O
-	O
frame	O
with	O
PKC	B-GENE
zeta	I-GENE
,	O
a	O
stop	O
codon	O
is	O
located	O
28	O
amino	O
acids	O
towards	O
the	O
N	O
-	O
terminus	O
of	O
the	O
divergence	O
point	O
and	O
the	O
intervening	O
sequence	O
lacks	O
an	O
expected	O
initiating	O
methionine	O
.	O
psi	B-GENE
PKC	I-GENE
zeta	I-GENE
is	O
non	O
-	O
functional	O
in	O
terms	O
of	O
protein	O
synthesis	O
since	O
Western	O
blotting	O
with	O
an	O
antibody	O
directed	O
against	O
the	O
C	O
-	O
terminus	O
of	O
PKC	B-GENE
zeta	I-GENE
failed	O
to	O
reveal	O
a	O
protein	O
smaller	O
than	O
PKC	B-GENE
zeta	I-GENE
,	O
and	O
synthetic	O
psi	B-GENE
PKC	I-GENE
zeta	I-GENE
RNA	I-GENE
failed	O
to	O
support	O
protein	O
synthesis	O
in	O
a	O
translation	O
system	O
in	O
vitro	O
.	O

Comparative	O
ultrafiltration	O
(	O
UF	O
)	O
studies	O
with	O
BiGG	O
and	O
standard	O
lactate	O
(	O
La	O
)	O
solutions	O
in	O
rabbits	O
showed	O
that	O
net	O
UF	O
with	O
La	O
solution	O
peaked	O
at	O
2	O
h	O
and	O
decreased	O
significantly	O
at	O
4	O
h	O
and	O
6	O
h	O
.	O

The	O
B	B-GENE
.	I-GENE
aphidicola	I-GENE
argS	I-GENE
-	I-GENE
rrn	I-GENE
DNA	I-GENE
fragments	I-GENE
from	O
endosymbionts	O
from	O
seven	O
species	O
of	O
aphids	O
had	O
promoter	O
activities	O
in	O
E	O
.	O
coli	O
which	O
ranged	O
from	O
6	O
to	O
135	O
%	O
of	O
that	O
observed	O
with	O
a	O
comparable	O
DNA	O
fragment	O
of	O
E	B-GENE
.	I-GENE
coli	I-GENE
rrnB	I-GENE
.	O

CONCLUSIONS	O
:	O
These	O
principally	O
structural	O
studies	O
support	O
the	O
hypothesis	O
that	O
the	O
thrombus	O
is	O
a	O
self	O
-	O
sustaining	O
entity	O
that	O
may	O
have	O
significance	O
in	O
the	O
pathophysiologic	O
mechanism	O
of	O
abdominal	O
aortic	O
aneurysms	O
.	O

The	O
authors	O
report	O
about	O
the	O
exeresis	O
of	O
a	O
pyelonephrictic	O
left	O
small	O
kidney	O
with	O
laparoscopic	O
surgery	O
.	O

AMPK	B-GENE
is	O
a	O
heterotrimer	O
composed	O
of	O
a	O
catalytic	O
subunit	O
(	O
alpha	O
)	O
and	O
two	O
regulatory	O
subunits	O
(	O
beta	O
and	O
gamma	O
)	O
.	O

The	O
genes	O
encoding	O
these	O
carotenoids	O
in	O
E	O
.	O
herbicola	O
Eho13	O
are	O
clustered	O
in	O
a	O
7	O
kb	O
DNA	O
fragment	O
.	O

Genetic	O
diagnosis	O
of	O
respiratory	O
diseases	O

Whereas	O
mutant	B-GENE
6C4	I-GENE
specified	O
a	O
wild	B-GENE
-	I-GENE
type	I-GENE
-	I-GENE
size	I-GENE
Pol	I-GENE
protein	I-GENE
,	O
we	O
detected	O
no	O
full	B-GENE
-	I-GENE
length	I-GENE
Pol	I-GENE
protein	I-GENE
in	O
7E4	O
-	O
infected	O
cell	O
extracts	O
.	O

Incidence	O
of	O
beta	O
-	O
thalassemia	O
carriers	O
and	O
those	O
deficient	O
in	O
erythrocyte	B-GENE
glucose	I-GENE
-	I-GENE
6	I-GENE
-	I-GENE
phosphate	I-GENE
dehydrogenase	I-GENE
in	O
the	O
greater	O
Buenos	O
Aires	O
area	O

Other	O
toxicities	O
attributed	O
to	O
CPT	O
-	O
11	O
included	O
dehydration	O
,	O
nausea	O
,	O
vomiting	O
,	O
and	O
asthenia	O
.	O

JCAHO	O
moves	O
to	O
rewrite	O
many	O
rules	O
to	O
lessen	O
hospitals	O
'	O
regulatory	O
burden	O
.	O

A	O
phylogenetic	O
comparison	O
of	O
32	O
species	O
showed	O
minor	O
differences	O
in	O
the	O
apoB	B-GENE
mRNA	I-GENE
sequence	I-GENE
,	O
and	O
the	O
apoB	B-GENE
mRNA	I-GENE
from	O
31	O
species	O
was	O
robustly	O
edited	O
in	O
vitro	O
.	O

The	O
expression	O
pattern	O
of	O
the	O
reporter	O
gene	O
was	O
compared	O
to	O
that	O
of	O
the	O
endogenous	B-GENE
PDGFbeta	I-GENE
r	I-GENE
gene	I-GENE
.	O

These	O
transcripts	O
directed	O
the	O
synthesis	O
of	O
three	O
proteins	O
:	O
the	O
virus	B-GENE
trans	I-GENE
-	I-GENE
activator	I-GENE
protein	I-GENE
(	O
EIAV	B-GENE
Tat	I-GENE
)	O
encoded	O
by	O
ORF	O
S1	O
,	O
a	O
protein	O
of	O
unknown	O
function	O
encoded	O
by	O
ORF	O
S2	O
,	O
and	O
the	O
virus	O
envelope	B-GENE
glycoprotein	I-GENE
.	O

In	O
addition	O
,	O
because	O
SB203580	O
had	O
no	O
effect	O
of	O
TNF	B-GENE
-	O
or	O
ceramide	O
-	O
induced	O
apoptosis	O
,	O
our	O
results	O
strongly	O
argue	O
against	O
a	O
role	O
for	O
p38	B-GENE
MAPK	I-GENE
in	O
the	O
induction	O
of	O
TNF	B-GENE
-	O
-	O
or	O
ceramide	O
-	O
induced	O
apoptosis	O
.	O

Seven	O
Zebu	O
cattle	O
were	O
also	O
exposed	O
to	O
challenge	O
at	O
the	O
same	O
time	O
.	O

To	O
study	O
the	O
signaling	O
pathways	O
that	O
regulate	O
cytoskeletal	O
rearrangements	O
in	O
T	O
lymphocytes	O
,	O
we	O
set	O
up	O
a	O
conjugate	O
formation	O
assay	O
using	O
Jurkat	O
T	O
cells	O
as	O
effectors	O
and	O
cell	O
-	O
sized	O
latex	O
beads	O
coated	O
with	O
various	O
antibodies	O
as	O
artificial	O
APCs	O
.	O

YACs	O
,	O
BACs	O
,	O
cosmids	O
,	O
and	O
STSs	O
are	O
defined	O
to	O
aid	O
in	O
further	O
study	O
of	O
this	O
gene	O
.	O

The	O
average	O
coefficient	O
of	O
variation	O
between	O
assays	O
for	O
gas	O
chromatography	O
mass	O
spectrometry	O
was	O
5	O
.	O
8	O
%	O
and	O
for	O
radioimmunoassay	O
was	O
12	O
.	O
3	O
%	O
,	O
while	O
the	O
average	O
coefficient	O
of	O
variation	O
within	O
assays	O
for	O
gas	O
chromatography	O
mass	O
spectrometry	O
was	O
4	O
.	O
9	O
%	O
and	O
for	O
radioimmunoassay	O
6	O
.	O
9	O
%	O
.	O

This	O
chimera	O
transduced	O
IL	B-GENE
-	I-GENE
4	I-GENE
-	O
specific	O
signals	O
in	O
response	O
to	O
IL	B-GENE
-	I-GENE
2	I-GENE
binding	O
and	O
dramatically	O
enhanced	O
type	O
2	O
responses	O
(	O
IL	B-GENE
-	I-GENE
4	I-GENE
,	O
IL	B-GENE
-	I-GENE
5	I-GENE
,	O
and	O
immunoglobulin	B-GENE
E	I-GENE
production	O
)	O
upon	O
in	O
vitro	O
TCR	B-GENE
stimulation	O
or	O
in	O
vivo	O
antigen	O
challenge	O
.	O

Soggy	B-GENE
,	O
a	O
spermatocyte	O
-	O
specific	O
gene	O
,	O
lies	O
3	O
.	O
8	O
kb	O
upstream	O
of	O
and	O
antipodal	O
to	O
TEAD	B-GENE
-	I-GENE
2	I-GENE
,	O
a	O
transcription	O
factor	O
expressed	O
at	O
the	O
beginning	O
of	O
mouse	O
development	O
.	O

We	O
previously	O
demonstrated	O
that	O
AKT2	B-GENE
,	O
a	O
member	O
of	O
protein	B-GENE
kinase	I-GENE
B	I-GENE
family	I-GENE
,	O
is	O
activated	O
by	O
a	O
number	O
of	O
growth	O
factors	O
via	O
Ras	B-GENE
and	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
signaling	O
pathways	O
.	O

This	O
demonstrates	O
the	O
presence	O
of	O
a	O
PKC	B-GENE
-	O
dependent	O
pathway	O
which	O
functions	O
independently	O
from	O
Lck	B-GENE
in	O
MAP	B-GENE
kinase	I-GENE
activation	O
.	O

Finally	O
,	O
transfection	O
of	O
Grb10	B-GENE
genes	I-GENE
with	O
specific	O
mutations	O
in	O
their	O
SH2	B-GENE
domains	I-GENE
induces	O
apoptosis	O
in	O
HTC	O
-	O
IR	O
and	O
COS	O
-	O
7	O
cells	O
.	O

Small	B-GENE
t	I-GENE
also	O
inhibited	O
the	O
dephosphorylation	O
of	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
PKA	B-GENE
)	O
-	O
phosphorylated	O
CREB	B-GENE
in	O
rat	O
liver	O
nuclear	O
extracts	O
.	O

Physical	O
map	O
of	O
the	O
genome	O
of	O
sonchus	O
yellow	O
net	O
virus	O
,	O
a	O
plant	O
rhabdovirus	O
with	O
six	O
genes	O
and	O
conserved	O
gene	O
junction	O
sequences	O
.	O

It	O
is	O
an	O
untested	O
argument	O
that	O
conventional	O
beta	B-GENE
-	I-GENE
adrenoceptor	I-GENE
antagonists	O
possess	O
unwanted	O
metabolic	O
effects	O
that	O
may	O
counter	O
some	O
of	O
their	O
potential	O
cardiac	O
benefits	O
.	O

However	O
,	O
it	O
is	O
not	O
easy	O
to	O
establish	O
the	O
diagnosis	O
of	O
thoracic	O
MFH	O
.	O

An	O
11	O
.	O
5	O
-	O
kb	O
intron	O
is	O
found	O
at	O
the	O
end	O
of	O
transmembrane	O
6	O
,	O
and	O
the	O
rest	O
of	O
the	O
ORF	O
is	O
in	O
exon	O
3	O
.	O

To	O
assay	O
for	O
sequences	O
that	O
could	O
potentially	O
regulate	O
Xenopus	B-GENE
proenkephalin	I-GENE
expression	O
,	O
we	O
transfected	O
constructs	O
that	O
contained	O
upstream	O
genomic	O
sequences	O
linked	O
to	O
the	O
CAT	B-GENE
reporter	I-GENE
gene	I-GENE
into	O
various	O
eukaryotic	O
cell	O
lines	O
.	O

It	O
is	O
also	O
conceivable	O
that	O
elevated	O
insulin	B-GENE
levels	O
may	O
cause	O
hypertriglyceridaemia	O
and	O
possibly	O
other	O
abnormalities	O
of	O
lipid	O
metabolism	O
.	O

The	O
effects	O
of	O
different	O
sources	O
of	O
commercial	O
rations	O
on	O
the	O
humoral	O
immune	O
response	O
of	O
broilers	O
to	O
Newcastle	O
disease	O
vaccination	O
.	O

To	O
quantify	O
the	O
normal	O
coupling	O
patterns	O
,	O
fresh	O
cadaveric	O
human	O
lumbar	O
spine	O
specimens	O
(	O
L1	O
-	O
S1	O
)	O
were	O
used	O
.	O

Deletion	O
mutations	O
were	O
constructed	O
,	O
removing	O
residues	O
2	O
-	O
30	O
,	O
31	O
-	O
60	O
,	O
61	O
-	O
90	O
,	O
and	O
49	O
-	O
78	O
of	O
the	O
N	O
-	O
terminal	O
cytoplasmic	O
domain	O
,	O
as	O
well	O
as	O
a	O
missense	O
mutation	O
of	O
a	O
dileucine	O
motif	O
.	O

When	O
the	O
measured	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
activity	O
in	O
the	O
pWP	O
-	O
transfected	O
cells	O
was	O
normalized	O
to	O
the	O
pCH110	O
-	O
transfected	O
cells	O
(	O
an	O
appropriate	O
control	O
if	O
the	O
SV40	B-GENE
early	I-GENE
region	I-GENE
promoter	I-GENE
functions	O
constitutively	O
in	O
various	O
cell	O
lines	O
)	O
,	O
the	O
results	O
suggested	O
that	O
the	O
promoter	O
region	O
of	O
the	O
PLP	B-GENE
gene	I-GENE
contains	O
the	O
information	O
necessary	O
for	O
initiation	O
of	O
transcription	O
in	O
a	O
C6	O
cell	O
-	O
specific	O
manner	O
.	O

Indigenous	O
microbial	O
flora	O
and	O
the	O
large	O
intestine	O
in	O
tadpoles	O
.	O

3	O
patients	O
with	O
acute	O
leukaemia	O
,	O
HLA	B-GENE
antibodies	O
and	O
thrombocytopenia	O
refractory	O
to	O
random	O
donor	O
platelet	O
transfusions	O
were	O
treated	O
with	O
high	O
-	O
dose	O
i	O
.	O
v	O
.	O
immunoglobulin	B-GENE
.	O

Plasma	B-GENE
renin	I-GENE
activity	O
in	O
end	O
-	O
stage	O
kidney	O
disease	O
.	O

Computer	O
system	O
trains	O
employees	O
to	O
meet	O
JCAHO	O
safety	O
ED	O
requirements	O
.	O

The	O
temporal	O
sequence	O
of	O
organ	O
failure	O
was	O
lung	O
,	O
clotting	O
system	O
,	O
kidney	O
,	O
and	O
liver	O
.	O

All	O
of	O
this	O
region	O
is	O
part	O
of	O
a	O
prominent	O
CpG	O
island	O
that	O
may	O
be	O
acting	O
as	O
an	O
extended	O
,	O
enhancer	O
-	O
independent	O
promoter	O
.	O

One	O
function	O
of	O
p53	B-GENE
is	O
in	O
regulating	O
cell	O
cycle	O
check	O
-	O
point	O
control	O
after	O
DNA	O
damage	O
.	O

100	O
.	O

IGF	B-GENE
-	I-GENE
I	I-GENE
levels	O
were	O
measured	O
in	O
the	O
CSF	O
of	O
11	O
children	O
with	O
autism	O
(	O
4	O
females	O
,	O
7	O
males	O
;	O
mean	O
age	O
3	O
.	O
8	O
years	O
,	O
SD	O
1	O
.	O
1	O
)	O
using	O
a	O
sensitive	O
radioimmunoassay	O
method	O
and	O
compared	O
with	O
levels	O
in	O
11	O
control	O
participants	O
(	O
6	O
females	O
,	O
5	O
males	O
;	O
mean	O
age	O
3	O
.	O
8	O
years	O
)	O
.	O

The	O
XPR2	B-GENE
gene	I-GENE
from	O
Yarrowia	O
lipolytica	O
encodes	O
an	O
inducible	O
alkaline	B-GENE
extracellular	I-GENE
protease	I-GENE
.	O

Two	O
closely	O
related	O
groups	O
of	O
transcripts	O
,	O
Sagrp1	B-GENE
and	O
Sagrp2	B-GENE
,	O
controlled	O
by	O
a	O
circadian	O
rhythm	O
have	O
been	O
isolated	O
.	O

In	O
patients	O
autografted	O
in	O
CR1	O
,	O
the	O
transplant	O
-	O
related	O
mortality	O
(	O
TRM	O
)	O
was	O
15	O
+	O
/	O
-	O
4	O
%	O
,	O
the	O
relapse	O
incidence	O
(	O
RI	O
)	O
was	O
58	O
+	O
/	O
-	O
5	O
%	O
,	O
the	O
leukaemia	O
-	O
free	O
survival	O
(	O
LFS	O
)	O
was	O
36	O
+	O
/	O
-	O
5	O
%	O
and	O
the	O
overall	O
survival	O
was	O
47	O
+	O
/	O
-	O
5	O
%	O
at	O
3	O
years	O
.	O

However	O
,	O
H19	B-GENE
and	O
IGF2	B-GENE
lie	O
within	O
a	O
larger	O
imprinted	O
domain	O
,	O
and	O
the	O
gene	O
specificity	O
of	O
H19	B-GENE
epimutation	O
has	O
been	O
a	O
persistent	O
question	O
.	O

Antibiotics	O
and	O
CDCA	O
-	O
mediation	O
are	O
essential	O
for	O
symptomatic	O
therapy	O
.	O

The	O
effectiveness	O
and	O
pathogenetic	O
expediency	O
of	O
correcting	O
disorders	O
of	O
lipid	O
metabolism	O
in	O
atherosclerosis	O
with	O
enterosorbents	O
is	O
substantiated	O
.	O

Adaptive	O
effects	O
of	O
repeated	O
immersion	O
exposure	O
on	O
the	O
human	O
body	O

The	O
human	O
cDNA	O
was	O
cloned	O
and	O
sequenced	O
;	O
it	O
was	O
shown	O
to	O
have	O
an	O
open	O
reading	O
frame	O
encoding	O
a	O
296	O
-	O
amino	O
-	O
acid	O
protein	O
in	O
which	O
could	O
be	O
identified	O
four	O
peptides	O
previously	O
identified	O
by	O
micro	O
-	O
sequencing	O
purified	O
protein	O
.	O

Octamer	O
recognition	O
is	O
mediated	O
by	O
the	O
POU	B-GENE
domain	O
,	O
a	O
conserved	O
structural	O
motif	O
which	O
-	O
-	O
like	O
the	O
zinc	O
finger	O
and	O
leucine	O
zipper	O
-	O
-	O
defines	O
a	O
family	O
of	O
related	O
transcription	O
factors	O
.	O

Copyright	O
1998	O
The	O
Association	O
for	O
the	O
Study	O
of	O
Animal	O
Behaviour	O
.	O

Dipetalonema	O
(	O
Acanthocheilonema	O
)	O
didelphis	O
sp	O
.	O
n	O
.	O

Forty	O
-	O
five	O
patients	O
with	O
recent	O
-	O
onset	O
hyperthyroidism	O
(	O
<	O
12	O
weeks	O
)	O
were	O
sex	O
and	O
menopause	O
stratified	O
and	O
randomly	O
allocated	O
to	O
treatment	O
with	O
carbimazole	O
(	O
Neotomizol	O
)	O
,	O
carbimazole	O
plus	O
low	O
dose	O
CT	O
(	O
Calsynar	O
;	O
100	O
IU	O
/	O
day	O
,	O
2	O
days	O
/	O
week	O
)	O
,	O
or	O
carbimazole	O
plus	O
high	O
dose	O
CT	O
(	O
Calsynar	O
;	O
100	O
IU	O
/	O
day	O
,	O
14	O
days	O
/	O
month	O
)	O
.	O

The	O
promyelocytic	B-GENE
leukemia	I-GENE
protein	I-GENE
interacts	O
with	O
Sp1	B-GENE
and	O
inhibits	O
its	O
transactivation	O
of	O
the	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
promoter	O
.	O

CTP	O
,	O
GDP	O
,	O
GTP	O
,	O
ITP	O
)	O
did	O
not	O
affect	O
the	O
response	O
.	O

Here	O
,	O
we	O
characterize	O
TCR	B-GENE
/	O
CD48	B-GENE
and	O
TCR	B-GENE
/	O
CD28	B-GENE
costimulation	O
in	O
T	O
cells	O
expressing	O
Lck	B-GENE
Src	B-GENE
homology	I-GENE
3	I-GENE
(	O
SH3	B-GENE
)	O
mutants	O
.	O

We	O
also	O
show	O
that	O
psbH	B-GENE
and	O
psbT	B-GENE
are	O
transcribed	O
from	O
the	O
upstream	O
psbB	B-GENE
gene	I-GENE
promoter	I-GENE
,	O
and	O
that	O
the	O
psbH	B-GENE
mRNA	I-GENE
has	O
its	O
own	O
target	O
sequence	O
for	O
Mbb1	B-GENE
function	O
.	O

Thus	O
,	O
it	O
appears	O
that	O
moxalactam	O
is	O
a	O
reliable	O
and	O
useful	O
antibiotic	O
for	O
the	O
treatment	O
of	O
complicated	O
urinary	O
tract	O
infections	O
.	O

In	O
the	O
second	O
,	O
37	O
students	O
were	O
given	O
trimethoprim	O
/	O
sulphamethoxazole	O
(	O
160	O
mg	O
TMP	O
-	O
SMX	O
800	O
mg	O
)	O
,	O
38	O
TMP	O
(	O
200	O
mg	O
)	O
,	O
and	O
in	O
35	O
a	O
placebo	O
was	O
given	O
b	O
.	O
i	O
.	O
d	O
.	O
for	O
five	O
days	O
.	O

CONCLUSION	O
:	O
Men	O
presenting	O
with	O
urethritis	O
and	O
women	O
presenting	O
with	O
PID	O
both	O
have	O
significantly	O
greater	O
peripheral	O
blood	O
mononuclear	O
cell	O
proliferative	O
responses	O
to	O
the	O
DK20	O
strain	O
of	O
C	O
trachomatis	O
than	O
controls	O
.	O

The	O
infection	O
of	O
cells	O
with	O
Moloney	O
murine	O
leukemia	O
virus	O
(	O
M	O
-	O
MuLV	O
)	O
causes	O
an	O
increase	O
in	O
specific	O
cellular	O
gene	O
products	O
,	O
including	O
the	O
major	B-GENE
histocompatibility	I-GENE
complex	I-GENE
(	I-GENE
MHC	I-GENE
)	I-GENE
class	I-GENE
I	I-GENE
antigens	I-GENE
.	O

Apparent	O
Buschke	O
-	O
Loewenstein	O
tumour	O
of	O
the	O
penis	O
.	O

The	O
orthologs	O
of	O
the	O
Y	B-GENE
(	I-GENE
1	I-GENE
)	I-GENE
and	O
Y	B-GENE
(	I-GENE
2	I-GENE
)	I-GENE
subtypes	I-GENE
display	O
high	O
amino	O
acid	O
sequence	O
identities	O
between	O
pig	O
,	O
human	O
,	O
and	O
mouse	O
(	O
92	O
%	O
-	O
94	O
%	O
)	O
,	O
whereas	O
the	O
Y	B-GENE
(	I-GENE
4	I-GENE
)	I-GENE
,	O
Y	B-GENE
(	I-GENE
5	I-GENE
)	I-GENE
,	O
and	O
y	B-GENE
(	I-GENE
6	I-GENE
)	I-GENE
subtypes	I-GENE
display	O
lower	O
identities	O
(	O
76	O
%	O
-	O
87	O
%	O
)	O
.	O

In	O
NIH	O
3T3	O
fibroblasts	O
the	O
high	O
affinity	O
IL	B-GENE
-	I-GENE
2R	I-GENE
bearing	O
a	O
deletion	O
of	O
a	O
region	O
rich	O
in	O
acidic	O
amino	O
acids	O
(	O
the	O
"	O
acidic	O
"	O
region	O
)	O
in	O
the	O
IL	B-GENE
-	I-GENE
2R	I-GENE
beta	I-GENE
-	I-GENE
chain	I-GENE
failed	O
to	O
induce	O
the	O
tyrosine	O
phosphorylation	O
of	O
MAP	B-GENE
kinase	I-GENE
as	O
well	O
as	O
the	O
expression	O
of	O
the	O
all	O
three	O
nuclear	O
proto	O
-	O
oncogenes	O
.	O

Activation	O
of	O
the	O
cytotactin	B-GENE
promoter	I-GENE
by	O
the	O
homeobox	B-GENE
-	I-GENE
containing	I-GENE
gene	I-GENE
Evx	I-GENE
-	I-GENE
1	I-GENE
.	O

Of	O
the	O
private	O
practices	O
accredited	O
in	O
August	O
1995	O
,	O
40	O
.	O
6	O
per	O
cent	O
(	O
122	O
)	O
participated	O
.	O

Enhanced	O
phospholipid	O
hydrolysis	O
with	O
free	O
fatty	O
acid	O
and	O
thromboxane	O
accumulation	O
,	O
increased	O
release	O
of	O
excitatory	O
amino	O
acids	O
,	O
and	O
decreased	O
tissue	O
magnesium	O
levels	O
may	O
each	O
serve	O
to	O
worsen	O
secondary	O
tissue	O
damage	O
and	O
diminish	O
neurologic	O
recovery	O
after	O
spinal	O
cord	O
injury	O
associated	O
with	O
acute	O
alcohol	O
intoxication	O
.	O

This	O
suggests	O
that	O
the	O
ratio	O
of	O
IL	B-GENE
-	I-GENE
6	I-GENE
to	O
IL	B-GENE
-	I-GENE
10	I-GENE
may	O
be	O
used	O
to	O
predict	O
the	O
injury	O
severity	O
after	O
trauma	O
.	O

With	O
six	O
reports	O
in	O
the	O
literature	O
that	O
show	O
there	O
is	O
an	O
order	O
to	O
melanoma	O
nodal	O
metastases	O
and	O
that	O
the	O
SLN	O
histology	O
is	O
reflective	O
of	O
the	O
histology	O
of	O
the	O
remainder	O
of	O
the	O
nodal	O
basin	O
,	O
the	O
more	O
conservative	O
SLN	O
biopsy	O
can	O
be	O
performed	O
to	O
adequately	O
stage	O
nodally	O
the	O
patient	O
with	O
melanoma	O
.	O

In	O
addition	O
,	O
a	O
double	O
mutant	O
(	O
E482A	O
,	O
D489A	O
)	O
which	O
removed	O
negative	O
charges	O
along	O
one	O
side	O
of	O
the	O
helix	O
had	O
negligible	O
effects	O
on	O
fusion	O
activity	O
.	O

Escherichia	O
coli	O
cells	O
expressing	O
a	O
mutant	B-GENE
glyV	I-GENE
(	O
glycine	B-GENE
tRNA	I-GENE
)	O
gene	O
have	O
a	O
UVM	O
-	O
constitutive	O
phenotype	O
:	O
implications	O
for	O
mechanisms	O
underlying	O
the	O
mutA	B-GENE
or	O
mutC	B-GENE
mutator	I-GENE
effect	O
.	O

Titres	O
of	O
antistreptolysin	B-GENE
O	I-GENE
in	O
mothers	O
of	O
children	O
affected	O
with	O
Down	O
'	O
s	O
syndrome	O
.	O

Synthetic	O
studies	O
on	O
furan	O
derivatives	O
by	O
the	O
wittig	O
reaction	O

Positive	O
linear	O
correlations	O
were	O
found	O
when	O
the	O
AUC	O
(	O
0	O
-	O
12	O
)	O
(	O
r	O
=	O
0	O
.	O
68	O
;	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
the	O
maximum	O
plasma	O
concentration	O
(	O
r	O
=	O
0	O
.	O
34	O
;	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
the	O
minimum	O
plasma	O
concentration	O
(	O
r	O
=	O
0	O
.	O
55	O
;	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
and	O
the	O
elimination	O
t1	O
/	O
2	O
(	O
r	O
=	O
0	O
.	O
46	O
;	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
were	O
regressed	O
with	O
age	O
.	O

Furthermore	O
,	O
the	O
social	O
learning	O
theory	O
of	O
depression	O
,	O
developed	O
by	O
Lewinsohn	O
,	O
is	O
described	O
.	O

Intramolecular	O
interaction	O
is	O
believed	O
to	O
result	O
in	O
the	O
formation	O
of	O
MxA	B-GENE
monomers	I-GENE
,	O
whereas	O
intermolecular	O
interaction	O
may	O
induce	O
the	O
formation	O
of	O
large	B-GENE
MxA	I-GENE
oligomers	I-GENE
.	O

Analysis	O
of	O
a	O
Het	B-GENE
-	O
mutation	O
in	O
Anabaena	O
sp	O
.	O
strain	O
PCC	O
7120	O
implicates	O
a	O
secondary	O
metabolite	O
in	O
the	O
regulation	O
of	O
heterocyst	O
spacing	O
.	O

He	O
presented	O
with	O
left	O
lower	O
abdominal	O
pain	O
and	O
hematoma	O
after	O
a	O
fall	O
.	O

To	O
this	O
end	O
we	O
generated	O
a	O
detailed	O
physical	O
map	O
of	O
the	O
genomic	O
region	O
spanning	O
between	O
sequence	O
-	O
tagged	O
site	O
markers	O
D16S518	B-GENE
and	O
D16S516	B-GENE
.	O

The	O
kinetics	O
of	O
erythromycin	O
(	O
E	O
.	O
)	O
was	O
studied	O
in	O
16	O
patients	O
with	O
different	O
degrees	O
of	O
impairment	O
of	O
renal	O
function	O
after	O
a	O
single	O
intravenous	O
dose	O
.	O

Lasting	O
paraplegia	O
caused	O
by	O
loss	O
of	O
lumbar	O
spinal	O
cord	O
interneurons	O
in	O
rats	O
:	O
no	O
direct	O
correlation	O
with	O
motor	O
neuron	O
loss	O
.	O

Gold	O
flaxseed	O
(	O
whole	O
or	O
ground	O
)	O
fed	O
at	O
levels	O
of	O
5	O
or	O
15	O
%	O
were	O
compared	O
to	O
a	O
1	O
.	O
5	O
%	O
menhaden	O
oil	O
or	O
a	O
typical	O
control	O
layer	O
ration	O
.	O

The	O
study	O
drugs	O
(	O
combination	O
vinblastine	O
-	O
CCNU	O
and	O
single	O
-	O
agent	O
triazinate	O
or	O
dactinomycin	O
)	O
failed	O
to	O
provide	O
any	O
meaningful	O
antitumor	O
activity	O
for	O
these	O
patients	O
with	O
advanced	O
renal	O
cell	O
cancer	O
.	O

Some	O
CHOP	B-GENE
-	O
C	B-GENE
/	I-GENE
EBP	I-GENE
heterodimers	O
apparently	O
bind	O
to	O
alternative	O
DNA	O
sequence	O
and	O
thereby	O
regulate	O
the	O
transcription	O
of	O
other	O
genes	O
.	O

Furthermore	O
,	O
addition	O
of	O
the	O
recombinant	B-GENE
NF	I-GENE
-	I-GENE
YA	I-GENE
subunit	I-GENE
restores	O
NF	B-GENE
-	I-GENE
Y	I-GENE
binding	O
.	O

Our	O
data	O
provide	O
the	O
first	O
evidence	O
that	O
differential	O
splicing	O
in	O
the	O
extracellular	O
region	O
of	O
a	O
receptor	O
gene	O
generates	O
receptor	O
variants	O
with	O
different	O
ligand	O
-	O
binding	O
specificities	O
.	O

Intrathecal	O
injections	O
of	O
small	O
volumes	O
of	O
the	O
alpha	B-GENE
2	I-GENE
-	I-GENE
adrenoceptor	I-GENE
agonists	O
,	O
xylazine	O
and	O
clonidine	O
,	O
into	O
the	O
cervical	O
region	O
of	O
the	O
spinal	O
cord	O
of	O
conscious	O
unrestrained	O
sheep	O
produced	O
a	O
dose	O
-	O
dependent	O
analgesia	O
of	O
the	O
forelimbs	O
as	O
measured	O
using	O
a	O
mechanical	O
pressure	O
device	O
.	O

The	O
specificity	O
of	O
the	O
transcriptional	O
activation	O
by	O
ISGF3	B-GENE
is	O
mediated	O
by	O
specific	O
elements	O
termed	O
IFN	B-GENE
-	I-GENE
stimulatory	I-GENE
response	I-GENE
element	I-GENE
(	O
ISRE	B-GENE
)	O
located	O
in	O
the	O
promoter	O
region	O
of	O
IFN	B-GENE
-	O
inducible	O
genes	O
.	O

Clinical	O
development	O
of	O
interleukin	B-GENE
-	I-GENE
10	I-GENE
.	O

Estrogen	O
has	O
positive	O
effects	O
on	O
mood	O
,	O
sexual	O
function	O
,	O
target	O
end	O
organs	O
and	O
cognitive	O
function	O
,	O
and	O
may	O
play	O
an	O
important	O
role	O
in	O
the	O
etiology	O
of	O
Alzheimer	O
'	O
s	O
Disease	O
by	O
acting	O
to	O
prevent	O
amyloid	O
plaque	O
formation	O
,	O
oxidative	O
stress	O
,	O
or	O
deterioration	O
of	O
the	O
cholinergic	O
neurotransmitter	O
system	O
.	O

The	O
system	O
consists	O
of	O
a	O
microcomputer	O
and	O
six	O
laboratory	O
analyzers	O
:	O
a	O
blood	O
gas	O
analyzer	O
,	O
a	O
flame	O
photometer	O
,	O
a	O
plasma	O
osmotic	O
pressure	O
meter	O
,	O
a	O
chloride	O
ion	O
titrator	O
,	O
a	O
blood	O
sugar	O
analyzer	O
,	O
and	O
a	O
hemoglobin	B-GENE
concentration	O
and	O
saturation	O
meter	O
.	O

Of	O
these	O
,	O
23	O
(	O
13	O
.	O
6	O
%	O
)	O
were	O
due	O
to	O
GIB	O
(	O
Upper	O
GIB	O
=	O
19	O
,	O
Lower	O
GIB	O
=	O
4	O
)	O
.	O

Hence	O
the	O
GAP1	B-GENE
gene	I-GENE
encodes	O
a	O
protein	O
with	O
characteristics	O
typical	O
of	O
integral	O
membrane	O
proteins	O
translocating	O
ligants	O
across	O
cellular	O
membranes	O
.	O

Soluble	O
fibrin	B-GENE
monomer	O
complexes	O
in	O
thromboembolism	O

S16	O
,	O
16	O
.	O
8	O
%	O
,	O
P	O
=	O
0	O
.	O
001	O
)	O
.	O

Microenvironments	O
dominated	O
by	O
cyanobacteria	O
(	O
BPC	O
)	O
had	O
a	O
higher	O
pH	O
(	O
pH	O
7	O
-	O
8	O
)	O
than	O
those	O
dominated	O
by	O
lichen	O
(	O
LTL	O
)	O
(	O
pH	O
4	O
.	O
5	O
-	O
5	O
.	O
5	O
)	O
.	O

Saturated	O
fatty	O
acids	O
induce	O
a	O
1	O
.	O
6	O
-	O
fold	O
increase	O
in	O
transcription	O
activity	O
,	O
whereas	O
a	O
large	O
family	O
of	O
unsaturated	O
fatty	O
acids	O
repress	O
OLE1	B-GENE
transcription	O
as	O
much	O
as	O
60	O
-	O
fold	O
.	O

A	O
third	O
GEF	B-GENE
,	O
GRP3	B-GENE
(	O
KIAA0846	B-GENE
)	O
,	O
activated	O
both	O
Ras	B-GENE
and	O
Rap1	B-GENE
and	O
shared	O
significant	O
sequence	O
homology	O
with	O
the	O
calcium	O
-	O
and	O
diacylglycerol	O
-	O
activated	O
GEFs	B-GENE
,	O
GRP1	B-GENE
and	O
GRP2	B-GENE
.	O

We	O
have	O
determined	O
the	O
molecular	O
organization	O
and	O
transcription	O
start	O
points	O
(	O
tsp	O
)	O
for	O
the	O
murine	O
gene	O
(	O
TK	B-GENE
)	O
encoding	O
thymidine	B-GENE
kinase	I-GENE
.	O

Effect	O
of	O
gentamycin	O
on	O
the	O
kidney	O
functional	O
state	O
in	O
experimental	O
pyelonephritis	O

The	O
time	O
-	O
dependent	O
changes	O
in	O
measured	O
facility	O
of	O
outflow	O
or	O
"	O
washout	O
phenomenon	O
"	O
appeared	O
to	O
result	O
from	O
the	O
gradual	O
dissolution	O
of	O
the	O
hyaluronidase	B-GENE
-	O
sensitive	O
component	O
of	O
the	O
barriers	O
to	O
aqueous	O
outflow	O
in	O
the	O
canine	O
eye	O
.	O

Melioidosis	O
in	O
Sika	O
deer	O
(	O
Cervus	O
nippon	O
nippon	O
)	O
.	O

Many	O
human	O
malignant	O
cells	O
lack	O
methylthioadenosine	B-GENE
phosphorylase	I-GENE
(	O
MTAP	B-GENE
)	O
enzyme	O
activity	O
.	O

Nucleocapsid	O
structure	O
and	O
thermostability	O
of	O
the	O
virion	O
,	O
nucleocapsid	O
and	O
polymerase	O
complex	O
.	O

We	O
propose	O
2	O
separate	O
PAI	B-GENE
-	I-GENE
1	I-GENE
inductory	O
pathways	O
for	O
PMA	O
and	O
IL	B-GENE
-	I-GENE
1alpha	I-GENE
in	O
HepG2	O
,	O
both	O
involving	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
activation	O
;	O
the	O
serum	O
-	O
induced	O
signaling	O
pathway	O
may	O
(	O
partially	O
)	O
overlap	O
with	O
the	O
PMA	O
-	O
activated	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
/	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
kinase	I-GENE
pathway	O
,	O
leading	O
to	O
c	B-GENE
-	I-GENE
Jun	I-GENE
homodimer	I-GENE
binding	O
to	O
the	O
PAI	B-GENE
-	I-GENE
1	I-GENE
TRE	O
.	O

Crude	O
drugs	O
from	O
aquatic	O
plants	O
.	O

Recurrence	O
of	O
the	O
hepatic	O
cyst	O
after	O
partial	O
excision	O
and	O
drainage	O
was	O
complicated	O
by	O
fistula	O
formation	O
between	O
the	O
cyst	O
and	O
the	O
duodenum	O
.	O

These	O
data	O
show	O
that	O
tyrosine	O
phosphorylation	O
by	O
FES	B-GENE
affects	O
the	O
interaction	O
of	O
BCR	B-GENE
with	O
multiple	O
signaling	O
partners	O
and	O
suggest	O
a	O
general	O
role	O
for	O
BCR	B-GENE
in	O
non	O
-	O
receptor	O
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
kinase	I-GENE
regulation	O
and	O
signal	O
transduction	O
.	O

Reversal	O
of	O
'	O
refractory	O
septic	O
shock	O
'	O
by	O
infusion	O
of	O
amrinone	O
and	O
angiotensin	B-GENE
II	I-GENE
in	O
an	O
anthracycline	O
-	O
treated	O
patient	O
.	O

Replication	O
regions	O
from	O
plant	O
-	O
pathogenic	O
Pseudomonas	O
syringae	O
plasmids	O
are	O
similar	O
to	O
ColE2	O
-	O
related	O
replicons	O
.	O

Comparison	O
of	O
dose	O
volume	O
histograms	O
revealed	O
that	O
the	O
6	O
-	O
field	O
plan	O
spared	O
relatively	O
more	O
heart	O
whereas	O
the	O
8	O
-	O
field	O
plan	O
spared	O
relatively	O
more	O
lung	O
.	O

STUDY	O
OBJECTIVE	O
:	O
to	O
characterize	O
gas	O
exchange	O
and	O
cardiopulmonary	O
performance	O
during	O
maximal	O
progressive	O
arm	O
crank	O
exercise	O
.	O

At	O
9	O
months	O
postpartum	O
,	O
serum	O
fT4	O
and	O
fT3	O
levels	O
were	O
low	O
normal	O
(	O
8	O
.	O
0	O
and	O
1	O
.	O
7	O
pmol	O
/	O
L	O
,	O
respectively	O
)	O
,	O
but	O
TSH	B-GENE
was	O
not	O
raised	O
(	O
0	O
.	O
4	O
mU	O
/	O
L	O
)	O
.	O

The	O
most	O
frequent	O
abnormality	O
was	O
GH	B-GENE
deficiency	O
(	O
six	O
cases	O
)	O
,	O
followed	O
by	O
gonadotropin	B-GENE
(	O
four	O
cases	O
)	O
,	O
cortisol	O
(	O
four	O
cases	O
)	O
,	O
and	O
TSH	B-GENE
(	O
one	O
case	O
)	O
,	O
whereas	O
four	O
patients	O
showed	O
high	O
serum	B-GENE
PRL	I-GENE
values	O
.	O

In	O
the	O
normal	O
controls	O
the	O
plasma	B-GENE
FPA	I-GENE
level	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
was	O
1	O
.	O
43	O
+	O
/	O
-	O
0	O
.	O
46	O
ng	O
/	O
ml	O
.	O

The	O
nramp2	B-GENE
gene	I-GENE
is	O
comprised	O
of	O
17	O
exons	O
and	O
spans	O
more	O
than	O
36	O
kb	O
.	O

Studies	O
on	O
recurrences	O
in	O
gingival	O
hyperplasia	O

BACKGROUND	O
:	O
In	O
lung	O
protective	O
strategy	O
,	O
positive	O
end	O
-	O
expiratory	O
pressure	O
(	O
PEEP	O
)	O
slightly	O
higher	O
than	O
the	O
Pflex	O
(	O
the	O
airway	O
pressure	O
corresponding	O
to	O
the	O
lower	O
inflection	O
point	O
(	O
LIP	O
)	O
on	O
the	O
inspiratory	O
pressure	O
-	O
volume	O
(	O
P	O
-	O
V	O
)	O
curve	O
measured	O
with	O
ZEEP	O
)	O
is	O
generally	O
recommended	O
.	O

Effect	O
of	O
a	O
constant	O
magnetic	O
field	O
on	O
different	O
models	O
of	O
carcinogenesis	O

FACS	O
analysis	O
demonstrated	O
that	O
MCs	O
had	O
reached	O
middle	O
to	O
late	O
G1	O
phase	O
of	O
cell	O
cycle	O
progression	O
at	O
this	O
timepoint	O
.	O

Nuclear	O
export	O
of	O
proteins	O
in	O
plants	O
:	O
AtXPO1	B-GENE
is	O
the	O
export	O
receptor	O
for	O
leucine	O
-	O
rich	O
nuclear	O
export	O
signals	O
in	O
Arabidopsis	O
thaliana	O
.	O

Strains	O
carrying	O
a	O
snf1	B-GENE
mutation	I-GENE
are	O
unable	O
to	O
grow	O
on	O
sucrose	O
,	O
galactose	O
,	O
maltose	O
,	O
melibiose	O
,	O
or	O
nonfermentable	O
carbon	O
sources	O
;	O
utilization	O
of	O
these	O
carbon	O
sources	O
is	O
regulated	O
by	O
glucose	O
repression	O
.	O

Similarly	O
,	O
beta	B-GENE
adrenoceptors	I-GENE
blockade	O
has	O
been	O
shown	O
to	O
be	O
of	O
value	O
in	O
achieving	O
continence	O
in	O
a	O
small	O
group	O
of	O
patients	O
.	O

The	O
contractile	O
effects	O
of	O
oxytocin	B-GENE
,	O
prostaglandin	O
F2	O
alpha	O
and	O
their	O
combined	O
use	O
on	O
human	O
pregnant	O
myometrium	O
were	O
studied	O
in	O
vitro	O
.	O

Effectively	O
,	O
the	O
upstream	O
,	O
housekeeping	O
-	O
type	O
promoter	O
responds	O
to	O
FIXK	B-GENE
and	O
positively	O
regulates	O
the	O
downstream	O
,	O
sigma	B-GENE
54	I-GENE
-	I-GENE
type	I-GENE
promoter	I-GENE
.	O

Km	O
values	O
of	O
the	O
uncoupled	O
enzymes	O
IIGlc	B-GENE
for	O
glucose	O
ranged	O
from	O
0	O
.	O
5	O
to	O
2	O
.	O
5	O
mM	O
,	O
2	O
orders	O
of	O
magnitude	O
higher	O
than	O
the	O
value	O
of	O
normal	O
IIGlc	B-GENE
.	O

Measurement	O
of	O
protein	O
in	O
natural	O
rubber	O
latex	O
.	O

Disruption	O
of	O
PML	B-GENE
subnuclear	I-GENE
domains	I-GENE
by	O
the	O
acidic	B-GENE
IE1	I-GENE
protein	I-GENE
of	O
human	O
cytomegalovirus	O
is	O
mediated	O
through	O
interaction	O
with	O
PML	B-GENE
and	O
may	O
modulate	O
a	O
RING	O
finger	O
-	O
dependent	O
cryptic	O
transactivator	O
function	O
of	O
PML	B-GENE
.	O

The	O
fate	O
of	O
ochratoxin	O
A	O
during	O
malting	O
and	O
brewing	O
.	O

To	O
further	O
investigate	O
the	O
role	O
of	O
PKR	B-GENE
in	O
transcriptional	O
signaling	O
,	O
we	O
expressed	O
the	O
wild	B-GENE
type	I-GENE
human	I-GENE
PKR	I-GENE
and	O
a	O
catalytically	O
inactive	O
dominant	O
negative	O
PKR	B-GENE
mutant	I-GENE
in	O
the	O
murine	O
pre	O
-	O
B	O
lymphoma	O
70Z	O
/	O
3	O
cells	O
.	O

Consistent	O
with	O
other	O
experiments	O
with	O
these	O
compounds	O
,	O
cocaine	O
was	O
the	O
most	O
potent	O
of	O
the	O
group	O
.	O

Atrial	O
dissociation	O
.	O

It	O
is	O
envisaged	O
that	O
the	O
WHOQOL	O
-	O
BREF	O
will	O
be	O
most	O
useful	O
in	O
studies	O
that	O
require	O
a	O
brief	O
assessment	O
of	O
quality	O
of	O
life	O
,	O
for	O
example	O
,	O
in	O
large	O
epidemiological	O
studies	O
and	O
clinical	O
trials	O
where	O
quality	O
of	O
life	O
is	O
of	O
interest	O
.	O

Hepatitis	B-GENE
B	I-GENE
immune	I-GENE
globulins	I-GENE
and	O
HIV	B-GENE
antibodies	I-GENE
.	O

One	O
cytoplasmic	O
target	O
which	O
reflects	O
the	O
functional	O
state	O
of	O
the	O
plastids	O
is	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
.	O

A	O
360	O
-	O
bp	O
DNA	O
fragment	O
located	O
over	O
500	O
bp	O
upstream	O
from	O
the	O
cfl	B-GENE
transcriptional	O
start	O
site	O
was	O
used	O
in	O
DNase	B-GENE
I	I-GENE
protection	O
assays	O
to	O
define	O
the	O
specific	O
bases	O
bound	O
by	O
CorR	B-GENE
.	O

A	O
relationship	O
between	O
the	O
immunological	O
changes	O
and	O
the	O
disease	O
stage	O
was	O
discovered	O
:	O
the	O
index	O
of	O
the	O
3H	O
-	O
thymidine	O
incorporation	O
was	O
found	O
to	O
be	O
67	O
.	O
9	O
at	O
the	O
stage	O
of	O
disease	O
exacerbation	O
,	O
and	O
208	O
.	O
8	O
at	O
the	O
stage	O
of	O
remission	O
;	O
the	O
complement	O
titre	O
reached	O
,	O
respectively	O
,	O
46	O
.	O
64	O
+	O
/	O
-	O
5	O
.	O
28	O
and	O
112	O
.	O
0	O
+	O
/	O
-	O
6	O
.	O
0	O
units	O
per	O
ml	O
.	O

In	O
the	O
spontaneous	O
abortion	O
group	O
,	O
the	O
levels	O
of	O
PAPP	B-GENE
-	I-GENE
A	I-GENE
were	O
significantly	O
lower	O
than	O
in	O
normal	O
pregnancy	O
but	O
higher	O
than	O
in	O
non	O
-	O
pregnant	O
controls	O
.	O

Maximum	O
likelihood	O
estimation	O
in	O
covariance	O
structure	O
analysis	O
with	O
truncated	O
data	O
.	O

The	O
gene	O
encoding	O
rat	O
peptidylglycine	B-GENE
alpha	I-GENE
-	I-GENE
amidating	I-GENE
monooxygenase	I-GENE
(	O
PAM	B-GENE
)	O
contains	O
26	O
protein	O
-	O
coding	O
exons	O
.	O

Whether	O
this	O
lack	O
of	O
preferential	O
repair	O
has	O
to	O
be	O
explained	O
by	O
a	O
defect	O
in	O
repair	O
or	O
in	O
general	O
transcription	O
is	O
unclear	O
at	O
present	O
.	O

Pretreatment	O
of	O
human	O
skin	O
with	O
tRA	O
inhibited	O
UV	O
induction	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
protein	I-GENE
and	O
,	O
consequently	O
,	O
AP	B-GENE
-	I-GENE
1	I-GENE
.	O
c	B-GENE
-	I-GENE
Jun	I-GENE
protein	I-GENE
inhibition	O
occurred	O
via	O
a	O
posttranscriptional	O
mechanism	O
,	O
since	O
tRA	O
did	O
not	O
inhibit	O
UV	O
induction	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
mRNA	I-GENE
.	O

MUS81	B-GENE
encodes	O
a	O
novel	O
helix	B-GENE
-	I-GENE
hairpin	I-GENE
-	I-GENE
helix	I-GENE
protein	I-GENE
involved	O
in	O
the	O
response	O
to	O
UV	O
-	O
and	O
methylation	O
-	O
induced	O
DNA	O
damage	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

All	O
possessed	O
cutaneous	O
receptive	O
fields	O
on	O
the	O
distal	O
segments	O
of	O
digits	O
2	O
,	O
3	O
,	O
or	O
4	O
.	O

In	O
situ	O
hybridization	O
reveals	O
strong	O
signals	O
for	O
Zep	B-GENE
mRNA	I-GENE
in	O
the	O
cerebellum	O
and	O
olfactory	O
bulb	O
with	O
moderate	O
signals	O
detected	O
in	O
the	O
hippocampus	O
and	O
cortex	O
.	O

A	O
series	O
of	O
sequence	O
fragments	O
were	O
placed	O
5	O
'	O
to	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
reporter	O
gene	O
and	O
ability	O
to	O
mediate	O
transcription	O
of	O
CAT	B-GENE
in	O
response	O
to	O
IFN	B-GENE
gamma	I-GENE
or	O
LPS	O
treatment	O
was	O
studied	O
following	O
transient	O
transfection	O
in	O
the	O
macrophage	O
-	O
like	O
cell	O
line	O
RAW	O
264	O
.	O
7	O
.	O

A	O
GT	O
-	O
rich	O
sequence	O
binding	O
the	O
transcription	B-GENE
factor	I-GENE
Sp1	I-GENE
is	O
crucial	O
for	O
high	O
expression	O
of	O
the	O
human	B-GENE
type	I-GENE
VII	I-GENE
collagen	I-GENE
gene	I-GENE
(	O
COL7A1	B-GENE
)	O
in	O
fibroblasts	O
and	O
keratinocytes	O
.	O

Using	O
in	O
vivo	O
genomic	O
dimethyl	O
sulfate	O
and	O
KMnO4	O
footprinting	O
,	O
we	O
showed	O
that	O
the	O
promoter	O
region	O
is	O
differentially	O
protected	O
,	O
depending	O
upon	O
which	O
holoenzyme	O
is	O
bound	O
.	O

We	O
conclude	O
that	O
these	O
cDNAs	O
belong	O
to	O
a	O
novel	O
GST	B-GENE
class	O
hereby	O
designated	O
Kappa	O
,	O
with	O
the	O
rat	B-GENE
GST	I-GENE
subunit	I-GENE
13	I-GENE
gene	I-GENE
designated	O
rGSTK1	B-GENE
and	O
the	O
human	O
gene	O
being	O
called	O
hGSTK1	B-GENE
.	O

At	O
onset	O
of	O
first	O
post	O
-	O
weaning	O
estrus	O
,	O
sows	O
received	O
either	O
an	O
intravulval	O
injection	O
of	O
3	O
.	O
75	O
mg	O
of	O
prostaglandin	O
analogue	O
(	O
PGF	O
)	O
or	O
,	O
served	O
as	O
a	O
non	O
-	O
injected	O
control	O
(	O
CON	O
)	O
.	O

Tbx6	B-GENE
maps	O
to	O
chromosome	O
7	O
and	O
does	O
not	O
appear	O
to	O
be	O
linked	O
to	O
any	O
known	O
mutation	O
.	O

Before	O
therapy	O
was	O
started	O
,	O
trabecular	O
bone	O
alterations	O
could	O
be	O
observed	O
which	O
were	O
typical	O
for	O
Paget	O
'	O
s	O
disease	O
of	O
bone	O
as	O
there	O
were	O
bulky	O
trabeculare	O
,	O
increased	O
remodelling	O
surfaces	O
and	O
giant	O
osteoclasts	O
.	O

At	O
11	O
.	O
5	O
years	O
of	O
follow	O
-	O
up	O
,	O
521	O
major	O
coronary	O
disease	O
events	O
had	O
occurred	O
,	O
261	O
fatal	O
and	O
260	O
non	O
-	O
fatal	O
.	O

However	O
,	O
additional	O
studies	O
on	O
cell	O
lines	O
and	O
whole	O
animals	O
are	O
required	O
to	O
understand	O
GnRH	B-GENE
signaling	O
in	O
the	O
context	O
of	O
other	O
hormones	O
during	O
the	O
reproductive	O
cycle	O
of	O
mouse	O
and	O
human	O
.	O

Total	O
meso	O
-	O
pore	O
volume	O
and	O
surface	O
area	O
ranged	O
from	O
0	O
.	O
004	O
-	O
0	O
.	O
08	O
cm3	O
g	O
(	O
-	O
1	O
)	O
and	O
from	O
0	O
.	O
33	O
-	O
6	O
.	O
9	O
m2	O
g	O
(	O
-	O
1	O
)	O
respectively	O
,	O
accounting	O
for	O
up	O
33	O
%	O
of	O
the	O
BET	O
surface	O
area	O
.	O

Contraindications	O
to	O
adenosine	O
and	O
drug	O
interactions	O
are	O
noted	O
in	O
this	O
article	O
.	O

The	O
extent	O
of	O
the	O
odontoblast	O
process	O
in	O
human	O
dentin	O
.	O

On	O
transfer	O
from	O
glucose	O
,	O
succinate	O
,	O
malate	O
,	O
or	O
glycerol	O
medium	O
to	O
citrate	O
medium	O
,	O
the	O
Cit	O
+	O
Escherichia	O
coli	O
strains	O
showed	O
a	O
delay	O
of	O
36	O
to	O
48	O
h	O
before	O
growth	O
.	O

The	O
index	O
patient	O
,	O
a	O
10	O
-	O
year	O
-	O
old	O
boy	O
,	O
presents	O
typical	O
symptoms	O
of	O
OPD	O
type	O
I	O
together	O
with	O
bowing	O
of	O
the	O
long	O
bones	O
and	O
abnormalities	O
of	O
the	O
thorax	O
and	O
spinal	O
column	O
.	O

After	O
enzymatic	O
hydrolysis	O
of	O
the	O
water	O
soluble	O
fraction	O
,	O
it	O
is	O
shown	O
that	O
28	O
%	O
is	O
again	O
extractable	O
by	O
DCM	O
of	O
which	O
57	O
%	O
consists	O
of	O
unchanged	O
SC4453	O
which	O
is	O
therefore	O
the	O
main	O
partner	O
of	O
conjugated	O
products	O
.	O

Additionally	O
,	O
the	O
members	O
of	O
this	O
family	O
display	O
strong	O
sequence	O
homologies	O
between	O
their	O
larger	O
C	O
-	O
terminal	O
effector	O
binding	O
/	O
oligomerization	O
domains	O
.	O

Microalbuminuria	O
:	O
a	O
marker	O
of	O
systemic	O
disease	O
.	O

Long	O
-	O
term	O
ambulatory	O
measurement	O
of	O
transcutaneous	O
arterial	O
CO2	O
pressure	O
(	O
PCO2	O
)	O
offers	O
an	O
opportunity	O
to	O
test	O
directly	O
the	O
co	O
-	O
occurrence	O
of	O
panic	O
and	O
hyperventilation	O
under	O
natural	O
conditions	O
.	O

An	O
association	O
was	O
found	O
between	O
zafirlukast	O
plasma	O
concentrations	O
and	O
increases	O
in	O
PC8SRaw	O
10	O
h	O
after	O
treatment	O
(	O
p	O
=	O
0	O
.	O
001	O
)	O
.	O

Most	O
interestingly	O
,	O
although	O
the	O
effector	O
plasmid	O
containing	O
the	O
ICP27	B-GENE
gene	I-GENE
had	O
little	O
effect	O
on	O
its	O
own	O
,	O
two	O
different	O
and	O
marked	O
effects	O
depending	O
on	O
the	O
target	O
were	O
observed	O
when	O
ICP27	B-GENE
was	O
combined	O
with	O
ICP4	B-GENE
or	O
ICP0	B-GENE
or	O
both	O
.	O

Water	O
pair	O
and	O
three	O
-	O
body	O
potential	O
of	O
spectroscopic	O
quality	O
from	O
Ab	O
initio	O
calculations	O

Because	O
the	O
wa	B-GENE
-	I-GENE
2	I-GENE
mutation	I-GENE
was	O
mapped	O
previously	O
to	O
the	O
vicinity	O
of	O
the	O
EGF	B-GENE
/	I-GENE
TGF	I-GENE
-	I-GENE
alpha	I-GENE
receptor	I-GENE
(	O
EGFR	B-GENE
)	O
gene	O
on	O
mouse	O
chromosome	O
11	O
,	O
we	O
hypothesized	O
that	O
the	O
wa	B-GENE
-	I-GENE
2	I-GENE
phenotype	I-GENE
might	O
result	O
from	O
a	O
defect	O
in	O
either	O
the	O
expression	O
or	O
activity	O
of	O
EGFR	B-GENE
,	O
or	O
both	O
.	O

4	O
)	O
Mutation	O
of	O
the	O
three	O
extracellular	O
cysteine	O
residues	O
of	O
GFKAR	B-GENE
beta	I-GENE
indicated	O
that	O
the	O
two	O
conserved	O
cysteine	O
residues	O
(	O
C305	O
and	O
C385	O
)	O
,	O
located	O
between	O
two	O
transmembrane	O
segments	O
,	O
form	O
a	O
solvent	O
-	O
accessible	O
disulfide	O
bond	O
.	O

R	O
of	O
the	O
chest	O
wall	O
was	O
maximum	O
(	O
35	O
.	O
6	O
cmH2O	O
.	O
L	O
-	O
1	O
.	O
sec	O
-	O
1	O
+	O
/	O
-	O
2	O
.	O
2	O
SE	O
)	O
at	O
0	O
.	O
2	O
Hz	O
-	O
10	O
ml	O
and	O
decreased	O
with	O
increasing	O
f	O
and	O
VT	O
,	O
although	O
the	O
VT	O
effect	O
diminished	O
at	O
the	O
higher	O
f	O
.	O

Time	O
dependence	O
of	O
frequency	O
potentiation	O
in	O
the	O
isolated	O
guinea	O
-	O
pig	O
'	O
s	O
atrium	O
.	O

Comparison	O
of	O
the	O
predicted	O
amino	O
acid	O
sequence	O
with	O
that	O
of	O
the	O
Drosophila	B-GENE
virilis	I-GENE
gene	I-GENE
shows	O
that	O
several	O
blocks	O
of	O
amino	O
acid	O
sequence	O
have	O
been	O
very	O
highly	O
conserved	O
.	O

The	O
N	O
-	O
terminal	O
exon1	O
had	O
no	O
homology	O
at	O
the	O
amino	O
acid	O
level	O
with	O
NGFI	B-GENE
-	I-GENE
B	I-GENE
,	O
the	O
mammalian	O
homologue	O
.	O

Although	O
RAD17	B-GENE
,	O
RAD24	B-GENE
and	O
MEC3	B-GENE
are	O
not	O
required	O
for	O
cell	O
cycle	O
arrest	O
when	O
S	O
phase	O
is	O
inhibited	O
by	O
hydroxyurea	O
(	O
HU	O
)	O
,	O
they	O
do	O
contribute	O
to	O
the	O
viability	O
of	O
yeast	O
cells	O
grown	O
in	O
the	O
presence	O
of	O
HU	O
,	O
possibly	O
because	O
they	O
are	O
required	O
for	O
the	O
repair	O
of	O
HU	O
-	O
induced	O
DNA	O
damage	O
.	O

Single	O
oblique	O
-	O
view	O
mammography	O
for	O
periodic	O
screening	O
for	O
breast	O
cancer	O
in	O
women	O
.	O

Conventional	O
toxicological	O
considerations	O
suggest	O
that	O
the	O
adverse	O
health	O
effects	O
of	O
any	O
necessary	O
increase	O
in	O
coal	O
combustion	O
effluents	O
would	O
be	O
greatest	O
per	O
unit	O
of	O
coal	O
in	O
those	O
areas	O
which	O
are	O
most	O
heavily	O
populated	O
and	O
have	O
the	O
highest	O
preexisting	O
levels	O
of	O
the	O
gas	O
-	O
aerosol	O
complex	O
.	O

The	O
arterial	O
blood	O
pressure	O
was	O
measured	O
by	O
using	O
bloody	O
method	O
in	O
anesthizied	O
animals	O
.	O

Nicotinic	B-GENE
receptor	I-GENE
antagonists	O
mecamylamine	O
(	O
0	O
.	O
5	O
and	O
1	O
mg	O
/	O
kg	O
)	O
and	O
hexamethonium	O
(	O
5	O
and	O
10	O
mg	O
/	O
kg	O
)	O
reduced	O
the	O
response	O
induced	O
by	O
nicotine	O
(	O
0	O
.	O
25	O
mg	O
/	O
kg	O
)	O
.	O

The	O
present	O
work	O
represents	O
an	O
attempt	O
to	O
develop	O
a	O
method	O
for	O
measuring	O
relative	O
blood	O
flow	O
in	O
intestinal	O
capillaries	O
,	O
by	O
the	O
use	O
of	O
sodium	O
fluorescein	O
(	O
Na	O
-	O
F	O
)	O
as	O
an	O
indicator	O
substance	O
.	O

The	O
matrix	O
of	O
the	O
CBs	O
contains	O
the	O
diagnostic	O
protein	O
p80	B-GENE
-	O
coilin	B-GENE
,	O
which	O
is	O
colocalized	O
with	O
the	O
U7	B-GENE
small	I-GENE
nuclear	I-GENE
ribonucleoprotein	I-GENE
(	O
snRNP	O
)	O
,	O
whereas	O
the	O
attached	O
and	O
embedded	O
B	O
-	O
snurposomes	O
contain	O
splicing	O
snRNPs	O
.	O

Tritium	O
concentrations	O
in	O
environmental	O
water	O
samples	O
were	O
found	O
to	O
be	O
determined	O
within	O
an	O
accuracy	O
of	O
10	O
%	O
by	O
this	O
method	O
when	O
Vi	O
/	O
Vf	O
was	O
14	O
-	O
25	O
.	O

The	O
results	O
of	O
this	O
study	O
suggest	O
that	O
in	O
patients	O
with	O
syndrome	O
X	O
,	O
myocardial	O
ischemia	O
frequently	O
develops	O
during	O
daily	O
life	O
;	O
silent	O
ischemia	O
is	O
an	O
important	O
component	O
of	O
this	O
syndrome	O
;	O
and	O
increased	O
oxygen	O
demand	O
in	O
the	O
presence	O
of	O
impaired	O
coronary	O
vasodilatory	O
capacity	O
is	O
not	O
the	O
only	O
cause	O
of	O
myocardial	O
ischemia	O
.	O

Two	O
patients	O
with	O
Ewing	O
'	O
s	O
sarcoma	O
relapsed	O
(	O
1	O
patient	O
with	O
both	O
local	O
and	O
distant	O
failure	O
)	O
at	O
26	O
and	O
58	O
months	O
and	O
were	O
again	O
rendered	O
disease	O
-	O
free	O
with	O
surgery	O
,	O
total	O
body	O
irradiation	O
and	O
further	O
chemotherapy	O
.	O

In	O
this	O
study	O
,	O
the	O
subcellular	O
location	O
,	O
domain	O
structure	O
,	O
and	O
biochemical	O
function	O
of	O
metaxin	B-GENE
were	O
investigated	O
.	O

Long	O
-	O
term	O
renal	O
function	O
in	O
on	O
-	O
heart	O
-	O
beating	O
donor	O
kidney	O
transplantation	O
:	O
a	O
single	O
-	O
center	O
experience	O
.	O

When	O
single	O
-	O
point	O
mutation	O
was	O
introduced	O
to	O
each	O
GC	O
box	O
,	O
EBS	B-GENE
,	O
and	O
GT	O
box	O
in	O
PFP9a20	B-GENE
,	O
at	O
least	O
3	O
-	O
fold	O
less	O
CAT	B-GENE
activity	O
was	O
observed	O
in	O
CTLL	O
-	O
R8	O
cells	O
.	O

Thirty	O
-	O
three	O
percent	O
had	O
elevated	O
titers	O
(	O
above	O
1	O
:	O
20	O
dilution	O
)	O
.	O

There	O
is	O
,	O
however	O
,	O
uncertainty	O
as	O
to	O
how	O
results	O
obtained	O
in	O
recent	O
experiments	O
scale	O
up	O
to	O
landscape	O
and	O
regional	O
levels	O
and	O
generalize	O
across	O
ecosystem	O
types	O
and	O
processes	O
.	O

Chest	O
X	O
-	O
P	O
revealed	O
an	O
abnormal	O
shadow	O
in	O
the	O
left	O
upper	O
lobe	O
.	O

Despite	O
these	O
high	O
initial	O
rates	O
of	O
transcription	O
,	O
of	O
all	O
the	O
promoter	O
constructs	O
only	O
LAT	B-GENE
-	O
LTR	O
was	O
able	O
to	O
remain	O
transcriptionally	O
active	O
after	O
the	O
establishment	O
of	O
a	O
latent	O
state	O
.	O

Unestablished	O
quail	O
myoblasts	O
were	O
infected	O
with	O
a	O
retroviral	O
vector	O
encoding	O
the	O
oncogenic	O
form	O
of	O
H	B-GENE
-	I-GENE
Ras	I-GENE
in	O
order	O
to	O
investigate	O
the	O
mechanism	O
by	O
which	O
this	O
oncoprotein	O
interferes	O
with	O
terminal	O
differentiation	O
.	O

Exhaled	O
NO	O
was	O
assessed	O
by	O
controlled	O
-	O
flow	O
chemoluminescence	O
after	O
adjusting	O
for	O
trapped	O
air	O
and	O
after	O
generating	O
pressure	O
in	O
the	O
oral	O
cavity	O
that	O
was	O
sufficient	O
to	O
close	O
the	O
soft	O
palate	O
(	O
Eco	O
Physics	O
CLD	O
77	O
AM	O
analyzer	O
)	O
.	O

SATB1	B-GENE
interacted	O
with	O
CDP	B-GENE
through	O
its	O
DNA	O
-	O
binding	O
domain	O
,	O
as	O
demonstrated	O
by	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
(	O
GST	B-GENE
)	O
pull	O
-	O
down	O
assays	O
.	O

Both	O
the	O
inactive	O
domain	B-GENE
II	I-GENE
P68	I-GENE
mutant	I-GENE
and	O
the	O
deletion	O
mutant	O
lacking	O
aa	O
91	O
-	O
243	O
were	O
less	O
inhibitory	O
to	O
growth	O
in	O
yeast	O
due	O
to	O
the	O
reduced	O
ability	O
to	O
phosphorylate	O
initiation	B-GENE
factor	I-GENE
2	I-GENE
alpha	I-GENE
in	O
vivo	O
.	O

Applying	O
the	O
experience	O
mentioned	O
above	O
,	O
4	O
-	O
META	O
was	O
used	O
to	O
bond	O
a	O
proprietary	O
photocuring	O
microfilled	O
composite	O
material	O
to	O
Class	O
V	O
cavities	O
in	O
freshly	O
extracted	O
human	O
teeth	O
.	O

As	O
the	O
mechanism	O
of	O
the	O
intractability	O
,	O
cell	O
function	O
involved	O
in	O
the	O
defense	O
against	O
infection	O
was	O
evaluated	O
.	O

IV	O
.	O

A	O
Premenstrual	O
Syndrome	O
,	O
the	O
late	O
luteal	O
phase	O
disorder	O
of	O
DSM	O
-	O
IIIR	O
criteria	O
,	O
was	O
identified	O
in	O
6	O
%	O
of	O
the	O
women	O
.	O

After	O
5	O
-	O
h	O
thermal	O
induction	O
of	O
cells	O
carrying	O
the	O
runaway	O
recombinant	O
pBS1	O
,	O
protein	B-GENE
B2	I-GENE
constituted	O
40	O
%	O
of	O
the	O
soluble	O
protein	O
fraction	O
of	O
the	O
cells	O
.	O

These	O
results	O
indicate	O
that	O
patients	O
with	O
SS	O
and	O
evidence	O
of	O
exercise	O
-	O
induced	O
ST	O
-	O
segment	O
depression	O
may	O
have	O
decreased	O
myocardial	O
oxygen	O
supply	O
due	O
to	O
low	O
hemoglobin	B-GENE
levels	O
and	O
increased	O
myocardial	O
oxygen	O
demand	O
(	O
elevated	O
double	O
products	O
)	O
when	O
compared	O
to	O
subjects	O
with	O
SS	O
who	O
do	O
not	O
have	O
exercise	O
-	O
induced	O
ST	O
-	O
segment	O
depression	O
.	O

The	O
highest	O
concentration	O
of	O
respirable	O
mineral	O
fibres	O
was	O
found	O
during	O
the	O
overhaul	O
of	O
a	O
truck	O
with	O
asbestos	O
insulation	O
;	O
respirable	O
fibre	O
concentration	O
reached	O
the	O
value	O
of	O
5	O
f	O
/	O
cm3	O
,	O
and	O
total	O
dust	O
concentration	O
-	O
the	O
value	O
of	O
about	O
80	O
mg	O
/	O
m3	O
.	O

Changes	O
in	O
the	O
size	O
and	O
organisation	O
of	O
the	O
brain	O
in	O
man	O
and	O
his	O
ancestors	O
.	O

Mechanisms	O
of	O
action	O
of	O
local	O
anaesthetics	O
.	O

Gastric	O
secretory	O
inhibition	O
induced	O
by	O
three	O
methyl	O
analogs	O
of	O
prostaglandin	O
E2	O
administered	O
intragastrically	O
to	O
man	O
.	O

By	O
contrast	O
,	O
footprint	O
II	O
at	O
position	O
-	O
125	O
is	O
common	O
to	O
both	O
HeLa	O
and	O
GH3	O
cell	O
extracts	O
and	O
overlies	O
a	O
15	O
-	O
base	O
-	O
pair	O
sequence	O
found	O
in	O
all	O
members	O
of	O
the	O
growth	B-GENE
hormone	I-GENE
gene	I-GENE
family	I-GENE
.	O

DNA	O
sequence	O
of	O
the	O
UL6	B-GENE
to	O
UL20	B-GENE
genes	I-GENE
of	O
infectious	O
laryngotracheitis	O
virus	O
and	O
characterization	O
of	O
the	O
UL10	B-GENE
gene	I-GENE
product	I-GENE
as	O
a	O
nonglycosylated	O
and	O
nonessential	O
virion	O
protein	O
.	O

Unlike	O
LANA1	B-GENE
,	O
LANA2	B-GENE
does	O
not	O
elicit	O
a	O
serologic	O
response	O
from	O
patients	O
with	O
KS	O
,	O
PEL	O
,	O
or	O
CD	O
as	O
measured	O
by	O
Western	O
blot	O
hybridization	O
.	O

CD4	B-GENE
degradation	O
mediated	O
by	O
Vpu	B-GENE
does	O
not	O
require	O
the	O
ER	O
chaperone	O
calnexin	B-GENE
and	O
is	O
dependent	O
on	O
an	O
intact	O
ubiquitin	B-GENE
-	O
conjugating	O
system	O
.	O

A	O
deletion	O
analysis	O
of	O
the	O
FAS1	B-GENE
promoter	I-GENE
lacking	O
the	O
previously	O
characterized	O
inositol	O
/	O
choline	O
-	O
responsive	O
-	O
element	O
motif	O
defined	O
a	O
region	O
(	O
nucleotides	O
-	O
760	O
to	O
-	O
850	O
)	O
responsible	O
for	O
most	O
of	O
the	O
remaining	O
activation	O
potency	O
.	O

Promoter	O
constructs	O
containing	O
mutations	O
in	O
the	O
PTRE	B-GENE
sequence	I-GENE
that	O
selectively	O
abolished	O
the	O
binding	O
of	O
either	O
one	O
or	O
both	O
complexes	O
exerted	O
opposite	O
effects	O
on	O
the	O
transcriptional	O
activity	O
of	O
trypsin	B-GENE
promoters	I-GENE
in	O
A	O
.	O
gambiae	O
and	O
Aedes	O
aegypti	O
cell	O
lines	O
.	O

This	O
preliminary	O
study	O
reports	O
an	O
initial	O
evaluation	O
of	O
HMPAO	O
-	O
SPECT	O
imaging	O
for	O
assessing	O
regional	O
alterations	O
in	O
brain	O
function	O
during	O
opiate	O
dependence	O
and	O
withdrawal	O
.	O

The	O
revaluation	O
at	O
the	O
end	O
of	O
the	O
study	O
showed	O
a	O
good	O
compliance	O
for	O
the	O
proposed	O
diet	O
scheme	O
by	O
children	O
,	O
but	O
a	O
poor	O
compliance	O
by	O
their	O
families	O
.	O

Cytostatic	O
activity	O
of	O
some	O
essential	O
oils	O
against	O
HEp	O
-	O
2	O
cells	O
.	O

Custom	O
-	O
made	O
orthoses	O
play	O
an	O
invaluable	O
role	O
in	O
achieving	O
a	O
wide	O
range	O
of	O
therapeutic	O
goals	O
:	O
improving	O
function	O
and	O
pinch	O
,	O
stabilizing	O
individual	O
joints	O
,	O
preventing	O
positional	O
contractures	O
,	O
protecting	O
joints	O
from	O
trauma	O
,	O
stretching	O
the	O
intrinsic	O
muscles	O
,	O
correcting	O
joint	O
-	O
and	O
soft	O
-	O
tissue	O
contractures	O
,	O
and	O
controlling	O
inflammation	O
.	O

Excess	O
recombinant	B-GENE
PTB	I-GENE
squelches	O
the	O
splicing	O
switch	O
and	O
reestablishes	O
exon	O
skipping	O
as	O
the	O
predominant	O
splicing	O
pathway	O
.	O

Among	O
women	O
,	O
plasma	B-GENE
factor	I-GENE
VII	I-GENE
:	O
Ag	O
was	O
inversely	O
associated	O
with	O
income	O
.	O

We	O
concluded	O
that	O
these	O
results	O
support	O
the	O
feasibility	O
and	O
usefulness	O
of	O
N	O
-	O
of	O
-	O
1	O
RCT	O
in	O
rheumatology	O
practice	O
.	O

K562	O
erythroleukemia	O
cells	O
stably	O
transfected	O
with	O
constructs	O
containing	O
the	O
human	B-GENE
Agamma	I-GENE
-	I-GENE
globin	I-GENE
promoter	I-GENE
linked	O
to	O
an	O
enhanced	B-GENE
green	I-GENE
fluorescent	I-GENE
protein	I-GENE
(	O
EGFP	B-GENE
)	O
reporter	O
,	O
with	O
or	O
without	O
HS2	O
,	O
were	O
analyzed	O
for	O
EGFP	B-GENE
expression	O
by	O
flow	O
cytometry	O
.	O

Recently	O
,	O
we	O
demonstrated	O
that	O
platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
(	I-GENE
PDGF	I-GENE
)	I-GENE
-	I-GENE
beta	I-GENE
receptor	I-GENE
stimulation	O
,	O
but	O
not	O
various	O
other	O
growth	O
factors	O
,	O
inhibits	O
transcription	O
of	O
alpha1D	B-GENE
-	O
,	O
but	O
not	O
alpha1A	B-GENE
-	O
or	O
alpha1B	B-GENE
-	I-GENE
ARs	I-GENE
,	O
resulting	O
in	O
reduced	O
norepinephrine	O
-	O
mediated	O
SMC	O
growth	O
.	O

(	O
A	O
short	O
account	O
of	O
Karl	O
Touton	O
'	O
s	O
life	O
is	O
also	O
included	O
.	O
)	O
After	O
reviewing	O
the	O
historical	O
development	O
of	O
the	O
concept	O
of	O
giant	O
cells	O
and	O
current	O
interpretations	O
of	O
their	O
nature	O
,	O
the	O
unitarian	O
view	O
of	O
polykaryons	O
now	O
favored	O
by	O
workers	O
in	O
the	O
field	O
is	O
extended	O
to	O
include	O
also	O
the	O
"	O
xanthelasmatic	O
giant	O
cell	O
"	O
of	O
Touton	O
,	O
whose	O
characteristic	O
appearance	O
is	O
determined	O
merely	O
by	O
the	O
presence	O
of	O
demonstrable	O
lipid	O
in	O
the	O
cytoplasm	O
.	O

It	O
has	O
also	O
been	O
previously	O
demonstrated	O
that	O
LPS	O
treatment	O
of	O
splenic	O
B	O
cells	O
from	O
athymic	O
mice	O
results	O
in	O
a	O
decrease	O
in	O
steady	O
state	O
mRNA	O
encoding	O
the	O
A	B-GENE
alpha	I-GENE
class	I-GENE
II	I-GENE
protein	I-GENE
.	O

After	O
birth	O
,	O
there	O
was	O
a	O
significantly	O
higher	O
increase	O
of	O
IgA	B-GENE
and	O
IgM	B-GENE
anti	I-GENE
-	I-GENE
M	I-GENE
.	I-GENE
leprae	I-GENE
antibody	I-GENE
activity	O
in	O
sera	O
taken	O
3	O
-	O
6	O
months	O
after	O
birth	O
from	O
babies	O
of	O
Group	O
1	O
compared	O
to	O
Group	O
2	O
,	O
but	O
the	O
IgA	B-GENE
and	O
IgM	B-GENE
activity	O
in	O
sera	O
taken	O
after	O
6	O
months	O
of	O
age	O
showed	O
the	O
same	O
increase	O
in	O
the	O
two	O
groups	O
.	O

Serum	O
estriol	O
levels	O
during	O
beta	B-GENE
-	I-GENE
receptor	I-GENE
agonist	O
infusion	O
in	O
the	O
third	O
trimester	O
of	O
pregnancy	O
.	O

These	O
tiny	O
premature	O
infants	O
also	O
received	O
PN	O
for	O
significantly	O
longer	O
periods	O
of	O
time	O
,	O
and	O
the	O
longer	O
the	O
infusions	O
were	O
administered	O
the	O
greater	O
was	O
the	O
risk	O
of	O
cholestasis	O
developing	O
.	O

We	O
show	O
that	O
sae1	B-GENE
-	I-GENE
1	I-GENE
and	O
sae3	B-GENE
-	I-GENE
1	I-GENE
mutations	I-GENE
each	O
confer	O
a	O
distinct	O
defect	O
in	O
meiotic	O
recombination	O
.	O
sae1	B-GENE
-	I-GENE
1	I-GENE
produces	O
recombinants	O
but	O
very	O
slowly	O
and	O
ultimately	O
to	O
less	O
than	O
half	O
the	O
wild	O
-	O
type	O
level	O
;	O
sae3	B-GENE
-	I-GENE
1	I-GENE
makes	O
persistent	O
hyper	O
-	O
resected	O
meiotic	O
double	O
-	O
strand	O
breaks	O
and	O
has	O
a	O
severe	O
defect	O
in	O
formation	O
of	O
recombinants	O
.	O

Patients	O
in	O
the	O
mucinous	O
cyst	O
group	O
had	O
significantly	O
lower	O
CA	B-GENE
125	I-GENE
cystic	O
fluid	O
levels	O
compared	O
with	O
women	O
with	O
endometriomas	O
and	O
dermoids	O
(	O
P	O
&	O
lt	O
;	O
0	O
.	O
05	O
)	O
.	O

The	O
brains	O
were	O
processed	O
according	O
to	O
the	O
tetramethylbenzidine	O
(	O
TMB	O
)	O
protocol	O
of	O
Mesulam	O
(	O
'	O
78	O
)	O
and	O
studied	O
with	O
darkfield	O
microscopy	O
.	O

Analysis	O
of	O
WT1	B-GENE
target	I-GENE
gene	I-GENE
expression	O
in	O
stably	O
transfected	O
cell	O
lines	O
.	O

Some	O
may	O
affect	O
the	O
folding	O
pathway	O
or	O
the	O
affinity	O
for	O
chaperonins	B-GENE
.	O

Amniotic	O
fluid	O
ionic	O
concentration	O
in	O
response	O
to	O
chronic	O
fetal	B-GENE
vasopressin	I-GENE
infusion	O
.	O

The	O
use	O
of	O
bentonite	O
in	O
the	O
compounding	O
of	O
hydrogels	O

VBP	B-GENE
and	O
a1	B-GENE
/	I-GENE
EBP	I-GENE
could	O
mediate	O
the	O
high	O
rates	O
of	O
ALV	O
and	O
RSV	B-GENE
LTR	I-GENE
-	O
enhanced	O
transcription	O
in	O
bursal	O
lymphoma	O
cells	O
and	O
many	O
other	O
cell	O
types	O
.	O

Insulin	B-GENE
therapy	O
has	O
been	O
expanded	O
by	O
development	O
of	O
human	B-GENE
insulin	I-GENE
and	O
new	O
modes	O
of	O
injection	O
,	O
including	O
insulin	B-GENE
pumps	O
.	O

Also	O
,	O
anti	B-GENE
-	I-GENE
HIV	I-GENE
gp120	I-GENE
and	O
anti	B-GENE
-	I-GENE
CD4	I-GENE
crosslinking	O
induced	O
a	O
10	O
-	O
15	O
-	O
fold	O
increase	O
in	O
levels	O
of	O
both	O
PI	B-GENE
3	I-GENE
-	I-GENE
and	I-GENE
PI	I-GENE
4	I-GENE
-	I-GENE
kinase	I-GENE
activity	O
in	O
anti	B-GENE
-	I-GENE
CD4	I-GENE
precipitates	O
.	O

The	O
genomic	O
organization	O
in	O
this	O
region	O
is	O
similar	O
to	O
the	O
neural	O
-	O
restricted	O
family	O
members	O
,	O
Hel	B-GENE
-	I-GENE
N1	I-GENE
(	O
ELAVL2	B-GENE
)	O
and	O
mHuD	B-GENE
(	O
Elavl4	B-GENE
)	O
.	O

Chronic	O
active	O
hepatitis	O
and	O
pregnancy	O
.	O

42nd	O
annual	O
meeting	O
of	O
the	O
American	O
Academy	O
of	O
Oral	O
Pathology	O
.	O

CONCLUSION	O
:	O
The	O
biodistribution	O
of	O
111In	O
IgG	B-GENE
is	O
similar	O
to	O
that	O
of	O
99mTc	O
-	O
HMPAO	O
-	O
labeled	O
leukocytes	O
.	O

In	O
vitro	O
DNA	O
binding	O
assays	O
indicate	O
that	O
the	O
elements	O
identified	O
can	O
specifically	O
interact	O
with	O
c	B-GENE
-	I-GENE
Ets	I-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
.	O

The	O
BCL	B-GENE
-	I-GENE
6	I-GENE
POZ	O
domain	O
and	O
other	O
POZ	O
domains	O
interact	O
with	O
the	O
co	O
-	O
repressors	O
N	B-GENE
-	I-GENE
CoR	I-GENE
and	O
SMRT	B-GENE
.	O

Since	O
it	O
is	O
often	O
necessary	O
to	O
resort	O
to	O
thoracotomy	O
as	O
a	O
final	O
step	O
in	O
making	O
such	O
a	O
diagnosis	O
,	O
we	O
have	O
sought	O
a	O
procedure	O
that	O
is	O
simpler	O
while	O
capable	O
of	O
providing	O
the	O
same	O
information	O
.	O

On	O
the	O
optic	O
tentacle	O
-	O
gonadal	O
axis	O
in	O
the	O
control	O
of	O
the	O
male	O
-	O
phase	O
ovotestis	O
in	O
the	O
slug	O
(	O
Ariolimax	O
californicus	O
)	O
.	O

The	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
inhibitor	O
GF	O
-	O
109203X	O
abolished	O
the	O
activation	O
by	O
phorbol	O
ester	O
and	O
inhibited	O
the	O
effect	O
of	O
CCK	B-GENE
by	O
78	O
%	O
but	O
had	O
no	O
effect	O
on	O
EGF	B-GENE
-	O
activated	O
MAPK	B-GENE
activity	O
.	O

Four	O
multicannulated	O
Holstein	O
steers	O
(	O
initial	O
BW	O
424	O
+	O
/	O
-	O
16	O
kg	O
)	O
were	O
used	O
in	O
a	O
4	O
x	O
4	O
Latin	O
square	O
to	O
determine	O
the	O
influence	O
of	O
protein	O
supplementation	O
on	O
forage	O
intake	O
,	O
site	O
and	O
extent	O
of	O
digestion	O
,	O
and	O
nutrient	O
flow	O
in	O
steers	O
consuming	O
dormant	O
bluestem	O
-	O
range	O
forage	O
(	O
2	O
.	O
3	O
%	O
CP	O
)	O
.	O

These	O
morphological	O
changes	O
are	O
associated	O
with	O
a	O
marked	O
induction	O
of	O
P450arom	B-GENE
gene	I-GENE
expression	O
.	O

This	O
residue	O
,	O
although	O
located	O
55	O
rather	O
than	O
35	O
residues	O
NH2	O
-	O
terminal	O
of	O
the	O
essential	O
glutamate	O
,	O
is	O
undoubtedly	O
the	O
analog	O
of	O
the	O
second	O
aspartate	O
of	O
the	O
Asp	O
-	O
Asp	O
-	O
35	O
-	O
Glu	O
motif	O
found	O
in	O
other	O
family	O
members	O
.	O

DNase	B-GENE
I	I-GENE
protection	O
analysis	O
as	O
well	O
as	O
oligonucleotide	O
competition	O
experiments	O
indicate	O
that	O
this	O
binding	O
is	O
sequence	O
specific	O
.	O

METHOD	O
:	O
After	O
eligibility	O
,	O
patients	O
were	O
randomly	O
allocated	O
in	O
one	O
of	O
the	O
following	O
groups	O
:	O
M	O
=	O
methylprednisolone	O
30	O
mg	O
.	O
kg	O
-	O
1	O
over	O
1	O
hour	O
,	O
followed	O
by	O
5	O
.	O
4	O
mg	O
.	O
kg	O
-	O
1	O
.	O
h	O
-	O
1	O
for	O
23	O
hours	O
,	O
N	O
=	O
nimodipine	O
0	O
.	O
015	O
mg	O
.	O
kg	O
-	O
1	O
.	O
h	O
-	O
1	O
over	O
2	O
hours	O
followed	O
by	O
0	O
.	O
03	O
mg	O
.	O
kg	O
-	O
1	O
.	O
h	O
-	O
1	O
for	O
7	O
days	O
,	O
MN	O
or	O
P	O
.	O

We	O
have	O
shown	O
previously	O
that	O
EGF	B-GENE
receptor	I-GENE
activation	O
stimulates	O
gastrin	B-GENE
gene	O
expression	O
through	O
a	O
GC	O
-	O
rich	O
element	O
called	O
gERE	O
.	O

To	O
determine	O
cis	O
-	O
acting	O
elements	O
controlling	O
the	O
rat	O
B	B-GENE
-	I-GENE
50	I-GENE
/	O
GAP	B-GENE
-	I-GENE
43	I-GENE
gene	O
expression	O
,	O
the	O
genomic	O
DNA	O
encoding	O
exon	O
1	O
and	O
the	O
5	O
'	O
flanking	O
sequence	O
was	O
isolated	O
.	O

The	O
traW	B-GENE
gene	I-GENE
of	I-GENE
the	I-GENE
Escherichia	I-GENE
coli	I-GENE
K	I-GENE
-	I-GENE
12	I-GENE
sex	I-GENE
factor	I-GENE
,	O
F	O
,	O
encodes	O
one	O
of	O
the	O
numerous	O
proteins	O
required	O
for	O
conjugative	O
transfer	O
of	O
this	O
plasmid	O
.	O

Profilins	B-GENE
IIa	I-GENE
and	I-GENE
IIb	I-GENE
are	O
also	O
present	O
in	O
humans	O
,	O
suggesting	O
that	O
all	O
mammals	O
have	O
three	O
profilin	B-GENE
isoforms	I-GENE
.	O

Results	O
on	O
the	O
use	O
of	O
amiodarone	O
in	O
the	O
prevention	O
of	O
paroxysmal	O
AF	O
have	O
been	O
equivocal	O
;	O
this	O
may	O
be	O
attributed	O
to	O
differences	O
in	O
defining	O
paroxysmal	O
AF	O
.	O

Nuclear	O
localization	O
of	O
this	O
SNF2	B-GENE
-	I-GENE
like	I-GENE
putative	O
helicase	B-GENE
is	O
dependent	O
on	O
a	O
nuclear	O
localization	O
sequence	O
located	O
in	O
the	O
NH2	O
-	O
terminal	O
region	O
.	O

Expression	O
of	O
these	O
chemokines	O
is	O
similar	O
in	O
that	O
both	O
require	O
the	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
element	I-GENE
and	O
additional	O
regions	O
such	O
as	O
the	O
CAAT	B-GENE
/	I-GENE
enhancer	I-GENE
binding	I-GENE
protein	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
)	O
element	O
of	O
the	O
IL	B-GENE
-	I-GENE
8	I-GENE
promoter	I-GENE
.	O

Any	O
opacity	O
on	O
a	O
chest	O
radiograph	O
has	O
a	O
wide	O
differential	O
diagnosis	O
.	O

Levels	O
of	O
p53	B-GENE
were	O
substantially	O
increased	O
by	O
E1A	B-GENE
expression	O
during	O
adenovirus	O
infection	O
.	O

This	O
pathway	O
has	O
been	O
reported	O
to	O
mediate	O
heterodimer	O
interactions	O
with	O
the	O
proapoptotic	O
regulator	O
,	O
Bad	B-GENE
.	O

The	O
toxicity	O
of	O
copper	O
to	O
the	O
collembolan	O
Folsomia	O
fimetaria	O
L	O
.	O
was	O
studied	O
in	O
soil	O
incubated	O
with	O
copper	O
sulfate	O
for	O
different	O
periods	O
before	O
the	O
introduction	O
of	O
collembolans	O
,	O
to	O
assess	O
the	O
effect	O
of	O
aging	O
of	O
contamination	O
on	O
the	O
toxicity	O
of	O
copper	O
.	O

Earlier	O
published	O
data	O
,	O
indicating	O
Sp1	B-GENE
binding	O
to	O
the	O
R1	B-GENE
alpha	I-GENE
/	I-GENE
beta	I-GENE
regions	I-GENE
,	O
could	O
not	O
be	O
confirmed	O
,	O
suggesting	O
that	O
the	O
R1	O
initiator	O
element	O
may	O
function	O
independent	O
of	O
Sp1	B-GENE
.	O

We	O
sought	O
to	O
test	O
whether	O
a	O
prolonged	O
infusion	O
of	O
magnesium	O
sulfate	O
(	O
MgSO	O
(	O
4	O
)	O
;	O
40	O
mmol	O
/	O
24	O
hours	O
)	O
would	O
normalize	O
QT	O
interval	O
variability	O
in	O
patients	O
with	O
compensated	O
heart	O
failure	O
.	O

Using	O
probes	O
containing	O
C	B-GENE
/	I-GENE
EBP	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
from	O
the	O
iNOS	B-GENE
gene	I-GENE
revealed	O
further	O
binding	O
of	O
different	O
complexes	O
,	O
all	O
of	O
which	O
were	O
strongly	O
inducible	O
by	O
cAMP	O
and	O
to	O
a	O
lower	O
extent	O
also	O
by	O
IL	B-GENE
-	I-GENE
1beta	I-GENE
.	O

Long	O
-	O
term	O
follow	O
-	O
up	O
of	O
kidney	O
donors	O
:	O
a	O
longitudinal	O
study	O
.	O

Gore	O
&	O
Associates	O
,	O
Inc	O
.	O
)	O
standard	O
wall	O
graft	O
segments	O
varying	O
in	O
length	O
from	O
4	O
to	O
12	O
cm	O
.	O

This	O
report	O
describes	O
the	O
isolation	O
and	O
recombinant	O
expression	O
of	O
a	O
cDNA	O
clone	O
encoding	O
HER4	B-GENE
,	O
the	O
fourth	O
member	O
of	O
the	O
human	B-GENE
epidermal	I-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
(	O
EGFR	B-GENE
)	O
family	O
.	O

Precision	O
of	O
data	O
from	O
models	O
of	O
sodium	O
kinetics	O
in	O
hemodialysis	O

Cytochrome	B-GENE
bd	I-GENE
biosynthesis	O
in	O
Escherichia	O
coli	O
:	O
the	O
sequences	O
of	O
the	O
cydC	B-GENE
and	O
cydD	B-GENE
genes	I-GENE
suggest	O
that	O
they	O
encode	O
the	O
components	O
of	O
an	O
ABC	B-GENE
membrane	I-GENE
transporter	I-GENE
.	O

We	O
exposed	O
Dorper	O
-	O
cross	O
ewes	O
at	O
approximately	O
120	O
-	O
135	O
days	O
of	O
gestation	O
to	O
a	O
hot	O
(	O
40	O
degrees	O
C	O
,	O
60	O
%	O
relative	O
humidity	O
)	O
and	O
a	O
cold	O
(	O
4	O
degrees	O
C	O
,	O
90	O
%	O
relative	O
humidity	O
)	O
environment	O
and	O
to	O
treadmill	O
exercise	O
(	O
2	O
.	O
1	O
km	O
/	O
h	O
,	O
5	O
degrees	O
gradient	O
)	O
and	O
measured	O
fetal	O
lamb	O
and	O
ewe	O
body	O
temperatures	O
using	O
previously	O
implanted	O
abdominal	O
radiotelemeters	O
.	O

Amino	O
-	O
terminal	O
polymorphisms	O
of	O
the	O
human	B-GENE
beta	I-GENE
2	I-GENE
-	I-GENE
adrenergic	I-GENE
receptor	I-GENE
impart	O
distinct	O
agonist	O
-	O
promoted	O
regulatory	O
properties	O
.	O

A	O
brief	O
discussion	O
for	O
the	O
relationship	O
among	O
these	O
formulas	O
is	O
given	O
.	O

The	O
embryology	O
of	O
the	O
vertebral	O
column	O
is	O
reviewed	O
briefly	O
,	O
and	O
the	O
origin	O
of	O
each	O
anomaly	O
of	O
the	O
C2	O
vertebra	O
is	O
traced	O
to	O
one	O
of	O
the	O
two	O
early	O
stages	O
in	O
development	O
as	O
follows	O
:	O
1	O
)	O
the	O
formation	O
of	O
the	O
mesenchymal	O
vertebra	O
or	O
2	O
)	O
its	O
induction	O
to	O
cartilage	O
.	O

Visualization	O
of	O
the	O
cells	O
by	O
phase	O
contrast	O
microscopy	O
indicated	O
that	O
murine	B-GENE
PKCepsilon	I-GENE
expression	O
in	O
the	O
presence	O
of	O
glycerol	O
resulted	O
in	O
a	O
significant	O
increase	O
in	O
the	O
number	O
of	O
yeast	O
cells	O
exhibiting	O
very	O
small	O
buds	O
.	O

12	O
per	O
cent	O
was	O
observed	O
with	O
the	O
use	O
of	O
tetracycline	O
and	O
4	O
-	O
epianhydrotetracycline	O
in	O
doses	O
of	O
1000	O
and	O
100gamma	O
per	O
embryo	O
respectively	O
.	O

The	O
DNA	O
-	O
binding	O
proteins	O
are	O
without	O
effect	O
on	O
the	O
transcription	O
of	O
plasmids	O
lacking	O
binding	O
sites	O
or	O
when	O
the	O
binding	O
sites	O
are	O
located	O
further	O
upstream	O
.	O

The	O
duration	O
of	O
PGE2	O
and	O
PGF2	O
alpha	O
elevations	O
as	O
well	O
as	O
the	O
peak	O
values	O
were	O
influenced	O
by	O
day	O
of	O
the	O
cycle	O
.	O

One	O
hundred	O
men	O
who	O
received	O
alpha	O
-	O
tocopherol	O
were	O
matched	O
on	O
age	O
,	O
study	O
center	O
,	O
and	O
length	O
of	O
time	O
between	O
blood	O
draws	O
to	O
100	O
men	O
who	O
received	O
a	O
placebo	O
.	O

Serum	B-GENE
angiogenin	I-GENE
concentrations	O
in	O
young	O
patients	O
with	O
diabetes	O
mellitus	O
.	O

Bodily	O
referents	O
and	O
the	O
experience	O
of	O
affect	O
.	O

We	O
studied	O
about	O
the	O
histological	O
findings	O
of	O
the	O
kidneys	O
including	O
of	O
the	O
infiltrated	O
macrophages	O
in	O
one	O
hour	O
post	O
-	O
transplantation	O
kidney	O
biopsies	O
(	O
one	O
hour	O
biopsies	O
)	O
and	O
re	O
-	O
biopsies	O
on	O
11	O
patients	O
.	O

The	O
human	B-GENE
lbc	I-GENE
oncogene	I-GENE
product	I-GENE
is	O
a	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
that	O
specifically	O
activates	O
the	O
Rho	B-GENE
small	I-GENE
GTP	I-GENE
binding	I-GENE
protein	I-GENE
,	O
thus	O
resulting	O
in	O
biologically	O
active	O
,	O
GTP	O
-	O
bound	O
Rho	B-GENE
,	O
which	O
in	O
turn	O
mediates	O
actin	B-GENE
cytoskeletal	O
reorganization	O
,	O
gene	O
transcription	O
,	O
and	O
entry	O
into	O
the	O
mitotic	O
S	O
phase	O
.	O

RESULTS	O
:	O
There	O
were	O
no	O
significant	O
differences	O
in	O
the	O
mean	O
serum	O
vitamin	O
A	O
,	O
E	O
concentrations	O
and	O
vitamin	O
E	O
/	O
cholesterol	O
ratio	O
between	O
pregnant	O
women	O
with	O
normal	O
hemoglobin	B-GENE
and	O
hemoglobinopathies	O
,	O
while	O
confounding	O
variables	O
that	O
might	O
affect	O
serum	O
vitamin	O
levels	O
i	O
.	O
e	O
.	O
maternal	O
age	O
,	O
gravida	O
,	O
BMI	O
,	O
gestational	O
age	O
,	O
hematocrit	O
,	O
hemoglobin	B-GENE
,	O
mean	O
corpuscular	O
hemoglobin	B-GENE
concentration	O
and	O
blood	O
group	O
were	O
not	O
different	O
.	O

These	O
data	O
indicate	O
that	O
SB	O
203580	O
sensitive	O
p38	B-GENE
MAP	I-GENE
kinases	I-GENE
are	O
not	O
involved	O
in	O
okadaic	O
acid	O
mediated	O
increases	O
in	O
TRE	O
DNA	O
binding	O
and	O
transactivation	O
.	O

In	O
contrast	O
,	O
group	O
II	O
showed	O
a	O
significant	O
improvement	O
in	O
peak	O
VO2	O
with	O
rate	O
adaptive	O
AV	O
delay	O
compared	O
to	O
fixed	O
AV	O
delay	O
programming	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

This	O
vector	O
should	O
be	O
applicable	O
for	O
high	O
-	O
throughput	O
characterization	O
of	O
new	O
open	O
reading	O
frames	O
found	O
in	O
genome	O
sequencing	O
.	O

Each	O
patient	O
was	O
seen	O
for	O
5	O
to	O
13	O
postsurgical	O
maintenance	O
visits	O
.	O

Evidence	O
for	O
a	O
role	O
of	O
Smad6	B-GENE
in	O
chick	O
cardiac	O
development	O
.	O

The	O
overall	O
response	O
rate	O
including	O
CR	O
and	O
PR	O
was	O
23	O
.	O
5	O
%	O
(	O
4	O
/	O
17	O
)	O
.	O

Left	O
ventricular	O
responses	O
to	O
dopamine	O
in	O
dilated	O
cardiomyopathy	O
as	O
assessed	O
by	O
two	O
-	O
dimensional	O
echocardiography	O
and	O
compared	O
with	O
findings	O
of	O
thallium	O
-	O
201	O
scintigraphy	O
.	O

RESULTS	O
:	O
Lateral	O
PF	O
OA	O
was	O
more	O
common	O
than	O
medial	O
PF	O
OA	O
(	O
P	O
<	O
0	O
.	O
0001	O
)	O
.	O

Moreover	O
,	O
we	O
show	O
that	O
GATA	B-GENE
-	I-GENE
1	I-GENE
and	O
Sp1	B-GENE
synergize	O
from	O
a	O
distance	O
in	O
constructs	O
designed	O
to	O
mimic	O
the	O
architecture	O
of	O
globin	B-GENE
locus	I-GENE
control	I-GENE
regions	I-GENE
and	O
downstream	O
globin	B-GENE
promoters	I-GENE
.	O

After	O
5	O
,	O
850	O
C14	O
BP	O
,	O
the	O
decrease	O
in	O
Acer	O
stands	O
could	O
be	O
attributed	O
to	O
fire	O
as	O
suggested	O
by	O
the	O
strong	O
increase	O
in	O
Betula	O
and	O
by	O
the	O
delayed	O
expansion	O
of	O
Pinus	O
cembra	O
.	O

4	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
6	O
micromol	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
)	O
but	O
was	O
not	O
changed	O
by	O
training	O
.	O

A	O
wide	O
conservation	O
of	O
iscSUA	B-GENE
genes	I-GENE
in	O
nature	O
and	O
evidence	O
that	O
NifU	B-GENE
and	O
NifS	B-GENE
participate	O
in	O
the	O
mobilization	O
of	O
iron	O
and	O
sulfur	O
for	O
nitrogenase	B-GENE
-	O
specific	O
iron	O
-	O
sulfur	O
cluster	O
formation	O
suggest	O
that	O
the	O
products	O
of	O
the	O
iscSUA	B-GENE
genes	I-GENE
could	O
play	O
a	O
general	O
role	O
in	O
the	O
formation	O
or	O
repair	O
of	O
iron	O
-	O
sulfur	O
clusters	O
.	O

RET	B-GENE
/	O
PTC	B-GENE
oncogenes	O
,	O
generated	O
by	O
chromosomal	O
rearrangements	O
in	O
papillary	O
thyroid	O
carcinomas	O
,	O
are	O
constitutively	O
activated	O
versions	O
of	O
proto	B-GENE
-	I-GENE
RET	I-GENE
,	O
a	O
gene	O
coding	O
for	O
a	O
receptor	B-GENE
-	I-GENE
type	I-GENE
tyrosine	I-GENE
kinase	I-GENE
(	O
TK	B-GENE
)	O
whose	O
ligand	O
is	O
still	O
unknown	O
.	O

Diclofenac	O
sodium	O
:	O
blood	O
concentration	O
of	O
the	O
slow	O
-	O
release	O
form	O
and	O
influence	O
on	O
the	O
metabolism	O
of	O
kallikrein	B-GENE
.	O

The	O
unc	B-GENE
-	I-GENE
101	I-GENE
,	O
sli	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
rok	B-GENE
-	I-GENE
1	I-GENE
genes	I-GENE
encode	O
a	O
distinct	O
set	O
of	O
negative	O
regulators	O
of	O
vulval	O
differentiation	O
.	O

Optimized	O
USF	B-GENE
and	O
MYC	B-GENE
DNA	O
-	O
binding	O
sites	O
,	O
which	O
differ	O
in	O
the	O
nucleotides	O
bordering	O
the	O
hexanucleotide	O
box	O
displace	O
the	O
E	B-GENE
-	I-GENE
C4	I-GENE
factor	I-GENE
in	O
competition	O
assays	O
but	O
with	O
lesser	O
efficiency	O
than	O
the	O
E	B-GENE
-	I-GENE
C4	I-GENE
site	I-GENE
itself	O
.	O

Fluorescent	O
in	O
situ	O
hybridization	O
(	O
FISH	O
)	O
analysis	O
showed	O
that	O
the	O
novel	O
regions	O
involved	O
in	O
the	O
NFKB2	B-GENE
rearrangement	O
originated	O
from	O
chromosome	O
7q34	O
,	O
thus	O
implying	O
the	O
occurrence	O
of	O
a	O
t	O
(	O
7	O
;	O
10	O
)	O
(	O
q34	O
;	O
q24	O
)	O
reciprocal	O
chromosomal	O
translocation	O
.	O

DESIGN	O
:	O
Intradermally	O
injected	O
human	O
squamous	O
cell	O
carcinoma	O
cells	O
were	O
grown	O
to	O
40	O
to	O
80	O
mm3	O
in	O
athymic	O
nude	O
mice	O
and	O
irradiated	O
with	O
675	O
-	O
nm	O
light	O
(	O
75	O
J	O
/	O
cm2	O
,	O
75	O
mW	O
/	O
cm2	O
)	O
24	O
hours	O
after	O
the	O
intraperitoneal	O
injection	O
of	O
SiPc	O
IV	O
(	O
1	O
.	O
0	O
mg	O
/	O
kg	O
)	O
.	O

The	O
effects	O
of	O
space	O
radiation	O
are	O
partially	O
known	O
on	O
astronauts	O
,	O
but	O
much	O
remains	O
to	O
be	O
discovered	O
.	O

First	O
,	O
the	O
amino	O
-	O
terminal	O
regulatory	O
arm	O
of	O
the	O
GDI	B-GENE
binds	O
to	O
the	O
switch	O
I	O
and	O
II	O
domains	O
of	O
Cdc42	B-GENE
leading	O
to	O
the	O
inhibition	O
of	O
both	O
GDP	O
dissociation	O
and	O
GTP	O
hydrolysis	O
.	O

There	O
are	O
two	O
regulatory	O
regions	O
between	O
the	O
US3	B-GENE
and	O
the	O
US6	B-GENE
transcription	I-GENE
units	I-GENE
.	O

In	O
the	O
virus	O
-	O
infected	O
cells	O
,	O
translation	O
of	O
the	O
M1	B-GENE
protein	I-GENE
was	O
reduced	O
to	O
10	O
to	O
20	O
%	O
of	O
that	O
of	O
the	O
wild	O
-	O
type	O
virus	O
;	O
however	O
,	O
the	O
translation	O
of	O
neither	O
the	O
nucleoprotein	O
nor	O
NS1	B-GENE
was	O
significantly	O
interfered	O
with	O
,	O
indicating	O
the	O
important	O
role	O
of	O
NS1	B-GENE
in	O
translational	O
stimulation	O
of	O
the	O
M1	B-GENE
protein	I-GENE
.	O

Thus	O
,	O
the	O
predicted	O
M3	O
ORF	O
is	O
a	O
functional	O
gene	O
that	O
encodes	O
an	O
abundant	O
secreted	O
protein	O
which	O
is	O
a	O
candidate	O
for	O
interacting	O
with	O
host	O
cellular	O
receptors	O
or	O
cytokines	O
.	O

There	O
was	O
a	O
positive	O
correlation	O
between	O
change	O
from	O
baseline	O
in	O
parietal	O
lobe	O
gray	O
-	O
matter	O
cytosolic	O
choline	O
,	O
expressed	O
in	O
terms	O
of	O
choline	O
/	O
creatine	O
resonance	O
ratios	O
,	O
and	O
cognitive	O
performance	O
as	O
measured	O
with	O
the	O
Alzheimer	O
'	O
s	O
Disease	O
Assessment	O
Scale	O
Cognitive	O
Subscale	O
.	O

The	O
protein	O
encoded	O
by	O
the	O
NF2	B-GENE
gene	I-GENE
has	O
a	O
similarity	O
to	O
ezrin	B-GENE
,	O
radixin	B-GENE
and	O
moesin	B-GENE
(	O
ERM	B-GENE
)	O
proteins	O
that	O
link	O
membrane	O
proteins	O
to	O
the	O
cytoskeleton	O
.	O

80	O
v	B-GENE
-	I-GENE
ets	I-GENE
-	O
encoded	O
amino	O
-	O
acids	O
located	O
immediately	O
after	O
the	O
v	B-GENE
-	I-GENE
myb	I-GENE
/	O
v	B-GENE
-	I-GENE
ets	I-GENE
junction	O
are	O
not	O
found	O
in	O
P54	B-GENE
/	O
56c	B-GENE
-	I-GENE
ets	I-GENE
,	O
the	O
translation	O
product	O
of	O
the	O
c	B-GENE
-	I-GENE
ets	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
,	O
nor	O
in	O
a	O
set	O
of	O
cellular	O
proteins	O
of	O
64	O
,	O
62	O
,	O
and	O
60	O
kDa	O
related	O
to	O
but	O
distinct	O
from	O
P54	B-GENE
/	O
56c	B-GENE
-	I-GENE
ets	I-GENE
.	O

Secretogranin	B-GENE
II	I-GENE
(	O
SgII	B-GENE
)	O
is	O
a	O
secretory	O
polypeptide	O
stored	O
in	O
large	O
dense	O
core	O
vesicles	O
of	O
neuroendocrine	O
and	O
neuronal	O
cells	O
.	O

In	O
contrast	O
translocation	O
of	O
G1	B-GENE
to	O
the	O
Golgi	O
was	O
not	O
observed	O
when	O
G1	B-GENE
was	O
coexpressed	O
with	O
NSm	B-GENE
,	O
although	O
NSm	B-GENE
itself	O
was	O
still	O
detected	O
in	O
the	O
Golgi	O
.	O

The	O
results	O
show	O
that	O
while	O
a	O
larger	O
polypeptide	O
substrate	O
carrying	O
the	O
HD1	B-GENE
/	I-GENE
3C	I-GENE
site	I-GENE
was	O
processed	O
more	O
efficiently	O
than	O
a	O
polypeptide	O
substrate	O
carrying	O
the	O
POL	B-GENE
/	I-GENE
Zn	I-GENE
site	I-GENE
,	O
cleavage	O
of	O
the	O
synthetic	O
peptide	O
substrates	O
containing	O
these	O
two	O
cleavage	O
sites	O
occurred	O
at	O
similar	O
efficiencies	O
.	O

GBF1	B-GENE
and	O
GBF2	B-GENE
mRNA	I-GENE
is	O
present	O
in	O
light	O
and	O
dark	O
grown	O
leaves	O
as	O
well	O
as	O
in	O
roots	O
.	O

In	O
this	O
technique	O
,	O
the	O
posterior	O
wall	O
of	O
the	O
neopharynx	O
consists	O
only	O
of	O
the	O
prevertebral	O
tissue	O
,	O
while	O
the	O
flap	O
forms	O
the	O
anterior	O
and	O
lateral	O
walls	O
.	O

These	O
data	O
may	O
indicate	O
redundancy	O
between	O
members	O
of	O
the	O
NGFI	B-GENE
-	I-GENE
B	I-GENE
/	O
Nurr1	B-GENE
/	O
Nor1	B-GENE
subfamily	O
and	O
could	O
explain	O
why	O
no	O
phenotypic	O
disturbances	O
have	O
yet	O
been	O
found	O
in	O
mice	O
in	O
which	O
the	O
NGFI	B-GENE
-	I-GENE
B	I-GENE
gene	I-GENE
has	O
been	O
inactivated	O
.	O

Activation	O
of	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
MAPK	B-GENE
)	O
pathway	O
enhances	O
long	O
-	O
range	O
transactivation	O
by	O
the	O
beta	B-GENE
-	I-GENE
globin	I-GENE
locus	I-GENE
control	I-GENE
region	I-GENE
(	O
LCR	O
)	O
(	O
W	O
.	O

The	O
gp41	B-GENE
peptide	I-GENE
(	I-GENE
Glu	I-GENE
-	I-GENE
Leu	I-GENE
-	I-GENE
Asp	I-GENE
-	I-GENE
Lys	I-GENE
-	I-GENE
Trp	I-GENE
-	I-GENE
Ala	I-GENE
)	I-GENE
fused	O
to	O
the	O
C	O
-	O
terminus	O
of	O
Sj	B-GENE
GST	I-GENE
forms	O
a	O
loop	O
stabilized	O
by	O
symmetry	O
-	O
related	O
GSTs	B-GENE
.	O

The	O
GST	B-GENE
-	O
CBL	B-GENE
-	O
LZIP	B-GENE
fusion	O
protein	O
contains	O
a	O
binding	O
site	O
for	O
the	O
SH2	B-GENE
domain	I-GENE
of	O
the	O
p85	B-GENE
subunit	I-GENE
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
,	O
which	O
mapped	O
to	O
Tyr731	O
,	O
which	O
is	O
present	O
in	O
the	O
sequence	O
YEAM	O
.	O

The	O
testes	O
of	O
8	O
specimens	O
of	O
Triturus	O
marmoratus	O
were	O
collected	O
during	O
each	O
month	O
of	O
1987	O
and	O
processed	O
for	O
electron	O
microscopy	O
and	O
light	O
microscopy	O
demonstration	O
of	O
testosterone	O
(	O
T	O
)	O
following	O
the	O
ABC	B-GENE
(	O
avidin	B-GENE
-	I-GENE
biotin	I-GENE
peroxidase	I-GENE
complex	I-GENE
)	O
method	O
.	O

We	O
have	O
generated	O
transgenic	O
fly	O
strains	O
with	O
mutations	O
affecting	O
specific	O
TRA	B-GENE
-	I-GENE
2	I-GENE
isoforms	I-GENE
to	O
investigate	O
their	O
individual	O
roles	O
in	O
regulating	O
the	O
alternative	O
processing	O
of	O
doublesex	B-GENE
,	O
exuperantia	B-GENE
and	O
tra	B-GENE
-	I-GENE
2	I-GENE
pre	I-GENE
-	I-GENE
mRNA	I-GENE
.	O

Few	O
triers	O
or	O
users	O
had	O
received	O
SLT	O
counseling	O
from	O
their	O
dentist	O
despite	O
high	O
dental	O
utilization	O
rates	O
.	O

There	O
has	O
been	O
no	O
significant	O
toxicity	O
associated	O
with	O
repeated	O
5	O
-	O
FU	O
instillation	O
into	O
the	O
airway	O
.	O

He	O
had	O
complained	O
of	O
fever	O
and	O
right	O
hypochondralgia	O
2	O
months	O
after	O
being	O
operated	O
for	O
appendicitis	O
.	O

Thus	O
,	O
apoptosis	O
in	O
hematopoietic	O
cells	O
is	O
the	O
end	O
result	O
of	O
a	O
conflict	O
between	O
death	O
and	O
survival	O
signals	O
,	O
rather	O
than	O
a	O
simple	O
death	O
by	O
default	O
.	O

Changes	O
in	O
testicular	O
testosterone	O
and	O
acid	O
and	O
alkaline	B-GENE
phosphatase	I-GENE
activity	O
in	O
testis	O
and	O
accessory	O
sex	O
organs	O
after	O
induction	O
of	O
varicocele	O
in	O
Noble	O
rats	O
.	O

The	O
reconstituted	O
RNA	B-GENE
polymerases	I-GENE
containing	O
the	O
mutant	O
alpha	O
subunits	O
were	O
examined	O
for	O
their	O
response	O
to	O
transcription	O
activation	O
by	O
cAMP	B-GENE
-	I-GENE
CRP	I-GENE
and	O
the	O
rrnBP1	B-GENE
UP	I-GENE
element	I-GENE
.	O

Changes	O
in	O
the	O
greater	O
omentum	O
of	O
mice	O
of	O
different	O
strains	O
after	O
intraperitoneal	O
immunization	O
with	O
sheep	O
erythrocytes	O
.	O

In	O
patients	O
,	O
750	O
mL	O
of	O
saline	O
lowered	O
DL	O
(	O
CO	O
)	O
(	O
-	O
8	O
%	O
,	O
P	O
<	O
0	O
.	O
01	O
versus	O
baseline	O
)	O
,	O
D	O
(	O
M	O
)	O
(	O
-	O
10	O
%	O
,	O
P	O
<	O
0	O
.	O
01	O
versus	O
baseline	O
)	O
,	O
aldosterone	O
(	O
-	O
29	O
%	O
,	O
P	O
<	O
0	O
.	O
01	O
versus	O
baseline	O
)	O
,	O
renin	B-GENE
(	O
-	O
52	O
%	O
,	O
P	O
<	O
0	O
.	O
01	O
versus	O
baseline	O
)	O
,	O
and	O
hematocrit	O
(	O
-	O
6	O
%	O
,	O
P	O
<	O
0	O
.	O
05	O
versus	O
baseline	O
)	O
and	O
increased	O
V	O
(	O
C	O
)	O
(	O
20	O
%	O
,	O
P	O
<	O
0	O
.	O
01	O
versus	O
baseline	O
)	O
,	O
without	O
changing	O
rap	O
and	O
wpp	O
.	O

Reversible	O
pressure	O
-	O
induced	O
amorphization	O
in	O
solid	O
C70	O
:	O
Raman	O
and	O
photoluminescence	O
study	O
.	O

Antibodies	O
against	O
REAP	B-GENE
-	I-GENE
1	I-GENE
inhibit	O
in	O
vitro	O
RNA	O
editing	O
reactions	O
confirming	O
its	O
role	O
in	O
RNA	O
editing	O
.	O

The	O
more	O
severe	O
the	O
CRF	O
,	O
the	O
more	O
likely	O
that	O
total	O
HDL	B-GENE
and	O
HDL2	B-GENE
cholesterol	I-GENE
will	O
be	O
low	O
.	O

A	O
conventional	O
N	O
-	O
terminal	O
signal	O
sequence	O
was	O
not	O
detected	O
in	O
the	O
NodO	B-GENE
protein	I-GENE
.	O

Mean	O
CD4	B-GENE
percentages	O
were	O
lower	O
postpartum	O
(	O
21	O
.	O
9	O
+	O
/	O
-	O
3	O
.	O
4	O
)	O
than	O
prepartum	O
(	O
45	O
.	O
1	O
+	O
/	O
-	O
6	O
.	O
7	O
)	O
in	O
all	O
five	O
patients	O
studied	O
,	O
although	O
proliferative	O
responses	O
to	O
the	O
mitogens	B-GENE
phytohemagglutinin	I-GENE
and	I-GENE
pokeweed	I-GENE
were	O
unchanged	O
during	O
the	O
study	O
period	O
.	O

Significance	O
of	O
the	O
determination	O
of	O
vascular	O
tonus	O
in	O
the	O
differential	O
diagnosis	O
of	O
rheumatic	O
and	O
arteriosclerotic	O
lesions	O
of	O
the	O
heart	O
and	O
vessels	O
in	O
middle	O
-	O
aged	O
and	O
elderly	O
persons	O
with	O
fibrillation	O
arrhythmia	O

The	O
disease	O
processes	O
that	O
affect	O
transplant	O
patients	O
both	O
before	O
and	O
after	O
transplantation	O
are	O
not	O
seen	O
frequently	O
in	O
the	O
general	O
practice	O
of	O
gastroenterology	O
.	O

In	O
Experiment	O
2	O
,	O
levels	O
were	O
:	O
amprolium	O
and	O
ethopabate	O
,	O
.	O
02	O
%	O
;	O
salinomycin	O
,	O
55	O
mg	O
/	O
kg	O
;	O
monensin	O
,	O
99	O
mg	O
/	O
kg	O
;	O
and	O
lasalocid	O
,	O
110	O
mg	O
/	O
kg	O
.	O

This	O
duplicated	O
genomic	O
region	O
is	O
also	O
linked	O
tightly	O
to	O
D1Z2	B-GENE
,	O
a	O
genetic	O
marker	O
containing	O
a	O
highly	O
polymorphic	O
VNTR	O
(	O
variable	O
number	O
tandem	O
repeat	O
)	O
consisting	O
of	O
an	O
unusual	O
40	O
-	O
bp	O
reiterated	O
sequence	O
.	O

The	O
level	O
of	O
transcription	O
generated	O
by	O
all	O
of	O
these	O
activators	O
is	O
greater	O
than	O
the	O
sum	O
of	O
the	O
levels	O
generated	O
by	O
individual	O
factors	O
,	O
a	O
phenomenon	O
designated	O
transcriptional	O
synergy	O
.	O

Aspartame	O
is	O
a	O
synthetic	O
sweetener	O
commonly	O
used	O
in	O
soft	O
drinks	O
and	O
many	O
foods	O
.	O

Under	O
control	O
conditions	O
and	O
in	O
the	O
presence	O
of	O
3	O
micromol	O
/	O
kg	O
MIB	O
and	O
VER	O
the	O
maximal	O
effect	O
of	O
noradrenaline	O
was	O
reached	O
at	O
0	O
.	O
1	O
micromol	O
/	O
kg	O
whereas	O
in	O
the	O
presence	O
of	O
10	O
micromol	O
/	O
kg	O
MIB	O
and	O
VER	O
it	O
was	O
reached	O
at	O
a	O
dose	O
of	O
1	O
micromol	O
/	O
kg	O
.	O

The	O
highly	O
conserved	O
region	O
of	O
U6	B-GENE
snRNA	I-GENE
has	O
a	O
structural	O
similarity	O
with	O
the	O
catalytic	O
domain	O
of	O
the	O
negative	O
strand	O
of	O
the	O
satellite	O
RNA	O
of	O
tobacco	O
ring	O
spot	O
virus	O
[	O
(	O
-	O
)	O
sTRSV	O
]	O
,	O
suggesting	O
that	O
the	O
highly	O
conserved	O
region	O
of	O
U6	B-GENE
snRNA	I-GENE
forms	O
the	O
catalytic	O
center	O
.	O

By	O
computed	O
homology	O
search	O
,	O
we	O
noticed	O
significant	O
similarities	O
between	O
US3	B-GENE
PK	I-GENE
and	O
p21	B-GENE
-	I-GENE
activated	I-GENE
kinase	I-GENE
(	O
PAK	B-GENE
)	O
,	O
which	O
is	O
activated	O
by	O
the	O
Cdc42	B-GENE
or	O
Rac	B-GENE
.	O

Using	O
transgenic	O
lines	O
a	O
detailed	O
analysis	O
of	O
the	O
Hoxa	B-GENE
-	I-GENE
7	I-GENE
enhancer	O
-	O
directed	O
expression	O
during	O
embryogenesis	O
was	O
performed	O
.	O
lacZ	B-GENE
expression	O
was	O
first	O
detected	O
in	O
the	O
allantois	O
at	O
day	O
7	O
.	O
5	O
p	O
.	O
c	O
.	O
and	O
in	O
mesoderm	O
and	O
ectoderm	O
at	O
day	O
8	O
.	O
5	O
of	O
gestation	O
.	O

Its	O
phosphorylation	O
strongly	O
potentiates	O
its	O
ability	O
to	O
activate	O
transcription	O
of	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
promoter	I-GENE
through	O
a	O
ternary	O
complex	O
assembled	O
on	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
serum	I-GENE
response	I-GENE
element	I-GENE
.	O

Drosophila	B-GENE
melanogaster	I-GENE
casein	I-GENE
kinase	I-GENE
II	I-GENE
(	O
DmCKII	B-GENE
)	O
is	O
composed	O
of	O
catalytic	O
(	O
alpha	O
)	O
and	O
regulatory	O
(	O
beta	O
)	O
subunits	O
associated	O
as	O
an	O
alpha2beta2	O
heterotetramer	O
.	O

Inhibition	O
of	O
DNA	B-GENE
topoisomerase	I-GENE
II	I-GENE
alpha	I-GENE
gene	I-GENE
expression	O
by	O
the	O
p53	B-GENE
tumor	I-GENE
suppressor	I-GENE
.	O

These	O
conditions	O
may	O
determine	O
an	O
increase	O
in	O
the	O
level	O
of	O
indoor	O
pollutants	O
(	O
tobacco	O
smoke	O
,	O
gases	O
produced	O
by	O
cooling	O
processes	O
etc	O
.	O
)	O
and	O
of	O
allergens	O
derived	O
from	O
mites	O
,	O
domestic	O
animals	O
and	O
cockroaches	O
.	O

Vav	B-GENE
and	O
Dbl	B-GENE
are	O
members	O
of	O
a	O
novel	O
class	O
of	O
oncogene	O
proteins	O
that	O
share	O
significant	O
sequence	O
identity	O
in	O
a	O
approximately	O
250	O
-	O
amino	O
-	O
acid	O
domain	O
,	O
designated	O
the	O
Dbl	B-GENE
homology	I-GENE
domain	I-GENE
.	O

METHODS	O
:	O
Levels	O
of	O
sIL	B-GENE
-	I-GENE
2R	I-GENE
were	O
measured	O
simultaneously	O
in	O
plasma	O
and	O
pleural	O
fluid	O
in	O
111	O
patients	O
with	O
pleural	O
effusions	O
of	O
unknown	O
causes	O
.	O

HCVR	O
-	O
L	O
significantly	O
increased	O
dVAS	O
/	O
dPCO2	O
to	O
4	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
7	O
mm	O
/	O
Torr	O
compared	O
to	O
HCVR	O
-	O
S	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Right	O
-	O
sided	O
hemiplegia	O
of	O
5	O
years	O
duration	O
occurred	O
in	O
the	O
remaining	O
case	O
.	O

Studies	O
on	O
the	O
excretion	O
of	O
selenium	O
in	O
urine	O
and	O
feces	O
and	O
distribution	O
in	O
the	O
organs	O
of	O
rats	O
by	O
a	O
method	O
of	O
radioactivity	O
measurement	O

The	O
LIF	B-GENE
appeared	O
to	O
be	O
released	O
by	O
the	O
patient	O
'	O
s	O
peripheral	O
blood	O
lymphocytes	O
when	O
cultured	O
with	O
optimal	O
doses	O
of	O
propranolol	O
.	O

In	O
addition	O
,	O
the	O
findings	O
confirmed	O
previous	O
studies	O
which	O
showed	O
that	O
monkeys	O
with	O
total	O
bilateral	O
striatectomies	O
could	O
require	O
the	O
ability	O
to	O
execute	O
accurate	O
visually	O
guided	O
reaches	O
.	O

The	O
greatest	O
risk	O
of	O
preterm	O
prelabour	O
rupture	O
of	O
membranes	O
(	O
PPROM	O
)	O
is	O
preterm	O
delivery	O
.	O

The	O
2	B-GENE
.	I-GENE
3	I-GENE
x	I-GENE
10	I-GENE
(	I-GENE
3	I-GENE
)	I-GENE
base	I-GENE
SUF12	I-GENE
+	I-GENE
transcript	I-GENE
contains	O
an	O
open	O
reading	O
frame	O
sufficient	O
to	O
encode	O
a	O
88	O
x	O
10	O
(	O
3	O
)	O
Mr	O
protein	O
.	O

This	O
regulation	O
is	O
mediated	O
by	O
several	O
kinases	O
that	O
phosphorylate	O
specific	O
residues	O
in	O
the	O
different	O
functional	O
domains	O
of	O
the	O
p53	B-GENE
molecule	I-GENE
.	O

In	O
group	O
I	O
during	O
the	O
pain	O
free	O
period	O
26	O
of	O
81	O
patients	O
had	O
positive	O
thallium	O
-	O
201	O
scans	O
,	O
whereas	O
20	O
patients	O
had	O
an	O
abnormal	O
ECG	O
at	O
that	O
time	O
;	O
during	O
angina	O
18	O
patients	O
had	O
transient	O
ECG	O
changes	O
.	O

We	O
examined	O
the	O
contribution	O
of	O
the	O
M	B-GENE
-	I-GENE
MuLV	I-GENE
enhancers	I-GENE
to	O
the	O
transcriptional	O
activity	O
and	O
pathogenesis	O
of	O
M	O
-	O
MuLV	O
by	O
constructing	O
LTRs	O
containing	O
heterologous	O
enhancer	O
elements	O
.	O

Acute	O
respiratory	O
distress	O
syndrome	O
.	O

Serum	O
creatinine	B-GENE
kinase	I-GENE
activity	O
was	O
7	O
,	O
800	O
-	O
17	O
,	O
500	O
U	O
/	O
l	O
,	O
making	O
acute	O
muscle	O
damage	O
likely	O
,	O
probably	O
rhabdomyolysis	O
.	O

Transcriptional	O
regulation	O
of	O
the	O
murine	B-GENE
k	I-GENE
-	I-GENE
fgf	I-GENE
gene	I-GENE
.	O

Fetal	O
arterial	O
and	O
sagittal	O
sinus	O
pH	O
,	O
base	O
excess	O
,	O
po2	O
,	O
and	O
oxygen	O
saturation	O
decreased	O
,	O
and	O
hydrogen	O
ion	O
concentrations	O
and	O
pco2	O
increased	O
during	O
asphyxia	O
alone	O
and	O
asphyxia	O
plus	O
isoflurane	O
-	O
oxygen	O
.	O

To	O
clarify	O
the	O
difference	O
,	O
both	O
the	O
Crk	B-GENE
II	I-GENE
and	O
Crk	B-GENE
II	I-GENE
-	I-GENE
23	I-GENE
,	O
proteins	O
were	O
expressed	O
in	O
E	O
.	O
coli	O
and	O
examined	O
their	O
binding	O
capacity	O
in	O
vitro	O
.	O

Growth	B-GENE
hormone	I-GENE
exerts	O
its	O
effects	O
on	O
the	O
ovarian	O
follicular	O
cycle	O
directly	O
or	O
by	O
local	O
production	O
of	O
insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
1	I-GENE
(	O
IGF	B-GENE
-	I-GENE
1	I-GENE
)	O
.	O

For	O
the	O
most	O
part	O
,	O
only	O
aerobic	O
microbial	O
degradation	O
systems	O
have	O
been	O
reported	O
so	O
far	O
.	O

This	O
is	O
mediated	O
by	O
vascular	O
remodeling	O
,	O
an	O
active	O
process	O
that	O
results	O
in	O
a	O
change	O
in	O
the	O
geometry	O
of	O
the	O
blood	O
vessel	O
.	O

The	O
results	O
suggest	O
that	O
the	O
posterior	O
wall	O
is	O
more	O
compliant	O
than	O
the	O
anterior	O
wall	O
(	O
that	O
is	O
,	O
for	O
a	O
given	O
difference	O
in	O
transmural	O
pressure	O
,	O
the	O
local	O
segment	O
length	O
change	O
of	O
the	O
posterior	O
wall	O
was	O
greater	O
)	O
.	O

Although	O
cardiac	O
output	O
decreased	O
slightly	O
with	O
PCF	O
,	O
hemodynamic	O
changes	O
due	O
to	O
PCF	O
were	O
unlikely	O
to	O
account	O
for	O
the	O
observed	O
fall	O
in	O
PaO2	O
.	O

Swarming	O
of	O
Moraxella	O

Two	O
patient	O
groups	O
were	O
studied	O
:	O
Type	O
I	O
-	O
-	O
with	O
a	O
new	O
ePTFE	O
graft	O
;	O
and	O
Type	O
II	O
-	O
-	O
with	O
thrombectomy	O
and	O
/	O
or	O
revision	O
of	O
a	O
previously	O
placed	O
ePTFE	O
graft	O
.	O

No	O
consensus	O
binding	O
sequence	O
could	O
be	O
discerned	O
in	O
these	O
fragments	O
and	O
bound	O
factor	O
is	O
in	O
rapid	O
equilibrium	O
with	O
unbound	O
.	O

As	O
a	O
quantitative	O
index	O
of	O
cochlear	O
function	O
,	O
2f1	O
-	O
f2	O
distortion	O
-	O
product	O
otoacoustic	O
emissions	O
(	O
DPOAEs	O
)	O
were	O
monitored	O
systematically	O
over	O
time	O
in	O
three	O
groups	O
of	O
rabbits	O
,	O
with	O
each	O
group	O
experiencing	O
a	O
unique	O
paradigm	O
that	O
incorporated	O
repeated	O
exposure	O
to	O
the	O
low	O
-	O
frequency	O
tone	O
.	O

Quasidiatomic	O
study	O
of	O
Ly	O
-	O
alpha	O
-	O
producing	O
H2	O
+	O
-	O
Ne	O
collisions	O
at	O
keV	O
energies	O
.	O

Detailed	O
analysis	O
of	O
the	O
predicted	O
amino	O
acid	O
sequence	O
revealed	O
sequence	O
elements	O
which	O
are	O
conserved	O
in	O
many	O
DNA	B-GENE
and	I-GENE
RNA	I-GENE
polymerases	I-GENE
.	O

139La	O
NQR	O
relaxation	O
and	O
microSR	O
study	O
of	O
Zn	O
-	O
doping	O
effects	O
in	O
La2CuO4	O
.	O

We	O
have	O
previously	O
reported	O
the	O
first	O
isolation	O
of	O
a	O
c	B-GENE
-	I-GENE
myc	I-GENE
-	I-GENE
null	I-GENE
cell	O
line	O
.	O

Our	O
study	O
investigated	O
the	O
hypothesis	O
that	O
the	O
combination	O
of	O
a	O
high	O
NaCl	O
diet	O
and	O
social	O
isolation	O
stress	O
would	O
increase	O
systolic	O
blood	O
pressure	O
(	O
SBP	O
)	O
and	O
endogenous	O
sodium	O
pump	O
ligands	O
(	O
SPL	O
)	O
,	O
ouabainlike	O
compound	O
(	O
OLC	O
)	O
,	O
and	O
marinobufagenin	O
(	O
MBG	O
)	O
.	O

Percentage	O
incremental	O
18	O
-	O
OHB	O
responses	O
to	O
metoclopramide	O
were	O
greater	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
in	O
the	O
subjects	O
after	O
5	O
days	O
on	O
a	O
200	O
-	O
meq	O
sodium	O
intake	O
than	O
after	O
5	O
days	O
on	O
a	O
10	O
-	O
meq	O
sodium	O
intake	O
.	O

An	O
additional	O
stimulation	O
of	O
D1	B-GENE
receptors	I-GENE
by	O
giving	O
SKF38393	O
30	O
min	O
later	O
produced	O
an	O
almost	O
continuous	O
pattern	O
of	O
jaw	O
openings	O
but	O
less	O
closure	O
movements	O
from	O
the	O
rest	O
position	O
,	O
and	O
the	O
openings	O
were	O
accompanied	O
by	O
frequent	O
tongue	O
protrusions	O
.	O

PURPOSE	O
:	O
Second	O
malignant	O
neoplasms	O
(	O
SMNs	O
)	O
are	O
a	O
rare	O
occurrence	O
after	O
the	O
successful	O
treatment	O
of	O
childhood	O
cancer	O
.	O

A	O
p53	B-GENE
cDNA	I-GENE
deletion	O
mutant	O
(	O
delta	O
pro	O
AE	O
)	O
,	O
which	O
lacks	O
this	O
entire	O
proline	O
-	O
rich	O
domain	O
(	O
deleted	O
for	O
amino	O
acids	O
62	O
-	O
91	O
)	O
,	O
was	O
created	O
and	O
characterized	O
for	O
a	O
variety	O
of	O
p53	B-GENE
functions	O
.	O

Mutations	O
in	O
nifR1	B-GENE
(	O
ntrC	B-GENE
)	O
and	O
nifR4	B-GENE
(	O
rpoN	B-GENE
,	O
encoding	O
sigma54	B-GENE
)	O
had	O
no	O
influence	O
on	O
xdh	B-GENE
gene	I-GENE
expression	O
.	O

Candidate	O
factors	O
have	O
been	O
identified	O
by	O
the	O
observation	O
that	O
changes	O
in	O
glucocorticoid	O
induction	O
parameters	O
in	O
CV	O
-	O
1	O
cells	O
could	O
be	O
reproduced	O
by	O
varying	O
the	O
cellular	O
levels	O
of	O
coactivators	O
[	O
transcriptional	B-GENE
intermediary	I-GENE
factor	I-GENE
2	I-GENE
(	O
TIF2	B-GENE
)	O
,	O
steroid	B-GENE
receptor	I-GENE
coactivator	I-GENE
1	I-GENE
(	O
SRC	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
and	O
amplified	B-GENE
in	I-GENE
breast	I-GENE
cancer	I-GENE
1	I-GENE
(	O
AIB1	B-GENE
)	O
]	O
,	O
comodulator	O
[	O
CREB	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CBP	B-GENE
)	O
]	O
,	O
or	O
corepressor	O
[	O
silencing	B-GENE
mediator	I-GENE
for	I-GENE
retinoid	I-GENE
and	I-GENE
thyroid	I-GENE
-	I-GENE
hormone	I-GENE
receptors	I-GENE
(	O
SMRT	B-GENE
)	O
]	O
without	O
concomitant	O
increases	O
in	O
GR	B-GENE
.	O

The	O
pyridostigmine	O
inhibited	O
AChE	B-GENE
recovered	O
only	O
in	O
the	O
100	O
mumol	O
kg	O
-	O
1	O
kg	O
oxime	O
groups	O
at	O
the	O
end	O
of	O
the	O
experiment	O
.	O

We	O
compared	O
retrospectively	O
the	O
efficacy	O
of	O
granulocyte	B-GENE
colony	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
G	B-GENE
-	I-GENE
CSF	I-GENE
)	O
alone	O
with	O
chemotherapy	O
plus	O
G	B-GENE
-	I-GENE
CSF	I-GENE
in	O
mobilizing	O
CD34	B-GENE
-	O
positive	O
cells	O
in	O
patients	O
with	O
malignant	O
lymphoma	O
.	O

An	O
additional	O
dose	O
of	O
20	O
-	O
25	O
Gy	O
was	O
delivered	O
to	O
the	O
site	O
of	O
original	O
involvement	O
using	O
an	O
implant	O
when	O
feasible	O
.	O

Activation	O
of	O
the	O
receptor	O
induces	O
Ret	B-GENE
phosphorylation	O
that	O
leads	O
the	O
survival	O
-	O
promoting	O
effects	O
.	O

Adenovirus	O
infection	O
of	O
hepatoma	O
cells	O
inhibited	O
transcription	O
of	O
the	O
phosphoenolpyruvate	B-GENE
carboxykinase	I-GENE
(	O
GTP	O
)	O
(	O
EC	B-GENE
4	I-GENE
.	I-GENE
1	I-GENE
.	I-GENE
1	I-GENE
.	I-GENE
32	I-GENE
)	O
(	O
PEPCK	B-GENE
)	O
gene	O
and	O
virtually	O
eliminated	O
transcription	O
of	O
a	O
chimeric	O
gene	O
which	O
contained	O
the	O
PEPCK	B-GENE
promoter	I-GENE
linked	O
to	O
the	O
structural	O
gene	O
for	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
.	O

Circulating	O
immune	O
complexes	O
were	O
determined	O
by	O
the	O
method	O
of	O
phagocytosis	O
and	O
immunofluorescence	O
.	O

LCCH1	B-GENE
was	O
identical	O
to	O
the	O
Rdl	B-GENE
gene	I-GENE
,	O
a	O
known	O
GABA	B-GENE
receptor	I-GENE
subunit	I-GENE
gene	I-GENE
from	O
D	O
.	O
melanogaster	O
,	O
whereas	O
LCCH2	B-GENE
and	O
LCCH3	B-GENE
were	O
novel	O
D	O
.	O
melanogaster	O
sequences	O
that	O
exhibited	O
structural	O
similarity	O
to	O
other	O
members	O
of	O
the	O
ligand	B-GENE
-	I-GENE
gated	I-GENE
chloride	I-GENE
channel	I-GENE
gene	I-GENE
family	I-GENE
.	O

In	O
this	O
report	O
,	O
we	O
investigated	O
whether	O
the	O
cleavage	O
of	O
the	O
RRKR	O
motif	O
of	O
MT	B-GENE
-	I-GENE
MMP1	I-GENE
by	O
Golgi	B-GENE
-	I-GENE
associated	I-GENE
furin	I-GENE
is	O
analogous	O
to	O
a	O
similar	O
enzyme	O
activation	O
mechanism	O
observed	O
with	O
stromelysin	B-GENE
-	I-GENE
3	I-GENE
.	O

Lifestyle	O
characteristics	O
were	O
ascertained	O
by	O
a	O
self	O
-	O
administered	O
questionnaire	O
.	O

The	O
oxalate	B-GENE
oxidase	I-GENE
method	O
results	O
in	O
a	O
mean	O
and	O
reference	O
interval	O
for	O
oxalate	O
excretion	O
that	O
are	O
comparable	O
with	O
those	O
by	O
isotope	O
dilution	O
,	O
gas	O
-	O
chromatographic	O
,	O
colorimetric	O
,	O
and	O
other	O
enzymic	O
procedures	O
.	O

Normal	O
replication	O
of	O
DNA	B-GENE
A	I-GENE
still	O
carrying	O
the	O
AC3	B-GENE
ORF	I-GENE
mutation	O
was	O
found	O
in	O
extracts	O
from	O
these	O
plants	O
.	O

Kohtz	O
,	O
J	O
.	O

These	O
data	O
are	O
discussed	O
in	O
the	O
context	O
of	O
the	O
pathogenesis	O
and	O
differential	O
diagnosis	O
of	O
EEC	O
.	O

These	O
data	O
suggest	O
that	O
the	O
fibrinogen	B-GENE
gamma	I-GENE
chain	I-GENE
region	I-GENE
Gly190	I-GENE
-	I-GENE
Val202	I-GENE
functions	O
as	O
a	O
minimal	O
recognition	O
sequence	O
for	O
the	O
leukocyte	O
integrin	O
CD11b	B-GENE
/	O
CD18	B-GENE
.	O

OBJECTIVE	O
:	O
The	O
audiologic	O
presentation	O
of	O
vestibular	O
schwannoma	O
(	O
VS	O
)	O
associated	O
with	O
neurofibromatosis	O
type	O
2	O
(	O
NF2	O
)	O
has	O
not	O
been	O
well	O
characterized	O
.	O

Siglec	B-GENE
-	I-GENE
9	I-GENE
is	O
predicted	O
to	O
contain	O
three	O
extracellular	O
immunoglobulin	B-GENE
-	I-GENE
like	I-GENE
domains	I-GENE
that	O
comprise	O
an	O
N	B-GENE
-	I-GENE
terminal	I-GENE
V	I-GENE
-	I-GENE
set	I-GENE
domain	I-GENE
and	O
two	O
C2	B-GENE
-	I-GENE
set	I-GENE
domains	I-GENE
,	O
a	O
transmembrane	O
region	O
and	O
a	O
cytoplasmic	O
tail	O
containing	O
two	O
putative	O
tyrosine	O
-	O
based	O
signaling	O
motifs	O
.	O

Development	O
of	O
P	O
carinii	O
pneumonia	O
was	O
associated	O
with	O
the	O
stage	O
of	O
Kaposi	O
'	O
s	O
sarcoma	O
,	O
B	O
subtype	O
disease	O
,	O
and	O
the	O
presence	O
of	O
0	O
.	O
20	O
X	O
10	O
(	O
9	O
)	O
/	O
L	O
(	O
200	O
/	O
mm3	O
)	O
or	O
fewer	O
CD4	B-GENE
cells	O
at	O
study	O
entry	O
.	O

Dermatophagoides	O
farinae	O
-	O
sensitized	O
lymphocytes	O
in	O
asthmatic	O
children	O
as	O
evaluated	O
by	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
(	O
IL	B-GENE
-	I-GENE
2	I-GENE
)	O
production	O
and	O
acquisition	O
of	O
IL	B-GENE
-	I-GENE
2	I-GENE
responsiveness	O

Adenocarcinoma	O
and	O
large	O
cell	O
carcinoma	O
have	O
a	O
worse	O
prognosis	O
than	O
squamous	O
cell	O
carcinoma	O
in	O
the	O
T1N1	O
and	O
T2N1	O
subsets	O
.	O

The	O
DNA	O
element	O
through	O
which	O
EBNA	B-GENE
-	I-GENE
3C	I-GENE
activates	O
the	O
LMP	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
includes	O
a	O
Spi	B-GENE
-	I-GENE
1	I-GENE
/	O
Spi	B-GENE
-	I-GENE
B	I-GENE
binding	O
site	O
,	O
previously	O
characterized	O
as	O
an	O
important	O
EBNA	B-GENE
-	I-GENE
2	I-GENE
response	I-GENE
element	I-GENE
.	O

Based	O
on	O
PCR	O
strategies	O
and	O
expression	O
studies	O
,	O
we	O
define	O
the	O
genomic	O
organization	O
of	O
the	O
FUT8b	B-GENE
gene	I-GENE
.	O

Cord	O
formation	O
in	O
BACTEC	O
7H12	O
medium	O
for	O
rapid	O
,	O
presumptive	O
identification	O
of	O
Mycobacterium	O
tuberculosis	O
complex	O
.	O

The	O
effect	O
of	O
the	O
NMDA	B-GENE
-	I-GENE
receptor	I-GENE
antagonist	O
(	O
+	O
/	O
-	O
)	O
-	O
CPP	O
on	O
the	O
conditioned	O
-	O
reflex	O
activation	O
of	O
an	O
operant	O
reaction	O
in	O
the	O
brain	O
electrical	O
self	O
-	O
stimulation	O
test	O
in	O
rats	O

Treatment	O
with	O
H7	O
did	O
not	O
affect	O
IL	B-GENE
-	I-GENE
4R	I-GENE
-	O
mediated	O
immediate	O
signaling	O
events	O
such	O
as	O
tyrosine	O
phosphorylation	O
of	O
Jak1	B-GENE
,	O
Jak3	B-GENE
,	O
insulin	B-GENE
receptor	I-GENE
substrate	I-GENE
(	I-GENE
IRS	I-GENE
)	I-GENE
-	I-GENE
1	I-GENE
and	O
IRS	B-GENE
-	I-GENE
2	I-GENE
,	O
or	O
tyrosine	O
phosphorylation	O
and	O
DNA	O
binding	O
of	O
Stat6	B-GENE
.	O

(	O
1982	O
)	O
.	O

Vasodilation	O
in	O
congestive	O
heart	O
failure	O
is	O
an	O
established	O
therapeutic	O
principal	O
.	O

The	O
translational	O
product	O
of	O
UL26	B-GENE
.	I-GENE
5	I-GENE
is	O
infected	B-GENE
-	I-GENE
cell	I-GENE
protein	I-GENE
35c	I-GENE
,	I-GENE
d	I-GENE
(	O
ICP35c	B-GENE
,	I-GENE
d	I-GENE
)	O
(	O
F	O
.	O

Our	O
experience	O
suggests	O
that	O
T2	O
weighting	O
is	O
adequate	O
and	O
is	O
the	O
method	O
of	O
choice	O
for	O
the	O
early	O
recognition	O
of	O
necrosis	O
of	O
the	O
lunate	O
.	O

Minor	O
changes	O
within	O
the	O
transmembrane	O
domains	O
(	O
TMs	O
)	O
sometimes	O
produced	O
major	O
effects	O
and	O
more	O
drastic	O
changes	O
in	O
the	O
TMs	O
ablated	O
surface	O
expression	O
entirely	O
.	O

Molecular	O
analysis	O
of	O
the	O
mannitol	O
operon	O
of	O
Clostridium	O
acetobutylicum	O
encoding	O
a	O
phosphotransferase	O
system	O
and	O
a	O
putative	O
PTS	O
-	O
modulated	O
regulator	O
.	O

Mammalian	O
chromosome	O
ends	O
contain	O
long	O
arrays	O
of	O
TTAGGG	O
repeats	O
that	O
are	O
complexed	O
to	O
a	O
telomere	O
specific	O
protein	O
,	O
the	O
TTAGGG	B-GENE
repeat	I-GENE
binding	I-GENE
factor	I-GENE
,	O
TRF1	B-GENE
.	O

HPV	O
-	O
16	O
MARs	O
are	O
context	O
dependent	O
transcriptional	O
enhancers	O
,	O
and	O
activated	O
expression	O
of	O
HPV	O
-	O
16	O
oncogenes	O
dependent	O
on	O
chromosomal	O
integration	O
may	O
positively	O
select	O
tumorigenic	O
cells	O
during	O
the	O
multistep	O
etiology	O
of	O
cervical	O
cancer	O
.	O

Vancomycin	O
and	O
tetracycline	O
eliminated	O
toxin	O
in	O
stools	O
and	O
delayed	O
death	O
.	O

This	O
combination	O
is	O
considered	O
pathognomonic	O
for	O
factitious	O
hyperinsulinism	O
.	O

The	O
duration	O
of	O
naloxone	O
appears	O
to	O
be	O
dose	O
-	O
related	O
,	O
statistically	O
significant	O
up	O
to	O
approximately	O
1	O
.	O
5	O
hr	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
report	O
the	O
entire	O
genomic	O
structure	O
of	O
KCNQ1	B-GENE
,	O
which	O
consists	O
of	O
19	O
exons	O
spanning	O
400	O
kb	O
on	O
chromosome	O
11p15	O
.	O
5	O
.	O

A	O
comparison	O
between	O
attenuation	O
-	O
corrected	O
and	O
-	O
uncorrected	O
transmission	O
-	O
emission	O
SPECT	O
images	O
obtained	O
with	O
Tl	O
-	O
201	O
in	O
CAD	O
patients	O

Reconstruction	O
time	O
for	O
a	O
64	O
x	O
64	O
matrix	O
is	O
approximately	O
45	O
s	O
/	O
transaxial	O
slice	O
.	O

The	O
hyperpigmentation	O
is	O
linked	O
to	O
the	O
presence	O
of	O
numerous	O
single	O
melanosomes	O
and	O
polymelanosomes	O
in	O
keratinocytes	O
at	O
all	O
levels	O
of	O
the	O
epidermis	O
,	O
and	O
in	O
dermal	O
Factor	B-GENE
XIIIa	I-GENE
-	O
positive	O
dendrocytes	O
.	O

The	O
immediate	O
and	O
remote	O
results	O
of	O
surgical	O
treatment	O
of	O
renal	O
adenocarcinomas	O
.	O

Six	O
patients	O
underwent	O
an	O
electrophysiologic	O
study	O
.	O

In	O
agreement	O
with	O
this	O
,	O
archaea	O
appear	O
to	O
lack	O
eIF5	B-GENE
,	O
eIF2B	B-GENE
and	O
the	O
lysine	O
-	O
rich	O
binding	O
domain	O
for	O
these	O
factors	O
in	O
their	O
eIF2beta	B-GENE
homolog	I-GENE
.	O

However	O
,	O
the	O
MCMI	O
-	O
III	O
group	O
profile	O
was	O
significantly	O
lower	O
in	O
magnitude	O
compared	O
with	O
the	O
MCMI	O
-	O
II	O
.	O

Spen	B-GENE
is	O
the	O
only	O
known	O
homeotic	B-GENE
protein	I-GENE
with	O
RNP	O
binding	O
motifs	O
,	O
which	O
indicates	O
that	O
splicing	O
,	O
transport	O
,	O
or	O
other	O
RNA	O
regulatory	O
steps	O
are	O
involved	O
in	O
the	O
diversification	O
of	O
segmental	O
morphology	O
.	O

The	O
existence	O
of	O
universal	O
non	O
-	O
specific	O
mechanism	O
of	O
action	O
of	O
external	O
factors	O
upon	O
the	O
living	O
tissue	O
based	O
on	O
the	O
DEL	O
-	O
reaction	O
is	O
suggested	O
.	O

The	O
impairment	O
of	O
the	O
nocturnal	O
secretion	O
was	O
related	O
to	O
the	O
subjects	O
'	O
age	O
and	O
,	O
for	O
the	O
GH	B-GENE
secretory	O
pattern	O
only	O
,	O
also	O
to	O
the	O
MMSE	O
score	O
.	O

In	O
this	O
study	O
,	O
we	O
cloned	O
the	O
full	O
-	O
length	O
cDNA	O
of	O
mouse	O
PAX4	B-GENE
by	O
RACE	O
(	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
)	O
using	O
RNA	O
from	O
MIN6	O
cells	O
,	O
a	O
mouse	O
insulinoma	O
cell	O
line	O
.	O

Sixteen	O
patients	O
(	O
25	O
.	O
4	O
%	O
)	O
encountered	O
rejection	O
while	O
weaning	O
at	O
median	O
period	O
of	O
9	O
.	O
5	O
months	O
(	O
range	O
,	O
1	O
-	O
63	O
months	O
)	O
from	O
the	O
start	O
of	O
weaning	O
.	O

Earlier	O
nonoptical	O
methods	O
probably	O
did	O
not	O
include	O
the	O
portion	O
of	O
the	O
film	O
that	O
contained	O
mucus	O
.	O

Antibodies	O
specific	O
to	O
the	O
different	O
members	O
of	O
the	O
Jun	B-GENE
and	O
Fos	B-GENE
family	I-GENE
of	I-GENE
transcription	I-GENE
factors	I-GENE
show	O
that	O
,	O
in	O
gel	O
retardation	O
assays	O
,	O
a	O
Jun	B-GENE
-	I-GENE
like	I-GENE
factor	I-GENE
is	O
a	O
component	O
of	O
the	O
H3	B-GENE
.	I-GENE
2	I-GENE
specific	I-GENE
complex	I-GENE
.	O

CONCLUSIONS	O
:	O
Results	O
of	O
this	O
study	O
suggest	O
that	O
both	O
male	O
and	O
female	O
soldiers	O
who	O
are	O
diagnosed	O
with	O
chlamydia	O
infections	O
have	O
relatively	O
high	O
risks	O
of	O
reinfection	O
through	O
their	O
20s	O
.	O

Here	O
we	O
report	O
that	O
point	O
mutations	O
of	O
the	O
Abd	B-GENE
-	I-GENE
B	I-GENE
gene	I-GENE
in	O
trans	O
suppress	O
the	O
Fab	B-GENE
-	I-GENE
7	I-GENE
phenotype	I-GENE
in	O
a	O
pairing	O
-	O
dependent	O
manner	O
and	O
thus	O
represent	O
a	O
type	O
of	O
transvection	O
.	O

The	O
glucose	O
effect	O
on	O
the	O
pyruvate	B-GENE
kinase	I-GENE
gene	I-GENE
is	O
reversibly	O
antagonized	O
by	O
agents	O
increasing	O
intracellular	O
cAMP	O
.	O

Here	O
,	O
we	O
report	O
the	O
isolation	O
of	O
a	O
new	O
spindle	O
checkpoint	O
gene	O
,	O
mph1	B-GENE
(	O
Mps1p	B-GENE
-	I-GENE
like	I-GENE
pombe	I-GENE
homolog	I-GENE
)	O
,	O
in	O
the	O
fission	O
yeast	O
Schizosaccharomyces	O
pombe	O
,	O
that	O
is	O
required	O
for	O
checkpoint	O
activation	O
in	O
response	O
to	O
spindle	O
defects	O
.	O
mph1	B-GENE
functions	O
upstream	O
of	O
mad2	B-GENE
,	O
a	O
previously	O
characterized	O
component	O
of	O
the	O
spindle	O
checkpoint	O
.	O

In	O
addition	O
,	O
measurements	O
of	O
shielded	O
and	O
unshielded	O
syringes	O
containing	O
99mTc	O
-	O
labelled	O
radiopharmaceuticals	O
were	O
carried	O
out	O
.	O

Combination	O
chemotherapy	O
in	O
advanced	O
ovarian	O
cancer	O
.	O

The	O
results	O
in	O
the	O
untreated	O
patients	O
demonstrate	O
the	O
primary	O
importance	O
of	O
bulk	O
reduction	O
at	O
initial	O
laparotomy	O
.	O

Vertebrate	O
U6	B-GENE
small	I-GENE
nuclear	I-GENE
RNA	I-GENE
(	O
snRNA	O
)	O
loci	O
exemplify	O
a	O
novel	O
class	O
of	O
polymerase	B-GENE
III	I-GENE
-	O
transcribed	O
genes	O
that	O
lack	O
an	O
intragenic	O
control	O
region	O
(	O
ICR	O
)	O
.	O

The	O
well	O
-	O
trained	O
group	O
was	O
measured	O
once	O
in	O
the	O
respiration	O
chamber	O
for	O
36	O
h	O
according	O
to	O
the	O
same	O
protocol	O
.	O

PtdIns	B-GENE
(	I-GENE
4	I-GENE
,	I-GENE
5	I-GENE
)	I-GENE
P2	I-GENE
synthesis	O
,	O
on	O
the	O
other	O
hand	O
,	O
is	O
only	O
moderately	O
affected	O
even	O
in	O
fab1Delta	B-GENE
mutants	I-GENE
.	O

Protein	O
sequencing	O
,	O
electrophoretic	O
mobility	O
shift	O
assay	O
,	O
and	O
immunoblot	O
analyses	O
identify	O
p54	B-GENE
and	O
p47	B-GENE
/	I-GENE
48	I-GENE
as	O
members	O
of	O
the	O
hepatocyte	B-GENE
nuclear	I-GENE
factor	I-GENE
3	I-GENE
(	O
HNF3	B-GENE
[	O
forkhead	B-GENE
]	O
)	O
family	O
of	O
transcription	O
factors	O
.	O
p54	B-GENE
belongs	O
to	O
the	O
subfamily	O
of	O
HNF3	B-GENE
beta	I-GENE
proteins	I-GENE
,	O
while	O
p47	B-GENE
/	I-GENE
48	I-GENE
binding	O
activity	O
includes	O
HNF3	B-GENE
gamma	I-GENE
.	O

Molecular	O
analysis	O
indicated	O
that	O
inactivation	O
of	O
H	B-GENE
-	I-GENE
2L	I-GENE
expression	O
in	O
nearly	O
every	O
null	O
clone	O
resulted	O
from	O
an	O
apparent	O
deletion	O
or	O
rearrangement	O
of	O
5	B-GENE
'	I-GENE
-	I-GENE
flanking	I-GENE
and	I-GENE
5	I-GENE
'	I-GENE
-	I-GENE
coding	I-GENE
H	I-GENE
-	I-GENE
2L	I-GENE
sequences	I-GENE
,	O
with	O
breakpoints	O
consistently	O
mapping	O
to	O
within	O
a	O
550	O
bp	O
GC	O
-	O
rich	O
region	O
between	O
exon	O
1	O
and	O
the	O
middle	O
of	O
intron	O
2	O
.	O

CBD	O
exploration	O
was	O
avoided	O
in	O
7	O
patients	O
with	O
normal	O
POC	O
.	O

These	O
mutations	O
prevent	O
FKBP12	B-GENE
-	O
rapamycin	O
binding	O
to	O
TOR2	B-GENE
,	O
as	O
assayed	O
with	O
the	O
two	O
-	O
hybrid	O
system	O
.	O

The	O
psbA	B-GENE
gene	I-GENE
encodes	O
the	O
D1	B-GENE
protein	I-GENE
of	O
photosystem	B-GENE
II	I-GENE
,	O
which	O
is	O
synthesized	O
at	O
very	O
high	O
rates	O
in	O
the	O
light	O
in	O
order	O
to	O
replace	O
photodamaged	O
protein	O
.	O

The	O
TCR	B-GENE
beta	I-GENE
enhancer	I-GENE
was	O
active	O
on	O
both	O
the	O
minimal	B-GENE
simian	I-GENE
virus	I-GENE
40	I-GENE
promoter	I-GENE
and	O
a	O
TCR	B-GENE
beta	I-GENE
variable	I-GENE
gene	I-GENE
promoter	I-GENE
in	O
both	O
TCR	B-GENE
alpha	I-GENE
/	I-GENE
beta	I-GENE
+	O
and	O
TCR	B-GENE
gamma	I-GENE
/	I-GENE
delta	I-GENE
+	O
T	O
cells	O
.	O

Fibrosis	O
of	O
the	O
adjacent	O
myocardium	O
was	O
seen	O
in	O
five	O
cases	O
.	O

Symptoms	O
,	O
skin	O
-	O
prick	O
tests	O
(	O
SPT	O
)	O
with	O
environmental	O
allergens	O
and	O
Pt	O
salt	O
,	O
total	O
serum	B-GENE
IgE	I-GENE
,	O
lung	O
function	O
,	O
and	O
bronchial	O
hyperresponsiveness	O
were	O
assessed	O
by	O
standard	O
procedures	O
.	O

These	O
findings	O
suggest	O
that	O
T3R	B-GENE
can	O
repress	O
or	O
activate	O
transcription	O
while	O
tethered	O
to	O
the	O
LBD	O
of	O
GAL4	B-GENE
-	O
RXR	B-GENE
and	O
that	O
heterodimerization	O
can	O
occur	O
in	O
vivo	O
without	O
stabilization	O
by	O
hormone	O
response	O
elements	O
.	O

During	O
4	O
%	O
O2	O
ventilation	O
,	O
baseline	O
pulmonary	O
vascular	O
resistance	O
(	O
PVR	O
)	O
and	O
the	O
dilator	O
response	O
to	O
both	O
ACh	O
and	O
SNP	O
were	O
greater	O
in	O
2D	O
lungs	O
.	O

HGF	B-GENE
treatment	O
increased	O
cyclin	B-GENE
A	I-GENE
,	O
cyclin	B-GENE
G1	I-GENE
and	O
nuclear	O
transcriptional	O
factor	O
(	O
NFkappaB	B-GENE
)	O
protein	O
expression	O
.	O

Surprisingly	O
,	O
in	O
adult	O
animals	O
,	O
the	O
suprabasal	O
expression	O
of	O
dnRXR	B-GENE
alpha	I-GENE
significantly	O
reduced	O
the	O
ability	O
of	O
topically	O
applied	O
tRA	O
to	O
stimulate	O
proliferation	O
of	O
undifferentiated	O
keratinocytes	O
in	O
the	O
basal	O
layer	O
of	O
epidermis	O
.	O

A	O
third	O
-	O
order	O
polynominal	O
fit	O
showed	O
a	O
good	O
correlation	O
for	O
the	O
parameter	O
Q	O
*	O
and	O
MTT	O
,	O
whereas	O
T	O
and	O
SImax	O
were	O
found	O
to	O
have	O
a	O
poor	O
correlation	O
.	O

This	O
article	O
focuses	O
on	O
a	O
general	O
approach	O
to	O
the	O
use	O
of	O
ARV	O
agents	O
.	O

Although	O
FKH2	B-GENE
is	O
redundant	O
with	O
FKH1	B-GENE
in	O
controlling	O
pseudohyphal	O
growth	O
,	O
the	O
two	O
genes	O
have	O
different	O
functions	O
in	O
silencing	O
HMRa	B-GENE
.	O

These	O
results	O
demonstrate	O
the	O
extensive	O
homology	O
in	O
sequence	O
among	O
light	O
chains	O
of	O
IgM	B-GENE
kappa	I-GENE
autoantibodies	I-GENE
and	O
indicate	O
that	O
a	O
particular	O
V	B-GENE
kappa	I-GENE
germ	I-GENE
line	I-GENE
gene	I-GENE
,	O
kappa	B-GENE
IIIb	I-GENE
,	O
is	O
expressed	O
as	O
a	O
phylogenetic	O
response	O
to	O
certain	O
self	O
antigens	O
or	O
as	O
part	O
of	O
a	O
selection	O
process	O
by	O
which	O
these	O
autoimmune	O
responses	O
are	O
regulated	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
the	O
influence	O
of	O
long	O
term	O
intravenous	O
administration	O
of	O
naftidrofuryl	O
(	O
Dusodril	O
-	O
Lipha	O
Arzn	O
)	O
twice	O
daily	O
in	O
a	O
dose	O
of	O
200	O
mg	O
in	O
continuous	O
,	O
4	O
-	O
hour	O
infusion	O
in	O
500	O
ml	O
0	O
.	O
9	O
%	O
NaCl	O
to	O
the	O
patients	O
suffering	O
from	O
a	O
peripheral	O
arterial	O
occlusive	O
disease	O
(	O
PAOD	O
)	O
in	O
a	O
clinical	O
condition	O
with	O
special	O
attention	O
paid	O
to	O
transcutaneous	O
partial	O
oxygen	O
pressure	O
measurements	O
(	O
tcPO2	O
)	O
and	O
rheographic	O
parameters	O
.	O

We	O
concluded	O
that	O
RXR	B-GENE
-	I-GENE
gamma	I-GENE
induced	O
terminal	O
differentiation	O
in	O
SCC	O
lines	O
,	O
suggesting	O
a	O
potential	O
tumor	O
suppressor	O
function	O
for	O
this	O
transcription	O
factor	O
.	O

Finally	O
,	O
there	O
is	O
now	O
appropriate	O
recognition	O
of	O
the	O
pivotal	O
role	O
of	O
BP	O
reduction	O
in	O
forestalling	O
pressure	O
-	O
related	O
cardiovascular	O
complications	O
,	O
even	O
among	O
high	O
-	O
risk	O
persons	O
with	O
diabetes	O
mellitus	O
and	O
renal	O
insufficiency	O
.	O

RNA	O
determinants	O
required	O
for	O
L4	B-GENE
-	O
mediated	O
attenuation	O
control	O
of	O
the	O
S10	B-GENE
r	I-GENE
-	I-GENE
protein	I-GENE
operon	I-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
.	O

The	O
psh3	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
gene	I-GENE
encodes	O
a	O
protein	O
of	O
215	O
amino	O
acids	O
,	O
which	O
shares	O
a	O
high	O
degree	O
of	O
structural	O
and	O
functional	O
similarity	O
with	O
Shr3p	B-GENE
.	O

A	O
very	O
large	O
PC	O
LAN	O
as	O
the	O
basis	O
for	O
a	O
hospital	O
information	O
system	O
.	O

A	O
rapid	O
mixing	O
device	O
for	O
quasielastic	O
light	O
scattering	O
studies	O
of	O
reacting	O
systems	O
.	O

After	O
institution	O
of	O
insulin	B-GENE
treatment	O
,	O
diabetic	O
control	O
was	O
improved	O
as	O
demonstrated	O
by	O
decreasing	O
levels	O
of	O
HbA1	B-GENE
.	O

It	O
is	O
not	O
tested	O
yet	O
,	O
whether	O
the	O
extent	O
of	O
glaucoma	O
damage	O
should	O
be	O
better	O
quantified	O
using	O
reference	O
plane	O
1	O
or	O
2	O
.	O

Based	O
on	O
the	O
deduced	O
amino	O
acid	O
sequence	O
identity	O
we	O
designated	O
GAPC1	B-GENE
and	O
GAPC2	B-GENE
as	O
group	O
I	O
(	O
97	O
%	O
identical	O
)	O
and	O
GAPC3	B-GENE
and	O
GAPC4	B-GENE
as	O
group	O
II	O
(	O
99	O
.	O
4	O
%	O
identical	O
)	O
.	O

In	O
analogy	O
to	O
human	B-GENE
CD70	I-GENE
,	O
mCD70	B-GENE
transcript	I-GENE
levels	O
are	O
strongly	O
but	O
transiently	O
up	O
-	O
regulated	O
during	O
lymphocyte	O
activation	O
,	O
which	O
is	O
in	O
line	O
with	O
a	O
role	O
for	O
the	O
CD27	B-GENE
-	I-GENE
CD70	I-GENE
receptor	I-GENE
pair	O
early	O
in	O
the	O
immune	O
response	O
.	O

Both	O
parameters	O
were	O
determined	O
in	O
an	O
individual	O
eye	O
by	O
applying	O
the	O
dye	O
first	O
by	O
iontophoresis	O
and	O
then	O
by	O
intravitreal	O
injection	O
,	O
which	O
allows	O
the	O
influence	O
of	O
fluorescein	O
glucuronide	O
on	O
the	O
fluorophotometric	O
measurements	O
to	O
be	O
excluded	O
.	O

Phase	O
I	O
clinical	O
trial	O
with	O
a	O
combination	O
of	O
methotrexate	O
and	O
mitomycin	O
C	O
.	O

A	O
total	O
of	O
114	O
animals	O
were	O
infected	O
by	O
E	O
.	O
coli	O
O2	O
:	O
K1	O
:	O
H4	O
by	O
the	O
hematogenic	O
route	O
.	O

Expression	O
of	O
a	O
cDNA	O
clone	O
in	O
yeast	O
containing	O
a	O
large	O
portion	O
of	O
the	O
open	O
reading	O
frame	O
produced	O
cAMP	B-GENE
PDEase	I-GENE
activity	O
identical	O
in	O
properties	O
to	O
the	O
Drosophila	O
enzyme	O
affected	O
by	O
the	O
dnc	B-GENE
mutation	I-GENE
.	O

CONCLUSIONS	O
:	O
These	O
results	O
suggest	O
that	O
,	O
by	O
interacting	O
with	O
cellular	O
transcription	O
factors	O
and	O
cofactors	O
,	O
vIRF	B-GENE
-	I-GENE
2	I-GENE
may	O
modulate	O
the	O
expression	O
of	O
the	O
early	O
inflammatory	O
genes	O
and	O
potentially	O
deregulate	O
the	O
immune	O
system	O
.	O

It	O
has	O
been	O
demonstrated	O
that	O
stimulation	O
of	O
the	O
pontomesencephalic	O
parabrachial	O
region	O
(	O
PBR	O
)	O
by	O
microinjection	O
of	O
cholinergic	O
drugs	O
or	O
electricity	O
in	O
the	O
cat	O
produces	O
potent	O
pain	O
suppression	O
which	O
is	O
not	O
antagonized	O
by	O
the	O
opiate	O
antagonist	O
,	O
naloxone	O
.	O

AIMS	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
assess	O
static	O
and	O
dynamic	O
bone	O
changes	O
in	O
patients	O
suffering	O
from	O
rickets	O
.	O

The	O
homeodomain	B-GENE
transcription	I-GENE
factor	I-GENE
CDP	B-GENE
/	O
cut	B-GENE
interacts	O
with	O
the	O
cell	O
cycle	O
regulatory	O
element	O
of	O
histone	B-GENE
H4	I-GENE
genes	I-GENE
packaged	O
into	O
nucleosomes	O
.	O

K	O
.	O
,	O
Weiss	O
,	O
M	O
.	O

Thus	O
,	O
IF	O
-	O
laser	O
therapy	O
has	O
a	O
certain	O
antioxidative	O
effect	O
by	O
increasing	O
SOD	B-GENE
activity	O
in	O
RA	O
patients	O
'	O
blood	O
cells	O
and	O
reducing	O
the	O
production	O
of	O
highly	O
reactive	O
oxygen	O
and	O
nitrogen	O
forms	O
.	O

During	O
hexamethylene	O
bisactamide	O
(	O
HMBA	O
)	O
-	O
induced	O
differentiation	O
of	O
murine	O
erythroleukemia	O
(	O
MEL	O
)	O
cells	O
erythroid	O
genes	O
are	O
transcriptionally	O
activated	O
while	O
c	B-GENE
-	I-GENE
myb	I-GENE
and	O
several	O
other	O
nuclear	O
proto	O
-	O
oncogenes	O
are	O
down	O
-	O
regulated	O
.	O

We	O
now	O
report	O
identification	O
and	O
analysis	O
of	O
transcriptional	O
activities	O
mediated	O
by	O
three	O
cis	O
-	O
acting	O
sites	O
within	O
a	O
90	O
-	O
bp	O
portion	O
of	O
the	O
rDNA	O
enhancer	O
designated	O
the	O
modulator	O
region	O
.	O

Background	O
reduction	O
with	O
various	O
agents	O
had	O
a	O
prominent	O
effect	O
on	O
DTIn1	O
as	O
well	O
as	O
99mTc	O
-	O
DTPA	O
biodistribution	O
.	O

Influence	O
of	O
copper	O
addition	O
.	O

In	O
human	O
WI38	O
cells	O
,	O
the	O
E1B	B-GENE
19K	I-GENE
gene	I-GENE
mutant	I-GENE
viruses	O
had	O
a	O
substantial	O
growth	O
advantage	O
over	O
the	O
wild	O
-	O
type	O
virus	O
,	O
yielding	O
500	O
-	O
fold	O
-	O
higher	O
titers	O
.	O

The	O
cooperation	O
between	O
health	O
and	O
hospital	O
services	O

The	O
N	O
-	O
terminal	O
sequence	O
of	O
the	O
extracellular	B-GENE
MEP20	I-GENE
,	O
TKVAS	B-GENE
,	O
was	O
found	O
at	O
aa	O
194	O
-	O
198	O
within	O
the	O
ORF	O
.	O

Furthermore	O
,	O
mutations	O
in	O
element	O
II	O
result	O
in	O
changes	O
in	O
the	O
RNA	O
structure	O
near	O
element	O
III	O
,	O
consistent	O
with	O
a	O
long	O
-	O
range	O
interaction	O
that	O
may	O
promote	O
translation	O
.	O

(	O
We	O
observed	O
a	O
ferritin	B-GENE
value	O
as	O
high	O
as	O
47	O
mg	O
/	O
L	O
in	O
one	O
patient	O
.	O
)	O
Results	O
with	O
all	O
these	O
kits	O
did	O
not	O
inter	O
-	O
compare	O
well	O
for	O
ferritin	B-GENE
concentrations	O
greater	O
than	O
300	O
micrograms	O
/	O
L	O
,	O
a	O
finding	O
that	O
casts	O
further	O
doubt	O
on	O
the	O
controversial	O
use	O
of	O
serum	B-GENE
ferritin	I-GENE
measurement	O
in	O
cases	O
of	O
iron	O
overload	O
.	O

Most	O
other	O
differences	O
between	O
these	O
two	O
Leporipoxviruses	O
are	O
located	O
in	O
the	O
telomeres	O
.	O

The	O
Tat	B-GENE
protein	I-GENE
coded	O
by	O
human	O
immunodeficiency	O
virus	O
(	O
HIV	O
)	O
is	O
a	O
strong	O
activator	O
of	O
viral	O
gene	O
expression	O
from	O
the	O
long	O
terminal	O
repeat	O
(	O
LTR	O
)	O
.	O

A	O
.	O

This	O
case	O
report	O
describes	O
the	O
treatment	O
of	O
a	O
patient	O
with	O
periodontosis	O
.	O

Upstream	O
tissue	B-GENE
inhibitor	I-GENE
of	I-GENE
metalloproteinases	I-GENE
-	I-GENE
1	I-GENE
(	I-GENE
TIMP	I-GENE
-	I-GENE
1	I-GENE
)	I-GENE
element	I-GENE
-	I-GENE
1	I-GENE
,	O
a	O
novel	O
and	O
essential	O
regulatory	O
DNA	O
motif	O
in	O
the	O
human	B-GENE
TIMP	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
promoter	I-GENE
,	O
directly	O
interacts	O
with	O
a	O
30	O
-	O
kDa	O
nuclear	O
protein	O
.	O

We	O
propose	O
that	O
U73	B-GENE
is	O
involved	O
in	O
methylation	O
of	O
the	O
G1739	O
residue	O
of	O
the	O
human	B-GENE
28S	I-GENE
rRNA	I-GENE
.	O

Also	O
,	O
the	O
placebo	O
nondepressed	O
patients	O
had	O
significantly	O
better	O
treatment	O
outcome	O
compared	O
with	O
the	O
placebo	O
depressed	O
patients	O
.	O

Animals	O
were	O
divided	O
into	O
six	O
equal	O
groups	O
as	O
follows	O
:	O
(	O
1	O
)	O
no	O
oral	O
drug	O
(	O
water	O
)	O
,	O
no	O
hemodilution	O
,	O
no	O
IV	O
drug	O
(	O
saline	O
)	O
;	O
(	O
2	O
)	O
oral	O
water	O
,	O
hemodilution	O
,	O
IV	O
saline	O
;	O
(	O
3	O
)	O
oral	O
water	O
,	O
no	O
hemodilution	O
,	O
IV	O
propranolol	O
;	O
(	O
4	O
)	O
oral	O
water	O
,	O
hemodilution	O
,	O
IV	O
propranolol	O
;	O
(	O
5	O
)	O
oral	O
propranolol	O
,	O
no	O
hemodilution	O
,	O
IV	O
saline	O
;	O
and	O
(	O
6	O
)	O
oral	O
propranolol	O
,	O
hemodilution	O
,	O
IV	O
saline	O
.	O

We	O
found	O
4	O
highly	O
conserved	O
regions	O
to	O
vertebrate	B-GENE
Hsp90	I-GENE
exclusively	O
and	O
27	O
amino	O
acids	O
conserved	O
among	O
but	O
differing	O
between	O
Hsp90	B-GENE
alpha	I-GENE
and	O
Hsp90	B-GENE
beta	I-GENE
sequences	I-GENE
.	O

Four	O
newborns	O
in	O
this	O
group	O
became	O
HBsAg	B-GENE
carriers	O
.	O

It	O
tends	O
to	O
be	O
higher	O
between	O
frazioni	O
of	O
the	O
same	O
community	O
than	O
between	O
communities	O
.	O

In	O
previous	O
studies	O
,	O
we	O
showed	O
that	O
the	O
nuclear	O
import	O
of	O
SREBP	B-GENE
-	I-GENE
2	I-GENE
occurs	O
via	O
the	O
direct	O
interaction	O
of	O
importin	B-GENE
beta	I-GENE
with	O
the	O
HLH	O
-	O
Zip	O
domain	O
.	O

The	O
destruction	O
of	O
the	O
mesometrium	O
did	O
not	O
lengthen	O
the	O
oestrous	O
cycle	O
.	O

Ftz	B-GENE
,	O
on	O
the	O
other	O
hand	O
,	O
influences	O
Ftz	B-GENE
-	O
F1	B-GENE
activity	O
by	O
interacting	O
with	O
its	O
AF	O
-	O
2	O
domain	O
in	O
a	O
manner	O
that	O
mimics	O
a	O
nuclear	O
receptor	O
coactivator	O
.	O

Type	O
C	O
units	O
summate	O
the	O
responses	O
to	O
the	O
two	O
-	O
tone	O
stimulus	O
,	O
and	O
show	O
little	O
or	O
no	O
inhibitory	O
influences	O
.	O

19	O
,	O
4967	O
-	O
4973	O
)	O
.	O

CONCLUSIONS	O
:	O
In	O
the	O
majority	O
of	O
patients	O
with	O
severe	O
ulcerative	O
colitis	O
,	O
circulating	O
concentrations	O
of	O
NOX	O
are	O
increased	O
at	O
presentation	O
and	O
fall	O
promptly	O
during	O
parenteral	O
steroid	O
therapy	O
,	O
irrespective	O
of	O
clinical	O
outcome	O
.	O

A	O
cDNA	O
for	O
human	B-GENE
microfibril	I-GENE
-	I-GENE
associated	I-GENE
glycoprotein	I-GENE
-	I-GENE
2	I-GENE
(	O
MAGP	B-GENE
-	I-GENE
2	I-GENE
)	O
was	O
used	O
to	O
screen	O
a	O
human	O
leukocyte	O
genomic	O
DNA	O
library	O
in	O
EMBL	O
-	O
3	O
vector	O
.	O

Screening	O
of	O
a	O
human	O
foetal	O
brain	O
genomic	O
DNA	O
library	O
allowed	O
us	O
to	O
isolate	O
an	O
EcoRI	B-GENE
-	O
EcoRI	B-GENE
fragment	O
containing	O
6	O
kb	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
,	O
the	O
open	O
reading	O
frame	O
and	O
4	O
kb	O
of	O
the	O
3	O
'	O
-	O
flanking	O
region	O
of	O
the	O
alpha2C4	B-GENE
gene	I-GENE
.	O

Using	O
gel	O
retardation	O
analysis	O
,	O
four	O
binding	O
sites	O
for	O
Rap1p	B-GENE
have	O
been	O
identified	O
within	O
the	O
promoter	O
of	O
the	O
RAP1	B-GENE
gene	I-GENE
.	O

They	O
are	O
transduced	O
through	O
TM	O
to	O
the	O
cytoplasmic	O
portion	O
(	O
cytoloops	O
and	O
the	O
C	O
-	O
terminal	O
tail	O
)	O
of	O
the	O
receptor	O
and	O
then	O
,	O
transferred	O
to	O
cytoplasmic	O
signaling	O
molecules	O
,	O
such	O
as	O
G	B-GENE
protein	I-GENE
.	O

Sgs	B-GENE
-	I-GENE
4	I-GENE
is	O
one	O
of	O
the	O
eight	O
known	O
genes	O
coding	O
for	O
larval	O
secretion	O
proteins	O
in	O
Drosophila	O
melanogaster	O
.	O

Unlike	O
CSK	B-GENE
,	O
the	O
SH3	B-GENE
domain	I-GENE
of	O
HYL	B-GENE
was	O
unique	O
since	O
the	O
ALYDY	O
motif	O
was	O
absent	O
.	O

This	O
enzyme	O
is	O
distinct	O
from	O
other	O
known	O
E3s	B-GENE
,	O
including	O
E3	B-GENE
alpha	I-GENE
/	O
UBR1	B-GENE
,	O
E3	B-GENE
beta	I-GENE
,	O
and	O
E6	B-GENE
-	I-GENE
AP	I-GENE
.	O

RESULTS	O
:	O
Although	O
low	O
levels	O
of	O
vIRF	B-GENE
-	I-GENE
2	I-GENE
mRNAs	I-GENE
can	O
be	O
detected	O
in	O
the	O
HHV	O
-	O
8	O
-	O
positive	O
BCBL	O
-	O
1	O
tumor	O
cell	O
line	O
,	O
12	O
-	O
0	O
-	O
tetradecanoylphorbol	O
-	O
13	O
-	O
acetate	O
(	O
TPA	O
)	O
treatment	O
does	O
not	O
stimulate	O
expression	O
of	O
vIRF	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
together	O
with	O
primary	O
lytic	O
cycle	O
genes	O
.	O

Primary	O
TJRs	O
were	O
clinically	O
evaluated	O
for	O
degree	O
of	O
osteoarthrosis	O
.	O

We	O
suggest	O
that	O
this	O
relatively	O
small	O
deletion	O
affects	O
a	O
segment	O
containing	O
3	B-GENE
'	I-GENE
VH	I-GENE
genes	I-GENE
with	O
important	O
regulatory	O
functions	O
,	O
the	O
loss	O
of	O
which	O
leads	O
to	O
the	O
ali	O
phenotype	O
.	O

Apoptosis	O
triggered	O
through	O
Fas	B-GENE
and	O
F	B-GENE
/	I-GENE
F	I-GENE
was	O
inhibited	O
by	O
coexpression	O
of	O
CrmA	B-GENE
and	O
p35	B-GENE
,	O
but	O
not	O
Bcl	B-GENE
-	I-GENE
xL	I-GENE
.	O

Expression	O
of	O
Helios	B-GENE
was	O
detected	O
in	O
the	O
earliest	O
hematopoietic	O
sites	O
of	O
the	O
embryo	O
,	O
in	O
hematopoietic	O
stem	O
cells	O
in	O
the	O
adult	O
and	O
was	O
subsequently	O
restricted	O
to	O
a	O
subset	O
of	O
cells	O
in	O
the	O
T	O
cell	O
lineage	O
.	O

It	O
produced	O
extrapyramidal	O
disturbances	O
in	O
nearly	O
every	O
subject	O
,	O
the	O
most	O
common	O
being	O
akathisia	O
and	O
the	O
most	O
severe	O
,	O
in	O
the	O
case	O
of	O
one	O
individual	O
,	O
being	O
acute	O
dystonia	O
.	O

Electron	O
microscopy	O
of	O
pH	O
7	O
.	O
5	O
-	O
treated	O
TMV	O
particles	O
incubated	O
in	O
SPN	B-GENE
-	O
treated	O
wheatgerm	O
extract	O
or	O
rabbit	O
reticulocyte	O
lysate	O
,	O
showed	O
that	O
approximately	O
10	O
%	O
of	O
virions	O
complexed	O
with	O
one	O
ribosome	O
and	O
approximately	O
10	O
%	O
with	O
two	O
bound	O
ribosomes	O
,	O
confirming	O
that	O
omega	O
at	O
least	O
had	O
been	O
uncoated	O
.	O

The	O
absorbance	O
of	O
the	O
eluent	O
was	O
monitored	O
at	O
254	O
nm	O
.	O

As	O
anticipated	O
,	O
both	O
intracellular	O
p54	B-GENE
-	O
SAPKbeta	B-GENE
activation	O
and	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
phosphorylation	O
are	O
blocked	O
by	O
co	O
-	O
transfection	O
with	O
the	O
MAP	B-GENE
kinase	I-GENE
specific	O
phosphatase	O
MKP3	B-GENE
/	O
PYST1	B-GENE
.	O

All	O
patients	O
studied	O
were	O
pregnant	O
women	O
and	O
their	O
delivered	O
children	O
.	O

PRP20	B-GENE
is	O
related	O
,	O
both	O
in	O
structure	O
and	O
function	O
,	O
to	O
the	O
RCC1	B-GENE
gene	I-GENE
of	O
mammals	O
and	O
the	O
PIM1	B-GENE
gene	I-GENE
of	O
Schizosaccharomyces	O
pombe	O
,	O
both	O
of	O
which	O
appear	O
to	O
regulate	O
entry	O
into	O
mitosis	O
and	O
chromosome	O
condensation	O
.	O

Using	O
this	O
oligonucleotide	O
as	O
a	O
probe	O
,	O
an	O
8	O
-	O
kilobase	O
HindIII	B-GENE
fragment	O
of	O
genomic	O
DNA	O
was	O
isolated	O
and	O
subjected	O
to	O
Sanger	O
dideoxy	O
DNA	O
sequencing	O
.	O

The	O
Rep	B-GENE
proteins	I-GENE
of	O
adeno	O
-	O
associated	O
virus	O
type	O
2	O
(	O
AAV	O
)	O
are	O
known	O
to	O
bind	O
to	O
Rep	B-GENE
recognition	I-GENE
sequences	I-GENE
(	O
RRSs	B-GENE
)	O
in	O
the	O
AAV	O
inverted	O
terminal	O
repeats	O
(	O
ITRs	O
)	O
,	O
the	O
AAV	B-GENE
p5	I-GENE
promoter	I-GENE
,	O
and	O
the	O
preferred	O
AAV	O
integration	O
site	O
in	O
human	O
chromosome	O
19	O
,	O
called	O
AAVS1	O
.	O

The	O
electrocardiogram	O
in	O
tachycardia	O
.	O

It	O
is	O
noteworthy	O
that	O
under	O
more	O
physiological	O
conditions	O
mimicking	O
the	O
cellular	O
GDP	O
/	O
GTP	O
ratio	O
,	O
Raf	B-GENE
enhances	O
the	O
GEF	B-GENE
-	O
stimulated	O
GDP	O
/	O
GTP	O
exchange	O
on	O
Ha	B-GENE
-	I-GENE
Ras	I-GENE
,	O
in	O
agreement	O
with	O
the	O
sequestration	O
of	O
Ras	B-GENE
.	I-GENE
GTP	I-GENE
by	O
Raf	B-GENE
.	O

In	O
this	O
study	O
,	O
we	O
show	O
that	O
HNF	B-GENE
-	I-GENE
4	I-GENE
,	O
a	O
member	O
of	O
the	O
steroid	B-GENE
hormone	I-GENE
receptor	I-GENE
superfamily	I-GENE
,	O
binds	O
the	O
AF	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
on	O
the	O
apoB	B-GENE
promoter	I-GENE
and	O
through	O
it	O
activates	O
transcription	O
in	O
transient	O
transfection	O
assays	O
in	O
both	O
liver	O
and	O
non	O
-	O
liver	O
cell	O
lines	O
,	O
HepG2	O
and	O
HeLa	O
,	O
respectively	O
.	O

In	O
Cos	O
7	O
cells	O
transfected	O
with	O
oCRF1var	B-GENE
,	O
cAMP	O
accumulation	O
was	O
only	O
observed	O
at	O
the	O
highest	O
concentration	O
of	O
oCRF	B-GENE
utilized	O
(	O
100	O
nM	O
)	O
.	O

Usefulness	O
of	O
glucocorticoids	O
in	O
the	O
treatment	O
of	O
congestive	O
heart	O
failure	O

RESULTS	O
:	O
In	O
76	O
trials	O
,	O
5	O
,	O
351	O
patients	O
received	O
24	O
different	O
regimens	O
of	O
droperidol	O
.	O

The	O
local	O
median	O
scores	O
(	O
ranges	O
)	O
of	O
the	O
above	O
tests	O
were	O
as	O
follows	O
-	O
AMT	O
:	O
9	O
(	O
6	O
-	O
10	O
)	O
;	O
CMMS	O
:	O
25	O
(	O
16	O
-	O
28	O
)	O
;	O
SBT	O
:	O
2	O
(	O
0	O
-	O
10	O
)	O
;	O
WL	O
-	O
i	O
:	O
17	O
(	O
8	O
-	O
27	O
)	O
;	O
WL	O
-	O
d	O
:	O
5	O
(	O
0	O
-	O
10	O
)	O
;	O
WL	O
-	O
r	O
:	O
9	O
(	O
1	O
-	O
10	O
)	O
;	O
ST	O
:	O
13	O
(	O
6	O
-	O
25	O
)	O
;	O
BNT	O
:	O
14	O
(	O
10	O
-	O
15	O
)	O
;	O
CPT	O
:	O
1	O
(	O
0	O
-	O
3	O
)	O
;	O
BDT	O
:	O
19	O
(	O
0	O
-	O
42	O
)	O
;	O
OAT	O
:	O
20	O
(	O
3	O
-	O
33	O
)	O
.	O

The	O
organization	O
of	O
the	O
MBP	B-GENE
-	I-GENE
A	I-GENE
gene	I-GENE
is	O
very	O
similar	O
to	O
the	O
arrangement	O
of	O
the	O
gene	O
encoding	O
the	O
highly	O
homologous	B-GENE
pulmonary	I-GENE
surfactant	I-GENE
apoprotein	I-GENE
,	O
although	O
one	O
of	O
the	O
intron	O
positions	O
is	O
shifted	O
by	O
a	O
single	O
amino	O
acid	O
.	O

Plasma	B-GENE
renin	I-GENE
activity	O
in	O
essential	O
arterial	O
hypertension	O
.	O

In	O
vitro	O
,	O
cytokine	O
-	O
or	O
hypoxia	O
-	O
induced	O
up	O
-	O
regulation	O
of	O
Fas	B-GENE
expression	O
is	O
associated	O
with	O
RTC	O
apoptosis	O
.	O

These	O
results	O
suggest	O
that	O
the	O
Reg1	B-GENE
-	O
Glc7	B-GENE
phosphatase	O
is	O
a	O
cytoplasmic	O
component	O
of	O
the	O
machinery	O
responsible	O
for	O
returning	O
Snf1	B-GENE
kinase	I-GENE
activity	O
to	O
its	O
basal	O
level	O
and	O
reestablishing	O
glucose	O
repression	O
.	O

To	O
explore	O
further	O
the	O
role	O
of	O
the	O
carboxyl	O
-	O
terminal	O
domain	O
in	O
determining	O
the	O
cell	O
cycle	O
function	O
of	O
CDC34	B-GENE
,	O
we	O
constructed	O
and	O
characterized	O
genes	O
encoding	O
chimeric	B-GENE
E2s	I-GENE
incorporating	O
sequences	O
from	O
CDC34	B-GENE
and	O
the	O
related	O
but	O
functionally	O
distinct	O
E2	B-GENE
RAD6	B-GENE
(	O
UBC2	B-GENE
)	O
.	O

In	O
F9	O
,	O
which	O
is	O
a	O
prototype	O
of	O
embryonal	O
carcinoma	O
cells	O
expressing	O
hst	B-GENE
,	O
the	O
expression	O
of	O
hst	B-GENE
gene	I-GENE
is	O
positively	O
regulated	O
by	O
a	O
downstream	O
octamer	O
motif	O
that	O
functions	O
as	O
an	O
enhancer	O
.	O

Furthermore	O
,	O
rubella	B-GENE
IgM	I-GENE
antibody	I-GENE
was	O
never	O
detected	O
after	O
immunization	O
in	O
women	O
who	O
were	O
HAI	O
-	O
negative	O
and	O
LA	O
-	O
positive	O
during	O
pregnancy	O
.	O

Since	O
simian	B-GENE
virus	I-GENE
40	I-GENE
(	I-GENE
SV40	I-GENE
)	I-GENE
large	I-GENE
T	I-GENE
antigen	I-GENE
and	O
human	B-GENE
papillomavirus	I-GENE
type	I-GENE
16	I-GENE
(	I-GENE
HPV16	I-GENE
)	I-GENE
E7	I-GENE
protein	I-GENE
also	O
bind	O
host	O
regulatory	O
factors	O
,	O
we	O
investigated	O
whether	O
these	O
viral	O
proteins	O
can	O
complement	O
E1A	B-GENE
mutants	I-GENE
which	O
are	O
defective	O
in	O
early	O
gene	O
activation	O
.	O

Only	O
viable	O
bacteria	O
at	O
a	O
high	O
concentration	O
induced	O
purulent	O
otitis	O
media	O
,	O
which	O
was	O
culture	O
positive	O
in	O
58	O
%	O
of	O
the	O
cases	O
on	O
day	O
4	O
.	O

Results	O
indicated	O
that	O
hobbies	O
/	O
leisure	O
activities	O
,	O
mobility	O
,	O
transport	O
,	O
social	O
relationships	O
,	O
working	O
capacity	O
,	O
energy	O
and	O
doing	O
things	O
slower	O
were	O
aspects	O
relevant	O
to	O
IPF	O
patients	O
'	O
QOL	O
.	O

Residues	O
that	O
affect	O
PLCbeta	B-GENE
and	O
adenylyl	B-GENE
cyclase	I-GENE
II	I-GENE
activity	O
are	O
found	O
on	O
opposite	O
sides	O
of	O
the	O
central	O
tunnel	O
,	O
suggesting	O
that	O
PLC	B-GENE
and	O
adenylyl	B-GENE
cyclase	I-GENE
,	O
like	O
the	O
alpha	O
subunit	O
,	O
make	O
many	O
contacts	O
on	O
the	O
top	O
surface	O
.	O

One	O
new	O
ORF	O
,	O
YBR0224	B-GENE
,	O
was	O
detected	O
,	O
coding	O
for	O
a	O
protein	O
with	O
918	O
amino	O
acids	O
.	O

The	O
law	O
and	O
the	O
chiropractor	O
.	O

A	O
distinct	O
5	O
'	O
-	O
sequence	O
in	O
clone	O
hMIWC2	O
suggested	O
an	O
alternative	O
upstream	O
transcription	O
initiation	O
site	O
.	O

Rectal	O
temperatures	O
after	O
the	O
walk	O
were	O
greater	O
(	O
P	O
<	O
.	O
001	O
)	O
in	O
native	O
Simmental	O
(	O
39	O
.	O
87	O
+	O
/	O
-	O
.	O
05	O
degrees	O
C	O
)	O
than	O
in	O
Bos	O
indicus	O
(	O
39	O
.	O
46	O
+	O
/	O
-	O
.	O
05	O
degrees	O
C	O
)	O
.	O

98	O
,	O
93	O
-	O
98	O
)	O
.	O

However	O
,	O
the	O
pre3	B-GENE
-	I-GENE
2	I-GENE
mutation	I-GENE
strengthened	O
phenotypes	O
induced	O
by	O
other	O
20	B-GENE
S	I-GENE
proteasomal	I-GENE
mutations	I-GENE
,	O
indicating	O
that	O
the	O
peptidylglutamyl	O
peptide	O
-	O
hydrolyzing	O
activity	O
has	O
to	O
fulfill	O
some	O
rescue	O
functions	O
.	O

A	O
mammalian	O
protein	O
called	O
RFX	B-GENE
or	O
NF	B-GENE
-	I-GENE
X	I-GENE
binds	O
to	O
the	O
X	O
box	O
(	O
or	O
X1	O
box	O
)	O
in	O
the	O
promoters	O
of	O
a	O
number	O
of	O
major	B-GENE
histocompatibility	I-GENE
(	I-GENE
MHC	I-GENE
)	I-GENE
class	I-GENE
II	I-GENE
genes	I-GENE
.	O

This	O
result	O
suggests	O
that	O
the	O
target	O
protein	O
specificity	O
of	O
E2s	B-GENE
can	O
be	O
altered	O
by	O
the	O
addition	O
of	O
appropriate	O
C	O
-	O
terminal	O
extensions	O
,	O
thus	O
providing	O
a	O
way	O
to	O
modify	O
the	O
selectivity	O
of	O
the	O
ubiquitin	B-GENE
system	O
.	O

This	O
pattern	O
of	O
expression	O
and	O
differential	O
processing	O
suggests	O
a	O
role	O
for	O
inrpk1	B-GENE
in	O
some	O
aspect	O
of	O
SD	O
photoperiodic	O
-	O
induced	O
flowering	O
in	O
morning	O
glory	O
.	O

Co	O
-	O
expression	O
of	O
a	O
gag	B-GENE
-	O
TRalpha	B-GENE
fusion	O
protein	O
in	O
AEV	O
-	O
transformed	O
cells	O
and	O
addition	O
of	O
ligand	O
derepresses	O
CAII	B-GENE
transcription	O
.	O

A	O
400	O
-	O
bp	O
fragment	O
(	O
bp	O
-	O
339	O
through	O
+	O
71	O
)	O
of	O
the	O
CD22	B-GENE
promoter	I-GENE
region	I-GENE
was	O
subcloned	O
into	O
a	O
pGEM	O
-	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
vector	O
and	O
after	O
transfection	O
into	O
B	O
and	O
T	O
cells	O
was	O
found	O
to	O
be	O
active	O
in	O
both	O
B	O
and	O
T	O
cells	O
.	O

This	O
suggests	O
that	O
the	O
duration	O
of	O
varicocele	O
per	O
se	O
could	O
affect	O
DHT	O
seminal	O
plasma	O
levels	O
.	O

Five	O
RNA	O
transcripts	O
of	O
about	O
1	O
.	O
2	O
to	O
1	O
.	O
7	O
kilobases	O
were	O
mapped	O
to	O
a	O
part	O
of	O
the	O
genome	O
of	O
insect	O
iridescent	O
virus	O
type	O
6	O
(	O
Chilo	O
iridescent	O
virus	O
;	O
CIV	O
)	O
between	O
genome	O
coordinates	O
0	O
.	O
832	O
and	O
0	O
.	O
856	O
within	O
the	O
EcoRI	B-GENE
DNA	I-GENE
fragment	I-GENE
F	I-GENE
.	O

Cutting	O
the	O
intraorbital	O
nerves	O
produced	O
a	O
temporary	O
retrieval	O
impairment	O
that	O
was	O
indistinguishable	O
from	O
that	O
produced	O
by	O
intramystacial	O
lidocaine	O
injection	O
.	O

The	O
comparisons	O
of	O
swimming	O
performance	O
before	O
and	O
after	O
treatments	O
with	O
deltamethrin	O
have	O
shown	O
a	O
significant	O
effect	O
on	O
locomotory	O
ability	O
of	O
rainbow	O
trout	O
which	O
at	O
the	O
end	O
of	O
strong	O
exposure	O
(	O
e	O
.	O
g	O
.	O

Increased	O
trabecular	O
spacing	O
,	O
such	O
as	O
it	O
occurs	O
in	O
osteoporosis	O
,	O
reduces	O
the	O
spatial	O
field	O
inhomogeneity	O
and	O
thus	O
prolongs	O
T2	O
*	O
,	O
which	O
has	O
been	O
shown	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

Decidual	B-GENE
/	I-GENE
trophoblast	I-GENE
prolactin	I-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
:	O
characterization	O
of	O
gene	O
structure	O
and	O
cell	O
-	O
specific	O
expression	O
.	O

Thus	O
,	O
the	O
cognitive	O
performance	O
of	O
elderly	O
subjects	O
could	O
be	O
trained	O
to	O
a	O
large	O
extent	O
.	O

The	O
map	O
is	O
based	O
on	O
the	O
CEPH	O
reference	O
pedigrees	O
and	O
includes	O
over	O
4000	O
new	O
genotypes	O
,	O
our	O
previously	O
reported	O
data	O
plus	O
29	O
allele	O
systems	O
from	O
the	O
published	O
CEPH	O
version	O
5	O
database	O
,	O
and	O
was	O
constructed	O
using	O
the	O
program	O
package	O
CRI	O
-	O
MAP	O
.	O

RMR	O
was	O
positively	O
correlated	O
with	O
TEF	O
(	O
r	O
=	O
0	O
.	O
613	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
and	O
net	O
TEF	O
(	O
r	O
=	O
0	O
.	O
648	O
,	O
p	O
<	O
0	O
.	O
005	O
)	O
in	O
the	O
luteal	O
but	O
not	O
the	O
follicular	O
phase	O
.	O

132	O
varix	O
ligations	O
were	O
performed	O
during	O
44	O
separate	O
EVL	O
sessions	O
.	O

Nine	O
individuals	O
who	O
were	O
stable	O
after	O
1	O
month	O
of	O
therapy	O
at	O
low	O
dosage	O
were	O
randomized	O
to	O
a	O
further	O
month	O
of	O
therapy	O
at	O
low	O
or	O
high	O
dosage	O
,	O
during	O
which	O
one	O
of	O
four	O
at	O
high	O
dosage	O
had	O
a	O
partial	O
response	O
,	O
and	O
none	O
of	O
five	O
at	O
low	O
dosage	O
manifested	O
response	O
.	O

A	O
factor	O
present	O
in	O
nuclear	O
extracts	O
of	O
wounded	O
potato	O
tubers	O
was	O
found	O
to	O
bind	O
specifically	O
to	O
nucleotides	O
located	O
between	O
-	O
135	O
to	O
-	O
105	O
,	O
suggesting	O
that	O
this	O
region	O
contains	O
important	O
cis	O
-	O
regulatory	O
elements	O
.	O

Two	O
genes	O
from	O
the	O
family	O
encoding	O
mouse	B-GENE
ribosomal	I-GENE
protein	I-GENE
S16	I-GENE
were	O
cloned	O
,	O
sequenced	O
,	O
and	O
analyzed	O
.	O

Bile	O
reflux	O
demonstrated	O
by	O
99m	O
Tc	O
disofenin	O
.	O

The	O
mode	O
of	O
action	O
is	O
often	O
suggested	O
as	O
an	O
explanation	O
for	O
the	O
different	O
slopes	O
of	O
concentration	O
-	O
effect	O
curves	O
.	O

Two	O
full	O
-	O
length	O
clones	O
(	O
pBCH1	O
and	O
pBCH2	O
)	O
were	O
isolated	O
.	O

In	O
dehydrated	O
animals	O
at	O
Ta	O
38	O
degrees	O
C	O
,	O
Tb	O
and	O
EWL	O
were	O
both	O
significantly	O
altered	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
from	O
the	O
normally	O
hydrated	O
state	O
and	O
were	O
measured	O
at	O
39	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
2	O
degree	O
C	O
and	O
0	O
.	O
84	O
+	O
/	O
-	O
0	O
.	O
09	O
W	O
.	O
kg	O
-	O
1	O
respectively	O
.	O

The	O
optimum	O
cooling	O
rate	O
from	O
RT	O
to	O
5	O
degrees	O
C	O
resulting	O
in	O
maximum	O
survival	O
of	O
human	O
spermatozoa	O
was	O
found	O
to	O
be	O
0	O
.	O
5	O
to	O
1	O
degree	O
per	O
minute	O
when	O
cooled	O
from	O
RT	O
to	O
5	O
degrees	O
C	O
and	O
subsequently	O
frozen	O
-	O
thawed	O
in	O
liquid	O
nitrogen	O
(	O
LN2	O
)	O
.	O

Replacement	O
of	O
a	O
valine	O
(	O
V68	O
)	O
in	O
the	O
ETS	B-GENE
domain	O
of	O
SAP1a	B-GENE
by	O
aspartic	O
acid	O
(	O
as	O
found	O
in	O
c	B-GENE
-	I-GENE
Ets	I-GENE
-	I-GENE
1	I-GENE
,	O
Elk	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
Net	B-GENE
)	O
enhanced	O
ternary	O
complex	O
formation	O
by	O
more	O
than	O
60	O
-	O
fold	O
.	O

Methylprednisolone	O
and	O
U	O
-	O
74006F	O
were	O
equally	O
effective	O
at	O
preventing	O
neurological	O
dysfunction	O
compared	O
to	O
the	O
control	O
group	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
;	O
U	O
-	O
78517F	O
was	O
slightly	O
less	O
effective	O
than	O
U	O
-	O
74006F	O
and	O
methylprednisolone	O
but	O
was	O
significantly	O
better	O
than	O
vehicle	O
in	O
preventing	O
neurological	O
dysfunction	O
.	O

Comparison	O
between	O
the	O
Ricketts	O
and	O
Bimler	O
therapeutic	O
technics	O
in	O
the	O
treatment	O
of	O
cases	O
of	O
class	O
II	O
,	O
division	O
I	O
mmalocclusion	O

Sample	O
size	O
requirement	O
for	O
repeated	O
measurements	O
in	O
continuous	O
data	O
.	O

Transfection	O
assays	O
using	O
the	O
first	O
600	O
bp	O
of	O
the	O
upstream	O
nucleotide	O
sequences	O
indicated	O
that	O
a	O
region	O
from	O
-	O
75	O
to	O
-	O
120	O
was	O
necessary	O
for	O
the	O
ALDH2	B-GENE
gene	I-GENE
expression	O
,	O
and	O
especially	O
NF	B-GENE
-	I-GENE
Y	I-GENE
/	O
CP1	B-GENE
binding	O
site	O
from	O
-	O
92	O
to	O
-	O
96	O
(	O
CCAAT	O
box	O
)	O
is	O
important	O
in	O
the	O
expression	O
of	O
the	O
gene	O
.	O

We	O
report	O
five	O
of	O
13	O
evaluable	O
patients	O
undergoing	O
allogeneic	O
sibling	O
BM	O
or	O
PBSC	O
transplantation	O
for	O
MM	O
between	O
1990	O
and	O
1997	O
who	O
met	O
the	O
criteria	O
for	O
adjuvant	O
alpha	B-GENE
-	I-GENE
IFN	I-GENE
therapy	O
.	O

Both	O
the	O
5	O
'	O
and	O
3	O
'	O
untranslated	O
regions	O
also	O
show	O
significant	O
similarity	O
to	O
the	O
murine	O
gene	O
,	O
with	O
79	O
and	O
70	O
%	O
sequence	O
identity	O
,	O
respectively	O
.	O

Plasma	O
Pi	O
,	O
tibia	O
breaking	O
strength	O
,	O
and	O
percentage	O
of	O
tibia	O
ash	O
were	O
increased	O
by	O
raising	O
dietary	O
Pav	O
in	O
the	O
presence	O
of	O
.	O
392	O
%	O
A1	O
with	O
either	O
level	O
of	O
Ca	O
.	O

A	O
minimal	O
region	O
which	O
stimulates	O
origin	O
function	O
mapped	O
to	O
50	O
amino	O
acids	O
within	O
the	O
C	O
-	O
terminus	O
of	O
Abf1p	B-GENE
.	O

Hepatocyte	B-GENE
growth	I-GENE
factor	I-GENE
(	O
HGF	B-GENE
)	O
is	O
an	O
inducible	O
cytokine	O
that	O
is	O
essential	O
for	O
the	O
normal	O
growth	O
and	O
development	O
of	O
various	O
tissues	O
,	O
such	O
as	O
the	O
liver	O
.	O

OBJECTIVE	O
:	O
To	O
summarise	O
quantitatively	O
the	O
association	O
between	O
moderate	O
alcohol	O
intake	O
and	O
biological	O
markers	O
of	O
risk	O
of	O
coronary	O
heart	O
disease	O
and	O
to	O
predict	O
how	O
these	O
changes	O
would	O
lower	O
the	O
risk	O
.	O

(	O
1991	O
)	O
EMBO	O
J	O
.	O

Tissue	O
-	O
specific	O
gene	O
regulation	O
of	O
eukaryotic	O
organisms	O
is	O
to	O
a	O
large	O
extent	O
mediated	O
by	O
transcription	O
factors	O
that	O
interact	O
with	O
genomic	O
DNA	O
sequences	O
in	O
a	O
sequence	O
-	O
specific	O
manner	O
.	O

Teratospermia	O
is	O
therefore	O
an	O
important	O
factor	O
in	O
evaluating	O
fertilization	O
capacity	O
.	O

Genomic	O
DNA	O
blot	O
analysis	O
indicates	O
that	O
the	O
trout	B-GENE
L2	I-GENE
locus	I-GENE
has	O
a	O
cluster	O
-	O
like	O
organization	O
similar	O
to	O
the	O
trout	B-GENE
L1	I-GENE
locus	I-GENE
and	O
the	O
IgL	B-GENE
locus	I-GENE
of	O
several	O
teleost	O
fish	O
.	O

Genetic	O
polymorphisms	O
in	O
the	O
5	O
'	O
-	O
flanking	O
region	O
change	O
transcriptional	O
regulation	O
of	O
the	O
human	B-GENE
cytochrome	I-GENE
P450IIE1	I-GENE
gene	I-GENE
.	O

As	O
exogenously	O
expressed	O
PKR	B-GENE
can	O
form	O
heterodimers	O
with	O
endogenous	B-GENE
PKR	I-GENE
,	O
the	O
results	O
obtained	O
on	O
the	O
functional	O
characterization	O
of	O
mutant	O
forms	O
of	O
PKR	B-GENE
have	O
been	O
taken	O
with	O
caution	O
.	O

Basal	O
JNK	B-GENE
MAPK	I-GENE
kinase	I-GENE
activity	O
was	O
also	O
specifically	O
induced	O
by	O
deltaEGFR	B-GENE
,	O
which	O
correlated	O
with	O
increased	O
phosphorylation	O
of	O
a	O
54	B-GENE
-	I-GENE
kDa	I-GENE
JNK2	I-GENE
protein	I-GENE
observed	O
in	O
deltaEGFR	B-GENE
-	O
containing	O
cells	O
.	O

Isolation	O
and	O
properties	O
of	O
Drosophila	B-GENE
melanogaster	I-GENE
ferritin	I-GENE
-	O
-	O
molecular	O
cloning	O
of	O
a	O
cDNA	O
that	O
encodes	O
one	O
subunit	O
,	O
and	O
localization	O
of	O
the	O
gene	O
on	O
the	O
third	O
chromosome	O
.	O

The	O
single	O
-	O
copy	O
U20	B-GENE
sequence	I-GENE
is	O
located	O
on	O
the	O
same	O
DNA	O
strand	O
as	O
the	O
nucleolin	B-GENE
mRNA	I-GENE
.	O

Maximum	O
baroreceptor	O
activity	O
measured	O
at	O
140	O
mm	O
Hg	O
and	O
the	O
slope	O
of	O
the	O
pressure	O
-	O
activity	O
curve	O
were	O
reduced	O
in	O
atherosclerotic	O
(	O
n	O
=	O
15	O
)	O
compared	O
with	O
normal	O
(	O
n	O
=	O
13	O
)	O
rabbits	O
(	O
425	O
+	O
/	O
-	O
34	O
versus	O
721	O
+	O
/	O
-	O
30	O
spikes	O
per	O
second	O
and	O
6	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
6	O
versus	O
10	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
8	O
spikes	O
per	O
second	O
per	O
mm	O
Hg	O
,	O
respectively	O
,	O
P	O
<	O
.	O
05	O
)	O
.	O

The	O
effective	O
use	O
of	O
superoxide	B-GENE
dismutase	I-GENE
from	O
human	O
erythrocytes	O
in	O
the	O
late	O
stages	O
of	O
experimental	O
influenza	O
infection	O

EMT	B-GENE
was	O
localized	O
to	O
chromosome	O
5q31	O
-	O
32	O
,	O
a	O
region	O
that	O
contains	O
the	O
genes	O
for	O
several	O
growth	O
factors	O
and	O
receptors	O
as	O
well	O
as	O
early	O
activation	O
genes	O
,	O
particularly	O
those	O
involved	O
in	O
the	O
hematopoietic	O
system	O
.	O

However	O
,	O
neither	O
SF	B-GENE
-	I-GENE
1	I-GENE
nor	O
NGF	B-GENE
-	I-GENE
IB	I-GENE
alone	O
,	O
binding	O
as	O
monomers	O
,	O
increases	O
transcription	O
.	O

Both	O
purH	B-GENE
and	O
purD	B-GENE
genes	I-GENE
constitute	O
a	O
single	O
operon	O
and	O
are	O
coregulated	O
in	O
expression	O
by	O
purines	O
as	O
other	O
purine	B-GENE
genes	I-GENE
are	O
.	O

Fluorescence	O
in	O
situ	O
hybridization	O
was	O
used	O
to	O
investigate	O
the	O
physical	O
distribution	O
and	O
revealed	O
that	O
both	O
retrotransposon	O
families	O
are	O
present	O
on	O
all	O
sugar	O
beet	O
chromosomes	O
and	O
largely	O
excluded	O
from	O
chromosomal	O
regions	O
harbouring	O
the	O
18S	B-GENE
-	O
5	B-GENE
.	I-GENE
8S	I-GENE
-	O
25S	B-GENE
rRNA	O
genes	O
.	O

Application	O
of	O
the	O
method	O
using	O
an	O
11	O
-	O
year	O
microseismicity	O
record	O
revealed	O
systematic	O
spatial	O
and	O
temporal	O
changes	O
in	O
the	O
slip	O
rate	O
that	O
were	O
synchronous	O
with	O
earthquake	O
activity	O
and	O
other	O
independent	O
measures	O
of	O
fault	O
-	O
zone	O
slip	O
.	O

Furthermore	O
,	O
we	O
have	O
identified	O
the	O
major	O
open	O
reading	O
frame	O
(	O
RF4	O
;	O
2	O
.	O
3	O
kb	O
)	O
as	O
being	O
essential	O
for	O
activation	O
,	O
and	O
we	O
have	O
shown	O
that	O
the	O
NF	B-GENE
kappa	I-GENE
B	I-GENE
,	O
SP1	B-GENE
,	O
and	O
TATA	O
box	O
motifs	O
in	O
the	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
LTR	I-GENE
are	O
all	O
required	O
for	O
full	O
induction	O
of	O
the	O
promoter	O
by	O
the	O
HHV	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
encoded	I-GENE
transactivator	I-GENE
.	O

Two	O
conserved	O
motifs	O
,	O
W89RKRRY94	O
and	O
P156KKIKP161	O
,	O
seemed	O
to	O
act	O
as	O
nuclear	O
addressing	O
signals	O
.	O

All	O
testosterone	O
treatments	O
raised	O
plasma	O
testosterone	O
concentrations	O
above	O
control	O
and	O
pretreatment	O
levels	O
(	O
testosterone	O
and	O
synovex	O
+	O
testosterone	O
>	O
synovex	O
>	O
control	O
;	O
all	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
educational	O
program	O
was	O
the	O
significant	O
factor	O
that	O
influenced	O
the	O
change	O
of	O
concern	O
trajectories	O
,	O
and	O
the	O
recurrent	O
/	O
non	O
-	O
recurrent	O
factor	O
influenced	O
the	O
change	O
of	O
concern	O
only	O
in	O
pamphlet	O
group	O
.	O

Biol	O
.	O

Snails	O
infected	O
with	O
three	O
or	O
five	O
miracidia	O
produced	O
more	O
metacercariae	O
than	O
those	O
infected	O
with	O
a	O
single	O
miracidium	O
.	O

Evidence	O
that	O
the	O
AT1A	B-GENE
receptor	I-GENE
activates	O
transcription	B-GENE
factor	I-GENE
-	I-GENE
Stat91	I-GENE
and	O
/	O
or	O
a	O
related	O
protein	O
.	O

Two	O
estimates	O
of	O
the	O
fractal	O
exponent	O
are	O
considered	O
which	O
do	O
not	O
suffer	O
from	O
this	O
limit	O
:	O
one	O
derived	O
from	O
the	O
Allan	O
variance	O
,	O
which	O
was	O
developed	O
by	O
the	O
authors	O
,	O
and	O
one	O
based	O
on	O
the	O
periodogram	O
.	O

The	O
full	O
-	O
length	O
cDNA	O
was	O
cloned	O
and	O
sequenced	O
,	O
and	O
the	O
inferred	O
amino	O
acid	O
sequence	O
was	O
found	O
to	O
encode	O
a	O
novel	O
protein	O
,	O
which	O
we	O
named	O
cystatin	B-GENE
M	I-GENE
,	O
with	O
40	O
%	O
homology	O
to	O
human	B-GENE
family	I-GENE
2	I-GENE
cystatins	I-GENE
and	O
similar	O
overall	O
structure	O
.	O

Thus	O
,	O
oxyR	B-GENE
mutants	I-GENE
are	O
locked	O
on	O
for	O
Ag43	B-GENE
expression	O
,	O
whereas	O
dam	B-GENE
mutants	I-GENE
are	O
locked	O
off	O
for	O
Ag43	B-GENE
expression	O
.	O

GH	B-GENE
induced	O
rapid	O
tyrosine	O
phosphorylation	O
of	O
a	O
protein	O
at	O
approximately	O
93	O
kDa	O
in	O
normal	O
fibroblasts	O
,	O
and	O
Western	O
blotting	O
with	O
STAT	B-GENE
-	I-GENE
specific	I-GENE
antibodies	I-GENE
revealed	O
STAT5	B-GENE
activation	O
(	O
phosphorylation	O
)	O
by	O
GH	O
.	O

The	O
team	O
physician	O
and	O
conditioning	O
of	O
athletes	O
for	O
sports	O
:	O
a	O
consensus	O
statement	O
.	O

Experimental	O
exposure	O
of	O
poults	O
with	O
each	O
of	O
two	O
strains	O
representing	O
the	O
rarely	O
reported	O
capsular	O
group	O
B	O
indicated	O
that	O
both	O
were	O
virulent	O
.	O

A	O
drop	O
of	O
methylprednisolone	O
acetate	O
or	O
vehicle	O
constituent	O
was	O
placed	O
on	O
the	O
dissected	O
plantar	O
nerve	O
proximal	O
to	O
the	O
stimulating	O
electrodes	O
after	O
recording	O
control	O
responses	O
(	O
A	O
-	O
fibre	O
volley	O
in	O
the	O
sciatic	O
nerve	O
and	O
C	O
-	O
fibre	O
evoked	O
reflex	O
discharge	O
in	O
flexor	O
motoneurons	O
)	O
.	O

Case	O
of	O
nephrotic	O
syndrome	O
caused	O
by	O
gold	O
preparations	O

Pax	B-GENE
-	I-GENE
6	I-GENE
constructs	O
lacking	O
the	O
C	O
-	O
terminal	O
activation	O
domain	O
repressed	O
betaB1	B-GENE
-	I-GENE
crystallin	I-GENE
promoter	I-GENE
activity	O
as	O
effectively	O
as	O
the	O
full	O
-	O
length	O
protein	O
,	O
but	O
the	O
PD	B-GENE
alone	O
or	O
Pax	B-GENE
-	I-GENE
6	I-GENE
(	I-GENE
5a	I-GENE
)	I-GENE
,	O
a	O
splice	O
variant	O
with	O
an	O
altered	O
PD	B-GENE
affecting	O
its	O
DNA	O
binding	O
specificity	O
,	O
did	O
not	O
.	O

It	O
is	O
considered	O
important	O
,	O
therefore	O
,	O
when	O
treating	O
diabetic	O
patients	O
with	O
peripheral	O
neuropathy	O
not	O
to	O
assume	O
that	O
the	O
diabetes	O
itself	O
is	O
the	O
cause	O
in	O
all	O
cases	O
.	O

A	O
retrospective	O
study	O
of	O
clozapine	O
and	O
electroencephalographic	O
abnormalities	O
in	O
schizophrenic	O
patients	O
.	O

While	O
working	O
on	O
the	O
toxicity	O
of	O
war	O
gases	O
.	O
he	O
formulated	O
'	O
Haber	O
'	O
s	O
rule	O
'	O
,	O
also	O
known	O
as	O
C	O
x	O
T	O
=	O
constant	O
in	O
order	O
to	O
characterize	O
the	O
toxicity	O
of	O
an	O
inhalant	O
.	O

Furthermore	O
,	O
the	O
regulation	O
conferred	O
on	O
a	O
reporter	O
gene	O
in	O
Drosophila	O
by	O
three	O
closely	O
related	O
sequences	O
demonstrates	O
that	O
even	O
subtle	O
sequence	O
changes	O
within	O
an	O
E	O
box	O
or	O
flanking	O
bases	O
have	O
dramatic	O
consequences	O
on	O
the	O
overall	O
repertoire	O
of	O
proteins	O
that	O
can	O
bind	O
in	O
vivo	O
.	O

The	O
Sensititre	O
MIC	O
panels	O
containing	O
meropenem	O
offer	O
a	O
convenient	O
and	O
valid	O
alternative	O
to	O
the	O
NCCLS	O
reference	O
method	O
for	O
the	O
susceptibility	O
testing	O
of	O
potential	O
pathogens	O
likely	O
to	O
be	O
recovered	O
from	O
mixed	O
infections	O
.	O

Two	O
putative	O
ATP	O
-	O
binding	O
domains	O
were	O
identified	O
,	O
one	O
in	O
the	O
amino	O
-	O
terminal	O
half	O
of	O
the	O
argA	B-GENE
-	I-GENE
encoded	I-GENE
protein	I-GENE
and	O
the	O
other	O
in	O
the	O
carboxy	O
-	O
terminal	O
half	O
.	O

Previously	O
,	O
we	O
identified	O
two	O
human	B-GENE
SMC	I-GENE
family	I-GENE
proteins	I-GENE
,	O
hCAP	B-GENE
-	I-GENE
C	I-GENE
and	O
hCAP	B-GENE
-	I-GENE
E	I-GENE
,	O
which	O
form	O
a	O
heterodimeric	O
complex	O
(	O
hCAP	B-GENE
-	I-GENE
C	I-GENE
-	O
hCAP	B-GENE
-	I-GENE
E	I-GENE
)	O
in	O
the	O
cell	O
.	O

There	O
were	O
no	O
major	O
postoperative	O
complications	O
and	O
at	O
follow	O
-	O
up	O
of	O
the	O
13	O
patients	O
at	O
10	O
to	O
26	O
months	O
after	O
operation	O
the	O
results	O
were	O
satisfactory	O
.	O

The	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
receptor	I-GENE
alpha	I-GENE
(	O
IL	B-GENE
-	I-GENE
2R	I-GENE
alpha	I-GENE
)	O
chain	O
gene	O
contains	O
a	O
sequence	O
similar	O
to	O
the	O
immunoglobulin	B-GENE
(	I-GENE
Ig	I-GENE
)	I-GENE
kappa	I-GENE
(	O
kappa	O
)	O
enhancer	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
binding	I-GENE
site	I-GENE
.	O

(	O
1996	O
)	O
J	O
.	O

The	O
presence	O
of	O
a	O
short	O
(	O
70	O
bp	O
)	O
intron	O
near	O
the	O
N	O
-	O
terminus	O
of	O
the	O
atX	B-GENE
gene	I-GENE
was	O
predicted	O
that	O
contains	O
the	O
canonical	O
GT	O
and	O
AG	O
dinucleotides	O
at	O
its	O
5	O
'	O
-	O
and	O
3	O
'	O
-	O
splicing	O
junctions	O
.	O

Studies	O
on	O
the	O
reaction	O
of	O
cytochrome	B-GENE
c	I-GENE
with	O
corticosteroids	O
.	O

In	O
accordance	O
with	O
Ann	O
Arbor	O
classification	O
,	O
we	O
observed	O
12	O
CS	O
IA	O
(	O
21	O
.	O
3	O
%	O
)	O
,	O
2	O
CS	O
IB	O
(	O
3	O
.	O
5	O
%	O
)	O
,	O
14	O
CS	O
IIA	O
(	O
25	O
.	O
4	O
%	O
)	O
and	O
27	O
CS	O
IIB	O
(	O
49	O
.	O
7	O
%	O
)	O
.	O

The	O
results	O
can	O
be	O
summarized	O
as	O
follows	O
.	O

The	O
level	O
of	O
expression	O
of	O
the	O
PDE	B-GENE
protein	I-GENE
was	O
monitored	O
by	O
immunoblot	O
analysis	O
using	O
two	O
specific	O
cAMP	B-GENE
-	I-GENE
PDE	I-GENE
polyclonal	I-GENE
antibodies	I-GENE
and	O
by	O
measuring	O
the	O
PDE	B-GENE
activity	O
.	O

HL	B-GENE
is	O
hypothesized	O
to	O
directly	O
couple	O
HDL	B-GENE
lipid	O
metabolism	O
to	O
tissue	O
/	O
cellular	O
lipid	O
metabolism	O
.	O

The	O
analysis	O
of	O
the	O
organization	O
of	O
the	O
sequence	O
of	O
the	O
human	O
ABP	B-GENE
/	O
DAO	B-GENE
gene	O
reveals	O
that	O
the	O
2	O
.	O
4	O
-	O
kilobase	O
messenger	O
RNA	O
is	O
transcribed	O
from	O
two	O
close	O
origins	O
identifying	O
the	O
proximal	O
promoter	O
.	O

Rottlerin	O
also	O
inhibited	O
the	O
activation	O
of	O
MAP	B-GENE
kinase	I-GENE
kinase	I-GENE
(	O
MEK	B-GENE
)	O
in	O
response	O
to	O
activated	O
Raf	B-GENE
,	O
but	O
had	O
no	O
effect	O
upon	O
c	B-GENE
-	I-GENE
Raf	I-GENE
activity	O
or	O
ERK	B-GENE
activation	O
by	O
activated	O
MEK	B-GENE
.	O

Especially	O
if	O
the	O
number	O
of	O
dimensions	O
of	O
the	O
samples	O
is	O
large	O
,	O
it	O
can	O
be	O
said	O
that	O
BPN	O
is	O
better	O
than	O
k	O
-	O
NN	O
in	O
classification	O
ability	O
.	O

Several	O
DNA	O
clones	O
were	O
obtained	O
by	O
this	O
procedure	O
,	O
one	O
of	O
which	O
,	O
clone	O
18	O
,	O
is	O
reported	O
and	O
characterized	O
here	O
.	O

Immunoprecipitation	O
of	O
cell	O
lysates	O
with	O
anti	B-GENE
-	I-GENE
phosphotyrosine	I-GENE
and	O
immunoblotting	O
showed	O
phosphorylated	O
forms	O
of	O
the	O
mitogenic	O
pathway	O
proteins	O
Shc	B-GENE
and	O
MAPK	B-GENE
in	O
addition	O
to	O
p185	B-GENE
(	O
neu	B-GENE
)	O
,	O
suggesting	O
that	O
the	O
Ras	B-GENE
to	O
MAPK	B-GENE
mitogenic	O
pathway	O
is	O
activated	O
.	O

The	O
sequence	O
immediately	O
upstream	O
of	O
the	O
translation	O
start	O
site	O
was	O
G	O
+	O
C	O
rich	O
(	O
greater	O
than	O
75	O
%	O
)	O
and	O
contained	O
a	O
consensus	O
CCAAT	O
sequence	O
despite	O
the	O
absence	O
of	O
a	O
TATA	O
box	O
.	O

The	O
development	O
of	O
various	O
pathological	O
lesions	O
in	O
thymus	O
,	O
spleen	O
,	O
lymph	O
nodes	O
and	O
bone	O
-	O
marrow	O
is	O
frequently	O
observed	O
.	O

RESULTS	O
:	O
After	O
3	O
weeks	O
of	O
therapy	O
,	O
the	O
patient	O
had	O
an	O
increase	O
in	O
platelet	O
count	O
from	O
a	O
baseline	O
of	O
5	O
,	O
000	O
to	O
8	O
,	O
000	O
/	O
microliter	O
to	O
a	O
maximal	O
level	O
of	O
33	O
,	O
000	O
/	O
microliter	O
.	O

In	O
the	O
latter	O
,	O
the	O
cells	O
and	O
adjacent	O
matrix	O
had	O
several	O
characteristics	O
of	O
fibrocartilage	O
,	O
including	O
chondrocytes	O
.	O

Radiation	O
sensitivity	O
of	O
rats	O
irradiated	O
in	O
a	O
condition	O
of	O
hypoxia	O

When	O
the	O
opioid	O
antagonist	O
was	O
administered	O
to	O
animals	O
24	O
hr	O
after	O
termination	O
of	O
single	O
or	O
multiple	O
exposures	O
to	O
restraint	O
,	O
NALT	O
-	O
induced	O
increases	O
in	O
basal	O
plasma	B-GENE
LH	I-GENE
were	O
significantly	O
attenuated	O
in	O
the	O
chronically	O
stressed	O
rats	O
compared	O
to	O
animals	O
subjected	O
to	O
stress	O
only	O
once	O
or	O
not	O
at	O
all	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Furthermore	O
,	O
CBP	B-GENE
/	O
p300	B-GENE
stimulated	O
both	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
-	O
and	O
Smad	B-GENE
-	O
induced	O
transcription	O
in	O
a	O
Smad4	B-GENE
/	O
DPC4	B-GENE
-	O
dependent	O
fashion	O
.	O

Analysis	O
of	O
exon	O
2	O
of	O
the	O
factor	B-GENE
IX	I-GENE
gene	I-GENE
revealed	O
a	O
C	O
-	O
-	O
>	O
T	O
mutation	O
in	O
codon	O
10	O
of	O
the	O
propeptide	O
region	O
,	O
resulting	O
in	O
the	O
substitution	O
of	O
alanine	O
by	O
valine	O
.	O

In	O
contrast	O
to	O
the	O
restricted	O
tissue	O
expression	O
of	O
gonadotropin	B-GENE
and	O
TSH	B-GENE
receptors	I-GENE
in	O
gonads	O
and	O
thyroid	O
,	O
respectively	O
,	O
LGR4	B-GENE
is	O
expressed	O
in	O
diverse	O
tissues	O
including	O
ovary	O
,	O
testis	O
,	O
adrenal	O
,	O
placenta	O
,	O
thymus	O
,	O
spinal	O
cord	O
,	O
and	O
thyroid	O
,	O
whereas	O
LGR5	B-GENE
is	O
found	O
in	O
muscle	O
,	O
placenta	O
,	O
spinal	O
cord	O
,	O
and	O
brain	O
.	O

We	O
now	O
show	O
that	O
purified	O
recombinant	O
c	B-GENE
-	I-GENE
sis	I-GENE
/	O
PDGF	B-GENE
can	O
induce	O
this	O
binding	O
activity	O
which	O
we	O
have	O
termed	O
SIF	B-GENE
,	O
for	O
sis	B-GENE
-	I-GENE
inducible	I-GENE
factor	I-GENE
.	O

Antinuclear	O
antibodies	O
,	O
rheumatoid	B-GENE
factor	I-GENE
and	O
C	B-GENE
-	I-GENE
reactive	I-GENE
protein	I-GENE
in	O
serum	O
of	O
normal	O
women	O
using	O
oral	O
contraceptives	O
.	O

We	O
report	O
here	O
that	O
AChE	B-GENE
activity	O
tends	O
to	O
decrease	O
in	O
individuals	O
sampled	O
in	O
tanks	O
at	O
a	O
salinity	O
of	O
30	O
per	O
thousand	O
as	O
temperature	O
increases	O
.	O

The	O
relationship	O
between	O
donor	O
status	O
for	O
antibody	O
to	O
hepatitis	B-GENE
B	I-GENE
core	I-GENE
antigen	I-GENE
and	O
the	O
occurrence	O
of	O
non	O
-	O
A	O
,	O
non	O
-	O
B	O
posttransfusion	O
hepatitis	O
in	O
the	O
recipient	O
was	O
prospectively	O
studied	O
in	O
112	O
patients	O
undergoing	O
open	O
-	O
heart	O
surgery	O
who	O
were	O
followed	O
for	O
6	O
.	O
5	O
months	O
after	O
surgery	O
.	O

Both	O
control	O
and	O
Mn	O
-	O
exposed	O
quail	O
accumulated	O
5	O
to	O
10	O
times	O
more	O
Mn	O
in	O
their	O
livers	O
than	O
similarly	O
treated	O
rodents	O
.	O

These	O
data	O
suggested	O
that	O
mutant	B-GENE
PS1	I-GENE
may	O
cause	O
disease	O
as	O
a	O
result	O
of	O
reduction	O
in	O
PS1	B-GENE
function	O
.	O

In	O
response	O
to	O
phosphorus	O
limitation	O
,	O
the	O
fungus	O
Neurospora	O
crassa	O
synthesizes	O
a	O
number	O
of	O
enzymes	O
that	O
function	O
to	O
bring	O
more	O
phosphate	O
into	O
the	O
cell	O
.	O

IL	B-GENE
-	I-GENE
6	I-GENE
was	O
detected	O
in	O
the	O
urine	O
of	O
52	O
%	O
of	O
children	O
with	O
pyelonephritis	O
compared	O
with	O
15	O
%	O
of	O
other	O
children	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

The	O
effects	O
of	O
pretreatment	O
with	O
the	O
non	O
-	O
competitive	O
NMDA	O
antagonist	O
(	O
+	O
)	O
MK	O
-	O
801	O
on	O
the	O
behavioral	O
alterations	O
induced	O
by	O
repeated	O
restraint	O
stress	O
were	O
investigated	O
.	O

Radiation	O
was	O
delivered	O
in	O
a	O
single	O
4	O
-	O
mJ	O
pulse	O
of	O
200	O
microseconds	O
duration	O
by	O
means	O
of	O
an	O
articulated	O
zirconium	O
fluoride	O
optical	O
fibre	O
and	O
a	O
320	O
-	O
microns	O
quartz	O
-	O
fibre	O
tip	O
.	O

MsEPV	O
genes	O
with	O
putative	O
functions	O
in	O
prevention	O
and	O
repair	O
of	O
DNA	O
damage	O
include	O
a	O
complete	O
base	O
excision	O
repair	O
pathway	O
(	O
uracil	B-GENE
DNA	I-GENE
glycosylase	I-GENE
,	O
AP	B-GENE
endonuclease	I-GENE
,	O
DNA	B-GENE
polymerase	I-GENE
beta	I-GENE
,	O
and	O
an	O
NAD	B-GENE
+	I-GENE
-	I-GENE
dependent	I-GENE
DNA	I-GENE
ligase	I-GENE
)	O
,	O
a	O
photoreactivation	O
repair	O
pathway	O
(	O
cyclobutane	B-GENE
pyrimidine	I-GENE
dimer	I-GENE
photolyase	I-GENE
)	O
,	O
a	O
LINE	B-GENE
-	I-GENE
type	I-GENE
reverse	I-GENE
transcriptase	I-GENE
,	O
and	O
a	O
mutT	B-GENE
homologue	I-GENE
.	O

In	O
isolated	O
olfactory	O
cilia	O
certain	O
odorants	O
elicit	O
a	O
rapid	O
and	O
transient	O
cAMP	O
response	O
,	O
terminated	O
by	O
a	O
concerted	O
process	O
which	O
requires	O
the	O
action	O
of	O
two	O
protein	O
kinases	O
,	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
(	O
PKA	B-GENE
)	O
and	O
a	O
receptor	B-GENE
-	I-GENE
specific	I-GENE
kinase	I-GENE
(	O
GRK3	B-GENE
)	O
(	O
Schleicher	O
,	O
S	O
.	O
,	O
Boekhoff	O
,	O
I	O
.	O

The	O
results	O
corroborate	O
the	O
proposed	O
physiological	O
function	O
of	O
CCoAOMT	B-GENE
in	O
elicited	O
plant	O
cells	O
and	O
may	O
shed	O
new	O
light	O
on	O
the	O
sequential	O
action	O
of	O
trans	O
-	O
active	O
factors	O
in	O
the	O
regulation	O
of	O
phenylpropanoid	O
genes	O
.	O

Two	O
hundred	O
and	O
eighty	O
-	O
three	O
patients	O
,	O
217	O
females	O
(	O
median	O
age	O
24	O
years	O
,	O
range	O
0	O
.	O
5	O
-	O
73	O
)	O
and	O
66	O
males	O
(	O
median	O
age	O
20	O
years	O
,	O
range	O
0	O
.	O
75	O
-	O
72	O
)	O
,	O
were	O
examined	O
.	O

Pneumatic	O
dilation	O
of	O
the	O
lower	O
esophageal	O
sphincter	O
was	O
accomplished	O
by	O
endoscopic	O
visualization	O
and	O
positioning	O
of	O
a	O
modified	O
polyurethane	O
dilator	O
(	O
90	O
F	O
diameter	O
)	O
without	O
fluoroscopy	O
in	O
17	O
consecutive	O
patients	O
with	O
advanced	O
symptomatic	O
achalasia	O
.	O

The	O
organotins	O
.	O

A	O
series	O
of	O
mutations	O
were	O
constructed	O
within	O
the	O
E2	B-GENE
open	O
reading	O
frame	O
which	O
delete	O
various	O
regions	O
of	O
the	O
conserved	O
DNA	O
binding	O
and	O
transactivation	O
domains	O
as	O
well	O
as	O
the	O
internal	O
hinge	O
region	O
.	O

These	O
data	O
indicate	O
that	O
chromatic	O
processing	O
in	O
areas	O
V1	O
and	O
V2	O
is	O
normal	O
after	O
V4	O
lesions	O
and	O
,	O
together	O
with	O
the	O
behavioural	O
evidence	O
,	O
that	O
these	O
areas	O
are	O
sufficient	O
for	O
some	O
basic	O
aspects	O
of	O
colour	O
perception	O
.	O

The	O
Cryotherapy	O
for	O
Retinopathy	O
of	O
Prematurity	O
Study	O
has	O
shown	O
that	O
this	O
number	O
can	O
be	O
halved	O
with	O
treatment	O
.	O

The	O
non	B-GENE
-	I-GENE
major	I-GENE
histocompatibility	I-GENE
complex	I-GENE
(	O
MHC	B-GENE
)	O
-	O
encoded	O
CD1	B-GENE
family	I-GENE
has	O
recently	O
emerged	O
as	O
a	O
new	O
antigen	O
-	O
presenting	O
system	O
that	O
is	O
distinct	O
from	O
either	O
MHC	B-GENE
class	I-GENE
I	I-GENE
or	I-GENE
class	I-GENE
II	I-GENE
molecules	I-GENE
.	O

Nitroglycerin	O
(	O
glyceryl	O
trinitrate	O
)	O
as	O
a	O
monoamine	B-GENE
oxidase	I-GENE
inhibitor	O
.	O

Doxazosin	O
produced	O
increases	O
in	O
both	O
mean	O
and	O
maximum	O
urinary	O
flow	O
rates	O
of	O
1	O
.	O
01	O
ml	O
/	O
s	O
and	O
3	O
.	O
2	O
ml	O
/	O
s	O
respectively	O
,	O
compared	O
with	O
0	O
.	O
21	O
ml	O
/	O
s	O
and	O
2	O
.	O
2	O
ml	O
/	O
s	O
on	O
placebo	O
.	O

We	O
determined	O
the	O
complete	O
nucleotide	O
sequence	O
of	O
the	O
gypsy	B-GENE
element	I-GENE
present	O
at	O
the	O
forked	B-GENE
locus	I-GENE
of	O
Drosophila	O
melanogaster	O
in	O
the	O
f1	O
allele	O
.	O

Cloning	O
and	O
nucleotide	O
sequence	O
analysis	O
reveals	O
that	O
BUR6	B-GENE
encodes	O
a	O
homolog	O
of	O
DRAP1	B-GENE
(	O
also	O
called	O
NC2alpha	B-GENE
)	O
,	O
a	O
mammalian	O
repressor	O
of	O
basal	O
transcription	O
.	O

The	O
ATF	B-GENE
/	O
CRE	O
site	O
is	O
also	O
essential	O
for	O
CD4	B-GENE
promoter	I-GENE
activation	O
by	O
forskolin	O
,	O
an	O
activator	O
of	O
adenylate	B-GENE
cyclase	I-GENE
.	O

These	O
results	O
point	O
towards	O
post	O
-	O
translational	O
steric	O
and	O
/	O
or	O
allosteric	O
control	O
of	O
EKLF	B-GENE
function	O
that	O
may	O
be	O
important	O
not	O
just	O
for	O
its	O
DNA	O
binding	O
ability	O
,	O
but	O
also	O
for	O
its	O
potential	O
to	O
interact	O
with	O
other	O
proteins	O
that	O
fully	O
establish	O
the	O
correct	O
stereospecific	O
array	O
leading	O
to	O
efficient	O
switching	O
of	O
beta	B-GENE
-	I-GENE
globin	I-GENE
transcription	O
during	O
development	O
.	O

They	O
are	O
growth	O
-	O
inhibited	O
by	O
TGF	B-GENE
-	I-GENE
beta1	I-GENE
.	O

Chronic	O
active	O
hepatitis	O
and	O
cirrhosis	O
of	O
the	O
liver	O
.	O

Colonization	O
increased	O
with	O
level	O
of	O
care	O
:	O
from	O
9	O
per	O
cent	O
in	O
independent	O
residents	O
of	O
apartments	O
to	O
60	O
per	O
cent	O
in	O
patients	O
on	O
an	O
acute	O
hospital	O
ward	O
(	O
P	O
less	O
than	O
0	O
.	O
0001	O
)	O
.	O

Interaction	O
of	O
the	O
v	B-GENE
-	I-GENE
rel	I-GENE
protein	I-GENE
with	O
an	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
DNA	I-GENE
binding	I-GENE
site	I-GENE
.	O

CVO2	O
saturation	O
is	O
a	O
reliable	O
and	O
sensitive	O
method	O
for	O
detecting	O
blood	O
loss	O
.	O

In	O
the	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
actin	I-GENE
intron	I-GENE
a	O
silent	O
branch	O
point	O
-	O
like	O
sequence	O
(	O
UACUAAG	O
)	O
is	O
located	O
7	O
nt	O
upstream	O
of	O
the	O
canonical	O
sequence	O
.	O

The	O
elevated	O
levels	O
of	O
inositol	O
phosphates	O
resulting	O
from	O
N	B-GENE
(	I-GENE
epi	I-GENE
)	I-GENE
alpha	I-GENE
qQ209L	I-GENE
expression	O
were	O
similar	O
to	O
those	O
obtained	O
with	O
carbachol	O
activation	O
of	O
the	O
M1	B-GENE
muscarinic	I-GENE
acetylcholine	I-GENE
receptor	I-GENE
.	O

To	O
increase	O
the	O
number	O
of	O
circulating	O
polymorphonuclear	O
neutrophils	O
,	O
the	O
patient	O
was	O
treated	O
with	O
recombinant	O
granulocyte	B-GENE
-	I-GENE
macrophage	I-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
(	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
)	O
at	O
a	O
dose	O
of	O
2	O
micrograms	O
protein	O
/	O
kg	O
bodyweight	O
s	O
.	O
c	O
.	O
/	O
12	O
h	O
.	O

PrRP	B-GENE
rapidly	O
and	O
transiently	O
activated	O
extracellular	B-GENE
signal	I-GENE
-	I-GENE
regulated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
ERK	B-GENE
)	O
in	O
both	O
types	O
of	O
cells	O
.	O

Nevertheless	O
,	O
PEG	O
influenced	O
in	O
vitro	O
drug	O
availability	O
considerably	O
,	O
by	O
increasing	O
both	O
drug	O
solubility	O
and	O
dissolution	O
rate	O
.	O

Reversible	O
topology	O
of	O
a	O
bifunctional	O
transmembrane	O
protein	O
depends	O
upon	O
the	O
charge	O
balance	O
around	O
its	O
transmembrane	O
domain	O
.	O

We	O
have	O
documented	O
previously	O
that	O
glucocorticoid	O
hormones	O
modulate	O
the	O
posttranslational	O
localization	O
of	O
cell	O
surface	O
mouse	O
mammary	O
tumor	O
virus	O
(	O
MMTV	O
)	O
glycoproteins	O
in	O
the	O
viral	O
-	O
infected	O
M1	O
.	O
54	O
rat	O
HTC	O
hepatoma	O
cell	O
line	O
.	O

Contrast	O
radiography	O
appears	O
to	O
be	O
an	O
especially	O
inaccurate	O
method	O
to	O
document	O
PUD	O
in	O
CF	O
because	O
the	O
duodenal	O
mucosa	O
typically	O
appears	O
nodular	O
and	O
distorted	O
with	O
poor	O
definition	O
of	O
the	O
mucosal	O
folds	O
.	O

Spodoptera	O
frugiperda	O
(	O
Sf9	O
)	O
cells	O
have	O
proved	O
a	O
suitable	O
cell	O
system	O
in	O
which	O
to	O
study	O
this	O
association	O
and	O
to	O
produce	O
recombinant	B-GENE
CR3	I-GENE
,	O
and	O
we	O
show	O
here	O
that	O
another	O
lepidopteran	O
cell	O
line	O
,	O
Trichoplusia	O
niTN	O
-	O
5B1	O
-	O
4	O
(	O
High	O
-	O
Five	O
)	O
cells	O
,	O
allows	O
the	O
recovery	O
of	O
large	O
amounts	O
of	O
functional	B-GENE
recombinant	I-GENE
CR3	I-GENE
.	O

Using	O
the	O
standard	O
scoring	O
,	O
children	O
with	O
full	O
scale	O
IQ	O
<	O
or	O
=	O
84	O
on	O
the	O
Wechsler	O
Preschool	O
and	O
Primary	O
Scale	O
of	O
Intelligence	O
at	O
age	O
4	O
-	O
5	O
years	O
were	O
poorly	O
identified	O
(	O
sensitivity	O
54	O
%	O
)	O
from	O
the	O
composite	O
S	O
-	O
B	O
IV	O
score	O
at	O
age	O
3	O
.	O

The	O
relation	O
between	O
the	O
changes	O
of	O
bone	O
density	O
and	O
the	O
level	O
of	O
blood	O
calcium	O
,	O
blood	O
phosphorus	O
and	O
alkaline	B-GENE
phosphatase	I-GENE
(	O
AKP	B-GENE
)	O
as	O
well	O
as	O
the	O
metabolism	O
of	O
vitamin	O
D	O
was	O
studied	O
.	O

To	O
clarify	O
the	O
mechanisms	O
that	O
regulate	O
transcription	O
of	O
the	O
GTP	B-GENE
cyclohydrolase	I-GENE
I	I-GENE
gene	I-GENE
and	O
to	O
generate	O
multiple	O
species	O
of	O
mRNA	O
,	O
we	O
isolated	O
genomic	O
DNA	O
clones	O
for	O
the	O
human	O
and	O
mouse	O
GTP	B-GENE
cyclohydrolase	I-GENE
I	I-GENE
genes	I-GENE
.	O

Perception	O
of	O
sweetness	O
cannot	O
be	O
used	O
to	O
accurately	O
meter	O
the	O
metabolizable	O
energy	O
or	O
nutritive	O
value	O
of	O
a	O
food	O
.	O

These	O
results	O
suggest	O
that	O
termination	O
is	O
a	O
highly	O
specific	O
event	O
,	O
and	O
not	O
merely	O
a	O
consequence	O
of	O
decreased	O
stability	O
of	O
the	O
EC	O
.	O

All	O
sows	O
nursed	O
nine	O
pigs	O
.	O

When	O
labeled	O
by	O
the	O
described	O
method	O
,	O
99mTc	O
on	O
DTPA	O
coupled	O
antibodies	O
shows	O
instability	O
in	O
serum	O
but	O
superior	O
stability	O
than	O
99mTc	O
on	O
antibodies	O
without	O
the	O
attached	O
DTPA	O
.	O

The	O
crystal	O
structure	O
of	O
the	O
yeast	O
Phe	B-GENE
-	I-GENE
tRNAPhe	I-GENE
ternary	I-GENE
complex	I-GENE
with	O
Thermus	O
aquaticus	O
EF	B-GENE
-	I-GENE
Tu	I-GENE
-	O
GDPNP	O
(	O
Phe	B-GENE
-	I-GENE
TC	I-GENE
)	O
has	O
previously	O
been	O
determined	O
as	O
one	O
representative	O
of	O
this	O
general	O
yet	O
highly	O
discriminating	O
complex	O
formation	O
.	O

Our	O
results	O
indicate	O
that	O
GCN4	B-GENE
contains	O
two	O
activation	O
domains	O
of	O
similar	O
potency	O
that	O
can	O
function	O
independently	O
to	O
promote	O
high	O
-	O
level	O
transcription	O
of	O
the	O
target	O
genes	O
HIS3	B-GENE
and	O
HIS4	B-GENE
.	O

U	O
.	O
S	O
.	O
A	O
.	O

Human	B-GENE
plastin	I-GENE
genes	I-GENE
.	O

Role	O
of	O
the	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
binding	I-GENE
protein	I-GENE
-	I-GENE
alpha	I-GENE
transcription	I-GENE
factor	I-GENE
in	O
the	O
glucocorticoid	O
stimulation	O
of	O
p21waf1	B-GENE
/	O
cip1	B-GENE
gene	O
promoter	O
activity	O
in	O
growth	O
-	O
arrested	O
rat	O
hepatoma	O
cells	O
.	O

We	O
also	O
demonstrate	O
that	O
a	O
p110RB1	B-GENE
mutant	I-GENE
,	O
which	O
is	O
refractory	O
to	O
cell	O
cycle	O
phosphorylation	O
but	O
intact	O
in	O
E1a	B-GENE
/	O
large	B-GENE
T	I-GENE
antigen	I-GENE
-	O
binding	O
properties	O
,	O
represses	O
EIIaE	B-GENE
with	O
50	O
-	O
to	O
80	O
-	O
fold	O
greater	O
efficiency	O
than	O
wild	B-GENE
-	I-GENE
type	I-GENE
p110RB1	I-GENE
.	O

For	O
the	O
target	O
stimuli	O
,	O
P3	O
amplitude	O
and	O
latency	O
were	O
negatively	O
correlated	O
and	O
most	O
tightly	O
coupled	O
over	O
the	O
frontal	O
-	O
central	O
and	O
right	O
medial	O
/	O
lateral	O
recording	O
sites	O
.	O

We	O
have	O
characterized	O
a	O
new	O
cDNA	O
,	O
33k	O
-	O
6	O
,	O
potentially	O
encoding	O
a	O
tobacco	B-GENE
33	I-GENE
kDa	I-GENE
chloroplast	I-GENE
RNP	I-GENE
(	I-GENE
cp33	I-GENE
)	I-GENE
homologue	I-GENE
.	O

Though	O
it	O
has	O
been	O
established	O
that	O
skinfold	O
anthropometry	O
has	O
severe	O
limitations	O
as	O
a	O
method	O
of	O
deriving	O
total	O
body	O
fat	O
(	O
TBF	O
)	O
,	O
the	O
possibility	O
that	O
the	O
problem	O
might	O
be	O
related	O
more	O
to	O
the	O
assumptions	O
implicit	O
in	O
densitometry	O
has	O
to	O
be	O
addressed	O
.	O

Gene	B-GENE
GPR	I-GENE
51	I-GENE
was	O
localized	O
by	O
radiation	O
hybrid	O
mapping	O
to	O
chromosome	O
9	O
,	O
4	O
.	O
81	O
cR	O
from	O
the	O
WI	O
-	O
8684	O
marker	O
,	O
and	O
proximal	O
to	O
the	O
hereditary	B-GENE
sensory	I-GENE
neuropathy	I-GENE
type	I-GENE
1	I-GENE
locus	I-GENE
.	O

A	O
)	O
During	O
O2	O
-	O
ischemia	O
both	O
extracellular	O
[	O
K	O
+	O
]	O
and	O
change	O
of	O
pH	O
in	O
the	O
subepicardium	O
are	O
significantly	O
less	O
than	O
in	O
the	O
midmyocardium	O
.	O

Some	O
of	O
these	O
physiological	O
responses	O
are	O
regulated	O
via	O
activation	O
of	O
transcription	O
factors	O
such	O
as	O
activator	B-GENE
protein	I-GENE
1	I-GENE
(	O
AP	B-GENE
-	I-GENE
1	I-GENE
)	O
.	O

The	O
1	O
.	O
6	O
-	O
kb	O
cDNA	O
(	O
CBF	B-GENE
-	I-GENE
A	I-GENE
)	O
encoding	O
285	O
amino	O
acids	O
(	O
aa	O
)	O
was	O
obtained	O
,	O
and	O
a	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
fusion	I-GENE
protein	I-GENE
,	O
bacterially	O
produced	O
from	O
the	O
cDNA	O
,	O
bound	O
to	O
DNA	O
fragments	O
containing	O
several	O
CArG	O
boxes	O
.	O

Alveoli	O
-	O
capillary	O
diffusion	O
.	O

The	O
pattern	O
of	O
expression	O
of	O
this	O
and	O
other	O
Chi26	B-GENE
/	O
Chi33	B-GENE
chimeric	O
promoters	O
suggest	O
that	O
the	O
E	B-GENE
-	I-GENE
region	I-GENE
contains	O
cis	O
-	O
acting	O
sequences	O
which	O
activate	O
transcription	O
in	O
aleurone	O
and	O
silence	O
transcription	O
in	O
leaves	O
.	O

Interobserver	O
agreement	O
of	O
the	O
Nottingham	O
histologic	O
grading	O
scheme	O
for	O
infiltrating	O
duct	O
carcinoma	O
breast	O
.	O

We	O
have	O
demonstrated	O
that	O
the	O
specific	O
determination	O
and	O
identification	O
of	O
plasma	O
FbDP	B-GENE
alone	O
is	O
not	O
sufficient	O
to	O
follow	O
the	O
effectiveness	O
of	O
thrombolytic	O
therapy	O
.	O

To	O
determine	O
the	O
role	O
of	O
the	O
transmembrane	O
region	O
of	O
HN	B-GENE
on	O
fusion	O
-	O
promoting	O
activity	O
,	O
mutant	B-GENE
HN	I-GENE
proteins	I-GENE
were	O
expressed	O
and	O
their	O
biological	O
activities	O
examined	O
.	O

Thus	O
,	O
transgene	O
expression	O
directed	O
by	O
both	O
the	O
human	O
and	O
mouse	B-GENE
Rb	I-GENE
promoters	I-GENE
is	O
restricted	O
to	O
a	O
subset	O
of	O
tissues	O
in	O
which	O
Rb	B-GENE
is	O
normally	O
expressed	O
during	O
embryogenesis	O
.	O

The	O
cDNA	O
is	O
predicted	O
to	O
encode	O
a	O
polypeptide	O
of	O
298	O
amino	O
acids	O
that	O
is	O
homologous	O
to	O
the	O
Y	B-GENE
-	I-GENE
box	I-GENE
(	I-GENE
inverted	I-GENE
CCAAT	I-GENE
)	I-GENE
family	I-GENE
of	I-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

RAP	B-GENE
has	O
been	O
shown	O
to	O
be	O
a	O
useful	O
vaccine	O
target	O
site	O
,	O
and	O
RIP	B-GENE
and	O
inhibitory	O
AIPs	B-GENE
as	O
therapeutic	O
molecules	O
to	O
prevent	O
and	O
suppress	O
S	O
.	O
aureus	O
infections	O
.	O

First	O
,	O
mutations	O
in	O
the	O
IFNgamma	B-GENE
-	I-GENE
activated	I-GENE
sequence	I-GENE
(	O
GAS	B-GENE
)	O
,	O
either	O
multimerized	O
or	O
in	O
the	O
context	O
of	O
the	O
1	B-GENE
.	I-GENE
7	I-GENE
-	I-GENE
kb	I-GENE
IRF	I-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
,	O
failed	O
to	O
mediate	O
a	O
PRL	B-GENE
response	O
,	O
showing	O
that	O
the	O
IRF	B-GENE
-	I-GENE
1	I-GENE
GAS	B-GENE
is	O
a	O
target	O
of	O
PRL	B-GENE
signaling	O
.	O

However	O
,	O
both	O
RAR	B-GENE
-	O
and	O
RXR	B-GENE
-	O
specific	O
ligands	O
increase	O
CaSki	O
number	O
by	O
>	O
or	O
=	O
20	O
%	O
.	O

Tight	O
-	O
binding	O
band	O
structure	O
calculations	O
for	O
beta	O
-	O
MNX	O
(	O
M	O
=	O
Zr	O
,	O
X	O
=	O
Cl	O
,	O
Br	O
;	O
M	O
=	O
Hf	O
,	O
X	O
=	O
Cl	O
)	O
,	O
ZrCl	O
,	O
and	O
Y	O
(	O
2	O
)	O
C	O
(	O
2	O
)	O
Br	O
(	O
2	O
)	O
are	O
reported	O
.	O

The	O
same	O
high	O
degree	O
of	O
sequence	O
homology	O
between	O
the	O
two	O
F	O
.	O
diplosiphon	O
PC	B-GENE
alpha	I-GENE
and	O
PC	B-GENE
beta	I-GENE
sequences	I-GENE
(	O
85	O
and	O
77	O
%	O
,	O
respectively	O
)	O
was	O
found	O
at	O
both	O
the	O
nucleotide	O
and	O
amino	O
acid	O
levels	O
,	O
and	O
similar	O
results	O
were	O
obtained	O
for	O
interspecies	O
comparisons	O
.	O

Interestingly	O
,	O
the	O
expression	O
of	O
Id4	B-GENE
in	O
Sertoli	O
cells	O
is	O
only	O
detectable	O
after	O
stimulation	O
with	O
FSH	B-GENE
or	O
cAMP	O
.	O

On	O
the	O
basis	O
of	O
the	O
physical	O
interactions	O
between	O
Sxl	B-GENE
and	O
Snf	B-GENE
,	O
we	O
present	O
a	O
model	O
for	O
Sxl	B-GENE
splicing	O
regulation	O
.	O

It	O
thus	O
seems	O
likely	O
that	O
genistein	O
affects	O
a	O
common	O
pathway	O
downstream	O
of	O
these	O
signals	O
.	O

LiF	O
thermoluminescence	O
dosimeters	O
(	O
TLD	O
)	O
in	O
chip	O
form	O
were	O
placed	O
onto	O
1	O
eyelid	O
,	O
the	O
skin	O
over	O
the	O
thyroid	O
,	O
and	O
the	O
patient	O
'	O
s	O
clothes	O
covering	O
the	O
region	O
of	O
breasts	O
and	O
ovaries	O
of	O
female	O
patients	O
and	O
the	O
testicles	O
of	O
male	O
patients	O
.	O

Several	O
positive	O
clones	O
were	O
isolated	O
,	O
one	O
of	O
which	O
encoded	O
the	O
C	O
-	O
terminal	O
253	O
amino	O
acids	O
of	O
a	O
putative	O
RNA	B-GENE
helicase	I-GENE
,	O
a	O
DEAD	B-GENE
box	I-GENE
protein	I-GENE
designated	O
DDX3	B-GENE
.	O

The	O
related	O
tumor	O
suppressor	O
,	O
p130	B-GENE
,	O
also	O
effects	O
this	O
function	O
.	O
p107	B-GENE
levels	O
increase	O
substantially	O
as	O
cells	O
progress	O
through	O
S	O
phase	O
.	O
p107	B-GENE
induction	O
of	O
E2F	B-GENE
DNA	O
binding	O
was	O
observed	O
primarily	O
in	O
S	O
phase	O
cells	O
coincident	O
with	O
the	O
increase	O
in	O
p107	B-GENE
protein	I-GENE
levels	O
.	O

We	O
conclude	O
from	O
these	O
observations	O
that	O
the	O
cTnC	B-GENE
3	I-GENE
'	I-GENE
Ile	I-GENE
element	I-GENE
is	O
a	O
composite	O
enhancer	O
that	O
functions	O
through	O
the	O
combined	O
interactions	O
of	O
at	O
least	O
five	O
regulatory	O
elements	O
and	O
their	O
cognate	O
binding	O
factors	O
:	O
three	O
or	O
four	O
E	O
-	O
boxes	O
,	O
a	O
MEF	B-GENE
-	I-GENE
2	I-GENE
site	I-GENE
,	O
and	O
a	O
MEF	B-GENE
-	I-GENE
3	I-GENE
site	I-GENE
.	O

These	O
data	O
suggest	O
that	O
the	O
secreted	O
,	O
truncated	O
receptor	O
encoded	O
by	O
the	O
2	B-GENE
.	I-GENE
6	I-GENE
-	I-GENE
kb	I-GENE
c	I-GENE
-	I-GENE
erbB	I-GENE
transcript	I-GENE
can	O
bind	O
to	O
TGF	B-GENE
alpha	I-GENE
and	O
may	O
play	O
an	O
important	O
growth	O
-	O
regulatory	O
function	O
in	O
vitro	O
.	O

In	O
this	O
paper	O
we	O
review	O
evidence	O
on	O
smoking	O
and	O
lung	O
cancer	O
among	O
Latinos	O
,	O
including	O
findings	O
from	O
several	O
unpublished	O
studies	O
and	O
technical	O
reports	O
.	O

Although	O
several	O
large	O
waterborne	O
outbreaks	O
occurred	O
during	O
the	O
past	O
decade	O
,	O
most	O
were	O
in	O
small	O
communities	O
.	O

Many	O
of	O
the	O
metabolic	O
effects	O
induced	O
by	O
thiazide	O
diuretics	O
,	O
however	O
,	O
can	O
be	O
limited	O
by	O
the	O
use	O
of	O
low	O
doses	O
.	O

Uptake	O
of	O
colicins	B-GENE
required	O
different	O
domains	O
in	O
TonB	B-GENE
,	O
for	O
colicin	B-GENE
B	I-GENE
and	I-GENE
M	I-GENE
around	O
residue	O
160	O
and	O
for	O
colicin	B-GENE
Ia	I-GENE
,	O
a	O
domain	O
closer	O
to	O
the	O
C	O
-	O
terminal	O
end	O
.	O

A	O
phase	O
II	O
study	O
of	O
interferon	B-GENE
-	I-GENE
alpha	I-GENE
,	O
interleukin	B-GENE
-	I-GENE
2	I-GENE
and	O
5	O
-	O
fluorouracil	O
in	O
advanced	O
renal	O
carcinoma	O
:	O
clinical	O
data	O
and	O
laboratory	O
evidence	O
of	O
protease	O
activation	O
.	O

Three	O
putative	O
ORFs	O
have	O
significant	O
homology	O
with	O
known	O
proteins	O
:	O
L0968	B-GENE
is	O
a	O
new	O
member	O
of	O
the	O
very	O
large	O
'	B-GENE
seripauperins	I-GENE
'	I-GENE
family	O
,	O
comprising	O
at	O
least	O
20	O
yeast	O
members	O
;	O
L1313	B-GENE
is	O
a	O
new	O
ABC	B-GENE
transporter	I-GENE
highly	O
homologous	O
to	O
the	O
yeast	O
cadmium	O
resistance	O
protein	O
Ycf1p	B-GENE
and	O
to	O
the	O
human	B-GENE
multidrug	I-GENE
resistance	I-GENE
protein	I-GENE
hMRP1	B-GENE
;	O
the	O
C	O
-	O
terminal	O
part	O
of	O
L1325	B-GENE
present	O
in	O
our	O
sequence	O
is	O
very	O
homologous	O
to	O
the	O
fruit	O
fly	O
abdominal	O
segment	O
formation	O
protein	O
Pumilio	B-GENE
.	O

Previously	O
,	O
we	O
reported	O
the	O
identification	O
of	O
a	O
23	O
-	O
kD	O
protein	O
that	O
interacts	O
with	O
zyxin	B-GENE
in	O
vitro	O
(	O
Sadler	O
et	O
al	O
.	O
,	O
1992	O
)	O
.	O

Most	O
significantly	O
,	O
the	O
cyclin	B-GENE
E	I-GENE
-	O
Cdk2	B-GENE
complex	O
is	O
maximally	O
active	O
at	O
the	O
G1	O
/	O
S	O
transition	O
,	O
and	O
overexpression	O
of	O
cyclin	B-GENE
E	I-GENE
decreases	O
the	O
time	O
it	O
takes	O
the	O
cell	O
to	O
complete	O
G1	O
and	O
enter	O
S	O
phase	O
.	O

In	O
this	O
report	O
,	O
we	O
demonstrate	O
that	O
FRS2	B-GENE
forms	O
a	O
complex	O
with	O
the	O
N	B-GENE
-	I-GENE
terminal	I-GENE
SH2	I-GENE
domain	I-GENE
of	O
the	O
protein	B-GENE
tyrosine	I-GENE
phosphatase	I-GENE
Shp2	I-GENE
in	O
response	O
to	O
FGF	B-GENE
stimulation	O
.	O

In	O
static	O
conditions	O
,	O
body	O
sway	O
was	O
assessed	O
using	O
a	O
conventional	O
force	O
platform	O
with	O
eyes	O
open	O
and	O
with	O
eyes	O
closed	O
.	O

Antiserum	O
raised	O
against	O
rat	B-GENE
liver	I-GENE
S6	I-GENE
kinase	I-GENE
specifically	O
immunoprecipitates	O
the	O
purified	O
32P	O
-	O
labeled	O
H4	O
hepatoma	O
insulin	O
-	O
stimulated	O
S6	B-GENE
kinase	I-GENE
.	O

In	O
vitro	O
,	O
SHIP	B-GENE
catalyzes	O
the	O
conversion	O
of	O
the	O
phosphoinositide	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
(	O
PI3K	B-GENE
)	O
product	O
phosphatidylinositol	O
3	O
,	O
4	O
,	O
5	O
-	O
trisphosphate	O
(	O
PIP3	O
)	O
into	O
phosphatidylinositol	O
3	O
,	O
4	O
-	O
bisphosphate	O
.	O

A	O
species	O
comparison	O
of	O
cDNA	O
sequences	O
and	O
isolation	O
of	O
a	O
genomic	O
clone	O
.	O

The	O
study	O
of	O
the	O
intensity	O
of	O
pain	O
evoked	O
by	O
heat	O
is	O
relatively	O
exhaustive	O
:	O
the	O
influence	O
of	O
various	O
local	O
,	O
stimulus	O
-	O
dependent	O
or	O
general	O
factors	O
upon	O
threshold	O
values	O
has	O
been	O
well	O
studied	O
,	O
as	O
has	O
the	O
relation	O
between	O
pain	O
and	O
stimulus	O
intensities	O
.	O

However	O
,	O
they	O
had	O
no	O
cross	O
-	O
resistance	O
to	O
quinolone	O
,	O
josamycin	O
and	O
tylosin	O
.	O

A	O
search	O
was	O
conducted	O
for	O
suppressors	O
of	O
the	O
inositol	O
auxotrophic	O
phenotype	O
of	O
the	O
ino4	B-GENE
-	I-GENE
8	I-GENE
mutant	I-GENE
of	O
yeast	O
.	O

Diabetic	O
osteopathy	O
.	O

A	O
simple	O
technique	O
for	O
obtaining	O
ultra	O
-	O
thin	O
sections	O
of	O
coccidian	O
oocysts	O
is	O
reported	O
.	O

These	O
data	O
,	O
taken	O
together	O
,	O
suggest	O
that	O
CRF	B-GENE
produces	O
its	O
behavioral	O
activating	O
and	O
anxiogenic	O
effects	O
,	O
at	O
least	O
in	O
part	O
,	O
by	O
increasing	O
the	O
activity	O
of	O
LC	O
noradrenergic	O
neurons	O
.	O

Moyamoya	O
is	O
an	O
intriguing	O
and	O
controversial	O
syndrome	O
.	O

An	O
ethnic	O
analysis	O
was	O
made	O
of	O
8947	O
cases	O
of	O
primary	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
tumors	O
seen	O
at	O
the	O
Armed	O
Forces	O
Institute	O
of	O
Pathology	O
(	O
AFIP	O
)	O
,	O
Washington	O
,	O
DC	O
,	O
from	O
1971	O
to	O
1985	O
.	O

SN	O
-	O
38	O
rebound	O
concentrations	O
were	O
observed	O
in	O
many	O
courses	O
at	O
about	O
0	O
.	O
5	O
to	O
1	O
hour	O
following	O
the	O
end	O
of	O
the	O
i	O
.	O
v	O
.	O
infusion	O
,	O
which	O
is	O
suggestive	O
of	O
enterohepatic	O
recycling	O
.	O

Kondo	O
effect	O
in	O
Cu	O
(	O
Fe	O
)	O
films	O
.	O

The	O
S3	B-GENE
protein	I-GENE
also	O
contains	O
a	O
DNA	O
repair	O
activity	O
,	O
efficiently	O
processing	O
8	O
-	O
oxoguanine	O
residues	O
in	O
DNA	O
via	O
an	O
N	B-GENE
-	I-GENE
glycosylase	I-GENE
/	O
apurinic	B-GENE
-	I-GENE
apyrimidinic	I-GENE
(	I-GENE
AP	I-GENE
)	I-GENE
lyase	I-GENE
activity	O
.	O

The	O
orf2	O
gene	O
product	O
is	O
a	O
protein	O
of	O
79	O
amino	O
acids	O
with	O
characteristics	O
similar	O
to	O
those	O
of	O
the	O
Tat	B-GENE
(	O
transactivator	B-GENE
)	O
proteins	O
of	O
the	O
ungulate	O
lentiviruses	O
.	O

This	O
paper	O
describes	O
a	O
longitudinal	O
study	O
in	O
which	O
clinical	O
parameters	O
and	O
aspartate	B-GENE
aminotransferase	I-GENE
(	O
AST	B-GENE
)	O
in	O
gingival	O
crevicular	O
fluid	O
(	O
GCF	O
)	O
were	O
monitored	O
bimonthly	O
over	O
a	O
6	O
-	O
12	O
months	O
period	O
in	O
970	O
sites	O
from	O
7	O
treated	O
periodontitis	O
patients	O
.	O

Our	O
results	O
show	O
that	O
unlike	O
the	O
case	O
for	O
sos1	B-GENE
,	O
sos2	B-GENE
gene	I-GENE
function	O
is	O
dispensable	O
for	O
normal	O
mouse	O
development	O
,	O
growth	O
,	O
and	O
fertility	O
.	O

This	O
finding	O
is	O
of	O
importance	O
because	O
it	O
completes	O
an	O
explanation	O
for	O
central	O
near	O
-	O
location	O
errors	O
in	O
the	O
partial	O
-	O
report	O
bar	O
-	O
probe	O
task	O
.	O

Patients	O
were	O
treated	O
with	O
either	O
4	O
.	O
8	O
million	O
units	O
of	O
procaine	O
penicillin	O
with	O
1	O
g	O
probenecid	O
,	O
3	O
.	O
5	O
or	O
4	O
.	O
5	O
g	O
of	O
ampicillin	O
with	O
1	O
g	O
probenecid	O
,	O
or	O
9	O
.	O
5	O
g	O
of	O
tetracycline	O
given	O
over	O
4	O
days	O
.	O

Here	O
,	O
we	O
analyzed	O
the	O
interaction	O
of	O
the	O
Lactococcus	B-GENE
lactis	I-GENE
Ll	I-GENE
.	I-GENE
LtrB	I-GENE
group	I-GENE
II	I-GENE
intron	I-GENE
endonuclease	I-GENE
with	O
its	O
DNA	O
target	O
site	O
by	O
DNA	O
footprinting	O
and	O
modification	O
-	O
interference	O
approaches	O
.	O

Treatment	O
of	O
JEA2	O
cells	O
with	O
interleukin	B-GENE
(	I-GENE
IL	I-GENE
)	I-GENE
-	I-GENE
7	I-GENE
induces	O
CBLB	B-GENE
phosphorylation	O
as	O
well	O
.	O

Plasmid	O
pNK21	O
,	O
in	O
which	O
2	O
.	O
05	O
-	O
kb	O
sequence	O
covering	O
the	O
region	O
encoding	O
the	O
nitrilase	B-GENE
was	O
was	O
placed	O
under	O
the	O
control	O
of	O
the	O
lac	B-GENE
promoter	I-GENE
,	O
directed	O
overproduction	O
of	O
enzymatically	B-GENE
active	I-GENE
nitrilase	I-GENE
in	O
response	O
to	O
addition	O
of	O
isopropyl	O
beta	O
-	O
D	O
-	O
thiogalactopyranoside	O
in	O
Escherichia	O
coli	O
.	O

Penicillamine	O
-	O
induced	O
myasthenia	O
gravis	O
associated	O
with	O
antibodies	O
to	O
acetylcholine	B-GENE
receptor	I-GENE
.	O

UV	O
cross	O
-	O
linking	O
and	O
Southwestern	O
analysis	O
suggested	O
that	O
KTP1	B-GENE
is	O
a	O
DNA	O
-	O
binding	O
protein	O
clearly	O
distinct	O
from	O
AP2	B-GENE
,	O
and	O
this	O
protein	O
may	O
be	O
responsible	O
for	O
the	O
basal	O
keratinocyte	O
-	O
specific	O
expression	O
of	O
the	O
BPAG1	B-GENE
gene	I-GENE
.	O

In	O
frozen	O
sections	O
the	O
spots	O
appear	O
as	O
blue	O
labelled	O
neurones	O
with	O
a	O
light	O
microscope	O
,	O
or	O
as	O
a	O
brilliant	O
red	O
neurones	O
surrounded	O
by	O
reddish	O
tissue	O
with	O
a	O
fluorescence	O
microscope	O
.	O

CONCLUSIONS	O
:	O
Elevation	O
of	O
TBARS	O
and	O
decrease	O
of	O
GSH	O
show	O
the	O
presence	O
of	O
oxidative	O
stress	O
during	O
the	O
PFD	O
treatment	O
with	O
hemodiafilter	O
SG3	O
.	O

Like	O
the	O
DMA	B-GENE
,	O
but	O
unlike	O
all	O
other	O
mammalian	B-GENE
class	I-GENE
II	I-GENE
A	I-GENE
genes	I-GENE
,	O
the	O
zebrafish	O
gene	O
codes	O
for	O
two	O
cysteine	O
residues	O
which	O
might	O
potentially	O
be	O
involved	O
in	O
the	O
formation	O
of	O
a	O
disulfide	O
bond	O
in	O
the	O
alpha	O
1	O
domain	O
.	O

For	O
any	O
given	O
age	O
,	O
high	O
-	O
stressed	O
plantaris	O
tendons	O
were	O
of	O
a	O
higher	O
fatigue	O
quality	O
than	O
low	O
-	O
stressed	O
extensor	O
tendons	O
.	O

A	O
mutated	B-GENE
ABF1	I-GENE
site	I-GENE
that	O
displays	O
a	O
very	O
low	O
affinity	O
for	O
ABF1	B-GENE
does	O
not	O
functionally	O
replace	O
the	O
ILV1	B-GENE
REB1	B-GENE
site	I-GENE
.	O

It	O
is	O
of	O
interest	O
that	O
,	O
aside	O
from	O
starvation	O
,	O
the	O
nutrition	O
catastrophes	O
of	O
the	O
past	O
,	O
including	O
scurvy	O
(	O
vitamin	O
C	O
deficiency	O
)	O
resulting	O
from	O
lack	O
of	O
fresh	O
vegetables	O
and	O
fruit	O
and	O
beriberi	O
(	O
vitamin	O
B1	O
deficiency	O
)	O
from	O
consumption	O
of	O
polished	O
rice	O
,	O
are	O
forgotten	O
and	O
only	O
of	O
interest	O
as	O
history	O
.	O

In	O
contrast	O
,	O
overexpression	O
of	O
the	O
DREB2A	B-GENE
cDNA	I-GENE
induced	O
weak	O
expression	O
of	O
the	O
target	O
genes	O
under	O
unstressed	O
conditions	O
and	O
caused	O
growth	O
retardation	O
of	O
the	O
transgenic	O
plants	O
.	O

In	O
vitro	O
,	O
c	B-GENE
-	I-GENE
Src	I-GENE
phosphorylated	O
FAK	B-GENE
Tyr	I-GENE
-	I-GENE
925	I-GENE
in	O
a	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
-	O
FAK	B-GENE
C	O
-	O
terminal	O
domain	O
fusion	O
protein	O
,	O
whereas	O
FAK	O
did	O
not	O
.	O

The	O
aetiology	O
and	O
management	O
of	O
diabetic	O
impotence	O
is	O
well	O
-	O
documented	O
;	O
the	O
effects	O
of	O
diabetes	O
on	O
female	O
sexuality	O
are	O
not	O
so	O
clear	O
.	O

The	O
percentage	O
distribution	O
of	O
types	O
of	O
fixation	O
disparity	O
curves	O
was	O
found	O
to	O
be	O
similar	O
to	O
some	O
previous	O
studies	O
,	O
with	O
a	O
higher	O
prevalence	O
of	O
Type	O
I	O
curve	O
(	O
64	O
.	O
3	O
%	O
)	O
,	O
followed	O
by	O
Type	O
II	O
(	O
28	O
.	O
6	O
%	O
)	O
and	O
Type	O
III	O
(	O
7	O
.	O
1	O
%	O
)	O
curves	O
.	O

1	O
.	O
23	O
)	O
as	O
a	O
PPARalpha	B-GENE
-	I-GENE
interacting	I-GENE
protein	I-GENE
.	O

Reading	O
disability	O
in	O
twins	O
.	O

Analysis	O
of	O
the	O
5	O
'	O
and	O
3	O
'	O
termini	O
of	O
the	O
transcripts	O
produced	O
in	O
vivo	O
from	O
the	O
puf	B-GENE
operon	I-GENE
of	I-GENE
R	I-GENE
.	I-GENE
sphaeroides	I-GENE
PUF	B-GENE
delta	I-GENE
348	I-GENE
-	I-GENE
420	I-GENE
(	O
three	O
transcripts	O
;	O
0	O
.	O
59	O
,	O
0	O
.	O
64	O
,	O
and	O
2	O
.	O
63	O
kilobases	O
)	O
lacking	O
the	O
puf	O
-	O
intercistronic	O
terminator	O
structure	O
were	O
identical	O
to	O
those	O
of	O
the	O
corresponding	O
puf	B-GENE
transcripts	I-GENE
derived	O
from	O
wild	O
-	O
type	O
R	O
.	O
sphaeroides	O
2	O
.	O
4	O
.	O
1	O
(	O
four	O
transcripts	O
;	O
0	O
.	O
50	O
,	O
0	O
.	O
66	O
,	O
0	O
.	O
71	O
,	O
and	O
2	O
.	O
7	O
kilobases	O
)	O
showing	O
that	O
the	O
transcripts	O
begin	O
and	O
end	O
at	O
the	O
same	O
sites	O
.	O

The	O
mean	O
amount	O
of	O
blood	O
loss	O
prior	O
to	O
time	O
of	O
injection	O
was	O
4	O
.	O
5	O
units	O
(	O
a	O
range	O
of	O
3	O
to	O
10	O
units	O
)	O
.	O

Several	O
of	O
the	O
drugs	O
used	O
in	O
the	O
management	O
of	O
MAC	O
have	O
been	O
associated	O
with	O
significant	O
drug	O
interactions	O
involving	O
the	O
cytochrome	B-GENE
P450	I-GENE
(	O
CYP	B-GENE
)	O
enzyme	O
system	O
.	O

Therapy	O
and	O
prevention	O
of	O
irreversible	O
shock	O
with	O
pharmacological	O
doses	O
of	O
some	O
corticosteroids	O

Suppression	O
of	O
the	O
cka1	B-GENE
delta	I-GENE
cka2	I-GENE
-	I-GENE
8	I-GENE
mutant	I-GENE
phenotype	O
occurs	O
by	O
interaction	O
of	O
CKB1	B-GENE
with	O
the	O
defective	O
,	O
cka2	B-GENE
-	I-GENE
8	I-GENE
-	O
encoded	O
,	O
catalytic	O
subunit	O
.	O

Historically	O
,	O
Cyps	B-GENE
were	O
first	O
identified	O
by	O
their	O
ability	O
to	O
bind	O
the	O
immunosuppressive	O
agent	O
cyclosporin	O
A	O
(	O
CsA	O
)	O
with	O
high	O
affinity	O
;	O
they	O
later	O
were	O
found	O
to	O
have	O
peptidyl	B-GENE
-	I-GENE
prolyl	I-GENE
cis	I-GENE
-	I-GENE
trans	I-GENE
isomerase	I-GENE
(	O
PPIase	B-GENE
)	O
activity	O
,	O
which	O
catalyzes	O
the	O
folding	O
of	O
oligopeptides	O
at	O
proline	O
-	O
peptide	O
bonds	O
in	O
vitro	O
and	O
may	O
be	O
important	O
for	O
protein	O
folding	O
in	O
vivo	O
.	O

Reduced	O
glutathione	O
in	O
whole	O
blood	O
decreases	O
within	O
a	O
blood	O
Se	O
range	O
of	O
1	O
.	O
01	O
to	O
2	O
.	O
28	O
micrograms	O
in	O
the	O
high	O
Se	O
area	O
.	O

Promoter	O
elements	O
and	O
transcriptional	O
control	O
of	O
the	O
mouse	B-GENE
acetylcholinesterase	I-GENE
gene	I-GENE
.	O

To	O
our	O
knowledge	O
108	O
cases	O
of	O
EAT	O
treated	O
by	O
catheter	O
ablation	O
of	O
the	O
ectopic	O
focus	O
are	O
reported	O
in	O
the	O
literature	O
with	O
a	O
success	O
rate	O
superior	O
to	O
90	O
%	O
.	O

The	O
authors	O
report	O
two	O
cases	O
of	O
orbital	O
cavernous	O
hemangioma	O
diagnosed	O
by	O
Tc	O
-	O
99m	O
RBC	O
SPECT	O
.	O

250	O
,	O
302	O
-	O
311	O
]	O
.	O

Arterial	O
compliance	O
measurements	O
using	O
intraarterial	O
pulse	O
contour	O
analysis	O
and	O
a	O
modified	O
Windkessel	O
model	O
were	O
carried	O
out	O
in	O
19	O
patients	O
with	O
isolated	O
systolic	O
hypertension	O
(	O
>	O
or	O
=	O
160	O
/	O
<	O
or	O
=	O
90	O
mm	O
Hg	O
)	O
and	O
compared	O
to	O
measurements	O
in	O
29	O
patients	O
with	O
essential	O
hypertension	O
(	O
diastolic	O
blood	O
pressure	O
[	O
BP	O
]	O
>	O
or	O
=	O
95	O
mm	O
Hg	O
)	O
and	O
47	O
normotensive	O
control	O
subjects	O
.	O

The	O
relationship	O
between	O
CSF	B-GENE
somatostatin	I-GENE
and	O
peripheral	O
thyroid	O
hormones	O
was	O
assessed	O
in	O
11	O
affectively	O
ill	O
patients	O
before	O
and	O
during	O
carbamazepine	O
treatment	O
.	O

Based	O
on	O
the	O
requirement	O
for	O
CREM	B-GENE
/	O
ICER	B-GENE
and	O
Rad6B	B-GENE
proteins	I-GENE
in	O
spermatogenesis	O
,	O
we	O
determined	O
expression	O
of	O
Cdc34	B-GENE
,	O
Rad6B	B-GENE
,	O
CREM	B-GENE
/	O
ICER	B-GENE
isoforms	O
,	O
and	O
the	O
Skp1	B-GENE
-	O
Cullin	B-GENE
-	O
F	O
-	O
box	O
ubiquitin	B-GENE
protein	O
ligase	O
subunits	O
Cul	B-GENE
-	I-GENE
1	I-GENE
and	O
Cul	B-GENE
-	I-GENE
2	I-GENE
,	O
which	O
are	O
associated	O
with	O
Cdc34	B-GENE
activity	O
during	O
murine	O
testicular	O
development	O
.	O

Since	O
the	O
early	O
1900s	O
,	O
a	O
genetic	O
hypothesis	O
has	O
been	O
suggested	O
.	O

Kettin	B-GENE
is	O
a	O
large	O
modular	O
protein	O
associated	O
with	O
thin	O
filaments	O
in	O
the	O
Z	O
-	O
disc	O
region	O
of	O
insect	O
muscles	O
.	O

To	O
probe	O
the	O
inter	O
-	O
relationship	O
between	O
the	O
virion	O
-	O
anchoring	O
function	O
and	O
the	O
oligomerization	O
function	O
,	O
we	O
constructed	O
two	O
serotype	O
3	O
(	O
T3	O
)	O
sigma	B-GENE
1	I-GENE
deletion	O
mutants	O
in	O
SV40	O
expression	O
vectors	O
,	O
one	O
lacking	O
the	O
hydrophobic	O
tail	O
and	O
the	O
hinge	O
,	O
and	O
the	O
other	O
lacking	O
an	O
adjacent	O
region	O
which	O
constituted	O
part	O
of	O
the	O
coiled	O
-	O
coil	O
.	O

This	O
is	O
the	O
first	O
description	O
of	O
an	O
integron	O
located	O
on	O
a	O
composite	O
transposon	O
.	O

By	O
means	O
of	O
early	O
detection	O
and	O
correction	O
of	O
the	O
possible	O
causes	O
,	O
the	O
goal	O
of	O
increasing	O
therapeutic	O
efficacy	O
can	O
be	O
achieved	O
.	O

METHODS	O
:	O
Single	O
white	O
flash	O
ERG	O
,	O
photopic	O
ERG	O
,	O
scotopic	O
ERG	O
and	O
flicker	O
ERG	O
were	O
recorded	O
in	O
30	O
cases	O
of	O
unilateral	O
CRVO	O
.	O

RESULT	O
(	O
S	O
)	O
:	O
A	O
prospective	O
study	O
was	O
conducted	O
with	O
44	O
cycles	O
for	O
34	O
couples	O
with	O
nafarelin	O
acetate	O
(	O
group	O
1	O
)	O
and	O
47	O
cycles	O
for	O
40	O
couples	O
with	O
buserelin	O
acetate	O
(	O
group	O
2	O
)	O
with	O
a	O
long	O
IVF	O
protocol	O
;	O
68	O
cycles	O
for	O
46	O
couples	O
with	O
nafarelin	O
acetate	O
(	O
group	O
3	O
)	O
and	O
56	O
cycles	O
for	O
39	O
couples	O
with	O
buserelin	O
acetate	O
(	O
group	O
4	O
)	O
with	O
a	O
short	O
IVF	O
protocol	O
;	O
39	O
cycles	O
for	O
32	O
couples	O
with	O
nafarelin	O
acetate	O
(	O
group	O
5	O
)	O
and	O
50	O
cycles	O
for	O
30	O
couples	O
with	O
buserelin	O
acetate	O
(	O
group	O
6	O
)	O
with	O
a	O
long	O
ICSI	O
protocol	O
;	O
and	O
87	O
cycles	O
for	O
60	O
couples	O
with	O
nafarelin	O
acetate	O
(	O
group	O
7	O
)	O
and	O
81	O
cycles	O
for	O
61	O
couples	O
with	O
buserelin	O
acetate	O
(	O
group	O
8	O
)	O
with	O
a	O
short	O
ICSI	O
protocol	O
.	O

Mutations	O
in	O
the	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
gene	I-GENE
result	O
in	O
the	O
lysosomal	O
storage	O
disorders	O
GM1	O
-	O
gangliosidosis	O
and	O
Morquio	O
B	O
syndrome	O
.	O

Angiographic	O
follow	O
-	O
up	O
was	O
obtained	O
in	O
92	O
%	O
of	O
patients	O
with	O
a	O
primary	O
success	O
of	O
angioplasty	O
.	O

However	O
,	O
it	O
is	O
only	O
loosely	O
associated	O
,	O
or	O
not	O
associated	O
,	O
with	O
viral	O
particles	O
.	O
gp170	B-GENE
is	O
generated	O
by	O
an	O
alternatively	O
spliced	O
Env	B-GENE
mRNA	I-GENE
using	O
a	O
splice	O
donor	O
and	O
splice	O
acceptor	O
pair	O
localized	O
within	O
the	O
env	B-GENE
open	I-GENE
reading	I-GENE
frame	I-GENE
(	I-GENE
ORF	I-GENE
)	I-GENE
,	O
which	O
is	O
normally	O
used	O
to	O
generate	O
Bell	B-GENE
and	O
Bet	B-GENE
transcripts	I-GENE
derived	O
from	O
the	O
internal	O
promoter	O
within	O
the	O
env	B-GENE
ORF	I-GENE
.	O
gp170	B-GENE
is	O
expressed	O
at	O
a	O
level	O
30	O
to	O
50	O
%	O
of	O
the	O
Env	B-GENE
precursor	I-GENE
gp130	B-GENE
.	O

They	O
are	O
both	O
insensitive	O
to	O
inhibitors	O
of	O
serine	B-GENE
and	I-GENE
aspartyl	I-GENE
proteinases	I-GENE
but	O
are	O
sensitive	O
to	O
sulfhydryl	O
reagents	O
and	O
0	O
.	O
5	O
mM	O
ZnCl2	O
.	O

The	O
Brassica	B-GENE
BTH1	I-GENE
gene	I-GENE
may	O
correspond	O
to	O
the	O
Arabidopsis	B-GENE
TH	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
.	O

Electron	O
microscopic	O
visualization	O
of	O
the	O
general	O
population	O
of	O
active	O
genes	O
in	O
flies	O
overexpressing	O
hnRNP	B-GENE
proteins	I-GENE
also	O
indicated	O
that	O
the	O
great	O
majority	O
of	O
genes	O
seemed	O
normal	O
in	O
terms	O
of	O
cotranscriptional	O
RNA	O
processing	O
events	O
,	O
although	O
there	O
were	O
a	O
few	O
abnormalities	O
consistent	O
with	O
rare	O
exon	O
-	O
skipping	O
events	O
.	O

ESR	O
spectra	O
of	O
Er3	O
+	O
in	O
SmB6	O
single	O
crystals	O
:	O
Dynamic	O
Jahn	O
-	O
Teller	O
effect	O
in	O
a	O
mixed	O
-	O
valence	O
compound	O
.	O

T	O
.	O
infestans	O
,	O
T	O
.	O
delpontei	O
,	O
T	O
.	O
rubrovaria	O
,	O
T	O
.	O
sordida	O
,	O
T	O
.	O
guasayana	O
and	O
T	O
.	O
vitticeps	O
from	O
infestans	O
subgroup	O
and	O
T	O
.	O
pallidipennis	O
from	O
rubrofasciata	O
,	O
were	O
studied	O
.	O

When	O
the	O
same	O
single	O
-	O
amino	O
-	O
acid	O
mutations	O
were	O
directly	O
introduced	O
into	O
the	O
parental	O
PV	O
/	O
CBV4	O
-	O
2A	O
genome	O
,	O
chimeric	O
viruses	O
with	O
a	O
large	O
-	O
plaque	O
phenotype	O
and	O
a	O
wild	O
-	O
type	O
PV	O
-	O
like	O
growth	O
pattern	O
were	O
obtained	O
upon	O
transfection	O
,	O
an	O
observation	O
demonstrating	O
that	O
these	O
point	O
mutations	O
alone	O
had	O
a	O
drastic	O
effect	O
on	O
the	O
growth	O
of	O
the	O
PV	O
/	O
CBV4	O
chimeric	O
virus	O
.	O

These	O
results	O
indicate	O
that	O
the	O
2127	O
-	O
bp	O
cDNA	O
encodes	O
a	O
functional	O
feline	O
L	B-GENE
/	I-GENE
B	I-GENE
/	I-GENE
K	I-GENE
-	I-GENE
type	I-GENE
ALP	I-GENE
expressed	O
on	O
cell	O
surfaces	O
via	O
phosphatidylinositol	O
-	O
glycan	O
linkage	O
.	O

Clinical	O
experience	O
gained	O
from	O
a	O
combined	O
study	O
of	O
252Cf	O
brachytherapy	O
by	O
the	O
staff	O
-	O
members	O
of	O
the	O
Research	O
Institute	O
of	O
Medical	O
Radiology	O
,	O
USSR	O
AMS	O
,	O
was	O
generalized	O
.	O

When	O
the	O
VBP	B-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
was	O
solely	O
expressed	O
,	O
it	O
located	O
to	O
the	O
cytoplasm	O
and	O
did	O
not	O
localize	O
to	O
the	O
nucleus	O
.	O

Inhibition	O
of	O
endogenous	B-GENE
Cdk2	I-GENE
by	O
dominant	B-GENE
negative	I-GENE
Cdk2	I-GENE
attenuated	O
phosphorylation	O
of	O
Thr447	O
,	O
Thr490	O
and	O
Thr497	O
,	O
but	O
had	O
no	O
effect	O
upon	O
Ser581	O
modification	O
.	O

Treatment	O
of	O
excessive	O
bleeding	O
after	O
cardiopulmonary	O
bypass	O
was	O
based	O
on	O
an	O
algorithm	O
using	O
point	O
-	O
of	O
-	O
care	O
testing	O
with	O
whole	O
blood	B-GENE
prothrombin	I-GENE
time	O
,	O
activated	O
partial	O
thromboplastin	B-GENE
time	O
,	O
heparinase	B-GENE
activated	O
clotting	O
time	O
,	O
and	O
platelet	O
count	O
.	O

Endocarditis	O
remains	O
a	O
life	O
-	O
threatening	O
disease	O
with	O
substantial	O
morbidity	O
and	O
mortality	O
.	O

Association	O
between	O
diaphragm	O
use	O
and	O
asymptomatic	O
bacteriuria	O
.	O

The	O
high	O
prevalence	O
of	O
atrial	O
septal	O
defect	O
in	O
tetralogy	O
of	O
Fallot	O
is	O
cited	O
as	O
a	O
possible	O
analogy	O
because	O
right	O
ventricular	O
pressure	O
is	O
high	O
and	O
right	O
ventricular	O
compliance	O
is	O
low	O
from	O
birth	O
.	O

Experience	O
in	O
a	O
Kenya	O
district	O
hospital	O

Moreover	O
,	O
we	O
studied	O
the	O
relationship	O
between	O
initial	O
percentage	O
of	O
bone	O
marrow	O
plasma	O
cells	O
and	O
prognosis	O
.	O

Analysis	O
of	O
larger	O
cDNA	O
clones	O
demonstrates	O
that	O
there	O
are	O
at	O
least	O
two	O
isoforms	O
of	O
RIP14	B-GENE
that	O
differ	O
in	O
the	O
N	O
-	O
terminal	O
(	O
A	O
and	O
B	O
)	O
and	O
hinge	O
(	O
D	O
)	O
domains	O
.	O

A	O
genomic	O
clone	O
of	O
the	O
chicken	B-GENE
osteopontin	I-GENE
-	I-GENE
encoding	I-GENE
gene	I-GENE
(	O
opn	B-GENE
)	O
was	O
isolated	O
and	O
found	O
to	O
be	O
organized	O
as	O
follows	O
:	O
an	O
untranslated	O
5	O
'	O
exon	O
;	O
a	O
signal	O
peptide	O
;	O
a	O
recognition	O
sequence	O
for	O
phosphorylation	O
by	O
casein	B-GENE
kinase	I-GENE
II	I-GENE
;	O
a	O
domain	O
containing	O
a	O
possible	O
O	O
-	O
linkage	O
site	O
for	O
glycosylation	O
;	O
a	O
second	O
casein	B-GENE
kinase	I-GENE
II	I-GENE
phosphorylation	I-GENE
site	I-GENE
;	O
an	O
exon	O
containing	O
three	O
functional	O
regions	O
,	O
the	O
poly	O
-	O
Asp	O
sequence	O
of	O
seven	O
consecutive	O
Asp	O
residues	O
,	O
the	O
RGD	B-GENE
integrin	I-GENE
recognition	I-GENE
site	I-GENE
and	O
a	O
potential	O
N	O
-	O
linkage	O
site	O
for	O
glycosylation	O
;	O
and	O
a	O
large	O
C	O
-	O
terminal	O
exon	O
which	O
also	O
contains	O
a	O
potential	O
N	O
-	O
linkage	O
site	O
for	O
glycosylation	O
.	O

The	O
entire	O
coding	O
region	O
of	O
an	O
ovine	B-GENE
endometrial	I-GENE
oxytocin	I-GENE
receptor	I-GENE
(	O
OTR	B-GENE
)	O
cDNA	O
was	O
generated	O
by	O
PCR	O
,	O
subcloned	O
into	O
the	O
SV40	B-GENE
major	I-GENE
late	I-GENE
promoter	I-GENE
expression	O
vector	O
pSVLJ	O
and	O
transiently	O
expressed	O
in	O
Cos	O
-	O
7	O
cells	O
.	O

Copyright	O
1999	O
Academic	O
Press	O
.	O

Critical	O
review	O
of	O
tests	O
for	O
the	O
HBs	B-GENE
antigen	I-GENE
in	O
the	O
detection	O
of	O
infectious	O
blood	O

Diff	O
-	O
Quik	O
stain	O
for	O
Tzanck	O
smears	O
.	O

Disease	O
-	O
free	O
interval	O
was	O
greater	O
in	O
node	O
-	O
negative	O
Lx	O
patients	O
for	O
both	O
T1	O
(	O
P	O
less	O
than	O
0	O
.	O
007	O
)	O
and	O
T2	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
presentations	O
.	O

Deletion	O
analysis	O
defines	O
distinct	O
functional	O
domains	O
for	O
protein	O
-	O
protein	O
and	O
nucleic	O
acid	O
interactions	O
in	O
the	O
ORF1	B-GENE
protein	I-GENE
of	O
mouse	O
LINE	B-GENE
-	I-GENE
1	I-GENE
.	O

Allergen	O
-	O
stimulated	O
levels	O
of	O
PGD2	O
were	O
1274	O
+	O
/	O
-	O
565	O
versus	O
1468	O
+	O
/	O
-	O
679	O
after	O
prednisone	O
;	O
likewise	O
,	O
allergen	O
-	O
stimulated	O
5	O
-	O
HETE	O
levels	O
were	O
95	O
+	O
/	O
-	O
21	O
versus	O
82	O
+	O
/	O
-	O
21	O
;	O
those	O
of	O
LTE4	O
were	O
54	O
+	O
/	O
-	O
20	O
versus	O
91	O
+	O
/	O
-	O
51	O
;	O
and	O
those	O
of	O
15	O
-	O
HETE	O
were	O
63	O
+	O
/	O
-	O
19	O
versus	O
60	O
+	O
/	O
-	O
25	O
.	O

To	O
confirm	O
the	O
data	O
obtained	O
using	O
the	O
HPLC	O
-	O
ESI	O
-	O
MS	O
procedure	O
,	O
fractions	O
of	O
the	O
glycosides	O
from	O
four	O
berries	O
were	O
separated	O
,	O
hydrolyzed	O
,	O
silylated	O
and	O
the	O
sugars	O
were	O
analyzed	O
using	O
gas	O
chromatography	O
-	O
mass	O
spectrometry	O
.	O

Usefulness	O
of	O
computerized	O
tomography	O
in	O
hemodialysis	O
patients	O
.	O

Prevalence	O
of	O
use	O
,	O
claims	O
volume	O
,	O
and	O
expenditures	O
were	O
compared	O
for	O
cisapride	O
,	O
proton	O
pump	O
inhibitors	O
,	O
histamine	B-GENE
-	I-GENE
2	I-GENE
receptor	I-GENE
antagonists	O
,	O
and	O
the	O
prokinetic	O
agent	O
metoclopramide	O
during	O
these	O
periods	O
.	O

However	O
,	O
the	O
quasiparticle	O
scattering	O
rate	O
tau	O
(	O
-	O
1	O
)	O
is	O
such	O
that	O
Planck	O
'	O
s	O
over	O
2pi	O
/	O
tau	O
approximately	O
6t	O
(	O
perpendicular	O
)	O
,	O
implying	O
that	O
kappa	O
-	O
(	O
BEDT	O
-	O
TTF	O
)	O
2Cu	O
(	O
NCS	O
)	O
(	O
2	O
)	O
meets	O
the	O
criterion	O
used	O
to	O
identify	O
interlayer	O
incoherence	O
.	O

The	O
deduced	O
gene	O
product	O
was	O
found	O
to	O
have	O
significant	O
sequence	O
similarity	O
to	O
the	O
yeast	B-GENE
and	I-GENE
prokaryotic	I-GENE
RNA	I-GENE
polymerase	I-GENE
subunits	I-GENE
involved	O
with	O
subunit	O
assembly	O
.	O

In	O
two	O
of	O
these	O
nine	O
patients	O
,	O
a	O
decrease	O
in	O
dyskinesia	O
score	O
was	O
observed	O
without	O
a	O
concomitant	O
worsening	O
of	O
parkinsonian	O
symptoms	O
,	O
whereas	O
in	O
the	O
remaining	O
seven	O
,	O
full	O
parkinsonian	O
akinesia	O
followed	O
THDL	O
administration	O
.	O

However	O
,	O
an	O
analogous	O
myristoylated	O
peptide	O
derived	O
from	O
c	B-GENE
-	I-GENE
Yes	I-GENE
also	O
has	O
no	O
inhibitory	O
activity	O
.	O

The	O
expression	O
of	O
the	O
leukocyte	B-GENE
EL	I-GENE
-	I-GENE
246	I-GENE
antigen	I-GENE
was	O
regulated	O
in	O
the	O
same	O
manner	O
as	O
L	B-GENE
-	I-GENE
selectin	I-GENE
and	O
EL	B-GENE
-	I-GENE
246	I-GENE
recognized	O
anti	B-GENE
-	I-GENE
L	I-GENE
-	I-GENE
selectin	I-GENE
mAb	I-GENE
affinity	O
-	O
purified	O
antigen	O
in	O
SDS	O
/	O
PAGE	O
Western	O
blot	O
analysis	O
.	O

A	O
proposed	O
method	O
.	O

The	O
two	O
SH3	B-GENE
domains	I-GENE
are	O
separated	O
by	O
a	O
54	O
amino	O
acid	O
linker	O
region	O
,	O
whose	O
length	O
is	O
highly	O
conserved	O
in	O
xenopus	O
,	O
chicken	O
,	O
and	O
mamalian	B-GENE
Crk	I-GENE
II	I-GENE
proteins	I-GENE
.	O

A	O
clinical	O
trial	O
of	O
a	O
new	O
mitomycin	O
C	O
derivative	O
,	O
KW	O
-	O
2083	O
(	O
7	O
-	O
N	O
-	O
(	O
p	O
-	O
hydroxyphenyl	O
)	O
-	O
mitomycin	O
C	O
)	O

In	O
patients	O
with	O
active	O
TB	O
,	O
cytokines	O
that	O
were	O
elevated	O
in	O
serum	O
were	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
,	O
IL	B-GENE
-	I-GENE
6	I-GENE
and	O
IL	B-GENE
-	I-GENE
10	I-GENE
.	O

Overexpression	O
of	O
p50	B-GENE
in	O
transient	O
cotransfection	O
studies	O
using	O
the	O
proximal	O
CRP	B-GENE
promoter	I-GENE
(	O
-	O
125	O
/	O
+	O
9	O
)	O
linked	O
to	O
a	O
luciferase	B-GENE
reporter	I-GENE
caused	O
a	O
3	O
-	O
fold	O
increase	O
of	O
luciferase	B-GENE
activity	O
,	O
while	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
overexpression	O
caused	O
an	O
18	O
-	O
fold	O
increase	O
;	O
simultaneous	O
overexpression	O
of	O
both	O
transcription	O
factors	O
increased	O
luciferase	B-GENE
activity	O
approximately	O
600	O
-	O
fold	O
.	O

Complexities	O
in	O
the	O
host	O
-	O
pathogen	O
interactions	O
during	O
actual	O
infection	O
with	O
Gram	O
-	O
negative	O
bacteria	O
may	O
account	O
for	O
the	O
difficulties	O
in	O
demonstrating	O
this	O
phenomena	O
in	O
vivo	O
.	O

PKCI	B-GENE
-	I-GENE
1	I-GENE
is	O
a	O
member	O
of	O
the	O
HIT	B-GENE
family	I-GENE
of	O
proteins	O
,	O
shown	O
by	O
sequence	O
identity	O
to	O
be	O
conserved	O
in	O
a	O
broad	O
range	O
of	O
organisms	O
including	O
mycoplasma	O
,	O
plants	O
,	O
and	O
humans	O
.	O

6	O
,	O
320	O
cells	O
/	O
mm3	O
,	O
respectively	O
;	O
P	O
less	O
than	O
.	O
005	O
)	O
;	O
twelve	O
(	O
86	O
%	O
)	O
of	O
the	O
14	O
inmates	O
who	O
developed	O
AIDS	O
had	O
counts	O
of	O
less	O
than	O
5	O
,	O
000	O
cells	O
/	O
mm3	O
,	O
compared	O
with	O
only	O
six	O
(	O
14	O
%	O
)	O
of	O
the	O
42	O
controls	O
(	O
P	O
less	O
than	O
.	O
00001	O
)	O
.	O

Hpr1	B-GENE
forms	O
,	O
together	O
with	O
Tho2	B-GENE
,	O
Mft1	B-GENE
,	O
and	O
Thp2	B-GENE
,	O
the	O
THO	B-GENE
complex	I-GENE
,	O
which	O
controls	O
transcription	O
elongation	O
and	O
genome	O
stability	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

A	O
new	O
model	O
for	O
objective	O
assessment	O
of	O
cervical	O
ripening	O
:	O
the	O
effect	O
of	O
prostaglandin	O
E2	O
and	O
prelabor	O
contractility	O
.	O

Insulin	B-GENE
-	O
secreting	O
islet	O
-	O
cell	O
tumours	O
of	O
the	O
pancreas	O
.	O

Suprapubic	O
and	O
intravesical	O
methods	O

Previous	O
work	O
established	O
that	O
the	O
TAL1	B-GENE
proteins	I-GENE
are	O
phosphorylated	O
exclusively	O
on	O
serine	O
and	O
identified	O
Ser122	O
as	O
a	O
substrate	O
for	O
the	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
ERK	B-GENE
-	I-GENE
1	I-GENE
.	O

The	O
use	O
of	O
ALAD	B-GENE
activity	O
and	O
EP	O
as	O
cumulative	O
lead	O
exposure	O
indicators	O
is	O
suggested	O
.	O

Immunofluorescence	O
obtained	O
using	O
antibodies	O
against	O
alphaI	B-GENE
SigmaI	I-GENE
/	I-GENE
+	I-GENE
+	I-GENE
betaI	I-GENE
SigmaI	I-GENE
spectrin	I-GENE
and	O
Abl	B-GENE
tyrosine	I-GENE
kinase	I-GENE
but	O
not	O
against	O
alphaII	B-GENE
/	I-GENE
betaII	I-GENE
spectrin	I-GENE
colocalized	O
with	O
the	O
overexpressed	O
green	B-GENE
fluorescent	I-GENE
protein	I-GENE
-	O
SH3	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
.	O

CONCLUSIONS	O
:	O
The	O
present	O
study	O
showed	O
it	O
is	O
possible	O
to	O
use	O
a	O
modified	O
Stroop	O
task	O
as	O
a	O
measure	O
of	O
implicit	O
processing	O
of	O
alcohol	O
stimuli	O
.	O

Furthermore	O
,	O
the	O
rapid	O
light	O
-	O
mediated	O
increase	O
of	O
CPRF	B-GENE
proteins	I-GENE
was	O
insensitive	O
to	O
transcriptional	O
inhibitors	O
,	O
suggesting	O
that	O
a	O
post	O
-	O
transcriptional	O
mechanism	O
controls	O
CPRF	B-GENE
accumulation	O
.	O

43	O
%	O
,	O
6	O
/	O
14	O
;	O
P	O
=	O
0	O
.	O
013	O
)	O
,	O
whereas	O
,	O
in	O
RCC	O
samples	O
with	O
VHL	B-GENE
methylation	O
or	O
mutation	O
,	O
the	O
frequency	O
of	O
3p14	O
-	O
p21	O
LOH	O
did	O
not	O
differ	O
from	O
that	O
of	O
sp25	O
-	O
p26	O
(	O
72	O
%	O
,	O
18	O
/	O
25	O
vs	O
.	O

One	O
patient	O
had	O
chronic	O
dysphoria	O
and	O
one	O
encephalopatia	O
toxica	O
.	O

A	O
single	O
clone	O
,	O
which	O
was	O
conserved	O
and	O
had	O
near	O
-	O
perfect	O
homology	O
to	O
eight	O
human	O
/	O
rodent	O
expressed	O
sequence	O
tags	O
,	O
was	O
used	O
as	O
template	O
for	O
5	O
'	O
and	O
3	O
'	O
rapid	O
amplification	O
of	O
cDNA	O
ends	O
and	O
SPICE	O
(	O
system	O
for	O
polymerase	O
chain	O
reaction	O
amplification	O
of	O
cDNA	O
ends	O
)	O
reactions	O
to	O
obtain	O
the	O
3	O
.	O
6	O
-	O
kb	O
cDNA	O
,	O
LGL2	B-GENE
(	O
Genbank	B-GENE
,	I-GENE
AF	I-GENE
110195	I-GENE
)	O
encoding	O
a	O
deduced	O
polypeptide	O
(	O
lgl2	B-GENE
)	O
of	O
963	O
amino	O
acids	O
.	O

Effect	O
of	O
dimethyl	O
sulfoxide	O
on	O
cooling	O
rates	O
of	O
unrestrained	O
rats	O
.	O

The	O
GIS	O
software	O
program	O
,	O
ArcView	O
,	O
was	O
used	O
for	O
spatial	O
analysis	O
and	O
distance	O
calculations	O
.	O
chi2	O
Tests	O
were	O
used	O
to	O
compare	O
the	O
distribution	O
of	O
the	O
characteristics	O
between	O
intersection	O
and	O
midblock	O
collisions	O
.	O

We	O
have	O
analyzed	O
the	O
role	O
of	O
the	O
HU	B-GENE
protein	I-GENE
in	O
invertasome	O
assembly	O
when	O
the	O
enhancer	O
is	O
located	O
at	O
variable	O
positions	O
close	O
to	O
one	O
of	O
the	O
recombination	O
sites	O
.	O

We	O
compared	O
these	O
responses	O
for	O
six	O
hatchling	O
and	O
eight	O
adult	O
Chrysemys	O
picta	O
from	O
an	O
Ohio	O
population	O
.	O

The	O
likelihood	O
of	O
death	O
was	O
more	O
than	O
3	O
times	O
higher	O
among	O
patients	O
in	O
the	O
ERA	O
-	O
II	O
group	O
(	O
mortality	O
risk	O
ratio	O
3	O
.	O
82	O
[	O
95	O
%	O
CI	O
1	O
.	O
48	O
%	O
to	O
9	O
.	O
84	O
]	O
,	O
p	O
=	O
0	O
.	O
006	O
)	O
.	O

Pros	O
and	O
cons	O
of	O
selective	O
inhibition	O
of	O
cyclooxygenase	B-GENE
-	I-GENE
2	I-GENE
versus	O
dual	O
lipoxygenase	B-GENE
/	O
cyclooxygenase	B-GENE
inhibition	O
:	O
is	O
two	O
better	O
than	O
one	O
?	O

INTERNET	O
is	O
literally	O
a	O
world	O
of	O
data	O
,	O
dialogue	O
,	O
and	O
discourse	O
on	O
any	O
topic	O
imaginable	O
,	O
right	O
at	O
your	O
fingertips	O
.	O

Here	O
we	O
show	O
that	O
the	O
nucleotide	O
in	O
the	O
middle	O
of	O
the	O
anticodon	O
(	O
i	O
.	O
e	O
.	O
,	O
psi	O
35	O
)	O
also	O
contributes	O
to	O
the	O
suppressor	O
efficiency	O
displayed	O
by	O
cytoplasmic	B-GENE
tRNA	I-GENE
(	I-GENE
Tyr	I-GENE
)	I-GENE
.	O

We	O
established	O
that	O
,	O
in	O
unstimulated	O
lymphocytes	O
,	O
the	O
Src	B-GENE
homology	I-GENE
2	I-GENE
(	O
SH2	B-GENE
)	O
and	O
SH3	B-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
protein	I-GENE
Grb2	B-GENE
and	O
the	O
p85	B-GENE
subunit	O
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
,	O
associate	O
constitutively	O
with	O
Cbl	B-GENE
via	O
their	O
SH3	B-GENE
domains	I-GENE
.	O

In	O
addition	O
,	O
Fc	B-GENE
epsilon	I-GENE
R1	I-GENE
cross	O
-	O
linking	O
activates	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
.	O

Similarly	O
,	O
an	O
increase	O
in	O
CAT	B-GENE
expression	O
from	O
the	O
same	O
construct	O
(	O
pBLCAT	O
-	O
ENDOA	B-GENE
)	O
was	O
also	O
observed	O
in	O
7AQS2	O
.	O
1	O
cells	O
.	O

Indirect	O
determination	O
of	O
maximal	O
O2	O
consumption	O
in	O
man	O
.	O

The	O
two	O
complexes	O
were	O
detected	O
with	O
a	O
similar	O
activation	O
kinetics	O
upon	O
IL	B-GENE
-	I-GENE
4	I-GENE
stimulation	O
.	O

Although	O
the	O
occurrence	O
of	O
any	O
ventricular	O
ectopic	O
activity	O
,	O
as	O
detected	O
by	O
either	O
or	O
both	O
methods	O
,	O
was	O
common	O
,	O
the	O
incidence	O
was	O
significantly	O
higher	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
in	O
patients	O
with	O
coronary	O
heart	O
disease	O
(	O
86	O
percent	O
;	O
77	O
/	O
90	O
)	O
,	O
as	O
compared	O
to	O
that	O
in	O
normal	O
subjects	O
(	O
40	O
percent	O
;	O
12	O
/	O
30	O
)	O
.	O

The	O
frequency	O
of	O
eating	O
dark	O
-	O
meat	O
fish	O
was	O
positively	O
associated	O
with	O
serum	O
eicosapentaenoic	O
acid	O
and	O
docosahexaenoic	O
acid	O
,	O
omega3	O
fatty	O
acids	O
,	O
and	O
inversely	O
associated	O
with	O
serum	O
stearic	O
acid	O
and	O
linoleic	O
acid	O
.	O

These	O
8	B-GENE
-	I-GENE
oxoguanine	I-GENE
DNA	I-GENE
glycosylases	I-GENE
,	O
hOgg1	B-GENE
(	O
human	O
)	O
and	O
mOgg1	B-GENE
(	O
murine	O
)	O
,	O
are	O
homologous	O
to	O
each	O
other	O
and	O
to	O
yeast	B-GENE
Ogg1	I-GENE
.	O

HDE	B-GENE
was	O
found	O
to	O
be	O
exclusively	O
targeted	O
to	O
and	O
imported	O
into	O
peroxisomes	O
in	O
both	O
heterologous	O
expression	O
systems	O
.	O

Taken	O
together	O
,	O
these	O
results	O
indicate	O
that	O
ICSBP	B-GENE
and	O
PU	B-GENE
.	I-GENE
1	I-GENE
are	O
critical	O
elements	O
for	O
IL	B-GENE
-	I-GENE
18	I-GENE
gene	I-GENE
expression	O
.	O

Model	O
experiments	O
on	O
pheasants	O
using	O
single	O
doses	O
of	O
the	O
insecticide	O
(	O
Lindane	O
)	O
the	O
herbicide	O
(	O
Terbutryn	O
)	O
a	O
mineral	O
fertilizer	O
(	O
calcium	O
ammonium	O
nitrate	O
)	O
and	O
the	O
fungicide	O
(	O
HCB	O
)	O
.	O

The	O
main	O
side	O
-	O
effects	O
were	O
myelosuppression	O
,	O
mucositis	O
and	O
peripheral	O
neuropathy	O
,	O
which	O
were	O
all	O
common	O
and	O
often	O
severe	O
.	O

The	O
decision	O
support	O
system	O
uses	O
the	O
network	O
at	O
its	O
core	O
and	O
helps	O
not	O
only	O
in	O
reaching	O
a	O
diagnosis	O
but	O
also	O
in	O
finding	O
the	O
optimal	O
way	O
to	O
reach	O
that	O
diagnosis	O
.	O

Metapsychiatry	O
is	O
a	O
term	O
born	O
of	O
necessity	O
to	O
designate	O
the	O
important	O
but	O
hitherto	O
unclassified	O
interface	O
between	O
psychiatry	O
and	O
mysticism	O
.	O

Repression	O
was	O
strictly	O
dependent	O
on	O
the	O
presence	O
of	O
upstream	O
Oshox1	B-GENE
binding	O
sites	O
in	O
the	O
reporter	O
gene	O
constructs	O
and	O
a	O
function	O
of	O
the	O
N	O
-	O
terminal	O
region	O
of	O
Oshox1	B-GENE
,	O
preceding	O
the	O
homeodomain	B-GENE
.	O

Experimental	O
studies	O
and	O
clinical	O
application	O
of	O
plasma	B-GENE
ACTH	I-GENE
radioimmunoassay	O
kit	O
without	O
extraction	O
process	O

Defects	O
in	O
RT6	B-GENE
expression	O
coincide	O
with	O
increased	O
susceptibility	O
in	O
animal	O
models	O
for	O
insulin	B-GENE
-	O
dependent	O
diabetes	O
mellitus	O
and	O
other	O
autoimmune	O
diseases	O
.	O

By	O
cloning	O
genes	O
encoding	O
benzene	O
-	O
degradative	O
enzymes	O
,	O
we	O
found	O
that	O
strain	O
JS150	O
also	O
carries	O
genes	O
for	O
a	O
toluene	B-GENE
/	I-GENE
benzene	I-GENE
-	I-GENE
2	I-GENE
-	I-GENE
monooxygenase	I-GENE
.	O

Thus	O
G17	B-GENE
targets	O
the	O
c	B-GENE
-	I-GENE
fos	I-GENE
promoter	I-GENE
CArG	I-GENE
sequence	I-GENE
via	O
Rho	B-GENE
A	I-GENE
-	O
dependent	O
pathways	O
,	O
and	O
Rho	B-GENE
A	I-GENE
appears	O
to	O
play	O
an	O
important	O
role	O
in	O
the	O
regulation	O
of	O
the	O
trophic	O
action	O
of	O
G17	B-GENE
.	O

By	O
contrast	O
with	O
ama	B-GENE
-	I-GENE
1	I-GENE
,	O
rpc	B-GENE
-	I-GENE
1	I-GENE
was	O
not	O
deleted	O
by	O
mDf4	O
or	O
larger	O
deficiencies	O
examined	O
,	O
indicating	O
that	O
these	O
genes	O
are	O
no	O
closer	O
than	O
150	O
kb	O
.	O

Expression	O
of	O
the	O
bacteriophage	B-GENE
T4	I-GENE
DNA	I-GENE
terminase	I-GENE
genes	I-GENE
16	I-GENE
and	I-GENE
17	I-GENE
yields	O
multiple	O
proteins	O
.	O

Rat	B-GENE
p8	I-GENE
mRNA	I-GENE
was	O
discovered	O
because	O
of	O
its	O
strong	O
activation	O
in	O
pancreas	O
during	O
the	O
acute	O
phase	O
of	O
pancreatitis	O
.	O

Dual	O
signal	O
peptides	O
mediate	O
the	O
signal	B-GENE
recognition	I-GENE
particle	I-GENE
/	O
Sec	B-GENE
-	O
independent	O
insertion	O
of	O
a	O
thylakoid	O
membrane	O
polyprotein	O
,	O
PsbY	B-GENE
.	O

Sequence	O
divergence	O
of	O
approximately	O
16	O
%	O
reduced	O
transformation	O
frequencies	O
by	O
at	O
least	O
10	O
-	O
fold	O
.	O

During	O
subsequent	O
CS	O
-	O
alone	O
trials	O
,	O
the	O
responses	O
of	O
(	O
+	O
)	O
MK	O
-	O
801	O
-	O
injected	O
mice	O
were	O
extinguished	O
as	O
easily	O
as	O
those	O
of	O
saline	O
-	O
injected	O
mice	O
.	O

The	O
three	O
respective	O
time	O
control	O
groups	O
(	O
C5	O
,	O
C10	O
,	O
and	O
C15	O
)	O
were	O
injected	O
with	O
saline	O
solution	O
.	O

Next	O
,	O
to	O
examine	O
the	O
regulation	O
mechanism	O
of	O
CD44	B-GENE
/	O
ERM	B-GENE
interaction	O
in	O
vivo	O
,	O
we	O
reexamined	O
the	O
immunoprecipitated	O
CD44	B-GENE
/	O
ERM	B-GENE
complex	O
from	O
BHK	O
cells	O
and	O
found	O
that	O
it	O
contains	O
Rho	B-GENE
-	I-GENE
GDP	I-GENE
dissociation	I-GENE
inhibitor	I-GENE
(	O
GDI	B-GENE
)	O
,	O
a	O
regulator	O
of	O
Rho	B-GENE
GTPase	I-GENE
.	O

Ten	O
patients	O
(	O
aged	O
28	O
-	O
76	O
years	O
)	O
with	O
a	O
terminal	O
jejunostomy	O
located	O
within	O
the	O
first	O
meter	O
of	O
jejunum	O
were	O
treated	O
by	O
infusion	O
of	O
an	O
elemental	O
diet	O
into	O
the	O
distal	O
small	O
bowel	O
(	O
IEDDSB	O
)	O
.	O

The	O
illuminator	O
uses	O
a	O
grain	O
-	O
of	O
-	O
wheat	O
light	O
bulb	O
and	O
an	O
adjustable	O
bulb	O
holder	O
fashioned	O
from	O
bent	O
paper	O
clips	O
.	O

The	O
goals	O
of	O
these	O
experiments	O
were	O
to	O
determine	O
whether	O
lactational	O
anestrus	O
would	O
be	O
prolonged	O
by	O
a	O
48	O
-	O
h	O
fast	O
at	O
days	O
13	O
and	O
14	O
postpartum	O
(	O
pp	O
)	O
and	O
,	O
if	O
so	O
,	O
to	O
determine	O
whether	O
this	O
effect	O
could	O
be	O
reversed	O
by	O
treatment	O
with	O
the	O
Ob	B-GENE
protein	I-GENE
leptin	B-GENE
.	O

The	O
kinetics	O
of	O
[	O
14C	O
]	O
NG	O
in	O
the	O
blood	O
of	O
the	O
dosed	O
animals	O
was	O
followed	O
.	O

RESULTS	O
:	O
In	O
patients	O
with	O
necrotising	O
fasciitis	O
the	O
arterial	O
PO2	O
rose	O
about	O
7	O
-	O
fold	O
whereas	O
the	O
arterial	O
PCO2	O
increased	O
only	O
slightly	O
during	O
exposure	O
to	O
2	O
.	O
5	O
absolute	O
atmospheres	O
(	O
ATA	O
)	O
of	O
oxygen	O
.	O

Coronary	O
arteriographies	O
and	O
ventriculographies	O
corresponding	O
to	O
274	O
consecutive	O
patients	O
(	O
January	O
,	O
1975	O
-	O
October	O
,	O
1978	O
)	O
with	O
significant	O
coronary	O
lesions	O
are	O
reviewed	O
.	O

The	O
data	O
show	O
that	O
processing	O
time	O
as	O
a	O
function	O
of	O
intensity	O
is	O
modified	O
not	O
only	O
at	O
the	O
retina	O
but	O
also	O
at	O
later	O
processing	O
sites	O
.	O

Lag	O
phases	O
were	O
14	O
.	O
89	O
hours	O
+	O
/	O
-	O
0	O
.	O
77	O
,	O
13	O
.	O
33	O
hours	O
+	O
/	O
-	O
0	O
.	O
50	O
,	O
20	O
.	O
22	O
hours	O
+	O
/	O
-	O
0	O
.	O
76	O
,	O
and	O
20	O
.	O
00	O
hours	O
+	O
/	O
-	O
0	O
.	O
79	O
,	O
respectively	O
,	O
for	O
endothelial	O
cell	O
-	O
induced	O
LDL	B-GENE
oxidation	O
.	O

Therefore	O
,	O
the	O
Ogg1	B-GENE
protein	I-GENE
is	O
a	O
eukaryotic	O
DNA	B-GENE
glycosylase	I-GENE
/	O
AP	B-GENE
lyase	I-GENE
.	O

Being	O
implicated	O
in	O
insulin	B-GENE
and	O
GK	B-GENE
gene	I-GENE
regulations	O
as	O
a	O
common	O
transcription	O
factor	O
,	O
IPF1	B-GENE
/	O
STF	B-GENE
-	I-GENE
1	I-GENE
/	O
PDX	B-GENE
-	I-GENE
1	I-GENE
is	O
likely	O
to	O
play	O
an	O
essential	O
role	O
in	O
maintaining	O
normal	O
beta	O
-	O
cell	O
functions	O
.	O

MATERIAL	O
AND	O
METHODS	O
:	O

Salt	O
wars	O
.	O

Finally	O
,	O
synthetic	O
peptides	O
corresponding	O
to	O
the	O
mutant	O
proteins	O
were	O
assessed	O
for	O
the	O
ability	O
to	O
act	O
as	O
substrates	O
for	O
PR	B-GENE
.	O

As	O
an	O
approach	O
to	O
the	O
determination	O
of	O
structure	O
-	O
function	O
relationships	O
in	O
the	O
PRP4	B-GENE
protein	I-GENE
,	O
we	O
have	O
isolated	O
more	O
than	O
fifty	O
new	O
alleles	O
of	O
the	O
PRP4	B-GENE
gene	I-GENE
through	O
random	O
and	O
site	O
-	O
directed	O
mutagenesis	O
,	O
and	O
have	O
analyzed	O
the	O
phenotypes	O
of	O
many	O
of	O
them	O
.	O

Brainstem	O
auditory	O
evoked	O
potential	O
responses	O
(	O
BAEPs	O
)	O
were	O
recorded	O
from	O
CZ	O
-	O
A1	O
and	O
CZ	O
-	O
A2	O
scalp	O
regions	O
in	O
23	O
hypertensive	O
and	O
14	O
normotensive	O
subjects	O
.	O

Although	O
the	O
Gly252Arg	O
substitution	O
observed	O
in	O
UM	O
:	O
JG5	O
is	O
non	O
-	O
conservative	O
,	O
it	O
was	O
not	O
possible	O
to	O
distinguish	O
whether	O
it	O
is	O
a	O
mutation	O
or	O
a	O
polymorphism	O
.	O

Two	O
SH2	B-GENE
domains	I-GENE
of	O
p120	B-GENE
Ras	B-GENE
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
bind	O
synergistically	O
to	O
tyrosine	O
phosphorylated	O
p190	B-GENE
Rho	O
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
.	O
p120	B-GENE
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
(	O
GAP	B-GENE
)	O
is	O
a	O
negative	O
regulator	O
of	O
Ras	B-GENE
that	O
functions	O
at	O
a	O
key	O
relay	O
point	O
in	O
signal	O
transduction	O
pathways	O
that	O
control	O
cell	O
proliferation	O
.	O

Phosphorylation	O
of	O
the	O
ras	B-GENE
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
(	O
GAP	B-GENE
)	O
by	O
the	O
p93c	B-GENE
-	I-GENE
fes	I-GENE
protein	B-GENE
-	I-GENE
tyrosine	I-GENE
kinase	I-GENE
in	O
vitro	O
and	O
formation	O
of	O
GAP	B-GENE
-	O
fes	B-GENE
complexes	O
via	O
an	O
SH2	B-GENE
domain	O
-	O
dependent	O
mechanism	O
.	O

This	O
resulted	O
in	O
a	O
shift	O
of	O
C1	O
/	O
C2	O
,	O
so	O
that	O
the	O
effect	O
of	O
collagen	B-GENE
was	O
more	O
pronounced	O
(	O
maximal	O
increase	O
of	O
C1	O
/	O
C2	O
=	O
134	O
%	O
)	O
than	O
ADP	O
(	O
maximal	O
increase	O
of	O
C1	O
/	O
C2	O
=	O
79	O
%	O
)	O
.	O

A	O
significant	O
increase	O
of	O
gastric	O
mucosal	O
permeability	O
was	O
observed	O
in	O
six	O
normal	O
human	O
subjects	O
after	O
instillation	O
of	O
ethanol	O
(	O
20	O
percent	O
v	O
/	O
v	O
)	O
.	O

Analysis	O
of	O
domain	O
deletion	O
mutants	O
demonstrated	O
strong	O
synergy	O
between	O
the	O
RRM	O
and	O
a	O
central	O
degenerate	O
RRM	O
repeat	O
in	O
binding	O
to	O
RNA	O
.	O

Overexpression	O
of	O
eIF4E	B-GENE
transforms	O
cells	O
,	O
and	O
mutations	O
in	O
eIF4E	B-GENE
arrest	O
cells	O
in	O
G	O
,	O
in	O
cdc33	B-GENE
mutants	I-GENE
.	O

ZF87	B-GENE
specifically	O
binds	O
the	O
ME1a1	O
element	O
with	O
higher	O
affinity	O
than	O
the	O
ME1a2	O
element	O
.	O

The	O
unusual	O
properties	O
of	O
TRAC	B-GENE
activity	O
and	O
its	O
relationship	O
,	O
if	O
any	O
,	O
with	O
the	O
enigmatic	O
Ku	B-GENE
protein	I-GENE
,	O
are	O
discussed	O
.	O

Structure	O
of	O
the	O
connective	O
stroma	O
of	O
the	O
epididymis	O
in	O
the	O
zebu	O

Characterization	O
of	O
regions	O
of	O
fibronectin	B-GENE
besides	O
the	O
arginine	O
-	O
glycine	O
-	O
aspartic	O
acid	O
sequence	O
required	O
for	O
adhesive	O
function	O
of	O
the	O
cell	O
-	O
binding	O
domain	O
using	O
site	O
-	O
directed	O
mutagenesis	O
.	O

These	O
data	O
suggest	O
that	O
multiple	O
genetic	O
recombination	O
among	O
bacteriophages	O
with	O
different	O
immunities	O
took	O
place	O
to	O
generate	O
the	O
prophage	O
VT1	O
-	O
Sakai	O
.	O

Transient	O
-	O
expression	O
assay	O
analysis	O
of	O
subclones	O
of	O
pPstI	O
-	O
G	O
localized	O
the	O
trans	O
-	O
active	O
factor	O
to	O
a	O
3	B-GENE
.	I-GENE
0	I-GENE
-	I-GENE
kilobase	I-GENE
XbaI	I-GENE
fragment	I-GENE
.	O

We	O
used	O
an	O
immobilized	O
template	O
-	O
based	O
assay	O
to	O
examine	O
transcription	O
termination	O
by	O
VA1	B-GENE
,	O
7SL	B-GENE
,	O
and	O
Alu	B-GENE
class	I-GENE
III	I-GENE
templates	O
and	O
the	O
role	O
of	O
transcript	O
release	O
in	O
the	O
pol	B-GENE
III	I-GENE
terminator	O
-	O
dependent	O
inhibition	O
of	O
processing	O
of	O
B1	B-GENE
-	O
Alu	B-GENE
transcripts	O
.	O

Concentrations	O
of	O
platelet	O
nitrite	O
and	O
total	O
nitrate	O
/	O
nitrite	O
were	O
determined	O
using	O
simple	O
and	O
sensitive	O
nitrate	O
/	O
nitrite	O
fluorometric	O
assay	O
techniques	O
.	O

Using	O
a	O
GTP	O
-	O
dependent	O
,	O
brefeldin	O
A	O
-	O
sensitive	O
in	O
vitro	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	O
assay	O
,	O
we	O
have	O
determined	O
here	O
the	O
parameters	O
of	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	O
reaction	O
.	O

By	O
using	O
methanol	O
-	O
0	O
.	O
15	O
M	O
borate	O
buffer	O
of	O
pH	O
8	O
.	O
0	O
,	O
cate	B-GENE
-	I-GENE
chol	I-GENE
-	I-GENE
O	I-GENE
-	I-GENE
methyltransferase	I-GENE
activity	O
might	O
be	O
assayed	O
.	O

Replacement	O
of	O
Val20	O
-	O
Leu21	O
with	O
Ala	O
-	O
Ala	O
produced	O
a	O
dimeric	B-GENE
RII	I-GENE
beta	I-GENE
protein	I-GENE
that	O
binds	O
AKAP75	B-GENE
approximately	O
4	O
%	O
as	O
avidly	O
as	O
wild	B-GENE
-	I-GENE
type	I-GENE
RII	I-GENE
beta	I-GENE
.	O

Plasmodium	O
vivax	O
malaria	O
.	O

Postcontrast	O
images	O
were	O
also	O
acquired	O
in	O
the	O
sagittal	O
(	O
six	O
patients	O
)	O
and	O
coronal	O
(	O
three	O
patients	O
)	O
planes	O
.	O

Conservation	O
of	O
this	O
zinc	O
finger	O
motif	O
from	O
yeast	O
to	O
mouse	O
and	O
human	O
implies	O
functional	O
importance	O
.	O

In	O
vitro	O
death	O
assays	O
with	O
transient	O
overexpression	O
of	O
deletion	O
constructs	O
of	O
both	O
isoforms	O
using	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
as	O
a	O
reporter	O
gene	O
in	O
MCF7	O
cells	O
suggest	O
the	O
following	O
:	O
1	O
)	O
the	O
nucleotide	O
binding	O
domain	O
may	O
act	O
as	O
a	O
negative	O
regulator	O
of	O
the	O
killing	O
activity	O
of	O
DEFCAP	B-GENE
;	O
2	O
)	O
the	O
LRR	B-GENE
/	O
CARD	B-GENE
represents	O
a	O
putative	O
constitutively	O
active	O
inducer	O
of	O
apoptosis	O
;	O
3	O
)	O
the	O
killing	O
activity	O
of	O
LRR	B-GENE
/	O
CARD	B-GENE
is	O
inhibitable	O
by	O
benzyloxycarbonyl	O
-	O
Val	O
-	O
Ala	O
-	O
Asp	O
(	O
OMe	O
)	O
-	O
fluoromethyl	O
ketone	O
and	O
to	O
a	O
lesser	O
extent	O
by	O
Asp	O
-	O
Glu	O
-	O
Val	O
-	O
Asp	O
(	O
OMe	O
)	O
-	O
fluoromethyl	O
ketone	O
;	O
and	O
4	O
)	O
the	O
CARD	B-GENE
is	O
critical	O
for	O
killing	O
activity	O
of	O
DEFCAP	B-GENE
.	O

Here	O
,	O
we	O
provide	O
direct	O
evidence	O
that	O
the	O
meiotic	O
defect	O
caused	O
by	O
either	O
unregulated	O
cAPK	B-GENE
activity	O
or	O
unregulated	O
ran1	B-GENE
+	I-GENE
kinase	I-GENE
activity	O
is	O
due	O
to	O
inability	O
to	O
induce	O
transcription	O
of	O
the	O
mei2	B-GENE
+	I-GENE
gene	I-GENE
,	O
which	O
is	O
required	O
for	O
meiotic	O
initiation	O
.	O

Sailer	O
,	O
K	O
.	O

The	O
terminal	O
a	O
sequence	O
of	O
the	O
herpes	O
simplex	O
virus	O
genome	O
contains	O
the	O
promoter	O
of	O
a	O
gene	O
located	O
in	O
the	O
repeat	O
sequences	O
of	O
the	O
L	O
component	O
.	O

The	O
Caenorhabditis	B-GENE
elegans	I-GENE
NK	I-GENE
-	I-GENE
2	I-GENE
class	I-GENE
homeoprotein	I-GENE
CEH	I-GENE
-	I-GENE
22	I-GENE
is	O
involved	O
in	O
combinatorial	O
activation	O
of	O
gene	O
expression	O
in	O
pharyngeal	O
muscle	O
.	O

As	O
tat	B-GENE
itself	O
dramatically	O
increases	O
HIV	O
-	O
1	O
gene	O
expression	O
,	O
it	O
too	O
is	O
presumably	O
regulated	O
in	O
the	O
latent	O
state	O
,	O
and	O
may	O
also	O
be	O
activated	O
by	O
mitogenic	O
stimulation	O
.	O

The	O
CBS	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
was	O
mapped	O
to	O
human	O
chromosome	O
10p12	O
between	O
markers	O
WI	B-GENE
-	I-GENE
8535	I-GENE
and	O
WI	B-GENE
-	I-GENE
4724	I-GENE
,	O
and	O
is	O
tightly	O
linked	O
to	O
the	O
two	O
STRP	O
markers	O
of	O
D10S1789	B-GENE
and	O
D10S550	B-GENE
.	O

We	O
have	O
previously	O
described	O
the	O
partial	O
purification	O
of	O
Ap4A	B-GENE
hydrolase	I-GENE
from	O
S	O
.	O
pombe	O
[	O
Robinson	O
,	O
de	O
la	O
Pena	O
and	O
Barnes	O
(	O
1993	O
)	O
Biochim	O
.	O

Both	O
flavoproteins	O
are	O
active	O
as	O
AhpC	B-GENE
reductases	I-GENE
and	O
mediate	O
electron	O
transfer	O
,	O
resulting	O
in	O
the	O
NADH	O
-	O
dependent	O
reduction	O
of	O
hydrogen	O
peroxide	O
and	O
cumene	O
hydroperoxide	O
.	O

Together	O
,	O
these	O
results	O
indicate	O
that	O
YTS1	B-GENE
is	O
a	O
bifunctional	O
protein	O
active	O
in	O
both	O
splicing	O
and	O
protein	O
synthesis	O
.	O

The	O
first	O
operon	O
,	O
orf1	O
-	O
tolQRA	B-GENE
,	O
is	O
iron	O
regulated	O
throughout	O
growth	O
,	O
but	O
iron	O
-	O
regulated	O
expression	O
of	O
tolB	B-GENE
and	O
oprL	B-GENE
fusions	I-GENE
occurs	O
only	O
in	O
late	O
log	O
phase	O
.	O

Thus	O
,	O
STK1	B-GENE
is	O
most	O
likely	O
the	O
human	B-GENE
homologue	I-GENE
of	I-GENE
MO15	I-GENE
.	O

The	O
human	B-GENE
IFI16	I-GENE
gene	I-GENE
is	O
a	O
member	O
of	O
an	O
interferon	B-GENE
-	O
inducible	O
family	O
of	O
mouse	O
and	O
human	O
genes	O
closely	O
linked	O
on	O
syntenic	O
regions	O
of	O
chromosome	O
1	O
.	O

Late	O
results	O
in	O
the	O
treatment	O
of	O
urotuberculosis	O

Blood	O
samples	O
for	O
determination	O
of	O
fibrinolytic	O
activity	O
and	O
factor	B-GENE
VIII	I-GENE
in	O
plasma	O
were	O
obtained	O
before	O
and	O
immediately	O
after	O
the	O
end	O
of	O
compression	O
and	O
application	O
of	O
a	O
stocking	O
,	O
respectively	O
.	O

Exon	O
A1a	O
encodes	O
most	O
of	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
.	O

Methylation	O
interference	O
analysis	O
established	O
at	O
single	O
nucleotide	O
resolution	O
that	O
purified	O
recombinant	O
Fos	B-GENE
and	O
Jun	B-GENE
proteins	I-GENE
bind	O
in	O
a	O
sequence	O
-	O
specific	O
manner	O
to	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
sites	I-GENE
within	O
the	O
VDRE	O
and	O
OC	B-GENE
box	I-GENE
.	O

Also	O
,	O
PTx	B-GENE
had	O
no	O
effect	O
on	O
shear	O
-	O
dependent	O
activation	O
of	O
JNK	B-GENE
.	O

Cardiovascular	O
effects	O
in	O
man	O
of	O
intravenous	O
prizidilol	O
hydrochloride	O
(	O
SK	O
&	O
F	O
92657	O
)	O
;	O
a	O
new	O
antihypertensive	O
agent	O
.	O

The	O
human	B-GENE
p18	I-GENE
gene	I-GENE
spans	O
at	O
least	O
7	O
.	O
5	O
kb	O
and	O
is	O
composed	O
of	O
three	O
exons	O
,	O
two	O
of	O
which	O
encode	O
the	O
p18	B-GENE
protein	I-GENE
.	O

Partial	O
characterization	O
of	O
the	O
CCAAT	O
box	O
in	O
the	O
promoter	O
of	O
the	O
hLGFBP	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
:	O
interaction	O
with	O
negatively	O
acting	O
transcription	O
factors	O
in	O
decidualized	O
human	O
endometrial	O
stromal	O
cells	O
.	O

Footprints	O
on	O
the	O
HPV	B-GENE
18	I-GENE
enhancer	I-GENE
show	O
five	O
protected	O
regions	O
with	O
homologies	O
to	O
NF1	B-GENE
,	O
AP1	B-GENE
and	O
EFII	B-GENE
transcription	I-GENE
factor	I-GENE
binding	I-GENE
motifs	I-GENE
.	O

These	O
cDNAs	O
were	O
found	O
to	O
be	O
derived	O
from	O
the	O
3	O
"	O
-	O
untranslated	O
region	O
(	O
3	O
"	O
-	O
UTR	O
)	O
of	O
the	O
methyl	B-GENE
-	I-GENE
CpG	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
2	I-GENE
gene	I-GENE
(	O
MeCP2	B-GENE
)	O
.	O

A	O
simple	O
algorithm	O
fitting	O
the	O
data	O
for	O
the	O
moving	O
192Ir	O
source	O
is	O
proposed	O
.	O

Univariate	O
and	O
multivariate	O
analysis	O
was	O
used	O
to	O
calculate	O
the	O
5	O
-	O
year	O
survival	O
probabilities	O
with	O
respect	O
to	O
the	O
following	O
variables	O
:	O
age	O
(	O
<	O
or	O
=	O
65	O
,	O
>	O
65	O
)	O
,	O
sex	O
,	O
depth	O
of	O
invasion	O
(	O
mucosal	O
,	O
submucosal	O
)	O
tumor	O
location	O
(	O
upper	O
,	O
middle	O
and	O
lower	O
third	O
)	O
,	O
gross	O
appearance	O
(	O
type	O
I	O
,	O
type	O
II	O
and	O
type	O
III	O
)	O
,	O
size	O
(	O
<	O
or	O
=	O
1	O
.	O
5	O
cm	O
,	O
>	O
1	O
.	O
5	O
cm	O
)	O
,	O
presence	O
or	O
absence	O
of	O
lymph	O
node	O
metastasis	O
,	O
histological	O
type	O
(	O
intestinal	O
,	O
diffuse	O
)	O
,	O
extent	O
of	O
lymphadenectomy	O
(	O
limited	O
or	O
extended	O
)	O
,	O
and	O
type	O
of	O
gastrectomy	O
(	O
total	O
or	O
distal	O
subtotal	O
)	O
.	O

Preventing	O
the	O
heterosexual	O
spread	O
of	O
HIV	O
into	O
this	O
vulnerable	O
population	O
is	O
a	O
formidable	O
public	O
health	O
challenge	O
.	O

Carotid	O
body	O
chemoreceptor	O
activity	O
as	O
recorded	O
from	O
the	O
petrosal	O
ganglion	O
in	O
cats	O
.	O

The	O
first	O
decision	O
in	O
management	O
is	O
to	O
consider	O
cardioversion	O
which	O
can	O
be	O
achieved	O
in	O
suitable	O
cases	O
electrically	O
,	O
or	O
pharmacologically	O
with	O
a	O
class	O
Ic	O
antiarrhythmic	O
drug	O
like	O
flecainide	O
or	O
propafenone	O
.	O

Several	O
studies	O
have	O
demonstrated	O
that	O
the	O
corticotropin	B-GENE
-	I-GENE
releasing	I-GENE
factor	I-GENE
test	O
(	O
CRF	B-GENE
)	O
is	O
useful	O
for	O
the	O
aetiological	O
diagnosis	O
of	O
Cushing	O
'	O
s	O
syndrome	O
:	O
in	O
Cushing	O
'	O
s	O
disease	O
,	O
as	O
opposed	O
to	O
ectopic	O
ACTH	B-GENE
secretion	O
syndrome	O
,	O
the	O
hypothalamus	O
-	O
pituitary	O
-	O
adrenal	O
(	O
HPA	O
)	O
axis	O
can	O
still	O
be	O
stimulated	O
by	O
CRF	B-GENE
.	O

The	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
/	O
Rel	B-GENE
transcription	O
factors	O
participate	O
in	O
the	O
activation	O
of	O
immune	O
system	O
regulatory	O
genes	O
and	O
viral	B-GENE
early	I-GENE
genes	I-GENE
including	O
the	O
human	B-GENE
immunodeficiency	I-GENE
virus	I-GENE
type	I-GENE
1	I-GENE
long	I-GENE
terminal	I-GENE
repeat	I-GENE
.	O

These	O
three	O
chromosomes	O
share	O
the	O
transferrin	B-GENE
gene	I-GENE
(	O
TF	B-GENE
)	O
,	O
the	O
myosin	B-GENE
light	I-GENE
polypeptide	I-GENE
3	I-GENE
gene	I-GENE
(	O
MYL3	B-GENE
)	O
,	O
and	O
the	O
acylpeptide	B-GENE
hydrolase	I-GENE
gene	I-GENE
(	O
APEH	B-GENE
)	O
.	O

The	O
preference	O
for	O
third	O
base	O
codon	O
in	O
Y	O
position	O
prolines	O
is	O
U	O
for	O
the	O
alpha	B-GENE
2	I-GENE
(	I-GENE
VI	I-GENE
)	I-GENE
collagen	I-GENE
as	O
it	O
is	O
for	O
the	O
human	B-GENE
fibrillar	I-GENE
collagen	I-GENE
genes	I-GENE
.	O

BK	B-GENE
-	O
induced	O
translocation	O
and	O
overexpression	O
of	O
PKC	B-GENE
isoforms	I-GENE
as	O
well	O
as	O
coexpression	O
of	O
inactive	O
or	O
constitutively	O
active	O
mutants	O
of	O
different	O
PKC	B-GENE
isozymes	I-GENE
provided	O
evidence	O
for	O
a	O
role	O
of	O
the	O
diacylglycerol	O
-	O
sensitive	O
PKCs	B-GENE
alpha	I-GENE
and	I-GENE
epsilon	I-GENE
in	O
BK	B-GENE
signaling	O
toward	O
MAPK	B-GENE
.	O

The	O
rate	O
of	O
decrease	O
of	O
PRA	O
after	O
REM	O
onset	O
closely	O
approximates	O
the	O
most	O
recent	O
estimations	O
of	O
PRA	O
half	O
-	O
life	O
,	O
which	O
suggests	O
that	O
REM	O
onset	O
is	O
associated	O
with	O
a	O
virtual	O
cessation	O
in	O
renin	B-GENE
production	O
.	O

The	O
second	O
(	O
control	O
)	O
group	O
was	O
represented	O
by	O
cases	O
diagnosed	O
as	O
HSIL	O
by	O
cytology	O
.	O

Clinical	O
trial	O
endpoints	O
based	O
on	O
magnitude	O
of	O
reduction	O
in	O
HIV	O
-	O
1	O
RNA	O
levels	O
provide	O
an	O
important	O
complement	O
to	O
endpoints	O
based	O
on	O
percentage	O
of	O
patients	O
achieving	O
complete	O
virologic	O
suppression	O
.	O

The	O
psi	B-GENE
zeta	I-GENE
gene	I-GENE
has	O
a	O
nonsense	O
mutation	O
in	O
exon	O
1	O
but	O
has	O
identical	O
promoter	O
sequence	O
and	O
RNA	O
processing	O
sites	O
to	O
the	O
zeta	B-GENE
gene	I-GENE
,	O
raising	O
the	O
possibility	O
that	O
both	O
psi	B-GENE
zeta	I-GENE
and	O
zeta	B-GENE
are	O
transcriptionally	O
active	O
.	O

The	O
expression	O
of	O
cor14b	B-GENE
was	O
strongly	O
impaired	O
in	O
the	O
barley	O
albino	O
mutant	O
an	O
,	O
suggesting	O
the	O
involvement	O
of	O
a	O
plastidial	O
factor	O
in	O
the	O
control	O
of	O
gene	O
expression	O
.	O

Pulse	O
monitors	O
in	O
outpatient	O
dental	O
anaesthesia	O
.	O

Synthesis	O
of	O
2	O
-	O
(	O
2	O
'	O
-	O
thiazolyl	O
)	O
alkanebenzimidazoles	O
-	O
-	O
potential	O
anthelmintics	O

Wild	O
type	O
MEKK1	B-GENE
enhances	O
promoter	O
activity	O
and	O
the	O
activity	O
can	O
be	O
inhibited	O
by	O
dominant	O
negative	O
MEKK1	B-GENE
,	O
MEK1	B-GENE
,	O
MEK7	B-GENE
,	O
MEK3	B-GENE
,	O
p38	B-GENE
/	O
RK	B-GENE
,	O
and	O
c	B-GENE
-	I-GENE
Jun	I-GENE
.	O

Tax	B-GENE
and	O
the	O
active	O
Tax	B-GENE
mutants	I-GENE
were	O
able	O
to	O
abrogate	O
the	O
G1	O
arrest	O
and	O
apoptosis	O
induced	O
by	O
p53	B-GENE
,	O
and	O
this	O
effect	O
does	O
not	O
correlate	O
with	O
an	O
altered	O
localization	O
of	O
nuclear	B-GENE
p53	I-GENE
or	O
with	O
the	O
disruption	O
of	O
p53	B-GENE
-	I-GENE
DNA	I-GENE
complexes	I-GENE
.	O

Chronic	O
,	O
recurrent	O
multifocal	O
osteomyelitis	O
.	O

Our	O
current	O
study	O
aims	O
at	O
clarifying	O
the	O
role	O
of	O
myristoylation	O
in	O
caveolar	O
targeting	O
using	O
well	O
-	O
characterized	O
acylation	O
mutants	O
of	O
two	O
model	O
proteins	O
,	O
namely	O
Gi1	B-GENE
alpha	I-GENE
and	O
c	B-GENE
-	I-GENE
Src	I-GENE
.	O

Single	O
substitutions	O
of	O
three	O
highly	O
conserved	O
phenylalanine	O
residues	O
(	O
Phe	O
-	O
15	O
,	O
Phe	O
-	O
17	O
,	O
Phe	O
-	O
27	O
)	O
by	O
alanine	O
and	O
substitution	O
of	O
one	O
histidine	O
(	O
His	O
-	O
29	O
)	O
by	O
glutamine	O
,	O
all	O
located	O
within	O
the	O
putative	O
RNA	O
-	O
binding	O
sites	O
RNP	B-GENE
-	I-GENE
1	I-GENE
and	O
RNP	B-GENE
-	I-GENE
2	I-GENE
,	O
abolished	O
the	O
nucleic	O
acid	O
-	O
binding	O
activity	O
of	O
CspB	B-GENE
.	O

The	O
lack	O
of	O
heterozygous	O
positions	O
essentially	O
facilitates	O
on	O
the	O
one	O
hand	O
the	O
data	O
analysis	O
and	O
on	O
the	O
other	O
hand	O
the	O
detection	O
of	O
new	O
alleles	O
.	O

BACKGROUND	O
:	O
The	O
extract	O
of	O
medicinal	O
plants	O
containing	O
curcumin	O
is	O
traditionally	O
believed	O
to	O
have	O
a	O
positive	O
contraction	O
effect	O
on	O
the	O
human	O
gall	O
-	O
bladder	O
.	O

Moreover	O
,	O
the	O
formation	O
of	O
the	O
complex	O
between	O
IclR	B-GENE
and	O
the	O
operator	O
/	O
promoter	O
region	O
has	O
been	O
found	O
to	O
be	O
impaired	O
by	O
phosphoenol	O
pyruvate	O
but	O
insensitive	O
to	O
acetate	O
,	O
acetyl	O
-	O
CoA	O
,	O
pyruvate	O
,	O
and	O
oxaloacetate	O
.	O

Immunoprecipitation	O
of	O
spinophilin	B-GENE
or	O
neurabin	B-GENE
from	O
crude	O
brain	O
extracts	O
selectively	O
coprecipitated	O
PP1gamma	B-GENE
(	I-GENE
1	I-GENE
)	I-GENE
over	O
PP1beta	B-GENE
.	O

Most	O
important	O
,	O
after	O
all	O
,	O
is	O
not	O
the	O
ionization	O
technique	O
but	O
the	O
stage	O
with	O
a	O
47	O
.	O
1	O
%	O
five	O
-	O
year	O
survival	O
rate	O
in	O
T1N0	O
as	O
compared	O
to	O
T2N0	O
with	O
28	O
.	O
6	O
%	O
and	O
T1N1	O
with	O
19	O
.	O
4	O
%	O
.	O

The	O
encoded	O
Arabidopsis	B-GENE
U3	I-GENE
snRNAs	I-GENE
can	O
be	O
folded	O
into	O
a	O
secondary	O
structure	O
which	O
is	O
more	O
similar	O
to	O
that	O
of	O
U3	B-GENE
RNAs	I-GENE
from	O
lower	O
eukaryotes	O
rather	O
than	O
from	O
metazoa	O
.	O

Cytokinetics	O
of	O
the	O
Krebs	O
2	O
carcinoma	O
.	O

We	O
investigated	O
whether	O
two	O
WT1	B-GENE
splice	I-GENE
variants	I-GENE
lacking	O
or	O
including	O
a	O
three	O
-	O
amino	O
-	O
acid	O
(	O
KTS	O
)	O
insertion	O
between	O
the	O
third	O
and	O
fourth	O
zinc	O
finger	O
in	O
the	O
DNA	O
-	O
binding	O
domain	O
could	O
repress	O
the	O
IR	B-GENE
promoter	I-GENE
in	O
vitro	O
.	O

These	O
back	O
mutations	O
led	O
to	O
a	O
modest	O
decrease	O
in	O
kinase	O
activity	O
,	O
decreased	O
tumorigenic	O
potential	O
in	O
chickens	O
,	O
and	O
an	O
unexpected	O
increase	O
in	O
transforming	O
activity	O
in	O
rat	O
cells	O
.	O

Extragonadal	O
endodermal	O
sinus	O
tumors	O
in	O
the	O
head	O
and	O
neck	O
are	O
very	O
rare	O
.	O

Plasma	O
NE	O
and	O
E	O
increased	O
to	O
significantly	O
higher	O
values	O
after	O
15	O
min	O
in	O
the	O
young	O
subjects	O
:	O
1	O
.	O
68	O
+	O
/	O
-	O
0	O
.	O
18	O
vs	O
.	O

Utility	O
of	O
thallium	O
-	O
201	O
scintigraphy	O
in	O
detecting	O
right	O
ventricular	O
dysfunction	O
in	O
pulmonary	O
embolism	O
.	O

E	O
.	O
granulosus	O
infection	O
has	O
been	O
confirmed	O
in	O
25	O
patients	O
(	O
20	O
.	O
6	O
%	O
)	O
,	O
in	O
16	O
cases	O
by	O
finding	O
parasite	O
protoscoleces	O
or	O
hooks	O
and	O
in	O
nine	O
cases	O
by	O
detection	O
of	O
an	O
antigen	O
specific	O
for	O
E	B-GENE
.	I-GENE
granulosus	I-GENE
,	I-GENE
antigen	I-GENE
5	I-GENE
(	O
Ag5	B-GENE
)	O
.	O

Transcription	O
of	O
FN	B-GENE
promoter	I-GENE
-	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
fusion	O
genes	O
carrying	O
the	O
base	O
substitution	O
in	O
one	O
or	O
more	O
of	O
these	O
G	O
-	O
rich	O
sequences	O
both	O
in	O
vivo	O
and	O
in	O
vitro	O
revealed	O
that	O
the	O
base	O
substitution	O
in	O
any	O
G	O
-	O
rich	O
sequence	O
results	O
in	O
reduction	O
of	O
promoter	O
activity	O
,	O
although	O
the	O
downstream	O
GC	O
box	O
(	O
GCd	O
)	O
plays	O
a	O
primary	O
role	O
.	O

Teboroxime	O
is	O
a	O
new	O
boronic	O
acid	O
adduct	O
of	O
technetium	O
dioxime	O
(	O
BATO	O
)	O
compound	O
that	O
demonstrates	O
favorable	O
characteristics	O
in	O
preliminary	O
studies	O
.	O

We	O
tested	O
several	O
growth	O
regulatory	O
genes	O
that	O
are	O
repressed	O
in	O
senescent	O
cells	O
for	O
ability	O
to	O
restore	O
activity	O
to	O
T	B-GENE
[	I-GENE
K1	I-GENE
]	I-GENE
.	O

It	O
is	O
our	O
conclusion	O
that	O
Sonoclot	O
coagulation	O
analysis	O
is	O
unlikely	O
to	O
identify	O
patients	O
with	O
prolonged	O
bleeding	O
time	O
in	O
whom	O
platelet	O
count	O
and	O
other	O
coagulation	O
factors	O
are	O
normal	O
.	O

The	O
single	O
copy	O
flotillin	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
is	O
located	O
at	O
6p21	O
.	O
3	O
in	O
the	O
MHC	B-GENE
class	I-GENE
I	I-GENE
region	I-GENE
and	O
consists	O
of	O
13	O
exons	O
over	O
15	O
kb	O
.	O

Low	O
plasma	O
glucose	O
concentrations	O
that	O
may	O
or	O
may	O
not	O
be	O
sufficiently	O
low	O
to	O
result	O
in	O
symptoms	O
can	O
be	O
observed	O
as	O
a	O
concomitant	O
of	O
several	O
diverse	O
diseases	O
.	O

However	O
,	O
patients	O
with	O
DPX	O
should	O
be	O
observed	O
for	O
the	O
potential	O
occurrence	O
of	O
an	O
associated	O
condition	O
.	O

The	O
effects	O
of	O
castor	O
oil	O
,	O
alone	O
,	O
as	O
well	O
as	O
in	O
combination	O
with	O
PGI2	O
and	O
indomethacin	O
on	O
gastrointestinal	O
functions	O
have	O
been	O
examined	O
in	O
rats	O
.	O

Effect	O
of	O
TNF	B-GENE
,	O
IL	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
IL	B-GENE
-	I-GENE
6	I-GENE
on	O
the	O
proliferation	O
of	O
human	O
Tenon	O
'	O
s	O
capsule	O
fibroblasts	O
in	O
tissue	O
culture	O
.	O

Previous	O
analysis	O
of	O
this	O
motif	O
in	O
the	O
lactose	B-GENE
permease	I-GENE
(	O
A	O
.	O

Also	O
,	O
the	O
RVW	O
hypertrophy	O
,	O
the	O
IVS	O
hypertrophy	O
,	O
and	O
the	O
RV	O
high	O
pressure	O
load	O
to	O
the	O
LV	O
through	O
the	O
IVS	O
may	O
be	O
related	O
to	O
the	O
small	O
LV	O
,	O
high	O
EF	O
,	O
and	O
abnormal	O
two	O
chamber	O
inflow	O
in	O
the	O
PS	O
group	O
before	O
BV	O
.	O

Several	O
reports	O
assert	O
that	O
prolactin	B-GENE
affects	O
the	O
delta	O
5	O
and	O
delta	O
4	O
pathways	O
through	O
its	O
effect	O
on	O
the	O
activity	O
of	O
3beta	B-GENE
-	I-GENE
hydroxysteroid	I-GENE
dehydrogenase	I-GENE
(	O
3beta	B-GENE
-	I-GENE
OHSD	I-GENE
)	O
.	O

Acidosis	O
provoked	O
by	O
30	O
%	O
CO2	O
irreversibly	O
increased	O
the	O
BDRT	O
,	O
however	O
the	O
TRT	O
were	O
not	O
changed	O
.	O

In	O
each	O
study	O
group	O
,	O
elevated	O
levels	O
of	O
serum	O
I	O
were	O
observed	O
.	O

A	O
decrease	O
was	O
also	O
found	O
of	O
the	O
levels	O
of	O
total	O
cholesterol	O
and	O
LDL	B-GENE
-	I-GENE
cholesterol	I-GENE
.	O

Sequencing	O
of	O
this	O
fragment	O
showed	O
that	O
the	O
MRP13	B-GENE
coding	O
region	O
specifies	O
a	O
324	O
-	O
amino	O
-	O
acid	O
basic	O
protein	O
with	O
a	O
calculated	O
Mr	O
of	O
37	O
,	O
366	O
.	O

Low	O
serum	B-GENE
C3	I-GENE
values	O
were	O
observed	O
in	O
all	O
11	O
children	O
at	O
some	O
stage	O
of	O
their	O
illness	O
.	O

In	O
spite	O
of	O
the	O
presence	O
of	O
a	O
physician	O
,	O
the	O
real	O
pathology	O
of	O
an	O
indian	O
population	O
of	O
Colombie	O
is	O
not	O
very	O
well	O
known	O
.	O

During	O
chordotonal	O
organ	O
development	O
,	O
the	O
3	O
'	O
enhancer	O
directs	O
expression	O
in	O
proneural	O
clusters	O
;	O
whereas	O
successive	O
modular	O
enhancers	O
located	O
in	O
the	O
5	O
'	O
region	O
drive	O
tissue	O
-	O
specific	O
expression	O
in	O
chordotonal	O
organ	O
precursors	O
in	O
the	O
embryo	O
and	O
larval	O
leg	O
,	O
wing	O
and	O
antennal	O
imaginal	O
discs	O
.	O

Is	O
conventional	O
sperm	O
analysis	O
of	O
any	O
use	O
?	O
The	O
computerised	O
records	O
of	O
867	O
couples	O
were	O
used	O
to	O
investigate	O
the	O
prognostic	O
significance	O
of	O
semen	O
volume	O
,	O
motility	O
,	O
density	O
and	O
morphology	O
.	O

The	O
effect	O
of	O
guaiphenesin	O
on	O
absorption	O
and	O
bioavailability	O
of	O
paracetamol	O
from	O
composite	O
analgesic	O
preparations	O
.	O

Detailed	O
comparison	O
of	O
the	O
urinary	O
excretion	O
of	O
purines	O
in	O
a	O
patient	O
with	O
the	O
Lesch	O
-	O
Nyhan	O
syndrome	O
and	O
a	O
control	O
subject	O
.	O

Antisense	O
oligonucleotides	O
complementary	O
to	O
the	O
5	O
'	O
end	O
of	O
PKC	B-GENE
-	I-GENE
zeta	I-GENE
mRNA	I-GENE
sequences	I-GENE
significantly	O
reduced	O
the	O
collagen	B-GENE
lattice	O
-	O
stimulated	O
alpha2	O
and	O
MMP	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
levels	O
.	O

Furthermore	O
,	O
ERK	B-GENE
phosphorylation	O
was	O
substantially	O
prolonged	O
in	O
LC	O
/	O
BRY	O
-	O
treated	O
cells	O
compared	O
to	O
those	O
exposed	O
to	O
BRY	O
alone	O
,	O
and	O
pretreatment	O
with	O
the	O
highly	O
specific	O
MEK	B-GENE
inhibitors	O
,	O
PD98059	O
,	O
U0126	O
,	O
and	O
SL327	O
,	O
opposed	O
ERK	B-GENE
activation	O
while	O
protecting	O
cells	O
from	O
LC	O
/	O
BRY	O
-	O
induced	O
lethality	O
.	O

The	O
most	O
valid	O
method	O
was	O
the	O
AXB	O
bearing	O
with	O
the	O
cephalometric	O
clinical	O
diagnosis	O
a	O
90	O
.	O
91	O
%	O
concordance	O
.	O

However	O
,	O
coligation	O
of	O
Fc	B-GENE
gamma	I-GENE
RIIB1	I-GENE
with	O
B	B-GENE
cell	I-GENE
Ag	I-GENE
receptors	I-GENE
(	O
BCR	B-GENE
)	O
inhibits	O
BCR	B-GENE
-	O
mediated	O
signaling	O
by	O
a	O
mechanism	O
that	O
may	O
involve	O
recruitment	O
of	O
phosphatases	B-GENE
SHP	I-GENE
-	I-GENE
1	I-GENE
,	O
SHP	B-GENE
-	I-GENE
2	I-GENE
,	O
and	O
the	O
SH2	B-GENE
containing	I-GENE
inositol	I-GENE
5	I-GENE
'	I-GENE
phosphatase	I-GENE
(	O
SHIP	B-GENE
)	O
to	O
the	O
phosphorylated	O
Fc	B-GENE
gamma	I-GENE
RIIB1	I-GENE
immunoreceptor	I-GENE
tyrosine	I-GENE
-	I-GENE
based	I-GENE
inhibitory	I-GENE
motif	I-GENE
.	O

At	O
the	O
first	O
phase	O
(	O
1	O
-	O
43	O
ms	O
for	O
the	O
VMN	O
and	O
1	O
-	O
10	O
ms	O
for	O
the	O
LN	O
)	O
the	O
hypothalamic	O
-	O
cortical	O
responses	O
completely	O
inhibited	O
the	O
formation	O
of	O
the	O
VC	O
response	O
to	O
the	O
light	O
stimulus	O
.	O

The	O
slope	O
of	O
QD	O
versus	O
QEMF	O
for	O
the	O
four	O
tubes	O
was	O
near	O
unity	O
.	O

The	O
sequence	O
of	O
the	O
127	B-GENE
residue	I-GENE
NrfF	I-GENE
polypeptide	I-GENE
,	I-GENE
M	I-GENE
(	I-GENE
r	I-GENE
)	I-GENE
14	I-GENE
,	I-GENE
522	I-GENE
,	O
is	O
strikingly	O
similar	O
to	O
the	O
CcI2	B-GENE
protein	I-GENE
of	O
R	O
.	O
capsulatus	O
,	O
especially	O
in	O
the	O
putative	O
haem	O
-	O
binding	O
motif	O
,	O
RCPQCQNQN	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

When	O
cotransfected	O
with	O
the	O
HIV	B-GENE
LTR	I-GENE
CAT	B-GENE
into	O
CV	O
-	O
1	O
cells	O
,	O
both	O
the	O
pCD41	B-GENE
and	O
pGD41	B-GENE
clones	O
trans	O
-	O
activated	O
the	O
HIV	B-GENE
LTR	I-GENE
.	O

From	O
this	O
comparison	O
of	O
aa	O
sequences	O
,	O
the	O
ATPK7	B-GENE
protein	I-GENE
is	O
considered	O
to	O
be	O
a	O
member	O
of	O
a	O
novel	O
subfamily	O
of	O
Ser	B-GENE
/	I-GENE
Thr	I-GENE
PKs	I-GENE
in	O
plants	O
.	O

It	O
is	O
very	O
probable	O
that	O
this	O
change	O
was	O
due	O
to	O
mechanical	O
effects	O
induced	O
by	O
injecting	O
a	O
hypertonic	O
solution	O
of	O
MT	O
-	O
141	O
at	O
a	O
rate	O
of	O
70	O
-	O
-	O
130	O
ml	O
/	O
dog	O
.	O

Both	O
viruses	O
express	O
the	O
mil	B-GENE
/	O
raf	B-GENE
oncogene	O
product	O
as	O
a	O
gag	B-GENE
-	I-GENE
fusion	I-GENE
polyprotein	O
,	O
while	O
the	O
myc	B-GENE
oncogene	O
of	O
MH2	O
is	O
expressed	O
via	O
a	O
subgenomic	O
mRNA	O
.	O

Furthermore	O
the	O
aldosterone	O
stimulating	O
effect	O
of	O
low	O
sodium	O
diet	O
(	O
17	O
children	O
)	O
,	O
severe	O
and	O
prolonged	O
vomiting	O
(	O
19	O
children	O
)	O
and	O
synthetic	O
ACTH	B-GENE
(	O
10	O
children	O
)	O
has	O
been	O
studied	O
by	O
our	O
modified	O
method	O
.	O

Transmural	O
metabolic	O
heterogeneity	O
at	O
high	O
cardiac	O
work	O
states	O
.	O

A	O
flow	O
probe	O
for	O
direct	O
measurement	O
of	O
blood	O
flow	O
of	O
the	O
mitral	O
valve	O
was	O
devised	O
.	O

The	O
adoption	O
of	O
a	O
twisted	O
structure	O
of	O
importin	B-GENE
-	I-GENE
beta	I-GENE
is	O
essential	O
for	O
the	O
protein	O
-	O
protein	O
interaction	O
required	O
for	O
nuclear	O
transport	O
.	O

Liver	O
disease	O
and	O
HCV	O
infection	O
after	O
transplantation	O
of	O
organs	O
from	O
hepatitis	B-GENE
C	I-GENE
antibody	I-GENE
positive	O
donors	O
.	O

To	O
investigate	O
whether	O
the	O
two	O
RPG	B-GENE
-	I-GENE
boxes	I-GENE
mediate	O
transcription	O
activation	O
of	O
both	O
the	O
L46	B-GENE
and	O
S24	B-GENE
gene	I-GENE
,	O
two	O
experimental	O
strategies	O
were	O
followed	O
:	O
cloning	O
of	O
the	O
respective	O
genes	O
on	O
multicopy	O
vectors	O
and	O
construction	O
of	O
fusion	O
genes	O
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
demonstrated	O
that	O
sequences	O
within	O
this	O
region	O
bind	O
members	O
of	O
the	O
Sp1	B-GENE
family	I-GENE
of	I-GENE
transcription	I-GENE
factors	I-GENE
.	O

The	O
prevalence	O
of	O
antibodies	O
to	O
HRES	B-GENE
-	I-GENE
1	I-GENE
peptides	I-GENE
pep14	I-GENE
-	I-GENE
24	I-GENE
and	I-GENE
pep117	I-GENE
-	I-GENE
127	I-GENE
was	O
determined	O
in	O
65	O
normal	O
blood	O
donors	O
and	O
146	O
patients	O
with	O
immunological	O
disorders	O
.	O

SCOF	B-GENE
-	I-GENE
1	I-GENE
localized	O
to	O
the	O
nucleus	O
but	O
did	O
not	O
bind	O
directly	O
to	O
either	O
C	O
-	O
repeat	O
/	O
dehydration	O
(	O
CRT	O
/	O
DRE	O
)	O
or	O
ABA	O
responsive	O
element	O
(	O
ABRE	O
)	O
,	O
cis	O
-	O
acting	O
DNA	O
regulatory	O
elements	O
present	O
in	O
COR	B-GENE
gene	I-GENE
promoters	I-GENE
.	O

To	O
date	O
,	O
6	O
mammalian	O
GRKs	B-GENE
have	O
been	O
identified	O
by	O
molecular	O
cloning	O
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
fulminant	O
neuropathy	O
with	O
severe	O
quadriparesis	O
associated	O
with	O
vincristine	O
chemotherapy	O
.	O

The	O
1	O
.	O
5	O
-	O
Mb	O
region	O
was	O
covered	O
by	O
137	O
cosmids	O
with	O
a	O
minimum	O
overlap	O
set	O
of	O
52	O
cosmids	O
assigned	O
to	O
17	O
bins	O
and	O
9	O
contigs	O
.	O

Homodimers	O
of	O
RIP60	B-GENE
(	O
replication	B-GENE
initiation	I-GENE
-	I-GENE
region	I-GENE
protein	I-GENE
60	I-GENE
kDA	I-GENE
)	O
purified	O
from	O
nuclear	O
extract	O
bind	O
two	O
ATT	O
-	O
rich	O
sites	O
in	O
oribeta	O
and	O
foster	O
the	O
formation	O
of	O
a	O
twisted	O
720	O
bp	O
DNA	O
loop	O
in	O
vitro	O
.	O

Effect	O
of	O
age	O
on	O
glucose	O
,	O
reducing	O
sugars	O
and	O
plasma	B-GENE
insulin	I-GENE
in	O
blood	O
of	O
milk	O
-	O
fed	O
calves	O
.	O

Principal	O
component	O
analysis	O
using	O
psychosocial	O
factors	O
in	O
women	O
showed	O
two	O
psychosocial	O
structures	O
,	O
i	O
.	O
e	O
.	O
the	O
second	O
principal	O
(	O
high	O
SOC	O
,	O
high	O
lifestyle	O
,	O
and	O
low	O
stress	O
)	O
and	O
the	O
4th	O
principal	O
components	O
(	O
high	O
supernatural	O
HLC	O
,	O
and	O
high	O
PHLC	O
)	O
.	O

In	O
response	O
to	O
acoustical	O
stimulation	O
the	O
properties	O
of	O
response	O
latency	O
,	O
discharge	O
pattern	O
,	O
frequency	O
tuning	O
,	O
binaural	O
interaction	O
,	O
and	O
habituation	O
were	O
examined	O
to	O
allow	O
an	O
appraisal	O
of	O
the	O
differentiation	O
of	O
the	O
MGB	O
by	O
electrophysiological	O
means	O
.	O

These	O
two	O
enhancer	O
elements	O
also	O
enhanced	O
transcription	O
when	O
fused	O
separately	O
to	O
the	O
basal	O
promoter	O
region	O
of	O
the	O
chicken	B-GENE
vimentin	I-GENE
gene	I-GENE
.	O

Availability	O
of	O
a	O
less	O
palatable	O
diet	O
(	O
chow	O
)	O
following	O
presentation	O
of	O
palatable	O
diets	O
will	O
not	O
result	O
in	O
diminished	O
caloric	O
intake	O
,	O
body	O
weight	O
,	O
obesity	O
and	O
hyperinsulinemia	O
.	O

Residues	O
of	O
Stauffer	O
R	O
-	O
3828	O
and	O
its	O
oxygen	O
analogue	O
in	O
the	O
body	O
tissues	O
of	O
cattle	O
fed	O
R	O
-	O
3828	O
in	O
the	O
diet	O
.	O

Type	O
II	O
neuroleptanalgesia	O
in	O
odonto	O
-	O
stomatology	O

In	O
addition	O
,	O
there	O
was	O
an	O
increase	O
in	O
the	O
amount	O
of	O
p120	B-GENE
Ras	I-GENE
-	O
specific	O
GTPase	B-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
(	O
GAP	B-GENE
)	O
and	O
GAP	B-GENE
-	O
associated	O
p190	O
.	O

OBJECTIVE	O
:	O
Respiratory	O
-	O
related	O
electromyographic	O
(	O
EMG	O
)	O
activity	O
of	O
the	O
superior	O
pharyngeal	O
constrictor	O
(	O
SPC	O
)	O
muscle	O
was	O
analyzed	O
during	O
the	O
early	O
stage	O
of	O
forced	O
breathing	O
.	O

Glutathione	B-GENE
reductase	I-GENE
activities	O
in	O
liver	O
,	O
kidney	O
,	O
lung	O
,	O
and	O
brain	O
were	O
not	O
affected	O
by	O
diet	O
.	O

LIP	O
and	O
DIP	O
are	O
less	O
common	O
IIPs	O
,	O
both	O
characterized	O
by	O
ground	O
-	O
glass	O
attenuation	O
.	O

Healthy	O
subjects	O
received	O
the	O
following	O
regimens	O
,	O
dosed	O
to	O
steady	O
state	O
:	O
trovafloxacin	O
300	O
mg	O
/	O
24	O
h	O
;	O
ciprofloxacin	O
400	O
mg	O
/	O
12	O
h	O
;	O
trovafloxacin	O
300	O
mg	O
/	O
24	O
h	O
plus	O
cefepime	O
2	O
g	O
/	O
12	O
h	O
,	O
and	O
ciprofloxacin	O
400	O
mg	O
/	O
12	O
h	O
plus	O
cefepime	O
2	O
g	O
/	O
12	O
h	O
.	O

The	O
data	O
obtained	O
with	O
cellular	O
RNA	O
from	O
HepG2	O
cells	O
demonstrated	O
that	O
transcription	O
is	O
initiated	O
891	O
bases	O
upstream	O
of	O
the	O
translation	O
-	O
start	O
site	O
and	O
that	O
the	O
polyadenylation	O
site	O
is	O
located	O
550	O
bases	O
downstream	O
of	O
the	O
stop	O
codon	O
.	O

To	O
investigate	O
possible	O
roles	O
for	O
HCP	B-GENE
during	O
late	O
erythroid	O
differentiation	O
,	O
effects	O
of	O
manipulating	O
HCP	B-GENE
expression	O
or	O
recruitment	O
on	O
EPO	B-GENE
-	O
induced	O
hemoglobinization	O
in	O
erythroleukemic	O
SKT6	O
cells	O
have	O
been	O
investigated	O
.	O

To	O
investigate	O
the	O
role	O
of	O
bHLH	B-GENE
proteins	I-GENE
in	O
MC3T3	O
-	O
E1	O
osteoblasts	O
,	O
which	O
undergo	O
a	O
developmental	O
sequence	O
in	O
vitro	O
,	O
we	O
analyzed	O
the	O
transcriptional	O
control	O
of	O
osteocalcin	B-GENE
gene	I-GENE
expression	O
by	O
stable	O
transfection	O
of	O
an	O
osteocalcin	B-GENE
promoter	I-GENE
-	O
luciferase	B-GENE
chimeric	O
gene	O
(	O
p637OC	B-GENE
-	I-GENE
luc	I-GENE
)	O
and	O
assessed	O
the	O
role	O
of	O
E	O
-	O
box	O
cis	O
-	O
acting	O
elements	O
in	O
osteocalcin	B-GENE
promoter	I-GENE
by	O
DNA	O
binding	O
assays	O
.	O

Genetic	O
linkage	O
mapping	O
of	O
the	O
CYP11A1	B-GENE
gene	I-GENE
encoding	O
the	O
cholesterol	O
side	O
-	O
chain	O
cleavage	O
P450scc	B-GENE
close	O
to	O
the	O
CYP1A1	B-GENE
gene	I-GENE
and	O
D15S204	B-GENE
in	O
the	O
chromosome	O
15q22	O
.	O
33	O
-	O
q23	O
region	O
.	O

Expression	O
,	O
characterization	O
,	O
and	O
genomic	O
structure	O
of	O
carp	B-GENE
JAK1	I-GENE
kinase	I-GENE
gene	I-GENE
.	O

Jornvall	O
,	O
B	O
.	O

Copyright	O
1998	O
Academic	O
Press	O
.	O

Three	O
modern	O
hematology	O
analyzers	O
(	O
Abbott	O
Cell	O
-	O
Dyn	O
3000	O
,	O
Coulter	O
STKS	O
,	O
and	O
Sysmex	O
NE	O
-	O
8000	O
)	O
with	O
high	O
throughput	O
and	O
5	O
-	O
part	O
differential	O
capability	O
were	O
evaluated	O
using	O
a	O
protocol	O
designed	O
by	O
a	O
quality	O
team	O
.	O

Effect	O
of	O
prostaglandin	O
E2	O
on	O
experimental	O
atherosclerosis	O
.	O

The	O
tro	B-GENE
operon	I-GENE
is	O
flanked	O
by	O
a	O
Holliday	B-GENE
structure	I-GENE
DNA	I-GENE
helicase	I-GENE
homolog	O
(	O
upstream	O
)	O
and	O
two	O
ORFs	O
representing	O
a	O
purine	B-GENE
nucleoside	I-GENE
phosphorylase	I-GENE
homolog	O
and	O
tpp15	B-GENE
,	O
a	O
previously	O
characterized	O
gene	O
encoding	O
a	O
membrane	O
lipoprotein	O
(	O
downstream	O
)	O
.	O

However	O
,	O
a	O
few	O
sites	O
in	O
the	O
genomes	O
of	O
EC	O
cells	O
permit	O
M	B-GENE
-	I-GENE
MuLVneo	I-GENE
delta	I-GENE
Enh	I-GENE
proviral	O
expression	O
.	O

We	O
have	O
been	O
developing	O
a	O
digital	O
fluoroscopic	O
imaging	O
system	O
to	O
replace	O
the	O
portal	O
films	O
that	O
are	O
currently	O
used	O
to	O
verify	O
patient	O
positioning	O
during	O
radiotherapy	O
treatments	O
.	O

We	O
have	O
utilized	O
transient	O
transfections	O
,	O
mutation	O
analysis	O
,	O
electromobility	O
gel	O
-	O
shifts	O
,	O
and	O
immunoblot	O
analysis	O
to	O
test	O
the	O
hypothesis	O
that	O
expression	O
of	O
the	O
CTalpha	B-GENE
gene	I-GENE
is	O
controlled	O
in	O
part	O
by	O
the	O
binding	O
of	O
three	O
trans	O
-	O
acting	O
nuclear	O
factors	O
,	O
Sp1	B-GENE
,	O
Sp2	B-GENE
,	O
and	O
Sp3	B-GENE
.	O

Determinants	O
of	O
recurrent	O
ischaemia	O
and	O
revascularisation	O
procedures	O
after	O
thrombolysis	O
with	O
recombinant	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
in	O
primary	O
coronary	O
occlusion	O
.	O

Interestingly	O
,	O
unlike	O
PAK65	B-GENE
,	O
HPK1	B-GENE
does	O
not	O
contain	O
the	O
small	B-GENE
GTPase	I-GENE
Rac1	B-GENE
/	O
Cdc42	B-GENE
-	O
binding	O
domain	O
and	O
does	O
not	O
bind	O
to	O
either	O
Rac1	B-GENE
or	O
Cdc42	B-GENE
,	O
suggesting	O
that	O
HPK1	B-GENE
.	O
activation	O
is	O
Rac1	B-GENE
/	O
Cdc42	B-GENE
-	O
independent	O
.	O

Transformations	O
with	O
circular	O
plasmids	O
yielded	O
slowly	O
and	O
irregularly	O
growing	O
geneticin	O
-	O
resistant	O
mycelia	O
in	O
which	O
1	O
%	O
of	O
nuclei	O
contained	O
plasmid	O
sequences	O
.	O

Using	O
a	O
combined	O
pharmacokinetic	O
-	O
pharmacodynamic	O
model	O
,	O
the	O
impact	O
of	O
various	O
factors	O
on	O
the	O
effective	O
bioavailability	O
and	O
on	O
its	O
estimation	O
,	O
using	O
the	O
intravenous	O
-	O
to	O
-	O
oral	O
dose	O
ratio	O
required	O
to	O
produce	O
the	O
same	O
area	O
under	O
the	O
response	O
time	O
curve	O
after	O
acute	O
administration	O
,	O
are	O
explored	O
.	O

We	O
found	O
that	O
in	O
anesthetized	O
,	O
paralyzed	O
cats	O
,	O
the	O
visual	O
evoked	O
potential	O
(	O
VEP	O
)	O
was	O
dependent	O
only	O
on	O
magnitude	O
of	O
delta	O
C	O
at	O
each	O
pattern	O
transition	O
,	O
and	O
was	O
independent	O
of	O
the	O
starting	O
or	O
ending	O
contrast	O
level	O
.	O

Plasmid	O
pSP64E6E7	O
which	O
contains	O
the	O
reading	O
frames	O
of	O
both	O
E6	B-GENE
and	O
E7	B-GENE
was	O
constructed	O
in	O
order	O
to	O
study	O
the	O
expression	O
of	O
both	O
proteins	O
in	O
a	O
coupled	O
transcription	O
/	O
rabbit	O
reticulocyte	O
translation	O
system	O
.	O

A	O
99m	O
Tc	O
bone	O
scan	O
showed	O
a	O
focal	O
area	O
of	O
an	O
increased	O
uptake	O
at	O
the	O
site	O
of	O
the	O
mass	O
below	O
the	O
calcaneus	O
.	O

In	O
addition	O
,	O
FOP	B-GENE
-	O
FGFR1	B-GENE
-	O
expressing	O
cells	O
show	O
constitutive	O
phosphorylation	O
of	O
the	O
positive	O
regulator	O
of	O
translation	O
p70S6	B-GENE
kinase	I-GENE
;	O
this	O
phosphorylation	O
is	O
inhibited	O
by	O
PI3	B-GENE
-	I-GENE
kinase	I-GENE
and	O
mTOR	B-GENE
(	O
mammalian	B-GENE
target	I-GENE
of	I-GENE
rapamycin	I-GENE
)	O
inhibitors	O
.	O

As	O
a	O
test	O
of	O
this	O
hypothesis	O
,	O
we	O
predicted	O
that	O
mice	O
which	O
have	O
altered	O
expression	O
of	O
class	O
I	O
gene	O
products	O
,	O
the	O
beta2	B-GENE
-	I-GENE
microglobulin	I-GENE
knockout	O
mice	O
,	O
[	B-GENE
beta2m	I-GENE
(	I-GENE
-	I-GENE
/	I-GENE
-	I-GENE
)	I-GENE
]	I-GENE
,	O
would	O
develop	O
Fe	O
overload	O
.	O

The	O
synthesis	O
of	O
endo	O
-	O
adduct	O
[	O
4aS	O
,	O
5S	O
,	O
8R	O
,	O
8aR	O
,	O
SS	O
]	O
-	O
9d	O
resulting	O
from	O
cycloaddition	O
on	O
the	O
substituted	O
C	O
(	O
2	O
)	O
-	O
C	O
(	O
3	O
)	O
double	O
bond	O
was	O
achieved	O
in	O
a	O
chemo	O
-	O
and	O
diastereoselective	O
way	O
from	O
quinone	O
1d	O
in	O
the	O
presence	O
of	O
ZnBr	O
(	O
2	O
)	O
.	O

Mad3	B-GENE
and	O
Mad4	B-GENE
:	O
novel	O
Max	B-GENE
-	O
interacting	O
transcriptional	O
repressors	O
that	O
suppress	O
c	B-GENE
-	I-GENE
myc	I-GENE
dependent	O
transformation	O
and	O
are	O
expressed	O
during	O
neural	O
and	O
epidermal	O
differentiation	O
.	O

Maximal	O
Expiratory	O
Flow	O
Rates	O
such	O
as	O
Peak	O
Expiratory	O
Flow	O
Rate	O
(	O
PEFR	O
)	O
,	O
rates	O
at	O
25	O
%	O
,	O
50	O
%	O
and	O
75	O
%	O
of	O
forced	O
vital	O
capacity	O
(	O
V	O
max	O
25	O
%	O
,	O
V	O
max	O
50	O
%	O
and	O
V	O
max	O
75	O
%	O
)	O
and	O
forced	O
expiratory	O
flow	O
during	O
the	O
middle	O
half	O
of	O
forced	O
vital	O
capacity	O
(	O
FEF	O
25	O
-	O
75	O
%	O
)	O
were	O
measured	O
in	O
273	O
healthy	O
non	O
-	O
smoking	O
adults	O
(	O
144	O
males	O
,	O
129	O
females	O
)	O
aged	O
15	O
-	O
63	O
years	O
living	O
in	O
Madras	O
.	O

This	O
polypeptide	O
includes	O
the	O
first	O
three	O
zinc	O
fingers	O
of	O
the	O
TFIIIA	B-GENE
DNA	I-GENE
binding	I-GENE
domain	I-GENE
.	O

Transcription	O
of	O
eukaryotic	O
tRNA	O
genes	O
is	O
dependent	O
on	O
the	O
A	O
-	O
and	O
B	O
-	O
Box	O
internal	O
control	O
regions	O
(	O
ICRs	O
)	O
and	O
the	O
upstream	O
transcription	O
modulatory	O
region	O
.	O

This	O
dose	O
of	O
Na3	O
citrate	O
produced	O
no	O
clinical	O
symptoms	O
suggestive	O
of	O
hypocalcaemia	O
in	O
these	O
subjects	O
,	O
even	O
though	O
the	O
use	O
of	O
acid	O
-	O
citrate	O
-	O
dextrose	O
,	O
NIH	O
formula	O
A	O
(	O
ACD	O
-	O
A	O
)	O
under	O
identical	O
conditions	O
has	O
been	O
reported	O
to	O
reduce	O
significantly	O
the	O
level	O
of	O
total	O
calcium	O
in	O
serum	O
,	O
and	O
concomitantly	O
increase	O
the	O
number	O
or	O
reactions	O
occurring	O
in	O
donors	O
.	O

Cough	O
-	O
CPR	O
,	O
a	O
deep	O
rhythmic	O
forceful	O
cough	O
repeated	O
30	O
-	O
60	O
times	O
per	O
minute	O
,	O
can	O
be	O
an	O
effective	O
resuscitative	O
technique	O
during	O
emergencies	O
occurring	O
in	O
the	O
cardiac	O
catheterization	O
laboratory	O
.	O

The	O
gene	O
encoding	O
the	O
Neisseria	B-GENE
lactamica	I-GENE
III	I-GENE
DNA	I-GENE
methyltransferase	I-GENE
(	O
M	B-GENE
.	I-GENE
NlaIII	I-GENE
)	O
which	O
recognizes	O
the	O
sequence	O
CATG	O
has	O
been	O
cloned	O
and	O
expressed	O
in	O
Escherichia	O
coli	O
.	O

A	O
multivariant	O
study	O
of	O
pituitary	O
adenoma	O
,	O
obtainment	O
of	O
two	O
logistic	O
regression	O
equations	O
as	O
an	O
auxiliary	O
support	O
in	O
the	O
diagnosis	O
of	O
these	O
tumors	O
.	O

Increased	O
TRE	O
DNA	O
binding	O
failed	O
to	O
lead	O
to	O
increased	O
transactivation	O
correlating	O
with	O
the	O
inability	O
of	O
SB	O
203580	O
to	O
increase	O
phosphorylation	O
of	O
these	O
AP	B-GENE
-	I-GENE
1	I-GENE
proteins	I-GENE
.	O

APL	O
patients	O
showed	O
a	O
low	O
,	O
yet	O
variable	O
,	O
level	O
of	O
JEM	B-GENE
-	I-GENE
1	I-GENE
mRNA	I-GENE
in	O
bone	O
marrow	O
.	O

The	O
cDNA	O
clones	O
encode	O
a	O
polypeptide	O
of	O
657	O
amino	O
acids	O
with	O
a	O
bHLH	O
(	O
basic	O
-	O
helix	O
-	O
loop	O
-	O
helix	O
)	O
domain	O
,	O
characteristic	O
of	O
a	O
large	O
family	O
of	O
transcription	O
factors	O
,	O
and	O
a	O
PAS	B-GENE
(	O
Per	B-GENE
-	O
Arnt	B-GENE
-	O
Sim	B-GENE
)	O
domain	O
in	O
the	O
amino	O
-	O
terminal	O
half	O
region	O
.	O

We	O
propose	O
that	O
the	O
cDNA	O
encodes	O
an	O
apical	O
plasma	O
membrane	O
protein	O
that	O
plays	O
a	O
role	O
in	O
the	O
functional	O
expression	O
of	O
the	O
amiloride	O
-	O
sensitive	O
epithelial	O
sodium	O
channel	O
.	O

Nedocromil	O
sodium	O
shifted	O
the	O
severity	O
of	O
the	O
early	O
allergic	O
reaction	O
(	O
EAR	O
)	O
from	O
mean	O
-	O
34	O
.	O
8	O
%	O
to	O
-	O
6	O
.	O
9	O
%	O
and	O
inhibited	O
the	O
later	O
allergic	O
reaction	O
(	O
LAR	O
)	O
from	O
-	O
30	O
.	O
5	O
%	O
to	O
+	O
0	O
.	O
4	O
%	O
(	O
p	O
less	O
than	O
0	O
.	O
005	O
)	O
.	O

Values	O
of	O
K1	O
and	O
Vd	O
were	O
significantly	O
increased	O
in	O
the	O
tumour	O
tissue	O
.	O

The	O
binding	O
of	O
PTB	B-GENE
was	O
antagonistic	O
to	O
the	O
binding	O
of	O
U2AF	B-GENE
to	O
the	O
enhancer	O
-	O
located	O
pyrimidine	O
tract	O
.	O

Our	O
results	O
separate	O
these	O
factors	O
into	O
four	O
regulatory	O
classes	O
:	O
(	O
i	O
)	O
constitutive	O
factors	O
,	O
such	O
as	O
Oct	B-GENE
-	I-GENE
1	I-GENE
and	O
probably	O
Sp1	B-GENE
,	O
that	O
are	O
expressed	O
in	O
thymocytes	O
at	O
all	O
stages	O
;	O
(	O
ii	O
)	O
inducible	O
factors	O
,	O
such	O
as	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
and	O
complexes	O
binding	O
to	O
the	O
region	O
of	O
a	O
CD28	B-GENE
response	I-GENE
element	I-GENE
,	O
that	O
can	O
be	O
activated	O
in	O
all	O
thymocytes	O
,	O
including	O
those	O
cells	O
(	O
CD4	B-GENE
+	I-GENE
CD8	B-GENE
+	I-GENE
TcRlow	B-GENE
)	O
that	O
can	O
undergo	O
selection	O
;	O
(	O
iii	O
)	O
inducible	O
factors	O
,	O
such	O
as	O
NF	B-GENE
-	I-GENE
AT	I-GENE
and	O
AP	B-GENE
-	I-GENE
1	I-GENE
,	O
that	O
can	O
be	O
activated	O
in	O
mature	O
(	O
CD4	B-GENE
+	I-GENE
CD8	B-GENE
-	I-GENE
TcRhigh	B-GENE
)	O
and	O
immature	O
(	O
CD4	B-GENE
-	I-GENE
CD8	B-GENE
-	I-GENE
TcR	B-GENE
-	I-GENE
)	O
thymocytes	O
alike	O
but	O
not	O
in	O
the	O
transitional	O
stages	O
when	O
the	O
cells	O
(	O
CD4	B-GENE
+	I-GENE
CD8	B-GENE
+	I-GENE
TcRlow	B-GENE
)	O
are	O
subject	O
to	O
selection	O
;	O
and	O
(	O
iv	O
)	O
a	O
factor	O
containing	O
CREB	B-GENE
,	O
which	O
can	O
be	O
activated	O
in	O
thymocytes	O
of	O
all	O
developmental	O
stages	O
by	O
culture	O
but	O
does	O
not	O
require	O
specific	O
induction	O
.	O

Similar	O
tissue	O
-	O
specific	O
patterns	O
are	O
observed	O
with	O
a	O
fusion	O
between	O
the	O
caufliflower	B-GENE
mosaic	I-GENE
virus	I-GENE
35S	I-GENE
RNA	I-GENE
promotor	I-GENE
and	O
the	O
GUS	B-GENE
gene	I-GENE
.	O

The	O
results	O
obtained	O
show	O
that	O
expression	O
of	O
the	O
gene	O
is	O
low	O
at	O
23	O
degrees	O
C	O
and	O
is	O
induced	O
rapidly	O
at	O
37	O
degrees	O
C	O
.	O

However	O
,	O
in	O
each	O
case	O
in	O
which	O
either	O
the	O
DQ	B-GENE
alpha	I-GENE
-	I-GENE
or	I-GENE
DQ	I-GENE
beta	I-GENE
-	I-GENE
chain	I-GENE
was	O
exchanged	O
,	O
major	O
alterations	O
or	O
reversals	O
of	O
this	O
pattern	O
of	O
interaction	O
were	O
observed	O
.	O

Two	O
methods	O
for	O
the	O
routine	O
determination	O
of	O
blood	O
hemoglobin	B-GENE
oxygen	O
affinity	O
are	O
described	O
.	O

The	O
cause	O
for	O
the	O
increase	O
in	O
plasma	B-GENE
ANP	I-GENE
levels	O
in	O
the	O
active	O
phase	O
remains	O
to	O
be	O
determined	O
.	O

The	O
effects	O
on	O
survival	O
of	O
adjuvant	O
treatments	O
,	O
including	O
pre	O
-	O
or	O
postoperative	O
systemic	O
or	O
postoperative	O
intra	O
-	O
arterial	O
chemotherapy	O
,	O
are	O
currently	O
under	O
evaluation	O
.	O

Malformations	O
of	O
the	O
regenerating	O
optic	O
tectum	O
of	O
larvae	O
of	O
the	O
Egyptian	O
toad	O
,	O
Bufo	O
regularis	O
Reuss	O
.	O

Immunological	O
studies	O
also	O
failed	O
to	O
demonstrate	O
any	O
significant	O
change	O
except	O
for	O
a	O
significant	O
increase	O
of	O
natural	O
killer	O
(	O
NK	O
)	O
cell	O
activity	O
after	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
infusion	O
.	O

We	O
have	O
used	O
systemic	O
application	O
of	O
the	O
ototoxic	O
drug	O
amikacin	O
,	O
to	O
induce	O
total	O
cochlear	O
haircell	O
loss	O
in	O
the	O
chinchilla	O
,	O
in	O
order	O
to	O
create	O
an	O
animal	O
model	O
of	O
profound	O
deafness	O
.	O

BACKGROUND	O
-	O
-	O
Platelet	B-GENE
activating	I-GENE
factor	I-GENE
(	O
PAF	B-GENE
)	O
has	O
been	O
implicated	O
in	O
the	O
pathogenesis	O
of	O
airway	O
hyperresponsiveness	O
in	O
asthma	O
.	O

To	O
be	O
a	O
nurse	O
.	O

Chronic	O
granulocytic	O
leukemia	O
in	O
children	O
.	O

Charcot	O
joints	O
.	O

Recombinant	B-GENE
apoA	I-GENE
-	I-GENE
I	I-GENE
protein	I-GENE
recovered	O
from	O
the	O
soluble	O
fraction	O
of	O
the	O
bacterial	O
cell	O
pellet	O
was	O
purified	O
to	O
greater	O
than	O
95	O
%	O
homogeneity	O
by	O
reversed	O
-	O
phase	O
high	O
-	O
performance	O
liquid	O
chromatography	O
.	O

Kaposi	O
'	O
s	O
sarcoma	O
-	O
associated	O
herpesvirus	O
/	O
human	O
herpesvirus	O
-	O
8	O
ORF50	B-GENE
gene	O
product	O
contains	O
a	O
potent	O
C	O
-	O
terminal	O
activation	O
domain	O
which	O
activates	O
gene	O
expression	O
via	O
a	O
specific	O
target	O
sequence	O
.	O

Comparison	O
of	O
the	O
5	O
'	O
flanking	O
regions	O
of	O
the	O
mouse	B-GENE
J	I-GENE
kappa	I-GENE
elements	I-GENE
,	O
including	O
the	O
conserved	O
putative	O
recombination	O
target	O
sequences	O
,	O
shows	O
no	O
obvious	O
differences	O
consistent	O
with	O
the	O
variation	O
in	O
recombinational	O
efficiency	O
,	O
so	O
we	O
conclude	O
that	O
,	O
although	O
the	O
consensus	O
heptamer	O
and	O
nonamer	O
signals	O
may	O
be	O
sufficient	O
to	O
identify	O
a	O
recombination	O
site	O
,	O
the	O
probability	O
that	O
that	O
site	O
will	O
be	O
used	O
depends	O
also	O
on	O
other	O
determinants	O
.	O

Further	O
interventions	O
were	O
:	O
nephrectomy	O
(	O
2x	O
)	O
,	O
resection	O
and	O
ligation	O
of	O
the	O
inferior	O
vena	O
cava	O
(	O
1x	O
)	O
,	O
resection	O
and	O
replacement	O
of	O
the	O
left	O
renal	O
vein	O
(	O
1x	O
)	O
.	O

Herein	O
,	O
we	O
report	O
that	O
CRE	O
-	O
decoy	O
oligonucleotide	O
treatment	O
results	O
in	O
an	O
increase	O
in	O
the	O
p53	B-GENE
protein	I-GENE
level	O
in	O
MCF	O
-	O
7	O
human	O
breast	O
cancer	O
cells	O
that	O
express	O
wild	O
-	O
type	O
p53	B-GENE
.	O

Competition	O
and	O
methylation	O
interference	O
assays	O
showed	O
that	O
the	O
binding	O
site	O
for	O
the	O
novel	O
factor	O
was	O
limited	O
to	O
nucleotides	O
in	O
the	O
3	O
'	O
half	O
of	O
the	O
kappa	B-GENE
B	I-GENE
site	I-GENE
.	O

We	O
have	O
introduced	O
the	O
same	O
change	O
in	O
a	O
yeast	B-GENE
tRNA	I-GENE
(	I-GENE
Trp	I-GENE
)	I-GENE
gene	I-GENE
and	O
demonstrated	O
that	O
the	O
tRNA	O
acts	O
as	O
an	O
efficient	O
amber	O
suppressor	O
in	O
vivo	O
.	O

Both	O
proteins	O
share	O
sequence	O
similarity	O
with	O
the	O
myelin	B-GENE
-	I-GENE
associated	I-GENE
glycoprotein	I-GENE
,	O
an	O
adhesion	O
molecule	O
of	O
oligodendrocytes	O
and	O
Schwann	O
cells	O
that	O
has	O
been	O
implicated	O
in	O
the	O
process	O
of	O
myelination	O
,	O
raising	O
the	O
important	O
question	O
of	O
whether	O
myelin	B-GENE
-	I-GENE
associated	I-GENE
glycoprotein	I-GENE
is	O
also	O
a	O
sialic	B-GENE
acid	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
.	O

The	O
predicted	O
5	O
'	O
and	O
3	O
'	O
ends	O
of	O
the	O
transcript	O
are	O
in	O
very	O
good	O
agreement	O
with	O
the	O
previously	O
determined	O
size	O
of	O
the	O
LEU3	B-GENE
message	O
.	O

These	O
clones	O
contain	O
most	O
of	O
the	O
exon	O
of	O
cyclin	B-GENE
D2	I-GENE
except	O
exon	O
5	O
.	O

By	O
24	O
h	O
,	O
there	O
was	O
no	O
significant	O
difference	O
in	O
FFA	O
levels	O
from	O
shams	O
.	O

The	O
clr1	B-GENE
locus	I-GENE
regulates	O
the	O
expression	O
of	O
the	O
cryptic	B-GENE
mating	I-GENE
-	I-GENE
type	I-GENE
loci	I-GENE
of	I-GENE
fission	I-GENE
yeast	I-GENE
.	O

The	O
odds	O
of	O
atopy	O
(	O
defined	O
as	O
a	O
positive	O
test	O
for	O
at	O
least	O
one	O
of	O
the	O
antigens	O
)	O
were	O
5	O
times	O
higher	O
(	O
odds	O
ratio	O
=	O
7	O
.	O
0	O
;	O
95	O
%	O
confidence	O
interval	O
=	O
1	O
.	O
6	O
-	O
31	O
.	O
1	O
%	O
;	O
p	O
=	O
0	O
.	O
01	O
)	O
in	O
the	O
uninfected	O
group	O
,	O
after	O
taking	O
into	O
account	O
the	O
potential	O
influence	O
of	O
gender	O
and	O
age	O
.	O

In	O
mouse	O
,	O
two	O
high	O
-	O
affinity	O
binding	O
sites	O
with	O
an	O
apparent	O
dissociation	O
constant	O
(	O
Kd	O
)	O
of	O
50	O
to	O
100	O
nM	O
have	O
been	O
mapped	O
in	O
the	O
5	O
'	O
ETS	B-GENE
upstream	O
from	O
the	O
early	O
pre	O
-	O
rRNA	O
processing	O
site	O
.	O

As	O
much	O
thrombin	B-GENE
was	O
formed	O
during	O
cardiopulmonary	O
bypass	O
(	O
measured	O
by	O
the	O
prothrombin	B-GENE
activation	I-GENE
fragment	I-GENE
F1	I-GENE
+	I-GENE
2	I-GENE
and	O
thrombin	B-GENE
-	O
antithrombin	B-GENE
complexes	O
)	O
as	O
in	O
normal	O
patients	O
,	O
showing	O
that	O
factor	B-GENE
XII	I-GENE
was	O
not	O
necessary	O
for	O
thrombin	B-GENE
generation	O
.	O

This	O
article	O
reviews	O
current	O
concepts	O
of	O
pathophysiology	O
and	O
summarises	O
clinical	O
features	O
,	O
natural	O
history	O
and	O
available	O
treatments	O
.	O

Pendulin	B-GENE
,	O
a	O
Drosophila	O
protein	O
with	O
cell	O
cycle	O
-	O
dependent	O
nuclear	O
localization	O
,	O
is	O
required	O
for	O
normal	O
cell	O
proliferation	O
.	O

The	O
phosphatase	O
active	O
site	O
is	O
located	O
within	O
residues	O
367	O
-	O
374	O
.	O

The	O
central	O
region	O
of	O
the	O
sarcomere	O
,	O
coincident	O
with	O
the	O
M	O
line	O
,	O
was	O
selectively	O
labeled	O
with	O
antibodies	O
to	O
the	O
short	O
C	O
-	O
terminal	O
form	O
.	O

Moreover	O
,	O
antibody	O
binding	O
to	O
the	O
same	O
two	O
determinants	O
was	O
also	O
inhibited	O
when	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
or	O
the	O
SH2	B-GENE
domains	I-GENE
bound	O
to	O
the	O
zeta	O
chain	O
or	O
to	O
a	O
2pY	B-GENE
-	I-GENE
ITAM	I-GENE
.	O

Interleukin	B-GENE
-	I-GENE
1	I-GENE
increased	O
the	O
noradrenaline	O
release	O
.	O

A	O
representative	O
group	O
of	O
patients	O
undergoing	O
open	O
radical	O
nephrectomy	O
for	O
clinical	O
T1	O
,	O
T2	O
lesions	O
was	O
also	O
identified	O
.	O

These	O
findings	O
indicate	O
that	O
KCTG	O
can	O
contribute	O
to	O
improved	O
monitoring	O
in	O
high	O
-	O
risk	O
pregnancies	O
.	O

These	O
extrachromosomal	O
copies	O
can	O
be	O
isolated	O
as	O
covalently	O
closed	O
molecules	O
with	O
lengths	O
around	O
3mu	O
.	O

Significant	O
reductions	O
were	O
noted	O
in	O
vertical	O
GRFs	O
per	O
newton	O
of	O
body	O
weight	O
exerted	O
at	O
10	O
%	O
(	O
P	O
=	O
0	O
.	O
0009	O
)	O
and	O
20	O
%	O
(	O
P	O
=	O
0	O
.	O
0383	O
)	O
of	O
stance	O
phase	O
and	O
in	O
anteroposterior	O
GRFs	O
exerted	O
at	O
10	O
%	O
(	O
P	O
=	O
0	O
.	O
0009	O
)	O
and	O
50	O
%	O
(	O
P	O
=	O
0	O
.	O
0033	O
)	O
of	O
stance	O
phase	O
when	O
ambulation	O
was	O
compared	O
with	O
and	O
without	O
the	O
orthotic	O
device	O
.	O

Similar	O
immunological	O
disturbances	O
were	O
observed	O
in	O
SCI	O
but	O
not	O
in	O
the	O
PC2	O
subgroup	O
,	O
i	O
.	O
e	O
.	O
patients	O
examined	O
later	O
than	O
6	O
months	O
after	O
injury	O
.	O

Trimethylcolchicinic	O
acid	O
methyl	O
ether	O
d	O
-	O
tartrate	O
(	O
TMCA	O
;	O
NSC	O
-	O
36351	O
)	O
was	O
administered	O
daily	O
by	O
mouth	O
to	O
71	O
patients	O
with	O
malignant	O
lymphomas	O
.	O

After	O
multivariate	O
analysis	O
,	O
TWA	O
correlated	O
with	O
age	O
(	O
P	O
=	O
0	O
.	O
02	O
)	O
and	O
LV	O
function	O
(	O
P	O
=	O
0	O
.	O
002	O
)	O
and	O
occurred	O
more	O
often	O
in	O
patients	O
after	O
nonanterior	O
MI	O
(	O
P	O
=	O
0	O
.	O
03	O
)	O
.	O

In	O
rats	O
exposed	O
to	O
Cd	O
for	O
30	O
d	O
,	O
the	O
levels	O
of	O
urinary	O
excretion	O
of	O
cAMP	O
after	O
treatment	O
with	O
parathyroid	B-GENE
hormone	I-GENE
(	O
PTH	B-GENE
)	O
,	O
parathyroidectomy	O
(	O
PTX	O
)	O
,	O
or	O
1	O
alpha	O
-	O
hydroxycholecalciferol	O
(	O
1	O
alpha	O
-	O
OH	O
-	O
D3	O
)	O
showed	O
almost	O
the	O
same	O
patterns	O
as	O
those	O
of	O
control	O
rats	O
:	O
the	O
response	O
of	O
urinary	O
cAMP	O
to	O
treatment	O
with	O
PTH	B-GENE
was	O
not	O
influenced	O
by	O
continuous	O
oral	O
administration	O
of	O
Cd	O
.	O

Receptor	B-GENE
-	I-GENE
type	I-GENE
serine	I-GENE
/	I-GENE
threonine	I-GENE
kinases	I-GENE
(	O
RSKs	B-GENE
)	O
have	O
been	O
organized	O
into	O
two	O
distinct	O
classes	O
known	O
as	O
types	O
I	O
and	O
II	O
on	O
the	O
basis	O
of	O
sequence	O
similarity	O
.	O

In	O
the	O
remaining	O
91	O
patients	O
(	O
group	O
2	O
)	O
,	O
Pseudomonas	O
(	O
18	O
)	O
,	O
coagulase	B-GENE
-	O
negative	O
Staphylococci	O
(	O
15	O
)	O
,	O
Staphylococcus	O
epidermidis	O
(	O
23	O
)	O
,	O
Staphylococcus	O
aureus	O
(	O
16	O
)	O
,	O
Corynebacterium	O
species	O
(	O
12	O
)	O
,	O
and	O
others	O
(	O
seven	O
)	O
were	O
isolated	O
.	O

This	O
cDNA	O
corresponded	O
to	O
FGF	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
FGF	B-GENE
-	I-GENE
BP	I-GENE
)	O
,	O
a	O
secreted	O
protein	O
previously	O
shown	O
to	O
bind	O
acidic	O
and	O
basic	B-GENE
FGF	I-GENE
and	O
to	O
modulate	O
their	O
activities	O
.	O

Electrophoretic	O
mobility	O
-	O
shift	O
assays	O
using	O
oligonucleotides	O
derived	O
from	O
these	O
sites	O
demonstrated	O
formation	O
of	O
specific	O
DNA	O
-	O
protein	O
complexes	O
.	O

For	O
the	O
P	B-GENE
transcript	I-GENE
from	O
phage	O
with	O
the	O
G	O
(	O
-	O
)	O
orientation	O
,	O
full	O
termination	O
activity	O
required	O
both	O
the	O
region	O
containing	O
the	O
stem	O
-	O
loop	O
structure	O
and	O
upstream	O
sequences	O
.	O

One	O
day	O
after	O
injection	O
48	O
%	O
of	O
the	O
injected	O
activity	O
was	O
in	O
the	O
skeleton	O
,	O
9	O
.	O
3	O
%	O
in	O
the	O
liver	O
,	O
3	O
%	O
in	O
the	O
kidneys	O
and	O
4	O
.	O
4	O
%	O
in	O
the	O
rest	O
of	O
the	O
organs	O
.	O

Of	O
these	O
four	O
PP2C	B-GENE
genes	I-GENE
,	O
the	O
expression	O
of	O
the	O
PP2Cbeta	B-GENE
gene	I-GENE
has	O
been	O
reported	O
to	O
be	O
tissue	O
-	O
specific	O
and	O
development	O
-	O
dependent	O
.	O

Combined	O
chemotherapy	O
with	O
VM	O
26	O
and	O
BCNU	O
for	O
recurrent	O
malignant	O
gliomas	O
after	O
operation	O
and	O
irradiation	O
.	O

Administration	O
of	O
FR	O
34235	O
reduced	O
aortic	O
blood	O
pressure	O
and	O
increased	O
cardiac	O
output	O
in	O
anesthetized	O
dogs	O
with	O
an	O
ameroid	O
-	O
induced	O
coronary	O
artery	O
occlusion	O
.	O

Alternative	O
immune	B-GENE
globulin	I-GENE
preparation	O
when	O
standard	O
immune	B-GENE
serum	I-GENE
globulin	I-GENE
is	O
not	O
available	O
.	O

Two	O
sibs	O
with	O
identical	O
features	O
of	O
short	O
-	O
limbed	O
dwarfism	O
,	O
a	O
normal	O
skull	O
and	O
face	O
and	O
normal	O
intelligence	O
are	O
described	O
.	O

Effect	O
of	O
a	O
high	O
sugar	O
intake	O
on	O
some	O
metabolic	O
and	O
regulatory	O
indicators	O
in	O
young	O
men	O
.	O

In	O
the	O
second	O
group	O
the	O
untreated	O
fellow	O
eye	O
was	O
microscopically	O
intact	O
,	O
but	O
was	O
shown	O
(	O
as	O
the	O
treated	O
eye	O
)	O
to	O
alter	O
the	O
concentration	O
of	O
uronic	O
acid	O
in	O
different	O
parts	O
of	O
the	O
sclera	O
.	O

Amplification	O
of	O
4q21	O
-	O
q22	O
and	O
the	O
MXR	B-GENE
gene	I-GENE
in	O
independently	O
derived	O
mitoxantrone	O
-	O
resistant	O
cell	O
lines	O
.	O

Expression	O
of	O
putative	O
constitutively	O
active	O
forms	O
of	O
DdMEK1	B-GENE
in	O
a	O
ddmek1	B-GENE
null	O
background	O
is	O
capable	O
,	O
at	O
least	O
partially	O
,	O
of	O
complementing	O
the	O
small	O
aggregate	O
size	O
defect	O
and	O
the	O
ability	O
to	O
activate	O
guanylyl	B-GENE
cyclase	I-GENE
.	O

Quantitative	O
Tl	O
-	O
201	O
analysis	O
after	O
stress	O
has	O
also	O
shown	O
viable	O
myocardium	O
in	O
most	O
mild	O
to	O
moderate	O
(	O
51	O
%	O
to	O
85	O
%	O
of	O
normal	O
uptake	O
)	O
irreversible	O
Tl	O
-	O
201	O
defects	O
.	O

However	O
,	O
ADAR1	B-GENE
and	O
the	O
related	O
deaminase	B-GENE
ADAR2	I-GENE
showed	O
significant	O
expression	O
in	O
all	O
regions	O
of	O
the	O
brain	O
examined	O
,	O
including	O
cortex	O
,	O
hippocampus	O
,	O
olfactory	O
bulb	O
,	O
and	O
striatum	O
,	O
where	O
the	O
5	B-GENE
-	I-GENE
HT2CR	I-GENE
pre	I-GENE
-	I-GENE
mRNA	I-GENE
was	O
extensively	O
edited	O
.	O

Psychophysical	O
evidence	O
is	O
given	O
for	O
the	O
existence	O
of	O
two	O
distinct	O
systems	O
in	O
human	O
vision	O
:	O
a	O
fast	O
,	O
sign	O
-	O
invariant	O
system	O
concerned	O
with	O
extracting	O
contours	O
and	O
a	O
slower	O
,	O
sign	O
-	O
sensitive	O
system	O
concerned	O
with	O
assigning	O
surface	O
color	O
.	O

Five	O
girls	O
with	O
Turner	O
'	O
s	O
syndrome	O
aged	O
12	O
to	O
17	O
years	O
showed	O
LH	B-GENE
values	O
(	O
5	O
.	O
0	O
-	O
14	O
.	O
5	O
IU	O
/	O
12	O
h	O
)	O
at	O
the	O
upper	O
end	O
of	O
or	O
slightly	O
above	O
the	O
normal	O
range	O
and	O
pathologically	O
high	O
values	O
(	O
22	O
.	O
2	O
-	O
43	O
.	O
5	O
IU	O
/	O
12	O
h	O
)	O
for	O
FSH	B-GENE
.	O

Thirty	O
-	O
seven	O
patients	O
with	O
severe	O
temporal	O
lobe	O
epilepsy	O
were	O
studied	O
interictally	O
with	O
[	O
18F	O
]	O
fluorodeoxyglucose	O
-	O
PET	O
in	O
each	O
of	O
three	O
conditions	O
:	O
resting	O
,	O
during	O
emotional	O
speech	O
,	O
and	O
while	O
performing	O
a	O
visual	O
recognition	O
task	O
.	O

The	O
sequence	O
of	O
Vac1p	B-GENE
contains	O
two	O
putative	O
zinc	O
-	O
binding	O
RING	O
motifs	O
,	O
a	O
zinc	O
finger	O
motif	O
,	O
and	O
a	O
coiled	O
-	O
coil	O
motif	O
.	O

Serum	O
concentrations	O
of	O
hormones	O
in	O
patients	O
classified	O
as	O
C	O
were	O
characteristically	O
and	O
inclined	O
to	O
be	O
hypergonadotropic	O
and	O
hypoestrogenic	O
.	O

Kinase	O
renaturation	O
tests	O
designed	O
to	O
detect	O
reactivated	O
protein	O
kinases	O
after	O
electrophoresis	O
in	O
sodium	O
dodecyl	O
sulfate	O
-	O
polyacrylamide	O
gels	O
revealed	O
the	O
presence	O
of	O
a	O
60	O
-	O
kDa	O
kinase	O
in	O
the	O
washed	O
immunoprecipitate	O
obtained	O
from	O
liver	O
cytosol	O
using	O
anti	B-GENE
-	I-GENE
AHR	I-GENE
antibody	I-GENE
(	O
IgG	B-GENE
)	O
and	O
protein	O
A	O
/	O
G	O
/	O
agarose	O
beads	O
but	O
not	O
when	O
a	O
nonspecific	O
IgG	B-GENE
was	O
used	O
instead	O
of	O
anti	B-GENE
-	I-GENE
AHR	I-GENE
antibody	I-GENE
.	O

The	O
immune	O
response	O
seems	O
to	O
be	O
partially	O
responsible	O
for	O
both	O
protection	O
and	O
the	O
destructive	O
consequences	O
of	O
chlamydial	O
infection	O
.	O

Activated	O
FGFR3	B-GENE
predominantly	O
interacts	O
with	O
GRB2	B-GENE
.	I-GENE
Sos	I-GENE
in	O
complex	O
with	O
a	O
previously	O
identified	O
90	O
-	O
kDa	O
protein	O
and	O
designated	O
protein	B-GENE
80K	I-GENE
-	I-GENE
H	I-GENE
.	O

We	O
generated	O
"	O
signature	O
"	O
oligonucleotides	O
from	O
these	O
CDR3s	B-GENE
and	O
probed	O
PCR	O
amplified	O
V	B-GENE
kappa	I-GENE
products	I-GENE
from	O
the	O
synovium	O
and	O
PBLs	O
of	O
the	O
same	O
patient	O
,	O
and	O
from	O
PBLs	O
and	O
spleen	O
of	O
individuals	O
without	O
rheumatic	O
disease	O
.	O

It	O
was	O
predicted	O
that	O
the	O
Stroop	O
task	O
would	O
trigger	O
greater	O
consumption	O
of	O
ice	O
cream	O
than	O
a	O
fearful	O
film	O
,	O
and	O
that	O
this	O
effect	O
would	O
be	O
more	O
pronounced	O
for	O
binge	O
-	O
eaters	O
than	O
non	O
-	O
binge	O
-	O
eaters	O
.	O

Patients	O
with	O
PLM	O
show	O
excessive	O
daytime	O
sleepiness	O
or	O
insomnia	O
.	O

Plasma	B-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
analysis	O
and	O
the	O
clinical	O
significance	O

Structure	O
and	O
regulation	O
of	O
KGD2	B-GENE
,	O
the	O
structural	O
gene	O
for	O
yeast	B-GENE
dihydrolipoyl	I-GENE
transsuccinylase	I-GENE
.	O

We	O
identified	O
two	O
potential	O
phosphorylation	O
sites	O
at	O
serine49	O
and	O
serine133	O
,	O
both	O
of	O
which	O
seem	O
to	O
be	O
necessary	O
for	O
Myf	B-GENE
-	I-GENE
5	I-GENE
activity	O
.	O

Exposure	O
of	O
raft	O
cultures	O
to	O
activators	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
,	O
such	O
as	O
phorbol	O
esters	O
,	O
results	O
in	O
the	O
further	O
induction	O
of	O
late	B-GENE
gene	I-GENE
expression	O
as	O
well	O
as	O
virion	O
assembly	O
.	O

Here	O
we	O
demonstrate	O
that	O
the	O
T	B-GENE
cell	I-GENE
antigen	I-GENE
receptor	I-GENE
zeta	I-GENE
-	I-GENE
chain	I-GENE
-	I-GENE
associated	I-GENE
ZAP	I-GENE
-	I-GENE
70	I-GENE
kinase	I-GENE
and	O
T	B-GENE
cell	I-GENE
antigen	I-GENE
receptor	I-GENE
zeta	I-GENE
-	I-GENE
chain	I-GENE
immunoreceptor	I-GENE
tyrosine	I-GENE
-	I-GENE
based	I-GENE
activation	I-GENE
motifs	I-GENE
are	O
essential	O
for	O
the	O
membrane	O
recruitment	O
of	O
SOS	B-GENE
and	O
Vav	B-GENE
.	O

Above	O
this	O
transition	O
temperature	O
the	O
calcium	O
antagonist	O
lowers	O
fm	O
more	O
pronouncedly	O
than	O
below	O
.	O

Behavioral	O
effects	O
of	O
benzodiazepine	O
ligands	O
in	O
non	O
-	O
dependent	O
,	O
diazepam	O
-	O
dependent	O
and	O
diazepam	O
-	O
withdrawn	O
baboons	O
.	O

Gastrointestinal	O
accumulation	O
of	O
indium	O
-	O
111	O
labelled	O
granulocytes	O
in	O
reactive	O
arthritis	O
.	O

TNF	B-GENE
-	I-GENE
alpha	I-GENE
stimulated	O
these	O
changes	O
in	O
part	O
by	O
increasing	O
transcription	O
and	O
stabilization	O
of	O
RNA	O
for	O
amphiregulin	B-GENE
,	O
an	O
EGF	B-GENE
receptor	I-GENE
ligand	O
,	O
and	O
amphiregulin	B-GENE
directly	O
increased	O
HPV	O
-	O
16	O
E6	B-GENE
/	O
E7	B-GENE
and	O
cyclin	B-GENE
A	I-GENE
RNAs	I-GENE
.	O

The	O
JNK	B-GENE
/	O
SAPK	B-GENE
activator	O
mixed	B-GENE
lineage	I-GENE
kinase	I-GENE
3	I-GENE
(	O
MLK3	B-GENE
)	O
transforms	O
NIH	O
3T3	O
cells	O
in	O
a	O
MEK	B-GENE
-	O
dependent	O
fashion	O
.	O

Biochemical	O
analyses	O
revealed	O
that	O
the	O
concentration	O
of	O
norepinephrine	O
was	O
reduced	O
significantly	O
in	O
cortex	O
-	O
hippocampus	O
and	O
olfactory	O
bulb	O
but	O
not	O
in	O
other	O
regions	O
,	O
while	O
dopamine	O
and	O
serotonin	O
levels	O
were	O
not	O
altered	O
in	O
any	O
brain	O
region	O
examined	O
.	O

A	O
mouth	O
asymmetry	O
study	O
.	O

Control	O
oligomers	O
of	O
scrambled	O
sequence	O
but	O
identical	O
base	O
composition	O
were	O
ineffective	O
,	O
and	O
no	O
TFO	O
-	O
induced	O
recombination	O
was	O
seen	O
in	O
a	O
control	O
LTK	O
(	O
-	O
)	O
cell	O
line	O
carrying	O
an	O
otherwise	O
identical	O
dual	O
TK	B-GENE
gene	I-GENE
construct	I-GENE
lacking	O
the	O
30	O
-	O
bp	O
polypurine	O
target	O
site	O
.	O

Transformation	O
of	O
chicken	O
embryo	O
fibroblasts	O
(	O
CEF	O
)	O
with	O
the	O
Gag	B-GENE
-	O
Crk	B-GENE
fusion	O
protein	O
results	O
in	O
the	O
elevation	O
of	O
tyrosine	O
phosphorylation	O
on	O
specific	O
cellular	O
proteins	O
with	O
molecular	O
weights	O
of	O
130	O
,	O
000	O
,	O
110	O
,	O
000	O
,	O
and	O
70	O
,	O
000	O
(	O
p130	B-GENE
,	O
p110	B-GENE
,	O
and	O
p70	B-GENE
,	O
respectively	O
)	O
,	O
an	O
event	O
which	O
has	O
been	O
correlated	O
with	O
cell	O
transformation	O
.	O

Tilisolol	O
and	O
carboxymethylcellulose	O
sodium	O
salt	O
(	O
CMC	O
)	O
were	O
used	O
as	O
the	O
model	O
ophthalmic	O
drug	O
and	O
viscous	O
polymer	O
,	O
respectively	O
.	O

OAT	O
has	O
become	O
safer	O
in	O
recent	O
years	O
,	O
particularly	O
if	O
monitored	O
in	O
special	O
anticoagulation	O
clinics	O
.	O

The	O
results	O
were	O
compared	O
with	O
the	O
findings	O
in	O
pair	O
-	O
fed	O
non	O
-	O
treated	O
animals	O
(	O
Control	O
Group	O
)	O
.	O

Our	O
data	O
are	O
in	O
line	O
with	O
the	O
hypothesis	O
that	O
E2F	B-GENE
functions	O
as	O
a	O
growth	O
-	O
and	O
cell	O
cycle	O
regulated	O
tethering	O
factor	O
between	O
Sp1	B-GENE
and	O
the	O
basic	O
transcription	O
machinery	O
.	O

Fetal	O
transplants	O
rescue	O
axial	O
muscle	O
representations	O
in	O
M1	O
cortex	O
of	O
neonatally	O
transected	O
rats	O
that	O
develop	O
weight	O
support	O
.	O

However	O
,	O
to	O
encourage	O
good	O
contact	O
between	O
the	O
farmers	O
and	O
the	O
inseminating	O
personnel	O
,	O
it	O
is	O
beneficial	O
that	O
herdsmen	O
are	O
present	O
when	O
cows	O
are	O
inseminated	O
.	O

Solution	O
of	O
the	O
Boltzmann	O
equation	O
in	O
a	O
random	O
magnetic	O
field	O
.	O

These	O
include	O
the	O
genes	O
,	O
undefined	B-GENE
1	I-GENE
(	O
UD1	B-GENE
)	O
,	O
UD2	B-GENE
,	O
and	O
UD3	B-GENE
,	O
each	O
coding	O
for	O
proteins	O
of	O
unknown	O
function	O
,	O
the	O
ken	B-GENE
gene	I-GENE
encoding	O
a	O
new	O
Kruppel	B-GENE
-	I-GENE
like	I-GENE
putative	I-GENE
transcription	I-GENE
factor	I-GENE
,	O
the	O
fly	O
homologues	O
of	O
the	O
mammalian	B-GENE
mitochondrial	I-GENE
trifunctional	I-GENE
enzyme	I-GENE
(	O
thiolase	B-GENE
)	O
,	O
and	O
the	O
TAR	B-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
-	I-GENE
43	I-GENE
(	O
TBPH	B-GENE
)	O
,	O
the	O
first	O
nonvertebrate	O
member	O
of	O
the	O
transmembrane	B-GENE
4	I-GENE
superfamily	I-GENE
(	O
TM4SF	B-GENE
)	O
gene	O
,	O
a	O
new	O
homeodomain	B-GENE
gene	I-GENE
,	O
and	O
a	O
gene	O
coding	O
for	O
a	O
putative	O
nuclear	O
binding	O
protein	O
(	O
PNBP	O
)	O
that	O
is	O
homologous	O
to	O
maleless	B-GENE
,	O
and	O
a	O
Copia	B-GENE
-	I-GENE
like	I-GENE
element	I-GENE
.	O

It	O
is	O
recommended	O
that	O
area	O
correction	O
be	O
attempted	O
in	O
bioequivalence	O
studies	O
of	O
drugs	O
where	O
high	O
intrasubject	O
variability	O
in	O
clearance	O
is	O
known	O
or	O
suspected	O
.	O

A	O
method	O
for	O
determining	O
the	O
toxicity	O
of	O
neutralizers	O
for	O
antimicrobial	O
agents	O
to	O
A	O
.	O
castellanii	O
was	O
also	O
evaluated	O
.	O

In	O
the	O
present	O
study	O
we	O
use	O
a	O
tnaC	B-GENE
-	O
UGA	O
-	O
'	B-GENE
lacZ	I-GENE
construct	O
lacking	O
the	O
tnaC	B-GENE
-	O
tnaA	B-GENE
spacer	O
region	O
to	O
analyze	O
the	O
effect	O
of	O
TnaC	B-GENE
synthesis	O
on	O
the	O
behavior	O
of	O
the	O
ribosome	O
that	O
translates	O
tnaC	B-GENE
.	O

Unlike	O
JNK	B-GENE
activation	O
,	O
ERK	B-GENE
activation	O
could	O
not	O
be	O
mapped	O
to	O
specific	O
reovirus	O
gene	O
segments	O
,	O
suggesting	O
that	O
ERK	B-GENE
activation	O
and	O
JNK	B-GENE
activation	O
are	O
triggered	O
by	O
different	O
events	O
during	O
virus	O
-	O
host	O
cell	O
interaction	O
.	O

Promoter	O
region	O
of	O
the	O
human	B-GENE
alpha	I-GENE
2A	I-GENE
adrenergic	I-GENE
receptor	I-GENE
gene	I-GENE
.	O

Analysis	O
of	O
deletion	O
and	O
substitution	O
mutations	O
in	O
the	O
MER2	B-GENE
5	I-GENE
'	I-GENE
exon	I-GENE
demonstrates	O
that	O
the	O
unusually	O
large	O
size	O
of	O
this	O
exon	O
plays	O
an	O
important	O
role	O
in	O
splicing	O
regulation	O
.	O

Schottky	O
-	O
barrier	O
heights	O
of	O
Ti	O
and	O
TiSi2	O
on	O
n	O
-	O
type	O
and	O
p	O
-	O
type	O
Si	O
(	O
100	O
)	O
.	O

In	O
-	O
111	O
-	O
BLMC	O
uptake	O
was	O
directly	O
proportional	O
to	O
Ki	B-GENE
-	I-GENE
67	I-GENE
/	O
MIB	B-GENE
-	I-GENE
1	I-GENE
activity	O
and	O
number	O
of	O
mitoses	O
in	O
tumor	O
tissue	O
.	O

The	O
majority	O
of	O
the	O
human	B-GENE
Ig	I-GENE
heavy	I-GENE
chain	I-GENE
(	I-GENE
IgH	I-GENE
)	I-GENE
constant	I-GENE
(	I-GENE
C	I-GENE
)	I-GENE
region	I-GENE
locus	I-GENE
has	O
been	O
cloned	O
and	O
mapped	O
.	O

On	O
guanidine	O
and	O
the	O
treatment	O
of	O
botulism	O
.	O

Excellent	O
results	O
were	O
recorded	O
in	O
390	O
(	O
83	O
.	O
69	O
%	O
)	O
of	O
the	O
patients	O
,	O
improvement	O
in	O
46	O
(	O
9	O
.	O
87	O
%	O
)	O
where	O
in	O
the	O
majority	O
a	O
varicose	O
complex	O
was	O
involved	O
.	O

By	O
differential	O
screening	O
of	O
a	O
Xenopus	O
laevis	O
egg	O
cDNA	O
library	O
,	O
we	O
have	O
isolated	O
a	O
2	O
,	O
111	O
bp	O
cDNA	O
which	O
corresponds	O
to	O
a	O
maternal	O
mRNA	O
specifically	O
deadenylated	O
after	O
fertilisation	O
.	O

Most	O
of	O
these	O
elements	O
are	O
adjacent	O
to	O
type	O
X	O
telomeric	O
repeats	O
,	O
and	O
regions	O
flanking	O
four	O
of	O
five	O
characterized	O
S	O
.	O
paradoxus	O
insertions	O
carry	O
autonomously	O
replicating	O
sequences	O
.	O

Mutational	O
analysis	O
of	O
the	O
putative	O
effector	O
domain	O
of	O
the	O
GTP	B-GENE
-	I-GENE
binding	I-GENE
Ypt1	I-GENE
protein	I-GENE
in	O
yeast	O
suggests	O
specific	O
regulation	O
by	O
a	O
novel	O
GAP	B-GENE
activity	O
.	O

We	O
recently	O
described	O
the	O
isolation	O
and	O
characterization	O
of	O
nontoxic	O
PAP	B-GENE
mutants	I-GENE
,	O
NT123	O
-	O
2	O
,	O
which	O
has	O
a	O
point	O
mutation	O
(	O
E176V	O
)	O
in	O
the	O
active	O
site	O
that	O
abolishes	O
enzymatic	O
activity	O
,	O
and	O
NT124	O
-	O
3	O
,	O
which	O
has	O
a	O
nonsense	O
mutation	O
that	O
results	O
in	O
deletion	O
of	O
the	O
C	O
-	O
terminal	O
25	O
aa	O
(	O
W237Stop	O
)	O
.	O

This	O
ligand	O
-	O
independent	O
pathway	O
can	O
function	O
through	O
another	O
androgen	O
-	O
regulated	O
promoter	O
as	O
shown	O
by	O
the	O
use	O
of	O
the	O
mouse	B-GENE
mammary	I-GENE
tumor	I-GENE
virus	I-GENE
MMTV	I-GENE
-	I-GENE
CAT	I-GENE
reporter	I-GENE
.	O

From	O
the	O
present	O
results	O
a	O
concept	O
of	O
hormone	O
-	O
dependent	O
AR	B-GENE
activation	O
is	O
proposed	O
,	O
which	O
requires	O
a	O
functional	O
,	O
direct	O
or	O
indirect	O
intramolecular	O
interaction	O
between	O
the	O
TAD	O
and	O
the	O
LBD	O
.	O

All	O
patients	O
were	O
peritonitis	O
-	O
free	O
at	O
least	O
6	O
weeks	O
before	O
each	O
PET	O
.	O

After	O
control	O
for	O
body	O
mass	O
index	O
,	O
trait	O
anxiety	O
and	O
anger	O
-	O
in	O
remained	O
independent	O
predictors	O
of	O
diastolic	O
blood	O
pressure	O
among	O
the	O
women	O
.	O

Studies	O
on	O
low	O
-	O
dose	O
oral	O
contraceptives	O
:	O
cervical	O
mucus	O
and	O
plasma	O
hormone	O
changes	O
in	O
relation	O
to	O
circulating	O
D	O
-	O
norgestrel	O
and	O
17alpha	O
ethynyl	O
-	O
estradiol	O
concentrations	O
.	O

The	O
predicted	O
vav	B-GENE
oncogene	I-GENE
protein	I-GENE
sequence	I-GENE
exhibits	O
several	O
motifs	O
reminiscent	O
of	O
transcriptional	O
factors	O
.	O

The	O
platelet	B-GENE
membrane	I-GENE
glycoprotein	I-GENE
IIb	I-GENE
/	I-GENE
IIIa	I-GENE
receptor	I-GENE
inhibitor	O
abciximab	O
is	O
used	O
for	O
the	O
treatment	O
of	O
patients	O
undergoing	O
high	O
-	O
risk	O
percutaneous	O
coronary	O
interventions	O
and	O
is	O
used	O
in	O
approximately	O
one	O
third	O
of	O
coronary	O
interventions	O
in	O
the	O
United	O
States	O
and	O
a	O
growing	O
number	O
of	O
procedures	O
in	O
Europe	O
.	O

The	O
mean	O
times	O
to	O
LNR	O
in	O
these	O
groups	O
were	O
42	O
.	O
0	O
months	O
(	O
range	O
,	O
3	O
.	O
0	O
-	O
194	O
.	O
5	O
months	O
)	O
and	O
49	O
.	O
0	O
months	O
(	O
range	O
,	O
3	O
.	O
6	O
-	O
209	O
.	O
0	O
months	O
)	O
respectively	O
.	O

Ultraviolet	O
crosslinking	O
experiments	O
using	O
element	O
B	O
revealed	O
the	O
specific	O
binding	O
of	O
two	O
proteins	O
of	O
approximately	O
43	O
and	O
80	O
kDa	O
.	O

The	O
cells	O
were	O
densely	O
ciliated	O
,	O
each	O
cilium	O
showing	O
a	O
typical	O
9	O
+	O
2	O
fibrilar	O
pattern	O
.	O

Searching	O
the	O
human	O
DNA	O
data	O
base	O
of	O
expressed	O
sequence	O
tags	O
(	O
EST	O
)	O
revealed	O
novel	O
partial	O
sequences	O
similar	O
to	O
,	O
but	O
distinct	O
from	O
,	O
the	O
sequences	O
of	O
the	O
previously	O
known	O
PEF	B-GENE
proteins	I-GENE
.	O

HBO	O
had	O
marked	O
effects	O
on	O
these	O
enzymes	O
:	O
lung	B-GENE
SOD	I-GENE
increased	O
(	O
guinea	O
pigs	O
47	O
%	O
,	O
rats	O
88	O
%	O
)	O
and	O
CAT	B-GENE
and	O
GSHPx	B-GENE
activities	O
decreased	O
(	O
33	O
%	O
)	O
in	O
brain	O
and	O
lung	O
.	O

RXRalpha	B-GENE
/	O
RARalpha	B-GENE
heterodimers	O
and	O
HNF	B-GENE
-	I-GENE
4	I-GENE
homodimers	I-GENE
bind	O
to	O
DR	O
-	O
1	O
motifs	O
on	O
elements	O
B	O
and	O
I4	O
,	O
respectively	O
.	O

Adenomas	O
in	O
the	O
upper	O
gastrointestinal	O
tract	O
were	O
found	O
in	O
all	O
of	O
the	O
patients	O
:	O
Vater	O
'	O
s	O
papilla	O
-	O
-	O
12	O
,	O
duodenum	O
-	O
-	O
nine	O
,	O
and	O
gastric	O
antrum	O
-	O
-	O
seven	O
.	O

A	O
new	O
direct	O
hemagglutination	O
test	O
(	O
HI	O
-	O
GONAVIS	O
)	O
for	O
urinary	O
LH	B-GENE
was	O
compared	O
with	O
the	O
serum	O
radioimmuno	O
-	O
assay	O
of	O
LH	B-GENE
.	O

Sucrose	O
produced	O
in	O
source	O
leaves	O
is	O
the	O
predominant	O
carbon	O
source	O
for	O
developing	O
sink	O
tissues	O
in	O
most	O
higher	O
plants	O
.	O

Accumulation	O
of	O
amines	O
in	O
the	O
isolated	O
perfused	O
rabbit	O
lung	O
.	O

They	O
also	O
show	O
that	O
M	O
.	O
malmoense	O
can	O
be	O
isolated	O
from	O
the	O
environment	O
which	O
may	O
be	O
the	O
source	O
of	O
the	O
infection	O
.	O

On	O
the	O
pharmacology	O
of	O
9	O
,	O
10	O
-	O
dihydro	O
-	O
10	O
-	O
(	O
1	O
-	O
methyl	O
-	O
4	O
-	O
piperidylidene	O
)	O
-	O
9	O
-	O
anthrol	O
(	O
WA	O
335	O
)	O
,	O
a	O
histamine	O
and	O
serotonin	O
antagonist	O

This	O
incompatibility	O
phenotype	O
requires	O
the	O
global	O
transcriptional	O
repressor	O
,	O
KorB	B-GENE
,	O
and	O
the	O
target	O
for	O
incC	B-GENE
-	O
mediated	O
incompatibility	O
is	O
a	O
KorB	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
(	I-GENE
O	I-GENE
(	I-GENE
B	I-GENE
)	I-GENE
)	I-GENE
.	O

Therefore	O
,	O
a	O
structural	O
interaction	O
between	O
PsaL	B-GENE
and	O
PsaI	B-GENE
may	O
stabilize	O
the	O
association	O
of	O
PsaL	B-GENE
with	O
the	O
photosystem	B-GENE
I	I-GENE
core	I-GENE
.	O

Binding	O
of	O
the	O
TorR	B-GENE
regulator	I-GENE
to	O
cis	O
-	O
acting	O
direct	O
repeats	O
activates	O
tor	B-GENE
operon	I-GENE
expression	O
.	O

Histological	O
and	O
immunophenotypic	O
studies	O
revealed	O
12	O
large	O
cell	O
lymphomas	O
(	O
11	O
B	O
cell	O
and	O
one	O
T	O
cell	O
)	O
,	O
two	O
small	O
noncleaved	O
cell	O
lymphomas	O
(	O
B	O
-	O
cell	O
phenotype	O
)	O
,	O
and	O
five	O
low	O
grade	O
B	O
-	O
cell	O
lymphomas	O
(	O
two	O
small	O
lymphocytic	O
and	O
three	O
follicular	O
mixed	O
lymphomas	O
)	O
.	O

The	O
subjects	O
were	O
17	O
patients	O
with	O
android	O
obesity	O
(	O
four	O
men	O
and	O
13	O
women	O
)	O
aged	O
21	O
to	O
58	O
years	O
with	O
a	O
body	O
mass	O
index	O
(	O
BMI	O
)	O
ranging	O
from	O
32	O
.	O
0	O
to	O
52	O
.	O
2	O
kg	O
/	O
m2	O
and	O
an	O
abdominal	O
-	O
gluteal	O
ratio	O
greater	O
than	O
1	O
.	O
0	O
.	O

A	O
mean	O
value	O
for	O
HbA1	B-GENE
greater	O
than	O
10	O
%	O
was	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
progression	O
of	O
retinopathy	O
and	O
a	O
mean	O
value	O
less	O
than	O
8	O
.	O
7	O
%	O
was	O
associated	O
with	O
a	O
diminished	O
risk	O
.	O

An	O
emended	O
diagnosis	O
of	O
Tylocephalum	O
is	O
proposed	O
excluding	O
this	O
feature	O
,	O
along	O
with	O
distribution	O
of	O
the	O
testes	O
in	O
the	O
preovarian	O
field	O
and	O
circummedullary	O
distribution	O
of	O
vitelline	O
follicles	O
.	O

Role	O
of	O
double	B-GENE
-	I-GENE
stranded	I-GENE
RNA	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
in	O
mediating	O
hypersensitivity	O
of	O
Fanconi	O
anemia	O
complementation	O
group	O
C	O
cells	O
to	O
interferon	B-GENE
gamma	I-GENE
,	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
,	O
and	O
double	O
-	O
stranded	O
RNA	O
.	O

Different	O
effects	O
of	O
reoxygenation	O
on	O
the	O
electrical	O
activity	O
of	O
ventricular	O
muscle	O
.	O

Similar	O
observations	O
were	O
obtained	O
when	O
these	O
mutated	O
versions	O
of	O
site	O
A	O
were	O
evaluated	O
by	O
transient	O
cotransfection	O
assays	O
in	O
CV1	O
cells	O
.	O

YLL031c	B-GENE
is	O
an	O
essential	O
gene	O
.	O

We	O
have	O
measured	O
percentage	O
O3	O
uptake	O
in	O
30	O
adult	O
Sprague	O
-	O
Dawley	O
rats	O
exposed	O
,	O
nose	O
only	O
,	O
for	O
1	O
hr	O
to	O
0	O
.	O
3	O
,	O
0	O
.	O
6	O
,	O
or	O
1	O
.	O
0	O
ppm	O
O3	O
.	O

Threefold	O
risks	O
were	O
observed	O
for	O
men	O
with	O
the	O
highest	O
level	O
of	O
intensity	O
and	O
for	O
those	O
with	O
the	O
highest	O
probability	O
of	O
EMF	O
exposure	O
,	O
although	O
women	O
with	O
heavy	O
EMF	O
exposure	O
did	O
not	O
experience	O
increased	O
risk	O
.	O

Further	O
,	O
cells	O
cotransfected	O
with	O
a	O
UF	B-GENE
promoter	I-GENE
-	O
luciferase	B-GENE
(	O
-	O
1935UF	B-GENE
-	O
Luc	B-GENE
)	O
reporter	O
gene	O
and	O
the	O
BTEB	B-GENE
expression	O
vector	O
had	O
2	O
-	O
fold	O
higher	O
Luc	B-GENE
activity	O
than	O
those	O
cotransfected	O
with	O
reporter	O
gene	O
and	O
pcDNA	O
-	O
3	O
.	O

Early	O
complement	O
components	O
,	O
C1q	B-GENE
and	O
C4	B-GENE
,	O
and	O
IgA	B-GENE
secretory	O
piece	O
were	O
absent	O
.	O

Although	O
IRS	B-GENE
-	I-GENE
1	I-GENE
,	I-GENE
-	I-GENE
2	I-GENE
,	I-GENE
and	I-GENE
-	I-GENE
4	I-GENE
are	O
similar	O
in	O
overall	O
structure	O
,	O
IRS	B-GENE
-	I-GENE
3	I-GENE
is	O
approximately	O
50	O
%	O
shorter	O
and	O
differs	O
with	O
respect	O
to	O
sites	O
of	O
tyrosine	O
phosphorylation	O
.	O

These	O
results	O
demonstrate	O
a	O
specific	O
association	O
of	O
SIV	O
and	O
HIV	B-GENE
-	I-GENE
2	I-GENE
nef	I-GENE
,	O
but	O
not	O
HIV	B-GENE
-	I-GENE
1	I-GENE
nef	I-GENE
,	O
with	O
TCRzeta	B-GENE
.	O

METHODS	O
:	O
We	O
retrospectively	O
analyzed	O
the	O
data	O
of	O
20	O
patients	O
who	O
underwent	O
both	O
gated	O
fluorine	O
18	O
deoxyglucose	O
(	O
FDG	O
)	O
-	O
PET	O
and	O
equilibrium	O
radionuclide	O
angiography	O
(	O
ERNA	O
)	O
.	O

The	O
distinct	O
spatial	O
pattern	O
of	O
expression	O
,	O
and	O
unusual	O
amino	O
acid	O
sequence	O
in	O
its	O
DNA	O
binding	O
domain	O
,	O
may	O
indicate	O
a	O
particular	O
role	O
for	O
DTEF	B-GENE
-	I-GENE
1	I-GENE
in	O
cell	O
-	O
specific	O
gene	O
regulation	O
.	O

Rac2	B-GENE
,	O
a	O
member	O
of	O
the	O
Rho	B-GENE
family	I-GENE
of	O
GTPases	B-GENE
,	O
is	O
highly	O
expressed	O
in	O
myeloid	O
cells	O
and	O
is	O
a	O
regulator	O
of	O
the	O
NADPH	B-GENE
-	I-GENE
oxidase	I-GENE
complex	I-GENE
.	O

The	O
yeast	B-GENE
mitochondrial	I-GENE
Hsp70	I-GENE
,	O
Ssc1p	B-GENE
,	O
functions	O
as	O
a	O
molecular	O
chaperone	O
with	O
its	O
partner	O
proteins	O
,	O
Mdj1p	B-GENE
(	O
DnaJ	B-GENE
homologue	I-GENE
)	O
and	O
Yge1p	B-GENE
(	O
GrpE	B-GENE
homologue	I-GENE
)	O
.	O

The	O
best	O
sequences	O
for	O
pelvic	O
study	O
are	O
,	O
in	O
our	O
experience	O
,	O
IR	O
or	O
short	O
TR	O
spin	O
-	O
echo	O
for	O
T1	O
-	O
weighted	O
images	O
,	O
and	O
spin	O
-	O
echo	O
with	O
1200	O
TR	O
for	O
T2	O
images	O
.	O

We	O
now	O
report	O
that	O
both	O
HSCR	B-GENE
mutations	O
impair	O
the	O
fixation	O
of	O
Shc	B-GENE
to	O
RET	B-GENE
and	O
consequently	O
prevent	O
its	O
phosphorylation	O
.	O

We	O
now	O
describe	O
a	O
HepG2	B-GENE
cell	I-GENE
casein	I-GENE
kinase	I-GENE
II	I-GENE
beta	I-GENE
subunit	I-GENE
cDNA	I-GENE
of	O
2	O
.	O
57	O
kb	O
containing	O
96	O
bases	O
of	O
5	O
'	O
untranslated	O
sequence	O
,	O
645	O
bases	O
of	O
open	O
reading	O
frame	O
,	O
and	O
1832	O
bases	O
of	O
3	O
'	O
untranslated	O
sequence	O
with	O
two	O
polyadenylation	O
consensus	O
signal	O
sequences	O
and	O
two	O
poly	O
(	O
A	O
)	O
stretches	O
.	O

Platelet	B-GENE
factor	I-GENE
4	I-GENE
levels	O
in	O
patients	O
with	O
coronary	O
artery	O
disease	O
.	O

Serum	O
pituitary	O
and	O
steroid	O
hormone	O
levels	O
in	O
the	O
adult	O
male	O
:	O
one	O
value	O
is	O
as	O
good	O
as	O
the	O
mean	O
of	O
three	O
.	O

Blood	O
ammonia	O
concentration	O
was	O
significantly	O
higher	O
in	O
males	O
at	O
70	O
,	O
80	O
and	O
90	O
%	O
of	O
VO2	O
peak	O
.	O

Here	O
,	O
we	O
describe	O
the	O
crystal	O
structure	O
at	O
2	O
.	O
5	O
A	O
resolution	O
of	O
a	O
fragment	O
of	O
the	O
integrase	B-GENE
of	I-GENE
Rous	I-GENE
sarcoma	I-GENE
virus	I-GENE
(	I-GENE
residues	I-GENE
49	I-GENE
-	I-GENE
286	I-GENE
)	I-GENE
containing	O
both	O
the	O
conserved	O
catalytic	O
domain	O
and	O
a	O
modulatory	O
DNA	O
-	O
binding	O
domain	O
(	O
C	O
domain	O
)	O
.	O

The	O
effect	O
on	O
kidney	O
length	O
was	O
considerably	O
prolonged	O
compared	O
with	O
the	O
vascular	O
effect	O
.	O

The	O
prevalence	O
of	O
microalbuminuria	O
,	O
defined	O
as	O
an	O
UAER	O
in	O
the	O
range	O
of	O
15	O
-	O
150	O
micrograms	O
min	O
-	O
1	O
in	O
an	O
overnight	O
urine	O
sample	O
,	O
was	O
3	O
%	O
(	O
95	O
%	O
C	O
.	O
I	O
.	O
interval	O
:	O
1	O
.	O
9	O
-	O
4	O
.	O
0	O
)	O
.	O

However	O
,	O
a	O
lesser	O
extent	O
effect	O
was	O
noticed	O
in	O
nonpregnant	O
than	O
seen	O
in	O
pregnant	O
rats	O
.	O

Despite	O
their	O
high	O
degree	O
of	O
sequence	O
similarity	O
,	O
all	O
five	O
RFC	B-GENE
genes	I-GENE
are	O
essential	O
for	O
cell	O
proliferation	O
in	O
S	O
.	O
cerevisiae	O
.	O

Rev	O
.	O

The	O
strongly	O
DNA	O
binding	O
p50	B-GENE
subunit	I-GENE
showed	O
only	O
very	O
weak	O
,	O
if	O
any	O
,	O
induction	O
of	O
gene	O
expression	O
.	O

Stability	O
of	O
125	O
I	O
-	O
labeled	O
insulin	B-GENE
used	O
in	O
radioimmunoassay	O
of	O
insulin	B-GENE
.	O

Influence	O
of	O
long	O
-	O
term	O
zimelidine	O
treatment	O
on	O
LSD	O
-	O
induced	O
behavioural	O
effects	O
.	O

Using	O
mammalian	O
expression	O
vectors	O
(	O
pRSV	O
-	O
neo	O
and	O
pSV2	O
-	O
neo	O
)	O
,	O
antisense	O
constructs	O
for	O
perforin	B-GENE
and	O
granzyme	B-GENE
B	I-GENE
were	O
independently	O
electroporated	O
into	O
YT	O
-	O
INDY	O
,	O
a	O
human	O
non	O
-	O
MHC	B-GENE
-	O
restricted	O
,	O
IL	B-GENE
-	I-GENE
2	I-GENE
-	O
independent	O
,	O
cytotoxic	O
lymphocyte	O
.	O

When	O
targeted	O
to	O
the	O
GAL1	B-GENE
promoter	I-GENE
by	O
fusing	O
with	O
the	O
Gal4p	B-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
domain	I-GENE
,	O
Sko1p	B-GENE
acts	O
as	O
an	O
Ssn6	B-GENE
/	O
Tup1p	B-GENE
-	O
dependent	O
repressor	O
regulated	O
by	O
osmotic	O
stress	O
.	O

Like	O
Rev	B-GENE
-	O
Erb	B-GENE
,	O
BD73	B-GENE
binds	O
as	O
a	O
monomer	O
to	O
a	O
DNA	O
sequence	O
which	O
consists	O
of	O
a	O
specific	O
A	O
/	O
T	O
-	O
rich	O
sequence	O
upstream	O
of	O
the	O
consensus	O
hexameric	O
half	O
-	O
site	O
specified	O
by	O
the	O
P	O
box	O
of	O
the	O
DNA	O
-	O
binding	O
domain	O
.	O

BACKGROUND	O
:	O
Allergic	O
rhinoconjunctivitis	O
is	O
a	O
common	O
disorder	O
,	O
affecting	O
>	O
20	O
%	O
of	O
people	O
of	O
all	O
socioeconomic	O
strata	O
.	O

INTERVENTIONS	O
:	O
Postoperative	O
follow	O
-	O
up	O
consisted	O
of	O
serial	O
determination	O
of	O
different	O
biochemical	O
markers	O
(	O
CK	B-GENE
,	O
CK	B-GENE
-	I-GENE
MB	I-GENE
,	O
cTnI	B-GENE
)	O
,	O
ECGs	O
,	O
and	O
echocardiography	O
.	O

The	O
striking	O
similarity	O
in	O
preference	O
for	O
mismatched	O
and	O
weakly	O
paired	O
nucleotides	O
for	O
binding	O
and	O
for	O
excision	O
suggests	O
a	O
functional	O
relationship	O
between	O
binding	O
and	O
cleavage	O
reactions	O
.	O

New	O
results	O
of	O
importance	O
for	O
optimization	O
of	O
the	O
postoperative	O
course	O
]	O
Complications	O
after	O
major	O
surgery	O
may	O
be	O
related	O
to	O
factors	O
in	O
the	O
surgical	O
stress	O
response	O
with	O
endocrine	O
-	O
metabolic	O
and	O
inflammatory	O
changes	O
.	O

Immunoblotting	O
showed	O
that	O
both	O
the	O
(	O
1	O
-	O
404	O
)	O
-	O
peptide	O
and	O
(	O
1	O
-	O
506	O
)	O
-	O
peptide	O
are	O
recognized	O
by	O
95J10	B-GENE
,	O
a	O
monoclonal	O
antibody	O
that	O
was	O
previously	O
raised	O
against	O
perlecan	B-GENE
-	I-GENE
(	I-GENE
24	I-GENE
-	I-GENE
404	I-GENE
)	I-GENE
-	I-GENE
peptide	I-GENE
expressed	O
in	O
Escherichia	O
coli	O
.	O

Tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
levels	O
were	O
measured	O
by	O
enzyme	O
-	O
linked	O
immunoabsorbent	O
assay	O
in	O
plasma	O
samples	O
obtained	O
from	O
the	O
hyperthermic	O
isolated	O
limb	O
perfusion	O
circuit	O
and	O
systemic	O
circulation	O
.	O

Serum	B-GENE
alpha	I-GENE
-	I-GENE
amylase	I-GENE
,	O
trypsin	B-GENE
,	O
trypsin	B-GENE
inhibitor	I-GENE
,	O
lipase	B-GENE
and	O
total	O
protease	O
activity	O
in	O
the	O
pancreatic	O
tissue	O
was	O
studied	O
as	O
indicator	O
of	O
the	O
treatment	O
efficacy	O
with	O
5	O
-	O
fluorouracil	O
electro	O
-	O
cumulation	O
.	O

The	O
possible	O
equivalency	O
of	O
a	O
short	O
form	O
and	O
the	O
long	O
form	O
of	O
the	O
Multiple	O
Affect	O
Adjective	O
Check	O
List	O
-	O
Revised	O
(	O
MAACL	O
-	O
R	O
;	O
Zuckerman	O
&	O
Lubin	O
,	O
1985	O
)	O
was	O
studied	O
by	O
correlating	O
both	O
forms	O
of	O
the	O
MAACL	O
-	O
R	O
with	O
the	O
State	O
Trait	O
Personality	O
Inventory	O
(	O
Spielberger	O
,	O
1995	O
)	O
;	O
the	O
Affect	O
Balance	O
Scale	O
(	O
Bradburn	O
,	O
1969	O
)	O
;	O
and	O
the	O
Sensation	O
Seeking	O
Scale	O
(	O
Zuckerman	O
,	O
1978	O
)	O
.	O

The	O
activity	O
of	O
platelet	B-GENE
factor	I-GENE
4	I-GENE
in	O
plasma	O
of	O
healthy	O
and	O
high	O
risk	O
newborns	O
.	O

Studies	O
of	O
HS2	B-GENE
-	I-GENE
gamma	I-GENE
gene	I-GENE
reporter	I-GENE
constructs	I-GENE
carrying	O
CACCC	O
box	O
deletions	O
revealed	O
that	O
the	O
CACCC	O
box	O
sequence	O
of	O
the	O
gamma	O
gene	O
promoter	O
mediates	O
the	O
activation	O
of	O
the	O
gamma	O
gene	O
by	O
FKLF	B-GENE
.	O

In	O
addition	O
,	O
mrp17	B-GENE
-	I-GENE
1	I-GENE
,	O
in	O
combination	O
with	O
some	O
mutations	O
affecting	O
another	O
mitochondrial	O
ribosomal	O
protein	O
,	O
caused	O
a	O
synthetic	O
defective	O
phenotype	O
.	O

Erdheim	O
-	O
Chester	O
disease	O
:	O
a	O
distinct	O
lipoidosis	O
or	O
part	O
of	O
the	O
spectrum	O
of	O
histiocytosis	O
?	O
Erdheim	O
-	O
Chester	O
disease	O
has	O
always	O
been	O
considered	O
a	O
distinct	O
lipoidosis	O
based	O
on	O
clinical	O
and	O
radiographic	O
criteria	O
.	O

The	O
ossification	O
was	O
located	O
on	O
the	O
left	O
side	O
of	O
C3	O
-	O
4	O
.	O

Characterization	O
of	O
human	B-GENE
activating	I-GENE
transcription	I-GENE
factor	I-GENE
4	I-GENE
,	O
a	O
transcriptional	O
activator	O
that	O
interacts	O
with	O
multiple	O
domains	O
of	O
cAMP	B-GENE
-	I-GENE
responsive	I-GENE
element	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CREB	B-GENE
)	O
-	O
binding	O
protein	O
.	O

If	O
the	O
size	O
of	O
the	O
cystic	O
liver	O
-	O
lesions	O
excludes	O
a	O
curative	O
operative	O
treatment	O
or	O
if	O
the	O
patient	O
refuses	O
surgery	O
,	O
the	O
indication	O
for	O
chemotherapy	O
with	O
mebendazole	O
is	O
given	O
.	O

The	O
Ixodes	O
fauna	O
in	O
the	O
Michourin	O
region	O
,	O
where	O
the	O
pastures	O
in	O
1971	O
were	O
grazed	O
only	O
by	O
sheep	O
,	O
shows	O
the	O
following	O
trends	O
:	O
H	O
.	O
punctata	O
and	O
R	O
.	O
turanicus	O
ticks	O
,	O
which	O
are	O
preferably	O
parasitising	O
in	O
sheep	O
,	O
increase	O
their	O
relative	O
share	O
.	O

The	O
contribution	O
of	O
residues	O
outside	O
the	O
Ras	B-GENE
binding	I-GENE
domain	I-GENE
of	O
Raf	B-GENE
(	O
RafRBD	B-GENE
)	O
to	O
Ras	B-GENE
-	O
Raf	B-GENE
interaction	O
and	O
Ras	B-GENE
-	O
dependent	O
Raf	B-GENE
activation	O
has	O
remained	O
unresolved	O
.	O

We	O
suggest	O
that	O
electrical	O
stimulation	O
of	O
the	O
NTS	O
in	O
rats	O
undergoing	O
such	O
surgical	O
preparation	O
to	O
observe	O
the	O
pressor	O
response	O
and	O
/	O
or	O
increase	O
in	O
pVP	O
,	O
represents	O
a	O
rapid	O
approach	O
for	O
screening	O
the	O
neurosecretory	O
function	O
of	O
the	O
central	O
neural	O
integration	O
to	O
release	O
vasopressin	B-GENE
.	O

CONCLUSION	O
/	O
INTERPRETATION	O
:	O
We	O
found	O
an	O
increased	O
risk	O
of	O
hip	O
fracture	O
in	O
women	O
younger	O
than	O
75	O
years	O
with	O
Type	O
I	O
diabetes	O
or	O
with	O
Type	O
II	O
diabetes	O
of	O
long	O
duration	O
.	O

Mean	O
24	O
h	O
urinary	O
excretion	O
values	O
confirmed	O
this	O
observation	O
.	O

Here	O
we	O
investigate	O
the	O
mechanism	O
of	O
TPA	O
induction	O
of	O
FGF	B-GENE
-	I-GENE
BP	I-GENE
gene	O
expression	O
in	O
the	O
human	O
ME	O
-	O
180	O
SCC	O
cell	O
line	O
.	O

They	O
represent	O
a	O
physiologically	O
more	O
meaningful	O
pattern	O
than	O
the	O
arithmetic	O
mean	O
with	O
standard	O
deviation	O
.	O

The	O
influence	O
of	O
gas	O
composition	O
in	O
the	O
air	O
cell	O
on	O
pipping	O
and	O
liver	O
metabolism	O
in	O
embryonic	O
chicks	O
.	O

However	O
,	O
FosB	B-GENE
-	I-GENE
L	I-GENE
and	O
FosB	B-GENE
-	I-GENE
S	I-GENE
do	O
not	O
differ	O
in	O
all	O
trans	O
-	O
regulatory	O
properties	O
:	O
Trans	O
-	O
activation	O
of	O
a	O
5x	O
TRE	B-GENE
-	I-GENE
CAT	I-GENE
reporter	O
construct	O
in	O
HeLa	O
and	O
NIH	O
-	O
3T3	O
cells	O
was	O
found	O
with	O
both	O
FosB	B-GENE
forms	O
.	O

Numerous	O
genes	O
of	O
this	O
family	O
have	O
been	O
identified	O
in	O
animals	O
,	O
with	O
the	O
largest	O
number	O
found	O
in	O
vertebrates	O
.	O

Mineralized	O
bone	O
nodule	O
formation	O
in	O
vitro	O
by	O
cell	O
populations	O
from	O
young	O
adult	O
rabbit	O
alveolar	O
bone	O
.	O

Soluble	O
extracts	O
from	O
FGF	B-GENE
-	O
treated	O
as	O
compared	O
with	O
quiescent	O
fibroblasts	O
exhibited	O
up	O
to	O
3	O
-	O
fold	O
higher	O
kinase	O
activity	O
towards	O
S6	B-GENE
in	O
exogenously	O
added	O
rat	B-GENE
liver	I-GENE
40S	I-GENE
ribosomes	I-GENE
and	O
a	O
synthetic	O
peptide	O
,	O
RRLSSLRA	O
.	O

In	O
conclusion	O
,	O
when	O
pulmonary	O
abnormalities	O
are	O
found	O
in	O
HTLV	O
-	O
1	O
carriers	O
,	O
we	O
should	O
be	O
careful	O
in	O
determining	O
whether	O
such	O
pulmonary	O
involvements	O
are	O
etiologically	O
related	O
to	O
HTLV	O
-	O
1	O
infection	O
.	O

We	O
found	O
that	O
48	O
%	O
of	O
the	O
patients	O
had	O
their	O
thoracolumbar	O
blood	O
supply	O
based	O
on	O
two	O
anterior	O
radiculospinal	O
arteries	O
the	O
lowest	O
of	O
which	O
was	O
located	O
at	O
,	O
or	O
lower	O
than	O
,	O
T12	O
,	O
and	O
the	O
second	O
and	O
higher	O
one	O
between	O
T6	O
and	O
T10	O
.	O

Cross	O
-	O
species	O
characterization	O
of	O
the	O
promoter	B-GENE
region	I-GENE
of	I-GENE
the	I-GENE
cystic	I-GENE
fibrosis	I-GENE
transmembrane	I-GENE
conductance	I-GENE
regulator	I-GENE
gene	I-GENE
reveals	O
multiple	O
levels	O
of	O
regulation	O
.	O

The	O
leader	O
peptide	O
was	O
hypothesized	O
to	O
inhibit	O
ribosome	O
release	O
at	O
the	O
tnaC	B-GENE
stop	I-GENE
codon	I-GENE
,	O
thereby	O
blocking	O
Rho	B-GENE
'	O
s	O
access	O
to	O
the	O
transcript	O
.	O

We	O
have	O
isolated	O
a	O
unique	O
murine	B-GENE
FLT3	I-GENE
cDNA	I-GENE
that	O
codes	O
for	O
a	O
variant	O
isoform	O
of	O
FLT3	B-GENE
,	O
devoid	O
of	O
the	O
fifth	O
Ig	B-GENE
-	I-GENE
like	I-GENE
domain	I-GENE
,	O
by	O
comparison	O
with	O
the	O
prototypic	O
form	O
.	O

Thus	O
,	O
22	O
%	O
of	O
MDS	O
responded	O
to	O
oral	O
PLAC	O
.	O

Plasma	B-GENE
beta	I-GENE
-	I-GENE
thromboglobulin	I-GENE
(	O
beta	B-GENE
-	I-GENE
TG	I-GENE
)	O
,	O
a	O
platelet	O
-	O
specific	O
protein	O
,	O
is	O
a	O
marker	O
of	O
intravascular	O
platelet	O
degranulation	O
.	O

The	O
Synechococcus	B-GENE
gene	I-GENE
rps1	I-GENE
encoding	O
S1	B-GENE
is	O
located	O
1	O
.	O
1	O
kb	O
downstream	O
from	O
psbB	B-GENE
,	O
which	O
encodes	O
the	O
photosystem	B-GENE
II	I-GENE
P680	I-GENE
chlorophyll	I-GENE
a	I-GENE
apoprotein	I-GENE
.	O

Additions	O
of	O
NH4	O
+	O
up	O
to	O
200	O
micrograms	O
1	O
(	O
-	O
1	O
)	O
were	O
not	O
stimulatory	O
,	O
whereas	O
at	O
1	O
.	O
0	O
mg	O
1	O
(	O
-	O
1	O
)	O
levels	O
,	O
Ke	O
was	O
50	O
%	O
greater	O
than	O
for	O
NO3	O
-	O
enriched	O
medium	O
.	O

Pretreatment	O
with	O
lipid	O
X	O
was	O
not	O
necessary	O
to	O
improve	O
survival	O
:	O
16	O
of	O
17	O
(	O
94	O
%	O
)	O
infected	O
and	O
visibly	O
ill	O
animals	O
that	O
received	O
lipid	O
X	O
and	O
ticarcillin	O
6	O
h	O
after	O
thigh	O
inoculation	O
survived	O
versus	O
30	O
of	O
44	O
(	O
68	O
%	O
)	O
control	O
animals	O
treated	O
with	O
ticarcillin	O
alone	O
(	O
P	O
less	O
than	O
0	O
.	O
0001	O
)	O
.	O

Between	O
1988	O
and	O
1994	O
,	O
data	O
from	O
3	O
large	O
sites	O
revealed	O
a	O
3	O
-	O
5	O
fold	O
increase	O
in	O
the	O
prevalence	O
of	O
antidepressant	O
(	O
ATD	O
)	O
treatment	O
for	O
U	O
.	O
S	O
.	O
youths	O
aged	O
2	O
-	O
19	O
years	O
.	O

4	O
.	O

RESULTS	O
:	O
Analysis	O
by	O
Pearson	O
'	O
s	O
correlation	O
showed	O
that	O
the	O
subjects	O
who	O
had	O
higher	O
scores	O
of	O
SSMS	O
during	O
the	O
drum	O
rotation	O
generated	O
the	O
following	O
:	O
a	O
)	O
a	O
higher	O
rating	O
of	O
over	O
-	O
all	O
sickness	O
(	O
r	O
=	O
0	O
.	O
76	O
)	O
;	O
b	O
)	O
a	O
higher	O
ratio	O
of	O
spectral	O
power	O
of	O
EGG	O
at	O
4	O
-	O
9	O
cycles	O
per	O
minute	O
(	O
cpm	O
)	O
between	O
drum	O
rotation	O
and	O
baseline	O
periods	O
(	O
r	O
=	O
0	O
.	O
63	O
)	O
;	O
c	O
)	O
a	O
higher	O
net	O
percent	O
increase	O
of	O
spectral	O
power	O
in	O
the	O
EEG	O
frequency	O
band	O
0	O
.	O
5	O
-	O
4	O
Hz	O
between	O
drum	O
rotation	O
and	O
baseline	O
periods	O
on	O
C3	O
(	O
r	O
=	O
0	O
.	O
29	O
)	O
and	O
C4	O
(	O
r	O
=	O
0	O
.	O
31	O
)	O
;	O
d	O
)	O
a	O
higher	O
ratio	O
of	O
spectral	O
power	O
of	O
EEG	O
frequency	O
band	O
0	O
.	O
5	O
-	O
4	O
Hz	O
between	O
drum	O
rotation	O
and	O
baseline	O
periods	O
on	O
C3	O
(	O
r	O
=	O
0	O
.	O
31	O
)	O
;	O
and	O
e	O
)	O
a	O
higher	O
level	O
of	O
net	O
increase	O
in	O
skin	O
conductance	O
from	O
baseline	O
to	O
drum	O
rotation	O
(	O
r	O
=	O
0	O
.	O
30	O
)	O
.	O

After	O
inhibition	O
of	O
monoamine	B-GENE
oxidase	I-GENE
with	O
pargyline	O
(	O
10	O
mg	O
/	O
kg	O
.	O
i	O
.	O
v	O
.	O
)	O
,	O
the	O
effects	O
of	O
tyramine	O
(	O
1000	O
micrograms	O
)	O
injected	O
into	O
the	O
hepatic	O
artery	O
were	O
potentiated	O
.	O

However	O
,	O
the	O
addition	O
of	O
intravenous	O
injection	O
of	O
FPFD	O
101	O
resulted	O
in	O
a	O
marked	O
improvement	O
in	O
their	O
symptoms	O
.	O

We	O
report	O
that	O
Gcn5	B-GENE
,	O
a	O
histone	B-GENE
H3	I-GENE
acetylase	I-GENE
,	O
plays	O
a	O
central	O
role	O
in	O
initiation	O
of	O
meiosis	O
via	O
effects	O
on	O
IME2	B-GENE
expression	O
.	O

In	O
the	O
presence	O
of	O
high	O
concentrations	O
(	O
propofol	O
100	O
microg	O
mL	O
-	O
1	O
,	O
thiopental	O
50	O
microg	O
mL	O
-	O
1	O
)	O
marked	O
relaxation	O
was	O
observed	O
(	O
propofol	O
-	O
32	O
%	O
up	O
to	O
-	O
49	O
%	O
,	O
P	O
<	O
0	O
,	O
05	O
;	O
thiopental	O
-	O
23	O
%	O
up	O
to	O
-	O
67	O
%	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

In	O
further	O
support	O
of	O
the	O
biological	O
significance	O
of	O
these	O
DNA	O
-	O
protein	O
interactions	O
,	O
the	O
IL2RA	B-GENE
oligonucleotide	O
from	O
-	O
291	O
to	O
-	O
245	O
proved	O
to	O
be	O
sufficient	O
in	O
either	O
orientation	O
to	O
confer	O
PMA	O
inducibility	O
to	O
the	O
mitogen	O
-	O
insensitive	O
thymidine	B-GENE
kinase	I-GENE
gene	I-GENE
promoter	I-GENE
in	O
Jurkat	O
cells	O
.	O

The	O
amino	O
acid	O
residues	O
and	O
subdomains	O
important	O
for	O
DNA	O
binding	O
,	O
hormone	O
binding	O
,	O
dimerization	O
,	O
and	O
transactivation	O
are	O
mostly	O
conserved	O
among	O
all	O
VDR	B-GENE
species	O
.	O

Here	O
,	O
we	O
describe	O
the	O
nucleotide	O
(	O
nt	O
)	O
sequence	O
and	O
genomic	O
organization	O
of	O
ipiB	B-GENE
and	O
ipiO	B-GENE
.	O

Specifically	O
,	O
we	O
demonstrate	O
that	O
this	O
25	O
-	O
base	O
pair	O
region	O
mediates	O
the	O
up	O
-	O
regulatory	O
effect	O
of	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
on	O
COL1A2	B-GENE
promoter	I-GENE
activity	O
and	O
allows	O
antagonistic	O
activity	O
of	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
on	O
the	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
effect	O
.	O

The	O
phosphatidylglycerol	B-GENE
/	I-GENE
phosphatidylinositol	I-GENE
transfer	I-GENE
protein	I-GENE
(	O
PG	B-GENE
/	I-GENE
PI	I-GENE
-	I-GENE
TP	I-GENE
)	O
is	O
a	O
new	O
and	O
original	O
phospholipid	B-GENE
transfer	I-GENE
protein	I-GENE
(	O
PLTP	B-GENE
)	O
isolated	O
from	O
the	O
Deuteromycete	O
,	O
Aspergillus	O
oryzae	O
.	O

A	O
5789	B-GENE
-	I-GENE
nucleotide	I-GENE
-	I-GENE
long	I-GENE
EcoRI	I-GENE
fragment	I-GENE
from	O
the	O
genome	O
of	O
Thermotoga	O
maritima	O
,	O
identified	O
by	O
cross	O
-	O
hybridization	O
to	O
L11	B-GENE
,	O
L1	B-GENE
,	O
L10	B-GENE
,	O
and	O
L12	B-GENE
ribosomal	I-GENE
protein	I-GENE
gene	I-GENE
sequences	I-GENE
from	I-GENE
Escherichia	I-GENE
coli	I-GENE
,	O
was	O
cloned	O
and	O
sequenced	O
.	O

Endotoxemia	O
and	O
bacteremia	O
in	O
patients	O
with	O
sepsis	O
syndrome	O
in	O
the	O
intensive	O
care	O
unit	O
.	O

Several	O
35	O
-	O
mm	O
slides	O
of	O
dystrophin	B-GENE
-	O
,	O
laminin	B-GENE
-	O
,	O
and	O
concanavalin	B-GENE
A	I-GENE
(	O
ConA	B-GENE
)	O
-	O
stained	O
muscle	O
sections	O
were	O
used	O
to	O
calculate	O
myofiber	O
cross	O
-	O
sectional	O
areas	O
and	O
to	O
compare	O
different	O
techniques	O
and	O
settings	O
of	O
an	O
image	O
capture	O
system	O
.	O

Indeed	O
,	O
after	O
a	O
single	O
oral	O
dose	O
,	O
the	O
role	O
of	O
the	O
mu	B-GENE
-	I-GENE
receptor	I-GENE
agonist	O
component	O
of	O
the	O
antinociceptive	O
effect	O
of	O
tramadol	O
appears	O
to	O
be	O
minor	O
,	O
with	O
most	O
of	O
the	O
analgesic	O
effect	O
being	O
attributable	O
to	O
nonopioid	O
properties	O
of	O
the	O
parent	O
compound	O
.	O

The	O
mRNA	O
for	O
this	O
protein	O
is	O
expressed	O
in	O
the	O
T	O
-	O
ALL	O
cell	O
line	O
Jurkat	O
and	O
has	O
been	O
designated	O
HUG1	B-GENE
,	O
for	O
HOX11	B-GENE
Upstream	I-GENE
Gene	I-GENE
.	O

In	O
solution	O
,	O
[	O
(	O
125	O
)	O
I	O
]	O
-	O
labeled	O
ankyrin	B-GENE
was	O
found	O
by	O
ND	O
-	O
PAGE3	O
to	O
enhance	O
the	O
affinity	O
of	O
spectrin	B-GENE
self	O
-	O
association	O
by	O
10	O
-	O
fold	O
.	O

The	O
MEF	B-GENE
-	I-GENE
2	I-GENE
proteins	I-GENE
are	O
a	O
family	O
of	O
transcriptional	O
activators	O
that	O
have	O
been	O
detected	O
in	O
a	O
wide	O
variety	O
of	O
cell	O
types	O
.	O

Jet	O
lag	O
and	O
melatonin	O
.	O

Manual	O
sample	O
clean	O
-	O
up	O
procedures	O
as	O
well	O
as	O
the	O
addition	O
of	O
an	O
internal	O
standard	O
are	O
not	O
needed	O
.	O

Treatment	O
of	O
diabetes	O
and	O
retinal	O
complications	O

In	O
contrast	O
,	O
an	O
N	B-GENE
-	I-GENE
terminal	I-GENE
RNAP	I-GENE
mutant	I-GENE
that	O
has	O
a	O
decreased	O
capacity	O
to	O
bind	O
single	O
-	O
stranded	O
RNA	O
forms	O
halted	O
complexes	O
with	O
much	O
lower	O
levels	O
of	O
stability	O
than	O
the	O
WT	O
enzyme	O
,	O
and	O
these	O
complexes	O
are	O
not	O
stabilized	O
by	O
the	O
presence	O
of	O
the	O
NT	O
strand	O
.	O

The	O
densities	O
ranged	O
between	O
2	O
and	O
3976	O
neurites	O
/	O
mm2	O
skin	O
surface	O
,	O
but	O
the	O
overlap	O
between	O
subjects	O
and	O
without	O
PHN	O
was	O
small	O
.	O

The	O
present	O
study	O
demonstrates	O
that	O
the	O
proto	B-GENE
-	I-GENE
oncogene	I-GENE
c	I-GENE
-	I-GENE
jun	I-GENE
represses	O
transcription	O
of	O
the	O
human	B-GENE
CG	I-GENE
alpha	I-GENE
and	O
CG	B-GENE
beta	I-GENE
promoters	I-GENE
.	O
c	B-GENE
-	I-GENE
Jun	I-GENE
repressed	O
the	O
CG	B-GENE
alpha	I-GENE
promoter	I-GENE
through	O
a	O
canonical	O
cAMP	O
response	O
element	O
(	O
CRE	O
)	O
that	O
is	O
known	O
to	O
bind	O
c	B-GENE
-	I-GENE
Jun	I-GENE
and	O
other	O
members	O
of	O
the	O
B	B-GENE
-	I-GENE
Zip	I-GENE
transcription	I-GENE
factor	I-GENE
family	I-GENE
.	O

The	O
mouse	O
lactoferrin	B-GENE
gene	O
promoter	O
was	O
active	O
in	O
human	O
endometrium	O
carcinoma	O
RL	O
95	O
-	O
2	O
cells	O
and	O
in	O
rat	O
glioma	O
C6	O
cells	O
.	O

This	O
is	O
the	O
first	O
report	O
that	O
the	O
PH	B-GENE
domain	I-GENE
of	O
an	O
IRS	B-GENE
protein	I-GENE
can	O
function	O
in	O
a	O
dominant	O
negative	O
manner	O
to	O
inhibit	O
insulin	B-GENE
signaling	O
.	O

Is	O
exposure	O
to	O
a	O
patient	O
with	O
Crohn	O
'	O
s	O
disease	O
an	O
environmental	O
factor	O
for	O
developing	O
the	O
disease	O
.	O

These	O
findings	O
suggest	O
that	O
low	O
-	O
power	O
laser	O
irradiation	O
can	O
be	O
used	O
for	O
promotion	O
of	O
vascularization	O
and	O
take	O
of	O
tissue	O
transplants	O
.	O

In	O
experiment	O
1	O
,	O
subjects	O
were	O
required	O
to	O
discriminate	O
male	O
from	O
female	O
faces	O
and	O
no	O
hemispheric	O
asymmetries	O
were	O
found	O
.	O

1	O
.	O

For	O
the	O
albino	O
,	O
both	O
the	O
ST1	O
and	O
ST2	O
spatial	O
responses	O
peak	O
at	O
around	O
0	O
.	O
3	O
cycles	O
deg	O
-	O
1	O
,	O
and	O
both	O
curves	O
are	O
displaced	O
considerably	O
to	O
the	O
low	O
spatial	O
frequency	O
side	O
of	O
the	O
normal	O
ST2	O
spatial	O
response	O
.	O

The	O
scores	O
for	O
these	O
three	O
factors	O
,	O
which	O
corresponded	O
to	O
recognizable	O
dimensions	O
of	O
depressive	O
illness	O
,	O
were	O
then	O
correlated	O
with	O
rCBF	O
.	O

The	O
etiology	O
was	O
established	O
in	O
73	O
(	O
76	O
.	O
8	O
%	O
)	O
out	O
of	O
95	O
cases	O
.	O

Depending	O
on	O
the	O
patient	O
'	O
s	O
body	O
position	O
telemetrically	O
measured	O
CSF	O
-	O
pressures	O
varied	O
between	O
-	O
20	O
cmH2O	O
in	O
erect	O
and	O
15	O
cmH2O	O
in	O
supine	O
position	O
.	O

Patients	O
received	O
either	O
sodium	O
cephalothin	O
or	O
placebo	O
intravenously	O
before	O
the	O
procedure	O
and	O
for	O
up	O
to	O
8	O
additional	O
doses	O
.	O

These	O
findings	O
suggest	O
that	O
NMDA	B-GENE
receptor	I-GENE
blockade	O
may	O
ameliorate	O
the	O
dyskinetic	O
complications	O
of	O
long	O
-	O
term	O
levodopa	O
therapy	O
,	O
without	O
diminishing	O
the	O
beneficial	O
effects	O
on	O
parkinsonian	O
signs	O
.	O

Before	O
flecainide	O
,	O
all	O
patients	O
had	O
easily	O
inducible	O
VT	O
that	O
was	O
morphologically	O
identical	O
to	O
their	O
spontaneously	O
occurring	O
arrhythmia	O
.	O

In	O
cells	O
infected	O
with	O
a	O
recombinant	O
vaccinia	O
virus	O
expressing	O
HCV	O
structural	O
proteins	O
(	O
core	B-GENE
,	O
E1	B-GENE
,	O
and	O
E2	B-GENE
)	O
,	O
DDX3	B-GENE
and	O
core	B-GENE
colocalized	O
in	O
distinct	O
spots	O
in	O
the	O
perinuclear	O
region	O
of	O
the	O
cytoplasm	O
.	O

However	O
,	O
PC12	O
cell	O
clones	O
which	O
expressed	O
p33rsu	B-GENE
-	I-GENE
1	I-GENE
at	O
an	O
increased	O
level	O
in	O
a	O
regulatable	O
fashion	O
in	O
response	O
to	O
dexamethasone	O
were	O
isolated	O
.	O

Differential	O
decay	O
of	O
a	O
polycistronic	O
Escherichia	O
coli	O
transcript	O
is	O
initiated	O
by	O
RNaseE	B-GENE
-	O
dependent	O
endonucleolytic	O
processing	O
.	O

An	O
incorrect	O
response	O
on	O
the	O
previous	O
trial	O
enhanced	O
the	O
accuracy	O
in	O
the	O
current	O
trial	O
only	O
in	O
the	O
left	O
visual	O
field	O
(	O
LVF	O
)	O
.	O

The	O
SEC27	B-GENE
gene	I-GENE
was	O
cloned	O
,	O
and	O
the	O
sequence	O
predicts	O
a	O
99	O
.	O
4	O
-	O
kDa	O
protein	O
with	O
45	O
%	O
sequence	O
identity	O
to	O
mammalian	O
beta	B-GENE
'	I-GENE
-	I-GENE
COP	I-GENE
.	O

Column	O
chromatographic	O
determination	O
of	O
polymyxin	O
B	O
sulfate	O
.	O

Subgroup	O
analysis	O
failed	O
to	O
show	O
any	O
benefit	O
for	O
etoposide	O
in	O
patients	O
with	O
monocytic	O
or	O
myelomonocytic	O
disease	O
,	O
or	O
in	O
any	O
other	O
diagnostic	O
subgroup	O
.	O

Monosulfates	O
of	O
16	O
-	O
oxygenated	O
ketonic	O
C19	O
steroids	O
in	O
adult	O
human	O
urine	O
.	O

A	O
case	O
of	O
2	O
cancers	O
of	O
the	O
colon	O

Pretoria	O
Pasteurisation	O
is	O
feasible	O
and	O
reliable	O
under	O
a	O
range	O
of	O
conditions	O
.	O

Computer	O
analysis	O
revealed	O
that	O
the	O
human	B-GENE
protein	I-GENE
P1	I-GENE
sequence	I-GENE
corresponding	O
to	O
amino	O
acid	O
residues	O
within	O
the	O
N	O
-	O
terminal	O
RNA	O
binding	O
domain	O
displays	O
high	O
homology	O
(	O
greater	O
than	O
54	O
%	O
identity	O
;	O
61	O
to	O
94	O
%	O
similarity	O
)	O
with	O
two	O
animal	O
virus	O
proteins	O
which	O
possess	O
RNA	O
binding	O
activity	O
(	O
vaccinia	B-GENE
virus	I-GENE
E3L	I-GENE
;	O
rotavirus	B-GENE
VP2	I-GENE
)	O
and	O
two	O
proteins	O
of	O
unknown	O
function	O
(	O
murine	B-GENE
TIK	I-GENE
;	O
rotavirus	B-GENE
NS34	I-GENE
)	O
,	O
but	O
which	O
are	O
likely	O
RNA	O
binding	O
proteins	O
.	O

C	B-GENE
/	I-GENE
EBP	I-GENE
delta	I-GENE
(	O
NFIL	B-GENE
-	I-GENE
6	I-GENE
beta	I-GENE
)	O
was	O
not	O
detected	O
in	O
complexes	O
utilizing	O
extracts	O
from	O
the	O
IL	B-GENE
-	I-GENE
1	I-GENE
nonproducing	O
T	O
cell	O
line	O
.	O

Noise	O
in	O
STM	O
due	O
to	O
atoms	O
moving	O
in	O
the	O
tunneling	O
space	O
.	O

However	O
,	O
mutations	O
of	O
the	O
C	O
-	O
rich	O
element	O
that	O
disrupted	O
a	O
GC	O
box	O
located	O
on	O
the	O
inverse	O
strand	O
eliminated	O
PMA	O
responsiveness	O
and	O
,	O
in	O
gel	O
mobility	O
shift	O
assays	O
,	O
eliminated	O
binding	O
of	O
Sp1	B-GENE
.	O

This	O
is	O
a	O
consensus	O
casein	B-GENE
kinase	I-GENE
II	I-GENE
(	O
CKII	B-GENE
)	O
site	O
and	O
,	O
using	O
purified	O
wild	O
-	O
type	O
and	O
mutant	O
proteins	O
,	O
we	O
show	O
that	O
it	O
is	O
the	O
main	O
CKII	B-GENE
site	I-GENE
in	O
the	O
body	O
of	O
the	O
N	O
-	O
terminal	O
complex	O
-	O
forming	O
region	O
.	O

Down	O
-	O
regulation	O
of	O
Id1	B-GENE
mRNA	I-GENE
correlated	O
with	O
mitogenesis	O
and	O
occurred	O
when	O
quiescent	O
cells	O
were	O
treated	O
with	O
growth	O
factors	O
that	O
activate	O
G	B-GENE
protein	I-GENE
-	I-GENE
coupled	I-GENE
receptors	I-GENE
and	O
receptor	B-GENE
protein	I-GENE
tyrosine	I-GENE
kinases	I-GENE
but	O
not	O
with	O
a	O
non	O
-	O
mitogenic	O
cAMP	O
analog	O
.	O

To	O
study	O
adaptive	O
processes	O
following	O
spinal	O
cord	O
injury	O
,	O
unstructured	O
audiotaped	O
interviews	O
were	O
conducted	O
on	O
an	O
almost	O
daily	O
basis	O
with	O
a	O
30	O
-	O
year	O
-	O
old	O
divorced	O
male	O
during	O
the	O
first	O
3	O
months	O
of	O
his	O
initial	O
comprehensive	O
inpatient	O
rehabilitation	O
.	O

Cloning	O
and	O
characterization	O
of	O
the	O
5	O
'	O
flanking	O
region	O
of	O
human	B-GENE
ATP	I-GENE
-	I-GENE
citrate	I-GENE
lyase	I-GENE
gene	I-GENE
.	O

The	O
broad	O
range	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
inhibitor	O
genistein	O
and	O
the	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
inhibitors	O
wortmannin	O
and	O
LY	O
294002	O
(	O
2	O
-	O
(	O
4	O
-	O
morpholinyl	O
)	O
-	O
8	O
-	O
phenyl	O
-	O
4H	O
-	O
1	O
-	O
benzopyran	O
-	O
4	O
-	O
one	O
)	O
also	O
blocked	O
adenosine	B-GENE
A3	I-GENE
receptor	I-GENE
stimulation	O
of	O
p42	B-GENE
/	O
p44	B-GENE
MAPK	O
.	O

Defective	O
concanavalin	B-GENE
A	I-GENE
-	O
induced	O
suppression	O
in	O
bancroftian	O
filariasis	O
.	O

Rising	O
antibody	O
titres	O
to	O
the	O
astrovirus	O
particles	O
were	O
demonstrated	O
in	O
one	O
child	O
,	O
and	O
IgM	B-GENE
was	O
also	O
demonstrated	O
in	O
this	O
patient	O
'	O
s	O
serum	O
.	O

Demonstration	O
of	O
changes	O
in	O
fetal	O
liver	O
erythropoiesis	O
using	O
echo	O
-	O
planar	O
magnetic	O
resonance	O
imaging	O
.	O

Conversely	O
the	O
rate	O
of	O
bioavailability	O
was	O
significantly	O
different	O
,	O
because	O
from	O
the	O
Reference	O
patch	O
the	O
release	O
rate	O
is	O
fast	O
in	O
the	O
first	O
24	O
h	O
,	O
leading	O
to	O
an	O
E2	O
peak	O
at	O
8	O
h	O
and	O
to	O
a	O
Cmax	O
in	O
average	O
at	O
23	O
h	O
.	O

Effects	O
of	O
dexamethasone	O
on	O
the	O
development	O
of	O
radiation	O
nephropathy	O
in	O
the	O
rat	O
.	O

Reaction	O
of	O
aromatic	O
/	O
heterocyclic	O
sulfonamides	O
possessing	O
free	O
amino	O
,	O
imino	O
or	O
hydrazino	O
moieties	O
with	O
7	O
-	O
chloro	O
-	O
4	O
-	O
chloromethylcoumarin	O
afforded	O
a	O
series	O
of	O
N	O
-	O
[	O
(	O
7	O
-	O
chloro	O
-	O
4	O
-	O
coumarinyl	O
)	O
-	O
methyl	O
]	O
-	O
derivatives	O
which	O
showed	O
effective	O
inhibition	O
of	O
three	O
carbonic	B-GENE
anhydrase	I-GENE
(	O
CA	B-GENE
)	O
isozymes	O
.	O

The	O
present	O
study	O
also	O
emphasizes	O
the	O
need	O
of	O
establishing	O
dose	O
-	O
response	O
curves	O
to	O
correctly	O
assess	O
the	O
relative	O
contribution	O
of	O
the	O
different	O
regions	O
of	O
steroid	B-GENE
hormone	I-GENE
receptors	I-GENE
in	O
activation	O
of	O
transcription	O
.	O

(	O
1986	O
)	O
described	O
optic	O
nerve	O
degenerations	O
in	O
patients	O
with	O
Alzheimer	O
'	O
s	O
disease	O
and	O
Sadun	O
published	O
a	O
dropout	O
of	O
retinal	O
ganglion	O
cells	O
that	O
range	O
from	O
30	O
%	O
to	O
60	O
%	O
.	O

In	O
addition	O
,	O
these	O
results	O
suggest	O
that	O
the	O
interactions	O
,	O
and	O
consequently	O
the	O
mechanisms	O
,	O
governing	O
transcriptional	O
activation	O
by	O
CTF	B-GENE
are	O
distinct	O
from	O
those	O
mediating	O
DNA	O
replication	O
.	O

These	O
proteins	O
,	O
called	O
variant	B-GENE
surface	I-GENE
glycoproteins	I-GENE
(	O
VSGs	B-GENE
)	O
,	O
are	O
expressed	O
from	O
a	O
specific	O
locus	O
,	O
the	O
VSG	B-GENE
gene	I-GENE
expression	I-GENE
site	I-GENE
(	I-GENE
ES	I-GENE
)	I-GENE
.	O

The	O
temporal	O
changes	O
in	O
the	O
plasma	O
concentration	O
of	O
immunoreactive	B-GENE
atrial	I-GENE
natriuretic	I-GENE
factor	I-GENE
(	O
iANF	B-GENE
)	O
were	O
studied	O
in	O
six	O
conscious	O
dogs	O
with	O
an	O
arteriovenous	O
(	O
AV	O
)	O
fistula	O
,	O
a	O
model	O
of	O
chronic	O
high	O
-	O
output	O
heart	O
failure	O
.	O

In	O
situ	O
hybridization	O
of	O
whole	O
-	O
mount	O
mouse	O
embryos	O
with	O
Mex5	B-GENE
antisense	I-GENE
RNA	I-GENE
provide	O
no	O
evidence	O
for	O
the	O
exclusion	O
of	O
Mex5	B-GENE
during	O
embryonic	O
development	O
.	O

Karyo	O
-	O
and	O
cytometric	O
investigations	O
of	O
cortical	O
layer	O
V	O
pyramidal	O
neurons	O
of	O
albino	O
rat	O
after	O
three	O
various	O
fixations	O

The	O
cloning	O
of	O
human	B-GENE
apo	I-GENE
B	I-GENE
-	I-GENE
100	I-GENE
has	O
provided	O
new	O
insights	O
into	O
the	O
structure	O
and	O
physicochemical	O
properties	O
of	O
apo	B-GENE
B	I-GENE
-	I-GENE
100	I-GENE
and	O
will	O
facilitate	O
studies	O
on	O
the	O
factors	O
modulating	O
apo	B-GENE
B	I-GENE
-	I-GENE
100	I-GENE
biosynthesis	O
and	O
the	O
expression	O
of	O
the	O
apo	B-GENE
B	I-GENE
-	I-GENE
100	I-GENE
gene	I-GENE
in	O
patients	O
with	O
dyslipoproteinemias	O
.	O

In	O
the	O
green	O
unicellular	O
alga	O
Chlamydomonas	O
eugametos	O
,	O
cellular	O
division	O
is	O
readily	O
synchronized	O
by	O
light	O
/	O
dark	O
cycles	O
.	O

Northern	O
blot	O
analysis	O
linked	O
Plk	B-GENE
expression	O
to	O
the	O
proliferative	O
activity	O
of	O
cells	O
and	O
tissues	O
.	O

A	O
1	O
.	O
5	O
-	O
month	O
-	O
old	O
boy	O
with	O
Sandifer	O
'	O
s	O
syndrome	O
is	O
described	O
.	O

A	O
40	O
-	O
fold	O
stimulation	O
of	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
activity	O
mediated	O
by	O
four	O
tandem	O
repeats	O
of	O
the	O
SNE	B-GENE
could	O
be	O
induced	O
within	O
2	O
h	O
(	O
and	O
up	O
to	O
250	O
-	O
fold	O
within	O
6	O
h	O
)	O
after	O
addition	O
of	O
TPA	O
in	O
DNA	O
-	O
transfected	O
U	O
-	O
937	O
cells	O
,	O
indicating	O
that	O
the	O
stimulation	O
appeared	O
likely	O
to	O
be	O
a	O
true	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
-	O
mediated	O
signal	O
transduction	O
event	O
rather	O
than	O
a	O
differentiation	O
response	O
.	O

A	O
silica	O
-	O
based	O
,	O
fluoride	O
-	O
free	O
placebo	O
containing	O
NaTPP	O
,	O
and	O
a	O
NaF	O
-	O
containing	O
silica	O
-	O
based	O
USP	O
reference	O
standard	O
toothpaste	O
were	O
used	O
as	O
negative	O
and	O
positive	O
control	O
toothpastes	O
,	O
respectively	O
.	O

Molecular	O
cloning	O
of	O
the	O
alpha	B-GENE
-	I-GENE
globin	I-GENE
transcription	I-GENE
factor	I-GENE
CP2	B-GENE
.	O

The	O
present	O
study	O
tries	O
to	O
associate	O
some	O
of	O
the	O
causes	O
of	O
hot	O
ischaemia	O
during	O
the	O
agony	O
of	O
the	O
corpse	O
donor	O
and	O
to	O
evaluate	O
those	O
that	O
may	O
be	O
caused	O
by	O
sympathetic	O
efference	O
during	O
removal	O
.	O

The	O
cost	O
and	O
effectiveness	O
of	O
nurse	O
education	O
-	O
-	O
1	O
.	O

Between	O
1988	O
and	O
1995	O
,	O
341	O
children	O
with	O
acute	O
myeloid	O
leukaemia	O
(	O
AML	O
)	O
were	O
treated	O
on	O
the	O
Medical	O
Research	O
Council	O
Acute	O
Myeloid	O
Leukaemia	O
Trial	O
(	O
MRC	O
AML10	O
)	O
.	O

Using	O
the	O
yeast	O
two	O
-	O
hybrid	O
system	O
,	O
we	O
have	O
isolated	O
an	O
835	O
amino	O
acid	O
RING	O
finger	O
(	O
C3HC4	O
zinc	O
finger	O
)	O
protein	O
,	O
TIF1	B-GENE
beta	I-GENE
(	O
also	O
named	O
KAP	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
that	O
specifically	O
interacts	O
with	O
the	O
KRAB	B-GENE
domain	I-GENE
of	O
the	O
human	O
zinc	O
finger	O
factor	O
KOX1	B-GENE
/	O
ZNF10	B-GENE
.	O

The	O
N	O
-	O
terminal	O
sequences	O
of	O
isoforms	O
beta	O
to	O
epsilon	O
contain	O
a	O
PEST	O
region	O
which	O
could	O
induce	O
rapid	O
intracellular	O
degradation	O
of	O
isoforms	O
beta	O
and	O
delta	O
.	O

Their	O
central	O
projections	O
were	O
indistinguishable	O
from	O
those	O
of	O
control	O
axons	O
in	O
all	O
four	O
trigeminal	O
subnuclei	O
.	O

Typicality	O
is	O
probably	O
a	O
better	O
representation	O
of	O
Alexander	O
,	O
Dunbar	O
and	O
others	O
'	O
conclusions	O
than	O
specificity	O
,	O
which	O
was	O
always	O
too	O
absolute	O
a	O
term	O
.	O

We	O
then	O
developed	O
a	O
yeast	O
artificial	O
chromosome	O
(	O
YAC	O
)	O
contig	O
for	O
this	O
region	O
.	O

In	O
addition	O
to	O
TAK1	B-GENE
,	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
also	O
stimulated	O
JNK	B-GENE
activity	O
.	O

The	O
study	O
was	O
carried	O
out	O
according	O
to	O
the	O
BSI	O
(	O
1980	O
)	O
recommendations	O
for	O
testing	O
restorative	O
materials	O
in	O
vivo	O
.	O

A	O
case	O
report	O
.	O

Sixteen	O
patients	O
on	O
maintenance	O
hemodialysis	O
underwent	O
dialysis	O
with	O
either	O
cuprophane	O
(	O
n	O
=	O
8	O
)	O
or	O
polymethylmethacrylate	O
(	O
PMMA	O
;	O
n	O
=	O
8	O
)	O
membranes	O
for	O
1	O
week	O
and	O
then	O
switched	O
to	O
the	O
opposite	O
membrane	O
during	O
the	O
second	O
week	O
.	O

No	O
significant	O
difference	O
in	O
plasma	O
ET	B-GENE
levels	O
was	O
found	O
between	O
cardiac	O
and	O
peripheral	O
sampling	O
sites	O
(	O
pulmonary	O
artery	O
;	O
1	O
.	O
07	O
+	O
/	O
-	O
0	O
.	O
28	O
,	O
right	O
atrium	O
;	O
1	O
.	O
02	O
+	O
/	O
-	O
0	O
.	O
28	O
,	O
peripheral	O
artery	O
;	O
1	O
.	O
12	O
+	O
/	O
-	O
0	O
.	O
23	O
,	O
peripheral	O
vein	O
;	O
1	O
.	O
14	O
+	O
/	O
-	O
0	O
.	O
38	O
fmol	O
/	O
ml	O
:	O
N	O
.	O
S	O
.	O
)	O
,	O
or	O
among	O
patients	O
with	O
uncomplicated	O
MI	O
,	O
unstable	O
angina	O
(	O
1	O
.	O
00	O
+	O
/	O
-	O
0	O
.	O
32	O
fmol	O
/	O
ml	O
)	O
,	O
and	O
healthy	O
subjects	O
(	O
1	O
.	O
01	O
+	O
/	O
-	O
0	O
.	O
29	O
fmol	O
/	O
ml	O
)	O
.	O

Oxalates	O
and	O
the	O
digestive	O
tract	O

Analysis	O
of	O
the	O
MCV	B-GENE
-	I-GENE
1	I-GENE
RPO1	I-GENE
revealed	O
high	O
amino	O
acid	O
homologies	O
to	O
the	O
corresponding	O
polypeptides	O
of	O
vaccinia	O
and	O
variola	O
virus	O
.	O

This	O
interaction	O
is	O
functional	O
as	O
it	O
leads	O
to	O
retargeting	O
of	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
p50	B-GENE
from	O
the	O
nucleus	O
to	O
the	O
cytoplasm	O
.	O

Point	O
mutations	O
of	O
Stat3	B-GENE
within	O
the	O
interacting	O
domains	O
blocked	O
both	O
physical	O
interaction	O
of	O
Stat3	B-GENE
with	O
c	B-GENE
-	I-GENE
Jun	I-GENE
and	O
their	O
cooperation	O
in	O
IL	B-GENE
-	I-GENE
6	I-GENE
-	O
induced	O
transcription	O
directed	O
by	O
the	O
alpha	B-GENE
(	I-GENE
2	I-GENE
)	I-GENE
-	I-GENE
macroglobulin	I-GENE
enhancer	I-GENE
.	O

Identification	O
of	O
masked	O
toxins	O
in	O
the	O
exotoxin	O
complex	O
of	O
Staphylococcus	O
pyogenes	O
und	O
Cl	O
.	O
perfringens	O
;	O
significance	O
of	O
their	O
existence	O
for	O
clarifying	O
of	O
the	O
masking	O
mechanism	O

Correlation	O
coefficients	O
between	O
SF	O
thickness	O
and	O
NIR	O
optical	O
density	O
readings	O
at	O
940	O
nm	O
(	O
OD1	O
)	O
and	O
950	O
nm	O
(	O
OD2	O
)	O
wavelengths	O
ranged	O
from	O
r	O
=	O
-	O
0	O
.	O
30	O
(	O
subscapula	O
)	O
to	O
r	O
=	O
-	O
0	O
.	O
67	O
(	O
biceps	O
)	O
for	O
OD1	O
and	O
r	O
=	O
-	O
0	O
.	O
39	O
(	O
axilla	O
)	O
to	O
r	O
=	O
-	O
0	O
.	O
68	O
(	O
biceps	O
)	O
for	O
OD2	O
.	O

Transfer	O
of	O
health	O
care	O
to	O
natives	O
holds	O
much	O
promise	O
,	O
lecturers	O
say	O
.	O

In	O
the	O
second	O
group	O
,	O
which	O
consisted	O
of	O
babies	O
of	O
33	O
to	O
36	O
weeks	O
of	O
gestational	O
age	O
,	O
haptoglobin	B-GENE
was	O
detected	O
in	O
6	O
infants	O
,	O
with	O
levels	O
less	O
than	O
25	O
mg	O
/	O
dl	O
in	O
3	O
.	O

The	O
clinical	O
picture	O
,	O
the	O
light	O
and	O
electron	O
microscopic	O
appearance	O
,	O
and	O
the	O
histochemical	O
findings	O
are	O
described	O
in	O
six	O
cases	O
of	O
fibroma	O
of	O
tendon	O
sheath	O
.	O

We	O
hypothesize	O
that	O
the	O
ability	O
of	O
these	O
acidic	O
activators	O
to	O
specifically	O
interact	O
with	O
multiple	O
components	O
of	O
the	O
transcription	O
initiation	O
complex	O
likely	O
underlies	O
the	O
dramatic	O
functional	O
synergy	O
exhibited	O
by	O
this	O
class	O
of	O
activation	O
domains	O
in	O
vivo	O
.	O

High	O
and	O
pathological	O
PAI	B-GENE
-	I-GENE
1	I-GENE
levels	O
before	O
and	O
after	O
the	O
VO	O
test	O
were	O
consistent	O
with	O
a	O
defective	O
fibrinolytic	O
potential	O
due	O
to	O
the	O
inhibitory	O
effect	O
of	O
PAI	B-GENE
-	I-GENE
1	I-GENE
on	O
plasminogen	B-GENE
activation	O
.	O

S	O
.	O
aureus	O
leakage	O
into	O
the	O
totally	O
submerged	O
test	O
specimens	O
was	O
detected	O
in	O
1	O
of	O
5	O
samples	O
incubated	O
for	O
4	O
weeks	O
,	O
while	O
no	O
leakage	O
was	O
detected	O
in	O
specimens	O
incubated	O
for	O
3	O
,	O
5	O
,	O
6	O
,	O
7	O
,	O
and	O
8	O
weeks	O
.	O

MAPKK	B-GENE
kinase	I-GENE
/	O
MEKK	B-GENE
phosphorylates	O
and	O
activates	O
its	O
downstream	O
protein	O
kinase	O
,	O
MAPK	B-GENE
kinase	I-GENE
/	O
MEK	B-GENE
,	O
which	O
in	O
turn	O
activates	O
MAPK	B-GENE
.	O

The	O
Prompt	O
and	O
Praise	O
condition	O
was	O
superior	O
to	O
the	O
other	O
two	O
conditions	O
in	O
encouraging	O
participation	O
in	O
low	O
-	O
interest	O
recreational	O
activities	O
.	O

The	O
author	O
describes	O
the	O
technique	O
in	O
detail	O
and	O
presents	O
the	O
findings	O
for	O
25	O
patients	O
(	O
10	O
men	O
and	O
15	O
women	O
)	O
examined	O
for	O
suspected	O
ileostomy	O
dysfunction	O
,	O
recurrent	O
Crohn	O
'	O
s	O
disease	O
or	O
ileal	O
obstruction	O
remote	O
from	O
the	O
stoma	O
.	O

Biochemical	O
studies	O
have	O
identified	O
a	O
cellular	O
non	B-GENE
-	I-GENE
P	I-GENE
element	I-GENE
-	I-GENE
encoded	I-GENE
DNA	I-GENE
binding	I-GENE
protein	I-GENE
,	O
termed	O
the	O
inverted	B-GENE
repeat	I-GENE
binding	I-GENE
protein	I-GENE
(	O
IRBP	B-GENE
)	O
,	O
that	O
specifically	O
interacts	O
with	O
the	O
outer	O
half	O
of	O
the	O
31	O
-	O
bp	O
terminal	O
inverted	O
repeats	O
.	O

These	O
findings	O
suggest	O
that	O
eIF5	B-GENE
-	O
eIF2beta	B-GENE
interaction	O
plays	O
an	O
essential	O
role	O
in	O
eIF5	B-GENE
function	O
in	O
eukaryotic	O
cells	O
.	O

The	O
delayed	O
activation	O
of	O
the	O
prostaglandin	B-GENE
G	I-GENE
/	I-GENE
H	I-GENE
synthase	I-GENE
-	I-GENE
2	I-GENE
promoter	O
in	O
bovine	O
granulosa	O
cells	O
is	O
associated	O
with	O
down	O
-	O
regulation	O
of	O
truncated	O
upstream	B-GENE
stimulatory	I-GENE
factor	I-GENE
-	I-GENE
2	I-GENE
.	O

Nb2	O
-	O
11C	O
cells	O
expressed	O
three	O
PNR	B-GENE
-	I-GENE
related	I-GENE
mRNA	I-GENE
transcripts	I-GENE
of	O
2	O
.	O
5	O
,	O
3	O
.	O
0	O
and	O
>	O
10	O
kb	O
.	O

E1A	B-GENE
+	O
cHa	B-GENE
-	I-GENE
ras	I-GENE
transformed	O
rat	O
embryo	O
fibroblast	O
cells	O
are	O
characterized	O
by	O
high	O
and	O
constitutive	O
DNA	O
binding	O
activities	O
of	O
AP	B-GENE
-	I-GENE
1	I-GENE
dimers	I-GENE
with	O
significantly	O
altered	O
composition	O
.	O

In	O
the	O
present	O
study	O
we	O
have	O
used	O
Southern	O
blot	O
analysis	O
to	O
demonstrate	O
that	O
TSG6	B-GENE
is	O
a	O
single	O
-	O
copy	O
gene	O
in	O
the	O
human	O
and	O
murine	O
species	O
.	O

CONCLUSIONS	O
:	O
Latanoprost	O
administered	O
once	O
daily	O
was	O
significantly	O
more	O
effective	O
in	O
reducing	O
IOP	O
compared	O
with	O
unoprostone	O
administered	O
twice	O
daily	O
in	O
patients	O
with	O
POAG	O
and	O
OH	O
.	O

Activation	O
of	O
HIV	O
gene	O
expression	O
by	O
UV	O
must	O
therefore	O
involve	O
additional	O
cellular	O
processes	O
,	O
such	O
as	O
those	O
triggered	O
by	O
DNA	O
damage	O
,	O
for	O
generation	O
of	O
a	O
full	O
gene	O
expression	O
response	O
.	O

One	O
promoter	O
,	O
p53P1	B-GENE
,	O
is	O
located	O
100	O
-	O
250	O
bp	O
upstream	O
of	O
the	O
218	O
-	O
bp	O
noncoding	O
first	O
exon	O
;	O
a	O
second	O
,	O
stronger	O
promoter	O
,	O
p53P2	B-GENE
,	O
maps	O
within	O
the	O
first	O
intron	O
.	O

Hydropathy	O
analysis	O
of	O
deduced	O
A4	O
amino	O
acid	O
sequence	O
revealed	O
four	O
putative	O
membrane	O
-	O
spanning	O
alpha	O
-	O
helices	O
.	O

This	O
study	O
includes	O
200	O
patients	O
treated	O
from	O
1964	O
to	O
1978	O
,	O
with	O
an	O
age	O
range	O
from	O
15	O
to	O
102	O
years	O
,	O
who	O
required	O
329	O
generators	O
.	O

There	O
is	O
little	O
similarity	O
among	O
the	O
sequences	O
upstream	O
from	O
the	O
CAP	O
site	O
of	O
the	O
Spec2	B-GENE
genes	I-GENE
except	O
the	O
TATA	O
consensus	O
sequence	O
and	O
a	O
repeating	O
trinucleotide	O
,	O
AAC	O
.	O

Radiological	O
imaging	O
such	O
as	O
UGI	O
series	O
and	O
CT	O
scan	O
was	O
useful	O
to	O
arrive	O
at	O
an	O
accurate	O
diagnosis	O
.	O

A	O
case	O
of	O
acquired	O
immune	O
deficiency	O
syndrome	O
before	O
1980	O
.	O

In	O
the	O
promoters	O
of	O
many	O
immediate	B-GENE
early	I-GENE
genes	I-GENE
,	O
including	O
c	B-GENE
-	I-GENE
fos	I-GENE
,	O
CArG	O
DNA	O
regulatory	O
elements	O
mediate	O
basal	O
constituitive	O
expression	O
and	O
rapid	O
and	O
transient	O
serum	O
induction	O
.	O

We	O
propose	O
that	O
optimal	O
transcription	O
of	O
the	O
gD	B-GENE
gene	I-GENE
depends	O
on	O
the	O
interaction	O
of	O
ICP4	B-GENE
with	O
multiple	O
binding	O
sites	O
across	O
the	O
gene	O
and	O
cellular	O
factors	O
that	O
recognize	O
specific	O
sequence	O
elements	O
in	O
the	O
promoter	O
.	O

Strains	O
lacking	O
a	O
functional	B-GENE
RPL16A	I-GENE
gene	I-GENE
grow	O
as	O
rapidly	O
as	O
wild	O
type	O
,	O
whereas	O
those	O
containing	O
a	O
null	O
allele	O
of	O
RPL16B	B-GENE
grow	O
more	O
slowly	O
than	O
wild	O
type	O
.	O

Maduromycosis	O
in	O
Italy	O

Cetn1	B-GENE
possesses	O
the	O
sequence	O
features	O
of	O
an	O
expressed	O
retroposon	O
:	O
the	O
gene	O
lacks	O
introns	O
,	O
the	O
open	O
reading	O
frame	O
is	O
not	O
interrupted	O
by	O
stop	O
codons	O
,	O
and	O
the	O
coding	O
region	O
is	O
flanked	O
by	O
a	O
pair	O
of	O
direct	O
repeats	O
.	O

Substitutions	O
of	O
Asp11	O
led	O
to	O
dominant	O
lethality	O
.	O

The	O
Sty1	B-GENE
kinase	I-GENE
is	O
stimulated	O
by	O
a	O
variety	O
of	O
different	O
stress	O
conditions	O
including	O
osmotic	O
and	O
oxidative	O
stress	O
and	O
heat	O
shock	O
.	O

Acute	O
toxicity	O
tests	O
were	O
conducted	O
to	O
measure	O
the	O
response	O
of	O
first	O
instar	O
Toxorhynchites	O
splendens	O
to	O
commonly	O
used	O
mosquito	O
adulticides	O
:	O
malathion	O
,	O
naled	O
and	O
resmethrin	O
.	O

We	O
prospectively	O
studied	O
serum	B-GENE
prolactin	I-GENE
(	O
PRL	B-GENE
)	O
elevation	O
after	O
different	O
types	O
of	O
documented	O
seizures	O
in	O
17	O
patients	O
.	O

To	O
further	O
identify	O
the	O
residues	O
responsible	O
for	O
the	O
activity	O
,	O
we	O
isolated	O
the	O
mutant	O
viruses	O
that	O
were	O
not	O
neutralized	O
with	O
the	O
soluble	O
form	O
of	O
MHV	B-GENE
receptor	I-GENE
proteins	I-GENE
,	O
since	O
such	O
mutants	O
were	O
expected	O
to	O
have	O
mutations	O
in	O
amino	O
acids	O
responsible	O
for	O
receptor	O
-	O
binding	O
activity	O
.	O

When	O
lipid	O
X	O
was	O
combined	O
with	O
ticarcillin	O
,	O
survival	O
differences	O
were	O
both	O
significant	O
and	O
prolonged	O
.	O

Furthermore	O
,	O
the	O
secondary	O
stress	O
responses	O
were	O
more	O
pronounced	O
and	O
the	O
ability	O
to	O
recover	O
from	O
them	O
seemed	O
to	O
be	O
impaired	O
in	O
exposed	O
fish	O
as	O
compared	O
to	O
unexposed	O
fish	O
.	O

Focal	O
glomerulosclerosis	O
-	O
like	O
disease	O
with	O
nephrotic	O
syndrome	O
in	O
a	O
horse	O
.	O

In	O
addition	O
,	O
both	O
activated	O
Ral	B-GENE
-	I-GENE
GDS	I-GENE
-	I-GENE
like	I-GENE
factor	O
and	O
Raf	B-GENE
stimulate	O
cyclin	B-GENE
D	I-GENE
(	I-GENE
1	I-GENE
)	I-GENE
transcription	O
and	O
E2F	B-GENE
activity	O
and	O
act	O
in	O
synergy	O
with	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
.	O

Treatment	O
with	O
polyinosinic	O
-	O
polycytidylic	O
acid	O
to	O
induce	O
expression	O
of	O
Cre	B-GENE
resulted	O
in	O
complete	O
disruption	O
of	O
the	O
Arnt	B-GENE
gene	I-GENE
and	O
loss	O
of	O
ARNT	B-GENE
messenger	I-GENE
RNA	I-GENE
(	O
mRNA	O
)	O
expression	O
in	O
liver	O
.	O

Twelve	O
patients	O
of	O
leprosy	O
with	O
arthritis	O
and	O
161	O
patients	O
without	O
arthritis	O
were	O
studied	O
for	O
immunological	O
parameters	O
like	O
immunoglobulins	B-GENE
(	O
IgG	B-GENE
,	O
IgM	B-GENE
,	O
IgA	B-GENE
)	O
,	O
C	B-GENE
-	I-GENE
reactive	I-GENE
proteins	I-GENE
and	O
rheumatoid	B-GENE
factor	I-GENE
.	O

The	O
biological	O
functions	O
of	O
rat	O
surfactant	B-GENE
protein	I-GENE
A	I-GENE
(	O
SP	B-GENE
-	I-GENE
A	I-GENE
)	O
,	O
an	O
oligomer	O
composed	O
of	O
18	O
polypeptide	O
subunits	O
derived	O
from	O
a	O
single	O
gene	O
,	O
are	O
dependent	O
on	O
intact	O
disulfide	O
bonds	O
.	O

DIC	O
and	O
low	O
grade	O
fibrinolysis	O
may	O
account	O
for	O
the	O
coagulation	O
abnormalities	O
of	O
the	O
syndrome	O
.	O

All	O
depressive	O
groups	O
showed	O
improved	O
error	O
measures	O
post	O
-	O
treatment	O
.	O

Plasmid	O
subclones	O
of	O
the	O
hr1a	B-GENE
-	O
containing	O
AcMNPV	O
HindIII	B-GENE
-	O
N	O
fragment	O
were	O
examined	O
for	O
their	O
ability	O
to	O
replicate	O
in	O
virus	O
-	O
infected	O
(	O
Spodoptera	O
frugiperda	O
)	O
Sf9	O
cells	O
,	O
and	O
to	O
stimulate	O
transcription	O
when	O
linked	O
in	O
cis	O
with	O
a	O
39K	B-GENE
gene	I-GENE
promoter	I-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
glucuronidase	I-GENE
fusion	I-GENE
and	O
cotransfected	O
into	O
cells	O
along	O
with	O
a	O
plasmid	O
(	O
ple	O
-	O
1	O
)	O
containing	O
the	O
gene	O
encoding	O
the	O
trans	O
-	O
acting	O
factor	O
IE	B-GENE
-	I-GENE
1	I-GENE
.	O

This	O
new	O
receptor	O
,	O
TOR	B-GENE
(	O
thymus	B-GENE
orphan	I-GENE
receptor	I-GENE
)	O
,	O
is	O
most	O
closely	O
related	O
in	O
both	O
its	O
DNA	O
-	O
binding	O
domain	O
and	O
ligand	O
-	O
binding	O
domain	O
,	O
90	O
%	O
and	O
53	O
%	O
,	O
respectively	O
,	O
to	O
ROR	B-GENE
alpha	I-GENE
/	O
RZR	B-GENE
alpha	I-GENE
and	O
clusters	O
with	O
these	O
two	O
receptors	O
and	O
RZR	B-GENE
beta	I-GENE
in	O
a	O
phylogenetic	O
tree	O
,	O
when	O
both	O
the	O
DNA	O
-	O
binding	O
domain	O
and	O
the	O
ligand	O
-	O
binding	O
domain	O
sequences	O
of	O
nuclear	O
receptors	O
are	O
compared	O
.	O

Immunofluorescence	O
tests	O
for	O
Borrelia	B-GENE
burgdorferi	I-GENE
serum	I-GENE
antibodies	I-GENE
had	O
positive	O
results	O
,	O
but	O
G	O
-	O
penicillin	O
treatment	O
was	O
ineffective	O
.	O

Laser	O
soldering	O
with	O
exogenous	O
fibrinogen	B-GENE
is	O
feasible	O
without	O
topical	O
administration	O
of	O
additional	O
clotting	O
agents	O
,	O
significantly	O
improves	O
the	O
bursting	O
strength	O
of	O
primary	O
laser	O
welded	O
anastomoses	O
,	O
and	O
appears	O
to	O
result	O
from	O
urokinase	B-GENE
-	O
resistant	O
fibrinogen	B-GENE
cross	O
-	O
linking	O
.	O

Raman	O
scattering	O
from	O
VO2	O
single	O
crystals	O
:	O
A	O
study	O
of	O
the	O
effects	O
of	O
surface	O
oxidation	O
.	O

Left	O
ventricular	O
insufficiency	O
requires	O
two	O
SP	O
/	O
patient	O
,	O
with	O
good	O
results	O
in	O
approximately	O
81	O
p	O
.	O
cent	O
.	O

Overexpression	O
of	O
wild	O
type	O
and	O
SeCys	O
/	O
Cys	O
mutant	O
of	O
human	B-GENE
thioredoxin	I-GENE
reductase	I-GENE
in	O
E	O
.	O
coli	O
:	O
the	O
role	O
of	O
selenocysteine	O
in	O
the	O
catalytic	O
activity	O
.	O

50	O
-	O
fold	O
increase	O
in	O
foreign	O
protein	O
production	O
.	O

A	O
rare	O
tRNA	B-GENE
-	I-GENE
Arg	I-GENE
(	I-GENE
CCU	I-GENE
)	I-GENE
that	O
regulates	O
Ty1	B-GENE
element	I-GENE
ribosomal	O
frameshifting	O
is	O
essential	O
for	O
Ty1	B-GENE
retrotransposition	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

In	O
addition	O
,	O
putative	O
binding	O
sites	O
for	O
SH3	B-GENE
and	O
SH2	B-GENE
domains	I-GENE
are	O
present	O
in	O
the	O
amino	O
-	O
terminal	O
half	O
of	O
the	O
molecule	O
.	O

The	O
technique	O
used	O
by	O
this	O
system	O
involves	O
a	O
transient	O
,	O
externally	O
applied	O
increase	O
in	O
resistance	O
to	O
breathing	O
.	O

Copyright	O
1999	O
Academic	O
Press	O
.	O

Vorozole	O
(	O
Rivizor	O
)	O
is	O
a	O
potent	O
and	O
stereospecific	O
inhibitor	O
of	O
aromatase	B-GENE
having	O
shown	O
promising	O
endocrine	O
effects	O
in	O
phase	O
I	O
studies	O
.	O

Mapping	O
the	O
5	O
'	O
and	O
3	O
'	O
termini	O
of	O
TED	B-GENE
RNAs	I-GENE
indicated	O
that	O
the	O
LTRs	O
have	O
a	O
retroviral	O
U3	O
-	O
R	O
-	O
U5	O
structural	O
organization	O
that	O
is	O
capable	O
of	O
directing	O
the	O
synthesis	O
of	O
transcripts	O
that	O
represent	O
potential	O
substrates	O
for	O
reverse	O
transcription	O
and	O
intermediates	O
in	O
transposition	O
.	O

A	O
Meis1	B-GENE
cDNA	I-GENE
clone	O
that	O
encoded	O
a	O
novel	O
member	O
of	O
the	O
homeobox	B-GENE
gene	I-GENE
family	I-GENE
was	O
identified	O
.	O

Cellular	O
lysates	O
were	O
analyzed	O
for	O
luciferase	B-GENE
and	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
activities	O
.	O

The	O
protein	O
contains	O
a	O
SHAQKYF	O
amino	O
acid	O
signature	O
motif	O
in	O
the	O
second	O
myb	B-GENE
-	I-GENE
like	I-GENE
repeat	I-GENE
,	O
which	O
is	O
highly	O
conserved	O
in	O
a	O
number	O
of	O
recently	O
identified	O
plant	B-GENE
myb	I-GENE
-	I-GENE
related	I-GENE
genes	I-GENE
,	O
thus	O
defining	O
a	O
new	O
class	O
of	O
plant	O
DNA	O
-	O
binding	O
proteins	O
.	O

However	O
,	O
sphincter	O
length	O
decreased	O
with	O
age	O
from	O
24	O
.	O
3	O
to	O
14	O
.	O
8	O
mm	O
.	O
,	O
maximal	O
urethral	O
pressure	O
from	O
88	O
.	O
7	O
to	O
55	O
cm	O
.	O
water	O
and	O
maximal	O
urethral	O
pressure	O
during	O
voluntary	O
contraction	O
from	O
221	O
.	O
4	O
to	O
166	O
.	O
3	O
cm	O
.	O
water	O
.	O

The	O
DF3	B-GENE
/	O
MUC1	B-GENE
gene	O
encodes	O
a	O
high	B-GENE
molecular	I-GENE
weight	I-GENE
mucin	I-GENE
-	I-GENE
like	I-GENE
glycoprotein	I-GENE
which	O
is	O
overexpressed	O
at	O
the	O
transcriptional	O
level	O
in	O
the	O
majority	O
of	O
human	O
breast	O
cancers	O
.	O

A	O
cephalothoracophagus	O
disymmetros	O
buffalo	O
calf	O
.	O

In	O
32	O
of	O
them	O
the	O
results	O
of	O
an	O
exercise	O
performance	O
test	O
based	O
on	O
heart	O
rate	O
response	O
to	O
submaximal	O
exercise	O
(	O
VO2	O
,	O
170	O
[	O
bpm	O
]	O
)	O
was	O
compared	O
with	O
another	O
index	O
of	O
physical	O
performance	O
capacity	O
,	O
which	O
is	O
independent	O
from	O
heart	O
rate	O
:	O
the	O
ventilatory	O
threshold	O
.	O

Treatment	O
with	O
KP	O
-	O
45	O
preparation	O
usually	O
resulted	O
in	O
partial	O
regression	O
of	O
tumor	O
growth	O
,	O
accompanied	O
by	O
improvement	O
of	O
the	O
clinical	O
state	O
of	O
these	O
patients	O
,	O
as	O
well	O
as	O
reappearance	O
of	O
normal	O
values	O
of	O
blood	O
picture	O
and	O
biochemical	O
parameters	O
.	O

Electromobility	O
shift	O
analysis	O
using	O
oligonucleotides	O
encompassing	O
the	O
proximal	O
,	O
distal	O
,	O
and	O
BED	O
/	O
AP	B-GENE
-	I-GENE
1	I-GENE
-	O
binding	O
regions	O
failed	O
to	O
demonstrate	O
selective	O
transactivation	O
after	O
CD2	B-GENE
signaling	O
of	O
LPMC	O
.	O

Four	O
families	O
of	O
homing	B-GENE
endonucleases	I-GENE
have	O
been	O
identified	O
,	O
including	O
the	O
LAGLIDADG	B-GENE
,	O
the	O
His	B-GENE
-	I-GENE
Cys	I-GENE
box	I-GENE
,	O
the	O
GIY	B-GENE
-	I-GENE
YIG	I-GENE
and	O
the	O
H	B-GENE
-	I-GENE
N	I-GENE
-	I-GENE
H	I-GENE
endonucleases	I-GENE
.	O

The	O
use	O
of	O
aluminum	O
hydroxide	O
was	O
associated	O
with	O
an	O
increase	O
in	O
fecal	O
fluoride	O
excretion	O
and	O
a	O
decrease	O
in	O
net	O
absorption	O
of	O
fluoride	O
regardless	O
of	O
the	O
intake	O
fluoride	O
,	O
calcium	O
,	O
phosphorus	O
,	O
or	O
magnesium	O
.	O

Administration	O
of	O
SnCl2	O
and	O
ZnSO4	O
(	O
group	O
V	O
)	O
resulted	O
in	O
a	O
decrease	O
of	O
ALA	B-GENE
-	I-GENE
D	I-GENE
activity	O
and	O
in	O
an	O
increase	O
in	O
CP	O
-	O
U	O
.	O

Coexistence	O
of	O
Turner	O
'	O
s	O
syndrome	O
and	O
schizophrenia	O

A	O
selectable	O
marker	O
for	O
transformation	O
was	O
constructed	O
by	O
transcriptional	O
fusion	O
of	O
a	O
Ustilago	B-GENE
maydis	I-GENE
heat	I-GENE
shock	I-GENE
gene	I-GENE
promoter	I-GENE
with	O
the	O
hygromycin	B-GENE
B	I-GENE
phosphotransferase	I-GENE
gene	I-GENE
of	I-GENE
Escherichia	I-GENE
coli	I-GENE
.	O

Moreover	O
,	O
FACT	B-GENE
specifically	O
interacts	O
with	O
nucleosomes	O
and	O
histone	O
H2A	B-GENE
/	O
H2B	B-GENE
dimers	O
,	O
indicating	O
that	O
it	O
may	O
work	O
by	O
promoting	O
nucleosome	O
disassembly	O
upon	O
transcription	O
.	O

All	O
exon	O
/	O
intron	O
splice	O
junctions	O
follow	O
the	O
GT	O
/	O
AG	O
rule	O
.	O

Acetoacetate	B-GENE
decarboxylase	I-GENE
(	O
ADC	B-GENE
)	O
(	O
EC4	B-GENE
.	I-GENE
1	I-GENE
.	I-GENE
1	I-GENE
.	I-GENE
4	I-GENE
)	O
of	O
Clostridium	O
acetobutylicum	O
DSM	O
792	O
was	O
purified	O
to	O
homogeneity	O
,	O
and	O
its	O
first	O
25	O
N	O
-	O
terminal	O
amino	O
acids	O
were	O
determined	O
.	O

These	O
studies	O
suggest	O
that	O
tandem	O
alpha	O
-	O
helices	O
located	O
near	O
the	O
C	O
-	O
terminus	O
of	O
PC	B-GENE
-	I-GENE
TP	I-GENE
facilitate	O
membrane	O
binding	O
and	O
extraction	O
of	O
phosphatidylcholines	O
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
the	O
mechanism	O
by	O
which	O
Tax	B-GENE
activates	O
gene	O
expression	O
in	O
conjunction	O
with	O
members	O
of	O
the	O
ATF	B-GENE
/	O
CREB	B-GENE
family	O
.	O

Repression	O
of	O
the	O
herpes	B-GENE
simplex	I-GENE
virus	I-GENE
1	I-GENE
alpha	I-GENE
4	I-GENE
gene	I-GENE
by	O
its	O
gene	O
product	O
(	O
ICP4	B-GENE
)	O
within	O
the	O
context	O
of	O
the	O
viral	O
genome	O
is	O
conditioned	O
by	O
the	O
distance	O
and	O
stereoaxial	O
alignment	O
of	O
the	O
ICP4	B-GENE
DNA	I-GENE
binding	I-GENE
site	I-GENE
relative	O
to	O
the	O
TATA	O
box	O
.	O

We	O
studied	O
18	O
dogs	O
,	O
anaesthetised	O
and	O
spontaneously	O
breathing	O
both	O
room	O
air	O
and	O
after	O
the	O
inhalation	O
of	O
a	O
gas	O
mixture	O
containing	O
10	O
%	O
CO2	O
,	O
20	O
.	O
9	O
%	O
O2	O
,	O
and	O
69	O
.	O
1	O
%	O
N2	O
,	O
to	O
determine	O
the	O
role	O
of	O
histamine	O
,	O
serotonin	O
,	O
and	O
acidaemia	O
in	O
pulmonary	O
hypertension	O
produced	O
by	O
hypercapnia	O
.	O

Disaster	O
medicine	O

In	O
both	O
liver	O
and	O
pancreatic	O
islet	O
,	O
glucokinase	B-GENE
is	O
subject	O
to	O
inhibition	O
by	O
a	O
regulatory	O
protein	O
(	O
GCKR	B-GENE
)	O
.	O

At	O
promoters	O
that	O
initiate	O
with	O
+	O
1	O
GGG	O
,	O
T7	B-GENE
RNAP	I-GENE
synthesizes	O
a	O
ladder	O
of	O
poly	O
(	O
G	O
)	O
products	O
as	O
a	O
result	O
of	O
slippage	O
of	O
the	O
transcript	O
on	O
the	O
three	O
C	O
residues	O
in	O
the	O
template	O
strand	O
from	O
+	O
1	O
to	O
+	O
3	O
.	O

Transcription	O
analysis	O
of	O
the	O
EcoRI	B-GENE
D	I-GENE
region	I-GENE
of	O
the	O
baculovirus	O
Autographa	O
californica	O
nuclear	O
polyhedrosis	O
virus	O
identifies	O
an	O
early	O
4	O
-	O
kilobase	O
RNA	O
encoding	O
the	O
essential	O
p143	B-GENE
gene	I-GENE
.	O

Vectorcardiography	O
in	O
coronary	O
patients	O
with	O
the	O
electrocardiographic	O
RS	O
segment	O
in	O
the	O
V1	O
lead	O

In	O
this	O
second	O
clinical	O
paper	O
,	O
the	O
genetic	O
features	O
of	O
the	O
case	O
of	O
microphthalmia	O
in	O
sheep	O
reported	O
by	O
Wagenaar	O
is	O
discussed	O
in	O
greater	O
detail	O
.	O

Both	O
the	O
arterial	O
and	O
venous	O
thrombi	O
were	O
clearly	O
discernible	O
at	O
2	O
to	O
8	O
h	O
after	O
injection	O
of	O
99Tcm	O
-	O
SZ	O
-	O
51	O
.	O

First	O
aid	O
.	O

However	O
,	O
the	O
blend	O
of	O
Metanil	O
yellow	O
and	O
Orange	O
II	O
(	O
1	O
:	O
1	O
)	O
resulted	O
in	O
the	O
D1	O
50	O
.	O
value	O
of	O
288	O
min	O
.	O

A	O
novel	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
(	O
PKC	B-GENE
)	O
-	O
interacting	O
protein	O
was	O
identified	O
by	O
the	O
yeast	O
two	O
-	O
hybrid	O
screening	O
using	O
the	O
regulatory	O
domain	O
of	O
PKC	B-GENE
beta	I-GENE
I	I-GENE
as	O
a	O
bait	O
.	O

In	O
this	O
study	O
,	O
we	O
show	O
that	O
the	O
activating	O
effect	O
of	O
this	O
mutation	O
is	O
not	O
the	O
result	O
of	O
creating	O
an	O
exonic	O
splicing	O
enhancer	O
(	O
ESE	O
)	O
or	O
disrupting	O
a	O
putative	O
secondary	O
structure	O
.	O

The	O
architecture	O
of	O
the	O
hRap1	B-GENE
Myb	B-GENE
domain	I-GENE
is	O
very	O
close	O
to	O
that	O
of	O
each	O
of	O
the	O
Myb	B-GENE
domains	I-GENE
from	O
TRF1	B-GENE
,	O
scRap1p	B-GENE
and	O
c	B-GENE
-	I-GENE
Myb	I-GENE
.	O

This	O
was	O
tragically	O
highlighted	O
by	O
the	O
death	O
of	O
a	O
17	O
year	O
old	O
dental	O
nurse	O
after	O
taking	O
a	O
single	O
1	O
g	O
tablet	O
of	O
sodium	O
nitrite	O
.	O

However	O
,	O
this	O
posttranslational	O
modification	O
of	O
the	O
gar2	B-GENE
protein	I-GENE
does	O
not	O
appear	O
to	O
be	O
essential	O
for	O
normal	O
production	O
of	O
18S	B-GENE
rRNA	I-GENE
.	O

The	O
BRSV	B-GENE
L	I-GENE
gene	I-GENE
is	O
6573	O
nt	O
in	O
length	O
and	O
the	O
derived	O
polypeptide	O
has	O
2162	O
aa	O
.	O

BRAP2	B-GENE
also	O
shares	O
significant	O
homology	O
with	O
a	O
hypothetical	O
protein	O
from	O
yeast	O
Saccharomyces	O
cerevisiae	O
,	O
especially	O
in	O
the	O
zinc	O
finger	O
region	O
.	O

We	O
have	O
isolated	O
and	O
determined	O
the	O
complete	O
nucleotide	O
sequence	O
of	O
another	O
operon	O
,	O
cpeCD	B-GENE
,	O
that	O
encodes	O
the	O
linker	O
proteins	O
associated	O
with	O
phycoerythrin	B-GENE
hexamers	I-GENE
in	O
the	O
phycobilisome	B-GENE
.	O

Here	O
,	O
we	O
describe	O
the	O
results	O
of	O
a	O
detailed	O
study	O
aimed	O
at	O
identifying	O
the	O
gene	O
or	O
genes	O
responsible	O
for	O
the	O
rapid	O
growth	O
-	O
arrest	O
response	O
obtained	O
with	O
human	O
chromosome	O
-	O
9	O
.	O

A	O
novel	O
Cdc42Hs	B-GENE
mutant	I-GENE
induces	O
cellular	O
transformation	O
.	O

We	O
identified	O
Tyr	O
(	O
112	O
)	O
and	O
Leu	O
(	O
175	O
)	O
within	O
the	O
RNA	O
-	O
binding	O
domain	O
of	O
the	O
U1	B-GENE
70K	I-GENE
protein	I-GENE
to	O
be	O
cross	O
-	O
linked	O
to	O
G	O
(	O
28	O
)	O
and	O
U	O
(	O
30	O
)	O
in	O
stem	O
-	O
loop	O
I	O
,	O
respectively	O
.	O

In	O
general	O
,	O
the	O
scallop	O
extract	O
potentiated	O
phototactic	O
suppression	O
.	O

Magnetic	O
field	O
influence	O
on	O
central	O
nervous	O
system	O
function	O
.	O

Only	O
Staphylococcus	O
xylosus	O
SX63	O
was	O
detected	O
as	O
a	O
strain	O
with	O
high	O
adherence	O
activity	O
.	O

Macrophages	O
:	O
modulators	O
of	O
immunity	O
.	O

METHODS	O
:	O
The	O
Die	O
Deutsche	O
Diabetes	O
Dialyse	O
Studie	O
is	O
a	O
prospective	O
randomized	O
placebo	O
-	O
controlled	O
trial	O
that	O
tests	O
the	O
hypothesis	O
that	O
atorvastatin	O
,	O
a	O
hydroxymethyl	B-GENE
-	I-GENE
glutaryl	I-GENE
coenzyme	I-GENE
A	I-GENE
reductase	I-GENE
inhibitor	O
,	O
decreases	O
the	O
rate	O
of	O
cardiovascular	O
mortality	O
and	O
of	O
nonfatal	O
myocardial	O
infarction	O
in	O
patients	O
with	O
type	O
2	O
diabetes	O
who	O
have	O
been	O
on	O
hemodialysis	O
treatment	O
for	O
no	O
more	O
than	O
two	O
years	O
.	O

An	O
OD	O
650	O
greater	O
than	O
0	O
.	O
15	O
appears	O
to	O
be	O
a	O
rapid	O
,	O
reliable	O
indicator	O
of	O
fetal	O
lung	O
maturity	O
.	O

This	O
high	O
dose	O
5	O
-	O
FU	O
+	O
Act	O
-	O
D	O
protocol	O
was	O
effective	O
for	O
drug	O
resistant	O
cases	O
with	O
MEA	O
protocol	O
.	O

Therefore	O
,	O
it	O
appears	O
that	O
GCN2	B-GENE
protein	I-GENE
kinase	I-GENE
function	O
is	O
stimulated	O
posttranslationally	O
in	O
amino	O
acid	O
-	O
starved	O
cells	O
.	O

CSEn	B-GENE
stimulated	O
transcription	O
of	O
a	O
variety	O
of	O
promoters	O
,	O
including	O
the	O
hCS	B-GENE
,	O
human	B-GENE
growth	I-GENE
hormone	I-GENE
,	O
thymidine	B-GENE
kinase	I-GENE
,	O
and	O
Rous	B-GENE
sarcoma	I-GENE
virus	I-GENE
promoters	I-GENE
,	O
in	O
human	O
choriocarcinoma	O
cell	O
lines	O
(	O
BeWo	O
and	O
JEG	O
-	O
3	O
)	O
but	O
not	O
HeLa	O
cells	O
or	O
rat	O
somatolactotrophes	O
(	O
GC	O
)	O
.	O

HIV	O
-	O
2	O
in	O
Spain	O
.	O

Reversal	O
of	O
mefloquine	O
resistance	O
in	O
rodent	O
Plasmodium	O
.	O

Airborne	O
rabies	O
encephalitis	O
:	O
demonstration	O
of	O
rabies	O
virus	O
in	O
the	O
human	O
central	O
nervous	O
system	O
.	O

No	O
promoter	O
activity	O
could	O
be	O
detected	O
with	O
various	O
mouse	B-GENE
Fli	I-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
-	O
CAT	B-GENE
constructs	O
containing	O
600	O
bp	O
of	O
the	O
5	O
'	O
flanking	O
region	O
,	O
the	O
complete	O
exon	O
1	O
,	O
the	O
5	O
'	O
end	O
of	O
intron	O
1	O
and	O
/	O
or	O
retroviral	O
LTR	O
sequence	O
.	O

We	O
now	O
show	O
that	O
the	O
FRAP	B-GENE
Ser2035	O
-	O
-	O
>	O
Ala	O
mutant	O
displays	O
similar	O
binding	O
affinity	O
when	O
compared	O
with	O
the	O
wild	O
-	O
type	O
protein	O
,	O
whereas	O
all	O
other	O
mutations	O
at	O
this	O
site	O
,	O
including	O
mimics	O
of	O
phosphoserine	O
,	O
abolish	O
binding	O
,	O
presumably	O
due	O
to	O
either	O
unfavorable	O
steric	O
interactions	O
or	O
induced	O
conformational	O
changes	O
.	O

These	O
findings	O
suggest	O
that	O
the	O
mechanism	O
of	O
ribosomal	O
frameshifting	O
at	O
the	O
PVM	O
signal	O
is	O
different	O
from	O
the	O
one	O
described	O
by	O
the	O
'	O
simultaneous	O
slippage	O
'	O
model	O
in	O
that	O
only	O
the	O
string	O
of	O
four	O
adenosine	O
nucleotides	O
represents	O
the	O
slippery	O
sequence	O
involved	O
in	O
a	O
-	O
1	O
P	O
-	O
site	O
slippage	O
.	O

The	O
fru	B-GENE
gene	I-GENE
has	O
seven	O
exons	O
spanning	O
15	O
-	O
kb	O
encoding	O
two	O
transcripts	O
with	O
ORFs	O
of	O
841	O
and	O
695	O
amino	O
acids	O
.	O

This	O
sequence	O
can	O
interact	O
with	O
at	O
least	O
two	O
proteins	O
in	O
a	O
fibroblast	O
nuclear	O
extract	O
that	O
have	O
binding	O
characteristics	O
of	O
an	O
Ets	B-GENE
family	I-GENE
protein	I-GENE
and	O
a	O
serum	B-GENE
response	I-GENE
factor	I-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
.	O

Response	O
properties	O
of	O
single	O
units	O
in	O
the	O
accessory	O
optic	O
system	O
of	O
the	O
dark	O
-	O
reared	O
cat	O
.	O

Effect	O
of	O
tetracycline	O
on	O
the	O
glycogen	O
-	O
producing	O
function	O
of	O
the	O
liver	O
and	O
intestinal	O
microflora	O
in	O
white	O
mice	O

Significantly	O
higher	O
levels	O
of	O
vitamin	O
C	O
and	O
catalase	B-GENE
activity	O
were	O
found	O
in	O
vegetarians	O
(	O
C	O
-	O
63	O
.	O
6	O
and	O
86	O
.	O
5	O
mumol	O
/	O
l	O
;	O
CAT	O
-	O
1497	O
and	O
1313	O
U	O
/	O
ml	O
for	O
males	O
and	O
females	O
,	O
respectively	O
)	O
when	O
compared	O
to	O
nonvegetarians	O
(	O
C	O
-	O
41	O
.	O
3	O
and	O
54	O
.	O
4	O
mumol	O
/	O
l	O
;	O
CAT	O
-	O
1192	O
and	O
1086	O
U	O
/	O
ml	O
)	O
.	O

However	O
,	O
only	O
plasma	B-GENE
fibrinogen	I-GENE
concentrations	O
showed	O
statistically	O
significant	O
positive	O
associations	O
with	O
IMT	O
in	O
both	O
groups	O
.	O

METHODS	O
.	O

Presently	O
,	O
we	O
made	O
chain	O
pair	O
switch	O
,	O
chimeric	O
,	O
and	O
site	O
mutant	B-GENE
gamma	I-GENE
delta	I-GENE
TCRs	I-GENE
and	O
transfected	O
them	O
into	O
TCR	O
-	O
mutant	O
Jurkat	O
T	O
cells	O
to	O
examine	O
the	O
effects	O
of	O
changing	O
the	O
TCR	B-GENE
gamma	I-GENE
junctional	I-GENE
region	I-GENE
sequences	I-GENE
on	O
reactivity	O
to	O
prenyl	B-GENE
pyrophosphate	I-GENE
Ags	I-GENE
.	O

The	O
molecular	O
dynamics	O
simulations	O
provide	O
insight	O
into	O
the	O
conformational	O
flexibility	O
of	O
these	O
analogs	O
.	O

Modified	O
Grocott	O
'	O
s	O
methenamine	O
silver	O
nitrate	O
method	O
for	O
quick	O
staining	O
of	O
Pneumocystis	O
carinii	O
.	O

The	O
control	O
of	O
human	B-GENE
aromatase	I-GENE
expression	O
is	O
complex	O
in	O
that	O
several	O
promoters	O
drive	O
aromatase	B-GENE
expression	O
in	O
a	O
tissue	O
-	O
specific	O
manner	O
.	O

Surprisingly	O
,	O
although	O
Mist1	B-GENE
binds	O
to	O
E	O
-	O
boxes	O
in	O
vivo	O
,	O
the	O
Mist1	B-GENE
protein	I-GENE
lacks	O
a	O
functional	O
transcription	O
activation	O
domain	O
.	O

Selective	O
upper	O
abdominal	O
sympathectomy	O
increased	O
basal	O
acid	O
output	O
in	O
rats	O
but	O
was	O
without	O
effect	O
on	O
stimulated	O
acid	O
output	O
,	O
serum	B-GENE
gastrin	I-GENE
concentration	O
,	O
and	O
gastric	B-GENE
mucosal	I-GENE
histidine	I-GENE
decarboxylase	I-GENE
activity	O
.	O

To	O
isolate	O
genes	O
that	O
contain	O
zinc	O
finger	O
motifs	O
,	O
a	O
human	O
brain	O
cDNA	O
library	O
was	O
screened	O
with	O
an	O
oligonucleotide	O
complementary	O
to	O
the	O
conserved	O
"	O
linker	O
"	O
sequence	O
between	O
adjacent	O
zinc	O
fingers	O
.	O

Transforming	B-GENE
growth	I-GENE
factor	I-GENE
beta	I-GENE
activates	O
the	O
promoter	O
of	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
inhibitor	O
p15INK4B	B-GENE
through	O
an	O
Sp1	B-GENE
consensus	I-GENE
site	I-GENE
.	O

Thus	O
,	O
in	O
addition	O
to	O
the	O
previously	O
characterized	O
FAS	B-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
1	I-GENE
interacting	O
with	O
the	O
inositol	O
/	O
choline	O
-	O
responsive	O
-	O
element	O
motif	O
,	O
a	O
second	O
motif	O
common	O
to	O
the	O
promoter	O
regions	O
of	O
both	O
FAS	B-GENE
genes	I-GENE
could	O
be	O
identified	O
.	O

Kluyveromyces	O
lactis	O
,	O
a	O
budding	O
yeast	O
related	O
to	O
Saccharomyces	O
cerevisiae	O
,	O
can	O
grow	O
on	O
a	O
wider	O
variety	O
of	O
substrates	O
and	O
shows	O
less	O
sensitivity	O
to	O
glucose	O
repression	O
than	O
does	O
Saccharomyces	O
cerevisiae	O
.	O

Sociological	O
analysis	O
of	O
the	O
family	O
.	O

Like	O
other	O
known	O
GCD	B-GENE
genes	I-GENE
,	O
GCD14	B-GENE
and	O
GCD15	B-GENE
are	O
therefore	O
probably	O
required	O
for	O
general	O
translation	O
initiation	O
in	O
addition	O
to	O
their	O
roles	O
in	O
GCN4	B-GENE
-	O
specific	O
translational	O
control	O
.	O

Sorting	O
information	O
to	O
the	O
chloroplastic	O
inner	O
envelope	O
is	O
contained	O
in	O
an	O
NH2	O
-	O
proximal	O
part	O
of	O
mature	B-GENE
IEP110	I-GENE
(	O
110N	B-GENE
)	O
.	O

Both	O
algorithms	O
have	O
been	O
implemented	O
and	O
applied	O
to	O
data	O
simulated	O
for	O
a	O
scanner	O
with	O
a	O
large	O
axial	O
aperture	O
(	O
30	O
degrees	O
)	O
,	O
and	O
also	O
to	O
data	O
acquired	O
with	O
the	O
ECAT	O
HR	O
and	O
the	O
ECAT	O
HR	O
+	O
scanners	O
.	O

BACKGROUND	O
:	O
Murine	B-GENE
Nramp	I-GENE
is	O
a	O
candidate	O
for	O
the	O
macrophage	O
resistance	O
gene	O
Ity	B-GENE
/	O
Lsh	B-GENE
/	O
Bcg	B-GENE
.	O

Serum	O
zinc	O
and	O
copper	O
levels	O
and	O
urine	O
copper	O
concentrations	O
in	O
men	O
were	O
significantly	O
lower	O
than	O
in	O
women	O
,	O
while	O
there	O
were	O
no	O
differences	O
in	O
serum	O
or	O
urinary	O
zinc	O
and	O
copper	O
levels	O
with	O
age	O
.	O

Pregnancy	O
was	O
ensued	O
in	O
4	O
cases	O
in	O
group	O
I	O
.	O

CONCLUSION	O
:	O
In	O
these	O
patients	O
control	O
of	O
ventricular	O
response	O
rate	O
with	O
either	O
HBA	O
+	O
VVIR	O
pacemaker	O
or	O
atrioventricular	O
modifying	O
drugs	O
+	O
VVI	O
pacemaker	O
will	O
lead	O
to	O
a	O
significant	O
improvement	O
in	O
exercise	O
duration	O
and	O
quality	O
of	O
life	O
.	O

Western	O
immunoblot	O
analysis	O
detected	O
p55gag	B-GENE
and	O
its	O
cleavage	O
products	O
p39	B-GENE
and	O
p27	B-GENE
in	O
purified	O
particles	O
derived	O
by	O
expression	O
of	O
gag	B-GENE
and	O
gag	B-GENE
-	O
pol	B-GENE
,	O
respectively	O
.	O

These	O
three	O
phases	O
of	O
cyclin	B-GENE
E	I-GENE
association	O
with	O
chromatin	O
may	O
facilitate	O
the	O
diverse	O
activities	O
of	O
cyclin	B-GENE
E	I-GENE
-	O
-	O
Cdk2	B-GENE
in	O
initiating	O
replication	O
,	O
blocking	O
rereplication	O
,	O
and	O
allowing	O
resetting	O
of	O
origins	O
after	O
mitosis	O
.	O

It	O
has	O
been	O
shown	O
that	O
renin	B-GENE
secretion	O
is	O
stimulated	O
by	O
endothelin	B-GENE
,	O
a	O
recently	O
discovered	O
peptide	O
with	O
strong	O
vasoconstrictive	O
properties	O
and	O
stimulating	O
effects	O
on	O
renin	B-GENE
secretion	O
.	O

A	O
higher	O
percentage	O
of	O
children	O
with	O
cerebral	O
malaria	O
(	O
40	O
per	O
cent	O
)	O
than	O
with	O
non	O
-	O
cerebral	O
malaria	O
(	O
29	O
per	O
cent	O
)	O
or	O
controls	O
(	O
20	O
per	O
cent	O
)	O
also	O
had	O
either	O
serum	B-GENE
ferritin	I-GENE
<	O
100	O
micrograms	O
/	O
l	O
and	O
inflammation	O
or	O
sTfR	B-GENE
>	O
7	O
.	O
3	O
mg	O
/	O
l	O
or	O
both	O
.	O

Patients	O
received	O
BPB	O
using	O
bupivacaine	O
2	O
mg	O
kg	O
-	O
1	O
with	O
adrenaline	O
1	O
in	O
200	O
,	O
000	O
,	O
either	O
with	O
or	O
without	O
hyaluronidase	B-GENE
3000	O
iu	O
,	O
in	O
a	O
volume	O
of	O
0	O
.	O
5	O
ml	O
per	O
2	O
.	O
54	O
cm	O
of	O
the	O
patient	O
'	O
s	O
height	O
.	O

The	O
rifampicin	O
resistance	O
of	O
uvsW	B-GENE
-	O
repressed	O
replication	O
suggests	O
that	O
it	O
involves	O
either	O
tertiary	O
initiation	O
or	O
some	O
novel	O
mode	O
of	O
initiation	O
.	O

Association	O
between	O
hyperhomocysteinemia	O
and	O
ischemic	O
heart	O
disease	O
in	O
Sri	O
Lankans	O
.	O

These	O
findings	O
suggest	O
that	O
the	O
proteolipids	O
of	O
the	O
vacuolar	B-GENE
H	I-GENE
+	I-GENE
-	I-GENE
ATPases	I-GENE
were	O
evolved	O
in	O
parallel	O
with	O
the	O
eubacterial	O
proteolipid	O
,	O
from	O
a	O
common	O
ancestral	O
gene	O
that	O
underwent	O
gene	O
duplication	O
.	O

Coexpression	O
of	O
c	B-GENE
-	I-GENE
Rel	I-GENE
in	O
combination	O
with	O
ATF	B-GENE
-	I-GENE
1	I-GENE
,	O
CREB2	B-GENE
,	O
or	O
ATF	B-GENE
-	I-GENE
1	I-GENE
/	O
CREB2	B-GENE
leads	O
to	O
synergistic	O
transactivation	O
of	O
a	O
CD28RE	B-GENE
-	I-GENE
TRE	I-GENE
reporter	I-GENE
plasmid	O
in	O
quiescent	O
Jurkat	O
T	O
-	O
cells	O
.	O

Characterization	O
of	O
a	O
cDNA	B-GENE
encoding	I-GENE
CNN	I-GENE
predicts	O
a	O
novel	O
structural	O
protein	O
with	O
three	O
leucine	O
zipper	O
motifs	O
and	O
several	O
coiled	O
-	O
coil	O
domains	O
exhibiting	O
limited	O
homology	O
to	O
the	O
rod	O
portion	O
of	O
myosin	B-GENE
.	O

It	O
is	O
suggested	O
that	O
the	O
loss	O
of	O
weight	O
,	O
the	O
decrease	O
in	O
food	O
intake	O
and	O
the	O
increase	O
in	O
brain	O
MOPEG	O
-	O
SO4	O
induced	O
by	O
cyanamide	O
reflect	O
possible	O
anorectic	O
properties	O
of	O
the	O
drug	O
.	O

The	O
differential	O
diagnosis	O
of	O
mineral	O
oil	O
lipidosis	O
in	O
lymph	O
nodes	O
with	O
reaction	O
to	O
radiopaque	O
oils	O
and	O
Whipple	O
'	O
s	O
disease	O
is	O
discussed	O
.	O

The	O
serum	O
levels	O
of	O
cortisol	O
and	O
prolactin	B-GENE
after	O
nasal	O
instillation	O
of	O
a	O
suspension	O
of	O
vaginal	O
exudate	O
showed	O
lower	O
values	O
than	O
in	O
control	O
conditions	O
(	O
nasal	O
instillation	O
of	O
saline	O
)	O
.	O

This	O
enhancer	O
element	O
functioned	O
in	O
a	O
position	O
-	O
and	O
orientation	O
-	O
independent	O
manner	O
both	O
on	O
the	O
Pax	B-GENE
-	I-GENE
QNR	I-GENE
P0	I-GENE
promoter	I-GENE
and	O
the	O
heterologous	B-GENE
thymidine	I-GENE
kinase	I-GENE
promoter	I-GENE
.	O

The	O
data	O
when	O
used	O
to	O
stimulate	O
the	O
collection	O
of	O
the	O
information	O
at	O
antenatal	O
or	O
postnatal	O
visits	O
,	O
nonetheless	O
provide	O
an	O
accurate	O
description	O
of	O
under	O
-	O
3	O
mortality	O
trends	O
and	O
differences	O
for	O
the	O
two	O
periods	O
examined	O
-	O
-	O
before	O
1984	O
and	O
before	O
1989	O
.	O

The	O
BHV	B-GENE
-	I-GENE
1	I-GENE
UL24	I-GENE
,	O
UL25	B-GENE
,	O
UL26	B-GENE
and	O
UL26	B-GENE
.	I-GENE
5	I-GENE
transcripts	I-GENE
all	O
terminated	O
at	O
a	O
common	O
3	O
'	O
-	O
polyadenylation	O
site	O
and	O
varied	O
significantly	O
in	O
their	O
relative	O
abundance	O
.	O

A	O
.	O

Ligand	O
binding	O
of	O
multi	O
-	O
chain	O
antigen	O
receptors	O
and	O
hematopoietin	B-GENE
/	O
cytokine	O
receptors	O
results	O
in	O
rapid	O
activation	O
of	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
(	O
PTK	B-GENE
)	O
-	O
dependent	O
signalling	O
molecules	O
such	O
as	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
(	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
)	O
.	O

Post	O
-	O
CPB	O
cardiac	O
index	O
was	O
superior	O
in	O
group	O
B	O
(	O
3	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
3	O
vs	O
.	O

The	O
regulatory	O
genes	O
cnrYXH	B-GENE
have	O
been	O
cloned	O
,	O
overexpressed	O
,	O
and	O
purified	O
in	O
Escherichia	O
coli	O
.	O

Cognitive	O
measures	O
of	O
attention	O
included	O
the	O
Stroop	O
and	O
Controlled	O
Oral	O
Word	O
Association	O
Test	O
using	O
the	O
letters	O
"	O
C	O
,	O
"	O
"	O
F	O
,	O
"	O
and	O
"	O
L	O
"	O
(	O
COWAT	O
,	O
CFL	O
version	O
)	O
.	O

The	O
objectives	O
of	O
this	O
study	O
were	O
1	O
)	O
to	O
quantify	O
the	O
comparative	O
structural	O
static	O
and	O
fatigue	O
properties	O
of	O
the	O
pointe	O
shoe	O
toe	O
box	O
,	O
and	O
2	O
)	O
to	O
evaluate	O
the	O
preferred	O
shoe	O
characteristics	O
as	O
determined	O
by	O
a	O
survey	O
of	O
local	O
dancers	O
.	O

When	O
linked	O
to	O
the	O
herpes	O
simplex	O
thymidine	B-GENE
kinase	I-GENE
minimal	O
promoter	O
,	O
this	O
fragment	O
acts	O
as	O
an	O
enhancing	O
element	O
in	O
Rcho	O
but	O
not	O
GC	O
cells	O
.	O

We	O
report	O
on	O
a	O
case	O
of	O
a	O
43	O
-	O
old	O
-	O
male	O
with	O
a	O
bronchogenic	O
cyst	O
in	O
the	O
distal	O
esophagus	O
,	O
which	O
was	O
misdiagnosed	O
as	O
a	O
malignant	O
esophageal	O
tumor	O
based	O
on	O
preoperative	O
imaging	O
and	O
high	O
levels	O
of	O
the	O
tumor	O
markers	O
CA	B-GENE
19	I-GENE
-	I-GENE
9	I-GENE
and	O
CA	B-GENE
125	I-GENE
.	O

Oscillatory	O
flow	O
is	O
reestablished	O
in	O
the	O
model	O
at	O
the	O
capillary	O
-	O
cerebrospinal	O
fluid	O
and	O
capillary	O
-	O
venous	O
interfaces	O
.	O

This	O
substrate	O
was	O
cleaved	O
efficiently	O
in	O
trans	O
by	O
protease	B-GENE
3C	I-GENE
derived	O
from	O
another	O
recombinant	O
vaccinia	O
virus	O
expressing	O
a	O
3C	B-GENE
precursor	I-GENE
protein	I-GENE
.	O

Human	B-GENE
and	I-GENE
murine	I-GENE
cytotoxic	I-GENE
T	I-GENE
lymphocyte	I-GENE
serine	I-GENE
proteases	I-GENE
:	O
subsite	O
mapping	O
with	O
peptide	O
thioester	O
substrates	O
and	O
inhibition	O
of	O
enzyme	O
activity	O
and	O
cytolysis	O
by	O
isocoumarins	O
.	O

The	O
human	B-GENE
Fc	I-GENE
gamma	I-GENE
receptor	I-GENE
gene	I-GENE
Fc	B-GENE
gamma	I-GENE
RIIA	I-GENE
is	O
expressed	O
in	O
platelets	O
,	O
neutrophils	O
,	O
monocytes	O
and	O
macrophages	O
.	O

Like	O
the	O
nuclear	O
envelope	O
,	O
the	O
intranuclear	O
double	O
membrane	O
lamellae	O
enclosed	O
a	O
defined	O
cisterna	O
that	O
was	O
interrupted	O
by	O
pores	O
but	O
,	O
unlike	O
the	O
nuclear	O
envelope	O
pores	O
,	O
they	O
lacked	O
NPCs	O
.	O

Regulation	O
of	O
the	O
human	B-GENE
stress	I-GENE
response	I-GENE
gene	I-GENE
GADD153	I-GENE
expression	O
:	O
role	O
of	O
ETS1	B-GENE
and	O
FLI	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
products	I-GENE
.	O

On	O
days	O
7	O
,	O
21	O
,	O
and	O
35	O
postinoculation	O
(	O
PI	O
)	O
,	O
all	O
birds	O
received	O
sheep	O
erythrocytes	O
intravenously	O
.	O

The	O
higher	O
level	O
of	O
calories	O
was	O
attained	O
by	O
an	O
increased	O
intake	O
of	O
carbohydrates	O
.	O

However	O
,	O
it	O
is	O
now	O
suggested	O
that	O
the	O
use	O
of	O
more	O
slowly	O
digested	O
starchy	O
foods	O
may	O
have	O
positive	O
health	O
benefits	O
.	O

Each	O
receptor	O
must	O
therefore	O
engage	O
a	O
unique	O
subset	O
of	O
the	O
available	O
signaling	O
elements	O
-	O
-	O
at	O
least	O
partly	O
through	O
the	O
selection	O
of	O
proteins	O
with	O
src	B-GENE
-	I-GENE
homology	I-GENE
2	I-GENE
domains	I-GENE
(	O
SH2	B-GENE
proteins	I-GENE
)	O
.	O

Hence	O
,	O
it	O
is	O
perhaps	O
not	O
necessary	O
to	O
perform	O
spinal	O
puncture	O
if	O
the	O
only	O
purpose	O
is	O
to	O
determine	O
the	O
CSF	O
/	O
serum	O
ratio	O
.	O

NSAIDS	O
and	O
the	O
microcirculation	O
of	O
the	O
stomach	O
.	O

Highly	O
significant	O
similarities	O
were	O
detected	O
between	O
the	O
N	O
-	O
terminal	O
region	O
of	O
P30	B-GENE
and	O
those	O
of	O
GENA	B-GENE
[	O
the	O
product	O
of	O
another	O
unidentified	O
gene	O
(	O
geneA	B-GENE
)	O
located	O
upstream	O
of	O
the	O
aceEF	B-GENE
-	O
lpd	B-GENE
operon	O
]	O
,	O
and	O
GNTR	B-GENE
(	O
a	O
putative	O
transcriptional	O
repressor	O
of	O
the	O
gluconate	B-GENE
operon	I-GENE
of	O
Bacillus	O
subtilis	O
)	O
.	O

Promoting	O
fat	O
utilisation	O
by	O
reducing	O
the	O
carbohydrate	O
-	O
fat	O
ratio	O
of	O
the	O
TPN	O
reduces	O
free	O
radical	O
activity	O
to	O
a	O
similar	O
extent	O
as	O
fat	O
exclusion	O
.	O

It	O
is	O
postulated	O
that	O
the	O
synthesis	O
of	O
the	O
peptidoglycan	O
layer	O
was	O
affected	O
by	O
the	O
antimetabolites	O
since	O
the	O
morphological	O
effects	O
were	O
strikingly	O
similar	O
to	O
those	O
caused	O
by	O
treatment	O
of	O
E	O
.	O
cloacae	O
with	O
disodium	O
edetate	O
plus	O
lysozyme	B-GENE
.	O

The	O
selective	O
5	B-GENE
-	I-GENE
HT2	I-GENE
receptor	I-GENE
blocker	O
ketanserin	O
was	O
found	O
to	O
reduce	O
maximal	O
urethral	O
pressures	O
in	O
healthy	O
females	O
by	O
about	O
40	O
%	O
without	O
reducing	O
blood	O
pressure	O
.	O

RESULTS	O
:	O
Of	O
10	O
,	O
709	O
,	O
701	O
chemistry	O
specimens	O
submitted	O
to	O
the	O
participating	O
laboratories	O
during	O
the	O
data	O
collection	O
period	O
,	O
37	O
,	O
208	O
(	O
0	O
.	O
35	O
%	O
)	O
were	O
rejected	O
prior	O
to	O
testing	O
.	O

Interestingly	O
,	O
VDR	B-GENE
was	O
able	O
to	O
bind	O
to	O
VDREs	O
with	O
high	O
affinity	O
and	O
to	O
fully	O
activate	O
transcription	O
in	O
intact	O
yeast	O
cells	O
in	O
the	O
presence	O
of	O
the	O
retinoid	B-GENE
X	I-GENE
receptor	I-GENE
(	O
RXR	B-GENE
)	O
.	O

The	O
newly	O
identified	O
repressor	O
element	O
is	O
a	O
rare	O
example	O
of	O
a	O
naturally	O
occurring	O
perfect	O
palindromic	O
binding	O
motif	O
for	O
the	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
/	O
Rel	B-GENE
family	O
of	O
transcription	O
factors	O
.	O

UV	O
-	O
cross	O
-	O
linking	O
studies	O
suggested	O
that	O
these	O
two	O
complexes	O
represent	O
one	O
and	O
two	O
molecules	O
of	O
ADR1	B-GENE
bound	O
to	O
DNA	O
.	O

Finally	O
,	O
the	O
conservation	O
of	O
the	O
two	O
residues	O
most	O
sensitive	O
to	O
mutations	O
(	O
Y949	O
and	O
Y953	O
)	O
in	O
TM11	O
,	O
and	O
in	O
the	O
homologous	O
TM5	O
,	O
of	O
all	O
mammalian	B-GENE
P	I-GENE
-	I-GENE
gps	I-GENE
and	O
also	O
in	O
other	O
ABC	B-GENE
transporters	I-GENE
,	O
suggests	O
that	O
these	O
residues	O
and	O
domains	O
may	O
play	O
an	O
important	O
role	O
in	O
structural	O
as	O
well	O
as	O
mechanistic	O
aspects	O
common	O
to	O
this	O
family	O
of	O
proteins	O
.	O

SF1	B-GENE
/	O
mBBP	B-GENE
utilizes	O
a	O
"	B-GENE
maxi	I-GENE
-	I-GENE
K	I-GENE
homology	I-GENE
"	I-GENE
(	O
maxi	B-GENE
-	I-GENE
KH	I-GENE
)	O
domain	O
for	O
recognition	O
of	O
the	O
single	O
-	O
stranded	O
BPS	O
and	O
requires	O
a	O
cooperative	O
interaction	O
with	O
splicing	O
factor	O
U2AF65	B-GENE
bound	O
to	O
an	O
adjacent	O
polypyrimidine	O
tract	O
(	O
PPT	O
)	O
for	O
high	O
-	O
affinity	O
binding	O
.	O

The	O
in	O
vivo	O
response	O
of	O
the	O
PacC	B-GENE
-	I-GENE
like	I-GENE
decamers	I-GENE
to	O
external	O
pH	O
was	O
dependent	O
on	O
the	O
status	O
of	O
the	O
pH	O
-	O
regulated	O
activator	O
YlRim101p	B-GENE
,	O
which	O
is	O
homologous	O
to	O
the	O
A	O
.	O
nidulans	O
PacC	B-GENE
regulator	O
.	O

Spongiosa	O
regeneration	O
in	O
the	O
millipore	O
chamber	O

MTX	O
therapy	O
decreased	O
Ga	O
-	O
67	O
uptake	O
in	O
liver	O
,	O
tumor	O
,	O
and	O
muscle	O
.	O

Each	O
of	O
these	O
materials	O
were	O
placed	O
by	O
means	O
of	O
three	O
different	O
placement	O
techniques	O
(	O
Bulk	O
pack	O
,	O
Horizontal	O
layering	O
and	O
Vertical	O
layering	O
)	O
into	O
class	O
II	O
cavities	O
in	O
extracted	O
human	O
molars	O
.	O

In	O
contrast	O
,	O
the	O
sequences	O
essential	O
for	O
the	O
transcription	O
of	O
EFT1	B-GENE
were	O
localized	O
to	O
the	O
region	O
between	O
the	O
start	O
ATG	O
and	O
the	O
stop	O
codon	O
of	O
the	O
VPS17	B-GENE
gene	I-GENE
that	O
terminates	O
267	O
nt	O
upstream	O
on	O
the	O
same	O
strand	O
.	O

No	O
transactivation	O
of	O
the	O
ovalbumin	B-GENE
promoter	I-GENE
(	O
pLovTATA	B-GENE
)	O
template	O
control	O
was	O
observed	O
.	O

Removal	O
of	O
cyclin	B-GENE
-	I-GENE
dependant	I-GENE
kinases	I-GENE
(	O
cdks	B-GENE
)	O
or	O
cdk2	B-GENE
from	O
these	O
extracts	O
using	O
affinity	O
matrices	O
severely	O
inhibits	O
initiation	O
of	O
S	O
phase	O
.	O

Consistent	O
with	O
this	O
hypothesis	O
,	O
stimulation	O
of	O
A	B-GENE
(	I-GENE
2A	I-GENE
)	I-GENE
-	I-GENE
R	I-GENE
or	O
PKA	B-GENE
enhanced	O
nuclear	B-GENE
aPKC	I-GENE
activity	O
.	O

Foreign	O
DNA	O
inserts	O
contained	O
within	O
the	O
fowlpox	O
virus	O
sequence	O
were	O
transferred	O
to	O
the	O
viral	O
genome	O
by	O
homologous	O
recombination	O
occurring	O
in	O
cells	O
infected	O
with	O
a	O
fowlpox	O
virus	O
temperature	O
-	O
sensitive	O
mutant	O
and	O
transfected	O
with	O
both	O
wild	O
-	O
type	O
viral	O
DNA	O
and	O
plasmid	O
DNA	O
.	O

JCAHO	O
to	O
use	O
ORYX	O
data	O
to	O
detect	O
sentinel	O
events	O
.	O

Comparisons	O
of	O
the	O
efficacy	O
of	O
benazepril	O
and	O
hydrochlorothiazide	O
alone	O
and	O
in	O
combination	O
have	O
shown	O
that	O
benazepril	O
20	O
mg	O
once	O
daily	O
is	O
as	O
effective	O
as	O
or	O
more	O
effective	O
in	O
lowering	O
diastolic	O
blood	O
pressure	O
than	O
hydrochlorothiazide	O
25	O
mg	O
once	O
daily	O
and	O
that	O
the	O
combination	O
of	O
benazepril	O
20	O
mg	O
and	O
hydrochlorothiazide	O
25	O
mg	O
has	O
a	O
possibly	O
synergistic	O
effect	O
on	O
diastolic	O
blood	O
pressure	O
.	O

Carcinoma	B-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
production	O
may	O
have	O
played	O
a	O
role	O
in	O
the	O
development	O
of	O
the	O
observed	O
renal	O
lesions	O
.	O

METHODS	O
:	O
The	O
study	O
population	O
included	O
70	O
patients	O
with	O
acute	O
coronary	O
syndromes	O
(	O
14	O
with	O
recent	O
acute	O
myocardial	O
infarction	O
and	O
56	O
with	O
unstable	O
angina	O
pectoris	O
)	O
,	O
105	O
patients	O
with	O
stable	O
angina	O
pectoris	O
,	O
and	O
75	O
control	O
subjects	O
.	O

Single	O
amino	O
acid	O
substitutions	O
were	O
shown	O
to	O
result	O
from	O
the	O
mutations	O
pdr1	B-GENE
-	I-GENE
2	I-GENE
(	O
M308I	O
)	O
,	O
pdr1	B-GENE
-	I-GENE
3	I-GENE
(	O
F815S	O
)	O
,	O
pdr1	B-GENE
-	I-GENE
6	I-GENE
(	O
K302Q	O
)	O
,	O
pdr1	B-GENE
-	I-GENE
7	I-GENE
(	O
P298A	O
)	O
and	O
pdr1	B-GENE
-	I-GENE
8	I-GENE
(	O
L1036	O
W	O
)	O
,	O
whereas	O
the	O
intragenic	O
suppressor	O
mutant	O
pdr1	B-GENE
-	I-GENE
100	I-GENE
is	O
deleted	O
for	O
the	O
two	O
amino	O
acids	O
L537	O
and	O
A538	O
.	O

However	O
,	O
no	O
statistical	O
difference	O
in	O
the	O
Ca	O
/	O
P	O
ratio	O
,	O
carbon	O
concentration	O
and	O
surface	O
energy	O
were	O
observed	O
with	O
different	O
heat	O
treatments	O
.	O

These	O
motions	O
were	O
found	O
in	O
the	O
N	O
-	O
and	O
C	O
-	O
terminal	O
tails	O
,	O
in	O
segment	O
33	O
-	O
35	O
which	O
forms	O
the	O
turn	O
between	O
beta	O
-	O
strands	O
S1	O
and	O
S2	O
,	O
and	O
residues	O
47	O
-	O
52	O
located	O
in	O
a	O
long	O
loop	O
preceding	O
strand	O
S3	O
.	O

Enterobius	O
vermicularis	O
eggs	O
were	O
demonstrated	O
during	O
microscopic	O
examination	O
of	O
a	O
smear	O
taken	O
from	O
the	O
posterior	O
fornix	O
of	O
the	O
vagina	O
.	O

Differentiation	O
of	O
porcine	O
mycoplasma	O
strains	O
by	O
means	O
of	O
a	O
simple	O
paper	O
chromatography	O
test	O
.	O

D	O
.	O
,	O
Hughes	O
,	O
F	O
.	O

We	O
further	O
showed	O
a	O
significant	O
repression	O
of	O
promoter	O
activity	O
(	O
>	O
40	O
fold	O
)	O
by	O
E2	B-GENE
-	I-GENE
2	I-GENE
(	O
lacking	O
the	O
amino	O
acid	O
sequence	O
RSRS	O
)	O
when	O
the	O
E47	B-GENE
reporter	I-GENE
construct	I-GENE
,	O
containing	O
a	O
hexameric	O
E	O
-	O
box	O
site	O
,	O
was	O
used	O
.	O

Sequence	O
analysis	O
of	O
AEBP2	B-GENE
cDNA	I-GENE
revealed	O
that	O
it	O
encodes	O
a	O
protein	O
containing	O
three	O
Gli	B-GENE
-	O
Kruppel	B-GENE
(	O
Cys2	O
-	O
His2	O
)	O
-	O
type	O
zinc	O
fingers	O
.	O

METHODS	O
:	O
The	O
prevalence	O
of	O
haemagglutination	B-GENE
inhibiting	I-GENE
(	I-GENE
HI	I-GENE
)	I-GENE
antibodies	I-GENE
to	O
JE	O
virus	O
(	O
JEV	O
)	O
,	O
West	O
Nile	O
virus	O
(	O
WNV	O
)	O
and	O
dengue	O
-	O
2	O
virus	O
(	O
DEN	O
-	O
2	O
)	O
was	O
detected	O
by	O
HI	O
test	O
and	O
IgM	B-GENE
antibody	I-GENE
capture	O
ELISA	O
(	O
MAC	O
ELISA	O
)	O
was	O
performed	O
to	O
determine	O
recent	O
infections	O
with	O
JE	O
virus	O
.	O

To	O
elucidate	O
the	O
mechanism	O
of	O
these	O
hormonal	O
effects	O
,	O
we	O
have	O
studied	O
the	O
regulatory	O
regions	O
of	O
the	O
PFK	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
in	O
transfection	O
experiments	O
.	O

Tryptophan	O
induction	O
prevents	O
Rho	B-GENE
-	O
dependent	O
transcription	O
termination	O
in	O
the	O
leader	O
region	O
of	O
the	O
operon	O
.	O

An	O
in	O
vitro	O
Raf	B-GENE
-	I-GENE
1	I-GENE
kinase	I-GENE
assay	O
,	O
however	O
,	O
failed	O
to	O
detect	O
LPS	O
-	O
induced	O
Raf	B-GENE
-	I-GENE
1	I-GENE
kinase	I-GENE
activity	O
in	O
RAW	O
264	O
.	O
7	O
cells	O
,	O
suggesting	O
that	O
in	O
RAW	O
264	O
.	O
7	O
cells	O
,	O
Raf	B-GENE
-	I-GENE
1	I-GENE
kinase	I-GENE
is	O
not	O
an	O
activating	O
component	O
of	O
the	O
LPS	O
signaling	O
pathway	O
regulating	O
MAPK	B-GENE
activity	O
or	O
sIL	B-GENE
-	I-GENE
1Ra	I-GENE
promoter	I-GENE
activity	O
.	O

Subjects	O
were	O
73	O
male	O
and	O
female	O
employees	O
of	O
the	O
Xerox	O
Corporation	O
joining	O
a	O
newly	O
developed	O
health	O
fitness	O
program	O
.	O

The	O
LT	B-GENE
-	I-GENE
beta	I-GENE
gene	I-GENE
is	O
expressed	O
in	O
lymphoid	O
cells	O
and	O
organs	O
,	O
but	O
little	O
is	O
known	O
about	O
its	O
inducible	O
regulation	O
.	O

Dose	O
-	O
dependent	O
pharmacokinetics	O
:	O
emphasis	O
on	O
phase	O
I	O
metabolism	O
.	O

There	O
were	O
no	O
differences	O
in	O
the	O
incidence	O
of	O
fractured	O
zonas	O
.	O

Our	O
Northern	O
and	O
Southern	O
blot	O
analyses	O
of	O
meningiomas	O
clearly	O
suggest	O
the	O
CLH	B-GENE
-	I-GENE
22	I-GENE
gene	I-GENE
may	O
be	O
involved	O
in	O
the	O
tumor	O
development	O
and	O
can	O
be	O
considered	O
as	O
a	O
candidate	O
for	O
a	O
tumor	O
suppressor	O
.	O

The	O
difference	O
between	O
the	O
results	O
in	O
the	O
high	O
dose	O
AHLG	B-GENE
and	O
in	O
the	O
control	O
group	O
was	O
significant	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
stress	O
/	O
BHV	O
-	O
1	O
model	O
resulted	O
in	O
a	O
mild	O
respiratory	O
infection	O
in	O
all	O
calves	O
with	O
no	O
difference	O
observed	O
between	O
treatment	O
groups	O
.	O

Cytomegalovirus	O
infection	O
-	O
-	O
modern	O
diagnosis	O

Genomic	O
organization	O
of	O
the	O
human	B-GENE
multidrug	I-GENE
resistance	I-GENE
(	I-GENE
MDR1	I-GENE
)	I-GENE
gene	I-GENE
and	O
origin	O
of	O
P	B-GENE
-	I-GENE
glycoproteins	I-GENE
.	O

The	O
pepI	B-GENE
gene	I-GENE
was	O
overexpressed	O
in	O
Escherichia	O
coli	O
.	O

Deep	O
bite	O
CL	O
II	O
Div	O
.	O

Negative	O
modulation	O
of	O
alpha1	B-GENE
(	I-GENE
I	I-GENE
)	I-GENE
procollagen	I-GENE
gene	I-GENE
expression	O
in	O
human	O
skin	O
fibroblasts	O
:	O
transcriptional	O
inhibition	O
by	O
interferon	B-GENE
-	I-GENE
gamma	I-GENE
.	O

Yet	O
IL	B-GENE
-	I-GENE
2	I-GENE
and	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
production	O
are	O
independently	O
regulated	O
,	O
as	O
demonstrated	O
by	O
their	O
differential	O
expression	O
in	O
certain	O
T	O
cell	O
subsets	O
,	O
suggesting	O
that	O
the	O
regulatory	O
elements	O
in	O
these	O
two	O
genes	O
must	O
differ	O
.	O

In	O
summary	O
,	O
FGFR3	B-GENE
signaling	O
pathway	O
utilizes	O
two	O
GRB2	B-GENE
-	I-GENE
containing	I-GENE
complexes	I-GENE
;	O
Shc	B-GENE
.	O
GRB2	B-GENE
.	O
Sos	B-GENE
and	O
80K	B-GENE
-	I-GENE
H	I-GENE
.	O
pp66	B-GENE
.	O
GRB2	B-GENE
.	O
Sos	B-GENE
;	O
these	O
two	O
complexes	O
may	O
alternatively	O
link	O
FGFG3	B-GENE
to	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
.	O

Resistance	O
to	O
Mup	O
was	O
classified	O
as	O
low	O
(	O
minimal	O
inhibitory	O
concentration	O
[	O
MIC	O
]	O
>	O
or	O
=	O
8	O
microg	O
/	O
mL	O
)	O
or	O
high	O
(	O
MIC	O
>	O
or	O
=	O
512	O
microg	O
/	O
mL	O
)	O
degree	O
.	O

STUDY	O
DESIGN	O
:	O
Retrospective	O
review	O
.	O

One	O
had	O
a	O
48	O
-	O
hour	O
cycle	O
and	O
the	O
other	O
a	O
24	O
-	O
hour	O
cycle	O
.	O

1	O
The	O
effects	O
of	O
high	O
doses	O
of	O
piretanide	O
,	O
a	O
new	O
diuretic	O
agent	O
chemically	O
related	O
to	O
frusemide	O
and	O
bumetanide	O
were	O
evaluated	O
in	O
twelve	O
patients	O
with	O
severe	O
chronic	O
renal	O
insufficiency	O
(	O
creatinine	O
clearance	O
below	O
25	O
ml	O
/	O
min	O
)	O
.	O

S1	B-GENE
nuclease	I-GENE
protection	O
mapping	O
and	O
primer	O
extension	O
analysis	O
allowed	O
us	O
to	O
propose	O
that	O
the	O
A	O
residue	O
located	O
19	O
bp	O
upstream	O
from	O
the	O
translation	O
initiation	O
codon	O
is	O
the	O
site	O
of	O
transcription	O
initiation	O
.	O

Various	O
stimuli	O
inactivate	O
IkappaB	B-GENE
alpha	I-GENE
by	O
triggering	O
phosphorylation	O
of	O
the	O
N	O
-	O
terminal	O
residues	O
Ser32	O
and	O
Ser36	O
.	O

A	O
mouse	O
brain	O
cDNA	O
library	O
in	O
lambdagt11	O
was	O
screened	O
for	O
this	O
association	O
,	O
and	O
two	O
positive	O
clones	O
encoding	O
tyrosine	B-GENE
phosphatase	I-GENE
SH	B-GENE
-	I-GENE
PTP2	I-GENE
were	O
isolated	O
.	O

Intensive	O
therapy	O
of	O
viral	O
hepatitis	O

Adjusting	O
a	O
steady	O
-	O
state	O
warfarin	O
dose	O
depends	O
on	O
the	O
measured	O
INR	O
values	O
and	O
clinical	O
factors	O
:	O
the	O
dose	O
does	O
not	O
need	O
to	O
be	O
adjusted	O
for	O
a	O
single	O
INR	O
that	O
is	O
slightly	O
out	O
of	O
range	O
,	O
and	O
most	O
changes	O
should	O
alter	O
the	O
total	O
weekly	O
dose	O
by	O
5	O
%	O
to	O
20	O
%	O
.	O

Successful	O
resolution	O
of	O
progressive	O
multifocal	O
leukoencephalopathy	O
after	O
combination	O
therapy	O
with	O
cidofovir	O
and	O
cytosine	O
arabinoside	O
.	O

The	O
DFGF	B-GENE
-	I-GENE
R	I-GENE
protein	I-GENE
may	O
thus	O
participate	O
in	O
receiving	O
spatial	O
cues	O
that	O
guide	O
tracheal	O
cell	O
outgrowth	O
.	O

FTF	O
(	O
Joint	O
Council	O
of	O
Civil	O
Servants	O
and	O
Functionaries	O
)	O
:	O
clarification	O
about	O
membership	O
in	O
the	O
main	O
organizations	O

The	O
differences	O
in	O
binding	O
(	O
Kdapp	O
)	O
,	O
incorporation	O
,	O
and	O
extension	O
kinetics	O
of	O
8	O
-	O
oxo	O
-	O
dGTP	O
compared	O
to	O
normal	O
dNTP	O
incorporation	O
at	O
template	O
8	O
-	O
oxo	O
-	O
G	O
adducts	O
indicate	O
that	O
polymerase	O
fidelity	O
does	O
not	O
depend	O
solely	O
upon	O
the	O
overall	O
geometry	O
of	O
Watson	O
-	O
Crick	O
base	O
pairs	O
and	O
reflects	O
the	O
asymmetry	O
of	O
the	O
enzyme	O
active	O
site	O
.	O

Retroviral	O
vector	O
producer	O
cell	O
populations	O
and	O
cell	O
clones	O
were	O
established	O
for	O
each	O
chLTR	B-GENE
vector	O
,	O
and	O
all	O
were	O
capable	O
of	O
yielding	O
high	O
vector	O
titers	O
(	O
>	O
10	O
(	O
5	O
)	O
G418R	B-GENE
cfu	O
/	O
ml	O
on	O
NIH	O
-	O
3T3	O
)	O
.	O

None	O
of	O
these	O
patients	O
developed	O
clinical	O
events	O
before	O
disappearance	O
of	O
the	O
phospholipid	O
-	O
dependent	O
inhibitors	O
of	O
coagulation	O
.	O

A	O
high	O
titer	O
of	O
anti	B-GENE
-	I-GENE
HBc	I-GENE
,	O
thus	O
suggested	O
to	O
be	O
an	O
indicator	O
of	O
persistent	O
hepatitis	O
B	O
virus	O
infection	O
,	O
was	O
found	O
rarely	O
in	O
seronegative	O
patients	O
with	O
chronic	O
hepatitis	O
,	O
non	O
-	O
alcoholic	O
cirrhosis	O
,	O
or	O
alcoholic	O
liver	O
diseases	O
.	O

Using	O
beta	B-GENE
1	I-GENE
-	I-GENE
AR	I-GENE
-	O
luciferase	B-GENE
reporter	O
recombinants	O
,	O
we	O
have	O
previously	O
determined	O
that	O
important	O
beta	B-GENE
1	I-GENE
-	I-GENE
AR	I-GENE
genetic	O
elements	O
controlling	O
expression	O
within	O
the	O
C6	O
glioma	O
cell	O
line	O
are	O
contained	O
within	O
the	O
region	O
-	O
396	O
to	O
-	O
299	O
,	O
relative	O
to	O
the	O
translational	O
start	O
site	O
.	O

It	O
is	O
not	O
well	O
known	O
that	O
giant	O
cell	O
arteritis	O
can	O
cause	O
fatal	O
complications	O
due	O
to	O
rupture	O
of	O
aortic	O
aneurysms	O
or	O
cerebral	O
and	O
myocardial	O
infarctions	O
.	O

Temporal	O
recruitment	O
of	O
the	O
mSin3A	B-GENE
-	O
histone	B-GENE
deacetylase	I-GENE
corepressor	O
complex	O
to	O
the	O
ETS	B-GENE
domain	I-GENE
transcription	I-GENE
factor	I-GENE
Elk	B-GENE
-	I-GENE
1	I-GENE
.	O

By	O
screening	O
a	O
human	O
testis	O
cDNA	O
library	O
with	O
a	O
probe	O
containing	O
the	O
mouse	B-GENE
PEA3	I-GENE
ETS	B-GENE
domain	O
,	O
we	O
isolated	O
a	O
2	O
.	O
2	O
kb	O
clone	O
containing	O
a	O
510	O
AA	O
open	O
reading	O
frame	O
.	O

It	O
is	O
also	O
affected	O
by	O
the	O
HAP2	B-GENE
/	I-GENE
3	I-GENE
/	I-GENE
4	I-GENE
transcription	I-GENE
factor	I-GENE
complex	I-GENE
and	O
by	O
SNF1	B-GENE
and	O
SSN6	B-GENE
.	O

The	O
gene	O
is	O
predicted	O
to	O
encode	O
an	O
880	O
-	O
amino	O
-	O
acid	O
protein	O
which	O
contains	O
two	O
C2H2	O
zinc	O
fingers	O
,	O
a	O
nuclear	O
localization	O
sequence	O
and	O
two	O
transcriptional	O
activation	O
domains	O
.	O

These	O
results	O
indicate	O
that	O
H	B-GENE
-	I-GENE
2RIIBP	I-GENE
(	O
i	O
)	O
is	O
a	O
member	O
of	O
the	O
superfamily	O
of	O
nuclear	B-GENE
hormone	I-GENE
receptors	I-GENE
and	O
(	O
ii	O
)	O
may	O
regulate	O
not	O
only	O
MHC	B-GENE
class	I-GENE
I	I-GENE
genes	I-GENE
but	O
also	O
genes	O
containing	O
the	O
ERE	O
and	O
related	O
sequences	O
.	O

Relaxant	O
effect	O
of	O
prostaglandin	O
E1	O
(	O
PGE1	O
)	O
and	O
papaverine	O
(	O
PAP	O
)	O
were	O
measured	O
in	O
strips	O
of	O
corpus	O
cavernosum	O
smooth	O
muscle	O
taken	O
from	O
a	O
healthy	O
control	O
group	O
of	O
men	O
(	O
A	O
;	O
n	O
=	O
5	O
)	O
,	O
from	O
arteriogenically	O
impotent	O
men	O
(	O
B	O
;	O
n	O
=	O
6	O
)	O
and	O
from	O
additionally	O
diabetic	O
impotent	O
men	O
(	O
C	O
;	O
n	O
=	O
5	O
)	O
with	O
venous	O
leakage	O
.	O

The	O
sensitivity	O
of	O
central	B-GENE
dopamine	I-GENE
receptors	I-GENE
was	O
assessed	O
with	O
the	O
growth	B-GENE
hormone	I-GENE
response	O
to	O
apomorphine	O
application	O
.	O

Pathogenesis	O
of	O
fever	O
.	O

The	O
occurrence	O
of	O
the	O
different	O
types	O
of	O
TCRB	B-GENE
rearrangement	O
patterns	O
has	O
implications	O
for	O
PCR	O
-	O
based	O
clonality	O
assessment	O
and	O
for	O
PCR	O
-	O
based	O
detection	O
of	O
minimal	O
residual	O
disease	O
via	O
TCRB	B-GENE
gene	I-GENE
analysis	O
.	O

In	O
many	O
other	O
contractile	O
protein	O
gene	O
families	O
,	O
genes	O
encoding	O
cardiac	O
isoforms	O
are	O
expressed	O
early	O
in	O
skeletal	O
muscle	O
development	O
and	O
are	O
later	O
repressed	O
.	O

The	O
NH2	O
-	O
terminal	O
fragments	O
were	O
tested	O
for	O
susceptibility	O
to	O
modification	O
with	O
Nalpha	O
-	O
(	O
3	O
-	O
maleimidylpropionyl	O
)	O
biocytin	O
,	O
which	O
attaches	O
a	O
biotin	O
group	O
to	O
cysteine	O
sulfhydryls	O
.	O

Directional	O
growth	O
of	O
a	O
smectic	O
-	O
A	O
-	O
smectic	O
-	O
B	O
interface	O
lying	O
along	O
a	O
forbidden	O
orientation	O
.	O

METHODS	O
:	O
We	O
performed	O
nasal	O
mupirocin	O
treatment	O
on	O
10	O
infants	O
who	O
were	O
MRSA	O
-	O
positive	O
either	O
in	O
the	O
nose	O
or	O
the	O
pharynx	O
and	O
evaluated	O
the	O
effect	O
of	O
mupirocin	O
on	O
the	O
eradication	O
of	O
MRSA	O
.	O

TOM1	B-GENE
encodes	O
a	O
member	O
of	O
the	O
hect	B-GENE
-	O
domain	O
-	O
containing	O
E3	B-GENE
ubiquitin	B-GENE
-	I-GENE
protein	I-GENE
ligase	I-GENE
family	O
that	O
is	O
required	O
for	O
growth	O
at	O
elevated	O
temperatures	O
.	O

Purified	O
preparations	O
of	O
all	O
four	O
AGT	O
mutants	O
showed	O
an	O
approximately	O
similar	O
degree	O
(	O
74	O
-	O
120	O
-	O
fold	O
)	O
of	O
reduction	O
in	O
the	O
rate	O
of	O
reaction	O
with	O
O6	O
-	O
benzylguanine	O
.	O

These	O
results	O
demonstrate	O
that	O
m2	B-GENE
receptors	I-GENE
couple	O
to	O
both	O
G	B-GENE
alpha	I-GENE
i2	I-GENE
and	O
G	B-GENE
alpha	I-GENE
i3	I-GENE
in	O
vivo	O
and	O
that	O
this	O
interaction	O
is	O
integral	O
to	O
both	O
positive	O
and	O
negative	O
regulatory	O
pathways	O
leading	O
to	O
activation	O
of	O
PLC	B-GENE
and	O
desensitization	O
of	O
receptor	O
signaling	O
.	O

This	O
is	O
the	O
first	O
clinical	O
case	O
report	O
of	O
NIHF	O
due	O
to	O
fetal	O
Kasabach	O
-	O
Merritt	O
syndrome	O
that	O
was	O
prenatally	O
diagnosed	O
by	O
sonography	O
,	O
computerized	O
tomography	O
,	O
and	O
percutaneous	O
umbilical	O
blood	O
sampling	O
.	O

The	O
cholesterol	B-GENE
7alpha	I-GENE
-	I-GENE
hydroxylase	I-GENE
gene	I-GENE
(	O
CYP7A	B-GENE
)	O
is	O
transcriptionally	O
regulated	O
by	O
a	O
number	O
of	O
factors	O
,	O
including	O
hormones	O
,	O
bile	O
acids	O
,	O
and	O
diurnal	O
rhythm	O
.	O

Restriction	O
mapping	O
showed	O
that	O
the	O
two	O
recombinant	O
plasmids	O
shared	O
an	O
EcoRI	B-GENE
fragment	I-GENE
of	O
8	O
.	O
9	O
kb	O
.	O

Two	O
mutants	O
,	O
mapping	O
at	O
the	O
HindIII	B-GENE
site	I-GENE
(	O
between	O
the	O
consensus	O
sequences	O
)	O
of	O
the	O
pSC101	B-GENE
tetA	I-GENE
promoter	I-GENE
,	O
were	O
studied	O
:	O
MA2	O
corresponds	O
to	O
a	O
4	O
bp	O
deletion	O
between	O
positions	O
-	O
12	O
and	O
-	O
15	O
;	O
B30	O
bears	O
a	O
44	O
bp	O
insertion	O
C	O
(	O
TA	O
)	O
21	O
G	O
at	O
the	O
HindIII	B-GENE
site	I-GENE
.	O

Meq	B-GENE
/	O
c	B-GENE
-	I-GENE
Jun	I-GENE
heterodimers	O
bind	O
to	O
an	O
AP1	B-GENE
-	I-GENE
like	I-GENE
sequence	I-GENE
in	O
the	O
meq	B-GENE
promoter	I-GENE
region	I-GENE
with	O
an	O
affinity	O
much	O
greater	O
than	O
that	O
of	O
Meq	B-GENE
/	O
Meq	B-GENE
or	O
c	B-GENE
-	I-GENE
Jun	I-GENE
/	O
c	B-GENE
-	I-GENE
Jun	I-GENE
homodimers	O
.	O

Infra	O
-	O
red	O
spectroscopy	O
of	O
tissues	O
in	O
the	O
700	O
-	O
400	O
cm	O
-	O
1	O
region	O
.	O

Although	O
no	O
detectable	O
phenotypes	O
are	O
associated	O
with	O
a	O
disruption	O
allele	O
of	O
ABP1	B-GENE
,	O
mutations	O
that	O
create	O
a	O
requirement	O
for	O
this	O
protein	O
have	O
now	O
been	O
isolated	O
in	O
the	O
previously	O
identified	O
gene	B-GENE
SAC6	I-GENE
and	O
in	O
two	O
new	O
genes	O
,	O
SLA1	B-GENE
and	O
SLA2	B-GENE
.	O

Comparison	O
of	O
bioreactive	O
and	O
immunoreactive	O
gastrin	B-GENE
.	O

The	O
claustrocortical	O
connection	O
was	O
investigated	O
in	O
13	O
cats	O
with	O
selective	O
injections	O
of	O
30	O
%	O
HRP	O
in	O
the	O
three	O
subdivisions	O
of	O
the	O
auditory	O
cortex	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

The	O
authors	O
report	O
a	O
case	O
of	O
a	O
painful	O
wrist	O
related	O
to	O
a	O
"	O
Manieux	O
muscle	O
"	O
of	O
the	O
dorsal	O
aspect	O
of	O
the	O
hand	O
.	O

A	O
significant	O
reduction	O
in	O
total	O
cellular	O
p27	B-GENE
protein	I-GENE
levels	O
and	O
a	O
moderate	O
reduction	O
in	O
p27	B-GENE
mRNA	I-GENE
are	O
observed	O
,	O
but	O
no	O
changes	O
in	O
Cdk	B-GENE
regulatory	O
kinases	O
and	O
phosphatases	O
occur	O
.	O

This	O
result	O
,	O
together	O
with	O
the	O
fact	O
that	O
unrearranged	B-GENE
V	I-GENE
kappa	I-GENE
genes	I-GENE
are	O
transcriptionally	O
silent	O
,	O
suggests	O
that	O
structural	O
features	O
of	O
both	O
the	O
V	B-GENE
kappa	I-GENE
and	O
C	B-GENE
kappa	I-GENE
loci	I-GENE
contribute	O
to	O
the	O
overall	O
transcriptional	O
efficiency	O
of	O
a	O
rearranged	B-GENE
V	I-GENE
kappa	I-GENE
-	I-GENE
C	I-GENE
kappa	I-GENE
gene	I-GENE
.	O

Level	O
II	O
mosaicism	O
occurred	O
in	O
0	O
.	O
9	O
per	O
cent	O
of	O
CVS	O
mesenchyme	O
and	O
1	O
.	O
5	O
per	O
cent	O
of	O
amniotic	O
fluid	O
cultures	O
and	O
in	O
general	O
was	O
not	O
perceived	O
to	O
be	O
of	O
sufficient	O
concern	O
to	O
warrant	O
cytogenetic	O
follow	O
-	O
up	O
studies	O
.	O

Measures	O
of	O
sedation	O
,	O
BIS	O
,	O
deltaBIS	O
(	O
absolute	O
change	O
of	O
BIS	O
after	O
a	O
painful	O
stimulus	O
)	O
,	O
memory	O
,	O
and	O
drug	O
concentration	O
were	O
obtained	O
at	O
each	O
target	O
drug	O
concentration	O
.	O

There	O
are	O
three	O
types	O
of	O
problems	O
:	O
problems	O
arising	O
before	O
the	O
drug	O
enters	O
the	O
body	O
(	O
solubilization	O
,	O
stabilization	O
and	O
improved	O
acceptability	O
)	O
;	O
problems	O
associated	O
with	O
the	O
penetration	O
and	O
fate	O
of	O
the	O
drug	O
in	O
the	O
body	O
(	O
absorption	O
,	O
barrier	O
crossing	O
,	O
duration	O
of	O
action	O
)	O
;	O
problems	O
relating	O
to	O
the	O
therapeutic	O
target	O
(	O
selective	O
local	O
delivery	O
)	O
.	O

The	O
structure	O
elucidation	O
of	O
the	O
iridoid	O
compounds	O
2	O
and	O
3	O
are	O
discussed	O
in	O
detail	O
.	O

Characterization	O
of	O
trinucleotide	O
-	O
and	O
tandem	O
repeat	O
-	O
containing	O
transcripts	O
obtained	O
from	O
human	O
spinal	O
cord	O
cDNA	O
library	O
by	O
high	O
-	O
density	O
filter	O
hybridization	O
.	O

CONCLUSION	O
:	O
Urbanisation	O
is	O
associated	O
with	O
an	O
increase	O
in	O
the	O
prevalence	O
rates	O
of	O
some	O
risk	O
behaviours	O
.	O

The	O
authors	O
emphasize	O
absence	O
of	O
specific	O
signs	O
of	O
vagal	O
involvement	O
,	O
importance	O
for	O
diagnosis	O
of	O
surgical	O
extirpation	O
,	O
and	O
mildness	O
of	O
post	O
operative	O
course	O
.	O

Growth	O
factors	O
promote	O
cell	O
survival	O
through	O
phosphorylation	O
of	O
Bad	B-GENE
,	O
resulting	O
in	O
its	O
dissociation	O
from	O
Bcl	B-GENE
-	I-GENE
2	I-GENE
and	O
Bcl	B-GENE
-	I-GENE
x	I-GENE
(	I-GENE
L	I-GENE
)	I-GENE
and	O
its	O
association	O
with	O
14	B-GENE
-	I-GENE
3	I-GENE
-	I-GENE
3tau	I-GENE
.	O

Both	O
in	O
the	O
Federal	O
Republic	O
of	O
Germany	O
and	O
in	O
some	O
neighbouring	O
countries	O
the	O
epizootic	O
situation	O
of	O
Aujeszky	O
'	O
s	O
disease	O
has	O
been	O
unsatisfactory	O
for	O
a	O
long	O
time	O
,	O
especially	O
in	O
areas	O
with	O
a	O
high	O
pig	O
density	O
.	O

The	O
sensitivity	O
of	O
99mTc	O
-	O
IgG	B-GENE
scintigraphy	O
ranged	O
between	O
71	O
%	O
and	O
100	O
%	O
.	O

Acad	O
.	O

Aggravation	O
of	O
peripheral	O
-	O
blood	O
cytopenia	O
during	O
the	O
first	O
weeks	O
and	O
hypocellularity	O
of	O
bone	O
-	O
marrow	O
aspirates	O
at	O
the	O
end	O
of	O
therapy	O
suggest	O
that	O
low	O
-	O
dose	O
Ara	O
C	O
exerts	O
its	O
main	O
activity	O
by	O
suppression	O
of	O
leukaemic	O
growth	O
,	O
rather	O
than	O
by	O
induction	O
of	O
differentiation	O
in	O
malignant	O
cells	O
.	O

Those	O
participating	O
in	O
this	O
investigation	O
(	O
65	O
centers	O
=	O
79	O
%	O
)	O
received	O
a	O
series	O
of	O
computer	O
disks	O
containing	O
50	O
99mTc	O
-	O
DMSA	O
studies	O
.	O

Probiotics	O
,	O
prebiotics	O
,	O
vaccination	O
,	O
and	O
acidification	O
of	O
drinking	O
water	O
were	O
assessed	O
as	O
means	O
of	O
reducing	O
Salmonella	O
.	O

Mutation	O
of	O
this	O
threonine	O
to	O
isoleucine	O
had	O
no	O
observable	O
effect	O
on	O
either	O
nuclear	O
localization	O
of	O
E1	B-GENE
or	O
DNA	O
replication	O
of	O
the	O
intact	O
viral	O
genome	O
.	O

The	O
inhibition	O
of	O
monoamine	B-GENE
oxidase	I-GENE
(	O
MAO	B-GENE
)	O
by	O
tranylcypromine	O
was	O
studied	O
in	O
6	O
healthy	O
volunteers	O
given	O
increasing	O
doses	O
of	O
10	O
,	O
15	O
,	O
20	O
and	O
25	O
mg	O
/	O
day	O
over	O
a	O
4	O
-	O
week	O
period	O
.	O

Myocardial	O
technetium	O
-	O
99m	O
-	O
teboroxime	O
uptake	O
during	O
adenosine	O
-	O
induced	O
hyperemia	O
in	O
dogs	O
with	O
either	O
a	O
critical	O
or	O
mild	O
coronary	O
stenosis	O
:	O
comparison	O
to	O
thallium	O
-	O
201	O
and	O
regional	O
blood	O
flow	O
.	O

Both	O
atracurium	O
1	O
-	O
100	O
mumol	O
litre	O
-	O
1	O
and	O
laudanosine	O
1	O
-	O
50	O
mumol	O
litre	O
-	O
1	O
enhanced	O
the	O
release	O
of	O
3H	O
-	O
NA	O
evoked	O
by	O
field	O
stimulation	O
(	O
2	O
Hz	O
,	O
24	O
stimuli	O
)	O
,	O
but	O
did	O
not	O
affect	O
resting	O
release	O
.	O

The	O
recovery	O
of	O
xanthomegnin	O
added	O
to	O
corn	O
samples	O
at	O
levels	O
of	O
0	O
.	O
75	O
-	O
-	O
9	O
.	O
6	O
mg	O
/	O
kg	O
averaged	O
41	O
%	O
with	O
a	O
coefficient	O
of	O
variation	O
of	O
25	O
%	O
.	O

Because	O
of	O
the	O
data	O
,	O
we	O
suggest	O
that	O
LAC9	B-GENE
contacts	O
positions	O
6	O
,	O
7	O
,	O
and	O
8	O
,	O
both	O
plus	O
and	O
minus	O
,	O
of	O
the	O
UAS	O
,	O
which	O
are	O
separated	O
by	O
more	O
than	O
one	O
turn	O
of	O
the	O
DNA	O
helix	O
,	O
and	O
twists	O
part	O
way	O
around	O
the	O
DNA	O
,	O
thus	O
protecting	O
the	O
broad	O
region	O
of	O
the	O
minor	O
groove	O
between	O
the	O
major	O
-	O
groove	O
contacts	O
.	O

Istanbul	O
,	O
Turkey	O
.	O

After	O
Northern	O
blot	O
hybridization	O
,	O
two	O
Cx31	B-GENE
transcripts	I-GENE
of	I-GENE
2	I-GENE
.	I-GENE
2	I-GENE
and	I-GENE
1	I-GENE
.	I-GENE
8	I-GENE
kb	I-GENE
were	O
detected	O
in	O
total	O
RNA	O
of	O
the	O
human	O
keratinocyte	O
cell	O
line	O
HaCaT	O
and	O
two	O
transcripts	O
of	O
2	O
.	O
2	O
and	O
1	O
.	O
9	O
kb	O
in	O
total	O
RNA	O
of	O
E6	B-GENE
/	O
E7	B-GENE
transfected	O
human	O
keratinocytes	O
(	O
HEK	O
cells	O
)	O
.	O

While	O
differential	O
expression	O
of	O
the	O
two	O
transcripts	O
was	O
not	O
found	O
,	O
the	O
promoter	O
controlling	O
LT1	B-GENE
/	O
LT2	B-GENE
transcription	O
is	O
regulated	O
in	O
a	O
cell	O
cycle	O
-	O
dependent	O
manner	O
.	O

SYC1	B-GENE
(	O
suppressor	B-GENE
of	I-GENE
yeast	I-GENE
cbf5	I-GENE
-	I-GENE
1	I-GENE
)	O
was	O
identified	O
as	O
a	O
multicopy	O
suppressor	O
of	O
cbf5	B-GENE
-	I-GENE
1	I-GENE
and	O
subsequently	O
was	O
found	O
to	O
be	O
identical	O
to	O
RRN3	B-GENE
,	O
an	O
RNA	B-GENE
polymerase	I-GENE
I	I-GENE
transcription	I-GENE
factor	I-GENE
.	O

Developmental	O
regulation	O
of	O
expression	O
of	O
the	O
malate	B-GENE
synthase	I-GENE
gene	I-GENE
in	O
transgenic	O
plants	O
.	O

All	O
three	O
SSV	O
-	O
transformed	O
cells	O
secreted	O
v	B-GENE
-	I-GENE
sis	I-GENE
gene	I-GENE
product	I-GENE
(	O
p44	B-GENE
)	O
.	O
p44	B-GENE
was	O
secreted	O
but	O
remained	O
tightly	O
associated	O
with	O
the	O
cell	O
surface	O
.	O

We	O
also	O
identified	O
a	O
DNA	O
fragment	O
,	O
10	O
.	O
7	O
kbp	O
upstream	O
from	O
the	O
first	O
coding	O
exon	O
of	O
human	B-GENE
aFGF	I-GENE
,	O
whose	O
sequence	O
is	O
conserved	O
in	O
both	O
the	O
primate	O
and	O
rodent	O
genomes	O
.	O

In	O
this	O
respect	O
,	O
the	O
promoter	O
structure	O
of	O
COX	B-GENE
genes	I-GENE
resemble	O
those	O
of	O
many	O
house	O
-	O
keeping	O
genes	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
of	O
the	O
FlaB2	B-GENE
polypeptide	I-GENE
was	O
92	O
%	O
identical	O
to	O
that	O
of	O
T	B-GENE
.	I-GENE
pallidum	I-GENE
FlaB2	I-GENE
,	O
with	O
a	O
76	O
%	O
identity	O
at	O
the	O
nucleotide	O
level	O
.	O

These	O
data	O
demonstrate	O
that	O
CCTalpha	B-GENE
can	O
be	O
regulated	O
by	O
lipids	O
by	O
two	O
independent	O
domains	O
:	O
(	O
i	O
)	O
the	O
three	O
amphipathic	O
alpha	O
-	O
helical	O
repeats	O
that	O
interact	O
with	O
both	O
neutral	O
and	O
anionic	O
lipid	O
mixtures	O
and	O
(	O
ii	O
)	O
the	O
last	O
57	O
residues	O
that	O
interact	O
with	O
anionic	O
lipids	O
.	O

Ion	O
-	O
Bernstein	O
-	O
wave	O
heating	O
and	O
improved	O
confinement	O
in	O
the	O
Alcator	O
C	O
tokamak	O
.	O

Of	O
3841	O
serum	O
samples	O
from	O
sows	O
received	O
from	O
the	O
Tennessee	O
State	O
Diagnostic	O
Laboratory	O
in	O
1991	O
-	O
1992	O
,	O
1130	O
were	O
positive	O
for	O
Toxoplasma	B-GENE
gondii	I-GENE
antibody	I-GENE
.	O

Morphometry	O
of	O
the	O
intestine	O
of	O
the	O
pig	O
.	O

The	O
subjects	O
were	O
started	O
on	O
indomethacin	O
25	O
mg	O
thrice	O
daily	O
.	O

Human	B-GENE
parvovirus	I-GENE
B19	I-GENE
gene	I-GENE
expression	O
from	O
the	O
viral	B-GENE
p6	I-GENE
promoter	I-GENE
(	O
B19p6	B-GENE
)	O
is	O
restricted	O
to	O
primary	O
human	O
hematopoietic	O
cells	O
undergoing	O
erythroid	O
differentiation	O
.	O

To	O
further	O
study	O
the	O
role	O
of	O
tTG	B-GENE
in	O
liver	O
disease	O
,	O
we	O
initiated	O
investigations	O
into	O
the	O
effect	O
of	O
a	O
proinflammatory	O
mediator	O
,	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
(	I-GENE
TNF	I-GENE
)	I-GENE
-	I-GENE
alpha	I-GENE
,	O
on	O
tTG	B-GENE
activity	O
in	O
cultured	O
liver	O
cells	O
.	O

The	O
atopic	O
disposition	O
,	O
indicated	O
by	O
positive	O
skin	O
reactions	O
and	O
IgE	B-GENE
antibody	O
titers	O
etc	O
.	O
,	O
and	O
the	O
bronchial	O
reactivity	O
to	O
inhaled	O
acetylcholine	O
were	O
examined	O
on	O
the	O
following	O
three	O
groups	O
:	O
(	O
1	O
)	O
20	O
young	O
adults	O
with	O
a	O
history	O
of	O
childhood	O
asthma	O
who	O
have	O
been	O
symptom	O
-	O
free	O
for	O
more	O
than	O
4	O
yr	O
;	O
(	O
2	O
)	O
20	O
current	O
asthmatics	O
,	O
and	O
(	O
3	O
)	O
20	O
healthy	O
young	O
adults	O
.	O

Continuous	O
arterial	O
blood	O
sampling	O
method	O
based	O
on	O
the	O
microsphere	O
model	O
was	O
used	O
as	O
a	O
quantitative	O
rCBF	O
measurement	O
.	O

Members	O
of	O
the	O
steroid	B-GENE
/	I-GENE
hormone	I-GENE
nuclear	I-GENE
receptor	I-GENE
superfamily	I-GENE
regulate	O
target	O
gene	O
transcription	O
via	O
recognition	O
and	O
association	O
with	O
specific	O
cis	O
-	O
acting	O
sequences	O
of	O
DNA	O
,	O
called	O
hormone	O
response	O
elements	O
(	O
HREs	O
)	O
.	O

Thomas	O
,	O
S	O
.	O
S	O
.	O

In	O
addition	O
to	O
these	O
cases	O
,	O
patients	O
w	O
with	O
high	O
Loa	O
microfilaremia	O
also	O
developed	O
milder	O
neurologic	O
manifestations	O
causing	O
functional	O
impairment	O
lasting	O
for	O
at	O
least	O
one	O
week	O
after	O
treatment	O
.	O

The	O
patient	O
demographics	O
(	O
means	O
+	O
/	O
-	O
standard	O
deviations	O
)	O
were	O
as	O
follows	O
:	O
age	O
,	O
57	O
+	O
/	O
-	O
12	O
years	O
;	O
sex	O
,	O
nine	O
males	O
and	O
three	O
females	O
;	O
APACHE	O
II	O
score	O
,	O
15	O
+	O
/	O
-	O
3	O
;	O
diagnosis	O
,	O
9	O
of	O
12	O
patients	O
with	O
pneumonia	O
.	O

Patients	O
with	O
binocular	O
pregeniculate	O
visual	O
loss	O
,	O
patients	O
with	O
balanced	O
binocular	O
pregeniculate	O
loss	O
without	O
RAPD	O
,	O
and	O
patients	O
with	O
monocular	O
pregeniculate	O
visual	O
loss	O
had	O
significantly	O
larger	O
pupils	O
than	O
age	O
-	O
matched	O
controls	O
.	O

In	O
contrast	O
,	O
corticotropin	B-GENE
releasing	I-GENE
factor	I-GENE
(	O
CRF	B-GENE
)	O
,	O
injected	O
centrally	O
produces	O
a	O
suppression	O
of	O
punished	O
and	O
non	O
-	O
punished	O
responding	O
in	O
the	O
conflict	O
test	O
consistent	O
with	O
its	O
hypothesized	O
role	O
in	O
mediating	O
behavioral	O
responses	O
to	O
stress	O
.	O

Analysis	O
of	O
replicative	O
intermediates	O
shows	O
that	O
plasmid	O
YRp7	O
,	O
which	O
contains	O
the	O
chromosomal	O
replicator	O
ARS1	O
,	O
initiates	O
bidirectional	O
replication	O
in	O
a	O
100	O
bp	O
region	O
within	O
the	O
sequence	O
required	O
for	O
autonomous	O
replication	O
in	O
vivo	O
.	O

Tag	B-GENE
expression	O
induced	O
apoptosis	O
in	O
mammary	O
epithelial	O
cells	O
during	O
late	O
pregnancy	O
.	O

Concentrations	O
of	O
Co	O
,	O
Cu	O
,	O
Fe	O
,	O
Hg	O
,	O
Mn	O
,	O
Sb	O
,	O
Se	O
and	O
Zn	O
in	O
IAEA	O
milk	O
(	O
dry	O
)	O
standard	O
A	O
-	O
11	O
were	O
re	O
-	O
evaluated	O
with	O
the	O
help	O
of	O
instrumental	O
and	O
radiochemical	O
neutron	O
activation	O
analysis	O
(	O
NAA	O
)	O
.	O

Here	O
we	O
show	O
that	O
these	O
sequences	O
are	O
essential	O
for	O
processing	O
of	O
U18	B-GENE
and	O
snR38	B-GENE
snoRNAs	I-GENE
and	O
that	O
they	O
compensate	O
for	O
the	O
lack	O
of	O
a	O
canonical	O
terminal	O
stem	O
.	O

In	O
serum	O
-	O
starved	O
NIH	O
3T3	O
cells	O
,	O
v	B-GENE
-	I-GENE
raf	I-GENE
increased	O
mdr1	B-GENE
promoter	I-GENE
activity	O
approximately	O
10	O
-	O
fold	O
compared	O
to	O
a	O
v	B-GENE
-	I-GENE
raf	I-GENE
frame	O
-	O
shift	O
control	O
.	O

An	O
insertion	O
sequence	O
element	O
(	O
IS1170	O
)	O
was	O
identified	O
upstream	O
of	O
the	O
nimC	B-GENE
gene	I-GENE
.	O

Two	O
genes	O
(	O
ptsI	B-GENE
and	O
ptsA	B-GENE
)	O
that	O
encode	O
homologues	O
of	O
the	O
energy	O
coupling	O
Enzyme	B-GENE
I	I-GENE
of	O
the	O
phosphoenolpyruvate	B-GENE
-	I-GENE
dependent	I-GENE
sugar	I-GENE
-	I-GENE
transporting	I-GENE
phosphotransferase	I-GENE
system	O
(	O
PTS	O
)	O
have	O
previously	O
been	O
identified	O
on	O
the	O
Escherichia	O
coli	O
chromosome	O
.	O

We	O
show	O
that	O
the	O
upstream	O
region	O
of	O
the	O
beta	B-GENE
-	I-GENE
MyHC	I-GENE
gene	I-GENE
(	O
-	O
5518	O
to	O
-	O
2490	O
relative	O
to	O
the	O
transcriptional	O
start	O
site	O
)	O
directed	O
high	O
levels	O
of	O
transcriptional	O
activity	O
only	O
when	O
stably	O
integrated	O
,	O
but	O
not	O
when	O
expressed	O
extrachromosomally	O
in	O
transient	O
assays	O
.	O

Although	O
the	O
cDNAs	O
of	O
HMG	B-GENE
-	I-GENE
14	I-GENE
and	O
HMG	B-GENE
-	I-GENE
17	I-GENE
do	O
not	O
cross	O
-	O
hybridize	O
,	O
they	O
have	O
several	O
similar	O
structural	O
features	O
:	O
the	O
open	O
reading	O
frame	O
comprises	O
only	O
23	O
%	O
of	O
the	O
transcripts	O
,	O
the	O
5	O
'	O
-	O
untranslated	O
region	O
is	O
extremely	O
GC	O
rich	O
whereas	O
the	O
3	O
'	O
-	O
untranslated	O
region	O
is	O
unusually	O
long	O
and	O
AT	O
rich	O
.	O

A	O
minimal	O
pheromone	O
induction	O
domain	O
,	O
delineated	O
as	O
residues	O
301	O
to	O
335	O
of	O
Ste12p	B-GENE
,	O
is	O
dependent	O
on	O
the	O
pheromone	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinase	I-GENE
pathway	O
for	O
induction	O
activity	O
.	O

The	O
IFNAR	B-GENE
chain	I-GENE
interacts	O
with	O
both	O
IFN	B-GENE
-	I-GENE
alpha	I-GENE
2	I-GENE
and	O
IFN	B-GENE
-	I-GENE
beta	I-GENE
,	O
as	O
demonstrated	O
by	O
cross	O
-	O
linking	O
.	O

To	O
assess	O
the	O
effect	O
on	O
thrombus	O
growth	O
,	O
we	O
determined	O
the	O
accretion	O
of	O
125I	O
-	O
labeled	O
fibrinogen	B-GENE
onto	O
autologous	O
non	O
-	O
radioactive	O
thrombi	O
preformed	O
in	O
the	O
jugular	O
veins	O
of	O
rabbits	O
.	O

In	O
the	O
other	O
two	O
cases	O
,	O
fluoxetine	O
adjunct	O
produced	O
benefits	O
with	O
no	O
additional	O
side	O
effects	O
.	O

This	O
radiolabeled	O
,	O
900	O
-	O
bp	O
amplicon	O
was	O
used	O
as	O
a	O
hybridization	O
probe	O
to	O
screen	O
a	O
cDNA	O
library	O
constructed	O
from	O
poly	O
(	O
A	O
)	O
(	O
+	O
)	O
RNA	O
isolated	O
from	O
induced	O
Taxus	O
cells	O
,	O
from	O
which	O
a	O
full	O
-	O
length	O
transacetylase	O
sequence	O
was	O
obtained	O
.	O

Similarly	O
,	O
TAM	B-GENE
-	I-GENE
67	I-GENE
reverted	O
the	O
morphology	O
of	O
the	O
AdoMetDC	B-GENE
-	I-GENE
antisense	I-GENE
expressors	I-GENE
.	O

For	O
the	O
second	O
phase	O
,	O
it	O
was	O
12	O
.	O
5	O
wk	O
for	O
RIR	O
and	O
10	O
for	O
WL	O
males	O
,	O
whereas	O
it	O
was	O
5	O
wk	O
for	O
RIR	O
and	O
6	O
for	O
WL	O
females	O
.	O

TFEC	B-GENE
RNA	I-GENE
is	O
found	O
in	O
many	O
tissues	O
of	O
adult	O
rats	O
,	O
but	O
the	O
relative	O
concentrations	O
of	O
TFEC	B-GENE
and	O
TFE3	B-GENE
RNAs	I-GENE
vary	O
considerably	O
in	O
these	O
different	O
tissues	O
.	O

RESULTS	O
:	O
Three	O
patients	O
did	O
not	O
tolerate	O
PPI	O
medication	O
and	O
were	O
managed	O
by	O
treatment	O
with	O
type	O
2	O
histamine	O
(	O
H2	O
)	O
blockers	O
.	O

VLA	B-GENE
-	I-GENE
4	I-GENE
integrin	I-GENE
cross	O
-	O
linking	O
on	O
human	O
monocytic	O
THP	O
-	O
1	O
cells	O
induces	O
tissue	O
factor	O
expression	O
by	O
a	O
mechanism	O
involving	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
.	O

Diethyldithiocarbamate	O
and	O
amphetamine	O
stereotype	O
behavior	O
.	O

This	O
result	O
,	O
together	O
with	O
the	O
fact	O
that	O
unrearranged	B-GENE
V	I-GENE
kappa	I-GENE
genes	I-GENE
are	O
transcriptionally	O
silent	O
,	O
suggests	O
that	O
structural	O
features	O
of	O
both	O
the	O
V	B-GENE
kappa	I-GENE
and	O
C	B-GENE
kappa	I-GENE
loci	I-GENE
contribute	O
to	O
the	O
overall	O
transcriptional	O
efficiency	O
of	O
a	O
rearranged	O
V	B-GENE
kappa	I-GENE
-	O
C	B-GENE
kappa	I-GENE
gene	O
.	O

Oct	B-GENE
-	I-GENE
1	I-GENE
is	O
a	O
ubiquitously	O
expressed	O
regulatory	O
gene	O
of	O
the	O
POU	B-GENE
domain	I-GENE
family	I-GENE
.	O

Both	O
RNA14	B-GENE
and	O
RNA15	B-GENE
wild	I-GENE
-	I-GENE
type	I-GENE
genes	I-GENE
,	O
when	O
cloned	O
on	O
a	O
multicopy	O
plasmid	O
,	O
are	O
able	O
to	O
suppress	O
the	O
temperature	O
-	O
sensitive	O
phenotype	O
of	O
strains	O
bearing	O
either	O
the	O
rna14	B-GENE
or	O
the	O
rna15	B-GENE
mutation	I-GENE
,	O
suggesting	O
that	O
the	O
encoded	O
proteins	O
could	O
interact	O
with	O
each	O
other	O
.	O

Recent	O
studies	O
have	O
concentrated	O
on	O
the	O
methods	O
of	O
preparation	O
of	O
coffee	O
,	O
which	O
vary	O
from	O
country	O
to	O
country	O
.	O

In	O
addition	O
,	O
while	O
GCN1	B-GENE
is	O
required	O
in	O
vivo	O
for	O
phosphorylation	O
of	O
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
by	O
GCN2	B-GENE
,	O
cell	O
extracts	O
from	O
gcn1	B-GENE
delta	I-GENE
strains	O
contained	O
wild	O
-	O
type	O
levels	O
of	O
GCN2	B-GENE
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
-	O
kinase	O
activity	O
.	O

Seven	O
patients	O
were	O
without	O
a	O
syndromic	O
diagnosis	O
.	O

Experimental	O
production	O
of	O
a	O
syndrome	O
analogous	O
to	O
hydramnios	O
in	O
the	O
rat	O
fetus	O

The	O
phP1	B-GENE
mutation	O
was	O
induced	O
by	O
insertion	O
of	O
a	O
1	O
.	O
2	O
-	O
kb	O
P	B-GENE
element	I-GENE
into	O
the	O
5	O
'	O
transcribed	O
nontranslated	O
region	O
of	O
the	O
proximal	O
polyhomeotic	B-GENE
gene	I-GENE
.	O

By	O
contrast	O
,	O
clonidine	O
(	O
1	O
micrograms	O
/	O
kg	O
)	O
elicited	O
an	O
immediate	O
and	O
prolonged	O
fall	O
in	O
blood	O
pressure	O
and	O
heart	O
rate	O
when	O
given	O
into	O
the	O
vertebral	O
artery	O
,	O
but	O
not	O
intravenously	O
.	O

Forty	O
-	O
eight	O
pregnant	O
adult	O
and	O
122	O
fetal	O
guinea	O
pigs	O
were	O
sacrificed	O
at	O
intervals	O
throughout	O
gestation	O
and	O
the	O
carcasses	O
analyzed	O
for	O
a	O
variety	O
of	O
growth	O
parameters	O
.	O

To	O
investigate	O
the	O
in	O
vivo	O
role	O
of	O
this	O
chimeric	B-GENE
bZIP	I-GENE
protein	I-GENE
in	O
oncogenic	O
transformation	O
,	O
its	O
expression	O
was	O
directed	O
to	O
the	O
lymphoid	O
compartments	O
of	O
transgenic	O
mice	O
.	O

The	O
MALDI	O
-	O
TOF	O
experiment	O
,	O
however	O
,	O
proved	O
to	O
be	O
superior	O
to	O
the	O
GC	O
experiment	O
,	O
particularly	O
with	O
regard	O
to	O
baseline	O
resolution	O
of	O
unsaturated	O
acids	O
.	O

The	O
mean	O
serum	O
CDT	O
increased	O
from	O
8	O
.	O
5	O
(	O
SD	O
2	O
.	O
2	O
)	O
U	O
/	O
l	O
to	O
16	O
.	O
6	O
(	O
SD	O
7	O
.	O
2	O
)	O
U	O
/	O
l	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

In	O
female	O
toads	O
,	O
Bufo	O
bufo	O
,	O
feeding	O
at	O
different	O
rates	O
,	O
the	O
uncorrected	O
value	O
of	O
n	O
was	O
0	O
.	O
44	O
,	O
when	O
metabolism	O
and	O
growth	O
were	O
expressed	O
as	O
kJ	O
kJ	O
-	O
1	O
.	O

In	O
contrast	O
,	O
vRel	B-GENE
lacks	O
a	O
strong	O
C	O
-	O
terminal	O
gene	O
activation	O
function	O
,	O
since	O
a	O
LexA	B-GENE
fusion	I-GENE
protein	I-GENE
containing	O
C	B-GENE
-	I-GENE
terminal	I-GENE
vRel	I-GENE
sequences	I-GENE
alone	O
only	O
weakly	O
activated	O
transcription	O
.	O

Our	O
study	O
reveals	O
a	O
consequence	O
of	O
adhesion	O
receptor	O
-	O
mediated	O
signaling	O
in	O
T	O
cells	O
,	O
which	O
is	O
potentially	O
important	O
in	O
the	O
regulation	O
of	O
T	O
cell	O
activation	O
,	O
including	O
production	O
of	O
cytokines	O
and	O
expression	O
of	O
proto	O
-	O
oncogenes	O
,	O
many	O
of	O
which	O
are	O
controlled	O
through	O
3	O
'	O
AU	O
-	O
rich	O
elements	O
.	O

Assessment	O
of	O
ammonia	O
and	O
urea	O
blood	O
content	O
in	O
metabolic	O
acid	O
-	O
base	O
disorders	O
in	O
white	O
rats	O
.	O

3	O
-	O
5	O
-	O
fold	O
increases	O
in	O
EGF	B-GENE
receptor	I-GENE
but	O
not	O
p185	B-GENE
(	O
neu	B-GENE
)	O
tyrosine	O
phosphorylation	O
occur	O
following	O
Gi	B-GENE
-	I-GENE
coupled	I-GENE
receptor	I-GENE
stimulation	O
.	O

So	O
it	O
is	O
sometimes	O
more	O
convenient	O
to	O
use	O
the	O
back	O
Radon	O
transform	O
R	O
-	O
1	O
and	O
then	O
to	O
correct	O
the	O
result	O
,	O
taking	O
into	O
account	O
attenuation	O
.	O

Immune	O
and	O
clinical	O
impact	O
of	O
Lactobacillus	O
acidophilus	O
on	O
asthma	O
.	O

These	O
results	O
indicate	O
that	O
(	O
1	O
)	O
RXR	B-GENE
-	O
TR	B-GENE
heterodimers	O
play	O
a	O
role	O
in	O
basal	O
transactivation	O
and	O
T3	O
suppression	O
of	O
negatively	O
regulated	O
genes	O
,	O
and	O
(	O
2	O
)	O
RXRs	B-GENE
increase	O
the	O
dominant	O
negative	O
effect	O
of	O
some	O
mutant	O
TRs	B-GENE
on	O
specific	O
negative	O
TREs	O
.	O

Injections	O
of	O
PD	O
solutions	O
with	O
13	O
.	O
6	O
,	O
22	O
.	O
7	O
,	O
and	O
38	O
.	O
6	O
g	O
/	O
liter	O
of	O
glucose	O
reduced	O
the	O
ingestion	O
of	O
sucrose	O
by	O
12	O
.	O
4	O
%	O
,	O
23	O
.	O
6	O
%	O
and	O
36	O
.	O
1	O
%	O
,	O
respectively	O
,	O
but	O
did	O
not	O
affect	O
the	O
ingestion	O
of	O
protein	O
.	O

To	O
examine	O
the	O
functional	O
relationship	O
between	O
distinct	O
cis	O
-	O
active	O
elements	O
within	O
the	O
distal	O
enhancer	O
region	O
of	O
the	O
rat	B-GENE
PRL	I-GENE
gene	I-GENE
,	O
we	O
have	O
used	O
deletional	O
and	O
mutational	O
analysis	O
of	O
that	O
region	O
in	O
transient	O
transfection	O
studies	O
in	O
GH3	O
pituitary	O
tumor	O
cells	O
.	O

While	O
there	O
is	O
growing	O
evidence	O
that	O
perception	O
and	O
imagery	O
share	O
common	O
neural	O
substrates	O
,	O
the	O
fact	O
that	O
D	O
.	O
F	O
.	O
shows	O
intact	O
visual	O
imagery	O
in	O
the	O
face	O
of	O
a	O
massive	O
perceptual	O
deficit	O
in	O
form	O
vision	O
challenges	O
recent	O
suggestions	O
that	O
these	O
two	O
psychological	O
processes	O
share	O
common	O
input	O
pathways	O
in	O
early	O
vision	O
.	O

Site	O
-	O
directed	O
mutagenesis	O
of	O
the	O
conserved	O
cysteine	O
residue	O
(	O
tom1C3235A	B-GENE
)	O
in	O
the	O
hect	B-GENE
-	I-GENE
domain	I-GENE
,	O
supposed	O
to	O
be	O
necessary	O
for	O
thioester	O
-	O
bond	O
formation	O
with	O
ubiquitin	B-GENE
,	O
abolished	O
the	O
gene	O
function	O
.	O

The	O
Seldinger	O
technique	O
for	O
difficult	O
transurethral	O
catheterization	O
:	O
a	O
gentle	O
alternative	O
to	O
suprapubic	O
puncture	O
(	O
Br	O
J	O
Surg	O
2000	O
;	O
87	O
:	O
1729	O
-	O
30	O
)	O
.	O

Gingival	O
retraction	O
for	O
class	O
V	O
restorations	O
.	O

The	O
amino	O
acid	O
sequence	O
of	O
the	O
protein	O
encoded	O
by	O
MSK1	B-GENE
is	O
homologous	O
to	O
yeast	B-GENE
cytoplasmic	I-GENE
lysyl	I-GENE
-	I-GENE
tRNA	I-GENE
synthetase	I-GENE
and	O
to	O
the	O
product	O
of	O
the	O
herC	B-GENE
gene	I-GENE
,	O
which	O
has	O
recently	O
been	O
suggested	O
to	O
code	O
for	O
the	O
Escherichia	O
coli	O
enzyme	O
.	O

In	O
contrast	O
to	O
p62	B-GENE
(	O
dok	B-GENE
)	O
,	O
DOKL	B-GENE
lacks	O
YxxP	O
motifs	O
in	O
the	O
C	O
terminus	O
and	O
does	O
not	O
bind	O
to	O
Ras	B-GENE
GTPase	I-GENE
-	I-GENE
activating	I-GENE
protein	I-GENE
(	O
RasGAP	B-GENE
)	O
upon	O
phosphorylation	O
.	O

The	O
presence	O
of	O
chloroquine	O
in	O
saliva	O
from	O
seven	O
healthy	O
volunteers	O
for	O
21	O
days	O
after	O
a	O
single	O
600	O
mg	O
oral	O
dose	O
of	O
the	O
drug	O
was	O
established	O
by	O
chromatographic	O
and	O
spectroscopic	O
methods	O
.	O

In	O
vitro	O
binding	O
studies	O
previously	O
showed	O
that	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
p50	B-GENE
homodimer	O
binds	O
the	O
switch	B-GENE
nuclear	I-GENE
B	I-GENE
-	I-GENE
site	I-GENE
protein	I-GENE
(	O
SNIP	B-GENE
)	O
of	O
the	O
S	B-GENE
gamma	I-GENE
3	I-GENE
tandem	I-GENE
repeat	I-GENE
.	O

If	O
,	O
however	O
,	O
myocardial	O
stunning	O
is	O
severe	O
,	O
and	O
it	O
involves	O
large	O
parts	O
of	O
the	O
LV	O
and	O
thus	O
impairs	O
global	O
LV	O
function	O
,	O
it	O
can	O
be	O
reversed	O
with	O
inotropic	O
agents	O
and	O
procedures	O
.	O

Similarly	O
,	O
interfering	O
with	O
MEKK	B-GENE
,	O
which	O
lies	O
upstream	O
of	O
JNK1	B-GENE
,	O
using	O
a	O
dominant	O
negative	O
expression	O
vector	O
reduced	O
MMP	B-GENE
-	I-GENE
9	I-GENE
promoter	I-GENE
activity	O
over	O
the	O
same	O
concentration	O
range	O
which	O
repressed	O
the	O
AP	B-GENE
-	I-GENE
1	I-GENE
-	O
thymidine	B-GENE
kinase	I-GENE
CAT	B-GENE
reporter	O
construct	O
.	O

The	O
7	B-GENE
.	I-GENE
2	I-GENE
kb	I-GENE
EcoRI	I-GENE
fragment	I-GENE
of	I-GENE
AfMNPV	I-GENE
was	O
cloned	O
and	O
the	O
nucleotide	O
sequences	O
of	O
the	O
polyhedrin	B-GENE
coding	O
region	O
and	O
its	O
flanking	O
regions	O
were	O
determined	O
.	O

Joint	O
ultrasonography	O
demonstrating	O
thickening	O
of	O
synoviae	O
and	O
tendons	O
has	O
become	O
a	O
useful	O
non	O
-	O
invasive	O
diagnostic	O
tool	O
,	O
although	O
it	O
is	O
not	O
specific	O
for	O
beta	B-GENE
2	I-GENE
-	I-GENE
M	I-GENE
amyloidosis	O
,	O
and	O
results	O
depend	O
on	O
observer	O
experience	O
.	O

Sequence	O
analyses	O
revealed	O
a	O
partial	O
941	O
bp	O
cDNA	O
that	O
encoded	O
a	O
313	O
-	O
amino	O
-	O
acid	O
polypeptide	O
.	O

Estimating	O
the	O
health	O
care	O
costs	O
of	O
smokers	O
.	O

Although	O
paclitaxel	O
alone	O
failed	O
to	O
induce	O
p38	B-GENE
MAPK	O
activation	O
,	O
subsequent	O
(	O
but	O
not	O
prior	O
)	O
exposure	O
to	O
PD98059	O
induced	O
a	O
dramatic	O
increase	O
in	O
p38	B-GENE
MAPK	O
phosphorylation	O
.	O

The	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
Cdk2	B-GENE
associates	O
with	O
cyclins	B-GENE
A	I-GENE
,	I-GENE
D	I-GENE
,	I-GENE
and	I-GENE
E	I-GENE
and	O
has	O
been	O
implicated	O
in	O
the	O
control	O
of	O
the	O
G1	O
to	O
S	O
phase	O
transition	O
in	O
mammals	O
.	O

Sequences	O
within	O
the	O
UAS2	O
element	O
of	O
the	O
ENO2	B-GENE
gene	I-GENE
bound	O
a	O
second	O
protein	O
which	O
corresponded	O
to	O
the	O
ABFI	B-GENE
(	O
autonomously	B-GENE
replicating	I-GENE
sequence	I-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
)	O
protein	O
.	O

Videoanalysis	O
confirms	O
the	O
ballistic	O
character	O
of	O
the	O
initial	O
phase	O
of	O
the	O
reaching	O
movement	O
.	O

Toward	O
this	O
end	O
,	O
we	O
used	O
two	O
cultured	O
colon	O
cancer	O
cell	O
lines	O
;	O
one	O
(	O
RKO	O
)	O
has	O
a	O
transcriptionally	O
activated	O
u	B-GENE
-	I-GENE
PAR	I-GENE
gene	I-GENE
,	O
and	O
the	O
other	O
(	O
GEO	O
)	O
overexpresses	O
the	O
receptor	O
only	O
after	O
phorbol	O
ester	O
treatment	O
.	O

Early	O
detection	O
and	O
signs	O
of	O
hepatoangiosarcoma	O
among	O
vinyl	O
chloride	O
workers	O
.	O

Many	O
retroviruses	O
,	O
including	O
the	O
human	O
and	O
simian	O
immunodeficiency	O
viruses	O
,	O
contain	O
a	O
leucine	O
zipper	O
-	O
like	O
repeat	O
in	O
a	O
highly	O
conserved	O
region	O
of	O
the	O
external	O
domain	O
of	O
the	O
transmembrane	O
(	O
TM	O
)	O
glycoprotein	O
.	O

Conversion	O
of	O
an	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
into	O
a	O
GABP	B-GENE
binding	O
site	O
is	O
likely	O
to	O
have	O
occurred	O
also	O
during	O
the	O
worldwide	O
spread	O
of	O
HIV	O
-	O
1	O
,	O
as	O
we	O
noticed	O
the	O
same	O
LTR	O
modification	O
in	O
subtype	O
E	O
isolates	O
from	O
Thailand	O
.	O

Bedbug	O
(	O
Cimex	O
lectularius	O
)	O
samples	O
adult	O
and	O
nymphs	O
either	O
engorged	O
or	O
starved	O
from	O
Central	O
Security	O
Forces	O
sleeping	O
wards	O
,	O
laboratory	O
animal	O
house	O
and	O
control	O
samples	O
from	O
laboratory	O
reared	O
colonies	O
were	O
ground	O
and	O
subjected	O
to	O
ELISA	O
test	O
of	O
hepatitis	B-GENE
B	I-GENE
surface	I-GENE
antigen	I-GENE
together	O
with	O
276	O
serum	O
samples	O
from	O
the	O
recruits	O
slept	O
in	O
those	O
wards	O
.	O

Ciprofloxacin	O
attained	O
a	O
peak	O
serum	O
concentration	O
of	O
1	O
.	O
2	O
mg	O
/	O
l	O
and	O
a	O
serum	O
half	O
-	O
life	O
of	O
34	O
min	O
.	O

As	O
usual	O
tests	O
,	O
such	O
as	O
"	O
time	O
"	O
of	O
cephalin	O
are	O
slightly	O
sensible	O
to	O
LMW	O
-	O
Hep	O
,	O
only	O
anti	O
-	O
Xa	O
activity	O
can	O
be	O
used	O
.	O

Although	O
they	O
are	O
similar	O
to	O
the	O
IL9R	B-GENE
gene	I-GENE
(	O
approximately	O
90	O
%	O
identity	O
)	O
,	O
none	O
of	O
these	O
copies	O
encodes	O
a	O
functional	O
receptor	O
:	O
none	O
of	O
them	O
contains	O
sequences	O
homologous	O
to	O
the	O
5	O
'	O
flanking	O
region	O
or	O
exon	O
1	O
of	O
the	O
IL9R	B-GENE
gene	I-GENE
,	O
and	O
the	O
remaining	O
ORFs	O
have	O
been	O
inactivated	O
by	O
various	O
point	O
mutations	O
and	O
deletions	O
.	O

In	O
two	O
patients	O
,	O
a	O
male	O
homosexual	O
and	O
an	O
hemophiliac	O
,	O
thrombocytopenia	O
was	O
associated	O
with	O
AIDS	O
-	O
related	O
complex	O
.	O

Choline	B-GENE
acetyltransferase	I-GENE
immunohistochemistry	O
combined	O
with	O
the	O
retrograde	O
transport	O
of	O
horseradish	B-GENE
peroxidase	I-GENE
showed	O
that	O
the	O
reticular	O
and	O
mediodorsal	O
thalamic	O
nuclei	O
of	O
the	O
cat	O
receive	O
an	O
important	O
input	O
from	O
cholinergic	O
and	O
non	O
-	O
cholinergic	O
neurons	O
of	O
substantia	O
innominata	O
and	O
adjacent	O
structures	O
in	O
the	O
basal	O
forebrain	O
.	O

Mortality	O
among	O
patients	O
with	O
CAVB	O
is	O
still	O
high	O
and	O
has	O
not	O
declined	O
within	O
the	O
last	O
decade	O
.	O

We	O
conclude	O
that	O
in	O
the	O
presence	O
of	O
fatty	O
acids	O
in	O
the	O
medium	O
transcription	O
of	O
SPS19	B-GENE
is	O
directly	O
regulated	O
by	O
both	O
Pip2p	B-GENE
-	O
Oaf1p	B-GENE
and	O
Adr1p	B-GENE
.	O

The	O
purified	O
RAG1	B-GENE
protein	I-GENE
overexpressed	O
in	O
E	O
.	O
coli	O
exhibited	O
the	O
expected	O
cleavage	O
activity	O
when	O
combined	O
with	O
RAG2	B-GENE
purified	O
from	O
transfected	O
293T	O
cells	O
.	O

Serum	O
triglycerides	O
also	O
showed	O
an	O
increase	O
from	O
birth	O
to	O
6	O
months	O
of	O
age	O
,	O
but	O
a	O
decrease	O
from	O
6	O
months	O
to	O
1	O
years	O
of	O
age	O
.	O

These	O
mutant	B-GENE
rps7	I-GENE
leaders	O
were	O
ligated	O
into	O
an	O
aadA	O
expression	O
cassette	O
and	O
transformed	O
into	O
the	O
chloroplast	O
of	O
C	O
.	O
reinhardtii	O
and	O
into	O
E	O
.	O
coli	O
.	O

The	O
use	O
of	O
medication	O
is	O
of	O
minor	O
importance	O
in	O
the	O
treatment	O
of	O
flight	O
phobia	O
.	O

We	O
previously	O
described	O
the	O
upregulation	O
of	O
the	O
MT2	B-GENE
antigen	I-GENE
during	O
urodele	O
limb	O
regeneration	O
and	O
characterized	O
the	O
MT2	B-GENE
antigen	I-GENE
as	O
a	O
310	O
-	O
to	O
325	O
-	O
kDa	O
chondroitin	O
-	O
sulfated	O
glycoprotein	O
with	O
a	O
core	O
protein	O
of	O
285	O
-	O
300	O
kDa	O
.	O

Southern	O
blot	O
analysis	O
following	O
reverse	O
transcription	O
and	O
PCR	O
showed	O
that	O
B2R	B-GENE
is	O
expressed	O
in	O
most	O
mouse	O
tissues	O
,	O
except	O
the	O
liver	O
and	O
spleen	O
,	O
which	O
is	O
consistent	O
with	O
the	O
wide	O
distribution	O
of	O
B2R	B-GENE
activity	O
as	O
deduced	O
from	O
pharmacological	O
studies	O
.	O

The	O
dynamics	O
of	O
N	O
-	O
interaction	O
and	O
N	O
-	O
retention	O
during	O
3	O
hr	O
CPB	O
was	O
quantified	O
with	O
autologous	O
In	O
-	O
111	O
labeled	O
neutrophils	O
(	O
INN	O
)	O
in	O
4	O
groups	O
of	O
20	O
Yorkshire	O
pigs	O
(	O
28	O
-	O
35	O
kg	O
,	O
5	O
sham	O
;	O
5	O
CPB	O
,	O
1	O
hr	O
;	O
5	O
CPB	O
,	O
3	O
hr	O
and	O
5	O
CPB	O
with	O
heparinized	O
circuit	O
,	O
3	O
hr	O
)	O
;	O
anesthetized	O
pigs	O
were	O
injected	O
with	O
INN	O
(	O
500	O
-	O
650	O
microCi	O
)	O
,	O
30	O
min	O
before	O
CPB	O
and	O
heparinized	O
,	O
and	O
underwent	O
CPB	O
with	O
a	O
roller	O
pump	O
,	O
a	O
hollow	O
fiber	O
OX	O
(	O
Bentley	O
CM	O
50	O
,	O
5	O
.	O
0	O
m2	O
)	O
and	O
AF	O
(	O
Bentley	O
AF	O
025	O
,	O
0	O
.	O
25	O
m2	O
)	O
at	O
2	O
.	O
5	O
-	O
3	O
.	O
6	O
l	O
/	O
min	O
for	O
3	O
hr	O
.	O

The	O
effect	O
of	O
the	O
negative	O
regulatory	O
element	O
is	O
negated	O
by	O
the	O
viral	B-GENE
IE2	I-GENE
protein	I-GENE
(	O
L	O
.	O

Cloning	O
of	O
the	O
GATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
that	O
regulates	O
endothelin	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
expression	O
in	O
endothelial	O
cells	O
.	O

John	O
'	O
s	O
wort	O

In	O
contrast	O
SF	B-GENE
,	O
but	O
not	O
GM	B-GENE
-	I-GENE
CSF	I-GENE
or	O
IL	B-GENE
-	I-GENE
3	I-GENE
,	O
induced	O
tyrosine	O
phosphorylation	O
of	O
phospholipase	B-GENE
C	I-GENE
-	I-GENE
gamma	I-GENE
(	O
PLC	B-GENE
-	I-GENE
gamma	I-GENE
)	O
.	O

Using	O
the	O
interaction	O
-	O
trap	O
assay	O
to	O
identify	O
candidate	O
proteins	O
that	O
bind	O
the	O
cytoplasmic	O
region	O
of	O
the	O
LAR	B-GENE
transmembrane	I-GENE
protein	I-GENE
tyrosine	I-GENE
phosphatase	I-GENE
(	O
PT	B-GENE
-	I-GENE
Pase	I-GENE
)	O
,	O
we	O
isolated	O
a	O
cDNA	O
encoding	O
a	O
2861	O
-	O
amino	O
acid	O
protein	O
termed	O
Trio	B-GENE
that	O
contains	O
three	O
enzyme	O
domains	O
:	O
two	O
functional	O
GEF	B-GENE
domains	I-GENE
and	O
a	O
protein	B-GENE
serine	I-GENE
/	I-GENE
threonine	I-GENE
kinase	I-GENE
(	O
PSK	B-GENE
)	O
domain	O
.	O

The	O
role	O
of	O
the	O
putative	O
C2	B-GENE
domain	O
of	O
Nedd4	B-GENE
has	O
not	O
been	O
elucidated	O
.	O

The	O
effect	O
on	O
FIV	B-GENE
LTR	I-GENE
promoter	I-GENE
activity	O
of	O
progressively	O
deleting	O
these	O
nuclear	O
factor	O
binding	O
sites	O
was	O
examined	O
by	O
linking	O
LTR	O
deletion	O
mutants	O
to	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
gene	O
.	O

Additionally	O
,	O
these	O
findings	O
have	O
important	O
implications	O
for	O
the	O
understanding	O
of	O
the	O
mechanisms	O
of	O
HIV	O
-	O
1	O
latency	O
and	O
reactivation	O
.	O

Furthermore	O
,	O
we	O
show	O
that	O
Nck	B-GENE
-	I-GENE
2	I-GENE
is	O
capable	O
of	O
recognizing	O
several	O
key	O
components	O
of	O
growth	B-GENE
factor	I-GENE
receptor	I-GENE
kinase	I-GENE
-	O
signaling	O
pathways	O
including	O
EGF	B-GENE
receptors	I-GENE
,	O
PDGF	B-GENE
receptor	I-GENE
-	I-GENE
beta	I-GENE
,	O
and	O
IRS	B-GENE
-	I-GENE
1	I-GENE
.	O

The	O
average	O
mean	O
difference	O
compared	O
with	O
the	O
low	O
and	O
the	O
intermediate	O
calcium	O
group	O
was	O
11	O
%	O
for	O
the	O
femoral	O
neck	O
,	O
8	O
-	O
11	O
%	O
for	O
the	O
lumbar	O
spine	O
and	O
5	O
-	O
6	O
%	O
for	O
total	O
body	O
BMDs	O
.	O

Although	O
the	O
number	O
of	O
kits	O
has	O
increased	O
,	O
the	O
precision	O
has	O
improved	O
,	O
showing	O
that	O
more	O
robust	O
methods	O
are	O
now	O
employed	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
contained	O
all	O
consensus	O
regions	O
for	O
S	B-GENE
-	I-GENE
adenosyl	I-GENE
methionine	I-GENE
methyltransferases	I-GENE
and	O
presented	O
26	O
%	O
identity	O
with	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
DHHB	I-GENE
-	I-GENE
methyltransferase	I-GENE
and	O
38	O
%	O
identity	O
with	O
the	O
rat	O
protein	O
,	O
as	O
well	O
as	O
with	O
a	O
bacterial	O
(	O
Escherichia	O
coli	O
and	O
Salmonella	O
typhimurium	O
)	O
methyltransferase	B-GENE
encoded	O
by	O
the	O
UBIG	B-GENE
gene	I-GENE
.	O

To	O
investigate	O
its	O
transcription	O
,	O
1	O
.	O
1	O
kilobases	O
of	O
the	O
5	O
'	O
-	O
flanking	O
sequence	O
were	O
fused	O
to	O
a	O
luciferase	B-GENE
reporter	I-GENE
gene	I-GENE
.	O

A	O
selective	O
transcriptional	O
induction	O
system	O
for	O
mammalian	O
cells	O
based	O
on	O
Gal4	B-GENE
-	O
estrogen	B-GENE
receptor	I-GENE
fusion	O
proteins	O
.	O

PATIENT	O
(	O
S	O
)	O
:	O
Two	O
hundred	O
thirty	O
-	O
eight	O
patients	O
with	O
RPLs	O
,	O
48	O
patients	O
with	O
recurrent	O
IVF	O
-	O
ET	O
failure	O
and	O
179	O
nonpregnant	O
and	O
120	O
pregnant	O
control	O
group	O
women	O
.	O

The	O
effects	O
of	O
oxalate	O
-	O
containing	O
products	O
on	O
the	O
exposed	O
dentine	O
surface	O
:	O
an	O
SEM	O
investigation	O
.	O

The	O
cyanobacterial	B-GENE
phycobilisome	I-GENE
is	O
a	O
large	O
protein	O
complex	O
located	O
on	O
the	O
photosynthetic	O
membrane	O
.	O

Up	O
to	O
1988	O
,	O
145	O
cases	O
had	O
been	O
reported	O
in	O
literature	O
and	O
32	O
cases	O
in	O
our	O
country	O
.	O

Lamivudine	O
therapy	O
for	O
acute	O
hepatitis	O
B	O
infection	O
following	O
peripheral	O
blood	O
stem	O
cell	O
transplantation	O
.	O

Disorganization	O
scores	O
of	O
the	O
hypertrophy	O
zone	O
and	O
trabecular	O
bone	O
were	O
low	O
,	O
approaching	O
normal	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
for	O
turkey	O
poults	O
fed	O
on	O
diets	O
with	O
phytase	B-GENE
supplementation	O
,	O
and	O
tibial	O
abnormality	O
scores	O
were	O
linearly	O
decreased	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
as	O
nP	O
levels	O
increased	O
(	O
zero	O
score	O
is	O
considered	O
normal	O
)	O
.	O

The	O
collicular	O
labels	O
found	O
after	O
injections	O
within	O
the	O
MST	O
area	O
exhibited	O
their	O
distribution	O
over	O
the	O
deep	O
SC	O
subdivision	O
,	O
whereas	O
they	O
spared	O
all	O
the	O
superficial	O
layers	O
but	O
the	O
deep	O
part	O
of	O
the	O
SO	O
.	O

Modern	O
aspects	O
of	O
shock	O
-	O
treatment	O
in	O
extensive	O
burns	O
(	O
author	O
'	O
s	O
transl	O
)	O

UVB	O
-	O
induced	O
association	O
of	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
(	I-GENE
TNF	I-GENE
)	I-GENE
receptor	I-GENE
1	I-GENE
/	O
TNF	B-GENE
receptor	I-GENE
-	I-GENE
associated	I-GENE
factor	I-GENE
-	I-GENE
2	I-GENE
mediates	O
activation	O
of	O
Rel	B-GENE
proteins	I-GENE
.	O

Mapping	O
of	O
the	O
region	O
in	O
KAP	B-GENE
-	I-GENE
1	I-GENE
required	O
for	O
HP1	B-GENE
interaction	O
showed	O
that	O
amino	O
acid	O
substitutions	O
which	O
abolish	O
HP1	B-GENE
binding	O
in	O
vitro	O
reduce	O
KAP	B-GENE
-	I-GENE
1	I-GENE
mediated	O
repression	O
in	O
vivo	O
.	O

However	O
,	O
whether	O
this	O
was	O
associated	O
with	O
spleen	O
removal	O
after	O
adjustment	O
for	O
risk	O
factors	O
was	O
not	O
determined	O
.	O

Taken	O
together	O
,	O
these	O
data	O
suggest	O
that	O
the	O
Smad3	B-GENE
/	O
Smad4	B-GENE
complex	O
has	O
at	O
least	O
two	O
separable	O
nuclear	O
functions	O
:	O
it	O
forms	O
a	O
rapid	O
,	O
yet	O
transient	O
sequence	O
-	O
specific	O
DNA	O
binding	O
complex	O
,	O
and	O
it	O
potentiates	O
AP1	B-GENE
-	O
dependent	O
transcriptional	O
activation	O
.	O

However	O
,	O
one	O
activity	O
binds	O
preferentially	O
to	O
G	O
+	O
C	O
-	O
rich	O
promoters	O
,	O
and	O
another	O
activity	O
appears	O
to	O
bind	O
preferentially	O
to	O
only	O
two	O
of	O
the	O
promoters	O
tested	O
.	O

The	O
donors	O
of	O
10	O
patients	O
were	O
ABO	O
-	O
incompatible	O
,	O
and	O
for	O
five	O
pairs	O
the	O
ABO	O
incompatibility	O
was	O
major	O
.	O

In	O
treatments	O
R1	O
and	O
R2	O
,	O
feed	O
quality	O
was	O
restricted	O
by	O
withholding	O
concentrates	O
for	O
3	O
and	O
4	O
.	O
5	O
mo	O
,	O
respectively	O
.	O

The	O
major	O
promoter	O
element	O
of	O
the	O
Xenopus	B-GENE
laevis	I-GENE
5S	I-GENE
RNA	I-GENE
gene	I-GENE
is	O
located	O
within	O
the	O
transcribed	O
region	O
of	O
the	O
gene	O
and	O
forms	O
the	O
binding	O
site	O
for	O
the	O
transcription	O
initiation	O
factor	O
TFIIIA	B-GENE
.	O

However	O
,	O
in	O
transient	O
transfection	O
assays	O
,	O
a	O
truncation	O
of	O
as	O
little	O
as	O
15	O
Nurr1	B-GENE
COOH	O
-	O
terminal	O
amino	O
acids	O
diminished	O
transcriptional	O
activation	O
of	O
B1A	B-GENE
-	O
thymidine	B-GENE
kinase	I-GENE
-	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	O
.	O

Small	O
cell	O
tumors	O
in	O
children	O
:	O
contribution	O
to	O
the	O
solution	O
of	O
the	O
problem	O
of	O
differential	O
diagnosis	O
with	O
immunohistochemistry	O
and	O
electron	O
microscopy	O

Four	O
experiments	O
examined	O
the	O
role	O
of	O
the	O
cholinergic	O
projections	O
from	O
the	O
septum	O
and	O
vertical	O
limb	O
nucleus	O
of	O
the	O
diagonal	O
band	O
of	O
Broca	O
(	O
VDB	O
)	O
in	O
acquisition	O
and	O
performance	O
of	O
a	O
conditional	O
visual	O
discrimination	O
.	O

Deletion	O
of	O
this	O
consensus	O
element	O
from	O
the	O
spo6	B-GENE
promoter	I-GENE
abolished	O
the	O
transcription	O
of	O
spo6	B-GENE
+	I-GENE
and	O
resulted	O
in	O
a	O
sporulation	O
deficiency	O
.	O

This	O
region	O
does	O
not	O
contain	O
a	O
consensus	O
estrogen	O
response	O
element	O
,	O
and	O
ER	B-GENE
binding	O
to	O
this	O
DNA	O
sequence	O
was	O
not	O
observed	O
.	O

We	O
have	O
previously	O
reported	O
that	O
analgesic	O
doses	O
of	O
morphine	O
accelerate	O
mortality	O
of	O
rats	O
exposed	O
to	O
hemorrhage	O
(	O
Feuerstein	O
and	O
Siren	O
:	O
Circ	O
Shock	O
19	O
:	O
293	O
-	O
300	O
,	O
1986	O
)	O
.	O

Microsporum	O
persicolor	O
,	O
an	O
easily	O
misinterpreted	O
dermatophyt	O

When	O
they	O
were	O
exposed	O
to	O
intermittent	O
schedules	O
of	O
punishment	O
(	O
fixed	O
-	O
interval	O
[	O
FI	O
]	O
120	O
s	O
or	O
FI	O
300	O
s	O
)	O
,	O
SIB	O
for	O
all	O
but	O
1	O
of	O
the	O
participants	O
increased	O
to	O
levels	O
similar	O
to	O
those	O
observed	O
during	O
baseline	O
.	O

These	O
results	O
suggest	O
that	O
1a	B-GENE
,	O
which	O
also	O
interacts	O
independently	O
with	O
the	O
ER	O
and	O
viral	O
RNA	O
,	O
is	O
a	O
key	O
organizer	O
of	O
RNA	O
replication	O
complex	O
assembly	O
.	O

Here	O
we	O
examine	O
the	O
population	O
of	O
gammaS	B-GENE
transcripts	I-GENE
in	O
adult	O
human	O
lens	O
and	O
the	O
structure	O
of	O
the	O
human	B-GENE
CRYGS	I-GENE
genes	I-GENE
.	O

PKK	B-GENE
exists	O
in	O
three	O
discernible	O
forms	O
at	O
steady	O
state	O
:	O
an	O
underphosphorylated	O
form	O
of	O
100	O
kDa	O
;	O
a	O
soluble	O
,	O
cytosolic	O
,	O
phosphorylated	O
form	O
of	O
110	O
kDa	O
;	O
and	O
a	O
phosphorylated	O
,	O
detergent	O
-	O
insoluble	O
form	O
of	O
112	O
kDa	O
.	O

The	O
lamina	O
densa	O
was	O
always	O
interrupted	O
by	O
numerous	O
small	O
gaps	O
and	O
in	O
some	O
areas	O
the	O
basement	O
membrane	O
could	O
not	O
be	O
identified	O
over	O
a	O
long	O
distance	O
.	O

The	O
human	B-GENE
CA11	I-GENE
gene	I-GENE
appears	O
to	O
be	O
located	O
between	O
the	O
secretor	B-GENE
type	I-GENE
alpha	I-GENE
(	I-GENE
1	I-GENE
,	I-GENE
2	I-GENE
)	I-GENE
-	I-GENE
fucosyltransferase	I-GENE
gene	I-GENE
cluster	I-GENE
(	O
FUT1	B-GENE
-	O
FUT2	B-GENE
-	O
FUT2P	B-GENE
)	O
and	O
the	O
D	B-GENE
-	I-GENE
site	I-GENE
binding	I-GENE
protein	I-GENE
gene	I-GENE
(	O
DBP	B-GENE
)	O
on	O
chromosome	O
19q13	O
.	O
3	O
.	O

A	O
score	O
(	O
APACHE	O
II	O
)	O
was	O
calculated	O
to	O
assess	O
the	O
severity	O
of	O
disease	O
.	O

To	O
determine	O
the	O
role	O
of	O
elevated	O
FAK	B-GENE
expression	O
in	O
facilitating	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
(	O
EGF	B-GENE
)	O
-	O
stimulated	O
human	O
adenocarcinoma	O
(	O
A549	O
)	O
cell	O
motility	O
,	O
antisense	O
oligonucleotides	O
were	O
used	O
to	O
reduce	O
FAK	B-GENE
protein	I-GENE
expression	O
>	O
75	O
%	O
.	O

Evaluation	O
of	O
materials	O
and	O
technics	O
in	O
vascular	O
surgery	O
using	O
111	O
-	O
Indium	O

Functional	O
importance	O
of	O
a	O
properly	O
folded	O
surface	O
loop	O
covering	O
the	O
catalytic	O
center	O
.	O

Hypoxia	O
decreased	O
the	O
rate	O
of	O
spontaneous	O
impulse	O
initiation	O
in	O
SA	O
nodal	O
fibers	O
by	O
decreasing	O
the	O
slope	O
of	O
diastolic	O
depolarization	O
.	O

Radiative	O
corrections	O
to	O
pi	O
l2	O
decays	O
.	O

The	O
availability	O
of	O
a	O
commercial	O
program	O
(	O
PCNONLIN	O
)	O
is	O
needed	O
to	O
carry	O
out	O
matrix	O
handling	O
calculations	O
.	O

The	O
levels	O
of	O
TPAR1	B-GENE
mRNAs	I-GENE
were	O
dramatically	O
down	O
-	O
regulated	O
in	O
regenerating	O
rat	O
liver	O
when	O
compared	O
to	O
normal	O
adult	O
liver	O
.	O

In	O
the	O
postoperative	O
patient	O
with	O
tetralogy	O
of	O
Fallot	O
with	O
symptomatic	O
ventricular	O
arrhythmias	O
,	O
it	O
is	O
concluded	O
that	O
electrophysiologic	O
study	O
is	O
useful	O
in	O
reproducing	O
clinical	O
episodes	O
of	O
VT	O
and	O
in	O
selecting	O
effective	O
antiarrhythmic	O
medication	O
;	O
a	O
small	O
number	O
of	O
patients	O
with	O
ventricular	O
premature	O
complexes	O
alone	O
will	O
have	O
inducible	O
sustained	O
VT	O
during	O
electrophysiologic	O
study	O
;	O
prognosis	O
of	O
these	O
patients	O
may	O
be	O
improved	O
by	O
treatment	O
that	O
results	O
in	O
prevention	O
of	O
VT	O
induction	O
;	O
and	O
in	O
patients	O
with	O
right	O
ventricular	O
hypertension	O
,	O
VT	O
is	O
likely	O
to	O
be	O
refractory	O
to	O
drug	O
treatment	O
.	O

Hip	O
fracture	O
mortality	O
and	O
prospective	O
payment	O
system	O
.	O

Primary	O
care	O
programs	O
for	O
the	O
indigent	O
.	O

In	O
human	O
myxoid	O
liposarcoma	O
,	O
a	O
chromosomal	O
rearrangement	O
leads	O
to	O
fusion	O
of	O
the	O
growth	O
-	O
arresting	O
and	O
DNA	O
-	O
damage	O
-	O
inducible	O
transcription	O
factor	O
CHOP	B-GENE
(	O
GADD153	B-GENE
)	O
to	O
a	O
peptide	O
fragment	O
encoded	O
by	O
the	O
TLS	B-GENE
gene	I-GENE
.	O

Categorisation	O
of	O
the	O
different	O
substructures	O
within	O
the	O
sections	O
allows	O
them	O
to	O
be	O
analysed	O
and	O
displayed	O
separately	O
.	O

Authors	O
present	O
the	O
anatomical	O
variations	O
of	O
the	O
course	O
of	O
the	O
inferior	O
mesenteric	O
artery	O
and	O
its	O
branches	O
in	O
62	O
human	O
fetus	O
.	O

This	O
mechanism	O
seems	O
to	O
be	O
involved	O
in	O
VIP	B-GENE
-	O
induced	O
PRL	B-GENE
gene	I-GENE
regulation	O
.	O

The	O
only	O
quantities	O
which	O
were	O
significantly	O
different	O
between	O
appendicitis	O
and	O
a	O
normal	O
appendix	O
were	O
sex	O
,	O
duration	O
of	O
symptoms	O
,	O
anorexia	O
and	O
vomiting	O
.	O

Signaling	O
through	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
and	O
Rac	B-GENE
/	O
Rho	B-GENE
does	O
not	O
duplicate	O
the	O
effects	O
of	O
activated	O
Ras	B-GENE
on	O
skeletal	O
myogenesis	O
.	O

The	O
survival	O
of	O
patients	O
with	O
a	O
short	O
bowel	O
,	O
even	O
if	O
they	O
need	O
long	O
-	O
term	O
parenteral	O
nutrition	O
,	O
is	O
good	O
.	O

Unlike	O
these	O
contaminant	O
-	O
responsive	O
T	O
cells	O
,	O
those	O
that	O
are	O
truly	O
specific	O
for	O
natural	O
AChR	B-GENE
epitopes	I-GENE
appear	O
less	O
heterogeneous	O
and	O
therefore	O
more	O
suitable	O
targets	O
for	O
selective	O
immunotherapy	O
.	O

CONCLUSIONS	O
:	O
This	O
initial	O
experience	O
indicates	O
that	O
there	O
is	O
short	O
-	O
to	O
middle	O
-	O
term	O
efficiency	O
and	O
safety	O
when	O
using	O
GKS	O
to	O
treat	O
MTLE	O
.	O

A	O
Brassica	O
cDNA	O
clone	O
encoding	O
a	O
bifunctional	O
hydroxymethylpyrimidine	B-GENE
kinase	I-GENE
/	O
thiamin	B-GENE
-	I-GENE
phosphate	I-GENE
pyrophosphorylase	I-GENE
involved	O
in	O
thiamin	O
biosynthesis	O
.	O

The	O
aims	O
of	O
this	O
study	O
were	O
to	O
examine	O
whether	O
the	O
EORTC	O
(	O
European	O
Organisation	O
for	O
Research	O
and	O
Treatment	O
of	O
Cancer	O
)	O
QLQ	O
-	O
C30	O
core	O
questionnaire	O
alone	O
could	O
distinguish	O
between	O
two	O
clinically	O
different	O
groups	O
of	O
patients	O
and	O
to	O
design	O
a	O
module	O
,	O
which	O
included	O
relevant	O
patient	O
-	O
defined	O
gastric	O
cancer	O
-	O
specific	O
variables	O
.	O

The	O
goal	O
of	O
our	O
work	O
was	O
to	O
determine	O
hearing	O
thresholds	O
in	O
patients	O
with	O
hearing	O
impairment	O
due	O
to	O
hereditary	O
motor	O
and	O
sensory	O
neuropathy	O
(	O
HMSN	O
I	O
)	O
.	O

Causal	O
modeling	O
combines	O
theory	O
and	O
research	O
,	O
and	O
because	O
the	O
interpretation	O
of	O
data	O
is	O
possible	O
only	O
within	O
the	O
context	O
of	O
the	O
proposed	O
theory	O
,	O
it	O
offers	O
an	O
important	O
method	O
for	O
advancing	O
the	O
science	O
while	O
maintaining	O
the	O
specificity	O
of	O
the	O
practice	O
.	O

Torsade	B-Disease
de	I-Disease
pointes	I-Disease
ventricular	B-Disease
tachycardia	I-Disease
during	O
low	O
dose	O
intermittent	O
dobutamine	B-Chemical
treatment	O
in	O
a	O
patient	O
with	O
dilated	B-Disease
cardiomyopathy	I-Disease
and	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
.	O

The	O
authors	O
describe	O
the	O
case	O
of	O
a	O
56	O
-	O
year	O
-	O
old	O
woman	O
with	O
chronic	O
,	O
severe	O
heart	B-Disease
failure	I-Disease
secondary	O
to	O
dilated	B-Disease
cardiomyopathy	I-Disease
and	O
absence	O
of	O
significant	O
ventricular	B-Disease
arrhythmias	I-Disease
who	O
developed	O
QT	B-Disease
prolongation	I-Disease
and	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
ventricular	B-Disease
tachycardia	I-Disease
during	O
one	O
cycle	O
of	O
intermittent	O
low	O
dose	O
(	O
2	O
.	O
5	O
mcg	O
/	O
kg	O
per	O
min	O
)	O
dobutamine	B-Chemical
.	O

This	O
report	O
of	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
ventricular	B-Disease
tachycardia	I-Disease
during	O
intermittent	O
dobutamine	B-Chemical
supports	O
the	O
hypothesis	O
that	O
unpredictable	O
fatal	O
arrhythmias	B-Disease
may	O
occur	O
even	O
with	O
low	O
doses	O
and	O
in	O
patients	O
with	O
no	O
history	O
of	O
significant	O
rhythm	O
disturbances	O
.	O

The	O
mechanisms	O
of	O
proarrhythmic	O
effects	O
of	O
Dubutamine	B-Chemical
are	O
discussed	O
.	O

Positive	O
skin	O
tests	O
in	O
late	O
reactions	O
to	O
radiographic	O
contrast	B-Chemical
media	I-Chemical
.	O

In	O
the	O
last	O
few	O
years	O
delayed	O
reactions	O
several	O
hours	O
after	O
the	O
injection	O
of	O
radiographic	O
and	O
contrast	B-Chemical
materials	I-Chemical
(	O
PRC	B-Chemical
)	O
have	O
been	O
described	O
with	O
increasing	O
frequency	O
.	O

The	O
authors	O
report	O
two	O
observations	O
on	O
patients	O
with	O
delayed	O
reactions	O
in	O
whom	O
intradermoreactions	O
(	O
IDR	O
)	O
and	O
patch	O
tests	O
to	O
a	O
series	O
of	O
ionic	O
and	O
non	O
ionic	O
PRC	B-Chemical
were	O
studied	O
.	O

After	O
angiography	O
by	O
the	O
venous	O
route	O
in	O
patient	O
n	O
degree	O
1	O
a	O
biphasic	O
reaction	O
with	O
an	O
immediate	O
reaction	O
(	O
dyspnea	B-Disease
,	O
loss	B-Disease
of	I-Disease
consciousness	I-Disease
)	O
and	O
delayed	O
macro	B-Disease
-	I-Disease
papular	I-Disease
rash	I-Disease
appeared	O
,	O
whilst	O
patient	O
n	O
degree	O
2	O
developed	O
a	O
generalised	O
sensation	O
of	O
heat	O
,	O
persistent	O
pain	B-Disease
at	O
the	O
site	O
of	O
injection	O
immediately	O
and	O
a	O
generalised	O
macro	O
-	O
papular	O
reaction	O
after	O
24	O
hours	O
.	O

The	O
skin	O
tests	O
revealed	O
positive	O
delayed	O
reactions	O
of	O
24	O
hours	O
and	O
48	O
hours	O
by	O
IDR	O
and	O
patch	O
tests	O
to	O
only	O
some	O
PRC	B-Chemical
with	O
common	O
chains	O
in	O
their	O
structures	O
.	O

The	O
positive	O
skin	O
tests	O
are	O
in	O
favour	O
of	O
immunological	O
reactions	O
and	O
may	O
help	O
in	O
diagnosis	O
of	O
allergy	B-Disease
in	O
the	O
patients	O
.	O

Risk	O
of	O
transient	O
hyperammonemic	B-Disease
encephalopathy	I-Disease
in	O
cancer	B-Disease
patients	O
who	O
received	O
continuous	O
infusion	O
of	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
with	O
the	O
complication	O
of	O
dehydration	B-Disease
and	O
infection	B-Disease
.	O

From	O
1986	O
to	O
1998	O
,	O
29	O
cancer	B-Disease
patients	O
who	O
had	O
32	O
episodes	O
of	O
transient	O
hyperammonemic	B-Disease
encephalopathy	I-Disease
related	O
to	O
continuous	O
infusion	O
of	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
were	O
identified	O
.	O

None	O
of	O
the	O
patients	O
had	O
decompensated	O
liver	B-Disease
disease	I-Disease
.	O

Onset	O
of	O
hyperammonemic	B-Disease
encephalopathy	I-Disease
varied	O
from	O
0	O
.	O
5	O
to	O
5	O
days	O
(	O
mean	O
:	O
2	O
.	O
6	O
+	O
/	O
-	O
1	O
.	O
3	O
days	O
)	O
after	O
the	O
initiation	O
of	O
chemotherapy	O
.	O

Plasma	O
ammonium	B-Chemical
level	O
ranged	O
from	O
248	O
to	O
2387	O
microg	O
%	O
(	O
mean	O
:	O
626	O
+	O
/	O
-	O
431	O
microg	O
%	O
)	O
.	O

Among	O
the	O
32	O
episodes	O
,	O
26	O
(	O
81	O
%	O
)	O
had	O
various	O
degrees	O
of	O
azotemia	B-Disease
,	O
18	O
(	O
56	O
%	O
)	O
occurred	O
during	O
bacterial	B-Disease
infections	I-Disease
and	O
14	O
(	O
44	O
%	O
)	O
without	O
infection	B-Disease
occurred	O
during	O
periods	O
of	O
dehydration	B-Disease
.	O

Higher	O
plasma	O
ammonium	B-Chemical
levels	O
and	O
more	O
rapid	O
onset	O
of	O
hyperammonemia	B-Disease
were	O
seen	O
in	O
18	O
patients	O
with	O
bacterial	B-Disease
infections	I-Disease
(	O
p	O
=	O
0	O
.	O
003	O
and	O
0	O
.	O
0006	O
,	O
respectively	O
)	O
and	O
in	O
nine	O
patients	O
receiving	O
high	O
daily	O
doses	O
(	O
2600	O
or	O
1800	O
mg	O
/	O
m2	O
)	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
(	O
p	O
=	O
0	O
.	O
0001	O
and	O
<	O
0	O
.	O
0001	O
,	O
respectively	O
)	O
.	O

In	O
25	O
out	O
of	O
32	O
episodes	O
(	O
78	O
%	O
)	O
,	O
plasma	O
ammonium	B-Chemical
levels	O
and	O
mental	O
status	O
returned	O
to	O
normal	O
within	O
2	O
days	O
after	O
adequate	O
management	O
.	O

In	O
conclusion	O
,	O
hyperammonemic	B-Disease
encephalopathy	I-Disease
can	O
occur	O
in	O
patients	O
receiving	O
continuous	O
infusion	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
.	O

Azotemia	B-Disease
,	O
body	O
fluid	O
insufficiency	O
and	O
bacterial	B-Disease
infections	I-Disease
were	O
frequently	O
found	O
in	O
these	O
patients	O
.	O

It	O
is	O
therefore	O
important	O
to	O
recognize	O
this	O
condition	O
in	O
patients	O
receiving	O
continuous	O
infusion	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
.	O

The	O
effects	O
of	O
quinine	B-Chemical
and	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
on	O
conditioned	O
place	O
preference	O
and	O
changes	O
in	O
motor	O
activity	O
induced	O
by	O
morphine	B-Chemical
in	O
rats	O
.	O

1	O
.	O

The	O
effects	O
of	O
two	O
unselective	O
potassium	B-Chemical
(	O
K	B-Chemical
(	O
+	O
)	O
-	O
)	O
channel	O
blockers	O
,	O
quinine	B-Chemical
(	O
12	O
.	O
5	O
,	O
25	O
and	O
50	O
mg	O
/	O
kg	O
)	O
and	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
(	O
1	O
and	O
2	O
mg	O
/	O
kg	O
)	O
,	O
on	O
conditioned	O
place	O
preference	O
and	O
biphasic	O
changes	O
in	O
motor	O
activity	O
induced	O
by	O
morphine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
)	O
were	O
tested	O
in	O
Wistar	O
rats	O
.	O

Quinine	B-Chemical
is	O
known	O
to	O
block	O
voltage	O
-	O
,	O
calcium	B-Chemical
-	O
and	O
ATP	B-Chemical
-	O
sensitive	O
K	B-Chemical
(	O
+	O
)	O
-	O
channels	O
while	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
is	O
known	O
to	O
block	O
voltage	O
-	O
sensitive	O
K	B-Chemical
(	O
+	O
)	O
-	O
channels	O
.	O

2	O
.	O

In	O
the	O
counterbalanced	O
method	O
,	O
quinine	B-Chemical
attenuated	O
morphine	B-Chemical
-	O
induced	O
place	O
preference	O
,	O
whereas	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
was	O
ineffective	O
.	O

In	O
the	O
motor	O
activity	O
test	O
measured	O
with	O
an	O
Animex	O
-	O
activity	O
meter	O
neither	O
of	O
the	O
K	B-Chemical
(	O
+	O
)	O
-	O
channel	O
blockers	O
affected	O
morphine	B-Chemical
-	O
induced	O
hypoactivity	B-Disease
,	O
but	O
both	O
K	B-Chemical
(	O
+	O
)	O
-	O
channel	O
blockers	O
prevented	O
morphine	B-Chemical
-	O
induced	O
secondary	O
hyperactivity	B-Disease
.	O

3	O
.	O

These	O
results	O
suggest	O
the	O
involvement	O
of	O
quinine	B-Chemical
-	O
sensitive	O
but	O
not	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
-	O
sensitive	O
K	B-Chemical
(	O
+	O
)	O
-	O
channels	O
in	O
morphine	B-Chemical
reward	O
.	O

It	O
is	O
also	O
suggested	O
that	O
the	O
blockade	O
of	O
K	B-Chemical
(	O
+	O
)	O
-	O
channels	O
sensitive	O
to	O
these	O
blockers	O
is	O
not	O
sufficient	O
to	O
prevent	O
morphine	B-Chemical
-	O
induced	O
hypoactivity	B-Disease
whereas	O
morphine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
seems	O
to	O
be	O
connected	O
to	O
both	O
quinine	B-Chemical
-	O
and	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
-	O
sensitive	O
K	B-Chemical
(	O
+	O
)	O
-	O
channels	O
.	O

Nociceptin	B-Chemical
/	O
orphanin	B-Chemical
FQ	I-Chemical
and	O
nocistatin	B-Chemical
on	O
learning	B-Disease
and	I-Disease
memory	I-Disease
impairment	I-Disease
induced	O
by	O
scopolamine	B-Chemical
in	O
mice	O
.	O

1	O
.	O

Nociceptin	B-Chemical
,	O
also	O
known	O
as	O
orphanin	B-Chemical
FQ	I-Chemical
,	O
is	O
an	O
endogenous	O
ligand	O
for	O
the	O
orphan	O
opioid	O
receptor	O
-	O
like	O
receptor	O
1	O
(	O
ORL1	O
)	O
and	O
involves	O
in	O
various	O
functions	O
in	O
the	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
nocistatin	B-Chemical
is	O
recently	O
isolated	O
from	O
the	O
same	O
precursor	O
as	O
nociceptin	B-Chemical
and	O
blocks	O
nociceptin	B-Chemical
-	O
induced	O
allodynia	B-Disease
and	O
hyperalgesia	B-Disease
.	O

2	O
.	O

Although	O
ORL1	O
receptors	O
which	O
display	O
a	O
high	O
degree	O
of	O
sequence	O
homology	O
with	O
classical	O
opioid	O
receptors	O
are	O
abundant	O
in	O
the	O
hippocampus	O
,	O
little	O
is	O
known	O
regarding	O
their	O
role	O
in	O
learning	O
and	O
memory	O
.	O

3	O
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
investigate	O
whether	O
nociceptin	B-Chemical
/	O
orphanin	B-Chemical
FQ	I-Chemical
and	O
nocistatin	B-Chemical
could	O
modulate	O
impairment	B-Disease
of	I-Disease
learning	I-Disease
and	I-Disease
memory	I-Disease
induced	O
by	O
scopolamine	B-Chemical
,	O
a	O
muscarinic	O
cholinergic	O
receptor	O
antagonist	O
,	O
using	O
spontaneous	O
alternation	O
of	O
Y	O
-	O
maze	O
and	O
step	O
-	O
down	O
type	O
passive	O
avoidance	O
tasks	O
in	O
mice	O
.	O

4	O
.	O

While	O
nocistatin	B-Chemical
(	O
0	O
.	O
5	O
-	O
5	O
.	O
0	O
nmol	O
mouse	O
-	O
1	O
,	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
administered	O
30	O
min	O
before	O
spontaneous	O
alternation	O
performance	O
or	O
the	O
training	O
session	O
of	O
the	O
passive	O
avoidance	O
task	O
,	O
had	O
no	O
effect	O
on	O
spontaneous	O
alternation	O
or	O
passive	O
avoidance	O
behaviours	O
,	O
a	O
lower	O
per	O
cent	O
alternation	O
and	O
shorter	O
median	O
step	O
-	O
down	O
latency	O
in	O
the	O
retention	O
test	O
were	O
obtained	O
in	O
nociceptin	B-Chemical
(	O
1	O
.	O
5	O
and	O
/	O
or	O
5	O
.	O
0	O
nmol	O
mouse	O
-	O
1	O
,	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
-	O
treated	O
normal	O
mice	O
.	O

5	O
.	O

Administration	O
of	O
nocistatin	B-Chemical
(	O
1	O
.	O
5	O
and	O
/	O
or	O
5	O
.	O
0	O
nmol	O
mouse	O
-	O
1	O
,	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
30	O
min	O
before	O
spontaneous	O
alternation	O
performance	O
or	O
the	O
training	O
session	O
of	O
the	O
passive	O
avoidance	O
task	O
,	O
attenuated	O
the	O
scopolamine	B-Chemical
-	O
induced	O
impairment	O
of	O
spontaneous	O
alternation	O
and	O
passive	O
avoidance	O
behaviours	O
.	O

6	O
.	O

These	O
results	O
indicated	O
that	O
nocistatin	B-Chemical
,	O
a	O
new	O
biologically	O
active	O
peptide	O
,	O
ameliorates	O
impairments	O
of	O
spontaneous	O
alternation	O
and	O
passive	O
avoidance	O
induced	O
by	O
scopolamine	B-Chemical
,	O
and	O
suggested	O
that	O
these	O
peptides	O
play	O
opposite	O
roles	O
in	O
learning	O
and	O
memory	O
.	O

Meloxicam	B-Chemical
-	O
induced	O
liver	B-Disease
toxicity	I-Disease
.	O

We	O
report	O
the	O
case	O
of	O
a	O
female	O
patient	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
who	O
developed	O
acute	O
cytolytic	O
hepatitis	B-Disease
due	O
to	O
meloxicam	B-Chemical
.	O

Recently	O
introduced	O
in	O
Belgium	O
,	O
meloxicam	B-Chemical
is	O
the	O
first	O
nonsteroidal	O
antiinflammatory	O
drug	O
with	O
selective	O
action	O
on	O
the	O
inducible	O
form	O
of	O
cyclooxygenase	O
2	O
.	O

The	O
acute	O
cytolytic	O
hepatitis	B-Disease
occurred	O
rapidly	O
after	O
meloxicam	B-Chemical
administration	O
and	O
was	O
associated	O
with	O
the	O
development	O
of	O
antinuclear	O
antibodies	O
suggesting	O
a	O
hypersensitivity	B-Disease
mechanism	O
.	O

This	O
first	O
case	O
of	O
meloxicam	B-Chemical
related	O
liver	B-Disease
toxicity	I-Disease
demonstrates	O
the	O
potential	O
of	O
this	O
drug	O
to	O
induce	O
hepatic	B-Disease
damage	I-Disease
.	O

Induction	O
of	O
apoptosis	O
by	O
remoxipride	B-Chemical
metabolites	O
in	O
HL60	O
and	O
CD34	O
+	O
/	O
CD19	O
-	O
human	O
bone	O
marrow	O
progenitor	O
cells	O
:	O
potential	O
relevance	O
to	O
remoxipride	B-Chemical
-	O
induced	O
aplastic	B-Disease
anemia	I-Disease
.	O

The	O
antipsychotic	O
agent	O
,	O
remoxipride	B-Chemical
[	O
(	B-Chemical
S	I-Chemical
)	I-Chemical
-	I-Chemical
(	I-Chemical
-	I-Chemical
)	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
bromo	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
[	I-Chemical
(	I-Chemical
1	I-Chemical
-	I-Chemical
ethyl	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
pyrrolidinyl	I-Chemical
)	I-Chemical
methyl	I-Chemical
]	I-Chemical
-	I-Chemical
2	I-Chemical
,	I-Chemical
6	I-Chemical
-	I-Chemical
dimethoxybenz	I-Chemical
amide	I-Chemical
]	O
has	O
been	O
associated	O
with	O
acquired	O
aplastic	B-Disease
anemia	I-Disease
.	O

We	O
have	O
examined	O
the	O
ability	O
of	O
remoxipride	B-Chemical
,	O
three	O
pyrrolidine	B-Chemical
ring	O
metabolites	O
and	O
five	O
aromatic	O
ring	O
metabolites	O
of	O
the	O
parent	O
compound	O
to	O
induce	O
apoptosis	O
in	O
HL60	O
cells	O
and	O
human	O
bone	O
marrow	O
progenitor	O
(	O
HBMP	O
)	O
cells	O
.	O

Cells	O
were	O
treated	O
for	O
0	O
-	O
24	O
h	O
with	O
each	O
compound	O
(	O
0	O
-	O
200	O
microM	O
)	O
.	O

Apoptosis	O
was	O
assessed	O
by	O
fluorescence	O
microscopy	O
in	O
Hoechst	B-Chemical
33342	I-Chemical
-	O
and	O
propidium	B-Chemical
iodide	I-Chemical
stained	O
cell	O
samples	O
.	O

Results	O
were	O
confirmed	O
by	O
determination	O
of	O
internucleosomal	O
DNA	O
fragmentation	O
using	O
gel	O
electrophoresis	O
for	O
HL60	O
cell	O
samples	O
and	O
terminal	O
deoxynucleotidyl	O
transferase	O
assay	O
in	O
HBMP	O
cells	O
.	O

The	O
catechol	B-Chemical
and	O
hydroquinone	B-Chemical
metabolites	O
,	O
NCQ436	B-Chemical
and	O
NCQ344	B-Chemical
,	O
induced	O
apoptosis	O
in	O
HL60	O
and	O
HBMP	O
cells	O
in	O
a	O
time	O
-	O
and	O
concentration	O
dependent	O
manner	O
,	O
while	O
the	O
phenols	B-Chemical
,	O
NCR181	O
,	O
FLA873	O
,	O
and	O
FLA797	B-Chemical
,	O
and	O
the	O
derivatives	O
formed	O
by	O
oxidation	O
of	O
the	O
pyrrolidine	B-Chemical
ring	O
,	O
FLA838	O
,	O
NCM001	O
,	O
and	O
NCL118	O
,	O
had	O
no	O
effect	O
.	O

No	O
necrosis	B-Disease
was	O
observed	O
in	O
cells	O
treated	O
with	O
NCQ436	B-Chemical
but	O
NCQ344	B-Chemical
had	O
a	O
biphasic	O
effect	O
in	O
both	O
cell	O
types	O
,	O
inducing	O
apoptosis	O
at	O
lower	O
concentrations	O
and	O
necrosis	B-Disease
at	O
higher	O
concentrations	O
.	O

These	O
data	O
show	O
that	O
the	O
catechol	B-Chemical
and	O
hydroquinone	B-Chemical
metabolites	O
of	O
remoxipride	B-Chemical
have	O
direct	O
toxic	O
effects	O
in	O
HL60	O
and	O
HBMP	O
cells	O
,	O
leading	O
to	O
apoptosis	O
,	O
while	O
the	O
phenol	B-Chemical
metabolites	O
were	O
inactive	O
.	O

Similarly	O
,	O
benzene	B-Chemical
-	O
derived	O
catechol	B-Chemical
and	O
hydroquinone	B-Chemical
,	O
but	O
not	O
phenol	B-Chemical
,	O
induce	O
apoptosis	O
in	O
HBMP	O
cells	O
[	O
Moran	O
et	O
al	O
.	O
,	O
Mol	O
.	O
Pharmacol	O
.	O
,	O
50	O
(	O
1996	O
)	O
610	O
-	O
615	O
]	O
.	O

We	O
propose	O
that	O
remoxipride	B-Chemical
and	O
benzene	B-Chemical
may	O
induce	O
aplastic	B-Disease
anemia	I-Disease
via	O
production	O
of	O
similar	O
reactive	O
metabolites	O
and	O
that	O
the	O
ability	O
of	O
NCQ436	B-Chemical
and	O
NCQ344	B-Chemical
to	O
induce	O
apoptosis	O
in	O
HBMP	O
cells	O
may	O
contribute	O
to	O
the	O
mechanism	O
underlying	O
acquired	O
aplastic	B-Disease
anemia	I-Disease
that	O
has	O
been	O
associated	O
with	O
remoxipride	B-Chemical
.	O

Synthesis	O
and	O
preliminary	O
pharmacological	O
investigations	O
of	O
1	B-Chemical
-	I-Chemical
(	I-Chemical
1	I-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
dihydro	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
acenaphthylenyl	I-Chemical
)	I-Chemical
piperazine	I-Chemical
derivatives	O
as	O
potential	O
atypical	O
antipsychotic	O
agents	O
in	O
mice	O
.	O

In	O
research	O
towards	O
the	O
development	O
of	O
new	O
atypical	O
antipsychotic	O
agents	O
,	O
one	O
strategy	O
is	O
that	O
the	O
dopaminergic	O
system	O
can	O
be	O
modulated	O
through	O
manipulation	O
of	O
the	O
serotonergic	O
system	O
.	O

The	O
synthesis	O
and	O
preliminary	O
pharmacological	O
evaluation	O
of	O
a	O
series	O
of	O
potential	O
atypical	O
antipsychotic	O
agents	O
based	O
on	O
the	O
structure	O
of	O
1	B-Chemical
-	I-Chemical
(	I-Chemical
1	I-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
dihydro	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
acenaphthylenyl	I-Chemical
)	I-Chemical
piperazine	I-Chemical
(	O
7	O
)	O
is	O
described	O
.	O

Compound	O
7e	O
,	O
5	B-Chemical
-	I-Chemical
{	I-Chemical
2	I-Chemical
-	I-Chemical
[	I-Chemical
4	I-Chemical
-	I-Chemical
(	I-Chemical
1	I-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
dihydro	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
acenaphthylenyl	I-Chemical
)	I-Chemical
piperazinyl	I-Chemical
]	I-Chemical
ethyl	I-Chemical
}	I-Chemical
-	I-Chemical
2	I-Chemical
,	I-Chemical
3	I-Chemical
-	I-Chemical
dihy	I-Chemical
dro	I-Chemical
-	I-Chemical
1H	I-Chemical
-	I-Chemical
indol	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
one	I-Chemical
,	O
from	O
this	O
series	O
showed	O
significant	O
affinities	O
at	O
the	O
5	O
-	O
HT1A	O
and	O
5	O
-	O
HT2A	O
receptors	O
and	O
moderate	O
affinity	O
at	O
the	O
D2	O
receptor	O
.	O

7e	O
exhibits	O
a	O
high	O
reversal	O
of	O
catalepsy	B-Disease
induced	O
by	O
haloperidol	B-Chemical
indicating	O
its	O
atypical	O
antipsychotic	O
nature	O
.	O

Sub	O
-	O
chronic	O
inhibition	O
of	O
nitric	B-Chemical
-	I-Chemical
oxide	I-Chemical
synthesis	O
modifies	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
and	O
the	O
number	O
of	O
NADPH	B-Chemical
-	O
diaphorase	O
neurons	O
in	O
mice	O
.	O

RATIONALE	O
:	O
NG	B-Chemical
-	I-Chemical
nitro	I-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
arginine	I-Chemical
(	O
L	B-Chemical
-	I-Chemical
NOARG	I-Chemical
)	O
,	O
an	O
inhibitor	O
of	O
nitric	B-Chemical
-	I-Chemical
oxide	I-Chemical
synthase	O
(	O
NOS	O
)	O
,	O
induces	O
catalepsy	B-Disease
in	O
mice	O
.	O

This	O
effect	O
undergoes	O
rapid	O
tolerance	O
,	O
showing	O
a	O
significant	O
decrease	O
after	O
2	O
days	O
of	O
sub	O
-	O
chronic	O
L	B-Chemical
-	I-Chemical
NOARG	I-Chemical
treatment	O
.	O

Nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
has	O
been	O
shown	O
to	O
influence	O
dopaminergic	O
neurotransmission	O
in	O
the	O
striatum	O
.	O

Neuroleptic	O
drugs	O
such	O
as	O
haloperidol	B-Chemical
,	O
which	O
block	O
dopamine	B-Chemical
receptors	O
,	O
also	O
cause	O
catalepsy	B-Disease
in	O
rodents	O
.	O

OBJECTIVES	O
:	O
To	O
investigate	O
the	O
effects	O
of	O
subchronic	O
L	B-Chemical
-	I-Chemical
NOARG	I-Chemical
treatment	O
in	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
and	O
the	O
number	O
of	O
NOS	O
neurons	O
in	O
areas	O
related	O
to	O
motor	O
control	O
.	O

METHODS	O
:	O
Male	O
albino	O
Swiss	O
mice	O
were	O
treated	O
sub	O
-	O
chronically	O
(	O
twice	O
a	O
day	O
for	O
4	O
days	O
)	O
with	O
L	B-Chemical
-	I-Chemical
NOARG	I-Chemical
(	O
40	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
or	O
haloperidol	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
.	O

Catalepsy	B-Disease
was	O
evaluated	O
at	O
the	O
beginning	O
and	O
the	O
end	O
of	O
the	O
treatments	O
.	O

Reduced	O
nicotinamide	B-Chemical
adenine	I-Chemical
dinucleotide	I-Chemical
phosphate	I-Chemical
-	O
diaphorase	O
(	O
NADPH	B-Chemical
-	O
d	O
)	O
histochemistry	O
was	O
also	O
employed	O
to	O
visualize	O
NOS	O
as	O
an	O
index	O
of	O
enzyme	O
expression	O
in	O
mice	O
brain	O
regions	O
related	O
to	O
motor	O
control	O
.	O

RESULTS	O
:	O
L	B-Chemical
-	I-Chemical
NOARG	I-Chemical
sub	O
-	O
chronic	O
administration	O
produced	O
tolerance	O
of	O
L	B-Chemical
-	I-Chemical
NOARG	I-Chemical
and	O
of	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
.	O

It	O
also	O
induced	O
an	O
increase	O
in	O
the	O
number	O
of	O
NADPH	B-Chemical
-	O
d	O
-	O
positive	O
cells	O
in	O
the	O
dorsal	O
part	O
of	O
the	O
caudate	O
and	O
accumbens	O
nuclei	O
compared	O
with	O
haloperidol	B-Chemical
and	O
in	O
the	O
pedunculopontine	O
tegmental	O
nucleus	O
compared	O
with	O
saline	O
.	O

In	O
contrast	O
,	O
there	O
was	O
a	O
decrease	O
in	O
NADPH	B-Chemical
-	O
d	O
neuron	O
number	O
in	O
the	O
substantia	O
nigra	O
,	O
pars	O
compacta	O
in	O
both	O
haloperidol	B-Chemical
-	O
treated	O
and	O
L	B-Chemical
-	I-Chemical
NOARG	I-Chemical
-	O
treated	O
animals	O
.	O

CONCLUSIONS	O
:	O
The	O
results	O
give	O
further	O
support	O
to	O
the	O
hypothesis	O
that	O
NO	B-Chemical
plays	O
a	O
role	O
in	O
motor	O
behavior	O
control	O
and	O
suggest	O
that	O
it	O
may	O
take	O
part	O
in	O
the	O
synaptic	O
changes	O
produced	O
by	O
antipsychotic	O
treatment	O
.	O

Prolonged	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
occurs	O
in	O
patients	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
after	O
both	O
dobutamine	B-Chemical
and	O
exercise	O
induced	O
myocardial	B-Disease
ischaemia	I-Disease
.	O

OBJECTIVE	O
:	O
To	O
determine	O
whether	O
pharmacological	O
stress	O
leads	O
to	O
prolonged	O
but	O
reversible	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
in	O
patients	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
,	O
similar	O
to	O
that	O
seen	O
after	O
exercise	O
.	O

DESIGN	O
:	O
A	O
randomised	O
crossover	O
study	O
of	O
recovery	O
time	O
of	O
systolic	O
and	O
diastolic	O
left	O
ventricular	O
function	O
after	O
exercise	O
and	O
dobutamine	B-Chemical
induced	O
ischaemia	B-Disease
.	O

SUBJECTS	O
:	O
10	O
patients	O
with	O
stable	B-Disease
angina	I-Disease
,	O
angiographically	O
proven	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
,	O
and	O
normal	O
left	O
ventricular	O
function	O
.	O

INTERVENTIONS	O
:	O
Treadmill	O
exercise	O
and	O
dobutamine	B-Chemical
stress	O
were	O
performed	O
on	O
different	O
days	O
.	O

Quantitative	O
assessment	O
of	O
systolic	O
and	O
diastolic	O
left	O
ventricular	O
function	O
was	O
performed	O
using	O
transthoracic	O
echocardiography	O
at	O
baseline	O
and	O
at	O
regular	O
intervals	O
after	O
each	O
test	O
.	O

RESULTS	O
:	O
Both	O
forms	O
of	O
stress	O
led	O
to	O
prolonged	O
but	O
reversible	O
systolic	O
and	O
diastolic	O
dysfunction	O
.	O

There	O
was	O
no	O
difference	O
in	O
the	O
maximum	O
double	O
product	O
(	O
p	O
=	O
0	O
.	O
53	O
)	O
or	O
ST	O
depression	B-Disease
(	O
p	O
=	O
0	O
.	O
63	O
)	O
with	O
either	O
form	O
of	O
stress	O
.	O

After	O
exercise	O
,	O
ejection	O
fraction	O
was	O
reduced	O
at	O
15	O
and	O
30	O
minutes	O
compared	O
with	O
baseline	O
(	O
mean	O
(	O
SEM	O
)	O
,	O
-	O
5	O
.	O
6	O
(	O
1	O
.	O
5	O
)	O
%	O
,	O
p	O
<	O
0	O
.	O
05	O
;	O
and	O
-	O
6	O
.	O
1	O
(	O
2	O
.	O
2	O
)	O
%	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
at	O
30	O
and	O
45	O
minutes	O
after	O
dobutamine	B-Chemical
(	O
-	O
10	O
.	O
8	O
(	O
1	O
.	O
8	O
)	O
%	O
and	O
-	O
5	O
.	O
5	O
(	O
1	O
.	O
8	O
)	O
%	O
,	O
both	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Regional	O
analysis	O
showed	O
a	O
reduction	O
in	O
the	O
worst	O
affected	O
segment	O
15	O
and	O
30	O
minutes	O
after	O
exercise	O
(	O
-	O
27	O
.	O
9	O
(	O
7	O
.	O
2	O
)	O
%	O
and	O
-	O
28	O
.	O
6	O
(	O
5	O
.	O
7	O
)	O
%	O
,	O
both	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
at	O
30	O
minutes	O
after	O
dobutamine	B-Chemical
(	O
-	O
32	O
(	O
5	O
.	O
3	O
)	O
%	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

The	O
isovolumic	O
relaxation	O
period	O
was	O
prolonged	O
45	O
minutes	O
after	O
each	O
form	O
of	O
stress	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

CONCLUSIONS	O
:	O
In	O
patients	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
,	O
dobutamine	B-Chemical
induced	O
ischaemia	B-Disease
results	O
in	O
prolonged	O
reversible	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
,	O
presumed	O
to	O
be	O
myocardial	B-Disease
stunning	I-Disease
,	O
similar	O
to	O
that	O
seen	O
after	O
exercise	O
.	O

Dobutamine	B-Chemical
induced	O
ischaemia	B-Disease
could	O
therefore	O
be	O
used	O
to	O
study	O
the	O
pathophysiology	O
of	O
this	O
phenomenon	O
further	O
in	O
patients	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
.	O

Anorexigens	O
and	O
pulmonary	B-Disease
hypertension	I-Disease
in	O
the	O
United	O
States	O
:	O
results	O
from	O
the	O
surveillance	O
of	O
North	O
American	O
pulmonary	B-Disease
hypertension	I-Disease
.	O

BACKGROUND	O
:	O
The	O
use	O
of	O
appetite	O
suppressants	O
in	O
Europe	O
has	O
been	O
associated	O
with	O
the	O
development	O
of	O
primary	B-Disease
pulmonary	I-Disease
hypertension	I-Disease
(	O
PPH	B-Disease
)	O
.	O

Recently	O
,	O
fenfluramine	B-Chemical
appetite	O
suppressants	O
became	O
widely	O
used	O
in	O
the	O
United	O
States	O
but	O
were	O
withdrawn	O
in	O
September	O
1997	O
because	O
of	O
concerns	O
over	O
adverse	O
effects	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
We	O
conducted	O
a	O
prospective	O
surveillance	O
study	O
on	O
patients	O
diagnosed	O
with	O
pulmonary	B-Disease
hypertension	I-Disease
at	O
12	O
large	O
referral	O
centers	O
in	O
North	O
America	O
.	O

Data	O
collected	O
on	O
patients	O
seen	O
from	O
September	O
1	O
,	O
1996	O
,	O
to	O
December	O
31	O
,	O
1997	O
,	O
included	O
the	O
cause	O
of	O
the	O
pulmonary	B-Disease
hypertension	I-Disease
and	O
its	O
severity	O
.	O

Patients	O
with	O
no	O
identifiable	O
cause	O
of	O
pulmonary	B-Disease
hypertension	I-Disease
were	O
classed	O
as	O
PPH	B-Disease
.	O

A	O
history	O
of	O
drug	O
exposure	O
also	O
was	O
taken	O
with	O
special	O
attention	O
on	O
the	O
use	O
of	O
antidepressants	O
,	O
anorexigens	O
,	O
and	O
amphetamines	B-Chemical
.	O

RESULTS	O
:	O
Five	O
hundred	O
seventy	O
-	O
nine	O
patients	O
were	O
studied	O
,	O
205	O
with	O
PPH	B-Disease
and	O
374	O
with	O
pulmonary	B-Disease
hypertension	I-Disease
from	O
other	O
causes	O
(	O
secondary	O
pulmonary	B-Disease
hypertension	I-Disease
[	O
SPH	O
]	O
)	O
.	O

The	O
use	O
of	O
anorexigens	O
was	O
common	O
in	O
both	O
groups	O
.	O

However	O
,	O
of	O
the	O
medications	O
surveyed	O
,	O
only	O
the	O
fenfluramines	B-Chemical
had	O
a	O
significant	O
preferential	O
association	O
with	O
PPH	B-Disease
as	O
compared	O
with	O
SPH	O
(	O
adjusted	O
odds	O
ratio	O
for	O
use	O
>	O
6	O
months	O
,	O
7	O
.	O
5	O
;	O
95	O
%	O
confidence	O
interval	O
,	O
1	O
.	O
7	O
to	O
32	O
.	O
4	O
)	O
.	O

The	O
association	O
was	O
stronger	O
with	O
longer	O
duration	O
of	O
use	O
when	O
compared	O
to	O
shorter	O
duration	O
of	O
use	O
and	O
was	O
more	O
pronounced	O
in	O
recent	O
users	O
than	O
in	O
remote	O
users	O
.	O

An	O
unexpectedly	O
high	O
(	O
11	O
.	O
4	O
%	O
)	O
number	O
of	O
patients	O
with	O
SPH	O
had	O
used	O
anorexigens	O
.	O

CONCLUSION	O
:	O
The	O
magnitude	O
of	O
the	O
association	O
with	O
PPH	B-Disease
,	O
the	O
increase	O
of	O
association	O
with	O
increasing	O
duration	O
of	O
use	O
,	O
and	O
the	O
specificity	O
for	O
fenfluramines	B-Chemical
are	O
consistent	O
with	O
previous	O
studies	O
indicating	O
that	O
fenfluramines	B-Chemical
are	O
causally	O
related	O
to	O
PPH	B-Disease
.	O

The	O
high	O
prevalence	O
of	O
anorexigen	O
use	O
in	O
patients	O
with	O
SPH	O
also	O
raises	O
the	O
possibility	O
that	O
these	O
drugs	O
precipitate	O
pulmonary	B-Disease
hypertension	I-Disease
in	O
patients	O
with	O
underlying	O
conditions	O
associated	O
with	O
SPH	O
.	O

Clinical	O
aspects	O
of	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
and	O
thrombosis	B-Disease
and	O
other	O
side	O
effects	O
of	O
heparin	B-Chemical
therapy	O
.	O

Heparin	B-Chemical
,	O
first	O
used	O
to	O
prevent	O
the	O
clotting	O
of	O
blood	O
in	O
vitro	O
,	O
has	O
been	O
clinically	O
used	O
to	O
treat	O
thrombosis	B-Disease
for	O
more	O
than	O
50	O
years	O
.	O

Although	O
several	O
new	O
anticoagulant	O
drugs	O
are	O
in	O
development	O
,	O
heparin	B-Chemical
remains	O
the	O
anticoagulant	O
of	O
choice	O
to	O
treat	O
acute	O
thrombotic	B-Disease
episodes	O
.	O

The	O
clinical	O
effects	O
of	O
heparin	B-Chemical
are	O
meritorious	O
,	O
but	O
side	O
effects	O
do	O
exist	O
.	O

Bleeding	B-Disease
is	O
the	O
primary	O
untoward	O
effect	O
of	O
heparin	B-Chemical
.	O

Major	O
bleeding	B-Disease
is	O
of	O
primary	O
concern	O
in	O
patients	O
receiving	O
heparin	B-Chemical
therapy	O
.	O

However	O
,	O
additional	O
important	O
untoward	O
effects	O
of	O
heparin	B-Chemical
therapy	O
include	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
,	O
heparin	B-Chemical
-	O
associated	O
osteoporosis	B-Disease
,	O
eosinophilia	B-Disease
,	O
skin	B-Disease
reactions	I-Disease
,	O
allergic	B-Disease
reactions	I-Disease
other	O
than	O
thrombocytopenia	B-Disease
,	O
alopecia	B-Disease
,	O
transaminasemia	O
,	O
hyperkalemia	B-Disease
,	O
hypoaldosteronism	B-Disease
,	O
and	O
priapism	B-Disease
.	O

These	O
side	O
effects	O
are	O
relatively	O
rare	O
in	O
a	O
given	O
individual	O
,	O
but	O
given	O
the	O
extremely	O
widespread	O
use	O
of	O
heparin	B-Chemical
,	O
some	O
are	O
quite	O
common	O
,	O
particularly	O
HITT	B-Disease
and	O
osteoporosis	B-Disease
.	O

Although	O
reasonable	O
incidences	O
of	O
many	O
of	O
these	O
side	O
effects	O
can	O
be	O
"	O
softly	O
"	O
deduced	O
from	O
current	O
reports	O
dealing	O
with	O
unfractionated	O
heparin	B-Chemical
,	O
at	O
present	O
the	O
incidences	O
of	O
these	O
side	O
effects	O
with	O
newer	O
low	O
molecular	O
weight	O
heparins	B-Chemical
appear	O
to	O
be	O
much	O
less	O
common	O
.	O

However	O
,	O
only	O
longer	O
experience	O
will	O
more	O
clearly	O
define	O
the	O
incidence	O
of	O
each	O
side	O
effect	O
with	O
low	O
molecular	O
weight	O
preparations	O
.	O

A	O
case	O
of	O
bilateral	O
optic	B-Disease
neuropathy	I-Disease
in	O
a	O
patient	O
on	O
tacrolimus	B-Chemical
(	O
FK506	B-Chemical
)	O
therapy	O
after	O
liver	O
transplantation	O
.	O

PURPOSE	O
:	O
To	O
report	O
a	O
case	O
of	O
bilateral	O
optic	B-Disease
neuropathy	I-Disease
in	O
a	O
patient	O
receiving	O
tacrolimus	B-Chemical
(	O
FK	B-Chemical
506	I-Chemical
,	O
Prograf	O
;	O
Fujisawa	O
USA	O
,	O
Inc	O
,	O
Deerfield	O
,	O
Illinois	O
)	O
for	O
immunosuppression	O
after	O
orthotropic	O
liver	O
transplantation	O
.	O

METHOD	O
:	O
Case	O
report	O
.	O

In	O
a	O
58	O
-	O
year	O
-	O
old	O
man	O
receiving	O
tacrolimus	B-Chemical
after	O
orthotropic	O
liver	O
transplantation	O
,	O
serial	O
neuro	O
-	O
ophthalmologic	O
examinations	O
and	O
laboratory	O
studies	O
were	O
performed	O
.	O

RESULTS	O
:	O
The	O
patient	O
had	O
episodic	O
deterioration	O
of	O
vision	O
in	O
both	O
eyes	O
,	O
with	O
clinical	O
features	O
resembling	O
ischemic	B-Disease
optic	I-Disease
neuropathies	I-Disease
.	O

Deterioration	B-Disease
of	I-Disease
vision	I-Disease
occurred	O
despite	O
discontinuation	O
of	O
the	O
tacrolimus	B-Chemical
.	O

CONCLUSION	O
:	O
Tacrolimus	B-Chemical
and	O
other	O
immunosuppressive	O
agents	O
may	O
be	O
associated	O
with	O
optic	B-Disease
nerve	I-Disease
toxicity	I-Disease
.	O

Hypercalcemia	B-Disease
,	O
arrhythmia	B-Disease
,	O
and	O
mood	O
stabilizers	O
.	O

Recent	O
findings	O
in	O
a	O
bipolar	B-Disease
patient	O
receiving	O
maintenance	O
lithium	B-Chemical
therapy	O
who	O
developed	O
hypercalcemia	B-Disease
and	O
severe	O
bradyarrhythmia	B-Disease
prompted	O
the	O
authors	O
to	O
conduct	O
a	O
retrospective	O
study	O
of	O
bipolar	B-Disease
patients	O
with	O
lithium	B-Chemical
-	O
associated	O
hypercalcemia	B-Disease
.	O

A	O
printout	O
of	O
all	O
cases	O
of	O
hypercalcemia	B-Disease
that	O
presented	O
during	O
a	O
1	O
-	O
year	O
period	O
was	O
generated	O
.	O

After	O
eliminating	O
spurious	O
hypercalcemias	B-Disease
or	O
those	O
associated	O
with	O
intravenous	O
fluids	O
,	O
the	O
authors	O
identified	O
18	O
non	O
-	O
lithium	B-Chemical
-	O
treated	O
patients	O
with	O
hypercalcemias	B-Disease
related	O
to	O
malignancies	B-Disease
and	O
other	O
medical	O
conditions	O
(	O
group	O
A	O
)	O
and	O
12	O
patients	O
with	O
lithium	B-Chemical
-	O
associated	O
hypercalcemia	B-Disease
(	O
group	O
B	O
)	O
.	O

Patients	O
in	O
group	O
B	O
were	O
not	O
comparable	O
to	O
those	O
in	O
group	O
A	O
,	O
as	O
the	O
latter	O
were	O
medically	O
compromised	O
and	O
were	O
receiving	O
multiple	O
pharmacotherapies	O
.	O

Thus	O
,	O
two	O
control	O
groups	O
were	O
generated	O
:	O
group	O
C1	O
,	O
which	O
included	O
age	O
-	O
and	O
sex	O
-	O
comparable	O
lithium	B-Chemical
-	O
treated	O
bipolar	B-Disease
normocalcemic	O
patients	O
,	O
and	O
group	O
C2	O
,	O
which	O
included	O
bipolar	B-Disease
normocalcemic	O
patients	O
treated	O
with	O
anticonvulsant	O
mood	O
stabilizers	O
.	O

The	O
electrocardiographic	O
(	O
ECG	O
)	O
findings	O
for	O
patients	O
in	O
group	O
B	O
were	O
compared	O
with	O
those	O
of	O
patients	O
in	O
groups	O
C1	O
and	O
C2	O
.	O

It	O
was	O
found	O
that	O
these	O
groups	O
did	O
not	O
differ	O
in	O
their	O
overall	O
frequency	O
of	O
ECG	O
abnormalities	O
;	O
however	O
,	O
there	O
were	O
significant	O
differences	O
in	O
the	O
frequency	O
of	O
conduction	O
defects	O
.	O

Patients	O
with	O
hypercalcemia	B-Disease
resulting	O
from	O
medical	O
diseases	O
and	O
bipolar	B-Disease
patients	O
with	O
lithium	B-Chemical
-	O
associated	O
hypercalcemia	B-Disease
had	O
significantly	O
higher	O
frequencies	O
of	O
conduction	O
defects	O
.	O

Patients	O
in	O
group	O
A	O
had	O
significant	O
mortality	O
at	O
2	O
-	O
year	O
follow	O
-	O
up	O
(	O
28	O
%	O
)	O
,	O
in	O
contrast	O
to	O
zero	O
mortality	O
in	O
the	O
other	O
three	O
groups	O
.	O

The	O
clinical	O
implications	O
of	O
these	O
findings	O
are	O
discussed	O
.	O

Attenuation	O
of	O
nephrotoxicity	B-Disease
by	O
a	O
novel	O
lipid	O
nanosphere	O
(	O
NS	O
-	O
718	O
)	O
incorporating	O
amphotericin	B-Chemical
B	I-Chemical
.	O

NS	O
-	O
718	O
,	O
a	O
lipid	O
nanosphere	O
incorporating	O
amphotericin	B-Chemical
B	I-Chemical
,	O
is	O
effective	O
against	O
pathogenic	O
fungi	O
and	O
has	O
low	O
toxicity	B-Disease
.	O

We	O
compared	O
the	O
toxicity	B-Disease
of	O
NS	O
-	O
718	O
with	O
that	O
of	O
Fungizone	B-Chemical
(	O
amphotericin	B-Chemical
B	I-Chemical
-	I-Chemical
sodium	I-Chemical
deoxycholate	I-Chemical
;	O
D	B-Chemical
-	I-Chemical
AmB	I-Chemical
)	O
in	O
vitro	O
using	O
renal	O
cell	O
cultures	O
and	O
in	O
vivo	O
by	O
biochemical	O
analysis	O
,	O
histopathological	O
study	O
of	O
the	O
kidney	O
and	O
pharmacokinetic	O
study	O
of	O
amphotericin	B-Chemical
B	I-Chemical
following	O
intravenous	O
infusion	O
of	O
the	O
formulation	O
in	O
rats	O
.	O

Incubation	O
with	O
NS	O
-	O
718	O
resulted	O
in	O
significantly	O
less	O
damage	O
of	O
cultured	O
human	O
renal	O
proximal	O
tubular	O
epithelial	O
cells	O
compared	O
with	O
D	B-Chemical
-	I-Chemical
AmB	I-Chemical
.	O

Serum	O
blood	O
urea	B-Chemical
and	O
creatinine	B-Chemical
concentrations	O
increased	O
significantly	O
in	O
rats	O
given	O
an	O
iv	O
infusion	O
of	O
D	B-Chemical
-	I-Chemical
AmB	I-Chemical
3	O
mg	O
/	O
kg	O
but	O
not	O
in	O
those	O
given	O
the	O
same	O
dose	O
of	O
NS	O
-	O
718	O
.	O

Histopathological	O
examination	O
of	O
the	O
kidney	O
showed	O
tubular	B-Disease
necrosis	I-Disease
in	O
D	B-Chemical
-	I-Chemical
AmB	I-Chemical
-	O
treated	O
rats	O
but	O
no	O
change	O
in	O
NS	O
-	O
718	O
-	O
treated	O
rats	O
.	O

Amphotericin	B-Chemical
B	I-Chemical
concentrations	O
in	O
the	O
kidney	O
in	O
NS	O
-	O
718	O
-	O
treated	O
rats	O
were	O
higher	O
than	O
those	O
in	O
D	B-Chemical
-	I-Chemical
AmB	I-Chemical
-	O
treated	O
rats	O
.	O

Our	O
in	O
vitro	O
and	O
in	O
vivo	O
results	O
suggest	O
that	O
incorporation	O
of	O
amphotericin	B-Chemical
B	I-Chemical
into	O
lipid	O
nanospheres	O
of	O
NS	O
-	O
718	O
attenuates	O
the	O
nephrotoxicity	B-Disease
of	O
amphotericin	B-Chemical
B	I-Chemical
.	O

Patterns	O
of	O
sulfadiazine	B-Chemical
acute	B-Disease
nephrotoxicity	I-Disease
.	O

Sulfadiazine	B-Chemical
acute	B-Disease
nephrotoxicity	I-Disease
is	O
reviving	O
specially	O
because	O
of	O
its	O
use	O
in	O
toxoplasmosis	B-Disease
in	O
HIV	O
-	O
positive	O
patients	O
.	O

We	O
report	O
4	O
cases	O
,	O
one	O
of	O
them	O
in	O
a	O
previously	O
healthy	O
person	O
.	O

Under	O
treatment	O
with	O
sulfadiazine	B-Chemical
they	O
developed	O
oliguria	B-Disease
,	O
abdominal	B-Disease
pain	I-Disease
,	O
renal	B-Disease
failure	I-Disease
and	O
showed	O
multiple	O
radiolucent	O
renal	B-Disease
calculi	I-Disease
in	O
echography	O
.	O

All	O
patients	O
recovered	O
their	O
previous	O
normal	O
renal	O
function	O
after	O
adequate	O
hydration	O
and	O
alcalinization	O
.	O

A	O
nephrostomy	O
tube	O
had	O
to	O
be	O
placed	O
in	O
one	O
of	O
the	O
patients	O
for	O
ureteral	B-Disease
lithiasis	I-Disease
in	O
a	O
single	O
functional	O
kidney	O
.	O

None	O
of	O
them	O
needed	O
dialysis	O
or	O
a	O
renal	O
biopsy	O
because	O
of	O
a	O
typical	O
benign	O
course	O
.	O

Treatment	O
with	O
sulfadiazine	B-Chemical
requires	O
exquisite	O
control	O
of	O
renal	O
function	O
,	O
an	O
increase	O
in	O
water	O
ingestion	O
and	O
possibly	O
the	O
alcalinization	O
of	O
the	O
urine	O
.	O

We	O
communicate	O
a	O
case	O
in	O
a	O
previously	O
healthy	O
person	O
,	O
a	O
fact	O
not	O
found	O
in	O
the	O
recent	O
literature	O
.	O

Probably	O
many	O
more	O
cases	O
are	O
not	O
detected	O
.	O

We	O
think	O
that	O
a	O
prospective	O
study	O
would	O
be	O
useful	O
.	O

Downbeat	B-Disease
nystagmus	I-Disease
associated	O
with	O
intravenous	O
patient	O
-	O
controlled	O
administration	O
of	O
morphine	B-Chemical
.	O

IMPLICATIONS	O
:	O
This	O
case	O
documents	O
a	O
patient	O
who	O
developed	O
dizziness	B-Disease
with	O
downbeating	B-Disease
nystagmus	I-Disease
while	O
receiving	O
a	O
relatively	O
large	O
dose	O
of	O
IV	O
patient	O
-	O
controlled	O
analgesia	O
morphine	B-Chemical
.	O

Although	O
there	O
have	O
been	O
case	O
reports	O
of	O
epidural	O
morphine	B-Chemical
with	O
these	O
symptoms	O
and	O
signs	O
,	O
this	O
has	O
not	O
been	O
previously	O
documented	O
with	O
IV	O
or	O
patient	O
-	O
controlled	O
analgesia	O
morphine	B-Chemical
.	O

Hemodynamic	O
and	O
antiadrenergic	O
effects	O
of	O
dronedarone	B-Chemical
and	O
amiodarone	B-Chemical
in	O
animals	O
with	O
a	O
healed	O
myocardial	B-Disease
infarction	I-Disease
.	O

The	O
hemodynamic	O
and	O
antiadrenergic	O
effects	O
of	O
dronedarone	B-Chemical
,	O
a	O
noniodinated	O
compound	O
structurally	O
related	O
to	O
amiodarone	B-Chemical
,	O
were	O
compared	O
with	O
those	O
of	O
amiodarone	B-Chemical
after	O
prolonged	O
oral	O
administration	O
,	O
both	O
at	O
rest	O
and	O
during	O
sympathetic	O
stimulation	O
in	O
conscious	O
dogs	O
with	O
a	O
healed	O
myocardial	B-Disease
infarction	I-Disease
.	O

All	O
dogs	O
(	O
n	O
=	O
6	O
)	O
randomly	O
received	O
orally	O
dronedarone	B-Chemical
(	O
10	O
and	O
30	O
mg	O
/	O
kg	O
)	O
,	O
amiodarone	B-Chemical
(	O
10	O
and	O
30	O
mg	O
/	O
kg	O
)	O
,	O
and	O
placebo	O
twice	O
daily	O
for	O
7	O
days	O
,	O
with	O
a	O
3	O
-	O
week	O
washout	O
between	O
consecutive	O
treatments	O
.	O

Heart	O
rate	O
(	O
HR	O
)	O
,	O
mean	O
arterial	O
pressure	O
(	O
MBP	O
)	O
,	O
positive	O
rate	O
of	O
increase	O
of	O
left	O
ventricular	O
pressure	O
(	O
+	O
LVdP	O
/	O
dt	O
)	O
,	O
echocardiographically	O
assessed	O
left	O
ventricular	O
ejection	O
fraction	O
(	O
LVEF	O
)	O
,	O
and	O
fractional	O
shortening	O
(	O
FS	O
)	O
,	O
as	O
well	O
as	O
chronotropic	O
response	O
to	O
isoproterenol	B-Chemical
and	O
exercise	O
-	O
induced	O
sympathetic	O
stimulation	O
were	O
evaluated	O
under	O
baseline	O
and	O
posttreatment	O
conditions	O
.	O

Resting	O
values	O
of	O
LVEF	O
,	O
FS	O
,	O
+	O
LVdP	O
/	O
dt	O
,	O
and	O
MBP	O
remained	O
unchanged	O
whatever	O
the	O
drug	O
and	O
the	O
dosing	O
regimen	O
,	O
whereas	O
resting	O
HR	O
was	O
significantly	O
and	O
dose	O
-	O
dependently	O
lowered	O
after	O
dronedarone	B-Chemical
and	O
to	O
a	O
lesser	O
extent	O
after	O
amiodarone	B-Chemical
.	O

Both	O
dronedarone	B-Chemical
and	O
amiodarone	B-Chemical
significantly	O
reduced	O
the	O
exercise	O
-	O
induced	O
tachycardia	B-Disease
and	O
,	O
at	O
the	O
highest	O
dose	O
,	O
decreased	O
the	O
isoproterenol	B-Chemical
-	O
induced	O
tachycardia	B-Disease
.	O

Thus	O
,	O
dronedarone	B-Chemical
and	O
amiodarone	B-Chemical
displayed	O
a	O
similar	O
level	O
of	O
antiadrenergic	O
effect	O
and	O
did	O
not	O
impair	O
the	O
resting	O
left	O
ventricular	O
function	O
.	O

Consequently	O
,	O
dronedarone	B-Chemical
might	O
be	O
particularly	O
suitable	O
for	O
the	O
treatment	O
and	O
prevention	O
of	O
various	O
clinical	O
arrhythmias	B-Disease
,	O
without	O
compromising	O
the	O
left	O
ventricular	O
function	O
.	O

Phase	O
2	O
trial	O
of	O
liposomal	O
doxorubicin	B-Chemical
(	O
40	O
mg	O
/	O
m	O
(	O
2	O
)	O
)	O
in	O
platinum	B-Chemical
/	O
paclitaxel	B-Chemical
-	O
refractory	O
ovarian	B-Disease
and	I-Disease
fallopian	I-Disease
tube	I-Disease
cancers	I-Disease
and	O
primary	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
peritoneum	I-Disease
.	O

BACKGROUND	O
:	O
Several	O
studies	O
have	O
demonstrated	O
liposomal	O
doxorubicin	B-Chemical
(	O
Doxil	B-Chemical
)	O
to	O
be	O
an	O
active	O
antineoplastic	O
agent	O
in	O
platinum	B-Chemical
-	O
resistant	O
ovarian	B-Disease
cancer	I-Disease
,	O
with	O
dose	O
limiting	O
toxicity	B-Disease
of	O
the	O
standard	O
dosing	O
regimen	O
(	O
50	O
mg	O
/	O
m	O
(	O
2	O
)	O
q	O
4	O
weeks	O
)	O
being	O
severe	O
erythrodysesthesia	B-Disease
(	O
"	O
hand	B-Disease
-	I-Disease
foot	I-Disease
syndrome	I-Disease
"	O
)	O
and	O
stomatitis	B-Disease
.	O

We	O
wished	O
to	O
develop	O
a	O
more	O
tolerable	O
liposomal	O
doxorubicin	B-Chemical
treatment	O
regimen	O
and	O
document	O
its	O
level	O
of	O
activity	O
in	O
a	O
well	O
-	O
defined	O
patient	O
population	O
with	O
platinum	B-Chemical
/	O
paclitaxel	B-Chemical
-	O
refractory	O
disease	O
.	O

METHODS	O
AND	O
MATERIALS	O
:	O
Patients	O
with	O
ovarian	B-Disease
or	I-Disease
fallopian	I-Disease
tube	I-Disease
cancers	I-Disease
or	O
primary	O
peritoneal	B-Disease
carcinoma	I-Disease
with	O
platinum	B-Chemical
/	O
paclitaxel	B-Chemical
-	O
refractory	O
disease	O
(	O
stable	O
or	O
progressive	O
disease	O
following	O
treatment	O
with	O
these	O
agents	O
or	O
previous	O
objective	O
response	O
<	O
3	O
months	O
in	O
duration	O
)	O
were	O
treated	O
with	O
liposomal	O
doxorubicin	B-Chemical
at	O
a	O
dose	O
of	O
40	O
mg	O
/	O
m	O
(	O
2	O
)	O
q	O
4	O
weeks	O
.	O

RESULTS	O
:	O
A	O
total	O
of	O
49	O
patients	O
(	O
median	O
age	O
:	O
60	O
;	O
range	O
41	O
-	O
81	O
)	O
entered	O
this	O
phase	O
2	O
trial	O
.	O

The	O
median	O
number	O
of	O
prior	O
regimens	O
was	O
2	O
(	O
range	O
:	O
1	O
-	O
6	O
)	O
.	O

Six	O
(	O
12	O
%	O
)	O
and	O
4	O
(	O
8	O
%	O
)	O
patients	O
experienced	O
grade	O
2	O
hand	B-Disease
-	I-Disease
foot	I-Disease
syndrome	I-Disease
and	O
stomatitis	B-Disease
,	O
respectively	O
(	O
no	O
episodes	O
of	O
grade	O
3	O
)	O
.	O

One	O
patient	O
developed	O
grade	O
3	O
diarrhea	B-Disease
requiring	O
hospitalization	O
for	O
hydration	O
.	O

Six	O
(	O
12	O
%	O
)	O
individuals	O
required	O
dose	O
reductions	O
.	O

The	O
median	O
number	O
of	O
courses	O
of	O
liposomal	O
doxorubicin	B-Chemical
administered	O
on	O
this	O
protocol	O
was	O
2	O
(	O
range	O
:	O
1	O
-	O
12	O
)	O
.	O

Four	O
of	O
44	O
patients	O
(	O
9	O
%	O
)	O
evaluable	O
for	O
response	O
exhibited	O
objective	O
and	O
subjective	O
evidence	O
of	O
an	O
antineoplastic	O
effect	O
of	O
therapy	O
.	O

CONCLUSION	O
:	O
This	O
modified	O
liposomal	O
doxorubicin	B-Chemical
regimen	O
results	O
in	O
less	O
toxicity	B-Disease
(	O
stomatitis	B-Disease
,	O
hand	B-Disease
-	I-Disease
foot	I-Disease
syndrome	I-Disease
)	O
than	O
the	O
standard	O
FDA	O
-	O
approved	O
dose	O
schedule	O
.	O

Definite	O
,	O
although	O
limited	O
,	O
antineoplastic	O
activity	O
is	O
observed	O
in	O
patients	O
with	O
well	O
-	O
defined	O
platinum	B-Chemical
-	O
and	O
paclitaxel	B-Chemical
-	O
refractory	O
ovarian	B-Disease
cancer	I-Disease
.	O

Efficacy	O
of	O
olanzapine	B-Chemical
in	O
acute	O
bipolar	B-Disease
mania	I-Disease
:	O
a	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
study	O
.	O

The	O
Olanzipine	B-Chemical
HGGW	O
Study	O
Group	O
.	O

BACKGROUND	O
:	O
We	O
compared	O
the	O
efficacy	O
and	O
safety	O
of	O
olanzapine	B-Chemical
vs	O
placebo	O
for	O
the	O
treatment	O
of	O
acute	O
bipolar	B-Disease
mania	I-Disease
.	O

METHODS	O
:	O
Four	O
-	O
week	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
parallel	O
study	O
.	O

A	O
total	O
of	O
115	O
patients	O
with	O
a	O
DSM	O
-	O
IV	O
diagnosis	O
of	O
bipolar	B-Disease
disorder	I-Disease
,	O
manic	B-Disease
or	O
mixed	O
,	O
were	O
randomized	O
to	O
olanzapine	B-Chemical
,	O
5	O
to	O
20	O
mg	O
/	O
d	O
(	O
n	O
=	O
55	O
)	O
,	O
or	O
placebo	O
(	O
n	O
=	O
60	O
)	O
.	O

The	O
primary	O
efficacy	O
measure	O
was	O
the	O
Young	O
-	O
Mania	B-Disease
Rating	O
Scale	O
(	O
Y	O
-	O
MRS	O
)	O
total	O
score	O
.	O

Response	O
and	O
euthymia	O
were	O
defined	O
,	O
a	O
priori	O
,	O
as	O
at	O
least	O
a	O
50	O
%	O
improvement	O
from	O
baseline	O
to	O
end	O
point	O
and	O
as	O
a	O
score	O
of	O
no	O
less	O
than	O
12	O
at	O
end	O
point	O
in	O
the	O
Y	O
-	O
MRS	O
total	O
score	O
,	O
respectively	O
.	O

Safety	O
was	O
assessed	O
using	O
adverse	O
events	O
,	O
Extrapyramidal	B-Disease
Symptom	I-Disease
(	O
EPS	B-Disease
)	O
rating	O
scales	O
,	O
laboratory	O
values	O
,	O
electrocardiograms	O
,	O
vital	O
signs	O
,	O
and	O
weight	O
change	O
.	O

RESULTS	O
:	O
Olanzapine	B-Chemical
-	O
treated	O
patients	O
demonstrated	O
a	O
statistically	O
significant	O
greater	O
mean	O
(	O
+	O
/	O
-	O
SD	O
)	O
improvement	O
in	O
Y	O
-	O
MRS	O
total	O
score	O
than	O
placebo	O
-	O
treated	O
patients	O
(	O
-	O
14	O
.	O
8	O
+	O
/	O
-	O
12	O
.	O
5	O
and	O
-	O
8	O
.	O
1	O
+	O
/	O
-	O
12	O
.	O
7	O
,	O
respectively	O
;	O
P	O
<	O
.	O
001	O
)	O
,	O
which	O
was	O
evident	O
at	O
the	O
first	O
postbaseline	O
observation	O
1	O
week	O
after	O
randomization	O
and	O
was	O
maintained	O
throughout	O
the	O
study	O
(	O
last	O
observation	O
carried	O
forward	O
)	O
.	O

Olanzapine	B-Chemical
-	O
treated	O
patients	O
demonstrated	O
a	O
higher	O
rate	O
of	O
response	O
(	O
65	O
%	O
vs	O
43	O
%	O
,	O
respectively	O
;	O
P	O
=	O
.	O
02	O
)	O
and	O
euthymia	O
(	O
61	O
%	O
vs	O
36	O
%	O
,	O
respectively	O
;	O
P	O
=	O
.	O
01	O
)	O
than	O
placebo	O
-	O
treated	O
patients	O
.	O

There	O
were	O
no	O
statistically	O
significant	O
differences	O
in	O
EPSs	B-Disease
between	O
groups	O
.	O

However	O
,	O
olanzapine	B-Chemical
-	O
treated	O
patients	O
had	O
a	O
statistically	O
significant	O
greater	O
mean	O
(	O
+	O
/	O
-	O
SD	O
)	O
weight	B-Disease
gain	I-Disease
than	O
placebo	O
-	O
treated	O
patients	O
(	O
2	O
.	O
1	O
+	O
/	O
-	O
2	O
.	O
8	O
vs	O
0	O
.	O
45	O
+	O
/	O
-	O
2	O
.	O
3	O
kg	O
,	O
respectively	O
)	O
and	O
also	O
experienced	O
more	O
treatment	O
-	O
emergent	O
somnolence	B-Disease
(	O
21	O
patients	O
[	O
38	O
.	O
2	O
%	O
]	O
vs	O
5	O
[	O
8	O
.	O
3	O
%	O
]	O
,	O
respectively	O
)	O
.	O

CONCLUSION	O
:	O
Olanzapine	B-Chemical
demonstrated	O
greater	O
efficacy	O
than	O
placebo	O
in	O
the	O
treatment	O
of	O
acute	O
bipolar	B-Disease
mania	I-Disease
and	O
was	O
generally	O
well	O
tolerated	O
.	O

The	O
effect	O
of	O
pupil	B-Disease
dilation	I-Disease
with	O
tropicamide	B-Chemical
on	O
vision	O
and	O
driving	O
simulator	O
performance	O
.	O

PURPOSE	O
:	O
To	O
assess	O
the	O
effect	O
of	O
pupil	B-Disease
dilation	I-Disease
on	O
vision	O
and	O
driving	O
ability	O
.	O

METHODS	O
:	O
A	O
series	O
of	O
tests	O
on	O
various	O
parameters	O
of	O
visual	O
function	O
and	O
driving	O
simulator	O
performance	O
were	O
performed	O
on	O
12	O
healthy	O
drivers	O
,	O
before	O
and	O
after	O
pupil	B-Disease
dilation	I-Disease
using	O
guttae	O
tropicamide	B-Chemical
1	O
%	O
.	O

A	O
driving	O
simulator	O
(	O
Transport	O
Research	O
Laboratory	O
)	O
was	O
used	O
to	O
measure	O
reaction	O
time	O
(	O
RT	O
)	O
,	O
speed	O
maintenance	O
and	O
steering	O
accuracy	O
.	O

Tests	O
of	O
basic	O
visual	O
function	O
included	O
high	O
-	O
and	O
low	O
-	O
contrast	O
visual	O
acuity	O
(	O
HCVA	O
and	O
LCVA	O
)	O
,	O
Pelli	O
-	O
Robson	O
contrast	O
threshold	O
(	O
CT	O
)	O
and	O
Goldmann	O
perimetry	O
(	O
FIELDS	O
)	O
.	O

Useful	O
Field	O
of	O
View	O
(	O
UFOV	O
-	O
-	O
a	O
test	O
of	O
visual	O
attention	O
)	O
was	O
also	O
undertaken	O
.	O

The	O
mean	O
differences	O
in	O
the	O
pre	O
-	O
and	O
post	O
-	O
dilatation	O
measurements	O
were	O
tested	O
for	O
statistical	O
significance	O
at	O
the	O
95	O
%	O
level	O
using	O
one	O
-	O
tail	O
paired	O
t	O
-	O
tests	O
.	O

RESULTS	O
:	O
Pupillary	B-Disease
dilation	I-Disease
resulted	O
in	O
a	O
statistically	O
significant	O
deterioration	O
in	O
CT	O
and	O
HCVA	O
only	O
.	O

Five	O
of	O
12	O
drivers	O
also	O
exhibited	O
deterioration	O
in	O
LCVA	O
,	O
CT	O
and	O
RT	O
.	O

Little	O
evidence	O
emerged	O
for	O
deterioration	O
in	O
FIELDS	O
and	O
UFOV	O
.	O

Also	O
,	O
7	O
of	O
12	O
drivers	O
appeared	O
to	O
adjust	O
their	O
driving	O
behaviour	O
by	O
reducing	O
their	O
speed	O
on	O
the	O
driving	O
simulator	O
,	O
leading	O
to	O
improved	O
steering	O
accuracy	O
.	O

CONCLUSIONS	O
:	O
Pupillary	B-Disease
dilation	I-Disease
may	O
lead	O
to	O
a	O
decrease	O
in	O
vision	O
and	O
daylight	O
driving	O
performance	O
in	O
young	O
people	O
.	O

A	O
larger	O
study	O
,	O
including	O
a	O
broader	O
spectrum	O
of	O
subjects	O
,	O
is	O
warranted	O
before	O
guidelines	O
can	O
be	O
recommended	O
.	O

A	O
case	O
of	O
isotretinoin	B-Disease
embryopathy	I-Disease
with	O
bilateral	O
anotia	B-Disease
and	O
Taussig	B-Disease
-	I-Disease
Bing	I-Disease
malformation	I-Disease
.	O

We	O
report	O
a	O
newborn	O
infant	O
with	O
multiple	O
congenital	O
anomalies	O
(	O
anotia	B-Disease
and	O
Taussig	B-Disease
-	I-Disease
Bing	I-Disease
malformation	I-Disease
)	O
due	O
to	O
exposure	O
to	O
isotretinoin	B-Chemical
within	O
the	O
first	O
trimester	O
.	O

In	O
this	O
paper	O
we	O
aim	O
to	O
draw	O
to	O
the	O
fact	O
that	O
caution	O
is	O
needed	O
when	O
prescribing	O
vitamin	B-Chemical
A	I-Chemical
-	O
containing	O
drugs	O
to	O
women	O
of	O
childbearing	O
years	O
.	O

Effect	O
of	O
methoxamine	B-Chemical
on	O
maximum	O
urethral	O
pressure	O
in	O
women	O
with	O
genuine	O
stress	B-Disease
incontinence	I-Disease
:	O
a	O
placebo	O
-	O
controlled	O
,	O
double	O
-	O
blind	O
crossover	O
study	O
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
evaluate	O
the	O
potential	O
role	O
for	O
a	O
selective	O
alpha1	O
-	O
adrenoceptor	O
agonist	O
in	O
the	O
treatment	O
of	O
urinary	B-Disease
stress	I-Disease
incontinence	I-Disease
.	O

A	O
randomised	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
,	O
crossover	O
study	O
design	O
was	O
employed	O
.	O

Half	O
log	O
incremental	O
doses	O
of	O
intravenous	O
methoxamine	B-Chemical
or	O
placebo	O
(	O
saline	O
)	O
were	O
administered	O
to	O
a	O
group	O
of	O
women	O
with	O
genuine	O
stress	B-Disease
incontinence	I-Disease
while	O
measuring	O
maximum	O
urethral	O
pressure	O
(	O
MUP	O
)	O
,	O
blood	O
pressure	O
,	O
heart	O
rate	O
,	O
and	O
symptomatic	O
side	O
effects	O
.	O

Methoxamine	B-Chemical
evoked	O
non	O
-	O
significant	O
increases	O
in	O
MUP	O
and	O
diastolic	O
blood	O
pressure	O
but	O
caused	O
a	B-Disease
significant	I-Disease
rise	I-Disease
in	I-Disease
systolic	I-Disease
blood	I-Disease
pressure	I-Disease
and	O
significant	O
fall	O
in	O
heart	O
rate	O
at	O
maximum	O
dosage	O
.	O

Systemic	O
side	O
effects	O
including	O
piloerection	O
,	O
headache	B-Disease
,	O
and	O
cold	O
extremities	O
were	O
experienced	O
in	O
all	O
subjects	O
.	O

The	O
results	O
indicate	O
that	O
the	O
clinical	O
usefulness	O
of	O
direct	O
,	O
peripherally	O
acting	O
sub	O
-	O
type	O
-	O
selective	O
alpha1	O
-	O
adrenoceptor	O
agonists	O
in	O
the	O
medical	O
treatment	O
of	O
stress	B-Disease
incontinence	I-Disease
may	O
be	O
limited	O
by	O
associated	O
piloerection	O
and	O
cardiovascular	O
side	O
effects	O
.	O

Hyperglycemic	B-Disease
effect	O
of	O
amino	B-Chemical
compounds	O
structurally	O
related	O
to	O
caproate	B-Chemical
in	O
rats	O
.	O

The	O
chronic	O
feeding	O
of	O
small	O
amounts	O
(	O
0	O
.	O
3	O
-	O
3	O
%	O
of	O
diet	O
weight	O
)	O
of	O
certain	O
amino	B-Chemical
derivatives	O
of	O
caproate	B-Chemical
resulted	O
in	O
hyperglycemia	B-Disease
,	O
an	O
elevated	O
glucose	B-Chemical
tolerance	O
curve	O
and	O
,	O
occasionally	O
,	O
glucosuria	B-Disease
.	O

Effective	O
compounds	O
included	O
norleucine	B-Chemical
,	O
norvaline	B-Chemical
,	O
glutamate	B-Chemical
,	O
epsilon	B-Chemical
-	I-Chemical
aminocaproate	I-Chemical
,	O
methionine	B-Chemical
,	O
and	O
leucine	B-Chemical
.	O

Toleration	O
of	O
high	O
doses	O
of	O
angiotensin	B-Chemical
-	I-Chemical
converting	I-Chemical
enzyme	I-Chemical
inhibitors	I-Chemical
in	O
patients	O
with	O
chronic	O
heart	B-Disease
failure	I-Disease
:	O
results	O
from	O
the	O
ATLAS	O
trial	O
.	O

The	O
Assessment	O
of	O
Treatment	O
with	O
Lisinopril	B-Chemical
and	O
Survival	O
.	O

BACKGROUND	O
:	O
Treatment	O
with	O
angiotensin	B-Chemical
-	I-Chemical
converting	I-Chemical
enzyme	I-Chemical
(	I-Chemical
ACE	I-Chemical
)	I-Chemical
inhibitors	I-Chemical
reduces	O
mortality	O
and	O
morbidity	O
in	O
patients	O
with	O
chronic	O
heart	B-Disease
failure	I-Disease
(	O
CHF	B-Disease
)	O
,	O
but	O
most	O
affected	O
patients	O
are	O
not	O
receiving	O
these	O
agents	O
or	O
are	O
being	O
treated	O
with	O
doses	O
lower	O
than	O
those	O
found	O
to	O
be	O
efficacious	O
in	O
trials	O
,	O
primarily	O
because	O
of	O
concerns	O
about	O
the	O
safety	O
and	O
tolerability	O
of	O
these	O
agents	O
,	O
especially	O
at	O
the	O
recommended	O
doses	O
.	O

The	O
present	O
study	O
examines	O
the	O
safety	O
and	O
tolerability	O
of	O
high	O
-	O
compared	O
with	O
low	O
-	O
dose	O
lisinopril	B-Chemical
in	O
CHF	B-Disease
.	O

METHODS	O
:	O
The	O
Assessment	O
of	O
Lisinopril	B-Chemical
and	O
Survival	O
study	O
was	O
a	O
multicenter	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
trial	O
in	O
which	O
patients	O
with	O
or	O
without	O
previous	O
ACE	B-Chemical
inhibitor	I-Chemical
treatment	O
were	O
stabilized	O
receiving	O
medium	O
-	O
dose	O
lisinopril	B-Chemical
(	O
12	O
.	O
5	O
or	O
15	O
.	O
0	O
mg	O
once	O
daily	O
[	O
OD	O
]	O
)	O
for	O
2	O
to	O
4	O
weeks	O
and	O
then	O
randomized	O
to	O
high	O
-	O
(	O
35	O
.	O
0	O
or	O
32	O
.	O
5	O
mg	O
OD	O
)	O
or	O
low	O
-	O
dose	O
(	O
5	O
.	O
0	O
or	O
2	O
.	O
5	O
mg	O
OD	O
)	O
groups	O
.	O

Patients	O
with	O
New	O
York	O
Heart	O
Association	O
classes	O
II	O
to	O
IV	O
CHF	B-Disease
and	O
left	O
ventricular	O
ejection	O
fractions	O
of	O
no	O
greater	O
than	O
0	O
.	O
30	O
(	O
n	O
=	O
3164	O
)	O
were	O
randomized	O
and	O
followed	O
up	O
for	O
a	O
median	O
of	O
46	O
months	O
.	O

We	O
examined	O
the	O
occurrence	O
of	O
adverse	O
events	O
and	O
the	O
need	O
for	O
discontinuation	O
and	O
dose	O
reduction	O
during	O
treatment	O
,	O
with	O
a	O
focus	O
on	O
hypotension	B-Disease
and	O
renal	B-Disease
dysfunction	I-Disease
.	O

RESULTS	O
:	O
Of	O
405	O
patients	O
not	O
previously	O
receiving	O
an	O
ACE	B-Chemical
inhibitor	I-Chemical
,	O
doses	O
in	O
only	O
4	O
.	O
2	O
%	O
could	O
not	O
be	O
titrated	O
to	O
the	O
medium	O
doses	O
required	O
for	O
randomization	O
because	O
of	O
symptoms	O
possibly	O
related	O
to	O
hypotension	B-Disease
(	O
2	O
.	O
0	O
%	O
)	O
or	O
because	O
of	O
renal	B-Disease
dysfunction	I-Disease
or	O
hyperkalemia	B-Disease
(	O
2	O
.	O
3	O
%	O
)	O
.	O

Doses	O
in	O
more	O
than	O
90	O
%	O
of	O
randomized	O
patients	O
in	O
the	O
high	O
-	O
and	O
low	O
-	O
dose	O
groups	O
were	O
titrated	O
to	O
their	O
assigned	O
target	O
,	O
and	O
the	O
mean	O
doses	O
of	O
blinded	O
medication	O
in	O
both	O
groups	O
remained	O
similar	O
throughout	O
the	O
study	O
.	O

Withdrawals	O
occurred	O
in	O
27	O
.	O
1	O
%	O
of	O
the	O
high	O
-	O
and	O
30	O
.	O
7	O
%	O
of	O
the	O
low	O
-	O
dose	O
groups	O
.	O

Subgroups	O
presumed	O
to	O
be	O
at	O
higher	O
risk	O
for	O
ACE	B-Chemical
inhibitor	I-Chemical
intolerance	O
(	O
blood	O
pressure	O
,	O
<	O
120	O
mm	O
Hg	O
;	O
creatinine	B-Chemical
,	O
>	O
or	O
=	O
132	O
.	O
6	O
micromol	O
/	O
L	O
[	O
>	O
or	O
=	O
1	O
.	O
5	O
mg	O
/	O
dL	O
]	O
;	O
age	O
,	O
>	O
or	O
=	O
70	O
years	O
;	O
and	O
patients	O
with	O
diabetes	B-Disease
)	O
generally	O
tolerated	O
the	O
high	O
-	O
dose	O
strategy	O
.	O

CONCLUSIONS	O
:	O
These	O
findings	O
demonstrate	O
that	O
ACE	B-Chemical
inhibitor	I-Chemical
therapy	O
in	O
most	O
patients	O
with	O
CHF	B-Disease
can	O
be	O
successfully	O
titrated	O
to	O
and	O
maintained	O
at	O
high	O
doses	O
,	O
and	O
that	O
more	O
aggressive	O
use	O
of	O
these	O
agents	O
is	O
warranted	O
.	O

Cocaine	B-Chemical
,	O
ethanol	B-Chemical
,	O
and	O
cocaethylene	B-Chemical
cardiotoxity	B-Disease
in	O
an	O
animal	O
model	O
of	O
cocaine	B-Disease
and	I-Disease
ethanol	I-Disease
abuse	I-Disease
.	O

OBJECTIVES	O
:	O
Simultaneous	O
abuse	B-Disease
of	I-Disease
cocaine	I-Disease
and	I-Disease
ethanol	I-Disease
affects	O
12	O
million	O
Americans	O
annually	O
.	O

In	O
combination	O
,	O
these	O
substances	O
are	O
substantially	O
more	O
toxic	O
than	O
either	O
drug	O
alone	O
.	O

Their	O
combined	O
cardiac	B-Disease
toxicity	I-Disease
may	O
be	O
due	O
to	O
independent	O
effects	O
of	O
each	O
drug	O
;	O
however	O
,	O
they	O
may	O
also	O
be	O
due	O
to	O
cocaethylene	B-Chemical
(	O
CE	B-Chemical
)	O
,	O
a	O
cocaine	B-Chemical
metabolite	O
formed	O
only	O
in	O
the	O
presence	O
of	O
ethanol	B-Chemical
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
delineate	O
the	O
role	O
of	O
CE	B-Chemical
in	O
the	O
combined	O
cardiotoxicity	B-Disease
of	O
cocaine	B-Chemical
and	O
ethanol	B-Chemical
in	O
a	O
model	O
simulating	O
their	O
abuse	O
.	O

METHODS	O
:	O
Twenty	O
-	O
three	O
dogs	O
were	O
randomized	O
to	O
receive	O
either	O
1	O
)	O
three	O
intravenous	O
(	O
IV	O
)	O
boluses	O
of	O
cocaine	B-Chemical
7	O
.	O
5	O
mg	O
/	O
kg	O
with	O
ethanol	B-Chemical
(	O
1	O
g	O
/	O
kg	O
)	O
as	O
an	O
IV	O
infusion	O
(	O
C	O
+	O
E	O
,	O
n	O
=	O
8	O
)	O
,	O
2	O
)	O
three	O
cocaine	B-Chemical
boluses	O
only	O
(	O
C	O
,	O
n	O
=	O
6	O
)	O
,	O
3	O
)	O
ethanol	B-Chemical
infusion	O
only	O
(	O
E	O
,	O
n	O
=	O
5	O
)	O
,	O
or	O
4	O
)	O
placebo	O
boluses	O
and	O
infusion	O
(	O
n	O
=	O
4	O
)	O
.	O

Hemodynamic	O
measurements	O
,	O
electrocardiograms	O
,	O
and	O
serum	O
drug	O
concentrations	O
were	O
obtained	O
at	O
baseline	O
,	O
and	O
then	O
at	O
fixed	O
time	O
intervals	O
after	O
each	O
drug	O
was	O
administered	O
.	O

RESULTS	O
:	O
Two	O
of	O
eight	O
dogs	O
in	O
the	O
C	O
+	O
E	O
group	O
experienced	O
cardiovascular	B-Disease
collapse	I-Disease
.	O

The	O
most	O
dramatic	O
hemodynamic	O
changes	O
occurred	O
after	O
each	O
cocaine	B-Chemical
bolus	O
in	O
the	O
C	O
+	O
E	O
and	O
C	O
only	O
groups	O
;	O
however	O
,	O
persistent	O
hemodynamic	O
changes	O
occurred	O
in	O
the	O
C	O
+	O
E	O
group	O
.	O

Peak	O
CE	B-Chemical
levels	O
were	O
associated	O
with	O
a	O
45	O
%	O
(	O
SD	O
+	O
/	O
-	O
22	O
%	O
,	O
95	O
%	O
CI	O
=	O
22	O
%	O
to	O
69	O
%	O
)	O
decrease	B-Disease
in	I-Disease
cardiac	I-Disease
output	I-Disease
(	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
a	O
56	O
%	O
(	O
SD	O
+	O
/	O
-	O
23	O
%	O
,	O
95	O
%	O
CI	O
=	O
32	O
%	O
to	O
80	O
%	O
)	O
decrease	O
in	O
dP	O
/	O
dt	O
(	O
max	O
)	O
(	O
p	O
<	O
.	O
006	O
)	O
,	O
and	O
a	O
23	O
%	O
(	O
SD	O
+	O
/	O
-	O
15	O
%	O
,	O
95	O
%	O
CI	O
=	O
7	O
%	O
to	O
49	O
%	O
)	O
decrease	O
in	O
SVO	O
(	O
2	O
)	O
(	O
p	O
<	O
0	O
.	O
025	O
)	O
.	O

Ventricular	B-Disease
arrhythmias	I-Disease
were	O
primarily	O
observed	O
in	O
the	O
C	O
+	O
E	O
group	O
,	O
in	O
which	O
four	O
of	O
eight	O
dogs	O
experienced	O
ventricular	B-Disease
tachycardia	I-Disease
.	O

CONCLUSIONS	O
:	O
Cocaine	B-Chemical
and	O
ethanol	B-Chemical
in	O
combination	O
were	O
more	O
toxic	O
than	O
either	O
substance	O
alone	O
.	O

Co	O
-	O
administration	O
resulted	O
in	O
prolonged	O
cardiac	B-Disease
toxicity	I-Disease
and	O
was	O
dysrhythmogenic	O
.	O

Peak	O
serum	O
cocaethylene	B-Chemical
concentrations	O
were	O
associated	O
with	O
prolonged	O
myocardial	B-Disease
depression	I-Disease
.	O

Worsening	O
of	O
Parkinsonism	B-Disease
after	O
the	O
use	O
of	O
veralipride	B-Chemical
for	O
treatment	O
of	O
menopause	O
:	O
case	O
report	O
.	O

We	O
describe	O
a	O
female	O
patient	O
with	O
stable	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
who	O
has	O
shown	O
a	O
marked	O
worsening	O
of	O
her	O
motor	O
functions	O
following	O
therapy	O
of	O
menopause	O
related	O
symptoms	O
with	O
veralipride	B-Chemical
,	O
as	O
well	O
as	O
the	O
improvement	O
of	O
her	O
symptoms	O
back	O
to	O
baseline	O
after	O
discontinuation	O
of	O
the	O
drug	O
.	O

We	O
emphasize	O
the	O
anti	O
-	O
dopaminergic	O
effect	O
of	O
veralipride	B-Chemical
.	O

Viracept	B-Chemical
and	O
irregular	B-Disease
heartbeat	I-Disease
warning	O
.	O

A	O
group	O
of	O
doctors	O
in	O
Boston	O
warn	O
that	O
the	O
protease	O
inhibitor	O
Viracept	B-Chemical
may	O
cause	O
an	O
irregular	B-Disease
heart	I-Disease
beat	I-Disease
,	O
known	O
as	O
bradycardia	B-Disease
,	O
in	O
people	O
with	O
HIV	O
.	O

Bradycardia	B-Disease
occurred	O
in	O
a	O
45	O
-	O
year	O
-	O
old	O
male	O
patient	O
who	O
was	O
Viracept	B-Chemical
in	O
combination	O
with	O
other	O
anti	O
-	O
HIV	O
drugs	O
.	O

The	O
symptoms	O
ceased	O
after	O
switching	O
to	O
another	O
drug	O
combination	O
.	O

Frequency	O
of	O
appearance	O
of	O
myeloperoxidase	O
-	O
antineutrophil	O
cytoplasmic	O
antibody	O
(	O
MPO	O
-	O
ANCA	O
)	O
in	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
patients	O
treated	O
with	O
propylthiouracil	B-Chemical
and	O
the	O
relationship	O
between	O
MPO	O
-	O
ANCA	O
and	O
clinical	O
manifestations	O
.	O

OBJECTIVE	O
:	O
Myeloperoxidase	O
antineutrophil	O
cytoplasmic	O
antibody	O
(	O
MPO	O
-	O
ANCA	O
)	O
-	O
positive	O
vasculitis	B-Disease
has	O
been	O
reported	O
in	O
patients	O
with	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
who	O
were	O
treated	O
with	O
propylthiouracil	B-Chemical
(	O
PTU	B-Chemical
)	O
.	O

The	O
appearance	O
of	O
MPO	O
-	O
ANCA	O
in	O
these	O
cases	O
was	O
suspected	O
of	O
being	O
related	O
to	O
PTU	B-Chemical
because	O
the	O
titres	O
of	O
MPO	O
-	O
ANCA	O
decreased	O
when	O
PTU	B-Chemical
was	O
stopped	O
.	O

Nevertheless	O
,	O
there	O
have	O
been	O
no	O
studies	O
on	O
the	O
temporal	O
relationship	O
between	O
the	O
appearance	O
of	O
MPO	O
-	O
ANCA	O
and	O
vasculitis	B-Disease
during	O
PTU	B-Chemical
therapy	O
,	O
or	O
on	O
the	O
incidence	O
of	O
MPO	O
-	O
ANCA	O
in	O
untreated	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
patients	O
.	O

Therefore	O
,	O
we	O
sought	O
to	O
address	O
these	O
parameters	O
in	O
patients	O
with	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
.	O

PATIENTS	O
:	O
We	O
investigated	O
102	O
untreated	O
patients	O
with	O
hyperthyroidism	B-Disease
due	O
to	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
for	O
the	O
presence	O
of	O
MPO	O
-	O
ANCA	O
,	O
and	O
for	O
the	O
development	O
vasculitis	B-Disease
after	O
starting	O
PTU	B-Chemical
therapy	O
.	O

Twenty	O
-	O
nine	O
of	O
them	O
were	O
later	O
excluded	O
because	O
of	O
adverse	O
effects	O
of	O
PTU	B-Chemical
or	O
because	O
the	O
observation	O
period	O
was	O
less	O
than	O
3	O
months	O
.	O

The	O
remaining	O
73	O
patients	O
(	O
55	O
women	O
and	O
18	O
men	O
)	O
,	O
all	O
of	O
whom	O
were	O
examined	O
for	O
more	O
than	O
3	O
months	O
,	O
were	O
adopted	O
as	O
the	O
subjects	O
of	O
the	O
investigation	O
.	O

The	O
median	O
observation	O
period	O
was	O
23	O
.	O
6	O
months	O
(	O
range	O
:	O
3	O
-	O
37	O
months	O
)	O
.	O

MEASUREMENTS	O
:	O
MPO	O
-	O
ANCA	O
was	O
measured	O
at	O
intervals	O
of	O
2	O
-	O
6	O
months	O
.	O

RESULTS	O
:	O
Before	O
treatment	O
,	O
the	O
MPO	O
-	O
ANCA	O
titres	O
of	O
all	O
102	O
untreated	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
patients	O
were	O
within	O
the	O
reference	O
range	O
(	O
below	O
10	O
U	O
/	O
ml	O
)	O
.	O

Three	O
(	O
4	O
.	O
1	O
%	O
)	O
of	O
the	O
73	O
patients	O
were	O
positive	O
for	O
MPO	O
-	O
ANCA	O
at	O
13	O
,	O
16	O
and	O
17	O
months	O
,	O
respectively	O
,	O
after	O
the	O
start	O
of	O
PTU	B-Chemical
therapy	O
.	O

In	O
two	O
of	O
them	O
,	O
the	O
MPO	O
-	O
ANCA	O
titres	O
transiently	O
increased	O
to	O
12	O
.	O
8	O
and	O
15	O
.	O
0	O
U	O
/	O
ml	O
,	O
respectively	O
,	O
despite	O
continued	O
PTU	B-Chemical
therapy	O
,	O
but	O
no	O
vasculitic	B-Disease
disorders	I-Disease
developed	O
.	O

In	O
the	O
third	O
patient	O
,	O
the	O
MPO	O
-	O
ANCA	O
titre	O
increased	O
to	O
204	O
U	O
/	O
ml	O
and	O
she	O
developed	O
a	O
higher	O
fever	B-Disease
,	O
oral	B-Disease
ulcers	I-Disease
and	O
polyarthralgia	B-Disease
,	O
but	O
the	O
symptoms	O
resolved	O
2	O
weeks	O
after	O
stopping	O
PTU	B-Chemical
therapy	O
,	O
and	O
the	O
MPO	O
-	O
ANCA	O
titre	O
decreased	O
to	O
20	O
.	O
7	O
U	O
/	O
ml	O
by	O
4	O
months	O
after	O
discontinuing	O
PTU	B-Chemical
.	O

CONCLUSIONS	O
:	O
PTU	B-Chemical
therapy	O
may	O
be	O
related	O
to	O
the	O
appearance	O
of	O
MPO	O
-	O
ANCA	O
,	O
but	O
MPO	O
-	O
ANCA	O
does	O
not	O
appear	O
to	O
be	O
closely	O
related	O
to	O
vasculitis	B-Disease
.	O

Prevalence	O
of	O
heart	B-Disease
disease	I-Disease
in	O
asymptomatic	O
chronic	O
cocaine	B-Chemical
users	O
.	O

To	O
determine	O
the	O
prevalence	O
of	O
heart	B-Disease
disease	I-Disease
in	O
outpatient	O
young	O
asymptomatic	O
chronic	O
cocaine	B-Chemical
users	O
,	O
35	O
cocaine	B-Chemical
users	O
and	O
32	O
age	O
-	O
matched	O
controls	O
underwent	O
resting	O
and	O
exercise	O
electrocardiography	O
(	O
ECG	O
)	O
and	O
Doppler	O
echocardiography	O
.	O

Findings	O
consistent	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
were	O
detected	O
in	O
12	O
(	O
34	O
%	O
)	O
patients	O
and	O
3	O
(	O
9	O
%	O
)	O
controls	O
(	O
p	O
=	O
0	O
.	O
01	O
)	O
.	O

Decreased	O
left	O
ventricular	O
systolic	O
function	O
was	O
demonstrated	O
in	O
5	O
(	O
14	O
%	O
)	O
patients	O
,	O
but	O
in	O
none	O
of	O
the	O
controls	O
(	O
p	O
=	O
0	O
.	O
055	O
)	O
.	O

Finally	O
,	O
resting	O
and	O
peak	O
exercise	O
abnormal	B-Disease
left	I-Disease
ventricular	I-Disease
filling	I-Disease
was	O
detected	O
in	O
38	O
and	O
35	O
%	O
of	O
patients	O
as	O
compared	O
to	O
19	O
and	O
9	O
%	O
of	O
controls	O
,	O
respectively	O
(	O
p	O
=	O
0	O
.	O
11	O
and	O
0	O
.	O
02	O
,	O
respectively	O
)	O
.	O

We	O
conclude	O
that	O
coronary	B-Disease
artery	I-Disease
or	I-Disease
myocardial	I-Disease
disease	I-Disease
is	O
common	O
(	O
38	O
%	O
)	O
in	O
young	O
asymptomatic	O
chronic	O
cocaine	B-Chemical
users	O
.	O

Therefore	O
,	O
screening	O
ECG	O
and	O
echocardiography	O
may	O
be	O
warranted	O
in	O
these	O
patients	O
.	O

Cardioprotective	O
effects	O
of	O
Picrorrhiza	O
kurroa	O
against	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	O
stress	O
in	O
rats	O
.	O

The	O
cardioprotective	O
effect	O
of	O
the	O
ethanol	B-Chemical
extract	O
of	O
Picrorrhiza	O
kurroa	O
rhizomes	O
and	O
roots	O
(	O
PK	O
)	O
on	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
with	O
respect	O
to	O
lipid	O
metabolism	O
in	O
serum	O
and	O
heart	O
tissue	O
has	O
been	O
investigated	O
.	O

Oral	O
pre	O
-	O
treatment	O
with	O
PK	O
(	O
80	O
mg	O
kg	O
(	O
-	O
1	O
)	O
day	O
(	O
-	O
1	O
)	O
for	O
15	O
days	O
)	O
significantly	O
prevented	O
the	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
and	O
maintained	O
the	O
rats	O
at	O
near	O
normal	O
status	O
.	O

Phase	O
2	O
early	O
afterdepolarization	O
as	O
a	O
trigger	O
of	O
polymorphic	O
ventricular	B-Disease
tachycardia	I-Disease
in	O
acquired	O
long	B-Disease
-	I-Disease
QT	I-Disease
syndrome	I-Disease
:	O
direct	O
evidence	O
from	O
intracellular	O
recordings	O
in	O
the	O
intact	O
left	O
ventricular	O
wall	O
.	O

BACKGROUND	O
:	O
This	O
study	O
examined	O
the	O
role	O
of	O
phase	O
2	O
early	O
afterdepolarization	O
(	O
EAD	O
)	O
in	O
producing	O
a	O
trigger	O
to	O
initiate	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
(	O
TdP	B-Disease
)	O
with	O
QT	B-Disease
prolongation	I-Disease
induced	O
by	O
dl	O
-	O
sotalol	B-Chemical
and	O
azimilide	B-Chemical
.	O

The	O
contribution	O
of	O
transmural	O
dispersion	O
of	O
repolarization	O
(	O
TDR	O
)	O
to	O
transmural	O
propagation	O
of	O
EAD	O
and	O
the	O
maintenance	O
of	O
TdP	B-Disease
was	O
also	O
evaluated	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
Transmembrane	O
action	O
potentials	O
from	O
epicardium	O
,	O
midmyocardium	O
,	O
and	O
endocardium	O
were	O
recorded	O
simultaneously	O
,	O
together	O
with	O
a	O
transmural	O
ECG	O
,	O
in	O
arterially	O
perfused	O
canine	O
and	O
rabbit	O
left	O
ventricular	O
preparations	O
.	O

dl	O
-	O
Sotalol	B-Chemical
preferentially	O
prolonged	O
action	O
potential	O
duration	O
(	O
APD	O
)	O
in	O
M	O
cells	O
dose	O
-	O
dependently	O
(	O
1	O
to	O
100	O
micromol	O
/	O
L	O
)	O
,	O
leading	O
to	O
QT	B-Disease
prolongation	I-Disease
and	O
an	O
increase	O
in	O
TDR	O
.	O

Azimilide	B-Chemical
,	O
however	O
,	O
significantly	O
prolonged	O
APD	O
and	O
QT	O
interval	O
at	O
concentrations	O
from	O
0	O
.	O
1	O
to	O
10	O
micromol	O
/	O
L	O
but	O
shortened	O
them	O
at	O
30	O
micromol	O
/	O
L	O
.	O

Unlike	O
dl	O
-	O
sotalol	B-Chemical
,	O
azimilide	B-Chemical
(	O
>	O
3	O
micromol	O
/	O
L	O
)	O
increased	O
epicardial	O
APD	O
markedly	O
,	O
causing	O
a	O
diminished	O
TDR	O
.	O

Although	O
both	O
dl	O
-	O
sotalol	B-Chemical
and	O
azimilide	B-Chemical
rarely	O
induced	O
EADs	O
in	O
canine	O
left	O
ventricles	O
,	O
they	O
produced	O
frequent	O
EADs	O
in	O
rabbits	O
,	O
in	O
which	O
more	O
pronounced	O
QT	B-Disease
prolongation	I-Disease
was	O
seen	O
.	O

An	O
increase	O
in	O
TDR	O
by	O
dl	O
-	O
sotalol	B-Chemical
facilitated	O
transmural	O
propagation	O
of	O
EADs	O
that	O
initiated	O
multiple	O
episodes	O
of	O
spontaneous	O
TdP	B-Disease
in	O
3	O
of	O
6	O
rabbit	O
left	O
ventricles	O
.	O

Of	O
note	O
,	O
although	O
azimilide	B-Chemical
(	O
3	O
to	O
10	O
micromol	O
/	O
L	O
)	O
increased	O
APD	O
more	O
than	O
dl	O
-	O
sotalol	B-Chemical
,	O
its	O
EADs	O
often	O
failed	O
to	O
propagate	O
transmurally	O
,	O
probably	O
because	O
of	O
a	O
diminished	O
TDR	O
.	O

CONCLUSIONS	O
:	O
This	O
study	O
provides	O
the	O
first	O
direct	O
evidence	O
from	O
intracellular	O
action	O
potential	O
recordings	O
that	O
phase	O
2	O
EAD	O
can	O
be	O
generated	O
from	O
intact	O
ventricular	O
wall	O
and	O
produce	O
a	O
trigger	O
to	O
initiate	O
the	O
onset	O
of	O
TdP	B-Disease
under	O
QT	B-Disease
prolongation	I-Disease
.	O

A	O
pilot	O
study	O
to	O
assess	O
the	O
safety	O
of	O
dobutamine	B-Chemical
stress	O
echocardiography	O
in	O
the	O
emergency	O
department	O
evaluation	O
of	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
.	O

STUDY	O
OBJECTIVE	O
:	O
Chest	B-Disease
pain	I-Disease
in	O
the	O
setting	O
of	O
cocaine	B-Chemical
use	O
poses	O
a	O
diagnostic	O
dilemma	O
.	O

Dobutamine	B-Chemical
stress	O
echocardiography	O
(	O
DSE	O
)	O
is	O
a	O
widely	O
available	O
and	O
sensitive	O
test	O
for	O
evaluating	O
cardiac	O
ischemia	B-Disease
.	O

Because	O
of	O
the	O
theoretical	O
concern	O
regarding	O
administration	O
of	O
dobutamine	B-Chemical
in	O
the	O
setting	O
of	O
cocaine	B-Chemical
use	O
,	O
we	O
conducted	O
a	O
pilot	O
study	O
to	O
assess	O
the	O
safety	O
of	O
DSE	O
in	O
emergency	O
department	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
.	O

METHODS	O
:	O
A	O
prospective	O
case	O
series	O
was	O
conducted	O
in	O
the	O
intensive	O
diagnostic	O
and	O
treatment	O
unit	O
in	O
the	O
ED	O
of	O
an	O
urban	O
tertiary	O
-	O
care	O
teaching	O
hospital	O
.	O

Patients	O
were	O
eligible	O
for	O
DSE	O
if	O
they	O
had	O
used	O
cocaine	B-Chemical
within	O
24	O
hours	O
preceding	O
the	O
onset	O
of	O
chest	B-Disease
pain	I-Disease
and	O
had	O
a	O
normal	O
ECG	O
and	O
tropinin	O
I	O
level	O
.	O

Patients	O
exhibiting	O
signs	O
of	O
continuing	O
cocaine	B-Chemical
toxicity	B-Disease
were	O
excluded	O
from	O
the	O
study	O
.	O

All	O
patients	O
were	O
admitted	O
to	O
the	O
hospital	O
for	O
serial	O
testing	O
after	O
the	O
DSE	O
testing	O
in	O
the	O
intensive	O
diagnostic	O
and	O
treatment	O
unit	O
.	O

RESULTS	O
:	O
Twenty	O
-	O
four	O
patients	O
were	O
enrolled	O
.	O

Two	O
patients	O
had	O
inadequate	O
resting	O
images	O
,	O
one	O
DSE	O
was	O
terminated	O
because	O
of	O
inferior	O
hypokinesis	B-Disease
,	O
another	O
DSE	O
was	O
terminated	O
because	O
of	O
a	O
rate	O
-	O
related	O
atrial	O
conduction	O
deficit	O
,	O
and	O
1	O
patient	O
did	O
not	O
reach	O
the	O
target	O
heart	O
rate	O
.	O

Thus	O
,	O
19	O
patients	O
completed	O
a	O
DSE	O
and	O
reached	O
their	O
target	O
heart	O
rates	O
.	O

None	O
of	O
the	O
patients	O
experienced	O
signs	O
of	O
exaggerated	O
adrenergic	O
response	O
,	O
which	O
was	O
defined	O
as	O
a	O
systolic	O
blood	O
pressure	O
of	O
greater	O
than	O
200	O
mm	O
Hg	O
or	O
the	O
occurrence	O
of	O
tachydysrhythmias	B-Disease
(	O
excluding	O
sinus	B-Disease
tachycardia	I-Disease
)	O
.	O

Further	O
suggesting	O
lack	O
of	O
exaggerated	O
adrenergic	O
response	O
,	O
13	O
(	O
65	O
%	O
)	O
of	O
20	O
patients	O
required	O
supplemental	O
atropine	B-Chemical
to	O
reach	O
their	O
target	O
heart	O
rates	O
.	O

CONCLUSION	O
:	O
No	O
exaggerated	O
adrenergic	O
response	O
was	O
detected	O
when	O
dobutamine	B-Chemical
was	O
administered	O
to	O
patients	O
with	O
cocaine	B-Chemical
-	O
related	O
chest	B-Disease
pain	I-Disease
.	O

Prenatal	O
cocaine	B-Chemical
exposure	O
and	O
cranial	O
sonographic	O
findings	O
in	O
preterm	B-Disease
infants	I-Disease
.	O

PURPOSE	O
:	O
Prenatal	O
cocaine	B-Chemical
exposure	O
has	O
been	O
linked	O
with	O
subependymal	O
hemorrhage	B-Disease
and	O
the	O
formation	O
of	O
cysts	B-Disease
that	O
are	O
detectable	O
on	O
cranial	O
sonography	O
in	O
neonates	O
born	O
at	O
term	O
.	O

We	O
sought	O
to	O
determine	O
if	O
prenatal	O
cocaine	B-Chemical
exposure	O
increases	O
the	O
incidence	O
of	O
subependymal	B-Disease
cysts	I-Disease
in	O
preterm	B-Disease
infants	I-Disease
.	O

METHODS	O
:	O
We	O
retrospectively	O
reviewed	O
the	O
medical	O
records	O
and	O
cranial	O
sonograms	O
obtained	O
during	O
a	O
1	O
-	O
year	O
period	O
on	O
122	O
premature	B-Disease
(	I-Disease
<	I-Disease
36	I-Disease
weeks	I-Disease
of	I-Disease
gestation	I-Disease
)	I-Disease
infants	I-Disease
.	O

Infants	O
were	O
categorized	O
into	O
1	O
of	O
2	O
groups	O
:	O
those	O
exposed	O
to	O
cocaine	B-Chemical
and	O
those	O
not	O
exposed	O
to	O
cocaine	B-Chemical
.	O

Infants	O
were	O
assigned	O
to	O
the	O
cocaine	B-Chemical
-	O
exposed	O
group	O
if	O
there	O
was	O
a	O
maternal	O
history	O
of	O
cocaine	B-Disease
abuse	I-Disease
during	O
pregnancy	O
or	O
if	O
maternal	O
or	O
neonatal	O
urine	O
toxicology	O
results	O
were	O
positive	O
at	O
the	O
time	O
of	O
delivery	O
.	O

RESULTS	O
:	O
Five	O
of	O
the	O
122	O
infants	O
were	O
excluded	O
from	O
the	O
study	O
because	O
of	O
insufficient	O
medical	O
and	O
drug	O
histories	O
.	O

The	O
incidence	O
of	O
subependymal	B-Disease
cysts	I-Disease
in	O
the	O
117	O
remaining	O
infants	O
was	O
14	O
%	O
(	O
16	O
of	O
117	O
)	O
.	O

The	O
incidence	O
of	O
subependymal	B-Disease
cysts	I-Disease
in	O
infants	O
exposed	O
to	O
cocaine	B-Chemical
prenatally	O
was	O
44	O
%	O
(	O
8	O
of	O
18	O
)	O
compared	O
with	O
8	O
%	O
(	O
8	O
of	O
99	O
)	O
in	O
the	O
unexposed	O
group	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

CONCLUSIONS	O
:	O
We	O
found	O
an	O
increased	O
incidence	O
of	O
subependymal	B-Disease
cyst	I-Disease
formation	O
in	O
preterm	B-Disease
infants	I-Disease
who	O
were	O
exposed	O
to	O
cocaine	B-Chemical
prenatally	O
.	O

This	O
result	O
is	O
consistent	O
with	O
results	O
of	O
similar	O
studies	O
in	O
term	O
infants	O
.	O

Thalidomide	B-Chemical
neuropathy	B-Disease
in	O
patients	O
treated	O
for	O
metastatic	O
prostate	B-Disease
cancer	I-Disease
.	O

We	O
prospectively	O
evaluated	O
thalidomide	B-Chemical
-	O
induced	O
neuropathy	B-Disease
using	O
electrodiagnostic	O
studies	O
.	O

Sixty	O
-	O
seven	O
men	O
with	O
metastatic	O
androgen	B-Chemical
-	O
independent	O
prostate	B-Disease
cancer	I-Disease
in	O
an	O
open	O
-	O
label	O
trial	O
of	O
oral	O
thalidomide	B-Chemical
underwent	O
neurologic	O
examinations	O
and	O
nerve	O
conduction	O
studies	O
(	O
NCS	O
)	O
prior	O
to	O
and	O
at	O
3	O
-	O
month	O
intervals	O
during	O
treatment	O
.	O

NCS	O
included	O
recording	O
of	O
sensory	O
nerve	O
action	O
potentials	O
(	O
SNAPs	O
)	O
from	O
median	O
,	O
radial	O
,	O
ulnar	O
,	O
and	O
sural	O
nerves	O
.	O

SNAP	O
amplitudes	O
for	O
each	O
nerve	O
were	O
expressed	O
as	O
the	O
percentage	O
of	O
its	O
baseline	O
,	O
and	O
the	O
mean	O
of	O
the	O
four	O
was	O
termed	O
the	O
SNAP	O
index	O
.	O

A	O
40	O
%	O
decline	O
in	O
the	O
SNAP	O
index	O
was	O
considered	O
clinically	O
significant	O
.	O

Thalidomide	B-Chemical
was	O
discontinued	O
in	O
55	O
patients	O
for	O
lack	O
of	O
therapeutic	O
response	O
.	O

Of	O
67	O
patients	O
initially	O
enrolled	O
,	O
24	O
remained	O
on	O
thalidomide	B-Chemical
for	O
3	O
months	O
,	O
8	O
remained	O
at	O
6	O
months	O
,	O
and	O
3	O
remained	O
at	O
9	O
months	O
.	O

Six	O
patients	O
developed	O
neuropathy	B-Disease
.	O

Clinical	O
symptoms	O
and	O
a	O
decline	O
in	O
the	O
SNAP	O
index	O
occurred	O
concurrently	O
.	O

Older	O
age	O
and	O
cumulative	O
dose	O
were	O
possible	O
contributing	O
factors	O
.	O

Neuropathy	B-Disease
may	O
thus	O
be	O
a	O
common	O
complication	O
of	O
thalidomide	B-Chemical
in	O
older	O
patients	O
.	O

The	O
SNAP	O
index	O
can	O
be	O
used	O
to	O
monitor	O
peripheral	B-Disease
neuropathy	I-Disease
,	O
but	O
not	O
for	O
early	O
detection	O
.	O

Overexpression	O
of	O
copper	B-Chemical
/	O
zinc	B-Chemical
-	O
superoxide	B-Chemical
dismutase	O
protects	O
from	O
kanamycin	B-Chemical
-	O
induced	O
hearing	B-Disease
loss	I-Disease
.	O

The	O
participation	O
of	O
reactive	O
oxygen	B-Chemical
species	O
in	O
aminoglycoside	B-Chemical
-	O
induced	O
ototoxicity	B-Disease
has	O
been	O
deduced	O
from	O
observations	O
that	O
aminoglycoside	B-Chemical
-	O
iron	B-Chemical
complexes	O
catalyze	O
the	O
formation	O
of	O
superoxide	B-Chemical
radicals	O
in	O
vitro	O
and	O
that	O
antioxidants	O
attenuate	O
ototoxicity	B-Disease
in	O
vivo	O
.	O

We	O
therefore	O
hypothesized	O
that	O
overexpression	O
of	O
Cu	B-Chemical
/	O
Zn	B-Chemical
-	O
superoxide	B-Chemical
dismutase	O
(	O
h	O
-	O
SOD1	O
)	O
should	O
protect	O
transgenic	O
mice	O
from	O
ototoxicity	B-Disease
.	O

Immunocytochemistry	O
confirmed	O
expression	O
of	O
h	O
-	O
SOD1	O
in	O
inner	O
ear	O
tissues	O
of	O
transgenic	O
C57BL	O
/	O
6	O
-	O
TgN	O
[	O
SOD1	O
]	O
3Cje	O
mice	O
.	O

Transgenic	O
and	O
nontransgenic	O
littermates	O
received	O
kanamycin	B-Chemical
(	O
400	O
mg	O
/	O
kg	O
body	O
weight	O
/	O
day	O
)	O
for	O
10	O
days	O
beginning	O
on	O
day	O
10	O
after	O
birth	O
.	O

Auditory	O
thresholds	O
were	O
tested	O
by	O
evoked	O
auditory	O
brain	O
stem	O
responses	O
at	O
1	O
month	O
after	O
birth	O
.	O

In	O
nontransgenic	O
animals	O
,	O
the	O
threshold	O
in	O
the	O
kanamycin	B-Chemical
-	O
treated	O
group	O
was	O
45	O
-	O
50	O
dB	O
higher	O
than	O
in	O
saline	O
-	O
injected	O
controls	O
.	O

In	O
the	O
transgenic	O
group	O
,	O
kanamycin	B-Chemical
increased	O
the	O
threshold	O
by	O
only	O
15	O
dB	O
over	O
the	O
respective	O
controls	O
.	O

The	O
effects	O
were	O
similar	O
at	O
12	O
and	O
24	O
kHz	O
.	O

The	O
protection	O
by	O
overexpression	O
of	O
superoxide	B-Chemical
dismutase	O
supports	O
the	O
hypothesis	O
that	O
oxidant	O
stress	O
plays	O
a	O
significant	O
role	O
in	O
aminoglycoside	B-Chemical
-	O
induced	O
ototoxicity	B-Disease
.	O

The	O
results	O
also	O
suggest	O
transgenic	O
animals	O
as	O
suitable	O
models	O
to	O
investigate	O
the	O
underlying	O
mechanisms	O
and	O
possible	O
strategies	O
for	O
prevention	O
.	O

Fatty	B-Disease
liver	I-Disease
induced	O
by	O
tetracycline	B-Chemical
in	O
the	O
rat	O
.	O

Dose	O
-	O
response	O
relationships	O
and	O
effect	O
of	O
sex	O
.	O

Dose	O
-	O
response	O
relationships	O
,	O
biochemical	O
mechanisms	O
,	O
and	O
sex	O
differences	O
in	O
the	O
experimental	O
fatty	B-Disease
liver	I-Disease
induced	O
by	O
tetracycline	B-Chemical
were	O
studied	O
in	O
the	O
intact	O
rat	O
and	O
with	O
the	O
isolated	O
perfused	O
rat	O
liver	O
in	O
vitro	O
.	O

In	O
the	O
intact	O
male	O
and	O
female	O
rat	O
,	O
no	O
direct	O
relationship	O
was	O
observed	O
between	O
dose	O
of	O
tetracycline	B-Chemical
and	O
hepatic	O
accumulation	O
of	O
triglyceride	B-Chemical
.	O

With	O
provision	O
of	O
adequate	O
oleic	B-Chemical
acid	I-Chemical
as	O
a	O
substrate	O
for	O
the	O
isolated	O
perfused	O
liver	O
,	O
a	O
direct	O
relationship	O
was	O
observed	O
between	O
dose	O
of	O
tetracycline	B-Chemical
and	O
both	O
accumulation	O
of	O
triglyceride	B-Chemical
in	O
the	O
liver	O
and	O
depression	B-Disease
of	O
output	O
of	O
triglyceride	B-Chemical
by	O
livers	O
from	O
male	O
and	O
female	O
rats	O
.	O

Marked	O
differences	O
were	O
observed	O
between	O
female	O
and	O
male	O
rats	O
with	O
regard	O
to	O
base	O
line	O
(	O
control	O
)	O
hepatic	O
concentration	O
of	O
triglyceride	B-Chemical
and	O
output	O
of	O
triglyceride	B-Chemical
.	O

Accumulation	O
of	O
hepatic	O
triglyceride	B-Chemical
,	O
as	O
a	O
per	O
cent	O
of	O
control	O
values	O
,	O
in	O
response	O
to	O
graded	O
doses	O
of	O
tetracycline	B-Chemical
,	O
did	O
not	O
differ	O
significantly	O
between	O
male	O
,	O
female	O
and	O
pregnant	O
rat	O
livers	O
.	O

However	O
,	O
livers	O
from	O
female	O
,	O
and	O
especially	O
pregnant	O
female	O
rats	O
,	O
were	O
strikingly	O
resistant	O
to	O
the	O
effects	O
of	O
tetracycline	B-Chemical
on	O
depression	B-Disease
of	O
output	O
of	O
triglyceride	B-Chemical
under	O
these	O
experimental	O
conditions	O
.	O

These	O
differences	O
between	O
the	O
sexes	O
could	O
not	O
be	O
related	O
to	O
altered	O
disposition	O
of	O
tetracycline	B-Chemical
or	O
altered	O
uptake	O
of	O
oleic	B-Chemical
acid	I-Chemical
.	O

Depressed	O
hepatic	O
secretion	O
of	O
triglyceride	B-Chemical
accounted	O
only	O
for	O
30	O
to	O
50	O
%	O
of	O
accumulated	O
hepatic	O
triglyceride	B-Chemical
,	O
indicating	O
that	O
additional	O
mechanisms	O
must	O
be	O
involved	O
in	O
the	O
production	O
of	O
the	O
triglyceride	B-Chemical
-	O
rich	O
fatty	B-Disease
liver	I-Disease
in	O
response	O
to	O
tetracycline	B-Chemical
.	O

Prednisone	B-Chemical
induces	O
anxiety	B-Disease
and	O
glial	O
cerebral	O
changes	O
in	O
rats	O
.	O

OBJECTIVE	O
:	O
To	O
assess	O
whether	O
prednisone	B-Chemical
(	O
PDN	B-Chemical
)	O
produces	O
anxiety	B-Disease
and	O
/	O
or	O
cerebral	O
glial	O
changes	O
in	O
rats	O
.	O

METHODS	O
:	O
Male	O
Wistar	O
rats	O
were	O
studied	O
and	O
3	O
groups	O
were	O
formed	O
(	O
8	O
rats	O
per	O
group	O
)	O
.	O

The	O
moderate	O
-	O
dose	O
group	O
received	O
5	O
mg	O
/	O
kg	O
/	O
day	O
PDN	B-Chemical
released	O
from	O
a	O
subcutaneous	O
implant	O
.	O

In	O
the	O
high	O
-	O
dose	O
group	O
,	O
implants	O
containing	O
PDN	B-Chemical
equivalent	O
to	O
60	O
mg	O
/	O
kg	O
/	O
day	O
were	O
applied	O
.	O

In	O
the	O
control	O
group	O
implants	O
contained	O
no	O
PDN	B-Chemical
.	O

Anxiety	B-Disease
was	O
assessed	O
using	O
an	O
open	O
field	O
and	O
elevated	O
plus	O
-	O
maze	O
devices	O
.	O

The	O
number	O
of	O
cells	O
and	O
cytoplasmic	O
transformation	O
of	O
astrocytes	O
and	O
microglia	O
cells	O
were	O
assessed	O
by	O
immunohistochemical	O
analyses	O
.	O

RESULTS	O
:	O
Anxiety	B-Disease
was	O
documented	O
in	O
both	O
groups	O
of	O
PDN	B-Chemical
treated	O
rats	O
compared	O
with	O
controls	O
.	O

The	O
magnitude	O
of	O
transformation	O
of	O
the	O
microglia	O
assessed	O
by	O
the	O
number	O
of	O
intersections	O
was	O
significantly	O
higher	O
in	O
the	O
PDN	B-Chemical
groups	O
than	O
in	O
controls	O
in	O
the	O
prefrontal	O
cortex	O
(	O
moderate	O
-	O
dose	O
,	O
24	O
.	O
1	O
;	O
high	O
-	O
dose	O
,	O
23	O
.	O
6	O
;	O
controls	O
18	O
.	O
7	O
;	O
p	O
<	O
0	O
.	O
01	O
)	O
and	O
striatum	O
(	O
moderate	O
-	O
dose	O
25	O
.	O
6	O
;	O
high	O
-	O
dose	O
26	O
.	O
3	O
;	O
controls	O
18	O
.	O
9	O
;	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
but	O
not	O
in	O
hippocampus	O
.	O

The	O
number	O
of	O
stained	O
microglia	O
cells	O
was	O
significantly	O
higher	O
in	O
the	O
PDN	B-Chemical
treated	O
groups	O
in	O
the	O
prefrontal	O
cortex	O
than	O
in	O
controls	O
(	O
moderate	O
-	O
dose	O
,	O
29	O
.	O
1	O
;	O
high	O
-	O
dose	O
,	O
28	O
.	O
4	O
;	O
control	O
,	O
17	O
.	O
7	O
cells	O
per	O
field	O
;	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Stained	O
microglia	O
cells	O
were	O
significantly	O
more	O
numerous	O
striatum	O
and	O
hippocampus	O
in	O
the	O
high	O
-	O
dose	O
group	O
compared	O
to	O
controls	O
.	O

CONCLUSION	O
:	O
Subacute	O
exposure	O
to	O
PDN	B-Chemical
induced	O
anxiety	B-Disease
and	O
reactivity	O
of	O
microglia	O
.	O

The	O
relevance	O
of	O
these	O
features	O
for	O
patients	O
using	O
PDN	B-Chemical
remains	O
to	O
be	O
elucidated	O
.	O

Phase	O
II	O
study	O
of	O
carboplatin	B-Chemical
and	O
liposomal	O
doxorubicin	B-Chemical
in	O
patients	O
with	O
recurrent	O
squamous	B-Disease
cell	I-Disease
carcinoma	I-Disease
of	I-Disease
the	I-Disease
cervix	I-Disease
.	O

BACKGROUND	O
:	O
The	O
activity	O
of	O
the	O
combination	O
of	O
carboplatin	B-Chemical
and	O
liposomal	O
doxorubicin	B-Chemical
was	O
tested	O
in	O
a	O
Phase	O
II	O
study	O
of	O
patients	O
with	O
recurrent	O
cervical	B-Disease
carcinoma	I-Disease
.	O

METHODS	O
:	O
The	O
combination	O
of	O
carboplatin	B-Chemical
(	O
area	O
under	O
the	O
concentration	O
curve	O
[	O
AUC	O
]	O
,	O
5	O
)	O
and	O
liposomal	O
doxorubicin	B-Chemical
(	O
Doxil	B-Chemical
;	O
starting	O
dose	O
,	O
40	O
mg	O
/	O
m	O
(	O
2	O
)	O
)	O
was	O
administered	O
intravenously	O
every	O
28	O
days	O
to	O
37	O
patients	O
with	O
recurrent	O
squamous	B-Disease
cell	I-Disease
cervical	I-Disease
carcinoma	I-Disease
to	O
determine	O
antitumor	O
activity	O
and	O
toxicity	B-Disease
profile	O
.	O

RESULTS	O
:	O
Twenty	O
-	O
nine	O
patients	O
were	O
assessable	O
for	O
response	O
,	O
and	O
35	O
patients	O
were	O
assessable	O
for	O
toxicity	B-Disease
.	O

The	O
overall	O
response	O
rate	O
was	O
38	O
%	O
,	O
the	O
median	O
time	O
to	O
response	O
was	O
10	O
weeks	O
,	O
the	O
median	O
duration	O
of	O
response	O
was	O
26	O
weeks	O
,	O
and	O
the	O
median	O
survival	O
was	O
37	O
weeks	O
.	O

The	O
main	O
toxic	O
effect	O
was	O
myelosuppression	B-Disease
,	O
with	O
Grade	O
3	O
and	O
4	O
neutropenia	B-Disease
in	O
16	O
patients	O
,	O
anemia	B-Disease
in	O
12	O
patients	O
,	O
thrombocytopenia	B-Disease
in	O
11	O
patients	O
,	O
and	O
neutropenic	B-Disease
fever	I-Disease
in	O
3	O
patients	O
.	O

Four	O
patients	O
had	O
five	O
infusion	O
-	O
related	O
reactions	O
during	O
the	O
infusion	O
of	O
liposomal	O
doxorubicin	B-Chemical
,	O
leading	O
to	O
treatment	O
discontinuation	O
in	O
three	O
patients	O
.	O

Grade	O
>	O
or	O
=	O
2	O
nonhematologic	O
toxicity	B-Disease
included	O
nausea	B-Disease
in	O
17	O
patients	O
,	O
emesis	B-Disease
in	O
14	O
patients	O
,	O
fatigue	B-Disease
in	O
9	O
patients	O
,	O
mucositis	B-Disease
and	O
/	O
or	O
stomatitis	B-Disease
in	O
8	O
patients	O
,	O
constipation	B-Disease
in	O
6	O
patients	O
,	O
weight	B-Disease
loss	I-Disease
in	O
5	O
patients	O
,	O
hand	B-Disease
-	I-Disease
foot	I-Disease
syndrome	I-Disease
in	O
2	O
patients	O
,	O
and	O
skin	B-Disease
reactions	I-Disease
in	O
3	O
patients	O
.	O

CONCLUSIONS	O
:	O
The	O
combination	O
of	O
carboplatin	B-Chemical
and	O
liposomal	O
doxorubicin	B-Chemical
has	O
modest	O
activity	O
in	O
patients	O
with	O
recurrent	O
cervical	B-Disease
carcinoma	I-Disease
.	O

Antimicrobial	O
-	O
induced	O
mania	B-Disease
(	O
antibiomania	B-Disease
)	O
:	O
a	O
review	O
of	O
spontaneous	O
reports	O
.	O

The	O
authors	O
reviewed	O
reported	O
cases	O
of	O
antibiotic	O
-	O
induced	O
manic	B-Disease
episodes	O
by	O
means	O
of	O
a	O
MEDLINE	O
and	O
PsychLit	O
search	O
for	O
reports	O
of	O
antibiotic	O
-	O
induced	O
mania	B-Disease
.	O

Unpublished	O
reports	O
were	O
requested	O
from	O
the	O
World	O
Health	O
Organization	O
(	O
WHO	O
)	O
and	O
the	O
Food	O
and	O
Drug	O
Administration	O
(	O
FDA	O
)	O
.	O

Twenty	O
-	O
one	O
reports	O
of	O
antimicrobial	O
-	O
induced	O
mania	B-Disease
were	O
found	O
in	O
the	O
literature	O
.	O

There	O
were	O
6	O
cases	O
implicating	O
clarithromycin	B-Chemical
,	O
13	O
implicating	O
isoniazid	B-Chemical
,	O
and	O
1	O
case	O
each	O
implicating	O
erythromycin	B-Chemical
and	O
amoxicillin	B-Chemical
.	O

The	O
WHO	O
reported	O
82	O
cases	O
.	O

Of	O
these	O
,	O
clarithromycin	B-Chemical
was	O
implicated	O
in	O
23	O
(	O
27	O
.	O
6	O
%	O
)	O
cases	O
,	O
ciprofloxacin	B-Chemical
in	O
12	O
(	O
14	O
.	O
4	O
%	O
)	O
cases	O
,	O
and	O
ofloxacin	B-Chemical
in	O
10	O
(	O
12	O
%	O
)	O
cases	O
.	O

Cotrimoxazole	B-Chemical
,	O
metronidazole	B-Chemical
,	O
and	O
erythromycin	B-Chemical
were	O
involved	O
in	O
15	O
reported	O
manic	B-Disease
episodes	O
.	O

Cases	O
reported	O
by	O
the	O
FDA	O
showed	O
clarithromycin	B-Chemical
and	O
ciprofloxacin	B-Chemical
to	O
be	O
the	O
most	O
frequently	O
associated	O
with	O
the	O
development	O
of	O
mania	B-Disease
.	O

Statistical	O
analysis	O
of	O
the	O
data	O
would	O
not	O
have	O
demonstrated	O
a	O
significant	O
statistical	O
correlative	O
risk	O
and	O
was	O
therefore	O
not	O
undertaken	O
.	O

Patients	O
have	O
an	O
increased	O
risk	O
of	O
developing	O
mania	B-Disease
while	O
being	O
treated	O
with	O
antimicrobials	O
.	O

Although	O
this	O
is	O
not	O
a	O
statistically	O
significant	O
risk	O
,	O
physicians	O
must	O
be	O
aware	O
of	O
the	O
effect	O
and	O
reversibility	O
.	O

Further	O
research	O
clearly	O
is	O
required	O
to	O
determine	O
the	O
incidence	O
of	O
antimicrobial	O
-	O
induced	O
mania	B-Disease
,	O
the	O
relative	O
risk	O
factors	O
of	O
developing	O
an	O
antimicrobial	O
-	O
induced	O
manic	B-Disease
episode	O
among	O
various	O
demographic	O
populations	O
,	O
and	O
the	O
incidence	O
of	O
patients	O
who	O
continue	O
to	O
have	O
persistent	O
affective	O
disorders	O
once	O
the	O
initial	O
episode	O
,	O
which	O
occurs	O
while	O
the	O
patient	O
is	O
taking	O
antibiotics	O
,	O
subsides	O
.	O

The	O
authors	O
elected	O
to	O
name	O
this	O
syndrome	O
"	O
antibiomania	B-Disease
.	O
"	O

Levodopa	B-Chemical
-	O
induced	O
ocular	B-Disease
dyskinesias	I-Disease
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Levodopa	B-Chemical
-	O
induced	O
ocular	B-Disease
dyskinesias	I-Disease
are	O
very	O
uncommon	O
.	O

Usually	O
they	O
occur	O
simultaneously	O
with	O
limb	O
peak	O
-	O
dose	O
choreatic	B-Disease
dyskinesias	I-Disease
.	O

We	O
report	O
on	O
a	O
patient	O
with	O
leftward	O
and	O
upward	O
deviations	O
of	O
gaze	O
during	O
the	O
peak	O
effect	O
of	O
levodopa	B-Chemical
,	O
and	O
hypothesize	O
that	O
a	O
severe	O
dopaminergic	O
denervation	O
in	O
the	O
caudate	O
nucleus	O
is	O
needed	O
for	O
the	O
appearance	O
of	O
these	O
levodopa	B-Chemical
-	O
induce	O
ocular	B-Disease
dyskinesias	I-Disease
.	O

A	O
comparison	O
of	O
glyceryl	B-Chemical
trinitrate	I-Chemical
with	O
diclofenac	B-Chemical
for	O
the	O
treatment	O
of	O
primary	O
dysmenorrhea	B-Disease
:	O
an	O
open	O
,	O
randomized	O
,	O
cross	O
-	O
over	O
trial	O
.	O

Primary	O
dysmenorrhea	B-Disease
is	O
a	O
syndrome	O
characterized	O
by	O
painful	O
uterine	O
contractility	O
caused	O
by	O
a	O
hypersecretion	O
of	O
endometrial	O
prostaglandins	B-Chemical
;	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
are	O
the	O
first	O
choice	O
for	O
its	O
treatment	O
.	O

However	O
,	O
in	O
vivo	O
and	O
in	O
vitro	O
studies	O
have	O
demonstrated	O
that	O
myometrial	O
cells	O
are	O
also	O
targets	O
of	O
the	O
relaxant	O
effects	O
of	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
determine	O
the	O
efficacy	O
of	O
glyceryl	B-Chemical
trinitrate	I-Chemical
(	O
GTN	B-Chemical
)	O
,	O
an	O
NO	B-Chemical
donor	O
,	O
in	O
the	O
resolution	O
of	O
primary	O
dysmenorrhea	B-Disease
in	O
comparison	O
with	O
diclofenac	B-Chemical
(	O
DCF	B-Chemical
)	O
.	O

A	O
total	O
of	O
24	O
patients	O
with	O
the	O
diagnosis	O
of	O
severe	O
primary	O
dysmenorrhea	B-Disease
were	O
studied	O
during	O
two	O
consecutive	O
menstrual	O
cycles	O
.	O

In	O
an	O
open	O
,	O
cross	O
-	O
over	O
,	O
controlled	O
design	O
,	O
patients	O
were	O
randomized	O
to	O
receive	O
either	O
DCF	B-Chemical
per	O
os	O
or	O
GTN	B-Chemical
patches	O
the	O
first	O
days	O
of	O
menses	O
,	O
when	O
menstrual	O
cramps	O
became	O
unendurable	O
.	O

In	O
the	O
subsequent	O
cycle	O
the	O
other	O
treatment	O
was	O
used	O
.	O

Patients	O
received	O
up	O
to	O
3	O
doses	O
/	O
day	O
of	O
50	O
mg	O
DCF	B-Chemical
or	O
2	O
.	O
5	O
mg	O
/	O
24	O
h	O
transdermal	O
GTN	B-Chemical
for	O
the	O
first	O
3	O
days	O
of	O
the	O
cycle	O
,	O
according	O
to	O
their	O
needs	O
.	O

The	O
participants	O
recorded	O
menstrual	O
symptoms	O
and	O
possible	O
side	O
-	O
effects	O
at	O
different	O
times	O
(	O
0	O
,	O
30	O
,	O
60	O
,	O
120	O
minutes	O
)	O
after	O
the	O
first	O
dose	O
of	O
medication	O
on	O
the	O
first	O
day	O
of	O
the	O
cycle	O
,	O
with	O
both	O
drugs	O
.	O

The	O
difference	O
in	O
pain	B-Disease
intensity	O
score	O
(	O
DPI	O
)	O
was	O
the	O
main	O
outcome	O
variable	O
.	O

Both	O
treatments	O
significantly	O
reduced	O
DPI	O
by	O
the	O
30th	O
minute	O
(	O
GTN	B-Chemical
,	O
-	O
12	O
.	O
8	O
+	O
/	O
-	O
17	O
.	O
9	O
;	O
DCF	B-Chemical
,	O
-	O
18	O
.	O
9	O
+	O
/	O
-	O
16	O
.	O
6	O
)	O
.	O

However	O
,	O
DCF	B-Chemical
continued	O
to	O
be	O
effective	O
in	O
reducing	O
pelvic	B-Disease
pain	I-Disease
for	O
two	O
hours	O
,	O
whereas	O
GTN	B-Chemical
scores	O
remained	O
more	O
or	O
less	O
stable	O
after	O
30	O
min	O
and	O
significantly	O
higher	O
than	O
those	O
for	O
DFC	O
(	O
after	O
one	O
hour	O
:	O
GTN	B-Chemical
,	O
-	O
12	O
.	O
8	O
+	O
/	O
-	O
17	O
.	O
9	O
;	O
DFC	O
,	O
-	O
18	O
.	O
9	O
+	O
/	O
-	O
16	O
.	O
6	O
and	O
after	O
two	O
hours	O
:	O
GTN	B-Chemical
,	O
-	O
23	O
.	O
7	O
+	O
/	O
-	O
20	O
.	O
5	O
;	O
DFC	O
,	O
-	O
59	O
.	O
7	O
+	O
/	O
-	O
17	O
.	O
9	O
,	O
p	O
=	O
0	O
.	O
0001	O
)	O
.	O

Low	B-Disease
back	I-Disease
pain	I-Disease
was	O
also	O
relieved	O
by	O
both	O
drugs	O
.	O

Headache	B-Disease
was	O
significantly	O
increased	O
by	O
GTN	B-Chemical
but	O
not	O
by	O
DCF	B-Chemical
.	O

Eight	O
patients	O
stopped	O
using	O
GTN	B-Chemical
because	O
headache	B-Disease
-	O
-	O
attributed	O
to	O
its	O
use	O
-	O
-	O
became	O
intolerable	O
.	O

These	O
findings	O
indicate	O
that	O
GTN	B-Chemical
has	O
a	O
reduced	O
efficacy	O
and	O
tolerability	O
by	O
comparison	O
with	O
DCF	B-Chemical
in	O
the	O
treatment	O
of	O
primary	O
dysmenorrhea	B-Disease
.	O

Temocapril	B-Chemical
,	O
a	O
long	O
-	O
acting	O
non	O
-	O
SH	O
group	O
angiotensin	B-Chemical
converting	O
enzyme	O
inhibitor	O
,	O
modulates	O
glomerular	B-Disease
injury	I-Disease
in	O
chronic	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
nephrosis	B-Disease
.	O

The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
determine	O
whether	O
chronic	O
administration	O
of	O
temocapril	B-Chemical
,	O
a	O
long	O
-	O
acting	O
non	O
-	O
SH	O
group	O
angiotensin	B-Chemical
converting	O
enzyme	O
(	O
ACE	O
)	O
inhibitor	O
,	O
reduced	O
proteinuria	B-Disease
,	O
inhibited	O
glomerular	O
hypertrophy	B-Disease
and	O
prevented	O
glomerulosclerosis	B-Disease
in	O
chronic	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
)	O
-	O
induced	O
nephrotic	B-Disease
rats	O
.	O

Nephrosis	B-Disease
was	O
induced	O
by	O
injection	O
of	O
PAN	B-Chemical
(	O
15mg	O
/	O
100g	O
body	O
weight	O
)	O
in	O
male	O
Sprague	O
-	O
Dawley	O
(	O
SD	O
)	O
rats	O
.	O

Four	O
groups	O
were	O
used	O
,	O
i	O
)	O
the	O
PAN	B-Chemical
group	O
(	O
14	O
)	O
,	O
ii	O
)	O
PAN	B-Chemical
/	O
temocapril	B-Chemical
(	O
13	O
)	O
,	O
iii	O
)	O
temocapril	B-Chemical
(	O
14	O
)	O
and	O
iv	O
)	O
untreated	O
controls	O
(	O
15	O
)	O
.	O

Temocapril	B-Chemical
(	O
8	O
mg	O
/	O
kg	O
/	O
day	O
)	O
was	O
administered	O
to	O
the	O
rats	O
which	O
were	O
killed	O
at	O
weeks	O
4	O
,	O
14	O
or	O
20	O
.	O

At	O
each	O
time	O
point	O
,	O
systolic	O
blood	O
pressure	O
(	O
BP	O
)	O
,	O
urinary	O
protein	O
excretion	O
and	O
renal	O
histopathological	O
findings	O
were	O
evaluated	O
,	O
and	O
morphometric	O
image	O
analysis	O
was	O
done	O
.	O

Systolic	O
BP	O
in	O
the	O
PAN	B-Chemical
group	O
was	O
significantly	O
high	O
at	O
4	O
,	O
14	O
and	O
20	O
weeks	O
,	O
but	O
was	O
normal	O
in	O
the	O
PAN	B-Chemical
/	O
temocapril	B-Chemical
group	O
.	O

Urinary	O
protein	O
excretion	O
in	O
the	O
PAN	B-Chemical
group	O
increased	O
significantly	O
,	O
peaking	O
at	O
8	O
days	O
,	O
then	O
decreased	O
at	O
4	O
weeks	O
,	O
but	O
rose	O
again	O
significantly	O
at	O
14	O
and	O
20	O
weeks	O
.	O

Temocapril	B-Chemical
did	O
not	O
attenuate	O
proteinuria	B-Disease
at	O
8	O
days	O
,	O
but	O
it	O
did	O
markedly	O
lower	O
it	O
from	O
weeks	O
4	O
to	O
20	O
.	O

The	O
glomerulosclerosis	B-Disease
index	O
(	O
GSI	O
)	O
was	O
6	O
.	O
21	O
%	O
at	O
4	O
weeks	O
and	O
respectively	O
25	O
.	O
35	O
%	O
and	O
30	O
.	O
49	O
%	O
at	O
14	O
and	O
20	O
weeks	O
in	O
the	O
PAN	B-Chemical
group	O
.	O

There	O
was	O
a	O
significant	O
correlation	O
between	O
urinary	O
protein	O
excretion	O
and	O
GSI	O
(	O
r	O
=	O
0	O
.	O
808	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
.	O

The	O
ratio	O
of	O
glomerular	O
tuft	O
area	O
to	O
the	O
area	O
of	O
Bowman	O
'	O
s	O
capsules	O
(	O
GT	O
/	O
BC	O
)	O
in	O
the	O
PAN	B-Chemical
group	O
was	O
significantly	O
increased	O
,	O
but	O
it	O
was	O
significantly	O
lower	O
in	O
the	O
PAN	B-Chemical
/	O
temocapril	B-Chemical
group	O
.	O

It	O
appears	O
that	O
temocapril	B-Chemical
was	O
effective	O
in	O
retarding	O
renal	O
progression	O
and	O
protected	O
renal	O
function	O
in	O
PAN	B-Chemical
neprotic	B-Disease
rats	O
.	O

Pulmonary	B-Disease
hypertension	I-Disease
after	O
ibuprofen	B-Chemical
prophylaxis	O
in	O
very	O
preterm	O
infants	O
.	O

We	O
report	O
three	O
cases	O
of	O
severe	O
hypoxaemia	B-Disease
after	O
ibuprofen	B-Chemical
administration	O
during	O
a	O
randomised	O
controlled	O
trial	O
of	O
prophylactic	O
treatment	O
of	O
patent	B-Disease
ductus	I-Disease
arteriosus	I-Disease
with	O
ibuprofen	B-Chemical
in	O
premature	O
infants	O
born	O
at	O
less	O
than	O
28	O
weeks	O
of	O
gestation	O
.	O

Echocardiography	O
showed	O
severely	O
decreased	O
pulmonary	O
blood	O
flow	O
.	O

Hypoxaemia	B-Disease
resolved	O
quickly	O
on	O
inhaled	O
nitric	B-Chemical
oxide	I-Chemical
therapy	O
.	O

We	O
suggest	O
that	O
investigators	O
involved	O
in	O
similar	O
trials	O
pay	O
close	O
attention	O
to	O
pulmonary	O
pressure	O
if	O
hypoxaemia	B-Disease
occurs	O
after	O
prophylactic	O
administration	O
of	O
ibuprofen	B-Chemical
.	O

Hyponatremia	B-Disease
and	O
syndrome	B-Disease
of	I-Disease
inappropriate	I-Disease
anti	I-Disease
-	I-Disease
diuretic	I-Disease
hormone	I-Disease
reported	O
with	O
the	O
use	O
of	O
Vincristine	B-Chemical
:	O
an	O
over	O
-	O
representation	O
of	O
Asians	O
?	O

PURPOSE	O
:	O
This	O
retrospective	O
study	O
used	O
a	O
pharmaceutical	O
company	O
'	O
s	O
global	O
safety	O
database	O
to	O
determine	O
the	O
reporting	O
rate	O
of	O
hyponatremia	B-Disease
and	O
/	O
or	O
syndrome	B-Disease
of	I-Disease
inappropriate	I-Disease
secretion	I-Disease
of	I-Disease
anti	I-Disease
-	I-Disease
diuretic	I-Disease
hormone	I-Disease
(	O
SIADH	B-Disease
)	O
among	O
vincristine	B-Chemical
-	O
treated	O
patients	O
and	O
to	O
explore	O
the	O
possibility	O
of	O
at	O
-	O
risk	O
population	O
subgroups	O
.	O

METHOD	O
:	O
We	O
searched	O
the	O
Eli	O
Lilly	O
and	O
Company	O
'	O
s	O
computerized	O
adverse	O
event	O
database	O
for	O
all	O
reported	O
cases	O
of	O
hyponatremia	B-Disease
and	O
/	O
or	O
SIADH	B-Disease
as	O
of	O
1	O
November	O
1999	O
that	O
had	O
been	O
reported	O
during	O
the	O
use	O
of	O
vincristine	B-Chemical
.	O

RESULTS	O
:	O
A	O
total	O
of	O
76	O
cases	O
of	O
hyponatremia	B-Disease
and	O
/	O
or	O
SIADH	B-Disease
associated	O
with	O
vincristine	B-Chemical
use	O
were	O
identified	O
.	O

The	O
overall	O
reporting	O
rate	O
was	O
estimated	O
to	O
be	O
1	O
.	O
3	O
/	O
100	O
,	O
000	O
treated	O
patients	O
.	O

The	O
average	O
age	O
of	O
patients	O
was	O
35	O
.	O
6	O
+	O
/	O
-	O
28	O
.	O
3	O
years	O
,	O
and	O
62	O
%	O
were	O
males	O
.	O

Approximately	O
75	O
%	O
of	O
the	O
patients	O
were	O
receiving	O
treatment	O
for	O
leukemia	B-Disease
or	O
lymphoma	B-Disease
.	O

Among	O
the	O
39	O
reports	O
that	O
included	O
information	O
on	O
race	O
,	O
the	O
racial	O
distribution	O
was	O
:	O
1	O
Black	O
,	O
3	O
Caucasian	O
,	O
and	O
35	O
Asian	O
.	O

CONCLUSION	O
:	O
Our	O
data	O
suggest	O
that	O
Asian	O
patients	O
may	O
be	O
at	O
increased	O
risk	O
of	O
hyponatremia	B-Disease
and	O
/	O
or	O
SIADH	B-Disease
associated	O
with	O
vincristine	B-Chemical
use	O
.	O

Although	O
the	O
overall	O
reported	O
rate	O
of	O
SIADH	B-Disease
associated	O
with	O
vincristine	B-Chemical
is	O
very	O
low	O
,	O
physicians	O
caring	O
for	O
Asian	O
oncology	O
patients	O
should	O
be	O
aware	O
of	O
this	O
potential	O
serious	O
but	O
reversible	O
adverse	O
event	O
.	O

Delayed	O
toxicity	B-Disease
of	O
cyclophosphamide	B-Chemical
on	O
the	O
bladder	O
of	O
DBA	O
/	O
2	O
and	O
C57BL	O
/	O
6	O
female	O
mouse	O
.	O

The	O
present	O
study	O
describes	O
the	O
delayed	O
development	O
of	O
a	O
severe	O
bladder	O
pathology	O
in	O
a	O
susceptible	O
strain	O
of	O
mice	O
(	O
DBA	O
/	O
2	O
)	O
but	O
not	O
in	O
a	O
resistant	O
strain	O
(	O
C57BL	O
/	O
6	O
)	O
when	O
both	O
were	O
treated	O
with	O
a	O
single	O
300	O
mg	O
/	O
kg	O
dose	O
of	O
cyclophosphamide	B-Chemical
(	O
CY	B-Chemical
)	O
.	O

Inbred	O
DBA	O
/	O
2	O
and	O
C57BL	O
/	O
6	O
female	O
mice	O
were	O
injected	O
with	O
CY	B-Chemical
,	O
and	O
the	O
effect	O
of	O
the	O
drug	O
on	O
the	O
bladder	O
was	O
assessed	O
during	O
100	O
days	O
by	O
light	O
microscopy	O
using	O
different	O
staining	O
procedures	O
,	O
and	O
after	O
30	O
days	O
by	O
conventional	O
electron	O
microscopy	O
.	O

Early	O
CY	B-Chemical
toxicity	B-Disease
caused	O
a	O
typical	O
haemorrhagic	B-Disease
cystitis	B-Disease
in	O
both	O
strains	O
that	O
was	O
completely	O
repaired	O
in	O
about	O
7	O
-	O
10	O
days	O
.	O

After	O
30	O
days	O
of	O
CY	B-Chemical
injection	O
ulcerous	O
and	O
non	O
-	O
ulcerous	O
forms	O
of	O
chronic	O
cystitis	B-Disease
appeared	O
in	O
86	O
%	O
of	O
DBA	O
/	O
2	O
mice	O
but	O
only	O
in	O
4	O
%	O
of	O
C57BL	O
/	O
6	O
mice	O
.	O

Delayed	O
cystitis	B-Disease
was	O
characterized	O
by	O
infiltration	O
and	O
transepithelial	O
passage	O
into	O
the	O
lumen	O
of	O
inflammatory	O
cells	O
and	O
by	O
frequent	O
exfoliation	O
of	O
the	O
urothelium	O
.	O

Mast	O
cells	O
appeared	O
in	O
the	O
connective	O
and	O
muscular	O
layers	O
of	O
the	O
bladder	O
at	O
a	O
much	O
higher	O
number	O
in	O
DBA	O
/	O
2	O
mice	O
than	O
in	O
C57BL	O
/	O
6	O
mice	O
or	O
untreated	O
controls	O
.	O

Electron	O
microscopy	O
disclosed	O
the	O
absence	O
of	O
the	O
typical	O
discoidal	O
vesicles	O
normally	O
present	O
in	O
the	O
cytoplasm	O
of	O
surface	O
cells	O
.	O

Instead	O
,	O
numerous	O
abnormal	O
vesicles	O
containing	O
one	O
or	O
several	O
dark	O
granules	O
were	O
observed	O
in	O
the	O
cytoplasm	O
of	O
cells	O
from	O
all	O
the	O
epithelial	O
layers	O
.	O

Delayed	O
cystitis	B-Disease
still	O
persisted	O
in	O
DBA	O
/	O
2	O
mice	O
100	O
days	O
after	O
treatment	O
.	O

These	O
results	O
indicate	O
that	O
delayed	O
toxicity	B-Disease
of	O
CY	B-Chemical
in	O
female	O
DBA	O
/	O
2	O
mice	O
causes	O
a	O
bladder	O
pathology	O
that	O
is	O
not	O
observed	O
in	O
C57BL	O
/	O
6	O
mice	O
.	O

This	O
pathology	O
resembles	O
interstitial	B-Disease
cystitis	I-Disease
in	O
humans	O
and	O
could	O
perhaps	O
be	O
used	O
as	O
an	O
animal	O
model	O
for	O
studies	O
on	O
the	O
disease	O
.	O

High	O
-	O
dose	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
/	O
folinic	B-Chemical
acid	I-Chemical
in	O
combination	O
with	O
three	O
-	O
weekly	O
mitomycin	B-Chemical
C	I-Chemical
in	O
the	O
treatment	O
of	O
advanced	O
gastric	B-Disease
cancer	I-Disease
.	O

A	O
phase	O
II	O
study	O
.	O

BACKGROUND	O
:	O
The	O
24	O
-	O
hour	O
continuous	O
infusion	O
of	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
and	O
folinic	B-Chemical
acid	I-Chemical
(	O
FA	B-Chemical
)	O
as	O
part	O
of	O
several	O
new	O
multidrug	O
chemotherapy	O
regimens	O
in	O
advanced	O
gastric	B-Disease
cancer	I-Disease
(	O
AGC	B-Disease
)	O
has	O
shown	O
to	O
be	O
effective	O
,	O
with	O
low	O
toxicity	B-Disease
.	O

In	O
a	O
previous	O
phase	O
II	O
study	O
with	O
3	O
-	O
weekly	O
bolus	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
,	O
FA	B-Chemical
and	O
mitomycin	B-Chemical
C	I-Chemical
(	O
MMC	B-Chemical
)	O
we	O
found	O
a	O
low	O
toxicity	B-Disease
rate	O
and	O
response	O
rates	O
comparable	O
to	O
those	O
of	O
regimens	O
such	O
as	O
ELF	O
,	O
FAM	O
or	O
FAMTX	O
,	O
and	O
a	O
promising	O
median	O
overall	O
survival	O
.	O

In	O
order	O
to	O
improve	O
this	O
MMC	B-Chemical
-	O
dependent	O
schedule	O
we	O
initiated	O
a	O
phase	O
II	O
study	O
with	O
high	O
-	O
dose	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
/	O
FA	B-Chemical
and	O
3	O
-	O
weekly	O
bolus	O
MMC	B-Chemical
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
From	O
February	O
,	O
1998	O
to	O
September	O
,	O
2000	O
we	O
recruited	O
33	O
patients	O
with	O
AGC	B-Disease
to	O
receive	O
weekly	O
24	O
-	O
hour	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
2	O
,	O
600	O
mg	O
/	O
m	O
(	O
2	O
)	O
preceded	O
by	O
2	O
-	O
hour	O
FA	B-Chemical
500	O
mg	O
/	O
m	O
(	O
2	O
)	O
for	O
6	O
weeks	O
,	O
followed	O
by	O
a	O
2	O
-	O
week	O
rest	O
period	O
.	O

Bolus	O
MMC	B-Chemical
10	O
mg	O
/	O
m	O
(	O
2	O
)	O
was	O
added	O
in	O
3	O
-	O
weekly	O
intervals	O
.	O

Treatment	O
given	O
on	O
an	O
outpatient	O
basis	O
,	O
using	O
portable	O
pump	O
systems	O
,	O
was	O
repeated	O
on	O
day	O
57	O
.	O

Patients	O
'	O
characteristics	O
were	O
:	O
male	O
/	O
female	O
ratio	O
20	O
/	O
13	O
;	O
median	O
age	O
57	O
(	O
27	O
-	O
75	O
)	O
years	O
;	O
median	O
WHO	O
status	O
1	O
(	O
0	O
-	O
2	O
)	O
.	O

18	O
patients	O
had	O
a	O
primary	O
AGC	B-Disease
,	O
and	O
15	O
showed	O
a	O
relapsed	O
AGC	B-Disease
.	O

Median	O
follow	O
-	O
up	O
was	O
11	O
.	O
8	O
months	O
(	O
range	O
of	O
those	O
surviving	O
:	O
2	O
.	O
7	O
-	O
11	O
.	O
8	O
months	O
)	O
.	O

RESULTS	O
:	O
32	O
patients	O
were	O
evaluable	O
for	O
response	O
-	O
complete	O
remission	O
9	O
.	O
1	O
%	O
(	O
n	O
=	O
3	O
)	O
,	O
partial	O
remission	O
45	O
.	O
5	O
%	O
(	O
n	O
=	O
15	O
)	O
,	O
no	O
change	O
27	O
.	O
3	O
%	O
(	O
n	O
=	O
9	O
)	O
,	O
progressive	O
disease	O
15	O
.	O
1	O
%	O
(	O
n	O
=	O
5	O
)	O
.	O

Median	O
overall	O
survival	O
time	O
was	O
10	O
.	O
2	O
months	O
[	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
:	O
8	O
.	O
7	O
-	O
11	O
.	O
6	O
]	O
,	O
and	O
median	O
progression	O
-	O
free	O
survival	O
time	O
was	O
7	O
.	O
6	O
months	O
(	O
95	O
%	O
CI	O
:	O
4	O
.	O
4	O
-	O
10	O
.	O
9	O
)	O
.	O

The	O
worst	O
toxicities	B-Disease
(	O
%	O
)	O
observed	O
were	O
(	O
CTC	O
-	O
NCI	O
1	O
/	O
2	O
/	O
3	O
)	O
:	O
leukopenia	B-Disease
45	O
.	O
5	O
/	O
18	O
.	O
2	O
/	O
6	O
.	O
1	O
,	O
thrombocytopenia	B-Disease
33	O
.	O
3	O
/	O
9	O
.	O
1	O
/	O
6	O
.	O
1	O
,	O
vomitus	B-Disease
24	O
.	O
2	O
/	O
9	O
.	O
1	O
/	O
0	O
,	O
diarrhea	B-Disease
36	O
.	O
4	O
/	O
6	O
.	O
1	O
/	O
3	O
.	O
0	O
,	O
stomatitis	B-Disease
18	O
.	O
2	O
/	O
9	O
.	O
1	O
/	O
0	O
,	O
hand	B-Disease
-	I-Disease
foot	I-Disease
syndrome	I-Disease
12	O
.	O
1	O
/	O
0	O
/	O
0	O
.	O

Two	O
patients	O
developed	O
hemolytic	B-Disease
-	I-Disease
uremic	I-Disease
syndrome	I-Disease
(	O
HUS	B-Disease
)	O
.	O

CONCLUSIONS	O
:	O
High	O
-	O
dose	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
/	O
FA	B-Chemical
/	O
MMC	B-Chemical
is	O
an	O
effective	O
and	O
well	O
-	O
tolerated	O
outpatient	O
regimen	O
for	O
AGC	B-Disease
(	O
objective	O
response	O
rate	O
54	O
.	O
6	O
%	O
)	O
.	O

It	O
may	O
serve	O
as	O
an	O
alternative	O
to	O
cisplatin	B-Chemical
-	O
containing	O
regimens	O
;	O
however	O
,	O
it	O
has	O
to	O
be	O
considered	O
that	O
possibly	O
HUS	B-Disease
may	O
occur	O
.	O

Persistent	O
sterile	O
leukocyturia	B-Disease
is	O
associated	O
with	O
impaired	B-Disease
renal	I-Disease
function	I-Disease
in	O
human	B-Disease
immunodeficiency	I-Disease
virus	I-Disease
type	I-Disease
1	I-Disease
-	I-Disease
infected	I-Disease
children	O
treated	O
with	O
indinavir	B-Chemical
.	O

BACKGROUND	O
:	O
Prolonged	O
administration	O
of	O
indinavir	B-Chemical
is	O
associated	O
with	O
the	O
occurrence	O
of	O
a	O
variety	O
of	O
renal	O
complications	O
in	O
adults	O
.	O

These	O
well	O
-	O
documented	O
side	O
effects	O
have	O
restricted	O
the	O
use	O
of	O
this	O
potent	O
protease	O
inhibitor	O
in	O
children	O
.	O

DESIGN	O
:	O
A	O
prospective	O
study	O
to	O
monitor	O
indinavir	B-Chemical
-	O
related	O
nephrotoxicity	B-Disease
in	O
a	O
cohort	O
of	O
30	O
human	B-Disease
immunodeficiency	I-Disease
virus	I-Disease
type	I-Disease
1	I-Disease
-	I-Disease
infected	I-Disease
children	O
treated	O
with	O
indinavir	B-Chemical
.	O

METHODS	O
:	O
Urinary	O
pH	O
,	O
albumin	O
,	O
creatinine	B-Chemical
,	O
the	O
presence	O
of	O
erythrocytes	O
,	O
leukocytes	O
,	O
bacteria	O
and	O
crystals	O
,	O
and	O
culture	O
were	O
analyzed	O
every	O
3	O
months	O
for	O
96	O
weeks	O
.	O

Serum	O
creatinine	B-Chemical
levels	O
were	O
routinely	O
determined	O
at	O
the	O
same	O
time	O
points	O
.	O

Steady	O
-	O
state	O
pharmacokinetics	O
of	O
indinavir	B-Chemical
were	O
done	O
at	O
week	O
4	O
after	O
the	O
initiation	O
of	O
indinavir	B-Chemical
.	O

RESULTS	O
:	O
The	O
cumulative	O
incidence	O
of	O
persistent	O
sterile	O
leukocyturia	B-Disease
(	O
>	O
or	O
=	O
75	O
cells	O
/	O
micro	O
L	O
in	O
at	O
least	O
2	O
consecutive	O
visits	O
)	O
after	O
96	O
weeks	O
was	O
53	O
%	O
.	O

Persistent	O
sterile	O
leukocyturia	B-Disease
was	O
frequently	O
associated	O
with	O
a	O
mild	O
increase	O
in	O
the	O
urine	O
albumin	O
/	O
creatinine	B-Chemical
ratio	O
and	O
by	O
microscopic	O
hematuria	B-Disease
.	O

The	O
cumulative	O
incidence	O
of	O
serum	O
creatinine	B-Chemical
levels	O
>	O
50	O
%	O
above	O
normal	O
was	O
33	O
%	O
after	O
96	O
weeks	O
.	O

Children	O
with	O
persistent	O
sterile	O
leukocyturia	B-Disease
more	O
frequently	O
had	O
serum	O
creatinine	B-Chemical
levels	O
of	O
50	O
%	O
above	O
normal	O
than	O
those	O
children	O
without	O
persistent	O
sterile	O
leukocyturia	B-Disease
.	O

In	O
children	O
younger	O
than	O
5	O
.	O
6	O
years	O
,	O
persistent	O
sterile	O
leukocyturia	B-Disease
was	O
significantly	O
more	O
frequent	O
than	O
in	O
older	O
children	O
.	O

A	O
higher	O
cumulative	O
incidence	O
of	O
persistent	O
leukocyturia	B-Disease
was	O
found	O
in	O
children	O
with	O
an	O
area	O
under	O
the	O
curve	O
>	O
19	O
mg	O
/	O
L	O
x	O
h	O
or	O
a	O
peak	O
serum	O
level	O
of	O
indinavir	B-Chemical
>	O
12	O
mg	O
/	O
L	O
.	O

In	O
4	O
children	O
,	O
indinavir	B-Chemical
was	O
discontinued	O
because	O
of	O
nephrotoxicity	B-Disease
.	O

Subsequently	O
,	O
the	O
serum	O
creatinine	B-Chemical
levels	O
decreased	O
,	O
the	O
urine	O
albumin	O
/	O
creatinine	B-Chemical
ratios	O
returned	O
to	O
zero	O
,	O
and	O
the	O
leukocyturia	B-Disease
disappeared	O
within	O
3	O
months	O
.	O

CONCLUSIONS	O
:	O
Children	O
treated	O
with	O
indinavir	B-Chemical
have	O
a	O
high	O
cumulative	O
incidence	O
of	O
persistent	O
sterile	O
leukocyturia	B-Disease
.	O

Children	O
with	O
persistent	O
sterile	O
leukocyturia	B-Disease
more	O
frequently	O
had	O
an	O
increase	O
in	O
serum	O
creatinine	B-Chemical
levels	O
of	O
>	O
50	O
%	O
above	O
normal	O
.	O

Younger	O
children	O
have	O
an	O
additional	O
risk	O
for	O
renal	O
complications	O
.	O

The	O
impairment	B-Disease
of	I-Disease
the	I-Disease
renal	I-Disease
function	I-Disease
in	O
these	O
children	O
occurred	O
in	O
the	O
absence	O
of	O
clinical	O
symptoms	O
of	O
nephrolithiasis	B-Disease
.	O

Indinavir	B-Chemical
-	O
associated	O
nephrotoxicity	B-Disease
must	O
be	O
monitored	O
closely	O
,	O
especially	O
in	O
children	O
with	O
risk	O
factors	O
such	O
as	O
persistent	O
sterile	O
leukocyturia	B-Disease
,	O
age	O
<	O
5	O
.	O
6	O
years	O
,	O
an	O
area	O
under	O
the	O
curve	O
of	O
indinavir	B-Chemical
>	O
19	O
mg	O
/	O
L	O
x	O
h	O
,	O
and	O
a	O
C	O
(	O
max	O
)	O
>	O
12	O
mg	O
/	O
L	O
.	O

Utility	O
of	O
troponin	O
I	O
in	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
.	O

Baseline	O
electrocardiogram	O
abnormalities	O
and	O
market	O
elevations	O
not	O
associated	O
with	O
myocardial	B-Disease
necrosis	I-Disease
make	O
accurate	O
diagnosis	O
of	O
myocardial	B-Disease
infarction	I-Disease
(	O
MI	B-Disease
)	O
difficult	O
in	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
.	O

Troponin	O
sampling	O
may	O
offer	O
greater	O
diagnostic	O
utility	O
in	O
these	O
patients	O
.	O

OBJECTIVE	O
:	O
To	O
assess	O
outcomes	O
based	O
on	O
troponin	O
positivity	O
in	O
patients	O
with	O
cocaine	B-Chemical
chest	B-Disease
pain	I-Disease
admitted	O
for	O
exclusion	O
of	O
MI	B-Disease
.	O

METHODS	O
:	O
Outcomes	O
were	O
examined	O
in	O
patients	O
admitted	O
for	O
possible	O
MI	B-Disease
after	O
cocaine	B-Chemical
use	O
.	O

All	O
patients	O
underwent	O
a	O
rapid	O
rule	O
-	O
in	O
protocol	O
that	O
included	O
serial	O
sampling	O
of	O
creatine	B-Chemical
kinase	O
(	O
CK	O
)	O
,	O
CK	O
-	O
MB	O
,	O
and	O
cardiac	O
troponin	O
I	O
(	O
cTnI	O
)	O
over	O
eight	O
hours	O
.	O

Outcomes	O
included	O
CK	O
-	O
MB	O
MI	B-Disease
(	O
CK	O
-	O
MB	O
>	O
or	O
=	O
8	O
ng	O
/	O
mL	O
with	O
a	O
relative	O
index	O
[	O
(	O
CK	O
-	O
MB	O
x	O
100	O
)	O
/	O
total	O
CK	O
]	O
>	O
or	O
=	O
4	O
,	O
cardiac	B-Disease
death	I-Disease
,	O
and	O
significant	O
coronary	B-Disease
disease	I-Disease
(	O
>	O
or	O
=	O
50	O
%	O
)	O
.	O

RESULTS	O
:	O
Of	O
the	O
246	O
admitted	O
patients	O
,	O
34	O
(	O
14	O
%	O
)	O
met	O
CK	O
-	O
MB	O
criteria	O
for	O
MI	B-Disease
and	O
38	O
(	O
16	O
%	O
)	O
had	O
cTnI	O
elevations	O
.	O

Angiography	O
was	O
performed	O
in	O
29	O
of	O
38	O
patients	O
who	O
were	O
cTnI	O
-	O
positive	O
,	O
with	O
significant	O
disease	O
present	O
in	O
25	O
(	O
86	O
%	O
)	O
.	O

Three	O
of	O
the	O
four	O
patients	O
without	O
significant	O
disease	O
who	O
had	O
cTnI	O
elevations	O
met	O
CK	O
-	O
MB	O
criteria	O
for	O
MI	B-Disease
,	O
and	O
the	O
other	O
had	O
a	O
peak	O
CK	O
-	O
MB	O
level	O
of	O
13	O
ng	O
/	O
mL	O
.	O

Sensitivities	O
,	O
specificities	O
,	O
and	O
positive	O
and	O
negative	O
likelihood	O
ratios	O
for	O
predicting	O
cardiac	B-Disease
death	I-Disease
or	O
significant	O
disease	O
were	O
high	O
for	O
both	O
CK	O
-	O
MB	O
MI	B-Disease
and	O
cTnI	O
and	O
were	O
not	O
significantly	O
different	O
.	O

CONCLUSIONS	O
:	O
Most	O
patients	O
with	O
cTnI	O
elevations	O
meet	O
CK	O
-	O
MB	O
criteria	O
for	O
MI	B-Disease
,	O
as	O
well	O
as	O
have	O
a	O
high	O
incidence	O
of	O
underlying	O
significant	O
disease	O
.	O

Troponin	O
appears	O
to	O
have	O
an	O
equivalent	O
diagnostic	O
accuracy	O
compared	O
with	O
CK	O
-	O
MB	O
for	O
diagnosing	O
necrosis	B-Disease
in	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
and	O
suspected	O
MI	B-Disease
.	O

Acute	O
interstitial	B-Disease
nephritis	I-Disease
due	O
to	O
nicergoline	B-Chemical
(	O
Sermion	B-Chemical
)	O
.	O

We	O
report	O
a	O
case	O
of	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
(	O
AIN	B-Disease
)	O
due	O
to	O
nicergoline	B-Chemical
(	O
Sermion	B-Chemical
)	O
.	O

A	O
50	O
-	O
year	O
-	O
old	O
patient	O
admitted	O
to	O
our	O
hospital	O
for	O
fever	B-Disease
and	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

Before	O
admission	O
,	O
he	O
had	O
been	O
taking	O
nicergoline	B-Chemical
and	O
bendazac	B-Chemical
lysine	I-Chemical
due	O
to	O
retinal	B-Disease
vein	I-Disease
occlusion	I-Disease
at	O
ophthalmologic	O
department	O
.	O

Thereafter	O
,	O
he	O
experienced	O
intermittent	O
fever	B-Disease
and	O
skin	B-Disease
rash	I-Disease
.	O

On	O
admission	O
,	O
clinical	O
symptoms	O
(	O
i	O
.	O
e	O
.	O
arthralgia	B-Disease
and	O
fever	B-Disease
)	O
and	O
laboratory	O
findings	O
(	O
i	O
.	O
e	O
.	O
eosinophilia	B-Disease
and	O
renal	B-Disease
failure	I-Disease
)	O
suggested	O
AIN	B-Disease
,	O
and	O
which	O
was	O
confirmed	O
by	O
pathologic	O
findings	O
on	O
renal	O
biopsy	O
.	O

A	O
lymphocyte	O
transformation	O
test	O
demonstrated	O
a	O
positive	O
result	O
against	O
nicergoline	B-Chemical
.	O

Treatment	O
was	O
consisted	O
of	O
withdrawal	O
of	O
nicergoline	B-Chemical
and	O
intravenous	O
methylprednisolone	B-Chemical
,	O
and	O
his	O
renal	O
function	O
was	O
completely	O
recovered	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
report	O
of	O
nicergoline	B-Chemical
-	O
associated	O
AIN	B-Disease
.	O

Neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
complicated	O
by	O
massive	O
intestinal	O
bleeding	B-Disease
in	O
a	O
patient	O
with	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
.	O

A	O
patient	O
with	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
(	O
CRF	B-Disease
)	O
developed	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
(	O
NMS	B-Disease
)	O
after	O
administration	O
of	O
risperidone	B-Chemical
and	O
levomepromazine	B-Chemical
.	O

In	O
addition	O
to	O
the	O
typical	O
symptoms	O
of	O
NMS	B-Disease
,	O
massive	O
intestinal	O
bleeding	B-Disease
was	O
observed	O
during	O
the	O
episode	O
.	O

This	O
report	O
suggests	O
that	O
NMS	B-Disease
in	O
a	O
patient	O
with	O
CRF	B-Disease
may	O
be	O
complicated	O
by	O
intestinal	O
bleeding	B-Disease
and	O
needs	O
special	O
caution	O
for	O
this	O
complication	O
.	O

Blood	O
brain	O
barrier	O
in	O
right	O
-	O
and	O
left	O
-	O
pawed	O
female	O
rats	O
assessed	O
by	O
a	O
new	O
staining	O
method	O
.	O

The	O
asymmetrical	O
breakdown	O
of	O
the	O
blood	O
-	O
brain	O
barrier	O
(	O
BBB	O
)	O
was	O
studied	O
in	O
female	O
rats	O
.	O

Paw	O
preference	O
was	O
assessed	O
by	O
a	O
food	O
reaching	O
test	O
.	O

Adrenaline	B-Chemical
-	O
induced	O
hypertension	B-Disease
was	O
used	O
to	O
destroy	O
the	O
BBB	O
,	O
which	O
was	O
evaluated	O
using	O
triphenyltetrazolium	B-Chemical
(	O
TTC	B-Chemical
)	O
staining	O
of	O
the	O
brain	O
slices	O
just	O
after	O
giving	O
adrenaline	B-Chemical
for	O
30	O
s	O
.	O

In	O
normal	O
rats	O
,	O
the	O
whole	O
brain	O
sections	O
exhibited	O
complete	O
staining	O
with	O
TTC	B-Chemical
.	O

After	O
adrenaline	B-Chemical
infusion	O
for	O
30	O
s	O
,	O
there	O
were	O
large	O
unstained	O
areas	O
in	O
the	O
left	O
brain	O
in	O
right	O
-	O
pawed	O
animals	O
,	O
and	O
vice	O
versa	O
in	O
left	O
-	O
pawed	O
animals	O
.	O

Similar	O
results	O
were	O
obtained	O
in	O
seizure	B-Disease
-	O
induced	O
breakdown	O
of	O
BBB	O
.	O

These	O
results	O
were	O
explained	O
by	O
an	O
asymmetric	O
cerebral	O
blood	O
flow	O
depending	O
upon	O
the	O
paw	O
preference	O
in	O
rats	O
.	O

It	O
was	O
suggested	O
that	O
this	O
new	O
method	O
and	O
the	O
results	O
are	O
consistent	O
with	O
contralateral	O
motor	O
control	O
that	O
may	O
be	O
important	O
in	O
determining	O
the	O
dominant	O
cerebral	O
hemisphere	O
in	O
animals	O
.	O

Carvedilol	B-Chemical
protects	O
against	O
doxorubicin	B-Chemical
-	O
induced	O
mitochondrial	O
cardiomyopathy	B-Disease
.	O

Several	O
cytopathic	O
mechanisms	O
have	O
been	O
suggested	O
to	O
mediate	O
the	O
dose	O
-	O
limiting	O
cumulative	O
and	O
irreversible	O
cardiomyopathy	B-Disease
caused	O
by	O
doxorubicin	B-Chemical
.	O

Recent	O
evidence	O
indicates	O
that	O
oxidative	O
stress	O
and	O
mitochondrial	B-Disease
dysfunction	I-Disease
are	O
key	O
factors	O
in	O
the	O
pathogenic	O
process	O
.	O

The	O
objective	O
of	O
this	O
investigation	O
was	O
to	O
test	O
the	O
hypothesis	O
that	O
carvedilol	B-Chemical
,	O
a	O
nonselective	O
beta	O
-	O
adrenergic	O
receptor	O
antagonist	O
with	O
potent	O
antioxidant	O
properties	O
,	O
protects	O
against	O
the	O
cardiac	O
and	O
hepatic	O
mitochondrial	O
bioenergetic	O
dysfunction	O
associated	O
with	O
subchronic	O
doxorubicin	B-Chemical
toxicity	B-Disease
.	O

Heart	O
and	O
liver	O
mitochondria	O
were	O
isolated	O
from	O
rats	O
treated	O
for	O
7	O
weeks	O
with	O
doxorubicin	B-Chemical
(	O
2	O
mg	O
/	O
kg	O
sc	O
/	O
week	O
)	O
,	O
carvedilol	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
ip	O
/	O
week	O
)	O
,	O
or	O
the	O
combination	O
of	O
the	O
two	O
drugs	O
.	O

Heart	O
mitochondria	O
isolated	O
from	O
doxorubicin	B-Chemical
-	O
treated	O
rats	O
exhibited	O
depressed	O
rates	O
for	O
state	O
3	O
respiration	O
(	O
336	O
+	O
/	O
-	O
26	O
versus	O
425	O
+	O
/	O
-	O
53	O
natom	O
O	O
/	O
min	O
/	O
mg	O
protein	O
)	O
and	O
a	O
lower	O
respiratory	O
control	O
ratio	O
(	O
RCR	O
)	O
(	O
4	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
6	O
versus	O
5	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
4	O
)	O
compared	O
with	O
cardiac	O
mitochondria	O
isolated	O
from	O
saline	O
-	O
treated	O
rats	O
.	O

Mitochondrial	O
calcium	B-Chemical
-	O
loading	O
capacity	O
and	O
the	O
activity	O
of	O
NADH	O
-	O
dehydrogenase	O
were	O
also	O
suppressed	O
in	O
cardiac	O
mitochondria	O
from	O
doxorubicin	B-Chemical
-	O
treated	O
rats	O
.	O

Doxorubicin	B-Chemical
treatment	O
also	O
caused	O
a	O
decrease	O
in	O
RCR	O
for	O
liver	O
mitochondria	O
(	O
3	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
9	O
versus	O
5	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
7	O
for	O
control	O
rats	O
)	O
and	O
inhibition	O
of	O
hepatic	O
cytochrome	O
oxidase	O
activity	O
.	O

Coadministration	O
of	O
carvedilol	B-Chemical
decreased	O
the	O
extent	O
of	O
cellular	O
vacuolization	O
in	O
cardiac	O
myocytes	O
and	O
prevented	O
the	O
inhibitory	O
effect	O
of	O
doxorubicin	B-Chemical
on	O
mitochondrial	O
respiration	O
in	O
both	O
heart	O
and	O
liver	O
.	O

Carvedilol	B-Chemical
also	O
prevented	O
the	O
decrease	O
in	O
mitochondrial	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
loading	O
capacity	O
and	O
the	O
inhibition	O
of	O
the	O
respiratory	O
complexes	O
of	O
heart	O
mitochondria	O
caused	O
by	O
doxorubicin	B-Chemical
.	O

Carvedilol	B-Chemical
by	O
itself	O
did	O
not	O
affect	O
any	O
of	O
the	O
parameters	O
measured	O
for	O
heart	O
or	O
liver	O
mitochondria	O
.	O

It	O
is	O
concluded	O
that	O
this	O
protection	O
by	O
carvedilol	B-Chemical
against	O
both	O
the	O
structural	O
and	O
functional	O
cardiac	O
tissue	O
damage	O
may	O
afford	O
significant	O
clinical	O
advantage	O
in	O
minimizing	O
the	O
dose	O
-	O
limiting	O
mitochondrial	B-Disease
dysfunction	I-Disease
and	O
cardiomyopathy	B-Disease
that	O
accompanies	O
long	O
-	O
term	O
doxorubicin	B-Chemical
therapy	O
in	O
cancer	B-Disease
patients	O
.	O

Cocaine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
is	O
more	O
influenced	O
by	O
adenosine	B-Chemical
receptor	O
agonists	O
than	O
amphetamine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
.	O

The	O
influence	O
of	O
adenosine	B-Chemical
receptor	O
agonists	O
and	O
antagonists	O
on	O
cocaine	B-Chemical
-	O
and	O
amphetamine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
was	O
examined	O
in	O
mice	O
.	O

All	O
adenosine	B-Chemical
receptor	O
agonists	O
significantly	O
decreased	B-Disease
the	I-Disease
locomotor	I-Disease
activity	I-Disease
in	O
mice	O
,	O
and	O
the	O
effects	O
were	O
dose	O
-	O
dependent	O
.	O

It	O
seems	O
that	O
adenosine	B-Chemical
A1	O
and	O
A2	O
receptors	O
might	O
be	O
involved	O
in	O
this	O
reaction	O
.	O

Moreover	O
,	O
all	O
adenosine	B-Chemical
receptor	O
agonists	O
:	O
2	B-Chemical
-	I-Chemical
p	I-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
carboxyethyl	I-Chemical
)	I-Chemical
phenethylamino	I-Chemical
-	I-Chemical
5	I-Chemical
'	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
ethylcarboxamidoadenosine	I-Chemical
(	O
CGS	B-Chemical
21680	I-Chemical
)	O
,	O
A2A	O
receptor	O
agonist	O
,	O
N6	B-Chemical
-	I-Chemical
cyclopentyladenosine	I-Chemical
(	O
CPA	B-Chemical
)	O
,	O
A1	O
receptor	O
agonist	O
,	O
and	O
5	B-Chemical
'	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
ethylcarboxamidoadenosine	I-Chemical
(	O
NECA	B-Chemical
)	O
,	O
A2	O
/	O
A1	O
receptor	O
agonist	O
significantly	O
and	O
dose	O
-	O
dependently	O
decreased	O
cocaine	B-Chemical
-	O
induced	O
locomotor	O
activity	O
.	O

CPA	B-Chemical
reduced	O
cocaine	B-Chemical
action	O
at	O
the	O
doses	O
which	O
,	O
given	O
alone	O
,	O
did	O
not	O
influence	O
motility	O
,	O
while	O
CGS	B-Chemical
21680	I-Chemical
and	O
NECA	B-Chemical
decreased	O
the	O
action	O
of	O
cocaine	B-Chemical
at	O
the	O
doses	O
which	O
,	O
given	O
alone	O
,	O
decreased	O
locomotor	O
activity	O
in	O
animals	O
.	O

These	O
results	O
suggest	O
the	O
involvement	O
of	O
both	O
adenosine	B-Chemical
receptors	O
in	O
the	O
action	O
of	O
cocaine	B-Chemical
although	O
agonists	O
of	O
A1	O
receptors	O
seem	O
to	O
have	O
stronger	O
influence	O
on	O
it	O
.	O

The	O
selective	O
blockade	O
of	O
A2	O
adenosine	B-Chemical
receptor	O
by	O
DMPX	B-Chemical
(	O
3	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
dimethyl	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
propargylxanthine	I-Chemical
)	O
significantly	O
enhanced	O
cocaine	B-Chemical
-	O
induced	O
locomotor	O
activity	O
of	O
animals	O
.	O

Caffeine	B-Chemical
had	O
similar	O
action	O
but	O
the	O
effect	O
was	O
not	O
significant	O
.	O

CPT	B-Chemical
(	O
8	B-Chemical
-	I-Chemical
cyclopentyltheophylline	I-Chemical
)	O
-	O
-	O
A1	O
receptor	O
antagonist	O
,	O
did	O
not	O
show	O
any	O
influence	O
in	O
this	O
test	O
.	O

Similarly	O
,	O
all	O
adenosine	B-Chemical
receptor	O
agonists	O
decreased	O
amphetamine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
,	O
but	O
at	O
the	O
higher	O
doses	O
than	O
those	O
which	O
were	O
active	O
in	O
cocaine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
.	O

The	O
selective	O
blockade	O
of	O
A2	O
adenosine	B-Chemical
receptors	O
(	O
DMPX	B-Chemical
)	O
and	O
non	O
-	O
selective	O
blockade	O
of	O
adenosine	B-Chemical
receptors	O
(	O
caffeine	B-Chemical
)	O
significantly	O
increased	O
the	O
action	O
of	O
amphetamine	B-Chemical
in	O
the	O
locomotor	O
activity	O
test	O
.	O

Our	O
results	O
have	O
shown	O
that	O
all	O
adenosine	B-Chemical
receptor	O
agonists	O
(	O
A1	O
and	O
A2	O
)	O
reduce	O
cocaine	B-Chemical
-	O
and	O
amphetamine	B-Chemical
-	O
induced	O
locomotor	O
activity	O
and	O
indicate	O
that	O
cocaine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
is	O
more	O
influenced	O
by	O
adenosine	B-Chemical
receptor	O
agonists	O
(	O
particularly	O
A1	O
receptors	O
)	O
than	O
amphetamine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
.	O

Amiodarone	B-Chemical
and	O
the	O
risk	O
of	O
bradyarrhythmia	B-Disease
requiring	O
permanent	O
pacemaker	O
in	O
elderly	O
patients	O
with	O
atrial	B-Disease
fibrillation	I-Disease
and	O
prior	O
myocardial	B-Disease
infarction	I-Disease
.	O

OBJECTIVES	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
determine	O
whether	O
the	O
use	O
of	O
amiodarone	B-Chemical
in	O
patients	O
with	O
atrial	B-Disease
fibrillation	I-Disease
(	O
AF	B-Disease
)	O
increases	O
the	O
risk	O
of	O
bradyarrhythmia	B-Disease
requiring	O
a	O
permanent	O
pacemaker	O
.	O

BACKGROUND	O
:	O
Reports	O
of	O
severe	O
bradyarrhythmia	B-Disease
during	O
amiodarone	B-Chemical
therapy	O
are	O
infrequent	O
and	O
limited	O
to	O
studies	O
assessing	O
the	O
therapy	O
'	O
s	O
use	O
in	O
the	O
management	O
of	O
patients	O
with	O
ventricular	B-Disease
arrhythmias	I-Disease
.	O

METHODS	O
:	O
A	O
study	O
cohort	O
of	O
8	O
,	O
770	O
patients	O
age	O
>	O
or	O
=	O
65	O
years	O
with	O
a	O
new	O
diagnosis	O
of	O
AF	B-Disease
was	O
identified	O
from	O
a	O
provincewide	O
database	O
of	O
Quebec	O
residents	O
with	O
a	O
myocardial	B-Disease
infarction	I-Disease
(	O
MI	B-Disease
)	O
between	O
1991	O
and	O
1999	O
.	O

Using	O
a	O
nested	O
case	O
-	O
control	O
design	O
,	O
477	O
cases	O
of	O
bradyarrhythmia	B-Disease
requiring	O
a	O
permanent	O
pacemaker	O
were	O
matched	O
(	O
1	O
:	O
4	O
)	O
to	O
1	O
,	O
908	O
controls	O
.	O

Multivariable	O
logistic	O
regression	O
was	O
used	O
to	O
estimate	O
the	O
odds	O
ratio	O
(	O
OR	O
)	O
of	O
pacemaker	O
insertion	O
associated	O
with	O
amiodarone	B-Chemical
use	O
,	O
controlling	O
for	O
baseline	O
risk	O
factors	O
and	O
exposure	O
to	O
sotalol	B-Chemical
,	O
Class	O
I	O
antiarrhythmic	O
agents	O
,	O
beta	O
-	O
blockers	O
,	O
calcium	B-Chemical
channel	O
blockers	O
,	O
and	O
digoxin	B-Chemical
.	O

RESULTS	O
:	O
amiodarone	B-Chemical
use	O
was	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
pacemaker	O
insertion	O
(	O
OR	O
:	O
2	O
.	O
14	O
,	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
:	O
1	O
.	O
30	O
to	O
3	O
.	O
54	O
)	O
.	O

This	O
effect	O
was	O
modified	O
by	O
gender	O
,	O
with	O
a	O
greater	O
risk	O
in	O
women	O
versus	O
men	O
(	O
OR	O
:	O
3	O
.	O
86	O
,	O
95	O
%	O
CI	O
:	O
1	O
.	O
70	O
to	O
8	O
.	O
75	O
vs	O
.	O
OR	O
:	O
1	O
.	O
52	O
,	O
95	O
%	O
CI	O
:	O
0	O
.	O
80	O
to	O
2	O
.	O
89	O
)	O
.	O

Digoxin	B-Chemical
was	O
the	O
only	O
other	O
medication	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
pacemaker	O
insertion	O
(	O
OR	O
:	O
1	O
.	O
78	O
,	O
95	O
%	O
CI	O
:	O
1	O
.	O
37	O
to	O
2	O
.	O
31	O
)	O
.	O

CONCLUSIONS	O
:	O
This	O
study	O
suggests	O
that	O
the	O
use	O
of	O
amiodarone	B-Chemical
in	O
elderly	O
patients	O
with	O
AF	B-Disease
and	O
a	O
previous	O
MI	B-Disease
increases	O
the	O
risk	O
of	O
bradyarrhythmia	B-Disease
requiring	O
a	O
permanent	O
pacemaker	O
.	O

The	O
finding	O
of	O
an	O
augmented	O
risk	O
of	O
pacemaker	O
insertion	O
in	O
elderly	O
women	O
receiving	O
amiodarone	B-Chemical
requires	O
further	O
investigation	O
.	O

Indomethacin	B-Chemical
-	O
induced	O
morphologic	O
changes	O
in	O
the	O
rat	O
urinary	O
bladder	O
epithelium	O
.	O

OBJECTIVES	O
:	O
To	O
evaluate	O
the	O
morphologic	O
changes	O
in	O
rat	O
urothelium	O
induced	O
by	O
indomethacin	B-Chemical
.	O

Nonsteroidal	O
anti	O
-	O
inflammatory	O
drug	O
-	O
induced	O
cystitis	B-Disease
is	O
a	O
poorly	O
recognized	O
and	O
under	O
-	O
reported	O
condition	O
.	O

In	O
addition	O
to	O
tiaprofenic	B-Chemical
acid	I-Chemical
,	O
indomethacin	B-Chemical
has	O
been	O
reported	O
to	O
be	O
associated	O
with	O
this	O
condition	O
.	O

METHODS	O
:	O
Three	O
groups	O
were	O
established	O
:	O
a	O
control	O
group	O
(	O
n	O
=	O
10	O
)	O
,	O
a	O
high	O
-	O
dose	O
group	O
(	O
n	O
=	O
10	O
)	O
,	O
treated	O
with	O
one	O
intraperitoneal	O
injection	O
of	O
indomethacin	B-Chemical
20	O
mg	O
/	O
kg	O
,	O
and	O
a	O
therapeutic	O
dose	O
group	O
(	O
n	O
=	O
10	O
)	O
in	O
which	O
oral	O
indomethacin	B-Chemical
was	O
administered	O
3	O
.	O
25	O
mg	O
/	O
kg	O
body	O
weight	O
daily	O
for	O
3	O
weeks	O
.	O

The	O
animals	O
were	O
then	O
killed	O
and	O
the	O
bladders	O
removed	O
for	O
light	O
and	O
electron	O
microscopic	O
studies	O
.	O

RESULTS	O
:	O
The	O
light	O
microscopic	O
findings	O
showed	O
some	O
focal	O
epithelial	O
degeneration	O
that	O
was	O
more	O
prominent	O
in	O
the	O
high	O
-	O
dose	O
group	O
.	O

When	O
compared	O
with	O
the	O
control	O
group	O
,	O
both	O
indomethacin	B-Chemical
groups	O
revealed	O
statistically	O
increased	O
numbers	O
of	O
mast	O
cells	O
in	O
the	O
mucosa	O
(	O
P	O
<	O
0	O
.	O
0001	O
)	O
and	O
penetration	O
of	O
lanthanum	B-Chemical
nitrate	I-Chemical
through	O
intercellular	O
areas	O
of	O
the	O
epithelium	O
.	O

Furthermore	O
,	O
the	O
difference	O
in	O
mast	O
cell	O
counts	O
between	O
the	O
high	O
and	O
therapeutic	O
dose	O
groups	O
was	O
also	O
statistically	O
significant	O
(	O
P	O
<	O
0	O
.	O
0001	O
)	O
.	O

CONCLUSIONS	O
:	O
Indomethacin	B-Chemical
resulted	O
in	O
histopathologic	O
findings	O
typical	O
of	O
interstitial	B-Disease
cystitis	I-Disease
,	O
such	O
as	O
leaky	O
bladder	O
epithelium	O
and	O
mucosal	O
mastocytosis	B-Disease
.	O

The	O
true	O
incidence	O
of	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drug	O
-	O
induced	O
cystitis	B-Disease
in	O
humans	O
must	O
be	O
clarified	O
by	O
prospective	O
clinical	O
trials	O
.	O

An	O
open	O
-	O
label	O
phase	O
II	O
study	O
of	O
low	O
-	O
dose	O
thalidomide	B-Chemical
in	O
androgen	B-Chemical
-	O
independent	O
prostate	B-Disease
cancer	I-Disease
.	O

The	O
antiangiogenic	O
effects	O
of	O
thalidomide	B-Chemical
have	O
been	O
assessed	O
in	O
clinical	O
trials	O
in	O
patients	O
with	O
various	O
solid	O
and	O
haematological	B-Disease
malignancies	I-Disease
.	O

Thalidomide	B-Chemical
blocks	O
the	O
activity	O
of	O
angiogenic	O
agents	O
including	O
bFGF	O
,	O
VEGF	O
and	O
IL	O
-	O
6	O
.	O

We	O
undertook	O
an	O
open	O
-	O
label	O
study	O
using	O
thalidomide	B-Chemical
100	O
mg	O
once	O
daily	O
for	O
up	O
to	O
6	O
months	O
in	O
20	O
men	O
with	O
androgen	B-Chemical
-	O
independent	O
prostate	B-Disease
cancer	I-Disease
.	O

The	O
mean	O
time	O
of	O
study	O
was	O
109	O
days	O
(	O
median	O
107	O
,	O
range	O
4	O
-	O
184	O
days	O
)	O
.	O

Patients	O
underwent	O
regular	O
measurement	O
of	O
prostate	O
-	O
specific	O
antigen	O
(	O
PSA	O
)	O
,	O
urea	B-Chemical
and	O
electrolytes	O
,	O
serum	O
bFGF	O
and	O
VEGF	O
.	O

Three	O
men	O
(	O
15	O
%	O
)	O
showed	O
a	O
decline	O
in	O
serum	O
PSA	O
of	O
at	O
least	O
50	O
%	O
,	O
sustained	O
throughout	O
treatment	O
.	O

Of	O
16	O
men	O
treated	O
for	O
at	O
least	O
2	O
months	O
,	O
six	O
(	O
37	O
.	O
5	O
%	O
)	O
showed	O
a	O
fall	O
in	O
absolute	O
PSA	O
by	O
a	O
median	O
of	O
48	O
%	O
.	O

Increasing	O
levels	O
of	O
serum	O
bFGF	O
and	O
VEGF	O
were	O
associated	O
with	O
progressive	O
disease	O
;	O
five	O
of	O
six	O
men	O
who	O
demonstrated	O
a	O
fall	O
in	O
PSA	O
also	O
showed	O
a	O
decline	O
in	O
bFGF	O
and	O
VEGF	O
levels	O
,	O
and	O
three	O
of	O
four	O
men	O
with	O
a	O
rising	O
PSA	O
showed	O
an	O
increase	O
in	O
both	O
growth	O
factors	O
.	O

Adverse	O
effects	O
included	O
constipation	B-Disease
,	O
morning	O
drowsiness	B-Disease
,	O
dizziness	B-Disease
and	O
rash	B-Disease
,	O
and	O
resulted	O
in	O
withdrawal	O
from	O
the	O
study	O
by	O
three	O
men	O
.	O

Evidence	O
of	O
peripheral	B-Disease
sensory	I-Disease
neuropathy	I-Disease
was	O
found	O
in	O
nine	O
of	O
13	O
men	O
before	O
treatment	O
.	O

In	O
the	O
seven	O
men	O
who	O
completed	O
six	O
months	O
on	O
thalidomide	B-Chemical
,	O
subclinical	O
evidence	O
of	O
peripheral	B-Disease
neuropathy	I-Disease
was	O
found	O
in	O
four	O
before	O
treatment	O
,	O
but	O
in	O
all	O
seven	O
at	O
repeat	O
testing	O
.	O

The	O
findings	O
indicate	O
that	O
thalidomide	B-Chemical
may	O
be	O
an	O
option	O
for	O
patients	O
who	O
have	O
failed	O
other	O
forms	O
of	O
therapy	O
,	O
provided	O
close	O
follow	O
-	O
up	O
is	O
maintained	O
for	O
development	O
of	O
peripheral	B-Disease
neuropathy	I-Disease
.	O

Central	B-Disease
nervous	I-Disease
system	I-Disease
toxicity	I-Disease
following	O
the	O
administration	O
of	O
levobupivacaine	B-Chemical
for	O
lumbar	O
plexus	O
block	O
:	O
A	O
report	O
of	O
two	O
cases	O
.	O

BACKGROUND	O
AND	O
OBJECTIVES	O
:	O
Central	B-Disease
nervous	I-Disease
system	I-Disease
and	I-Disease
cardiac	I-Disease
toxicity	I-Disease
following	O
the	O
administration	O
of	O
local	O
anesthetics	O
is	O
a	O
recognized	O
complication	O
of	O
regional	O
anesthesia	O
.	O

Levobupivacaine	B-Chemical
,	O
the	O
pure	O
S	O
(	O
-	O
)	O
enantiomer	O
of	O
bupivacaine	B-Chemical
,	O
was	O
developed	O
to	O
improve	O
the	O
cardiac	O
safety	O
profile	O
of	O
bupivacaine	B-Chemical
.	O

We	O
describe	O
2	O
cases	O
of	O
grand	B-Disease
mal	I-Disease
seizures	I-Disease
following	O
accidental	O
intravascular	O
injection	O
of	O
levobupivacaine	B-Chemical
.	O

CASE	O
REPORT	O
:	O
Two	O
patients	O
presenting	O
for	O
elective	O
orthopedic	O
surgery	O
of	O
the	O
lower	O
limb	O
underwent	O
blockade	O
of	O
the	O
lumbar	O
plexus	O
via	O
the	O
posterior	O
approach	O
.	O

Immediately	O
after	O
the	O
administration	O
of	O
levobupivacaine	B-Chemical
0	O
.	O
5	O
%	O
with	O
epinephrine	B-Chemical
2	O
.	O
5	O
microgram	O
/	O
mL	O
,	O
the	O
patients	O
developed	O
grand	B-Disease
mal	I-Disease
seizures	I-Disease
,	O
despite	O
negative	O
aspiration	O
for	O
blood	O
and	O
no	O
clinical	O
signs	O
of	O
intravenous	O
epinephrine	B-Chemical
administration	O
.	O

The	O
seizures	B-Disease
were	O
successfully	O
treated	O
with	O
sodium	B-Chemical
thiopental	I-Chemical
in	O
addition	O
to	O
succinylcholine	B-Chemical
in	O
1	O
patient	O
.	O

Neither	O
patient	O
developed	O
signs	O
of	O
cardiovascular	B-Disease
toxicity	I-Disease
.	O

Both	O
patients	O
were	O
treated	O
preoperatively	O
with	O
beta	O
-	O
adrenergic	O
antagonist	O
medications	O
,	O
which	O
may	O
have	O
masked	O
the	O
cardiovascular	O
signs	O
of	O
the	O
unintentional	O
intravascular	O
administration	O
of	O
levobupivacaine	B-Chemical
with	O
epinephrine	B-Chemical
.	O

CONCLUSIONS	O
:	O
Although	O
levobupivacaine	B-Chemical
may	O
have	O
a	O
safer	O
cardiac	B-Disease
toxicity	I-Disease
profile	O
than	O
racemic	O
bupivacaine	B-Chemical
,	O
if	O
adequate	O
amounts	O
of	O
levobupivacaine	B-Chemical
reach	O
the	O
circulation	O
,	O
it	O
will	O
result	O
in	O
convulsions	B-Disease
.	O

Plasma	O
concentrations	O
sufficient	O
to	O
result	O
in	O
central	B-Disease
nervous	I-Disease
system	I-Disease
toxicity	I-Disease
did	O
not	O
produce	O
manifestations	O
of	O
cardiac	B-Disease
toxicity	I-Disease
in	O
these	O
2	O
patients	O
.	O

Amiodarone	B-Chemical
-	O
induced	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
during	O
bladder	O
irrigation	O
:	O
an	O
unusual	O
presentation	O
-	O
-	O
a	O
case	O
report	O
.	O

The	O
authors	O
present	O
a	O
case	O
of	O
early	O
(	O
within	O
4	O
days	O
)	O
development	O
of	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
(	O
TdP	B-Disease
)	O
associated	O
with	O
oral	O
amiodarone	B-Chemical
therapy	O
.	O

Consistent	O
with	O
other	O
reports	O
this	O
case	O
of	O
TdP	B-Disease
occurred	O
in	O
the	O
context	O
of	O
multiple	O
exacerbating	O
factors	O
including	O
hypokalemia	B-Disease
and	O
digoxin	B-Chemical
excess	O
.	O

Transient	O
prolongation	O
of	O
the	O
QT	O
during	O
bladder	O
irrigation	O
prompted	O
the	O
episode	O
of	O
TdP	B-Disease
.	O

It	O
is	O
well	O
known	O
that	O
bradycardia	B-Disease
exacerbates	O
acquired	O
TdP	B-Disease
.	O

The	O
authors	O
speculate	O
that	O
the	O
increased	O
vagal	O
tone	O
during	O
bladder	O
irrigation	O
,	O
a	O
vagal	O
maneuver	O
,	O
in	O
the	O
context	O
of	O
amiodarone	B-Chemical
therapy	O
resulted	O
in	O
amiodarone	B-Chemical
-	O
induced	O
proarrhythmia	B-Disease
.	O

In	O
the	O
absence	O
of	O
amiodarone	B-Chemical
therapy	O
,	O
a	O
second	O
bladder	O
irrigation	O
did	O
not	O
induce	O
TdP	B-Disease
despite	O
hypokalemia	B-Disease
and	O
hypomagnesemia	B-Disease
.	O

Anaesthetic	O
complications	O
associated	O
with	O
myotonia	B-Disease
congenita	I-Disease
:	O
case	O
study	O
and	O
comparison	O
with	O
other	O
myotonic	B-Disease
disorders	I-Disease
.	O

Myotonia	B-Disease
congenita	I-Disease
(	O
MC	B-Disease
)	O
is	O
caused	O
by	O
a	O
defect	O
in	O
the	O
skeletal	O
muscle	O
chloride	B-Chemical
channel	O
function	O
,	O
which	O
may	O
cause	O
sustained	B-Disease
membrane	I-Disease
depolarisation	I-Disease
.	O

We	O
describe	O
a	O
previously	O
healthy	O
32	O
-	O
year	O
-	O
old	O
woman	O
who	O
developed	O
a	O
life	O
-	O
threatening	O
muscle	B-Disease
spasm	I-Disease
and	O
secondary	O
ventilation	O
difficulties	O
following	O
a	O
preoperative	O
injection	O
of	O
suxamethonium	B-Chemical
.	O

The	O
muscle	B-Disease
spasms	I-Disease
disappeared	O
spontaneously	O
and	O
the	O
surgery	O
proceeded	O
without	O
further	O
problems	O
.	O

When	O
subsequently	O
questioned	O
,	O
she	O
reported	O
minor	O
symptoms	O
suggesting	O
a	O
myotonic	B-Disease
condition	I-Disease
.	O

Myotonia	B-Disease
was	O
found	O
on	O
clinical	O
examination	O
and	O
EMG	O
.	O

The	O
diagnosis	O
MC	B-Disease
was	O
confirmed	O
genetically	O
.	O

Neither	O
the	O
patient	O
nor	O
the	O
anaesthetist	O
were	O
aware	O
of	O
the	O
diagnosis	O
before	O
this	O
potentially	O
lethal	O
complication	O
occurred	O
.	O

We	O
give	O
a	O
brief	O
overview	O
of	O
ion	B-Disease
channel	I-Disease
disorders	I-Disease
including	O
malignant	B-Disease
hyperthermia	I-Disease
and	O
their	O
anaesthetic	O
considerations	O
.	O

Respiratory	O
pattern	O
in	O
a	O
rat	O
model	O
of	O
epilepsy	B-Disease
.	O

PURPOSE	O
:	O
Apnea	B-Disease
is	O
known	O
to	O
occur	O
during	O
seizures	B-Disease
,	O
but	O
systematic	O
studies	O
of	O
ictal	O
respiratory	O
changes	O
in	O
adults	O
are	O
few	O
.	O

Data	O
regarding	O
respiratory	O
pattern	O
defects	O
during	O
interictal	O
periods	O
also	O
are	O
scarce	O
.	O

Here	O
we	O
sought	O
to	O
generate	O
information	O
with	O
regard	O
to	O
the	O
interictal	O
period	O
in	O
animals	O
with	O
pilocarpine	B-Chemical
-	O
induced	O
epilepsy	B-Disease
.	O

METHODS	O
:	O
Twelve	O
rats	O
(	O
six	O
chronically	O
epileptic	B-Disease
animals	O
and	O
six	O
controls	O
)	O
were	O
anesthetized	O
,	O
given	O
tracheotomies	O
,	O
and	O
subjected	O
to	O
hyperventilation	B-Disease
or	O
hypoventilation	O
conditions	O
.	O

Breathing	O
movements	O
caused	O
changes	O
in	O
thoracic	O
volume	O
and	O
forced	O
air	O
to	O
flow	O
tidally	O
through	O
a	O
pneumotachograph	O
.	O

This	O
flow	O
was	O
measured	O
by	O
using	O
a	O
differential	O
pressure	O
transducer	O
,	O
passed	O
through	O
a	O
polygraph	O
,	O
and	O
from	O
this	O
to	O
a	O
computer	O
with	O
custom	O
software	O
that	O
derived	O
ventilation	O
(	O
VE	O
)	O
,	O
tidal	O
volume	O
(	O
VT	O
)	O
,	O
inspiratory	O
time	O
(	O
TI	O
)	O
,	O
expiratory	O
time	O
(	O
TE	O
)	O
,	O
breathing	O
frequency	O
(	O
f	O
)	O
,	O
and	O
mean	O
inspiratory	O
flow	O
(	O
VT	O
/	O
TI	O
)	O
on	O
a	O
breath	O
-	O
by	O
-	O
breath	O
basis	O
.	O

RESULTS	O
:	O
The	O
hyperventilation	B-Disease
maneuver	O
caused	O
a	O
decrease	O
in	O
spontaneous	O
ventilation	O
in	O
pilocarpine	B-Chemical
-	O
treated	O
and	O
control	O
rats	O
.	O

Although	O
VE	O
had	O
a	O
similar	O
decrease	O
in	O
both	O
groups	O
,	O
in	O
the	O
epileptic	B-Disease
group	O
,	O
the	O
decrease	O
in	O
VE	O
was	O
due	O
to	O
a	O
significant	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
increase	O
in	O
TE	O
peak	O
in	O
relation	O
to	O
that	O
of	O
the	O
control	O
animals	O
.	O

The	O
hypoventilation	O
maneuver	O
led	O
to	O
an	O
increase	O
in	O
the	O
arterial	O
Paco2	O
,	O
followed	O
by	O
an	O
increase	O
in	O
VE	O
.	O

In	O
the	O
epileptic	B-Disease
group	O
,	O
the	O
increase	O
in	O
VE	O
was	O
mediated	O
by	O
a	O
significant	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
decrease	O
in	O
TE	O
peak	O
compared	O
with	O
the	O
control	O
group	O
.	O

Systemic	O
application	O
of	O
KCN	O
,	O
to	O
evaluate	O
the	O
effects	O
of	O
peripheral	O
chemoreception	O
activation	O
on	O
ventilation	O
,	O
led	O
to	O
a	O
similar	O
increase	O
in	O
VE	O
for	O
both	O
groups	O
.	O

CONCLUSIONS	O
:	O
The	O
data	O
indicate	O
that	O
pilocarpine	B-Chemical
-	O
treated	O
animals	O
have	O
an	O
altered	O
ability	O
to	O
react	O
to	O
(	O
or	O
compensate	O
for	O
)	O
blood	O
gas	O
changes	O
with	O
changes	O
in	O
ventilation	O
and	O
suggest	O
that	O
it	O
is	O
centrally	O
determined	O
.	O

We	O
speculate	O
on	O
the	O
possible	O
relation	O
of	O
the	O
current	O
findings	O
on	O
treating	O
different	O
epilepsy	B-Disease
-	O
associated	O
conditions	O
.	O

Fatal	O
myeloencephalopathy	B-Disease
due	O
to	O
intrathecal	O
vincristine	B-Chemical
administration	O
.	O

Vincristine	B-Chemical
was	O
accidentally	O
given	O
intrathecally	O
to	O
a	O
child	O
with	O
leukaemia	B-Disease
,	O
producing	O
sensory	B-Disease
and	I-Disease
motor	I-Disease
dysfunction	I-Disease
followed	O
by	O
encephalopathy	B-Disease
and	O
death	O
.	O

Separate	O
times	O
for	O
administering	O
vincristine	B-Chemical
and	O
intrathecal	O
therapy	O
is	O
recommended	O
.	O

Progesterone	B-Chemical
potentiation	O
of	O
bupivacaine	B-Chemical
arrhythmogenicity	O
in	O
pentobarbital	B-Chemical
-	O
anesthetized	O
rats	O
and	O
beating	O
rat	O
heart	O
cell	O
cultures	O
.	O

The	O
effects	O
of	O
progesterone	B-Chemical
treatment	O
on	O
bupivacaine	B-Chemical
arrhythmogenicity	O
in	O
beating	O
rat	O
heart	O
myocyte	O
cultures	O
and	O
on	O
anesthetized	O
rats	O
were	O
determined	O
.	O

After	O
determining	O
the	O
bupivacaine	B-Chemical
AD50	O
(	O
the	O
concentration	O
of	O
bupivacaine	B-Chemical
that	O
caused	O
50	O
%	O
of	O
all	O
beating	O
rat	O
heart	O
myocyte	O
cultures	O
to	O
become	O
arrhythmic	B-Disease
)	O
,	O
we	O
determined	O
the	O
effect	O
of	O
1	O
-	O
hour	O
progesterone	B-Chemical
HCl	B-Chemical
exposure	O
on	O
myocyte	O
contractile	O
rhythm	O
.	O

Each	O
concentration	O
of	O
progesterone	B-Chemical
(	O
6	O
.	O
25	O
,	O
12	O
.	O
5	O
,	O
25	O
,	O
and	O
50	O
micrograms	O
/	O
ml	O
)	O
caused	O
a	O
significant	O
and	O
concentration	O
-	O
dependent	O
reduction	O
in	O
the	O
AD50	O
for	O
bupivacaine	B-Chemical
.	O

Estradiol	B-Chemical
treatment	O
also	O
increased	O
the	O
arrhythmogenicity	O
of	O
bupivacaine	B-Chemical
in	O
myocyte	O
cultures	O
,	O
but	O
was	O
only	O
one	O
fourth	O
as	O
potent	O
as	O
progesterone	B-Chemical
.	O

Neither	O
progesterone	B-Chemical
nor	O
estradiol	B-Chemical
effects	O
on	O
bupivacaine	B-Chemical
arrhythmogenicity	O
were	O
potentiated	O
by	O
epinephrine	B-Chemical
.	O

Chronic	O
progesterone	B-Chemical
pretreatment	O
(	O
5	O
mg	O
/	O
kg	O
/	O
day	O
for	O
21	O
days	O
)	O
caused	O
a	O
significant	O
increase	O
in	O
bupivacaine	B-Chemical
arrhythmogenicity	O
in	O
intact	O
pentobarbital	B-Chemical
-	O
anesthetized	O
rats	O
.	O

There	O
was	O
a	O
significant	O
decrease	O
in	O
the	O
time	O
to	O
onset	O
of	O
arrhythmia	B-Disease
as	O
compared	O
with	O
control	O
nonprogesterone	O
-	O
treated	O
rats	O
(	O
6	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
3	O
vs	O
.	O
30	O
.	O
8	O
+	O
/	O
-	O
2	O
.	O
5	O
min	O
,	O
mean	O
+	O
/	O
-	O
SE	O
)	O
.	O

The	O
results	O
of	O
this	O
study	O
indicate	O
that	O
progesterone	B-Chemical
can	O
potentiate	O
bupivacaine	B-Chemical
arrhythmogenicity	O
both	O
in	O
vivo	O
and	O
in	O
vitro	O
.	O

Potentiation	O
of	O
bupivacaine	B-Chemical
arrhythmia	B-Disease
in	O
myocyte	O
cultures	O
suggests	O
that	O
this	O
effect	O
is	O
at	O
least	O
partly	O
mediated	O
at	O
the	O
myocyte	O
level	O
.	O

Increased	O
serum	O
soluble	O
Fas	O
in	O
patients	O
with	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
due	O
to	O
paracetamol	B-Chemical
overdose	B-Disease
.	O

BACKGROUND	O
/	O
AIMS	O
:	O
Experimental	O
studies	O
have	O
suggested	O
that	O
apoptosis	O
via	O
the	O
Fas	O
/	O
Fas	O
Ligand	O
signaling	O
system	O
may	O
play	O
an	O
important	O
role	O
in	O
the	O
development	O
of	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
investigate	O
the	O
soluble	O
form	O
of	O
Fas	O
in	O
patients	O
with	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
.	O

METHODOLOGY	O
:	O
Serum	O
levels	O
of	O
sFas	O
(	O
soluble	O
Fas	O
)	O
were	O
measured	O
by	O
ELISA	O
in	O
24	O
patients	O
with	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
and	O
10	O
normal	O
control	O
subjects	O
.	O

Serum	O
levels	O
of	O
tumor	B-Disease
necrosis	B-Disease
factor	O
-	O
alpha	O
and	O
interferon	O
-	O
gamma	O
were	O
also	O
determined	O
by	O
ELISA	O
.	O

RESULTS	O
:	O
Serum	O
sFas	O
was	O
significantly	O
increased	O
in	O
patients	O
with	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
(	O
median	O
,	O
26	O
.	O
8	O
U	O
/	O
mL	O
;	O
range	O
,	O
6	O
.	O
9	O
-	O
52	O
.	O
7	O
U	O
/	O
mL	O
)	O
compared	O
to	O
the	O
normal	O
controls	O
(	O
median	O
,	O
8	O
.	O
6	O
U	O
/	O
mL	O
;	O
range	O
,	O
6	O
.	O
5	O
-	O
12	O
.	O
0	O
U	O
/	O
mL	O
,	O
P	O
<	O
0	O
.	O
0001	O
)	O
.	O

Levels	O
were	O
significantly	O
greater	O
in	O
patients	O
with	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
due	O
to	O
paracetamol	B-Chemical
overdose	B-Disease
(	O
median	O
,	O
28	O
.	O
7	O
U	O
/	O
mL	O
;	O
range	O
,	O
12	O
.	O
8	O
-	O
52	O
.	O
7	O
U	O
/	O
mL	O
,	O
n	O
=	O
17	O
)	O
than	O
those	O
due	O
to	O
non	O
-	O
A	O
to	O
E	O
hepatitis	B-Disease
(	O
median	O
,	O
12	O
.	O
5	O
U	O
/	O
mL	O
;	O
range	O
,	O
6	O
.	O
9	O
-	O
46	O
.	O
0	O
U	O
/	O
mL	O
,	O
n	O
=	O
7	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

There	O
was	O
no	O
relationship	O
of	O
sFas	O
to	O
eventual	O
outcome	O
in	O
the	O
patients	O
.	O

A	O
significant	O
correlation	O
was	O
observed	O
between	O
serum	O
sFas	O
levels	O
and	O
aspartate	B-Chemical
aminotransferase	O
(	O
r	O
=	O
0	O
.	O
613	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

CONCLUSIONS	O
:	O
The	O
increased	O
concentration	O
of	O
sFas	O
in	O
serum	O
of	O
patients	O
with	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
may	O
reflect	O
activation	O
of	O
Fas	O
-	O
mediated	O
apoptosis	O
in	O
the	O
liver	O
and	O
this	O
together	O
with	O
increased	O
tumor	B-Disease
necrosis	B-Disease
factor	O
-	O
alpha	O
may	O
be	O
an	O
important	O
factor	O
in	O
liver	O
cell	O
loss	O
.	O

Bilateral	O
subthalamic	O
nucleus	O
stimulation	O
for	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

High	O
frequency	O
stimulation	O
of	O
the	O
subthalamic	O
nucleus	O
(	O
STN	O
)	O
is	O
known	O
to	O
ameliorate	O
the	O
signs	O
and	O
symptoms	O
of	O
advanced	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

AIM	O
:	O
We	O
studied	O
the	O
effect	O
of	O
high	O
frequency	O
STN	O
stimulation	O
in	O
23	O
patients	O
.	O

METHOD	O
:	O
Twenty	O
-	O
three	O
patients	O
suffering	O
from	O
severe	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
Stages	O
III	O
-	O
V	O
on	O
Hoehn	O
and	O
Yahr	O
scale	O
)	O
and	O
,	O
particularly	O
bradykinesia	B-Disease
,	O
rigidity	B-Disease
,	O
and	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
underwent	O
bilateral	O
implantation	O
of	O
electrodes	O
in	O
the	O
STN	O
.	O

Preoperative	O
and	O
postoperative	O
assessments	O
of	O
these	O
patients	O
at	O
1	O
,	O
3	O
,	O
6	O
and	O
12	O
months	O
follow	O
-	O
up	O
,	O
in	O
"	O
on	O
"	O
and	O
"	O
off	O
"	O
drug	O
conditions	O
,	O
was	O
carried	O
out	O
using	O
Unified	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
Disease	I-Disease
Rating	O
Scale	O
,	O
Hoehn	O
and	O
Yahr	O
staging	O
,	O
England	O
activities	O
of	O
daily	O
living	O
score	O
and	O
video	O
recordings	O
.	O

RESULTS	O
:	O
After	O
one	O
year	O
of	O
electrical	O
stimulation	O
of	O
the	O
STN	O
,	O
the	O
patients	O
'	O
scores	O
for	O
activities	O
of	O
daily	O
living	O
and	O
motor	O
examination	O
scores	O
(	O
Unified	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
Disease	I-Disease
Rating	O
Scale	O
parts	O
II	O
and	O
III	O
)	O
off	O
medication	O
improved	O
by	O
62	O
%	O
and	O
61	O
%	O
respectively	O
(	O
p	O
<	O
0	O
.	O
0005	O
)	O
.	O

The	O
subscores	O
for	O
the	O
akinesia	B-Disease
,	O
rigidity	B-Disease
,	O
tremor	B-Disease
and	O
gait	O
also	O
improved	O
.	O

(	O
p	O
<	O
0	O
.	O
0005	O
)	O
.	O

The	O
average	O
levodopa	B-Chemical
dose	O
decreased	O
from	O
813	O
mg	O
to	O
359	O
mg	O
.	O

The	O
cognitive	O
functions	O
remained	O
unchanged	O
.	O

Two	O
patients	O
developed	O
device	O
-	O
related	O
complications	O
and	O
two	O
patients	O
experienced	O
abnormal	O
weight	O
gain	O
.	O

CONCLUSION	O
:	O
Bilateral	O
subthalamic	O
nucleus	O
stimulation	O
is	O
an	O
effective	O
treatment	O
for	O
advanced	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

It	O
reduces	O
the	O
severity	O
of	O
"	O
off	O
"	O
phase	O
symptoms	O
,	O
improves	O
the	O
axial	O
symptoms	O
and	O
reduces	O
levodopa	B-Chemical
requirements	O
.	O

The	O
reduction	O
in	O
the	O
levodopa	B-Chemical
dose	O
is	O
useful	O
in	O
controlling	O
drug	B-Disease
-	I-Disease
induced	I-Disease
dyskinesias	I-Disease
.	O

Acute	B-Disease
renal	I-Disease
failure	I-Disease
occurring	O
during	O
intravenous	O
desferrioxamine	B-Chemical
therapy	O
:	O
recovery	O
after	O
haemodialysis	O
.	O

A	O
patient	O
with	O
transfusion	O
-	O
dependent	O
thalassemia	B-Disease
was	O
undergoing	O
home	O
intravenous	O
desferrioxamine	B-Chemical
(	O
DFX	B-Chemical
)	O
treatment	O
by	O
means	O
of	O
a	O
totally	O
implanted	O
system	O
because	O
of	O
his	O
poor	O
compliance	O
with	O
the	O
nightly	O
subcutaneous	O
therapy	O
.	O

Due	O
to	O
an	O
accidental	O
malfunctioning	O
of	O
the	O
infusion	O
pump	O
,	O
the	O
patient	O
was	O
inadvertently	O
administered	O
a	O
toxic	O
dosage	O
of	O
the	O
drug	O
which	O
caused	O
renal	B-Disease
insufficiency	I-Disease
.	O

Given	O
the	O
progressive	O
deterioration	O
of	O
the	O
symptoms	O
and	O
of	O
the	O
laboratory	O
values	O
,	O
despite	O
adequate	O
medical	O
treatment	O
,	O
a	O
decision	O
was	O
made	O
to	O
introduce	O
haemodialytical	O
therapy	O
in	O
order	O
to	O
remove	O
the	O
drug	O
and	O
therapy	O
reduce	O
the	O
nephrotoxicity	B-Disease
.	O

From	O
the	O
results	O
obtained	O
,	O
haemodialysis	O
can	O
therefore	O
be	O
suggested	O
as	O
a	O
useful	O
therapy	O
in	O
rare	O
cases	O
of	O
progressive	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
caused	O
by	O
desferrioxamine	B-Chemical
.	O

Ocular	O
motility	O
changes	O
after	O
subtenon	O
carboplatin	B-Chemical
chemotherapy	O
for	O
retinoblastoma	B-Disease
.	O

BACKGROUND	O
:	O
Focal	O
subtenon	O
carboplatin	B-Chemical
injections	O
have	O
recently	O
been	O
used	O
as	O
a	O
presumably	O
toxicity	B-Disease
-	O
free	O
adjunct	O
to	O
systemic	O
chemotherapy	O
for	O
intraocular	O
retinoblastoma	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
report	O
our	O
clinical	O
experience	O
with	O
abnormal	B-Disease
ocular	I-Disease
motility	I-Disease
in	O
patients	O
treated	O
with	O
subtenon	O
carboplatin	B-Chemical
chemotherapy	O
.	O

METHODS	O
:	O
We	O
noted	O
abnormal	B-Disease
ocular	I-Disease
motility	I-Disease
in	O
10	O
consecutive	O
patients	O
with	O
retinoblastoma	B-Disease
who	O
had	O
received	O
subtenon	O
carboplatin	B-Chemical
.	O

During	O
ocular	O
manipulation	O
under	O
general	O
anesthesia	O
,	O
we	O
assessed	O
their	O
eyes	O
by	O
forced	O
duction	O
testing	O
,	O
comparing	O
ocular	O
motility	O
after	O
tumor	B-Disease
control	O
with	O
ocular	O
motility	O
at	O
diagnosis	O
.	O

Eyes	O
subsequently	O
enucleated	O
because	O
of	O
treatment	O
failure	O
(	O
n	O
=	O
4	O
)	O
were	O
examined	O
histologically	O
.	O

RESULTS	O
:	O
Limitation	O
of	O
ocular	O
motility	O
was	O
detected	O
in	O
all	O
12	O
eyes	O
of	O
10	O
patients	O
treated	O
for	O
intraocular	O
retinoblastoma	B-Disease
with	O
1	O
to	O
6	O
injections	O
of	O
subtenon	O
carboplatin	B-Chemical
as	O
part	O
of	O
multimodality	O
therapy	O
.	O

Histopathological	O
examination	O
revealed	O
many	O
lipophages	O
in	O
the	O
periorbital	O
fat	O
surrounding	O
the	O
optic	O
nerve	O
in	O
1	O
eye	O
,	O
indicative	O
of	O
phagocytosis	O
of	O
previously	O
existing	O
fat	O
cells	O
and	O
suggesting	O
prior	O
fat	O
necrosis	B-Disease
.	O

The	O
enucleations	O
were	O
technically	O
difficult	O
and	O
hazardous	O
for	O
globe	O
rupture	B-Disease
because	O
of	O
extensive	O
orbital	O
soft	O
tissue	O
adhesions	O
.	O

CONCLUSIONS	O
:	O
Subtenon	O
carboplatin	B-Chemical
chemotherapy	O
is	O
associated	O
with	O
significant	O
fibrosis	B-Disease
of	O
orbital	O
soft	O
tissues	O
,	O
leading	O
to	O
mechanical	O
restriction	O
of	O
eye	O
movements	O
and	O
making	O
subsequent	O
enucleation	O
difficult	O
.	O

Subtenon	O
carboplatin	B-Chemical
is	O
not	O
free	O
of	O
toxicity	B-Disease
,	O
and	O
its	O
use	O
is	O
best	O
restricted	O
to	O
specific	O
indications	O
.	O

Ethambutol	B-Chemical
and	O
optic	B-Disease
neuropathy	I-Disease
.	O

PURPOSE	O
:	O
To	O
demonstrate	O
the	O
association	O
between	O
ethambutol	B-Chemical
and	O
optic	B-Disease
neuropathy	I-Disease
.	O

METHOD	O
:	O
Thirteen	O
patients	O
who	O
developed	O
optic	B-Disease
neuropathy	I-Disease
after	O
being	O
treated	O
with	O
ethambutol	B-Chemical
for	O
tuberculosis	B-Disease
of	I-Disease
the	I-Disease
lung	I-Disease
or	I-Disease
lymph	I-Disease
node	I-Disease
at	O
Siriraj	O
Hospital	O
between	O
1997	O
and	O
2001	O
were	O
retrospectively	O
reviewed	O
.	O

The	O
clinical	O
characteristics	O
and	O
initial	O
and	O
final	O
visual	O
acuity	O
were	O
analyzed	O
to	O
determine	O
visual	O
outcome	O
.	O

RESULTS	O
:	O
All	O
patients	O
had	O
optic	B-Disease
neuropathy	I-Disease
between	O
1	O
to	O
6	O
months	O
(	O
mean	O
=	O
2	O
.	O
9	O
months	O
)	O
after	O
starting	O
ethambutol	B-Chemical
therapy	O
at	O
a	O
dosage	O
ranging	O
from	O
13	O
to	O
20	O
mg	O
/	O
kg	O
/	O
day	O
(	O
mean	O
=	O
17	O
mg	O
/	O
kg	O
/	O
day	O
)	O
.	O

Seven	O
(	O
54	O
%	O
)	O
of	O
the	O
13	O
patients	O
experienced	O
visual	O
recovery	O
after	O
stopping	O
the	O
drug	O
.	O

Of	O
6	O
patients	O
with	O
irreversible	O
visual	B-Disease
impairment	I-Disease
,	O
4	O
patients	O
had	O
diabetes	B-Disease
mellitus	I-Disease
,	O
glaucoma	B-Disease
and	O
a	O
history	O
of	O
heavy	O
smoking	O
.	O

CONCLUSION	O
:	O
Early	O
recognition	O
of	O
optic	B-Disease
neuropathy	I-Disease
should	O
be	O
considered	O
in	O
patients	O
with	O
ethambutol	B-Chemical
therapy	O
.	O

A	O
low	O
dose	O
and	O
prompt	O
discontinuation	O
of	O
the	O
drug	O
is	O
recommended	O
particularly	O
in	O
individuals	O
with	O
diabetes	B-Disease
mellitus	I-Disease
,	O
glaucoma	B-Disease
or	O
who	O
are	O
heavy	O
smokers	O
.	O

Treatment	O
of	O
compensatory	O
gustatory	B-Disease
hyperhidrosis	I-Disease
with	O
topical	O
glycopyrrolate	B-Chemical
.	O

Gustatory	B-Disease
hyperhidrosis	I-Disease
is	O
facial	O
sweating	B-Disease
usually	O
associated	O
with	O
the	O
eating	O
of	O
hot	O
spicy	O
food	O
or	O
even	O
smelling	O
this	O
food	O
.	O

Current	O
options	O
of	O
treatment	O
include	O
oral	O
anticholinergic	O
drugs	O
,	O
the	O
topical	O
application	O
of	O
anticholinergics	O
or	O
aluminum	B-Chemical
chloride	I-Chemical
,	O
and	O
the	O
injection	O
of	O
botulinum	O
toxin	O
.	O

Thirteen	O
patients	O
have	O
been	O
treated	O
to	O
date	O
with	O
1	O
.	O
5	O
%	O
or	O
2	O
%	O
topical	O
glycopyrrolate	B-Chemical
.	O

All	O
patients	O
had	O
gustatory	B-Disease
hyperhidrosis	I-Disease
,	O
which	O
interfered	O
with	O
their	O
social	O
activities	O
,	O
after	O
transthroacic	O
endoscopic	O
sympathectomy	O
,	O
and	O
which	O
was	O
associated	O
with	O
compensatory	O
focal	O
hyperhidrosis	B-Disease
.	O

After	O
applying	O
topical	O
glycopyrrolate	B-Chemical
,	O
the	O
subjective	O
effect	O
was	O
excellent	O
(	O
no	O
sweating	B-Disease
after	O
eating	O
hot	O
spicy	O
food	O
)	O
in	O
10	O
patients	O
(	O
77	O
%	O
)	O
,	O
and	O
fair	O
(	O
clearly	O
reduced	O
sweating	B-Disease
)	O
in	O
3	O
patients	O
(	O
23	O
%	O
)	O
.	O

All	O
had	O
reported	O
incidents	O
of	O
being	O
very	O
embarrassed	O
whilst	O
eating	O
hot	O
spicy	O
foods	O
.	O

Adverse	O
effects	O
included	O
a	O
mildly	O
dry	B-Disease
mouth	I-Disease
and	O
a	O
sore	B-Disease
throat	I-Disease
in	O
2	O
patients	O
(	O
2	O
%	O
glycopyrrolate	B-Chemical
)	O
,	O
a	O
light	O
headache	B-Disease
in	O
1	O
patient	O
(	O
1	O
.	O
5	O
%	O
glycopyrrolate	B-Chemical
)	O
.	O

The	O
topical	O
application	O
of	O
a	O
glycopyrrolate	B-Chemical
pad	O
appeared	O
to	O
be	O
safe	O
,	O
efficacious	O
,	O
well	O
tolerated	O
,	O
and	O
a	O
convenient	O
method	O
of	O
treatment	O
for	O
moderate	O
to	O
severe	O
symptoms	O
of	O
gustatory	B-Disease
hyperhidrosis	I-Disease
in	O
post	O
transthoracic	O
endoscopic	O
sympathectomy	O
or	O
sympathicotomy	O
patients	O
,	O
with	O
few	O
side	O
effects	O
.	O

Neuroleptic	B-Chemical
-	O
associated	O
hyperprolactinemia	B-Disease
.	O

Can	O
it	O
be	O
treated	O
with	O
bromocriptine	B-Chemical
?	O

Six	O
stable	O
psychiatric	O
outpatients	O
with	O
hyperprolactinemia	B-Disease
and	O
amenorrhea	B-Disease
/	O
oligomenorrhea	B-Disease
associated	O
with	O
their	O
neuroleptic	B-Chemical
medications	I-Chemical
were	O
treated	O
with	O
bromocriptine	B-Chemical
.	O

Daily	O
dosages	O
of	O
5	O
-	O
10	O
mg	O
corrected	O
the	O
hyperprolactinemia	B-Disease
and	O
restored	O
menstruation	O
in	O
four	O
of	O
the	O
six	O
patients	O
.	O

One	O
woman	O
,	O
however	O
,	O
developed	O
worsened	O
psychiatric	B-Disease
symptoms	I-Disease
while	O
taking	O
bromocriptine	B-Chemical
,	O
and	O
it	O
was	O
discontinued	O
.	O

Thus	O
,	O
three	O
of	O
six	O
patients	O
had	O
their	O
menstrual	O
irregularity	O
successfully	O
corrected	O
with	O
bromocriptine	B-Chemical
.	O

This	O
suggests	O
that	O
bromocriptine	B-Chemical
should	O
be	O
further	O
evaluated	O
as	O
potential	O
therapy	O
for	O
neuroleptic	B-Chemical
-	O
associated	O
hyperprolactinemia	B-Disease
and	O
amenorrhea	B-Disease
/	O
galactorrhea	B-Disease
.	O

Ethacrynic	B-Chemical
acid	I-Chemical
-	O
induced	O
convulsions	B-Disease
and	O
brain	O
neurotransmitters	O
in	O
mice	O
.	O

Intracerebroventricular	O
injection	O
of	O
ethacrynic	B-Chemical
acid	I-Chemical
(	O
50	O
%	O
convulsive	B-Disease
dose	O
;	O
50	O
micrograms	O
/	O
mouse	O
)	O
accelerated	O
the	O
synthesis	O
/	O
turnover	O
of	O
5	B-Chemical
-	I-Chemical
hydroxytryptamine	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
)	O
but	O
suppressed	O
the	O
synthesis	O
of	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
and	O
acetylcholine	B-Chemical
in	O
mouse	O
brain	O
.	O

These	O
effects	O
were	O
completely	O
antagonized	O
by	O
pretreatment	O
with	O
a	O
glutamate	B-Chemical
/	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
antagonist	O
,	O
aminophosphonovaleric	B-Chemical
acid	I-Chemical
.	O

In	O
ethacrynic	B-Chemical
acid	I-Chemical
-	O
induced	O
convulsions	B-Disease
,	O
these	O
neurotransmitter	O
systems	O
may	O
be	O
differentially	O
modulated	O
,	O
probably	O
through	O
activation	O
of	O
glutaminergic	O
neurons	O
in	O
the	O
brain	O
.	O

Pharmacology	O
of	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acidA	I-Chemical
receptor	O
complex	O
after	O
the	O
in	O
vivo	O
administration	O
of	O
the	O
anxioselective	O
and	O
anticonvulsant	O
beta	B-Chemical
-	I-Chemical
carboline	I-Chemical
derivative	O
abecarnil	B-Chemical
.	O

In	O
rodents	O
,	O
the	O
effect	O
of	O
the	O
beta	B-Chemical
-	I-Chemical
carboline	I-Chemical
derivative	O
isopropyl	B-Chemical
-	I-Chemical
6	I-Chemical
-	I-Chemical
benzyloxy	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
methoxymethyl	I-Chemical
-	I-Chemical
beta	I-Chemical
-	I-Chemical
carboline	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
carboxylate	I-Chemical
(	O
abecarrnil	B-Chemical
)	O
,	O
a	O
new	O
ligand	O
for	O
benzodiazepine	B-Chemical
receptors	O
possessing	O
anxiolytic	O
and	O
anticonvulsant	O
properties	O
,	O
was	O
evaluated	O
on	O
the	O
function	O
of	O
central	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
(	O
GABA	B-Chemical
)	O
A	O
receptor	O
complex	O
,	O
both	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

Added	O
in	O
vitro	O
to	O
rat	O
cortical	O
membrane	O
preparation	O
,	O
abecarnil	B-Chemical
increased	O
[	O
3H	O
]	O
GABA	B-Chemical
binding	O
,	O
enhanced	O
muscimol	B-Chemical
-	O
stimulated	O
36Cl	O
-	O
uptake	O
and	O
reduced	O
the	O
binding	O
of	O
t	B-Chemical
-	I-Chemical
[	I-Chemical
35S	I-Chemical
]	I-Chemical
butylbicyclophosphorothionate	I-Chemical
(	O
[	B-Chemical
35S	I-Chemical
]	I-Chemical
TBPS	I-Chemical
)	O
.	O

These	O
effects	O
were	O
similar	O
to	O
those	O
induced	O
by	O
diazepam	B-Chemical
,	O
whereas	O
the	O
partial	O
agonist	O
Ro	B-Chemical
16	I-Chemical
-	I-Chemical
6028	I-Chemical
(	O
tert	B-Chemical
-	I-Chemical
butyl	I-Chemical
-	I-Chemical
(	I-Chemical
S	I-Chemical
)	I-Chemical
-	I-Chemical
8	I-Chemical
-	I-Chemical
bromo	I-Chemical
-	I-Chemical
11	I-Chemical
,	I-Chemical
12	I-Chemical
,	I-Chemical
13	I-Chemical
,	I-Chemical
13a	I-Chemical
-	I-Chemical
tetrahydro	I-Chemical
-	I-Chemical
9	I-Chemical
-	I-Chemical
oxo	I-Chemical
-	I-Chemical
9H	I-Chemical
-	I-Chemical
imidazo	I-Chemical
[	I-Chemical
1	I-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
a	I-Chemical
]	I-Chemical
-	I-Chemical
pyrrolo	I-Chemical
-	I-Chemical
[	I-Chemical
2	I-Chemical
,	I-Chemical
1	I-Chemical
-	I-Chemical
c	I-Chemical
]	I-Chemical
[	I-Chemical
1	I-Chemical
,	I-Chemical
4	I-Chemical
]	I-Chemical
benzodiazepine	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
carboxylate	I-Chemical
)	O
showed	O
very	O
weak	O
efficacy	O
in	O
these	O
biochemical	O
tests	O
.	O

After	O
i	O
.	O
p	O
.	O
injection	O
to	O
rats	O
,	O
abecarnil	B-Chemical
and	O
diazepam	B-Chemical
decreased	O
in	O
a	O
time	O
-	O
dependent	O
and	O
dose	O
-	O
related	O
(	O
0	O
.	O
25	O
-	O
20	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
manner	O
[	B-Chemical
35S	I-Chemical
]	I-Chemical
TBPS	I-Chemical
binding	O
measured	O
ex	O
vivo	O
in	O
the	O
cerebral	O
cortex	O
.	O

Moreover	O
,	O
both	O
drugs	O
at	O
the	O
dose	O
of	O
0	O
.	O
5	O
mg	O
/	O
kg	O
antagonized	O
completely	O
the	O
convulsant	O
activity	O
and	O
the	O
increase	O
of	O
[	B-Chemical
35S	I-Chemical
]	I-Chemical
TBPS	I-Chemical
binding	O
induced	O
by	O
isoniazide	B-Chemical
(	O
350	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
as	O
well	O
as	O
the	O
increase	O
of	O
[	B-Chemical
35S	I-Chemical
]	I-Chemical
TBPS	I-Chemical
binding	O
induced	O
by	O
foot	O
-	O
shock	O
stress	O
.	O

To	O
better	O
correlate	O
the	O
biochemical	O
and	O
the	O
pharmacological	O
effects	O
,	O
we	O
studied	O
the	O
action	O
of	O
abecarnil	B-Chemical
on	O
[	B-Chemical
35S	I-Chemical
]	I-Chemical
TBPS	I-Chemical
binding	O
,	O
exploratory	O
motility	O
and	O
on	O
isoniazid	B-Chemical
-	O
induced	O
biochemical	O
and	O
pharmacological	O
effects	O
in	O
mice	O
.	O

In	O
these	O
animals	O
,	O
abecarnil	B-Chemical
produced	O
a	O
paralleled	O
dose	O
-	O
dependent	O
(	O
0	O
.	O
05	O
-	O
1	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
reduction	O
of	O
both	O
motor	O
behavior	O
and	O
cortical	O
[	O
35S	O
]	O
TBPS	O
binding	O
.	O

Moreover	O
,	O
0	O
.	O
05	O
mg	O
/	O
kg	O
of	O
this	O
beta	B-Chemical
-	I-Chemical
carboline	I-Chemical
reduced	O
markedly	O
the	O
increase	O
of	O
[	B-Chemical
35S	I-Chemical
]	I-Chemical
TBPS	I-Chemical
binding	O
and	O
the	O
convulsions	B-Disease
induced	O
by	O
isoniazid	B-Chemical
(	O
200	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Recurrent	O
myocardial	B-Disease
infarction	I-Disease
in	O
a	O
postpartum	O
patient	O
receiving	O
bromocriptine	B-Chemical
.	O

Myocardial	B-Disease
infarction	I-Disease
in	O
puerperium	O
is	O
infrequently	O
reported	O
.	O

Spasm	B-Disease
,	O
coronary	O
dissection	O
,	O
or	O
atheromatous	O
etiology	O
has	O
been	O
described	O
.	O

Bromocriptine	B-Chemical
has	O
been	O
implicated	O
in	O
several	O
previous	O
case	O
reports	O
of	O
myocardial	B-Disease
infarction	I-Disease
in	O
the	O
puerperium	O
.	O

Our	O
case	O
(	O
including	O
an	O
inadvertent	O
rechallenge	O
)	O
suggests	O
such	O
a	O
relationship	O
.	O

Although	O
generally	O
regarded	O
as	O
"	O
safe	O
,	O
"	O
possible	O
serious	O
cardiac	O
effects	O
of	O
bromocriptine	B-Chemical
should	O
be	O
acknowledged	O
.	O

Asterixis	B-Disease
induced	O
by	O
carbamazepine	B-Chemical
therapy	O
.	O

There	O
are	O
very	O
few	O
reports	O
about	O
asterixis	B-Disease
as	O
a	O
side	O
effect	O
of	O
treatment	O
with	O
psychopharmacologic	O
agents	O
.	O

In	O
this	O
report	O
we	O
present	O
four	O
patients	O
treated	O
with	O
a	O
combination	O
of	O
different	O
psychotropic	O
drugs	O
,	O
in	O
whom	O
asterixis	B-Disease
was	O
triggered	O
either	O
by	O
adding	O
carbamazepine	B-Chemical
(	O
CBZ	B-Chemical
)	O
to	O
a	O
treatment	O
regimen	O
,	O
or	O
by	O
increasing	O
its	O
dosage	O
.	O

Neither	O
dosage	O
nor	O
serum	O
levels	O
of	O
CBZ	B-Chemical
were	O
in	O
a	O
higher	O
range	O
.	O

We	O
consider	O
asterixis	B-Disease
to	O
be	O
an	O
easily	O
overlooked	O
sign	O
of	O
neurotoxicity	B-Disease
,	O
which	O
may	O
occur	O
even	O
at	O
low	O
or	O
moderate	O
dosage	O
levels	O
,	O
if	O
certain	O
drugs	O
as	O
lithium	B-Chemical
or	O
clozapine	B-Chemical
are	O
used	O
in	O
combination	O
with	O
CBZ	B-Chemical
.	O

Pharmacodynamics	O
of	O
the	O
hypotensive	B-Disease
effect	O
of	O
levodopa	B-Chemical
in	O
parkinsonian	B-Disease
patients	O
.	O

Blood	O
pressure	O
effects	O
of	O
i	O
.	O
v	O
.	O
levodopa	B-Chemical
were	O
examined	O
in	O
parkinsonian	B-Disease
patients	O
with	O
stable	O
and	O
fluctuating	O
responses	O
to	O
levodopa	B-Chemical
.	O

The	O
magnitude	O
of	O
the	O
hypotensive	B-Disease
effect	O
of	O
levodopa	B-Chemical
was	O
concentration	O
dependent	O
and	O
was	O
fit	O
to	O
an	O
Emax	O
model	O
in	O
fluctuating	O
responders	O
.	O

Stable	O
responders	O
demonstrated	O
a	O
small	O
hypotensive	B-Disease
response	O
.	O

Baseline	O
blood	O
pressures	O
were	O
higher	O
in	O
fluctuating	O
patients	O
;	O
a	O
higher	O
baseline	O
blood	O
pressure	O
correlated	O
with	O
greater	O
hypotensive	B-Disease
effects	O
.	O

Antiparkinsonian	O
effects	O
of	O
levodopa	B-Chemical
temporally	O
correlated	O
with	O
blood	O
pressure	O
changes	O
.	O

Phenylalanine	B-Chemical
,	O
a	O
large	O
neutral	O
amino	B-Chemical
acid	I-Chemical
(	O
LNAA	O
)	O
competing	O
with	O
levodopa	B-Chemical
for	O
transport	O
across	O
the	O
blood	O
-	O
brain	O
barrier	O
,	O
reduced	O
the	O
hypotensive	B-Disease
and	O
antiparkinsonian	O
effects	O
of	O
levodopa	B-Chemical
.	O

We	O
conclude	O
that	O
levodopa	B-Chemical
has	O
a	O
central	O
hypotensive	B-Disease
action	O
that	O
parallels	O
the	O
motor	O
effects	O
in	O
fluctuating	O
patients	O
.	O

The	O
hypotensive	B-Disease
effect	O
appears	O
to	O
be	O
related	O
to	O
the	O
higher	O
baseline	O
blood	O
pressure	O
we	O
observed	O
in	O
fluctuating	O
patients	O
relative	O
to	O
stable	O
patients	O
.	O

Syndrome	B-Disease
of	I-Disease
inappropriate	I-Disease
secretion	I-Disease
of	I-Disease
antidiuretic	I-Disease
hormone	I-Disease
after	O
infusional	O
vincristine	B-Chemical
.	O

A	O
77	O
-	O
year	O
-	O
old	O
woman	O
with	O
refractory	O
multiple	B-Disease
myeloma	I-Disease
was	O
treated	O
with	O
a	O
4	O
-	O
day	O
continuous	O
intravenous	O
infusion	O
of	O
vincristine	B-Chemical
and	O
doxorubicin	B-Chemical
and	O
4	O
days	O
of	O
oral	O
dexamethasone	B-Chemical
.	O

Nine	O
days	O
after	O
her	O
second	O
cycle	O
she	O
presented	O
with	O
lethargy	B-Disease
and	O
weakness	B-Disease
associated	O
with	O
hyponatremia	B-Disease
.	O

Evaluation	O
revealed	O
the	O
syndrome	B-Disease
of	I-Disease
inappropriate	I-Disease
secretion	I-Disease
of	I-Disease
antidiuretic	I-Disease
hormone	I-Disease
,	O
which	O
was	O
attributed	O
to	O
the	O
vincristine	B-Chemical
infusion	O
.	O

After	O
normal	O
serum	O
sodium	B-Chemical
levels	O
returned	O
,	O
further	O
doxorubicin	B-Chemical
and	O
dexamethasone	B-Chemical
chemotherapy	O
without	O
vincristine	B-Chemical
did	O
not	O
produce	O
this	O
complication	O
.	O

Heart	B-Disease
failure	I-Disease
:	O
to	O
digitalise	O
or	O
not	O
?	O

The	O
view	O
against	O
.	O

Despite	O
extensive	O
clinical	O
experience	O
the	O
role	O
of	O
digoxin	B-Chemical
is	O
still	O
not	O
well	O
defined	O
.	O

In	O
patients	O
with	O
atrial	B-Disease
fibrillation	I-Disease
digoxin	B-Chemical
is	O
beneficial	O
for	O
ventricular	O
rate	O
control	O
.	O

For	O
patients	O
in	O
sinus	O
rhythm	O
and	O
heart	B-Disease
failure	I-Disease
the	O
situation	O
is	O
less	O
clear	O
.	O

Digoxin	B-Chemical
has	O
a	O
narrow	O
therapeutic	O
:	O
toxic	O
ratio	O
and	O
concentrations	O
are	O
affected	O
by	O
a	O
number	O
of	O
drugs	O
.	O

Also	O
,	O
digoxin	B-Chemical
has	O
undesirable	O
effects	O
such	O
as	O
increasing	O
peripheral	O
resistance	O
and	O
myocardial	O
demands	O
,	O
and	O
causing	O
arrhythmias	B-Disease
.	O

There	O
is	O
a	O
paucity	O
of	O
data	O
from	O
well	O
-	O
designed	O
trials	O
.	O

The	O
trials	O
that	O
are	O
available	O
are	O
generally	O
small	O
with	O
limitations	O
in	O
design	O
and	O
these	O
show	O
variation	O
in	O
patient	O
benefit	O
.	O

More	O
convincing	O
evidence	O
is	O
required	O
showing	O
that	O
digoxin	B-Chemical
improves	O
symptoms	O
or	O
exercise	O
capacity	O
.	O

Furthermore	O
,	O
no	O
trial	O
has	O
had	O
sufficient	O
power	O
to	O
evaluate	O
mortality	O
.	O

Pooled	O
analysis	O
of	O
the	O
effects	O
of	O
other	O
inotropic	O
drugs	O
shows	O
an	O
excess	O
mortality	O
and	O
there	O
is	O
a	O
possibility	O
that	O
digoxin	B-Chemical
may	O
increase	O
mortality	O
after	O
myocardial	B-Disease
infarction	I-Disease
(	O
MI	B-Disease
)	O
.	O

Angiotensin	B-Chemical
-	O
converting	O
enzyme	O
(	O
ACE	O
)	O
inhibitors	O
should	O
be	O
used	O
first	O
as	O
they	O
are	O
safer	O
,	O
do	O
not	O
require	O
blood	O
level	O
monitoring	O
,	O
modify	O
progression	O
of	O
disease	O
,	O
relieve	O
symptoms	O
,	O
improve	O
exercise	O
tolerance	O
and	O
reduce	O
mortality	O
.	O

Caution	O
should	O
be	O
exercised	O
in	O
using	O
digoxin	B-Chemical
until	O
large	O
mortality	O
trials	O
are	O
completed	O
showing	O
either	O
benefit	O
or	O
harm	O
.	O

Until	O
then	O
digoxin	B-Chemical
should	O
be	O
considered	O
a	O
third	O
-	O
line	O
therapy	O
.	O

Isradipine	B-Chemical
treatment	O
for	O
hypertension	B-Disease
in	O
general	O
practice	O
in	O
Hong	O
Kong	O
.	O

A	O
6	O
-	O
week	O
open	O
study	O
of	O
the	O
introduction	O
of	O
isradipine	B-Chemical
treatment	O
was	O
conducted	O
in	O
general	O
practice	O
in	O
Hong	O
Kong	O
.	O

303	O
Chinese	O
patients	O
with	O
mild	O
to	O
moderate	O
hypertension	B-Disease
entered	O
the	O
study	O
.	O

Side	O
effects	O
were	O
reported	O
in	O
21	O
%	O
of	O
patients	O
and	O
caused	O
withdrawal	O
from	O
the	O
study	O
in	O
3	O
patients	O
.	O

The	O
main	O
side	O
-	O
effects	O
were	O
headache	B-Disease
,	O
dizziness	B-Disease
,	O
palpitation	B-Disease
and	O
flushing	B-Disease
and	O
these	O
were	O
not	O
more	O
frequent	O
than	O
reported	O
in	O
other	O
studies	O
with	O
isradipine	B-Chemical
or	O
with	O
placebo	O
.	O

Supine	O
blood	O
pressure	O
was	O
reduced	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
from	O
170	O
+	O
/	O
-	O
20	O
/	O
102	O
+	O
/	O
-	O
6	O
mmHg	O
to	O
153	O
+	O
/	O
-	O
19	O
/	O
92	O
+	O
/	O
-	O
8	O
,	O
147	O
+	O
/	O
-	O
18	O
/	O
88	O
+	O
/	O
-	O
7	O
and	O
144	O
+	O
/	O
-	O
14	O
/	O
87	O
+	O
/	O
-	O
6	O
mmHg	O
at	O
2	O
,	O
4	O
and	O
6	O
weeks	O
respectively	O
in	O
evaluable	O
patients	O
.	O

Similar	O
reductions	O
occurred	O
in	O
standing	O
blood	O
pressure	O
and	O
there	O
was	O
no	O
evidence	O
of	O
postural	B-Disease
hypotension	I-Disease
.	O

Normalization	O
and	O
responder	O
rates	O
at	O
6	O
weeks	O
were	O
86	O
%	O
and	O
69	O
%	O
respectively	O
.	O

Dosage	O
was	O
increased	O
from	O
2	O
.	O
5	O
mg	O
b	O
.	O
d	O
.	O
to	O
5	O
mg	O
b	O
.	O
d	O
.	O
at	O
4	O
weeks	O
in	O
patients	O
with	O
diastolic	O
blood	O
pressure	O
greater	O
than	O
90	O
mmHg	O
and	O
their	O
further	O
response	O
was	O
greater	O
than	O
those	O
remaining	O
on	O
2	O
.	O
5	O
mg	O
b	O
.	O
d	O
.	O

Pharmacological	O
characteristics	O
and	O
side	O
effects	O
of	O
a	O
new	O
galenic	O
formulation	O
of	O
propofol	B-Chemical
without	O
soyabean	O
oil	O
.	O

We	O
compared	O
the	O
pharmacokinetics	O
,	O
pharmacodynamics	O
and	O
safety	O
profile	O
of	O
a	O
new	O
galenic	O
formulation	O
of	O
propofol	B-Chemical
(	O
AM149	O
1	O
%	O
)	O
,	O
which	O
does	O
not	O
contain	O
soyabean	O
oil	O
,	O
with	O
a	O
standard	O
formulation	O
of	O
propofol	B-Chemical
(	O
Disoprivan	B-Chemical
1	O
%	O
)	O
.	O

In	O
a	O
randomised	O
,	O
double	O
-	O
blind	O
,	O
cross	O
-	O
over	O
study	O
,	O
30	O
healthy	O
volunteers	O
received	O
a	O
single	O
intravenous	O
bolus	O
injection	O
of	O
2	O
.	O
5	O
mg	O
.	O
kg	O
-	O
1	O
propofol	B-Chemical
.	O

Plasma	O
propofol	B-Chemical
levels	O
were	O
measured	O
for	O
48	O
h	O
following	O
drug	O
administration	O
and	O
evaluated	O
according	O
to	O
a	O
three	O
-	O
compartment	O
model	O
.	O

The	O
pharmacodynamic	O
parameters	O
assessed	O
included	O
induction	O
and	O
emergence	O
times	O
,	O
respiratory	O
and	O
cardiovascular	O
effects	O
,	O
and	O
pain	B-Disease
on	O
injection	O
.	O

Patients	O
were	O
monitored	O
for	O
side	O
effects	O
over	O
48	O
h	O
.	O

Owing	O
to	O
a	O
high	O
incidence	O
of	O
thrombophlebitis	B-Disease
,	O
the	O
study	O
was	O
terminated	O
prematurely	O
and	O
only	O
the	O
data	O
of	O
the	O
two	O
parallel	O
treatment	O
groups	O
(	O
15	O
patients	O
in	O
each	O
group	O
)	O
were	O
analysed	O
.	O

Plasma	O
concentrations	O
did	O
not	O
differ	O
significantly	O
between	O
the	O
two	O
formulations	O
.	O

Anaesthesia	O
induction	O
and	O
emergence	O
times	O
,	O
respiratory	O
and	O
cardiovascular	O
variables	O
showed	O
no	O
significant	O
differences	O
between	O
the	O
two	O
treatment	O
groups	O
.	O

Pain	B-Disease
on	O
injection	O
(	O
80	O
vs	O
.	O
20	O
%	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
and	O
thrombophlebitis	B-Disease
(	O
93	O
.	O
3	O
vs	O
.	O
6	O
.	O
6	O
%	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
occurred	O
more	O
frequently	O
with	O
AM149	O
than	O
with	O
Disoprivan	B-Chemical
.	O

Although	O
both	O
formulations	O
had	O
similar	O
pharmacokinetic	O
and	O
pharmacodynamic	O
profiles	O
the	O
new	O
formulation	O
is	O
not	O
suitable	O
for	O
clinical	O
use	O
due	O
to	O
the	O
high	O
incidence	O
of	O
thrombophlebitis	B-Disease
produced	O
.	O

Pure	B-Disease
red	I-Disease
cell	I-Disease
aplasia	I-Disease
,	O
toxic	B-Disease
dermatitis	I-Disease
and	O
lymphadenopathy	B-Disease
in	O
a	O
patient	O
taking	O
diphenylhydantoin	B-Chemical
.	O

A	O
patient	O
taking	O
diphenylhydantoin	B-Chemical
for	O
3	O
weeks	O
developed	O
a	O
generalized	O
skin	B-Disease
rash	I-Disease
,	O
lymphadenopathy	B-Disease
and	O
pure	B-Disease
red	I-Disease
cell	I-Disease
aplasia	I-Disease
.	O

After	O
withdrawal	O
of	O
the	O
pharmacon	O
all	O
symptoms	O
disappeared	O
spontaneously	O
.	O

Skin	B-Disease
rash	I-Disease
is	O
a	O
well	O
-	O
known	O
complication	O
of	O
diphenylhydantoin	B-Chemical
treatment	O
as	O
is	O
benign	O
and	O
malignant	O
lymphadenopathy	B-Disease
.	O

Pure	B-Disease
red	I-Disease
cell	I-Disease
aplasia	I-Disease
associated	O
with	O
diphenylhydantoin	B-Chemical
medication	O
has	O
been	O
reported	O
in	O
3	O
patients	O
.	O

The	O
exact	O
mechanism	O
by	O
which	O
diphenylhydantoin	B-Chemical
exerts	O
its	O
toxic	O
effects	O
is	O
not	O
known	O
.	O

In	O
this	O
patient	O
the	O
time	O
relation	O
between	O
the	O
ingestion	O
of	O
diphenylhydantoin	B-Chemical
and	O
the	O
occurrence	O
of	O
the	O
skin	B-Disease
rash	I-Disease
,	O
lymphadenopathy	B-Disease
and	O
pure	B-Disease
red	I-Disease
cell	I-Disease
aplasia	I-Disease
is	O
very	O
suggestive	O
of	O
a	O
direct	O
connection	O
.	O

Vinorelbine	B-Chemical
-	O
related	O
cardiac	O
events	O
:	O
a	O
meta	O
-	O
analysis	O
of	O
randomized	O
clinical	O
trials	O
.	O

Several	O
cases	O
of	O
cardiac	O
adverse	O
reactions	O
related	O
to	O
vinorelbine	B-Chemical
(	O
VNR	B-Chemical
)	O
have	O
been	O
reported	O
in	O
the	O
literature	O
.	O

In	O
order	O
to	O
quantify	O
the	O
incidence	O
of	O
these	O
cardiac	O
events	O
,	O
we	O
performed	O
a	O
meta	O
-	O
analysis	O
of	O
clinical	O
trials	O
comparing	O
VNR	B-Chemical
with	O
other	O
chemotherapeutic	O
agents	O
in	O
the	O
treatment	O
of	O
various	O
malignancies	B-Disease
.	O

Randomized	O
clinical	O
trials	O
comparing	O
VNR	B-Chemical
with	O
other	O
drugs	O
in	O
the	O
treatment	O
of	O
cancer	B-Disease
were	O
searched	O
in	O
Medline	O
,	O
Embase	O
,	O
Evidence	O
-	O
based	O
Medicine	O
Reviews	O
databases	O
and	O
the	O
Cochrane	O
library	O
from	O
1987	O
to	O
2002	O
.	O

Outcomes	O
of	O
interest	O
were	O
severe	O
cardiac	O
events	O
,	O
toxic	O
deaths	O
and	O
cardiac	O
event	O
-	O
related	O
deaths	O
reported	O
in	O
each	O
publication	O
.	O

We	O
found	O
19	O
trials	O
,	O
involving	O
2441	O
patients	O
treated	O
by	O
VNR	B-Chemical
and	O
2050	O
control	O
patients	O
.	O

The	O
incidence	O
of	O
cardiac	O
events	O
with	O
VNR	B-Chemical
was	O
1	O
.	O
19	O
%	O
[	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
(	O
0	O
.	O
75	O
;	O
1	O
.	O
67	O
)	O
]	O
.	O

There	O
was	O
no	O
difference	O
in	O
the	O
risk	O
of	O
cardiac	O
events	O
between	O
VNR	B-Chemical
and	O
other	O
drugs	O
[	O
odds	O
ratio	O
:	O
0	O
.	O
92	O
,	O
95	O
%	O
CI	O
(	O
0	O
.	O
54	O
;	O
1	O
.	O
55	O
)	O
]	O
.	O

The	O
risk	O
of	O
VNR	B-Chemical
cardiac	O
events	O
was	O
similar	O
to	O
vindesine	B-Chemical
(	O
VDS	B-Chemical
)	O
and	O
other	O
cardiotoxic	B-Disease
drugs	O
[	O
fluorouracil	B-Chemical
,	O
anthracyclines	B-Chemical
,	O
gemcitabine	B-Chemical
(	O
GEM	B-Chemical
)	O
em	O
leader	O
]	O
.	O

Even	O
if	O
it	O
did	O
not	O
reach	O
statistical	O
significance	O
because	O
of	O
a	O
few	O
number	O
of	O
cases	O
,	O
the	O
risk	O
was	O
lower	O
in	O
trials	O
excluding	O
patients	O
with	O
cardiac	O
history	O
,	O
and	O
seemed	O
to	O
be	O
higher	O
in	O
trials	O
including	O
patients	O
with	O
pre	O
-	O
existing	O
cardiac	B-Disease
diseases	I-Disease
.	O

Vinorelbine	B-Chemical
-	O
related	O
cardiac	O
events	O
concern	O
about	O
1	O
%	O
of	O
treated	O
patients	O
in	O
clinical	O
trials	O
.	O

However	O
,	O
the	O
risk	O
associated	O
with	O
VNR	B-Chemical
seems	O
to	O
be	O
similar	O
to	O
that	O
of	O
other	O
chemotherapeutic	O
agents	O
in	O
the	O
same	O
indications	O
.	O

MRI	O
findings	O
of	O
hypoxic	O
cortical	O
laminar	O
necrosis	B-Disease
in	O
a	O
child	O
with	O
hemolytic	B-Disease
anemia	I-Disease
crisis	O
.	O

We	O
present	O
magnetic	O
resonance	O
imaging	O
findings	O
of	O
a	O
5	O
-	O
year	O
-	O
old	O
girl	O
who	O
had	O
a	O
rapidly	O
installing	O
hemolytic	B-Disease
anemia	I-Disease
crisis	O
induced	O
by	O
trimethoprim	B-Chemical
-	I-Chemical
sulfomethoxazole	I-Chemical
,	O
resulting	O
in	O
cerebral	B-Disease
anoxia	I-Disease
leading	O
to	O
permanent	O
damage	O
.	O

Magnetic	O
Resonance	O
imaging	O
revealed	O
cortical	O
laminar	O
necrosis	B-Disease
in	O
arterial	O
border	O
zones	O
in	O
both	O
cerebral	O
hemispheres	O
,	O
ischemic	O
changes	O
in	O
subcortical	O
white	O
matter	O
of	O
left	O
cerebral	O
hemisphere	O
,	O
and	O
in	O
the	O
left	O
putamen	O
.	O

Although	O
cortical	O
laminar	O
necrosis	B-Disease
is	O
a	O
classic	O
entity	O
in	O
adulthood	O
related	O
to	O
conditions	O
of	O
energy	O
depletions	O
,	O
there	O
are	O
few	O
reports	O
available	O
in	O
children	O
.	O

A	O
wide	O
review	O
of	O
the	O
literature	O
is	O
also	O
presented	O
.	O

The	O
natural	O
history	O
of	O
Vigabatrin	B-Chemical
associated	O
visual	B-Disease
field	I-Disease
defects	I-Disease
in	O
patients	O
electing	O
to	O
continue	O
their	O
medication	O
.	O

PURPOSE	O
:	O
To	O
determine	O
the	O
natural	O
history	O
of	O
visual	B-Disease
field	I-Disease
defects	I-Disease
in	O
a	O
group	O
of	O
patients	O
known	O
to	O
have	O
Vigabatrin	B-Chemical
-	O
associated	O
changes	O
who	O
elected	O
to	O
continue	O
the	O
medication	O
because	O
of	O
good	O
seizure	B-Disease
control	O
.	O

METHODS	O
:	O
All	O
patients	O
taking	O
Vigabatrin	B-Chemical
alone	O
or	O
in	O
combination	O
with	O
other	O
antiepileptic	O
drugs	O
for	O
at	O
least	O
5	O
years	O
(	O
range	O
5	O
-	O
12	O
years	O
)	O
were	O
entered	O
into	O
a	O
visual	O
surveillance	O
programme	O
.	O

Patients	O
were	O
followed	O
up	O
at	O
6	O
-	O
monthly	O
intervals	O
for	O
not	O
less	O
than	O
18	O
months	O
(	O
range	O
18	O
-	O
43	O
months	O
)	O
.	O

In	O
all	O
,	O
16	O
patients	O
with	O
unequivocal	O
defects	O
continued	O
the	O
medication	O
.	O

Following	O
already	O
published	O
methodology	O
(	O
Eye	O
2002	O
;	O
16	O
;	O
567	O
-	O
571	O
)	O
monocular	O
mean	O
radial	O
degrees	O
(	O
MRDs	O
)	O
to	O
the	O
I	O
/	O
4e	O
isopter	O
on	O
Goldmann	O
perimetry	O
was	O
calculated	O
for	O
the	O
right	O
eye	O
at	O
the	O
time	O
of	O
discovery	O
of	O
a	O
visual	B-Disease
field	I-Disease
defect	I-Disease
and	O
again	O
after	O
not	O
less	O
than	O
18	O
months	O
follow	O
-	O
up	O
.	O

RESULTS	O
:	O
Mean	O
right	O
eye	O
MRD	O
at	O
presentation	O
was	O
36	O
.	O
98	O
degrees	O
(	O
range	O
22	O
.	O
25	O
-	O
51	O
.	O
0	O
)	O
,	O
compared	O
to	O
38	O
.	O
40	O
degrees	O
(	O
range	O
22	O
.	O
5	O
-	O
49	O
.	O
75	O
)	O
after	O
follow	O
-	O
up	O
;	O
P	O
=	O
0	O
.	O
338	O
unpaired	O
t	O
-	O
test	O
.	O

Only	O
one	O
patient	O
demonstrated	O
a	O
deterioration	B-Disease
in	I-Disease
visual	I-Disease
field	I-Disease
during	O
the	O
study	O
period	O
and	O
discontinued	O
treatment	O
.	O

CONCLUSION	O
:	O
Established	O
visual	B-Disease
field	I-Disease
defects	I-Disease
presumed	O
to	O
be	O
due	O
to	O
Vigabatrin	B-Chemical
therapy	O
did	O
not	O
usually	O
progress	O
in	O
spite	O
of	O
continuing	O
use	O
of	O
the	O
medication	O
.	O

These	O
data	O
give	O
support	O
to	O
the	O
hypothesis	O
that	O
the	O
pathogenesis	O
of	O
Vigabatrin	B-Chemical
-	O
associated	O
visual	B-Disease
field	I-Disease
defects	I-Disease
may	O
be	O
an	O
idiosyncratic	O
adverse	O
drug	O
reaction	O
rather	O
than	O
dose	O
-	O
dependent	O
toxicity	B-Disease
.	O

Induction	O
of	O
rosaceiform	O
dermatitis	B-Disease
during	O
treatment	O
of	O
facial	B-Disease
inflammatory	I-Disease
dermatoses	I-Disease
with	O
tacrolimus	B-Chemical
ointment	O
.	O

BACKGROUND	O
:	O
Tacrolimus	B-Chemical
ointment	O
is	O
increasingly	O
used	O
for	O
anti	O
-	O
inflammatory	O
treatment	O
of	O
sensitive	O
areas	O
such	O
as	O
the	O
face	O
,	O
and	O
recent	O
observations	O
indicate	O
that	O
the	O
treatment	O
is	O
effective	O
in	O
steroid	B-Chemical
-	O
aggravated	O
rosacea	B-Disease
and	O
perioral	B-Disease
dermatitis	I-Disease
.	O

We	O
report	O
on	O
rosaceiform	O
dermatitis	B-Disease
as	O
a	O
complication	O
of	O
treatment	O
with	O
tacrolimus	B-Chemical
ointment	O
.	O

OBSERVATIONS	O
:	O
Six	O
adult	O
patients	O
with	O
inflammatory	B-Disease
facial	I-Disease
dermatoses	I-Disease
were	O
treated	O
with	O
tacrolimus	B-Chemical
ointment	O
because	O
of	O
the	O
ineffectiveness	O
of	O
standard	O
treatments	O
.	O

Within	O
2	O
to	O
3	O
weeks	O
of	O
initially	O
effective	O
and	O
well	O
-	O
tolerated	O
treatment	O
,	O
3	O
patients	O
with	O
a	O
history	O
of	O
rosacea	B-Disease
and	O
1	O
with	O
a	O
history	O
of	O
acne	B-Disease
experienced	O
sudden	O
worsening	O
with	O
pustular	O
rosaceiform	O
lesions	O
.	O

Biopsy	O
revealed	O
an	O
abundance	O
of	O
Demodex	O
mites	O
in	O
2	O
of	O
these	O
patients	O
.	O

In	O
1	O
patient	O
with	O
eyelid	O
eczema	B-Disease
,	O
rosaceiform	O
periocular	B-Disease
dermatitis	I-Disease
gradually	O
appeared	O
after	O
3	O
weeks	O
of	O
treatment	O
.	O

In	O
1	O
patient	O
with	O
atopic	B-Disease
dermatitis	I-Disease
,	O
telangiectatic	O
and	O
papular	B-Disease
rosacea	I-Disease
insidiously	O
appeared	O
after	O
5	O
months	O
of	O
treatment	O
.	O

CONCLUSIONS	O
:	O
Our	O
observations	O
suggest	O
that	O
the	O
spectrum	O
of	O
rosaceiform	O
dermatitis	B-Disease
as	O
a	O
complication	O
of	O
treatment	O
with	O
tacrolimus	B-Chemical
ointment	O
is	O
heterogeneous	O
.	O

A	O
variety	O
of	O
factors	O
,	O
such	O
as	O
vasoactive	O
properties	O
of	O
tacrolimus	B-Chemical
,	O
proliferation	O
of	O
Demodex	O
due	O
to	O
local	O
immunosuppression	O
,	O
and	O
the	O
occlusive	O
properties	O
of	O
the	O
ointment	O
,	O
may	O
be	O
involved	O
in	O
the	O
observed	O
phenomena	O
.	O

Future	O
studies	O
are	O
needed	O
to	O
identify	O
individual	O
risk	O
factors	O
.	O

Intravascular	O
hemolysis	B-Disease
and	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
following	O
intermittent	O
rifampin	B-Chemical
therapy	O
.	O

Renal	B-Disease
failure	I-Disease
is	O
a	O
rare	O
complication	O
associated	O
with	O
the	O
use	O
of	O
rifampin	B-Chemical
.	O

Intravascular	O
hemolysis	B-Disease
leading	O
to	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
following	O
rifampin	B-Chemical
therapy	O
is	O
extremely	O
rare	O
.	O

Two	O
patients	O
with	O
leprosy	B-Disease
who	O
developed	O
hemolysis	B-Disease
and	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
following	O
rifampin	B-Chemical
are	O
reported	O
.	O

Structural	O
abnormalities	O
in	O
the	O
brains	O
of	O
human	O
subjects	O
who	O
use	O
methamphetamine	B-Chemical
.	O

We	O
visualize	O
,	O
for	O
the	O
first	O
time	O
,	O
the	O
profile	O
of	O
structural	B-Disease
deficits	I-Disease
in	I-Disease
the	I-Disease
human	I-Disease
brain	I-Disease
associated	O
with	O
chronic	O
methamphetamine	B-Chemical
(	O
MA	B-Chemical
)	O
abuse	O
.	O

Studies	O
of	O
human	O
subjects	O
who	O
have	O
used	O
MA	B-Chemical
chronically	O
have	O
revealed	O
deficits	O
in	O
dopaminergic	O
and	O
serotonergic	O
systems	O
and	O
cerebral	O
metabolic	B-Disease
abnormalities	I-Disease
.	O

Using	O
magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
and	O
new	O
computational	O
brain	O
-	O
mapping	O
techniques	O
,	O
we	O
determined	O
the	O
pattern	O
of	O
structural	O
brain	O
alterations	O
associated	O
with	O
chronic	O
MA	B-Chemical
abuse	O
in	O
human	O
subjects	O
and	O
related	O
these	O
deficits	O
to	O
cognitive	B-Disease
impairment	I-Disease
.	O

We	O
used	O
high	O
-	O
resolution	O
MRI	O
and	O
surface	O
-	O
based	O
computational	O
image	O
analyses	O
to	O
map	O
regional	O
abnormalities	B-Disease
in	I-Disease
the	I-Disease
cortex	I-Disease
,	I-Disease
hippocampus	I-Disease
,	I-Disease
white	I-Disease
matter	I-Disease
,	I-Disease
and	I-Disease
ventricles	I-Disease
in	O
22	O
human	O
subjects	O
who	O
used	O
MA	B-Chemical
and	O
21	O
age	O
-	O
matched	O
,	O
healthy	O
controls	O
.	O

Cortical	O
maps	O
revealed	O
severe	O
gray	O
-	O
matter	O
deficits	O
in	O
the	O
cingulate	O
,	O
limbic	O
,	O
and	O
paralimbic	O
cortices	O
of	O
MA	B-Chemical
abusers	O
(	O
averaging	O
11	O
.	O
3	O
%	O
below	O
control	O
;	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

On	O
average	O
,	O
MA	B-Chemical
abusers	O
had	O
7	O
.	O
8	O
%	O
smaller	O
hippocampal	O
volumes	O
than	O
control	O
subjects	O
(	O
p	O
<	O
0	O
.	O
01	O
;	O
left	O
,	O
p	O
=	O
0	O
.	O
01	O
;	O
right	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
and	O
significant	O
white	O
-	O
matter	O
hypertrophy	B-Disease
(	O
7	O
.	O
0	O
%	O
;	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

Hippocampal	O
deficits	O
were	O
mapped	O
and	O
correlated	O
with	O
memory	O
performance	O
on	O
a	O
word	O
-	O
recall	O
test	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

MRI	O
-	O
based	O
maps	O
suggest	O
that	O
chronic	O
methamphetamine	B-Chemical
abuse	O
causes	O
a	O
selective	O
pattern	O
of	O
cerebral	O
deterioration	O
that	O
contributes	O
to	O
impaired	B-Disease
memory	I-Disease
performance	I-Disease
.	O

MA	B-Chemical
may	O
selectively	O
damage	O
the	O
medial	O
temporal	O
lobe	O
and	O
,	O
consistent	O
with	O
metabolic	O
studies	O
,	O
the	O
cingulate	O
-	O
limbic	O
cortex	O
,	O
inducing	O
neuroadaptation	O
,	O
neuropil	O
reduction	O
,	O
or	O
cell	O
death	O
.	O

Prominent	O
white	O
-	O
matter	O
hypertrophy	B-Disease
may	O
result	O
from	O
altered	O
myelination	O
and	O
adaptive	O
glial	O
changes	O
,	O
including	O
gliosis	B-Disease
secondary	O
to	O
neuronal	B-Disease
damage	I-Disease
.	O

These	O
brain	O
substrates	O
may	O
help	O
account	O
for	O
the	O
symptoms	O
of	O
MA	B-Chemical
abuse	O
,	O
providing	O
therapeutic	O
targets	O
for	O
drug	O
-	O
induced	O
brain	B-Disease
injury	I-Disease
.	O

Disruption	O
of	O
hepatic	O
lipid	O
homeostasis	O
in	O
mice	O
after	O
amiodarone	B-Chemical
treatment	O
is	O
associated	O
with	O
peroxisome	O
proliferator	O
-	O
activated	O
receptor	O
-	O
alpha	O
target	O
gene	O
activation	O
.	O

Amiodarone	B-Chemical
,	O
an	O
efficacious	O
and	O
widely	O
used	O
antiarrhythmic	O
agent	O
,	O
has	O
been	O
reported	O
to	O
cause	O
hepatotoxicity	B-Disease
in	O
some	O
patients	O
.	O

To	O
gain	O
insight	O
into	O
the	O
mechanism	O
of	O
this	O
unwanted	O
effect	O
,	O
mice	O
were	O
administered	O
various	O
doses	O
of	O
amiodarone	B-Chemical
and	O
examined	O
for	O
changes	O
in	O
hepatic	O
histology	O
and	O
gene	O
regulation	O
.	O

Amiodarone	B-Chemical
induced	O
hepatomegaly	B-Disease
,	O
hepatocyte	O
microvesicular	O
lipid	O
accumulation	O
,	O
and	O
a	O
significant	O
decrease	O
in	O
serum	O
triglycerides	B-Chemical
and	O
glucose	B-Chemical
.	O

Northern	O
blot	O
analysis	O
of	O
hepatic	O
RNA	O
revealed	O
a	O
dose	O
-	O
dependent	O
increase	O
in	O
the	O
expression	O
of	O
a	O
number	O
of	O
genes	O
critical	O
for	O
fatty	B-Chemical
acid	I-Chemical
oxidation	O
,	O
lipoprotein	O
assembly	O
,	O
and	O
lipid	O
transport	O
.	O

Many	O
of	O
these	O
genes	O
are	O
regulated	O
by	O
the	O
peroxisome	O
proliferator	O
-	O
activated	O
receptor	O
-	O
alpha	O
(	O
PPARalpha	O
)	O
,	O
a	O
ligand	O
-	O
activated	O
nuclear	O
hormone	O
receptor	O
transcription	O
factor	O
.	O

The	O
absence	O
of	O
induction	O
of	O
these	O
genes	O
as	O
well	O
as	O
hepatomegaly	B-Disease
in	O
PPARalpha	O
knockout	O
[	O
PPARalpha	O
-	O
/	O
-	O
]	O
mice	O
indicated	O
that	O
the	O
effects	O
of	O
amiodarone	B-Chemical
were	O
dependent	O
upon	O
the	O
presence	O
of	O
a	O
functional	O
PPARalpha	O
gene	O
.	O

Compared	O
to	O
wild	O
-	O
type	O
mice	O
,	O
treatment	O
of	O
PPARalpha	O
-	O
/	O
-	O
mice	O
with	O
amiodarone	B-Chemical
resulted	O
in	O
an	O
increased	O
rate	O
and	O
extent	O
of	O
total	O
body	O
weight	B-Disease
loss	I-Disease
.	O

The	O
inability	O
of	O
amiodarone	B-Chemical
to	O
directly	O
activate	O
either	O
human	O
or	O
mouse	O
PPARalpha	O
transiently	O
expressed	O
in	O
human	O
HepG2	O
hepatoma	B-Disease
cells	O
indicates	O
that	O
the	O
effects	O
of	O
amiodarone	B-Chemical
on	O
the	O
function	O
of	O
this	O
receptor	O
were	O
indirect	O
.	O

Based	O
upon	O
these	O
results	O
,	O
we	O
conclude	O
that	O
amiodarone	B-Chemical
disrupts	O
hepatic	O
lipid	O
homeostasis	O
and	O
that	O
the	O
increased	O
expression	O
of	O
PPARalpha	O
target	O
genes	O
is	O
secondary	O
to	O
this	O
toxic	O
effect	O
.	O

These	O
results	O
provide	O
important	O
new	O
mechanistic	O
information	O
regarding	O
the	O
hepatotoxic	B-Disease
effects	O
of	O
amiodarone	B-Chemical
and	O
indicate	O
that	O
PPARalpha	O
protects	O
against	O
amiodarone	B-Chemical
-	O
induced	O
hepatotoxicity	B-Disease
.	O

Safety	O
and	O
compliance	O
with	O
once	O
-	O
daily	O
niacin	B-Chemical
extended	I-Chemical
-	I-Chemical
release	I-Chemical
/	I-Chemical
lovastatin	I-Chemical
as	O
initial	O
therapy	O
in	O
the	O
Impact	O
of	O
Medical	O
Subspecialty	O
on	O
Patient	O
Compliance	O
to	O
Treatment	O
(	O
IMPACT	O
)	O
study	O
.	O

Niacin	B-Chemical
extended	I-Chemical
-	I-Chemical
release	I-Chemical
/	I-Chemical
lovastatin	I-Chemical
is	O
a	O
new	O
combination	O
product	O
approved	O
for	O
treatment	O
of	O
primary	O
hypercholesterolemia	B-Disease
and	O
mixed	O
dyslipidemia	B-Disease
.	O

This	O
open	O
-	O
labeled	O
,	O
multicenter	O
study	O
evaluated	O
the	O
safety	O
of	O
bedtime	O
niacin	B-Chemical
extended	I-Chemical
-	I-Chemical
release	I-Chemical
/	I-Chemical
lovastatin	I-Chemical
when	O
dosed	O
as	O
initial	O
therapy	O
and	O
patient	O
compliance	O
to	O
treatment	O
in	O
various	O
clinical	O
practice	O
settings	O
.	O

A	O
total	O
of	O
4	O
,	O
499	O
patients	O
with	O
dyslipidemia	B-Disease
requiring	O
drug	O
intervention	O
was	O
enrolled	O
at	O
1	O
,	O
081	O
sites	O
.	O

Patients	O
were	O
treated	O
with	O
1	O
tablet	O
(	O
500	O
mg	O
of	O
niacin	B-Chemical
extended	O
-	O
release	O
/	O
20	O
mg	O
of	O
lovastatin	B-Chemical
)	O
once	O
nightly	O
for	O
4	O
weeks	O
and	O
then	O
2	O
tablets	O
for	O
8	O
weeks	O
.	O

Patients	O
also	O
received	O
dietary	O
counseling	O
,	O
educational	O
materials	O
,	O
and	O
reminders	O
to	O
call	O
a	O
toll	O
-	O
free	O
number	O
that	O
provided	O
further	O
education	O
about	O
dyslipidemia	B-Disease
and	O
niacin	B-Chemical
extended	I-Chemical
-	I-Chemical
release	I-Chemical
/	I-Chemical
lovastatin	I-Chemical
.	O

Primary	O
end	O
points	O
were	O
study	O
compliance	O
,	O
increases	O
in	O
liver	O
transaminases	O
to	O
>	O
3	O
times	O
the	O
upper	O
limit	O
of	O
normal	O
,	O
and	O
clinical	O
myopathy	B-Disease
.	O

Final	O
study	O
status	O
was	O
available	O
for	O
4	O
,	O
217	O
patients	O
(	O
94	O
%	O
)	O
.	O

Compliance	O
to	O
niacin	B-Chemical
extended	I-Chemical
-	I-Chemical
release	I-Chemical
/	I-Chemical
lovastatin	I-Chemical
was	O
77	O
%	O
,	O
with	O
3	O
,	O
245	O
patients	O
completing	O
the	O
study	O
.	O

Patients	O
in	O
the	O
southeast	O
and	O
those	O
enrolled	O
by	O
endocrinologists	O
had	O
the	O
lowest	O
compliance	O
and	O
highest	O
adverse	O
event	O
rates	O
.	O

Flushing	B-Disease
was	O
the	O
most	O
common	O
adverse	O
event	O
,	O
reported	O
by	O
18	O
%	O
of	O
patients	O
and	O
leading	O
to	O
discontinuation	O
by	O
6	O
%	O
.	O

Incidence	O
of	O
increased	O
aspartate	B-Chemical
aminotransferase	O
and	O
/	O
or	O
alanine	B-Chemical
aminotransferase	O
>	O
3	O
times	O
the	O
upper	O
limit	O
of	O
normal	O
was	O
<	O
0	O
.	O
3	O
%	O
.	O

An	O
increase	O
of	O
creatine	B-Chemical
phosphokinase	O
to	O
>	O
5	O
times	O
the	O
upper	O
limit	O
of	O
normal	O
occurred	O
in	O
0	O
.	O
24	O
%	O
of	O
patients	O
,	O
and	O
no	O
cases	O
of	O
drug	O
-	O
induced	O
myopathy	B-Disease
were	O
observed	O
.	O

Niacin	B-Chemical
extended	I-Chemical
-	I-Chemical
release	I-Chemical
/	I-Chemical
lovastatin	I-Chemical
1	O
,	O
000	O
/	O
40	O
mg	O
,	O
dosed	O
as	O
initial	O
therapy	O
,	O
was	O
associated	O
with	O
good	O
compliance	O
and	O
safety	O
and	O
had	O
very	O
low	O
incidences	O
of	O
increased	O
liver	O
and	O
muscle	O
enzymes	O
.	O

Protective	O
effect	O
of	O
Terminalia	B-Chemical
chebula	I-Chemical
against	O
experimental	O
myocardial	B-Disease
injury	I-Disease
induced	O
by	O
isoproterenol	B-Chemical
.	O

Cardioprotective	O
effect	O
of	O
ethanolic	B-Chemical
extract	I-Chemical
of	I-Chemical
Terminalia	I-Chemical
chebula	I-Chemical
fruits	I-Chemical
(	O
500	O
mg	O
/	O
kg	O
body	O
wt	O
)	O
was	O
examined	O
in	O
isoproterenol	B-Chemical
(	O
200	O
mg	O
/	O
kg	O
body	O
wt	O
)	O
induced	O
myocardial	B-Disease
damage	I-Disease
in	O
rats	O
.	O

In	O
isoproterenol	B-Chemical
administered	O
rats	O
,	O
the	O
level	O
of	O
lipid	O
peroxides	B-Chemical
increased	O
significantly	O
in	O
the	O
serum	O
and	O
heart	O
.	O

A	O
significant	O
decrease	O
was	O
observed	O
in	O
the	O
activity	O
of	O
the	O
myocardial	O
marker	O
enzymes	O
with	O
a	O
concomitant	O
increase	O
in	O
their	O
activity	O
in	O
serum	O
.	O

Histopathological	O
examination	O
was	O
carried	O
out	O
to	O
confirm	O
the	O
myocardial	O
necrosis	B-Disease
.	O

T	B-Chemical
.	I-Chemical
chebula	I-Chemical
extract	I-Chemical
pretreatment	O
was	O
found	O
to	O
ameliorate	O
the	O
effect	O
of	O
isoproterenol	B-Chemical
on	O
lipid	O
peroxide	B-Chemical
formation	O
and	O
retained	O
the	O
activities	O
of	O
the	O
diagnostic	O
marker	O
enzymes	O
.	O

A	O
case	O
of	O
postoperative	O
anxiety	B-Disease
due	O
to	O
low	O
dose	O
droperidol	B-Chemical
used	O
with	O
patient	O
-	O
controlled	O
analgesia	O
.	O

A	O
multiparous	O
woman	O
in	O
good	O
psychological	O
health	O
underwent	O
urgent	O
caesarean	O
section	O
in	O
labour	O
.	O

Postoperatively	O
,	O
she	O
was	O
given	O
a	O
patient	O
-	O
controlled	O
analgesia	O
device	O
delivering	O
boluses	O
of	O
diamorphine	B-Chemical
0	O
.	O
5	O
mg	O
and	O
droperidol	B-Chemical
0	O
.	O
025	O
mg	O
.	O

Whilst	O
using	O
the	O
device	O
she	O
gradually	O
became	O
anxious	O
,	O
the	O
feeling	O
worsening	O
after	O
each	O
bolus	O
.	O

The	O
diagnosis	O
of	O
droperidol	B-Chemical
-	O
induced	O
psychological	B-Disease
disturbance	I-Disease
was	O
not	O
made	O
straight	O
away	O
although	O
on	O
subsequent	O
close	O
questioning	O
the	O
patient	O
gave	O
a	O
very	O
clear	O
history	O
.	O

After	O
she	O
had	O
received	O
a	O
total	O
of	O
only	O
0	O
.	O
9	O
mg	O
droperidol	B-Chemical
,	O
a	O
syringe	O
containing	O
diamorphine	B-Chemical
only	O
was	O
substituted	O
and	O
her	O
unease	O
resolved	O
completely	O
.	O

We	O
feel	O
that	O
,	O
although	O
the	O
dramatic	O
extrapyramidal	O
side	O
effects	O
of	O
dopaminergic	O
antiemetics	O
are	O
well	O
known	O
,	O
more	O
subtle	O
manifestations	O
may	O
easily	O
be	O
overlooked	O
.	O

Accurate	O
patient	O
history	O
contributes	O
to	O
differentiating	O
diabetes	B-Disease
insipidus	I-Disease
:	O
a	O
case	O
study	O
.	O

This	O
case	O
study	O
highlights	O
the	O
important	O
contribution	O
of	O
nursing	O
in	O
obtaining	O
an	O
accurate	O
health	O
history	O
.	O

The	O
case	O
discussed	O
herein	O
initially	O
appeared	O
to	O
be	O
neurogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
(	O
DI	B-Disease
)	O
secondary	O
to	O
a	O
traumatic	B-Disease
brain	I-Disease
injury	I-Disease
.	O

The	O
nursing	O
staff	O
,	O
by	O
reviewing	O
the	O
patient	O
'	O
s	O
health	O
history	O
with	O
his	O
family	O
,	O
discovered	O
a	O
history	O
of	O
polydipsia	B-Disease
and	O
long	O
-	O
standing	O
lithium	B-Chemical
use	O
.	O

Lithium	B-Chemical
is	O
implicated	O
in	O
drug	O
-	O
induced	O
nephrogenic	B-Disease
DI	I-Disease
,	O
and	O
because	O
the	O
patient	O
had	O
not	O
received	O
lithium	B-Chemical
since	O
being	O
admitted	O
to	O
the	O
hospital	O
,	O
his	O
treatment	O
changed	O
to	O
focus	O
on	O
nephrogenic	B-Disease
DI	I-Disease
.	O

By	O
combining	O
information	O
from	O
the	O
patient	O
history	O
,	O
the	O
physical	O
examination	O
,	O
and	O
radiologic	O
and	O
laboratory	O
studies	O
,	O
the	O
critical	O
care	O
team	O
demonstrated	O
that	O
the	O
patient	O
had	O
been	O
self	O
-	O
treating	O
his	O
lithium	B-Chemical
-	O
induced	O
nephrogenic	B-Disease
DI	I-Disease
and	O
developed	O
neurogenic	B-Disease
DI	I-Disease
secondary	O
to	O
brain	B-Disease
trauma	I-Disease
.	O

Thus	O
successful	O
treatment	O
required	O
that	O
nephrogenic	O
and	O
neurogenic	B-Disease
DI	I-Disease
be	O
treated	O
concomitantly	O
.	O

Factors	O
contributing	O
to	O
ribavirin	B-Chemical
-	O
induced	O
anemia	B-Disease
.	O

BACKGROUND	O
AND	O
AIM	O
:	O
Interferon	B-Chemical
and	O
ribavirin	B-Chemical
combination	O
therapy	O
for	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
produces	O
hemolytic	B-Disease
anemia	I-Disease
.	O

This	O
study	O
was	O
conducted	O
to	O
identify	O
the	O
factors	O
contributing	O
to	O
ribavirin	B-Chemical
-	O
induced	O
anemia	B-Disease
.	O

METHODS	O
:	O
Eighty	O
-	O
eight	O
patients	O
with	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
who	O
received	O
interferon	B-Chemical
-	I-Chemical
alpha	I-Chemical
-	I-Chemical
2b	I-Chemical
at	O
a	O
dose	O
of	O
6	O
MU	O
administered	O
intramuscularly	O
for	O
24	O
weeks	O
in	O
combination	O
with	O
ribavirin	B-Chemical
administered	O
orally	O
at	O
a	O
dose	O
of	O
600	O
mg	O
or	O
800	O
mg	O
participated	O
in	O
the	O
study	O
.	O

A	O
hemoglobin	O
concentration	O
of	O
<	O
10	O
g	O
/	O
dL	O
was	O
defined	O
as	O
ribavirin	B-Chemical
-	O
induced	O
anemia	B-Disease
.	O

RESULTS	O
:	O
Ribavirin	B-Chemical
-	O
induced	O
anemia	B-Disease
occurred	O
in	O
18	O
(	O
20	O
.	O
5	O
%	O
)	O
patients	O
during	O
treatment	O
.	O

A	O
2	O
g	O
/	O
dL	O
decrease	O
in	O
hemoglobin	O
concentrations	O
in	O
patients	O
with	O
anemia	B-Disease
was	O
observed	O
at	O
week	O
2	O
after	O
the	O
start	O
of	O
treatment	O
.	O

The	O
hemoglobin	O
concentration	O
in	O
patients	O
with	O
>	O
or	O
=	O
2	O
g	O
/	O
dL	O
decrease	O
at	O
week	O
2	O
was	O
observed	O
to	O
be	O
significantly	O
lower	O
even	O
after	O
week	O
2	O
than	O
in	O
patients	O
with	O
<	O
2	O
g	O
/	O
dL	O
decrease	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

A	O
significant	O
relationship	O
was	O
observed	O
between	O
the	O
rate	O
of	O
reduction	O
of	O
hemoglobin	O
concentrations	O
at	O
week	O
2	O
and	O
the	O
severity	O
of	O
anemia	B-Disease
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Such	O
factors	O
as	O
sex	O
(	O
female	O
)	O
,	O
age	O
(	O
>	O
or	O
=	O
60	O
years	O
old	O
)	O
,	O
and	O
the	O
ribavirin	B-Chemical
dose	O
by	O
body	O
weight	O
(	O
12	O
mg	O
/	O
kg	O
or	O
more	O
)	O
were	O
significant	O
by	O
univariate	O
analysis	O
.	O

CONCLUSIONS	O
:	O
Careful	O
administration	O
is	O
necessary	O
in	O
patients	O
>	O
or	O
=	O
60	O
years	O
old	O
,	O
in	O
female	O
patients	O
,	O
and	O
in	O
patients	O
receiving	O
a	O
ribavirin	B-Chemical
dose	O
of	O
12	O
mg	O
/	O
kg	O
or	O
more	O
.	O

Patients	O
who	O
experience	O
a	O
fall	O
in	O
hemoglobin	O
concentrations	O
of	O
2	O
g	O
/	O
dL	O
or	O
more	O
at	O
week	O
2	O
after	O
the	O
start	O
of	O
treatment	O
should	O
be	O
monitored	O
with	O
particular	O
care	O
.	O

Zidovudine	B-Chemical
-	O
induced	O
hepatitis	B-Disease
.	O

A	O
case	O
of	O
acute	O
hepatitis	B-Disease
induced	O
by	O
zidovudine	B-Chemical
in	O
a	O
38	O
-	O
year	O
-	O
old	O
patient	O
with	O
AIDS	B-Disease
is	O
presented	O
.	O

The	O
mechanism	O
whereby	O
the	O
hepatitis	B-Disease
was	O
induced	O
is	O
not	O
known	O
.	O

However	O
,	O
the	O
patient	O
tolerated	O
well	O
an	O
alternative	O
reverse	O
transcriptase	O
inhibitor	O
,	O
2	B-Chemical
'	I-Chemical
3	I-Chemical
'	I-Chemical
dideoxyinosine	I-Chemical
.	O

Physicians	O
caring	O
for	O
patients	O
with	O
AIDS	B-Disease
should	O
be	O
aware	O
of	O
this	O
hitherto	O
rarely	O
reported	O
complication	O
.	O

Oxidative	O
damage	O
precedes	O
nitrative	O
damage	O
in	O
adriamycin	B-Chemical
-	O
induced	O
cardiac	O
mitochondrial	B-Disease
injury	I-Disease
.	O

The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
determine	O
if	O
elevated	O
reactive	O
oxygen	B-Chemical
(	O
ROS	O
)	O
/	O
nitrogen	B-Chemical
species	O
(	O
RNS	O
)	O
reported	O
to	O
be	O
present	O
in	O
adriamycin	B-Chemical
(	O
ADR	B-Chemical
)	O
-	O
induced	O
cardiotoxicity	B-Disease
actually	O
resulted	O
in	O
cardiomyocyte	O
oxidative	O
/	O
nitrative	O
damage	O
,	O
and	O
to	O
quantitatively	O
determine	O
the	O
time	O
course	O
and	O
subcellular	O
localization	O
of	O
these	O
postulated	O
damage	O
products	O
using	O
an	O
in	O
vivo	O
approach	O
.	O

B6C3	O
mice	O
were	O
treated	O
with	O
a	O
single	O
dose	O
of	O
20	O
mg	O
/	O
kg	O
ADR	B-Chemical
.	O

Ultrastructural	O
damage	O
and	O
levels	O
of	O
4	B-Chemical
-	I-Chemical
hydroxy	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
nonenal	I-Chemical
(	O
4HNE	B-Chemical
)	O
-	O
protein	O
adducts	O
and	O
3	B-Chemical
-	I-Chemical
nitrotyrosine	I-Chemical
(	O
3NT	B-Chemical
)	O
were	O
analyzed	O
.	O

Quantitative	O
ultrastructural	O
damage	O
using	O
computerized	O
image	O
techniques	O
showed	O
cardiomyocyte	O
injury	O
as	O
early	O
as	O
3	O
hours	O
,	O
with	O
mitochondria	O
being	O
the	O
most	O
extensively	O
and	O
progressively	O
injured	O
subcellular	O
organelle	O
.	O

Analysis	O
of	O
4HNE	B-Chemical
protein	O
adducts	O
by	O
immunogold	O
electron	O
microscopy	O
showed	O
appearance	O
of	O
4HNE	B-Chemical
protein	O
adducts	O
in	O
mitochondria	O
as	O
early	O
as	O
3	O
hours	O
,	O
with	O
a	O
peak	O
at	O
6	O
hours	O
and	O
subsequent	O
decline	O
at	O
24	O
hours	O
.	O

3NT	B-Chemical
levels	O
were	O
significantly	O
increased	O
in	O
all	O
subcellular	O
compartments	O
at	O
6	O
hours	O
and	O
subsequently	O
declined	O
at	O
24	O
hours	O
.	O

Our	O
data	O
showed	O
ADR	B-Chemical
induced	O
4HNE	B-Chemical
-	O
protein	O
adducts	O
in	O
mitochondria	O
at	O
the	O
same	O
time	O
point	O
as	O
when	O
mitochondrial	B-Disease
injury	I-Disease
initially	O
appeared	O
.	O

These	O
results	O
document	O
for	O
the	O
first	O
time	O
in	O
vivo	O
that	O
mitochondrial	B-Disease
oxidative	I-Disease
damage	I-Disease
precedes	O
nitrative	O
damage	O
.	O

The	O
progressive	O
nature	O
of	O
mitochondrial	B-Disease
injury	I-Disease
suggests	O
that	O
mitochondria	O
,	O
not	O
other	O
subcellular	O
organelles	O
,	O
are	O
the	O
major	O
site	O
of	O
intracellular	O
injury	O
.	O

Sotalol	B-Chemical
-	O
induced	O
coronary	B-Disease
spasm	I-Disease
in	O
a	O
patient	O
with	O
dilated	B-Disease
cardiomyopathy	I-Disease
associated	O
with	O
sustained	O
ventricular	B-Disease
tachycardia	I-Disease
.	O

A	O
54	O
-	O
year	O
-	O
old	O
man	O
with	O
severe	O
left	O
ventricular	B-Disease
dysfunction	I-Disease
due	O
to	O
dilated	B-Disease
cardiomyopathy	I-Disease
was	O
referred	O
to	O
our	O
hospital	O
for	O
symptomatic	O
incessant	O
sustained	O
ventricular	B-Disease
tachycardia	I-Disease
(	O
VT	B-Disease
)	O
.	O

After	O
the	O
administration	O
of	O
nifekalant	B-Chemical
hydrochloride	I-Chemical
,	O
sustained	O
VT	B-Disease
was	O
terminated	O
.	O

An	O
alternate	O
class	O
III	O
agent	O
,	O
sotalol	B-Chemical
,	O
was	O
also	O
effective	O
for	O
the	O
prevention	O
of	O
VT	B-Disease
.	O

However	O
,	O
one	O
month	O
after	O
switching	O
over	O
nifekalant	B-Chemical
to	O
sotalol	B-Chemical
,	O
a	O
short	O
duration	O
of	O
ST	O
elevation	O
was	O
documented	O
in	O
ECG	O
monitoring	O
at	O
almost	O
the	O
same	O
time	O
for	O
three	O
consecutive	O
days	O
.	O

ST	O
elevation	O
with	O
chest	O
discomfort	O
disappeared	O
since	O
he	O
began	O
taking	O
long	O
-	O
acting	O
diltiazem	B-Chemical
.	O

Coronary	B-Disease
vasospasm	I-Disease
may	O
be	O
induced	O
by	O
the	O
non	O
-	O
selective	O
beta	O
-	O
blocking	O
properties	O
of	O
sotalol	B-Chemical
.	O

Effects	O
of	O
the	O
antidepressant	O
trazodone	B-Chemical
,	O
a	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
2A	O
/	O
2C	O
receptor	O
antagonist	O
,	O
on	O
dopamine	B-Chemical
-	O
dependent	O
behaviors	O
in	O
rats	O
.	O

RATIONALE	O
:	O
5	B-Chemical
-	I-Chemical
Hydroxytryptamine	I-Chemical
,	O
via	O
stimulation	O
of	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
2C	O
receptors	O
,	O
exerts	O
a	O
tonic	O
inhibitory	O
influence	O
on	O
dopaminergic	O
neurotransmission	O
,	O
whereas	O
activation	O
of	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
2A	O
receptors	O
enhances	O
stimulated	O
DAergic	O
neurotransmission	O
.	O

The	O
antidepressant	O
trazodone	B-Chemical
is	O
a	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
2A	O
/	O
2C	O
receptor	O
antagonist	O
.	O

OBJECTIVES	O
:	O
To	O
evaluate	O
the	O
effect	O
of	O
trazodone	B-Chemical
treatment	O
on	O
behaviors	O
dependent	O
on	O
the	O
functional	O
status	O
of	O
the	O
nigrostriatal	O
DAergic	O
system	O
.	O

METHODS	O
:	O
The	O
effect	O
of	O
pretreatment	O
with	O
trazodone	B-Chemical
on	O
dexamphetamine	B-Chemical
-	O
and	O
apomorphine	B-Chemical
-	O
induced	O
oral	B-Disease
stereotypies	I-Disease
,	O
on	O
catalepsy	B-Disease
induced	O
by	O
haloperidol	B-Chemical
and	O
apomorphine	B-Chemical
(	O
0	O
.	O
05	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
,	O
on	O
ergometrine	B-Chemical
-	O
induced	O
wet	O
dog	O
shake	O
(	O
WDS	O
)	O
behavior	O
and	O
fluoxetine	B-Chemical
-	O
induced	O
penile	O
erections	O
was	O
studied	O
in	O
rats	O
.	O

We	O
also	O
investigated	O
whether	O
trazodone	B-Chemical
induces	O
catalepsy	B-Disease
in	O
rats	O
.	O

RESULTS	O
:	O
Trazodone	B-Chemical
at	O
2	O
.	O
5	O
-	O
20	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
did	O
not	O
induce	O
catalepsy	B-Disease
,	O
and	O
did	O
not	O
antagonize	O
apomorphine	B-Chemical
(	O
1	O
.	O
5	O
and	O
3	O
mg	O
/	O
kg	O
)	O
stereotypy	O
and	O
apomorphine	B-Chemical
(	O
0	O
.	O
05	O
mg	O
/	O
kg	O
)	O
-	O
induced	O
catalepsy	B-Disease
.	O

However	O
,	O
pretreatment	O
with	O
5	O
,	O
10	O
and	O
20	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
trazodone	B-Chemical
enhanced	O
dexamphetamine	B-Chemical
stereotypy	O
,	O
and	O
antagonized	O
haloperidol	B-Chemical
catalepsy	B-Disease
,	O
ergometrine	B-Chemical
-	O
induced	O
WDS	O
behavior	O
and	O
fluoxetine	B-Chemical
-	O
induced	O
penile	O
erections	O
.	O

Trazodone	B-Chemical
at	O
30	O
,	O
40	O
and	O
50	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
induced	O
catalepsy	B-Disease
and	O
antagonized	O
apomorphine	B-Chemical
and	O
dexamphetamine	B-Chemical
stereotypies	O
.	O

CONCLUSIONS	O
:	O
Our	O
results	O
indicate	O
that	O
trazodone	B-Chemical
at	O
2	O
.	O
5	O
-	O
20	O
mg	O
/	O
kg	O
does	O
not	O
block	O
pre	O
-	O
and	O
postsynaptic	O
striatal	O
D2	O
DA	O
receptors	O
,	O
while	O
at	O
30	O
,	O
40	O
and	O
50	O
mg	O
/	O
kg	O
it	O
blocks	O
postsynaptic	O
striatal	O
D2	O
DA	O
receptors	O
.	O

Furthermore	O
,	O
at	O
5	O
,	O
10	O
and	O
20	O
mg	O
/	O
kg	O
,	O
trazodone	B-Chemical
blocks	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
2A	O
and	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
2C	O
receptors	O
.	O

We	O
suggest	O
that	O
trazodone	B-Chemical
(	O
5	O
,	O
10	O
and	O
20	O
mg	O
/	O
kg	O
)	O
,	O
by	O
blocking	O
the	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
2C	O
receptors	O
,	O
releases	O
the	O
nigrostriatal	O
DAergic	O
neurons	O
from	O
tonic	O
inhibition	O
caused	O
by	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
,	O
and	O
thereby	O
potentiates	O
dexamphetamine	B-Chemical
stereotypy	O
and	O
antagonizes	O
haloperidol	B-Chemical
catalepsy	B-Disease
.	O

Swallowing	B-Disease
abnormalities	I-Disease
and	O
dyskinesia	B-Disease
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Gastrointestinal	B-Disease
abnormalities	I-Disease
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
have	O
been	O
known	O
for	O
almost	O
two	O
centuries	O
,	O
but	O
many	O
aspects	O
concerning	O
their	O
pathophysiology	O
have	O
not	O
been	O
completely	O
clarified	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
characterize	O
the	O
oropharyngeal	O
dynamics	O
in	O
PD	B-Disease
patients	O
with	O
and	O
without	O
levodopa	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
.	O

Fifteen	O
dyskinetic	B-Disease
,	O
12	O
nondyskinetic	O
patients	O
,	O
and	O
a	O
control	O
group	O
were	O
included	O
.	O

Patients	O
were	O
asked	O
about	O
dysphagia	B-Disease
and	O
evaluated	O
with	O
the	O
Unified	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
Disease	I-Disease
Rating	O
Scale	O
Parts	O
II	O
and	O
III	O
and	O
the	O
Hoehn	O
and	O
Yahr	O
scale	O
.	O

Deglutition	O
was	O
assessed	O
using	O
modified	O
barium	B-Chemical
swallow	O
with	O
videofluoroscopy	O
.	O

Nondyskinetic	O
patients	O
,	O
but	O
not	O
the	O
dyskinetic	B-Disease
ones	O
,	O
showed	O
less	O
oropharyngeal	O
swallowing	O
efficiency	O
(	O
OPSE	O
)	O
for	O
liquid	O
food	O
than	O
controls	O
(	O
Dunnett	O
,	O
P	O
=	O
0	O
.	O
02	O
)	O
.	O

Dyskinetic	B-Disease
patients	O
tended	O
to	O
have	O
a	O
greater	O
OPSE	O
than	O
nondyskinetic	O
(	O
Dunnett	O
,	O
P	O
=	O
0	O
.	O
06	O
)	O
.	O

Patients	O
who	O
were	O
using	O
a	O
higher	O
dose	O
of	O
levodopa	B-Chemical
had	O
a	O
greater	O
OPSE	O
and	O
a	O
trend	O
toward	O
a	O
smaller	O
oral	O
transit	O
time	O
(	O
Pearson	O
'	O
s	O
correlation	O
,	O
P	O
=	O
0	O
.	O
01	O
and	O
0	O
.	O
08	O
,	O
respectively	O
)	O
.	O

Neither	O
the	O
report	O
of	O
dysphagia	B-Disease
nor	O
any	O
of	O
the	O
PD	B-Disease
severity	O
parameters	O
correlated	O
to	O
the	O
videofluoroscopic	O
variables	O
.	O

In	O
the	O
current	O
study	O
,	O
dyskinetic	B-Disease
patients	O
performed	O
better	O
in	O
swallowing	O
function	O
,	O
which	O
could	O
be	O
explained	O
on	O
the	O
basis	O
of	O
a	O
greater	O
levodopa	B-Chemical
dose	O
.	O

Our	O
results	O
suggest	O
a	O
role	O
for	O
levodopa	B-Chemical
in	O
the	O
oral	O
phase	O
of	O
deglutition	O
and	O
confirm	O
that	O
dysphagia	B-Disease
is	O
not	O
a	O
good	O
predictor	O
of	O
deglutition	O
alterations	O
in	O
PD	B-Disease
.	O

Inhibition	O
of	O
nuclear	O
factor	O
-	O
kappaB	O
activation	O
attenuates	O
tubulointerstitial	B-Disease
nephritis	I-Disease
induced	O
by	O
gentamicin	B-Chemical
.	O

BACKGROUND	O
:	O
Animals	O
treated	O
with	O
gentamicin	B-Chemical
can	O
show	O
residual	O
areas	O
of	O
interstitial	O
fibrosis	B-Disease
in	O
the	O
renal	O
cortex	O
.	O

This	O
study	O
investigated	O
the	O
expression	O
of	O
nuclear	O
factor	O
-	O
kappaB	O
(	O
NF	O
-	O
kappaB	O
)	O
,	O
mitogen	O
-	O
activated	O
protein	O
(	O
MAP	O
)	O
kinases	O
and	O
macrophages	O
in	O
the	O
renal	O
cortex	O
and	O
structural	O
and	O
functional	O
renal	O
changes	O
of	O
rats	O
treated	O
with	O
gentamicin	B-Chemical
or	O
gentamicin	B-Chemical
+	O
pyrrolidine	B-Chemical
dithiocarbamate	I-Chemical
(	O
PDTC	B-Chemical
)	O
,	O
an	O
NF	O
-	O
kappaB	O
inhibitor	O
.	O

METHODS	O
:	O
38	O
female	O
Wistar	O
rats	O
were	O
injected	O
with	O
gentamicin	B-Chemical
,	O
40	O
mg	O
/	O
kg	O
,	O
twice	O
a	O
day	O
for	O
9	O
days	O
,	O
38	O
with	O
gentamicin	B-Chemical
+	O
PDTC	B-Chemical
,	O
and	O
28	O
with	O
0	O
.	O
15	O
M	O
NaCl	B-Chemical
solution	O
.	O

The	O
animals	O
were	O
killed	O
5	O
and	O
30	O
days	O
after	O
these	O
injections	O
and	O
the	O
kidneys	O
were	O
removed	O
for	O
histological	O
and	O
immunohistochemical	O
studies	O
.	O

The	O
results	O
of	O
the	O
immunohistochemical	O
studies	O
were	O
scored	O
according	O
to	O
the	O
extent	O
of	O
staining	O
.	O

The	O
fractional	O
interstitial	O
area	O
was	O
determined	O
by	O
morphometry	O
.	O

RESULTS	O
:	O
Gentamicin	B-Chemical
-	O
treated	O
rats	O
presented	O
a	O
transitory	O
increase	O
in	O
plasma	O
creatinine	B-Chemical
levels	O
.	O

Increased	O
ED	O
-	O
1	O
,	O
MAP	O
kinases	O
and	O
NF	O
-	O
kappaB	O
staining	O
were	O
also	O
observed	O
in	O
the	O
renal	O
cortex	O
from	O
all	O
gentamicin	B-Chemical
-	O
treated	O
rats	O
compared	O
to	O
control	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
animals	O
killed	O
on	O
day	O
30	O
also	O
presented	O
fibrosis	B-Disease
in	O
the	O
renal	O
cortex	O
despite	O
the	O
recovery	O
of	O
renal	O
function	O
.	O

Treatment	O
with	O
PDTC	B-Chemical
reduced	O
the	O
functional	O
and	O
structural	O
changes	O
induced	O
by	O
gentamicin	B-Chemical
.	O

CONCLUSIONS	O
:	O
These	O
data	O
show	O
that	O
inhibition	O
of	O
NF	O
-	O
kappaB	O
activation	O
attenuates	O
tubulointerstitial	B-Disease
nephritis	I-Disease
induced	O
by	O
gentamicin	B-Chemical
.	O

Glucose	B-Chemical
metabolism	O
in	O
patients	O
with	O
schizophrenia	B-Disease
treated	O
with	O
atypical	O
antipsychotic	O
agents	O
:	O
a	O
frequently	O
sampled	O
intravenous	O
glucose	B-Chemical
tolerance	O
test	O
and	O
minimal	O
model	O
analysis	O
.	O

BACKGROUND	O
:	O
While	O
the	O
incidence	O
of	O
new	O
-	O
onset	O
diabetes	B-Disease
mellitus	I-Disease
may	O
be	O
increasing	O
in	O
patients	O
with	O
schizophrenia	B-Disease
treated	O
with	O
certain	O
atypical	O
antipsychotic	O
agents	O
,	O
it	O
remains	O
unclear	O
whether	O
atypical	O
agents	O
are	O
directly	O
affecting	O
glucose	B-Chemical
metabolism	O
or	O
simply	O
increasing	O
known	O
risk	O
factors	O
for	O
diabetes	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
study	O
the	O
2	O
drugs	O
most	O
clearly	O
implicated	O
(	O
clozapine	B-Chemical
and	O
olanzapine	B-Chemical
)	O
and	O
risperidone	B-Chemical
using	O
a	O
frequently	O
sampled	O
intravenous	O
glucose	B-Chemical
tolerance	O
test	O
.	O

DESIGN	O
:	O
A	O
cross	O
-	O
sectional	O
design	O
in	O
stable	O
,	O
treated	O
patients	O
with	O
schizophrenia	B-Disease
evaluated	O
using	O
a	O
frequently	O
sampled	O
intravenous	O
glucose	B-Chemical
tolerance	O
test	O
and	O
the	O
Bergman	O
minimal	O
model	O
analysis	O
.	O

SETTING	O
:	O
Subjects	O
were	O
recruited	O
from	O
an	O
urban	O
community	O
mental	O
health	O
clinic	O
and	O
were	O
studied	O
at	O
a	O
general	O
clinical	O
research	O
center	O
.	O

Patients	O
Fifty	O
subjects	O
signed	O
informed	O
consent	O
and	O
41	O
underwent	O
the	O
frequently	O
sampled	O
intravenous	O
glucose	B-Chemical
tolerance	O
test	O
.	O

Thirty	O
-	O
six	O
nonobese	O
subjects	O
with	O
schizophrenia	B-Disease
or	O
schizoaffective	B-Disease
disorder	I-Disease
,	O
matched	O
by	O
body	O
mass	O
index	O
and	O
treated	O
with	O
either	O
clozapine	B-Chemical
,	O
olanzapine	B-Chemical
,	O
or	O
risperidone	B-Chemical
,	O
were	O
included	O
in	O
the	O
analysis	O
.	O

MAIN	O
OUTCOME	O
MEASURES	O
:	O
Fasting	O
plasma	O
glucose	B-Chemical
and	O
fasting	O
serum	O
insulin	O
levels	O
,	O
insulin	B-Disease
sensitivity	I-Disease
index	O
,	O
homeostasis	O
model	O
assessment	O
of	O
insulin	B-Disease
resistance	I-Disease
,	O
and	O
glucose	B-Chemical
effectiveness	O
.	O

RESULTS	O
:	O
The	O
mean	O
+	O
/	O
-	O
SD	O
duration	O
of	O
treatment	O
with	O
the	O
identified	O
atypical	O
antipsychotic	O
agent	O
was	O
68	O
.	O
3	O
+	O
/	O
-	O
28	O
.	O
9	O
months	O
(	O
clozapine	B-Chemical
)	O
,	O
29	O
.	O
5	O
+	O
/	O
-	O
17	O
.	O
5	O
months	O
(	O
olanzapine	B-Chemical
)	O
,	O
and	O
40	O
.	O
9	O
+	O
/	O
-	O
33	O
.	O
7	O
(	O
risperidone	B-Chemical
)	O
.	O

Fasting	O
serum	O
insulin	O
concentrations	O
differed	O
among	O
groups	O
(	O
F	O
(	O
33	O
)	O
=	O
3	O
.	O
35	O
;	O
P	O
=	O
.	O
047	O
)	O
(	O
clozapine	B-Chemical
>	O
olanzapine	B-Chemical
>	O
risperidone	B-Chemical
)	O
with	O
significant	O
differences	O
between	O
clozapine	B-Chemical
and	O
risperidone	B-Chemical
(	O
t	O
(	O
33	O
)	O
=	O
2	O
.	O
32	O
;	O
P	O
=	O
.	O
03	O
)	O
and	O
olanzapine	B-Chemical
and	O
risperidone	B-Chemical
(	O
t	O
(	O
33	O
)	O
=	O
2	O
.	O
15	O
;	O
P	O
=	O
.	O
04	O
)	O
.	O

There	O
was	O
a	O
significant	O
difference	O
in	O
insulin	B-Disease
sensitivity	I-Disease
index	O
among	O
groups	O
(	O
F	O
(	O
33	O
)	O
=	O
10	O
.	O
66	O
;	O
P	O
<	O
.	O
001	O
)	O
(	O
clozapine	B-Chemical
<	O
olanzapine	B-Chemical
<	O
risperidone	B-Chemical
)	O
,	O
with	O
subjects	O
who	O
received	O
clozapine	B-Chemical
and	O
olanzapine	B-Chemical
exhibiting	O
significant	O
insulin	B-Disease
resistance	I-Disease
compared	O
with	O
subjects	O
who	O
were	O
treated	O
with	O
risperidone	B-Chemical
(	O
clozapine	B-Chemical
vs	O
risperidone	B-Chemical
,	O
t	O
(	O
33	O
)	O
=	O
-	O
4	O
.	O
29	O
;	O
P	O
<	O
.	O
001	O
;	O
olanzapine	B-Chemical
vs	O
risperidone	B-Chemical
,	O
t	O
(	O
33	O
)	O
=	O
-	O
3	O
.	O
62	O
;	O
P	O
=	O
.	O
001	O
[	O
P	O
<	O
.	O
001	O
]	O
)	O
.	O

The	O
homeostasis	O
model	O
assessment	O
of	O
insulin	B-Disease
resistance	I-Disease
also	O
differed	O
significantly	O
among	O
groups	O
(	O
F	O
(	O
33	O
)	O
=	O
4	O
.	O
92	O
;	O
P	O
=	O
.	O
01	O
)	O
(	O
clozapine	B-Chemical
>	O
olanzapine	B-Chemical
>	O
risperidone	B-Chemical
)	O
(	O
clozapine	B-Chemical
vs	O
risperidone	B-Chemical
,	O
t	O
(	O
33	O
)	O
=	O
2	O
.	O
94	O
;	O
P	O
=	O
.	O
006	O
;	O
olanzapine	B-Chemical
vs	O
risperidone	B-Chemical
,	O
t	O
(	O
33	O
)	O
=	O
2	O
.	O
42	O
;	O
P	O
=	O
.	O
02	O
)	O
.	O

There	O
was	O
a	O
significant	O
difference	O
among	O
groups	O
in	O
glucose	B-Chemical
effectiveness	O
(	O
F	O
(	O
30	O
)	O
=	O
4	O
.	O
18	O
;	O
P	O
=	O
.	O
02	O
)	O
(	O
clozapine	B-Chemical
<	O
olanzapine	B-Chemical
<	O
risperidone	B-Chemical
)	O
with	O
significant	O
differences	O
between	O
clozapine	B-Chemical
and	O
risperidone	B-Chemical
(	O
t	O
(	O
30	O
)	O
=	O
-	O
2	O
.	O
59	O
;	O
P	O
=	O
.	O
02	O
)	O
and	O
olanzapine	B-Chemical
and	O
risperidone	B-Chemical
(	O
t	O
(	O
30	O
)	O
=	O
-	O
2	O
.	O
34	O
,	O
P	O
=	O
.	O
03	O
)	O
.	O

CONCLUSIONS	O
:	O
Both	O
nonobese	O
clozapine	B-Chemical
-	O
and	O
olanzapine	B-Chemical
-	O
treated	O
groups	O
displayed	O
significant	O
insulin	B-Disease
resistance	I-Disease
and	O
impairment	O
of	O
glucose	B-Chemical
effectiveness	O
compared	O
with	O
risperidone	B-Chemical
-	O
treated	O
subjects	O
.	O

Patients	O
taking	O
clozapine	B-Chemical
and	O
olanzapine	B-Chemical
must	O
be	O
examined	O
for	O
insulin	B-Disease
resistance	I-Disease
and	O
its	O
consequences	O
.	O

Thoracic	B-Disease
hematomyelia	I-Disease
secondary	O
to	O
coumadin	B-Chemical
anticoagulant	O
therapy	O
:	O
a	O
case	O
report	O
.	O

A	O
case	O
of	O
thoracic	B-Disease
hematomyelia	I-Disease
secondary	O
to	O
anticoagulant	O
therapy	O
is	O
presented	O
.	O

Clinical	O
features	O
,	O
similar	O
to	O
2	O
other	O
previously	O
reported	O
cases	O
,	O
are	O
discussed	O
.	O

A	O
high	O
index	O
of	O
suspicion	O
may	O
lead	O
to	O
a	O
quick	O
diagnostic	O
procedure	O
and	O
successful	O
decompressive	O
surgery	O
.	O

Mania	B-Disease
associated	O
with	O
fluoxetine	B-Chemical
treatment	O
in	O
adolescents	O
.	O

Fluoxetine	B-Chemical
,	O
a	O
selective	O
serotonin	B-Chemical
reuptake	O
inhibitor	O
,	O
is	O
gaining	O
increased	O
acceptance	O
in	O
the	O
treatment	O
of	O
adolescent	O
depression	B-Disease
.	O

Generally	O
safe	O
and	O
well	O
tolerated	O
by	O
adults	O
,	O
fluoxetine	B-Chemical
has	O
been	O
reported	O
to	O
induce	O
mania	B-Disease
.	O

The	O
cases	O
of	O
five	O
depressed	B-Disease
adolescents	O
,	O
14	O
-	O
16	O
years	O
of	O
age	O
,	O
who	O
developed	O
mania	B-Disease
during	O
pharmacotherapy	O
with	O
fluoxetine	B-Chemical
,	O
are	O
reported	O
here	O
.	O

Apparent	O
risk	O
factors	O
for	O
the	O
development	O
of	O
mania	B-Disease
or	O
hypomania	B-Disease
during	O
fluoxetine	B-Chemical
pharmacotherapy	O
in	O
this	O
population	O
were	O
the	O
combination	O
of	O
attention	B-Disease
-	I-Disease
deficit	I-Disease
hyperactivity	I-Disease
disorder	I-Disease
and	O
affective	O
instability	O
;	O
major	O
depression	B-Disease
with	O
psychotic	B-Disease
features	O
;	O
a	O
family	O
history	O
of	O
affective	B-Disease
disorder	I-Disease
,	O
especially	O
bipolar	B-Disease
disorder	I-Disease
;	O
and	O
a	O
diagnosis	O
of	O
bipolar	B-Disease
disorder	I-Disease
.	O

Further	O
study	O
is	O
needed	O
to	O
determine	O
the	O
optimal	O
dosage	O
and	O
to	O
identify	O
risk	O
factors	O
that	O
increase	O
individual	O
vulnerability	O
to	O
fluoxetine	B-Chemical
induced	O
mania	B-Disease
in	O
adolescents	O
.	O

Acute	B-Disease
renal	I-Disease
insufficiency	I-Disease
after	O
high	O
-	O
dose	O
melphalan	B-Chemical
in	O
patients	O
with	O
primary	B-Disease
systemic	I-Disease
amyloidosis	I-Disease
during	O
stem	O
cell	O
transplantation	O
.	O

BACKGROUND	O
:	O
Patients	O
with	O
primary	B-Disease
systemic	I-Disease
amyloidosis	I-Disease
(	O
AL	B-Disease
)	O
have	O
a	O
poor	O
prognosis	O
.	O

Median	O
survival	O
time	O
from	O
standard	O
treatments	O
is	O
only	O
17	O
months	O
.	O

High	O
-	O
dose	O
intravenous	O
melphalan	B-Chemical
followed	O
by	O
peripheral	O
blood	O
stem	O
cell	O
transplant	O
(	O
PBSCT	O
)	O
appears	O
to	O
be	O
the	O
most	O
promising	O
therapy	O
,	O
but	O
treatment	O
mortality	O
can	O
be	O
high	O
.	O

The	O
authors	O
have	O
noted	O
the	O
development	O
of	O
acute	B-Disease
renal	I-Disease
insufficiency	I-Disease
immediately	O
after	O
melphalan	B-Chemical
conditioning	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
further	O
examine	O
its	O
risk	O
factors	O
and	O
impact	O
on	O
posttransplant	O
mortality	O
.	O

METHODS	O
:	O
Consecutive	O
AL	B-Disease
patients	O
who	O
underwent	O
PBSCT	O
were	O
studied	O
retrospectively	O
.	O

Acute	B-Disease
renal	I-Disease
insufficiency	I-Disease
(	O
ARI	B-Disease
)	O
after	O
high	O
-	O
dose	O
melphalan	B-Chemical
was	O
defined	O
by	O
a	O
minimum	O
increase	O
of	O
0	O
.	O
5	O
mg	O
/	O
dL	O
(	O
44	O
micromol	O
/	O
L	O
)	O
in	O
the	O
serum	O
creatinine	B-Chemical
level	O
that	O
is	O
greater	O
than	O
50	O
%	O
of	O
baseline	O
immediately	O
after	O
conditioning	O
.	O

Urine	O
sediment	O
score	O
was	O
the	O
sum	O
of	O
the	O
individual	O
types	O
of	O
sediment	O
identified	O
on	O
urine	O
microscopy	O
.	O

RESULTS	O
:	O
Of	O
the	O
80	O
patients	O
studied	O
,	O
ARI	B-Disease
developed	O
in	O
18	O
.	O
8	O
%	O
of	O
the	O
patients	O
after	O
high	O
-	O
dose	O
melphalan	B-Chemical
.	O

Univariate	O
analysis	O
identified	O
age	O
,	O
hypoalbuminemia	B-Disease
,	O
heavy	O
proteinuria	B-Disease
,	O
diuretic	O
use	O
,	O
and	O
urine	O
sediment	O
score	O
(	O
>	O
3	O
)	O
as	O
risk	O
factors	O
.	O

Age	O
and	O
urine	O
sediment	O
score	O
remained	O
independently	O
significant	O
risk	O
factors	O
in	O
the	O
multivariate	O
analysis	O
.	O

Patients	O
who	O
had	O
ARI	B-Disease
after	O
high	O
-	O
dose	O
melphalan	B-Chemical
underwent	O
dialysis	O
more	O
often	O
(	O
P	O
=	O
0	O
.	O
007	O
)	O
,	O
and	O
had	O
a	O
worse	O
1	O
-	O
year	O
survival	O
(	O
P	O
=	O
0	O
.	O
03	O
)	O
.	O

CONCLUSION	O
:	O
The	O
timing	O
of	O
renal	B-Disease
injury	I-Disease
strongly	O
suggests	O
melphalan	B-Chemical
as	O
the	O
causative	O
agent	O
.	O

Ongoing	O
tubular	B-Disease
injury	I-Disease
may	O
be	O
a	O
prerequisite	O
for	O
renal	B-Disease
injury	I-Disease
by	O
melphalan	B-Chemical
as	O
evidenced	O
by	O
the	O
active	O
urinary	O
sediment	O
.	O

Development	O
of	O
ARI	B-Disease
adversely	O
affected	O
the	O
outcome	O
after	O
PBSCT	O
.	O

Effective	O
preventive	O
measures	O
may	O
help	O
decrease	O
the	O
treatment	O
mortality	O
of	O
PBSCT	O
in	O
AL	B-Disease
patients	O
.	O

Focal	O
cerebral	B-Disease
ischemia	I-Disease
in	O
rats	O
:	O
effect	O
of	O
phenylephrine	B-Chemical
-	O
induced	O
hypertension	B-Disease
during	O
reperfusion	O
.	O

After	O
180	O
min	O
of	O
temporary	O
middle	B-Disease
cerebral	I-Disease
artery	I-Disease
occlusion	I-Disease
in	O
spontaneously	O
hypertensive	B-Disease
rats	O
,	O
the	O
effect	O
of	O
phenylephrine	B-Chemical
-	O
induced	O
hypertension	B-Disease
on	O
ischemic	B-Disease
brain	I-Disease
injury	I-Disease
and	O
blood	O
-	O
brain	O
barrier	O
permeability	O
was	O
determined	O
.	O

Blood	O
pressure	O
was	O
manipulated	O
by	O
one	O
of	O
the	O
following	O
schedules	O
during	O
120	O
min	O
of	O
reperfusion	O
:	O
Control	O
,	O
normotensive	O
reperfusion	O
;	O
90	O
/	O
hypertension	B-Disease
(	O
90	O
/	O
HTN	B-Disease
)	O
,	O
blood	O
pressure	O
was	O
increased	O
by	O
35	O
mm	O
Hg	O
during	O
the	O
initial	O
90	O
min	O
of	O
reperfusion	O
only	O
;	O
15	O
/	O
hypertension	B-Disease
(	O
15	O
/	O
HTN	B-Disease
)	O
,	O
normotensive	O
reperfusion	O
for	O
30	O
min	O
followed	O
by	O
15	O
min	O
of	O
hypertension	B-Disease
and	O
75	O
min	O
of	O
normotension	O
.	O

Part	O
A	O
,	O
for	O
eight	O
rats	O
in	O
each	O
group	O
brain	B-Disease
injury	I-Disease
was	O
evaluated	O
by	O
staining	O
tissue	O
using	O
2	B-Chemical
,	I-Chemical
3	I-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
triphenyltetrazolium	I-Chemical
chloride	I-Chemical
and	O
edema	B-Disease
was	O
evaluated	O
by	O
microgravimetry	O
.	O

Part	O
B	O
,	O
for	O
eight	O
different	O
rats	O
in	O
each	O
group	O
blood	O
-	O
brain	O
barrier	O
permeability	O
was	O
evaluated	O
by	O
measuring	O
the	O
amount	O
and	O
extent	O
of	O
extravasation	O
of	O
Evans	O
Blue	O
dye	O
.	O

Brain	B-Disease
injury	I-Disease
(	O
percentage	O
of	O
the	O
ischemic	B-Disease
hemisphere	I-Disease
)	O
was	O
less	O
in	O
the	O
15	O
/	O
HTN	B-Disease
group	O
(	O
16	O
+	O
/	O
-	O
6	O
,	O
mean	O
+	O
/	O
-	O
SD	O
)	O
versus	O
the	O
90	O
/	O
HTN	B-Disease
group	O
(	O
30	O
+	O
/	O
-	O
6	O
)	O
,	O
which	O
was	O
in	O
turn	O
less	O
than	O
the	O
control	O
group	O
(	O
42	O
+	O
/	O
-	O
5	O
)	O
.	O

Specific	O
gravity	O
was	O
greater	O
in	O
the	O
15	O
/	O
HTN	B-Disease
group	O
(	O
1	O
.	O
043	O
+	O
/	O
-	O
0	O
.	O
002	O
)	O
versus	O
the	O
90	O
/	O
HTN	B-Disease
(	O
1	O
.	O
036	O
+	O
/	O
-	O
0	O
.	O
003	O
)	O
and	O
control	O
(	O
1	O
.	O
037	O
+	O
/	O
-	O
0	O
.	O
003	O
)	O
groups	O
.	O

Evans	B-Chemical
Blue	I-Chemical
(	O
mug	O
g	O
-	O
1	O
of	O
brain	O
tissue	O
)	O
was	O
greater	O
in	O
the	O
90	O
/	O
HTN	B-Disease
group	O
(	O
24	O
.	O
4	O
+	O
/	O
-	O
6	O
.	O
0	O
)	O
versus	O
the	O
control	O
group	O
(	O
12	O
.	O
3	O
+	O
/	O
-	O
4	O
.	O
1	O
)	O
,	O
which	O
was	O
in	O
turn	O
greater	O
than	O
the	O
15	O
/	O
HTN	B-Disease
group	O
(	O
7	O
.	O
3	O
+	O
/	O
-	O
3	O
.	O
2	O
)	O
.	O

This	O
study	O
supports	O
a	O
hypothesis	O
that	O
during	O
reperfusion	O
,	O
a	O
short	O
interval	O
of	O
hypertension	B-Disease
decreases	O
brain	B-Disease
injury	I-Disease
and	O
edema	B-Disease
;	O
and	O
that	O
sustained	O
hypertension	B-Disease
increases	O
the	O
risk	O
of	O
vasogenic	B-Disease
edema	I-Disease
.	O

People	O
aged	O
over	O
75	O
in	O
atrial	B-Disease
fibrillation	I-Disease
on	O
warfarin	B-Chemical
:	O
the	O
rate	O
of	O
major	O
hemorrhage	B-Disease
and	O
stroke	B-Disease
in	O
more	O
than	O
500	O
patient	O
-	O
years	O
of	O
follow	O
-	O
up	O
.	O

OBJECTIVES	O
:	O
To	O
determine	O
the	O
incidence	O
of	O
major	O
hemorrhage	B-Disease
and	O
stroke	B-Disease
in	O
people	O
aged	O
76	O
and	O
older	O
with	O
atrial	B-Disease
fibrillation	I-Disease
on	O
adjusted	O
-	O
dose	O
warfarin	B-Chemical
who	O
had	O
been	O
recently	O
been	O
admitted	O
to	O
hospital	O
.	O

DESIGN	O
:	O
A	O
retrospective	O
observational	O
cohort	O
study	O
.	O

SETTING	O
:	O
A	O
major	O
healthcare	O
network	O
involving	O
four	O
tertiary	O
hospitals	O
.	O

PARTICIPANTS	O
:	O
Two	O
hundred	O
thirty	O
-	O
five	O
patients	O
aged	O
76	O
and	O
older	O
admitted	O
to	O
a	O
major	O
healthcare	O
network	O
between	O
July	O
1	O
,	O
2001	O
,	O
and	O
June	O
30	O
,	O
2002	O
,	O
with	O
atrial	B-Disease
fibrillation	I-Disease
on	O
warfarin	B-Chemical
were	O
enrolled	O
.	O

MEASUREMENTS	O
:	O
Information	O
regarding	O
major	O
bleeding	B-Disease
episodes	O
,	O
strokes	B-Disease
,	O
and	O
warfarin	B-Chemical
use	O
was	O
obtained	O
from	O
patients	O
,	O
relatives	O
,	O
primary	O
physicians	O
,	O
and	O
medical	O
records	O
.	O

RESULTS	O
:	O
Two	O
hundred	O
twenty	O
-	O
eight	O
patients	O
(	O
42	O
%	O
men	O
)	O
with	O
a	O
mean	O
age	O
of	O
81	O
.	O
1	O
(	O
range	O
76	O
-	O
94	O
)	O
were	O
included	O
in	O
the	O
analysis	O
.	O

Total	O
follow	O
-	O
up	O
on	O
warfarin	B-Chemical
was	O
530	O
years	O
(	O
mean	O
28	O
months	O
)	O
.	O

There	O
were	O
53	O
major	O
hemorrhages	B-Disease
,	O
for	O
an	O
annual	O
rate	O
of	O
10	O
.	O
0	O
%	O
,	O
including	O
24	O
(	O
45	O
.	O
3	O
%	O
)	O
life	O
-	O
threatening	O
and	O
five	O
(	O
9	O
.	O
4	O
%	O
)	O
fatal	O
bleeds	O
.	O

The	O
annual	O
stroke	B-Disease
rate	O
after	O
initiation	O
of	O
warfarin	B-Chemical
was	O
2	O
.	O
6	O
%	O
.	O

CONCLUSION	O
:	O
The	O
rate	O
of	O
major	O
hemorrhage	B-Disease
was	O
high	O
in	O
this	O
old	O
,	O
frail	O
group	O
,	O
but	O
excluding	O
fatalities	O
,	O
resulted	O
in	O
no	O
long	O
-	O
term	O
sequelae	O
,	O
and	O
the	O
stroke	B-Disease
rate	O
on	O
warfarin	B-Chemical
was	O
low	O
,	O
demonstrating	O
how	O
effective	O
warfarin	B-Chemical
treatment	O
is	O
.	O

Safety	O
of	O
celecoxib	B-Chemical
in	O
patients	O
with	O
adverse	O
skin	B-Disease
reactions	I-Disease
to	O
acetaminophen	B-Chemical
(	O
paracetamol	B-Chemical
)	O
and	O
nimesulide	B-Chemical
associated	O
or	O
not	O
with	O
common	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
.	O

BACKGROUND	O
:	O
Acetaminophen	B-Chemical
(	O
paracetamol	B-Chemical
-	O
-	O
P	B-Chemical
)	O
and	O
Nimesulide	B-Chemical
(	O
N	B-Chemical
)	O
are	O
widely	O
used	O
analgesic	O
-	O
antipyretic	O
/	O
anti	O
-	O
inflammatory	O
drugs	O
.	O

The	O
rate	O
of	O
adverse	O
hypersensitivity	B-Disease
reactions	O
to	O
these	O
agents	O
is	O
generally	O
low	O
.	O

On	O
the	O
contrary	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
(	O
NSAIDs	O
)	O
are	O
commonly	O
involved	O
in	O
such	O
reactions	O
.	O

Celecoxib	B-Chemical
(	O
CE	B-Chemical
)	O
is	O
a	O
novel	O
drug	O
,	O
with	O
high	O
selectivity	O
and	O
affinity	O
for	O
COX	O
-	O
2	O
enzyme	O
.	O

OBJECTIVE	O
:	O
We	O
evaluated	O
the	O
tolerability	O
of	O
CE	B-Chemical
in	O
a	O
group	O
of	O
patients	O
with	O
documented	O
history	O
of	O
adverse	O
cutaneous	B-Disease
reactions	I-Disease
to	O
P	B-Chemical
and	O
N	B-Chemical
associated	O
or	O
not	O
to	O
classic	O
NSAIDs	O
.	O

METHODS	O
:	O
We	O
studied	O
9	O
patients	O
with	O
hypersensitivity	B-Disease
to	O
P	B-Chemical
and	O
N	B-Chemical
with	O
or	O
without	O
associated	O
reactions	O
to	O
classic	O
NSAIDs	O
.	O

The	O
diagnosis	O
of	O
P	B-Chemical
and	O
N	B-Chemical
-	O
induced	O
skin	B-Disease
reactions	I-Disease
was	O
based	O
in	O
vivo	O
challenge	O
.	O

The	O
placebo	O
was	O
blindly	O
administered	O
at	O
the	O
beginning	O
of	O
each	O
challenge	O
.	O

After	O
three	O
days	O
,	O
a	O
cumulative	O
dosage	O
of	O
200	O
mg	O
of	O
CE	B-Chemical
in	O
refracted	O
doses	O
were	O
given	O
.	O

After	O
2	O
-	O
3	O
days	O
,	O
a	O
single	O
dose	O
of	O
200	O
mg	O
was	O
administered	O
.	O

All	O
patients	O
were	O
observed	O
for	O
6	O
hours	O
after	O
each	O
challenge	O
,	O
and	O
controlled	O
again	O
after	O
24	O
hours	O
to	O
exclude	O
delayed	O
reactions	O
.	O

The	O
challenge	O
was	O
considered	O
positive	O
if	O
one	O
or	O
more	O
of	O
the	O
following	O
appeared	O
:	O
erythema	B-Disease
,	O
rush	O
or	O
urticaria	B-Disease
-	O
angioedema	B-Disease
.	O

RESULTS	O
:	O
No	O
reaction	O
was	O
observed	O
with	O
placebo	O
and	O
eight	O
patients	O
(	O
88	O
.	O
8	O
%	O
)	O
tolerated	O
CE	B-Chemical
.	O

Only	O
one	O
patient	O
developed	O
a	O
moderate	O
angioedema	B-Disease
of	O
the	O
lips	O
.	O

CONCLUSION	O
:	O
Only	O
one	O
hypersensitivity	B-Disease
reaction	O
to	O
CE	B-Chemical
was	O
documented	O
among	O
9	O
P	B-Chemical
and	O
N	B-Chemical
-	O
highly	O
NSAIDs	O
intolerant	O
patients	O
.	O

Thus	O
,	O
we	O
conclude	O
that	O
CE	B-Chemical
is	O
a	O
reasonably	O
safe	O
alternative	O
to	O
be	O
used	O
in	O
subjects	O
who	O
do	O
not	O
tolerate	O
P	B-Chemical
and	O
N	B-Chemical
.	O

Case	O
-	O
control	O
study	O
of	O
regular	O
analgesic	O
and	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
use	O
and	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
.	O

BACKGROUND	O
:	O
Studies	O
on	O
the	O
association	O
between	O
the	O
long	O
-	O
term	O
use	O
of	O
aspirin	B-Chemical
and	O
other	O
analgesic	O
and	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drugs	O
(	O
NSAIDs	O
)	O
and	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
(	O
ESRD	B-Disease
)	O
have	O
given	O
conflicting	O
results	O
.	O

In	O
order	O
to	O
examine	O
this	O
association	O
,	O
a	O
case	O
-	O
control	O
study	O
with	O
incident	O
cases	O
of	O
ESRD	B-Disease
was	O
carried	O
out	O
.	O

METHODS	O
:	O
The	O
cases	O
were	O
all	O
patients	O
entering	O
the	O
local	O
dialysis	O
program	O
because	O
of	O
ESRD	B-Disease
in	O
the	O
study	O
area	O
between	O
June	O
1	O
,	O
1995	O
and	O
November	O
30	O
,	O
1997	O
.	O

They	O
were	O
classified	O
according	O
to	O
the	O
underlying	O
disease	O
,	O
which	O
had	O
presumably	O
led	O
them	O
to	O
ESRD	B-Disease
.	O

Controls	O
were	O
patients	O
admitted	O
to	O
the	O
same	O
hospitals	O
from	O
where	O
the	O
cases	O
arose	O
,	O
also	O
matched	O
by	O
age	O
and	O
sex	O
.	O

Odds	O
ratios	O
were	O
calculated	O
using	O
a	O
conditional	O
logistic	O
model	O
,	O
including	O
potential	O
confounding	O
factors	O
,	O
both	O
for	O
the	O
whole	O
study	O
population	O
and	O
for	O
the	O
various	O
underlying	O
diseases	O
.	O

RESULTS	O
:	O
Five	O
hundred	O
and	O
eighty	O
-	O
three	O
cases	O
and	O
1190	O
controls	O
were	O
included	O
in	O
the	O
analysis	O
.	O

Long	O
-	O
term	O
use	O
of	O
any	O
analgesic	O
was	O
associated	O
with	O
an	O
overall	O
odds	O
ratio	O
of	O
1	O
.	O
22	O
(	O
95	O
%	O
CI	O
,	O
0	O
.	O
89	O
-	O
1	O
.	O
66	O
)	O
.	O

For	O
specific	O
groups	O
of	O
drugs	O
,	O
the	O
risks	O
were	O
1	O
.	O
56	O
(	O
1	O
.	O
05	O
-	O
2	O
.	O
30	O
)	O
for	O
aspirin	B-Chemical
,	O
1	O
.	O
03	O
(	O
0	O
.	O
60	O
-	O
1	O
.	O
76	O
)	O
for	O
pyrazolones	B-Chemical
,	O
0	O
.	O
80	O
(	O
0	O
.	O
39	O
-	O
1	O
.	O
63	O
)	O
for	O
paracetamol	B-Chemical
,	O
and	O
0	O
.	O
94	O
(	O
0	O
.	O
57	O
-	O
1	O
.	O
56	O
)	O
for	O
nonaspirin	O
NSAIDs	O
.	O

The	O
risk	O
of	O
ESRD	B-Disease
associated	O
with	O
aspirin	B-Chemical
was	O
related	O
to	O
the	O
cumulated	O
dose	O
and	O
duration	O
of	O
use	O
,	O
and	O
it	O
was	O
particularly	O
high	O
among	O
the	O
subset	O
of	O
patients	O
with	O
vascular	O
nephropathy	B-Disease
as	O
underlying	O
disease	O
[	O
2	O
.	O
35	O
(	O
1	O
.	O
17	O
-	O
4	O
.	O
72	O
)	O
]	O
.	O

CONCLUSION	O
:	O
Our	O
data	O
indicate	O
that	O
long	O
-	O
term	O
use	O
of	O
nonaspirin	O
analgesic	O
drugs	O
and	O
NSAIDs	O
is	O
not	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
ESRD	B-Disease
.	O

However	O
,	O
the	O
chronic	O
use	O
of	O
aspirin	B-Chemical
may	O
increase	O
the	O
risk	O
of	O
ESRD	B-Disease
.	O

Two	O
cases	O
of	O
amisulpride	B-Chemical
overdose	B-Disease
:	O
a	O
cause	O
for	O
prolonged	B-Disease
QT	I-Disease
syndrome	I-Disease
.	O

Two	O
cases	O
of	O
deliberate	O
self	O
-	O
poisoning	B-Disease
with	O
5	O
g	O
and	O
3	O
.	O
6	O
g	O
of	O
amisulpride	B-Chemical
,	O
respectively	O
,	O
are	O
reported	O
.	O

In	O
both	O
cases	O
,	O
QT	B-Disease
prolongation	I-Disease
and	O
hypocalcaemia	B-Disease
were	O
noted	O
.	O

The	O
QT	B-Disease
prolongation	I-Disease
appeared	O
to	O
respond	O
to	O
administration	O
of	O
i	O
.	O
v	O
.	O
calcium	B-Chemical
gluconate	I-Chemical
.	O

Growth	O
-	O
associated	O
protein	O
43	O
expression	O
in	O
hippocampal	O
molecular	O
layer	O
of	O
chronic	O
epileptic	B-Disease
rats	O
treated	O
with	O
cycloheximide	B-Chemical
.	O

PURPOSE	O
:	O
GAP43	O
has	O
been	O
thought	O
to	O
be	O
linked	O
with	O
mossy	O
fiber	O
sprouting	O
(	O
MFS	O
)	O
in	O
various	O
experimental	O
models	O
of	O
epilepsy	B-Disease
.	O

To	O
investigate	O
how	O
GAP43	O
expression	O
(	O
GAP43	O
-	O
ir	O
)	O
correlates	O
with	O
MFS	O
,	O
we	O
assessed	O
the	O
intensity	O
(	O
densitometry	O
)	O
and	O
extension	O
(	O
width	O
)	O
of	O
GAP43	O
-	O
ir	O
in	O
the	O
inner	O
molecular	O
layer	O
of	O
the	O
dentate	O
gyrus	O
(	O
IML	O
)	O
of	O
rats	O
subject	O
to	O
status	B-Disease
epilepticus	I-Disease
induced	O
by	O
pilocarpine	B-Chemical
(	O
Pilo	B-Chemical
)	O
,	O
previously	O
injected	O
or	O
not	O
with	O
cycloheximide	B-Chemical
(	O
CHX	B-Chemical
)	O
,	O
which	O
has	O
been	O
shown	O
to	O
inhibit	O
MFS	O
.	O

METHODS	O
:	O
CHX	B-Chemical
was	O
injected	O
before	O
the	O
Pilo	B-Chemical
injection	O
in	O
adult	O
Wistar	O
rats	O
.	O

The	O
Pilo	B-Chemical
group	O
was	O
injected	O
with	O
the	O
same	O
drugs	O
,	O
except	O
for	O
CHX	B-Chemical
.	O

Animals	O
were	O
killed	O
between	O
30	O
and	O
60	O
days	O
later	O
,	O
and	O
brain	O
sections	O
were	O
processed	O
for	O
GAP43	O
immunohistochemistry	O
.	O

RESULTS	O
:	O
Densitometry	O
showed	O
no	O
significant	O
difference	O
regarding	O
GAP43	O
-	O
ir	O
in	O
the	O
IML	O
between	O
Pilo	B-Chemical
,	O
CHX	B-Chemical
+	O
Pilo	B-Chemical
,	O
and	O
control	O
groups	O
.	O

However	O
,	O
the	O
results	O
of	O
the	O
width	O
of	O
the	O
GAP43	O
-	O
ir	O
band	O
in	O
the	O
IML	O
showed	O
that	O
CHX	B-Chemical
+	O
Pilo	B-Chemical
and	O
control	O
animals	O
had	O
a	O
significantly	O
larger	O
band	O
(	O
p	O
=	O
0	O
.	O
03	O
)	O
as	O
compared	O
with	O
that	O
in	O
the	O
Pilo	B-Chemical
group	O
.	O

CONCLUSIONS	O
:	O
Our	O
current	O
finding	O
that	O
animals	O
in	O
the	O
CHX	B-Chemical
+	O
Pilo	B-Chemical
group	O
have	O
a	O
GAP43	O
-	O
ir	O
band	O
in	O
the	O
IML	O
,	O
similar	O
to	O
that	O
of	O
controls	O
,	O
reinforces	O
prior	O
data	O
on	O
the	O
blockade	O
of	O
MFS	O
in	O
these	O
animals	O
.	O

The	O
change	O
in	O
GAP43	O
-	O
ir	O
present	O
in	O
Pilo	B-Chemical
-	O
treated	O
animals	O
was	O
a	O
thinning	O
of	O
the	O
band	O
to	O
a	O
very	O
narrow	O
layer	O
just	O
above	O
the	O
granule	O
cell	O
layer	O
that	O
is	O
likely	O
to	O
be	O
associated	O
with	O
the	O
loss	O
of	O
hilar	O
cell	O
projections	O
that	O
express	O
GAP	O
-	O
43	O
.	O

Nicotine	B-Chemical
antagonizes	O
caffeine	B-Chemical
-	O
but	O
not	O
pentylenetetrazole	B-Chemical
-	O
induced	O
anxiogenic	O
effect	O
in	O
mice	O
.	O

RATIONALE	O
:	O
Nicotine	B-Chemical
and	O
caffeine	B-Chemical
are	O
widely	O
consumed	O
licit	O
psychoactive	O
drugs	O
worldwide	O
.	O

Epidemiological	O
studies	O
showed	O
that	O
they	O
were	O
generally	O
used	O
concurrently	O
.	O

Although	O
some	O
studies	O
in	O
experimental	O
animals	O
indicate	O
clear	O
pharmacological	O
interactions	O
between	O
them	O
,	O
no	O
studies	O
have	O
shown	O
a	O
specific	O
interaction	O
on	O
anxiety	B-Disease
responses	O
.	O

OBJECTIVES	O
:	O
The	O
present	O
study	O
investigates	O
the	O
effects	O
of	O
nicotine	B-Chemical
on	O
anxiety	B-Disease
induced	O
by	O
caffeine	B-Chemical
and	O
another	O
anxiogenic	O
drug	O
,	O
pentylenetetrazole	B-Chemical
,	O
in	O
mice	O
.	O

The	O
elevated	O
plus	O
-	O
maze	O
(	O
EPM	O
)	O
test	O
was	O
used	O
to	O
evaluate	O
the	O
effects	O
of	O
drugs	O
on	O
anxiety	B-Disease
.	O

METHODS	O
:	O
Adult	O
male	O
Swiss	O
Webster	O
mice	O
(	O
25	O
-	O
32	O
g	O
)	O
were	O
given	O
nicotine	B-Chemical
(	O
0	O
.	O
05	O
-	O
0	O
.	O
25	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
or	O
saline	O
10	O
min	O
before	O
caffeine	B-Chemical
(	O
70	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
or	O
pentylenetetrazole	B-Chemical
(	O
15	O
and	O
30	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
injections	O
.	O

After	O
15	O
min	O
,	O
mice	O
were	O
evaluated	O
for	O
their	O
open	O
-	O
and	O
closed	O
-	O
arm	O
time	O
and	O
entries	O
on	O
the	O
EPM	O
for	O
a	O
10	O
-	O
min	O
session	O
.	O

Locomotor	O
activity	O
was	O
recorded	O
for	O
individual	O
groups	O
by	O
using	O
the	O
same	O
treatment	O
protocol	O
with	O
the	O
EPM	O
test	O
.	O

RESULTS	O
:	O
Nicotine	B-Chemical
(	O
0	O
.	O
05	O
-	O
0	O
.	O
25	O
mg	O
/	O
kg	O
)	O
itself	O
did	O
not	O
produce	O
any	O
significant	O
effect	O
in	O
the	O
EPM	O
test	O
,	O
whereas	O
caffeine	B-Chemical
(	O
70	O
mg	O
/	O
kg	O
)	O
and	O
pentylenetetrazole	B-Chemical
(	O
30	O
mg	O
/	O
kg	O
)	O
produced	O
an	O
anxiogenic	O
effect	O
,	O
apparent	O
with	O
decreases	O
in	O
open	O
-	O
arm	O
time	O
and	O
entry	O
.	O

Nicotine	B-Chemical
(	O
0	O
.	O
25	O
mg	O
/	O
kg	O
)	O
pretreatment	O
blocked	O
the	O
caffeine	B-Chemical
-	O
but	O
not	O
pentylenetetrazole	B-Chemical
-	O
induced	O
anxiety	B-Disease
.	O

Administration	O
of	O
each	O
drug	O
and	O
their	O
combinations	O
did	O
not	O
produce	O
any	O
effect	O
on	O
locomotor	O
activity	O
.	O

CONCLUSIONS	O
:	O
Our	O
results	O
suggest	O
that	O
the	O
antagonistic	O
effect	O
of	O
nicotine	B-Chemical
on	O
caffeine	B-Chemical
-	O
induced	O
anxiety	B-Disease
is	O
specific	O
to	O
caffeine	B-Chemical
,	O
instead	O
of	O
a	O
non	O
-	O
specific	O
anxiolytic	O
effect	O
.	O

Thus	O
,	O
it	O
may	O
extend	O
the	O
current	O
findings	O
on	O
the	O
interaction	O
between	O
nicotine	B-Chemical
and	O
caffeine	B-Chemical
.	O

Long	O
term	O
hormone	O
therapy	O
for	O
perimenopausal	O
and	O
postmenopausal	O
women	O
.	O

BACKGROUND	O
:	O
Hormone	O
therapy	O
(	O
HT	O
)	O
is	O
widely	O
used	O
for	O
controlling	O
menopausal	B-Disease
symptoms	I-Disease
.	O

It	O
has	O
also	O
been	O
used	O
for	O
the	O
management	O
and	O
prevention	O
of	O
cardiovascular	B-Disease
disease	I-Disease
,	O
osteoporosis	B-Disease
and	O
dementia	B-Disease
in	O
older	O
women	O
but	O
the	O
evidence	O
supporting	O
its	O
use	O
for	O
these	O
indications	O
is	O
largely	O
observational	O
.	O

OBJECTIVES	O
:	O
To	O
assess	O
the	O
effect	O
of	O
long	O
-	O
term	O
HT	O
on	O
mortality	O
,	O
heart	B-Disease
disease	I-Disease
,	O
venous	B-Disease
thromboembolism	I-Disease
,	O
stroke	B-Disease
,	O
transient	B-Disease
ischaemic	I-Disease
attacks	I-Disease
,	O
breast	B-Disease
cancer	I-Disease
,	O
colorectal	B-Disease
cancer	I-Disease
,	O
ovarian	B-Disease
cancer	I-Disease
,	O
endometrial	B-Disease
cancer	I-Disease
,	O
gallbladder	B-Disease
disease	I-Disease
,	O
cognitive	O
function	O
,	O
dementia	B-Disease
,	O
fractures	B-Disease
and	O
quality	O
of	O
life	O
.	O

SEARCH	O
STRATEGY	O
:	O
We	O
searched	O
the	O
following	O
databases	O
up	O
to	O
November	O
2004	O
:	O
the	O
Cochrane	O
Menstrual	O
Disorders	O
and	O
Subfertility	O
Group	O
Trials	O
Register	O
,	O
Cochrane	O
Central	O
Register	O
of	O
Controlled	O
Trials	O
(	O
CENTRAL	O
)	O
,	O
MEDLINE	O
,	O
EMBASE	O
,	O
Biological	O
Abstracts	O
.	O

Relevant	O
non	O
-	O
indexed	O
journals	O
and	O
conference	O
abstracts	O
were	O
also	O
searched	O
.	O

SELECTION	O
CRITERIA	O
:	O
Randomised	O
double	O
-	O
blind	O
trials	O
of	O
HT	O
(	O
oestrogens	B-Chemical
with	O
or	O
without	O
progestogens	B-Chemical
)	O
versus	O
placebo	O
,	O
taken	O
for	O
at	O
least	O
one	O
year	O
by	O
perimenopausal	O
or	O
postmenopausal	O
women	O
.	O

DATA	O
COLLECTION	O
AND	O
ANALYSIS	O
:	O
Fifteen	O
RCTs	O
were	O
included	O
.	O

Trials	O
were	O
assessed	O
for	O
quality	O
and	O
two	O
review	O
authors	O
extracted	O
data	O
independently	O
.	O

They	O
calculated	O
risk	O
ratios	O
for	O
dichotomous	O
outcomes	O
and	O
weighted	O
mean	O
differences	O
for	O
continuous	O
outcomes	O
.	O

Clinical	O
heterogeneity	O
precluded	O
meta	O
-	O
analysis	O
for	O
most	O
outcomes	O
.	O

MAIN	O
RESULTS	O
:	O
All	O
the	O
statistically	O
significant	O
results	O
were	O
derived	O
from	O
the	O
two	O
biggest	O
trials	O
.	O

In	O
relatively	O
healthy	O
women	O
,	O
combined	O
continuous	O
HT	O
significantly	O
increased	O
the	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
or	O
coronary	O
event	O
(	O
after	O
one	O
year	O
'	O
s	O
use	O
)	O
,	O
stroke	B-Disease
(	O
after	O
3	O
years	O
)	O
,	O
breast	B-Disease
cancer	I-Disease
(	O
after	O
5	O
years	O
)	O
and	O
gallbladder	B-Disease
disease	I-Disease
.	O

Long	O
-	O
term	O
oestrogen	B-Chemical
-	O
only	O
HT	O
also	O
significantly	O
increased	O
the	O
risk	O
of	O
stroke	B-Disease
and	O
gallbladder	B-Disease
disease	I-Disease
.	O

Overall	O
,	O
the	O
only	O
statistically	O
significant	O
benefits	O
of	O
HT	O
were	O
a	O
decreased	O
incidence	O
of	O
fractures	B-Disease
and	O
colon	B-Disease
cancer	I-Disease
with	O
long	O
-	O
term	O
use	O
.	O

Among	O
relatively	O
healthy	O
women	O
over	O
65	O
years	O
taking	O
continuous	O
combined	O
HT	O
,	O
there	O
was	O
a	O
statistically	O
significant	O
increase	O
in	O
the	O
incidence	O
of	O
dementia	B-Disease
.	O

Among	O
women	O
with	O
cardiovascular	B-Disease
disease	I-Disease
,	O
long	O
-	O
term	O
use	O
of	O
combined	O
continuous	O
HT	O
significantly	O
increased	O
the	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
.	O

No	O
trials	O
focussed	O
specifically	O
on	O
younger	O
women	O
.	O

However	O
,	O
one	O
trial	O
analysed	O
subgroups	O
of	O
2839	O
relatively	O
healthy	O
50	O
to	O
59	O
year	O
-	O
old	O
women	O
taking	O
combined	O
continuous	O
HT	O
and	O
1637	O
taking	O
oestrogen	B-Chemical
-	O
only	O
HT	O
,	O
versus	O
similar	O
-	O
sized	O
placebo	O
groups	O
.	O

The	O
only	O
significantly	O
increased	O
risk	O
reported	O
was	O
for	O
venous	B-Disease
thromboembolism	I-Disease
in	O
women	O
taking	O
combined	O
continuous	O
HT	O
;	O
their	O
absolute	O
risk	O
remained	O
very	O
low	O
.	O

AUTHORS	O
'	O
CONCLUSIONS	O
:	O
HT	O
is	O
not	O
indicated	O
for	O
the	O
routine	O
management	O
of	O
chronic	B-Disease
disease	I-Disease
.	O

We	O
need	O
more	O
evidence	O
on	O
the	O
safety	O
of	O
HT	O
for	O
menopausal	O
symptom	O
control	O
,	O
though	O
short	O
-	O
term	O
use	O
appears	O
to	O
be	O
relatively	O
safe	O
for	O
healthy	O
younger	O
women	O
.	O

Drug	B-Disease
-	I-Disease
induced	I-Disease
liver	I-Disease
injury	I-Disease
:	O
an	O
analysis	O
of	O
461	O
incidences	O
submitted	O
to	O
the	O
Spanish	O
registry	O
over	O
a	O
10	O
-	O
year	O
period	O
.	O

BACKGROUND	O
&	O
AIMS	O
:	O
Progress	O
in	O
the	O
understanding	O
of	O
susceptibility	O
factors	O
to	O
drug	B-Disease
-	I-Disease
induced	I-Disease
liver	I-Disease
injury	I-Disease
(	O
DILI	B-Disease
)	O
and	O
outcome	O
predictability	O
are	O
hampered	O
by	O
the	O
lack	O
of	O
systematic	O
programs	O
to	O
detect	O
bona	O
fide	O
cases	O
.	O

METHODS	O
:	O
A	O
cooperative	O
network	O
was	O
created	O
in	O
1994	O
in	O
Spain	O
to	O
identify	O
all	O
suspicions	O
of	O
DILI	B-Disease
following	O
a	O
prospective	O
structured	O
report	O
form	O
.	O

The	O
liver	B-Disease
damage	I-Disease
was	O
characterized	O
according	O
to	O
hepatocellular	O
,	O
cholestatic	B-Disease
,	O
and	O
mixed	O
laboratory	O
criteria	O
and	O
to	O
histologic	O
criteria	O
when	O
available	O
.	O

Further	O
evaluation	O
of	O
causality	O
assessment	O
was	O
centrally	O
performed	O
.	O

RESULTS	O
:	O
Since	O
April	O
1994	O
to	O
August	O
2004	O
,	O
461	O
out	O
of	O
570	O
submitted	O
cases	O
,	O
involving	O
505	O
drugs	O
,	O
were	O
deemed	O
to	O
be	O
related	O
to	O
DILI	B-Disease
.	O

The	O
antiinfective	O
group	O
of	O
drugs	O
was	O
the	O
more	O
frequently	O
incriminated	O
,	O
amoxicillin	B-Chemical
-	I-Chemical
clavulanate	I-Chemical
accounting	O
for	O
the	O
12	O
.	O
8	O
%	O
of	O
the	O
whole	O
series	O
.	O

The	O
hepatocellular	O
pattern	O
of	O
damage	O
was	O
the	O
most	O
common	O
(	O
58	O
%	O
)	O
,	O
was	O
inversely	O
correlated	O
with	O
age	O
(	O
P	O
<	O
.	O
0001	O
)	O
,	O
and	O
had	O
the	O
worst	O
outcome	O
(	O
Cox	O
regression	O
,	O
P	O
<	O
.	O
034	O
)	O
.	O

Indeed	O
,	O
the	O
incidence	O
of	O
liver	O
transplantation	O
and	O
death	O
in	O
this	O
group	O
was	O
11	O
.	O
7	O
%	O
if	O
patients	O
had	O
jaundice	B-Disease
at	O
presentation	O
,	O
whereas	O
the	O
corresponding	O
figure	O
was	O
3	O
.	O
8	O
%	O
in	O
nonjaundiced	O
patients	O
(	O
P	O
<	O
.	O
04	O
)	O
.	O

Factors	O
associated	O
with	O
the	O
development	O
of	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
were	O
female	O
sex	O
(	O
OR	O
=	O
25	O
;	O
95	O
%	O
CI	O
:	O
4	O
.	O
1	O
-	O
151	O
;	O
P	O
<	O
.	O
0001	O
)	O
,	O
hepatocellular	O
damage	O
(	O
OR	O
=	O
7	O
.	O
9	O
;	O
95	O
%	O
CI	O
:	O
1	O
.	O
6	O
-	O
37	O
;	O
P	O
<	O
.	O
009	O
)	O
,	O
and	O
higher	O
baseline	O
plasma	O
bilirubin	B-Chemical
value	O
(	O
OR	O
=	O
1	O
.	O
15	O
;	O
95	O
%	O
CI	O
:	O
1	O
.	O
09	O
-	O
1	O
.	O
22	O
;	O
P	O
<	O
.	O
0001	O
)	O
.	O

CONCLUSIONS	O
:	O
Patients	O
with	O
drug	O
-	O
induced	O
hepatocellular	O
jaundice	B-Disease
have	O
11	O
.	O
7	O
%	O
chance	O
of	O
progressing	O
to	O
death	O
or	O
transplantation	O
.	O

Amoxicillin	B-Chemical
-	I-Chemical
clavulanate	I-Chemical
stands	O
out	O
as	O
the	O
most	O
common	O
drug	O
related	O
to	O
DILI	B-Disease
.	O

Morphological	O
evaluation	O
of	O
the	O
effect	O
of	O
d	B-Chemical
-	I-Chemical
ribose	I-Chemical
on	O
adriamycin	B-Chemical
-	O
evoked	O
cardiotoxicity	B-Disease
in	O
rats	O
.	O

The	O
influence	O
of	O
d	B-Chemical
-	I-Chemical
ribose	I-Chemical
on	O
adriamycin	B-Chemical
-	O
induced	O
myocardiopathy	B-Disease
in	O
rats	O
was	O
studied	O
.	O

Adriamycin	B-Chemical
in	O
the	O
cumulative	O
dose	O
of	O
25	O
mg	O
/	O
kg	O
evoked	O
fully	O
developed	O
cardiac	B-Disease
toxicity	I-Disease
.	O

D	B-Chemical
-	I-Chemical
ribose	I-Chemical
in	O
the	O
multiple	O
doses	O
of	O
200	O
mg	O
/	O
kg	O
did	O
not	O
influence	O
ADR	B-Chemical
cardiotoxicity	B-Disease
.	O

In	O
vivo	O
evidences	O
suggesting	O
the	O
role	O
of	O
oxidative	O
stress	O
in	O
pathogenesis	O
of	O
vancomycin	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
:	O
protection	O
by	O
erdosteine	B-Chemical
.	O

The	O
aims	O
of	O
this	O
study	O
were	O
to	O
examine	O
vancomycin	B-Chemical
(	O
VCM	B-Chemical
)	O
-	O
induced	O
oxidative	O
stress	O
that	O
promotes	O
production	O
of	O
reactive	O
oxygen	B-Chemical
species	O
(	O
ROS	O
)	O
and	O
to	O
investigate	O
the	O
role	O
of	O
erdosteine	B-Chemical
,	O
an	O
expectorant	O
agent	O
,	O
which	O
has	O
also	O
antioxidant	O
properties	O
,	O
on	O
kidney	O
tissue	O
against	O
the	O
possible	O
VCM	B-Chemical
-	O
induced	O
renal	B-Disease
impairment	I-Disease
in	O
rats	O
.	O

Rats	O
were	O
divided	O
into	O
three	O
groups	O
:	O
sham	O
,	O
VCM	B-Chemical
and	O
VCM	B-Chemical
plus	O
erdosteine	B-Chemical
.	O

VCM	B-Chemical
was	O
administrated	O
intraperitoneally	O
(	O
i	O
.	O
p	O
.	O
)	O
with	O
200mgkg	O
(	O
-	O
1	O
)	O
twice	O
daily	O
for	O
7	O
days	O
.	O

Erdosteine	B-Chemical
was	O
administered	O
orally	O
.	O

VCM	B-Chemical
administration	O
to	O
control	O
rats	O
significantly	O
increased	O
renal	O
malondialdehyde	B-Chemical
(	O
MDA	B-Chemical
)	O
and	O
urinary	O
N	O
-	O
acetyl	O
-	O
beta	O
-	O
d	O
-	O
glucosaminidase	O
(	O
NAG	O
,	O
a	O
marker	O
of	O
renal	B-Disease
tubular	I-Disease
injury	I-Disease
)	O
excretion	O
but	O
decreased	O
superoxide	B-Chemical
dismutase	O
(	O
SOD	O
)	O
and	O
catalase	O
(	O
CAT	O
)	O
activities	O
.	O

Erdosteine	B-Chemical
administration	O
with	O
VCM	B-Chemical
injections	O
caused	O
significantly	O
decreased	O
renal	O
MDA	B-Chemical
and	O
urinary	O
NAG	O
excretion	O
,	O
and	O
increased	O
SOD	O
activity	O
,	O
but	O
not	O
CAT	O
activity	O
in	O
renal	O
tissue	O
when	O
compared	O
with	O
VCM	B-Chemical
alone	O
.	O

Erdosteine	B-Chemical
showed	O
histopathological	O
protection	O
against	O
VCM	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
.	O

There	O
were	O
a	O
significant	O
dilatation	O
of	O
tubular	O
lumens	O
,	O
extensive	O
epithelial	O
cell	O
vacuolization	O
,	O
atrophy	B-Disease
,	O
desquamation	B-Disease
,	O
and	O
necrosis	B-Disease
in	O
VCM	B-Chemical
-	O
treated	O
rats	O
more	O
than	O
those	O
of	O
the	O
control	O
and	O
the	O
erdosteine	B-Chemical
groups	O
.	O

Erdosteine	B-Chemical
caused	O
a	O
marked	O
reduction	O
in	O
the	O
extent	O
of	O
tubular	O
damage	O
.	O

It	O
is	O
concluded	O
that	O
oxidative	O
tubular	O
damage	O
plays	O
an	O
important	O
role	O
in	O
the	O
VCM	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
and	O
the	O
modulation	O
of	O
oxidative	O
stress	O
with	O
erdosteine	B-Chemical
reduces	O
the	O
VCM	B-Chemical
-	O
induced	O
kidney	B-Disease
damage	I-Disease
both	O
at	O
the	O
biochemical	O
and	O
histological	O
levels	O
.	O

Gemfibrozil	B-Chemical
-	O
lovastatin	B-Chemical
therapy	O
for	O
primary	O
hyperlipoproteinemias	B-Disease
.	O

The	O
specific	O
aim	O
of	O
this	O
retrospective	O
,	O
observational	O
study	O
was	O
to	O
assess	O
safety	O
and	O
efficacy	O
of	O
long	O
-	O
term	O
(	O
21	O
months	O
/	O
patient	O
)	O
,	O
open	O
-	O
label	O
,	O
gemfibrozil	B-Chemical
-	O
lovastatin	B-Chemical
treatment	O
in	O
80	O
patients	O
with	O
primary	O
mixed	O
hyperlipidemia	B-Disease
(	O
68	O
%	O
of	O
whom	O
had	O
atherosclerotic	B-Disease
vascular	I-Disease
disease	I-Disease
)	O
.	O

Because	O
ideal	O
lipid	O
targets	O
were	O
not	O
reached	O
(	O
low	O
-	O
density	O
lipoprotein	O
(	O
LDL	O
)	O
cholesterol	B-Chemical
less	O
than	O
130	O
mg	O
/	O
dl	O
,	O
high	O
-	O
density	O
lipoprotein	O
(	O
HDL	O
)	O
cholesterol	B-Chemical
greater	O
than	O
35	O
mg	O
/	O
dl	O
,	O
or	O
total	O
cholesterol	B-Chemical
/	O
HDL	O
cholesterol	B-Chemical
less	O
than	O
4	O
.	O
5	O
mg	O
/	O
dl	O
)	O
with	O
diet	O
plus	O
a	O
single	O
drug	O
,	O
gemfibrozil	B-Chemical
(	O
1	O
.	O
2	O
g	O
/	O
day	O
)	O
-	O
lovastatin	B-Chemical
(	O
primarily	O
20	O
or	O
40	O
mg	O
)	O
treatment	O
was	O
given	O
.	O

Follow	O
-	O
up	O
visits	O
were	O
scheduled	O
with	O
2	O
-	O
drug	O
therapy	O
every	O
6	O
to	O
8	O
weeks	O
,	O
an	O
average	O
of	O
10	O
.	O
3	O
visits	O
per	O
patient	O
,	O
with	O
741	O
batteries	O
of	O
6	O
liver	O
function	O
tests	O
and	O
714	O
creatine	B-Chemical
phosphokinase	O
levels	O
measured	O
.	O

Only	O
1	O
of	O
the	O
4	O
,	O
446	O
liver	O
function	O
tests	O
(	O
0	O
.	O
02	O
%	O
)	O
,	O
a	O
gamma	O
glutamyl	O
transferase	O
,	O
was	O
greater	O
than	O
or	O
equal	O
to	O
3	O
times	O
the	O
upper	O
normal	O
limit	O
.	O

Of	O
the	O
714	O
creatine	B-Chemical
phosphokinase	O
levels	O
,	O
9	O
%	O
were	O
high	O
;	O
only	O
1	O
(	O
0	O
.	O
1	O
%	O
)	O
was	O
greater	O
than	O
or	O
equal	O
to	O
3	O
times	O
the	O
upper	O
normal	O
limit	O
.	O

With	O
2	O
-	O
drug	O
therapy	O
,	O
mean	O
total	O
cholesterol	B-Chemical
decreased	O
22	O
%	O
from	O
255	O
to	O
200	O
mg	O
/	O
dl	O
,	O
triglyceride	B-Chemical
levels	O
decreased	O
35	O
%	O
from	O
236	O
to	O
154	O
mg	O
/	O
dl	O
,	O
LDL	O
cholesterol	B-Chemical
decreased	O
26	O
%	O
from	O
176	O
to	O
131	O
mg	O
/	O
dl	O
,	O
and	O
the	O
total	O
cholesterol	B-Chemical
/	O
HDL	O
cholesterol	B-Chemical
ratio	O
decreased	O
24	O
%	O
from	O
7	O
.	O
1	O
to	O
5	O
.	O
4	O
,	O
all	O
p	O
less	O
than	O
or	O
equal	O
to	O
0	O
.	O
0001	O
.	O

Myositis	B-Disease
,	O
attributable	O
to	O
the	O
drug	O
combination	O
and	O
symptomatic	O
enough	O
to	O
discontinue	O
it	O
,	O
occurred	O
in	O
3	O
%	O
of	O
patients	O
,	O
and	O
in	O
1	O
%	O
with	O
concurrent	O
high	O
creatine	B-Chemical
phosphokinase	O
(	O
769	O
U	O
/	O
liter	O
)	O
;	O
no	O
patients	O
had	O
rhabdomyolysis	B-Disease
or	O
myoglobinuria	B-Disease
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Does	O
domperidone	B-Chemical
potentiate	O
mirtazapine	B-Chemical
-	O
associated	O
restless	B-Disease
legs	I-Disease
syndrome	I-Disease
?	O

There	O
is	O
now	O
evidence	O
to	O
suggest	O
a	O
central	O
role	O
for	O
the	O
dopaminergic	O
system	O
in	O
restless	B-Disease
legs	I-Disease
syndrome	I-Disease
(	O
RLS	B-Disease
)	O
.	O

For	O
example	O
,	O
the	O
symptoms	O
of	O
RLS	B-Disease
can	O
be	O
dramatically	O
improved	O
by	O
levodopa	B-Chemical
and	O
dopamine	B-Chemical
agonists	O
,	O
whereas	O
central	O
dopamine	B-Chemical
D2	O
receptor	O
antagonists	O
can	O
induce	O
or	O
aggravate	O
RLS	B-Disease
symptoms	O
.	O

To	O
our	O
knowledge	O
,	O
there	O
is	O
no	O
previous	O
report	O
regarding	O
whether	O
domperidone	B-Chemical
,	O
a	O
peripheral	O
dopamine	B-Chemical
D2	O
receptor	O
antagonist	O
,	O
can	O
also	O
induce	O
or	O
aggravate	O
symptoms	O
of	O
RLS	B-Disease
.	O

Mirtazapine	B-Chemical
,	O
the	O
first	O
noradrenergic	O
and	O
specific	O
serotonergic	O
antidepressant	O
(	O
NaSSA	O
)	O
,	O
has	O
been	O
associated	O
with	O
RLS	B-Disease
in	O
several	O
recent	O
publications	O
.	O

The	O
authors	O
report	O
here	O
a	O
depressed	O
patient	O
comorbid	O
with	O
postprandial	B-Disease
dyspepsia	I-Disease
who	O
developed	O
RLS	B-Disease
after	O
mirtazapine	B-Chemical
had	O
been	O
added	O
to	O
his	O
domperidone	B-Chemical
therapy	O
.	O

Our	O
patient	O
started	O
to	O
have	O
symptoms	O
of	O
RLS	B-Disease
only	O
after	O
he	O
had	O
been	O
treated	O
with	O
mirtazapine	B-Chemical
,	O
and	O
his	O
RLS	B-Disease
symptoms	O
resolved	O
completely	O
upon	O
discontinuation	O
of	O
his	O
mirtazapine	B-Chemical
.	O

Such	O
a	O
temporal	O
relationship	O
between	O
the	O
use	O
of	O
mirtazapine	B-Chemical
and	O
the	O
symptoms	O
of	O
RLS	B-Disease
in	O
our	O
patient	O
did	O
not	O
support	O
a	O
potentiating	O
effect	O
of	O
domperione	B-Chemical
on	O
mirtazapine	B-Chemical
-	O
associated	O
RLS	B-Disease
.	O

However	O
,	O
physicians	O
should	O
be	O
aware	O
of	O
the	O
possibility	O
that	O
mirtazapine	B-Chemical
can	O
be	O
associated	O
with	O
RLS	B-Disease
in	O
some	O
individuals	O
,	O
especially	O
those	O
receiving	O
concomitant	O
dopamine	B-Chemical
D2	O
receptor	O
antagonists	O
.	O

Antiandrogenic	O
therapy	O
can	O
cause	O
coronary	B-Disease
arterial	I-Disease
disease	I-Disease
.	O

AIM	O
:	O
To	O
study	O
the	O
change	O
of	O
lipid	O
metabolism	O
by	O
antiandrogen	O
therapy	O
in	O
patients	O
with	O
prostate	B-Disease
cancer	I-Disease
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
We	O
studied	O
with	O
a	O
2	O
.	O
5	O
years	O
follow	O
-	O
up	O
the	O
changes	O
in	O
plasma	O
cholesterols	B-Chemical
(	O
C	B-Chemical
)	O
,	O
triglycerides	B-Chemical
(	O
TG	B-Chemical
)	O
,	O
lipoproteins	O
(	O
LP	O
)	O
,	O
and	O
apolipoproteins	O
(	O
Apo	O
)	O
B	O
-	O
100	O
,	O
A	O
-	O
I	O
,	O
and	O
A	O
-	O
II	O
pro	O
fi	O
les	O
in	O
24	O
patients	O
of	O
mean	O
age	O
60	O
years	O
with	O
low	O
risk	O
prostate	B-Disease
cancer	I-Disease
(	O
stage	O
:	O
T1cN0M0	O
,	O
Gleason	O
score	O
:	O
2	O
-	O
5	O
)	O
during	O
treatment	O
with	O
cyproterone	B-Chemical
acetate	I-Chemical
(	O
CPA	B-Chemical
)	O
without	O
surgical	O
management	O
or	O
radiation	O
therapy	O
.	O

RESULTS	O
:	O
Significant	O
decreases	O
of	O
HDL	O
-	O
C	O
,	O
Apo	O
A	O
-	O
I	O
and	O
Apo	O
A	O
-	O
II	O
and	O
an	O
increase	O
of	O
triglyceride	B-Chemical
levels	O
in	O
VLDL	O
were	O
induced	O
by	O
CPA	B-Chemical
.	O

After	O
a	O
period	O
of	O
2	O
.	O
5	O
years	O
on	O
CPA	B-Chemical
treatment	O
,	O
four	O
patients	O
out	O
of	O
twenty	O
-	O
four	O
were	O
found	O
to	O
be	O
affected	O
by	O
coronary	B-Disease
heart	I-Disease
disease	I-Disease
.	O

CONCLUSIONS	O
:	O
Ischaemic	O
coronary	B-Disease
arteriosclerosis	I-Disease
with	O
an	O
incidence	O
rate	O
of	O
16	O
.	O
6	O
%	O
as	O
caused	O
by	O
prolonged	O
CPA	B-Chemical
therapy	O
is	O
mediated	O
through	O
changes	O
in	O
HDL	O
cholesterol	B-Chemical
,	O
Apo	O
A	O
-	O
I	O
and	O
Apo	O
A	O
-	O
II	O
pro	O
fi	O
les	O
,	O
other	O
than	O
the	O
well	O
-	O
known	O
hyperglyceridemic	B-Disease
effect	I-Disease
caused	O
by	O
estrogen	B-Chemical
.	O

5	B-Chemical
-	I-Chemical
Fluorouracil	I-Chemical
cardiotoxicity	B-Disease
induced	O
by	O
alpha	B-Chemical
-	I-Chemical
fluoro	I-Chemical
-	I-Chemical
beta	I-Chemical
-	I-Chemical
alanine	I-Chemical
.	O

Cardiotoxicity	B-Disease
is	O
a	O
rare	O
complication	O
occurring	O
during	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
treatment	O
for	O
malignancies	B-Disease
.	O

We	O
herein	O
report	O
the	O
case	O
of	O
a	O
70	O
-	O
year	O
-	O
old	O
man	O
with	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
,	O
in	O
whom	O
a	O
high	O
serum	O
level	O
of	O
alpha	B-Chemical
-	I-Chemical
fluoro	I-Chemical
-	I-Chemical
beta	I-Chemical
-	I-Chemical
alanine	I-Chemical
(	O
FBAL	B-Chemical
)	O
was	O
observed	O
.	O

The	O
patient	O
,	O
who	O
had	O
unresectable	O
colon	B-Disease
cancer	I-Disease
metastases	O
to	O
the	O
liver	O
and	O
lung	O
,	O
was	O
referred	O
to	O
us	O
for	O
chemotherapy	O
from	O
an	O
affiliated	O
hospital	O
;	O
he	O
had	O
no	O
cardiac	O
history	O
.	O

After	O
admission	O
,	O
the	O
patient	O
received	O
a	O
continuous	O
intravenous	O
infusion	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
(	O
1000	O
mg	O
/	O
day	O
)	O
,	O
during	O
which	O
precordial	B-Disease
pain	I-Disease
with	O
right	B-Disease
bundle	I-Disease
branch	I-Disease
block	I-Disease
occurred	O
concomitantly	O
with	O
a	O
high	O
serum	O
FBAL	B-Chemical
concentration	O
of	O
1955	O
ng	O
/	O
ml	O
.	O

Both	O
the	O
precordial	B-Disease
pain	I-Disease
and	O
the	O
electrocardiographic	O
changes	O
disappeared	O
spontaneously	O
after	O
the	O
discontinuation	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
.	O

As	O
the	O
precordial	B-Disease
pain	I-Disease
in	O
this	O
patient	O
was	O
considered	O
to	O
have	O
been	O
due	O
to	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
,	O
the	O
administration	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
was	O
abandoned	O
.	O

Instead	O
,	O
oral	O
administration	O
of	O
S	O
-	O
1	O
(	O
a	O
derivative	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
,	O
at	O
200	O
mg	O
/	O
day	O
twice	O
a	O
week	O
,	O
was	O
instituted	O
,	O
because	O
S	O
-	O
1	O
has	O
a	O
strong	O
inhibitory	O
effect	O
on	O
dihydropyrimidine	B-Chemical
dehydrogenase	O
,	O
which	O
catalyzes	O
the	O
degradative	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
into	O
FBAL	B-Chemical
.	O

The	O
serum	O
FBAL	B-Chemical
concentration	O
subsequently	O
decreased	O
to	O
352	O
ng	O
/	O
ml	O
,	O
the	O
same	O
as	O
the	O
value	O
measured	O
on	O
the	O
first	O
day	O
of	O
S	O
-	O
1	O
administration	O
.	O

Thereafter	O
,	O
no	O
cardiac	B-Disease
symptoms	I-Disease
were	O
observed	O
.	O

The	O
patient	O
achieved	O
a	O
partial	O
response	O
6	O
months	O
after	O
the	O
initiation	O
of	O
the	O
S	O
-	O
1	O
treatment	O
.	O

The	O
experience	O
of	O
this	O
case	O
,	O
together	O
with	O
a	O
review	O
of	O
the	O
literature	O
,	O
suggests	O
that	O
FBAL	B-Chemical
is	O
related	O
to	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

S	O
-	O
1	O
may	O
be	O
administered	O
safely	O
to	O
patients	O
with	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

Hepatocellular	B-Disease
carcinoma	I-Disease
in	O
Fanconi	B-Disease
'	I-Disease
s	I-Disease
anemia	I-Disease
treated	O
with	O
androgen	B-Chemical
and	O
corticosteroid	B-Chemical
.	O

The	O
case	O
of	O
an	O
11	O
-	O
year	O
-	O
old	O
boy	O
is	O
reported	O
who	O
was	O
known	O
to	O
have	O
Fanconi	B-Disease
'	I-Disease
s	I-Disease
anemia	I-Disease
for	O
3	O
years	O
and	O
was	O
treated	O
with	O
androgens	B-Chemical
,	O
corticosteroids	B-Chemical
and	O
transfusions	O
.	O

Two	O
weeks	O
before	O
his	O
death	O
he	O
was	O
readmitted	O
because	O
of	O
aplastic	O
crisis	O
with	O
septicemia	B-Disease
and	O
marked	O
abnormalities	O
in	O
liver	O
function	O
and	O
died	O
of	O
hemorrhagic	B-Disease
bronchopneumonia	I-Disease
.	O

At	O
autopsy	O
peliosis	B-Disease
and	O
multiple	O
hepatic	B-Disease
tumors	I-Disease
were	O
found	O
which	O
histologically	O
proved	O
to	O
be	O
well	O
-	O
differentiated	O
hepatocellular	B-Disease
carcinoma	I-Disease
.	O

This	O
case	O
contributes	O
to	O
the	O
previous	O
observations	O
that	O
non	O
-	O
metastasizing	O
hepatic	B-Disease
neoplasms	I-Disease
and	O
peliosis	B-Disease
can	O
develop	O
in	O
patients	O
with	O
androgen	B-Chemical
-	O
and	O
corticosteroid	B-Chemical
-	O
treated	O
Fanconi	B-Disease
'	I-Disease
s	I-Disease
anemia	I-Disease
.	O

The	O
influence	O
of	O
the	O
time	O
interval	O
between	O
monoHER	B-Chemical
and	O
doxorubicin	B-Chemical
administration	O
on	O
the	O
protection	O
against	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
in	O
mice	O
.	O

PURPOSE	O
:	O
Despite	O
its	O
well	O
-	O
known	O
cardiotoxicity	B-Disease
,	O
the	O
anthracyclin	O
doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
continues	O
to	O
be	O
an	O
effective	O
and	O
widely	O
used	O
chemotherapeutic	O
agent	O
.	O

DOX	B-Chemical
-	O
induced	O
cardiac	B-Disease
damage	I-Disease
presumably	O
results	O
from	O
the	O
formation	O
of	O
free	O
radicals	O
by	O
DOX	B-Chemical
.	O

Reactive	O
oxygen	B-Chemical
species	O
particularly	O
affect	O
the	O
cardiac	O
myocytes	O
because	O
these	O
cells	O
seem	O
to	O
have	O
a	O
relatively	O
poor	O
antioxidant	O
defense	O
system	O
.	O

The	O
semisynthetic	O
flavonoid	B-Chemical
monohydroxyethylrutoside	B-Chemical
(	O
monoHER	B-Chemical
)	O
showed	O
cardioprotection	O
against	O
DOX	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
through	O
its	O
radical	O
scavenging	O
and	O
iron	B-Chemical
chelating	O
properties	O
.	O

Because	O
of	O
the	O
relatively	O
short	O
final	O
half	O
-	O
life	O
of	O
monoHER	B-Chemical
(	O
about	O
30	O
min	O
)	O
,	O
it	O
is	O
expected	O
that	O
the	O
time	O
interval	O
between	O
monoHER	B-Chemical
and	O
DOX	B-Chemical
might	O
be	O
of	O
influence	O
on	O
the	O
cardioprotective	O
effect	O
of	O
monoHER	B-Chemical
.	O

Therefore	O
,	O
the	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
this	O
possible	O
effect	O
.	O

METHODS	O
:	O
Six	O
groups	O
of	O
6	O
BALB	O
/	O
c	O
mice	O
were	O
treated	O
with	O
saline	O
,	O
DOX	B-Chemical
alone	O
or	O
DOX	B-Chemical
(	O
4	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
preceded	O
by	O
monoHER	B-Chemical
(	O
500	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
with	O
an	O
interval	O
of	O
10	O
,	O
30	O
,	O
60	O
or	O
120	O
min	O
.	O

After	O
a	O
6	O
-	O
week	O
treatment	O
period	O
and	O
additional	O
observation	O
for	O
2	O
weeks	O
,	O
the	O
mice	O
were	O
sacrificed	O
.	O

Their	O
cardiac	O
tissues	O
were	O
processed	O
for	O
light	O
microscopy	O
,	O
after	O
which	O
cardiomyocyte	B-Disease
damage	I-Disease
was	O
evaluated	O
according	O
to	O
Billingham	O
(	O
in	O
Cancer	B-Disease
Treat	O
Rep	O
62	O
(	O
6	O
)	O
:	O
865	O
-	O
872	O
,	O
1978	O
)	O
.	O

Microscopic	O
evaluation	O
revealed	O
that	O
treatment	O
with	O
DOX	B-Chemical
alone	O
induced	O
significant	O
cardiac	B-Disease
damage	I-Disease
in	O
comparison	O
to	O
the	O
saline	O
control	O
group	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

RESULTS	O
:	O
The	O
number	O
of	O
damaged	O
cardiomyocytes	O
was	O
9	O
.	O
6	O
-	O
fold	O
(	O
95	O
%	O
CI	O
4	O
.	O
4	O
-	O
21	O
.	O
0	O
)	O
higher	O
in	O
mice	O
treated	O
with	O
DOX	B-Chemical
alone	O
than	O
that	O
in	O
animals	O
of	O
the	O
control	O
group	O
.	O

The	O
ratio	O
of	O
aberrant	O
cardiomyocytes	O
in	O
mice	O
treated	O
with	O
DOX	B-Chemical
preceded	O
by	O
monoHER	B-Chemical
and	O
those	O
in	O
mice	O
treated	O
with	O
saline	O
ranged	O
from	O
1	O
.	O
6	O
to	O
2	O
.	O
8	O
(	O
mean	O
2	O
.	O
2	O
,	O
95	O
%	O
CI	O
1	O
.	O
2	O
-	O
4	O
.	O
1	O
,	O
P	O
=	O
0	O
.	O
019	O
)	O
.	O

The	O
mean	O
protective	O
effect	O
by	O
adding	O
monoHER	B-Chemical
before	O
DOX	B-Chemical
led	O
to	O
a	O
significant	O
4	O
.	O
4	O
-	O
fold	O
reduction	O
(	O
P	O
<	O
0	O
.	O
001	O
,	O
95	O
%	O
CI	O
2	O
.	O
3	O
-	O
8	O
.	O
2	O
)	O
of	O
abnormal	O
cardiomyocytes	O
.	O

This	O
protective	O
effect	O
did	O
not	O
depend	O
on	O
the	O
time	O
interval	O
between	O
monoHER	B-Chemical
and	O
DOX	B-Chemical
administration	O
(	O
P	O
=	O
0	O
.	O
345	O
)	O
.	O

CONCLUSION	O
:	O
The	O
results	O
indicate	O
that	O
in	O
an	O
outpatient	O
clinical	O
setting	O
monoHER	B-Chemical
may	O
be	O
administered	O
shortly	O
before	O
DOX	B-Chemical
.	O

Clinical	O
evaluation	O
of	O
adverse	O
effects	O
during	O
bepridil	B-Chemical
administration	O
for	O
atrial	B-Disease
fibrillation	I-Disease
and	I-Disease
flutter	I-Disease
.	O

BACKGROUND	O
:	O
Bepridil	B-Chemical
hydrochloride	I-Chemical
(	O
Bpd	B-Chemical
)	O
has	O
attracted	O
attention	O
as	O
an	O
effective	O
drug	O
for	O
atrial	B-Disease
fibrillation	I-Disease
(	O
AF	B-Disease
)	O
and	O
atrial	B-Disease
flutter	I-Disease
(	O
AFL	B-Disease
)	O
.	O

However	O
,	O
serious	O
adverse	O
effects	O
,	O
including	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
(	O
Tdp	B-Disease
)	O
,	O
have	O
been	O
reported	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
Adverse	O
effects	O
of	O
Bpd	B-Chemical
requiring	O
discontinuation	O
of	O
treatment	O
were	O
evaluated	O
.	O

Bpd	B-Chemical
was	O
administered	O
to	O
459	O
patients	O
(	O
361	O
males	O
,	O
63	O
+	O
/	O
-	O
12	O
years	O
old	O
)	O
comprising	O
378	O
AF	B-Disease
and	O
81	O
AFL	B-Disease
cases	O
.	O

Mean	O
left	O
ventricular	O
ejection	O
fraction	O
and	O
atrial	O
dimension	O
(	O
LAD	O
)	O
were	O
66	O
+	O
/	O
-	O
11	O
%	O
and	O
40	O
+	O
/	O
-	O
6	O
mm	O
,	O
respectively	O
.	O

Adverse	O
effects	O
were	O
observed	O
in	O
19	O
patients	O
(	O
4	O
%	O
)	O
during	O
an	O
average	O
follow	O
-	O
up	O
of	O
20	O
months	O
.	O

There	O
was	O
marked	O
QT	B-Disease
prolongation	I-Disease
greater	O
than	O
0	O
.	O
55	O
s	O
in	O
13	O
patients	O
,	O
bradycardia	B-Disease
less	O
than	O
40	O
beats	O
/	O
min	O
in	O
6	O
patients	O
,	O
dizziness	B-Disease
and	O
general	O
fatigue	B-Disease
in	O
1	O
patient	O
each	O
.	O

In	O
4	O
of	O
13	O
patients	O
with	O
QT	B-Disease
prolongation	I-Disease
,	O
Tdp	B-Disease
occurred	O
.	O

The	O
major	O
triggering	O
factors	O
of	O
Tdp	B-Disease
were	O
hypokalemia	B-Disease
and	O
sudden	O
decrease	O
in	O
heart	O
rate	O
.	O

There	O
were	O
no	O
differences	O
in	O
the	O
clinical	O
backgrounds	O
of	O
the	O
patients	O
with	O
and	O
without	O
Tdp	B-Disease
other	O
than	O
LAD	O
and	O
age	O
,	O
which	O
were	O
larger	O
and	O
older	O
in	O
the	O
patients	O
with	O
Tdp	B-Disease
.	O

CONCLUSION	O
:	O
Careful	O
observation	O
of	O
serum	O
potassium	B-Chemical
concentration	O
and	O
the	O
ECG	O
should	O
always	O
be	O
done	O
during	O
Bpd	B-Chemical
administration	O
,	O
particularly	O
in	O
elderly	O
patients	O
.	O

Enhanced	O
isoproterenol	B-Chemical
-	O
induced	O
cardiac	B-Disease
hypertrophy	I-Disease
in	O
transgenic	O
rats	O
with	O
low	O
brain	O
angiotensinogen	O
.	O

We	O
have	O
previously	O
shown	O
that	O
a	O
permanent	O
deficiency	O
in	O
the	O
brain	O
renin	O
-	O
angiotensin	B-Chemical
system	O
(	O
RAS	O
)	O
may	O
increase	O
the	O
sensitivity	O
of	O
the	O
baroreflex	O
control	O
of	O
heart	O
rate	O
.	O

In	O
this	O
study	O
we	O
aimed	O
at	O
studying	O
the	O
involvement	O
of	O
the	O
brain	O
RAS	O
in	O
the	O
cardiac	O
reactivity	O
to	O
the	O
beta	O
-	O
adrenoceptor	O
(	O
beta	O
-	O
AR	O
)	O
agonist	O
isoproterenol	B-Chemical
(	O
Iso	B-Chemical
)	O
.	O

Transgenic	O
rats	O
with	O
low	O
brain	O
angiotensinogen	O
(	O
TGR	O
)	O
were	O
used	O
.	O

In	O
isolated	O
hearts	O
,	O
Iso	B-Chemical
induced	O
a	O
significantly	O
greater	O
increase	O
in	O
left	O
ventricular	O
(	O
LV	O
)	O
pressure	O
and	O
maximal	O
contraction	O
(	O
+	O
dP	O
/	O
dt	O
(	O
max	O
)	O
)	O
in	O
the	O
TGR	O
than	O
in	O
the	O
Sprague	O
-	O
Dawley	O
(	O
SD	O
)	O
rats	O
.	O

LV	B-Disease
hypertrophy	I-Disease
induced	O
by	O
Iso	B-Chemical
treatment	O
was	O
significantly	O
higher	O
in	O
TGR	O
than	O
in	O
SD	O
rats	O
(	O
in	O
g	O
LV	O
wt	O
/	O
100	O
g	O
body	O
wt	O
,	O
0	O
.	O
28	O
+	O
/	O
-	O
0	O
.	O
004	O
vs	O
.	O
0	O
.	O
24	O
+	O
/	O
-	O
0	O
.	O
004	O
,	O
respectively	O
)	O
.	O

The	O
greater	O
LV	B-Disease
hypertrophy	I-Disease
in	O
TGR	O
rats	O
was	O
associated	O
with	O
more	O
pronounced	O
downregulation	O
of	O
beta	O
-	O
AR	O
and	O
upregulation	O
of	O
LV	O
beta	O
-	O
AR	O
kinase	O
-	O
1	O
mRNA	O
levels	O
compared	O
with	O
those	O
in	O
SD	O
rats	O
.	O

The	O
decrease	O
in	O
the	O
heart	O
rate	O
(	O
HR	O
)	O
induced	O
by	O
the	O
beta	O
-	O
AR	O
antagonist	O
metoprolol	B-Chemical
in	O
conscious	O
rats	O
was	O
significantly	O
attenuated	O
in	O
TGR	O
compared	O
with	O
SD	O
rats	O
(	O
-	O
9	O
.	O
9	O
+	O
/	O
-	O
1	O
.	O
7	O
%	O
vs	O
.	O
-	O
18	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
5	O
%	O
)	O
,	O
whereas	O
the	O
effect	O
of	O
parasympathetic	O
blockade	O
by	O
atropine	B-Chemical
on	O
HR	O
was	O
similar	O
in	O
both	O
strains	O
.	O

These	O
results	O
indicate	O
that	O
TGR	O
are	O
more	O
sensitive	O
to	O
beta	O
-	O
AR	O
agonist	O
-	O
induced	O
cardiac	B-Disease
inotropic	I-Disease
response	O
and	O
hypertrophy	B-Disease
,	O
possibly	O
due	O
to	O
chronically	O
low	O
sympathetic	O
outflow	O
directed	O
to	O
the	O
heart	O
.	O

Drug	O
-	O
induced	O
long	B-Disease
QT	I-Disease
syndrome	I-Disease
in	O
injection	O
drug	O
users	O
receiving	O
methadone	B-Chemical
:	O
high	O
frequency	O
in	O
hospitalized	O
patients	O
and	O
risk	O
factors	O
.	O

BACKGROUND	O
:	O
Drug	O
-	O
induced	O
long	B-Disease
QT	I-Disease
syndrome	I-Disease
is	O
a	O
serious	O
adverse	O
drug	O
reaction	O
.	O

Methadone	B-Chemical
prolongs	O
the	O
QT	O
interval	O
in	O
vitro	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

In	O
the	O
inpatient	O
setting	O
,	O
the	O
frequency	O
of	O
QT	B-Disease
interval	I-Disease
prolongation	I-Disease
with	O
methadone	B-Chemical
treatment	O
,	O
its	O
dose	O
dependence	O
,	O
and	O
the	O
importance	O
of	O
cofactors	O
such	O
as	O
drug	O
-	O
drug	O
interactions	O
remain	O
unknown	O
.	O

METHODS	O
:	O
We	O
performed	O
a	O
systematic	O
,	O
retrospective	O
study	O
comparing	O
active	O
or	O
former	O
intravenous	O
drug	O
users	O
receiving	O
methadone	B-Chemical
and	O
those	O
not	O
receiving	O
methadone	B-Chemical
among	O
all	O
patients	O
hospitalized	O
over	O
a	O
5	O
-	O
year	O
period	O
in	O
a	O
tertiary	O
care	O
hospital	O
.	O

A	O
total	O
of	O
167	O
patients	O
receiving	O
methadone	B-Chemical
fulfilled	O
the	O
inclusion	O
criteria	O
and	O
were	O
compared	O
with	O
a	O
control	O
group	O
of	O
80	O
injection	O
drug	O
users	O
not	O
receiving	O
methadone	B-Chemical
.	O

In	O
addition	O
to	O
methadone	B-Chemical
dose	O
,	O
15	O
demographic	O
,	O
biological	O
,	O
and	O
pharmacological	O
variables	O
were	O
considered	O
as	O
potential	O
risk	O
factors	O
for	O
QT	B-Disease
prolongation	I-Disease
.	O

RESULTS	O
:	O
Among	O
167	O
methadone	B-Chemical
maintenance	O
patients	O
,	O
the	O
prevalence	O
of	O
QTc	O
prolongation	O
to	O
0	O
.	O
50	O
second	O
(	O
(	O
1	O
/	O
2	O
)	O
)	O
or	O
longer	O
was	O
16	O
.	O
2	O
%	O
compared	O
with	O
0	O
%	O
in	O
80	O
control	O
subjects	O
.	O

Six	O
patients	O
(	O
3	O
.	O
6	O
%	O
)	O
in	O
the	O
methadone	B-Chemical
group	O
presented	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
.	O

QTc	O
length	O
was	O
weakly	O
but	O
significantly	O
associated	O
with	O
methadone	B-Chemical
daily	O
dose	O
(	O
Spearman	O
rank	O
correlation	O
coefficient	O
,	O
0	O
.	O
20	O
;	O
P	O
<	O
.	O
01	O
)	O
.	O

Multivariate	O
regression	O
analysis	O
allowed	O
attribution	O
of	O
31	O
.	O
8	O
%	O
of	O
QTc	O
variability	O
to	O
methadone	B-Chemical
dose	O
,	O
cytochrome	O
P	O
-	O
450	O
3A4	O
drug	O
-	O
drug	O
interactions	O
,	O
hypokalemia	B-Disease
,	O
and	O
altered	O
liver	O
function	O
.	O

CONCLUSIONS	O
:	O
QT	B-Disease
interval	I-Disease
prolongation	I-Disease
in	O
methadone	B-Chemical
maintenance	O
patients	O
hospitalized	O
in	O
a	O
tertiary	O
care	O
center	O
is	O
a	O
frequent	O
finding	O
.	O

Methadone	B-Chemical
dose	O
,	O
presence	O
of	O
cytochrome	O
P	O
-	O
450	O
3A4	O
inhibitors	O
,	O
potassium	B-Chemical
level	O
,	O
and	O
liver	O
function	O
contribute	O
to	O
QT	B-Disease
prolongation	I-Disease
.	O

Long	B-Disease
QT	I-Disease
syndrome	I-Disease
can	O
occur	O
with	O
low	O
doses	O
of	O
methadone	B-Chemical
.	O

Mechanisms	O
of	O
hypertension	B-Disease
induced	O
by	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
deficiency	O
:	O
focus	O
on	O
venous	O
function	O
.	O

Loss	O
of	O
endothelial	O
cell	O
-	O
derived	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
in	O
hypertension	B-Disease
is	O
a	O
hallmark	O
of	O
arterial	B-Disease
dysfunction	I-Disease
.	O

Experimental	O
hypertension	B-Disease
created	O
by	O
the	O
removal	O
of	O
NO	B-Chemical
,	O
however	O
,	O
involves	O
mechanisms	O
in	O
addition	O
to	O
decreased	O
arterial	O
vasodilator	O
activity	O
.	O

These	O
include	O
augmented	O
endothelin	O
-	O
1	O
(	O
ET	O
-	O
1	O
)	O
release	O
,	O
increased	O
sympathetic	O
nervous	O
system	O
activity	O
,	O
and	O
elevated	O
tissue	O
oxidative	O
stress	O
.	O

We	O
hypothesized	O
that	O
increased	O
venous	O
smooth	O
muscle	O
(	O
venomotor	O
)	O
tone	O
plays	O
a	O
role	O
in	O
Nomega	B-Chemical
-	I-Chemical
nitro	I-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
arginine	I-Chemical
(	O
LNNA	B-Chemical
)	O
hypertension	B-Disease
through	O
these	O
mechanisms	O
.	O

Rats	O
were	O
treated	O
with	O
the	O
NO	B-Chemical
synthase	O
inhibitor	O
LNNA	B-Chemical
(	O
0	O
.	O
5	O
g	O
/	O
L	O
in	O
drinking	O
water	O
)	O
for	O
2	O
weeks	O
.	O

Mean	O
arterial	O
pressure	O
of	O
conscious	O
rats	O
was	O
119	O
+	O
/	O
-	O
2	O
mm	O
Hg	O
in	O
control	O
and	O
194	O
+	O
/	O
-	O
5	O
mm	O
Hg	O
in	O
LNNA	B-Chemical
rats	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Carotid	O
arteries	O
and	O
vena	O
cava	O
were	O
removed	O
for	O
measurement	O
of	O
isometric	O
contraction	O
.	O

Maximal	O
contraction	O
to	O
norepinephrine	B-Chemical
was	O
modestly	O
reduced	O
in	O
arteries	O
from	O
LNNA	B-Chemical
compared	O
with	O
control	O
rats	O
whereas	O
the	O
maximum	O
contraction	O
to	O
ET	O
-	O
1	O
was	O
significantly	O
reduced	O
(	O
54	O
%	O
control	O
)	O
.	O

Maximum	O
contraction	O
of	O
vena	O
cava	O
to	O
norepinephrine	B-Chemical
(	O
37	O
%	O
control	O
)	O
also	O
was	O
reduced	O
but	O
no	O
change	O
in	O
response	O
to	O
ET	O
-	O
1	O
was	O
observed	O
.	O

Mean	O
circulatory	O
filling	O
pressure	O
,	O
an	O
in	O
vivo	O
measure	O
of	O
venomotor	O
tone	O
,	O
was	O
not	O
elevated	O
in	O
LNNA	B-Chemical
hypertension	B-Disease
at	O
1	O
or	O
2	O
weeks	O
after	O
LNNA	B-Chemical
.	O

The	O
superoxide	B-Chemical
scavenger	O
tempol	B-Chemical
(	O
30	O
,	O
100	O
,	O
and	O
300	O
micromol	O
kg	O
(	O
-	O
1	O
)	O
,	O
IV	O
)	O
did	O
not	O
change	O
arterial	O
pressure	O
in	O
control	O
rats	O
but	O
caused	O
a	O
dose	O
-	O
dependent	O
decrease	O
in	O
LNNA	B-Chemical
rats	O
(	O
-	O
18	O
+	O
/	O
-	O
8	O
,	O
-	O
26	O
+	O
/	O
-	O
15	O
,	O
and	O
-	O
54	O
+	O
/	O
-	O
11	O
mm	O
Hg	O
)	O
.	O

Similarly	O
,	O
ganglionic	O
blockade	O
with	O
hexamethonium	B-Chemical
caused	O
a	O
significantly	O
greater	O
fall	O
in	O
LNNA	B-Chemical
hypertensive	B-Disease
rats	O
(	O
76	O
+	O
/	O
-	O
9	O
mm	O
Hg	O
)	O
compared	O
with	O
control	O
rats	O
(	O
35	O
+	O
/	O
-	O
10	O
mm	O
Hg	O
)	O
.	O

Carotid	O
arteries	O
,	O
vena	O
cava	O
,	O
and	O
sympathetic	O
ganglia	O
from	O
LNNA	B-Chemical
rats	O
had	O
higher	O
basal	O
levels	O
of	O
superoxide	B-Chemical
compared	O
with	O
those	O
from	O
control	O
rats	O
.	O

These	O
data	O
suggest	O
that	O
while	O
NO	B-Chemical
deficiency	O
increases	O
oxidative	O
stress	O
and	O
sympathetic	O
activity	O
in	O
both	O
arterial	O
and	O
venous	O
vessels	O
,	O
the	O
impact	O
on	O
veins	O
does	O
not	O
make	O
a	O
major	O
contribution	O
to	O
this	O
form	O
of	O
hypertension	B-Disease
.	O

Association	O
of	O
DRD2	O
polymorphisms	O
and	O
chlorpromazine	B-Chemical
-	O
induced	O
extrapyramidal	B-Disease
syndrome	I-Disease
in	O
Chinese	O
schizophrenic	B-Disease
patients	O
.	O

AIM	O
:	O
Extrapyramidal	B-Disease
syndrome	I-Disease
(	O
EPS	B-Disease
)	O
is	O
most	O
commonly	O
affected	O
by	O
typical	O
antipsychotic	O
drugs	O
that	O
have	O
a	O
high	O
affinity	O
with	O
the	O
D2	O
receptor	O
.	O

Recently	O
,	O
many	O
research	O
groups	O
have	O
reported	O
on	O
the	O
positive	O
relationship	O
between	O
the	O
genetic	O
variations	O
in	O
the	O
DRD2	O
gene	O
and	O
the	O
therapeutic	O
response	O
in	O
schizophrenia	B-Disease
patients	O
as	O
a	O
result	O
of	O
the	O
role	O
of	O
variations	O
in	O
the	O
receptor	O
in	O
modulating	O
receptor	O
expression	O
.	O

In	O
this	O
study	O
,	O
we	O
evaluate	O
the	O
role	O
DRD2	O
plays	O
in	O
chlorpromazine	B-Chemical
-	O
induced	O
EPS	B-Disease
in	O
schizophrenic	B-Disease
patients	O
.	O

METHODS	O
:	O
We	O
identified	O
seven	O
SNP	O
(	O
single	O
nucleotide	O
polymorphism	O
)	O
(	O
-	O
141Cins	O
>	O
del	O
,	O
TaqIB	O
,	O
TaqID	O
,	O
Ser311Cys	O
,	O
rs6275	O
,	O
rs6277	O
and	O
TaqIA	O
)	O
in	O
the	O
DRD2	O
gene	O
in	O
146	O
schizophrenic	B-Disease
inpatients	O
(	O
59	O
with	O
EPS	B-Disease
and	O
87	O
without	O
EPS	B-Disease
according	O
to	O
the	O
Simpson	O
-	O
Angus	O
Scale	O
)	O
treated	O
with	O
chlorpromazine	B-Chemical
after	O
8	O
weeks	O
.	O

The	O
alleles	O
of	O
all	O
loci	O
were	O
determined	O
by	O
PCR	O
(	O
polymerase	O
chain	O
reaction	O
)	O
.	O

RESULTS	O
:	O
Polymorphisms	O
TaqID	O
,	O
Ser311Cys	O
and	O
rs6277	O
were	O
not	O
polymorphic	O
in	O
the	O
population	O
recruited	O
in	O
the	O
present	O
study	O
.	O

No	O
statistical	O
significance	O
was	O
found	O
in	O
the	O
allele	O
distribution	O
of	O
-	O
141Cins	O
>	O
del	O
,	O
TaqIB	O
,	O
rs6275	O
and	O
TaqIA	O
or	O
in	O
the	O
estimated	O
haplotypes	O
(	O
constituted	O
by	O
TaqIB	O
,	O
rs6275	O
and	O
TaqIA	O
)	O
in	O
linkage	O
disequilibrium	O
between	O
the	O
two	O
groups	O
.	O

CONCLUSION	O
:	O
Our	O
results	O
did	O
not	O
lend	O
strong	O
support	O
to	O
the	O
view	O
that	O
the	O
genetic	O
variation	O
of	O
the	O
DRD2	O
gene	O
plays	O
a	O
major	O
role	O
in	O
the	O
individually	O
variable	O
adverse	O
effect	O
induced	O
by	O
chlorpromazine	B-Chemical
,	O
at	O
least	O
in	O
Chinese	O
patients	O
with	O
schizophrenia	B-Disease
.	O

Our	O
results	O
confirmed	O
a	O
previous	O
study	O
on	O
the	O
relationship	O
between	O
DRD2	O
and	O
EPS	B-Disease
in	O
Caucasians	O
.	O

Physical	O
training	O
decreases	O
susceptibility	O
to	O
subsequent	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
in	O
the	O
rat	O
.	O

Regular	O
motor	O
activity	O
has	O
many	O
benefits	O
for	O
mental	O
and	O
physical	O
condition	O
but	O
its	O
implications	O
for	O
epilepsy	B-Disease
are	O
still	O
controversial	O
.	O

In	O
order	O
to	O
elucidate	O
this	O
problem	O
,	O
we	O
have	O
studied	O
the	O
effect	O
of	O
long	O
-	O
term	O
physical	O
activity	O
on	O
susceptibility	O
to	O
subsequent	O
seizures	B-Disease
.	O

Male	O
Wistar	O
rats	O
were	O
subjected	O
to	O
repeated	O
training	O
sessions	O
in	O
a	O
treadmill	O
and	O
swimming	O
pool	O
.	O

Thereafter	O
,	O
seizures	B-Disease
were	O
induced	O
by	O
pilocarpine	B-Chemical
injections	O
in	O
trained	O
and	O
non	O
-	O
trained	O
control	O
groups	O
.	O

During	O
the	O
acute	O
period	O
of	O
status	B-Disease
epilepticus	I-Disease
,	O
we	O
measured	O
:	O
(	O
1	O
)	O
the	O
latency	O
of	O
the	O
first	O
motor	O
sign	O
,	O
(	O
2	O
)	O
the	O
intensity	O
of	O
seizures	B-Disease
,	O
(	O
3	O
)	O
the	O
time	O
when	O
it	O
occurred	O
within	O
the	O
6	O
-	O
h	O
observation	O
period	O
,	O
and	O
(	O
4	O
)	O
the	O
time	O
when	O
the	O
acute	O
period	O
ended	O
.	O

All	O
these	O
behavioral	O
parameters	O
showed	O
statistically	O
significant	O
changes	O
suggesting	O
that	O
regular	O
physical	O
exercises	O
decrease	O
susceptibility	O
to	O
subsequently	O
induced	O
seizures	B-Disease
and	O
ameliorate	O
the	O
course	O
of	O
experimentally	O
induced	O
status	B-Disease
epilepticus	I-Disease
.	O

Tonic	O
dopaminergic	O
stimulation	O
impairs	B-Disease
associative	I-Disease
learning	I-Disease
in	O
healthy	O
subjects	O
.	O

Endogenous	O
dopamine	B-Chemical
plays	O
a	O
central	O
role	O
in	O
salience	O
coding	O
during	O
associative	O
learning	O
.	O

Administration	O
of	O
the	O
dopamine	B-Chemical
precursor	O
levodopa	B-Chemical
enhances	O
learning	O
in	O
healthy	O
subjects	O
and	O
stroke	B-Disease
patients	O
.	O

Because	O
levodopa	B-Chemical
increases	O
both	O
phasic	O
and	O
tonic	O
dopaminergic	O
neurotransmission	O
,	O
the	O
critical	O
mechanism	O
mediating	O
the	O
enhancement	O
of	O
learning	O
is	O
unresolved	O
.	O

We	O
here	O
probed	O
how	O
selective	O
tonic	O
dopaminergic	O
stimulation	O
affects	O
associative	O
learning	O
.	O

Forty	O
healthy	O
subjects	O
were	O
trained	O
in	O
a	O
novel	O
vocabulary	O
of	O
45	O
concrete	O
nouns	O
over	O
the	O
course	O
of	O
5	O
consecutive	O
training	O
days	O
in	O
a	O
prospective	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
design	O
.	O

Subjects	O
received	O
the	O
tonically	O
stimulating	O
dopamine	B-Chemical
-	O
receptor	O
agonist	O
pergolide	B-Chemical
(	O
0	O
.	O
1	O
mg	O
)	O
vs	O
placebo	O
120	O
min	O
before	O
training	O
on	O
each	O
training	O
day	O
.	O

The	O
dopamine	B-Chemical
agonist	O
significantly	O
impaired	B-Disease
novel	I-Disease
word	I-Disease
learning	I-Disease
compared	O
to	O
placebo	O
.	O

This	O
learning	O
decrement	O
persisted	O
up	O
to	O
the	O
last	O
follow	O
-	O
up	O
4	O
weeks	O
post	O
-	O
training	O
.	O

Subjects	O
treated	O
with	O
pergolide	B-Chemical
also	O
showed	O
restricted	O
emotional	O
responses	O
compared	O
to	O
the	O
PLACEBO	O
group	O
.	O

The	O
extent	O
of	O
'	O
flattened	O
'	O
affect	O
with	O
pergolide	B-Chemical
was	O
related	O
to	O
the	O
degree	O
of	O
learning	O
inhibition	O
.	O

These	O
findings	O
suggest	O
that	O
tonic	O
occupation	O
of	O
dopamine	B-Chemical
receptors	O
impairs	O
learning	O
by	O
competition	O
with	O
phasic	O
dopamine	B-Chemical
signals	O
.	O

Thus	O
,	O
phasic	O
signaling	O
seems	O
to	O
be	O
the	O
critical	O
mechanism	O
by	O
which	O
dopamine	B-Chemical
enhances	O
associative	O
learning	O
in	O
healthy	O
subjects	O
and	O
stroke	B-Disease
patients	O
.	O

Minocycline	B-Chemical
-	O
induced	O
vasculitis	B-Disease
fulfilling	O
the	O
criteria	O
of	O
polyarteritis	B-Disease
nodosa	I-Disease
.	O

A	O
47	O
-	O
year	O
-	O
old	O
man	O
who	O
had	O
been	O
taking	O
minocycline	B-Chemical
for	O
palmoplantar	B-Disease
pustulosis	I-Disease
developed	O
fever	B-Disease
,	O
myalgias	B-Disease
,	O
polyneuropathy	B-Disease
,	O
and	O
testicular	B-Disease
pain	I-Disease
,	O
with	O
elevated	O
C	O
-	O
reactive	O
protein	O
(	O
CRP	O
)	O
.	O

Neither	O
myeloperoxidase	O
-	O
nor	O
proteinase	O
-	O
3	O
-	O
antineutrophil	O
cytoplasmic	O
antibody	O
was	O
positive	O
.	O

These	O
manifestations	O
met	O
the	O
American	O
College	O
of	O
Rheumatology	O
1990	O
criteria	O
for	O
the	O
classification	O
of	O
polyarteritis	B-Disease
nodosa	I-Disease
.	O

Stopping	O
minocycline	B-Chemical
led	O
to	O
amelioration	O
of	O
symptoms	O
and	O
normalization	O
of	O
CRP	O
level	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
second	O
case	O
of	O
minocycline	B-Chemical
-	O
induced	O
vasculitis	B-Disease
satisfying	O
the	O
criteria	O
.	O

Differential	O
diagnosis	O
for	O
drug	O
-	O
induced	O
disease	O
is	O
invaluable	O
even	O
for	O
patients	O
with	O
classical	O
polyarteritis	B-Disease
nodosa	I-Disease
.	O

Intramuscular	O
hepatitis	B-Disease
B	I-Disease
immune	O
globulin	O
combined	O
with	O
lamivudine	B-Chemical
in	O
prevention	O
of	O
hepatitis	B-Disease
B	I-Disease
recurrence	O
after	O
liver	O
transplantation	O
.	O

BACKGROUND	O
:	O
Combined	O
hepatitis	B-Disease
B	I-Disease
immune	O
globulin	O
(	O
HBIg	O
)	O
and	O
lamivudine	B-Chemical
in	O
prophylaxis	O
of	O
the	O
recurrence	O
of	O
hepatitis	B-Disease
B	I-Disease
after	O
liver	O
transplantation	O
has	O
significantly	O
improved	O
the	O
survival	O
of	O
HBsAg	B-Chemical
positive	O
patients	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
evaluate	O
the	O
outcomes	O
of	O
liver	O
transplantation	O
for	O
patients	O
with	O
hepatitis	B-Disease
B	I-Disease
virus	O
(	O
HBV	O
)	O
.	O

METHODS	O
:	O
A	O
retrospective	O
chart	O
analysis	O
and	O
a	O
review	O
of	O
the	O
organ	O
transplant	O
database	O
identified	O
51	O
patients	O
(	O
43	O
men	O
and	O
8	O
women	O
)	O
transplanted	O
for	O
benign	O
HBV	O
-	O
related	O
cirrhotic	B-Disease
diseases	I-Disease
between	O
June	O
2002	O
and	O
December	O
2004	O
who	O
had	O
survived	O
more	O
than	O
3	O
months	O
.	O

HBIg	O
was	O
administered	O
intravenously	O
during	O
the	O
first	O
week	O
and	O
intramuscularly	O
thereafter	O
.	O

RESULTS	O
:	O
At	O
a	O
median	O
follow	O
-	O
up	O
of	O
14	O
.	O
1	O
months	O
,	O
the	O
overall	O
recurrence	O
rate	O
in	O
the	O
51	O
patients	O
was	O
3	O
.	O
9	O
%	O
(	O
2	O
/	O
51	O
)	O
.	O

The	O
overall	O
patient	O
survival	O
was	O
88	O
.	O
3	O
%	O
,	O
and	O
82	O
.	O
4	O
%	O
after	O
1	O
and	O
2	O
years	O
,	O
respectively	O
.	O

A	O
daily	O
oral	O
dose	O
of	O
100	O
mg	O
lamivudine	B-Chemical
for	O
2	O
weeks	O
before	O
transplantation	O
for	O
10	O
patients	O
enabled	O
57	O
.	O
1	O
%	O
(	O
4	O
/	O
7	O
)	O
and	O
62	O
.	O
5	O
%	O
(	O
5	O
/	O
8	O
)	O
of	O
HBV	O
-	O
DNA	O
and	O
HBeAg	B-Chemical
positive	O
patients	O
respectively	O
to	O
convert	O
to	O
be	O
negative	O
.	O

Intramuscular	O
HBIg	O
was	O
well	O
tolerated	O
in	O
all	O
patients	O
.	O

CONCLUSION	O
:	O
Lamivudine	B-Chemical
combined	O
with	O
intramuscular	O
HBIg	O
can	O
effectively	O
prevent	O
allograft	O
from	O
the	O
recurrence	O
of	O
HBV	O
after	O
liver	O
transplantation	O
.	O

Anticonvulsant	O
effect	O
of	O
eslicarbazepine	B-Chemical
acetate	I-Chemical
(	O
BIA	B-Chemical
2	I-Chemical
-	I-Chemical
093	I-Chemical
)	O
on	O
seizures	B-Disease
induced	O
by	O
microperfusion	O
of	O
picrotoxin	B-Chemical
in	O
the	O
hippocampus	O
of	O
freely	O
moving	O
rats	O
.	O

Eslicarbazepine	B-Chemical
acetate	I-Chemical
(	O
BIA	B-Chemical
2	I-Chemical
-	I-Chemical
093	I-Chemical
,	O
S	B-Chemical
-	I-Chemical
(	I-Chemical
-	I-Chemical
)	I-Chemical
-	I-Chemical
10	I-Chemical
-	I-Chemical
acetoxy	I-Chemical
-	I-Chemical
10	I-Chemical
,	I-Chemical
11	I-Chemical
-	I-Chemical
dihydro	I-Chemical
-	I-Chemical
5H	I-Chemical
-	I-Chemical
dibenzo	I-Chemical
/	I-Chemical
b	I-Chemical
,	I-Chemical
f	I-Chemical
/	I-Chemical
azepine	I-Chemical
-	I-Chemical
5	I-Chemical
-	I-Chemical
carboxamide	I-Chemical
)	O
is	O
a	O
novel	O
antiepileptic	O
drug	O
,	O
now	O
in	O
Phase	O
III	O
clinical	O
trials	O
,	O
designed	O
with	O
the	O
aim	O
of	O
improving	O
efficacy	O
and	O
safety	O
in	O
comparison	O
with	O
the	O
structurally	O
related	O
drugs	O
carbamazepine	B-Chemical
(	O
CBZ	B-Chemical
)	O
and	O
oxcarbazepine	B-Chemical
(	O
OXC	B-Chemical
)	O
.	O

We	O
have	O
studied	O
the	O
effects	O
of	O
oral	O
treatment	O
with	O
eslicarbazepine	B-Chemical
acetate	I-Chemical
on	O
a	O
whole	O
-	O
animal	O
model	O
in	O
which	O
partial	O
seizures	B-Disease
can	O
be	O
elicited	O
repeatedly	O
on	O
different	O
days	O
without	O
changes	O
in	O
threshold	O
or	O
seizure	B-Disease
patterns	O
.	O

In	O
the	O
animals	O
treated	O
with	O
threshold	O
doses	O
of	O
picrotoxin	B-Chemical
,	O
the	O
average	O
number	O
of	O
seizures	B-Disease
was	O
2	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
2	O
,	O
and	O
average	O
seizure	B-Disease
duration	O
was	O
39	O
.	O
5	O
+	O
/	O
-	O
8	O
.	O
4s	O
.	O

Pre	O
-	O
treatment	O
with	O
a	O
dose	O
of	O
30	O
mg	O
/	O
kg	O
2h	O
before	O
picrotoxin	B-Chemical
microperfusion	O
prevented	O
seizures	B-Disease
in	O
the	O
75	O
%	O
of	O
the	O
rats	O
.	O

Lower	O
doses	O
(	O
3	O
and	O
10mg	O
/	O
kg	O
)	O
did	O
not	O
suppress	O
seizures	B-Disease
,	O
however	O
,	O
after	O
administration	O
of	O
10mg	O
/	O
kg	O
,	O
significant	O
reductions	O
in	O
seizures	B-Disease
duration	O
(	O
24	O
.	O
3	O
+	O
/	O
-	O
6	O
.	O
8s	O
)	O
and	O
seizure	B-Disease
number	O
(	O
1	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
34	O
)	O
were	O
found	O
.	O

No	O
adverse	O
effects	O
of	O
eslicarbazepine	B-Chemical
acetate	I-Chemical
were	O
observed	O
in	O
the	O
behavioral	O
/	O
EEG	O
patterns	O
studied	O
,	O
including	O
sleep	O
/	O
wakefulness	O
cycle	O
,	O
at	O
the	O
doses	O
studied	O
.	O

Acute	B-Disease
renal	I-Disease
failure	I-Disease
associated	O
with	O
prolonged	O
intake	O
of	O
slimming	O
pills	O
containing	O
anthraquinones	B-Chemical
.	O

Chinese	B-Chemical
herbal	I-Chemical
medicine	O
preparations	O
are	O
widely	O
available	O
and	O
often	O
regarded	O
by	O
the	O
public	O
as	O
natural	O
and	O
safe	O
remedies	O
for	O
a	O
variety	O
of	O
medical	O
conditions	O
.	O

Nephropathy	B-Disease
caused	O
by	O
Chinese	B-Chemical
herbs	I-Chemical
has	O
previously	O
been	O
reported	O
,	O
usually	O
involving	O
the	O
use	O
of	O
aristolochic	B-Chemical
acids	I-Chemical
.	O

We	O
report	O
a	O
23	O
-	O
year	O
-	O
old	O
woman	O
who	O
developed	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
following	O
prolonged	O
use	O
of	O
a	O
proprietary	O
Chinese	B-Chemical
herbal	I-Chemical
slimming	O
pill	O
that	O
contained	O
anthraquinone	B-Chemical
derivatives	O
,	O
extracted	O
from	O
Rhizoma	O
Rhei	O
(	O
rhubarb	O
)	O
.	O

The	O
renal	B-Disease
injury	I-Disease
was	O
probably	O
aggravated	O
by	O
the	O
concomitant	O
intake	O
of	O
a	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drug	O
,	O
diclofenac	B-Chemical
.	O

Renal	O
pathology	O
was	O
that	O
of	O
hypocellular	O
interstitial	O
fibrosis	B-Disease
.	O

Spontaneous	O
renal	O
recovery	O
occurred	O
upon	O
cessation	O
of	O
the	O
slimming	O
pills	O
,	O
but	O
mild	O
interstitial	O
fibrosis	B-Disease
and	O
tubular	O
atrophy	B-Disease
was	O
still	O
evident	O
histologically	O
4	O
months	O
later	O
.	O

Although	O
a	O
causal	O
relationship	O
between	O
the	O
use	O
of	O
an	O
anthraquinone	B-Chemical
-	O
containing	O
herbal	O
agent	O
and	O
renal	B-Disease
injury	I-Disease
remains	O
to	O
be	O
proven	O
,	O
phytotherapy	O
-	O
associated	O
interstitial	O
nephropathy	B-Disease
should	O
be	O
considered	O
in	O
patients	O
who	O
present	O
with	O
unexplained	O
renal	B-Disease
failure	I-Disease
.	O

Chloroacetaldehyde	B-Chemical
as	O
a	O
sulfhydryl	B-Chemical
reagent	O
:	O
the	O
role	O
of	O
critical	O
thiol	B-Chemical
groups	O
in	O
ifosfamide	B-Chemical
nephropathy	B-Disease
.	O

Chloroacetaldehyde	B-Chemical
(	O
CAA	B-Chemical
)	O
is	O
a	O
metabolite	O
of	O
the	O
alkylating	O
agent	O
ifosfamide	B-Chemical
(	O
IFO	B-Chemical
)	O
and	O
putatively	O
responsible	O
for	O
renal	B-Disease
damage	I-Disease
following	O
anti	O
-	O
tumor	B-Disease
therapy	O
with	O
IFO	B-Chemical
.	O

Depletion	O
of	O
sulfhydryl	B-Chemical
(	O
SH	B-Chemical
)	O
groups	O
has	O
been	O
reported	O
from	O
cell	O
culture	O
,	O
animal	O
and	O
clinical	O
studies	O
.	O

In	O
this	O
work	O
the	O
effect	O
of	O
CAA	B-Chemical
on	O
human	O
proximal	O
tubule	O
cells	O
in	O
primary	O
culture	O
(	O
hRPTEC	O
)	O
was	O
investigated	O
.	O

Toxicity	B-Disease
of	O
CAA	B-Chemical
was	O
determined	O
by	O
protein	O
content	O
,	O
cell	O
number	O
,	O
LDH	O
release	O
,	O
trypan	B-Chemical
blue	I-Chemical
exclusion	O
assay	O
and	O
caspase	O
-	O
3	O
activity	O
.	O

Free	O
thiols	B-Chemical
were	O
measured	O
by	O
the	O
method	O
of	O
Ellman	O
.	O

CAA	B-Chemical
reduced	O
hRPTEC	O
cell	O
number	O
and	O
protein	O
,	O
induced	O
a	O
loss	O
in	O
free	O
intracellular	O
thiols	B-Chemical
and	O
an	O
increase	O
in	O
necrosis	B-Disease
markers	O
.	O

CAA	B-Chemical
but	O
not	O
acrolein	B-Chemical
inhibited	O
the	O
cysteine	B-Chemical
proteases	O
caspase	O
-	O
3	O
,	O
caspase	O
-	O
8	O
and	O
cathepsin	O
B	O
.	O

Caspase	O
activation	O
by	O
cisplatin	B-Chemical
was	O
inhibited	O
by	O
CAA	B-Chemical
.	O

In	O
cells	O
stained	O
with	O
fluorescent	O
dyes	O
targeting	O
lysosomes	O
,	O
CAA	B-Chemical
induced	O
an	O
increase	O
in	O
lysosomal	O
size	O
and	O
lysosomal	O
leakage	O
.	O

The	O
effects	O
of	O
CAA	B-Chemical
on	O
cysteine	B-Chemical
protease	O
activities	O
and	O
thiols	B-Chemical
could	O
be	O
reproduced	O
in	O
cell	O
lysate	O
.	O

Acidification	O
,	O
which	O
slowed	O
the	O
reaction	O
of	O
CAA	B-Chemical
with	O
thiol	B-Chemical
donors	O
,	O
could	O
also	O
attenuate	O
effects	O
of	O
CAA	B-Chemical
on	O
necrosis	B-Disease
markers	O
,	O
thiol	B-Chemical
depletion	O
and	O
cysteine	B-Chemical
protease	O
inhibition	O
in	O
living	O
cells	O
.	O

Thus	O
,	O
CAA	B-Chemical
directly	O
reacts	O
with	O
cellular	O
protein	O
and	O
non	O
-	O
protein	O
thiols	B-Chemical
,	O
mediating	O
its	O
toxicity	B-Disease
on	O
hRPTEC	O
.	O

This	O
effect	O
can	O
be	O
reduced	O
by	O
acidification	O
.	O

Therefore	O
,	O
urinary	O
acidification	O
could	O
be	O
an	O
option	O
to	O
prevent	O
IFO	B-Chemical
nephropathy	B-Disease
in	O
patients	O
.	O

Stereological	O
methods	O
reveal	O
the	O
robust	O
size	O
and	O
stability	O
of	O
ectopic	O
hilar	O
granule	O
cells	O
after	O
pilocarpine	B-Chemical
-	O
induced	O
status	B-Disease
epilepticus	I-Disease
in	O
the	O
adult	O
rat	O
.	O

Following	O
status	B-Disease
epilepticus	I-Disease
in	O
the	O
rat	O
,	O
dentate	O
granule	O
cell	O
neurogenesis	O
increases	O
greatly	O
,	O
and	O
many	O
of	O
the	O
new	O
neurons	O
appear	O
to	O
develop	O
ectopically	O
,	O
in	O
the	O
hilar	O
region	O
of	O
the	O
hippocampal	O
formation	O
.	O

It	O
has	O
been	O
suggested	O
that	O
the	O
ectopic	O
hilar	O
granule	O
cells	O
could	O
contribute	O
to	O
the	O
spontaneous	O
seizures	B-Disease
that	O
ultimately	O
develop	O
after	O
status	B-Disease
epilepticus	I-Disease
.	O

However	O
,	O
the	O
population	O
has	O
never	O
been	O
quantified	O
,	O
so	O
it	O
is	O
unclear	O
whether	O
it	O
is	O
substantial	O
enough	O
to	O
have	O
a	O
strong	O
influence	O
on	O
epileptogenesis	O
.	O

To	O
quantify	O
this	O
population	O
,	O
the	O
total	O
number	O
of	O
ectopic	O
hilar	O
granule	O
cells	O
was	O
estimated	O
using	O
unbiased	O
stereology	O
at	O
different	O
times	O
after	O
pilocarpine	B-Chemical
-	O
induced	O
status	B-Disease
epilepticus	I-Disease
.	O

The	O
number	O
of	O
hilar	O
neurons	O
immunoreactive	O
for	O
Prox	O
-	O
1	O
,	O
a	O
granule	O
-	O
cell	O
-	O
specific	O
marker	O
,	O
was	O
estimated	O
using	O
the	O
optical	O
fractionator	O
method	O
.	O

The	O
results	O
indicate	O
that	O
the	O
size	O
of	O
the	O
hilar	O
ectopic	O
granule	O
cell	O
population	O
after	O
status	B-Disease
epilepticus	I-Disease
is	O
substantial	O
,	O
and	O
stable	O
over	O
time	O
.	O

Interestingly	O
,	O
the	O
size	O
of	O
the	O
population	O
appears	O
to	O
be	O
correlated	O
with	O
the	O
frequency	O
of	O
behavioral	O
seizures	B-Disease
,	O
because	O
animals	O
with	O
more	O
ectopic	O
granule	O
cells	O
in	O
the	O
hilus	O
have	O
more	O
frequent	O
behavioral	O
seizures	B-Disease
.	O

The	O
hilar	O
ectopic	O
granule	O
cell	O
population	O
does	O
not	O
appear	O
to	O
vary	O
systematically	O
across	O
the	O
septotemporal	O
axis	O
,	O
although	O
it	O
is	O
associated	O
with	O
an	O
increase	O
in	O
volume	O
of	O
the	O
hilus	O
.	O

The	O
results	O
provide	O
new	O
insight	O
into	O
the	O
potential	O
role	O
of	O
ectopic	O
hilar	O
granule	O
cells	O
in	O
the	O
pilocarpine	B-Chemical
model	O
of	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
.	O

A	O
prospective	O
,	O
open	O
-	O
label	O
trial	O
of	O
galantamine	B-Chemical
in	O
autistic	B-Disease
disorder	I-Disease
.	O

OBJECTIVE	O
:	O
Post	O
-	O
mortem	O
studies	O
have	O
reported	O
abnormalities	O
of	O
the	O
cholinergic	O
system	O
in	O
autism	B-Disease
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
assess	O
the	O
use	O
of	O
galantamine	B-Chemical
,	O
an	O
acetylcholinesterase	O
inhibitor	O
and	O
nicotinic	O
receptor	O
modulator	O
,	O
in	O
the	O
treatment	O
of	O
interfering	O
behaviors	O
in	O
children	O
with	O
autism	B-Disease
.	O

METHODS	O
:	O
Thirteen	O
medication	O
-	O
free	O
children	O
with	O
autism	B-Disease
(	O
mean	O
age	O
,	O
8	O
.	O
8	O
+	O
/	O
-	O
3	O
.	O
5	O
years	O
)	O
participated	O
in	O
a	O
12	O
-	O
week	O
,	O
open	O
-	O
label	O
trial	O
of	O
galantamine	B-Chemical
.	O

Patients	O
were	O
rated	O
monthly	O
by	O
parents	O
on	O
the	O
Aberrant	O
Behavior	O
Checklist	O
(	O
ABC	O
)	O
and	O
the	O
Conners	O
'	O
Parent	O
Rating	O
Scale	O
-	O
Revised	O
,	O
and	O
by	O
a	O
physician	O
using	O
the	O
Children	O
'	O
s	O
Psychiatric	O
Rating	O
Scale	O
and	O
the	O
Clinical	O
Global	O
Impressions	O
scale	O
.	O

RESULTS	O
:	O
Patients	O
showed	O
a	O
significant	O
reduction	O
in	O
parent	O
-	O
rated	O
irritability	B-Disease
and	O
social	O
withdrawal	O
on	O
the	O
ABC	O
as	O
well	O
as	O
significant	O
improvements	O
in	O
emotional	O
lability	O
and	O
inattention	O
on	O
the	O
Conners	O
'	O
Parent	O
Rating	O
Scale	O
-	O
-	O
Revised	O
.	O

Similarly	O
,	O
clinician	O
ratings	O
showed	O
reductions	O
in	O
the	O
anger	O
subscale	O
of	O
the	O
Children	O
'	O
s	O
Psychiatric	O
Rating	O
Scale	O
.	O

Eight	O
of	O
13	O
participants	O
were	O
rated	O
as	O
responders	O
on	O
the	O
basis	O
of	O
their	O
improvement	O
scores	O
on	O
the	O
Clinical	O
Global	O
Impressions	O
scale	O
.	O

Overall	O
,	O
galantamine	B-Chemical
was	O
well	O
-	O
tolerated	O
,	O
with	O
no	O
significant	O
adverse	O
effects	O
apart	O
from	O
headaches	B-Disease
in	O
one	O
patient	O
.	O

CONCLUSION	O
:	O
In	O
this	O
open	O
trial	O
,	O
galantamine	B-Chemical
was	O
well	O
-	O
tolerated	O
and	O
appeared	O
to	O
be	O
beneficial	O
for	O
the	O
treatment	O
of	O
interfering	O
behaviors	O
in	O
children	O
with	O
autism	B-Disease
,	O
particularly	O
aggression	B-Disease
,	O
behavioral	B-Disease
dyscontrol	I-Disease
,	O
and	O
inattention	B-Disease
.	O

Further	O
controlled	O
trials	O
are	O
warranted	O
.	O

Randomized	O
comparison	O
of	O
olanzapine	B-Chemical
versus	O
risperidone	B-Chemical
for	O
the	O
treatment	O
of	O
first	O
-	O
episode	O
schizophrenia	B-Disease
:	O
4	O
-	O
month	O
outcomes	O
.	O

OBJECTIVE	O
:	O
The	O
authors	O
compared	O
4	O
-	O
month	O
treatment	O
outcomes	O
for	O
olanzapine	B-Chemical
versus	O
risperidone	B-Chemical
in	O
patients	O
with	O
first	O
-	O
episode	O
schizophrenia	B-Disease
spectrum	O
disorders	O
.	O

METHOD	O
:	O
One	O
hundred	O
twelve	O
subjects	O
(	O
70	O
%	O
male	O
;	O
mean	O
age	O
=	O
23	O
.	O
3	O
years	O
[	O
SD	O
=	O
5	O
.	O
1	O
]	O
)	O
with	O
first	O
-	O
episode	O
schizophrenia	B-Disease
(	O
75	O
%	O
)	O
,	O
schizophreniform	B-Disease
disorder	I-Disease
(	O
17	O
%	O
)	O
,	O
or	O
schizoaffective	B-Disease
disorder	I-Disease
(	O
8	O
%	O
)	O
were	O
randomly	O
assigned	O
to	O
treatment	O
with	O
olanzapine	B-Chemical
(	O
2	O
.	O
5	O
-	O
20	O
mg	O
/	O
day	O
)	O
or	O
risperidone	B-Chemical
(	O
1	O
-	O
6	O
mg	O
/	O
day	O
)	O
.	O

RESULTS	O
:	O
Response	O
rates	O
did	O
not	O
significantly	O
differ	O
between	O
olanzapine	B-Chemical
(	O
43	O
.	O
7	O
%	O
,	O
95	O
%	O
CI	O
=	O
28	O
.	O
8	O
%	O
-	O
58	O
.	O
6	O
%	O
)	O
and	O
risperidone	B-Chemical
(	O
54	O
.	O
3	O
%	O
,	O
95	O
%	O
CI	O
=	O
39	O
.	O
9	O
%	O
-	O
68	O
.	O
7	O
%	O
)	O
.	O

Among	O
those	O
responding	O
to	O
treatment	O
,	O
more	O
subjects	O
in	O
the	O
olanzapine	B-Chemical
group	O
(	O
40	O
.	O
9	O
%	O
,	O
95	O
%	O
CI	O
=	O
16	O
.	O
8	O
%	O
-	O
65	O
.	O
0	O
%	O
)	O
than	O
in	O
the	O
risperidone	B-Chemical
group	O
(	O
18	O
.	O
9	O
%	O
,	O
95	O
%	O
CI	O
=	O
0	O
%	O
-	O
39	O
.	O
2	O
%	O
)	O
had	O
subsequent	O
ratings	O
not	O
meeting	O
response	O
criteria	O
.	O

Negative	O
symptom	O
outcomes	O
and	O
measures	O
of	O
parkinsonism	B-Disease
and	O
akathisia	B-Disease
did	O
not	O
differ	O
between	O
medications	O
.	O

Extrapyramidal	B-Disease
symptom	I-Disease
severity	O
scores	O
were	O
1	O
.	O
4	O
(	O
95	O
%	O
CI	O
=	O
1	O
.	O
2	O
-	O
1	O
.	O
6	O
)	O
with	O
risperidone	B-Chemical
and	O
1	O
.	O
2	O
(	O
95	O
%	O
CI	O
=	O
1	O
.	O
0	O
-	O
1	O
.	O
4	O
)	O
with	O
olanzapine	B-Chemical
.	O

Significantly	O
more	O
weight	B-Disease
gain	I-Disease
occurred	O
with	O
olanzapine	B-Chemical
than	O
with	O
risperidone	B-Chemical
:	O
the	O
increase	O
in	O
weight	O
at	O
4	O
months	O
relative	O
to	O
baseline	O
weight	O
was	O
17	O
.	O
3	O
%	O
(	O
95	O
%	O
CI	O
=	O
14	O
.	O
2	O
%	O
-	O
20	O
.	O
5	O
%	O
)	O
with	O
olanzapine	B-Chemical
and	O
11	O
.	O
3	O
%	O
(	O
95	O
%	O
CI	O
=	O
8	O
.	O
4	O
%	O
-	O
14	O
.	O
3	O
%	O
)	O
with	O
risperidone	B-Chemical
.	O

Body	O
mass	O
index	O
at	O
baseline	O
and	O
at	O
4	O
months	O
was	O
24	O
.	O
3	O
(	O
95	O
%	O
CI	O
=	O
22	O
.	O
8	O
-	O
25	O
.	O
7	O
)	O
versus	O
28	O
.	O
2	O
(	O
95	O
%	O
CI	O
=	O
26	O
.	O
7	O
-	O
29	O
.	O
7	O
)	O
with	O
olanzapine	B-Chemical
and	O
23	O
.	O
9	O
(	O
95	O
%	O
CI	O
=	O
22	O
.	O
5	O
-	O
25	O
.	O
3	O
)	O
versus	O
26	O
.	O
7	O
(	O
95	O
%	O
CI	O
=	O
25	O
.	O
2	O
-	O
28	O
.	O
2	O
)	O
with	O
risperidone	B-Chemical
.	O

CONCLUSIONS	O
:	O
Clinical	O
outcomes	O
with	O
risperidone	B-Chemical
were	O
equal	O
to	O
those	O
with	O
olanzapine	B-Chemical
,	O
and	O
response	O
may	O
be	O
more	O
stable	O
.	O

Olanzapine	B-Chemical
may	O
have	O
an	O
advantage	O
for	O
motor	O
side	O
effects	O
.	O

Both	O
medications	O
caused	O
substantial	O
rapid	O
weight	B-Disease
gain	I-Disease
,	O
but	O
weight	B-Disease
gain	I-Disease
was	O
greater	O
with	O
olanzapine	B-Chemical
.	O

Early	O
paracentral	O
visual	B-Disease
field	I-Disease
loss	I-Disease
in	O
patients	O
taking	O
hydroxychloroquine	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
review	O
the	O
natural	O
history	O
and	O
ocular	O
and	O
systemic	O
adverse	O
effects	O
of	O
patients	O
taking	O
hydroxychloroquine	B-Chemical
sulfate	I-Chemical
who	O
attended	O
an	O
ophthalmic	O
screening	O
program	O
.	O

DESIGN	O
:	O
Retrospective	O
study	O
.	O

RESULTS	O
:	O
Records	O
of	O
262	O
patients	O
who	O
were	O
taking	O
hydroxychloroquine	B-Chemical
and	O
screened	O
in	O
the	O
Department	O
of	O
Ophthalmology	O
were	O
reviewed	O
.	O

Of	O
the	O
262	O
patients	O
,	O
14	O
(	O
18	O
%	O
)	O
of	O
76	O
who	O
had	O
stopped	O
treatment	O
at	O
the	O
time	O
of	O
the	O
study	O
experienced	O
documented	O
adverse	O
effects	O
.	O

Systemic	O
adverse	O
effects	O
occurred	O
in	O
8	O
patients	O
(	O
10	O
.	O
5	O
%	O
)	O
and	O
ocular	O
adverse	O
effects	O
,	O
in	O
5	O
(	O
6	O
.	O
5	O
%	O
)	O
.	O

Thirty	O
-	O
five	O
patients	O
(	O
13	O
.	O
4	O
%	O
)	O
had	O
visual	B-Disease
field	I-Disease
abnormalities	I-Disease
,	O
which	O
were	O
attributed	O
to	O
hydroxychloroquine	B-Chemical
treatment	O
in	O
4	O
patients	O
(	O
1	O
.	O
5	O
%	O
)	O
.	O

Three	O
of	O
the	O
4	O
patients	O
were	O
taking	O
less	O
than	O
6	O
.	O
5	O
mg	O
/	O
kg	O
per	O
day	O
and	O
all	O
patients	O
had	O
normal	O
renal	O
and	O
liver	O
function	O
test	O
results	O
.	O

CONCLUSIONS	O
:	O
The	O
current	O
study	O
used	O
a	O
protocol	O
of	O
visual	O
acuity	O
and	O
color	O
vision	O
assessment	O
,	O
funduscopy	O
,	O
and	O
Humphrey	O
10	O
-	O
2	O
visual	O
field	O
testing	O
and	O
shows	O
that	O
visual	B-Disease
field	I-Disease
defects	I-Disease
appeared	O
before	O
any	O
corresponding	O
changes	O
in	O
any	O
other	O
tested	O
clinical	O
parameters	O
;	O
the	O
defects	O
were	O
reproducible	O
and	O
the	O
test	O
parameters	O
were	O
reliable	O
.	O

Patients	O
taking	O
hydroxychloroquine	B-Chemical
can	O
demonstrate	O
a	O
toxic	O
reaction	O
in	O
the	O
retina	O
despite	O
the	O
absence	O
of	O
known	O
risk	O
factors	O
.	O

Screening	O
,	O
including	O
Humphrey	O
10	O
-	O
2	O
visual	O
field	O
assessment	O
,	O
is	O
recommended	O
2	O
years	O
after	O
the	O
initial	O
baseline	O
and	O
yearly	O
thereafter	O
.	O

Peri	O
-	O
operative	O
atrioventricular	B-Disease
block	I-Disease
as	O
a	O
result	O
of	O
chemotherapy	O
with	O
epirubicin	B-Chemical
and	O
paclitaxel	B-Chemical
.	O

A	O
47	O
-	O
year	O
-	O
old	O
woman	O
presented	O
for	O
mastectomy	O
and	O
immediate	O
latissimus	O
dorsi	O
flap	O
reconstruction	O
having	O
been	O
diagnosed	O
with	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
breast	I-Disease
6	O
months	O
previously	O
.	O

In	O
the	O
preceding	O
months	O
she	O
had	O
received	O
neo	O
-	O
adjuvant	O
chemotherapy	O
with	O
epirubicin	B-Chemical
,	O
paclitaxel	B-Chemical
(	O
Taxol	B-Chemical
)	O
and	O
cyclophosphamide	B-Chemical
.	O

This	O
had	O
been	O
apparently	O
uncomplicated	O
and	O
she	O
had	O
maintained	O
a	O
remarkably	O
high	O
level	O
of	O
physical	O
activity	O
.	O

She	O
was	O
found	O
to	O
be	O
bradycardic	B-Disease
at	O
pre	O
-	O
operative	O
assessment	O
but	O
had	O
no	O
cardiac	O
symptoms	O
.	O

Second	O
degree	O
Mobitz	O
type	O
II	O
atrioventricular	B-Disease
block	I-Disease
was	O
diagnosed	O
on	O
electrocardiogram	O
,	O
and	O
temporary	O
transvenous	O
ventricular	O
pacing	O
instituted	O
in	O
the	O
peri	O
-	O
operative	O
period	O
.	O

We	O
discuss	O
how	O
evidence	O
-	O
based	O
guidelines	O
would	O
not	O
have	O
been	O
helpful	O
in	O
this	O
case	O
,	O
and	O
how	O
chemotherapy	O
can	O
exhibit	O
substantial	O
cardiotoxicity	B-Disease
that	O
may	O
develop	O
over	O
many	O
years	O
.	O

We	O
suggest	O
that	O
patients	O
who	O
have	O
received	O
chemotherapy	O
at	O
any	O
time	O
should	O
have	O
a	O
pre	O
-	O
operative	O
electrocardiogram	O
even	O
if	O
they	O
are	O
asymptomatic	O
.	O

Risks	O
and	O
benefits	O
of	O
COX	B-Chemical
-	I-Chemical
2	I-Chemical
inhibitors	I-Chemical
vs	O
non	O
-	O
selective	O
NSAIDs	O
:	O
does	O
their	O
cardiovascular	O
risk	O
exceed	O
their	O
gastrointestinal	O
benefit	O
?	O

A	O
retrospective	O
cohort	O
study	O
.	O

OBJECTIVES	O
:	O
The	O
risk	O
of	O
acute	B-Disease
myocardial	I-Disease
infarction	I-Disease
(	O
AMI	B-Disease
)	O
with	O
COX	B-Chemical
-	I-Chemical
2	I-Chemical
inhibitors	I-Chemical
may	O
offset	O
their	O
gastrointestinal	O
(	O
GI	O
)	O
benefit	O
compared	O
with	O
non	O
-	O
selective	O
(	O
NS	O
)	O
non	B-Chemical
-	I-Chemical
steroidal	I-Chemical
anti	I-Chemical
-	I-Chemical
inflammatory	I-Chemical
drugs	I-Chemical
(	O
NSAIDs	O
)	O
.	O

We	O
aimed	O
to	O
compare	O
the	O
risks	O
of	O
hospitalization	O
for	O
AMI	B-Disease
and	O
GI	B-Disease
bleeding	I-Disease
among	O
elderly	O
patients	O
using	O
COX	B-Chemical
-	I-Chemical
2	I-Chemical
inhibitors	I-Chemical
,	O
NS	O
-	O
NSAIDs	O
and	O
acetaminophen	B-Chemical
.	O

METHODS	O
:	O
We	O
conducted	O
a	O
retrospective	O
cohort	O
study	O
using	O
administrative	O
data	O
of	O
patients	O
>	O
or	O
=	O
65	O
years	O
of	O
age	O
who	O
filled	O
a	O
prescription	O
for	O
NSAID	O
or	O
acetaminophen	B-Chemical
during	O
1999	O
-	O
2002	O
.	O

Outcomes	O
were	O
compared	O
using	O
Cox	O
regression	O
models	O
with	O
time	O
-	O
dependent	O
exposures	O
.	O

RESULTS	O
:	O
Person	O
-	O
years	O
of	O
exposure	O
among	O
non	O
-	O
users	O
of	O
aspirin	B-Chemical
were	O
:	O
75	O
,	O
761	O
to	O
acetaminophen	B-Chemical
,	O
42	O
,	O
671	O
to	O
rofecoxib	B-Chemical
65	O
,	O
860	O
to	O
celecoxib	B-Chemical
,	O
and	O
37	O
,	O
495	O
to	O
NS	O
-	O
NSAIDs	O
.	O

Among	O
users	O
of	O
aspirin	B-Chemical
,	O
they	O
were	O
:	O
14	O
,	O
671	O
to	O
rofecoxib	B-Chemical
,	O
22	O
,	O
875	O
to	O
celecoxib	B-Chemical
,	O
9	O
,	O
832	O
to	O
NS	O
-	O
NSAIDs	O
and	O
38	O
,	O
048	O
to	O
acetaminophen	B-Chemical
.	O

Among	O
non	O
-	O
users	O
of	O
aspirin	B-Chemical
,	O
the	O
adjusted	O
hazard	O
ratios	O
(	O
95	O
%	O
confidence	O
interval	O
)	O
of	O
hospitalization	O
for	O
AMI	B-Disease
/	O
GI	O
vs	O
the	O
acetaminophen	B-Chemical
(	O
with	O
no	O
aspirin	B-Chemical
)	O
group	O
were	O
:	O
rofecoxib	B-Chemical
1	O
.	O
27	O
(	O
1	O
.	O
13	O
,	O
1	O
.	O
42	O
)	O
,	O
celecoxib	B-Chemical
0	O
.	O
93	O
(	O
0	O
.	O
83	O
,	O
1	O
.	O
03	O
)	O
,	O
naproxen	B-Chemical
1	O
.	O
59	O
(	O
1	O
.	O
31	O
,	O
1	O
.	O
93	O
)	O
,	O
diclofenac	B-Chemical
1	O
.	O
17	O
(	O
0	O
.	O
99	O
,	O
1	O
.	O
38	O
)	O
and	O
ibuprofen	B-Chemical
1	O
.	O
05	O
(	O
0	O
.	O
74	O
,	O
1	O
.	O
51	O
)	O
.	O

Among	O
users	O
of	O
aspirin	B-Chemical
,	O
they	O
were	O
:	O
rofecoxib	B-Chemical
1	O
.	O
73	O
(	O
1	O
.	O
52	O
,	O
1	O
.	O
98	O
)	O
,	O
celecoxib	B-Chemical
1	O
.	O
34	O
(	O
1	O
.	O
19	O
,	O
1	O
.	O
52	O
)	O
,	O
ibuprofen	B-Chemical
1	O
.	O
51	O
(	O
0	O
.	O
95	O
,	O
2	O
.	O
41	O
)	O
,	O
diclofenac	B-Chemical
1	O
.	O
69	O
(	O
1	O
.	O
35	O
,	O
2	O
.	O
10	O
)	O
,	O
naproxen	B-Chemical
1	O
.	O
35	O
(	O
0	O
.	O
97	O
,	O
1	O
.	O
88	O
)	O
and	O
acetaminophen	B-Chemical
1	O
.	O
29	O
(	O
1	O
.	O
17	O
,	O
1	O
.	O
42	O
)	O
.	O

CONCLUSION	O
:	O
Among	O
non	O
-	O
users	O
of	O
aspirin	B-Chemical
,	O
naproxen	B-Chemical
seemed	O
to	O
carry	O
the	O
highest	O
risk	O
for	O
AMI	B-Disease
/	O
GI	B-Disease
bleeding	I-Disease
.	O

The	O
AMI	B-Disease
/	O
GI	O
toxicity	B-Disease
of	O
celecoxib	B-Chemical
was	O
similar	O
to	O
that	O
of	O
acetaminophen	B-Chemical
and	O
seemed	O
to	O
be	O
better	O
than	O
those	O
of	O
rofecoxib	B-Chemical
and	O
NS	O
-	O
NSAIDs	O
.	O

Among	O
users	O
of	O
aspirin	B-Chemical
,	O
both	O
celecoxib	B-Chemical
and	O
naproxen	B-Chemical
seemed	O
to	O
be	O
the	O
least	O
toxic	O
.	O

Quinine	B-Chemical
-	O
induced	O
arrhythmia	B-Disease
in	O
a	O
patient	O
with	O
severe	B-Disease
malaria	I-Disease
.	O

It	O
was	O
reported	O
that	O
there	O
was	O
a	O
case	O
of	O
severe	B-Disease
malaria	I-Disease
patient	O
with	O
jaundice	B-Disease
who	O
presented	O
with	O
arrhythmia	B-Disease
(	O
premature	B-Disease
ventricular	I-Disease
contraction	I-Disease
)	O
while	O
getting	O
quinine	B-Chemical
infusion	O
was	O
reported	O
.	O

A	O
man	O
,	O
25	O
years	O
old	O
,	O
was	O
admitted	O
to	O
hospital	O
with	O
high	O
fever	B-Disease
,	O
chill	B-Disease
,	O
vomiting	B-Disease
,	O
jaundice	B-Disease
.	O

The	O
patient	O
was	O
fully	O
conscious	O
,	O
blood	O
pressure	O
120	O
/	O
80	O
mmHg	O
,	O
pulse	O
rate	O
100	O
x	O
/	O
minute	O
,	O
regular	O
.	O

On	O
admission	O
,	O
laboratory	O
examination	O
showed	O
Plasmodium	O
falciparum	O
(	O
+	O
+	O
+	O
+	O
)	O
,	O
total	O
bilirubin	B-Chemical
8	O
.	O
25	O
mg	O
/	O
dL	O
,	O
conjugated	O
bilirubin	B-Chemical
4	O
.	O
36	O
mg	O
/	O
dL	O
,	O
unconjugated	O
bilirubin	B-Chemical
3	O
.	O
89	O
mg	O
/	O
dL	O
,	O
potassium	B-Chemical
3	O
.	O
52	O
meq	O
/	O
L	O
Patient	O
was	O
diagnosed	O
as	O
severe	B-Disease
malaria	I-Disease
with	O
jaundice	B-Disease
and	O
got	O
quinine	B-Chemical
infusion	O
in	O
dextrose	B-Chemical
5	O
%	O
500	O
mg	O
/	O
8	O
hour	O
.	O

On	O
the	O
second	O
day	O
the	O
patient	O
had	O
vomitus	B-Disease
,	O
diarrhea	B-Disease
,	O
tinnitus	B-Disease
,	O
loss	B-Disease
of	I-Disease
hearing	I-Disease
.	O

After	O
30	O
hours	O
of	O
quinine	B-Chemical
infusion	O
the	O
patient	O
felt	O
palpitation	B-Disease
and	O
electrocardiography	O
(	O
ECG	O
)	O
recording	O
showed	O
premature	B-Disease
ventricular	I-Disease
contraction	I-Disease
(	O
PVC	B-Disease
)	O
>	O
5	O
x	O
/	O
minute	O
,	O
trigemini	O
,	O
constant	O
type	O
-	O
-	O
sinoatrial	B-Disease
block	I-Disease
,	O
positive	O
U	O
wave	O
.	O

He	O
was	O
treated	O
with	O
lidocaine	B-Chemical
50	O
mg	O
intravenously	O
followed	O
by	O
infusion	O
1500	O
mg	O
in	O
dextrose	B-Chemical
5	O
%	O
/	O
24	O
hour	O
and	O
potassium	B-Chemical
aspartate	I-Chemical
tablet	O
.	O

Quinine	B-Chemical
infusion	O
was	O
discontinued	O
and	O
changed	O
with	O
sulfate	O
quinine	B-Chemical
tablets	O
.	O

Three	O
hours	O
later	O
the	O
patient	O
felt	O
better	O
,	O
the	O
frequency	O
of	O
PVC	B-Disease
reduced	O
to	O
4	O
-	O
5	O
x	O
/	O
minute	O
and	O
on	O
the	O
third	O
day	O
ECG	O
was	O
normal	O
,	O
potassium	B-Chemical
level	O
was	O
3	O
.	O
34	O
meq	O
/	O
L	O
.	O

He	O
was	O
discharged	O
on	O
7th	O
day	O
in	O
good	O
condition	O
.	O

Quinine	B-Chemical
,	O
like	O
quinidine	B-Chemical
,	O
is	O
a	O
chincona	O
alkaloid	O
that	O
has	O
anti	O
-	O
arrhythmic	B-Disease
property	O
,	O
although	O
it	O
also	O
pro	O
-	O
arrhythmic	B-Disease
that	O
can	O
cause	O
various	O
arrhythmias	B-Disease
,	O
including	O
severe	O
arrhythmia	B-Disease
such	O
as	O
multiple	O
PVC	B-Disease
.	O

Administration	O
of	O
parenteral	O
quinine	B-Chemical
must	O
be	O
done	O
carefully	O
and	O
with	O
good	O
observation	O
because	O
of	O
its	O
pro	O
-	O
arrhythmic	B-Disease
effect	O
,	O
especially	O
in	O
older	O
patients	O
who	O
have	O
heart	B-Disease
diseases	I-Disease
or	O
patients	O
with	O
electrolyte	B-Disease
disorder	I-Disease
(	O
hypokalemia	B-Disease
)	O
which	O
frequently	O
occurs	O
due	O
to	O
vomiting	B-Disease
and	O
or	O
diarrhea	B-Disease
in	O
malaria	B-Disease
cases	O
.	O

Penicillamine	B-Chemical
-	O
related	O
lichenoid	B-Disease
dermatitis	I-Disease
and	O
utility	O
of	O
zinc	B-Chemical
acetate	I-Chemical
in	O
a	O
Wilson	B-Disease
disease	I-Disease
patient	O
with	O
hepatic	O
presentation	O
,	O
anxiety	B-Disease
and	O
SPECT	O
abnormalities	O
.	O

Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
is	O
an	O
autosomal	O
recessive	O
disorder	O
of	O
hepatic	O
copper	B-Chemical
metabolism	O
with	O
consequent	O
copper	B-Chemical
accumulation	O
and	O
toxicity	B-Disease
in	O
many	O
tissues	O
and	O
consequent	O
hepatic	B-Disease
,	I-Disease
neurologic	I-Disease
and	I-Disease
psychiatric	I-Disease
disorders	I-Disease
.	O

We	O
report	O
a	O
case	O
of	O
Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
with	O
chronic	B-Disease
liver	I-Disease
disease	I-Disease
;	O
moreover	O
,	O
in	O
our	O
patient	O
,	O
presenting	O
also	O
with	O
high	O
levels	O
of	O
state	O
anxiety	B-Disease
without	O
depression	B-Disease
,	O
99mTc	O
-	O
ECD	O
-	O
SPECT	O
showed	O
cortical	O
hypoperfusion	O
in	O
frontal	O
lobes	O
,	O
more	O
marked	O
on	O
the	O
left	O
frontal	O
lobe	O
.	O

During	O
the	O
follow	O
-	O
up	O
of	O
our	O
patient	O
,	O
penicillamine	B-Chemical
was	O
interrupted	O
after	O
the	O
appearance	O
of	O
a	O
lichenoid	B-Disease
dermatitis	I-Disease
,	O
and	O
zinc	B-Chemical
acetate	I-Chemical
permitted	O
to	O
continue	O
the	O
successful	O
treatment	O
of	O
the	O
patient	O
without	O
side	O
-	O
effects	O
.	O

In	O
our	O
case	O
the	O
therapy	O
with	O
zinc	B-Chemical
acetate	I-Chemical
represented	O
an	O
effective	O
treatment	O
for	O
a	O
Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
patient	O
in	O
which	O
penicillamine	B-Chemical
-	O
related	O
side	O
effects	O
appeared	O
.	O

The	O
safety	O
of	O
the	O
zinc	B-Chemical
acetate	I-Chemical
allowed	O
us	O
to	O
avoid	O
other	O
potentially	O
toxic	O
chelating	O
drugs	O
;	O
this	O
observation	O
is	O
in	O
line	O
with	O
the	O
growing	O
evidence	O
on	O
the	O
efficacy	O
of	O
the	O
drug	O
in	O
the	O
treatment	O
of	O
Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Since	O
most	O
of	O
Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
penicillamine	B-Chemical
-	O
treated	O
patients	O
do	O
not	O
seem	O
to	O
develop	O
this	O
skin	B-Disease
lesion	I-Disease
,	O
it	O
could	O
be	O
conceivable	O
that	O
a	O
specific	O
genetic	O
factor	O
is	O
involved	O
in	O
drug	O
response	O
.	O

Further	O
studies	O
are	O
needed	O
for	O
a	O
better	O
clarification	O
of	O
Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
therapy	O
,	O
and	O
in	O
particular	O
to	O
differentiate	O
specific	O
therapies	O
for	O
different	O
Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
phenotypes	O
.	O

A	O
dramatic	O
drop	B-Disease
in	I-Disease
blood	I-Disease
pressure	I-Disease
following	O
prehospital	O
GTN	B-Chemical
administration	O
.	O

A	O
male	O
in	O
his	O
sixties	O
with	O
no	O
history	O
of	O
cardiac	O
chest	B-Disease
pain	I-Disease
awoke	O
with	O
chest	B-Disease
pain	I-Disease
following	O
an	O
afternoon	O
sleep	O
.	O

The	O
patient	O
did	O
not	O
self	O
medicate	O
.	O

The	O
patient	O
'	O
s	O
observations	O
were	O
within	O
normal	O
limits	O
,	O
he	O
was	O
administered	O
oxygen	B-Chemical
via	O
a	O
face	O
mask	O
and	O
glyceryl	B-Chemical
trinitrate	I-Chemical
(	O
GTN	B-Chemical
)	O
.	O

Several	O
minutes	O
after	O
the	O
GTN	B-Chemical
the	O
patient	O
experienced	O
a	O
sudden	O
drop	B-Disease
in	I-Disease
blood	I-Disease
pressure	I-Disease
and	O
heart	O
rate	O
,	O
this	O
was	O
rectified	O
by	O
atropine	B-Chemical
sulphate	I-Chemical
and	O
a	O
fluid	O
challenge	O
.	O

There	O
was	O
no	O
further	O
deterioration	O
in	O
the	O
patient	O
'	O
s	O
condition	O
during	O
transport	O
to	O
hospital	O
.	O

There	O
are	O
very	O
few	O
documented	O
case	O
like	O
this	O
in	O
the	O
prehospital	O
scientific	O
literature	O
.	O

The	O
cause	O
appears	O
to	O
be	O
the	O
Bezold	O
-	O
Jarish	O
reflex	O
,	O
stimulation	O
of	O
the	O
ventricular	O
walls	O
which	O
in	O
turn	O
decreases	O
sympathetic	O
outflow	O
from	O
the	O
vasomotor	O
centre	O
.	O

Prehospital	O
care	O
providers	O
who	O
are	O
managing	O
any	O
patient	O
with	O
a	O
syncopal	B-Disease
episode	I-Disease
that	O
fails	O
to	O
recover	O
within	O
a	O
reasonable	O
time	O
frame	O
should	O
consider	O
the	O
Bezold	O
-	O
Jarisch	O
reflex	O
as	O
the	O
cause	O
and	O
manage	O
the	O
patient	O
accordingly	O
.	O

Chronic	O
lesion	O
of	O
rostral	O
ventrolateral	O
medulla	O
in	O
spontaneously	O
hypertensive	B-Disease
rats	O
.	O

We	O
studied	O
the	O
effects	O
of	O
chronic	O
selective	O
neuronal	O
lesion	O
of	O
rostral	O
ventrolateral	O
medulla	O
on	O
mean	O
arterial	O
pressure	O
,	O
heart	O
rate	O
,	O
and	O
neurogenic	O
tone	O
in	O
conscious	O
,	O
unrestrained	O
spontaneously	O
hypertensive	B-Disease
rats	O
.	O

The	O
lesions	O
were	O
placed	O
via	O
bilateral	O
microinjections	O
of	O
30	O
nmol	O
/	O
200	O
nl	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartic	I-Chemical
acid	I-Chemical
.	O

The	O
restimulation	O
of	O
this	O
area	O
with	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartic	I-Chemical
acid	I-Chemical
15	O
days	O
postlesion	O
failed	O
to	O
produce	O
a	O
pressor	O
response	O
.	O

One	O
day	O
postlesion	O
,	O
the	O
resting	O
mean	O
arterial	O
pressure	O
was	O
significantly	O
decreased	O
in	O
lesioned	O
rats	O
when	O
compared	O
with	O
sham	O
rats	O
(	O
100	O
+	O
/	O
-	O
7	O
versus	O
173	O
+	O
/	O
-	O
4	O
mm	O
Hg	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Fifteen	O
days	O
later	O
,	O
the	O
lesioned	O
group	O
still	O
showed	O
values	O
significantly	O
lower	O
than	O
the	O
sham	O
group	O
(	O
150	O
+	O
/	O
-	O
6	O
versus	O
167	O
+	O
/	O
-	O
5	O
mm	O
Hg	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

No	O
significant	O
heart	O
rate	O
differences	O
were	O
observed	O
between	O
the	O
sham	O
and	O
lesioned	O
groups	O
.	O

The	O
ganglionic	O
blocker	O
trimethaphan	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
caused	O
similar	O
reductions	O
in	O
mean	O
arterial	O
pressure	O
in	O
both	O
lesioned	O
and	O
sham	O
groups	O
.	O

The	O
trimethaphan	B-Chemical
-	O
induced	O
hypotension	B-Disease
was	O
accompanied	O
by	O
a	O
significant	O
bradycardia	B-Disease
in	O
lesioned	O
rats	O
(	O
-	O
32	O
+	O
/	O
-	O
13	O
beats	O
per	O
minute	O
)	O
but	O
a	O
tachycardia	B-Disease
in	O
sham	O
rats	O
(	O
+	O
33	O
+	O
/	O
-	O
12	O
beats	O
per	O
minute	O
)	O
1	O
day	O
postlesion	O
.	O

Therefore	O
,	O
rostral	O
ventrolateral	O
medulla	O
neurons	O
appear	O
to	O
play	O
a	O
significant	O
role	O
in	O
maintaining	O
hypertension	B-Disease
in	O
conscious	O
spontaneously	O
hypertensive	B-Disease
rats	O
.	O

Spinal	O
or	O
suprabulbar	O
structures	O
could	O
be	O
responsible	O
for	O
the	O
gradual	O
recovery	O
of	O
the	O
hypertension	B-Disease
in	O
the	O
lesioned	O
rats	O
.	O

Acute	B-Disease
encephalopathy	I-Disease
and	O
cerebral	B-Disease
vasospasm	I-Disease
after	O
multiagent	O
chemotherapy	O
including	O
PEG	B-Chemical
-	I-Chemical
asparaginase	I-Chemical
and	O
intrathecal	O
cytarabine	B-Chemical
for	O
the	O
treatment	O
of	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
.	O

A	O
7	O
-	O
year	O
-	O
old	O
girl	O
with	O
an	O
unusual	O
reaction	O
to	O
induction	O
chemotherapy	O
for	O
precursor	O
B	O
-	O
cell	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
(	O
ALL	B-Disease
)	O
is	O
described	O
.	O

The	O
patient	O
developed	O
acute	B-Disease
encephalopathy	I-Disease
evidenced	O
by	O
behavioral	O
changes	O
,	O
aphasia	B-Disease
,	O
incontinence	B-Disease
,	O
visual	B-Disease
hallucinations	I-Disease
,	O
and	O
right	O
-	O
sided	O
weakness	B-Disease
with	O
diffuse	O
cerebral	B-Disease
vasospasm	I-Disease
on	O
magnetic	O
resonance	O
angiography	O
after	O
the	O
administration	O
of	O
intrathecal	O
cytarabine	B-Chemical
.	O

Vincristine	B-Chemical
,	O
dexamethasone	B-Chemical
,	O
and	O
polyethylene	B-Chemical
glycol	I-Chemical
-	I-Chemical
asparaginase	I-Chemical
were	O
also	O
administered	O
before	O
the	O
episode	O
as	O
part	O
of	O
induction	O
therapy	O
.	O

Neurologic	O
status	O
returned	O
to	O
baseline	O
within	O
10	O
days	O
of	O
the	O
acute	O
event	O
,	O
and	O
magnetic	O
resonance	O
angiography	O
findings	O
returned	O
to	O
normal	O
4	O
months	O
later	O
.	O

Comparison	O
of	O
valsartan	B-Chemical
/	O
hydrochlorothiazide	B-Chemical
combination	O
therapy	O
at	O
doses	O
up	O
to	O
320	O
/	O
25	O
mg	O
versus	O
monotherapy	O
:	O
a	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
study	O
followed	O
by	O
long	O
-	O
term	O
combination	O
therapy	O
in	O
hypertensive	B-Disease
adults	O
.	O

BACKGROUND	O
:	O
One	O
third	O
of	O
patients	O
treated	O
for	O
hypertension	B-Disease
attain	O
adequate	O
blood	O
pressure	O
(	O
BP	O
)	O
control	O
,	O
and	O
multidrug	O
regimens	O
are	O
often	O
required	O
.	O

Given	O
the	O
lifelong	O
nature	O
of	O
hypertension	B-Disease
,	O
there	O
is	O
a	O
need	O
to	O
evaluate	O
the	O
long	O
-	O
term	O
efficacy	O
and	O
tolerability	O
of	O
higher	O
doses	O
of	O
combination	O
anti	O
-	O
hypertensive	B-Disease
therapies	O
.	O

OBJECTIVE	O
:	O
This	O
study	O
investigated	O
the	O
efficacy	O
and	O
tolerability	O
of	O
valsartan	B-Chemical
(	O
VAL	B-Chemical
)	O
or	O
hydrochlorothiazide	B-Chemical
(	O
HCTZ	B-Chemical
)	O
-	O
monotherapy	O
and	O
higher	O
-	O
dose	O
combinations	O
in	O
patients	O
with	O
essential	B-Disease
hypertension	I-Disease
.	O

METHODS	O
:	O
The	O
first	O
part	O
of	O
this	O
study	O
was	O
an	O
8	O
-	O
week	O
,	O
multicenter	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
controlled	O
,	O
parallel	O
-	O
group	O
trial	O
.	O

Patients	O
with	O
essential	B-Disease
hypertension	I-Disease
(	O
mean	O
sitting	O
diastolic	O
BP	O
[	O
MSDBP	O
]	O
,	O
>	O
or	O
=	O
95	O
mm	O
Hg	O
and	O
<	O
110	O
mm	O
Hg	O
)	O
were	O
randomized	O
to	O
1	O
of	O
8	O
treatment	O
groups	O
:	O
VAL	B-Chemical
160	O
or	O
320	O
mg	O
;	O
HCTZ	B-Chemical
12	O
.	O
5	O
or	O
25	O
mg	O
;	O
VAL	B-Chemical
/	O
HCTZ	B-Chemical
160	O
/	O
12	O
.	O
5	O
,	O
320	O
/	O
12	O
.	O
5	O
,	O
or	O
320	O
/	O
25	O
mg	O
;	O
or	O
placebo	O
.	O

Mean	O
changes	O
in	O
MSDBP	O
and	O
mean	O
sitting	O
systolic	O
BP	O
(	O
MSSBP	O
)	O
were	O
analyzed	O
at	O
the	O
8	O
-	O
week	O
core	O
study	O
end	O
point	O
.	O

VAL	B-Chemical
/	O
HCTZ	B-Chemical
320	O
/	O
12	O
.	O
5	O
and	O
320	O
/	O
25	O
mg	O
were	O
further	O
investigated	O
in	O
a	O
54	O
-	O
week	O
,	O
open	O
-	O
label	O
extension	O
.	O

Response	O
was	O
defined	O
as	O
MSDBP	O
<	O
90	O
mm	O
Hg	O
or	O
a	O
>	O
or	O
=	O
10	O
mm	O
Hg	O
decrease	O
compared	O
to	O
baseline	O
.	O

Control	O
was	O
defined	O
as	O
MSDBP	O
<	O
90	O
mm	O
Hg	O
compared	O
with	O
baseline	O
.	O

Tolerability	O
was	O
assessed	O
by	O
monitoring	O
adverse	O
events	O
at	O
randomization	O
and	O
all	O
subsequent	O
study	O
visits	O
and	O
regular	O
evaluation	O
of	O
hematology	O
and	O
blood	O
chemistry	O
.	O

RESULTS	O
:	O
A	O
total	O
of	O
1346	O
patients	O
were	O
randomized	O
into	O
the	O
8	O
-	O
week	O
core	O
study	O
(	O
734	O
men	O
,	O
612	O
women	O
;	O
924	O
white	O
,	O
291	O
black	O
,	O
23	O
Asian	O
,	O
108	O
other	O
;	O
mean	O
age	O
,	O
52	O
.	O
7	O
years	O
;	O
mean	O
weight	O
,	O
92	O
.	O
6	O
kg	O
)	O
.	O

All	O
active	O
treatments	O
were	O
associated	O
with	O
significantly	O
reduced	O
MSSBP	O
and	O
MSDBP	O
during	O
the	O
core	O
8	O
-	O
week	O
study	O
,	O
with	O
each	O
monotherapy	O
significantly	O
contributing	O
to	O
the	O
overall	O
effect	O
of	O
combination	O
therapy	O
(	O
VAL	B-Chemical
and	O
HCTZ	B-Chemical
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Each	O
combination	O
was	O
associated	O
with	O
significantly	O
greater	O
reductions	O
in	O
MSSBP	O
and	O
MSDBP	O
compared	O
with	O
the	O
monotherapies	O
and	O
placebo	O
(	O
all	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

The	O
mean	O
reduction	O
in	O
MSSBP	O
/	O
MSDBP	O
with	O
VAL	B-Chemical
/	O
HCTZ	B-Chemical
320	O
/	O
25	O
mg	O
was	O
24	O
.	O
7	O
/	O
16	O
.	O
6	O
mm	O
Hg	O
,	O
compared	O
with	O
5	O
.	O
9	O
/	O
7	O
.	O
0	O
mm	O
Hg	O
with	O
placebo	O
.	O

The	O
reduction	O
in	O
MSSBP	O
was	O
significantly	O
greater	O
with	O
VAL	B-Chemical
/	O
HCTZ	B-Chemical
320	O
/	O
25	O
mg	O
compared	O
with	O
VAL	B-Chemical
/	O
HCTZ	B-Chemical
160	O
/	O
12	O
.	O
5	O
mg	O
(	O
P	O
<	O
0	O
.	O
002	O
)	O
.	O

Rates	O
of	O
response	O
and	O
BP	O
control	O
were	O
significantly	O
higher	O
in	O
the	O
groups	O
that	O
received	O
combination	O
treatment	O
compared	O
with	O
those	O
that	O
received	O
monotherapy	O
.	O

The	O
incidence	O
of	O
hypokalemia	B-Disease
was	O
lower	O
with	O
VAL	B-Chemical
/	O
HCTZ	B-Chemical
combinations	O
(	O
1	O
.	O
8	O
%	O
-	O
6	O
.	O
1	O
%	O
)	O
than	O
with	O
HCTZ	B-Chemical
monotherapies	O
(	O
7	O
.	O
1	O
%	O
-	O
13	O
.	O
3	O
%	O
)	O
.	O

The	O
majority	O
of	O
adverse	O
events	O
in	O
the	O
core	O
study	O
were	O
of	O
mild	O
to	O
moderate	O
severity	O
.	O

The	O
efficacy	O
and	O
tolerability	O
of	O
VAL	B-Chemical
/	O
HCTZ	B-Chemical
combinations	O
were	O
maintained	O
during	O
the	O
extension	O
(	O
797	O
patients	O
)	O
.	O

CONCLUSIONS	O
:	O
In	O
this	O
study	O
population	O
,	O
combination	O
therapies	O
with	O
VAL	B-Chemical
/	O
HCTZ	B-Chemical
were	O
associated	O
with	O
significantly	O
greater	O
BP	O
reductions	O
compared	O
with	O
either	O
monotherapy	O
,	O
were	O
well	O
tolerated	O
,	O
and	O
were	O
associated	O
with	O
less	O
hypokalemia	B-Disease
than	O
HCTZ	B-Chemical
alone	O
.	O

Succimer	B-Chemical
chelation	O
improves	O
learning	O
,	O
attention	O
,	O
and	O
arousal	O
regulation	O
in	O
lead	B-Chemical
-	O
exposed	O
rats	O
but	O
produces	O
lasting	O
cognitive	B-Disease
impairment	I-Disease
in	O
the	O
absence	O
of	O
lead	B-Chemical
exposure	O
.	O

BACKGROUND	O
:	O
There	O
is	O
growing	O
pressure	O
for	O
clinicians	O
to	O
prescribe	O
chelation	O
therapy	O
at	O
only	O
slightly	O
elevated	O
blood	O
lead	B-Chemical
levels	O
.	O

However	O
,	O
very	O
few	O
studies	O
have	O
evaluated	O
whether	O
chelation	O
improves	O
cognitive	O
outcomes	O
in	O
Pb	B-Chemical
-	O
exposed	O
children	O
,	O
or	O
whether	O
these	O
agents	O
have	O
adverse	O
effects	O
that	O
may	O
affect	O
brain	O
development	O
in	O
the	O
absence	O
of	O
Pb	B-Chemical
exposure	O
.	O

OBJECTIVES	O
:	O
The	O
present	O
study	O
was	O
designed	O
to	O
answer	O
these	O
questions	O
,	O
using	O
a	O
rodent	O
model	O
of	O
early	O
childhood	O
Pb	B-Chemical
exposure	O
and	O
treatment	O
with	O
succimer	B-Chemical
,	O
a	O
widely	O
used	O
chelating	O
agent	O
for	O
the	O
treatment	O
of	O
Pb	B-Disease
poisoning	I-Disease
.	O

RESULTS	O
:	O
Pb	B-Chemical
exposure	O
produced	O
lasting	O
impairments	B-Disease
in	I-Disease
learning	I-Disease
,	I-Disease
attention	I-Disease
,	I-Disease
inhibitory	I-Disease
control	I-Disease
,	I-Disease
and	I-Disease
arousal	I-Disease
regulation	I-Disease
,	O
paralleling	O
the	O
areas	O
of	O
dysfunction	O
seen	O
in	O
Pb	B-Chemical
-	O
exposed	O
children	O
.	O

Succimer	B-Chemical
treatment	O
of	O
the	O
Pb	B-Chemical
-	O
exposed	O
rats	O
significantly	O
improved	O
learning	O
,	O
attention	O
,	O
and	O
arousal	O
regulation	O
,	O
although	O
the	O
efficacy	O
of	O
the	O
treatment	O
varied	O
as	O
a	O
function	O
of	O
the	O
Pb	B-Chemical
exposure	O
level	O
and	O
the	O
specific	O
functional	O
deficit	O
.	O

In	O
contrast	O
,	O
succimer	B-Chemical
treatment	O
of	O
rats	O
not	O
previously	O
exposed	O
to	O
Pb	B-Chemical
produced	O
lasting	O
and	O
pervasive	O
cognitive	B-Disease
and	I-Disease
affective	I-Disease
dysfunction	I-Disease
comparable	O
in	O
magnitude	O
to	O
that	O
produced	O
by	O
the	O
higher	O
Pb	B-Chemical
exposure	O
regimen	O
.	O

CONCLUSIONS	O
:	O
These	O
are	O
the	O
first	O
data	O
,	O
to	O
our	O
knowledge	O
,	O
to	O
show	O
that	O
treatment	O
with	O
any	O
chelating	O
agent	O
can	O
alleviate	O
cognitive	B-Disease
deficits	I-Disease
due	O
to	O
Pb	B-Chemical
exposure	O
.	O

These	O
findings	O
suggest	O
that	O
it	O
may	O
be	O
possible	O
to	O
identify	O
a	O
succimer	B-Chemical
treatment	O
protocol	O
that	O
improves	O
cognitive	O
outcomes	O
in	O
Pb	B-Chemical
-	O
exposed	O
children	O
.	O

However	O
,	O
they	O
also	O
suggest	O
that	O
succimer	B-Chemical
treatment	O
should	O
be	O
strongly	O
discouraged	O
for	O
children	O
who	O
do	O
not	O
have	O
elevated	O
tissue	O
levels	O
of	O
Pb	B-Chemical
or	O
other	O
heavy	O
metals	O
.	O

Caffeine	B-Chemical
challenge	O
test	O
in	O
panic	B-Disease
disorder	I-Disease
and	O
depression	B-Disease
with	O
panic	B-Disease
attacks	I-Disease
.	O

Our	O
aim	O
was	O
to	O
observe	O
if	O
patients	O
with	O
panic	B-Disease
disorder	I-Disease
(	O
PD	B-Disease
)	O
and	O
patients	O
with	O
major	B-Disease
depression	I-Disease
with	O
panic	B-Disease
attacks	I-Disease
(	O
MDP	B-Disease
)	O
(	O
Diagnostic	O
and	O
Statistical	O
Manual	O
of	O
Mental	B-Disease
Disorders	I-Disease
,	O
Fourth	O
Edition	O
criteria	O
)	O
respond	O
in	O
a	O
similar	O
way	O
to	O
the	O
induction	O
of	O
panic	B-Disease
attacks	I-Disease
by	O
an	O
oral	O
caffeine	B-Chemical
challenge	O
test	O
.	O

We	O
randomly	O
selected	O
29	O
patients	O
with	O
PD	B-Disease
,	O
27	O
with	O
MDP	B-Disease
,	O
25	O
with	O
major	B-Disease
depression	I-Disease
without	O
panic	B-Disease
attacks	I-Disease
(	O
MD	B-Disease
)	O
,	O
and	O
28	O
healthy	O
volunteers	O
.	O

The	O
patients	O
had	O
no	O
psychotropic	O
drug	O
for	O
at	O
least	O
a	O
4	O
-	O
week	O
period	O
.	O

In	O
a	O
randomized	O
double	O
-	O
blind	O
experiment	O
performed	O
in	O
2	O
occasions	O
7	O
days	O
apart	O
,	O
480	O
mg	O
caffeine	B-Chemical
and	O
a	O
caffeine	B-Chemical
-	O
free	O
(	O
placebo	O
)	O
solution	O
were	O
administered	O
in	O
a	O
coffee	O
form	O
and	O
anxiety	B-Disease
scales	O
were	O
applied	O
before	O
and	O
after	O
each	O
test	O
.	O

A	O
total	O
of	O
58	O
.	O
6	O
%	O
(	O
n	O
=	O
17	O
)	O
of	O
patients	O
with	O
PD	B-Disease
,	O
44	O
.	O
4	O
%	O
(	O
n	O
=	O
12	O
)	O
of	O
patients	O
with	O
MDP	B-Disease
,	O
12	O
.	O
0	O
%	O
(	O
n	O
=	O
3	O
)	O
of	O
patients	O
with	O
MD	B-Disease
,	O
and	O
7	O
.	O
1	O
%	O
(	O
n	O
=	O
2	O
)	O
of	O
control	O
subjects	O
had	O
a	O
panic	B-Disease
attack	I-Disease
after	O
the	O
480	O
-	O
mg	O
caffeine	B-Chemical
challenge	O
test	O
(	O
chi	O
(	O
2	O
)	O
(	O
3	O
)	O
=	O
16	O
.	O
22	O
,	O
P	O
=	O
.	O
001	O
)	O
.	O

The	O
patients	O
with	O
PD	B-Disease
and	O
MDP	B-Disease
were	O
more	O
sensitive	O
to	O
caffeine	B-Chemical
than	O
were	O
patients	O
with	O
MD	B-Disease
and	O
healthy	O
volunteers	O
.	O

No	O
panic	B-Disease
attack	I-Disease
was	O
observed	O
after	O
the	O
caffeine	B-Chemical
-	O
free	O
solution	O
intake	O
.	O

The	O
patients	O
with	O
MD	B-Disease
had	O
a	O
lower	O
heart	O
rate	O
response	O
to	O
the	O
test	O
than	O
all	O
the	O
other	O
groups	O
(	O
2	O
-	O
way	O
analysis	O
of	O
variance	O
,	O
group	O
by	O
time	O
interaction	O
with	O
Greenhouse	O
-	O
Geisser	O
correction	O
:	O
F	O
(	O
3	O
,	O
762	O
)	O
=	O
2	O
.	O
85	O
,	O
P	O
=	O
.	O
026	O
)	O
.	O

Our	O
data	O
suggest	O
that	O
there	O
is	O
an	O
association	O
between	O
panic	B-Disease
attacks	I-Disease
,	O
no	O
matter	O
if	O
associated	O
with	O
PD	B-Disease
or	O
MDP	B-Disease
,	O
and	O
hyperreactivity	O
to	O
an	O
oral	O
caffeine	B-Chemical
challenge	O
test	O
.	O

Mitral	O
annuloplasty	O
as	O
a	O
ventricular	O
restoration	O
method	O
for	O
the	O
failing	B-Disease
left	I-Disease
ventricle	I-Disease
:	O
a	O
pilot	O
study	O
.	O

BACKGROUND	O
AND	O
AIM	O
OF	O
THE	O
STUDY	O
:	O
Undersized	O
mitral	O
annuloplasty	O
(	O
MAP	O
)	O
is	O
effective	O
in	O
patients	O
with	O
dilated	B-Disease
cardiomyopathy	I-Disease
and	O
functional	O
mitral	B-Disease
regurgitation	I-Disease
(	O
MR	B-Disease
)	O
since	O
,	O
as	O
well	O
as	O
addressing	O
the	O
MR	B-Disease
,	O
the	O
MAP	O
may	O
also	O
reshape	O
the	O
dilated	O
left	O
ventricular	O
(	O
LV	O
)	O
base	O
.	O

However	O
,	O
the	O
direct	O
benefits	O
of	O
this	O
possible	O
reshaping	O
on	O
LV	O
function	O
in	O
the	O
absence	O
of	O
underlying	O
MR	B-Disease
remain	O
incompletely	O
understood	O
.	O

The	O
study	O
aim	O
was	O
to	O
identify	O
these	O
benefits	O
in	O
a	O
canine	O
model	O
of	O
acute	O
heart	B-Disease
failure	I-Disease
.	O

METHODS	O
:	O
Six	O
dogs	O
underwent	O
MAP	O
with	O
a	O
prosthetic	O
band	O
on	O
the	O
posterior	O
mitral	O
annulus	O
,	O
using	O
four	O
mattress	O
sutures	O
.	O

The	O
sutures	O
were	O
passed	O
individually	O
through	O
four	O
tourniquets	O
and	O
exteriorized	O
untied	O
via	O
the	O
left	O
atriotomy	O
.	O

Sonomicrometry	O
crystals	O
were	O
implanted	O
around	O
the	O
mitral	O
annulus	O
and	O
left	O
ventricle	O
to	O
measure	O
geometry	O
and	O
regional	O
function	O
.	O

Acute	O
heart	B-Disease
failure	I-Disease
was	O
induced	O
by	O
propranolol	B-Chemical
and	O
volume	O
loading	O
after	O
weaning	O
from	O
cardiopulmonary	O
bypass	O
;	O
an	O
absence	O
of	O
MR	B-Disease
was	O
confirmed	O
by	O
echocardiography	O
.	O

MAP	O
was	O
accomplished	O
by	O
cinching	O
the	O
tourniquets	O
.	O

Data	O
were	O
acquired	O
at	O
baseline	O
,	O
after	O
induction	O
of	O
acute	O
heart	B-Disease
failure	I-Disease
,	O
and	O
after	O
MAP	O
.	O

RESULTS	O
:	O
MAP	O
decreased	O
mitral	O
annular	O
dimensions	O
in	O
both	O
commissure	O
-	O
commissure	O
and	O
septal	O
-	O
lateral	O
directions	O
.	O

Concomitantly	O
,	O
the	O
diastolic	O
diameter	O
of	O
the	O
LV	O
base	O
and	O
LV	O
sphericity	O
decreased	O
(	O
i	O
.	O
e	O
.	O
,	O
improved	O
)	O
from	O
37	O
.	O
4	O
+	O
/	O
-	O
9	O
.	O
3	O
to	O
35	O
.	O
9	O
+	O
/	O
-	O
10	O
mm	O
(	O
p	O
=	O
0	O
.	O
063	O
)	O
,	O
and	O
from	O
67	O
.	O
9	O
+	O
/	O
-	O
18	O
.	O
6	O
%	O
to	O
65	O
.	O
3	O
+	O
/	O
-	O
18	O
.	O
9	O
%	O
(	O
p	O
=	O
0	O
.	O
016	O
)	O
,	O
respectively	O
.	O

Decreases	O
were	O
evident	O
in	O
both	O
LV	O
end	O
-	O
diastolic	O
pressure	O
(	O
from	O
17	O
+	O
/	O
-	O
7	O
to	O
15	O
+	O
/	O
-	O
6	O
mmHg	O
,	O
p	O
=	O
0	O
.	O
0480	O
and	O
Tau	O
(	O
from	O
48	O
+	O
/	O
-	O
8	O
to	O
45	O
+	O
/	O
-	O
8	O
ms	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
,	O
while	O
fractional	O
shortening	O
at	O
the	O
LV	O
base	O
increased	O
from	O
7	O
.	O
7	O
+	O
/	O
-	O
4	O
.	O
5	O
%	O
to	O
9	O
.	O
4	O
+	O
/	O
-	O
4	O
.	O
5	O
%	O
(	O
p	O
=	O
0	O
.	O
045	O
)	O
.	O

After	O
MAP	O
,	O
increases	O
were	O
identified	O
in	O
both	O
cardiac	O
output	O
(	O
from	O
1	O
.	O
54	O
+	O
/	O
-	O
0	O
.	O
57	O
to	O
1	O
.	O
65	O
+	O
/	O
-	O
0	O
.	O
57	O
1	O
/	O
min	O
)	O
and	O
Emax	O
(	O
from	O
1	O
.	O
86	O
+	O
/	O
-	O
0	O
.	O
9	O
to	O
2	O
.	O
41	O
+	O
/	O
-	O
1	O
.	O
31	O
mmHg	O
/	O
ml	O
)	O
.	O

CONCLUSION	O
:	O
The	O
data	O
acquired	O
suggest	O
that	O
isolated	O
MAP	O
may	O
have	O
certain	O
benefits	O
on	O
LV	O
dimension	O
/	O
function	O
in	O
acute	O
heart	B-Disease
failure	I-Disease
,	O
even	O
in	O
the	O
absence	O
of	O
MR	B-Disease
.	O

However	O
,	O
further	O
investigations	O
are	O
warranted	O
in	O
a	O
model	O
of	O
chronic	O
heart	B-Disease
failure	I-Disease
.	O

Piperacillin	B-Chemical
/	I-Chemical
tazobactam	I-Chemical
-	O
induced	O
seizure	B-Disease
rapidly	O
reversed	O
by	O
high	O
flux	O
hemodialysis	O
in	O
a	O
patient	O
on	O
peritoneal	O
dialysis	O
.	O

Despite	O
popular	O
use	O
of	O
piperacillin	B-Chemical
,	O
the	O
dire	O
neurotoxicity	B-Disease
associated	O
with	O
piperacillin	B-Chemical
still	O
goes	O
unrecognized	O
,	O
leading	O
to	O
a	O
delay	O
in	O
appropriate	O
management	O
.	O

We	O
report	O
a	O
57	O
-	O
year	O
-	O
old	O
woman	O
with	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
receiving	O
continuous	O
ambulatory	O
peritoneal	O
dialysis	O
(	O
CAPD	O
)	O
,	O
who	O
developed	O
slurred	O
speech	O
,	O
tremor	B-Disease
,	O
bizarre	O
behavior	O
,	O
progressive	O
mental	O
confusion	B-Disease
,	O
and	O
2	O
episodes	O
of	O
generalized	O
tonic	B-Disease
-	I-Disease
clonic	I-Disease
seizure	I-Disease
(	O
GTCS	B-Disease
)	O
after	O
5	O
doses	O
of	O
piperacillin	B-Chemical
/	I-Chemical
tazobactam	I-Chemical
(	O
2	O
g	O
/	O
250	O
mg	O
)	O
were	O
given	O
for	O
bronchiectasis	B-Disease
with	O
secondary	B-Disease
infection	I-Disease
.	O

The	O
laboratory	O
data	O
revealed	O
normal	O
plasma	O
electrolyte	O
and	O
ammonia	B-Chemical
levels	O
but	O
leukocytosis	B-Disease
.	O

Neurologic	O
examinations	O
showed	O
dysarthria	B-Disease
and	O
bilateral	O
Babinski	O
sign	O
.	O

Computed	O
tomography	O
of	O
brain	O
and	O
electroencephalogram	O
were	O
unremarkable	O
.	O

Despite	O
the	O
use	O
of	O
antiepileptic	O
agents	O
,	O
another	O
GTCS	B-Disease
episode	O
recurred	O
after	O
the	O
sixth	O
dose	O
of	O
piperacillin	B-Chemical
/	I-Chemical
tazobactam	I-Chemical
.	O

Brain	O
magnetic	O
resonance	O
imaging	O
did	O
not	O
demonstrate	O
acute	O
infarction	B-Disease
and	O
organic	B-Disease
brain	I-Disease
lesions	I-Disease
.	O

Initiation	O
of	O
high	O
-	O
flux	O
hemodialysis	O
rapidly	O
reversed	O
the	O
neurologic	O
symptoms	O
within	O
4	O
hours	O
.	O

Piperacillin	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
should	O
be	O
considered	O
in	O
any	O
uremic	B-Disease
patients	O
with	O
unexplained	O
neurological	O
manifestations	O
.	O

CAPD	O
is	O
inefficient	O
in	O
removing	O
piperacillin	B-Chemical
,	O
whereas	O
hemodialysis	O
can	O
rapidly	O
terminate	O
the	O
piperacillin	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
.	O

Frequency	O
of	O
transient	O
ipsilateral	O
vocal	B-Disease
cord	I-Disease
paralysis	I-Disease
in	O
patients	O
undergoing	O
carotid	O
endarterectomy	O
under	O
local	O
anesthesia	O
.	O

BACKGROUND	O
:	O
Especially	O
because	O
of	O
improvements	O
in	O
clinical	O
neurologic	O
monitoring	O
,	O
carotid	O
endarterectomy	O
done	O
under	O
local	O
anesthesia	O
has	O
become	O
the	O
technique	O
of	O
choice	O
in	O
several	O
centers	O
.	O

Temporary	O
ipsilateral	O
vocal	B-Disease
nerve	I-Disease
palsies	I-Disease
due	O
to	O
local	O
anesthetics	O
have	O
been	O
described	O
,	O
however	O
.	O

Such	O
complications	O
are	O
most	O
important	O
in	O
situations	O
where	O
there	O
is	O
a	O
pre	O
-	O
existing	O
contralateral	O
paralysis	B-Disease
.	O

We	O
therefore	O
examined	O
the	O
effect	O
of	O
local	O
anesthesia	O
on	O
vocal	O
cord	O
function	O
to	O
better	O
understand	O
its	O
possible	O
consequences	O
.	O

METHODS	O
:	O
This	O
prospective	O
study	O
included	O
28	O
patients	O
undergoing	O
carotid	O
endarterectomy	O
under	O
local	O
anesthesia	O
.	O

Vocal	O
cord	O
function	O
was	O
evaluated	O
before	O
,	O
during	O
,	O
and	O
after	O
surgery	O
(	O
postoperative	O
day	O
1	O
)	O
using	O
flexible	O
laryngoscopy	O
.	O

Anesthesia	O
was	O
performed	O
by	O
injecting	O
20	O
to	O
40	O
mL	O
of	O
a	O
mixture	O
of	O
long	O
-	O
acting	O
(	O
ropivacaine	B-Chemical
)	O
and	O
short	O
-	O
acting	O
(	O
prilocaine	B-Chemical
)	O
anesthetic	O
.	O

RESULTS	O
:	O
All	O
patients	O
had	O
normal	O
vocal	O
cord	O
function	O
preoperatively	O
.	O

Twelve	O
patients	O
(	O
43	O
%	O
)	O
were	O
found	O
to	O
have	O
intraoperative	O
ipsilateral	O
vocal	B-Disease
cord	I-Disease
paralysis	I-Disease
.	O

It	O
resolved	O
in	O
all	O
cases	O
<	O
or	O
=	O
24	O
hours	O
.	O

There	O
were	O
no	O
significant	O
differences	O
in	O
operating	O
time	O
or	O
volume	O
or	O
frequency	O
of	O
anesthetic	O
administration	O
in	O
patients	O
with	O
temporary	O
vocal	B-Disease
cord	I-Disease
paralysis	I-Disease
compared	O
with	O
those	O
without	O
.	O

CONCLUSION	O
:	O
Local	O
anesthesia	O
led	O
to	O
temporary	O
ipsilateral	O
vocal	B-Disease
cord	I-Disease
paralysis	I-Disease
in	O
almost	O
half	O
of	O
these	O
patients	O
.	O

Because	O
pre	O
-	O
existing	O
paralysis	B-Disease
is	O
of	O
a	O
relevant	O
frequency	O
(	O
up	O
to	O
3	O
%	O
)	O
,	O
a	O
preoperative	O
evaluation	O
of	O
vocal	O
cord	O
function	O
before	O
carotid	O
endarterectomy	O
under	O
local	O
anesthesia	O
is	O
recommended	O
to	O
avoid	O
intraoperative	O
bilateral	O
paralysis	B-Disease
.	O

In	O
patients	O
with	O
preoperative	O
contralateral	O
vocal	B-Disease
cord	I-Disease
paralysis	I-Disease
,	O
surgery	O
under	O
general	O
anesthesia	O
should	O
be	O
considered	O
.	O

Impaired	B-Disease
fear	I-Disease
recognition	I-Disease
in	O
regular	O
recreational	O
cocaine	B-Chemical
users	O
.	O

INTRODUCTION	O
:	O
The	O
ability	O
to	O
read	O
facial	O
expressions	O
is	O
essential	O
for	O
normal	O
human	O
social	O
interaction	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
conduct	O
the	O
first	O
investigation	O
of	O
facial	O
expression	O
recognition	O
performance	O
in	O
recreational	O
cocaine	B-Chemical
users	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
Three	O
groups	O
,	O
comprised	O
of	O
21	O
cocaine	B-Chemical
naive	O
participants	O
(	O
CN	O
)	O
,	O
30	O
occasional	O
cocaine	B-Chemical
(	O
OC	O
)	O
,	O
and	O
48	O
regular	O
recreational	O
cocaine	B-Chemical
(	O
RC	O
)	O
users	O
,	O
were	O
compared	O
.	O

An	O
emotional	O
facial	O
expression	O
(	O
EFE	O
)	O
task	O
consisting	O
of	O
a	O
male	O
and	O
female	O
face	O
expressing	O
six	O
basic	O
emotions	O
(	O
happiness	O
,	O
surprise	O
,	O
sadness	O
,	O
anger	O
,	O
fear	O
,	O
and	O
disgust	O
)	O
was	O
administered	O
.	O

Mean	O
percent	O
accuracy	O
and	O
latencies	O
for	O
correct	O
responses	O
across	O
eight	O
presentations	O
of	O
each	O
basic	O
emotion	O
were	O
derived	O
.	O

Participants	O
were	O
also	O
assessed	O
with	O
the	O
"	O
Eyes	O
task	O
"	O
to	O
investigate	O
their	O
ability	O
to	O
recognize	O
more	O
complex	O
emotional	O
states	O
and	O
the	O
Symptom	O
CheckList	O
-	O
90	O
-	O
Revised	O
to	O
measure	O
psychopathology	O
.	O

RESULTS	O
:	O
There	O
were	O
no	O
group	O
differences	O
in	O
psychopathology	O
or	O
"	O
eyes	O
task	O
"	O
performance	O
,	O
but	O
the	O
RC	O
group	O
,	O
who	O
otherwise	O
had	O
similar	O
illicit	O
substance	O
use	O
histories	O
to	O
the	O
OC	O
group	O
,	O
exhibited	O
impaired	B-Disease
fear	I-Disease
recognition	I-Disease
accuracy	O
compared	O
to	O
the	O
OC	O
and	O
CN	O
groups	O
.	O

The	O
RC	O
group	O
also	O
correctly	O
identified	O
anger	O
,	O
fear	O
,	O
happiness	O
,	O
and	O
surprise	O
,	O
more	O
slowly	O
than	O
CN	O
,	O
but	O
not	O
OC	O
participants	O
.	O

The	O
OC	O
group	O
was	O
slower	O
than	O
CN	O
when	O
correctly	O
identifying	O
disgust	O
.	O

The	O
selective	O
deficit	B-Disease
in	I-Disease
fear	I-Disease
recognition	I-Disease
accuracy	O
manifested	O
by	O
the	O
RC	O
group	O
cannot	O
be	O
explained	O
by	O
the	O
subacute	O
effects	O
of	O
cocaine	B-Chemical
,	O
or	O
ecstasy	B-Chemical
,	O
because	O
recent	O
and	O
less	O
recent	O
users	O
of	O
these	O
drugs	O
within	O
this	O
group	O
were	O
similarly	O
impaired	O
.	O

Possible	O
parallels	O
between	O
RC	O
users	O
and	O
psychopaths	B-Disease
with	O
respect	O
to	O
impaired	B-Disease
fear	I-Disease
recognition	I-Disease
,	O
amygdala	B-Disease
dysfunction	I-Disease
,	O
and	O
etiology	O
are	O
discussed	O
.	O

Damage	B-Disease
of	I-Disease
substantia	I-Disease
nigra	I-Disease
pars	I-Disease
reticulata	I-Disease
during	O
pilocarpine	B-Chemical
-	O
induced	O
status	B-Disease
epilepticus	I-Disease
in	O
the	O
rat	O
:	O
immunohistochemical	O
study	O
of	O
neurons	O
,	O
astrocytes	O
and	O
serum	O
-	O
protein	O
extravasation	O
.	O

The	O
substantia	O
nigra	O
has	O
a	O
gating	O
function	O
controlling	O
the	O
spread	O
of	O
epileptic	B-Disease
seizure	I-Disease
activity	O
.	O

Additionally	O
,	O
in	O
models	O
of	O
prolonged	B-Disease
status	I-Disease
epilepticus	I-Disease
the	O
pars	O
reticulata	O
of	O
substantia	O
nigra	O
(	O
SNR	O
)	O
suffers	O
from	O
a	O
massive	O
lesion	O
which	O
may	O
arise	O
from	O
a	O
massive	O
metabolic	B-Disease
derangement	I-Disease
and	O
hyperexcitation	O
developing	O
in	O
the	O
activated	O
SNR	O
.	O

In	O
this	O
study	O
,	O
status	B-Disease
epilepticus	I-Disease
was	O
induced	O
by	O
systemic	O
injection	O
of	O
pilocarpine	B-Chemical
in	O
rats	O
.	O

The	O
neuropathology	O
of	O
SNR	O
was	O
investigated	O
using	O
immunohistochemical	O
techniques	O
with	O
the	O
major	O
emphasis	O
on	O
the	O
time	O
-	O
course	O
of	O
changes	O
in	O
neurons	O
and	O
astrocytes	O
.	O

Animals	O
surviving	O
20	O
,	O
30	O
,	O
40	O
,	O
60	O
min	O
,	O
2	O
,	O
3	O
,	O
6	O
hours	O
,	O
1	O
,	O
2	O
,	O
and	O
3	O
days	O
after	O
induction	O
of	O
status	B-Disease
epilepticus	I-Disease
were	O
perfusion	O
-	O
fixed	O
,	O
and	O
brains	O
processed	O
for	O
immunohistochemical	O
staining	O
of	O
SNR	O
.	O

Nissl	O
-	O
staining	O
and	O
antibodies	O
against	O
the	O
neuron	O
-	O
specific	O
calcium	B-Chemical
-	O
binding	O
protein	O
,	O
parvalbumin	O
,	O
served	O
to	O
detect	O
neuronal	B-Disease
damage	I-Disease
in	O
SNR	O
.	O

Antibodies	O
against	O
the	O
astroglia	O
-	O
specific	O
cytoskeletal	O
protein	O
,	O
glial	O
fibrillary	O
acidic	O
protein	O
(	O
GFAP	O
)	O
,	O
and	O
against	O
the	O
glial	O
calcium	B-Chemical
-	O
binding	O
protein	O
,	O
S	O
-	O
100	O
protein	O
,	O
were	O
used	O
to	O
assess	O
the	O
status	O
of	O
astrocytes	O
.	O

Immunohistochemical	O
staining	O
for	O
serum	O
-	O
albumin	O
and	O
immunoglobulins	O
in	O
brain	O
tissue	O
was	O
taken	O
as	O
indicator	O
of	O
blood	O
-	O
brain	O
barrier	O
disturbances	O
and	O
vasogenic	B-Disease
edema	I-Disease
formation	O
.	O

Immunohistochemical	O
staining	O
indicated	O
loss	O
of	O
GFAP	O
-	O
staining	O
already	O
at	O
30	O
min	O
after	O
induction	O
of	O
seizures	B-Disease
in	O
an	O
oval	O
focus	O
situated	O
in	O
the	O
center	O
of	O
SNR	O
while	O
sparing	O
medial	O
and	O
lateral	O
aspects	O
.	O

At	O
1	O
h	O
there	O
was	O
additional	O
vacuolation	O
in	O
S	O
-	O
100	O
protein	O
staining	O
.	O

By	O
2	O
hours	O
,	O
parvalbumin	O
-	O
staining	O
changed	O
in	O
the	O
central	O
SNR	O
indicating	O
neuronal	B-Disease
damage	I-Disease
,	O
and	O
Nissl	O
-	O
staining	O
visualized	O
some	O
neuronal	O
distortion	O
.	O

Staining	O
for	O
serum	O
-	O
proteins	O
occurred	O
in	O
a	O
patchy	O
manner	O
throughout	O
the	O
forebrain	O
during	O
the	O
first	O
hours	O
.	O

By	O
6	O
h	O
,	O
vasogenic	B-Disease
edema	I-Disease
covered	O
the	O
lesioned	B-Disease
SNR	I-Disease
.	O

By	O
24	O
h	O
,	O
glial	O
and	O
neuronal	O
markers	O
indicated	O
a	O
massive	O
lesion	O
in	O
the	O
center	O
of	O
SNR	O
.	O

By	O
48	O
-	O
72	O
h	O
,	O
astrocytes	O
surrounding	O
the	O
lesion	O
increased	O
in	O
size	O
,	O
and	O
polymorphic	O
phagocytotic	O
cells	O
invaded	O
the	O
damaged	O
area	O
.	O

In	O
a	O
further	O
group	O
of	O
animals	O
surviving	O
1	O
to	O
5	O
days	O
,	O
conventional	O
paraffin	O
-	O
sections	O
confirmed	O
the	O
neuronal	O
and	O
glial	O
damage	B-Disease
of	I-Disease
SNR	I-Disease
.	O

Additional	O
pathology	O
of	O
similar	O
quality	O
was	O
found	O
in	O
the	O
globus	O
pallidus	O
.	O

Since	O
astrocytes	O
were	O
always	O
damaged	O
in	O
parallel	O
with	O
neurons	O
in	O
SNR	O
it	O
is	O
proposed	O
that	O
the	O
anatomical	O
and	O
functional	O
interrelationship	O
between	O
neurons	O
and	O
astrocytes	O
is	O
particularly	O
tight	O
in	O
SNR	O
.	O

Both	O
cell	O
elements	O
may	O
suffer	O
in	O
common	O
from	O
metabolic	O
disturbance	O
and	O
neurotransmitter	B-Disease
dysfunction	I-Disease
as	O
occur	O
during	O
massive	O
status	B-Disease
epilepticus	I-Disease
.	O

Neuroprotective	O
effects	O
of	O
melatonin	B-Chemical
upon	O
the	O
offspring	O
cerebellar	O
cortex	O
in	O
the	O
rat	O
model	O
of	O
BCNU	B-Chemical
-	O
induced	O
cortical	B-Disease
dysplasia	I-Disease
.	O

Cortical	B-Disease
dysplasia	I-Disease
is	O
a	O
malformation	O
characterized	O
by	O
defects	O
in	O
proliferation	O
,	O
migration	O
and	O
maturation	O
.	O

This	O
study	O
was	O
designed	O
to	O
evaluate	O
the	O
alterations	O
in	O
offspring	O
rat	O
cerebellum	O
induced	O
by	O
maternal	O
exposure	O
to	O
carmustine	B-Chemical
-	O
[	O
1	B-Chemical
,	I-Chemical
3	I-Chemical
-	I-Chemical
bis	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
chloroethyl	I-Chemical
)	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
nitrosoure	I-Chemical
]	O
(	O
BCNU	B-Chemical
)	O
and	O
to	O
investigate	O
the	O
effects	O
of	O
exogenous	O
melatonin	B-Chemical
upon	O
cerebellar	O
BCNU	B-Chemical
-	O
induced	O
cortical	B-Disease
dysplasia	I-Disease
,	O
using	O
histological	O
and	O
biochemical	O
analyses	O
.	O

Pregnant	O
Wistar	O
rats	O
were	O
assigned	O
to	O
five	O
groups	O
:	O
intact	O
-	O
control	O
,	O
saline	O
-	O
control	O
,	O
melatonin	B-Chemical
-	O
treated	O
,	O
BCNU	B-Chemical
-	O
exposed	O
and	O
BCNU	B-Chemical
-	O
exposed	O
plus	O
melatonin	B-Chemical
.	O

Rats	O
were	O
exposed	O
to	O
BCNU	B-Chemical
on	O
embryonic	O
day	O
15	O
and	O
melatonin	B-Chemical
was	O
given	O
until	O
delivery	O
.	O

Immuno	O
/	O
histochemistry	O
and	O
electron	O
microscopy	O
were	O
carried	O
out	O
on	O
the	O
offspring	O
cerebellum	O
,	O
and	O
levels	O
of	O
malondialdehyde	B-Chemical
and	O
superoxide	B-Chemical
dismutase	O
were	O
determined	O
.	O

Histopathologically	O
,	O
typical	O
findings	O
were	O
observed	O
in	O
the	O
cerebella	O
from	O
the	O
control	O
groups	O
,	O
but	O
the	O
findings	O
consistent	O
with	O
early	O
embryonic	O
development	O
were	O
noted	O
in	O
BCNU	B-Chemical
-	O
exposed	O
cortical	B-Disease
dysplasia	I-Disease
group	O
.	O

There	O
was	O
a	O
marked	O
increase	O
in	O
the	O
number	O
of	O
TUNEL	O
positive	O
cells	O
and	O
nestin	O
positive	O
cells	O
in	O
BCNU	B-Chemical
-	O
exposed	O
group	O
,	O
but	O
a	O
decreased	O
immunoreactivity	O
to	O
glial	O
fibrillary	O
acidic	O
protein	O
,	O
synaptophysin	O
and	O
transforming	O
growth	O
factor	O
beta1	O
was	O
observed	O
,	O
indicating	O
a	O
delayed	O
maturation	O
,	O
and	O
melatonin	B-Chemical
significantly	O
reversed	O
these	O
changes	O
.	O

Malondialdehyde	B-Chemical
level	O
in	O
BCNU	B-Chemical
-	O
exposed	O
group	O
was	O
higher	O
than	O
those	O
in	O
control	O
groups	O
and	O
melatonin	B-Chemical
decreased	O
malondialdehyde	B-Chemical
levels	O
in	O
BCNU	B-Chemical
group	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
,	O
while	O
there	O
were	O
no	O
significant	O
differences	O
in	O
the	O
superoxide	B-Chemical
dismutase	O
levels	O
between	O
these	O
groups	O
.	O

These	O
data	O
suggest	O
that	O
exposure	O
of	O
animals	O
to	O
BCNU	B-Chemical
during	O
pregnancy	O
leads	O
to	O
delayed	O
maturation	O
of	O
offspring	O
cerebellum	O
and	O
melatonin	B-Chemical
protects	O
the	O
cerebellum	O
against	O
the	O
effects	O
of	O
BCNU	B-Chemical
.	O

Reduced	O
cardiotoxicity	B-Disease
of	O
doxorubicin	B-Chemical
given	O
in	O
the	O
form	O
of	O
N	B-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
hydroxypropyl	I-Chemical
)	I-Chemical
methacrylamide	I-Chemical
conjugates	O
:	O
and	O
experimental	O
study	O
in	O
the	O
rat	O
.	O

A	O
rat	O
model	O
was	O
used	O
to	O
evaluate	O
the	O
general	O
acute	O
toxicity	B-Disease
and	O
the	O
late	O
cardiotoxicity	B-Disease
of	O
4	O
mg	O
/	O
kg	O
doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
given	O
either	O
as	O
free	O
drug	O
or	O
in	O
the	O
form	O
of	O
three	O
N	B-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
hydroxypropyl	I-Chemical
)	I-Chemical
methacrylamide	I-Chemical
(	O
HPMA	B-Chemical
)	O
copolymer	O
conjugates	O
.	O

In	O
these	O
HPMA	B-Chemical
copolymers	O
,	O
DOX	B-Chemical
was	O
covalently	O
bound	O
via	O
peptide	O
linkages	O
that	O
were	O
either	O
non	O
-	O
biodegradable	O
(	O
Gly	O
-	O
Gly	O
)	O
or	O
degradable	O
by	O
lysosomal	O
proteinases	O
(	O
Gly	B-Chemical
-	I-Chemical
Phe	I-Chemical
-	I-Chemical
Leu	I-Chemical
-	I-Chemical
Gly	I-Chemical
)	O
.	O

In	O
addition	O
,	O
one	O
biodegradable	O
conjugate	O
containing	O
galactosamine	B-Chemical
was	O
used	O
;	O
this	O
residue	O
was	O
targeted	O
to	O
the	O
liver	O
.	O

Over	O
the	O
first	O
3	O
weeks	O
after	O
the	O
i	O
.	O
v	O
.	O
administration	O
of	O
free	O
and	O
polymer	O
-	O
bound	O
DOX	B-Chemical
,	O
all	O
animals	O
showed	O
a	O
transient	O
reduction	O
in	O
body	O
weight	O
.	O

However	O
,	O
the	O
maximal	O
reduction	O
in	O
body	O
weight	O
seen	O
in	O
animals	O
that	O
received	O
polymer	O
-	O
bound	O
DOX	B-Chemical
(	O
4	O
mg	O
/	O
kg	O
)	O
was	O
significantly	O
lower	O
than	O
that	O
observed	O
in	O
those	O
that	O
received	O
free	O
DOX	B-Chemical
(	O
4	O
mg	O
/	O
kg	O
)	O
or	O
a	O
mixture	O
of	O
the	O
unmodified	O
parent	O
HPMA	B-Chemical
copolymer	O
and	O
free	O
DOX	B-Chemical
(	O
4	O
mg	O
/	O
kg	O
;	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Throughout	O
the	O
study	O
(	O
20	O
weeks	O
)	O
,	O
deaths	O
related	O
to	O
cardiotoxicity	B-Disease
were	O
observed	O
only	O
in	O
animals	O
that	O
received	O
either	O
free	O
DOX	B-Chemical
or	O
the	O
mixture	O
of	O
HPMA	B-Chemical
copolymer	O
and	O
free	O
DOX	B-Chemical
;	O
in	O
these	O
cases	O
,	O
histological	O
investigations	O
revealed	O
marked	O
changes	O
in	O
the	O
heart	O
that	O
were	O
consistent	O
with	O
DOX	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

Sequential	O
measurements	O
of	O
cardiac	O
output	O
in	O
surviving	O
animals	O
that	O
received	O
either	O
free	O
DOX	B-Chemical
or	O
the	O
mixture	O
of	O
HPMA	B-Chemical
copolymer	O
and	O
free	O
DOX	B-Chemical
showed	O
a	O
reduction	O
of	O
approximately	O
30	O
%	O
in	O
function	O
beginning	O
at	O
the	O
4th	O
week	O
after	O
drug	O
administration	O
.	O

The	O
heart	O
rate	O
in	O
these	O
animals	O
was	O
approximately	O
12	O
%	O
lower	O
than	O
that	O
measured	O
in	O
age	O
-	O
matched	O
control	O
rats	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Animals	O
that	O
were	O
given	O
the	O
HPMA	B-Chemical
copolymer	O
conjugates	O
containing	O
DOX	B-Chemical
exhibited	O
no	O
significant	O
change	O
in	O
cardiac	O
output	O
throughout	O
the	O
study	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

In	O
addition	O
,	O
no	O
significant	O
histological	O
change	O
was	O
observed	O
in	O
the	O
heart	O
of	O
animals	O
that	O
received	O
DOX	B-Chemical
in	O
the	O
form	O
of	O
HPMA	B-Chemical
copolymer	O
conjugates	O
and	O
were	O
killed	O
at	O
the	O
end	O
of	O
the	O
study	O
.	O

However	O
,	O
these	O
animals	O
had	O
shown	O
a	O
significant	O
increase	O
in	O
heart	O
rate	O
beginning	O
at	O
8	O
weeks	O
after	O
drug	O
administration	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Corneal	B-Disease
ulcers	I-Disease
associated	O
with	O
aerosolized	O
crack	B-Chemical
cocaine	I-Chemical
use	O
.	O

PURPOSE	O
:	O
We	O
report	O
4	O
cases	O
of	O
corneal	B-Disease
ulcers	I-Disease
associated	O
with	O
drug	B-Disease
abuse	I-Disease
.	O

The	O
pathogenesis	O
of	O
these	O
ulcers	B-Disease
and	O
management	O
of	O
these	O
patients	O
are	O
also	O
reviewed	O
.	O

METHODS	O
:	O
Review	O
of	O
all	O
cases	O
of	O
corneal	B-Disease
ulcers	I-Disease
associated	O
with	O
drug	B-Disease
abuse	I-Disease
seen	O
at	O
our	O
institution	O
from	O
July	O
2006	O
to	O
December	O
2006	O
.	O

RESULTS	O
:	O
Four	O
patients	O
with	O
corneal	B-Disease
ulcers	I-Disease
associated	O
with	O
crack	B-Chemical
cocaine	I-Chemical
use	O
were	O
reviewed	O
.	O

All	O
corneal	B-Disease
ulcers	I-Disease
were	O
cultured	O
,	O
and	O
the	O
patients	O
were	O
admitted	O
to	O
the	O
hospital	O
for	O
intensive	O
topical	O
antibiotic	O
treatment	O
.	O

Each	O
patient	O
received	O
comprehensive	O
health	O
care	O
,	O
including	O
medical	O
and	O
substance	B-Disease
abuse	I-Disease
consultations	O
.	O

Streptococcal	O
organisms	O
were	O
found	O
in	O
3	O
cases	O
and	O
Capnocytophaga	O
and	O
Brevibacterium	O
casei	O
in	O
1	O
patient	O
.	O

The	O
infections	B-Disease
responded	O
to	O
antibiotic	O
treatment	O
.	O

Two	O
patients	O
needed	O
a	O
lateral	O
tarsorrhaphy	O
for	O
persistent	O
epithelial	B-Disease
defects	I-Disease
.	O

CONCLUSIONS	O
:	O
Aerosolized	O
crack	B-Chemical
cocaine	I-Chemical
use	O
can	O
be	O
associated	O
with	O
the	O
development	O
of	O
corneal	B-Disease
ulcers	I-Disease
.	O

Drug	B-Disease
abuse	I-Disease
provides	O
additional	O
challenges	O
for	O
management	O
.	O

Not	O
only	O
treatment	O
of	O
their	O
infections	B-Disease
but	O
also	O
the	O
overall	O
poor	O
health	O
of	O
the	O
patients	O
and	O
increased	O
risk	O
of	O
noncompliance	O
need	O
to	O
be	O
addressed	O
.	O

Comprehensive	O
care	O
may	O
provide	O
the	O
patient	O
the	O
opportunity	O
to	O
discontinue	O
their	O
substance	B-Disease
abuse	I-Disease
,	O
improve	O
their	O
overall	O
health	O
,	O
and	O
prevent	O
future	O
corneal	O
complications	O
.	O

Topical	O
0	O
.	O
025	O
%	O
capsaicin	B-Chemical
in	O
chronic	O
post	B-Disease
-	I-Disease
herpetic	I-Disease
neuralgia	I-Disease
:	O
efficacy	O
,	O
predictors	O
of	O
response	O
and	O
long	O
-	O
term	O
course	O
.	O

In	O
order	O
to	O
evaluate	O
the	O
efficacy	O
,	O
time	O
-	O
course	O
of	O
action	O
and	O
predictors	O
of	O
response	O
to	O
topical	O
capsaicin	B-Chemical
,	O
39	O
patients	O
with	O
chronic	O
post	B-Disease
-	I-Disease
herpetic	I-Disease
neuralgia	I-Disease
(	O
PHN	B-Disease
)	O
,	O
median	O
duration	O
24	O
months	O
,	O
were	O
treated	O
with	O
0	O
.	O
025	O
%	O
capsaicin	B-Chemical
cream	O
for	O
8	O
weeks	O
.	O

During	O
therapy	O
the	O
patients	O
rated	O
their	O
pain	B-Disease
on	O
a	O
visual	O
analogue	O
scale	O
(	O
VAS	O
)	O
and	O
a	O
verbal	O
outcome	O
scale	O
.	O

A	O
follow	O
-	O
up	O
investigation	O
was	O
performed	O
10	O
-	O
12	O
months	O
after	O
study	O
onset	O
on	O
the	O
patients	O
who	O
had	O
improved	O
.	O

Nineteen	O
patients	O
(	O
48	O
.	O
7	O
%	O
)	O
substantially	O
improved	O
after	O
the	O
8	O
-	O
week	O
trial	O
;	O
5	O
(	O
12	O
.	O
8	O
%	O
)	O
discontinued	O
therapy	O
due	O
to	O
side	O
-	O
effects	O
such	O
as	O
intolerable	O
capsaicin	B-Chemical
-	O
induced	O
burning	O
sensations	O
(	O
4	O
)	O
or	O
mastitis	B-Disease
(	O
1	O
)	O
;	O
15	O
(	O
38	O
.	O
5	O
%	O
)	O
reported	O
no	O
benefit	O
.	O

The	O
decrease	O
in	O
VAS	O
ratings	O
was	O
significant	O
after	O
2	O
weeks	O
of	O
continuous	O
application	O
.	O

Of	O
the	O
responders	O
72	O
.	O
2	O
%	O
were	O
still	O
improved	O
at	O
the	O
follow	O
-	O
up	O
;	O
only	O
one	O
-	O
third	O
of	O
them	O
had	O
continued	O
application	O
irregularly	O
.	O

Treatment	O
effect	O
was	O
not	O
dependent	O
on	O
patient	O
'	O
s	O
age	O
,	O
duration	O
or	O
localization	O
of	O
PHN	B-Disease
(	O
trigeminal	O
involvement	O
was	O
excluded	O
)	O
,	O
sensory	B-Disease
disturbance	I-Disease
or	O
pain	B-Disease
character	O
.	O

Treatment	O
response	O
was	O
not	O
correlated	O
with	O
the	O
incidence	O
,	O
time	O
-	O
course	O
or	O
severity	O
of	O
capsaicin	B-Chemical
-	O
induced	O
burning	O
.	O

If	O
confirmed	O
in	O
controlled	O
trials	O
,	O
the	O
long	O
-	O
term	O
results	O
of	O
this	O
open	O
,	O
non	O
-	O
randomized	O
study	O
might	O
indicate	O
that	O
the	O
analgesic	O
effect	O
of	O
capsaicin	B-Chemical
in	O
PHN	B-Disease
is	O
mediated	O
by	O
both	O
interference	O
with	O
neuropeptide	O
metabolism	O
and	O
morphological	O
changes	O
(	O
perhaps	O
degeneration	O
)	O
of	O
nociceptive	O
afferents	O
.	O

Myo	B-Chemical
-	I-Chemical
inositol	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
phosphate	I-Chemical
(	O
MIP	B-Chemical
)	O
synthase	O
inhibition	O
:	O
in	O
-	O
vivo	O
study	O
in	O
rats	O
.	O

Lithium	B-Chemical
and	O
valproate	B-Chemical
are	O
the	O
prototypic	O
mood	O
stabilizers	O
and	O
have	O
diverse	O
structures	O
and	O
targets	O
.	O

Both	O
drugs	O
influence	O
inositol	B-Chemical
metabolism	O
.	O

Lithium	B-Chemical
inhibits	O
IMPase	O
and	O
valproate	B-Chemical
inhibits	O
MIP	B-Chemical
synthase	O
.	O

This	O
study	O
shows	O
that	O
MIP	B-Chemical
synthase	O
inhibition	O
does	O
not	O
replicate	O
or	O
augment	O
the	O
effects	O
of	O
lithium	B-Chemical
in	O
the	O
inositol	B-Chemical
sensitive	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
model	O
.	O

This	O
lack	O
of	O
effects	O
may	O
stem	O
from	O
the	O
low	O
contribution	O
of	O
de	O
-	O
novo	O
synthesis	O
to	O
cellular	O
inositol	B-Chemical
supply	O
or	O
to	O
the	O
inhibition	O
of	O
the	O
de	O
-	O
novo	O
synthesis	O
by	O
lithium	B-Chemical
itself	O
.	O

Non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
-	O
associated	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
with	O
granular	O
tubular	O
basement	O
membrane	O
deposits	O
.	O

Acute	B-Disease
tubulo	I-Disease
-	I-Disease
interstitial	I-Disease
nephritis	I-Disease
(	O
ATIN	B-Disease
)	O
is	O
an	O
important	O
cause	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
resulting	O
from	O
a	O
variety	O
of	O
insults	O
,	O
including	O
immune	O
complex	O
-	O
mediated	O
tubulo	B-Disease
-	I-Disease
interstitial	I-Disease
injury	I-Disease
,	O
but	O
drugs	O
such	O
as	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
(	O
NSAIDs	O
)	O
are	O
a	O
far	O
more	O
frequent	O
cause	O
.	O

Overall	O
,	O
as	O
an	O
entity	O
,	O
ATIN	B-Disease
remains	O
under	O
-	O
diagnosed	O
,	O
as	O
symptoms	O
resolve	O
spontaneously	O
if	O
the	O
medication	O
is	O
stopped	O
.	O

We	O
report	O
on	O
a	O
14	O
-	O
year	O
-	O
old	O
boy	O
who	O
developed	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
2	O
weeks	O
after	O
aortic	O
valve	O
surgery	O
.	O

He	O
was	O
put	O
on	O
aspirin	B-Chemical
following	O
surgery	O
and	O
took	O
ibuprofen	B-Chemical
for	O
fever	B-Disease
for	O
nearly	O
a	O
week	O
prior	O
to	O
presentation	O
.	O

He	O
then	O
presented	O
to	O
the	O
emergency	O
department	O
feeling	O
quite	O
ill	O
and	O
was	O
found	O
to	O
have	O
a	O
blood	B-Chemical
urea	I-Chemical
nitrogen	I-Chemical
(	O
BUN	B-Chemical
)	O
concentration	O
of	O
of	O
147	O
mg	O
/	O
dl	O
,	O
creatinine	B-Chemical
of	O
15	O
.	O
3	O
mg	O
/	O
dl	O
and	O
serum	O
potassium	B-Chemical
of	O
8	O
.	O
7	O
mEq	O
/	O
l	O
.	O

Dialysis	O
was	O
immediately	O
initiated	O
.	O

A	O
kidney	O
biopsy	O
showed	O
inflammatory	O
infiltrate	O
consistent	O
with	O
ATIN	B-Disease
.	O

However	O
,	O
in	O
the	O
tubular	O
basement	O
membrane	O
(	O
TBM	O
)	O
,	O
very	O
intense	O
granular	O
deposits	O
of	O
polyclonal	O
IgG	O
and	O
C3	O
were	O
noted	O
.	O

He	O
needed	O
dialysis	O
for	O
2	O
weeks	O
and	O
was	O
treated	O
successfully	O
with	O
steroids	B-Chemical
for	O
6	O
months	O
.	O

His	O
renal	O
recovery	O
and	O
disappearance	O
of	O
proteinuria	B-Disease
took	O
a	O
year	O
.	O

In	O
conclusion	O
,	O
this	O
is	O
a	O
first	O
report	O
of	O
NSAIDs	O
-	O
associated	O
ATIN	B-Disease
,	O
showing	O
deposits	O
of	O
granular	O
immune	O
complex	O
present	O
only	O
in	O
the	O
TBM	O
and	O
not	O
in	O
the	O
glomeruli	O
.	O

Rifampicin	B-Chemical
-	O
associated	O
segmental	O
necrotizing	O
glomerulonephritis	B-Disease
in	O
staphylococcal	B-Disease
endocarditis	I-Disease
.	O

Segmental	O
necrotising	O
glomerulonephritis	B-Disease
has	O
been	O
reported	O
as	O
complication	O
of	O
rifampicin	B-Chemical
therapy	O
in	O
patients	O
receiving	O
treatment	O
for	O
tuberculosis	B-Disease
.	O

Changing	O
epidemiology	O
of	O
infections	B-Disease
such	O
as	O
infective	B-Disease
endocarditis	I-Disease
(	O
IE	B-Disease
)	O
has	O
led	O
to	O
an	O
increase	O
in	O
the	O
use	O
of	O
rifampicin	B-Chemical
for	O
Staphylococcal	B-Disease
infections	I-Disease
.	O

We	O
describe	O
a	O
case	O
of	O
a	O
patient	O
with	O
Staphylococcal	B-Disease
IE	I-Disease
who	O
developed	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
secondary	O
to	O
a	O
segmental	O
necrotising	O
glomerulonephritis	B-Disease
while	O
being	O
treated	O
with	O
rifampicin	B-Chemical
,	O
and	O
review	O
the	O
literature	O
regarding	O
this	O
complication	O
of	O
rifampicin	B-Chemical
therapy	O
.	O

Rate	O
of	O
YMDD	O
motif	O
mutants	O
in	O
lamivudine	B-Chemical
-	O
untreated	O
Iranian	O
patients	O
with	O
chronic	B-Disease
hepatitis	I-Disease
B	I-Disease
virus	I-Disease
infection	I-Disease
.	O

BACKGROUND	O
:	O
Lamivudine	B-Chemical
is	O
used	O
for	O
the	O
treatment	O
of	O
chronic	B-Disease
hepatitis	I-Disease
B	I-Disease
patients	O
.	O

Recent	O
studies	O
show	O
that	O
the	O
YMDD	O
motif	O
mutants	O
(	O
resistant	O
hepatitis	B-Disease
B	I-Disease
virus	O
)	O
occur	O
as	O
natural	O
genome	O
variability	O
in	O
lamivudine	B-Chemical
-	O
untreated	O
chronic	B-Disease
hepatitis	I-Disease
B	I-Disease
patients	O
.	O

In	O
this	O
study	O
we	O
aimed	O
to	O
determine	O
the	O
rate	O
of	O
YMDD	O
motif	O
mutants	O
in	O
lamivudine	B-Chemical
-	O
untreated	O
chronic	B-Disease
hepatitis	I-Disease
B	I-Disease
patients	O
in	O
Iran	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
A	O
total	O
of	O
77	O
chronic	B-Disease
hepatitis	I-Disease
B	I-Disease
patients	O
who	O
had	O
not	O
been	O
treated	O
with	O
lamivudine	B-Chemical
were	O
included	O
in	O
the	O
study	O
.	O

Serum	O
samples	O
from	O
patients	O
were	O
tested	O
by	O
polymerase	O
chain	O
reaction	O
-	O
restriction	O
fragment	O
length	O
polymorphism	O
(	O
PCR	O
-	O
RFLP	O
)	O
for	O
detection	O
of	O
YMDD	O
motif	O
mutants	O
.	O

All	O
patients	O
were	O
also	O
tested	O
for	O
liver	O
enzymes	O
,	O
anti	O
-	O
HCV	O
,	O
HBeAg	B-Chemical
,	O
and	O
anti	O
-	O
HBe	O
.	O

RESULTS	O
:	O
Of	O
the	O
77	O
patients	O
enrolled	O
in	O
the	O
study	O
,	O
73	O
%	O
were	O
male	O
and	O
27	O
%	O
were	O
female	O
.	O

Mean	O
ALT	O
and	O
AST	O
levels	O
were	O
124	O
.	O
4	O
+	O
/	O
-	O
73	O
.	O
4	O
and	O
103	O
.	O
1	O
+	O
/	O
-	O
81	O
IU	O
/	O
l	O
,	O
respectively	O
.	O

HBeAg	B-Chemical
was	O
positive	O
in	O
40	O
%	O
and	O
anti	O
-	O
HBe	O
in	O
60	O
%	O
of	O
the	O
patients	O
.	O

Anti	O
-	O
HCV	O
was	O
negative	O
in	O
all	O
of	O
them	O
.	O

YMDD	O
motif	O
mutants	O
were	O
not	O
detected	O
in	O
any	O
of	O
the	O
patients	O
despite	O
the	O
liver	O
enzyme	O
levels	O
and	O
the	O
presence	O
of	O
HBeAg	B-Chemical
or	O
anti	O
-	O
HBe	O
.	O

CONCLUSION	O
:	O
Although	O
the	O
natural	O
occurrence	O
of	O
YMDD	O
motif	O
mutants	O
in	O
lamivudine	B-Chemical
-	O
untreated	O
patients	O
with	O
chronic	B-Disease
hepatitis	I-Disease
B	I-Disease
has	O
been	O
reported	O
,	O
these	O
mutants	O
were	O
not	O
detected	O
in	O
Iranian	O
lamivudine	B-Chemical
-	O
untreated	O
chronic	B-Disease
hepatitis	I-Disease
B	I-Disease
patients	O
.	O

Branch	O
retinal	B-Disease
vein	I-Disease
occlusion	I-Disease
and	O
fluoxetine	B-Chemical
.	O

A	O
case	O
of	O
branch	O
retinal	B-Disease
vein	I-Disease
occlusion	I-Disease
associated	O
with	O
fluoxetine	B-Chemical
-	O
induced	O
secondary	O
hypertension	B-Disease
is	O
described	O
.	O

Although	O
an	O
infrequent	O
complication	O
of	O
selective	O
serotonin	B-Chemical
reuptake	O
inhibitor	O
therapy	O
,	O
it	O
is	O
important	O
that	O
ophthalmologists	O
are	O
aware	O
that	O
these	O
agents	O
can	O
cause	O
hypertension	B-Disease
because	O
this	O
class	O
of	O
drugs	O
is	O
widely	O
prescribed	O
.	O

The	O
differential	O
effects	O
of	O
bupivacaine	B-Chemical
and	O
lidocaine	B-Chemical
on	O
prostaglandin	B-Chemical
E2	I-Chemical
release	O
,	O
cyclooxygenase	O
gene	O
expression	O
and	O
pain	B-Disease
in	O
a	O
clinical	O
pain	B-Disease
model	O
.	O

BACKGROUND	O
:	O
In	O
addition	O
to	O
blocking	O
nociceptive	O
input	O
from	O
surgical	O
sites	O
,	O
long	O
-	O
acting	O
local	O
anesthetics	O
might	O
directly	O
modulate	O
inflammation	B-Disease
.	O

In	O
the	O
present	O
study	O
,	O
we	O
describe	O
the	O
proinflammatory	O
effects	O
of	O
bupivacaine	B-Chemical
on	O
local	O
prostaglandin	B-Chemical
E2	I-Chemical
(	O
PGE2	B-Chemical
)	O
production	O
and	O
cyclooxygenase	O
(	O
COX	O
)	O
gene	O
expression	O
that	O
increases	O
postoperative	B-Disease
pain	I-Disease
in	O
human	O
subjects	O
.	O

METHODS	O
:	O
Subjects	O
(	O
n	O
=	O
114	O
)	O
undergoing	O
extraction	O
of	O
impacted	O
third	O
molars	O
received	O
either	O
2	O
%	O
lidocaine	B-Chemical
or	O
0	O
.	O
5	O
%	O
bupivacaine	B-Chemical
before	O
surgery	O
and	O
either	O
rofecoxib	B-Chemical
50	O
mg	O
or	O
placebo	O
orally	O
90	O
min	O
before	O
surgery	O
and	O
for	O
the	O
following	O
48	O
h	O
.	O

Oral	O
mucosal	O
biopsies	O
were	O
taken	O
before	O
surgery	O
and	O
48	O
h	O
after	O
surgery	O
.	O

After	O
extraction	O
,	O
a	O
microdialysis	O
probe	O
was	O
placed	O
at	O
the	O
surgical	O
site	O
for	O
PGE2	B-Chemical
and	O
thromboxane	B-Chemical
B2	I-Chemical
(	O
TXB2	B-Chemical
)	O
measurements	O
.	O

RESULTS	O
:	O
The	O
bupivacaine	B-Chemical
/	O
rofecoxib	B-Chemical
group	O
reported	O
significantly	O
less	O
pain	B-Disease
,	O
as	O
assessed	O
by	O
a	O
visual	O
analog	O
scale	O
,	O
compared	O
with	O
the	O
other	O
three	O
treatment	O
groups	O
over	O
the	O
first	O
4	O
h	O
.	O

However	O
,	O
the	O
bupivacaine	B-Chemical
/	O
placebo	O
group	O
reported	O
significantly	O
more	O
pain	B-Disease
at	O
24	O
h	O
and	O
PGE2	B-Chemical
levels	O
during	O
the	O
first	O
4	O
h	O
were	O
significantly	O
higher	O
than	O
the	O
other	O
three	O
treatment	O
groups	O
.	O

Moreover	O
,	O
bupivacaine	B-Chemical
significantly	O
increased	O
COX	O
-	O
2	O
gene	O
expression	O
at	O
48	O
h	O
as	O
compared	O
with	O
the	O
lidocaine	B-Chemical
/	O
placebo	O
group	O
.	O

Thromboxane	B-Chemical
levels	O
were	O
not	O
significantly	O
affected	O
by	O
any	O
of	O
the	O
treatments	O
,	O
indicating	O
that	O
the	O
effects	O
seen	O
were	O
attributable	O
to	O
inhibition	O
of	O
COX	O
-	O
2	O
,	O
but	O
not	O
COX	O
-	O
1	O
.	O

CONCLUSIONS	O
:	O
These	O
results	O
suggest	O
that	O
bupivacaine	B-Chemical
stimulates	O
COX	O
-	O
2	O
gene	O
expression	O
after	O
tissue	B-Disease
injury	I-Disease
,	O
which	O
is	O
associated	O
with	O
higher	O
PGE2	B-Chemical
production	O
and	O
pain	B-Disease
after	O
the	O
local	O
anesthetic	O
effect	O
dissipates	O
.	O

p75NTR	O
expression	O
in	O
rat	O
urinary	O
bladder	O
sensory	O
neurons	O
and	O
spinal	O
cord	O
with	O
cyclophosphamide	B-Chemical
-	O
induced	O
cystitis	B-Disease
.	O

A	O
role	O
for	O
nerve	O
growth	O
factor	O
(	O
NGF	O
)	O
in	O
contributing	O
to	O
increased	O
voiding	O
frequency	O
and	O
altered	O
sensation	O
from	O
the	O
urinary	O
bladder	O
has	O
been	O
suggested	O
.	O

Previous	O
studies	O
have	O
examined	O
the	O
expression	O
and	O
regulation	O
of	O
tyrosine	B-Chemical
kinase	O
receptors	O
(	O
Trks	O
)	O
in	O
micturition	O
reflexes	O
with	O
urinary	B-Disease
bladder	I-Disease
inflammation	I-Disease
.	O

The	O
present	O
studies	O
examine	O
the	O
expression	O
and	O
regulation	O
of	O
another	O
receptor	O
known	O
to	O
bind	O
NGF	O
,	O
p75	O
(	O
NTR	O
)	O
,	O
after	O
various	O
durations	O
of	O
bladder	B-Disease
inflammation	I-Disease
induced	O
by	O
cyclophosphamide	B-Chemical
(	O
CYP	B-Chemical
)	O
.	O

CYP	B-Chemical
-	O
induced	O
cystitis	B-Disease
increased	O
(	O
P	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
p75	O
(	O
NTR	O
)	O
expression	O
in	O
the	O
superficial	O
lateral	O
and	O
medial	O
dorsal	O
horn	O
in	O
L1	O
-	O
L2	O
and	O
L6	O
-	O
S1	O
spinal	O
segments	O
.	O

The	O
number	O
of	O
p75	O
(	O
NTR	O
)	O
-	O
immunoreactive	O
(	O
-	O
IR	O
)	O
cells	O
in	O
the	O
lumbosacral	O
dorsal	O
root	O
ganglia	O
(	O
DRG	O
)	O
also	O
increased	O
(	O
P	O
<	O
or	O
=	O
0	O
.	O
05	O
)	O
with	O
CYP	B-Chemical
-	O
induced	O
cystitis	B-Disease
(	O
acute	O
,	O
intermediate	O
,	O
and	O
chronic	O
)	O
.	O

Quantitative	O
,	O
real	O
-	O
time	O
polymerase	O
chain	O
reaction	O
also	O
demonstrated	O
significant	O
increases	O
(	O
P	O
<	O
or	O
=	O
0	O
.	O
01	O
)	O
in	O
p75	O
(	O
NTR	O
)	O
mRNA	O
in	O
DRG	O
with	O
intermediate	O
and	O
chronic	O
CYP	B-Chemical
-	O
induced	O
cystitis	B-Disease
.	O

Retrograde	O
dye	O
-	O
tracing	O
techniques	O
with	O
Fastblue	O
were	O
used	O
to	O
identify	O
presumptive	O
bladder	O
afferent	O
cells	O
in	O
the	O
lumbosacral	O
DRG	O
.	O

In	O
bladder	O
afferent	O
cells	O
in	O
DRG	O
,	O
p75	O
(	O
NTR	O
)	O
-	O
IR	O
was	O
also	O
increased	O
(	O
P	O
<	O
or	O
=	O
0	O
.	O
01	O
)	O
with	O
cystitis	B-Disease
.	O

In	O
addition	O
to	O
increases	O
in	O
p75	O
(	O
NTR	O
)	O
-	O
IR	O
in	O
DRG	O
cell	O
bodies	O
,	O
increases	O
(	O
P	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
in	O
pericellular	O
(	O
encircling	O
DRG	O
cells	O
)	O
p75	O
(	O
NTR	O
)	O
-	O
IR	O
in	O
DRG	O
also	O
increased	O
.	O

Confocal	O
analyses	O
demonstrated	O
that	O
pericellular	O
p75	O
(	O
NTR	O
)	O
-	O
IR	O
was	O
not	O
colocalized	O
with	O
the	O
glial	O
marker	O
,	O
glial	O
fibrillary	O
acidic	O
protein	O
(	O
GFAP	O
)	O
.	O

These	O
studies	O
demonstrate	O
that	O
p75	O
(	O
NTR	O
)	O
expression	O
in	O
micturition	O
reflexes	O
is	O
present	O
constitutively	O
and	O
modified	O
by	O
bladder	B-Disease
inflammation	I-Disease
.	O

The	O
functional	O
significance	O
of	O
p75	O
(	O
NTR	O
)	O
expression	O
in	O
micturition	O
reflexes	O
remains	O
to	O
be	O
determined	O
.	O

Azathioprine	B-Chemical
-	O
induced	O
suicidal	O
erythrocyte	O
death	O
.	O

BACKGROUND	O
:	O
Azathioprine	B-Chemical
is	O
widely	O
used	O
as	O
an	O
immunosuppressive	O
drug	O
.	O

The	O
side	O
effects	O
of	O
azathioprine	B-Chemical
include	O
anemia	B-Disease
,	O
which	O
has	O
been	O
attributed	O
to	O
bone	O
marrow	O
suppression	O
.	O

Alternatively	O
,	O
anemia	B-Disease
could	O
result	O
from	O
accelerated	O
suicidal	O
erythrocyte	O
death	O
or	O
eryptosis	O
,	O
which	O
is	O
characterized	O
by	O
exposure	O
of	O
phosphatidylserine	B-Chemical
(	O
PS	B-Chemical
)	O
at	O
the	O
erythrocyte	O
surface	O
and	O
by	O
cell	O
shrinkage	O
.	O

METHODS	O
:	O
The	O
present	O
experiments	O
explored	O
whether	O
azathioprine	B-Chemical
influences	O
eryptosis	O
.	O

According	O
to	O
annexin	O
V	O
binding	O
,	O
erythrocytes	O
from	O
patients	O
indeed	O
showed	O
a	O
significant	O
increase	O
of	O
PS	B-Chemical
exposure	O
within	O
1	O
week	O
of	O
treatment	O
with	O
azathioprine	B-Chemical
.	O

In	O
a	O
second	O
series	O
,	O
cytosolic	O
Ca2	B-Chemical
+	O
activity	O
(	O
Fluo3	B-Chemical
fluorescence	O
)	O
,	O
cell	O
volume	O
(	O
forward	O
scatter	O
)	O
,	O
and	O
PS	B-Chemical
-	O
exposure	O
(	O
annexin	O
V	O
binding	O
)	O
were	O
determined	O
by	O
FACS	O
analysis	O
in	O
erythrocytes	O
from	O
healthy	O
volunteers	O
.	O

RESULTS	O
:	O
Exposure	O
to	O
azathioprine	B-Chemical
(	O
>	O
or	O
=	O
2	O
microg	O
/	O
mL	O
)	O
for	O
48	O
hours	O
increased	O
cytosolic	O
Ca2	B-Chemical
+	O
activity	O
and	O
annexin	O
V	O
binding	O
and	O
decreased	O
forward	O
scatter	O
.	O

The	O
effect	O
of	O
azathioprine	B-Chemical
on	O
both	O
annexin	O
V	O
binding	O
and	O
forward	O
scatter	O
was	O
significantly	O
blunted	O
in	O
the	O
nominal	O
absence	O
of	O
extracellular	O
Ca2	B-Chemical
+	O
.	O

CONCLUSIONS	O
:	O
Azathioprine	B-Chemical
triggers	O
suicidal	O
erythrocyte	O
death	O
,	O
an	O
effect	O
presumably	O
contributing	O
to	O
azathioprine	B-Chemical
-	O
induced	O
anemia	B-Disease
.	O

Levetiracetam	B-Chemical
as	O
an	O
adjunct	O
to	O
phenobarbital	B-Chemical
treatment	O
in	O
cats	O
with	O
suspected	O
idiopathic	B-Disease
epilepsy	I-Disease
.	O

OBJECTIVE	O
:	O
To	O
assess	O
pharmacokinetics	O
,	O
efficacy	O
,	O
and	O
tolerability	O
of	O
oral	O
levetiracetam	B-Chemical
administered	O
as	O
an	O
adjunct	O
to	O
phenobarbital	B-Chemical
treatment	O
in	O
cats	O
with	O
poorly	O
controlled	O
suspected	O
idiopathic	B-Disease
epilepsy	I-Disease
.	O

DESIGN	O
-	O
Open	O
-	O
label	O
,	O
noncomparative	O
clinical	O
trial	O
.	O

ANIMALS	O
:	O
12	O
cats	O
suspected	O
to	O
have	O
idiopathic	B-Disease
epilepsy	I-Disease
that	O
was	O
poorly	O
controlled	O
with	O
phenobarbital	B-Chemical
or	O
that	O
had	O
unacceptable	O
adverse	O
effects	O
when	O
treated	O
with	O
phenobarbital	B-Chemical
.	O

PROCEDURES	O
:	O
Cats	O
were	O
treated	O
with	O
levetiracetam	B-Chemical
(	O
20	O
mg	O
/	O
kg	O
[	O
9	O
.	O
1	O
mg	O
/	O
lb	O
]	O
,	O
PO	O
,	O
q	O
8	O
h	O
)	O
.	O

After	O
a	O
minimum	O
of	O
1	O
week	O
of	O
treatment	O
,	O
serum	O
levetiracetam	B-Chemical
concentrations	O
were	O
measured	O
before	O
and	O
2	O
,	O
4	O
,	O
and	O
6	O
hours	O
after	O
drug	O
administration	O
,	O
and	O
maximum	O
and	O
minimum	O
serum	O
concentrations	O
and	O
elimination	O
half	O
-	O
life	O
were	O
calculated	O
.	O

Seizure	B-Disease
frequencies	O
before	O
and	O
after	O
initiation	O
of	O
levetiracetam	B-Chemical
treatment	O
were	O
compared	O
,	O
and	O
adverse	O
effects	O
were	O
recorded	O
.	O

RESULTS	O
:	O
Median	O
maximum	O
serum	O
levetiracetam	B-Chemical
concentration	O
was	O
25	O
.	O
5	O
microg	O
/	O
mL	O
,	O
median	O
minimum	O
serum	O
levetiracetam	B-Chemical
concentration	O
was	O
8	O
.	O
3	O
microg	O
/	O
mL	O
,	O
and	O
median	O
elimination	O
half	O
-	O
life	O
was	O
2	O
.	O
9	O
hours	O
.	O

Median	O
seizure	B-Disease
frequency	O
prior	O
to	O
treatment	O
with	O
levetiracetam	B-Chemical
(	O
2	O
.	O
1	O
seizures	B-Disease
/	O
mo	O
)	O
was	O
significantly	O
higher	O
than	O
median	O
seizure	B-Disease
frequency	O
after	O
initiation	O
of	O
levetiracetam	B-Chemical
treatment	O
(	O
0	O
.	O
42	O
seizures	B-Disease
/	O
mo	O
)	O
,	O
and	O
7	O
of	O
10	O
cats	O
were	O
classified	O
as	O
having	O
responded	O
to	O
levetiracetam	B-Chemical
treatment	O
(	O
ie	O
,	O
reduction	O
in	O
seizure	B-Disease
frequency	O
of	O
>	O
or	O
=	O
50	O
%	O
)	O
.	O

Two	O
cats	O
had	O
transient	O
lethargy	B-Disease
and	O
inappetence	B-Disease
.	O

CONCLUSIONS	O
AND	O
CLINICAL	O
RELEVANCE	O
:	O
Results	O
suggested	O
that	O
levetiracetam	B-Chemical
is	O
well	O
tolerated	O
in	O
cats	O
and	O
may	O
be	O
useful	O
as	O
an	O
adjunct	O
to	O
phenobarbital	B-Chemical
treatment	O
in	O
cats	O
with	O
idiopathic	B-Disease
epilepsy	I-Disease
.	O

Serotonin	B-Chemical
reuptake	O
inhibitors	O
,	O
paranoia	B-Disease
,	O
and	O
the	O
ventral	O
basal	O
ganglia	O
.	O

Antidepressants	O
have	O
previously	O
been	O
associated	O
with	O
paranoid	B-Disease
reactions	O
in	O
psychiatric	O
patients	O
.	O

Five	O
cases	O
of	O
paranoid	B-Disease
exacerbation	O
with	O
the	O
serotonin	B-Chemical
reuptake	O
inhibitors	O
fluoxetine	B-Chemical
and	O
amitriptyline	B-Chemical
are	O
reported	O
here	O
.	O

Elements	O
common	O
to	O
these	O
cases	O
included	O
a	O
history	O
of	O
paranoid	B-Disease
symptomatology	O
and	O
the	O
concomitant	O
occurrence	O
of	O
depressive	B-Disease
and	I-Disease
psychotic	I-Disease
symptoms	I-Disease
.	O

Complicated	O
depressive	B-Disease
disorders	I-Disease
(	O
including	O
atypicality	O
of	O
course	O
and	O
symptomatology	O
,	O
chronicity	O
,	O
psychosis	B-Disease
,	O
bipolarity	O
,	O
and	O
secondary	O
onset	O
in	O
the	O
course	O
of	O
a	O
primary	O
psychosis	B-Disease
)	O
may	O
present	O
particular	O
vulnerability	O
to	O
paranoid	B-Disease
exacerbations	O
associated	O
with	O
serotonin	B-Chemical
reuptake	O
inhibitors	O
.	O

Although	O
the	O
pharmacology	O
and	O
neurobiology	O
of	O
paranoia	B-Disease
remain	O
cryptic	O
,	O
several	O
mechanisms	O
,	O
including	O
5HT3	O
receptor	O
-	O
mediated	O
dopamine	B-Chemical
release	O
,	O
beta	O
-	O
noradrenergic	O
receptor	O
downregulation	O
,	O
or	O
GABAB	O
receptor	O
upregulation	O
acting	O
in	O
the	O
vicinity	O
of	O
the	O
ventral	O
basal	O
ganglia	O
(	O
possibly	O
in	O
lateral	O
orbitofrontal	O
or	O
anterior	O
cingulate	O
circuits	O
)	O
,	O
might	O
apply	O
to	O
this	O
phenomenon	O
.	O

These	O
cases	O
call	O
attention	O
to	O
possible	O
paranoid	B-Disease
exacerbations	O
with	O
serotonin	B-Chemical
reuptake	O
blockers	O
in	O
select	O
patients	O
and	O
raise	O
neurobiological	O
considerations	O
regarding	O
paranoia	B-Disease
.	O

Clinical	O
comparison	O
of	O
cardiorespiratory	O
effects	O
during	O
unilateral	O
and	O
conventional	O
spinal	O
anaesthesia	O
.	O

BACKGROUND	O
:	O
Spinal	O
anaesthesia	O
is	O
widely	O
employed	O
in	O
clinical	O
practice	O
but	O
has	O
the	O
main	O
drawback	O
of	O
post	O
-	O
spinal	O
block	O
hypotension	B-Disease
.	O

Efforts	O
must	O
therefore	O
continue	O
to	O
be	O
made	O
to	O
obviate	O
this	O
setback	O
OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
cardiovascular	O
and	O
respiratory	O
changes	O
during	O
unilateral	O
and	O
conventional	O
spinal	O
anaesthesia	O
.	O

METHODS	O
:	O
With	O
ethical	O
approval	O
,	O
we	O
studied	O
74	O
American	O
Society	O
of	O
Anesthesiologists	O
(	O
ASA	O
)	O
,	O
physical	O
status	O
class	O
1	O
and	O
2	O
patients	O
scheduled	O
for	O
elective	O
unilateral	O
lower	O
limb	O
surgery	O
.	O

Patients	O
were	O
randomly	O
allocated	O
into	O
one	O
of	O
two	O
groups	O
:	O
lateral	O
and	O
conventional	O
spinal	O
anaesthesia	O
groups	O
.	O

In	O
the	O
lateral	O
position	O
with	O
operative	O
side	O
down	O
,	O
patients	O
recived	O
10	O
mg	O
(	O
2mls	O
)	O
of	O
0	O
.	O
5	O
%	O
hyperbaric	O
bupivacaine	B-Chemical
through	O
a	O
25	O
-	O
gauge	O
spinal	O
needle	O
.	O

Patients	O
in	O
the	O
unilateral	O
group	O
were	O
maintained	O
in	O
the	O
lateral	O
position	O
for	O
15	O
minutes	O
following	O
spinal	O
injection	O
while	O
those	O
in	O
the	O
conventional	O
group	O
were	O
turned	O
supine	O
immediately	O
after	O
injection	O
.	O

Blood	O
pressure	O
,	O
heart	O
rate	O
,	O
respiratory	O
rate	O
and	O
oxygen	B-Chemical
saturation	O
were	O
monitored	O
over	O
1	O
hour	O
.	O

RESULTS	O
:	O
Three	O
patients	O
(	O
8	O
.	O
1	O
%	O
)	O
in	O
the	O
unilateral	O
group	O
and	O
5	O
(	O
13	O
.	O
5	O
%	O
)	O
in	O
the	O
conventional	O
group	O
developed	O
hypotension	B-Disease
,	O
P	O
=	O
0	O
.	O
71	O
.	O

Four	O
(	O
10	O
.	O
8	O
%	O
)	O
patients	O
in	O
the	O
conventional	O
group	O
and	O
1	O
(	O
2	O
.	O
7	O
%	O
)	O
in	O
the	O
unilateral	O
group	O
,	O
P	O
=	O
0	O
.	O
17	O
required	O
epinephrine	B-Chemical
infusion	O
to	O
treat	O
hypotension	B-Disease
.	O

Patients	O
in	O
the	O
conventional	O
group	O
had	O
statistically	O
significant	O
greater	O
fall	O
in	O
the	O
systolic	O
blood	O
pressures	O
at	O
15	O
,	O
30	O
and	O
45	O
minutes	O
when	O
compared	O
to	O
the	O
baseline	O
(	O
P	O
=	O
0	O
.	O
003	O
,	O
0	O
.	O
001	O
and	O
0	O
.	O
004	O
)	O
.	O

The	O
mean	O
respiratory	O
rate	O
and	O
oxygen	B-Chemical
saturations	O
in	O
the	O
two	O
groups	O
were	O
similar	O
.	O

CONCLUSION	O
:	O
Compared	O
to	O
conventional	O
spinal	O
anaesthesia	O
,	O
unilateral	O
spinal	O
anaesthesia	O
was	O
associated	O
with	O
fewer	O
cardiovascular	O
perturbations	O
.	O

Also	O
,	O
the	O
type	O
of	O
spinal	O
block	O
instituted	O
affected	O
neither	O
the	O
respiratory	O
rate	O
nor	O
the	O
arterial	O
oxygen	B-Chemical
saturation	O
.	O

Spectrum	O
of	O
adverse	O
events	O
after	O
generic	O
HAART	O
in	O
southern	O
Indian	O
HIV	B-Disease
-	I-Disease
infected	I-Disease
patients	O
.	O

To	O
determine	O
the	O
incidence	O
of	O
clinically	O
significant	O
adverse	O
events	O
after	O
long	O
-	O
term	O
,	O
fixed	O
-	O
dose	O
,	O
generic	O
highly	O
active	O
antiretroviral	O
therapy	O
(	O
HAART	O
)	O
use	O
among	O
HIV	B-Disease
-	I-Disease
infected	I-Disease
individuals	O
in	O
South	O
India	O
,	O
we	O
examined	O
the	O
experiences	O
of	O
3154	O
HIV	B-Disease
-	I-Disease
infected	I-Disease
individuals	O
who	O
received	O
a	O
minimum	O
of	O
3	O
months	O
of	O
generic	O
HAART	O
between	O
February	O
1996	O
and	O
December	O
2006	O
at	O
a	O
tertiary	O
HIV	O
care	O
referral	O
center	O
in	O
South	O
India	O
.	O

The	O
most	O
common	O
regimens	O
were	O
3TC	B-Chemical
+	O
d4T	B-Chemical
+	O
nevirapine	B-Chemical
(	O
NVP	B-Chemical
)	O
(	O
54	O
.	O
8	O
%	O
)	O
,	O
zidovudine	B-Chemical
(	O
AZT	B-Chemical
)	O
+	O
3TC	B-Chemical
+	O
NVP	B-Chemical
(	O
14	O
.	O
5	O
%	O
)	O
,	O
3TC	B-Chemical
+	O
d4T	B-Chemical
+	O
efavirenz	B-Chemical
(	O
EFV	B-Chemical
)	O
(	O
20	O
.	O
1	O
%	O
)	O
,	O
and	O
AZT	B-Chemical
+	O
3TC	B-Chemical
+	O
EFV	B-Chemical
(	O
5	O
.	O
4	O
%	O
)	O
.	O

The	O
most	O
common	O
adverse	O
events	O
and	O
median	O
CD4	O
at	O
time	O
of	O
event	O
were	O
rash	B-Disease
(	O
15	O
.	O
2	O
%	O
;	O
CD4	O
,	O
285	O
cells	O
/	O
microL	O
)	O
and	O
peripheral	B-Disease
neuropathy	I-Disease
(	O
9	O
.	O
0	O
%	O
and	O
348	O
cells	O
/	O
microL	O
)	O
.	O

Clinically	O
significant	O
anemia	B-Disease
(	O
hemoglobin	O
<	O
7	O
g	O
/	O
dL	O
)	O
was	O
observed	O
in	O
5	O
.	O
4	O
%	O
of	O
patients	O
(	O
CD4	O
,	O
165	O
cells	O
/	O
microL	O
)	O
and	O
hepatitis	B-Disease
(	O
clinical	O
jaundice	B-Disease
with	O
alanine	B-Chemical
aminotransferase	O
>	O
5	O
times	O
upper	O
limits	O
of	O
normal	O
)	O
in	O
3	O
.	O
5	O
%	O
of	O
patients	O
(	O
CD4	O
,	O
260	O
cells	O
/	O
microL	O
)	O
.	O

Women	O
were	O
significantly	O
more	O
likely	O
to	O
experience	O
lactic	B-Disease
acidosis	I-Disease
,	O
while	O
men	O
were	O
significantly	O
more	O
likely	O
to	O
experience	O
immune	B-Disease
reconstitution	I-Disease
syndrome	I-Disease
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Among	O
the	O
patients	O
with	O
1	O
year	O
of	O
follow	O
-	O
up	O
,	O
NVP	B-Chemical
therapy	O
was	O
significantly	O
associated	O
with	O
developing	O
rash	B-Disease
and	O
d4T	B-Chemical
therapy	O
with	O
developing	O
peripheral	B-Disease
neuropathy	I-Disease
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Anemia	B-Disease
and	O
hepatitis	B-Disease
often	O
occur	O
within	O
12	O
weeks	O
of	O
initiating	O
generic	O
HAART	O
.	O

Frequent	O
and	O
early	O
monitoring	O
for	O
these	O
toxicities	B-Disease
is	O
warranted	O
in	O
developing	O
countries	O
where	O
generic	O
HAART	O
is	O
increasingly	O
available	O
.	O

Thalidomide	B-Chemical
and	O
sensory	B-Disease
neurotoxicity	I-Disease
:	O
a	O
neurophysiological	O
study	O
.	O

BACKGROUND	O
:	O
Recent	O
studies	O
confirmed	O
a	O
high	O
incidence	O
of	O
sensory	B-Disease
axonal	I-Disease
neuropathy	I-Disease
in	O
patients	O
treated	O
with	O
different	O
doses	O
of	O
thalidomide	B-Chemical
.	O

The	O
study	O
'	O
s	O
aims	O
were	O
to	O
measure	O
variations	O
in	O
sural	O
nerve	O
sensory	O
action	O
potential	O
(	O
SAP	O
)	O
amplitude	O
in	O
patients	O
with	O
refractory	O
cutaneous	B-Disease
lupus	I-Disease
erythematosus	I-Disease
(	O
CLE	B-Disease
)	O
treated	O
with	O
thalidomide	B-Chemical
and	O
use	O
these	O
findings	O
to	O
identify	O
the	O
neurotoxic	B-Disease
potential	O
of	O
thalidomide	B-Chemical
and	O
the	O
recovery	O
capacity	O
of	O
sensory	O
fibres	O
after	O
discontinuation	O
of	O
treatment	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Clinical	O
and	O
electrophysiological	O
data	O
in	O
12	O
female	O
patients	O
with	O
CLE	B-Disease
during	O
treatment	O
with	O
thalidomide	B-Chemical
and	O
up	O
to	O
47	O
months	O
after	O
discontinuation	O
of	O
treatment	O
were	O
analysed	O
.	O

Sural	O
nerve	O
SAP	O
amplitude	O
reduction	O
>	O
or	O
=	O
40	O
%	O
was	O
the	O
criteria	O
for	O
discontinuing	O
therapy	O
.	O

RESULTS	O
:	O
During	O
treatment	O
,	O
11	O
patients	O
showed	O
a	O
reduction	O
in	O
sural	O
nerve	O
SAP	O
amplitude	O
compared	O
to	O
baseline	O
values	O
(	O
9	O
with	O
a	O
reduction	O
>	O
or	O
=	O
50	O
%	O
and	O
2	O
<	O
50	O
%	O
)	O
.	O

One	O
patient	O
showed	O
no	O
changes	O
in	O
SAP	O
amplitude	O
.	O

Five	O
patients	O
complained	O
of	O
paresthesias	B-Disease
and	O
leg	O
cramps	B-Disease
.	O

After	O
thalidomide	B-Chemical
treatment	O
,	O
sural	O
SAP	O
amplitude	O
recovered	O
in	O
3	O
patients	O
.	O

At	O
detection	O
of	O
reduction	O
in	O
sural	O
nerve	O
SAP	O
amplitude	O
,	O
the	O
median	O
thalidomide	B-Chemical
cumulative	O
dose	O
was	O
21	O
.	O
4	O
g	O
.	O

The	O
threshold	O
neurotoxic	B-Disease
dosage	O
is	O
lower	O
than	O
previously	O
reported	O
.	O

CONCLUSIONS	O
:	O
Sural	O
nerve	O
SAP	O
amplitude	O
reduction	O
is	O
a	O
reliable	O
and	O
sensitive	O
marker	O
of	O
degeneration	O
and	O
recovery	O
of	O
sensory	O
fibres	O
.	O

This	O
electrophysiological	O
parameter	O
provides	O
information	O
about	O
subclinical	O
neurotoxic	B-Disease
potential	O
of	O
thalidomide	B-Chemical
but	O
is	O
not	O
helpful	O
in	O
predicting	O
the	O
appearance	O
of	O
sensory	O
symptoms	O
.	O

Five	O
cases	O
of	O
encephalitis	B-Disease
during	O
treatment	O
of	O
loiasis	B-Disease
with	O
diethylcarbamazine	B-Chemical
.	O

Five	O
cases	O
of	O
encephalitis	B-Disease
following	O
treatment	O
with	O
diethylcarbamazine	B-Chemical
(	O
DEC	B-Chemical
)	O
were	O
observed	O
in	O
Congolese	O
patients	O
with	O
Loa	O
loa	O
filariasis	B-Disease
.	O

Two	O
cases	O
had	O
a	O
fatal	O
outcome	O
and	O
one	O
resulted	O
in	O
severe	O
sequelae	O
.	O

The	O
notable	O
fact	O
was	O
that	O
this	O
complication	O
occurred	O
in	O
three	O
patients	O
hospitalized	O
before	O
treatment	O
began	O
,	O
with	O
whom	O
particularly	O
strict	O
therapeutic	O
precautions	O
were	O
taken	O
,	O
i	O
.	O
e	O
.	O
,	O
initial	O
dose	O
less	O
than	O
10	O
mg	O
of	O
DEC	B-Chemical
,	O
very	O
gradual	O
dose	O
increases	O
,	O
and	O
associated	O
anti	O
-	O
allergic	O
treatment	O
.	O

This	O
type	O
of	O
drug	O
-	O
induced	O
complication	O
may	O
not	O
be	O
that	O
uncommon	O
in	O
highly	O
endemic	O
regions	O
.	O

It	O
occurs	O
primarily	O
,	O
but	O
not	O
exclusively	O
,	O
in	O
subjects	O
presenting	O
with	O
a	O
high	O
microfilarial	O
load	O
.	O

The	O
relationship	O
between	O
the	O
occurrence	O
of	O
encephalitis	B-Disease
and	O
the	O
decrease	O
in	O
microfilaremia	B-Disease
is	O
evident	O
.	O

The	O
pathophysiological	O
mechanisms	O
are	O
discussed	O
in	O
the	O
light	O
of	O
these	O
observations	O
and	O
the	O
few	O
other	O
comments	O
on	O
this	O
subject	O
published	O
in	O
the	O
literature	O
.	O

Amiodarone	B-Chemical
-	O
related	O
pulmonary	B-Disease
mass	I-Disease
and	O
unique	O
membranous	B-Disease
glomerulonephritis	I-Disease
in	O
a	O
patient	O
with	O
valvular	B-Disease
heart	I-Disease
disease	I-Disease
:	O
Diagnostic	O
pitfall	O
and	O
new	O
findings	O
.	O

Amiodarone	B-Chemical
is	O
an	O
anti	O
-	O
arrhythmic	B-Disease
drug	O
for	O
life	O
-	O
threatening	O
tachycardia	B-Disease
,	O
but	O
various	O
adverse	O
effects	O
have	O
been	O
reported	O
.	O

Reported	O
herein	O
is	O
an	O
autopsy	O
case	O
of	O
valvular	B-Disease
heart	I-Disease
disease	I-Disease
,	O
in	O
a	O
patient	O
who	O
developed	O
a	O
lung	B-Disease
mass	I-Disease
(	O
1	O
.	O
5	O
cm	O
in	O
diameter	O
)	O
and	O
proteinuria	B-Disease
(	O
2	O
.	O
76	O
g	O
/	O
day	O
)	O
after	O
treatment	O
with	O
amiodarone	B-Chemical
for	O
a	O
long	O
time	O
.	O

The	O
lung	B-Disease
mass	I-Disease
was	O
highly	O
suspected	O
to	O
be	O
lung	B-Disease
cancer	I-Disease
on	O
CT	O
and	O
positron	O
emission	O
tomography	O
,	O
but	O
histologically	O
the	O
lesion	O
was	O
composed	O
of	O
lymphoplasmacytic	O
infiltrates	O
in	O
alveolar	O
walls	O
and	O
intra	O
-	O
alveolar	O
accumulation	O
of	O
foamy	O
macrophages	O
containing	O
characteristic	O
myelinoid	O
bodies	O
,	O
indicating	O
that	O
it	O
was	O
an	O
amiodarone	B-Chemical
-	O
related	O
lesion	O
.	O

In	O
addition	O
,	O
the	O
lung	O
tissue	O
had	O
unevenly	O
distributed	O
hemosiderin	B-Disease
deposition	O
,	O
and	O
abnormally	O
tortuous	O
capillaries	O
were	O
seen	O
in	O
the	O
mass	O
and	O
in	O
heavily	O
hemosiderotic	B-Disease
lung	O
portions	O
outside	O
the	O
mass	O
.	O

In	O
the	O
kidneys	O
,	O
glomeruli	O
had	O
membrane	O
spikes	O
,	O
prominent	O
swelling	O
of	O
podocytes	O
and	O
subepithelial	O
deposits	O
,	O
which	O
were	O
sometimes	O
large	O
and	O
hump	O
-	O
like	O
.	O

Autoimmune	B-Disease
diseases	I-Disease
,	O
viral	B-Disease
hepatitis	I-Disease
,	O
malignant	O
neoplasms	B-Disease
or	O
other	O
diseases	O
with	O
a	O
known	O
relationship	O
to	O
membranous	B-Disease
glomerulonephritis	I-Disease
were	O
not	O
found	O
.	O

The	O
present	O
case	O
highlights	O
the	O
possibility	O
that	O
differential	O
diagnosis	O
between	O
an	O
amiodarone	B-Chemical
-	O
related	O
pulmonary	B-Disease
lesion	I-Disease
and	O
a	O
neoplasm	B-Disease
can	O
be	O
very	O
difficult	O
radiologically	O
,	O
and	O
suggests	O
that	O
membranous	B-Disease
glomerulonephritis	I-Disease
might	O
be	O
another	O
possible	O
complication	O
of	O
amiodarone	B-Chemical
treatment	O
.	O

Risk	O
of	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
associated	O
with	O
initial	O
sulphonylurea	B-Chemical
treatment	O
of	O
patients	O
with	O
type	B-Disease
2	I-Disease
diabetes	I-Disease
:	O
a	O
matched	O
case	O
-	O
control	O
study	O
.	O

AIMS	O
:	O
This	O
study	O
sought	O
to	O
assess	O
the	O
risk	O
of	O
developing	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
(	O
CAD	B-Disease
)	O
associated	O
with	O
initial	O
treatment	O
of	O
type	B-Disease
2	I-Disease
diabetes	I-Disease
with	O
different	O
sulphonylureas	B-Chemical
.	O

METHODS	O
:	O
In	O
type	B-Disease
2	I-Disease
diabetic	I-Disease
patients	O
,	O
cases	O
who	O
developed	O
CAD	B-Disease
were	O
compared	O
retrospectively	O
with	O
controls	O
that	O
did	O
not	O
.	O

The	O
20	O
-	O
year	O
risk	O
of	O
CAD	B-Disease
at	O
diagnosis	O
of	O
diabetes	B-Disease
,	O
using	O
the	O
UKPDS	O
risk	O
engine	O
,	O
was	O
used	O
to	O
match	O
cases	O
with	O
controls	O
.	O

RESULTS	O
:	O
The	O
76	O
cases	O
of	O
CAD	B-Disease
were	O
compared	O
with	O
152	O
controls	O
.	O

The	O
hazard	O
of	O
developing	O
CAD	B-Disease
(	O
95	O
%	O
CI	O
)	O
associated	O
with	O
initial	O
treatment	O
increased	O
by	O
2	O
.	O
4	O
-	O
fold	O
(	O
1	O
.	O
3	O
-	O
4	O
.	O
3	O
,	O
P	O
=	O
0	O
.	O
004	O
)	O
with	O
glibenclamide	B-Chemical
;	O
2	O
-	O
fold	O
(	O
0	O
.	O
9	O
-	O
4	O
.	O
6	O
,	O
P	O
=	O
0	O
.	O
099	O
)	O
with	O
glipizide	B-Chemical
;	O
2	O
.	O
9	O
-	O
fold	O
(	O
1	O
.	O
6	O
-	O
5	O
.	O
1	O
,	O
P	O
=	O
0	O
.	O
000	O
)	O
with	O
either	O
,	O
and	O
was	O
unchanged	O
with	O
metformin	B-Chemical
.	O

The	O
hazard	O
decreased	O
0	O
.	O
3	O
-	O
fold	O
(	O
0	O
.	O
7	O
-	O
1	O
.	O
7	O
,	O
P	O
=	O
0	O
.	O
385	O
)	O
with	O
glimepiride	B-Chemical
,	O
0	O
.	O
4	O
-	O
fold	O
(	O
0	O
.	O
7	O
-	O
1	O
.	O
3	O
,	O
P	O
=	O
0	O
.	O
192	O
)	O
with	O
gliclazide	B-Chemical
,	O
and	O
0	O
.	O
4	O
-	O
fold	O
(	O
0	O
.	O
7	O
-	O
1	O
.	O
1	O
,	O
P	O
=	O
0	O
.	O
09	O
)	O
with	O
either	O
.	O

CONCLUSIONS	O
:	O
Initiating	O
treatment	O
of	O
type	B-Disease
2	I-Disease
diabetes	I-Disease
with	O
glibenclamide	B-Chemical
or	O
glipizide	B-Chemical
is	O
associated	O
with	O
increased	O
risk	O
of	O
CAD	B-Disease
in	O
comparison	O
to	O
gliclazide	B-Chemical
or	O
glimepiride	B-Chemical
.	O

If	O
confirmed	O
,	O
this	O
may	O
be	O
important	O
because	O
most	O
Indian	O
patients	O
receive	O
the	O
cheaper	O
older	O
sulphonylureas	B-Chemical
,	O
and	O
present	O
guidelines	O
do	O
not	O
distinguish	O
between	O
individual	O
agents	O
.	O

Reduced	O
progression	O
of	O
adriamycin	B-Chemical
nephropathy	B-Disease
in	O
spontaneously	O
hypertensive	B-Disease
rats	O
treated	O
by	O
losartan	B-Chemical
.	O

BACKGROUND	O
:	O
The	O
aim	O
of	O
the	O
study	O
was	O
to	O
investigate	O
the	O
antihypertensive	O
effects	O
of	O
angiotensin	B-Chemical
II	I-Chemical
type	O
-	O
1	O
receptor	O
blocker	O
,	O
losartan	B-Chemical
,	O
and	O
its	O
potential	O
in	O
slowing	O
down	O
renal	B-Disease
disease	I-Disease
progression	O
in	O
spontaneously	O
hypertensive	B-Disease
rats	O
(	O
SHR	O
)	O
with	O
adriamycin	B-Chemical
(	O
ADR	B-Chemical
)	O
nephropathy	B-Disease
.	O

METHODS	O
:	O
Six	O
-	O
month	O
-	O
old	O
female	O
SHR	O
were	O
randomly	O
selected	O
in	O
six	O
groups	O
.	O

Two	O
control	O
groups	O
(	O
SH	O
(	O
6	O
)	O
,	O
SH	O
(	O
12	O
)	O
)	O
received	O
vehicle	O
.	O

Groups	O
ADR	B-Chemical
(	O
6	O
)	O
,	O
ADR	B-Chemical
+	O
LOS	B-Chemical
(	O
6	O
)	O
and	O
ADR	B-Chemical
(	O
12	O
)	O
,	O
and	O
ADR	B-Chemical
+	O
LOS	B-Chemical
(	O
12	O
)	O
received	O
ADR	B-Chemical
(	O
2	O
mg	O
/	O
kg	O
/	O
b	O
.	O
w	O
.	O
i	O
.	O
v	O
.	O
)	O
twice	O
in	O
a	O
3	O
-	O
week	O
interval	O
.	O

Group	O
ADR	B-Chemical
+	O
LOS	B-Chemical
(	O
6	O
)	O
received	O
losartan	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
/	O
b	O
.	O
w	O
.	O
/	O
day	O
by	O
gavages	O
)	O
for	O
6	O
weeks	O
and	O
group	O
ADR	B-Chemical
+	O
LOS	B-Chemical
(	O
12	O
)	O
for	O
12	O
weeks	O
after	O
second	O
injection	O
of	O
ADR	B-Chemical
.	O

Animals	O
were	O
killed	O
after	O
6	O
or	O
12	O
weeks	O
,	O
respectively	O
.	O

Haemodynamic	O
measurements	O
were	O
performed	O
on	O
anaesthetized	O
animals	O
,	O
blood	O
and	O
urine	O
samples	O
were	O
taken	O
for	O
biochemical	O
analysis	O
and	O
the	O
left	O
kidney	O
was	O
processed	O
for	O
morphological	O
studies	O
.	O

RESULTS	O
:	O
Short	O
-	O
term	O
losartan	B-Chemical
treatment	O
,	O
besides	O
antihypertensive	O
effect	O
,	O
improved	O
glomerular	O
filtration	O
rate	O
and	O
ameliorated	O
glomerulosclerosis	B-Disease
resulting	O
in	O
decreased	O
proteinuria	B-Disease
.	O

Prolonged	O
treatment	O
with	O
losartan	B-Chemical
showed	O
further	O
reduction	O
of	O
glomerulosclerosis	B-Disease
associated	O
with	O
reduced	O
progression	O
of	O
tubular	O
atrophy	B-Disease
and	O
interstitial	B-Disease
fibrosis	I-Disease
,	O
thus	O
preventing	O
heavy	O
proteinuria	B-Disease
and	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
.	O

Losartan	B-Chemical
reduced	O
uraemia	B-Disease
and	O
increased	O
urea	B-Chemical
clearance	O
in	O
advanced	O
ADR	B-Chemical
nephropathy	B-Disease
in	O
SHR	O
.	O

Histological	O
examination	O
showed	O
that	O
losartan	B-Chemical
could	O
prevent	O
tubular	O
atrophy	B-Disease
,	O
interstitial	O
infiltration	O
and	O
fibrosis	B-Disease
in	O
ADR	B-Chemical
nephropathy	B-Disease
.	O

CONCLUSION	O
:	O
Losartan	B-Chemical
reduces	O
the	O
rate	O
of	O
progression	O
of	O
ADR	B-Chemical
-	O
induced	O
focal	B-Disease
segmental	I-Disease
glomerulosclerosis	I-Disease
to	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
in	O
SHR	O
.	O

The	O
risks	O
of	O
aprotinin	O
and	O
tranexamic	B-Chemical
acid	I-Chemical
in	O
cardiac	O
surgery	O
:	O
a	O
one	O
-	O
year	O
follow	O
-	O
up	O
of	O
1188	O
consecutive	O
patients	O
.	O

BACKGROUND	O
:	O
Our	O
aim	O
was	O
to	O
investigate	O
postoperative	O
complications	O
and	O
mortality	O
after	O
administration	O
of	O
aprotinin	O
compared	O
to	O
tranexamic	B-Chemical
acid	I-Chemical
in	O
an	O
unselected	O
,	O
consecutive	O
cohort	O
.	O

METHODS	O
:	O
Perioperative	O
data	O
from	O
consecutive	O
cardiac	O
surgery	O
patients	O
were	O
prospectively	O
collected	O
between	O
September	O
2005	O
and	O
June	O
2006	O
in	O
a	O
university	O
-	O
affiliated	O
clinic	O
(	O
n	O
=	O
1188	O
)	O
.	O

During	O
the	O
first	O
5	O
mo	O
,	O
596	O
patients	O
received	O
aprotinin	O
(	O
Group	O
A	O
)	O
;	O
in	O
the	O
next	O
5	O
mo	O
,	O
592	O
patients	O
were	O
treated	O
with	O
tranexamic	B-Chemical
acid	I-Chemical
(	O
Group	O
T	O
)	O
.	O

Except	O
for	O
antifibrinolytic	O
therapy	O
,	O
the	O
anesthetic	O
and	O
surgical	O
protocols	O
remained	O
unchanged	O
.	O

RESULTS	O
:	O
The	O
pre	O
-	O
and	O
intraoperative	O
variables	O
were	O
comparable	O
between	O
the	O
treatment	O
groups	O
.	O

Postoperatively	O
,	O
a	O
significantly	O
higher	O
incidence	O
of	O
seizures	B-Disease
was	O
found	O
in	O
Group	O
T	O
(	O
4	O
.	O
6	O
%	O
vs	O
1	O
.	O
2	O
%	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

This	O
difference	O
was	O
also	O
significant	O
in	O
the	O
primary	O
valve	O
surgery	O
and	O
the	O
high	O
risk	O
surgery	O
subgroups	O
(	O
7	O
.	O
9	O
%	O
vs	O
1	O
.	O
2	O
%	O
,	O
P	O
=	O
0	O
.	O
003	O
;	O
7	O
.	O
3	O
%	O
vs	O
2	O
.	O
4	O
%	O
,	O
P	O
=	O
0	O
.	O
035	O
,	O
respectively	O
)	O
.	O

Persistent	O
atrial	O
fibrillation	O
(	O
7	O
.	O
9	O
%	O
vs	O
2	O
.	O
3	O
%	O
,	O
P	O
=	O
0	O
.	O
020	O
)	O
and	O
renal	B-Disease
failure	I-Disease
(	O
9	O
.	O
7	O
%	O
vs	O
1	O
.	O
7	O
%	O
,	O
P	O
=	O
0	O
.	O
002	O
)	O
were	O
also	O
more	O
common	O
in	O
Group	O
T	O
,	O
in	O
the	O
primary	O
valve	O
surgery	O
subgroup	O
.	O

On	O
the	O
contrary	O
,	O
among	O
primary	O
coronary	O
artery	O
bypass	O
surgery	O
patients	O
,	O
there	O
were	O
more	O
acute	O
myocardial	B-Disease
infarctions	I-Disease
and	O
renal	B-Disease
dysfunction	I-Disease
in	O
Group	O
A	O
(	O
5	O
.	O
8	O
%	O
vs	O
2	O
.	O
0	O
%	O
,	O
P	O
=	O
0	O
.	O
027	O
;	O
22	O
.	O
5	O
%	O
vs	O
15	O
.	O
2	O
%	O
,	O
P	O
=	O
0	O
.	O
036	O
,	O
respectively	O
)	O
.	O

The	O
1	O
-	O
yr	O
mortality	O
was	O
significantly	O
higher	O
after	O
aprotinin	O
treatment	O
in	O
the	O
high	O
risk	O
surgery	O
group	O
(	O
17	O
.	O
7	O
%	O
vs	O
9	O
.	O
8	O
%	O
,	O
P	O
=	O
0	O
.	O
034	O
)	O
.	O

CONCLUSION	O
:	O
Both	O
antifibrinolytic	O
drugs	O
bear	O
the	O
risk	O
of	O
adverse	O
outcome	O
depending	O
on	O
the	O
type	O
of	O
cardiac	O
surgery	O
.	O

Administration	O
of	O
aprotinin	O
should	O
be	O
avoided	O
in	O
coronary	O
artery	O
bypass	O
graft	O
and	O
high	O
risk	O
patients	O
,	O
whereas	O
administration	O
of	O
tranexamic	B-Chemical
acid	I-Chemical
is	O
not	O
recommended	O
in	O
valve	O
surgery	O
.	O

Delirium	B-Disease
in	O
an	O
elderly	O
woman	O
possibly	O
associated	O
with	O
administration	O
of	O
misoprostol	B-Chemical
.	O

Misoprostol	B-Chemical
has	O
been	O
associated	O
with	O
adverse	O
reactions	O
,	O
including	O
gastrointestinal	O
symptoms	O
,	O
gynecologic	O
problems	O
,	O
and	O
headache	B-Disease
.	O

Changes	O
in	O
mental	O
status	O
,	O
however	O
,	O
have	O
not	O
been	O
reported	O
.	O

We	O
present	O
a	O
case	O
in	O
which	O
an	O
89	O
-	O
year	O
-	O
old	O
woman	O
in	O
a	O
long	O
-	O
term	O
care	O
facility	O
became	O
confused	O
after	O
the	O
initiation	O
of	O
misoprostol	B-Chemical
therapy	O
.	O

The	O
patient	O
'	O
s	O
change	O
in	O
mental	O
status	O
was	O
first	O
reported	O
nine	O
days	O
after	O
the	O
initiation	O
of	O
therapy	O
.	O

Her	O
delirium	B-Disease
significantly	O
improved	O
after	O
misoprostol	B-Chemical
was	O
discontinued	O
and	O
her	O
mental	O
status	O
returned	O
to	O
normal	O
within	O
a	O
week	O
.	O

Because	O
no	O
other	O
factors	O
related	O
to	O
this	O
patient	O
changed	O
significantly	O
,	O
the	O
delirium	B-Disease
experienced	O
by	O
this	O
patient	O
possibly	O
resulted	O
from	O
misoprostol	B-Chemical
therapy	O
.	O

The	O
biological	O
properties	O
of	O
the	O
optical	O
isomers	O
of	O
propranolol	B-Chemical
and	O
their	O
effects	O
on	O
cardiac	B-Disease
arrhythmias	I-Disease
.	O

1	O
.	O

The	O
optical	O
isomers	O
of	O
propranolol	B-Chemical
have	O
been	O
compared	O
for	O
their	O
beta	O
-	O
blocking	O
and	O
antiarrhythmic	O
activities	O
.	O
2	O
.	O

In	O
blocking	O
the	O
positive	O
inotropic	O
and	O
chronotropic	O
responses	O
to	O
isoprenaline	B-Chemical
,	O
(	O
+	O
)	O
-	O
propranolol	B-Chemical
had	O
less	O
than	O
one	O
hundredth	O
the	O
potency	O
of	O
(	O
-	O
)	O
-	O
propranolol	B-Chemical
.	O

At	O
dose	O
levels	O
of	O
(	O
+	O
)	O
-	O
propranolol	B-Chemical
which	O
attenuated	O
the	O
responses	O
to	O
isoprenaline	B-Chemical
,	O
there	O
was	O
a	O
significant	O
prolongation	O
of	O
the	O
PR	O
interval	O
of	O
the	O
electrocardiogram	O
.	O
3	O
.	O

The	O
metabolic	O
responses	O
to	O
isoprenaline	B-Chemical
in	O
dogs	O
(	O
an	O
increase	O
in	O
circulating	O
glucose	B-Chemical
,	O
lactate	B-Chemical
and	O
free	O
fatty	B-Chemical
acids	I-Chemical
)	O
were	O
all	O
blocked	O
by	O
(	O
-	O
)	O
-	O
propranolol	B-Chemical
.	O

(	O
+	O
)	O
-	O
Propranolol	B-Chemical
had	O
no	O
effect	O
on	O
fatty	B-Chemical
acid	I-Chemical
mobilization	O
but	O
significantly	O
reduced	O
the	O
increments	O
in	O
both	O
lactate	B-Chemical
and	O
glucose	B-Chemical
.	O
4	O
.	O

Both	O
isomers	O
of	O
propranolol	B-Chemical
possessed	O
similar	O
depressant	O
potency	O
on	O
isolated	O
atrial	O
muscle	O
taken	O
from	O
guinea	O
-	O
pigs	O
.	O
5	O
.	O

The	O
isomers	O
of	O
propranolol	B-Chemical
exhibited	O
similar	O
local	O
anaesthetic	O
potencies	O
on	O
an	O
isolated	O
frog	O
nerve	O
preparation	O
at	O
a	O
level	O
approximately	O
three	O
times	O
that	O
of	O
procaine	B-Chemical
.	O

The	O
racemic	O
compound	O
was	O
significantly	O
less	O
potent	O
than	O
either	O
isomer	O
.	O
6	O
.	O

Both	O
isomers	O
of	O
propranolol	B-Chemical
were	O
capable	O
of	O
preventing	O
adrenaline	B-Chemical
-	O
induced	O
cardiac	B-Disease
arrhythmias	I-Disease
in	O
cats	O
anaesthetized	O
with	O
halothane	B-Chemical
,	O
but	O
the	O
mean	O
dose	O
of	O
(	O
-	O
)	O
-	O
propranolol	B-Chemical
was	O
0	O
.	O
09	O
+	O
/	O
-	O
0	O
.	O
02	O
mg	O
/	O
kg	O
whereas	O
that	O
of	O
(	O
+	O
)	O
-	O
propranolol	B-Chemical
was	O
4	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
2	O
mg	O
/	O
kg	O
.	O

At	O
the	O
effective	O
dose	O
level	O
of	O
(	O
+	O
)	O
-	O
propranolol	B-Chemical
there	O
was	O
a	O
significant	O
prolongation	O
of	O
the	O
PR	O
interval	O
of	O
the	O
electrocardiogram	O
.	O

Blockade	O
of	O
arrhythmias	B-Disease
with	O
both	O
isomers	O
was	O
surmountable	O
by	O
increasing	O
the	O
dose	O
of	O
adrenaline	B-Chemical
.	O
7	O
.	O

Both	O
isomers	O
of	O
propranolol	B-Chemical
were	O
also	O
capable	O
of	O
reversing	O
ventricular	B-Disease
tachycardia	I-Disease
caused	O
by	O
ouabain	B-Chemical
in	O
anaesthetized	O
cats	O
and	O
dogs	O
.	O

The	O
dose	O
of	O
(	O
-	O
)	O
-	O
propranolol	B-Chemical
was	O
significantly	O
smaller	O
than	O
that	O
of	O
(	O
+	O
)	O
-	O
propranolol	B-Chemical
in	O
both	O
species	O
but	O
much	O
higher	O
than	O
that	O
required	O
to	O
produce	O
evidence	O
of	O
beta	O
-	O
blockade	O
.	O
8	O
.	O

The	O
implications	O
of	O
these	O
results	O
are	O
discussed	O
.	O

Topotecan	B-Chemical
in	O
combination	O
with	O
radiotherapy	O
in	O
unresectable	O
glioblastoma	B-Disease
:	O
a	O
phase	O
2	O
study	O
.	O

Improving	O
glioblastoma	B-Disease
multiforme	I-Disease
(	O
GBM	B-Disease
)	O
treatment	O
with	O
radio	O
-	O
chemotherapy	O
remains	O
a	O
challenge	O
.	O

Topotecan	B-Chemical
is	O
an	O
attractive	O
option	O
as	O
it	O
exhibits	O
growth	O
inhibition	O
of	O
human	O
glioma	B-Disease
as	O
well	O
as	O
brain	O
penetration	O
.	O

The	O
present	O
study	O
assessed	O
the	O
combination	O
of	O
radiotherapy	O
(	O
60	O
Gy	O
/	O
30	O
fractions	O
/	O
40	O
days	O
)	O
and	O
topotecan	B-Chemical
(	O
0	O
.	O
9	O
mg	O
/	O
m	O
(	O
2	O
)	O
/	O
day	O
on	O
days	O
1	O
-	O
5	O
on	O
weeks	O
1	O
,	O
3	O
and	O
5	O
)	O
in	O
50	O
adults	O
with	O
histologically	O
proven	O
and	O
untreated	O
GBM	B-Disease
.	O

The	O
incidence	O
of	O
non	O
-	O
hematological	O
toxicities	B-Disease
was	O
low	O
and	O
grade	O
3	O
-	O
4	O
hematological	O
toxicities	B-Disease
were	O
reported	O
in	O
20	O
patients	O
(	O
mainly	O
lymphopenia	B-Disease
and	O
neutropenia	B-Disease
)	O
.	O

Partial	O
response	O
and	O
stabilization	O
rates	O
were	O
2	O
%	O
and	O
32	O
%	O
,	O
respectively	O
,	O
with	O
an	O
overall	O
time	O
to	O
progression	O
of	O
12	O
weeks	O
.	O

One	O
-	O
year	O
overall	O
survival	O
(	O
OS	O
)	O
rate	O
was	O
42	O
%	O
,	O
with	O
a	O
median	O
OS	O
of	O
40	O
weeks	O
.	O

Topotecan	B-Chemical
in	O
combination	O
with	O
radiotherapy	O
was	O
well	O
tolerated	O
.	O

However	O
,	O
while	O
response	O
and	O
stabilization	O
concerned	O
one	O
-	O
third	O
of	O
the	O
patients	O
,	O
the	O
study	O
did	O
not	O
show	O
increased	O
benefits	O
in	O
terms	O
of	O
survival	O
in	O
patients	O
with	O
unresectable	O
GBM	B-Disease
.	O

Long	O
-	O
term	O
lithium	B-Chemical
therapy	O
leading	O
to	O
hyperparathyroidism	B-Disease
:	O
a	O
case	O
report	O
.	O

PURPOSE	O
:	O
This	O
paper	O
reviews	O
the	O
effect	O
of	O
chronic	O
lithium	B-Chemical
therapy	O
on	O
serum	O
calcium	B-Chemical
level	O
and	O
parathyroid	O
glands	O
,	O
its	O
pathogenesis	O
,	O
and	O
treatment	O
options	O
.	O

We	O
examined	O
the	O
case	O
of	O
a	O
lithium	B-Chemical
-	O
treated	O
patient	O
who	O
had	O
recurrent	O
hypercalcemia	B-Disease
to	O
better	O
understand	O
the	O
disease	O
process	O
.	O

CONCLUSION	O
:	O
Primary	B-Disease
hyperparathyroidism	I-Disease
is	O
a	O
rare	O
but	O
potentially	O
life	O
-	O
threatening	O
side	O
effect	O
of	O
long	O
-	O
term	O
lithium	B-Chemical
therapy	O
.	O

Careful	O
patient	O
selection	O
and	O
long	O
-	O
term	O
follow	O
-	O
up	O
can	O
reduce	O
morbidity	O
.	O

PRACTICAL	O
IMPLICATIONS	O
:	O
As	O
much	O
as	O
15	O
%	O
of	O
lithium	B-Chemical
-	O
treated	O
patients	O
become	O
hypercalcemic	B-Disease
.	O

By	O
routinely	O
monitoring	O
serum	O
calcium	B-Chemical
levels	O
,	O
healthcare	O
providers	O
can	O
improve	O
the	O
quality	O
of	O
life	O
of	O
this	O
patient	O
group	O
.	O

Comparison	O
of	O
laryngeal	O
mask	O
with	O
endotracheal	O
tube	O
for	O
anesthesia	O
in	O
endoscopic	O
sinus	O
surgery	O
.	O

BACKGROUND	O
:	O
The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
compare	O
surgical	O
conditions	O
,	O
including	O
the	O
amount	O
of	O
intraoperative	O
bleeding	B-Disease
as	O
well	O
as	O
intraoperative	O
blood	O
pressure	O
,	O
during	O
functional	O
endoscopic	O
sinus	O
surgery	O
(	O
FESS	O
)	O
using	O
flexible	O
reinforced	O
laryngeal	O
mask	O
airway	O
(	O
FRLMA	O
)	O
versus	O
endotracheal	O
tube	O
(	O
ETT	O
)	O
in	O
maintaining	O
controlled	O
hypotension	B-Disease
anesthesia	O
induced	O
by	O
propofol	B-Chemical
-	O
remifentanil	B-Chemical
total	O
i	O
.	O
v	O
.	O
anesthesia	O
(	O
TIVA	O
)	O
.	O

METHODS	O
:	O
Sixty	O
normotensive	O
American	O
Society	O
of	O
Anesthesiologists	O
I	O
-	O
II	O
adult	O
patients	O
undergoing	O
FESS	O
under	O
controlled	O
hypotension	B-Disease
anesthesia	O
caused	O
by	O
propofol	B-Chemical
-	O
remifentanil	B-Chemical
-	O
TIVA	O
were	O
randomly	O
assigned	O
into	O
two	O
groups	O
:	O
group	O
I	O
,	O
FRLMA	O
;	O
group	O
II	O
,	O
ETT	O
.	O

Hemorrhage	B-Disease
was	O
measured	O
and	O
the	O
visibility	O
of	O
the	O
operative	O
field	O
was	O
evaluated	O
according	O
to	O
a	O
six	O
-	O
point	O
scale	O
.	O

RESULTS	O
:	O
Controlled	O
hypotension	B-Disease
was	O
achieved	O
within	O
a	O
shorter	O
period	O
using	O
laryngeal	O
mask	O
using	O
lower	O
rates	O
of	O
remifentanil	B-Chemical
infusion	O
and	O
lower	O
total	O
dose	O
of	O
remifentanil	B-Chemical
.	O

CONCLUSION	O
:	O
In	O
summary	O
,	O
our	O
results	O
indicate	O
that	O
airway	O
management	O
using	O
FRLMA	O
during	O
controlled	O
hypotension	B-Disease
anesthesia	O
provided	O
better	O
surgical	O
conditions	O
in	O
terms	O
of	O
quality	O
of	O
operative	O
field	O
and	O
blood	O
loss	O
and	O
allowed	O
for	O
convenient	O
induced	O
hypotension	B-Disease
with	O
low	O
doses	O
of	O
remifentanil	B-Chemical
during	O
TIVA	O
in	O
patients	O
undergoing	O
FESS	O
.	O

Nonalcoholic	B-Disease
fatty	I-Disease
liver	I-Disease
disease	I-Disease
during	O
valproate	B-Chemical
therapy	O
.	O

Valproic	B-Chemical
acid	I-Chemical
(	O
VPA	B-Chemical
)	O
is	O
effective	O
for	O
the	O
treatment	O
of	O
many	O
types	O
of	O
epilepsy	B-Disease
,	O
but	O
its	O
use	O
can	O
be	O
associated	O
with	O
an	O
increase	O
in	O
body	O
weight	O
.	O

We	O
report	O
a	O
case	O
of	O
nonalcoholic	B-Disease
fatty	I-Disease
liver	I-Disease
disease	I-Disease
(	O
NAFLD	B-Disease
)	O
arising	O
in	O
a	O
child	O
who	O
developed	O
obesity	B-Disease
during	O
VPA	B-Chemical
treatment	O
.	O

Laboratory	O
data	O
revealed	O
hyperinsulinemia	B-Disease
with	O
insulin	B-Disease
resistance	I-Disease
.	O

After	O
the	O
withdrawal	O
of	O
VPA	B-Chemical
therapy	O
,	O
our	O
patient	O
showed	O
a	O
significant	O
weight	B-Disease
loss	I-Disease
,	O
a	O
decrease	O
of	O
body	O
mass	O
index	O
,	O
and	O
normalization	O
of	O
metabolic	O
and	O
endocrine	O
parameters	O
;	O
moreover	O
,	O
ultrasound	O
measurements	O
showed	O
a	O
complete	O
normalization	O
.	O

The	O
present	O
case	O
suggests	O
that	O
obesity	B-Disease
,	O
hyperinsulinemia	B-Disease
,	O
insulin	B-Disease
resistance	I-Disease
,	O
and	O
long	O
-	O
term	O
treatment	O
with	O
VPA	B-Chemical
may	O
be	O
all	O
associated	O
with	O
the	O
development	O
of	O
NAFLD	B-Disease
;	O
this	O
side	O
effect	O
is	O
reversible	O
after	O
VPA	B-Chemical
withdrawal	O
.	O

Carbimazole	B-Chemical
induced	O
ANCA	B-Disease
positive	I-Disease
vasculitis	I-Disease
.	O

Anti	B-Chemical
-	I-Chemical
thyroid	I-Chemical
drugs	I-Chemical
,	O
like	O
carbimazole	B-Chemical
and	O
propylthiouracil	B-Chemical
(	O
PTU	B-Chemical
)	O
are	O
commonly	O
prescribed	O
for	O
the	O
treatment	O
of	O
hyperthyroidism	B-Disease
.	O

One	O
should	O
be	O
aware	O
of	O
the	O
side	O
effects	O
of	O
antithyroid	B-Chemical
medications	I-Chemical
.	O

Antineutrophil	B-Disease
cytoplasmic	I-Disease
antibody	I-Disease
(	I-Disease
ANCA	I-Disease
)	I-Disease
-	I-Disease
-	I-Disease
associated	I-Disease
vasculitis	I-Disease
is	O
a	O
potentially	O
life	O
-	O
threatening	O
adverse	O
effect	O
of	O
antithyroidmedications	B-Chemical
.	O

We	O
report	O
a	O
patient	O
with	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
who	O
developed	O
ANCA	O
positive	O
carbimazole	B-Chemical
induced	O
vasculitis	B-Disease
.	O

The	O
episode	O
was	O
characterized	O
by	O
a	O
vasculitic	B-Disease
skin	B-Disease
rash	I-Disease
associated	O
with	O
large	O
joint	O
arthritis	B-Disease
,	O
pyrexia	B-Disease
and	O
parotiditis	B-Disease
but	O
no	O
renal	O
or	O
pulmonary	O
involvement	O
.	O

He	O
was	O
referred	O
to	O
us	O
for	O
neurological	O
evaluation	O
because	O
he	O
had	O
difficulty	O
in	O
getting	O
up	O
from	O
squatting	O
position	O
and	O
was	O
suspected	O
to	O
have	O
myositis	B-Disease
.	O

Carbimazole	B-Chemical
and	O
methimazole	B-Chemical
have	O
a	O
lower	O
incidence	O
of	O
reported	O
ANCA	O
positive	O
side	O
effects	O
than	O
PUT	O
.	O

To	O
the	O
best	O
of	O
our	O
knowledge	O
this	O
is	O
the	O
first	O
ANCA	O
positive	O
carbimazole	B-Chemical
induced	O
vasculitis	B-Disease
case	O
reported	O
from	O
India	O
.	O

Aspirin	B-Chemical
for	O
the	O
primary	O
prevention	O
of	O
cardiovascular	O
events	O
:	O
an	O
update	O
of	O
the	O
evidence	O
for	O
the	O
U	O
.	O
S	O
.	O

Preventive	O
Services	O
Task	O
Force	O
.	O

BACKGROUND	O
:	O
Coronary	B-Disease
heart	I-Disease
disease	I-Disease
and	O
cerebrovascular	B-Disease
disease	I-Disease
are	O
leading	O
causes	O
of	O
death	O
in	O
the	O
United	O
States	O
.	O

In	O
2002	O
,	O
the	O
U	O
.	O
S	O
.	O

Preventive	O
Services	O
Task	O
Force	O
(	O
USPSTF	O
)	O
strongly	O
recommended	O
that	O
clinicians	O
discuss	O
aspirin	B-Chemical
with	O
adults	O
who	O
are	O
at	O
increased	O
risk	O
for	O
coronary	B-Disease
heart	I-Disease
disease	I-Disease
.	O

PURPOSE	O
:	O
To	O
determine	O
the	O
benefits	O
and	O
harms	O
of	O
taking	O
aspirin	B-Chemical
for	O
the	O
primary	O
prevention	O
of	O
myocardial	B-Disease
infarctions	I-Disease
,	O
strokes	B-Disease
,	O
and	O
death	O
.	O

DATA	O
SOURCES	O
:	O
MEDLINE	O
and	O
Cochrane	O
Library	O
(	O
search	O
dates	O
,	O
1	O
January	O
2001	O
to	O
28	O
August	O
2008	O
)	O
,	O
recent	O
systematic	O
reviews	O
,	O
reference	O
lists	O
of	O
retrieved	O
articles	O
,	O
and	O
suggestions	O
from	O
experts	O
.	O

STUDY	O
SELECTION	O
:	O
English	O
-	O
language	O
randomized	O
,	O
controlled	O
trials	O
(	O
RCTs	O
)	O
;	O
case	O
-	O
control	O
studies	O
;	O
meta	O
-	O
analyses	O
;	O
and	O
systematic	O
reviews	O
of	O
aspirin	B-Chemical
versus	O
control	O
for	O
the	O
primary	O
prevention	O
of	O
cardiovascular	B-Disease
disease	I-Disease
(	O
CVD	B-Disease
)	O
were	O
selected	O
to	O
answer	O
the	O
following	O
questions	O
:	O
Does	O
aspirin	B-Chemical
decrease	O
coronary	O
heart	O
events	O
,	O
strokes	B-Disease
,	O
death	O
from	O
coronary	O
heart	O
events	O
or	O
stroke	B-Disease
,	O
or	O
all	O
-	O
cause	O
mortality	O
in	O
adults	O
without	O
known	O
CVD	B-Disease
?	O

Does	O
aspirin	B-Chemical
increase	O
gastrointestinal	B-Disease
bleeding	I-Disease
or	O
hemorrhagic	B-Disease
strokes	I-Disease
?	O

DATA	O
EXTRACTION	O
:	O
All	O
studies	O
were	O
reviewed	O
,	O
abstracted	O
,	O
and	O
rated	O
for	O
quality	O
by	O
using	O
predefined	O
USPSTF	O
criteria	O
.	O

DATA	O
SYNTHESIS	O
:	O
New	O
evidence	O
from	O
1	O
good	O
-	O
quality	O
RCT	O
,	O
1	O
good	O
-	O
quality	O
meta	O
-	O
analysis	O
,	O
and	O
2	O
fair	O
-	O
quality	O
subanalyses	O
of	O
RCTs	O
demonstrates	O
that	O
aspirin	B-Chemical
use	O
reduces	O
the	O
number	O
of	O
CVD	B-Disease
events	O
in	O
patients	O
without	O
known	O
CVD	B-Disease
.	O

Men	O
in	O
these	O
studies	O
experienced	O
fewer	O
myocardial	B-Disease
infarctions	I-Disease
and	O
women	O
experienced	O
fewer	O
ischemic	O
strokes	B-Disease
.	O

Aspirin	B-Chemical
does	O
not	O
seem	O
to	O
affect	O
CVD	B-Disease
mortality	O
or	O
all	O
-	O
cause	O
mortality	O
in	O
either	O
men	O
or	O
women	O
.	O

The	O
use	O
of	O
aspirin	B-Chemical
for	O
primary	O
prevention	O
increases	O
the	O
risk	O
for	O
major	O
bleeding	B-Disease
events	O
,	O
primarily	O
gastrointestinal	B-Disease
bleeding	I-Disease
events	O
,	O
in	O
both	O
men	O
and	O
women	O
.	O

Men	O
have	O
an	O
increased	O
risk	O
for	O
hemorrhagic	B-Disease
strokes	I-Disease
with	O
aspirin	B-Chemical
use	O
.	O

A	O
new	O
RCT	O
and	O
meta	O
-	O
analysis	O
suggest	O
that	O
the	O
risk	O
for	O
hemorrhagic	B-Disease
strokes	I-Disease
in	O
women	O
is	O
not	O
statistically	O
significantly	O
increased	O
.	O

LIMITATIONS	O
:	O
New	O
evidence	O
on	O
aspirin	B-Chemical
for	O
the	O
primary	O
prevention	O
of	O
CVD	B-Disease
is	O
limited	O
.	O

The	O
dose	O
of	O
aspirin	B-Chemical
used	O
in	O
the	O
RCTs	O
varied	O
,	O
which	O
prevented	O
the	O
estimation	O
of	O
the	O
most	O
appropriate	O
dose	O
for	O
primary	O
prevention	O
.	O

Several	O
of	O
the	O
RCTs	O
were	O
conducted	O
within	O
populations	O
of	O
health	O
professionals	O
,	O
which	O
potentially	O
limits	O
generalizability	O
.	O

CONCLUSION	O
:	O
Aspirin	B-Chemical
reduces	O
the	O
risk	O
for	O
myocardial	B-Disease
infarction	I-Disease
in	O
men	O
and	O
strokes	B-Disease
in	O
women	O
.	O

Aspirin	B-Chemical
use	O
increases	O
the	O
risk	O
for	O
serious	O
bleeding	B-Disease
events	O
.	O

Reducing	O
harm	O
associated	O
with	O
anticoagulation	O
:	O
practical	O
considerations	O
of	O
argatroban	B-Chemical
therapy	O
in	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
.	O

Argatroban	B-Chemical
is	O
a	O
hepatically	O
metabolized	O
,	O
direct	O
thrombin	O
inhibitor	O
used	O
for	O
prophylaxis	O
or	O
treatment	O
of	O
thrombosis	B-Disease
in	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
(	O
HIT	B-Disease
)	O
and	O
for	O
patients	O
with	O
or	O
at	O
risk	O
of	O
HIT	B-Disease
undergoing	O
percutaneous	O
coronary	O
intervention	O
(	O
PCI	O
)	O
.	O

The	O
objective	O
of	O
this	O
review	O
is	O
to	O
summarize	O
practical	O
considerations	O
of	O
argatroban	B-Chemical
therapy	O
in	O
HIT	B-Disease
.	O

The	O
US	O
FDA	O
-	O
recommended	O
argatroban	B-Chemical
dose	O
in	O
HIT	B-Disease
is	O
2	O
microg	O
/	O
kg	O
/	O
min	O
(	O
reduced	O
in	O
patients	O
with	O
hepatic	B-Disease
impairment	I-Disease
and	O
in	O
paediatric	O
patients	O
)	O
,	O
adjusted	O
to	O
achieve	O
activated	O
partial	O
thromboplastin	O
times	O
(	O
aPTTs	O
)	O
1	O
.	O
5	O
-	O
3	O
times	O
baseline	O
(	O
not	O
>	O
100	O
seconds	O
)	O
.	O

Contemporary	O
experiences	O
indicate	O
that	O
reduced	O
doses	O
are	O
also	O
needed	O
in	O
patients	O
with	O
conditions	O
associated	O
with	O
hepatic	O
hypoperfusion	O
,	O
e	O
.	O
g	O
.	O
heart	B-Disease
failure	I-Disease
,	O
yet	O
are	O
unnecessary	O
for	O
renal	B-Disease
dysfunction	I-Disease
,	O
adult	O
age	O
,	O
sex	O
,	O
race	O
/	O
ethnicity	O
or	O
obesity	B-Disease
.	O

Argatroban	B-Chemical
0	O
.	O
5	O
-	O
1	O
.	O
2	O
microg	O
/	O
kg	O
/	O
min	O
typically	O
supports	O
therapeutic	O
aPTTs	O
.	O

The	O
FDA	O
-	O
recommended	O
dose	O
during	O
PCI	O
is	O
25	O
microg	O
/	O
kg	O
/	O
min	O
(	O
350	O
microg	O
/	O
kg	O
initial	O
bolus	O
)	O
,	O
adjusted	O
to	O
achieve	O
activated	O
clotting	O
times	O
(	O
ACTs	O
)	O
of	O
300	O
-	O
450	O
sec	O
.	O

For	O
PCI	O
,	O
argatroban	B-Chemical
has	O
not	O
been	O
investigated	O
in	O
hepatically	O
impaired	O
patients	O
;	O
dose	O
adjustment	O
is	O
unnecessary	O
for	O
adult	O
age	O
,	O
sex	O
,	O
race	O
/	O
ethnicity	O
or	O
obesity	B-Disease
,	O
and	O
lesser	O
doses	O
may	O
be	O
adequate	O
with	O
concurrent	O
glycoprotein	O
IIb	O
/	O
IIIa	O
inhibition	O
.	O

Argatroban	B-Chemical
prolongs	O
the	O
International	O
Normalized	O
Ratio	O
,	O
and	O
published	O
approaches	O
for	O
monitoring	O
the	O
argatroban	B-Chemical
-	O
to	O
-	O
warfarin	B-Chemical
transition	O
should	O
be	O
followed	O
.	O

Major	O
bleeding	B-Disease
with	O
argatroban	B-Chemical
is	O
0	O
-	O
10	O
%	O
in	O
the	O
non	O
-	O
interventional	O
setting	O
and	O
0	O
-	O
5	O
.	O
8	O
%	O
periprocedurally	O
.	O

Argatroban	B-Chemical
has	O
no	O
specific	O
antidote	O
,	O
and	O
if	O
excessive	O
anticoagulation	O
occurs	O
,	O
argatroban	B-Chemical
infusion	O
should	O
be	O
stopped	O
or	O
reduced	O
.	O

Improved	O
familiarity	O
of	O
healthcare	O
professionals	O
with	O
argatroban	B-Chemical
therapy	O
in	O
HIT	B-Disease
,	O
including	O
in	O
special	O
populations	O
and	O
during	O
PCI	O
,	O
may	O
facilitate	O
reduction	O
of	O
harm	O
associated	O
with	O
HIT	B-Disease
(	O
e	O
.	O
g	O
.	O
fewer	O
thromboses	O
)	O
or	O
its	O
treatment	O
(	O
e	O
.	O
g	O
.	O
fewer	O
argatroban	B-Chemical
medication	O
errors	O
)	O
.	O

Rhabdomyolysis	B-Disease
and	O
brain	O
ischemic	B-Disease
stroke	I-Disease
in	O
a	O
heroin	B-Chemical
-	O
dependent	O
male	O
under	O
methadone	B-Chemical
maintenance	O
therapy	O
.	O

OBJECTIVE	O
:	O
There	O
are	O
several	O
complications	O
associated	O
with	O
heroin	B-Disease
abuse	I-Disease
,	O
some	O
of	O
which	O
are	O
life	O
-	O
threatening	O
.	O

Methadone	B-Chemical
may	O
aggravate	O
this	O
problem	O
.	O

METHOD	O
:	O
A	O
clinical	O
case	O
description	O
.	O

RESULTS	O
:	O
A	O
33	O
-	O
year	O
-	O
old	O
man	O
presented	O
with	O
rhabdomyolysis	B-Disease
and	O
cerebral	O
ischemic	B-Disease
stroke	I-Disease
after	O
intravenous	O
heroin	B-Chemical
.	O

He	O
had	O
used	O
heroin	B-Chemical
since	O
age	O
20	O
,	O
and	O
had	O
used	O
150	O
mg	O
methadone	B-Chemical
daily	O
for	O
6	O
months	O
.	O

He	O
was	O
found	O
unconsciousness	B-Disease
at	O
home	O
and	O
was	O
sent	O
to	O
our	O
hospital	O
.	O

In	O
the	O
ER	O
,	O
his	O
opiate	O
level	O
was	O
4497	O
ng	O
/	O
ml	O
.	O

In	O
the	O
ICU	O
,	O
we	O
found	O
rhabdomyolysis	B-Disease
,	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
and	O
acute	O
respiratory	B-Disease
failure	I-Disease
.	O

After	O
transfer	O
to	O
an	O
internal	O
ward	O
,	O
we	O
noted	O
aphasia	B-Disease
and	O
weakness	B-Disease
of	O
his	O
left	O
limbs	O
.	O

After	O
MRI	O
,	O
we	O
found	O
cerebral	B-Disease
ischemic	I-Disease
infarction	I-Disease
.	O

CONCLUSION	O
:	O
Those	O
using	O
methadone	B-Chemical
and	O
heroin	B-Chemical
simultaneously	O
may	O
increase	O
risk	O
of	O
rhabdomyolysis	B-Disease
and	O
ischemic	B-Disease
stroke	I-Disease
.	O

Patients	O
under	O
methadone	B-Chemical
maintenance	O
therapy	O
should	O
be	O
warned	O
regarding	O
these	O
serious	O
adverse	O
events	O
.	O

Hypotheses	O
of	O
heroin	B-Chemical
-	O
related	O
rhabdomyolysis	B-Disease
and	O
stroke	B-Disease
in	O
heroin	B-Chemical
abusers	O
are	O
discussed	O
.	O

Increased	O
vulnerability	O
to	O
6	B-Chemical
-	I-Chemical
hydroxydopamine	I-Chemical
lesion	O
and	O
reduced	O
development	O
of	O
dyskinesias	B-Disease
in	O
mice	O
lacking	O
CB1	O
cannabinoid	O
receptors	O
.	O

Motor	O
impairment	O
,	O
dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
neuronal	O
activity	O
and	O
proenkephalin	B-Chemical
(	O
PENK	B-Chemical
)	O
gene	O
expression	O
in	O
the	O
caudate	O
-	O
putamen	O
(	O
CPu	O
)	O
were	O
measured	O
in	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
-	O
lesioned	O
and	O
treated	O
(	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
+	I-Chemical
benserazide	I-Chemical
)	O
CB1	O
KO	O
and	O
WT	O
mice	O
.	O

A	O
lesion	O
induced	O
by	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
produced	O
more	O
severe	O
motor	O
deterioration	O
in	O
CB1	O
KO	O
mice	O
accompanied	O
by	O
more	O
loss	O
of	O
DA	B-Chemical
neurons	O
and	O
increased	O
PENK	B-Chemical
gene	O
expression	O
in	O
the	O
CPu	O
.	O

Oxidative	O
/	O
nitrosative	O
and	O
neuroinflammatory	O
parameters	O
were	O
estimated	O
in	O
the	O
CPu	O
and	O
cingulate	O
cortex	O
(	O
Cg	O
)	O
.	O

CB1	O
KO	O
mice	O
exhibited	O
higher	O
MDA	B-Chemical
levels	O
and	O
iNOS	O
protein	O
expression	O
in	O
the	O
CPu	O
and	O
Cg	O
compared	O
to	O
WT	O
mice	O
.	O

Treatment	O
with	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
+	I-Chemical
benserazide	I-Chemical
(	O
12	O
weeks	O
)	O
resulted	O
in	O
less	O
severe	O
dyskinesias	B-Disease
in	O
CB1	O
KO	O
than	O
in	O
WT	O
mice	O
.	O

The	O
results	O
revealed	O
that	O
the	O
lack	O
of	O
cannabinoid	O
CB1	O
receptors	O
increased	O
the	O
severity	O
of	O
motor	O
impairment	O
and	O
DA	B-Chemical
lesion	O
,	O
and	O
reduced	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
-	O
induced	O
dyskinesias	B-Disease
.	O

These	O
results	O
suggest	O
that	O
activation	O
of	O
CB1	O
receptors	O
offers	O
neuroprotection	O
against	O
dopaminergic	O
lesion	O
and	O
the	O
development	O
of	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
-	O
induced	O
dyskinesias	B-Disease
.	O

Hepatocellular	O
oxidant	O
stress	O
following	O
intestinal	O
ischemia	B-Disease
-	O
reperfusion	B-Disease
injury	I-Disease
.	O

Reperfusion	O
of	O
ischemic	B-Disease
intestine	O
results	O
in	O
acute	O
liver	B-Disease
dysfunction	I-Disease
characterized	O
by	O
hepatocellular	O
enzyme	O
release	O
into	O
plasma	O
,	O
reduction	O
in	O
bile	O
flow	O
rate	O
,	O
and	O
neutrophil	O
sequestration	O
within	O
the	O
liver	O
.	O

The	O
pathophysiology	O
underlying	O
this	O
acute	O
hepatic	B-Disease
injury	I-Disease
is	O
unknown	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
determine	O
whether	O
oxidants	O
are	O
associated	O
with	O
the	O
hepatic	B-Disease
injury	I-Disease
and	O
to	O
determine	O
the	O
relative	O
value	O
of	O
several	O
indirect	O
methods	O
of	O
assessing	O
oxidant	O
exposure	O
in	O
vivo	O
.	O

Rats	O
were	O
subjected	O
to	O
a	O
standardized	O
intestinal	O
ischemia	B-Disease
-	O
reperfusion	B-Disease
injury	I-Disease
.	O

Hepatic	O
tissue	O
was	O
assayed	O
for	O
lipid	O
peroxidation	O
products	O
and	O
oxidized	B-Chemical
and	I-Chemical
reduced	I-Chemical
glutathione	I-Chemical
.	O

There	O
was	O
no	O
change	O
in	O
hepatic	O
tissue	O
total	O
glutathione	B-Chemical
following	O
intestinal	O
ischemia	B-Disease
-	O
reperfusion	B-Disease
injury	I-Disease
.	O

Oxidized	B-Chemical
glutathione	I-Chemical
(	O
GSSG	B-Chemical
)	O
increased	O
significantly	O
following	O
30	O
and	O
60	O
min	O
of	O
reperfusion	O
.	O

There	O
was	O
no	O
increase	O
in	O
any	O
of	O
the	O
products	O
of	O
lipid	O
peroxidation	O
associated	O
with	O
this	O
injury	O
.	O

An	O
increase	O
in	O
GSSG	B-Chemical
within	O
hepatic	O
tissue	O
during	O
intestinal	O
reperfusion	O
suggests	O
exposure	O
of	O
hepatocytes	O
to	O
an	O
oxidant	O
stress	O
.	O

The	O
lack	O
of	O
a	O
significant	O
increase	O
in	O
products	O
of	O
lipid	O
peroxidation	O
suggests	O
that	O
the	O
oxidant	O
stress	O
is	O
of	O
insufficient	O
magnitude	O
to	O
result	O
in	O
irreversible	O
injury	O
to	O
hepatocyte	O
cell	O
membranes	O
.	O

These	O
data	O
also	O
suggest	O
that	O
the	O
measurement	O
of	O
tissue	O
GSSG	B-Chemical
may	O
be	O
a	O
more	O
sensitive	O
indicator	O
of	O
oxidant	O
stress	O
than	O
measurement	O
of	O
products	O
of	O
lipid	O
peroxidation	O
.	O

Animal	O
model	O
of	O
mania	B-Disease
induced	O
by	O
ouabain	B-Chemical
:	O
Evidence	O
of	O
oxidative	O
stress	O
in	O
submitochondrial	O
particles	O
of	O
the	O
rat	O
brain	O
.	O

The	O
intracerebroventricular	O
(	O
ICV	O
)	O
administration	O
of	O
ouabain	B-Chemical
(	O
a	O
Na	B-Chemical
(	O
+	O
)	O
/	O
K	B-Chemical
(	O
+	O
)	O
-	O
ATPase	O
inhibitor	O
)	O
in	O
rats	O
has	O
been	O
suggested	O
to	O
mimic	O
some	O
symptoms	O
of	O
human	O
bipolar	B-Disease
mania	I-Disease
.	O

Clinical	O
studies	O
have	O
shown	O
that	O
bipolar	B-Disease
disorder	I-Disease
may	O
be	O
related	O
to	O
mitochondrial	B-Disease
dysfunction	I-Disease
.	O

Herein	O
,	O
we	O
investigated	O
the	O
behavioral	O
and	O
biochemical	O
effects	O
induced	O
by	O
the	O
ICV	O
administration	O
of	O
ouabain	B-Chemical
in	O
rats	O
.	O

To	O
achieve	O
this	O
aim	O
,	O
the	O
effects	O
of	O
ouabain	B-Chemical
injection	O
immediately	O
after	O
and	O
7	O
days	O
following	O
a	O
single	O
ICV	O
administration	O
(	O
at	O
concentrations	O
of	O
10	O
(	O
-	O
2	O
)	O
and	O
10	O
(	O
-	O
3	O
)	O
M	O
)	O
on	O
locomotion	O
was	O
measured	O
using	O
the	O
open	O
-	O
field	O
test	O
.	O

Additionally	O
,	O
thiobarbituric	B-Chemical
acid	I-Chemical
reactive	O
substances	O
(	O
TBARSs	O
)	O
and	O
superoxide	B-Chemical
production	O
were	O
measured	O
in	O
submitochondrial	O
particles	O
of	O
the	O
prefrontal	O
cortex	O
,	O
hippocampus	O
,	O
striatum	O
and	O
amygdala	O
.	O

Our	O
findings	O
demonstrated	O
that	O
ouabain	B-Chemical
at	O
10	O
(	O
-	O
2	O
)	O
and	O
10	O
(	O
-	O
3	O
)	O
M	O
induced	O
hyperlocomotion	B-Disease
in	O
rats	O
,	O
and	O
this	O
response	O
remained	O
up	O
to	O
7	O
days	O
following	O
a	O
single	O
ICV	O
injection	O
.	O

In	O
addition	O
,	O
we	O
observed	O
that	O
the	O
persistent	O
increase	O
in	O
the	O
rat	O
spontaneous	O
locomotion	O
is	O
associated	O
with	O
increased	O
TBARS	O
levels	O
and	O
superoxide	B-Chemical
generation	O
in	O
submitochondrial	O
particles	O
in	O
the	O
prefrontal	O
cortex	O
,	O
striatum	O
and	O
amygdala	O
.	O

In	O
conclusion	O
,	O
ouabain	B-Chemical
-	O
induced	O
mania	B-Disease
-	O
like	O
behavior	O
may	O
provide	O
a	O
useful	O
animal	O
model	O
to	O
test	O
the	O
hypothesis	O
of	O
the	O
involvement	O
of	O
oxidative	O
stress	O
in	O
bipolar	B-Disease
disorder	I-Disease
.	O

Intraoperative	O
dialysis	O
during	O
liver	O
transplantation	O
with	O
citrate	B-Chemical
dialysate	O
.	O

Liver	O
transplantation	O
for	O
acutely	O
ill	O
patients	O
with	O
fulminant	B-Disease
liver	I-Disease
failure	I-Disease
carries	O
high	O
intraoperative	O
and	O
immediate	O
postoperative	O
risks	O
.	O

These	O
are	O
increased	O
with	O
the	O
presence	O
of	O
concomitant	O
acute	B-Disease
kidney	I-Disease
injury	I-Disease
(	O
AKI	B-Disease
)	O
and	O
intraoperative	O
dialysis	O
is	O
sometimes	O
required	O
to	O
allow	O
the	O
transplant	O
to	O
proceed	O
.	O

The	O
derangements	O
in	O
the	O
procoagulant	O
and	O
anticoagulant	O
pathways	O
during	O
fulminant	B-Disease
liver	I-Disease
failure	I-Disease
can	O
lead	O
to	O
difficulties	O
with	O
anticoagulation	O
during	O
dialysis	O
,	O
especially	O
when	O
continued	O
in	O
the	O
operating	O
room	O
.	O

Systemic	O
anticoagulation	O
is	O
unsafe	O
and	O
regional	O
citrate	B-Chemical
anticoagulation	O
in	O
the	O
absence	O
of	O
a	O
functional	O
liver	O
carries	O
the	O
risk	O
of	O
citrate	B-Chemical
toxicity	B-Disease
.	O

Citrate	B-Chemical
dialysate	O
,	O
a	O
new	O
dialysate	O
with	O
citric	B-Chemical
acid	I-Chemical
can	O
be	O
used	O
for	O
anticoagulation	O
in	O
patients	O
who	O
cannot	O
tolerate	O
heparin	B-Chemical
or	O
regional	O
citrate	B-Chemical
.	O

We	O
report	O
a	O
case	O
of	O
a	O
40	O
-	O
year	O
-	O
old	O
female	O
with	O
acetaminophen	B-Chemical
-	O
induced	O
fulminant	B-Disease
liver	I-Disease
failure	I-Disease
with	O
associated	O
AKI	B-Disease
who	O
underwent	O
intraoperative	O
dialytic	O
support	O
during	O
liver	O
transplantation	O
anticoagulated	O
with	O
citrate	B-Chemical
dialysate	O
during	O
the	O
entire	O
procedure	O
.	O

The	O
patient	O
tolerated	O
the	O
procedure	O
well	O
without	O
any	O
signs	O
of	O
citrate	B-Chemical
toxicity	B-Disease
and	O
maintained	O
adequate	O
anticoagulation	O
for	O
patency	O
of	O
the	O
dialysis	O
circuit	O
.	O

Citrate	B-Chemical
dialysate	O
is	O
a	O
safe	O
alternative	O
for	O
intradialytic	O
support	O
of	O
liver	O
transplantation	O
in	O
fulminant	B-Disease
liver	I-Disease
failure	I-Disease
.	O

Delirium	B-Disease
in	O
a	O
patient	O
with	O
toxic	O
flecainide	B-Chemical
plasma	O
concentrations	O
:	O
the	O
role	O
of	O
a	O
pharmacokinetic	O
drug	O
interaction	O
with	O
paroxetine	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
describe	O
a	O
case	O
of	O
flecainide	B-Chemical
-	O
induced	O
delirium	B-Disease
associated	O
with	O
a	O
pharmacokinetic	O
drug	O
interaction	O
with	O
paroxetine	B-Chemical
.	O

CASE	O
SUMMARY	O
:	O
A	O
69	O
-	O
year	O
-	O
old	O
white	O
female	O
presented	O
to	O
the	O
emergency	O
department	O
with	O
a	O
history	O
of	O
confusion	B-Disease
and	O
paranoia	B-Disease
over	O
the	O
past	O
several	O
days	O
.	O

On	O
admission	O
the	O
patient	O
was	O
taking	O
carvedilol	B-Chemical
12	O
mg	O
twice	O
daily	O
,	O
warfarin	B-Chemical
2	O
mg	O
/	O
day	O
,	O
folic	B-Chemical
acid	I-Chemical
1	O
mg	O
/	O
day	O
,	O
levothyroxine	B-Chemical
100	O
microg	O
/	O
day	O
,	O
pantoprazole	B-Chemical
40	O
mg	O
/	O
day	O
,	O
paroxetine	B-Chemical
40	O
mg	O
/	O
day	O
,	O
and	O
flecainide	B-Chemical
100	O
mg	O
twice	O
daily	O
.	O

Flecainide	B-Chemical
had	O
been	O
started	O
2	O
weeks	O
prior	O
for	O
atrial	B-Disease
fibrillation	I-Disease
.	O

Laboratory	O
test	O
findings	O
on	O
admission	O
were	O
notable	O
only	O
for	O
a	O
flecainide	B-Chemical
plasma	O
concentration	O
of	O
1360	O
microg	O
/	O
L	O
(	O
reference	O
range	O
200	O
-	O
1000	O
)	O
.	O

A	O
metabolic	O
drug	O
interaction	O
between	O
flecainide	B-Chemical
and	O
paroxetine	B-Chemical
,	O
which	O
the	O
patient	O
had	O
been	O
taking	O
for	O
more	O
than	O
5	O
years	O
,	O
was	O
considered	O
.	O

Paroxetine	B-Chemical
was	O
discontinued	O
and	O
the	O
dose	O
of	O
flecainide	B-Chemical
was	O
reduced	O
to	O
50	O
mg	O
twice	O
daily	O
.	O

Her	O
delirium	B-Disease
resolved	O
3	O
days	O
later	O
.	O

DISCUSSION	O
:	O
Flecainide	B-Chemical
and	O
pharmacologically	O
similar	O
agents	O
that	O
interact	O
with	O
sodium	B-Chemical
channels	O
may	O
cause	O
delirium	B-Disease
in	O
susceptible	O
patients	O
.	O

A	O
MEDLINE	O
search	O
(	O
1966	O
-	O
January	O
2009	O
)	O
revealed	O
one	O
in	O
vivo	O
pharmacokinetic	O
study	O
on	O
the	O
interaction	O
between	O
flecainide	B-Chemical
,	O
a	O
CYP2D6	O
substrate	O
,	O
and	O
paroxetine	B-Chemical
,	O
a	O
CYP2D6	O
inhibitor	O
,	O
as	O
well	O
as	O
3	O
case	O
reports	O
of	O
flecainide	B-Chemical
-	O
induced	O
delirium	B-Disease
.	O

According	O
to	O
the	O
Naranjo	O
probability	O
scale	O
,	O
flecainide	B-Chemical
was	O
the	O
probable	O
cause	O
of	O
the	O
patient	O
'	O
s	O
delirium	B-Disease
;	O
the	O
Horn	O
Drug	O
Interaction	O
Probability	O
Scale	O
indicates	O
a	O
possible	O
pharmacokinetic	O
drug	O
interaction	O
between	O
flecainide	B-Chemical
and	O
paroxetine	B-Chemical
.	O

CONCLUSIONS	O
:	O
Supratherapeutic	O
flecainide	B-Chemical
plasma	O
concentrations	O
may	O
cause	O
delirium	B-Disease
.	O

Because	O
toxicity	B-Disease
may	O
occur	O
when	O
flecainide	B-Chemical
is	O
prescribed	O
with	O
paroxetine	B-Chemical
and	O
other	O
potent	O
CYP2D6	O
inhibitors	O
,	O
flecainide	B-Chemical
plasma	O
concentrations	O
should	O
be	O
monitored	O
closely	O
with	O
commencement	O
of	O
CYP2D6	O
inhibitors	O
.	O

Efficacy	O
of	O
everolimus	B-Chemical
(	O
RAD001	B-Chemical
)	O
in	O
patients	O
with	O
advanced	O
NSCLC	B-Disease
previously	O
treated	O
with	O
chemotherapy	O
alone	O
or	O
with	O
chemotherapy	O
and	O
EGFR	O
inhibitors	O
.	O

BACKGROUND	O
:	O
Treatment	O
options	O
are	O
scarce	O
in	O
pretreated	O
advanced	O
non	B-Disease
-	I-Disease
small	I-Disease
-	I-Disease
cell	I-Disease
lung	I-Disease
cancer	I-Disease
(	O
NSCLC	B-Disease
)	O
patients	O
.	O

RAD001	B-Chemical
,	O
an	O
oral	O
inhibitor	O
of	O
the	O
mammalian	O
target	O
of	O
rapamycin	B-Chemical
(	O
mTOR	O
)	O
,	O
has	O
shown	O
phase	O
I	O
efficacy	O
in	O
NSCLC	B-Disease
.	O

METHODS	O
:	O
Stage	O
IIIb	O
or	O
IV	O
NSCLC	B-Disease
patients	O
,	O
with	O
two	O
or	O
fewer	O
prior	O
chemotherapy	O
regimens	O
,	O
one	O
platinum	B-Chemical
based	O
(	O
stratum	O
1	O
)	O
or	O
both	O
chemotherapy	O
and	O
epidermal	O
growth	O
factor	O
receptor	O
tyrosine	B-Chemical
kinase	O
inhibitors	O
(	O
stratum	O
2	O
)	O
,	O
received	O
RAD001	B-Chemical
10	O
mg	O
/	O
day	O
until	O
progression	O
or	O
unacceptable	O
toxicity	B-Disease
.	O

Primary	O
objective	O
was	O
overall	O
response	O
rate	O
(	O
ORR	O
)	O
.	O

Analyses	O
of	O
markers	O
associated	O
with	O
the	O
mTOR	O
pathway	O
were	O
carried	O
out	O
on	O
archival	O
tumor	B-Disease
from	O
a	O
subgroup	O
using	O
immunohistochemistry	O
(	O
IHC	O
)	O
and	O
direct	O
mutation	O
sequencing	O
.	O

RESULTS	O
:	O
Eighty	O
-	O
five	O
patients	O
were	O
enrolled	O
,	O
42	O
in	O
stratum	O
1	O
and	O
43	O
in	O
stratum	O
.	O

ORR	O
was	O
4	O
.	O
7	O
%	O
(	O
7	O
.	O
1	O
%	O
stratum	O
1	O
;	O
2	O
.	O
3	O
%	O
stratum	O
2	O
)	O
.	O

Overall	O
disease	O
control	O
rate	O
was	O
47	O
.	O
1	O
%	O
.	O

Median	O
progression	O
-	O
free	O
survivals	O
(	O
PFSs	O
)	O
were	O
2	O
.	O
6	O
(	O
stratum	O
1	O
)	O
and	O
2	O
.	O
7	O
months	O
(	O
stratum	O
2	O
)	O
.	O

Common	O
>	O
or	O
=	O
grade	O
3	O
events	O
were	O
fatigue	B-Disease
,	O
dyspnea	B-Disease
,	O
stomatitis	B-Disease
,	O
anemia	B-Disease
,	O
and	O
thrombocytopenia	B-Disease
.	O

Pneumonitis	B-Disease
,	O
probably	O
or	O
possibly	O
related	O
,	O
mainly	O
grade	O
1	O
/	O
2	O
,	O
occurred	O
in	O
25	O
%	O
.	O

Cox	O
regression	O
analysis	O
of	O
IHC	O
scores	O
found	O
that	O
only	O
phospho	O
AKT	O
(	O
pAKT	O
)	O
was	O
a	O
significant	O
independent	O
predictor	O
of	O
worse	O
PFS	O
.	O

CONCLUSIONS	O
:	O
RAD001	B-Chemical
10	O
mg	O
/	O
day	O
was	O
well	O
tolerated	O
,	O
showing	O
modest	O
clinical	O
activity	O
in	O
pretreated	O
NSCLC	B-Disease
.	O

Evaluation	O
of	O
RAD001	B-Chemical
plus	O
standard	O
therapy	O
for	O
metastatic	O
NSCLC	B-Disease
continues	O
.	O

Posttransplant	O
anemia	B-Disease
:	O
the	O
role	O
of	O
sirolimus	B-Chemical
.	O

Posttransplant	O
anemia	B-Disease
is	O
a	O
common	O
problem	O
that	O
may	O
hinder	O
patients	O
'	O
quality	O
of	O
life	O
.	O

It	O
occurs	O
in	O
12	O
to	O
76	O
%	O
of	O
patients	O
,	O
and	O
is	O
most	O
common	O
in	O
the	O
immediate	O
posttransplant	O
period	O
.	O

A	O
variety	O
of	O
factors	O
have	O
been	O
identified	O
that	O
increase	O
the	O
risk	O
of	O
posttransplant	O
anemia	B-Disease
,	O
of	O
which	O
the	O
level	O
of	O
renal	O
function	O
is	O
most	O
important	O
.	O

Sirolimus	B-Chemical
,	O
a	O
mammalian	O
target	O
of	O
rapamycin	B-Chemical
inhibitor	O
,	O
has	O
been	O
implicated	O
as	O
playing	O
a	O
special	O
role	O
in	O
posttransplant	O
anemia	B-Disease
.	O

This	O
review	O
considers	O
anemia	B-Disease
associated	O
with	O
sirolimus	B-Chemical
,	O
including	O
its	O
presentation	O
,	O
mechanisms	O
,	O
and	O
management	O
.	O

Coronary	O
computerized	O
tomography	O
angiography	O
for	O
rapid	O
discharge	O
of	O
low	O
-	O
risk	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
.	O

BACKGROUND	O
:	O
Most	O
patients	O
presenting	O
to	O
emergency	O
departments	O
(	O
EDs	O
)	O
with	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
are	O
admitted	O
for	O
at	O
least	O
12	O
hours	O
and	O
receive	O
a	O
"	O
rule	O
out	O
acute	B-Disease
coronary	I-Disease
syndrome	I-Disease
"	O
protocol	O
,	O
often	O
with	O
noninvasive	O
testing	O
prior	O
to	O
discharge	O
.	O

In	O
patients	O
without	O
cocaine	B-Chemical
use	O
,	O
coronary	O
computerized	O
tomography	O
angiography	O
(	O
CTA	O
)	O
has	O
been	O
shown	O
to	O
be	O
useful	O
for	O
identifying	O
a	O
group	O
of	O
patients	O
at	O
low	O
risk	O
for	O
cardiac	O
events	O
who	O
can	O
be	O
safely	O
discharged	O
.	O

It	O
is	O
unclear	O
whether	O
a	O
coronary	O
CTA	O
strategy	O
would	O
be	O
efficacious	O
in	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
,	O
as	O
coronary	B-Disease
vasospasm	I-Disease
may	O
account	O
for	O
some	O
of	O
the	O
ischemia	B-Disease
.	O

We	O
studied	O
whether	O
a	O
negative	O
coronary	O
CTA	O
in	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
could	O
identify	O
a	O
subset	O
safe	O
for	O
discharge	O
.	O

METHODS	O
:	O
We	O
prospectively	O
evaluated	O
the	O
safety	O
of	O
coronary	O
CTA	O
for	O
low	O
-	O
risk	O
patients	O
who	O
presented	O
to	O
the	O
ED	O
with	O
cocaineassociated	O
chest	B-Disease
pain	I-Disease
(	O
self	O
-	O
reported	O
or	O
positive	O
urine	O
test	O
)	O
.	O

Consecutive	O
patients	O
received	O
either	O
immediate	O
coronary	O
CTA	O
in	O
the	O
ED	O
(	O
without	O
serial	O
markers	O
)	O
or	O
underwent	O
coronary	O
CTA	O
after	O
a	O
brief	O
observation	O
period	O
with	O
serial	O
cardiac	O
marker	O
measurements	O
.	O

Patients	O
with	O
negative	O
coronary	O
CTA	O
(	O
maximal	O
stenosis	B-Disease
less	O
than	O
50	O
%	O
)	O
were	O
discharged	O
.	O

The	O
main	O
outcome	O
was	O
30	O
-	O
day	O
cardiovascular	O
death	O
or	O
myocardial	B-Disease
infarction	I-Disease
.	O

RESULTS	O
:	O
A	O
total	O
of	O
59	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
chest	B-Disease
pain	I-Disease
were	O
evaluated	O
.	O

Patients	O
had	O
a	O
mean	O
age	O
of	O
45	O
.	O
6	O
+	O
/	O
-	O
6	O
.	O
6	O
yrs	O
and	O
were	O
86	O
%	O
black	O
,	O
66	O
%	O
male	O
.	O

Seventy	O
-	O
nine	O
percent	O
had	O
a	O
normal	O
or	O
nonspecific	O
ECG	O
and	O
85	O
%	O
had	O
a	O
TIMI	O
score	O
<	O
2	O
.	O

Twenty	O
patients	O
received	O
coronary	O
CTA	O
immediately	O
in	O
the	O
ED	O
,	O
18	O
of	O
whom	O
were	O
discharged	O
following	O
CTA	O
(	O
90	O
%	O
)	O
.	O

Thirty	O
-	O
nine	O
received	O
coronary	O
CTA	O
after	O
a	O
brief	O
observation	O
period	O
,	O
with	O
37	O
discharged	O
home	O
following	O
CTA	O
(	O
95	O
%	O
)	O
.	O

Six	O
patients	O
had	O
coronary	B-Disease
stenosis	I-Disease
>	O
or	O
=	O
50	O
%	O
.	O

During	O
the	O
30	O
-	O
day	O
follow	O
-	O
up	O
period	O
,	O
no	O
patients	O
died	O
of	O
a	O
cardiovascular	O
event	O
(	O
0	O
%	O
;	O
95	O
%	O
CI	O
,	O
0	O
-	O
6	O
.	O
1	O
%	O
)	O
and	O
no	O
patient	O
sustained	O
a	O
nonfatal	O
myocardial	B-Disease
infarction	I-Disease
(	O
0	O
%	O
;	O
95	O
%	O
CI	O
,	O
0	O
-	O
6	O
.	O
1	O
%	O
)	O
.	O

CONCLUSIONS	O
:	O
Although	O
cocaine	B-Chemical
-	O
associated	O
myocardial	B-Disease
ischemia	I-Disease
can	O
result	O
from	O
coronary	O
vasoconstriction	O
,	O
patients	O
with	O
cocaine	B-Chemical
associated	O
chest	B-Disease
pain	I-Disease
,	O
a	O
non	O
-	O
ischemic	B-Disease
ECG	O
,	O
and	O
a	O
TIMI	O
risk	O
score	O
<	O
2	O
may	O
be	O
safely	O
discharged	O
from	O
the	O
ED	O
after	O
a	O
negative	O
coronary	O
CTA	O
with	O
a	O
low	O
risk	O
of	O
30	O
-	O
day	O
adverse	O
events	O
.	O

Bilateral	O
haemorrhagic	B-Disease
infarction	I-Disease
of	I-Disease
the	I-Disease
globus	I-Disease
pallidus	I-Disease
after	O
cocaine	B-Chemical
and	O
alcohol	B-Chemical
intoxication	O
.	O

Cocaine	B-Chemical
is	O
a	O
risk	O
factor	O
for	O
both	O
ischemic	B-Disease
and	I-Disease
haemorrhagic	I-Disease
stroke	I-Disease
.	O

We	O
present	O
the	O
case	O
of	O
a	O
31	O
-	O
year	O
-	O
old	O
man	O
with	O
bilateral	O
ischemia	B-Disease
of	I-Disease
the	I-Disease
globus	I-Disease
pallidus	I-Disease
after	O
excessive	O
alcohol	B-Chemical
and	O
intranasal	O
cocaine	B-Chemical
use	O
.	O

Drug	O
-	O
related	O
globus	B-Disease
pallidus	I-Disease
infarctions	I-Disease
are	O
most	O
often	O
associated	O
with	O
heroin	B-Chemical
.	O

Bilateral	O
basal	B-Disease
ganglia	I-Disease
infarcts	I-Disease
after	O
the	O
use	O
of	O
cocaine	B-Chemical
,	O
without	O
concurrent	O
heroin	B-Chemical
use	O
,	O
have	O
never	O
been	O
reported	O
.	O

In	O
our	O
patient	O
,	O
transient	O
cardiac	B-Disease
arrhythmia	I-Disease
or	O
respiratory	B-Disease
dysfunction	I-Disease
related	O
to	O
cocaine	B-Chemical
and	O
/	O
or	O
ethanol	B-Chemical
use	O
were	O
the	O
most	O
likely	O
causes	O
of	O
cerebral	B-Disease
hypoperfusion	I-Disease
.	O

Late	O
fulminant	O
posterior	B-Disease
reversible	I-Disease
encephalopathy	I-Disease
syndrome	I-Disease
after	O
liver	O
transplant	O
.	O

OBJECTIVES	O
:	O
Posterior	B-Disease
leukoencephalopathy	I-Disease
due	O
to	O
calcineurin	O
-	O
inhibitor	O
-	O
related	O
neurotoxicity	B-Disease
is	O
a	O
rare	O
but	O
severe	O
complication	O
that	O
results	O
from	O
treatment	O
with	O
immunosuppressive	O
agents	O
(	O
primarily	O
those	O
administered	O
after	O
a	O
liver	O
or	O
kidney	O
transplant	O
)	O
.	O

The	O
pathophysiologic	O
mechanisms	O
of	O
that	O
disorder	O
remain	O
unknown	O
.	O

CASE	O
:	O
We	O
report	O
the	O
case	O
of	O
a	O
46	O
-	O
year	O
-	O
old	O
woman	O
who	O
received	O
a	O
liver	O
transplant	O
in	O
our	O
center	O
as	O
treatment	O
for	O
alcoholic	B-Disease
cirrhosis	I-Disease
and	O
in	O
whom	O
either	O
a	O
fulminant	O
course	O
of	O
posterior	B-Disease
leukoencephalopathy	I-Disease
or	O
posterior	B-Disease
reversible	I-Disease
encephalopathy	I-Disease
syndrome	I-Disease
developed	O
110	O
days	O
after	O
transplant	O
.	O

After	O
an	O
initially	O
uneventful	O
course	O
after	O
the	O
transplant	O
,	O
the	O
patient	O
rapidly	O
fell	O
into	O
deep	O
coma	O
.	O

RESULTS	O
:	O
Cerebral	O
MRI	O
scan	O
showed	O
typical	O
signs	O
of	O
enhancement	O
in	O
the	O
pontine	O
and	O
posterior	O
regions	O
.	O

Switching	O
the	O
immunosuppressive	O
regimen	O
from	O
tacrolimus	B-Chemical
to	O
cyclosporine	B-Chemical
did	O
not	O
improve	O
the	O
clinical	O
situation	O
.	O

The	O
termination	O
of	O
treatment	O
with	O
any	O
calcineurin	O
inhibitor	O
resulted	O
in	O
a	O
complete	O
resolution	O
of	O
that	O
complication	O
.	O

CONCLUSIONS	O
:	O
Posterior	B-Disease
reversible	I-Disease
encephalopathy	I-Disease
syndrome	I-Disease
after	O
liver	O
transplant	O
is	O
rare	O
.	O

We	O
recommend	O
a	O
complete	O
cessation	O
of	O
any	O
calcineurin	O
inhibitor	O
rather	O
than	O
a	O
dose	O
reduction	O
.	O

Prolonged	O
hypothermia	B-Disease
as	O
a	O
bridge	O
to	O
recovery	O
for	O
cerebral	B-Disease
edema	I-Disease
and	O
intracranial	B-Disease
hypertension	I-Disease
associated	O
with	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
.	O

BACKGROUND	O
:	O
To	O
review	O
evidence	O
-	O
based	O
treatment	O
options	O
in	O
patients	O
with	O
cerebral	B-Disease
edema	I-Disease
complicating	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
(	O
FHF	B-Disease
)	O
and	O
discuss	O
the	O
potential	O
applications	O
of	O
hypothermia	B-Disease
.	O

METHOD	O
:	O
Case	O
-	O
based	O
observations	O
from	O
a	O
medical	O
intensive	O
care	O
unit	O
(	O
MICU	O
)	O
in	O
a	O
tertiary	O
care	O
facility	O
in	O
a	O
27	O
-	O
year	O
-	O
old	O
female	O
with	O
FHF	B-Disease
from	O
acetaminophen	B-Chemical
and	O
resultant	O
cerebral	B-Disease
edema	I-Disease
.	O

RESULTS	O
:	O
Our	O
patient	O
was	O
admitted	O
to	O
the	O
MICU	O
after	O
being	O
found	O
unresponsive	O
with	O
presumed	O
toxicity	B-Disease
from	O
acetaminophen	B-Chemical
which	O
was	O
ingested	O
over	O
a	O
2	O
-	O
day	O
period	O
.	O

The	O
patient	O
had	O
depressed	O
of	O
mental	O
status	O
lasting	O
at	O
least	O
24	O
h	O
prior	O
to	O
admission	O
.	O

Initial	O
evaluation	O
confirmed	O
FHF	B-Disease
from	O
acetaminophen	B-Chemical
and	O
cerebral	B-Disease
edema	I-Disease
.	O

The	O
patient	O
was	O
treated	O
with	O
hyperosmolar	O
therapy	O
,	O
hyperventilation	B-Disease
,	O
sedation	O
,	O
and	O
chemical	O
paralysis	B-Disease
.	O

Her	O
intracranial	O
pressure	O
remained	O
elevated	O
despite	O
maximal	O
medical	O
therapy	O
.	O

We	O
then	O
initiated	O
therapeutic	O
hypothermia	B-Disease
which	O
was	O
continued	O
for	O
5	O
days	O
.	O

At	O
re	O
-	O
warming	O
,	O
patient	O
had	O
resolution	O
of	O
her	O
cerebral	B-Disease
edema	I-Disease
and	O
intracranial	B-Disease
hypertension	I-Disease
.	O

At	O
discharge	O
,	O
she	O
had	O
complete	O
recovery	O
of	O
neurological	O
and	O
hepatic	O
functions	O
.	O

CONCLUSION	O
:	O
In	O
patients	O
with	O
FHF	B-Disease
and	O
cerebral	B-Disease
edema	I-Disease
from	O
acetaminophen	B-Chemical
overdose	B-Disease
,	O
prolonged	O
therapeutic	O
hypothermia	B-Disease
could	O
potentially	O
be	O
used	O
as	O
a	O
life	O
saving	O
therapy	O
and	O
a	O
bridge	O
to	O
hepatic	O
and	O
neurological	O
recovery	O
.	O

A	O
clinical	O
trial	O
of	O
hypothermia	B-Disease
in	O
patients	O
with	O
this	O
condition	O
is	O
warranted	O
.	O

Binasal	B-Disease
visual	I-Disease
field	I-Disease
defects	I-Disease
are	O
not	O
specific	O
to	O
vigabatrin	B-Chemical
.	O

This	O
study	O
investigated	O
the	O
visual	B-Disease
defects	I-Disease
associated	O
with	O
the	O
antiepileptic	O
drug	O
vigabatrin	B-Chemical
(	O
VGB	B-Chemical
)	O
.	O

Two	O
hundred	O
four	O
people	O
with	O
epilepsy	B-Disease
were	O
grouped	O
on	O
the	O
basis	O
of	O
antiepileptic	O
drug	O
therapy	O
(	O
current	O
,	O
previous	O
,	O
or	O
no	O
exposure	O
to	O
VGB	B-Chemical
)	O
.	O

Groups	O
were	O
matched	O
with	O
respect	O
to	O
age	O
,	O
gender	O
,	O
and	O
seizure	B-Disease
frequency	O
.	O

All	O
patients	O
underwent	O
objective	O
assessment	O
of	O
electrophysiological	O
function	O
(	O
wide	O
-	O
field	O
multifocal	O
electroretinography	O
)	O
and	O
conventional	O
visual	O
field	O
testing	O
(	O
static	O
perimetry	O
)	O
.	O

Bilateral	O
visual	O
field	O
constriction	O
was	O
observed	O
in	O
59	O
%	O
of	O
patients	O
currently	O
taking	O
VGB	B-Chemical
,	O
43	O
%	O
of	O
patients	O
who	O
previously	O
took	O
VGB	B-Chemical
,	O
and	O
24	O
%	O
of	O
patients	O
with	O
no	O
exposure	O
to	O
VGB	B-Chemical
.	O

Assessment	O
of	O
retinal	O
function	O
revealed	O
abnormal	O
responses	O
in	O
48	O
%	O
of	O
current	O
VGB	B-Chemical
users	O
and	O
22	O
%	O
of	O
prior	O
VGB	B-Chemical
users	O
,	O
but	O
in	O
none	O
of	O
the	O
patients	O
without	O
previous	O
exposure	O
to	O
VGB	B-Chemical
.	O

Bilateral	B-Disease
visual	I-Disease
field	I-Disease
abnormalities	I-Disease
are	O
common	O
in	O
the	O
treated	O
epilepsy	B-Disease
population	O
,	O
irrespective	O
of	O
drug	O
history	O
.	O

Assessment	O
by	O
conventional	O
static	O
perimetry	O
may	O
neither	O
be	O
sufficiently	O
sensitive	O
nor	O
specific	O
to	O
reliably	O
identify	O
retinal	B-Disease
toxicity	I-Disease
associated	O
with	O
VGB	B-Chemical
.	O

Smoking	O
of	O
crack	B-Chemical
cocaine	I-Chemical
as	O
a	O
risk	O
factor	O
for	O
HIV	B-Disease
infection	I-Disease
among	O
people	O
who	O
use	O
injection	O
drugs	O
.	O

BACKGROUND	O
:	O
Little	O
is	O
known	O
about	O
the	O
possible	O
role	O
that	O
smoking	O
crack	B-Chemical
cocaine	I-Chemical
has	O
on	O
the	O
incidence	O
of	O
HIV	B-Disease
infection	I-Disease
.	O

Given	O
the	O
increasing	O
use	O
of	O
crack	B-Chemical
cocaine	I-Chemical
,	O
we	O
sought	O
to	O
examine	O
whether	O
use	O
of	O
this	O
illicit	O
drug	O
has	O
become	O
a	O
risk	O
factor	O
for	O
HIV	B-Disease
infection	I-Disease
.	O

METHODS	O
:	O
We	O
included	O
data	O
from	O
people	O
participating	O
in	O
the	O
Vancouver	O
Injection	O
Drug	O
Users	O
Study	O
who	O
reported	O
injecting	O
illicit	O
drugs	O
at	O
least	O
once	O
in	O
the	O
month	O
before	O
enrolment	O
,	O
lived	O
in	O
the	O
greater	O
Vancouver	O
area	O
,	O
were	O
HIV	O
-	O
negative	O
at	O
enrolment	O
and	O
completed	O
at	O
least	O
1	O
follow	O
-	O
up	O
study	O
visit	O
.	O

To	O
determine	O
whether	O
the	O
risk	O
of	O
HIV	B-Disease
seroconversion	I-Disease
among	O
daily	O
smokers	O
of	O
crack	B-Chemical
cocaine	I-Chemical
changed	O
over	O
time	O
,	O
we	O
used	O
Cox	O
proportional	O
hazards	O
regression	O
and	O
divided	O
the	O
study	O
into	O
3	O
periods	O
:	O
May	O
1	O
,	O
1996	O
-	O
Nov	O
.	O

30	O
,	O
1999	O
(	O
period	O
1	O
)	O
,	O
Dec	O
.	O

1	O
,	O
1999	O
-	O
Nov	O
.	O

30	O
,	O
2002	O
(	O
period	O
2	O
)	O
,	O
and	O
Dec	O
.	O

1	O
,	O
2002	O
-	O
Dec	O
.	O

30	O
,	O
2005	O
(	O
period	O
3	O
)	O
.	O

RESULTS	O
:	O
Overall	O
,	O
1048	O
eligible	O
injection	O
drug	O
users	O
were	O
included	O
in	O
our	O
study	O
.	O

Of	O
these	O
,	O
137	O
acquired	O
HIV	B-Disease
infection	I-Disease
during	O
follow	O
-	O
up	O
.	O

The	O
mean	O
proportion	O
of	O
participants	O
who	O
reported	O
daily	O
smoking	O
of	O
crack	B-Chemical
cocaine	I-Chemical
increased	O
from	O
11	O
.	O
6	O
%	O
in	O
period	O
1	O
to	O
39	O
.	O
7	O
%	O
in	O
period	O
3	O
.	O

After	O
adjusting	O
for	O
potential	O
confounders	O
,	O
we	O
found	O
that	O
the	O
risk	O
of	O
HIV	B-Disease
seroconversion	I-Disease
among	O
participants	O
who	O
were	O
daily	O
smokers	O
of	O
crack	B-Chemical
cocaine	I-Chemical
increased	O
over	O
time	O
(	O
period	O
1	O
:	O
hazard	O
ratio	O
[	O
HR	O
]	O
1	O
.	O
03	O
,	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
0	O
.	O
57	O
-	O
1	O
.	O
85	O
;	O
period	O
2	O
:	O
HR	O
1	O
.	O
68	O
,	O
95	O
%	O
CI	O
1	O
.	O
01	O
-	O
2	O
.	O
80	O
;	O
and	O
period	O
3	O
:	O
HR	O
2	O
.	O
74	O
,	O
95	O
%	O
CI	O
1	O
.	O
06	O
-	O
7	O
.	O
11	O
)	O
.	O

INTERPRETATION	O
:	O
Smoking	O
of	O
crack	B-Chemical
cocaine	I-Chemical
was	O
found	O
to	O
be	O
an	O
independent	O
risk	O
factor	O
for	O
HIV	B-Disease
seroconversion	I-Disease
among	O
people	O
who	O
were	O
injection	O
drug	O
users	O
.	O

This	O
finding	O
points	O
to	O
the	O
urgent	O
need	O
for	O
evidence	O
-	O
based	O
public	O
health	O
initiatives	O
targeted	O
at	O
people	O
who	O
smoke	O
crack	B-Chemical
cocaine	I-Chemical
.	O

Fluoxetine	B-Chemical
improves	O
the	O
memory	B-Disease
deficits	I-Disease
caused	O
by	O
the	O
chemotherapy	O
agent	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
.	O

Cancer	B-Disease
patients	O
who	O
have	O
been	O
treated	O
with	O
systemic	O
adjuvant	O
chemotherapy	O
have	O
described	O
experiencing	O
deteriorations	O
in	O
cognition	O
.	O

A	O
widely	O
used	O
chemotherapeutic	O
agent	O
,	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
,	O
readily	O
crosses	O
the	O
blood	O
-	O
brain	O
barrier	O
and	O
so	O
could	O
have	O
a	O
direct	O
effect	O
on	O
brain	O
function	O
.	O

In	O
particular	O
this	O
anti	O
mitotic	O
drug	O
could	O
reduce	O
cell	O
proliferation	O
in	O
the	O
neurogenic	O
regions	O
of	O
the	O
adult	O
brain	O
.	O

In	O
contrast	O
reports	O
indicate	O
that	O
hippocampal	O
dependent	O
neurogenesis	O
and	O
cognition	O
are	O
enhanced	O
by	O
the	O
SSRI	B-Chemical
antidepressant	O
Fluoxetine	B-Chemical
.	O

In	O
this	O
investigation	O
the	O
behavioural	O
effects	O
of	O
chronic	O
(	O
two	O
week	O
)	O
treatment	O
with	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
and	O
(	O
three	O
weeks	O
)	O
with	O
Fluoxetine	B-Chemical
either	O
separately	O
or	O
in	O
combination	O
with	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
were	O
tested	O
on	O
adult	O
Lister	O
hooded	O
rats	O
.	O

Behavioural	O
effects	O
were	O
tested	O
using	O
a	O
context	O
dependent	O
conditioned	O
emotional	O
response	O
test	O
(	O
CER	O
)	O
which	O
showed	O
that	O
animals	O
treated	O
with	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
had	O
a	O
significant	O
reduction	O
in	O
freezing	O
time	O
compared	O
to	O
controls	O
.	O

A	O
separate	O
group	O
of	O
animals	O
was	O
tested	O
using	O
a	O
hippocampal	O
dependent	O
spatial	O
working	O
memory	O
test	O
,	O
the	O
object	O
location	O
recognition	O
test	O
(	O
OLR	O
)	O
.	O

Animals	O
treated	O
only	O
with	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
showed	O
significant	O
deficits	O
in	O
their	O
ability	O
to	O
carry	O
out	O
the	O
OLR	O
task	O
but	O
co	O
administration	O
of	O
Fluoxetine	B-Chemical
improved	O
their	O
performance	O
.	O

5	B-Chemical
-	I-Chemical
FU	I-Chemical
chemotherapy	O
caused	O
a	O
significant	O
reduction	O
in	O
the	O
number	O
of	O
proliferating	O
cells	O
in	O
the	O
sub	O
granular	O
zone	O
of	O
the	O
dentate	O
gyrus	O
compared	O
to	O
controls	O
.	O

This	O
reduction	O
was	O
eliminated	O
when	O
Fluoxetine	B-Chemical
was	O
co	O
administered	O
with	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
.	O

Fluoxetine	B-Chemical
on	O
its	O
own	O
had	O
no	O
effect	O
on	O
proliferating	O
cell	O
number	O
or	O
behaviour	O
.	O

These	O
findings	O
suggest	O
that	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
can	O
negatively	O
affect	O
both	O
cell	O
proliferation	O
and	O
hippocampal	O
dependent	O
working	O
memory	O
and	O
that	O
these	O
deficits	O
can	O
be	O
reversed	O
by	O
the	O
simultaneous	O
administration	O
of	O
the	O
antidepressant	O
Fluoxetine	B-Chemical
.	O

Liver	O
-	O
specific	O
ablation	O
of	O
integrin	O
-	O
linked	O
kinase	O
in	O
mice	O
results	O
in	O
enhanced	O
and	O
prolonged	O
cell	O
proliferation	O
and	O
hepatomegaly	B-Disease
after	O
phenobarbital	B-Chemical
administration	O
.	O

We	O
have	O
recently	O
demonstrated	O
that	O
disruption	O
of	O
extracellular	O
matrix	O
(	O
ECM	O
)	O
/	O
integrin	O
signaling	O
via	O
elimination	O
of	O
integrin	O
-	O
linked	O
kinase	O
(	O
ILK	O
)	O
in	O
hepatocytes	O
interferes	O
with	O
signals	O
leading	O
to	O
termination	O
of	O
liver	O
regeneration	O
.	O

This	O
study	O
investigates	O
the	O
role	O
of	O
ILK	O
in	O
liver	O
enlargement	O
induced	O
by	O
phenobarbital	B-Chemical
(	O
PB	B-Chemical
)	O
.	O

Wild	O
-	O
type	O
(	O
WT	O
)	O
and	O
ILK	O
:	O
liver	O
-	O
/	O
-	O
mice	O
were	O
given	O
PB	B-Chemical
(	O
0	O
.	O
1	O
%	O
in	O
drinking	O
water	O
)	O
for	O
10	O
days	O
.	O

Livers	O
were	O
harvested	O
on	O
2	O
,	O
5	O
,	O
and	O
10	O
days	O
during	O
PB	B-Chemical
administration	O
.	O

In	O
the	O
hepatocyte	O
-	O
specific	O
ILK	O
/	O
liver	O
-	O
/	O
-	O
mice	O
,	O
the	O
liver	O
:	O
body	O
weight	O
ratio	O
was	O
more	O
than	O
double	O
as	O
compared	O
to	O
0	O
h	O
at	O
day	O
2	O
(	O
2	O
.	O
5	O
times	O
)	O
,	O
while	O
at	O
days	O
5	O
and	O
10	O
,	O
it	O
was	O
enlarged	O
three	O
times	O
.	O

In	O
the	O
WT	O
mice	O
,	O
the	O
increase	O
was	O
as	O
expected	O
from	O
previous	O
literature	O
(	O
1	O
.	O
8	O
times	O
)	O
and	O
seems	O
to	O
have	O
leveled	O
off	O
after	O
day	O
2	O
.	O

There	O
were	O
slightly	O
increased	O
proliferating	O
cell	O
nuclear	O
antigen	O
-	O
positive	O
cells	O
in	O
the	O
ILK	O
/	O
liver	O
-	O
/	O
-	O
animals	O
at	O
day	O
2	O
as	O
compared	O
to	O
WT	O
after	O
PB	B-Chemical
administration	O
.	O

In	O
the	O
WT	O
animals	O
,	O
the	O
proliferative	O
response	O
had	O
come	O
back	O
to	O
normal	O
by	O
days	O
5	O
and	O
10	O
.	O

Hepatocytes	O
of	O
the	O
ILK	O
/	O
liver	O
-	O
/	O
-	O
mice	O
continued	O
to	O
proliferate	O
up	O
until	O
day	O
10	O
.	O

ILK	O
/	O
liver	O
-	O
/	O
-	O
mice	O
also	O
showed	O
increased	O
expression	O
of	O
key	O
genes	O
involved	O
in	O
hepatocyte	O
proliferation	O
at	O
different	O
time	O
points	O
during	O
PB	B-Chemical
administration	O
.	O

In	O
summary	O
,	O
ECM	O
proteins	O
communicate	O
with	O
the	O
signaling	O
machinery	O
of	O
dividing	O
cells	O
via	O
ILK	O
to	O
regulate	O
hepatocyte	O
proliferation	O
and	O
termination	O
of	O
the	O
proliferative	O
response	O
.	O

Lack	O
of	O
ILK	O
in	O
the	O
hepatocytes	O
imparts	O
prolonged	O
proliferative	O
response	O
not	O
only	O
to	O
stimuli	O
related	O
to	O
liver	O
regeneration	O
but	O
also	O
to	O
xenobiotic	O
chemical	O
mitogens	O
,	O
such	O
as	O
PB	B-Chemical
.	O

Decreased	O
Expression	O
of	O
Na	B-Chemical
/	O
K	B-Chemical
-	O
ATPase	O
,	O
NHE3	O
,	O
NBC1	O
,	O
AQP1	O
and	O
OAT	O
in	O
Gentamicin	B-Chemical
-	O
induced	O
Nephropathy	B-Disease
.	O

The	O
present	O
study	O
was	O
aimed	O
to	O
determine	O
whether	O
there	O
is	O
an	O
altered	O
regulation	O
of	O
tubular	O
transporters	O
in	O
gentamicin	B-Chemical
-	O
induced	O
nephropathy	B-Disease
.	O

Sprague	O
-	O
Dawley	O
male	O
rats	O
(	O
200	O
~	O
250	O
g	O
)	O
were	O
subcutaneously	O
injected	O
with	O
gentamicin	B-Chemical
(	O
100	O
mg	O
/	O
kg	O
per	O
day	O
)	O
for	O
7	O
days	O
,	O
and	O
the	O
expression	O
of	O
tubular	O
transporters	O
was	O
determined	O
by	O
immunoblotting	O
and	O
immunohistochemistry	O
.	O

The	O
mRNA	O
and	O
protein	O
expression	O
of	O
OAT	O
was	O
also	O
determined	O
.	O

Gentamicin	B-Chemical
-	O
treated	O
rats	O
exhibited	O
significantly	O
decreased	O
creatinine	B-Chemical
clearance	O
along	O
with	O
increased	O
plasma	O
creatinine	B-Chemical
levels	O
.	O

Accordingly	O
,	O
the	O
fractional	O
excretion	O
of	O
sodium	B-Chemical
increased	O
.	O

Urine	O
volume	O
was	O
increased	O
,	O
while	O
urine	O
osmolality	O
and	O
free	O
water	O
reabsorption	O
were	O
decreased	O
.	O

Immunoblotting	O
and	O
immunohistochemistry	O
revealed	O
decreased	O
expression	O
of	O
Na	B-Chemical
(	O
+	O
)	O
/	O
K	B-Chemical
(	O
+	O
)	O
-	O
ATPase	O
,	O
NHE3	O
,	O
NBC1	O
,	O
and	O
AQP1	O
in	O
the	O
kidney	O
of	O
gentamicin	B-Chemical
-	O
treated	O
rats	O
.	O

The	O
expression	O
of	O
OAT1	O
and	O
OAT3	O
was	O
also	O
decreased	O
.	O

Gentamicin	B-Chemical
-	O
induced	O
nephropathy	B-Disease
may	O
at	O
least	O
in	O
part	O
be	O
causally	O
related	O
with	O
a	O
decreased	O
expression	O
of	O
Na	B-Chemical
(	O
+	O
)	O
/	O
K	B-Chemical
(	O
+	O
)	O
-	O
ATPase	O
,	O
NHE3	O
,	O
NBC1	O
,	O
AQP1	O
and	O
OAT	O
.	O

Acute	B-Disease
renal	I-Disease
failure	I-Disease
after	O
high	O
-	O
dose	O
methotrexate	B-Chemical
therapy	O
in	O
a	O
patient	O
with	O
ileostomy	O
.	O

High	O
-	O
dose	O
methotrexate	B-Chemical
(	O
HD	O
-	O
MTX	B-Chemical
)	O
is	O
an	O
important	O
treatment	O
for	O
Burkitt	B-Disease
lymphoma	I-Disease
,	O
but	O
can	O
cause	O
hepatic	B-Disease
and	I-Disease
renal	I-Disease
toxicity	I-Disease
when	O
its	O
clearance	O
is	O
delayed	O
.	O

We	O
report	O
a	O
case	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
after	O
HD	O
-	O
MTX	B-Chemical
therapy	O
in	O
a	O
patient	O
with	O
ileostomy	O
,	O
The	O
patient	O
was	O
a	O
3	O
-	O
year	O
-	O
old	O
boy	O
who	O
had	O
received	O
a	O
living	O
-	O
related	O
liver	O
transplantation	O
for	O
congenital	O
biliary	B-Disease
atresia	I-Disease
.	O

At	O
day	O
833	O
after	O
the	O
transplantation	O
,	O
he	O
was	O
diagnosed	O
with	O
PTLD	B-Disease
(	O
post	B-Disease
-	I-Disease
transplantation	I-Disease
lymphoproliferative	I-Disease
disorder	I-Disease
,	O
Burkitt	B-Disease
-	I-Disease
type	I-Disease
malignant	I-Disease
lymphoma	I-Disease
)	O
.	O

During	O
induction	O
therapy	O
,	O
he	O
suffered	O
ileal	O
perforation	O
and	O
ileostomy	O
was	O
performed	O
.	O

Subsequent	O
HD	O
-	O
MTX	B-Chemical
therapy	O
caused	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
that	O
required	O
continuous	O
hemodialysis	O
.	O

We	O
supposed	O
that	O
intravascular	O
hypovolemia	B-Disease
due	O
to	O
substantial	O
drainage	O
from	O
the	O
ileostoma	O
caused	O
acute	B-Disease
prerenal	I-Disease
failure	I-Disease
.	O

After	O
recovery	O
of	O
his	O
renal	O
function	O
,	O
we	O
could	O
safely	O
treat	O
the	O
patient	O
with	O
HD	O
-	O
MTX	B-Chemical
therapy	O
by	O
controlling	O
drainage	O
from	O
ileostoma	O
with	O
total	O
parenteral	O
nutrition	O
.	O

Longitudinal	O
association	O
of	O
alcohol	B-Chemical
use	O
with	O
HIV	B-Disease
disease	I-Disease
progression	O
and	O
psychological	O
health	O
of	O
women	O
with	O
HIV	O
.	O

We	O
evaluated	O
the	O
association	O
of	O
alcohol	B-Chemical
consumption	O
and	O
depression	B-Disease
,	O
and	O
their	O
effects	O
on	O
HIV	B-Disease
disease	I-Disease
progression	O
among	O
women	O
with	O
HIV	O
.	O

The	O
study	O
included	O
871	O
women	O
with	O
HIV	O
who	O
were	O
recruited	O
from	O
1993	O
-	O
1995	O
in	O
four	O
US	O
cities	O
.	O

The	O
participants	O
had	O
physical	O
examination	O
,	O
medical	O
record	O
extraction	O
,	O
and	O
venipuncture	O
,	O
CD4	O
+	O
T	O
-	O
cell	O
counts	O
determination	O
,	O
measurement	O
of	O
depression	B-Disease
symptoms	O
(	O
using	O
the	O
self	O
-	O
report	O
Center	O
for	O
Epidemiological	O
Studies	O
-	O
Depression	B-Disease
Scale	O
)	O
,	O
and	O
alcohol	B-Chemical
use	O
assessment	O
at	O
enrollment	O
,	O
and	O
semiannually	O
until	O
March	O
2000	O
.	O

Multilevel	O
random	O
coefficient	O
ordinal	O
models	O
as	O
well	O
as	O
multilevel	O
models	O
with	O
joint	O
responses	O
were	O
used	O
in	O
the	O
analysis	O
.	O

There	O
was	O
no	O
significant	O
association	O
between	O
level	O
of	O
alcohol	B-Chemical
use	O
and	O
CD4	O
+	O
T	O
-	O
cell	O
counts	O
.	O

When	O
participants	O
were	O
stratified	O
by	O
antiretroviral	O
therapy	O
(	O
ART	O
)	O
use	O
,	O
the	O
association	O
between	O
alcohol	B-Chemical
and	O
CD4	O
+	O
T	O
-	O
cell	O
did	O
not	O
reach	O
statistical	O
significance	O
.	O

The	O
association	O
between	O
alcohol	B-Chemical
consumption	O
and	O
depression	B-Disease
was	O
significant	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Depression	B-Disease
had	O
a	O
significant	O
negative	O
effect	O
on	O
CD4	O
+	O
T	O
-	O
cell	O
counts	O
over	O
time	O
regardless	O
of	O
ART	O
use	O
.	O

Our	O
findings	O
suggest	O
that	O
alcohol	B-Chemical
consumption	O
has	O
a	O
direct	O
association	O
with	O
depression	B-Disease
.	O

Moreover	O
,	O
depression	B-Disease
is	O
associated	O
with	O
HIV	B-Disease
disease	I-Disease
progression	O
.	O

Our	O
findings	O
have	O
implications	O
for	O
the	O
provision	O
of	O
alcohol	B-Chemical
use	O
interventions	O
and	O
psychological	O
resources	O
to	O
improve	O
the	O
health	O
of	O
women	O
with	O
HIV	O
.	O

Chemokine	O
CCL2	O
and	O
its	O
receptor	O
CCR2	O
are	O
increased	O
in	O
the	O
hippocampus	O
following	O
pilocarpine	B-Chemical
-	O
induced	O
status	B-Disease
epilepticus	I-Disease
.	O

BACKGROUND	O
:	O
Neuroinflammation	B-Disease
occurs	O
after	O
seizures	B-Disease
and	O
is	O
implicated	O
in	O
epileptogenesis	O
.	O

CCR2	O
is	O
a	O
chemokine	O
receptor	O
for	O
CCL2	O
and	O
their	O
interaction	O
mediates	O
monocyte	O
infiltration	O
in	O
the	O
neuroinflammatory	B-Disease
cascade	O
triggered	O
in	O
different	O
brain	O
pathologies	O
.	O

In	O
this	O
work	O
CCR2	O
and	O
CCL2	O
expression	O
were	O
examined	O
following	O
status	B-Disease
epilepticus	I-Disease
(	O
SE	B-Disease
)	O
induced	O
by	O
pilocarpine	B-Chemical
injection	O
.	O

METHODS	O
:	O
SE	B-Disease
was	O
induced	O
by	O
pilocarpine	B-Chemical
injection	O
.	O

Control	O
rats	O
were	O
injected	O
with	O
saline	O
instead	O
of	O
pilocarpine	B-Chemical
.	O

Five	O
days	O
after	O
SE	B-Disease
,	O
CCR2	O
staining	O
in	O
neurons	O
and	O
glial	O
cells	O
was	O
examined	O
using	O
imunohistochemical	O
analyses	O
.	O

The	O
number	O
of	O
CCR2	O
positive	O
cells	O
was	O
determined	O
using	O
stereology	O
probes	O
in	O
the	O
hippocampus	O
.	O

CCL2	O
expression	O
in	O
the	O
hippocampus	O
was	O
examined	O
by	O
molecular	O
assay	O
.	O

RESULTS	O
:	O
Increased	O
CCR2	O
was	O
observed	O
in	O
the	O
hippocampus	O
after	O
SE	B-Disease
.	O

Seizures	B-Disease
also	O
resulted	O
in	O
alterations	O
to	O
the	O
cell	O
types	O
expressing	O
CCR2	O
.	O

Increased	O
numbers	O
of	O
neurons	O
that	O
expressed	O
CCR2	O
was	O
observed	O
following	O
SE	B-Disease
.	O

Microglial	O
cells	O
were	O
more	O
closely	O
apposed	O
to	O
the	O
CCR2	O
-	O
labeled	O
cells	O
in	O
SE	B-Disease
rats	O
.	O

In	O
addition	O
,	O
rats	O
that	O
experienced	O
SE	B-Disease
exhibited	O
CCR2	O
-	O
labeling	O
in	O
populations	O
of	O
hypertrophied	B-Disease
astrocytes	O
,	O
especially	O
in	O
CA1	O
and	O
dentate	O
gyrus	O
.	O

These	O
CCR2	O
+	O
astroctytes	O
were	O
not	O
observed	O
in	O
control	O
rats	O
.	O

Examination	O
of	O
CCL2	O
expression	O
showed	O
that	O
it	O
was	O
elevated	O
in	O
the	O
hippocampus	O
following	O
SE	B-Disease
.	O

CONCLUSION	O
:	O
The	O
data	O
show	O
that	O
CCR2	O
and	O
CCL2	O
are	O
up	O
-	O
regulated	O
in	O
the	O
hippocampus	O
after	O
pilocarpine	B-Chemical
-	O
induced	O
SE	B-Disease
.	O

Seizures	B-Disease
also	O
result	O
in	O
changes	O
to	O
CCR2	O
receptor	O
expression	O
in	O
neurons	O
and	O
astrocytes	O
.	O

These	O
changes	O
might	O
be	O
involved	O
in	O
detrimental	O
neuroplasticity	O
and	O
neuroinflammatory	B-Disease
changes	O
that	O
occur	O
following	O
seizures	B-Disease
.	O

Metallothionein	B-Chemical
induction	O
reduces	O
caspase	O
-	O
3	O
activity	O
and	O
TNFalpha	O
levels	O
with	O
preservation	O
of	O
cognitive	O
function	O
and	O
intact	O
hippocampal	O
neurons	O
in	O
carmustine	B-Chemical
-	O
treated	O
rats	O
.	O

Hippocampal	O
integrity	O
is	O
essential	O
for	O
cognitive	O
functions	O
.	O

On	O
the	O
other	O
hand	O
,	O
induction	O
of	O
metallothionein	B-Chemical
(	O
MT	B-Chemical
)	O
by	O
ZnSO	B-Chemical
(	I-Chemical
4	I-Chemical
)	I-Chemical
and	O
its	O
role	O
in	O
neuroprotection	O
has	O
been	O
documented	O
.	O

The	O
present	O
study	O
aimed	O
to	O
explore	O
the	O
effect	O
of	O
MT	B-Chemical
induction	O
on	O
carmustine	B-Chemical
(	O
BCNU	B-Chemical
)	O
-	O
induced	O
hippocampal	O
cognitive	B-Disease
dysfunction	I-Disease
in	O
rats	O
.	O

A	O
total	O
of	O
60	O
male	O
Wistar	O
albino	O
rats	O
were	O
randomly	O
divided	O
into	O
four	O
groups	O
(	O
15	O
/	O
group	O
)	O
:	O
The	O
control	O
group	O
injected	O
with	O
single	O
doses	O
of	O
normal	O
saline	O
(	O
i	O
.	O
c	O
.	O
v	O
)	O
followed	O
24	O
h	O
later	O
by	O
BCNU	B-Chemical
solvent	O
(	O
i	O
.	O
v	O
)	O
.	O

The	O
second	O
group	O
administered	O
ZnSO	B-Chemical
(	I-Chemical
4	I-Chemical
)	I-Chemical
(	O
0	O
.	O
1	O
micromol	O
/	O
10	O
microl	O
normal	O
saline	O
,	O
i	O
.	O
c	O
.	O
v	O
,	O
once	O
)	O
then	O
BCNU	B-Chemical
solvent	O
(	O
i	O
.	O
v	O
)	O
after	O
24	O
h	O
.	O

Third	O
group	O
received	O
BCNU	B-Chemical
(	O
20	O
mg	O
/	O
kg	O
,	O
i	O
.	O
v	O
,	O
once	O
)	O
24	O
h	O
after	O
injection	O
with	O
normal	O
saline	O
(	O
i	O
.	O
c	O
.	O
v	O
)	O
.	O

Fourth	O
group	O
received	O
a	O
single	O
dose	O
of	O
ZnSO	B-Chemical
(	I-Chemical
4	I-Chemical
)	I-Chemical
(	O
0	O
.	O
1	O
micromol	O
/	O
10	O
microl	O
normal	O
saline	O
,	O
i	O
.	O
c	O
.	O
v	O
)	O
then	O
BCNU	B-Chemical
(	O
20	O
mg	O
/	O
kg	O
,	O
i	O
.	O
v	O
,	O
once	O
)	O
after	O
24	O
h	O
.	O

The	O
obtained	O
data	O
revealed	O
that	O
BCNU	B-Chemical
administration	O
resulted	O
in	O
deterioration	B-Disease
of	I-Disease
learning	I-Disease
and	I-Disease
short	I-Disease
-	I-Disease
term	I-Disease
memory	I-Disease
(	O
STM	O
)	O
,	O
as	O
measured	O
by	O
using	O
radial	O
arm	O
water	O
maze	O
,	O
accompanied	O
with	O
decreased	O
hippocampal	O
glutathione	B-Chemical
reductase	O
(	O
GR	O
)	O
activity	O
and	O
reduced	O
glutathione	B-Chemical
(	O
GSH	B-Chemical
)	O
content	O
.	O

Also	O
,	O
BCNU	B-Chemical
administration	O
increased	O
serum	O
tumor	B-Disease
necrosis	B-Disease
factor	O
-	O
alpha	O
(	O
TNFalpha	O
)	O
,	O
hippocampal	O
MT	B-Chemical
and	O
malondialdehyde	B-Chemical
(	O
MDA	B-Chemical
)	O
contents	O
as	O
well	O
as	O
caspase	O
-	O
3	O
activity	O
in	O
addition	O
to	O
histological	O
alterations	O
.	O

ZnSO	B-Chemical
(	I-Chemical
4	I-Chemical
)	I-Chemical
pretreatment	O
counteracted	O
BCNU	B-Chemical
-	O
induced	O
inhibition	O
of	O
GR	O
and	O
depletion	O
of	O
GSH	B-Chemical
and	O
resulted	O
in	O
significant	O
reduction	O
in	O
the	O
levels	O
of	O
MDA	B-Chemical
and	O
TNFalpha	O
as	O
well	O
as	O
the	O
activity	O
of	O
caspase	O
-	O
3	O
.	O

The	O
histological	O
features	O
were	O
improved	O
in	O
hippocampus	O
of	O
rats	O
treated	O
with	O
ZnSO	B-Chemical
(	I-Chemical
4	I-Chemical
)	I-Chemical
+	O
BCNU	B-Chemical
compared	O
to	O
only	O
BCNU	B-Chemical
-	O
treated	O
animals	O
.	O

In	O
conclusion	O
,	O
MT	B-Chemical
induction	O
halts	O
BCNU	B-Chemical
-	O
induced	O
hippocampal	O
toxicity	B-Disease
as	O
it	O
prevented	O
GR	O
inhibition	O
and	O
GSH	B-Chemical
depletion	O
and	O
counteracted	O
the	O
increased	O
levels	O
of	O
TNFalpha	O
,	O
MDA	B-Chemical
and	O
caspase	O
-	O
3	O
activity	O
with	O
subsequent	O
preservation	O
of	O
cognition	O
.	O

Fatal	O
carbamazepine	B-Chemical
induced	O
fulminant	B-Disease
eosinophilic	I-Disease
(	O
hypersensitivity	B-Disease
)	O
myocarditis	B-Disease
:	O
emphasis	O
on	O
anatomical	O
and	O
histological	O
characteristics	O
,	O
mechanisms	O
and	O
genetics	O
of	O
drug	B-Disease
hypersensitivity	I-Disease
and	O
differential	O
diagnosis	O
.	O

The	O
most	O
severe	O
adverse	O
reactions	O
to	O
carbamazepine	B-Chemical
have	O
been	O
observed	O
in	O
the	O
haemopoietic	O
system	O
,	O
the	O
liver	O
and	O
the	O
cardiovascular	O
system	O
.	O

A	O
frequently	O
fatal	O
,	O
although	O
exceptionally	O
rare	O
side	O
effect	O
of	O
carbamazepine	B-Chemical
is	O
necrotizing	O
eosinophilic	O
(	O
hypersensitivity	B-Disease
)	O
myocarditis	B-Disease
.	O

We	O
report	O
a	O
case	O
of	O
hypersensitivity	B-Disease
myocarditis	B-Disease
secondary	O
to	O
administration	O
of	O
carbamazepine	B-Chemical
.	O

Acute	O
hypersensitivity	B-Disease
myocarditis	B-Disease
was	O
not	O
suspected	O
clinically	O
,	O
and	O
the	O
diagnosis	O
was	O
made	O
post	O
-	O
mortem	O
.	O

Histology	O
revealed	O
diffuse	O
infiltration	O
of	O
the	O
myocardium	O
by	O
eosinophils	O
and	O
lymphocytes	O
with	O
myocyte	O
damage	O
.	O

Clinically	O
,	O
death	O
was	O
due	O
to	O
cardiogenic	B-Disease
shock	I-Disease
.	O

To	O
best	O
of	O
our	O
knowledge	O
this	O
is	O
the	O
second	O
case	O
of	O
fatal	O
carbamazepine	B-Chemical
induced	O
myocarditis	B-Disease
reported	O
in	O
English	O
literature	O
.	O

Neuropsychiatric	O
behaviors	O
in	O
the	O
MPTP	B-Chemical
marmoset	O
model	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

OBJECTIVES	O
:	O
Neuropsychiatric	O
symptoms	O
are	O
increasingly	O
recognised	O
as	O
a	O
significant	O
problem	O
in	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
.	O

These	O
symptoms	O
may	O
be	O
due	O
to	O
'	O
sensitisation	O
'	O
following	O
repeated	O
levodopa	B-Chemical
treatment	O
or	O
a	O
direct	O
effect	O
of	O
dopamine	B-Chemical
on	O
the	O
disease	O
state	O
.	O

The	O
levodopa	B-Chemical
-	O
treated	O
MPTP	B-Chemical
-	O
lesioned	O
marmoset	O
was	O
used	O
as	O
a	O
model	O
of	O
neuropsychiatric	B-Disease
symptoms	I-Disease
in	O
PD	B-Disease
patients	O
.	O

Here	O
we	O
compare	O
the	O
time	O
course	O
of	O
levodopa	B-Chemical
-	O
induced	O
motor	O
fluctuations	O
and	O
neuropsychiatric	B-Disease
-	I-Disease
like	I-Disease
behaviors	I-Disease
to	O
determine	O
the	O
relationship	O
between	O
duration	O
of	O
treatment	O
and	O
onset	O
of	O
symptoms	O
.	O

METHODS	O
:	O
Marmosets	O
were	O
administered	O
1	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
phenyl	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
2	I-Chemical
,	I-Chemical
3	I-Chemical
,	I-Chemical
6	I-Chemical
-	I-Chemical
tetrahydropyridine	I-Chemical
(	O
2	O
.	O
0	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
for	O
five	O
days	O
,	O
resulting	O
in	O
stable	O
parkinsonism	B-Disease
.	O

Levodopa	B-Chemical
(	O
15	O
mg	O
/	O
kg	O
and	O
benserazide	B-Chemical
,	O
3	O
.	O
75	O
mg	O
/	O
kg	O
)	O
p	O
.	O
o	O
.	O

b	O
.	O
i	O
.	O
d	O
,	O
was	O
administered	O
for	O
30	O
days	O
.	O

Animals	O
were	O
evaluated	O
for	O
parkinsonian	B-Disease
disability	I-Disease
,	O
dyskinesia	B-Disease
and	O
on	O
-	O
time	O
(	O
motor	O
fluctuations	O
)	O
and	O
neuropsychiatric	B-Disease
-	I-Disease
like	I-Disease
behaviors	I-Disease
on	O
Day	O
0	O
(	O
prior	O
to	O
levodopa	B-Chemical
)	O
and	O
on	O
Days	O
1	O
,	O
7	O
,	O
13	O
,	O
27	O
and	O
30	O
of	O
treatment	O
using	O
post	O
hoc	O
DVD	O
analysis	O
by	O
a	O
trained	O
rater	O
,	O
blind	O
to	O
the	O
treatment	O
day	O
.	O

RESULTS	O
:	O
The	O
neuropsychiatric	B-Disease
-	I-Disease
like	I-Disease
behavior	I-Disease
rating	O
scale	O
demonstrated	O
high	O
interrater	O
reliability	O
between	O
three	O
trained	O
raters	O
of	O
differing	O
professional	O
backgrounds	O
.	O

As	O
anticipated	O
,	O
animals	O
exhibited	O
a	O
progressive	O
increase	O
in	O
levodopa	B-Chemical
-	O
induced	O
motor	O
fluctuations	O
,	O
dyskinesia	B-Disease
and	O
wearing	O
-	O
off	O
,	O
that	O
correlated	O
with	O
the	O
duration	O
of	O
levodopa	B-Chemical
therapy	O
.	O

In	O
contrast	O
,	O
levodopa	B-Chemical
-	O
induced	O
neuropsychiatric	B-Disease
-	I-Disease
like	I-Disease
behaviors	I-Disease
were	O
present	O
on	O
Day	O
1	O
of	O
levodopa	B-Chemical
treatment	O
and	O
their	O
severity	O
did	O
not	O
correlate	O
with	O
duration	O
of	O
treatment	O
.	O

CONCLUSIONS	O
:	O
The	O
data	O
suggest	O
that	O
neuropsychiatric	B-Disease
disorders	I-Disease
in	O
PD	B-Disease
are	O
more	O
likely	O
an	O
interaction	O
between	O
levodopa	B-Chemical
and	O
the	O
disease	O
state	O
than	O
a	O
consequence	O
of	O
sensitisation	O
to	O
repeated	O
dopaminergic	O
therapy	O
.	O

Contrast	B-Chemical
medium	I-Chemical
nephrotoxicity	B-Disease
after	O
renal	O
artery	O
and	O
coronary	O
angioplasty	O
.	O

BACKGROUND	O
:	O
Renal	B-Disease
dysfunction	I-Disease
induced	O
by	O
iodinated	O
contrast	B-Chemical
medium	I-Chemical
(	O
CM	B-Chemical
)	O
administration	O
can	O
minimize	O
the	O
benefit	O
of	O
the	O
interventional	O
procedure	O
in	O
patients	O
undergoing	O
renal	O
angioplasty	O
(	O
PTRA	O
)	O
.	O

PURPOSE	O
:	O
To	O
compare	O
the	O
susceptibility	O
to	O
nephrotoxic	B-Disease
effect	O
of	O
CM	B-Chemical
in	O
patients	O
undergoing	O
PTRA	O
with	O
that	O
of	O
patients	O
submitted	O
to	O
percutaneous	O
coronary	O
intervention	O
(	O
PCI	O
)	O
.	O

MATERIAL	O
AND	O
METHODS	O
:	O
A	O
total	O
of	O
33	O
patients	O
successfully	O
treated	O
with	O
PTRA	O
(	O
PTRA	O
group	O
,	O
mean	O
age	O
70	O
+	O
/	O
-	O
12	O
years	O
,	O
23	O
female	O
,	O
basal	O
creatinine	B-Chemical
1	O
.	O
46	O
+	O
/	O
-	O
0	O
.	O
79	O
,	O
range	O
0	O
.	O
7	O
-	O
4	O
.	O
9	O
mg	O
/	O
dl	O
)	O
were	O
compared	O
with	O
33	O
patients	O
undergoing	O
successful	O
PCI	O
(	O
PCI	O
group	O
)	O
,	O
matched	O
for	O
basal	O
creatinine	B-Chemical
(	O
1	O
.	O
44	O
+	O
/	O
-	O
0	O
.	O
6	O
,	O
range	O
0	O
.	O
7	O
-	O
3	O
.	O
4	O
mg	O
/	O
dl	O
)	O
,	O
gender	O
,	O
and	O
age	O
.	O

In	O
both	O
groups	O
postprocedural	O
(	O
48	O
h	O
)	O
serum	O
creatinine	B-Chemical
was	O
measured	O
.	O

RESULTS	O
:	O
Postprocedural	O
creatinine	B-Chemical
level	O
decreased	O
nonsignificantly	O
in	O
the	O
PTRA	O
group	O
(	O
1	O
.	O
46	O
+	O
/	O
-	O
0	O
.	O
8	O
vs	O
.	O
1	O
.	O
34	O
+	O
/	O
-	O
0	O
.	O
5	O
mg	O
/	O
dl	O
,	O
P	O
=	O
NS	O
)	O
and	O
increased	O
significantly	O
in	O
the	O
PCI	O
group	O
(	O
1	O
.	O
44	O
+	O
/	O
-	O
0	O
.	O
6	O
vs	O
.	O
1	O
.	O
57	O
+	O
/	O
-	O
0	O
.	O
7	O
mg	O
/	O
dl	O
,	O
P	O
<	O
0	O
.	O
02	O
)	O
.	O

Changes	O
in	O
serum	O
creatinine	B-Chemical
after	O
intervention	O
(	O
after	O
-	O
before	O
)	O
were	O
significantly	O
different	O
between	O
the	O
PTRA	O
and	O
PCI	O
groups	O
(	O
-	O
0	O
.	O
12	O
+	O
/	O
-	O
0	O
.	O
5	O
vs	O
.	O
0	O
.	O
13	O
+	O
/	O
-	O
0	O
.	O
3	O
,	O
P	O
=	O
0	O
.	O
014	O
)	O
.	O

This	O
difference	O
was	O
not	O
related	O
to	O
either	O
a	O
different	O
clinical	O
risk	O
profile	O
or	O
to	O
the	O
volume	O
of	O
CM	B-Chemical
administered	O
.	O

CONCLUSION	O
:	O
In	O
this	O
preliminary	O
study	O
patients	O
submitted	O
to	O
PTRA	O
showed	O
a	O
lower	O
susceptibility	O
to	O
renal	B-Disease
damage	I-Disease
induced	O
by	O
CM	B-Chemical
administration	O
than	O
PCI	O
patients	O
.	O

The	O
effectiveness	O
of	O
PTRA	O
on	O
renal	O
function	O
seems	O
to	O
be	O
barely	O
influenced	O
by	O
CM	B-Chemical
toxicity	B-Disease
.	O

Diphenhydramine	B-Chemical
prevents	O
the	O
haemodynamic	O
changes	O
of	O
cimetidine	B-Chemical
in	O
ICU	O
patients	O
.	O

Cimetidine	B-Chemical
,	O
a	O
histamine	B-Chemical
2	O
(	O
H2	O
)	O
antagonist	O
,	O
produces	O
a	O
decrease	O
in	O
arterial	O
pressure	O
due	O
to	O
vasodilatation	O
,	O
especially	O
in	O
critically	O
ill	O
patients	O
.	O

This	O
may	O
be	O
because	O
cimetidine	B-Chemical
acts	O
as	O
a	O
histamine	B-Chemical
agonist	O
.	O

We	O
,	O
therefore	O
,	O
investigated	O
the	O
effects	O
of	O
the	O
histamine	B-Chemical
1	O
(	O
H1	O
)	O
receptor	O
antagonist	O
,	O
diphenhydramine	B-Chemical
,	O
on	O
the	O
haemodynamic	O
changes	O
observed	O
after	O
cimetidine	B-Chemical
in	O
ICU	O
patients	O
.	O

Each	O
patient	O
was	O
studied	O
on	O
two	O
separate	O
days	O
.	O

In	O
a	O
random	O
fashion	O
,	O
they	O
received	O
cimetidine	B-Chemical
200	O
mg	O
iv	O
on	O
one	O
day	O
,	O
and	O
on	O
the	O
other	O
,	O
a	O
pretreatment	O
of	O
diphenhydramine	B-Chemical
40	O
mg	O
iv	O
with	O
cimetidine	B-Chemical
200	O
mg	O
iv	O
.	O

In	O
the	O
non	O
-	O
pretreatment	O
group	O
,	O
mean	O
arterial	O
pressure	O
(	O
MAP	O
)	O
decreased	O
from	O
107	O
.	O
4	O
+	O
/	O
-	O
8	O
.	O
4	O
mmHg	O
to	O
86	O
.	O
7	O
+	O
/	O
-	O
11	O
.	O
4	O
mmHg	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
two	O
minutes	O
after	O
cimetidine	B-Chemical
.	O

Also	O
,	O
systemic	O
vascular	O
resistance	O
(	O
SVR	O
)	O
decreased	O
during	O
the	O
eight	O
-	O
minute	O
observation	O
period	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

In	O
contrast	O
,	O
in	O
the	O
pretreatment	O
group	O
,	O
little	O
haemodynamic	O
change	O
was	O
seen	O
.	O

We	O
conclude	O
that	O
an	O
H1	O
antagonist	O
may	O
be	O
useful	O
in	O
preventing	O
hypotension	B-Disease
caused	O
by	O
iv	O
cimetidine	B-Chemical
,	O
since	O
the	O
vasodilating	O
activity	O
of	O
cimetidine	B-Chemical
is	O
mediated	O
,	O
in	O
part	O
,	O
through	O
the	O
H1	O
receptor	O
.	O

Medical	O
and	O
psychiatric	O
outcomes	O
for	O
patients	O
transplanted	O
for	O
acetaminophen	B-Chemical
-	O
induced	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
:	O
a	O
case	O
-	O
control	O
study	O
.	O

BACKGROUND	O
:	O
Acetaminophen	B-Chemical
-	O
induced	O
hepatotoxicity	B-Disease
is	O
the	O
most	O
common	O
cause	O
of	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
(	O
ALF	B-Disease
)	O
in	O
the	O
UK	O
.	O

Patients	O
often	O
consume	O
the	O
drug	O
with	O
suicidal	O
intent	O
or	O
with	O
a	O
background	O
of	O
substance	O
dependence	O
.	O

AIMS	O
AND	O
METHODS	O
:	O
We	O
compared	O
the	O
severity	O
of	O
pretransplant	O
illness	O
,	O
psychiatric	O
co	O
-	O
morbidity	O
,	O
medical	O
and	O
psychosocial	O
outcomes	O
of	O
all	O
patients	O
who	O
had	O
undergone	O
liver	O
transplantation	O
(	O
LT	O
)	O
emergently	O
between	O
1999	O
-	O
2004	O
for	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
(	O
n	O
=	O
36	O
)	O
with	O
age	O
-	O
and	O
sex	O
-	O
matched	O
patients	O
undergoing	O
emergent	O
LT	O
for	O
non	O
-	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
(	O
n	O
=	O
35	O
)	O
and	O
elective	O
LT	O
for	O
chronic	B-Disease
liver	I-Disease
disease	I-Disease
(	O
CLD	B-Disease
,	O
n	O
=	O
34	O
)	O
.	O

RESULTS	O
:	O
Acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
patients	O
undergoing	O
LT	O
had	O
a	O
greater	O
severity	O
of	O
pre	O
-	O
LT	O
illness	O
reflected	O
by	O
higher	O
Acute	O
Physiology	O
and	O
Chronic	O
Health	O
Evaluation	O
II	O
scores	O
and	O
requirement	O
for	O
organ	O
support	O
compared	O
with	O
the	O
other	O
two	O
groups	O
.	O

Twenty	O
(	O
56	O
%	O
)	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
patients	O
had	O
a	O
formal	O
psychiatric	O
diagnosis	O
before	O
LT	O
(	O
non	O
-	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
=	O
0	O
/	O
35	O
,	O
CLD	B-Disease
=	O
2	O
/	O
34	O
;	O
P	O
<	O
0	O
.	O
01	O
for	O
all	O
)	O
and	O
nine	O
(	O
25	O
%	O
)	O
had	O
a	O
previous	O
suicide	O
attempt	O
.	O

During	O
follow	O
-	O
up	O
(	O
median	O
5	O
years	O
)	O
,	O
there	O
were	O
no	O
significant	O
differences	O
in	O
rejection	O
(	O
acute	O
and	O
chronic	O
)	O
,	O
graft	O
failure	O
or	O
survival	O
between	O
the	O
groups	O
(	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
1	O
year	O
87	O
%	O
,	O
5	O
years	O
75	O
%	O
;	O
non	O
-	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
88	O
%	O
,	O
78	O
%	O
;	O
CLD	B-Disease
93	O
%	O
,	O
82	O
%	O
:	O
P	O
>	O
0	O
.	O
6	O
log	O
rank	O
)	O
.	O

Two	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
patients	O
reattempted	O
suicide	O
post	O
-	O
LT	O
(	O
one	O
died	O
8	O
years	O
post	O
-	O
LT	O
)	O
.	O

CONCLUSIONS	O
:	O
Despite	O
a	O
high	O
prevalence	O
of	O
psychiatric	O
disturbance	O
,	O
outcomes	O
for	O
patients	O
transplanted	O
emergently	O
for	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
were	O
comparable	O
to	O
those	O
transplanted	O
for	O
non	O
-	O
acetaminophen	B-Chemical
-	O
induced	O
ALF	B-Disease
and	O
electively	O
for	O
CLD	B-Disease
.	O

Multidisciplinary	O
approaches	O
with	O
long	O
-	O
term	O
psychiatric	O
follow	O
-	O
up	O
may	O
contribute	O
to	O
low	O
post	O
-	O
transplant	O
suicide	O
rates	O
seen	O
and	O
low	O
rates	O
of	O
graft	O
loss	O
because	O
of	O
non	O
-	O
compliance	O
.	O

Antithrombotic	O
drug	O
use	O
,	O
cerebral	B-Disease
microbleeds	I-Disease
,	O
and	O
intracerebral	B-Disease
hemorrhage	I-Disease
:	O
a	O
systematic	O
review	O
of	O
published	O
and	O
unpublished	O
studies	O
.	O

BACKGROUND	O
AND	O
PURPOSE	O
:	O
Cerebral	B-Disease
microbleeds	I-Disease
(	O
MB	B-Disease
)	O
are	O
potential	O
risk	O
factors	O
for	O
intracerebral	B-Disease
hemorrhage	I-Disease
(	O
ICH	B-Disease
)	O
,	O
but	O
it	O
is	O
unclear	O
if	O
they	O
are	O
a	O
contraindication	O
to	O
using	O
antithrombotic	O
drugs	O
.	O

Insights	O
could	O
be	O
gained	O
by	O
pooling	O
data	O
on	O
MB	B-Disease
frequency	O
stratified	O
by	O
antithrombotic	O
use	O
in	O
cohorts	O
with	O
ICH	B-Disease
and	O
ischemic	B-Disease
stroke	I-Disease
(	O
IS	B-Disease
)	O
/	O
transient	B-Disease
ischemic	I-Disease
attack	I-Disease
(	O
TIA	B-Disease
)	O
.	O

METHODS	O
:	O
We	O
performed	O
a	O
systematic	O
review	O
of	O
published	O
and	O
unpublished	O
data	O
from	O
cohorts	O
with	O
stroke	B-Disease
or	O
TIA	B-Disease
to	O
compare	O
the	O
presence	O
of	O
MB	B-Disease
in	O
:	O
(	O
1	O
)	O
antithrombotic	O
users	O
vs	O
nonantithrombotic	O
users	O
with	O
ICH	B-Disease
;	O
(	O
2	O
)	O
antithrombotic	O
users	O
vs	O
nonusers	O
with	O
IS	B-Disease
/	O
TIA	B-Disease
;	O
and	O
(	O
3	O
)	O
ICH	B-Disease
vs	O
ischemic	B-Disease
events	O
stratified	O
by	O
antithrombotic	O
use	O
.	O

We	O
also	O
analyzed	O
published	O
and	O
unpublished	O
follow	O
-	O
up	O
data	O
to	O
determine	O
the	O
risk	O
of	O
ICH	B-Disease
in	O
antithrombotic	O
users	O
with	O
MB	B-Disease
.	O

RESULTS	O
:	O
In	O
a	O
pooled	O
analysis	O
of	O
1460	O
ICH	B-Disease
and	O
3817	O
IS	B-Disease
/	O
TIA	B-Disease
,	O
MB	B-Disease
were	O
more	O
frequent	O
in	O
ICH	B-Disease
vs	O
IS	B-Disease
/	O
TIA	B-Disease
in	O
all	O
treatment	O
groups	O
,	O
but	O
the	O
excess	O
increased	O
from	O
2	O
.	O
8	O
(	O
odds	O
ratio	O
;	O
range	O
,	O
2	O
.	O
3	O
-	O
3	O
.	O
5	O
)	O
in	O
nonantithrombotic	O
users	O
to	O
5	O
.	O
7	O
(	O
range	O
,	O
3	O
.	O
4	O
-	O
9	O
.	O
7	O
)	O
in	O
antiplatelet	O
users	O
and	O
8	O
.	O
0	O
(	O
range	O
,	O
3	O
.	O
5	O
-	O
17	O
.	O
8	O
)	O
in	O
warfarin	B-Chemical
users	O
(	O
P	O
difference	O
=	O
0	O
.	O
01	O
)	O
.	O

There	O
was	O
also	O
an	O
excess	O
of	O
MB	B-Disease
in	O
warfarin	B-Chemical
users	O
vs	O
nonusers	O
with	O
ICH	B-Disease
(	O
OR	O
,	O
2	O
.	O
7	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
6	O
-	O
4	O
.	O
4	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
but	O
none	O
in	O
warfarin	B-Chemical
users	O
with	O
IS	B-Disease
/	O
TIA	B-Disease
(	O
OR	O
,	O
1	O
.	O
3	O
;	O
95	O
%	O
CI	O
,	O
0	O
.	O
9	O
-	O
1	O
.	O
7	O
;	O
P	O
=	O
0	O
.	O
33	O
;	O
P	O
difference	O
=	O
0	O
.	O
01	O
)	O
.	O

There	O
was	O
a	O
smaller	O
excess	O
of	O
MB	B-Disease
in	O
antiplatelet	O
users	O
vs	O
nonusers	O
with	O
ICH	B-Disease
(	O
OR	O
,	O
1	O
.	O
7	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
3	O
-	O
2	O
.	O
3	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
but	O
findings	O
were	O
similar	O
for	O
antiplatelet	O
users	O
with	O
IS	B-Disease
/	O
TIA	B-Disease
(	O
OR	O
,	O
1	O
.	O
4	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
2	O
-	O
1	O
.	O
7	O
;	O
P	O
<	O
0	O
.	O
001	O
;	O
P	O
difference	O
=	O
0	O
.	O
25	O
)	O
.	O

In	O
pooled	O
follow	O
-	O
up	O
data	O
for	O
768	O
antithrombotic	O
users	O
,	O
presence	O
of	O
MB	B-Disease
at	O
baseline	O
was	O
associated	O
with	O
a	O
substantially	O
increased	O
risk	O
of	O
subsequent	O
ICH	B-Disease
(	O
OR	O
,	O
12	O
.	O
1	O
;	O
95	O
%	O
CI	O
,	O
3	O
.	O
4	O
-	O
42	O
.	O
5	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

CONCLUSIONS	O
:	O
The	O
excess	O
of	O
MB	B-Disease
in	O
warfarin	B-Chemical
users	O
with	O
ICH	B-Disease
compared	O
to	O
other	O
groups	O
suggests	O
that	O
MB	B-Disease
increase	O
the	O
risk	O
of	O
warfarin	B-Chemical
-	O
associated	O
ICH	B-Disease
.	O

Limited	O
prospective	O
data	O
corroborate	O
these	O
findings	O
,	O
but	O
larger	O
prospective	O
studies	O
are	O
urgently	O
required	O
.	O

Studies	O
of	O
synergy	O
between	O
morphine	B-Chemical
and	O
a	O
novel	O
sodium	B-Chemical
channel	O
blocker	O
,	O
CNSB002	B-Chemical
,	O
in	O
rat	O
models	O
of	O
inflammatory	O
and	O
neuropathic	B-Disease
pain	I-Disease
.	O

OBJECTIVE	O
:	O
This	O
study	O
determined	O
the	O
antihyperalgesic	O
effect	O
of	O
CNSB002	B-Chemical
,	O
a	O
sodium	B-Chemical
channel	O
blocker	O
with	O
antioxidant	O
properties	O
given	O
alone	O
and	O
in	O
combinations	O
with	O
morphine	B-Chemical
in	O
rat	O
models	O
of	O
inflammatory	O
and	O
neuropathic	B-Disease
pain	I-Disease
.	O

DESIGN	O
:	O
Dose	O
response	O
curves	O
for	O
nonsedating	O
doses	O
of	O
morphine	B-Chemical
and	O
CNSB002	B-Chemical
given	O
intraperitoneally	O
alone	O
and	O
together	O
in	O
combinations	O
were	O
constructed	O
for	O
antihyperalgesic	O
effect	O
using	O
paw	O
withdrawal	O
from	O
noxious	O
heat	O
in	O
two	O
rat	O
pain	B-Disease
models	O
:	O
carrageenan	B-Chemical
-	O
induced	O
paw	O
inflammation	B-Disease
and	O
streptozotocin	B-Chemical
(	O
STZ	B-Chemical
)	O
-	O
induced	O
diabetic	B-Disease
neuropathy	I-Disease
.	O

RESULTS	O
:	O
The	O
maximum	O
nonsedating	O
doses	O
were	O
:	O
morphine	B-Chemical
,	O
3	O
.	O
2	O
mg	O
/	O
kg	O
;	O
CNSB002	B-Chemical
10	O
.	O
0	O
mg	O
/	O
kg	O
;	O
5	O
.	O
0	O
mg	O
/	O
kg	O
CNSB002	B-Chemical
with	O
morphine	B-Chemical
3	O
.	O
2	O
mg	O
/	O
kg	O
in	O
combination	O
.	O

The	O
doses	O
calculated	O
to	O
cause	O
50	O
%	O
reversal	O
of	O
hyperalgesia	B-Disease
(	O
ED50	O
)	O
were	O
7	O
.	O
54	O
(	O
1	O
.	O
81	O
)	O
and	O
4	O
.	O
83	O
(	O
1	O
.	O
54	O
)	O
in	O
the	O
carrageenan	B-Chemical
model	O
and	O
44	O
.	O
18	O
(	O
1	O
.	O
37	O
)	O
and	O
9	O
.	O
14	O
(	O
1	O
.	O
24	O
)	O
in	O
the	O
STZ	B-Chemical
-	O
induced	O
neuropathy	B-Disease
model	O
for	O
CNSB002	B-Chemical
and	O
morphine	B-Chemical
,	O
respectively	O
(	O
mg	O
/	O
kg	O
;	O
mean	O
,	O
SEM	O
)	O
.	O

These	O
values	O
were	O
greater	O
than	O
the	O
maximum	O
nonsedating	O
doses	O
.	O

The	O
ED50	O
values	O
for	O
morphine	B-Chemical
when	O
given	O
in	O
combination	O
with	O
CNSB002	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
)	O
were	O
less	O
than	O
the	O
maximum	O
nonsedating	O
dose	O
:	O
0	O
.	O
56	O
(	O
1	O
.	O
55	O
)	O
in	O
the	O
carrageenan	B-Chemical
model	O
and	O
1	O
.	O
37	O
(	O
1	O
.	O
23	O
)	O
in	O
the	O
neuropathy	B-Disease
model	O
(	O
mg	O
/	O
kg	O
;	O
mean	O
,	O
SEM	O
)	O
.	O

The	O
antinociception	O
after	O
morphine	B-Chemical
(	O
3	O
.	O
2	O
mg	O
/	O
kg	O
)	O
was	O
increased	O
by	O
co	O
-	O
administration	O
with	O
CNSB002	B-Chemical
from	O
28	O
.	O
0	O
and	O
31	O
.	O
7	O
%	O
to	O
114	O
.	O
6	O
and	O
56	O
.	O
9	O
%	O
reversal	O
of	O
hyperalgesia	B-Disease
in	O
the	O
inflammatory	O
and	O
neuropathic	B-Disease
models	O
,	O
respectively	O
(	O
P	O
<	O
0	O
.	O
01	O
;	O
one	O
-	O
way	O
analysis	O
of	O
variance	O
-	O
significantly	O
greater	O
than	O
either	O
drug	O
given	O
alone	O
)	O
.	O

CONCLUSIONS	O
:	O
The	O
maximum	O
antihyperalgesic	O
effect	O
achievable	O
with	O
nonsedating	O
doses	O
of	O
morphine	B-Chemical
may	O
be	O
increased	O
significantly	O
when	O
the	O
drug	O
is	O
used	O
in	O
combination	O
with	O
CNSB002	B-Chemical
.	O

Heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
:	O
a	O
practical	O
review	O
.	O

Heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
(	O
HIT	B-Disease
)	O
remains	O
under	O
-	O
recognized	O
despite	O
its	O
potentially	O
devastating	O
outcomes	O
.	O

It	O
begins	O
when	O
heparin	B-Chemical
exposure	O
stimulates	O
the	O
formation	O
of	O
heparin	B-Chemical
-	O
platelet	O
factor	O
4	O
antibodies	O
,	O
which	O
in	O
turn	O
triggers	O
the	O
release	O
of	O
procoagulant	O
platelet	O
particles	O
.	O

Thrombosis	B-Disease
and	O
thrombocytopenia	B-Disease
that	O
follow	O
comprise	O
the	O
2	O
hallmark	O
traits	O
of	O
HIT	B-Disease
,	O
with	O
the	O
former	O
largely	O
responsible	O
for	O
significant	O
vascular	O
complications	O
.	O

The	O
prevalence	O
of	O
HIT	B-Disease
varies	O
among	O
several	O
subgroups	O
,	O
with	O
greater	O
incidence	O
in	O
surgical	O
as	O
compared	O
with	O
medical	O
populations	O
.	O

HIT	B-Disease
must	O
be	O
acknowledged	O
for	O
its	O
intense	O
predilection	O
for	O
thrombosis	B-Disease
and	O
suspected	O
whenever	O
thrombosis	B-Disease
occurs	O
after	O
heparin	B-Chemical
exposure	O
.	O

Early	O
recognition	O
that	O
incorporates	O
the	O
clinical	O
and	O
serologic	O
clues	O
is	O
paramount	O
to	O
timely	O
institution	O
of	O
treatment	O
,	O
as	O
its	O
delay	O
may	O
result	O
in	O
catastrophic	O
outcomes	O
.	O

The	O
treatment	O
of	O
HIT	B-Disease
mandates	O
an	O
immediate	O
cessation	O
of	O
all	O
heparin	B-Chemical
exposure	O
and	O
the	O
institution	O
of	O
an	O
antithrombotic	O
therapy	O
,	O
most	O
commonly	O
using	O
a	O
direct	B-Chemical
thrombin	I-Chemical
inhibitor	I-Chemical
.	O

Current	O
"	O
diagnostic	O
"	O
tests	O
,	O
which	O
primarily	O
include	O
functional	O
and	O
antigenic	O
assays	O
,	O
have	O
more	O
of	O
a	O
confirmatory	O
than	O
diagnostic	O
role	O
in	O
the	O
management	O
of	O
HIT	B-Disease
.	O

Special	O
attention	O
must	O
be	O
paid	O
to	O
cardiac	O
patients	O
who	O
are	O
often	O
exposed	O
to	O
heparin	B-Chemical
multiple	O
times	O
during	O
their	O
course	O
of	O
treatment	O
.	O

Direct	B-Chemical
thrombin	I-Chemical
inhibitors	I-Chemical
are	O
appropriate	O
,	O
evidence	O
-	O
based	O
alternatives	O
to	O
heparin	B-Chemical
in	O
patients	O
with	O
a	O
history	O
of	O
HIT	B-Disease
,	O
who	O
need	O
to	O
undergo	O
percutaneous	O
coronary	O
intervention	O
.	O

As	O
heparin	B-Chemical
remains	O
one	O
of	O
the	O
most	O
frequently	O
used	O
medications	O
today	O
with	O
potential	O
for	O
HIT	B-Disease
with	O
every	O
heparin	B-Chemical
exposure	O
,	O
a	O
close	O
vigilance	O
of	O
platelet	O
counts	O
must	O
be	O
practiced	O
whenever	O
heparin	B-Chemical
is	O
initiated	O
.	O

Abductor	O
paralysis	B-Disease
after	O
botox	B-Chemical
injection	O
for	O
adductor	B-Disease
spasmodic	I-Disease
dysphonia	I-Disease
.	O

OBJECTIVES	O
/	O
HYPOTHESIS	O
:	O
Botulinum	O
toxin	O
(	O
Botox	B-Chemical
)	O
injections	O
into	O
the	O
thyroarytenoid	O
muscles	O
are	O
the	O
current	O
standard	O
of	O
care	O
for	O
adductor	B-Disease
spasmodic	I-Disease
dysphonia	I-Disease
(	O
ADSD	B-Disease
)	O
.	O

Reported	O
adverse	O
effects	O
include	O
a	O
period	O
of	O
breathiness	O
,	O
throat	B-Disease
pain	I-Disease
,	O
and	O
difficulty	O
with	O
swallowing	O
liquids	O
.	O

Here	O
we	O
report	O
multiple	O
cases	O
of	O
bilateral	O
abductor	O
paralysis	B-Disease
following	O
Botox	B-Chemical
injections	O
for	O
ADSD	B-Disease
,	O
a	O
complication	O
previously	O
unreported	O
.	O

STUDY	O
DESIGN	O
:	O
Retrospective	O
case	O
series	O
.	O

METHODS	O
:	O
Patients	O
that	O
received	O
Botox	B-Chemical
injections	O
for	O
spasmodic	B-Disease
dysphonia	I-Disease
between	O
January	O
2000	O
and	O
October	O
2009	O
were	O
evaluated	O
.	O

Patients	O
with	O
ADSD	B-Disease
were	O
identified	O
.	O

The	O
number	O
of	O
treatments	O
received	O
and	O
adverse	O
effects	O
were	O
noted	O
.	O

For	O
patients	O
with	O
bilateral	O
abductor	O
paralysis	B-Disease
,	O
age	O
,	O
sex	O
,	O
paralytic	O
Botox	B-Chemical
dose	O
,	O
prior	O
Botox	B-Chemical
dose	O
,	O
and	O
course	O
following	O
paralysis	B-Disease
were	O
noted	O
.	O

RESULTS	O
:	O
From	O
a	O
database	O
of	O
452	O
patients	O
receiving	O
Botox	B-Chemical
,	O
352	O
patients	O
had	O
been	O
diagnosed	O
with	O
ADSD	B-Disease
.	O

Of	O
these	O
352	O
patients	O
,	O
eight	O
patients	O
suffered	O
bilateral	O
abductor	O
paralysis	B-Disease
,	O
and	O
two	O
suffered	O
this	O
complication	O
twice	O
.	O

All	O
affected	O
patients	O
were	O
females	O
over	O
the	O
age	O
of	O
50	O
years	O
.	O

Most	O
patients	O
had	O
received	O
treatments	O
prior	O
to	O
abductor	O
paralysis	B-Disease
and	O
continued	O
receiving	O
after	O
paralysis	B-Disease
.	O

Seven	O
patients	O
recovered	O
after	O
a	O
brief	O
period	O
of	O
activity	O
restrictions	O
,	O
and	O
one	O
underwent	O
a	O
tracheotomy	O
.	O

The	O
incidence	O
of	O
abductor	O
paralysis	B-Disease
after	O
Botox	B-Chemical
injection	O
for	O
ADSD	B-Disease
was	O
0	O
.	O
34	O
%	O
.	O

CONCLUSIONS	O
:	O
Bilateral	O
abductor	O
paralysis	B-Disease
is	O
a	O
rare	O
complication	O
of	O
Botox	B-Chemical
injections	O
for	O
ADSD	B-Disease
,	O
causing	O
difficulty	O
with	O
breathing	O
upon	O
exertion	O
.	O

The	O
likely	O
mechanism	O
of	O
paralysis	B-Disease
is	O
diffusion	O
of	O
Botox	B-Chemical
around	O
the	O
muscular	O
process	O
of	O
the	O
arytenoid	O
to	O
the	O
posterior	O
cricoarytenoid	O
muscles	O
.	O

The	O
paralysis	B-Disease
is	O
temporary	O
,	O
and	O
watchful	O
waiting	O
with	O
restriction	O
of	O
activity	O
is	O
the	O
recommended	O
management	O
.	O

Mitochondrial	B-Disease
impairment	I-Disease
contributes	O
to	O
cocaine	B-Chemical
-	O
induced	O
cardiac	B-Disease
dysfunction	I-Disease
:	O
Prevention	O
by	O
the	O
targeted	O
antioxidant	O
MitoQ	B-Chemical
.	O

The	O
goal	O
of	O
this	O
study	O
was	O
to	O
assess	O
mitochondrial	O
function	O
and	O
ROS	O
production	O
in	O
an	O
experimental	O
model	O
of	O
cocaine	B-Chemical
-	O
induced	O
cardiac	B-Disease
dysfunction	I-Disease
.	O

We	O
hypothesized	O
that	O
cocaine	B-Disease
abuse	I-Disease
may	O
lead	O
to	O
altered	O
mitochondrial	O
function	O
that	O
in	O
turn	O
may	O
cause	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
.	O

Seven	O
days	O
of	O
cocaine	B-Chemical
administration	O
to	O
rats	O
led	O
to	O
an	O
increased	O
oxygen	B-Chemical
consumption	O
detected	O
in	O
cardiac	O
fibers	O
,	O
specifically	O
through	O
complex	O
I	O
and	O
complex	O
III	O
.	O

ROS	O
levels	O
were	O
increased	O
,	O
specifically	O
in	O
interfibrillar	O
mitochondria	O
.	O

In	O
parallel	O
there	O
was	O
a	O
decrease	O
in	O
ATP	B-Chemical
synthesis	O
,	O
whereas	O
no	O
difference	O
was	O
observed	O
in	O
subsarcolemmal	O
mitochondria	O
.	O

This	O
uncoupling	O
effect	O
on	O
oxidative	O
phosphorylation	O
was	O
not	O
detectable	O
after	O
short	O
-	O
term	O
exposure	O
to	O
cocaine	B-Chemical
,	O
suggesting	O
that	O
these	O
mitochondrial	B-Disease
abnormalities	I-Disease
were	O
a	O
late	O
rather	O
than	O
a	O
primary	O
event	O
in	O
the	O
pathological	O
response	O
to	O
cocaine	B-Chemical
.	O

MitoQ	B-Chemical
,	O
a	O
mitochondrial	O
-	O
targeted	O
antioxidant	O
,	O
was	O
shown	O
to	O
completely	O
prevent	O
these	O
mitochondrial	B-Disease
abnormalities	I-Disease
as	O
well	O
as	O
cardiac	B-Disease
dysfunction	I-Disease
characterized	O
here	O
by	O
a	O
diastolic	B-Disease
dysfunction	I-Disease
studied	O
with	O
a	O
conductance	O
catheter	O
to	O
obtain	O
pressure	O
-	O
volume	O
data	O
.	O

Taken	O
together	O
,	O
these	O
results	O
extend	O
previous	O
studies	O
and	O
demonstrate	O
that	O
cocaine	B-Chemical
-	O
induced	O
cardiac	B-Disease
dysfunction	I-Disease
may	O
be	O
due	O
to	O
a	O
mitochondrial	B-Disease
defect	I-Disease
.	O

Trimethoprim	B-Chemical
-	O
induced	O
immune	O
hemolytic	B-Disease
anemia	I-Disease
in	O
a	O
pediatric	O
oncology	O
patient	O
presenting	O
as	O
an	O
acute	O
hemolytic	O
transfusion	O
reaction	O
.	O

A	O
10	O
-	O
year	O
-	O
old	O
male	O
with	O
acute	B-Disease
leukemia	I-Disease
presented	O
with	O
post	O
-	O
chemotherapy	O
anemia	B-Disease
.	O

During	O
red	O
cell	O
transfusion	O
,	O
he	O
developed	O
hemoglobinuria	B-Disease
.	O

Transfusion	O
reaction	O
workup	O
was	O
negative	O
.	O

Drug	O
-	O
induced	O
immune	O
hemolytic	B-Disease
anemia	I-Disease
was	O
suspected	O
because	O
of	O
positive	O
direct	O
antiglobulin	O
test	O
,	O
negative	O
eluate	O
,	O
and	O
microspherocytes	O
on	O
smear	O
pre	O
-	O
and	O
post	O
-	O
transfusion	O
.	O

Drug	O
studies	O
using	O
the	O
indirect	O
antiglobulin	O
test	O
were	O
strongly	O
positive	O
with	O
trimethoprim	B-Chemical
and	O
trimethoprim	B-Chemical
-	I-Chemical
sulfamethoxazole	I-Chemical
but	O
negative	O
with	O
sulfamethoxazole	B-Chemical
.	O

The	O
patient	O
recovered	O
after	O
discontinuing	O
the	O
drug	O
,	O
with	O
no	O
recurrence	O
in	O
2	O
years	O
.	O

Other	O
causes	O
of	O
anemia	B-Disease
should	O
be	O
considered	O
in	O
patients	O
with	O
worse	O
-	O
than	O
-	O
expected	O
anemia	B-Disease
after	O
chemotherapy	O
.	O

Furthermore	O
,	O
hemolysis	B-Disease
during	O
transfusion	O
is	O
not	O
always	O
a	O
transfusion	O
reaction	O
.	O

Verapamil	B-Chemical
stimulation	O
test	O
in	O
hyperprolactinemia	B-Disease
:	O
loss	O
of	O
prolactin	O
response	O
in	O
anatomic	O
or	O
functional	O
stalk	O
effect	O
.	O

AIM	O
:	O
Verapamil	B-Chemical
stimulation	O
test	O
was	O
previously	O
investigated	O
as	O
a	O
tool	O
for	O
differential	O
diagnosis	O
of	O
hyperprolactinemia	B-Disease
,	O
but	O
with	O
conflicting	O
results	O
.	O

Macroprolactinemia	B-Disease
was	O
never	O
considered	O
in	O
those	O
previous	O
studies	O
.	O

Here	O
,	O
we	O
aimed	O
to	O
re	O
-	O
investigate	O
the	O
diagnostic	O
value	O
of	O
verapamil	B-Chemical
in	O
a	O
population	O
who	O
were	O
all	O
screened	O
for	O
macroprolactinemia	B-Disease
.	O

Prolactin	O
responses	O
to	O
verapamil	B-Chemical
in	O
65	O
female	O
patients	O
(	O
age	O
:	O
29	O
.	O
9	O
+	O
/	O
-	O
8	O
.	O
1	O
years	O
)	O
with	O
hyperprolactinemia	B-Disease
were	O
tested	O
in	O
a	O
descriptive	O
,	O
matched	O
case	O
-	O
control	O
study	O
.	O

METHODS	O
:	O
Verapamil	B-Chemical
80	O
mg	O
,	O
p	O
.	O
o	O
.	O
was	O
administered	O
,	O
and	O
then	O
PRL	O
levels	O
were	O
measured	O
at	O
8th	O
and	O
16th	O
hours	O
,	O
by	O
immunometric	O
chemiluminescence	O
.	O

Verapamil	B-Chemical
responsiveness	O
was	O
determined	O
by	O
peak	O
percent	O
change	O
in	O
basal	O
prolactin	O
levels	O
(	O
PRL	O
)	O
.	O

RESULTS	O
:	O
Verapamil	B-Chemical
significantly	O
increased	O
PRL	O
levels	O
in	O
healthy	O
controls	O
(	O
N	O
.	O
8	O
,	O
PRL	O
:	O
183	O
%	O
)	O
,	O
macroprolactinoma	B-Disease
(	O
N	O
.	O
8	O
,	O
PRL	O
:	O
7	O
%	O
)	O
,	O
microprolactinoma	B-Disease
(	O
N	O
.	O
19	O
,	O
PRL	O
:	O
21	O
%	O
)	O
,	O
macroprolactinemia	B-Disease
(	O
N	O
.	O
23	O
,	O
PRL	O
:	O
126	O
%	O
)	O
,	O
but	O
not	O
in	O
pseudoprolactinoma	B-Disease
(	O
N	O
.	O
8	O
,	O
PRL	O
:	O
0	O
.	O
8	O
%	O
)	O
,	O
and	O
risperidone	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
(	O
N	O
.	O
7	O
,	O
PRL	O
:	O
3	O
%	O
)	O
.	O

ROC	O
curve	O
analysis	O
revealed	O
that	O
unresponsiveness	O
to	O
verapamil	B-Chemical
defined	O
as	O
PRL	O
<	O
7	O
%	O
,	O
discriminated	O
anatomical	O
or	O
functional	O
stalk	O
effect	O
(	O
sensitivity	O
:	O
74	O
%	O
,	O
specificity	O
:	O
73	O
%	O
,	O
AUC	O
:	O
0	O
.	O
855	O
+	O
/	O
-	O
0	O
.	O
04	O
,	O
P	O
<	O
0	O
.	O
001	O
,	O
CI	O
:	O
0	O
.	O
768	O
-	O
0	O
.	O
942	O
)	O
associated	O
with	O
pseudoprolactinoma	B-Disease
or	O
risperidone	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
,	O
respectively	O
.	O

CONCLUSION	O
:	O
Verapamil	B-Chemical
responsiveness	O
is	O
not	O
a	O
reliable	O
finding	O
for	O
the	O
differential	O
diagnosis	O
of	O
hyperprolactinemia	B-Disease
.	O

However	O
,	O
verapamil	B-Chemical
unresponsiveness	O
discriminates	O
stalk	O
effect	O
(	O
i	O
.	O
e	O
.	O
,	O
anatomically	O
or	O
functionally	O
inhibited	O
dopaminergic	O
tonus	O
)	O
from	O
other	O
causes	O
of	O
hyperprolactinemia	B-Disease
with	O
varying	O
degrees	O
of	O
responsiveness	O
.	O

Blockade	O
of	O
endothelial	O
-	O
mesenchymal	O
transition	O
by	O
a	O
Smad3	O
inhibitor	O
delays	O
the	O
early	O
development	O
of	O
streptozotocin	B-Chemical
-	O
induced	O
diabetic	B-Disease
nephropathy	I-Disease
.	O

OBJECTIVE	O
:	O
A	O
multicenter	O
,	O
controlled	O
trial	O
showed	O
that	O
early	O
blockade	O
of	O
the	O
renin	O
-	O
angiotensin	B-Chemical
system	O
in	O
patients	O
with	O
type	B-Disease
1	I-Disease
diabetes	I-Disease
and	O
normoalbuminuria	O
did	O
not	O
retard	O
the	O
progression	O
of	O
nephropathy	B-Disease
,	O
suggesting	O
that	O
other	O
mechanism	O
(	O
s	O
)	O
are	O
involved	O
in	O
the	O
pathogenesis	O
of	O
early	O
diabetic	B-Disease
nephropathy	I-Disease
(	O
diabetic	B-Disease
nephropathy	I-Disease
)	O
.	O

We	O
have	O
previously	O
demonstrated	O
that	O
endothelial	O
-	O
mesenchymal	O
-	O
transition	O
(	O
EndoMT	O
)	O
contributes	O
to	O
the	O
early	O
development	O
of	O
renal	O
interstitial	O
fibrosis	B-Disease
independently	O
of	O
microalbuminuria	O
in	O
mice	O
with	O
streptozotocin	B-Chemical
(	O
STZ	B-Chemical
)	O
-	O
induced	O
diabetes	B-Disease
.	O

In	O
the	O
present	O
study	O
,	O
we	O
hypothesized	O
that	O
blocking	O
EndoMT	O
reduces	O
the	O
early	O
development	O
of	O
diabetic	B-Disease
nephropathy	I-Disease
.	O

RESEARCH	O
DESIGN	O
AND	O
METHODS	O
:	O
EndoMT	O
was	O
induced	O
in	O
a	O
mouse	O
pancreatic	O
microvascular	O
endothelial	O
cell	O
line	O
(	O
MMEC	O
)	O
in	O
the	O
presence	O
of	O
advanced	O
glycation	O
end	O
products	O
(	O
AGEs	O
)	O
and	O
in	O
the	O
endothelial	O
lineage	O
-	O
traceble	O
mouse	O
line	O
Tie2	O
-	O
Cre	O
;	O
Loxp	O
-	O
EGFP	O
by	O
administration	O
of	O
AGEs	O
,	O
with	O
nonglycated	O
mouse	O
albumin	O
serving	O
as	O
a	O
control	O
.	O

Phosphorylated	O
Smad3	O
was	O
detected	O
by	O
immunoprecipitation	O
/	O
Western	O
blotting	O
and	O
confocal	O
microscopy	O
.	O

Blocking	O
studies	O
using	O
receptor	O
for	O
AGE	O
siRNA	O
and	O
a	O
specific	O
inhibitor	O
of	O
Smad3	O
(	O
SIS3	O
)	O
were	O
performed	O
in	O
MMECs	O
and	O
in	O
STZ	B-Chemical
-	O
induced	O
diabetic	B-Disease
nephropathy	I-Disease
in	O
Tie2	O
-	O
Cre	O
;	O
Loxp	O
-	O
EGFP	O
mice	O
.	O

RESULTS	O
:	O
Confocal	O
microscopy	O
and	O
real	O
-	O
time	O
PCR	O
demonstrated	O
that	O
AGEs	O
induced	O
EndoMT	O
in	O
MMECs	O
and	O
in	O
Tie2	O
-	O
Cre	O
;	O
Loxp	O
-	O
EGFP	O
mice	O
.	O

Immunoprecipitation	O
/	O
Western	O
blotting	O
showed	O
that	O
Smad3	O
was	O
activated	O
by	O
AGEs	O
but	O
was	O
inhibited	O
by	O
SIS3	O
in	O
MMECs	O
and	O
in	O
STZ	B-Chemical
-	O
induced	O
diabetic	B-Disease
nephropathy	I-Disease
.	O

Confocal	O
microscopy	O
and	O
real	O
-	O
time	O
PCR	O
further	O
demonstrated	O
that	O
SIS3	O
abrogated	O
EndoMT	O
,	O
reduced	O
renal	O
fibrosis	B-Disease
,	O
and	O
retarded	O
progression	O
of	O
nephropathy	B-Disease
.	O

CONCLUSIONS	O
:	O
EndoMT	O
is	O
a	O
novel	O
pathway	O
leading	O
to	O
early	O
development	O
of	O
diabetic	B-Disease
nephropathy	I-Disease
.	O

Blockade	O
of	O
EndoMT	O
by	O
SIS3	O
may	O
provide	O
a	O
new	O
strategy	O
to	O
retard	O
the	O
progression	O
of	O
diabetic	B-Disease
nephropathy	I-Disease
and	O
other	O
diabetes	B-Disease
complications	I-Disease
.	O

Cytostatic	O
and	O
anti	O
-	O
angiogenic	O
effects	O
of	O
temsirolimus	B-Chemical
in	O
refractory	O
mantle	B-Disease
cell	I-Disease
lymphoma	I-Disease
.	O

Mantle	B-Disease
cell	I-Disease
lymphoma	I-Disease
(	O
MCL	B-Disease
)	O
is	O
a	O
rare	O
and	O
aggressive	O
type	O
of	O
B	B-Disease
-	I-Disease
cell	I-Disease
non	I-Disease
-	I-Disease
Hodgkin	I-Disease
'	I-Disease
s	I-Disease
lymphoma	I-Disease
.	O

Patients	O
become	O
progressively	O
refractory	O
to	O
conventional	O
chemotherapy	O
,	O
and	O
their	O
prognosis	O
is	O
poor	O
.	O

However	O
,	O
a	O
38	O
%	O
remission	O
rate	O
has	O
been	O
recently	O
reported	O
in	O
refractory	O
MCL	B-Disease
treated	O
with	O
temsirolimus	B-Chemical
,	O
a	O
mTOR	O
inhibitor	O
.	O
Here	O
we	O
had	O
the	O
opportunity	O
to	O
study	O
a	O
case	O
of	O
refractory	O
MCL	B-Disease
who	O
had	O
tumor	B-Disease
regression	O
two	O
months	O
after	O
temsirolimus	B-Chemical
treatment	O
,	O
and	O
a	O
progression	O
-	O
free	O
survival	O
of	O
10	O
months	O
.	O

In	O
this	O
case	O
,	O
lymph	O
node	O
biopsies	O
were	O
performed	O
before	O
and	O
six	O
months	O
after	O
temsirolimus	B-Chemical
therapy	O
.	O

Comparison	O
of	O
the	O
two	O
biopsies	O
showed	O
that	O
temsirolimus	B-Chemical
inhibited	O
tumor	B-Disease
cell	O
proliferation	O
through	O
cell	O
cycle	O
arrest	O
,	O
but	O
did	O
not	O
induce	O
any	O
change	O
in	O
the	O
number	O
of	O
apoptotic	O
tumor	B-Disease
cells	O
.	O

Apart	O
from	O
this	O
cytostatic	O
effect	O
,	O
temsirolimus	B-Chemical
had	O
an	O
antiangiogenic	O
effect	O
with	O
decrease	O
of	O
tumor	B-Disease
microvessel	O
density	O
and	O
of	O
VEGF	O
expression	O
.	O

Moreover	O
,	O
numerous	O
patchy	O
,	O
well	O
-	O
limited	O
fibrotic	O
areas	O
,	O
compatible	O
with	O
post	O
-	O
necrotic	B-Disease
tissue	O
repair	O
,	O
were	O
found	O
after	O
6	O
-	O
month	O
temsirolimus	B-Chemical
therapy	O
.	O

Thus	O
,	O
temsirolimus	B-Chemical
reduced	O
tumor	B-Disease
burden	O
through	O
associated	O
cytostatic	O
and	O
anti	O
-	O
angiogenic	O
effects	O
.	O
This	O
dual	O
effect	O
of	O
temsirolimus	B-Chemical
on	O
tumor	B-Disease
tissue	O
could	O
contribute	O
to	O
its	O
recently	O
reported	O
efficiency	O
in	O
refractory	O
MCL	B-Disease
resistant	O
to	O
conventional	O
chemotherapy	O
.	O

Acute	B-Disease
renal	I-Disease
failure	I-Disease
due	O
to	O
rifampicin	B-Chemical
.	O

A	O
23	O
-	O
year	O
-	O
old	O
male	O
patient	O
with	O
bacteriologically	O
proven	O
pulmonary	B-Disease
tuberculosis	I-Disease
was	O
treated	O
with	O
the	O
various	O
regimens	O
of	O
antituberculosis	O
drugs	O
for	O
nearly	O
15	O
months	O
.	O

Rifampicin	B-Chemical
was	O
administered	O
thrice	O
as	O
one	O
of	O
the	O
3	O
-	O
4	O
drug	O
regimen	O
and	O
each	O
time	O
he	O
developed	O
untoward	O
side	O
effects	O
like	O
nausea	B-Disease
,	O
vomiting	B-Disease
and	O
fever	B-Disease
with	O
chills	O
and	O
rigors	O
.	O

The	O
last	O
such	O
episode	O
was	O
of	O
acute	O
renal	O
failure	O
at	O
which	O
stage	O
the	O
patient	O
was	O
seen	O
by	O
the	O
authors	O
of	O
this	O
report	O
.	O

The	O
patient	O
,	O
however	O
,	O
made	O
a	O
full	O
recovery	O
.	O

Syncope	B-Disease
caused	O
by	O
hyperkalemia	B-Disease
during	O
use	O
of	O
a	O
combined	O
therapy	O
with	O
the	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
inhibitor	O
and	O
spironolactone	B-Chemical
.	O

A	O
76	O
year	O
-	O
old	O
woman	O
with	O
a	O
history	O
of	O
coronary	O
artery	O
bypass	O
grafting	O
and	O
prior	O
myocardial	B-Disease
infarction	I-Disease
was	O
transferred	O
to	O
the	O
emergency	O
room	O
with	O
loss	B-Disease
of	I-Disease
consciousness	I-Disease
due	O
to	O
marked	O
bradycardia	B-Disease
caused	O
by	O
hyperkalemia	B-Disease
.	O

The	O
concentration	O
of	O
serum	O
potassium	B-Chemical
was	O
high	O
,	O
and	O
normal	O
sinus	O
rhythm	O
was	O
restored	O
after	O
correction	O
of	O
the	O
serum	O
potassium	B-Chemical
level	O
.	O

The	O
cause	O
of	O
hyperkalemia	B-Disease
was	O
considered	O
to	O
be	O
several	O
doses	O
of	O
spiranolactone	B-Chemical
,	O
an	O
aldosterone	B-Chemical
antagonist	O
,	O
in	O
addition	O
to	O
the	O
long	O
-	O
term	O
intake	O
of	O
ramipril	B-Chemical
,	O
an	O
ACE	O
inhibitor	O
.	O

This	O
case	O
is	O
a	O
good	O
example	O
of	O
electrolyte	O
imbalance	O
causing	O
acute	O
life	O
-	O
threatening	O
cardiac	O
events	O
.	O

Clinicians	O
should	O
be	O
alert	O
to	O
the	O
possibility	O
of	O
hyperkalemia	B-Disease
,	O
especially	O
in	O
elderly	O
patients	O
using	O
ACE	O
/	O
ARB	O
in	O
combination	O
with	O
potassium	B-Chemical
sparing	O
agents	O
and	O
who	O
have	O
mild	O
renal	B-Disease
disturbance	I-Disease
.	O

Diffuse	O
skeletal	O
pain	B-Disease
after	O
administration	O
of	O
alendronate	B-Chemical
.	O

BACKGROUND	O
:	O
Osteoporosis	B-Disease
is	O
caused	O
by	O
bone	O
resorption	O
in	O
excess	O
of	O
bone	O
formation	O
,	O
and	O
bisphosphonates	B-Chemical
,	O
are	O
used	O
to	O
inhibit	O
bone	O
resorption	O
.	O

Alendronate	B-Chemical
,	O
a	O
biphosphonate	B-Chemical
,	O
is	O
effective	O
for	O
both	O
the	O
treatment	O
and	O
prevention	O
of	O
osteoporosis	B-Disease
in	O
postmenopausal	O
women	O
.	O

Side	O
effects	O
are	O
relatively	O
few	O
and	O
prominently	O
gastrointestinal	O
.	O

Musculoskeletal	B-Disease
pain	I-Disease
may	O
be	O
an	O
important	O
side	O
effect	O
in	O
these	O
patients	O
.	O

We	O
presented	O
a	O
patient	O
admitted	O
to	O
our	O
out	O
-	O
patient	O
clinic	O
with	O
diffuse	O
skeletal	O
pain	B-Disease
after	O
three	O
consecutive	O
administration	O
of	O
alendronate	B-Chemical
.	O

CONCLUSION	O
:	O
We	O
conclude	O
that	O
patients	O
with	O
osteoporosis	B-Disease
can	O
report	O
pain	B-Disease
,	O
and	O
bisphosphonate	B-Chemical
-	O
related	O
pain	B-Disease
should	O
also	O
be	O
considered	O
before	O
ascribing	O
this	O
complaint	O
to	O
osteoporosis	B-Disease
.	O

Cerebrospinal	O
fluid	O
penetration	O
of	O
high	O
-	O
dose	O
daptomycin	B-Chemical
in	O
suspected	O
Staphylococcus	O
aureus	O
meningitis	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
methicillin	B-Chemical
-	O
sensitive	O
Staphylococcus	O
aureus	O
(	O
MSSA	O
)	O
bacteremia	B-Disease
with	O
suspected	O
MSSA	O
meningitis	B-Disease
treated	O
with	O
high	O
-	O
dose	O
daptomycin	B-Chemical
assessed	O
with	O
concurrent	O
serum	O
and	O
cerebrospinal	O
fluid	O
(	O
CSF	O
)	O
concentrations	O
.	O

CASE	O
SUMMARY	O
:	O
A	O
54	O
-	O
year	O
-	O
old	O
male	O
presented	O
to	O
the	O
emergency	O
department	O
with	O
generalized	O
weakness	B-Disease
and	O
presumed	O
health	O
-	O
care	O
-	O
associated	O
pneumonia	B-Disease
shown	O
on	O
chest	O
radiograph	O
.	O

Treatment	O
was	O
empirically	O
initiated	O
with	O
vancomycin	B-Chemical
,	O
levofloxacin	B-Chemical
,	O
and	O
piperacillin	B-Chemical
/	O
tazobactam	B-Chemical
.	O

Blood	O
cultures	O
revealed	O
S	O
.	O
aureus	O
susceptible	O
to	O
oxacillin	B-Chemical
.	O

Empiric	O
antibiotic	O
treatment	O
was	O
narrowed	O
to	O
nafcillin	B-Chemical
on	O
day	O
4	O
.	O

On	O
day	O
8	O
,	O
the	O
patient	O
developed	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
(	O
serum	O
creatinine	B-Chemical
1	O
.	O
9	O
mg	O
/	O
dL	O
,	O
increased	O
from	O
1	O
.	O
2	O
mg	O
/	O
dL	O
the	O
previous	O
day	O
and	O
0	O
.	O
8	O
mg	O
/	O
dL	O
on	O
admission	O
)	O
.	O

The	O
patient	O
'	O
s	O
Glasgow	O
Coma	O
Score	O
was	O
3	O
,	O
with	O
normal	O
findings	O
shown	O
on	O
computed	O
tomography	O
scan	O
of	O
the	O
head	O
72	O
hours	O
following	O
an	O
episode	O
of	O
cardiac	B-Disease
arrest	I-Disease
on	O
day	O
10	O
.	O

The	O
patient	O
experienced	O
relapsing	O
MSSA	O
bacteremia	B-Disease
on	O
day	O
9	O
,	O
increasing	O
the	O
suspicion	O
for	O
a	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
infection	B-Disease
.	O

Nafcillin	B-Chemical
was	O
discontinued	O
and	O
daptomycin	B-Chemical
9	O
mg	O
/	O
kg	O
daily	O
was	O
initiated	O
for	O
suspected	O
meningitis	B-Disease
and	O
was	O
continued	O
until	O
the	O
patient	O
'	O
s	O
death	O
on	O
day	O
16	O
.	O

Daptomycin	B-Chemical
serum	O
and	O
CSF	O
trough	O
concentrations	O
were	O
11	O
.	O
21	O
ug	O
/	O
mL	O
and	O
0	O
.	O
52	O
ug	O
/	O
mL	O
,	O
respectively	O
,	O
prior	O
to	O
the	O
third	O
dose	O
.	O

Lumbar	O
puncture	O
results	O
were	O
inconclusive	O
and	O
no	O
further	O
blood	O
cultures	O
were	O
positive	O
for	O
MSSA	O
.	O

Creatine	B-Chemical
kinase	O
levels	O
were	O
normal	O
prior	O
to	O
daptomycin	B-Chemical
therapy	O
and	O
were	O
not	O
reassessed	O
.	O

DISCUSSION	O
:	O
Daptomycin	B-Chemical
was	O
initiated	O
in	O
our	O
patient	O
secondary	O
to	O
possible	O
nafcillin	B-Chemical
-	O
induced	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
and	O
relapsing	O
bacteremia	B-Disease
.	O

At	O
a	O
dose	O
of	O
9	O
mg	O
/	O
kg	O
,	O
resultant	O
penetration	O
of	O
5	O
%	O
was	O
higher	O
than	O
in	O
previous	O
reports	O
,	O
more	O
consistent	O
with	O
inflamed	O
meninges	O
.	O

CONCLUSIONS	O
:	O
High	O
-	O
dose	O
daptomycin	B-Chemical
may	O
be	O
an	O
alternative	O
option	O
for	O
MSSA	O
bacteremia	B-Disease
with	O
or	O
without	O
a	O
CNS	O
source	O
in	O
patients	O
who	O
have	O
failed	O
or	O
cannot	O
tolerate	O
standard	O
therapy	O
.	O

Further	O
clinical	O
evaluation	O
in	O
patients	O
with	O
confirmed	O
meningitis	B-Disease
is	O
warranted	O
.	O

The	O
role	O
of	O
nitric	B-Chemical
oxide	I-Chemical
in	O
convulsions	B-Disease
induced	O
by	O
lindane	B-Chemical
in	O
rats	O
.	O

Lindane	B-Chemical
is	O
an	O
organochloride	O
pesticide	O
and	O
scabicide	O
.	O

It	O
evokes	O
convulsions	B-Disease
mainly	O
trough	O
the	O
blockage	O
of	O
GABA	B-Chemical
(	O
A	O
)	O
receptors	O
.	O

Nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
,	O
gaseous	O
neurotransmitter	O
,	O
has	O
contradictor	O
role	O
in	O
epileptogenesis	O
due	O
to	O
opposite	O
effects	O
of	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
,	O
precursor	O
of	O
NO	B-Chemical
syntheses	O
(	O
NOS	O
)	O
,	O
and	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
(	O
NOS	O
inhibitor	O
)	O
observed	O
in	O
different	O
epilepsy	B-Disease
models	O
.	O

The	O
aim	O
of	O
the	O
current	O
study	O
was	O
to	O
determine	O
the	O
effects	O
of	O
NO	B-Chemical
on	O
the	O
behavioral	O
and	O
EEG	O
characteristics	O
of	O
lindane	B-Chemical
-	O
induced	O
epilepsy	B-Disease
in	O
male	O
Wistar	O
albino	O
rats	O
.	O

The	O
administration	O
of	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
(	O
600	O
,	O
800	O
and	O
1000	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
in	O
dose	O
-	O
dependent	O
manner	O
significantly	O
increased	O
convulsion	B-Disease
incidence	O
and	O
severity	O
and	O
shortened	O
latency	O
time	O
to	O
first	O
convulsion	B-Disease
elicited	O
by	O
lower	O
lindane	B-Chemical
dose	O
(	O
4	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
.	O

On	O
the	O
contrary	O
,	O
pretreatment	O
with	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
(	O
500	O
,	O
700	O
and	O
900	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
decreased	O
convulsion	B-Disease
incidence	O
and	O
severity	O
and	O
prolonged	O
latency	O
time	O
to	O
convulsion	B-Disease
following	O
injection	O
with	O
a	O
convulsive	B-Disease
dose	O
of	O
lindane	B-Chemical
(	O
8	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
.	O

EEG	O
analyses	O
showed	O
increase	O
of	O
number	O
and	O
duration	O
of	O
ictal	O
periods	O
in	O
EEG	O
of	O
rats	O
receiving	O
l	B-Chemical
-	I-Chemical
arginine	I-Chemical
prior	O
to	O
lindane	B-Chemical
and	O
decrease	O
of	O
this	O
number	O
in	O
rats	O
pretreated	O
with	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
.	O

These	O
results	O
support	O
the	O
conclusion	O
that	O
NO	B-Chemical
plays	O
a	O
role	O
of	O
endogenous	O
convulsant	O
in	O
rat	O
model	O
of	O
lindane	B-Chemical
seizures	B-Disease
.	O

Severe	O
polyneuropathy	B-Disease
and	O
motor	O
loss	O
after	O
intrathecal	O
thiotepa	B-Chemical
combination	O
chemotherapy	O
:	O
description	O
of	O
two	O
cases	O
.	O

Two	O
cases	O
of	O
severe	O
delayed	O
neurologic	B-Disease
toxicity	I-Disease
related	O
to	O
the	O
administration	O
of	O
intrathecal	O
(	O
IT	O
)	O
combination	O
chemotherapy	O
including	O
thiotepa	B-Chemical
(	O
TSPA	B-Chemical
)	O
are	O
presented	O
.	O

Both	O
cases	O
developed	O
axonal	B-Disease
neuropathy	I-Disease
with	O
motor	O
predominance	O
in	O
the	O
lower	O
extremities	O
1	O
and	O
6	O
months	O
after	O
IT	O
chemotherapy	O
was	O
administered	O
.	O

Neurologic	B-Disease
toxicities	I-Disease
have	O
been	O
described	O
with	O
IT	O
-	O
methotrexate	B-Chemical
,	O
IT	O
-	O
cytosine	B-Chemical
arabinoside	I-Chemical
and	O
IT	O
-	O
TSPA	B-Chemical
.	O

To	O
our	O
knowledge	O
,	O
however	O
,	O
axonal	B-Disease
neuropathy	I-Disease
following	O
administration	O
of	O
these	O
three	O
agents	O
has	O
not	O
been	O
previously	O
described	O
.	O

In	O
spite	O
of	O
the	O
fact	O
that	O
TSPA	B-Chemical
is	O
a	O
useful	O
IT	O
agent	O
,	O
its	O
combination	O
with	O
MTX	B-Chemical
,	O
ara	B-Chemical
-	I-Chemical
C	I-Chemical
and	O
radiotherapy	O
could	O
cause	O
severe	O
neurotoxicity	B-Disease
.	O

This	O
unexpected	O
complication	O
indicates	O
the	O
need	O
for	O
further	O
toxicology	O
research	O
on	O
IT	O
-	O
TSPA	B-Chemical
.	O

Effects	O
of	O
cromakalim	B-Chemical
and	O
pinacidil	B-Chemical
on	O
large	O
epicardial	O
and	O
small	O
coronary	O
arteries	O
in	O
conscious	O
dogs	O
.	O

The	O
effects	O
of	O
i	O
.	O
v	O
.	O
bolus	O
administration	O
of	O
cromakalim	B-Chemical
(	O
1	O
-	O
10	O
micrograms	O
/	O
kg	O
)	O
and	O
pinacidil	B-Chemical
(	O
3	O
-	O
100	O
micrograms	O
/	O
kg	O
)	O
on	O
large	O
(	O
circumflex	O
artery	O
)	O
and	O
small	O
coronary	O
arteries	O
and	O
on	O
systemic	O
hemodynamics	O
were	O
investigated	O
in	O
chronically	O
instrumented	O
conscious	O
dogs	O
and	O
compared	O
to	O
those	O
of	O
nitroglycerin	B-Chemical
(	O
0	O
.	O
03	O
-	O
10	O
micrograms	O
/	O
kg	O
)	O
.	O

Nitroglycerin	B-Chemical
,	O
up	O
to	O
0	O
.	O
3	O
micrograms	O
/	O
kg	O
,	O
selectively	O
increased	O
circumflex	O
artery	O
diameter	O
(	O
CxAD	O
)	O
without	O
simultaneously	O
affecting	O
any	O
other	O
cardiac	O
or	O
systemic	O
hemodynamic	O
parameter	O
.	O

In	O
contrast	O
,	O
cromakalim	B-Chemical
and	O
pinacidil	B-Chemical
at	O
all	O
doses	O
and	O
nitroglycerin	B-Chemical
at	O
doses	O
higher	O
than	O
0	O
.	O
3	O
micrograms	O
/	O
kg	O
simultaneously	O
and	O
dose	O
-	O
dependently	O
increased	O
CxAD	O
,	O
coronary	O
blood	O
flow	O
and	O
heart	O
rate	O
and	O
decreased	O
coronary	O
vascular	O
resistance	O
and	O
aortic	O
pressure	O
.	O

Cromakalim	B-Chemical
was	O
approximately	O
8	O
-	O
to	O
9	O
.	O
5	O
-	O
fold	O
more	O
potent	O
than	O
pinacidil	B-Chemical
in	O
increasing	O
CxAD	O
.	O

Vasodilation	O
of	O
large	O
and	O
small	O
coronary	O
vessels	O
and	O
hypotension	B-Disease
induced	O
by	O
cromakalim	B-Chemical
and	O
pinacidil	B-Chemical
were	O
not	O
affected	O
by	O
prior	O
combined	O
beta	B-Chemical
adrenergic	I-Chemical
and	I-Chemical
muscarinic	I-Chemical
receptors	I-Chemical
blockade	I-Chemical
but	O
drug	O
-	O
induced	O
tachycardia	B-Disease
was	O
abolished	O
.	O

When	O
circumflex	O
artery	O
blood	O
flow	O
was	O
maintained	O
constant	O
,	O
the	O
increases	O
in	O
CxAD	O
induced	O
by	O
cromakalim	B-Chemical
(	O
10	O
micrograms	O
/	O
kg	O
)	O
,	O
pinacidil	B-Chemical
(	O
30	O
micrograms	O
/	O
kg	O
)	O
and	O
nitroglycerin	B-Chemical
(	O
10	O
micrograms	O
/	O
kg	O
)	O
were	O
reduced	O
by	O
68	O
+	O
/	O
-	O
7	O
,	O
54	O
+	O
/	O
-	O
9	O
and	O
1	O
+	O
/	O
-	O
1	O
%	O
,	O
respectively	O
.	O

Thus	O
,	O
whereas	O
nitroglycerin	B-Chemical
preferentially	O
and	O
flow	O
-	O
independently	O
dilates	O
large	O
coronary	O
arteries	O
,	O
cromakalim	B-Chemical
and	O
pinacidil	B-Chemical
dilate	O
both	O
large	O
and	O
small	O
coronary	O
arteries	O
and	O
this	O
effect	O
is	O
not	O
dependent	O
upon	O
the	O
simultaneous	O
beta	O
adrenoceptors	O
-	O
mediated	O
rise	O
in	O
myocardial	O
metabolic	O
demand	O
.	O

Finally	O
,	O
two	O
mechanisms	O
at	O
least	O
,	O
direct	O
vasodilation	O
and	O
flow	O
dependency	O
,	O
are	O
involved	O
in	O
the	O
cromakalim	B-Chemical
-	O
and	O
pinacidil	B-Chemical
-	O
induced	O
increase	O
in	O
CxAD	O
.	O

Mefenamic	B-Chemical
acid	I-Chemical
-	O
induced	O
neutropenia	B-Disease
and	O
renal	B-Disease
failure	I-Disease
in	O
elderly	O
females	O
with	O
hypothyroidism	B-Disease
.	O

We	O
report	O
mefenamic	B-Chemical
acid	I-Chemical
-	O
induced	O
non	O
-	O
oliguric	O
renal	B-Disease
failure	I-Disease
and	O
severe	O
neutropenia	B-Disease
occurring	O
simultaneously	O
in	O
two	O
elderly	O
females	O
.	O

The	O
neutropenia	B-Disease
was	O
due	O
to	O
maturation	O
arrest	O
of	O
the	O
myeloid	O
series	O
in	O
one	O
patient	O
.	O

Both	O
patients	O
were	O
also	O
hypothyroid	B-Disease
,	O
but	O
it	O
is	O
not	O
clear	O
whether	O
this	O
was	O
a	O
predisposing	O
factor	O
to	O
the	O
development	O
of	O
these	O
adverse	O
reactions	O
.	O

However	O
,	O
it	O
would	O
seem	O
prudent	O
not	O
to	O
use	O
mefenamic	B-Chemical
acid	I-Chemical
in	O
hypothyroid	B-Disease
patients	O
until	O
the	O
hypothyroidism	B-Disease
has	O
been	O
corrected	O
.	O

Etiology	O
of	O
hypercalcemia	B-Disease
in	O
hemodialysis	O
patients	O
on	O
calcium	B-Chemical
carbonate	I-Chemical
therapy	O
.	O

Fourteen	O
of	O
39	O
dialysis	O
patients	O
(	O
36	O
%	O
)	O
became	O
hypercalcemic	B-Disease
after	O
switching	O
to	O
calcium	B-Chemical
carbonate	I-Chemical
as	O
their	O
principal	O
phosphate	B-Chemical
binder	O
.	O

In	O
order	O
to	O
identify	O
risk	O
factors	O
associated	O
with	O
the	O
development	O
of	O
hypercalcemia	B-Disease
,	O
indirect	O
parameters	O
of	O
intestinal	O
calcium	B-Chemical
reabsorption	O
and	O
bone	O
turnover	O
rate	O
in	O
these	O
14	O
patients	O
were	O
compared	O
with	O
results	O
in	O
14	O
eucalcemic	O
patients	O
matched	O
for	O
age	O
,	O
sex	O
,	O
length	O
of	O
time	O
on	O
dialysis	O
,	O
and	O
etiology	O
of	O
renal	B-Disease
disease	I-Disease
.	O

In	O
addition	O
to	O
experiencing	O
hypercalcemic	B-Disease
episodes	O
with	O
peak	O
calcium	B-Chemical
values	O
of	O
2	O
.	O
7	O
to	O
3	O
.	O
8	O
mmol	O
/	O
L	O
(	O
10	O
.	O
7	O
to	O
15	O
.	O
0	O
mg	O
/	O
dL	O
)	O
,	O
patients	O
in	O
the	O
hypercalcemic	B-Disease
group	O
exhibited	O
a	O
significant	O
increase	O
in	O
the	O
mean	O
calcium	B-Chemical
concentration	O
obtained	O
during	O
6	O
months	O
before	O
the	O
switch	O
,	O
compared	O
with	O
the	O
mean	O
value	O
obtained	O
during	O
the	O
7	O
months	O
of	O
observation	O
after	O
the	O
switch	O
(	O
2	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
03	O
to	O
2	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
03	O
mmol	O
/	O
L	O
[	O
9	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
2	O
to	O
10	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
1	O
mg	O
/	O
dL	O
]	O
,	O
P	O
=	O
0	O
.	O
006	O
)	O
.	O

In	O
contrast	O
,	O
eucalcemic	O
patients	O
exhibited	O
no	O
change	O
in	O
mean	O
calcium	B-Chemical
values	O
over	O
the	O
same	O
time	O
period	O
(	O
2	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
05	O
to	O
2	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
05	O
mmol	O
/	O
L	O
[	O
9	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
2	O
to	O
9	O
.	O
2	O
+	O
/	O
-	O
0	O
.	O
2	O
mg	O
/	O
dL	O
]	O
)	O
.	O

CaCO3	B-Chemical
dosage	O
,	O
calculated	O
dietary	O
calcium	B-Chemical
intake	O
,	O
and	O
circulating	O
levels	O
of	O
vitamin	B-Chemical
D	I-Chemical
metabolites	O
were	O
similar	O
in	O
both	O
groups	O
.	O

Physical	O
activity	O
index	O
and	O
predialysis	O
serum	O
bicarbonate	B-Chemical
levels	O
also	O
were	O
similar	O
in	O
both	O
groups	O
.	O

However	O
,	O
there	O
was	O
a	O
significant	O
difference	O
in	O
parameters	O
reflecting	O
bone	O
turnover	O
rates	O
between	O
groups	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Late	O
-	O
onset	O
scleroderma	B-Disease
renal	I-Disease
crisis	I-Disease
induced	O
by	O
tacrolimus	B-Chemical
and	O
prednisolone	B-Chemical
:	O
a	O
case	O
report	O
.	O

Scleroderma	B-Disease
renal	I-Disease
crisis	I-Disease
(	O
SRC	B-Disease
)	O
is	O
a	O
rare	O
complication	O
of	O
systemic	B-Disease
sclerosis	I-Disease
(	O
SSc	B-Disease
)	O
but	O
can	O
be	O
severe	O
enough	O
to	O
require	O
temporary	O
or	O
permanent	O
renal	O
replacement	O
therapy	O
.	O

Moderate	O
to	O
high	O
dose	O
corticosteroid	B-Chemical
use	O
is	O
recognized	O
as	O
a	O
major	O
risk	O
factor	O
for	O
SRC	B-Disease
.	O

Furthermore	O
,	O
there	O
have	O
been	O
reports	O
of	O
thrombotic	B-Disease
microangiopathy	I-Disease
precipitated	O
by	O
cyclosporine	B-Chemical
in	O
patients	O
with	O
SSc	B-Disease
.	O

In	O
this	O
article	O
,	O
we	O
report	O
a	O
patient	O
with	O
SRC	B-Disease
induced	O
by	O
tacrolimus	B-Chemical
and	O
corticosteroids	B-Chemical
.	O

The	O
aim	O
of	O
this	O
work	O
is	O
to	O
call	O
attention	O
to	O
the	O
risk	O
of	O
tacrolimus	B-Chemical
use	O
in	O
patients	O
with	O
SSc	B-Disease
.	O

Methyldopa	B-Chemical
-	O
induced	O
hemolytic	B-Disease
anemia	I-Disease
in	O
a	O
15	O
year	O
old	O
presenting	O
as	O
near	O
-	O
syncope	B-Disease
.	O

Methyldopa	B-Chemical
is	O
an	O
antihypertensive	O
medication	O
which	O
is	O
available	O
generically	O
and	O
under	O
the	O
trade	O
name	O
Aldomet	B-Chemical
that	O
is	O
widely	O
prescribed	O
in	O
the	O
adult	O
population	O
and	O
infrequently	O
used	O
in	O
children	O
.	O

Methyldopa	B-Chemical
causes	O
an	O
autoimmune	B-Disease
hemolytic	I-Disease
anemia	I-Disease
in	O
a	O
small	O
percentage	O
of	O
patients	O
who	O
take	O
the	O
drug	O
.	O

We	O
report	O
a	O
case	O
of	O
methyldopa	B-Chemical
-	O
induced	O
hemolytic	B-Disease
anemia	I-Disease
in	O
a	O
15	O
-	O
year	O
-	O
old	O
boy	O
who	O
presented	O
to	O
the	O
emergency	B-Disease
department	I-Disease
with	O
near	O
-	O
syncope	B-Disease
.	O

The	O
boy	O
had	O
been	O
treated	O
with	O
intravenous	O
methyldopa	B-Chemical
during	O
a	O
trauma	B-Disease
admission	O
seven	O
weeks	O
prior	O
to	O
presentation	O
.	O

Evaluation	O
revealed	O
a	O
hemoglobin	O
of	O
three	O
grams	O
,	O
3	O
+	O
Coombs	O
'	O
test	O
with	O
polyspecific	O
anti	O
-	O
human	O
globulin	O
and	O
monospecific	O
IgG	O
reagents	O
,	O
and	O
a	O
warm	O
reacting	O
autoantibody	O
.	O

Transfusion	O
and	O
corticosteroid	B-Chemical
therapy	O
resulted	O
in	O
a	O
complete	O
recovery	O
of	O
the	O
patient	O
.	O

Emergency	O
physicians	O
treating	O
children	O
must	O
be	O
aware	O
of	O
this	O
syndrome	O
in	O
order	O
to	O
diagnose	O
and	O
treat	O
it	O
correctly	O
.	O

A	O
brief	O
review	O
of	O
autoimmune	O
and	O
drug	O
-	O
induced	O
hemolytic	B-Disease
anemias	I-Disease
is	O
provided	O
.	O

The	O
risk	O
and	O
associated	O
factors	O
of	O
methamphetamine	B-Chemical
psychosis	B-Disease
in	O
methamphetamine	B-Chemical
-	O
dependent	O
patients	O
in	O
Malaysia	O
.	O

OBJECTIVE	O
:	O
The	O
objective	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
risk	O
of	O
lifetime	O
and	O
current	O
methamphetamine	B-Chemical
-	O
induced	O
psychosis	B-Disease
in	O
patients	O
with	O
methamphetamine	B-Chemical
dependence	O
.	O

The	O
association	O
between	O
psychiatric	O
co	O
-	O
morbidity	O
and	O
methamphetamine	B-Chemical
-	O
induced	O
psychosis	B-Disease
was	O
also	O
studied	O
.	O

METHODS	O
:	O
This	O
was	O
a	O
cross	O
-	O
sectional	O
study	O
conducted	O
concurrently	O
at	O
a	O
teaching	O
hospital	O
and	O
a	O
drug	O
rehabilitation	O
center	O
in	O
Malaysia	O
.	O

Patients	O
with	O
the	O
diagnosis	O
of	O
methamphetamine	B-Chemical
based	O
on	O
DSM	O
-	O
IV	O
were	O
interviewed	O
using	O
the	O
Mini	O
International	O
Neuropsychiatric	O
Interview	O
(	O
M	O
.	O
I	O
.	O
N	O
.	O
I	O
.	O
)	O
for	O
methamphetamine	B-Chemical
-	O
induced	O
psychosis	B-Disease
and	O
other	O
Axis	O
I	O
psychiatric	B-Disease
disorders	I-Disease
.	O

The	O
information	O
on	O
sociodemographic	O
background	O
and	O
drug	O
use	O
history	O
was	O
obtained	O
from	O
interview	O
or	O
medical	O
records	O
.	O

RESULTS	O
:	O
Of	O
292	O
subjects	O
,	O
47	O
.	O
9	O
%	O
of	O
the	O
subjects	O
had	O
a	O
past	O
history	O
of	O
psychotic	B-Disease
symptoms	I-Disease
and	O
13	O
.	O
0	O
%	O
of	O
the	O
patients	O
were	O
having	O
current	O
psychotic	B-Disease
symptoms	I-Disease
.	O

Co	O
-	O
morbid	O
major	O
depressive	B-Disease
disorder	I-Disease
(	O
OR	O
=	O
7	O
.	O
18	O
,	O
95	O
CI	O
=	O
2	O
.	O
612	O
-	O
19	O
.	O
708	O
)	O
,	O
bipolar	B-Disease
disorder	I-Disease
(	O
OR	O
=	O
13	O
.	O
807	O
,	O
95	O
CI	O
=	O
5	O
.	O
194	O
-	O
36	O
.	O
706	O
)	O
,	O
antisocial	B-Disease
personality	I-Disease
disorder	I-Disease
(	O
OR	O
=	O
12	O
.	O
619	O
,	O
95	O
CI	O
=	O
6	O
.	O
702	O
-	O
23	O
.	O
759	O
)	O
and	O
heavy	O
methamphetamine	B-Chemical
uses	O
were	O
significantly	O
associated	O
with	O
lifetime	O
methamphetamine	B-Chemical
-	O
induced	O
psychosis	B-Disease
after	O
adjusted	O
for	O
other	O
factors	O
.	O

Major	B-Disease
depressive	I-Disease
disorder	I-Disease
(	O
OR	O
=	O
2	O
.	O
870	O
,	O
CI	O
=	O
1	O
.	O
154	O
-	O
7	O
.	O
142	O
)	O
and	O
antisocial	B-Disease
personality	I-Disease
disorder	I-Disease
(	O
OR	O
=	O
3	O
.	O
299	O
,	O
95	O
CI	O
=	O
1	O
.	O
375	O
-	O
7	O
.	O
914	O
)	O
were	O
the	O
only	O
factors	O
associated	O
with	O
current	O
psychosis	B-Disease
.	O

CONCLUSION	O
:	O
There	O
was	O
a	O
high	O
risk	O
of	O
psychosis	B-Disease
in	O
patients	O
with	O
methamphetamine	B-Chemical
dependence	O
.	O

It	O
was	O
associated	O
with	O
co	O
-	O
morbid	O
affective	B-Disease
disorder	I-Disease
,	O
antisocial	B-Disease
personality	I-Disease
,	O
and	O
heavy	O
methamphetamine	B-Chemical
use	O
.	O

It	O
is	O
recommended	O
that	O
all	O
cases	O
of	O
methamphetamine	B-Chemical
dependence	O
should	O
be	O
screened	O
for	O
psychotic	B-Disease
symptoms	I-Disease
.	O

Cerebellar	O
sensory	O
processing	O
alterations	O
impact	O
motor	O
cortical	O
plasticity	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
:	O
clues	O
from	O
dyskinetic	B-Disease
patients	O
.	O

The	O
plasticity	O
of	O
primary	O
motor	O
cortex	O
(	O
M1	O
)	O
in	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
and	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
(	O
LIDs	B-Disease
)	O
is	O
severely	O
impaired	O
.	O

We	O
recently	O
reported	O
in	O
young	O
healthy	O
subjects	O
that	O
inhibitory	O
cerebellar	O
stimulation	O
enhanced	O
the	O
sensorimotor	O
plasticity	O
of	O
M1	O
that	O
was	O
induced	O
by	O
paired	O
associative	O
stimulation	O
(	O
PAS	O
)	O
.	O

This	O
study	O
demonstrates	O
that	O
the	O
deficient	O
sensorimotor	O
M1	O
plasticity	O
in	O
16	O
patients	O
with	O
LIDs	B-Disease
could	O
be	O
reinstated	O
by	O
a	O
single	O
session	O
of	O
real	O
inhibitory	O
cerebellar	O
stimulation	O
but	O
not	O
sham	O
stimulation	O
.	O

This	O
was	O
evident	O
only	O
when	O
a	O
sensory	O
component	O
was	O
involved	O
in	O
the	O
induction	O
of	O
plasticity	O
,	O
indicating	O
that	O
cerebellar	O
sensory	O
processing	O
function	O
is	O
involved	O
in	O
the	O
resurgence	O
of	O
M1	O
plasticity	O
.	O

The	O
benefit	O
of	O
inhibitory	O
cerebellar	O
stimulation	O
on	O
LIDs	B-Disease
is	O
known	O
.	O

To	O
explore	O
whether	O
this	O
benefit	O
is	O
linked	O
to	O
the	O
restoration	O
of	O
sensorimotor	O
plasticity	O
of	O
M1	O
,	O
we	O
conducted	O
an	O
additional	O
study	O
looking	O
at	O
changes	O
in	O
LIDs	B-Disease
and	O
PAS	O
-	O
induced	O
plasticity	O
after	O
10	O
sessions	O
of	O
either	O
bilateral	O
,	O
real	O
inhibitory	O
cerebellar	O
stimulation	O
or	O
sham	O
stimulation	O
.	O

Only	O
real	O
and	O
not	O
sham	O
stimulation	O
had	O
an	O
antidyskinetic	O
effect	O
and	O
it	O
was	O
paralleled	O
by	O
a	O
resurgence	O
in	O
the	O
sensorimotor	O
plasticity	O
of	O
M1	O
.	O

These	O
results	O
suggest	O
that	O
alterations	O
in	O
cerebellar	O
sensory	O
processing	O
function	O
,	O
occurring	O
secondary	O
to	O
abnormal	O
basal	O
ganglia	O
signals	O
reaching	O
it	O
,	O
may	O
be	O
an	O
important	O
element	O
contributing	O
to	O
the	O
maladaptive	O
sensorimotor	O
plasticity	O
of	O
M1	O
and	O
the	O
emergence	O
of	O
abnormal	B-Disease
involuntary	I-Disease
movements	I-Disease
.	O

The	O
long	O
-	O
term	O
safety	O
of	O
danazol	B-Chemical
in	O
women	O
with	O
hereditary	B-Disease
angioedema	I-Disease
.	O

Although	O
the	O
short	O
-	O
term	O
safety	O
(	O
less	O
than	O
or	O
equal	O
to	O
6	O
months	O
)	O
of	O
danazol	B-Chemical
has	O
been	O
established	O
in	O
a	O
variety	O
of	O
settings	O
,	O
no	O
information	O
exists	O
as	O
to	O
its	O
long	O
-	O
term	O
safety	O
.	O

We	O
therefore	O
investigated	O
the	O
long	O
-	O
term	O
safety	O
of	O
danazol	B-Chemical
by	O
performing	O
a	O
retrospective	O
chart	O
review	O
of	O
60	O
female	O
patients	O
with	O
hereditary	B-Disease
angioedema	I-Disease
treated	O
with	O
danazol	B-Chemical
for	O
a	O
continuous	O
period	O
of	O
6	O
months	O
or	O
longer	O
.	O

The	O
mean	O
age	O
of	O
the	O
patients	O
was	O
35	O
.	O
2	O
years	O
and	O
the	O
mean	O
duration	O
of	O
therapy	O
was	O
59	O
.	O
7	O
months	O
.	O

Virtually	O
all	O
patients	O
experienced	O
one	O
or	O
more	O
adverse	O
reactions	O
.	O

Menstrual	B-Disease
abnormalities	I-Disease
(	O
79	O
%	O
)	O
,	O
weight	B-Disease
gain	I-Disease
(	O
60	O
%	O
)	O
,	O
muscle	B-Disease
cramps	I-Disease
/	O
myalgias	B-Disease
(	O
40	O
%	O
)	O
,	O
and	O
transaminase	O
elevations	O
(	O
40	O
%	O
)	O
were	O
the	O
most	O
common	O
adverse	O
reactions	O
.	O

The	O
drug	O
was	O
discontinued	O
due	O
to	O
adverse	O
reactions	O
in	O
8	O
patients	O
.	O

No	O
patient	O
has	O
died	O
or	O
suffered	O
any	O
apparent	O
long	O
-	O
term	O
sequelae	O
that	O
were	O
directly	O
attributable	O
to	O
the	O
drug	O
.	O

We	O
conclude	O
that	O
,	O
despite	O
a	O
relatively	O
high	O
incidence	O
of	O
adverse	O
reactions	O
,	O
danazol	B-Chemical
has	O
proven	O
to	O
be	O
remarkably	O
safe	O
over	O
the	O
long	O
-	O
term	O
in	O
this	O
group	O
of	O
patients	O
.	O

The	O
function	O
of	O
P2X3	O
receptor	O
and	O
NK1	O
receptor	O
antagonists	O
on	O
cyclophosphamide	B-Chemical
-	O
induced	O
cystitis	B-Disease
in	O
rats	O
.	O

PURPOSE	O
:	O
The	O
purpose	O
of	O
the	O
study	O
is	O
to	O
explore	O
the	O
function	O
of	O
P2X3	O
and	O
NK1	O
receptors	O
antagonists	O
on	O
cyclophosphamide	B-Chemical
(	O
CYP	B-Chemical
)	O
-	O
induced	O
cystitis	B-Disease
in	O
rats	O
.	O

METHODS	O
:	O
Sixty	O
female	O
Sprague	O
-	O
Dawley	O
(	O
SD	O
)	O
rats	O
were	O
randomly	O
divided	O
into	O
three	O
groups	O
.	O

The	O
rats	O
in	O
the	O
control	O
group	O
were	O
intraperitoneally	O
(	O
i	O
.	O
p	O
.	O
)	O
injected	O
with	O
0	O
.	O
9	O
%	O
saline	O
(	O
4	O
ml	O
/	O
kg	O
)	O
;	O
the	O
rats	O
in	O
the	O
model	O
group	O
were	O
i	O
.	O
p	O
.	O
injected	O
with	O
CYP	B-Chemical
(	O
150	O
mg	O
/	O
kg	O
)	O
;	O
and	O
the	O
rats	O
in	O
the	O
intervention	O
group	O
were	O
i	O
.	O
p	O
.	O
injected	O
with	O
CYP	B-Chemical
with	O
subsequently	O
perfusion	O
of	O
bladder	O
with	O
P2X3	O
and	O
NK1	O
receptors	O
'	O
antagonists	O
,	O
Suramin	B-Chemical
and	O
GR	B-Chemical
82334	I-Chemical
.	O

Spontaneous	O
pain	B-Disease
behaviors	O
following	O
the	O
administration	O
of	O
CYP	B-Chemical
were	O
observed	O
.	O

Urodynamic	O
parameters	O
,	O
bladder	O
pressure	O
-	O
volume	O
curve	O
,	O
maximum	O
voiding	O
pressure	O
(	O
MVP	O
)	O
,	O
and	O
maximum	O
cystometric	O
capacity	O
(	O
MCC	O
)	O
,	O
were	O
recorded	O
.	O

Pathological	O
changes	O
in	O
bladder	O
tissue	O
were	O
observed	O
.	O

Immunofluorescence	O
was	O
used	O
to	O
detect	O
the	O
expression	O
of	O
P2X3	O
and	O
NK1	O
receptors	O
in	O
bladder	O
.	O

RESULTS	O
:	O
Cyclophosphamide	B-Chemical
treatment	O
increased	O
the	O
spontaneous	O
pain	B-Disease
behaviors	O
scores	O
.	O

The	O
incidence	O
of	O
bladder	O
instability	O
during	O
urine	O
storage	O
period	O
of	O
model	O
group	O
was	O
significantly	O
higher	O
than	O
intervention	O
group	O
(	O
X	O
(	O
2	O
)	O
=	O
7	O
.	O
619	O
,	O
P	O
=	O
0	O
.	O
007	O
)	O
and	O
control	O
group	O
(	O
X	O
(	O
2	O
)	O
=	O
13	O
.	O
755	O
,	O
P	O
=	O
0	O
.	O
000	O
)	O
.	O

MCC	O
in	O
the	O
model	O
group	O
was	O
lower	O
than	O
the	O
control	O
and	O
intervention	O
groups	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Histological	O
changes	O
evident	O
in	O
model	O
and	O
intervention	O
groups	O
rats	O
'	O
bladder	O
included	O
edema	B-Disease
,	O
vasodilation	O
,	O
and	O
infiltration	O
of	O
inflammatory	O
cells	O
.	O

In	O
model	O
group	O
,	O
the	O
expression	O
of	O
P2X3	O
receptor	O
increased	O
in	O
urothelium	O
and	O
suburothelium	O
,	O
and	O
NK1	O
receptor	O
increased	O
in	O
suburothelium	O
,	O
while	O
the	O
expression	O
of	O
them	O
in	O
intervention	O
group	O
was	O
lower	O
.	O

CONCLUSIONS	O
:	O
In	O
CYP	B-Chemical
-	O
induced	O
cystitis	B-Disease
,	O
the	O
expression	O
of	O
P2X3	O
and	O
NK1	O
receptors	O
increased	O
in	O
urothelium	O
and	O
/	O
or	O
suburothelium	O
.	O

Perfusion	O
of	O
bladder	O
with	O
P2X3	O
and	O
NK1	O
receptors	O
antagonists	O
ameliorated	O
the	O
bladder	O
function	O
.	O

Patient	O
tolerance	O
study	O
of	O
topical	O
chlorhexidine	B-Chemical
diphosphanilate	I-Chemical
:	O
a	O
new	O
topical	O
agent	O
for	O
burns	B-Disease
.	O

Effective	O
topical	O
antimicrobial	O
agents	O
decrease	O
infection	B-Disease
and	O
mortality	O
in	O
burn	B-Disease
patients	O
.	O

Chlorhexidine	B-Chemical
phosphanilate	I-Chemical
(	O
CHP	B-Chemical
)	O
,	O
a	O
new	O
broad	O
-	O
spectrum	O
antimicrobial	O
agent	O
,	O
has	O
been	O
evaluated	O
as	O
a	O
topical	O
burn	B-Disease
wound	O
dressing	O
in	O
cream	O
form	O
,	O
but	O
preliminary	O
clinical	O
trials	O
reported	O
that	O
it	O
was	O
painful	O
upon	O
application	O
.	O

This	O
study	O
compared	O
various	O
concentrations	O
of	O
CHP	B-Chemical
to	O
determine	O
if	O
a	O
tolerable	O
concentration	O
could	O
be	O
identified	O
with	O
retention	O
of	O
antimicrobial	O
efficacy	O
.	O

Twenty	O
-	O
nine	O
burn	B-Disease
patients	O
,	O
each	O
with	O
two	O
similar	O
burns	B-Disease
which	O
could	O
be	O
separately	O
treated	O
,	O
were	O
given	O
pairs	O
of	O
treatments	O
at	O
successive	O
12	O
-	O
h	O
intervals	O
over	O
a	O
3	O
-	O
day	O
period	O
.	O

One	O
burn	B-Disease
site	O
was	O
treated	O
with	O
each	O
of	O
four	O
different	O
CHP	B-Chemical
concentrations	O
,	O
from	O
0	O
.	O
25	O
per	O
cent	O
to	O
2	O
per	O
cent	O
,	O
their	O
vehicle	O
,	O
and	O
1	O
per	O
cent	O
silver	B-Chemical
sulphadiazine	I-Chemical
(	O
AgSD	B-Chemical
)	O
cream	O
,	O
an	O
antimicrobial	O
agent	O
frequently	O
used	O
for	O
topical	O
treatment	O
of	O
burn	B-Disease
wounds	O
.	O

The	O
other	O
site	O
was	O
always	O
treated	O
with	O
AgSD	B-Chemical
cream	O
.	O

There	O
was	O
a	O
direct	O
relationship	O
between	O
CHP	B-Chemical
concentration	O
and	O
patients	O
'	O
ratings	O
of	O
pain	B-Disease
on	O
an	O
analogue	O
scale	O
.	O

The	O
0	O
.	O
25	O
per	O
cent	O
CHP	B-Chemical
cream	O
was	O
closest	O
to	O
AgSD	B-Chemical
in	O
pain	B-Disease
tolerance	O
;	O
however	O
,	O
none	O
of	O
the	O
treatments	O
differed	O
statistically	O
from	O
AgSD	B-Chemical
or	O
from	O
each	O
other	O
.	O

In	O
addition	O
,	O
ease	O
of	O
application	O
of	O
CHP	B-Chemical
creams	O
was	O
less	O
satisfactory	O
than	O
that	O
of	O
AgSD	B-Chemical
.	O

It	O
was	O
concluded	O
that	O
formulations	O
at	O
or	O
below	O
0	O
.	O
5	O
per	O
cent	O
CHP	B-Chemical
may	O
prove	O
acceptable	O
for	O
wound	O
care	O
,	O
but	O
the	O
vehicle	O
system	O
needs	O
pharmaceutical	O
improvement	O
to	O
render	O
it	O
more	O
tolerable	O
and	O
easier	O
to	O
use	O
.	O

Acute	O
hepatitis	B-Disease
associated	O
with	O
clopidogrel	B-Chemical
:	O
a	O
case	O
report	O
and	O
review	O
of	O
the	O
literature	O
.	O

Drug	O
-	O
induced	O
hepatotoxicity	B-Disease
is	O
a	O
common	O
cause	O
of	O
acute	O
hepatitis	B-Disease
,	O
and	O
the	O
recognition	O
of	O
the	O
responsible	O
drug	O
may	O
be	O
difficult	O
.	O

We	O
describe	O
a	O
case	O
of	O
clopidogrel	B-Chemical
-	O
related	O
acute	O
hepatitis	B-Disease
.	O

The	O
diagnosis	O
is	O
strongly	O
suggested	O
by	O
an	O
accurate	O
medical	O
history	O
and	O
liver	O
biopsy	O
.	O

Reports	O
about	O
cases	O
of	O
hepatotoxicity	B-Disease
due	O
to	O
clopidogrel	B-Chemical
are	O
increasing	O
in	O
the	O
last	O
few	O
years	O
,	O
after	O
the	O
increased	O
use	O
of	O
this	O
drug	O
.	O

In	O
conclusion	O
,	O
we	O
believe	O
that	O
physicians	O
should	O
carefully	O
consider	O
the	O
risk	O
of	O
drug	O
-	O
induced	O
hepatic	B-Disease
injury	I-Disease
when	O
clopidogrel	B-Chemical
is	O
prescribed	O
.	O

Bortezomib	B-Chemical
and	O
dexamethasone	B-Chemical
as	O
salvage	O
therapy	O
in	O
patients	O
with	O
relapsed	O
/	O
refractory	O
multiple	B-Disease
myeloma	I-Disease
:	O
analysis	O
of	O
long	O
-	O
term	O
clinical	O
outcomes	O
.	O

Bortezomib	B-Chemical
(	O
bort	B-Chemical
)	O
-	O
dexamethasone	B-Chemical
(	O
dex	B-Chemical
)	O
is	O
an	O
effective	O
therapy	O
for	O
relapsed	O
/	O
refractory	O
(	O
R	O
/	O
R	O
)	O
multiple	B-Disease
myeloma	I-Disease
(	O
MM	B-Disease
)	O
.	O

This	O
retrospective	O
study	O
investigated	O
the	O
combination	O
of	O
bort	B-Chemical
(	O
1	O
.	O
3	O
mg	O
/	O
m	O
(	O
2	O
)	O
on	O
days	O
1	O
,	O
4	O
,	O
8	O
,	O
and	O
11	O
every	O
3	O
weeks	O
)	O
and	O
dex	B-Chemical
(	O
20	O
mg	O
on	O
the	O
day	O
of	O
and	O
the	O
day	O
after	O
bort	B-Chemical
)	O
as	O
salvage	O
treatment	O
in	O
85	O
patients	O
with	O
R	O
/	O
R	O
MM	B-Disease
after	O
prior	O
autologous	O
stem	O
cell	O
transplantation	O
or	O
conventional	O
chemotherapy	O
.	O

The	O
median	O
number	O
of	O
prior	O
lines	O
of	O
therapy	O
was	O
2	O
.	O

Eighty	O
-	O
seven	O
percent	O
of	O
the	O
patients	O
had	O
received	O
immunomodulatory	O
drugs	O
included	O
in	O
some	O
line	O
of	O
therapy	O
before	O
bort	B-Chemical
-	O
dex	B-Chemical
.	O

The	O
median	O
number	O
of	O
bort	B-Chemical
-	O
dex	B-Chemical
cycles	O
was	O
6	O
,	O
up	O
to	O
a	O
maximum	O
of	O
12	O
cycles	O
.	O

On	O
an	O
intention	O
-	O
to	O
-	O
treat	O
basis	O
,	O
55	O
%	O
of	O
the	O
patients	O
achieved	O
at	O
least	O
partial	O
response	O
,	O
including	O
19	O
%	O
CR	O
and	O
35	O
%	O
achieved	O
at	O
least	O
very	O
good	O
partial	O
response	O
.	O

Median	O
durations	O
of	O
response	O
,	O
time	O
to	O
next	O
therapy	O
and	O
treatment	O
-	O
free	O
interval	O
were	O
8	O
,	O
11	O
.	O
2	O
,	O
and	O
5	O
.	O
1	O
months	O
,	O
respectively	O
.	O

The	O
most	O
relevant	O
adverse	O
event	O
was	O
peripheral	B-Disease
neuropathy	I-Disease
,	O
which	O
occurred	O
in	O
78	O
%	O
of	O
the	O
patients	O
(	O
grade	O
II	O
,	O
38	O
%	O
;	O
grade	O
III	O
,	O
21	O
%	O
)	O
and	O
led	O
to	O
treatment	O
discontinuation	O
in	O
6	O
%	O
.	O

With	O
a	O
median	O
follow	O
up	O
of	O
22	O
months	O
,	O
median	O
time	O
to	O
progression	O
,	O
progression	O
-	O
free	O
survival	O
(	O
PFS	O
)	O
and	O
overall	O
survival	O
(	O
OS	O
)	O
were	O
8	O
.	O
9	O
,	O
8	O
.	O
7	O
,	O
and	O
22	O
months	O
,	O
respectively	O
.	O

Prolonged	O
PFS	O
and	O
OS	O
were	O
observed	O
in	O
patients	O
achieving	O
CR	O
and	O
receiving	O
bort	B-Chemical
-	O
dex	B-Chemical
a	O
single	O
line	O
of	O
prior	O
therapy	O
.	O

Bort	B-Chemical
-	O
dex	B-Chemical
was	O
an	O
effective	O
salvage	O
treatment	O
for	O
MM	B-Disease
patients	O
,	O
particularly	O
for	O
those	O
in	O
first	O
relapse	O
.	O

Pubertal	O
exposure	O
to	O
Bisphenol	B-Chemical
A	I-Chemical
increases	O
anxiety	B-Disease
-	O
like	O
behavior	O
and	O
decreases	O
acetylcholinesterase	O
activity	O
of	O
hippocampus	O
in	O
adult	O
male	O
mice	O
.	O

The	O
negative	O
effects	O
of	O
Bisphenol	B-Chemical
A	I-Chemical
(	O
BPA	B-Chemical
)	O
on	O
neurodevelopment	O
and	O
behaviors	O
have	O
been	O
well	O
established	O
.	O

Acetylcholinesterase	O
(	O
AChE	O
)	O
is	O
a	O
regulatory	O
enzyme	O
which	O
is	O
involved	O
in	O
anxiety	B-Disease
-	O
like	O
behavior	O
.	O

This	O
study	O
investigated	O
behavioral	O
phenotypes	O
and	O
AChE	O
activity	O
in	O
male	O
mice	O
following	O
BPA	B-Chemical
exposure	O
during	O
puberty	O
.	O

On	O
postnatal	O
day	O
(	O
PND	O
)	O
35	O
,	O
male	O
mice	O
were	O
exposed	O
to	O
50mg	O
BPA	B-Chemical
/	O
kg	O
diet	O
per	O
day	O
for	O
a	O
period	O
of	O
35	O
days	O
.	O

On	O
PND71	O
,	O
a	O
behavioral	O
assay	O
was	O
performed	O
using	O
the	O
elevated	O
plus	O
maze	O
(	O
EPM	O
)	O
and	O
the	O
light	O
/	O
dark	O
test	O
.	O

In	O
addition	O
,	O
AChE	O
activity	O
was	O
measured	O
in	O
the	O
prefrontal	O
cortex	O
,	O
hypothalamus	O
,	O
cerebellum	O
and	O
hippocampus	O
.	O

Results	O
from	O
our	O
behavioral	O
phenotyping	O
indicated	O
that	O
anxiety	B-Disease
-	O
like	O
behavior	O
was	O
increased	O
in	O
mice	O
exposed	O
to	O
BPA	B-Chemical
.	O

AChE	O
activity	O
was	O
significantly	O
decreased	O
in	O
the	O
hippocampus	O
of	O
mice	O
with	O
BPA	B-Chemical
compared	O
to	O
control	O
mice	O
,	O
whereas	O
no	O
difference	O
was	O
found	O
in	O
the	O
prefrontal	O
cortex	O
,	O
hypothalamus	O
and	O
cerebellum	O
.	O

Our	O
findings	O
showed	O
that	O
pubertal	O
BPA	B-Chemical
exposure	O
increased	O
anxiety	B-Disease
-	O
like	O
behavior	O
,	O
which	O
may	O
be	O
associated	O
with	O
decreased	O
AChE	O
activity	O
of	O
the	O
hippocampus	O
in	O
adult	O
male	O
mice	O
.	O

Further	O
studies	O
are	O
necessary	O
to	O
investigate	O
the	O
cholinergic	O
signaling	O
of	O
the	O
hippocampus	O
in	O
PBE	O
induced	O
anxiety	B-Disease
-	O
like	O
behaviors	O
.	O

Biochemical	O
effects	O
of	O
Solidago	O
virgaurea	O
extract	O
on	O
experimental	O
cardiotoxicity	B-Disease
.	O

Cardiovascular	B-Disease
diseases	I-Disease
(	O
CVDs	B-Disease
)	O
are	O
the	O
major	O
health	O
problem	O
of	O
advanced	O
as	O
well	O
as	O
developing	O
countries	O
of	O
the	O
world	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
the	O
protective	O
effect	O
of	O
the	O
Solidago	O
virgaurea	O
extract	O
on	O
isoproterenol	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
in	O
rats	O
.	O

The	O
subcutaneous	O
injection	O
of	O
isoproterenol	B-Chemical
(	O
30	O
mg	O
/	O
kg	O
)	O
into	O
rats	O
twice	O
at	O
an	O
interval	O
of	O
24	O
h	O
,	O
for	O
two	O
consecutive	O
days	O
,	O
led	O
to	O
a	O
significant	O
increase	O
in	O
serum	O
lactate	B-Chemical
dehydrogenase	O
,	O
creatine	B-Chemical
phosphokinase	O
,	O
alanine	B-Chemical
transaminase	O
,	O
aspartate	B-Chemical
transaminase	O
,	O
and	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
activities	O
,	O
total	O
cholesterol	B-Chemical
,	O
triglycerides	B-Chemical
,	O
free	O
serum	O
fatty	B-Chemical
acid	I-Chemical
,	O
cardiac	O
tissue	O
malondialdehyde	B-Chemical
(	O
MDA	B-Chemical
)	O
,	O
and	O
nitric	B-Chemical
oxide	I-Chemical
levels	O
and	O
a	O
significant	O
decrease	O
in	O
levels	O
of	O
glutathione	B-Chemical
and	O
superoxide	B-Chemical
dismutase	O
in	O
cardiac	O
tissue	O
as	O
compared	O
to	O
the	O
normal	O
control	O
group	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Pretreatment	O
with	O
S	O
.	O
virgaurea	O
extract	O
for	O
5	O
weeks	O
at	O
a	O
dose	O
of	O
250	O
mg	O
/	O
kg	O
followed	O
by	O
isoproterenol	B-Chemical
injection	O
significantly	O
prevented	O
the	O
observed	O
alterations	O
.	O

Captopril	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
/	O
day	O
,	O
given	O
orally	O
)	O
,	O
an	O
inhibitor	O
of	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
used	O
as	O
a	O
standard	O
cardioprotective	O
drug	O
,	O
was	O
used	O
as	O
a	O
positive	O
control	O
in	O
this	O
study	O
.	O

The	O
data	O
of	O
the	O
present	O
study	O
suggest	O
that	O
S	O
.	O
virgaurea	O
extract	O
exerts	O
its	O
protective	O
effect	O
by	O
decreasing	O
MDA	B-Chemical
level	O
and	O
increasing	O
the	O
antioxidant	O
status	O
in	O
isoproterenol	B-Chemical
-	O
treated	O
rats	O
.	O

The	O
study	O
emphasizes	O
the	O
beneficial	O
action	O
of	O
S	O
.	O
virgaurea	O
extract	O
as	O
a	O
cardioprotective	O
agent	O
.	O

"	O
Real	O
-	O
world	O
"	O
data	O
on	O
the	O
efficacy	O
and	O
safety	O
of	O
lenalidomide	B-Chemical
and	O
dexamethasone	B-Chemical
in	O
patients	O
with	O
relapsed	O
/	O
refractory	O
multiple	B-Disease
myeloma	I-Disease
who	O
were	O
treated	O
according	O
to	O
the	O
standard	O
clinical	O
practice	O
:	O
a	O
study	O
of	O
the	O
Greek	O
Myeloma	B-Disease
Study	O
Group	O
.	O

Lenalidomide	B-Chemical
and	O
dexamethasone	B-Chemical
(	O
RD	B-Chemical
)	O
is	O
a	O
standard	O
of	O
care	O
for	O
relapsed	O
/	O
refractory	O
multiple	B-Disease
myeloma	I-Disease
(	O
RRMM	B-Disease
)	O
,	O
but	O
there	O
is	O
limited	O
published	O
data	O
on	O
its	O
efficacy	O
and	O
safety	O
in	O
the	O
"	O
real	O
world	O
"	O
(	O
RW	O
)	O
,	O
according	O
to	O
the	O
International	O
Society	O
of	O
Pharmacoeconomics	O
and	O
Outcomes	O
Research	O
definition	O
.	O

We	O
studied	O
212	O
RRMM	B-Disease
patients	O
who	O
received	O
RD	B-Chemical
in	O
RW	O
.	O

Objective	O
response	O
(	O
>	O
PR	O
(	O
partial	O
response	O
)	O
)	O
rate	O
was	O
77	O
.	O
4	O
%	O
(	O
complete	O
response	O
(	O
CR	O
)	O
,	O
20	O
.	O
2	O
%	O
)	O
.	O

Median	O
time	O
to	O
first	O
and	O
best	O
response	O
was	O
2	O
and	O
5	O
months	O
,	O
respectively	O
.	O

Median	O
time	O
to	O
CR	O
when	O
RD	B-Chemical
was	O
given	O
as	O
2nd	O
or	O
>	O
2	O
(	O
nd	O
)	O
-	O
line	O
treatment	O
at	O
4	O
and	O
11	O
months	O
,	O
respectively	O
.	O

Quality	O
of	O
response	O
was	O
independent	O
of	O
previous	O
lines	O
of	O
therapies	O
or	O
previous	O
exposure	O
to	O
thalidomide	B-Chemical
or	O
bortezomib	B-Chemical
.	O

Median	O
duration	O
of	O
response	O
was	O
34	O
.	O
4	O
months	O
,	O
and	O
it	O
was	O
higher	O
in	O
patients	O
who	O
received	O
RD	B-Chemical
until	O
progression	O
(	O
not	O
reached	O
versus	O
19	O
months	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Improvement	O
of	O
humoral	O
immunity	O
occurred	O
in	O
60	O
%	O
of	O
responders	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
and	O
in	O
the	O
majority	O
of	O
patients	O
who	O
achieved	O
stable	O
disease	O
.	O

Adverse	O
events	O
were	O
reported	O
in	O
68	O
.	O
9	O
%	O
of	O
patients	O
(	O
myelosuppression	B-Disease
in	O
49	O
.	O
4	O
%	O
)	O
and	O
12	O
.	O
7	O
%	O
of	O
patients	O
needed	O
hospitalization	O
.	O

Peripheral	B-Disease
neuropathy	I-Disease
was	O
observed	O
only	O
in	O
2	O
.	O
5	O
%	O
of	O
patients	O
and	O
deep	B-Disease
vein	I-Disease
thrombosis	I-Disease
in	O
5	O
.	O
7	O
%	O
.	O

Dose	O
reductions	O
were	O
needed	O
in	O
31	O
%	O
of	O
patients	O
and	O
permanent	O
discontinuation	O
in	O
38	O
.	O
9	O
%	O
.	O

Median	O
time	O
to	O
treatment	O
discontinuation	O
was	O
16	O
.	O
8	O
months	O
.	O

Performance	O
status	O
(	O
PS	O
)	O
and	O
initial	O
lenalidomide	B-Chemical
dose	O
predicted	O
for	O
treatment	O
discontinuation	O
.	O

Extra	O
-	O
medullary	O
relapses	O
occurred	O
in	O
3	O
.	O
8	O
%	O
of	O
patients	O
.	O

Our	O
study	O
confirms	O
that	O
RD	B-Chemical
is	O
effective	O
and	O
safe	O
in	O
RRMM	B-Disease
in	O
the	O
RW	O
;	O
it	O
produces	O
durable	O
responses	O
especially	O
in	O
patients	O
who	O
continue	O
on	O
treatment	O
till	O
progression	O
and	O
improves	O
humoral	O
immunity	O
even	O
in	O
patients	O
with	O
stable	O
disease	O
.	O

The	O
cytogenetic	O
action	O
of	O
ifosfamide	B-Chemical
,	O
mesna	B-Chemical
,	O
and	O
their	O
combination	O
on	O
peripheral	O
rabbit	O
lymphocytes	O
:	O
an	O
in	O
vivo	O
/	O
in	O
vitro	O
cytogenetic	O
study	O
.	O

Ifosfamide	B-Chemical
(	O
IFO	B-Chemical
)	O
is	O
an	O
alkylating	O
nitrogen	B-Chemical
mustard	O
,	O
administrated	O
as	O
an	O
antineoplasmic	O
agent	O
.	O

It	O
is	O
characterized	O
by	O
its	O
intense	O
urotoxic	O
action	O
,	O
leading	O
to	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

This	O
side	O
effect	O
of	O
IFO	B-Chemical
raises	O
the	O
requirement	O
for	O
the	O
co	O
-	O
administration	O
with	O
sodium	B-Chemical
2	I-Chemical
-	I-Chemical
sulfanylethanesulfonate	I-Chemical
(	O
Mesna	B-Chemical
)	O
aiming	O
to	O
avoid	O
or	O
minimize	O
this	O
effect	O
.	O

IFO	B-Chemical
and	O
Mesna	B-Chemical
were	O
administrated	O
separately	O
on	O
rabbit	O
'	O
s	O
lymphocytes	O
in	O
vivo	O
,	O
which	O
were	O
later	O
developed	O
in	O
vitro	O
.	O

Cytogenetic	O
markers	O
for	O
sister	O
chromatid	O
exchanges	O
(	O
SCEs	O
)	O
,	O
proliferation	O
rate	O
index	O
(	O
PRI	O
)	O
and	O
Mitotic	O
Index	O
were	O
recorded	O
.	O

Mesna	B-Chemical
'	O
s	O
action	O
,	O
in	O
conjunction	O
with	O
IFO	B-Chemical
reduces	O
the	O
frequency	O
of	O
SCEs	O
,	O
in	O
comparison	O
with	O
the	O
SCEs	O
recordings	O
obtained	O
when	O
IFO	B-Chemical
is	O
administered	O
alone	O
.	O

In	O
addition	O
to	O
this	O
,	O
when	O
high	O
concentrations	O
of	O
Mesna	B-Chemical
were	O
administered	O
alone	O
significant	O
reductions	O
of	O
the	O
PRI	O
were	O
noted	O
,	O
than	O
with	O
IFO	B-Chemical
acting	O
at	O
the	O
same	O
concentration	O
on	O
the	O
lymphocytes	O
.	O

Mesna	B-Chemical
significantly	O
reduces	O
IFO	B-Chemical
'	O
s	O
genotoxicity	B-Disease
,	O
while	O
when	O
administered	O
in	O
high	O
concentrations	O
it	O
acts	O
in	O
an	O
inhibitory	O
fashion	O
on	O
the	O
cytostatic	O
action	O
of	O
the	O
drug	O
.	O

Risk	O
factors	O
and	O
predictors	O
of	O
levodopa	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
among	O
multiethnic	O
Malaysians	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Chronic	O
pulsatile	O
levodopa	B-Chemical
therapy	O
for	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
leads	O
to	O
the	O
development	O
of	O
motor	O
fluctuations	O
and	O
dyskinesia	B-Disease
.	O

We	O
studied	O
the	O
prevalence	O
and	O
predictors	O
of	O
levodopa	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
among	O
multiethnic	O
Malaysian	O
patients	O
with	O
PD	B-Disease
.	O

METHODS	O
:	O
This	O
is	O
a	O
cross	O
-	O
sectional	O
study	O
involving	O
95	O
patients	O
with	O
PD	B-Disease
on	O
uninterrupted	O
levodopa	B-Chemical
therapy	O
for	O
at	O
least	O
6	O
months	O
.	O

The	O
instrument	O
used	O
was	O
the	O
UPDRS	O
questionnaires	O
.	O

The	O
predictors	O
of	O
dyskinesia	B-Disease
were	O
determined	O
using	O
multivariate	O
logistic	O
regression	O
analysis	O
.	O

RESULTS	O
:	O
The	O
mean	O
age	O
was	O
65	O
.	O
6	O
+	O
8	O
.	O
5	O
years	O
.	O

The	O
mean	O
onset	O
age	O
was	O
58	O
.	O
5	O
+	O
9	O
.	O
8	O
years	O
.	O

The	O
median	O
disease	O
duration	O
was	O
6	O
(	O
7	O
)	O
years	O
.	O

Dyskinesia	B-Disease
was	O
present	O
in	O
44	O
%	O
(	O
n	O
=	O
42	O
)	O
with	O
median	O
levodopa	B-Chemical
therapy	O
of	O
3	O
years	O
.	O

There	O
were	O
64	O
.	O
3	O
%	O
Chinese	O
,	O
31	O
%	O
Malays	O
,	O
and	O
3	O
.	O
7	O
%	O
Indians	O
and	O
other	O
ethnic	O
groups	O
.	O

Eighty	O
-	O
one	O
percent	O
of	O
patients	O
with	O
dyskinesia	B-Disease
had	O
clinical	O
fluctuations	O
.	O

Patients	O
with	O
dyskinesia	B-Disease
had	O
lower	O
onset	O
age	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
longer	O
duration	O
of	O
levodopa	B-Chemical
therapy	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
longer	O
disease	O
duration	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
higher	O
total	O
daily	O
levodopa	B-Chemical
dose	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
and	O
higher	O
total	O
UPDRS	O
scores	O
(	O
p	O
=	O
0	O
.	O
005	O
)	O
than	O
patients	O
without	O
dyskinesia	B-Disease
.	O

The	O
three	O
significant	O
predictors	O
of	O
dyskinesia	B-Disease
were	O
duration	O
of	O
levodopa	B-Chemical
therapy	O
,	O
onset	O
age	O
,	O
and	O
total	O
daily	O
levodopa	B-Chemical
dose	O
.	O

CONCLUSIONS	O
:	O
The	O
prevalence	O
of	O
levodopa	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
in	O
our	O
patients	O
was	O
44	O
%	O
.	O

The	O
most	O
significant	O
predictors	O
were	O
duration	O
of	O
levodopa	B-Chemical
therapy	O
,	O
total	O
daily	O
levodopa	B-Chemical
dose	O
,	O
and	O
onset	O
age	O
.	O

Dose	O
-	O
dependent	O
neurotoxicity	B-Disease
of	O
high	O
-	O
dose	O
busulfan	B-Chemical
in	O
children	O
:	O
a	O
clinical	O
and	O
pharmacological	O
study	O
.	O

Busulfan	B-Chemical
is	O
known	O
to	O
be	O
neurotoxic	B-Disease
in	O
animals	O
and	O
humans	O
,	O
but	O
its	O
acute	O
neurotoxicity	B-Disease
remains	O
poorly	O
characterized	O
in	O
children	O
.	O

We	O
report	O
here	O
a	O
retrospective	O
study	O
of	O
123	O
children	O
(	O
median	O
age	O
,	O
6	O
.	O
5	O
years	O
)	O
receiving	O
high	O
-	O
dose	O
busulfan	B-Chemical
in	O
combined	O
chemotherapy	O
before	O
bone	O
marrow	O
transplantation	O
for	O
malignant	O
solid	O
tumors	B-Disease
,	O
brain	B-Disease
tumors	I-Disease
excluded	O
.	O

Busulfan	B-Chemical
was	O
given	O
p	O
.	O
o	O
.	O
,	O
every	O
6	O
hours	O
for	O
16	O
doses	O
over	O
4	O
days	O
.	O

Two	O
total	O
doses	O
were	O
consecutively	O
used	O
:	O
16	O
mg	O
/	O
kg	O
,	O
then	O
600	O
mg	O
/	O
m2	O
.	O

The	O
dose	O
calculation	O
on	O
the	O
basis	O
of	O
body	O
surface	O
area	O
results	O
in	O
higher	O
doses	O
in	O
young	O
children	O
than	O
in	O
older	O
patients	O
(	O
16	O
to	O
28	O
mg	O
/	O
kg	O
)	O
.	O

Ninety	O
-	O
six	O
patients	O
were	O
not	O
given	O
anticonvulsive	O
prophylaxis	O
;	O
7	O
(	O
7	O
.	O
5	O
%	O
)	O
developed	O
seizures	B-Disease
during	O
the	O
4	O
days	O
of	O
the	O
busulfan	B-Chemical
course	O
or	O
within	O
24	O
h	O
after	O
the	O
last	O
dosing	O
.	O

When	O
the	O
total	O
busulfan	B-Chemical
dose	O
was	O
taken	O
into	O
account	O
,	O
there	O
was	O
a	O
significant	O
difference	O
in	O
terms	O
of	O
neurotoxicity	B-Disease
incidence	O
among	O
patients	O
under	O
16	O
mg	O
/	O
kg	O
(	O
1	O
of	O
57	O
,	O
1	O
.	O
7	O
%	O
)	O
and	O
patients	O
under	O
600	O
mg	O
/	O
m2	O
(	O
6	O
of	O
39	O
,	O
15	O
.	O
4	O
%	O
)	O
(	O
P	O
less	O
than	O
0	O
.	O
02	O
)	O
.	O

Twenty	O
-	O
seven	O
patients	O
were	O
given	O
a	O
600	O
-	O
mg	O
/	O
m2	O
busulfan	B-Chemical
total	O
dose	O
with	O
continuous	O
i	O
.	O
v	O
.	O
infusion	O
of	O
clonazepam	B-Chemical
;	O
none	O
had	O
any	O
neurological	B-Disease
symptoms	I-Disease
.	O

Busulfan	B-Chemical
levels	O
were	O
measured	O
by	O
a	O
gas	O
chromatographic	O
-	O
mass	O
spectrometry	O
assay	O
in	O
the	O
plasma	O
and	O
cerebrospinal	O
fluid	O
of	O
9	O
children	O
without	O
central	B-Disease
nervous	I-Disease
system	I-Disease
disease	I-Disease
under	O
600	O
mg	O
/	O
m2	O
busulfan	B-Chemical
with	O
clonazepam	B-Chemical
:	O
busulfan	B-Chemical
cerebrospinal	O
fluid	O
:	O
plasma	O
ratio	O
was	O
1	O
.	O
39	O
.	O

This	O
was	O
significantly	O
different	O
(	O
P	O
less	O
than	O
0	O
.	O
02	O
)	O
from	O
the	O
cerebrospinal	O
fluid	O
:	O
plasma	O
ratio	O
previously	O
defined	O
in	O
children	O
receiving	O
a	O
16	O
-	O
mg	O
/	O
kg	O
total	O
dose	O
of	O
busulfan	B-Chemical
.	O

This	O
study	O
shows	O
that	O
busulfan	B-Chemical
neurotoxicity	B-Disease
is	O
dose	O
-	O
dependent	O
in	O
children	O
and	O
efficiently	O
prevented	O
by	O
clonazepam	B-Chemical
.	O

A	O
busulfan	B-Chemical
dose	O
calculated	O
on	O
the	O
basis	O
of	O
body	O
surface	O
area	O
,	O
resulting	O
in	O
higher	O
doses	O
in	O
young	O
children	O
,	O
was	O
followed	O
by	O
increased	O
neurotoxicity	B-Disease
,	O
close	O
to	O
neurotoxicity	B-Disease
incidence	O
observed	O
in	O
adults	O
.	O

Since	O
plasma	O
pharmacokinetic	O
studies	O
showed	O
a	O
faster	O
busulfan	B-Chemical
clearance	O
in	O
children	O
than	O
in	O
adults	O
,	O
this	O
new	O
dose	O
may	O
approximate	O
more	O
closely	O
the	O
adult	O
systemic	O
exposure	O
obtained	O
after	O
the	O
usual	O
16	O
-	O
mg	O
/	O
kg	O
total	O
dose	O
,	O
with	O
potential	O
inferences	O
in	O
terms	O
of	O
anticancer	O
or	O
myeloablative	O
effects	O
.	O

The	O
busulfan	B-Chemical
dose	O
in	O
children	O
and	O
infants	O
undergoing	O
bone	O
marrow	O
transplantation	O
should	O
be	O
reconsidered	O
on	O
the	O
basis	O
of	O
pharmacokinetic	O
studies	O
.	O

An	O
unexpected	O
diagnosis	O
in	O
a	O
renal	O
-	O
transplant	O
patient	O
with	O
proteinuria	B-Disease
treated	O
with	O
everolimus	B-Chemical
:	O
AL	B-Disease
amyloidosis	B-Disease
.	O

Proteinuria	B-Disease
is	O
an	O
expected	O
complication	O
in	O
transplant	O
patients	O
treated	O
with	O
mammalian	O
target	O
of	O
rapamycin	B-Chemical
inhibitors	O
(	O
mTOR	O
-	O
i	O
)	O
.	O

However	O
,	O
clinical	O
suspicion	O
should	O
always	O
be	O
supported	O
by	O
histological	O
evidence	O
in	O
order	O
to	O
investigate	O
potential	O
alternate	O
diagnoses	O
such	O
as	O
acute	O
or	O
chronic	O
rejection	O
,	O
interstitial	O
fibrosis	B-Disease
and	O
tubular	O
atrophy	B-Disease
,	O
or	O
recurrent	O
or	O
de	O
novo	O
glomerulopathy	B-Disease
.	O

In	O
this	O
case	O
we	O
report	O
the	O
unexpected	O
diagnosis	O
of	O
amyloidosis	B-Disease
in	O
a	O
renal	O
-	O
transplant	O
patient	O
with	O
pre	O
-	O
transplant	O
monoclonal	O
gammapathy	O
of	O
undetermined	O
significance	O
who	O
developed	O
proteinuria	B-Disease
after	O
conversion	O
from	O
tacrolimus	B-Chemical
to	O
everolimus	B-Chemical
.	O

Long	O
-	O
term	O
oral	O
galactose	B-Chemical
treatment	O
prevents	O
cognitive	B-Disease
deficits	I-Disease
in	O
male	O
Wistar	O
rats	O
treated	O
intracerebroventricularly	O
with	O
streptozotocin	B-Chemical
.	O

Basic	O
and	O
clinical	O
research	O
has	O
demonstrated	O
that	O
dementia	B-Disease
of	O
sporadic	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
sAD	O
)	O
type	O
is	O
associated	O
with	O
dysfunction	O
of	O
the	O
insulin	O
-	O
receptor	O
(	O
IR	O
)	O
system	O
followed	O
by	O
decreased	O
glucose	B-Chemical
transport	O
via	O
glucose	B-Chemical
transporter	O
GLUT4	O
and	O
decreased	O
glucose	B-Chemical
metabolism	O
in	O
brain	O
cells	O
.	O

An	O
alternative	O
source	O
of	O
energy	O
is	O
d	B-Chemical
-	I-Chemical
galactose	I-Chemical
(	O
the	O
C	O
-	O
4	O
-	O
epimer	O
of	O
d	B-Chemical
-	I-Chemical
glucose	I-Chemical
)	O
which	O
is	O
transported	O
into	O
the	O
brain	O
by	O
insulin	O
-	O
independent	O
GLUT3	O
transporter	O
where	O
it	O
might	O
be	O
metabolized	O
to	O
glucose	B-Chemical
via	O
the	O
Leloir	O
pathway	O
.	O

Exclusively	O
parenteral	O
daily	O
injections	O
of	O
galactose	B-Chemical
induce	O
memory	B-Disease
deterioration	I-Disease
in	O
rodents	O
and	O
are	O
used	O
to	O
generate	O
animal	O
aging	O
model	O
,	O
but	O
the	O
effects	O
of	O
oral	O
galactose	B-Chemical
treatment	O
on	O
cognitive	O
functions	O
have	O
never	O
been	O
tested	O
.	O

We	O
have	O
investigated	O
the	O
effects	O
of	O
continuous	O
daily	O
oral	O
galactose	B-Chemical
(	O
200	O
mg	O
/	O
kg	O
/	O
day	O
)	O
treatment	O
on	O
cognitive	B-Disease
deficits	I-Disease
in	O
streptozotocin	B-Chemical
-	O
induced	O
(	O
STZ	B-Chemical
-	O
icv	O
)	O
rat	O
model	O
of	O
sAD	O
,	O
tested	O
by	O
Morris	O
Water	O
Maze	O
and	O
Passive	O
Avoidance	O
test	O
,	O
respectively	O
.	O

One	O
month	O
of	O
oral	O
galactose	B-Chemical
treatment	O
initiated	O
immediately	O
after	O
the	O
STZ	B-Chemical
-	O
icv	O
administration	O
,	O
successfully	O
prevented	O
development	O
of	O
the	O
STZ	B-Chemical
-	O
icv	O
-	O
induced	O
cognitive	B-Disease
deficits	I-Disease
.	O

Beneficial	O
effect	O
of	O
oral	O
galactose	B-Chemical
was	O
independent	O
of	O
the	O
rat	O
age	O
and	O
of	O
the	O
galactose	B-Chemical
dose	O
ranging	O
from	O
100	O
to	O
300	O
mg	O
/	O
kg	O
/	O
day	O
.	O

Additionally	O
,	O
oral	O
galactose	B-Chemical
administration	O
led	O
to	O
the	O
appearance	O
of	O
galactose	B-Chemical
in	O
the	O
blood	O
.	O

The	O
increase	O
of	O
galactose	B-Chemical
concentration	O
in	O
the	O
cerebrospinal	O
fluid	O
was	O
several	O
times	O
lower	O
after	O
oral	O
than	O
after	O
parenteral	O
administration	O
of	O
the	O
same	O
galactose	B-Chemical
dose	O
.	O

Oral	O
galactose	B-Chemical
exposure	O
might	O
have	O
beneficial	O
effects	O
on	O
learning	O
and	O
memory	O
ability	O
and	O
could	O
be	O
worth	O
investigating	O
for	O
improvement	O
of	O
cognitive	B-Disease
deficits	I-Disease
associated	O
with	O
glucose	B-Disease
hypometabolism	I-Disease
in	O
AD	B-Disease
.	O

An	O
investigation	O
of	O
the	O
pattern	O
of	O
kidney	B-Disease
injury	I-Disease
in	O
HIV	O
-	O
positive	O
persons	O
exposed	O
to	O
tenofovir	B-Chemical
disoproxil	I-Chemical
fumarate	I-Chemical
:	O
an	O
examination	O
of	O
a	O
large	O
population	O
database	O
(	O
MHRA	O
database	O
)	O
.	O

The	O
potential	O
for	O
tenofovir	B-Chemical
to	O
cause	O
a	O
range	O
of	O
kidney	O
syndromes	O
has	O
been	O
established	O
from	O
mechanistic	O
and	O
randomised	O
clinical	O
trials	O
.	O

However	O
,	O
the	O
exact	O
pattern	O
of	O
kidney	O
involvement	O
is	O
still	O
uncertain	O
.	O

We	O
undertook	O
a	O
descriptive	O
analysis	O
of	O
Yellow	O
Card	O
records	O
of	O
407	O
HIV	O
-	O
positive	O
persons	O
taking	O
tenofovir	B-Chemical
disoproxil	I-Chemical
fumarate	I-Chemical
(	O
TDF	B-Chemical
)	O
as	O
part	O
of	O
their	O
antiretroviral	O
therapy	O
regimen	O
and	O
submitted	O
to	O
the	O
Medicines	O
and	O
Healthcare	O
Products	O
Regulatory	O
Agency	O
(	O
MHRA	O
)	O
with	O
suspected	O
kidney	O
adverse	O
effects	O
.	O

Reports	O
that	O
satisfy	O
defined	O
criteria	O
were	O
classified	O
as	O
acute	B-Disease
kidney	I-Disease
injury	I-Disease
,	O
kidney	B-Disease
tubular	I-Disease
dysfunction	I-Disease
and	O
Fanconi	B-Disease
syndrome	I-Disease
.	O

Of	O
the	O
407	O
Yellow	O
Card	O
records	O
analysed	O
,	O
106	O
satisfied	O
criteria	O
for	O
TDF	B-Chemical
-	O
related	O
kidney	B-Disease
disease	I-Disease
,	O
of	O
which	O
53	O
(	O
50	O
%	O
)	O
had	O
features	O
of	O
kidney	B-Disease
tubular	I-Disease
dysfunction	I-Disease
,	O
35	O
(	O
33	O
%	O
)	O
were	O
found	O
to	O
have	O
features	O
of	O
glomerular	B-Disease
dysfunction	I-Disease
and	O
18	O
(	O
17	O
%	O
)	O
had	O
Fanconi	B-Disease
syndrome	I-Disease
.	O

The	O
median	O
TDF	B-Chemical
exposure	O
was	O
316	O
days	O
(	O
interquartile	O
range	O
120	O
-	O
740	O
)	O
.	O

The	O
incidence	O
of	O
hospitalisation	O
for	O
TDF	B-Chemical
kidney	O
adverse	O
effects	O
was	O
high	O
,	O
particularly	O
amongst	O
patients	O
with	O
features	O
of	O
Fanconi	B-Disease
syndrome	I-Disease
.	O

The	O
pattern	O
of	O
kidney	O
syndromes	O
in	O
this	O
population	O
series	O
mirrors	O
that	O
reported	O
in	O
randomised	O
clinical	O
trials	O
.	O

Cessation	O
of	O
TDF	B-Chemical
was	O
associated	O
with	O
complete	O
restoration	O
of	O
kidney	O
function	O
in	O
up	O
half	O
of	O
the	O
patients	O
in	O
this	O
report	O
.	O

Incidence	O
of	O
postoperative	B-Disease
delirium	I-Disease
is	O
high	O
even	O
in	O
a	O
population	O
without	O
known	O
risk	O
factors	O
.	O

PURPOSE	O
:	O
Postoperative	B-Disease
delirium	I-Disease
is	O
a	O
recognized	O
complication	O
in	O
populations	O
at	O
risk	O
.	O

The	O
aim	O
of	O
this	O
study	O
is	O
to	O
assess	O
the	O
prevalence	O
of	O
early	O
postoperative	B-Disease
delirium	I-Disease
in	O
a	O
population	O
without	O
known	O
risk	O
factors	O
admitted	O
to	O
the	O
ICU	O
for	O
postoperative	O
monitoring	O
after	O
elective	O
major	O
surgery	O
.	O

The	O
secondary	O
outcome	O
investigated	O
is	O
to	O
identify	O
eventual	O
independent	O
risk	O
factors	O
among	O
demographic	O
data	O
and	O
anesthetic	O
drugs	O
used	O
.	O

METHODS	O
:	O
An	O
observational	O
,	O
prospective	O
study	O
was	O
conducted	O
on	O
a	O
consecutive	O
cohort	O
of	O
patients	O
admitted	O
to	O
our	O
ICU	O
within	O
and	O
for	O
at	O
least	O
24	O
h	O
after	O
major	O
surgical	O
procedures	O
.	O

Exclusion	O
criteria	O
were	O
any	O
preexisting	O
predisposing	O
factor	O
for	O
delirium	B-Disease
or	O
other	O
potentially	O
confounding	O
neurological	B-Disease
dysfunctions	I-Disease
.	O

Patients	O
were	O
assessed	O
daily	O
using	O
the	O
confusion	B-Disease
assessment	O
method	O
for	O
the	O
ICU	O
scale	O
for	O
3	O
days	O
after	O
the	O
surgical	O
procedure	O
.	O

Early	O
postoperative	B-Disease
delirium	I-Disease
incidence	O
risk	O
factors	O
were	O
then	O
assessed	O
through	O
three	O
different	O
multiple	O
regression	O
models	O
.	O

RESULTS	O
:	O
According	O
to	O
the	O
confusion	O
assessment	O
method	O
for	O
the	O
ICU	O
scale	O
,	O
28	O
%	O
of	O
patients	O
were	O
diagnosed	O
with	O
early	O
postoperative	B-Disease
delirium	I-Disease
.	O

The	O
use	O
of	O
thiopentone	B-Chemical
was	O
significantly	O
associated	O
with	O
an	O
eight	O
-	O
fold	O
-	O
higher	O
risk	O
for	O
delirium	B-Disease
compared	O
to	O
propofol	B-Chemical
(	O
57	O
.	O
1	O
%	O
vs	O
.	O
7	O
.	O
1	O
%	O
,	O
RR	O
=	O
8	O
.	O
0	O
,	O
X2	O
=	O
4	O
.	O
256	O
;	O
df	O
=	O
1	O
;	O
0	O
.	O
05	O
<	O
p	O
<	O
0	O
.	O
02	O
)	O
.	O

CONCLUSION	O
:	O
In	O
this	O
study	O
early	O
postoperative	B-Disease
delirium	I-Disease
was	O
found	O
to	O
be	O
a	O
very	O
common	O
complication	O
after	O
major	O
surgery	O
,	O
even	O
in	O
a	O
population	O
without	O
known	O
risk	O
factors	O
.	O

Thiopentone	B-Chemical
was	O
independently	O
associated	O
with	O
an	O
increase	O
in	O
its	O
relative	O
risk	O
.	O

A	O
single	O
neurotoxic	B-Disease
dose	O
of	O
methamphetamine	B-Chemical
induces	O
a	O
long	O
-	O
lasting	O
depressive	B-Disease
-	O
like	O
behaviour	O
in	O
mice	O
.	O

Methamphetamine	B-Chemical
(	O
METH	B-Chemical
)	O
triggers	O
a	O
disruption	O
of	O
the	O
monoaminergic	O
system	O
and	O
METH	B-Chemical
abuse	O
leads	O
to	O
negative	O
emotional	O
states	O
including	O
depressive	B-Disease
symptoms	I-Disease
during	O
drug	O
withdrawal	O
.	O

However	O
,	O
it	O
is	O
currently	O
unknown	O
if	O
the	O
acute	O
toxic	O
dosage	O
of	O
METH	B-Chemical
also	O
causes	O
a	O
long	O
-	O
lasting	O
depressive	B-Disease
phenotype	O
and	O
persistent	O
monoaminergic	O
deficits	O
.	O

Thus	O
,	O
we	O
now	O
assessed	O
the	O
depressive	B-Disease
-	O
like	O
behaviour	O
in	O
mice	O
at	O
early	O
and	O
long	O
-	O
term	O
periods	O
following	O
a	O
single	O
high	O
METH	B-Chemical
dose	O
(	O
30	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
.	O

METH	B-Chemical
did	O
not	O
alter	O
the	O
motor	O
function	O
and	O
procedural	O
memory	O
of	O
mice	O
as	O
assessed	O
by	O
swimming	O
speed	O
and	O
escape	O
latency	O
to	O
find	O
the	O
platform	O
in	O
a	O
cued	O
version	O
of	O
the	O
water	O
maze	O
task	O
.	O

However	O
,	O
METH	B-Chemical
significantly	O
increased	O
the	O
immobility	O
time	O
in	O
the	O
tail	O
suspension	O
test	O
at	O
3	O
and	O
49	O
days	O
post	O
-	O
administration	O
.	O

This	O
depressive	B-Disease
-	O
like	O
profile	O
induced	O
by	O
METH	B-Chemical
was	O
accompanied	O
by	O
a	O
marked	O
depletion	O
of	O
frontostriatal	O
dopaminergic	O
and	O
serotonergic	O
neurotransmission	O
,	O
indicated	O
by	O
a	O
reduction	O
in	O
the	O
levels	O
of	O
dopamine	B-Chemical
,	O
DOPAC	B-Chemical
and	O
HVA	B-Chemical
,	O
tyrosine	B-Chemical
hydroxylase	O
and	O
serotonin	B-Chemical
,	O
observed	O
at	O
both	O
3	O
and	O
49	O
days	O
post	O
-	O
administration	O
.	O

In	O
parallel	O
,	O
another	O
neurochemical	O
feature	O
of	O
depression	B-Disease
-	O
-	O
astroglial	O
dysfunction	O
-	O
-	O
was	O
unaffected	O
in	O
the	O
cortex	O
and	O
the	O
striatal	O
levels	O
of	O
the	O
astrocytic	O
protein	O
marker	O
,	O
glial	O
fibrillary	O
acidic	O
protein	O
,	O
were	O
only	O
transiently	O
increased	O
at	O
3	O
days	O
.	O

These	O
findings	O
demonstrate	O
for	O
the	O
first	O
time	O
that	O
a	O
single	O
high	O
dose	O
of	O
METH	B-Chemical
induces	O
long	O
-	O
lasting	O
depressive	B-Disease
-	O
like	O
behaviour	O
in	O
mice	O
associated	O
with	O
a	O
persistent	O
disruption	O
of	O
frontostriatal	O
dopaminergic	O
and	O
serotonergic	O
homoeostasis	O
.	O

Linezolid	B-Chemical
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
.	O

Many	O
systemic	O
antimicrobials	O
have	O
been	O
implicated	O
to	O
cause	O
ocular	O
adverse	O
effects	O
.	O

This	O
is	O
especially	O
relevant	O
in	O
multidrug	O
therapy	O
where	O
more	O
than	O
one	O
drug	O
can	O
cause	O
a	O
similar	O
ocular	O
adverse	O
effect	O
.	O

We	O
describe	O
a	O
case	O
of	O
progressive	O
loss	B-Disease
of	I-Disease
vision	I-Disease
associated	O
with	O
linezolid	B-Chemical
therapy	O
.	O

A	O
45	O
-	O
year	O
-	O
old	O
male	O
patient	O
who	O
was	O
on	O
treatment	O
with	O
multiple	O
second	O
-	O
line	O
anti	O
-	O
tuberculous	O
drugs	O
including	O
linezolid	B-Chemical
and	O
ethambutol	B-Chemical
for	O
extensively	B-Disease
drug	I-Disease
-	I-Disease
resistant	I-Disease
tuberculosis	I-Disease
(	O
XDR	B-Disease
-	I-Disease
TB	I-Disease
)	O
presented	O
to	O
us	O
with	O
painless	O
progressive	O
loss	B-Disease
of	I-Disease
vision	I-Disease
in	O
both	O
eyes	O
.	O

Color	O
vision	O
was	O
defective	O
and	O
fundus	O
examination	O
revealed	O
optic	B-Disease
disc	I-Disease
edema	I-Disease
in	O
both	O
eyes	O
.	O

Ethambutol	B-Chemical
-	O
induced	O
toxic	B-Disease
optic	I-Disease
neuropathy	I-Disease
was	O
suspected	O
and	O
tablet	O
ethambutol	B-Chemical
was	O
withdrawn	O
.	O

Deterioration	B-Disease
of	I-Disease
vision	I-Disease
occurred	O
despite	O
withdrawal	O
of	O
ethambutol	B-Chemical
.	O

Discontinuation	O
of	O
linezolid	B-Chemical
resulted	O
in	O
marked	O
improvement	O
of	O
vision	O
.	O

Our	O
report	O
emphasizes	O
the	O
need	O
for	O
monitoring	O
of	O
visual	O
function	O
in	O
patients	O
on	O
long	O
-	O
term	O
linezolid	B-Chemical
treatment	O
.	O

Resuscitation	O
with	O
lipid	O
,	O
epinephrine	B-Chemical
,	O
or	O
both	O
in	O
levobupivacaine	B-Chemical
-	O
induced	O
cardiac	B-Disease
toxicity	I-Disease
in	O
newborn	O
piglets	O
.	O

BACKGROUND	O
:	O
The	O
optimal	O
dosing	O
regimens	O
of	O
lipid	O
emulsion	O
,	O
epinephrine	B-Chemical
,	O
or	O
both	O
are	O
not	O
yet	O
determined	O
in	O
neonates	O
in	O
cases	O
of	O
local	O
anaesthetic	O
systemic	O
toxicity	B-Disease
(	O
LAST	O
)	O
.	O

METHODS	O
:	O
Newborn	O
piglets	O
received	O
levobupivacaine	B-Chemical
until	O
cardiovascular	B-Disease
collapse	I-Disease
occurred	O
.	O

Standard	O
cardiopulmonary	O
resuscitation	O
was	O
started	O
and	O
electrocardiogram	O
(	O
ECG	O
)	O
was	O
monitored	O
for	O
ventricular	B-Disease
tachycardia	I-Disease
,	O
fibrillation	B-Disease
,	O
or	O
QRS	O
prolongation	O
.	O

Piglets	O
were	O
then	O
randomly	O
allocated	O
to	O
four	O
groups	O
:	O
control	O
(	O
saline	O
)	O
,	O
Intralipid	O
(	O
)	O
alone	O
,	O
epinephrine	B-Chemical
alone	O
,	O
or	O
a	O
combination	O
of	O
Intralipd	O
plus	O
epinephrine	B-Chemical
.	O

Resuscitation	O
continued	O
for	O
30	O
min	O
or	O
until	O
there	O
was	O
a	O
return	O
of	O
spontaneous	O
circulation	O
(	O
ROSC	O
)	O
accompanied	O
by	O
a	O
mean	O
arterial	O
pressure	O
at	O
or	O
superior	O
to	O
the	O
baseline	O
pressure	O
and	O
normal	O
sinus	O
rhythm	O
for	O
a	O
period	O
of	O
30	O
min	O
.	O

RESULTS	O
:	O
ROSC	O
was	O
achieved	O
in	O
only	O
one	O
of	O
the	O
control	O
piglets	O
compared	O
with	O
most	O
of	O
the	O
treated	O
piglets	O
.	O

Mortality	O
was	O
not	O
significantly	O
different	O
between	O
the	O
three	O
treatment	O
groups	O
,	O
but	O
was	O
significantly	O
lower	O
in	O
all	O
the	O
treatment	O
groups	O
compared	O
with	O
control	O
.	O

The	O
number	O
of	O
ECG	O
abnormalities	O
was	O
zero	O
in	O
the	O
Intralipid	O
only	O
group	O
,	O
but	O
14	O
and	O
17	O
,	O
respectively	O
,	O
in	O
the	O
epinephrine	B-Chemical
and	O
epinephrine	B-Chemical
plus	O
lipid	O
groups	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

CONCLUSIONS	O
:	O
Lipid	O
emulsion	O
with	O
or	O
without	O
epinephrine	B-Chemical
,	O
or	O
epinephrine	B-Chemical
alone	O
were	O
equally	O
effective	O
in	O
achieving	O
a	O
return	O
to	O
spontaneous	O
circulation	O
in	O
this	O
model	O
of	O
LAST	O
.	O

Epinephrine	B-Chemical
alone	O
or	O
in	O
combination	O
with	O
lipid	O
was	O
associated	O
with	O
an	O
increased	O
number	O
of	O
ECG	O
abnormalities	O
compared	O
with	O
lipid	O
emulsion	O
alone	O
.	O

Incidence	O
of	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
type	I-Disease
II	I-Disease
and	O
postoperative	O
recovery	O
of	O
platelet	O
count	O
in	O
liver	O
graft	O
recipients	O
:	O
a	O
retrospective	O
cohort	O
analysis	O
.	O

BACKGROUND	O
:	O
Thrombocytopenia	B-Disease
in	O
patients	O
with	O
end	B-Disease
-	I-Disease
stage	I-Disease
liver	I-Disease
disease	I-Disease
is	O
a	O
common	O
disorder	O
caused	O
mainly	O
by	O
portal	B-Disease
hypertension	I-Disease
,	O
low	O
levels	O
of	O
thrombopoetin	O
,	O
and	O
endotoxemia	B-Disease
.	O

The	O
impact	O
of	O
immune	O
-	O
mediated	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
type	I-Disease
II	I-Disease
(	O
HIT	B-Disease
type	I-Disease
II	I-Disease
)	O
as	O
a	O
cause	O
of	O
thrombocytopenia	B-Disease
after	O
liver	O
transplantation	O
is	O
not	O
yet	O
understood	O
,	O
with	O
few	O
literature	O
citations	O
reporting	O
contradictory	O
results	O
.	O

The	O
aim	O
of	O
our	O
study	O
was	O
to	O
demonstrate	O
the	O
perioperative	O
course	O
of	O
thrombocytopenia	B-Disease
after	O
liver	O
transplantation	O
and	O
determine	O
the	O
occurrence	O
of	O
clinical	O
HIT	B-Disease
type	I-Disease
II	I-Disease
.	O

METHOD	O
:	O
We	O
retrospectively	O
evaluated	O
the	O
medical	O
records	O
of	O
205	O
consecutive	O
adult	O
patients	O
who	O
underwent	O
full	O
-	O
size	O
liver	O
transplantation	O
between	O
January	O
2006	O
and	O
December	O
2010	O
due	O
to	O
end	B-Disease
-	I-Disease
stage	I-Disease
or	I-Disease
malignant	I-Disease
liver	I-Disease
disease	I-Disease
.	O

Preoperative	O
platelet	O
count	O
,	O
postoperative	O
course	O
of	O
platelets	O
,	O
and	O
clinical	O
signs	O
of	O
HIT	B-Disease
type	I-Disease
II	I-Disease
were	O
analyzed	O
.	O

RESULTS	O
:	O
A	O
total	O
of	O
155	O
(	O
75	O
.	O
6	O
%	O
)	O
of	O
205	O
patients	O
had	O
thrombocytopenia	B-Disease
before	O
transplantation	O
,	O
significantly	O
influenced	O
by	O
Model	O
of	O
End	B-Disease
-	I-Disease
Stage	I-Disease
Liver	I-Disease
Disease	I-Disease
score	O
and	O
liver	B-Disease
cirrhosis	I-Disease
.	O

The	O
platelet	O
count	O
exceeded	O
100	O
,	O
000	O
/	O
uL	O
in	O
most	O
of	O
the	O
patients	O
(	O
n	O
=	O
193	O
)	O
at	O
a	O
medium	O
of	O
7	O
d	O
.	O

Regarding	O
HIT	B-Disease
II	I-Disease
,	O
there	O
were	O
four	O
(	O
1	O
.	O
95	O
%	O
)	O
patients	O
with	O
a	O
background	O
of	O
HIT	B-Disease
type	I-Disease
II	I-Disease
.	O

CONCLUSIONS	O
:	O
The	O
incidence	O
of	O
HIT	B-Disease
in	O
patients	O
with	O
end	B-Disease
-	I-Disease
stage	I-Disease
hepatic	I-Disease
failure	I-Disease
is	O
,	O
with	O
about	O
1	O
.	O
95	O
%	O
,	O
rare	O
.	O

For	O
further	O
reduction	O
of	O
HIT	B-Disease
type	I-Disease
II	I-Disease
,	O
the	O
use	O
of	O
intravenous	O
heparin	B-Chemical
should	O
be	O
avoided	O
and	O
the	O
prophylactic	O
anticoagulation	O
should	O
be	O
performed	O
with	O
low	O
-	O
molecular	O
-	O
weight	O
heparin	B-Chemical
after	O
normalization	O
of	O
platelet	O
count	O
.	O

Takotsubo	B-Disease
syndrome	I-Disease
(	O
or	O
apical	B-Disease
ballooning	I-Disease
syndrome	I-Disease
)	O
secondary	O
to	O
Zolmitriptan	B-Chemical
.	O

Takotsubo	B-Disease
syndrome	I-Disease
(	O
TS	B-Disease
)	O
,	O
also	O
known	O
as	O
broken	B-Disease
heart	I-Disease
syndrome	I-Disease
,	O
is	O
characterized	O
by	O
left	O
ventricle	O
apical	O
ballooning	O
with	O
elevated	O
cardiac	O
biomarkers	O
and	O
electrocardiographic	O
changes	O
suggestive	O
of	O
an	O
acute	B-Disease
coronary	I-Disease
syndrome	I-Disease
(	O
ie	O
,	O
ST	O
-	O
segment	O
elevation	O
,	O
T	O
wave	O
inversions	O
,	O
and	O
pathologic	O
Q	O
waves	O
)	O
.	O

We	O
report	O
a	O
case	O
of	O
54	O
-	O
year	O
-	O
old	O
woman	O
with	O
medical	O
history	O
of	O
mitral	B-Disease
valve	I-Disease
prolapse	I-Disease
and	O
migraines	B-Disease
,	O
who	O
was	O
admitted	O
to	O
the	O
hospital	O
for	O
substernal	O
chest	B-Disease
pain	I-Disease
and	O
electrocardiogram	O
demonstrated	O
1	O
/	O
2	O
mm	O
ST	O
-	O
segment	O
elevation	O
in	O
leads	O
II	O
,	O
III	O
,	O
aVF	O
,	O
V5	O
,	O
and	O
V6	O
and	O
positive	O
troponin	O
I	O
.	O

Emergent	O
coronary	O
angiogram	O
revealed	O
normal	O
coronary	O
arteries	O
with	O
moderately	O
reduced	O
left	O
ventricular	O
ejection	O
fraction	O
with	O
wall	O
motion	O
abnormalities	O
consistent	O
with	O
TS	B-Disease
.	O

Detailed	O
history	O
obtained	O
retrospectively	O
revealed	O
that	O
the	O
patient	O
took	O
zolmitriptan	B-Chemical
sparingly	O
only	O
when	O
she	O
had	O
migraines	B-Disease
.	O

But	O
before	O
this	O
event	O
,	O
she	O
was	O
taking	O
zolmitriptan	B-Chemical
2	O
-	O
3	O
times	O
daily	O
for	O
several	O
days	O
because	O
of	O
a	O
persistent	O
migraine	B-Disease
headache	I-Disease
.	O

She	O
otherwise	O
reported	O
that	O
she	O
is	O
quite	O
active	O
,	O
rides	O
horses	O
,	O
and	O
does	O
show	O
jumping	O
without	O
any	O
limitations	O
in	O
her	O
physical	O
activity	O
.	O

There	O
was	O
no	O
evidence	O
of	O
any	O
recent	O
stress	O
or	O
status	B-Disease
migrainosus	I-Disease
.	O

Extensive	O
literature	O
search	O
revealed	O
multiple	O
cases	O
of	O
coronary	B-Disease
artery	I-Disease
vasospasm	I-Disease
secondary	O
to	O
zolmitriptan	B-Chemical
,	O
but	O
none	O
of	O
the	O
cases	O
were	O
associated	O
with	O
TS	B-Disease
.	O

Depression	B-Disease
,	O
impulsiveness	B-Disease
,	O
sleep	O
,	O
and	O
memory	O
in	O
past	O
and	O
present	O
polydrug	O
users	O
of	O
3	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
methylenedioxymethamphetamine	I-Chemical
(	O
MDMA	B-Chemical
,	O
ecstasy	B-Chemical
)	O
.	O

RATIONALE	O
:	O
Ecstasy	B-Chemical
(	O
3	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
methylenedioxymethamphetamine	I-Chemical
,	O
MDMA	B-Chemical
)	O
is	O
a	O
worldwide	O
recreational	O
drug	O
of	O
abuse	O
.	O

Unfortunately	O
,	O
the	O
results	O
from	O
human	O
research	O
investigating	O
its	O
psychological	O
effects	O
have	O
been	O
inconsistent	O
.	O

OBJECTIVES	O
:	O
The	O
present	O
study	O
aimed	O
to	O
be	O
the	O
largest	O
to	O
date	O
in	O
sample	O
size	O
and	O
5HT	O
-	O
related	O
behaviors	O
;	O
the	O
first	O
to	O
compare	O
present	O
ecstasy	B-Chemical
users	O
with	O
past	O
users	O
after	O
an	O
abstinence	O
of	O
4	O
or	O
more	O
years	O
,	O
and	O
the	O
first	O
to	O
include	O
robust	O
controls	O
for	O
other	O
recreational	O
substances	O
.	O

METHODS	O
:	O
A	O
sample	O
of	O
997	O
participants	O
(	O
52	O
%	O
male	O
)	O
was	O
recruited	O
to	O
four	O
control	O
groups	O
(	O
non	O
-	O
drug	O
(	O
ND	O
)	O
,	O
alcohol	B-Chemical
/	O
nicotine	B-Chemical
(	O
AN	B-Chemical
)	O
,	O
cannabis	B-Chemical
/	O
alcohol	B-Chemical
/	O
nicotine	B-Chemical
(	O
CAN	B-Chemical
)	O
,	O
non	O
-	O
ecstasy	B-Chemical
polydrug	O
(	O
PD	O
)	O
)	O
,	O
and	O
two	O
ecstasy	B-Chemical
polydrug	O
groups	O
(	O
present	O
(	O
MDMA	B-Chemical
)	O
and	O
past	O
users	O
(	O
EX	O
-	O
MDMA	B-Chemical
)	O
.	O

Participants	O
completed	O
a	O
drug	O
history	O
questionnaire	O
,	O
Beck	O
Depression	B-Disease
Inventory	O
,	O
Barratt	O
Impulsiveness	B-Disease
Scale	O
,	O
Pittsburgh	O
Sleep	O
Quality	O
Index	O
,	O
and	O
Wechsler	O
Memory	O
Scale	O
-	O
Revised	O
which	O
,	O
in	O
total	O
,	O
provided	O
13	O
psychometric	O
measures	O
.	O

RESULTS	O
:	O
While	O
the	O
CAN	B-Chemical
and	O
PD	O
groups	O
tended	O
to	O
record	O
greater	O
deficits	O
than	O
the	O
non	O
-	O
drug	O
controls	O
,	O
the	O
MDMA	B-Chemical
and	O
EX	O
-	O
MDMA	B-Chemical
groups	O
recorded	O
greater	O
deficits	O
than	O
all	O
the	O
control	O
groups	O
on	O
ten	O
of	O
the	O
13	O
psychometric	O
measures	O
.	O

Strikingly	O
,	O
despite	O
prolonged	O
abstinence	O
(	O
mean	O
,	O
4	O
.	O
98	O
;	O
range	O
,	O
4	O
-	O
9	O
years	O
)	O
,	O
past	O
ecstasy	B-Chemical
users	O
showed	O
few	O
signs	O
of	O
recovery	O
.	O

Compared	O
with	O
present	O
ecstasy	B-Chemical
users	O
,	O
the	O
past	O
users	O
showed	O
no	O
change	O
for	O
ten	O
measures	O
,	O
increased	O
impairment	O
for	O
two	O
measures	O
,	O
and	O
improvement	O
on	O
just	O
one	O
measure	O
.	O

CONCLUSIONS	O
:	O
Given	O
this	O
record	O
of	O
impaired	B-Disease
memory	I-Disease
and	O
clinically	O
significant	O
levels	O
of	O
depression	B-Disease
,	O
impulsiveness	B-Disease
,	O
and	O
sleep	B-Disease
disturbance	I-Disease
,	O
the	O
prognosis	O
for	O
the	O
current	O
generation	O
of	O
ecstasy	B-Chemical
users	O
is	O
a	O
major	O
cause	O
for	O
concern	O
.	O

Association	O
of	O
common	O
genetic	O
variants	O
of	O
HOMER1	O
gene	O
with	O
levodopa	B-Chemical
adverse	O
effects	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
patients	O
.	O

Levodopa	B-Chemical
is	O
the	O
most	O
effective	O
symptomatic	O
therapy	O
for	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
,	O
but	O
its	O
chronic	O
use	O
could	O
lead	O
to	O
chronic	O
adverse	O
outcomes	O
,	O
such	O
as	O
motor	O
fluctuations	O
,	O
dyskinesia	B-Disease
and	O
visual	B-Disease
hallucinations	I-Disease
.	O

HOMER1	O
is	O
a	O
protein	O
with	O
pivotal	O
function	O
in	O
glutamate	B-Chemical
transmission	O
,	O
which	O
has	O
been	O
related	O
to	O
the	O
pathogenesis	O
of	O
these	O
complications	O
.	O

This	O
study	O
investigates	O
whether	O
polymorphisms	O
in	O
the	O
HOMER1	O
gene	O
promoter	O
region	O
are	O
associated	O
with	O
the	O
occurrence	O
of	O
the	O
chronic	O
complications	O
of	O
levodopa	B-Chemical
therapy	O
.	O

A	O
total	O
of	O
205	O
patients	O
with	O
idiopathic	B-Disease
Parkinson	I-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
were	O
investigated	O
.	O

Patients	O
were	O
genotyped	O
for	O
rs4704559	O
,	O
rs10942891	O
and	O
rs4704560	O
by	O
allelic	O
discrimination	O
with	O
Taqman	O
assays	O
.	O

The	O
rs4704559	O
G	O
allele	O
was	O
associated	O
with	O
a	O
lower	O
prevalence	O
of	O
dyskinesia	B-Disease
(	O
prevalence	O
ratio	O
(	O
PR	O
)	O
=	O
0	O
.	O
615	O
,	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
0	O
.	O
426	O
-	O
0	O
.	O
887	O
,	O
P	O
=	O
0	O
.	O
009	O
)	O
and	O
visual	B-Disease
hallucinations	I-Disease
(	O
PR	O
=	O
0	O
.	O
515	O
,	O
95	O
%	O
CI	O
0	O
.	O
295	O
-	O
0	O
.	O
899	O
,	O
P	O
=	O
0	O
.	O
020	O
)	O
.	O

Our	O
data	O
suggest	O
that	O
HOMER1	O
rs4704559	O
G	O
allele	O
has	O
a	O
protective	O
role	O
for	O
the	O
development	O
of	O
levodopa	B-Chemical
adverse	O
effects	O
.	O

Crocin	B-Chemical
improves	O
lipid	O
dysregulation	O
in	O
subacute	O
diazinon	B-Chemical
exposure	O
through	O
ERK1	O
/	O
2	O
pathway	O
in	O
rat	O
liver	O
.	O

INTRODUCTION	O
:	O
Diazinon	B-Chemical
Yis	O
one	O
of	O
the	O
most	O
broadly	O
used	O
organophosphorus	B-Chemical
insecticides	O
in	O
agriculture	O
.	O

It	O
has	O
been	O
shown	O
that	O
exposure	O
to	O
diazinon	B-Chemical
may	O
interfere	O
with	O
lipid	O
metabolism	O
.	O

Moreover	O
,	O
the	O
hypolipidemic	O
effect	O
of	O
crocin	B-Chemical
has	O
been	O
established	O
.	O

Earlier	O
studies	O
revealed	O
the	O
major	O
role	O
of	O
Extracellular	O
signal	O
-	O
regulated	O
kinase	O
(	O
ERK	O
)	O
pathways	O
in	O
low	O
-	O
density	O
lipoprotein	O
receptor	O
(	O
LDLr	O
)	O
expression	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
changes	O
in	O
the	O
regulation	O
of	O
lipid	O
metabolism	O
,	O
ERK	O
and	O
LDLr	O
expression	O
in	O
the	O
liver	O
of	O
rats	O
exposed	O
to	O
subacute	O
diazinon	B-Chemical
.	O

Furthermore	O
ameliorating	O
effect	O
of	O
crocin	B-Chemical
on	O
diazinon	B-Chemical
induced	O
disturbed	O
cholesterol	B-Chemical
homeostasis	O
was	O
studied	O
.	O

METHODS	O
:	O
24	O
Rats	O
were	O
divided	O
into	O
4	O
groups	O
and	O
received	O
following	O
treatments	O
for	O
4	O
weeks	O
;	O
Corn	O
oil	O
(	O
control	O
)	O
,	O
diazinon	B-Chemical
(	O
15mg	O
/	O
kg	O
per	O
day	O
,	O
orally	O
)	O
and	O
crocin	B-Chemical
(	O
12	O
.	O
5	O
and	O
25mg	O
/	O
kg	O
per	O
day	O
,	O
intraperitoneally	O
)	O
in	O
combination	O
with	O
diazinon	B-Chemical
(	O
15	O
mg	O
/	O
kg	O
)	O
.	O

The	O
levels	O
of	O
cholesterol	B-Chemical
,	O
triglyceride	B-Chemical
and	O
LDL	O
in	O
blood	O
of	O
rats	O
were	O
analyzed	O
.	O

Moreover	O
mRNA	O
levels	O
of	O
LDLr	O
and	O
ERK1	O
/	O
2	O
as	O
well	O
as	O
protein	O
levels	O
of	O
total	O
and	O
activated	O
forms	O
of	O
ERK1	O
/	O
2	O
in	O
rat	O
liver	O
were	O
evaluated	O
by	O
Western	O
blotting	O
and	O
quantitative	O
real	O
time	O
polymerase	O
chain	O
reaction	O
analysis	O
.	O

RESULTS	O
:	O
Our	O
data	O
showed	O
that	O
subacute	O
exposure	O
to	O
diazinon	B-Chemical
significantly	O
increased	O
concentrations	O
of	O
cholesterol	B-Chemical
,	O
triglyceride	B-Chemical
and	O
LDL	O
.	O

Moreover	O
diazinon	B-Chemical
decreased	O
ERK1	O
/	O
2	O
protein	O
phosphorylation	O
and	O
LDLr	O
transcript	O
.	O

Crocin	B-Chemical
reduced	O
inhibition	O
of	O
ERK	O
activation	O
and	O
diazinon	B-Chemical
-	O
induced	O
hyperlipemia	B-Disease
and	O
increased	O
levels	O
of	O
LDLr	O
transcript	O
.	O

CONCLUSIONS	O
:	O
Crocin	B-Chemical
may	O
be	O
considered	O
as	O
a	O
novel	O
protective	O
agent	O
in	O
diazinon	B-Chemical
-	O
induced	O
hyperlipemia	B-Disease
through	O
modulating	O
of	O
ERK	O
pathway	O
and	O
increase	O
of	O
LDLr	O
expression	O
.	O

GEM	B-Chemical
-	O
P	O
chemotherapy	O
is	O
active	O
in	O
the	O
treatment	O
of	O
relapsed	O
Hodgkin	B-Disease
lymphoma	I-Disease
.	O

Hodgkin	B-Disease
lymphoma	I-Disease
(	O
HL	B-Disease
)	O
is	O
a	O
relatively	O
chemosensitive	O
malignancy	B-Disease
.	O

However	O
,	O
for	O
those	O
who	O
relapse	O
,	O
high	O
-	O
dose	O
chemotherapy	O
with	O
autologous	O
stem	O
cell	O
transplant	O
is	O
the	O
treatment	O
of	O
choice	O
which	O
relies	O
on	O
adequate	O
disease	O
control	O
with	O
salvage	O
chemotherapy	O
.	O

Regimens	O
commonly	O
used	O
often	O
require	O
inpatient	O
administration	O
and	O
can	O
be	O
difficult	O
to	O
deliver	O
due	O
to	O
toxicity	B-Disease
.	O

Gemcitabine	B-Chemical
and	O
cisplatin	B-Chemical
have	O
activity	O
in	O
HL	B-Disease
,	O
non	O
-	O
overlapping	O
toxicity	B-Disease
with	O
first	O
-	O
line	O
chemotherapeutics	O
,	O
and	O
may	O
be	O
delivered	O
in	O
an	O
outpatient	O
setting	O
.	O

In	O
this	O
retrospective	O
single	O
-	O
centre	O
analysis	O
,	O
patients	O
with	O
relapsed	O
or	O
refractory	O
HL	B-Disease
treated	O
with	O
gemcitabine	B-Chemical
1	O
,	O
000	O
mg	O
/	O
m	O
(	O
2	O
)	O
day	O
(	O
D	O
)	O
1	O
,	O
D8	O
and	O
D15	O
;	O
methylprednisolone	B-Chemical
1	O
,	O
000	O
mg	O
D1	O
-	O
5	O
;	O
and	O
cisplatin	B-Chemical
100	O
mg	O
/	O
m	O
(	O
2	O
)	O
D15	O
,	O
every	O
28	O
days	O
(	O
GEM	B-Chemical
-	O
P	O
)	O
were	O
included	O
.	O

Demographic	O
,	O
survival	O
,	O
response	O
and	O
toxicity	B-Disease
data	O
were	O
recorded	O
.	O

Forty	O
-	O
one	O
eligible	O
patients	O
were	O
identified	O
:	O
median	O
age	O
27	O
.	O

One	O
hundred	O
and	O
twenty	O
-	O
two	O
cycles	O
of	O
GEM	B-Chemical
-	O
P	O
were	O
administered	O
in	O
total	O
(	O
median	O
3	O
cycles	O
;	O
range	O
1	O
-	O
6	O
)	O
.	O

Twenty	O
of	O
41	O
(	O
48	O
%	O
)	O
patients	O
received	O
GEM	B-Chemical
-	O
P	O
as	O
second	O
-	O
line	O
treatment	O
and	O
11	O
/	O
41	O
(	O
27	O
%	O
)	O
as	O
third	O
-	O
line	O
therapy	O
.	O

Overall	O
response	O
rate	O
(	O
ORR	O
)	O
to	O
GEM	B-Chemical
-	O
P	O
in	O
the	O
entire	O
cohort	O
was	O
80	O
%	O
(	O
complete	O
response	O
(	O
CR	O
)	O
37	O
%	O
,	O
partial	O
response	O
44	O
%	O
)	O
with	O
14	O
/	O
15	O
CR	O
confirmed	O
as	O
a	O
metabolic	O
CR	O
on	O
PET	O
and	O
ORR	O
of	O
85	O
%	O
in	O
the	O
20	O
second	O
-	O
line	O
patients	O
.	O

The	O
most	O
common	O
grade	O
3	O
/	O
4	O
toxicities	B-Disease
were	O
haematological	O
:	O
neutropenia	B-Disease
54	O
%	O
and	O
thrombocytopenia	B-Disease
51	O
%	O
.	O

Median	O
follow	O
-	O
up	O
from	O
the	O
start	O
of	O
GEM	B-Chemical
-	O
P	O
was	O
4	O
.	O
5	O
years	O
.	O

Following	O
GEM	B-Chemical
-	O
P	O
,	O
5	O
-	O
year	O
progression	O
-	O
free	O
survival	O
was	O
46	O
%	O
(	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
,	O
30	O
-	O
62	O
%	O
)	O
and	O
5	O
-	O
year	O
overall	O
survival	O
was	O
59	O
%	O
(	O
95	O
%	O
CI	O
,	O
43	O
-	O
74	O
%	O
)	O
.	O

Fourteen	O
of	O
41	O
patients	O
proceeded	O
directly	O
to	O
autologous	O
transplant	O
.	O

GEM	B-Chemical
-	O
P	O
is	O
a	O
salvage	O
chemotherapy	O
with	O
relatively	O
high	O
response	O
rates	O
,	O
leading	O
to	O
successful	O
transplantation	O
in	O
appropriate	O
patients	O
,	O
in	O
the	O
treatment	O
of	O
relapsed	O
or	O
refractory	O
HL	B-Disease
.	O

Basal	O
functioning	O
of	O
the	O
hypothalamic	O
-	O
pituitary	O
-	O
adrenal	O
(	O
HPA	O
)	O
axis	O
and	O
psychological	O
distress	O
in	O
recreational	O
ecstasy	B-Chemical
polydrug	O
users	O
.	O

RATIONALE	O
:	O
Ecstasy	B-Chemical
(	O
MDMA	B-Chemical
)	O
is	O
a	O
psychostimulant	O
drug	O
which	O
is	O
increasingly	O
associated	O
with	O
psychobiological	B-Disease
dysfunction	I-Disease
.	O

While	O
some	O
recent	O
studies	O
suggest	O
acute	O
changes	O
in	O
neuroendocrine	O
function	O
,	O
less	O
is	O
known	O
about	O
long	O
-	O
term	O
changes	O
in	O
HPA	O
functionality	O
in	O
recreational	O
users	O
.	O

OBJECTIVES	O
:	O
The	O
current	O
study	O
is	O
the	O
first	O
to	O
explore	O
the	O
effects	O
of	O
ecstasy	B-Chemical
-	O
polydrug	O
use	O
on	O
psychological	O
distress	O
and	O
basal	O
functioning	O
of	O
the	O
HPA	O
axis	O
through	O
assessing	O
the	O
secretion	O
of	O
cortisol	B-Chemical
across	O
the	O
diurnal	O
period	O
.	O

METHOD	O
:	O
Seventy	O
-	O
six	O
participants	O
(	O
21	O
nonusers	O
,	O
29	O
light	O
ecstasy	B-Chemical
-	O
polydrug	O
users	O
,	O
26	O
heavy	O
ecstasy	B-Chemical
-	O
polydrug	O
users	O
)	O
completed	O
a	O
substance	O
use	O
inventory	O
and	O
measures	O
of	O
psychological	O
distress	O
at	O
baseline	O
,	O
then	O
two	O
consecutive	O
days	O
of	O
cortisol	B-Chemical
sampling	O
(	O
on	O
awakening	O
,	O
30	O
min	O
post	O
awakening	O
,	O
between	O
1400	O
and	O
1600	O
hours	O
and	O
pre	O
bedtime	O
)	O
.	O

On	O
day	O
2	O
,	O
participants	O
also	O
attended	O
the	O
laboratory	O
to	O
complete	O
a	O
20	O
-	O
min	O
multitasking	O
stressor	O
.	O

RESULTS	O
:	O
Both	O
user	O
groups	O
exhibited	O
significantly	O
greater	O
levels	O
of	O
anxiety	B-Disease
and	O
depression	B-Disease
than	O
nonusers	O
.	O

On	O
day	O
1	O
,	O
all	O
participants	O
exhibited	O
a	O
typical	O
cortisol	B-Chemical
profile	O
,	O
though	O
light	O
users	O
had	O
significantly	O
elevated	O
levels	O
pre	O
-	O
bed	O
.	O

On	O
day	O
2	O
,	O
heavy	O
users	O
demonstrated	O
elevated	O
levels	O
upon	O
awakening	O
and	O
all	O
ecstasy	B-Chemical
-	O
polydrug	O
users	O
demonstrated	O
elevated	O
pre	O
-	O
bed	O
levels	O
compared	O
to	O
non	O
-	O
users	O
.	O

Significant	O
between	O
group	O
differences	O
were	O
also	O
observed	O
in	O
afternoon	O
cortisol	B-Chemical
levels	O
and	O
in	O
overall	O
cortisol	B-Chemical
secretion	O
across	O
the	O
day	O
.	O

CONCLUSIONS	O
:	O
The	O
increases	O
in	O
anxiety	B-Disease
and	O
depression	B-Disease
are	O
in	O
line	O
with	O
previous	O
observations	O
in	O
recreational	O
ecstasy	B-Chemical
-	O
polydrug	O
users	O
.	O

Dysregulated	O
diurnal	O
cortisol	B-Chemical
may	O
be	O
indicative	O
of	O
inappropriate	O
anticipation	O
of	O
forthcoming	O
demands	O
and	O
hypersecretion	O
may	O
lead	O
to	O
the	O
increased	O
psychological	O
and	O
physical	O
morbidity	O
associated	O
with	O
heavy	O
recreational	O
use	O
of	O
ecstasy	B-Chemical
.	O

Ifosfamide	B-Chemical
related	O
encephalopathy	B-Disease
:	O
the	O
need	O
for	O
a	O
timely	O
EEG	O
evaluation	O
.	O

BACKGROUND	O
:	O
Ifosfamide	B-Chemical
is	O
an	O
alkylating	O
agent	O
useful	O
in	O
the	O
treatment	O
of	O
a	O
wide	O
range	O
of	O
cancers	B-Disease
including	O
sarcomas	B-Disease
,	O
lymphoma	B-Disease
,	O
gynecologic	B-Disease
and	I-Disease
testicular	I-Disease
cancers	I-Disease
.	O

Encephalopathy	B-Disease
has	O
been	O
reported	O
in	O
10	O
-	O
40	O
%	O
of	O
patients	O
receiving	O
high	O
-	O
dose	O
IV	O
ifosfamide	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
highlight	O
the	O
role	O
of	O
electroencephalogram	O
(	O
EEG	O
)	O
in	O
the	O
early	O
detection	O
and	O
management	O
of	O
ifosfamide	B-Chemical
related	O
encephalopathy	B-Disease
.	O

METHODS	O
:	O
Retrospective	O
chart	O
review	O
including	O
clinical	O
data	O
and	O
EEG	O
recordings	O
was	O
done	O
on	O
five	O
patients	O
,	O
admitted	O
to	O
MD	O
Anderson	O
Cancer	B-Disease
Center	O
between	O
years	O
2009	O
and	O
2012	O
,	O
who	O
developed	O
ifosfamide	B-Chemical
related	O
acute	O
encephalopathy	B-Disease
.	O

RESULTS	O
:	O
All	O
five	O
patients	O
experienced	O
symptoms	O
of	O
encephalopathy	B-Disease
soon	O
after	O
(	O
within	O
12	O
h	O
-	O
2	O
days	O
)	O
receiving	O
ifosfamide	B-Chemical
.	O

Two	O
patients	O
developed	O
generalized	O
convulsions	B-Disease
while	O
one	O
patient	O
developed	O
continuous	O
non	B-Disease
-	I-Disease
convulsive	I-Disease
status	I-Disease
epilepticus	I-Disease
(	O
NCSE	B-Disease
)	O
that	O
required	O
ICU	O
admission	O
and	O
intubation	O
.	O

Initial	O
EEG	O
showed	O
epileptiform	O
discharges	O
in	O
three	O
patients	O
;	O
run	O
of	O
triphasic	O
waves	O
in	O
one	O
patient	O
and	O
moderate	O
degree	O
diffuse	O
generalized	O
slowing	O
.	O

Mixed	O
pattern	O
with	O
the	O
presence	O
of	O
both	O
sharps	O
and	O
triphasic	O
waves	O
were	O
also	O
noted	O
.	O

Repeat	O
EEGs	O
within	O
24	O
_	O
h	O
of	O
symptom	O
onset	O
showed	O
marked	O
improvement	O
that	O
was	O
correlated	O
with	O
clinical	O
improvement	O
.	O

CONCLUSIONS	O
:	O
Severity	O
of	O
ifosfamide	B-Chemical
related	O
encephalopathy	B-Disease
correlates	O
with	O
EEG	O
changes	O
.	O

We	O
suggest	O
a	O
timely	O
EEG	O
evaluation	O
for	O
patients	O
receiving	O
ifosfamide	B-Chemical
who	O
develop	O
features	O
of	O
encephalopathy	B-Disease
.	O

Incidence	O
of	O
contrast	B-Chemical
-	O
induced	O
nephropathy	B-Disease
in	O
hospitalised	O
patients	O
with	O
cancer	B-Disease
.	O

OBJECTIVES	O
:	O
To	O
determine	O
the	O
frequency	O
of	O
and	O
possible	O
factors	O
related	O
to	O
contrast	B-Chemical
-	O
induced	O
nephropathy	B-Disease
(	O
CIN	O
)	O
in	O
hospitalised	O
patients	O
with	O
cancer	B-Disease
.	O

METHODS	O
:	O
Ninety	O
adult	O
patients	O
were	O
enrolled	O
.	O

Patients	O
with	O
risk	O
factors	O
for	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
were	O
excluded	O
.	O

Blood	O
samples	O
were	O
examined	O
the	O
day	O
before	O
contrast	B-Chemical
-	O
enhanced	O
computed	O
tomography	O
(	O
CT	O
)	O
and	O
serially	O
for	O
3	O
days	O
thereafter	O
.	O

CIN	O
was	O
defined	O
as	O
an	O
increase	O
in	O
serum	O
creatinine	B-Chemical
(	O
Cr	B-Chemical
)	O
of	O
0	O
.	O
5	O
mg	O
/	O
dl	O
or	O
more	O
,	O
or	O
elevation	O
of	O
Cr	B-Chemical
to	O
25	O
%	O
over	O
baseline	O
.	O

Relationships	O
between	O
CIN	O
and	O
possible	O
risk	O
factors	O
were	O
investigated	O
.	O

RESULTS	O
:	O
CIN	O
was	O
detected	O
in	O
18	O
/	O
90	O
(	O
20	O
%	O
)	O
patients	O
.	O

CIN	O
developed	O
in	O
25	O
.	O
5	O
%	O
patients	O
who	O
underwent	O
chemotherapy	O
and	O
in	O
11	O
%	O
patients	O
who	O
did	O
not	O
(	O
P	O
=	O
0	O
.	O
1	O
)	O
.	O

CIN	O
more	O
frequently	O
developed	O
in	O
patients	O
who	O
had	O
undergone	O
CT	O
within	O
45	O
days	O
after	O
the	O
last	O
chemotherapy	O
(	O
P	O
=	O
0	O
.	O
005	O
)	O
;	O
it	O
was	O
also	O
an	O
independent	O
risk	O
factor	O
(	O
P	O
=	O
0	O
.	O
017	O
)	O
.	O

CIN	O
was	O
significantly	O
more	O
after	O
treatment	O
with	O
bevacizumab	B-Chemical
/	O
irinotecan	B-Chemical
(	O
P	O
=	O
0	O
.	O
021	O
)	O
and	O
in	O
patients	O
with	O
hypertension	B-Disease
(	O
P	O
=	O
0	O
.	O
044	O
)	O
.	O

CONCLUSIONS	O
:	O
The	O
incidence	O
of	O
CIN	O
after	O
CT	O
in	O
hospitalised	O
oncological	O
patients	O
was	O
20	O
%	O
.	O

CIN	O
developed	O
4	O
.	O
5	O
-	O
times	O
more	O
frequently	O
in	O
patients	O
with	O
cancer	B-Disease
who	O
had	O
undergone	O
recent	O
chemotherapy	O
.	O

Hypertension	B-Disease
and	O
the	O
combination	O
of	O
bevacizumab	B-Chemical
/	O
irinotecan	B-Chemical
may	O
be	O
additional	O
risk	O
factors	O
for	O
CIN	O
development	O
.	O

KEY	O
POINTS	O
:	O
.	O

Contrast	B-Chemical
-	O
induced	O
nephropathy	B-Disease
(	O
CIN	O
)	O
is	O
a	O
concern	O
for	O
oncological	O
patients	O
undergoing	O
CT	O
.	O

.	O
CIN	O
occurs	O
more	O
often	O
when	O
CT	O
is	O
performed	O
<	O
45	O
days	O
after	O
chemotherapy	O
.	O

.	O
Hypertension	B-Disease
and	O
treatment	O
with	O
bevacizumab	B-Chemical
appear	O
to	O
be	O
additional	O
risk	O
factors	O
.	O

Syndrome	B-Disease
of	I-Disease
inappropriate	I-Disease
antidiuretic	I-Disease
hormone	I-Disease
secretion	O
associated	O
with	O
desvenlafaxine	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
syndrome	B-Disease
of	I-Disease
inappropriate	I-Disease
anti	I-Disease
-	I-Disease
diuretic	I-Disease
hormone	I-Disease
(	O
SIADH	B-Disease
)	O
secretion	O
associated	O
with	O
desvenlafaxine	B-Chemical
.	O

CASE	O
SUMMARY	O
:	O
A	O
57	O
-	O
year	O
old	O
female	O
with	O
hyponatraemia	B-Disease
.	O

Her	O
medications	O
included	O
desvenlafaxine	B-Chemical
,	O
and	O
symptoms	O
included	O
nausea	B-Disease
,	O
anxiety	B-Disease
and	O
confusion	B-Disease
.	O

The	O
serum	O
sodium	B-Chemical
at	O
this	O
time	O
was	O
120	O
mmol	O
/	O
L	O
,	O
serum	O
osmolality	O
was	O
263	O
mosmol	O
/	O
kg	O
,	O
urine	O
osmolality	O
410	O
mosmol	O
/	O
kg	O
and	O
urine	O
sodium	B-Chemical
63	O
mmol	O
/	O
L	O
,	O
consistent	O
with	O
a	O
diagnosis	O
of	O
SIADH	B-Disease
.	O

Desvenlafaxine	B-Chemical
was	O
ceased	O
and	O
fluid	O
restriction	O
implemented	O
.	O

After	O
4	O
days	O
the	O
sodium	B-Chemical
increased	O
to	O
128	O
mmol	O
/	O
L	O
and	O
fluid	O
restriction	O
was	O
relaxed	O
.	O

During	O
her	O
further	O
3	O
weeks	O
inpatient	O
admission	O
the	O
serum	O
sodium	B-Chemical
ranged	O
from	O
134	O
to	O
137	O
mmol	O
/	O
L	O
during	O
treatment	O
with	O
mirtazapine	B-Chemical
.	O

DISCUSSION	O
:	O
SIADH	B-Disease
has	O
been	O
widely	O
reported	O
with	O
a	O
range	O
of	O
antidepressants	O
.	O

This	O
case	O
report	O
suggests	O
that	O
desvenlafaxine	B-Chemical
might	O
cause	O
clinically	O
significant	O
hyponatremia	B-Disease
.	O

CONCLUSIONS	O
:	O
Clinicians	O
should	O
be	O
aware	O
of	O
the	O
potential	O
for	O
antidepressants	O
to	O
cause	O
hyponatremia	B-Disease
,	O
and	O
take	O
appropriate	O
corrective	O
action	O
where	O
necessary	O
.	O

Oxidative	O
stress	O
on	O
cardiotoxicity	B-Disease
after	O
treatment	O
with	O
single	O
and	O
multiple	O
doses	O
of	O
doxorubicin	B-Chemical
.	O

The	O
mechanism	O
of	O
doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
-	O
induced	O
cardiotoxicity	B-Disease
remains	O
controversial	O
.	O

Wistar	O
rats	O
(	O
n	O
=	O
66	O
)	O
received	O
DOX	B-Chemical
injections	O
intraperitoneally	O
and	O
were	O
randomly	O
assigned	O
to	O
2	O
experimental	O
protocols	O
:	O
(	O
1	O
)	O
rats	O
were	O
killed	O
before	O
(	O
-	O
24	O
h	O
,	O
n	O
=	O
8	O
)	O
and	O
24	O
h	O
after	O
(	O
+	O
24	O
h	O
,	O
n	O
=	O
8	O
)	O
a	O
single	O
dose	O
of	O
DOX	B-Chemical
(	O
4	O
mg	O
/	O
kg	O
body	O
weight	O
)	O
to	O
determine	O
the	O
DOX	B-Chemical
acute	O
effect	O
and	O
(	O
2	O
)	O
rats	O
(	O
n	O
=	O
58	O
)	O
received	O
4	O
injections	O
of	O
DOX	B-Chemical
(	O
4	O
mg	O
/	O
kg	O
body	O
weight	O
/	O
week	O
)	O
and	O
were	O
killed	O
before	O
the	O
first	O
injection	O
(	O
M0	O
)	O
and	O
1	O
week	O
after	O
each	O
injection	O
(	O
M1	O
,	O
M2	O
,	O
M3	O
,	O
and	O
M4	O
)	O
to	O
determine	O
the	O
chronological	O
effects	O
.	O

Animals	O
used	O
at	O
M0	O
(	O
n	O
=	O
8	O
)	O
were	O
also	O
used	O
at	O
moment	O
-	O
24	O
h	O
of	O
acute	O
study	O
.	O

Cardiac	O
total	O
antioxidant	O
performance	O
(	O
TAP	O
)	O
,	O
DNA	O
damage	O
,	O
and	O
morphology	O
analyses	O
were	O
carried	O
out	O
at	O
each	O
time	O
point	O
.	O

Single	O
dose	O
of	O
DOX	B-Chemical
was	O
associated	O
with	O
increased	O
cardiac	B-Disease
disarrangement	I-Disease
,	O
necrosis	B-Disease
,	O
and	O
DNA	O
damage	O
(	O
strand	O
breaks	O
(	O
SBs	O
)	O
and	O
oxidized	O
pyrimidines	O
)	O
and	O
decreased	O
TAP	O
.	O

The	O
chronological	O
study	O
showed	O
an	O
effect	O
of	O
a	O
cumulative	O
dose	O
on	O
body	O
weight	O
(	O
R	O
=	O
-	O
0	O
.	O
99	O
,	O
p	O
=	O
0	O
.	O
011	O
)	O
,	O
necrosis	B-Disease
(	O
R	O
=	O
1	O
.	O
00	O
,	O
p	O
=	O
0	O
.	O
004	O
)	O
,	O
TAP	O
(	O
R	O
=	O
0	O
.	O
95	O
,	O
p	O
=	O
0	O
.	O
049	O
)	O
,	O
and	O
DNA	O
SBs	O
(	O
R	O
=	O
-	O
0	O
.	O
95	O
,	O
p	O
=	O
0	O
.	O
049	O
)	O
.	O

DNA	O
SBs	O
damage	O
was	O
negatively	O
associated	O
with	O
TAP	O
(	O
R	O
=	O
-	O
0	O
.	O
98	O
,	O
p	O
=	O
0	O
.	O
018	O
)	O
,	O
and	O
necrosis	B-Disease
(	O
R	O
=	O
-	O
0	O
.	O
97	O
,	O
p	O
=	O
0	O
.	O
027	O
)	O
.	O

Our	O
results	O
suggest	O
that	O
oxidative	O
damage	O
is	O
associated	O
with	O
acute	O
cardiotoxicity	B-Disease
induced	O
by	O
a	O
single	O
dose	O
of	O
DOX	B-Chemical
only	O
.	O

Increased	O
resistance	O
to	O
the	O
oxidative	O
stress	O
is	O
plausible	O
for	O
the	O
multiple	O
dose	O
of	O
DOX	B-Chemical
.	O

Thus	O
,	O
different	O
mechanisms	O
may	O
be	O
involved	O
in	O
acute	O
toxicity	B-Disease
versus	O
chronic	O
toxicity	B-Disease
.	O

Tacrolimus	B-Chemical
-	O
related	O
seizure	B-Disease
after	O
pediatric	O
liver	O
transplantation	O
-	O
-	O
a	O
single	O
-	O
center	O
experience	O
.	O

To	O
identify	O
the	O
risk	O
factors	O
for	O
new	O
-	O
onset	O
seizures	B-Disease
after	O
pediatric	O
LT	O
and	O
to	O
assess	O
their	O
clinical	O
implications	O
and	O
long	O
-	O
term	O
prognosis	O
.	O

The	O
clinical	O
and	O
laboratory	O
data	O
of	O
27	O
consecutive	O
children	O
who	O
underwent	O
LT	O
from	O
January	O
2007	O
to	O
December	O
2010	O
in	O
our	O
center	O
were	O
analyzed	O
retrospectively	O
.	O

Patients	O
were	O
divided	O
into	O
seizures	B-Disease
group	O
and	O
a	O
non	O
-	O
seizures	B-Disease
group	O
.	O

Pre	O
-	O
operative	O
,	O
intra	O
-	O
operative	O
,	O
and	O
post	O
-	O
operative	O
data	O
were	O
collected	O
.	O

Seizures	B-Disease
occurred	O
in	O
four	O
children	O
,	O
an	O
incidence	O
of	O
14	O
.	O
8	O
%	O
.	O

All	O
exhibited	O
generalized	O
tonic	B-Disease
-	I-Disease
clonic	I-Disease
seizures	I-Disease
within	O
the	O
first	O
two	O
wk	O
after	O
LT	O
.	O

Univariate	O
analysis	O
showed	O
that	O
the	O
risk	O
factors	O
associated	O
with	O
seizures	B-Disease
after	O
pediatric	O
LT	O
included	O
gender	O
,	O
pediatric	O
end	B-Disease
-	I-Disease
stage	I-Disease
liver	I-Disease
disease	I-Disease
score	O
before	O
surgery	O
,	O
Child	O
-	O
Pugh	O
score	O
before	O
surgery	O
,	O
serum	O
total	O
bilirubin	B-Chemical
after	O
surgery	O
,	O
and	O
trough	O
TAC	B-Chemical
level	O
.	O

Multivariate	O
analysis	O
showed	O
that	O
trough	O
TAC	B-Chemical
level	O
was	O
the	O
only	O
independent	O
risk	O
factor	O
associated	O
with	O
the	O
seizures	B-Disease
.	O

All	O
children	O
who	O
experienced	O
seizures	B-Disease
survived	O
with	O
good	O
graft	O
function	O
and	O
remained	O
seizure	B-Disease
-	O
free	O
without	O
anti	O
-	O
epileptic	B-Disease
drugs	O
over	O
a	O
mean	O
follow	O
-	O
up	O
period	O
of	O
33	O
.	O
7	O
+	O
14	O
.	O
6	O
months	O
.	O

High	O
trough	O
TAC	B-Chemical
level	O
was	O
the	O
predominant	O
factor	O
that	O
contributed	O
to	O
seizures	B-Disease
in	O
the	O
early	O
post	O
-	O
operative	O
period	O
after	O
pediatric	O
LT	O
.	O

High	O
PELD	O
and	O
Child	O
-	O
Pugh	O
scores	O
before	O
LT	O
and	O
high	O
post	O
-	O
operative	O
serum	O
Tbil	O
may	O
be	O
contributory	O
risk	O
factors	O
for	O
TAC	B-Chemical
-	O
related	O
seizures	B-Disease
.	O

The	O
flavonoid	B-Chemical
apigenin	B-Chemical
delays	O
forgetting	O
of	O
passive	O
avoidance	O
conditioning	O
in	O
rats	O
.	O

The	O
present	O
experiments	O
were	O
performed	O
to	O
study	O
the	O
effect	O
of	O
the	O
flavonoid	B-Chemical
apigenin	B-Chemical
(	O
20	O
mg	O
/	O
kg	O
intraperitoneally	O
(	O
i	O
.	O
p	O
.	O
)	O
,	O
1	O
h	O
before	O
acquisition	O
)	O
,	O
on	O
24	O
h	O
retention	O
performance	O
and	O
forgetting	O
of	O
a	O
step	O
-	O
through	O
passive	O
avoidance	O
task	O
,	O
in	O
young	O
male	O
Wistar	O
rats	O
.	O

There	O
were	O
no	O
differences	O
between	O
saline	O
-	O
and	O
apigenin	B-Chemical
-	O
treated	O
groups	O
in	O
the	O
24	O
h	O
retention	O
trial	O
.	O

Furthermore	O
,	O
apigenin	B-Chemical
did	O
not	O
prevent	O
the	O
amnesia	B-Disease
induced	O
by	O
scopolamine	B-Chemical
(	O
1mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
,	O
30	O
min	O
before	O
the	O
acquisition	O
)	O
.	O

The	O
saline	O
-	O
and	O
apigenin	B-Chemical
-	O
treated	O
rats	O
that	O
did	O
not	O
step	O
through	O
into	O
the	O
dark	O
compartment	O
during	O
the	O
cut	O
-	O
off	O
time	O
(	O
540	O
s	O
)	O
were	O
retested	O
weekly	O
for	O
up	O
to	O
eight	O
weeks	O
.	O

In	O
the	O
saline	O
treated	O
group	O
,	O
the	O
first	O
significant	O
decline	O
in	O
passive	O
avoidance	O
response	O
was	O
observed	O
at	O
four	O
weeks	O
,	O
and	O
complete	O
memory	B-Disease
loss	I-Disease
was	O
found	O
five	O
weeks	O
after	O
the	O
acquisition	O
of	O
the	O
passive	O
avoidance	O
task	O
.	O

At	O
the	O
end	O
of	O
the	O
experimental	O
period	O
,	O
60	O
%	O
of	O
the	O
animals	O
treated	O
with	O
apigenin	B-Chemical
still	O
did	O
not	O
step	O
through	O
.	O

These	O
data	O
suggest	O
that	O
1	O
)	O
apigenin	B-Chemical
delays	O
the	O
long	O
-	O
term	O
forgetting	O
but	O
did	O
not	O
modulate	O
the	O
24	O
h	O
retention	O
of	O
fear	O
memory	O
and	O
2	O
)	O
the	O
obtained	O
beneficial	O
effect	O
of	O
apigenin	B-Chemical
on	O
the	O
passive	O
avoidance	O
conditioning	O
is	O
mediated	O
by	O
mechanisms	O
that	O
do	O
not	O
implicate	O
its	O
action	O
on	O
the	O
muscarinic	O
cholinergic	O
system	O
.	O

Histamine	B-Chemical
antagonists	O
and	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
-	O
induced	O
hypotension	B-Disease
in	O
cardiac	O
surgical	O
patients	O
.	O

Hemodynamic	O
effects	O
and	O
histamine	B-Chemical
release	O
by	O
bolus	O
injection	O
of	O
0	O
.	O
35	O
mg	O
/	O
kg	O
of	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
were	O
studied	O
in	O
24	O
patients	O
.	O

H1	O
-	O
and	O
H2	O
-	O
histamine	B-Chemical
antagonists	O
or	O
placebo	O
were	O
given	O
before	O
dosing	O
with	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
in	O
a	O
randomized	O
double	O
-	O
blind	O
fashion	O
to	O
four	O
groups	O
:	O
group	O
1	O
-	O
-	O
placebo	O
;	O
group	O
2	O
-	O
-	O
cimetidine	B-Chemical
,	O
4	O
mg	O
/	O
kg	O
,	O
plus	O
placebo	O
;	O
group	O
3	O
-	O
-	O
chlorpheniramine	B-Chemical
,	O
0	O
.	O
1	O
mg	O
/	O
kg	O
,	O
plus	O
placebo	O
;	O
and	O
group	O
4	O
-	O
-	O
cimetidine	B-Chemical
plus	O
chlorpheniramine	B-Chemical
.	O

Histamine	B-Chemical
release	O
occurred	O
in	O
most	O
patients	O
,	O
the	O
highest	O
level	O
2	O
minutes	O
after	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
dosing	O
.	O

Group	O
1	O
had	O
a	O
moderate	O
negative	O
correlation	O
between	O
plasma	O
histamine	B-Chemical
change	O
and	O
systemic	O
vascular	O
resistance	O
(	O
r	O
=	O
0	O
.	O
58	O
;	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
not	O
present	O
in	O
group	O
4	O
.	O

Prior	O
dosing	O
with	O
antagonists	O
partially	O
prevented	O
the	O
fall	O
in	O
systemic	O
vascular	O
resistance	O
.	O

These	O
data	O
demonstrate	O
that	O
the	O
hemodynamic	O
changes	O
associated	O
with	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
dosing	O
are	O
only	O
partially	O
explained	O
by	O
histamine	B-Chemical
release	O
.	O

Thus	O
prior	O
dosing	O
with	O
H1	O
-	O
and	O
H2	O
-	O
antagonists	O
provides	O
only	O
partial	O
protection	O
.	O

Cholecystokinin	B-Chemical
-	I-Chemical
octapeptide	I-Chemical
restored	O
morphine	B-Chemical
-	O
induced	O
hippocampal	O
long	O
-	O
term	O
potentiation	O
impairment	O
in	O
rats	O
.	O

Cholecystokinin	B-Chemical
-	I-Chemical
octapeptide	I-Chemical
(	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
)	O
,	O
which	O
is	O
a	O
typical	O
brain	O
-	O
gut	O
peptide	O
,	O
exerts	O
a	O
wide	O
range	O
of	O
biological	O
activities	O
on	O
the	O
central	O
nervous	O
system	O
.	O

We	O
have	O
previously	O
reported	O
that	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
significantly	O
alleviated	O
morphine	B-Chemical
-	O
induced	O
amnesia	B-Disease
and	O
reversed	O
spine	O
density	O
decreases	O
in	O
the	O
CA1	O
region	O
of	O
the	O
hippocampus	O
in	O
morphine	B-Chemical
-	O
treated	O
animals	O
.	O

Here	O
,	O
we	O
investigated	O
the	O
effects	O
of	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
on	O
long	O
-	O
term	O
potentiation	O
(	O
LTP	O
)	O
in	O
the	O
lateral	O
perforant	O
path	O
(	O
LPP	O
)	O
-	O
granule	O
cell	O
synapse	O
of	O
rat	O
dentate	O
gyrus	O
(	O
DG	O
)	O
in	O
acute	O
saline	O
or	O
morphine	B-Chemical
-	O
treated	O
rats	O
.	O

Population	O
spikes	O
(	O
PS	O
)	O
,	O
which	O
were	O
evoked	O
by	O
stimulation	O
of	O
the	O
LPP	O
,	O
were	O
recorded	O
in	O
the	O
DG	O
region	O
.	O

Acute	O
morphine	B-Chemical
(	O
30mg	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
treatment	O
significantly	O
attenuated	O
hippocampal	O
LTP	O
and	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
(	O
1ug	O
,	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
restored	O
the	O
amplitude	O
of	O
PS	O
that	O
was	O
attenuated	O
by	O
morphine	B-Chemical
injection	O
.	O

Furthermore	O
,	O
microinjection	O
of	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
(	O
0	O
.	O
1	O
and	O
1ug	O
,	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
also	O
significantly	O
augmented	O
hippocampal	O
LTP	O
in	O
saline	O
-	O
treated	O
(	O
1ml	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
rats	O
.	O

Pre	O
-	O
treatment	O
of	O
the	O
CCK2	O
receptor	O
antagonist	O
L	O
-	O
365	O
,	O
260	O
(	O
10ug	O
,	O
i	O
.	O
c	O
.	O
v	O
)	O
reversed	O
the	O
effects	O
of	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
,	O
but	O
the	O
CCK1	O
receptor	O
antagonist	O
L	O
-	O
364	O
,	O
718	O
(	O
10ug	O
,	O
i	O
.	O
c	O
.	O
v	O
)	O
did	O
not	O
.	O

The	O
present	O
results	O
demonstrate	O
that	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
attenuates	O
the	O
effect	O
of	O
morphine	B-Chemical
on	O
hippocampal	O
LTP	O
through	O
CCK2	O
receptors	O
and	O
suggest	O
an	O
ameliorative	O
function	O
of	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
on	O
morphine	B-Chemical
-	O
induced	O
memory	B-Disease
impairment	I-Disease
.	O

Glial	O
activation	O
and	O
post	O
-	O
synaptic	O
neurotoxicity	B-Disease
:	O
the	O
key	O
events	O
in	O
Streptozotocin	B-Chemical
(	O
ICV	O
)	O
induced	O
memory	B-Disease
impairment	I-Disease
in	O
rats	O
.	O

In	O
the	O
present	O
study	O
the	O
role	O
of	O
glial	O
activation	O
and	O
post	O
synaptic	O
toxicity	B-Disease
in	O
ICV	O
Streptozotocin	B-Chemical
(	O
STZ	B-Chemical
)	O
induced	O
memory	B-Disease
impaired	I-Disease
rats	O
was	O
explored	O
.	O

In	O
experiment	O
set	O
up	O
1	O
:	O
Memory	B-Disease
deficit	I-Disease
was	O
found	O
in	O
Morris	O
water	O
maze	O
test	O
on	O
14	O
-	O
16	O
days	O
after	O
STZ	B-Chemical
(	O
ICV	O
;	O
3mg	O
/	O
Kg	O
)	O
administration	O
.	O

STZ	B-Chemical
causes	O
increased	O
expression	O
of	O
GFAP	O
,	O
CD11b	O
and	O
TNF	O
-	O
a	O
indicating	O
glial	O
activation	O
and	O
neuroinflammation	B-Disease
.	O

STZ	B-Chemical
also	O
significantly	O
increased	O
the	O
level	O
of	O
ROS	O
,	O
nitrite	B-Chemical
,	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
and	O
reduced	O
the	O
mitochondrial	O
activity	O
in	O
synaptosomal	O
preparation	O
illustrating	O
free	O
radical	O
generation	O
and	O
excitotoxicity	B-Disease
.	O

Increased	O
expression	O
and	O
activity	O
of	O
Caspase	O
-	O
3	O
was	O
also	O
observed	O
in	O
STZ	B-Chemical
treated	O
rat	O
which	O
specify	O
apoptotic	O
cell	O
death	O
in	O
hippocampus	O
and	O
cortex	O
.	O

STZ	B-Chemical
treatment	O
showed	O
decrease	O
expression	O
of	O
post	O
synaptic	O
markers	O
CaMKIIa	O
and	O
PSD	O
-	O
95	O
,	O
while	O
,	O
expression	O
of	O
pre	O
synaptic	O
markers	O
(	O
synaptophysin	O
and	O
SNAP	O
-	O
25	O
)	O
remains	O
unaltered	O
indicating	O
selective	O
post	O
synaptic	O
neurotoxicity	B-Disease
.	O

Oral	O
treatment	O
with	O
Memantine	B-Chemical
(	O
10mg	O
/	O
kg	O
)	O
and	O
Ibuprofen	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
)	O
daily	O
for	O
13	O
days	O
attenuated	O
STZ	B-Chemical
induced	O
glial	O
activation	O
,	O
apoptotic	O
cell	O
death	O
and	O
post	O
synaptic	O
neurotoxicity	B-Disease
in	O
rat	O
brain	O
.	O

Further	O
,	O
in	O
experiment	O
set	O
up	O
2	O
:	O
where	O
memory	O
function	O
was	O
not	O
affected	O
i	O
.	O
e	O
.	O
7	O
-	O
9	O
days	O
after	O
STZ	B-Chemical
treatment	O
.	O

The	O
level	O
of	O
GFAP	O
,	O
CD11b	O
,	O
TNF	O
-	O
a	O
,	O
ROS	O
and	O
nitrite	B-Chemical
levels	O
were	O
increased	O
.	O

On	O
the	O
other	O
hand	O
,	O
apoptotic	O
marker	O
,	O
synaptic	O
markers	O
,	O
mitochondrial	O
activity	O
and	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
levels	O
remained	O
unaffected	O
.	O

Collective	O
data	O
indicates	O
that	O
neuroinflammatory	B-Disease
process	O
and	O
oxidative	O
stress	O
occurs	O
earlier	O
to	O
apoptosis	O
and	O
does	O
not	O
affect	O
memory	O
function	O
.	O

Present	O
study	O
clearly	O
suggests	O
that	O
glial	O
activation	O
and	O
post	O
synaptic	O
neurotoxicity	B-Disease
are	O
the	O
key	O
factors	O
in	O
STZ	B-Chemical
induced	O
memory	B-Disease
impairment	I-Disease
and	O
neuronal	O
cell	O
death	O
.	O

Comparison	O
of	O
effects	O
of	O
isotonic	O
sodium	B-Chemical
chloride	I-Chemical
with	O
diltiazem	B-Chemical
in	O
prevention	O
of	O
contrast	B-Chemical
-	O
induced	O
nephropathy	B-Disease
.	O

INTRODUCTION	O
AND	O
OBJECTIVE	O
:	O
Contrast	B-Chemical
-	O
induced	O
nephropathy	B-Disease
(	O
CIN	O
)	O
significantly	O
increases	O
the	O
morbidity	O
and	O
mortality	O
of	O
patients	O
.	O

The	O
aim	O
of	O
this	O
study	O
is	O
to	O
investigate	O
and	O
compare	O
the	O
protective	O
effects	O
of	O
isotonic	O
sodium	B-Chemical
chloride	I-Chemical
with	O
sodium	B-Chemical
bicarbonate	I-Chemical
infusion	O
and	O
isotonic	O
sodium	B-Chemical
chloride	I-Chemical
infusion	O
with	O
diltiazem	B-Chemical
,	O
a	O
calcium	B-Chemical
channel	O
blocker	O
,	O
in	O
preventing	O
CIN	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
Our	O
study	O
included	O
patients	O
who	O
were	O
administered	O
30	O
-	O
60	O
mL	O
of	O
iodinated	O
contrast	B-Chemical
agent	O
for	O
percutaneous	O
coronary	O
angiography	O
(	O
PCAG	O
)	O
,	O
all	O
with	O
creatinine	B-Chemical
values	O
between	O
1	O
.	O
1	O
and	O
3	O
.	O
1	O
mg	O
/	O
dL	O
.	O

Patients	O
were	O
divided	O
into	O
three	O
groups	O
and	O
each	O
group	O
had	O
20	O
patients	O
.	O

The	O
first	O
group	O
of	O
patients	O
was	O
administered	O
isotonic	O
sodium	B-Chemical
chloride	I-Chemical
;	O
the	O
second	O
group	O
was	O
administered	O
a	O
solution	O
that	O
of	O
5	O
%	O
dextrose	B-Chemical
and	O
sodium	B-Chemical
bicarbonate	I-Chemical
,	O
while	O
the	O
third	O
group	O
was	O
administered	O
isotonic	O
sodium	B-Chemical
chloride	I-Chemical
before	O
and	O
after	O
the	O
contrast	B-Chemical
injection	O
.	O

The	O
third	O
group	O
received	O
an	O
additional	O
injection	O
of	O
diltiazem	B-Chemical
the	O
day	O
before	O
and	O
first	O
2	O
days	O
after	O
the	O
contrast	B-Chemical
injection	O
.	O

All	O
of	O
the	O
patients	O
'	O
plasma	O
blood	B-Chemical
urea	I-Chemical
nitrogen	I-Chemical
(	O
BUN	B-Chemical
)	O
and	O
creatinine	B-Chemical
levels	O
were	O
measured	O
on	O
the	O
second	O
and	O
seventh	O
day	O
after	O
the	O
administration	O
of	O
intravenous	O
contrast	B-Chemical
material	O
.	O

RESULTS	O
:	O
The	O
basal	O
creatinine	B-Chemical
levels	O
were	O
similar	O
for	O
all	O
three	O
groups	O
(	O
p	O
>	O
0	O
.	O
05	O
)	O
.	O

Among	O
a	O
total	O
of	O
60	O
patients	O
included	O
in	O
the	O
study	O
,	O
16	O
patients	O
developed	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
(	O
ARF	B-Disease
)	O
on	O
the	O
second	O
day	O
after	O
contrast	B-Chemical
material	O
was	O
injected	O
(	O
26	O
.	O
6	O
%	O
)	O
.	O

The	O
number	O
of	O
patients	O
who	O
developed	O
ARF	B-Disease
on	O
the	O
second	O
day	O
after	O
the	O
injection	O
in	O
the	O
first	O
group	O
was	O
five	O
(	O
25	O
%	O
)	O
,	O
in	O
the	O
second	O
group	O
was	O
six	O
(	O
30	O
%	O
)	O
and	O
the	O
third	O
group	O
was	O
five	O
(	O
25	O
%	O
)	O
(	O
p	O
>	O
0	O
.	O
05	O
)	O
.	O

CONCLUSION	O
:	O
There	O
was	O
no	O
significant	O
difference	O
between	O
isotonic	O
sodium	B-Chemical
chloride	I-Chemical
,	O
sodium	B-Chemical
bicarbonate	I-Chemical
and	O
isotonic	O
sodium	B-Chemical
chloride	I-Chemical
with	O
diltiazem	B-Chemical
application	O
in	O
prevention	O
of	O
CIN	O
.	O

Neurocognitive	O
and	O
neuroradiologic	O
central	O
nervous	O
system	O
late	O
effects	O
in	O
children	O
treated	O
on	O
Pediatric	O
Oncology	O
Group	O
(	O
POG	O
)	O
P9605	O
(	O
standard	O
risk	O
)	O
and	O
P9201	O
(	O
lesser	O
risk	O
)	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
protocols	O
(	O
ACCL0131	O
)	O
:	O
a	O
methotrexate	B-Chemical
consequence	O
?	O

A	O
report	O
from	O
the	O
Children	O
'	O
s	O
Oncology	O
Group	O
.	O

Concerns	O
about	O
long	O
-	O
term	O
methotrexate	B-Chemical
(	O
MTX	B-Chemical
)	O
neurotoxicity	B-Disease
in	O
the	O
1990s	O
led	O
to	O
modifications	O
in	O
intrathecal	O
(	O
IT	O
)	O
therapy	O
,	O
leucovorin	O
rescue	O
,	O
and	O
frequency	O
of	O
systemic	O
MTX	B-Chemical
administration	O
in	O
children	O
with	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
.	O

In	O
this	O
study	O
,	O
neurocognitive	O
outcomes	O
and	O
neuroradiologic	O
evidence	O
of	O
leukoencephalopathy	B-Disease
were	O
compared	O
in	O
children	O
treated	O
with	O
intense	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
-	O
directed	O
therapy	O
(	O
P9605	O
)	O
versus	O
those	O
receiving	O
fewer	O
CNS	O
-	O
directed	O
treatment	O
days	O
during	O
intensive	O
consolidation	O
(	O
P9201	O
)	O
.	O

A	O
total	O
of	O
66	O
children	O
from	O
16	O
Pediatric	O
Oncology	O
Group	O
institutions	O
with	O
"	O
standard	O
-	O
risk	O
"	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
,	O
1	O
.	O
00	O
to	O
9	O
.	O
99	O
years	O
at	O
diagnosis	O
,	O
without	O
evidence	O
of	O
CNS	O
leukemia	B-Disease
at	O
diagnosis	O
were	O
enrolled	O
on	O
ACCL0131	O
:	O
28	O
from	O
P9201	O
and	O
38	O
from	O
P9605	O
.	O

Magnetic	O
resonance	O
imaging	O
scans	O
and	O
standard	O
neuropsychological	O
tests	O
were	O
performed	O
>	O
2	O
.	O
6	O
years	O
after	O
the	O
end	O
of	O
treatment	O
.	O

Significantly	O
more	O
P9605	O
patients	O
developed	O
leukoencephalopathy	B-Disease
compared	O
with	O
P9201	O
patients	O
(	O
68	O
%	O
,	O
95	O
%	O
confidence	O
interval	O
49	O
%	O
-	O
83	O
%	O
vs	O
.	O
22	O
%	O
,	O
95	O
%	O
confidence	O
interval	O
5	O
%	O
-	O
44	O
%	O
;	O
P	O
=	O
0	O
.	O
001	O
)	O
identified	O
as	O
late	O
as	O
7	O
.	O
7	O
years	O
after	O
the	O
end	O
of	O
treatment	O
.	O

Overall	O
,	O
40	O
%	O
of	O
patients	O
scored	O
<	O
85	O
on	O
either	O
Verbal	O
or	O
Performance	O
IQ	O
.	O

Children	O
on	O
both	O
studies	O
had	O
significant	O
attention	B-Disease
problems	I-Disease
,	O
but	O
P9605	O
children	O
scored	O
below	O
average	O
on	O
more	O
neurocognitive	O
measures	O
than	O
those	O
treated	O
on	O
P9201	O
(	O
82	O
%	O
,	O
14	O
/	O
17	O
measures	O
vs	O
.	O
24	O
%	O
,	O
4	O
/	O
17	O
measures	O
)	O
.	O

This	O
supports	O
ongoing	O
concerns	O
about	O
intensive	O
MTX	B-Chemical
exposure	O
as	O
a	O
major	O
contributor	O
to	O
CNS	O
late	O
effects	O
.	O

Tranexamic	B-Chemical
acid	I-Chemical
overdosage	O
-	O
induced	O
generalized	O
seizure	B-Disease
in	O
renal	B-Disease
failure	I-Disease
.	O

We	O
report	O
a	O
45	O
-	O
year	O
-	O
old	O
lady	O
with	O
chronic	B-Disease
kidney	I-Disease
disease	I-Disease
stage	O
4	O
due	O
to	O
chronic	O
tubulointerstial	B-Disease
disease	I-Disease
.	O

She	O
was	O
admitted	O
to	O
our	O
center	O
for	O
severe	O
anemia	B-Disease
due	O
to	O
menorrhagia	B-Disease
and	O
deterioration	B-Disease
of	I-Disease
renal	I-Disease
function	I-Disease
.	O

She	O
was	O
infused	O
three	O
units	O
of	O
packed	O
cells	O
during	O
a	O
session	O
of	O
hemodialysis	O
.	O

Tranexamic	B-Chemical
acid	I-Chemical
(	O
TNA	B-Chemical
)	O
1	O
g	O
8	O
-	O
hourly	O
was	O
administered	O
to	O
her	O
to	O
control	O
bleeding	B-Disease
per	O
vaginum	O
.	O

Two	O
hours	O
after	O
the	O
sixth	O
dose	O
of	O
TNA	B-Chemical
,	O
she	O
had	O
an	O
episode	O
of	O
generalized	O
tonic	B-Disease
clonic	I-Disease
convulsions	I-Disease
.	O

TNA	B-Chemical
was	O
discontinued	O
.	O

Investigations	O
of	O
the	O
patient	O
revealed	O
no	O
biochemical	O
or	O
structural	O
central	O
nervous	B-Disease
system	I-Disease
abnormalities	I-Disease
that	O
could	O
have	O
provoked	O
the	O
convulsions	B-Disease
.	O

She	O
did	O
not	O
require	O
any	O
further	O
dialytic	O
support	O
.	O

She	O
had	O
no	O
further	O
episodes	O
of	O
convulsion	B-Disease
till	O
dis	O
-	O
charge	O
and	O
during	O
the	O
two	O
months	O
of	O
follow	O
-	O
up	O
.	O

Thus	O
,	O
the	O
precipitating	O
cause	O
of	O
convulsions	B-Disease
was	O
believed	O
to	O
be	O
an	O
overdose	B-Disease
of	O
TNA	B-Chemical
.	O

Pre	O
-	O
treatment	O
of	O
bupivacaine	B-Chemical
-	O
induced	O
cardiovascular	B-Disease
depression	I-Disease
using	O
different	O
lipid	O
formulations	O
of	O
propofol	B-Chemical
.	O

BACKGROUND	O
:	O
Pre	O
-	O
treatment	O
with	O
lipid	O
emulsions	O
has	O
been	O
shown	O
to	O
increase	O
lethal	O
doses	O
of	O
bupivacaine	B-Chemical
,	O
and	O
the	O
lipid	O
content	O
of	O
propofol	B-Chemical
may	O
alleviate	O
bupivacaine	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

The	O
aim	O
of	O
this	O
study	O
is	O
to	O
investigate	O
the	O
effects	O
of	O
propofol	B-Chemical
in	O
intralipid	O
or	O
medialipid	O
emulsions	O
on	O
bupivacaine	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

METHODS	O
:	O
Rats	O
were	O
anaesthetised	O
with	O
ketamine	B-Chemical
and	O
were	O
given	O
0	O
.	O
5	O
mg	O
/	O
kg	O
/	O
min	O
propofol	B-Chemical
in	O
intralipid	O
(	O
Group	O
P	O
)	O
,	O
propofol	B-Chemical
in	O
medialipid	O
(	O
Group	O
L	O
)	O
,	O
or	O
saline	O
(	O
Group	O
C	O
)	O
over	O
20	O
min	O
.	O

Thereafter	O
,	O
2	O
mg	O
/	O
kg	O
/	O
min	O
bupivacaine	B-Chemical
0	O
.	O
5	O
%	O
was	O
infused	O
.	O

We	O
recorded	O
time	O
to	O
first	O
dysrhythmia	B-Disease
occurrence	O
,	O
respective	O
times	O
to	O
25	O
%	O
and	O
50	O
%	O
reduction	O
of	O
the	O
heart	O
rate	O
(	O
HR	O
)	O
and	O
mean	O
arterial	O
pressure	O
,	O
and	O
time	O
to	O
asystole	B-Disease
and	O
total	O
amount	O
of	O
bupivacaine	B-Chemical
consumption	O
.	O

Blood	O
and	O
tissue	O
samples	O
were	O
collected	O
following	O
asystole	B-Disease
.	O

RESULTS	O
:	O
The	O
time	O
to	O
first	O
dysrhythmia	B-Disease
occurrence	O
,	O
time	O
to	O
25	O
%	O
and	O
50	O
%	O
reductions	O
in	O
HR	O
,	O
and	O
time	O
to	O
asystole	B-Disease
were	O
longer	O
in	O
Group	O
P	O
than	O
the	O
other	O
groups	O
.	O

The	O
cumulative	O
bupivacaine	B-Chemical
dose	O
given	O
at	O
those	O
time	O
points	O
was	O
higher	O
in	O
Group	O
P	O
.	O
Plasma	O
bupivacaine	B-Chemical
levels	O
were	O
significantly	O
lower	O
in	O
Group	O
P	O
than	O
in	O
Group	O
C	O
.	O
Bupivacaine	B-Chemical
levels	O
in	O
the	O
brain	O
and	O
heart	O
were	O
significantly	O
lower	O
in	O
Group	O
P	O
and	O
Group	O
L	O
than	O
in	O
Group	O
C	O
.	O

CONCLUSION	O
:	O
We	O
conclude	O
that	O
pre	O
-	O
treatment	O
with	O
propofol	B-Chemical
in	O
intralipid	O
,	O
compared	O
with	O
propofol	B-Chemical
in	O
medialipid	O
or	O
saline	O
,	O
delayed	O
the	O
onset	O
of	O
bupivacaine	B-Chemical
-	O
induced	O
cardiotoxic	B-Disease
effects	O
as	O
well	O
as	O
reduced	O
plasma	O
bupivacaine	B-Chemical
levels	O
.	O

Further	O
studies	O
are	O
needed	O
to	O
explore	O
tissue	O
bupivacaine	B-Chemical
levels	O
of	O
propofol	B-Chemical
in	O
medialipid	O
and	O
adapt	O
these	O
results	O
to	O
clinical	O
practice	O
.	O

Drug	B-Disease
-	I-Disease
Induced	I-Disease
Acute	I-Disease
Liver	I-Disease
Injury	I-Disease
Within	O
12	O
Hours	O
After	O
Fluvastatin	B-Chemical
Therapy	O
.	O

Although	O
statins	B-Chemical
are	O
generally	O
well	O
-	O
tolerated	O
drugs	O
,	O
recent	O
cases	O
of	O
drug	B-Disease
-	I-Disease
induced	I-Disease
liver	I-Disease
injury	I-Disease
associated	O
with	O
their	O
use	O
have	O
been	O
reported	O
.	O

A	O
52	O
-	O
year	O
-	O
old	O
Chinese	O
man	O
reported	O
with	O
liver	B-Disease
damage	I-Disease
,	O
which	O
appeared	O
12	O
hours	O
after	O
beginning	O
treatment	O
with	O
fluvastatin	B-Chemical
.	O

Patient	O
presented	O
with	O
complaints	O
of	O
increasing	O
nausea	B-Disease
,	O
anorexia	B-Disease
,	O
and	O
upper	O
abdominal	B-Disease
pain	I-Disease
.	O

His	O
laboratory	O
values	O
showed	O
elevated	O
creatine	B-Chemical
kinase	O
and	O
transaminases	O
.	O

Testing	O
for	O
autoantibodies	O
was	O
also	O
negative	O
.	O

The	O
liver	O
biochemistries	O
eventually	O
normalized	O
within	O
3	O
weeks	O
of	O
stopping	O
the	O
fluvastatin	B-Chemical
.	O

Therefore	O
,	O
when	O
prescribing	O
statins	O
,	O
the	O
possibility	O
of	O
hepatic	B-Disease
damage	I-Disease
should	O
be	O
taken	O
into	O
account	O
.	O

Fluconazole	B-Chemical
associated	O
agranulocytosis	B-Disease
and	O
thrombocytopenia	B-Disease
.	O

CASE	O
:	O
We	O
describe	O
a	O
second	O
case	O
of	O
fluconazole	B-Chemical
associated	O
agranulocytosis	B-Disease
with	O
thrombocytopenia	B-Disease
and	O
recovery	O
upon	O
discontinuation	O
of	O
therapy	O
.	O

The	O
patient	O
began	O
to	O
have	O
changes	O
in	O
white	O
blood	O
cells	O
and	O
platelets	O
within	O
48	O
h	O
of	O
administration	O
of	O
fluconazole	B-Chemical
and	O
began	O
to	O
recover	O
with	O
48	O
h	O
of	O
discontinuation	O
.	O

This	O
case	O
highlights	O
that	O
drug	O
-	O
induced	O
blood	B-Disease
dyscrasias	I-Disease
can	O
occur	O
unexpectedly	O
as	O
a	O
result	O
of	O
treatment	O
with	O
a	O
commonly	O
used	O
drug	O
thought	O
to	O
be	O
"	O
safe	O
"	O
.	O

CONCLUSION	O
:	O
According	O
to	O
Naranjo	O
'	O
s	O
algorithm	O
the	O
likelihood	O
that	O
our	O
patient	O
'	O
s	O
agranulocytosis	B-Disease
and	O
thrombocytopenia	B-Disease
occurred	O
as	O
a	O
result	O
of	O
therapy	O
with	O
fluconazole	B-Chemical
is	O
probable	O
,	O
with	O
a	O
total	O
of	O
six	O
points	O
.	O

We	O
feel	O
that	O
the	O
weight	O
of	O
the	O
overall	O
evidence	O
of	O
this	O
evidence	O
is	O
strong	O
.	O

In	O
particular	O
the	O
temporal	O
relationship	O
of	O
bone	B-Disease
marrow	I-Disease
suppression	I-Disease
to	O
the	O
initiation	O
of	O
fluconazole	B-Chemical
and	O
the	O
abatement	O
of	O
symptoms	O
that	O
rapidly	O
reversed	O
immediately	O
following	O
discontinuation	O
.	O

Two	O
-	O
dimensional	O
speckle	O
tracking	O
echocardiography	O
combined	O
with	O
high	O
-	O
sensitive	O
cardiac	O
troponin	O
T	O
in	O
early	O
detection	O
and	O
prediction	O
of	O
cardiotoxicity	B-Disease
during	O
epirubicine	B-Chemical
-	O
based	O
chemotherapy	O
.	O

AIMS	O
:	O
To	O
investigate	O
whether	O
alterations	O
of	O
myocardial	B-Disease
strain	I-Disease
and	O
high	O
-	O
sensitive	O
cardiac	O
troponin	O
T	O
(	O
cTnT	O
)	O
could	O
predict	O
future	O
cardiac	B-Disease
dysfunction	I-Disease
in	O
patients	O
after	O
epirubicin	B-Chemical
exposure	O
.	O

METHODS	O
:	O
Seventy	O
-	O
five	O
patients	O
with	O
non	B-Disease
-	I-Disease
Hodgkin	I-Disease
lymphoma	I-Disease
treated	O
with	O
epirubicin	B-Chemical
were	O
studied	O
.	O

Blood	O
collection	O
and	O
echocardiography	O
were	O
performed	O
at	O
baseline	O
,	O
1	O
day	O
after	O
the	O
third	O
cycle	O
,	O
and	O
1	O
day	O
after	O
completion	O
of	O
chemotherapy	O
.	O

Patients	O
were	O
studied	O
using	O
echocardiography	O
during	O
follow	O
-	O
up	O
.	O

Global	O
longitudinal	O
(	O
GLS	O
)	O
,	O
circumferential	O
(	O
GCS	O
)	O
,	O
and	O
radial	O
strain	O
(	O
GRS	O
)	O
were	O
calculated	O
using	O
speckle	O
tracking	O
echocardiography	O
.	O

Left	O
ventricular	O
ejection	O
fraction	O
was	O
analysed	O
by	O
real	O
-	O
time	O
3D	O
echocardiography	O
.	O

Cardiotoxicity	B-Disease
was	O
defined	O
as	O
a	O
reduction	O
of	O
the	O
LVEF	O
of	O
>	O
5	O
%	O
to	O
<	O
55	O
%	O
with	O
symptoms	O
of	O
heart	B-Disease
failure	I-Disease
or	O
an	O
asymptomatic	O
reduction	O
of	O
the	O
LVEF	O
of	O
>	O
10	O
%	O
to	O
<	O
55	O
%	O
.	O

RESULTS	O
:	O
Fourteen	O
patients	O
(	O
18	O
.	O
67	O
%	O
)	O
developed	O
cardiotoxicity	B-Disease
after	O
treatment	O
.	O

GLS	O
(	O
-	O
18	O
.	O
48	O
+	O
1	O
.	O
72	O
%	O
vs	O
.	O
-	O
15	O
.	O
96	O
+	O
1	O
.	O
6	O
%	O
)	O
,	O
GCS	O
(	O
-	O
20	O
.	O
93	O
+	O
2	O
.	O
86	O
%	O
vs	O
.	O
-	O
19	O
.	O
20	O
+	O
3	O
.	O
21	O
%	O
)	O
,	O
and	O
GRS	O
(	O
39	O
.	O
23	O
+	O
6	O
.	O
44	O
%	O
vs	O
.	O
34	O
.	O
98	O
+	O
6	O
.	O
2	O
%	O
)	O
were	O
markedly	O
reduced	O
and	O
cTnT	O
was	O
elevated	O
from	O
0	O
.	O
0010	O
+	O
0	O
.	O
0020	O
to	O
0	O
.	O
0073	O
+	O
0	O
.	O
0038	O
ng	O
/	O
mL	O
(	O
P	O
all	O
<	O
0	O
.	O
01	O
)	O
at	O
the	O
completion	O
of	O
chemotherapy	O
compared	O
with	O
baseline	O
values	O
.	O

A	O
>	O
15	O
.	O
9	O
%	O
decrease	O
in	O
GLS	O
[	O
sensitivity	O
,	O
86	O
%	O
;	O
specificity	O
,	O
75	O
%	O
;	O
area	O
under	O
the	O
curve	O
(	O
AUC	O
)	O
=	O
0	O
.	O
815	O
;	O
P	O
=	O
0	O
.	O
001	O
]	O
and	O
a	O
>	O
0	O
.	O
004	O
ng	O
/	O
mL	O
elevation	O
in	O
cTnT	O
(	O
sensitivity	O
,	O
79	O
%	O
;	O
specificity	O
,	O
64	O
%	O
;	O
AUC	O
=	O
0	O
.	O
757	O
;	O
P	O
=	O
0	O
.	O
005	O
)	O
from	O
baseline	O
to	O
the	O
third	O
cycle	O
of	O
chemotherapy	O
predicted	O
later	O
cardiotoxicity	B-Disease
.	O

The	O
decrease	O
in	O
GLS	O
remained	O
the	O
only	O
independent	O
predictor	O
of	O
cardiotoxicity	B-Disease
(	O
P	O
=	O
0	O
.	O
000	O
)	O
.	O

CONCLUSIONS	O
:	O
GLS	O
combined	O
with	O
cTnT	O
may	O
provide	O
a	O
reliable	O
and	O
non	O
-	O
invasive	O
method	O
to	O
predict	O
cardiac	B-Disease
dysfunction	I-Disease
in	O
patients	O
receiving	O
anthracycline	B-Chemical
-	O
based	O
chemotherapy	O
.	O

Prevention	O
of	O
etomidate	B-Chemical
-	O
induced	O
myoclonus	B-Disease
:	O
which	O
is	O
superior	O
:	O
Fentanyl	B-Chemical
,	O
midazolam	B-Chemical
,	O
or	O
a	O
combination	O
?	O

A	O
Retrospective	O
comparative	O
study	O
.	O

BACKGROUND	O
:	O
In	O
this	O
retrospective	O
comparative	O
study	O
,	O
we	O
aimed	O
to	O
compare	O
the	O
effectiveness	O
of	O
fentanyl	B-Chemical
,	O
midazolam	B-Chemical
,	O
and	O
a	O
combination	O
of	O
fentanyl	B-Chemical
and	O
midazolam	B-Chemical
to	O
prevent	O
etomidate	B-Chemical
-	O
induced	O
myoclonus	B-Disease
.	O

MATERIAL	O
AND	O
METHODS	O
:	O
This	O
study	O
was	O
performed	O
based	O
on	O
anesthesia	O
records	O
.	O

Depending	O
on	O
the	O
drugs	O
that	O
would	O
be	O
given	O
before	O
the	O
induction	O
of	O
anesthesia	O
with	O
etomidate	B-Chemical
,	O
the	O
patients	O
were	O
separated	O
into	O
4	O
groups	O
:	O
no	O
pretreatment	O
(	O
Group	O
NP	O
)	O
,	O
fentanyl	B-Chemical
1	O
ug	O
.	O
kg	O
-	O
1	O
(	O
Group	O
F	O
)	O
,	O
midazolam	B-Chemical
0	O
.	O
03	O
mg	O
.	O
kg	O
-	O
1	O
(	O
Group	O
M	O
)	O
,	O
and	O
midazolam	B-Chemical
0	O
.	O
015	O
mg	O
.	O
kg	O
-	O
1	O
+	O
fentanyl	B-Chemical
0	O
.	O
5	O
ug	O
.	O
kg	O
-	O
1	O
(	O
Group	O
FM	O
)	O
.	O

Patients	O
who	O
received	O
the	O
same	O
anesthetic	O
procedure	O
were	O
selected	O
:	O
2	O
minutes	O
after	O
intravenous	O
injections	O
of	O
the	O
pretreatment	O
drugs	O
,	O
anesthesia	O
is	O
induced	O
with	O
0	O
.	O
3	O
mg	O
.	O
kg	O
-	O
1	O
etomidate	B-Chemical
injected	O
intravenously	O
over	O
a	O
period	O
of	O
20	O
-	O
30	O
seconds	O
.	O

Myoclonic	B-Disease
movements	I-Disease
are	O
evaluated	O
,	O
which	O
were	O
observed	O
and	O
graded	O
according	O
to	O
clinical	O
severity	O
during	O
the	O
2	O
minutes	O
after	O
etomidate	B-Chemical
injection	O
.	O

The	O
severity	O
of	O
pain	B-Disease
due	O
to	O
etomidate	B-Chemical
injection	O
,	O
mean	O
arterial	O
pressure	O
,	O
heart	O
rate	O
,	O
and	O
adverse	O
effects	O
were	O
also	O
evaluated	O
.	O

RESULTS	O
:	O
Study	O
results	O
showed	O
that	O
myoclonus	B-Disease
incidence	O
was	O
85	O
%	O
,	O
40	O
%	O
,	O
70	O
%	O
,	O
and	O
25	O
%	O
in	O
Group	O
NP	O
,	O
Group	O
F	O
,	O
Group	O
M	O
,	O
and	O
Group	O
FM	O
,	O
respectively	O
,	O
and	O
were	O
significantly	O
lower	O
in	O
Group	O
F	O
and	O
Group	O
FM	O
.	O

CONCLUSIONS	O
:	O
We	O
conclude	O
that	O
pretreatment	O
with	O
fentanyl	B-Chemical
or	O
combination	O
of	O
fentanyl	B-Chemical
and	O
midazolam	B-Chemical
was	O
effective	O
in	O
preventing	O
etomidate	B-Chemical
-	O
induced	O
myoclonus	B-Disease
.	O

Convulsant	O
effect	O
of	O
lindane	B-Chemical
and	O
regional	O
brain	O
concentration	O
of	O
GABA	B-Chemical
and	O
dopamine	B-Chemical
.	O

Lindane	B-Chemical
(	O
gamma	B-Chemical
-	I-Chemical
hexachlorocyclohexane	I-Chemical
)	O
is	O
an	O
organochlorine	O
insecticide	O
with	O
known	O
neurotoxic	B-Disease
effects	O
.	O

Its	O
mechanism	O
of	O
action	O
is	O
not	O
well	O
understood	O
although	O
it	O
has	O
been	O
proposed	O
that	O
lindane	B-Chemical
acts	O
as	O
a	O
non	O
-	O
competitive	O
antagonist	O
at	O
the	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
(	O
GABA	B-Chemical
)	O
-	O
A	O
receptor	O
.	O

We	O
studied	O
the	O
effect	O
of	O
lindane	B-Chemical
(	O
150	O
mg	O
/	O
kg	O
)	O
on	O
the	O
GABAergic	O
and	O
dopaminergic	O
systems	O
by	O
measuring	O
the	O
concentration	O
of	O
GABA	B-Chemical
,	O
dopamine	B-Chemical
and	O
its	O
metabolites	O
in	O
7	O
brain	O
areas	O
at	O
the	O
onset	O
of	O
seizures	B-Disease
.	O

All	O
animals	O
suffered	O
tonic	O
convulsions	B-Disease
at	O
18	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
4	O
min	O
after	O
lindane	B-Chemical
administration	O
.	O

The	O
concentration	O
of	O
GABA	B-Chemical
was	O
only	O
slightly	O
but	O
significantly	O
decreased	O
in	O
the	O
colliculi	O
without	O
modifications	O
in	O
the	O
other	O
areas	O
.	O

The	O
concentration	O
of	O
dopamine	B-Chemical
was	O
increased	O
in	O
the	O
mesencephalon	O
and	O
that	O
of	O
its	O
metabolite	O
DOPAC	B-Chemical
was	O
also	O
increased	O
in	O
the	O
mesencephalon	O
and	O
the	O
striatum	O
.	O

Cholestatic	B-Disease
presentation	O
of	O
yellow	O
phosphorus	B-Chemical
poisoning	B-Disease
.	O

Yellow	O
phosphorus	B-Chemical
,	O
a	O
component	O
of	O
certain	O
pesticide	O
pastes	O
and	O
fireworks	O
,	O
is	O
well	O
known	O
to	O
cause	O
hepatotoxicity	B-Disease
.	O

Poisoning	B-Disease
with	O
yellow	O
phosphorus	B-Chemical
classically	O
manifests	O
with	O
acute	B-Disease
hepatitis	I-Disease
leading	O
to	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
which	O
may	O
need	O
liver	O
transplantation	O
.	O

We	O
present	O
a	O
case	O
of	O
yellow	O
phosphorus	B-Chemical
poisoning	B-Disease
in	O
which	O
a	O
patient	O
presented	O
with	O
florid	O
clinical	O
features	O
of	O
cholestasis	B-Disease
highlighting	O
the	O
fact	O
that	O
cholestasis	B-Disease
can	O
rarely	O
be	O
a	O
presenting	O
feature	O
of	O
yellow	O
phosphorus	B-Chemical
hepatotoxicity	B-Disease
.	O

Vasovagal	B-Disease
syncope	I-Disease
and	O
severe	O
bradycardia	B-Disease
following	O
intranasal	O
dexmedetomidine	B-Chemical
for	O
pediatric	O
procedural	O
sedation	O
.	O

We	O
report	O
syncope	B-Disease
and	O
bradycardia	B-Disease
in	O
an	O
11	O
-	O
year	O
-	O
old	O
girl	O
following	O
administration	O
of	O
intranasal	O
dexmedetomidine	B-Chemical
for	O
sedation	O
for	O
a	O
voiding	O
cystourethrogram	O
.	O

Following	O
successful	O
completion	O
of	O
VCUG	O
and	O
a	O
60	O
-	O
min	O
recovery	O
period	O
,	O
the	O
patient	O
'	O
s	O
level	O
of	O
consciousness	O
and	O
vital	O
signs	O
returned	O
to	O
presedation	O
levels	O
.	O

Upon	O
leaving	O
the	O
sedation	O
area	O
,	O
the	O
patient	O
collapsed	O
,	O
with	O
no	O
apparent	O
inciting	O
event	O
.	O

The	O
patient	O
quickly	O
regained	O
consciousness	O
and	O
no	O
injury	O
occurred	O
.	O

The	O
primary	O
abnormality	O
found	O
was	O
persistent	O
bradycardia	B-Disease
,	O
and	O
she	O
was	O
admitted	O
to	O
the	O
hospital	O
for	O
telemetric	O
observation	O
.	O

The	O
bradycardia	B-Disease
lasted	O
~	O
2	O
h	O
,	O
and	O
further	O
cardiac	O
workup	O
revealed	O
no	O
underlying	O
abnormality	O
.	O

Unanticipated	O
and	O
previously	O
unreported	O
outcomes	O
may	O
be	O
witnessed	O
as	O
we	O
expand	O
the	O
use	O
of	O
certain	O
sedatives	O
to	O
alternative	O
routes	O
of	O
administration	O
.	O

Paradoxical	O
severe	O
agitation	B-Disease
induced	O
by	O
add	O
-	O
on	O
high	O
-	O
doses	O
quetiapine	B-Chemical
in	O
schizo	B-Disease
-	I-Disease
affective	I-Disease
disorder	I-Disease
.	O

We	O
report	O
the	O
case	O
of	O
a	O
35	O
-	O
year	O
-	O
old	O
patient	O
suffering	O
from	O
schizo	B-Disease
-	I-Disease
affective	I-Disease
disorder	I-Disease
since	O
the	O
age	O
of	O
19	O
years	O
,	O
treated	O
by	O
a	O
combination	O
of	O
first	O
-	O
generation	O
antipsychotics	O
,	O
zuclopenthixol	B-Chemical
(	O
100	O
mg	O
/	O
day	O
)	O
and	O
lithium	B-Chemical
(	O
1200	O
mg	O
/	O
day	O
)	O
(	O
serum	O
lithium	B-Chemical
=	O
0	O
.	O
85	O
mEq	O
/	O
l	O
)	O
.	O

This	O
patient	O
had	O
no	O
associated	O
personality	B-Disease
disorder	I-Disease
(	O
particularly	O
no	O
antisocial	B-Disease
disorder	I-Disease
)	O
and	O
no	O
substance	B-Disease
abuse	I-Disease
disorder	I-Disease
.	O

Within	O
the	O
48	O
h	O
following	O
the	O
gradual	O
introduction	O
of	O
quetiapine	B-Chemical
(	O
up	O
to	O
600	O
mg	O
/	O
day	O
)	O
,	O
the	O
patient	O
presented	O
severe	O
agitation	B-Disease
without	O
an	O
environmental	O
explanation	O
,	O
contrasting	O
with	O
the	O
absence	O
of	O
a	O
history	O
of	O
aggressiveness	B-Disease
or	O
personality	B-Disease
disorder	I-Disease
.	O

The	O
diagnoses	O
of	O
manic	B-Disease
shift	O
and	O
akathisia	B-Disease
were	O
dismissed	O
.	O

The	O
withdrawal	O
and	O
the	O
gradual	O
reintroduction	O
of	O
quetiapine	B-Chemical
2	O
weeks	O
later	O
,	O
which	O
led	O
to	O
another	O
severe	O
agitation	B-Disease
,	O
enabled	O
us	O
to	O
attribute	O
the	O
agitation	B-Disease
specifically	O
to	O
quetiapine	B-Chemical
.	O

Antioxidant	O
effects	O
of	O
bovine	O
lactoferrin	O
on	O
dexamethasone	B-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
rat	O
.	O

Dexamethasone	B-Chemical
-	O
(	O
Dex	B-Chemical
-	O
)	O
induced	O
hypertension	B-Disease
is	O
associated	O
with	O
enhanced	O
oxidative	O
stress	O
.	O

Lactoferrin	O
(	O
LF	O
)	O
is	O
an	O
iron	B-Chemical
-	O
binding	O
glycoprotein	O
with	O
antihypertensive	O
properties	O
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
the	O
effect	O
of	O
chronic	O
administration	O
of	O
LF	O
on	O
oxidative	O
stress	O
and	O
hypertension	B-Disease
upon	O
Dex	B-Chemical
administration	O
.	O

Male	O
Wistar	O
rats	O
were	O
treated	O
by	O
Dex	B-Chemical
(	O
30	O
u	O
g	O
/	O
kg	O
/	O
day	O
subcutaneously	O
)	O
or	O
saline	O
for	O
14	O
days	O
.	O

Oral	O
bovine	O
LF	O
(	O
30	O
,	O
100	O
,	O
300	O
mg	O
/	O
kg	O
)	O
was	O
given	O
from	O
day	O
8	O
to	O
14	O
in	O
a	O
reversal	O
study	O
.	O

In	O
a	O
prevention	O
study	O
,	O
rats	O
received	O
4	O
days	O
of	O
LF	O
treatment	O
followed	O
by	O
Dex	B-Chemical
and	O
continued	O
during	O
the	O
test	O
period	O
.	O

Systolic	O
blood	O
pressure	O
(	O
SBP	O
)	O
was	O
measured	O
using	O
tail	O
-	O
cuff	O
method	O
.	O

Thymus	O
weight	O
was	O
used	O
as	O
a	O
marker	O
of	O
glucocorticoid	O
activity	O
.	O

Plasma	O
hydrogen	B-Chemical
peroxide	I-Chemical
(	O
H2O2	B-Chemical
)	O
concentration	O
and	O
ferric	O
reducing	O
antioxidant	O
power	O
(	O
FRAP	O
)	O
value	O
were	O
determined	O
.	O

Dexamethasone	B-Chemical
significantly	O
increased	O
SBP	O
and	O
plasma	O
H2O2	B-Chemical
level	O
and	O
decreased	O
thymus	O
and	O
body	O
weights	O
.	O

LF	O
lowered	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
and	O
dose	O
dependently	O
prevented	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
Dex	B-Chemical
-	O
induced	O
hypertension	B-Disease
.	O

LF	O
prevented	O
body	O
weight	B-Disease
loss	I-Disease
and	O
significantly	O
reduced	O
the	O
elevated	O
plasma	O
H2O2	B-Chemical
and	O
increased	O
FRAP	O
values	O
.	O

Chronic	O
administration	O
of	O
LF	O
strongly	O
reduced	O
the	O
blood	O
pressure	O
and	O
production	O
of	O
ROS	O
and	O
improved	O
antioxidant	O
capacity	O
in	O
Dex	B-Chemical
-	O
induced	O
hypertension	B-Disease
,	O
suggesting	O
the	O
role	O
of	O
inhibition	O
of	O
oxidative	O
stress	O
as	O
another	O
mechanism	O
of	O
antihypertensive	O
action	O
of	O
LF	O
.	O

The	O
association	O
between	O
tranexamic	B-Chemical
acid	I-Chemical
and	O
convulsive	B-Disease
seizures	B-Disease
after	O
cardiac	O
surgery	O
:	O
a	O
multivariate	O
analysis	O
in	O
11	O
529	O
patients	O
.	O

Because	O
of	O
a	O
lack	O
of	O
contemporary	O
data	O
regarding	O
seizures	B-Disease
after	O
cardiac	O
surgery	O
,	O
we	O
undertook	O
a	O
retrospective	O
analysis	O
of	O
prospectively	O
collected	O
data	O
from	O
11	O
529	O
patients	O
in	O
whom	O
cardiopulmonary	O
bypass	O
was	O
used	O
from	O
January	O
2004	O
to	O
December	O
2010	O
.	O

A	O
convulsive	B-Disease
seizure	B-Disease
was	O
defined	O
as	O
a	O
transient	O
episode	O
of	O
disturbed	O
brain	O
function	O
characterised	O
by	O
abnormal	B-Disease
involuntary	I-Disease
motor	I-Disease
movements	I-Disease
.	O

Multivariate	O
regression	O
analysis	O
was	O
performed	O
to	O
identify	O
independent	O
predictors	O
of	O
postoperative	O
seizures	B-Disease
.	O

A	O
total	O
of	O
100	O
(	O
0	O
.	O
9	O
%	O
)	O
patients	O
developed	O
postoperative	O
convulsive	B-Disease
seizures	B-Disease
.	O

Generalised	B-Disease
and	I-Disease
focal	I-Disease
seizures	I-Disease
were	O
identified	O
in	O
68	O
and	O
32	O
patients	O
,	O
respectively	O
.	O

The	O
median	O
(	O
IQR	O
[	O
range	O
]	O
)	O
time	O
after	O
surgery	O
when	O
the	O
seizure	B-Disease
occurred	O
was	O
7	O
(	O
6	O
-	O
12	O
[	O
1	O
-	O
216	O
]	O
)	O
h	O
and	O
8	O
(	O
6	O
-	O
11	O
[	O
4	O
-	O
18	O
]	O
)	O
h	O
,	O
respectively	O
.	O

Epileptiform	O
findings	O
on	O
electroencephalography	O
were	O
seen	O
in	O
19	O
patients	O
.	O

Independent	O
predictors	O
of	O
postoperative	O
seizures	B-Disease
included	O
age	O
,	O
female	O
sex	O
,	O
redo	O
cardiac	O
surgery	O
,	O
calcification	O
of	O
ascending	O
aorta	O
,	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
,	O
deep	O
hypothermic	B-Disease
circulatory	O
arrest	O
,	O
duration	O
of	O
aortic	O
cross	O
-	O
clamp	O
and	O
tranexamic	B-Chemical
acid	I-Chemical
.	O

When	O
tested	O
in	O
a	O
multivariate	O
regression	O
analysis	O
,	O
tranexamic	B-Chemical
acid	I-Chemical
was	O
a	O
strong	O
independent	O
predictor	O
of	O
seizures	B-Disease
(	O
OR	O
14	O
.	O
3	O
,	O
95	O
%	O
CI	O
5	O
.	O
5	O
-	O
36	O
.	O
7	O
;	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Patients	O
with	O
convulsive	B-Disease
seizures	B-Disease
had	O
2	O
.	O
5	O
times	O
higher	O
in	O
-	O
hospital	O
mortality	O
rates	O
and	O
twice	O
the	O
length	O
of	O
hospital	O
stay	O
compared	O
with	O
patients	O
without	O
convulsive	B-Disease
seizures	B-Disease
.	O

Mean	O
(	O
IQR	O
[	O
range	O
]	O
)	O
length	O
of	O
stay	O
in	O
the	O
intensive	O
care	O
unit	O
was	O
115	O
(	O
49	O
-	O
228	O
[	O
32	O
-	O
481	O
]	O
)	O
h	O
in	O
patients	O
with	O
convulsive	B-Disease
seizures	B-Disease
compared	O
with	O
26	O
(	O
22	O
-	O
69	O
[	O
14	O
-	O
1080	O
]	O
)	O
h	O
in	O
patients	O
without	O
seizures	B-Disease
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Convulsive	B-Disease
seizures	B-Disease
are	O
a	O
serious	O
postoperative	B-Disease
complication	I-Disease
after	O
cardiac	O
surgery	O
.	O

As	O
tranexamic	B-Chemical
acid	I-Chemical
is	O
the	O
only	O
modifiable	O
factor	O
,	O
its	O
administration	O
,	O
particularly	O
in	O
doses	O
exceeding	O
80	O
mg	O
.	O
kg	O
(	O
-	O
1	O
)	O
,	O
should	O
be	O
weighed	O
against	O
the	O
risk	O
of	O
postoperative	O
seizures	B-Disease
.	O

Dysfunctional	B-Disease
overnight	I-Disease
memory	I-Disease
consolidation	O
in	O
ecstasy	B-Chemical
users	O
.	O

Sleep	O
plays	O
an	O
important	O
role	O
in	O
the	O
consolidation	O
and	O
integration	O
of	O
memory	O
in	O
a	O
process	O
called	O
overnight	O
memory	O
consolidation	O
.	O

Previous	O
studies	O
indicate	O
that	O
ecstasy	B-Chemical
users	O
have	O
marked	O
and	O
persistent	O
neurocognitive	O
and	O
sleep	B-Disease
-	I-Disease
related	I-Disease
impairments	I-Disease
.	O

We	O
extend	O
past	O
research	O
by	O
examining	O
overnight	O
memory	O
consolidation	O
among	O
regular	O
ecstasy	B-Chemical
users	O
(	O
n	O
=	O
12	O
)	O
and	O
drug	O
naive	O
healthy	O
controls	O
(	O
n	O
=	O
26	O
)	O
.	O

Memory	O
recall	O
of	O
word	O
pairs	O
was	O
evaluated	O
before	O
and	O
after	O
a	O
period	O
of	O
sleep	O
,	O
with	O
and	O
without	O
interference	O
prior	O
to	O
testing	O
.	O

In	O
addition	O
,	O
we	O
assessed	O
neurocognitive	O
performances	O
across	O
tasks	O
of	O
learning	O
,	O
memory	O
and	O
executive	O
functioning	O
.	O

Ecstasy	B-Chemical
users	O
demonstrated	O
impaired	B-Disease
overnight	I-Disease
memory	I-Disease
consolidation	O
,	O
a	O
finding	O
that	O
was	O
more	O
pronounced	O
following	O
associative	O
interference	O
.	O

Additionally	O
,	O
ecstasy	B-Chemical
users	O
demonstrated	O
impairments	O
on	O
tasks	O
recruiting	O
frontostriatal	O
and	O
hippocampal	O
neural	O
circuitry	O
,	O
in	O
the	O
domains	O
of	O
proactive	O
interference	O
memory	O
,	O
long	O
-	O
term	O
memory	O
,	O
encoding	O
,	O
working	O
memory	O
and	O
complex	O
planning	O
.	O

We	O
suggest	O
that	O
ecstasy	B-Chemical
-	O
associated	O
dysfunction	O
in	O
fronto	O
-	O
temporal	O
circuitry	O
may	O
underlie	O
overnight	O
consolidation	O
memory	B-Disease
impairments	I-Disease
in	O
regular	O
ecstasy	B-Chemical
users	O
.	O

Normoammonemic	O
encephalopathy	B-Disease
:	O
solely	O
valproate	B-Chemical
induced	O
or	O
multiple	O
mechanisms	O
?	O

A	O
77	O
-	O
year	O
-	O
old	O
woman	O
presented	O
with	O
subacute	O
onset	O
progressive	O
confusion	B-Disease
,	O
aggression	B-Disease
,	O
auditory	B-Disease
hallucinations	I-Disease
and	O
delusions	B-Disease
.	O

In	O
the	O
preceding	O
months	O
,	O
the	O
patient	O
had	O
a	O
number	O
of	O
admissions	O
with	O
transient	O
unilateral	O
hemiparesis	B-Disease
with	O
facial	O
droop	O
,	O
and	O
had	O
been	O
started	O
on	O
valproate	B-Chemical
for	O
presumed	O
hemiplegic	B-Disease
migraine	I-Disease
.	O

Valproate	B-Chemical
was	O
withdrawn	O
soon	O
after	O
admission	O
and	O
her	O
cognitive	O
abilities	O
have	O
gradually	O
improved	O
over	O
3	O
months	O
of	O
follow	O
-	O
up	O
.	O

Valproate	B-Chemical
levels	O
taken	O
prior	O
to	O
withdrawal	O
were	O
subtherapeutic	O
and	O
the	O
patient	O
was	O
normoammonaemic	O
.	O

EEG	O
undertaken	O
during	O
inpatient	O
stay	O
showed	O
changes	O
consistent	O
with	O
encephalopathy	B-Disease
,	O
and	O
low	O
titre	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
receptor	O
antibodies	O
were	O
present	O
in	O
this	O
patient	O
.	O

The	O
possible	O
aetiologies	O
of	O
valproate	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
and	O
NMDA	B-Chemical
receptor	O
-	O
associated	O
encephalitis	B-Disease
present	O
a	O
diagnostic	O
dilemma	O
.	O

We	O
present	O
a	O
putative	O
combinatorial	O
hypothesis	O
to	O
explain	O
this	O
patient	O
'	O
s	O
symptoms	O
.	O

Cerebellar	B-Disease
and	I-Disease
oculomotor	I-Disease
dysfunction	I-Disease
induced	O
by	O
rapid	O
infusion	O
of	O
pethidine	B-Chemical
.	O

Pethidine	B-Chemical
is	O
an	O
opioid	O
that	O
gains	O
its	O
popularity	O
for	O
the	O
effective	O
pain	B-Disease
control	O
through	O
acting	O
on	O
the	O
opioid	O
-	O
receptors	O
.	O

However	O
,	O
rapid	O
pain	B-Disease
relief	O
sometimes	O
brings	O
about	O
unfavourable	O
side	O
effects	O
that	O
largely	O
limit	O
its	O
clinical	O
utility	O
.	O

Common	O
side	O
effects	O
include	O
nausea	B-Disease
,	O
vomiting	B-Disease
and	O
hypotension	B-Disease
.	O

In	O
patients	O
with	O
impaired	B-Disease
renal	I-Disease
and	I-Disease
liver	I-Disease
function	I-Disease
,	O
and	O
those	O
who	O
need	O
long	O
-	O
term	O
pain	B-Disease
control	O
,	O
pethidine	B-Chemical
may	O
cause	O
excitatory	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
effects	O
through	O
its	O
neurotoxic	B-Disease
metabolite	O
,	O
norpethidine	B-Chemical
,	O
resulting	O
in	O
irritability	B-Disease
and	O
seizure	B-Disease
attack	O
.	O

On	O
the	O
contrary	O
,	O
though	O
not	O
clinically	O
apparent	O
,	O
pethidine	B-Chemical
potentially	O
causes	O
inhibitory	O
impacts	O
on	O
the	O
CNS	O
and	O
impairs	O
normal	O
cerebellar	O
and	O
oculomotor	O
function	O
in	O
the	O
short	O
term	O
.	O

In	O
this	O
case	O
report	O
,	O
we	O
highlight	O
opioid	O
'	O
s	O
inhibitory	O
side	O
effects	O
on	O
the	O
cerebellar	O
structure	O
that	O
causes	O
dysmetria	B-Disease
,	O
dysarthria	B-Disease
,	O
reduced	O
smooth	O
pursuit	O
gain	O
and	O
decreased	O
saccadic	O
velocity	O
.	O

Baboon	B-Disease
syndrome	I-Disease
induced	O
by	O
ketoconazole	B-Chemical
.	O

A	O
27	O
-	O
year	O
-	O
old	O
male	O
patient	O
presented	O
with	O
a	O
maculopapular	B-Disease
eruption	I-Disease
on	O
the	O
flexural	O
areas	O
and	O
buttocks	O
after	O
using	O
oral	O
ketoconazole	B-Chemical
.	O

The	O
patient	O
was	O
diagnosed	O
with	O
drug	O
-	O
induced	O
baboon	B-Disease
syndrome	I-Disease
based	O
on	O
his	O
history	O
,	O
which	O
included	O
prior	O
sensitivity	O
to	O
topical	O
ketoconazole	B-Chemical
,	O
a	O
physical	O
examination	O
,	O
and	O
histopathological	O
findings	O
.	O

Baboon	B-Disease
syndrome	I-Disease
is	O
a	O
drug	O
-	O
or	O
contact	O
allergen	O
-	O
related	O
maculopapular	B-Disease
eruption	I-Disease
that	O
typically	O
involves	O
the	O
flexural	O
and	O
gluteal	O
areas	O
.	O

To	O
the	O
best	O
of	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
reported	O
case	O
of	O
ketoconazole	B-Chemical
-	O
induced	O
baboon	B-Disease
syndrome	I-Disease
in	O
the	O
English	O
literature	O
.	O

A	O
Case	O
of	O
Sudden	B-Disease
Cardiac	I-Disease
Death	I-Disease
due	O
to	O
Pilsicainide	B-Chemical
-	O
Induced	O
Torsades	B-Disease
de	I-Disease
Pointes	I-Disease
.	O

An	O
84	O
-	O
year	O
-	O
old	O
male	O
received	O
oral	O
pilsicainide	B-Chemical
,	O
a	O
pure	O
sodium	B-Chemical
channel	O
blocker	O
with	O
slow	O
recovery	O
kinetics	O
,	O
to	O
convert	O
his	O
paroxysmal	O
atrial	B-Disease
fibrillation	I-Disease
to	O
a	O
sinus	O
rhythm	O
;	O
the	O
patient	O
developed	O
sudden	B-Disease
cardiac	I-Disease
death	I-Disease
two	O
days	O
later	O
.	O

The	O
Holter	O
electrocardiogram	O
,	O
which	O
was	O
worn	O
by	O
chance	O
,	O
revealed	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
with	O
gradually	O
prolonged	O
QT	O
intervals	O
.	O

This	O
drug	O
is	O
rapidly	O
absorbed	O
from	O
the	O
gastrointestinal	O
tract	O
,	O
and	O
most	O
of	O
it	O
is	O
excreted	O
from	O
the	O
kidney	O
.	O

Although	O
the	O
patient	O
'	O
s	O
renal	O
function	O
was	O
not	O
highly	O
impaired	O
and	O
the	O
dose	O
of	O
pilsicainide	B-Chemical
was	O
low	O
,	O
the	O
plasma	O
concentration	O
of	O
pilsicainide	B-Chemical
may	O
have	O
been	O
high	O
,	O
which	O
can	O
produce	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
in	O
the	O
octogenarian	O
.	O

Although	O
the	O
oral	O
administration	O
of	O
class	O
IC	O
drugs	O
,	O
including	O
pilsicainide	B-Chemical
,	O
is	O
effective	O
to	O
terminate	O
atrial	B-Disease
fibrillation	I-Disease
,	O
careful	O
consideration	O
must	O
be	O
taken	O
before	O
giving	O
these	O
drugs	O
to	O
octogenarians	O
.	O

All	B-Chemical
-	I-Chemical
trans	I-Chemical
retinoic	I-Chemical
acid	I-Chemical
-	O
induced	O
inflammatory	O
myositis	B-Disease
in	O
a	O
patient	O
with	O
acute	B-Disease
promyelocytic	I-Disease
leukemia	I-Disease
.	O

All	B-Chemical
-	I-Chemical
trans	I-Chemical
retinoic	I-Chemical
acid	I-Chemical
(	O
ATRA	B-Chemical
)	O
,	O
a	O
component	O
of	O
standard	O
therapy	O
for	O
acute	B-Disease
promyelocytic	I-Disease
leukemia	I-Disease
(	O
APL	B-Disease
)	O
,	O
is	O
associated	O
with	O
potentially	O
serious	O
but	O
treatable	O
adverse	O
effects	O
involving	O
numerous	O
organ	O
systems	O
,	O
including	O
rare	O
skeletal	O
muscle	O
involvement	O
.	O

Only	O
a	O
handful	O
of	O
cases	O
of	O
ATRA	B-Chemical
-	O
induced	O
myositis	B-Disease
in	O
children	O
have	O
been	O
reported	O
,	O
and	O
none	O
in	O
the	O
radiology	O
literature	O
.	O

We	O
present	O
such	O
a	O
case	O
in	O
a	O
15	O
-	O
year	O
-	O
old	O
boy	O
with	O
APL	B-Disease
,	O
where	O
recognition	O
of	O
imaging	O
findings	O
played	O
a	O
crucial	O
role	O
in	O
making	O
the	O
diagnosis	O
and	O
facilitated	O
prompt	O
,	O
effective	O
treatment	O
.	O

Tolerability	O
of	O
lomustine	B-Chemical
in	O
combination	O
with	O
cyclophosphamide	B-Chemical
in	O
dogs	O
with	O
lymphoma	B-Disease
.	O

This	O
retrospective	O
study	O
describes	O
toxicity	B-Disease
associated	O
with	O
a	O
protocol	O
of	O
lomustine	B-Chemical
(	O
CCNU	B-Chemical
)	O
and	O
cyclophosphamide	B-Chemical
(	O
CTX	B-Chemical
)	O
in	O
dogs	O
with	O
lymphoma	B-Disease
.	O

CCNU	B-Chemical
was	O
administered	O
per	O
os	O
(	O
PO	O
)	O
at	O
a	O
targeted	O
dosage	O
of	O
60	O
mg	O
/	O
m	O
(	O
2	O
)	O
body	O
surface	O
area	O
on	O
day	O
0	O
,	O
CTX	B-Chemical
was	O
administered	O
PO	O
at	O
a	O
targeted	O
dosage	O
of	O
250	O
mg	O
/	O
m	O
(	O
2	O
)	O
divided	O
over	O
days	O
0	O
through	O
4	O
,	O
and	O
all	O
dogs	O
received	O
prophylactic	O
antibiotics	O
.	O

Ninety	O
treatments	O
were	O
given	O
to	O
the	O
57	O
dogs	O
included	O
in	O
the	O
study	O
.	O

Neutropenia	B-Disease
was	O
the	O
principal	O
toxic	O
effect	O
,	O
and	O
the	O
overall	O
frequency	O
of	O
grade	O
4	O
neutropenia	B-Disease
after	O
the	O
first	O
treatment	O
of	O
CCNU	B-Chemical
/	O
CTX	B-Chemical
was	O
30	O
%	O
(	O
95	O
%	O
confidence	O
interval	O
,	O
19	O
-	O
43	O
%	O
)	O
.	O

The	O
mean	O
body	O
weight	O
of	O
dogs	O
with	O
grade	O
4	O
neutropenia	B-Disease
(	O
19	O
.	O
7	O
kg	O
+	O
13	O
.	O
4	O
kg	O
)	O
was	O
significantly	O
less	O
than	O
the	O
mean	O
body	O
weight	O
of	O
dogs	O
that	O
did	O
not	O
develop	O
grade	O
4	O
neutropenia	B-Disease
(	O
31	O
.	O
7	O
kg	O
+	O
12	O
.	O
4	O
kg	O
;	O
P	O
=	O
.	O
005	O
)	O
.	O

One	O
dog	O
(	O
3	O
%	O
)	O
developed	O
hematologic	O
changes	O
suggestive	O
of	O
hepatotoxicity	B-Disease
.	O

No	O
dogs	O
had	O
evidence	O
of	O
either	O
renal	B-Disease
toxicity	I-Disease
or	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

Adverse	O
gastrointestinal	O
effects	O
were	O
uncommon	O
.	O

On	O
the	O
basis	O
of	O
the	O
findings	O
reported	O
herein	O
,	O
a	O
dose	O
of	O
60	O
mg	O
/	O
m	O
(	O
2	O
)	O
of	O
CCNU	B-Chemical
combined	O
with	O
250	O
mg	O
/	O
m	O
(	O
2	O
)	O
of	O
CTX	B-Chemical
(	O
divided	O
over	O
5	O
days	O
)	O
q	O
4	O
wk	O
is	O
tolerable	O
in	O
tumor	B-Disease
-	O
bearing	O
dogs	O
.	O

Nelarabine	B-Chemical
neurotoxicity	B-Disease
with	O
concurrent	O
intrathecal	O
chemotherapy	O
:	O
Case	O
report	O
and	O
review	O
of	O
literature	O
.	O

Severe	O
nelarabine	B-Chemical
neurotoxicity	B-Disease
in	O
a	O
patient	O
who	O
received	O
concurrent	O
intrathecal	O
(	O
IT	O
)	O
chemotherapy	O
is	O
reported	O
.	O

A	O
37	O
-	O
year	O
-	O
old	O
Caucasian	O
woman	O
with	O
a	O
history	O
of	O
T	B-Disease
-	I-Disease
cell	I-Disease
lymphoblastic	I-Disease
lymphoma	I-Disease
was	O
admitted	O
for	O
relapsed	O
disease	O
.	O

She	O
was	O
originally	O
treated	O
with	O
induction	O
chemotherapy	O
followed	O
by	O
an	O
autologous	O
transplant	O
.	O

She	O
developed	O
relapsed	O
disease	O
10	O
months	O
later	O
with	O
leukemic	B-Disease
involvement	O
.	O

She	O
was	O
re	O
-	O
induced	O
with	O
nelarabine	B-Chemical
1500	O
mg	O
/	O
m	O
(	O
2	O
)	O
on	O
days	O
1	O
,	O
3	O
,	O
and	O
5	O
with	O
1	O
dose	O
of	O
IT	O
cytarabine	B-Chemical
100	O
mg	O
on	O
day	O
2	O
as	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
prophylaxis	O
.	O

At	O
the	O
time	O
of	O
treatment	O
,	O
she	O
was	O
on	O
continuous	O
renal	O
replacement	O
therapy	O
due	O
to	O
sequelae	O
of	O
tumor	B-Disease
lysis	I-Disease
syndrome	I-Disease
(	O
TLS	B-Disease
)	O
.	O

She	O
tolerated	O
therapy	O
well	O
,	O
entered	O
a	O
complete	O
remission	O
,	O
and	O
recovered	O
her	O
renal	O
function	O
.	O

She	O
received	O
a	O
second	O
cycle	O
of	O
nelarabine	B-Chemical
without	O
additional	O
IT	O
prophylaxis	O
one	O
month	O
later	O
.	O

A	O
week	O
after	O
this	O
second	O
cycle	O
,	O
she	O
noted	O
numbness	O
in	O
her	O
lower	O
extremities	O
.	O

Predominantly	O
sensory	O
,	O
though	O
also	O
motor	O
and	O
autonomic	O
,	O
peripheral	B-Disease
neuropathy	I-Disease
started	O
in	O
her	O
feet	O
,	O
ascended	O
proximally	O
to	O
the	O
mid	O
-	O
thoracic	O
region	O
,	O
and	O
eventually	O
included	O
her	O
distal	O
upper	O
extremities	O
.	O

A	O
magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
of	O
her	O
spine	O
demonstrated	O
changes	O
from	O
C2	O
to	O
C6	O
consistent	O
with	O
subacute	O
combined	O
degeneration	O
.	O

Nelarabine	B-Chemical
was	O
felt	O
to	O
be	O
the	O
cause	O
of	O
her	O
symptoms	O
.	O

Her	O
neuropathy	B-Disease
stabilized	O
and	O
showed	O
slight	O
improvement	O
and	O
ultimately	O
received	O
an	O
unrelated	O
,	O
reduced	O
-	O
intensity	O
allogeneic	O
transplant	O
while	O
in	O
complete	O
remission	O
,	O
but	O
relapsed	O
disease	O
10	O
weeks	O
later	O
.	O

She	O
is	O
currently	O
being	O
treated	O
with	O
best	O
supportive	O
care	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
published	O
case	O
report	O
of	O
severe	O
neurotoxicity	B-Disease
caused	O
by	O
nelarabine	B-Chemical
in	O
a	O
patient	O
who	O
received	O
concurrent	O
IT	O
chemotherapy	O
.	O

Valproate	B-Chemical
-	O
induced	O
hyperammonemic	B-Disease
encephalopathy	B-Disease
in	O
a	O
renal	O
transplanted	O
patient	O
.	O

Neurological	B-Disease
complications	I-Disease
after	O
renal	O
transplantation	O
constitute	O
an	O
important	O
cause	O
of	O
morbidity	O
and	O
mortality	O
.	O

Their	O
differential	O
diagnosis	O
is	O
difficult	O
and	O
essential	O
for	O
subsequent	O
patient	O
'	O
s	O
management	O
.	O

Valproate	B-Chemical
-	O
induced	O
hyperammonemic	B-Disease
encephalopathy	B-Disease
is	O
an	O
uncommon	O
but	O
serious	O
effect	O
of	O
valproate	B-Chemical
treatment	O
.	O

Here	O
,	O
we	O
describe	O
the	O
case	O
of	O
a	O
15	O
-	O
year	O
-	O
old	O
girl	O
who	O
was	O
on	O
a	O
long	O
-	O
term	O
therapy	O
with	O
valproate	B-Chemical
due	O
to	O
epilepsy	B-Disease
and	O
revealed	O
impaired	B-Disease
consciousness	I-Disease
with	O
hyperammonemia	B-Disease
12	O
days	O
after	O
renal	O
transplantation	O
.	O

After	O
withdraw	O
of	O
valproate	B-Chemical
,	O
patients	O
'	O
symptoms	O
resolved	O
within	O
24	O
h	O
.	O

Clinicians	O
should	O
increase	O
their	O
awareness	O
for	O
potential	O
complication	O
of	O
valproate	B-Chemical
,	O
especially	O
in	O
transplanted	O
patients	O
.	O

Necrotising	B-Disease
fasciitis	I-Disease
after	O
bortezomib	B-Chemical
and	O
dexamethasone	B-Chemical
-	O
containing	O
regimen	O
in	O
an	O
elderly	O
patient	O
of	O
Waldenstrom	B-Disease
macroglobulinaemia	I-Disease
.	O

Bortezomib	B-Chemical
and	O
high	O
-	O
dose	O
dexamethasone	B-Chemical
-	O
containing	O
regimens	O
are	O
considered	O
to	O
be	O
generally	O
tolerable	O
with	O
few	O
severe	O
bacterial	B-Disease
infections	I-Disease
in	O
patients	O
with	O
B	O
-	O
cell	O
malignancies	B-Disease
.	O

However	O
,	O
information	O
is	O
limited	O
concerning	O
the	O
safety	O
of	O
the	O
regimen	O
in	O
elderly	O
patients	O
.	O

We	O
report	O
a	O
case	O
of	O
a	O
76	O
-	O
year	O
-	O
old	O
man	O
with	O
Waldenstrom	B-Disease
macroglobulinaemia	I-Disease
who	O
suffered	O
necrotising	B-Disease
fasciitis	I-Disease
without	O
neutropenia	B-Disease
after	O
the	O
combination	O
treatment	O
with	O
bortezomib	B-Chemical
,	O
high	O
-	O
dose	O
dexamethasone	B-Chemical
and	O
rituximab	O
.	O

Despite	O
immediate	O
intravenous	O
antimicrobial	O
therapy	O
,	O
he	O
succumbed	O
23	O
h	O
after	O
the	O
onset	O
.	O

Physicians	O
should	O
recognise	O
the	O
possibility	O
of	O
fatal	O
bacterial	B-Disease
infections	I-Disease
related	O
to	O
bortezomib	B-Chemical
plus	O
high	O
-	O
dose	O
dexamethasone	B-Chemical
in	O
elderly	O
patients	O
,	O
and	O
we	O
believe	O
this	O
case	O
warrants	O
further	O
investigation	O
.	O

An	O
integrated	O
characterization	O
of	O
serological	O
,	O
pathological	O
,	O
and	O
functional	O
events	O
in	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

Many	O
efficacious	O
cancer	B-Disease
treatments	O
cause	O
significant	O
cardiac	O
morbidity	O
,	O
yet	O
biomarkers	O
or	O
functional	O
indices	O
of	O
early	O
damage	O
,	O
which	O
would	O
allow	O
monitoring	O
and	O
intervention	O
,	O
are	O
lacking	O
.	O

In	O
this	O
study	O
,	O
we	O
have	O
utilized	O
a	O
rat	O
model	O
of	O
progressive	O
doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
-	O
induced	O
cardiomyopathy	B-Disease
,	O
applying	O
multiple	O
approaches	O
,	O
including	O
cardiac	O
magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
,	O
to	O
provide	O
the	O
most	O
comprehensive	O
characterization	O
to	O
date	O
of	O
the	O
timecourse	O
of	O
serological	O
,	O
pathological	O
,	O
and	O
functional	O
events	O
underlying	O
this	O
toxicity	B-Disease
.	O

Hannover	O
Wistar	O
rats	O
were	O
dosed	O
with	O
1	O
.	O
25	O
mg	O
/	O
kg	O
DOX	B-Chemical
weekly	O
for	O
8	O
weeks	O
followed	O
by	O
a	O
4	O
week	O
off	O
-	O
dosing	O
"	O
recovery	O
"	O
period	O
.	O

Electron	O
microscopy	O
of	O
the	O
myocardium	O
revealed	O
subcellular	B-Disease
degeneration	I-Disease
and	O
marked	O
mitochondrial	O
changes	O
after	O
a	O
single	O
dose	O
.	O

Histopathological	O
analysis	O
revealed	O
progressive	O
cardiomyocyte	B-Disease
degeneration	I-Disease
,	O
hypertrophy	B-Disease
/	O
cytomegaly	O
,	O
and	O
extensive	O
vacuolation	O
after	O
two	O
doses	O
.	O

Extensive	O
replacement	O
fibrosis	B-Disease
(	O
quantified	O
by	O
Sirius	O
red	O
staining	O
)	O
developed	O
during	O
the	O
off	O
-	O
dosing	O
period	O
.	O

Functional	O
indices	O
assessed	O
by	O
cardiac	O
MRI	O
(	O
including	O
left	O
ventricular	O
ejection	O
fraction	O
(	O
LVEF	O
)	O
,	O
cardiac	O
output	O
,	O
and	O
E	O
/	O
A	O
ratio	O
)	O
declined	O
progressively	O
,	O
reaching	O
statistical	O
significance	O
after	O
two	O
doses	O
and	O
culminating	O
in	O
"	O
clinical	O
"	O
LV	B-Disease
dysfunction	I-Disease
by	O
12	O
weeks	O
.	O

Significant	O
increases	O
in	O
peak	O
myocardial	O
contrast	O
enhancement	O
and	O
serological	O
cardiac	O
troponin	O
I	O
(	O
cTnI	O
)	O
emerged	O
after	O
eight	O
doses	O
,	O
importantly	O
preceding	O
the	O
LVEF	O
decline	O
to	O
<	O
50	O
%	O
.	O

Troponin	O
I	O
levels	O
positively	O
correlated	O
with	O
delayed	O
and	O
peak	O
gadolinium	B-Chemical
contrast	O
enhancement	O
,	O
histopathological	O
grading	O
,	O
and	O
diastolic	B-Disease
dysfunction	I-Disease
.	O

In	O
summary	O
,	O
subcellular	O
cardiomyocyte	B-Disease
degeneration	I-Disease
was	O
the	O
earliest	O
marker	O
,	O
followed	O
by	O
progressive	O
functional	O
decline	O
and	O
histopathological	O
manifestations	O
.	O

Myocardial	O
contrast	O
enhancement	O
and	O
elevations	O
in	O
cTnI	O
occurred	O
later	O
.	O

However	O
,	O
all	O
indices	O
predated	O
"	O
clinical	O
"	O
LV	B-Disease
dysfunction	I-Disease
and	O
thus	O
warrant	O
further	O
evaluation	O
as	O
predictive	O
biomarkers	O
.	O

Intradermal	O
glutamate	B-Chemical
and	O
capsaicin	B-Chemical
injections	O
:	O
intra	O
-	O
and	O
interindividual	O
variability	O
of	O
provoked	O
hyperalgesia	B-Disease
and	O
allodynia	B-Disease
.	O

Intradermal	O
injections	O
of	O
glutamate	B-Chemical
and	O
capsaicin	B-Chemical
are	O
attractive	O
to	O
use	O
in	O
human	O
experimental	O
pain	B-Disease
models	O
because	O
hyperalgesia	B-Disease
and	O
allodynia	B-Disease
mimic	O
isolated	O
aspects	O
of	O
clinical	O
pain	B-Disease
disorders	I-Disease
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
the	O
reproducibility	O
of	O
these	O
models	O
.	O

Twenty	O
healthy	O
male	O
volunteers	O
(	O
mean	O
age	O
24	O
years	O
;	O
range	O
18	O
-	O
38	O
years	O
)	O
received	O
intradermal	O
injections	O
of	O
glutamate	B-Chemical
and	O
capsaicin	B-Chemical
in	O
the	O
volar	O
forearm	O
.	O

Magnitudes	O
of	O
secondary	O
pinprick	O
hyperalgesia	B-Disease
and	O
brush	O
-	O
evoked	O
allodynia	B-Disease
were	O
investigated	O
using	O
von	O
Frey	O
filaments	O
(	O
gauges	O
10	O
,	O
15	O
,	O
60	O
and	O
100	O
g	O
)	O
and	O
brush	O
strokes	O
.	O

Areas	O
of	O
secondary	B-Disease
hyperalgesia	I-Disease
and	O
allodynia	B-Disease
were	O
quantified	O
immediately	O
after	O
injection	O
and	O
after	O
15	O
,	O
30	O
and	O
60	O
min	O
.	O

Two	O
identical	O
experiments	O
separated	O
by	O
at	O
least	O
7	O
days	O
were	O
performed	O
.	O

Reproducibility	O
across	O
and	O
within	O
volunteers	O
(	O
inter	O
-	O
and	O
intra	O
-	O
individual	O
variation	O
,	O
respectively	O
)	O
was	O
assessed	O
using	O
intraclass	O
correlation	O
coefficient	O
(	O
ICC	O
)	O
and	O
coefficient	O
of	O
variation	O
(	O
CV	O
)	O
.	O

Secondary	O
pinprick	O
hyperalgesia	B-Disease
was	O
observed	O
as	O
a	O
marked	O
increase	O
in	O
the	O
visual	O
analogue	O
scale	O
(	O
VAS	O
)	O
response	O
to	O
von	O
Frey	O
gauges	O
60	O
and	O
100	O
g	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
after	O
glutamate	B-Chemical
injection	O
.	O

For	O
capsaicin	B-Chemical
,	O
secondary	O
pinprick	O
hyperalgesia	B-Disease
was	O
detected	O
with	O
all	O
von	O
Frey	O
gauges	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Glutamate	B-Chemical
evoked	O
reproducible	O
VAS	O
response	O
to	O
all	O
von	O
Frey	O
gauges	O
(	O
ICC	O
>	O
0	O
.	O
60	O
)	O
and	O
brush	O
strokes	O
(	O
ICC	O
>	O
0	O
.	O
83	O
)	O
.	O

Capsaicin	B-Chemical
injection	O
was	O
reproducible	O
for	O
secondary	B-Disease
hyperalgesia	I-Disease
(	O
ICC	O
>	O
0	O
.	O
70	O
)	O
and	O
allodynia	B-Disease
(	O
ICC	O
>	O
0	O
.	O
71	O
)	O
.	O

Intra	O
-	O
individual	O
variability	O
was	O
generally	O
lower	O
for	O
the	O
VAS	O
response	O
to	O
von	O
Frey	O
and	O
brush	O
compared	O
with	O
areas	O
of	O
secondary	B-Disease
hyperalgesia	I-Disease
and	O
allodynia	B-Disease
.	O

In	O
conclusion	O
,	O
glutamate	B-Chemical
and	O
capsaicin	B-Chemical
yield	O
reproducible	O
hyperalgesic	B-Disease
and	O
allodynic	B-Disease
responses	O
,	O
and	O
the	O
present	O
model	O
is	O
well	O
suited	O
for	O
basic	O
research	O
,	O
as	O
well	O
as	O
for	O
assessing	O
the	O
modulation	O
of	O
central	O
phenomena	O
.	O

Ocular	O
-	O
specific	O
ER	O
stress	O
reduction	O
rescues	O
glaucoma	B-Disease
in	O
murine	O
glucocorticoid	O
-	O
induced	O
glaucoma	B-Disease
.	O

Administration	O
of	O
glucocorticoids	O
induces	O
ocular	B-Disease
hypertension	I-Disease
in	O
some	O
patients	O
.	O

If	O
untreated	O
,	O
these	O
patients	O
can	O
develop	O
a	O
secondary	O
glaucoma	B-Disease
that	O
resembles	O
primary	B-Disease
open	I-Disease
-	I-Disease
angle	I-Disease
glaucoma	I-Disease
(	O
POAG	B-Disease
)	O
.	O

The	O
underlying	O
pathology	O
of	O
glucocorticoid	O
-	O
induced	O
glaucoma	B-Disease
is	O
not	O
fully	O
understood	O
,	O
due	O
in	O
part	O
to	O
lack	O
of	O
an	O
appropriate	O
animal	O
model	O
.	O

Here	O
,	O
we	O
developed	O
a	O
murine	O
model	O
of	O
glucocorticoid	O
-	O
induced	O
glaucoma	B-Disease
that	O
exhibits	O
glaucoma	B-Disease
features	O
that	O
are	O
observed	O
in	O
patients	O
.	O

Treatment	O
of	O
WT	O
mice	O
with	O
topical	O
ocular	O
0	O
.	O
1	O
%	O
dexamethasone	B-Chemical
led	O
to	O
elevation	O
of	O
intraocular	O
pressure	O
(	O
IOP	O
)	O
,	O
functional	O
and	O
structural	O
loss	O
of	O
retinal	B-Disease
ganglion	I-Disease
cells	O
,	O
and	O
axonal	B-Disease
degeneration	I-Disease
,	O
resembling	O
glucocorticoid	O
-	O
induced	O
glaucoma	B-Disease
in	O
human	O
patients	O
.	O

Furthermore	O
,	O
dexamethasone	B-Chemical
-	O
induced	O
ocular	B-Disease
hypertension	I-Disease
was	O
associated	O
with	O
chronic	O
ER	O
stress	O
of	O
the	O
trabecular	O
meshwork	O
(	O
TM	O
)	O
.	O

Similar	O
to	O
patients	O
,	O
withdrawal	O
of	O
dexamethasone	B-Chemical
treatment	O
reduced	O
elevated	O
IOP	O
and	O
ER	O
stress	O
in	O
this	O
animal	O
model	O
.	O

Dexamethasone	B-Chemical
induced	O
the	O
transcriptional	O
factor	O
CHOP	O
,	O
a	O
marker	O
for	O
chronic	O
ER	O
stress	O
,	O
in	O
the	O
anterior	O
segment	O
tissues	O
,	O
and	O
Chop	O
deletion	O
reduced	O
ER	O
stress	O
in	O
these	O
tissues	O
and	O
prevented	O
dexamethasone	B-Chemical
-	O
induced	O
ocular	B-Disease
hypertension	I-Disease
.	O

Furthermore	O
,	O
reduction	O
of	O
ER	O
stress	O
in	O
the	O
TM	O
with	O
sodium	B-Chemical
4	I-Chemical
-	I-Chemical
phenylbutyrate	I-Chemical
prevented	O
dexamethasone	B-Chemical
-	O
induced	O
ocular	B-Disease
hypertension	I-Disease
in	O
WT	O
mice	O
.	O

Our	O
data	O
indicate	O
that	O
ER	O
stress	O
contributes	O
to	O
glucocorticoid	O
-	O
induced	O
ocular	B-Disease
hypertension	I-Disease
and	O
suggest	O
that	O
reducing	O
ER	O
stress	O
has	O
potential	O
as	O
a	O
therapeutic	O
strategy	O
for	O
treating	O
glucocorticoid	O
-	O
induced	O
glaucoma	B-Disease
.	O

Effects	O
of	O
ginsenosides	B-Chemical
on	O
opioid	O
-	O
induced	O
hyperalgesia	B-Disease
in	O
mice	O
.	O

Opioid	O
-	O
induced	O
hyperalgesia	B-Disease
(	O
OIH	B-Disease
)	O
is	O
characterized	O
by	O
nociceptive	O
sensitization	O
caused	O
by	O
the	O
cessation	O
of	O
chronic	O
opioid	O
use	O
.	O

OIH	B-Disease
can	O
limit	O
the	O
clinical	O
use	O
of	O
opioid	O
analgesics	O
and	O
complicate	O
withdrawal	O
from	O
opioid	B-Disease
addiction	I-Disease
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
the	O
effects	O
of	O
Re	B-Chemical
,	I-Chemical
Rg1	I-Chemical
,	I-Chemical
and	I-Chemical
Rb1	I-Chemical
ginsenosides	I-Chemical
,	O
the	O
bioactive	O
components	O
of	O
ginseng	O
,	O
on	O
OIH	B-Disease
.	O

OIH	B-Disease
was	O
achieved	O
in	O
mice	O
after	O
subcutaneous	O
administration	O
of	O
morphine	B-Chemical
for	O
7	O
consecutive	O
days	O
three	O
times	O
per	O
day	O
.	O

During	O
withdrawal	O
(	O
days	O
8	O
and	O
9	O
)	O
,	O
these	O
mice	O
were	O
administered	O
Re	B-Chemical
,	O
Rg1	B-Chemical
,	O
or	O
Rb1	B-Chemical
intragastrically	O
two	O
times	O
per	O
day	O
.	O

On	O
the	O
test	O
day	O
(	O
day	O
10	O
)	O
,	O
mice	O
were	O
subjected	O
to	O
the	O
thermal	O
sensitivity	O
test	O
and	O
the	O
acetic	B-Chemical
acid	I-Chemical
-	O
induced	O
writhing	O
test	O
.	O

Re	B-Chemical
(	O
300	O
mg	O
/	O
kg	O
)	O
inhibited	O
OIH	B-Disease
in	O
both	O
the	O
thermal	O
sensitivity	O
test	O
and	O
the	O
acetic	B-Chemical
acid	I-Chemical
-	O
induced	O
writhing	O
test	O
.	O

However	O
,	O
the	O
Rg1	B-Chemical
and	I-Chemical
Rb1	I-Chemical
ginsenosides	I-Chemical
failed	O
to	O
prevent	O
OIH	B-Disease
in	O
either	O
test	O
.	O

Furthermore	O
,	O
Rg1	B-Chemical
showed	O
a	O
tendency	O
to	O
aggravate	O
OIH	B-Disease
in	O
the	O
acetic	B-Chemical
acid	I-Chemical
-	O
induced	O
writhing	O
test	O
.	O

Our	O
data	O
suggested	O
that	O
the	O
ginsenoside	B-Chemical
Re	I-Chemical
,	O
but	O
not	O
Rg1	B-Chemical
or	O
Rb1	B-Chemical
,	O
may	O
contribute	O
toward	O
reversal	O
of	O
OIH	B-Disease
.	O

A	O
comparison	O
of	O
severe	O
hemodynamic	O
disturbances	O
between	O
dexmedetomidine	B-Chemical
and	O
propofol	B-Chemical
for	O
sedation	O
in	O
neurocritical	O
care	O
patients	O
.	O

OBJECTIVE	O
:	O
Dexmedetomidine	B-Chemical
and	O
propofol	B-Chemical
are	O
commonly	O
used	O
sedatives	O
in	O
neurocritical	O
care	O
as	O
they	O
allow	O
for	O
frequent	O
neurologic	O
examinations	O
.	O

However	O
,	O
both	O
agents	O
are	O
associated	O
with	O
significant	O
hemodynamic	O
side	O
effects	O
.	O

The	O
primary	O
objective	O
of	O
this	O
study	O
is	O
to	O
compare	O
the	O
prevalence	O
of	O
severe	O
hemodynamic	O
effects	O
in	O
neurocritical	O
care	O
patients	O
receiving	O
dexmedetomidine	B-Chemical
and	O
propofol	B-Chemical
.	O

DESIGN	O
:	O
Multicenter	O
,	O
retrospective	O
,	O
propensity	O
-	O
matched	O
cohort	O
study	O
.	O

SETTING	O
:	O
Neurocritical	O
care	O
units	O
at	O
two	O
academic	O
medical	O
centers	O
with	O
dedicated	O
neurocritical	O
care	O
teams	O
and	O
board	O
-	O
certified	O
neurointensivists	O
.	O

PATIENTS	O
:	O
Neurocritical	O
care	O
patients	O
admitted	O
between	O
July	O
2009	O
and	O
September	O
2012	O
were	O
evaluated	O
and	O
then	O
matched	O
1	O
:	O
1	O
based	O
on	O
propensity	O
scoring	O
of	O
baseline	O
characteristics	O
.	O

INTERVENTIONS	O
:	O
Continuous	O
sedation	O
with	O
dexmedetomidine	B-Chemical
or	O
propofol	B-Chemical
.	O

MEASUREMENTS	O
AND	O
MAIN	O
RESULTS	O
:	O
A	O
total	O
of	O
342	O
patients	O
(	O
105	O
dexmedetomidine	B-Chemical
and	O
237	O
propofol	B-Chemical
)	O
were	O
included	O
in	O
the	O
analysis	O
,	O
with	O
190	O
matched	O
(	O
95	O
in	O
each	O
group	O
)	O
by	O
propensity	O
score	O
.	O

The	O
primary	O
outcome	O
of	O
this	O
study	O
was	O
a	O
composite	O
of	O
severe	O
hypotension	B-Disease
(	O
mean	O
arterial	O
pressure	O
<	O
60	O
mm	O
Hg	O
)	O
and	O
bradycardia	B-Disease
(	O
heart	O
rate	O
<	O
50	O
beats	O
/	O
min	O
)	O
during	O
sedative	O
infusion	O
.	O

No	O
difference	O
in	O
the	O
primary	O
composite	O
outcome	O
in	O
both	O
the	O
unmatched	O
(	O
30	O
%	O
vs	O
30	O
%	O
,	O
p	O
=	O
0	O
.	O
94	O
)	O
or	O
matched	O
cohorts	O
(	O
28	O
%	O
vs	O
34	O
%	O
,	O
p	O
=	O
0	O
.	O
35	O
)	O
could	O
be	O
found	O
.	O

When	O
analyzed	O
separately	O
,	O
no	O
differences	O
could	O
be	O
found	O
in	O
the	O
prevalence	O
of	O
severe	O
hypotension	B-Disease
or	O
bradycardia	B-Disease
in	O
either	O
the	O
unmatched	O
or	O
matched	O
cohorts	O
.	O

CONCLUSIONS	O
:	O
Severe	O
hypotension	B-Disease
and	O
bradycardia	B-Disease
occur	O
at	O
similar	O
prevalence	O
in	O
neurocritical	O
care	O
patients	O
who	O
receive	O
dexmedetomidine	B-Chemical
or	O
propofol	B-Chemical
.	O

Providers	O
should	O
similarly	O
consider	O
the	O
likelihood	O
of	O
hypotension	B-Disease
or	O
bradycardia	B-Disease
before	O
starting	O
either	O
sedative	O
.	O

Hydroxytyrosol	B-Chemical
ameliorates	O
oxidative	O
stress	O
and	O
mitochondrial	B-Disease
dysfunction	I-Disease
in	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
in	O
rats	O
with	O
breast	B-Disease
cancer	I-Disease
.	O

Oxidative	O
stress	O
is	O
involved	O
in	O
several	O
processes	O
including	O
cancer	B-Disease
,	O
aging	O
and	O
cardiovascular	B-Disease
disease	I-Disease
,	O
and	O
has	O
been	O
shown	O
to	O
potentiate	O
the	O
therapeutic	O
effect	O
of	O
drugs	O
such	O
as	O
doxorubicin	B-Chemical
.	O

Doxorubicin	B-Chemical
causes	O
significant	O
cardiotoxicity	B-Disease
characterized	O
by	O
marked	O
increases	O
in	O
oxidative	O
stress	O
and	O
mitochondrial	B-Disease
dysfunction	I-Disease
.	O

Herein	O
,	O
we	O
investigate	O
whether	O
doxorubicin	B-Chemical
-	O
associated	O
chronic	O
cardiac	B-Disease
toxicity	I-Disease
can	O
be	O
ameliorated	O
with	O
the	O
antioxidant	O
hydroxytyrosol	B-Chemical
in	O
rats	O
with	O
breast	B-Disease
cancer	I-Disease
.	O

Thirty	O
-	O
six	O
rats	O
bearing	O
breast	B-Disease
tumors	I-Disease
induced	O
chemically	O
were	O
divided	O
into	O
4	O
groups	O
:	O
control	O
,	O
hydroxytyrosol	B-Chemical
(	O
0	O
.	O
5mg	O
/	O
kg	O
,	O
5days	O
/	O
week	O
)	O
,	O
doxorubicin	B-Chemical
(	O
1mg	O
/	O
kg	O
/	O
week	O
)	O
,	O
and	O
doxorubicin	B-Chemical
plus	O
hydroxytyrosol	B-Chemical
.	O

Cardiac	B-Disease
disturbances	I-Disease
at	O
the	O
cellular	O
and	O
mitochondrial	O
level	O
,	O
mitochondrial	O
electron	O
transport	O
chain	O
complexes	O
I	O
-	O
IV	O
and	O
apoptosis	O
-	O
inducing	O
factor	O
,	O
and	O
oxidative	O
stress	O
markers	O
have	O
been	O
analyzed	O
.	O

Hydroxytyrosol	B-Chemical
improved	O
the	O
cardiac	B-Disease
disturbances	I-Disease
enhanced	O
by	O
doxorubicin	B-Chemical
by	O
significantly	O
reducing	O
the	O
percentage	O
of	O
altered	O
mitochondria	O
and	O
oxidative	O
damage	O
.	O

These	O
results	O
suggest	O
that	O
hydroxytyrosol	B-Chemical
improve	O
the	O
mitochondrial	O
electron	O
transport	O
chain	O
.	O

This	O
study	O
demonstrates	O
that	O
hydroxytyrosol	B-Chemical
protect	O
rat	O
heart	B-Disease
damage	I-Disease
provoked	O
by	O
doxorubicin	B-Chemical
decreasing	O
oxidative	O
damage	O
and	O
mitochondrial	O
alterations	O
.	O

Amiodarone	B-Chemical
-	O
induced	O
myxoedema	B-Disease
coma	I-Disease
.	O

A	O
62	O
-	O
year	O
-	O
old	O
man	O
was	O
found	O
to	O
have	O
bradycardia	B-Disease
,	O
hypothermia	B-Disease
and	O
respiratory	B-Disease
failure	I-Disease
3	O
weeks	O
after	O
initiation	O
of	O
amiodarone	B-Chemical
therapy	O
for	O
atrial	B-Disease
fibrillation	I-Disease
.	O

Thyroid	O
-	O
stimulating	O
hormone	O
was	O
found	O
to	O
be	O
168	O
uIU	O
/	O
mL	O
(	O
nl	O
.	O
0	O
.	O
3	O
-	O
5	O
uIU	O
/	O
mL	O
)	O
and	O
free	O
thyroxine	B-Chemical
(	O
FT4	O
)	O
was	O
<	O
0	O
.	O
2	O
ng	O
/	O
dL	O
(	O
nl	O
.	O
0	O
.	O
8	O
-	O
1	O
.	O
8	O
ng	O
/	O
dL	O
)	O
.	O

He	O
received	O
intravenous	O
fluids	O
,	O
vasopressor	O
therapy	O
and	O
stress	O
dose	O
steroids	B-Chemical
;	O
he	O
was	O
intubated	O
and	O
admitted	O
to	O
the	O
intensive	O
care	O
unit	O
.	O

He	O
received	O
500	O
ug	O
of	O
intravenous	O
levothyroxine	B-Chemical
in	O
the	O
first	O
18	O
h	O
of	O
therapy	O
,	O
and	O
150	O
ug	O
intravenous	O
daily	O
thereafter	O
.	O

Haemodynamic	O
improvement	O
,	O
along	O
with	O
complete	O
recovery	O
of	O
mental	O
status	O
,	O
occurred	O
after	O
48	O
h	O
.	O

Twelve	O
hours	O
after	O
the	O
initiation	O
of	O
therapy	O
,	O
FT4	O
was	O
0	O
.	O
96	O
ng	O
/	O
dL	O
.	O

The	O
patient	O
was	O
maintained	O
on	O
levothyroxine	B-Chemical
175	O
(	O
g	O
POorally	O
daily	O
.	O

A	O
thyroid	O
ultrasound	O
showed	O
diffuse	O
heterogeneity	O
.	O

The	O
24	O
hour	O
excretion	O
of	O
iodine	B-Chemical
was	O
3657	O
(	O
mcg	O
(	O
25	O
-	O
756	O
(	O
mcg	O
)	O
.	O

The	O
only	O
two	O
cases	O
of	O
amiodarone	B-Chemical
-	O
induced	O
myxoedema	B-Disease
coma	I-Disease
in	O
the	O
literature	O
report	O
patient	O
death	O
despite	O
supportive	O
therapy	O
and	O
thyroid	O
hormone	O
replacement	O
.	O

This	O
case	O
represents	O
the	O
most	O
thoroughly	O
investigated	O
case	O
of	O
amiodarone	B-Chemical
-	O
induced	O
myxoedema	B-Disease
coma	I-Disease
with	O
a	O
history	O
significant	O
for	O
subclinical	O
thyroid	B-Disease
disease	I-Disease
.	O

Use	O
of	O
argatroban	B-Chemical
and	O
catheter	O
-	O
directed	O
thrombolysis	B-Disease
with	O
alteplase	O
in	O
an	O
oncology	O
patient	O
with	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
with	O
thrombosis	B-Disease
.	O

PURPOSE	O
:	O
The	O
case	O
of	O
an	O
oncology	O
patient	O
who	O
developed	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
with	O
thrombosis	B-Disease
(	O
HITT	B-Disease
)	O
and	O
was	O
treated	O
with	O
argatroban	B-Chemical
plus	O
catheter	O
-	O
directed	O
thrombolysis	B-Disease
(	O
CDT	O
)	O
with	O
alteplase	O
is	O
presented	O
.	O

SUMMARY	O
:	O
A	O
63	O
-	O
year	O
-	O
old	O
Caucasian	O
man	O
with	O
renal	O
amyloidosis	B-Disease
undergoing	O
peripheral	O
blood	O
stem	O
cell	O
collection	O
for	O
an	O
autologous	O
stem	O
cell	O
transplant	O
developed	O
extensive	O
bilateral	O
upper	B-Disease
-	I-Disease
extremity	I-Disease
deep	I-Disease
venous	I-Disease
thrombosis	I-Disease
(	O
DVT	B-Disease
)	O
and	O
pulmonary	B-Disease
embolism	I-Disease
secondary	O
to	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
.	O

A	O
continuous	O
i	O
.	O
v	O
.	O
infusion	O
of	O
argatroban	B-Chemical
was	O
initiated	O
,	O
and	O
the	O
patient	O
was	O
managed	O
on	O
the	O
general	O
medical	O
floor	O
.	O

After	O
one	O
week	O
of	O
therapy	O
,	O
he	O
was	O
transferred	O
to	O
the	O
intensive	O
care	O
unit	O
with	O
cardiopulmonary	O
compromise	O
related	O
to	O
superior	B-Disease
vena	I-Disease
cava	I-Disease
(	I-Disease
SVC	I-Disease
)	I-Disease
syndrome	I-Disease
.	O

A	O
percutaneous	O
mechanical	O
thrombectomy	O
and	O
CDT	O
with	O
alteplase	O
were	O
attempted	O
,	O
but	O
the	O
procedure	O
was	O
aborted	O
due	O
to	O
epistaxis	B-Disease
.	O

The	O
epistaxis	B-Disease
resolved	O
the	O
next	O
day	O
,	O
and	O
the	O
patient	O
was	O
restarted	O
on	O
argatroban	B-Chemical
.	O

A	O
second	O
percutaneous	O
mechanical	O
thrombectomy	O
was	O
performed	O
six	O
days	O
later	O
and	O
resulted	O
in	O
partial	O
revascularization	O
of	O
the	O
SVC	O
and	O
central	O
veins	O
.	O

Postthrombectomy	O
continuous	O
CDT	O
with	O
alteplase	O
was	O
commenced	O
while	O
argatroban	B-Chemical
was	O
withheld	O
,	O
and	O
complete	O
patency	O
of	O
the	O
SVC	O
and	O
central	O
veins	O
was	O
achieved	O
after	O
three	O
days	O
of	O
therapy	O
.	O

Alteplase	O
was	O
discontinued	O
,	O
and	O
the	O
patient	O
was	O
reinitiated	O
on	O
argatroban	B-Chemical
;	O
ultimately	O
,	O
he	O
was	O
transitioned	O
to	O
warfarin	B-Chemical
for	O
long	O
-	O
term	O
anticoagulation	O
.	O

Although	O
the	O
patient	O
recovered	O
,	O
he	O
experienced	O
permanent	O
vision	B-Disease
and	I-Disease
hearing	I-Disease
loss	I-Disease
,	O
as	O
well	O
as	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
.	O

CONCLUSION	O
:	O
A	O
63	O
-	O
year	O
-	O
old	O
man	O
with	O
renal	O
amyloidosis	B-Disease
and	O
SVC	B-Disease
syndrome	I-Disease
secondary	O
to	O
HITT	B-Disease
was	O
successfully	O
treated	O
with	O
argatroban	B-Chemical
and	O
CDT	O
with	O
alteplase	O
.	O

Effects	O
of	O
dehydroepiandrosterone	B-Chemical
in	O
amphetamine	B-Chemical
-	O
induced	O
schizophrenia	B-Disease
models	O
in	O
mice	O
.	O

OBJECTIVE	O
:	O
To	O
examine	O
the	O
effects	O
of	O
dehydroepiandrosterone	B-Chemical
(	O
DHEA	B-Chemical
)	O
on	O
animal	O
models	O
of	O
schizophrenia	B-Disease
.	O

METHODS	O
:	O
Seventy	O
Swiss	O
albino	O
female	O
mice	O
(	O
25	O
-	O
35	O
g	O
)	O
were	O
divided	O
into	O
4	O
groups	O
:	O
amphetamine	B-Chemical
-	O
free	O
(	O
control	O
)	O
,	O
amphetamine	B-Chemical
,	O
50	O
,	O
and	O
100	O
mg	O
/	O
kg	O
DHEA	B-Chemical
.	O

The	O
DHEA	B-Chemical
was	O
administered	O
intraperitoneally	O
(	O
ip	O
)	O
for	O
5	O
days	O
.	O

Amphetamine	B-Chemical
(	O
3	O
mg	O
/	O
kg	O
ip	O
)	O
induced	O
hyper	B-Disease
locomotion	O
,	O
apomorphine	B-Chemical
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
subcutaneously	O
[	O
sc	O
]	O
)	O
induced	O
climbing	O
,	O
and	O
haloperidol	B-Chemical
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
sc	O
)	O
induced	O
catalepsy	B-Disease
tests	O
were	O
used	O
as	O
animal	O
models	O
of	O
schizophrenia	B-Disease
.	O

The	O
study	O
was	O
conducted	O
at	O
the	O
Animal	O
Experiment	O
Laboratories	O
,	O
Department	O
of	O
Pharmacology	O
,	O
Medical	O
School	O
,	O
Eskisehir	O
Osmangazi	O
University	O
,	O
Eskisehir	O
,	O
Turkey	O
between	O
March	O
and	O
May	O
2012	O
.	O

Statistical	O
analysis	O
was	O
carried	O
out	O
using	O
Kruskal	O
-	O
Wallis	O
test	O
for	O
hyper	B-Disease
locomotion	O
,	O
and	O
one	O
-	O
way	O
ANOVA	O
for	O
climbing	O
and	O
catalepsy	B-Disease
tests	O
.	O

RESULTS	O
:	O
In	O
the	O
amphetamine	B-Chemical
-	O
induced	O
locomotion	O
test	O
,	O
there	O
were	O
significant	O
increases	O
in	O
all	O
movements	O
compared	O
with	O
the	O
amphetamine	B-Chemical
-	O
free	O
group	O
.	O

Both	O
DHEA	B-Chemical
50	O
mg	O
/	O
kg	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
and	O
100	O
mg	O
/	O
kg	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
significantly	O
decreased	O
all	O
movements	O
compared	O
with	O
the	O
amphetamine	B-Chemical
-	O
induced	O
locomotion	O
group	O
.	O

There	O
was	O
a	O
significant	O
difference	O
between	O
groups	O
in	O
the	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
test	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

There	O
was	O
no	O
significant	O
difference	O
between	O
groups	O
in	O
terms	O
of	O
total	O
climbing	O
time	O
in	O
the	O
apomorphine	B-Chemical
-	O
induced	O
climbing	O
test	O
(	O
p	O
>	O
0	O
.	O
05	O
)	O
.	O

CONCLUSION	O
:	O
We	O
observed	O
that	O
DHEA	B-Chemical
reduced	O
locomotor	O
activity	O
and	O
increased	O
catalepsy	B-Disease
at	O
both	O
doses	O
,	O
while	O
it	O
had	O
no	O
effect	O
on	O
climbing	O
behavior	O
.	O

We	O
suggest	O
that	O
DHEA	B-Chemical
displays	O
typical	O
neuroleptic	O
-	O
like	O
effects	O
,	O
and	O
may	O
be	O
used	O
in	O
the	O
treatment	O
of	O
schizophrenia	B-Disease
.	O

Availability	O
of	O
human	O
induced	O
pluripotent	O
stem	O
cell	O
-	O
derived	O
cardiomyocytes	O
in	O
assessment	O
of	O
drug	O
potential	O
for	O
QT	B-Disease
prolongation	I-Disease
.	O

Field	O
potential	O
duration	O
(	O
FPD	O
)	O
in	O
human	O
-	O
induced	O
pluripotent	O
stem	O
cell	O
-	O
derived	O
cardiomyocytes	O
(	O
hiPS	O
-	O
CMs	O
)	O
,	O
which	O
can	O
express	O
QT	O
interval	O
in	O
an	O
electrocardiogram	O
,	O
is	O
reported	O
to	O
be	O
a	O
useful	O
tool	O
to	O
predict	O
K	B-Chemical
(	O
+	O
)	O
channel	O
and	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
channel	O
blocker	O
effects	O
on	O
QT	O
interval	O
.	O

However	O
,	O
there	O
is	O
no	O
report	O
showing	O
that	O
this	O
technique	O
can	O
be	O
used	O
to	O
predict	O
multichannel	O
blocker	O
potential	O
for	O
QT	B-Disease
prolongation	I-Disease
.	O

The	O
aim	O
of	O
this	O
study	O
is	O
to	O
show	O
that	O
FPD	O
from	O
MEA	O
(	O
Multielectrode	O
array	O
)	O
of	O
hiPS	O
-	O
CMs	O
can	O
detect	O
QT	B-Disease
prolongation	I-Disease
induced	O
by	O
multichannel	O
blockers	O
.	O

hiPS	O
-	O
CMs	O
were	O
seeded	O
onto	O
MEA	O
and	O
FPD	O
was	O
measured	O
for	O
2min	O
every	O
10min	O
for	O
30min	O
after	O
drug	O
exposure	O
for	O
the	O
vehicle	O
and	O
each	O
drug	O
concentration	O
.	O

IKr	O
and	O
IKs	O
blockers	O
concentration	O
-	O
dependently	O
prolonged	O
corrected	O
FPD	O
(	O
FPDc	O
)	O
,	O
whereas	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
channel	O
blockers	O
concentration	O
-	O
dependently	O
shortened	O
FPDc	O
.	O

Also	O
,	O
the	O
multichannel	O
blockers	O
Amiodarone	B-Chemical
,	O
Paroxetine	B-Chemical
,	O
Terfenadine	B-Chemical
and	O
Citalopram	B-Chemical
prolonged	O
FPDc	O
in	O
a	O
concentration	O
dependent	O
manner	O
.	O

Finally	O
,	O
the	O
IKr	O
blockers	O
,	O
Terfenadine	B-Chemical
and	O
Citalopram	B-Chemical
,	O
which	O
are	O
reported	O
to	O
cause	O
Torsade	B-Disease
de	I-Disease
Pointes	I-Disease
(	O
TdP	B-Disease
)	O
in	O
clinical	O
practice	O
,	O
produced	O
early	O
afterdepolarization	O
(	O
EAD	O
)	O
.	O

hiPS	O
-	O
CMs	O
using	O
MEA	O
system	O
and	O
FPDc	O
can	O
predict	O
the	O
effects	O
of	O
drug	O
candidates	O
on	O
QT	O
interval	O
.	O

This	O
study	O
also	O
shows	O
that	O
this	O
assay	O
can	O
help	O
detect	O
EAD	O
for	O
drugs	O
with	O
TdP	B-Disease
potential	O
.	O

Dermal	O
developmental	O
toxicity	B-Disease
of	O
N	O
-	O
phenylimide	O
herbicides	O
in	O
rats	O
.	O

BACKGROUND	O
:	O
S	B-Chemical
-	I-Chemical
53482	I-Chemical
and	O
S	B-Chemical
-	I-Chemical
23121	I-Chemical
are	O
N	O
-	O
phenylimide	O
herbicides	O
and	O
produced	O
embryolethality	B-Disease
,	O
teratogenicity	B-Disease
(	O
mainly	O
ventricular	B-Disease
septal	I-Disease
defects	I-Disease
and	O
wavy	O
ribs	O
)	O
,	O
and	O
growth	B-Disease
retardation	I-Disease
in	O
rats	O
in	O
conventional	O
oral	O
developmental	O
toxicity	B-Disease
studies	O
.	O

Our	O
objective	O
in	O
this	O
study	O
was	O
to	O
investigate	O
whether	O
the	O
compounds	O
induce	O
developmental	O
toxicity	B-Disease
via	O
the	O
dermal	O
route	O
,	O
which	O
is	O
more	O
relevant	O
to	O
occupational	O
exposure	O
,	O
hence	O
better	O
addressing	O
human	O
health	O
risks	O
.	O

METHODS	O
:	O
S	B-Chemical
-	I-Chemical
53482	I-Chemical
was	O
administered	O
dermally	O
to	O
rats	O
at	O
30	O
,	O
100	O
,	O
and	O
300	O
mg	O
/	O
kg	O
during	O
organogenesis	O
,	O
and	O
S	B-Chemical
-	I-Chemical
23121	I-Chemical
was	O
administered	O
at	O
200	O
,	O
400	O
,	O
and	O
800	O
mg	O
/	O
kg	O
(	O
the	O
maximum	O
applicable	O
dose	O
level	O
)	O
.	O

Fetuses	O
were	O
obtained	O
by	O
a	O
Cesarean	O
section	O
and	O
examined	O
for	O
external	O
,	O
visceral	O
,	O
and	O
skeletal	O
alterations	O
.	O

RESULTS	O
:	O
Dermal	O
exposure	O
of	O
rats	O
to	O
S	B-Chemical
-	I-Chemical
53482	I-Chemical
at	O
300	O
mg	O
/	O
kg	O
produced	O
patterns	O
of	O
developmental	O
toxicity	B-Disease
similar	O
to	O
those	O
resulting	O
from	O
oral	O
exposure	O
.	O

Toxicity	B-Disease
included	O
embryolethality	B-Disease
,	O
teratogenicity	B-Disease
,	O
and	O
growth	B-Disease
retardation	I-Disease
.	O

Dermal	O
administration	O
of	O
S	B-Chemical
-	I-Chemical
23121	I-Chemical
at	O
800	O
mg	O
/	O
kg	O
resulted	O
in	O
an	O
increased	O
incidence	O
of	O
embryonic	B-Disease
death	I-Disease
and	O
ventricular	B-Disease
septal	I-Disease
defect	I-Disease
,	O
but	O
retarded	O
fetal	O
growth	O
was	O
not	O
observed	O
as	O
it	O
was	O
following	O
oral	O
exposure	O
to	O
S	B-Chemical
-	I-Chemical
23121	I-Chemical
.	O

CONCLUSIONS	O
:	O
Based	O
on	O
the	O
results	O
,	O
S	B-Chemical
-	I-Chemical
53482	I-Chemical
and	O
S	B-Chemical
-	I-Chemical
23121	I-Chemical
were	O
teratogenic	B-Disease
when	O
administered	O
dermally	O
to	O
pregnant	O
rats	O
as	O
were	O
the	O
compounds	O
administered	O
orally	O
.	O

Thus	O
,	O
investigation	O
of	O
the	O
mechanism	O
and	O
its	O
human	O
relevancy	O
become	O
more	O
important	O
.	O

Rates	O
of	O
Renal	B-Disease
Toxicity	I-Disease
in	O
Cancer	B-Disease
Patients	O
Receiving	O
Cisplatin	B-Chemical
With	O
and	O
Without	O
Mannitol	B-Chemical
.	O

BACKGROUND	O
:	O
Cisplatin	B-Chemical
is	O
a	O
widely	O
used	O
antineoplastic	O
.	O

One	O
of	O
the	O
major	O
complications	O
of	O
cisplatin	B-Chemical
use	O
is	O
dose	O
-	O
limiting	O
nephrotoxicity	B-Disease
.	O

There	O
are	O
many	O
strategies	O
to	O
prevent	O
this	O
toxicity	B-Disease
,	O
including	O
the	O
use	O
of	O
mannitol	B-Chemical
as	O
a	O
nephroprotectant	O
in	O
combination	O
with	O
hydration	O
.	O

OBJECTIVE	O
:	O
We	O
aimed	O
to	O
evaluate	O
the	O
rates	O
of	O
cisplatin	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
in	O
cancer	B-Disease
patients	O
receiving	O
single	O
-	O
agent	O
cisplatin	B-Chemical
with	O
and	O
without	O
mannitol	B-Chemical
.	O

METHODS	O
:	O
This	O
single	O
-	O
center	O
retrospective	O
analysis	O
was	O
a	O
quasi	O
experiment	O
created	O
by	O
the	O
national	O
mannitol	B-Chemical
shortage	O
.	O

Data	O
were	O
collected	O
on	O
adult	O
cancer	B-Disease
patients	O
receiving	O
single	O
-	O
agent	O
cisplatin	B-Chemical
as	O
an	O
outpatient	O
from	O
January	O
2011	O
to	O
September	O
2012	O
.	O

The	O
primary	O
outcome	O
was	O
acute	B-Disease
kidney	I-Disease
injury	I-Disease
(	O
AKI	B-Disease
)	O
.	O

RESULTS	O
:	O
We	O
evaluated	O
143	O
patients	O
who	O
received	O
single	O
-	O
agent	O
cisplatin	B-Chemical
;	O
97	O
.	O
2	O
%	O
of	O
patients	O
had	O
head	B-Disease
and	I-Disease
neck	I-Disease
cancer	I-Disease
as	O
their	O
primary	O
malignancy	B-Disease
.	O

Patients	O
who	O
did	O
not	O
receive	O
mannitol	B-Chemical
were	O
more	O
likely	O
to	O
develop	O
nephrotoxicity	B-Disease
:	O
odds	O
ratio	O
[	O
OR	O
]	O
=	O
2	O
.	O
646	O
(	O
95	O
%	O
CI	O
=	O
1	O
.	O
008	O
,	O
6	O
.	O
944	O
;	O
P	O
=	O
0	O
.	O
048	O
)	O
.	O

Patients	O
who	O
received	O
the	O
100	O
mg	O
/	O
m	O
(	O
2	O
)	O
dosing	O
and	O
patients	O
who	O
had	O
a	O
history	O
of	O
hypertension	B-Disease
also	O
had	O
a	O
higher	O
likelihood	O
of	O
developing	O
nephrotoxicity	B-Disease
:	O
OR	O
=	O
11	O
.	O
494	O
(	O
95	O
%	O
CI	O
=	O
4	O
.	O
149	O
,	O
32	O
.	O
258	O
;	O
P	O
<	O
0	O
.	O
0001	O
)	O
and	O
OR	O
=	O
3	O
.	O
219	O
(	O
95	O
%	O
CI	O
=	O
1	O
.	O
228	O
,	O
8	O
.	O
439	O
;	O
P	O
=	O
0	O
.	O
017	O
)	O
,	O
respectively	O
.	O

CONCLUSIONS	O
:	O
When	O
limited	O
quantities	O
of	O
mannitol	B-Chemical
are	O
available	O
,	O
it	O
should	O
preferentially	O
be	O
given	O
to	O
patients	O
at	O
particularly	O
high	O
risk	O
of	O
nephrotoxicity	B-Disease
.	O

Our	O
analysis	O
suggests	O
that	O
those	O
patients	O
receiving	O
the	O
dosing	O
schedule	O
of	O
100	O
mg	O
/	O
m	O
(	O
2	O
)	O
cisplatin	B-Chemical
every	O
3	O
weeks	O
and	O
those	O
with	O
hypertension	B-Disease
are	O
at	O
the	O
greatest	O
risk	O
of	O
nephrotoxicity	B-Disease
and	O
would	O
benefit	O
from	O
the	O
addition	O
of	O
mannitol	B-Chemical
.	O

Metformin	B-Chemical
protects	O
against	O
seizures	B-Disease
,	O
learning	B-Disease
and	I-Disease
memory	I-Disease
impairments	I-Disease
and	O
oxidative	O
damage	O
induced	O
by	O
pentylenetetrazole	B-Chemical
-	O
induced	O
kindling	O
in	O
mice	O
.	O

Cognitive	B-Disease
impairment	I-Disease
,	O
the	O
most	O
common	O
and	O
severe	O
comorbidity	O
of	O
epilepsy	B-Disease
,	O
greatly	O
diminishes	O
the	O
quality	O
of	O
life	O
.	O

However	O
,	O
current	O
therapeutic	O
interventions	O
for	O
epilepsy	B-Disease
can	O
also	O
cause	O
untoward	O
cognitive	O
effects	O
.	O

Thus	O
,	O
there	O
is	O
an	O
urgent	O
need	O
for	O
new	O
kinds	O
of	O
agents	O
targeting	O
both	O
seizures	B-Disease
and	O
cognition	B-Disease
deficits	I-Disease
.	O

Oxidative	O
stress	O
is	O
considered	O
to	O
play	O
an	O
important	O
role	O
in	O
epileptogenesis	O
and	O
cognitive	B-Disease
deficits	I-Disease
,	O
and	O
antioxidants	O
have	O
a	O
putative	O
antiepileptic	O
potential	O
.	O

Metformin	B-Chemical
,	O
the	O
most	O
commonly	O
prescribed	O
antidiabetic	O
oral	O
drug	O
,	O
has	O
antioxidant	O
properties	O
.	O

This	O
study	O
was	O
designed	O
to	O
evaluate	O
the	O
ameliorative	O
effects	O
of	O
metformin	B-Chemical
on	O
seizures	B-Disease
,	O
cognitive	B-Disease
impairment	I-Disease
and	O
brain	O
oxidative	O
stress	O
markers	O
observed	O
in	O
pentylenetetrazole	B-Chemical
-	O
induced	O
kindling	O
animals	O
.	O

Male	O
C57BL	O
/	O
6	O
mice	O
were	O
administered	O
with	O
subconvulsive	O
dose	O
of	O
pentylenetetrazole	B-Chemical
(	O
37	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
every	O
other	O
day	O
for	O
14	O
injections	O
.	O

Metformin	B-Chemical
was	O
injected	O
intraperitoneally	O
in	O
dose	O
of	O
200mg	O
/	O
kg	O
along	O
with	O
alternate	O
-	O
day	O
PTZ	B-Chemical
.	O

We	O
found	O
that	O
metformin	B-Chemical
suppressed	O
the	O
progression	O
of	O
kindling	O
,	O
ameliorated	O
the	O
cognitive	B-Disease
impairment	I-Disease
and	O
decreased	O
brain	O
oxidative	O
stress	O
.	O

Thus	O
the	O
present	O
study	O
concluded	O
that	O
metformin	B-Chemical
may	O
be	O
a	O
potential	O
agent	O
for	O
the	O
treatment	O
of	O
epilepsy	B-Disease
as	O
well	O
as	O
a	O
protective	O
medicine	O
against	O
cognitive	B-Disease
impairment	I-Disease
induced	O
by	O
seizures	B-Disease
.	O

P53	O
inhibition	O
exacerbates	O
late	O
-	O
stage	O
anthracycline	B-Chemical
cardiotoxicity	B-Disease
.	O

AIMS	O
:	O
Doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
is	O
an	O
effective	O
anti	O
-	O
cancer	B-Disease
therapeutic	O
,	O
but	O
is	O
associated	O
with	O
both	O
acute	O
and	O
late	O
-	O
stage	O
cardiotoxicity	B-Disease
.	O

Children	O
are	O
particularly	O
sensitive	O
to	O
DOX	B-Chemical
-	O
induced	O
heart	B-Disease
failure	I-Disease
.	O

Here	O
,	O
the	O
impact	O
of	O
p53	O
inhibition	O
on	O
acute	O
vs	O
.	O
late	O
-	O
stage	O
DOX	B-Chemical
cardiotoxicity	B-Disease
was	O
examined	O
in	O
a	O
juvenile	O
model	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
Two	O
-	O
week	O
-	O
old	O
MHC	O
-	O
CB7	O
mice	O
(	O
which	O
express	O
dominant	O
-	O
interfering	O
p53	O
in	O
cardiomyocytes	O
)	O
and	O
their	O
non	O
-	O
transgenic	O
(	O
NON	O
-	O
TXG	O
)	O
littermates	O
received	O
weekly	O
DOX	B-Chemical
injections	O
for	O
5	O
weeks	O
(	O
25	O
mg	O
/	O
kg	O
cumulative	O
dose	O
)	O
.	O

One	O
week	O
after	O
the	O
last	O
DOX	B-Chemical
treatment	O
(	O
acute	O
stage	O
)	O
,	O
MHC	O
-	O
CB7	O
mice	O
exhibited	O
improved	O
cardiac	O
function	O
and	O
lower	O
levels	O
of	O
cardiomyocyte	O
apoptosis	O
when	O
compared	O
with	O
the	O
NON	O
-	O
TXG	O
mice	O
.	O

Surprisingly	O
,	O
by	O
13	O
weeks	O
following	O
the	O
last	O
DOX	B-Chemical
treatment	O
(	O
late	O
stage	O
)	O
,	O
MHC	O
-	O
CB7	O
exhibited	O
a	O
progressive	O
decrease	O
in	O
cardiac	O
function	O
and	O
higher	O
rates	O
of	O
cardiomyocyte	O
apoptosis	O
when	O
compared	O
with	O
NON	O
-	O
TXG	O
mice	O
.	O

p53	O
inhibition	O
blocked	O
transient	O
DOX	B-Chemical
-	O
induced	O
STAT3	O
activation	O
in	O
MHC	O
-	O
CB7	O
mice	O
,	O
which	O
was	O
associated	O
with	O
enhanced	O
induction	O
of	O
the	O
DNA	O
repair	O
proteins	O
Ku70	O
and	O
Ku80	O
.	O

Mice	O
with	O
cardiomyocyte	O
-	O
restricted	O
deletion	O
of	O
STAT3	O
exhibited	O
worse	O
cardiac	O
function	O
,	O
higher	O
levels	O
of	O
cardiomyocyte	O
apoptosis	O
,	O
and	O
a	O
greater	O
induction	O
of	O
Ku70	O
and	O
Ku80	O
in	O
response	O
to	O
DOX	B-Chemical
treatment	O
during	O
the	O
acute	O
stage	O
when	O
compared	O
with	O
control	O
animals	O
.	O

CONCLUSION	O
:	O
These	O
data	O
support	O
a	O
model	O
wherein	O
a	O
p53	O
-	O
dependent	O
cardioprotective	O
pathway	O
,	O
mediated	O
via	O
STAT3	O
activation	O
,	O
mitigates	O
DOX	B-Chemical
-	O
induced	O
myocardial	O
stress	O
during	O
drug	O
delivery	O
.	O

Furthermore	O
,	O
these	O
data	O
suggest	O
an	O
explanation	O
as	O
to	O
how	O
p53	O
inhibition	O
can	O
result	O
in	O
cardioprotection	O
during	O
drug	O
treatment	O
and	O
,	O
paradoxically	O
,	O
enhanced	O
cardiotoxicity	B-Disease
long	O
after	O
the	O
cessation	O
of	O
drug	O
treatment	O
.	O

Metronidazole	B-Chemical
-	O
induced	O
encephalopathy	B-Disease
:	O
an	O
uncommon	O
scenario	O
.	O

Metronidazole	B-Chemical
can	O
produce	O
neurological	O
complications	O
although	O
it	O
is	O
not	O
a	O
common	O
scenario	O
.	O

We	O
present	O
a	O
case	O
where	O
a	O
patient	O
developed	O
features	O
of	O
encephalopathy	B-Disease
following	O
prolonged	O
metronidazole	B-Chemical
intake	O
.	O

Magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
brain	O
showed	O
abnormal	O
signal	O
intensity	O
involving	O
both	O
dentate	O
nuclei	O
of	O
cerebellum	O
and	O
splenium	O
of	O
corpus	O
callosum	O
.	O

The	O
diagnosis	O
of	O
metronidazole	B-Chemical
toxicity	B-Disease
was	O
made	O
by	O
the	O
MRI	O
findings	O
and	O
supported	O
clinically	O
.	O

Aconitine	B-Chemical
-	O
induced	O
Ca2	B-Chemical
+	O
overload	O
causes	O
arrhythmia	B-Disease
and	O
triggers	O
apoptosis	O
through	O
p38	O
MAPK	O
signaling	O
pathway	O
in	O
rats	O
.	O

Aconitine	B-Chemical
is	O
a	O
major	O
bioactive	O
diterpenoid	O
alkaloid	O
with	O
high	O
content	O
derived	O
from	O
herbal	O
aconitum	O
plants	O
.	O

Emerging	O
evidence	O
indicates	O
that	O
voltage	O
-	O
dependent	O
Na	B-Chemical
(	O
+	O
)	O
channels	O
have	O
pivotal	O
roles	O
in	O
the	O
cardiotoxicity	B-Disease
of	O
aconitine	B-Chemical
.	O

However	O
,	O
no	O
reports	O
are	O
available	O
on	O
the	O
role	O
of	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
in	O
aconitine	B-Chemical
poisoning	B-Disease
.	O

In	O
this	O
study	O
,	O
we	O
explored	O
the	O
importance	O
of	O
pathological	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
signaling	O
in	O
aconitine	B-Chemical
poisoning	B-Disease
in	O
vitro	O
and	O
in	O
vivo	O
.	O

We	O
found	O
that	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
overload	O
lead	O
to	O
accelerated	O
beating	O
rhythm	O
in	O
adult	O
rat	O
ventricular	O
myocytes	O
and	O
caused	O
arrhythmia	B-Disease
in	O
conscious	O
freely	O
moving	O
rats	O
.	O

To	O
investigate	O
effects	O
of	O
aconitine	B-Chemical
on	O
myocardial	B-Disease
injury	I-Disease
,	O
we	O
performed	O
cytotoxicity	B-Disease
assay	O
in	O
neonatal	O
rat	O
ventricular	O
myocytes	O
(	O
NRVMs	O
)	O
,	O
as	O
well	O
as	O
measured	O
lactate	B-Chemical
dehydrogenase	O
level	O
in	O
the	O
culture	O
medium	O
of	O
NRVMs	O
and	O
activities	O
of	O
serum	O
cardiac	O
enzymes	O
in	O
rats	O
.	O

The	O
results	O
showed	O
that	O
aconitine	B-Chemical
resulted	O
in	O
myocardial	B-Disease
injury	I-Disease
and	O
reduced	O
NRVMs	O
viability	O
dose	O
-	O
dependently	O
.	O

To	O
confirm	O
the	O
pro	O
-	O
apoptotic	O
effects	O
,	O
we	O
performed	O
flow	O
cytometric	O
detection	O
,	O
cardiac	O
histology	O
,	O
transmission	O
electron	O
microscopy	O
and	O
terminal	O
deoxynucleotidyl	O
transferase	O
-	O
mediated	O
dUTP	B-Chemical
-	O
biotin	B-Chemical
nick	O
end	O
labeling	O
assay	O
.	O

The	O
results	O
showed	O
that	O
aconitine	B-Chemical
stimulated	O
apoptosis	O
time	O
-	O
dependently	O
.	O

The	O
expression	O
analysis	O
of	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
handling	O
proteins	O
demonstrated	O
that	O
aconitine	B-Chemical
promoted	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
overload	O
through	O
the	O
expression	O
regulation	O
of	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
handling	O
proteins	O
.	O

The	O
expression	O
analysis	O
of	O
apoptosis	O
-	O
related	O
proteins	O
revealed	O
that	O
pro	O
-	O
apoptotic	O
protein	O
expression	O
was	O
upregulated	O
,	O
and	O
anti	O
-	O
apoptotic	O
protein	O
BCL	O
-	O
2	O
expression	O
was	O
downregulated	O
.	O

Furthermore	O
,	O
increased	O
phosphorylation	O
of	O
MAPK	O
family	O
members	O
,	O
especially	O
the	O
P	O
-	O
P38	O
/	O
P38	O
ratio	O
was	O
found	O
in	O
cardiac	O
tissues	O
.	O

Hence	O
,	O
our	O
results	O
suggest	O
that	O
aconitine	B-Chemical
significantly	O
aggravates	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
overload	O
and	O
causes	O
arrhythmia	B-Disease
and	O
finally	O
promotes	O
apoptotic	O
development	O
via	O
phosphorylation	O
of	O
P38	O
mitogen	O
-	O
activated	O
protein	O
kinase	O
.	O

Chronic	O
treatment	O
with	O
metformin	B-Chemical
suppresses	O
toll	O
-	O
like	O
receptor	O
4	O
signaling	O
and	O
attenuates	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
following	O
myocardial	B-Disease
infarction	I-Disease
.	O

Acute	O
treatment	O
with	O
metformin	B-Chemical
has	O
a	O
protective	O
effect	O
in	O
myocardial	B-Disease
infarction	I-Disease
by	O
suppression	O
of	O
inflammatory	O
responses	O
due	O
to	O
activation	O
of	O
AMP	B-Chemical
-	O
activated	O
protein	O
kinase	O
(	O
AMPK	O
)	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
effect	O
of	O
chronic	O
pre	O
-	O
treatment	O
with	O
metformin	B-Chemical
on	O
cardiac	B-Disease
dysfunction	I-Disease
and	O
toll	O
-	O
like	O
receptor	O
4	O
(	O
TLR4	O
)	O
activities	O
following	O
myocardial	B-Disease
infarction	I-Disease
and	O
their	O
relation	O
with	O
AMPK	O
were	O
assessed	O
.	O

Male	O
Wistar	O
rats	O
were	O
randomly	O
assigned	O
to	O
one	O
of	O
5	O
groups	O
(	O
n	O
=	O
6	O
)	O
:	O
normal	O
control	O
and	O
groups	O
were	O
injected	O
isoproterenol	B-Chemical
after	O
chronic	O
pre	O
-	O
treatment	O
with	O
0	O
,	O
25	O
,	O
50	O
,	O
or	O
100mg	O
/	O
kg	O
of	O
metformin	B-Chemical
twice	O
daily	O
for	O
14	O
days	O
.	O

Isoproterenol	B-Chemical
(	O
100mg	O
/	O
kg	O
)	O
was	O
injected	O
subcutaneously	O
on	O
the	O
13th	O
and	O
14th	O
days	O
to	O
induce	O
acute	B-Disease
myocardial	I-Disease
infarction	I-Disease
.	O

Isoproterenol	B-Chemical
alone	O
decreased	O
left	O
ventricular	O
systolic	O
pressure	O
and	O
myocardial	O
contractility	O
indexed	O
as	O
LVdp	O
/	O
dtmax	O
and	O
LVdp	O
/	O
dtmin	O
.	O

The	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
was	O
significantly	O
lower	O
in	O
the	O
groups	O
treated	O
with	O
25	O
and	O
50mg	O
/	O
kg	O
of	O
metformin	B-Chemical
.	O

Metfromin	O
markedly	O
lowered	O
isoproterenol	B-Chemical
-	O
induced	O
elevation	O
in	O
the	O
levels	O
of	O
TLR4	O
mRNA	O
,	O
myeloid	O
differentiation	O
protein	O
88	O
(	O
MyD88	O
)	O
,	O
tumor	B-Disease
necrosis	B-Disease
factor	O
-	O
alpha	O
(	O
TNF	O
-	O
a	O
)	O
,	O
and	O
interleukin	O
6	O
(	O
IL	O
-	O
6	O
)	O
in	O
the	O
heart	O
tissues	O
.	O

Similar	O
changes	O
were	O
also	O
seen	O
in	O
the	O
serum	O
levels	O
of	O
TNF	O
-	O
a	O
and	O
IL	O
-	O
6	O
.	O

However	O
,	O
the	O
lower	O
doses	O
of	O
25	O
and	O
50mg	O
/	O
kg	O
were	O
more	O
effective	O
than	O
100mg	O
/	O
kg	O
.	O

Phosphorylated	O
AMPKa	O
(	O
p	O
-	O
AMPK	O
)	O
in	O
the	O
myocardium	O
was	O
significantly	O
elevated	O
by	O
25mg	O
/	O
kg	O
of	O
metformin	B-Chemical
,	O
slightly	O
by	O
50mg	O
/	O
kg	O
,	O
but	O
not	O
by	O
100mg	O
/	O
kg	O
.	O

Chronic	O
pre	O
-	O
treatment	O
with	O
metformin	B-Chemical
reduces	O
post	O
-	O
myocardial	B-Disease
infarction	I-Disease
cardiac	O
dysfunction	O
and	O
suppresses	O
inflammatory	O
responses	O
,	O
possibly	O
through	O
inhibition	O
of	O
TLR4	O
activities	O
.	O

This	O
mechanism	O
can	O
be	O
considered	O
as	O
a	O
target	O
to	O
protect	O
infarcted	O
myocardium	O
.	O

Unusual	O
complications	O
of	O
antithyroid	O
drug	O
therapy	O
:	O
four	O
case	O
reports	O
and	O
review	O
of	O
literature	O
.	O

Two	O
cases	O
of	O
propylthiouracil	B-Chemical
-	O
associated	O
acute	O
hepatitis	B-Disease
,	O
one	O
case	O
of	O
fatal	O
methimazole	B-Chemical
-	O
associated	O
hepatocellular	B-Disease
necrosis	I-Disease
and	O
one	O
case	O
of	O
propylthiouracil	B-Chemical
-	O
associated	O
lupus	B-Disease
-	I-Disease
like	I-Disease
syndrome	I-Disease
are	O
described	O
.	O

The	O
literature	O
related	O
to	O
antithyroid	O
drug	O
side	O
effects	O
and	O
the	O
mechanisms	O
for	O
their	O
occurrence	O
are	O
reviewed	O
and	O
the	O
efficacy	O
and	O
complications	O
of	O
thyroidectomy	O
and	O
radioiodine	O
compared	O
to	O
those	O
of	O
antithyroid	O
drugs	O
.	O

It	O
is	O
concluded	O
that	O
in	O
most	O
circumstances	O
131I	O
is	O
the	O
therapy	O
of	O
choice	O
for	O
hyperthyroidism	B-Disease
.	O

Neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
induced	O
by	O
combination	O
therapy	O
with	O
tetrabenazine	B-Chemical
and	O
tiapride	B-Chemical
in	O
a	O
Japanese	O
patient	O
with	O
Huntington	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
at	O
the	O
terminal	O
stage	O
of	O
recurrent	O
breast	B-Disease
cancer	I-Disease
.	O

We	O
herein	O
describe	O
the	O
case	O
of	O
an	O
81	O
-	O
year	O
-	O
old	O
Japanese	O
woman	O
with	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
that	O
occurred	O
36	O
days	O
after	O
the	O
initiation	O
of	O
combination	O
therapy	O
with	O
tiapride	B-Chemical
(	O
75	O
mg	O
/	O
day	O
)	O
and	O
tetrabenazine	B-Chemical
(	O
12	O
.	O
5	O
mg	O
/	O
day	O
)	O
for	O
Huntington	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

The	O
patient	O
had	O
been	O
treated	O
with	O
tiapride	B-Chemical
or	O
tetrabenazine	B-Chemical
alone	O
without	O
any	O
adverse	O
effects	O
before	O
the	O
administration	O
of	O
the	O
combination	O
therapy	O
.	O

She	O
also	O
had	O
advanced	O
breast	B-Disease
cancer	I-Disease
when	O
the	O
combination	O
therapy	O
was	O
initiated	O
.	O

To	O
the	O
best	O
of	O
our	O
knowledge	O
,	O
the	O
occurrence	O
of	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
due	O
to	O
combination	O
therapy	O
with	O
tetrabenazine	B-Chemical
and	O
tiapride	B-Chemical
has	O
not	O
been	O
previously	O
reported	O
.	O

Tetrabenazine	B-Chemical
should	O
be	O
administered	O
very	O
carefully	O
in	O
combination	O
with	O
other	O
neuroleptic	B-Chemical
drugs	I-Chemical
,	O
particularly	O
in	O
patients	O
with	O
a	O
worsening	O
general	O
condition	O
.	O

A	O
metoprolol	B-Chemical
-	O
terbinafine	B-Chemical
combination	O
induced	O
bradycardia	B-Disease
.	O

To	O
report	O
a	O
sinus	B-Disease
bradycardia	I-Disease
induced	O
by	O
metoprolol	B-Chemical
and	O
terbinafine	B-Chemical
drug	O
-	O
drug	O
interaction	O
and	O
its	O
management	O
.	O

A	O
63	O
year	O
-	O
old	O
Caucasian	O
man	O
on	O
metoprolol	B-Chemical
200	O
mg	O
/	O
day	O
for	O
stable	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
was	O
prescribed	O
a	O
90	O
-	O
day	O
course	O
of	O
oral	O
terbinafine	B-Chemical
250	O
mg	O
/	O
day	O
for	O
onychomycosis	B-Disease
.	O

On	O
the	O
49th	O
day	O
of	O
terbinafine	B-Chemical
therapy	O
,	O
he	O
was	O
brought	O
to	O
the	O
emergency	O
room	O
for	O
a	O
decrease	O
of	O
his	O
global	O
health	O
status	O
,	O
confusion	B-Disease
and	O
falls	O
.	O

The	O
electrocardiogram	O
revealed	O
a	O
37	O
beats	O
/	O
min	O
sinus	B-Disease
bradycardia	I-Disease
.	O

A	O
score	O
of	O
7	O
on	O
the	O
Naranjo	O
adverse	B-Disease
drug	I-Disease
reaction	I-Disease
probability	O
scale	O
indicates	O
a	O
probable	O
relationship	O
between	O
the	O
patient	O
'	O
s	O
sinus	B-Disease
bradycardia	I-Disease
and	O
the	O
drug	O
interaction	O
between	O
metoprolol	B-Chemical
and	O
terbinafine	B-Chemical
.	O

The	O
heart	O
rate	O
ameliorated	O
first	O
with	O
a	O
decrease	O
in	O
the	O
dose	O
of	O
metoprolol	B-Chemical
.	O

It	O
was	O
subsequently	O
changed	O
to	O
bisoprolol	B-Chemical
and	O
the	O
heart	O
rate	O
remained	O
normal	O
.	O

By	O
inhibiting	O
the	O
cytochrome	O
P450	O
2D6	O
,	O
terbinafine	B-Chemical
had	O
decreased	O
metoprolol	B-Chemical
'	O
s	O
clearance	O
,	O
leading	O
in	O
metoprolol	B-Chemical
accumulation	O
which	O
has	O
resulted	O
in	O
clinically	O
significant	O
sinus	B-Disease
bradycardia	I-Disease
.	O

Optochiasmatic	O
and	O
peripheral	B-Disease
neuropathy	I-Disease
due	O
to	O
ethambutol	B-Chemical
overtreatment	O
.	O

Ethambutol	B-Chemical
is	O
known	O
to	O
cause	O
optic	B-Disease
neuropathy	I-Disease
and	O
,	O
more	O
rarely	O
,	O
axonal	O
polyneuropathy	B-Disease
.	O

We	O
characterize	O
the	O
clinical	O
,	O
neurophysiological	O
,	O
and	O
neuroimaging	O
findings	O
in	O
a	O
72	O
-	O
year	O
-	O
old	O
man	O
who	O
developed	O
visual	B-Disease
loss	I-Disease
and	O
paresthesias	B-Disease
after	O
11	O
weeks	O
of	O
exposure	O
to	O
a	O
supratherapeutic	O
dose	O
of	O
ethambutol	B-Chemical
.	O

This	O
case	O
demonstrates	O
the	O
selective	O
vulnerability	O
of	O
the	O
anterior	O
visual	O
pathways	O
and	O
peripheral	O
nerves	O
to	O
ethambutol	B-Chemical
toxicity	B-Disease
.	O

Testosterone	B-Chemical
ameliorates	O
streptozotocin	B-Chemical
-	O
induced	O
memory	B-Disease
impairment	I-Disease
in	O
male	O
rats	O
.	O

AIM	O
:	O
To	O
study	O
the	O
effects	O
of	O
testosterone	B-Chemical
on	O
streptozotocin	B-Chemical
(	O
STZ	B-Chemical
)	O
-	O
induced	O
memory	B-Disease
impairment	I-Disease
in	O
male	O
rats	O
.	O

METHODS	O
:	O
Adult	O
male	O
Wistar	O
rats	O
were	O
intracerebroventricularly	O
(	O
icv	O
)	O
infused	O
with	O
STZ	B-Chemical
(	O
750	O
ug	O
)	O
on	O
d	O
1	O
and	O
d	O
3	O
,	O
and	O
a	O
passive	O
avoidance	O
task	O
was	O
assessed	O
2	O
weeks	O
after	O
the	O
first	O
injection	O
of	O
STZ	B-Chemical
.	O

Castration	O
surgery	O
was	O
performed	O
in	O
another	O
group	O
of	O
rats	O
,	O
and	O
the	O
passive	O
avoidance	O
task	O
was	O
assessed	O
4	O
weeks	O
after	O
the	O
operation	O
.	O

Testosterone	B-Chemical
(	O
1	O
mg	O
.	O
kg	O
(	O
-	O
1	O
)	O
.	O
d	O
(	O
-	O
1	O
)	O
,	O
sc	O
)	O
,	O
the	O
androgen	B-Chemical
receptor	O
antagonist	O
flutamide	B-Chemical
(	O
10	O
mg	O
.	O
kg	O
(	O
-	O
1	O
)	O
.	O
d	O
(	O
-	O
1	O
)	O
,	O
ip	O
)	O
,	O
the	O
estrogen	B-Chemical
receptor	O
antagonist	O
tamoxifen	B-Chemical
(	O
1	O
mg	O
.	O
kg	O
(	O
-	O
1	O
)	O
.	O
d	O
(	O
-	O
1	O
)	O
,	O
ip	O
)	O
or	O
the	O
aromatase	O
inhibitor	O
letrozole	B-Chemical
(	O
4	O
mg	O
.	O
kg	O
(	O
-	O
1	O
)	O
.	O
d	O
(	O
-	O
1	O
)	O
,	O
ip	O
)	O
were	O
administered	O
for	O
6	O
d	O
after	O
the	O
first	O
injection	O
of	O
STZ	B-Chemical
.	O

RESULTS	O
:	O
STZ	B-Chemical
administration	O
and	O
castration	O
markedly	O
decreased	O
both	O
STL1	O
(	O
the	O
short	O
memory	O
)	O
and	O
STL2	O
(	O
the	O
long	O
memory	O
)	O
in	O
passive	O
avoidance	O
tests	O
.	O

Testosterone	B-Chemical
replacement	O
almost	O
restored	O
the	O
STL1	O
and	O
STL2	O
in	O
castrated	O
rats	O
,	O
and	O
significantly	O
prolonged	O
the	O
STL1	O
and	O
STL2	O
in	O
STZ	B-Chemical
-	O
treated	O
rats	O
.	O

Administration	O
of	O
flutamide	B-Chemical
,	O
letrozole	B-Chemical
or	O
tamoxifen	B-Chemical
significantly	O
impaired	B-Disease
the	I-Disease
memory	I-Disease
in	O
intact	O
rats	O
,	O
and	O
significantly	O
attenuated	O
the	O
testosterone	B-Chemical
replacement	O
in	O
improving	O
STZ	B-Chemical
-	O
and	O
castration	O
-	O
induced	O
memory	B-Disease
impairment	I-Disease
.	O

CONCLUSION	O
:	O
Testosterone	B-Chemical
administration	O
ameliorates	O
STZ	B-Chemical
-	O
and	O
castration	O
-	O
induced	O
memory	B-Disease
impairment	I-Disease
in	O
male	O
Wistar	O
rats	O
.	O

Behavioral	O
and	O
neurochemical	O
studies	O
in	O
mice	O
pretreated	O
with	O
garcinielliptone	B-Chemical
FC	I-Chemical
in	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

Garcinielliptone	B-Chemical
FC	I-Chemical
(	O
GFC	B-Chemical
)	O
isolated	O
from	O
hexanic	O
fraction	O
seed	O
extract	O
of	O
species	O
Platonia	O
insignis	O
Mart	O
.	O

It	O
is	O
widely	O
used	O
in	O
folk	O
medicine	O
to	O
treat	O
skin	B-Disease
diseases	I-Disease
in	O
both	O
humans	O
and	O
animals	O
as	O
well	O
as	O
the	O
seed	O
decoction	O
has	O
been	O
used	O
to	O
treat	O
diarrheas	B-Disease
and	O
inflammatory	B-Disease
diseases	I-Disease
.	O

However	O
,	O
there	O
is	O
no	O
research	O
on	O
GFC	B-Chemical
effects	O
in	O
the	O
central	O
nervous	O
system	O
of	O
rodents	O
.	O

The	O
present	O
study	O
aimed	O
to	O
evaluate	O
the	O
GFC	B-Chemical
effects	O
at	O
doses	O
of	O
25	O
,	O
50	O
or	O
75	O
mg	O
/	O
kg	O
on	O
seizure	B-Disease
parameters	O
to	O
determine	O
their	O
anticonvulsant	O
activity	O
and	O
its	O
effects	O
on	O
amino	B-Chemical
acid	I-Chemical
(	O
r	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
(	O
GABA	B-Chemical
)	O
,	O
glutamine	B-Chemical
,	O
aspartate	B-Chemical
and	O
glutathione	B-Chemical
)	O
levels	O
as	O
well	O
as	O
on	O
acetylcholinesterase	O
(	O
AChE	O
)	O
activity	O
in	O
mice	O
hippocampus	O
after	O
seizures	B-Disease
.	O

GFC	B-Chemical
produced	O
an	O
increased	O
latency	O
to	O
first	O
seizure	B-Disease
,	O
at	O
doses	O
25mg	O
/	O
kg	O
(	O
20	O
.	O
12	O
+	O
2	O
.	O
20	O
min	O
)	O
,	O
50mg	O
/	O
kg	O
(	O
20	O
.	O
95	O
+	O
2	O
.	O
21	O
min	O
)	O
or	O
75	O
mg	O
/	O
kg	O
(	O
23	O
.	O
43	O
+	O
1	O
.	O
99	O
min	O
)	O
when	O
compared	O
with	O
seized	O
mice	O
.	O

In	O
addition	O
,	O
GABA	B-Chemical
content	O
of	O
mice	O
hippocampus	O
treated	O
with	O
GFC75	O
plus	O
P400	O
showed	O
an	O
increase	O
of	O
46	O
.	O
90	O
%	O
when	O
compared	O
with	O
seized	O
mice	O
.	O

In	O
aspartate	B-Chemical
,	O
glutamine	B-Chemical
and	O
glutamate	B-Chemical
levels	O
detected	O
a	O
decrease	O
of	O
5	O
.	O
21	O
%	O
,	O
13	O
.	O
55	O
%	O
and	O
21	O
.	O
80	O
%	O
,	O
respectively	O
in	O
mice	O
hippocampus	O
treated	O
with	O
GFC75	O
plus	O
P400	O
when	O
compared	O
with	O
seized	O
mice	O
.	O

Hippocampus	O
mice	O
treated	O
with	O
GFC75	O
plus	O
P400	O
showed	O
an	O
increase	O
in	O
AChE	O
activity	O
(	O
63	O
.	O
30	O
%	O
)	O
when	O
compared	O
with	O
seized	O
mice	O
.	O

The	O
results	O
indicate	O
that	O
GFC	B-Chemical
can	O
exert	O
anticonvulsant	O
activity	O
and	O
reduce	O
the	O
frequency	O
of	O
installation	O
of	O
pilocarpine	B-Chemical
-	O
induced	O
status	B-Disease
epilepticus	I-Disease
,	O
as	O
demonstrated	O
by	O
increase	O
in	O
latency	O
to	O
first	O
seizure	B-Disease
and	O
decrease	O
in	O
mortality	O
rate	O
of	O
animals	O
.	O

In	O
conclusion	O
,	O
our	O
data	O
suggest	O
that	O
GFC	B-Chemical
may	O
influence	O
in	O
epileptogenesis	O
and	O
promote	O
anticonvulsant	O
actions	O
in	O
pilocarpine	B-Chemical
model	O
by	O
modulating	O
the	O
GABA	B-Chemical
and	O
glutamate	B-Chemical
contents	O
and	O
of	O
AChE	O
activity	O
in	O
seized	O
mice	O
hippocampus	O
.	O

This	O
compound	O
may	O
be	O
useful	O
to	O
produce	O
neuronal	O
protection	O
and	O
it	O
can	O
be	O
considered	O
as	O
an	O
anticonvulsant	O
agent	O
.	O

Standard	O
operating	O
procedures	O
for	O
antibiotic	O
therapy	O
and	O
the	O
occurrence	O
of	O
acute	B-Disease
kidney	I-Disease
injury	I-Disease
:	O
a	O
prospective	O
,	O
clinical	O
,	O
non	O
-	O
interventional	O
,	O
observational	O
study	O
.	O

INTRODUCTION	O
:	O
Acute	B-Disease
kidney	I-Disease
injury	I-Disease
(	O
AKI	B-Disease
)	O
occurs	O
in	O
7	O
%	O
of	O
hospitalized	O
and	O
66	O
%	O
of	O
Intensive	O
Care	O
Unit	O
(	O
ICU	O
)	O
patients	O
.	O

It	O
increases	O
mortality	O
,	O
hospital	O
length	O
of	O
stay	O
,	O
and	O
costs	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
investigate	O
,	O
whether	O
there	O
is	O
an	O
association	O
between	O
adherence	O
to	O
guidelines	O
(	O
standard	O
operating	O
procedures	O
(	O
SOP	O
)	O
)	O
for	O
potentially	O
nephrotoxic	B-Disease
antibiotics	O
and	O
the	O
occurrence	O
of	O
AKI	B-Disease
.	O

METHODS	O
:	O
This	O
study	O
was	O
carried	O
out	O
as	O
a	O
prospective	O
,	O
clinical	O
,	O
non	O
-	O
interventional	O
,	O
observational	O
study	O
.	O

Data	O
collection	O
was	O
performed	O
over	O
a	O
total	O
of	O
170	O
days	O
in	O
three	O
ICUs	O
at	O
Charite	O
-	O
Universitaetsmedizin	O
Berlin	O
.	O

A	O
total	O
of	O
675	O
patients	O
were	O
included	O
;	O
163	O
of	O
these	O
had	O
therapy	O
with	O
vancomycin	B-Chemical
,	O
gentamicin	B-Chemical
,	O
or	O
tobramycin	B-Chemical
;	O
were	O
>	O
18	O
years	O
;	O
and	O
treated	O
in	O
the	O
ICU	O
for	O
>	O
24	O
hours	O
.	O

Patients	O
with	O
an	O
adherence	O
to	O
SOP	O
>	O
70	O
%	O
were	O
classified	O
into	O
the	O
high	O
adherence	O
group	O
(	O
HAG	O
)	O
and	O
patients	O
with	O
an	O
adherence	O
of	O
<	O
70	O
%	O
into	O
the	O
low	O
adherence	O
group	O
(	O
LAG	O
)	O
.	O

AKI	B-Disease
was	O
defined	O
according	O
to	O
RIFLE	O
criteria	O
.	O

Adherence	O
to	O
SOPs	O
was	O
evaluated	O
by	O
retrospective	O
expert	O
audit	O
.	O

Development	O
of	O
AKI	B-Disease
was	O
compared	O
between	O
groups	O
with	O
exact	O
Chi2	O
-	O
test	O
and	O
multivariate	O
logistic	O
regression	O
analysis	O
(	O
two	O
-	O
sided	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

RESULTS	O
:	O
LAG	O
consisted	O
of	O
75	O
patients	O
(	O
46	O
%	O
)	O
versus	O
88	O
HAG	O
patients	O
(	O
54	O
%	O
)	O
.	O

AKI	B-Disease
occurred	O
significantly	O
more	O
often	O
in	O
LAG	O
with	O
36	O
%	O
versus	O
21	O
%	O
in	O
HAG	O
(	O
P	O
=	O
0	O
.	O
035	O
)	O
.	O

Basic	O
characteristics	O
were	O
comparable	O
,	O
except	O
an	O
increased	O
rate	O
of	O
soft	O
tissue	O
infections	B-Disease
in	O
LAG	O
.	O

Multivariate	O
analysis	O
revealed	O
an	O
odds	O
ratio	O
of	O
2	O
.	O
5	O
-	O
fold	O
for	O
LAG	O
to	O
develop	O
AKI	B-Disease
compared	O
with	O
HAG	O
(	O
95	O
%	O
confidence	O
interval	O
1	O
.	O
195	O
to	O
5	O
.	O
124	O
,	O
P	O
=	O
0	O
.	O
039	O
)	O
.	O

CONCLUSION	O
:	O
Low	O
adherence	O
to	O
SOPs	O
for	O
potentially	O
nephrotoxic	B-Disease
antibiotics	O
was	O
associated	O
with	O
a	O
higher	O
occurrence	O
of	O
AKI	B-Disease
.	O

TRIAL	O
REGISTRATION	O
:	O
Current	O
Controlled	O
Trials	O
ISRCTN54598675	O
.	O

Registered	O
17	O
August	O
2007	O
.	O

Rhabdomyolysis	B-Disease
in	O
a	O
hepatitis	B-Disease
C	I-Disease
virus	I-Disease
infected	I-Disease
patient	O
treated	O
with	O
telaprevir	B-Chemical
and	O
simvastatin	B-Chemical
.	O

A	O
46	O
-	O
year	O
old	O
man	O
with	O
a	O
chronic	O
hepatitis	B-Disease
C	I-Disease
virus	I-Disease
infection	I-Disease
received	O
triple	O
therapy	O
with	O
ribavirin	B-Chemical
,	O
pegylated	B-Chemical
interferon	I-Chemical
and	O
telaprevir	B-Chemical
.	O

The	O
patient	O
also	O
received	O
simvastatin	B-Chemical
.	O

One	O
month	O
after	O
starting	O
the	O
antiviral	O
therapy	O
,	O
the	O
patient	O
was	O
admitted	O
to	O
the	O
hospital	O
because	O
he	O
developed	O
rhabdomyolysis	B-Disease
.	O

At	O
admission	O
simvastatin	B-Chemical
and	O
all	O
antiviral	O
drugs	O
were	O
discontinued	O
because	O
toxicity	B-Disease
due	O
to	O
a	O
drug	O
-	O
drug	O
interaction	O
was	O
suspected	O
.	O

The	O
creatine	B-Chemical
kinase	O
peaked	O
at	O
62	O
,	O
246	O
IU	O
/	O
L	O
and	O
the	O
patient	O
was	O
treated	O
with	O
intravenous	O
normal	O
saline	O
.	O

The	O
patient	O
'	O
s	O
renal	O
function	O
remained	O
unaffected	O
.	O

Fourteen	O
days	O
after	O
hospitalization	O
,	O
creatine	B-Chemical
kinase	O
level	O
had	O
returned	O
to	O
230	O
IU	O
/	O
L	O
and	O
the	O
patient	O
was	O
discharged	O
.	O

Telaprevir	B-Chemical
was	O
considered	O
the	O
probable	O
causative	O
agent	O
of	O
an	O
interaction	O
with	O
simvastatin	B-Chemical
according	O
to	O
the	O
Drug	O
Interaction	O
Probability	O
Scale	O
.	O

The	O
interaction	O
is	O
due	O
to	O
inhibition	O
of	O
CYP3A4	O
-	O
mediated	O
simvastatin	B-Chemical
clearance	O
.	O

Simvastatin	B-Chemical
plasma	O
concentration	O
increased	O
30	O
times	O
in	O
this	O
patient	O
and	O
statin	B-Chemical
induced	O
muscle	B-Disease
toxicity	I-Disease
is	O
related	O
to	O
the	O
concentration	O
of	O
the	O
statin	B-Chemical
in	O
blood	O
.	O

In	O
conclusion	O
,	O
with	O
this	O
case	O
we	O
illustrate	O
that	O
telaprevir	B-Chemical
as	O
well	O
as	O
statins	B-Chemical
are	O
susceptible	O
to	O
clinical	O
relevant	O
drug	O
-	O
drug	O
interactions	O
.	O

Combination	O
of	O
bortezomib	B-Chemical
,	O
thalidomide	B-Chemical
,	O
and	O
dexamethasone	B-Chemical
(	O
VTD	O
)	O
as	O
a	O
consolidation	O
therapy	O
after	O
autologous	O
stem	O
cell	O
transplantation	O
for	O
symptomatic	O
multiple	B-Disease
myeloma	I-Disease
in	O
Japanese	O
patients	O
.	O

Consolidation	O
therapy	O
for	O
patients	O
with	O
multiple	B-Disease
myeloma	I-Disease
(	O
MM	B-Disease
)	O
has	O
been	O
widely	O
adopted	O
to	O
improve	O
treatment	O
response	O
following	O
autologous	O
stem	O
cell	O
transplantation	O
.	O

In	O
this	O
study	O
,	O
we	O
retrospectively	O
analyzed	O
the	O
safety	O
and	O
efficacy	O
of	O
combination	O
regimen	O
of	O
bortezomib	B-Chemical
,	O
thalidomide	B-Chemical
,	O
and	O
dexamethasone	B-Chemical
(	O
VTD	O
)	O
as	O
consolidation	O
therapy	O
in	O
24	O
Japanese	O
patients	O
with	O
newly	O
diagnosed	O
MM	B-Disease
.	O

VTD	O
consisted	O
of	O
bortezomib	B-Chemical
at	O
a	O
dose	O
of	O
1	O
.	O
3	O
mg	O
/	O
m	O
(	O
2	O
)	O
and	O
dexamethasone	B-Chemical
at	O
a	O
dose	O
of	O
40	O
mg	O
/	O
day	O
on	O
days	O
1	O
,	O
8	O
,	O
15	O
,	O
and	O
22	O
of	O
a	O
35	O
-	O
day	O
cycle	O
,	O
with	O
daily	O
oral	O
thalidomide	B-Chemical
at	O
a	O
dose	O
of	O
100	O
mg	O
/	O
day	O
.	O

Grade	O
3	O
-	O
4	O
neutropenia	B-Disease
and	O
thrombocytopenia	B-Disease
were	O
documented	O
in	O
four	O
and	O
three	O
patients	O
(	O
17	O
and	O
13	O
%	O
)	O
,	O
respectively	O
,	O
but	O
drug	O
dose	O
reduction	O
due	O
to	O
cytopenia	B-Disease
was	O
not	O
required	O
in	O
any	O
case	O
.	O

Peripheral	B-Disease
neuropathy	I-Disease
was	O
common	O
(	O
63	O
%	O
)	O
,	O
but	O
severe	O
grade	O
3	O
-	O
4	O
peripheral	B-Disease
neuropathy	I-Disease
was	O
not	O
observed	O
.	O

Very	O
good	O
partial	O
response	O
or	O
better	O
response	O
(	O
>	O
VGPR	O
)	O
rates	O
before	O
and	O
after	O
consolidation	O
therapy	O
were	O
54	O
and	O
79	O
%	O
,	O
respectively	O
.	O

Patients	O
had	O
a	O
significant	O
probability	O
of	O
improving	O
from	O
<	O
VGPR	O
before	O
consolidation	O
therapy	O
to	O
>	O
VGPR	O
after	O
consolidation	O
therapy	O
(	O
p	O
=	O
0	O
.	O
041	O
)	O
.	O

The	O
VTD	O
regimen	O
may	O
be	O
safe	O
and	O
effective	O
as	O
a	O
consolidation	O
therapy	O
in	O
the	O
treatment	O
of	O
MM	O
in	O
Japanese	O
population	O
.	O

Conversion	O
to	O
sirolimus	B-Chemical
ameliorates	O
cyclosporine	B-Chemical
-	O
induced	O
nephropathy	B-Disease
in	O
the	O
rat	O
:	O
focus	O
on	O
serum	O
,	O
urine	O
,	O
gene	O
,	O
and	O
protein	O
renal	O
expression	O
biomarkers	O
.	O

Protocols	O
of	O
conversion	O
from	O
cyclosporin	B-Chemical
A	I-Chemical
(	O
CsA	B-Chemical
)	O
to	O
sirolimus	B-Chemical
(	O
SRL	B-Chemical
)	O
have	O
been	O
widely	O
used	O
in	O
immunotherapy	O
after	O
transplantation	O
to	O
prevent	O
CsA	B-Chemical
-	O
induced	O
nephropathy	B-Disease
,	O
but	O
the	O
molecular	O
mechanisms	O
underlying	O
these	O
protocols	O
remain	O
nuclear	O
.	O

This	O
study	O
aimed	O
to	O
identify	O
the	O
molecular	O
pathways	O
and	O
putative	O
biomarkers	O
of	O
CsA	B-Chemical
-	O
to	O
-	O
SRL	B-Chemical
conversion	O
in	O
a	O
rat	O
model	O
.	O

Four	O
animal	O
groups	O
(	O
n	O
=	O
6	O
)	O
were	O
tested	O
during	O
9	O
weeks	O
:	O
control	O
,	O
CsA	B-Chemical
,	O
SRL	B-Chemical
,	O
and	O
conversion	O
(	O
CsA	B-Chemical
for	O
3	O
weeks	O
followed	O
by	O
SRL	B-Chemical
for	O
6	O
weeks	O
)	O
.	O

Classical	O
and	O
emergent	O
serum	O
,	O
urinary	O
,	O
and	O
kidney	O
tissue	O
(	O
gene	O
and	O
protein	O
expression	O
)	O
markers	O
were	O
assessed	O
.	O

Renal	B-Disease
lesions	I-Disease
were	O
analyzed	O
in	O
hematoxylin	B-Chemical
and	O
eosin	B-Chemical
,	O
periodic	O
acid	O
-	O
Schiff	O
,	O
and	O
Masson	O
'	O
s	O
trichrome	O
stains	O
.	O

SRL	B-Chemical
-	O
treated	O
rats	O
presented	O
proteinuria	B-Disease
and	O
NGAL	O
(	O
serum	O
and	O
urinary	O
)	O
as	O
the	O
best	O
markers	O
of	O
renal	B-Disease
impairment	I-Disease
.	O

Short	O
CsA	B-Chemical
treatment	O
presented	O
slight	O
or	O
even	O
absent	O
kidney	B-Disease
lesions	I-Disease
and	O
TGF	O
-	O
b	O
,	O
NF	O
-	O
kb	O
,	O
mTOR	O
,	O
PCNA	O
,	O
TP53	O
,	O
KIM	O
-	O
1	O
,	O
and	O
CTGF	O
as	O
relevant	O
gene	O
and	O
protein	O
changes	O
.	O

Prolonged	O
CsA	B-Chemical
exposure	O
aggravated	O
renal	B-Disease
damage	I-Disease
,	O
without	O
clear	O
changes	O
on	O
the	O
traditional	O
markers	O
,	O
but	O
with	O
changes	O
in	O
serums	O
TGF	O
-	O
b	O
and	O
IL	O
-	O
7	O
,	O
TBARs	O
clearance	O
,	O
and	O
kidney	O
TGF	O
-	O
b	O
and	O
mTOR	O
.	O

Conversion	O
to	O
SRL	B-Chemical
prevented	O
CsA	B-Chemical
-	O
induced	O
renal	B-Disease
damage	I-Disease
evolution	O
(	O
absent	O
/	O
mild	O
grade	O
lesions	O
)	O
,	O
while	O
NGAL	O
(	O
serum	O
versus	O
urine	O
)	O
seems	O
to	O
be	O
a	O
feasible	O
biomarker	O
of	O
CsA	B-Chemical
replacement	O
to	O
SRL	B-Chemical
.	O

Kinin	O
B2	O
receptor	O
deletion	O
and	O
blockage	O
ameliorates	O
cisplatin	B-Chemical
-	O
induced	O
acute	B-Disease
renal	I-Disease
injury	I-Disease
.	O

Cisplatin	B-Chemical
treatment	O
has	O
been	O
adopted	O
in	O
some	O
chemotherapies	O
;	O
however	O
,	O
this	O
drug	O
can	O
induce	O
acute	B-Disease
kidney	I-Disease
injury	I-Disease
due	O
its	O
ability	O
to	O
negatively	O
affect	O
renal	O
function	O
,	O
augment	O
serum	O
levels	O
of	O
creatinine	B-Chemical
and	O
urea	B-Chemical
,	O
increase	O
the	O
acute	B-Disease
tubular	I-Disease
necrosis	I-Disease
score	O
and	O
up	O
-	O
regulate	O
cytokines	O
(	O
e	O
.	O
g	O
.	O
,	O
IL	O
-	O
1b	O
and	O
TNF	O
-	O
a	O
)	O
.	O

The	O
kinin	O
B2	O
receptor	O
has	O
been	O
associated	O
with	O
the	O
inflammation	B-Disease
process	O
,	O
as	O
well	O
as	O
the	O
regulation	O
of	O
cytokine	O
expression	O
,	O
and	O
its	O
deletion	O
resulted	O
in	O
an	O
improvement	O
in	O
the	O
diabetic	B-Disease
nephropathy	I-Disease
status	O
.	O

To	O
examine	O
the	O
role	O
of	O
the	O
kinin	O
B2	O
receptor	O
in	O
cisplatin	B-Chemical
-	O
induced	O
acute	B-Disease
kidney	I-Disease
injury	I-Disease
,	O
kinin	O
B2	O
receptor	O
knockout	O
mice	O
were	O
challenged	O
with	O
cisplatin	B-Chemical
.	O

Additionally	O
,	O
WT	O
mice	O
were	O
treated	O
with	O
a	O
B2	O
receptor	O
antagonist	O
after	O
cisplatin	B-Chemical
administration	O
.	O

B2	O
receptor	O
-	O
deficient	O
mice	O
were	O
less	O
sensitive	O
to	O
this	O
drug	O
than	O
the	O
WT	O
mice	O
,	O
as	O
shown	O
by	O
reduced	O
weight	B-Disease
loss	I-Disease
,	O
better	O
preservation	O
of	O
kidney	O
function	O
,	O
down	O
regulation	O
of	O
inflammatory	O
cytokines	O
and	O
less	O
acute	B-Disease
tubular	I-Disease
necrosis	I-Disease
.	O

Moreover	O
,	O
treatment	O
with	O
the	O
kinin	O
B2	O
receptor	O
antagonist	O
effectively	O
reduced	O
the	O
levels	O
of	O
serum	O
creatinine	B-Chemical
and	O
blood	O
urea	B-Chemical
after	O
cisplatin	B-Chemical
administration	O
.	O

Thus	O
,	O
our	O
data	O
suggest	O
that	O
the	O
kinin	O
B2	O
receptor	O
is	O
involved	O
in	O
cisplatin	B-Chemical
-	O
induced	O
acute	B-Disease
kidney	I-Disease
injury	I-Disease
by	O
mediating	O
the	O
necrotic	B-Disease
process	O
and	O
the	O
expression	O
of	O
inflammatory	O
cytokines	O
,	O
thus	O
resulting	O
in	O
declined	O
renal	O
function	O
.	O

These	O
results	O
highlight	O
the	O
kinin	O
B2	O
receptor	O
antagonist	O
treatment	O
in	O
amelioration	O
of	O
nephrotoxicity	B-Disease
induced	O
by	O
cisplatin	B-Chemical
therapy	O
.	O

Safety	O
and	O
efficacy	O
of	O
fluocinolone	B-Chemical
acetonide	I-Chemical
intravitreal	O
implant	O
(	O
0	O
.	O
59	O
mg	O
)	O
in	O
birdshot	B-Disease
retinochoroidopathy	I-Disease
.	O

PURPOSE	O
:	O
To	O
report	O
the	O
treatment	O
outcomes	O
of	O
the	O
fluocinolone	B-Chemical
acetonide	I-Chemical
intravitreal	O
implant	O
(	O
0	O
.	O
59	O
mg	O
)	O
in	O
patients	O
with	O
birdshot	B-Disease
retinochoroidopathy	I-Disease
whose	O
disease	O
is	O
refractory	O
or	O
intolerant	O
to	O
conventional	O
immunomodulatory	O
therapy	O
.	O

METHODS	O
:	O
A	O
retrospective	O
case	O
series	O
involving	O
11	O
birdshot	B-Disease
retinochoroidopathy	I-Disease
patients	O
(	O
11	O
eyes	O
)	O
.	O

Eleven	O
patients	O
(	O
11	O
eyes	O
)	O
underwent	O
surgery	O
for	O
fluocinolone	B-Chemical
acetonide	I-Chemical
implant	O
(	O
0	O
.	O
59	O
mg	O
)	O
.	O

Treatment	O
outcomes	O
of	O
interest	O
were	O
noted	O
at	O
baseline	O
,	O
before	O
fluocinolone	B-Chemical
acetonide	I-Chemical
implant	O
,	O
and	O
then	O
at	O
6	O
months	O
,	O
1	O
year	O
,	O
2	O
years	O
,	O
3	O
years	O
,	O
and	O
beyond	O
3	O
years	O
.	O

Disease	O
activity	O
markers	O
,	O
including	O
signs	O
of	O
ocular	O
inflammation	B-Disease
,	O
evidence	O
of	O
retinal	B-Disease
vasculitis	I-Disease
,	O
Swedish	O
interactive	O
threshold	O
algorithm	O
-	O
short	O
wavelength	O
automated	O
perimetry	O
Humphrey	O
visual	O
field	O
analysis	O
,	O
electroretinographic	O
parameters	O
,	O
and	O
optical	O
coherence	O
tomography	O
were	O
recorded	O
.	O

Data	O
on	O
occurrence	O
of	O
cataract	B-Disease
and	O
raised	B-Disease
intraocular	I-Disease
pressure	I-Disease
were	O
collected	O
in	O
all	O
eyes	O
.	O

RESULTS	O
:	O
Intraocular	O
inflammation	B-Disease
was	O
present	O
in	O
54	O
.	O
5	O
,	O
9	O
.	O
9	O
,	O
11	O
.	O
1	O
,	O
and	O
0	O
%	O
of	O
patients	O
at	O
baseline	O
,	O
6	O
months	O
,	O
1	O
year	O
,	O
2	O
years	O
,	O
3	O
years	O
,	O
and	O
beyond	O
3	O
years	O
after	O
receiving	O
the	O
implant	O
,	O
respectively	O
.	O

Active	O
vasculitis	B-Disease
was	O
noted	O
in	O
36	O
.	O
3	O
%	O
patients	O
at	O
baseline	O
and	O
0	O
%	O
at	O
3	O
years	O
of	O
follow	O
-	O
up	O
.	O

More	O
than	O
20	O
%	O
(	O
47	O
.	O
61	O
-	O
67	O
.	O
2	O
%	O
)	O
reduction	O
in	O
central	O
retinal	O
thickness	O
was	O
noted	O
in	O
all	O
patients	O
with	O
cystoid	B-Disease
macular	I-Disease
edema	I-Disease
at	O
6	O
months	O
,	O
1	O
year	O
,	O
2	O
years	O
,	O
and	O
3	O
years	O
postimplant	O
.	O

At	O
baseline	O
,	O
54	O
.	O
5	O
%	O
patients	O
were	O
on	O
immunomodulatory	O
agents	O
.	O

This	O
percentage	O
decreased	O
to	O
45	O
.	O
45	O
,	O
44	O
.	O
4	O
,	O
and	O
14	O
.	O
28	O
%	O
at	O
1	O
year	O
,	O
2	O
years	O
,	O
and	O
3	O
years	O
postimplant	O
,	O
respectively	O
.	O

Adverse	O
events	O
included	O
increased	B-Disease
intraocular	I-Disease
pressure	I-Disease
(	O
54	O
.	O
5	O
%	O
)	O
and	O
cataract	B-Disease
formation	O
(	O
100	O
%	O
)	O
.	O

CONCLUSION	O
:	O
The	O
data	O
suggest	O
that	O
fluocinolone	B-Chemical
acetonide	I-Chemical
implant	O
(	O
0	O
.	O
59	O
mg	O
)	O
helps	O
to	O
control	O
inflammation	B-Disease
in	O
otherwise	O
treatment	O
-	O
refractory	O
cases	O
of	O
birdshot	B-Disease
retinochoroidopathy	I-Disease
.	O

It	O
is	O
associated	O
with	O
significant	O
side	O
effects	O
of	O
cataract	B-Disease
and	O
ocular	B-Disease
hypertension	I-Disease
requiring	O
treatment	O
.	O

Optimal	O
precurarizing	O
dose	O
of	O
rocuronium	B-Chemical
to	O
decrease	O
fasciculation	B-Disease
and	O
myalgia	B-Disease
following	O
succinylcholine	B-Chemical
administration	O
.	O

BACKGROUND	O
:	O
Succinylcholine	B-Chemical
commonly	O
produces	O
frequent	O
adverse	O
effects	O
,	O
including	O
muscle	B-Disease
fasciculation	I-Disease
and	O
myalgia	B-Disease
.	O

The	O
current	O
study	O
identified	O
the	O
optimal	O
dose	O
of	O
rocuronium	B-Chemical
to	O
prevent	O
succinylcholine	B-Chemical
-	O
induced	O
fasciculation	B-Disease
and	O
myalgia	B-Disease
and	O
evaluated	O
the	O
influence	O
of	O
rocuronium	B-Chemical
on	O
the	O
speed	O
of	O
onset	O
produced	O
by	O
succinylcholine	B-Chemical
.	O

METHODS	O
:	O
This	O
randomized	O
,	O
double	O
-	O
blinded	O
study	O
was	O
conducted	O
in	O
100	O
patients	O
randomly	O
allocated	O
into	O
five	O
groups	O
of	O
20	O
patients	O
each	O
.	O

Patients	O
were	O
randomized	O
to	O
receive	O
0	O
.	O
02	O
,	O
0	O
.	O
03	O
,	O
0	O
.	O
04	O
,	O
0	O
.	O
05	O
and	O
0	O
.	O
06	O
mg	O
/	O
kg	O
rocuronium	B-Chemical
as	O
a	O
precurarizing	O
dose	O
.	O

Neuromuscular	O
monitoring	O
after	O
each	O
precurarizing	O
dose	O
was	O
recorded	O
from	O
the	O
adductor	O
pollicis	O
muscle	O
using	O
acceleromyography	O
with	O
train	O
-	O
of	O
-	O
four	O
stimulation	O
of	O
the	O
ulnar	O
nerve	O
.	O

All	O
patients	O
received	O
succinylcholine	B-Chemical
1	O
.	O
5	O
mg	O
/	O
kg	O
at	O
2	O
minutes	O
after	O
the	O
precurarization	O
,	O
and	O
were	O
assessed	O
the	O
incidence	O
and	O
severity	O
of	O
fasciculations	B-Disease
,	O
while	O
myalgia	B-Disease
was	O
assessed	O
at	O
24	O
hours	O
after	O
surgery	O
.	O

RESULTS	O
:	O
The	O
incidence	O
and	O
severity	O
of	O
visible	O
muscle	B-Disease
fasciculation	I-Disease
was	O
significantly	O
less	O
with	O
increasing	O
the	O
amount	O
of	O
precurarizing	O
dose	O
of	O
rocuronium	B-Chemical
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Those	O
of	O
myalgia	B-Disease
tend	O
to	O
decrease	O
according	O
to	O
increasing	O
the	O
amount	O
of	O
precurarizing	O
dose	O
of	O
rocuronium	B-Chemical
,	O
but	O
there	O
was	O
no	O
significance	O
(	O
P	O
=	O
0	O
.	O
072	O
)	O
.	O

The	O
onset	O
time	O
of	O
succinylcholine	B-Chemical
was	O
significantly	O
longer	O
with	O
increasing	O
the	O
amount	O
of	O
precurarizing	O
dose	O
of	O
rocuronium	B-Chemical
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

CONCLUSIONS	O
:	O
Precurarization	O
with	O
0	O
.	O
04	O
mg	O
/	O
kg	O
rocuronium	B-Chemical
was	O
the	O
optimal	O
dose	O
considering	O
the	O
reduction	O
in	O
the	O
incidence	O
and	O
severity	O
of	O
fasciculation	B-Disease
and	O
myalgia	B-Disease
with	O
acceptable	O
onset	O
time	O
,	O
and	O
the	O
safe	O
and	O
effective	O
precurarization	O
.	O

Absence	O
of	O
PKC	O
-	O
alpha	O
attenuates	O
lithium	B-Chemical
-	O
induced	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
.	O

Lithium	B-Chemical
,	O
an	O
effective	O
antipsychotic	O
,	O
induces	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
(	O
NDI	B-Disease
)	O
in	O
40	O
%	O
of	O
patients	O
.	O

The	O
decreased	O
capacity	O
to	O
concentrate	O
urine	O
is	O
likely	O
due	O
to	O
lithium	B-Chemical
acutely	O
disrupting	O
the	O
cAMP	B-Chemical
pathway	O
and	O
chronically	O
reducing	O
urea	B-Chemical
transporter	O
(	O
UT	O
-	O
A1	O
)	O
and	O
water	O
channel	O
(	O
AQP2	O
)	O
expression	O
in	O
the	O
inner	O
medulla	O
.	O

Targeting	O
an	O
alternative	O
signaling	O
pathway	O
,	O
such	O
as	O
PKC	O
-	O
mediated	O
signaling	O
,	O
may	O
be	O
an	O
effective	O
method	O
of	O
treating	O
lithium	B-Chemical
-	O
induced	O
polyuria	B-Disease
.	O

PKC	O
-	O
alpha	O
null	O
mice	O
(	O
PKCa	O
KO	O
)	O
and	O
strain	O
-	O
matched	O
wild	O
type	O
(	O
WT	O
)	O
controls	O
were	O
treated	O
with	O
lithium	B-Chemical
for	O
0	O
,	O
3	O
or	O
5	O
days	O
.	O

WT	O
mice	O
had	O
increased	O
urine	O
output	O
and	O
lowered	O
urine	O
osmolality	O
after	O
3	O
and	O
5	O
days	O
of	O
treatment	O
whereas	O
PKCa	O
KO	O
mice	O
had	O
no	O
change	O
in	O
urine	O
output	O
or	O
concentration	O
.	O

Western	O
blot	O
analysis	O
revealed	O
that	O
AQP2	O
expression	O
in	O
medullary	O
tissues	O
was	O
lowered	O
after	O
3	O
and	O
5	O
days	O
in	O
WT	O
mice	O
;	O
however	O
,	O
AQP2	O
was	O
unchanged	O
in	O
PKCa	O
KO	O
.	O

Similar	O
results	O
were	O
observed	O
with	O
UT	O
-	O
A1	O
expression	O
.	O

Animals	O
were	O
also	O
treated	O
with	O
lithium	B-Chemical
for	O
6	O
weeks	O
.	O

Lithium	B-Chemical
-	O
treated	O
WT	O
mice	O
had	O
19	O
-	O
fold	O
increased	O
urine	O
output	O
whereas	O
treated	O
PKCa	O
KO	O
animals	O
had	O
a	O
4	O
-	O
fold	O
increase	O
in	O
output	O
.	O

AQP2	O
and	O
UT	O
-	O
A1	O
expression	O
was	O
lowered	O
in	O
6	O
week	O
lithium	B-Chemical
-	O
treated	O
WT	O
animals	O
whereas	O
in	O
treated	O
PKCa	O
KO	O
mice	O
,	O
AQP2	O
was	O
only	O
reduced	O
by	O
2	O
-	O
fold	O
and	O
UT	O
-	O
A1	O
expression	O
was	O
unaffected	O
.	O

Urinary	O
sodium	B-Chemical
,	O
potassium	B-Chemical
and	O
calcium	B-Chemical
were	O
elevated	O
in	O
lithium	B-Chemical
-	O
fed	O
WT	O
but	O
not	O
in	O
lithium	B-Chemical
-	O
fed	O
PKCa	O
KO	O
mice	O
.	O

Our	O
data	O
show	O
that	O
ablation	O
of	O
PKCa	O
preserves	O
AQP2	O
and	O
UT	O
-	O
A1	O
protein	O
expression	O
and	O
localization	O
in	O
lithium	B-Chemical
-	O
induced	O
NDI	B-Disease
,	O
and	O
prevents	O
the	O
development	O
of	O
the	O
severe	O
polyuria	B-Disease
associated	O
with	O
lithium	B-Chemical
therapy	O
.	O

Is	O
Dysguesia	B-Disease
Going	O
to	O
be	O
a	O
Rare	O
or	O
a	O
Common	O
Side	O
-	O
effect	O
of	O
Amlodipine	B-Chemical
?	O

A	O
very	O
rare	O
side	O
-	O
effect	O
of	O
amlodipine	B-Chemical
is	O
dysguesia	B-Disease
.	O

A	O
review	O
of	O
the	O
literature	O
produced	O
only	O
one	O
case	O
.	O

We	O
report	O
a	O
case	O
about	O
a	O
female	O
with	O
essential	O
hypertension	B-Disease
on	O
drug	O
treatment	O
with	O
amlodipine	B-Chemical
developed	O
loss	B-Disease
of	I-Disease
taste	I-Disease
sensation	I-Disease
.	O

Condition	O
moderately	O
improved	O
on	O
stoppage	O
of	O
the	O
drug	O
for	O
25	O
days	O
.	O

We	O
conclude	O
that	O
amlodipine	B-Chemical
can	O
cause	O
dysguesia	B-Disease
.	O

Here	O
,	O
we	O
describe	O
the	O
clinical	O
presentation	O
and	O
review	O
the	O
relevant	O
literature	O
on	O
amlodipine	B-Chemical
and	O
dysguesia	B-Disease
.	O

Rhabdomyolysis	B-Disease
in	O
association	O
with	O
simvastatin	B-Chemical
and	O
dosage	O
increment	O
in	O
clarithromycin	B-Chemical
.	O

Clarithromycin	B-Chemical
is	O
the	O
most	O
documented	O
cytochrome	O
P450	O
3A4	O
(	O
CYP3A4	O
)	O
inhibitor	O
to	O
cause	O
an	O
adverse	O
interaction	O
with	O
simvastatin	B-Chemical
.	O

This	O
particular	O
case	O
is	O
of	O
interest	O
as	O
rhabdomyolysis	B-Disease
only	O
occurred	O
after	O
an	O
increase	O
in	O
the	O
dose	O
of	O
clarithromycin	B-Chemical
.	O

The	O
patient	O
developed	O
raised	O
cardiac	O
biomarkers	O
without	O
any	O
obvious	O
cardiac	O
issues	O
,	O
a	O
phenomenon	O
that	O
has	O
been	O
linked	O
to	O
rhabdomyolysis	B-Disease
previously	O
.	O

To	O
date	O
,	O
there	O
has	O
been	O
no	O
reported	O
effect	O
of	O
rhabdomyolysis	B-Disease
on	O
the	O
structure	O
and	O
function	O
of	O
cardiac	O
muscle	O
.	O

Clinicians	O
need	O
to	O
be	O
aware	O
of	O
prescribing	O
concomitant	O
medications	O
that	O
increase	O
the	O
risk	O
of	O
myopathy	B-Disease
or	O
inhibit	O
the	O
CYP3A4	O
enzyme	O
.	O

Our	O
case	O
suggests	O
that	O
troponin	O
elevation	O
could	O
be	O
associated	O
with	O
statin	B-Chemical
induced	O
rhabdomyolysis	B-Disease
,	O
which	O
may	O
warrant	O
further	O
studies	O
.	O

Characterization	O
of	O
a	O
novel	O
BCHE	O
"	O
silent	O
"	O
allele	O
:	O
point	O
mutation	O
(	O
p	O
.	O
Val204Asp	O
)	O
causes	O
loss	O
of	O
activity	O
and	O
prolonged	O
apnea	B-Disease
with	O
suxamethonium	B-Chemical
.	O

Butyrylcholinesterase	B-Disease
deficiency	I-Disease
is	O
characterized	O
by	O
prolonged	O
apnea	B-Disease
after	O
the	O
use	O
of	O
muscle	O
relaxants	O
(	O
suxamethonium	B-Chemical
or	O
mivacurium	B-Chemical
)	O
in	O
patients	O
who	O
have	O
mutations	O
in	O
the	O
BCHE	O
gene	O
.	O

Here	O
,	O
we	O
report	O
a	O
case	O
of	O
prolonged	O
neuromuscular	O
block	O
after	O
administration	O
of	O
suxamethonium	B-Chemical
leading	O
to	O
the	O
discovery	O
of	O
a	O
novel	O
BCHE	O
variant	O
(	O
c	O
.	O
695T	O
>	O
A	O
,	O
p	O
.	O
Val204Asp	O
)	O
.	O

Inhibition	O
studies	O
,	O
kinetic	O
analysis	O
and	O
molecular	O
dynamics	O
were	O
undertaken	O
to	O
understand	O
how	O
this	O
mutation	O
disrupts	O
the	O
catalytic	O
triad	O
and	O
determines	O
a	O
"	O
silent	O
"	O
phenotype	O
.	O

Low	O
activity	O
of	O
patient	O
plasma	O
butyrylcholinesterase	O
with	O
butyrylthiocholine	B-Chemical
(	O
BTC	B-Chemical
)	O
and	O
benzoylcholine	B-Chemical
,	O
and	O
values	O
of	O
dibucaine	B-Chemical
and	O
fluoride	B-Chemical
numbers	O
fit	O
with	O
heterozygous	O
atypical	O
silent	O
genotype	O
.	O

Electrophoretic	O
analysis	O
of	O
plasma	O
BChE	O
of	O
the	O
proband	O
and	O
his	O
mother	O
showed	O
that	O
patient	O
has	O
a	O
reduced	O
amount	O
of	O
tetrameric	O
enzyme	O
in	O
plasma	O
and	O
that	O
minor	O
fast	O
-	O
moving	O
BChE	O
components	O
:	O
monomer	O
,	O
dimer	O
,	O
and	O
monomer	O
-	O
albumin	O
conjugate	O
are	O
missing	O
.	O

Kinetic	O
analysis	O
showed	O
that	O
the	O
p	O
.	O
Val204Asp	O
/	O
p	O
.	O
Asp70Gly	O
-	O
p	O
.	O
Ala539Thr	O
BChE	O
displays	O
a	O
pure	O
Michaelian	O
behavior	O
with	O
BTC	B-Chemical
as	O
the	O
substrate	O
.	O

Both	O
catalytic	O
parameters	O
Km	O
=	O
265	O
uM	O
for	O
BTC	B-Chemical
,	O
two	O
times	O
higher	O
than	O
that	O
of	O
the	O
atypical	O
enzyme	O
,	O
and	O
a	O
low	O
Vmax	O
are	O
consistent	O
with	O
the	O
absence	O
of	O
activity	O
against	O
suxamethonium	B-Chemical
.	O

Molecular	O
dynamic	O
(	O
MD	O
)	O
simulations	O
showed	O
that	O
the	O
overall	O
effect	O
of	O
the	O
mutation	O
p	O
.	O
Val204Asp	O
is	O
disruption	O
of	O
hydrogen	B-Chemical
bonding	O
between	O
Gln223	O
and	O
Glu441	O
,	O
leading	O
Ser198	O
and	O
His438	O
to	O
move	O
away	O
from	O
each	O
other	O
with	O
subsequent	O
disruption	O
of	O
the	O
catalytic	O
triad	O
functionality	O
regardless	O
of	O
the	O
type	O
of	O
substrate	O
.	O

MD	O
also	O
showed	O
that	O
the	O
enzyme	O
volume	O
is	O
increased	O
,	O
suggesting	O
a	O
pre	O
-	O
denaturation	O
state	O
.	O

This	O
fits	O
with	O
the	O
reduced	O
concentration	O
of	O
p	O
.	O
Ala204Asp	O
/	O
p	O
.	O
Asp70Gly	O
-	O
p	O
.	O
Ala539Thr	O
tetrameric	O
enzyme	O
in	O
the	O
plasma	O
and	O
non	O
-	O
detectable	O
fast	O
moving	O
-	O
bands	O
on	O
electrophoresis	O
gels	O
.	O

Delayed	O
anemia	B-Disease
after	O
treatment	O
with	O
injectable	O
artesunate	B-Chemical
in	O
the	O
Democratic	O
Republic	O
of	O
the	O
Congo	O
:	O
a	O
manageable	O
issue	O
.	O

Cases	O
of	O
delayed	O
hemolytic	B-Disease
anemia	I-Disease
have	O
been	O
described	O
after	O
treatment	O
with	O
injectable	O
artesunate	B-Chemical
,	O
the	O
current	O
World	O
Health	O
Organization	O
(	O
WHO	O
)	O
-	O
recommended	O
first	O
-	O
line	O
drug	O
for	O
the	O
treatment	O
of	O
severe	O
malaria	B-Disease
.	O

A	O
total	O
of	O
350	O
patients	O
(	O
215	O
[	O
61	O
.	O
4	O
%	O
]	O
<	O
5	O
years	O
of	O
age	O
and	O
135	O
[	O
38	O
.	O
6	O
%	O
]	O
>	O
5	O
years	O
of	O
age	O
)	O
were	O
followed	O
-	O
up	O
after	O
treatment	O
with	O
injectable	O
artesunate	B-Chemical
for	O
severe	O
malaria	B-Disease
in	O
hospitals	O
and	O
health	O
centers	O
of	O
the	O
Democratic	O
Republic	O
of	O
the	O
Congo	O
.	O

Complete	O
series	O
of	O
hemoglobin	O
(	O
Hb	O
)	O
measurements	O
were	O
available	O
for	O
201	O
patients	O
.	O

A	O
decrease	O
in	O
Hb	O
levels	O
between	O
2	O
and	O
5	O
g	O
/	O
dL	O
was	O
detected	O
in	O
23	O
(	O
11	O
.	O
4	O
%	O
)	O
patients	O
during	O
the	O
follow	O
-	O
up	O
period	O
.	O

For	O
five	O
patients	O
,	O
Hb	O
levels	O
decreased	O
below	O
5	O
g	O
/	O
dL	O
during	O
at	O
least	O
one	O
follow	O
-	O
up	O
visit	O
.	O

All	O
cases	O
of	O
delayed	O
anemia	B-Disease
were	O
clinically	O
manageable	O
and	O
resolved	O
within	O
one	O
month	O
.	O

Regulation	O
of	O
signal	O
transducer	O
and	O
activator	O
of	O
transcription	O
3	O
and	O
apoptotic	O
pathways	O
by	O
betaine	B-Chemical
attenuates	O
isoproterenol	B-Chemical
-	O
induced	O
acute	O
myocardial	B-Disease
injury	I-Disease
in	O
rats	O
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
investigate	O
the	O
cardioprotective	O
effects	O
of	O
betaine	B-Chemical
on	O
acute	O
myocardial	B-Disease
ischemia	I-Disease
induced	O
experimentally	O
in	O
rats	O
focusing	O
on	O
regulation	O
of	O
signal	O
transducer	O
and	O
activator	O
of	O
transcription	O
3	O
(	O
STAT3	O
)	O
and	O
apoptotic	O
pathways	O
as	O
the	O
potential	O
mechanism	O
underlying	O
the	O
drug	O
effect	O
.	O

Male	O
Sprague	O
Dawley	O
rats	O
were	O
treated	O
with	O
betaine	B-Chemical
(	O
100	O
,	O
200	O
,	O
and	O
400	O
mg	O
/	O
kg	O
)	O
orally	O
for	O
40	O
days	O
.	O

Acute	O
myocardial	B-Disease
ischemic	I-Disease
injury	I-Disease
was	O
induced	O
in	O
rats	O
by	O
subcutaneous	O
injection	O
of	O
isoproterenol	B-Chemical
(	O
85	O
mg	O
/	O
kg	O
)	O
,	O
for	O
two	O
consecutive	O
days	O
.	O

Serum	O
cardiac	O
marker	O
enzyme	O
,	O
histopathological	O
variables	O
and	O
expression	O
of	O
protein	O
levels	O
were	O
analyzed	O
.	O

Oral	O
administration	O
of	O
betaine	B-Chemical
(	O
200	O
and	O
400	O
mg	O
/	O
kg	O
)	O
significantly	O
reduced	O
the	O
level	O
of	O
cardiac	O
marker	O
enzyme	O
in	O
the	O
serum	O
and	O
prevented	O
left	O
ventricular	B-Disease
remodeling	I-Disease
.	O

Western	O
blot	O
analysis	O
showed	O
that	O
isoproterenol	B-Chemical
-	O
induced	O
phosphorylation	O
of	O
STAT3	O
was	O
maintained	O
or	O
further	O
enhanced	O
by	O
betaine	B-Chemical
treatment	O
in	O
myocardium	O
.	O

Furthermore	O
,	O
betaine	B-Chemical
(	O
200	O
and	O
400	O
mg	O
/	O
kg	O
)	O
treatment	O
increased	O
the	O
ventricular	O
expression	O
of	O
Bcl	O
-	O
2	O
and	O
reduced	O
the	O
level	O
of	O
Bax	O
,	O
therefore	O
causing	O
a	O
significant	O
increase	O
in	O
the	O
ratio	O
of	O
Bcl	O
-	O
2	O
/	O
Bax	O
.	O

The	O
protective	O
role	O
of	O
betaine	B-Chemical
on	O
myocardial	B-Disease
damage	I-Disease
was	O
further	O
confirmed	O
by	O
histopathological	O
examination	O
.	O

In	O
summary	O
,	O
our	O
results	O
showed	O
that	O
betaine	B-Chemical
pretreatment	O
attenuated	O
isoproterenol	B-Chemical
-	O
induced	O
acute	O
myocardial	B-Disease
ischemia	I-Disease
via	O
the	O
regulation	O
of	O
STAT3	O
and	O
apoptotic	O
pathways	O
.	O

Quetiapine	B-Chemical
-	O
induced	O
neutropenia	B-Disease
in	O
a	O
bipolar	B-Disease
patient	O
with	O
hepatocellular	B-Disease
carcinoma	I-Disease
.	O

OBJECTIVE	O
:	O
Quetiapine	B-Chemical
is	O
a	O
dibenzothiazepine	O
derivative	O
,	O
similar	O
to	O
clozapine	B-Chemical
,	O
which	O
has	O
the	O
highest	O
risk	O
of	O
causing	O
blood	B-Disease
dyscrasias	I-Disease
,	O
especially	O
neutropenia	B-Disease
.	O

There	O
are	O
some	O
case	O
reports	O
about	O
this	O
side	O
effect	O
of	O
quetiapine	B-Chemical
,	O
but	O
possible	O
risk	O
factors	O
are	O
seldom	O
discussed	O
and	O
identified	O
.	O

A	O
case	O
of	O
a	O
patient	O
with	O
hepatocellular	B-Disease
carcinoma	I-Disease
that	O
developed	O
neutropenia	B-Disease
after	O
treatment	O
with	O
quetiapine	B-Chemical
is	O
described	O
here	O
.	O

CASE	O
REPORT	O
:	O
A	O
62	O
-	O
year	O
-	O
old	O
Taiwanese	O
widow	O
with	O
bipolar	B-Disease
disorder	I-Disease
was	O
diagnosed	O
with	O
hepatocellular	B-Disease
carcinoma	I-Disease
at	O
age	O
60	O
.	O

She	O
developed	O
leucopenia	B-Disease
after	O
being	O
treated	O
with	O
quetiapine	B-Chemical
.	O

After	O
quetiapine	B-Chemical
was	O
discontinued	O
,	O
her	O
white	O
blood	O
cell	O
count	O
returned	O
to	O
normal	O
.	O

CONCLUSIONS	O
:	O
Although	O
neutropenia	B-Disease
is	O
not	O
a	O
common	O
side	O
effect	O
of	O
quetiapine	B-Chemical
,	O
physicians	O
should	O
be	O
cautious	O
about	O
its	O
presentation	O
and	O
associated	O
risk	O
factors	O
.	O

Hepatic	B-Disease
dysfunction	I-Disease
may	O
be	O
one	O
of	O
the	O
possible	O
risk	O
factors	O
,	O
and	O
concomitant	O
fever	B-Disease
may	O
be	O
a	O
diagnostic	O
marker	O
for	O
adverse	O
reaction	O
to	O
quetiapine	B-Chemical
.	O

Lateral	O
antebrachial	O
cutaneous	O
neuropathy	B-Disease
after	O
steroid	B-Chemical
injection	O
at	O
lateral	O
epicondyle	O
.	O

BACKGROUND	O
AND	O
OBJECTIVES	O
:	O
This	O
report	O
aimed	O
to	O
present	O
a	O
case	O
of	O
lateral	O
antebrachial	O
cutaneous	O
neuropathy	B-Disease
(	O
LACNP	O
)	O
that	O
occurred	O
after	O
a	O
steroid	B-Chemical
injection	O
in	O
the	O
lateral	O
epicondyle	O
to	O
treat	O
lateral	B-Disease
epicondylitis	I-Disease
in	O
a	O
40	O
-	O
year	O
-	O
old	O
woman	O
.	O

MATERIAL	O
AND	O
METHOD	O
:	O
A	O
40	O
-	O
year	O
-	O
old	O
woman	O
presented	O
with	O
decreased	O
sensation	O
and	O
paresthesia	B-Disease
over	O
her	O
right	O
lateral	O
forearm	O
;	O
the	O
paresthesia	B-Disease
had	O
occurred	O
after	O
a	O
steroid	B-Chemical
injection	O
in	O
the	O
right	O
lateral	O
epicondyle	O
3	O
months	O
before	O
.	O

Her	O
sensation	O
of	O
light	O
touch	O
and	O
pain	B-Disease
was	O
diminished	O
over	O
the	O
lateral	O
side	O
of	O
the	O
right	O
forearm	O
and	O
wrist	O
area	O
.	O

RESULTS	O
:	O
The	O
sensory	O
action	O
potential	O
amplitude	O
of	O
the	O
right	O
lateral	O
antebrachial	O
cutaneous	O
nerve	O
(	O
LACN	O
)	O
(	O
6	O
.	O
2	O
uV	O
)	O
was	O
lower	O
than	O
that	O
of	O
the	O
left	O
(	O
13	O
.	O
1	O
uV	O
)	O
.	O

The	O
difference	O
of	O
amplitude	O
between	O
both	O
sides	O
was	O
significant	O
because	O
there	O
was	O
more	O
than	O
a	O
50	O
%	O
reduction	O
.	O

She	O
was	O
diagnosed	O
with	O
right	O
LACNP	O
(	O
mainly	O
axonal	O
involvement	O
)	O
on	O
the	O
basis	O
of	O
the	O
clinical	O
manifestation	O
and	O
the	O
electrodiagnostic	O
findings	O
.	O

Her	O
symptoms	O
improved	O
through	O
physical	O
therapy	O
but	O
persisted	O
to	O
some	O
degree	O
.	O

CONCLUSION	O
:	O
This	O
report	O
describes	O
the	O
case	O
of	O
a	O
woman	O
with	O
LACNP	O
that	O
developed	O
after	O
a	O
steroid	B-Chemical
injection	O
for	O
the	O
treatment	O
of	O
lateral	B-Disease
epicondylitis	I-Disease
.	O

An	O
electrodiagnostic	O
study	O
,	O
including	O
a	O
nerve	O
conduction	O
study	O
of	O
the	O
LACN	O
,	O
was	O
helpful	O
to	O
diagnose	O
right	O
LACNP	O
and	O
to	O
find	O
the	O
passage	O
of	O
the	O
LACN	O
on	O
the	O
lateral	O
epicondyle	O
.	O

Curcumin	B-Chemical
prevents	O
maleate	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
:	O
relation	O
to	O
hemodynamic	O
alterations	O
,	O
oxidative	O
stress	O
,	O
mitochondrial	O
oxygen	B-Chemical
consumption	O
and	O
activity	O
of	O
respiratory	O
complex	O
I	O
.	O

The	O
potential	O
protective	O
effect	O
of	O
the	O
dietary	O
antioxidant	O
curcumin	B-Chemical
(	O
120	O
mg	O
/	O
Kg	O
/	O
day	O
for	O
6	O
days	O
)	O
against	O
the	O
renal	B-Disease
injury	I-Disease
induced	O
by	O
maleate	B-Chemical
was	O
evaluated	O
.	O

Tubular	O
proteinuria	B-Disease
and	O
oxidative	O
stress	O
were	O
induced	O
by	O
a	O
single	O
injection	O
of	O
maleate	B-Chemical
(	O
400	O
mg	O
/	O
kg	O
)	O
in	O
rats	O
.	O

Maleate	B-Chemical
-	O
induced	O
renal	B-Disease
injury	I-Disease
included	O
increase	O
in	O
renal	O
vascular	O
resistance	O
and	O
in	O
the	O
urinary	O
excretion	O
of	O
total	O
protein	O
,	O
glucose	B-Chemical
,	O
sodium	B-Chemical
,	O
neutrophil	O
gelatinase	O
-	O
associated	O
lipocalin	O
(	O
NGAL	O
)	O
and	O
N	O
-	O
acetyl	O
b	O
-	O
D	O
-	O
glucosaminidase	O
(	O
NAG	O
)	O
,	O
upregulation	O
of	O
kidney	B-Disease
injury	I-Disease
molecule	O
(	O
KIM	O
)	O
-	O
1	O
,	O
decrease	O
in	O
renal	O
blood	O
flow	O
and	O
claudin	O
-	O
2	O
expression	O
besides	O
of	O
necrosis	B-Disease
and	O
apoptosis	O
of	O
tubular	O
cells	O
on	O
24	O
h	O
.	O

Oxidative	O
stress	O
was	O
determined	O
by	O
measuring	O
the	O
oxidation	O
of	O
lipids	O
and	O
proteins	O
and	O
diminution	O
in	O
renal	O
Nrf2	O
levels	O
.	O

Studies	O
were	O
also	O
conducted	O
in	O
renal	O
epithelial	O
LLC	O
-	O
PK1	O
cells	O
and	O
in	O
mitochondria	O
isolated	O
from	O
kidneys	O
of	O
all	O
the	O
experimental	O
groups	O
.	O

Maleate	B-Chemical
induced	O
cell	O
damage	O
and	O
reactive	O
oxygen	B-Chemical
species	O
(	O
ROS	O
)	O
production	O
in	O
LLC	O
-	O
PK1	O
cells	O
in	O
culture	O
.	O

In	O
addition	O
,	O
maleate	B-Chemical
treatment	O
reduced	O
oxygen	B-Chemical
consumption	O
in	O
ADP	B-Chemical
-	O
stimulated	O
mitochondria	O
and	O
diminished	O
respiratory	O
control	O
index	O
when	O
using	O
malate	B-Chemical
/	O
glutamate	B-Chemical
as	O
substrate	O
.	O

The	O
activities	O
of	O
both	O
complex	O
I	O
and	O
aconitase	O
were	O
also	O
diminished	O
.	O

All	O
the	O
above	O
-	O
described	O
alterations	O
were	O
prevented	O
by	O
curcumin	B-Chemical
.	O

It	O
is	O
concluded	O
that	O
curcumin	B-Chemical
is	O
able	O
to	O
attenuate	O
in	O
vivo	O
maleate	B-Chemical
-	O
induced	O
nephropathy	B-Disease
and	O
in	O
vitro	O
cell	O
damage	O
.	O

The	O
in	O
vivo	O
protection	O
was	O
associated	O
to	O
the	O
prevention	O
of	O
oxidative	O
stress	O
and	O
preservation	O
of	O
mitochondrial	O
oxygen	B-Chemical
consumption	O
and	O
activity	O
of	O
respiratory	O
complex	O
I	O
,	O
and	O
the	O
in	O
vitro	O
protection	O
was	O
associated	O
to	O
the	O
prevention	O
of	O
ROS	O
production	O
.	O

Anticonvulsant	O
actions	O
of	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
on	O
the	O
lithium	B-Chemical
-	O
pilocarpine	B-Chemical
model	O
of	O
status	B-Disease
epilepticus	I-Disease
in	O
rats	O
.	O

MK	B-Chemical
-	I-Chemical
801	I-Chemical
,	O
a	O
noncompetitive	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
receptor	O
antagonist	O
,	O
was	O
tested	O
for	O
anticonvulsant	O
effects	O
in	O
rats	O
using	O
two	O
seizure	B-Disease
models	O
,	O
coadministration	O
of	O
lithium	B-Chemical
and	O
pilocarpine	B-Chemical
and	O
administration	O
of	O
a	O
high	O
dose	O
of	O
pilocarpine	B-Chemical
alone	O
.	O

Three	O
major	O
results	O
are	O
reported	O
.	O

First	O
,	O
pretreatment	O
with	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
produced	O
an	O
effective	O
and	O
dose	O
-	O
dependent	O
anticonvulsant	O
action	O
with	O
the	O
lithium	B-Chemical
-	O
pilocarpine	B-Chemical
model	O
but	O
not	O
with	O
rats	O
treated	O
with	O
pilocarpine	B-Chemical
alone	O
,	O
suggesting	O
that	O
different	O
biochemical	O
mechanisms	O
control	O
seizures	B-Disease
in	O
these	O
two	O
models	O
.	O

Second	O
,	O
the	O
anticonvulsant	O
effect	O
of	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
in	O
the	O
lithium	B-Chemical
-	O
pilocarpine	B-Chemical
model	O
only	O
occurred	O
after	O
initial	O
periods	O
of	O
seizure	B-Disease
activity	O
.	O

This	O
observation	O
is	O
suggested	O
to	O
be	O
an	O
in	O
vivo	O
demonstration	O
of	O
the	O
conclusion	O
derived	O
from	O
in	O
vitro	O
experiments	O
that	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
binding	O
requires	O
agonist	O
-	O
induced	O
opening	O
of	O
the	O
channel	O
sites	O
of	O
the	O
NMDA	B-Chemical
receptor	O
.	O

Third	O
,	O
although	O
it	O
is	O
relatively	O
easy	O
to	O
block	O
seizures	B-Disease
induced	O
by	O
lithium	B-Chemical
and	O
pilocarpine	B-Chemical
by	O
administration	O
of	O
anticonvulsants	O
prior	O
to	O
pilocarpine	B-Chemical
,	O
it	O
is	O
more	O
difficult	O
to	O
terminate	O
ongoing	O
status	B-Disease
epilepticus	I-Disease
and	O
block	O
the	O
lethality	O
of	O
the	O
seizures	B-Disease
.	O

Administration	O
of	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
30	O
or	O
60	O
min	O
after	O
pilocarpine	B-Chemical
,	O
i	O
.	O
e	O
.	O
,	O
during	O
status	B-Disease
epilepticus	I-Disease
,	O
gradually	O
reduced	O
electrical	O
and	O
behavioral	O
seizure	B-Disease
activity	O
and	O
greatly	O
enhanced	O
the	O
survival	O
rate	O
.	O

These	O
results	O
suggest	O
that	O
activation	O
of	O
NMDA	B-Chemical
receptors	O
plays	O
an	O
important	O
role	O
in	O
status	B-Disease
epilepticus	I-Disease
and	O
brain	B-Disease
damage	I-Disease
in	O
the	O
lithium	B-Chemical
-	O
pilocarpine	B-Chemical
model	O
.	O

This	O
was	O
further	O
supported	O
by	O
results	O
showing	O
that	O
nonconvulsive	O
doses	O
of	O
NMDA	B-Chemical
and	O
pilocarpine	B-Chemical
were	O
synergistic	O
,	O
resulting	O
in	O
status	B-Disease
epilepticus	I-Disease
and	O
subsequent	O
mortality	O
.	O

Continuous	O
infusion	O
tobramycin	B-Chemical
combined	O
with	O
carbenicillin	B-Chemical
for	O
infections	B-Disease
in	O
cancer	B-Disease
patients	O
.	O

The	O
cure	O
rate	O
of	O
infections	B-Disease
in	O
cancer	B-Disease
patients	O
is	O
adversely	O
affected	O
by	O
neutropenia	B-Disease
(	O
less	O
than	O
1	O
,	O
000	O
/	O
mm3	O
)	O
.	O

In	O
particular	O
,	O
patients	O
with	O
severe	O
neutropenia	B-Disease
(	O
less	O
than	O
100	O
/	O
mm3	O
)	O
have	O
shown	O
a	O
poor	O
response	O
to	O
antibiotics	O
.	O

To	O
overcome	O
the	O
adverse	O
effects	O
of	O
neutropenia	B-Disease
,	O
tobramycin	B-Chemical
was	O
given	O
by	O
continuous	O
infusion	O
and	O
combined	O
with	O
intermittent	O
carbenicillin	B-Chemical
.	O

Tobramycin	B-Chemical
was	O
given	O
to	O
a	O
total	O
daily	O
dose	O
of	O
300	O
mg	O
/	O
m2	O
and	O
carbenicillin	B-Chemical
was	O
given	O
at	O
a	O
dose	O
of	O
5	O
gm	O
every	O
four	O
hours	O
.	O

There	O
were	O
125	O
infectious	O
episodes	O
in	O
116	O
cancer	B-Disease
patients	O
receiving	O
myelosuppressive	O
chemotherapy	O
.	O

The	O
overall	O
cure	O
rate	O
was	O
70	O
%	O
.	O

Pneumonia	B-Disease
was	O
the	O
most	O
common	O
infection	B-Disease
and	O
61	O
%	O
of	O
59	O
episodes	O
were	O
cured	O
.	O

Gram	O
-	O
negative	O
bacilli	O
were	O
the	O
most	O
common	O
causative	O
organisms	O
and	O
69	O
%	O
of	O
these	O
infections	B-Disease
were	O
cured	O
.	O

The	O
most	O
common	O
pathogen	O
was	O
Klebsiella	O
pneumoniae	B-Disease
and	O
this	O
,	O
together	O
with	O
Escherichia	O
coli	O
and	O
Pseudomonas	O
aeruginosa	O
,	O
accounted	O
for	O
74	O
%	O
of	O
all	O
gram	B-Disease
-	I-Disease
negative	I-Disease
bacillary	I-Disease
infections	I-Disease
.	O

Response	O
was	O
not	O
influenced	O
by	O
the	O
initial	O
neutrophil	O
count	O
,	O
with	O
a	O
62	O
%	O
cure	O
rate	O
for	O
39	O
episodes	O
associated	O
with	O
severe	O
neutropenia	B-Disease
.	O

However	O
,	O
failure	O
of	O
the	O
neutrophil	O
count	O
to	O
increase	O
during	O
therapy	O
adversely	O
affected	O
response	O
.	O

Azotemia	B-Disease
was	O
the	O
major	O
side	O
effect	O
recognized	O
,	O
and	O
it	O
occurred	O
in	O
11	O
%	O
of	O
episodes	O
.	O

Major	O
azotemia	B-Disease
(	O
serum	O
creatinine	B-Chemical
greater	O
than	O
2	O
.	O
5	O
mg	O
/	O
dl	O
or	O
BUN	O
greater	O
than	O
50	O
mg	O
/	O
dl	O
)	O
occurred	O
in	O
only	O
2	O
%	O
.	O

Azotemia	B-Disease
was	O
not	O
related	O
to	O
duration	O
of	O
therapy	O
or	O
serum	O
tobramycin	B-Chemical
concentration	O
.	O

This	O
antibiotic	O
regimen	O
showed	O
both	O
therapeutic	O
efficacy	O
and	O
acceptable	O
renal	B-Disease
toxicity	I-Disease
for	O
these	O
patients	O
.	O

Incidence	O
of	O
solid	O
tumours	B-Disease
among	O
pesticide	O
applicators	O
exposed	O
to	O
the	O
organophosphate	B-Chemical
insecticide	O
diazinon	B-Chemical
in	O
the	O
Agricultural	O
Health	O
Study	O
:	O
an	O
updated	O
analysis	O
.	O

OBJECTIVE	O
:	O
Diazinon	B-Chemical
,	O
a	O
common	O
organophosphate	B-Chemical
insecticide	O
with	O
genotoxic	O
properties	O
,	O
was	O
previously	O
associated	O
with	O
lung	B-Disease
cancer	I-Disease
in	O
the	O
Agricultural	O
Health	O
Study	O
(	O
AHS	O
)	O
cohort	O
,	O
but	O
few	O
other	O
epidemiological	O
studies	O
have	O
examined	O
diazinon	B-Chemical
-	O
associated	O
cancer	B-Disease
risk	O
.	O

We	O
used	O
updated	O
diazinon	B-Chemical
exposure	O
and	O
cancer	B-Disease
incidence	O
information	O
to	O
evaluate	O
solid	O
tumour	B-Disease
risk	O
in	O
the	O
AHS	O
.	O

METHODS	O
:	O
Male	O
pesticide	O
applicators	O
in	O
Iowa	O
and	O
North	O
Carolina	O
reported	O
lifetime	O
diazinon	B-Chemical
use	O
at	O
enrolment	O
(	O
1993	O
-	O
1997	O
)	O
and	O
follow	O
-	O
up	O
(	O
1998	O
-	O
2005	O
)	O
;	O
cancer	B-Disease
incidence	O
was	O
assessed	O
through	O
2010	O
(	O
North	O
Carolina	O
)	O
/	O
2011	O
(	O
Iowa	O
)	O
.	O

Among	O
applicators	O
with	O
usage	O
information	O
sufficient	O
to	O
evaluate	O
exposure	O
-	O
response	O
patterns	O
,	O
we	O
used	O
Poisson	O
regression	O
to	O
estimate	O
adjusted	O
rate	O
ratios	O
(	O
RRs	O
)	O
and	O
95	O
%	O
CI	O
for	O
cancer	B-Disease
sites	O
with	O
>	O
10	O
exposed	O
cases	O
for	O
both	O
lifetime	O
(	O
LT	O
)	O
exposure	O
days	O
and	O
intensity	O
-	O
weighted	O
(	O
IW	O
)	O
lifetime	O
exposure	O
days	O
(	O
accounting	O
for	O
factors	O
impacting	O
exposure	O
)	O
.	O

RESULTS	O
:	O
We	O
observed	O
elevated	O
lung	B-Disease
cancer	I-Disease
risks	O
(	O
N	O
=	O
283	O
)	O
among	O
applicators	O
with	O
the	O
greatest	O
number	O
of	O
LT	O
(	O
RR	O
=	O
1	O
.	O
60	O
;	O
95	O
%	O
CI	O
1	O
.	O
11	O
to	O
2	O
.	O
31	O
;	O
Ptrend	O
=	O
0	O
.	O
02	O
)	O
and	O
IW	O
days	O
of	O
diazinon	B-Chemical
use	O
(	O
RR	O
=	O
1	O
.	O
41	O
;	O
95	O
%	O
CI	O
0	O
.	O
98	O
to	O
2	O
.	O
04	O
;	O
Ptrend	O
=	O
0	O
.	O
08	O
)	O
.	O

Kidney	B-Disease
cancer	I-Disease
(	O
N	O
=	O
94	O
)	O
risks	O
were	O
non	O
-	O
significantly	O
elevated	O
(	O
RRLT	O
days	O
=	O
1	O
.	O
77	O
;	O
95	O
%	O
CI	O
0	O
.	O
90	O
to	O
3	O
.	O
51	O
;	O
Ptrend	O
=	O
0	O
.	O
09	O
;	O
RRIW	O
days	O
1	O
.	O
37	O
;	O
95	O
%	O
CI	O
0	O
.	O
64	O
to	O
2	O
.	O
92	O
;	O
Ptrend	O
=	O
0	O
.	O
50	O
)	O
,	O
as	O
were	O
risks	O
for	O
aggressive	O
prostate	B-Disease
cancer	I-Disease
(	O
N	O
=	O
656	O
)	O
.	O

CONCLUSIONS	O
:	O
Our	O
updated	O
evaluation	O
of	O
diazinon	B-Chemical
provides	O
additional	O
evidence	O
of	O
an	O
association	O
with	O
lung	B-Disease
cancer	I-Disease
risk	O
.	O

Newly	O
identified	O
links	O
to	O
kidney	B-Disease
cancer	I-Disease
and	O
associations	O
with	O
aggressive	O
prostate	B-Disease
cancer	I-Disease
require	O
further	O
evaluation	O
.	O

Associations	O
of	O
Ozone	B-Chemical
and	O
PM2	O
.	O
5	O
Concentrations	O
With	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
Disease	I-Disease
Among	O
Participants	O
in	O
the	O
Agricultural	O
Health	O
Study	O
.	O

OBJECTIVE	O
:	O
This	O
study	O
describes	O
associations	O
of	O
ozone	B-Chemical
and	O
fine	O
particulate	B-Chemical
matter	I-Chemical
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
observed	O
among	O
farmers	O
in	O
North	O
Carolina	O
and	O
Iowa	O
.	O

METHODS	O
:	O
We	O
used	O
logistic	O
regression	O
to	O
determine	O
the	O
associations	O
of	O
these	O
pollutants	O
with	O
self	O
-	O
reported	O
,	O
doctor	O
-	O
diagnosed	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Daily	O
predicted	O
pollutant	O
concentrations	O
were	O
used	O
to	O
derive	O
surrogates	O
of	O
long	O
-	O
term	O
exposure	O
and	O
link	O
them	O
to	O
study	O
participants	O
'	O
geocoded	O
addresses	O
.	O

RESULTS	O
:	O
We	O
observed	O
positive	O
associations	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
with	O
ozone	B-Chemical
(	O
odds	O
ratio	O
=	O
1	O
.	O
39	O
;	O
95	O
%	O
CI	O
:	O
0	O
.	O
98	O
to	O
1	O
.	O
98	O
)	O
and	O
fine	O
particulate	B-Chemical
matter	I-Chemical
(	O
odds	O
ratio	O
=	O
1	O
.	O
34	O
;	O
95	O
%	O
CI	O
:	O
0	O
.	O
93	O
to	O
1	O
.	O
93	O
)	O
in	O
North	O
Carolina	O
but	O
not	O
in	O
Iowa	O
.	O

CONCLUSIONS	O
:	O
The	O
plausibility	O
of	O
an	O
effect	O
of	O
ambient	O
concentrations	O
of	O
these	O
pollutants	O
on	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
risk	O
is	O
supported	O
by	O
experimental	O
data	O
demonstrating	O
damage	O
to	O
dopaminergic	O
neurons	O
at	O
relevant	O
concentrations	O
.	O

Additional	O
studies	O
are	O
needed	O
to	O
address	O
uncertainties	O
related	O
to	O
confounding	O
and	O
to	O
examine	O
temporal	O
aspects	O
of	O
the	O
associations	O
we	O
observed	O
.	O

Low	O
functional	O
programming	O
of	O
renal	O
AT2R	O
mediates	O
the	O
developmental	O
origin	O
of	O
glomerulosclerosis	B-Disease
in	O
adult	O
offspring	O
induced	O
by	O
prenatal	O
caffeine	B-Chemical
exposure	O
.	O

UNASSIGNED	O
:	O
Our	O
previous	O
study	O
has	O
indicated	O
that	O
prenatal	O
caffeine	B-Chemical
exposure	O
(	O
PCE	O
)	O
could	O
induce	O
intrauterine	B-Disease
growth	I-Disease
retardation	I-Disease
(	O
IUGR	B-Disease
)	O
of	O
offspring	O
.	O

Recent	O
research	O
suggested	O
that	O
IUGR	B-Disease
is	O
a	O
risk	O
factor	O
for	O
glomerulosclerosis	B-Disease
.	O

However	O
,	O
whether	O
PCE	O
could	O
induce	O
glomerulosclerosis	B-Disease
and	O
its	O
underlying	O
mechanisms	O
remain	O
unknown	O
.	O

This	O
study	O
aimed	O
to	O
demonstrate	O
the	O
induction	O
to	O
glomerulosclerosis	B-Disease
in	O
adult	O
offspring	O
by	O
PCE	O
and	O
its	O
intrauterine	O
programming	O
mechanisms	O
.	O

A	O
rat	O
model	O
of	O
IUGR	B-Disease
was	O
established	O
by	O
PCE	O
,	O
male	O
fetuses	O
and	O
adult	O
offspring	O
at	O
the	O
age	O
of	O
postnatal	O
week	O
24	O
were	O
euthanized	O
.	O

The	O
results	O
revealed	O
that	O
the	O
adult	O
offspring	O
kidneys	O
in	O
the	O
PCE	O
group	O
exhibited	O
glomerulosclerosis	B-Disease
as	O
well	O
as	O
interstitial	B-Disease
fibrosis	I-Disease
,	O
accompanied	O
by	O
elevated	O
levels	O
of	O
serum	O
creatinine	B-Chemical
and	O
urine	O
protein	O
.	O

Renal	O
angiotensin	B-Chemical
II	I-Chemical
receptor	O
type	O
2	O
(	O
AT2R	O
)	O
gene	O
expression	O
in	O
adult	O
offspring	O
was	O
reduced	O
by	O
PCE	O
,	O
whereas	O
the	O
renal	O
angiotensin	B-Chemical
II	I-Chemical
receptor	O
type	O
1a	O
(	O
AT1aR	O
)	O
/	O
AT2R	O
expression	O
ratio	O
was	O
increased	O
.	O

The	O
fetal	O
kidneys	O
in	O
the	O
PCE	O
group	O
displayed	O
an	O
enlarged	O
Bowman	O
'	O
s	O
space	O
and	O
a	O
shrunken	O
glomerular	O
tuft	O
,	O
accompanied	O
by	O
a	O
reduced	O
cortex	O
width	O
and	O
an	O
increase	O
in	O
the	O
nephrogenic	O
zone	O
/	O
cortical	O
zone	O
ratio	O
.	O

Observation	O
by	O
electronic	O
microscope	O
revealed	O
structural	O
damage	O
of	O
podocytes	O
;	O
the	O
reduced	O
expression	O
level	O
of	O
podocyte	O
marker	O
genes	O
,	O
nephrin	O
and	O
podocin	O
,	O
was	O
also	O
detected	O
by	O
q	O
-	O
PCR	O
.	O

Moreover	O
,	O
AT2R	O
gene	O
and	O
protein	O
expressions	O
in	O
fetal	O
kidneys	O
were	O
inhibited	O
by	O
PCE	O
,	O
associated	O
with	O
the	O
repression	O
of	O
the	O
gene	O
expression	O
of	O
glial	O
-	O
cell	O
-	O
line	O
-	O
derived	O
neurotrophic	O
factor	O
(	O
GDNF	O
)	O
/	O
tyrosine	B-Chemical
kinase	O
receptor	O
(	O
c	O
-	O
Ret	O
)	O
signaling	O
pathway	O
.	O

These	O
results	O
demonstrated	O
that	O
PCE	O
could	O
induce	O
dysplasia	B-Disease
of	I-Disease
fetal	I-Disease
kidneys	I-Disease
as	O
well	O
as	O
glomerulosclerosis	B-Disease
of	O
adult	O
offspring	O
,	O
and	O
the	O
low	O
functional	O
programming	O
of	O
renal	O
AT2R	O
might	O
mediate	O
the	O
developmental	O
origin	O
of	O
adult	O
glomerulosclerosis	B-Disease
.	O

1	B-Chemical
,	I-Chemical
3	I-Chemical
-	I-Chemical
Butadiene	I-Chemical
,	O
CML	B-Disease
and	O
the	O
t	O
(	O
9	O
:	O
22	O
)	O
translocation	O
:	O
A	O
reality	O
check	O
.	O

UNASSIGNED	O
:	O
Epidemiological	O
studies	O
of	O
1	B-Chemical
,	I-Chemical
3	I-Chemical
-	I-Chemical
butadiene	I-Chemical
have	O
suggest	O
that	O
exposures	O
to	O
humans	O
are	O
associated	O
with	O
chronic	B-Disease
myeloid	I-Disease
leukemia	I-Disease
(	O
CML	B-Disease
)	O
.	O

CML	B-Disease
has	O
a	O
well	O
-	O
documented	O
association	O
with	O
ionizing	O
radiation	O
,	O
but	O
reports	O
of	O
associations	O
with	O
chemical	O
exposures	O
have	O
been	O
questioned	O
.	O

Ionizing	O
radiation	O
is	O
capable	O
of	O
inducing	O
the	O
requisite	O
CML	B-Disease
-	O
associated	O
t	O
(	O
9	O
:	O
22	O
)	O
translocation	O
(	O
Philadelphia	B-Disease
chromosome	I-Disease
)	O
in	O
appropriate	O
cells	O
in	O
vitro	O
but	O
,	O
thus	O
far	O
,	O
chemicals	O
have	O
not	O
shown	O
this	O
capacity	O
.	O

We	O
have	O
proposed	O
that	O
1	B-Chemical
,	I-Chemical
3	I-Chemical
-	I-Chemical
butadiene	I-Chemical
metabolites	O
be	O
so	O
tested	O
as	O
a	O
reality	O
check	O
on	O
the	O
epidemiological	O
reports	O
.	O

In	O
order	O
to	O
conduct	O
reliable	O
testing	O
in	O
this	O
regard	O
,	O
it	O
is	O
essential	O
that	O
a	O
positive	O
control	O
for	O
induction	O
be	O
available	O
.	O

We	O
have	O
used	O
ionizing	O
radiation	O
to	O
develop	O
such	O
a	O
control	O
.	O

Results	O
described	O
here	O
demonstrate	O
that	O
this	O
agent	O
does	O
in	O
fact	O
induce	O
pathogenic	O
t	O
(	O
9	O
:	O
22	O
)	O
translocations	O
in	O
a	O
human	O
myeloid	O
cell	O
line	O
in	O
vitro	O
,	O
but	O
does	O
so	O
at	O
low	O
frequencies	O
.	O

Conditions	O
that	O
will	O
be	O
required	O
for	O
studies	O
of	O
1	B-Chemical
,	I-Chemical
3	I-Chemical
-	I-Chemical
butadiene	I-Chemical
are	O
discussed	O
.	O

Cancer	B-Disease
incidence	O
and	O
metolachlor	B-Chemical
use	O
in	O
the	O
Agricultural	O
Health	O
Study	O
:	O
An	O
update	O
.	O

UNASSIGNED	O
:	O
Metolachlor	B-Chemical
,	O
a	O
widely	O
used	O
herbicide	O
,	O
is	O
classified	O
as	O
a	O
Group	O
C	O
carcinogen	O
by	O
the	O
U	O
.	O
S	O
.	O

Environmental	O
Protection	O
Agency	O
based	O
on	O
increased	O
liver	B-Disease
neoplasms	I-Disease
in	O
female	O
rats	O
.	O

Epidemiologic	O
studies	O
of	O
the	O
health	O
effects	O
of	O
metolachlor	B-Chemical
have	O
been	O
limited	O
.	O

The	O
Agricultural	O
Health	O
Study	O
(	O
AHS	O
)	O
is	O
a	O
prospective	O
cohort	O
study	O
including	O
licensed	O
private	O
and	O
commercial	O
pesticide	O
applicators	O
in	O
Iowa	O
and	O
North	O
Carolina	O
enrolled	O
1993	O
-	O
1997	O
.	O

We	O
evaluated	O
cancer	B-Disease
incidence	O
through	O
2010	O
/	O
2011	O
(	O
NC	O
/	O
IA	O
)	O
for	O
49	O
,	O
616	O
applicators	O
,	O
53	O
%	O
of	O
whom	O
reported	O
ever	O
using	O
metolachlor	B-Chemical
.	O

We	O
used	O
Poisson	O
regression	O
to	O
evaluate	O
relations	O
between	O
two	O
metrics	O
of	O
metolachlor	B-Chemical
use	O
(	O
lifetime	O
days	O
,	O
intensity	O
-	O
weighted	O
lifetime	O
days	O
)	O
and	O
cancer	B-Disease
incidence	O
.	O

We	O
saw	O
no	O
association	O
between	O
metolachlor	B-Chemical
use	O
and	O
incidence	O
of	O
all	O
cancers	B-Disease
combined	O
(	O
n	O
=	O
5	O
,	O
701	O
with	O
a	O
5	O
-	O
year	O
lag	O
)	O
or	O
most	O
site	O
-	O
specific	O
cancers	B-Disease
.	O

For	O
liver	B-Disease
cancer	I-Disease
,	O
in	O
analyses	O
restricted	O
to	O
exposed	O
workers	O
,	O
elevations	O
observed	O
at	O
higher	O
categories	O
of	O
use	O
were	O
not	O
statistically	O
significant	O
.	O

However	O
,	O
trends	O
for	O
both	O
lifetime	O
and	O
intensity	O
-	O
weighted	O
lifetime	O
days	O
of	O
metolachor	B-Chemical
use	O
were	O
positive	O
and	O
statistically	O
significant	O
with	O
an	O
unexposed	O
reference	O
group	O
.	O

A	O
similar	O
pattern	O
was	O
observed	O
for	O
follicular	B-Disease
cell	I-Disease
lymphoma	I-Disease
,	O
but	O
no	O
other	O
lymphoma	B-Disease
subtypes	O
.	O

An	O
earlier	O
suggestion	O
of	O
increased	O
lung	B-Disease
cancer	I-Disease
risk	O
at	O
high	O
levels	O
of	O
metolachlor	B-Chemical
use	O
in	O
this	O
cohort	O
was	O
not	O
confirmed	O
in	O
this	O
update	O
.	O

This	O
suggestion	O
of	O
an	O
association	O
between	O
metolachlor	B-Chemical
and	O
liver	B-Disease
cancer	I-Disease
among	O
pesticide	O
applicators	O
is	O
a	O
novel	O
finding	O
and	O
echoes	O
observation	O
of	O
increased	O
liver	B-Disease
neoplasms	I-Disease
in	O
some	O
animal	O
studies	O
.	O

However	O
,	O
our	O
findings	O
for	O
both	O
liver	B-Disease
cancer	I-Disease
and	O
follicular	O
cell	O
lymphoma	B-Disease
warrant	O
follow	O
-	O
up	O
to	O
better	O
differentiate	O
effects	O
of	O
metolachlor	B-Chemical
use	O
from	O
other	O
factors	O
.	O

Mechanisms	O
Underlying	O
Latent	O
Disease	O
Risk	O
Associated	O
with	O
Early	O
-	O
Life	O
Arsenic	B-Chemical
Exposure	O
:	O
Current	O
Research	O
Trends	O
and	O
Scientific	O
Gaps	O
.	O

BACKGROUND	O
:	O
Millions	O
of	O
individuals	O
worldwide	O
,	O
particularly	O
those	O
living	O
in	O
rural	O
and	O
developing	O
areas	O
,	O
are	O
exposed	O
to	O
harmful	O
levels	O
of	O
inorganic	B-Chemical
arsenic	I-Chemical
(	O
iAs	B-Chemical
)	O
in	O
their	O
drinking	O
water	O
.	O

Inorganic	B-Chemical
As	I-Chemical
exposure	O
during	O
key	O
developmental	O
periods	O
is	O
associated	O
with	O
a	O
variety	O
of	O
adverse	O
health	O
effects	O
including	O
those	O
that	O
are	O
evident	O
in	O
adulthood	O
.	O

There	O
is	O
considerable	O
interest	O
in	O
identifying	O
the	O
molecular	O
mechanisms	O
that	O
relate	O
early	O
-	O
life	O
iAs	B-Chemical
exposure	O
to	O
the	O
development	O
of	O
these	O
latent	O
diseases	O
,	O
particularly	O
in	O
relationship	O
to	O
cancer	B-Disease
.	O

OBJECTIVES	O
:	O
This	O
work	O
summarizes	O
research	O
on	O
the	O
molecular	O
mechanisms	O
that	O
underlie	O
the	O
increased	O
risk	O
of	O
cancer	B-Disease
development	O
in	O
adulthood	O
that	O
is	O
associated	O
with	O
early	O
-	O
life	O
iAs	B-Chemical
exposure	O
.	O

DISCUSSION	O
:	O
Epigenetic	O
reprogramming	O
that	O
imparts	O
functional	O
changes	O
in	O
gene	O
expression	O
,	O
the	O
development	O
of	O
cancer	B-Disease
stem	O
cells	O
,	O
and	O
immunomodulation	O
are	O
plausible	O
underlying	O
mechanisms	O
by	O
which	O
early	O
-	O
life	O
iAs	B-Chemical
exposure	O
elicits	O
latent	O
carcinogenic	O
effects	O
.	O

CONCLUSIONS	O
:	O
Evidence	O
is	O
mounting	O
that	O
relates	O
early	O
-	O
life	O
iAs	B-Chemical
exposure	O
and	O
cancer	B-Disease
development	O
later	O
in	O
life	O
.	O

Future	O
research	O
should	O
include	O
animal	O
studies	O
that	O
address	O
mechanistic	O
hypotheses	O
and	O
studies	O
of	O
human	O
populations	O
that	O
integrate	O
early	O
-	O
life	O
exposure	O
,	O
molecular	O
alterations	O
,	O
and	O
latent	O
disease	O
outcomes	O
.	O

Nifedipine	B-Chemical
induced	O
bradycardia	B-Disease
in	O
a	O
patient	O
with	O
autonomic	B-Disease
neuropathy	I-Disease
.	O

An	O
80	O
year	O
old	O
diabetic	B-Disease
male	O
with	O
evidence	O
of	O
peripheral	B-Disease
and	I-Disease
autonomic	I-Disease
neuropathy	I-Disease
was	O
admitted	O
with	O
chest	B-Disease
pain	I-Disease
.	O

He	O
was	O
found	O
to	O
have	O
atrial	B-Disease
flutter	I-Disease
at	O
a	O
ventricular	O
rate	O
of	O
70	O
/	O
min	O
which	O
slowed	O
down	O
to	O
30	O
-	O
40	O
/	O
min	O
when	O
nifedipine	B-Chemical
(	O
60	O
mg	O
)	O
in	O
3	O
divided	O
doses	O
,	O
during	O
which	O
he	O
was	O
paced	O
at	O
a	O
rate	O
of	O
70	O
/	O
min	O
.	O

This	O
is	O
inconsistent	O
with	O
the	O
well	O
-	O
established	O
finding	O
that	O
nifedipine	B-Chemical
induces	O
tachycardia	B-Disease
in	O
normally	O
innervated	O
hearts	O
.	O

However	O
,	O
in	O
hearts	O
deprived	O
of	O
compensatory	O
sympathetic	O
drive	O
,	O
it	O
may	O
lead	O
to	O
bradycardia	B-Disease
.	O

The	O
effect	O
of	O
haloperidol	B-Chemical
in	O
cocaine	B-Chemical
and	O
amphetamine	B-Chemical
intoxication	O
.	O

The	O
effectiveness	O
of	O
haloperidol	B-Chemical
pretreatment	O
in	O
preventing	O
the	O
toxic	O
effects	O
of	O
high	O
doses	O
of	O
amphetamine	B-Chemical
and	O
cocaine	B-Chemical
was	O
studied	O
in	O
rats	O
.	O

In	O
this	O
model	O
,	O
toxic	O
effects	O
were	O
induced	O
by	O
intraperitoneal	O
(	O
i	O
.	O
p	O
.	O
)	O
injection	O
of	O
amphetamine	B-Chemical
75	O
mg	O
/	O
kg	O
(	O
100	O
%	O
death	O
rate	O
)	O
or	O
cocaine	B-Chemical
70	O
mg	O
/	O
kg	O
(	O
82	O
%	O
death	O
rate	O
)	O
.	O

Haloperidol	B-Chemical
failed	O
to	O
prevent	O
amphetamine	B-Chemical
-	O
induced	O
seizures	B-Disease
,	O
but	O
did	O
lower	O
the	O
mortality	O
rate	O
at	O
most	O
doses	O
tested	O
.	O

Haloperidol	B-Chemical
decreased	O
the	O
incidence	O
of	O
cocaine	B-Chemical
-	O
induced	O
seizures	B-Disease
at	O
the	O
two	O
highest	O
doses	O
,	O
but	O
the	O
lowering	O
of	O
the	O
mortality	O
rate	O
did	O
not	O
reach	O
statistical	O
significance	O
at	O
any	O
dose	O
.	O

These	O
data	O
suggest	O
a	O
protective	O
role	O
for	O
the	O
central	O
dopamine	B-Chemical
blocker	O
haloperidol	B-Chemical
against	O
death	O
from	O
high	O
-	O
dose	O
amphetamine	B-Chemical
exposure	O
without	O
reducing	O
the	O
incidence	O
of	O
seizures	B-Disease
.	O

In	O
contrast	O
,	O
haloperidol	B-Chemical
demonstrated	O
an	O
ability	O
to	O
reduce	O
cocaine	B-Chemical
-	O
induced	O
seizures	B-Disease
without	O
significantly	O
reducing	O
mortality	O
.	O

Autoradiographic	O
evidence	O
of	O
estrogen	B-Chemical
binding	O
sites	O
in	O
nuclei	O
of	O
diethylstilbesterol	B-Chemical
induced	O
hamster	O
renal	B-Disease
carcinomas	I-Disease
.	O

Estrogen	B-Chemical
binding	O
sites	O
were	O
demonstrated	O
by	O
autoradiography	O
in	O
one	O
transplantable	O
and	O
five	O
primary	O
diethylstilbesterol	B-Chemical
induced	O
renal	B-Disease
carcinomas	I-Disease
in	O
three	O
hamsters	O
.	O

Radiolabelling	O
,	O
following	O
the	O
in	O
vivo	O
injection	O
of	O
3H	O
-	O
17	O
beta	O
estradiol	B-Chemical
,	O
was	O
increased	O
only	O
over	O
the	O
nuclei	O
of	O
tumor	B-Disease
cells	O
;	O
stereologic	O
analysis	O
revealed	O
a	O
4	O
.	O
5	O
-	O
to	O
6	O
.	O
7	O
-	O
times	O
higher	O
concentration	O
of	O
reduced	O
silver	B-Chemical
grains	O
over	O
nuclei	O
than	O
cytoplasm	O
of	O
these	O
cells	O
.	O

Despite	O
rapid	O
tubular	O
excretion	O
of	O
estradiol	B-Chemical
which	O
peaked	O
in	O
less	O
than	O
1	O
h	O
,	O
the	O
normal	O
cells	O
did	O
not	O
appear	O
to	O
bind	O
the	O
ligand	O
.	O

This	O
is	O
the	O
first	O
published	O
report	O
documenting	O
the	O
preferential	O
in	O
vivo	O
binding	O
of	O
estrogen	B-Chemical
to	O
nuclei	O
of	O
cells	O
in	O
estrogen	B-Chemical
induced	O
hamster	O
renal	B-Disease
carcinomas	I-Disease
.	O

Bradycardia	B-Disease
due	O
to	O
biperiden	B-Chemical
.	O

In	O
a	O
38	O
-	O
year	O
-	O
old	O
male	O
patient	O
suffering	O
from	O
a	O
severe	O
postzosteric	B-Disease
trigeminal	B-Disease
neuralgia	I-Disease
,	O
intravenous	O
application	O
of	O
10	O
mg	O
biperiden	B-Chemical
lactate	I-Chemical
led	O
to	O
a	O
long	O
-	O
lasting	O
paradoxical	O
reaction	O
characterized	O
by	O
considerable	O
bradycardia	B-Disease
,	O
dysarthria	B-Disease
,	O
and	O
dysphagia	B-Disease
.	O

The	O
heart	O
rate	O
was	O
back	O
to	O
normal	O
within	O
12	O
hours	O
upon	O
administration	O
of	O
orciprenaline	B-Chemical
under	O
cardiac	O
monitoring	O
in	O
an	O
intensive	O
care	O
unit	O
.	O

Bradycardia	B-Disease
induced	O
by	O
biperiden	B-Chemical
is	O
attributed	O
to	O
the	O
speed	O
of	O
injection	O
and	O
to	O
a	O
dose	O
-	O
related	O
dual	O
effect	O
of	O
atropine	B-Chemical
-	O
like	O
drugs	O
on	O
muscarine	B-Chemical
receptors	O
.	O

Deliberate	O
hypotension	B-Disease
induced	O
by	O
labetalol	B-Chemical
with	O
halothane	B-Chemical
,	O
enflurane	B-Chemical
or	O
isoflurane	B-Chemical
for	O
middle	O
-	O
ear	O
surgery	O
.	O

The	O
feasibility	O
of	O
using	O
labetalol	B-Chemical
,	O
an	O
alpha	O
-	O
and	O
beta	O
-	O
adrenergic	O
blocking	O
agent	O
,	O
as	O
a	O
hypotensive	B-Disease
agent	O
in	O
combination	O
with	O
inhalation	O
anaesthetics	O
(	O
halothane	B-Chemical
,	O
enflurane	B-Chemical
or	O
isoflurane	B-Chemical
)	O
was	O
studied	O
in	O
23	O
adult	O
patients	O
undergoing	O
middle	O
-	O
ear	O
surgery	O
.	O

The	O
mean	O
arterial	O
pressure	O
was	O
decreased	O
from	O
86	O
+	O
/	O
-	O
5	O
(	O
s	O
.	O
e	O
.	O
mean	O
)	O
mmHg	O
to	O
52	O
+	O
/	O
-	O
1	O
mmHg	O
(	O
11	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
7	O
to	O
6	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
1	O
kPa	O
)	O
for	O
98	O
+	O
/	O
-	O
10	O
min	O
in	O
the	O
halothane	B-Chemical
(	O
H	B-Chemical
)	O
group	O
,	O
from	O
79	O
+	O
/	O
-	O
5	O
to	O
53	O
+	O
/	O
-	O
1	O
mmHg	O
(	O
10	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
7	O
to	O
7	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
1	O
kPa	O
)	O
for	O
129	O
+	O
/	O
-	O
11	O
min	O
in	O
the	O
enflurane	B-Chemical
(	O
E	B-Chemical
)	O
group	O
,	O
and	O
from	O
80	O
+	O
/	O
-	O
4	O
to	O
49	O
+	O
/	O
-	O
1	O
mmHg	O
(	O
10	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
5	O
to	O
6	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
1	O
kPa	O
)	O
for	O
135	O
+	O
/	O
-	O
15	O
min	O
in	O
the	O
isoflurane	B-Chemical
(	O
I	B-Chemical
)	O
group	O
.	O

The	O
mean	O
H	B-Chemical
concentration	O
during	O
hypotension	B-Disease
in	O
the	O
inspiratory	O
gas	O
was	O
0	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
1	O
vol	O
%	O
,	O
the	O
mean	O
E	B-Chemical
concentration	O
1	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
2	O
vol	O
%	O
,	O
and	O
the	O
mean	O
I	B-Chemical
concentration	O
1	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
1	O
vol	O
%	O
.	O

In	O
addition	O
,	O
the	O
patients	O
received	O
fentanyl	B-Chemical
and	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
.	O

The	O
initial	O
dose	O
of	O
labetalol	B-Chemical
for	O
lowering	O
blood	O
pressure	O
was	O
similar	O
,	O
0	O
.	O
52	O
-	O
0	O
.	O
59	O
mg	O
/	O
kg	O
,	O
in	O
all	O
the	O
groups	O
.	O

During	O
hypotension	B-Disease
,	O
the	O
heart	O
rate	O
was	O
stable	O
without	O
tachy	B-Disease
-	I-Disease
or	I-Disease
bradycardia	I-Disease
.	O

The	O
operating	O
conditions	O
regarding	O
bleeding	B-Disease
were	O
estimated	O
in	O
a	O
double	O
-	O
blind	O
manner	O
,	O
and	O
did	O
not	O
differ	O
significantly	O
between	O
the	O
groups	O
.	O

During	O
hypotension	B-Disease
,	O
the	O
serum	O
creatinine	B-Chemical
concentration	O
rose	O
significantly	O
in	O
all	O
groups	O
from	O
the	O
values	O
before	O
hypotension	B-Disease
and	O
returned	O
postoperatively	O
to	O
the	O
initial	O
level	O
in	O
the	O
other	O
groups	O
,	O
except	O
the	O
isoflurane	B-Chemical
group	O
.	O

After	O
hypotension	B-Disease
there	O
was	O
no	O
rebound	O
phenomenon	O
in	O
either	O
blood	O
pressure	O
or	O
heart	O
rate	O
.	O

These	O
results	O
indicate	O
that	O
labetalol	B-Chemical
induces	O
easily	O
adjustable	O
hypotension	B-Disease
without	O
compensatory	O
tachycardia	B-Disease
and	O
rebound	O
hypertension	B-Disease
.	O

Convulsion	B-Disease
following	O
intravenous	O
fluorescein	B-Chemical
angiography	O
.	O

Tonic	B-Disease
-	I-Disease
clonic	I-Disease
seizures	I-Disease
followed	O
intravenous	O
fluorescein	B-Chemical
injection	O
for	O
fundus	O
angiography	O
in	O
a	O
47	O
-	O
year	O
-	O
old	O
male	O
.	O

Despite	O
precautions	O
this	O
adverse	O
reaction	O
recurred	O
on	O
re	O
-	O
exposure	O
to	O
intravenous	O
fluorescein	B-Chemical
.	O

Pharmacology	O
of	O
ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
(	O
phenytoin	B-Chemical
prodrug	O
)	O
.	O

ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
,	O
the	O
disodium	B-Chemical
phosphate	I-Chemical
ester	I-Chemical
of	O
3	B-Chemical
-	I-Chemical
hydroxymethyl	I-Chemical
-	I-Chemical
5	I-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
diphenylhydantoin	I-Chemical
,	O
is	O
a	O
prodrug	O
of	O
phenytoin	B-Chemical
with	O
advantageous	O
physicochemical	O
properties	O
.	O

ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
is	O
rapidly	O
converted	O
enzymatically	O
to	O
phenytoin	B-Chemical
in	O
vivo	O
.	O

ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
and	O
phenytoin	B-Chemical
sodium	I-Chemical
have	O
equivalent	O
anticonvulsant	O
activity	O
against	O
seizures	B-Disease
induced	O
by	O
maximal	O
electroshock	O
(	O
MES	O
)	O
in	O
mice	O
following	O
i	O
.	O
p	O
.	O
,	O
oral	O
,	O
or	O
i	O
.	O
v	O
.	O
administration	O
.	O

The	O
ED50	O
doses	O
were	O
16	O
mg	O
/	O
kg	O
for	O
i	O
.	O
v	O
.	O
ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
and	O
8	O
mg	O
/	O
kg	O
for	O
i	O
.	O
v	O
.	O
phenytoin	B-Chemical
sodium	I-Chemical
.	O

ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
and	O
phenytoin	B-Chemical
sodium	I-Chemical
have	O
similar	O
antiarrhythmic	O
activity	O
against	O
ouabain	B-Chemical
-	O
induced	O
ventricular	B-Disease
tachycardia	I-Disease
in	O
anesthetized	O
dogs	O
.	O

The	O
total	O
doses	O
of	O
ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
or	O
phenytoin	B-Chemical
sodium	I-Chemical
necessary	O
to	O
convert	O
the	O
arrhythmia	B-Disease
to	O
a	O
normal	O
sinus	O
rhythm	O
were	O
24	O
+	O
/	O
-	O
6	O
and	O
14	O
+	O
/	O
-	O
3	O
mg	O
/	O
kg	O
,	O
respectively	O
.	O

Only	O
phenytoin	B-Chemical
sodium	I-Chemical
displayed	O
in	O
vitro	O
antiarrhythmic	O
activity	O
against	O
strophanthidin	B-Chemical
-	O
induced	O
arrhythmias	B-Disease
in	O
guinea	O
pig	O
right	O
atria	O
.	O

In	O
anesthetized	O
dogs	O
,	O
a	O
high	O
dose	O
of	O
ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
(	O
31	O
mg	O
/	O
kg	O
)	O
was	O
infused	O
over	O
15	O
,	O
20	O
,	O
and	O
30	O
min	O
and	O
the	O
responses	O
were	O
compared	O
to	O
an	O
equimolar	O
dose	O
of	O
phenytoin	B-Chemical
sodium	I-Chemical
(	O
21	O
mg	O
/	O
kg	O
)	O
.	O

The	O
ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
and	O
phenytoin	B-Chemical
sodium	I-Chemical
treatments	O
produced	O
similar	O
marked	O
reductions	O
in	O
diastolic	O
blood	O
pressure	O
and	O
contractile	O
force	O
(	O
LVdP	O
/	O
dt	O
)	O
.	O

The	O
maximum	O
effects	O
of	O
each	O
treatment	O
occurred	O
at	O
the	O
time	O
of	O
maximum	O
phenytoin	B-Chemical
sodium	I-Chemical
levels	O
.	O

Acute	O
toxicity	B-Disease
studies	O
of	O
ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
and	O
phenytoin	B-Chemical
sodium	I-Chemical
were	O
carried	O
out	O
in	O
mice	O
,	O
rats	O
,	O
rabbits	O
,	O
and	O
dogs	O
by	O
i	O
.	O
v	O
.	O
,	O
i	O
.	O
m	O
.	O
,	O
and	O
i	O
.	O
p	O
.	O
routes	O
of	O
administration	O
.	O

The	O
systemic	O
toxic	O
signs	O
of	O
both	O
agents	O
were	O
similar	O
and	O
occurred	O
at	O
approximately	O
equivalent	O
doses	O
.	O

Importantly	O
,	O
the	O
local	O
irritation	O
of	O
ACC	B-Chemical
-	I-Chemical
9653	I-Chemical
was	O
markedly	O
less	O
than	O
phenytoin	B-Chemical
sodium	I-Chemical
following	O
i	O
.	O
m	O
.	O
administration	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Tachyphylaxis	O
to	O
systemic	O
but	O
not	O
to	O
airway	O
responses	O
during	O
prolonged	O
therapy	O
with	O
high	O
dose	O
inhaled	O
salbutamol	B-Chemical
in	O
asthmatics	B-Disease
.	O

High	O
doses	O
of	O
inhaled	O
salbutamol	B-Chemical
produce	O
substantial	O
improvements	O
in	O
airway	O
response	O
in	O
patients	O
with	O
asthma	B-Disease
,	O
and	O
are	O
associated	O
with	O
dose	O
-	O
dependent	O
systemic	O
beta	O
-	O
adrenoceptor	O
responses	O
.	O

The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
whether	O
tachyphylaxis	O
occurs	O
during	O
prolonged	O
treatment	O
with	O
high	O
dose	O
inhaled	O
salbutamol	B-Chemical
.	O

Twelve	O
asthmatic	B-Disease
patients	O
(	O
FEV1	O
,	O
81	O
+	O
/	O
-	O
4	O
%	O
predicted	O
)	O
,	O
requiring	O
only	O
occasional	O
inhaled	O
beta	O
-	O
agonists	O
as	O
their	O
sole	O
therapy	O
,	O
were	O
given	O
a	O
14	O
-	O
day	O
treatment	O
with	O
high	O
dose	O
inhaled	O
salbutamol	B-Chemical
(	O
HDS	O
)	O
,	O
4	O
,	O
000	O
micrograms	O
daily	O
,	O
low	O
dose	O
inhaled	O
salbutamol	B-Chemical
(	O
LDS	O
)	O
,	O
800	O
micrograms	O
daily	O
,	O
or	O
placebo	O
(	O
PI	O
)	O
by	O
metered	O
-	O
dose	O
inhaler	O
in	O
a	O
double	O
-	O
blind	O
,	O
randomized	O
crossover	O
design	O
.	O

During	O
the	O
14	O
-	O
day	O
run	O
-	O
in	O
and	O
during	O
washout	O
periods	O
,	O
inhaled	O
beta	O
-	O
agonists	O
were	O
withheld	O
and	O
ipratropium	B-Chemical
bromide	I-Chemical
was	O
substituted	O
for	O
rescue	O
purposes	O
.	O

At	O
the	O
end	O
of	O
each	O
14	O
-	O
day	O
treatment	O
,	O
a	O
dose	O
-	O
response	O
curve	O
(	O
DRC	O
)	O
was	O
performed	O
,	O
and	O
airway	O
(	O
FEV1	O
,	O
FEF25	O
-	O
75	O
)	O
chronotropic	O
(	O
HR	O
)	O
,	O
tremor	B-Disease
,	O
and	O
metabolic	O
(	O
K	B-Chemical
,	O
Glu	B-Chemical
)	O
responses	O
were	O
measured	O
at	O
each	O
step	O
(	O
from	O
100	O
to	O
4	O
,	O
000	O
micrograms	O
)	O
.	O

Treatment	O
had	O
no	O
significant	O
effect	O
on	O
baseline	O
values	O
.	O

There	O
were	O
dose	O
-	O
dependent	O
increases	O
in	O
FEV1	O
and	O
FEF25	O
-	O
75	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
and	O
pretreatment	O
with	O
HDS	O
did	O
not	O
displace	O
the	O
DRC	O
to	O
the	O
right	O
.	O

DRC	O
for	O
HR	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
K	B-Chemical
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
and	O
Glu	B-Chemical
(	O
p	O
less	O
than	O
0	O
.	O
005	O
)	O
were	O
attenuated	O
after	O
treatment	O
with	O
HDS	O
compared	O
with	O
PI	O
.	O

There	O
were	O
also	O
differences	O
between	O
HDS	O
and	O
LDS	O
for	O
HR	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
and	O
Glu	B-Chemical
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
responses	O
.	O

Frequency	O
and	O
severity	O
of	O
subjective	O
adverse	O
effects	O
were	O
also	O
reduced	O
after	O
HDS	O
:	O
tremor	B-Disease
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
palpitations	B-Disease
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Phenytoin	B-Chemical
induced	O
fatal	O
hepatic	B-Disease
injury	I-Disease
.	O

A	O
61	O
year	O
old	O
female	O
developed	O
fatal	O
hepatic	B-Disease
failure	I-Disease
after	O
phenytoin	B-Chemical
administration	O
.	O

A	O
typical	O
multisystem	O
clinical	O
pattern	O
precedes	O
the	O
manifestations	O
of	O
hepatic	B-Disease
injury	I-Disease
.	O

The	O
hematologic	O
,	O
biochemical	O
and	O
pathologic	O
features	O
indicate	O
a	O
mixed	O
hepatocellular	B-Disease
damage	I-Disease
due	O
to	O
drug	B-Disease
hypersensitivity	I-Disease
.	O

In	O
a	O
patient	O
receiving	O
phenytoin	B-Chemical
who	O
presents	O
a	O
viral	O
-	O
like	O
illness	O
,	O
early	O
recognition	O
and	O
discontinuation	O
of	O
the	O
drug	O
are	O
mandatory	O
.	O

Treatment	O
of	O
lethal	O
pertussis	B-Chemical
vaccine	I-Chemical
reaction	O
with	O
histamine	B-Chemical
H1	O
antagonists	O
.	O

We	O
studied	O
mortality	O
after	O
pertussis	B-Disease
immunization	O
in	O
the	O
mouse	O
.	O

Without	O
treatment	O
,	O
73	O
of	O
92	O
animals	O
(	O
80	O
%	O
)	O
died	O
after	O
injection	O
of	O
bovine	O
serum	O
albumin	O
(	O
BSA	O
)	O
on	O
day	O
+	O
7	O
of	O
pertussis	B-Disease
immunization	O
.	O

After	O
pretreatment	O
with	O
3	O
mg	O
of	O
cyproheptadine	B-Chemical
,	O
2	O
mg	O
mianserin	B-Chemical
,	O
or	O
2	O
mg	O
chlorpheniramine	B-Chemical
,	O
only	O
5	O
of	O
105	O
animals	O
(	O
5	O
%	O
)	O
died	O
after	O
receiving	O
BSA	O
on	O
day	O
+	O
7	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Blockade	O
of	O
histamine	B-Chemical
H1	O
receptors	O
may	O
reduce	O
mortality	O
in	O
pertussis	B-Disease
immunization	O
-	O
induced	O
encephalopathy	B-Disease
in	O
mice	O
.	O

Support	O
for	O
adrenaline	B-Chemical
-	O
hypertension	B-Disease
hypothesis	O
:	O
18	O
hour	O
pressor	O
effect	O
after	O
6	O
hours	O
adrenaline	B-Chemical
infusion	O
.	O

In	O
a	O
double	O
blind	O
,	O
crossover	O
study	O
6	O
h	O
infusions	O
of	O
adrenaline	B-Chemical
(	O
15	O
ng	O
/	O
kg	O
/	O
min	O
;	O
1	O
ng	O
=	O
5	O
.	O
458	O
pmol	O
)	O
,	O
noradrenaline	B-Chemical
(	O
30	O
ng	O
/	O
kg	O
/	O
min	O
;	O
1	O
ng	O
=	O
5	O
.	O
911	O
pmol	O
)	O
,	O
and	O
a	O
5	O
%	O
dextrose	B-Chemical
solution	O
(	O
5	O
.	O
4	O
ml	O
/	O
h	O
)	O
,	O
were	O
given	O
to	O
ten	O
healthy	O
volunteers	O
in	O
random	O
order	O
2	O
weeks	O
apart	O
.	O

By	O
means	O
of	O
intra	O
-	O
arterial	O
ambulatory	O
monitoring	O
the	O
haemodynamic	O
effects	O
were	O
followed	O
for	O
18	O
h	O
after	O
the	O
infusions	O
were	O
stopped	O
.	O

Adrenaline	B-Chemical
,	O
but	O
not	O
noradrenaline	B-Chemical
,	O
caused	O
a	O
delayed	O
and	O
protracted	O
pressor	O
effect	O
.	O

Over	O
the	O
total	O
postinfusion	O
period	O
systolic	O
and	O
diastolic	O
arterial	O
pressure	O
were	O
6	O
(	O
SEM	O
2	O
)	O
%	O
and	O
7	O
(	O
2	O
)	O
%	O
,	O
respectively	O
,	O
higher	O
than	O
after	O
dextrose	B-Chemical
infusion	O
(	O
ANOVA	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Thus	O
,	O
"	O
stress	O
"	O
levels	O
of	O
adrenaline	B-Chemical
(	O
230	O
pg	O
/	O
ml	O
)	O
for	O
6	O
h	O
cause	O
a	O
delayed	O
and	O
protracted	O
pressor	O
effect	O
.	O

These	O
findings	O
are	O
strong	O
support	O
for	O
the	O
adrenaline	B-Chemical
-	O
hypertension	B-Disease
hypothesis	O
in	O
man	O
.	O

Effect	O
of	O
alkylxanthines	B-Chemical
on	O
gentamicin	B-Chemical
-	O
induced	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
in	O
the	O
rat	O
.	O

Adenosine	B-Chemical
antagonists	O
have	O
been	O
previously	O
shown	O
to	O
be	O
of	O
benefit	O
in	O
some	O
ischaemic	B-Disease
and	O
nephrotoxic	B-Disease
models	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
(	O
ARF	B-Disease
)	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
effects	O
of	O
three	O
alkylxanthines	B-Chemical
with	O
different	O
potencies	O
as	O
adenosine	B-Chemical
antagonists	O
8	B-Chemical
-	I-Chemical
phenyltheophylline	I-Chemical
,	O
theophylline	B-Chemical
and	O
enprofylline	B-Chemical
,	O
were	O
examined	O
in	O
rats	O
developing	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
after	O
4	O
daily	O
injections	O
of	O
gentamicin	B-Chemical
(	O
200	O
mg	O
kg	O
-	O
1	O
)	O
.	O

Renal	O
function	O
was	O
assessed	O
by	O
biochemical	O
(	O
plasma	O
urea	B-Chemical
and	O
creatinine	B-Chemical
)	O
,	O
functional	O
(	O
urine	O
analysis	O
and	O
[	O
3H	O
]	O
inulin	O
and	O
[	O
14C	O
]	O
p	B-Chemical
-	I-Chemical
aminohippuric	I-Chemical
acid	I-Chemical
clearances	O
)	O
and	O
morphological	O
(	O
degree	O
of	O
necrosis	B-Disease
)	O
indices	O
.	O

The	O
various	O
drug	O
treatments	O
produced	O
improvements	O
in	O
some	O
,	O
but	O
not	O
all	O
,	O
measurements	O
of	O
renal	O
function	O
.	O

However	O
,	O
any	O
improvement	O
produced	O
by	O
drug	O
treatment	O
was	O
largely	O
a	O
result	O
of	O
a	O
beneficial	O
effect	O
exerted	O
by	O
its	O
vehicle	O
(	O
polyethylene	B-Chemical
glycol	I-Chemical
and	O
NaOH	B-Chemical
)	O
.	O

The	O
lack	O
of	O
any	O
consistent	O
protective	O
effect	O
noted	O
with	O
the	O
alkylxanthines	B-Chemical
tested	O
in	O
the	O
present	O
study	O
indicates	O
that	O
adenosine	B-Chemical
plays	O
little	O
,	O
if	O
any	O
,	O
pathophysiological	O
role	O
in	O
gentamicin	B-Chemical
-	O
induced	O
ARF	B-Disease
.	O

Adverse	O
ocular	O
reactions	O
possibly	O
associated	O
with	O
isotretinoin	B-Chemical
.	O

A	O
total	O
of	O
261	O
adverse	O
ocular	O
reactions	O
occurred	O
in	O
237	O
patients	O
who	O
received	O
isotretinoin	B-Chemical
,	O
a	O
commonly	O
used	O
drug	O
in	O
the	O
treatment	O
of	O
severe	O
cystic	O
acne	B-Disease
.	O

Blepharoconjunctivitis	B-Disease
,	O
subjective	O
complaints	O
of	O
dry	B-Disease
eyes	I-Disease
,	O
blurred	B-Disease
vision	I-Disease
,	O
contact	O
lens	O
intolerance	O
,	O
and	O
photodermatitis	B-Disease
are	O
reversible	O
side	O
effects	O
.	O

More	O
serious	O
ocular	O
adverse	O
reactions	O
include	O
papilledema	B-Disease
,	O
pseudotumor	B-Disease
cerebri	I-Disease
,	O
and	O
white	O
or	O
gray	O
subepithelial	O
corneal	B-Disease
opacities	I-Disease
;	O
all	O
of	O
these	O
are	O
reversible	O
if	O
the	O
drug	O
is	O
discontinued	O
.	O

Reported	O
cases	O
of	O
decreased	O
dark	O
adaptation	O
are	O
under	O
investigation	O
.	O

Isotretinoin	B-Chemical
is	O
contraindicated	O
in	O
pregnancy	O
because	O
of	O
the	O
many	O
reported	O
congenital	B-Disease
abnormalities	I-Disease
after	O
maternal	O
use	O
(	O
including	O
microphthalmos	B-Disease
,	O
orbital	O
hypertelorism	B-Disease
,	O
and	O
optic	B-Disease
nerve	I-Disease
hypoplasia	I-Disease
)	O
.	O

Procaterol	B-Chemical
and	O
terbutaline	B-Chemical
in	O
bronchial	B-Disease
asthma	I-Disease
.	O

A	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
,	O
cross	O
-	O
over	O
study	O
.	O

Procaterol	B-Chemical
,	O
a	O
new	O
beta	O
-	O
2	O
adrenoceptor	O
stimulant	O
,	O
was	O
studied	O
in	O
a	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
,	O
cross	O
-	O
over	O
trial	O
in	O
patients	O
with	O
bronchial	B-Disease
asthma	I-Disease
.	O

Oral	O
procaterol	B-Chemical
50	O
micrograms	O
b	O
.	O
d	O
.	O
,	O
procaterol	B-Chemical
100	O
micrograms	O
b	O
.	O
d	O
.	O
,	O
and	O
terbutaline	B-Chemical
5	O
mg	O
t	O
.	O
i	O
.	O
d	O
.	O
,	O
were	O
compared	O
when	O
given	O
randomly	O
in	O
1	O
-	O
week	O
treatment	O
periods	O
.	O

The	O
best	O
clinical	O
effect	O
was	O
found	O
with	O
terbutaline	B-Chemical
.	O

Both	O
anti	O
-	O
asthmatic	B-Disease
and	O
tremorgenic	B-Disease
effects	O
of	O
procaterol	B-Chemical
were	O
dose	O
-	O
related	O
.	O

Procaterol	B-Chemical
appeared	O
effective	O
in	O
the	O
doses	O
tested	O
,	O
and	O
a	O
twice	O
daily	O
regimen	O
would	O
appear	O
to	O
be	O
suitable	O
with	O
this	O
drug	O
.	O

Subacute	O
effects	O
of	O
propranolol	B-Chemical
and	O
B	O
24	O
/	O
76	O
on	O
isoproterenol	B-Chemical
-	O
induced	O
rat	O
heart	B-Disease
hypertrophy	I-Disease
in	O
correlation	O
with	O
blood	O
pressure	O
.	O

We	O
compared	O
the	O
potential	O
beta	O
-	O
receptor	O
blocker	O
,	O
B	O
24	O
/	O
76	O
i	O
.	O
e	O
.	O
1	O
-	O
(	O
2	O
,	O
4	O
-	O
dichlorophenoxy	O
)	O
-	O
3	O
[	O
2	O
-	O
3	O
,	O
4	O
-	O
dimethoxyphenyl	O
)	O
ethanolamino	O
]	O
-	O
prop	O
an	O
-	O
2	O
-	O
ol	O
,	O
which	O
is	O
characterized	O
by	O
beta	O
1	O
-	O
adrenoceptor	O
blocking	O
and	O
beta	O
2	O
-	O
adrenoceptor	O
stimulating	O
properties	O
with	O
propranolol	B-Chemical
.	O

The	O
studies	O
were	O
performed	O
using	O
an	O
experimental	O
model	O
of	O
isoproterenol	B-Chemical
-	O
induced	O
heart	B-Disease
hypertrophy	I-Disease
in	O
rats	O
.	O

A	O
correlation	O
of	O
the	O
blood	O
pressure	O
was	O
neither	O
found	O
in	O
the	O
development	O
nor	O
in	O
the	O
attempt	O
to	O
suppress	O
the	O
development	O
of	O
heart	B-Disease
hypertrophy	I-Disease
with	O
the	O
two	O
beta	O
-	O
receptor	O
blockers	O
.	O

Both	O
beta	O
-	O
blockers	O
influenced	O
the	O
development	O
of	O
hypertrophy	B-Disease
to	O
a	O
different	O
,	O
but	O
not	O
reproducible	O
extent	O
.	O

It	O
was	O
possible	O
to	O
suppress	O
the	O
increased	O
ornithine	B-Chemical
decarboxylase	O
activity	O
with	O
both	O
beta	O
-	O
blockers	O
in	O
hypertrophied	B-Disease
hearts	I-Disease
,	O
but	O
there	O
was	O
no	O
effect	O
on	O
the	O
heart	O
mass	O
.	O

Neither	O
propranolol	B-Chemical
nor	O
B	O
24	O
/	O
76	O
could	O
stop	O
the	O
changes	O
in	O
the	O
characteristic	O
myosin	O
isoenzyme	O
pattern	O
of	O
the	O
hypertrophied	B-Disease
rat	O
heart	O
.	O

Thus	O
,	O
the	O
investigations	O
did	O
not	O
provide	O
any	O
evidence	O
that	O
the	O
beta	O
-	O
receptor	O
blockers	O
propranolol	B-Chemical
and	O
B	O
24	O
/	O
76	O
have	O
the	O
potency	O
to	O
prevent	O
isoproterenol	B-Chemical
from	O
producing	O
heart	B-Disease
hypertrophy	I-Disease
.	O

Increased	O
anxiogenic	O
effects	O
of	O
caffeine	B-Chemical
in	O
panic	B-Disease
disorders	I-Disease
.	O

The	O
effects	O
of	O
oral	O
administration	O
of	O
caffeine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
)	O
on	O
behavioral	O
ratings	O
,	O
somatic	O
symptoms	O
,	O
blood	O
pressure	O
and	O
plasma	O
levels	O
of	O
3	B-Chemical
-	I-Chemical
methoxy	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
hydroxyphenethyleneglycol	I-Chemical
(	O
MHPG	B-Chemical
)	O
and	O
cortisol	B-Chemical
were	O
determined	O
in	O
17	O
healthy	O
subjects	O
and	O
21	O
patients	O
meeting	O
DSM	O
-	O
III	O
criteria	O
for	O
agoraphobia	B-Disease
with	O
panic	B-Disease
attacks	I-Disease
or	O
panic	B-Disease
disorder	I-Disease
.	O

Caffeine	B-Chemical
produced	O
significantly	O
greater	O
increases	O
in	O
subject	O
-	O
rated	O
anxiety	B-Disease
,	O
nervousness	O
,	O
fear	O
,	O
nausea	B-Disease
,	O
palpitations	B-Disease
,	O
restlessness	B-Disease
,	O
and	O
tremors	B-Disease
in	O
the	O
patients	O
compared	O
with	O
healthy	O
subjects	O
.	O

In	O
the	O
patients	O
,	O
but	O
not	O
the	O
healthy	O
subjects	O
,	O
these	O
symptoms	O
were	O
significantly	O
correlated	O
with	O
plasma	O
caffeine	B-Chemical
levels	O
.	O

Seventy	O
-	O
one	O
percent	O
of	O
the	O
patients	O
reported	O
that	O
the	O
behavioral	O
effects	O
of	O
caffeine	B-Chemical
were	O
similar	O
to	O
those	O
experienced	O
during	O
panic	B-Disease
attacks	I-Disease
.	O

Caffeine	B-Chemical
did	O
not	O
alter	O
plasma	O
MHPG	B-Chemical
levels	O
in	O
either	O
the	O
healthy	O
subjects	O
or	O
patients	O
.	O

Caffeine	B-Chemical
increased	O
plasma	O
cortisol	B-Chemical
levels	O
equally	O
in	O
the	O
patient	O
and	O
healthy	O
groups	O
.	O

Because	O
caffeine	B-Chemical
is	O
an	O
adenosine	B-Chemical
receptor	O
antagonist	O
,	O
these	O
results	O
suggest	O
that	O
some	O
panic	B-Disease
disorder	I-Disease
patients	O
may	O
have	O
abnormalities	B-Disease
in	I-Disease
neuronal	I-Disease
systems	I-Disease
involving	O
adenosine	B-Chemical
.	O

Patients	O
with	O
anxiety	B-Disease
disorders	I-Disease
may	O
benefit	O
by	O
avoiding	O
caffeine	B-Chemical
-	O
containing	O
foods	O
and	O
beverages	O
.	O

Comparison	O
of	O
the	O
effect	O
of	O
oxitropium	B-Chemical
bromide	I-Chemical
and	O
of	O
slow	O
-	O
release	O
theophylline	B-Chemical
on	O
nocturnal	O
asthma	B-Disease
.	O

The	O
effects	O
of	O
a	O
new	O
inhaled	O
antimuscarinic	O
drug	O
,	O
oxitropium	B-Chemical
bromide	I-Chemical
,	O
and	O
of	O
a	O
slow	O
-	O
release	O
theophylline	B-Chemical
preparation	O
upon	O
nocturnal	O
asthma	B-Disease
were	O
compared	O
in	O
a	O
placebo	O
-	O
controlled	O
double	O
-	O
blind	O
study	O
.	O

Two	O
samples	O
were	O
studied	O
:	O
12	O
patients	O
received	O
oxitropium	B-Chemical
at	O
600	O
micrograms	O
(	O
6	O
subjects	O
)	O
or	O
at	O
400	O
micrograms	O
t	O
.	O
i	O
.	O
d	O
.	O

(	O
6	O
subjects	O
)	O
whereas	O
11	O
received	O
theophylline	B-Chemical
at	O
300	O
mg	O
b	O
.	O
i	O
.	O
d	O
.	O

Morning	O
dipping	O
,	O
assessed	O
by	O
the	O
fall	O
in	O
peak	O
flow	O
overnight	O
,	O
was	O
significantly	O
reduced	O
in	O
the	O
periods	O
when	O
either	O
active	O
drug	O
was	O
taken	O
,	O
whereas	O
no	O
difference	O
was	O
noticed	O
during	O
the	O
placebo	O
administration	O
.	O

No	O
significant	O
difference	O
was	O
noticed	O
between	O
results	O
obtained	O
with	O
either	O
active	O
drug	O
,	O
as	O
well	O
as	O
with	O
either	O
dosage	O
of	O
oxitropium	B-Chemical
.	O

No	O
subject	O
reported	O
side	O
effects	O
of	O
oxitropium	B-Chemical
,	O
as	O
compared	O
to	O
three	O
subjects	O
reporting	O
nausea	B-Disease
,	O
vomiting	B-Disease
and	O
tremors	B-Disease
after	O
theophylline	B-Chemical
.	O

Oxitropium	B-Chemical
proves	O
to	O
be	O
a	O
valuable	O
alternative	O
to	O
theophylline	B-Chemical
in	O
nocturnal	O
asthma	B-Disease
,	O
since	O
it	O
is	O
equally	O
potent	O
,	O
safer	O
and	O
does	O
not	O
require	O
the	O
titration	O
of	O
dosage	O
.	O

Penicillin	B-Chemical
anaphylaxis	B-Disease
.	O

A	O
case	O
of	O
oral	O
penicillin	B-Chemical
anaphylaxis	B-Disease
is	O
described	O
,	O
and	O
the	O
terminology	O
,	O
occurrence	O
,	O
clinical	O
manifestations	O
,	O
pathogenesis	O
,	O
prevention	O
,	O
and	O
treatment	O
of	O
anaphylaxis	B-Disease
are	O
reviewed	O
.	O

Emergency	O
physicians	O
should	O
be	O
aware	O
of	O
oral	O
penicillin	B-Chemical
anaphylaxis	B-Disease
in	O
order	O
to	O
prevent	O
its	O
occurrence	O
by	O
prescribing	O
the	O
antibiotic	O
judiciously	O
and	O
knowledgeably	O
and	O
to	O
offer	O
optimal	O
medical	O
therapy	O
once	O
this	O
life	O
-	O
threatening	O
reaction	O
has	O
begun	O
.	O

Reversible	O
valproic	B-Chemical
acid	I-Chemical
-	O
induced	O
dementia	B-Disease
:	O
a	O
case	O
report	O
.	O

Reversible	O
valproic	B-Chemical
acid	I-Chemical
-	O
induced	O
dementia	B-Disease
was	O
documented	O
in	O
a	O
21	O
-	O
year	O
-	O
old	O
man	O
with	O
epilepsy	B-Disease
who	O
had	O
a	O
3	O
-	O
year	O
history	O
of	O
insidious	O
progressive	O
decline	O
in	O
global	O
cognitive	O
abilities	O
documented	O
by	O
serial	O
neuropsychological	O
studies	O
.	O

Repeat	O
neuropsychological	O
testing	O
7	O
weeks	O
after	O
discontinuation	O
of	O
the	O
drug	O
revealed	O
dramatic	O
improvement	O
in	O
IQ	O
,	O
memory	O
,	O
naming	O
,	O
and	O
other	O
tasks	O
commensurate	O
with	O
clinical	O
recovery	O
in	O
his	O
intellectual	O
capacity	O
.	O

Possible	O
pathophysiological	O
mechanisms	O
which	O
may	O
have	O
been	O
operative	O
in	O
this	O
case	O
include	O
:	O
a	O
direct	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
toxic	O
effect	O
of	O
valproic	B-Chemical
acid	I-Chemical
;	O
a	O
paradoxical	O
epileptogenic	O
effect	O
secondary	O
to	O
the	O
drug	O
;	O
and	O
an	O
indirect	O
CNS	O
toxic	O
effect	O
mediated	O
through	O
valproic	B-Chemical
acid	I-Chemical
-	O
induced	O
hyperammonemia	B-Disease
.	O

Reversal	O
of	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
of	O
passive	O
avoidance	O
by	O
pre	O
-	O
and	O
post	O
-	O
training	O
naloxone	B-Chemical
.	O

In	O
a	O
series	O
of	O
five	O
experiments	O
,	O
the	O
modulating	O
role	O
of	O
naloxone	B-Chemical
on	O
a	O
scopolamine	B-Chemical
-	O
induced	O
retention	B-Disease
deficit	I-Disease
in	O
a	O
passive	O
avoidance	O
paradigm	O
was	O
investigated	O
in	O
mice	O
.	O

Scopolamine	B-Chemical
,	O
but	O
not	O
methyl	B-Chemical
scopolamine	I-Chemical
(	O
1	O
and	O
3	O
mg	O
/	O
kg	O
)	O
,	O
induced	O
an	O
amnesia	B-Disease
as	O
measured	O
by	O
latency	O
and	O
duration	O
parameters	O
.	O

Naloxone	B-Chemical
(	O
0	O
.	O
3	O
,	O
1	O
,	O
3	O
,	O
and	O
10	O
mg	O
/	O
kg	O
)	O
injected	O
prior	O
to	O
training	O
attenuated	O
the	O
retention	B-Disease
deficit	I-Disease
with	O
a	O
peak	O
of	O
activity	O
at	O
3	O
mg	O
/	O
kg	O
.	O

The	O
effect	O
of	O
naloxone	B-Chemical
could	O
be	O
antagonized	O
with	O
morphine	B-Chemical
(	O
1	O
,	O
3	O
,	O
and	O
10	O
mg	O
/	O
kg	O
)	O
,	O
demonstrating	O
the	O
opioid	O
specificity	O
of	O
the	O
naloxone	B-Chemical
effect	O
.	O

Post	O
-	O
training	O
administration	O
of	O
naloxone	B-Chemical
(	O
3	O
mg	O
/	O
kg	O
)	O
as	O
a	O
single	O
or	O
as	O
a	O
split	O
dose	O
also	O
attenuated	O
the	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
.	O

Control	O
experiments	O
indicated	O
that	O
neither	O
an	O
increase	O
in	O
pain	B-Disease
sensitivity	O
(	O
pre	O
-	O
training	O
naloxone	B-Chemical
)	O
nor	O
an	O
induced	O
aversive	O
state	O
(	O
post	O
-	O
training	O
naloxone	B-Chemical
)	O
appear	O
to	O
be	O
responsible	O
for	O
the	O
influence	O
of	O
naloxone	B-Chemical
on	O
the	O
scopolamine	B-Chemical
-	O
induced	O
retention	B-Disease
deficit	I-Disease
.	O

These	O
results	O
extend	O
previous	O
findings	O
implicating	O
a	O
cholinergic	O
-	O
opioid	O
interaction	O
in	O
memory	O
processes	O
.	O

A	O
possible	O
mechanism	O
for	O
this	O
interaction	O
involving	O
the	O
septo	O
-	O
hippocampal	O
cholinergic	O
pathway	O
is	O
discussed	O
.	O

Electron	O
microscopic	O
investigations	O
of	O
the	O
cyclophosphamide	B-Chemical
-	O
induced	O
lesions	B-Disease
of	I-Disease
the	I-Disease
urinary	I-Disease
bladder	I-Disease
of	O
the	O
rat	O
and	O
their	O
prevention	O
by	O
mesna	B-Chemical
.	O

Fully	O
developed	O
cyclophosphamide	B-Chemical
-	O
induced	O
cystitis	B-Disease
is	O
characterized	O
by	O
nearly	O
complete	O
detachment	O
of	O
the	O
urothelium	O
,	O
severe	O
submucosal	O
edema	B-Disease
owing	O
to	O
damage	O
to	O
the	O
microvascular	O
bed	O
and	O
focal	O
muscle	O
necroses	B-Disease
.	O

The	O
initial	O
response	O
to	O
the	O
primary	O
attack	O
by	O
the	O
cyclophosphamide	B-Chemical
metabolites	O
seems	O
to	O
be	O
fragmentation	O
of	O
the	O
luminal	B-Chemical
membrane	O
.	O

This	O
damages	O
the	O
cellular	O
barrier	O
against	O
the	O
hypertonic	O
urine	O
.	O

Subsequent	O
breaks	O
in	O
the	O
lateral	O
cell	O
membranes	O
of	O
the	O
superficial	O
cells	O
and	O
in	O
all	O
the	O
plasma	O
membranes	O
of	O
the	O
intermediate	O
and	O
basal	O
cells	O
,	O
intercellular	O
and	O
intracellular	O
edema	B-Disease
and	O
disintegration	O
of	O
the	O
desmosomes	O
and	O
hemidesmosomes	O
lead	O
to	O
progressive	O
degeneration	O
and	O
detachment	O
of	O
the	O
epithelial	O
cells	O
with	O
exposure	O
and	O
splitting	O
of	O
the	O
basal	O
membrane	O
.	O

The	O
morphological	O
changes	O
of	O
the	O
endothelial	O
cells	O
,	O
which	O
become	O
more	O
pronounced	O
in	O
the	O
later	O
stages	O
of	O
the	O
experiment	O
,	O
the	O
involvement	O
of	O
blood	O
vessels	O
regardless	O
of	O
their	O
diameter	O
and	O
the	O
location	O
-	O
dependent	O
extent	O
of	O
the	O
damage	O
indicate	O
a	O
direct	O
type	O
of	O
damage	O
which	O
is	O
preceded	O
by	O
a	O
mediator	O
-	O
induced	O
increase	O
in	O
permeability	O
,	O
the	O
morphological	O
correlate	O
of	O
which	O
is	O
the	O
formation	O
of	O
gaps	O
in	O
the	O
interendothelial	O
cell	O
connections	O
on	O
the	O
venules	O
.	O

These	O
changes	O
can	O
be	O
effectively	O
prevented	O
by	O
mesna	B-Chemical
.	O

The	O
only	O
sign	O
of	O
a	O
possible	O
involvement	O
is	O
the	O
increase	O
in	O
the	O
number	O
of	O
specific	O
granules	O
with	O
a	O
presumed	O
lysosomal	O
function	O
in	O
the	O
superficial	O
cells	O
.	O

Increase	O
in	O
intragastric	O
pressure	O
during	O
suxamethonium	B-Chemical
-	O
induced	O
muscle	B-Disease
fasciculations	I-Disease
in	O
children	O
:	O
inhibition	O
by	O
alfentanil	B-Chemical
.	O

Changes	O
in	O
intragastric	O
pressure	O
after	O
the	O
administration	O
of	O
suxamethonium	B-Chemical
1	O
.	O
5	O
mg	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
were	O
studied	O
in	O
32	O
children	O
(	O
mean	O
age	O
6	O
.	O
9	O
yr	O
)	O
pretreated	O
with	O
either	O
physiological	O
saline	O
or	O
alfentanil	B-Chemical
50	O
micrograms	O
kg	O
-	O
1	O
.	O

Anaesthesia	O
was	O
induced	O
with	O
thiopentone	B-Chemical
5	O
mg	O
kg	O
-	O
1	O
.	O

The	O
incidence	O
and	O
intensity	O
of	O
muscle	B-Disease
fasciculations	I-Disease
caused	O
by	O
suxamethonium	B-Chemical
were	O
significantly	O
greater	O
in	O
the	O
control	O
than	O
in	O
the	O
alfentanil	B-Chemical
group	O
.	O

The	O
intragastric	O
pressure	O
during	O
muscle	B-Disease
fasciculations	I-Disease
was	O
significantly	O
higher	O
in	O
the	O
control	O
group	O
(	O
16	O
+	O
/	O
-	O
0	O
.	O
7	O
(	O
SEM	O
)	O
cm	O
H2O	B-Chemical
)	O
than	O
in	O
the	O
alfentanil	B-Chemical
group	O
(	O
7	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
5	O
(	O
SEM	O
)	O
cm	O
H2O	B-Chemical
)	O
.	O

The	O
increase	O
in	O
intragastric	O
pressure	O
was	O
directly	O
related	O
to	O
the	O
intensity	O
of	O
muscle	B-Disease
fasciculations	I-Disease
(	O
regression	O
line	O
:	O
y	O
=	O
0	O
.	O
5	O
+	O
4	O
.	O
78x	O
with	O
r	O
of	O
0	O
.	O
78	O
)	O
.	O

It	O
is	O
concluded	O
that	O
intragastric	O
pressure	O
increases	O
significantly	O
during	O
muscle	B-Disease
fasciculations	I-Disease
caused	O
by	O
suxamethonium	B-Chemical
in	O
healthy	O
children	O
.	O

Alfentanil	B-Chemical
50	O
micrograms	O
kg	O
-	O
1	O
effectively	O
inhibits	O
the	O
incidence	O
and	O
intensity	O
of	O
suxamethonium	B-Chemical
-	O
induced	O
muscle	B-Disease
fasciculations	I-Disease
;	O
moreover	O
,	O
intragastric	O
pressure	O
remains	O
at	O
its	O
control	O
value	O
.	O

Acute	O
insulin	O
treatment	O
normalizes	O
the	O
resistance	O
to	O
the	O
cardiotoxic	B-Disease
effect	O
of	O
isoproterenol	B-Chemical
in	O
streptozotocin	B-Chemical
diabetic	B-Disease
rats	O
.	O

A	O
morphometric	O
study	O
of	O
isoproterenol	B-Chemical
induced	O
myocardial	O
fibrosis	B-Disease
.	O

The	O
acute	O
effect	O
of	O
insulin	O
treatment	O
on	O
the	O
earlier	O
reported	O
protective	O
effect	O
of	O
streptozotocin	B-Chemical
diabetes	B-Disease
against	O
the	O
cardiotoxic	B-Disease
effect	O
of	O
high	O
doses	O
of	O
isoproterenol	B-Chemical
(	O
ISO	B-Chemical
)	O
was	O
investigated	O
in	O
rats	O
.	O

Thirty	O
to	O
135	O
min	O
after	O
the	O
injection	O
of	O
crystalline	O
insulin	O
,	O
ISO	B-Chemical
was	O
given	O
subcutaneously	O
and	O
when	O
ISO	B-Chemical
induced	O
fibrosis	B-Disease
in	O
the	O
myocardium	O
was	O
morphometrically	O
analyzed	O
7	O
days	O
later	O
,	O
a	O
highly	O
significant	O
correlation	O
(	O
r	O
=	O
0	O
.	O
83	O
,	O
2	O
p	O
=	O
0	O
.	O
006	O
)	O
to	O
the	O
slope	O
of	O
the	O
fall	O
in	O
blood	O
glucose	B-Chemical
after	O
insulin	O
treatment	O
appeared	O
.	O

The	O
myocardial	O
content	O
of	O
catecholamines	B-Chemical
was	O
estimated	O
in	O
these	O
8	O
day	O
diabetic	B-Disease
rats	O
.	O

The	O
norepinephrine	B-Chemical
content	O
was	O
significantly	O
increased	O
while	O
epinephrine	B-Chemical
remained	O
unchanged	O
.	O

An	O
enhanced	O
sympathetic	O
nervous	O
system	O
activity	O
with	O
a	O
consequent	O
down	O
regulation	O
of	O
the	O
myocardial	O
beta	O
-	O
adrenergic	O
receptors	O
could	O
,	O
therefore	O
,	O
explain	O
this	O
catecholamine	B-Chemical
resistance	O
.	O

The	O
rapid	O
reversion	O
after	O
insulin	O
treatment	O
excludes	O
the	O
possibility	O
that	O
streptozotocin	B-Chemical
in	O
itself	O
causes	O
the	O
ISO	B-Chemical
resistance	O
and	O
points	O
towards	O
a	O
direct	O
insulin	O
effect	O
on	O
myocardial	O
catecholamine	B-Chemical
sensitivity	O
in	O
diabetic	B-Disease
rats	O
.	O

The	O
phenomenon	O
described	O
might	O
elucidate	O
pathogenetic	O
mechanisms	O
behind	O
toxic	O
myocardial	O
cell	O
degeneration	O
and	O
may	O
possibly	O
have	O
relevance	O
for	O
acute	O
cardiovascular	O
complications	O
in	O
diabetic	B-Disease
patients	O
.	O

Differential	O
effects	O
of	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
on	O
seizures	B-Disease
produced	O
by	O
pilocarpine	B-Chemical
in	O
rats	O
.	O

The	O
muscarinic	O
cholinergic	O
agonist	O
pilocarpine	B-Chemical
induces	O
in	O
rats	O
seizures	B-Disease
and	O
status	B-Disease
epilepticus	I-Disease
followed	O
by	O
widespread	O
damage	O
to	O
the	O
forebrain	O
.	O

The	O
present	O
study	O
was	O
designed	O
to	O
investigate	O
the	O
effect	O
of	O
5	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
,	O
sodium	B-Chemical
salicylate	I-Chemical
,	O
phenylbutazone	B-Chemical
,	O
indomethacin	B-Chemical
,	O
ibuprofen	B-Chemical
and	O
mefenamic	B-Chemical
acid	I-Chemical
,	O
on	O
seizures	B-Disease
produced	O
by	O
pilocarpine	B-Chemical
.	O

Pretreatment	O
of	O
rats	O
with	O
sodium	B-Chemical
salicylate	I-Chemical
,	O
ED50	O
103	O
mg	O
/	O
kg	O
(	O
60	O
-	O
174	O
)	O
,	O
and	O
phenylbutazone	B-Chemical
,	O
59	O
mg	O
/	O
kg	O
(	O
50	O
-	O
70	O
)	O
converted	O
the	O
non	O
-	O
convulsant	O
dose	O
of	O
pilocarpine	B-Chemical
,	O
200	O
mg	O
/	O
kg	O
,	O
to	O
a	O
convulsant	O
one	O
.	O

Indomethacin	B-Chemical
,	O
1	O
-	O
10	O
mg	O
/	O
kg	O
,	O
and	O
ibuprofen	B-Chemical
,	O
10	O
-	O
100	O
mg	O
/	O
kg	O
,	O
failed	O
to	O
modulate	O
seizures	B-Disease
produced	O
by	O
pilocarpine	B-Chemical
.	O

Mefenamic	B-Chemical
acid	I-Chemical
,	O
26	O
(	O
22	O
-	O
30	O
)	O
mg	O
/	O
kg	O
,	O
prevented	O
seizures	B-Disease
and	O
protected	O
rats	O
from	O
seizure	B-Disease
-	O
related	O
brain	B-Disease
damage	I-Disease
induced	O
by	O
pilocarpine	B-Chemical
,	O
380	O
mg	O
/	O
kg	O
.	O

These	O
results	O
indicate	O
that	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
differentially	O
modulate	O
the	O
threshold	O
for	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

Acute	B-Disease
neurologic	I-Disease
dysfunction	I-Disease
after	O
high	O
-	O
dose	O
etoposide	B-Chemical
therapy	O
for	O
malignant	B-Disease
glioma	I-Disease
.	O

Etoposide	B-Chemical
(	O
VP	B-Chemical
-	I-Chemical
16	I-Chemical
-	I-Chemical
213	I-Chemical
)	O
has	O
been	O
used	O
in	O
the	O
treatment	O
of	O
many	O
solid	O
tumors	B-Disease
and	O
hematologic	B-Disease
malignancies	I-Disease
.	O

When	O
used	O
in	O
high	O
doses	O
and	O
in	O
conjunction	O
with	O
autologous	O
bone	O
marrow	O
transplantation	O
,	O
this	O
agent	O
has	O
activity	O
against	O
several	O
treatment	O
-	O
resistant	O
cancers	B-Disease
including	O
malignant	B-Disease
glioma	I-Disease
.	O

In	O
six	O
of	O
eight	O
patients	O
(	O
75	O
%	O
)	O
who	O
we	O
treated	O
for	O
recurrent	O
or	O
resistant	O
glioma	B-Disease
,	O
sudden	O
severe	O
neurologic	B-Disease
deterioration	I-Disease
occurred	O
.	O

This	O
developed	O
a	O
median	O
of	O
9	O
days	O
after	O
initiation	O
of	O
high	O
-	O
dose	O
etoposide	B-Chemical
therapy	O
.	O

Significant	O
clinical	O
manifestations	O
have	O
included	O
confusion	B-Disease
,	O
papilledema	B-Disease
,	O
somnolence	B-Disease
,	O
exacerbation	O
of	O
motor	B-Disease
deficits	I-Disease
,	O
and	O
sharp	O
increase	O
in	O
seizure	B-Disease
activity	O
.	O

These	O
abnormalities	O
resolved	O
rapidly	O
after	O
initiation	O
of	O
high	O
-	O
dose	O
intravenous	O
dexamethasone	B-Chemical
therapy	O
.	O

In	O
all	O
patients	O
,	O
computerized	O
tomographic	O
(	O
CT	O
)	O
brain	O
scans	O
demonstrated	O
stability	O
in	O
tumor	B-Disease
size	O
and	O
peritumor	O
edema	B-Disease
when	O
compared	O
with	O
pretransplant	O
scans	O
.	O

This	O
complication	O
appears	O
to	O
represent	O
a	O
significant	O
new	O
toxicity	B-Disease
of	O
high	O
-	O
dose	O
etoposide	B-Chemical
therapy	O
for	O
malignant	B-Disease
glioma	I-Disease
.	O

Progressive	O
bile	B-Disease
duct	I-Disease
injury	I-Disease
after	O
thiabendazole	B-Chemical
administration	O
.	O

A	O
27	O
-	O
yr	O
-	O
old	O
man	O
developed	O
jaundice	B-Disease
2	O
wk	O
after	O
exposure	O
to	O
thiabendazole	B-Chemical
.	O

Cholestasis	B-Disease
persisted	O
for	O
3	O
yr	O
,	O
at	O
which	O
time	O
a	O
liver	O
transplant	O
was	O
performed	O
.	O

Two	O
liver	O
biopsy	O
specimens	O
and	O
the	O
hepatectomy	O
specimen	O
were	O
remarkable	O
for	O
almost	O
complete	O
disappearance	O
of	O
interlobular	O
bile	O
ducts	O
.	O

Prominent	O
fibrosis	B-Disease
and	O
hepatocellular	O
regeneration	O
were	O
also	O
present	O
;	O
however	O
,	O
the	O
lobular	O
architecture	O
was	O
preserved	O
.	O

This	O
case	O
represents	O
an	O
example	O
of	O
"	O
idiosyncratic	O
"	O
drug	B-Disease
-	I-Disease
induced	I-Disease
liver	I-Disease
damage	I-Disease
in	O
which	O
the	O
primary	O
target	O
of	O
injury	O
is	O
the	O
bile	O
duct	O
.	O

An	O
autoimmune	O
pathogenesis	O
of	O
the	O
bile	B-Disease
duct	I-Disease
destruction	I-Disease
is	O
suggested	O
.	O

Differential	O
effects	O
of	O
1	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dihydropyridine	I-Chemical
calcium	B-Chemical
channel	I-Chemical
blockers	I-Chemical
:	O
therapeutic	O
implications	O
.	O

Increasing	O
recognition	O
of	O
the	O
importance	O
of	O
calcium	B-Chemical
in	O
the	O
pathogenesis	O
of	O
cardiovascular	B-Disease
disease	I-Disease
has	O
stimulated	O
research	O
into	O
the	O
use	O
of	O
calcium	B-Chemical
channel	I-Chemical
blocking	I-Chemical
agents	I-Chemical
for	O
treatment	O
of	O
a	O
variety	O
of	O
cardiovascular	B-Disease
diseases	I-Disease
.	O

The	O
favorable	O
efficacy	O
and	O
tolerability	O
profiles	O
of	O
these	O
agents	O
make	O
them	O
attractive	O
therapeutic	O
modalities	O
.	O

Clinical	O
applications	O
of	O
calcium	B-Chemical
channel	I-Chemical
blockers	I-Chemical
parallel	O
their	O
tissue	O
selectivity	O
.	O

In	O
contrast	O
to	O
verapamil	B-Chemical
and	O
diltiazem	B-Chemical
,	O
which	O
are	O
roughly	O
equipotent	O
in	O
their	O
actions	O
on	O
the	O
heart	O
and	O
vascular	O
smooth	O
muscle	O
,	O
the	O
dihydropyridine	B-Chemical
calcium	B-Chemical
channel	I-Chemical
blockers	I-Chemical
are	O
a	O
group	O
of	O
potent	O
peripheral	O
vasodilator	O
agents	O
that	O
exert	O
minimal	O
electrophysiologic	O
effects	O
on	O
cardiac	O
nodal	O
or	O
conduction	O
tissue	O
.	O

As	O
the	O
first	O
dihydropyridine	B-Chemical
available	O
for	O
use	O
in	O
the	O
United	O
States	O
,	O
nifedipine	B-Chemical
controls	O
angina	B-Disease
and	O
hypertension	B-Disease
with	O
minimal	O
depression	O
of	O
cardiac	O
function	O
.	O

Additional	O
members	O
of	O
this	O
group	O
of	O
calcium	B-Chemical
channel	I-Chemical
blockers	I-Chemical
have	O
been	O
studied	O
for	O
a	O
variety	O
of	O
indications	O
for	O
which	O
they	O
may	O
offer	O
advantages	O
over	O
current	O
therapy	O
.	O

Once	O
or	O
twice	O
daily	O
dosage	O
possible	O
with	O
nitrendipine	B-Chemical
and	O
nisoldipine	B-Chemical
offers	O
a	O
convenient	O
administration	O
schedule	O
,	O
which	O
encourages	O
patient	O
compliance	O
in	O
long	O
-	O
term	O
therapy	O
of	O
hypertension	B-Disease
.	O

The	O
coronary	O
vasodilating	O
properties	O
of	O
nisoldipine	B-Chemical
have	O
led	O
to	O
the	O
investigation	O
of	O
this	O
agent	O
for	O
use	O
in	O
angina	B-Disease
.	O

Selectivity	O
for	O
the	O
cerebrovascular	O
bed	O
makes	O
nimodipine	B-Chemical
potentially	O
useful	O
in	O
the	O
treatment	O
of	O
subarachnoid	B-Disease
hemorrhage	I-Disease
,	O
migraine	B-Disease
headache	I-Disease
,	O
dementia	B-Disease
,	O
and	O
stroke	B-Disease
.	O

In	O
general	O
,	O
the	O
dihydropyridine	B-Chemical
calcium	B-Chemical
channel	I-Chemical
blockers	I-Chemical
are	O
usually	O
well	O
tolerated	O
,	O
with	O
headache	B-Disease
,	O
facial	O
flushing	B-Disease
,	O
palpitations	B-Disease
,	O
edema	B-Disease
,	O
nausea	B-Disease
,	O
anorexia	B-Disease
,	O
and	O
dizziness	B-Disease
being	O
the	O
more	O
common	O
adverse	O
effects	O
.	O

The	O
enhancement	O
of	O
aminonucleoside	B-Chemical
nephrosis	B-Disease
by	O
the	O
co	O
-	O
administration	O
of	O
protamine	O
.	O

An	O
experimental	O
model	O
of	O
focal	B-Disease
segmental	I-Disease
glomerular	I-Disease
sclerosis	I-Disease
(	O
FSGS	B-Disease
)	O
was	O
developed	O
in	O
rats	O
by	O
the	O
combined	O
administration	O
of	O
puromycin	B-Chemical
-	I-Chemical
aminonucleoside	I-Chemical
(	O
AMNS	B-Chemical
)	O
and	O
protamine	B-Chemical
sulfate	I-Chemical
(	O
PS	B-Chemical
)	O
.	O

Male	O
Sprague	O
-	O
Dawley	O
rats	O
,	O
uninephrectomized	O
three	O
weeks	O
before	O
,	O
received	O
daily	O
injections	O
of	O
subcutaneous	O
AMNS	B-Chemical
(	O
1	O
mg	O
/	O
100	O
g	O
body	O
wt	O
)	O
and	O
intravenous	O
PS	B-Chemical
(	O
2	O
separated	O
doses	O
of	O
2	O
.	O
5	O
mg	O
/	O
100	O
g	O
body	O
wt	O
)	O
for	O
four	O
days	O
.	O

The	O
series	O
of	O
injections	O
were	O
repeated	O
another	O
three	O
times	O
at	O
10	O
day	O
intervals	O
.	O

The	O
animals	O
were	O
sacrificed	O
on	O
days	O
24	O
,	O
52	O
,	O
and	O
80	O
.	O

They	O
developed	O
nephrotic	B-Disease
syndrome	I-Disease
and	O
finally	O
renal	B-Disease
failure	I-Disease
.	O

The	O
time	O
-	O
course	O
curve	O
of	O
creatinine	B-Chemical
clearance	O
dropped	O
and	O
showed	O
significant	O
difference	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
from	O
that	O
of	O
each	O
control	O
group	O
,	O
such	O
as	O
,	O
AMNS	B-Chemical
alone	O
,	O
PS	B-Chemical
alone	O
or	O
saline	O
injected	O
.	O

Their	O
glomeruli	O
showed	O
changes	O
of	O
progressive	O
FSGS	B-Disease
.	O

The	O
ultrastructural	O
studies	O
in	O
the	O
initial	O
stage	O
revealed	O
significant	O
lack	O
of	O
particles	O
of	O
perfused	O
ruthenium	B-Chemical
red	O
on	O
the	O
lamina	O
rara	O
externa	O
and	O
marked	O
changes	O
in	O
epithelial	O
cell	O
cytoplasm	O
.	O

Therefore	O
,	O
it	O
is	O
suggested	O
that	O
the	O
administration	O
of	O
PS	B-Chemical
enhances	O
the	O
toxicity	B-Disease
of	O
AMNS	B-Chemical
on	O
the	O
glomerulus	O
and	O
readily	O
produces	O
progressive	O
FSGS	B-Disease
in	O
rats	O
resulting	O
in	O
the	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
.	O

Theophylline	B-Chemical
neurotoxicity	B-Disease
in	O
pregnant	O
rats	O
.	O

The	O
purpose	O
of	O
this	O
investigation	O
was	O
to	O
determine	O
whether	O
the	O
neurotoxicity	B-Disease
of	O
theophylline	B-Chemical
is	O
altered	O
in	O
advanced	O
pregnancy	O
.	O

Sprague	O
-	O
Dawley	O
rats	O
that	O
were	O
20	O
days	O
pregnant	O
and	O
nonpregnant	O
rats	O
of	O
the	O
same	O
age	O
and	O
strain	O
received	O
infusions	O
of	O
aminophylline	B-Chemical
until	O
onset	O
of	O
maximal	O
seizures	B-Disease
which	O
occurred	O
after	O
28	O
and	O
30	O
minutes	O
respectively	O
.	O

Theophylline	B-Chemical
concentrations	O
at	O
this	O
endpoint	O
in	O
serum	O
(	O
total	O
)	O
and	O
CSF	O
were	O
similar	O
but	O
serum	O
(	O
free	O
)	O
and	O
brain	O
concentrations	O
were	O
slightly	O
different	O
in	O
pregnant	O
rats	O
.	O

Theophylline	B-Chemical
serum	O
protein	O
binding	O
determined	O
by	O
equilibrium	O
dialysis	O
was	O
lower	O
in	O
pregnant	O
rats	O
.	O

Fetal	O
serum	O
concentrations	O
at	O
onset	O
of	O
seizures	B-Disease
in	O
the	O
mother	O
were	O
similar	O
to	O
maternal	O
brain	O
and	O
CSF	O
concentrations	O
and	O
correlated	O
significantly	O
with	O
the	O
former	O
.	O

It	O
is	O
concluded	O
that	O
advanced	O
pregnancy	O
has	O
a	O
negligible	O
effect	O
on	O
the	O
neurotoxic	B-Disease
response	O
to	O
theophylline	B-Chemical
in	O
rats	O
.	O

Hyperkalemia	B-Disease
induced	O
by	O
indomethacin	B-Chemical
and	O
naproxen	B-Chemical
and	O
reversed	O
by	O
fludrocortisone	B-Chemical
.	O

We	O
have	O
described	O
a	O
patient	O
with	O
severe	O
rheumatoid	B-Disease
arthritis	I-Disease
and	O
a	O
history	O
of	O
mefenamic	B-Chemical
acid	I-Chemical
nephropathy	B-Disease
in	O
whom	O
hyperkalemia	B-Disease
and	O
inappropriate	O
hypoaldosteronism	B-Disease
were	O
caused	O
by	O
both	O
indomethacin	B-Chemical
and	O
naproxen	B-Chemical
,	O
without	O
major	O
decline	O
in	O
renal	O
function	O
.	O

It	O
is	O
likely	O
that	O
preexisting	O
renal	B-Disease
disease	I-Disease
predisposed	O
this	O
patient	O
to	O
type	B-Disease
IV	I-Disease
renal	I-Disease
tubular	I-Disease
acidosis	I-Disease
with	O
prostaglandin	B-Chemical
synthetase	O
inhibitors	O
.	O

Because	O
he	O
was	O
unable	O
to	O
discontinue	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drug	O
therapy	O
,	O
fludrocortisone	B-Chemical
was	O
added	O
,	O
correcting	O
the	O
hyperkalemia	B-Disease
and	O
allowing	O
indomethacin	B-Chemical
therapy	O
to	O
be	O
continued	O
safely	O
.	O

Hypotension	B-Disease
as	O
a	O
manifestation	O
of	O
cardiotoxicity	B-Disease
in	O
three	O
patients	O
receiving	O
cisplatin	B-Chemical
and	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
.	O

Cardiac	O
symptoms	O
,	O
including	O
hypotension	B-Disease
,	O
developed	O
in	O
three	O
patients	O
with	O
advanced	O
colorectal	B-Disease
carcinoma	I-Disease
while	O
being	O
treated	O
with	O
cisplatin	B-Chemical
(	O
CDDP	B-Chemical
)	O
and	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
.	O

In	O
two	O
patients	O
,	O
hypotension	B-Disease
was	O
associated	O
with	O
severe	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
.	O

All	O
three	O
patients	O
required	O
therapy	O
discontinuation	O
.	O

Cardiac	O
enzymes	O
remained	O
normal	O
despite	O
transient	O
electrocardiographic	O
(	O
EKG	O
)	O
changes	O
.	O

The	O
presentation	O
and	O
cardiac	O
evaluation	O
(	O
hemodynamic	O
,	O
echocardiographic	O
,	O
and	O
scintigraphic	O
)	O
of	O
these	O
patients	O
suggest	O
new	O
manifestations	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
cardiotoxicity	B-Disease
that	O
may	O
be	O
influenced	O
by	O
CDDP	B-Chemical
.	O

The	O
possible	O
pathophysiologic	O
mechanisms	O
are	O
discussed	O
.	O

Fatal	O
aplastic	B-Disease
anemia	I-Disease
in	O
a	O
patient	O
treated	O
with	O
carbamazepine	B-Chemical
.	O

A	O
case	O
of	O
fatal	O
aplastic	B-Disease
anemia	I-Disease
due	O
to	O
carbamazepine	B-Chemical
treatment	O
in	O
an	O
epileptic	B-Disease
woman	O
is	O
reported	O
.	O

Despite	O
concerns	O
of	O
fatal	O
bone	B-Disease
marrow	I-Disease
toxicity	I-Disease
due	O
to	O
carbamazepine	B-Chemical
,	O
this	O
is	O
only	O
the	O
fourth	O
documented	O
and	O
published	O
report	O
.	O

Carbamazepine	B-Chemical
is	O
a	O
safe	O
drug	O
,	O
but	O
physicians	O
and	O
patients	O
should	O
be	O
aware	O
of	O
the	O
exceedingly	O
rare	O
but	O
potentially	O
fatal	O
side	O
effects	O
,	O
better	O
prevented	O
by	O
clinical	O
than	O
by	O
laboratory	O
monitoring	O
.	O

Participation	O
of	O
a	O
bulbospinal	O
serotonergic	O
pathway	O
in	O
the	O
rat	O
brain	O
in	O
clonidine	B-Chemical
-	O
induced	O
hypotension	B-Disease
and	O
bradycardia	B-Disease
.	O

The	O
effects	O
of	O
microinjection	O
of	O
clonidine	B-Chemical
(	O
1	O
-	O
10	O
micrograms	O
in	O
1	O
microliter	O
)	O
into	O
a	O
region	O
adjacent	O
to	O
the	O
ventrolateral	O
surface	O
of	O
the	O
medulla	O
oblongata	O
on	O
cardiovascular	O
function	O
were	O
assessed	O
in	O
urethane	B-Chemical
-	O
anesthetized	O
rats	O
.	O

Intramedullary	O
administration	O
of	O
clonidine	B-Chemical
,	O
but	O
not	O
saline	O
vehicle	O
,	O
caused	O
a	O
dose	O
-	O
dependent	O
decrease	O
in	O
both	O
the	O
mean	O
arterial	O
pressure	O
and	O
the	O
heart	O
rate	O
.	O

The	O
clonidine	B-Chemical
-	O
induced	O
hypotension	B-Disease
was	O
antagonized	O
by	O
prior	O
spinal	O
transection	O
,	O
but	O
not	O
bilateral	O
vagotomy	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
clonidine	B-Chemical
-	O
induced	O
bradycardia	B-Disease
was	O
antagonized	O
by	O
prior	O
bilateral	O
vagotomy	O
,	O
but	O
not	O
spinal	O
transection	O
.	O

Furthermore	O
,	O
selective	O
destruction	O
of	O
the	O
spinal	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
nerves	O
,	O
produced	O
by	O
bilateral	O
spinal	O
injection	O
of	O
5	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
dihydroxytryptamine	I-Chemical
,	O
reduced	O
the	O
magnitude	O
of	O
the	O
vasodepressor	O
or	O
the	O
bradycardiac	B-Disease
responses	O
to	O
clonidine	B-Chemical
microinjected	O
into	O
the	O
area	O
near	O
the	O
ventrolateral	O
surface	O
of	O
the	O
medulla	O
oblongata	O
in	O
rats	O
.	O

The	O
data	O
indicate	O
that	O
a	O
bulbospinal	O
serotonergic	O
pathway	O
is	O
involved	O
in	O
development	O
of	O
clonidine	B-Chemical
-	O
induced	O
hypotension	B-Disease
and	O
bradycardia	B-Disease
.	O

The	O
induced	O
hypotension	B-Disease
is	O
brought	O
about	O
by	O
a	O
decrease	O
in	O
sympathetic	O
efferent	O
activity	O
,	O
whereas	O
the	O
induced	O
bradycardia	B-Disease
was	O
due	O
to	O
an	O
increase	O
in	O
vagal	O
efferent	O
activity	O
.	O

Hypertension	B-Disease
in	O
neuroblastoma	B-Disease
induced	O
by	O
imipramine	B-Chemical
.	O

Hypertension	B-Disease
is	O
a	O
well	O
-	O
known	O
finding	O
in	O
some	O
patients	O
with	O
neuroblastoma	B-Disease
.	O

However	O
,	O
it	O
has	O
not	O
previously	O
been	O
described	O
in	O
association	O
with	O
the	O
use	O
of	O
Imipramine	B-Chemical
.	O

We	O
report	O
the	O
occurrence	O
of	O
severe	O
hypertension	B-Disease
(	O
blood	O
pressure	O
190	O
/	O
160	O
)	O
in	O
a	O
4	O
-	O
year	O
-	O
old	O
girl	O
with	O
neuroblastoma	B-Disease
who	O
was	O
given	O
Imipramine	B-Chemical
to	O
control	O
a	O
behavior	B-Disease
disorder	I-Disease
.	O

It	O
was	O
determined	O
later	O
that	O
this	O
patient	O
'	O
s	O
tumor	B-Disease
was	O
recurring	O
at	O
the	O
time	O
of	O
her	O
hypertensive	B-Disease
episode	O
.	O

Since	O
she	O
had	O
no	O
blood	O
pressure	O
elevation	O
at	O
initial	O
diagnosis	O
and	O
none	O
following	O
discontinuation	O
of	O
the	O
Imipramine	B-Chemical
(	O
when	O
she	O
was	O
in	O
florid	O
relapse	O
)	O
,	O
we	O
believe	O
that	O
this	O
drug	O
rather	O
than	O
her	O
underlying	O
disease	O
alone	O
caused	O
her	O
hypertension	B-Disease
.	O

The	O
mechanism	O
for	O
this	O
reaction	O
is	O
believed	O
to	O
be	O
increased	O
levels	O
of	O
vasoactive	O
catecholamines	B-Chemical
due	O
to	O
interference	O
of	O
their	O
physiologic	O
inactivation	O
by	O
Imipramine	B-Chemical
.	O

From	O
this	O
experience	O
,	O
we	O
urge	O
extreme	O
caution	O
in	O
the	O
use	O
of	O
tricyclic	O
antidepressants	O
in	O
children	O
with	O
active	O
neuroblastoma	B-Disease
.	O

Rechallenge	O
of	O
patients	O
who	O
developed	O
oral	B-Disease
candidiasis	I-Disease
or	O
hoarseness	B-Disease
with	O
beclomethasone	B-Chemical
dipropionate	I-Chemical
.	O

Of	O
158	O
asthmatic	B-Disease
patients	O
who	O
were	O
placed	O
on	O
inhaled	O
beclomethasone	B-Chemical
,	O
15	O
(	O
9	O
.	O
5	O
%	O
)	O
developed	O
either	O
hoarseness	B-Disease
(	O
8	O
)	O
,	O
oral	O
thrush	B-Disease
(	O
6	O
)	O
,	O
or	O
both	O
(	O
1	O
)	O
.	O

When	O
their	O
adverse	O
reactions	O
subsided	O
,	O
seven	O
of	O
these	O
15	O
patients	O
were	O
rechallenged	O
with	O
inhaled	O
beclomethasone	B-Chemical
.	O

These	O
included	O
five	O
cases	O
who	O
developed	O
hoarseness	B-Disease
and	O
three	O
who	O
developed	O
Candidiasis	B-Disease
.	O

One	O
patient	O
had	O
both	O
.	O

Oral	O
thrush	B-Disease
did	O
not	O
recur	O
,	O
but	O
60	O
%	O
(	O
3	O
/	O
5	O
)	O
of	O
patients	O
with	O
hoarseness	B-Disease
had	O
recurrence	O
.	O

We	O
conclude	O
that	O
patients	O
may	O
be	O
restarted	O
on	O
inhaled	O
beclomethasone	B-Chemical
when	O
clinically	O
indicated	O
;	O
however	O
,	O
because	O
of	O
the	O
high	O
recurrence	O
rate	O
,	O
patients	O
who	O
develop	O
hoarseness	B-Disease
should	O
not	O
be	O
re	O
-	O
challenged	O
.	O

Concomitant	O
use	O
of	O
oral	O
prednisone	B-Chemical
and	O
topical	O
beclomethasone	B-Chemical
may	O
increase	O
the	O
risk	O
of	O
developing	O
hoarseness	B-Disease
or	O
candidiasis	B-Disease
.	O

Cyclophosphamide	B-Chemical
cardiotoxicity	B-Disease
:	O
an	O
analysis	O
of	O
dosing	O
as	O
a	O
risk	O
factor	O
.	O

Patients	O
who	O
undergo	O
bone	O
marrow	O
transplantation	O
are	O
generally	O
immunosuppressed	O
with	O
a	O
dose	O
of	O
cyclophosphamide	B-Chemical
(	O
CYA	B-Chemical
)	O
which	O
is	O
usually	O
calculated	O
based	O
on	O
the	O
patient	O
'	O
s	O
weight	O
.	O

At	O
these	O
high	O
doses	O
of	O
CYA	B-Chemical
,	O
serious	O
cardiotoxicity	B-Disease
may	O
occur	O
,	O
but	O
definitive	O
risk	O
factors	O
for	O
the	O
development	O
of	O
such	O
cardiotoxicity	B-Disease
have	O
not	O
been	O
described	O
.	O

Since	O
chemotherapeutic	O
agent	O
toxicity	B-Disease
generally	O
correlates	O
with	O
dose	O
per	O
body	O
surface	O
area	O
,	O
we	O
retrospectively	O
calculated	O
the	O
dose	O
of	O
CYA	B-Chemical
in	O
patients	O
transplanted	O
at	O
our	O
institution	O
to	O
determine	O
whether	O
the	O
incidence	O
of	O
CYA	B-Chemical
cardiotoxicity	B-Disease
correlated	O
with	O
the	O
dose	O
per	O
body	O
surface	O
area	O
.	O

Eighty	O
patients	O
who	O
were	O
to	O
receive	O
CYA	B-Chemical
50	O
mg	O
/	O
kg	O
/	O
d	O
for	O
four	O
days	O
as	O
preparation	O
for	O
marrow	O
grafting	O
underwent	O
a	O
total	O
of	O
84	O
transplants	O
for	O
aplastic	B-Disease
anemia	I-Disease
,	O
Wiskott	B-Disease
-	I-Disease
Aldrich	I-Disease
syndrome	I-Disease
,	O
or	O
severe	B-Disease
combined	I-Disease
immunodeficiency	I-Disease
syndrome	I-Disease
.	O

Fourteen	O
of	O
84	O
(	O
17	O
%	O
)	O
patients	O
had	O
symptoms	O
and	O
signs	O
consistent	O
with	O
CYA	B-Chemical
cardiotoxicity	B-Disease
within	O
ten	O
days	O
of	O
receiving	O
1	O
to	O
4	O
doses	O
of	O
CYA	B-Chemical
.	O

Six	O
of	O
the	O
14	O
patients	O
died	O
with	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
.	O

The	O
dose	O
of	O
CYA	B-Chemical
per	O
body	O
surface	O
area	O
was	O
calculated	O
for	O
all	O
patients	O
and	O
the	O
patients	O
were	O
divided	O
into	O
two	O
groups	O
based	O
on	O
daily	O
CYA	B-Chemical
dose	O
:	O
Group	O
1	O
,	O
CYA	B-Chemical
less	O
than	O
or	O
equal	O
to	O
1	O
.	O
55	O
g	O
/	O
m2	O
/	O
d	O
;	O
Group	O
2	O
,	O
CYA	B-Chemical
greater	O
than	O
1	O
.	O
55	O
g	O
/	O
m2	O
/	O
d	O
.	O

Cardiotoxicity	B-Disease
that	O
was	O
thought	O
to	O
be	O
related	O
to	O
CYA	B-Chemical
occurred	O
in	O
1	O
/	O
32	O
(	O
3	O
%	O
)	O
of	O
patients	O
in	O
Group	O
1	O
and	O
in	O
13	O
/	O
52	O
(	O
25	O
%	O
)	O
patients	O
in	O
Group	O
2	O
(	O
P	O
less	O
than	O
0	O
.	O
025	O
)	O
.	O

Congestive	B-Disease
heart	I-Disease
failure	I-Disease
caused	O
or	O
contributed	O
to	O
death	O
in	O
0	O
/	O
32	O
patients	O
in	O
Group	O
1	O
v	O
6	O
/	O
52	O
(	O
12	O
%	O
)	O
of	O
patients	O
in	O
Group	O
2	O
(	O
P	O
less	O
than	O
0	O
.	O
25	O
)	O
.	O

There	O
was	O
no	O
difference	O
in	O
the	O
rate	O
of	O
engraftment	O
of	O
evaluable	O
patients	O
in	O
the	O
two	O
groups	O
(	O
P	O
greater	O
than	O
0	O
.	O
5	O
)	O
.	O

We	O
conclude	O
that	O
the	O
CYA	B-Chemical
cardiotoxicity	B-Disease
correlates	O
with	O
CYA	B-Chemical
dosage	O
as	O
calculated	O
by	O
body	O
surface	O
area	O
,	O
and	O
that	O
patients	O
with	O
aplastic	B-Disease
anemia	I-Disease
and	O
immunodeficiencies	B-Disease
can	O
be	O
effectively	O
prepared	O
for	O
bone	O
marrow	O
grafting	O
at	O
a	O
CYA	B-Chemical
dose	O
of	O
1	O
.	O
55	O
g	O
/	O
m2	O
/	O
d	O
for	O
four	O
days	O
with	O
a	O
lower	O
incidence	O
of	O
cardiotoxicity	B-Disease
than	O
patients	O
whose	O
CYA	B-Chemical
dosage	O
is	O
calculated	O
based	O
on	O
weight	O
.	O

This	O
study	O
reaffirms	O
the	O
principle	O
that	O
drug	O
toxicity	B-Disease
correlates	O
with	O
dose	O
per	O
body	O
surface	O
area	O
.	O

Studies	O
of	O
risk	O
factors	O
for	O
aminoglycoside	B-Chemical
nephrotoxicity	B-Disease
.	O

The	O
epidemiology	O
of	O
aminoglycoside	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
is	O
not	O
fully	O
understood	O
.	O

Experimental	O
studies	O
in	O
healthy	O
human	O
volunteers	O
indicate	O
aminoglycosides	B-Chemical
cause	O
proximal	O
tubular	O
damage	O
in	O
most	O
patients	O
,	O
but	O
rarely	O
,	O
if	O
ever	O
,	O
cause	O
glomerular	B-Disease
or	I-Disease
tubular	I-Disease
dysfunction	I-Disease
.	O

Clinical	O
trials	O
of	O
aminoglycosides	B-Chemical
in	O
seriously	O
ill	O
patients	O
indicate	O
that	O
the	O
relative	O
risk	O
for	O
developing	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
during	O
therapy	O
ranges	O
from	O
8	O
to	O
10	O
and	O
that	O
the	O
attributable	O
risk	O
is	O
70	O
%	O
to	O
80	O
%	O
.	O

Further	O
analysis	O
of	O
these	O
data	O
suggests	O
that	O
the	O
duration	O
of	O
therapy	O
,	O
plasma	O
aminoglycoside	B-Chemical
levels	O
,	O
liver	B-Disease
disease	I-Disease
,	O
advanced	O
age	O
,	O
high	O
initial	O
estimated	O
creatinine	B-Chemical
clearance	O
and	O
,	O
possibly	O
,	O
female	O
gender	O
all	O
increase	O
the	O
risk	O
for	O
nephrotoxicity	B-Disease
.	O

Other	O
causes	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
,	O
such	O
as	O
shock	B-Disease
,	O
appear	O
to	O
have	O
an	O
additive	O
effect	O
.	O

Predictive	O
models	O
have	O
been	O
developed	O
from	O
these	O
analyses	O
that	O
should	O
be	O
useful	O
for	O
identifying	O
patients	O
at	O
high	O
risk	O
.	O

These	O
models	O
may	O
also	O
be	O
useful	O
in	O
developing	O
insights	O
into	O
the	O
pathophysiology	O
of	O
aminoglycoside	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
.	O

Central	O
action	O
of	O
narcotic	O
analgesics	O
.	O

Part	O
IV	O
.	O

Noradrenergic	O
influences	O
on	O
the	O
activity	O
of	O
analgesics	O
in	O
rats	O
.	O

The	O
effect	O
of	O
clonidine	B-Chemical
,	O
naphazoline	B-Chemical
and	O
xylometazoline	B-Chemical
on	O
analgesia	O
induced	O
by	O
morphine	B-Chemical
,	O
codeine	B-Chemical
,	O
fentanyl	B-Chemical
and	O
pentazocine	B-Chemical
,	O
and	O
on	O
cataleptic	B-Disease
effect	O
of	O
morphine	B-Chemical
,	O
codine	B-Chemical
and	O
fentanyl	B-Chemical
was	O
studied	O
in	O
rats	O
.	O

The	O
biochemical	O
assays	O
on	O
the	O
influence	O
of	O
four	O
analgesics	O
on	O
the	O
brain	O
concentration	O
and	O
turnover	O
of	O
noradrenaline	B-Chemical
(	O
NA	B-Chemical
)	O
were	O
also	O
performed	O
.	O

It	O
was	O
found	O
that	O
three	O
drugs	O
stimulating	O
central	O
NA	B-Chemical
receptors	O
failed	O
to	O
affect	O
the	O
analgesic	O
ED50	O
of	O
all	O
antinociceptive	O
agents	O
and	O
they	O
enhanced	O
catalepsy	B-Disease
induced	O
by	O
morphine	B-Chemical
and	O
fentanyl	B-Chemical
.	O

Codeine	B-Chemical
catalepsy	B-Disease
was	O
increased	O
by	O
clonidine	B-Chemical
and	O
decreased	O
by	O
naphazoline	B-Chemical
and	O
xylometazoline	B-Chemical
.	O

The	O
brain	O
concentration	O
of	O
NA	B-Chemical
was	O
not	O
changed	O
by	O
morphine	B-Chemical
and	O
fentanyl	B-Chemical
,	O
but	O
one	O
of	O
the	O
doses	O
of	O
codeine	B-Chemical
(	O
45	O
mg	O
/	O
kg	O
)	O
slightly	O
enhanced	O
it	O
.	O

Pentazocine	B-Chemical
dose	O
-	O
dependently	O
decreased	O
the	O
brain	O
level	O
of	O
NA	B-Chemical
.	O

The	O
rate	O
of	O
NA	B-Chemical
turnover	O
was	O
not	O
altered	O
by	O
analgesics	O
except	O
for	O
the	O
higher	O
dose	O
of	O
fentanyl	B-Chemical
(	O
0	O
.	O
2	O
mg	O
/	O
kg	O
)	O
following	O
which	O
the	O
disappearance	O
of	O
NA	B-Chemical
from	O
the	O
brain	O
was	O
diminished	O
.	O

The	O
results	O
are	O
discussed	O
in	O
the	O
light	O
of	O
various	O
and	O
non	O
-	O
uniform	O
data	O
from	O
the	O
literature	O
.	O

It	O
is	O
suggested	O
that	O
in	O
rats	O
the	O
brain	O
NA	B-Chemical
plays	O
a	O
less	O
important	O
function	O
than	O
the	O
other	O
monoamines	B-Chemical
in	O
the	O
behavioural	O
activity	O
of	O
potent	O
analgesics	O
.	O

Flurothyl	B-Chemical
seizure	B-Disease
thresholds	O
in	O
mice	O
treated	O
neonatally	O
with	O
a	O
single	O
injection	O
of	O
monosodium	B-Chemical
glutamate	I-Chemical
(	O
MSG	B-Chemical
)	O
:	O
evaluation	O
of	O
experimental	O
parameters	O
in	O
flurothyl	B-Chemical
seizure	B-Disease
testing	O
.	O

Monosodium	B-Chemical
glutamate	I-Chemical
(	O
MSG	B-Chemical
)	O
administration	O
to	O
neonatal	O
rodents	O
produces	O
convulsions	B-Disease
and	O
results	O
in	O
numerous	O
biochemical	O
and	O
behavioral	O
deficits	O
.	O

These	O
studies	O
were	O
undertaken	O
to	O
determine	O
if	O
neonatal	O
administration	O
of	O
MSG	B-Chemical
produced	O
permanent	O
alterations	O
in	O
seizure	B-Disease
susceptibility	O
,	O
since	O
previous	O
investigations	O
were	O
inconclusive	O
.	O

A	O
flurothyl	B-Chemical
ether	B-Chemical
seizure	B-Disease
screening	O
technique	O
was	O
used	O
to	O
evaluate	O
seizure	B-Disease
susceptibility	O
in	O
adult	O
mice	O
that	O
received	O
neonatal	O
injections	O
of	O
MSG	B-Chemical
(	O
4	O
mg	O
/	O
g	O
and	O
1	O
mg	O
/	O
g	O
)	O
.	O

MSG	B-Chemical
treatment	O
resulted	O
in	O
significant	O
reductions	O
in	O
whole	O
brain	O
weight	O
but	O
did	O
not	O
alter	O
seizure	B-Disease
threshold	O
.	O

A	O
naloxone	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
)	O
challenge	O
was	O
also	O
ineffective	O
in	O
altering	O
the	O
seizure	B-Disease
thresholds	O
of	O
either	O
control	O
of	O
MSG	B-Chemical
-	O
treated	O
mice	O
.	O

Flurothyl	B-Chemical
ether	B-Chemical
produced	O
hypothermia	B-Disease
which	O
was	O
correlated	O
with	O
the	O
duration	O
of	O
flurothyl	B-Chemical
exposure	O
;	O
however	O
,	O
the	O
relationship	O
of	O
hypothermia	B-Disease
to	O
seizure	B-Disease
induction	O
was	O
unclear	O
.	O

Flurothyl	B-Chemical
seizure	B-Disease
testing	O
proved	O
to	O
be	O
a	O
rapid	O
and	O
reliable	O
technique	O
with	O
which	O
to	O
evaluate	O
seizure	B-Disease
susceptibility	O
.	O

Susceptibility	O
to	O
seizures	B-Disease
produced	O
by	O
pilocarpine	B-Chemical
in	O
rats	O
after	O
microinjection	O
of	O
isoniazid	B-Chemical
or	O
gamma	B-Chemical
-	I-Chemical
vinyl	I-Chemical
-	I-Chemical
GABA	I-Chemical
into	O
the	O
substantia	O
nigra	O
.	O

Pilocarpine	B-Chemical
,	O
given	O
intraperitoneally	O
to	O
rats	O
,	O
reproduces	O
the	O
neuropathological	O
sequelae	O
of	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
and	O
provides	O
a	O
relevant	O
animal	O
model	O
for	O
studying	O
mechanisms	O
of	O
buildup	O
of	O
convulsive	B-Disease
activity	O
and	O
pathways	O
operative	O
in	O
the	O
generalization	O
and	O
propagation	O
of	O
seizures	B-Disease
within	O
the	O
forebrain	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
effects	O
of	O
manipulating	O
the	O
activity	O
of	O
the	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
(	O
GABA	B-Chemical
)	O
-	O
mediated	O
synaptic	O
inhibition	O
within	O
the	O
substantia	O
nigra	O
on	O
seizures	B-Disease
produced	O
by	O
pilocarpine	B-Chemical
in	O
rats	O
,	O
were	O
investigated	O
.	O

In	O
animals	O
pretreated	O
with	O
microinjections	O
of	O
isoniazid	B-Chemical
,	O
150	O
micrograms	O
,	O
an	O
inhibitor	O
of	O
activity	O
of	O
the	O
GABA	B-Chemical
-	O
synthesizing	O
enzyme	O
,	O
L	B-Chemical
-	I-Chemical
glutamic	I-Chemical
acid	I-Chemical
decarboxylase	O
,	O
into	O
the	O
substantia	O
nigra	O
pars	O
reticulata	O
(	O
SNR	O
)	O
,	O
bilaterally	O
,	O
non	O
-	O
convulsant	O
doses	O
of	O
pilocarpine	B-Chemical
,	O
100	O
and	O
200	O
mg	O
/	O
kg	O
,	O
resulted	O
in	O
severe	O
motor	O
limbic	O
seizures	B-Disease
and	O
status	B-Disease
epilepticus	I-Disease
.	O

Electroencephalographic	O
and	O
behavioral	O
monitoring	O
revealed	O
a	O
profound	O
reduction	O
of	O
the	O
threshold	O
for	O
pilocarpine	B-Chemical
-	O
induced	O
convulsions	B-Disease
.	O

Morphological	O
analysis	O
of	O
frontal	O
forebrain	O
sections	O
with	O
light	O
microscopy	O
revealed	O
seizure	B-Disease
-	O
related	O
damage	O
to	O
the	O
hippocampal	O
formation	O
,	O
thalamus	O
,	O
amygdala	O
,	O
olfactory	O
cortex	O
,	O
substantia	O
nigra	O
and	O
neocortex	O
,	O
which	O
is	O
typically	O
observed	O
with	O
pilocarpine	B-Chemical
in	O
doses	O
exceeding	O
350	O
mg	O
/	O
kg	O
.	O

Bilateral	O
intrastriatal	O
injections	O
of	O
isoniazid	B-Chemical
did	O
not	O
augment	O
seizures	B-Disease
produced	O
by	O
pilocarpine	B-Chemical
,	O
200	O
mg	O
/	O
kg	O
.	O

Application	O
of	O
an	O
irreversible	O
inhibitor	O
of	O
GABA	B-Chemical
transaminase	O
,	O
gamma	B-Chemical
-	I-Chemical
vinyl	I-Chemical
-	I-Chemical
GABA	I-Chemical
(	O
D	B-Chemical
,	I-Chemical
L	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
amino	I-Chemical
-	I-Chemical
hex	I-Chemical
-	I-Chemical
5	I-Chemical
-	I-Chemical
enoic	I-Chemical
acid	I-Chemical
)	O
,	O
5	O
micrograms	O
,	O
into	O
the	O
SNR	O
,	O
bilaterally	O
,	O
suppressed	O
the	O
appearance	O
of	O
electrographic	O
and	O
behavioral	O
seizures	B-Disease
produced	O
by	O
pilocarpine	B-Chemical
,	O
380	O
mg	O
/	O
kg	O
.	O

This	O
treatment	O
was	O
also	O
sufficient	O
to	O
protect	O
animals	O
from	O
the	O
occurrence	O
of	O
brain	B-Disease
damage	I-Disease
.	O

Microinjections	O
of	O
gamma	B-Chemical
-	I-Chemical
vinyl	I-Chemical
-	I-Chemical
GABA	I-Chemical
,	O
5	O
micrograms	O
,	O
into	O
the	O
dorsal	O
striatum	O
,	O
bilaterally	O
,	O
failed	O
to	O
prevent	O
the	O
development	O
of	O
convulsions	B-Disease
produced	O
by	O
pilocarpine	B-Chemical
,	O
380	O
mg	O
/	O
kg	O
.	O

The	O
results	O
demonstrate	O
that	O
the	O
threshold	O
for	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
in	O
rats	O
is	O
subjected	O
to	O
the	O
regulation	O
of	O
the	O
GABA	B-Chemical
-	O
mediated	O
synaptic	O
inhibition	O
within	O
the	O
substantia	O
nigra	O
.	O

Human	O
and	O
canine	O
ventricular	O
vasoactive	O
intestinal	O
polypeptide	O
:	O
decrease	O
with	O
heart	B-Disease
failure	I-Disease
.	O

Vasoactive	O
intestinal	O
polypeptide	O
(	O
VIP	O
)	O
is	O
a	O
systemic	O
and	O
coronary	O
vasodilator	O
that	O
may	O
have	O
positive	O
inotropic	O
properties	O
.	O

Myocardial	O
levels	O
of	O
VIP	O
were	O
assayed	O
before	O
and	O
after	O
the	O
development	O
of	O
heart	B-Disease
failure	I-Disease
in	O
two	O
canine	O
models	O
.	O

In	O
the	O
first	O
,	O
cobalt	B-Chemical
cardiomyopathy	B-Disease
was	O
induced	O
in	O
eight	O
dogs	O
;	O
VIP	O
(	O
by	O
radioimmunoassay	O
)	O
decreased	O
from	O
35	O
+	O
/	O
-	O
11	O
pg	O
/	O
mg	O
protein	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
to	O
5	O
+	O
/	O
-	O
4	O
pg	O
/	O
mg	O
protein	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

In	O
six	O
dogs	O
with	O
doxorubicin	B-Chemical
-	O
induced	O
heart	B-Disease
failure	I-Disease
,	O
VIP	O
decreased	O
from	O
31	O
+	O
/	O
-	O
7	O
to	O
11	O
+	O
/	O
-	O
4	O
pg	O
/	O
mg	O
protein	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

In	O
addition	O
,	O
VIP	O
content	O
of	O
left	O
ventricular	O
muscle	O
of	O
resected	O
failing	O
hearts	O
in	O
10	O
patients	O
receiving	O
a	O
heart	O
transplant	O
was	O
compared	O
with	O
the	O
papillary	O
muscles	O
in	O
14	O
patients	O
(	O
five	O
with	O
rheumatic	B-Disease
disease	I-Disease
,	O
nine	O
with	O
myxomatous	B-Disease
degeneration	I-Disease
)	O
receiving	O
mitral	O
valve	O
prostheses	O
.	O

The	O
lowest	O
myocardial	O
VIP	O
concentration	O
was	O
found	O
in	O
the	O
hearts	O
of	O
patients	O
with	O
coronary	B-Disease
disease	I-Disease
(	O
one	O
patient	O
receiving	O
a	O
transplant	O
and	O
three	O
receiving	O
mitral	O
prostheses	O
)	O
(	O
6	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
9	O
pg	O
/	O
mg	O
protein	O
)	O
.	O

The	O
other	O
patients	O
undergoing	O
transplantation	O
had	O
an	O
average	O
ejection	O
fraction	O
of	O
17	O
%	O
+	O
/	O
-	O
6	O
%	O
and	O
a	O
VIP	O
level	O
of	O
8	O
.	O
8	O
+	O
/	O
-	O
3	O
.	O
9	O
pg	O
/	O
mg	O
protein	O
.	O

The	O
hearts	O
without	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
(	O
average	O
ejection	O
fraction	O
of	O
this	O
group	O
62	O
%	O
+	O
/	O
-	O
10	O
%	O
)	O
had	O
a	O
VIP	O
concentration	O
of	O
14	O
.	O
1	O
+	O
/	O
-	O
7	O
.	O
9	O
pg	O
/	O
mg	O
protein	O
,	O
and	O
this	O
was	O
greater	O
than	O
in	O
hearts	O
of	O
the	O
patients	O
with	O
coronary	B-Disease
disease	I-Disease
and	O
the	O
hearts	O
of	O
patients	O
receiving	O
a	O
transplant	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Myocardial	O
catecholamines	B-Chemical
were	O
also	O
determined	O
in	O
14	O
subjects	O
;	O
a	O
weak	O
correlation	O
(	O
r	O
=	O
0	O
.	O
57	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
between	O
the	O
tissue	O
concentrations	O
of	O
VIP	O
and	O
norepinephrine	B-Chemical
was	O
noted	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Non	O
-	O
invasive	O
detection	O
of	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
by	O
body	O
surface	O
electrocardiographic	O
mapping	O
after	O
dipyridamole	B-Chemical
infusion	O
.	O

Electrocardiographic	O
changes	O
after	O
dipyridamole	B-Chemical
infusion	O
(	O
0	O
.	O
568	O
mg	O
/	O
kg	O
/	O
4	O
min	O
)	O
were	O
studied	O
in	O
41	O
patients	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
and	O
compared	O
with	O
those	O
after	O
submaximal	O
treadmill	O
exercise	O
by	O
use	O
of	O
the	O
body	O
surface	O
mapping	O
technique	O
.	O

Patients	O
were	O
divided	O
into	O
three	O
groups	O
;	O
19	O
patients	O
without	O
myocardial	B-Disease
infarction	I-Disease
(	O
non	O
-	O
MI	B-Disease
group	O
)	O
,	O
14	O
with	O
anterior	B-Disease
infarction	I-Disease
(	O
ANT	B-Disease
-	I-Disease
MI	I-Disease
)	O
and	O
eight	O
with	O
inferior	B-Disease
infarction	I-Disease
(	O
INF	B-Disease
-	I-Disease
MI	I-Disease
)	O
.	O

Eighty	O
-	O
seven	O
unipolar	O
electrocardiograms	O
(	O
ECGs	O
)	O
distributed	O
over	O
the	O
entire	O
thoracic	O
surface	O
were	O
simultaneously	O
recorded	O
.	O

After	O
dipyridamole	B-Chemical
,	O
ischemic	B-Disease
ST	O
-	O
segment	O
depression	B-Disease
(	O
0	O
.	O
05	O
mV	O
or	O
more	O
)	O
was	O
observed	O
in	O
84	O
%	O
of	O
the	O
non	O
-	O
MI	B-Disease
group	O
,	O
29	O
%	O
of	O
the	O
ANT	B-Disease
-	I-Disease
MI	I-Disease
group	O
,	O
63	O
%	O
of	O
the	O
INF	B-Disease
-	I-Disease
MI	I-Disease
group	O
and	O
61	O
%	O
of	O
the	O
total	O
population	O
.	O

Exercise	O
-	O
induced	O
ST	O
depression	B-Disease
was	O
observed	O
in	O
84	O
%	O
of	O
the	O
non	O
-	O
MI	B-Disease
group	O
,	O
43	O
%	O
of	O
the	O
ANT	B-Disease
-	I-Disease
MI	I-Disease
group	O
,	O
38	O
%	O
of	O
the	O
INF	B-Disease
-	I-Disease
MI	I-Disease
group	O
and	O
61	O
%	O
of	O
the	O
total	O
.	O

For	O
individual	O
patients	O
,	O
there	O
were	O
no	O
obvious	O
differences	O
between	O
the	O
body	O
surface	O
distribution	O
of	O
ST	O
depression	B-Disease
in	O
both	O
tests	O
.	O

The	O
increase	O
in	O
pressure	O
rate	O
product	O
after	O
dipyridamole	B-Chemical
was	O
significantly	O
less	O
than	O
that	O
during	O
the	O
treadmill	O
exercise	O
.	O

The	O
data	O
suggest	O
that	O
the	O
dipyridamole	B-Chemical
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
is	O
caused	O
by	O
the	O
inhomogenous	O
distribution	O
of	O
myocardial	O
blood	O
flow	O
.	O

We	O
conclude	O
that	O
the	O
dipyridamole	B-Chemical
ECG	O
test	O
is	O
as	O
useful	O
as	O
the	O
exercise	O
ECG	O
test	O
for	O
the	O
assessment	O
of	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
.	O

Bradycardia	B-Disease
after	O
high	O
-	O
dose	O
intravenous	O
methylprednisolone	B-Chemical
therapy	O
.	O

In	O
5	O
consecutive	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
who	O
received	O
intravenous	O
high	O
-	O
dose	O
methylprednisolone	B-Chemical
(	O
MP	B-Chemical
)	O
therapy	O
(	O
1	O
g	O
daily	O
for	O
2	O
or	O
3	O
consecutive	O
days	O
)	O
,	O
a	O
decline	O
in	O
pulse	O
rate	O
was	O
observed	O
,	O
most	O
pronounced	O
on	O
day	O
4	O
.	O

In	O
one	O
of	O
the	O
5	O
patients	O
the	O
bradycardia	B-Disease
was	O
associated	O
with	O
complaints	O
of	O
substernal	O
pressure	O
.	O

Reversal	O
to	O
normal	O
heart	O
rate	O
was	O
found	O
on	O
day	O
7	O
.	O

Electrocardiographic	O
registrations	O
showed	O
sinus	B-Disease
bradycardia	I-Disease
in	O
all	O
cases	O
.	O

No	O
significant	O
changes	O
in	O
plasma	O
concentrations	O
of	O
electrolytes	O
were	O
found	O
.	O

Careful	O
observation	O
of	O
patients	O
receiving	O
high	O
-	O
dose	O
MP	B-Chemical
is	O
recommended	O
.	O

High	O
-	O
dose	O
MP	B-Chemical
may	O
be	O
contraindicated	O
in	O
patients	O
with	O
known	O
heart	B-Disease
disease	I-Disease
.	O

Two	O
cases	O
of	O
downbeat	B-Disease
nystagmus	I-Disease
and	O
oscillopsia	B-Disease
associated	O
with	O
carbamazepine	B-Chemical
.	O

Downbeat	B-Disease
nystagmus	I-Disease
is	O
often	O
associated	O
with	O
structural	O
lesions	O
at	O
the	O
craniocervical	O
junction	O
,	O
but	O
has	O
occasionally	O
been	O
reported	O
as	O
a	O
manifestation	O
of	O
metabolic	O
imbalance	O
or	O
drug	O
intoxication	O
.	O

We	O
recorded	O
the	O
eye	O
movements	O
of	O
two	O
patients	O
with	O
reversible	O
downbeat	B-Disease
nystagmus	I-Disease
related	O
to	O
carbamazepine	B-Chemical
therapy	O
.	O

The	O
nystagmus	B-Disease
of	O
both	O
patients	O
resolved	O
after	O
reduction	O
of	O
the	O
serum	O
carbamazepine	B-Chemical
levels	O
.	O

Neuroradiologic	O
investigations	O
including	O
magnetic	O
resonance	O
imaging	O
scans	O
in	O
both	O
patients	O
showed	O
no	O
evidence	O
of	O
intracranial	O
abnormality	O
.	O

In	O
patients	O
with	O
downbeat	B-Disease
nystagmus	I-Disease
who	O
are	O
taking	O
anticonvulsant	O
medications	O
,	O
consideration	O
should	O
be	O
given	O
to	O
reduction	O
in	O
dose	O
before	O
further	O
investigation	O
is	O
undertaken	O
.	O

Improvement	O
by	O
denopamine	B-Chemical
(	O
TA	B-Chemical
-	I-Chemical
064	I-Chemical
)	O
of	O
pentobarbital	B-Chemical
-	O
induced	O
cardiac	B-Disease
failure	I-Disease
in	O
the	O
dog	O
heart	O
-	O
lung	O
preparation	O
.	O

The	O
efficacy	O
of	O
denopamine	B-Chemical
,	O
an	O
orally	O
active	O
beta	O
1	O
-	O
adrenoceptor	O
agonist	O
,	O
in	O
improving	O
cardiac	B-Disease
failure	I-Disease
was	O
assessed	O
in	O
dog	O
heart	O
-	O
lung	O
preparations	O
.	O

Cardiac	O
functions	O
depressed	O
by	O
pentobarbital	B-Chemical
(	O
118	O
+	O
/	O
-	O
28	O
mg	O
;	O
mean	O
value	O
+	O
/	O
-	O
SD	O
)	O
such	O
that	O
cardiac	O
output	O
and	O
maximum	O
rate	O
of	O
rise	O
of	O
left	O
ventricular	O
pressure	O
(	O
LV	O
dP	O
/	O
dt	O
max	O
)	O
had	O
been	O
reduced	O
by	O
about	O
35	O
%	O
and	O
26	O
%	O
of	O
the	O
respective	O
controls	O
were	O
improved	O
by	O
denopamine	B-Chemical
(	O
10	O
-	O
300	O
micrograms	O
)	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

With	O
100	O
micrograms	O
denopamine	B-Chemical
,	O
almost	O
complete	O
restoration	O
of	O
cardiac	O
performance	O
was	O
attained	O
,	O
associated	O
with	O
a	O
slight	O
increase	O
in	O
heart	O
rate	O
.	O

No	O
arrhythmias	B-Disease
were	O
induced	O
by	O
these	O
doses	O
of	O
denopamine	B-Chemical
.	O

The	O
results	O
warrant	O
clinical	O
trials	O
of	O
denopamine	B-Chemical
in	O
the	O
treatment	O
of	O
cardiac	B-Disease
failure	I-Disease
.	O

Clonazepam	B-Chemical
monotherapy	O
for	O
epilepsy	B-Disease
in	O
childhood	O
.	O

Sixty	O
patients	O
(	O
age	O
-	O
range	O
one	O
month	O
to	O
14	O
years	O
)	O
with	O
other	O
types	O
of	O
epilepsy	B-Disease
than	O
infantile	B-Disease
spasms	I-Disease
were	O
treated	O
with	O
clonazepam	B-Chemical
.	O

Disappearance	O
of	O
seizures	B-Disease
and	O
normalization	O
of	O
abnormal	O
EEG	O
with	O
disappearance	O
of	O
seizures	B-Disease
were	O
recognized	O
in	O
77	O
%	O
and	O
50	O
%	O
,	O
respectively	O
.	O

Seizures	B-Disease
disappeared	O
in	O
71	O
%	O
of	O
the	O
patients	O
with	O
generalized	O
seizures	B-Disease
and	O
89	O
%	O
of	O
partial	O
seizures	B-Disease
.	O

Improvement	O
of	O
abnormal	O
EEG	O
was	O
noticed	O
in	O
76	O
%	O
of	O
diffuse	O
paroxysms	O
and	O
in	O
67	O
%	O
of	O
focal	O
paroxysms	O
.	O

In	O
excellent	O
cases	O
,	O
mean	O
effective	O
dosages	O
were	O
0	O
.	O
086	O
+	O
/	O
-	O
0	O
.	O
021	O
mg	O
/	O
kg	O
/	O
day	O
in	O
infants	O
and	O
0	O
.	O
057	O
+	O
/	O
-	O
0	O
.	O
022	O
mg	O
/	O
kg	O
/	O
day	O
in	O
schoolchildren	O
,	O
this	O
difference	O
was	O
statistically	O
significant	O
(	O
p	O
less	O
than	O
0	O
.	O
005	O
)	O
.	O

The	O
incidence	O
of	O
side	O
effects	O
such	O
as	O
drowsiness	B-Disease
and	O
ataxia	B-Disease
was	O
only	O
5	O
%	O
.	O

Postmarketing	O
study	O
of	O
timolol	B-Chemical
-	O
hydrochlorothiazide	B-Chemical
antihypertensive	O
therapy	O
.	O

A	O
postmarketing	O
surveillance	O
study	O
was	O
conducted	O
to	O
determine	O
the	O
safety	O
and	O
efficacy	O
of	O
a	O
fixed	O
-	O
ratio	O
combination	O
containing	O
10	O
mg	O
of	O
timolol	B-Chemical
maleate	I-Chemical
and	O
25	O
mg	O
of	O
hydrochlorothiazide	B-Chemical
,	O
administered	O
twice	O
daily	O
for	O
one	O
month	O
to	O
hypertensive	B-Disease
patients	O
.	O

Data	O
on	O
9	O
,	O
037	O
patients	O
were	O
collected	O
by	O
1	O
,	O
455	O
participating	O
physicians	O
.	O

Mean	O
systolic	O
blood	O
pressure	O
decreased	O
25	O
mmHg	O
and	O
mean	O
diastolic	O
blood	O
pressure	O
declined	O
15	O
mmHg	O
after	O
one	O
month	O
of	O
timolol	B-Chemical
-	O
hydrochlorothiazide	B-Chemical
therapy	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
,	O
both	O
comparisons	O
)	O
.	O

Age	O
,	O
race	O
,	O
and	O
sex	O
appeared	O
to	O
have	O
no	O
influence	O
on	O
the	O
decrease	O
in	O
blood	O
pressure	O
.	O

The	O
antihypertensive	O
effect	O
of	O
the	O
drug	O
was	O
greater	O
in	O
patients	O
with	O
more	O
severe	O
hypertension	B-Disease
.	O

Overall	O
,	O
1	O
,	O
453	O
patients	O
experienced	O
a	O
total	O
of	O
2	O
,	O
658	O
adverse	O
events	O
,	O
the	O
most	O
common	O
being	O
fatigue	B-Disease
,	O
dizziness	B-Disease
,	O
and	O
weakness	B-Disease
.	O

Treatment	O
in	O
590	O
patients	O
was	O
discontinued	O
because	O
of	O
adverse	O
events	O
.	O

Salicylate	B-Chemical
nephropathy	B-Disease
in	O
the	O
Gunn	O
rat	O
:	O
potential	O
role	O
of	O
prostaglandins	B-Chemical
.	O

We	O
examined	O
the	O
potential	O
role	O
of	O
prostaglandins	B-Chemical
in	O
the	O
development	O
of	O
analgesic	O
nephropathy	B-Disease
in	O
the	O
Gunn	O
strain	O
of	O
rat	O
.	O

The	O
homozygous	O
Gunn	O
rats	O
have	O
unconjugated	O
hyperbilirubinemia	B-Disease
due	O
to	O
the	O
absence	O
of	O
glucuronyl	B-Chemical
transferase	O
,	O
leading	O
to	O
marked	O
bilirubin	B-Chemical
deposition	O
in	O
renal	O
medulla	O
and	O
papilla	O
.	O

These	O
rats	O
are	O
also	O
highly	O
susceptible	O
to	O
develop	O
papillary	B-Disease
necrosis	I-Disease
with	O
analgesic	O
administration	O
.	O

We	O
used	O
homozygous	O
(	O
jj	O
)	O
and	O
phenotypically	O
normal	O
heterozygous	O
(	O
jJ	O
)	O
animals	O
.	O

Four	O
groups	O
of	O
rats	O
(	O
n	O
=	O
7	O
)	O
were	O
studied	O
:	O
jj	O
and	O
jJ	O
rats	O
treated	O
either	O
with	O
aspirin	B-Chemical
300	O
mg	O
/	O
kg	O
every	O
other	O
day	O
or	O
sham	O
-	O
treated	O
.	O

After	O
one	O
week	O
,	O
slices	O
of	O
cortex	O
,	O
outer	O
and	O
inner	O
medulla	O
from	O
one	O
kidney	O
were	O
incubated	O
in	O
buffer	O
and	O
prostaglandin	B-Chemical
synthesis	O
was	O
determined	O
by	O
radioimmunoassay	O
.	O

The	O
other	O
kidney	O
was	O
examined	O
histologically	O
.	O

A	O
marked	O
corticomedullary	O
gradient	O
of	O
prostaglandin	B-Chemical
synthesis	O
was	O
observed	O
in	O
all	O
groups	O
.	O

PGE2	B-Chemical
synthesis	O
was	O
significantly	O
higher	O
in	O
outer	O
medulla	O
,	O
but	O
not	O
cortex	O
or	O
inner	O
medulla	O
,	O
of	O
jj	O
(	O
38	O
+	O
/	O
-	O
6	O
ng	O
/	O
mg	O
prot	O
)	O
than	O
jJ	O
rats	O
(	O
15	O
+	O
/	O
-	O
3	O
)	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Aspirin	B-Chemical
treatment	O
reduced	O
PGE2	B-Chemical
synthesis	O
in	O
all	O
regions	O
,	O
but	O
outer	O
medullary	O
PGE2	B-Chemical
remained	O
higher	O
in	O
jj	O
(	O
18	O
+	O
/	O
-	O
3	O
)	O
than	O
jJ	O
rats	O
(	O
9	O
+	O
/	O
-	O
2	O
)	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

PGF2	B-Chemical
alpha	I-Chemical
was	O
also	O
significantly	O
higher	O
in	O
the	O
outer	O
medulla	O
of	O
jj	O
rats	O
with	O
and	O
without	O
aspirin	B-Chemical
administration	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
changes	O
in	O
renal	O
prostaglandin	B-Chemical
synthesis	O
were	O
accompanied	O
by	O
evidence	O
of	O
renal	B-Disease
damage	I-Disease
in	O
aspirin	B-Chemical
-	O
treated	O
jj	O
but	O
not	O
jJ	O
rats	O
as	O
evidenced	O
by	O
:	O
increased	O
incidence	O
and	O
severity	O
of	O
hematuria	B-Disease
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
;	O
increased	O
serum	O
creatinine	B-Chemical
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
;	O
and	O
increase	O
in	O
outer	O
medullary	O
histopathologic	O
lesions	O
(	O
p	O
less	O
than	O
0	O
.	O
005	O
compared	O
to	O
either	O
sham	O
-	O
treated	O
jj	O
or	O
aspirin	B-Chemical
-	O
treated	O
jJ	O
)	O
.	O

These	O
results	O
suggest	O
that	O
enhanced	O
prostaglandin	B-Chemical
synthesis	O
contributes	O
to	O
maintenance	O
of	O
renal	O
function	O
and	O
morphological	O
integrity	O
,	O
and	O
that	O
inhibition	O
of	O
prostaglandin	B-Chemical
synthesis	O
may	O
lead	O
to	O
pathological	B-Disease
renal	I-Disease
medullary	I-Disease
lesions	I-Disease
and	O
deterioration	B-Disease
of	I-Disease
renal	I-Disease
function	I-Disease
.	O

Prophylactic	O
lidocaine	B-Chemical
in	O
the	O
early	O
phase	O
of	O
suspected	O
myocardial	B-Disease
infarction	I-Disease
.	O

Four	O
hundred	O
two	O
patients	O
with	O
suspected	O
myocardial	B-Disease
infarction	I-Disease
seen	O
within	O
6	O
hours	O
of	O
the	O
onset	O
of	O
symptoms	O
entered	O
a	O
double	O
-	O
blind	O
randomized	O
trial	O
of	O
lidocaine	B-Chemical
vs	O
placebo	O
.	O

During	O
the	O
1	O
hour	O
after	O
administration	O
of	O
the	O
drug	O
the	O
incidence	O
of	O
ventricular	B-Disease
fibrillation	I-Disease
or	O
sustained	O
ventricular	B-Disease
tachycardia	I-Disease
among	O
the	O
204	O
patients	O
with	O
acute	O
myocardial	B-Disease
infarction	I-Disease
was	O
low	O
,	O
1	O
.	O
5	O
%	O
.	O

Lidocaine	B-Chemical
,	O
given	O
in	O
a	O
300	O
mg	O
dose	O
intramuscularly	O
followed	O
by	O
100	O
mg	O
intravenously	O
,	O
did	O
not	O
prevent	O
sustained	O
ventricular	B-Disease
tachycardia	I-Disease
,	O
although	O
there	O
was	O
a	O
significant	O
reduction	O
in	O
the	O
number	O
of	O
patients	O
with	O
warning	O
arrhythmias	B-Disease
between	O
15	O
and	O
45	O
minutes	O
after	O
the	O
administration	O
of	O
lidocaine	B-Chemical
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
average	O
plasma	O
lidocaine	B-Chemical
level	O
10	O
minutes	O
after	O
administration	O
for	O
patients	O
without	O
a	O
myocardial	B-Disease
infarction	I-Disease
was	O
significantly	O
higher	O
than	O
that	O
for	O
patients	O
with	O
an	O
acute	O
infarction	B-Disease
.	O

The	O
mean	O
plasma	O
lidocaine	B-Chemical
level	O
of	O
patients	O
on	O
beta	O
-	O
blocking	O
agents	O
was	O
no	O
different	O
from	O
that	O
in	O
patients	O
not	O
on	O
beta	O
blocking	O
agents	O
.	O

During	O
the	O
1	O
-	O
hour	O
study	O
period	O
,	O
the	O
incidence	O
of	O
central	O
nervous	O
system	O
side	O
effects	O
was	O
significantly	O
greater	O
in	O
the	O
lidocaine	B-Chemical
group	O
,	O
hypotension	B-Disease
occurred	O
in	O
11	O
patients	O
,	O
nine	O
of	O
whom	O
had	O
received	O
lidocaine	B-Chemical
,	O
and	O
four	O
patients	O
died	O
from	O
asystole	B-Disease
,	O
three	O
of	O
whom	O
had	O
had	O
lidocaine	B-Chemical
.	O

We	O
cannot	O
advocate	O
the	O
administration	O
of	O
lidocaine	B-Chemical
prophylactically	O
in	O
the	O
early	O
hours	O
of	O
suspected	O
myocardial	B-Disease
infarction	I-Disease
.	O

Evidence	O
for	O
a	O
cholinergic	O
role	O
in	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
.	O

Experiments	O
in	O
mice	O
tested	O
previous	O
evidence	O
that	O
activation	O
of	O
cholinergic	O
systems	O
promotes	O
catalepsy	B-Disease
and	O
that	O
cholinergic	O
mechanisms	O
need	O
to	O
be	O
intact	O
for	O
full	O
expression	O
of	O
neuroleptic	B-Chemical
-	O
induced	O
catalepsy	B-Disease
.	O

Large	O
doses	O
of	O
the	O
cholinomimetic	O
,	O
pilocarpine	B-Chemical
,	O
could	O
induce	O
catalepsy	B-Disease
when	O
peripheral	O
cholinergic	O
receptors	O
were	O
blocked	O
.	O

Low	O
doses	O
of	O
pilocarpine	B-Chemical
caused	O
a	O
pronounced	O
enhancement	O
of	O
the	O
catalepsy	B-Disease
that	O
was	O
induced	O
by	O
the	O
dopaminergic	O
blocker	O
,	O
haloperidol	B-Chemical
.	O

A	O
muscarinic	O
receptor	O
blocker	O
,	O
atropine	B-Chemical
,	O
disrupted	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
.	O

Intracranial	O
injection	O
of	O
an	O
acetylcholine	B-Chemical
-	O
synthesis	O
inhibitor	O
,	O
hemicholinium	B-Chemical
,	O
prevented	O
the	O
catalepsy	B-Disease
that	O
is	O
usually	O
induced	O
by	O
haloperidol	B-Chemical
.	O

These	O
findings	O
suggest	O
the	O
hypothesis	O
that	O
the	O
catalepsy	B-Disease
that	O
is	O
produced	O
by	O
neuroleptics	B-Chemical
such	O
as	O
haloperidol	B-Chemical
is	O
actually	O
mediated	O
by	O
intrinsic	O
central	O
cholinergic	O
systems	O
.	O

Alternatively	O
,	O
activation	O
of	O
central	O
cholinergic	O
systems	O
could	O
promote	O
catalepsy	B-Disease
by	O
suppression	O
of	O
dopaminergic	O
systems	O
.	O

Cardiovascular	B-Disease
dysfunction	I-Disease
and	O
hypersensitivity	B-Disease
to	O
sodium	B-Chemical
pentobarbital	I-Chemical
induced	O
by	O
chronic	O
barium	B-Chemical
chloride	I-Chemical
ingestion	O
.	O

Barium	B-Chemical
-	O
supplemented	O
Long	O
-	O
Evans	O
hooded	O
rats	O
were	O
characterized	O
by	O
a	O
persistent	O
hypertension	B-Disease
that	O
was	O
evident	O
after	O
1	O
month	O
of	O
barium	B-Chemical
(	O
100	O
micrograms	O
/	O
ml	O
mineral	O
fortified	O
water	O
)	O
treatment	O
.	O

Analysis	O
of	O
in	O
vivo	O
myocardial	O
excitability	O
,	O
contractility	O
,	O
and	O
metabolic	O
characteristics	O
at	O
16	O
months	O
revealed	O
other	O
significant	O
barium	B-Chemical
-	O
induced	O
disturbances	B-Disease
within	I-Disease
the	I-Disease
cardiovascular	I-Disease
system	I-Disease
.	O

The	O
most	O
distinctive	O
aspect	O
of	O
the	O
barium	B-Chemical
effect	O
was	O
a	O
demonstrated	O
hypersensitivity	B-Disease
of	O
the	O
cardiovascular	O
system	O
to	O
sodium	B-Chemical
pentobarbital	I-Chemical
.	O

Under	O
barbiturate	B-Chemical
anesthesia	O
,	O
virtually	O
all	O
of	O
the	O
myocardial	O
contractile	O
indices	O
were	O
depressed	O
significantly	O
in	O
barium	B-Chemical
-	O
exposed	O
rats	O
relative	O
to	O
the	O
corresponding	O
control	O
-	O
fed	O
rats	O
.	O

The	O
lack	O
of	O
a	O
similar	O
response	O
to	O
ketamine	B-Chemical
and	O
xylazine	B-Chemical
anesthesia	O
revealed	O
that	O
the	O
cardiovascular	O
actions	O
of	O
sodium	B-Chemical
pentobarbital	I-Chemical
in	O
barium	B-Chemical
-	O
treated	O
rats	O
were	O
linked	O
specifically	O
to	O
this	O
anesthetic	O
,	O
and	O
were	O
not	O
representative	O
of	O
a	O
generalized	O
anesthetic	O
response	O
.	O

Other	O
myocardial	O
pathophysiologic	O
and	O
metabolic	O
changes	O
induced	O
by	O
barium	B-Chemical
were	O
manifest	O
,	O
irrespective	O
of	O
the	O
anesthetic	O
employed	O
.	O

The	O
contractile	O
element	O
shortening	O
velocity	O
of	O
the	O
cardiac	O
muscle	O
fibers	O
was	O
significantly	O
slower	O
in	O
both	O
groups	O
of	O
barium	B-Chemical
-	O
treated	O
rats	O
relative	O
to	O
the	O
control	O
groups	O
,	O
irrespective	O
of	O
the	O
anesthetic	O
regimen	O
.	O

Similarly	O
,	O
significant	O
disturbances	O
in	O
myocardial	O
energy	O
metabolism	O
were	O
detected	O
in	O
the	O
barium	B-Chemical
-	O
exposed	O
rats	O
which	O
were	O
consistent	O
with	O
the	O
reduced	O
contractile	O
element	O
shortening	O
velocity	O
.	O

In	O
addition	O
,	O
the	O
excitability	O
of	O
the	O
cardiac	O
conduction	O
system	O
was	O
depressed	O
preferentially	O
in	O
the	O
atrioventricular	O
nodal	O
region	O
of	O
hearts	O
from	O
barium	B-Chemical
-	O
exposed	O
rats	O
.	O

Overall	O
,	O
the	O
altered	O
cardiac	O
contractility	O
and	O
excitability	O
characteristics	O
,	O
the	O
myocardial	O
metabolic	B-Disease
disturbances	I-Disease
,	O
and	O
the	O
hypersensitivity	B-Disease
of	O
the	O
cardiovascular	O
system	O
to	O
sodium	B-Chemical
pentobarbital	I-Chemical
suggest	O
the	O
existence	O
of	O
a	O
heretofore	O
undescribed	O
cardiomyopathic	B-Disease
disorder	I-Disease
induced	O
by	O
chronic	O
barium	B-Chemical
exposure	O
.	O

These	O
experimental	O
findings	O
represent	O
the	O
first	O
indication	O
that	O
life	O
-	O
long	O
barium	B-Chemical
ingestion	O
may	O
have	O
significant	O
adverse	O
effects	O
on	O
the	O
mammalian	O
cardiovascular	O
system	O
.	O

Propranolol	B-Chemical
antagonism	O
of	O
phenylpropanolamine	B-Chemical
-	O
induced	O
hypertension	B-Disease
.	O

Phenylpropanolamine	B-Chemical
(	O
PPA	B-Chemical
)	O
overdose	B-Disease
can	O
cause	O
severe	O
hypertension	B-Disease
,	O
intracerebral	B-Disease
hemorrhage	I-Disease
,	O
and	O
death	O
.	O

We	O
studied	O
the	O
efficacy	O
and	O
safety	O
of	O
propranolol	B-Chemical
in	O
the	O
treatment	O
of	O
PPA	B-Chemical
-	O
induced	O
hypertension	B-Disease
.	O

Subjects	O
received	O
propranolol	B-Chemical
either	O
by	O
mouth	O
for	O
48	O
hours	O
before	O
PPA	B-Chemical
or	O
as	O
a	O
rapid	O
intravenous	O
infusion	O
after	O
PPA	B-Chemical
.	O

PPA	B-Chemical
,	O
75	O
mg	O
alone	O
,	O
increased	O
blood	O
pressure	O
(	O
31	O
+	O
/	O
-	O
14	O
mm	O
Hg	O
systolic	O
,	O
20	O
+	O
/	O
-	O
5	O
mm	O
Hg	O
diastolic	O
)	O
,	O
and	O
propranolol	B-Chemical
pretreatment	O
antagonized	O
this	O
increase	O
(	O
12	O
+	O
/	O
-	O
10	O
mm	O
Hg	O
systolic	O
,	O
10	O
+	O
/	O
-	O
7	O
mm	O
Hg	O
diastolic	O
)	O
.	O

Intravenous	O
propranolol	B-Chemical
after	O
PPA	B-Chemical
also	O
decreased	O
blood	O
pressure	O
.	O

Left	O
ventricular	O
function	O
(	O
assessed	O
by	O
echocardiography	O
)	O
showed	O
that	O
PPA	B-Chemical
increased	O
the	O
stroke	B-Disease
volume	O
30	O
%	O
(	O
from	O
62	O
.	O
5	O
+	O
/	O
-	O
20	O
.	O
9	O
to	O
80	O
.	O
8	O
+	O
/	O
-	O
22	O
.	O
4	O
ml	O
)	O
,	O
the	O
ejection	O
fraction	O
9	O
%	O
(	O
from	O
64	O
%	O
+	O
/	O
-	O
10	O
%	O
to	O
70	O
%	O
+	O
/	O
-	O
7	O
%	O
)	O
,	O
and	O
cardiac	O
output	O
14	O
%	O
(	O
from	O
3	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
6	O
to	O
4	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
0	O
L	O
/	O
min	O
)	O
.	O

Intravenous	O
propranolol	B-Chemical
reversed	O
these	O
effects	O
.	O

Systemic	O
vascular	O
resistance	O
was	O
increased	O
by	O
PPA	B-Chemical
28	O
%	O
(	O
from	O
1710	O
+	O
/	O
-	O
200	O
to	O
2190	O
+	O
/	O
-	O
700	O
dyne	O
X	O
sec	O
/	O
cm5	O
)	O
and	O
was	O
further	O
increased	O
by	O
propranolol	B-Chemical
22	O
%	O
(	O
to	O
2660	O
+	O
/	O
-	O
1200	O
dyne	O
X	O
sec	O
/	O
cm5	O
)	O
.	O

We	O
conclude	O
that	O
PPA	B-Chemical
increases	O
blood	O
pressure	O
by	O
increasing	O
systemic	O
vascular	O
resistance	O
and	O
cardiac	O
output	O
,	O
and	O
that	O
propranolol	B-Chemical
antagonizes	O
this	O
increase	O
by	O
reversing	O
the	O
effect	O
of	O
PPA	B-Chemical
on	O
cardiac	O
output	O
.	O

That	O
propranolol	B-Chemical
antagonizes	O
the	O
pressor	O
effect	O
of	O
PPA	B-Chemical
is	O
in	O
contrast	O
to	O
the	O
interaction	O
in	O
which	O
propranolol	B-Chemical
enhances	O
the	O
pressor	O
effect	O
of	O
norepinephrine	B-Chemical
.	O

This	O
is	O
probably	O
because	O
PPA	B-Chemical
has	O
less	O
beta	O
2	O
activity	O
than	O
does	O
norepinephrine	B-Chemical
.	O

Mesangial	O
function	O
and	O
glomerular	B-Disease
sclerosis	I-Disease
in	O
rats	O
with	O
aminonucleoside	B-Chemical
nephrosis	B-Disease
.	O

The	O
possible	O
relationship	O
between	O
mesangial	B-Disease
dysfunction	I-Disease
and	O
development	O
of	O
glomerular	B-Disease
sclerosis	I-Disease
was	O
studied	O
in	O
the	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
)	O
model	O
.	O

Five	O
male	O
Wistar	O
rats	O
received	O
repeated	O
subcutaneous	O
PAN	B-Chemical
injections	O
;	O
five	O
controls	O
received	O
saline	O
only	O
.	O

After	O
4	O
weeks	O
the	O
PAN	B-Chemical
rats	O
were	O
severely	O
proteinuric	B-Disease
(	O
190	O
+	O
/	O
-	O
80	O
mg	O
/	O
24	O
hr	O
)	O
,	O
and	O
all	O
rats	O
were	O
given	O
colloidal	O
carbon	B-Chemical
(	O
CC	O
)	O
intravenously	O
.	O

At	O
5	O
months	O
glomerular	B-Disease
sclerosis	I-Disease
was	O
found	O
in	O
7	O
.	O
6	O
+	O
/	O
-	O
3	O
.	O
4	O
%	O
of	O
the	O
glomeruli	O
of	O
PAN	B-Chemical
rats	O
;	O
glomeruli	O
of	O
the	O
controls	O
were	O
normal	O
.	O

Glomeruli	O
of	O
PAN	B-Chemical
rats	O
contained	O
significantly	O
more	O
CC	O
than	O
glomeruli	O
of	O
controls	O
.	O

Glomeruli	O
with	O
sclerosis	B-Disease
contained	O
significantly	O
more	O
CC	O
than	O
non	O
-	O
sclerotic	O
glomeruli	O
in	O
the	O
same	O
kidneys	O
.	O

CC	O
was	O
preferentially	O
localized	O
within	O
the	O
sclerotic	O
areas	O
of	O
the	O
affected	O
glomeruli	O
.	O

Since	O
mesangial	O
CC	O
clearance	O
from	O
the	O
mesangium	O
did	O
not	O
change	O
during	O
chronic	O
PAN	B-Chemical
treatment	O
,	O
we	O
conclude	O
that	O
this	O
preferential	O
CC	O
localization	O
within	O
the	O
lesions	O
is	O
caused	O
by	O
an	O
increased	O
CC	O
uptake	O
shortly	O
after	O
injection	O
in	O
apparent	O
vulnerable	O
areas	O
where	O
sclerosis	B-Disease
will	O
develop	O
subsequently	O
.	O

Cluster	O
analysis	O
showed	O
a	O
random	O
distribution	O
of	O
lesions	O
in	O
the	O
PAN	B-Chemical
glomeruli	O
in	O
concordance	O
with	O
the	O
random	O
localization	O
of	O
mesangial	O
areas	O
with	O
dysfunction	O
in	O
this	O
model	O
.	O

Similar	O
to	O
the	O
remnant	O
kidney	O
model	O
in	O
PAN	B-Chemical
nephrosis	B-Disease
the	O
development	O
of	O
glomerular	B-Disease
sclerosis	I-Disease
may	O
be	O
related	O
to	O
"	O
mesangial	O
overloading	O
.	O
"	O

Relationship	O
between	O
nicotine	B-Chemical
-	O
induced	O
seizures	B-Disease
and	O
hippocampal	O
nicotinic	O
receptors	O
.	O

A	O
controversy	O
has	O
existed	O
for	O
several	O
years	O
concerning	O
the	O
physiological	O
relevance	O
of	O
the	O
nicotinic	O
receptor	O
measured	O
by	O
alpha	O
-	O
bungarotoxin	O
binding	O
.	O

Using	O
mice	O
derived	O
from	O
a	O
classical	O
F2	O
and	O
backcross	O
genetic	O
design	O
,	O
a	O
relationship	O
between	O
nicotine	B-Chemical
-	O
induced	O
seizures	B-Disease
and	O
alpha	O
-	O
bungarotoxin	O
nicotinic	O
receptor	O
concentration	O
was	O
found	O
.	O

Mice	O
sensitive	O
to	O
the	O
convulsant	O
effects	O
of	O
nicotine	B-Chemical
had	O
greater	O
alpha	O
-	O
bungarotoxin	O
binding	O
in	O
the	O
hippocampus	O
than	O
seizure	B-Disease
insensitive	O
mice	O
.	O

The	O
binding	O
sites	O
from	O
seizure	B-Disease
sensitive	O
and	O
resistant	O
mice	O
were	O
equally	O
affected	O
by	O
treatment	O
with	O
dithiothreitol	B-Chemical
,	O
trypsin	O
or	O
heat	O
.	O

Thus	O
it	O
appears	O
that	O
the	O
difference	O
between	O
seizure	B-Disease
sensitive	O
and	O
insensitive	O
animals	O
may	O
be	O
due	O
to	O
a	O
difference	O
in	O
hippocampal	O
nicotinic	O
receptor	O
concentration	O
as	O
measured	O
with	O
alpha	O
-	O
bungarotoxin	O
binding	O
.	O

The	O
role	O
of	O
p	B-Chemical
-	I-Chemical
aminophenol	I-Chemical
in	O
acetaminophen	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
:	O
effect	O
of	O
bis	B-Chemical
(	I-Chemical
p	I-Chemical
-	I-Chemical
nitrophenyl	I-Chemical
)	I-Chemical
phosphate	I-Chemical
on	O
acetaminophen	B-Chemical
and	O
p	B-Chemical
-	I-Chemical
aminophenol	I-Chemical
nephrotoxicity	B-Disease
and	O
metabolism	O
in	O
Fischer	O
344	O
rats	O
.	O

Acetaminophen	B-Chemical
(	O
APAP	B-Chemical
)	O
produces	O
proximal	O
tubular	B-Disease
necrosis	I-Disease
in	O
Fischer	O
344	O
(	O
F344	O
)	O
rats	O
.	O

Recently	O
,	O
p	B-Chemical
-	I-Chemical
aminophenol	I-Chemical
(	O
PAP	B-Chemical
)	O
,	O
a	O
known	O
potent	O
nephrotoxicant	O
,	O
was	O
identified	O
as	O
a	O
metabolite	O
of	O
APAP	B-Chemical
in	O
F344	O
rats	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
determine	O
if	O
PAP	B-Chemical
formation	O
is	O
a	O
requisite	O
step	O
in	O
APAP	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
.	O

Therefore	O
,	O
the	O
effect	O
of	O
bis	B-Chemical
(	I-Chemical
p	I-Chemical
-	I-Chemical
nitrophenyl	I-Chemical
)	I-Chemical
phosphate	I-Chemical
(	O
BNPP	B-Chemical
)	O
,	O
an	O
acylamidase	O
inhibitor	O
,	O
on	O
APAP	B-Chemical
and	O
PAP	B-Chemical
nephrotoxicity	B-Disease
and	O
metabolism	O
was	O
determined	O
.	O

BNPP	B-Chemical
(	O
1	O
to	O
8	O
mM	O
)	O
reduced	O
APAP	B-Chemical
deacetylation	O
and	O
covalent	O
binding	O
in	O
F344	O
renal	O
cortical	O
homogenates	O
in	O
a	O
concentration	O
-	O
dependent	O
manner	O
.	O

Pretreatment	O
of	O
animals	O
with	O
BNPP	B-Chemical
prior	O
to	O
APAP	B-Chemical
or	O
PAP	B-Chemical
administration	O
resulted	O
in	O
marked	O
reduction	O
of	O
APAP	B-Chemical
(	O
900	O
mg	O
/	O
kg	O
)	O
nephrotoxicity	B-Disease
but	O
not	O
PAP	B-Chemical
nephrotoxicity	B-Disease
.	O

This	O
result	O
was	O
not	O
due	O
to	O
altered	O
disposition	O
of	O
either	O
APAP	B-Chemical
or	O
acetylated	O
metabolites	O
in	O
plasma	O
or	O
renal	O
cortical	O
and	O
hepatic	O
tissue	O
.	O

Rather	O
,	O
BNPP	B-Chemical
pretreatment	O
reduced	O
the	O
fraction	O
of	O
APAP	B-Chemical
excreted	O
as	O
PAP	B-Chemical
by	O
64	O
and	O
75	O
%	O
after	O
APAP	B-Chemical
doses	O
of	O
750	O
and	O
900	O
mg	O
/	O
kg	O
.	O

BNPP	B-Chemical
did	O
not	O
alter	O
the	O
excretion	O
of	O
APAP	B-Chemical
or	O
any	O
of	O
its	O
non	O
-	O
deacetylated	O
metabolites	O
nor	O
did	O
BNPP	B-Chemical
alter	O
excretion	O
of	O
PAP	B-Chemical
or	O
its	O
metabolites	O
after	O
PAP	B-Chemical
doses	O
of	O
150	O
and	O
300	O
mg	O
/	O
kg	O
.	O

Therefore	O
,	O
the	O
BNPP	B-Chemical
-	O
induced	O
reduction	O
in	O
APAP	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
appears	O
to	O
be	O
due	O
to	O
inhibition	O
of	O
APAP	B-Chemical
deacetylation	O
.	O

It	O
is	O
concluded	O
that	O
PAP	B-Chemical
formation	O
,	O
in	O
vivo	O
,	O
accounts	O
,	O
at	O
least	O
in	O
part	O
,	O
for	O
APAP	B-Chemical
-	O
induced	O
renal	B-Disease
tubular	I-Disease
necrosis	I-Disease
.	O

Morphine	B-Chemical
-	O
induced	O
seizures	B-Disease
in	O
newborn	O
infants	O
.	O

Two	O
neonates	O
suffered	O
from	O
generalized	O
seizures	B-Disease
during	O
the	O
course	O
of	O
intravenous	O
morphine	B-Chemical
sulfate	I-Chemical
for	O
post	O
-	O
operative	O
analgesia	O
.	O

They	O
received	O
morphine	B-Chemical
in	O
doses	O
of	O
32	O
micrograms	O
/	O
kg	O
/	O
hr	O
and	O
40	O
micrograms	O
/	O
kg	O
/	O
hr	O
larger	O
than	O
a	O
group	O
of	O
10	O
neonates	O
who	O
received	O
6	O
-	O
24	O
micrograms	O
/	O
kg	O
/	O
hr	O
and	O
had	O
no	O
seizures	B-Disease
.	O

Plasma	O
concentrations	O
of	O
morphine	B-Chemical
in	O
these	O
neonates	O
was	O
excessive	O
(	O
60	O
and	O
90	O
mg	O
/	O
ml	O
)	O
.	O

Other	O
known	O
reasons	O
for	O
seizures	B-Disease
were	O
ruled	O
out	O
and	O
the	O
convulsions	B-Disease
stopped	O
a	O
few	O
hours	O
after	O
cessation	O
of	O
morphine	B-Chemical
and	O
did	O
not	O
reoccur	O
in	O
the	O
subsequent	O
8	O
months	O
.	O

It	O
is	O
suggested	O
that	O
post	O
-	O
operative	O
intravenous	O
morphine	B-Chemical
should	O
not	O
exceed	O
20	O
micrograms	O
/	O
kg	O
/	O
ml	O
in	O
neonates	O
.	O

Indomethacin	B-Chemical
induced	O
hypotension	B-Disease
in	O
sodium	B-Chemical
and	O
volume	O
depleted	O
rats	O
.	O

After	O
a	O
single	O
oral	O
dose	O
of	O
4	O
mg	O
/	O
kg	O
indomethacin	B-Chemical
(	O
IDM	B-Chemical
)	O
to	O
sodium	B-Chemical
and	O
volume	O
depleted	O
rats	O
plasma	O
renin	O
activity	O
(	O
PRA	O
)	O
and	O
systolic	O
blood	O
pressure	O
fell	O
significantly	O
within	O
four	O
hours	O
.	O

In	O
sodium	B-Chemical
repleted	O
animals	O
indomethacin	B-Chemical
did	O
not	O
change	O
systolic	O
blood	O
pressure	O
(	O
BP	O
)	O
although	O
plasma	O
renin	O
activity	O
was	O
decreased	O
.	O

Thus	O
,	O
indomethacin	B-Chemical
by	O
inhibition	O
of	O
prostaglandin	B-Chemical
synthesis	O
may	O
diminish	O
the	O
blood	O
pressure	O
maintaining	O
effect	O
of	O
the	O
stimulated	O
renin	O
-	O
angiotensin	B-Chemical
system	O
in	O
sodium	B-Chemical
and	O
volume	O
depletion	O
.	O

On	O
the	O
antiarrhythmic	O
activity	O
of	O
one	O
N	O
-	O
substituted	O
piperazine	B-Chemical
derivative	O
of	O
trans	B-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
amino	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
hydroxy	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
2	I-Chemical
,	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
tetrahydroanaphthalene	I-Chemical
.	O

The	O
antiarrhythmic	O
activity	O
of	O
the	O
compound	O
N	B-Chemical
-	I-Chemical
(	I-Chemical
trans	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
hydroxy	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
2	I-Chemical
,	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
tetrahydro	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
naphthyl	I-Chemical
)	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
(	I-Chemical
3	I-Chemical
-	I-Chemical
oxo	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
phenyl	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
methylpropyl	I-Chemical
)	I-Chemical
-	I-Chemical
piperazine	I-Chemical
hydrochloride	I-Chemical
,	O
referred	O
to	O
as	O
P11	B-Chemical
,	O
is	O
studied	O
on	O
anaesthesized	O
cats	O
and	O
Wistar	O
albino	O
rats	O
,	O
as	O
well	O
as	O
on	O
non	O
-	O
anaesthesized	O
rabbits	O
.	O

Four	O
types	O
of	O
experimental	O
arrhythmia	B-Disease
are	O
used	O
-	O
-	O
with	O
BaCl2	B-Chemical
,	O
with	O
chloroform	B-Chemical
-	O
adrenaline	B-Chemical
,	O
with	O
strophantine	B-Chemical
G	I-Chemical
and	O
with	O
aconitine	B-Chemical
.	O

The	O
compound	O
P11	B-Chemical
is	O
introduced	O
in	O
doses	O
of	O
0	O
.	O
25	O
and	O
0	O
.	O
50	O
mg	O
/	O
kg	O
intravenously	O
and	O
10	O
mg	O
/	O
kg	O
orally	O
.	O

The	O
compound	O
manifests	O
antiarrhythmic	O
activity	O
in	O
all	O
models	O
of	O
experimental	O
arrhythmia	B-Disease
used	O
,	O
causing	O
greatest	O
inhibition	O
on	O
the	O
arrhythmia	B-Disease
induced	O
by	O
chloroform	B-Chemical
-	O
adrenaline	B-Chemical
(	O
in	O
90	O
per	O
cent	O
)	O
and	O
with	O
BaCl2	B-Chemical
(	O
in	O
84	O
per	O
cent	O
)	O
.	O

The	O
results	O
obtained	O
are	O
associated	O
with	O
the	O
beta	O
-	O
adrenoblocking	O
and	O
with	O
the	O
membrane	O
-	O
stabilizing	O
action	O
of	O
the	O
compound	O
.	O

Recurrent	O
subarachnoid	B-Disease
hemorrhage	I-Disease
associated	O
with	O
aminocaproic	B-Chemical
acid	I-Chemical
therapy	O
and	O
acute	B-Disease
renal	I-Disease
artery	I-Disease
thrombosis	I-Disease
.	O

Case	O
report	O
.	O

Epsilon	B-Chemical
aminocaproic	I-Chemical
acid	I-Chemical
(	O
EACA	B-Chemical
)	O
has	O
been	O
used	O
to	O
prevent	O
rebleeding	O
in	O
patients	O
with	O
subarachnoid	B-Disease
hemorrhage	I-Disease
(	O
SAH	B-Disease
)	O
.	O

Although	O
this	O
agent	O
does	O
decrease	O
the	O
frequency	O
of	O
rebleeding	O
,	O
several	O
reports	O
have	O
described	O
thrombotic	B-Disease
complications	O
of	O
EACA	B-Chemical
therapy	O
.	O

These	O
complications	O
have	O
included	O
clinical	O
deterioration	O
and	O
intracranial	B-Disease
vascular	I-Disease
thrombosis	I-Disease
in	O
patients	O
with	O
SAH	B-Disease
,	O
arteriolar	O
and	O
capillary	O
fibrin	O
thrombi	B-Disease
in	O
patients	O
with	O
fibrinolytic	O
syndromes	O
treated	O
with	O
EACA	B-Chemical
,	O
or	O
other	O
thromboembolic	B-Disease
phenomena	I-Disease
.	O

Since	O
intravascular	O
fibrin	O
thrombi	B-Disease
are	O
often	O
observed	O
in	O
patients	O
with	O
fibrinolytic	O
disorders	O
,	O
EACA	B-Chemical
should	O
not	O
be	O
implicated	O
in	O
the	O
pathogenesis	O
of	O
fibrin	O
thrombi	B-Disease
in	O
patients	O
with	O
disseminated	B-Disease
intravascular	I-Disease
coagulation	I-Disease
or	O
other	O
"	O
consumption	B-Disease
coagulopathies	I-Disease
.	O
"	O
This	O
report	O
describes	O
subtotal	O
infarction	B-Disease
of	O
the	O
kidney	O
due	O
to	O
thrombosis	B-Disease
of	I-Disease
a	I-Disease
normal	I-Disease
renal	I-Disease
artery	I-Disease
.	O

This	O
occlusion	O
occurred	O
after	O
EACA	B-Chemical
therapy	O
in	O
a	O
patient	O
with	O
SAH	B-Disease
and	O
histopathological	O
documentation	O
of	O
recurrent	O
SAH	B-Disease
.	O

The	O
corresponding	O
clinical	O
event	O
was	O
characterized	O
by	O
marked	O
hypertension	B-Disease
and	O
abrupt	O
neurological	O
deterioration	O
.	O

Effect	O
of	O
vincristine	B-Chemical
sulfate	I-Chemical
on	O
Pseudomonas	B-Disease
infections	I-Disease
in	O
monkeys	O
.	O

In	O
rhesus	O
monkeys	O
,	O
intravenous	O
challenge	O
with	O
0	O
.	O
6	O
x	O
10	O
(	O
10	O
)	O
to	O
2	O
.	O
2	O
x	O
10	O
(	O
10	O
)	O
Pseudomonas	O
aeruginosa	O
organisms	O
caused	O
acute	O
illness	O
of	O
4	O
to	O
5	O
days	O
'	O
duration	O
with	O
spontaneous	O
recovery	O
in	O
13	O
of	O
15	O
monkeys	O
;	O
blood	O
cultures	O
became	O
negative	O
3	O
to	O
17	O
days	O
after	O
challenge	O
.	O

Leukocytosis	B-Disease
was	O
observed	O
in	O
all	O
monkeys	O
.	O

Intravenous	O
or	O
intratracheal	O
inoculation	O
of	O
2	O
.	O
0	O
to	O
2	O
.	O
5	O
mg	O
of	O
vincristine	B-Chemical
sulfate	I-Chemical
was	O
followed	O
by	O
leukopenia	B-Disease
in	O
4	O
to	O
5	O
days	O
.	O

Intravenous	O
inoculation	O
of	O
4	O
.	O
2	O
x	O
10	O
(	O
10	O
)	O
to	O
7	O
.	O
8	O
x	O
10	O
(	O
10	O
)	O
pyocin	O
type	O
6	O
Pseudomonas	O
organisms	O
in	O
monkeys	O
given	O
vincristine	B-Chemical
sulfate	I-Chemical
4	O
days	O
previously	O
resulted	O
in	O
fatal	O
infection	B-Disease
in	O
11	O
of	O
14	O
monkeys	O
,	O
whereas	O
none	O
of	O
four	O
receiving	O
Pseudomonas	O
alone	O
died	O
.	O

These	O
studies	O
suggest	O
that	O
an	O
antimetabolite	O
-	O
induced	O
leukopenia	B-Disease
predisposes	O
to	O
severe	O
Pseudomonas	O
sepsis	B-Disease
and	O
that	O
such	O
monkeys	O
may	O
serve	O
as	O
a	O
biological	O
model	O
for	O
study	O
of	O
comparative	O
efficacy	O
of	O
antimicrobial	O
agents	O
.	O

Modification	O
by	O
propranolol	B-Chemical
of	O
cardiovascular	O
effects	O
of	O
induced	O
hypoglycaemia	B-Disease
.	O

The	O
cardiovascular	O
effects	O
of	O
hypoglycaemia	B-Disease
,	O
with	O
and	O
without	O
beta	O
-	O
blockade	O
,	O
were	O
compared	O
in	O
fourteen	O
healthy	O
men	O
.	O

Eight	O
received	O
insulin	O
alone	O
,	O
and	O
eight	O
,	O
including	O
two	O
of	O
the	O
original	O
insulin	O
-	O
only	O
group	O
,	O
were	O
given	O
propranolol	B-Chemical
and	O
insulin	O
.	O

In	O
the	O
insulin	O
-	O
group	O
the	O
period	O
of	O
hypoglycaemia	B-Disease
was	O
associated	O
with	O
an	O
increase	O
in	O
heart	O
-	O
rate	O
and	O
a	O
fall	O
in	O
diastolic	O
blood	O
-	O
pressure	O
.	O

In	O
the	O
propranolol	B-Chemical
-	O
insulin	O
group	O
there	O
was	O
a	O
significant	O
fall	O
in	O
heart	O
-	O
rate	O
in	O
most	O
subjects	O
and	O
an	O
increase	O
in	O
diastolic	O
pressure	O
.	O

Typical	O
S	O
-	O
T	O
/	O
T	O
changes	O
occurred	O
in	O
the	O
insulin	O
-	O
group	O
but	O
in	O
none	O
of	O
the	O
propranolol	B-Chemical
-	O
insulin	O
group	O
.	O

Hypertension	B-Disease
in	O
diabetics	B-Disease
prone	O
to	O
hypoglycaemia	B-Disease
attacks	O
should	O
not	O
be	O
treated	O
with	O
beta	O
-	O
blockers	O
because	O
these	O
drugs	O
may	O
cause	O
a	O
sharp	O
rise	O
in	O
blood	O
-	O
pressure	O
in	O
such	O
patients	O
.	O

Long	O
-	O
term	O
propranolol	B-Chemical
therapy	O
in	O
pregnancy	O
:	O
maternal	O
and	O
fetal	O
outcome	O
.	O

Propranolol	B-Chemical
,	O
a	O
beta	O
-	O
adrenergic	O
blocking	O
agent	O
,	O
has	O
found	O
an	O
important	O
position	O
in	O
the	O
practice	O
of	O
medicine	O
.	O

Its	O
use	O
in	O
pregnancy	O
,	O
however	O
,	O
is	O
an	O
open	O
question	O
as	O
a	O
number	O
of	O
detrimental	O
side	O
effects	O
have	O
been	O
reported	O
in	O
the	O
fetus	O
and	O
neonate	O
.	O

Ten	O
patients	O
and	O
12	O
pregnancies	O
are	O
reported	O
where	O
chronic	O
propranolol	B-Chemical
has	O
been	O
administered	O
.	O

Five	O
patients	O
with	O
serial	O
pregnancies	O
with	O
and	O
without	O
propranolol	B-Chemical
therapy	O
are	O
also	O
examined	O
.	O

Maternal	O
,	O
fetal	O
,	O
and	O
neonatal	O
complications	O
are	O
examined	O
.	O

An	O
attempt	O
is	O
made	O
to	O
differentiate	O
drug	O
-	O
related	O
complications	O
from	O
maternal	O
disease	O
-	O
-	O
related	O
complications	O
.	O

We	O
conclude	O
that	O
previously	O
reported	O
hypoglycemia	B-Disease
,	O
hyperbilirubinemia	B-Disease
,	O
polycythemia	B-Disease
,	O
neonatal	B-Disease
apnea	I-Disease
,	O
and	O
bradycardia	B-Disease
are	O
not	O
invariable	O
and	O
cannot	O
be	O
statistically	O
correlated	O
with	O
chronic	O
propranolol	B-Chemical
therapy	O
.	O

Growth	B-Disease
retardation	I-Disease
,	O
however	O
,	O
appears	O
to	O
be	O
significant	O
in	O
both	O
of	O
our	O
series	O
.	O

Central	O
excitatory	O
actions	O
of	O
flurazepam	B-Chemical
.	O

Toxic	O
actions	O
of	O
flurazepam	B-Chemical
(	O
FZP	B-Chemical
)	O
were	O
studied	O
in	O
cats	O
,	O
mice	O
and	O
rats	O
.	O

High	O
doses	O
caused	O
an	O
apparent	O
central	O
excitation	O
,	O
most	O
clearly	O
seen	O
as	O
clonic	O
convulsions	B-Disease
,	O
superimposed	O
on	O
general	O
depression	B-Disease
.	O

Following	O
a	O
lethal	O
dose	O
,	O
death	O
was	O
always	O
associated	O
with	O
convulsions	B-Disease
.	O

Comparing	O
the	O
relative	O
sensitivity	O
to	O
central	O
depression	B-Disease
and	O
excitation	O
revealed	O
that	O
rats	O
were	O
least	O
likely	O
to	O
have	O
convulsions	B-Disease
at	O
doses	O
that	O
did	O
not	O
first	O
cause	O
loss	B-Disease
of	I-Disease
consciousness	I-Disease
,	O
while	O
cats	O
most	O
clearly	O
showed	O
marked	O
central	O
excitatory	O
actions	O
.	O

Signs	O
of	O
FZP	B-Chemical
toxocity	B-Disease
in	O
cats	O
included	O
excessive	O
salivation	B-Disease
,	O
extreme	O
apprehensive	O
behavior	O
,	O
retching	O
,	O
muscle	B-Disease
tremors	I-Disease
and	O
convulsions	B-Disease
.	O

An	O
interaction	O
between	O
FZP	B-Chemical
and	O
pentylenetetrazol	B-Chemical
(	O
PTZ	B-Chemical
)	O
was	O
shown	O
by	O
pretreating	O
mice	O
with	O
FZP	B-Chemical
before	O
PTZ	B-Chemical
challenge	O
.	O

As	O
a	O
function	O
of	O
dose	O
,	O
FZP	B-Chemical
first	O
protected	O
against	O
convulsions	B-Disease
and	O
death	O
.	O

At	O
higher	O
doses	O
,	O
however	O
,	O
convulsions	B-Disease
again	O
emerged	O
.	O

These	O
doses	O
of	O
FZP	B-Chemical
were	O
lower	O
than	O
those	O
that	O
would	O
alone	O
cause	O
convulsions	B-Disease
.	O

These	O
results	O
may	O
be	O
relevant	O
to	O
the	O
use	O
of	O
FZP	B-Chemical
in	O
clinical	O
situations	O
in	O
which	O
there	O
is	O
increased	O
neural	O
excitability	O
,	O
such	O
as	O
epilepsy	B-Disease
or	O
sedative	O
-	O
hypnotic	O
drug	O
withdrawal	O
.	O

Use	O
of	O
propranolol	B-Chemical
in	O
the	O
treatment	O
of	O
idiopathic	B-Disease
orthostatic	I-Disease
hypotension	I-Disease
.	O

Five	O
patients	O
with	O
idiopathic	B-Disease
orthostatic	I-Disease
hypotension	I-Disease
who	O
had	O
physiologic	O
and	O
biochemical	O
evidence	O
of	O
severe	O
autonomic	O
dysfunction	O
were	O
included	O
in	O
the	O
study	O
.	O

They	O
all	O
exhibited	O
markedly	O
reduced	O
plasma	O
catecholamines	B-Chemical
and	O
plasma	O
renin	O
activity	O
in	O
both	O
recumbent	O
and	O
upright	O
positions	O
and	O
had	O
marked	O
hypersensitivity	B-Disease
to	O
the	O
pressor	O
effects	O
of	O
infused	O
norepinephrine	B-Chemical
.	O

Treatment	O
with	O
propanolol	B-Chemical
administered	O
intravenously	O
(	O
1	O
-	O
5	O
mg	O
)	O
produced	O
increases	O
in	O
supine	O
and	O
upright	O
blood	O
pressure	O
in	O
4	O
of	O
the	O
5	O
individuals	O
with	O
rises	O
ranging	O
from	O
11	O
/	O
6	O
to	O
22	O
/	O
11	O
mmHg	O
.	O

Chronic	O
oral	O
administration	O
of	O
propranolol	B-Chemical
(	O
40	O
-	O
160	O
mg	O
/	O
day	O
)	O
also	O
elevated	O
the	O
blood	O
pressures	O
of	O
these	O
individuals	O
with	O
increases	O
in	O
the	O
order	O
of	O
20	O
-	O
35	O
/	O
15	O
-	O
25	O
mmg	O
being	O
observed	O
.	O

In	O
1	O
patient	O
,	O
marked	O
hypertension	B-Disease
was	O
induced	O
by	O
propranolol	B-Chemical
and	O
the	O
drug	O
had	O
to	O
be	O
withdrawn	O
.	O

It	O
otherwise	O
was	O
well	O
tolerated	O
and	O
no	O
important	O
side	O
effects	O
were	O
observed	O
.	O

Treatment	O
has	O
been	O
continued	O
in	O
3	O
individuals	O
for	O
6	O
-	O
13	O
months	O
with	O
persistence	O
of	O
the	O
pressor	O
effect	O
,	O
although	O
there	O
appears	O
to	O
have	O
been	O
some	O
decrease	O
in	O
the	O
degree	O
of	O
response	O
with	O
time	O
.	O

Hemodynamic	O
measurements	O
in	O
1	O
of	O
the	O
patients	O
demonstrated	O
an	O
increase	O
in	O
total	O
peripheral	O
resistance	O
and	O
essentially	O
no	O
change	O
in	O
cardiac	O
output	O
following	O
propranolol	B-Chemical
therapy	O
.	O

The	O
studies	O
suggest	O
that	O
propranolol	B-Chemical
is	O
a	O
useful	O
drug	O
in	O
selected	O
patients	O
with	O
severe	O
idiopathic	B-Disease
orthostatic	I-Disease
hypotension	I-Disease
.	O

Total	O
intravenous	O
anesthesia	O
with	O
etomidate	B-Chemical
.	O

III	O
.	O

Some	O
observations	O
in	O
adults	O
.	O

An	O
investigation	O
was	O
undertaken	O
to	O
determine	O
the	O
dosage	O
of	O
etomidate	B-Chemical
required	O
to	O
maintain	O
sleep	O
in	O
adults	O
undergoing	O
surgery	O
under	O
regional	O
local	O
anesthesia	O
.	O

Premedication	O
of	O
diazepam	B-Chemical
10	O
mg	O
and	O
atropine	B-Chemical
0	O
.	O
5	O
mg	O
was	O
given	O
,	O
and	O
sleep	O
was	O
induced	O
and	O
maintained	O
by	O
intermittent	O
intravenous	O
injections	O
of	O
etomidate	B-Chemical
0	O
.	O
1	O
/	O
mg	O
/	O
kg	O
,	O
given	O
whenever	O
the	O
patient	O
would	O
open	O
his	O
eyes	O
on	O
request	O
.	O

A	O
mean	O
overall	O
dose	O
of	O
etomidate	B-Chemical
17	O
.	O
4	O
microgram	O
/	O
kg	O
/	O
min	O
.	O
was	O
required	O
to	O
maintain	O
sleep	O
,	O
but	O
great	O
individual	O
variation	O
occurred	O
,	O
with	O
older	O
patients	O
requiring	O
less	O
drug	O
.	O

The	O
investigation	O
was	O
discontinued	O
after	O
18	O
patients	O
because	O
of	O
the	O
frequency	O
and	O
intensity	O
of	O
side	O
-	O
effects	O
,	O
particularly	O
pain	B-Disease
and	O
myoclonia	B-Disease
,	O
which	O
caused	O
the	O
technique	O
to	O
be	O
abandoned	O
in	O
two	O
cases	O
.	O

It	O
is	O
considered	O
unlikely	O
that	O
etomidate	B-Chemical
will	O
prove	O
to	O
be	O
the	O
hypnotic	O
of	O
choice	O
for	O
a	O
totally	O
intravenous	O
anesthetic	O
technique	O
in	O
adults	O
because	O
of	O
the	O
high	O
incidence	O
of	O
myoclonia	B-Disease
after	O
prolonged	O
administration	O
.	O

In	O
several	O
patients	O
uncontrollable	O
muscle	O
movements	O
persisted	O
for	O
many	O
minutes	O
after	O
complete	O
recovery	O
of	O
consciousness	O
.	O

Evidence	O
for	O
cardiac	O
beta	O
2	O
-	O
adrenoceptors	O
in	O
man	O
.	O

We	O
compared	O
the	O
effects	O
of	O
single	O
doses	O
of	O
50	O
mg	O
atenolol	B-Chemical
(	O
cardioselective	O
)	O
,	O
40	O
mg	O
propranolol	B-Chemical
(	O
nonselective	O
)	O
,	O
and	O
placebo	O
on	O
both	O
exercise	O
-	O
and	O
isoproterenol	B-Chemical
-	O
induced	O
tachycardia	B-Disease
in	O
two	O
experiments	O
involving	O
nine	O
normal	O
subjects	O
.	O

Maximal	O
exercise	O
heart	O
rate	O
was	O
reduced	O
from	O
187	O
+	O
/	O
-	O
4	O
(	O
SEM	O
)	O
after	O
placebo	O
to	O
146	O
+	O
/	O
-	O
7	O
bpm	O
after	O
atenolol	B-Chemical
and	O
138	O
+	O
/	O
-	O
6	O
bpm	O
after	O
propranolol	B-Chemical
,	O
but	O
there	O
were	O
no	O
differences	O
between	O
the	O
drugs	O
.	O

The	O
effects	O
on	O
isoproterenol	B-Chemical
tachycardia	B-Disease
were	O
determined	O
before	O
and	O
after	O
atropine	B-Chemical
(	O
0	O
.	O
04	O
mg	O
/	O
kg	O
IV	O
)	O
.	O

Isoproterenol	B-Chemical
sensitivity	O
was	O
determined	O
as	O
the	O
intravenous	O
dose	O
that	O
increased	O
heart	O
rate	O
by	O
25	O
bpm	O
(	O
CD25	O
)	O
and	O
this	O
was	O
increased	O
from	O
1	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
3	O
micrograms	O
after	O
placebo	O
to	O
38	O
.	O
9	O
+	O
/	O
-	O
8	O
.	O
3	O
micrograms	O
after	O
propranolol	B-Chemical
and	O
8	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
7	O
micrograms	O
after	O
atenolol	B-Chemical
.	O

The	O
difference	O
in	O
the	O
effects	O
of	O
the	O
two	O
was	O
significant	O
.	O

After	O
atropine	B-Chemical
the	O
CD25	O
was	O
unchanged	O
after	O
placebo	O
(	O
2	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
3	O
micrograms	O
)	O
and	O
atenolol	B-Chemical
(	O
7	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
3	O
micrograms	O
)	O
;	O
it	O
was	O
reduced	O
after	O
propranolol	B-Chemical
(	O
24	O
.	O
8	O
+	O
/	O
-	O
5	O
.	O
0	O
micrograms	O
)	O
,	O
but	O
remained	O
different	O
from	O
atenolol	B-Chemical
.	O

This	O
change	O
with	O
propranolol	B-Chemical
sensitivity	O
was	O
calculated	O
as	O
the	O
apparent	O
Ka	O
,	O
this	O
was	O
unchanged	O
by	O
atropine	B-Chemical
(	O
11	O
.	O
7	O
+	O
/	O
-	O
2	O
.	O
1	O
and	O
10	O
.	O
1	O
+	O
/	O
-	O
2	O
.	O
5	O
ml	O
/	O
ng	O
)	O
.	O

These	O
data	O
are	O
consistent	O
with	O
the	O
hypothesis	O
that	O
exercise	O
-	O
induced	O
tachycardia	B-Disease
results	O
largely	O
from	O
beta	O
1	O
-	O
receptor	O
activation	O
that	O
is	O
blocked	O
by	O
both	O
cardioselective	O
and	O
nonselective	O
drugs	O
,	O
whereas	O
isoproterenol	B-Chemical
activates	O
both	O
beta	O
1	O
-	O
and	O
beta	O
2	O
-	O
receptors	O
so	O
that	O
after	O
cardioselective	O
blockade	O
there	O
remains	O
a	O
beta	O
2	O
-	O
component	O
that	O
can	O
be	O
blocked	O
with	O
a	O
nonselective	O
drug	O
.	O

While	O
there	O
appear	O
to	O
be	O
beta	O
2	O
-	O
receptors	O
in	O
the	O
human	O
heart	O
,	O
their	O
physiologic	O
or	O
pathologic	O
roles	O
remain	O
to	O
be	O
defined	O
.	O

Hormones	O
and	O
risk	O
of	O
breast	B-Disease
cancer	I-Disease
.	O

This	O
paper	O
reports	O
the	O
results	O
of	O
a	O
study	O
of	O
50	O
menopausal	O
women	O
receiving	O
hormonal	O
replacement	O
therapy	O
.	O

The	O
majority	O
(	O
29	O
)	O
had	O
surgical	O
menopause	O
;	O
their	O
mean	O
age	O
was	O
45	O
.	O
7	O
years	O
.	O

It	O
was	O
hypothesized	O
that	O
progestins	B-Chemical
could	O
equilibrate	O
the	O
effects	O
of	O
the	O
estrogenic	O
stimulation	O
on	O
the	O
mammary	O
and	O
endometrial	O
target	O
tissues	O
of	O
women	O
on	O
hormonal	O
replacement	O
therapy	O
.	O

The	O
treatment	O
schedule	O
consisted	O
of	O
conjugated	B-Chemical
estrogens	I-Chemical
(	O
Premarin	B-Chemical
)	O
1	O
.	O
25	O
mg	O
/	O
day	O
for	O
21	O
days	O
and	O
Medroxyprogesterone	B-Chemical
acetate	I-Chemical
10	O
mg	O
/	O
day	O
for	O
10	O
days	O
in	O
each	O
month	O
.	O

The	O
mean	O
treatment	O
period	O
was	O
18	O
months	O
.	O

During	O
the	O
follow	O
-	O
up	O
period	O
,	O
attention	O
was	O
paid	O
to	O
breast	O
modifications	O
as	O
evidenced	O
by	O
symptomatology	O
,	O
physical	O
examination	O
,	O
and	O
plate	O
thermography	O
.	O

Mastodynia	B-Disease
was	O
reported	O
by	O
21	O
patients	O
,	O
and	O
physical	O
examination	O
revealed	O
a	O
light	O
increase	O
in	O
breast	O
firmness	O
in	O
12	O
women	O
and	O
a	O
moderate	O
increase	O
in	O
breast	O
nodularity	O
in	O
2	O
women	O
.	O

Themography	O
confirmed	O
the	O
existence	O
of	O
an	O
excessive	O
breast	O
stimulation	O
in	O
1	O
women	O
who	O
complained	O
of	O
moderate	O
mastodynia	B-Disease
and	O
in	O
5	O
of	O
the	O
7	O
women	O
who	O
complained	O
of	O
severe	O
mastodynia	B-Disease
.	O

Normalization	O
was	O
obtained	O
by	O
halving	O
the	O
estrogen	B-Chemical
dose	O
.	O

These	O
results	O
suggest	O
that	O
hormonal	O
replacement	O
therapy	O
can	O
be	O
safely	O
prescribed	O
if	O
the	O
following	O
criteria	O
are	O
satisfied	O
:	O
1	O
)	O
preliminary	O
evaluation	O
of	O
patients	O
from	O
a	O
clinical	O
,	O
metabolic	O
,	O
cytologic	O
,	O
and	O
mammographic	O
perspective	O
;	O
2	O
)	O
cyclic	O
treatment	O
schedule	O
,	O
with	O
a	O
progestative	O
phase	O
of	O
10	O
days	O
;	O
and	O
3	O
)	O
periodic	O
complete	O
follow	O
-	O
up	O
,	O
with	O
accurate	O
thermographic	O
evaluation	O
of	O
the	O
breast	O
target	O
tissues	O
.	O

Early	O
infections	B-Disease
in	O
kidney	O
,	O
heart	O
,	O
and	O
liver	O
transplant	O
recipients	O
on	O
cyclosporine	B-Chemical
.	O

Eighty	O
-	O
one	O
renal	O
,	O
seventeen	O
heart	O
,	O
and	O
twenty	O
-	O
four	O
liver	O
transplant	O
patients	O
were	O
followed	O
for	O
infection	B-Disease
.	O

Seventeen	O
renal	O
patients	O
received	O
azathioprine	B-Chemical
(	O
Aza	B-Chemical
)	O
and	O
prednisone	B-Chemical
as	O
part	O
of	O
a	O
randomized	O
trial	O
of	O
immunosuppression	O
with	O
21	O
cyclosporine	B-Chemical
-	O
and	O
-	O
prednisone	B-Chemical
-	O
treated	O
renal	O
transplant	O
patients	O
.	O

All	O
others	O
received	O
cyclosporine	B-Chemical
and	O
prednisone	B-Chemical
.	O

The	O
randomized	O
Aza	B-Chemical
patients	O
had	O
more	O
overall	O
infections	B-Disease
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
more	O
nonviral	O
infections	B-Disease
(	O
P	O
less	O
than	O
0	O
.	O
02	O
)	O
than	O
the	O
randomized	O
cyclosporine	B-Chemical
patients	O
.	O

Heart	O
and	O
liver	O
patients	O
had	O
more	O
infections	B-Disease
than	O
cyclosporine	B-Chemical
renal	O
patients	O
but	O
fewer	O
infections	B-Disease
than	O
the	O
Aza	B-Chemical
renal	O
patients	O
.	O

There	O
were	O
no	O
infectious	O
deaths	O
in	O
renal	O
transplant	O
patients	O
on	O
cyclosporine	B-Chemical
or	O
Aza	B-Chemical
,	O
but	O
infection	B-Disease
played	O
a	O
major	O
role	O
in	O
3	O
out	O
of	O
6	O
cardiac	O
transplant	O
deaths	O
and	O
in	O
8	O
out	O
of	O
9	O
liver	O
transplant	O
deaths	O
.	O

Renal	O
patients	O
on	O
cyclosporine	B-Chemical
had	O
the	O
fewest	O
bacteremias	B-Disease
.	O

Analysis	O
of	O
site	O
of	O
infection	B-Disease
showed	O
a	O
preponderance	O
of	O
abdominal	B-Disease
infections	I-Disease
in	O
liver	O
patients	O
,	O
intrathoracic	O
infections	B-Disease
in	O
heart	O
patients	O
,	O
and	O
urinary	B-Disease
tract	I-Disease
infections	I-Disease
in	O
renal	O
patients	O
.	O

Pulmonary	O
infections	B-Disease
were	O
less	O
common	O
in	O
cyclosporine	B-Chemical
-	O
treated	O
renal	O
patients	O
than	O
in	O
Aza	B-Chemical
-	O
treated	O
patients	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Aza	B-Chemical
patients	O
had	O
significantly	O
more	O
staphylococcal	B-Disease
infections	I-Disease
than	O
all	O
other	O
transplant	O
groups	O
(	O
P	O
less	O
than	O
0	O
.	O
005	O
)	O
,	O
and	O
systemic	O
fungal	B-Disease
infections	I-Disease
occurred	O
only	O
in	O
the	O
liver	O
transplant	O
group	O
.	O

Cytomegalovirus	O
(	O
CMV	O
)	O
shedding	O
or	O
serological	O
rises	O
in	O
antibody	O
titer	O
,	O
or	O
both	O
occurred	O
in	O
78	O
%	O
of	O
cyclosporine	B-Chemical
patients	O
and	O
76	O
%	O
of	O
Aza	B-Chemical
patients	O
.	O

Of	O
the	O
cyclosporine	B-Chemical
patients	O
,	O
15	O
%	O
had	O
symptoms	O
related	O
to	O
CMV	B-Disease
infection	I-Disease
.	O

Serological	O
evidence	O
for	O
Epstein	B-Disease
Barr	I-Disease
Virus	I-Disease
infection	I-Disease
was	O
found	O
in	O
20	O
%	O
of	O
65	O
cyclosporine	B-Chemical
patients	O
studied	O
.	O

Three	O
had	O
associated	O
symptoms	O
,	O
and	O
one	O
developed	O
a	O
lymphoma	B-Disease
.	O

Structure	O
-	O
activity	O
and	O
dose	O
-	O
effect	O
relationships	O
of	O
the	O
antagonism	O
of	O
picrotoxin	B-Chemical
-	O
induced	O
seizures	B-Disease
by	O
cholecystokinin	B-Chemical
,	O
fragments	O
and	O
analogues	O
of	O
cholecystokinin	B-Chemical
in	O
mice	O
.	O

Intraperitoneal	O
administration	O
of	O
cholecystokinin	B-Chemical
octapeptide	I-Chemical
sulphate	O
ester	O
(	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
-	O
SE	O
)	O
and	O
nonsulphated	O
cholecystokinin	B-Chemical
octapeptide	I-Chemical
(	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
-	O
NS	O
)	O
enhanced	O
the	O
latency	O
of	O
seizures	B-Disease
induced	O
by	O
picrotoxin	B-Chemical
in	O
mice	O
.	O

Experiments	O
with	O
N	O
-	O
and	O
C	O
-	O
terminal	O
fragments	O
revealed	O
that	O
the	O
C	O
-	O
terminal	O
tetrapeptide	O
(	O
CCK	O
-	O
5	O
-	O
8	O
)	O
was	O
the	O
active	O
centre	O
of	O
the	O
CCK	O
octapeptide	O
molecule	O
.	O

The	O
analogues	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
-	O
SE	O
and	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
-	O
NS	O
(	O
dose	O
range	O
0	O
.	O
2	O
-	O
6	O
.	O
4	O
mumol	O
/	O
kg	O
)	O
and	O
caerulein	B-Chemical
dose	O
range	O
0	O
.	O
1	O
-	O
0	O
.	O
8	O
mumol	O
/	O
kg	O
)	O
showed	O
bell	O
-	O
shaped	O
dose	O
-	O
effect	O
curves	O
,	O
with	O
the	O
greatest	O
maximum	O
inhibition	O
for	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
-	O
NS	O
.	O

The	O
peptide	O
CCK	O
-	O
5	O
-	O
8	O
had	O
weak	O
anticonvulsant	O
activity	O
in	O
comparison	O
to	O
the	O
octapeptides	O
,	O
3	O
.	O
2	O
mumol	O
/	O
kg	O
and	O
larger	O
doses	O
of	O
the	O
reference	O
drug	O
,	O
diazepam	B-Chemical
,	O
totally	O
prevented	O
picrotoxin	B-Chemical
-	O
induced	O
seizures	B-Disease
and	O
mortality	O
.	O

The	O
maximum	O
effect	O
of	O
the	O
peptides	O
tested	O
was	O
less	O
than	O
that	O
of	O
diazepam	B-Chemical
.	O

Experiments	O
with	O
analogues	O
and	O
derivatives	O
of	O
CCK	O
-	O
5	O
-	O
8	O
demonstrated	O
that	O
the	O
effectiveness	O
of	O
the	O
beta	O
-	O
alanyl	O
derivatives	O
of	O
CCK	O
-	O
5	O
-	O
8	O
were	O
enhanced	O
and	O
that	O
they	O
were	O
equipotent	O
with	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
-	O
SE	O
.	O

Of	O
the	O
CCK	O
-	O
2	O
-	O
8	O
analogues	O
,	O
Ser	O
(	O
SO3H	O
)	O
7	O
-	O
Ac	O
-	O
CCK	O
-	O
2	O
-	O
8	O
-	O
SE	O
and	O
Thr	O
(	O
SO3H	O
)	O
7	O
-	O
Ac	O
-	O
CCK	O
-	O
2	O
-	O
8	O
-	O
SE	O
and	O
Hyp	O
(	O
SO3H	O
)	O
-	O
Ac	O
-	O
CCK	O
-	O
2	O
-	O
8	O
-	O
SE	O
were	O
slightly	O
more	O
active	O
than	O
CCK	B-Chemical
-	I-Chemical
8	I-Chemical
-	O
SE	O
.	O

Vasopressin	B-Chemical
as	O
a	O
possible	O
contributor	O
to	O
hypertension	B-Disease
.	O

The	O
role	O
of	O
vasopressin	B-Chemical
as	O
a	O
pressor	O
agent	O
to	O
the	O
hypertensive	B-Disease
process	O
was	O
examined	O
.	O

Vasopressin	B-Chemical
plays	O
a	O
major	O
role	O
in	O
the	O
pathogenesis	O
of	O
DOCA	B-Chemical
-	O
salt	O
hypertension	B-Disease
,	O
since	O
the	O
elevation	O
of	O
blood	O
pressure	O
was	O
not	O
substantial	O
in	O
the	O
rats	O
with	O
lithium	B-Chemical
-	O
treated	O
diabetes	B-Disease
insipidus	I-Disease
after	O
DOCA	B-Chemical
-	O
salt	O
treatment	O
.	O

Administration	O
of	O
DDAVP	B-Chemical
which	O
has	O
antidiuretic	O
action	O
but	O
minimal	O
vasopressor	O
effect	O
failed	O
to	O
increase	O
blood	O
pressure	O
to	O
the	O
levels	O
observed	O
after	O
administration	O
of	O
AVP	O
.	O

Furthermore	O
,	O
the	O
pressor	O
action	O
of	O
vasopressin	B-Chemical
appears	O
to	O
be	O
important	O
in	O
the	O
development	O
of	O
this	O
model	O
of	O
hypertension	B-Disease
,	O
since	O
the	O
enhanced	O
pressor	O
responsiveness	O
to	O
the	O
hormone	O
was	O
observed	O
in	O
the	O
initial	O
stage	O
of	O
hypertension	B-Disease
.	O

Increased	O
secretion	O
of	O
vasopressin	B-Chemical
from	O
neurohypophysis	O
also	O
promotes	O
the	O
function	O
of	O
the	O
hormone	O
as	O
a	O
pathogenetic	O
factor	O
in	O
hypertension	B-Disease
.	O

An	O
unproportional	O
release	O
of	O
vasopressin	B-Chemical
compared	O
to	O
plasma	O
osmolality	O
may	O
be	O
induced	O
by	O
the	O
absence	O
of	O
an	O
adjusting	O
control	O
of	O
angiotensin	B-Chemical
II	O
forming	O
and	O
receptor	O
binding	O
capacity	O
for	O
sodium	B-Chemical
balance	O
in	O
the	O
brain	O
.	O

However	O
,	O
the	O
role	O
of	O
vasopressin	B-Chemical
remains	O
to	O
be	O
determined	O
in	O
human	O
essential	O
hypertension	B-Disease
.	O

Toxic	B-Disease
hepatitis	I-Disease
induced	O
by	O
disulfiram	B-Chemical
in	O
a	O
non	O
-	O
alcoholic	O
.	O

A	O
reversible	O
toxic	B-Disease
liver	I-Disease
damage	I-Disease
was	O
observed	O
in	O
a	O
non	O
-	O
alcoholic	O
woman	O
treated	O
with	O
disulfiram	B-Chemical
.	O

The	O
causative	O
relationship	O
was	O
proven	O
by	O
challenge	O
.	O

Atrial	B-Disease
thrombosis	I-Disease
involving	O
the	O
heart	O
of	O
F	O
-	O
344	O
rats	O
ingesting	O
quinacrine	B-Chemical
hydrochloride	I-Chemical
.	O

Quinacrine	B-Chemical
hydrochloride	I-Chemical
is	O
toxic	O
for	O
the	O
heart	O
of	O
F	O
-	O
344	O
rats	O
.	O

Rats	O
treated	O
with	O
500	O
ppm	O
quinacrine	B-Chemical
hydrochloride	I-Chemical
in	O
the	O
diet	O
all	O
developed	O
a	O
high	O
incidence	O
of	O
left	O
atrial	B-Disease
thrombosis	I-Disease
.	O

The	O
lesion	O
was	O
associated	O
with	O
cardiac	B-Disease
hypertrophy	I-Disease
and	O
dilatation	O
and	O
focal	O
myocardial	B-Disease
degeneration	I-Disease
.	O

Rats	O
died	O
from	O
cardiac	B-Disease
hypertrophy	I-Disease
with	O
severe	O
acute	O
and	O
chronic	O
congestion	O
of	O
the	O
lungs	O
,	O
liver	O
,	O
and	O
other	O
organs	O
.	O

Seventy	O
percent	O
of	O
rats	O
given	O
250	O
ppm	O
quinacrine	B-Chemical
hydrochloride	I-Chemical
and	O
1	O
,	O
000	O
ppm	O
sodium	B-Chemical
nitrite	I-Chemical
simultaneously	O
in	O
the	O
diet	O
had	O
thrombosis	B-Disease
of	O
the	O
atria	O
of	O
the	O
heart	O
,	O
while	O
untreated	O
control	O
rats	O
in	O
this	O
laboratory	O
did	O
not	O
have	O
atrial	B-Disease
thrombosis	I-Disease
.	O

Sodium	B-Chemical
nitrite	I-Chemical
in	O
combination	O
with	O
quinacrine	B-Chemical
hydrochloride	I-Chemical
appeared	O
to	O
have	O
no	O
additional	O
effect	O
.	O

Alternating	B-Disease
sinus	I-Disease
rhythm	I-Disease
and	O
intermittent	O
sinoatrial	B-Disease
block	I-Disease
induced	O
by	O
propranolol	B-Chemical
.	O

Alternating	B-Disease
sinus	I-Disease
rhythm	I-Disease
and	O
intermittent	O
sinoatrial	B-Disease
(	I-Disease
S	I-Disease
-	I-Disease
A	I-Disease
)	I-Disease
block	I-Disease
was	O
observed	O
in	O
a	O
57	O
-	O
year	O
-	O
old	O
woman	O
,	O
under	O
treatment	O
for	O
angina	B-Disease
with	O
80	O
mg	O
propranolol	B-Chemical
daily	O
.	O

The	O
electrocardiogram	O
showed	O
alternation	O
of	O
long	O
and	O
short	O
P	O
-	O
P	O
intervals	O
and	O
occasional	O
pauses	O
.	O

These	O
pauses	O
were	O
always	O
preceded	O
by	O
the	O
short	O
P	O
-	O
P	O
intervals	O
and	O
were	O
usually	O
followed	O
by	O
one	O
or	O
two	O
P	O
-	O
P	O
intervals	O
of	O
0	O
.	O
92	O
-	O
0	O
.	O
95	O
s	O
representing	O
the	O
basic	O
sinus	O
cycle	O
.	O

Following	O
these	O
basic	O
sinus	O
cycles	O
,	O
alternating	B-Disease
rhythm	I-Disease
started	O
with	O
the	O
longer	O
P	O
-	O
P	O
interval	O
.	O

The	O
long	O
P	O
-	O
P	O
intervals	O
ranged	O
between	O
1	O
.	O
04	O
-	O
1	O
.	O
12	O
s	O
and	O
the	O
short	O
P	O
-	O
P	O
intervals	O
between	O
0	O
.	O
80	O
-	O
0	O
.	O
84	O
s	O
,	O
respectively	O
.	O

The	O
duration	O
of	O
the	O
pauses	O
were	O
equal	O
or	O
almost	O
equal	O
to	O
one	O
short	O
plus	O
one	O
long	O
P	O
-	O
P	O
interval	O
or	O
to	O
twice	O
the	O
basic	O
sinus	O
cycle	O
.	O

In	O
one	O
recording	O
a	O
short	O
period	O
of	O
regular	O
sinus	O
rhythm	O
with	O
intermittent	O
2	O
/	O
1	O
S	B-Disease
-	I-Disease
A	I-Disease
block	I-Disease
was	O
observed	O
.	O

This	O
short	O
period	O
of	O
sinus	O
rhythm	O
was	O
interrupted	O
by	O
sudden	O
prolongation	O
of	O
the	O
P	O
-	O
P	O
interval	O
starting	O
the	O
alternative	O
rhythm	O
.	O

There	O
were	O
small	O
changes	O
in	O
the	O
shape	O
of	O
the	O
P	O
waves	O
and	O
P	O
-	O
R	O
intervals	O
.	O

S	O
-	O
A	O
conduction	O
through	O
two	O
pathways	O
,	O
the	O
first	O
with	O
2	O
/	O
1	O
block	O
the	O
second	O
having	O
0	O
.	O
12	O
-	O
0	O
.	O
14	O
s	O
longer	O
conduction	O
time	O
and	O
with	O
occasional	O
2	O
/	O
1	O
block	O
was	O
proposed	O
for	O
the	O
explanation	O
of	O
the	O
alternating	O
P	O
-	O
P	O
interval	O
and	O
other	O
electrocardiographic	O
features	O
seen	O
.	O

Atropine	B-Chemical
1	O
mg	O
given	O
intravenously	O
resulted	O
in	O
shortening	O
of	O
all	O
P	O
-	O
P	O
intervals	O
without	O
changing	O
the	O
rhythm	O
.	O

The	O
abnormal	O
rhythm	O
disappeared	O
with	O
the	O
withdrawal	O
of	O
propranolol	B-Chemical
and	O
when	O
the	O
drug	O
was	O
restarted	O
a	O
2	O
/	O
1	O
S	B-Disease
-	I-Disease
A	I-Disease
block	I-Disease
was	O
seen	O
.	O

This	O
was	O
accepted	O
as	O
evidence	O
for	O
propranolol	B-Chemical
being	O
the	O
cause	O
of	O
this	O
conduction	B-Disease
disorder	I-Disease
.	O

Antitumor	O
effect	O
,	O
cardiotoxicity	B-Disease
,	O
and	O
nephrotoxicity	B-Disease
of	O
doxorubicin	B-Chemical
in	O
the	O
IgM	O
solid	O
immunocytoma	B-Disease
-	O
bearing	O
LOU	O
/	O
M	O
/	O
WSL	O
rat	O
.	O

Antitumor	O
activity	O
,	O
cardiotoxicity	B-Disease
,	O
and	O
nephrotoxicity	B-Disease
induced	O
by	O
doxorubicin	B-Chemical
were	O
studied	O
in	O
LOU	O
/	O
M	O
/	O
WSL	O
inbred	O
rats	O
each	O
bearing	O
a	O
transplantable	O
solid	O
IgM	O
immunocytoma	B-Disease
.	O

Animals	O
with	O
a	O
tumor	B-Disease
(	O
diameter	O
,	O
15	O
.	O
8	O
+	O
/	O
-	O
3	O
.	O
3	O
mm	O
)	O
were	O
treated	O
with	O
iv	O
injections	O
of	O
doxorubicin	B-Chemical
on	O
5	O
consecutive	O
days	O
,	O
followed	O
by	O
1	O
weekly	O
injection	O
for	O
7	O
weeks	O
(	O
dose	O
range	O
,	O
0	O
.	O
015	O
-	O
4	O
.	O
0	O
mg	O
/	O
kg	O
body	O
wt	O
)	O
.	O

Tumor	B-Disease
regression	O
was	O
observed	O
with	O
0	O
.	O
5	O
mg	O
doxorubicin	B-Chemical
/	O
kg	O
.	O

Complete	O
disappearance	O
of	O
the	O
tumor	B-Disease
was	O
induced	O
with	O
1	O
.	O
0	O
mg	O
doxorubicin	B-Chemical
/	O
kg	O
.	O

Histologic	O
evidence	O
of	O
cardiotoxicity	B-Disease
scored	O
as	O
grade	O
III	O
was	O
only	O
observed	O
at	O
a	O
dose	O
of	O
1	O
.	O
0	O
mg	O
doxorubicin	B-Chemical
/	O
kg	O
.	O

Light	O
microscopic	O
evidence	O
of	O
renal	B-Disease
damage	I-Disease
was	O
seen	O
above	O
a	O
dose	O
of	O
0	O
.	O
5	O
mg	O
doxorubicin	B-Chemical
/	O
kg	O
,	O
which	O
resulted	O
in	O
albuminuria	B-Disease
and	O
very	O
low	O
serum	O
albumin	O
levels	O
.	O

In	O
the	O
group	O
that	O
received	O
1	O
.	O
0	O
mg	O
doxorubicin	B-Chemical
/	O
kg	O
,	O
the	O
serum	O
albumin	O
level	O
decreased	O
from	O
33	O
.	O
6	O
+	O
/	O
-	O
4	O
.	O
1	O
to	O
1	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
5	O
g	O
/	O
liter	O
.	O

Ascites	B-Disease
and	O
hydrothorax	B-Disease
were	O
observed	O
simultaneously	O
.	O

The	O
same	O
experiments	O
were	O
performed	O
with	O
non	O
-	O
tumor	B-Disease
-	O
bearing	O
rats	O
,	O
in	O
which	O
no	O
major	O
differences	O
were	O
observed	O
.	O

In	O
conclusion	O
,	O
antitumor	O
activity	O
,	O
cardiotoxicity	B-Disease
,	O
and	O
nephrotoxicity	B-Disease
were	O
studied	O
simultaneously	O
in	O
the	O
same	O
LOU	O
/	O
M	O
/	O
WSL	O
rat	O
.	O

Albuminuria	B-Disease
due	O
to	O
renal	B-Disease
damage	I-Disease
led	O
to	O
extremely	O
low	O
serum	O
albumin	O
levels	O
,	O
so	O
ascites	B-Disease
and	O
hydrothorax	B-Disease
were	O
not	O
necessarily	O
a	O
consequence	O
of	O
the	O
observed	O
cardiomyopathy	B-Disease
.	O

Intraoperative	O
bradycardia	B-Disease
and	O
hypotension	B-Disease
associated	O
with	O
timolol	B-Chemical
and	O
pilocarpine	B-Chemical
eye	O
drops	O
.	O

A	O
69	O
-	O
yr	O
-	O
old	O
man	O
,	O
who	O
was	O
concurrently	O
being	O
treated	O
with	O
pilocarpine	B-Chemical
nitrate	I-Chemical
and	O
timolol	B-Chemical
maleate	I-Chemical
eye	O
drops	O
,	O
developed	O
a	O
bradycardia	B-Disease
and	O
became	O
hypotensive	B-Disease
during	O
halothane	B-Chemical
anaesthesia	O
.	O

Both	O
timolol	B-Chemical
and	O
pilocarpine	B-Chemical
were	O
subsequently	O
identified	O
in	O
a	O
24	O
-	O
h	O
collection	O
of	O
urine	O
.	O

Timolol	B-Chemical
(	O
but	O
not	O
pilocarpine	B-Chemical
)	O
was	O
detected	O
in	O
a	O
sample	O
of	O
plasma	O
removed	O
during	O
surgery	O
;	O
the	O
plasma	O
concentration	O
of	O
timolol	B-Chemical
(	O
2	O
.	O
6	O
ng	O
ml	O
-	O
1	O
)	O
was	O
consistent	O
with	O
partial	O
beta	O
-	O
adrenoceptor	O
blockade	O
.	O

It	O
is	O
postulated	O
that	O
this	O
action	O
may	O
have	O
been	O
enhanced	O
during	O
halothane	B-Chemical
anaesthesia	O
with	O
resultant	O
bradycardia	B-Disease
and	O
hypotension	B-Disease
.	O

Pilocarpine	B-Chemical
may	O
have	O
had	O
a	O
contributory	O
effect	O
.	O

Succinylcholine	B-Chemical
apnoea	B-Disease
:	O
attempted	O
reversal	O
with	O
anticholinesterases	O
.	O

Anticholinesterases	O
were	O
administered	O
in	O
an	O
attempt	O
to	O
antagonize	O
prolonged	O
neuromuscular	B-Disease
blockade	I-Disease
following	O
the	O
administration	O
of	O
succinylcholine	B-Chemical
in	O
a	O
patient	O
later	O
found	O
to	O
be	O
homozygous	O
for	O
atypical	O
plasma	O
cholinesterase	O
.	O

Edrophonium	B-Chemical
10	O
mg	O
,	O
given	O
74	O
min	O
after	O
succinylcholine	B-Chemical
,	O
when	O
train	O
-	O
of	O
-	O
four	O
stimulation	O
was	O
characteristic	O
of	O
phase	O
II	O
block	O
,	O
produced	O
partial	O
antagonism	O
which	O
was	O
not	O
sustained	O
.	O

Repeated	O
doses	O
of	O
edrophonium	B-Chemical
to	O
70	O
mg	O
and	O
neostigmine	B-Chemical
to	O
2	O
.	O
5	O
mg	O
did	O
not	O
antagonize	O
or	O
augment	O
the	O
block	O
.	O

Spontaneous	O
respiration	O
recommenced	O
200	O
min	O
after	O
succinylcholine	B-Chemical
administration	O
.	O

It	O
is	O
concluded	O
that	O
anticholinesterases	O
are	O
only	O
partially	O
effective	O
in	O
restoring	O
neuromuscular	O
function	O
in	O
succinylcholine	B-Chemical
apnoea	B-Disease
despite	O
muscle	O
twitch	O
activity	O
typical	O
of	O
phase	O
II	O
block	O
.	O

Effect	O
of	O
doxorubicin	B-Chemical
on	O
[	B-Chemical
omega	I-Chemical
-	I-Chemical
I	I-Chemical
-	I-Chemical
131	I-Chemical
]	I-Chemical
heptadecanoic	I-Chemical
acid	I-Chemical
myocardial	O
scintigraphy	O
and	O
echocardiography	O
in	O
dogs	O
.	O

The	O
effects	O
of	O
serial	O
treatment	O
with	O
doxorubicin	B-Chemical
on	O
dynamic	O
myocardial	O
scintigraphy	O
with	O
[	B-Chemical
omega	I-Chemical
-	I-Chemical
I	I-Chemical
-	I-Chemical
131	I-Chemical
]	I-Chemical
heptadecanoic	I-Chemical
acid	I-Chemical
(	O
I	B-Chemical
-	I-Chemical
131	I-Chemical
HA	I-Chemical
)	O
,	O
and	O
on	O
global	O
left	O
-	O
ventricular	O
function	O
determined	O
echocardiographically	O
,	O
were	O
studied	O
in	O
a	O
group	O
of	O
nine	O
mongrel	O
dogs	O
.	O

Total	O
extractable	O
myocardial	O
lipid	O
was	O
compared	O
postmortem	O
between	O
a	O
group	O
of	O
control	O
dogs	O
and	O
doxorubicin	B-Chemical
-	O
treated	O
dogs	O
.	O

A	O
significant	O
and	O
then	O
progressive	O
fall	O
in	O
global	O
LV	O
function	O
was	O
observed	O
at	O
a	O
cumulative	O
doxorubicin	B-Chemical
dose	O
of	O
4	O
mg	O
/	O
kg	O
.	O

A	O
significant	O
increase	O
in	O
the	O
myocardial	O
t1	O
/	O
2	O
of	O
the	O
I	B-Chemical
-	I-Chemical
131	I-Chemical
HA	I-Chemical
was	O
observed	O
only	O
at	O
a	O
higher	O
cumulative	O
dose	O
,	O
10	O
mg	O
/	O
kg	O
.	O

No	O
significant	O
alteration	O
in	O
total	O
extractable	O
myocardial	O
lipids	O
was	O
observed	O
between	O
control	O
dogs	O
and	O
those	O
treated	O
with	O
doxorubicin	B-Chemical
.	O

Our	O
findings	O
suggest	O
that	O
the	O
changes	O
leading	O
to	O
an	O
alteration	O
of	O
myocardial	O
dynamic	O
imaging	O
with	O
I	B-Chemical
-	I-Chemical
131	I-Chemical
HA	I-Chemical
are	O
not	O
the	O
initiating	O
factor	O
in	O
doxorubicin	B-Chemical
cardiotoxicity	B-Disease
.	O

Hemodynamics	O
and	O
myocardial	O
metabolism	O
under	O
deliberate	O
hypotension	B-Disease
.	O

An	O
experimental	O
study	O
in	O
dogs	O
.	O

Coronary	O
blood	O
flow	O
,	O
cardiac	O
work	O
and	O
metabolism	O
were	O
studied	O
in	O
dogs	O
under	O
sodium	B-Chemical
nitroprusside	I-Chemical
(	O
SNP	B-Chemical
)	O
and	O
trimetaphan	B-Chemical
(	O
TMP	B-Chemical
)	O
deliberate	O
hypotension	B-Disease
(	O
20	O
%	O
and	O
40	O
%	O
mean	O
pressure	O
decrease	O
from	O
baseline	O
)	O
.	O

Regarding	O
the	O
effects	O
of	O
drug	O
-	O
induced	O
hypotension	B-Disease
on	O
coronary	O
blood	O
flow	O
,	O
aortic	O
and	O
coronary	O
sinus	O
metabolic	O
data	O
(	O
pH	O
,	O
pO2	O
,	O
pCO2	O
)	O
we	O
could	O
confirm	O
that	O
nitroprusside	B-Chemical
hypotension	B-Disease
could	O
be	O
safely	O
used	O
to	O
30	O
%	O
mean	O
blood	O
pressure	O
decrease	O
from	O
control	O
,	O
trimetaphan	B-Chemical
hypotension	B-Disease
to	O
20	O
%	O
mean	O
blood	O
pressure	O
decrease	O
.	O

Cardiac	O
work	O
was	O
significantly	O
reduced	O
during	O
SNP	B-Chemical
hypotension	B-Disease
.	O

Myocardial	O
O2	B-Chemical
consumption	O
and	O
O2	B-Chemical
availability	O
were	O
directly	O
dependent	O
on	O
the	O
coronary	O
perfusion	O
.	O

Careful	O
invasive	O
monitoring	O
of	O
the	O
blood	O
pressure	O
,	O
blood	O
gases	O
and	O
of	O
the	O
ECG	O
ST	O
-	O
T	O
segment	O
is	O
mandatory	O
.	O

Evidence	O
for	O
a	O
selective	O
brain	O
noradrenergic	O
involvement	O
in	O
the	O
locomotor	O
stimulant	O
effects	O
of	O
amphetamine	B-Chemical
in	O
the	O
rat	O
.	O

Male	O
rats	O
received	O
the	O
noradrenaline	B-Chemical
neurotoxin	O
DSP4	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
)	O
7	O
days	O
prior	O
to	O
injection	O
of	O
D	B-Chemical
-	I-Chemical
amphetamine	I-Chemical
(	O
10	O
or	O
40	O
mumol	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
.	O

The	O
hyperactivity	B-Disease
induced	O
by	O
D	B-Chemical
-	I-Chemical
amphetamine	I-Chemical
(	O
10	O
mumol	O
/	O
kg	O
)	O
was	O
significantly	O
reduced	O
by	O
DSP4	B-Chemical
pretreatment	O
.	O

However	O
,	O
the	O
increased	O
rearings	O
and	O
the	O
amphetamine	B-Chemical
-	O
induced	O
stereotypies	B-Disease
were	O
not	O
blocked	O
by	O
pretreatment	O
with	O
DSP4	B-Chemical
.	O

The	O
reduction	O
of	O
amphetamine	B-Chemical
hyperactivity	B-Disease
induced	O
by	O
DSP4	B-Chemical
was	O
blocked	O
by	O
pretreatment	O
with	O
the	O
noradrenaline	B-Chemical
-	O
uptake	O
blocking	O
agent	O
,	O
desipramine	B-Chemical
,	O
which	O
prevents	O
the	O
neurotoxic	B-Disease
action	O
of	O
DSP4	B-Chemical
.	O

The	O
present	O
results	O
suggest	O
a	O
selective	O
involvement	O
of	O
central	O
noradrenergic	O
neurones	O
in	O
the	O
locomotor	O
stimulant	O
effect	O
of	O
amphetamine	B-Chemical
in	O
the	O
rat	O
.	O

Accelerated	B-Disease
junctional	I-Disease
rhythms	I-Disease
during	O
oral	O
verapamil	B-Chemical
therapy	O
.	O

This	O
study	O
examined	O
the	O
frequency	O
of	O
atrioventricular	O
(	O
AV	O
)	O
dissociation	O
and	O
accelerated	B-Disease
junctional	I-Disease
rhythms	I-Disease
in	O
59	O
patients	O
receiving	O
oral	O
verapamil	B-Chemical
.	O

Accelerated	B-Disease
junctional	I-Disease
rhythms	I-Disease
and	O
AV	O
dissociation	O
were	O
frequent	O
in	O
patients	O
with	O
supraventricular	B-Disease
tachyarrhythmias	I-Disease
,	O
particularly	O
AV	O
nodal	O
reentry	O
.	O

Verapamil	B-Chemical
administration	O
to	O
these	O
patients	O
led	O
to	O
an	O
asymptomatic	O
increase	O
in	O
activity	O
of	O
these	O
junctional	O
pacemakers	O
.	O

In	O
patients	O
with	O
various	O
chest	B-Disease
pain	I-Disease
syndromes	O
,	O
verapamil	B-Chemical
neither	O
increased	O
the	O
frequency	O
of	O
junctional	O
rhythms	O
nor	O
suppressed	O
their	O
role	O
as	O
escape	O
rhythms	O
under	O
physiologically	O
appropriate	O
circumstances	O
.	O

Interstrain	O
variation	O
in	O
acute	O
toxic	O
response	O
to	O
caffeine	B-Chemical
among	O
inbred	O
mice	O
.	O

Acute	O
toxic	O
dosage	O
-	O
dependent	O
behavioral	O
effects	O
of	O
caffeine	B-Chemical
were	O
compared	O
in	O
adult	O
males	O
from	O
seven	O
inbred	O
mouse	O
strains	O
(	O
A	O
/	O
J	O
,	O
BALB	O
/	O
cJ	O
,	O
CBA	O
/	O
J	O
,	O
C3H	O
/	O
HeJ	O
,	O
C57BL	O
/	O
6J	O
,	O
DBA	O
/	O
2J	O
,	O
SWR	O
/	O
J	O
)	O
.	O

C57BL	O
/	O
6J	O
,	O
chosen	O
as	O
a	O
"	O
prototypic	O
"	O
mouse	O
strain	O
,	O
was	O
used	O
to	O
determine	O
behavioral	O
responses	O
to	O
a	O
broad	O
range	O
(	O
5	O
-	O
500	O
mg	O
/	O
kg	O
)	O
of	O
caffeine	B-Chemical
doses	O
.	O

Five	O
phenotypic	O
characteristics	O
-	O
-	O
locomotor	O
activity	O
,	O
righting	O
ability	O
,	O
clonic	B-Disease
seizure	I-Disease
induction	O
,	O
stress	O
-	O
induced	O
lethality	O
,	O
death	O
without	O
external	O
stress	O
-	O
-	O
were	O
scored	O
at	O
various	O
caffeine	B-Chemical
doses	O
in	O
drug	O
-	O
naive	O
animals	O
under	O
empirically	O
optimized	O
,	O
rigidly	O
constant	O
experimental	O
conditions	O
.	O

Mice	O
(	O
n	O
=	O
12	O
for	O
each	O
point	O
)	O
received	O
single	O
IP	O
injections	O
of	O
a	O
fixed	O
volume	O
/	O
g	O
body	O
weight	O
of	O
physiological	O
saline	O
carrier	O
with	O
or	O
without	O
caffeine	B-Chemical
in	O
doses	O
ranging	O
from	O
125	O
-	O
500	O
mg	O
/	O
kg	O
.	O

Loss	O
of	O
righting	O
ability	O
was	O
scored	O
at	O
1	O
,	O
3	O
,	O
5	O
min	O
post	O
dosing	O
and	O
at	O
5	O
min	O
intervals	O
thereafter	O
for	O
20	O
min	O
.	O

In	O
the	O
same	O
animals	O
the	O
occurrence	O
of	O
clonic	B-Disease
seizures	I-Disease
was	O
scored	O
as	O
to	O
time	O
of	O
onset	O
and	O
severity	O
for	O
20	O
min	O
after	O
drug	O
administration	O
.	O

When	O
these	O
proceeded	O
to	O
tonic	B-Disease
seizures	I-Disease
,	O
death	O
occurred	O
in	O
less	O
than	O
20	O
min	O
.	O

Animals	O
surviving	O
for	O
20	O
min	O
were	O
immediately	O
stressed	O
by	O
a	O
swim	O
test	O
in	O
25	O
degrees	O
C	O
water	O
,	O
and	O
death	O
-	O
producing	O
tonic	B-Disease
seizures	I-Disease
were	O
scored	O
for	O
2	O
min	O
.	O

In	O
other	O
animals	O
locomotor	O
activity	O
was	O
measured	O
15	O
or	O
60	O
min	O
after	O
caffeine	B-Chemical
administration	O
.	O

By	O
any	O
single	O
behavioral	O
criterion	O
or	O
a	O
combination	O
of	O
these	O
criteria	O
,	O
marked	O
differences	O
in	O
response	O
to	O
toxic	O
caffeine	B-Chemical
doses	O
were	O
observed	O
between	O
strains	O
.	O

These	O
results	O
indicate	O
that	O
behavioral	O
toxicity	B-Disease
testing	O
of	O
alkylxanthines	B-Chemical
in	O
a	O
single	O
mouse	O
strain	O
may	O
be	O
misleading	O
and	O
suggest	O
that	O
toxic	O
responses	O
of	O
the	O
central	O
nervous	O
system	O
to	O
this	O
class	O
of	O
compounds	O
are	O
genetically	O
influenced	O
in	O
mammals	O
.	O

Treatment	O
of	O
ovarian	B-Disease
cancer	I-Disease
with	O
a	O
combination	O
of	O
cis	B-Chemical
-	I-Chemical
platinum	I-Chemical
,	O
adriamycin	B-Chemical
,	O
cyclophosphamide	B-Chemical
and	O
hexamethylmelamine	B-Chemical
.	O

During	O
the	O
last	O
2	O
1	O
/	O
2	O
years	O
,	O
38	O
patients	O
with	O
ovarian	B-Disease
cancer	I-Disease
were	O
treated	O
with	O
a	O
combination	O
of	O
cisplatinum	B-Chemical
(	O
CPDD	B-Chemical
)	O
,	O
50	O
mg	O
/	O
m2	O
,	O
adriamycin	B-Chemical
,	O
30	O
mg	O
/	O
m2	O
,	O
cyclophosphamide	B-Chemical
,	O
300	O
mg	O
/	O
m2	O
,	O
on	O
day	O
1	O
;	O
and	O
hexamethylmelamine	B-Chemical
(	O
HMM	B-Chemical
)	O
,	O
6	O
mg	O
/	O
kg	O
daily	O
,	O
for	O
14	O
days	O
.	O

Each	O
course	O
was	O
repeated	O
monthly	O
.	O

2	O
patients	O
had	O
stage	O
II	O
,	O
14	O
stage	O
III	O
and	O
22	O
stage	O
IV	O
disease	O
.	O

14	O
of	O
the	O
38	O
patients	O
were	O
previously	O
treated	O
with	O
chemotherapy	O
,	O
1	O
with	O
radiation	O
,	O
6	O
with	O
both	O
chemotherapy	O
and	O
radiation	O
,	O
and	O
17	O
did	O
not	O
have	O
any	O
treatment	O
before	O
CPDD	B-Chemical
combination	O
.	O

31	O
of	O
the	O
38	O
cases	O
(	O
81	O
.	O
5	O
%	O
)	O
demonstrated	O
objective	O
responses	O
lasting	O
for	O
2	O
months	O
or	O
more	O
.	O

These	O
responses	O
were	O
partial	O
in	O
19	O
and	O
complete	O
in	O
12	O
cases	O
.	O

Hematologic	B-Disease
toxicity	I-Disease
was	O
moderate	O
and	O
with	O
reversible	O
anemia	B-Disease
developing	O
in	O
71	O
%	O
of	O
patients	O
.	O

Gastrointestinal	O
side	O
effects	O
from	O
CPDD	B-Chemical
were	O
universal	O
.	O

HMM	B-Chemical
gastrointestinal	B-Disease
toxicity	I-Disease
necessitated	O
discontinuation	O
of	O
the	O
drug	O
in	O
5	O
patients	O
.	O

Severe	O
nephrotoxicity	B-Disease
was	O
observed	O
in	O
2	O
patients	O
but	O
was	O
reversible	O
.	O

There	O
were	O
no	O
drug	O
-	O
related	O
deaths	O
.	O

Nontraumatic	O
dissecting	B-Disease
aneurysm	I-Disease
of	O
the	O
basilar	O
artery	O
.	O

A	O
case	O
of	O
nontraumatic	O
dissecting	B-Disease
aneurysm	I-Disease
of	O
the	O
basilar	O
artery	O
in	O
association	O
with	O
hypertension	B-Disease
,	O
smoke	O
,	O
and	O
oral	B-Chemical
contraceptives	I-Chemical
is	O
reported	O
in	O
a	O
young	O
female	O
patient	O
with	O
a	O
locked	B-Disease
-	I-Disease
in	I-Disease
syndrome	I-Disease
.	O

A	O
method	O
for	O
the	O
measurement	O
of	O
tremor	B-Disease
,	O
and	O
a	O
comparison	O
of	O
the	O
effects	O
of	O
tocolytic	O
beta	O
-	O
mimetics	O
.	O

A	O
method	O
permitting	O
measurement	O
of	O
finger	O
tremor	B-Disease
as	O
a	O
displacement	O
-	O
time	O
curve	O
is	O
described	O
,	O
using	O
a	O
test	O
system	O
with	O
simple	O
amplitude	O
calibration	O
.	O

The	O
coordinates	O
of	O
the	O
inversion	O
points	O
of	O
the	O
displacement	O
-	O
time	O
curves	O
were	O
transferred	O
through	O
graphical	O
input	O
equipment	O
to	O
punched	O
tape	O
.	O

By	O
means	O
of	O
a	O
computer	O
program	O
,	O
periods	O
and	O
amplitudes	O
of	O
tremor	B-Disease
oscillations	O
were	O
calculated	O
and	O
classified	O
.	O

The	O
event	O
frequency	O
for	O
each	O
class	O
of	O
periods	O
and	O
amplitudes	O
was	O
determined	O
.	O

The	O
actions	O
of	O
fenoterol	B-Chemical
-	I-Chemical
hydrobromide	I-Chemical
,	O
ritodrin	B-Chemical
-	I-Chemical
HCl	I-Chemical
and	O
placebo	O
given	O
to	O
10	O
healthy	O
subjects	O
by	O
intravenous	O
infusion	O
in	O
a	O
double	O
-	O
blind	O
crossover	O
study	O
were	O
tested	O
by	O
this	O
method	O
.	O

At	O
therapeutic	O
doses	O
both	O
substances	O
raised	O
the	O
mean	O
tremor	B-Disease
amplitude	O
to	O
about	O
three	O
times	O
the	O
control	O
level	O
.	O

At	O
the	O
same	O
time	O
,	O
the	O
mean	O
period	O
within	O
each	O
class	O
of	O
amplitudes	O
shortened	O
by	O
10	O
-	O
-	O
20	O
ms	O
,	O
whereas	O
the	O
mean	O
periods	O
calculated	O
from	O
all	O
oscillations	O
together	O
did	O
not	O
change	O
significantly	O
.	O

After	O
the	O
end	O
of	O
fenoterol	B-Chemical
-	I-Chemical
hydrobromide	I-Chemical
infusion	O
,	O
tremor	B-Disease
amplitudes	O
decreased	O
significantly	O
faster	O
than	O
those	O
following	O
ritodrin	B-Chemical
-	I-Chemical
HCl	I-Chemical
infusion	O
.	O

Propylthiouracil	B-Chemical
-	O
induced	O
hepatic	B-Disease
damage	I-Disease
.	O

Two	O
cases	O
of	O
propylthiouracil	B-Chemical
-	O
induced	O
liver	B-Disease
damage	I-Disease
have	O
been	O
observed	O
.	O

The	O
first	O
case	O
is	O
of	O
an	O
acute	O
type	O
of	O
damage	O
,	O
proven	O
by	O
rechallenge	O
;	O
the	O
second	O
presents	O
a	O
clinical	O
and	O
histologic	O
picture	O
resembling	O
chronic	B-Disease
active	I-Disease
hepatitis	I-Disease
,	O
with	O
spontaneous	O
remission	O
.	O

Studies	O
on	O
the	O
bradycardia	B-Disease
induced	O
by	O
bepridil	B-Chemical
.	O

Bepridil	B-Chemical
,	O
a	O
novel	O
active	O
compound	O
for	O
prophylactic	O
treatment	O
of	O
anginal	B-Disease
attacks	I-Disease
,	O
induced	O
persistent	O
bradycardia	B-Disease
and	O
a	O
non	O
-	O
specific	O
anti	O
-	O
tachycardial	B-Disease
effect	O
,	O
the	O
mechanisms	O
of	O
which	O
were	O
investigated	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

In	O
vitro	O
perfusion	O
of	O
bepridil	B-Chemical
in	O
the	O
life	O
-	O
support	O
medium	O
for	O
isolated	O
sino	O
-	O
atrial	O
tissue	O
from	O
rabbit	O
heart	O
,	O
caused	O
a	O
reduction	O
in	O
action	O
potential	O
(	O
AP	O
)	O
spike	O
frequency	O
(	O
recorded	O
by	O
KCl	B-Chemical
microelectrodes	O
)	O
starting	O
at	O
doses	O
of	O
5	O
X	O
10	O
(	O
-	O
6	O
)	O
M	O
.	O

This	O
effect	O
was	O
dose	O
-	O
dependent	O
up	O
to	O
concentrations	O
of	O
5	O
X	O
10	O
(	O
-	O
5	O
)	O
M	O
,	O
whereupon	O
blockade	O
of	O
sinus	O
activity	O
set	O
in	O
.	O

Bepridil	B-Chemical
at	O
a	O
dose	O
of	O
5	O
X	O
10	O
(	O
-	O
6	O
)	O
M	O
,	O
induced	O
a	O
concomitant	O
reduction	O
in	O
AP	O
amplitude	O
(	O
falling	O
from	O
71	O
+	O
/	O
-	O
8	O
mV	O
to	O
47	O
+	O
/	O
-	O
6	O
mV	O
)	O
,	O
maximum	O
systolic	O
depolarization	O
velocity	O
(	O
phase	O
0	O
)	O
which	O
fell	O
from	O
1	O
.	O
85	O
+	O
/	O
-	O
0	O
.	O
35	O
V	O
/	O
s	O
to	O
0	O
.	O
84	O
+	O
/	O
-	O
0	O
.	O
28	O
V	O
/	O
s	O
,	O
together	O
with	O
maximum	O
diastolic	O
depolarization	O
velocity	O
(	O
phase	O
4	O
)	O
which	O
fell	O
from	O
38	O
+	O
/	O
-	O
3	O
mV	O
/	O
s	O
to	O
24	O
+	O
/	O
-	O
5	O
mV	O
/	O
s	O
.	O

In	O
vivo	O
injection	O
of	O
bepridil	B-Chemical
at	O
a	O
dose	O
of	O
5	O
mg	O
/	O
kg	O
(	O
i	O
.	O
v	O
.	O
)	O
into	O
6	O
anaesthetized	O
dogs	O
which	O
had	O
undergone	O
ablation	O
of	O
all	O
the	O
extrinsic	O
cardiac	O
afferent	O
nerve	O
supply	O
,	O
together	O
with	O
a	O
bilateral	O
medullo	O
-	O
adrenalectomy	O
,	O
caused	O
a	O
marked	O
reduction	O
in	O
heart	O
rate	O
which	O
fell	O
from	O
98	O
.	O
7	O
+	O
/	O
-	O
4	O
.	O
2	O
beats	O
/	O
min	O
to	O
76	O
+	O
/	O
-	O
5	O
.	O
3	O
beats	O
/	O
min	O
sustained	O
for	O
more	O
than	O
45	O
min	O
.	O

It	O
is	O
concluded	O
that	O
bepridil	B-Chemical
reduces	O
heart	O
rate	O
by	O
acting	O
directly	O
on	O
the	O
sinus	O
node	O
.	O

This	O
effect	O
,	O
which	O
results	O
in	O
a	O
flattening	O
of	O
the	O
phase	O
0	O
and	O
phase	O
4	O
slope	O
,	O
together	O
with	O
a	O
longer	O
AP	O
duration	O
,	O
may	O
be	O
due	O
to	O
an	O
increase	O
in	O
the	O
time	O
constants	O
of	O
slow	O
inward	O
ionic	O
currents	O
(	O
already	O
demonstrated	O
elsewhere	O
)	O
,	O
but	O
also	O
to	O
an	O
increased	O
time	O
constant	O
for	O
deactivation	O
of	O
the	O
outward	O
potassium	B-Chemical
current	O
(	O
Ip	O
)	O
.	O

Hepatitis	B-Disease
and	O
renal	B-Disease
tubular	I-Disease
acidosis	I-Disease
after	O
anesthesia	O
with	O
methoxyflurane	B-Chemical
.	O

A	O
69	O
-	O
year	O
-	O
old	O
man	O
operated	O
for	O
acute	B-Disease
cholecystitis	I-Disease
under	O
methoxyflurane	B-Chemical
anesthesia	O
developed	O
postoperatively	O
a	O
hepatic	B-Disease
insufficiency	I-Disease
syndrome	I-Disease
and	O
renal	B-Disease
tubular	I-Disease
acidosis	I-Disease
.	O

Massive	O
bleeding	B-Disease
appeared	O
during	O
surgery	O
which	O
lasted	O
for	O
six	O
hours	O
.	O

Postoperative	O
evolution	O
under	O
supportive	O
therapy	O
was	O
favourable	O
.	O

Complete	O
recovery	O
was	O
confirmed	O
by	O
repeated	O
controls	O
performed	O
over	O
a	O
period	O
of	O
one	O
year	O
after	O
surgery	O
.	O

Pituitary	O
response	O
to	O
luteinizing	O
hormone	O
-	O
releasing	O
hormone	O
during	O
haloperidol	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
.	O

The	O
effects	O
of	O
a	O
6	O
-	O
hour	O
infusion	O
with	O
haloperidol	B-Chemical
on	O
serum	O
prolactin	O
and	O
luteinizing	O
hormone	O
(	O
LH	O
)	O
levels	O
was	O
studied	O
in	O
a	O
group	O
of	O
male	O
subjects	O
.	O

Five	O
hours	O
after	O
starting	O
the	O
infusions	O
,	O
a	O
study	O
of	O
the	O
pituitary	O
responses	O
to	O
LH	O
-	O
releasing	O
hormone	O
(	O
LH	O
-	O
RH	O
)	O
was	O
carried	O
out	O
.	O

Control	O
patients	O
received	O
infusions	O
of	O
0	O
.	O
9	O
%	O
NaCl	B-Chemical
solution	O
.	O

During	O
the	O
course	O
of	O
haloperidol	B-Chemical
infusions	O
,	O
significant	O
hyperprolactinemia	B-Disease
was	O
found	O
,	O
together	O
with	O
an	O
abolished	O
pituitary	O
response	O
to	O
LH	O
-	O
RH	O
,	O
as	O
compared	O
with	O
responses	O
of	O
control	O
subjects	O
.	O

Antirifampicin	O
antibodies	O
in	O
acute	O
rifampicin	B-Chemical
-	O
associated	O
renal	B-Disease
failure	I-Disease
.	O

5	O
patients	O
with	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
(	O
3	O
with	O
thrombopenia	B-Disease
and	O
hemolysis	B-Disease
)	O
induced	O
by	O
the	O
reintroduction	O
of	O
rifampicin	B-Chemical
are	O
described	O
.	O

No	O
correlation	O
was	O
found	O
between	O
the	O
severity	O
of	O
clinical	O
manifestations	O
and	O
the	O
total	O
dose	O
taken	O
by	O
the	O
patients	O
.	O

In	O
all	O
but	O
1	O
patient	O
,	O
antirifampicin	O
antibodies	O
were	O
detected	O
.	O

Antibodies	O
suggested	O
to	O
be	O
of	O
the	O
IgM	O
class	O
were	O
detected	O
in	O
all	O
3	O
patients	O
with	O
hematological	B-Disease
disorders	I-Disease
.	O

The	O
pattern	O
of	O
non	O
-	O
specific	O
acute	B-Disease
tubular	I-Disease
necrosis	I-Disease
found	O
in	O
the	O
2	O
biopsied	O
patients	O
,	O
indistinguishable	O
from	O
that	O
of	O
ischemic	O
origin	O
,	O
raised	O
the	O
possibility	O
of	O
a	O
vascular	O
-	O
mediated	O
damage	O
.	O

In	O
3	O
patients	O
,	O
the	O
possibility	O
of	O
a	O
triggering	O
immunoallergic	O
mechanism	O
is	O
discussed	O
.	O

Cardiovascular	O
effects	O
of	O
hypotension	B-Disease
induced	O
by	O
adenosine	B-Chemical
triphosphate	I-Chemical
and	O
sodium	B-Chemical
nitroprusside	I-Chemical
on	O
dogs	O
with	O
denervated	O
hearts	O
.	O

Adenosine	B-Chemical
triphosphate	I-Chemical
(	O
ATP	B-Chemical
)	O
and	O
sodium	B-Chemical
nitroprusside	I-Chemical
(	O
SNP	B-Chemical
)	O
are	O
administered	O
to	O
patients	O
to	O
induce	O
and	O
control	O
hypotension	B-Disease
during	O
anesthesia	O
.	O

SNP	B-Chemical
is	O
authorized	O
for	O
clinical	O
use	O
in	O
USA	O
and	O
UK	O
,	O
and	O
ATP	B-Chemical
is	O
clinically	O
used	O
in	O
other	O
countries	O
such	O
as	O
Japan	O
.	O

We	O
investigated	O
how	O
these	O
two	O
drugs	O
act	O
on	O
the	O
cardiovascular	O
systems	O
of	O
20	O
dogs	O
whose	O
hearts	O
had	O
been	O
denervated	O
by	O
a	O
procedure	O
we	O
had	O
devised	O
.	O

ATP	B-Chemical
(	O
10	O
dogs	O
)	O
or	O
SNP	B-Chemical
(	O
10	O
dogs	O
)	O
was	O
administered	O
to	O
reduce	O
mean	O
arterial	O
pressure	O
by	O
30	O
%	O
to	O
70	O
%	O
of	O
control	O
.	O

Before	O
,	O
during	O
and	O
after	O
induced	O
hypotension	B-Disease
,	O
we	O
measured	O
major	O
cardiovascular	O
parameters	O
.	O

Hypotension	B-Disease
induced	O
by	O
ATP	B-Chemical
was	O
accompanied	O
by	O
significant	O
decreases	O
in	O
mean	O
pulmonary	O
arterial	O
pressure	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
central	O
venous	O
pressure	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
left	O
ventricular	O
end	O
-	O
diastolic	O
pressure	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
total	O
peripheral	O
resistance	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
rate	O
pressure	O
product	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
total	O
body	O
oxygen	B-Chemical
consumption	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
and	O
heart	O
rate	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
;	O
all	O
these	O
variables	O
returned	O
normal	O
within	O
30	O
min	O
after	O
ATP	B-Chemical
was	O
stopped	O
.	O

Cardiac	O
output	O
did	O
not	O
change	O
.	O

During	O
hypotension	B-Disease
produced	O
by	O
SNP	B-Chemical
similar	O
decreases	O
were	O
observed	O
in	O
mean	O
pulmonary	O
arterial	O
pressure	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
central	O
venous	O
pressure	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
left	O
ventricular	O
end	O
-	O
diastolic	O
pressure	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
total	O
peripheral	O
resistance	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
rate	O
pressure	O
product	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
,	O
and	O
oxygen	B-Chemical
content	O
difference	O
between	O
arterial	O
and	O
mixed	O
venous	O
blood	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
while	O
heart	O
rate	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
and	O
cardiac	O
output	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
were	O
increased	O
.	O

Recoveries	O
of	O
heart	O
rate	O
and	O
left	O
ventricular	O
end	O
-	O
diastolic	O
pressure	O
were	O
not	O
shown	O
within	O
60	O
min	O
after	O
SNP	B-Chemical
had	O
been	O
stopped	O
.	O

Both	O
ATP	B-Chemical
and	O
SNP	B-Chemical
should	O
act	O
on	O
the	O
pacemaker	O
tissue	O
of	O
the	O
heart	O
.	O

Comparative	O
study	O
:	O
Endografine	B-Chemical
(	O
diatrizoate	B-Chemical
)	O
,	O
Vasurix	B-Chemical
polyvidone	I-Chemical
(	O
acetrizoate	B-Chemical
)	O
,	O
Dimer	B-Chemical
-	I-Chemical
X	I-Chemical
(	O
iocarmate	B-Chemical
)	O
and	O
Hexabrix	B-Chemical
(	O
ioxaglate	B-Chemical
)	O
in	O
hysterosalpingography	O
.	O

Side	O
effects	O
of	O
hysterosalpingography	O
with	O
Dimer	B-Chemical
-	I-Chemical
X	I-Chemical
,	O
Hexabrix	B-Chemical
,	O
Vasurix	B-Chemical
polyvidone	I-Chemical
and	O
Endografine	B-Chemical
in	O
142	O
consecutive	O
patients	O
,	O
receiving	O
one	O
of	O
the	O
four	O
tested	O
media	O
were	O
evaluated	O
from	O
replies	O
to	O
postal	O
questionnaires	O
.	O

The	O
Dimer	B-Chemical
-	I-Chemical
X	I-Chemical
group	O
had	O
a	O
higher	O
incidence	O
of	O
nausea	B-Disease
and	O
dizziness	B-Disease
.	O

The	O
Endografine	B-Chemical
group	O
had	O
a	O
higher	O
incidence	O
of	O
abdominal	B-Disease
pain	I-Disease
.	O

These	O
differences	O
occur	O
especially	O
in	O
the	O
age	O
groups	O
under	O
30	O
years	O
.	O

Hexabrix	B-Chemical
and	O
Vasurix	B-Chemical
polyvidone	I-Chemical
are	O
considered	O
the	O
best	O
contrast	B-Chemical
media	I-Chemical
for	O
hysterosalpingography	O
and	O
perhaps	O
because	O
of	O
its	O
low	O
toxicity	B-Disease
Hexabrix	B-Chemical
should	O
be	O
preferred	O
.	O

Post	O
-	O
suxamethonium	B-Chemical
pains	B-Disease
in	O
Nigerian	O
surgical	O
patients	O
.	O

Contrary	O
to	O
an	O
earlier	O
report	O
by	O
Coxon	O
,	O
scoline	B-Chemical
pain	B-Disease
occurs	O
in	O
African	O
negroes	O
.	O

Its	O
incidence	O
was	O
determined	O
in	O
a	O
prospective	O
study	O
involving	O
a	O
total	O
of	O
100	O
Nigerian	O
patients	O
(	O
50	O
out	O
-	O
patients	O
and	O
50	O
in	O
-	O
patients	O
)	O
.	O

About	O
62	O
%	O
of	O
the	O
out	O
-	O
patients	O
developed	O
scoline	B-Chemical
pain	B-Disease
as	O
compared	O
with	O
about	O
26	O
%	O
among	O
the	O
in	O
-	O
patients	O
.	O

The	O
abolition	O
of	O
muscle	O
fasciculations	B-Disease
(	O
by	O
0	O
.	O
075mg	O
/	O
kg	O
dose	O
of	O
Fazadinium	B-Chemical
)	O
did	O
not	O
influence	O
the	O
occurrence	O
of	O
scoline	B-Chemical
pain	B-Disease
.	O

Neither	O
the	O
type	O
of	O
induction	O
agent	O
(	O
Althesin	B-Chemical
or	O
Thiopentone	B-Chemical
)	O
nor	O
the	O
salt	O
preparation	O
of	O
suxamethonium	B-Chemical
used	O
(	O
chloride	B-Chemical
or	O
bromide	B-Chemical
)	O
,	O
affected	O
the	O
incidence	O
of	O
scoline	B-Chemical
pain	B-Disease
.	O

Invasive	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
renal	I-Disease
pelvis	I-Disease
following	O
cyclophosphamide	B-Chemical
therapy	O
for	O
nonmalignant	O
disease	O
.	O

A	O
47	O
-	O
year	O
-	O
old	O
woman	O
with	O
right	O
hydroureteronephrosis	B-Disease
due	O
to	O
ureterovesical	O
junction	O
obstruction	O
had	O
gross	O
hematuria	B-Disease
after	O
being	O
treated	O
for	O
five	O
years	O
wtih	O
cyclophosphamide	B-Chemical
for	O
cerebral	B-Disease
vasculitis	I-Disease
.	O

A	O
right	O
nephroureterectomy	O
was	O
required	O
for	O
control	O
of	O
bleeding	B-Disease
.	O

The	O
pathology	O
specimen	O
contained	O
clinically	O
occult	O
invasive	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
renal	I-Disease
pelvis	I-Disease
.	O

Although	O
the	O
ability	O
of	O
cyclophosphamide	B-Chemical
to	O
cause	O
hemorrhagic	B-Disease
cystitis	I-Disease
and	O
urine	O
cytologic	O
abnormalities	O
indistinguishable	O
from	O
high	O
grade	O
carcinoma	B-Disease
is	O
well	O
known	O
,	O
it	O
is	O
less	O
widely	O
appreciated	O
that	O
it	O
is	O
also	O
associated	O
with	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
urinary	I-Disease
tract	I-Disease
.	O

Twenty	O
carcinomas	B-Disease
of	I-Disease
the	I-Disease
urinary	I-Disease
bladder	I-Disease
and	O
one	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
prostate	I-Disease
have	O
been	O
reported	O
in	O
association	O
with	O
its	O
use	O
.	O

The	O
present	O
case	O
is	O
the	O
first	O
carcinoma	B-Disease
of	I-Disease
the	I-Disease
renal	I-Disease
pelvis	I-Disease
reported	O
in	O
association	O
with	O
cyclophosphamide	B-Chemical
treatment	O
.	O

It	O
is	O
the	O
third	O
urinary	B-Disease
tract	I-Disease
cancer	I-Disease
reported	O
in	O
association	O
with	O
cyclophosphamide	B-Chemical
treatment	O
for	O
nonmalignant	O
disease	O
.	O

The	O
association	O
of	O
the	O
tumor	B-Disease
with	O
preexisting	O
hydroureteronephrosis	B-Disease
suggests	O
that	O
stasis	O
prolonged	O
and	O
intensified	O
exposure	O
of	O
upper	O
urinary	O
tract	O
epithelium	O
to	O
cyclophosphamide	B-Chemical
.	O

Patients	O
who	O
are	O
candidates	O
for	O
long	O
-	O
term	O
cyclophosphamide	B-Chemical
treatment	O
should	O
be	O
routinely	O
evaluated	O
for	O
obstructive	B-Disease
uropathy	I-Disease
.	O

Medial	O
changes	O
in	O
arterial	O
spasm	B-Disease
induced	O
by	O
L	B-Chemical
-	I-Chemical
norepinephrine	I-Chemical
.	O

In	O
normal	O
rats	O
,	O
the	O
media	O
of	O
small	O
arteries	O
(	O
0	O
.	O
4	O
-	O
-	O
0	O
.	O
2	O
mm	O
in	O
diameter	O
)	O
previously	O
was	O
shown	O
to	O
contain	O
intracellular	O
vacuoles	O
,	O
identified	O
ultrastructurally	O
as	O
herniations	O
of	O
one	O
smooth	O
muscle	O
cell	O
into	O
another	O
.	O

The	O
hypothesis	O
that	O
intense	O
vasoconstriction	O
would	O
increase	O
the	O
number	O
of	O
such	O
vacuoles	O
has	O
been	O
tested	O
.	O

In	O
the	O
media	O
of	O
the	O
saphenous	O
artery	O
and	O
its	O
distal	O
branch	O
,	O
vasoconstriction	O
induced	O
by	O
L	B-Chemical
-	I-Chemical
norepinephrine	I-Chemical
produced	O
many	O
cell	O
-	O
to	O
-	O
cell	O
hernias	B-Disease
within	O
15	O
minutes	O
.	O

At	O
1	O
day	O
their	O
number	O
was	O
reduced	O
to	O
about	O
1	O
/	O
10	O
of	O
the	O
original	O
number	O
.	O

By	O
7	O
days	O
the	O
vessel	O
was	O
almost	O
restored	O
to	O
normal	O
.	O

Triple	O
stimulation	O
over	O
1	O
day	O
induced	O
more	O
severe	O
changes	O
in	O
the	O
media	O
.	O

These	O
findings	O
suggest	O
that	O
smooth	O
muscle	O
cells	O
are	O
susceptible	O
to	O
damage	O
in	O
the	O
course	O
of	O
their	O
specific	O
function	O
.	O

The	O
experimental	O
data	O
are	O
discussed	O
in	O
relation	O
to	O
medial	O
changes	O
observed	O
in	O
other	O
instances	O
of	O
arterial	O
spasm	B-Disease
.	O

Endothelial	O
changes	O
that	O
developed	O
in	O
the	O
same	O
experimental	O
model	O
were	O
described	O
in	O
a	O
previous	O
paper	O
.	O

Bilateral	O
retinal	B-Disease
artery	I-Disease
and	I-Disease
choriocapillaris	I-Disease
occlusion	I-Disease
following	O
the	O
injection	O
of	O
long	O
-	O
acting	O
corticosteroid	B-Chemical
suspensions	O
in	O
combination	O
with	O
other	O
drugs	O
:	O
I	O
.	O

Clinical	O
studies	O
.	O

Two	O
well	O
-	O
documented	O
cases	O
of	O
bilateral	O
retinal	B-Disease
artery	I-Disease
and	I-Disease
choriocapillaris	I-Disease
occlusions	I-Disease
with	O
blindness	B-Disease
following	O
head	O
and	O
neck	O
soft	O
-	O
tissue	O
injection	O
with	O
methylprednisolone	B-Chemical
acetate	I-Chemical
in	O
combination	O
with	O
lidocaine	B-Chemical
,	O
epinephrine	B-Chemical
,	O
or	O
penicillin	B-Chemical
are	O
reported	O
.	O

One	O
case	O
had	O
only	O
a	O
unilateral	O
injection	O
.	O

The	O
acute	O
observations	O
included	O
hazy	O
sensorium	O
,	O
superior	O
gaze	O
palsy	B-Disease
,	O
pupillary	B-Disease
abnormalities	I-Disease
,	O
and	O
conjunctival	O
hemorrhages	B-Disease
with	O
edema	B-Disease
.	O

Follow	O
-	O
up	O
changes	O
showed	O
marked	O
visual	B-Disease
loss	I-Disease
,	O
constricted	O
visual	O
fields	O
,	O
optic	O
nerve	O
pallor	O
,	O
vascular	O
attenuation	O
,	O
and	O
chorioretinal	B-Disease
atrophy	I-Disease
.	O

The	O
literature	O
is	O
reviewed	O
,	O
and	O
possible	O
causes	O
are	O
discussed	O
.	O

Abnormalities	O
of	O
the	O
pupil	O
and	O
visual	O
-	O
evoked	O
potential	O
in	O
quinine	B-Chemical
amblyopia	B-Disease
.	O

Total	O
blindness	B-Disease
with	O
a	O
transient	O
tonic	B-Disease
pupillary	I-Disease
response	O
,	O
denervation	O
supersensitivity	O
,	O
and	O
abnormal	O
visual	O
-	O
evoked	O
potentials	O
developed	O
in	O
a	O
54	O
-	O
year	O
-	O
old	O
man	O
after	O
the	O
use	O
of	O
quinine	B-Chemical
sulfate	I-Chemical
for	O
leg	B-Disease
cramps	I-Disease
.	O

He	O
later	O
recovered	O
normal	O
visual	O
acuity	O
.	O

A	O
transient	O
tonic	B-Disease
pupillary	I-Disease
response	O
,	O
denervation	O
supersensitivity	O
,	O
and	O
abnormal	O
visual	O
-	O
evoked	O
potentials	O
in	O
quinine	B-Chemical
toxicity	B-Disease
,	O
to	O
our	O
knowledge	O
,	O
have	O
not	O
been	O
previously	O
reported	O
.	O

Suxamethonium	B-Chemical
-	O
induced	O
jaw	B-Disease
stiffness	I-Disease
and	O
myalgia	B-Disease
associated	O
with	O
atypical	O
cholinesterase	O
:	O
case	O
report	O
.	O

An	O
11	O
-	O
year	O
-	O
old	O
boy	O
was	O
given	O
halothane	B-Chemical
,	O
nitrous	B-Chemical
oxide	I-Chemical
and	O
oxygen	B-Chemical
,	O
pancuronium	B-Chemical
0	O
.	O
4	O
mg	O
and	O
suxamethonium	B-Chemical
100	O
mg	O
for	O
induction	O
of	O
anaesthesia	O
.	O

In	O
response	O
to	O
this	O
a	O
marked	O
jaw	B-Disease
stiffness	I-Disease
occurred	O
which	O
lasted	O
for	O
two	O
minutes	O
and	O
the	O
anaesthesia	O
were	O
terminated	O
.	O

Four	O
hours	O
of	O
apnoea	B-Disease
ensued	O
and	O
he	O
suffered	O
generalized	O
severe	O
myalgia	B-Disease
lasting	O
for	O
one	O
week	O
.	O

He	O
was	O
found	O
to	O
have	O
atypical	O
plasma	O
cholinesterase	O
with	O
a	O
dibucaine	B-Chemical
number	O
of	O
12	O
,	O
indicating	O
homozygocity	O
.	O

This	O
was	O
verified	O
by	O
study	O
of	O
the	O
family	O
.	O

The	O
case	O
shows	O
that	O
prolonged	B-Disease
jaw	I-Disease
rigidity	I-Disease
and	O
myalgia	B-Disease
may	O
occur	O
after	O
suxamethonium	B-Chemical
in	O
patients	O
with	O
atypical	O
cholinesterase	O
despite	O
pretreatment	O
with	O
pancuronium	B-Chemical
.	O

Indomethacin	B-Chemical
-	O
induced	O
hyperkalemia	B-Disease
in	O
three	O
patients	O
with	O
gouty	B-Disease
arthritis	I-Disease
.	O

We	O
describe	O
three	O
patients	O
in	O
whom	O
severe	O
,	O
life	O
-	O
threatening	O
hyperkalemia	B-Disease
and	O
renal	B-Disease
insufficiency	I-Disease
developed	O
after	O
treatment	O
of	O
acute	O
gouty	B-Disease
arthritis	I-Disease
with	O
indomethacin	B-Chemical
.	O

This	O
complication	O
may	O
result	O
from	O
an	O
inhibition	O
of	O
prostaglandin	B-Chemical
synthesis	O
and	O
consequent	O
hyporeninemic	B-Disease
hypoaidosteronism	I-Disease
.	O

Careful	O
attention	O
to	O
renal	O
function	O
and	O
potassium	B-Chemical
balance	O
in	O
patients	O
receiving	O
indomethacin	B-Chemical
or	O
other	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
agents	O
,	O
particularly	O
in	O
those	O
patients	O
with	O
diabetes	B-Disease
mellitus	I-Disease
or	O
preexisting	O
renal	B-Disease
disease	I-Disease
,	O
will	O
help	O
prevent	O
this	O
potentially	O
serious	O
complication	O
.	O

Etomidate	B-Chemical
:	O
a	O
foreshortened	O
clinical	O
trial	O
.	O

A	O
clinical	O
evaluation	O
of	O
etomidate	B-Chemical
for	O
outpatient	O
cystoscopy	O
was	O
embarked	O
upon	O
.	O

Unpremedicated	O
patients	O
were	O
given	O
fentanyl	B-Chemical
1	O
microgram	O
/	O
kg	O
followed	O
by	O
etomidate	B-Chemical
0	O
.	O
3	O
mg	O
/	O
kg	O
.	O

Anaesthesia	O
was	O
maintained	O
with	O
intermittent	O
etomidate	B-Chemical
in	O
2	O
-	O
4	O
mg	O
doses	O
.	O

Patients	O
were	O
interviewed	O
personally	O
later	O
the	O
same	O
day	O
,	O
and	O
by	O
questionnaire	O
three	O
to	O
four	O
weeks	O
later	O
.	O

The	O
trial	O
was	O
discontinued	O
after	O
20	O
cases	O
because	O
of	O
an	O
unacceptable	O
incidence	O
of	O
side	O
effects	O
.	O

Venous	O
pain	B-Disease
occurred	O
in	O
68	O
%	O
of	O
patients	O
and	O
50	O
%	O
had	O
redness	O
,	O
pain	B-Disease
or	O
swelling	B-Disease
related	O
to	O
the	O
injection	O
site	O
,	O
in	O
some	O
cases	O
lasting	O
up	O
to	O
three	O
weeks	O
after	O
anaesthesia	O
.	O

Skeletal	O
movements	O
occurred	O
in	O
50	O
%	O
of	O
patients	O
;	O
30	O
%	O
experienced	O
respiratory	B-Disease
upset	I-Disease
,	O
one	O
sufficiently	O
severe	O
to	O
necessitate	O
abandoning	O
the	O
technique	O
.	O

Nausea	B-Disease
and	O
vomiting	B-Disease
occurred	O
in	O
40	O
%	O
and	O
25	O
%	O
had	O
disturbing	O
emergence	O
psychoses	B-Disease
.	O

Levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
are	O
improved	O
by	O
fluoxetine	B-Chemical
.	O

We	O
evaluated	O
the	O
severity	O
of	O
motor	B-Disease
disability	I-Disease
and	O
dyskinesias	B-Disease
in	O
seven	O
levodopa	B-Chemical
-	O
responsive	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
after	O
an	O
acute	O
challenge	O
with	O
the	O
mixed	O
dopamine	B-Chemical
agonist	O
,	O
apomorphine	B-Chemical
,	O
before	O
and	O
after	O
the	O
administration	O
of	O
fluoxetine	B-Chemical
(	O
20	O
mg	O
twice	O
per	O
day	O
)	O
for	O
11	O
+	O
/	O
-	O
1	O
days	O
.	O

After	O
fluoxetine	B-Chemical
treatment	O
,	O
there	O
was	O
a	O
significant	O
47	O
%	O
improvement	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
of	O
apomorphine	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
without	O
modification	O
of	O
parkinsonian	B-Disease
motor	B-Disease
disability	I-Disease
.	O

The	O
dyskinesias	B-Disease
were	O
reduced	O
predominantly	O
in	O
the	O
lower	O
limbs	O
during	O
the	O
onset	O
and	O
disappearance	O
of	O
dystonic	B-Disease
dyskinesias	I-Disease
(	O
onset	O
-	O
and	O
end	O
-	O
of	O
-	O
dose	O
dyskinesias	B-Disease
)	O
and	O
in	O
the	O
upper	O
limbs	O
during	O
choreic	B-Disease
mid	I-Disease
-	I-Disease
dose	I-Disease
dyskinesias	I-Disease
.	O

The	O
results	O
suggest	O
that	O
increased	O
brain	O
serotoninergic	O
transmission	O
with	O
fluoxetine	B-Chemical
may	O
reduce	O
levodopa	B-Chemical
-	O
or	O
dopamine	B-Chemical
agonist	O
-	O
induced	O
dyskinesias	B-Disease
without	O
aggravating	O
parkinsonian	B-Disease
motor	B-Disease
disability	I-Disease
.	O

A	O
large	O
population	O
-	O
based	O
follow	O
-	O
up	O
study	O
of	O
trimethoprim	B-Chemical
-	I-Chemical
sulfamethoxazole	I-Chemical
,	O
trimethoprim	B-Chemical
,	O
and	O
cephalexin	B-Chemical
for	O
uncommon	O
serious	O
drug	B-Disease
toxicity	I-Disease
.	O

We	O
conducted	O
a	O
population	O
-	O
based	O
45	O
-	O
day	O
follow	O
-	O
up	O
study	O
of	O
232	O
,	O
390	O
people	O
who	O
were	O
prescribed	O
trimethoprim	B-Chemical
-	I-Chemical
sulfamethoxazole	I-Chemical
(	O
TMP	B-Chemical
-	I-Chemical
SMZ	I-Chemical
)	O
,	O
266	O
,	O
951	O
prescribed	O
trimethoprim	B-Chemical
alone	O
,	O
and	O
196	O
,	O
397	O
prescribed	O
cephalexin	B-Chemical
,	O
to	O
estimate	O
the	O
risk	O
of	O
serious	O
liver	B-Disease
,	I-Disease
blood	I-Disease
,	I-Disease
skin	I-Disease
,	I-Disease
and	I-Disease
renal	I-Disease
disorders	I-Disease
resulting	O
in	O
referral	O
or	O
hospitalization	O
associated	O
with	O
these	O
drugs	O
.	O

The	O
results	O
were	O
based	O
on	O
information	O
recorded	O
on	O
office	O
computers	O
by	O
selected	O
general	O
practitioners	O
in	O
the	O
United	O
Kingdom	O
,	O
together	O
with	O
a	O
review	O
of	O
clinical	O
records	O
.	O

The	O
risk	O
of	O
clinically	O
important	O
idiopathic	O
liver	B-Disease
disease	I-Disease
was	O
similar	O
for	O
persons	O
prescribed	O
TMP	B-Chemical
-	I-Chemical
SMZ	I-Chemical
(	O
5	O
.	O
2	O
/	O
100	O
,	O
000	O
)	O
and	O
those	O
prescribed	O
trimethoprim	B-Chemical
alone	O
(	O
3	O
.	O
8	O
/	O
100	O
,	O
000	O
)	O
.	O

The	O
risk	O
for	O
those	O
prescribed	O
cephalexin	B-Chemical
was	O
somewhat	O
lower	O
(	O
2	O
.	O
0	O
/	O
100	O
,	O
000	O
)	O
.	O

Only	O
five	O
patients	O
experienced	O
blood	O
disorders	O
,	O
one	O
of	O
whom	O
was	O
exposed	O
to	O
TMP	B-Chemical
-	I-Chemical
SMZ	I-Chemical
;	O
of	O
seven	O
with	O
erythema	B-Disease
multiforme	I-Disease
and	O
Stevens	B-Disease
-	I-Disease
Johnson	I-Disease
syndrome	I-Disease
,	O
four	O
were	O
exposed	O
to	O
TMP	B-Chemical
-	I-Chemical
SMZ	I-Chemical
.	O

The	O
one	O
case	O
of	O
toxic	B-Disease
epidermal	I-Disease
necrolysis	I-Disease
occurred	O
in	O
a	O
patient	O
who	O
took	O
cephalexin	B-Chemical
.	O

Finally	O
,	O
only	O
five	O
cases	O
of	O
acute	O
parenchymal	O
renal	B-Disease
disease	I-Disease
occurred	O
,	O
none	O
likely	O
to	O
be	O
caused	O
by	O
a	O
study	O
drug	O
.	O

We	O
conclude	O
that	O
the	O
risk	O
of	O
the	O
serious	O
diseases	O
studied	O
is	O
small	O
for	O
the	O
three	O
agents	O
,	O
and	O
compares	O
reasonably	O
with	O
the	O
risk	O
for	O
many	O
other	O
antibiotics	O
.	O

Clinical	O
safety	O
of	O
lidocaine	B-Chemical
in	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
myocardial	B-Disease
infarction	I-Disease
.	O

STUDY	O
OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
safety	O
of	O
lidocaine	B-Chemical
in	O
the	O
setting	O
of	O
cocaine	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
(	O
MI	B-Disease
)	O
.	O

DESIGN	O
:	O
A	O
retrospective	O
,	O
multicenter	O
study	O
.	O

SETTING	O
:	O
Twenty	O
-	O
nine	O
university	O
,	O
university	O
-	O
affiliated	O
,	O
or	O
community	O
hospitals	O
during	O
a	O
6	O
-	O
year	O
period	O
(	O
total	O
of	O
117	O
cumulative	O
hospital	O
-	O
years	O
)	O
.	O

PARTICIPANTS	O
:	O
Patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
MI	B-Disease
who	O
received	O
lidocaine	B-Chemical
in	O
the	O
emergency	O
department	O
.	O

RESULTS	O
:	O
Of	O
29	O
patients	O
who	O
received	O
lidocaine	B-Chemical
in	O
the	O
setting	O
of	O
cocaine	B-Chemical
-	O
associated	O
MI	B-Disease
,	O
no	O
patient	O
died	O
;	O
exhibited	O
bradydysrhythmias	B-Disease
,	O
ventricular	B-Disease
tachycardia	I-Disease
,	O
or	O
ventricular	B-Disease
fibrillation	I-Disease
;	O
or	O
experienced	O
seizures	B-Disease
after	O
administration	O
of	O
lidocaine	B-Chemical
(	O
95	O
%	O
confidence	O
interval	O
,	O
0	O
%	O
to	O
11	O
%	O
)	O
.	O

CONCLUSION	O
:	O
Despite	O
theoretical	O
concerns	O
that	O
lidocaine	B-Chemical
may	O
enhance	O
cocaine	B-Chemical
toxicity	B-Disease
,	O
the	O
use	O
of	O
lidocaine	B-Chemical
in	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
MI	B-Disease
was	O
not	O
associated	O
with	O
significant	O
cardiovascular	B-Disease
or	I-Disease
central	I-Disease
nervous	I-Disease
system	I-Disease
toxicity	I-Disease
.	O

Experimental	O
progressive	O
muscular	B-Disease
dystrophy	I-Disease
and	O
its	O
treatment	O
with	O
high	O
doses	O
anabolizing	O
agents	O
.	O

We	O
are	O
still	O
a	O
long	O
way	O
from	O
discovering	O
an	O
unequivocal	O
pathogenetic	O
interpretation	O
of	O
progressive	O
muscular	B-Disease
dystrophy	I-Disease
in	O
man	O
.	O

Noteworthy	O
efforts	O
have	O
been	O
made	O
in	O
the	O
experimental	O
field	O
;	O
a	O
recessive	O
autosomic	O
form	O
found	O
in	O
the	O
mouse	O
seems	O
to	O
bear	O
the	O
closest	O
resemblance	O
to	O
the	O
human	O
form	O
from	O
the	O
genetic	O
point	O
of	O
view	O
.	O

Myopathy	B-Disease
due	O
to	O
lack	O
of	O
vitamin	B-Chemical
E	I-Chemical
and	O
myopathy	B-Disease
induced	O
by	O
certain	O
viruses	O
have	O
much	O
in	O
common	O
anatomically	O
and	O
pathologically	O
with	O
the	O
human	O
form	O
.	O

The	O
authors	O
induced	O
myodystrophy	B-Disease
in	O
the	O
rat	O
by	O
giving	O
it	O
a	O
diet	O
lacking	O
in	O
vitamin	B-Chemical
E	I-Chemical
.	O

The	O
pharmacological	O
characteristics	O
of	O
vitamin	B-Chemical
E	I-Chemical
and	O
the	O
degenerative	O
changes	O
brought	O
about	O
by	O
its	O
deficiency	O
,	O
especially	O
in	O
the	O
muscles	O
,	O
are	O
illustrated	O
.	O

It	O
is	O
thus	O
confirmed	O
that	O
the	O
histological	O
characteristics	O
of	O
myopathic	B-Disease
rat	O
muscle	O
induced	O
experimentally	O
are	O
extraordinarily	O
similar	O
to	O
those	O
of	O
human	O
myopathy	B-Disease
as	O
confirmed	O
during	O
biopsies	O
performed	O
at	O
the	O
Orthopaedic	O
Traumatological	O
Centre	O
,	O
Florence	O
.	O

The	O
encouraging	O
results	O
obtained	O
in	O
various	O
authoratative	O
departments	O
in	O
myopathic	B-Disease
patients	O
by	O
using	O
anabolizing	O
steroids	B-Chemical
have	O
encouraged	O
the	O
authors	O
to	O
investigate	O
the	O
beneficial	O
effects	O
of	O
one	O
anabolizing	O
agent	O
(	O
Dianabol	B-Chemical
,	O
CIBA	B-Chemical
)	O
at	O
high	O
doses	O
in	O
rats	O
rendered	O
myopathic	B-Disease
by	O
a	O
diet	O
deficient	O
in	O
vitamin	B-Chemical
E	I-Chemical
.	O

In	O
this	O
way	O
they	O
obtained	O
appreciable	O
changes	O
in	O
body	O
weight	O
(	O
increased	O
from	O
50	O
to	O
70	O
g	O
after	O
forty	O
days	O
at	O
a	O
dose	O
of	O
5	O
mg	O
per	O
day	O
of	O
anabolizing	O
agent	O
)	O
,	O
but	O
most	O
of	O
all	O
they	O
found	O
histological	O
changes	O
due	O
to	O
"	O
regenerative	O
"	O
changes	O
in	O
the	O
muscle	O
tissue	O
,	O
which	O
however	O
maintained	O
its	O
myopathic	B-Disease
characteristics	O
in	O
the	O
control	O
animals	O
that	O
were	O
not	O
treated	O
with	O
the	O
anabolizing	O
agent	O
.	O

The	O
authors	O
conclude	O
by	O
affirming	O
the	O
undoubted	O
efficacy	O
of	O
the	O
anabolizing	O
steroids	B-Chemical
in	O
experimental	O
myopathic	B-Disease
disease	I-Disease
,	O
but	O
they	O
have	O
reservations	O
as	O
to	O
the	O
transfer	O
of	O
the	O
results	O
into	O
the	O
human	O
field	O
,	O
where	O
high	O
dosage	O
cannot	O
be	O
carried	O
out	O
continuously	O
because	O
of	O
the	O
effects	O
of	O
the	O
drug	O
on	O
virility	O
;	O
because	O
the	O
tissue	O
injury	O
too	O
often	O
occurs	O
at	O
an	O
irreversible	O
stage	O
vis	O
-	O
a	O
-	O
vis	O
the	O
"	O
regeneration	O
"	O
of	O
the	O
muscle	O
tissue	O
;	O
and	O
finally	O
because	O
the	O
dystrophic	O
injurious	O
agent	O
is	O
certainly	O
not	O
the	O
lack	O
of	O
vitamin	B-Chemical
E	I-Chemical
but	O
something	O
as	O
yet	O
unknown	O
.	O

Paclitaxel	B-Chemical
3	O
-	O
hour	O
infusion	O
given	O
alone	O
and	O
combined	O
with	O
carboplatin	B-Chemical
:	O
preliminary	O
results	O
of	O
dose	O
-	O
escalation	O
trials	O
.	O

Paclitaxel	B-Chemical
(	O
Taxol	B-Chemical
;	O
Bristol	O
-	O
Myers	O
Squibb	O
Company	O
,	O
Princeton	O
,	O
NJ	O
)	O
by	O
3	O
-	O
hour	O
infusion	O
was	O
combined	O
with	O
carboplatin	B-Chemical
in	O
a	O
phase	O
I	O
/	O
II	O
study	O
directed	O
to	O
patients	O
with	O
non	B-Disease
-	I-Disease
small	I-Disease
cell	I-Disease
lung	I-Disease
cancer	I-Disease
.	O

Carboplatin	B-Chemical
was	O
given	O
at	O
a	O
fixed	O
target	O
area	O
under	O
the	O
concentration	O
-	O
time	O
curve	O
of	O
6	O
.	O
0	O
by	O
the	O
Calvert	O
formula	O
,	O
whereas	O
paclitaxel	B-Chemical
was	O
escalated	O
in	O
patient	O
cohorts	O
from	O
150	O
mg	O
/	O
m2	O
(	O
dose	O
level	O
I	O
)	O
to	O
175	O
,	O
200	O
,	O
225	O
,	O
and	O
250	O
mg	O
/	O
m2	O
.	O

The	O
225	O
mg	O
/	O
m2	O
level	O
was	O
expanded	O
for	O
the	O
phase	O
II	O
study	O
since	O
the	O
highest	O
level	O
achieved	O
(	O
250	O
mg	O
/	O
m2	O
)	O
required	O
modification	O
because	O
of	O
nonhematologic	O
toxicities	B-Disease
(	O
arthralgia	B-Disease
and	O
sensory	B-Disease
neuropathy	I-Disease
)	O
.	O

Therapeutic	O
effects	O
were	O
noted	O
at	O
all	O
dose	O
levels	O
,	O
with	O
objective	O
responses	O
in	O
17	O
(	O
two	O
complete	O
and	O
15	O
partial	O
regressions	O
)	O
of	O
41	O
previously	O
untreated	O
patients	O
.	O

Toxicities	B-Disease
were	O
compared	O
with	O
a	O
cohort	O
of	O
patients	O
in	O
a	O
phase	O
I	O
trial	O
of	O
paclitaxel	B-Chemical
alone	O
at	O
identical	O
dose	O
levels	O
.	O

Carboplatin	B-Chemical
did	O
not	O
appear	O
to	O
add	O
to	O
the	O
hematologic	B-Disease
toxicities	I-Disease
observed	O
,	O
and	O
the	O
paclitaxel	B-Chemical
/	O
carboplatin	B-Chemical
combination	O
could	O
be	O
dosed	O
every	O
3	O
weeks	O
.	O

The	O
dose	O
-	O
dependent	O
effect	O
of	O
misoprostol	B-Chemical
on	O
indomethacin	B-Chemical
-	O
induced	O
renal	B-Disease
dysfunction	I-Disease
in	O
well	O
compensated	O
cirrhosis	B-Disease
.	O

Misoprostol	B-Chemical
(	O
200	O
micrograms	O
)	O
has	O
been	O
shown	O
to	O
acutely	O
counteract	O
the	O
indomethacin	B-Chemical
-	O
induced	O
renal	B-Disease
dysfunction	I-Disease
in	O
well	O
compensated	O
cirrhotic	B-Disease
patients	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
determine	O
if	O
the	O
prophylactic	O
value	O
of	O
misoprostol	B-Chemical
was	O
dose	O
-	O
dependent	O
.	O

Parameters	O
of	O
renal	O
hemodynamics	O
and	O
tubular	O
sodium	B-Chemical
and	O
water	O
handling	O
were	O
assessed	O
by	O
clearance	O
techniques	O
in	O
26	O
well	O
compensated	O
cirrhotic	B-Disease
patients	O
before	O
and	O
after	O
an	O
oral	O
combination	O
of	O
50	O
mg	O
of	O
indomethacin	B-Chemical
and	O
various	O
doses	O
of	O
misoprostol	B-Chemical
.	O

The	O
200	O
-	O
micrograms	O
dose	O
was	O
able	O
to	O
totally	O
abolish	O
the	O
deleterious	O
renal	O
effects	O
of	O
indomethacin	B-Chemical
,	O
whereas	O
the	O
800	O
-	O
micrograms	O
dose	O
resulted	O
in	O
significant	O
worsening	O
of	O
renal	O
hemodynamics	O
and	O
sodium	B-Chemical
retention	O
.	O

These	O
changes	O
were	O
maximal	O
in	O
the	O
hour	O
immediately	O
after	O
medications	O
and	O
slowly	O
returned	O
toward	O
base	O
-	O
line	O
levels	O
thereafter	O
.	O

These	O
results	O
suggest	O
that	O
the	O
renal	O
protective	O
effects	O
of	O
misoprostol	B-Chemical
is	O
dose	O
-	O
dependent	O
.	O

However	O
,	O
until	O
this	O
apparent	O
ability	O
of	O
200	O
micrograms	O
of	O
misoprostol	B-Chemical
to	O
prevent	O
the	O
adverse	O
effects	O
of	O
indomethacin	B-Chemical
on	O
renal	O
function	O
is	O
confirmed	O
with	O
chronic	O
frequent	O
dosing	O
,	O
it	O
would	O
be	O
prudent	O
to	O
avoid	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
therapy	O
in	O
patients	O
with	O
cirrhosis	B-Disease
.	O

Increased	O
frequency	O
and	O
severity	O
of	O
angio	B-Disease
-	I-Disease
oedema	I-Disease
related	O
to	O
long	O
-	O
term	O
therapy	O
with	O
angiotensin	B-Chemical
-	I-Chemical
converting	I-Chemical
enzyme	I-Chemical
inhibitor	I-Chemical
in	O
two	O
patients	O
.	O

Adverse	O
reactions	O
to	O
drugs	O
are	O
well	O
recognized	O
as	O
a	O
cause	O
of	O
acute	O
or	O
chronic	O
urticaria	B-Disease
,	O
and	O
angio	B-Disease
-	I-Disease
oedema	I-Disease
.	O

Angiotensin	B-Chemical
-	I-Chemical
converting	I-Chemical
enzyme	I-Chemical
(	I-Chemical
ACE	I-Chemical
)	I-Chemical
inhibitors	I-Chemical
,	O
used	O
to	O
treat	O
hypertension	B-Disease
and	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
,	O
were	O
introduced	O
in	O
Europe	O
in	O
the	O
middle	O
of	O
the	O
eighties	O
,	O
and	O
the	O
use	O
of	O
these	O
drugs	O
has	O
increased	O
progressively	O
.	O

Soon	O
after	O
the	O
introduction	O
of	O
ACE	B-Chemical
inhibitors	I-Chemical
,	O
acute	O
bouts	O
of	O
angio	B-Disease
-	I-Disease
oedema	I-Disease
were	O
reported	O
in	O
association	O
with	O
the	O
use	O
of	O
these	O
drugs	O
.	O

We	O
wish	O
to	O
draw	O
attention	O
to	O
the	O
possibility	O
of	O
adverse	O
reactions	O
to	O
ACE	B-Chemical
inhibitors	I-Chemical
after	O
long	O
-	O
term	O
use	O
and	O
in	O
patients	O
with	O
pre	O
-	O
existing	O
angio	B-Disease
-	I-Disease
oedema	I-Disease
.	O

Myoclonus	B-Disease
associated	O
with	O
lorazepam	B-Chemical
therapy	O
in	O
very	O
-	O
low	O
-	O
birth	O
-	O
weight	O
infants	O
.	O

Lorazepam	B-Chemical
is	O
being	O
used	O
with	O
increasing	O
frequency	O
as	O
a	O
sedative	O
in	O
the	O
newborn	O
and	O
the	O
young	O
infant	O
.	O

Concern	O
has	O
been	O
raised	O
with	O
regard	O
to	O
the	O
safety	O
of	O
lorazepam	B-Chemical
in	O
this	O
age	O
group	O
,	O
especially	O
in	O
very	O
-	O
low	O
-	O
birth	O
-	O
weight	O
(	O
VLBW	O
;	O
<	O
1	O
,	O
500	O
g	O
)	O
infants	O
.	O

Three	O
young	O
infants	O
,	O
all	O
of	O
birth	O
weight	O
<	O
1	O
,	O
500	O
g	O
,	O
experienced	O
myoclonus	B-Disease
following	O
the	O
intravenous	O
administration	O
of	O
lorazepam	B-Chemical
.	O

The	O
potential	O
neurotoxic	B-Disease
effects	O
of	O
the	O
drug	O
(	O
and	O
its	O
vehicle	O
)	O
in	O
this	O
population	O
are	O
discussed	O
.	O

Injectable	O
lorazepam	B-Chemical
should	O
be	O
used	O
with	O
caution	O
in	O
VLBW	O
infants	O
.	O

Transvenous	O
right	O
ventricular	O
pacing	O
during	O
cardiopulmonary	O
resuscitation	O
of	O
pediatric	O
patients	O
with	O
acute	O
cardiomyopathy	B-Disease
.	O

We	O
describe	O
the	O
cardiopulmonary	O
resuscitation	O
efforts	O
on	O
five	O
patients	O
who	O
presented	O
in	O
acute	O
circulatory	B-Disease
failure	I-Disease
from	O
myocardial	B-Disease
dysfunction	I-Disease
.	O

Three	O
patients	O
had	O
acute	O
viral	O
myocarditis	B-Disease
,	O
one	O
had	O
a	O
carbamazepine	B-Chemical
-	O
induced	O
acute	O
eosinophilic	B-Disease
myocarditis	I-Disease
,	O
and	O
one	O
had	O
cardiac	O
hemosiderosis	O
resulting	O
in	O
acute	O
cardiogenic	B-Disease
shock	I-Disease
.	O

All	O
patients	O
were	O
continuously	O
monitored	O
with	O
central	O
venous	O
and	O
arterial	O
catheters	O
in	O
addition	O
to	O
routine	O
noninvasive	O
monitoring	O
.	O

An	O
introducer	O
sheath	O
,	O
a	O
pacemaker	O
,	O
and	O
sterile	O
pacing	O
wires	O
were	O
made	O
readily	O
available	O
for	O
the	O
patients	O
,	O
should	O
the	O
need	O
arise	O
to	O
terminate	O
resistant	O
cardiac	O
dysrhythmias	B-Disease
.	O

All	O
patients	O
developed	O
cardiocirculatory	O
arrest	O
associated	O
with	O
extreme	O
hypotension	B-Disease
and	O
dysrhythmias	B-Disease
within	O
the	O
first	O
48	O
hours	O
of	O
their	O
admission	O
to	O
the	O
pediatric	O
intensive	O
care	O
unit	O
(	O
PICU	O
)	O
.	O

Right	O
ventricular	O
pacemaker	O
wires	O
were	O
inserted	O
in	O
all	O
of	O
them	O
during	O
cardiopulmonary	O
resuscitation	O
(	O
CPR	O
)	O
.	O

In	O
four	O
patients	O
,	O
cardiac	O
pacing	O
was	O
used	O
,	O
resulting	O
in	O
a	O
temporary	O
captured	O
rhythm	O
and	O
restoration	O
of	O
their	O
cardiac	O
output	O
.	O

These	O
patients	O
had	O
a	O
second	O
event	O
of	O
cardiac	B-Disease
arrest	I-Disease
,	O
resulting	O
in	O
death	O
,	O
within	O
10	O
to	O
60	O
minutes	O
.	O

In	O
one	O
patient	O
,	O
cardiac	O
pacing	O
was	O
not	O
used	O
,	O
because	O
he	O
converted	O
to	O
normal	O
sinus	O
rhythm	O
by	O
electrical	O
defibrillation	O
within	O
three	O
minutes	O
of	O
initiating	O
CPR	O
.	O

We	O
conclude	O
that	O
cardiac	O
pacing	O
during	O
resuscitative	O
efforts	O
in	O
pediatric	O
patients	O
suffering	O
from	O
acute	O
myocardial	B-Disease
dysfunction	I-Disease
may	O
not	O
have	O
long	O
-	O
term	O
value	O
in	O
and	O
of	O
itself	O
;	O
however	O
,	O
if	O
temporary	O
hemodynamic	O
stability	O
is	O
achieved	O
by	O
this	O
procedure	O
,	O
it	O
may	O
provide	O
additional	O
time	O
needed	O
to	O
institute	O
other	O
therapeutic	O
modalities	O
.	O

Efficacy	O
and	O
safety	O
of	O
granisetron	B-Chemical
,	O
a	O
selective	O
5	B-Chemical
-	I-Chemical
hydroxytryptamine	I-Chemical
-	O
3	O
receptor	O
antagonist	O
,	O
in	O
the	O
prevention	O
of	O
nausea	B-Disease
and	O
vomiting	B-Disease
induced	O
by	O
high	O
-	O
dose	O
cisplatin	B-Chemical
.	O

PURPOSE	O
:	O
To	O
assess	O
the	O
antiemetic	O
effects	O
and	O
safety	O
profile	O
of	O
four	O
different	O
doses	O
of	O
granisetron	B-Chemical
(	O
Kytril	B-Chemical
;	O
SmithKline	O
Beecham	O
Pharmaceuticals	O
,	O
Philadelphia	O
,	O
PA	O
)	O
when	O
administered	O
as	O
a	O
single	O
intravenous	O
(	O
IV	O
)	O
dose	O
for	O
prophylaxis	O
of	O
cisplatin	B-Chemical
-	O
induced	O
nausea	B-Disease
and	O
vomiting	B-Disease
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
One	O
hundred	O
eighty	O
-	O
four	O
chemotherapy	O
-	O
naive	O
patients	O
receiving	O
high	O
-	O
dose	O
cisplatin	B-Chemical
(	O
81	O
to	O
120	O
mg	O
/	O
m2	O
)	O
were	O
randomized	O
to	O
receive	O
one	O
of	O
four	O
granisetron	B-Chemical
doses	O
(	O
5	O
,	O
10	O
,	O
20	O
,	O
or	O
40	O
micrograms	O
/	O
kg	O
)	O
administered	O
before	O
chemotherapy	O
.	O

Patients	O
were	O
observed	O
on	O
an	O
inpatient	O
basis	O
for	O
18	O
to	O
24	O
hours	O
,	O
and	O
vital	O
signs	O
,	O
nausea	B-Disease
,	O
vomiting	B-Disease
,	O
retching	O
,	O
and	O
appetite	O
were	O
assessed	O
.	O

Safety	O
analyses	O
included	O
incidence	O
of	O
adverse	O
experiences	O
and	O
laboratory	O
parameter	O
changes	O
.	O

RESULTS	O
:	O
After	O
granisetron	B-Chemical
doses	O
of	O
5	O
,	O
10	O
,	O
20	O
,	O
and	O
40	O
micrograms	O
/	O
kg	O
,	O
a	O
major	O
response	O
(	O
<	O
or	O
=	O
two	O
vomiting	B-Disease
or	O
retching	O
episodes	O
,	O
and	O
no	O
antiemetic	O
rescue	O
)	O
was	O
recorded	O
in	O
23	O
%	O
,	O
57	O
%	O
,	O
58	O
%	O
,	O
and	O
60	O
%	O
of	O
patients	O
,	O
respectively	O
,	O
and	O
a	O
complete	O
response	O
(	O
no	O
vomiting	B-Disease
or	O
retching	O
,	O
and	O
no	O
antiemetic	O
rescue	O
)	O
in	O
18	O
%	O
,	O
41	O
%	O
,	O
40	O
%	O
,	O
and	O
47	O
%	O
of	O
patients	O
,	O
respectively	O
.	O

There	O
was	O
a	O
statistically	O
longer	O
time	O
to	O
first	O
episode	O
of	O
nausea	B-Disease
(	O
P	O
=	O
.	O
0015	O
)	O
and	O
vomiting	B-Disease
(	O
P	O
=	O
.	O
0001	O
)	O
,	O
and	O
fewer	O
patients	O
were	O
administered	O
additional	O
antiemetic	O
medication	O
in	O
the	O
10	O
-	O
micrograms	O
/	O
kg	O
dosing	O
groups	O
than	O
in	O
the	O
5	O
-	O
micrograms	O
/	O
kg	O
dosing	O
group	O
.	O

As	O
granisetron	B-Chemical
dose	O
increased	O
,	O
appetite	O
return	O
increased	O
(	O
P	O
=	O
.	O
040	O
)	O
.	O

Headache	B-Disease
was	O
the	O
most	O
frequently	O
reported	O
adverse	O
event	O
(	O
20	O
%	O
)	O
.	O

CONCLUSION	O
:	O
A	O
single	O
10	O
-	O
,	O
20	O
-	O
,	O
or	O
40	O
-	O
micrograms	O
/	O
kg	O
dose	O
of	O
granisetron	B-Chemical
was	O
effective	O
in	O
controlling	O
vomiting	B-Disease
in	O
57	O
%	O
to	O
60	O
%	O
of	O
patients	O
who	O
received	O
cisplatin	B-Chemical
at	O
doses	O
greater	O
than	O
81	O
mg	O
/	O
m2	O
and	O
totally	O
prevented	O
vomiting	B-Disease
in	O
40	O
%	O
to	O
47	O
%	O
of	O
patients	O
.	O

There	O
were	O
no	O
statistically	O
significant	O
differences	O
in	O
efficacy	O
between	O
the	O
10	O
-	O
micrograms	O
/	O
kg	O
dose	O
and	O
the	O
20	O
-	O
and	O
40	O
-	O
micrograms	O
/	O
kg	O
doses	O
.	O

Granisetron	B-Chemical
was	O
well	O
tolerated	O
at	O
all	O
doses	O
.	O

Adverse	O
interaction	O
between	O
clonidine	B-Chemical
and	O
verapamil	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
report	O
two	O
cases	O
of	O
a	O
possible	O
adverse	O
interaction	O
between	O
clonidine	B-Chemical
and	O
verapamil	B-Chemical
resulting	O
in	O
atrioventricular	B-Disease
(	I-Disease
AV	I-Disease
)	I-Disease
block	I-Disease
in	O
both	O
patients	O
and	O
severe	O
hypotension	B-Disease
in	O
one	O
patient	O
.	O

CASE	O
SUMMARIES	O
:	O
A	O
54	O
-	O
year	O
-	O
old	O
woman	O
with	O
hyperaldosteronism	B-Disease
was	O
treated	O
with	O
verapamil	B-Chemical
480	O
mg	O
/	O
d	O
and	O
spironolactone	B-Chemical
100	O
mg	O
/	O
d	O
.	O

After	O
the	O
addition	O
of	O
a	O
minimal	O
dose	O
of	O
clonidine	B-Chemical
(	O
0	O
.	O
15	O
mg	O
bid	O
)	O
,	O
she	O
developed	O
complete	O
AV	B-Disease
block	I-Disease
and	O
severe	O
hypotension	B-Disease
,	O
which	O
resolved	O
upon	O
cessation	O
of	O
all	O
medications	O
.	O

A	O
65	O
-	O
year	O
-	O
old	O
woman	O
was	O
treated	O
with	O
extended	O
-	O
release	O
verapamil	B-Chemical
240	O
mg	O
/	O
d	O
.	O

After	O
the	O
addition	O
of	O
clonidine	B-Chemical
0	O
.	O
15	O
mg	O
bid	O
she	O
developed	O
complete	O
AV	B-Disease
block	I-Disease
,	O
which	O
resolved	O
after	O
all	O
therapy	O
was	O
stopped	O
.	O

DISCUSSION	O
:	O
An	O
adverse	O
interaction	O
between	O
clonidine	B-Chemical
and	O
verapamil	B-Chemical
has	O
not	O
been	O
reported	O
previously	O
.	O

We	O
describe	O
two	O
such	O
cases	O
and	O
discuss	O
the	O
various	O
mechanisms	O
that	O
might	O
cause	O
such	O
an	O
interaction	O
.	O

Clinicians	O
should	O
be	O
acquainted	O
with	O
this	O
possibly	O
fatal	O
interaction	O
between	O
two	O
commonly	O
used	O
antihypertensive	O
drugs	O
.	O

CONCLUSIONS	O
:	O
Caution	O
is	O
recommended	O
in	O
combining	O
clonidine	B-Chemical
and	O
verapamil	B-Chemical
therapy	O
,	O
even	O
in	O
patients	O
who	O
do	O
not	O
have	O
sinus	O
or	O
AV	O
node	O
dysfunction	O
.	O

The	O
two	O
drugs	O
may	O
act	O
synergistically	O
on	O
both	O
the	O
AV	O
node	O
and	O
the	O
peripheral	O
circulation	O
.	O

Pharmacological	O
studies	O
on	O
a	O
new	O
dihydrothienopyridine	B-Chemical
calcium	I-Chemical
antagonist	O
,	O
S	B-Chemical
-	I-Chemical
312	I-Chemical
-	I-Chemical
d	I-Chemical
.	O

5th	O
communication	O
:	O
anticonvulsant	O
effects	O
in	O
mice	O
.	O

S	B-Chemical
-	I-Chemical
312	I-Chemical
,	O
S	B-Chemical
-	I-Chemical
312	I-Chemical
-	I-Chemical
d	I-Chemical
,	O
but	O
not	O
S	B-Chemical
-	I-Chemical
312	I-Chemical
-	I-Chemical
l	I-Chemical
,	O
L	O
-	O
type	O
calcium	B-Chemical
channel	O
antagonists	O
,	O
showed	O
anticonvulsant	O
effects	O
on	O
the	O
audiogenic	B-Disease
tonic	I-Disease
convulsions	I-Disease
in	O
DBA	O
/	O
2	O
mice	O
;	O
and	O
their	O
ED50	O
values	O
were	O
18	O
.	O
4	O
(	O
12	O
.	O
8	O
-	O
27	O
.	O
1	O
)	O
mg	O
/	O
kg	O
,	O
p	O
.	O
o	O
.	O
and	O
15	O
.	O
0	O
(	O
10	O
.	O
2	O
-	O
23	O
.	O
7	O
)	O
mg	O
/	O
kg	O
,	O
p	O
.	O
o	O
.	O
,	O
respectively	O
,	O
while	O
that	O
of	O
flunarizine	B-Chemical
was	O
34	O
.	O
0	O
(	O
26	O
.	O
0	O
-	O
44	O
.	O
8	O
)	O
mg	O
/	O
kg	O
,	O
p	O
.	O
o	O
.	O

Although	O
moderate	O
anticonvulsant	O
effects	O
of	O
S	B-Chemical
-	I-Chemical
312	I-Chemical
-	I-Chemical
d	I-Chemical
in	O
higher	O
doses	O
were	O
observed	O
against	O
the	O
clonic	O
convulsions	B-Disease
induced	O
by	O
pentylenetetrazole	B-Chemical
(	O
85	O
mg	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
or	O
bemegride	B-Chemical
(	O
40	O
mg	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
,	O
no	O
effects	O
were	O
observed	O
in	O
convulsions	B-Disease
induced	O
by	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
,	O
picrotoxin	B-Chemical
,	O
or	O
electroshock	O
in	O
Slc	O
:	O
ddY	O
mice	O
.	O

S	B-Chemical
-	I-Chemical
312	I-Chemical
-	I-Chemical
d	I-Chemical
may	O
be	O
useful	O
in	O
the	O
therapy	O
of	O
certain	O
types	O
of	O
human	O
epilepsy	B-Disease
.	O

Transmural	O
myocardial	B-Disease
infarction	I-Disease
with	O
sumatriptan	B-Chemical
.	O

For	O
sumatriptan	B-Chemical
,	O
tightness	O
in	O
the	O
chest	O
caused	O
by	O
an	O
unknown	O
mechanism	O
has	O
been	O
reported	O
in	O
3	O
-	O
5	O
%	O
of	O
users	O
.	O

We	O
describe	O
a	O
47	O
-	O
year	O
-	O
old	O
woman	O
with	O
an	O
acute	O
myocardial	B-Disease
infarction	I-Disease
after	O
administration	O
of	O
sumatriptan	B-Chemical
6	O
mg	O
subcutaneously	O
for	O
cluster	B-Disease
headache	I-Disease
.	O

The	O
patient	O
had	O
no	O
history	O
of	O
underlying	O
ischaemic	B-Disease
heart	I-Disease
disease	I-Disease
or	O
Prinzmetal	B-Disease
'	I-Disease
s	I-Disease
angina	I-Disease
.	O

She	O
recovered	O
without	O
complications	O
.	O

Flumazenil	B-Chemical
induces	O
seizures	B-Disease
and	O
death	O
in	O
mixed	O
cocaine	B-Chemical
-	O
diazepam	B-Chemical
intoxications	O
.	O

STUDY	O
HYPOTHESIS	O
:	O
Administration	O
of	O
the	O
benzodiazepine	B-Chemical
antagonist	O
flumazenil	B-Chemical
may	O
unmask	O
seizures	B-Disease
in	O
mixed	O
cocaine	B-Chemical
-	O
benzodiazepine	B-Chemical
intoxication	O
.	O

DESIGN	O
:	O
Male	O
Sprague	O
-	O
Dawley	O
rats	O
received	O
100	O
mg	O
/	O
kg	O
cocaine	B-Chemical
IP	O
alone	O
,	O
5	O
mg	O
/	O
kg	O
diazepam	B-Chemical
alone	O
,	O
or	O
a	O
combination	O
of	O
diazepam	B-Chemical
and	O
cocaine	B-Chemical
.	O

Three	O
minutes	O
later	O
,	O
groups	O
were	O
challenged	O
with	O
vehicle	O
or	O
flumazenil	B-Chemical
5	O
or	O
10	O
mg	O
/	O
kg	O
IP	O
.	O

Animal	O
behavior	O
,	O
seizures	B-Disease
(	O
time	O
to	O
and	O
incidence	O
)	O
,	O
death	O
(	O
time	O
to	O
and	O
incidence	O
)	O
,	O
and	O
cortical	O
EEG	O
tracings	O
were	O
recorded	O
.	O

INTERVENTIONS	O
:	O
Administration	O
of	O
flumazenil	B-Chemical
to	O
animals	O
after	O
they	O
had	O
received	O
a	O
combination	O
dose	O
of	O
cocaine	B-Chemical
and	O
diazepam	B-Chemical
.	O

RESULTS	O
:	O
In	O
group	O
1	O
,	O
animals	O
received	O
cocaine	B-Chemical
followed	O
by	O
vehicle	O
.	O

This	O
resulted	O
in	O
100	O
%	O
developing	O
seizures	B-Disease
and	O
death	O
.	O

Group	O
2	O
received	O
diazepam	B-Chemical
alone	O
followed	O
by	O
vehicle	O
.	O

Animals	O
became	O
somnolent	O
and	O
none	O
died	O
.	O

Group	O
3	O
received	O
diazepam	B-Chemical
followed	O
by	O
5	O
mg	O
/	O
kg	O
flumazenil	B-Chemical
.	O

Animals	O
became	O
somnolent	O
after	O
diazepam	B-Chemical
and	O
then	O
active	O
after	O
flumazenil	B-Chemical
administration	O
.	O

In	O
group	O
4	O
,	O
a	O
combination	O
of	O
cocaine	B-Chemical
and	O
diazepam	B-Chemical
was	O
administered	O
simultaneously	O
.	O

This	O
resulted	O
in	O
no	O
overt	O
or	O
EEG	O
-	O
detectable	O
seizures	B-Disease
and	O
a	O
50	O
%	O
incidence	O
of	O
death	O
.	O

Group	O
5	O
received	O
a	O
similar	O
combination	O
of	O
cocaine	B-Chemical
and	O
diazepam	B-Chemical
,	O
followed	O
later	O
by	O
5	O
mg	O
/	O
kg	O
flumazenil	B-Chemical
.	O

This	O
resulted	O
in	O
an	O
increased	O
incidence	O
of	O
seizures	B-Disease
,	O
90	O
%	O
(	O
P	O
<	O
.	O
01	O
)	O
,	O
and	O
death	O
,	O
100	O
%	O
(	O
P	O
<	O
or	O
=	O
.	O
01	O
)	O
,	O
compared	O
with	O
group	O
4	O
.	O

Group	O
6	O
received	O
cocaine	B-Chemical
and	O
diazepam	B-Chemical
followed	O
by	O
10	O
mg	O
/	O
kg	O
flumazenil	B-Chemical
.	O

This	O
also	O
resulted	O
in	O
an	O
increased	O
incidence	O
of	O
seizures	B-Disease
,	O
90	O
%	O
(	O
P	O
<	O
or	O
=	O
.	O
01	O
)	O
,	O
and	O
death	O
,	O
90	O
%	O
(	O
P	O
<	O
or	O
=	O
.	O
05	O
)	O
,	O
compared	O
with	O
group	O
4	O
.	O

CONCLUSION	O
:	O
Flumazenil	B-Chemical
can	O
unmask	O
seizures	B-Disease
and	O
increase	O
the	O
incidence	O
of	O
death	O
in	O
a	O
model	O
of	O
combined	O
cocaine	B-Chemical
-	O
diazepam	B-Chemical
intoxications	O
.	O

Mechanisms	O
for	O
protective	O
effects	O
of	O
free	O
radical	O
scavengers	O
on	O
gentamicin	B-Chemical
-	O
mediated	O
nephropathy	B-Disease
in	O
rats	O
.	O

Studies	O
were	O
performed	O
to	O
examine	O
the	O
mechanisms	O
for	O
the	O
protective	O
effects	O
of	O
free	O
radical	O
scavengers	O
on	O
gentamicin	B-Chemical
(	O
GM	B-Chemical
)	O
-	O
mediated	O
nephropathy	B-Disease
.	O

Administration	O
of	O
GM	B-Chemical
at	O
40	O
mg	O
/	O
kg	O
sc	O
for	O
13	O
days	O
to	O
rats	O
induced	O
a	O
significant	O
reduction	O
in	O
renal	O
blood	O
flow	O
(	O
RBF	O
)	O
and	O
inulin	O
clearance	O
(	O
CIn	O
)	O
as	O
well	O
as	O
marked	O
tubular	B-Disease
damage	I-Disease
.	O

A	O
significant	O
reduction	O
in	O
urinary	O
guanosine	B-Chemical
3	I-Chemical
'	I-Chemical
,	I-Chemical
5	I-Chemical
'	I-Chemical
-	I-Chemical
cyclic	I-Chemical
monophosphate	I-Chemical
(	O
cGMP	B-Chemical
)	O
excretion	O
and	O
a	O
significant	O
increase	O
in	O
renal	O
cortical	O
renin	O
and	O
endothelin	O
-	O
1	O
contents	O
were	O
also	O
observed	O
in	O
GM	B-Chemical
-	O
mediated	O
nephropathy	B-Disease
.	O

Superoxide	B-Chemical
dismutase	O
(	O
SOD	O
)	O
or	O
dimethylthiourea	B-Chemical
(	O
DMTU	B-Chemical
)	O
significantly	O
lessened	O
the	O
GM	B-Chemical
-	O
induced	O
decrement	O
in	O
CIn	O
.	O

The	O
SOD	O
-	O
induced	O
increase	O
in	O
glomerular	O
filtration	O
rate	O
was	O
associated	O
with	O
a	O
marked	O
improvement	O
in	O
RBF	O
,	O
an	O
increase	O
in	O
urinary	O
cGMP	B-Chemical
excretion	O
,	O
and	O
a	O
decrease	O
in	O
renal	O
renin	O
and	O
endothelin	O
-	O
1	O
content	O
.	O

SOD	O
did	O
not	O
attenuate	O
the	O
tubular	B-Disease
damage	I-Disease
.	O

In	O
contrast	O
,	O
DMTU	B-Chemical
significantly	O
reduced	O
the	O
tubular	B-Disease
damage	I-Disease
and	O
lipid	O
peroxidation	O
,	O
but	O
it	O
did	O
not	O
affect	O
renal	O
hemodynamics	O
and	O
vasoactive	O
substances	O
.	O

Neither	O
SOD	O
nor	O
DMTU	B-Chemical
affected	O
the	O
renal	O
cortical	O
GM	B-Chemical
content	O
in	O
GM	B-Chemical
-	O
treated	O
rats	O
.	O

These	O
results	O
suggest	O
that	O
1	O
)	O
both	O
SOD	O
and	O
DMTU	B-Chemical
have	O
protective	O
effects	O
on	O
GM	B-Chemical
-	O
mediated	O
nephropathy	B-Disease
,	O
2	O
)	O
the	O
mechanisms	O
for	O
the	O
protective	O
effects	O
differ	O
for	O
SOD	O
and	O
DMTU	B-Chemical
,	O
and	O
3	O
)	O
superoxide	B-Chemical
anions	O
play	O
a	O
critical	O
role	O
in	O
GM	B-Chemical
-	O
induced	O
renal	O
vasoconstriction	O
.	O

Cephalothin	B-Chemical
-	O
induced	O
immune	O
hemolytic	B-Disease
anemia	I-Disease
.	O

A	O
patient	O
with	O
renal	B-Disease
disease	I-Disease
developed	O
Coombs	O
-	O
positive	O
hemolytic	B-Disease
anemia	I-Disease
while	O
receiving	O
cephalothin	B-Chemical
therapy	O
.	O

An	O
anti	O
-	O
cephalothin	B-Chemical
IgG	O
antibody	O
was	O
detected	O
in	O
the	O
patient	O
'	O
s	O
serum	O
and	O
in	O
the	O
eluates	O
from	O
her	O
erythrocytes	O
.	O

In	O
addition	O
,	O
nonimmunologic	O
binding	O
of	O
normal	O
and	O
patient	O
'	O
s	O
serum	O
proteins	O
to	O
her	O
own	O
and	O
cephalothin	B-Chemical
-	O
coated	O
normal	O
red	O
cells	O
was	O
demonstrated	O
.	O

Skin	O
tests	O
and	O
in	O
vitro	O
lymphocyte	O
stimulation	O
revealed	O
that	O
the	O
patient	O
was	O
sensitized	O
to	O
cephalothin	B-Chemical
and	O
also	O
to	O
ampicillin	B-Chemical
.	O

Careful	O
investigation	O
of	O
drug	O
-	O
induced	O
hemolytic	B-Disease
anemias	I-Disease
reveals	O
the	O
complexity	O
of	O
the	O
immune	O
mechanisms	O
involved	O
.	O

Assessment	O
of	O
cardiomyocyte	O
DNA	O
synthesis	O
during	O
hypertrophy	B-Disease
in	O
adult	O
mice	O
.	O

The	O
ability	O
of	O
cardiomyocytes	O
to	O
synthesize	O
DNA	O
in	O
response	O
to	O
experimentally	O
induced	O
cardiac	B-Disease
hypertrophy	I-Disease
was	O
assessed	O
in	O
adult	O
mice	O
.	O

Isoproterenol	B-Chemical
delivered	O
by	O
osmotic	O
minipump	O
implantation	O
in	O
adult	O
C3Heb	O
/	O
FeJ	O
mice	O
resulted	O
in	O
a	O
46	O
%	O
increase	O
in	O
heart	O
weight	O
and	O
a	O
19	O
.	O
3	O
%	O
increase	O
in	O
cardiomyocyte	O
area	O
.	O

No	O
DNA	O
synthesis	O
,	O
as	O
assessed	O
by	O
autoradiographic	O
analysis	O
of	O
isolated	O
cardiomyocytes	O
,	O
was	O
observed	O
in	O
control	O
or	O
hypertrophic	B-Disease
hearts	I-Disease
.	O

A	O
survey	O
of	O
15	O
independent	O
inbred	O
strains	O
of	O
mice	O
revealed	O
that	O
ventricular	O
cardiomyocyte	O
nuclear	O
number	O
ranged	O
from	O
3	O
to	O
13	O
%	O
mononucleate	O
,	O
suggesting	O
that	O
cardiomyocyte	O
terminal	O
differentiation	O
is	O
influenced	O
directly	O
or	O
indirectly	O
by	O
genetic	O
background	O
.	O

To	O
determine	O
whether	O
the	O
capacity	O
for	O
reactive	O
DNA	O
synthesis	O
was	O
also	O
subject	O
to	O
genetic	O
regulation	O
,	O
cardiac	B-Disease
hypertrophy	I-Disease
was	O
induced	O
in	O
the	O
strains	O
of	O
mice	O
comprising	O
the	O
extremes	O
of	O
the	O
nuclear	O
number	O
survey	O
.	O

These	O
data	O
indicate	O
that	O
adult	O
mouse	O
atrial	O
and	O
ventricular	O
cardiomyocytes	O
do	O
not	O
synthesize	O
DNA	O
in	O
response	O
to	O
isoproterenol	B-Chemical
-	O
induced	O
cardiac	B-Disease
hypertrophy	I-Disease
.	O

Central	O
cardiovascular	O
effects	O
of	O
AVP	B-Chemical
and	O
ANP	O
in	O
normotensive	O
and	O
spontaneously	O
hypertensive	B-Disease
rats	O
.	O

The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
compare	O
influence	O
of	O
central	O
arginine	B-Chemical
vasopressin	I-Chemical
(	O
AVP	B-Chemical
)	O
and	O
of	O
atrial	O
natriuretic	O
peptide	O
(	O
ANP	O
)	O
on	O
control	O
of	O
arterial	O
blood	O
pressure	O
(	O
MAP	O
)	O
and	O
heart	O
rate	O
(	O
HR	O
)	O
in	O
normotensive	O
(	O
WKY	O
)	O
and	O
spontaneously	O
hypertensive	B-Disease
(	O
SHR	O
)	O
rats	O
.	O

Three	O
series	O
of	O
experiments	O
were	O
performed	O
on	O
30	O
WKY	O
and	O
30	O
SHR	O
,	O
chronically	O
instrumented	O
with	O
guide	O
tubes	O
in	O
the	O
lateral	O
ventricle	O
(	O
LV	O
)	O
and	O
arterial	O
and	O
venous	O
catheters	O
.	O

MAP	O
and	O
HR	O
were	O
monitored	O
before	O
and	O
after	O
i	O
.	O
v	O
.	O
injections	O
of	O
either	O
vehicle	O
or	O
1	O
,	O
10	O
and	O
50	O
ng	O
of	O
AVP	B-Chemical
and	O
25	O
,	O
125	O
and	O
500	O
ng	O
of	O
ANP	O
.	O

Sensitivity	O
of	O
cardiac	O
component	O
of	O
baroreflex	O
(	O
CCB	O
)	O
,	O
expressed	O
as	O
a	O
slope	O
of	O
the	O
regression	O
line	O
was	O
determined	O
from	O
relationships	O
between	O
systolic	O
arterial	O
pressure	O
(	O
SAP	O
)	O
and	O
HR	O
period	O
(	O
HRp	O
)	O
during	O
phenylephrine	B-Chemical
(	O
Phe	B-Chemical
)	O
-	O
induced	O
hypertension	B-Disease
and	O
sodium	B-Chemical
nitroprusside	I-Chemical
(	O
SN	B-Chemical
)	O
-	O
induced	O
hypotension	B-Disease
.	O

CCB	O
was	O
measured	O
before	O
and	O
after	O
administration	O
of	O
either	O
vehicle	O
,	O
AVP	B-Chemical
,	O
ANP	O
,	O
or	O
both	O
peptides	O
together	O
.	O

Increases	O
of	O
MAP	O
occurred	O
after	O
LV	O
administration	O
of	O
1	O
,	O
10	O
and	O
50	O
ng	O
of	O
AVP	B-Chemical
in	O
WKY	O
and	O
of	O
10	O
and	O
50	O
ng	O
in	O
SHR	O
.	O

ANP	O
did	O
not	O
cause	O
significant	O
changes	O
in	O
MAP	O
in	O
both	O
strains	O
as	O
compared	O
to	O
vehicle	O
,	O
but	O
it	O
abolished	O
AVP	B-Chemical
-	O
induced	O
MAP	O
increase	O
in	O
WKY	O
and	O
SHR	O
.	O

CCB	O
was	O
reduced	O
in	O
WKY	O
and	O
SHR	O
after	O
LV	O
administration	O
of	O
AVP	B-Chemical
during	O
SN	B-Chemical
-	O
induced	O
hypotension	B-Disease
.	O

In	O
SHR	O
but	O
not	O
in	O
WKY	O
administration	O
of	O
ANP	O
,	O
AVP	B-Chemical
and	O
ANP	O
+	O
AVP	B-Chemical
decreased	O
CCB	O
during	O
Phe	B-Chemical
-	O
induced	O
MAP	O
elevation	O
.	O

The	O
results	O
indicate	O
that	O
centrally	O
applied	O
AVP	B-Chemical
and	O
ANP	O
exert	O
differential	O
effects	O
on	O
blood	O
pressure	O
and	O
baroreflex	O
control	O
of	O
heart	O
rate	O
in	O
WKY	O
and	O
SHR	O
and	O
suggest	O
interaction	O
of	O
these	O
two	O
peptides	O
in	O
blood	O
pressure	O
regulation	O
at	O
the	O
level	O
of	O
central	O
nervous	O
system	O
.	O

Cutaneous	O
exposure	O
to	O
warfarin	B-Chemical
-	O
like	O
anticoagulant	O
causing	O
an	O
intracerebral	B-Disease
hemorrhage	I-Disease
:	O
a	O
case	O
report	O
.	O

A	O
case	O
of	O
intercerebral	O
hematoma	B-Disease
due	O
to	O
warfarin	B-Chemical
-	O
induced	O
coagulopathy	B-Disease
is	O
presented	O
.	O

The	O
39	O
-	O
year	O
-	O
old	O
woman	O
had	O
spread	O
a	O
warfarin	B-Chemical
-	O
type	O
rat	O
poison	O
around	O
her	O
house	O
weekly	O
using	O
her	O
bare	O
hands	O
,	O
with	O
no	O
washing	O
post	O
application	O
.	O

Percutaneous	O
absorption	O
of	O
warfarin	B-Chemical
causing	O
coagulopathy	B-Disease
,	O
reported	O
three	O
times	O
in	O
the	O
past	O
,	O
is	O
a	O
significant	O
risk	O
if	O
protective	O
measures	O
,	O
such	O
as	O
gloves	O
,	O
are	O
not	O
used	O
.	O

An	O
adverse	O
drug	O
interaction	O
with	O
piroxicam	B-Chemical
,	O
which	O
she	O
took	O
occasionally	O
,	O
may	O
have	O
exacerbated	O
the	O
coagulopathy	B-Disease
.	O

Pediatric	O
heart	O
transplantation	O
without	O
chronic	O
maintenance	O
steroids	B-Chemical
.	O

From	O
1986	O
to	O
February	O
1993	O
,	O
40	O
children	O
aged	O
2	O
months	O
to	O
18	O
years	O
(	O
average	O
age	O
10	O
.	O
4	O
+	O
/	O
-	O
5	O
.	O
8	O
years	O
)	O
underwent	O
heart	O
transplantation	O
.	O

Indications	O
for	O
transplantation	O
were	O
idiopathic	B-Disease
cardiomyopathy	I-Disease
(	O
52	O
%	O
)	O
,	O
congenital	B-Disease
heart	I-Disease
disease	I-Disease
(	O
35	O
%	O
)	O
with	O
and	O
without	O
prior	O
repair	O
(	O
71	O
%	O
and	O
29	O
%	O
,	O
respectively	O
)	O
,	O
hypertrophic	B-Disease
cardiomyopathy	I-Disease
(	O
5	O
%	O
)	O
,	O
valvular	B-Disease
heart	I-Disease
disease	I-Disease
(	O
3	O
%	O
)	O
,	O
and	O
doxorubicin	B-Chemical
cardiomyopathy	B-Disease
(	O
5	O
%	O
)	O
.	O

Patients	O
were	O
managed	O
with	O
cyclosporine	B-Chemical
and	O
azathioprine	B-Chemical
.	O

No	O
prophylaxis	O
with	O
antilymphocyte	O
globulin	O
was	O
used	O
.	O

Steroids	B-Chemical
were	O
given	O
to	O
39	O
%	O
of	O
patients	O
for	O
refractory	O
rejection	O
,	O
but	O
weaning	O
was	O
always	O
attempted	O
and	O
generally	O
successful	O
(	O
64	O
%	O
)	O
.	O

Five	O
patients	O
(	O
14	O
%	O
)	O
received	O
maintenance	O
steroids	B-Chemical
.	O

Four	O
patients	O
died	O
in	O
the	O
perioperative	O
period	O
and	O
one	O
died	O
4	O
months	O
later	O
.	O

There	O
have	O
been	O
no	O
deaths	O
related	O
to	O
rejection	O
or	O
infection	B-Disease
.	O

Average	O
follow	O
-	O
up	O
was	O
36	O
+	O
/	O
-	O
19	O
months	O
(	O
range	O
1	O
to	O
65	O
months	O
)	O
.	O

Cumulative	O
survival	O
is	O
88	O
%	O
at	O
5	O
years	O
.	O

In	O
patients	O
less	O
than	O
7	O
years	O
of	O
age	O
,	O
rejection	O
was	O
monitored	O
noninvasively	O
.	O

In	O
the	O
first	O
postoperative	O
month	O
,	O
89	O
%	O
of	O
patients	O
were	O
treated	O
for	O
rejection	O
.	O

Freedom	O
from	O
serious	O
infections	B-Disease
was	O
83	O
%	O
at	O
1	O
month	O
and	O
65	O
%	O
at	O
1	O
year	O
.	O

Cytomegalovirus	B-Disease
infections	I-Disease
were	O
treated	O
successfully	O
with	O
ganciclovir	B-Chemical
in	O
11	O
patients	O
.	O

No	O
impairment	O
of	O
growth	O
was	O
observed	O
in	O
children	O
who	O
underwent	O
transplantation	O
compared	O
with	O
a	O
control	O
population	O
.	O

Twenty	O
-	O
one	O
patients	O
(	O
60	O
%	O
)	O
have	O
undergone	O
annual	O
catheterizations	O
and	O
no	O
sign	O
of	O
graft	O
atherosclerosis	B-Disease
has	O
been	O
observed	O
.	O

Seizures	B-Disease
occurred	O
in	O
five	O
patients	O
(	O
14	O
%	O
)	O
and	O
hypertension	B-Disease
was	O
treated	O
in	O
10	O
patients	O
(	O
28	O
%	O
)	O
.	O

No	O
patient	O
was	O
disabled	O
and	O
no	O
lymphoproliferative	B-Disease
disorder	I-Disease
was	O
observed	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Delirium	B-Disease
during	O
fluoxetine	B-Chemical
treatment	O
.	O

A	O
case	O
report	O
.	O

The	O
correlation	O
between	O
high	O
serum	O
tricyclic	O
antidepressant	O
concentrations	O
and	O
central	O
nervous	O
system	O
side	O
effects	O
has	O
been	O
well	O
established	O
.	O

Only	O
a	O
few	O
reports	O
exist	O
,	O
however	O
,	O
on	O
the	O
relationship	O
between	O
the	O
serum	O
concentrations	O
of	O
selective	O
serotonin	B-Chemical
reuptake	O
inhibitors	O
(	O
SSRIs	O
)	O
and	O
their	O
toxic	O
effects	O
.	O

In	O
some	O
cases	O
,	O
a	O
high	O
serum	O
concentration	O
of	O
citalopram	B-Chemical
(	O
>	O
600	O
nmol	O
/	O
L	O
)	O
in	O
elderly	O
patients	O
has	O
been	O
associated	O
with	O
increased	O
somnolence	B-Disease
and	O
movement	B-Disease
difficulties	I-Disease
.	O

Widespread	O
cognitive	B-Disease
disorders	I-Disease
,	O
such	O
as	O
delirium	B-Disease
,	O
have	O
not	O
been	O
previously	O
linked	O
with	O
high	O
blood	O
levels	O
of	O
SSRIs	O
.	O

In	O
this	O
report	O
,	O
we	O
describe	O
a	O
patient	O
with	O
acute	O
hyperkinetic	B-Disease
delirium	B-Disease
connected	O
with	O
a	O
high	O
serum	O
total	O
fluoxetine	B-Chemical
(	O
fluoxetine	B-Chemical
plus	O
desmethylfluoxetine	B-Chemical
)	O
concentration	O
.	O

Pulmonary	B-Disease
edema	I-Disease
and	O
shock	B-Disease
after	O
high	O
-	O
dose	O
aracytine	B-Chemical
-	I-Chemical
C	I-Chemical
for	O
lymphoma	B-Disease
;	O
possible	O
role	O
of	O
TNF	O
-	O
alpha	O
and	O
PAF	O
.	O

Four	O
out	O
of	O
23	O
consecutive	O
patients	O
treated	O
with	O
high	O
-	O
dose	O
Ara	B-Chemical
-	I-Chemical
C	I-Chemical
for	O
lymphomas	B-Disease
in	O
our	O
institution	O
developed	O
a	O
strikingly	O
similar	O
syndrome	O
during	O
the	O
perfusion	O
.	O

It	O
was	O
characterized	O
by	O
the	O
onset	O
of	O
fever	B-Disease
,	O
diarrhea	B-Disease
,	O
shock	B-Disease
,	O
pulmonary	B-Disease
edema	I-Disease
,	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
,	O
metabolic	B-Disease
acidosis	I-Disease
,	O
weight	B-Disease
gain	I-Disease
and	O
leukocytosis	B-Disease
.	O

Thorough	O
bacteriological	O
screening	O
failed	O
to	O
provide	O
evidence	O
of	O
infection	B-Disease
.	O

Sequential	O
biological	O
assays	O
of	O
IL	O
-	O
1	O
,	O
IL	O
-	O
2	O
,	O
TNF	O
and	O
PAF	O
were	O
performed	O
during	O
Ara	B-Chemical
-	I-Chemical
C	I-Chemical
infusion	O
to	O
ten	O
patients	O
,	O
including	O
the	O
four	O
who	O
developed	O
the	O
syndrome	O
.	O

TNF	O
and	O
PAF	O
activity	O
was	O
found	O
in	O
the	O
serum	O
of	O
respectively	O
two	O
and	O
four	O
of	O
the	O
cases	O
,	O
but	O
not	O
in	O
the	O
six	O
controls	O
.	O

As	O
TNF	O
and	O
PAF	O
are	O
thought	O
to	O
be	O
involved	O
in	O
the	O
development	O
of	O
septic	O
shock	B-Disease
and	O
adult	B-Disease
respiratory	I-Disease
distress	I-Disease
syndrome	I-Disease
,	O
we	O
hypothesize	O
that	O
high	O
-	O
dose	O
Ara	B-Chemical
-	I-Chemical
C	I-Chemical
may	O
be	O
associated	O
with	O
cytokine	O
release	O
.	O

Protective	O
effect	O
of	O
clentiazem	B-Chemical
against	O
epinephrine	B-Chemical
-	O
induced	O
cardiac	B-Disease
injury	I-Disease
in	O
rats	O
.	O

We	O
investigated	O
the	O
effects	O
of	O
clentiazem	B-Chemical
,	O
a	O
1	B-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
benzothiazepine	I-Chemical
calcium	B-Chemical
antagonist	O
,	O
on	O
epinephrine	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
in	O
rats	O
.	O

With	O
2	O
-	O
week	O
chronic	O
epinephrine	B-Chemical
infusion	O
,	O
16	O
of	O
30	O
rats	O
died	O
within	O
4	O
days	O
,	O
and	O
severe	O
ischemic	B-Disease
lesions	I-Disease
and	O
fibrosis	B-Disease
of	O
the	O
left	O
ventricles	O
were	O
observed	O
.	O

In	O
epinephrine	B-Chemical
-	O
treated	O
rats	O
,	O
left	O
atrial	O
and	O
left	O
ventricular	O
papillary	O
muscle	O
contractile	O
responses	O
to	O
isoproterenol	B-Chemical
were	O
reduced	O
,	O
but	O
responses	O
to	O
calcium	B-Chemical
were	O
normal	O
or	O
enhanced	O
compared	O
to	O
controls	O
.	O

Left	O
ventricular	O
alpha	O
and	O
beta	O
adrenoceptor	O
densities	O
were	O
also	O
reduced	O
compared	O
to	O
controls	O
.	O

Treatment	O
with	O
clentiazem	B-Chemical
prevented	O
epinephrine	B-Chemical
-	O
induced	O
death	O
(	O
P	O
<	O
.	O
05	O
)	O
,	O
and	O
attenuated	O
the	O
ventricular	O
ischemic	B-Disease
lesions	I-Disease
and	O
fibrosis	B-Disease
,	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

Left	O
atrial	O
and	O
left	O
ventricular	O
papillary	O
muscle	O
contractile	O
responses	O
to	O
isoproterenol	B-Chemical
were	O
reduced	O
compared	O
to	O
controls	O
in	O
groups	O
treated	O
with	O
clentiazem	B-Chemical
alone	O
,	O
but	O
combined	O
with	O
epinephrine	B-Chemical
,	O
clentiazem	B-Chemical
restored	O
left	O
atrial	O
responses	O
and	O
enhanced	O
left	O
ventricular	O
papillary	O
responses	O
to	O
isoproterenol	B-Chemical
.	O

On	O
the	O
other	O
hand	O
clentiazem	B-Chemical
did	O
not	O
prevent	O
epinephrine	B-Chemical
-	O
induced	O
down	O
-	O
regulation	O
of	O
alpha	O
and	O
beta	O
adrenoceptors	O
.	O

Interestingly	O
,	O
clentiazem	B-Chemical
,	O
infused	O
alone	O
,	O
resulted	O
in	O
decreased	O
adrenergic	O
receptor	O
densities	O
in	O
the	O
left	O
ventricle	O
.	O

Clentiazem	B-Chemical
also	O
did	O
not	O
prevent	O
the	O
enhanced	O
responses	O
to	O
calcium	B-Chemical
seen	O
in	O
the	O
epinephrine	B-Chemical
-	O
treated	O
animals	O
,	O
although	O
the	O
high	O
dose	O
of	O
clentiazem	B-Chemical
partially	O
attenuated	O
the	O
maximal	O
response	O
to	O
calcium	B-Chemical
compared	O
to	O
epinephrine	B-Chemical
-	O
treated	O
animals	O
.	O

In	O
conclusion	O
,	O
clentiazem	B-Chemical
attenuated	O
epinephrine	B-Chemical
-	O
induced	O
cardiac	B-Disease
injury	I-Disease
,	O
possibly	O
through	O
its	O
effect	O
on	O
the	O
adrenergic	O
pathway	O
.	O

Kaliuretic	O
effect	O
of	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
treatment	O
in	O
parkinsonian	B-Disease
patients	O
.	O

Hypokalemia	B-Disease
,	O
sometimes	O
severe	O
,	O
was	O
observed	O
in	O
some	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
-	O
treated	O
parkinsonian	B-Disease
patients	O
.	O

The	O
influence	O
of	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
on	O
the	O
renal	O
excretion	O
of	O
potassium	B-Chemical
was	O
studied	O
in	O
3	O
patients	O
with	O
hypokalemia	B-Disease
and	O
in	O
5	O
normokalemic	O
patients	O
by	O
determination	O
of	O
renal	O
plasma	O
flow	O
,	O
glomerular	O
filtration	O
rate	O
,	O
plasma	O
concentration	O
of	O
potassium	B-Chemical
and	O
sodium	B-Chemical
as	O
well	O
as	O
urinary	O
excretion	O
of	O
potassium	B-Chemical
,	O
sodium	B-Chemical
and	O
aldosterone	B-Chemical
.	O

L	B-Chemical
-	I-Chemical
Dopa	I-Chemical
intake	O
was	O
found	O
to	O
cause	O
an	O
increased	O
excretion	O
of	O
potassium	B-Chemical
,	O
and	O
sometimes	O
also	O
of	O
sodium	B-Chemical
,	O
in	O
the	O
hypokalemic	O
but	O
not	O
in	O
the	O
normokalemic	O
patients	O
.	O

This	O
effect	O
on	O
the	O
renal	O
function	O
could	O
be	O
prohibited	O
by	O
the	O
administration	O
of	O
a	O
peripheral	O
dopa	O
decarbodylase	O
inhibitor	O
.	O

It	O
is	O
not	O
known	O
why	O
this	O
effect	O
occurred	O
in	O
some	O
individuals	O
but	O
not	O
in	O
others	O
,	O
but	O
our	O
results	O
indicate	O
a	O
correlation	O
between	O
aldosterone	B-Chemical
production	O
and	O
this	O
renal	O
effect	O
of	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
.	O

Cocaine	B-Chemical
induced	O
myocardial	B-Disease
ischemia	I-Disease
.	O

We	O
report	O
a	O
case	O
of	O
myocardial	B-Disease
ischemia	I-Disease
induced	O
by	O
cocaine	B-Chemical
.	O

The	O
ischemia	B-Disease
probably	O
induced	O
by	O
coronary	B-Disease
artery	I-Disease
spasm	I-Disease
was	O
reversed	O
by	O
nitroglycerin	B-Chemical
and	O
calcium	B-Chemical
blocking	O
agents	O
.	O

Doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
monitored	O
by	O
ECG	O
in	O
freely	O
moving	O
mice	O
.	O

A	O
new	O
model	O
to	O
test	O
potential	O
protectors	O
.	O

In	O
laboratory	O
animals	O
,	O
histology	O
is	O
most	O
commonly	O
used	O
to	O
study	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

However	O
,	O
for	O
monitoring	O
during	O
treatment	O
,	O
large	O
numbers	O
of	O
animals	O
are	O
needed	O
.	O

Recently	O
we	O
developed	O
a	O
new	O
method	O
to	O
measure	O
ECG	O
values	O
in	O
freely	O
moving	O
mice	O
by	O
telemetry	O
.	O

With	O
this	O
model	O
we	O
investigated	O
the	O
effect	O
of	O
chronic	O
doxorubicin	B-Chemical
administration	O
on	O
the	O
ECG	O
of	O
freely	O
moving	O
BALB	O
/	O
c	O
mice	O
and	O
the	O
efficacy	O
of	O
ICRF	B-Chemical
-	I-Chemical
187	I-Chemical
as	O
a	O
protective	O
agent	O
.	O

The	O
ST	O
interval	O
significantly	O
widened	O
from	O
15	O
.	O
0	O
+	O
/	O
-	O
1	O
.	O
5	O
to	O
56	O
.	O
8	O
+	O
/	O
-	O
11	O
.	O
8	O
ms	O
in	O
week	O
10	O
(	O
7	O
weekly	O
doses	O
of	O
4	O
mg	O
/	O
kg	O
doxorubicin	B-Chemical
given	O
i	O
.	O
v	O
.	O
plus	O
3	O
weeks	O
of	O
observation	O
)	O
.	O

The	O
ECG	O
of	O
the	O
control	O
animals	O
did	O
not	O
change	O
during	O
the	O
entire	O
study	O
.	O

After	O
sacrifice	O
the	O
hearts	O
of	O
doxorubicin	B-Chemical
-	O
treated	O
animals	O
were	O
enlarged	O
and	O
the	O
atria	O
were	O
hypertrophic	B-Disease
.	O

As	O
this	O
schedule	O
exerted	O
more	O
toxicity	B-Disease
than	O
needed	O
to	O
investigate	O
protective	O
agents	O
,	O
the	O
protection	O
of	O
ICRF	B-Chemical
-	I-Chemical
187	I-Chemical
was	O
determined	O
using	O
a	O
dose	O
schedule	O
with	O
lower	O
general	O
toxicity	B-Disease
(	O
6	O
weekly	O
doses	O
of	O
4	O
mg	O
/	O
kg	O
doxorubicin	B-Chemical
given	O
i	O
.	O
v	O
.	O
plus	O
2	O
weeks	O
of	O
observation	O
)	O
.	O

On	O
this	O
schedule	O
,	O
the	O
animals	O
'	O
hearts	O
appeared	O
normal	O
after	O
sacrifice	O
and	O
ICRF	B-Chemical
-	I-Chemical
187	I-Chemical
(	O
50	O
mg	O
/	O
kg	O
given	O
i	O
.	O
p	O
.	O
1	O
h	O
before	O
doxorubicin	B-Chemical
)	O
provided	O
almost	O
full	O
protection	O
.	O

These	O
data	O
were	O
confirmed	O
by	O
histology	O
.	O

The	O
results	O
indicate	O
that	O
this	O
new	O
model	O
is	O
very	O
sensitive	O
and	O
enables	O
monitoring	O
of	O
the	O
development	O
of	O
cardiotoxicity	B-Disease
with	O
time	O
.	O

These	O
findings	O
result	O
in	O
a	O
model	O
that	O
allows	O
the	O
testing	O
of	O
protectors	O
against	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
as	O
demonstrated	O
by	O
the	O
protection	O
provided	O
by	O
ICRF	B-Chemical
-	I-Chemical
187	I-Chemical
.	O

Epinephrine	B-Chemical
dysrhythmogenicity	O
is	O
not	O
enhanced	O
by	O
subtoxic	O
bupivacaine	B-Chemical
in	O
dogs	O
.	O

Since	O
bupivacaine	B-Chemical
and	O
epinephrine	B-Chemical
may	O
both	O
precipitate	O
dysrhythmias	B-Disease
,	O
circulating	O
bupivacaine	B-Chemical
during	O
regional	O
anesthesia	O
could	O
potentiate	O
dysrhythmogenic	O
effects	O
of	O
epinephrine	B-Chemical
.	O

We	O
therefore	O
examined	O
whether	O
bupivacaine	B-Chemical
alters	O
the	O
dysrhythmogenicity	O
of	O
subsequent	O
administration	O
of	O
epinephrine	B-Chemical
in	O
conscious	O
,	O
healthy	O
dogs	O
and	O
in	O
anesthetized	O
dogs	O
with	O
myocardial	B-Disease
infarction	I-Disease
.	O

Forty	O
-	O
one	O
conscious	O
dogs	O
received	O
10	O
micrograms	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
epinephrine	B-Chemical
.	O

Seventeen	O
animals	O
responded	O
with	O
ventricular	B-Disease
tachycardia	I-Disease
(	O
VT	B-Disease
)	O
within	O
3	O
min	O
.	O

After	O
3	O
h	O
,	O
these	O
responders	O
randomly	O
received	O
1	O
or	O
2	O
mg	O
/	O
kg	O
bupivacaine	B-Chemical
or	O
saline	O
over	O
5	O
min	O
,	O
followed	O
by	O
10	O
micrograms	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
epinephrine	B-Chemical
.	O

In	O
the	O
bupivacaine	B-Chemical
groups	O
,	O
epinephrine	B-Chemical
caused	O
fewer	O
prodysrhythmic	O
effects	O
than	O
without	O
bupivacaine	B-Chemical
.	O

VT	B-Disease
appeared	O
in	O
fewer	O
dogs	O
and	O
at	O
a	O
later	O
time	O
,	O
and	O
there	O
were	O
more	O
sinoatrial	O
beats	O
and	O
less	O
ectopies	O
.	O

Epinephrine	B-Chemical
shortened	O
QT	O
less	O
after	O
bupivacaine	B-Chemical
than	O
in	O
control	O
animals	O
.	O

One	O
day	O
after	O
experimental	O
myocardial	B-Disease
infarction	I-Disease
,	O
six	O
additional	O
halothane	B-Chemical
-	O
anesthetized	O
dogs	O
received	O
4	O
micrograms	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
epinephrine	B-Chemical
until	O
VT	B-Disease
appeared	O
.	O

After	O
45	O
min	O
,	O
1	O
mg	O
/	O
kg	O
bupivacaine	B-Chemical
was	O
injected	O
over	O
5	O
min	O
,	O
again	O
followed	O
by	O
4	O
micrograms	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
epinephrine	B-Chemical
.	O

In	O
these	O
dogs	O
,	O
the	O
prodysrhythmic	O
response	O
to	O
epinephrine	B-Chemical
was	O
also	O
mitigated	O
by	O
preceding	O
bupivacaine	B-Chemical
.	O

Bupivacaine	B-Chemical
antagonizes	O
epinephrine	B-Chemical
dysrhythmogenicity	O
in	O
conscious	O
dogs	O
susceptible	O
to	O
VT	B-Disease
and	O
in	O
anesthetized	O
dogs	O
with	O
spontaneous	O
postinfarct	O
dysrhythmias	B-Disease
.	O

There	O
is	O
no	O
evidence	O
that	O
systemic	O
subtoxic	O
bupivacaine	B-Chemical
administration	O
enhances	O
the	O
dysrhythmogenicity	O
of	O
subsequent	O
epinephrine	B-Chemical
.	O

Milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
induced	O
by	O
1	B-Chemical
,	I-Chemical
25	I-Chemical
(	I-Chemical
OH	I-Chemical
)	I-Chemical
2D	I-Chemical
in	O
a	O
patient	O
with	O
hypoparathyroidism	B-Disease
.	O

Milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
was	O
first	O
described	O
70	O
years	O
ago	O
in	O
the	O
context	O
of	O
the	O
treatment	O
of	O
peptic	B-Disease
ulcer	I-Disease
disease	I-Disease
with	O
large	O
amounts	O
of	O
calcium	B-Chemical
and	O
alkali	B-Chemical
.	O

Although	O
with	O
current	O
ulcer	B-Disease
therapy	O
(	O
H	O
-	O
2	O
blockers	O
,	O
omeprazole	B-Chemical
,	O
and	O
sucralfate	B-Chemical
)	O
,	O
the	O
frequency	O
of	O
milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
has	O
decreased	O
significantly	O
,	O
the	O
classic	O
triad	O
of	O
hypercalcemia	B-Disease
,	O
alkalosis	B-Disease
,	O
and	O
renal	B-Disease
impairment	I-Disease
remains	O
the	O
hallmark	O
of	O
the	O
syndrome	O
.	O

Milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
can	O
present	O
serious	O
and	O
occasionally	O
life	O
-	O
threatening	O
illness	O
unless	O
diagnosed	O
and	O
treated	O
appropriately	O
.	O

This	O
article	O
presents	O
a	O
patient	O
with	O
hypoparathyroidism	B-Disease
who	O
was	O
treated	O
with	O
calcium	B-Chemical
carbonate	I-Chemical
and	O
calcitriol	B-Chemical
resulting	O
in	O
two	O
admissions	O
to	O
the	O
hospital	O
for	O
milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
.	O

The	O
patient	O
was	O
successfully	O
treated	O
with	O
intravenous	O
pamidronate	B-Chemical
on	O
his	O
first	O
admission	O
and	O
with	O
hydrocortisone	B-Chemical
on	O
the	O
second	O
.	O

This	O
illustrates	O
intravenous	O
pamidronate	B-Chemical
as	O
a	O
valuable	O
therapeutic	O
tool	O
when	O
milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
presents	O
as	O
hypercalcemic	B-Disease
emergency	I-Disease
.	O

Famotidine	B-Chemical
-	O
associated	O
delirium	B-Disease
.	O

A	O
series	O
of	O
six	O
cases	O
.	O

Famotidine	B-Chemical
is	O
a	O
histamine	O
H2	O
-	O
receptor	O
antagonist	O
used	O
in	O
inpatient	O
settings	O
for	O
prevention	O
of	O
stress	O
ulcers	B-Disease
and	O
is	O
showing	O
increasing	O
popularity	O
because	O
of	O
its	O
low	O
cost	O
.	O

Although	O
all	O
of	O
the	O
currently	O
available	O
H2	O
-	O
receptor	O
antagonists	O
have	O
shown	O
the	O
propensity	O
to	O
cause	O
delirium	B-Disease
,	O
only	O
two	O
previously	O
reported	O
cases	O
have	O
been	O
associated	O
with	O
famotidine	B-Chemical
.	O

The	O
authors	O
report	O
on	O
six	O
cases	O
of	O
famotidine	B-Chemical
-	O
associated	O
delirium	B-Disease
in	O
hospitalized	O
patients	O
who	O
cleared	O
completely	O
upon	O
removal	O
of	O
famotidine	B-Chemical
.	O

The	O
pharmacokinetics	O
of	O
famotidine	B-Chemical
are	O
reviewed	O
,	O
with	O
no	O
change	O
in	O
its	O
metabolism	O
in	O
the	O
elderly	O
population	O
seen	O
.	O

The	O
implications	O
of	O
using	O
famotidine	B-Chemical
in	O
elderly	O
persons	O
are	O
discussed	O
.	O

Encephalopathy	B-Disease
during	O
amitriptyline	B-Chemical
therapy	O
:	O
are	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
and	O
serotonin	B-Disease
syndrome	I-Disease
spectrum	O
disorders	O
?	O

This	O
report	O
describes	O
a	O
case	O
of	O
encephalopathy	B-Disease
developed	O
in	O
the	O
course	O
of	O
amitriptyline	B-Chemical
therapy	O
,	O
during	O
a	O
remission	O
of	O
unipolar	B-Disease
depression	I-Disease
.	O

This	O
patient	O
could	O
have	O
been	O
diagnosed	O
as	O
having	O
either	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
(	O
NMS	B-Disease
)	O
or	O
serotonin	B-Disease
syndrome	I-Disease
(	O
SS	B-Disease
)	O
.	O

The	O
major	O
determinant	O
of	O
the	O
symptoms	O
may	O
have	O
been	O
dopamine	B-Chemical
/	O
serotonin	B-Chemical
imbalance	O
in	O
the	O
central	O
nervous	O
system	O
.	O

The	O
NMS	B-Disease
-	O
like	O
encephalopathy	B-Disease
that	O
develops	O
in	O
association	O
with	O
the	O
use	O
of	O
antidepressants	O
indicates	O
that	O
NMS	B-Disease
and	O
SS	B-Disease
are	O
spectrum	O
disorders	O
induced	O
by	O
drugs	O
with	O
both	O
antidopaminergic	O
and	O
serotonergic	O
effects	O
.	O

Genetic	O
separation	O
of	O
tumor	B-Disease
growth	O
and	O
hemorrhagic	B-Disease
phenotypes	O
in	O
an	O
estrogen	B-Chemical
-	O
induced	O
tumor	B-Disease
.	O

Chronic	O
administration	O
of	O
estrogen	B-Chemical
to	O
the	O
Fischer	O
344	O
(	O
F344	O
)	O
rat	O
induces	O
growth	O
of	O
large	O
,	O
hemorrhagic	B-Disease
pituitary	B-Disease
tumors	I-Disease
.	O

Ten	O
weeks	O
of	O
diethylstilbestrol	B-Chemical
(	O
DES	B-Chemical
)	O
treatment	O
caused	O
female	O
F344	O
rat	O
pituitaries	O
to	O
grow	O
to	O
an	O
average	O
of	O
109	O
.	O
2	O
+	O
/	O
-	O
6	O
.	O
3	O
mg	O
(	O
mean	O
+	O
/	O
-	O
SE	O
)	O
versus	O
11	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
4	O
mg	O
for	O
untreated	O
rats	O
,	O
and	O
to	O
become	O
highly	O
hemorrhagic	B-Disease
.	O

The	O
same	O
DES	B-Chemical
treatment	O
produced	O
no	O
significant	O
growth	O
(	O
8	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
5	O
mg	O
for	O
treated	O
females	O
versus	O
8	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
1	O
for	O
untreated	O
females	O
)	O
or	O
morphological	O
changes	O
in	O
Brown	O
Norway	O
(	O
BN	O
)	O
rat	O
pituitaries	O
.	O

An	O
F1	O
hybrid	O
of	O
F344	O
and	O
BN	O
exhibited	O
significant	O
pituitary	O
growth	O
after	O
10	O
weeks	O
of	O
DES	B-Chemical
treatment	O
with	O
an	O
average	O
mass	O
of	O
26	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
7	O
mg	O
compared	O
with	O
8	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
9	O
mg	O
for	O
untreated	O
rats	O
.	O

Surprisingly	O
,	O
the	O
F1	O
hybrid	O
tumors	B-Disease
were	O
not	O
hemorrhagic	B-Disease
and	O
had	O
hemoglobin	O
content	O
and	O
outward	O
appearance	O
identical	O
to	O
that	O
of	O
BN	O
.	O

Expression	O
of	O
both	O
growth	O
and	O
morphological	O
changes	O
is	O
due	O
to	O
multiple	O
genes	O
.	O

However	O
,	O
while	O
DES	B-Chemical
-	O
induced	O
pituitary	O
growth	O
exhibited	O
quantitative	O
,	O
additive	O
inheritance	O
,	O
the	O
hemorrhagic	B-Disease
phenotype	O
exhibited	O
recessive	O
,	O
epistatic	O
inheritance	O
.	O

Only	O
5	O
of	O
the	O
160	O
F2	O
pituitaries	O
exhibited	O
the	O
hemorrhagic	B-Disease
phenotype	O
;	O
36	O
of	O
the	O
160	O
F2	O
pituitaries	O
were	O
in	O
the	O
F344	O
range	O
of	O
mass	O
,	O
but	O
31	O
of	O
these	O
were	O
not	O
hemorrhagic	B-Disease
,	O
indicating	O
that	O
the	O
hemorrhagic	B-Disease
phenotype	O
is	O
not	O
merely	O
a	O
consequence	O
of	O
extensive	O
growth	O
.	O

The	O
hemorrhagic	B-Disease
F2	O
pituitaries	O
were	O
all	O
among	O
the	O
most	O
massive	O
,	O
indicating	O
that	O
some	O
of	O
the	O
genes	O
regulate	O
both	O
phenotypes	O
.	O

Increased	O
expression	O
of	O
neuronal	O
nitric	B-Chemical
oxide	I-Chemical
synthase	O
in	O
bladder	O
afferent	O
pathways	O
following	O
chronic	O
bladder	B-Disease
irritation	I-Disease
.	O

Immunocytochemical	O
techniques	O
were	O
used	O
to	O
examine	O
alterations	O
in	O
the	O
expression	O
of	O
neuronal	O
nitric	B-Chemical
oxide	I-Chemical
synthase	O
(	O
NOS	O
)	O
in	O
bladder	O
pathways	O
following	O
acute	O
and	O
chronic	O
irritation	B-Disease
of	I-Disease
the	I-Disease
urinary	I-Disease
tract	I-Disease
of	O
the	O
rat	O
.	O

Chemical	O
cystitis	B-Disease
was	O
induced	O
by	O
cyclophosphamide	B-Chemical
(	O
CYP	B-Chemical
)	O
which	O
is	O
metabolized	O
to	O
acrolein	B-Chemical
,	O
an	O
irritant	O
eliminated	O
in	O
the	O
urine	O
.	O

Injection	O
of	O
CYP	B-Chemical
(	O
n	O
=	O
10	O
,	O
75	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
2	O
hours	O
prior	O
to	O
perfusion	O
(	O
acute	O
treatment	O
)	O
of	O
the	O
animals	O
increased	O
Fos	O
-	O
immunoreactivity	O
(	O
IR	O
)	O
in	O
neurons	O
in	O
the	O
dorsal	O
commissure	O
,	O
dorsal	O
horn	O
,	O
and	O
autonomic	O
regions	O
of	O
spinal	O
segments	O
(	O
L1	O
-	O
L2	O
and	O
L6	O
-	O
S1	O
)	O
which	O
receive	O
afferent	O
inputs	O
from	O
the	O
bladder	O
,	O
urethra	O
,	O
and	O
ureter	O
.	O

Fos	O
-	O
IR	O
in	O
the	O
spinal	O
cord	O
was	O
not	O
changed	O
in	O
rats	O
receiving	O
chronic	O
CYP	B-Chemical
treatment	O
(	O
n	O
=	O
15	O
,	O
75	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
,	O
every	O
3rd	O
day	O
for	O
2	O
weeks	O
)	O
.	O

In	O
control	O
animals	O
and	O
in	O
animals	O
treated	O
acutely	O
with	O
CYP	B-Chemical
,	O
only	O
small	O
numbers	O
of	O
NOS	O
-	O
IR	O
cells	O
(	O
0	O
.	O
5	O
-	O
0	O
.	O
7	O
cell	O
profiles	O
/	O
sections	O
)	O
were	O
detected	O
in	O
the	O
L6	O
-	O
S1	O
dorsal	O
root	O
ganglia	O
(	O
DRG	O
)	O
.	O

Chronic	O
CYP	B-Chemical
administration	O
significantly	O
(	O
P	O
<	O
or	O
=	O
.	O
002	O
)	O
increased	O
bladder	O
weight	O
by	O
60	O
%	O
and	O
increased	O
(	O
7	O
-	O
to	O
11	O
-	O
fold	O
)	O
the	O
numbers	O
of	O
NOS	O
-	O
immunoreactive	O
(	O
IR	O
)	O
afferent	O
neurons	O
in	O
the	O
L6	O
-	O
S1	O
DRG	O
.	O

A	O
small	O
increase	O
(	O
1	O
.	O
5	O
-	O
fold	O
)	O
also	O
occurred	O
in	O
the	O
L1	O
DRG	O
,	O
but	O
no	O
change	O
was	O
detected	O
in	O
the	O
L2	O
and	O
L5	O
DRG	O
.	O

Bladder	O
afferent	O
cells	O
in	O
the	O
L6	O
-	O
S1	O
DRG	O
labeled	O
by	O
Fluorogold	O
(	O
40	O
microliters	O
)	O
injected	O
into	O
the	O
bladder	O
wall	O
did	O
not	O
exhibit	O
NOS	O
-	O
IR	O
in	O
control	O
animals	O
;	O
however	O
,	O
following	O
chronic	O
CYP	B-Chemical
administration	O
,	O
a	O
significant	O
percentage	O
of	O
bladder	O
afferent	O
neurons	O
were	O
NOS	O
-	O
IR	O
:	O
L6	O
(	O
19	O
.	O
8	O
+	O
/	O
-	O
4	O
.	O
6	O
%	O
)	O
and	O
S1	O
(	O
25	O
.	O
3	O
+	O
/	O
-	O
2	O
.	O
9	O
%	O
)	O
.	O

These	O
results	O
indicate	O
that	O
neuronal	O
gene	O
expression	O
in	O
visceral	O
sensory	O
pathways	O
can	O
be	O
upregulated	O
by	O
chemical	O
irritation	O
of	O
afferent	O
receptors	O
in	O
the	O
urinary	O
tract	O
and	O
/	O
or	O
that	O
pathological	O
changes	O
in	O
the	O
urinary	O
tract	O
can	O
initiate	O
chemical	O
signals	O
that	O
alter	O
the	O
chemical	O
properties	O
of	O
visceral	O
afferent	O
neurons	O
.	O

Effects	O
of	O
a	O
new	O
calcium	B-Chemical
antagonist	O
,	O
CD	B-Chemical
-	I-Chemical
832	I-Chemical
,	O
on	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
in	O
dogs	O
with	O
partial	O
coronary	B-Disease
stenosis	I-Disease
.	O

Effects	O
of	O
CD	B-Chemical
-	I-Chemical
832	I-Chemical
on	O
isoproterenol	B-Chemical
(	O
ISO	B-Chemical
)	O
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
were	O
studied	O
in	O
dogs	O
with	O
partial	O
coronary	B-Disease
stenosis	I-Disease
of	O
the	O
left	O
circumflex	O
coronary	O
artery	O
and	O
findings	O
were	O
compared	O
with	O
those	O
for	O
nifedipine	B-Chemical
or	O
diltiazem	B-Chemical
.	O

In	O
the	O
presence	O
of	O
coronary	B-Disease
artery	I-Disease
stenosis	I-Disease
,	O
3	O
-	O
min	O
periods	O
of	O
intracoronary	O
ISO	B-Chemical
infusion	O
(	O
10	O
ng	O
/	O
kg	O
/	O
min	O
)	O
increased	O
heart	O
rate	O
and	O
maximal	O
rate	O
of	O
left	O
ventricular	O
pressure	O
rise	O
,	O
which	O
resulted	O
in	O
a	O
decrease	O
in	O
percentage	O
segmental	O
shortening	O
and	O
ST	O
-	O
segment	O
elevation	O
of	O
the	O
epicardial	O
electrocardiogram	O
.	O

After	O
the	O
control	O
ISO	B-Chemical
infusion	O
with	O
stenosis	B-Disease
was	O
performed	O
,	O
equihypotensive	O
doses	O
of	O
CD	B-Chemical
-	I-Chemical
832	I-Chemical
(	O
3	O
and	O
10	O
micrograms	O
/	O
kg	O
/	O
min	O
,	O
n	O
=	O
7	O
)	O
,	O
nifedipine	B-Chemical
(	O
1	O
and	O
3	O
micrograms	O
/	O
kg	O
/	O
min	O
,	O
n	O
=	O
9	O
)	O
or	O
diltiazem	B-Chemical
(	O
10	O
and	O
30	O
micrograms	O
/	O
kg	O
/	O
min	O
,	O
n	O
=	O
7	O
)	O
were	O
infused	O
5	O
min	O
before	O
and	O
during	O
the	O
second	O
and	O
third	O
ISO	B-Chemical
infusion	O
.	O

Both	O
CD	B-Chemical
-	I-Chemical
832	I-Chemical
and	O
diltiazem	B-Chemical
,	O
but	O
not	O
nifedipine	B-Chemical
,	O
significantly	O
reduced	O
the	O
increase	O
in	O
heart	O
rate	O
induced	O
by	O
ISO	B-Chemical
infusion	O
.	O

In	O
contrast	O
to	O
nifedipine	B-Chemical
,	O
CD	B-Chemical
-	I-Chemical
832	I-Chemical
(	O
10	O
micrograms	O
/	O
kg	O
/	O
min	O
)	O
prevented	O
the	O
decrease	O
in	O
percentage	O
segmental	O
shortening	O
from	O
32	O
+	O
/	O
-	O
12	O
%	O
to	O
115	O
+	O
/	O
-	O
26	O
%	O
of	O
the	O
control	O
value	O
(	O
P	O
<	O
.	O
01	O
)	O
and	O
ST	O
-	O
segment	O
elevation	O
from	O
5	O
.	O
6	O
+	O
/	O
-	O
1	O
.	O
0	O
mV	O
to	O
1	O
.	O
6	O
+	O
/	O
-	O
1	O
.	O
3	O
mV	O
(	O
P	O
<	O
.	O
01	O
)	O
at	O
3	O
min	O
after	O
ISO	B-Chemical
infusion	O
with	O
stenosis	B-Disease
.	O

Diltiazem	B-Chemical
(	O
30	O
micrograms	O
/	O
kg	O
/	O
min	O
)	O
also	O
prevented	O
the	O
decrease	O
in	O
percentage	O
segmental	O
shortening	O
from	O
34	O
+	O
/	O
-	O
14	O
%	O
to	O
63	O
+	O
/	O
-	O
18	O
%	O
of	O
the	O
control	O
value	O
(	O
P	O
<	O
.	O
05	O
)	O
and	O
ST	O
-	O
segment	O
elevation	O
from	O
4	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
7	O
mV	O
to	O
2	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
7	O
mV	O
(	O
P	O
<	O
.	O
01	O
)	O
at	O
3	O
min	O
after	O
ISO	B-Chemical
infusion	O
with	O
stenosis	B-Disease
.	O

These	O
data	O
show	O
that	O
CD	B-Chemical
-	I-Chemical
832	I-Chemical
improves	O
myocardial	B-Disease
ischemia	I-Disease
during	O
ISO	B-Chemical
infusion	O
with	O
stenosis	B-Disease
and	O
suggest	O
that	O
the	O
negative	O
chronotropic	O
property	O
of	O
CD	B-Chemical
-	I-Chemical
832	I-Chemical
plays	O
a	O
major	O
role	O
in	O
the	O
beneficial	O
effects	O
of	O
CD	B-Chemical
-	I-Chemical
832	I-Chemical
.	O

The	O
effect	O
of	O
recombinant	O
human	O
insulin	O
-	O
like	O
growth	O
factor	O
-	O
I	O
on	O
chronic	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
nephropathy	B-Disease
in	O
rats	O
.	O

We	O
recently	O
demonstrated	O
that	O
recombinant	O
hGH	O
exacerbates	O
renal	O
functional	O
and	O
structural	O
injury	O
in	O
chronic	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
)	O
nephropathy	B-Disease
,	O
an	O
experimental	O
model	O
of	O
glomerular	B-Disease
disease	I-Disease
.	O

Therefore	O
,	O
we	O
examined	O
whether	O
recombinant	O
human	O
(	O
rh	O
)	O
IGF	O
-	O
I	O
is	O
a	O
safer	O
alternative	O
for	O
the	O
treatment	O
of	O
growth	B-Disease
failure	I-Disease
in	O
rats	O
with	O
chronic	O
PAN	B-Chemical
nephropathy	B-Disease
.	O

The	O
glomerulopathy	B-Disease
was	O
induced	O
by	O
seven	O
serial	O
injections	O
of	O
PAN	B-Chemical
over	O
12	O
wk	O
.	O

Experimental	O
animals	O
(	O
n	O
=	O
6	O
)	O
received	O
rhIGF	O
-	O
I	O
,	O
400	O
micrograms	O
/	O
d	O
,	O
whereas	O
control	O
rats	O
(	O
n	O
=	O
6	O
)	O
received	O
the	O
vehicle	O
.	O

rhIGF	O
-	O
I	O
improved	O
weight	O
gain	O
by	O
14	O
%	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
without	O
altering	O
hematocrit	O
or	O
blood	O
pressure	O
in	O
rats	O
with	O
renal	B-Disease
disease	I-Disease
.	O

Urinary	O
protein	O
excretion	O
was	O
unaltered	O
by	O
rhIGF	O
-	O
I	O
treatment	O
in	O
rats	O
with	O
chronic	O
PAN	B-Chemical
nephropathy	B-Disease
.	O

After	O
12	O
wk	O
,	O
the	O
inulin	O
clearance	O
was	O
higher	O
in	O
rhIGF	O
-	O
I	O
-	O
treated	O
rats	O
,	O
0	O
.	O
48	O
+	O
/	O
-	O
0	O
.	O
08	O
versus	O
0	O
.	O
24	O
+	O
/	O
-	O
0	O
.	O
06	O
mL	O
/	O
min	O
/	O
100	O
g	O
of	O
body	O
weight	O
in	O
untreated	O
PAN	B-Chemical
nephropathy	B-Disease
animals	O
,	O
p	O
<	O
0	O
.	O
05	O
.	O

The	O
improvement	O
in	O
GFR	O
was	O
not	O
associated	O
with	O
enhanced	O
glomerular	B-Disease
hypertrophy	I-Disease
or	O
increased	O
segmental	O
glomerulosclerosis	B-Disease
,	O
tubulointerstitial	B-Disease
injury	I-Disease
,	O
or	O
renal	O
cortical	O
malondialdehyde	B-Chemical
content	O
.	O

In	O
rats	O
with	O
PAN	B-Chemical
nephropathy	B-Disease
,	O
administration	O
of	O
rhIGF	O
-	O
I	O
increased	O
IGF	O
-	O
I	O
and	O
GH	O
receptor	O
gene	O
expression	O
,	O
without	O
altering	O
the	O
steady	O
state	O
level	O
of	O
IGF	O
-	O
I	O
receptor	O
mRNA	O
.	O

In	O
normal	O
rats	O
with	O
intact	O
kidneys	O
,	O
rhIGF	O
-	O
I	O
administration	O
(	O
n	O
=	O
4	O
)	O
did	O
not	O
alter	O
weight	O
gain	O
,	O
blood	O
pressure	O
,	O
proteinuria	B-Disease
,	O
GFR	O
,	O
glomerular	O
planar	O
area	O
,	O
renal	O
cortical	O
malondialdehyde	B-Chemical
content	O
,	O
or	O
glomerular	O
or	O
tubulointerstitial	B-Disease
damage	I-Disease
,	O
compared	O
with	O
untreated	O
animals	O
(	O
n	O
=	O
4	O
)	O
.	O

rhIGF	O
-	O
I	O
treatment	O
reduced	O
the	O
steady	O
state	O
renal	O
IGF	O
-	O
I	O
mRNA	O
level	O
but	O
did	O
not	O
modify	O
gene	O
expression	O
of	O
the	O
IGF	O
-	O
I	O
or	O
GH	O
receptors	O
.	O

We	O
conclude	O
that	O
:	O
1	O
)	O
administration	O
of	O
rhIGF	O
-	O
I	O
improves	O
growth	O
and	O
GFR	O
in	O
rats	O
with	O
chronic	O
PAN	B-Chemical
nephropathy	B-Disease
and	O
2	O
)	O
unlike	O
rhGH	O
,	O
long	O
-	O
term	O
use	O
of	O
rhIGF	O
-	O
I	O
does	O
not	O
worsen	O
renal	O
functional	O
and	O
structural	O
injury	O
in	O
this	O
disease	O
model	O
.	O

Nefiracetam	B-Chemical
(	O
DM	B-Chemical
-	I-Chemical
9384	I-Chemical
)	O
reverses	O
apomorphine	B-Chemical
-	O
induced	O
amnesia	B-Disease
of	O
a	O
passive	O
avoidance	O
response	O
:	O
delayed	O
emergence	O
of	O
the	O
memory	O
retention	O
effects	O
.	O

Nefiracetam	B-Chemical
is	O
a	O
novel	O
pyrrolidone	B-Chemical
derivative	O
which	O
attenuates	O
scopolamine	B-Chemical
-	O
induced	O
learning	B-Disease
and	I-Disease
post	I-Disease
-	I-Disease
training	I-Disease
consolidation	I-Disease
deficits	I-Disease
.	O

Given	O
that	O
apomorphine	B-Chemical
inhibits	O
passive	O
avoidance	O
retention	O
when	O
given	O
during	O
training	O
or	O
in	O
a	O
defined	O
10	O
-	O
12h	O
post	O
-	O
training	O
period	O
,	O
we	O
evaluated	O
the	O
ability	O
of	O
nefiracetam	B-Chemical
to	O
attenuate	O
amnesia	B-Disease
induced	O
by	O
dopaminergic	O
agonism	O
.	O

A	O
step	O
-	O
down	O
passive	O
avoidance	O
paradigm	O
was	O
employed	O
and	O
nefiracetam	B-Chemical
(	O
3	O
mg	O
/	O
kg	O
)	O
and	O
apomorphine	B-Chemical
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
)	O
were	O
given	O
alone	O
or	O
in	O
combination	O
during	O
training	O
and	O
at	O
the	O
10	O
-	O
12h	O
post	O
-	O
training	O
period	O
of	O
consolidation	O
.	O

Co	O
-	O
administration	O
of	O
nefiracetam	B-Chemical
and	O
apomorphine	B-Chemical
during	O
training	O
or	O
10h	O
thereafter	O
produced	O
no	O
significant	O
anti	O
-	O
amnesic	O
effect	O
.	O

However	O
,	O
administration	O
of	O
nefiracetam	B-Chemical
during	O
training	O
completely	O
reversed	O
the	O
amnesia	B-Disease
induced	O
by	O
apomorphine	B-Chemical
at	O
the	O
10h	O
post	O
-	O
training	O
time	O
and	O
the	O
converse	O
was	O
also	O
true	O
.	O

These	O
effects	O
were	O
not	O
mediated	O
by	O
a	O
dopaminergic	O
mechanism	O
as	O
nefiracetam	B-Chemical
,	O
at	O
millimolar	O
concentrations	O
,	O
failed	O
to	O
displace	O
either	O
[	O
3H	O
]	O
SCH	B-Chemical
23390	I-Chemical
or	O
[	O
3H	O
]	O
spiperone	B-Chemical
binding	O
from	O
D1	O
or	O
D2	O
dopamine	B-Chemical
receptor	O
subtypes	O
,	O
respectively	O
.	O

It	O
is	O
suggested	O
that	O
nefiracetam	B-Chemical
augments	O
molecular	O
processes	O
in	O
the	O
early	O
stages	O
of	O
events	O
which	O
ultimately	O
lead	O
to	O
consolidation	O
of	O
memory	O
.	O

Phenytoin	B-Chemical
encephalopathy	B-Disease
as	O
probable	O
idiosyncratic	O
reaction	O
:	O
case	O
report	O
.	O

A	O
case	O
of	O
phenytoin	B-Chemical
(	O
DPH	B-Chemical
)	O
encephalopathy	B-Disease
with	O
increasing	O
seizures	B-Disease
and	O
EEG	O
and	O
mental	O
changes	O
is	O
described	O
.	O

Despite	O
adequate	O
oral	O
dosage	O
of	O
DPH	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
/	O
daily	O
)	O
the	O
plasma	O
level	O
was	O
very	O
low	O
(	O
2	O
.	O
8	O
microgramg	O
/	O
ml	O
)	O
.	O

The	O
encephalopathy	B-Disease
was	O
probably	O
an	O
idiosyncratic	O
and	O
not	O
toxic	O
or	O
allergic	O
reaction	O
.	O

In	O
fact	O
the	O
concentration	O
of	O
free	O
DPH	B-Chemical
was	O
normal	O
,	O
the	O
patient	O
presented	O
a	O
retarded	O
morbilliform	O
rash	B-Disease
during	O
DPH	B-Chemical
treatment	O
,	O
the	O
protidogram	O
was	O
normal	O
,	O
and	O
an	O
intradermic	O
DPH	B-Chemical
injection	O
had	O
no	O
local	O
effect	O
.	O

The	O
authors	O
conclude	O
that	O
in	O
a	O
patient	O
starting	O
DPH	B-Chemical
treatment	O
an	O
unexpected	O
increase	O
in	O
seizures	B-Disease
,	O
with	O
EEG	O
and	O
mental	O
changes	O
occurring	O
simultaneously	O
,	O
should	O
alert	O
the	O
physician	O
to	O
the	O
possible	O
need	O
for	O
eliminating	O
DPH	B-Chemical
from	O
the	O
therapeutic	O
regimen	O
,	O
even	O
if	O
plasma	O
concentrations	O
are	O
low	O
.	O

Prevention	O
and	O
treatment	O
of	O
endometrial	B-Disease
disease	I-Disease
in	O
climacteric	O
women	O
receiving	O
oestrogen	B-Chemical
therapy	O
.	O

The	O
treatment	O
regimens	O
are	O
described	O
in	O
74	O
patients	O
with	O
endometrial	B-Disease
disease	I-Disease
among	O
850	O
climacteric	O
women	O
receiving	O
oestrogen	B-Chemical
therapy	O
.	O

Cystic	O
hyperplasia	B-Disease
was	O
associated	O
with	O
unopposed	O
oestrogen	B-Chemical
therapy	O
without	O
progestagen	B-Chemical
.	O

Two	O
courses	O
of	O
21	O
days	O
of	O
5	O
mg	O
norethisterone	B-Chemical
daily	O
caused	O
reversion	O
to	O
normal	O
in	O
all	O
57	O
cases	O
of	O
cystic	O
hyperplasia	B-Disease
and	O
6	O
of	O
the	O
8	O
cases	O
of	O
atypical	O
hyperplasia	B-Disease
.	O

4	O
cases	O
of	O
endometrial	B-Disease
carcinoma	I-Disease
referred	O
from	O
elsewhere	O
demonstrated	O
the	O
problems	O
of	O
inappropriate	O
and	O
unsupervised	O
unopposed	O
oestrogen	B-Chemical
therapy	O
and	O
the	O
difficulty	O
in	O
distinguishing	O
severe	O
hyperplasia	B-Disease
from	O
malignancy	B-Disease
.	O

Cyclical	O
low	O
-	O
dose	O
oestrogen	B-Chemical
therapy	O
with	O
7	O
-	O
-	O
13	O
days	O
of	O
progestagen	B-Chemical
does	O
not	O
seem	O
to	O
increase	O
the	O
risk	O
of	O
endometrial	B-Disease
hyperplasia	I-Disease
or	O
carcinoma	B-Disease
.	O

Effects	O
of	O
exercise	O
on	O
the	O
severity	O
of	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
.	O

The	O
effect	O
of	O
exercise	O
on	O
the	O
severity	O
of	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
was	O
studied	O
in	O
male	O
rats	O
.	O

Ninety	O
-	O
three	O
rats	O
were	O
randomly	O
divided	O
into	O
three	O
groups	O
.	O

The	O
exercise	O
-	O
isoproterenol	B-Chemical
(	O
E	O
-	O
1	O
)	O
and	O
exercise	O
control	O
(	O
EC	O
)	O
groups	O
exercised	O
daily	O
for	O
thirty	O
days	O
on	O
a	O
treadmill	O
at	O
1	O
mph	O
,	O
2	O
%	O
grade	O
while	O
animals	O
of	O
the	O
sedentary	O
-	O
isoproterenol	B-Chemical
(	O
S	O
-	O
I	O
)	O
group	O
remained	O
sedentary	O
.	O

Eight	O
animals	O
were	O
assigned	O
to	O
the	O
sedentary	O
control	O
(	O
SC	O
)	O
group	O
which	O
remained	O
sedentary	O
throughout	O
the	O
experimental	O
period	O
.	O

Forty	O
-	O
eight	O
hours	O
after	O
the	O
final	O
exercise	O
period	O
,	O
S	O
-	O
I	O
and	O
E	O
-	O
I	O
animals	O
received	O
a	O
single	O
subcutaneous	O
injection	O
of	O
isoproterenol	B-Chemical
(	O
250	O
mg	O
/	O
kg	O
body	O
weight	O
)	O
.	O

Animals	O
of	O
the	O
S	O
-	O
I	O
group	O
exhibited	O
significantly	O
(	O
Pp	O
less	O
than	O
0	O
.	O
05	O
)	O
greater	O
mortality	O
from	O
the	O
effects	O
of	O
isoproterenol	B-Chemical
than	O
animals	O
of	O
the	O
E	O
-	O
I	O
group	O
.	O

Serum	O
CPK	O
activity	O
for	O
E	O
-	O
I	O
animals	O
was	O
significantly	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
greater	O
than	O
for	O
animals	O
in	O
the	O
S	O
-	O
I	O
and	O
EC	O
groups	O
twenty	O
hours	O
following	O
isoproterenol	B-Chemical
injection	O
.	O

No	O
statistically	O
significant	O
differences	O
were	O
observed	O
between	O
the	O
two	O
isoproterenol	B-Chemical
treated	O
groups	O
for	O
severity	O
of	O
the	O
induced	O
lesions	O
,	O
changes	O
in	O
heart	O
weight	O
,	O
or	O
heart	O
weight	O
to	O
body	O
weight	O
ratios	O
.	O

The	O
results	O
indicated	O
that	O
exercise	O
reduced	O
the	O
mortality	O
associated	O
with	O
the	O
effects	O
of	O
large	O
dosages	O
of	O
isoproterenol	B-Chemical
but	O
had	O
little	O
on	O
the	O
severity	O
of	O
the	O
infarction	B-Disease
.	O

Human	O
corticotropin	B-Chemical
-	O
releasing	O
hormone	O
and	O
thyrotropin	B-Chemical
-	O
releasing	O
hormone	O
modulate	O
the	O
hypercapnic	B-Disease
ventilatory	O
response	O
in	O
humans	O
.	O

Human	O
corticotropin	B-Chemical
-	O
releasing	O
hormone	O
(	O
hCRH	O
)	O
and	O
thyrotropin	B-Chemical
-	O
releasing	O
hormone	O
(	O
TRH	O
)	O
are	O
known	O
to	O
stimulate	O
ventilation	O
after	O
i	O
.	O
v	O
.	O
administration	O
in	O
humans	O
.	O

In	O
a	O
placebo	O
-	O
controlled	O
,	O
single	O
-	O
blind	O
study	O
we	O
aimed	O
to	O
clarify	O
if	O
both	O
peptides	O
act	O
by	O
altering	O
central	O
chemosensitivity	O
.	O

Two	O
subsequent	O
CO2	B-Chemical
-	O
rebreathing	O
tests	O
were	O
performed	O
in	O
healthy	O
young	O
volunteers	O
.	O

During	O
the	O
first	O
test	O
0	O
.	O
9	O
%	O
NaCl	B-Chemical
was	O
given	O
i	O
.	O
v	O
.	O
;	O
during	O
the	O
second	O
test	O
200	O
micrograms	O
of	O
hCRH	O
(	O
n	O
=	O
12	O
)	O
or	O
400	O
micrograms	O
of	O
TRH	O
(	O
n	O
=	O
6	O
)	O
was	O
administered	O
i	O
.	O
v	O
.	O
Nine	O
subjects	O
received	O
0	O
.	O
9	O
%	O
NaCl	B-Chemical
i	O
.	O
v	O
.	O
during	O
both	O
rebreathing	O
manoeuvres	O
.	O

The	O
CO2	B-Chemical
-	O
response	O
curves	O
for	O
the	O
two	O
tests	O
were	O
compared	O
within	O
the	O
same	O
subject	O
.	O

In	O
the	O
hCRH	O
group	O
a	O
marked	O
parallel	O
shift	O
of	O
the	O
CO2	B-Chemical
-	O
response	O
curve	O
to	O
the	O
left	O
was	O
observed	O
after	O
hCRH	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

The	O
same	O
effect	O
occurred	O
following	O
TRH	O
but	O
was	O
less	O
striking	O
(	O
P	O
=	O
0	O
.	O
05	O
)	O
.	O

hCRH	O
and	O
TRH	O
caused	O
a	O
reduction	O
in	O
the	O
CO2	B-Chemical
threshold	O
.	O

The	O
CO2	B-Chemical
-	O
response	O
curves	O
in	O
the	O
control	O
group	O
were	O
nearly	O
identical	O
.	O

The	O
results	O
indicate	O
an	O
additive	O
effect	O
of	O
both	O
releasing	O
hormones	O
on	O
the	O
hypercapnic	B-Disease
ventilatory	O
response	O
in	O
humans	O
,	O
presumably	O
independent	O
of	O
central	O
chemosensitivity	O
.	O

Lamivudine	B-Chemical
is	O
effective	O
in	O
suppressing	O
hepatitis	B-Disease
B	I-Disease
virus	O
DNA	O
in	O
Chinese	O
hepatitis	B-Chemical
B	I-Chemical
surface	I-Chemical
antigen	I-Chemical
carriers	O
:	O
a	O
placebo	O
-	O
controlled	O
trial	O
.	O

Lamivudine	B-Chemical
is	O
a	O
novel	O
2	B-Chemical
'	I-Chemical
,	I-Chemical
3	I-Chemical
'	I-Chemical
-	I-Chemical
dideoxy	I-Chemical
cytosine	I-Chemical
analogue	O
that	O
has	O
potent	O
inhibitory	O
effects	O
on	O
hepatitis	B-Disease
B	I-Disease
virus	O
replication	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

We	O
performed	O
a	O
single	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
study	O
to	O
assess	O
its	O
effectiveness	O
and	O
safety	O
in	O
Chinese	O
hepatitis	B-Chemical
B	I-Chemical
surface	I-Chemical
antigen	I-Chemical
(	O
HBsAg	B-Chemical
)	O
carriers	O
.	O

Forty	O
-	O
two	O
Chinese	O
HBsAg	B-Chemical
carriers	O
were	O
randomized	O
to	O
receive	O
placebo	O
(	O
6	O
patients	O
)	O
or	O
lamivudine	B-Chemical
orally	O
in	O
dosages	O
of	O
25	O
mg	O
,	O
100	O
mg	O
,	O
or	O
300	O
mg	O
daily	O
(	O
12	O
patients	O
for	O
each	O
dosage	O
)	O
.	O

The	O
drug	O
was	O
given	O
for	O
4	O
weeks	O
.	O

The	O
patients	O
were	O
closely	O
monitored	O
clinically	O
,	O
biochemically	O
,	O
and	O
serologically	O
up	O
to	O
4	O
weeks	O
after	O
drug	O
treatment	O
.	O

All	O
36	O
patients	O
receiving	O
lamivudine	B-Chemical
had	O
a	O
decrease	O
in	O
hepatitis	B-Disease
B	I-Disease
virus	O
(	O
HBV	O
)	O
DNA	O
values	O
of	O
>	O
90	O
%	O
(	O
P	O
<	O
.	O
001	O
compared	O
with	O
placebo	O
)	O
.	O

Although	O
25	O
mg	O
of	O
lamivudine	B-Chemical
was	O
slightly	O
less	O
effective	O
than	O
100	O
mg	O
(	O
P	O
=	O
.	O
011	O
)	O
and	O
300	O
mg	O
(	O
P	O
=	O
.	O
005	O
)	O
,	O
it	O
still	O
induced	O
94	O
%	O
suppression	O
of	O
HBV	O
DNA	O
after	O
the	O
fourth	O
week	O
of	O
therapy	O
.	O

HBV	O
DNA	O
values	O
returned	O
to	O
pretreatment	O
levels	O
within	O
4	O
weeks	O
of	O
cessation	O
of	O
therapy	O
.	O

There	O
was	O
no	O
change	O
in	O
the	O
hepatitis	B-Disease
B	I-Disease
e	O
antigen	O
status	O
or	O
in	O
aminotransferase	O
levels	O
.	O

No	O
serious	O
adverse	O
events	O
were	O
observed	O
.	O

In	O
conclusion	O
,	O
a	O
4	O
-	O
week	O
course	O
of	O
lamivudine	B-Chemical
was	O
safe	O
and	O
effective	O
in	O
suppression	O
of	O
HBV	O
DNA	O
in	O
Chinese	O
HBsAg	B-Chemical
carriers	O
.	O

The	O
suppression	O
was	O
>	O
90	O
%	O
but	O
reversible	O
.	O

Studies	O
with	O
long	O
-	O
term	O
lamivudine	B-Chemical
administration	O
should	O
be	O
performed	O
to	O
determine	O
if	O
prolonged	O
suppression	O
of	O
HBV	O
DNA	O
can	O
be	O
achieved	O
.	O

Population	O
-	O
based	O
study	O
of	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
associated	O
with	O
various	O
oral	B-Chemical
contraceptives	I-Chemical
.	O

BACKGROUND	O
:	O
Four	O
studies	O
published	O
since	O
December	O
,	O
1995	O
,	O
reported	O
that	O
the	O
incidence	O
of	O
venous	B-Disease
thromboembolism	I-Disease
(	O
VTE	B-Disease
)	O
was	O
higher	O
in	O
women	O
who	O
used	O
oral	B-Chemical
contraceptives	I-Chemical
(	O
OCs	B-Chemical
)	O
containing	O
the	O
third	O
-	O
generation	O
progestagens	B-Chemical
gestodene	B-Chemical
or	O
desogestrel	B-Chemical
than	O
in	O
users	O
of	O
OCs	B-Chemical
containing	O
second	O
-	O
generation	O
progestagens	B-Chemical
.	O

However	O
,	O
confounding	O
and	O
bias	O
in	O
the	O
design	O
of	O
these	O
studies	O
may	O
have	O
affected	O
the	O
findings	O
.	O

The	O
aim	O
of	O
our	O
study	O
was	O
to	O
re	O
-	O
examine	O
the	O
association	O
between	O
risk	O
of	O
VTE	B-Disease
and	O
OC	B-Chemical
use	O
with	O
a	O
different	O
study	O
design	O
and	O
analysis	O
to	O
avoid	O
some	O
of	O
the	O
bias	O
and	O
confounding	O
of	O
the	O
earlier	O
studies	O
.	O

METHODS	O
:	O
We	O
used	O
computer	O
records	O
of	O
patients	O
from	O
143	O
general	O
practices	O
in	O
the	O
UK	O
.	O

The	O
study	O
was	O
based	O
on	O
the	O
medical	O
records	O
of	O
about	O
540	O
,	O
000	O
women	O
born	O
between	O
1941	O
and	O
1981	O
.	O

All	O
women	O
who	O
had	O
a	O
recorded	O
diagnosis	O
of	O
deep	B-Disease
-	I-Disease
vein	I-Disease
thrombosis	I-Disease
,	O
venous	B-Disease
thrombosis	I-Disease
not	O
otherwise	O
specified	O
,	O
or	O
pulmonary	O
embolus	O
during	O
the	O
study	O
period	O
,	O
and	O
who	O
had	O
been	O
treated	O
with	O
an	O
anticoagulant	O
were	O
identified	O
as	O
potential	O
cases	O
of	O
VTE	B-Disease
.	O

We	O
did	O
a	O
cohort	O
analysis	O
to	O
estimate	O
and	O
compare	O
incidence	O
of	O
VTE	B-Disease
in	O
users	O
of	O
the	O
main	O
OC	B-Chemical
preparations	O
,	O
and	O
a	O
nested	O
case	O
-	O
control	O
study	O
to	O
calculate	O
the	O
odds	O
ratios	O
of	O
VTE	B-Disease
associated	O
with	O
use	O
of	O
different	O
types	O
of	O
OC	B-Chemical
,	O
after	O
adjustment	O
for	O
potential	O
confounding	O
factors	O
.	O

In	O
the	O
case	O
-	O
control	O
study	O
,	O
we	O
matched	O
cases	O
to	O
controls	O
by	O
exact	O
year	O
of	O
birth	O
,	O
practice	O
,	O
and	O
current	O
use	O
of	O
OCs	B-Chemical
.	O

We	O
used	O
a	O
multiple	O
logistic	O
regression	O
model	O
that	O
included	O
body	O
-	O
mass	O
index	O
,	O
number	O
of	O
cycles	O
,	O
change	O
in	O
type	O
of	O
OC	B-Chemical
prescribed	O
within	O
3	O
months	O
of	O
the	O
event	O
,	O
previous	O
pregnancy	O
,	O
and	O
concurrent	O
disease	O
.	O

FINDINGS	O
:	O
85	O
women	O
met	O
the	O
inclusion	O
criteria	O
for	O
VTE	B-Disease
,	O
two	O
of	O
whom	O
were	O
users	O
of	O
progestagen	B-Chemical
-	O
only	O
OCs	B-Chemical
.	O

Of	O
the	O
83	O
cases	O
of	O
VTE	B-Disease
associated	O
with	O
use	O
of	O
combined	O
OCs	B-Chemical
,	O
43	O
were	O
recorded	O
as	O
deep	B-Disease
-	I-Disease
vein	I-Disease
thrombosis	I-Disease
,	O
35	O
as	O
pulmonary	O
thrombosis	B-Disease
,	O
and	O
five	O
as	O
venous	B-Disease
thrombosis	I-Disease
not	O
otherwise	O
specified	O
.	O

The	O
crude	O
rate	O
of	O
VTE	B-Disease
per	O
10	O
,	O
000	O
woman	O
-	O
years	O
was	O
4	O
.	O
10	O
in	O
current	O
users	O
of	O
any	O
OC	B-Chemical
,	O
3	O
.	O
10	O
in	O
users	O
of	O
second	O
-	O
generation	O
OCs	B-Chemical
,	O
and	O
4	O
.	O
96	O
in	O
users	O
of	O
third	O
-	O
generation	O
preparations	O
.	O

After	O
adjustment	O
for	O
age	O
,	O
the	O
rate	O
ratio	O
of	O
VTE	B-Disease
in	O
users	O
of	O
third	O
-	O
generation	O
relative	O
to	O
second	O
-	O
generation	O
OCs	B-Chemical
was	O
1	O
.	O
68	O
(	O
95	O
%	O
CI	O
1	O
.	O
04	O
-	O
2	O
.	O
75	O
)	O
.	O

Logistic	O
regression	O
showed	O
no	O
significant	O
difference	O
in	O
the	O
risk	O
of	O
VTE	B-Disease
between	O
users	O
of	O
third	O
-	O
generation	O
and	O
second	O
-	O
generation	O
OCs	B-Chemical
.	O

Among	O
users	O
of	O
third	O
-	O
generation	O
progestagens	B-Chemical
,	O
the	O
risk	O
of	O
VTE	B-Disease
was	O
higher	O
in	O
users	O
of	O
desogestrel	B-Chemical
with	O
20	O
g	O
ethinyloestradiol	B-Chemical
than	O
in	O
users	O
of	O
gestodene	B-Chemical
or	O
desogestrel	B-Chemical
with	O
30	O
g	O
ethinyloestradiol	B-Chemical
.	O

With	O
all	O
second	O
-	O
generation	O
OCs	B-Chemical
as	O
the	O
reference	O
,	O
the	O
odds	O
ratios	O
for	O
VTE	B-Disease
were	O
3	O
.	O
49	O
(	O
1	O
.	O
21	O
-	O
10	O
.	O
12	O
)	O
for	O
desogestrel	B-Chemical
plus	O
20	O
g	O
ethinyloestradiol	B-Chemical
and	O
1	O
.	O
18	O
(	O
0	O
.	O
66	O
-	O
2	O
.	O
17	O
)	O
for	O
the	O
other	O
third	O
-	O
generation	O
progestagens	B-Chemical
.	O

INTERPRETATION	O
:	O
The	O
previously	O
reported	O
increase	O
in	O
odds	O
ratio	O
associated	O
with	O
third	O
-	O
generation	O
OCs	B-Chemical
when	O
compared	O
with	O
second	O
-	O
generation	O
products	O
is	O
likely	O
to	O
have	O
been	O
the	O
result	O
of	O
residual	O
confounding	O
by	O
age	O
.	O

The	O
increased	O
odds	O
ratio	O
associated	O
with	O
products	O
containing	O
20	O
micrograms	O
ethinyloestradiol	B-Chemical
and	O
desogestrel	B-Chemical
compared	O
with	O
the	O
30	O
micrograms	O
product	O
is	O
biologically	O
implausible	O
,	O
and	O
is	O
likely	O
to	O
be	O
the	O
result	O
of	O
preferential	O
prescribing	O
and	O
,	O
thus	O
,	O
confounding	O
.	O

MK	B-Chemical
-	I-Chemical
801	I-Chemical
augments	O
pilocarpine	B-Chemical
-	O
induced	O
electrographic	O
seizure	B-Disease
but	O
protects	O
against	O
brain	B-Disease
damage	I-Disease
in	O
rats	O
.	O

1	O
.	O

The	O
authors	O
examined	O
the	O
anticonvulsant	O
effects	O
of	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
on	O
the	O
pilocarpine	B-Chemical
-	O
induced	O
seizure	B-Disease
model	O
.	O

Intraperitoneal	O
injection	O
of	O
pilocarpine	B-Chemical
(	O
400	O
mg	O
/	O
kg	O
)	O
induced	O
tonic	B-Disease
and	I-Disease
clonic	I-Disease
seizure	I-Disease
.	O

Scopolamine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
)	O
and	O
pentobarbital	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
)	O
prevented	O
development	O
of	O
pilocarpine	B-Chemical
-	O
induced	O
behavioral	O
seizure	B-Disease
but	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
)	O
did	O
not	O
.	O

2	O
.	O

An	O
electrical	O
seizure	B-Disease
measured	O
with	O
hippocampal	O
EEG	O
appeared	O
in	O
the	O
pilocarpine	B-Chemical
-	O
treated	O
group	O
.	O

Scopolamine	B-Chemical
and	O
pentobarbital	B-Chemical
blocked	O
the	O
pilocarpine	B-Chemical
-	O
induced	O
electrographic	O
seizure	B-Disease
,	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
treatment	O
augmented	O
the	O
electrographic	O
seizure	B-Disease
induced	O
by	O
pilocarpine	B-Chemical
.	O

3	O
.	O

Brain	B-Disease
damage	I-Disease
was	O
assessed	O
by	O
examining	O
the	O
hippocampus	O
microscopically	O
.	O

Pilocarpine	B-Chemical
produced	O
neuronal	B-Disease
death	I-Disease
in	O
the	O
hippocampus	O
,	O
which	O
showed	O
pyknotic	O
changes	O
.	O

Pentobarbital	B-Chemical
,	O
scopolamine	B-Chemical
and	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
protected	O
the	O
brain	B-Disease
damage	I-Disease
by	O
pilocarpine	B-Chemical
,	O
though	O
in	O
the	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
-	O
treated	O
group	O
,	O
the	O
pyramidal	O
cells	O
of	O
hippocampus	O
appeared	O
darker	O
than	O
normal	O
.	O

In	O
all	O
treatments	O
,	O
granule	O
cells	O
of	O
the	O
dentate	O
gyrus	O
were	O
not	O
affected	O
.	O

4	O
.	O

These	O
results	O
indicate	O
that	O
status	B-Disease
epilepticus	I-Disease
induced	O
by	O
pilocarpine	B-Chemical
is	O
initiated	O
by	O
cholinergic	O
overstimulation	O
and	O
propagated	O
by	O
glutamatergic	O
transmission	O
,	O
the	O
elevation	O
of	O
which	O
may	O
cause	O
brain	B-Disease
damage	I-Disease
through	O
an	O
excitatory	O
NMDA	B-Chemical
receptor	O
-	O
mediated	O
mechanism	O
.	O

Paclitaxel	B-Chemical
,	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
,	O
and	O
folinic	B-Chemical
acid	I-Chemical
in	O
metastatic	O
breast	B-Disease
cancer	I-Disease
:	O
BRE	O
-	O
26	O
,	O
a	O
phase	O
II	O
trial	O
.	O

5	B-Chemical
-	I-Chemical
Fluorouracil	I-Chemical
plus	O
folinic	B-Chemical
acid	I-Chemical
and	O
paclitaxel	B-Chemical
(	O
Taxol	B-Chemical
;	O
Bristol	O
-	O
Myers	O
Squibb	O
Company	O
,	O
Princeton	O
,	O
NJ	O
)	O
are	O
effective	O
salvage	O
therapies	O
for	O
metastatic	O
breast	B-Disease
cancer	I-Disease
patients	O
.	O

Paclitaxel	B-Chemical
and	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
have	O
additive	O
cytotoxicity	B-Disease
in	O
MCF	O
-	O
7	O
cell	O
lines	O
.	O

We	O
performed	O
a	O
phase	O
II	O
trial	O
of	O
paclitaxel	B-Chemical
175	O
mg	O
/	O
m2	O
over	O
3	O
hours	O
on	O
day	O
I	O
followed	O
by	O
folinic	B-Chemical
acid	I-Chemical
300	O
mg	O
over	O
1	O
hour	O
before	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
350	O
mg	O
/	O
m2	O
on	O
days	O
1	O
to	O
3	O
every	O
28	O
days	O
(	O
TFL	O
)	O
in	O
women	O
with	O
metastatic	O
breast	B-Disease
cancer	I-Disease
.	O

Analysis	O
is	O
reported	O
on	O
37	O
patients	O
with	O
a	O
minimum	O
of	O
6	O
months	O
follow	O
-	O
up	O
who	O
received	O
a	O
total	O
of	O
192	O
cycles	O
of	O
TFL	O
:	O
nine	O
cycles	O
(	O
5	O
%	O
)	O
were	O
associated	O
with	O
grade	O
3	O
/	O
4	O
neutropenia	B-Disease
requiring	O
hospitalization	O
;	O
seven	O
(	O
4	O
%	O
)	O
cycles	O
in	O
two	O
patients	O
required	O
granulocyte	B-Chemical
colony	I-Chemical
-	I-Chemical
stimulating	I-Chemical
factor	I-Chemical
due	O
to	O
neutropenia	B-Disease
;	O
no	O
patient	O
required	O
platelet	O
transfusions	O
.	O

Grade	O
3	O
/	O
4	O
nonhematologic	O
toxicities	B-Disease
were	O
uncommon	O
.	O

Among	O
the	O
34	O
patients	O
evaluable	O
for	O
response	O
,	O
there	O
were	O
three	O
complete	O
responses	O
(	O
9	O
%	O
)	O
and	O
18	O
partial	O
responses	O
(	O
53	O
%	O
)	O
for	O
an	O
overall	O
response	O
rate	O
of	O
62	O
%	O
.	O

Of	O
the	O
19	O
evaluable	O
patients	O
with	O
prior	O
doxorubicin	B-Chemical
exposure	O
,	O
11	O
(	O
58	O
%	O
)	O
responded	O
compared	O
with	O
nine	O
of	O
15	O
(	O
60	O
%	O
)	O
without	O
prior	O
doxorubicin	B-Chemical
.	O

Plasma	O
paclitaxel	B-Chemical
concentrations	O
were	O
measured	O
at	O
the	O
completion	O
of	O
paclitaxel	B-Chemical
infusion	O
and	O
at	O
24	O
hours	O
in	O
19	O
patients	O
.	O

TFL	O
is	O
an	O
active	O
,	O
well	O
-	O
tolerated	O
regimen	O
in	O
metastatic	O
breast	B-Disease
cancer	I-Disease
.	O

Efficacy	O
and	O
proarrhythmia	B-Disease
with	O
the	O
use	O
of	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
for	O
sustained	O
ventricular	B-Disease
tachyarrhythmias	I-Disease
.	O

This	O
study	O
prospectively	O
evaluated	O
the	O
clinical	O
efficacy	O
,	O
the	O
incidence	O
of	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
,	O
and	O
the	O
presumable	O
risk	O
factors	O
for	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
in	O
patients	O
treated	O
with	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
for	O
sustained	O
ventricular	B-Disease
tachyarrhythmias	I-Disease
.	O

Eighty	O
-	O
one	O
consecutive	O
patients	O
(	O
54	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
,	O
and	O
20	O
with	O
dilated	B-Disease
cardiomyopathy	I-Disease
)	O
with	O
inducible	O
sustained	O
ventricular	B-Disease
tachycardia	I-Disease
or	O
ventricular	B-Disease
fibrillation	I-Disease
received	O
oral	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
to	O
prevent	O
induction	O
of	O
the	O
ventricular	B-Disease
tachyarrhythmia	I-Disease
.	O

During	O
oral	O
loading	O
with	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
,	O
continuous	O
electrocardiographic	O
(	O
ECG	O
)	O
monitoring	O
was	O
performed	O
.	O

Those	O
patients	O
in	O
whom	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
prevented	O
induction	O
of	O
ventricular	B-Disease
tachycardia	I-Disease
or	O
ventricular	B-Disease
fibrillation	I-Disease
were	O
discharged	O
with	O
the	O
drug	O
and	O
followed	O
up	O
on	O
an	O
outpatient	O
basis	O
for	O
21	O
+	O
/	O
-	O
18	O
months	O
.	O

Induction	O
of	O
the	O
ventricular	B-Disease
tachyarrhythmia	I-Disease
was	O
prevented	O
by	O
oral	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
in	O
35	O
(	O
43	O
%	O
)	O
patients	O
;	O
the	O
ventricular	B-Disease
tachyarrhythmia	I-Disease
remained	O
inducible	O
in	O
40	O
(	O
49	O
%	O
)	O
patients	O
;	O
and	O
two	O
(	O
2	O
.	O
5	O
%	O
)	O
patients	O
did	O
not	O
tolerate	O
even	O
40	O
mg	O
of	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
once	O
daily	O
.	O

Four	O
(	O
5	O
%	O
)	O
patients	O
had	O
from	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
during	O
the	O
initial	O
oral	O
treatment	O
with	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
.	O

Neither	O
ECG	O
[	O
sinus	O
-	O
cycle	O
length	O
(	O
SCL	O
)	O
,	O
QT	O
or	O
QTc	O
interval	O
,	O
or	O
U	O
wave	O
]	O
nor	O
clinical	O
parameters	O
identified	O
patients	O
at	O
risk	O
for	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
.	O

However	O
,	O
the	O
oral	O
dose	O
of	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
was	O
significantly	O
lower	O
in	O
patients	O
with	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
(	O
200	O
+	O
/	O
-	O
46	O
vs	O
.	O
328	O
+	O
/	O
-	O
53	O
mg	O
/	O
day	O
;	O
p	O
=	O
0	O
.	O
0017	O
)	O
.	O

Risk	O
factors	O
associated	O
with	O
the	O
development	O
of	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
were	O
the	O
appearance	O
of	O
an	O
U	O
wave	O
(	O
p	O
=	O
0	O
.	O
049	O
)	O
,	O
female	O
gender	O
(	O
p	O
=	O
0	O
.	O
015	O
)	O
,	O
and	O
significant	O
dose	O
-	O
corrected	O
changes	O
of	O
SCL	O
,	O
QT	O
interval	O
,	O
and	O
QTc	O
interval	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

During	O
follow	O
-	O
up	O
,	O
seven	O
(	O
20	O
%	O
)	O
patients	O
had	O
a	O
nonfatal	O
ventricular	B-Disease
tachycardia	I-Disease
recurrence	O
,	O
and	O
two	O
(	O
6	O
%	O
)	O
patients	O
died	O
suddenly	O
.	O

One	O
female	O
patient	O
with	O
stable	O
cardiac	B-Disease
disease	I-Disease
had	O
recurrent	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
after	O
2	O
years	O
of	O
successful	O
treatment	O
with	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
.	O

Torsades	B-Disease
de	I-Disease
pointes	I-Disease
occurred	O
early	O
during	O
treatment	O
even	O
with	O
low	O
doses	O
of	O
oral	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
.	O

Pronounced	O
changes	O
in	O
the	O
surface	O
ECG	O
(	O
cycle	O
length	O
,	O
QT	O
,	O
and	O
QTc	O
)	O
in	O
relation	O
to	O
the	O
dose	O
of	O
oral	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
might	O
identify	O
a	O
subgroup	O
of	O
patients	O
with	O
an	O
increased	O
risk	O
for	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
.	O

Other	O
ECG	O
parameters	O
before	O
the	O
application	O
of	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
did	O
not	O
identify	O
patients	O
at	O
increased	O
risk	O
for	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
.	O

Recurrence	O
rates	O
of	O
ventricular	B-Disease
tachyarrhythmias	I-Disease
are	O
high	O
despite	O
complete	O
suppression	O
of	O
the	O
arrhythmia	B-Disease
during	O
programmed	O
stimulation	O
.	O

Therefore	O
programmed	O
electrical	O
stimulation	O
in	O
the	O
case	O
of	O
d	B-Chemical
,	I-Chemical
l	I-Chemical
-	I-Chemical
sotalol	I-Chemical
seems	O
to	O
be	O
of	O
limited	O
prognostic	O
value	O
.	O

Chronic	O
hyperprolactinemia	B-Disease
and	O
changes	O
in	O
dopamine	B-Chemical
neurons	O
.	O

The	O
tuberoinfundibular	O
dopaminergic	O
(	O
TIDA	O
)	O
system	O
is	O
known	O
to	O
inhibit	O
prolactin	O
(	O
PRL	O
)	O
secretion	O
.	O

In	O
young	O
animals	O
this	O
system	O
responds	O
to	O
acute	O
elevations	O
in	O
serum	O
PRL	O
by	O
increasing	O
its	O
activity	O
.	O

However	O
,	O
this	O
responsiveness	O
is	O
lost	O
in	O
aging	O
rats	O
with	O
chronically	O
high	O
serum	O
PRL	O
levels	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
induce	O
hyperprolactinemia	B-Disease
in	O
rats	O
for	O
extended	O
periods	O
of	O
time	O
and	O
examine	O
its	O
effects	O
on	O
dopaminergic	O
systems	O
in	O
the	O
brain	O
.	O

Hyperprolactinemia	B-Disease
was	O
induced	O
by	O
treatment	O
with	O
haloperidol	B-Chemical
,	O
a	O
dopamine	B-Chemical
receptor	O
antagonist	O
,	O
and	O
Palkovits	O
'	O
microdissection	O
technique	O
in	O
combination	O
with	O
high	O
-	O
performance	O
liquid	O
chromatography	O
was	O
used	O
to	O
measure	O
neurotransmitter	O
concentrations	O
in	O
several	O
areas	O
of	O
the	O
brain	O
.	O

After	O
6	O
months	O
of	O
hyperprolactinemia	B-Disease
,	O
dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
concentrations	O
in	O
the	O
median	O
eminence	O
(	O
ME	O
)	O
increased	O
by	O
84	O
%	O
over	O
the	O
control	O
group	O
.	O

Nine	O
months	O
of	O
hyperprolactinemia	B-Disease
produced	O
a	O
50	O
%	O
increase	O
in	O
DA	B-Chemical
concentrations	O
in	O
the	O
ME	O
over	O
the	O
control	O
group	O
.	O

However	O
,	O
DA	B-Chemical
response	O
was	O
lost	O
if	O
a	O
9	O
-	O
month	O
long	O
haloperidol	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
was	O
followed	O
by	O
a	O
1	O
1	O
/	O
2	O
month	O
-	O
long	O
extremely	O
high	O
increase	O
in	O
serum	O
PRL	O
levels	O
produced	O
by	O
implantation	O
of	O
MMQ	O
cells	O
under	O
the	O
kidney	O
capsule	O
.	O

There	O
was	O
no	O
change	O
in	O
the	O
levels	O
of	O
DA	B-Chemical
,	O
norepinephrine	B-Chemical
(	O
NE	B-Chemical
)	O
,	O
serotonin	B-Chemical
(	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
)	O
,	O
or	O
their	O
metabolites	O
in	O
the	O
arcuate	O
nucleus	O
(	O
AN	O
)	O
,	O
medial	O
preoptic	O
area	O
(	O
MPA	O
)	O
,	O
caudate	O
putamen	O
(	O
CP	O
)	O
,	O
substantia	O
nigra	O
(	O
SN	O
)	O
,	O
and	O
zona	O
incerta	O
(	O
ZI	O
)	O
,	O
except	O
for	O
a	O
decrease	O
in	O
5	B-Chemical
-	I-Chemical
hydroxyindoleacetic	I-Chemical
acid	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
HIAA	I-Chemical
)	O
in	O
the	O
AN	O
after	O
6	O
-	O
months	O
of	O
hyperprolactinemia	B-Disease
and	O
an	O
increase	O
in	O
DA	B-Chemical
concentrations	O
in	O
the	O
AN	O
after	O
9	O
-	O
months	O
of	O
hyperprolactinemia	B-Disease
.	O

These	O
results	O
demonstrate	O
that	O
hyperprolactinemia	B-Disease
specifically	O
affects	O
TIDA	O
neurons	O
and	O
these	O
effects	O
vary	O
,	O
depending	O
on	O
the	O
duration	O
and	O
intensity	O
of	O
hyperprolactinemia	B-Disease
.	O

The	O
age	O
-	O
related	O
decrease	O
in	O
hypothalamic	O
dopamine	B-Chemical
function	O
may	O
be	O
associated	O
with	O
increases	O
in	O
PRL	O
secretion	O
.	O

Treatment	O
-	O
related	O
disseminated	O
necrotizing	O
leukoencephalopathy	B-Disease
with	O
characteristic	O
contrast	O
enhancement	O
of	O
the	O
white	O
matter	O
.	O

This	O
report	O
describes	O
unique	O
contrast	O
enhancement	O
of	O
the	O
white	O
matter	O
on	O
T1	O
-	O
weighted	O
magnetic	O
resonance	O
images	O
of	O
two	O
patients	O
with	O
disseminated	O
necrotizing	O
leukoencephalopathy	B-Disease
,	O
which	O
developed	O
from	O
acute	B-Disease
lymphoblastic	I-Disease
leukemia	I-Disease
treated	O
with	O
high	O
-	O
dose	O
methotrexate	B-Chemical
.	O

In	O
both	O
patients	O
,	O
the	O
enhancement	O
was	O
more	O
pronounced	O
near	O
the	O
base	O
of	O
the	O
brain	O
than	O
at	O
the	O
vertex	O
.	O

Necropsy	O
of	O
the	O
first	O
case	O
revealed	O
loss	B-Disease
of	I-Disease
myelination	I-Disease
and	O
necrosis	B-Disease
of	O
the	O
white	O
matter	O
.	O

Possible	O
mechanisms	O
causing	O
such	O
a	O
leukoencephalopathy	B-Disease
are	O
discussed	O
.	O

Thrombotic	B-Disease
complications	O
in	O
acute	B-Disease
promyelocytic	I-Disease
leukemia	I-Disease
during	O
all	B-Chemical
-	I-Chemical
trans	I-Chemical
-	I-Chemical
retinoic	I-Chemical
acid	I-Chemical
therapy	O
.	O

A	O
case	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
,	O
due	O
to	O
occlusion	B-Disease
of	I-Disease
renal	I-Disease
vessels	I-Disease
in	O
a	O
patient	O
with	O
acute	B-Disease
promyelocytic	I-Disease
leukemia	I-Disease
(	O
APL	B-Disease
)	O
treated	O
with	O
all	B-Chemical
-	I-Chemical
trans	I-Chemical
-	I-Chemical
retinoic	I-Chemical
acid	I-Chemical
(	O
ATRA	B-Chemical
)	O
and	O
tranexamic	B-Chemical
acid	I-Chemical
has	O
been	O
described	O
recently	O
.	O

We	O
report	O
a	O
case	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
in	O
an	O
APL	B-Disease
patient	O
treated	O
with	O
ATRA	B-Chemical
alone	O
.	O

This	O
case	O
further	O
supports	O
the	O
concern	O
about	O
thromboembolic	B-Disease
complications	O
associated	O
with	O
ATRA	B-Chemical
therapy	O
in	O
APL	B-Disease
patients	O
.	O

The	O
patients	O
,	O
a	O
43	O
-	O
year	O
-	O
old	O
man	O
,	O
presented	O
all	O
the	O
signs	O
and	O
symptoms	O
of	O
APL	B-Disease
and	O
was	O
included	O
in	O
a	O
treatment	O
protocol	O
with	O
ATRA	B-Chemical
.	O

After	O
10	O
days	O
of	O
treatment	O
,	O
he	O
developed	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
that	O
was	O
completely	O
reversible	O
after	O
complete	O
remission	O
of	O
APL	B-Disease
was	O
achieved	O
and	O
therapy	O
discontinued	O
.	O

We	O
conclude	O
that	O
ATRA	B-Chemical
is	O
a	O
valid	O
therapeutic	O
choice	O
for	O
patients	O
with	O
APL	B-Disease
,	O
although	O
the	O
procoagulant	O
tendency	O
is	O
not	O
completely	O
corrected	O
.	O

Thrombotic	B-Disease
events	O
,	O
however	O
,	O
could	O
be	O
avoided	O
by	O
using	O
low	O
-	O
dose	O
heparin	B-Chemical
.	O

Pupillary	O
changes	O
associated	O
with	O
the	O
development	O
of	O
stimulant	O
-	O
induced	O
mania	B-Disease
:	O
a	O
case	O
report	O
.	O

A	O
30	O
-	O
year	O
-	O
old	O
cocaine	B-Chemical
-	O
dependent	O
man	O
who	O
was	O
a	O
subject	O
in	O
a	O
study	O
evaluating	O
the	O
anticraving	O
efficacy	O
of	O
the	O
stimulant	O
medication	O
diethylpropion	B-Chemical
(	O
DEP	B-Chemical
)	O
became	O
manic	B-Disease
during	O
his	O
second	O
week	O
on	O
the	O
study	O
drug	O
.	O

Pupillometric	O
changes	O
while	O
on	O
DEP	B-Chemical
,	O
especially	O
changes	O
in	O
the	O
total	O
power	O
of	O
pupillary	B-Disease
oscillation	I-Disease
,	O
were	O
dramatically	O
different	O
than	O
those	O
observed	O
in	O
the	O
eight	O
other	O
study	O
subjects	O
who	O
did	O
not	O
become	O
manic	B-Disease
.	O

The	O
large	O
changes	O
in	O
total	O
power	O
of	O
pupillary	B-Disease
oscillation	I-Disease
occurred	O
a	O
few	O
days	O
before	O
the	O
patient	O
became	O
fully	O
manic	B-Disease
.	O

Such	O
medication	O
-	O
associated	O
changes	O
in	O
the	O
total	O
power	O
of	O
pupillary	B-Disease
oscillation	I-Disease
might	O
be	O
of	O
utility	O
in	O
identifying	O
persons	O
at	O
risk	O
for	O
manic	B-Disease
-	O
like	O
adverse	O
effects	O
during	O
the	O
medical	O
use	O
of	O
psychomotor	O
stimulants	O
or	O
sympathomimetic	O
agents	O
.	O

Fetal	O
risks	O
due	O
to	O
warfarin	B-Chemical
therapy	O
during	O
pregnancy	O
.	O

Two	O
mothers	O
with	O
heart	O
valve	O
prosthesis	O
were	O
treated	O
with	O
warfarin	B-Chemical
during	O
pregnancy	O
.	O

In	O
the	O
first	O
case	O
a	O
caesarean	O
section	O
was	O
done	O
one	O
week	O
after	O
replacement	O
of	O
warfarin	B-Chemical
with	O
heparin	B-Chemical
.	O

The	O
baby	O
died	O
of	O
cerebral	B-Disease
and	I-Disease
pulmonary	I-Disease
hemorrhage	I-Disease
.	O

The	O
second	O
mother	O
had	O
a	O
male	O
infant	O
by	O
caesarean	O
section	O
.	O

The	O
baby	O
showed	O
warfarin	B-Chemical
-	O
induced	O
embryopathy	B-Disease
with	O
nasal	B-Disease
hypoplasia	I-Disease
and	O
stippled	B-Disease
epiphyses	I-Disease
(	O
chondrodysplasia	B-Disease
punctata	I-Disease
)	O
.	O

Nasal	B-Disease
hypoplasia	I-Disease
with	O
or	O
without	O
stippled	B-Disease
epiphyses	I-Disease
has	O
now	O
been	O
reported	O
in	O
11	O
infants	O
born	O
to	O
mothers	O
treated	O
with	O
warfarin	B-Chemical
during	O
the	O
first	O
trimester	O
,	O
and	O
a	O
causal	O
association	O
is	O
probable	O
.	O

In	O
view	O
of	O
the	O
risks	O
to	O
both	O
mother	O
and	O
fetus	O
in	O
women	O
with	O
prosthetic	O
cardiac	O
valves	O
it	O
is	O
recommended	O
that	O
therapeutic	O
abortion	O
be	O
advised	O
as	O
the	O
first	O
alternative	O
.	O

The	O
negative	O
mucosal	O
potential	O
:	O
separating	O
central	O
and	O
peripheral	O
effects	O
of	O
NSAIDs	O
in	O
man	O
.	O

OBJECTIVE	O
:	O
We	O
wanted	O
to	O
test	O
whether	O
assessment	O
of	O
both	O
a	O
central	O
pain	B-Disease
-	O
related	O
signal	O
(	O
chemo	O
-	O
somatosensory	O
evoked	O
potential	O
,	O
CSSEP	O
)	O
and	O
a	O
concomitantly	O
recorded	O
peripheral	O
signal	O
(	O
negative	O
mucosal	O
potential	O
,	O
NMP	O
)	O
allows	O
for	O
separation	O
of	O
central	O
and	O
peripheral	O
effects	O
of	O
NSAIDs	O
.	O

For	O
this	O
purpose	O
,	O
experimental	O
conditions	O
were	O
created	O
in	O
which	O
NSAIDs	O
had	O
previously	O
been	O
observed	O
to	O
produce	O
effects	O
on	O
phasic	O
and	O
tonic	O
pain	B-Disease
by	O
either	O
central	O
or	O
peripheral	O
mechanisms	O
.	O

METHODS	O
:	O
According	O
to	O
a	O
double	O
-	O
blind	O
,	O
randomised	O
,	O
controlled	O
,	O
threefold	O
cross	O
-	O
over	O
design	O
,	O
18	O
healthy	O
subjects	O
(	O
11	O
males	O
,	O
7	O
females	O
;	O
mean	O
age	O
26	O
years	O
)	O
received	O
either	O
placebo	O
,	O
400	O
mg	O
ibuprofen	B-Chemical
,	O
or	O
800	O
mg	O
ibuprofen	B-Chemical
.	O

Phasic	O
pain	B-Disease
was	O
applied	O
by	O
means	O
of	O
short	O
pulses	O
of	O
CO2	B-Chemical
to	O
the	O
nasal	O
mucosa	O
(	O
stimulus	O
duration	O
500	O
ms	O
,	O
interval	O
approximately	O
60	O
s	O
)	O
,	O
and	O
tonic	O
pain	B-Disease
was	O
induced	O
in	O
the	O
nasal	O
cavity	O
by	O
means	O
of	O
dry	O
air	O
of	O
controlled	O
temperature	O
,	O
humidity	O
and	O
flow	O
rate	O
(	O
22	O
degrees	O
C	O
,	O
0	O
%	O
relative	O
humidity	O
,	O
145	O
ml	O
.	O
s	O
-	O
1	O
)	O
.	O

Both	O
CSSEPs	O
as	O
central	O
and	O
NMPs	O
as	O
peripheral	O
correlates	O
of	O
pain	B-Disease
were	O
obtained	O
in	O
response	O
to	O
the	O
CO2	B-Chemical
stimuli	O
.	O

Additionally	O
,	O
the	O
subjects	O
rated	O
the	O
intensity	O
of	O
both	O
phasic	O
and	O
tonic	O
pain	B-Disease
by	O
means	O
of	O
visual	O
analogue	O
scales	O
.	O

RESULTS	O
:	O
As	O
described	O
earlier	O
,	O
administration	O
of	O
ibuprofen	B-Chemical
was	O
followed	O
by	O
a	O
decrease	O
in	O
tonic	O
pain	B-Disease
but	O
-	O
relative	O
to	O
placebo	O
-	O
an	O
increase	O
in	O
correlates	O
of	O
phasic	O
pain	B-Disease
,	O
indicating	O
a	O
specific	O
effect	O
of	O
ibuprofen	B-Chemical
on	O
the	O
interaction	O
between	O
the	O
pain	B-Disease
stimuli	O
under	O
these	O
special	O
experimental	O
conditions	O
.	O

Based	O
on	O
the	O
similar	O
behaviour	O
of	O
CSSEP	O
and	O
NMP	O
,	O
it	O
was	O
concluded	O
that	O
the	O
pharmacological	O
process	O
underlying	O
this	O
phenomenon	O
was	O
localised	O
in	O
the	O
periphery	O
.	O

By	O
means	O
of	O
the	O
simultaneous	O
recording	O
of	O
interrelated	O
peripheral	O
and	O
central	O
electrophysiologic	O
correlates	O
of	O
nociception	O
,	O
it	O
was	O
possible	O
to	O
separate	O
central	O
and	O
peripheral	O
effects	O
of	O
an	O
NSAID	O
.	O

The	O
major	O
advantage	O
of	O
this	O
pain	B-Disease
model	O
is	O
the	O
possibility	O
of	O
obtaining	O
peripheral	O
pain	B-Disease
-	O
related	O
activity	O
directly	O
using	O
a	O
non	O
-	O
invasive	O
technique	O
in	O
humans	O
.	O

Effect	O
of	O
D	B-Chemical
-	I-Chemical
Glucarates	I-Chemical
on	O
basic	O
antibiotic	O
-	O
induced	O
renal	B-Disease
damage	I-Disease
in	O
rats	O
.	O

Dehydrated	B-Disease
rats	O
regularly	O
develop	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
following	O
single	O
injection	O
of	O
aminoglycoside	B-Chemical
antibiotics	O
combined	O
with	O
dextran	O
or	O
of	O
antibiotics	O
only	O
.	O

Oral	O
administration	O
of	O
2	B-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
di	I-Chemical
-	I-Chemical
O	I-Chemical
-	I-Chemical
acetyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
glucaro	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
6	I-Chemical
,	I-Chemical
3	I-Chemical
-	I-Chemical
dilactone	I-Chemical
protected	O
rats	O
against	O
renal	B-Disease
failure	I-Disease
induced	O
by	O
kanamycin	B-Chemical
-	O
dextran	O
.	O

The	O
protective	O
effect	O
was	O
prevalent	O
among	O
D	B-Chemical
-	I-Chemical
glucarates	I-Chemical
,	O
and	O
also	O
to	O
other	O
saccharic	B-Chemical
acid	I-Chemical
,	O
hexauronic	B-Chemical
acids	I-Chemical
and	O
hexaaldonic	B-Chemical
acids	I-Chemical
,	O
although	O
to	O
a	O
lesser	O
degree	O
,	O
but	O
not	O
to	O
a	O
hexaaldose	O
,	O
sugar	B-Chemical
alcohols	I-Chemical
,	O
substances	O
inthe	O
TCA	B-Chemical
cycle	O
and	O
other	O
acidic	O
compounds	O
.	O

D	B-Chemical
-	I-Chemical
Glucarates	I-Chemical
were	O
effective	O
against	O
renal	B-Disease
damage	I-Disease
induced	O
by	O
peptide	O
antibiotics	O
as	O
well	O
as	O
various	O
aminoglycoside	B-Chemical
antibitocis	O
.	O

Dose	O
-	O
responses	O
were	O
observed	O
in	O
the	O
protective	O
effect	O
of	O
D	B-Chemical
-	I-Chemical
Glucarates	I-Chemical
.	O

With	O
a	O
D	B-Chemical
-	I-Chemical
glucarate	I-Chemical
of	O
a	O
fixed	O
size	O
of	O
dose	O
,	O
approximately	O
the	O
same	O
degree	O
of	O
protection	O
was	O
obtained	O
against	O
renal	B-Disease
damages	I-Disease
induced	O
by	O
different	O
basic	O
antibiotics	O
despite	O
large	O
disparities	O
in	O
administration	O
doses	O
of	O
different	O
antibiotics	O
.	O

D	B-Chemical
-	I-Chemical
Glucarates	I-Chemical
had	O
the	O
ability	O
to	O
prevent	O
renal	B-Disease
damage	I-Disease
but	O
not	O
to	O
cure	O
it	O
.	O

Rats	O
excreted	O
acidic	O
urine	O
when	O
they	O
were	O
spared	O
from	O
renal	B-Disease
lesions	I-Disease
by	O
monosaccharides	B-Chemical
.	O

The	O
reduction	O
effect	O
of	O
D	B-Chemical
-	I-Chemical
glucarates	I-Chemical
against	O
nephrotoxicity	B-Disease
of	O
basic	O
antibiotics	O
was	O
discussed	O
.	O

Acute	O
severe	O
depression	B-Disease
following	O
peri	O
-	O
operative	O
ondansetron	B-Chemical
.	O

A	O
41	O
-	O
year	O
-	O
old	O
woman	O
with	O
a	O
strong	O
history	O
of	O
postoperative	B-Disease
nausea	I-Disease
and	I-Disease
vomiting	I-Disease
presented	O
for	O
abdominal	O
hysterectomy	O
3	O
months	O
after	O
a	O
previous	O
anaesthetic	O
where	O
ondansetron	B-Chemical
prophylaxis	O
had	O
been	O
used	O
.	O

She	O
had	O
developed	O
a	O
severe	O
acute	O
major	B-Disease
depression	I-Disease
disorder	I-Disease
almost	O
immediately	O
thereafter	O
,	O
possibly	O
related	O
to	O
the	O
use	O
of	O
a	O
serotonin	B-Chemical
antagonist	O
.	O

Nine	O
years	O
before	O
she	O
had	O
experienced	O
a	O
self	O
-	O
limited	O
puerperal	O
depressive	B-Disease
episode	I-Disease
.	O

Anaesthesia	O
with	O
a	O
propofol	B-Chemical
infusion	O
and	O
avoidance	O
of	O
serotonin	B-Chemical
antagonists	O
provided	O
a	O
nausea	B-Disease
-	O
free	O
postoperative	O
course	O
without	O
exacerbation	O
of	O
the	O
depression	B-Disease
disorder	I-Disease
.	O

Hypertensive	B-Disease
response	O
during	O
dobutamine	B-Chemical
stress	O
echocardiography	O
.	O

Among	O
3	O
,	O
129	O
dobutamine	B-Chemical
stress	O
echocardiographic	O
studies	O
,	O
a	O
hypertensive	B-Disease
response	O
,	O
defined	O
as	O
systolic	O
blood	O
pressure	O
(	O
BP	O
)	O
>	O
or	O
=	O
220	O
mm	O
Hg	O
and	O
/	O
or	O
diastolic	O
BP	O
>	O
or	O
=	O
110	O
mm	O
Hg	O
,	O
occurred	O
in	O
30	O
patients	O
(	O
1	O
%	O
)	O
.	O

Patients	O
with	O
this	O
response	O
more	O
often	O
had	O
a	O
history	O
of	O
hypertension	B-Disease
and	O
had	O
higher	O
resting	O
systolic	O
and	O
diastolic	O
BP	O
before	O
dobutamine	B-Chemical
infusion	O
.	O

Continuously	O
nebulized	O
albuterol	B-Chemical
in	O
severe	O
exacerbations	O
of	O
asthma	B-Disease
in	O
adults	O
:	O
a	O
case	O
-	O
controlled	O
study	O
.	O

A	O
retrospective	O
,	O
case	O
-	O
controlled	O
analysis	O
comparing	O
patients	O
admitted	O
to	O
a	O
medical	O
intensive	O
care	O
unit	O
with	O
severe	O
exacerbations	O
of	O
asthma	B-Disease
who	O
received	O
continuously	O
nebulized	O
albuterol	B-Chemical
(	O
CNA	O
)	O
versus	O
intermittent	O
albuterol	B-Chemical
(	O
INA	O
)	O
treatments	O
is	O
reported	O
.	O

Forty	O
matched	O
pairs	O
of	O
patients	O
with	O
asthma	B-Disease
are	O
compared	O
.	O

CNA	O
was	O
administered	O
for	O
a	O
mean	O
of	O
11	O
+	O
/	O
-	O
10	O
hr	O
.	O

The	O
incidence	O
of	O
cardiac	B-Disease
dysrhythmias	I-Disease
was	O
similar	O
between	O
groups	O
.	O

Symptomatic	O
hypokalemia	B-Disease
did	O
not	O
occur	O
.	O

CNA	O
patients	O
had	O
higher	O
heart	O
rates	O
during	O
treatment	O
,	O
which	O
may	O
reflect	O
severity	O
of	O
illness	O
.	O

The	O
incidence	O
of	O
intubation	O
was	O
similar	O
.	O

We	O
conclude	O
that	O
CNA	O
and	O
INA	O
demonstrated	O
similar	O
profiles	O
with	O
regard	O
to	O
safety	O
,	O
morbidity	O
,	O
and	O
mortality	O
.	O

Paraplegia	B-Disease
following	O
intrathecal	O
methotrexate	B-Chemical
:	O
report	O
of	O
a	O
case	O
and	O
review	O
of	O
the	O
literature	O
.	O

A	O
patient	O
who	O
developed	O
paraplegia	B-Disease
following	O
the	O
intrathecal	O
instillation	O
of	O
methotrexate	B-Chemical
is	O
discribed	O
.	O

The	O
ten	O
previously	O
reported	O
cases	O
of	O
this	O
unusual	O
complication	O
are	O
reviewed	O
.	O

The	O
following	O
factors	O
appear	O
to	O
predispose	O
to	O
the	O
development	O
of	O
this	O
complication	O
:	O
abnormal	O
cerebrospinal	O
dynamics	O
related	O
to	O
the	O
presence	O
of	O
central	B-Disease
nervous	I-Disease
system	I-Disease
leukemia	I-Disease
,	O
and	O
epidural	O
cerebrospinal	O
leakage	O
;	O
elevated	O
cerebrospinal	O
fluid	O
methothexate	B-Chemical
concentration	O
related	O
to	O
abnormal	O
cerebrospinal	O
fluid	O
dynamics	O
and	O
to	O
inappropriately	O
high	O
methotrexate	B-Chemical
doses	O
based	O
on	O
body	O
surface	O
area	O
calculations	O
in	O
older	O
children	O
and	O
adults	O
;	O
the	O
presence	O
of	O
neurotoxic	B-Disease
preservatives	O
in	O
commercially	O
available	O
methotrexate	B-Chemical
preparations	O
and	O
diluents	O
;	O
and	O
the	O
use	O
of	O
methotrexate	B-Chemical
diluents	O
of	O
unphysiologic	O
pH	O
,	O
ionic	O
content	O
and	O
osmolarity	O
.	O

The	O
role	O
of	O
methotrexate	B-Chemical
contaminants	O
,	O
local	O
folate	B-Disease
deficiency	I-Disease
,	O
and	O
cranial	O
irradiation	O
in	O
the	O
pathogenesis	O
of	O
intrathecal	O
methotrexate	B-Chemical
toxicity	B-Disease
is	O
unclear	O
.	O

The	O
incidence	O
of	O
neurotoxicity	B-Disease
may	O
be	O
reduced	O
by	O
employing	O
lower	O
doses	O
of	O
methotrexate	B-Chemical
in	O
the	O
presence	O
of	O
central	B-Disease
nervous	I-Disease
system	I-Disease
leukemia	I-Disease
,	O
in	O
older	O
children	O
and	O
adults	O
,	O
and	O
in	O
the	O
presence	O
of	O
epidural	O
leakage	O
.	O

Only	O
preservative	O
-	O
free	O
methotrexate	B-Chemical
in	O
Elliott	O
'	O
s	O
B	O
Solution	O
at	O
a	O
concentration	O
of	O
not	O
more	O
than	O
1	O
mg	O
/	O
ml	O
should	O
be	O
used	O
for	O
intrathecal	O
administration	O
.	O

Periodic	O
monitoring	O
of	O
cerebruspinal	O
fluid	O
methotrexate	B-Chemical
levels	O
may	O
be	O
predictive	O
of	O
the	O
development	O
of	O
serious	O
neurotoxicity	B-Disease
.	O

Hyperosmolar	B-Disease
nonketotic	I-Disease
coma	I-Disease
precipitated	O
by	O
lithium	B-Chemical
-	O
induced	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
.	O

A	O
45	O
-	O
year	O
-	O
old	O
man	O
,	O
with	O
a	O
10	O
-	O
year	O
history	O
of	O
manic	B-Disease
depression	I-Disease
treated	O
with	O
lithium	B-Chemical
,	O
was	O
admitted	O
with	O
hyperosmolar	B-Disease
,	I-Disease
nonketotic	I-Disease
coma	I-Disease
.	O

He	O
gave	O
a	O
five	O
-	O
year	O
history	O
of	O
polyuria	B-Disease
and	O
polydipsia	B-Disease
,	O
during	O
which	O
time	O
urinalysis	O
had	O
been	O
negative	O
for	O
glucose	B-Chemical
.	O

After	O
recovery	O
from	O
hyperglycaemia	B-Disease
,	O
he	O
remained	O
polyuric	B-Disease
despite	O
normal	O
blood	O
glucose	B-Chemical
concentrations	O
;	O
water	O
deprivation	O
testing	O
indicated	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
,	O
likely	O
to	O
be	O
lithium	B-Chemical
-	O
induced	O
.	O

We	O
hypothesize	O
that	O
when	O
this	O
man	O
developed	O
type	B-Disease
2	I-Disease
diabetes	I-Disease
,	O
chronic	O
polyuria	B-Disease
due	O
to	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
was	O
sufficient	O
to	O
precipitate	O
hyperosmolar	O
dehydration	B-Disease
.	O

Effects	O
of	O
the	O
intracoronary	O
infusion	O
of	O
cocaine	B-Chemical
on	O
left	O
ventricular	O
systolic	O
and	O
diastolic	O
function	O
in	O
humans	O
.	O

BACKGROUND	O
:	O
In	O
dogs	O
,	O
a	O
large	O
amount	O
of	O
intravenous	O
cocaine	B-Chemical
causes	O
a	O
profound	O
deterioration	B-Disease
of	I-Disease
left	I-Disease
ventricular	I-Disease
(	I-Disease
LV	I-Disease
)	I-Disease
systolic	I-Disease
function	I-Disease
and	O
an	O
increase	O
in	O
LV	O
end	O
-	O
diastolic	O
pressure	O
.	O

This	O
study	O
was	O
done	O
to	O
assess	O
the	O
influence	O
of	O
a	O
high	O
intracoronary	O
cocaine	B-Chemical
concentration	O
on	O
LV	O
systolic	O
and	O
diastolic	O
function	O
in	O
humans	O
.	O

METHODS	O
AND	O
RESULTS	O
:	O
In	O
20	O
patients	O
(	O
14	O
men	O
and	O
6	O
women	O
aged	O
39	O
to	O
72	O
years	O
)	O
referred	O
for	O
cardiac	O
catheterization	O
for	O
the	O
evaluation	O
of	O
chest	B-Disease
pain	I-Disease
,	O
we	O
measured	O
heart	O
rate	O
,	O
systemic	O
arterial	O
pressure	O
,	O
LV	O
pressure	O
and	O
its	O
first	O
derivative	O
(	O
dP	O
/	O
dt	O
)	O
,	O
and	O
LV	O
volumes	O
and	O
ejection	O
fraction	O
before	O
and	O
during	O
the	O
final	O
2	O
to	O
3	O
minutes	O
of	O
a	O
15	O
-	O
minute	O
intracoronary	O
infusion	O
of	O
saline	O
(	O
n	O
=	O
10	O
,	O
control	O
subjects	O
)	O
or	O
cocaine	B-Chemical
hydrochloride	I-Chemical
1	O
mg	O
/	O
min	O
(	O
n	O
=	O
10	O
)	O
.	O

No	O
variable	O
changed	O
with	O
saline	O
.	O

With	O
cocaine	B-Chemical
,	O
the	O
drug	O
concentration	O
in	O
blood	O
obtained	O
from	O
the	O
coronary	O
sinus	O
was	O
3	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
4	O
(	O
mean	O
+	O
/	O
-	O
SD	O
)	O
mg	O
/	O
L	O
,	O
similar	O
in	O
magnitude	O
to	O
the	O
blood	O
cocaine	B-Chemical
concentration	O
reported	O
in	O
abusers	O
dying	O
of	O
cocaine	B-Chemical
intoxication	O
.	O

Cocaine	B-Chemical
induced	O
no	O
significant	O
change	O
in	O
heart	O
rate	O
,	O
LV	O
dP	O
/	O
dt	O
(	O
positive	O
or	O
negative	O
)	O
,	O
or	O
LV	O
end	O
-	O
diastolic	O
volume	O
,	O
but	O
it	O
caused	O
an	O
increase	O
in	O
systolic	O
and	O
mean	O
arterial	O
pressures	O
,	O
LV	O
end	O
-	O
diastolic	O
pressure	O
,	O
and	O
LV	O
end	O
-	O
systolic	O
volume	O
,	O
as	O
well	O
as	O
a	O
decrease	O
in	O
LV	O
ejection	O
fraction	O
.	O

CONCLUSIONS	O
:	O
In	O
humans	O
,	O
the	O
intracoronary	O
infusion	O
of	O
cocaine	B-Chemical
sufficient	O
in	O
amount	O
to	O
achieve	O
a	O
high	O
drug	O
concentration	O
in	O
coronary	O
sinus	O
blood	O
causes	O
a	O
deterioration	B-Disease
of	I-Disease
LV	I-Disease
systolic	I-Disease
and	I-Disease
diastolic	I-Disease
performance	I-Disease
.	O

Ascending	O
dose	O
tolerance	O
study	O
of	O
intramuscular	O
carbetocin	B-Chemical
administered	O
after	O
normal	O
vaginal	O
birth	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
the	O
maximum	O
tolerated	O
dose	O
(	O
MTD	O
)	O
of	O
carbetocin	B-Chemical
(	O
a	O
long	O
-	O
acting	O
synthetic	O
analogue	O
of	O
oxytocin	B-Chemical
)	O
,	O
when	O
administered	O
immediately	O
after	O
vaginal	O
delivery	O
at	O
term	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
Carbetocin	B-Chemical
was	O
given	O
as	O
an	O
intramuscular	O
injection	O
immediately	O
after	O
the	O
birth	O
of	O
the	O
infant	O
in	O
45	O
healthy	O
women	O
with	O
normal	O
singleton	O
pregnancies	O
who	O
delivered	O
vaginally	O
at	O
term	O
.	O

Dosage	O
groups	O
of	O
15	O
,	O
30	O
,	O
50	O
,	O
75	O
,	O
100	O
,	O
125	O
,	O
150	O
,	O
175	O
or	O
200	O
microg	O
carbetocin	B-Chemical
were	O
assigned	O
to	O
blocks	O
of	O
three	O
women	O
according	O
to	O
the	O
continual	O
reassessment	O
method	O
(	O
CRM	O
)	O
.	O

RESULTS	O
:	O
All	O
dosage	O
groups	O
consisted	O
of	O
three	O
women	O
,	O
except	O
those	O
with	O
100	O
microg	O
(	O
n	O
=	O
6	O
)	O
and	O
200	O
microg	O
(	O
n	O
=	O
18	O
)	O
.	O

Recorded	O
were	O
dose	O
-	O
limiting	O
adverse	O
events	O
:	O
hyper	B-Disease
-	I-Disease
or	I-Disease
hypotension	I-Disease
(	O
three	O
)	O
,	O
severe	O
abdominal	B-Disease
pain	I-Disease
(	O
0	O
)	O
,	O
vomiting	B-Disease
(	O
0	O
)	O
and	O
retained	B-Disease
placenta	I-Disease
(	O
four	O
)	O
.	O

Serious	O
adverse	O
events	O
occurred	O
in	O
seven	O
women	O
:	O
six	O
cases	O
with	O
blood	B-Disease
loss	I-Disease
>	O
or	O
=	O
1000	O
ml	O
,	O
four	O
cases	O
of	O
manual	O
placenta	O
removal	O
,	O
five	O
cases	O
of	O
additional	O
oxytocics	O
administration	O
and	O
five	O
cases	O
of	O
blood	O
transfusion	O
.	O

Maximum	O
blood	B-Disease
loss	I-Disease
was	O
greatest	O
at	O
the	O
upper	O
and	O
lower	O
dose	O
levels	O
,	O
and	O
lowest	O
in	O
the	O
70	O
-	O
125	O
microg	O
dose	O
range	O
.	O

Four	O
out	O
of	O
six	O
cases	O
with	O
blood	B-Disease
loss	I-Disease
>	O
or	O
=	O
1000	O
ml	O
occurred	O
in	O
the	O
200	O
microg	O
group	O
.	O

The	O
majority	O
of	O
additional	O
administration	O
of	O
oxytocics	O
(	O
4	O
/	O
5	O
)	O
and	O
blood	O
transfusion	O
(	O
3	O
/	O
5	O
)	O
occurred	O
in	O
the	O
dose	O
groups	O
of	O
200	O
microg	O
.	O

All	O
retained	O
placentae	O
were	O
found	O
in	O
the	O
group	O
of	O
200	O
microg	O
.	O

CONCLUSION	O
:	O
The	O
MTD	O
was	O
calculated	O
to	O
be	O
at	O
200	O
microg	O
carbetocin	B-Chemical
.	O

Heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
,	O
paradoxical	O
thromboembolism	B-Disease
,	O
and	O
other	O
side	O
effects	O
of	O
heparin	B-Chemical
therapy	O
.	O

Although	O
several	O
new	O
anticoagulant	O
drugs	O
are	O
in	O
development	O
,	O
heparin	B-Chemical
remains	O
the	O
drug	O
of	O
choice	O
for	O
most	O
anticoagulation	O
needs	O
.	O

The	O
clinical	O
effects	O
of	O
heparin	B-Chemical
are	O
meritorious	O
,	O
but	O
side	O
effects	O
do	O
exist	O
.	O

Important	O
untoward	O
effects	O
of	O
heparin	B-Chemical
therapy	O
including	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
,	O
heparin	B-Chemical
-	O
associated	O
osteoporosis	B-Disease
,	O
eosinophilia	B-Disease
,	O
skin	B-Disease
reactions	I-Disease
,	O
allergic	B-Disease
reactions	I-Disease
other	O
than	O
thrombocytopenia	B-Disease
and	O
alopecia	B-Disease
will	O
be	O
discussed	O
in	O
this	O
article	O
.	O

Nonopaque	O
crystal	O
deposition	O
causing	O
ureteric	B-Disease
obstruction	I-Disease
in	O
patients	O
with	O
HIV	O
undergoing	O
indinavir	B-Chemical
therapy	O
.	O

OBJECTIVE	O
:	O
We	O
describe	O
the	O
unique	O
CT	O
features	O
of	O
ureteric	B-Disease
calculi	I-Disease
in	O
six	O
HIV	B-Disease
-	I-Disease
infected	I-Disease
patients	O
receiving	O
indinavir	B-Chemical
,	O
the	O
most	O
commonly	O
used	O
HIV	O
protease	O
inhibitor	O
,	O
which	O
is	O
associated	O
with	O
an	O
increased	O
incidence	O
of	O
urolithiasis	B-Disease
.	O

CONCLUSION	O
:	O
Ureteric	B-Disease
obstruction	I-Disease
caused	O
by	O
precipitated	O
indinavir	B-Chemical
crystals	O
may	O
be	O
difficult	O
to	O
diagnose	O
with	O
unenhanced	O
CT	O
.	O

The	O
calculi	O
are	O
not	O
opaque	O
,	O
and	O
secondary	O
signs	O
of	O
obstruction	O
may	O
be	O
absent	O
or	O
minimal	O
and	O
should	O
be	O
sought	O
carefully	O
.	O

Images	O
may	O
need	O
to	O
be	O
obtained	O
using	O
i	O
.	O
v	O
.	O
contrast	O
material	O
to	O
enable	O
diagnosis	O
of	O
ureteric	B-Disease
stones	I-Disease
or	I-Disease
obstruction	I-Disease
in	O
patients	O
with	O
HIV	B-Disease
infection	I-Disease
who	O
receive	O
indinavir	B-Chemical
therapy	O
.	O

Ischemic	B-Disease
colitis	I-Disease
and	O
sumatriptan	B-Chemical
use	O
.	O

Sumatriptan	B-Chemical
succinate	I-Chemical
,	O
a	O
serotonin	B-Chemical
-	O
1	O
(	O
5	B-Chemical
-	I-Chemical
hydroxytryptamine	I-Chemical
-	O
1	O
)	O
receptor	O
agonist	O
,	O
is	O
an	O
antimigraine	O
drug	O
that	O
is	O
reported	O
to	O
act	O
by	O
selectively	O
constricting	O
intracranial	O
arteries	O
.	O

Recently	O
,	O
vasopressor	O
responses	O
that	O
are	O
distinct	O
from	O
the	O
cranial	O
circulation	O
have	O
been	O
demonstrated	O
to	O
occur	O
in	O
the	O
systemic	O
,	O
pulmonary	O
,	O
and	O
coronary	O
circulations	O
.	O

Cases	O
have	O
been	O
published	O
of	O
coronary	B-Disease
vasospasm	I-Disease
,	O
myocardial	B-Disease
ischemia	I-Disease
,	O
and	O
myocardial	B-Disease
infarction	I-Disease
occurring	O
after	O
sumatriptan	B-Chemical
use	O
.	O

We	O
report	O
on	O
the	O
development	O
of	O
8	O
serious	O
cases	O
of	O
ischemic	B-Disease
colitis	I-Disease
in	O
patients	O
with	O
migraine	B-Disease
treated	O
with	O
sumatriptan	B-Chemical
.	O

Pallidotomy	O
with	O
the	O
gamma	O
knife	O
:	O
a	O
positive	O
experience	O
.	O

51	O
patients	O
with	O
medically	O
refractory	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
underwent	O
stereotactic	O
posteromedial	O
pallidotomy	O
between	O
August	O
1993	O
and	O
February	O
1997	O
for	O
treatment	O
of	O
bradykinesia	B-Disease
,	O
rigidity	B-Disease
,	O
and	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
-	O
induced	O
dyskinesias	B-Disease
.	O

In	O
29	O
patients	O
,	O
the	O
pallidotomies	O
were	O
performed	O
with	O
the	O
Leksell	O
Gamma	O
Knife	O
and	O
in	O
22	O
they	O
were	O
performed	O
with	O
the	O
standard	O
radiofrequency	O
(	O
RF	O
)	O
method	O
.	O

Clinical	O
assessment	O
as	O
well	O
as	O
blinded	O
ratings	O
of	O
Unified	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
Disease	I-Disease
Rating	O
Scale	O
(	O
UPDRS	O
)	O
scores	O
were	O
carried	O
out	O
pre	O
-	O
and	O
postoperatively	O
.	O

Mean	O
follow	O
-	O
up	O
time	O
is	O
20	O
.	O
6	O
months	O
(	O
range	O
6	O
-	O
48	O
)	O
and	O
all	O
except	O
4	O
patients	O
have	O
been	O
followed	O
more	O
than	O
one	O
year	O
.	O

85	O
percent	O
of	O
patients	O
with	O
dyskinesias	B-Disease
were	O
relieved	O
of	O
symptoms	O
,	O
regardless	O
of	O
whether	O
the	O
pallidotomies	O
were	O
performed	O
with	O
the	O
Gamma	O
Knife	O
or	O
radiofrequency	O
methods	O
.	O

About	O
2	O
/	O
3	O
of	O
the	O
patients	O
in	O
both	O
Gamma	O
Knife	O
and	O
radiofrequency	O
groups	O
showed	O
improvements	O
in	O
bradykinesia	B-Disease
and	O
rigidity	B-Disease
,	O
although	O
when	O
considered	O
as	O
a	O
group	O
neither	O
the	O
Gamma	O
Knife	O
nor	O
the	O
radiofrequency	O
group	O
showed	O
statistically	O
significant	O
improvements	O
in	O
UPDRS	O
scores	O
.	O

One	O
patient	O
in	O
the	O
Gamma	O
Knife	O
group	O
(	O
3	O
.	O
4	O
%	O
)	O
developed	O
a	O
homonymous	B-Disease
hemianopsia	I-Disease
9	O
months	O
following	O
treatment	O
and	O
5	O
patients	O
(	O
27	O
.	O
7	O
%	O
)	O
in	O
the	O
radiofrequency	O
group	O
became	O
transiently	O
confused	O
postoperatively	O
.	O

No	O
other	O
complications	O
were	O
seen	O
.	O

Gamma	O
Knife	O
pallidotomy	O
is	O
as	O
effective	O
as	O
radiofrequency	O
pallidotomy	O
in	O
controlling	O
certain	O
of	O
the	O
symptoms	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

It	O
may	O
be	O
the	O
only	O
practical	O
technique	O
available	O
in	O
certain	O
patients	O
,	O
such	O
as	O
those	O
who	O
take	O
anticoagulants	O
,	O
have	O
bleeding	B-Disease
diatheses	O
or	O
serious	O
systemic	O
medical	O
illnesses	O
.	O

It	O
is	O
a	O
viable	O
option	O
for	O
other	O
patients	O
as	O
well	O
.	O

Centrally	O
mediated	O
cardiovascular	O
effects	O
of	O
intracisternal	O
application	O
of	O
carbachol	B-Chemical
in	O
anesthetized	O
rats	O
.	O

The	O
pressor	O
response	O
to	O
the	O
intracisternal	O
(	O
i	O
.	O
c	O
.	O
)	O
injection	O
of	O
carbachol	B-Chemical
(	O
1	O
mug	O
)	O
in	O
anesthetized	O
rats	O
was	O
analyzed	O
.	O

This	O
response	O
was	O
significantly	O
reduced	O
by	O
the	O
intravenous	O
(	O
i	O
.	O
v	O
.	O
)	O
injection	O
of	O
guanethidine	B-Chemical
(	O
5	O
mg	O
)	O
,	O
hexamethonium	B-Chemical
(	O
10	O
mg	O
)	O
or	O
phentolamine	B-Chemical
(	O
5	O
mg	O
)	O
,	O
and	O
conversely	O
,	O
potentiated	O
by	O
i	O
.	O
v	O
.	O
desmethylimipramine	B-Chemical
(	O
0	O
.	O
3	O
mg	O
)	O
,	O
while	O
propranolol	B-Chemical
(	O
0	O
.	O
5	O
mg	O
)	O
i	O
.	O
v	O
.	O
selectively	O
inhibited	O
the	O
enlargement	B-Disease
of	I-Disease
pulse	I-Disease
pressure	I-Disease
and	O
the	O
tachycardia	B-Disease
following	O
i	O
.	O
c	O
.	O
carbachol	B-Chemical
(	O
1	O
mug	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
pressor	O
response	O
to	O
i	O
.	O
c	O
.	O
carbachol	B-Chemical
(	O
1	O
mug	O
)	O
was	O
almost	O
completely	O
blocked	O
by	O
i	O
.	O
c	O
.	O
atropine	B-Chemical
(	O
3	O
mug	O
)	O
or	O
hexamethonium	B-Chemical
(	O
500	O
mug	O
)	O
,	O
and	O
significantly	O
reduced	O
by	O
i	O
.	O
c	O
.	O
chlorpromazine	B-Chemical
(	O
50	O
mug	O
)	O
but	O
significantly	O
potentiated	O
by	O
i	O
.	O
c	O
.	O
desmethylimipramine	B-Chemical
(	O
30	O
mug	O
)	O
.	O

The	O
pressor	O
response	O
to	O
i	O
.	O
c	O
.	O
carbachol	B-Chemical
(	O
1	O
mug	O
)	O
remained	O
unchanged	O
after	O
sectioning	O
of	O
the	O
bilateral	O
cervical	O
vagal	O
nerves	O
but	O
disappeared	O
after	O
sectioning	O
of	O
the	O
spinal	O
cord	O
(	O
C7	O
-	O
C8	O
)	O
.	O

From	O
the	O
above	O
result	O
it	O
is	O
suggested	O
that	O
the	O
pressor	O
response	O
to	O
i	O
.	O
c	O
.	O
carbachol	B-Chemical
ortral	O
and	O
peripheral	O
adrenergic	O
mechanisms	O
,	O
and	O
that	O
the	O
sympathetic	O
trunk	O
is	O
the	O
main	O
pathway	O
.	O

Neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
and	O
methylphenidate	B-Chemical
.	O

A	O
1	O
-	O
year	O
-	O
old	O
female	O
presented	O
with	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
probably	O
caused	O
by	O
methylphenidate	B-Chemical
.	O

She	O
had	O
defects	O
in	O
the	O
supratentorial	O
brain	O
including	O
the	O
basal	O
ganglia	O
and	O
the	O
striatum	O
(	O
multicystic	B-Disease
encephalomalacia	I-Disease
)	O
due	O
to	O
severe	O
perinatal	O
hypoxic	B-Disease
-	I-Disease
ischemic	I-Disease
encephalopathy	I-Disease
,	O
which	O
was	O
considered	O
to	O
be	O
a	O
possible	O
predisposing	O
factor	O
causing	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
.	O

A	O
dopaminergic	O
blockade	O
mechanism	O
generally	O
is	O
accepted	O
as	O
the	O
pathogenesis	O
of	O
this	O
syndrome	O
.	O

However	O
,	O
methylphenidate	B-Chemical
is	O
a	O
dopamine	B-Chemical
agonist	O
via	O
the	O
inhibition	O
of	O
uptake	O
of	O
dopamine	B-Chemical
,	O
and	O
therefore	O
dopaminergic	O
systems	O
in	O
the	O
brainstem	O
(	O
mainly	O
the	O
midbrain	O
)	O
and	O
the	O
spinal	O
cord	O
were	O
unlikely	O
to	O
participate	O
in	O
the	O
onset	O
of	O
this	O
syndrome	O
.	O

A	O
relative	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
-	O
ergic	O
deficiency	O
might	O
occur	O
because	O
diazepam	B-Chemical
,	O
a	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
-	O
mimetic	O
agent	O
,	O
was	O
strikingly	O
effective	O
.	O

This	O
is	O
the	O
first	O
reported	O
patient	O
with	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
probably	O
caused	O
by	O
methylphenidate	B-Chemical
.	O

Differential	O
effects	O
of	O
17alpha	B-Chemical
-	I-Chemical
ethinylestradiol	I-Chemical
on	O
the	O
neutral	O
and	O
acidic	O
pathways	O
of	O
bile	B-Chemical
salt	I-Chemical
synthesis	O
in	O
the	O
rat	O
.	O

Effects	O
of	O
17alpha	B-Chemical
-	I-Chemical
ethinylestradiol	I-Chemical
(	O
EE	B-Chemical
)	O
on	O
the	O
neutral	O
and	O
acidic	O
biosynthetic	O
pathways	O
of	O
bile	B-Chemical
salt	I-Chemical
(	O
BS	B-Chemical
)	O
synthesis	O
were	O
evaluated	O
in	O
rats	O
with	O
an	O
intact	O
enterohepatic	O
circulation	O
and	O
in	O
rats	O
with	O
long	O
-	O
term	O
bile	O
diversion	O
to	O
induce	O
BS	B-Chemical
synthesis	O
.	O

For	O
this	O
purpose	O
,	O
bile	B-Chemical
salt	I-Chemical
pool	O
composition	O
,	O
synthesis	O
of	O
individual	O
BS	B-Chemical
in	O
vivo	O
,	O
hepatic	O
activities	O
,	O
and	O
expression	O
levels	O
of	O
cholesterol	B-Chemical
7alpha	O
-	O
hydroxylase	O
(	O
CYP7A	O
)	O
,	O
and	O
sterol	B-Chemical
27	O
-	O
hydroxylase	O
(	O
CYP27	O
)	O
,	O
as	O
well	O
as	O
of	O
other	O
enzymes	O
involved	O
in	O
BS	B-Chemical
synthesis	O
,	O
were	O
analyzed	O
in	O
rats	O
treated	O
with	O
EE	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
,	O
3	O
days	O
)	O
or	O
its	O
vehicle	O
.	O

BS	B-Chemical
pool	O
size	O
was	O
decreased	O
by	O
27	O
%	O
but	O
total	O
BS	B-Chemical
synthesis	O
was	O
not	O
affected	O
by	O
EE	B-Chemical
in	O
intact	O
rats	O
.	O

Synthesis	O
of	O
cholate	B-Chemical
was	O
reduced	O
by	O
68	O
%	O
in	O
EE	B-Chemical
-	O
treated	O
rats	O
,	O
while	O
that	O
of	O
chenodeoxycholate	B-Chemical
was	O
increased	O
by	O
60	O
%	O
.	O

The	O
recently	O
identified	O
Delta22	O
-	O
isomer	O
of	O
beta	O
-	O
muricholate	O
contributed	O
for	O
5	O
.	O
4	O
%	O
and	O
18	O
.	O
3	O
%	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
to	O
the	O
pool	O
in	O
control	O
and	O
EE	B-Chemical
-	O
treated	O
rats	O
,	O
respectively	O
,	O
but	O
could	O
not	O
be	O
detected	O
in	O
bile	O
after	O
exhaustion	O
of	O
the	O
pool	O
.	O

A	O
clear	O
reduction	O
of	O
BS	B-Chemical
synthesis	O
was	O
found	O
in	O
bile	O
-	O
diverted	O
rats	O
treated	O
with	O
EE	B-Chemical
,	O
yet	O
biliary	O
BS	B-Chemical
composition	O
was	O
only	O
minimally	O
affected	O
.	O

Activity	O
of	O
CYP7A	O
was	O
decreased	O
by	O
EE	B-Chemical
in	O
both	O
intact	O
and	O
bile	O
-	O
diverted	O
rats	O
,	O
whereas	O
the	O
activity	O
of	O
the	O
CYP27	O
was	O
not	O
affected	O
.	O

Hepatic	O
mRNA	O
levels	O
of	O
CYP7A	O
were	O
significantly	O
reduced	O
by	O
EE	B-Chemical
in	O
bile	O
-	O
diverted	O
rats	O
only	O
;	O
CYP27	O
mRNA	O
levels	O
were	O
not	O
affected	O
by	O
EE	B-Chemical
.	O

In	O
addition	O
,	O
mRNA	O
levels	O
of	O
sterol	B-Chemical
12alpha	O
-	O
hydroxylase	O
and	O
lithocholate	O
6beta	O
-	O
hydroxylase	O
were	O
increased	O
by	O
bile	O
diversion	O
and	O
suppressed	O
by	O
EE	B-Chemical
.	O

This	O
study	O
shows	O
that	O
17alpha	B-Chemical
-	I-Chemical
ethinylestradiol	I-Chemical
(	O
EE	B-Chemical
)	O
-	O
induced	O
intrahepatic	B-Disease
cholestasis	I-Disease
in	O
rats	O
is	O
associated	O
with	O
selective	O
inhibition	O
of	O
the	O
neutral	O
pathway	O
of	O
bile	B-Chemical
salt	I-Chemical
(	O
BS	B-Chemical
)	O
synthesis	O
.	O

Simultaneous	O
impairment	O
of	O
other	O
enzymes	O
in	O
the	O
BS	B-Chemical
biosynthetic	O
pathways	O
may	O
contribute	O
to	O
overall	O
effects	O
of	O
EE	B-Chemical
on	O
BS	B-Chemical
synthesis	O
.	O

Glibenclamide	B-Chemical
-	O
sensitive	O
hypotension	B-Disease
produced	O
by	O
helodermin	B-Chemical
assessed	O
in	O
the	O
rat	O
.	O

The	O
effects	O
of	O
helodermin	B-Chemical
,	O
a	O
basic	O
35	O
-	O
amino	B-Chemical
acid	I-Chemical
peptide	O
isolated	O
from	O
the	O
venom	O
of	O
a	O
lizard	O
salivary	O
gland	O
,	O
on	O
arterial	O
blood	O
pressure	O
and	O
heart	O
rate	O
were	O
examined	O
in	O
the	O
rat	O
,	O
focusing	O
on	O
the	O
possibility	O
that	O
activation	O
of	O
ATP	B-Chemical
sensitive	O
K	B-Chemical
+	O
(	O
K	B-Chemical
(	O
ATP	B-Chemical
)	O
)	O
channels	O
is	O
involved	O
in	O
the	O
responses	O
.	O

The	O
results	O
were	O
also	O
compared	O
with	O
those	O
of	O
vasoactive	O
intestinal	O
polypeptide	O
(	O
VIP	O
)	O
.	O

Helodermin	B-Chemical
produced	O
hypotension	B-Disease
in	O
a	O
dose	O
-	O
dependent	O
manner	O
with	O
approximately	O
similar	O
potency	O
and	O
duration	O
to	O
VIP	O
.	O

Hypotension	B-Disease
induced	O
by	O
both	O
peptides	O
was	O
significantly	O
attenuated	O
by	O
glibenclamide	B-Chemical
,	O
which	O
abolished	O
a	O
levcromakalim	B-Chemical
-	O
produced	O
decrease	O
in	O
arterial	O
blood	O
pressure	O
.	O

Oxyhemoglobin	O
did	O
not	O
affect	O
helodermin	B-Chemical
-	O
induced	O
hypotension	B-Disease
,	O
whereas	O
it	O
shortened	O
the	O
duration	O
of	O
acetylcholine	B-Chemical
(	O
ACh	B-Chemical
)	O
-	O
produced	O
hypotension	B-Disease
.	O

These	O
findings	O
suggest	O
that	O
helodermin	B-Chemical
-	O
produced	O
hypotension	B-Disease
is	O
partly	O
attributable	O
to	O
the	O
activation	O
of	O
glibenclamide	B-Chemical
-	O
sensitive	O
K	B-Chemical
+	O
channels	O
(	O
K	B-Chemical
(	O
ATP	B-Chemical
)	O
channels	O
)	O
,	O
which	O
presumably	O
exist	O
on	O
arterial	O
smooth	O
muscle	O
cells	O
.	O

EDRF	O
(	O
endothelium	O
-	O
derived	O
relaxing	O
factor	O
)	O
/	O
nitric	B-Chemical
oxide	I-Chemical
does	O
not	O
seem	O
to	O
play	O
an	O
important	O
role	O
in	O
the	O
peptide	O
-	O
produced	O
hypotension	B-Disease
.	O

Long	O
-	O
term	O
efficacy	O
and	O
adverse	O
event	O
of	O
nifedipine	B-Chemical
sustained	O
-	O
release	O
tablets	O
for	O
cyclosporin	B-Chemical
A	I-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
patients	O
with	O
psoriasis	B-Disease
.	O

Thirteen	O
psoriatic	B-Disease
patients	O
with	O
hypertension	B-Disease
during	O
the	O
course	O
of	O
cyclosporin	B-Chemical
A	I-Chemical
therapy	O
were	O
treated	O
for	O
25	O
months	O
with	O
a	O
calcium	B-Chemical
channel	O
blocker	O
,	O
sustained	O
-	O
release	O
nifedipine	B-Chemical
,	O
to	O
study	O
the	O
clinical	O
antihypertensive	O
effects	O
and	O
adverse	O
events	O
during	O
treatment	O
with	O
both	O
drugs	O
.	O

Seven	O
of	O
the	O
13	O
patients	O
had	O
exhibited	O
a	O
subclinical	O
hypertensive	B-Disease
state	O
before	O
cyclosporin	B-Chemical
A	I-Chemical
therapy	O
.	O

Both	O
systolic	O
and	O
diastolic	O
blood	O
pressures	O
of	O
these	O
13	O
patients	O
were	O
decreased	O
significantly	O
after	O
4	O
weeks	O
of	O
nifedipine	B-Chemical
therapy	O
,	O
and	O
blood	O
pressure	O
was	O
maintained	O
within	O
the	O
normal	O
range	O
thereafter	O
for	O
25	O
months	O
.	O

The	O
adverse	O
events	O
during	O
combined	O
therapy	O
with	O
cyclosporin	B-Chemical
A	I-Chemical
and	O
nifedipine	B-Chemical
included	O
an	O
increase	O
in	O
blood	B-Chemical
urea	I-Chemical
nitrogen	I-Chemical
levels	O
in	O
9	O
of	O
the	O
13	O
patients	O
and	O
development	O
of	O
gingival	B-Disease
hyperplasia	I-Disease
in	O
2	O
of	O
the	O
13	O
patients	O
.	O

Our	O
findings	O
indicate	O
that	O
sustained	O
-	O
release	O
nifedipine	B-Chemical
is	O
useful	O
for	O
hypertensive	B-Disease
psoriatic	B-Disease
patients	O
under	O
long	O
-	O
term	O
treatment	O
with	O
cyclosporin	B-Chemical
A	I-Chemical
,	O
but	O
that	O
these	O
patients	O
should	O
be	O
monitored	O
for	O
gingival	B-Disease
hyperplasia	I-Disease
.	O

In	O
spite	O
of	O
medical	O
help	O
:	O
the	O
puzzle	O
of	O
an	O
eighteenth	O
-	O
century	O
Prime	O
Minister	O
'	O
s	O
illness	O
.	O

Abstract	O

Medical	O
History	O
,	O
1990	O
,	O
34	O
:	O
178	O
-	O
184	O
.	O

IN	O
SPITE	O
OF	O
MEDICAL	O
HELP	O
:	O
THE	O
PUZZLE	O
OF	O
AN	O

EIGHTEENTH	O
-	O
CENTURY	O
PRIME	O
MINISTER	O
'	O
S	O

ILLNESS	O

by	O

MARJORIE	O
BLOY	O
*	O

Charles	O
Watson	O
Wentworth	O
,	O
second	O
Marquis	O
of	O
Rockingham	O
,	O
died	O
suddenly	O
and	O
unexpectedly	O
on	O
1	O
July	O
1782	O
,	O
when	O
he	O
was	O
only	O
52	O
years	O
old	O
.	O

He	O
had	O
suffered	O
-	O
or	O
enjoyed	O
-	O
ill	O
health	O
all	O
his	O
life	O
but	O
in	O
1782	O
appeared	O
to	O
be	O
no	O
worse	O
than	O
he	O
had	O
ever	O
been	O
.	O

His	O
death	O
in	O
London	O
terminated	O
his	O
second	O
period	O
of	O
office	O
as	O
Prime	O
Minister	O
,	O
to	O
which	O
he	O
had	O
been	O
appointed	O
only	O
14	O
weeks	O
earlier	O
.	O

In	O
May	O
he	O
had	O
reported	O
to	O
the	O
Duke	O
of	O
Portland	O
that	O
he	O
had	O
"	O
for	O
some	O
weeks	O
past	O
undergone	O
much	O
Pain	O
and	O
much	O
inconvenience	O
from	O
something	O
similar	O
to	O
my	O
old	O
Complaint	O
in	O
my	O
Side	O
and	O
Stomach	O
"	O
but	O
that	O
he	O
felt	O
much	O
better	O
than	O
he	O
had	O
.	O
'	O
By	O
17	O
June	O
he	O
was	O
recovering	O
from	O
both	O
influenza	O
and	O
his	O
"	O
old	O
complaint	O
"	O
.	O
2	O
On	O
1	O
July	O
he	O
died	O
and	O
on	O
the	O
20th	O
he	O
was	O
interred	O
in	O
York	O
Minster	O
.	O

The	O
first	O
recorded	O
bout	O
of	O
illness	O
suffered	O
by	O
the	O
marquis	O
,	O
then	O
Lord	O
Higham	O
,	O
was	O
in	O
July	O
1741	O
when	O
the	O
11	O
-	O
year	O
-	O
old	O
was	O
"	O
a	O
little	O
indisposed	O
,	O
something	O
Feaverish	O
I	O
guess	O
it	O
proceeds	O
from	O
Worms	O
and	O
will	O
Soon	O
be	O
removed	O
"	O
.	O
3	O
He	O
also	O
had	O
a	O
rash	O
and	O
it	O
was	O
thought	O
that	O
the	O
cause	O
of	O
the	O
problem	O
was	O
that	O
the	O
boy	B
had	O
overheated	O
himself	O
.	O
4	O
He	O
was	O
still	O
ill	O
at	O
the	O
beginning	O
of	O
August	O
:	O
he	O
had	O
been	O
"	O
much	O
out	O
of	O
order	O
"	O
for	O
a	O
long	O
time	O
but	O
had	O
been	O
recommended	O
to	O
take	O
warm	O
baths	O
by	O
Dr	O
Wilmot	O
and	O
Mr	O
Ranby	O
when	O
they	O
were	O
consulted	O
in	O
London	O
.	O
5	O
Charles	O
'	O
s	O
aunt	O
,	O
Lady	O
Isabella	O
Finch	O
,	O
was	O
sure	O
that	O
the	O
baths	O
"	O
and	O
other	O
Things	O
They	O
'	O
ll	O
prescribe	O
will	O
in	O
a	O
short	O
Time	O
entirely	O
Cure	O
his	O
Complaints	O
w	O
[	O
hic	O
]	O
h	O
neither	O
of	O
Them	O
thought	O
proceed	O
from	O
any	O
dangerous	O
Causes	O
"	O
.	O
6	O
In	O
spite	O
of	O
Lady	O
Isabella	O
'	O
s	O
hopes	O
,	O
Charles	O
did	O
not	O
greatly	O
improve	O
,	O
even	O
though	O
his	O
mother	O
believed	O
that	O
he	O
continued	O
mending	O
every	O
day	O
.	O

The	O
main	O
reason	O
that	O
Higham	O
and	O
his	O
mother	O
had	O
gone	O
to	O
London	O
to	O
consult	O
Dr	O
Wilmot	O
and	O
Mr	O

*	O
Marjorie	O
Bloy	O
,	O
Ph	O
.	O
D	O
.	O
,	O
18	O
Farm	O
View	O
Road	O
,	O
Kimberworth	O
,	O
Rotherham	O
,	O
S	O
.	O

Yorks	O
.	O

S61	O
2BA	O
.	O

The	O
Rockingham	O
Papers	O
are	O
in	O
the	O
holdings	O
of	O
the	O
Wentworth	O
Woodhouse	O
Muniments	O
at	O
Sheffield	O
City	O
Archives	O
Department	O
,	O
Sheffield	O
City	O
Library	O
.	O

I	O
am	O
grateful	O
to	O
Dr	O
R	O
.	O

S	O
.	O

Morton	O
for	O
his	O
advice	O
and	O
help	O
with	O
the	O
diagnostic	O
sections	O
of	O
this	O
essay	O
.	O

'	O
WWM	O
,	O
RI	O
-	O
2094	O
.	O

Rockingham	O
to	O
Portland	O
,	O
25	O
May	O
1782	O
.	O

2WWM	O
,	O
RI	O
-	O
2094	O
.	O

Rockingham	O
to	O
Charlemont	O
,	O
17	O
June	O
1782	O
.	O

3	O
WWM	O
,	O
M8	O
-	O
25	O
.	O

Malton	O
to	O
Nottingham	O
,	O
after	O
16	O
June	O
1741	O
.	O

4	O
WWM	O
,	O
M8	O
-	O
26	O
.	O

Lady	O
Finch	O
to	O
Lady	O
Malton	O
,	O
30	O
July	O
1741	O
.	O

5	O
WWM	O
,	O
M8	O
-	O
28	O
.	O

Winchelsea	O
to	O
Malton	O
,	O
7	O
August	O
1741	O
.	O

6	O
WWM	O
,	O
M8	O
-	O
29	O
.	O

Lady	O
Finch	O
to	O
Malton	O
,	O
7	O
August	O
1741	O
.	O

178	O

An	O
eighteenth	O
-	O
century	O
Prime	O
Minister	O
'	O
s	O
illness	O

Ranby	O
was	O
his	O
mother	O
'	O
s	O
concern	O
about	O
a	O
"	O
swelling	O
in	O
a	O
certain	O
part	O
which	O
was	O
larger	O
than	O
when	O
we	O
left	O
Wentworth	O
"	O
.	O

The	O
doctors	O
hoped	O
that	O
it	O
would	O
burst	O
outwards	O
"	O
which	O
they	O
assure	O
me	O
will	O
be	O
the	O
safest	O
way	O
and	O
give	O
the	O
poor	O
Monkey	O
but	O
very	O
little	O
pain	O
'	O
7	O

On	O
20	O
August	O
Lord	O
Winchelsea	O
,	O
Higham	O
'	O
s	O
uncle	O
,	O
surprised	O
to	O
see	O
the	O
boy	B
so	O
well	O
and	O
brisk	O
,	O
hoped	O
that	O
Charles	O
was	O
"	O
now	O
safe	O
from	O
this	O
complaint	O
"	O
-	O
the	O
same	O
one	O
from	O
which	O
he	O
had	O
suffered	O
in	O
1738	O
-	O
39	O
-	O
but	O
thought	O
that	O
he	O
would	O
never	O
be	O
safe	O
"	O
if	O
he	O
continues	O
the	O
practice	O
of	O
overheating	O
himself	O
and	O
then	O
drinking	O
Cold	O
Water	O
"	O
.	O

He	O
said	O
that	O
Charles	O
was	O
of	O
a	O
"	O
pretty	O
healthy	O
strong	O
Constitution	O
"	O
;	O
8	O
Lady	O
Malton	O
was	O
not	O
so	O
sure	O
.	O

The	O
same	O
day	O
she	O
wrote	O
a	O
progress	O
report	O
to	O
her	O
husband	O
saying	O
that	O
Charles	O
'	O
s	O
swelling	O
continued	O
to	O
grow	O
,	O
as	O
did	O
the	O
pain	O
"	O
in	O
that	O
part	O
(	O
but	O
not	O
the	O
lease	O
[	O
sic	O
]	O
trouble	O
in	O
making	O
Water	O
or	O
going	O
to	O
Stool	O
)	O
&	O
less	O
Fever	O
than	O
c	O
[	O
oulJd	O
be	O
imagined	O
where	O
Matter	O
is	O
as	O
they	O
now	O
imagine	O
certainly	O
gathering	O
and	O
must	O
end	O
in	O
an	O
operation	O
"	O
.	O

In	O
spite	O
of	O
it	O
all	O
,	O
Charles	O
was	O
in	O
fine	O
spirits	O
.	O
9	O
Lady	O
Malton	O
dosed	O
the	O
boy	B
with	O
cinchona	B
bark	O
,	O
which	O
removed	O
the	O
pains	O
in	O
his	O
legs	O
and	O
reduced	O
his	O
fever	O
,	O
and	O
she	O
was	O
convinced	O
that	O
they	O
would	O
soon	O
have	O
"	O
a	O
clear	O
Stage	O
to	O
act	O
in	O
a	O
proper	O
manner	O
a	O
[	O
bou	O
]	O
t	O
his	O
other	O
Complaints	O
w	O
[	O
hic	O
]	O
h	O
the	O
Learned	O
assure	O
me	O
are	O
to	O
be	O
conquered	O
also	O
"	O
.	O

10	O
Charles	O
was	O
soon	O
allowed	O
to	O
eat	O
meat	O
and	O
Mr	O
Ranby	O
still	O
assured	O
her	O
that	O
the	O
swelling	O
would	O
break	O
outwards	O
.	O

1	O
"	O
Three	O
days	O
later	O
he	O
decided	O
to	O
lance	O
it	O
,	O
even	O
though	O
Dr	O
Bourne	O
disagreed	O
.	O

The	O
boy	B
'	O
s	O
mother	O
was	O
puzzled	O
because	O
the	O
swelling	O
"	O
sometimes	O
pushes	O
forward	O
very	O
fast	O
then	O
retires	O
a	O
little	O
"	O
but	O
the	O
doctor	O
and	O
Ranby	O
seemed	O
happy	O
with	O
his	O
condition	O
.	O
'	O
2	O
At	O
this	O
point	O
the	O
letters	O
cease	O
,	O
presumably	O
because	O
Malton	O
arrived	O
in	O
London	O
with	O
his	O
daughters	O
,	O
to	O
have	O
them	O
inoculated	O
against	O
smallpox	B
,	O
but	O
a	O
later	O
letter	O
states	O
that	O
surgery	O
to	O
open	O
the	O
swelling	O
was	O
not	O
undertaken	O
.	O

13	O

By	O
the	O
end	O
of	O
October	O
the	O
correspondence	O
had	O
recommenced	O
.	O

Charles	O
was	O
ill	O
again	O
.	O

He	O
was	O
just	O
the	O
same	O
as	O
when	O
he	O
left	O
Kensington	O
,	O
so	O
John	O
Bourne	O
had	O
bled	O
him	O
and	O
the	O
child	B
had	O
started	O
on	O
Sir	O
Edward	O
Hulse	O
'	O
s	O
prescription	O
,	O
unfortunately	O
not	O
defined	O
in	O
the	O
letter	O
,	O
but	O
which	O
was	O
apparently	O
as	O
bad	O
as	O
the	O
last	O
one	O
,	O
if	O
not	O
worse	O
.	O

Lady	O
Malton	O
thought	O
that	O
"	O
with	O
such	O
a	O
State	O
of	O
Blood	O
the	O
Continuation	O
of	O
Health	O
cannot	O
be	O
expected	O
"	O
but	O
was	O
hopeful	O
that	O
the	O
"	O
Cinnabar	O
may	O
prove	O
a	O
more	O
Efficacious	O
remedie	O
than	O
any	O
than	O
has	O
been	O
tryed	O
yet	O
"	O
"	O
.	O
"	O
4	O
That	O
night	O
she	O
applied	O
"	O
a	O
Blister	O
.	O
.	O
.	O
without	O
the	O
least	O
Symptom	O
or	O
tendency	O
to	O
anything	O
like	O
Strangury	O
"	O
.	O

He	O
bore	O
the	O
treatment	O
well	O
,	O
as	O
he	O
had	O
done	O
three	O
years	O
previously	O
,	O
and	O
it	O
seemed	O
so	O
successful	O
that	O
Lady	O
Malton	O
was	O
"	O
determined	O
to	O
keep	O
it	O
running	O
full	O
as	O
long	O
as	O
I	O
did	O
last	O
time	O
by	O
the	O
help	O
of	O
John	O
Borne	O
[	O
sic	O
]	O
with	O
much	O
ease	O
to	O
the	O
Dear	O
Child	B
"	O
.	O
'	O
5	O
She	O

7	O
WWM	O
,	O
M7	O
-	O
51	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
18	O
August	O
1741	O
.	O

8	O
WWM	O
,	O
M2	O
-	O
84	O
.	O

Winchelsea	O
to	O
Malton	O
,	O
20	O
August	O
1741	O
.	O

9	O
WWM	O
,	O
M7	O
-	O
52	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
20	O
August	O
1741	O
.	O

'	O
0	O
WWM	O
,	O
M7	O
-	O
53	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
25	O
August	O
1741	O
.	O

WWM	O
,	O
M7	O
-	O
54	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
29	O
August	O
1741	O
.	O

WWM	O
,	O
M7	O
-	O
55	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
1	O
September	O
1741	O
.	O

3	O
WWM	O
,	O
R170	O
-	O
20	O
.	O

Nicol6	O
Scanagati	O
of	O
Padua	O
,	O
20	O
July	O
1750	O
.	O

I	O
am	O
grateful	O
to	O
Fr	O
John	O
McMahon	O
and	O
Dr	O
Stephen	O
Bemrose	O
for	O
their	O
translations	O
of	O
this	O
letter	O
.	O

4	O
WWM	O
,	O
M7	O
-	O
14	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
31	O
October	O
1741	O
.	O

5	O
WWM	O
,	O
M7	O
-	O
19	O
.	O

Lady	O
Malton	O
to	O
Lady	O
Finch	O
,	O
2	O
November	O
1741	O
.	O

179	O

Marjorie	O
Bloy	O

continued	O
with	O
the	O
blister	O
and	O
applied	O
"	O
ointment	O
with	O
flyes	O
"	O
,	O
apparently	O
some	O
sort	O
of	O
irritant	O
potion	O
,	O
with	O
no	O
sign	O
of	O
strangury	O
.	O

Charles	O
found	O
her	O
treatment	O
"	O
not	O
near	O
the	O
pain	O
he	O
expected	O
"	O
and	O
she	O
was	O
"	O
full	O
of	O
hopes	O
that	O
he	O
will	O
rec	O
[	O
eiv	O
]	O
e	O
great	O
benefit	O
from	O
it	O
"	O
.	O
1	O

Apart	O
from	O
his	O
other	O
troubles	O
,	O
one	O
of	O
Charles	O
'	O
s	O
knees	O
had	O
swollen	O
but	O
this	O
had	O
much	O
abated	O
since	O
the	O
application	O
of	O
the	O
blisters	O
which	O
Lady	O
Malton	O
believed	O
"	O
must	O
be	O
acting	O
upon	O
the	O
whole	O
Mass	O
of	O
Blood	O
"	O
since	O
it	O
had	O
"	O
reached	O
the	O
remote	O
part	O
"	O
.	O

She	O
thought	O
that	O
Sir	O
Edward	O
Hulse	O
'	O
s	O
powders	O
were	O
too	O
slow	O
in	O
taking	O
effect	O
although	O
the	O
boy	B
took	O
them	O
very	O
quietly	O
.	O
'	O
7	O
Sir	O
Edward	O
did	O
not	O
"	O
apprehend	O
any	O
great	O
danger	O
from	O
the	O
Siziness	O
[	O
thickness	O
]	O
of	O
Charles	O
'	O
blood	O
"	O
;	O
Lady	O
Malton	O
thought	O
that	O
the	O
condition	O
was	O
the	O
cause	O
of	O
all	O
the	O
child	B
'	O
s	O
problems	O
,	O
which	O
would	O
not	O
end	O
until	O
it	O
was	O
set	O
to	O
rights	O
.	O

At	O
any	O
rate	O
,	O
he	O
was	O
fit	O
enough	O
to	O
go	O
hunting	O
.	O
'	O
8	O
Charles	O
continued	O
in	O
the	O
same	O
state	O
of	O
health	O
.	O

He	O
slept	O
well	O
at	O
night	O
,	O
ate	O
more	O
than	O
his	O
mother	O
thought	O
was	O
good	O
for	O
him	O
,	O
and	O
was	O
able	O
to	O
exercise	O
strenuously	O
without	O
tiring	O
.	O

He	O
put	O
on	O
no	O
weight	O
though	O
,	O
and	O
"	O
as	O
for	O
them	O
swellings	O
at	O
his	O
throat	O
,	O
they	O
are	O
almost	O
gone	O
one	O
day	O
and	O
rise	O
the	O
next	O
"	O
.	O

His	O
mother	O
did	O
not	O
expect	O
a	O
speedy	O
recovery	O
and	O
"	O
if	O
the	O
D	O
[	O
octo	O
]	O
rs	O
think	O
him	O
in	O
a	O
good	O
state	O
of	O
health	O
now	O
,	O
I	O
s	O
[	O
houl	O
]	O
d	O
be	O
glad	O
to	O
see	O
him	O
in	O
a	O
better	O
"	O
.	O
'	O
9	O
He	O
began	O
to	O
improve	O
and	O
by	O
the	O
end	O
of	O
November	O
even	O
she	O
thought	O
he	O
was	O
on	O
the	O
mend	O
and	O
gaining	O
weight	O
.	O
20	O
Unfortunately	O
,	O
Lady	O
Malton	O
again	O
had	O
cause	O
for	O
concern	O
over	O
his	O
health	O
in	O
January	O
1742	O
when	O
he	O
began	O
to	O
suffer	O
from	O
an	O
intermittent	O
hoarseness	O
.	O
2	O
'	O
Otherwise	O
he	O
was	O
as	O
well	O
as	O
one	O
could	O
expect	O
,	O
with	O
no	O
other	O
complaints	O
.	O
22	O
It	O
was	O
not	O
to	O
last	O
.	O

In	O
May	O
1742	O
Charles	O
and	O
his	O
mother	O
were	O
again	O
in	O
Bristol	O
,	O
taking	O
the	O
waters	O
because	O
he	O
had	O
been	O
indisposed	O
.	O

Lady	O
Malton	O
thought	O
the	O
waters	O
were	O
doing	O
them	O
good	O
because	O
they	O
were	O
both	O
being	O
violently	O
sick	O
.	O
23	O
However	O
,	O
Charles	O
had	O
had	O
no	O
dinner	O
on	O
25	O
or	O
26	O
May	O
and	O
was	O
hot	O
,	O
lazy	O
,	O
and	O
inclined	O
to	O
stir	O
,	O
"	O
from	O
which	O
I	O
conclude	O
he	O
is	O
not	O
well	O
,	O
.	O

.	O
.	O
and	O
therefore	O
Intend	O
to	O
give	O
him	O
a	O
gentle	O
Vomit	O
.	O
.	O
.	O
and	O
to	O
let	O
him	O
take	O
his	O
old	O
Remedie	O
the	O
Salt	O
Draughts	O
for	O
a	O
few	O
Daies	O
which	O
I	O
dare	O
say	O
will	O
set	O
him	O
quite	O
to	O
rights	O
"	O
.	O
24	O
By	O
29	O
May	O
Dr	O
Boume	O
had	O
bled	O
the	O
boy	B
"	O
which	O
succeeded	O
very	O
well	O
but	O
.	O
.	O
.	O
found	O
it	O
[	O
his	O
blood	O
]	O
as	O
bad	O
as	O
ever	O
"	O
.	O

The	O
waters	O
were	O
not	O
working	O
"	O
but	O
there	O
is	O
a	O
great	O
deal	O
for	O
them	O
to	O
do	O
which	O
grant	O
God	O
they	O
may	O
effect	O
"	O
.	O

The	O
weather	O
had	O
turned	O
warm	O
so	O
Lady	O
Malton	O
had	O
"	O
shorn	O
him	O
.	O
.	O
.	O
which	O
has	O
display	O
'	O
d	O
a	O
most	O
scabby	O
head	O
and	O
indeed	O
several	O
other	O
untoward	O
Blotches	O
he	O
has	O
out	O
upon	O
other	O
parts	O
of	O
his	O
Body	O
"	O
,	O
which	O
made	O
her	O
uneasy	O
.	O
25	O
The	O
blotches	O
on	O
his	O
head	O
were	O
not	O
numerous	O
"	O
yet	O
they	O
made	O
up	O
in	O
quality	O
for	O
so	O
virulent	O
a	O
Corrosive	O
Humour	O
is	O
not	O
easily	O
conceived	O
without	O
seeing	O
it	O
"	O
.	O

The	O
pustules	O
on	O
his	O
body	O
were	O
of	O
the	O
same	O
sort	O

16	O
WWM	O
,	O
M7	O
-	O
17	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
4	O
November	O
1741	O
.	O

7	O
WWM	O
,	O
M7	O
-	O
18	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
4	O
November	O
1741	O
.	O

18	O
WWM	O
,	O
M7	O
-	O
16	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
7	O
November	O
1741	O
.	O

'	O
9WWM	O
,	O
M7	O
-	O
15	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
9	O
November	O
1741	O
.	O

20	O
WWM	O
,	O
M7	O
-	O
22	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
25	O
November	O
1741	O
.	O

21	O
WWM	O
,	O
M7	O
-	O
1	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
25	O
January	O
1742	O
.	O

22	O
WWM	O
,	O
M7	O
-	O
4	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
8	O
February	O
1742	O
and	O
WWM	O
,	O
M7	O
-	O
9	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
22	O
February	O
1742	O
.	O

23	O
WWM	O
,	O
M7	O
-	O
29	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
12	O
May	O
1742	O
.	O

24	O
WWM	O
,	O
M7	O
-	O
35	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
26	O
May	O
1742	O
.	O

25	O
WWM	O
,	O
M7	O
-	O
36	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
29	O
May	O
1742	O
.	O

180	O

An	O
eighteenth	O
-	O
century	O
Prime	O
Minister	O
'	O
s	O
illness	O

and	O
his	O
mother	O
intended	O
to	O
put	O
plasters	O
on	O
them	O
to	O
prevent	O
them	O
from	O
spreading	O
.	O

Charles	O
was	O
also	O
feverish	O
;	O
his	O
glands	O
were	O
swollen	O
and	O
his	O
pulse	O
was	O
erratic	O
"	O
but	O
out	O
of	O
compassion	O
to	O
you	O
I	O
must	O
tell	O
you	O
that	O
he	O
is	O
with	O
me	O
as	O
Brisk	O
and	O
lively	O
as	O
you	O
ever	O
Saw	O
him	O
"	O
.	O

Lady	O
Malton	O
had	O
called	O
in	O
two	O
eminent	O
Bristol	O
men	B
,	O
Dr	O
Logan	O
and	O
Mr	O
Pye	O
,	O
to	O
treat	O
the	O
boy	B
;	O
Mr	O
Pye	O
prescribed	O
"	O
the	O
Precipitate	O
Per	O
se	O
"	O
as	O
the	O
cure	O
for	O
the	O
"	O
hectic	O
"	O
.	O

Pye	O
made	O
it	O
himself	O
and	O
said	O
that	O
it	O
was	O
the	O
only	O
remedy	O
that	O
would	O
work	O
.	O

Clearly	O
Charles	O
was	O
impatient	O
to	O
be	O
cured	O
because	O
he	O
told	O
his	O
mother	O
to	O
give	O
him	O
the	O
medicine	O
"	O
to	O
cure	O
me	O
which	O
I	O
am	O
sure	O
it	O
will	O
do	O
or	O
shoot	O
me	O
through	O
the	O
head	O
at	O
once	O
"	O
.	O

She	O
thought	O
that	O
this	O
attitude	O
was	O
"	O
odd	O
from	O
one	O
of	O
his	O
Age	O
and	O
[	O
it	O
]	O
does	O
not	O
a	O
little	O
disturb	O
"	O
.	O
26	O
The	O
blotches	O
began	O
to	O
burst	O
and	O
indent	O
but	O
the	O
doctor	O
thought	O
that	O
all	O
would	O
be	O
well	O
in	O
the	O
end	O
.	O
27	O
Meanwhile	O
,	O
Charles	O
was	O
still	O
losing	O
weight	O
even	O
though	O
"	O
he	O
had	O
none	O
to	O
spare	O
before	O
"	O
and	O
he	O
was	O
inclined	O
to	O
be	O
lazy	O
which	O
was	O
not	O
his	O
natural	O
turn	O
.	O

His	O
father	O
recommended	O
some	O
unknown	O
cure	O
which	O
he	O
called	O
Gascoin	O
'	O
s	O
Powder	O
-	O
a	O
dose	O
of	O
five	O
grains	O
made	O
up	O
with	O
syrup	O
into	O
a	O
pill	O
-	O
every	O
night	O
.	O

To	O
make	O
matters	O
worse	O
,	O
the	O
doctors	O
disagreed	O
about	O
the	O
treatment	O
.	O

"	O
Dr	O
Pye	O
is	O
Vehemently	O
for	O
the	O
P	O
.	O

Per	O
se	O
,	O
Dr	O
Logan	O
saies	O
that	O
it	O
is	O
a	O
Medicine	O
that	O
may	O
prove	O
too	O
rough	O
in	O
its	O
operation	O
for	O
his	O
Constitution	O
&	O
therefore	O
begs	O
a	O
tryal	O
of	O
Beazor	O
mineral	O
[	O
gall	O
stones	O
from	O
a	O
goat	B
]	O
and	O
Viper	O
Broth	O
"	O
.	O

The	O
Bristol	O
water	O
had	O
not	O
yet	O
acted	O
"	O
because	O
his	O
case	O
is	O
of	O
too	O
obstinate	O
a	O
Nature	O
"	O
and	O
Lady	O
Malton	O
herself	O
was	O
satisfied	O
that	O
since	O
nothing	O
else	O
had	O
worked	O
to	O
cure	O
the	O
boy	B
,	O
the	O
time	O
had	O
come	O
to	O
try	O
mercurials	O
,	O
even	O
though	O
she	O
knew	O
that	O
they	O
were	O
"	O
powerful	O
and	O
perhaps	O
in	O
some	O
cases	O
hazardous	O
medicines	O
"	O
.	O
28	O
She	O
wanted	O
to	O
see	O
some	O
remedy	O
succeed	O
but	O
was	O
"	O
afraid	O
of	O
violent	O
ones	O
and	O
at	O
the	O
same	O
time	O
vastly	O
distrustfull	O
[	O
sic	O
]	O
of	O
mild	O
ones	O
"	O
.	O

It	O
would	O
appear	O
that	O
the	O
"	O
precipitate	O
Per	O
se	O
"	O
,	O
probably	O
mercury	O
-	O
based	O
,	O
could	O
be	O
a	O
kill	O
-	O
or	O
-	O
cure	O
remedy	O
.	O

Her	O
"	O
terrors	O
"	O
did	O
not	O
arise	O
from	O
any	O
immediate	O
danger	O
to	O
her	O
son	O
,	O
and	O
her	O
"	O
perfect	O
Knowledge	O
"	O
of	O
his	O
disorder	O
convinced	O
her	O
that	O
whatever	O
remedies	O
he	O
took	O
,	O
the	O
cure	O
was	O
in	O
the	O
hands	O
of	O
God	O
.	O
29	O

To	O
add	O
to	O
Charles	O
'	O
disorders	O
,	O
on	O
12	O
June	O
he	O
developed	O
a	O
"	O
very	O
inflamed	O
bad	O
Eye	O
.	O
.	O
.	O
the	O
same	O
Eye	O
that	O
.	O
.	O
.	O

he	O
did	O
not	O
see	O
so	O
well	O
of	O
[	O
as	O
]	O
the	O
other	O
.	O
.	O
.	O

He	O
sais	O
[	O
sic	O
]	O
that	O
from	O
that	O
eye	O
Alone	O
he	O
can	O
Scarcely	O
distinguish	O
anything	O
"	O
.	O

The	O
doctors	O
suggested	O
bathing	O
the	O
eye	O
:	O
Lady	O
Malton	O
knew	O
that	O
the	O
"	O
frightful	O
symptoms	O
"	O
which	O
were	O
"	O
shocking	O
to	O
behold	O
"	O
were	O
a	O
result	O
of	O
"	O
the	O
Same	O
as	O
produces	O
all	O
the	O
rest	O
of	O
his	O
complaints	O
in	O
whichever	O
Shape	O
they	O
appear	O
"	O
.	O

30	O
The	O
eye	O
was	O
very	O
bloodshot	O
and	O
inflamed	O
;	O
the	O
eyelid	O
was	O
swollen	O
so	O
he	O
could	O
hardly	O
open	O
it	O
.	O

The	O
other	O
eye	O
was	O
dull	O
and	O
"	O
he	O
had	O
very	O
little	O
sight	O
of	O
it	O
"	O
.	O
31	O
By	O
14	O
June	O
the	O
eye	O
problem	O
had	O
eased	O
somewhat	O
but	O
Lady	O
Malton	O
could	O
find	O
no	O
cause	O
to	O
attribute	O
the	O
improvement	O
to	O
any	O
of	O
the	O
"	O
cures	O
"	O
.	O

Charles	O
was	O
still	O
being	O
subjected	O
to	O
Bristol	O
water	O
,	O
Beazor	O
mineral	O
,	O
Viper	O
broth	O
,	O
cinnabar	O
and	O
the	O
precipitate	O
per	O
se	O
.	O
32	O
She	O
decided	O
to	O
take	O
the	O
boy	B
home	O
to	O
Wentworth	O
because	O
he	O
was	O

26	O
WWM	O
,	O
M7	O
-	O
38	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
1	O
June	O
1742	O
.	O

27	O
WWM	O
,	O
M7	O
-	O
39	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
2	O
June	O
1742	O
.	O

28	O
WWM	O
,	O
M7	O
-	O
41	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
5	O
June	O
1742	O
.	O

29	O
WWM	O
,	O
M7	O
-	O
43	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
7	O
June	O
1742	O
.	O

30	O
WWM	O
,	O
M7	O
-	O
45	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
12	O
June	O
1742	O
.	O

31	O
WWM	O
,	O
M7	O
-	O
56	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
undated	O
:	O
12	O
June	O
?	O

1742	O
.	O

32	O
WWM	O
,	O
M7	O
-	O
46	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
14	O
June	O
?	O

1742	O
.	O

181	O

Marjorie	O
Bloy	O

more	O
likely	O
to	O
recover	O
there	O
than	O
anywhere	O
else	O
.	O
33	O
He	O
still	O
ate	O
and	O
slept	O
well	O
and	O
was	O
"	O
pretty	O
cheerful	O
but	O
his	O
looks	O
are	O
bitter	O
bad	O
still	O
.	O

The	O
flesh	O
he	O
lost	O
in	O
the	O
Accidental	O
Feavour	O
he	O
has	O
not	O
Recover	O
'	O
d	O
and	O
his	O
complexion	O
is	O
of	O
the	O
most	O
sickly	O
sort	O
his	O
hands	O
of	O
the	O
same	O
Hue	O
his	O
legs	O
are	O
tollerable	O
[	O
sic	O
]	O
well	O
"	O
.	O
34	O

They	O
returned	O
to	O
Wentworth	O
in	O
short	O
stages	O
and	O
by	O
6	O
September	O
Higham	O
was	O
"	O
perfectly	O
recovered	O
.	O

.	O
.	O
after	O
the	O
long	O
and	O
successful	O
Care	O
that	O
Lady	O
Malton	O
has	O
taken	O
"	O
of	O
him	O
.	O
35	O
In	O
May	O
1743	O
he	O
was	O
inoculated	O
against	O
smallpox	B
and	O
made	O
a	O
perfect	O
recovery	O
after	O
which	O
he	O
caught	O
cold	O
"	O
by	O
stripping	O
when	O
He	O
was	O
hot	O
"	O
.	O
36	O
Lord	O
Higham	O
does	O
not	O
seem	O
to	O
have	O
been	O
seriously	O
ill	O
after	O
that	O
until	O
,	O
at	O
the	O
age	O
of	O
19	O
,	O
he	O
undertook	O
his	O
Grand	O
Tour	O
in	O
1749	O
.	O

In	O
July	O
1750	O
,	O
by	O
then	O
Lord	O
Malton	O
,	O
he	O
had	O
cause	O
to	O
consult	O
Nicolo	O
Scanagati	O
in	O
Padua	O
for	O
the	O
treatment	O
of	O
gonorrhoea	O
.	O

Scanagati	O
produced	O
a	O
lengthy	O
medical	O
report	O
of	O
Malton	O
'	O
s	O
treatment	O
,	O
presumably	O
for	O
his	O
English	O
doctor	O
'	O
s	O
enlightenment	O
.	O
37	O
The	O
initial	O
treatment	O
was	O
an	O
"	O
electuary	O
,	O
consisting	O
of	O
three	O
ounces	O
of	O
emollient	O
,	O
three	O
drams	O
of	O
powdered	O
jalap	B
,	O
a	O
half	O
[	O
dram	O
]	O
of	O
purified	O
nitre	O
,	O
bound	O
together	O
with	O
lemon	B
juice	O
taken	O
twice	O
a	O
day	O
"	O
.	O

The	O
result	O
was	O
satisfactory	O
:	O
"	O
The	O
dark	O
greenish	O
poison	O
was	O
oozing	O
slowly	O
from	O
his	O
penis	O
,	O
which	O
was	O
all	O
contracted	O
and	O
the	O
sharp	O
and	O
constant	O
pain	O
extended	O
from	O
the	O
perineum	O
up	O
to	O
the	O
urinary	O
bladder	O
,	O
producing	O
small	O
swellings	O
now	O
in	O
this	O
place	O
,	O
now	O
in	O
that	O
.	O
"	O
There	O
was	O
a	O
fierce	O
burning	O
sensation	O
in	O
the	O
glands	O
,	O
which	O
prevented	O
him	O
from	O
sleeping	O
.	O

Because	O
of	O
this	O
,	O
it	O
seemed	O
reasonable	O
to	O
bathe	O
that	O
part	O
in	O
tepid	O
water	O
and	O
milk	O
,	O
and	O
to	O
apply	O
poultices	O
to	O
the	O
areas	O
affected	O
by	O
swelling	O
and	O
contractions	O
,	O
together	O
with	O
cold	O
drinks	O
and	O
a	O
few	O
grains	O
of	O
laudanum	O
at	O
night	O
.	O

Malton	O
was	O
blooded	O
regularly	O
besides	O
being	O
given	O
purgatives	O
;	O
the	O
treatment	O
then	O
moved	O
on	O
to	O
the	O
administration	O
of	O
mercury	O
,	O
both	O
internal	O
and	O
on	O
the	O
gums	O
,	O
since	O
it	O
was	O
widely	O
believed	O
at	O
the	O
time	O
that	O
gonorrhoea	O
and	O
syphilis	O
were	O
steps	O
of	O
the	O
same	O
disease	O
,	O
"	O
the	O
Venereal	O
"	O
.	O

Scanagati	O
at	O
this	O
point	O
ruled	O
out	O
the	O
suggestion	O
of	O
syphilitic	O
chancre	O
because	O
Malton	O
'	O
s	O
urine	O
was	O
fine	O
and	O
light	O
with	O
a	O
pungent	O
odour	O
.	O

Scanagati	O
did	O
ask	O
if	O
Malton	O
had	O
previously	O
ever	O
had	O
a	O
similar	O
peculiarity	O
of	O
his	O
urine	O
.	O

Malton	O
replied	O
that	O
when	O
he	O
was	O
very	O
young	O
and	O
still	O
inexperienced	O
sexually	O
,	O
for	O
some	O
time	O
following	O
a	O
fever	O
he	O
had	O
had	O
the	O
same	O
unusual	O
urine	O
,	O
and	O
indeed	O
that	O
on	O
one	O
occasion	O
this	O
symptom	O
coincided	O
with	O
certain	O
tumours	O
on	O
the	O
testicles	O
.	O

It	O
was	O
only	O
by	O
chance	O
that	O
he	O
had	O
not	O
had	O
recourse	O
to	O
surgery	O
,	O
the	O
reason	O
being	O
that	O
he	O
was	O
also	O
afflicted	O
with	O
a	O
throat	O
infection	O
-	O
to	O
which	O
he	O
was	O
prone	O
-	O
and	O
therefore	O
had	O
his	O
vein	O
opened	O
four	O
times	O
.	O

Thereupon	O
the	O
inflammation	O
subsided	O
,	O
and	O
equally	O
the	O
tumours	O
and	O
sediment	O
disappeared	O
.	O

He	O
told	O
me	O
that	O
as	O
a	O
youth	O
he	O
had	O
sometimes	O
experienced	O
some	O
difficulty	O
and	O
a	O
burning	O
sensation	O
when	O
urinating	O
,	O
which	O
subsided	O
when	O
his	O
blood	O
was	O
let	O
and	O
with	O
the	O
application	O
of	O
poultices	O
.	O

I	O
observed	O
that	O
from	O
time	O
to	O
time	O
his	O
face	O
and	O
body	O
were	O
covered	O
with	O
purplish	O
spots	O
,	O
which	O
,	O
having	O
produced	O
a	O
little	O
fluid	O
,	O
would	O
disappearas	O
indeed	O
happened	O
in	O
the	O
course	O
of	O
the	O
cure	O
,	O
at	O
the	O
end	O
of	O
which	O
his	O
face	O
was	O
entirely	O

33	O
WWM	O
,	O
M7	O
-	O
47	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
15	O
June	O
1742	O
.	O

34	O
WWM	O
,	O
M7	O
-	O
48	O
.	O

Lady	O
to	O
Lord	O
Malton	O
,	O
16	O
June	O
1742	O
.	O

35	O
WWM	O
,	O
M2	O
-	O
104	O
/	O
5	O
.	O

Lady	O
Finch	O
to	O
Lady	O
Malton	O
,	O
6	O
September	O
1742	O
.	O

36	O
WWM	O
,	O
M2	O
-	O
135	O
.	O

Lady	O
Finch	O
to	O
Malton	O
,	O
18	O
June	O
1742	O
.	O

37	O
WWM	O
,	O
R170	O
-	O
20	O
.	O

Nicol6	O
Scanagati	O
'	O
s	O
report	O
.	O

182	O

An	O
eighteenth	O
-	O
century	O
Prime	O
Minister	O
'	O
s	O
illness	O

free	O
from	O
these	O
spots	O
.	O

From	O
this	O
observation	O
,	O
it	O
seemed	O
to	O
me	O
simple	O
to	O
deduce	O
both	O
the	O
original	O
cause	O
and	O
the	O
more	O
immediate	O
cause	O
of	O
the	O
said	O
sediment	O
:	O
namely	O
a	O
natural	O
complexion	O
of	O
humours	O
which	O
are	O
exacerbated	O
by	O
muriatic	O
[	O
i	O
.	O
e	O
.	O
,	O
acidic	O
]	O
sourness	O
,	O
together	O
with	O
the	O
marked	O
inflammation	O
of	O
the	O
blood	O
and	O
the	O
motion	O
of	O
the	O
contracted	O
poison	O
.	O

Scanagati	O
then	O
recommended	O
the	O
continuation	O
of	O
the	O
electuary	O
made	O
of	O
emollient	O
,	O
guaiacum	O
resin	O
,	O
balsam	O
,	O
rhubarb	B
,	O
and	O
nitre	O
.	O

What	O
does	O
all	O
this	O
add	O
up	O
to	O
in	O
terms	O
of	O
diagnosis	O
?	O

The	O
early	O
illness	O
is	O
a	O
mystery	O
.	O

Did	O
he	O
have	O
an	O
inguinal	O
hernia	O
;	O
or	O
perhaps	O
mumps	O
or	O
epididymitis	O
?	O

His	O
was	O
a	O
childless	O
marriage	O
.	O

He	O
seems	O
to	O
have	O
been	O
too	O
fit	O
for	O
the	O
illness	O
to	O
have	O
been	O
rheumatic	O
fever	O
.	O

Cystitis	O
was	O
not	O
uncommon	O
and	O
this	O
could	O
certainly	O
lead	O
to	O
"	O
strangury	O
"	O
.	O

Perhaps	O
Rockingham	O
suffered	O
from	O
a	O
congenital	O
defect	O
of	O
his	O
urinogenitary	O
system	O
which	O
would	O
result	O
in	O
recurrent	O
attacks	O
of	O
cystitis	O
and	O
might	O
cause	O
long	O
-	O
term	O
damage	O
to	O
the	O
urinary	O
tract	O
and	O
eventual	O
destruction	O
of	O
the	O
kidneys	O
,	O
precipitating	O
sudden	O
and	O
unexpected	O
death	O
.	O

Another	O
possibility	O
might	O
be	O
diabetes	O
.	O

Rockingham	O
had	O
a	O
urinary	O
infection	O
and	O
certainly	O
suffered	O
from	O
recurrent	O
skin	O
infections	O
,	O
although	O
it	O
appears	O
from	O
Scanagati	O
'	O
s	O
report	O
that	O
these	O
cleared	O
up	O
when	O
mercury	O
was	O
administered	O
.	O

Certainly	O
the	O
marquis	O
complained	O
often	O
about	O
pains	O
in	O
his	O
side	O
and	O
stomach	O
and	O
made	O
no	O
secret	O
of	O
his	O
"	O
old	O
complaint	O
"	O
.	O

He	O
was	O
noticeably	O
less	O
physically	O
active	O
as	O
he	O
moved	O
into	O
his	O
thirties	O
and	O
only	O
occasionally	O
exerted	O
himself	O
by	O
riding	O
any	O
distance	O
,	O
even	O
though	O
he	O
had	O
enjoyed	O
hunting	O
when	O
he	O
was	O
younger	O
.	O

He	O
found	O
the	O
pains	O
caused	O
by	O
his	O
"	O
old	O
complaint	O
"	O
made	O
him	O
feel	O
so	O
ill	O
that	O
he	O
was	O
unable	O
to	O
concentrate	O
on	O
"	O
any	O
Manner	O
of	O
Business	O
"	O
and	O
on	O
occasion	O
it	O
seemed	O
likely	O
to	O
prevent	O
him	O
from	O
attending	O
Parliament	O
.	O
38	O
He	O
may	O
well	O
have	O
suffered	O
from	O
a	O
problem	O
with	O
gallstones	O
from	O
an	O
early	O
age	O
.	O
39	O
He	O
appears	O
to	O
have	O
suffered	O
from	O
a	O
nervous	O
disorder	O
which	O
manifested	O
itself	O
in	O
severe	O
palpitations	O
,	O
trembling	O
,	O
and	O
other	O
types	O
of	O
physical	O
discomforts	O
such	O
as	O
boils	O
and	O
headaches	O
with	O
which	O
he	O
was	O
frequently	O
afflicted	O
.	O
40	O
He	O
probably	O
had	O
constipation	O
too	O
,	O
since	O
he	O
was	O
always	O
dosing	O
himself	O
with	O
purgatives	O
.	O

In	O
fact	O
in	O
April	O
1772	O
the	O
Duke	O
of	O
Richmond	O
decided	O
that	O
Rockingham	O
'	O
s	O
real	O
problem	O
was	O
a	O
"	O
surfeit	O
of	O
physick	O
"	O
41	O
although	O
Edmund	O
Burke	O
noted	O
in	O
June	O
1772	O
that	O
the	O
marquis	O
had	O
had	O
a	O
long	O
and	O
severe	O
illness	O
.	O
42	O
Whatever	O
his	O
many	O
and	O
varied	O
ailments	O
,	O
Rockingham	O
survived	O
until	O
he	O
was	O
52	O
in	O
spite	O
of	O
the	O
attentions	O
of	O
both	O
doctors	O
and	O
quacks	O
and	O
that	O
,	O
for	O
the	O
mid	O
-	O
eighteenth	O
century	O
,	O
was	O
a	O
good	O
age	O
.	O

The	O
mystery	O
still	O
remains	O
,	O
however	O
.	O

Contemporary	O
opinion	O
had	O
it	O
that	O
he	O
died	O
of	O
pneumonia	O
but	O
it	O
must	O
have	O
struck	O

38	O
WWM	O
,	O
R153	O
-	O
1	O
.	O

Rockingham	O
to	O
Burke	O
,	O
31	O
October	O
1767	O
;	O
WWM	O
,	O
RI	O
-	O
1238	O
.	O

Rockingham	O
to	O
Dowdeswell	O
,	O
20	O
October	O
1769	O
;	O
WWM	O
,	O
RI	O
-	O
1928	O
.	O

Rockingham	O
to	O
Savile	O
,	O
September	O
1780	O
.	O

39	O
Ross	O
J	O
.	O

S	O
.	O

Hoffman	O
,	O
The	O
Marquis	O
.	O

A	O
study	O
of	O
Lord	O
Rockingham	O
,	O
1730	O
-	O
1782	O
,	O
New	O
York	O
,	O
Fordham	O
University	O
Press	O
,	O
1973	O
,	O
p	O
.	O

35	O
.	O

This	O
is	O
the	O
only	O
recent	O
biography	O
of	O
the	O
second	O
Marquis	O
of	O
Rockingham	O
,	O
and	O
does	O
not	O
deal	O
with	O
his	O
illnesses	O
.	O

Although	O
he	O
does	O
not	O
give	O
the	O
source	O
of	O
his	O
information	O
,	O
Hoffman	O
asserts	O
that	O
Rockingham	O
was	O
in	O
Bath	O
between	O
March	O
and	O
August	O
1761	O
suffering	O
from	O
gallstones	O
.	O

The	O
marquis	O
would	O
then	O
have	O
been	O
31	O
years	O
old	O
.	O

40	O
Historical	O
Manuscripts	O
Commission	O
,	O
Lindley	O
Wood	O
,	O
p	O
.	O

184	O
.	O

41	O
WWM	O
,	O
RI	O
-	O
1403	O
.	O

Richmond	O
to	O
Rockingham	O
,	O
26	O
April	O
1772	O
.	O

42	O
Burke	O
to	O
James	O
de	O
Lancey	O
,	O
30	O
June	O
1772	O
.	O

The	O
correspondence	O
of	O
Edmund	O
Burke	O
,	O
vol	O
.	O

2	O
,	O
ed	O
.	O

T	O
.	O

W	O
.	O

Copeland	O
and	O
others	O
,	O
Cambridge	O
University	O
Press	O
,	O
1958	O
-	O
1978	O
,	O
p	O
.	O

311	O
.	O

183	O

Marjorie	O
Bloy	O

suddenly	O
:	O
it	O
was	O
only	O
two	O
weeks	O
from	O
him	O
"	O
recovering	O
"	O
to	O
dying	O
.	O

Another	O
almost	O
contemporary	O
account	O
of	O
the	O
marquis	O
'	O
s	O
death	O
came	O
from	O
the	O
Earl	O
of	O
Albemarle	O
.	O

He	O
noted	O
that	O
Rockingham	O
had	O
"	O
for	O
some	O
time	O
past	O
been	O
afflicted	O
with	O
water	O
on	O
the	O
chest	O
:	O
and	O
to	O
this	O
well	O
-	O
known	O
malady	O
was	O
superadded	O
the	O
then	O
novel	O
disease	O
of	O
influenza	O
"	O
.	O
43	O
This	O
conceivably	O
could	O
be	O
an	O
uninformed	O
account	O
,	O
handed	O
down	O
orally	O
by	O
surviving	O
members	O
of	O
the	O
marquis	O
'	O
s	O
family	O
,	O
of	O
emphysema	O
.	O

More	O
fascinating	O
than	O
the	O
diagnosis	O
of	O
the	O
cause	O
of	O
death	O
,	O
however	O
,	O
is	O
-	O
what	O
was	O
wrong	O
with	O
him	O
during	O
his	O
lifetime	O
?	O

Or	O
is	O
it	O
yet	O
another	O
example	O
of	O
the	O
"	O
English	O
disease	O
"	O
:	O
hypochondria	O
?	O

43Albemarle	O
,	O
George	O
Thomas	O
,	O
Earl	O
of	O
,	O
Memoirs	O
of	O
the	O
Marquis	O
of	O
Rockingham	O
and	O
his	O
contemporaries	O
,	O
London	O
,	O
Richard	O
Bentley	O
,	O
2	O
vols	O
.	O
,	O
1852	O
,	O
vol	O
.	O

2	O
,	O
p	O
.	O

483	O
.	O

This	O
is	O
the	O
only	O
contemporary	O
work	O
concerning	O
Rockingham	O
,	O
but	O
does	O
not	O
mention	O
his	O
early	O
life	O
and	O
illnesses	O
.	O

184	O

Tissue	O
-	O
dependent	O
isoforms	O
of	O
mammalian	O
Fox	O
-	O
1	O
homologs	O
are	O
associated	O
with	O
tissue	O
-	O
specific	O
splicing	O
activities	O

Abstract	O

An	O
intronic	O
hexanucleotide	O
UGCAUG	O
has	O
been	O
shown	O
to	O
play	O
a	O
critical	O
role	O
in	O
the	O
regulation	O
of	O
tissue	O
-	O
specific	O
alternative	O
splicing	O
of	O
pre	O
-	O
mRNAs	O
in	O
a	O
wide	O
range	O
of	O
tissues	O
.	O

Vertebrate	O
Fox	O
-	O
1	O
has	O
been	O
shown	O
to	O
bind	O
to	O
this	O
element	O
,	O
in	O
a	O
highly	O
sequence	O
-	O
specific	O
manner	O
,	O
through	O
its	O
RNA	O
recognition	O
motif	O
(	O
RRM	O
)	O
.	O

In	O
mammals	O
,	O
there	O
are	O
at	O
least	O
two	O
Fox	O
-	O
1	O
-	O
related	O
genes	O
,	O
ataxin	O
-	O
2	O
binding	O
protein	O
1	O
(	O
A2BP1	O
)	O
/	O
Fox	O
-	O
1	O
and	O
Fxh	O
/	O
Rbm9	O
,	O
which	O
encode	O
an	O
identical	O
RRM	O
.	O

Here	O
,	O
we	O
demonstrate	O
that	O
both	O
mouse	B
Fxh	O
and	O
A2BP1	O
transcripts	O
undergo	O
tissue	O
-	O
specific	O
alternative	O
splicing	O
,	O
generating	O
protein	O
isoforms	O
specific	O
to	O
brain	O
and	O
muscle	O
.	O

These	O
tissue	O
-	O
specific	O
isoforms	O
are	O
characterized	O
for	O
their	O
abilities	O
to	O
regulate	O
neural	O
cell	O
-	O
specific	O
alternative	O
splicing	O
of	O
a	O
cassette	O
exon	O
,	O
N30	O
,	O
in	O
the	O
non	O
-	O
muscle	O
myosin	O
heavy	O
chain	O
II	O
-	O
B	O
pre	O
-	O
mRNA	O
,	O
previously	O
shown	O
to	O
be	O
regulated	O
through	O
an	O
intronic	O
distal	O
downstream	O
enhancer	O
(	O
IDDE	O
)	O
.	O

All	O
Fxh	O
and	O
A2BP1	O
isoforms	O
with	O
the	O
RRM	O
are	O
capable	O
of	O
binding	O
to	O
the	O
IDDE	O
in	O
vitro	O
through	O
the	O
UGCAUG	O
elements	O
.	O

Each	O
isoform	O
,	O
however	O
,	O
shows	O
quantitative	O
differences	O
in	O
splicing	O
activity	O
and	O
nuclear	O
distribution	O
in	O
transfected	O
cells	O
.	O

All	O
Fxh	O
isoforms	O
and	O
a	O
brain	O
isoform	O
of	O
A2BP1	O
show	O
a	O
predominant	O
nuclear	O
localization	O
.	O

Brain	O
isoforms	O
of	O
both	O
Fxh	O
and	O
A2BP1	O
promote	O
N30	O
splicing	O
much	O
more	O
efficiently	O
than	O
do	O
the	O
muscle	O
-	O
specific	O
isoforms	O
.	O

Skeletal	O
muscles	O
express	O
additional	O
isoforms	O
that	O
lack	O
a	O
part	O
of	O
the	O
RRM	O
.	O

These	O
isoforms	O
are	O
incapable	O
of	O
activating	O
neural	O
cell	O
-	O
specific	O
splicing	O
and	O
,	O
moreover	O
,	O
can	O
inhibit	O
UGCAUG	O
-	O
dependent	O
N30	O
splicing	O
.	O

These	O
findings	O
suggest	O
that	O
tissue	O
-	O
specific	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
play	O
an	O
important	O
role	O
in	O
determining	O
tissue	O
specificity	O
of	O
UGCAUG	O
-	O
mediated	O
alternative	O
splicing	O
.	O

INTRODUCTION	O

Alternative	O
splicing	O
of	O
pre	O
-	O
mRNA	O
is	O
one	O
of	O
the	O
fundamental	O
mechanisms	O
for	O
the	O
regulation	O
of	O
gene	O
expression	O
in	O
higher	O
eukaryotes	O
(	O
1	O
,	O
2	O
)	O
.	O

Developmentally	O
regulated	O
,	O
cell	O
type	O
-	O
or	O
tissue	O
-	O
specific	O
,	O
and	O
signal	O
-	O
induced	O
alternative	O
splicing	O
of	O
pre	O
-	O
mRNAs	O
takes	O
place	O
in	O
multicellular	O
organisms	O
throughout	O
their	O
lifetimes	O
.	O

Misregulation	O
or	O
abnormalities	O
in	O
pre	O
-	O
mRNA	O
splicing	O
,	O
in	O
some	O
instances	O
,	O
leads	O
to	O
cellular	O
dysfunctions	O
found	O
in	O
human	B
and	O
animal	O
diseases	O
(	O
3	O
-	O
5	O
)	O
.	O

Using	O
various	O
model	O
systems	O
of	O
regulated	O
alternative	O
splicing	O
,	O
a	O
number	O
of	O
pre	O
-	O
mRNA	O
features	O
that	O
influence	O
alternative	O
splice	O
site	O
selection	O
have	O
been	O
defined	O
(	O
1	O
,	O
2	O
)	O
.	O

These	O
include	O
enhancer	O
and	O
repressor	O
RNA	O
sequences	O
located	O
in	O
exons	O
and	O
introns	O
.	O

Identification	O
of	O
RNA	O
-	O
binding	O
proteins	O
targeting	O
these	O
cis	O
-	O
regulatory	O
elements	O
is	O
currently	O
in	O
progress	O
.	O

In	O
vertebrates	O
,	O
participation	O
of	O
the	O
SR	O
family	O
proteins	O
and	O
hnRNP	O
proteins	O
,	O
such	O
as	O
PTB	O
and	O
hnRNPA1	O
,	O
in	O
alternative	O
splicing	O
regulation	O
via	O
binding	O
to	O
the	O
cis	O
-	O
regulatory	O
elements	O
have	O
been	O
shown	O
in	O
many	O
tissue	O
-	O
specific	O
splicing	O
models	O
(	O
6	O
,	O
7	O
)	O
.	O

Although	O
these	O
RNA	O
-	O
binding	O
proteins	O
are	O
ubiquitously	O
expressed	O
,	O
their	O
different	O
abundance	O
in	O
different	O
cells	O
,	O
differences	O
in	O
their	O
post	O
-	O
translational	O
modifications	O
in	O
different	O
cellular	O
contexts	O
and	O
their	O
different	O
abilities	O
to	O
assemble	O
multiprotein	O
complexes	O
in	O
different	O
pre	O
-	O
mRNA	O
contexts	O
are	O
thought	O
to	O
contribute	O
to	O
the	O
determination	O
of	O
cell	O
type	O
-	O
specific	O
patterns	O
of	O
alternative	O
splicing	O
.	O

For	O
the	O
last	O
few	O
years	O
,	O
tissue	O
-	O
specific	O
and	O
tissue	O
-	O
enriched	O
RNA	O
-	O
binding	O
proteins	O
have	O
begun	O
to	O
be	O
identified	O
as	O
splicing	O
regulators	O
.	O

These	O
include	O
brain	O
-	O
specific	O
(	O
or	O
enriched	O
)	O
Nova	O
-	O
1	O
,	O
nPTB	O
(	O
brPTB	O
)	O
and	O
some	O
of	O
the	O
CELF	O
family	O
proteins	O
(	O
8	O
-	O
12	O
)	O
.	O

Discovery	O
of	O
these	O
proteins	O
has	O
had	O
a	O
great	O
impact	O
on	O
studies	O
aimed	O
at	O
understanding	O
the	O
molecular	O
mechanisms	O
of	O
alternative	O
splicing	O
regulation	O
.	O

One	O
of	O
the	O
intronic	O
cis	O
-	O
elements	O
,	O
which	O
are	O
involved	O
in	O
tissue	O
-	O
specific	O
or	O
differentiation	O
stage	O
-	O
dependent	O
regulation	O
of	O
alternative	O
splicing	O
,	O
is	O
the	O
hexanucleotide	O
UGCAUG	O
.	O

The	O
importance	O
of	O
this	O
element	O
was	O
originally	O
recognized	O
in	O
fibronectin	O
pre	O
-	O
mRNA	O
by	O
Huh	O
and	O
Hynes	O
(	O
13	O
)	O
.	O

Since	O
then	O
,	O
alternative	O
splicing	O
specific	O
to	O
a	O
variety	O
of	O
tissues	O
or	O
cell	O
types	O
,	O
including	O
neural	O
cells	O
,	O
muscles	O
,	O
epithelial	O
cells	O
and	O
erythrocytes	O
,	O
has	O
been	O
shown	O
to	O
be	O
modulated	O
via	O
this	O
element	O
(	O
14	O
-	O
21	O
)	O
.	O

Recently	O
,	O
Jin	O
et	O
al	O
.	O

(	O
21	O
)	O
discovered	O
that	O
a	O
zebrafish	B
homolog	O
of	O
Caenorhabditis	B
elegans	I
Fox	O
-	O
1	O
(	O
22	O
)	O
could	O
bind	O
specifically	O
to	O
the	O
pentanucleotide	O
GCAUG	O
by	O
in	O
vitro	O
selection	O
from	O
randomized	O
RNA	O
sequences	O
.	O

This	O
pentanucleotide	O
is	O
almost	O
identical	O
to	O
the	O
hexanucleotide	O
UGCAUG	O
except	O
for	O
the	O
first	O
U	O
.	O

Moreover	O
,	O
the	O
zebrafish	B
Fox	O
-	O
1	O
homolog	O
,	O
as	O
well	O
as	O
the	O
mouse	B
Fox	O
-	O
1	O
homolog	O
,	O
are	O
capable	O
of	O
repressing	O
the	O
inclusion	O
of	O
an	O
alternative	O
cassette	O
exon	O
of	O
the	O
ATP	O
synthase	O
F1	O
gamma	O
pre	O
-	O
mRNA	O
via	O
binding	O
to	O
GCAUG	O
,	O
which	O
mimics	O
muscle	O
-	O
specific	O
exclusion	O
of	O
this	O
exon	O
.	O

This	O
mouse	B
homolog	O
is	O
identical	O
to	O
the	O
ataxin	O
-	O
2	O
binding	O
protein	O
1	O
(	O
A2BP1	O
)	O
,	O
which	O
has	O
been	O
previously	O
cloned	O
in	O
humans	B
and	O
mice	B
as	O
the	O
cDNA	O
encoding	O
a	O
protein	O
,	O
which	O
interacts	O
with	O
ataxin	O
-	O
2	O
,	O
the	O
product	O
of	O
the	O
causative	O
gene	O
for	O
spinocerebellar	O
ataxia	O
type	O
2	O
(	O
23	O
,	O
24	O
)	O
.	O

In	O
addition	O
to	O
A2BP1	O
/	O
Fox	O
-	O
1	O
,	O
another	O
mouse	B
homolog	O
of	O
C	B
.	I
elegans	I
Fox	O
-	O
1	O
,	O
Fxh	O
,	O
has	O
been	O
independently	O
cloned	O
as	O
a	O
cDNA	O
,	O
which	O
is	O
induced	O
by	O
androgen	O
in	O
motor	O
neurons	O
(	O
25	O
)	O
.	O

Of	O
note	O
is	O
that	O
A2BP1	O
/	O
Fox	O
-	O
1	O
and	O
Fxh	O
share	O
an	O
identical	O
RNA	O
recognition	O
motif	O
(	O
RRM	O
)	O
at	O
the	O
amino	O
acid	O
level	O
.	O

Therefore	O
,	O
two	O
genes	O
in	O
the	O
mouse	B
genome	O
encode	O
homologs	O
of	O
nematode	O
Fox	O
-	O
1	O
.	O

According	O
to	O
the	O
names	O
given	O
by	O
the	O
first	O
cDNA	O
cloning	O
,	O
we	O
used	O
the	O
nomenclature	O
of	O
A2BP1	O
and	O
Fxh	O
in	O
this	O
report	O
.	O

A2BP1	O
and	O
Fxh	O
have	O
been	O
named	O
A2BP1	O
and	O
Rbm9	O
,	O
respectively	O
,	O
in	O
the	O
human	B
and	O
mouse	B
genomes	O
.	O

We	O
have	O
been	O
studying	O
regulatory	O
mechanisms	O
of	O
neural	O
cell	O
-	O
specific	O
alternative	O
splicing	O
using	O
the	O
non	O
-	O
muscle	O
myosin	O
heavy	O
chain	O
II	O
-	O
B	O
(	O
NMHC	O
-	O
B	O
)	O
gene	O
as	O
a	O
model	O
system	O
(	O
14	O
,	O
26	O
)	O
.	O

NMHC	O
-	O
B	O
mRNA	O
is	O
expressed	O
ubiquitously	O
.	O

However	O
,	O
an	O
alternative	O
exon	O
,	O
N30	O
,	O
which	O
encodes	O
a	O
30	O
nt	O
coding	O
sequence	O
,	O
is	O
included	O
in	O
the	O
mRNAs	O
from	O
some	O
neural	O
cells	O
,	O
but	O
is	O
skipped	O
in	O
those	O
from	O
all	O
other	O
cells	O
in	O
mammals	O
and	O
birds	O
(	O
27	O
,	O
28	O
)	O
.	O

In	O
cultured	O
cells	O
,	O
a	O
switch	O
in	O
N30	O
splicing	O
from	O
exclusion	O
to	O
inclusion	O
can	O
be	O
seen	O
in	O
neural	O
retinoblastoma	O
Y79	O
cells	O
during	O
the	O
post	O
-	O
mitotic	O
and	O
differentiated	O
stages	O
triggered	O
by	O
butyrate	O
treatment	O
.	O

We	O
have	O
previously	O
defined	O
an	O
intronic	O
distal	O
downstream	O
enhancer	O
(	O
IDDE	O
)	O
,	O
which	O
confers	O
neural	O
cell	O
specificity	O
on	O
N30	O
inclusion	O
,	O
using	O
this	O
cell	O
line	O
(	O
14	O
)	O
.	O

The	O
IDDE	O
includes	O
two	O
copies	O
of	O
UGCAUG	O
.	O

Mutation	O
of	O
these	O
hexanucleotides	O
results	O
in	O
N30	O
skipping	O
in	O
post	O
-	O
mitotic	O
differentiated	O
Y79	O
cells	O
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
the	O
possible	O
involvement	O
of	O
A2BP1	O
and	O
Fxh	O
in	O
the	O
regulation	O
of	O
N30	O
splicing	O
.	O

To	O
this	O
end	O
,	O
we	O
have	O
isolated	O
cDNA	O
clones	O
for	O
A2BP1	O
and	O
Fxh	O
from	O
brain	O
and	O
muscles	O
.	O

cDNA	O
cloning	O
revealed	O
the	O
existence	O
of	O
tissue	O
-	O
specific	O
(	O
enriched	O
)	O
isoforms	O
of	O
both	O
A2BP1	O
and	O
Fxh	O
.	O

Of	O
importance	O
,	O
different	O
isoforms	O
of	O
A2BP1	O
and	O
Fxh	O
show	O
different	O
activities	O
with	O
respect	O
to	O
N30	O
splicing	O
as	O
well	O
as	O
different	O
subcellular	O
localizations	O
.	O

MATERIALS	O
AND	O
METHODS	O

Database	O
disposition	O

The	O
sequences	O
reported	O
in	O
this	O
paper	O
have	O
been	O
deposited	O
in	O
the	O
GenBank	O
database	O
with	O
accession	O
numbers	O
AY659951	O
(	O
F011	O
)	O
,	O
AY659952	O
(	O
F411	O
)	O
,	O
AY659953	O
(	O
F402	O
)	O
,	O
AY659954	O
(	O
A016	O
)	O
,	O
AY659955	O
(	O
A030	O
)	O
,	O
AY659956	O
(	O
A713	O
)	O
,	O
AY659957	O
(	O
A715	O
)	O
and	O
AY659958	O
(	O
A704	O
)	O
.	O

RNA	O
preparation	O
and	O
RT	O
-	O
PCR	O

Total	O
RNAs	O
were	O
isolated	O
from	O
mouse	B
tissues	O
and	O
cultured	O
cells	O
using	O
an	O
RNA	O
isolation	O
kit	O
(	O
Stratagene	O
)	O
or	O
an	O
RNeasy	O
mini	O
kit	O
(	O
Qiagen	O
)	O
.	O

To	O
obtain	O
the	O
full	O
-	O
length	O
coding	O
regions	O
of	O
cDNAs	O
for	O
Fxh	O
and	O
A2BP1	O
,	O
RT	O
-	O
PCRs	O
were	O
performed	O
using	O
Superscript	O
II	O
RNase	O
H	O
-	O
reverse	O
transcriptase	O
(	O
Invitrogen	O
)	O
and	O
Pfu	O
Turbo	O
DNA	O
polymerase	O
(	O
Stratagene	O
)	O
.	O

The	O
PCR	O
primers	O
used	O
to	O
obtain	O
all	O
Fxh	O
cDNAs	O
were	O
5	O
'	O
-	O
ctcaggcctccactagttAT	O
-	O
3	O
'	O
and	O
5	O
'	O
-	O
ctcaggcctcctctagaaGT	O
-	O
3	O
'	O
.	O

The	O
upstream	O
primers	O
for	O
the	O
brain	O
(	O
A016	O
and	O
A030	O
)	O
and	O
muscle	O
(	O
A713	O
,	O
A715	O
and	O
A704	O
)	O
A2BP1	O
cDNAs	O
were	O
5	O
'	O
-	O
ctcaggcctccactagtgAT	O
-	O
3	O
'	O
and	O
5	O
'	O
-	O
ctcaggcctccactagtcAT	O
-	O
3	O
'	O
,	O
respectively	O
,	O
and	O
the	O
downstream	O
primer	O
for	O
all	O
A2BP1	O
cDNAs	O
was	O
5	O
'	O
-	O
ctcaggcctcctctagagAT	O
-	O
3	O
'	O
.	O

Lower	O
case	O
letters	O
represent	O
adapter	O
sequences	O
including	O
restriction	O
enzyme	O
sites	O
.	O

5	O
'	O
Rapid	O
amplification	O
of	O
cDNA	O
ends	O
(	O
RACE	O
)	O
was	O
performed	O
using	O
Marathon	O
-	O
Ready	O
cDNA	O
(	O
BD	O
Biosciences	O
Clontech	O
)	O
.	O

For	O
the	O
analysis	O
of	O
minigene	O
and	O
NMHC	O
-	O
B	O
mRNAs	O
,	O
RT	O
-	O
PCRs	O
were	O
performed	O
as	O
described	O
previously	O
(	O
14	O
,	O
26	O
)	O
.	O

Sequences	O
of	O
primers	O
P1	O
-	O
P9	O
shown	O
in	O
Figures	O
1	O
,	O
4	O
and	O
6	O
are	O
as	O
follows	O
:	O
P1	O
,	O
5	O
'	O
-	O
AATTCACCCAGCAACCAGAA	O
-	O
3	O
'	O
;	O
P2	O
,	O
5	O
'	O
-	O
TAGAGGGATGTAAGTGTTGA	O
-	O
3	O
'	O
;	O
P3	O
,	O
5	O
'	O
-	O
CAGAGGGCGGACAGTGTATG	O
-	O
3	O
'	O
;	O
P4	O
,	O
5	O
'	O
-	O
GGCGGCAGGGGCGAGGGCAT	O
-	O
3	O
'	O
;	O
P5	O
,	O
5	O
'	O
-	O
CCGTGGTCGCACCGTGTACA	O
-	O
3	O
'	O
;	O
P6	O
,	O
5	O
'	O
-	O
CAGCGGCAGTGGCAGGGGTG	O
-	O
3	O
'	O
;	O
P7	O
,	O
5	O
'	O
-	O
AGGAAGAAAGGACCATAATA	O
-	O
3	O
'	O
;	O
P8	O
,	O
5	O
'	O
-	O
CCTCCACCCAGCTCCAGTTG	O
-	O
3	O
'	O
;	O
and	O
P9	O
,	O
5	O
'	O
-	O
CCTGTAGTTATTAAATCCTT	O
-	O
3	O
'	O
.	O

Preparation	O
of	O
expression	O
constructs	O
and	O
minigenes	O

The	O
cDNAs	O
of	O
Fxh	O
and	O
A2BP1	O
were	O
introduced	O
into	O
a	O
plasmid	O
pCS3	O
+	O
MT	O
,	O
which	O
contains	O
a	O
myc	O
-	O
epitope	O
,	O
and	O
its	O
modified	O
version	O
pCS3	O
+	O
MT	O
+	O
NLS	O
,	O
which	O
in	O
addition	O
contains	O
the	O
nuclear	O
localization	O
signal	O
(	O
NLS	O
)	O
of	O
the	O
SV40	B
large	O
T	O
antigen	O
(	O
26	O
)	O
.	O

Minigenes	O
G	O
,	O
J	O
without	O
the	O
IDDE	O
,	O
and	O
H	O
with	O
the	O
wild	O
-	O
type	O
IDDE	O
are	O
the	O
same	O
as	O
minigenes	O
W	O
,	O
D4	O
and	O
Cm0	O
,	O
respectively	O
in	O
ref	O
.	O

(	O
14	O
)	O
.	O

The	O
201	O
nt	O
IDDEs	O
with	O
mutations	O
were	O
generated	O
by	O
recombinant	O
PCR	O
using	O
the	O
appropriate	O
primers	O
,	O
which	O
included	O
mutated	O
sequences	O
.	O

The	O
hexanucleotide	O
TGCATG	O
sequences	O
at	O
the	O
5	O
'	O
and	O
3	O
'	O
sides	O
were	O
changed	O
to	O
GTTACT	O
and	O
ACCTAC	O
,	O
respectively	O
.	O

Electrophoresis	O
mobility	O
shift	O
assay	O

Template	O
DNAs	O
for	O
in	O
vitro	O
RNA	O
transcription	O
were	O
prepared	O
by	O
PCR	O
using	O
the	O
wild	O
-	O
type	O
and	O
mutant	O
IDDEs	O
in	O
the	O
minigenes	O
as	O
templates	O
and	O
an	O
upstream	O
primer	O
that	O
included	O
the	O
T7	O
promoter	O
sequence	O
at	O
the	O
5	O
'	O
end	O
.	O

The	O
probe	O
and	O
competitor	O
RNAs	O
were	O
transcribed	O
by	O
T7	O
RNA	O
polymerase	O
in	O
the	O
presence	O
of	O
[	O
alpha	O
-	O
32P	O
]	O
UTP	O
and	O
a	O
trace	O
amount	O
of	O
[	O
35S	O
]	O
UTP	O
alpha	O
S	O
,	O
respectively	O
,	O
using	O
a	O
MAXIscript	O
kit	O
(	O
Ambion	O
)	O
.	O

Mole	O
concentrations	O
of	O
synthesized	O
RNAs	O
were	O
estimated	O
by	O
radioactivities	O
.	O

Fxh	O
and	O
A2BP1	O
proteins	O
with	O
a	O
myc	O
tag	O
were	O
synthesized	O
in	O
vitro	O
by	O
using	O
a	O
TNT	O
quick	O
-	O
coupled	O
transcription	O
/	O
translation	O
system	O
(	O
Promega	O
)	O
from	O
pCS3	O
+	O
MT	O
constructs	O
,	O
which	O
include	O
the	O
SP6	O
promoter	O
.	O

Binding	O
reactions	O
were	O
carried	O
out	O
in	O
a	O
10	O
mu	O
l	O
mixture	O
that	O
contains	O
10	O
mM	O
HEPES	O
(	O
pH	O
7	O
.	O
9	O
)	O
,	O
2	O
mM	O
MgCl2	O
,	O
50	O
mM	O
KCl	O
,	O
5	O
%	O
glycerol	O
,	O
0	O
.	O
5	O
mM	O
DTT	O
,	O
5	O
mu	O
g	O
tRNA	O
,	O
1	O
mu	O
l	O
reticulocyte	O
lysate	O
reaction	O
mixture	O
and	O
15	O
fmol	O
of	O
probe	O
,	O
on	O
ice	O
for	O
20	O
-	O
30	O
min	O
.	O

An	O
aliquot	O
of	O
5	O
mu	O
g	O
of	O
heparin	O
was	O
added	O
to	O
the	O
reaction	O
10	O
min	O
before	O
gel	O
electrophoresis	O
.	O

The	O
reaction	O
mixtures	O
were	O
analyzed	O
by	O
electrophoresis	O
in	O
a	O
6	O
%	O
polyacrylamide	O
gel	O
using	O
a	O
0	O
.	O
5	O
x	O
TBE	O
buffer	O
(	O
Invitrogen	O
)	O
.	O

Cell	O
culture	O
and	O
transfection	O

The	O
human	B
retinoblastoma	O
cell	O
line	O
Y79	O
was	O
cultured	O
and	O
transfected	O
with	O
DNAs	O
as	O
described	O
previously	O
(	O
14	O
,	O
26	O
)	O
.	O

Total	O
amounts	O
of	O
transfected	O
DNAs	O
were	O
adjusted	O
to	O
be	O
constant	O
by	O
addition	O
of	O
the	O
empty	O
vector	O
.	O

Either	O
Lipofectin	O
(	O
Invitrogen	O
)	O
or	O
Effectene	O
transfection	O
reagent	O
(	O
Qiagen	O
)	O
was	O
used	O
for	O
the	O
transfection	O
.	O

For	O
stable	O
transfection	O
,	O
the	O
pCS3	O
+	O
MT	O
expression	O
constructs	O
were	O
co	O
-	O
transfected	O
with	O
a	O
plasmid	O
carrying	O
a	O
neomycin	O
resistant	O
gene	O
and	O
selected	O
by	O
0	O
.	O
2	O
mM	O
geneticin	O
(	O
Invitrogen	O
)	O
.	O

For	O
differentiation	O
of	O
Y79	O
cells	O
,	O
cells	O
were	O
plated	O
on	O
the	O
poly	O
-	O
d	O
-	O
lysine	O
-	O
coated	O
plates	O
and	O
then	O
treated	O
with	O
2	O
.	O
0	O
-	O
2	O
.	O
5	O
mM	O
sodium	O
butyrate	O
for	O
4	O
-	O
5	O
days	O
.	O

HeLa	O
cells	O
were	O
cultured	O
as	O
described	O
and	O
transfected	O
with	O
DNA	O
using	O
Effectene	O
reagent	O
(	O
14	O
,	O
26	O
)	O
.	O

Immunoblot	O
analysis	O

Samples	O
that	O
required	O
both	O
protein	O
and	O
mRNA	O
analysis	O
were	O
split	O
upon	O
harvesting	O
.	O

Total	O
cell	O
proteins	O
were	O
subjected	O
to	O
SDS	O
-	O
PAGE	O
and	O
blotted	O
as	O
described	O
previously	O
(	O
26	O
)	O
.	O

The	O
primary	O
antibodies	O
used	O
are	O
monoclonal	O
antibodies	O
to	O
a	O
myc	O
-	O
epitope	O
(	O
Invitrogen	O
)	O
and	O
green	O
fluorescent	O
protein	O
(	O
GFP	O
)	O
(	O
Clontech	O
)	O
.	O

Binding	O
of	O
antibodies	O
was	O
detected	O
with	O
the	O
SuperSignal	O
System	O
(	O
Pierce	O
)	O
or	O
ECL	O
(	O
Amersham	O
)	O
.	O

Immunofluorescent	O
microscopy	O

HeLa	O
or	O
Y79	O
cells	O
grown	O
in	O
a	O
four	O
-	O
chamber	O
glass	O
slide	O
were	O
transfected	O
as	O
described	O
above	O
.	O

Cells	O
were	O
fixed	O
with	O
10	O
%	O
formaldehyde	O
24	O
-	O
48	O
h	O
after	O
transfection	O
,	O
and	O
permealized	O
with	O
0	O
.	O
5	O
%	O
Triton	O
X	O
-	O
100	O
then	O
blocked	O
with	O
5	O
%	O
goat	B
serum	O
.	O

Primary	O
antibodies	O
used	O
were	O
mouse	B
anti	O
-	O
myc	O
(	O
Invitrogen	O
)	O
,	O
rabbit	B
anti	O
-	O
NMHC	O
-	O
B	O
(	O
29	O
)	O
.	O

Secondary	O
antibodies	O
were	O
Alexa	O
Fluor	O
594	O
goat	B
anti	O
-	O
mouse	B
IgG	O
and	O
Alexa	O
Fluor	O
488	O
goat	B
anti	O
-	O
rabbit	B
IgG	O
(	O
Molecular	O
Probes	O
)	O
.	O

DAPI	O
was	O
used	O
for	O
DNA	O
staining	O
.	O

Specimens	O
were	O
mounted	O
in	O
ProLong	O
antifed	O
kit	O
(	O
Molecular	O
Probe	O
)	O
.	O

The	O
images	O
were	O
collected	O
using	O
Leica	O
SP	O
confocal	O
microscopy	O
(	O
Leica	O
)	O
.	O

RESULTS	O

Tissue	O
-	O
dependent	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
and	O
their	O
subcellular	O
distribution	O

The	O
A2BP1	O
mRNAs	O
are	O
detected	O
almost	O
exclusively	O
in	O
brain	O
and	O
striated	O
muscles	O
(	O
heart	O
and	O
skeletal	O
muscles	O
)	O
in	O
adult	O
mice	B
,	O
whereas	O
the	O
Fxh	O
mRNAs	O
are	O
expressed	O
in	O
a	O
wide	O
variety	O
of	O
tissues	O
with	O
the	O
highest	O
expression	O
in	O
brain	O
and	O
heart	O
[	O
(	O
21	O
,	O
25	O
)	O
and	O
S	O
.	O
Kawamoto	O
,	O
unpublished	O
data	O
]	O
.	O

These	O
expression	O
profiles	O
prompted	O
us	O
to	O
characterize	O
the	O
mRNAs	O
of	O
A2BP1	O
and	O
Fxh	O
in	O
brain	O
and	O
muscles	O
.	O

We	O
have	O
cloned	O
cDNAs	O
for	O
two	O
gene	O
transcripts	O
from	O
brain	O
,	O
heart	O
and	O
skeletal	O
muscles	O
by	O
RT	O
-	O
PCR	O
and	O
5	O
'	O
RACE	O
.	O

The	O
isolated	O
cDNAs	O
are	O
schematically	O
presented	O
with	O
genomic	O
structures	O
in	O
Figure	O
1	O
(	O
for	O
amino	O
acid	O
sequences	O
see	O
also	O
Figure	O
8	O
)	O
.	O

Both	O
gene	O
transcripts	O
are	O
found	O
to	O
undergo	O
tissue	O
-	O
specific	O
alternative	O
splicing	O
.	O

In	O
both	O
cases	O
,	O
brain	O
and	O
striated	O
muscles	O
express	O
unique	O
splice	O
variants	O
generated	O
by	O
mutually	O
exclusive	O
splicing	O
of	O
exons	O
B40	O
and	O
M43	O
,	O
respectively	O
,	O
which	O
provide	O
different	O
coding	O
sequences	O
in	O
the	O
middle	O
of	O
the	O
carboxyl	O
half	O
of	O
the	O
molecules	O
.	O

Southern	O
blot	O
analysis	O
of	O
the	O
RT	O
-	O
PCR	O
products	O
of	O
the	O
Fxh	O
mRNAs	O
from	O
the	O
different	O
tissues	O
probed	O
by	O
oligonucleotides	O
corresponding	O
to	O
B40	O
and	O
M43	O
shows	O
that	O
M43	O
is	O
exclusively	O
used	O
in	O
heart	O
and	O
skeletal	O
muscles	O
,	O
while	O
B40	O
is	O
predominantly	O
used	O
in	O
brain	O
(	O
Figure	O
2A	O
)	O
.	O

Digestion	O
of	O
the	O
RT	O
-	O
PCR	O
products	O
of	O
the	O
A2BP1	O
mRNAs	O
with	O
restriction	O
enzymes	O
unique	O
to	O
B40	O
and	O
M43	O
demonstrates	O
that	O
B40	O
and	O
M43	O
are	O
used	O
almost	O
exclusively	O
in	O
brain	O
and	O
muscles	O
,	O
respectively	O
(	O
Figure	O
2B	O
)	O
.	O

A2BP1	O
contains	O
an	O
additional	O
cassette	O
type	O
alternative	O
exon	O
A53	O
,	O
consisting	O
of	O
53	O
nt	O
.	O

Inclusion	O
and	O
exclusion	O
of	O
exon	O
A53	O
results	O
in	O
two	O
different	O
amino	O
acid	O
sequences	O
at	O
the	O
C	O
-	O
terminal	O
region	O
owing	O
to	O
a	O
frame	O
shift	O
.	O

In	O
the	O
case	O
of	O
the	O
A2BP1	O
gene	O
,	O
moreover	O
,	O
it	O
appears	O
that	O
brain	O
and	O
striated	O
muscle	O
utilize	O
alternative	O
promoters	O
,	O
resulting	O
in	O
different	O
amino	O
acid	O
sequences	O
at	O
the	O
N	O
-	O
terminus	O
.	O

The	O
5	O
'	O
RACE	O
of	O
skeletal	O
muscle	O
mRNAs	O
yielded	O
essentially	O
a	O
single	O
species	O
of	O
sequence	O
with	O
29	O
unique	O
N	O
-	O
terminal	O
amino	O
acids	O
.	O

The	O
5	O
'	O
RACE	O
using	O
brain	O
mRNAs	O
;	O
however	O
,	O
yielded	O
multiple	O
products	O
with	O
multiple	O
deduced	O
amino	O
acid	O
sequences	O
,	O
all	O
of	O
which	O
differ	O
from	O
the	O
muscle	O
amino	O
acid	O
sequence	O
at	O
the	O
very	O
N	O
-	O
terminus	O
.	O

Here	O
,	O
we	O
focus	O
our	O
analysis	O
on	O
a	O
clone	O
containing	O
nine	O
unique	O
amino	O
acids	O
at	O
the	O
N	O
-	O
terminus	O
,	O
which	O
was	O
obtained	O
most	O
frequently	O
.	O

Exon	O
-	O
intron	O
organization	O
of	O
Fxh	O
and	O
A2BP1	O
shows	O
remarkable	O
similarities	O
and	O
a	O
RRM	O
is	O
encoded	O
in	O
four	O
exons	O
(	O
Figure	O
1B	O
)	O
.	O

Of	O
note	O
is	O
that	O
the	O
significant	O
amounts	O
of	O
Fxh	O
and	O
A2BP1	O
mRNAs	O
from	O
skeletal	O
muscles	O
are	O
missing	O
a	O
part	O
of	O
the	O
RRM	O
by	O
exon	O
skipping	O
.	O

Typically	O
,	O
as	O
shown	O
in	O
Figure	O
2C	O
,	O
they	O
lack	O
the	O
93	O
nt	O
exon	O
that	O
encodes	O
RNP1	O
,	O
one	O
of	O
the	O
two	O
most	O
critical	O
motifs	O
of	O
the	O
RRM	O
(	O
30	O
)	O
.	O

Some	O
of	O
them	O
lack	O
almost	O
the	O
entire	O
RRM	O
(	O
e	O
.	O
g	O
.	O
F402	O
in	O
Figure	O
1A	O
)	O
.	O

To	O
examine	O
the	O
subcellular	O
distribution	O
of	O
each	O
isoform	O
of	O
Fxh	O
and	O
A2BP1	O
,	O
myc	O
-	O
tagged	O
proteins	O
were	O
transiently	O
expressed	O
in	O
cultured	O
cells	O
and	O
immunostained	O
with	O
an	O
anti	O
-	O
myc	O
antibody	O
.	O

Initially	O
,	O
HeLa	O
cells	O
were	O
used	O
to	O
investigate	O
subcellular	O
localization	O
,	O
since	O
these	O
cells	O
are	O
more	O
suited	O
for	O
these	O
studies	O
.	O

Representative	O
confocal	O
images	O
are	O
shown	O
in	O
Figure	O
3A	O
.	O

DAPI	O
and	O
anti	O
-	O
NMHC	O
-	O
B	O
antibodies	O
serve	O
as	O
markers	O
for	O
nuclei	O
and	O
cytoplasm	O
,	O
respectively	O
.	O

As	O
noted	O
,	O
the	O
ratio	O
of	O
protein	O
distributed	O
between	O
nuclei	O
and	O
cytoplasm	O
differs	O
among	O
the	O
proteins	O
.	O

All	O
isoforms	O
of	O
Fxh	O
have	O
a	O
predominant	O
nuclear	O
localization	O
.	O

The	O
brain	O
isoform	O
of	O
A2BP1	O
without	O
the	O
A53	O
exon	O
(	O
A016	O
)	O
localizes	O
to	O
both	O
nuclei	O
and	O
cytoplasm	O
,	O
whereas	O
the	O
other	O
brain	O
isoform	O
with	O
the	O
A53	O
exon	O
(	O
A030	O
)	O
localizes	O
predominantly	O
to	O
cytoplasm	O
with	O
only	O
a	O
minimum	O
being	O
in	O
the	O
nuclei	O
.	O

The	O
relative	O
amounts	O
of	O
both	O
muscle	O
isoforms	O
of	O
A2BP1	O
(	O
A713	O
and	O
A715	O
)	O
are	O
somewhat	O
between	O
the	O
amounts	O
of	O
the	O
two	O
brain	O
isoforms	O
.	O

These	O
data	O
are	O
summarized	O
in	O
Figure	O
1A	O
.	O

The	O
subcellular	O
distribution	O
of	O
representative	O
isoforms	O
(	O
F011	O
,	O
A016	O
and	O
A030	O
)	O
was	O
also	O
examined	O
in	O
retinoblastoma	O
Y79	O
cells	O
,	O
which	O
were	O
used	O
as	O
host	O
cells	O
for	O
the	O
transfection	O
experiments	O
in	O
order	O
to	O
characterize	O
splicing	O
activities	O
of	O
Fxh	O
and	O
A2BP	O
proteins	O
(	O
see	O
below	O
)	O
.	O

Although	O
Y79	O
cells	O
have	O
a	O
spherical	O
shape	O
and	O
have	O
only	O
thin	O
cytoplasm	O
,	O
exogenously	O
expressed	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
show	O
a	O
similar	O
subcellular	O
distribution	O
as	O
in	O
HeLa	O
cells	O
(	O
Figure	O
3B	O
)	O
.	O

F011	O
localizes	O
predominantly	O
to	O
nuclei	O
,	O
A016	O
to	O
both	O
nuclei	O
and	O
cytoplasm	O
and	O
A030	O
predominantly	O
to	O
cytoplasm	O
.	O

Specific	O
interaction	O
of	O
Fxh	O
and	O
A2BP1	O
with	O
IDDE	O
via	O
a	O
hexanucleotide	O
UGCAUG	O

Fxh	O
and	O
A2BP1	O
share	O
an	O
identical	O
RRM	O
and	O
A2BP1	O
has	O
been	O
reported	O
to	O
bind	O
specifically	O
to	O
the	O
pentanucleotide	O
GCAUG	O
through	O
this	O
RRM	O
(	O
21	O
)	O
.	O

We	O
have	O
previously	O
reported	O
that	O
the	O
IDDE	O
of	O
the	O
NMHC	O
-	O
B	O
transcript	O
,	O
which	O
is	O
indispensable	O
for	O
the	O
regulation	O
of	O
neural	O
cell	O
-	O
specific	O
cassette	O
type	O
exon	O
N30	O
splicing	O
,	O
has	O
two	O
copies	O
of	O
GCAUG	O
(	O
14	O
)	O
.	O

Therefore	O
,	O
we	O
investigated	O
whether	O
Fxh	O
and	O
/	O
or	O
A2BP1	O
bound	O
to	O
the	O
IDDE	O
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
(	O
EMSAs	O
)	O
were	O
carried	O
out	O
using	O
labeled	O
IDDE	O
and	O
in	O
vitro	O
transcribed	O
and	O
translated	O
Fxh	O
and	O
A2BP1	O
,	O
which	O
include	O
a	O
myc	O
-	O
epitope	O
.	O

Since	O
all	O
Fxh	O
and	O
A2BP1	O
isoforms	O
,	O
except	O
F402	O
and	O
A704	O
,	O
contain	O
the	O
identical	O
RRM	O
,	O
representative	O
isoforms	O
were	O
analyzed	O
.	O

The	O
expression	O
of	O
F011	O
in	O
reticulocyte	O
lysate	O
causes	O
the	O
formation	O
of	O
a	O
RNA	O
-	O
protein	O
complex	O
whose	O
migration	O
shift	O
distinguishes	O
it	O
from	O
those	O
of	O
the	O
control	O
reticulocyte	O
lysate	O
(	O
C	O
in	O
Figure	O
4B	O
,	O
lanes	O
3	O
and	O
10	O
)	O
.	O

The	O
unlabeled	O
wild	O
-	O
type	O
IDDE	O
competes	O
with	O
the	O
probe	O
efficiently	O
for	O
the	O
formation	O
of	O
the	O
specific	O
complex	O
C	O
(	O
Figure	O
4B	O
,	O
lane	O
4	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
mutant	O
mc	O
(	O
Figure	O
4A	O
)	O
,	O
which	O
has	O
a	O
mutation	O
in	O
both	O
copies	O
of	O
UGCAUG	O
,	O
does	O
not	O
(	O
Figure	O
4B	O
,	O
lane	O
7	O
)	O
.	O

The	O
mutant	O
ma	O
,	O
which	O
has	O
a	O
mutation	O
in	O
the	O
hexanucleotide	O
at	O
the	O
5	O
'	O
side	O
,	O
shows	O
less	O
efficient	O
competition	O
,	O
compared	O
with	O
mb	O
,	O
which	O
has	O
a	O
mutation	O
in	O
the	O
3	O
'	O
side	O
of	O
the	O
hexanucleotide	O
(	O
Figure	O
4B	O
,	O
lanes	O
5	O
and	O
6	O
)	O
,	O
indicating	O
that	O
the	O
nucleotides	O
at	O
the	O
5	O
'	O
side	O
are	O
more	O
important	O
than	O
those	O
at	O
the	O
3	O
'	O
side	O
.	O

The	O
presence	O
of	O
an	O
anti	O
-	O
myc	O
antibody	O
,	O
but	O
not	O
a	O
non	O
-	O
specific	O
antibody	O
,	O
inhibits	O
the	O
formation	O
of	O
the	O
specific	O
complex	O
(	O
Figure	O
4B	O
,	O
lane	O
8	O
)	O
.	O

Synthesis	O
of	O
the	O
full	O
-	O
length	O
F011	O
protein	O
using	O
a	O
reticulocyte	O
lysate	O
and	O
specificity	O
of	O
the	O
myc	O
antibody	O
for	O
the	O
expressed	O
protein	O
are	O
verified	O
by	O
immunoblot	O
analysis	O
(	O
Figure	O
4B	O
,	O
lanes	O
11	O
and	O
12	O
)	O
.	O

A016	O
and	O
A030	O
show	O
essentially	O
identical	O
results	O
to	O
those	O
with	O
F011	O
(	O
data	O
not	O
shown	O
)	O
.	O

These	O
results	O
indicate	O
that	O
Fxh	O
and	O
A2BP1	O
can	O
bind	O
to	O
the	O
IDDE	O
and	O
that	O
the	O
hexanucleotide	O
UGCAUG	O
is	O
required	O
for	O
their	O
binding	O
.	O

Fxh	O
and	O
A2BP1	O
enhance	O
N30	O
inclusion	O
in	O
a	O
UGCAUG	O
-	O
dependent	O
manner	O

To	O
study	O
whether	O
Fxh	O
and	O
A2BP1	O
regulate	O
neural	O
cell	O
-	O
specific	O
splicing	O
via	O
binding	O
to	O
UGCAUG	O
,	O
the	O
Fxh	O
and	O
A2BP1	O
expression	O
constructs	O
were	O
co	O
-	O
transfected	O
into	O
retinoblastoma	O
Y79	O
cells	O
with	O
a	O
number	O
of	O
the	O
reporter	O
minigene	O
constructs	O
,	O
which	O
include	O
the	O
wild	O
-	O
type	O
or	O
a	O
mutant	O
version	O
of	O
UGCAUG	O
in	O
the	O
IDDE	O
(	O
Figure	O
4A	O
)	O
.	O

Minigenes	O
H	O
and	O
J	O
consist	O
of	O
the	O
exons	O
E5	O
,	O
N30	O
and	O
E6	O
and	O
their	O
flanking	O
introns	O
with	O
some	O
deletions	O
in	O
the	O
introns	O
.	O

The	O
IDDE	O
with	O
or	O
without	O
mutations	O
in	O
the	O
hexanucleotide	O
is	O
included	O
or	O
excluded	O
between	O
N30	O
and	O
E6	O
.	O

As	O
described	O
above	O
,	O
each	O
isoform	O
of	O
Fxh	O
and	O
A2BP1	O
enters	O
the	O
nucleus	O
to	O
a	O
different	O
extent	O
.	O

To	O
see	O
the	O
effects	O
of	O
different	O
proteins	O
on	O
N30	O
splicing	O
itself	O
,	O
independent	O
of	O
their	O
differential	O
properties	O
in	O
nuclear	O
localization	O
,	O
an	O
exogenous	O
NLS	O
was	O
added	O
to	O
the	O
expressed	O
proteins	O
.	O

Since	O
Fxh	O
and	O
A2BP1	O
proteins	O
contain	O
the	O
identical	O
RRM	O
,	O
and	O
F011	O
,	O
A016	O
and	O
A030	O
all	O
show	O
the	O
same	O
UGCAUG	O
-	O
dependent	O
binding	O
to	O
the	O
IDDE	O
in	O
vitro	O
,	O
F011	O
and	O
A030	O
were	O
used	O
for	O
these	O
experiments	O
.	O

Host	O
cells	O
Y79	O
at	O
the	O
proliferating	O
stage	O
exclude	O
the	O
N30	O
exon	O
in	O
~	O
90	O
%	O
of	O
the	O
endogenous	O
NMHC	O
-	O
B	O
mRNAs	O
(	O
e	O
.	O
g	O
.	O
see	O
Figure	O
6A	O
,	O
lane	O
1	O
)	O
.	O

As	O
shown	O
in	O
Figure	O
4C	O
,	O
the	O
mRNAs	O
derived	O
from	O
minigene	O
J	O
exclude	O
N30	O
without	O
exogenous	O
expression	O
of	O
Fxh	O
or	O
A2BP1	O
in	O
Y79	O
cells	O
,	O
similar	O
to	O
the	O
endogenous	O
NMHC	O
-	O
B	O
mRNAs	O
(	O
Figure	O
4C	O
,	O
upper	O
panel	O
,	O
lanes	O
1	O
-	O
5	O
)	O
.	O

However	O
,	O
in	O
the	O
presence	O
of	O
exogenous	O
expression	O
of	O
F011	O
and	O
A030	O
,	O
the	O
N30	O
inclusion	O
is	O
increased	O
(	O
Figure	O
4C	O
,	O
upper	O
panel	O
,	O
lanes	O
7	O
and	O
12	O
)	O
.	O

The	O
N30	O
inclusion	O
is	O
absolutely	O
dependent	O
on	O
the	O
presence	O
of	O
the	O
IDDE	O
(	O
Figure	O
4C	O
,	O
upper	O
panel	O
,	O
lanes	O
6	O
and	O
11	O
)	O
.	O

Moreover	O
,	O
mutation	O
of	O
either	O
one	O
of	O
the	O
two	O
copies	O
of	O
UGCAUG	O
(	O
ma	O
,	O
mb	O
)	O
abolishes	O
the	O
inclusion	O
of	O
N30	O
(	O
Figure	O
4C	O
,	O
upper	O
panel	O
,	O
lanes	O
8	O
-	O
10	O
,	O
13	O
-	O
15	O
)	O
.	O

In	O
the	O
context	O
of	O
minigene	O
H	O
,	O
which	O
contains	O
shorter	O
introns	O
,	O
the	O
larger	O
extent	O
of	O
N30	O
inclusion	O
is	O
induced	O
by	O
either	O
F011	O
or	O
A030	O
overexpression	O
(	O
Figure	O
4C	O
,	O
middle	O
panel	O
,	O
lanes	O
7	O
and	O
12	O
)	O
.	O

The	O
N30	O
inclusion	O
of	O
the	O
minigene	O
H	O
mRNAs	O
also	O
depends	O
on	O
the	O
presence	O
of	O
the	O
IDDE	O
(	O
Figure	O
4C	O
,	O
middle	O
panel	O
,	O
lanes	O
6	O
and	O
11	O
)	O
.	O

Mutation	O
of	O
both	O
copies	O
of	O
UGCAUG	O
(	O
mc	O
)	O
results	O
in	O
a	O
complete	O
loss	O
of	O
N30	O
inclusion	O
(	O
Figure	O
4C	O
,	O
middle	O
panel	O
,	O
lanes	O
10	O
and	O
15	O
)	O
.	O

The	O
mutant	O
ma	O
shows	O
stronger	O
inhibition	O
of	O
N30	O
inclusion	O
compared	O
with	O
mb	O
(	O
Figure	O
4C	O
,	O
middle	O
panel	O
,	O
lanes	O
8	O
and	O
9	O
)	O
.	O

This	O
observation	O
is	O
consistent	O
with	O
the	O
competition	O
experiments	O
of	O
the	O
EMSA	O
shown	O
in	O
Figure	O
4B	O
,	O
indicating	O
that	O
the	O
5	O
'	O
hexanucleotide	O
is	O
more	O
important	O
than	O
the	O
3	O
'	O
hexanucleotide	O
for	O
binding	O
of	O
Fxh	O
or	O
A2BP1	O
to	O
the	O
IDDE	O
as	O
well	O
as	O
an	O
activation	O
of	O
N30	O
splicing	O
.	O

Comparable	O
amounts	O
of	O
F011	O
and	O
A030	O
are	O
expressed	O
in	O
each	O
transfection	O
as	O
verified	O
by	O
immunoblots	O
using	O
an	O
anti	O
-	O
myc	O
antibody	O
(	O
Figure	O
4C	O
,	O
lower	O
panel	O
,	O
lanes	O
6	O
-	O
17	O
)	O
.	O

Since	O
minigenes	O
J	O
and	O
H	O
lack	O
a	O
portion	O
of	O
the	O
intron	O
between	O
exons	O
N30	O
and	O
E6	O
and	O
,	O
therefore	O
,	O
the	O
IDDE	O
is	O
located	O
~	O
100	O
nt	O
downstream	O
of	O
N30	O
,	O
instead	O
of	O
1	O
.	O
5	O
kb	O
as	O
in	O
the	O
native	O
gene	O
,	O
we	O
also	O
analyzed	O
the	O
effects	O
of	O
Fxh	O
and	O
A2BP1	O
on	O
the	O
N30	O
splicing	O
of	O
the	O
wild	O
-	O
type	O
minigene	O
G	O
,	O
which	O
includes	O
full	O
-	O
length	O
introns	O
among	O
E5	O
,	O
N30	O
and	O
E6	O
(	O
Figure	O
4A	O
)	O
.	O

As	O
shown	O
in	O
Figure	O
4C	O
(	O
right	O
panel	O
)	O
,	O
both	O
F011	O
and	O
A030	O
are	O
capable	O
of	O
promoting	O
N30	O
inclusion	O
,	O
with	O
F011	O
showing	O
a	O
higher	O
activity	O
(	O
Figure	O
4C	O
,	O
lanes	O
16	O
and	O
17	O
)	O
.	O

Although	O
A030	O
can	O
promote	O
N30	O
inclusion	O
as	O
efficiently	O
as	O
F011	O
in	O
the	O
contexts	O
of	O
the	O
minigene	O
J	O
and	O
H	O
transcripts	O
,	O
it	O
can	O
do	O
so	O
less	O
efficiently	O
than	O
F011	O
in	O
the	O
context	O
of	O
the	O
minigene	O
G	O
transcript	O
.	O

Interpretation	O
of	O
this	O
observation	O
will	O
be	O
discussed	O
below	O
.	O

Taken	O
together	O
,	O
Fxh	O
and	O
A2BP1	O
can	O
activate	O
N30	O
inclusion	O
in	O
an	O
IDDE	O
-	O
dependent	O
manner	O
.	O

The	O
hexanucleotide	O
motif	O
UGCAUG	O
is	O
indispensable	O
for	O
this	O
activation	O
.	O

Differential	O
activities	O
of	O
alternatively	O
spliced	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
in	O
promoting	O
N30	O
inclusion	O

Both	O
Fxh	O
and	O
A2BP1	O
mRNAs	O
are	O
expressed	O
in	O
brain	O
and	O
A2BP1	O
is	O
also	O
expressed	O
in	O
striated	O
muscles	O
and	O
Fxh	O
is	O
expressed	O
in	O
an	O
even	O
wider	O
variety	O
of	O
tissues	O
.	O

As	O
demonstrated	O
above	O
,	O
however	O
,	O
both	O
Fxh	O
and	O
A2BP1	O
transcripts	O
undergo	O
tissue	O
-	O
dependent	O
alternative	O
splicing	O
,	O
producing	O
muscle	O
-	O
specific	O
and	O
brain	O
-	O
enriched	O
isoforms	O
.	O

Therefore	O
,	O
the	O
relative	O
activity	O
of	O
individual	O
isoform	O
of	O
Fxh	O
and	O
A2BP1	O
in	O
promoting	O
N30	O
inclusion	O
was	O
compared	O
using	O
minigene	O
G	O
.	O

First	O
,	O
in	O
order	O
to	O
evaluate	O
the	O
relative	O
specific	O
activity	O
of	O
each	O
isoform	O
in	O
the	O
splicing	O
reaction	O
separately	O
from	O
its	O
ability	O
to	O
localize	O
to	O
nuclei	O
,	O
an	O
exogenous	O
NLS	O
was	O
included	O
in	O
the	O
expressed	O
protein	O
to	O
equalize	O
the	O
nuclear	O
concentration	O
of	O
the	O
expressed	O
protein	O
in	O
these	O
experiments	O
.	O

Essentially	O
,	O
all	O
of	O
the	O
expressed	O
proteins	O
with	O
the	O
exogenous	O
NLS	O
are	O
localized	O
to	O
the	O
nucleus	O
(	O
data	O
not	O
shown	O
)	O
.	O

Therefore	O
,	O
the	O
relative	O
nuclear	O
concentrations	O
of	O
the	O
expressed	O
proteins	O
can	O
be	O
estimated	O
easily	O
by	O
immunoblots	O
.	O

As	O
shown	O
in	O
immunoblots	O
in	O
Figure	O
5A	O
,	O
similar	O
quantities	O
of	O
proteins	O
are	O
expressed	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

Expression	O
of	O
the	O
brain	O
isoform	O
F011	O
causes	O
a	O
dose	O
-	O
dependent	O
increase	O
in	O
N30	O
inclusion	O
and	O
the	O
extent	O
of	O
N30	O
inclusion	O
reaches	O
a	O
plateau	O
with	O
~	O
85	O
%	O
of	O
the	O
mRNAs	O
including	O
N30	O
.	O

In	O
contrast	O
,	O
inclusion	O
of	O
N30	O
promoted	O
by	O
F411	O
,	O
the	O
predominant	O
isoform	O
from	O
skeletal	O
muscles	O
,	O
reaches	O
a	O
plateau	O
with	O
only	O
40	O
%	O
of	O
the	O
mRNAs	O
.	O

With	O
respect	O
to	O
A2BP1	O
,	O
the	O
brain	O
isoform	O
A030	O
shows	O
higher	O
activity	O
in	O
N30	O
inclusion	O
than	O
the	O
muscle	O
isoform	O
A715	O
,	O
which	O
shows	O
almost	O
no	O
activation	O
,	O
as	O
shown	O
in	O
Figure	O
5A	O
.	O

Including	O
additional	O
isoforms	O
,	O
the	O
activities	O
of	O
individual	O
isoforms	O
with	O
an	O
exogenous	O
NLS	O
in	O
promoting	O
N30	O
inclusion	O
are	O
shown	O
in	O
Figure	O
5B	O
(	O
lanes	O
8	O
-	O
13	O
)	O
and	O
are	O
also	O
summarized	O
in	O
Figure	O
1A	O
(	O
nls	O
)	O
.	O

Special	O
care	O
was	O
taken	O
to	O
ensure	O
that	O
a	O
similar	O
quantity	O
of	O
each	O
protein	O
was	O
expressed	O
and	O
,	O
if	O
not	O
,	O
different	O
amounts	O
were	O
tested	O
to	O
obtain	O
comparable	O
expression	O
.	O

In	O
the	O
presence	O
of	O
the	O
exogenous	O
NLS	O
(	O
nls	O
)	O
,	O
F011	O
and	O
A016	O
show	O
the	O
highest	O
activities	O
among	O
all	O
isoforms	O
tested	O
.	O

A30	O
shows	O
a	O
considerably	O
lower	O
activity	O
than	O
A016	O
.	O

Each	O
of	O
the	O
muscle	O
isoforms	O
(	O
F411	O
,	O
A713	O
and	O
A715	O
)	O
has	O
a	O
lower	O
activity	O
than	O
that	O
of	O
their	O
brain	O
counterparts	O
(	O
F011	O
,	O
A016	O
and	O
A030	O
,	O
respectively	O
)	O
.	O

As	O
expected	O
,	O
isoforms	O
lacking	O
a	O
part	O
or	O
all	O
of	O
the	O
RRM	O
(	O
F402	O
and	O
A704	O
)	O
have	O
no	O
activity	O
for	O
N30	O
inclusion	O
.	O

Next	O
,	O
the	O
splicing	O
activities	O
of	O
the	O
wild	O
-	O
type	O
proteins	O
without	O
an	O
exogenous	O
NLS	O
were	O
examined	O
.	O

Representative	O
data	O
are	O
shown	O
in	O
Figure	O
5B	O
(	O
lanes	O
2	O
-	O
7	O
)	O
and	O
the	O
relative	O
activities	O
are	O
summarized	O
in	O
Figure	O
1A	O
(	O
wt	O
)	O
.	O

The	O
protein	O
amounts	O
detected	O
by	O
immunoblots	O
in	O
these	O
experiments	O
represent	O
the	O
total	O
amounts	O
of	O
the	O
proteins	O
distributed	O
to	O
both	O
the	O
nuclei	O
and	O
the	O
cytoplasm	O
.	O

The	O
splicing	O
activities	O
of	O
the	O
wild	O
-	O
type	O
proteins	O
are	O
consistent	O
with	O
the	O
activities	O
that	O
combine	O
the	O
splicing	O
activities	O
of	O
the	O
proteins	O
with	O
the	O
exogenous	O
NLS	O
and	O
the	O
activities	O
of	O
the	O
native	O
proteins	O
to	O
localize	O
to	O
nuclei	O
.	O

In	O
the	O
absence	O
of	O
the	O
exogenous	O
NLS	O
(	O
wt	O
)	O
,	O
the	O
brain	O
isoforms	O
F011	O
,	O
and	O
A016	O
to	O
a	O
lesser	O
extent	O
,	O
are	O
still	O
capable	O
of	O
activating	O
N30	O
inclusion	O
efficiently	O
.	O

The	O
muscle	O
isoforms	O
for	O
both	O
Fxh	O
and	O
A2BP1	O
(	O
F411	O
,	O
A713	O
and	O
A715	O
)	O
,	O
as	O
well	O
as	O
the	O
brain	O
isoform	O
A030	O
,	O
show	O
only	O
minimal	O
activities	O
.	O

Therefore	O
,	O
F011	O
and	O
A016	O
appear	O
to	O
have	O
the	O
most	O
physiological	O
relevance	O
to	O
N30	O
splicing	O
activation	O
.	O

Overexpression	O
of	O
Fxh	O
and	O
A2BP1	O
activates	O
N30	O
inclusion	O
of	O
endogenous	O
NMHC	O
-	O
B	O
mRNAs	O

The	O
human	B
NMHC	O
-	O
B	O
gene	O
consists	O
of	O
41	O
constitutive	O
exons	O
and	O
3	O
alternative	O
exons	O
.	O

Its	O
pre	O
-	O
mRNA	O
is	O
~	O
156	O
kb	O
in	O
length	O
and	O
it	O
is	O
much	O
more	O
complex	O
than	O
the	O
pre	O
-	O
mRNA	O
from	O
the	O
minigenes	O
.	O

In	O
addition	O
,	O
the	O
minigene	O
pre	O
-	O
mRNAs	O
are	O
driven	O
by	O
a	O
heterologous	O
promoter	O
.	O

Therefore	O
,	O
we	O
next	O
examined	O
if	O
Fxh	O
and	O
A2BP1	O
were	O
capable	O
of	O
promoting	O
N30	O
inclusion	O
of	O
the	O
endogenous	O
transcript	O
.	O

Y79	O
cells	O
were	O
stably	O
transfected	O
with	O
the	O
expression	O
construct	O
for	O
F011	O
or	O
A016	O
.	O

Both	O
F011	O
and	O
A016	O
are	O
enriched	O
in	O
the	O
brain	O
and	O
show	O
higher	O
activation	O
of	O
N30	O
inclusion	O
in	O
the	O
minigene	O
transcripts	O
.	O

mRNAs	O
encoding	O
endogenous	O
NMHC	O
-	O
B	O
were	O
analyzed	O
by	O
using	O
RT	O
-	O
PCR	O
.	O

As	O
shown	O
in	O
Figure	O
6	O
,	O
the	O
inclusion	O
of	O
exon	O
N30	O
with	O
and	O
without	O
another	O
alternative	O
exon	O
,	O
R18	O
,	O
in	O
the	O
endogenous	O
mRNAs	O
is	O
markedly	O
increased	O
in	O
the	O
clones	O
which	O
were	O
stably	O
transfected	O
with	O
the	O
construct	O
for	O
F011	O
or	O
A016	O
containing	O
an	O
exogenous	O
NLS	O
(	O
Figure	O
6	O
,	O
lanes	O
4	O
and	O
5	O
)	O
.	O

Although	O
to	O
a	O
lesser	O
extent	O
,	O
transfection	O
of	O
the	O
wild	O
-	O
type	O
constructs	O
without	O
an	O
exogenous	O
NLS	O
also	O
results	O
in	O
a	O
significant	O
increase	O
in	O
N30	O
inclusion	O
(	O
Figure	O
6	O
,	O
lanes	O
2	O
and	O
3	O
)	O
.	O

Thus	O
,	O
exogenously	O
expressed	O
Fxh	O
and	O
A2BP1	O
are	O
capable	O
of	O
activating	O
N30	O
inclusion	O
not	O
only	O
in	O
the	O
transcripts	O
from	O
the	O
minigenes	O
,	O
but	O
also	O
in	O
those	O
from	O
the	O
native	O
NMHC	O
-	O
B	O
gene	O
in	O
Y79	O
cells	O
.	O

Fxh	O
may	O
cooperate	O
with	O
other	O
factor	O
(	O
s	O
)	O
to	O
promote	O
N30	O
inclusion	O

To	O
address	O
the	O
role	O
of	O
endogenous	O
Fxh	O
and	O
its	O
potential	O
interaction	O
with	O
other	O
proteins	O
in	O
promoting	O
N30	O
inclusion	O
,	O
we	O
made	O
use	O
of	O
an	O
isoform	O
of	O
Fxh	O
,	O
F402	O
,	O
which	O
lacks	O
the	O
RRM	O
.	O

The	O
mutant	O
proteins	O
lacking	O
an	O
RRM	O
for	O
other	O
RNA	O
-	O
binding	O
proteins	O
have	O
previously	O
been	O
reported	O
to	O
function	O
in	O
a	O
dominant	O
-	O
negative	O
fashion	O
and	O
inhibit	O
the	O
activities	O
of	O
the	O
wild	O
-	O
type	O
proteins	O
(	O
26	O
,	O
31	O
)	O
.	O

Therefore	O
,	O
the	O
effects	O
of	O
F402	O
on	O
the	O
N30	O
inclusion	O
of	O
minigene	O
H	O
mRNAs	O
were	O
examined	O
in	O
the	O
context	O
of	O
the	O
Y79	O
cells	O
treated	O
with	O
butyrate	O
.	O

Upon	O
butyrate	O
treatment	O
,	O
as	O
reported	O
previously	O
,	O
Y79	O
cells	O
enter	O
in	O
a	O
post	O
-	O
mitotic	O
and	O
differentiated	O
stage	O
,	O
and	O
importantly	O
,	O
the	O
endogenous	O
as	O
well	O
as	O
the	O
minigene	O
mRNAs	O
in	O
those	O
cells	O
include	O
N30	O
to	O
a	O
large	O
extent	O
,	O
unlike	O
those	O
in	O
the	O
untreated	O
cells	O
that	O
predominantly	O
exclude	O
N30	O
(	O
14	O
)	O
.	O

As	O
shown	O
in	O
Figure	O
7	O
,	O
in	O
the	O
absence	O
of	O
exogenous	O
expression	O
of	O
F402	O
,	O
large	O
quantities	O
of	O
the	O
mRNAs	O
derived	O
from	O
minigene	O
H	O
-	O
wt	O
,	O
which	O
contains	O
the	O
wild	O
-	O
type	O
IDDE	O
,	O
include	O
N30	O
(	O
Figure	O
7	O
,	O
upper	O
panel	O
,	O
lane	O
4	O
)	O
.	O

In	O
contrast	O
,	O
only	O
small	O
quantities	O
of	O
N30	O
inclusion	O
are	O
detected	O
in	O
the	O
mRNAs	O
from	O
minigene	O
H	O
-	O
mc	O
,	O
which	O
has	O
mutations	O
in	O
both	O
copies	O
of	O
UGCAUG	O
in	O
the	O
IDDE	O
(	O
Figure	O
7	O
,	O
upper	O
panel	O
,	O
lane	O
8	O
)	O
.	O

Therefore	O
,	O
the	O
butyrate	O
-	O
treated	O
Y79	O
cells	O
contain	O
factor	O
(	O
s	O
)	O
,	O
which	O
are	O
capable	O
of	O
activating	O
the	O
UGCAUG	O
-	O
dependent	O
N30	O
inclusion	O
.	O

Co	O
-	O
transfection	O
of	O
the	O
wild	O
-	O
type	O
minigene	O
H	O
-	O
wt	O
with	O
the	O
F402	O
expression	O
construct	O
causes	O
a	O
dose	O
-	O
dependent	O
inhibition	O
of	O
N30	O
inclusion	O
(	O
Figure	O
7	O
,	O
lanes	O
1	O
-	O
3	O
)	O
,	O
indicating	O
that	O
F402	O
has	O
an	O
antagonistic	O
effect	O
on	O
the	O
endogenous	O
factors	O
with	O
respect	O
to	O
N30	O
inclusion	O
.	O

Notably	O
,	O
the	O
UGCAUG	O
-	O
independent	O
N30	O
inclusion	O
seen	O
in	O
the	O
mutant	O
minigene	O
H	O
-	O
mc	O
is	O
not	O
affected	O
by	O
the	O
co	O
-	O
expression	O
of	O
F402	O
(	O
Figure	O
7	O
,	O
lanes	O
5	O
-	O
7	O
)	O
,	O
indicating	O
that	O
the	O
inhibitory	O
activity	O
of	O
F402	O
depends	O
on	O
the	O
UGCAUG	O
element	O
.	O

The	O
parallel	O
experiment	O
with	O
the	O
F011	O
expression	O
construct	O
does	O
not	O
show	O
a	O
significant	O
effect	O
on	O
N30	O
splicing	O
in	O
either	O
the	O
wild	O
-	O
type	O
or	O
mutant	O
minigene	O
(	O
Figure	O
7	O
,	O
lanes	O
9	O
-	O
16	O
)	O
.	O

This	O
may	O
be	O
due	O
to	O
the	O
fact	O
that	O
N30	O
inclusion	O
of	O
the	O
wild	O
-	O
type	O
minigene	O
mRNAs	O
has	O
already	O
reached	O
a	O
maximal	O
level	O
and	O
is	O
consistent	O
with	O
the	O
idea	O
that	O
butyrate	O
-	O
treated	O
Y79	O
cells	O
contain	O
sufficient	O
amounts	O
of	O
protein	O
(	O
s	O
)	O
functionally	O
equivalent	O
to	O
F011	O
,	O
which	O
can	O
promote	O
N30	O
inclusion	O
in	O
a	O
UGCAUG	O
-	O
dependent	O
manner	O
.	O

Since	O
F402	O
does	O
not	O
bind	O
to	O
the	O
UGCAUG	O
element	O
,	O
and	O
has	O
a	O
UGCAUG	O
-	O
dependent	O
antagonistic	O
effect	O
on	O
N30	O
splicing	O
,	O
it	O
most	O
probably	O
disrupts	O
protein	O
-	O
protein	O
interactions	O
of	O
the	O
endogenous	O
proteins	O
that	O
are	O
required	O
for	O
the	O
UGCAUG	O
-	O
dependent	O
activation	O
of	O
N30	O
splicing	O
.	O

Endogenous	O
Fxh	O
(	O
and	O
/	O
or	O
A2BP1	O
)	O
would	O
be	O
a	O
good	O
candidate	O
whose	O
function	O
could	O
be	O
antagonized	O
by	O
exogenously	O
expressed	O
F402	O
.	O

Thus	O
,	O
this	O
observation	O
suggests	O
that	O
the	O
endogenous	O
Fxh	O
has	O
an	O
effect	O
on	O
the	O
activation	O
of	O
N30	O
splicing	O
and	O
that	O
other	O
proteins	O
cooperate	O
with	O
Fxh	O
for	O
N30	O
activation	O
.	O

Since	O
muscle	O
cells	O
express	O
the	O
RRM	O
-	O
defective	O
isoforms	O
to	O
a	O
significant	O
extent	O
(	O
Figure	O
2C	O
)	O
and	O
the	O
wild	O
-	O
type	O
F402	O
localize	O
to	O
nuclei	O
efficiently	O
,	O
this	O
also	O
raises	O
the	O
possibility	O
that	O
the	O
RRM	O
-	O
defective	O
isoforms	O
may	O
have	O
an	O
inhibitory	O
function	O
on	O
the	O
N30	O
splicing	O
in	O
muscle	O
cells	O
.	O

DISCUSSION	O

Two	O
major	O
findings	O
are	O
described	O
in	O
this	O
report	O
.	O

First	O
,	O
Fxh	O
and	O
A2BP1	O
facilitate	O
neural	O
cell	O
-	O
specific	O
inclusion	O
of	O
the	O
cassette	O
-	O
type	O
exon	O
via	O
binding	O
to	O
the	O
specific	O
intronic	O
sequence	O
UGCAUG	O
.	O

In	O
addition	O
to	O
a	O
minigene	O
model	O
system	O
,	O
Fxh	O
and	O
A2BP1	O
are	O
capable	O
of	O
facilitating	O
N30	O
inclusion	O
of	O
the	O
endogenous	O
pre	O
-	O
mRNA	O
.	O

This	O
result	O
provides	O
an	O
important	O
demonstration	O
of	O
physiological	O
relevance	O
and	O
supports	O
the	O
notion	O
that	O
the	O
NMHC	O
-	O
B	O
pre	O
-	O
mRNA	O
is	O
likely	O
to	O
be	O
the	O
true	O
target	O
for	O
Fxh	O
or	O
A2BP1	O
-	O
mediated	O
regulation	O
.	O

However	O
,	O
whether	O
the	O
endogenous	O
Fxh	O
or	O
A2BP1	O
regulates	O
endogenous	O
NMHC	O
-	O
B	O
pre	O
-	O
mRNA	O
splicing	O
needs	O
to	O
be	O
determined	O
in	O
a	O
future	O
study	O
.	O

In	O
vertebrates	O
,	O
small	O
interfering	O
RNAs	O
and	O
gene	O
targeting	O
strategies	O
have	O
recently	O
been	O
used	O
successfully	O
to	O
address	O
the	O
roles	O
of	O
endogenous	O
splicing	O
regulators	O
in	O
alternative	O
splicing	O
of	O
endogenous	O
target	O
pre	O
-	O
mRNAs	O
(	O
8	O
,	O
32	O
-	O
36	O
)	O
.	O

A	O
second	O
and	O
more	O
novel	O
finding	O
is	O
the	O
identification	O
of	O
tissue	O
-	O
specific	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
with	O
different	O
splicing	O
activities	O
as	O
well	O
as	O
different	O
subcellular	O
localizations	O
.	O

This	O
finding	O
raises	O
the	O
possibility	O
that	O
the	O
products	O
of	O
the	O
Fxh	O
and	O
A2BP1	O
genes	O
can	O
contribute	O
to	O
a	O
mechanism	O
as	O
to	O
how	O
tissue	O
specificity	O
of	O
alternative	O
splicing	O
is	O
achieved	O
.	O

Many	O
splicing	O
factors	O
are	O
detected	O
not	O
only	O
in	O
the	O
nuclei	O
,	O
but	O
also	O
in	O
the	O
cytoplasm	O
(	O
37	O
)	O
.	O

They	O
are	O
shuttling	O
between	O
the	O
nucleus	O
and	O
the	O
cytoplasm	O
and	O
,	O
in	O
some	O
instances	O
,	O
extracellular	O
stimuli	O
trigger	O
changes	O
in	O
subcellular	O
distribution	O
of	O
these	O
proteins	O
.	O

Such	O
translocations	O
have	O
been	O
reported	O
for	O
hnRNPA1	O
and	O
PTB	O
(	O
38	O
,	O
39	O
)	O
.	O

Moreover	O
,	O
a	O
number	O
of	O
RNA	O
-	O
binding	O
proteins	O
have	O
been	O
demonstrated	O
to	O
play	O
a	O
role	O
in	O
multiple	O
steps	O
during	O
gene	O
expression	O
in	O
different	O
subcellular	O
compartments	O
,	O
such	O
as	O
pre	O
-	O
mRNA	O
processing	O
in	O
nuclei	O
,	O
mRNA	O
export	O
from	O
nuclei	O
to	O
cytoplasm	O
and	O
mRNA	O
localization	O
,	O
stability	O
and	O
translation	O
in	O
cytoplasm	O
(	O
37	O
,	O
40	O
)	O
.	O

Therefore	O
,	O
not	O
surprisingly	O
,	O
Fxh	O
and	O
A2BP1	O
isoforms	O
were	O
found	O
to	O
be	O
distributed	O
in	O
both	O
the	O
nuclei	O
and	O
the	O
cytoplasm	O
in	O
HeLa	O
and	O
Y79	O
cells	O
.	O

However	O
,	O
the	O
relative	O
ratios	O
of	O
proteins	O
distributed	O
between	O
the	O
two	O
subcellular	O
compartments	O
at	O
steady	O
-	O
state	O
differ	O
among	O
the	O
isoforms	O
.	O

In	O
agreement	O
with	O
Jin	O
et	O
al	O
.	O

(	O
21	O
)	O
,	O
substantial	O
amounts	O
of	O
the	O
brain	O
isoform	O
A016	O
are	O
detected	O
in	O
nuclei	O
.	O

Other	O
A2BP1	O
isoforms	O
,	O
the	O
brain	O
isoform	O
A030	O
and	O
the	O
muscle	O
isoforms	O
A713	O
and	O
A715	O
,	O
are	O
only	O
poorly	O
detected	O
in	O
nuclei	O
.	O

This	O
observation	O
is	O
consistent	O
with	O
the	O
reports	O
where	O
endogenous	O
A2BP1	O
in	O
cerebellar	O
Purkinje	O
cells	O
,	O
hippocampus	O
neurons	O
and	O
cardiac	O
myocytes	O
were	O
shown	O
to	O
be	O
localized	O
essentially	O
to	O
the	O
cytoplasm	O
(	O
23	O
,	O
24	O
)	O
.	O

Thus	O
,	O
inclusion	O
and	O
exclusion	O
of	O
A53	O
and	O
differences	O
in	O
the	O
very	O
N	O
-	O
terminal	O
sequences	O
results	O
in	O
A2BP1	O
isoforms	O
with	O
a	O
distinct	O
subcellular	O
localization	O
.	O

It	O
is	O
likely	O
that	O
A2BP1	O
proteins	O
have	O
multiple	O
roles	O
,	O
involving	O
both	O
nuclear	O
and	O
cytoplasmic	O
events	O
.	O

In	O
contrast	O
,	O
all	O
three	O
Fxh	O
isoforms	O
predominantly	O
localized	O
to	O
the	O
nuclei	O
.	O

Therefore	O
,	O
in	O
terms	O
of	O
their	O
localization	O
,	O
Fxh	O
proteins	O
are	O
better	O
candidates	O
for	O
regulators	O
of	O
the	O
pre	O
-	O
mRNA	O
splicing	O
that	O
takes	O
place	O
in	O
nuclei	O
.	O

Of	O
note	O
,	O
however	O
,	O
our	O
preliminary	O
results	O
of	O
5	O
'	O
RACE	O
,	O
as	O
well	O
as	O
the	O
EST	O
database	O
,	O
detect	O
multiple	O
5	O
'	O
end	O
sequences	O
for	O
both	O
Fxh	O
and	O
A2BP1	O
mRNAs	O
,	O
which	O
are	O
presumably	O
generated	O
by	O
alternative	O
promoters	O
and	O
alternative	O
splicing	O
.	O

The	O
diversity	O
of	O
the	O
5	O
'	O
end	O
cDNA	O
sequences	O
leads	O
to	O
the	O
generation	O
of	O
a	O
number	O
of	O
unique	O
N	O
-	O
terminal	O
amino	O
acid	O
sequences	O
.	O

Therefore	O
,	O
this	O
study	O
does	O
not	O
exclude	O
the	O
possible	O
existence	O
of	O
other	O
isoforms	O
with	O
different	O
subcellular	O
localizations	O
for	O
both	O
Fxh	O
and	O
A2BP1	O
.	O

Our	O
study	O
also	O
does	O
not	O
exclude	O
the	O
possibility	O
that	O
some	O
of	O
the	O
isoforms	O
translocate	O
between	O
the	O
nucleus	O
and	O
the	O
cytoplasm	O
following	O
stimuli	O
.	O

The	O
main	O
aim	O
of	O
this	O
study	O
is	O
to	O
determine	O
the	O
relative	O
activities	O
of	O
tissue	O
-	O
dependent	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
in	O
neural	O
cell	O
-	O
specific	O
and	O
UGCAUG	O
element	O
-	O
dependent	O
alternative	O
splicing	O
.	O

To	O
obtain	O
an	O
indication	O
of	O
the	O
relative	O
specific	O
activity	O
of	O
each	O
isoform	O
in	O
transfected	O
cells	O
,	O
the	O
same	O
amounts	O
of	O
the	O
expressed	O
proteins	O
should	O
be	O
available	O
for	O
the	O
splicing	O
reaction	O
in	O
the	O
nuclei	O
.	O

For	O
this	O
reason	O
,	O
an	O
exogenous	O
NLS	O
was	O
included	O
in	O
the	O
expressed	O
proteins	O
.	O

Essentially	O
,	O
all	O
of	O
the	O
expressed	O
proteins	O
with	O
the	O
exogenous	O
NLS	O
localized	O
to	O
nuclei	O
.	O

Thus	O
,	O
the	O
amounts	O
of	O
the	O
expressed	O
proteins	O
determined	O
by	O
immunoblots	O
represent	O
the	O
nuclear	O
concentrations	O
.	O

The	O
analysis	O
using	O
the	O
proteins	O
expressed	O
with	O
the	O
exogenous	O
NLS	O
allowed	O
us	O
to	O
compare	O
directly	O
the	O
splicing	O
activities	O
of	O
these	O
proteins	O
.	O

Furthermore	O
,	O
this	O
analysis	O
also	O
allowed	O
us	O
to	O
define	O
the	O
critical	O
regions	O
of	O
the	O
proteins	O
for	O
splicing	O
activation	O
.	O

As	O
shown	O
in	O
Figure	O
5	O
,	O
the	O
splicing	O
activities	O
of	O
the	O
various	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
are	O
intrinsically	O
different	O
,	O
regardless	O
of	O
the	O
subcellular	O
localization	O
properties	O
of	O
the	O
wild	O
-	O
type	O
proteins	O
.	O

Among	O
the	O
isoforms	O
tested	O
in	O
this	O
study	O
,	O
F011	O
and	O
A016	O
,	O
which	O
include	O
B40	O
,	O
are	O
found	O
to	O
have	O
higher	O
activities	O
in	O
promoting	O
N30	O
inclusion	O
.	O

When	O
the	O
primary	O
amino	O
acid	O
sequences	O
,	O
outside	O
of	O
the	O
RRM	O
,	O
of	O
these	O
two	O
proteins	O
are	O
compared	O
,	O
the	O
C	O
-	O
terminal	O
regions	O
(	O
amino	O
acids	O
190	O
-	O
377	O
of	O
F011	O
)	O
show	O
a	O
higher	O
homology	O
with	O
71	O
%	O
identity	O
,	O
whereas	O
the	O
N	O
-	O
terminal	O
regions	O
(	O
amino	O
acids	O
1	O
-	O
112	O
of	O
F011	O
)	O
show	O
only	O
53	O
%	O
identity	O
.	O

The	O
C	O
-	O
terminal	O
region	O
includes	O
four	O
subregions	O
of	O
nearly	O
identical	O
stretches	O
of	O
amino	O
acids	O
(	O
Figure	O
8	O
,	O
I	O
-	O
IV	O
)	O
.	O

One	O
subregion	O
(	O
II	O
)	O
includes	O
13	O
amino	O
acids	O
encoded	O
by	O
exon	O
B40	O
.	O

Substitution	O
of	O
this	O
subregion	O
with	O
exon	O
M43	O
in	O
Fxh	O
causes	O
substantial	O
changes	O
in	O
amino	O
acid	O
sequences	O
resulting	O
in	O
only	O
a	O
21	O
%	O
identity	O
in	O
this	O
region	O
between	O
F011	O
and	O
F411	O
.	O

Another	O
subregion	O
(	O
IV	O
)	O
is	O
located	O
at	O
the	O
C	O
-	O
terminal	O
end	O
and	O
A030	O
lacks	O
this	O
homologous	O
region	O
by	O
the	O
inclusion	O
of	O
exon	O
A53	O
,	O
which	O
results	O
in	O
a	O
frame	O
shift	O
.	O

Since	O
F411	O
and	O
A030	O
show	O
poor	O
splicing	O
activation	O
compared	O
with	O
F011	O
and	O
A016	O
,	O
respectively	O
,	O
these	O
two	O
subregions	O
of	O
F011	O
and	O
A016	O
appear	O
to	O
serve	O
as	O
activation	O
domains	O
,	O
presumably	O
by	O
interacting	O
with	O
other	O
proteins	O
.	O

This	O
notion	O
is	O
supported	O
by	O
the	O
finding	O
that	O
the	O
RRM	O
-	O
lacking	O
isoform	O
F402	O
,	O
which	O
includes	O
the	O
same	O
subregions	O
II	O
and	O
IV	O
as	O
F011	O
,	O
functions	O
apparently	O
as	O
a	O
dominant	O
-	O
negative	O
mutant	O
to	O
the	O
wild	O
-	O
type	O
Fxh	O
,	O
consistent	O
with	O
the	O
interpretation	O
that	O
the	O
mutant	O
and	O
wild	O
-	O
type	O
are	O
competing	O
to	O
interact	O
with	O
other	O
protein	O
(	O
s	O
)	O
.	O

To	O
date	O
,	O
Fyn	O
tyrosine	O
kinase	O
and	O
estrogen	O
receptor	O
-	O
alpha	O
have	O
been	O
reported	O
to	O
interact	O
with	O
Fxh	O
,	O
and	O
ataxin	O
-	O
2	O
with	O
A2BP1	O
(	O
23	O
,	O
41	O
,	O
42	O
)	O
.	O

Whether	O
these	O
proteins	O
participate	O
in	O
the	O
regulation	O
of	O
pre	O
-	O
mRNA	O
splicing	O
is	O
currently	O
unknown	O
.	O

Of	O
interest	O
,	O
A030	O
with	O
the	O
exogenous	O
NLS	O
activates	O
N30	O
splicing	O
as	O
efficiently	O
as	O
F011	O
in	O
the	O
pre	O
-	O
mRNAs	O
derived	O
from	O
minigenes	O
J	O
and	O
H	O
,	O
which	O
contain	O
the	O
shorter	O
intron	O
,	O
whereas	O
this	O
isoform	O
poorly	O
activates	O
N30	O
splicing	O
in	O
the	O
pre	O
-	O
mRNA	O
from	O
minigene	O
G	O
,	O
which	O
contains	O
the	O
full	O
-	O
length	O
intron	O
.	O

This	O
observation	O
implies	O
that	O
the	O
interactions	O
of	O
A030	O
with	O
different	O
factors	O
are	O
required	O
in	O
the	O
different	O
pre	O
-	O
mRNA	O
contexts	O
.	O

Therefore	O
,	O
the	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
described	O
here	O
may	O
have	O
different	O
effects	O
on	O
other	O
UGCAUG	O
-	O
regulated	O
alternative	O
splicing	O
.	O

The	O
involvement	O
of	O
the	O
hexanucleotide	O
UGCAUG	O
in	O
regulated	O
alternative	O
splicing	O
has	O
been	O
experimentally	O
demonstrated	O
in	O
a	O
number	O
of	O
neural	O
cell	O
-	O
specific	O
,	O
as	O
well	O
as	O
other	O
tissue	O
-	O
specific	O
,	O
model	O
systems	O
(	O
13	O
-	O
21	O
)	O
.	O

This	O
hexanucleotide	O
element	O
plays	O
a	O
role	O
,	O
in	O
most	O
cases	O
,	O
as	O
an	O
enhancer	O
in	O
regulating	O
alternative	O
splicing	O
of	O
cassette	O
-	O
type	O
exons	O
as	O
well	O
as	O
mutually	O
exclusive	O
exons	O
.	O

Furthermore	O
,	O
computational	O
analysis	O
has	O
revealed	O
that	O
UGCAUG	O
is	O
over	O
-	O
represented	O
in	O
the	O
introns	O
in	O
which	O
splicing	O
is	O
regulated	O
,	O
compared	O
with	O
the	O
constitutively	O
spliced	O
introns	O
(	O
43	O
)	O
.	O

This	O
analysis	O
also	O
pointed	O
to	O
the	O
UGCAUG	O
element	O
as	O
playing	O
a	O
role	O
in	O
the	O
regulation	O
of	O
tissue	O
-	O
specific	O
alternative	O
splicing	O
in	O
a	O
wide	O
range	O
of	O
tissues	O
,	O
but	O
not	O
in	O
specific	O
tissues	O
.	O

To	O
date	O
,	O
KH	O
-	O
type	O
splicing	O
regulatory	O
protein	O
(	O
KSRP	O
)	O
(	O
44	O
)	O
,	O
A2BP1	O
(	O
21	O
)	O
and	O
Fxh	O
(	O
this	O
study	O
)	O
are	O
known	O
to	O
be	O
capable	O
of	O
binding	O
to	O
UGCAUG	O
.	O

KSRP	O
is	O
expressed	O
ubiquitously	O
and	O
tissue	O
-	O
specific	O
variants	O
of	O
this	O
gene	O
have	O
not	O
been	O
described	O
so	O
far	O
.	O

In	O
this	O
study	O
,	O
we	O
have	O
described	O
the	O
existence	O
of	O
tissue	O
-	O
dependent	O
isoforms	O
of	O
Fxh	O
and	O
A2BP1	O
,	O
which	O
,	O
while	O
not	O
identical	O
in	O
some	O
areas	O
of	O
the	O
molecule	O
,	O
may	O
contain	O
the	O
same	O
RRM	O
.	O

The	O
physiological	O
relevance	O
of	O
these	O
isoforms	O
is	O
that	O
they	O
have	O
different	O
splicing	O
activities	O
and	O
different	O
subcellular	O
localizations	O
.	O

The	O
brain	O
isoforms	O
promote	O
N30	O
inclusion	O
more	O
efficiently	O
than	O
the	O
muscle	O
isoforms	O
of	O
both	O
Fxh	O
and	O
A2BP1	O
.	O

The	O
isoforms	O
lacking	O
the	O
RRM	O
are	O
normally	O
expressed	O
to	O
a	O
significant	O
extent	O
in	O
skeletal	O
muscles	O
.	O

This	O
isoform	O
is	O
incapable	O
of	O
activating	O
N30	O
splicing	O
and	O
,	O
moreover	O
,	O
can	O
inhibit	O
N30	O
inclusion	O
.	O

The	O
properties	O
of	O
these	O
isoforms	O
are	O
consistent	O
with	O
Fxh	O
and	O
A2BP1	O
acting	O
as	O
regulators	O
for	O
N30	O
splicing	O
,	O
since	O
N30	O
is	O
included	O
in	O
neuronal	O
cells	O
,	O
but	O
excluded	O
in	O
muscles	O
.	O

Therefore	O
,	O
despite	O
the	O
tissue	O
-	O
independent	O
occurrence	O
of	O
UGCAUG	O
as	O
a	O
regulatory	O
element	O
,	O
given	O
the	O
tissue	O
-	O
dependent	O
isoforms	O
of	O
the	O
UGCAUG	O
-	O
binding	O
proteins	O
(	O
Fxh	O
and	O
A2BP1	O
)	O
with	O
different	O
activities	O
,	O
the	O
hexanucleotide	O
UGCAUG	O
could	O
confer	O
tissue	O
specificity	O
on	O
regulated	O
splicing	O
.	O

One	O
of	O
the	O
major	O
problems	O
in	O
understanding	O
the	O
mechanisms	O
responsible	O
for	O
alternative	O
pre	O
-	O
mRNA	O
splicing	O
is	O
the	O
manner	O
in	O
which	O
tissue	O
specificity	O
is	O
determined	O
.	O

In	O
vertebrates	O
,	O
to	O
date	O
,	O
only	O
a	O
few	O
tissue	O
-	O
specific	O
proteins	O
have	O
been	O
identified	O
as	O
splicing	O
regulators	O
(	O
8	O
-	O
12	O
)	O
.	O

Here	O
,	O
we	O
have	O
shown	O
that	O
the	O
tissue	O
-	O
dependent	O
isoforms	O
of	O
the	O
sequence	O
-	O
specific	O
RNA	O
-	O
binding	O
proteins	O
,	O
which	O
themselves	O
are	O
generated	O
by	O
alternative	O
splicing	O
,	O
have	O
different	O
activities	O
in	O
tissue	O
-	O
specific	O
alternative	O
splicing	O
of	O
target	O
pre	O
-	O
mRNA	O
.	O

Therefore	O
,	O
these	O
isoforms	O
play	O
a	O
role	O
in	O
the	O
determination	O
of	O
tissue	O
specificity	O
of	O
target	O
pre	O
-	O
mRNA	O
splicing	O
.	O

The	O
discovery	O
of	O
these	O
tissue	O
-	O
dependent	O
isoforms	O
of	O
the	O
UGCAUG	O
-	O
binding	O
proteins	O
with	O
different	O
splicing	O
activities	O
adds	O
an	O
important	O
new	O
dimension	O
to	O
the	O
molecular	O
mechanisms	O
responsible	O
for	O
regulating	O
tissue	O
-	O
dependent	O
alternative	O
splicing	O
mediated	O
via	O
UGCAUG	O
.	O

Mutations	O
of	O
PIK3CA	O
in	O
gastric	O
adenocarcinoma	O

Abstract	O

Background	O

Activation	O
of	O
the	O
phosphatidylinositol	O
3	O
-	O
kinase	O
(	O
PI3K	O
)	O
through	O
mutational	O
inactivation	O
of	O
PTEN	O
tumour	O
suppressor	O
gene	O
is	O
common	O
in	O
diverse	O
cancer	O
types	O
,	O
but	O
rarely	O
reported	O
in	O
gastric	O
cancer	O
.	O

Recently	O
,	O
mutations	O
in	O
PIK3CA	O
,	O
which	O
encodes	O
the	O
p110	O
alpha	O
catalytic	O
subunit	O
of	O
PI3K	O
,	O
have	O
been	O
identified	O
in	O
various	O
human	B
cancers	O
,	O
including	O
3	O
of	O
12	O
gastric	O
cancers	O
.	O

Eighty	O
percent	O
of	O
these	O
reported	O
mutations	O
clustered	O
within	O
2	O
regions	O
involving	O
the	O
helical	O
and	O
kinase	O
domains	O
.	O

In	O
vitro	O
study	O
on	O
one	O
of	O
the	O
"	O
hot	O
-	O
spot	O
"	O
mutants	O
has	O
demonstrated	O
it	O
as	O
an	O
activating	O
mutation	O
.	O

Methods	O

Based	O
on	O
these	O
data	O
,	O
we	O
initiated	O
PIK3CA	O
mutation	O
screening	O
in	O
94	O
human	B
gastric	O
cancers	O
by	O
direct	O
sequencing	O
of	O
the	O
gene	O
regions	O
in	O
which	O
80	O
%	O
of	O
all	O
the	O
known	O
PIK3CA	O
mutations	O
were	O
found	O
.	O

We	O
also	O
examined	O
PIK3CA	O
expression	O
level	O
by	O
extracting	O
data	O
from	O
the	O
previous	O
large	O
-	O
scale	O
gene	O
expression	O
profiling	O
study	O
.	O

Using	O
Significance	O
Analysis	O
of	O
Microarrays	O
(	O
SAM	O
)	O
,	O
we	O
further	O
searched	O
for	O
genes	O
that	O
show	O
correlating	O
expression	O
with	O
PIK3CA	O
.	O

Results	O

We	O
have	O
identified	O
PIK3CA	O
mutations	O
in	O
4	O
cases	O
(	O
4	O
.	O
3	O
%	O
)	O
,	O
all	O
involving	O
the	O
previously	O
reported	O
hotspots	O
.	O

Among	O
these	O
4	O
cases	O
,	O
3	O
tumours	O
demonstrated	O
microsatellite	O
instability	O
and	O
2	O
tumours	O
harboured	O
concurrent	O
KRAS	O
mutation	O
.	O

Data	O
extracted	O
from	O
microarray	O
studies	O
showed	O
an	O
increased	O
expression	O
of	O
PIK3CA	O
in	O
gastric	O
cancers	O
when	O
compared	O
with	O
the	O
non	O
-	O
neoplastic	O
gastric	O
mucosae	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

SAM	O
further	O
identified	O
2910	O
genes	O
whose	O
expression	O
levels	O
were	O
positively	O
associated	O
with	O
that	O
of	O
PIK3CA	O
.	O

Conclusion	O

Our	O
data	O
suggested	O
that	O
activation	O
of	O
the	O
PI3K	O
signalling	O
pathway	O
in	O
gastric	O
cancer	O
may	O
be	O
achieved	O
through	O
up	O
-	O
regulation	O
or	O
mutation	O
of	O
PIK3CA	O
,	O
in	O
which	O
the	O
latter	O
may	O
be	O
a	O
consequence	O
of	O
mismatch	O
repair	O
deficiency	O
.	O

Background	O

The	O
phosphatidylinositol	O
3	O
-	O
kinase	O
(	O
PI3K	O
)	O
-	O
AKT	O
signalling	O
pathway	O
is	O
involved	O
in	O
the	O
regulation	O
of	O
diverse	O
cellular	O
processes	O
,	O
including	O
cell	O
growth	O
,	O
survival	O
and	O
motility	O
.	O

Abnormal	O
activation	O
of	O
this	O
pathway	O
is	O
frequently	O
observed	O
in	O
various	O
cancer	O
types	O
,	O
leading	O
to	O
aberrant	O
cell	O
cycle	O
progression	O
,	O
altered	O
adhesion	O
and	O
motility	O
,	O
inhibition	O
of	O
apoptosis	O
and	O
induction	O
of	O
angiogenesis	O
[	O
1	O
]	O
.	O

It	O
has	O
been	O
previously	O
reported	O
that	O
genetic	O
alterations	O
involving	O
various	O
members	O
along	O
this	O
signalling	O
pathway	O
could	O
lead	O
to	O
its	O
activation	O
in	O
cancer	O
.	O

These	O
include	O
mutation	O
,	O
allelic	O
loss	O
or	O
promoter	O
methylation	O
of	O
the	O
negative	O
regulator	O
PTEN	O
[	O
2	O
]	O
;	O
or	O
alternatively	O
,	O
chromosomal	O
amplification	O
or	O
over	O
-	O
expression	O
of	O
the	O
positive	O
regulators	O
PIK3CA	O
[	O
3	O
-	O
5	O
]	O
and	O
the	O
various	O
AKT	O
kinases	O
[	O
6	O
,	O
7	O
]	O
.	O

Furthermore	O
,	O
changes	O
in	O
other	O
related	O
pathways	O
that	O
are	O
commonly	O
altered	O
in	O
cancer	O
,	O
such	O
as	O
those	O
involved	O
in	O
growth	O
factor	O
stimulation	O
via	O
the	O
G	O
-	O
protein	O
-	O
coupled	O
receptors	O
or	O
through	O
direct	O
interaction	O
with	O
the	O
activated	O
form	O
of	O
small	O
GTPase	O
RAS	O
,	O
can	O
also	O
lead	O
to	O
PI3K	O
-	O
AKT	O
pathway	O
activation	O
[	O
8	O
]	O
.	O

Activation	O
of	O
this	O
pathway	O
results	O
in	O
the	O
phosphorylation	O
of	O
AKT	O
at	O
Thr	O
-	O
308	O
/	O
309	O
and	O
Ser	O
-	O
473	O
/	O
474	O
.	O

These	O
phosphorylated	O
forms	O
of	O
AKT	O
proteins	O
have	O
been	O
detected	O
by	O
Western	O
blot	O
or	O
immunohistochemistry	O
in	O
various	O
cancer	O
types	O
,	O
suggesting	O
the	O
frequent	O
activation	O
of	O
PI3K	O
-	O
AKT	O
pathway	O
in	O
the	O
carcinogenic	O
process	O
[	O
7	O
,	O
9	O
]	O
.	O

Although	O
genetic	O
changes	O
along	O
the	O
PI3K	O
-	O
AKT	O
pathway	O
have	O
been	O
repeatedly	O
documented	O
in	O
brain	O
,	O
ovarian	O
,	O
endometrial	O
,	O
breast	O
,	O
prostate	O
and	O
thyroid	O
cancers	O
[	O
1	O
,	O
2	O
]	O
,	O
reports	O
on	O
its	O
mechanism	O
of	O
activation	O
in	O
gastric	O
cancer	O
are	O
limited	O
.	O

Gastric	O
cancer	O
is	O
the	O
second	O
most	O
common	O
cancer	O
worldwide	O
but	O
its	O
molecular	O
basis	O
of	O
tumourigenesis	O
is	O
still	O
poorly	O
understood	O
.	O

Previous	O
immunohistochemical	O
study	O
has	O
demonstrated	O
the	O
presence	O
of	O
the	O
phosphorylated	O
form	O
of	O
AKT	O
in	O
78	O
%	O
of	O
gastric	O
cancer	O
[	O
10	O
]	O
,	O
suggesting	O
that	O
activation	O
of	O
this	O
pathway	O
may	O
also	O
be	O
common	O
in	O
gastric	O
cancer	O
.	O

Though	O
loss	O
of	O
heterozygosity	O
(	O
LOH	O
)	O
involving	O
the	O
PTEN	O
locus	O
has	O
been	O
demonstrated	O
in	O
47	O
%	O
of	O
gastric	O
cancer	O
in	O
a	O
recent	O
study	O
,	O
mutation	O
or	O
promoter	O
methylation	O
was	O
absent	O
even	O
in	O
cases	O
with	O
LOH	O
[	O
11	O
]	O
.	O

Thus	O
data	O
from	O
this	O
study	O
could	O
not	O
support	O
the	O
two	O
-	O
hit	O
inactivation	O
of	O
PTEN	O
in	O
gastric	O
cancer	O
,	O
while	O
the	O
biological	O
significance	O
of	O
PTEN	O
haploinsufficiency	O
remains	O
controversial	O
.	O

Alternatively	O
,	O
amplification	O
of	O
AKT1	O
has	O
been	O
reported	O
in	O
a	O
single	O
case	O
of	O
gastric	O
cancer	O
[	O
12	O
]	O
,	O
and	O
amplification	O
of	O
PIK3CA	O
associated	O
with	O
elevated	O
mRNA	O
levels	O
has	O
been	O
found	O
in	O
36	O
%	O
of	O
gastric	O
cancer	O
[	O
11	O
]	O
.	O

More	O
recently	O
,	O
Samuels	O
et	O
al	O
.	O
screened	O
a	O
diverse	O
spectrum	O
of	O
human	B
cancers	O
for	O
mutation	O
in	O
16	O
PI3K	O
or	O
PI3K	O
-	O
like	O
genes	O
and	O
found	O
a	O
high	O
frequency	O
of	O
somatic	O
mutation	O
in	O
PIK3CA	O
,	O
which	O
encodes	O
the	O
p110	O
alpha	O
catalytic	O
subunit	O
.	O

Major	O
screening	O
in	O
colorectal	O
cancer	O
(	O
CRC	O
)	O
identified	O
PIK3CA	O
mutations	O
in	O
74	O
out	O
of	O
234	O
(	O
32	O
%	O
)	O
cases	O
,	O
while	O
mutations	O
were	O
also	O
noted	O
in	O
3	O
out	O
of	O
12	O
(	O
25	O
%	O
)	O
gastric	O
cancers	O
.	O

Reported	O
mutations	O
were	O
mostly	O
of	O
missense	O
type	O
,	O
and	O
clustered	O
within	O
2	O
regions	O
in	O
the	O
helical	O
and	O
kinase	O
domains	O
.	O

Expression	O
of	O
a	O
"	O
hot	O
-	O
spot	O
"	O
mutant	O
,	O
H1047R	O
,	O
conferred	O
a	O
significant	O
up	O
-	O
regulation	O
of	O
lipid	O
kinase	O
activity	O
of	O
PIK3CA	O
,	O
suggesting	O
it	O
as	O
an	O
activating	O
mutation	O
[	O
13	O
]	O
.	O

In	O
this	O
study	O
,	O
we	O
have	O
examined	O
a	O
series	O
of	O
94	O
human	B
gastric	O
adenocarcinomas	O
for	O
PIK3CA	O
mutation	O
.	O

We	O
have	O
also	O
examined	O
PIK3CA	O
expression	O
level	O
by	O
extracting	O
data	O
from	O
a	O
large	O
-	O
scale	O
gene	O
expression	O
profiling	O
study	O
previously	O
performed	O
for	O
these	O
cases	O
[	O
14	O
,	O
15	O
]	O
.	O

Using	O
SAM	O
,	O
genes	O
with	O
significant	O
correlating	O
expression	O
with	O
PIK3CA	O
have	O
also	O
been	O
identified	O
.	O

Methods	O

Patient	B
samples	O
preparation	O

DNA	O
samples	O
used	O
for	O
sequencing	O
were	O
prepared	O
from	O
frozen	O
tumour	O
and	O
non	O
-	O
tumour	O
gastric	O
mucosae	O
from	O
94	O
gastric	O
cancer	O
patients	B
who	O
underwent	O
gastrectomy	O
in	O
the	O
Department	O
of	O
Surgery	O
,	O
Queen	O
Mary	O
Hospital	O
,	O
The	O
University	O
of	O
Hong	O
Kong	O
,	O
as	O
previously	O
described	O
[	O
16	O
]	O
.	O

Majority	O
of	O
the	O
frozen	O
samples	O
(	O
n	O
=	O
81	O
)	O
showed	O
tumour	O
component	O
of	O
over	O
70	O
%	O
,	O
whereas	O
in	O
13	O
cases	O
a	O
lower	O
proportion	O
between	O
50	O
to	O
70	O
%	O
was	O
accepted	O
due	O
to	O
the	O
tumours	O
'	O
inherent	O
diffuse	O
infiltrative	O
nature	O
with	O
entrapment	O
of	O
non	O
-	O
neoplastic	O
components	O
.	O

Analysis	O
for	O
microsatellite	O
instability	O
(	O
MSI	O
)	O
,	O
BRAF	O
and	O
KRAS	O
mutation	O
have	O
been	O
performed	O
and	O
reported	O
previously	O
[	O
16	O
]	O
.	O

RNA	O
preparation	O
and	O
gene	O
expression	O
profiling	O
using	O
a	O
cDNA	O
microarray	O
containing	O
44	O
,	O
500	O
cDNA	O
clones	O
,	O
representing	O
around	O
30	O
,	O
300	O
unique	O
genes	O
,	O
has	O
been	O
performed	O
and	O
reported	O
in	O
90	O
of	O
these	O
tumours	O
in	O
comparison	O
to	O
22	O
non	O
-	O
tumour	O
gastric	O
mucosae	O
[	O
14	O
,	O
15	O
]	O
.	O

This	O
study	O
was	O
approved	O
by	O
the	O
Ethics	O
Committee	O
of	O
the	O
University	O
of	O
Hong	O
Kong	O
.	O

Mutational	O
screening	O

Mutation	O
screening	O
of	O
PIK3CA	O
was	O
performed	O
for	O
exons	O
9	O
and	O
20	O
,	O
covering	O
the	O
mutational	O
hotspots	O
;	O
and	O
for	O
exon	O
18	O
,	O
from	O
which	O
a	O
mutation	O
was	O
found	O
in	O
a	O
gastric	O
cancer	O
.	O

Mutations	O
in	O
these	O
3	O
exons	O
constituted	O
80	O
%	O
of	O
all	O
PIK3CA	O
mutations	O
detected	O
in	O
the	O
previous	O
study	O
[	O
13	O
]	O
.	O

PIK3CA	O
intron	O
-	O
specific	O
external	O
amplification	O
primers	O
and	O
internal	O
sequencing	O
primers	O
were	O
designed	O
according	O
to	O
the	O
previous	O
study	O
[	O
13	O
]	O
with	O
some	O
modifications	O
[	O
see	O
Additional	O
file	O
1	O
]	O
.	O

In	O
particular	O
,	O
primers	O
for	O
exon	O
9	O
have	O
been	O
modified	O
to	O
avoid	O
amplification	O
of	O
homologous	O
sequences	O
located	O
in	O
other	O
chromosomes	O
.	O

PCR	O
products	O
were	O
generated	O
using	O
the	O
external	O
primers	O
and	O
directly	O
sequenced	O
using	O
the	O
internal	O
primers	O
with	O
the	O
DYEnamic	O
(	O
TM	O
)	O
ET	O
Terminator	O
Cycle	O
Sequencing	O
Kit	O
(	O
Amersham	O
Biosciences	O
,	O
Freiburg	O
,	O
Germany	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instruction	O
.	O

Electrophoresis	O
was	O
performed	O
in	O
the	O
ABI	O
Prism	O
(	O
R	O
)	O
3700	O
DNA	O
Analyzer	O
(	O
Applied	O
Biosystems	O
,	O
Foster	O
City	O
,	O
CA	O
,	O
USA	O
)	O
.	O

For	O
each	O
exon	O
,	O
PCR	O
products	O
were	O
generated	O
from	O
2	O
independent	O
PCR	O
reactions	O
for	O
sequencing	O
of	O
the	O
forward	O
and	O
reverse	O
strands	O
.	O

For	O
exon	O
9	O
,	O
2	O
independent	O
PCR	O
followed	O
by	O
sequencing	O
of	O
the	O
forward	O
strand	O
were	O
performed	O
.	O

Analysis	O
of	O
the	O
chromatograms	O
was	O
performed	O
using	O
the	O
mutation	O
analysis	O
software	O
Mutation	O
Explorer	O
(	O
TM	O
)	O
(	O
SoftGenetics	O
,	O
State	O
College	O
,	O
PA	O
,	O
USA	O
)	O
.	O

Extraction	O
of	O
expression	O
data	O
and	O
statistical	O
analysis	O

Gene	O
expression	O
data	O
were	O
extracted	O
from	O
the	O
microarray	O
database	O
containing	O
126	O
samples	O
(	O
90	O
gastric	O
cancers	O
,	O
14	O
lymph	O
node	O
metastasis	O
and	O
22	O
non	O
-	O
tumour	O
gastric	O
mucosae	O
)	O
based	O
on	O
a	O
3	O
-	O
fold	O
signal	O
above	O
background	O
ratio	O
for	O
either	O
channel	O
and	O
with	O
80	O
%	O
good	O
data	O
[	O
14	O
]	O
.	O

Gene	O
expression	O
data	O
from	O
20	O
,	O
336	O
cDNA	O
clones	O
satisfied	O
this	O
selection	O
criteria	O
and	O
were	O
extracted	O
,	O
which	O
included	O
a	O
cDNA	O
clone	O
corresponding	O
to	O
PIK3CA	O
(	O
IMAGE	O
clone	O
number	O
345430	O
,	O
GenBank	O
accession	O
no	O
.	O
W72473	O
)	O
.	O

Expression	O
data	O
for	O
PIK3CA	O
was	O
extracted	O
and	O
the	O
differences	O
in	O
expression	O
levels	O
between	O
tumour	O
and	O
non	O
-	O
tumour	O
tissues	O
were	O
examined	O
using	O
the	O
Student	O
'	O
s	O
t	O
-	O
Test	O
.	O

SAM	O
was	O
performed	O
to	O
identify	O
genes	O
with	O
significant	O
correlating	O
expression	O
with	O
PIK3CA	O
[	O
17	O
]	O
.	O

The	O
missing	O
values	O
in	O
the	O
dataset	O
were	O
estimated	O
by	O
a	O
K	O
-	O
nearest	O
neighbours	O
impute	O
algorithm	O
using	O
10	O
nearest	O
neighbour	O
[	O
18	O
]	O
followed	O
by	O
5000	O
permutations	O
in	O
the	O
SAM	O
analysis	O
.	O

Results	O

Among	O
the	O
94	O
gastric	O
adenocarcinoma	O
analysed	O
,	O
we	O
have	O
detected	O
PIK3CA	O
mutation	O
in	O
4	O
cases	O
.	O

Two	O
cases	O
harboured	O
the	O
mutation	O
A3140G	O
(	O
H1047R	O
)	O
in	O
exon	O
20	O
,	O
and	O
the	O
other	O
2	O
cases	O
with	O
mutations	O
G1624A	O
(	O
E542K	O
)	O
and	O
G1633A	O
(	O
E545K	O
)	O
in	O
exon	O
9	O
.	O

Representative	O
sequence	O
chromatograms	O
are	O
shown	O
in	O
figure	O
1	O
.	O

All	O
four	O
mutations	O
were	O
absent	O
in	O
the	O
corresponding	O
non	O
-	O
neoplastic	O
mucosae	O
and	O
thus	O
were	O
confirmed	O
as	O
somatic	O
mutations	O
.	O

Though	O
the	O
overall	O
mutation	O
frequency	O
(	O
4	O
.	O
3	O
%	O
)	O
was	O
lower	O
than	O
that	O
of	O
the	O
previous	O
study	O
,	O
the	O
nature	O
of	O
the	O
4	O
mutations	O
found	O
were	O
consistent	O
with	O
those	O
identified	O
at	O
the	O
reported	O
hotspots	O
.	O

In	O
particular	O
,	O
the	O
H1047R	O
mutation	O
has	O
been	O
reported	O
in	O
2	O
gastric	O
cancers	O
and	O
15	O
colorectal	O
cancers	O
[	O
13	O
]	O
.	O

While	O
the	O
E542K	O
and	O
the	O
E545K	O
mutations	O
were	O
not	O
found	O
in	O
gastric	O
cancer	O
in	O
the	O
previous	O
series	O
,	O
a	O
large	O
number	O
of	O
colorectal	O
tumours	O
did	O
harbour	O
these	O
2	O
mutations	O
.	O

PIK3CA	O
mutation	O
spectrum	O
and	O
their	O
corresponding	O
clinico	O
-	O
pathological	O
features	O
were	O
listed	O
in	O
Table	O
1	O
.	O

We	O
noted	O
a	O
higher	O
tendency	O
of	O
high	O
-	O
level	O
MSI	O
in	O
gastric	O
cancers	O
with	O
PIK3CA	O
mutations	O
(	O
3	O
in	O
4	O
,	O
75	O
%	O
)	O
than	O
in	O
those	O
without	O
(	O
18	O
in	O
90	O
,	O
20	O
%	O
)	O
.	O

Moreover	O
,	O
though	O
the	O
overall	O
incidence	O
of	O
KRAS	O
mutation	O
in	O
the	O
studied	O
population	O
was	O
low	O
(	O
8	O
in	O
94	O
)	O
,	O
2	O
of	O
the	O
4	O
gastric	O
cancers	O
with	O
PIK3CA	O
mutation	O
also	O
harboured	O
a	O
KRAS	O
mutation	O
.	O

Since	O
over	O
-	O
expression	O
of	O
PIK3CA	O
has	O
been	O
reported	O
in	O
gastric	O
cancer	O
[	O
11	O
]	O
,	O
we	O
have	O
also	O
extracted	O
PIK3CA	O
expression	O
data	O
from	O
our	O
previous	O
cDNA	O
microarray	O
study	O
of	O
these	O
cases	O
[	O
14	O
,	O
15	O
]	O
.	O

We	O
have	O
confirmed	O
that	O
expression	O
level	O
of	O
PIK3CA	O
was	O
significantly	O
higher	O
in	O
gastric	O
cancers	O
(	O
n	O
=	O
87	O
,	O
mean	O
=	O
0	O
.	O
099	O
,	O
SD	O
=	O
0	O
.	O
428	O
)	O
when	O
compared	O
with	O
non	O
-	O
neoplastic	O
gastric	O
mucosae	O
(	O
n	O
=	O
22	O
,	O
mean	O
=	O
-	O
0	O
.	O
418	O
,	O
SD	O
=	O
0	O
.	O
426	O
;	O
Student	O
'	O
s	O
t	O
-	O
Test	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Using	O
PIK3CA	O
expression	O
level	O
as	O
a	O
continuous	O
variable	O
for	O
SAM	O
analysis	O
[	O
17	O
]	O
,	O
we	O
found	O
2910	O
cDNA	O
clones	O
(	O
corresponding	O
to	O
about	O
2546	O
unique	O
genes	O
)	O
whose	O
expression	O
associated	O
positively	O
with	O
PIK3CA	O
expression	O
(	O
median	O
number	O
of	O
false	O
significant	O
=	O
0	O
.	O
372	O
,	O
Delta	O
=	O
1	O
.	O
107	O
)	O
[	O
see	O
Additional	O
file	O
2	O
]	O
.	O

Interestingly	O
,	O
no	O
gene	O
was	O
found	O
to	O
be	O
negatively	O
associated	O
with	O
PIK3CA	O
expression	O
.	O

Discussion	O

In	O
this	O
study	O
,	O
we	O
have	O
reported	O
the	O
presence	O
of	O
PIK3CA	O
gene	O
mutation	O
in	O
4	O
.	O
3	O
%	O
of	O
gastric	O
cancer	O
.	O

A	O
high	O
tendency	O
(	O
3	O
in	O
4	O
)	O
of	O
mismatch	O
repair	O
deficiency	O
was	O
noted	O
in	O
cases	O
harbouring	O
PIK3CA	O
mutation	O
.	O

Though	O
the	O
small	O
number	O
of	O
PIK3CA	O
mutations	O
in	O
our	O
study	O
may	O
not	O
justify	O
statistical	O
claim	O
of	O
significance	O
;	O
suggestion	O
of	O
such	O
,	O
despite	O
of	O
its	O
not	O
being	O
mentioned	O
by	O
the	O
authors	O
,	O
can	O
be	O
found	O
from	O
a	O
previous	O
study	O
in	O
CRC	O
by	O
Samuels	O
et	O
al	O
.	O
.	O

From	O
their	O
study	O
of	O
33	O
MSI	O
and	O
201	O
microsatellite	O
stable	O
(	O
MSS	O
)	O
CRC	O
cases	O
,	O
PIK3CA	O
mutation	O
was	O
present	O
in	O
48	O
%	O
of	O
the	O
MSI	O
tumours	O
,	O
but	O
only	O
in	O
29	O
%	O
of	O
the	O
MSS	O
tumours	O
.	O

A	O
significant	O
association	O
would	O
have	O
been	O
revealed	O
if	O
statistical	O
analysis	O
had	O
been	O
applied	O
(	O
Fisher	O
'	O
s	O
exact	O
test	O
,	O
p	O
=	O
0	O
.	O
014	O
)	O
[	O
13	O
]	O
.	O

Gastrointestinal	O
tract	O
cancers	O
with	O
MSI	O
are	O
known	O
to	O
have	O
a	O
different	O
molecular	O
pathway	O
of	O
tumour	O
evolution	O
compared	O
with	O
their	O
MSS	O
counterparts	O
[	O
19	O
,	O
20	O
]	O
.	O

This	O
can	O
be	O
attributed	O
to	O
their	O
propensity	O
for	O
frameshift	O
mutations	O
in	O
repeat	O
sequences	O
,	O
resulting	O
in	O
selective	O
disruption	O
of	O
genes	O
with	O
such	O
sequences	O
within	O
their	O
coding	O
regions	O
.	O

With	O
2	O
poly	O
-	O
adenine	O
tracts	O
within	O
its	O
coding	O
region	O
,	O
PTEN	O
can	O
be	O
inactivated	O
through	O
frameshift	O
mutations	O
in	O
MSI	O
CRC	O
,	O
resulting	O
in	O
the	O
selective	O
targeting	O
of	O
the	O
PI3K	O
-	O
AKT	O
signalling	O
pathway	O
[	O
21	O
,	O
22	O
]	O
.	O

It	O
is	O
also	O
known	O
that	O
mismatch	O
repair	O
deficiency	O
would	O
lead	O
to	O
an	O
elevated	O
rate	O
of	O
missense	O
mutation	O
due	O
to	O
impaired	O
single	O
nucleotide	O
mismatch	O
repair	O
[	O
23	O
]	O
.	O

Thus	O
,	O
the	O
observed	O
higher	O
incidence	O
of	O
PIK3CA	O
missense	O
mutation	O
in	O
MSI	O
colorectal	O
and	O
gastric	O
cancers	O
suggests	O
yet	O
another	O
mechanism	O
for	O
the	O
activation	O
of	O
the	O
PI3K	O
-	O
AKT	O
signalling	O
pathway	O
through	O
mismatch	O
repair	O
deficiency	O
.	O

Our	O
data	O
also	O
showed	O
a	O
higher	O
tendency	O
of	O
KRAS	O
mutation	O
in	O
cases	O
with	O
PIK3CA	O
mutations	O
(	O
2	O
in	O
4	O
)	O
than	O
in	O
those	O
without	O
(	O
6	O
in	O
90	O
)	O
.	O

Yet	O
again	O
due	O
to	O
the	O
low	O
incidence	O
of	O
both	O
mutations	O
in	O
our	O
samples	O
,	O
statistical	O
significance	O
may	O
not	O
be	O
claimed	O
.	O

In	O
the	O
study	O
by	O
Samuels	O
et	O
al	O
.	O
,	O
some	O
of	O
the	O
colorectal	O
tumours	O
with	O
PIK3CA	O
mutation	O
also	O
harboured	O
KRAS	O
or	O
BRAF	O
mutation	O
[	O
13	O
]	O
.	O

The	O
PI3K	O
-	O
AKT	O
pathway	O
is	O
known	O
to	O
have	O
a	O
close	O
association	O
with	O
the	O
RAS	O
-	O
MEKK	O
signalling	O
pathway	O
[	O
8	O
]	O
.	O

Constitutively	O
active	O
RAS	O
can	O
interact	O
with	O
the	O
catalytic	O
subunit	O
of	O
PI3K	O
and	O
lead	O
to	O
its	O
activation	O
.	O

Ras	O
-	O
dependent	O
PI3K	O
activation	O
contributes	O
to	O
the	O
transforming	O
phenotype	O
by	O
mediating	O
anchorage	O
-	O
independent	O
growth	O
,	O
cytoskeletal	O
reorganisation	O
and	O
apoptosis	O
evasion	O
.	O

It	O
has	O
been	O
observed	O
that	O
genes	O
involved	O
in	O
the	O
same	O
signalling	O
pathway	O
may	O
manifest	O
mutations	O
in	O
cancer	O
cells	O
in	O
a	O
mutually	O
exclusive	O
manner	O
,	O
presumably	O
due	O
to	O
the	O
lack	O
of	O
selective	O
growth	O
advantage	O
in	O
having	O
a	O
second	O
hit	O
in	O
the	O
already	O
altered	O
pathway	O
.	O

A	O
prominent	O
example	O
is	O
the	O
mutually	O
exclusive	O
occurrence	O
of	O
the	O
BRAF	O
hotspot	O
mutation	O
(	O
V600E	O
)	O
and	O
KRAS	O
mutations	O
in	O
colorectal	O
cancer	O
[	O
24	O
,	O
25	O
]	O
.	O

However	O
,	O
there	O
exist	O
other	O
examples	O
of	O
alterations	O
in	O
multiple	O
components	O
of	O
the	O
same	O
signalling	O
pathway	O
that	O
may	O
lead	O
to	O
a	O
multi	O
-	O
level	O
modulation	O
of	O
its	O
activity	O
.	O

For	O
example	O
,	O
non	O
-	O
V600E	O
BRAF	O
mutations	O
tend	O
to	O
occur	O
together	O
with	O
KRAS	O
mutations	O
[	O
26	O
]	O
,	O
and	O
inactivation	O
of	O
the	O
secreted	O
frizzled	O
-	O
related	O
proteins	O
(	O
antagonists	O
of	O
WNT	O
)	O
by	O
promoter	O
methylation	O
frequently	O
coincides	O
with	O
mutations	O
in	O
the	O
Adenomatous	O
Polyposis	O
Coli	O
gene	O
to	O
achieve	O
multi	O
-	O
level	O
activation	O
of	O
the	O
WNT	O
signalling	O
pathway	O
in	O
colorectal	O
cancers	O
[	O
27	O
]	O
.	O

Whether	O
PIK3CA	O
functions	O
independently	O
from	O
RAS	O
,	O
or	O
acts	O
synergistically	O
with	O
RAS	O
to	O
produce	O
additive	O
effects	O
on	O
the	O
activation	O
of	O
the	O
same	O
pathway	O
awaits	O
further	O
clarification	O
.	O

By	O
extracting	O
data	O
from	O
microarray	O
,	O
we	O
have	O
confirmed	O
the	O
up	O
-	O
regulation	O
of	O
PIK3CA	O
expression	O
in	O
gastric	O
cancer	O
tissues	O
compared	O
with	O
the	O
non	O
-	O
neoplastic	O
gastric	O
mucosae	O
and	O
identified	O
a	O
large	O
number	O
of	O
genes	O
that	O
showed	O
a	O
significant	O
positive	O
correlation	O
in	O
expression	O
level	O
with	O
PIK3CA	O
.	O

These	O
genes	O
participate	O
in	O
diverse	O
cellular	O
processes	O
with	O
177	O
as	O
putative	O
cell	O
cycle	O
-	O
regulated	O
genes	O
[	O
28	O
]	O
and	O
126	O
mapped	O
to	O
genes	O
with	O
known	O
functions	O
in	O
cell	O
cycle	O
regulation	O
,	O
cell	O
proliferation	O
or	O
DNA	O
replication	O
[	O
see	O
Additional	O
file	O
2	O
]	O
.	O

While	O
some	O
of	O
these	O
genes	O
maybe	O
induced	O
by	O
PIK3CA	O
,	O
others	O
maybe	O
co	O
-	O
ordinately	O
regulated	O
by	O
common	O
upstream	O
signals	O
.	O

Expression	O
data	O
set	O
at	O
one	O
point	O
was	O
limited	O
in	O
differentiating	O
the	O
above	O
cause	O
and	O
consequence	O
,	O
yet	O
it	O
certainly	O
revealed	O
the	O
complexity	O
of	O
the	O
carcinogenic	O
process	O
and	O
the	O
intricate	O
relationship	O
of	O
PIK3CA	O
signalling	O
with	O
other	O
cellular	O
processes	O
.	O

Contrary	O
to	O
our	O
expectation	O
,	O
the	O
incidence	O
of	O
PIK3CA	O
mutation	O
found	O
in	O
the	O
current	O
study	O
(	O
4	O
%	O
)	O
is	O
much	O
lower	O
compared	O
with	O
that	O
observed	O
by	O
Samuel	O
et	O
al	O
.	O

(	O
25	O
%	O
)	O
[	O
13	O
]	O
.	O

The	O
reason	O
for	O
discrepancy	O
may	O
simply	O
be	O
a	O
result	O
of	O
sample	O
bias	O
as	O
the	O
previous	O
study	O
involved	O
only	O
a	O
small	O
number	O
of	O
gastric	O
cancers	O
(	O
n	O
=	O
12	O
)	O
.	O

However	O
,	O
ethnic	O
differences	O
can	O
also	O
be	O
another	O
possibility	O
.	O

The	O
diverse	O
pathological	O
spectrum	O
and	O
aetiological	O
factors	O
of	O
gastric	O
cancers	O
in	O
different	O
geographical	O
locations	O
may	O
be	O
paralleled	O
by	O
differences	O
in	O
molecular	O
pathway	O
of	O
tumour	O
development	O
.	O

Since	O
our	O
current	O
study	O
is	O
only	O
based	O
on	O
a	O
Chinese	O
population	O
with	O
an	O
intermediate	O
gastric	O
cancer	O
incidence	O
,	O
further	O
studies	O
involving	O
patients	B
from	O
different	O
ethnic	O
groups	O
will	O
be	O
able	O
to	O
address	O
this	O
possibility	O
.	O

Conclusion	O

Large	O
-	O
scale	O
screening	O
of	O
gastric	O
adenocarcinomas	O
for	O
PIK3CA	O
mutations	O
revealed	O
a	O
mutation	O
incidence	O
of	O
4	O
.	O
3	O
%	O
.	O

Increased	O
PIK3CA	O
expression	O
level	O
was	O
observed	O
in	O
gastric	O
tumours	O
compared	O
with	O
non	O
-	O
neoplastic	O
mucosae	O
.	O

This	O
increase	O
in	O
PIK3CA	O
level	O
was	O
associated	O
with	O
the	O
elevated	O
expression	O
of	O
a	O
large	O
number	O
of	O
genes	O
,	O
which	O
may	O
constitute	O
the	O
upstream	O
regulators	O
or	O
downstream	O
targets	O
of	O
PIK3CA	O
along	O
the	O
PI3K	O
signalling	O
pathway	O
.	O

Competing	O
interests	O

The	O
author	O
(	O
s	O
)	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

VSWL	O
carried	O
out	O
the	O
molecular	O
analysis	O
,	O
performed	O
data	O
analysis	O
and	O
drafted	O
the	O
manuscript	O
.	O

CWW	O
,	O
TLC	O
,	O
WZ	O
assisted	O
in	O
the	O
molecular	O
analysis	O
.	O

KMC	O
provided	O
the	O
clinical	O
data	O
.	O

ASWC	O
assisted	O
in	O
data	O
analysis	O
and	O
edited	O
the	O
manuscript	O
.	O

SS	O
and	O
XC	O
participated	O
in	O
the	O
microarray	O
study	O
and	O
data	O
analysis	O
.	O

STY	O
and	O
SYL	O
conceived	O
of	O
the	O
study	O
,	O
participated	O
in	O
its	O
design	O
,	O
coordination	O
and	O
data	O
analysis	O
,	O
and	O
edited	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O

Supplementary	O
Material	O

Identification	O
of	O
kinectin	O
as	O
a	O
novel	O
Beh	O
c	O
et	O
'	O
s	O
disease	O
autoantigen	O

Abstract	O

There	O
has	O
been	O
some	O
evidence	O
that	O
Beh	O
c	O
et	O
'	O
s	O
disease	O
(	O
BD	O
)	O
has	O
a	O
significant	O
autoimmune	O
component	O
but	O
the	O
molecular	O
identity	O
of	O
putative	O
autoantigens	O
has	O
not	O
been	O
well	O
characterized	O
.	O

In	O
the	O
initial	O
analysis	O
of	O
the	O
autoantibody	O
profile	O
in	O
39	O
Chinese	O
BD	O
patients	B
,	O
autoantibodies	O
to	O
cellular	O
proteins	O
were	O
uncovered	O
in	O
23	O
%	O
as	O
determined	O
by	O
immunoblotting	O
.	O

We	O
have	O
now	O
identified	O
one	O
of	O
the	O
major	O
autoantibody	O
specificities	O
using	O
expression	O
cloning	O
.	O

Serum	O
from	O
a	O
BD	O
patient	B
was	O
used	O
as	O
a	O
probe	O
to	O
immunoscreen	O
a	O
lambda	O
ZAP	O
expression	O
cDNA	O
library	O
.	O

Candidate	O
autoantigen	O
cDNAs	O
were	O
characterized	O
by	O
direct	O
nucleotide	O
sequencing	O
and	O
their	O
expressed	O
products	O
were	O
examined	O
for	O
reactivity	O
to	O
the	O
entire	O
panel	O
of	O
BD	O
sera	O
using	O
immunoprecipitation	O
.	O

Reactivity	O
was	O
also	O
examined	O
with	O
normal	O
control	O
sera	O
and	O
disease	O
control	O
sera	O
from	O
patients	B
with	O
lupus	O
and	O
Sj	O
o	O
gren	O
'	O
s	O
syndrome	O
.	O

Six	O
independent	O
candidate	O
clones	O
were	O
isolated	O
from	O
the	O
cDNA	O
library	O
screen	O
and	O
were	O
identified	O
as	O
overlapping	O
partial	O
human	B
kinectin	O
cDNAs	O
.	O

The	O
finding	O
that	O
kinectin	O
was	O
an	O
autoantigen	O
was	O
verified	O
in	O
9	O
out	O
of	O
39	O
(	O
23	O
%	O
)	O
BD	O
patient	B
sera	O
by	O
immunoprecipitation	O
of	O
the	O
in	O
vitro	O
translation	O
products	O
.	O

Sera	O
from	O
controls	O
showed	O
no	O
reactivity	O
.	O

The	O
significance	O
of	O
kinectin	O
as	O
a	O
participant	O
in	O
autoimmune	O
pathogenesis	O
in	O
BD	O
and	O
the	O
potential	O
use	O
of	O
autoantibody	O
to	O
kinectin	O
in	O
serodiagnostics	O
are	O
discussed	O
.	O

Introduction	O

Beh	O
c	O
et	O
'	O
s	O
disease	O
(	O
BD	O
)	O
is	O
a	O
systemic	O
vasculitic	O
disease	O
typified	O
by	O
a	O
triad	O
of	O
symptoms	O
including	O
recurrent	O
oral	O
ulcers	O
,	O
genital	O
ulcers	O
and	O
uveitis	O
.	O

In	O
addition	O
,	O
skin	O
,	O
joint	O
,	O
large	O
vessels	O
,	O
nervous	O
system	O
and	O
gastrointestinal	O
systems	O
may	O
be	O
involved	O
.	O

BD	O
is	O
a	O
global	O
disease	O
but	O
has	O
the	O
highest	O
prevalence	O
in	O
the	O
region	O
along	O
the	O
ancient	O
'	O
Silk	O
Road	O
'	O
in	O
China	O
.	O

The	O
etiopathogenesis	O
of	O
the	O
disease	O
remains	O
unclear	O
but	O
microbial	O
agent	O
triggers	O
,	O
environmental	O
factors	O
,	O
genetic	O
predisposition	O
,	O
neutrophil	O
hyperfunction	O
,	O
endothelial	O
cell	O
dysfunction	O
and	O
immunological	O
abnormalities	O
involving	O
both	O
T	O
and	O
B	O
cells	O
have	O
been	O
implicated	O
.	O

Increasing	O
amounts	O
of	O
research	O
evidence	O
supports	O
the	O
possibility	O
that	O
it	O
is	O
an	O
immune	O
-	O
mediated	O
vasculitis	O
,	O
and	O
that	O
abnormal	O
T	O
-	O
cell	O
and	O
B	O
-	O
cell	O
reactions	O
and	O
autoantigen	O
-	O
driven	O
autoimmunity	O
play	O
pivotal	O
roles	O
[	O
1	O
]	O
.	O

Systemic	O
lupus	O
erythematosus	O
(	O
SLE	O
)	O
is	O
the	O
prototypic	O
systemic	O
autoimmune	O
rheumatic	O
disease	O
with	O
autoantibodies	O
against	O
cellular	O
(	O
particularly	O
nuclear	O
)	O
antigens	O
,	O
some	O
of	O
which	O
are	O
critically	O
implicated	O
in	O
the	O
autoimmune	O
pathology	O
while	O
others	O
provide	O
valuable	O
serodiagnostic	O
markers	O
for	O
the	O
disease	O
.	O

Unlike	O
the	O
picture	O
in	O
SLE	O
and	O
other	O
related	O
rheumatic	O
diseases	O
,	O
in	O
BD	O
,	O
antinuclear	O
antibodies	O
and	O
antibodies	O
to	O
neutrophil	O
cytoplasmic	O
antigens	O
etc	O
.	O
are	O
not	O
present	O
.	O

To	O
date	O
,	O
since	O
neither	O
a	O
specific	O
autoantibody	O
nor	O
pathognomonic	O
pathological	O
index	O
is	O
available	O
to	O
help	O
establish	O
the	O
diagnosis	O
of	O
BD	O
,	O
it	O
is	O
largely	O
or	O
solely	O
based	O
on	O
clinical	O
manifestations	O
[	O
2	O
]	O
,	O
and	O
a	O
dilemma	O
in	O
diagnosis	O
is	O
not	O
a	O
rare	O
occurrence	O
in	O
clinical	O
practice	O
.	O

Nevertheless	O
,	O
since	O
the	O
1960s	O
,	O
there	O
have	O
been	O
reports	O
of	O
autoantibodies	O
against	O
certain	O
unknown	O
components	O
of	O
human	B
oral	O
mucosa	O
in	O
sera	O
of	O
patients	B
with	O
BD	O
.	O

Since	O
then	O
,	O
sporadic	O
reports	O
on	O
findings	O
of	O
autoantibodies	O
in	O
this	O
disease	O
have	O
been	O
described	O
,	O
such	O
as	O
antibodies	O
to	O
retinal	O
antigen	O
(	O
s	O
)	O
,	O
heat	O
shock	O
protein	O
(	O
HSP	O
)	O
of	O
some	O
strains	O
of	O
Streptococcus	B
sanguis	I
cross	O
-	O
reactive	O
with	O
human	B
HSP	O
polypeptide	O
[	O
3	O
]	O
,	O
antibodies	O
to	O
endothelial	O
cell	O
antigens	O
(	O
AECA	O
)	O
and	O
antibodies	O
to	O
alpha	O
-	O
tropomyosin	O
[	O
4	O
,	O
5	O
]	O
,	O
attesting	O
to	O
the	O
complicated	O
humoral	O
immune	O
disorders	O
in	O
this	O
disease	O
.	O

This	O
investigation	O
was	O
aimed	O
at	O
defining	O
target	O
cellular	O
autoantigens	O
using	O
time	O
-	O
tested	O
and	O
well	O
-	O
established	O
molecular	O
techniques	O
.	O

Immunoscreening	O
of	O
expression	O
libraries	O
using	O
BD	O
sera	O
was	O
used	O
since	O
this	O
approach	O
has	O
been	O
successfully	O
employed	O
in	O
the	O
characterization	O
of	O
many	O
clinically	O
relevant	O
antigens	O
in	O
systemic	O
rheumatic	O
diseases	O
such	O
as	O
SS	O
-	O
A	O
/	O
Ro	O
[	O
6	O
-	O
9	O
]	O
and	O
SS	O
-	O
B	O
/	O
La	O
[	O
10	O
]	O
antigens	O
in	O
Sj	O
o	O
gren	O
'	O
s	O
syndrome	O
(	O
SjS	O
)	O
and	O
centromere	O
antigen	O
CENP	O
-	O
B	O
[	O
11	O
]	O
in	O
scleroderma	O
.	O

In	O
addition	O
,	O
we	O
have	O
been	O
successful	O
in	O
using	O
this	O
strategy	O
to	O
identify	O
interesting	O
autoantigens	O
that	O
have	O
other	O
biological	O
significance	O
.	O

Examples	O
of	O
these	O
include	O
NOR90	O
/	O
hUBF	O
[	O
12	O
]	O
,	O
p80	O
-	O
coilin	O
[	O
13	O
]	O
,	O
Golgi	O
autoantigens	O
[	O
14	O
-	O
16	O
]	O
and	O
,	O
more	O
recently	O
,	O
GW182	O
[	O
17	O
]	O
.	O

Materials	O
and	O
methods	O

Patients	B
and	O
sera	O

The	O
currently	O
used	O
empirical	O
criteria	O
for	O
the	O
diagnosis	O
of	O
BD	O
in	O
this	O
study	O
were	O
the	O
criteria	O
proposed	O
by	O
the	O
International	O
Study	O
Group	O
for	O
BD	O
(	O
abbreviated	O
as	O
'	O
International	O
Criteria	O
'	O
)	O
[	O
2	O
]	O
.	O

The	O
study	O
subjects	O
of	O
39	O
Chinese	O
BD	O
patients	B
comprised	O
17	O
males	O
and	O
22	O
females	O
,	O
mean	O
age	O
37	O
+	O
/	O
-	O
11	O
.	O
3	O
years	O
old	O
,	O
who	O
were	O
divided	O
into	O
two	O
subgroups	O
:	O
25	O
typical	O
BD	O
patients	B
(	O
Group	O
I	O
,	O
satisfying	O
the	O
International	O
Criteria	O
)	O
and	O
14	O
clinically	O
diagnosed	O
BD	O
patients	B
who	O
had	O
recurrent	O
oral	O
ulcers	O
and	O
one	O
of	O
the	O
symptoms	O
of	O
genital	O
ulcers	O
,	O
eye	O
symptoms	O
or	O
skin	O
lesions	O
as	O
defined	O
by	O
the	O
International	O
Criteria	O
,	O
as	O
well	O
as	O
additional	O
symptom	O
(	O
s	O
)	O
closely	O
related	O
to	O
BD	O
as	O
listed	O
in	O
the	O
International	O
Criteria	O
,	O
that	O
is	O
,	O
gastrointestinal	O
ulcerations	O
,	O
deep	O
vein	O
thrombosis	O
or	O
arthralgia	O
/	O
arthritis	O
without	O
evidence	O
that	O
the	O
latter	O
symptoms	O
might	O
be	O
related	O
to	O
any	O
other	O
disease	O
(	O
Group	O
II	O
,	O
defined	O
as	O
'	O
probable	O
BD	O
'	O
in	O
this	O
study	O
)	O
.	O

Disease	O
controls	O
included	O
10	O
patients	B
with	O
SLE	O
and	O
10	O
with	O
SjS	O
,	O
all	O
satisfying	O
corresponding	O
international	O
classification	O
criteria	O
.	O

All	O
BD	O
patients	B
and	O
disease	O
controls	O
involved	O
in	O
the	O
study	O
were	O
patients	B
treated	O
at	O
the	O
Rheumatology	O
Department	O
of	O
Ren	O
Ji	O
Hospital	O
,	O
Shanghai	O
,	O
China	O
,	O
where	O
their	O
clinical	O
data	O
and	O
serum	O
samples	O
were	O
collected	O
.	O

Twenty	O
normal	O
control	O
sera	O
were	O
randomly	O
selected	O
from	O
healthy	O
blood	O
donors	O
working	O
in	O
the	O
same	O
hospital	O
.	O

This	O
study	O
was	O
approved	O
by	O
the	O
institution	O
review	O
board	O
of	O
Ren	O
Ji	O
Hospital	O
which	O
is	O
affiliated	O
with	O
Shanghai	O
Second	O
Medical	O
University	O
,	O
and	O
each	O
patient	B
involved	O
gave	O
informed	O
consent	O
.	O

All	O
serum	O
samples	O
were	O
preserved	O
at	O
-	O
20	O
degrees	O
C	O
or	O
-	O
70	O
degrees	O
C	O
until	O
use	O
.	O

Cell	O
lines	O
and	O
cell	O
extracts	O

HeLa	O
(	O
ATCC	O
CCL	O
2	O
.	O
2	O
)	O
and	O
T24	O
(	O
human	B
transitional	O
cell	O
bladder	O
carcinoma	O
)	O
were	O
obtained	O
from	O
the	O
American	O
Type	O
Culture	O
Collection	O
(	O
Rockville	O
,	O
MD	O
,	O
USA	O
)	O
.	O

A	O
bovine	B
aortic	O
endothelial	O
cell	O
line	O
was	O
kindly	O
provided	O
by	O
Dr	O
Eugene	O
G	O
Levin	O
from	O
the	O
Scripps	O
Research	O
Institute	O
(	O
La	O
Jolla	O
,	O
CA	O
,	O
USA	O
)	O
.	O

Cells	O
were	O
cultured	O
in	O
DMEM	O
containing	O
10	O
%	O
calf	B
serum	O
,	O
harvested	O
and	O
extracted	O
in	O
Buffer	O
A	O
(	O
150	O
mM	O
NaCl	O
,	O
10	O
mM	O
Tris	O
-	O
HCl	O
,	O
pH7	O
.	O
2	O
,	O
0	O
.	O
5	O
%	O
Nonidet	O
P	O
-	O
40	O
)	O
with	O
protease	O
inhibitor	O
(	O
Complete	O
(	O
TM	O
)	O
;	O
Boehringer	O
Mannheim	O
,	O
Indianapolis	O
,	O
IN	O
,	O
USA	O
)	O
.	O

For	O
the	O
preparation	O
of	O
whole	O
cell	O
extract	O
,	O
10	O
volumes	O
of	O
Laemmli	O
gel	O
sample	O
buffer	O
[	O
18	O
]	O
were	O
added	O
to	O
the	O
cell	O
pellet	O
,	O
boiled	O
for	O
3	O
min	O
and	O
stored	O
at	O
-	O
20	O
degrees	O
C	O
until	O
use	O
.	O

Western	O
blot	O

Whole	O
cell	O
lysates	O
from	O
bovine	B
aortic	O
endothelial	O
cell	O
,	O
HeLa	O
and	O
T24	O
cells	O
were	O
resolved	O
individually	O
by	O
discontinuous	O
7	O
.	O
5	O
%	O
gel	O
SDS	O
-	O
PAGE	O
according	O
to	O
Laemmli	O
'	O
s	O
method	O
[	O
18	O
]	O
.	O

Immunoblotting	O
was	O
performed	O
as	O
described	O
by	O
Towbin	O
et	O
al	O
.	O

[	O
19	O
]	O
with	O
modifications	O
.	O

Nitrocellulose	O
strips	O
were	O
blocked	O
with	O
3	O
%	O
nonfat	O
milk	O
in	O
PBS	O
containing	O
0	O
.	O
05	O
%	O
Tween	O
-	O
20	O
(	O
PBS	O
-	O
T	O
)	O
and	O
then	O
incubated	O
with	O
BD	O
patient	B
sera	O
and	O
normal	O
control	O
sera	O
(	O
1	O
:	O
100	O
dilution	O
)	O
at	O
room	O
temperature	O
for	O
1	O
h	O
.	O

Filters	O
were	O
washed	O
extensively	O
with	O
PBS	O
-	O
T	O
to	O
remove	O
any	O
unbound	O
antibodies	O
.	O

Bound	O
antibodies	O
were	O
detected	O
with	O
polyvalent	O
,	O
peroxidase	O
-	O
conjugated	O
goat	B
anti	O
-	O
human	B
Ig	O
and	O
visualized	O
by	O
incubating	O
the	O
nitrocellulose	O
strips	O
in	O
chemiluminescent	O
reagents	O
(	O
NEN	O
Life	O
Science	O
Products	O
Inc	O
.	O
,	O
Boston	O
,	O
MA	O
,	O
USA	O
)	O
and	O
exposing	O
to	O
Kodak	O
XAR	O
-	O
5	O
films	O
.	O

Screening	O
of	O
phage	O
cDNA	O
expression	O
library	O
with	O
antibody	O
probes	O

Serum	O
from	O
a	O
BD	O
patient	B
showing	O
the	O
highest	O
antibody	O
titer	O
in	O
immunoblotting	O
was	O
selected	O
as	O
a	O
probe	O
and	O
used	O
at	O
a	O
dilution	O
of	O
1	O
:	O
300	O
for	O
initial	O
immunoscreening	O
of	O
approximately	O
106	O
recombinants	O
from	O
a	O
T24	O
cDNA	O
expression	O
library	O
.	O

The	O
latter	O
was	O
constructed	O
in	O
lambda	O
ZAPExpress	O
vector	O
(	O
Stratagene	O
,	O
La	O
Jolla	O
,	O
CA	O
,	O
USA	O
)	O
and	O
screened	O
as	O
previously	O
described	O
[	O
20	O
-	O
22	O
]	O
.	O

All	O
screenings	O
were	O
performed	O
on	O
duplicate	O
isopropyl	O
beta	O
-	O
D	O
-	O
thiogalactoside	O
(	O
IPTG	O
)	O
pre	O
-	O
impregnated	O
nitrocellulose	O
filters	O
,	O
and	O
immunoreactive	O
clones	O
were	O
detected	O
by	O
chemiluminescence	O
.	O

Positive	O
phages	O
were	O
subsequently	O
plaque	O
purified	O
to	O
100	O
%	O
by	O
two	O
repeated	O
rounds	O
of	O
screening	O
at	O
low	O
plaque	O
densities	O
.	O

Before	O
screening	O
the	O
cDNA	O
library	O
,	O
the	O
BD	O
serum	O
was	O
extensively	O
adsorbed	O
against	O
bacteria	O
and	O
wild	O
-	O
type	O
lambda	O
ZAP	O
phage	O
mixture	O
to	O
reduce	O
background	O
binding	O
.	O

Analysis	O
of	O
candidate	O
cDNAs	O

Purified	O
candidate	O
plaques	O
were	O
subcloned	O
in	O
vivo	O
into	O
pBK	O
-	O
CMV	O
plasmids	O
using	O
ExAssist	O
(	O
TM	O
)	O
helper	O
phage	O
as	O
recommended	O
in	O
the	O
manufacturer	O
'	O
s	O
instructions	O
(	O
Stratagene	O
)	O
.	O

The	O
recombinant	O
pBK	O
-	O
CMV	O
plasmids	O
were	O
then	O
purified	O
using	O
QIAprep	O
Spin	O
Minprep	O
Kit	O
(	O
Qiagen	O
,	O
Valencia	O
,	O
CA	O
,	O
USA	O
)	O
.	O

Restriction	O
enzyme	O
digestion	O
of	O
plasmids	O
with	O
EcoRI	O
and	O
XhoI	O
and	O
electrophoresis	O
in	O
a	O
standard	O
1	O
.	O
0	O
%	O
agarose	O
gel	O
was	O
used	O
to	O
analyze	O
the	O
length	O
of	O
cDNA	O
insert	O
of	O
each	O
candidate	O
plasmid	O
.	O

The	O
complete	O
nucleotide	O
sequence	O
was	O
determined	O
using	O
Bigdye	O
terminator	O
sequencing	O
and	O
a	O
semi	O
-	O
automated	O
sequencer	O
model	O
377	O
(	O
ABI	O
,	O
Foster	O
City	O
,	O
CA	O
,	O
USA	O
)	O
.	O

Both	O
nucleotide	O
and	O
deduced	O
amino	O
acid	O
sequences	O
were	O
analyzed	O
for	O
similarity	O
with	O
known	O
sequences	O
using	O
BLAST	O
search	O
[	O
23	O
]	O
and	O
ExPASy	O
Proteomics	O
tools	O
.	O

Secondary	O
structure	O
analysis	O
for	O
coiled	O
-	O
coil	O
motifs	O
was	O
conducted	O
with	O
the	O
software	O
program	O
COILS	O
[	O
24	O
]	O
.	O

Immunoprecipitation	O
of	O
in	O
vitro	O
translation	O
products	O

Candidate	O
cDNA	O
clones	O
were	O
used	O
as	O
templates	O
for	O
in	O
vitro	O
transcription	O
and	O
translation	O
and	O
the	O
products	O
were	O
used	O
as	O
substrates	O
for	O
immunoprecipitation	O
to	O
confirm	O
the	O
specificity	O
of	O
reaction	O
with	O
BD	O
sera	O
.	O

In	O
brief	O
,	O
1	O
mu	O
g	O
of	O
the	O
pBK	O
-	O
CMV	O
plasmid	O
identified	O
in	O
the	O
screening	O
outlined	O
above	O
was	O
added	O
as	O
template	O
in	O
a	O
50	O
-	O
mu	O
l	O
reaction	O
for	O
the	O
coupled	O
in	O
vitro	O
transcription	O
and	O
translation	O
reaction	O
with	O
a	O
rabbit	B
reticulocyte	O
lysate	O
system	O
(	O
Promega	O
,	O
Madison	O
,	O
WI	O
,	O
USA	O
)	O
in	O
the	O
presence	O
of	O
35S	O
-	O
methionine	O
(	O
Trans	O
-	O
35S	O
label	O
;	O
ICN	O
Biochemicals	O
,	O
Costa	O
Mesa	O
,	O
CA	O
,	O
USA	O
)	O
and	O
RNasin	O
(	O
R	O
)	O
Ribonuclease	O
Inhibitor	O
(	O
Stratagene	O
)	O
as	O
recommended	O
by	O
the	O
manufacturer	O
(	O
Promega	O
)	O
.	O

Translation	O
was	O
carried	O
out	O
at	O
30	O
degrees	O
C	O
for	O
1	O
.	O
5	O
h	O
.	O

Products	O
were	O
analyzed	O
in	O
a	O
12	O
.	O
5	O
%	O
gel	O
SDS	O
-	O
PAGE	O
and	O
stored	O
at	O
-	O
80	O
degrees	O
C	O
for	O
further	O
immunoprecipitation	O
analysis	O
.	O

The	O
in	O
vitro	O
translation	O
proteins	O
were	O
examined	O
for	O
reactivity	O
by	O
sera	O
using	O
immunoprecipitation	O
described	O
[	O
8	O
,	O
25	O
]	O
.	O

Results	O
and	O
discussion	O

Autoantibody	O
detection	O
in	O
sera	O
from	O
BD	O
patients	B

Initial	O
examination	O
of	O
a	O
group	O
of	O
39	O
BD	O
patients	B
using	O
indirect	O
immunofluorescence	O
(	O
IIF	O
)	O
on	O
a	O
HEp	O
-	O
2	O
cell	O
substrate	O
did	O
not	O
yield	O
any	O
characteristic	O
nuclear	O
or	O
cytoplasmic	O
staining	O
patterns	O
.	O

BD	O
is	O
thought	O
by	O
some	O
to	O
be	O
a	O
vasculitic	O
disease	O
involving	O
pathophysiology	O
of	O
endothelial	O
cells	O
,	O
and	O
antibody	O
to	O
endothelial	O
cell	O
antigen	O
(	O
AECA	O
)	O
has	O
been	O
reported	O
.	O

Reports	O
on	O
the	O
prevalence	O
of	O
AECA	O
have	O
varied	O
largely	O
and	O
alpha	O
-	O
enolase	O
was	O
reported	O
as	O
one	O
of	O
the	O
putative	O
target	O
antigens	O
[	O
26	O
]	O
.	O

In	O
this	O
study	O
,	O
the	O
use	O
of	O
bovine	B
aortic	O
endothelial	O
cells	O
as	O
substrate	O
for	O
IIF	O
did	O
not	O
provide	O
any	O
additional	O
data	O
.	O

However	O
,	O
Western	O
blot	O
analysis	O
of	O
the	O
BD	O
sera	O
began	O
to	O
show	O
some	O
interesting	O
autoreactivity	O
using	O
cell	O
lysates	O
from	O
both	O
HeLa	O
and	O
bovine	B
aortic	O
endothelial	O
cells	O
.	O

HeLa	O
cells	O
were	O
initially	O
used	O
for	O
this	O
analysis	O
because	O
they	O
are	O
commonly	O
used	O
in	O
the	O
laboratory	O
as	O
Western	O
blot	O
substrate	O
.	O

Fig	O
.	O

1	O
illustrates	O
the	O
common	O
reactivity	O
to	O
49	O
kDa	O
and	O
120	O
kDa	O
proteins	O
in	O
the	O
endothelial	O
cell	O
lysates	O
.	O

These	O
antigens	O
were	O
also	O
detected	O
in	O
HeLa	O
and	O
T24	O
cells	O
;	O
the	O
latter	O
cell	O
line	O
was	O
analyzed	O
because	O
our	O
laboratory	O
at	O
The	O
Scripps	O
Research	O
Institute	O
has	O
produced	O
an	O
excellent	O
expression	O
cDNA	O
library	O
from	O
the	O
T24	O
line	O
and	O
the	O
positive	O
result	O
with	O
the	O
T24	O
cell	O
extracts	O
allowed	O
us	O
to	O
screen	O
the	O
T24	O
library	O
.	O

Ig	O
isotype	O
analysis	O
showed	O
that	O
all	O
reactivity	O
was	O
largely	O
IgG	O
antibodies	O
.	O

Since	O
the	O
49	O
kDa	O
and	O
120	O
kDa	O
bands	O
were	O
observed	O
in	O
cell	O
extracts	O
from	O
bovine	B
as	O
well	O
as	O
human	B
cell	O
lines	O
,	O
these	O
autoantigens	O
might	O
be	O
evolutionarily	O
conserved	O
.	O

In	O
total	O
,	O
nine	O
out	O
of	O
39	O
BD	O
sera	O
(	O
23	O
%	O
)	O
had	O
autoantibody	O
to	O
the	O
49	O
kDa	O
antigen	O
and	O
eight	O
(	O
20	O
%	O
)	O
to	O
the	O
120	O
kDa	O
antigen	O
.	O

Four	O
BD	O
sera	O
(	O
10	O
%	O
)	O
reacted	O
with	O
both	O
proteins	O
.	O

Additionally	O
,	O
sera	O
that	O
showed	O
common	O
reactivity	O
to	O
the	O
120	O
kDa	O
protein	O
also	O
demonstrated	O
a	O
common	O
band	O
that	O
migrated	O
at	O
~	O
150	O
kDa	O
,	O
although	O
it	O
appeared	O
weaker	O
than	O
the	O
120	O
kDa	O
band	O
.	O

These	O
antigens	O
appeared	O
to	O
have	O
different	O
molecular	O
weights	O
than	O
those	O
of	O
the	O
known	O
autoantigens	O
in	O
systemic	O
rheumatic	O
diseases	O
.	O

In	O
addition	O
,	O
other	O
reactive	O
bands	O
were	O
detected	O
but	O
they	O
were	O
not	O
as	O
commonly	O
shared	O
as	O
the	O
49	O
kDa	O
and	O
120	O
kDa	O
bands	O
.	O

The	O
49	O
kDa	O
protein	O
was	O
shown	O
to	O
be	O
distinct	O
from	O
48	O
kDa	O
SS	O
-	O
B	O
/	O
La	O
or	O
50	O
kDa	O
Jo	O
-	O
1	O
proteins	O
(	O
Fig	O
.	O
1	O
)	O
.	O

The	O
120	O
kDa	O
antigen	O
was	O
also	O
shown	O
to	O
migrate	O
differently	O
from	O
alanyl	O
tRNA	O
synthetase	O
in	O
another	O
Western	O
blot	O
analysis	O
(	O
data	O
not	O
shown	O
)	O
and	O
did	O
not	O
share	O
any	O
apparent	O
crossreactive	O
epitopes	O
with	O
the	O
49	O
kDa	O
antigen	O
.	O

Western	O
blot	O
analyses	O
of	O
20	O
normal	O
control	O
sera	O
did	O
not	O
show	O
the	O
reactivities	O
observed	O
with	O
BD	O
sera	O
.	O

In	O
order	O
to	O
further	O
characterize	O
these	O
autoreactivities	O
,	O
a	O
serum	O
sample	O
from	O
the	O
Group	O
I	O
definitive	O
BD	O
patients	B
with	O
the	O
strongest	O
reactivity	O
to	O
49	O
kDa	O
and	O
120	O
kDa	O
antigens	O
(	O
Fig	O
.	O
1	O
,	O
lane	O
2	O
)	O
was	O
selected	O
as	O
antibody	O
probe	O
for	O
expression	O
library	O
screening	O
.	O

Kinectin	O
identified	O
as	O
a	O
novel	O
BD	O
autoantigen	O

After	O
screening	O
500	O
,	O
000	O
clones	O
from	O
the	O
T24	O
cell	O
lambda	O
ZAPExpress	O
expression	O
library	O
,	O
seven	O
immunoreactive	O
clones	O
were	O
isolated	O
and	O
plaque	O
purified	O
in	O
two	O
to	O
three	O
rounds	O
to	O
achieve	O
100	O
%	O
homogeneity	O
.	O

The	O
cDNA	O
inserts	O
were	O
subcloned	O
in	O
vivo	O
into	O
pBK	O
-	O
CMV	O
plasmids	O
,	O
analyzed	O
by	O
restriction	O
digestion	O
using	O
EcoRI	O
and	O
XhoI	O
enzymes	O
,	O
and	O
submitted	O
to	O
direct	O
nucleotide	O
sequencing	O
across	O
the	O
polylinker	O
arms	O
.	O

The	O
cDNA	O
inserts	O
represented	O
six	O
independent	O
clones	O
designated	O
BD41	O
(	O
identical	O
to	O
BD44	O
)	O
,	O
BD481	O
,	O
BD42	O
,	O
BD47	O
,	O
BD482	O
and	O
BD49	O
.	O

Their	O
identities	O
were	O
established	O
as	O
overlapping	O
partial	O
cDNAs	O
of	O
human	B
kinectin	O
,	O
ranging	O
from	O
1	O
.	O
9	O
kb	O
to	O
3	O
kb	O
(	O
Fig	O
.	O
2a	O
)	O
.	O

The	O
full	O
-	O
length	O
human	B
kinectin	O
(	O
GenBank	O
accession	O
number	O
NM	O
_	O
182926	O
[	O
27	O
]	O
)	O
has	O
4	O
,	O
816	O
bases	O
containing	O
an	O
open	O
reading	O
frame	O
coding	O
1	O
,	O
357	O
amino	O
acid	O
residues	O
with	O
molecular	O
mass	O
156	O
kDa	O
.	O

All	O
six	O
cDNAs	O
lacked	O
the	O
5	O
'	O
portion	O
of	O
the	O
kinectin	O
sequence	O
to	O
different	O
degrees	O
but	O
spanned	O
a	O
sequence	O
of	O
kinectin	O
that	O
extended	O
to	O
the	O
3	O
'	O
-	O
untranslated	O
region	O
.	O

Secondary	O
structure	O
analysis	O
of	O
kinectin	O
protein	O
using	O
the	O
program	O
COILS	O
identified	O
a	O
long	O
region	O
of	O
alpha	O
-	O
helical	O
coiled	O
-	O
coil	O
domain	O
that	O
extended	O
from	O
amino	O
acid	O
residue	O
327	O
to	O
the	O
C	O
-	O
terminus	O
(	O
Fig	O
.	O
2a	O
,	O
hatched	O
boxes	O
)	O
.	O

In	O
vitro	O
coupled	O
transcription	O
and	O
translation	O
of	O
BD44	O
and	O
BD42	O
clones	O
directed	O
the	O
synthesis	O
of	O
[	O
35S	O
]	O
-	O
methionine	O
-	O
labeled	O
polypeptides	O
that	O
migrated	O
at	O
95	O
and	O
60	O
kDa	O
,	O
respectively	O
,	O
in	O
addition	O
to	O
smaller	O
polypeptides	O
(	O
Fig	O
.	O
2b	O
)	O
.	O

These	O
products	O
had	O
predicted	O
molecular	O
weights	O
of	O
103	O
kDa	O
and	O
75	O
kDa	O
.	O

Kinectin	O
was	O
initially	O
identified	O
in	O
chick	B
embryo	O
brain	O
microsome	O
as	O
an	O
integral	O
membrane	O
protein	O
anchored	O
in	O
endoplasmic	O
reticulum	O
and	O
involved	O
in	O
kinesin	O
-	O
driven	O
vesicle	O
motility	O
along	O
microtubules	O
[	O
28	O
,	O
29	O
]	O
.	O

Kinectin	O
consists	O
of	O
a	O
120	O
-	O
kDa	O
and	O
a	O
160	O
-	O
kDa	O
polypeptide	O
interacting	O
through	O
the	O
alpha	O
-	O
helical	O
coiled	O
-	O
coil	O
domain	O
to	O
form	O
a	O
heterodimer	O
[	O
30	O
]	O
.	O

The	O
full	O
-	O
length	O
kinectin	O
is	O
the	O
160	O
kDa	O
polypeptide	O
containing	O
an	O
N	O
-	O
terminal	O
transmembrane	O
helix	O
followed	O
by	O
a	O
bipartite	O
nuclear	O
localization	O
sequence	O
and	O
two	O
C	O
-	O
terminal	O
leucine	O
zipper	O
motifs	O
.	O

We	O
presume	O
that	O
the	O
120	O
kDa	O
polypeptide	O
detected	O
in	O
Western	O
blot	O
(	O
Fig	O
.	O
1	O
)	O
is	O
the	O
truncated	O
version	O
of	O
the	O
160	O
-	O
kDa	O
polypeptide	O
,	O
lacking	O
the	O
N	O
-	O
terminal	O
first	O
232	O
amino	O
acids	O
[	O
30	O
]	O
.	O

The	O
N	O
-	O
terminus	O
of	O
the	O
160	O
-	O
kDa	O
polypeptide	O
consists	O
of	O
a	O
transmembrane	O
domain	O
that	O
anchors	O
kinectin	O
to	O
endoplasmic	O
reticulum	O
[	O
30	O
,	O
31	O
]	O
.	O

This	O
120	O
kDa	O
polypeptide	O
is	O
probably	O
the	O
predominant	O
form	O
detected	O
in	O
the	O
Western	O
blot	O
analysis	O
(	O
Fig	O
.	O
1	O
)	O
because	O
of	O
its	O
preferential	O
solubility	O
due	O
to	O
the	O
omission	O
of	O
the	O
N	O
-	O
terminal	O
transmembrane	O
domain	O
.	O

Other	O
functions	O
for	O
kinectin	O
have	O
been	O
reported	O
.	O

Yeast	B
two	O
-	O
hybrid	O
screen	O
studies	O
from	O
several	O
laboratories	O
have	O
revealed	O
the	O
interaction	O
of	O
the	O
Rho	O
family	O
of	O
GTPase	O
with	O
kinectin	O
,	O
and	O
have	O
shown	O
the	O
functional	O
links	O
among	O
RhoG	O
,	O
kinectin	O
and	O
kinesin	O
,	O
with	O
kinectin	O
as	O
a	O
key	O
effector	O
of	O
RhoG	O
microtubule	O
-	O
dependent	O
cellular	O
activity	O
[	O
32	O
]	O
.	O

Kinectin	O
was	O
also	O
identified	O
as	O
an	O
important	O
constituent	O
of	O
integrin	O
-	O
based	O
adhesion	O
complexes	O
,	O
which	O
link	O
integrins	O
to	O
the	O
cytoskeleton	O
and	O
recruit	O
signaling	O
molecules	O
[	O
33	O
]	O
.	O

A	O
new	O
study	O
reported	O
that	O
a	O
kinectin	O
isoform	O
lacking	O
a	O
major	O
portion	O
of	O
the	O
kinesin	O
-	O
binding	O
domain	O
is	O
very	O
probably	O
the	O
most	O
conservative	O
form	O
of	O
kinectin	O
;	O
it	O
does	O
not	O
bind	O
kinesin	O
but	O
act	O
as	O
a	O
membrane	O
anchor	O
for	O
the	O
translation	O
elongation	O
factor	O
-	O
1	O
delta	O
in	O
the	O
endoplasmic	O
reticulum	O
[	O
34	O
]	O
.	O

Prevalence	O
and	O
specificity	O
of	O
anti	O
-	O
kinectin	O
autoantibodies	O

The	O
in	O
vitro	O
[	O
35S	O
]	O
-	O
methionine	O
-	O
labeled	O
translation	O
product	O
of	O
BD44	O
,	O
representing	O
the	O
largest	O
recombinant	O
kinectin	O
fragment	O
available	O
,	O
was	O
used	O
as	O
the	O
antigen	O
substrate	O
in	O
an	O
immunoprecipitation	O
assay	O
.	O

Out	O
of	O
39	O
BD	O
patient	B
sera	O
,	O
nine	O
(	O
23	O
%	O
)	O
recognized	O
the	O
BD44	O
translation	O
product	O
(	O
Fig	O
.	O
3	O
)	O
,	O
whereas	O
sera	O
from	O
20	O
normal	O
controls	O
,	O
10	O
SLE	O
and	O
10	O
SjS	O
patients	B
did	O
not	O
show	O
reactivity	O
.	O

Among	O
the	O
nine	O
anti	O
-	O
kinectin	O
positive	O
patients	B
,	O
six	O
(	O
6	O
/	O
25	O
,	O
24	O
%	O
)	O
were	O
from	O
Group	O
I	O
(	O
definitive	O
BD	O
)	O
including	O
the	O
BD	O
patient	B
whose	O
serum	O
was	O
used	O
in	O
the	O
immunoscreening	O
of	O
expression	O
cDNA	O
library	O
,	O
and	O
three	O
(	O
3	O
/	O
14	O
,	O
21	O
.	O
4	O
%	O
)	O
patients	B
were	O
from	O
the	O
Group	O
II	O
(	O
probable	O
BD	O
)	O
in	O
this	O
study	O
.	O

According	O
to	O
the	O
Fisher	O
Exact	O
Probability	O
calculation	O
(	O
P	O
=	O
1	O
.	O
00	O
)	O
,	O
there	O
is	O
no	O
statistically	O
significant	O
difference	O
for	O
antibody	O
to	O
kinectin	O
between	O
the	O
two	O
groups	O
.	O

The	O
combined	O
data	O
substantiated	O
the	O
finding	O
that	O
kinectin	O
is	O
an	O
autoantigen	O
that	O
can	O
be	O
recognized	O
by	O
sera	O
from	O
23	O
%	O
of	O
Chinese	O
BD	O
patients	B
in	O
this	O
study	O
with	O
at	O
least	O
one	O
immunoreactive	O
region	O
or	O
autoepitope	O
residing	O
within	O
the	O
BD44	O
encoded	O
polypeptide	O
.	O

Currently	O
,	O
there	O
are	O
more	O
than	O
six	O
diagnostic	O
/	O
classification	O
criteria	O
for	O
BD	O
,	O
among	O
which	O
the	O
International	O
Criteria	O
have	O
been	O
applied	O
most	O
extensively	O
due	O
to	O
its	O
relatively	O
high	O
sensitivity	O
(	O
91	O
%	O
)	O
and	O
specificity	O
(	O
96	O
%	O
)	O
[	O
2	O
]	O
.	O

As	O
discussed	O
above	O
,	O
differential	O
diagnosis	O
of	O
BD	O
might	O
be	O
confusing	O
in	O
clinical	O
practice	O
since	O
no	O
specific	O
laboratory	O
test	O
is	O
available	O
,	O
and	O
some	O
patients	B
may	O
have	O
symptoms	O
and	O
signs	O
strongly	O
suggestive	O
of	O
BD	O
but	O
do	O
not	O
fully	O
satisfy	O
the	O
International	O
Criteria	O
,	O
as	O
in	O
the	O
Group	O
II	O
(	O
probable	O
BD	O
)	O
patients	B
in	O
our	O
study	O
group	O
.	O

A	O
number	O
of	O
investigators	O
have	O
pointed	O
out	O
that	O
a	O
comprehensive	O
analysis	O
of	O
the	O
clinical	O
data	O
for	O
a	O
given	O
patient	B
is	O
very	O
important	O
for	O
correct	O
clinical	O
diagnosis	O
of	O
BD	O
,	O
and	O
that	O
classification	O
/	O
diagnosis	O
criteria	O
,	O
including	O
the	O
International	O
Criteria	O
,	O
should	O
be	O
followed	O
but	O
should	O
not	O
be	O
exclusive	O
.	O

The	O
observation	O
that	O
three	O
out	O
of	O
14	O
patients	B
in	O
the	O
probable	O
BD	O
group	O
also	O
had	O
antibody	O
to	O
kinectin	O
and	O
the	O
similar	O
percentage	O
of	O
positive	O
reactors	O
between	O
this	O
group	O
and	O
Group	O
I	O
(	O
21	O
.	O
4	O
%	O
versus	O
24	O
%	O
)	O
supports	O
this	O
notion	O
.	O

The	O
further	O
use	O
of	O
non	O
-	O
clinical	O
parameters	O
such	O
as	O
immunological	O
biomarkers	O
as	O
adjuncts	O
to	O
identify	O
BD	O
patients	B
could	O
be	O
of	O
help	O
in	O
the	O
classification	O
of	O
this	O
disease	O
entity	O

While	O
our	O
work	O
was	O
ongoing	O
,	O
anti	O
-	O
kinectin	O
antibodies	O
were	O
reported	O
in	O
sera	O
from	O
patients	B
with	O
hepatocellular	O
carcinoma	O
(	O
HCC	O
)	O
[	O
35	O
,	O
36	O
]	O
and	O
aplastic	O
anemia	O
[	O
37	O
,	O
38	O
]	O
.	O

The	O
first	O
HCC	O
report	O
[	O
35	O
]	O
identified	O
kinectin	O
as	O
a	O
tumor	O
-	O
associated	O
antigen	O
from	O
the	O
screening	O
of	O
an	O
autologous	O
cDNA	O
library	O
constructed	O
from	O
the	O
cancer	O
of	O
a	O
30	O
-	O
year	O
-	O
old	O
patient	B
from	O
Guangxi	O
,	O
China	O
.	O

This	O
report	O
stated	O
that	O
four	O
out	O
of	O
five	O
HCC	O
patients	B
tested	O
were	O
positive	O
for	O
anti	O
-	O
kinectin	O
antibody	O
[	O
35	O
]	O
.	O

In	O
2004	O
,	O
another	O
laboratory	O
also	O
reported	O
the	O
cloning	O
of	O
kinectin	O
as	O
a	O
tumor	O
-	O
associated	O
antigen	O
from	O
a	O
(	O
presumably	O
)	O
different	O
30	O
-	O
year	O
-	O
old	O
Chinese	O
HCC	O
patient	B
[	O
36	O
]	O
.	O

In	O
contrast	O
,	O
anti	O
-	O
kinectin	O
antibodies	O
were	O
not	O
detected	O
in	O
other	O
studies	O
of	O
HCC	O
patients	B
associated	O
with	O
our	O
laboratory	O
[	O
39	O
,	O
40	O
]	O
.	O

The	O
reports	O
of	O
anti	O
-	O
kinectin	O
antibodies	O
in	O
aplastic	O
anemia	O
are	O
also	O
very	O
interesting	O
[	O
37	O
,	O
38	O
]	O
.	O

The	O
initial	O
report	O
by	O
Hirano	O
et	O
al	O
.	O
identified	O
kinectin	O
by	O
screening	O
an	O
aplastic	O
anemia	O
patient	B
for	O
candidate	O
antigens	O
using	O
a	O
Clontech	O
human	B
fetal	O
liver	O
cDNA	O
expression	O
library	O
and	O
it	O
was	O
concluded	O
that	O
seven	O
out	O
of	O
18	O
aplastic	O
anemia	O
patients	B
were	O
positive	O
for	O
anti	O
-	O
kinectin	O
while	O
none	O
of	O
the	O
normal	O
or	O
disease	O
controls	O
had	O
this	O
antibody	O
[	O
37	O
]	O
.	O

In	O
their	O
recent	O
report	O
,	O
Hirano	O
et	O
al	O
.	O
reported	O
that	O
anti	O
-	O
kinectin	O
antibodies	O
were	O
found	O
in	O
39	O
%	O
of	O
aplastic	O
anemia	O
patients	B
from	O
the	O
United	O
States	O
but	O
only	O
in	O
three	O
out	O
of	O
30	O
(	O
10	O
%	O
)	O
cases	O
in	O
Japan	O
[	O
38	O
]	O
.	O

In	O
our	O
study	O
reported	O
here	O
,	O
kinectin	O
antibodies	O
were	O
only	O
detected	O
in	O
BD	O
patients	B
and	O
not	O
in	O
normal	O
controls	O
and	O
SLE	O
and	O
SjS	O
disease	O
controls	O
.	O

None	O
of	O
the	O
BD	O
patients	B
with	O
anti	O
-	O
kinectin	O
had	O
signs	O
of	O
HCC	O
or	O
aplastic	O
anemia	O
at	O
the	O
time	O
of	O
diagnosis	O
and	O
at	O
up	O
to	O
4	O
years	O
of	O
follow	O
-	O
up	O
.	O

Mapping	O
of	O
epitope	O
(	O
s	O
)	O
recognized	O
by	O
anti	O
-	O
kinectin	O
antibodies	O
may	O
shed	O
light	O
on	O
the	O
question	O
of	O
whether	O
different	O
autoepitopes	O
reside	O
within	O
the	O
kinectin	O
molecule	O
recognized	O
by	O
sera	O
from	O
different	O
diseases	O
.	O

Kinectin	O
-	O
a	O
new	O
member	O
of	O
coiled	O
-	O
coil	O
cytoplasmic	O
autoantigens	O

We	O
have	O
recently	O
reviewed	O
the	O
literature	O
on	O
the	O
growing	O
number	O
of	O
cytoplasmic	O
autoantigens	O
rich	O
in	O
alpha	O
-	O
helical	O
coiled	O
-	O
coil	O
domains	O
as	O
typified	O
from	O
our	O
study	O
of	O
Golgi	O
autoantigens	O
[	O
41	O
]	O
.	O

Golgi	O
autoantigens	O
are	O
generally	O
high	O
molecular	O
weight	O
proteins	O
between	O
100	O
and	O
350	O
kDa	O
and	O
rich	O
in	O
coiled	O
-	O
coil	O
domains	O
in	O
the	O
central	O
region	O
with	O
non	O
-	O
coiled	O
-	O
coil	O
or	O
globular	O
domains	O
at	O
both	O
N	O
and	O
C	O
termini	O
.	O

Golgi	O
autoantigens	O
are	O
displayed	O
on	O
the	O
cytoplasmic	O
face	O
of	O
the	O
Golgi	O
complex	O
and	O
are	O
not	O
localized	O
to	O
apoptotic	O
blebs	O
during	O
apoptosis	O
[	O
42	O
]	O
.	O

Giantin	O
,	O
the	O
highest	O
molecular	O
weight	O
Golgi	O
autoantigen	O
reported	O
,	O
is	O
the	O
predominant	O
target	O
of	O
human	B
anti	O
-	O
Golgi	O
complex	O
antibodies	O
and	O
multiple	O
non	O
-	O
cross	O
-	O
reactive	O
epitopes	O
have	O
been	O
mapped	O
spanning	O
the	O
350	O
kDa	O
protein	O
[	O
43	O
]	O
.	O

Other	O
high	O
molecular	O
weight	O
autoantigens	O
with	O
similar	O
features	O
have	O
been	O
reported	O
in	O
cytoplasmic	O
and	O
mitotic	O
organelles	O
suggesting	O
that	O
these	O
selected	O
proteins	O
become	O
autoimmunogenic	O
based	O
on	O
their	O
subcellular	O
association	O
and	O
molecular	O
features	O
[	O
41	O
]	O
.	O

For	O
example	O
,	O
in	O
the	O
endosomal	O
compartment	O
,	O
the	O
two	O
known	O
autoantigens	O
are	O
early	O
endosomal	O
protein	O
EEA1	O
(	O
180	O
kDa	O
)	O
[	O
44	O
]	O
and	O
CLIP	O
-	O
170	O
(	O
170	O
kDa	O
)	O
[	O
45	O
]	O
.	O

There	O
is	O
also	O
a	O
series	O
of	O
centrosomal	O
autoantigens	O
identified	O
as	O
coiled	O
-	O
coil	O
-	O
rich	O
proteins	O
including	O
pericentrin	O
,	O
a	O
220	O
kDa	O
protein	O
[	O
46	O
]	O
,	O
ninein	O
,	O
a	O
protein	O
with	O
alternatively	O
spliced	O
products	O
of	O
245	O
and	O
249	O
kDa	O
[	O
47	O
]	O
,	O
Cep250	O
(	O
250	O
kDa	O
)	O
and	O
Cep110	O
(	O
110	O
kDa	O
)	O
[	O
48	O
]	O
.	O

Centromere	O
autoantigens	O
have	O
been	O
described	O
but	O
the	O
two	O
interesting	O
ones	O
related	O
to	O
this	O
discussion	O
are	O
CENP	O
-	O
E	O
[	O
49	O
]	O
and	O
CENP	O
-	O
F	O
[	O
50	O
]	O
;	O
both	O
are	O
high	O
molecular	O
weight	O
proteins	O
(	O
312	O
to	O
400	O
kDa	O
)	O
and	O
have	O
the	O
same	O
type	O
of	O
overall	O
structure	O
as	O
discussed	O
above	O
.	O

NuMA	O
is	O
another	O
large	O
coiled	O
-	O
coil	O
protein	O
located	O
at	O
the	O
mitotic	O
spindle	O
pole	O
and	O
is	O
the	O
most	O
common	O
target	O
autoantigen	O
in	O
sera	O
with	O
mitotic	O
spindle	O
apparatus	O
staining	O
[	O
51	O
]	O
.	O

Non	O
-	O
muscle	O
myosin	O
(	O
~	O
200	O
kDa	O
)	O
is	O
a	O
cytoskeletal	O
autoantigen	O
[	O
52	O
]	O
that	O
falls	O
in	O
the	O
same	O
group	O
of	O
high	O
molecular	O
weight	O
and	O
coiled	O
-	O
coil	O
-	O
rich	O
autoantigens	O
.	O

These	O
endosomal	O
,	O
centrosomal	O
,	O
mitotic	O
apparatus	O
and	O
intracellular	O
autoantigens	O
are	O
,	O
like	O
the	O
golgins	O
,	O
proteins	O
with	O
high	O
molecular	O
weights	O
and	O
an	O
overall	O
high	O
content	O
of	O
coiled	O
-	O
coil	O
domains	O
.	O

The	O
combination	O
of	O
these	O
two	O
physical	O
features	O
in	O
autoantigens	O
may	O
contribute	O
to	O
the	O
induction	O
and	O
production	O
of	O
autoimmune	O
antibodies	O
in	O
certain	O
disease	O
states	O
.	O

Kinectin	O
is	O
an	O
integral	O
membrane	O
protein	O
largely	O
confined	O
to	O
the	O
endoplasmic	O
reticulum	O
[	O
28	O
,	O
31	O
]	O
and	O
it	O
fits	O
into	O
this	O
new	O
category	O
of	O
autoantigens	O
that	O
are	O
large	O
coiled	O
-	O
coil	O
rich	O
proteins	O
(	O
>	O
=	O
100	O
kDa	O
)	O
in	O
the	O
cytoplasm	O
.	O

Conclusion	O

Here	O
we	O
report	O
the	O
detection	O
of	O
kinectin	O
autoantibody	O
in	O
23	O
%	O
of	O
Chinese	O
patients	B
with	O
BD	O
.	O

The	O
identity	O
of	O
kinectin	O
as	O
a	O
BD	O
-	O
related	O
autoantigen	O
has	O
not	O
been	O
reported	O
to	O
date	O
.	O

Autoantibody	O
reaction	O
against	O
kinectin	O
in	O
BD	O
observed	O
in	O
this	O
study	O
further	O
confirms	O
the	O
autoimmune	O
involvement	O
in	O
BD	O
and	O
may	O
provide	O
new	O
inroads	O
into	O
elucidating	O
the	O
immunopathogenesis	O
of	O
the	O
disease	O
.	O

In	O
an	O
effort	O
to	O
clarify	O
the	O
association	O
of	O
BD	O
with	O
antibody	O
to	O
kinectin	O
,	O
it	O
is	O
essential	O
to	O
measure	O
antibody	O
to	O
kinectin	O
in	O
larger	O
patient	B
populations	O
including	O
both	O
BD	O
,	O
probable	O
BD	O
and	O
important	O
autoimmune	O
rheumatic	O
diseases	O
such	O
as	O
SLE	O
,	O
SjS	O
,	O
rheumatoid	O
arthritis	O
etc	O
.	O
,	O
as	O
well	O
as	O
those	O
diseases	O
not	O
easily	O
differentiated	O
from	O
BD	O
,	O
such	O
as	O
recurrent	O
aphthous	O
oral	O
ulcer	O
,	O
Reiter	O
'	O
s	O
syndrome	O
,	O
inflammatory	O
bowel	O
diseases	O
etc	O
.	O

On	O
the	O
other	O
hand	O
,	O
further	O
analysis	O
of	O
the	O
association	O
of	O
anti	O
-	O
kinectin	O
antibody	O
with	O
different	O
manifestations	O
or	O
disease	O
'	O
subtypes	O
'	O
of	O
BD	O
is	O
another	O
important	O
project	O
.	O

Anti	O
-	O
kinectin	O
is	O
clearly	O
only	O
one	O
of	O
the	O
antigen	O
-	O
antibody	O
systems	O
identified	O
because	O
there	O
were	O
many	O
other	O
antibodies	O
observed	O
in	O
the	O
Western	O
blot	O
analysis	O
of	O
BD	O
sera	O
.	O

Using	O
other	O
sera	O
for	O
immunoscreening	O
would	O
probably	O
lead	O
to	O
the	O
identification	O
of	O
other	O
potentially	O
important	O
antigen	O
-	O
antibody	O
systems	O
.	O

Abbreviations	O

AECA	O
=	O
antibody	O
to	O
endothelial	O
cell	O
antigen	O
;	O
BD	O
=	O
Beh	O
c	O
et	O
'	O
s	O
disease	O
;	O
DMEM	O
=	O
Dulbecco	O
'	O
s	O
modified	O
Eagle	O
'	O
s	O
medium	O
;	O
HCC	O
=	O
hepatocellular	O
carcinoma	O
;	O
HSP	O
=	O
heat	O
shock	O
protein	O
;	O
IIF	O
=	O
indirect	O
immunofluorescence	O
;	O
PBS	O
=	O
phosphate	O
buffered	O
saline	O
;	O
SjS	O
=	O
Sj	O
o	O
gren	O
'	O
s	O
syndrome	O
;	O
SLE	O
=	O
systemic	O
lupus	O
erythematosus	O
.	O

Competing	O
interests	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

YL	O
performed	O
the	O
study	O
and	O
drafted	O
the	O
manuscript	O
.	O

PY	O
provided	O
technical	O
help	O
throughout	O
the	O
study	O
.	O

SLC	O
and	O
EMT	O
conceived	O
the	O
study	O
,	O
participated	O
in	O
the	O
design	O
and	O
helped	O
in	O
the	O
analysis	O
of	O
the	O
data	O
.	O

EKLC	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
,	O
interpreted	O
data	O
and	O
helped	O
to	O
draft	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

EndoNet	O
:	O
an	O
information	O
resource	O
about	O
endocrine	O
networks	O

Abstract	O

EndoNet	O
is	O
a	O
new	O
database	O
that	O
provides	O
information	O
about	O
the	O
components	O
of	O
endocrine	O
networks	O
and	O
their	O
relations	O
.	O

It	O
focuses	O
on	O
the	O
endocrine	O
cell	O
-	O
to	O
-	O
cell	O
communication	O
and	O
enables	O
the	O
analysis	O
of	O
intercellular	O
regulatory	O
pathways	O
in	O
humans	B
.	O

In	O
the	O
EndoNet	O
data	O
model	O
,	O
two	O
classes	O
of	O
components	O
span	O
a	O
bipartite	O
directed	O
graph	O
.	O

One	O
class	O
represents	O
the	O
hormones	O
(	O
in	O
the	O
broadest	O
sense	O
)	O
secreted	O
by	O
defined	O
donor	O
cells	O
.	O

The	O
other	O
class	O
consists	O
of	O
the	O
acceptor	O
or	O
target	O
cells	O
expressing	O
the	O
corresponding	O
hormone	O
receptors	O
.	O

The	O
identity	O
and	O
anatomical	O
environment	O
of	O
cell	O
types	O
,	O
tissues	O
and	O
organs	O
is	O
defined	O
through	O
references	O
to	O
the	O
CYTOMER	O
(	O
R	O
)	O
ontology	O
.	O

With	O
the	O
EndoNet	O
user	O
interface	O
,	O
it	O
is	O
possible	O
to	O
query	O
the	O
database	O
for	O
hormones	O
,	O
receptors	O
or	O
tissues	O
and	O
to	O
combine	O
several	O
items	O
from	O
different	O
search	O
rounds	O
in	O
one	O
complex	O
result	O
set	O
,	O
from	O
which	O
a	O
network	O
can	O
be	O
reconstructed	O
and	O
visualized	O
.	O

For	O
each	O
entity	O
,	O
a	O
detailed	O
characteristics	O
page	O
is	O
available	O
.	O

Some	O
well	O
-	O
established	O
endocrine	O
pathways	O
are	O
offered	O
as	O
showcases	O
in	O
the	O
form	O
of	O
predefined	O
result	O
sets	O
.	O

These	O
sets	O
can	O
be	O
used	O
as	O
a	O
starting	O
point	O
for	O
a	O
more	O
complex	O
query	O
or	O
for	O
obtaining	O
a	O
quick	O
overview	O
.	O

The	O
EndoNet	O
database	O
is	O
accessible	O
at	O
.	O

INTRODUCTION	O

Theoretical	O
analyses	O
in	O
the	O
post	O
-	O
sequencing	O
era	O
,	O
in	O
particular	O
in	O
the	O
context	O
of	O
systems	O
biology	O
approaches	O
,	O
increasingly	O
investigate	O
the	O
properties	O
of	O
all	O
kinds	O
of	O
pathways	O
and	O
networks	O
such	O
as	O
metabolic	O
and	O
signaling	O
pathways	O
.	O

It	O
is	O
commonly	O
accepted	O
that	O
we	O
need	O
formal	O
descriptions	O
of	O
these	O
networks	O
to	O
make	O
systematic	O
use	O
of	O
the	O
overwhelming	O
body	O
of	O
facts	O
gathered	O
over	O
decades	O
of	O
laboratory	O
work	O
both	O
in	O
narrow	O
or	O
global	O
scale	O
.	O

Corresponding	O
databases	O
have	O
been	O
created	O
and	O
are	O
available	O
now	O
for	O
metabolic	O
networks	O
(	O
KEGG	O
)	O
(	O
1	O
,	O
2	O
)	O
,	O
protein	O
interaction	O
networks	O
(	O
BIND	O
and	O
DIP	O
)	O
(	O
3	O
,	O
4	O
)	O
and	O
signaling	O
pathways	O
(	O
CSNDB	O
,	O
Patika	O
and	O
TRANSPATH	O
(	O
R	O
)	O
)	O
(	O
5	O
-	O
8	O
)	O
,	O
just	O
to	O
name	O
a	O
few	O
.	O

So	O
far	O
,	O
however	O
,	O
their	O
main	O
focus	O
is	O
on	O
intracellular	O
processes	O
.	O

Intercellular	O
signaling	O
is	O
addressed	O
only	O
insofar	O
as	O
usually	O
the	O
pathways	O
modeled	O
start	O
with	O
extracellular	O
ligands	O
,	O
and	O
as	O
there	O
exist	O
catalogs	O
and	O
databases	O
about	O
secreted	O
proteins	O
,	O
or	O
the	O
'	O
secretome	O
'	O
,	O
of	O
certain	O
systems	O
(	O
9	O
-	O
12	O
)	O
.	O

This	O
shortcoming	O
is	O
part	O
of	O
the	O
more	O
comprehensive	O
problem	O
,	O
the	O
genotype	O
-	O
phenotype	O
gap	O
:	O
from	O
a	O
certain	O
genotype	O
,	O
we	O
are	O
able	O
to	O
infer	O
a	O
'	O
molecular	O
phenotype	O
'	O
,	O
but	O
for	O
correlating	O
it	O
with	O
a	O
more	O
complex	O
phenotype	O
such	O
as	O
a	O
biological	O
process	O
,	O
or	O
even	O
a	O
certain	O
disease	O
and	O
its	O
clinical	O
appearance	O
,	O
we	O
still	O
depend	O
largely	O
on	O
the	O
mere	O
description	O
of	O
an	O
observed	O
correlation	O
.	O

There	O
is	O
no	O
way	O
to	O
infer	O
such	O
a	O
phenotype	O
through	O
all	O
the	O
different	O
layers	O
of	O
increasing	O
complexity	O
between	O
genomic	O
DNA	O
sequences	O
and	O
the	O
physiological	O
function	O
of	O
whole	O
organs	O
and	O
their	O
interplay	O
within	O
an	O
organism	O
.	O

There	O
may	O
be	O
principal	O
barriers	O
preventing	O
such	O
an	O
inference	O
across	O
different	O
complexity	O
levels	O
,	O
but	O
even	O
to	O
explore	O
these	O
limits	O
,	O
we	O
have	O
to	O
make	O
attempts	O
to	O
bridge	O
the	O
genotype	O
-	O
phenotype	O
gap	O
.	O

We	O
have	O
to	O
do	O
the	O
next	O
step	O
towards	O
modeling	O
intercellular	O
networks	O
that	O
are	O
inextricably	O
linked	O
to	O
the	O
physiology	O
of	O
multicellular	O
organisms	O
(	O
13	O
)	O
.	O

Being	O
one	O
of	O
the	O
most	O
complex	O
constructs	O
in	O
the	O
body	O
,	O
the	O
endocrine	O
system	O
comprises	O
numerous	O
cells	O
and	O
tissues	O
that	O
secrete	O
hormones	O
which	O
pass	O
through	O
the	O
body	O
,	O
activate	O
specific	O
receptors	O
of	O
target	O
cells	O
and	O
initiate	O
there	O
multiple	O
intracellular	O
signaling	O
pathways	O
.	O

Here	O
,	O
we	O
present	O
a	O
new	O
database	O
,	O
EndoNet	O
,	O
which	O
provides	O
information	O
about	O
the	O
components	O
of	O
endocrine	O
networks	O
and	O
their	O
relations	O
,	O
and	O
enables	O
the	O
analysis	O
of	O
intercellular	O
regulatory	O
pathways	O
in	O
humans	B
.	O

The	O
EndoNet	O
database	O
is	O
accessible	O
at	O
.	O

RESULTS	O

The	O
biological	O
schema	O
of	O
endocrine	O
actions	O

Development	O
and	O
function	O
of	O
different	O
organs	O
as	O
well	O
as	O
the	O
response	O
of	O
a	O
whole	O
multicellular	O
organism	O
to	O
its	O
environment	O
is	O
coordinated	O
through	O
a	O
complex	O
communication	O
system	O
between	O
specialized	O
cells	O
that	O
are	O
part	O
of	O
its	O
organs	O
.	O

This	O
communication	O
is	O
mostly	O
mediated	O
by	O
hormones	O
.	O

In	O
a	O
broader	O
sense	O
,	O
this	O
functional	O
class	O
of	O
biomolecules	O
also	O
comprises	O
growth	O
factors	O
,	O
cytokines	O
,	O
chemokines	O
and	O
other	O
signal	O
transmitters	O
.	O

This	O
generic	O
view	O
is	O
supported	O
,	O
for	O
instance	O
,	O
by	O
the	O
definition	O
given	O
for	O
'	O
hormone	O
activity	O
'	O
by	O
Gene	O
Ontology	O
(	O
GO	O
)	O
(	O
14	O
)	O
:	O
'	O
Any	O
substance	O
formed	O
in	O
very	O
small	O
amounts	O
in	O
one	O
specialized	O
organ	O
or	O
group	O
of	O
cells	O
and	O
carried	O
(	O
sometimes	O
in	O
the	O
bloodstream	O
)	O
to	O
another	O
organ	O
or	O
group	O
of	O
cells	O
,	O
in	O
the	O
same	O
organism	O
,	O
upon	O
which	O
it	O
has	O
a	O
specific	O
regulatory	O
action	O
'	O
.	O

This	O
definition	O
is	O
also	O
broad	O
enough	O
to	O
include	O
modes	O
of	O
hormonal	O
actions	O
as	O
diverse	O
as	O
endocrine	O
,	O
paracrine	O
and	O
autocrine	O
effects	O
.	O

Accordingly	O
,	O
with	O
the	O
term	O
'	O
hormone	O
'	O
one	O
might	O
refer	O
to	O
any	O
extracellular	O
substance	O
that	O
induces	O
specific	O
responses	O
in	O
target	O
cell	O
and	O
helps	O
to	O
coordinate	O
growth	O
,	O
differentiation	O
,	O
gene	O
expression	O
and	O
metabolic	O
activities	O
of	O
various	O
cells	O
,	O
tissues	O
and	O
organs	O
in	O
multicellular	O
organisms	O
(	O
15	O
)	O
.	O

Hormones	O
can	O
be	O
classified	O
based	O
on	O
their	O
chemical	O
nature	O
,	O
solubility	O
,	O
the	O
distance	O
over	O
which	O
the	O
signal	O
acts	O
and	O
so	O
on	O
(	O
15	O
,	O
16	O
)	O
.	O

From	O
the	O
viewpoint	O
of	O
genome	O
-	O
phenotype	O
relations	O
,	O
it	O
is	O
reasonable	O
to	O
distinguish	O
between	O
polypeptide	O
,	O
thus	O
,	O
genome	O
-	O
encoded	O
hormones	O
,	O
on	O
one	O
hand	O
,	O
and	O
those	O
low	O
-	O
molecular	O
weight	O
hormones	O
such	O
as	O
steroids	O
,	O
with	O
only	O
the	O
machinery	O
of	O
their	O
synthesis	O
being	O
genome	O
-	O
encoded	O
,	O
on	O
the	O
other	O
hand	O
.	O

Another	O
classification	O
of	O
hormones	O
,	O
which	O
seems	O
to	O
be	O
overlapping	O
with	O
the	O
previous	O
one	O
refers	O
to	O
the	O
intracellular	O
location	O
of	O
their	O
receptors	O
and	O
,	O
thus	O
,	O
how	O
the	O
subsequent	O
signal	O
is	O
further	O
transduced	O
:	O
membrane	O
-	O
bound	O
receptors	O
usually	O
trigger	O
more	O
or	O
less	O
complex	O
signaling	O
cascades	O
towards	O
the	O
nucleus	O
,	O
whereas	O
nuclear	O
receptors	O
,	O
mainly	O
bound	O
by	O
low	O
-	O
molecular	O
weight	O
hormones	O
,	O
have	O
a	O
very	O
short	O
signaling	O
pathway	O
downstream	O
since	O
they	O
act	O
as	O
transcription	O
factors	O
themselves	O
(	O
15	O
,	O
16	O
)	O
.	O

In	O
intercellular	O
communication	O
,	O
we	O
can	O
basically	O
differentiate	O
between	O
two	O
kinds	O
of	O
cells	O
:	O
donor	O
cells	O
which	O
synthesize	O
and	O
secrete	O
a	O
hormone	O
,	O
and	O
acceptor	O
cells	O
which	O
express	O
a	O
hormone	O
receptor	O
(	O
Figure	O
1a	O
)	O
.	O

Donor	O
cells	O
become	O
active	O
under	O
the	O
influence	O
of	O
an	O
external	O
,	O
mostly	O
environmental	O
,	O
stimulus	O
.	O

In	O
the	O
acceptor	O
cell	O
,	O
binding	O
of	O
the	O
hormone	O
to	O
a	O
receptor	O
triggers	O
an	O
intracellular	O
signal	O
transduction	O
cascade	O
with	O
different	O
kinds	O
of	O
end	O
nodes	O
and	O
effects	O
:	O
transcription	O
factors	O
affecting	O
the	O
gene	O
expression	O
program	O
of	O
the	O
acceptor	O
cell	O
,	O
metabolic	O
enzymes	O
controlling	O
the	O
cell	O
'	O
s	O
metabolism	O
,	O
structural	O
components	O
which	O
define	O
the	O
acceptor	O
'	O
s	O
morphological	O
features	O
,	O
or	O
components	O
of	O
the	O
secretory	O
apparatus	O
regulating	O
the	O
release	O
of	O
other	O
extracellular	O
molecules	O
.	O

If	O
synthesis	O
and	O
secretion	O
of	O
another	O
hormone	O
is	O
among	O
the	O
effects	O
exerted	O
by	O
receptor	O
activation	O
,	O
the	O
acceptor	O
is	O
turned	O
into	O
a	O
donor	O
cell	O
,	O
thus	O
becoming	O
an	O
internal	O
node	O
of	O
the	O
organism	O
'	O
s	O
endocrine	O
network	O
.	O

Acceptor	O
cells	O
which	O
do	O
not	O
become	O
producers	O
of	O
another	O
hormone	O
are	O
called	O
'	O
terminal	O
target	O
cells	O
'	O
of	O
the	O
endocrine	O
network	O
,	O
but	O
finally	O
constitute	O
the	O
overall	O
physiological	O
effect	O
of	O
the	O
respective	O
hormonal	O
pathway	O
,	O
or	O
simply	O
the	O
phenotype	O
(	O
Figure	O
1a	O
)	O
.	O

The	O
EndoNet	O
data	O
model	O

In	O
the	O
EndoNet	O
data	O
model	O
,	O
two	O
classes	O
of	O
entities	O
-	O
-	O
hormones	O
(	O
in	O
the	O
broadest	O
sense	O
)	O
and	O
their	O
acceptor	O
or	O
target	O
cells	O
expressing	O
the	O
corresponding	O
receptors	O
-	O
-	O
span	O
a	O
bipartite	O
directed	O
graph	O
.	O

Since	O
one	O
and	O
the	O
same	O
hormone	O
may	O
be	O
secreted	O
by	O
multiple	O
cell	O
types	O
(	O
donor	O
cells	O
)	O
,	O
each	O
such	O
secretion	O
event	O
is	O
represented	O
by	O
a	O
hormone	O
node	O
on	O
its	O
own	O
.	O

Similarly	O
,	O
each	O
cell	O
type	O
known	O
to	O
express	O
a	O
hormone	O
receptor	O
(	O
acceptor	O
cell	O
)	O
leads	O
to	O
an	O
individual	O
node	O
.	O

The	O
graph	O
'	O
s	O
edges	O
represent	O
hormone	O
transport	O
and	O
binding	O
to	O
a	O
receptor	O
(	O
intercellular	O
edges	O
)	O
,	O
on	O
one	O
hand	O
,	O
and	O
triggering	O
or	O
inhibition	O
of	O
hormone	O
secretion	O
by	O
a	O
receptor	O
activated	O
by	O
hormone	O
binding	O
(	O
intracellular	O
edges	O
)	O
,	O
on	O
the	O
other	O
hand	O
.	O

Optionally	O
,	O
an	O
edge	O
representing	O
the	O
transport	O
of	O
a	O
hormone	O
can	O
be	O
subdivided	O
by	O
introducing	O
the	O
transport	O
medium	O
(	O
usually	O
blood	O
)	O
as	O
an	O
additional	O
,	O
intermediary	O
node	O
.	O

Thus	O
,	O
in	O
the	O
conceptual	O
schema	O
of	O
the	O
EndoNet	O
database	O
(	O
Figure	O
1b	O
)	O
,	O
the	O
links	O
between	O
cells	O
/	O
organs	O
and	O
hormone	O
define	O
donor	O
cells	O
(	O
'	O
D	O
'	O
)	O
,	O
those	O
between	O
cells	O
/	O
organs	O
and	O
receptors	O
acceptor	O
cells	O
(	O
'	O
A	O
'	O
)	O
.	O

If	O
an	O
acceptor	O
cell	O
synthesizes	O
another	O
hormone	O
in	O
response	O
to	O
an	O
incoming	O
signal	O
,	O
it	O
becomes	O
an	O
internal	O
node	O
in	O
the	O
emerging	O
hormonal	O
network	O
.	O

In	O
EndoNet	O
,	O
the	O
pathway	O
between	O
a	O
hormone	O
receptor	O
expressed	O
in	O
an	O
acceptor	O
cell	O
and	O
a	O
hormone	O
synthesized	O
in	O
the	O
same	O
cell	O
(	O
intracellular	O
edge	O
)	O
is	O
handled	O
as	O
a	O
black	O
box	O
.	O

In	O
case	O
of	O
genome	O
-	O
encoded	O
peptide	O
hormones	O
,	O
cross	O
-	O
references	O
to	O
entries	O
in	O
the	O
TRANSPATH	O
(	O
R	O
)	O
database	O
,	O
which	O
describe	O
the	O
signaling	O
cascade	O
starting	O
from	O
the	O
hormone	O
'	O
s	O
receptor	O
and	O
ending	O
at	O
the	O
hormone	O
'	O
s	O
gene	O
,	O
are	O
provided	O
,	O
if	O
available	O
.	O

Datasets	O
on	O
non	O
-	O
peptide	O
hormones	O
will	O
in	O
future	O
be	O
enriched	O
by	O
a	O
specific	O
metabolic	O
add	O
-	O
on	O
which	O
will	O
include	O
references	O
to	O
the	O
databases	O
KEGG	O
(	O
1	O
)	O
and	O
BRENDA	O
(	O
17	O
)	O
,	O
allowing	O
for	O
further	O
characterization	O
of	O
the	O
steps	O
performed	O
during	O
the	O
hormone	O
'	O
s	O
synthesis	O
and	O
the	O
regulation	O
of	O
both	O
activity	O
and	O
expression	O
of	O
the	O
enzymes	O
involved	O
.	O

By	O
now	O
,	O
the	O
EndoNet	O
structure	O
already	O
allows	O
for	O
including	O
descriptions	O
of	O
the	O
physiological	O
effects	O
induced	O
by	O
hormone	O
binding	O
(	O
see	O
below	O
,	O
Future	O
Developments	O
)	O
.	O

The	O
contents	O
of	O
EndoNet	O

In	O
the	O
present	O
version	O
of	O
EndoNet	O
,	O
and	O
as	O
a	O
first	O
approach	O
,	O
we	O
consider	O
the	O
endocrine	O
(	O
hormonal	O
)	O
network	O
of	O
the	O
human	B
body	O
.	O

For	O
each	O
molecule	O
(	O
hormone	O
or	O
receptor	O
)	O
,	O
a	O
primary	O
name	O
and	O
synonyms	O
are	O
given	O
.	O

In	O
case	O
of	O
peptide	O
hormones	O
,	O
the	O
sequence	O
of	O
the	O
processed	O
polypeptide	O
,	O
rather	O
than	O
that	O
of	O
the	O
protein	O
precursor	O
,	O
is	O
specified	O
.	O

For	O
a	O
multimeric	O
protein	O
hormone	O
,	O
the	O
subunit	O
composition	O
as	O
well	O
as	O
the	O
sequences	O
of	O
all	O
subunits	O
are	O
stored	O
;	O
the	O
same	O
holds	O
true	O
for	O
hormone	O
receptors	O
.	O

Additionally	O
,	O
all	O
peptide	O
hormone	O
and	O
receptor	O
datasets	O
have	O
links	O
to	O
HumanPSD	O
(	O
TM	O
)	O
(	O
18	O
)	O
and	O
to	O
the	O
Swiss	O
-	O
Prot	O
database	O
,	O
The	O
structures	O
of	O
non	O
-	O
peptide	O
hormones	O
can	O
be	O
accessed	O
through	O
the	O
corresponding	O
hyperlinks	O
to	O
the	O
KEGG	O
COMPOUND	O
section	O
.	O

Finally	O
,	O
all	O
molecules	O
may	O
have	O
links	O
to	O
the	O
TRANSPATH	O
(	O
R	O
)	O
database	O
.	O

As	O
described	O
,	O
EndoNet	O
utilizes	O
data	O
about	O
the	O
tissues	O
from	O
which	O
hormones	O
are	O
secreted	O
and	O
in	O
which	O
receptors	O
are	O
expressed	O
to	O
define	O
donor	O
and	O
acceptor	O
cells	O
,	O
respectively	O
.	O

The	O
identity	O
and	O
anatomical	O
environment	O
of	O
cell	O
types	O
,	O
tissues	O
and	O
organs	O
is	O
defined	O
through	O
references	O
to	O
the	O
CYTOMER	O
(	O
R	O
)	O
ontology	O
(	O
19	O
,	O
20	O
)	O
;	O
in	O
the	O
numerous	O
cases	O
where	O
the	O
receptors	O
are	O
ubiquitously	O
expressed	O
,	O
just	O
the	O
root	O
term	O
'	O
human	B
body	O
'	O
is	O
linked	O
.	O

Data	O
on	O
whether	O
a	O
hormone	O
'	O
s	O
synthesis	O
is	O
triggered	O
or	O
inhibited	O
by	O
another	O
hormone	O
through	O
its	O
respective	O
receptor	O
in	O
a	O
particular	O
cell	O
was	O
obtained	O
by	O
manual	O
selection	O
from	O
textbooks	O
[	O
e	O
.	O
g	O
.	O
(	O
16	O
)	O
,	O
]	O
,	O
monographies	O
(	O
21	O
)	O
,	O
original	O
literature	O
,	O
the	O
EST	O
library	O
information	O
and	O
the	O
linked	O
databases	O
(	O
TRANSPATH	O
(	O
R	O
)	O
,	O
HumanPSD	O
(	O
TM	O
)	O
and	O
Swiss	O
-	O
Prot	O
)	O
.	O

The	O
contents	O
of	O
EndoNet	O
are	O
summarized	O
in	O
Table	O
1	O
.	O

Web	O
interface	O
,	O
queries	O
and	O
visualization	O

EndoNet	O
can	O
be	O
accessed	O
through	O
the	O
WWW	O
via	O
a	O
JSP	O
-	O
based	O
web	O
interface	O
.	O

Hormones	O
,	O
receptors	O
and	O
tissues	O
can	O
be	O
queried	O
for	O
their	O
names	O
,	O
and	O
detailed	O
information	O
on	O
all	O
identified	O
components	O
is	O
available	O
through	O
individual	O
characteristics	O
pages	O
.	O

Each	O
hormone	O
'	O
s	O
individual	O
entry	O
page	O
displays	O
its	O
source	O
and	O
target	O
tissues	O
(	O
donor	O
and	O
acceptor	O
cells	O
)	O
as	O
well	O
as	O
its	O
receptors	O
,	O
along	O
with	O
some	O
molecular	O
data	O
.	O

Similarly	O
,	O
each	O
receptor	O
entry	O
exhibits	O
the	O
tissues	O
in	O
which	O
the	O
receptor	O
is	O
expressed	O
,	O
and	O
the	O
hormones	O
it	O
interacts	O
with	O
.	O

Finally	O
,	O
each	O
tissue	O
entry	O
lists	O
the	O
hormone	O
receptors	O
that	O
are	O
found	O
in	O
,	O
as	O
well	O
as	O
the	O
hormones	O
that	O
are	O
synthesized	O
and	O
secreted	O
by	O
the	O
tissue	O
.	O

It	O
is	O
also	O
indicated	O
whether	O
the	O
corresponding	O
tissue	O
exerts	O
gender	O
-	O
specific	O
properties	O
;	O
additional	O
information	O
based	O
on	O
the	O
CYTOMER	O
(	O
R	O
)	O
ontology	O
is	O
available	O
through	O
the	O
corresponding	O
link	O
on	O
the	O
tissue	O
detail	O
page	O
.	O

Instead	O
of	O
searching	O
for	O
a	O
name	O
of	O
a	O
hormone	O
,	O
one	O
can	O
also	O
browse	O
the	O
hierarchical	O
hormone	O
classification	O
featured	O
by	O
EndoNet	O
(	O
available	O
at	O
the	O
'	O
Search	O
'	O
page	O
)	O
.	O

Each	O
query	O
result	O
can	O
be	O
used	O
as	O
starting	O
point	O
for	O
an	O
extended	O
query	O
.	O

Different	O
items	O
of	O
interest	O
can	O
be	O
selected	O
and	O
added	O
to	O
a	O
common	O
result	O
set	O
.	O

Since	O
several	O
search	O
results	O
can	O
be	O
combined	O
,	O
it	O
is	O
possible	O
to	O
create	O
sets	O
with	O
multiple	O
search	O
parameters	O
.	O

At	O
any	O
step	O
of	O
this	O
incremental	O
retrieval	O
process	O
,	O
the	O
sets	O
of	O
hormones	O
,	O
receptors	O
and	O
tissues	O
obtained	O
so	O
far	O
can	O
be	O
used	O
as	O
starting	O
points	O
for	O
reconstructing	O
a	O
network	O
by	O
a	O
depth	O
-	O
first	O
graph	O
traversal	O
algorithm	O
.	O

The	O
maximum	O
number	O
of	O
steps	O
can	O
be	O
selected	O
separately	O
for	O
the	O
upstream	O
and	O
downstream	O
part	O
of	O
the	O
reconstruction	O
process	O
.	O

Subsequently	O
,	O
the	O
graph	O
will	O
be	O
displayed	O
using	O
a	O
Graphviz	O
-	O
based	O
visualization	O
method	O
[	O
(	O
22	O
)	O
,	O
]	O
.	O

In	O
the	O
resulting	O
image	O
,	O
hormones	O
and	O
receptors	O
are	O
represented	O
as	O
nodes	O
grouped	O
together	O
into	O
subgraphs	O
representing	O
the	O
tissues	O
(	O
cells	O
/	O
organs	O
)	O
they	O
are	O
secreted	O
from	O
or	O
expressed	O
in	O
,	O
respectively	O
(	O
Figure	O
2	O
)	O
.	O

Autocrine	O
loops	O
(	O
donor	O
and	O
acceptor	O
cell	O
being	O
identical	O
)	O
are	O
treated	O
specially	O
for	O
visualization	O
.	O

On	O
demand	O
,	O
the	O
hormones	O
'	O
transport	O
media	O
can	O
be	O
included	O
in	O
the	O
visualization	O
of	O
intercellular	O
edges	O
,	O
enabling	O
the	O
user	O
to	O
choose	O
between	O
different	O
complexities	O
of	O
output	O
.	O

Intracellular	O
edges	O
,	O
which	O
connect	O
a	O
receptor	O
to	O
a	O
hormone	O
,	O
represent	O
the	O
influence	O
of	O
a	O
receptor	O
'	O
s	O
activation	O
on	O
the	O
secretion	O
of	O
a	O
hormone	O
from	O
the	O
same	O
cell	O
and	O
are	O
displayed	O
differently	O
,	O
depending	O
on	O
whether	O
this	O
influence	O
is	O
triggering	O
or	O
inhibitory	O
in	O
nature	O
.	O

The	O
graph	O
is	O
displayed	O
as	O
a	O
clickable	O
image	O
map	O
,	O
linking	O
each	O
entity	O
to	O
its	O
detailed	O
characteristics	O
page	O
,	O
thus	O
making	O
the	O
database	O
entries	O
accessible	O
from	O
the	O
graphical	O
overview	O
of	O
a	O
network	O
,	O
too	O
.	O

The	O
graph	O
is	O
available	O
in	O
two	O
different	O
formats	O
:	O
PNG	O
and	O
SVG	O
.	O

While	O
virtually	O
every	O
browser	O
supports	O
PNG	O
(	O
a	O
'	O
pixel	O
'	O
or	O
'	O
bitmap	O
'	O
format	O
)	O
,	O
only	O
a	O
few	O
of	O
them	O
provide	O
a	O
zoom	O
functionality	O
for	O
bitmap	O
pictures	O
.	O

Scalable	O
vector	O
graphics	O
,	O
(	O
SVG	O
)	O
provides	O
more	O
functionality	O
(	O
including	O
perfect	O
image	O
quality	O
throughout	O
all	O
zoom	O
factors	O
)	O
,	O
but	O
until	O
now	O
most	O
browsers	O
do	O
not	O
support	O
SVG	O
natively	O
and	O
require	O
an	O
SVG	O
plugin	O
(	O
)	O
for	O
displaying	O
this	O
vector	O
-	O
based	O
format	O
.	O

Some	O
well	O
-	O
established	O
endocrine	O
pathways	O
are	O
offered	O
as	O
showcases	O
in	O
the	O
form	O
of	O
predefined	O
result	O
sets	O
.	O

For	O
instance	O
,	O
sets	O
representing	O
the	O
hypothalamic	O
-	O
hypophyseal	O
axis	O
with	O
a	O
focus	O
on	O
either	O
thyroid	O
hormones	O
,	O
adrenal	O
hormones	O
,	O
growth	O
hormones	O
or	O
prolactin	O
are	O
provided	O
.	O

These	O
predefined	O
sets	O
can	O
be	O
used	O
for	O
obtaining	O
a	O
quick	O
overview	O
or	O
as	O
starting	O
points	O
for	O
more	O
complex	O
queries	O
.	O

FUTURE	O
DEVELOPMENTS	O

Among	O
the	O
important	O
improvements	O
of	O
EndoNet	O
which	O
we	O
are	O
currently	O
working	O
on	O
is	O
the	O
possibility	O
to	O
represent	O
intercellular	O
communication	O
at	O
different	O
levels	O
of	O
the	O
hierarchical	O
organization	O
of	O
organs	O
,	O
tissues	O
and	O
cells	O
in	O
the	O
organism	O
,	O
as	O
well	O
as	O
to	O
distinguish	O
between	O
such	O
communications	O
in	O
male	O
and	O
female	O
organisms	O
.	O

These	O
options	O
will	O
be	O
introduced	O
by	O
a	O
tighter	O
integration	O
with	O
the	O
CYTOMER	O
-	O
based	O
ontology	O
(	O
19	O
,	O
20	O
)	O
.	O

The	O
next	O
step	O
will	O
be	O
to	O
expand	O
the	O
contents	O
of	O
EndoNet	O
towards	O
the	O
details	O
of	O
the	O
processes	O
occurring	O
in	O
the	O
transport	O
medium	O
,	O
usually	O
the	O
blood	O
.	O

Since	O
not	O
all	O
hormones	O
are	O
transported	O
as	O
free	O
molecules	O
and	O
some	O
hydrophobic	O
hormones	O
(	O
e	O
.	O
g	O
.	O
steroids	O
and	O
thyroids	O
)	O
need	O
to	O
be	O
bound	O
to	O
specific	O
carrier	O
proteins	O
,	O
proper	O
description	O
of	O
such	O
transporters	O
and	O
their	O
interaction	O
with	O
the	O
corresponding	O
hormones	O
will	O
be	O
required	O
.	O

It	O
is	O
planned	O
to	O
involve	O
quantitative	O
data	O
about	O
the	O
regular	O
or	O
pathological	O
levels	O
of	O
the	O
hormones	O
,	O
the	O
overall	O
kinetics	O
of	O
each	O
hormone	O
in	O
the	O
blood	O
(	O
monotonous	O
decay	O
,	O
oscillating	O
concentrations	O
,	O
increase	O
in	O
response	O
to	O
certain	O
stimuli	O
,	O
etc	O
.	O
)	O
,	O
its	O
turnover	O
and	O
metabolic	O
products	O
,	O
etc	O
.	O

That	O
will	O
allow	O
utilization	O
of	O
EndoNet	O
contents	O
for	O
diagnostic	O
purposes	O
.	O

In	O
future	O
,	O
the	O
EndoNet	O
data	O
model	O
will	O
be	O
extended	O
in	O
order	O
to	O
incorporate	O
external	O
stimuli	O
(	O
e	O
.	O
g	O
.	O
light	O
)	O
and	O
physiological	O
states	O
(	O
stress	O
,	O
age	O
,	O
etc	O
.	O
)	O
in	O
a	O
formalized	O
manner	O
,	O
allowing	O
to	O
determine	O
whether	O
or	O
not	O
and	O
in	O
which	O
quantity	O
a	O
hormone	O
will	O
be	O
secreted	O
under	O
the	O
given	O
circumstances	O
.	O

EndoNet	O
will	O
then	O
link	O
the	O
physiological	O
effects	O
of	O
hormones	O
with	O
the	O
intracellular	O
molecular	O
processes	O
leading	O
to	O
its	O
synthesis	O
and	O
secretion	O
in	O
the	O
donor	O
cells	O
,	O
and	O
to	O
the	O
effects	O
on	O
its	O
acceptor	O
cells	O
.	O

At	O
many	O
places	O
of	O
these	O
intracellular	O
and	O
intercellular	O
networks	O
,	O
genetically	O
determined	O
aberrations	O
may	O
cause	O
specific	O
,	O
sometimes	O
pathological	O
phenotypes	O
.	O

Thus	O
,	O
EndoNet	O
will	O
enable	O
to	O
bridge	O
the	O
gap	O
between	O
known	O
genotypes	O
and	O
their	O
molecular	O
and	O
clinical	O
phenotypes	O
in	O
this	O
area	O
of	O
medical	O
research	O
and	O
its	O
applications	O
.	O

DISCUSSION	O

At	O
its	O
present	O
state	O
,	O
EndoNet	O
provides	O
a	O
high	O
coverage	O
of	O
molecules	O
that	O
are	O
conventionally	O
considered	O
as	O
hormones	O
as	O
well	O
as	O
other	O
molecules	O
that	O
are	O
involved	O
in	O
intercellular	O
communication	O
,	O
such	O
as	O
growth	O
factors	O
,	O
lymphokines	O
and	O
chemokines	O
and	O
their	O
known	O
receptors	O
.	O

The	O
aim	O
of	O
the	O
database	O
is	O
to	O
provide	O
a	O
useful	O
resource	O
for	O
studying	O
the	O
principal	O
features	O
of	O
hormonal	O
networks	O
in	O
a	O
comprehensive	O
way	O
,	O
as	O
it	O
was	O
done	O
more	O
exemplarily	O
in	O
the	O
past	O
for	O
these	O
kinds	O
of	O
networks	O
(	O
23	O
)	O
,	O
but	O
was	O
done	O
globally	O
for	O
many	O
other	O
intracellular	O
network	O
types	O
,	O
such	O
as	O
metabolic	O
,	O
protein	O
interaction	O
and	O
transcription	O
networks	O
[	O
reviewed	O
in	O
(	O
24	O
,	O
25	O
)	O
]	O
.	O

EndoNet	O
database	O
certainly	O
is	O
not	O
yet	O
complete	O
but	O
will	O
grow	O
rapidly	O
.	O

Gender	O
differences	O
in	O
factors	O
influencing	O
insulin	O
resistance	O
in	O
elderly	O
hyperlipemic	O
non	O
-	O
diabetic	O
subjects	O

Abstract	O

Background	O

The	O
increase	O
in	O
the	O
prevalence	O
of	O
insulin	O
resistance	O
-	O
related	O
metabolic	O
syndrome	O
,	O
a	O
disorder	O
that	O
greatly	O
increases	O
the	O
risk	O
of	O
diabetes	O
,	O
heart	O
attack	O
and	O
stroke	O
,	O
is	O
alarming	O
.	O

One	O
of	O
the	O
most	O
frequent	O
and	O
early	O
symptoms	O
of	O
metabolic	O
syndrome	O
is	O
hypertriglyceridemia	O
.	O

We	O
examined	O
the	O
gender	O
differences	O
between	O
various	O
metabolic	O
factors	O
related	O
to	O
insulin	O
resistance	O
in	O
elderly	O
non	O
-	O
diabetic	O
men	B
and	O
postmenopausal	O
women	B
of	O
comparable	O
age	O
suffering	O
from	O
hypertriglyceridemia	O
,	O
and	O
compared	O
them	O
with	O
healthy	O
subjects	O
of	O
equal	O
age	O
.	O

Results	O

The	O
indexes	O
of	O
insulin	O
resistance	O
HOMA	O
IR	O
and	O
QUICKI	O
were	O
significantly	O
higher	O
in	O
both	O
hyperlipemic	O
men	B
and	O
women	B
than	O
in	O
controls	O
;	O
95	O
%	O
confidence	O
limits	O
of	O
hyperlipemic	O
subjects	O
did	O
not	O
overlap	O
with	O
controls	O
.	O

In	O
both	O
normolipemic	O
and	O
hyperlipemic	O
men	B
and	O
women	B
serum	O
leptin	O
correlated	O
significantly	O
with	O
insulin	O
resistance	O
,	O
while	O
HDL	O
-	O
cholesterol	O
correlated	O
inversely	O
with	O
HOMA	O
-	O
IR	O
only	O
in	O
women	B
(	O
both	O
normo	O
-	O
and	O
hyperlipemic	O
)	O
,	O
and	O
serum	O
tumor	O
necrosis	O
factor	O
alpha	O
(	O
TNF	O
alpha	O
)	O
only	O
in	O
hyperlipemic	O
women	B
.	O

According	O
to	O
results	O
of	O
multiple	O
regression	O
analysis	O
with	O
HOMA	O
-	O
IR	O
as	O
a	O
dependent	O
variable	O
,	O
leptin	O
played	O
a	O
significant	O
role	O
in	O
determining	O
insulin	O
resistance	O
in	O
both	O
genders	O
,	O
but	O
-	O
aside	O
from	O
leptin	O
-	O
triglycerides	O
,	O
TNF	O
alpha	O
and	O
decreased	O
HDL	O
-	O
cholesterol	O
were	O
significant	O
determinants	O
in	O
women	B
,	O
while	O
body	O
mass	O
index	O
and	O
decreased	O
HDL	O
-	O
cholesterol	O
were	O
significant	O
determinants	O
in	O
men	B
.	O

The	O
coefficient	O
of	O
determination	O
(	O
R2	O
)	O
of	O
HOMA	O
IR	O
by	O
above	O
mentioned	O
metabolic	O
variables	O
was	O
in	O
women	B
above	O
60	O
%	O
,	O
in	O
men	B
only	O
about	O
40	O
%	O
.	O

Conclusion	O

The	O
significant	O
role	O
of	O
serum	O
leptin	O
in	O
determination	O
of	O
insulin	O
resistance	O
in	O
both	O
elderly	O
men	B
and	O
postmenopausal	O
women	B
of	O
equal	O
age	O
was	O
confirmed	O
.	O

However	O
,	O
the	O
study	O
also	O
revealed	O
significant	O
gender	O
differences	O
:	O
in	O
women	B
a	O
strong	O
influence	O
of	O
triglycerides	O
,	O
TNF	O
alpha	O
and	O
decreased	O
HDL	O
-	O
cholesterol	O
,	O
in	O
men	B
only	O
a	O
mild	O
role	O
of	O
BMI	O
and	O
decreased	O
HDL	O
-	O
cholesterol	O
.	O

Background	O

In	O
association	O
with	O
pandemic	O
obesity	O
the	O
prevalence	O
of	O
the	O
insulin	O
resistance	O
-	O
related	O
metabolic	O
syndrome	O
is	O
constantly	O
growing	O
[	O
1	O
]	O
.	O

As	O
a	O
consequence	O
of	O
this	O
fact	O
,	O
type	O
2	O
diabetes	O
mellitus	O
and	O
cardiovascular	O
mortality	O
occurs	O
in	O
much	O
younger	O
age	O
groups	O
[	O
2	O
]	O
.	O

A	O
typical	O
hyperlipemia	O
,	O
consisting	O
of	O
an	O
increase	O
of	O
serum	O
triglycerides	O
and	O
a	O
decrease	O
of	O
serum	O
HDL	O
-	O
cholesterol	O
,	O
is	O
a	O
characteristic	O
and	O
an	O
early	O
symptom	O
of	O
this	O
syndrome	O
[	O
3	O
]	O
.	O

With	O
increasing	O
age	O
,	O
body	O
mass	O
index	O
(	O
BMI	O
)	O
and	O
adiposity	O
,	O
insulin	O
sensitivity	O
declines	O
and	O
the	O
number	O
of	O
cardiovascular	O
risk	O
factors	O
increases	O
in	O
both	O
genders	O
[	O
4	O
-	O
6	O
]	O
.	O

It	O
was	O
repeatedly	O
demonstrated	O
that	O
plasma	O
concentration	O
of	O
leptin	O
-	O
a	O
hormone	O
produced	O
mainly	O
by	O
adipose	O
tissue	O
-	O
is	O
substantially	O
higher	O
in	O
all	O
age	O
groups	O
of	O
women	B
than	O
in	O
men	B
[	O
7	O
-	O
10	O
]	O
.	O

This	O
may	O
be	O
caused	O
by	O
different	O
size	O
and	O
/	O
or	O
distribution	O
of	O
fat	O
tissue	O
compartments	O
influenced	O
by	O
hormones	O
:	O
estrogens	O
stimulate	O
,	O
whereas	O
testosterone	O
inhibits	O
leptin	O
secretion	O
.	O

In	O
women	B
subcutaneous	O
fat	O
mass	O
prevails	O
-	O
and	O
during	O
augmentation	O
of	O
overweight	O
it	O
increases	O
-	O
while	O
in	O
men	B
intra	O
-	O
abdominal	O
fat	O
mass	O
prevails	O
[	O
11	O
-	O
13	O
]	O
.	O

Subcutaneous	O
fat	O
in	O
particular	O
serves	O
as	O
a	O
substantial	O
source	O
of	O
tumor	O
necrosis	O
factor	O
alpha	O
(	O
TNF	O
alpha	O
)	O
,	O
which	O
represents	O
one	O
of	O
the	O
factors	O
that	O
interfere	O
with	O
insulin	O
signal	O
transduction	O
into	O
the	O
cells	O
[	O
14	O
-	O
16	O
]	O
.	O

Leptin	O
,	O
TNF	O
alpha	O
and	O
some	O
other	O
factors	O
are	O
abundantly	O
expressed	O
in	O
adipose	O
tissue	O
and	O
contribute	O
to	O
the	O
insulin	O
resistance	O
that	O
accompanies	O
overweight	O
and	O
obesity	O
.	O

Leptin	O
correlates	O
positively	O
with	O
hyperinsulinemia	O
,	O
BMI	O
,	O
fat	O
mass	O
and	O
hypertriglyceridemia	O
,	O
respectively	O
,	O
and	O
correlates	O
inversely	O
with	O
HDL	O
-	O
cholesterol	O
and	O
lean	O
body	O
mass	O
[	O
17	O
-	O
25	O
]	O
.	O

The	O
incidence	O
and	O
mortality	O
of	O
ischemic	O
heart	O
disease	O
and	O
of	O
other	O
consequences	O
of	O
atherosclerosis	O
increases	O
with	O
age	O
in	O
both	O
genders	O
,	O
especially	O
after	O
the	O
age	O
of	O
sixty	O
.	O

In	O
premenopausal	O
women	B
,	O
however	O
,	O
the	O
incidence	O
of	O
these	O
disorders	O
is	O
considerably	O
less	O
frequent	O
than	O
in	O
men	B
of	O
appropriate	O
age	O
.	O

After	O
the	O
menopause	O
the	O
prevalence	O
of	O
metabolic	O
syndrome	O
and	O
cardiovascular	O
mortality	O
in	O
women	B
gradually	O
increases	O
,	O
attaining	O
values	O
comparable	O
to	O
men	B
at	O
about	O
the	O
age	O
of	O
70	O
[	O
2	O
,	O
26	O
]	O
.	O

Paradoxically	O
,	O
it	O
takes	O
place	O
at	O
the	O
time	O
when	O
serum	O
leptin	O
concentration	O
in	O
women	B
has	O
relatively	O
decreased	O
[	O
27	O
,	O
28	O
]	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
analyze	O
the	O
interrelations	O
between	O
several	O
metabolic	O
variables	O
and	O
factors	O
related	O
to	O
insulin	O
resistance	O
in	O
groups	O
of	O
both	O
normal	O
and	O
hyperlipemic	O
postmenopausal	O
women	B
and	O
men	B
of	O
appropriate	O
age	O
,	O
and	O
to	O
attempt	O
to	O
elucidate	O
the	O
gender	O
differences	O
and	O
some	O
pathophysiologic	O
mechanisms	O
of	O
these	O
differences	O
.	O

We	O
compared	O
homeostatic	O
indexes	O
of	O
insulin	O
resistance	O
HOMA	O
IR	O
and	O
QUICKI	O
,	O
serum	O
lipid	O
and	O
insulin	O
parameters	O
,	O
uric	O
acid	O
,	O
leptin	O
and	O
TNF	O
alpha	O
between	O
groups	O
of	O
subjects	O
without	O
apparent	O
symptoms	O
of	O
metabolic	O
syndrome	O
,	O
and	O
groups	O
showing	O
mild	O
hypertriglyceridemia	O
with	O
decreased	O
HDL	O
-	O
cholesterol	O
.	O

In	O
addition	O
,	O
serum	O
concentration	O
of	O
the	O
heart	O
fraction	O
of	O
fatty	O
acid	O
binding	O
protein	O
(	O
hFATP	O
)	O
was	O
explored	O
as	O
a	O
factor	O
that	O
might	O
reflect	O
the	O
regulative	O
role	O
of	O
PPAR	O
gamma	O
in	O
lipid	O
homeostasis	O
[	O
29	O
,	O
30	O
]	O
,	O
and	O
serum	O
IgG	O
anticardiolipin	O
(	O
ACL	O
-	O
IgG	O
)	O
was	O
investigated	O
as	O
an	O
indirect	O
indicator	O
of	O
oxidized	O
lipid	O
fractions	O
related	O
to	O
atherosclerotic	O
complications	O
[	O
31	O
,	O
32	O
]	O
.	O

Methods	O

Subjects	O

The	O
study	O
was	O
carried	O
out	O
on	O
70	O
out	O
-	O
patients	B
of	O
the	O
Metabolic	O
Center	O
at	O
the	O
hospital	O
in	O
Sternberk	O
,	O
Czech	O
Republic	O
.	O

From	O
these	O
,	O
40	O
patients	B
(	O
20	O
men	B
and	O
20	O
women	B
)	O
were	O
selected	O
with	O
mild	O
hyperlipidemia	O
,	O
i	O
.	O
e	O
.	O
with	O
plasma	O
triglyceride	O
concentration	O
exceeding	O
2	O
.	O
0	O
mmol	O
/	O
l	O
,	O
total	O
cholesterol	O
exceeding	O
6	O
.	O
0	O
mmol	O
/	O
l	O
,	O
LDL	O
cholesterol	O
exceeding	O
4	O
.	O
0	O
mmol	O
/	O
l	O
,	O
and	O
with	O
HDL	O
cholesterol	O
concentration	O
in	O
men	B
under	O
1	O
.	O
0	O
mmol	O
/	O
l	O
,	O
and	O
in	O
women	B
under	O
1	O
.	O
2	O
mmol	O
/	O
l	O
.	O

These	O
groups	O
were	O
denominated	O
as	O
"	O
hyperlipemic	O
"	O
.	O

Two	O
other	O
groups	O
(	O
10	O
men	B
and	O
20	O
women	B
)	O
with	O
approximately	O
normal	O
serum	O
values	O
of	O
these	O
variables	O
were	O
taken	O
as	O
"	O
controls	O
"	O
.	O

The	O
average	O
age	O
in	O
men	B
was	O
59	O
.	O
1	O
+	O
/	O
-	O
10	O
.	O
6	O
y	O
,	O
and	O
in	O
women	B
59	O
.	O
4	O
+	O
/	O
-	O
10	O
.	O
1	O
y	O
,	O
respectively	O
.	O

The	O
differences	O
between	O
lipid	O
parameters	O
of	O
hyperlipemic	O
and	O
control	O
groups	O
were	O
highly	O
statistically	O
significant	O
,	O
while	O
the	O
age	O
differences	O
were	O
insignificant	O
(	O
see	O
Table	O
1	O
)	O
.	O

None	O
of	O
the	O
patients	B
had	O
clinically	O
apparent	O
diabetes	O
mellitus	O
,	O
but	O
some	O
of	O
the	O
hyperlipemic	O
patients	B
exerted	O
impaired	O
glucose	O
tolerance	O
or	O
impaired	O
fasting	O
glucose	O
(	O
values	O
between	O
6	O
.	O
1	O
and	O
7	O
.	O
0	O
mmol	O
/	O
l	O
,	O
or	O
between	O
6	O
.	O
1	O
and	O
7	O
.	O
8	O
mmol	O
/	O
l	O
,	O
respectively	O
)	O
.	O

None	O
of	O
the	O
patients	B
was	O
treated	O
with	O
insulin	O
,	O
peroral	O
antidiabetics	O
or	O
antihyperlipemic	O
drugs	O
;	O
some	O
of	O
them	O
were	O
treated	O
with	O
antihypertensive	O
therapy	O
.	O

No	O
signs	O
of	O
major	O
clinical	O
or	O
laboratory	O
symptoms	O
of	O
other	O
diseases	O
were	O
present	O
in	O
any	O
group	O
of	O
the	O
explored	O
patients	B
.	O

Blood	O
samples	O
were	O
obtained	O
in	O
the	O
morning	O
via	O
a	O
venipuncture	O
after	O
overnight	O
fasting	O
.	O

After	O
clotting	O
the	O
serum	O
was	O
separated	O
and	O
stored	O
at	O
-	O
20	O
degrees	O
until	O
used	O
.	O

An	O
informed	O
consent	O
was	O
obtained	O
from	O
all	O
probands	O
.	O

Body	O
mass	O
indexes	O
(	O
BMI	O
)	O
,	O
defined	O
as	O
weight	O
in	O
kilograms	O
divided	O
by	O
the	O
square	O
of	O
height	O
in	O
meters	O
,	O
were	O
calculated	O
.	O

Biochemical	O
methods	O

Serum	O
leptin	O
concentrations	O
were	O
measured	O
by	O
a	O
sandwich	O
ELISA	O
test	O
kit	O
(	O
Human	B
Leptin	O
ELISA	O
,	O
BioVendor	O
Laboratory	O
Medicine	O
,	O
Inc	O
,	O
Czech	O
Republic	O
)	O
.	O

Its	O
sensitivity	O
limit	O
was	O
0	O
.	O
2	O
ng	O
/	O
ml	O
,	O
intraassay	O
CV	O
6	O
.	O
1	O
%	O
at	O
the	O
level	O
of	O
7	O
.	O
5	O
ng	O
/	O
m	O
,	O
inter	O
-	O
assay	O
CV	O
8	O
.	O
5	O
%	O
at	O
the	O
level	O
of	O
4	O
.	O
8	O
ng	O
/	O
ml	O
.	O

Tetramethylbenzidine	O
was	O
used	O
as	O
a	O
substrate	O
;	O
quality	O
controls	O
were	O
human	B
based	O
.	O

Several	O
other	O
hormones	O
and	O
peptides	O
were	O
estimated	O
by	O
routine	O
immunochemical	O
tests	O
:	O
insulin	O
,	O
C	O
-	O
peptide	O
,	O
TNF	O
alpha	O
(	O
IMMULITE	O
,	O
Diagnostic	O
Products	O
Corporation	O
,	O
Los	O
Angeles	O
,	O
CA	O
,	O
U	O
.	O
S	O
.	O
A	O
.	O
)	O
,	O
proinsulin	O
intact	O
(	O
DAKO	O
,	O
Denmark	O
)	O
,	O
IgG	O
anticardiolipin	O
(	O
ACL	O
-	O
IgG	O
,	O
IMMCO	O
Diagnostics	O
,	O
Buffalo	O
,	O
NY	O
,	O
U	O
.	O
S	O
.	O
A	O
.	O
)	O
and	O
heart	O
fatty	O
acid	O
binding	O
protein	O
(	O
hFABP	O
,	O
Hbt	O
HUMAN	O
H	O
-	O
FABP	O
,	O
HyCult	O
Biotechnology	O
,	O
Uden	O
,	O
the	O
Netherlands	O
)	O
.	O

Serum	O
concentration	O
of	O
glucose	O
,	O
total	O
cholesterol	O
,	O
triglycerides	O
,	O
HDL	O
-	O
cholesterol	O
,	O
LDL	O
-	O
cholesterol	O
,	O
Apoprotein	O
B	O
and	O
uric	O
acid	O
were	O
measured	O
on	O
a	O
ILAB	O
-	O
600	O
biochemical	O
analyzer	O
(	O
Instrumentation	O
Laboratory	O
,	O
Lexington	O
,	O
Ma	O
,	O
U	O
.	O
S	O
.	O
A	O
.	O
)	O
using	O
BioVendor	O
sets	O
.	O

All	O
samples	O
were	O
processed	O
and	O
examined	O
according	O
to	O
principles	O
of	O
good	O
laboratory	O
practice	O
and	O
under	O
constant	O
intralaboratory	O
and	O
external	O
quality	O
control	O
.	O

The	O
homeostatic	O
indexes	O
of	O
insulin	O
resistance	O
(	O
HOMA	O
IR	O
and	O
QUICKI	O
)	O
were	O
calculated	O
according	O
to	O
the	O
homeostasis	O
model	O
of	O
assessment	O
[	O
33	O
-	O
35	O
]	O
as	O
follows	O
:	O

HOMA	O
IR	O
=	O
fasting	O
insulin	O
(	O
mu	O
U	O
/	O
ml	O
)	O
*	O
fasting	O
glucose	O
(	O
mmol	O
/	O
l	O
)	O
/	O
22	O
.	O
5	O
;	O

QUICKI	O
=	O
1	O
/	O
[	O
log	O
fasting	O
insulin	O
(	O
mu	O
U	O
/	O
ml	O
)	O
+	O
log	O
fasting	O
glucose	O
(	O
mg	O
/	O
100	O
ml	O
)	O
]	O
.	O

Statistics	O

Statistical	O
analysis	O
was	O
performed	O
using	O
the	O
Version	O
6	O
SAS	O
/	O
STAT	O
software	O
(	O
SAS	O
Institute	O
,	O
Inc	O
.	O
,	O
Cary	O
,	O
NC	O
,	O
U	O
.	O
S	O
.	O
A	O
.	O
)	O
.	O

The	O
Shapiro	O
-	O
Wilks	O
tests	O
were	O
used	O
in	O
testing	O
the	O
normality	O
of	O
distribution	O
.	O

Some	O
of	O
the	O
data	O
obtained	O
were	O
not	O
normally	O
distributed	O
.	O

The	O
statistical	O
significance	O
of	O
differences	O
between	O
the	O
means	O
in	O
the	O
hyperlipemic	O
and	O
control	O
groups	O
were	O
evaluated	O
using	O
the	O
unpaired	O
Student	O
'	O
s	O
T	O
-	O
test	O
in	O
the	O
case	O
of	O
normal	O
distribution	O
of	O
data	O
sets	O
,	O
and	O
using	O
the	O
Kolmogorov	O
-	O
Smirnov	O
test	O
when	O
at	O
least	O
in	O
one	O
of	O
the	O
data	O
sets	O
the	O
normal	O
distribution	O
was	O
excluded	O
.	O

Spearman	O
'	O
s	O
rank	O
-	O
order	O
correlation	O
was	O
used	O
for	O
correlation	O
analysis	O
.	O

Multiple	O
regression	O
analysis	O
was	O
performed	O
using	O
HOMA	O
IR	O
indexes	O
of	O
insulin	O
resistance	O
as	O
dependent	O
variables	O
,	O
and	O
other	O
metabolic	O
and	O
hormonal	O
factors	O
(	O
lipid	O
parameters	O
,	O
BMI	O
,	O
leptin	O
,	O
TNF	O
alpha	O
,	O
hFABP	O
,	O
ACL	O
-	O
IgG	O
)	O
as	O
independent	O
variables	O
.	O

The	O
so	O
-	O
called	O
step	O
-	O
down	O
regression	O
model	O
was	O
used	O
to	O
select	O
dominant	O
independent	O
variables	O
.	O

Various	O
four	O
-	O
member	O
groups	O
of	O
independent	O
(	O
explanatory	O
)	O
variables	O
were	O
used	O
for	O
the	O
analysis	O
and	O
the	O
non	O
-	O
zero	O
intercept	O
was	O
taken	O
into	O
account	O
.	O

The	O
independent	O
variables	O
were	O
then	O
dropped	O
,	O
one	O
at	O
a	O
time	O
;	O
at	O
each	O
stage	O
one	O
variable	O
making	O
the	O
least	O
contribution	O
to	O
the	O
dependent	O
variable	O
(	O
i	O
.	O
e	O
.	O
that	O
showed	O
the	O
least	O
p	O
-	O
value	O
in	O
the	O
test	O
of	O
the	O
regression	O
coefficient	O
being	O
zero	O
)	O
was	O
excluded	O
.	O

The	O
coefficient	O
of	O
determination	O
R2	O
,	O
which	O
can	O
be	O
viewed	O
as	O
a	O
percentage	O
explaining	O
the	O
total	O
variance	O
,	O
was	O
simultaneously	O
monitored	O
.	O

A	O
great	O
drop	O
in	O
R2	O
after	O
excluding	O
some	O
independent	O
variable	O
enabled	O
selection	O
of	O
those	O
independent	O
variables	O
that	O
could	O
be	O
thought	O
to	O
be	O
the	O
most	O
important	O
determinants	O
of	O
the	O
dependent	O
variable	O
.	O

Results	O

Table	O
1	O
demonstrates	O
mean	O
parameters	O
in	O
individual	O
groups	O
of	O
subjects	O
matched	O
according	O
to	O
sex	O
,	O
lipid	O
parameters	O
and	O
age	O
.	O

While	O
the	O
age	O
of	O
all	O
four	O
groups	O
did	O
not	O
differ	O
substantially	O
,	O
the	O
concentrations	O
of	O
total	O
serum	O
cholesterol	O
,	O
triglycerides	O
,	O
HDL	O
-	O
cholesterol	O
and	O
LDL	O
-	O
cholesterol	O
differ	O
very	O
significantly	O
in	O
both	O
male	O
and	O
female	O
hyperlipemic	O
groups	O
as	O
compared	O
with	O
controls	O
.	O

In	O
addition	O
,	O
the	O
concentration	O
of	O
triglycerides	O
in	O
control	O
women	B
was	O
significantly	O
higher	O
than	O
in	O
control	O
men	B
,	O
the	O
concentration	O
of	O
triglycerides	O
in	O
hyperlipemic	O
women	B
was	O
lower	O
than	O
in	O
hyperlipemic	O
men	B
,	O
and	O
the	O
concentration	O
of	O
HDL	O
-	O
cholesterol	O
in	O
hyperlipemic	O
women	B
was	O
very	O
significantly	O
higher	O
when	O
compared	O
with	O
hyperlipemic	O
men	B
.	O

Table	O
2	O
shows	O
the	O
values	O
of	O
other	O
metabolic	O
and	O
insulin	O
parameters	O
,	O
factors	O
related	O
to	O
insulin	O
resistance	O
and	O
indexes	O
of	O
insulin	O
resistance	O
,	O
respectively	O
.	O

Body	O
mass	O
indexes	O
and	O
uric	O
acid	O
concentration	O
were	O
significantly	O
higher	O
in	O
hyperlipemic	O
men	B
as	O
compared	O
to	O
controls	O
,	O
but	O
not	O
in	O
hyperlipemic	O
women	B
.	O

Uric	O
acid	O
concentration	O
was	O
substantially	O
lower	O
in	O
hyperlipemic	O
women	B
than	O
in	O
hyperlipemic	O
men	B
.	O

Plasma	O
concentrations	O
of	O
glycemia	O
,	O
insulin	O
and	O
intact	O
proinsulin	O
were	O
significantly	O
higher	O
in	O
both	O
hyperlipemic	O
men	B
and	O
women	B
as	O
compared	O
with	O
controls	O
of	O
identical	O
gender	O
,	O
while	O
the	O
concentration	O
of	O
leptin	O
increased	O
only	O
in	O
hyperlipemic	O
men	B
.	O

However	O
,	O
serum	O
leptin	O
concentrations	O
of	O
both	O
control	O
and	O
hyperlipemic	O
women	B
were	O
significantly	O
higher	O
than	O
in	O
corresponding	O
groups	O
of	O
men	B
.	O

Serum	O
concentrations	O
of	O
TNF	O
alpha	O
,	O
hFABP	O
and	O
ACL	O
-	O
IgG	O
in	O
hyperlipemic	O
groups	O
of	O
both	O
men	B
and	O
women	B
were	O
not	O
significantly	O
different	O
from	O
control	O
groups	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
indexes	O
of	O
insulin	O
resistance	O
HOMA	O
IR	O
and	O
QUICKI	O
differed	O
very	O
significantly	O
in	O
hyperlipemic	O
groups	O
of	O
both	O
men	B
and	O
women	B
as	O
compared	O
with	O
corresponding	O
control	O
groups	O
,	O
more	O
distinctly	O
in	O
women	B
.	O

From	O
Fig	O
.	O

1	O
,	O
presenting	O
95	O
%	O
confidence	O
limits	O
of	O
insulin	O
resistance	O
indexes	O
HOMA	O
IR	O
and	O
QUICKI	O
,	O
we	O
concluded	O
that	O
in	O
groups	O
of	O
hyperlipemic	O
patients	B
of	O
both	O
genders	O
the	O
insulin	O
resistance	O
was	O
substantially	O
higher	O
than	O
in	O
control	O
groups	O
;	O
the	O
groups	O
did	O
not	O
overlap	O
each	O
other	O
.	O

In	O
Table	O
3	O
the	O
results	O
of	O
Spearman	O
'	O
s	O
correlations	O
between	O
insulin	O
resistance	O
index	O
HOMA	O
IR	O
and	O
various	O
metabolic	O
parameters	O
are	O
presented	O
.	O

In	O
the	O
control	O
group	O
of	O
men	B
,	O
positive	O
significant	O
correlation	O
between	O
HOMA	O
IR	O
and	O
serum	O
leptin	O
concentration	O
,	O
and	O
inverse	O
significant	O
correlation	O
between	O
HOMA	O
IR	O
and	O
ACL	O
IgG	O
,	O
respectively	O
,	O
were	O
found	O
.	O

In	O
the	O
control	O
group	O
of	O
women	B
,	O
the	O
significance	O
of	O
Spearman	O
'	O
s	O
correlation	O
between	O
HOMA	O
IR	O
and	O
leptin	O
was	O
more	O
expressive	O
;	O
inverse	O
correlation	O
between	O
HOMA	O
IR	O
and	O
HDL	O
-	O
cholesterol	O
was	O
also	O
present	O
.	O

In	O
the	O
hyperlipemic	O
group	O
of	O
men	B
,	O
the	O
significance	O
of	O
the	O
correlation	O
between	O
HOMA	O
IR	O
was	O
more	O
expressive	O
in	O
relation	O
to	O
the	O
control	O
group	O
,	O
and	O
no	O
significant	O
correlation	O
between	O
HOMA	O
IR	O
and	O
ACL	O
IgG	O
was	O
found	O
.	O

In	O
the	O
hyperlipemic	O
group	O
of	O
women	B
,	O
however	O
,	O
the	O
significance	O
of	O
Spearman	O
'	O
s	O
correlation	O
between	O
HOMA	O
IR	O
and	O
serum	O
leptin	O
concentration	O
weakened	O
,	O
the	O
inverse	O
correlation	O
between	O
HOMA	O
IR	O
and	O
HDL	O
-	O
cholesterol	O
remained	O
approximately	O
unchanged	O
,	O
and	O
a	O
positive	O
correlation	O
between	O
HOMA	O
IR	O
and	O
serum	O
concentration	O
of	O
TNF	O
alpha	O
appeared	O
.	O

Table	O
4	O
shows	O
results	O
of	O
multiple	O
regression	O
analysis	O
,	O
when	O
data	O
from	O
both	O
control	O
and	O
hyperlipemic	O
groups	O
of	O
each	O
gender	O
were	O
judged	O
together	O
.	O

HOMA	O
IR	O
was	O
considered	O
as	O
a	O
dependent	O
variable	O
and	O
differently	O
changed	O
constellations	O
of	O
metabolic	O
and	O
other	O
factors	O
were	O
taken	O
as	O
independent	O
variables	O
.	O

In	O
men	B
,	O
BMI	O
and	O
leptin	O
seemed	O
to	O
play	O
a	O
main	O
role	O
in	O
influencing	O
the	O
insulin	O
resistance	O
index	O
HOMA	O
IR	O
,	O
while	O
TGL	O
,	O
ACL	O
IgG	O
and	O
LDL	O
-	O
cholesterol	O
didn	O
'	O
t	O
play	O
any	O
significant	O
role	O
(	O
see	O
left	O
columns	O
of	O
Table	O
4	O
)	O
.	O

The	O
decreasing	O
of	O
HDL	O
-	O
cholesterol	O
concentration	O
may	O
also	O
have	O
some	O
influence	O
(	O
see	O
a	O
significant	O
drop	O
of	O
R2	O
after	O
exclusion	O
of	O
this	O
factor	O
in	O
Table	O
4A	O
,	O
4B	O
)	O
.	O

But	O
in	O
the	O
presence	O
of	O
leptin	O
in	O
the	O
group	O
of	O
independent	O
factors	O
,	O
the	O
drop	O
of	O
R2	O
after	O
exclusion	O
of	O
HDL	O
-	O
cholesterol	O
from	O
these	O
factors	O
was	O
minimal	O
(	O
see	O
Table	O
4C	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
after	O
the	O
exclusion	O
of	O
TNF	O
alpha	O
from	O
the	O
group	O
of	O
independent	O
variables	O
(	O
see	O
Table	O
4B	O
,	O
4D	O
)	O
the	O
value	O
of	O
R2	O
has	O
unexpectedly	O
risen	O
,	O
which	O
could	O
reflect	O
the	O
interference	O
of	O
TNF	O
alpha	O
with	O
factors	O
increasing	O
the	O
insulin	O
resistance	O
.	O

In	O
women	B
(	O
see	O
right	O
columns	O
of	O
Table	O
4	O
)	O
,	O
the	O
maximal	O
values	O
of	O
R2	O
were	O
achieved	O
with	O
combination	O
of	O
independent	O
variables	O
containing	O
TGL	O
,	O
leptin	O
and	O
HDL	O
-	O
cholesterol	O
(	O
about	O
60	O
%	O
influence	O
on	O
HOMA	O
IR	O
!	O
-	O
see	O
Table	O
4A	O
,	O
4B	O
,	O
4C	O
)	O
.	O

TNF	O
alpha	O
seemed	O
to	O
play	O
quite	O
a	O
different	O
role	O
than	O
in	O
men	B
:	O
after	O
exclusion	O
of	O
this	O
factor	O
from	O
the	O
group	O
of	O
independent	O
factors	O
R2significantly	O
decreased	O
(	O
see	O
Table	O
4B	O
,	O
4D	O
)	O
.	O

In	O
contrast	O
to	O
men	B
,	O
the	O
role	O
of	O
BMI	O
seemed	O
to	O
be	O
minimal	O
.	O

As	O
in	O
men	B
,	O
the	O
role	O
of	O
ACL	O
IgG	O
and	O
LDL	O
-	O
cholesterol	O
in	O
influencing	O
HOMA	O
IR	O
was	O
negligible	O
,	O
but	O
in	O
contrast	O
to	O
men	B
,	O
hFABP	O
might	O
play	O
a	O
certain	O
role	O
in	O
this	O
process	O
(	O
see	O
Table	O
4D	O
)	O
.	O

Generally	O
,	O
the	O
insulin	O
resistance	O
(	O
represented	O
by	O
HOMA	O
IR	O
)	O
was	O
in	O
men	B
much	O
less	O
influenced	O
by	O
metabolic	O
variables	O
than	O
in	O
women	B
;	O
while	O
in	O
women	B
in	O
some	O
combinations	O
of	O
dependent	O
variables	O
R2	O
reached	O
64	O
%	O
,	O
in	O
men	B
the	O
maximal	O
value	O
of	O
R2	O
was	O
only	O
39	O
%	O
.	O

Discussion	O

In	O
our	O
previous	O
paper	O
[	O
36	O
]	O
,	O
the	O
mean	O
value	O
of	O
HOMA	O
IR	O
in	O
healthy	O
subjects	O
of	O
both	O
genders	O
and	O
of	O
age	O
comparable	O
with	O
our	O
controls	O
was	O
1	O
.	O
57	O
+	O
/	O
-	O
0	O
.	O
87	O
,	O
and	O
the	O
mean	O
value	O
of	O
index	O
QUICKI	O
0	O
.	O
366	O
+	O
/	O
-	O
0	O
.	O
029	O
,	O
respectively	O
.	O

These	O
values	O
,	O
as	O
well	O
as	O
the	O
95	O
%	O
confidence	O
limits	O
,	O
correspond	O
to	O
values	O
found	O
in	O
controls	O
in	O
this	O
study	O
.	O

In	O
accordance	O
with	O
many	O
previous	O
papers	O
,	O
serum	O
concentrations	O
of	O
leptin	O
in	O
women	B
(	O
both	O
control	O
and	O
hyperlipemic	O
)	O
were	O
substantially	O
higher	O
than	O
in	O
men	B
.	O

In	O
the	O
control	O
group	O
of	O
women	B
the	O
correlation	O
between	O
leptin	O
and	O
HOMA	O
IR	O
was	O
highly	O
significant	O
.	O

However	O
,	O
in	O
hyperlipemic	O
women	B
the	O
significance	O
of	O
this	O
correlation	O
lessened	O
,	O
because	O
HOMA	O
IR	O
increased	O
considerably	O
(	O
and	O
significantly	O
)	O
but	O
serum	O
concentration	O
of	O
leptin	O
only	O
slightly	O
(	O
insignificantly	O
)	O
.	O

In	O
men	B
the	O
significance	O
of	O
correlations	O
between	O
serum	O
leptin	O
and	O
HOMA	O
IR	O
was	O
high	O
and	O
approximately	O
the	O
same	O
in	O
both	O
the	O
control	O
and	O
hyperlipemic	O
groups	O
,	O
because	O
the	O
values	O
of	O
HOMA	O
IR	O
as	O
well	O
as	O
serum	O
leptin	O
have	O
nearly	O
doubled	O
in	O
hyperlipemic	O
in	O
relation	O
to	O
control	O
groups	O
.	O

In	O
non	O
-	O
hyperlipemic	O
postmenopausal	O
women	B
the	O
high	O
concentration	O
of	O
serum	O
leptin	O
was	O
not	O
associated	O
with	O
higher	O
insulin	O
resistance	O
:	O
HOMA	O
IR	O
did	O
not	O
differ	O
substantially	O
from	O
men	B
.	O

A	O
significant	O
increase	O
of	O
insulin	O
resistance	O
in	O
hyperlipemic	O
women	B
was	O
associated	O
by	O
only	O
slight	O
and	O
insignificant	O
increase	O
of	O
leptin	O
concentration	O
.	O

According	O
to	O
Spearman	O
'	O
s	O
correlations	O
,	O
an	O
increase	O
of	O
serum	O
TNF	O
alpha	O
and	O
/	O
or	O
a	O
decrease	O
of	O
HDL	O
-	O
cholesterol	O
might	O
also	O
play	O
a	O
distinct	O
role	O
in	O
this	O
respect	O
.	O

(	O
see	O
Table	O
3	O
)	O
.	O

In	O
contrast	O
to	O
women	B
,	O
in	O
hyperlipemic	O
men	B
the	O
increase	O
of	O
insulin	O
resistance	O
index	O
was	O
approximately	O
proportional	O
with	O
the	O
increase	O
of	O
leptin	O
concentration	O
.	O

Multiple	O
regression	O
analysis	O
affirmed	O
the	O
importance	O
of	O
leptin	O
serum	O
in	O
increasing	O
of	O
insulin	O
resistance	O
in	O
both	O
genders	O
.	O

In	O
men	B
,	O
only	O
BMI	O
and	O
HDL	O
-	O
cholesterol	O
from	O
other	O
factors	O
studied	O
seemed	O
to	O
play	O
a	O
certain	O
role	O
,	O
but	O
the	O
maximal	O
values	O
of	O
influencing	O
HOMA	O
IR	O
reached	O
only	O
39	O
%	O
,	O
with	O
leptin	O
and	O
BMI	O
being	O
the	O
more	O
important	O
factors	O
.	O

On	O
the	O
other	O
hand	O
,	O
in	O
women	B
the	O
maximal	O
determination	O
of	O
HOMA	O
IR	O
as	O
high	O
as	O
60	O
%	O
was	O
registered	O
in	O
combination	O
of	O
serum	O
leptin	O
,	O
TGL	O
and	O
decreased	O
HDL	O
-	O
cholesterol	O
as	O
independent	O
factors	O
;	O
the	O
role	O
of	O
BMI	O
was	O
insignificant	O
.	O

It	O
is	O
not	O
known	O
how	O
leptin	O
is	O
regulated	O
.	O

A	O
strong	O
correlation	O
between	O
plasma	O
leptin	O
and	O
fasting	O
insulin	O
undoubtedly	O
exists	O
,	O
but	O
hyperleptinemia	O
in	O
both	O
obese	O
and	O
lean	O
humans	B
is	O
not	O
likely	O
the	O
result	O
of	O
hyperinsulinemia	O
[	O
37	O
]	O
.	O

A	O
relationship	O
between	O
leptin	O
and	O
insulin	O
dependent	O
on	O
sex	O
or	O
BMI	O
was	O
reported	O
,	O
but	O
relationship	O
between	O
triglyceride	O
concentrations	O
and	O
leptin	O
was	O
independent	O
of	O
sex	O
,	O
BMI	O
,	O
and	O
insulin	O
[	O
18	O
,	O
24	O
]	O
.	O

Hyperleptinemia	O
,	O
as	O
an	O
early	O
sign	O
of	O
obesity	O
,	O
was	O
closely	O
linked	O
to	O
subcutaneous	O
fat	O
mass	O
[	O
39	O
,	O
40	O
]	O
.	O

Percentage	O
of	O
body	O
fat	O
has	O
been	O
shown	O
to	O
be	O
the	O
strongest	O
predictor	O
of	O
leptin	O
levels	O
even	O
in	O
lean	O
women	B
[	O
41	O
]	O
.	O

Leptin	O
was	O
highly	O
correlated	O
with	O
percentage	O
of	O
body	O
fat	O
and	O
with	O
fat	O
mass	O
in	O
adults	O
irrespective	O
of	O
gender	O
and	O
age	O
;	O
however	O
,	O
the	O
mean	O
determinant	O
of	O
leptin	O
plasma	O
concentration	O
in	O
men	B
and	O
postmenopausal	O
women	B
was	O
BMI	O
,	O
while	O
in	O
premenopausal	O
women	B
it	O
was	O
only	O
the	O
fat	O
mass	O
[	O
42	O
]	O
.	O

These	O
findings	O
contrast	O
with	O
our	O
results	O
showing	O
minimal	O
influence	O
of	O
BMI	O
on	O
HOMA	O
IR	O
in	O
postmenopausal	O
women	B
.	O

All	O
factors	O
mentioned	O
are	O
connected	O
with	O
fat	O
tissue	O
:	O
leptin	O
and	O
TNF	O
alpha	O
are	O
directly	O
produced	O
chiefly	O
by	O
adipocytes	O
,	O
BMI	O
growth	O
is	O
obviously	O
accompanied	O
by	O
fat	O
mass	O
increase	O
,	O
and	O
the	O
typical	O
hypertriglyceridemia	O
associated	O
with	O
a	O
decrease	O
of	O
HDL	O
-	O
cholesterol	O
goes	O
along	O
with	O
obesity	O
and	O
fat	O
mass	O
growth	O
.	O

The	O
gender	O
differences	O
in	O
circulating	O
leptin	O
were	O
best	O
explained	O
by	O
percentage	O
of	O
body	O
fat	O
and	O
-	O
inversely	O
-	O
by	O
lean	O
body	O
mass	O
[	O
25	O
]	O
.	O

In	O
both	O
genders	O
the	O
intra	O
-	O
abdominal	O
fat	O
correlated	O
with	O
insulin	O
resistance	O
,	O
while	O
the	O
subcutaneous	O
fat	O
correlated	O
with	O
circulating	O
leptin	O
[	O
11	O
,	O
12	O
]	O
.	O

In	O
men	B
obesity	O
led	O
to	O
a	O
prevalent	O
increase	O
of	O
intra	O
-	O
abdominal	O
fat	O
,	O
while	O
in	O
women	B
of	O
subcutaneous	O
fat	O
[	O
13	O
]	O
.	O

Influences	O
of	O
different	O
compartments	O
of	O
adipose	O
tissues	O
could	O
elucidate	O
the	O
variability	O
of	O
correlations	O
between	O
insulin	O
resistance	O
and	O
high	O
leptin	O
concentrations	O
in	O
lean	O
and	O
obese	O
subjects	O
of	O
both	O
genders	O
[	O
43	O
]	O
.	O

In	O
our	O
non	O
-	O
hyperlipemic	O
postmenopausal	O
women	B
the	O
content	O
of	O
subcutaneous	O
fat	O
mass	O
might	O
be	O
higher	O
than	O
in	O
non	O
-	O
hyperlipemic	O
men	B
of	O
appropriate	O
age	O
,	O
which	O
indicated	O
a	O
higher	O
serum	O
concentration	O
of	O
leptin	O
.	O

However	O
,	O
the	O
insulin	O
resistance	O
-	O
related	O
to	O
intra	O
-	O
abdominal	O
fat	O
mass	O
-	O
did	O
not	O
differ	O
from	O
men	B
.	O

The	O
significant	O
increase	O
of	O
insulin	O
resistance	O
and	O
leptin	O
concentration	O
in	O
hyperlipemic	O
men	B
might	O
reflect	O
the	O
growing	O
content	O
of	O
both	O
subcutaneous	O
and	O
intra	O
-	O
abdominal	O
fat	O
mass	O
(	O
see	O
the	O
significant	O
increase	O
of	O
BMI	O
)	O
.	O

In	O
hyperlipemic	O
women	B
the	O
significant	O
increase	O
of	O
insulin	O
resistance	O
accompanying	O
only	O
minimal	O
insignificant	O
increase	O
of	O
leptin	O
could	O
be	O
caused	O
by	O
prevalent	O
growing	O
of	O
intra	O
-	O
abdominal	O
fat	O
mass	O
.	O

In	O
elderly	O
postmenopausal	O
women	B
,	O
an	O
association	O
between	O
leptin	O
and	O
plasma	O
lipoprotein	O
concentration	O
was	O
found	O
which	O
depended	O
on	O
adiposity	O
[	O
17	O
]	O
,	O
and	O
inverse	O
correlations	O
between	O
serum	O
leptin	O
and	O
HDL	O
-	O
cholesterol	O
were	O
described	O
[	O
44	O
]	O
.	O

In	O
our	O
study	O
,	O
insulin	O
resistance	O
in	O
women	B
seemed	O
to	O
be	O
more	O
notably	O
than	O
in	O
men	B
influenced	O
by	O
lipid	O
disorders	O
,	O
i	O
.	O
e	O
.	O
positively	O
by	O
serum	O
triglycerides	O
and	O
inversely	O
by	O
HDL	O
-	O
cholesterol	O
.	O

These	O
findings	O
might	O
be	O
important	O
in	O
considering	O
the	O
concept	O
of	O
treatment	O
of	O
insulin	O
resistance	O
-	O
related	O
disorders	O
in	O
postmenopausal	O
women	B
.	O

The	O
significant	O
role	O
of	O
TNF	O
alpha	O
in	O
insulin	O
resistance	O
,	O
caused	O
by	O
inhibiting	O
the	O
transduction	O
of	O
insulin	O
signaling	O
and	O
by	O
down	O
-	O
regulation	O
of	O
glucose	O
transporter	O
GLUT	O
-	O
4	O
and	O
insulin	O
receptor	O
substrate	O
-	O
1	O
,	O
has	O
been	O
repeatedly	O
confirmed	O
[	O
45	O
-	O
48	O
]	O
.	O

Our	O
results	O
supported	O
these	O
findings	O
unambiguously	O
only	O
in	O
women	B
,	O
while	O
in	O
men	B
TNF	O
alpha	O
seemed	O
paradoxically	O
to	O
interfere	O
with	O
other	O
factors	O
-	O
mainly	O
BMI	O
and	O
leptin	O
-	O
in	O
influencing	O
insulin	O
resistance	O
,	O
thus	O
playing	O
a	O
quite	O
different	O
role	O
.	O

Previously	O
it	O
was	O
found	O
[	O
46	O
]	O
that	O
correlation	O
between	O
serum	O
TNF	O
alpha	O
on	O
the	O
one	O
side	O
,	O
and	O
insulin	O
,	O
HOMA	O
IR	O
,	O
serum	O
triglycerids	O
,	O
respectively	O
,	O
on	O
the	O
other	O
side	O
,	O
was	O
substantially	O
more	O
significant	O
in	O
women	B
than	O
in	O
men	B
.	O

Serum	O
concentration	O
of	O
TNF	O
alpha	O
in	O
patients	B
with	O
type	O
2	O
diabetes	O
of	O
both	O
genders	O
correlated	O
only	O
with	O
the	O
quantity	O
of	O
intra	O
-	O
abdominal	O
fat	O
compartment	O
[	O
50	O
]	O
.	O

Visceral	O
obesity	O
correlated	O
with	O
plasmatic	O
aldosterone	O
and	O
with	O
insulin	O
resistance	O
only	O
in	O
premenopausal	O
women	B
,	O
but	O
not	O
in	O
men	B
[	O
51	O
]	O
.	O

From	O
all	O
these	O
data	O
we	O
might	O
support	O
our	O
above	O
mentioned	O
conclusion	O
-	O
that	O
rising	O
of	O
insulin	O
resistance	O
in	O
hyperlipemic	O
women	B
was	O
associated	O
with	O
an	O
increase	O
of	O
intra	O
-	O
abdominal	O
fat	O
,	O
because	O
this	O
fat	O
mass	O
in	O
particular	O
is	O
a	O
source	O
of	O
TNF	O
alpha	O
,	O
which	O
interfered	O
with	O
insulin	O
sensitivity	O
only	O
in	O
women	B
.	O

We	O
came	O
to	O
this	O
conclusion	O
irrespective	O
of	O
the	O
finding	O
that	O
the	O
increase	O
of	O
serum	O
TNF	O
alpha	O
in	O
hyperlipemic	O
women	B
was	O
statistically	O
insignificant	O
;	O
results	O
of	O
Spearman	O
'	O
s	O
correlation	O
(	O
Table	O
3	O
)	O
and	O
multiple	O
regression	O
analysis	O
confirm	O
a	O
distinct	O
role	O
of	O
this	O
factor	O
.	O

In	O
hyperlipemic	O
men	B
not	O
only	O
the	O
serum	O
concentration	O
of	O
TNF	O
alpha	O
has	O
decreased	O
instead	O
of	O
increasing	O
,	O
but	O
according	O
to	O
multiple	O
regression	O
analysis	O
it	O
played	O
a	O
quite	O
different	O
role	O
in	O
influencing	O
insulin	O
sensitivity	O
,	O
interfering	O
with	O
factors	O
that	O
determined	O
insulin	O
resistance	O
(	O
leptin	O
and	O
BMI	O
)	O
.	O

In	O
the	O
control	O
group	O
of	O
men	B
IgG	O
anticardiolipin	O
was	O
inversely	O
correlated	O
to	O
HOMA	O
IR	O
.	O

The	O
significance	O
of	O
this	O
finding	O
is	O
not	O
clear	O
.	O

These	O
antibodies	O
indicate	O
vascular	O
and	O
thrombotic	O
complications	O
and	O
oxidative	O
modification	O
of	O
lipoproteins	O
[	O
52	O
,	O
53	O
]	O
and	O
may	O
represent	O
an	O
increased	O
risk	O
of	O
atherogenic	O
and	O
inflammatory	O
complications	O
.	O

In	O
this	O
case	O
,	O
however	O
,	O
their	O
growing	O
might	O
be	O
connected	O
with	O
an	O
increase	O
in	O
insulin	O
sensitivity	O
.	O

Anyway	O
,	O
ACL	O
IgG	O
evidently	O
did	O
not	O
participate	O
significantly	O
in	O
influencing	O
the	O
increase	O
of	O
insulin	O
resistance	O
associated	O
with	O
hyperlipidemia	O
,	O
although	O
other	O
anti	O
-	O
cardiolipin	O
correlations	O
could	O
be	O
masked	O
by	O
the	O
relatively	O
large	O
inter	O
-	O
individual	O
variations	O
in	O
this	O
parameter	O
.	O

Neither	O
serum	O
concentration	O
of	O
hFABP	O
,	O
a	O
factor	O
ensuring	O
transmembrane	O
transport	O
and	O
oxidative	O
metabolisation	O
of	O
long	O
-	O
chain	O
fatty	O
acids	O
[	O
54	O
,	O
55	O
]	O
,	O
was	O
significantly	O
changed	O
in	O
hyperlipemic	O
and	O
insulin	O
resistant	O
subjects	O
of	O
both	O
genders	O
.	O

This	O
factor	O
was	O
very	O
weakly	O
associated	O
only	O
with	O
HOMA	O
IR	O
in	O
women	B
(	O
see	O
Table	O
4D	O
)	O
,	O
indicating	O
that	O
enhanced	O
metabolisation	O
of	O
fatty	O
acids	O
in	O
cells	O
might	O
to	O
some	O
degree	O
contribute	O
to	O
insulin	O
resistance	O
.	O

Conclusions	O

In	O
postmenopausal	O
women	B
as	O
well	O
as	O
in	O
men	B
of	O
approximately	O
equal	O
age	O
serum	O
leptin	O
plays	O
a	O
significant	O
role	O
as	O
an	O
important	O
determinant	O
of	O
insulin	O
resistance	O
.	O

In	O
addition	O
to	O
this	O
factor	O
,	O
in	O
women	B
the	O
grade	O
of	O
insulin	O
resistance	O
is	O
very	O
considerably	O
influenced	O
by	O
serum	O
triglycerides	O
,	O
tumor	O
necrosis	O
factor	O
alpha	O
,	O
and	O
by	O
decreased	O
concentration	O
of	O
HDL	O
-	O
cholesterol	O
,	O
while	O
in	O
men	B
only	O
a	O
mild	O
influence	O
of	O
BMI	O
and	O
decreased	O
HDL	O
-	O
cholesterol	O
is	O
observed	O
.	O

These	O
findings	O
are	O
explained	O
as	O
a	O
consequence	O
of	O
gender	O
-	O
related	O
differences	O
in	O
adipose	O
tissue	O
composition	O
and	O
/	O
or	O
distribution	O
in	O
both	O
normal	O
-	O
weight	O
and	O
over	O
-	O
weight	O
subjects	O
and	O
should	O
be	O
taken	O
into	O
account	O
in	O
treatment	O
of	O
patients	B
with	O
metabolic	O
risk	O
factors	O
of	O
cardiovascular	O
diseases	O
.	O

List	O
of	O
abbreviations	O

HDL	O
-	O
Cholesterol	O
=	O
high	O
-	O
density	O
cholesterol	O

LDL	O
-	O
cholesterol	O
=	O
low	O
-	O
density	O
cholesterol	O

HOMA	O
IR	O
=	O
Homeostasis	O
Assessment	O
of	O
Insulin	O
Resistance	O

=	O
fasting	O
insulin	O
(	O
mu	O
U	O
/	O
ml	O
)	O
*	O
fasting	O
glucose	O
(	O
mmol	O
/	O
l	O
)	O
/	O
22	O
,	O
5	O

QUICKI	O
=	O
1	O
/	O
[	O
log	O
fasting	O
insulin	O
(	O
mu	O
U	O
/	O
ml	O
)	O
+	O
log	O
fasting	O
glucose	O
(	O
mg	O
/	O
100	O
ml	O
)	O
]	O

TNF	O
alpha	O
=	O
tumor	O
necrosis	O
factor	O
alpha	O

BMI	O
=	O
body	O
mass	O
index	O

R2	O
=	O
coefficient	O
of	O
determination	O

hFABP	O
=	O
heart	O
fatty	O
acid	O
binding	O
protein	O

ACL	O
-	O
IgG	O
=	O
IgG	O
fraction	O
of	O
anticardiolipin	O

TGL	O
=	O
triglycerides	O

GLUT	O
-	O
4	O
=	O
glucose	O
transporter	O
-	O
4	O

PPAR	O
gamma	O
=	O
Peroxisome	O
Proliferator	O
-	O
Associated	O
Receptor	O
gamma	O

CV	O
=	O
coefficient	O
of	O
variation	O

Authors	O
'	O
contributions	O

Dr	O
.	O
Radka	O
Lichnovsk	O
a	O
collected	O
the	O
clinical	O
material	O
,	O
performed	O
analysis	O
of	O
biochemical	O
values	O
and	O
edited	O
the	O
manuscript	O
.	O

Dr	O
.	O
Simona	O
Gwozdziewiczov	O
a	O
performed	O
analysis	O
of	O
clinical	O
and	O
biochemical	O
data	O
and	O
edited	O
the	O
manuscript	O
.	O

Prof	O
.	O

Jir	O
i	O
Hreb	O
i	O
cek	O
initiated	O
the	O
study	O
,	O
participated	O
in	O
its	O
design	O
and	O
coordination	O
,	O
and	O
wrote	O
and	O
edited	O
the	O
manuscript	O
.	O

Alexithymia	O
and	O
anxiety	O
in	O
female	O
chronic	O
pain	O
patients	B

Abstract	O

Objectives	O

Alexithymia	O
is	O
highly	O
prevalent	O
among	O
chronic	O
pain	O
patients	B
.	O

Pain	O
is	O
a	O
remarkable	O
cause	O
for	O
high	O
levels	O
of	O
chronic	O
anxiety	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
investigate	O
the	O
prevalence	O
of	O
alexithymia	O
and	O
to	O
determine	O
anxiety	O
levels	O
among	O
DSM	O
-	O
IV	O
somatoform	O
pain	O
disorder	O
(	O
chronic	O
pain	O
)	O
female	O
patients	B
and	O
to	O
examine	O
the	O
relationship	O
between	O
alexithymia	O
and	O
the	O
self	O
-	O
reporting	O
of	O
pain	O
.	O

Methods	O

Thirty	O
adult	O
females	O
(	O
mean	O
age	O
:	O
34	O
,	O
63	O
+	O
/	O
-	O
10	O
,	O
62	O
years	O
)	O
,	O
who	O
applied	O
to	O
the	O
outpatient	O
psychiatry	O
clinic	O
at	O
a	O
public	O
hospital	O
with	O
the	O
diagnosis	O
of	O
chronic	O
pain	O
disorder	O
(	O
DSM	O
-	O
IV	O
)	O
,	O
were	O
included	O
in	O
the	O
study	O
.	O

Thirty	O
seven	O
healthy	O
females	O
(	O
mean	O
age	O
:	O
34	O
,	O
46	O
+	O
/	O
-	O
7	O
,	O
43	O
years	O
)	O
,	O
who	O
matched	O
for	O
sociodemographic	O
features	O
with	O
the	O
patient	B
group	O
,	O
consisted	O
the	O
control	O
group	O
.	O

A	O
sociodemographic	O
data	O
form	O
,	O
26	O
-	O
item	O
Toronto	O
Alexithymia	O
Scale	O
(	O
TAS	O
-	O
26	O
)	O
,	O
Spielberger	O
Trait	O
Anxiety	O
Inventory	O
(	O
STAI	O
)	O
were	O
administered	O
to	O
each	O
subject	O
and	O
information	O
was	O
obtained	O
on	O
several	O
aspects	O
of	O
the	O
patients	B
'	O
pain	O
,	O
including	O
intensity	O
(	O
measured	O
by	O
VAS	O
)	O
,	O
and	O
duration	O
.	O

Results	O

Chronic	O
pain	O
patients	B
were	O
found	O
significantly	O
more	O
alexithymic	O
than	O
controls	O
.	O

There	O
was	O
a	O
positive	O
correlation	O
between	O
TAS	O
-	O
26	O
scores	O
and	O
the	O
duration	O
of	O
pain	O
.	O

The	O
alexithymic	O
and	O
nonalexithymic	O
group	O
did	O
not	O
differ	O
in	O
their	O
perception	O
of	O
pain	O
.	O

Neither	O
positive	O
correlation	O
nor	O
significant	O
difference	O
was	O
found	O
between	O
alexithymia	O
and	O
trait	O
anxiety	O
in	O
pain	O
patients	B
.	O

Discussion	O

Alexithymia	O
may	O
be	O
important	O
in	O
addressing	O
the	O
diversity	O
of	O
subjective	O
factors	O
involved	O
in	O
pain	O
.	O

The	O
conceptualization	O
of	O
alexithymia	O
as	O
a	O
personality	O
trait	O
as	O
well	O
as	O
a	O
secondary	O
state	O
reaction	O
is	O
underlined	O
by	O
our	O
data	O
.	O

Background	O

The	O
original	O
definition	O
of	O
alexithymia	O
is	O
the	O
inability	O
to	O
identify	O
and	O
use	O
verbal	O
language	O
to	O
describe	O
feelings	O
[	O
1	O
,	O
2	O
]	O
.	O

Alexithymia	O
has	O
been	O
associated	O
with	O
a	O
variety	O
of	O
psychiatric	O
disorders	O
as	O
well	O
as	O
physical	O
illness	O
[	O
3	O
-	O
10	O
]	O
.	O

As	O
a	O
measure	O
,	O
Toronto	O
Alexithymia	O
Scale	O
was	O
significantly	O
correlated	O
with	O
the	O
measures	O
of	O
the	O
tendency	O
to	O
experience	O
and	O
report	O
physical	O
signs	O
and	O
symptoms	O
[	O
11	O
]	O
.	O

Several	O
studies	O
have	O
found	O
a	O
high	O
prevalence	O
of	O
alexithymia	O
in	O
pain	O
patients	B
.	O

Chronic	O
pain	O
patients	B
frequently	O
exhibit	O
many	O
of	O
the	O
core	O
features	O
of	O
alexithymia	O
,	O
such	O
as	O
problems	O
in	O
identifying	O
and	O
describing	O
subjective	O
feelings	O
,	O
impoverished	O
imaginative	O
abilities	O
,	O
and	O
excessive	O
preoccupation	O
with	O
physical	O
symptoms	O
and	O
external	O
events	O
.	O

Although	O
several	O
studies	O
have	O
found	O
a	O
high	O
prevalence	O
of	O
alexithymia	O
in	O
pain	O
patients	B
,	O
the	O
way	O
alexithymia	O
may	O
possibly	O
influence	O
pain	O
experience	O
is	O
still	O
unclear	O
[	O
12	O
,	O
13	O
]	O
.	O

DSM	O
-	O
IV	O
-	O
TR	O
defines	O
pain	O
disorder	O
as	O
the	O
presence	O
of	O
pain	O
that	O
is	O
"	O
the	O
predominant	O
focus	O
of	O
clinical	O
attention	O
"	O
[	O
14	O
]	O
.	O

In	O
chronic	O
pain	O
disorder	O
,	O
patients	B
complain	O
of	O
chronic	O
pain	O
,	O
for	O
which	O
no	O
physical	O
etiology	O
could	O
be	O
found	O
or	O
the	O
underlying	O
disorder	O
is	O
insufficient	O
in	O
explaining	O
the	O
symptoms	O
.	O

The	O
pain	O
causes	O
clinically	O
significant	O
distress	O
or	O
impairment	O
in	O
social	O
,	O
occupational	O
,	O
or	O
other	O
important	O
areas	O
of	O
functioning	O
.	O

Psychological	O
factors	O
are	O
judged	O
to	O
have	O
an	O
important	O
role	O
in	O
the	O
onset	O
,	O
severity	O
,	O
exacerbation	O
,	O
or	O
maintenance	O
of	O
the	O
pain	O
[	O
15	O
]	O
.	O

The	O
alexithymic	O
person	B
'	O
s	O
difficulty	O
in	O
identifying	O
and	O
describing	O
feelings	O
may	O
increase	O
symptom	O
reporting	O
by	O
several	O
mechanisms	O
.	O

Consequently	O
,	O
due	O
to	O
the	O
difficulty	O
to	O
experience	O
and	O
express	O
emotions	O
,	O
alexithymia	O
has	O
been	O
linked	O
with	O
somatosensory	O
amplification	O
,	O
which	O
is	O
the	O
tendency	O
to	O
focus	O
on	O
benign	O
somatic	O
sensations	O
.	O

Alexithymic	O
subjects	O
are	O
considered	O
to	O
focus	O
on	O
somatic	O
manifestations	O
of	O
emotional	O
arousal	O
,	O
resulting	O
in	O
misinterpretation	O
of	O
somatic	O
sensations	O
as	O
signs	O
of	O
physical	O
illness	O
[	O
12	O
,	O
13	O
,	O
16	O
]	O
.	O

Accordingly	O
,	O
previous	O
studies	O
have	O
found	O
evidence	O
of	O
an	O
association	O
between	O
alexithymia	O
and	O
the	O
development	O
of	O
functional	O
somatic	O
symptoms	O
,	O
as	O
seen	O
in	O
patients	B
with	O
somatoform	O
disorders	O
.	O

On	O
the	O
other	O
hand	O
,	O
alexithymia	O
may	O
also	O
occur	O
as	O
a	O
secondary	O
state	O
reaction	O
in	O
response	O
to	O
severe	O
and	O
chronic	O
medical	O
illness	O
[	O
17	O
-	O
21	O
]	O
.	O

Based	O
on	O
previous	O
findings	O
,	O
these	O
factors	O
are	O
worth	O
receiving	O
more	O
attention	O
in	O
terms	O
of	O
clinical	O
research	O
.	O

The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
the	O
prevalence	O
of	O
alexithymia	O
among	O
DSM	O
-	O
IV	O
somatoform	O
pain	O
disorder	O
(	O
chronic	O
pain	O
)	O
female	O
patients	B
and	O
to	O
examine	O
the	O
relationship	O
between	O
alexithymia	O
and	O
the	O
self	O
-	O
reporting	O
of	O
pain	O
in	O
this	O
group	O
of	O
patients	B
.	O

Besides	O
,	O
the	O
study	O
searched	O
for	O
the	O
anxiety	O
levels	O
of	O
chronic	O
pain	O
patients	B
with	O
or	O
without	O
alexithymia	O
.	O

Materials	O
and	O
methods	O

Sample	O

The	O
sample	O
consisted	O
of	O
30	O
females	O
who	O
applied	O
to	O
the	O
outpatient	O
psychiatry	O
clinic	O
at	O
a	O
public	O
hospital	O
and	O
who	O
met	O
DSM	O
-	O
IV	O
diagnostic	O
criteria	O
for	O
chronic	O
pain	O
disorder	O
.	O

Patients	B
with	O
concomitant	O
psychiatric	O
disorders	O
,	O
such	O
as	O
major	O
depression	O
,	O
anxiety	O
disorders	O
and	O
somatoform	O
disorders	O
other	O
than	O
pain	O
disorder	O
were	O
excluded	O
.	O

Patients	B
either	O
directly	O
applied	O
to	O
the	O
psychiatry	O
clinic	O
themselves	O
or	O
were	O
referred	O
for	O
psychiatric	O
assessment	O
from	O
another	O
outpatient	O
clinic	O
,	O
mainly	O
physical	O
medicine	O
and	O
rehabilitation	O
.	O

After	O
complete	O
description	O
of	O
the	O
study	O
,	O
written	O
informed	O
consent	O
was	O
obtained	O
from	O
each	O
subject	O
.	O

The	O
control	O
group	O
was	O
37	O
healthy	O
females	O
,	O
who	O
matched	O
for	O
age	O
,	O
and	O
education	O
with	O
the	O
subjects	O
.	O

All	O
subjects	O
participated	O
voluntarily	O
in	O
the	O
study	O
and	O
gave	O
consent	O
after	O
the	O
procedure	O
had	O
been	O
fully	O
explained	O
to	O
them	O
.	O

The	O
mean	O
age	O
of	O
the	O
patients	B
and	O
the	O
healthy	O
controls	O
was	O
34	O
,	O
63	O
+	O
/	O
-	O
10	O
,	O
62	O
(	O
range	O
:	O
16	O
-	O
62	O
)	O
and	O
34	O
,	O
46	O
+	O
/	O
-	O
7	O
,	O
43	O
(	O
range	O
:	O
22	O
-	O
57	O
)	O
years	O
and	O
the	O
educational	O
level	O
was	O
6	O
,	O
13	O
+	O
/	O
-	O
3	O
,	O
03	O
(	O
range	O
:	O
5	O
-	O
11	O
)	O
and	O
6	O
,	O
59	O
+	O
/	O
-	O
2	O
,	O
9	O
(	O
range	O
:	O
5	O
-	O
14	O
)	O
years	O
,	O
respectively	O
.	O

There	O
were	O
no	O
significant	O
differences	O
between	O
the	O
two	O
groups	O
with	O
respect	O
to	O
age	O
(	O
t	O
=	O
0	O
,	O
79	O
,	O
df	O
=	O
65	O
,	O
P	O
>	O
0	O
,	O
05	O
)	O
,	O
educational	O
level	O
(	O
t	O
=	O
1	O
,	O
02	O
,	O
df	O
=	O
65	O
,	O
P	O
>	O
0	O
,	O
05	O
)	O
,	O
and	O
marital	O
status	O
(	O
x2	O
=	O
0	O
,	O
51	O
,	O
df	O
=	O
1	O
,	O
P	O
>	O
0	O
,	O
05	O
)	O
.	O

Measures	O

A	O
detailed	O
sociodemographic	O
data	O
form	O
was	O
used	O
for	O
all	O
subjects	O
.	O

All	O
participants	B
were	O
applied	O
Structured	O
Clinical	O
Interview	O
for	O
DSM	O
-	O
IV	O
(	O
SCID	O
-	O
I	O
)	O
[	O
22	O
]	O
,	O
Turkish	O
version	O
[	O
23	O
]	O
.	O

Regarding	O
the	O
pain	O
assessment	O
,	O
information	O
was	O
first	O
obtained	O
on	O
several	O
aspects	O
of	O
the	O
patients	B
'	O
pain	O
,	O
such	O
as	O
intensity	O
,	O
and	O
duration	O
.	O

Pain	O
intensity	O
was	O
measured	O
by	O
Visual	O
Analogue	O
Scale	O
(	O
VAS	O
)	O
,	O
using	O
a	O
horizontal	O
10	O
-	O
cm	O
line	O
with	O
the	O
statement	O
'	O
no	O
pain	O
at	O
all	O
'	O
at	O
the	O
extreme	O
left	O
-	O
hand	O
end	O
and	O
'	O
the	O
worst	O
possible	O
pain	O
'	O
or	O
'	O
unbearable	O
'	O
at	O
the	O
right	O
-	O
hand	O
extreme	O
.	O

VAS	O
is	O
scored	O
by	O
measuring	O
the	O
distance	O
from	O
the	O
end	O
of	O
the	O
scale	O
indicating	O
absence	O
of	O
pain	O
(	O
or	O
no	O
distress	O
or	O
no	O
pain	O
relief	O
)	O
to	O
the	O
place	O
marked	O
by	O
the	O
patient	B
[	O
24	O
]	O
.	O

The	O
psychometric	O
scales	O
used	O
in	O
the	O
study	O
were	O
the	O
26	O
-	O
item	O
Toronto	O
Alexithymia	O
Scale	O
(	O
TAS	O
-	O
26	O
]	O
and	O
the	O
Trait	O
Anxiety	O
Inventory	O
(	O
STAI	O
)	O
,	O
which	O
were	O
both	O
validated	O
in	O
Turkish	O
population	O
studies	O
[	O
25	O
-	O
28	O
]	O
.	O

TAS	O
is	O
a	O
psychometrically	O
well	O
validated	O
and	O
reliable	O
instrument	O
in	O
the	O
assessment	O
of	O
alexithymia	O
.	O
TAS	O
has	O
been	O
validated	O
in	O
Turkish	O
studies	O
as	O
a	O
true	O
or	O
false	O
scale	O
.	O

Twenty	O
-	O
six	O
items	O
are	O
scored	O
either	O
as	O
1	O
or	O
0	O
and	O
the	O
higher	O
scores	O
indicate	O
higher	O
degrees	O
of	O
alexithymia	O
.	O

TAS	O
has	O
an	O
interval	O
consistency	O
of	O
0	O
.	O
65	O
[	O
Kuder	O
-	O
Richardson	O
)	O
and	O
test	O
-	O
retest	O
reliability	O
is	O
r	O
=	O
0	O
.	O
71	O
,	O
p	O
<	O
0	O
.	O
01	O
in	O
Turkish	O
reliability	O
and	O
validity	O
study	O
.	O

The	O
sample	O
was	O
divided	O
into	O
nonalexithymic	O
and	O
alexityhmic	O
groups	O
,	O
with	O
the	O
recommended	O
cut	O
-	O
off	O
score	O
of	O
11	O
[	O
27	O
]	O
.	O

Spielberger	O
Trait	O
Anxiety	O
Inventory	O
(	O
STAI	O
)	O
is	O
one	O
of	O
the	O
two	O
sections	O
of	O
the	O
Spielberger	O
Anxiety	O
Inventory	O
(	O
the	O
other	O
,	O
measuring	O
state	O
anxiety	O
)	O
.	O

'	O
Trait	O
anxiety	O
'	O
has	O
been	O
defined	O
as	O
anxiety	O
proneness	O
,	O
that	O
is	O
,	O
the	O
tendency	O
to	O
respond	O
to	O
situations	O
perceived	O
as	O
threatening	O
with	O
elevations	O
in	O
the	O
intensity	O
of	O
state	O
anxiety	O
[	O
26	O
]	O
.	O

Statistical	O
analysis	O

In	O
order	O
to	O
determine	O
the	O
relative	O
importance	O
of	O
a	O
number	O
of	O
factors	O
in	O
pain	O
disorders	O
,	O
we	O
used	O
both	O
correlation	O
analyses	O
.	O

The	O
alexithymic	O
and	O
nonalexithymic	O
groups	O
were	O
compared	O
using	O
the	O
independent	O
sample	O
t	O
-	O
tests	O
on	O
scores	O
of	O
psychological	O
tests	O
.	O

The	O
statistical	O
procedure	O
,	O
which	O
was	O
carried	O
out	O
by	O
a	O
SPSS	O
package	O
program	O
for	O
Windows	O
using	O
Chi	O
-	O
square	O
,	O
Fisher	O
'	O
s	O
exact	O
test	O
,	O
two	O
tailed	O
t	O
test	O
and	O
Pearson	O
correlation	O
coefficients	O
,	O
was	O
also	O
used	O
to	O
determine	O
group	O
differences	O
(	O
alexithymics	O
versus	O
nonalexithymics	O
)	O
in	O
sociodemographic	O
variables	O
and	O
various	O
aspects	O
of	O
pain	O
.	O

Results	O

In	O
the	O
chronic	O
pain	O
group	O
,	O
56	O
.	O
7	O
%	O
of	O
patients	B
(	O
n	O
=	O
17	O
)	O
had	O
a	O
score	O
greater	O
than	O
11	O
on	O
the	O
TAS	O
-	O
26	O
,	O
and	O
were	O
considered	O
alexithymic	O
.	O

The	O
mean	O
TAS	O
-	O
26	O
score	O
of	O
the	O
alexithymic	O
group	O
(	O
n	O
=	O
17	O
)	O
was	O
17	O
.	O
88	O
+	O
/	O
-	O
3	O
.	O
43	O
and	O
the	O
nonalexithymic	O
group	O
(	O
n	O
=	O
13	O
)	O
was	O
8	O
.	O
39	O
+	O
/	O
-	O
2	O
.	O
02	O
.	O

Age	O
(	O
t	O
=	O
1	O
,	O
38	O
,	O
df	O
=	O
28	O
,	O
p	O
>	O
0	O
,	O
18	O
)	O
,	O
education	O
(	O
t	O
=	O
-	O
0	O
,	O
21	O
,	O
df	O
=	O
28	O
,	O
p	O
>	O
0	O
,	O
16	O
)	O
and	O
marital	O
status	O
(	O
x2	O
=	O
0	O
,	O
27	O
,	O
df	O
=	O
1	O
,	O
p	O
>	O
0	O
,	O
87	O
)	O
were	O
not	O
associated	O
with	O
alexithymia	O
(	O
Table	O
1	O
)	O
.	O

In	O
the	O
control	O
group	O
,	O
24	O
,	O
3	O
%	O
of	O
patients	B
(	O
n	O
=	O
9	O
)	O
were	O
alexithymic	O
according	O
to	O
TAS	O
-	O
26	O
.	O

The	O
mean	O
TAS	O
-	O
26	O
score	O
of	O
the	O
alexithymic	O
group	O
(	O
n	O
=	O
9	O
)	O
was	O
13	O
,	O
82	O
+	O
/	O
-	O
1	O
,	O
93	O
and	O
the	O
nonalexithymic	O
group	O
(	O
n	O
=	O
28	O
)	O
was	O
10	O
,	O
33	O
+	O
/	O
-	O
0	O
,	O
86	O
.	O

Alexithymia	O
was	O
not	O
associated	O
with	O
age	O
(	O
t	O
=	O
-	O
1	O
,	O
08	O
,	O
df	O
=	O
35	O
,	O
p	O
>	O
0	O
,	O
29	O
)	O
,	O
educational	O
level	O
(	O
t	O
=	O
1	O
,	O
1	O
,	O
df	O
=	O
35	O
,	O
p	O
>	O
0	O
,	O
28	O
)	O
,	O
or	O
marital	O
status	O
(	O
x2	O
=	O
0	O
,	O
74	O
,	O
df	O
=	O
1	O
,	O
p	O
>	O
0	O
,	O
79	O
)	O
or	O
anxiety	O
levels	O
in	O
the	O
control	O
subjects	O
(	O
Table	O
1	O
)	O
.	O

The	O
duration	O
and	O
severity	O
of	O
pain	O
,	O
TAS	O
-	O
26	O
scores	O
,	O
and	O
STAI	O
scores	O
of	O
the	O
female	O
pain	O
patients	B
are	O
shown	O
in	O
Table	O
2	O
.	O

Comparison	O
of	O
the	O
alexithymics	O
with	O
nonalexithymics	O
on	O
either	O
the	O
severity	O
of	O
pain	O
or	O
pain	O
duration	O
showed	O
no	O
statistical	O
significance	O
(	O
t	O
=	O
0	O
,	O
64	O
,	O
df	O
=	O
28	O
,	O
p	O
>	O
0	O
,	O
52	O
,	O
t	O
=	O
2	O
,	O
05	O
,	O
df	O
=	O
28	O
,	O
p	O
>	O
0	O
,	O
05	O
,	O
respectively	O
)	O
.	O

TAS	O
-	O
26	O
score	O
and	O
duration	O
of	O
pain	O
were	O
found	O
positively	O
correlated	O
(	O
r	O
=	O
0	O
,	O
50	O
,	O
n	O
=	O
30	O
,	O
p	O
>	O
0	O
,	O
005	O
)	O
.	O

STAI	O
(	O
trait	O
)	O
scores	O
of	O
the	O
alexithymics	O
in	O
the	O
pain	O
group	O
did	O
not	O
significantly	O
differ	O
from	O
the	O
nonlalexithymics	O
(	O
t	O
=	O
0	O
,	O
06	O
,	O
df	O
=	O
28	O
,	O
p	O
>	O
0	O
,	O
95	O
)	O
and	O
besides	O
,	O
TAS	O
-	O
26	O
and	O
STAI	O
scores	O
were	O
not	O
correlated	O
(	O
r	O
=	O
0	O
,	O
06	O
,	O
p	O
>	O
0	O
,	O
72	O
)	O
.	O

In	O
summary	O
,	O
there	O
are	O
three	O
points	O
to	O
be	O
emphasized	O
.	O

First	O
,	O
chronic	O
pain	O
patients	B
were	O
found	O
significantly	O
more	O
alexithymic	O
than	O
controls	O
(	O
56	O
,	O
7	O
%	O
to	O
24	O
,	O
3	O
%	O
)	O
.	O

Second	O
,	O
a	O
positive	O
correlation	O
was	O
observed	O
between	O
TAS	O
-	O
26	O
scores	O
and	O
duration	O
of	O
pain	O
.	O

Third	O
,	O
neither	O
positive	O
correlation	O
nor	O
significant	O
difference	O
was	O
found	O
between	O
alexithymia	O
and	O
trait	O
anxiety	O
in	O
pain	O
patients	B
.	O

Discussion	O

The	O
results	O
of	O
the	O
present	O
study	O
suggest	O
that	O
patients	B
with	O
chronic	O
pain	O
disorder	O
are	O
more	O
alexithymic	O
than	O
individuals	O
with	O
no	O
pain	O
.	O

This	O
finding	O
is	O
consistent	O
with	O
results	O
obtained	O
with	O
earlier	O
measures	O
of	O
alexithymia	O
[	O
11	O
-	O
13	O
]	O
.	O

Although	O
they	O
may	O
share	O
common	O
clinical	O
features	O
,	O
alexithymia	O
and	O
somatoform	O
pain	O
are	O
independent	O
constructs	O
.	O

Alexithymia	O
may	O
be	O
a	O
consequence	O
to	O
the	O
effects	O
of	O
severe	O
physical	O
symptoms	O
,	O
such	O
as	O
a	O
reduced	O
quality	O
of	O
life	O
and	O
limitations	O
in	O
daily	O
activities	O
.	O

Besides	O
,	O
alexithymia	O
may	O
be	O
conceptualized	O
as	O
a	O
personality	O
trait	O
as	O
well	O
as	O
a	O
secondary	O
state	O
reaction	O
[	O
2	O
,	O
3	O
,	O
15	O
-	O
17	O
]	O
.	O

In	O
this	O
study	O
,	O
the	O
question	O
investigated	O
was	O
whether	O
alexithymia	O
has	O
any	O
correlation	O
with	O
the	O
duration	O
or	O
severity	O
of	O
the	O
pain	O
itself	O
.	O

There	O
were	O
no	O
significant	O
differences	O
between	O
alexithymic	O
and	O
nonalexitymic	O
patients	B
on	O
self	O
reports	O
of	O
current	O
pain	O
severity	O
.	O

This	O
is	O
in	O
accordance	O
with	O
Cox	O
'	O
s	O
study	O
[	O
1994	O
]	O
in	O
which	O
it	O
was	O
further	O
pointed	O
out	O
that	O
alexithymic	O
patients	B
were	O
found	O
to	O
use	O
significantly	O
more	O
verbal	O
descriptors	O
of	O
pain	O
compared	O
to	O
nonalexithymic	O
patients	B
[	O
13	O
]	O
.	O

In	O
our	O
study	O
,	O
pain	O
intensity	O
was	O
only	O
evaluated	O
by	O
using	O
VAS	O
.	O

One	O
problem	O
in	O
trying	O
to	O
measure	O
the	O
intensity	O
of	O
pain	O
is	O
the	O
lack	O
of	O
an	O
objective	O
way	O
.	O

Pain	O
is	O
a	O
subjective	O
experience	O
and	O
each	O
patient	B
may	O
communicate	O
in	O
a	O
different	O
way	O
,	O
verbally	O
or	O
nonverbally	O
[	O
29	O
]	O
.	O

Patients	B
in	O
this	O
sample	O
were	O
sufferers	O
of	O
chronic	O
pain	O
,	O
who	O
had	O
already	O
chosen	O
an	O
approved	O
way	O
of	O
expressing	O
their	O
distress	O
.	O

Since	O
this	O
is	O
true	O
regardless	O
of	O
alexithymia	O
,	O
alexithymic	O
groups	O
and	O
nonalexithymic	O
groups	O
in	O
this	O
sample	O
showed	O
no	O
difference	O
on	O
pain	O
severity	O
.	O

The	O
positive	O
correlation	O
between	O
alexithymia	O
and	O
the	O
duration	O
of	O
pain	O
in	O
this	O
sample	O
supports	O
the	O
assumption	O
of	O
a	O
two	O
-	O
way	O
hypothesis	O
.	O

It	O
is	O
often	O
assumed	O
that	O
pain	O
can	O
be	O
caused	O
by	O
alexithymic	O
personality	O
traits	O
and	O
also	O
that	O
severe	O
and	O
chronic	O
pain	O
may	O
cause	O
emotional	O
change	O
.	O

One	O
of	O
the	O
limitations	O
of	O
this	O
study	O
is	O
that	O
because	O
of	O
the	O
cross	O
-	O
sectional	O
design	O
,	O
we	O
are	O
unable	O
to	O
draw	O
conclusions	O
about	O
the	O
direction	O
of	O
causality	O
between	O
alexithymia	O
and	O
pain	O
.	O

The	O
duration	O
of	O
the	O
patients	B
'	O
pain	O
could	O
approximately	O
be	O
determined	O
,	O
yet	O
the	O
preexisting	O
level	O
of	O
alexithymia	O
was	O
not	O
known	O
.	O

In	O
the	O
usual	O
absence	O
of	O
internal	O
stimuli	O
,	O
alexithymic	O
person	B
may	O
be	O
expected	O
to	O
maintain	O
an	O
external	O
focus	O
of	O
attention	O
,	O
such	O
as	O
pain	O
.	O

Symptom	O
chronicity	O
may	O
force	O
the	O
alexithymic	O
person	B
to	O
attent	O
to	O
and	O
amplify	O
this	O
somatic	O
sensation	O
.	O

Difficulties	O
in	O
the	O
ability	O
to	O
identify	O
and	O
differentiate	O
emotions	O
and	O
somatic	O
experiences	O
are	O
core	O
features	O
of	O
the	O
alexithymic	O
construct	O
.	O

Therefore	O
,	O
alexithymic	O
patients	B
might	O
be	O
expected	O
to	O
differ	O
from	O
nonalexithymic	O
ones	O
in	O
their	O
anxiety	O
levels	O
.	O

Yet	O
,	O
in	O
our	O
pain	O
group	O
alexithymic	O
patients	B
showed	O
no	O
significant	O
difference	O
from	O
the	O
nonalexithymics	O
on	O
trait	O
anxiety	O
.	O

Besides	O
,	O
alexithymia	O
and	O
anxiety	O
were	O
not	O
correlated	O
at	O
all	O
.	O

The	O
reasons	O
may	O
be	O
lying	O
in	O
the	O
specific	O
characteristics	O
of	O
this	O
patient	B
group	O
itself	O
.	O

The	O
study	O
included	O
patients	B
suffering	O
from	O
chronic	O
symptoms	O
;	O
with	O
an	O
average	O
of	O
7	O
,	O
44	O
+	O
/	O
-	O
6	O
,	O
82	O
years	O
of	O
pain	O
in	O
the	O
alexithymic	O
and	O
3	O
,	O
31	O
+	O
/	O
-	O
2	O
,	O
79	O
years	O
in	O
the	O
nonalexithymic	O
groups	O
.	O

Persistency	O
of	O
any	O
physical	O
symptom	O
may	O
bring	O
along	O
alexithymia	O
as	O
a	O
coping	O
strategy	O
.	O

In	O
their	O
paper	O
,	O
Crook	O
and	O
Tunks	O
(	O
1988	O
)	O
examined	O
the	O
types	O
of	O
coping	O
strategies	O
used	O
by	O
persistent	O
pain	O
sufferers	O
and	O
addressed	O
to	O
the	O
importance	O
to	O
alter	O
their	O
attitudes	O
and	O
behavior	O
that	O
tend	O
toward	O
catastrophizing	O
,	O
avoidance	O
and	O
withdrawal	O
,	O
rather	O
than	O
simply	O
concentrate	O
on	O
trying	O
to	O
teach	O
them	O
techniques	O
for	O
'	O
coping	O
with	O
stress	O
'	O
to	O
help	O
persistent	O
pain	O
sufferers	O
[	O
30	O
]	O
.	O

Sufferers	O
of	O
chronic	O
symptoms	O
in	O
this	O
sample	O
were	O
members	O
of	O
a	O
subgroup	O
who	O
have	O
been	O
seeking	O
medical	O
care	O
for	O
a	O
long	O
time	O
and	O
besides	O
given	O
the	O
chance	O
of	O
being	O
referred	O
to	O
a	O
psychiatrist	O
.	O

Therefore	O
,	O
alexithymic	O
or	O
not	O
,	O
their	O
anxiety	O
might	O
have	O
induced	O
unique	O
coping	O
strategies	O
and	O
illness	O
behavior	O
.	O

Alexithymia	O
may	O
be	O
important	O
in	O
addressing	O
the	O
diversity	O
of	O
subjective	O
factors	O
involved	O
in	O
pain	O
[	O
31	O
]	O
.	O

It	O
is	O
not	O
known	O
whether	O
it	O
should	O
be	O
addressed	O
in	O
the	O
treatment	O
of	O
pain	O
patients	B
,	O
but	O
a	O
high	O
level	O
of	O
alexithymia	O
may	O
effect	O
the	O
nature	O
of	O
assessment	O
.	O

In	O
summary	O
,	O
the	O
conceptualization	O
of	O
alexithymia	O
as	O
a	O
personality	O
trait	O
as	O
well	O
as	O
a	O
secondary	O
state	O
reaction	O
is	O
underlined	O
by	O
our	O
data	O
.	O

However	O
,	O
regarding	O
the	O
cross	O
-	O
sectional	O
design	O
of	O
this	O
study	O
,	O
only	O
limited	O
conclusions	O
can	O
be	O
drawn	O
about	O
the	O
nature	O
of	O
the	O
causal	O
relationship	O
between	O
alexithymia	O
and	O
chronic	O
pain	O
.	O

Therefore	O
,	O
future	O
longitudinal	O
studies	O
assessing	O
the	O
cause	O
of	O
alexithymic	O
characteristics	O
are	O
required	O
to	O
fully	O
elucidate	O
the	O
concepts	O
of	O
primary	O
and	O
secondary	O
alexithymia	O
.	O

Molecular	O
polymorphism	O
,	O
differentiation	O
and	O
introgression	O
in	O
the	O
period	O
gene	O
between	O
Lutzomyia	B
intermedia	I
and	O
Lutzomyia	B
whitmani	I

Abstract	O

Background	O

Lutzomyia	B
intermedia	I
and	O
Lutzomyia	B
whitmani	I
(	O
Diptera	O
:	O
Psychodidae	O
)	O
are	O
important	O
and	O
very	O
closely	O
related	O
vector	O
species	O
of	O
cutaneous	O
leishmaniasis	O
in	O
Brazil	O
,	O
which	O
are	O
distinguishable	O
by	O
a	O
few	O
morphological	O
differences	O
.	O

There	O
is	O
evidence	O
of	O
mitochondrial	O
introgression	O
between	O
the	O
two	O
species	O
but	O
it	O
is	O
not	O
clear	O
whether	O
gene	O
flow	O
also	O
occurs	O
in	O
nuclear	O
genes	O
.	O

Results	O

We	O
analyzed	O
the	O
molecular	O
variation	O
within	O
the	O
clock	O
gene	O
period	O
(	O
per	O
)	O
of	O
these	O
two	O
species	O
in	O
five	O
different	O
localities	O
in	O
Eastern	O
Brazil	O
.	O

AMOVA	O
and	O
Fst	O
estimates	O
showed	O
no	O
evidence	O
for	O
geographical	O
differentiation	O
within	O
species	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
values	O
were	O
highly	O
significant	O
for	O
both	O
analyses	O
between	O
species	O
.	O

The	O
two	O
species	O
show	O
no	O
fixed	O
differences	O
and	O
a	O
higher	O
number	O
of	O
shared	O
polymorphisms	O
compared	O
to	O
exclusive	O
mutations	O
.	O

In	O
addition	O
,	O
some	O
haplotypes	O
that	O
are	O
"	O
typical	O
"	O
of	O
one	O
species	O
were	O
found	O
in	O
some	O
individuals	O
of	O
the	O
other	O
species	O
suggesting	O
either	O
the	O
persistence	O
of	O
old	O
polymorphisms	O
or	O
the	O
occurrence	O
of	O
introgression	O
.	O

Two	O
tests	O
of	O
gene	O
flow	O
,	O
one	O
based	O
on	O
linkage	O
disequilibrium	O
and	O
a	O
MCMC	O
analysis	O
based	O
on	O
coalescence	O
,	O
suggest	O
that	O
the	O
two	O
species	O
might	O
be	O
exchanging	O
alleles	O
at	O
the	O
per	O
locus	O
.	O

Conclusion	O

Introgression	O
might	O
be	O
occurring	O
between	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
in	O
period	O
,	O
a	O
gene	O
controlling	O
behavioral	O
rhythms	O
in	O
Drosophila	O
.	O

This	O
result	O
raises	O
the	O
question	O
of	O
whether	O
similar	O
phenomena	O
are	O
occurring	O
at	O
other	O
loci	O
controlling	O
important	O
aspects	O
of	O
behavior	O
and	O
vectorial	O
capacity	O
.	O

Background	O

The	O
Phlebotominae	O
sand	O
flies	O
Lutzomyia	B
intermedia	I
Lutz	O
&	O
Neiva	O
1912	O
and	O
Lutzomyia	B
whitmani	I
Antunes	O
&	O
Coutinho	O
1912	O
are	O
vectors	O
of	O
cutaneous	O
leishmaniasis	O
in	O
Brazil	O
.	O

These	O
are	O
closely	O
related	O
species	O
that	O
can	O
be	O
only	O
distinguished	O
by	O
a	O
few	O
morphological	O
differences	O
[	O
1	O
]	O
and	O
both	O
show	O
high	O
anthropophily	O
and	O
reported	O
natural	O
infections	O
with	O
Leishmania	O
in	O
different	O
regions	O
of	O
Brazil	O
[	O
2	O
]	O
.	O

Despite	O
their	O
importance	O
as	O
vectors	O
,	O
only	O
a	O
handful	O
of	O
studies	O
have	O
been	O
carried	O
out	O
in	O
these	O
two	O
species	O
using	O
molecular	O
techniques	O
[	O
3	O
-	O
6	O
]	O
.	O

One	O
of	O
the	O
most	O
important	O
findings	O
from	O
an	O
epidemiological	O
perspective	O
is	O
the	O
evidence	O
obtained	O
for	O
introgression	O
between	O
the	O
two	O
species	O
using	O
mitochondrial	O
DNA	O
[	O
4	O
]	O
.	O

This	O
was	O
particularly	O
interesting	O
because	O
apparently	O
,	O
only	O
lineages	O
of	O
L	B
.	I
whitmani	I
sympatric	O
with	O
L	B
.	I
intermedia	I
have	O
been	O
involved	O
in	O
cutaneous	O
leishmaniasis	O
transmission	O
in	O
the	O
peridomestic	O
environment	O
[	O
4	O
]	O
,	O
which	O
suggests	O
that	O
genes	O
controlling	O
aspects	O
of	O
vectorial	O
capacity	O
could	O
be	O
passing	O
from	O
one	O
species	O
to	O
the	O
other	O
.	O

In	O
fact	O
,	O
mitochondrial	O
introgression	O
has	O
been	O
reported	O
in	O
other	O
sand	O
fly	O
species	O
[	O
7	O
,	O
8	O
]	O
suggesting	O
that	O
might	O
be	O
a	O
common	O
phenomenon	O
in	O
these	O
insect	O
vectors	O
.	O

However	O
,	O
because	O
mitochondrial	O
genes	O
can	O
introgress	O
relatively	O
easily	O
between	O
closely	O
related	O
species	O
[	O
9	O
]	O
,	O
it	O
becomes	O
important	O
to	O
examine	O
whether	O
introgression	O
can	O
occur	O
with	O
nuclear	O
genes	O
.	O

The	O
Drosophila	O
period	O
(	O
per	O
)	O
gene	O
homologue	O
was	O
isolated	O
in	O
sand	O
flies	O
by	O
Peixoto	O
et	O
al	O
.	O

[	O
10	O
]	O
.	O

This	O
circadian	O
clock	O
gene	O
was	O
originally	O
identified	O
using	O
mutagenesis	O
by	O
Konopka	O
and	O
Benzer	O
[	O
11	O
]	O
,	O
but	O
is	O
also	O
known	O
to	O
control	O
the	O
differences	O
in	O
the	O
"	O
lovesong	O
"	O
rhythms	O
between	O
D	B
.	I
melanogaster	I
and	O
D	B
.	I
simulans	I
[	O
12	O
]	O
,	O
that	O
are	O
important	O
to	O
the	O
sexual	O
isolation	O
between	O
these	O
two	O
species	O
[	O
13	O
-	O
15	O
]	O
.	O

In	O
addition	O
,	O
per	O
was	O
implicated	O
in	O
the	O
control	O
of	O
species	O
-	O
specific	O
circadian	O
mating	O
rhythms	O
in	O
Drosophila	O
and	O
Bractocera	O
,	O
which	O
might	O
also	O
constitute	O
a	O
reproductive	O
isolation	O
mechanism	O
[	O
16	O
-	O
18	O
]	O
.	O

Thus	O
per	O
may	O
possibly	O
represent	O
an	O
example	O
of	O
a	O
Drosophila	O
speciation	O
gene	O
[	O
19	O
]	O
,	O
and	O
in	O
fact	O
it	O
has	O
been	O
used	O
as	O
a	O
molecular	O
marker	O
in	O
a	O
number	O
of	O
speciation	O
and	O
evolutionary	O
studies	O
,	O
not	O
only	O
in	O
Drosophila	O
(	O
reviewed	O
in	O
[	O
20	O
]	O
)	O
but	O
also	O
in	O
other	O
insects	O
(	O
e	O
.	O
g	O
.	O
[	O
21	O
]	O
)	O
including	O
sand	O
flies	O
[	O
22	O
-	O
24	O
]	O
.	O

Because	O
per	O
controls	O
the	O
circadian	O
clock	O
in	O
different	O
insects	O
[	O
25	O
]	O
,	O
it	O
is	O
almost	O
certainly	O
involved	O
in	O
the	O
rhythms	O
of	O
activity	O
and	O
biting	O
of	O
sand	O
flies	O
[	O
26	O
]	O
,	O
which	O
are	O
very	O
important	O
to	O
leishmaniasis	O
transmission	O
.	O

In	O
addition	O
,	O
per	O
might	O
be	O
involved	O
in	O
reproductive	O
isolation	O
in	O
sand	O
flies	O
,	O
via	O
mating	O
rhythms	O
,	O
or	O
via	O
their	O
"	O
lovesongs	O
"	O
[	O
2	O
,	O
27	O
]	O
.	O
per	O
is	O
thus	O
a	O
particularly	O
interesting	O
marker	O
,	O
among	O
the	O
few	O
available	O
,	O
for	O
an	O
introgression	O
analysis	O
in	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
.	O

Evidence	O
for	O
introgression	O
in	O
per	O
might	O
suggest	O
that	O
gene	O
flow	O
between	O
these	O
two	O
vector	O
species	O
is	O
occurring	O
at	O
other	O
genes	O
controlling	O
important	O
aspects	O
of	O
behavior	O
and	O
vectorial	O
capacity	O
.	O

It	O
might	O
also	O
suggest	O
that	O
per	O
does	O
not	O
have	O
a	O
strong	O
role	O
in	O
their	O
reproductive	O
isolation	O
.	O

In	O
the	O
current	O
study	O
,	O
we	O
analyzed	O
the	O
molecular	O
variation	O
within	O
the	O
per	O
gene	O
of	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
in	O
five	O
different	O
localities	O
in	O
Eastern	O
Brazil	O
.	O

Results	O

Polymorphism	O
and	O
divergence	O
between	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I

A	O
total	O
of	O
68	O
sequences	O
from	O
L	B
.	I
intermedia	I
and	O
53	O
from	O
L	B
.	I
whitmani	I
homologue	O
to	O
a	O
fragment	O
of	O
the	O
period	O
gene	O
were	O
analyzed	O
from	O
populations	O
of	O
five	O
localities	O
in	O
Eastern	O
Brazil	O
(	O
Fig	O
1	O
)	O
.	O

The	O
alignment	O
of	O
72	O
variable	O
sites	O
is	O
shown	O
in	O
Fig	O
2	O
.	O

Although	O
most	O
of	O
the	O
changes	O
are	O
either	O
synonymous	O
or	O
occur	O
within	O
the	O
58	O
bp	O
intron	O
,	O
non	O
-	O
synonymous	O
substitutions	O
are	O
observed	O
causing	O
9	O
amino	O
acid	O
differences	O
among	O
the	O
sequences	O
(	O
Fig	O
2	O
)	O
.	O

Table	O
1	O
shows	O
the	O
number	O
of	O
sequences	O
of	O
each	O
population	O
of	O
the	O
two	O
species	O
,	O
the	O
number	O
of	O
polymorphic	O
sites	O
(	O
S	O
)	O
and	O
the	O
estimates	O
of	O
molecular	O
polymorphism	O
theta	O
(	O
based	O
on	O
the	O
total	O
number	O
of	O
mutations	O
)	O
and	O
pi	O
.	O

Table	O
1	O
also	O
shows	O
the	O
Tajima	O
'	O
s	O
[	O
28	O
]	O
and	O
Fu	O
&	O
Li	O
'	O
s	O
[	O
29	O
]	O
statistics	O
.	O

Within	O
each	O
species	O
,	O
all	O
populations	O
present	O
similar	O
levels	O
of	O
polymorphism	O
with	O
the	O
exception	O
of	O
L	B
.	I
whitmani	I
from	O
Ilh	O
e	O
us	O
,	O
which	O
seems	O
to	O
be	O
less	O
polymorphic	O
than	O
the	O
others	O
.	O

This	O
population	O
was	O
also	O
the	O
only	O
one	O
presenting	O
a	O
significant	O
value	O
in	O
the	O
Fu	O
&	O
Li	O
test	O
but	O
only	O
at	O
the	O
5	O
%	O
level	O
.	O

Finally	O
,	O
the	O
last	O
column	O
of	O
Table	O
1	O
presents	O
the	O
recombination	O
estimator	O
gamma	O
[	O
30	O
]	O
indicating	O
that	O
both	O
species	O
show	O
evidence	O
of	O
intragenic	O
recombination	O
in	O
the	O
per	O
gene	O
.	O

To	O
investigate	O
the	O
level	O
of	O
intra	O
and	O
interspecific	O
differences	O
,	O
initially	O
an	O
AMOVA	O
was	O
carried	O
out	O
as	O
shown	O
in	O
Table	O
2	O
.	O

The	O
results	O
show	O
a	O
non	O
-	O
significant	O
within	O
species	O
and	O
a	O
significant	O
between	O
species	O
molecular	O
variation	O
at	O
the	O
per	O
locus	O
.	O

Table	O
3	O
shows	O
a	O
more	O
detailed	O
analysis	O
of	O
the	O
intraspecific	O
differentiation	O
among	O
populations	O
of	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
.	O

None	O
of	O
the	O
pairwise	O
and	O
overall	O
fixation	O
indexes	O
(	O
Fst	O
)	O
are	O
significant	O
in	O
the	O
case	O
of	O
L	B
.	I
intermedia	I
and	O
only	O
one	O
(	O
Posse	O
x	O
Ilh	O
e	O
us	O
)	O
has	O
a	O
borderline	O
significant	O
value	O
in	O
L	B
.	I
whitmani	I
.	O

The	O
results	O
therefore	O
show	O
that	O
no	O
significant	O
geographical	O
heterogeneity	O
was	O
detected	O
among	O
the	O
populations	O
of	O
the	O
two	O
species	O
.	O

The	O
estimated	O
number	O
of	O
migrants	O
per	O
generation	O
,	O
based	O
on	O
the	O
overall	O
Fst	O
values	O
,	O
is	O
20	O
.	O
683	O
for	O
L	B
.	I
intermedia	I
and	O
23	O
.	O
125	O
for	O
L	B
.	I
whitmani	I
.	O

Table	O
4	O
shows	O
measures	O
for	O
DNA	O
divergence	O
between	O
species	O
(	O
Dxy	O
and	O
Da	O
)	O
,	O
as	O
well	O
as	O
the	O
Fst	O
and	O
Nm	O
values	O
considering	O
each	O
species	O
as	O
a	O
unique	O
population	O
.	O

Dxy	O
is	O
the	O
average	O
number	O
of	O
nucleotide	O
substitutions	O
per	O
site	O
between	O
alleles	O
from	O
two	O
different	O
populations	O
and	O
Da	O
is	O
the	O
number	O
of	O
net	O
nucleotide	O
substitutions	O
between	O
two	O
populations	O
.	O

Table	O
4	O
also	O
shows	O
the	O
number	O
of	O
polymorphisms	O
exclusive	O
for	O
each	O
species	O
(	O
Sint	O
and	O
Swhit	O
)	O
,	O
the	O
number	O
of	O
shared	O
polymorphisms	O
(	O
Ss	O
)	O
and	O
the	O
number	O
of	O
fixed	O
differences	O
(	O
Sf	O
)	O
between	O
species	O
.	O

As	O
one	O
can	O
note	O
,	O
there	O
is	O
a	O
high	O
number	O
of	O
shared	O
polymorphisms	O
between	O
species	O
,	O
and	O
no	O
fixed	O
differences	O
between	O
them	O
suggesting	O
either	O
the	O
persistence	O
of	O
ancestral	O
polymorphisms	O
or	O
the	O
occurrence	O
of	O
introgression	O
.	O

In	O
fact	O
,	O
there	O
is	O
one	O
shared	O
haplotype	O
between	O
the	O
two	O
species	O
(	O
IPO13	O
,	O
WPO10	O
and	O
WPO19	O
)	O
and	O
three	O
L	B
.	I
whitmani	I
sequences	O
(	O
WAC02	O
,	O
WPO13	O
and	O
WPO14	O
)	O
which	O
show	O
only	O
one	O
nucleotide	O
difference	O
to	O
"	O
typical	O
"	O
L	B
.	I
intermedia	I
haplotypes	O
(	O
see	O
also	O
below	O
)	O
.	O

Genealogy	O
of	O
period	O
sequences	O

A	O
phylogenetic	O
analysis	O
of	O
the	O
period	O
gene	O
sequences	O
from	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
was	O
carried	O
out	O
with	O
the	O
Minimum	O
Evolution	O
method	O
using	O
the	O
Kimura	O
2	O
-	O
parameter	O
distance	O
(	O
Fig	O
3	O
)	O
.	O

A	O
sequence	O
from	O
L	B
.	I
umbratilis	I
,	O
a	O
related	O
species	O
from	O
the	O
same	O
subgenus	O
Nyssomyia	O
,	O
was	O
used	O
as	O
outgroup	O
[	O
24	O
]	O
.	O

The	O
tree	O
shows	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
as	O
non	O
-	O
monophyletic	O
.	O

However	O
,	O
despite	O
the	O
low	O
bootstrap	O
values	O
,	O
which	O
are	O
below	O
50	O
%	O
in	O
most	O
cases	O
,	O
there	O
is	O
a	O
large	O
group	O
that	O
contains	O
most	O
L	B
.	I
intermedia	I
sequences	O
and	O
a	O
second	O
large	O
group	O
with	O
most	O
L	B
.	I
whitmani	I
sequences	O
.	O

A	O
few	O
other	O
sequences	O
are	O
clustered	O
outside	O
these	O
two	O
main	O
groups	O
.	O

It	O
is	O
interesting	O
to	O
note	O
that	O
there	O
are	O
three	O
L	B
.	I
whitmani	I
alleles	O
(	O
WAC2	O
,	O
WPO13	O
and	O
WPO14	O
)	O
inside	O
L	B
.	I
intermedia	I
main	O
group	O
,	O
as	O
well	O
as	O
one	O
L	B
.	I
intermedia	I
allele	O
(	O
ICP16	O
)	O
inside	O
the	O
L	B
.	I
whitmani	I
main	O
group	O
.	O

In	O
addition	O
,	O
a	O
second	O
L	B
.	I
intermedia	I
allele	O
(	O
IPO13	O
)	O
is	O
a	O
shared	O
haplotype	O
between	O
the	O
two	O
species	O
as	O
mentioned	O
above	O
.	O

Again	O
,	O
the	O
results	O
suggest	O
either	O
the	O
persistence	O
of	O
ancestral	O
polymorphisms	O
or	O
the	O
occurrence	O
of	O
introgression	O
between	O
the	O
two	O
species	O
.	O

Very	O
similar	O
results	O
were	O
obtained	O
using	O
the	O
maximum	O
likelihood	O
algorithm	O
as	O
implemented	O
in	O
PAUP	O
4	O
.	O
0b10	O
software	O
[	O
31	O
]	O
(	O
data	O
not	O
shown	O
)	O
.	O

As	O
mentioned	O
before	O
,	O
there	O
is	O
evidence	O
of	O
intragenic	O
recombination	O
in	O
the	O
per	O
gene	O
fragment	O
of	O
both	O
species	O
(	O
see	O
Table	O
1	O
)	O
and	O
for	O
that	O
reason	O
the	O
bifurcating	O
tree	O
shown	O
in	O
Fig	O
3	O
has	O
to	O
be	O
viewed	O
with	O
caution	O
,	O
as	O
different	O
regions	O
of	O
the	O
gene	O
might	O
have	O
different	O
phylogenetic	O
histories	O
[	O
32	O
]	O
.	O

Therefore	O
,	O
we	O
constructed	O
Minimum	O
Evolution	O
trees	O
with	O
the	O
two	O
most	O
polymorphic	O
non	O
-	O
recombining	O
blocks	O
of	O
the	O
per	O
gene	O
fragment	O
identified	O
using	O
the	O
Hudson	O
and	O
Kaplan	O
[	O
33	O
]	O
method	O
available	O
in	O
the	O
DNAsp	O
4	O
.	O
1	O
program	O
[	O
34	O
]	O
.	O

We	O
did	O
not	O
observed	O
major	O
changes	O
in	O
the	O
genealogy	O
of	O
the	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
per	O
sequences	O
,	O
especially	O
regarding	O
the	O
five	O
haplotypes	O
(	O
ICP16	O
,	O
IPO13	O
,	O
WAC2	O
,	O
WPO13	O
and	O
WPO14	O
)	O
that	O
clearly	O
cluster	O
with	O
sequences	O
of	O
the	O
other	O
species	O
(	O
data	O
not	O
shown	O
)	O
.	O

Finally	O
,	O
a	O
haplotype	O
network	O
was	O
estimated	O
from	O
per	O
sequences	O
using	O
statistical	O
parsimony	O
,	O
as	O
described	O
by	O
Templeton	O
et	O
al	O
.	O

[	O
35	O
]	O
and	O
implemented	O
in	O
the	O
TCS1	O
.	O
21	O
software	O
[	O
36	O
]	O
(	O
Fig	O
4	O
)	O
.	O

A	O
small	O
number	O
of	O
ambiguities	O
were	O
resolved	O
as	O
suggested	O
by	O
Crandall	O
and	O
Templeton	O
[	O
37	O
]	O
.	O

The	O
haplotype	O
network	O
shows	O
connections	O
between	O
sequences	O
from	O
each	O
species	O
,	O
separating	O
most	O
of	O
the	O
sequences	O
of	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
in	O
two	O
groups	O
.	O

No	O
intraspecific	O
geographical	O
structuring	O
was	O
found	O
.	O

Once	O
again	O
,	O
some	O
of	O
the	O
L	B
.	I
whitmani	I
sequences	O
(	O
WAC2	O
,	O
WAC10	O
,	O
WPO13	O
and	O
WPO14	O
)	O
appear	O
more	O
closely	O
related	O
to	O
L	B
.	I
intermedia	I
haplotypes	O
.	O

In	O
addition	O
,	O
one	O
L	B
.	I
intermedia	I
allele	O
(	O
ICP16	O
)	O
is	O
connected	O
by	O
a	O
small	O
number	O
of	O
mutations	O
to	O
some	O
of	O
the	O
main	O
L	B
.	I
whitmani	I
haplotypes	O
and	O
IPO13	O
is	O
a	O
shared	O
haplotype	O
between	O
the	O
two	O
species	O
.	O

These	O
results	O
confirm	O
the	O
same	O
putative	O
introgressed	O
sequences	O
indicated	O
by	O
the	O
phylogenetic	O
reconstructions	O
.	O

LD	O
test	O
of	O
introgression	O

We	O
tested	O
the	O
hypothesis	O
of	O
gene	O
flow	O
between	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
using	O
a	O
method	O
based	O
on	O
linkage	O
disequilibrium	O
(	O
LD	O
)	O
developed	O
by	O
Machado	O
et	O
al	O
.	O

[	O
38	O
]	O
.	O

In	O
this	O
test	O
,	O
x	O
is	O
the	O
difference	O
between	O
the	O
average	O
LD	O
found	O
among	O
all	O
pairs	O
of	O
shared	O
polymorphisms	O
(	O
DSS	O
)	O
between	O
the	O
two	O
species	O
and	O
the	O
average	O
LD	O
among	O
all	O
pairs	O
of	O
sites	O
for	O
which	O
one	O
member	O
is	O
a	O
shared	O
polymorphism	O
and	O
the	O
other	O
is	O
an	O
exclusive	O
polymorphism	O
(	O
DSX	O
)	O
.	O

In	O
case	O
of	O
gene	O
flow	O
x	O
should	O
tend	O
to	O
be	O
positive	O
[	O
see	O
[	O
38	O
]	O
for	O
more	O
details	O
]	O
.	O

Because	O
of	O
limitations	O
on	O
the	O
total	O
number	O
of	O
sequences	O
that	O
could	O
be	O
handled	O
by	O
the	O
WH	O
program	O
we	O
could	O
not	O
perform	O
the	O
simulations	O
with	O
all	O
sequences	O
.	O

Therefore	O
,	O
we	O
carried	O
out	O
the	O
LD	O
test	O
of	O
introgression	O
between	O
each	O
pair	O
of	O
sympatric	O
populations	O
of	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
from	O
the	O
localities	O
of	O
Posse	O
,	O
Afonso	O
Claudio	O
and	O
Corte	O
de	O
Pedra	O
.	O

The	O
input	O
files	O
were	O
prepared	O
using	O
the	O
values	O
of	O
recombination	O
and	O
linkage	O
disequilibrium	O
calculated	O
by	O
the	O
SITES	O
program	O
[	O
30	O
]	O
for	O
each	O
population	O
(	O
data	O
not	O
shown	O
)	O
.	O

Although	O
no	O
significant	O
values	O
were	O
found	O
for	O
the	O
smaller	O
samples	O
of	O
Afonso	O
Claudio	O
and	O
Corte	O
de	O
Pedra	O
,	O
the	O
results	O
(	O
Table	O
5	O
)	O
present	O
evidence	O
for	O
introgression	O
in	O
the	O
period	O
gene	O
in	O
both	O
directions	O
(	O
from	O
L	B
.	I
intermedia	I
to	O
L	B
.	I
whitmani	I
and	O
vice	O
-	O
versa	O
)	O
in	O
the	O
locality	O
of	O
Posse	O
.	O

Isolation	O
with	O
Migration	O
model	O

To	O
further	O
examine	O
the	O
gene	O
flow	O
between	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
we	O
used	O
the	O
IM	O
software	O
[	O
39	O
]	O
.	O

The	O
Isolation	O
with	O
Migration	O
model	O
has	O
six	O
demographic	O
parameters	O
that	O
include	O
two	O
migration	O
rates	O
,	O
one	O
for	O
each	O
population	O
.	O

The	O
IM	O
software	O
estimates	O
the	O
posterior	O
probability	O
for	O
each	O
of	O
the	O
model	O
parameters	O
,	O
fitting	O
the	O
Isolation	O
with	O
Migration	O
model	O
to	O
the	O
data	O
.	O

One	O
of	O
the	O
assumptions	O
of	O
this	O
model	O
is	O
that	O
the	O
loci	O
studied	O
do	O
not	O
have	O
internal	O
recombination	O
.	O

Therefore	O
,	O
we	O
identified	O
four	O
different	O
non	O
-	O
recombining	O
blocks	O
of	O
our	O
fragment	O
of	O
per	O
,	O
which	O
were	O
then	O
treated	O
as	O
different	O
loci	O
in	O
the	O
analysis	O
.	O

The	O
four	O
-	O
gametes	O
test	O
[	O
33	O
]	O
implemented	O
in	O
DnaSP4	O
.	O
1	O
was	O
used	O
for	O
the	O
identification	O
of	O
possible	O
recombination	O
events	O
.	O

Since	O
the	O
program	O
estimates	O
parameters	O
for	O
a	O
pair	O
of	O
closely	O
related	O
populations	O
or	O
species	O
,	O
all	O
sequences	O
of	O
each	O
species	O
were	O
used	O
in	O
the	O
analysis	O
as	O
a	O
single	O
population	O
.	O

We	O
performed	O
MCMC	O
runs	O
using	O
the	O
IM	O
software	O
with	O
different	O
seed	O
numbers	O
,	O
in	O
order	O
to	O
guarantee	O
convergence	O
of	O
the	O
sample	O
.	O

Maximum	O
likelihood	O
estimates	O
of	O
migration	O
parameters	O
revealed	O
a	O
non	O
-	O
zero	O
value	O
for	O
both	O
species	O
,	O
m1	O
=	O
1	O
.	O
398	O
and	O
m2	O
=	O
1	O
.	O
014	O
(	O
m1	O
-	O
from	O
L	B
.	I
whitmani	I
towards	O
L	B
.	I
intermedia	I
;	O
m2	O
-	O
from	O
L	B
.	I
whitmani	I
towards	O
L	B
.	I
intermedia	I
)	O
.	O

Fig	O
5	O
shows	O
the	O
posterior	O
distributions	O
for	O
migration	O
rates	O
and	O
reveals	O
a	O
null	O
probability	O
for	O
the	O
absence	O
of	O
migration	O
from	O
L	B
.	I
whitmani	I
towards	O
L	B
.	I
intermedia	I
.	O

In	O
addition	O
,	O
the	O
absence	O
of	O
migration	O
in	O
the	O
opposite	O
direction	O
is	O
not	O
included	O
in	O
the	O
95	O
%	O
confidence	O
interval	O
(	O
values	O
range	O
from	O
0	O
.	O
222	O
to	O
8	O
.	O
898	O
)	O
,	O
thus	O
supporting	O
the	O
presence	O
of	O
migration	O
in	O
both	O
directions	O
.	O

The	O
conversion	O
of	O
the	O
migration	O
rate	O
estimate	O
to	O
population	O
migration	O
rate	O
per	O
generation	O
(	O
m1	O
and	O
m2	O
)	O
is	O
not	O
accurate	O
when	O
the	O
population	O
size	O
is	O
based	O
on	O
a	O
single	O
locus	O
.	O

However	O
,	O
the	O
average	O
of	O
the	O
migrant	O
number	O
per	O
generation	O
for	O
both	O
species	O
was	O
very	O
close	O
to	O
the	O
Nm	O
estimate	O
based	O
on	O
Fst	O
values	O
(	O
Nm	O
~	O
0	O
.	O
49	O
in	O
Table	O
4	O
,	O
m1	O
~	O
0	O
.	O
52	O
and	O
m2	O
~	O
0	O
.	O
34	O
)	O
.	O

Discussion	O

There	O
is	O
some	O
evidence	O
that	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
might	O
represent	O
sibling	O
-	O
species	O
complexes	O
in	O
Brazil	O
.	O

Lutzomyia	B
neivai	I
Pinto	O
1926	O
,	O
a	O
sibling	O
of	O
L	B
.	I
intermedia	I
is	O
found	O
in	O
parts	O
of	O
Southern	O
and	O
Western	O
Brazil	O
and	O
some	O
other	O
countries	O
of	O
South	O
America	O
[	O
40	O
]	O
.	O

The	O
present	O
study	O
did	O
not	O
include	O
populations	O
of	O
this	O
species	O
.	O

In	O
the	O
case	O
of	O
L	B
.	I
whitmani	I
,	O
mitochondrial	O
data	O
[	O
3	O
,	O
6	O
]	O
indicates	O
three	O
main	O
lineages	O
in	O
Brazil	O
:	O
an	O
Amazonian	O
group	O
,	O
a	O
North	O
-	O
South	O
group	O
and	O
a	O
Northeast	O
group	O
.	O

We	O
did	O
not	O
find	O
strong	O
evidence	O
of	O
a	O
geographical	O
differentiation	O
in	O
the	O
period	O
gene	O
among	O
populations	O
of	O
L	B
.	I
whitmani	I
although	O
one	O
of	O
the	O
pairwise	O
Fst	O
comparisons	O
(	O
Posse	O
x	O
Ilh	O
e	O
us	O
)	O
was	O
significant	O
at	O
the	O
5	O
%	O
level	O
.	O

When	O
we	O
compare	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
,	O
we	O
find	O
a	O
highly	O
significant	O
Fst	O
value	O
(	O
0	O
.	O
3373	O
)	O
,	O
which	O
is	O
however	O
smaller	O
than	O
that	O
observed	O
for	O
the	O
period	O
gene	O
between	O
sympatric	O
siblings	O
of	O
Lutzomyia	B
longipalpis	I
(	O
Fst	O
=	O
0	O
.	O
3952	O
)	O
[	O
23	O
]	O
,	O
a	O
complex	O
of	O
cryptic	O
species	O
that	O
are	O
vectors	O
of	O
American	O
visceral	O
leishmaniasis	O
.	O

Therefore	O
,	O
despite	O
the	O
presence	O
of	O
diagnostic	O
morphological	O
characters	O
to	O
identify	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
[	O
1	O
]	O
the	O
level	O
of	O
molecular	O
divergence	O
in	O
period	O
is	O
not	O
as	O
high	O
as	O
the	O
cryptic	O
L	B
.	I
longipalpis	I
siblings	O
.	O

Even	O
though	O
it	O
is	O
hard	O
to	O
distinguish	O
introgression	O
from	O
the	O
persistence	O
of	O
ancestral	O
polymorphisms	O
,	O
a	O
test	O
of	O
gene	O
flow	O
based	O
on	O
the	O
signature	O
introgression	O
leaves	O
on	O
the	O
patterns	O
of	O
linkage	O
disequilibrium	O
[	O
38	O
]	O
as	O
well	O
as	O
simulations	O
that	O
fit	O
the	O
"	O
Isolation	O
with	O
Migration	O
"	O
model	O
to	O
the	O
data	O
suggest	O
that	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
might	O
be	O
exchanging	O
alleles	O
at	O
the	O
per	O
locus	O
.	O

This	O
is	O
further	O
supported	O
by	O
the	O
presence	O
of	O
shared	O
haplotypes	O
between	O
the	O
two	O
species	O
in	O
Posse	O
and	O
very	O
similar	O
sequences	O
in	O
all	O
sympatric	O
populations	O
.	O

There	O
is	O
mounting	O
evidence	O
that	O
introgression	O
plays	O
a	O
major	O
role	O
in	O
the	O
evolution	O
of	O
closely	O
related	O
insect	O
vector	O
species	O
.	O

Introgression	O
among	O
vectors	O
may	O
have	O
important	O
epidemiological	O
consequences	O
.	O

Gene	O
flow	O
in	O
loci	O
that	O
affect	O
vectorial	O
capacity	O
,	O
such	O
as	O
those	O
controlling	O
host	O
preference	O
and	O
susceptibility	O
to	O
parasite	O
infection	O
,	O
can	O
change	O
the	O
transmission	O
patterns	O
and	O
consequently	O
make	O
the	O
disease	O
control	O
a	O
harder	O
task	O
.	O

Introgression	O
of	O
genes	O
that	O
control	O
adaptation	O
to	O
particular	O
types	O
of	O
environment	O
can	O
also	O
have	O
a	O
major	O
impact	O
on	O
the	O
spread	O
of	O
vector	O
-	O
borne	O
diseases	O
as	O
was	O
proposed	O
for	O
the	O
major	O
African	O
malaria	O
vector	O
Anopheles	B
gambiae	I
[	O
41	O
]	O
.	O

The	O
same	O
can	O
be	O
said	O
about	O
genes	O
controlling	O
insecticide	O
resistance	O
.	O

For	O
example	O
,	O
Weill	O
et	O
al	O
.	O

[	O
42	O
]	O
found	O
a	O
kdr	O
mutation	O
responsible	O
for	O
pyrethroid	O
resistance	O
in	O
the	O
Mopti	O
form	O
of	O
Anopheles	B
gambiae	I
,	O
a	O
normally	O
susceptible	O
taxon	O
of	O
this	O
species	O
complex	O
.	O

Sequence	O
analysis	O
reveals	O
that	O
this	O
resistant	O
allele	O
probably	O
originates	O
through	O
introgression	O
from	O
the	O
Savanna	O
form	O
.	O

Although	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
are	O
closely	O
related	O
and	O
only	O
distinguished	O
by	O
a	O
few	O
morphological	O
differences	O
,	O
they	O
do	O
show	O
differentiation	O
in	O
some	O
other	O
important	O
traits	O
.	O

For	O
example	O
,	O
in	O
Posse	O
,	O
one	O
of	O
the	O
localities	O
we	O
studied	O
,	O
the	O
two	O
species	O
show	O
differences	O
in	O
abundance	O
during	O
the	O
year	O
.	O

L	B
.	I
intermedia	I
is	O
more	O
abundant	O
in	O
the	O
summer	O
while	O
L	B
.	I
whitmani	I
is	O
more	O
frequent	O
in	O
the	O
winter	O
months	O
[	O
2	O
]	O
.	O

They	O
also	O
show	O
differences	O
in	O
microhabitat	O
preferences	O
,	O
L	B
.	I
intermedia	I
being	O
more	O
common	O
in	O
the	O
peridomestic	O
area	O
while	O
L	B
.	I
whitmani	I
is	O
found	O
mainly	O
in	O
the	O
surrounding	O
forest	O
[	O
2	O
]	O
.	O

In	O
addition	O
,	O
the	O
two	O
species	O
show	O
marked	O
differences	O
in	O
their	O
tendencies	O
to	O
bite	O
humans	B
in	O
the	O
early	O
morning	O
,	O
with	O
L	B
.	I
whitmani	I
showing	O
higher	O
feeding	O
rates	O
than	O
L	B
.	I
intermedia	I
[	O
26	O
]	O
.	O

Therefore	O
,	O
despite	O
the	O
evidence	O
of	O
introgression	O
in	O
the	O
period	O
gene	O
in	O
this	O
locality	O
,	O
there	O
are	O
important	O
ecological	O
and	O
behavioral	O
differences	O
between	O
the	O
two	O
species	O
in	O
Posse	O
suggesting	O
that	O
gene	O
flow	O
is	O
probably	O
rather	O
limited	O
in	O
loci	O
controlling	O
these	O
traits	O
.	O

Hence	O
,	O
it	O
is	O
yet	O
not	O
clear	O
whether	O
introgression	O
has	O
played	O
an	O
important	O
role	O
in	O
the	O
evolution	O
of	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
.	O

Further	O
work	O
with	O
other	O
genes	O
might	O
help	O
clarify	O
the	O
issue	O
.	O

Conclusion	O

Evidence	O
for	O
introgression	O
between	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
obtained	O
using	O
mitochondrial	O
DNA	O
[	O
4	O
]	O
seems	O
to	O
be	O
corroborated	O
by	O
our	O
data	O
on	O
the	O
period	O
gene	O
,	O
a	O
nuclear	O
marker	O
.	O

Nevertheless	O
,	O
considering	O
that	O
period	O
is	O
potentially	O
involved	O
in	O
reproductive	O
isolation	O
and	O
might	O
be	O
,	O
therefore	O
,	O
less	O
prone	O
to	O
introgression	O
than	O
the	O
"	O
average	O
"	O
gene	O
[	O
43	O
]	O
,	O
it	O
is	O
possible	O
that	O
much	O
higher	O
levels	O
of	O
gene	O
flow	O
between	O
the	O
two	O
species	O
occur	O
at	O
other	O
genes	O
.	O

It	O
might	O
,	O
on	O
the	O
other	O
hand	O
,	O
suggest	O
that	O
this	O
behavioral	O
gene	O
,	O
or	O
at	O
least	O
the	O
fragment	O
we	O
analyzed	O
,	O
did	O
not	O
play	O
a	O
role	O
in	O
speciation	O
between	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
.	O

In	O
fact	O
the	O
same	O
has	O
been	O
suggested	O
for	O
some	O
Drosophila	O
species	O
[	O
44	O
]	O
despite	O
per	O
'	O
s	O
role	O
controlling	O
lovesong	O
and	O
mating	O
rhythm	O
differences	O
between	O
D	B
.	I
melanogaster	I
and	O
D	B
.	I
simulans	I
[	O
13	O
-	O
16	O
]	O
.	O

Although	O
the	O
evidence	O
for	O
introgression	O
in	O
the	O
per	O
gene	O
between	O
L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
is	O
not	O
overwhelming	O
,	O
it	O
does	O
indicate	O
the	O
need	O
to	O
extend	O
this	O
analysis	O
to	O
other	O
loci	O
in	O
the	O
future	O
.	O

We	O
are	O
currently	O
isolating	O
new	O
molecular	O
markers	O
in	O
the	O
two	O
species	O
to	O
carry	O
out	O
a	O
multi	O
-	O
locus	O
approach	O
[	O
39	O
]	O
that	O
might	O
help	O
determining	O
how	O
much	O
variation	O
in	O
gene	O
flow	O
and	O
differentiation	O
there	O
is	O
across	O
the	O
genome	O
of	O
these	O
two	O
very	O
important	O
leishmaniasis	O
vectors	O
.	O

Methods	O

Sand	O
fly	O
samples	O

Sand	O
fly	O
samples	O
used	O
in	O
this	O
work	O
were	O
all	O
the	O
F1	O
generation	O
from	O
wild	O
collected	O
females	O
from	O
the	O
Brazilian	O
localities	O
of	O
Posse	O
(	O
Petr	O
o	O
polis	O
,	O
Rio	O
de	O
Janeiro	O
State	O
,	O
22	O
degrees	O
30	O
'	O
S	O
43	O
degrees	O
10	O
'	O
W	O
)	O
,	O
Jacarepagu	O
a	O
(	O
Rio	O
de	O
Janeiro	O
,	O
Rio	O
de	O
Janeiro	O
State	O
,	O
22	O
degrees	O
55	O
'	O
S	O
43	O
degrees	O
21	O
'	O
W	O
)	O
,	O
Afonso	O
Claudio	O
(	O
Esp	O
i	O
rito	O
Santo	O
State	O
,	O
20	O
degrees	O
04	O
'	O
S	O
41	O
degrees	O
07	O
'	O
W	O
)	O
,	O
Corte	O
de	O
Pedra	O
(	O
Presidente	O
Tancredo	O
Neves	O
,	O
Bahia	O
State	O
,	O
13	O
degrees	O
27	O
'	O
S	O
39	O
degrees	O
25	O
'	O
W	O
)	O
and	O
Ilh	O
e	O
us	O
(	O
Bahia	O
State	O
,	O
14	O
degrees	O
50	O
'	O
S	O
39	O
degrees	O
06	O
'	O
W	O
)	O
.	O

L	B
.	I
intermedia	I
and	O
L	B
.	I
whitmani	I
were	O
identified	O
according	O
to	O
Young	O
and	O
Duncan	O
[	O
1	O
]	O
.	O

The	O
progeny	O
of	O
each	O
wild	O
caught	O
female	O
was	O
raised	O
separately	O
according	O
to	O
Souza	O
et	O
al	O
.	O

[	O
45	O
]	O
and	O
only	O
one	O
F1	O
male	O
of	O
each	O
female	O
was	O
used	O
for	O
the	O
molecular	O
analysis	O
,	O
which	O
included	O
68	O
individuals	O
of	O
L	B
.	I
intermedia	I
(	O
12	O
from	O
Afonso	O
Claudio	O
,	O
18	O
from	O
Posse	O
,	O
20	O
from	O
Corte	O
de	O
Pedra	O
and	O
18	O
from	O
Jacarepagu	O
a	O
)	O
and	O
51	O
individuals	O
of	O
L	B
.	I
whitmani	I
(	O
12	O
from	O
Afonso	O
Claudio	O
,	O
17	O
from	O
Posse	O
,	O
3	O
from	O
Corte	O
de	O
Pedra	O
and	O
19	O
from	O
Ilh	O
e	O
us	O
)	O
.	O

Note	O
that	O
,	O
although	O
the	O
distribution	O
of	O
the	O
two	O
species	O
shows	O
considerable	O
overlap	O
in	O
Eastern	O
Brazil	O
,	O
in	O
many	O
localities	O
only	O
one	O
species	O
is	O
found	O
or	O
is	O
far	O
more	O
abundant	O
than	O
the	O
other	O
.	O

There	O
are	O
also	O
seasonal	O
and	O
microhabitat	O
differences	O
in	O
abundance	O
between	O
them	O
in	O
areas	O
of	O
sympatry	O
[	O
2	O
]	O
.	O

DNA	O
methods	O

Genomic	O
DNA	O
was	O
prepared	O
according	O
to	O
Jowett	O
[	O
46	O
]	O
with	O
slight	O
modifications	O
and	O
the	O
PCR	O
was	O
carried	O
out	O
for	O
30	O
cycles	O
at	O
95	O
degrees	O
C	O
for	O
30	O
sec	O
,	O
60	O
degrees	O
C	O
for	O
30	O
sec	O
and	O
72	O
degrees	O
C	O
for	O
30	O
sec	O
,	O
using	O
Abgene	O
,	O
Amersham	O
Biosciences	O
or	O
Biotools	O
reagents	O
according	O
to	O
manufacturers	O
directions	O
.	O

The	O
per	O
primer	O
sequences	O
are	O
:	O
5llper2	O
:	O
5	O
'	O
-	O
AGCATCCTTTTGTAGCAAAC	O
-	O
3	O
'	O
(	O
forward	O
)	O
and	O
3llper2	O
:	O
5	O
'	O
-	O
TCAGATGAACTCTTGCTGTC	O
-	O
3	O
'	O
(	O
reverse	O
)	O
.	O

These	O
primers	O
amplify	O
a	O
486	O
bp	O
fragment	O
of	O
the	O
sand	O
fly	O
per	O
gene	O
homologue	O
that	O
includes	O
part	O
of	O
the	O
PAS	O
/	O
CLD	O
domain	O
,	O
an	O
intron	O
(	O
58	O
bp	O
)	O
and	O
the	O
beginning	O
of	O
the	O
perS	O
domain	O
[	O
24	O
]	O
.	O

The	O
amplified	O
fragments	O
were	O
cloned	O
using	O
the	O
pMOSBlue	O
blunt	O
ended	O
cloning	O
kit	O
(	O
Amersham	O
Biosciences	O
)	O
and	O
plasmid	O
DNA	O
preparation	O
was	O
carried	O
out	O
using	O
the	O
"	O
Flexiprep	O
"	O
Kit	O
(	O
Amersham	O
Biosciences	O
)	O
.	O

Cloned	O
PCR	O
fragments	O
were	O
sequenced	O
at	O
Funda	O
c	O
a	O
o	O
Oswaldo	O
Cruz	O
and	O
at	O
University	O
of	O
Leicester	O
using	O
ABI	O
377	O
sequencers	O
.	O

With	O
the	O
exception	O
of	O
two	O
L	B
.	I
whitmani	I
individuals	O
from	O
Corte	O
de	O
Pedra	O
(	O
see	O
below	O
)	O
,	O
only	O
one	O
sequence	O
of	O
each	O
sand	O
fly	O
(	O
representing	O
one	O
of	O
the	O
two	O
possible	O
alleles	O
)	O
was	O
used	O
in	O
the	O
analysis	O
but	O
an	O
average	O
of	O
three	O
sequences	O
per	O
individual	O
were	O
obtained	O
in	O
order	O
to	O
check	O
possible	O
PCR	O
induced	O
mutations	O
.	O

In	O
addition	O
,	O
PCR	O
fragments	O
were	O
also	O
sequenced	O
directly	O
in	O
some	O
cases	O
for	O
the	O
same	O
reason	O
.	O

In	O
the	O
case	O
of	O
the	O
two	O
L	B
.	I
whitmani	I
mentioned	O
above	O
6	O
and	O
9	O
clones	O
were	O
sequenced	O
respectively	O
from	O
specimens	O
WCP01	O
and	O
WCP03	O
to	O
determine	O
both	O
alleles	O
simply	O
to	O
increase	O
the	O
size	O
of	O
this	O
small	O
sample	O
.	O

Negative	O
controls	O
were	O
performed	O
for	O
all	O
amplification	O
reactions	O
.	O

In	O
addition	O
,	O
PCR	O
,	O
cloning	O
and	O
sequencing	O
were	O
repeated	O
for	O
two	O
individuals	O
to	O
confirm	O
putative	O
introgressed	O
sequences	O
and	O
to	O
exclude	O
the	O
possibility	O
that	O
they	O
were	O
the	O
result	O
of	O
PCR	O
contamination	O
.	O

Finally	O
,	O
for	O
at	O
least	O
two	O
individuals	O
with	O
putative	O
introgressed	O
sequences	O
,	O
we	O
could	O
define	O
the	O
other	O
allele	O
from	O
additional	O
clones	O
(	O
not	O
included	O
in	O
the	O
analysis	O
)	O
,	O
which	O
showed	O
to	O
be	O
typical	O
of	O
the	O
species	O
,	O
indicating	O
no	O
identification	O
problems	O
.	O

The	O
sequences	O
were	O
submitted	O
to	O
GenBank	O
(	O
accession	O
numbers	O
AY927062	O
to	O
AY927182	O
)	O
.	O

Sequence	O
analyses	O

The	O
preliminary	O
sequence	O
editing	O
was	O
carried	O
out	O
using	O
the	O
Wisconsin	O
Package	O
Version	O
9	O
.	O
1	O
,	O
Genetics	O
Computer	O
Group	O
(	O
GCG	O
)	O
,	O
Madison	O
,	O
and	O
ClustalX	O
[	O
47	O
]	O
was	O
used	O
to	O
perform	O
the	O
multiple	O
alignment	O
.	O

Analyses	O
of	O
population	O
polymorphisms	O
and	O
differentiation	O
between	O
populations	O
were	O
carried	O
out	O
using	O
DNAsp4	O
.	O
1	O
[	O
34	O
]	O
and	O
ProSeq	O
[	O
48	O
]	O
softwares	O
,	O
while	O
Arlequin	O
v	O
.	O

2	O
.	O
0	O
[	O
49	O
]	O
was	O
used	O
for	O
an	O
analysis	O
of	O
molecular	O
variance	O
(	O
AMOVA	O
)	O
between	O
populations	O
.	O

The	O
Minimum	O
Evolution	O
phylogenetic	O
tree	O
was	O
constructed	O
using	O
MEGA	O
3	O
.	O
1	O
software	O
[	O
50	O
]	O
.	O

The	O
haplotype	O
network	O
was	O
estimated	O
using	O
TCS1	O
.	O
21	O
[	O
36	O
]	O
.	O

Recombination	O
and	O
linkage	O
disequilibrium	O
analyses	O
were	O
performed	O
using	O
the	O
DNAsp4	O
.	O
1	O
and	O
SITES	O
program	O
[	O
30	O
]	O
.	O

Linkage	O
disequilibrium	O
simulations	O
were	O
carried	O
out	O
by	O
the	O
WH	O
program	O
[	O
51	O
,	O
52	O
]	O
and	O
Markov	O
Chain	O
Monte	O
Carlo	O
(	O
MCMC	O
)	O
simulations	O
of	O
the	O
isolation	O
with	O
migration	O
model	O
were	O
performed	O
using	O
the	O
algorithm	O
implemented	O
in	O
the	O
IM	O
program	O
[	O
39	O
]	O
.	O

Authors	O
'	O
contributions	O

CJM	O
generate	O
and	O
analyzed	O
all	O
the	O
data	O
and	O
drafted	O
the	O
manuscript	O
.	O

NAS	O
and	O
CAC	O
collected	O
and	O
maintained	O
sand	O
fly	O
samples	O
.	O

CPK	O
helped	O
to	O
write	O
the	O
manuscript	O
and	O
supervised	O
CJM	O
during	O
her	O
stay	O
in	O
Leicester	O
.	O

AAP	O
is	O
the	O
principal	O
investigator	O
,	O
participated	O
in	O
its	O
design	O
and	O
coordination	O
,	O
and	O
helped	O
to	O
write	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Presence	O
of	O
antibodies	O
against	O
cyclic	O
citrullinated	O
peptides	O
in	O
patients	B
with	O
'	O
rhupus	O
'	O
:	O
a	O
cross	O
-	O
sectional	O
study	O

Abstract	O

'	O
Rhupus	O
'	O
is	O
a	O
rare	O
condition	O
sharing	O
features	O
of	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
and	O
systemic	O
lupus	O
erythematosus	O
(	O
SLE	O
)	O
.	O

If	O
rhupus	O
is	O
a	O
distinctive	O
entity	O
,	O
an	O
overlap	O
between	O
RA	O
and	O
SLE	O
or	O
a	O
subset	O
of	O
SLE	O
is	O
currently	O
debated	O
.	O

This	O
study	O
was	O
performed	O
to	O
explore	O
the	O
prevalence	O
of	O
antibodies	O
against	O
cyclic	O
citrullinated	O
peptides	O
(	O
anti	O
-	O
CCP	O
antibodies	O
)	O
in	O
rhupus	O
.	O

Patients	B
meeting	O
American	O
College	O
of	O
Rheumatology	O
criteria	O
for	O
RA	O
,	O
SLE	O
,	O
or	O
both	O
were	O
included	O
.	O

Clinical	O
and	O
radiographic	O
features	O
were	O
recorded	O
and	O
sera	O
were	O
searched	O
for	O
anti	O
-	O
CCP	O
antibodies	O
,	O
rheumatoid	O
factor	O
,	O
antinuclear	O
antibodies	O
,	O
anti	O
-	O
extractable	O
nuclear	O
antigens	O
,	O
and	O
antibodies	O
against	O
double	O
-	O
stranded	O
DNA	O
(	O
anti	O
-	O
dsDNA	O
antibodies	O
)	O
.	O

Seven	O
patients	B
for	O
each	O
group	O
were	O
included	O
.	O

Clinical	O
and	O
serological	O
features	O
for	O
RA	O
or	O
SLE	O
were	O
similar	O
between	O
rhupus	O
and	O
RA	O
patients	B
,	O
and	O
between	O
rhupus	O
and	O
SLE	O
patients	B
,	O
respectively	O
.	O

Values	O
for	O
anti	O
-	O
CCP	O
antibodies	O
obtained	O
were	O
significantly	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
higher	O
in	O
RA	O
(	O
6	O
/	O
7	O
)	O
and	O
rhupus	O
(	O
4	O
/	O
7	O
)	O
than	O
in	O
SLE	O
patients	B
(	O
0	O
/	O
7	O
)	O
and	O
healthy	O
subjects	O
(	O
0	O
/	O
7	O
)	O
.	O

Our	O
data	O
support	O
the	O
possibility	O
that	O
rhupus	O
is	O
an	O
overlap	O
between	O
RA	O
and	O
SLE	O
,	O
because	O
highly	O
specific	O
autoantibodies	O
for	O
RA	O
(	O
anti	O
-	O
CCP	O
)	O
and	O
for	O
SLE	O
(	O
anti	O
-	O
dsDNA	O
and	O
anti	O
-	O
Sm	O
)	O
are	O
detected	O
in	O
coexistence	O
.	O

Introduction	O

The	O
clinical	O
coexistence	O
of	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
and	O
systemic	O
lupus	O
erythematosus	O
(	O
SLE	O
)	O
was	O
first	O
described	O
in	O
1969	O
by	O
Kantor	O
and	O
was	O
termed	O
'	O
rhupus	O
syndrome	O
'	O
by	O
Schur	O
(	O
both	O
cited	O
in	O
[	O
1	O
]	O
)	O
.	O

Since	O
then	O
,	O
fewer	O
than	O
100	O
cases	O
of	O
rhupus	O
have	O
been	O
published	O
[	O
1	O
-	O
3	O
]	O
.	O

In	O
an	O
epidemiological	O
study	O
including	O
about	O
7	O
,	O
000	O
new	O
patients	B
,	O
the	O
prevalence	O
of	O
RA	O
was	O
15	O
%	O
and	O
for	O
SLE	O
it	O
was	O
8	O
.	O
9	O
%	O
.	O

The	O
expected	O
coincidence	O
of	O
RA	O
and	O
SLE	O
by	O
chance	O
would	O
therefore	O
be	O
1	O
.	O
2	O
%	O
.	O

However	O
,	O
the	O
observed	O
prevalence	O
of	O
rhupus	O
was	O
0	O
.	O
09	O
%	O
,	O
less	O
than	O
one	O
-	O
tenth	O
of	O
that	O
expected	O
[	O
1	O
]	O
.	O

Previous	O
reports	O
have	O
shown	O
that	O
the	O
patients	B
with	O
rhupus	O
display	O
an	O
array	O
of	O
autoantibodies	O
including	O
anti	O
-	O
double	O
-	O
stranded	O
DNA	O
(	O
anti	O
-	O
dsDNA	O
)	O
,	O
anti	O
-	O
Sm	O
(	O
both	O
highly	O
specific	O
for	O
SLE	O
)	O
,	O
anti	O
-	O
SSA	O
,	O
anti	O
-	O
SSB	O
,	O
anti	O
-	O
ribonucleoprotein	O
,	O
antinuclear	O
antibodies	O
(	O
ANA	O
)	O
,	O
anti	O
-	O
cardiolipins	O
,	O
and	O
rheumatoid	O
factor	O
(	O
RF	O
)	O
[	O
1	O
,	O
2	O
]	O
.	O

However	O
,	O
no	O
study	O
has	O
yet	O
been	O
performed	O
to	O
investigate	O
the	O
presence	O
of	O
antibodies	O
against	O
cyclic	O
citrullinated	O
peptides	O
(	O
anti	O
-	O
CCP	O
antibodies	O
)	O
,	O
which	O
have	O
a	O
specificity	O
for	O
RA	O
of	O
96	O
to	O
98	O
%	O
(	O
for	O
second	O
-	O
generation	O
assays	O
(	O
anti	O
-	O
CCP2	O
)	O
)	O
[	O
4	O
,	O
5	O
]	O
.	O

Recent	O
data	O
have	O
confirmed	O
that	O
these	O
antibodies	O
are	O
rarely	O
if	O
ever	O
present	O
in	O
other	O
autoimmune	O
diseases	O
such	O
as	O
SLE	O
,	O
Sj	O
o	O
gren	O
'	O
s	O
syndrome	O
(	O
SS	O
)	O
,	O
scleroderma	O
and	O
myositis	O
[	O
6	O
]	O
.	O

Nowadays	O
,	O
it	O
is	O
a	O
matter	O
of	O
debate	O
whether	O
rhupus	O
is	O
a	O
clinically	O
and	O
immunologically	O
distinctive	O
entity	O
[	O
2	O
]	O
,	O
a	O
true	O
overlap	O
between	O
SLE	O
and	O
RA	O
[	O
7	O
]	O
,	O
or	O
a	O
subgroup	O
of	O
patients	B
with	O
lupus	O
[	O
8	O
]	O
.	O

This	O
descriptive	O
,	O
cross	O
-	O
sectional	O
study	O
was	O
performed	O
to	O
investigate	O
the	O
frequency	O
of	O
anti	O
-	O
CCP	O
antibodies	O
in	O
a	O
cohort	O
of	O
patients	B
with	O
rhupus	O
.	O

Materials	O
and	O
methods	O

We	O
included	O
all	O
patients	B
fulfilling	O
American	O
College	O
of	O
Rheumatology	O
(	O
ACR	O
)	O
classification	O
criteria	O
for	O
both	O
RA	O
[	O
9	O
]	O
and	O
SLE	O
[	O
10	O
]	O
who	O
belonged	O
to	O
our	O
cohorts	O
of	O
patients	B
with	O
RA	O
and	O
with	O
SLE	O
.	O

Comparisons	O
were	O
made	O
with	O
age	O
-	O
and	O
gender	O
-	O
matched	O
patients	B
with	O
RA	O
and	O
with	O
SLE	O
,	O
and	O
healthy	O
subjects	O
.	O

The	O
study	O
was	O
approved	O
by	O
the	O
local	O
ethics	O
committee	O
,	O
and	O
informed	O
consent	O
was	O
obtained	O
.	O

Serum	O
samples	O
were	O
obtained	O
and	O
stored	O
at	O
-	O
75	O
degrees	O
C	O
until	O
use	O
.	O

Sera	O
were	O
analyzed	O
for	O
anti	O
-	O
CCP2	O
antibodies	O
by	O
ELISA	O
(	O
Inova	O
Diagnostics	O
,	O
San	O
Diego	O
,	O
CA	O
,	O
USA	O
)	O
with	O
a	O
cutoff	O
value	O
of	O
60	O
U	O
/	O
ml	O
.	O

Fine	O
antinuclear	O
reactivities	O
(	O
ELISA	O
;	O
Inova	O
Diagnostics	O
)	O
,	O
RF	O
(	O
nephelometry	O
)	O
,	O
ANA	O
(	O
indirect	O
immunofluorescence	O
on	O
HEp	O
-	O
2	O
slides	O
)	O
,	O
and	O
anti	O
-	O
dsDNA	O
(	O
indirect	O
immunofluorescence	O
on	O
Crithidia	O
luciliae	O
substrate	O
)	O
antibodies	O
were	O
also	O
determined	O
.	O

Except	O
for	O
healthy	O
individuals	O
,	O
standard	O
radiographs	O
of	O
hands	O
were	O
available	O
.	O

For	O
statistical	O
analysis	O
,	O
ANOVA	O
and	O
the	O
Mann	O
-	O
Whitney	O
U	O
test	O
were	O
performed	O
as	O
appropriate	O
with	O
GraphPad	O
Prism	O
4	O
.	O
0	O
software	O
(	O
GraphPad	O
Inc	O
,	O
San	O
Diego	O
,	O
CA	O
,	O
USA	O
)	O
.	O

Results	O

Seven	O
female	O
patients	B
with	O
a	O
median	O
age	O
of	O
44	O
years	O
(	O
range	O
25	O
to	O
64	O
)	O
met	O
our	O
inclusion	O
criteria	O
.	O

The	O
major	O
clinical	O
and	O
laboratory	O
findings	O
are	O
presented	O
in	O
Table	O
1	O
.	O

Healthy	O
individuals	O
and	O
all	O
patients	B
belonged	O
to	O
cohorts	O
from	O
the	O
same	O
ethnic	O
group	O
(	O
Hispanic	O
mestizo	O
)	O
.	O

No	O
differences	O
in	O
demographic	O
data	O
were	O
found	O
between	O
groups	O
.	O

Mean	O
ACR	O
criteria	O
for	O
SLE	O
were	O
5	O
.	O
57	O
(	O
range	O
4	O
to	O
8	O
)	O
in	O
the	O
SLE	O
group	O
,	O
and	O
5	O
.	O
57	O
(	O
4	O
to	O
8	O
)	O
in	O
the	O
rhupus	O
group	O
.	O

In	O
the	O
same	O
way	O
,	O
mean	O
ACR	O
criteria	O
for	O
RA	O
were	O
6	O
(	O
4	O
to	O
7	O
)	O
in	O
the	O
RA	O
group	O
,	O
and	O
5	O
.	O
14	O
(	O
4	O
to	O
6	O
)	O
for	O
the	O
patients	B
with	O
rhupus	O
.	O

In	O
all	O
patients	B
with	O
rhupus	O
,	O
RA	O
was	O
presented	O
as	O
the	O
initial	O
disease	O
,	O
as	O
has	O
been	O
described	O
previously	O
[	O
2	O
]	O
.	O

In	O
accordance	O
with	O
another	O
report	O
,	O
in	O
two	O
patients	B
the	O
disease	O
started	O
during	O
their	O
childhood	O
as	O
juvenile	O
chronic	O
arthritis	O
[	O
1	O
]	O
.	O

Anti	O
-	O
CCP	O
antibodies	O
were	O
found	O
in	O
four	O
of	O
seven	O
(	O
57	O
%	O
)	O
patients	B
with	O
rhupus	O
,	O
and	O
in	O
six	O
of	O
seven	O
(	O
86	O
%	O
)	O
patients	B
with	O
RA	O
,	O
whereas	O
neither	O
patients	B
with	O
SLE	O
nor	O
healthy	O
individuals	O
showed	O
reactivity	O
.	O

When	O
the	O
concentrations	O
in	O
each	O
group	O
were	O
compared	O
,	O
a	O
statistical	O
significant	O
difference	O
between	O
groups	O
was	O
found	O
(	O
ANOVA	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
mean	O
concentration	O
of	O
anti	O
-	O
CCP	O
antibodies	O
was	O
584	O
U	O
/	O
ml	O
(	O
range	O
0	O
to	O
1	O
,	O
237	O
)	O
in	O
patients	B
with	O
rhupus	O
(	O
Figure	O
1	O
)	O
,	O
875	O
U	O
/	O
ml	O
(	O
0	O
to	O
1	O
,	O
178	O
)	O
in	O
the	O
RA	O
group	O
(	O
not	O
significant	O
compared	O
with	O
rhupus	O
)	O
,	O
1	O
U	O
/	O
ml	O
(	O
0	O
to	O
10	O
)	O
for	O
SLE	O
individuals	O
(	O
p	O
<	O
0	O
.	O
05	O
compared	O
with	O
rhupus	O
)	O
,	O
and	O
0	O
U	O
/	O
ml	O
(	O
0	O
to	O
2	O
)	O
for	O
healthy	O
controls	O
(	O
p	O
<	O
0	O
.	O
05	O
compared	O
with	O
rhupus	O
)	O
.	O

Two	O
of	O
three	O
patients	B
with	O
rhupus	O
who	O
were	O
negative	O
for	O
anti	O
-	O
CCP	O
antibodies	O
were	O
also	O
negative	O
for	O
anti	O
-	O
dsDNA	O
antibodies	O
,	O
RF	O
and	O
anti	O
-	O
extractable	O
nuclear	O
antigen	O
antibodies	O
,	O
although	O
both	O
patients	B
met	O
RA	O
and	O
SLE	O
classification	O
criteria	O
,	O
including	O
ANA	O
and	O
erosive	O
arthritis	O
.	O

Differences	O
in	O
ANA	O
,	O
anti	O
-	O
dsDNA	O
and	O
anti	O
-	O
extractable	O
nuclear	O
antigen	O
autoantibodies	O
between	O
patients	B
with	O
rhupus	O
and	O
those	O
with	O
SLE	O
were	O
not	O
found	O
.	O

We	O
also	O
found	O
no	O
difference	O
in	O
the	O
prevalence	O
of	O
RF	O
between	O
patients	B
with	O
rhupus	O
and	O
those	O
with	O
RA	O
.	O

Surprisingly	O
,	O
one	O
healthy	O
subject	O
was	O
positive	O
for	O
RF	O
,	O
ANA	O
and	O
anti	O
-	O
SSA	O
antibodies	O
,	O
although	O
she	O
was	O
asymptomatic	O
and	O
no	O
features	O
of	O
any	O
disease	O
were	O
found	O
.	O

Discussion	O

The	O
close	O
association	O
between	O
different	O
type	O
II	O
human	B
leukocyte	O
antigen	O
(	O
HLA	O
)	O
molecules	O
and	O
the	O
risk	O
of	O
RA	O
is	O
well	O
established	O
.	O

These	O
major	O
histocompatibility	O
complex	O
(	O
MHC	O
)	O
class	O
II	O
molecules	O
share	O
the	O
same	O
amino	O
acid	O
sequence	O
(	O
QKRAA	O
or	O
QRRAA	O
)	O
in	O
positions	O
69	O
to	O
74	O
of	O
the	O
beta	O
-	O
chain	O
,	O
namely	O
the	O
'	O
shared	O
epitope	O
'	O
.	O

Recent	O
works	O
have	O
demonstrated	O
that	O
this	O
'	O
shared	O
epitope	O
'	O
preferentially	O
binds	O
peptides	O
containing	O
the	O
non	O
-	O
standard	O
amino	O
acid	O
citrulline	O
(	O
deiminated	O
arginine	O
)	O
[	O
11	O
]	O
.	O

In	O
addition	O
,	O
an	O
abnormally	O
increased	O
function	O
of	O
the	O
enzyme	O
peptidylarginine	O
deiminase	O
4	O
(	O
PAD4	O
;	O
responsible	O
for	O
the	O
deimination	O
of	O
arginine	O
)	O
and	O
an	O
elevated	O
anti	O
-	O
CCP	O
autoantibody	O
production	O
in	O
patients	B
with	O
RA	O
have	O
been	O
demonstrated	O
[	O
12	O
]	O
.	O

These	O
facts	O
have	O
built	O
the	O
first	O
bridge	O
between	O
cellular	O
and	O
humoral	O
autoimmunity	O
in	O
a	O
major	O
rheumatic	O
disease	O
,	O
supporting	O
a	O
pathogenetic	O
role	O
for	O
an	O
abnormal	O
metabolism	O
of	O
citrulline	O
in	O
the	O
development	O
of	O
RA	O
[	O
13	O
,	O
14	O
]	O
.	O

Patients	B
with	O
SLE	O
are	O
often	O
part	O
of	O
the	O
control	O
group	O
when	O
determining	O
the	O
specificity	O
of	O
anti	O
-	O
CCP	O
antibodies	O
for	O
RA	O
[	O
15	O
]	O
,	O
although	O
some	O
studies	O
have	O
been	O
performed	O
specifically	O
on	O
patients	B
with	O
SLE	O
.	O

These	O
studies	O
contribute	O
some	O
clues	O
to	O
the	O
role	O
of	O
anti	O
-	O
CCP	O
antibodies	O
in	O
rhupus	O
.	O

Mediwake	O
and	O
colleagues	O
[	O
16	O
]	O
,	O
in	O
a	O
study	O
exploring	O
the	O
predictive	O
value	O
of	O
anti	O
-	O
CCP	O
antibodies	O
to	O
distinguish	O
erosive	O
arthritis	O
in	O
SLE	O
,	O
found	O
ten	O
patients	B
(	O
out	O
of	O
231	O
)	O
with	O
erosive	O
arthritis	O
,	O
two	O
of	O
whom	O
had	O
anti	O
-	O
CCP	O
antibodies	O
.	O

In	O
concord	O
with	O
this	O
,	O
Hoffman	O
and	O
colleagues	O
[	O
15	O
]	O
demonstrate	O
that	O
three	O
patients	B
with	O
erosive	O
arthritis	O
,	O
included	O
in	O
a	O
cohort	O
of	O
235	O
patients	B
with	O
SLE	O
,	O
were	O
positive	O
for	O
anti	O
-	O
CCP	O
antibodies	O
.	O

These	O
authors	O
suggest	O
that	O
the	O
presence	O
of	O
anti	O
-	O
CCP	O
antibodies	O
can	O
predispose	O
for	O
a	O
chronic	O
RA	O
-	O
like	O
arthritis	O
in	O
patients	B
with	O
SLE	O
.	O

Additionally	O
Weissman	O
and	O
colleagues	O
[	O
17	O
]	O
demonstrated	O
that	O
patients	B
with	O
SLE	O
can	O
display	O
radiographic	O
abnormalities	O
similar	O
to	O
those	O
of	O
RA	O
,	O
although	O
the	O
presence	O
of	O
marginal	O
erosions	O
is	O
a	O
rare	O
finding	O
.	O

In	O
the	O
present	O
study	O
we	O
demonstrate	O
that	O
the	O
patients	B
with	O
rhupus	O
show	O
a	O
very	O
similar	O
arthritis	O
pattern	O
(	O
including	O
erosive	O
disease	O
)	O
and	O
similar	O
autoantibody	O
production	O
(	O
RF	O
and	O
anti	O
-	O
CCP	O
antibodies	O
)	O
to	O
those	O
in	O
patients	B
with	O
RA	O
.	O

In	O
addition	O
,	O
patients	B
with	O
rhupus	O
display	O
a	O
clinical	O
and	O
serological	O
profile	O
indistinguishable	O
from	O
patients	B
with	O
SLE	O
.	O

Moreover	O
,	O
the	O
presence	O
of	O
other	O
coexistent	O
autoimmune	O
diseases	O
was	O
similar	O
in	O
all	O
groups	O
of	O
patients	B
(	O
two	O
patients	B
with	O
rhupus	O
,	O
three	O
patients	B
with	O
RA	O
,	O
and	O
three	O
patients	B
with	O
SLE	O
also	O
had	O
SS	O
)	O
.	O

We	O
found	O
high	O
titers	O
of	O
anti	O
-	O
CCP	O
antibodies	O
in	O
four	O
of	O
seven	O
(	O
57	O
%	O
)	O
patients	B
with	O
rhupus	O
,	O
a	O
frequency	O
similar	O
to	O
that	O
reported	O
for	O
RA	O
[	O
4	O
]	O
.	O

This	O
finding	O
,	O
together	O
with	O
the	O
clinical	O
similarity	O
,	O
supports	O
the	O
contention	O
that	O
rhupus	O
belongs	O
to	O
the	O
RA	O
spectrum	O
.	O

The	O
high	O
prevalence	O
of	O
anti	O
-	O
CCP	O
antibodies	O
in	O
RA	O
found	O
in	O
our	O
study	O
could	O
be	O
explained	O
by	O
a	O
selection	O
bias	O
because	O
only	O
patients	B
with	O
RA	O
with	O
an	O
aggressive	O
disease	O
(	O
namely	O
erosive	O
arthritis	O
and	O
RF	O
+	O
)	O
were	O
included	O
.	O

In	O
contrast	O
,	O
the	O
mean	O
ACR	O
criterion	O
for	O
SLE	O
was	O
similar	O
between	O
patients	B
with	O
rhupus	O
and	O
those	O
with	O
SLE	O
,	O
including	O
the	O
'	O
robust	O
'	O
features	O
of	O
SLE	O
such	O
as	O
renal	O
and	O
neurological	O
involvement	O
,	O
and	O
anti	O
-	O
dsDNA	O
and	O
anti	O
-	O
Sm	O
antibodies	O
.	O

These	O
clinical	O
and	O
serological	O
features	O
shared	O
between	O
patients	B
with	O
rhupus	O
and	O
those	O
with	O
SLE	O
also	O
place	O
rhupus	O
in	O
the	O
SLE	O
spectrum	O
.	O

Titration	O
of	O
anti	O
-	O
CCP	O
antibodies	O
in	O
the	O
rhupus	O
group	O
clearly	O
shows	O
a	O
bimodal	O
distribution	O
,	O
suggesting	O
the	O
existence	O
of	O
two	O
different	O
subpopulations	O
.	O

Because	O
of	O
the	O
small	O
number	O
of	O
patients	B
,	O
we	O
are	O
unable	O
to	O
define	O
the	O
differential	O
features	O
underlying	O
each	O
subset	O
.	O

However	O
,	O
two	O
of	O
three	O
patients	B
negative	O
for	O
anti	O
-	O
CCP	O
antibodies	O
were	O
also	O
negative	O
for	O
both	O
RF	O
and	O
anti	O
-	O
dsDNA	O
antibodies	O
.	O

Conclusion	O

On	O
the	O
basis	O
of	O
the	O
presence	O
of	O
shared	O
clinical	O
features	O
of	O
RA	O
(	O
mainly	O
erosive	O
arthritis	O
)	O
and	O
SLE	O
(	O
including	O
renal	O
and	O
neurological	O
involvement	O
)	O
along	O
with	O
the	O
presence	O
of	O
anti	O
-	O
dsDNA	O
and	O
anti	O
-	O
CCP	O
autoantibodies	O
in	O
our	O
patients	B
with	O
rhupus	O
,	O
our	O
findings	O
strongly	O
support	O
the	O
contention	O
that	O
rhupus	O
is	O
a	O
true	O
overlap	O
between	O
RA	O
and	O
SLE	O
,	O
not	O
merely	O
a	O
part	O
of	O
the	O
clinical	O
spectrum	O
of	O
the	O
articular	O
involvement	O
seen	O
in	O
SLE	O
.	O

Moreover	O
,	O
on	O
the	O
basis	O
of	O
the	O
mean	O
ACR	O
criteria	O
for	O
both	O
diseases	O
,	O
we	O
have	O
confirmed	O
that	O
patients	B
with	O
rhupus	O
have	O
more	O
RA	O
-	O
associated	O
and	O
less	O
SLE	O
-	O
associated	O
damage	O
,	O
an	O
issue	O
that	O
has	O
been	O
suggested	O
previously	O
[	O
2	O
]	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
report	O
exploring	O
the	O
prevalence	O
of	O
anti	O
-	O
CCP	O
antibodies	O
specifically	O
in	O
patients	B
with	O
rhupus	O
.	O

More	O
studies	O
are	O
needed	O
to	O
expand	O
the	O
pathogenetic	O
knowledge	O
of	O
this	O
overlap	O
syndrome	O
.	O

Abbreviations	O

ANA	O
=	O
antinuclear	O
antibodies	O
;	O
anti	O
-	O
CCP	O
antibodies	O
=	O
antibodies	O
against	O
cyclic	O
citrullinated	O
peptides	O
;	O
anti	O
-	O
dsDNA	O
antibodies	O
=	O
antibodies	O
against	O
double	O
-	O
stranded	O
DNA	O
;	O
ELISA	O
=	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
;	O
RA	O
=	O
rheumatoid	O
arthritis	O
;	O
RF	O
=	O
rheumatoid	O
factor	O
;	O
SLE	O
=	O
systemic	O
lupus	O
erythematosus	O
;	O
SS	O
=	O
Sj	O
o	O
gren	O
'	O
s	O
syndrome	O
.	O

Competing	O
interests	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

LA	O
-	O
G	O
participated	O
in	O
the	O
conception	O
and	O
design	O
of	O
the	O
experiments	O
,	O
in	O
the	O
acquisition	O
,	O
analysis	O
and	O
interpretation	O
of	O
data	O
,	O
and	O
was	O
involved	O
in	O
drafting	O
the	O
manuscript	O
.	O

RS	O
performed	O
the	O
immunoassays	O
.	O

RM	O
-	O
V	O
participated	O
in	O
the	O
analysis	O
and	O
interpretation	O
of	O
data	O
and	O
performed	O
the	O
statistical	O
analysis	O
.	O

LG	O
-	O
G	O
participated	O
in	O
the	O
analysis	O
and	O
interpretation	O
of	O
data	O
.	O

AV	O
participated	O
in	O
the	O
recruitment	O
of	O
patients	B
and	O
the	O
acquisition	O
of	O
data	O
.	O

RB	O
participated	O
in	O
the	O
interpretation	O
of	O
data	O
,	O
revising	O
the	O
manuscript	O
for	O
intellectual	O
content	O
and	O
giving	O
the	O
final	O
approval	O
of	O
the	O
version	O
to	O
be	O
published	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Identification	O
of	O
a	O
human	B
peripheral	O
blood	O
monocyte	O
subset	O
that	O
differentiates	O
into	O
osteoclasts	O

Abstract	O

Increased	O
bone	O
resorption	O
mediated	O
by	O
osteoclasts	O
causes	O
various	O
diseases	O
such	O
as	O
osteoporosis	O
and	O
bone	O
erosion	O
in	O
rheumatoid	O
arthritis	O
(	O
RA	O
)	O
.	O

Osteoclasts	O
are	O
derived	O
from	O
the	O
monocyte	O
/	O
macrophage	O
lineage	O
,	O
but	O
the	O
precise	O
origin	O
remains	O
unclear	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
show	O
that	O
the	O
purified	O
CD16	O
-	O
human	B
peripheral	O
blood	O
monocyte	O
subset	O
,	O
but	O
not	O
the	O
CD16	O
+	O
monocyte	O
subset	O
,	O
differentiates	O
into	O
osteoclast	O
by	O
stimulation	O
with	O
receptor	O
activator	O
of	O
NF	O
-	O
kappa	O
B	O
ligand	O
(	O
RANKL	O
)	O
in	O
combination	O
with	O
macrophage	O
colony	O
-	O
stimulating	O
factor	O
(	O
M	O
-	O
CSF	O
)	O
.	O

Integrin	O
-	O
beta	O
3	O
mRNA	O
and	O
the	O
integrin	O
-	O
alpha	O
v	O
beta	O
3	O
heterodimer	O
were	O
only	O
expressed	O
on	O
CD16	O
-	O
monocytes	O
,	O
when	O
they	O
were	O
stimulated	O
with	O
RANKL	O
+	O
M	O
-	O
CSF	O
.	O

Downregulation	O
of	O
beta	O
3	O
-	O
subunit	O
expression	O
by	O
small	O
interfering	O
RNA	O
targeting	O
beta	O
3	O
abrogated	O
osteoclastogenesis	O
from	O
the	O
CD16	O
-	O
monocyte	O
subset	O
.	O

In	O
contrast	O
,	O
the	O
CD16	O
+	O
monocyte	O
subset	O
expressed	O
larger	O
amounts	O
of	O
tumor	O
necrosis	O
factor	O
alpha	O
and	O
IL	O
-	O
6	O
than	O
the	O
CD16	O
-	O
subset	O
,	O
which	O
was	O
further	O
enhanced	O
by	O
RANKL	O
stimulation	O
.	O

Examination	O
of	O
RA	O
synovial	O
tissue	O
showed	O
accumulation	O
of	O
both	O
CD16	O
+	O
and	O
CD16	O
-	O
macrophages	O
.	O

Our	O
results	O
suggest	O
that	O
peripheral	O
blood	O
monocytes	O
consist	O
of	O
two	O
functionally	O
heterogeneous	O
subsets	O
with	O
distinct	O
responses	O
to	O
RANKL	O
.	O

Osteoclasts	O
seem	O
to	O
originate	O
from	O
CD16	O
-	O
monocytes	O
,	O
and	O
integrin	O
beta	O
3	O
is	O
necessary	O
for	O
osteoclastogenesis	O
.	O

Blockade	O
of	O
accumulation	O
and	O
activation	O
of	O
CD16	O
-	O
monocytes	O
could	O
therefore	O
be	O
a	O
beneficial	O
approach	O
as	O
an	O
anti	O
-	O
bone	O
resorptive	O
therapy	O
,	O
especially	O
for	O
RA	O
.	O

Introduction	O

Rheumatoid	O
arthritis	O
(	O
RA	O
)	O
is	O
an	O
autoimmune	O
disease	O
characterized	O
by	O
chronic	O
inflammation	O
and	O
proliferation	O
of	O
the	O
synovium	O
in	O
multiple	O
joints	O
.	O

A	O
large	O
number	O
of	O
inflammatory	O
cells	O
,	O
including	O
T	O
cells	O
,	O
B	O
cells	O
,	O
macrophages	O
and	O
dendritic	O
cells	O
,	O
accumulate	O
in	O
the	O
affected	O
synovium	O
,	O
and	O
these	O
inflammatory	O
cells	O
,	O
together	O
with	O
fibroblast	O
-	O
like	O
synoviocytes	O
,	O
express	O
various	O
cytokines	O
,	O
such	O
as	O
tumor	O
necrosis	O
factor	O
alpha	O
(	O
TNF	O
alpha	O
)	O
,	O
IL	O
-	O
6	O
and	O
receptor	O
activator	O
of	O
NF	O
-	O
kappa	O
B	O
ligand	O
(	O
RANKL	O
)	O
,	O
which	O
are	O
known	O
to	O
induce	O
differentiation	O
and	O
activation	O
of	O
osteoclasts	O
.	O

The	O
inflammatory	O
synovial	O
tissue	O
,	O
known	O
as	O
pannus	O
,	O
invades	O
the	O
articular	O
bone	O
and	O
causes	O
focal	O
bone	O
erosion	O
,	O
which	O
is	O
the	O
hallmark	O
of	O
RA	O
.	O

Histopathologically	O
,	O
osteoclasts	O
are	O
present	O
at	O
the	O
interface	O
of	O
the	O
pannus	O
and	O
bone	O
.	O

Interestingly	O
,	O
the	O
deletion	O
of	O
RANKL	O
or	O
c	O
-	O
Fos	O
gene	O
,	O
which	O
is	O
important	O
for	O
osteoclastogenesis	O
,	O
results	O
in	O
minimal	O
bone	O
destruction	O
in	O
mouse	B
models	O
of	O
arthritis	O
[	O
1	O
,	O
2	O
]	O
.	O

Furthermore	O
,	O
other	O
studies	O
indicated	O
that	O
inhibition	O
of	O
osteoclastogenesis	O
by	O
osteoprotegerin	O
,	O
a	O
decoy	O
receptor	O
for	O
RANKL	O
,	O
limits	O
bone	O
destruction	O
in	O
experimental	O
models	O
of	O
arthritis	O
.	O

These	O
studies	O
suggest	O
that	O
osteoclasts	O
are	O
involved	O
in	O
focal	O
bone	O
erosion	O
in	O
RA	O
[	O
3	O
]	O
.	O

Osteoclasts	O
are	O
derived	O
from	O
the	O
monocyte	O
/	O
macrophage	O
lineage	O
.	O

It	O
is	O
reported	O
that	O
osteoclast	O
precursors	O
reside	O
in	O
human	B
peripheral	O
blood	O
monocytes	O
[	O
4	O
,	O
5	O
]	O
.	O

A	O
marked	O
increase	O
of	O
the	O
circulating	O
osteoclast	O
precursors	O
was	O
demonstrated	O
in	O
patients	B
with	O
erosive	O
psoriatic	O
arthritis	O
as	O
well	O
as	O
in	O
arthritic	O
TNF	O
alpha	O
transgenic	O
mice	B
[	O
6	O
,	O
7	O
]	O
.	O

It	O
was	O
also	O
shown	O
that	O
peripheral	O
monocytes	O
differentiate	O
into	O
osteoclasts	O
when	O
seeded	O
on	O
RANKL	O
/	O
osteoclast	O
differentiation	O
factor	O
-	O
producing	O
RA	O
synovial	O
fibroblasts	O
[	O
8	O
]	O
.	O

In	O
addition	O
,	O
RA	O
synovial	O
macrophages	O
thought	O
to	O
originate	O
from	O
peripheral	O
blood	O
monocytes	O
were	O
shown	O
to	O
differentiate	O
into	O
osteoclasts	O
[	O
9	O
,	O
10	O
]	O
.	O

Monocytes	O
are	O
therefore	O
involved	O
not	O
only	O
in	O
synovial	O
inflammation	O
,	O
but	O
also	O
in	O
bone	O
remodeling	O
as	O
potential	O
precursors	O
for	O
synovial	O
macrophages	O
and	O
osteoclasts	O
.	O

Human	B
peripheral	O
blood	O
monocytes	O
consist	O
of	O
two	O
major	O
subsets	O
,	O
CD16	O
+	O
and	O
CD16	O
-	O
,	O
comprising	O
5	O
-	O
10	O
%	O
and	O
90	O
-	O
95	O
%	O
of	O
the	O
monocytes	O
,	O
respectively	O
.	O

These	O
two	O
subsets	O
exhibit	O
different	O
chemotaxis	O
activities	O
and	O
potential	O
of	O
cytokine	O
production	O
[	O
11	O
,	O
12	O
]	O
.	O

Moreover	O
,	O
activation	O
of	O
the	O
Toll	O
-	O
like	O
receptor	O
induces	O
distinct	O
subsets	O
,	O
CD1b	O
+	O
dendritic	O
cells	O
and	O
DC	O
-	O
SIGN	O
+	O
(	O
dendritic	O
cell	O
-	O
specific	O
C	O
-	O
type	O
lectin	O
ICAM	O
-	O
3	O
-	O
grabbing	O
nonintegrin	O
)	O
macrophages	O
from	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O
,	O
respectively	O
[	O
13	O
]	O
.	O

It	O
has	O
not	O
been	O
revealed	O
,	O
however	O
,	O
which	O
monocyte	O
subset	O
develops	O
into	O
osteoclasts	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
determined	O
the	O
human	B
peripheral	O
blood	O
monocyte	O
subset	O
that	O
differentiates	O
into	O
osteoclasts	O
,	O
and	O
revealed	O
that	O
each	O
subset	O
exhibits	O
a	O
different	O
response	O
for	O
osteoclastogenic	O
stimuli	O
.	O

Materials	O
and	O
methods	O

Purification	O
of	O
peripheral	O
blood	O
monocytes	O

Peripheral	O
blood	O
monocytes	O
from	O
healthy	O
donors	O
were	O
collected	O
using	O
Ficoll	O
-	O
Conray	O
(	O
Imuuno	O
-	O
Biological	O
Laboratories	O
,	O
Gunma	O
,	O
Japan	O
)	O
gradient	O
centrifugation	O
.	O

Negative	O
selection	O
of	O
monocytes	O
was	O
performed	O
using	O
MACS	O
microbeads	O
(	O
Miltenyi	O
Biotec	O
,	O
Auburn	O
,	O
CA	O
,	O
USA	O
)	O
according	O
to	O
the	O
protocol	O
supplied	O
by	O
the	O
manufacturer	O
.	O

The	O
purified	O
monocytes	O
were	O
separated	O
into	O
two	O
subsets	O
,	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O
,	O
using	O
CD16	O
MicroBeads	O
(	O
Miltenyi	O
Biotec	O
)	O
.	O

Flow	O
cytometry	O
analysis	O
using	O
FITC	O
-	O
conjugated	O
mouse	B
anti	O
-	O
CD14	O
mAb	O
(	O
MY4	O
;	O
Bechman	O
Coulter	O
,	O
Fullerton	O
,	O
CA	O
,	O
USA	O
)	O
and	O
phycoerythin	O
-	O
conjugated	O
mouse	B
anti	O
-	O
CD16	O
mAb	O
(	O
3G8	O
;	O
BD	O
Biosciences	O
,	O
San	O
Jose	O
,	O
CA	O
,	O
USA	O
)	O
showed	O
that	O
the	O
purities	O
of	O
the	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O
were	O
more	O
than	O
90	O
%	O
and	O
92	O
%	O
,	O
respectively	O
.	O

For	O
the	O
other	O
experiment	O
,	O
monocytes	O
were	O
purified	O
using	O
CD14	O
MicroBeads	O
(	O
Miltenyi	O
Biotec	O
)	O
,	O
and	O
then	O
stained	O
either	O
with	O
FITC	O
-	O
conjugated	O
mouse	B
anti	O
-	O
CD33	O
mAb	O
(	O
MY9	O
;	O
Bechman	O
Coulter	O
)	O
or	O
phycoerythin	O
-	O
conjugated	O
mouse	B
anti	O
-	O
CD16	O
mAb	O
(	O
3G8	O
)	O
.	O

Cell	O
sorting	O
of	O
the	O
stained	O
cells	O
was	O
performed	O
using	O
a	O
FACS	O
Vantage	O
cytometer	O
(	O
BD	O
Biosciences	O
)	O
or	O
a	O
MoFlo	O
cell	O
sorter	O
(	O
Dako	O
,	O
Glostrup	O
,	O
Denmark	O
)	O
.	O

Osteoclast	O
differentiation	O

Purified	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O
(	O
5	O
x	O
104	O
cells	O
/	O
well	O
)	O
were	O
incubated	O
in	O
96	O
-	O
well	O
plates	O
in	O
alpha	O
MEM	O
(	O
Sigma	O
,	O
St	O
Louis	O
,	O
MO	O
,	O
USA	O
)	O
with	O
heat	O
-	O
inactivated	O
10	O
%	O
fetal	O
bovine	B
serum	O
(	O
FBS	O
)	O
(	O
Sigma	O
)	O
or	O
with	O
Ultra	O
-	O
Low	O
IgG	O
FBS	O
(	O
IgG	O
<	O
5	O
mu	O
g	O
/	O
ml	O
;	O
Invitrogen	O
,	O
Carlsbad	O
,	O
CA	O
,	O
USA	O
)	O
,	O
and	O
where	O
indicated	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
(	O
Peprotech	O
,	O
Rocky	O
Hill	O
,	O
NJ	O
,	O
USA	O
)	O
.	O

For	O
the	O
other	O
experiments	O
,	O
varied	O
numbers	O
of	O
CD16	O
+	O
monocytes	O
(	O
1	O
x	O
103	O
,	O
2	O
.	O
5	O
x	O
103	O
,	O
5	O
x	O
103	O
)	O
were	O
mixed	O
with	O
CD16	O
-	O
monocytes	O
(	O
5	O
x	O
104	O
cells	O
/	O
well	O
)	O
,	O
and	O
were	O
cultured	O
in	O
96	O
-	O
well	O
plates	O
in	O
alpha	O
MEM	O
with	O
heat	O
-	O
inactivated	O
10	O
%	O
FBS	O
.	O

The	O
medium	O
was	O
replaced	O
with	O
fresh	O
medium	O
3	O
days	O
later	O
,	O
and	O
after	O
incubation	O
for	O
7	O
days	O
the	O
cells	O
were	O
stained	O
for	O
tartrate	O
-	O
resistant	O
acid	O
phosphatase	O
(	O
TRAP	O
)	O
expression	O
using	O
a	O
commercial	O
kit	O
(	O
Hokudo	O
,	O
Sapporo	O
,	O
Japan	O
)	O
.	O

The	O
number	O
of	O
TRAP	O
-	O
positive	O
multinucleated	O
cells	O
(	O
MNC	O
)	O
in	O
three	O
randomly	O
selected	O
fields	O
examined	O
at	O
100	O
x	O
magnification	O
or	O
the	O
total	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
per	O
well	O
was	O
counted	O
under	O
light	O
microscopy	O
.	O

Resorption	O
assay	O

Monocytes	O
were	O
seeded	O
onto	O
plates	O
coated	O
with	O
calcium	O
phosphate	O
thin	O
films	O
(	O
Biocoat	O
Osteologic	O
;	O
BD	O
Biosciences	O
)	O
and	O
were	O
incubated	O
with	O
RANKL	O
(	O
40	O
ng	O
/	O
ml	O
)	O
+	O
M	O
-	O
CSF	O
(	O
25	O
ng	O
/	O
ml	O
)	O
for	O
7	O
days	O
.	O

The	O
cells	O
were	O
then	O
lysed	O
in	O
bleach	O
solution	O
(	O
6	O
%	O
NaOCl	O
,	O
5	O
.	O
2	O
%	O
NaCl	O
)	O
.	O

The	O
resorption	O
lacunae	O
were	O
examined	O
under	O
light	O
microscopy	O
.	O

Enzyme	O
-	O
linked	O
immunosorbent	O
assay	O

Purified	O
monocytes	O
were	O
cultured	O
in	O
96	O
-	O
well	O
plates	O
where	O
indicated	O
either	O
with	O
RANKL	O
or	O
M	O
-	O
CSF	O
for	O
24	O
hours	O
.	O

Concentrations	O
of	O
TNF	O
alpha	O
and	O
IL	O
-	O
6	O
in	O
the	O
culture	O
supernatant	O
were	O
measured	O
with	O
an	O
ELISA	O
kit	O
(	O
BioSourse	O
International	O
,	O
Camarillo	O
,	O
CA	O
,	O
USA	O
)	O
.	O

For	O
experiments	O
of	O
matrix	O
metalloproteinase	O
(	O
MMP	O
)	O
-	O
9	O
and	O
TRAP	O
-	O
5b	O
,	O
culture	O
supernatants	O
were	O
collected	O
on	O
day	O
7	O
and	O
the	O
concentrations	O
of	O
these	O
enzymes	O
were	O
measured	O
using	O
an	O
MMP	O
-	O
9	O
ELISA	O
kit	O
(	O
Amersham	O
Biosciences	O
,	O
Piscataway	O
,	O
NJ	O
,	O
USA	O
)	O
or	O
a	O
TRAP	O
-	O
5b	O
ELISA	O
kit	O
(	O
Suomen	O
,	O
Turku	O
,	O
Finland	O
)	O
.	O

Reverse	O
transcriptase	O
-	O
polymerase	O
chain	O
reaction	O

Monocytes	O
(	O
1	O
x	O
106	O
cells	O
/	O
well	O
)	O
were	O
cultured	O
in	O
six	O
-	O
well	O
plates	O
with	O
M	O
-	O
CSF	O
alone	O
or	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
for	O
3	O
days	O
.	O

Total	O
RNA	O
was	O
extracted	O
using	O
RNeasy	O
Micro	O
(	O
Qiagen	O
,	O
Valencia	O
,	O
CA	O
,	O
USA	O
)	O
.	O

The	O
RNA	O
was	O
then	O
treated	O
with	O
DNase	O
I	O
(	O
Qiagen	O
)	O
.	O

The	O
oligo	O
(	O
dT	O
)	O
-	O
primed	O
cDNA	O
was	O
synthesized	O
using	O
Superscript	O
II	O
reverse	O
transcriptase	O
(	O
Invitrogen	O
)	O
.	O

The	O
amount	O
of	O
cDNA	O
for	O
amplification	O
was	O
adjusted	O
by	O
the	O
amount	O
of	O
RNA	O
measured	O
by	O
an	O
optical	O
density	O
meter	O
and	O
also	O
by	O
beta	O
-	O
actin	O
or	O
GAPDH	O
PCR	O
products	O
.	O

One	O
microliter	O
of	O
cDNA	O
was	O
amplified	O
in	O
a	O
50	O
mu	O
l	O
final	O
volume	O
containing	O
25	O
pmol	O
appropriate	O
primer	O
pair	O
,	O
10	O
pmol	O
each	O
of	O
the	O
four	O
deoxynucleotide	O
triphosphates	O
,	O
and	O
5	O
units	O
FastStart	O
Taq	O
DNA	O
Polymerase	O
(	O
Roche	O
,	O
Manheim	O
,	O
Germany	O
)	O
in	O
a	O
thermal	O
cycler	O
(	O
PTC	O
-	O
200	O
;	O
MJ	O
GeneWorks	O
,	O
Waltham	O
,	O
MA	O
,	O
USA	O
)	O
.	O

The	O
PCR	O
conditions	O
were	O
25	O
-	O
40	O
cycles	O
of	O
denaturation	O
(	O
95	O
degrees	O
C	O
for	O
30	O
s	O
)	O
,	O
annealing	O
(	O
60	O
-	O
62	O
degrees	O
C	O
for	O
1	O
min	O
)	O
and	O
extension	O
(	O
72	O
degrees	O
C	O
for	O
1	O
min	O
)	O
.	O

The	O
sequences	O
of	O
the	O
primers	O
are	O
presented	O
in	O
Table	O
1	O
.	O

The	O
PCR	O
products	O
were	O
separated	O
by	O
electrophoresis	O
through	O
2	O
%	O
agarose	O
gel	O
.	O

Western	O
immunoblot	O
analysis	O

Purified	O
monocytes	O
were	O
cultured	O
for	O
3	O
days	O
in	O
the	O
presence	O
of	O
40	O
ng	O
/	O
ml	O
M	O
-	O
CSF	O
with	O
or	O
without	O
25	O
ng	O
/	O
ml	O
RANKL	O
.	O

Cells	O
were	O
lysed	O
in	O
RIPA	O
Lysis	O
buffer	O
(	O
upstate	O
,	O
Lake	O
Placid	O
,	O
NY	O
,	O
USA	O
)	O
containing	O
protease	O
inhibitors	O
(	O
Roche	O
)	O
for	O
15	O
min	O
at	O
4	O
degrees	O
C	O
.	O

A	O
total	O
of	O
20	O
mu	O
g	O
protein	O
was	O
boiled	O
in	O
the	O
presence	O
of	O
6	O
x	O
sodium	O
dodecyl	O
sulfate	O
sample	O
buffer	O
,	O
and	O
was	O
separated	O
on	O
7	O
.	O
5	O
%	O
or	O
10	O
%	O
sodium	O
dodecyl	O
sulfate	O
-	O
polyacrylamide	O
gel	O
(	O
ATTO	O
,	O
Tokyo	O
,	O
Japan	O
)	O
.	O

Proteins	O
were	O
then	O
electrotransferred	O
to	O
a	O
polyvinylidene	O
fluoride	O
microporous	O
membrane	O
(	O
Millipore	O
,	O
Billerica	O
,	O
MA	O
,	O
USA	O
)	O
in	O
a	O
semidry	O
system	O
.	O

Membranes	O
were	O
incubated	O
in	O
10	O
%	O
skim	O
milk	O
prepared	O
in	O
phosphate	O
-	O
buffered	O
saline	O
(	O
PBS	O
)	O
containing	O
0	O
.	O
1	O
%	O
Tween	O
20	O
,	O
and	O
were	O
subjected	O
to	O
immunoblotting	O
.	O

Antibodies	O
used	O
were	O
goat	B
anti	O
-	O
RANK	O
antibody	O
(	O
Techne	O
Corporation	O
,	O
Minneapolis	O
,	O
MN	O
,	O
USA	O
)	O
,	O
goat	B
anti	O
-	O
c	O
-	O
fms	O
antibody	O
(	O
R	O
&	O
D	O
systems	O
,	O
Minneapolis	O
,	O
MN	O
,	O
USA	O
)	O
,	O
and	O
mouse	B
anti	O
-	O
beta	O
-	O
actin	O
mAb	O
(	O
AC	O
-	O
15	O
;	O
Sigma	O
)	O
.	O

Peroxidase	O
-	O
conjugated	O
rabbit	B
anti	O
-	O
goat	B
IgG	O
antibody	O
(	O
Dako	O
)	O
or	O
peroxidase	O
-	O
conjugated	O
rabbit	B
anti	O
-	O
mouse	B
IgG	O
antibody	O
(	O
Dako	O
)	O
was	O
used	O
as	O
the	O
second	O
antibody	O
.	O

The	O
signals	O
were	O
visualized	O
by	O
chemiluminescence	O
reagent	O
(	O
ECL	O
;	O
Amersham	O
Biocsiences	O
,	O
Little	O
Chalfont	O
,	O
UK	O
)	O
.	O

Cell	O
surface	O
expression	O
of	O
c	O
-	O
fms	O

The	O
following	O
mAbs	O
were	O
used	O
for	O
analysis	O
of	O
c	O
-	O
fms	O
expression	O
:	O
Alexa	O
647	O
-	O
conjugated	O
anti	O
-	O
CD14	O
mAb	O
(	O
UCHM1	O
;	O
Serotec	O
,	O
Oxford	O
,	O
UK	O
)	O
,	O
FITC	O
-	O
conjugated	O
anti	O
-	O
CD16	O
mAb	O
(	O
3G8	O
;	O
Bechman	O
Coulter	O
)	O
and	O
phycoerythin	O
-	O
conjugated	O
anti	O
-	O
c	O
-	O
fms	O
mAb	O
(	O
61708	O
;	O
R	O
&	O
D	O
systems	O
)	O
.	O

Alexa	O
647	O
-	O
conjugated	O
mouse	B
IgG2a	O
(	O
Serotec	O
)	O
,	O
FITC	O
-	O
conjugated	O
mouse	B
IgG1	O
(	O
BD	O
Biosciences	O
)	O
and	O
phycoerythin	O
-	O
conjugated	O
mouse	B
IgG1	O
(	O
Bechman	O
Coulter	O
)	O
were	O
used	O
as	O
isotype	O
controls	O
.	O

Peripheral	O
blood	O
monocytes	O
(	O
1	O
x	O
105	O
cells	O
)	O
were	O
incubated	O
with	O
1	O
mu	O
g	O
human	B
IgG	O
for	O
15	O
minutes	O
,	O
and	O
were	O
then	O
stained	O
with	O
three	O
fluorochrome	O
-	O
labeled	O
mAbs	O
for	O
45	O
minutes	O
on	O
ice	O
.	O

The	O
stained	O
cells	O
were	O
analyzed	O
with	O
a	O
FACS	O
Calibur	O
(	O
BD	O
Biosciences	O
)	O
.	O

Immunofluorescent	O
staining	O

Monocytes	O
(	O
8	O
x	O
104	O
cells	O
/	O
well	O
)	O
were	O
allowed	O
to	O
adhere	O
on	O
96	O
-	O
well	O
plates	O
overnight	O
or	O
were	O
cultured	O
with	O
M	O
-	O
CSF	O
and	O
RANKL	O
for	O
2	O
-	O
4	O
days	O
.	O

The	O
cells	O
were	O
fixed	O
in	O
acetone	O
and	O
then	O
stained	O
with	O
anti	O
-	O
alpha	O
v	O
beta	O
3	O
mAb	O
(	O
LM609	O
;	O
Chemicon	O
,	O
Temecula	O
,	O
CA	O
,	O
USA	O
)	O
or	O
mouse	B
IgG1	O
(	O
11711	O
;	O
R	O
&	O
D	O
Systems	O
)	O
as	O
an	O
isotype	O
-	O
matched	O
control	O
.	O

Alexa	O
fluor546	O
-	O
conjugated	O
goat	B
anti	O
-	O
mouse	B
IgG1	O
antibody	O
(	O
Molecular	O
Probes	O
,	O
Eugene	O
,	O
OR	O
,	O
USA	O
)	O
was	O
used	O
as	O
the	O
second	O
antibody	O
.	O

TOTO	O
-	O
3	O
(	O
Molecular	O
Probes	O
)	O
was	O
used	O
for	O
nuclear	O
staining	O
.	O

Flow	O
cytometric	O
analysis	O
of	O
p38	O
MAPK	O
and	O
ERK1	O
/	O
2	O
phosphorylation	O

Purified	O
monocytes	O
were	O
cultured	O
in	O
the	O
presence	O
of	O
25	O
ng	O
/	O
ml	O
M	O
-	O
CSF	O
for	O
3	O
days	O
,	O
and	O
were	O
either	O
left	O
unstimulated	O
or	O
were	O
stimulated	O
with	O
40	O
ng	O
/	O
ml	O
RANKL	O
at	O
37	O
degrees	O
C	O
.	O

Stimulations	O
were	O
stopped	O
by	O
adding	O
an	O
equal	O
volume	O
of	O
PhosFlow	O
Fix	O
Buffer	O
I	O
solution	O
(	O
BD	O
Biosciences	O
)	O
to	O
the	O
cell	O
culture	O
.	O

After	O
incubation	O
for	O
10	O
minutes	O
at	O
37	O
degrees	O
C	O
,	O
the	O
cells	O
were	O
permeabilized	O
by	O
washing	O
twice	O
at	O
room	O
temperature	O
in	O
PhosFlow	O
Perm	O
/	O
Wash	O
Buffer	O
I	O
(	O
BD	O
Biosciences	O
)	O
.	O

A	O
total	O
of	O
1	O
x	O
105	O
cells	O
was	O
then	O
Fc	O
blocked	O
with	O
1	O
mu	O
g	O
human	B
IgG	O
for	O
15	O
minutes	O
,	O
and	O
was	O
stained	O
with	O
Alexa	O
Fluor	O
647	O
-	O
conjugated	O
mAb	O
either	O
to	O
phospho	O
-	O
p38	O
MAPK	O
(	O
T180	O
/	O
Y182	O
)	O
or	O
to	O
phospho	O
-	O
ERK1	O
/	O
2	O
(	O
T202	O
/	O
Y204	O
)	O
(	O
BD	O
Biosciences	O
)	O
for	O
30	O
minutes	O
at	O
room	O
temperature	O
.	O

Alexa	O
Fluor	O
647	O
-	O
conjugated	O
mouse	B
IgG1	O
(	O
BD	O
Biosciences	O
)	O
was	O
used	O
as	O
an	O
isotype	O
control	O
.	O

The	O
cells	O
were	O
washed	O
in	O
PhosFlow	O
Perm	O
/	O
Wash	O
Buffer	O
I	O
,	O
and	O
were	O
analyzed	O
by	O
flow	O
cytometry	O
,	O
as	O
already	O
described	O
.	O

RNA	O
interference	O

RNA	O
oligonucleotides	O
(	O
iGENE	O
,	O
Tsukuba	O
,	O
Japan	O
)	O
were	O
designed	O
based	O
on	O
the	O
algorithm	O
that	O
incorporates	O
single	O
nucleotide	O
polymorphism	O
and	O
homology	O
screening	O
to	O
ensure	O
a	O
target	O
-	O
specific	O
RNA	O
interference	O
effect	O
.	O

The	O
following	O
sense	O
and	O
antisense	O
oligonucleotides	O
were	O
used	O
:	O
integrin	O
beta	O
3	O
,	O
5	O
'	O
-	O
GCU	O
UCA	O
AUG	O
AGG	O
AAG	O
UGA	O
AGA	O
AGC	O
A	O
-	O
AG	O
and	O
3	O
'	O
-	O
UA	O
-	O
CGA	O
AGU	O
UAC	O
UCC	O
UUC	O
ACU	O
UCU	O
UCG	O
U	O
;	O
randomized	O
control	O
,	O
5	O
'	O
-	O
CGA	O
UUC	O
GCU	O
AGA	O
CCG	O
GCU	O
UCA	O
UUG	O
C	O
-	O
AG	O
and	O
3	O
'	O
-	O
UA	O
-	O
GCU	O
AAG	O
CGA	O
UCU	O
GGC	O
CGA	O
AGU	O
AAC	O
G	O
;	O
and	O
lamin	O
,	O
5	O
'	O
-	O
GAG	O
GAA	O
CUG	O
GAC	O
UUC	O
CAG	O
AAG	O
AAC	O
A	O
-	O
AG	O
and	O
3	O
'	O
-	O
UA	O
-	O
CUC	O
CUU	O
GAC	O
CUG	O
AAG	O
GUC	O
UUC	O
UUG	O
U	O
.	O

CD16	O
-	O
monocytes	O
(	O
8	O
x	O
104	O
cells	O
/	O
well	O
)	O
were	O
incubated	O
in	O
96	O
-	O
well	O
plates	O
in	O
optimem	O
(	O
Invitrogen	O
)	O
.	O

After	O
1	O
hour	O
,	O
siRNAs	O
were	O
transfected	O
into	O
the	O
cells	O
using	O
oligofectamine	O
(	O
Qiagen	O
)	O
based	O
on	O
the	O
method	O
recommended	O
by	O
the	O
manufacturer	O
.	O

After	O
2	O
hours	O
,	O
the	O
cells	O
were	O
washed	O
once	O
with	O
PBS	O
,	O
followed	O
by	O
the	O
addition	O
of	O
alpha	O
MEM	O
supplemented	O
with	O
10	O
%	O
FBS	O
,	O
M	O
-	O
CSF	O
and	O
RANKL	O
.	O

After	O
a	O
2	O
-	O
day	O
incubation	O
,	O
the	O
beta	O
3	O
mRNA	O
expression	O
was	O
analyzed	O
by	O
RT	O
-	O
PCR	O
with	O
different	O
PCR	O
cycles	O
,	O
as	O
described	O
earlier	O
.	O

Immunofluorescent	O
staining	O
for	O
the	O
alpha	O
v	O
beta	O
3	O
heterodimer	O
was	O
also	O
performed	O
as	O
described	O
above	O
,	O
and	O
numbers	O
of	O
alpha	O
v	O
beta	O
3	O
-	O
positive	O
cells	O
were	O
counted	O
in	O
randomly	O
selected	O
three	O
fields	O
at	O
100	O
x	O
magnification	O
.	O

Seven	O
days	O
after	O
the	O
transfection	O
of	O
siRNAs	O
,	O
the	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
in	O
five	O
fields	O
examined	O
at	O
100	O
x	O
magnification	O
was	O
counted	O
under	O
light	O
microscopy	O
.	O

Inhibition	O
of	O
osteoclastogenesis	O
with	O
cyclic	O
RGDfV	O
peptide	O

CD16	O
-	O
monocytes	O
were	O
incubated	O
in	O
96	O
-	O
well	O
plates	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
for	O
2	O
days	O
.	O

A	O
medium	O
containing	O
either	O
cyclic	O
RGDfV	O
peptide	O
(	O
Arg	O
-	O
Gly	O
-	O
Asp	O
-	O
D	O
-	O
Phe	O
-	O
Val	O
)	O
(	O
Calbiochem	O
,	O
San	O
Diego	O
,	O
CA	O
,	O
USA	O
)	O
or	O
dimethyl	O
sulfoxide	O
was	O
then	O
added	O
.	O

After	O
incubation	O
for	O
a	O
further	O
5	O
days	O
,	O
the	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
in	O
five	O
fields	O
examined	O
at	O
100	O
x	O
magnification	O
was	O
counted	O
under	O
light	O
microscopy	O
.	O

Immunohistochemistry	O

Synovial	O
tissue	O
samples	O
were	O
obtained	O
during	O
total	O
knee	O
joint	O
replacement	O
surgery	O
from	O
four	O
RA	O
patients	B
.	O

Signed	O
consent	O
forms	O
were	O
obtained	O
before	O
the	O
operation	O
.	O

The	O
experimental	O
protocol	O
was	O
approved	O
by	O
the	O
ethics	O
committee	O
of	O
the	O
Tokyo	O
Medical	O
and	O
Dental	O
University	O
.	O

RA	O
was	O
diagnosed	O
according	O
to	O
the	O
American	O
College	O
of	O
Rheumatology	O
criteria	O
[	O
14	O
]	O
.	O

Double	O
immunofluorescent	O
staining	O
for	O
CD68	O
and	O
CD16	O
antigens	O
was	O
conducted	O
on	O
optimal	O
cutting	O
temperature	O
-	O
embedded	O
sections	O
of	O
frozen	O
synovial	O
samples	O
.	O

Eight	O
-	O
micrometer	O
-	O
thick	O
cryostat	O
sections	O
of	O
RA	O
synovium	O
were	O
fixed	O
in	O
acetone	O
for	O
3	O
minutes	O
and	O
were	O
then	O
rehydrated	O
in	O
PBS	O
for	O
5	O
minutes	O
.	O

The	O
samples	O
were	O
incubated	O
in	O
5	O
mu	O
g	O
/	O
ml	O
proteinase	O
K	O
(	O
Roche	O
)	O
,	O
50	O
mM	O
ethylenediamine	O
tetraacetic	O
acid	O
,	O
100	O
mM	O
Tris	O
-	O
HCl	O
,	O
pH	O
8	O
.	O
0	O
,	O
for	O
15	O
minutes	O
at	O
room	O
temperature	O
followed	O
by	O
a	O
wash	O
in	O
PBS	O
.	O

The	O
samples	O
were	O
then	O
blocked	O
with	O
10	O
%	O
goat	B
serum	O
in	O
PBS	O
for	O
60	O
minutes	O
at	O
room	O
temperature	O
,	O
and	O
were	O
incubated	O
with	O
anti	O
-	O
CD16	O
mAb	O
(	O
3G8	O
;	O
Immunotech	O
,	O
Marseille	O
,	O
France	O
)	O
or	O
mouse	B
IgG1	O
(	O
11711	O
)	O
as	O
an	O
isotype	O
-	O
matched	O
control	O
in	O
1	O
%	O
bovine	B
serum	O
albumin	O
/	O
PBS	O
for	O
60	O
minutes	O
at	O
room	O
temperature	O
.	O

The	O
samples	O
were	O
then	O
washed	O
three	O
times	O
in	O
PBS	O
,	O
for	O
5	O
minutes	O
each	O
,	O
and	O
incubated	O
with	O
Alexa	O
fluor546	O
-	O
conjugated	O
goat	B
anti	O
-	O
mouse	B
IgG1	O
antibody	O
(	O
Molecular	O
Probes	O
)	O
in	O
1	O
%	O
bovine	B
serum	O
albumin	O
/	O
PBS	O
for	O
60	O
minutes	O
at	O
room	O
temperature	O
.	O

The	O
samples	O
were	O
then	O
sequentially	O
stained	O
for	O
CD68	O
antigen	O
in	O
a	O
manner	O
similar	O
to	O
that	O
used	O
for	O
CD16	O
staining	O
.	O

The	O
samples	O
were	O
stained	O
with	O
anti	O
-	O
CD68	O
mAb	O
(	O
PGM1	O
;	O
Immunotech	O
)	O
or	O
mouse	B
IgG3	O
(	O
6A3	O
;	O
MBL	O
,	O
Nagoya	O
,	O
Japan	O
)	O
followed	O
by	O
labeling	O
with	O
Alexa	O
fluor488	O
-	O
conjugated	O
goat	B
anti	O
-	O
mouse	B
IgG3	O
antibody	O
(	O
Molecular	O
Probes	O
)	O
.	O

The	O
samples	O
were	O
examined	O
by	O
confocal	O
laser	O
scanning	O
microscope	O
(	O
Olympus	O
,	O
Tokyo	O
,	O
Japan	O
)	O
.	O

Statistical	O
analysis	O

Data	O
are	O
expressed	O
as	O
the	O
mean	O
+	O
/	O
-	O
standard	O
error	O
of	O
the	O
mean	O
.	O

A	O
nonpaired	O
Student	O
'	O
s	O
t	O
test	O
was	O
used	O
for	O
comparison	O
,	O
using	O
the	O
StatView	O
program	O
(	O
Abacus	O
Concepts	O
,	O
Berkeley	O
,	O
CA	O
,	O
USA	O
)	O
.	O

P	O
<	O
0	O
.	O
05	O
was	O
considered	O
statistically	O
significant	O
.	O

Results	O

Induction	O
of	O
osteoclasts	O
from	O
CD16	O
-	O
peripheral	O
blood	O
monocytes	O

To	O
identify	O
the	O
monocyte	O
subset	O
that	O
differentiates	O
into	O
osteoclasts	O
,	O
we	O
examined	O
osteoclast	O
formation	O
from	O
CD16	O
+	O
and	O
CD16	O
-	O
human	B
peripheral	O
blood	O
monocytes	O
.	O

The	O
monocyte	O
subsets	O
were	O
purified	O
using	O
magnetic	O
beads	O
.	O

Incubation	O
with	O
M	O
-	O
CSF	O
alone	O
did	O
not	O
induce	O
osteoclast	O
formation	O
from	O
either	O
subset	O
(	O
Figure	O
1a	O
)	O
.	O

Culture	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
induced	O
a	O
significant	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
from	O
the	O
CD16	O
-	O
subset	O
,	O
whereas	O
only	O
few	O
CD16	O
+	O
monocytes	O
differentiated	O
into	O
TRAP	O
-	O
positive	O
MNC	O
(	O
Figure	O
1a	O
,	O
b	O
)	O
.	O

We	O
then	O
assessed	O
the	O
bone	O
resorptive	O
ability	O
by	O
culturing	O
cells	O
on	O
calcium	O
phosphate	O
-	O
coated	O
plates	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
.	O

Resorption	O
lacunae	O
were	O
detected	O
only	O
in	O
the	O
CD16	O
-	O
subset	O
(	O
Figure	O
1c	O
)	O
,	O
indicating	O
the	O
TRAP	O
-	O
positive	O
CD16	O
-	O
-	O
derived	O
MNC	O
possessed	O
the	O
osteoclast	O
phenotype	O
.	O

Similar	O
results	O
were	O
obtained	O
using	O
purified	O
monocytes	O
by	O
FACS	O
sorting	O
(	O
purities	O
:	O
CD16	O
+	O
,	O
96	O
%	O
;	O
CD16	O
-	O
,	O
97	O
%	O
)	O
.	O

The	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
induced	O
were	O
36	O
+	O
/	O
-	O
3	O
cells	O
/	O
well	O
and	O
348	O
+	O
/	O
-	O
13	O
cells	O
/	O
well	O
from	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O
,	O
respectively	O
.	O

To	O
exclude	O
the	O
possibility	O
that	O
the	O
anti	O
-	O
CD16	O
antibody	O
used	O
for	O
isolation	O
of	O
CD16	O
+	O
monocytes	O
inhibits	O
osteoclast	O
formation	O
,	O
we	O
separated	O
the	O
two	O
subsets	O
,	O
CD33low	O
monocytes	O
and	O
CD33high	O
monocytes	O
,	O
using	O
anti	O
-	O
CD33	O
mAb	O
and	O
a	O
fluorescent	O
cell	O
sorter	O
,	O
since	O
it	O
was	O
reported	O
that	O
CD33low	O
monocytes	O
correspond	O
to	O
CD16	O
+	O
,	O
and	O
that	O
CD33high	O
correspond	O
to	O
CD16	O
-	O
monocytes	O
[	O
15	O
]	O
.	O

On	O
average	O
,	O
the	O
CD33low	O
population	O
contained	O
CD16	O
-	O
(	O
10	O
.	O
2	O
%	O
)	O
/	O
CD16	O
+	O
(	O
89	O
.	O
8	O
%	O
)	O
monocytes	O
,	O
and	O
the	O
CD33high	O
population	O
contained	O
CD16	O
-	O
(	O
86	O
.	O
3	O
%	O
)	O
/	O
CD16	O
+	O
(	O
13	O
.	O
7	O
%	O
)	O
monocytes	O
.	O

Culture	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
induced	O
TRAP	O
-	O
positive	O
MNC	O
from	O
CD33high	O
monocytes	O
,	O
whereas	O
no	O
or	O
few	O
CD33low	O
monocytes	O
differentiated	O
into	O
TRAP	O
-	O
positive	O
MNC	O
(	O
CD33low	O
vs	O
CD33high	O
,	O
2	O
+	O
/	O
-	O
1	O
vs	O
192	O
+	O
/	O
-	O
71	O
cells	O
/	O
well	O
;	O
n	O
=	O
3	O
)	O
.	O

TRAP	O
-	O
5b	O
and	O
MMP	O
-	O
9	O
in	O
the	O
culture	O
supernatants	O
,	O
both	O
of	O
which	O
are	O
known	O
to	O
be	O
produced	O
by	O
osteoclasts	O
,	O
were	O
measured	O
by	O
ELISA	O
.	O

The	O
concentrations	O
of	O
both	O
enzymes	O
were	O
significantly	O
higher	O
in	O
the	O
culture	O
supernatant	O
of	O
CD16	O
-	O
monocytes	O
than	O
in	O
that	O
of	O
CD16	O
+	O
monocytes	O
(	O
Figure	O
1d	O
)	O
.	O

These	O
results	O
suggest	O
that	O
the	O
CD16	O
-	O
peripheral	O
blood	O
monocyte	O
subset	O
,	O
but	O
not	O
the	O
CD16	O
+	O
subset	O
,	O
differentiate	O
into	O
osteoclasts	O
by	O
incubation	O
with	O
RANKL	O
+	O
M	O
-	O
CSF	O
.	O

CD16	O
+	O
monocytes	O
do	O
not	O
affect	O
the	O
osteoclastogenesis	O
from	O
CD16	O
-	O
monocytes	O

To	O
examine	O
whether	O
CD16	O
+	O
monocytes	O
affect	O
osteoclastogenesis	O
from	O
CD16	O
-	O
monocytes	O
,	O
varied	O
numbers	O
of	O
CD16	O
+	O
monocytes	O
were	O
mixed	O
with	O
CD16	O
-	O
monocytes	O
(	O
5	O
x	O
104	O
cells	O
/	O
well	O
)	O
,	O
and	O
were	O
cultured	O
for	O
7	O
days	O
in	O
the	O
presence	O
of	O
M	O
-	O
CSF	O
+	O
RANKL	O
.	O

The	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
was	O
not	O
altered	O
by	O
the	O
presence	O
of	O
CD16	O
+	O
monocytes	O
(	O
Figure	O
2	O
)	O
.	O

The	O
results	O
indicated	O
that	O
CD16	O
+	O
monocytes	O
did	O
not	O
hamper	O
or	O
enhance	O
the	O
osteoclastogenesis	O
from	O
CD16	O
-	O
monocytes	O
.	O

Differences	O
in	O
cytokine	O
production	O
by	O
RANKL	O
-	O
stimulated	O
or	O
M	O
-	O
CSF	O
-	O
stimulated	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O

To	O
compare	O
the	O
biological	O
response	O
of	O
CD16	O
+	O
and	O
CD16	O
-	O
subsets	O
with	O
either	O
RANKL	O
or	O
M	O
-	O
CSF	O
stimulation	O
,	O
we	O
measured	O
the	O
amount	O
of	O
TNF	O
alpha	O
and	O
IL	O
-	O
6	O
production	O
after	O
exposure	O
of	O
cells	O
to	O
various	O
concentrations	O
of	O
RANKL	O
or	O
M	O
-	O
CSF	O
with	O
an	O
ELISA	O
.	O

Without	O
RANKL	O
the	O
CD16	O
+	O
subset	O
produced	O
a	O
significant	O
amount	O
of	O
TNF	O
alpha	O
and	O
IL	O
-	O
6	O
,	O
whereas	O
the	O
CD16	O
-	O
subset	O
produced	O
undetectable	O
levels	O
(	O
Figure	O
3a	O
)	O
.	O

RANKL	O
stimulation	O
increased	O
TNF	O
alpha	O
production	O
from	O
both	O
subsets	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
,	O
although	O
the	O
CD16	O
+	O
subset	O
produced	O
more	O
TNF	O
alpha	O
than	O
did	O
the	O
CD16	O
-	O
subset	O
.	O

RANKL	O
stimulation	O
also	O
enhanced	O
IL	O
-	O
6	O
production	O
from	O
the	O
CD16	O
+	O
subset	O
,	O
but	O
not	O
from	O
the	O
CD16	O
-	O
subset	O
.	O

M	O
-	O
CSF	O
stimulation	O
increased	O
TNF	O
alpha	O
and	O
IL	O
-	O
6	O
production	O
from	O
both	O
subsets	O
,	O
although	O
the	O
CD16	O
+	O
subset	O
produced	O
more	O
than	O
the	O
CD16	O
-	O
subset	O
(	O
Figure	O
3b	O
)	O
.	O

These	O
results	O
suggest	O
that	O
CD16	O
+	O
monocytes	O
also	O
respond	O
both	O
to	O
RANKL	O
and	O
M	O
-	O
CSF	O
stimulation	O
,	O
although	O
such	O
stimulation	O
does	O
not	O
result	O
in	O
differentiation	O
into	O
osteoclasts	O
.	O

CD16	O
+	O
monocytes	O
were	O
also	O
noted	O
to	O
express	O
higher	O
amounts	O
of	O
inflammatory	O
cytokines	O
compared	O
with	O
CD16	O
-	O
monocytes	O
with	O
or	O
without	O
RANKL	O
or	O
M	O
-	O
CSF	O
stimulation	O
.	O

Comparison	O
of	O
expression	O
levels	O
of	O
molecules	O
involved	O
in	O
osteoclastogenesis	O
between	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O

Diverse	O
molecules	O
are	O
involved	O
in	O
RANKL	O
/	O
RANK	O
and	O
its	O
costimulatory	O
signal	O
transduction	O
pathways	O
[	O
16	O
]	O
.	O

The	O
different	O
response	O
to	O
RANKL	O
+	O
M	O
-	O
CSF	O
stimulation	O
between	O
the	O
CD16	O
+	O
monocyte	O
subset	O
and	O
the	O
CD16	O
-	O
monocytes	O
subset	O
might	O
be	O
explained	O
by	O
the	O
expression	O
profiles	O
of	O
these	O
molecules	O
.	O

We	O
therefore	O
examined	O
the	O
mRNA	O
levels	O
of	O
the	O
following	O
molecules	O
:	O
receptor	O
activator	O
of	O
NF	O
-	O
kappa	O
B	O
(	O
RANK	O
)	O
,	O
the	O
receptor	O
for	O
RANKL	O
;	O
c	O
-	O
fms	O
,	O
the	O
receptor	O
for	O
M	O
-	O
CSF	O
;	O
tumor	O
necrosis	O
factor	O
receptor	O
-	O
associated	O
factor	O
6	O
(	O
TRAF	O
-	O
6	O
)	O
,	O
the	O
adaptor	O
protein	O
for	O
RANK	O
;	O
c	O
-	O
Fos	O
and	O
nuclear	O
factor	O
of	O
activated	O
T	O
cells	O
c1	O
(	O
NFATc1	O
)	O
,	O
transcription	O
factors	O
that	O
are	O
essential	O
for	O
osteoclastogenesis	O
;	O
DNAX	O
-	O
activation	O
protein	O
12	O
(	O
DAP12	O
)	O
and	O
Fc	O
receptor	O
gamma	O
chain	O
(	O
FcR	O
gamma	O
)	O
,	O
adaptor	O
proteins	O
known	O
to	O
deliver	O
costimulatory	O
signals	O
in	O
RANKL	O
-	O
induced	O
osteoclastogenesis	O
;	O
signal	O
regulatory	O
protein	O
beta	O
1	O
(	O
SIRP	O
-	O
beta	O
1	O
)	O
,	O
triggering	O
receptor	O
expressed	O
on	O
myeloid	O
cells	O
2	O
(	O
TREM	O
-	O
2	O
)	O
and	O
osteoclast	O
-	O
associated	O
receptor	O
(	O
OSCAR	O
)	O
,	O
transmembrane	O
receptors	O
that	O
associate	O
with	O
either	O
DAP12	O
or	O
FcR	O
gamma	O
;	O
and	O
alpha	O
v	O
and	O
beta	O
3	O
,	O
integrins	O
known	O
to	O
be	O
expressed	O
as	O
the	O
alpha	O
v	O
beta	O
3	O
heterodimer	O
on	O
osteoclasts	O
.	O

The	O
mRNA	O
levels	O
of	O
RANK	O
,	O
c	O
-	O
fms	O
,	O
TRAF	O
-	O
6	O
,	O
DAP12	O
and	O
SIRP	O
-	O
beta	O
1	O
under	O
the	O
baseline	O
condition	O
(	O
no	O
stimulation	O
)	O
varied	O
between	O
the	O
donors	O
;	O
however	O
,	O
we	O
did	O
not	O
find	O
consistent	O
differences	O
in	O
the	O
mRNA	O
levels	O
of	O
these	O
molecules	O
between	O
the	O
CD16	O
+	O
monocyte	O
subset	O
and	O
the	O
CD16	O
-	O
monocyte	O
subset	O
among	O
three	O
to	O
six	O
donors	O
(	O
Figure	O
4a	O
)	O
.	O

The	O
mRNA	O
levels	O
of	O
other	O
molecules	O
,	O
apart	O
from	O
integrin	O
beta	O
3	O
,	O
were	O
similar	O
between	O
the	O
two	O
subsets	O
under	O
the	O
no	O
-	O
stimulation	O
condition	O
.	O

Although	O
the	O
mRNA	O
levels	O
of	O
RANK	O
,	O
c	O
-	O
fms	O
,	O
DAP12	O
,	O
FcR	O
gamma	O
,	O
TREM	O
-	O
2	O
and	O
OSCAR	O
increased	O
in	O
response	O
to	O
M	O
-	O
CSF	O
alone	O
or	O
M	O
-	O
CSF	O
+	O
RANKL	O
in	O
both	O
subsets	O
,	O
the	O
expression	O
levels	O
were	O
not	O
significantly	O
different	O
between	O
the	O
two	O
subsets	O
.	O

Expressions	O
of	O
TRAF	O
-	O
6	O
,	O
c	O
-	O
Fos	O
and	O
SIRP	O
-	O
beta	O
1	O
mRNA	O
did	O
not	O
change	O
following	O
stimulation	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
.	O

Of	O
note	O
,	O
the	O
expression	O
of	O
NFATc1	O
mRNA	O
was	O
enhanced	O
by	O
M	O
-	O
CSF	O
+	O
RANKL	O
treatment	O
only	O
in	O
the	O
CD16	O
-	O
subset	O
.	O

Furthermore	O
,	O
expression	O
of	O
integrin	O
alpha	O
v	O
in	O
both	O
subsets	O
was	O
enhanced	O
by	O
M	O
-	O
CSF	O
with	O
or	O
without	O
RANKL	O
;	O
however	O
,	O
the	O
expression	O
level	O
was	O
greater	O
in	O
the	O
CD16	O
-	O
subset	O
.	O

It	O
was	O
noted	O
that	O
integrin	O
-	O
beta	O
3	O
mRNA	O
was	O
detected	O
only	O
in	O
the	O
CD16	O
-	O
subset	O
and	O
was	O
increased	O
by	O
M	O
-	O
CSF	O
+	O
RANKL	O
stimulation	O
,	O
but	O
not	O
by	O
M	O
-	O
CSF	O
alone	O
.	O

The	O
protein	O
expression	O
of	O
RANK	O
under	O
the	O
baseline	O
condition	O
was	O
weakly	O
detected	O
in	O
both	O
subsets	O
,	O
and	O
the	O
levels	O
were	O
varied	O
between	O
donors	O
by	O
western	O
immunoblotting	O
.	O

The	O
protein	O
expression	O
of	O
c	O
-	O
fms	O
was	O
weakly	O
detected	O
in	O
unstimulated	O
CD16	O
+	O
monocytes	O
,	O
but	O
not	O
in	O
CD16	O
-	O
monocytes	O
(	O
Figure	O
4b	O
)	O
.	O

Flow	O
cytometry	O
analysis	O
of	O
c	O
-	O
fms	O
in	O
fresh	O
monocytes	O
,	O
however	O
,	O
showed	O
that	O
both	O
subsets	O
express	O
the	O
molecule	O
on	O
the	O
cell	O
surface	O
(	O
Figure	O
4c	O
)	O
.	O

Expressions	O
of	O
both	O
RANK	O
and	O
c	O
-	O
fms	O
were	O
upregulated	O
by	O
M	O
-	O
CSF	O
alone	O
and	O
by	O
M	O
-	O
CSF	O
+	O
RANKL	O
,	O
and	O
we	O
did	O
not	O
find	O
consistent	O
differences	O
in	O
the	O
protein	O
levels	O
of	O
these	O
molecules	O
between	O
the	O
two	O
monocyte	O
subsets	O
.	O

The	O
profiles	O
of	O
expression	O
levels	O
of	O
molecules	O
involved	O
in	O
RANKL	O
/	O
RANK	O
and	O
its	O
costimulatory	O
pathways	O
are	O
similar	O
between	O
the	O
two	O
subsets	O
,	O
except	O
for	O
NFATc1	O
,	O
integrin	O
alpha	O
v	O
and	O
integrin	O
beta	O
3	O
.	O

We	O
therefore	O
assumed	O
that	O
the	O
distinct	O
induction	O
of	O
NFATc1	O
,	O
integrin	O
alpha	O
v	O
and	O
integrin	O
beta	O
3	O
in	O
response	O
to	O
RANKL	O
stimulation	O
among	O
the	O
two	O
monocyte	O
subsets	O
might	O
explain	O
the	O
differences	O
in	O
their	O
abilities	O
to	O
differentiate	O
into	O
osteoclasts	O
.	O

RANKL	O
stimulation	O
induces	O
alpha	O
v	O
beta	O
3	O
expression	O
on	O
CD16	O
-	O
monocytes	O

The	O
integrin	O
-	O
beta	O
3	O
subunit	O
binds	O
to	O
integrin	O
alpha	O
v	O
only	O
and	O
is	O
expressed	O
as	O
the	O
heterodimeric	O
protein	O
alpha	O
v	O
beta	O
3	O
on	O
monocytes	O
and	O
osteoclasts	O
[	O
17	O
]	O
.	O

We	O
examined	O
the	O
expression	O
of	O
alpha	O
v	O
beta	O
3	O
on	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O
by	O
immunofluorescent	O
staining	O
.	O

Neither	O
unstimulated	O
nor	O
M	O
-	O
CSF	O
-	O
stimulated	O
monocyte	O
subsets	O
expressed	O
alpha	O
v	O
beta	O
3	O
(	O
Figure	O
4d	O
and	O
data	O
not	O
shown	O
)	O
.	O

After	O
48	O
and	O
72	O
hours	O
of	O
treatment	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
,	O
alpha	O
v	O
beta	O
3	O
-	O
positive	O
mononuclear	O
cells	O
were	O
observed	O
in	O
CD16	O
-	O
monocyte	O
cultures	O
but	O
not	O
in	O
CD16	O
+	O
monocyte	O
cultures	O
.	O

At	O
96	O
hours	O
,	O
both	O
alpha	O
v	O
beta	O
3	O
-	O
positive	O
mononuclear	O
cells	O
and	O
multinucleated	O
cells	O
were	O
present	O
in	O
the	O
CD16	O
-	O
monocyte	O
culture	O
.	O

The	O
results	O
indicated	O
that	O
alpha	O
v	O
beta	O
3	O
was	O
selectively	O
expressed	O
on	O
CD16	O
-	O
monocytes	O
in	O
the	O
presence	O
of	O
M	O
-	O
CSF	O
+	O
RANKL	O
,	O
and	O
the	O
expression	O
was	O
revealed	O
before	O
the	O
cells	O
differentiate	O
into	O
typical	O
multinucleated	O
osteoclasts	O
.	O

RANKL	O
activates	O
ERK	O
and	O
p38	O
kinases	O
only	O
in	O
CD16	O
-	O
monocytes	O

Since	O
ERK	O
and	O
p38	O
MAPK	O
are	O
essential	O
in	O
RANKL	O
-	O
induced	O
osteoclastogenesis	O
[	O
18	O
-	O
20	O
]	O
,	O
we	O
next	O
examined	O
whether	O
these	O
kinases	O
were	O
activated	O
differently	O
in	O
CD16	O
+	O
monocytes	O
and	O
in	O
CD16	O
-	O
monocytes	O
.	O

Purified	O
monocytes	O
were	O
precultured	O
with	O
25	O
ng	O
/	O
ml	O
M	O
-	O
CSF	O
for	O
3	O
days	O
to	O
enhance	O
RANK	O
expression	O
,	O
and	O
were	O
then	O
treated	O
with	O
RANKL	O
.	O

The	O
RANKL	O
treatment	O
induced	O
phosphorylation	O
of	O
both	O
ERK	O
and	O
p38	O
MAPK	O
in	O
CD16	O
-	O
monocytes	O
at	O
5	O
minutes	O
postexposure	O
,	O
although	O
the	O
p38	O
MAPK	O
phosphorylation	O
was	O
weak	O
.	O

Both	O
phosphorylations	O
declined	O
to	O
a	O
basal	O
level	O
within	O
20	O
minutes	O
(	O
Figure	O
5	O
)	O
.	O

In	O
contrast	O
,	O
ERK	O
and	O
p38	O
MAPK	O
were	O
not	O
detectably	O
phosphorylated	O
in	O
CD16	O
+	O
monocytes	O
with	O
RANKL	O
.	O

siRNA	O
targeting	O
integrin	O
beta	O
3	O
inhibits	O
osteoclastogenesis	O
from	O
CD16	O
-	O
monocytes	O

The	O
integrin	O
-	O
beta	O
3	O
cytoplasmic	O
domain	O
is	O
essential	O
for	O
activation	O
of	O
intracellular	O
signals	O
from	O
alpha	O
v	O
beta	O
3	O
heterodimers	O
[	O
17	O
]	O
.	O

We	O
therefore	O
examined	O
the	O
involvement	O
of	O
alpha	O
v	O
beta	O
3	O
in	O
RANKL	O
+	O
M	O
-	O
CSF	O
-	O
induced	O
osteoclastogenesis	O
in	O
human	B
CD16	O
-	O
monocytes	O
using	O
siRNA	O
targeting	O
the	O
integrin	O
-	O
beta	O
3	O
subunit	O
.	O

The	O
integrin	O
-	O
beta	O
3	O
siRNA	O
or	O
control	O
randomized	O
siRNA	O
were	O
transfected	O
into	O
CD16	O
-	O
monocytes	O
.	O

At	O
48	O
hours	O
post	O
-	O
transfection	O
,	O
we	O
determined	O
the	O
integrin	O
-	O
beta	O
3	O
mRNA	O
level	O
and	O
alpha	O
v	O
beta	O
3	O
heterodimer	O
protein	O
expression	O
.	O

The	O
integrin	O
-	O
beta	O
3	O
mRNA	O
level	O
was	O
reduced	O
in	O
the	O
integrin	O
-	O
beta	O
3	O
siRNA	O
-	O
transfected	O
monocytes	O
compared	O
with	O
control	O
siRNA	O
-	O
transfected	O
monocytes	O
(	O
Figure	O
6a	O
)	O
.	O

The	O
alpha	O
v	O
beta	O
3	O
heterodimer	O
expression	O
was	O
evaluated	O
by	O
immunofluorescent	O
staining	O
.	O

The	O
number	O
of	O
alpha	O
v	O
beta	O
3	O
-	O
positive	O
cells	O
was	O
significantly	O
decreased	O
in	O
integrin	O
-	O
beta	O
3	O
siRNA	O
-	O
transfected	O
monocytes	O
compared	O
with	O
that	O
in	O
control	O
siRNA	O
(	O
Figure	O
6b	O
)	O
.	O

After	O
7	O
days	O
of	O
incubation	O
,	O
the	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
was	O
counted	O
.	O

Transfection	O
with	O
integrin	O
-	O
beta	O
3	O
siRNA	O
significantly	O
reduced	O
the	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
compared	O
with	O
control	O
siRNA	O
transfection	O
(	O
Figure	O
6c	O
)	O
.	O

In	O
addition	O
,	O
the	O
use	O
of	O
siRNA	O
directed	O
toward	O
a	O
different	O
site	O
of	O
integrin	O
-	O
beta	O
3	O
mRNA	O
also	O
inhibited	O
osteoclast	O
formation	O
from	O
CD16	O
-	O
monocytes	O
(	O
data	O
not	O
shown	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
siRNA	O
that	O
targeted	O
lamin	O
,	O
which	O
was	O
used	O
as	O
a	O
negative	O
control	O
,	O
did	O
not	O
inhibit	O
the	O
induction	O
of	O
osteoclasts	O
(	O
data	O
not	O
shown	O
)	O
.	O

These	O
results	O
indicate	O
the	O
importance	O
of	O
integrin	O
beta	O
3	O
in	O
RANKL	O
-	O
induced	O
osteoclast	O
formation	O
from	O
CD16	O
-	O
peripheral	O
blood	O
monocytes	O
.	O

Cyclic	O
RGDfV	O
peptide	O
inhibits	O
the	O
osteoclastogenesis	O
from	O
CD16	O
-	O
monocytes	O

Integrin	O
alpha	O
v	O
beta	O
3	O
recognizes	O
a	O
common	O
tripeptide	O
sequence	O
,	O
RGD	O
(	O
Arg	O
-	O
Gly	O
-	O
Asp	O
)	O
,	O
which	O
is	O
present	O
in	O
bone	O
matrix	O
proteins	O
such	O
as	O
vitronectin	O
and	O
fibronectin	O
[	O
21	O
]	O
.	O

Cyclic	O
RGDfV	O
peptide	O
(	O
Arg	O
-	O
Gly	O
-	O
Asp	O
-	O
D	O
-	O
Phe	O
-	O
Val	O
)	O
inhibits	O
binding	O
of	O
the	O
RGD	O
-	O
containing	O
molecules	O
to	O
alpha	O
v	O
beta	O
3	O
[	O
22	O
]	O
.	O

To	O
investigate	O
the	O
role	O
of	O
ligand	O
binding	O
to	O
the	O
alpha	O
v	O
beta	O
3	O
heterodimer	O
in	O
the	O
osteoclastogenesis	O
,	O
we	O
examined	O
whether	O
cyclic	O
RGDfV	O
peptide	O
inhibits	O
the	O
formation	O
of	O
osteoclasts	O
.	O

Cyclic	O
RGDfV	O
peptide	O
significantly	O
reduced	O
the	O
number	O
of	O
TRAP	O
-	O
positive	O
MNC	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
(	O
Figure	O
6d	O
)	O
.	O

The	O
results	O
imply	O
possible	O
involvement	O
of	O
ligand	O
bindings	O
to	O
alpha	O
v	O
beta	O
3	O
in	O
the	O
osteoclastogenesis	O
.	O

Knockdown	O
of	O
integrin	O
beta	O
3	O
did	O
not	O
affect	O
the	O
expression	O
of	O
NFATc1	O
mRNA	O

In	O
the	O
next	O
step	O
,	O
we	O
determined	O
whether	O
integrin	O
-	O
beta	O
3	O
-	O
siRNA	O
-	O
induced	O
inhibition	O
of	O
the	O
osteoclastogenesis	O
reflects	O
downregulation	O
of	O
NFATc1	O
,	O
which	O
is	O
a	O
key	O
transcription	O
factor	O
in	O
osteoclastogenesis	O
[	O
23	O
]	O
.	O

For	O
this	O
purpose	O
,	O
we	O
compared	O
NFATc1	O
mRNA	O
levels	O
between	O
integrin	O
beta	O
3	O
and	O
control	O
siRNA	O
-	O
transfected	O
monocytes	O
.	O

Interestingly	O
,	O
integrin	O
-	O
beta	O
3	O
knockdown	O
did	O
not	O
alter	O
the	O
NFATc1	O
mRNA	O
level	O
(	O
Figure	O
7	O
)	O
,	O
suggesting	O
that	O
signal	O
transduction	O
mediated	O
by	O
integrin	O
beta	O
3	O
does	O
not	O
affect	O
the	O
expression	O
of	O
NFATc1	O
.	O

Detection	O
of	O
CD16	O
+	O
and	O
CD16	O
-	O
macrophages	O
in	O
synovium	O
of	O
RA	O
patients	B

RA	O
synovial	O
macrophages	O
are	O
derived	O
from	O
peripheral	O
blood	O
monocytes	O
,	O
and	O
their	O
recruitment	O
into	O
the	O
synovium	O
is	O
facilitated	O
by	O
various	O
adhesion	O
molecules	O
and	O
chemokines	O
[	O
24	O
]	O
.	O

To	O
analyze	O
CD16	O
expression	O
on	O
synovial	O
macrophages	O
,	O
RA	O
synovial	O
tissues	O
were	O
double	O
-	O
stained	O
for	O
CD16	O
and	O
a	O
macrophage	O
marker	O
,	O
CD68	O
.	O

CD16	O
-	O
/	O
CD68	O
+	O
macrophages	O
were	O
widespread	O
in	O
the	O
synovium	O
.	O

Although	O
less	O
frequent	O
,	O
CD16	O
+	O
/	O
CD68	O
+	O
macrophages	O
were	O
also	O
observed	O
both	O
in	O
the	O
synovial	O
intima	O
and	O
subintima	O
(	O
Figure	O
8	O
)	O
.	O

The	O
presence	O
of	O
two	O
subsets	O
of	O
macrophages	O
,	O
CD16	O
+	O
and	O
CD16	O
-	O
,	O
in	O
RA	O
synovium	O
indicates	O
that	O
both	O
CD16	O
+	O
and	O
CD16	O
-	O
peripheral	O
blood	O
monocytes	O
are	O
recruited	O
into	O
the	O
synovium	O
.	O

Discussion	O

Human	B
peripheral	O
blood	O
monocytes	O
are	O
a	O
heterogeneous	O
population	O
,	O
and	O
they	O
are	O
divided	O
into	O
two	O
subsets	O
based	O
on	O
the	O
expression	O
of	O
CD16	O
.	O

The	O
CD16	O
+	O
and	O
CD16	O
-	O
monocyte	O
subsets	O
show	O
functional	O
differences	O
in	O
migration	O
,	O
cytokine	O
production	O
and	O
differentiation	O
into	O
macrophages	O
or	O
dendritic	O
cells	O
[	O
11	O
-	O
13	O
,	O
15	O
]	O
.	O

We	O
focused	O
on	O
the	O
heterogeneity	O
of	O
the	O
monocytes	O
,	O
and	O
the	O
primary	O
question	O
addressed	O
in	O
this	O
study	O
was	O
which	O
monocyte	O
subset	O
could	O
be	O
the	O
source	O
of	O
osteoclasts	O
.	O

The	O
results	O
demonstrated	O
that	O
CD16	O
-	O
peripheral	O
blood	O
monocytes	O
,	O
but	O
not	O
CD16	O
+	O
monocytes	O
,	O
differentiated	O
in	O
vitro	O
into	O
osteoclasts	O
by	O
treatment	O
with	O
RANKL	O
+	O
M	O
-	O
CSF	O
.	O

To	O
investigate	O
the	O
molecular	O
mechanisms	O
of	O
the	O
different	O
response	O
to	O
RANKL	O
and	O
the	O
differentiation	O
into	O
osteoclasts	O
between	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O
,	O
we	O
examined	O
the	O
expression	O
of	O
molecules	O
known	O
to	O
be	O
involved	O
in	O
osteoclastogenesis	O
.	O

The	O
expression	O
profiles	O
of	O
integrin	O
alpha	O
v	O
,	O
integrin	O
beta	O
3	O
and	O
NFATc1	O
were	O
different	O
between	O
the	O
two	O
subsets	O
.	O

Integrin	O
alpha	O
v	O
beta	O
3	O
heterodimer	O
was	O
expressed	O
only	O
on	O
RANKL	O
and	O
M	O
-	O
CSF	O
-	O
stimulated	O
CD16	O
-	O
monocytes	O
.	O

It	O
is	O
known	O
that	O
alpha	O
v	O
beta	O
3	O
expressed	O
on	O
osteoclasts	O
is	O
important	O
in	O
bone	O
resorption	O
as	O
well	O
as	O
in	O
attachment	O
of	O
osteoclasts	O
to	O
the	O
bone	O
matrix	O
[	O
25	O
]	O
.	O

It	O
was	O
recently	O
reported	O
that	O
bone	O
marrow	O
macrophages	O
of	O
integrin	O
-	O
beta	O
3	O
-	O
deficient	O
mice	B
could	O
not	O
differentiate	O
into	O
mature	O
osteoclasts	O
in	O
vitro	O
,	O
suggesting	O
that	O
alpha	O
v	O
beta	O
3	O
is	O
involved	O
not	O
only	O
in	O
activation	O
,	O
but	O
also	O
in	O
differentiation	O
,	O
of	O
osteoclasts	O
in	O
mice	B
[	O
26	O
,	O
27	O
]	O
.	O

The	O
authors	O
also	O
showed	O
that	O
alpha	O
v	O
beta	O
3	O
and	O
c	O
-	O
fms	O
share	O
a	O
common	O
intracellular	O
signaling	O
pathway	O
,	O
including	O
the	O
activation	O
of	O
ERK	O
and	O
the	O
induction	O
of	O
c	O
-	O
Fos	O
[	O
27	O
]	O
,	O
both	O
of	O
which	O
are	O
essential	O
for	O
osteoclastogenesis	O
[	O
28	O
,	O
29	O
]	O
.	O

In	O
addition	O
,	O
it	O
was	O
reported	O
that	O
echistatin	O
,	O
an	O
alpha	O
v	O
beta	O
3	O
antagonist	O
,	O
inhibited	O
osteoclast	O
formation	O
of	O
mouse	B
bone	O
marrow	O
cells	O
[	O
30	O
]	O
.	O

In	O
accordance	O
with	O
these	O
reports	O
,	O
our	O
data	O
showed	O
that	O
knockdown	O
of	O
integrin	O
-	O
beta	O
3	O
expression	O
resulted	O
in	O
downregulation	O
of	O
the	O
alpha	O
v	O
beta	O
3	O
heterodimer	O
,	O
and	O
abrogated	O
osteoclastogenesis	O
from	O
human	B
peripheral	O
blood	O
CD16	O
-	O
monocytes	O
.	O

We	O
also	O
showed	O
that	O
blocking	O
of	O
adhesive	O
ligands	O
to	O
bind	O
to	O
alpha	O
v	O
beta	O
3	O
by	O
RGDfV	O
peptide	O
inhibited	O
osteoclast	O
formation	O
from	O
CD16	O
-	O
monocytes	O
.	O

Taken	O
together	O
,	O
the	O
process	O
of	O
ligand	O
binding	O
to	O
alpha	O
v	O
beta	O
3	O
may	O
be	O
involved	O
in	O
the	O
osteoclastogenesis	O
.	O

Blockade	O
of	O
alpha	O
v	O
beta	O
3	O
could	O
therefore	O
be	O
a	O
therapeutically	O
beneficial	O
approach	O
to	O
modulate	O
osteoclastogenesis	O
.	O

Indeed	O
,	O
integrin	O
alpha	O
v	O
beta	O
3	O
antagonists	O
effectively	O
treated	O
osteoporosis	O
in	O
mice	B
,	O
rats	B
and	O
humans	B
,	O
and	O
protected	O
bone	O
destruction	O
in	O
rat	O
adjuvant	O
-	O
induced	O
arthritis	O
in	O
vivo	O
[	O
31	O
-	O
34	O
]	O
.	O

Of	O
note	O
,	O
it	O
is	O
reported	O
that	O
patients	B
with	O
Iraqi	O
-	O
Jewish	O
-	O
type	O
Glanzmann	O
thrombasthenia	O
who	O
are	O
deficient	O
in	O
integrin	O
beta	O
3	O
do	O
not	O
develop	O
osteopetrosis	O
because	O
of	O
the	O
upregulation	O
of	O
alpha	O
2	O
beta	O
1	O
expression	O
on	O
osteoclasts	O
,	O
although	O
the	O
bone	O
-	O
resorptive	O
ability	O
of	O
the	O
osteoclasts	O
was	O
decreased	O
in	O
vitro	O
[	O
35	O
]	O
.	O

The	O
function	O
of	O
alpha	O
v	O
beta	O
3	O
in	O
vivo	O
in	O
osteoclast	O
formation	O
and	O
resorptive	O
function	O
could	O
therefore	O
be	O
partially	O
compensated	O
by	O
other	O
integrins	O
.	O

Although	O
all	O
the	O
multinucleated	O
osteoclasts	O
expressed	O
alpha	O
v	O
beta	O
3	O
(	O
Figure	O
4d	O
)	O
[	O
36	O
]	O
,	O
a	O
small	O
number	O
of	O
M	O
-	O
CSF	O
+	O
RANKL	O
-	O
stimulated	O
mononuclear	O
CD16	O
-	O
monocytes	O
expressed	O
alpha	O
v	O
beta	O
3	O
(	O
Figure	O
4d	O
)	O
.	O

Multinucleated	O
osteoclasts	O
are	O
formed	O
by	O
fusion	O
of	O
osteoclast	O
precursor	O
cells	O
[	O
37	O
]	O
.	O

It	O
was	O
reported	O
that	O
alpha	O
v	O
beta	O
3	O
is	O
involved	O
in	O
the	O
migration	O
of	O
osteoclast	O
precursors	O
[	O
30	O
]	O
.	O

The	O
alpha	O
v	O
beta	O
3	O
-	O
positive	O
cells	O
could	O
therefore	O
be	O
forced	O
to	O
migrate	O
by	O
the	O
ligands	O
and	O
may	O
fuse	O
with	O
closed	O
alpha	O
v	O
beta	O
3	O
-	O
negative	O
cells	O
.	O

Alternatively	O
,	O
only	O
alpha	O
v	O
beta	O
3	O
-	O
positive	O
cells	O
may	O
be	O
fused	O
with	O
each	O
other	O
.	O

It	O
is	O
possible	O
to	O
consider	O
that	O
signaling	O
from	O
CD16	O
by	O
anti	O
-	O
CD16	O
mAb	O
-	O
coated	O
magnetic	O
beads	O
,	O
which	O
were	O
used	O
for	O
the	O
cell	O
separation	O
,	O
or	O
by	O
IgG	O
contained	O
in	O
FBS	O
might	O
inhibit	O
osteoclastogenesis	O
from	O
CD16	O
+	O
monocytes	O
.	O

We	O
therefore	O
separated	O
the	O
two	O
subsets	O
using	O
anti	O
-	O
CD33	O
mAb	O
and	O
a	O
fluorescent	O
cell	O
sorter	O
,	O
and	O
stimulated	O
the	O
cells	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
.	O

The	O
results	O
showed	O
that	O
CD33low	O
monocytes	O
,	O
which	O
correspond	O
to	O
CD16	O
+	O
monocytes	O
,	O
still	O
could	O
not	O
differentiate	O
into	O
osteoclasts	O
.	O

CD16	O
is	O
a	O
heterodimer	O
consisting	O
of	O
Fc	O
gamma	O
IIIa	O
and	O
Fc	O
gamma	O
,	O
and	O
has	O
low	O
affinity	O
for	O
the	O
Fc	O
region	O
of	O
IgG	O
.	O

Aggregation	O
of	O
CD16	O
by	O
immune	O
complexes	O
leads	O
to	O
transmission	O
of	O
activating	O
signals	O
via	O
the	O
immunoreceptor	O
tyrosine	O
-	O
based	O
activation	O
motif	O
in	O
the	O
gamma	O
chain	O
[	O
38	O
]	O
.	O

We	O
also	O
assessed	O
osteoclastogenesis	O
from	O
the	O
two	O
monocyte	O
subsets	O
using	O
IgG	O
-	O
depleted	O
bovine	B
serum	O
.	O

Even	O
in	O
the	O
IgG	O
-	O
free	O
medium	O
,	O
CD16	O
-	O
monocytes	O
but	O
not	O
CD16	O
+	O
monocytes	O
differentiated	O
into	O
osteoclasts	O
(	O
data	O
not	O
shown	O
)	O
.	O

We	O
could	O
therefore	O
exclude	O
the	O
possibility	O
that	O
signal	O
transduction	O
through	O
CD16	O
inhibits	O
osteoclastogenesis	O
from	O
CD16	O
+	O
monocytes	O
.	O

NFATc1	O
is	O
a	O
key	O
transcription	O
factor	O
in	O
osteoclastogenesis	O
[	O
16	O
]	O
.	O

In	O
the	O
present	O
study	O
,	O
stimulation	O
with	O
M	O
-	O
CSF	O
+	O
RANKL	O
increased	O
the	O
NFATc1	O
mRNA	O
expression	O
in	O
the	O
CD16	O
-	O
subset	O
only	O
,	O
similar	O
to	O
integrin	O
alpha	O
v	O
and	O
integrin	O
beta	O
3	O
.	O

The	O
differences	O
in	O
NFATc1	O
induction	O
might	O
therefore	O
also	O
explain	O
the	O
difference	O
in	O
osteoclastogenesis	O
between	O
the	O
two	O
monocyte	O
subsets	O
.	O

It	O
is	O
of	O
interest	O
that	O
knockdown	O
of	O
integrin	O
beta	O
3	O
did	O
not	O
lower	O
the	O
mRNA	O
level	O
of	O
NFATc1	O
.	O

This	O
result	O
supports	O
the	O
notion	O
that	O
NFATc1	O
is	O
located	O
upstream	O
of	O
integrin	O
-	O
beta	O
3	O
expression	O
[	O
39	O
]	O
.	O

It	O
is	O
also	O
possible	O
that	O
parallel	O
activation	O
of	O
two	O
signaling	O
pathways	O
mediated	O
by	O
integrin	O
beta	O
3	O
and	O
NFATc1	O
contributes	O
to	O
osteoclastogenesis	O
independently	O
or	O
cooperatively	O
.	O

Further	O
studies	O
are	O
needed	O
to	O
determine	O
the	O
mechanisms	O
of	O
integrin	O
beta	O
3	O
involvement	O
in	O
RANKL	O
/	O
RANK	O
-	O
mediated	O
osteoclast	O
differentiation	O
.	O

It	O
has	O
been	O
demonstrated	O
that	O
MAPK	O
families	O
,	O
ERK	O
and	O
p38	O
MAPK	O
,	O
were	O
activated	O
by	O
RANKL	O
-	O
induced	O
intracellular	O
signalings	O
in	O
osteoclasts	O
and	O
osteoclast	O
precursors	O
[	O
18	O
,	O
19	O
]	O
.	O

In	O
addition	O
,	O
these	O
kinases	O
are	O
involved	O
in	O
the	O
differentiation	O
of	O
osteoclasts	O
[	O
20	O
]	O
.	O

We	O
showed	O
that	O
RANKL	O
stimulation	O
induced	O
phosphorylation	O
of	O
ERK	O
and	O
p38	O
MAPK	O
only	O
in	O
CD16	O
-	O
monocytes	O
.	O

It	O
is	O
suggested	O
that	O
differential	O
activation	O
of	O
these	O
kinases	O
may	O
partially	O
explain	O
the	O
distinct	O
properties	O
of	O
the	O
two	O
monocyte	O
subsets	O
upon	O
RANKL	O
stimulation	O
.	O

Our	O
results	O
showed	O
that	O
CD16	O
+	O
monocytes	O
produce	O
higher	O
levels	O
of	O
inflammatory	O
cytokines	O
including	O
TNF	O
alpha	O
and	O
IL	O
-	O
6	O
compared	O
with	O
CD16	O
-	O
monocytes	O
.	O

These	O
results	O
are	O
consistent	O
with	O
the	O
previous	O
report	O
showing	O
that	O
CD16	O
+	O
monocytes	O
produced	O
larger	O
amounts	O
of	O
TNF	O
alpha	O
upon	O
lipopolysaccharide	O
or	O
lipopeptide	O
stimulation	O
than	O
did	O
CD16	O
-	O
monocytes	O
[	O
40	O
]	O
.	O

Interestingly	O
,	O
we	O
showed	O
that	O
stimulation	O
either	O
with	O
RANKL	O
or	O
M	O
-	O
CSF	O
upregulated	O
the	O
TNF	O
alpha	O
and	O
IL	O
-	O
6	O
production	O
by	O
CD16	O
+	O
monocytes	O
.	O

A	O
marked	O
increase	O
of	O
CD16	O
+	O
monocytes	O
in	O
peripheral	O
blood	O
is	O
reported	O
in	O
inflammatory	O
diseases	O
,	O
such	O
as	O
infection	O
,	O
malignancy	O
,	O
Kawasaki	O
disease	O
and	O
RA	O
[	O
41	O
-	O
44	O
]	O
.	O

Taken	O
together	O
,	O
CD16	O
+	O
monocytes	O
may	O
be	O
an	O
important	O
source	O
of	O
inflammatory	O
cytokines	O
.	O

In	O
mice	B
,	O
peripheral	O
blood	O
Ly	O
-	O
6Chigh	O
monocytes	O
,	O
which	O
are	O
thought	O
to	O
correspond	O
to	O
human	B
CD16	O
-	O
monocytes	O
,	O
increase	O
in	O
inflammatory	O
conditions	O
,	O
and	O
these	O
cells	O
are	O
recruited	O
into	O
sites	O
of	O
inflammation	O
[	O
45	O
]	O
.	O

In	O
contrast	O
,	O
Ly	O
-	O
6Clow	O
monocytes	O
,	O
which	O
are	O
thought	O
to	O
correspond	O
to	O
human	B
CD16	O
+	O
,	O
migrate	O
into	O
noninflamed	O
tissues	O
[	O
12	O
]	O
.	O

These	O
data	O
on	O
mouse	B
monocytes	O
seem	O
to	O
be	O
in	O
contrast	O
to	O
the	O
data	O
on	O
human	B
monocytes	O
,	O
which	O
show	O
expansion	O
of	O
CD16	O
+	O
monocytes	O
in	O
inflammatory	O
conditions	O
where	O
they	O
produce	O
larger	O
amounts	O
of	O
inflammatory	O
cytokines	O
.	O

At	O
present	O
,	O
it	O
is	O
not	O
clear	O
whether	O
mouse	B
monocyte	O
subsets	O
,	O
Ly	O
-	O
6Clow	O
/	O
Ly	O
-	O
6Chigh	O
,	O
represent	O
human	B
monocyte	O
subsets	O
,	O
CD16	O
+	O
/	O
CD16	O
-	O
monocytes	O
,	O
and	O
whether	O
the	O
biologic	O
functions	O
of	O
mouse	B
monocytes	O
are	O
analogous	O
to	O
those	O
of	O
human	B
monocytes	O
.	O

In	O
mice	B
,	O
blood	O
monocytes	O
newly	O
released	O
from	O
the	O
bone	O
marrow	O
are	O
exclusively	O
Ly	O
-	O
6Chigh	O
and	O
the	O
level	O
of	O
Ly	O
-	O
6C	O
is	O
downregulated	O
while	O
in	O
circulation	O
[	O
45	O
]	O
.	O

It	O
is	O
thus	O
suggested	O
that	O
in	O
mice	B
the	O
two	O
monocyte	O
subsets	O
differing	O
in	O
Ly	O
-	O
6C	O
expression	O
represent	O
different	O
stages	O
in	O
the	O
maturation	O
pathway	O
.	O

In	O
the	O
human	B
,	O
transition	O
from	O
CD16	O
-	O
monocytes	O
to	O
CD16	O
+	O
monocytes	O
is	O
observed	O
upon	O
culture	O
with	O
IL	O
-	O
10	O
,	O
M	O
-	O
CSF	O
and	O
transforming	O
growth	O
factor	O
beta	O
in	O
vitro	O
[	O
42	O
,	O
46	O
]	O
.	O

Similar	O
to	O
mouse	B
monocytes	O
,	O
therefore	O
,	O
human	B
peripheral	O
blood	O
CD16	O
-	O
monocytes	O
may	O
also	O
maturate	O
into	O
CD16	O
+	O
monocytes	O
.	O

It	O
is	O
reported	O
that	O
a	O
significant	O
number	O
of	O
RA	O
synovial	O
cells	O
in	O
the	O
intima	O
express	O
CD16	O
,	O
suggesting	O
that	O
CD16	O
+	O
cells	O
are	O
synovial	O
macrophages	O
[	O
47	O
]	O
.	O

We	O
confirmed	O
that	O
both	O
CD16	O
+	O
and	O
CD16	O
-	O
macrophages	O
accumulate	O
in	O
the	O
RA	O
synovium	O
by	O
double	O
-	O
color	O
immunohistochemical	O
staining	O
for	O
CD68	O
and	O
CD16	O
.	O

A	O
number	O
of	O
chemokines	O
are	O
abundantly	O
expressed	O
in	O
the	O
RA	O
synovium	O
[	O
24	O
,	O
48	O
]	O
.	O

Among	O
these	O
cytokines	O
,	O
MCP	O
-	O
1	O
,	O
MIP	O
-	O
1	O
alpha	O
,	O
SDF	O
-	O
1	O
,	O
RANTES	O
and	O
fractalkine	O
can	O
induce	O
migration	O
of	O
CD16	O
-	O
monocytes	O
in	O
vitro	O
(	O
[	O
11	O
,	O
12	O
]	O
and	O
unpublished	O
data	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
migration	O
of	O
CD16	O
+	O
monocytes	O
is	O
induced	O
only	O
by	O
fractalkine	O
.	O

These	O
chemokines	O
therefore	O
seem	O
to	O
play	O
an	O
important	O
role	O
in	O
recruitment	O
of	O
CD16	O
+	O
and	O
CD16	O
-	O
monocytes	O
from	O
the	O
circulating	O
pool	O
into	O
the	O
RA	O
synovium	O
.	O

The	O
osteoclast	O
inducers	O
are	O
also	O
produced	O
in	O
the	O
RA	O
synovium	O
.	O

RANKL	O
is	O
expressed	O
by	O
synovial	O
fibroblasts	O
and	O
activated	O
T	O
cells	O
[	O
49	O
-	O
51	O
]	O
,	O
while	O
M	O
-	O
CSF	O
is	O
expressed	O
on	O
RA	O
synovial	O
macrophages	O
and	O
fibroblasts	O
[	O
52	O
,	O
53	O
]	O
.	O

TNF	O
alpha	O
and	O
IL	O
-	O
6	O
,	O
which	O
are	O
mainly	O
expressed	O
on	O
RA	O
synovial	O
macrophages	O
and	O
fibroblasts	O
,	O
respectively	O
,	O
could	O
also	O
enhance	O
osteoclast	O
differentiation	O
[	O
54	O
]	O
.	O

Collectively	O
,	O
it	O
is	O
probable	O
that	O
the	O
recruited	O
CD16	O
-	O
monocytes	O
/	O
macrophages	O
differentiate	O
into	O
osteoclasts	O
in	O
the	O
RA	O
synovium	O
,	O
and	O
contribute	O
to	O
bone	O
destruction	O
.	O

On	O
the	O
other	O
hand	O
,	O
CD16	O
+	O
monocytes	O
/	O
macrophages	O
might	O
also	O
be	O
involved	O
in	O
RA	O
pathogenesis	O
by	O
producing	O
inflammatory	O
cytokines	O
including	O
TNF	O
alpha	O
and	O
IL	O
-	O
6	O
.	O

Since	O
TNF	O
alpha	O
and	O
IL	O
-	O
6	O
enhance	O
osteoclast	O
formation	O
[	O
54	O
,	O
55	O
]	O
,	O
CD16	O
+	O
monocytes	O
/	O
macrophages	O
may	O
also	O
contribute	O
to	O
osteoclastogenesis	O
in	O
RA	O
synovium	O
.	O

Conclusion	O

We	O
have	O
shown	O
that	O
human	B
peripheral	O
blood	O
monocytes	O
consist	O
of	O
two	O
functionally	O
heterogeneous	O
subsets	O
with	O
distinct	O
response	O
to	O
osteoclastogenic	O
stimuli	O
.	O

Osteoclasts	O
seem	O
to	O
originate	O
from	O
CD16	O
-	O
monocytes	O
,	O
and	O
integrin	O
beta	O
3	O
is	O
necessary	O
for	O
the	O
osteoclastogenesis	O
.	O

The	O
blockade	O
of	O
accumulation	O
and	O
activation	O
of	O
CD16	O
-	O
monocytes	O
could	O
therefore	O
be	O
a	O
beneficial	O
approach	O
as	O
an	O
anti	O
-	O
bone	O
resorptive	O
therapy	O
,	O
especially	O
for	O
RA	O
.	O

Abbreviations	O

DAP	O
=	O
DNAX	O
-	O
activation	O
protein	O
;	O
ELISA	O
=	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
;	O
FBS	O
=	O
fetal	O
bovine	B
serum	O
;	O
FcR	O
gamma	O
=	O
Fc	O
receptor	O
gamma	O
chain	O
;	O
IL	O
=	O
interleukin	O
;	O
FITC	O
=	O
fluorescein	O
isothiocianate	O
;	O
mAb	O
,	O
monoclonal	O
antibody	O
;	O
M	O
-	O
CSF	O
=	O
macrophage	O
colony	O
-	O
stimulating	O
factor	O
;	O
MEM	O
=	O
modified	O
Eagle	O
'	O
s	O
medium	O
;	O
MMP	O
=	O
matrix	O
metalloproteinase	O
;	O
MNC	O
=	O
multinucleated	O
cells	O
;	O
NF	O
=	O
nuclear	O
factor	O
;	O
OSCAR	O
=	O
osteoclast	O
-	O
associated	O
receptor	O
;	O
PBS	O
=	O
phosphate	O
-	O
buffered	O
saline	O
;	O
PCR	O
=	O
polymerase	O
chain	O
reaction	O
;	O
RA	O
=	O
rheumatoid	O
arthritis	O
;	O
RANK	O
=	O
receptor	O
activator	O
of	O
NF	O
-	O
kappa	O
B	O
;	O
RANKL	O
=	O
receptor	O
activator	O
of	O
NF	O
-	O
kappa	O
B	O
ligand	O
;	O
RT	O
=	O
reverse	O
transcriptase	O
;	O
siRNA	O
=	O
small	O
interfering	O
RNA	O
;	O
SIRP	O
-	O
beta	O
1	O
=	O
signal	O
regulatory	O
protein	O
-	O
beta	O
1	O
;	O
TNF	O
alpha	O
=	O
tumor	O
necrosis	O
factor	O
alpha	O
;	O
TRAF	O
=	O
tumor	O
necrosis	O
factor	O
receptor	O
-	O
associated	O
factor	O
;	O
TRAP	O
=	O
tartrate	O
-	O
resistant	O
acid	O
phosphatase	O
;	O
TREM	O
=	O
triggering	O
receptor	O
expressed	O
on	O
myeloid	O
cells	O
.	O

Competing	O
interests	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

YK	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
,	O
carried	O
out	O
the	O
experiments	O
and	O
statistical	O
analysis	O
,	O
and	O
drafted	O
the	O
manuscript	O
.	O

KH	O
and	O
KT	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
and	O
its	O
coordination	O
.	O

TN	O
and	O
NM	O
conceived	O
of	O
the	O
study	O
,	O
participated	O
in	O
its	O
design	O
and	O
coordination	O
,	O
and	O
helped	O
to	O
draft	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Embryonic	O
sympathoblasts	O
transiently	O
express	O
TrkB	O
in	O
vivo	O
and	O
proliferate	O
in	O
response	O
to	O
brain	O
-	O
derived	O
neurotrophic	O
factor	O
in	O
vitro	O

Abstract	O

Background	O

Nerve	O
growth	O
factor	O
and	O
neurotrophin	O
-	O
3	O
are	O
involved	O
in	O
the	O
development	O
of	O
sympathetic	O
neurons	O
;	O
however	O
,	O
whether	O
brain	O
derived	O
neurotrophic	O
factor	O
also	O
plays	O
a	O
role	O
is	O
not	O
known	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
determine	O
whether	O
BDNF	O
and	O
its	O
receptor	O
,	O
TrkB	O
,	O
are	O
expressed	O
during	O
the	O
development	O
of	O
paravertebral	O
sympathetic	O
ganglia	O
in	O
vivo	O
and	O
to	O
determine	O
the	O
effect	O
of	O
BDNF	O
in	O
vitro	O
.	O

Results	O

As	O
neural	O
crest	O
cells	O
coalesce	O
to	O
form	O
sympathetic	O
ganglia	O
,	O
TrkB	O
-	O
positive	O
cells	O
are	O
seen	O
in	O
both	O
chicken	B
and	O
mouse	B
embryos	O
.	O

In	O
chicken	B
embryos	O
,	O
TrkB	O
-	O
expressing	O
cells	O
first	O
appear	O
at	O
Hamburger	O
-	O
Hamilton	O
Stage	O
(	O
St	O
)	O
27	O
and	O
they	O
co	O
-	O
express	O
HNK	O
-	O
1	O
,	O
confirming	O
that	O
they	O
are	O
migrating	O
neural	O
crest	O
cells	O
.	O

The	O
TrkB	O
-	O
positive	O
cells	O
lack	O
neural	O
markers	O
at	O
this	O
stage	O
;	O
however	O
,	O
they	O
migrate	O
with	O
other	O
neurally	O
differentiating	O
cells	O
that	O
are	O
TrkA	O
and	O
TrkC	O
-	O
positive	O
.	O

By	O
St	O
.	O

29	O
/	O
30	O
,	O
TrkB	O
-	O
positive	O
cells	O
begin	O
to	O
express	O
the	O
neural	O
specific	O
markers	O
Hu	O
C	O
/	O
D	O
and	O
Islet	O
-	O
1	O
;	O
eventually	O
,	O
all	O
TrkB	O
positive	O
cells	O
commence	O
neural	O
differentiation	O
.	O

By	O
St	O
.	O

34	O
,	O
TrkB	O
and	O
TrkC	O
staining	O
are	O
lost	O
.	O

BDNF	O
transcript	O
expression	O
parallels	O
that	O
of	O
TrkB	O
.	O

In	O
the	O
mouse	B
,	O
TrkB	O
-	O
positive	O
cells	O
surround	O
newly	O
formed	O
sympathetic	O
ganglia	O
and	O
a	O
small	O
number	O
of	O
TrkB	O
positive	O
cells	O
that	O
co	O
-	O
express	O
tyrosine	O
hydroxylase	O
are	O
seen	O
within	O
ganglia	O
between	O
E13	O
.	O
5	O
-	O
15	O
.	O

In	O
cell	O
culture	O
,	O
many	O
cells	O
from	O
St	O
.	O

29	O
-	O
30	O
chicken	B
lumbar	O
sympathetic	O
ganglia	O
express	O
neural	O
markers	O
and	O
are	O
dividing	O
,	O
indicating	O
that	O
they	O
are	O
sympathoblasts	O
.	O

Sympathoblasts	O
and	O
neurons	O
require	O
both	O
nerve	O
growth	O
factor	O
and	O
neurotrophin	O
-	O
3	O
for	O
survival	O
.	O

BDNF	O
increases	O
the	O
number	O
of	O
cells	O
expressing	O
neural	O
markers	O
in	O
culture	O
by	O
increasing	O
number	O
of	O
cells	O
that	O
incorporate	O
bromodeoxyuridine	O
.	O

In	O
contrast	O
,	O
most	O
TrkB	O
-	O
positive	O
sympathetic	O
cells	O
in	O
vivo	O
are	O
not	O
actively	O
proliferating	O
between	O
E6	O
-	O
E8	O
.	O

Conclusion	O

Developing	O
paravertebral	O
sympathetic	O
ganglia	O
in	O
avian	O
and	O
murine	O
embryos	O
contain	O
a	O
subpopulation	O
of	O
sympathoblasts	O
that	O
transiently	O
express	O
TrkB	O
and	O
ultimately	O
commence	O
neuronal	O
differentiation	O
.	O

These	O
TrkB	O
expressing	O
sympathoblasts	O
are	O
not	O
actively	O
dividing	O
in	O
vivo	O
;	O
yet	O
,	O
when	O
placed	O
in	O
vitro	O
,	O
will	O
divide	O
in	O
response	O
to	O
BDNF	O
.	O

This	O
suggests	O
that	O
the	O
availability	O
of	O
BDNF	O
in	O
vivo	O
fails	O
to	O
reach	O
a	O
threshold	O
necessary	O
to	O
induce	O
proliferation	O
.	O

We	O
suggest	O
that	O
excess	O
TrkB	O
stimulation	O
of	O
sympathoblasts	O
in	O
vivo	O
may	O
lead	O
to	O
the	O
genesis	O
of	O
neuroblastoma	O
.	O

Background	O

Neural	O
crest	O
cells	O
destined	O
to	O
become	O
paravertebral	O
sympathetic	O
neurons	O
proliferate	O
and	O
differentiate	O
during	O
migration	O
and	O
gangliogenesis	O
.	O

In	O
chicken	B
embryos	O
,	O
migrating	O
neural	O
crest	O
cells	O
express	O
catecholamines	O
at	O
Hamburger	O
/	O
Hamilton	O
Stage	O
(	O
St	O
.	O
)	O
19	O
,	O
and	O
these	O
cells	O
form	O
the	O
primary	O
sympathetic	O
chain	O
dorsolateral	O
to	O
the	O
aorta	O
at	O
St	O
.	O

22	O
(	O
E3	O
.	O
5	O
)	O
[	O
1	O
]	O
.	O

Between	O
St	O
.	O

23	O
(	O
E4	O
)	O
and	O
St	O
.	O

28	O
(	O
E6	O
)	O
,	O
these	O
cells	O
disperse	O
and	O
undergo	O
a	O
secondary	O
migration	O
to	O
form	O
the	O
paravertebral	O
sympathetic	O
chain	O
that	O
resides	O
ventral	O
to	O
the	O
spinal	O
cord	O
and	O
dorsal	O
root	O
ganglion	O
[	O
1	O
]	O
.	O

After	O
ganglia	O
coalesce	O
,	O
sympathoblasts	O
express	O
markers	O
of	O
neuronal	O
differentiation	O
,	O
such	O
as	O
Q211	O
and	O
tyrosine	O
hydroxylase	O
(	O
TH	O
)	O
,	O
at	O
a	O
time	O
when	O
they	O
also	O
incorporate	O
[	O
3H	O
]	O
-	O
thymidine	O
[	O
2	O
]	O
.	O

Time	O
lapse	O
photography	O
has	O
shown	O
that	O
cultured	O
E15	O
.	O
5	O
-	O
E16	O
.	O
5	O
sympathetic	O
neurons	O
from	O
rat	B
embryos	O
extend	O
axons	O
while	O
they	O
divide	O
[	O
3	O
-	O
5	O
]	O
.	O

Although	O
proliferation	O
appears	O
to	O
be	O
an	O
important	O
process	O
to	O
expand	O
the	O
sympathetic	O
neuron	O
population	O
during	O
differentiation	O
,	O
the	O
mechanisms	O
that	O
guide	O
sympathoblast	O
proliferation	O
have	O
not	O
been	O
identified	O
.	O

The	O
development	O
of	O
sympathetic	O
neurons	O
is	O
guided	O
by	O
neurotrophins	O
.	O

Neurotrophin	O
-	O
3	O
(	O
NT	O
-	O
3	O
)	O
binds	O
to	O
its	O
receptor	O
,	O
TrkC	O
,	O
to	O
promote	O
the	O
survival	O
of	O
cultured	O
sympathoblasts	O
from	O
early	O
lumbar	O
paravertebral	O
ganglia	O
[	O
6	O
]	O
.	O

Nerve	O
growth	O
factor	O
(	O
NGF	O
)	O
signals	O
through	O
its	O
receptor	O
,	O
TrkA	O
,	O
to	O
promote	O
the	O
survival	O
of	O
sympathetic	O
neurons	O
upon	O
target	O
innervation	O
[	O
7	O
]	O
.	O

There	O
are	O
severe	O
sympathetic	O
defects	O
in	O
the	O
superior	O
cervical	O
ganglion	O
of	O
individual	O
NT	O
-	O
3	O
and	O
NGF	O
knockout	O
mice	B
[	O
8	O
-	O
10	O
]	O
.	O

Furthermore	O
,	O
there	O
is	O
no	O
additional	O
cell	O
death	O
in	O
the	O
superior	O
cervical	O
ganglion	O
of	O
NT	O
-	O
3	O
and	O
NGF	O
double	O
knockout	O
mouse	B
embryos	O
,	O
suggesting	O
that	O
all	O
of	O
the	O
neurons	O
are	O
dependent	O
on	O
both	O
neurotrophins	O
for	O
survival	O
[	O
11	O
]	O
.	O

There	O
is	O
also	O
an	O
increase	O
in	O
sympathetic	O
neuron	O
cell	O
death	O
in	O
TrkA	O
knockout	O
mice	B
[	O
12	O
]	O
.	O

However	O
,	O
in	O
TrkB	O
and	O
BDNF	O
knockout	O
mice	B
,	O
there	O
is	O
no	O
apparent	O
phenotype	O
in	O
the	O
superior	O
cervical	O
ganglion	O
,	O
and	O
there	O
is	O
little	O
evidence	O
that	O
TrkB	O
or	O
BDNF	O
is	O
expressed	O
in	O
sympathetic	O
ganglia	O
.	O

Thus	O
,	O
it	O
is	O
generally	O
thought	O
that	O
TrkB	O
and	O
BDNF	O
have	O
little	O
or	O
no	O
roles	O
in	O
guiding	O
the	O
development	O
of	O
sympathetic	O
neurons	O
.	O

In	O
addition	O
to	O
their	O
developmental	O
functions	O
,	O
neurotrophin	O
receptors	O
regulate	O
cell	O
behavior	O
in	O
neuroblastoma	O
,	O
a	O
tumor	O
found	O
in	O
sympathetic	O
ganglia	O
and	O
adrenal	O
medulla	O
.	O

Tumors	O
that	O
express	O
TrkA	O
often	O
spontaneously	O
regress	O
,	O
while	O
those	O
that	O
express	O
TrkB	O
and	O
its	O
ligand	O
,	O
brain	O
-	O
derived	O
neurotrophic	O
factor	O
(	O
BDNF	O
)	O
,	O
grow	O
aggressively	O
,	O
are	O
invasive	O
,	O
and	O
fail	O
to	O
respond	O
to	O
chemotherapeutic	O
agents	O
[	O
13	O
]	O
.	O

The	O
presence	O
of	O
TrkA	O
in	O
neuroblastoma	O
tumors	O
is	O
consistent	O
with	O
its	O
expression	O
in	O
developing	O
sympathetic	O
neurons	O
,	O
and	O
suggests	O
that	O
regressive	O
neuroblastoma	O
tumors	O
arise	O
from	O
early	O
sympathetic	O
neurons	O
that	O
express	O
TrkA	O
.	O

The	O
function	O
of	O
TrkB	O
in	O
early	O
sympathetic	O
development	O
is	O
unknown	O
,	O
which	O
makes	O
understanding	O
the	O
etiology	O
of	O
aggressive	O
neuroblastoma	O
tumors	O
difficult	O
.	O

Based	O
on	O
its	O
function	O
in	O
neuroblastoma	O
tumors	O
,	O
we	O
hypothesize	O
that	O
BDNF	O
and	O
TrkB	O
expression	O
in	O
differentiating	O
sympathoblasts	O
is	O
responsible	O
for	O
expanding	O
the	O
neuronal	O
population	O
through	O
proliferation	O
.	O

We	O
sought	O
to	O
determine	O
whether	O
BDNF	O
and	O
TrkB	O
are	O
involved	O
in	O
sympathetic	O
development	O
.	O

We	O
report	O
that	O
during	O
early	O
embryonic	O
development	O
,	O
TrkB	O
is	O
expressed	O
in	O
a	O
subset	O
of	O
differentiating	O
sympathoblasts	O
in	O
both	O
avian	O
and	O
murine	O
embryos	O
.	O

We	O
also	O
find	O
that	O
BDNF	O
promotes	O
the	O
proliferation	O
of	O
TrkB	O
-	O
positive	O
sympathoblasts	O
in	O
cell	O
culture	O
.	O

However	O
,	O
the	O
majority	O
of	O
TrkB	O
positive	O
cells	O
in	O
vivo	O
fail	O
to	O
take	O
up	O
bromodeoxyuridine	O
(	O
BrdU	O
)	O
over	O
a	O
24	O
hr	O
period	O
,	O
suggesting	O
that	O
endogenous	O
BDNF	O
concentrations	O
do	O
not	O
reach	O
a	O
threshold	O
necessary	O
to	O
stimulate	O
proliferation	O
of	O
sympathoblasts	O
.	O

Shortly	O
after	O
all	O
of	O
the	O
TrkB	O
positive	O
cells	O
commence	O
neuronal	O
differentiation	O
,	O
TrkB	O
immunoreactivity	O
is	O
lost	O
.	O

These	O
results	O
suggest	O
that	O
prolonged	O
expression	O
and	O
/	O
or	O
activation	O
of	O
TrkB	O
signaling	O
at	O
these	O
early	O
stages	O
may	O
be	O
an	O
early	O
event	O
triggering	O
the	O
formation	O
of	O
neuroblastoma	O
.	O

Results	O

TrkB	O
is	O
expressed	O
during	O
migration	O
of	O
neural	O
crest	O
cells	O
to	O
sympathetic	O
ganglia	O

We	O
first	O
determined	O
whether	O
TrkB	O
is	O
expressed	O
in	O
neural	O
crest	O
-	O
derived	O
cells	O
in	O
the	O
region	O
ventral	O
to	O
the	O
spinal	O
cord	O
and	O
dorsal	O
root	O
ganglia	O
where	O
sympathetic	O
ganglia	O
coalesce	O
between	O
Hamburger	O
/	O
Hamilton	O
Stages	O
(	O
St	O
.	O
)	O
25	O
-	O
28	O
/	O
29	O
.	O

To	O
identify	O
cells	O
that	O
have	O
commenced	O
neuronal	O
differentiation	O
,	O
transverse	O
sections	O
of	O
the	O
lumbar	O
spinal	O
column	O
region	O
were	O
stained	O
with	O
antibodies	O
against	O
Hu	O
C	O
/	O
D	O
[	O
14	O
]	O
,	O
a	O
neuronal	O
-	O
specific	O
RNA	O
-	O
binding	O
protein	O
,	O
or	O
Islet	O
-	O
1	O
,	O
a	O
transcription	O
factor	O
found	O
in	O
sympathetic	O
neurons	O
[	O
15	O
]	O
.	O

We	O
found	O
that	O
Hu	O
C	O
/	O
D	O
and	O
Islet	O
-	O
1	O
are	O
expressed	O
in	O
the	O
same	O
cells	O
both	O
in	O
vivo	O
and	O
in	O
vitro	O
throughout	O
sympathetic	O
development	O
.	O

In	O
experiments	O
done	O
between	O
St	O
.	O

25	O
and	O
28	O
,	O
Islet	O
-	O
1	O
staining	O
appeared	O
weaker	O
than	O
Hu	O
C	O
/	O
D	O
staining	O
,	O
and	O
thus	O
we	O
used	O
Hu	O
C	O
/	O
D	O
to	O
identify	O
differentiating	O
neurons	O
at	O
these	O
stages	O
.	O

At	O
later	O
stages	O
,	O
Islet	O
-	O
1	O
was	O
used	O
to	O
facilitate	O
the	O
identification	O
of	O
neurons	O
because	O
of	O
the	O
nuclear	O
location	O
of	O
its	O
immunoreactivity	O
.	O

Cells	O
expressing	O
Hu	O
C	O
/	O
D	O
are	O
first	O
detected	O
at	O
St	O
.	O

25	O
ventral	O
to	O
the	O
spinal	O
cord	O
and	O
dorsal	O
root	O
ganglion	O
and	O
lateral	O
to	O
the	O
dorsal	O
aorta	O
(	O
Figure	O
1A	O
,	O
1B	O
)	O
.	O

By	O
St	O
.	O

26	O
,	O
the	O
number	O
of	O
cells	O
that	O
express	O
Hu	O
C	O
/	O
D	O
in	O
this	O
region	O
increases	O
dramatically	O
(	O
Figure	O
1C	O
)	O
.	O

TrkB	O
-	O
expressing	O
cells	O
first	O
appear	O
at	O
St	O
.	O

27	O
in	O
the	O
same	O
region	O
and	O
are	O
adjacent	O
to	O
Hu	O
C	O
/	O
D	O
-	O
positive	O
cells	O
(	O
Figure	O
1D	O
,	O
2A	O
,	O
2H	O
)	O
.	O

TrkB	O
-	O
positive	O
cells	O
co	O
-	O
localize	O
with	O
a	O
neural	O
crest	O
marker	O
,	O
HNK	O
-	O
1	O
(	O
Figures	O
2B	O
,	O
2C	O
,	O
2D	O
)	O
.	O

The	O
Hu	O
C	O
/	O
D	O
-	O
positive	O
cells	O
in	O
this	O
region	O
are	O
likely	O
to	O
be	O
sympathetic	O
neurons	O
,	O
since	O
they	O
appear	O
in	O
the	O
region	O
where	O
sympathetic	O
ganglia	O
form	O
and	O
express	O
tyrosine	O
hydroxylase	O
,	O
a	O
rate	O
-	O
limiting	O
enzyme	O
in	O
the	O
synthesis	O
of	O
catecholamines	O
(	O
Figures	O
2E	O
,	O
2F	O
,	O
2G	O
)	O
.	O

At	O
St	O
.	O

28	O
/	O
29	O
,	O
the	O
cells	O
begin	O
to	O
coalesce	O
ventral	O
to	O
the	O
dorsal	O
root	O
ganglion	O
and	O
the	O
Hu	O
C	O
/	O
D	O
-	O
positive	O
cells	O
and	O
TrkB	O
-	O
positive	O
cells	O
remain	O
as	O
two	O
separate	O
cell	O
populations	O
(	O
Figure	O
1E	O
)	O
;	O
however	O
,	O
shortly	O
afterwards	O
,	O
all	O
of	O
the	O
TrkB	O
-	O
positive	O
cells	O
begin	O
to	O
express	O
Islet	O
-	O
1	O
(	O
Figure	O
3B	O
)	O
and	O
Hu	O
C	O
/	O
D	O
(	O
data	O
not	O
shown	O
)	O
.	O

Developmental	O
regulation	O
of	O
TrkA	O
,	O
TrkB	O
,	O
TrkC	O
,	O
and	O
BDNF	O
expression	O

In	O
contrast	O
to	O
TrkB	O
,	O
the	O
other	O
neurotrophin	O
receptors	O
,	O
TrkA	O
and	O
TrkC	O
,	O
are	O
co	O
-	O
expressed	O
in	O
both	O
Hu	O
C	O
/	O
D	O
-	O
positive	O
and	O
Hu	O
C	O
/	O
D	O
-	O
negative	O
cells	O
at	O
St	O
.	O

27	O
(	O
Figures	O
2I	O
,	O
2J	O
)	O
.	O

We	O
find	O
that	O
approximately	O
30	O
%	O
of	O
the	O
Islet	O
-	O
1	O
-	O
positive	O
cells	O
express	O
TrkA	O
(	O
Figure	O
3A	O
)	O
,	O
while	O
50	O
%	O
express	O
TrkB	O
(	O
Figure	O
3B	O
)	O
and	O
100	O
%	O
express	O
TrkC	O
(	O
Figure	O
3C	O
)	O
at	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
.	O

Thus	O
,	O
all	O
developing	O
neurons	O
express	O
TrkC	O
in	O
combination	O
with	O
either	O
TrkA	O
or	O
TrkB	O
.	O

By	O
St	O
.	O

31	O
(	O
E7	O
)	O
,	O
the	O
number	O
of	O
TrkA	O
-	O
positive	O
,	O
Islet	O
-	O
1	O
-	O
positive	O
cells	O
increases	O
to	O
100	O
%	O
(	O
Figure	O
3D	O
)	O
and	O
immunoreactivities	O
for	O
both	O
TrkB	O
and	O
TrkC	O
appear	O
dispersed	O
(	O
Figure	O
3E	O
,	O
3F	O
)	O
.	O

By	O
St	O
.	O

34	O
(	O
E8	O
)	O
,	O
TrkA	O
expression	O
is	O
well	O
-	O
sustained	O
(	O
Figure	O
3G	O
)	O
and	O
TrkB	O
and	O
TrkC	O
immunoreactivities	O
are	O
lost	O
(	O
Figure	O
3H	O
,	O
3I	O
)	O
.	O

We	O
also	O
examined	O
the	O
early	O
development	O
of	O
murine	O
sympathetic	O
ganglia	O
(	O
Figure	O
4	O
)	O
.	O

At	O
E13	O
,	O
the	O
newly	O
formed	O
lumbar	O
sympathetic	O
ganglia	O
can	O
be	O
observed	O
ventral	O
to	O
the	O
spinal	O
cord	O
and	O
notochord	O
by	O
their	O
staining	O
for	O
Hu	O
C	O
/	O
D	O
and	O
TH	O
(	O
Figure	O
4A	O
)	O
.	O

TrkB	O
-	O
positive	O
cells	O
can	O
be	O
seen	O
surrounding	O
developing	O
ganglia	O
,	O
as	O
well	O
as	O
in	O
occasional	O
cells	O
within	O
the	O
ganglia	O
(	O
Figure	O
4C	O
,	O
D	O
)	O
.	O

These	O
TrkB	O
-	O
positive	O
cells	O
within	O
the	O
ganglia	O
co	O
-	O
express	O
TH	O
and	O
are	O
seen	O
at	O
a	O
frequency	O
of	O
1	O
-	O
2	O
cells	O
per	O
section	O
starting	O
at	O
E13	O
(	O
Figure	O
4A	O
-	O
D	O
)	O
and	O
are	O
still	O
present	O
at	O
E15	O
.	O
5	O
(	O
data	O
not	O
shown	O
)	O
.	O

In	O
neuroblastoma	O
cells	O
,	O
BDNF	O
is	O
co	O
-	O
expressed	O
with	O
TrkB	O
,	O
suggesting	O
that	O
autocrine	O
stimulation	O
is	O
a	O
means	O
by	O
which	O
proliferation	O
is	O
sustained	O
in	O
the	O
transformed	O
cells	O
.	O

To	O
test	O
whether	O
BDNF	O
,	O
the	O
ligand	O
for	O
TrkB	O
,	O
was	O
present	O
in	O
embryonic	O
chick	B
sympathetic	O
ganglia	O
,	O
we	O
used	O
quantitative	O
real	O
-	O
time	O
PCR	O
with	O
TaqMan	O
probes	O
to	O
determine	O
the	O
relative	O
abundance	O
of	O
BDNF	O
transcripts	O
in	O
total	O
RNA	O
extracted	O
from	O
lumbar	O
sympathetic	O
ganglia	O
at	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
,	O
St	O
.	O

31	O
(	O
E7	O
)	O
,	O
St	O
.	O

34	O
(	O
E8	O
)	O
,	O
and	O
E9	O
.	O

BDNF	O
expression	O
within	O
the	O
ganglia	O
parallels	O
that	O
of	O
TrkB	O
:	O
BDNF	O
mRNA	O
expression	O
levels	O
are	O
highest	O
at	O
St	O
29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
,	O
and	O
these	O
levels	O
decrease	O
2	O
-	O
fold	O
at	O
St	O
.	O

31	O
(	O
E7	O
)	O
and	O
St	O
.	O

34	O
(	O
E8	O
;	O
Figure	O
5	O
)	O
.	O

By	O
E9	O
,	O
BDNF	O
levels	O
are	O
7	O
times	O
lower	O
than	O
at	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
;	O
Figure	O
5	O
)	O
.	O

NT3	O
and	O
NGF	O
promote	O
survival	O
of	O
differentiating	O
sympathetic	O
neurons	O
in	O
culture	O

To	O
determine	O
the	O
effect	O
of	O
neurotrophins	O
,	O
we	O
cultured	O
cells	O
dispersed	O
from	O
lumbar	O
sympathetic	O
ganglia	O
at	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
because	O
,	O
at	O
this	O
stage	O
,	O
ganglion	O
formation	O
is	O
complete	O
,	O
the	O
number	O
of	O
TrkA	O
-	O
,	O
TrkB	O
-	O
,	O
and	O
TrkC	O
-	O
positive	O
cells	O
have	O
peaked	O
,	O
and	O
all	O
Trk	O
-	O
expressing	O
cells	O
have	O
initiated	O
neural	O
differentiation	O
.	O

First	O
,	O
we	O
identified	O
markers	O
expressed	O
by	O
acutely	O
isolated	O
cells	O
.	O

As	O
shown	O
in	O
Table	O
1	O
,	O
80	O
-	O
91	O
%	O
of	O
the	O
cells	O
are	O
p75	O
neurotrophin	O
receptor	O
(	O
NTR	O
)	O
-	O
positive	O
,	O
indicating	O
that	O
most	O
of	O
the	O
cells	O
are	O
neural	O
crest	O
-	O
derived	O
and	O
little	O
mesenchymal	O
contamination	O
is	O
introduced	O
by	O
the	O
isolation	O
procedure	O
.	O

In	O
addition	O
,	O
28	O
-	O
33	O
%	O
of	O
the	O
cultured	O
cells	O
express	O
the	O
neural	O
marker	O
Hu	O
C	O
/	O
D	O
.	O

Approximately	O
half	O
of	O
these	O
Hu	O
C	O
/	O
D	O
-	O
positive	O
cells	O
express	O
TrkB	O
.	O

Conversely	O
,	O
all	O
of	O
the	O
TrkB	O
positive	O
cells	O
express	O
Hu	O
C	O
/	O
D	O
.	O

These	O
TrkB	O
-	O
positive	O
cells	O
comprise	O
approximately	O
14	O
-	O
17	O
%	O
of	O
the	O
total	O
cell	O
population	O
.	O

We	O
then	O
determined	O
how	O
many	O
of	O
the	O
acutely	O
isolated	O
cells	O
were	O
proliferating	O
by	O
incubating	O
them	O
for	O
12	O
hrs	O
in	O
BrdU	O
-	O
containing	O
medium	O
.	O

For	O
these	O
experiments	O
,	O
we	O
identified	O
differentiating	O
neurons	O
with	O
the	O
transcription	O
factor	O
Islet	O
-	O
1	O
because	O
this	O
marker	O
labels	O
nuclei	O
,	O
thus	O
it	O
co	O
localizes	O
with	O
any	O
BrdU	O
that	O
has	O
been	O
incorporated	O
into	O
the	O
DNA	O
,	O
allowing	O
us	O
to	O
determine	O
whether	O
the	O
cell	O
had	O
undergone	O
S	O
-	O
phase	O
of	O
the	O
cell	O
cycle	O
.	O

After	O
12	O
hrs	O
in	O
BrdU	O
,	O
59	O
%	O
of	O
Islet	O
-	O
1	O
-	O
positive	O
nuclei	O
stain	O
for	O
BrdU	O
immunoreactivity	O
.	O

Thus	O
,	O
cultures	O
of	O
St	O
.	O

29	O
/	O
30	O
sympathetic	O
ganglia	O
contain	O
many	O
cells	O
that	O
proliferate	O
while	O
exhibiting	O
markers	O
of	O
neuronal	O
differentiation	O
,	O
confirming	O
previous	O
observations	O
[	O
2	O
]	O
.	O

We	O
call	O
these	O
dividing	O
neuronal	O
precursors	O
sympathoblasts	O
.	O

The	O
remaining	O
non	O
-	O
BrdU	O
incorporating	O
,	O
Islet	O
-	O
1	O
positive	O
cells	O
are	O
likely	O
to	O
be	O
post	O
mitotic	O
neurons	O
.	O

Finally	O
,	O
we	O
determined	O
the	O
trophic	O
requirements	O
of	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
sympathetic	O
neurons	O
and	O
sympathoblasts	O
.	O

We	O
monitored	O
cultures	O
over	O
a	O
three	O
day	O
period	O
after	O
plating	O
and	O
counted	O
the	O
number	O
of	O
phase	O
bright	O
cells	O
with	O
neurites	O
,	O
a	O
morphological	O
feature	O
of	O
both	O
neurons	O
and	O
sympathoblasts	O
.	O

In	O
the	O
absence	O
of	O
trophic	O
factors	O
,	O
more	O
than	O
2	O
/	O
3	O
of	O
the	O
cells	O
die	O
by	O
24	O
hours	O
in	O
culture	O
and	O
BDNF	O
,	O
NT	O
-	O
3	O
,	O
or	O
NGF	O
alone	O
is	O
not	O
sufficient	O
to	O
promote	O
survival	O
(	O
Figure	O
6	O
)	O
.	O

However	O
,	O
NGF	O
together	O
with	O
NT	O
-	O
3	O
supports	O
the	O
survival	O
of	O
a	O
significantly	O
larger	O
number	O
of	O
cells	O
(	O
Figure	O
6	O
)	O
.	O

For	O
the	O
subsequent	O
experiments	O
,	O
all	O
neurons	O
were	O
cultured	O
with	O
25	O
ng	O
/	O
ml	O
NT	O
-	O
3	O
and	O
1	O
mu	O
g	O
/	O
ml	O
7S	O
NGF	O
to	O
optimize	O
survival	O
.	O

BDNF	O
promotes	O
proliferation	O
of	O
TrkB	O
-	O
positive	O
sympathetic	O
neurons	O
in	O
culture	O

To	O
determine	O
the	O
effects	O
of	O
BDNF	O
,	O
cultures	O
of	O
cells	O
from	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
sympathetic	O
ganglia	O
were	O
supplemented	O
with	O
200	O
ng	O
/	O
ml	O
BDNF	O
and	O
the	O
number	O
of	O
neurons	O
and	O
sympathoblasts	O
were	O
counted	O
at	O
24	O
,	O
48	O
,	O
and	O
72	O
hours	O
using	O
phase	O
microscopy	O
(	O
Figure	O
7A	O
)	O
.	O

A	O
1	O
.	O
6	O
-	O
fold	O
increase	O
in	O
the	O
number	O
of	O
neurons	O
due	O
to	O
BDNF	O
is	O
observed	O
by	O
24	O
hours	O
and	O
this	O
number	O
does	O
not	O
increase	O
further	O
at	O
48	O
or	O
72	O
hours	O
.	O

This	O
effect	O
of	O
BDNF	O
is	O
concentration	O
-	O
dependent	O
with	O
an	O
EC50	O
of	O
75	O
ng	O
/	O
ml	O
(	O
Figure	O
7B	O
)	O
.	O

To	O
test	O
whether	O
the	O
increase	O
in	O
the	O
number	O
of	O
neurons	O
and	O
sympathoblasts	O
caused	O
by	O
BDNF	O
is	O
due	O
to	O
the	O
differentiation	O
of	O
pluripotent	O
neural	O
crest	O
cells	O
,	O
we	O
quantified	O
the	O
effects	O
of	O
BDNF	O
on	O
the	O
number	O
of	O
neurally	O
differentiating	O
cells	O
(	O
Hu	O
C	O
/	O
D	O
-	O
positive	O
)	O
versus	O
the	O
number	O
of	O
non	O
-	O
neuronal	O
cells	O
(	O
Hu	O
C	O
/	O
D	O
-	O
negative	O
)	O
after	O
identifying	O
all	O
neural	O
crest	O
-	O
derived	O
cells	O
by	O
staining	O
for	O
p75NTR	O
in	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
cultures	O
.	O

If	O
BDNF	O
increases	O
the	O
number	O
of	O
neurons	O
and	O
sympathoblasts	O
by	O
inducing	O
a	O
non	O
-	O
neuronal	O
cell	O
to	O
express	O
Hu	O
C	O
/	O
D	O
,	O
then	O
we	O
expected	O
that	O
the	O
total	O
cell	O
number	O
would	O
remain	O
the	O
same	O
and	O
that	O
there	O
would	O
be	O
a	O
decrease	O
in	O
the	O
number	O
of	O
non	O
-	O
neuronal	O
cells	O
as	O
well	O
as	O
a	O
corresponding	O
increase	O
in	O
the	O
number	O
of	O
neurons	O
.	O

After	O
24	O
hours	O
,	O
BDNF	O
significantly	O
increases	O
the	O
number	O
of	O
p75NTR	O
-	O
positive	O
cells	O
as	O
well	O
as	O
the	O
number	O
of	O
Hu	O
C	O
/	O
D	O
-	O
positive	O
cells	O
(	O
Figure	O
8A	O
)	O
.	O

However	O
,	O
there	O
was	O
no	O
statistically	O
significant	O
change	O
in	O
the	O
number	O
of	O
non	O
-	O
neuronal	O
cells	O
.	O

Thus	O
,	O
it	O
is	O
unlikely	O
that	O
BDNF	O
increases	O
the	O
number	O
of	O
neurons	O
and	O
sympathoblasts	O
by	O
inducing	O
differentiation	O
of	O
non	O
-	O
neuronal	O
cells	O
.	O

To	O
determine	O
whether	O
the	O
increase	O
in	O
the	O
total	O
number	O
of	O
neurons	O
and	O
sympathoblasts	O
is	O
caused	O
by	O
BDNF	O
-	O
induced	O
proliferation	O
,	O
control	O
and	O
BDNF	O
-	O
treated	O
sympathetic	O
cultures	O
were	O
exposed	O
to	O
BrdU	O
for	O
12	O
hours	O
after	O
plating	O
,	O
and	O
the	O
number	O
of	O
cells	O
that	O
incorporated	O
BrdU	O
into	O
their	O
DNA	O
was	O
determined	O
after	O
24	O
hours	O
in	O
culture	O
.	O

Even	O
in	O
the	O
control	O
condition	O
,	O
a	O
number	O
of	O
cells	O
in	O
the	O
culture	O
are	O
dividing	O
,	O
giving	O
a	O
high	O
baseline	O
of	O
BrdU	O
incorporation	O
(	O
Figure	O
8B	O
)	O
.	O

When	O
BDNF	O
is	O
added	O
,	O
the	O
total	O
number	O
of	O
BrdU	O
positive	O
cells	O
increases	O
approximately	O
1	O
.	O
6	O
-	O
fold	O
(	O
Figure	O
8B	O
)	O
.	O

This	O
BDNF	O
-	O
induced	O
increase	O
in	O
the	O
total	O
number	O
of	O
BrdU	O
positive	O
cells	O
occurs	O
in	O
sympathoblasts	O
because	O
the	O
number	O
of	O
Islet	O
-	O
1	O
-	O
positive	O
nuclei	O
from	O
control	O
cultures	O
that	O
label	O
with	O
BrdU	O
is	O
268	O
+	O
/	O
-	O
59	O
and	O
BDNF	O
treatment	O
raises	O
this	O
number	O
to	O
424	O
+	O
/	O
-	O
80	O
,	O
which	O
corresponds	O
to	O
an	O
increase	O
of	O
1	O
.	O
6	O
-	O
fold	O
.	O

This	O
accounts	O
for	O
the	O
1	O
.	O
6	O
-	O
fold	O
increase	O
in	O
total	O
neuron	O
number	O
and	O
total	O
BrdU	O
-	O
positive	O
cells	O
described	O
above	O
.	O

We	O
then	O
confirmed	O
that	O
BDNF	O
acts	O
on	O
TrkB	O
-	O
positive	O
cells	O
:	O
BDNF	O
increases	O
the	O
number	O
of	O
TrkB	O
-	O
expressing	O
cells	O
that	O
incorporate	O
BrdU	O
2	O
.	O
6	O
-	O
4	O
-	O
fold	O
over	O
control	O
(	O
Table	O
2	O
)	O
and	O
it	O
also	O
increases	O
the	O
overall	O
number	O
of	O
TrkB	O
-	O
positive	O
cells	O
2	O
-	O
2	O
.	O
5	O
-	O
fold	O
over	O
control	O
(	O
Table	O
2	O
)	O
.	O

BDNF	O
does	O
not	O
increase	O
the	O
number	O
of	O
BrdU	O
-	O
positive	O
,	O
TrkB	O
-	O
negative	O
cells	O
or	O
the	O
overall	O
number	O
of	O
TrkB	O
-	O
negative	O
cells	O
(	O
Table	O
2	O
)	O
.	O

In	O
further	O
support	O
that	O
BDNF	O
acts	O
directly	O
on	O
TrkB	O
-	O
expressing	O
cells	O
,	O
an	O
antibody	O
directed	O
against	O
the	O
extracellular	O
domain	O
of	O
TrkB	O
completely	O
prevents	O
the	O
effect	O
of	O
BDNF	O
in	O
promoting	O
proliferation	O
of	O
TrkB	O
-	O
positive	O
,	O
but	O
not	O
TrkB	O
-	O
negative	O
cells	O
(	O
compare	O
Figure	O
9A	O
to	O
9B	O
)	O
.	O

Thus	O
,	O
the	O
effect	O
of	O
BDNF	O
is	O
restricted	O
to	O
the	O
population	O
that	O
expresses	O
TrkB	O
,	O
which	O
are	O
developing	O
sympathoblasts	O
.	O

To	O
determine	O
whether	O
TrkB	O
-	O
positive	O
cells	O
are	O
actively	O
proliferating	O
in	O
vivo	O
,	O
embryos	O
were	O
injected	O
with	O
BrdU	O
at	O
St	O
.	O

27	O
and	O
harvested	O
at	O
St	O
.	O

29	O
,	O
approximately	O
24	O
hrs	O
later	O
.	O

The	O
majority	O
(	O
85	O
-	O
90	O
%	O
)	O
of	O
TrkB	O
-	O
positive	O
cells	O
do	O
not	O
incorporate	O
BrdU	O
into	O
their	O
nuclei	O
under	O
basal	O
conditions	O
in	O
vivo	O
(	O
Figure	O
10	O
)	O
,	O
although	O
a	O
few	O
TrkB	O
positive	O
cells	O
with	O
labeled	O
nuclei	O
could	O
be	O
observed	O
(	O
arrows	O
)	O
.	O

This	O
contrasts	O
with	O
our	O
observation	O
that	O
71	O
-	O
76	O
%	O
of	O
TrkB	O
-	O
positive	O
cells	O
incorporate	O
BrdU	O
in	O
culture	O
after	O
treatment	O
with	O
BDNF	O
(	O
Table	O
2	O
)	O
,	O
suggesting	O
that	O
endogenous	O
BDNF	O
does	O
not	O
achieve	O
a	O
threshold	O
sufficient	O
to	O
support	O
a	O
high	O
level	O
of	O
sympathoblast	O
proliferation	O
in	O
vivo	O
.	O

Discussion	O

We	O
report	O
that	O
the	O
neurotrophin	O
receptor	O
TrkB	O
is	O
expressed	O
in	O
a	O
subset	O
of	O
embryonic	O
sympathoblasts	O
during	O
the	O
early	O
development	O
of	O
lumbar	O
paravertebral	O
sympathetic	O
ganglia	O
in	O
chicken	B
and	O
mouse	B
embryos	O
.	O

In	O
the	O
chicken	B
,	O
TrkB	O
expression	O
is	O
transient	O
,	O
and	O
completely	O
lost	O
by	O
St	O
34	O
(	O
E8	O
)	O
.	O

Since	O
BDNF	O
induces	O
the	O
proliferation	O
of	O
sympathoblasts	O
in	O
cell	O
culture	O
,	O
yet	O
in	O
vivo	O
there	O
is	O
little	O
proliferation	O
observed	O
in	O
TrkB	O
-	O
positive	O
cells	O
in	O
nascent	O
ganglia	O
,	O
we	O
propose	O
that	O
if	O
TrkB	O
activation	O
becomes	O
unregulated	O
by	O
excess	O
BDNF	O
or	O
constitutive	O
phosphorylation	O
of	O
TrkB	O
[	O
16	O
]	O
,	O
this	O
transient	O
population	O
of	O
TrkB	O
-	O
positive	O
sympathoblasts	O
may	O
trigger	O
the	O
genesis	O
of	O
neuroblastoma	O
,	O
a	O
childhood	O
tumor	O
found	O
in	O
the	O
paravertebral	O
chain	O
and	O
adrenal	O
medulla	O
.	O

The	O
two	O
populations	O
of	O
sympathoblasts	O
that	O
we	O
observe	O
support	O
previous	O
findings	O
of	O
heterogeneity	O
among	O
developing	O
sympathetic	O
neurons	O
and	O
neural	O
crest	O
cells	O
.	O

Early	O
sympathetic	O
ganglia	O
contain	O
at	O
least	O
two	O
subpopulations	O
:	O
early	O
differentiating	O
neurons	O
that	O
lack	O
TrkB	O
expression	O
and	O
express	O
TrkA	O
and	O
TrkC	O
,	O
and	O
late	O
differentiating	O
sympathoblasts	O
that	O
express	O
TrkB	O
.	O

Explant	O
cultures	O
of	O
sympathetic	O
ganglia	O
from	O
E16	O
chick	B
embryos	O
give	O
rise	O
to	O
two	O
neuronal	O
populations	O
:	O
one	O
that	O
remains	O
close	O
to	O
the	O
explant	O
,	O
and	O
one	O
that	O
migrates	O
away	O
from	O
the	O
explant	O
[	O
1	O
]	O
.	O

In	O
addition	O
,	O
early	O
neuronal	O
subpopulations	O
have	O
been	O
observed	O
in	O
cultures	O
of	O
neural	O
crest	O
cells	O
from	O
St	O
.	O

13	O
/	O
14	O
quail	O
embryos	O
as	O
evidenced	O
by	O
the	O
expression	O
of	O
neuronal	O
cell	O
type	O
-	O
specific	O
gangliosides	O
[	O
17	O
]	O
.	O

Perhaps	O
these	O
different	O
subpopulations	O
will	O
ultimately	O
give	O
rise	O
to	O
the	O
two	O
neurochemically	O
distinct	O
populations	O
found	O
in	O
lumbar	O
sympathetic	O
ganglia	O
:	O
the	O
noradrenergic	O
,	O
NPY	O
-	O
containing	O
neurons	O
that	O
innervate	O
internal	O
organs	O
and	O
enteric	O
ganglia	O
and	O
the	O
cholinergic	O
,	O
VIP	O
-	O
containing	O
neurons	O
that	O
innervate	O
vasculature	O
in	O
the	O
hind	O
limbs	O
.	O

The	O
effects	O
of	O
BDNF	O
and	O
TrkB	O
deletion	O
and	O
over	O
expression	O
have	O
been	O
studied	O
on	O
superior	O
cervical	O
ganglion	O
and	O
preganglionic	O
neurons	O
in	O
thoracic	O
segments	O
of	O
the	O
spinal	O
column	O
,	O
but	O
not	O
on	O
paravertebral	O
sympathetic	O
neurons	O
.	O

In	O
the	O
superior	O
cervical	O
ganglion	O
,	O
an	O
increase	O
in	O
the	O
number	O
of	O
neurons	O
of	O
BDNF	O
null	O
mice	B
is	O
likely	O
due	O
to	O
apoptosis	O
induced	O
by	O
BDNF	O
via	O
p75NTR	O
[	O
18	O
]	O
.	O

In	O
contrast	O
,	O
the	O
responses	O
of	O
paravertebral	O
sympathetic	O
neurons	O
to	O
BDNF	O
are	O
complex	O
and	O
subtype	O
dependent	O
.	O

Over	O
expression	O
of	O
BDNF	O
leads	O
to	O
an	O
increase	O
in	O
the	O
number	O
of	O
noradrenergic	O
fibers	O
innervating	O
the	O
erector	O
pilli	O
muscles	O
of	O
hair	O
follicles	O
,	O
while	O
noradrenergic	O
fibers	O
innervating	O
blood	O
vessels	O
were	O
unaffected	O
[	O
19	O
]	O
.	O

If	O
our	O
results	O
indicating	O
that	O
BDNF	O
promotes	O
proliferation	O
of	O
TrkB	O
-	O
positive	O
sympathoblasts	O
in	O
the	O
chicken	B
embryo	O
can	O
be	O
extrapolated	O
to	O
the	O
subset	O
of	O
TrkB	O
-	O
positive	O
sympathoblasts	O
in	O
murine	O
ganglia	O
,	O
then	O
these	O
TrkB	O
-	O
positive	O
cells	O
may	O
be	O
neurons	O
destined	O
to	O
innervate	O
the	O
erector	O
pilli	O
.	O

In	O
other	O
studies	O
,	O
TrkB	O
null	O
mice	B
showed	O
no	O
changes	O
in	O
morphology	O
or	O
cell	O
number	O
in	O
superior	O
cervical	O
ganglia	O
[	O
12	O
]	O
or	O
in	O
the	O
intermediolateral	O
column	O
[	O
20	O
]	O
;	O
but	O
this	O
may	O
not	O
be	O
predictive	O
of	O
a	O
phenotype	O
in	O
the	O
lumbar	O
paravertebral	O
chain	O
.	O

It	O
is	O
thus	O
possible	O
that	O
BDNF	O
/	O
TrkB	O
signaling	O
could	O
play	O
a	O
specific	O
role	O
in	O
other	O
regions	O
of	O
the	O
paravertebral	O
sympathetic	O
chain	O
,	O
such	O
as	O
the	O
lumbar	O
region	O
.	O

However	O
,	O
if	O
TrkB	O
-	O
positive	O
cells	O
are	O
not	O
normally	O
actively	O
proliferating	O
in	O
vivo	O
,	O
then	O
it	O
would	O
not	O
be	O
surprising	O
that	O
the	O
development	O
of	O
the	O
paravertebral	O
sympathetic	O
chain	O
is	O
not	O
disrupted	O
in	O
TrkB	O
or	O
BDNF	O
null	O
mice	B
.	O

It	O
may	O
be	O
more	O
informative	O
to	O
examine	O
mice	B
that	O
over	O
express	O
BDNF	O
on	O
a	O
promoter	O
that	O
targets	O
expression	O
to	O
embryonic	O
lumbar	O
ganglia	O
.	O

Unfortunately	O
,	O
such	O
mice	B
do	O
not	O
exist	O
.	O

Our	O
findings	O
that	O
the	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
sympathoblasts	O
are	O
dependent	O
on	O
both	O
NT	O
-	O
3	O
and	O
NGF	O
for	O
survival	O
in	O
culture	O
are	O
consistent	O
with	O
previous	O
work	O
on	O
mouse	B
sympathoblasts	O
from	O
the	O
superior	O
cervical	O
ganglion	O
[	O
11	O
]	O
.	O

In	O
these	O
studies	O
,	O
NT	O
-	O
3	O
and	O
NGF	O
deletion	O
separately	O
led	O
to	O
a	O
decrease	O
in	O
the	O
number	O
of	O
sympathetic	O
neurons	O
at	O
E17	O
.	O
5	O
compared	O
to	O
control	O
.	O

Deletion	O
of	O
both	O
NT	O
-	O
3	O
and	O
NGF	O
together	O
did	O
not	O
enhance	O
cell	O
death	O
.	O

In	O
contrast	O
,	O
cultured	O
rat	B
superior	O
cervical	O
ganglion	O
sympathetic	O
neurons	O
respond	O
to	O
NT	O
-	O
3	O
at	O
E14	O
.	O
5	O
and	O
then	O
to	O
NGF	O
at	O
E19	O
.	O
5	O
,	O
although	O
time	O
points	O
in	O
between	O
were	O
not	O
analyzed	O
[	O
6	O
]	O
.	O

In	O
addition	O
to	O
promoting	O
survival	O
,	O
NT	O
-	O
3	O
,	O
NGF	O
,	O
and	O
BDNF	O
also	O
induce	O
proliferation	O
of	O
various	O
neuronal	O
precursors	O
at	O
different	O
stages	O
of	O
development	O
.	O

NT	O
-	O
3	O
can	O
promote	O
the	O
incorporation	O
of	O
[	O
3H	O
]	O
-	O
thymidine	O
into	O
cultured	O
quail	O
neural	O
crest	O
cells	O
from	O
the	O
trunk	O
region	O
[	O
21	O
,	O
22	O
]	O
,	O
Later	O
in	O
rat	B
sympathetic	O
development	O
,	O
NT	O
-	O
3	O
supports	O
survival	O
of	O
neurons	O
,	O
but	O
does	O
not	O
promote	O
proliferation	O
[	O
6	O
]	O
,	O
which	O
is	O
consistent	O
with	O
our	O
results	O
.	O

NGF	O
promotes	O
an	O
increase	O
in	O
BrdU	O
incorporation	O
from	O
25	O
%	O
to	O
35	O
%	O
in	O
the	O
DRG	O
cervical	O
segment	O
2	O
in	O
the	O
chick	B
embryo	O
[	O
23	O
]	O
.	O

In	O
chicken	B
embryos	O
that	O
are	O
treated	O
with	O
NGF	O
in	O
ovo	O
at	O
St	O
.	O

18	O
and	O
21	O
,	O
there	O
is	O
an	O
increase	O
in	O
BrdU	O
uptake	O
after	O
formation	O
of	O
the	O
primary	O
sympathetic	O
chain	O
at	O
St	O
.	O

23	O
[	O
24	O
]	O
.	O

Since	O
NGF	O
does	O
not	O
appear	O
to	O
affect	O
proliferation	O
of	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
chick	B
sympathoblasts	O
,	O
NGF	O
may	O
only	O
promote	O
proliferation	O
in	O
primary	O
,	O
but	O
not	O
secondary	O
chain	O
sympathoblasts	O
.	O

Motor	O
neuron	O
progenitors	O
in	O
the	O
ventral	O
neural	O
tube	O
from	O
the	O
chick	B
embryo	O
express	O
TrkB	O
and	O
when	O
ventral	O
neural	O
tube	O
explants	O
are	O
treated	O
with	O
BDNF	O
,	O
there	O
is	O
an	O
increase	O
in	O
the	O
number	O
of	O
motor	O
neurons	O
produced	O
and	O
BrdU	O
incorporation	O
[	O
25	O
]	O
.	O

BDNF	O
also	O
promotes	O
the	O
proliferation	O
of	O
cultured	O
neuroblastoma	O
cells	O
[	O
13	O
]	O
.	O

Taken	O
together	O
,	O
these	O
results	O
are	O
consistent	O
with	O
our	O
findings	O
that	O
NT	O
-	O
3	O
and	O
NGF	O
do	O
not	O
promote	O
proliferation	O
of	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
sympathoblasts	O
,	O
and	O
support	O
the	O
assertion	O
that	O
BDNF	O
promotes	O
proliferation	O
of	O
TrkB	O
-	O
positive	O
sympathoblasts	O
in	O
culture	O
.	O

Our	O
observations	O
suggest	O
a	O
transient	O
function	O
of	O
TrkB	O
during	O
early	O
sympathetic	O
development	O
in	O
supporting	O
proliferation	O
of	O
this	O
early	O
subpopulation	O
of	O
sympathoblasts	O
.	O

However	O
,	O
the	O
in	O
vivo	O
labeling	O
suggests	O
that	O
only	O
a	O
minority	O
(	O
10	O
-	O
20	O
%	O
)	O
of	O
this	O
population	O
is	O
dividing	O
during	O
the	O
window	O
that	O
TrkB	O
is	O
expressed	O
.	O

In	O
light	O
of	O
the	O
very	O
strong	O
proliferative	O
effect	O
produced	O
in	O
cell	O
culture	O
,	O
these	O
TrkB	O
expressing	O
cells	O
could	O
respond	O
more	O
strongly	O
if	O
endogenous	O
BDNF	O
rises	O
to	O
higher	O
levels	O
,	O
or	O
if	O
the	O
mechanism	O
that	O
down	O
regulates	O
TrkB	O
expression	O
becomes	O
nonfunctional	O
.	O

Such	O
events	O
could	O
trigger	O
an	O
early	O
proliferative	O
event	O
that	O
leads	O
to	O
a	O
cascade	O
of	O
changes	O
that	O
initiates	O
transformation	O
of	O
cells	O
to	O
neuroblastoma	O
.	O

Thus	O
,	O
these	O
early	O
TrkB	O
expressing	O
cells	O
help	O
solve	O
the	O
puzzle	O
as	O
to	O
why	O
TrkB	O
is	O
expressed	O
in	O
aggressive	O
and	O
invasive	O
forms	O
of	O
neuroblastoma	O
,	O
particularly	O
because	O
BDNF	O
induces	O
cultured	O
neuroblastoma	O
cells	O
to	O
become	O
more	O
proliferative	O
,	O
invasive	O
,	O
angiogenic	O
,	O
and	O
resistant	O
to	O
chemotherapeutic	O
reagents	O
than	O
untreated	O
cultures	O
[	O
13	O
]	O
.	O

Future	O
studies	O
will	O
determine	O
whether	O
constitutive	O
expression	O
of	O
BDNF	O
and	O
TrkB	O
in	O
the	O
chick	B
embryo	O
sustains	O
proliferation	O
of	O
differentiating	O
sympathoblasts	O
.	O

Conclusion	O

We	O
have	O
identified	O
a	O
time	O
point	O
during	O
development	O
when	O
differentiating	O
lumbar	O
sympathetic	O
neurons	O
transiently	O
express	O
TrkB	O
and	O
proliferate	O
in	O
response	O
to	O
high	O
concentrations	O
of	O
BDNF	O
in	O
culture	O
.	O

These	O
studies	O
suggest	O
that	O
elevated	O
BDNF	O
expression	O
above	O
basal	O
levels	O
and	O
signaling	O
through	O
TrkB	O
may	O
be	O
a	O
mechanism	O
that	O
contributes	O
to	O
the	O
onset	O
of	O
neuroblastoma	O
.	O

A	O
further	O
understanding	O
of	O
the	O
two	O
populations	O
of	O
sympathetic	O
neurons	O
and	O
the	O
fate	O
of	O
the	O
TrkB	O
-	O
positive	O
cells	O
will	O
provide	O
additional	O
insight	O
into	O
the	O
development	O
of	O
paravertebral	O
sympathetic	O
ganglia	O
and	O
the	O
genesis	O
of	O
neuroblastoma	O
.	O

Methods	O

Preparation	O
of	O
tissue	O
for	O
immunohistochemistry	O

The	O
lumbar	O
spinal	O
column	O
and	O
surrounding	O
tissues	O
were	O
dissected	O
from	O
chicken	B
embryos	O
at	O
the	O
indicated	O
stages	O
and	O
placed	O
in	O
Zamboni	O
'	O
s	O
fixative	O
(	O
4	O
%	O
(	O
w	O
/	O
v	O
)	O
paraformaldehyde	O
,	O
15	O
%	O
(	O
v	O
/	O
v	O
)	O
picric	O
acid	O
in	O
0	O
.	O
1	O
M	O
sodium	O
phosphate	O
buffer	O
,	O
pH	O
7	O
.	O
4	O
)	O
for	O
two	O
hours	O
at	O
room	O
temperature	O
.	O

Mouse	B
embryos	O
at	O
13	O
-	O
15	O
days	O
post	O
-	O
coitus	O
were	O
collected	O
according	O
to	O
an	O
IACUC	O
-	O
approved	O
protocol	O
to	O
Dr	O
.	O
L	O
.	O

Sherman	O
at	O
the	O
Oregon	O
Health	O
and	O
Science	O
University	O
.	O

The	O
mouse	B
embryos	O
were	O
immersion	O
-	O
fixed	O
in	O
Zamboni	O
'	O
s	O
fixative	O
overnight	O
at	O
4	O
degrees	O
C	O
then	O
washed	O
with	O
phosphate	O
buffered	O
saline	O
(	O
PBS	O
;	O
130	O
mM	O
NaCl	O
,	O
20	O
mM	O
sodium	O
phosphate	O
buffer	O
,	O
pH	O
7	O
.	O
4	O
)	O
.	O

Fixed	O
tissues	O
were	O
equilibrated	O
in	O
30	O
%	O
sucrose	O
in	O
1	O
x	O
phosphate	O
-	O
buffered	O
saline	O
(	O
PBS	O
)	O
.	O

Fixed	O
mouse	B
embryos	O
were	O
shipped	O
to	O
Vermont	O
in	O
sucrose	O
.	O

Transverse	O
30	O
mu	O
M	O
sections	O
of	O
the	O
spinal	O
columns	O
were	O
cut	O
at	O
on	O
a	O
Microm	O
HM	O
cryostat	O
(	O
knife	O
temperature	O
:	O
16	O
degrees	O
C	O
;	O
object	O
temperature	O
:	O
23	O
degrees	O
C	O
)	O
and	O
collected	O
on	O
Superfrost	O
Plus	O
slides	O
(	O
Fisher	O
)	O
.	O

Sections	O
were	O
dried	O
at	O
room	O
temperature	O
,	O
washed	O
in	O
1	O
x	O
PBS	O
and	O
incubated	O
overnight	O
in	O
blocking	O
buffer	O
(	O
1	O
x	O
PBS	O
consisting	O
of	O
10	O
%	O
(	O
v	O
/	O
v	O
)	O
heat	O
-	O
inactivated	O
horse	B
serum	O
(	O
Invitrogen	O
/	O
Gibco	O
)	O
,	O
0	O
.	O
5	O
%	O
Triton	O
X	O
-	O
100	O
(	O
Sigma	O
)	O
,	O
and	O
0	O
.	O
1	O
%	O
sodium	O
azide	O
(	O
Fisher	O
)	O
)	O
.	O

Immunohistochemistry	O

Sections	O
were	O
incubated	O
with	O
primary	O
antibodies	O
overnight	O
at	O
4	O
degrees	O
C	O
,	O
followed	O
by	O
incubation	O
with	O
secondary	O
antibodies	O
for	O
2	O
hours	O
at	O
room	O
temperature	O
.	O

Primary	O
antibodies	O
used	O
were	O
:	O
rabbit	B
anti	O
-	O
p75	O
(	O
1	O
:	O
1500	O
,	O
generous	O
gift	O
from	O
Louis	O
Reichardt	O
,	O
UCSF	O
[	O
26	O
]	O
)	O
,	O
mouse	B
IgG2b	O
anti	O
-	O
Hu	O
C	O
/	O
D	O
,	O
(	O
1	O
:	O
250	O
,	O
Molecular	O
Probes	O
)	O
;	O
mouse	B
IgG1	O
anti	O
-	O
Islet	O
-	O
1	O
,	O
(	O
1	O
:	O
10	O
,	O
Developmental	O
Studies	O
Hybridoma	O
Bank	O
)	O
;	O
rabbit	B
anti	O
-	O
chicken	B
TrkA	O
(	O
1	O
:	O
500	O
)	O
;	O
rabbit	B
anti	O
-	O
chicken	B
TrkB	O
(	O
1	O
:	O
500	O
)	O
;	O
rabbit	B
anti	O
-	O
chicken	B
TrkC	O
(	O
1	O
:	O
500	O
)	O
(	O
all	O
Trk	O
antibodies	O
were	O
generous	O
gifts	O
of	O
Dr	O
.	O
Louis	O
Reichardt	O
,	O
UCSF	O
[	O
26	O
-	O
28	O
]	O
)	O
;	O
mouse	B
anti	O
-	O
HNK	O
-	O
1	O
(	O
1	O
:	O
50	O
,	O
Developmental	O
Studies	O
Hybridoma	O
Bank	O
)	O
;	O
mouse	B
IgG2a	O
anti	O
-	O
tyrosine	O
hydroxylase	O
(	O
1	O
:	O
10	O
,	O
Developmental	O
Studies	O
Hybridoma	O
Bank	O
)	O
,	O
sheep	B
anti	O
-	O
BrdU	O
(	O
1	O
:	O
100	O
,	O
Biodesign	O
International	O
)	O
,	O
rabbit	B
anti	O
-	O
tyrosine	O
hydroxylase	O
(	O
1	O
:	O
100	O
,	O
Chemicon	O
)	O
,	O
and	O
goat	B
anti	O
-	O
TrkB	O
(	O
1	O
:	O
1000	O
,	O
R	O
&	O
D	O
Systems	O
)	O
.	O

Immunofluorescence	O
was	O
imaged	O
using	O
a	O
Nikon	O
C1	O
confocal	O
mounted	O
on	O
a	O
Nikon	O
Eclipse	O
E800	O
microscope	O
with	O
a	O
10	O
x	O
Plan	O
Apo	O
(	O
NA	O
0	O
.	O
785	O
)	O
air	O
objective	O
or	O
a	O
60	O
x	O
Plan	O
Apo	O
(	O
NA	O
1	O
.	O
4	O
)	O
oil	O
objective	O
lens	O
,	O
E7	O
-	O
C1	O
software	O
,	O
and	O
UV	O
,	O
Argon	O
,	O
and	O
He	O
/	O
Ne	O
lasers	O
exciting	O
at	O
408	O
,	O
488	O
,	O
and	O
543	O
nm	O
and	O
emitting	O
at	O
404	O
500	O
-	O
530	O
,	O
and	O
555	O
-	O
615	O
nm	O
,	O
respectively	O
.	O

A	O
Nikon	O
Eclipse	O
E800	O
microscope	O
in	O
the	O
nearby	O
COBRE	O
Molecular	O
/	O
Cellular	O
Core	O
Facility	O
was	O
used	O
for	O
counting	O
immunofluorescent	O
cells	O
at	O
200	O
x	O
using	O
epifluorescence	O
optics	O
.	O

RNA	O
Extraction	O
/	O
cDNA	O
synthesis	O

Sympathetic	O
ganglia	O
were	O
removed	O
from	O
chick	B
embryos	O
and	O
RNA	O
was	O
isolated	O
using	O
TriReagent	O
(	O
Molecular	O
Research	O
Center	O
)	O
,	O
an	O
acidified	O
guanidinium	O
with	O
phenol	O
extraction	O
method	O
[	O
29	O
]	O
.	O

RNA	O
was	O
transcribed	O
to	O
cDNA	O
using	O
oligo	O
-	O
dT	O
with	O
Superscript	O
II	O
Reverse	O
Transcriptase	O
(	O
Invitrogen	O
)	O
at	O
42	O
degrees	O
C	O
for	O
1	O
hour	O
.	O

Real	O
-	O
time	O
PCR	O

Relative	O
RNA	O
levels	O
were	O
determined	O
using	O
quantitative	O
real	O
-	O
time	O
PCR	O
with	O
an	O
ABI	O
7500	O
Fast	O
Real	O
Time	O
PCR	O
System	O
.	O

TaqMan	O
probes	O
were	O
used	O
to	O
quantify	O
the	O
progression	O
of	O
the	O
PCR	O
reaction	O
and	O
reactions	O
were	O
normalized	O
using	O
the	O
constitutively	O
expressed	O
gene	O
chick	B
ribosomal	O
binding	O
protein	O
s17	O
(	O
CHRPS	O
)	O
.	O

The	O
sequences	O
were	O
used	O
for	O
primer	O
/	O
probes	O
sets	O
:	O
for	O
BDNF	O
:	O
forward	O
:	O
5	O
'	O
-	O
AGCCCAGTGAGGAAAACAAG	O
-	O
3	O
'	O
,	O
reverse	O
:	O
5	O
'	O
-	O
ACTCCTCGAGCAGAAAGAGC	O
-	O
3	O
'	O
,	O
probe	O
:	O
5	O
'	O
-	O
[	O
6	O
-	O
FAM	O
]	O
-	O
TACACATCCCGAGTCATGCT	O
-	O
[	O
BHQ	O
]	O
-	O
3	O
'	O
;	O
for	O
CHRPS	O
(	O
chick	B
ribosomal	O
binding	O
protein	O
S	O
-	O
17	O
)	O
:	O
5	O
'	O
AACGACTTCCACACCAACAA	O
'	O
,	O
reverse	O
:	O
5	O
'	O
CTTCATCAGGTGGGTGACAT	O
'	O
,	O
probe	O
:	O
5	O
'	O
-	O
[	O
6	O
-	O
FAM	O
]	O
-	O
CGCCATCATCCCCAGCAAGA	O
[	O
BHQ	O
]	O
-	O
3	O
'	O
.	O

Primers	O
and	O
probes	O
were	O
synthesized	O
by	O
Operon	O
Technologies	O
,	O
Inc	O
(	O
Alameda	O
,	O
CA	O
)	O
.	O

The	O
primers	O
for	O
BDNF	O
were	O
validated	O
against	O
primers	O
for	O
CHRPS	O
according	O
to	O
an	O
Applied	O
BioSystems	O
protocol	O
by	O
serially	O
diluting	O
the	O
target	O
cDNA	O
1	O
:	O
10	O
,	O
determining	O
the	O
cycle	O
threshold	O
(	O
Ct	O
)	O
for	O
each	O
reaction	O
,	O
and	O
plotting	O
the	O
Ct	O
versus	O
log	O
concentration	O
.	O

Slopes	O
of	O
the	O
resulting	O
lines	O
were	O
calculated	O
and	O
primers	O
were	O
accepted	O
if	O
their	O
Ct	O
slopes	O
were	O
between	O
-	O
3	O
.	O
2	O
and	O
-	O
3	O
.	O
4	O
(	O
a	O
perfect	O
efficiency	O
of	O
1	O
.	O
0	O
yields	O
a	O
slope	O
of	O
-	O
3	O
.	O
3	O
)	O
.	O

To	O
analyze	O
the	O
data	O
,	O
the	O
delta	O
Ct	O
method	O
of	O
relative	O
quantification	O
was	O
used	O
,	O
where	O
the	O
Ct	O
of	O
Chrps	O
was	O
subtracted	O
from	O
the	O
Ct	O
of	O
the	O
gene	O
of	O
interest	O
(	O
Delta	O
Ct	O
)	O
and	O
the	O
arbitrary	O
units	O
of	O
mRNA	O
were	O
expressed	O
as	O
10000	O
/	O
2	O
^	O
(	O
Delta	O
Ct	O
)	O
.	O

Cell	O
culture	O

Sympathetic	O
neurons	O
were	O
cultured	O
as	O
previously	O
described	O
[	O
30	O
]	O
with	O
a	O
few	O
modifications	O
.	O

Sympathetic	O
ganglia	O
were	O
removed	O
from	O
the	O
lumbar	O
region	O
of	O
the	O
paravertebral	O
chain	O
of	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
chick	B
embryos	O
and	O
placed	O
in	O
Modified	O
Puck	O
'	O
s	O
solution	O
with	O
glucose	O
(	O
MPG	O
)	O
.	O

The	O
cells	O
were	O
dissociated	O
by	O
incubation	O
of	O
sympathetic	O
ganglia	O
with	O
0	O
.	O
1	O
%	O
trypsin	O
in	O
MPG	O
at	O
37	O
degrees	O
C	O
for	O
10	O
minutes	O
followed	O
by	O
triturating	O
with	O
a	O
fire	O
polished	O
9	O
"	O
Pasteur	O
pipette	O
.	O

Cells	O
were	O
then	O
resuspended	O
in	O
Dulbecco	O
'	O
s	O
Modified	O
Eagle	O
Medium	O
(	O
DMEM	O
)	O
consisting	O
of	O
10	O
%	O
horse	B
serum	O
,	O
2	O
%	O
fetal	O
calf	O
serum	O
,	O
and	O
10	O
mg	O
/	O
ml	O
penicillin	O
/	O
streptomycin	O
.	O

For	O
neurotrophin	O
studies	O
,	O
the	O
culture	O
medium	O
was	O
supplemented	O
with	O
25	O
ng	O
/	O
ml	O
NT	O
-	O
3	O
(	O
R	O
&	O
D	O
Systems	O
)	O
and	O
1	O
mu	O
g	O
/	O
ml	O
7S	O
NGF	O
(	O
Alomone	O
Labs	O
)	O
upon	O
plating	O
,	O
and	O
50	O
ng	O
/	O
ml	O
,	O
100	O
ng	O
/	O
ml	O
,	O
or	O
200	O
ng	O
/	O
ml	O
BDNF	O
(	O
R	O
&	O
D	O
Systems	O
)	O
once	O
the	O
cells	O
adhered	O
to	O
the	O
wells	O
.	O

Cells	O
were	O
plated	O
on	O
poly	O
-	O
D	O
-	O
lysine	O
/	O
laminin	O
coated	O
wells	O
or	O
cover	O
slips	O
(	O
Fisher	O
)	O
as	O
previously	O
described	O
[	O
30	O
]	O
.	O

Quantification	O
of	O
neurons	O
and	O
sympathoblasts	O
using	O
phase	O
microscopy	O

Embryonic	O
sympathoblasts	O
and	O
neurons	O
are	O
small	O
,	O
phase	O
bright	O
cells	O
with	O
neurites	O
.	O

The	O
total	O
number	O
of	O
cells	O
with	O
neurites	O
the	O
length	O
of	O
two	O
cell	O
bodies	O
were	O
counted	O
in	O
10	O
non	O
-	O
overlapping	O
fields	O
of	O
view	O
evenly	O
spaced	O
in	O
a	O
grid	O
-	O
like	O
pattern	O
across	O
the	O
bottom	O
of	O
a	O
well	O
from	O
a	O
24	O
well	O
plate	O
at	O
200	O
x	O
using	O
a	O
Nikon	O
Eclipse	O
TE200	O
microscope	O
.	O

BrdU	O
labeling	O

For	O
in	O
vitro	O
studies	O
,	O
approximately	O
2	O
hours	O
after	O
plating	O
cells	O
from	O
St	O
.	O

29	O
/	O
30	O
(	O
E6	O
.	O
5	O
)	O
sympathetic	O
ganglia	O
,	O
cells	O
were	O
labeled	O
with	O
10	O
mu	O
M	O
bromodeoxyuridine	O
(	O
BrdU	O
,	O
Sigma	O
)	O
for	O
12	O
hours	O
at	O
37	O
degrees	O
C	O
.	O

Following	O
this	O
labeling	O
period	O
,	O
cells	O
were	O
incubated	O
in	O
complete	O
medium	O
without	O
BrdU	O
for	O
an	O
additional	O
10	O
hrs	O
.	O

Cells	O
were	O
then	O
fixed	O
in	O
Zamboni	O
'	O
s	O
fixative	O
for	O
30	O
min	O
at	O
room	O
temperature	O
and	O
rinsed	O
with	O
1	O
x	O
PBS	O
.	O

For	O
in	O
vivo	O
studies	O
,	O
25	O
mu	O
g	O
BrdU	O
was	O
injected	O
into	O
the	O
amnion	O
of	O
chick	B
embryos	O
at	O
St	O
.	O

27	O
.	O

The	O
cells	O
and	O
sections	O
were	O
denatured	O
with	O
2	O
N	O
HCl	O
at	O
37	O
degrees	O
C	O
for	O
1	O
hr	O
,	O
and	O
were	O
then	O
neutralized	O
with	O
0	O
.	O
1	O
M	O
borate	O
buffer	O
,	O
pH	O
8	O
.	O
5	O
,	O
for	O
10	O
min	O
at	O
room	O
temperature	O
.	O

Immunochemistry	O
was	O
performed	O
as	O
described	O
above	O
.	O

Abbreviations	O

BDNF	O
,	O
brain	O
-	O
derived	O
neurotrophic	O
factor	O
;	O
BrdU	O
,	O
Bromodeoxyuridine	O
;	O
DA	O
,	O
dorsal	O
aorta	O
;	O
DMEM	O
,	O
Dulbecco	O
'	O
s	O
Modified	O
Eagle	O
'	O
s	O
Medium	O
;	O
DRG	O
,	O
dorsal	O
root	O
ganglion	O
;	O
E	O
,	O
embryonic	O
day	O
;	O
HS	O
,	O
horse	B
serum	O
;	O
MPG	O
,	O
Modified	O
Puck	O
'	O
s	O
solution	O
with	O
glucose	O
;	O
NGF	O
,	O
nerve	O
growth	O
factor	O
;	O
NC	O
,	O
notochord	O
;	O
NT	O
,	O
neural	O
tube	O
;	O
NT	O
-	O
3	O
,	O
neurotrophin	O
-	O
3	O
;	O
NTR	O
,	O
neurotrophin	O
receptor	O
;	O
PBS	O
,	O
phosphate	O
-	O
buffered	O
saline	O
;	O
SC	O
,	O
spinal	O
cord	O
;	O
SCG	O
,	O
superior	O
cervical	O
ganglion	O
;	O
SEM	O
,	O
standard	O
error	O
of	O
the	O
mean	O
;	O
SG	O
,	O
sympathetic	O
ganglion	O
;	O
St	O
.	O
,	O
stage	O
;	O
w	O
/	O
v	O
,	O
weight	O
/	O
volume	O
;	O
v	O
/	O
v	O
,	O
volume	O
/	O
volume	O
.	O

Authors	O
'	O
contributions	O

JAS	O
designed	O
the	O
experiments	O
,	O
performed	O
the	O
experiments	O
,	O
analyzed	O
the	O
data	O
,	O
and	O
wrote	O
the	O
manuscript	O
.	O

GLSS	O
contributed	O
intellectually	O
to	O
the	O
conception	O
and	O
design	O
of	O
this	O
study	O
,	O
and	O
assisted	O
in	O
the	O
interpretation	O
of	O
the	O
results	O
.	O

RN	O
supervised	O
the	O
study	O
,	O
participated	O
in	O
the	O
design	O
of	O
experiments	O
,	O
edited	O
the	O
manuscript	O
,	O
and	O
obtained	O
funding	O
for	O
the	O
project	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Video	O
analysis	O
of	O
the	O
escape	O
flight	O
of	O
Pileated	B
Woodpecker	I
Dryocopus	B
pileatus	I
:	O
does	O
the	O
Ivory	B
-	I
billed	I
Woodpecker	I
Campephilus	B
principalis	I
persist	O
in	O
continental	O
North	O
America	O
?	O

Abstract	O

Background	O

The	O
apparent	O
rediscovery	O
of	O
the	O
Ivory	B
-	I
billed	I
Woodpecker	I
Campephilus	B
principalis	I
in	O
Arkansas	O
,	O
USA	O
,	O
previously	O
feared	O
extinct	O
,	O
was	O
supported	O
by	O
video	O
evidence	O
of	O
a	O
single	O
bird	O
in	O
flight	O
(	O
Fitzpatrick	O
et	O
al	O
,	O
Science	O
2005	O
,	O
308	O
:	O
1460	O
-	O
1462	O
)	O
.	O

Plumage	O
patterns	O
and	O
wingbeat	O
frequency	O
of	O
the	O
putative	O
Ivory	B
-	I
billed	I
Woodpecker	I
were	O
said	O
to	O
be	O
incompatible	O
with	O
the	O
only	O
possible	O
confusion	O
species	O
native	O
to	O
the	O
area	O
,	O
the	O
Pileated	B
Woodpecker	I
Dryocopus	B
pileatus	I
.	O

Results	O

New	O
video	O
analysis	O
of	O
Pileated	B
Woodpeckers	I
in	O
escape	O
flights	O
comparable	O
to	O
that	O
of	O
the	O
putative	O
Ivory	B
-	I
billed	I
Woodpecker	I
filmed	O
in	O
Arkansas	O
shows	O
that	O
Pileated	B
Woodpeckers	I
can	O
display	O
a	O
wingbeat	O
frequency	O
equivalent	O
to	O
that	O
of	O
the	O
Arkansas	O
bird	O
during	O
escape	O
flight	O
.	O

The	O
critical	O
frames	O
from	O
the	O
Arkansas	O
video	O
that	O
were	O
used	O
to	O
identify	O
the	O
bird	O
as	O
an	O
Ivory	B
-	I
billed	I
Woodpecker	I
are	O
shown	O
to	O
be	O
equally	O
,	O
or	O
more	O
,	O
compatible	O
with	O
the	O
Pileated	B
Woodpecker	I
.	O

Conclusion	O

The	O
identification	O
of	O
the	O
bird	O
filmed	O
in	O
Arkansas	O
in	O
April	O
2004	O
as	O
an	O
Ivory	B
-	I
billed	I
Woodpecker	I
is	O
best	O
regarded	O
as	O
unsafe	O
.	O

The	O
similarities	O
between	O
the	O
Arkansas	O
bird	O
and	O
known	O
Pileated	B
Woodpeckers	I
suggest	O
that	O
it	O
was	O
most	O
likely	O
a	O
Pileated	B
Woodpecker	I
.	O

Background	O

The	O
reported	O
rediscovery	O
of	O
the	O
Ivory	B
-	I
billed	I
Woodpecker	I
in	O
2004	O
-	O
5	O
in	O
the	O
Big	O
Woods	O
of	O
Arkansas	O
gave	O
new	O
impetus	O
to	O
efforts	O
to	O
conserve	O
the	O
mature	O
bottomland	O
woodlands	O
of	O
the	O
south	O
-	O
eastern	O
USA	O
.	O

Several	O
sightings	O
have	O
been	O
reported	O
without	O
photographic	O
evidence	O
being	O
obtained	O
[	O
1	O
]	O
.	O

Unless	O
sightings	O
are	O
,	O
however	O
,	O
independently	O
verifiable	O
on	O
the	O
basis	O
of	O
photographic	O
or	O
other	O
recorded	O
evidence	O
,	O
the	O
possibility	O
that	O
mistakes	O
have	O
been	O
made	O
cannot	O
be	O
eliminated	O
.	O

Crucial	O
to	O
the	O
scientific	O
case	O
for	O
the	O
persistence	O
of	O
the	O
Ivory	B
-	I
billed	I
Woodpecker	I
was	O
a	O
4	O
s	O
video	O
of	O
a	O
large	O
woodpecker	O
in	O
flight	O
recorded	O
by	O
M	O
.	O
D	O
.	O

Luneau	O
on	O
25	O
April	O
2004	O
(	O
henceforth	O
referred	O
to	O
as	O
the	O
'	O
Luneau	O
video	O
'	O
)	O
and	O
published	O
in	O
2005	O
[	O
1	O
]	O
,	O
which	O
was	O
claimed	O
to	O
be	O
inconsistent	O
with	O
the	O
plumage	O
patterns	O
of	O
the	O
superficially	O
similar	O
Pileated	B
Woodpecker	I
(	O
a	O
common	O
resident	O
bird	O
of	O
the	O
area	O
)	O
.	O

Both	O
species	O
are	O
large	O
,	O
black	O
-	O
and	O
-	O
white	O
woodpeckers	O
[	O
2	O
]	O
.	O

The	O
upperwing	O
of	O
the	O
Ivory	B
-	I
billed	I
Woodpecker	I
is	O
black	O
,	O
with	O
white	O
secondary	O
feathers	O
and	O
white	O
on	O
some	O
inner	O
primary	O
feathers	O
.	O

Pileated	B
Woodpeckers	I
have	O
a	O
largely	O
black	O
upperwing	O
,	O
with	O
white	O
restricted	O
to	O
the	O
'	O
wrist	O
'	O
due	O
to	O
white	O
bases	O
to	O
the	O
primary	O
feathers	O
.	O

The	O
underwing	O
of	O
Pileated	B
Woodpecker	I
has	O
all	O
-	O
white	O
underwing	O
coverts	O
,	O
giving	O
an	O
appearance	O
of	O
a	O
white	O
underwing	O
with	O
a	O
broad	O
black	O
outline	O
(	O
the	O
black	O
flight	O
feathers	O
)	O
.	O

These	O
plumage	O
differences	O
result	O
in	O
the	O
Ivory	B
-	I
billed	I
Woodpecker	I
having	O
a	O
white	O
trailing	O
edge	O
to	O
the	O
wings	O
(	O
upper	O
and	O
lower	O
sides	O
)	O
,	O
whereas	O
the	O
Pileated	B
Woodpecker	I
has	O
a	O
black	O
trailing	O
edge	O
to	O
the	O
wings	O
.	O

Both	O
species	O
have	O
black	O
wing	O
-	O
tips	O
.	O

These	O
and	O
other	O
plumage	O
characteristics	O
are	O
shown	O
in	O
[	O
1	O
,	O
2	O
]	O
.	O

The	O
wingbeat	O
frequency	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
was	O
measured	O
at	O
8	O
.	O
6	O
beats	O
s	O
-	O
1	O
,	O
similar	O
to	O
that	O
inferred	O
from	O
archival	O
sound	O
recording	O
of	O
a	O
single	O
Ivory	B
-	I
billed	I
Woodpecker	I
,	O
but	O
claimed	O
to	O
be	O
outside	O
the	O
range	O
of	O
Pileated	B
Woodpeckers	I
(	O
which	O
generally	O
have	O
slower	O
wingbeats	O
)	O
[	O
1	O
,	O
3	O
]	O
.	O

Sibley	O
et	O
al	O
[	O
4	O
]	O
questioned	O
the	O
video	O
evidence	O
,	O
in	O
particular	O
providing	O
alternative	O
explanations	O
for	O
the	O
plumage	O
patterns	O
of	O
the	O
Luneau	O
bird	O
in	O
flight	O
and	O
at	O
rest	O
.	O

They	O
pointed	O
out	O
individual	O
frames	O
of	O
the	O
Luneau	O
video	O
that	O
appear	O
to	O
show	O
three	O
features	O
that	O
are	O
each	O
inconsistent	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
:	O
(	O
1	O
)	O
apparently	O
black	O
secondary	O
feathers	O
on	O
the	O
upper	O
surface	O
of	O
the	O
left	O
wing	O
,	O
(	O
2	O
)	O
particularly	O
bright	O
white	O
primary	O
bases	O
,	O
and	O
(	O
3	O
)	O
a	O
black	O
band	O
curving	O
smoothly	O
round	O
the	O
wing	O
tip	O
(	O
see	O
Figure	O
3	O
in	O
[	O
4	O
]	O
)	O
.	O

They	O
hypothesized	O
that	O
flexing	O
of	O
a	O
Pileated	B
Woodpecker	I
'	O
s	O
wings	O
during	O
flight	O
could	O
produce	O
the	O
appearance	O
of	O
white	O
trailing	O
edges	O
on	O
both	O
wings	O
in	O
low	O
-	O
quality	O
videos	O
[	O
4	O
]	O
.	O

They	O
offered	O
,	O
however	O
,	O
no	O
direct	O
evidence	O
to	O
show	O
that	O
this	O
could	O
cause	O
a	O
video	O
of	O
a	O
Pileated	B
Woodpecker	I
to	O
look	O
like	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
.	O

Fitzpatrick	O
et	O
al	O
[	O
5	O
]	O
in	O
turn	O
rebutted	O
some	O
aspects	O
of	O
the	O
hypothesis	O
of	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
,	O
publishing	O
video	O
stills	O
of	O
Pileated	B
Woodpeckers	I
,	O
and	O
a	O
model	O
of	O
a	O
Pileated	B
Woodpecker	I
,	O
that	O
appeared	O
to	O
show	O
a	O
black	O
trailing	O
edge	O
to	O
the	O
wings	O
inconsistent	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
and	O
the	O
Luneau	O
video	O
.	O

Fitzpatrick	O
et	O
al	O
[	O
5	O
]	O
neither	O
rebutted	O
nor	O
discussed	O
the	O
three	O
key	O
inconsistencies	O
described	O
above	O
.	O

Without	O
further	O
evidence	O
,	O
this	O
became	O
largely	O
a	O
theoretical	O
debate	O
over	O
interpretation	O
of	O
field	O
characters	O
that	O
were	O
barely	O
visible	O
in	O
the	O
very	O
small	O
images	O
originally	O
obtained	O
.	O

On	O
one	O
hand	O
,	O
as	O
pointed	O
out	O
in	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
,	O
some	O
of	O
the	O
frames	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
do	O
appear	O
to	O
be	O
inconsistent	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
flight	O
pattern	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
is	O
asserted	O
to	O
be	O
atypical	O
for	O
Pileated	B
Woodpecker	I
(	O
but	O
matching	O
anecdotal	O
descriptions	O
of	O
Ivory	B
-	I
billed	I
Woodpecker	I
)	O
.	O

Furthermore	O
,	O
the	O
general	O
impression	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
was	O
that	O
there	O
is	O
far	O
too	O
much	O
white	O
in	O
the	O
wings	O
for	O
it	O
to	O
be	O
a	O
Pileated	B
Woodpecker	I
,	O
and	O
that	O
if	O
it	O
was	O
a	O
Pileated	O
,	O
then	O
it	O
must	O
be	O
an	O
aberrant	O
one	O
with	O
abnormally	O
extensive	O
white	O
plumage	O
.	O

Such	O
birds	O
occasionally	O
occur	O
,	O
and	O
have	O
been	O
observed	O
in	O
the	O
Arkansas	O
study	O
area	O
[	O
6	O
]	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
determine	O
whether	O
the	O
flight	O
and	O
plumage	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
really	O
was	O
inconsistent	O
with	O
either	O
a	O
normal	O
or	O
partial	O
albino	O
Pileated	B
Woodpecker	I
.	O

Independent	O
analyses	O
of	O
the	O
plumage	O
patterns	O
and	O
wingbeat	O
frequencies	O
observable	O
in	O
Pileated	B
Woodpeckers	I
are	O
presented	O
,	O
and	O
it	O
is	O
concluded	O
that	O
the	O
identification	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
as	O
definite	O
Ivory	B
-	I
billed	I
Woodpecker	I
is	O
probably	O
unsafe	O
.	O

Results	O

On	O
January	O
28	O
and	O
February	O
5	O
,	O
2006	O
,	O
David	O
Nolin	O
(	O
DN	O
)	O
video	O
-	O
recorded	O
Pileated	B
Woodpeckers	I
Dryocopus	B
pileatus	I
at	O
a	O
bird	O
-	O
feeder	O
in	O
Dayton	O
,	O
Ohio	O
,	O
USA	O
.	O

A	O
Hi	O
-	O
8	O
Sony	O
Handycam	O
was	O
used	O
,	O
hand	O
-	O
held	O
,	O
at	O
approximately	O
5	O
m	O
from	O
the	O
feeder	O
.	O

Birds	O
on	O
the	O
tree	O
trunk	O
were	O
alarmed	O
by	O
movement	O
,	O
and	O
their	O
escape	O
flights	O
recorded	O
.	O

Four	O
escape	O
flights	O
were	O
captured	O
that	O
approximate	O
to	O
that	O
recorded	O
for	O
the	O
putative	O
Ivory	B
-	I
billed	I
Woodpecker	I
Campephilus	B
principalis	I
by	O
Luneau	O
in	O
April	O
2004	O
and	O
published	O
in	O
Fitzpatrick	O
et	O
al	O
[	O
1	O
]	O
.	O

The	O
videos	O
are	O
not	O
directly	O
equivalent	O
because	O
the	O
Pileated	B
Woodpeckers	I
made	O
only	O
short	O
escape	O
flights	O
to	O
nearby	O
trees	O
,	O
whereas	O
the	O
putative	O
Ivory	B
-	I
billed	I
Woodpecker	I
in	O
the	O
Luneau	O
video	O
showed	O
little	O
sign	O
of	O
coming	O
to	O
rest	O
before	O
being	O
lost	O
from	O
view	O
.	O

Nevertheless	O
,	O
interesting	O
comparisons	O
can	O
be	O
made	O
.	O

Wingbeat	O
frequency	O
of	O
Pileated	B
Woodpecker	I

The	O
woodpecker	O
in	O
the	O
Luneau	O
video	O
maintains	O
a	O
steady	O
rapid	O
wingbeat	O
rate	O
of	O
8	O
.	O
6	O
beats	O
s	O
-	O
1	O
for	O
at	O
least	O
8	O
wingbeats	O
[	O
1	O
]	O
,	O
a	O
figure	O
that	O
was	O
confirmed	O
by	O
independent	O
analysis	O
during	O
preparation	O
of	O
this	O
paper	O
.	O

The	O
Pileated	B
woodpeckers	I
in	O
DN	O
'	O
s	O
video	O
do	O
not	O
do	O
this	O
-	O
after	O
initial	O
rapid	O
flapping	O
immediately	O
after	O
take	O
-	O
off	O
,	O
they	O
settle	O
into	O
a	O
more	O
relaxed	O
level	O
flight	O
.	O

As	O
shown	O
in	O
Tables	O
1	O
and	O
2	O
,	O
although	O
the	O
mean	O
wingbeat	O
frequencies	O
of	O
the	O
Pileated	B
Woodpeckers	I
in	O
DN	O
'	O
s	O
video	O
are	O
slower	O
than	O
the	O
8	O
.	O
6	O
s	O
-	O
1	O
recorded	O
for	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
[	O
1	O
,	O
3	O
,	O
5	O
]	O
the	O
first	O
four	O
wingbeats	O
,	O
the	O
initial	O
escape	O
response	O
,	O
are	O
faster	O
than	O
those	O
claimed	O
for	O
Pileated	B
Woodpeckers	I
in	O
the	O
literature	O
[	O
1	O
,	O
3	O
,	O
5	O
]	O
.	O

For	O
the	O
four	O
escape	O
flights	O
,	O
the	O
mean	O
frequency	O
values	O
for	O
the	O
first	O
four	O
wingbeats	O
are	O
7	O
.	O
1	O
,	O
6	O
.	O
7	O
,	O
8	O
.	O
6	O
,	O
and	O
8	O
.	O
0	O
s	O
-	O
1	O
,	O
respectively	O
.	O

The	O
8	O
.	O
6	O
beats	O
s	O
-	O
1	O
of	O
the	O
bird	O
identified	O
in	O
the	O
Luneau	O
video	O
,	O
while	O
consistent	O
with	O
the	O
limited	O
data	O
(	O
n	O
=	O
1	O
;	O
see	O
Discussion	O
)	O
for	O
Ivory	B
-	I
billed	I
Woodpecker	I
,	O
is	O
equally	O
consistent	O
with	O
Pileated	B
Woodpecker	I
in	O
its	O
initial	O
escape	O
flight	O
.	O

The	O
bird	O
in	O
the	O
Luneau	O
video	O
maintains	O
a	O
frequency	O
of	O
8	O
.	O
6	O
s	O
-	O
1	O
for	O
the	O
next	O
four	O
wingbeats	O
too	O
,	O
whereas	O
the	O
Pileated	B
Woodpeckers	I
recorded	O
here	O
all	O
slowed	O
their	O
flight	O
as	O
they	O
prepared	O
to	O
land	O
in	O
nearby	O
trees	O
.	O

There	O
are	O
no	O
data	O
to	O
suggest	O
whether	O
Pileated	B
Woodpeckers	I
can	O
maintain	O
a	O
wingbeat	O
frequency	O
approaching	O
8	O
.	O
6	O
s	O
-	O
1	O
for	O
eight	O
or	O
more	O
wingbeats	O
,	O
like	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
.	O

It	O
remains	O
possible	O
that	O
the	O
flight	O
pattern	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
is	O
unusual	O
for	O
Pileated	B
Woodpecker	I
,	O
but	O
a	O
frequency	O
of	O
8	O
.	O
6	O
s	O
-	O
1	O
is	O
consistent	O
with	O
a	O
Pileated	B
Woodpecker	I
gaining	O
initial	O
speed	O
and	O
height	O
in	O
escape	O
flight	O
,	O
and	O
by	O
itself	O
cannot	O
be	O
taken	O
as	O
strong	O
evidence	O
that	O
the	O
Luneau	O
video	O
bird	O
was	O
an	O
Ivory	B
-	I
billed	I
Woodpecker	I
.	O

This	O
is	O
discussed	O
further	O
below	O
.	O

Plumage	O
pattern	O
of	O
Pileated	B
Woodpeckers	I
in	O
flight	O

The	O
video	O
of	O
Pileated	B
Woodpeckers	I
in	O
flight	O
was	O
obtained	O
in	O
avi	O
format	O
,	O
decompiled	O
and	O
examined	O
frame	O
by	O
frame	O
.	O

Comparisons	O
of	O
Pileated	B
Woodpecker	I
images	O
with	O
key	O
images	O
of	O
Luneau	O
video	O
are	O
shown	O
in	O
Figures	O
1	O
and	O
2	O
,	O
and	O
suggest	O
a	O
genuine	O
resemblance	O
between	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
and	O
a	O
Pileated	B
Woodpecker	I
.	O

Analysis	O
is	O
complicated	O
by	O
the	O
different	O
digital	O
processing	O
of	O
the	O
two	O
videos	O
,	O
and	O
in	O
the	O
case	O
of	O
the	O
Nolin	O
videos	O
it	O
is	O
important	O
to	O
concentrate	O
only	O
on	O
those	O
frames	O
or	O
part	O
-	O
frames	O
where	O
apparent	O
plumage	O
features	O
are	O
not	O
an	O
artifact	O
of	O
blurred	O
images	O
.	O

Thirty	O
-	O
six	O
frames	O
from	O
the	O
fourth	O
example	O
of	O
Pileated	O
escape	O
flight	O
,	O
which	O
most	O
resembled	O
the	O
flight	O
path	O
of	O
the	O
Luneau	O
video	O
bird	O
,	O
were	O
analysed	O
systematically	O
frame	O
by	O
frame	O
.	O

They	O
represent	O
seven	O
complete	O
wingbeats	O
(	O
1	O
.	O
20	O
s	O
from	O
the	O
middle	O
of	O
the	O
second	O
wingbeat	O
to	O
middle	O
of	O
wingbeat	O
9	O
)	O
and	O
were	O
directly	O
compared	O
frame	O
-	O
by	O
-	O
frame	O
with	O
the	O
equivalent	O
fields	O
(	O
middle	O
wingbeat	O
2	O
-	O
middle	O
wingbeat	O
9	O
)	O
of	O
the	O
Luneau	O
video	O
.	O

This	O
comparison	O
is	O
shown	O
in	O
Figure	O
3	O
.	O

The	O
images	O
of	O
the	O
birds	O
are	O
not	O
identical	O
,	O
but	O
in	O
every	O
frame	O
of	O
the	O
36	O
frames	O
available	O
,	O
there	O
are	O
sufficient	O
similarities	O
to	O
suggest	O
that	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
is	O
consistent	O
with	O
the	O
known	O
Pileated	B
Woodpecker	I
.	O

Further	O
comparisons	O
of	O
the	O
Luneau	O
bird	O
with	O
the	O
other	O
three	O
Pileated	B
escape	O
flights	O
recorded	O
are	O
presented	O
in	O
the	O
supplementary	O
material	O
(	O
see	O
Additional	O
file	O
1	O
)	O
.	O

Key	O
findings	O
of	O
the	O
video	O
analysis	O
are	O
:	O

1	O
.	O

Pileated	B
Woodpeckers	I
flying	O
near	O
-	O
horizontally	O
away	O
from	O
the	O
observer	O
show	O
much	O
more	O
white	O
in	O
poor	O
-	O
quality	O
video	O
than	O
would	O
be	O
expected	O
from	O
their	O
general	O
plumage	O
pattern	O
.	O

They	O
present	O
an	O
appearance	O
of	O
a	O
black	O
-	O
bodied	O
bird	O
with	O
largely	O
white	O
wings	O
and	O
black	O
wingtips	O
,	O
very	O
similar	O
to	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
;	O
compare	O
in	O
particular	O
Figure	O
1B	O
,	O
frame	O
758	O
,	O
with	O
Figure	O
1A	O
,	O
frame	O
283	O
.	O
3	O
.	O

The	O
expected	O
appearance	O
of	O
the	O
upperwing	O
of	O
Pileated	B
Woodpecker	I
-	O
mostly	O
black	O
with	O
a	O
small	O
white	O
patch	O
at	O
the	O
base	O
of	O
the	O
primaries	O
-	O
is	O
often	O
not	O
seen	O
,	O
and	O
is	O
only	O
clearly	O
resolvable	O
when	O
birds	O
are	O
flying	O
near	O
-	O
vertically	O
before	O
landing	O
on	O
a	O
tree	O
trunk	O
;	O
something	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
did	O
not	O
do	O
.	O

2	O
.	O

The	O
black	O
trailing	O
edge	O
to	O
the	O
underwing	O
of	O
Pileated	B
Woodpecker	I
is	O
often	O
very	O
inconspicuous	O
and	O
may	O
disappear	O
completely	O
.	O

Due	O
to	O
motion	O
and	O
flexion	O
of	O
the	O
wing	O
,	O
the	O
black	O
trailing	O
edge	O
is	O
much	O
more	O
obvious	O
towards	O
the	O
wingtips	O
.	O

This	O
produces	O
an	O
apparent	O
plumage	O
pattern	O
that	O
matches	O
the	O
patterns	O
shown	O
by	O
the	O
Luneau	O
video	O
bird	O
(	O
compare	O
Figure	O
1B	O
,	O
frames	O
175	O
and	O
457	O
with	O
Figure	O
1A	O
,	O
frames	O
300	O
and	O
416	O
.	O
7	O
)	O
.	O

In	O
many	O
frames	O
of	O
Pileated	B
Woodpecker	I
,	O
a	O
black	O
trailing	O
edge	O
to	O
the	O
wing	O
is	O
discernable	O
(	O
though	O
due	O
to	O
bleeding	O
of	O
white	O
as	O
a	O
video	O
artifact	O
,	O
it	O
appears	O
narrower	O
than	O
it	O
really	O
is	O
)	O
.	O

However	O
,	O
analysis	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
in	O
light	O
of	O
images	O
of	O
known	O
Pileated	B
Woodpeckers	I
confirms	O
that	O
a	O
similar	O
black	O
trailing	O
edge	O
to	O
the	O
wing	O
is	O
discernable	O
in	O
some	O
frames	O
of	O
the	O
Luneau	O
video	O
(	O
compare	O
Figure	O
1B	O
,	O
frame	O
775	O
with	O
Figure	O
1A	O
,	O
frame	O
366	O
.	O
7	O
:	O
the	O
apparent	O
plumage	O
patterns	O
are	O
similar	O
,	O
and	O
inconsistent	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
)	O
.	O

It	O
is	O
argued	O
here	O
that	O
the	O
hypothesis	O
put	O
forward	O
in	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
is	O
correct	O
,	O
and	O
that	O
the	O
black	O
trailing	O
edge	O
of	O
the	O
underwing	O
of	O
Pileated	B
Woodpecker	I
can	O
indeed	O
,	O
due	O
to	O
flexion	O
of	O
the	O
wings	O
during	O
the	O
downstroke	O
,	O
be	O
misinterpreted	O
as	O
the	O
black	O
leading	O
edge	O
and	O
wingtips	O
of	O
the	O
upperwing	O
of	O
an	O
Ivory	B
-	I
billed	I
Woodpecker	I
.	O

3	O
.	O

Figure	O
3	O
shows	O
that	O
the	O
plumage	O
patterns	O
shown	O
by	O
the	O
Luneau	O
bird	O
,	O
throughout	O
several	O
wingbeat	O
cycles	O
,	O
are	O
compatible	O
with	O
Pileated	B
Woodpecker	I
.	O

The	O
three	O
plumage	O
features	O
described	O
in	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
that	O
are	O
incompatible	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
(	O
black	O
secondary	O
feathers	O
on	O
upper	O
surface	O
of	O
left	O
wing	O
,	O
brighter	O
white	O
primary	O
bases	O
,	O
and	O
a	O
black	O
band	O
curling	O
round	O
the	O
wing	O
tip	O
)	O
are	O
seen	O
consistently	O
in	O
the	O
Luneau	O
video	O
and	O
are	O
recapitulated	O
throughout	O
the	O
video	O
of	O
Pileated	B
Woodpecker	I
.	O

Discussion	O

Evidence	O
is	O
presented	O
here	O
to	O
show	O
that	O
the	O
distinctive	O
plumage	O
features	O
of	O
Pileated	B
Woodpecker	I
are	O
surprisingly	O
difficult	O
to	O
resolve	O
in	O
poor	O
-	O
quality	O
video	O
of	O
birds	O
in	O
escape	O
flight	O
away	O
from	O
the	O
camera	O
,	O
and	O
that	O
they	O
can	O
show	O
apparent	O
plumage	O
patterns	O
that	O
might	O
more	O
readily	O
be	O
associated	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
.	O

Irrespective	O
of	O
the	O
identity	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
,	O
this	O
knowledge	O
will	O
be	O
critical	O
to	O
assessment	O
of	O
further	O
claims	O
of	O
Ivory	B
-	I
billed	I
Woodpeckers	I
during	O
the	O
current	O
intensive	O
search	O
effort	O
.	O

It	O
is	O
,	O
however	O
,	O
suggested	O
here	O
that	O
critical	O
frames	O
used	O
for	O
identification	O
of	O
the	O
Luneau	O
video	O
woodpecker	O
as	O
an	O
Ivory	B
-	I
billed	I
Woodpecker	I
are	O
also	O
consistent	O
with	O
Pileated	B
Woodpecker	I
.	O

The	O
wingbeat	O
frequency	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
is	O
also	O
perhaps	O
consistent	O
with	O
Pileated	B
Woodpecker	I
,	O
at	O
least	O
for	O
short	O
periods	O
of	O
flight	O
.	O

Analysis	O
of	O
the	O
videos	O
of	O
Pileated	B
Woodpecker	I
has	O
supported	O
the	O
hypothesised	O
interpretations	O
of	O
key	O
frames	O
of	O
the	O
Luneau	O
video	O
by	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
.	O

Although	O
the	O
rebuttal	O
of	O
that	O
comment	O
in	O
Fitzpatrick	O
et	O
al	O
[	O
5	O
]	O
asserted	O
that	O
flexion	O
and	O
motion	O
of	O
wings	O
of	O
Pileated	B
Woodpeckers	I
could	O
not	O
produce	O
the	O
images	O
seen	O
in	O
the	O
Luneau	O
video	O
,	O
it	O
has	O
been	O
shown	O
here	O
that	O
they	O
can	O
.	O

The	O
Luneau	O
video	O
as	O
presented	O
in	O
Fitzpatrick	O
et	O
al	O
[	O
1	O
]	O
,	O
shows	O
features	O
that	O
are	O
consistent	O
with	O
Pileated	B
Woodpecker	I
,	O
and	O
inconsistent	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
.	O

It	O
is	O
argued	O
in	O
this	O
paper	O
that	O
,	O
in	O
fact	O
,	O
the	O
black	O
trailing	O
edge	O
of	O
the	O
wing	O
of	O
a	O
Pileated	B
Woodpecker	I
is	O
seen	O
clearly	O
in	O
the	O
Luneau	O
video	O
,	O
during	O
the	O
downstroke	O
of	O
the	O
wingbeat	O
cycle	O
,	O
but	O
that	O
it	O
has	O
been	O
misinterpreted	O
as	O
black	O
wingtips	O
(	O
Figure	O
1	O
,	O
2	O
,	O
3	O
)	O
.	O

A	O
fuller	O
analysis	O
of	O
the	O
Luneau	O
video	O
by	O
the	O
Cornell	O
University	O
team	O
is	O
presented	O
online	O
[	O
7	O
]	O
.	O

Although	O
it	O
is	O
not	O
peer	O
-	O
reviewed	O
,	O
the	O
points	O
this	O
article	O
makes	O
should	O
be	O
taken	O
into	O
account	O
.	O

The	O
authors	O
summarise	O
nine	O
diagnostic	O
traits	O
from	O
their	O
analysis	O
of	O
the	O
Luneau	O
video	O
that	O
identify	O
the	O
bird	O
as	O
Ivory	B
-	I
billed	I
Woodpecker	I
.	O

These	O
are	O
listed	O
and	O
discussed	O
point	O
-	O
by	O
point	O
below	O
.	O

1	O
.	O

'	O
The	O
underwing	O
pattern	O
in	O
flight	O
consistently	O
appears	O
largely	O
white	O
,	O
giving	O
the	O
appearance	O
of	O
having	O
black	O
wingtips	O
but	O
lacking	O
any	O
black	O
along	O
the	O
rear	O
,	O
or	O
trailing	O
edge	O
.	O
'	O

Data	O
presented	O
in	O
this	O
paper	O
show	O
that	O
this	O
statement	O
is	O
not	O
wholly	O
supported	O
,	O
and	O
in	O
any	O
case	O
the	O
underwing	O
of	O
Pileated	B
Woodpeckers	I
can	O
present	O
the	O
same	O
appearance	O
.	O

2	O
.	O

'	O
The	O
upperwing	O
pattern	O
in	O
flight	O
consistently	O
shows	O
a	O
broad	O
,	O
white	O
trailing	O
edge	O
,	O
with	O
no	O
frames	O
demonstrating	O
the	O
conspicuous	O
dark	O
rear	O
border	O
to	O
be	O
expected	O
of	O
normal	O
Pileated	B
Woodpeckers	I
.	O
'	O

Notwithstanding	O
that	O
certain	O
frames	O
of	O
the	O
Luneau	O
video	O
(	O
e	O
.	O
g	O
.	O
frame	O
350	O
)	O
do	O
appear	O
to	O
show	O
a	O
black	O
trailing	O
edge	O
to	O
the	O
upperwing	O
,	O
data	O
presented	O
in	O
this	O
paper	O
shows	O
that	O
,	O
at	O
this	O
angle	O
of	O
view	O
and	O
resolution	O
of	O
video	O
,	O
Pileated	B
Woodpeckers	I
also	O
may	O
fail	O
to	O
show	O
this	O
feature	O
.	O

This	O
analysis	O
has	O
shown	O
that	O
the	O
hypothesis	O
presented	O
in	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
is	O
plausible	O
,	O
i	O
.	O
e	O
.	O
that	O
some	O
of	O
the	O
frames	O
interpreted	O
by	O
[	O
1	O
]	O
to	O
show	O
the	O
upperwing	O
of	O
an	O
Ivory	B
-	I
billed	I
Woodpecker	I
may	O
in	O
fact	O
show	O
large	O
amounts	O
of	O
white	O
and	O
the	O
black	O
trailing	O
edge	O
from	O
the	O
underwing	O
of	O
a	O
Pileated	B
Woodpecker	I
.	O

3	O
.	O

'	O
The	O
wings	O
are	O
longer	O
relative	O
to	O
the	O
body	O
diameter	O
than	O
in	O
Pileated	B
Woodpecker	I
and	O
consistent	O
with	O
the	O
wing	O
shape	O
of	O
Ivory	B
-	I
billed	I
Woodpecker	I
.	O
'	O

Fitzpatrick	O
et	O
al	O
[	O
5	O
]	O
agreed	O
that	O
accurate	O
measurements	O
were	O
not	O
possible	O
from	O
the	O
video	O
images	O
presented	O
in	O
their	O
original	O
paper	O
[	O
1	O
]	O
,	O
and	O
it	O
seems	O
unlikely	O
that	O
much	O
confidence	O
can	O
be	O
placed	O
in	O
the	O
wing	O
-	O
length	O
measurements	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
.	O

Comparison	O
of	O
,	O
for	O
example	O
,	O
Figure	O
1A	O
,	O
frame	O
283	O
.	O
3	O
with	O
Figure	O
1B	O
,	O
frame	O
578	O
suggests	O
that	O
any	O
differences	O
will	O
be	O
very	O
difficult	O
to	O
prove	O
.	O

4	O
.	O

'	O
Reenactment	O
of	O
the	O
scene	O
using	O
life	O
-	O
sized	O
,	O
realistically	O
painted	O
,	O
dynamically	O
flapping	O
models	O
produced	O
images	O
remarkably	O
similar	O
to	O
those	O
of	O
the	O
Luneau	O
video	O
using	O
the	O
Ivory	B
-	I
billed	I
Woodpecker	I
model	O
,	O
and	O
images	O
clearly	O
identifiable	O
as	O
Pileated	B
Woodpecker	I
using	O
a	O
model	O
of	O
that	O
species	O
.	O
'	O

Interpretation	O
of	O
model	O
re	O
-	O
enactments	O
is	O
hampered	O
by	O
the	O
fact	O
that	O
the	O
stiff	O
,	O
flat	O
-	O
winged	O
models	O
cannot	O
reflect	O
the	O
wing	O
flexion	O
and	O
curvature	O
of	O
real	O
birds	O
.	O

Reenactment	O
of	O
the	O
scene	O
using	O
real	O
Pileated	B
Woodpeckers	I
has	O
produced	O
images	O
remarkably	O
similar	O
to	O
the	O
Luneau	O
video	O
.	O

5	O
.	O

'	O
The	O
wingbeat	O
frequency	O
is	O
8	O
.	O
6	O
beats	O
per	O
second	O
,	O
which	O
is	O
almost	O
identical	O
to	O
that	O
recorded	O
for	O
Ivory	B
-	I
billed	I
Woodpecker	I
(	O
as	O
documented	O
by	O
one	O
acoustic	O
record	O
from	O
1935	O
)	O
.	O

The	O
wing	O
-	O
beat	O
frequencies	O
of	O
Pileated	B
Woodpecker	I
are	O
not	O
known	O
to	O
exceed	O
7	O
.	O
5	O
beats	O
per	O
second	O
,	O
and	O
more	O
typically	O
range	O
between	O
3	O
and	O
6	O
beats	O
per	O
second	O
.	O
'	O

The	O
fact	O
that	O
in	O
only	O
four	O
recorded	O
escape	O
flights	O
of	O
Pileated	B
Woodpecker	I
,	O
two	O
were	O
recorded	O
for	O
which	O
the	O
initial	O
escape	O
flight	O
wingbeat	O
frequency	O
(	O
8	O
.	O
0	O
s	O
-	O
1	O
and	O
8	O
.	O
6	O
s	O
-	O
1	O
)	O
exceeded	O
that	O
previously	O
recorded	O
for	O
this	O
species	O
shows	O
that	O
previous	O
datasets	O
were	O
too	O
limited	O
to	O
make	O
this	O
conclusion	O
.	O

Birds	O
flap	O
more	O
rapidly	O
at	O
take	O
off	O
to	O
gain	O
altitude	O
and	O
speed	O
than	O
they	O
do	O
in	O
sustained	O
level	O
flight	O
:	O
Pileated	B
Woodpecker	I
flight	O
data	O
in	O
the	O
literature	O
[	O
1	O
,	O
4	O
,	O
5	O
]	O
was	O
derived	O
from	O
the	O
work	O
of	O
Tobalske	O
[	O
8	O
]	O
,	O
which	O
explicitly	O
excluded	O
the	O
initial	O
take	O
-	O
off	O
period	O
,	O
and	O
therefore	O
cannot	O
be	O
used	O
to	O
support	O
the	O
elimination	O
of	O
Pileated	B
Woodpecker	I
in	O
the	O
Luneau	O
video	O
.	O

Furthermore	O
,	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
is	O
consistently	O
gaining	O
height	O
from	O
a	O
low	O
position	O
above	O
water	O
and	O
,	O
whatever	O
its	O
species	O
,	O
might	O
be	O
expected	O
to	O
flap	O
more	O
rapidly	O
than	O
if	O
it	O
were	O
in	O
level	O
flight	O
.	O

Tanner	O
[	O
9	O
]	O
noted	O
that	O
Pileated	B
Woodpeckers	I
can	O
maintain	O
extended	O
fast	O
direct	O
flight	O
.	O

He	O
was	O
of	O
the	O
opinion	O
that	O
flight	O
pattern	O
was	O
not	O
a	O
useful	O
character	O
for	O
separating	O
the	O
two	O
species	O
in	O
the	O
field	O
,	O
and	O
that	O
Pileated	B
Woodpeckers	I
frequently	O
fly	O
in	O
a	O
manner	O
that	O
was	O
in	O
no	O
way	O
different	O
to	O
Ivory	B
-	I
billed	I
Woodpeckers	I
.	O

The	O
figure	O
of	O
8	O
.	O
6	O
wingbeats	O
per	O
second	O
for	O
the	O
Luneau	O
bird	O
(	O
data	O
reanalysed	O
here	O
)	O
is	O
taken	O
as	O
consistent	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
on	O
the	O
basis	O
of	O
analysis	O
of	O
a	O
single	O
archival	O
audio	O
recording	O
[	O
3	O
]	O
.	O

The	O
Ivory	B
-	I
billed	I
Woodpecker	I
in	O
that	O
audio	O
tape	O
is	O
clearly	O
flapping	O
its	O
wings	O
,	O
but	O
without	O
accompanying	O
visual	O
confirmation	O
it	O
is	O
not	O
clear	O
that	O
it	O
is	O
in	O
flight	O
.	O

In	O
general	O
,	O
larger	O
birds	O
are	O
expected	O
to	O
flap	O
their	O
wings	O
more	O
slowly	O
than	O
smaller	O
birds	O
of	O
comparable	O
wing	O
morphology	O
.	O

Tobalske	O
[	O
8	O
]	O
showed	O
that	O
,	O
across	O
species	O
,	O
smaller	O
woodpeckers	O
tend	O
to	O
flap	O
more	O
quickly	O
than	O
larger	O
ones	O
,	O
and	O
that	O
there	O
was	O
considerable	O
intraspecific	O
variation	O
.	O

The	O
assertion	O
that	O
Ivory	B
-	I
billed	I
Woodpeckers	I
flap	O
their	O
wings	O
more	O
quickly	O
than	O
Pileated	B
Woodpeckers	I
is	O
therefore	O
counterintuitive	O
.	O

Further	O
comment	O
is	O
conjecture	O
:	O
while	O
the	O
flight	O
pattern	O
and	O
wing	O
posture	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
may	O
be	O
unusual	O
,	O
it	O
has	O
not	O
been	O
shown	O
that	O
it	O
is	O
outside	O
the	O
range	O
of	O
variability	O
of	O
Pileated	B
Woodpecker	I
,	O
and	O
cannot	O
therefore	O
be	O
used	O
to	O
eliminate	O
the	O
possibility	O
that	O
it	O
was	O
the	O
commoner	O
species	O
.	O

6	O
.	O

'	O
White	O
plumage	O
on	O
the	O
back	O
is	O
visible	O
on	O
the	O
retreating	O
bird	O
as	O
it	O
begins	O
to	O
gain	O
altitude	O
.	O

Ivory	B
-	I
billed	I
Woodpecker	I
has	O
white	O
on	O
the	O
back	O
;	O
Pileated	B
Woodpecker	I
has	O
entirely	O
black	O
back	O
.	O
'	O

This	O
was	O
discussed	O
by	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
,	O
who	O
argued	O
that	O
the	O
images	O
thought	O
to	O
show	O
white	O
on	O
the	O
dorsum	O
were	O
too	O
small	O
to	O
be	O
accepted	O
uncritically	O
.	O

In	O
all	O
the	O
frames	O
of	O
the	O
Luneau	O
video	O
that	O
appear	O
to	O
show	O
white	O
on	O
the	O
dorsum	O
,	O
the	O
bird	O
is	O
distant	O
(	O
dorsal	O
white	O
is	O
not	O
visible	O
on	O
the	O
higher	O
resolution	O
images	O
earlier	O
in	O
the	O
video	O
)	O
and	O
partially	O
obscured	O
,	O
making	O
it	O
difficult	O
to	O
distinguish	O
dorsum	O
from	O
wing	O
.	O

Spurious	O
areas	O
of	O
white	O
pixels	O
appear	O
as	O
artifacts	O
in	O
both	O
videos	O
.	O

Nevertheless	O
,	O
this	O
remains	O
the	O
best	O
evidence	O
that	O
the	O
Luneau	O
bird	O
was	O
not	O
a	O
standard	O
Pileated	B
Woodpecker	I
.	O

7	O
.	O

'	O
The	O
dorsal	O
view	O
of	O
the	O
right	O
wing	O
as	O
it	O
begins	O
to	O
unfold	O
shows	O
a	O
triangle	O
of	O
white	O
that	O
matches	O
in	O
size	O
and	O
position	O
the	O
white	O
on	O
the	O
folded	O
wing	O
of	O
an	O
Ivory	B
-	I
billed	I
Woodpecker	I
beginning	O
to	O
launch	O
into	O
flight	O
.	O
'	O

No	O
further	O
comment	O
is	O
provided	O
here	O
.	O

An	O
alternative	O
explanation	O
was	O
offered	O
by	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
and	O
rebutted	O
by	O
Fitzpatrick	O
et	O
al	O
[	O
5	O
]	O
.	O

The	O
statement	O
requires	O
a	O
degree	O
of	O
certainty	O
about	O
the	O
position	O
of	O
the	O
wing	O
.	O

(	O
8	O
)	O
'	O
The	O
distance	O
between	O
the	O
wrist	O
area	O
and	O
the	O
tip	O
of	O
the	O
tail	O
(	O
32	O
-	O
36	O
cm	O
,	O
as	O
measured	O
when	O
the	O
bird	O
begins	O
to	O
take	O
flight	O
)	O
is	O
comparable	O
to	O
known	O
measurements	O
of	O
Ivory	B
-	I
billed	I
Woodpecker	I
and	O
considerably	O
larger	O
than	O
even	O
the	O
largest	O
Pileated	B
Woodpecker	I
we	O
measured	O
.	O
'	O

As	O
stated	O
under	O
(	O
3	O
)	O
,	O
above	O
,	O
there	O
is	O
general	O
agreement	O
that	O
accurate	O
measurements	O
are	O
not	O
possible	O
from	O
the	O
Luneau	O
video	O
because	O
too	O
many	O
uncontrolled	O
variables	O
are	O
involved	O
[	O
4	O
,	O
5	O
]	O
.	O

9	O
.	O

'	O
Only	O
20	O
seconds	O
before	O
the	O
woodpecker	O
flees	O
,	O
a	O
bird	O
with	O
the	O
size	O
and	O
color	O
pattern	O
of	O
an	O
Ivory	B
-	I
billed	I
Woodpecker	I
was	O
perched	O
within	O
3	O
m	O
of	O
the	O
site	O
from	O
which	O
the	O
woodpecker	O
took	O
flight	O
.	O
'	O

This	O
would	O
be	O
a	O
strong	O
argument	O
if	O
it	O
could	O
be	O
shown	O
that	O
the	O
object	O
in	O
question	O
was	O
a	O
bird	O
and	O
not	O
,	O
as	O
is	O
now	O
apparently	O
thought	O
likely	O
,	O
a	O
section	O
of	O
branch	O
or	O
tree	O
stump	O
[	O
10	O
]	O
.	O

The	O
Luneau	O
video	O
reveals	O
several	O
white	O
triangular	O
patches	O
apparently	O
visible	O
on	O
or	O
around	O
tree	O
trunks	O
,	O
most	O
or	O
all	O
of	O
which	O
must	O
therefore	O
be	O
images	O
of	O
tree	O
topography	O
or	O
video	O
artifacts	O
.	O

This	O
was	O
discussed	O
in	O
the	O
literature	O
(	O
see	O
[	O
4	O
,	O
5	O
]	O
)	O
.	O

Central	O
to	O
the	O
identification	O
of	O
the	O
flying	O
bird	O
seen	O
in	O
the	O
Luneau	O
video	O
was	O
the	O
evidence	O
that	O
plumage	O
and	O
flight	O
patterns	O
were	O
inconsistent	O
with	O
Pileated	B
Woodpecker	I
.	O

A	O
very	O
basic	O
video	O
analysis	O
presented	O
here	O
has	O
suggested	O
that	O
this	O
may	O
not	O
be	O
the	O
case	O
,	O
and	O
that	O
further	O
research	O
is	O
needed	O
.	O

Any	O
identification	O
of	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
as	O
an	O
Ivory	B
-	I
bill	I
must	O
take	O
into	O
account	O
the	O
data	O
presented	O
here	O
and	O
in	O
Sibley	O
et	O
al	O
[	O
4	O
]	O
,	O
which	O
shows	O
it	O
is	O
largely	O
consistent	O
with	O
Pileated	B
Woodpecker	I
and	O
points	O
out	O
apparent	O
inconsistencies	O
with	O
Ivory	B
-	I
billed	I
Woodpecker	I
.	O

This	O
does	O
not	O
of	O
course	O
necessarily	O
imply	O
that	O
the	O
Ivory	B
-	I
billed	I
Woodpecker	I
is	O
extinct	O
,	O
nor	O
indeed	O
entirely	O
rule	O
out	O
the	O
possibility	O
that	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
was	O
one	O
.	O

There	O
appears	O
to	O
be	O
no	O
reason	O
to	O
question	O
the	O
anecdotal	O
sight	O
records	O
of	O
Ivory	B
-	I
billed	I
Woodpecker	I
presented	O
in	O
Fitzpatrick	O
et	O
al	O
[	O
1	O
]	O
(	O
or	O
in	O
many	O
online	O
sources	O
)	O
,	O
because	O
some	O
of	O
them	O
appear	O
credible	O
,	O
albeit	O
brief	O
.	O

Audio	O
evidence	O
has	O
since	O
been	O
published	O
[	O
11	O
]	O
although	O
this	O
too	O
is	O
far	O
from	O
conclusive	O
.	O

However	O
,	O
to	O
regard	O
the	O
Luneau	O
video	O
by	O
itself	O
as	O
presenting	O
anything	O
other	O
than	O
an	O
unidentified	O
woodpecker	O
falls	O
below	O
the	O
standards	O
of	O
proof	O
normally	O
required	O
for	O
scientific	O
publication	O
:	O
the	O
images	O
are	O
not	O
good	O
enough	O
.	O

The	O
Ivory	B
-	I
billed	I
Woodpecker	I
may	O
persist	O
in	O
continental	O
North	O
America	O
,	O
and	O
there	O
is	O
enough	O
anecdotal	O
evidence	O
to	O
make	O
this	O
a	O
possibility	O
,	O
but	O
the	O
Luneau	O
video	O
does	O
not	O
support	O
the	O
case	O
.	O

The	O
balance	O
of	O
evidence	O
would	O
suggest	O
that	O
the	O
bird	O
in	O
the	O
Luneau	O
video	O
is	O
more	O
likely	O
to	O
have	O
been	O
a	O
Pileated	B
Woodpecker	I
,	O
but	O
the	O
search	O
for	O
Ivory	B
-	I
billed	I
Woodpecker	I
should	O
continue	O
.	O

While	O
this	O
paper	O
was	O
under	O
review	O
,	O
a	O
report	O
of	O
sight	O
records	O
and	O
sound	O
recordings	O
of	O
Ivory	B
-	I
billed	I
Woodpeckers	I
was	O
published	O
from	O
a	O
location	O
in	O
Florida	O
[	O
12	O
]	O
.	O

This	O
very	O
exciting	O
claim	O
is	O
strengthened	O
by	O
reports	O
of	O
sighting	O
of	O
the	O
white	O
dorsal	O
stripes	O
on	O
one	O
bird	O
in	O
flight	O
.	O

Unfortunately	O
,	O
several	O
sightings	O
were	O
made	O
without	O
optical	O
aids	O
and	O
cannot	O
be	O
considered	O
proven	O
.	O

The	O
'	O
kent	O
'	O
calls	O
recorded	O
from	O
the	O
Florida	O
location	O
are	O
spectrographically	O
similar	O
to	O
the	O
'	O
bleat	O
'	O
calls	O
of	O
young	O
White	B
-	I
tailed	I
Deer	I
,	O
as	O
described	O
in	O
Richardson	O
et	O
al	O
[	O
13	O
]	O
.	O

A	O
clear	O
photograph	O
will	O
be	O
required	O
from	O
this	O
location	O
too	O
before	O
the	O
presence	O
of	O
Ivory	B
-	I
billed	I
Woodpeckers	I
can	O
be	O
considered	O
confirmed	O
.	O

It	O
is	O
hoped	O
that	O
this	O
paper	O
will	O
help	O
with	O
assessment	O
of	O
any	O
further	O
low	O
quality	O
photographs	O
or	O
videos	O
.	O

Conclusion	O

Flight	O
and	O
plumage	O
patterns	O
of	O
the	O
putative	O
Ivory	B
-	I
billed	I
Woodpecker	I
recorded	O
in	O
Arkansas	O
in	O
2005	O
are	O
recapitulated	O
by	O
confirmed	O
Pileated	B
Woodpeckers	I
.	O

The	O
bird	O
in	O
the	O
Arkansas	O
video	O
is	O
best	O
regarded	O
as	O
not	O
fully	O
identified	O
,	O
and	O
is	O
probably	O
a	O
Pileated	B
Woodpecker	I
.	O

Methods	O

Video	O
recording	O

Pileated	B
Woodpeckers	I
were	O
attracted	O
to	O
a	O
bird	O
feeder	O
containing	O
suet	O
at	O
Grants	O
Trail	O
,	O
Dayton	O
,	O
OH	O
45459	O
.	O

The	O
suet	O
feeder	O
was	O
placed	O
approximately	O
2	O
.	O
1	O
m	O
high	O
on	O
a	O
tree	O
trunk	O
,	O
and	O
the	O
distance	O
to	O
the	O
suet	O
feeder	O
from	O
the	O
observation	O
point	O
was	O
approximately	O
5	O
m	O
.	O

Birds	O
on	O
the	O
feeder	O
were	O
startled	O
by	O
movement	O
of	O
window	O
blinds	O
on	O
January	O
28	O
and	O
February	O
5	O
,	O
2006	O
,	O
and	O
their	O
escape	O
flights	O
were	O
filmed	O
using	O
a	O
Sony	O
Hi	O
-	O
8	O
SteadyShot	O
video	O
camera	O
at	O
29	O
.	O
97	O
frames	O
s	O
-	O
1	O
.	O

At	O
least	O
two	O
birds	O
feature	O
in	O
the	O
videos	O
,	O
male	O
and	O
female	O
.	O

Analogue	O
tape	O
was	O
converted	O
to	O
digital	O
by	O
connecting	O
the	O
Hi	O
-	O
8	O
camera	O
directly	O
to	O
a	O
Sony	O
DCR	O
-	O
HC30	O
digital	O
video	O
camera	O
and	O
recording	O
onto	O
that	O
camera	O
'	O
s	O
mini	O
dv	O
cassette	O
.	O

The	O
resulting	O
images	O
were	O
converted	O
to	O
an	O
avi	O
file	O
using	O
Windows	O
Movie	O
Maker	O
on	O
a	O
Windows	O
XP	O
PC	O
.	O

The	O
video	O
is	O
freely	O
available	O
in	O
wmv	O
format	O
[	O
14	O
]	O
and	O
in	O
avi	O
format	O
from	O
the	O
author	O
or	O
David	O
Nolin	O
(	O
via	O
the	O
author	O
)	O
.	O

The	O
video	O
was	O
decompiled	O
using	O
Blaze	O
Media	O
Pro	O
(	O
Mystik	O
Media	O
,	O
Hampstead	O
,	O
NC	O
,	O
USA	O
)	O
for	O
a	O
detailed	O
analysis	O
.	O

Import	O
into	O
Avid	O
(	O
R	O
)	O
Xpress	O
Pro	O
HD	O
for	O
deinterlacing	O
did	O
not	O
reduce	O
the	O
wing	O
flicker	O
seen	O
in	O
the	O
images	O
,	O
and	O
further	O
professional	O
processing	O
could	O
not	O
improve	O
the	O
resolution	O
,	O
so	O
the	O
original	O
decompiled	O
file	O
was	O
used	O
for	O
analysis	O
.	O

Hence	O
some	O
frames	O
contain	O
two	O
overlaid	O
images	O
,	O
which	O
may	O
lower	O
the	O
resolution	O
in	O
some	O
cases	O
.	O

The	O
decompiled	O
file	O
was	O
examined	O
frame	O
by	O
frame	O
and	O
compared	O
to	O
the	O
decompiled	O
images	O
of	O
the	O
putative	O
Ivory	B
-	I
billed	I
Woodpecker	I
presented	O
in	O
Fitzpatrick	O
et	O
al	O
[	O
1	O
]	O
.	O

Wingbeat	O
frequencies	O
were	O
calculated	O
by	O
noting	O
the	O
frame	O
number	O
of	O
the	O
midpoint	O
of	O
the	O
downstroke	O
of	O
each	O
wingbeat	O
(	O
e	O
.	O
g	O
.	O
Figure	O
1B	O
,	O
frame	O
758	O
)	O
and	O
calculating	O
the	O
length	O
of	O
time	O
taken	O
per	O
wingbeat	O
as	O
(	O
number	O
of	O
frames	O
between	O
downstroke	O
midpoints	O
)	O
/	O
29	O
.	O
97	O
.	O

Authors	O
'	O
contributions	O

JMC	O
performed	O
the	O
data	O
analysis	O
and	O
drafted	O
the	O
manuscript	O
.	O

Supplementary	O
Material	O

A	O
global	O
gene	O
evolution	O
analysis	O
on	O
Vibrionaceae	O
family	O
using	O
phylogenetic	O
profile	O

Abstract	O

Background	O

Vibrionaceae	O
represent	O
a	O
significant	O
portion	O
of	O
the	O
cultivable	O
heterotrophic	O
sea	O
bacteria	O
;	O
they	O
strongly	O
affect	O
nutrient	O
cycling	O
and	O
some	O
species	O
are	O
devastating	O
pathogens	O
.	O

In	O
this	O
work	O
we	O
propose	O
an	O
improved	O
phylogenetic	O
profile	O
analysis	O
on	O
14	O
Vibrionaceae	O
genomes	O
,	O
to	O
study	O
the	O
evolution	O
of	O
this	O
family	O
on	O
the	O
basis	O
of	O
gene	O
content	O
.	O

The	O
phylogenetic	O
profile	O
is	O
based	O
on	O
the	O
observation	O
that	O
genes	O
involved	O
in	O
the	O
same	O
process	O
(	O
e	O
.	O
g	O
.	O
metabolic	O
pathway	O
or	O
structural	O
complex	O
)	O
tend	O
to	O
be	O
concurrently	O
present	O
or	O
absent	O
within	O
different	O
genomes	O
.	O

This	O
allows	O
the	O
prediction	O
of	O
hypothetical	O
functions	O
on	O
the	O
basis	O
of	O
a	O
shared	O
phylogenetic	O
profiles	O
.	O

Moreover	O
this	O
approach	O
is	O
useful	O
to	O
identify	O
putative	O
laterally	O
transferred	O
elements	O
on	O
the	O
basis	O
of	O
their	O
presence	O
on	O
distantly	O
phylogenetically	O
related	O
bacteria	O
.	O

Results	O

Vibrionaceae	O
ORFs	O
were	O
aligned	O
against	O
all	O
the	O
available	O
bacterial	O
proteomes	O
.	O

Phylogenetic	O
profile	O
is	O
defined	O
as	O
an	O
array	O
of	O
distances	O
,	O
based	O
on	O
aminoacid	O
substitution	O
matrixes	O
,	O
from	O
single	O
genes	O
to	O
all	O
their	O
orthologues	O
.	O

Final	O
phylogenetic	O
profiles	O
,	O
derived	O
from	O
non	O
-	O
redundant	O
list	O
of	O
all	O
ORFs	O
,	O
was	O
defined	O
as	O
the	O
median	O
of	O
all	O
the	O
profiles	O
belonging	O
to	O
the	O
cluster	O
.	O

The	O
resulting	O
phylogenetic	O
profiles	O
matrix	O
contains	O
gene	O
clusters	O
on	O
the	O
rows	O
and	O
organisms	O
on	O
the	O
columns	O
.	O

Cluster	O
analysis	O
identified	O
groups	O
of	O
"	O
core	O
genes	O
"	O
with	O
a	O
widespread	O
high	O
similarity	O
across	O
all	O
the	O
organisms	O
and	O
several	O
clusters	O
that	O
contain	O
genes	O
homologous	O
only	O
to	O
a	O
limited	O
set	O
of	O
organisms	O
.	O

On	O
each	O
of	O
these	O
clusters	O
,	O
COG	O
class	O
enrichment	O
has	O
been	O
calculated	O
.	O

The	O
analysis	O
reveals	O
that	O
clusters	O
of	O
core	O
genes	O
have	O
the	O
highest	O
number	O
of	O
enriched	O
classes	O
,	O
while	O
the	O
others	O
are	O
enriched	O
just	O
for	O
few	O
of	O
them	O
like	O
DNA	O
replication	O
,	O
recombination	O
and	O
repair	O
.	O

Conclusion	O

We	O
found	O
that	O
mobile	O
elements	O
have	O
heterogeneous	O
profiles	O
not	O
only	O
across	O
the	O
entire	O
set	O
of	O
organisms	O
,	O
but	O
also	O
within	O
Vibrionaceae	O
;	O
this	O
confirms	O
their	O
great	O
influence	O
on	O
bacteria	O
evolution	O
even	O
inside	O
the	O
same	O
family	O
.	O

Furthermore	O
,	O
several	O
hypothetical	O
proteins	O
highly	O
correlate	O
with	O
mobile	O
elements	O
profiles	O
suggesting	O
a	O
possible	O
horizontal	O
transfer	O
mechanism	O
for	O
the	O
evolution	O
of	O
these	O
genes	O
.	O

Finally	O
,	O
we	O
suggested	O
the	O
putative	O
role	O
of	O
some	O
ORFs	O
having	O
an	O
unknown	O
function	O
on	O
the	O
basis	O
of	O
their	O
phylogenetic	O
profile	O
similarity	O
to	O
well	O
characterized	O
genes	O
.	O

Background	O

Over	O
the	O
past	O
ten	O
years	O
,	O
a	O
great	O
number	O
of	O
microbial	O
genomes	O
have	O
been	O
sequenced	O
covering	O
a	O
wide	O
representation	O
of	O
prokaryots	O
as	O
well	O
as	O
multiple	O
strains	O
of	O
some	O
species	O
.	O

The	O
study	O
of	O
these	O
genomes	O
both	O
by	O
computational	O
and	O
experimental	O
approaches	O
has	O
highly	O
improved	O
our	O
understanding	O
on	O
physiology	O
,	O
phylogenetic	O
relationship	O
and	O
pathogenicity	O
of	O
many	O
organisms	O
.	O

Furthermore	O
,	O
it	O
has	O
provided	O
new	O
knowledge	O
on	O
microbial	O
genome	O
evolution	O
,	O
revealing	O
a	O
gene	O
core	O
shared	O
by	O
the	O
great	O
majority	O
of	O
bacteria	O
,	O
genes	O
characteristic	O
of	O
particular	O
groups	O
and	O
"	O
novel	O
"	O
genes	O
that	O
possibly	O
originated	O
by	O
lateral	O
gene	O
transfer	O
from	O
some	O
unknown	O
source	O
.	O

Analysis	O
performed	O
on	O
closely	O
related	O
genomes	O
revealed	O
that	O
a	O
substantial	O
fraction	O
of	O
genes	O
in	O
any	O
genome	O
seem	O
to	O
be	O
strain	O
specific	O
.	O

These	O
genes	O
might	O
sometime	O
arise	O
by	O
gene	O
duplication	O
followed	O
by	O
a	O
rapid	O
divergence	O
,	O
or	O
by	O
lineage	O
-	O
specific	O
loss	O
of	O
genes	O
in	O
one	O
strain	O
,	O
resulting	O
in	O
a	O
unique	O
gene	O
in	O
other	O
strains	O
.	O

However	O
,	O
there	O
are	O
several	O
lines	O
of	O
evidence	O
indicating	O
that	O
lateral	O
gene	O
transfer	O
may	O
be	O
the	O
main	O
mechanism	O
to	O
acquire	O
novel	O
genes	O
.	O

Indeed	O
,	O
this	O
could	O
be	O
one	O
of	O
the	O
main	O
forces	O
driving	O
bacterial	O
adaptation	O
and	O
evolution	O
.	O

Phage	O
DNA	O
is	O
thought	O
to	O
be	O
one	O
of	O
the	O
main	O
vectors	O
for	O
lateral	O
gene	O
transfer	O
among	O
bacteria	O
[	O
1	O
]	O
and	O
many	O
virulence	O
factors	O
from	O
bacterial	O
pathogen	O
are	O
phage	O
encoded	O
[	O
2	O
]	O
.	O

For	O
example	O
,	O
the	O
genes	O
for	O
CT	O
,	O
the	O
most	O
important	O
virulence	O
factor	O
of	O
V	B
.	I
cholerae	I
,	O
are	O
encoded	O
in	O
the	O
genome	O
of	O
phage	O
CTX	O
phi	O
,	O
integrated	O
in	O
the	O
bacterial	O
chromosome	O
1	O
.	O

Since	O
lateral	O
gene	O
transfer	O
plays	O
a	O
relevant	O
role	O
in	O
bacterial	O
evolution	O
,	O
the	O
reconstruction	O
of	O
phylogeny	O
is	O
very	O
complex	O
and	O
phylogenetic	O
trees	O
built	O
by	O
standard	O
sequence	O
analysis	O
may	O
not	O
lead	O
to	O
a	O
reliable	O
picture	O
of	O
the	O
evolutionary	O
history	O
.	O

In	O
fact	O
,	O
alternative	O
trees	O
can	O
be	O
obtained	O
when	O
different	O
proteins	O
are	O
considered	O
.	O

For	O
many	O
aspects	O
the	O
classification	O
of	O
bacteria	O
on	O
the	O
basis	O
of	O
their	O
global	O
gene	O
content	O
may	O
give	O
a	O
better	O
description	O
of	O
their	O
evolutionary	O
history	O
.	O

This	O
may	O
be	O
particularly	O
important	O
when	O
bacteria	O
of	O
the	O
same	O
group	O
are	O
compared	O
,	O
since	O
newly	O
acquired	O
genes	O
could	O
be	O
relevant	O
to	O
confer	O
peculiar	O
features	O
that	O
allows	O
the	O
exploitation	O
of	O
different	O
ecological	O
niches	O
.	O

In	O
this	O
study	O
we	O
propose	O
a	O
bioinformatic	O
procedure	O
to	O
investigate	O
bacterial	O
genome	O
evolution	O
,	O
taking	O
into	O
account	O
the	O
global	O
gene	O
content	O
,	O
as	O
well	O
as	O
sequence	O
similarity	O
.	O

We	O
based	O
our	O
analysis	O
on	O
modified	O
phylogenetic	O
profiles	O
[	O
3	O
]	O
;	O
however	O
,	O
we	O
do	O
not	O
consider	O
only	O
the	O
presence	O
/	O
absence	O
of	O
orthologue	O
genes	O
,	O
but	O
also	O
their	O
distance	O
,	O
based	O
on	O
a	O
substitution	O
matrix	O
.	O

A	O
phylogenetic	O
profile	O
is	O
a	O
non	O
-	O
sequence	O
-	O
homology	O
-	O
based	O
method	O
developed	O
to	O
infer	O
a	O
possible	O
functional	O
relationship	O
between	O
genes	O
.	O

It	O
is	O
based	O
on	O
the	O
idea	O
that	O
proteins	O
that	O
are	O
involved	O
in	O
the	O
same	O
metabolic	O
pathway	O
or	O
structural	O
complex	O
are	O
likely	O
to	O
evolve	O
in	O
a	O
correlate	O
fashion	O
and	O
during	O
evolution	O
appear	O
phylogenetically	O
linked	O
,	O
showing	O
a	O
tendency	O
to	O
be	O
either	O
preserved	O
or	O
eliminated	O
as	O
a	O
whole	O
.	O

Therefore	O
,	O
genes	O
showing	O
similar	O
phylogenetic	O
profiles	O
are	O
likely	O
to	O
be	O
functionally	O
related	O
.	O

We	O
extended	O
the	O
use	O
of	O
phylogenetic	O
profiles	O
to	O
produce	O
an	O
evolutionary	O
tree	O
based	O
on	O
a	O
hierarchical	O
clusterization	O
of	O
organisms	O
with	O
similar	O
phylogenetic	O
profiles	O
.	O

For	O
this	O
study	O
we	O
took	O
the	O
whole	O
gene	O
dataset	O
of	O
320	O
prokaryotic	O
genomes	O
,	O
however	O
,	O
we	O
limited	O
the	O
analysis	O
to	O
the	O
orthologous	O
groups	O
that	O
are	O
present	O
in	O
at	O
least	O
one	O
of	O
the	O
14	O
considered	O
species	O
of	O
the	O
Vibrionaceae	O
family	O
.	O

These	O
bacteria	O
belong	O
to	O
the	O
Gammaproteobacteria	O
group	O
and	O
are	O
highly	O
abundant	O
in	O
aquatic	O
environment	O
,	O
they	O
strongly	O
influence	O
nutrient	O
cycling	O
and	O
various	O
species	O
are	O
also	O
devastating	O
pathogens	O
.	O

Since	O
we	O
focused	O
our	O
analysis	O
on	O
this	O
particular	O
group	O
,	O
the	O
aim	O
of	O
this	O
study	O
is	O
not	O
the	O
construction	O
of	O
a	O
global	O
evolutionary	O
tree	O
,	O
but	O
rather	O
a	O
Vibrionaceae	O
perspective	O
of	O
bacterial	O
diversity	O
,	O
based	O
on	O
phylogenetic	O
profiles	O
.	O

Results	O
and	O
discussion	O

Phylogenetic	O
matrix	O

The	O
analysis	O
was	O
performed	O
on	O
14	O
bacteria	O
belonging	O
to	O
the	O
Vibrionaceae	O
family	O
(	O
Table	O
1	O
)	O
.	O

The	O
redundant	O
list	O
of	O
Vibrionaceae	O
ORFs	O
was	O
clustered	O
to	O
reduce	O
the	O
number	O
of	O
proteins	O
to	O
analyze	O
and	O
the	O
phylogenetic	O
profile	O
for	O
each	O
cluster	O
was	O
calculated	O
as	O
described	O
in	O
the	O
Method	O
section	O
.	O

Many	O
authors	O
proposed	O
and	O
successfully	O
applied	O
different	O
measure	O
methods	O
to	O
calculate	O
the	O
phylogenetic	O
profile	O
values	O
.	O

Pellegrini	O
et	O
al	O
.	O

[	O
3	O
]	O
firstly	O
proposed	O
a	O
phylogenetic	O
profile	O
described	O
as	O
a	O
string	O
of	O
bits	O
,	O
each	O
bit	O
representing	O
the	O
absence	O
or	O
presence	O
of	O
an	O
homologous	O
gene	O
in	O
a	O
given	O
genome	O
.	O

This	O
method	O
lacks	O
a	O
weighting	O
procedure	O
,	O
giving	O
the	O
same	O
weight	O
(	O
value	O
1	O
)	O
to	O
all	O
the	O
sequences	O
that	O
are	O
considered	O
homologous	O
given	O
a	O
similarity	O
threshold	O
.	O

Enault	O
and	O
colleagues	O
proposed	O
an	O
improved	O
phylogenetic	O
profile	O
based	O
on	O
a	O
normalized	O
Blastp	O
bit	O
score	O
[	O
4	O
]	O
.	O

This	O
method	O
,	O
compared	O
to	O
the	O
approach	O
implemented	O
by	O
Pellegrini	O
,	O
allows	O
weighting	O
each	O
point	O
of	O
the	O
profile	O
proportionally	O
to	O
the	O
length	O
and	O
the	O
quality	O
of	O
the	O
alignment	O
.	O

Jingchun	O
and	O
colleagues	O
optimized	O
the	O
phylogenetic	O
profiles	O
method	O
by	O
integrating	O
phylogenetic	O
relationships	O
among	O
reference	O
organisms	O
and	O
sequence	O
homology	O
information	O
,	O
based	O
on	O
E	O
-	O
value	O
score	O
,	O
to	O
improve	O
prediction	O
accuracy	O
[	O
5	O
]	O
.	O

The	O
measure	O
index	O
I	O
proposed	O
in	O
this	O
work	O
is	O
similar	O
to	O
the	O
others	O
described	O
above	O
,	O
taking	O
into	O
account	O
both	O
the	O
quality	O
and	O
the	O
length	O
of	O
the	O
alignment	O
using	O
a	O
substitution	O
matrix	O
.	O

Moreover	O
our	O
approach	O
considers	O
also	O
the	O
total	O
length	O
of	O
the	O
sequences	O
,	O
penalizing	O
good	O
alignments	O
occurring	O
between	O
ORFs	O
having	O
different	O
lengths	O
and	O
taking	O
into	O
consideration	O
that	O
ORFs	O
could	O
differentiate	O
mainly	O
for	O
the	O
presence	O
of	O
functional	O
domains	O
.	O

The	O
final	O
phylogenetic	O
profile	O
for	O
each	O
cluster	O
was	O
defined	O
as	O
the	O
median	O
of	O
all	O
the	O
profiles	O
belonging	O
to	O
the	O
cluster	O
,	O
named	O
"	O
meta	O
-	O
profile	O
"	O
,	O
which	O
describes	O
the	O
profile	O
of	O
conserved	O
ORFs	O
belonging	O
to	O
an	O
entire	O
family	O
.	O

Hierarchical	O
cluster	O
analysis	O

A	O
hierarchical	O
cluster	O
analysis	O
was	O
performed	O
on	O
the	O
entire	O
phylogenetic	O
profile	O
matrix	O
and	O
it	O
was	O
calculated	O
a	O
statistical	O
support	O
based	O
on	O
bootstrap	O
method	O
for	O
the	O
nodes	O
of	O
the	O
columns	O
tree	O
(	O
Fig	O
1	O
)	O
.	O

The	O
branch	O
tree	O
colors	O
represent	O
the	O
bootstrap	O
percentage	O
support	O
.	O

This	O
constitutes	O
a	O
phylogenetic	O
tree	O
based	O
on	O
gene	O
content	O
using	O
Vibrionaceae	O
ORFs	O
as	O
a	O
reference	O
.	O

Genomes	O
belonging	O
to	O
the	O
same	O
taxonomic	O
group	O
tend	O
to	O
cluster	O
together	O
and	O
the	O
Vibrionaceae	O
species	O
are	O
closely	O
related	O
.	O

As	O
expected	O
,	O
according	O
to	O
the	O
Vibrionaceae	O
branch	O
lengths	O
it	O
is	O
evident	O
that	O
variability	O
within	O
this	O
group	O
is	O
higher	O
compared	O
to	O
the	O
other	O
groups	O
.	O

The	O
dataset	O
used	O
for	O
phylogenetic	O
matrix	O
calculation	O
is	O
indeed	O
composed	O
by	O
Vibrionaceae	O
ORFs	O
.	O

This	O
implies	O
that	O
the	O
similarity	O
measures	O
between	O
these	O
ORFs	O
and	O
the	O
corresponding	O
orthologues	O
will	O
be	O
nearly	O
zero	O
in	O
most	O
of	O
the	O
other	O
species	O
and	O
significantly	O
higher	O
in	O
the	O
Vibrionaceae	O
family	O
,	O
increasing	O
the	O
variability	O
into	O
this	O
group	O
.	O

Moreover	O
the	O
average	O
percentage	O
of	O
clusters	O
shared	O
by	O
the	O
Vibrionaceae	O
members	O
is	O
only	O
47	O
.	O
5	O
%	O
(	O
average	O
number	O
of	O
shared	O
clusters	O
divided	O
by	O
the	O
total	O
number	O
of	O
clusters	O
)	O
that	O
again	O
indicates	O
a	O
high	O
variability	O
inside	O
this	O
family	O
.	O

It	O
is	O
also	O
interesting	O
to	O
note	O
that	O
organisms	O
belonging	O
to	O
the	O
same	O
or	O
closely	O
related	O
taxa	O
split	O
into	O
different	O
subgroups	O
.	O

This	O
highlights	O
the	O
existence	O
of	O
a	O
high	O
variability	O
among	O
lineages	O
,	O
due	O
to	O
genetic	O
and	O
evolutionary	O
processes	O
such	O
as	O
lateral	O
gene	O
transfer	O
,	O
concerted	O
evolution	O
and	O
gene	O
duplication	O
[	O
6	O
]	O
.	O

In	O
terms	O
of	O
gene	O
content	O
,	O
the	O
organisms	O
more	O
related	O
to	O
the	O
Vibrionaceae	O
belong	O
to	O
the	O
gamma	O
and	O
beta	O
proteobacteria	O
.	O

In	O
particular	O
Altermonadales	O
,	O
Enterobacteriales	O
and	O
Burkholderiales	O
are	O
closely	O
related	O
to	O
Vibrionaceae	O
,	O
and	O
share	O
the	O
higher	O
number	O
of	O
cluster	O
of	O
genes	O
(	O
average	O
percentage	O
of	O
20	O
%	O
)	O
.	O

As	O
expected	O
,	O
Archea	O
are	O
the	O
most	O
distant	O
group	O
sharing	O
just	O
3	O
.	O
8	O
%	O
of	O
clusters	O
.	O

Clusters	O
and	O
genes	O
distribution	O
,	O
as	O
shown	O
in	O
Fig	O
2	O
,	O
reveals	O
that	O
the	O
number	O
of	O
clusters	O
and	O
genes	O
shared	O
by	O
the	O
organisms	O
decreases	O
as	O
the	O
number	O
of	O
organisms	O
considered	O
increases	O
.	O

The	O
analysis	O
was	O
performed	O
considering	O
for	O
each	O
cluster	O
profile	O
the	O
number	O
of	O
organisms	O
sharing	O
the	O
same	O
numbers	O
of	O
clusters	O
(	O
and	O
genes	O
)	O
.	O

The	O
majority	O
of	O
gene	O
cluster	O
groups	O
no	O
more	O
than	O
21	O
species	O
on	O
a	O
total	O
of	O
320	O
.	O

The	O
highest	O
blue	O
spike	O
corresponds	O
to	O
the	O
higher	O
number	O
of	O
genes	O
shared	O
by	O
105	O
groups	O
of	O
14	O
organisms	O
.	O

Among	O
these	O
groups	O
,	O
as	O
expected	O
,	O
Vibrionaceae	O
are	O
highly	O
represented	O
.	O

Other	O
species	O
represented	O
are	O
Colwellia	B
psychrerythraea	I
34H	I
and	O
Shewanella	B
oneidensis	I
,	O
that	O
belong	O
to	O
the	O
Alteromonadales	O
family	O
.	O

The	O
cluster	O
analysis	O
performed	O
on	O
genes	O
is	O
shown	O
in	O
Fig	O
.	O

3	O
.	O

From	O
now	O
on	O
,	O
to	O
avoid	O
confusing	O
interpretation	O
between	O
clusters	O
derived	O
from	O
the	O
cluster	O
analysis	O
and	O
cluster	O
derived	O
from	O
the	O
ORFs	O
clustering	O
we	O
will	O
use	O
the	O
term	O
"	O
gene	O
"	O
in	O
place	O
of	O
cluster	O
of	O
ORFs	O
.	O

The	O
different	O
gradient	O
of	O
color	O
,	O
from	O
bright	O
to	O
dark	O
red	O
,	O
represents	O
decreasing	O
similarity	O
values	O
.	O

The	O
cluster	O
analysis	O
allows	O
the	O
detection	O
of	O
three	O
main	O
groups	O
of	O
genes	O
.	O

The	O
first	O
one	O
(	O
Fig	O
3	O
,	O
panel	O
B	O
)	O
contains	O
the	O
most	O
conserved	O
and	O
established	O
genes	O
shared	O
almost	O
by	O
all	O
the	O
organisms	O
.	O

These	O
core	O
genes	O
can	O
be	O
defined	O
as	O
the	O
set	O
of	O
all	O
genes	O
shared	O
as	O
orthologous	O
by	O
all	O
members	O
of	O
an	O
evolutionary	O
coherent	O
group	O
.	O

In	O
our	O
analysis	O
we	O
identify	O
four	O
clusters	O
,	O
for	O
a	O
total	O
of	O
145	O
genes	O
,	O
shared	O
by	O
all	O
the	O
320	O
organisms	O
.	O

The	O
ORFs	O
belonging	O
to	O
these	O
clusters	O
are	O
predicted	O
to	O
codify	O
for	O
the	O
ATP	O
binding	O
subunit	O
of	O
ABC	O
transporters	O
(	O
annotated	O
as	O
ABC	O
-	O
type	O
polar	O
amino	O
acid	O
transport	O
system	O
,	O
ABC	O
-	O
type	O
antimicrobial	O
peptide	O
transport	O
system	O
,	O
ABC	O
-	O
type	O
histidine	O
transport	O
system	O
and	O
ABC	O
-	O
type	O
transport	O
system	O
involved	O
in	O
lysophospholipase	O
L1	O
biosynthesis	O
)	O
.	O

This	O
finding	O
is	O
surprising	O
since	O
this	O
is	O
the	O
first	O
report	O
where	O
these	O
ORFs	O
are	O
assigned	O
to	O
the	O
core	O
genes	O
.	O

Anyway	O
two	O
different	O
explanations	O
can	O
be	O
traced	O
.	O

First	O
,	O
it	O
is	O
known	O
that	O
the	O
ABC	O
transporters	O
represent	O
an	O
essential	O
transport	O
system	O
in	O
the	O
prokaryotes	O
and	O
that	O
their	O
ATP	O
binding	O
subunits	O
are	O
apparently	O
overrepresented	O
compared	O
to	O
the	O
other	O
two	O
subunits	O
(	O
ligand	O
binding	O
and	O
permease	O
subunit	O
)	O
in	O
all	O
genomes	O
sequenced	O
thus	O
far	O
[	O
7	O
]	O
.	O

Second	O
,	O
one	O
organism	O
,	O
Buchnera	B
aphidicola	I
,	O
presents	O
these	O
genes	O
with	O
a	O
similarity	O
just	O
below	O
the	O
cut	O
-	O
off	O
used	O
for	O
the	O
analysis	O
,	O
but	O
they	O
have	O
been	O
considered	O
since	O
it	O
is	O
well	O
known	O
that	O
in	O
this	O
mutualistic	O
endosymbiont	O
the	O
accelerated	O
evolution	O
and	O
AT	O
bias	O
affect	O
all	O
its	O
genes	O
,	O
including	O
the	O
16S	O
rRNA	O
[	O
8	O
,	O
9	O
]	O
.	O

The	O
dataset	O
used	O
for	O
the	O
analysis	O
includes	O
genomes	O
in	O
draft	O
quality	O
(	O
Vibrio	B
cholerae	I
0395	I
,	O
Vibrio	B
cholerae	I
MO10	I
,	O
Vibrio	B
cholerae	I
RC385	I
,	O
Vibrio	B
cholerae	I
V51	I
,	O
Vibrio	B
cholerae	I
V52	I
,	O
Photobacterium	B
profundum	I
3TCK	I
,	O
Vibrio	B
MED222	I
,	O
Vibrio	B
splendidus12B01	I
)	O
.	O

Wrong	O
ORFs	O
prediction	O
or	O
missing	O
genes	O
due	O
to	O
incomplete	O
genome	O
sequences	O
can	O
explain	O
the	O
low	O
number	O
of	O
core	O
genes	O
identified	O
.	O

To	O
avoid	O
such	O
problems	O
we	O
repeated	O
the	O
analysis	O
excluding	O
the	O
draft	O
genomes	O
and	O
thus	O
considering	O
312	O
genomes	O
.	O

The	O
results	O
,	O
reported	O
in	O
Table	O
2	O
,	O
show	O
an	O
increased	O
number	O
of	O
the	O
core	O
genes	O
and	O
in	O
particular	O
ribosomal	O
proteins	O
and	O
tRNA	O
synthetase	O
,	O
as	O
reported	O
by	O
Charlesbois	O
and	O
Doolittle	O
[	O
10	O
]	O
.	O

This	O
could	O
be	O
considered	O
as	O
a	O
sort	O
of	O
"	O
minimal	O
genome	O
"	O
containing	O
the	O
group	O
of	O
genes	O
that	O
are	O
necessary	O
to	O
maintain	O
a	O
free	O
-	O
living	O
organism	O
.	O

The	O
low	O
number	O
of	O
genes	O
shared	O
by	O
all	O
the	O
organisms	O
can	O
be	O
due	O
to	O
many	O
factors	O
.	O

First	O
of	O
all	O
we	O
used	O
the	O
Vibrionaceae	O
ORFs	O
as	O
a	O
reference	O
,	O
limiting	O
the	O
number	O
of	O
genes	O
we	O
were	O
able	O
to	O
identify	O
.	O

It	O
was	O
further	O
demonstrated	O
that	O
the	O
core	O
gene	O
size	O
decreases	O
as	O
more	O
genome	O
sequences	O
are	O
analyzed	O
[	O
10	O
]	O
.	O

Genes	O
that	O
are	O
considered	O
to	O
belong	O
to	O
the	O
core	O
set	O
when	O
close	O
organisms	O
are	O
compared	O
,	O
are	O
classified	O
as	O
flexible	O
genes	O
when	O
distantly	O
related	O
genomes	O
are	O
analyzed	O
[	O
6	O
]	O
.	O

Finally	O
,	O
genes	O
within	O
core	O
genomes	O
might	O
be	O
transferred	O
or	O
replaced	O
,	O
introducing	O
new	O
versions	O
of	O
existing	O
genes	O
into	O
genomes	O
.	O

Such	O
transfers	O
can	O
replace	O
even	O
highly	O
conserved	O
genes	O
by	O
non	O
-	O
homologous	O
counterparts	O
but	O
the	O
advantages	O
provided	O
are	O
difficult	O
to	O
explain	O
.	O

It	O
is	O
also	O
to	O
take	O
into	O
consideration	O
that	O
many	O
symbiotic	O
and	O
parasitic	O
bacteria	O
undergo	O
a	O
reduction	O
of	O
their	O
genomes	O
,	O
loosing	O
many	O
genes	O
required	O
by	O
free	O
-	O
living	O
cell	O
.	O

The	O
second	O
group	O
(	O
Fig	O
3	O
,	O
panel	O
C	O
)	O
represents	O
genes	O
shared	O
mainly	O
among	O
Vibrionaceae	O
and	O
other	O
gamma	O
proteobacteria	O
(	O
as	O
Altermonadales	O
,	O
Burkholderiales	O
and	O
Enterobactidiales	O
)	O
.	O

Finally	O
,	O
the	O
third	O
group	O
(	O
Fig	O
.	O
3	O
,	O
panel	O
D	O
)	O
is	O
composed	O
by	O
genes	O
that	O
are	O
mainly	O
specific	O
to	O
the	O
Vibrionaceae	O
.	O

k	O
-	O
mean	O
cluster	O
analysis	O
and	O
cluster	O
enrichment	O

We	O
performed	O
a	O
k	O
-	O
means	O
cluster	O
analysis	O
,	O
setting	O
the	O
k	O
value	O
to	O
14	O
.	O

As	O
shown	O
in	O
Fig	O
.	O

4	O
,	O
the	O
clusters	O
3	O
,	O
4	O
,	O
11	O
,	O
13	O
and	O
14	O
contain	O
the	O
higher	O
percentage	O
of	O
genes	O
,	O
accounting	O
for	O
more	O
that	O
50	O
%	O
of	O
the	O
total	O
genes	O
,	O
while	O
clusters	O
9	O
and	O
10	O
contain	O
the	O
lower	O
number	O
of	O
ORFs	O
(	O
3	O
%	O
of	O
genes	O
)	O
.	O

The	O
variance	O
in	O
each	O
k	O
-	O
means	O
cluster	O
is	O
very	O
low	O
(	O
Fig	O
.	O
4	O
)	O
,	O
meaning	O
that	O
the	O
clusters	O
contain	O
genes	O
with	O
compact	O
and	O
similar	O
profiles	O
.	O

As	O
described	O
in	O
Fig	O
.	O

4	O
,	O
the	O
majority	O
of	O
the	O
clusters	O
(	O
1	O
,	O
2	O
,	O
3	O
,	O
4	O
,	O
5	O
,	O
6	O
,	O
7	O
,	O
9	O
,	O
12	O
,	O
13	O
)	O
contains	O
genes	O
with	O
a	O
similar	O
profile	O
,	O
with	O
the	O
average	O
values	O
(	O
red	O
line	O
)	O
near	O
zero	O
,	O
except	O
for	O
the	O
presence	O
of	O
some	O
spikes	O
correspondent	O
to	O
an	O
increasing	O
similarity	O
with	O
some	O
isolated	O
organisms	O
.	O

As	O
shown	O
in	O
Table	O
3	O
,	O
clusters	O
1	O
,	O
3	O
,	O
4	O
,	O
5	O
,	O
and	O
9	O
contains	O
genes	O
that	O
have	O
a	O
high	O
similarity	O
in	O
a	O
small	O
subset	O
of	O
organisms	O
.	O

The	O
majority	O
of	O
these	O
ORFs	O
are	O
annotated	O
as	O
hypothetical	O
proteins	O
or	O
phage	O
related	O
proteins	O
.	O

Clusters	O
8	O
,	O
10	O
and	O
14	O
present	O
genes	O
shared	O
among	O
almost	O
all	O
the	O
organisms	O
.	O

In	O
particular	O
cluster	O
10	O
is	O
composed	O
by	O
the	O
core	O
genes	O
described	O
before	O
having	O
an	O
high	O
value	O
of	O
similarity	O
widespread	O
among	O
all	O
the	O
organisms	O
;	O
cluster	O
8	O
contains	O
genes	O
shared	O
mainly	O
by	O
gamma	O
proteobacteria	O
and	O
cluster	O
14	O
is	O
composed	O
of	O
genes	O
in	O
common	O
between	O
Vibrionaceae	O
and	O
Enterobacteriaceae	O
.	O

A	O
functional	O
annotation	O
has	O
been	O
performed	O
on	O
each	O
gene	O
cluster	O
using	O
COG	O
(	O
Cluster	O
of	O
Orthologous	O
Genes	O
)	O
,	O
KEGG	O
pathway	O
map	O
and	O
GO	O
databases	O
.	O

For	O
each	O
k	O
-	O
mean	O
cluster	O
the	O
enrichment	O
probability	O
with	O
respect	O
to	O
the	O
total	O
number	O
of	O
clusters	O
has	O
been	O
obtained	O
with	O
the	O
hypergeometric	O
distribution	O
.	O

Fig	O
.	O

5	O
shows	O
COG	O
enrichment	O
results	O
for	O
each	O
cluster	O
.	O

As	O
expected	O
clusters	O
represented	O
by	O
conserved	O
genes	O
(	O
cluster	O
8	O
,	O
10	O
and	O
14	O
)	O
have	O
the	O
higher	O
number	O
of	O
enriched	O
COG	O
codes	O
,	O
while	O
cluster	O
specific	O
of	O
few	O
organisms	O
are	O
characterized	O
by	O
a	O
small	O
number	O
of	O
enriched	O
COGs	O
.	O

The	O
majority	O
of	O
clusters	O
presents	O
COG	O
codes	O
enrichment	O
for	O
S	O
(	O
function	O
unknown	O
)	O
,	O
R	O
(	O
poorly	O
characterized	O
)	O
and	O
-	O
(	O
absence	O
of	O
COG	O
code	O
)	O
categories	O
.	O

This	O
is	O
due	O
to	O
the	O
large	O
abundance	O
of	O
unknown	O
and	O
hypothetical	O
proteins	O
presents	O
in	O
the	O
Vibrionaceae	O
proteomes	O
.	O

It	O
is	O
worth	O
noting	O
that	O
cluster	O
3	O
,	O
mainly	O
represented	O
by	O
Photobacterium	B
profundum	I
SS9	I
ORFs	O
,	O
is	O
enriched	O
only	O
by	O
C	O
(	O
Energy	O
production	O
and	O
conversion	O
)	O
,	O
L	O
(	O
DNA	O
replication	O
,	O
recombination	O
and	O
repair	O
)	O
and	O
M	O
(	O
Cell	O
envelope	O
biogenesis	O
,	O
outer	O
membrane	O
)	O
.	O

Probably	O
the	O
L	O
class	O
overrepresentation	O
is	O
determined	O
by	O
the	O
high	O
number	O
of	O
transposons	O
that	O
are	O
present	O
in	O
the	O
SS9	O
genome	O
[	O
11	O
]	O
.	O

The	O
role	O
played	O
by	O
these	O
transposable	O
elements	O
in	O
the	O
survival	O
of	O
this	O
deep	O
-	O
sea	O
bacterium	O
it	O
is	O
still	O
a	O
matter	O
of	O
debate	O
[	O
12	O
]	O
.	O

In	O
addition	O
V	B
.	I
vulnificus	I
YJ016	I
and	O
V	B
.	I
vulnificus	I
CMCP6	I
(	O
cluster	O
13	O
)	O
seem	O
to	O
share	O
genes	O
belonging	O
to	O
the	O
enriched	O
COG	O
classes	O
K	O
(	O
Transcription	O
)	O
,	O
L	O
and	O
T	O
(	O
Signal	O
transduction	O
mechanisms	O
)	O
.	O

It	O
was	O
previously	O
reported	O
an	O
enrichment	O
in	O
genes	O
belonging	O
to	O
the	O
transcription	O
class	O
in	O
the	O
genome	O
of	O
V	B
.	I
vulnificus	I
respect	O
to	O
the	O
V	B
.	I
cholerae	I
genome	O
[	O
13	O
]	O
.	O

This	O
class	O
is	O
clearly	O
related	O
to	O
the	O
T	O
class	O
and	O
seems	O
to	O
indicate	O
that	O
this	O
organism	O
is	O
able	O
to	O
receive	O
and	O
translate	O
in	O
a	O
transcriptional	O
response	O
specific	O
environmental	O
signals	O
.	O

Despite	O
this	O
,	O
the	O
large	O
majority	O
of	O
the	O
genes	O
in	O
clusters	O
3	O
and	O
13	O
lacks	O
COG	O
annotation	O
.	O

Cluster	O
7	O
,	O
as	O
shown	O
in	O
Table	O
3	O
,	O
accounts	O
organisms	O
with	O
large	O
genome	O
size	O
(	O
see	O
Table	O
1	O
)	O
.	O

This	O
can	O
explain	O
the	O
fact	O
the	O
this	O
cluster	O
contains	O
almost	O
all	O
the	O
COG	O
class	O
enriched	O
and	O
suggests	O
a	O
more	O
complex	O
and	O
flexible	O
life	O
-	O
style	O
of	O
these	O
organisms	O
compared	O
to	O
the	O
other	O
Vibrionaceae	O
members	O
.	O

KEGG	O
annotation	O
is	O
limited	O
to	O
metabolic	O
or	O
structural	O
complex	O
network	O
and	O
so	O
a	O
reduced	O
number	O
of	O
genes	O
have	O
a	O
KEGG	O
entry	O
.	O

This	O
causes	O
the	O
presence	O
of	O
clusters	O
without	O
enriched	O
map	O
(	O
cluster	O
2	O
-	O
5	O
,	O
7	O
,	O
13	O
,	O
see	O
Fig	O
5	O
)	O
.	O

Also	O
in	O
this	O
case	O
,	O
the	O
clusters	O
presenting	O
the	O
higher	O
number	O
of	O
significant	O
KEGG	O
map	O
are	O
those	O
containing	O
the	O
conserved	O
genes	O
.	O

The	O
most	O
enriched	O
KEGG	O
clusters	O
are	O
cluster	O
14	O
,	O
10	O
and	O
8	O
accounting	O
for	O
the	O
majority	O
of	O
the	O
metabolic	O
pathways	O
.	O

Cluster	O
1	O
is	O
enriched	O
for	O
map3080	O
(	O
type	O
IV	O
secretion	O
system	O
)	O
.	O

In	O
fact	O
V	B
.	I
fischeri	I
genome	O
contains	O
10	O
separate	O
pilus	O
gene	O
clusters	O
,	O
including	O
eight	O
type	O
-	O
IV	O
pilus	O
loci	O
.	O

The	O
presence	O
of	O
multiple	O
pilus	O
gene	O
clusters	O
suggests	O
that	O
different	O
pili	O
may	O
be	O
expressed	O
in	O
different	O
environments	O
or	O
during	O
multiple	O
stages	O
of	O
its	O
development	O
as	O
a	O
symbiont	O
[	O
14	O
]	O
.	O

Cluster	O
11	O
is	O
enriched	O
for	O
map3090	O
(	O
type	O
II	O
secretion	O
system	O
)	O
.	O

The	O
type	O
II	O
pathway	O
is	O
conserved	O
among	O
gram	O
-	O
negative	O
bacteria	O
,	O
including	O
many	O
pathogens	O
,	O
and	O
secretes	O
a	O
variety	O
of	O
virulence	O
factors	O
and	O
degradative	O
enzymes	O
[	O
15	O
]	O
.	O

Cluster	O
9	O
is	O
enriched	O
for	O
map	O
00860	O
(	O
Porphyrin	O
and	O
chlorophyll	O
metabolism	O
)	O
.	O

These	O
genes	O
are	O
involved	O
in	O
the	O
cobalamin	O
(	O
coenzyme	O
B12	O
)	O
biosynthetic	O
pathway	O
[	O
16	O
]	O
.	O

Some	O
organisms	O
,	O
such	O
as	O
Salmonella	B
typhimurium	I
and	O
Klebsiella	B
pneumoniae	I
,	O
can	O
synthesize	O
cobalamin	O
de	O
novo	O
[	O
17	O
]	O
,	O
while	O
E	B
.	I
coli	I
and	O
large	O
part	O
of	O
the	O
Vibrionaceae	O
perform	O
cobalamin	O
biosynthesis	O
only	O
when	O
provided	O
with	O
cobinamide	O
.	O

It	O
is	O
interesting	O
to	O
observe	O
that	O
the	O
genes	O
belonging	O
to	O
the	O
de	O
novo	O
pathway	O
are	O
only	O
shared	O
by	O
Archea	O
,	O
some	O
other	O
organisms	O
like	O
Salmonella	O
,	O
Pseudomonas	O
and	O
Vibrio	B
MED222	I
.	O

Finally	O
cluster	O
6	O
is	O
enriched	O
by	O
map2010	O
(	O
ABC	O
transporter	O
)	O
,	O
map2020	O
(	O
two	O
-	O
component	O
system	O
)	O
,	O
map2030	O
and	O
map2031	O
(	O
bacterial	O
chemotaxis	O
)	O
,	O
map2040	O
(	O
Flagellar	O
assembly	O
)	O
and	O
map3090	O
(	O
type	O
II	O
secretion	O
system	O
)	O
.	O

This	O
cluster	O
contains	O
genes	O
shared	O
with	O
a	O
high	O
similarity	O
by	O
all	O
Vibrio	O
and	O
with	O
a	O
lower	O
similarity	O
with	O
Photobacterium	B
profundum	I
species	O
.	O

Among	O
the	O
Vibrio	O
species	O
the	O
organisms	O
showing	O
the	O
highest	O
similarity	O
(	O
Tab	O
.	O
3	O
)	O
are	O
V	B
.	I
cholerae	I
strains	O
.	O

Vibrionaceae	O
specific	O
genes	O

We	O
identify	O
1940	O
clusters	O
specific	O
to	O
the	O
Vibrionaceae	O
.	O

All	O
the	O
Vibrionaceae	O
considered	O
in	O
the	O
analysis	O
share	O
108	O
clusters	O
.	O

Among	O
these	O
genes	O
we	O
identify	O
ToxR	O
and	O
ToxS	O
genes	O
.	O

ToxR	O
gene	O
encodes	O
a	O
transmembrane	O
regulatory	O
protein	O
firstly	O
identified	O
in	O
V	B
.	I
cholerae	I
,	O
in	O
which	O
it	O
co	O
-	O
ordinates	O
many	O
virulence	O
factors	O
in	O
response	O
to	O
several	O
environmental	O
parameters	O
[	O
18	O
]	O
.	O

V	B
.	I
cholerae	I
ToxR	O
activity	O
is	O
enhanced	O
by	O
a	O
second	O
transmembrane	O
protein	O
,	O
ToxS	O
,	O
encoded	O
downstream	O
toxR	O
[	O
19	O
]	O
.	O

This	O
family	O
of	O
proteins	O
is	O
involved	O
in	O
response	O
to	O
temperature	O
,	O
pH	O
,	O
osmolarity	O
and	O
in	O
Photobacterium	B
profundum	I
SS9	I
,	O
a	O
piezophilic	O
bacterium	O
,	O
to	O
hydrostatic	O
pressure	O
[	O
20	O
]	O
.	O

The	O
widespread	O
presence	O
of	O
these	O
genes	O
among	O
the	O
Vibrionaceae	O
suggests	O
their	O
importance	O
in	O
regulatory	O
mechanisms	O
.	O

We	O
identify	O
two	O
other	O
noteworthy	O
groups	O
of	O
genes	O
composed	O
by	O
257	O
and	O
160	O
genes	O
respectively	O
shared	O
just	O
by	O
two	O
strains	O
,	O
mainly	O
annotated	O
as	O
"	O
hypothetical	O
protein	O
"	O
.	O

The	O
first	O
group	O
of	O
genes	O
is	O
shared	O
between	O
Photobacterium	B
profundum	I
SS9	I
and	O
Photobacterium	B
profundum	I
3TCK	I
,	O
while	O
the	O
second	O
is	O
shared	O
between	O
V	B
.	I
vulnificus	I
CMCP6	I
and	O
YJ016	B
.	O

These	O
strains	O
are	O
closely	O
related	O
and	O
this	O
explains	O
the	O
high	O
number	O
of	O
shared	O
genes	O
;	O
while	O
,	O
inside	O
the	O
Vibrionaceae	O
family	O
,	O
the	O
number	O
of	O
specific	O
shared	O
genes	O
highly	O
decreases	O
,	O
showing	O
a	O
high	O
inter	O
-	O
species	O
variability	O
(	O
Fig	O
.	O
6	O
)	O

Prophages	O
and	O
transposases	O

Prophages	O
recover	O
different	O
biological	O
roles	O
both	O
as	O
quantitatively	O
important	O
genetic	O
elements	O
of	O
the	O
bacterial	O
chromosome	O
,	O
and	O
as	O
vectors	O
of	O
lateral	O
gene	O
transfer	O
among	O
bacteria	O
,	O
due	O
to	O
their	O
characters	O
of	O
mobile	O
DNA	O
elements	O
.	O

Indeed	O
,	O
numerous	O
virulence	O
factors	O
from	O
bacterial	O
pathogens	O
are	O
phage	O
encoded	O
.	O

It	O
was	O
postulated	O
that	O
this	O
role	O
of	O
prophages	O
is	O
not	O
limited	O
to	O
pathogenic	O
bacteria	O
but	O
some	O
adaptations	O
of	O
nonpathogenic	O
strains	O
to	O
their	O
ecological	O
niche	O
might	O
also	O
be	O
mediated	O
by	O
prophages	O
acquisition	O
[	O
21	O
]	O
.	O

To	O
better	O
understand	O
the	O
importance	O
of	O
mobile	O
elements	O
within	O
Vibrionaceae	O
family	O
,	O
we	O
performed	O
a	O
hierarchical	O
cluster	O
analysis	O
using	O
gene	O
profiles	O
annotated	O
as	O
"	O
phage	O
protein	O
"	O
and	O
"	O
transposase	O
"	O
,	O
for	O
a	O
total	O
of	O
172	O
clusters	O
of	O
genes	O
(	O
Fig	O
7	O
)	O
.	O

We	O
found	O
that	O
a	O
high	O
inter	O
-	O
strain	O
genetic	O
variability	O
exists	O
and	O
phages	O
and	O
transposases	O
are	O
both	O
shared	O
by	O
almost	O
all	O
Vibrionaceae	O
,	O
and	O
specific	O
to	O
just	O
some	O
organisms	O
.	O

We	O
identified	O
five	O
major	O
clusters	O
of	O
mobile	O
elements	O
that	O
are	O
specific	O
to	O
a	O
single	O
organism	O
.	O

A	O
group	O
composed	O
by	O
26	O
clusters	O
containing	O
both	O
transposase	O
and	O
phage	O
proteins	O
seem	O
to	O
be	O
unique	O
to	O
V	B
.	I
splendiduds	I
12B01	I
(	O
Fig	O
7	O
)	O
.	O

Another	O
one	O
composed	O
by	O
16	O
clusters	O
is	O
specific	O
of	O
V	B
.	I
vulnificus	I
CMCP6	I
(	O
Fig	O
7	O
)	O
while	O
V	B
.	I
parahaemoliticus	I
has	O
a	O
cluster	O
of	O
11	O
genes	O
(	O
Fig	O
7	O
)	O
.	O

Moreover	O
there	O
is	O
another	O
group	O
of	O
transposases	O
and	O
phage	O
genes	O
shared	O
mainly	O
by	O
V	B
.	I
cholerae	I
0395	O
,	O
Shewanella	B
oneidensis	I
and	O
V	B
.	I
cholerae	I
V51	O
(	O
Fig	O
7	O
)	O
.	O

Finally	O
a	O
big	O
cluster	O
of	O
almost	O
30	O
genes	O
,	O
all	O
predicted	O
to	O
codify	O
for	O
transposases	O
,	O
was	O
found	O
in	O
P	B
.	I
profundum	I
SS9	I
genome	O
(	O
Fig	O
.	O
7	O
)	O
.	O

The	O
high	O
presence	O
of	O
transposases	O
in	O
this	O
bacterium	O
seems	O
to	O
correlate	O
with	O
its	O
deep	O
-	O
sea	O
habitat	O
,	O
a	O
feature	O
presumably	O
shared	O
with	O
other	O
deep	O
-	O
sea	O
microorganisms	O
[	O
12	O
]	O
.	O

As	O
shown	O
in	O
Fig	O
7	O
,	O
many	O
of	O
the	O
clusters	O
well	O
conserved	O
in	O
an	O
organism	O
,	O
are	O
partially	O
shared	O
with	O
a	O
low	O
similarity	O
by	O
other	O
organisms	O
.	O

This	O
agrees	O
with	O
the	O
idea	O
that	O
prophages	O
are	O
not	O
maintained	O
in	O
the	O
genome	O
over	O
a	O
long	O
period	O
of	O
time	O
and	O
part	O
of	O
their	O
genes	O
may	O
be	O
deleted	O
from	O
the	O
chromosome	O
.	O

Moreover	O
,	O
microarray	O
analysis	O
and	O
PCR	O
scanning	O
demonstrated	O
that	O
prophages	O
are	O
frequently	O
strain	O
specific	O
within	O
a	O
given	O
bacterial	O
species	O
[	O
22	O
-	O
24	O
]	O
.	O

According	O
to	O
the	O
modular	O
theory	O
of	O
phage	O
evolution	O
,	O
phage	O
genomes	O
are	O
mosaics	O
of	O
modules	O
,	O
groups	O
of	O
genes	O
functionally	O
related	O
,	O
that	O
are	O
free	O
to	O
recombine	O
in	O
genetic	O
exchanges	O
between	O
distinct	O
phages	O
infecting	O
the	O
same	O
cell	O
[	O
21	O
]	O
.	O

This	O
can	O
result	O
in	O
the	O
occurrences	O
of	O
different	O
part	O
of	O
phage	O
distributed	O
in	O
far	O
related	O
genomes	O
.	O

Phylogenetic	O
profile	O
of	O
some	O
transposases	O
is	O
similar	O
to	O
the	O
phage	O
ones	O
,	O
suggesting	O
a	O
possible	O
transfer	O
mechanism	O
phage	O
-	O
mediated	O
for	O
such	O
mobile	O
elements	O
.	O

Conclusion	O

In	O
this	O
work	O
we	O
propose	O
an	O
improved	O
phylogenetic	O
profile	O
analysis	O
on	O
14	O
Vibrionaceae	O
genomes	O
,	O
to	O
study	O
this	O
family	O
on	O
the	O
basis	O
of	O
gene	O
content	O
.	O

Using	O
a	O
phylogenetic	O
profile	O
for	O
each	O
cluster	O
of	O
genes	O
defined	O
as	O
the	O
median	O
of	O
all	O
the	O
profiles	O
belonging	O
to	O
the	O
cluster	O
(	O
meta	O
-	O
profile	O
)	O
we	O
investigate	O
the	O
evolution	O
of	O
groups	O
of	O
ORFs	O
belonging	O
to	O
the	O
entire	O
family	O
.	O

A	O
two	O
-	O
way	O
cluster	O
analysis	O
allows	O
us	O
to	O
identify	O
similarity	O
structures	O
on	O
the	O
entire	O
phylogenetic	O
matrix	O
composed	O
by	O
8	O
,	O
239	O
clusters	O
of	O
genes	O
and	O
320	O
organisms	O
.	O

The	O
phylogenetic	O
tree	O
obtained	O
with	O
the	O
cluster	O
analysis	O
does	O
not	O
reflect	O
the	O
global	O
evolutionary	O
tree	O
because	O
of	O
the	O
Vibrionaceae	O
ORFs	O
dataset	O
used	O
for	O
the	O
analysis	O
,	O
but	O
rather	O
can	O
be	O
considered	O
as	O
the	O
Vibrionaceae	O
perspective	O
of	O
bacterial	O
diversity	O
.	O

The	O
phylogenetic	O
tree	O
reflects	O
the	O
evolutionary	O
processes	O
that	O
shape	O
genomes	O
,	O
as	O
lateral	O
gene	O
transfer	O
,	O
genes	O
genesis	O
and	O
loss	O
.	O

In	O
this	O
context	O
,	O
the	O
tree	O
allows	O
to	O
group	O
together	O
genomes	O
on	O
the	O
base	O
of	O
their	O
global	O
gene	O
content	O
.	O

We	O
found	O
that	O
genomes	O
belonging	O
to	O
the	O
same	O
taxonomic	O
group	O
tend	O
to	O
cluster	O
together	O
and	O
that	O
Vibrionaceae	O
species	O
are	O
closely	O
related	O
.	O

Moreover	O
organisms	O
belonging	O
to	O
the	O
same	O
or	O
closely	O
related	O
taxa	O
split	O
into	O
different	O
subgroups	O
,	O
confirming	O
the	O
existence	O
of	O
a	O
high	O
variability	O
among	O
lineages	O
,	O
due	O
to	O
genetic	O
and	O
evolutionary	O
process	O
such	O
as	O
lateral	O
gene	O
transfer	O
,	O
concerted	O
evolution	O
and	O
genes	O
duplication	O
.	O

On	O
the	O
other	O
hand	O
several	O
groups	O
of	O
genes	O
characterised	O
by	O
different	O
homogeneous	O
profiles	O
have	O
been	O
identified	O
.	O

In	O
particular	O
we	O
found	O
,	O
1	O
)	O
a	O
set	O
of	O
conserved	O
genes	O
(	O
with	O
a	O
high	O
similarity	O
values	O
across	O
all	O
organisms	O
)	O
that	O
reflects	O
the	O
"	O
minimal	O
genome	O
"	O
composition	O
defined	O
in	O
other	O
previous	O
works	O
;	O
2	O
)	O
a	O
set	O
of	O
genes	O
mainly	O
shared	O
by	O
Vibrionaceae	O
and	O
other	O
Gamma	O
proteobacteria	O
and	O
3	O
)	O
genes	O
specific	O
to	O
different	O
sets	O
of	O
Vibrionaceae	O
.	O

Finally	O
a	O
further	O
analysis	O
on	O
prophage	O
and	O
transposase	O
has	O
confirmed	O
the	O
high	O
inter	O
-	O
strain	O
genetic	O
variability	O
even	O
among	O
closely	O
related	O
species	O
.	O

The	O
increasing	O
number	O
of	O
genomes	O
included	O
in	O
this	O
type	O
of	O
analysis	O
surely	O
add	O
new	O
sorces	O
of	O
variability	O
and	O
noise	O
,	O
anyway	O
we	O
think	O
that	O
the	O
use	O
of	O
meta	O
-	O
profiles	O
can	O
be	O
useful	O
for	O
complexity	O
reduction	O
and	O
data	O
analysis	O
to	O
study	O
global	O
gene	O
evolution	O
.	O

Methods	O

Datasets	O

The	O
Vibrionaceae	O
species	O
used	O
in	O
this	O
analysis	O
were	O
selected	O
among	O
the	O
freely	O
available	O
complete	O
and	O
draft	O
genome	O
sequences	O
.	O

The	O
proteomes	O
of	O
V	B
.	I
cholerae	I
N16961	I
,	O
V	B
.	I
parahaemolyticus	I
,	O
V	B
.	I
vulnificus	I
YJ016	I
,	O
V	B
.	I
vulnificus	I
CMCP6	I
,	O
V	B
.	I
fischeri	I
ES114	I
,	O
Photobacterium	B
profundum	I
SS9	I
were	O
downloaded	O
from	O
the	O
NCBI	O
ftp	O
site	O
[	O
25	O
]	O
.	O

Protein	O
sequences	O
of	O
Vibrio	B
cholerae	I
MO10	I
,	O
Vibrio	B
cholerae	I
0395	I
,	O
Vibrio	B
cholerae	I
RC385	I
,	O
Vibrio	B
cholerae	I
V51	I
,	O
Vibrio	B
cholerae	I
V52	I
were	O
downloaded	O
from	O
the	O
NCBI	O
genome	O
database	O
,	O
while	O
sequences	O
of	O
Vibrio	B
MED222	I
,	O
Vibrio	B
splendidus	I
12B01	I
,	O
Photobacterium	B
profundum	I
3TCK	I
from	O
the	O
J	O
.	O

Craig	O
Venter	O
Institute	O
web	O
site	O
.	O

The	O
320	O
complete	O
genomes	O
update	O
at	O
03	O
/	O
06	O
were	O
downloaded	O
from	O
the	O
NCBI	O
ftp	O
site	O
.	O

Similarity	O
search	O
and	O
phylogenetic	O
profile	O
construction	O

All	O
the	O
Vibrionaceae	O
ORFs	O
were	O
merged	O
generating	O
a	O
redundant	O
list	O
of	O
59	O
,	O
669	O
proteins	O
and	O
were	O
compared	O
to	O
all	O
open	O
reading	O
frame	O
from	O
320	O
bacterial	O
and	O
archeal	O
genomes	O
using	O
Blastp	O
.	O

To	O
determine	O
the	O
presence	O
of	O
an	O
orthologous	O
we	O
used	O
a	O
combination	O
of	O
three	O
different	O
thresholds	O
;	O
a	O
similarity	O
value	O
equal	O
to	O
or	O
higher	O
than	O
30	O
%	O
,	O
an	O
alignment	O
length	O
equal	O
or	O
higher	O
than	O
70	O
%	O
and	O
an	O
Evalue	O
score	O
lower	O
than	O
or	O
equal	O
to	O
e	O
-	O
6	O
.	O

After	O
determining	O
the	O
presence	O
of	O
an	O
orthologous	O
gene	O
,	O
we	O
computed	O
a	O
similarity	O
index	O
I	O
for	O
each	O
pair	O
of	O
orthologous	O
(	O
a	O
point	O
of	O
the	O
phylogenetic	O
profile	O
)	O
as	O
follow	O
:	O

I	O
=	O
SqsSqq	O
.	O
min	O
(	O
lq	O
,	O
ls	O
)	O
max	O
(	O
lq	O
,	O
ls	O
)	O

MathType	O
@	O
MTEF	O
@	O
5	O
@	O
5	O
@	O
+	O
=	O
feaafiart1ev1aaatCvA	O
=	O
wiFfYdH8Gipec8Eeeu0x	O
=	O
OqFfea0dXdd9vqai	O
=	O
hGuQ8kuc9pgc9s8qqaq	O
=	O
dirpe0xb9q8qiLsFr0	O
=	O
vr0	O
=	O
vr0dc8meaabaqaciaaca	O
@	O
532D	O
@	O

where	O
lq	O
and	O
ls	O
are	O
the	O
query	O
and	O
subject	O
length	O
sequence	O
respectively	O
and	O
Sqs	O
is	O
the	O
similarity	O
score	O
between	O
the	O
query	O
and	O
the	O
subject	O
sequence	O
.	O

Sqs	O
is	O
defined	O
as	O
follow	O
:	O

Sqs	O
=	O
sum	O
i	O
=	O
1M	O
alpha	O
Aqi	O
,	O
Asi	O
+	O
GP	O

MathType	O
@	O
MTEF	O
@	O
5	O
@	O
5	O
@	O
+	O
=	O
feaafiart1ev1aaatCvA	O
=	O
wiFfYdH8Gipec8Eeeu0x	O
=	O
OqFfea0dXdd9vqai	O
=	O
hGuQ8kuc9pgc9s8qqaq	O
=	O
dirpe0xb9q8qiLsFr0	O
=	O
vr0	O
=	O
vr0dc8meaabaqaciaaca	O
@	O
4620	O
@	O

where	O
M	O
is	O
the	O
match	O
length	O
between	O
the	O
query	O
and	O
subject	O
sequence	O
;	O
Aqi	O
and	O
Asi	O
respectively	O
the	O
query	O
and	O
subject	O
amino	O
acid	O
in	O
position	O
i	O
;	O
alpha	O
the	O
BLOSUM	O
substitution	O
matrix	O
value	O
for	O
amino	O
acid	O
pair	O
Aqi	O
,	O
Asi	O
and	O
GP	O
the	O
gap	O
penalty	O
.	O

GP	O
is	O
defined	O
as	O
follow	O
:	O

GP	O
=	O
GOP	O
+	O
GEP	O
(	O
k	O
-	O
1	O
)	O

where	O
GOP	O
is	O
the	O
Gap	O
Open	O
Penalty	O
set	O
to	O
-	O
11	O
,	O
GEP	O
the	O
Gap	O
Extension	O
Penalty	O
set	O
to	O
-	O
1	O
and	O
k	O
the	O
gap	O
length	O
.	O

Sqq	O
represents	O
the	O
score	O
of	O
the	O
self	O
-	O
aligned	O
query	O
sequence	O
.	O

Sqs	O
is	O
always	O
smaller	O
than	O
Sqq	O
and	O
the	O
score	O
S	O
range	O
between	O
0	O
and	O
1	O
.	O

In	O
order	O
to	O
take	O
into	O
account	O
also	O
the	O
different	O
sequence	O
lengths	O
,	O
we	O
multiplied	O
the	O
score	O
S	O
by	O
the	O
ratio	O
between	O
the	O
minimum	O
length	O
between	O
query	O
and	O
subject	O
and	O
the	O
maximum	O
length	O
between	O
query	O
and	O
subjects	O
.	O

In	O
this	O
way	O
the	O
total	O
score	O
is	O
weighted	O
on	O
the	O
base	O
of	O
the	O
length	O
,	O
resulting	O
in	O
a	O
lower	O
similarity	O
value	O
if	O
the	O
lengths	O
of	O
the	O
sequences	O
are	O
different	O
.	O

The	O
phylogenetic	O
profile	O
for	O
each	O
ORF	O
is	O
an	O
array	O
of	O
index	O
I	O
with	O
length	O
equal	O
to	O
the	O
number	O
of	O
genomes	O
considered	O
(	O
320	O
)	O
.	O

ORFs	O
clustering	O

The	O
redundant	O
list	O
of	O
59	O
,	O
669	O
Vibrionaceae	O
ORFs	O
contained	O
multiple	O
copies	O
of	O
the	O
same	O
genes	O
due	O
to	O
the	O
presence	O
of	O
conserved	O
genes	O
in	O
the	O
considered	O
genomes	O
.	O

In	O
order	O
to	O
reduce	O
the	O
redundancy	O
,	O
we	O
clustered	O
proteins	O
using	O
a	O
two	O
-	O
step	O
approach	O
.	O

The	O
first	O
step	O
is	O
based	O
on	O
COG	O
(	O
Cluster	O
of	O
Othologous	O
Genes	O
)	O
annotation	O
.	O

COG	O
classifies	O
conserved	O
genes	O
according	O
to	O
their	O
homologous	O
relationships	O
.	O

All	O
the	O
Vibrionaceae	O
ORFs	O
were	O
annotated	O
using	O
COG	O
clusters	O
and	O
proteins	O
sharing	O
the	O
same	O
COG	O
code	O
were	O
considered	O
belonging	O
to	O
the	O
same	O
cluster	O
.	O

In	O
particular	O
,	O
the	O
annotation	O
process	O
consists	O
of	O
a	O
similarity	O
search	O
of	O
all	O
the	O
ORFs	O
against	O
the	O
COG	O
proteins	O
using	O
blast	O
and	O
considering	O
the	O
best	O
hit	O
for	O
each	O
protein	O
.	O

43	O
,	O
024	O
ORFs	O
presented	O
a	O
similarity	O
with	O
a	O
COG	O
entry	O
,	O
producing	O
2	O
,	O
463	O
different	O
clusters	O
.	O

In	O
the	O
second	O
step	O
,	O
the	O
remaining	O
16	O
,	O
645	O
ORFs	O
without	O
similarity	O
with	O
any	O
COG	O
entry	O
were	O
clustered	O
using	O
CD	O
-	O
HIT	O
software	O
[	O
26	O
]	O
.	O

CD	O
-	O
HIT	O
program	O
clusters	O
protein	O
sequence	O
database	O
at	O
high	O
sequence	O
identity	O
threshold	O
and	O
efficiently	O
removes	O
high	O
sequence	O
redundancy	O
.	O

This	O
last	O
clustering	O
process	O
produced	O
9	O
,	O
613	O
different	O
groups	O
of	O
similar	O
proteins	O
.	O

Finally	O
from	O
the	O
12	O
,	O
076	O
total	O
clusters	O
obtained	O
by	O
this	O
methodology	O
,	O
those	O
composed	O
by	O
ORFs	O
that	O
do	O
not	O
have	O
any	O
ortologous	O
genes	O
(	O
with	O
a	O
phylogenetic	O
profile	O
composed	O
by	O
an	O
array	O
with	O
all	O
zero	O
values	O
except	O
for	O
one	O
position	O
match	O
with	O
itself	O
)	O
were	O
eliminated	O
,	O
resulting	O
in	O
a	O
dataset	O
composed	O
by	O
8	O
,	O
239	O
distinct	O
clusters	O
.	O

The	O
final	O
phylogenetic	O
profile	O
for	O
each	O
cluster	O
(	O
meta	O
-	O
profile	O
)	O
was	O
defined	O
as	O
the	O
median	O
of	O
all	O
the	O
profiles	O
belonging	O
to	O
the	O
cluster	O
.	O

At	O
the	O
end	O
of	O
these	O
procedures	O
the	O
final	O
phylogenetic	O
matrix	O
was	O
composed	O
by	O
8	O
,	O
239	O
rows	O
(	O
cluster	O
of	O
genes	O
)	O
and	O
320	O
columns	O
(	O
organisms	O
)	O
.	O

In	O
each	O
cell	O
the	O
median	O
of	O
the	O
index	O
in	O
the	O
cluster	O
was	O
reported	O
.	O

Cluster	O
analysis	O

Several	O
clustering	O
techniques	O
have	O
been	O
used	O
to	O
identify	O
the	O
similarity	O
structure	O
underneath	O
our	O
data	O
.	O

A	O
k	O
-	O
means	O
and	O
a	O
two	O
-	O
way	O
hierarchical	O
cluster	O
analysis	O
with	O
Euclidean	O
distance	O
and	O
complete	O
linkage	O
were	O
performed	O
on	O
the	O
phylogenetic	O
matrix	O
.	O

The	O
goal	O
of	O
a	O
cluster	O
analysis	O
is	O
to	O
partition	O
the	O
elements	O
into	O
subsets	O
without	O
any	O
constrains	O
or	O
a	O
priori	O
information	O
,	O
so	O
that	O
two	O
criteria	O
are	O
satisfied	O
:	O
homogeneity	O
,	O
elements	O
inside	O
a	O
cluster	O
are	O
highly	O
similar	O
to	O
each	O
other	O
;	O
and	O
separation	O
,	O
elements	O
from	O
different	O
clusters	O
have	O
low	O
similarity	O
to	O
each	O
other	O
.	O

The	O
Figure	O
of	O
Merit	O
(	O
FOM	O
)	O
is	O
a	O
measure	O
of	O
fit	O
of	O
the	O
expression	O
patterns	O
for	O
the	O
clusters	O
produced	O
by	O
a	O
particular	O
algorithm	O
that	O
estimates	O
the	O
predictive	O
power	O
of	O
a	O
clustering	O
algorithm	O
.	O

It	O
is	O
computed	O
by	O
removing	O
each	O
sample	O
in	O
turn	O
from	O
the	O
data	O
set	O
,	O
clustering	O
genes	O
based	O
on	O
the	O
remaining	O
data	O
,	O
and	O
calculating	O
the	O
fit	O
of	O
the	O
withheld	O
sample	O
to	O
the	O
clustering	O
pattern	O
obtained	O
from	O
the	O
other	O
samples	O
.	O

On	O
our	O
data	O
FOM	O
analysis	O
identified	O
the	O
best	O
number	O
of	O
k	O
-	O
means	O
clusters	O
between	O
10	O
and	O
15	O
.	O

We	O
decided	O
to	O
set	O
k	O
(	O
in	O
the	O
k	O
-	O
means	O
analysis	O
)	O
equal	O
to	O
14	O
.	O

In	O
each	O
of	O
these	O
14	O
clusters	O
subsequent	O
hierarchical	O
cluster	O
analysis	O
was	O
performed	O
with	O
bootstrap	O
cluster	O
assessment	O
.	O

All	O
the	O
previous	O
analyses	O
were	O
performed	O
with	O
TMEV	O
software	O
[	O
27	O
]	O
,	O
freely	O
available	O
at	O
[	O
28	O
]	O
.	O

Enrichment	O
categories	O

Each	O
cluster	O
of	O
genes	O
has	O
been	O
annotated	O
according	O
to	O
COG	O
code	O
,	O
GO	O
terms	O
and	O
KEGG	O
pathway	O
maps	O
.	O

Class	O
enrichment	O
(	O
with	O
respect	O
to	O
the	O
entire	O
matrix	O
)	O
has	O
been	O
calculated	O
according	O
to	O
the	O
hypergeometric	O
distribution	O
that	O
was	O
used	O
to	O
obtain	O
the	O
chance	O
probability	O
of	O
observing	O
the	O
number	O
of	O
genes	O
annotated	O
with	O
a	O
particular	O
COG	O
,	O
GO	O
and	O
KEGG	O
category	O
among	O
the	O
selected	O
cluster	O
.	O

The	O
probability	O
P	O
of	O
observing	O
at	O
least	O
k	O
genes	O
of	O
a	O
functional	O
category	O
within	O
a	O
group	O
of	O
n	O
genes	O
is	O
given	O
by	O
:	O

P	O
=	O
sum	O
i	O
=	O
kn	O
(	O
fi	O
)	O
(	O
g	O
-	O
fn	O
-	O
i	O
)	O
(	O
gn	O
)	O

MathType	O
@	O
MTEF	O
@	O
5	O
@	O
5	O
@	O
+	O
=	O
feaafiart1ev1aaatCvA	O
=	O
wiFfYdH8Gipec8Eeeu0x	O
=	O
OqFfea0dXdd9vqai	O
=	O
hGuQ8kuc9pgc9s8qqaq	O
=	O
dirpe0xb9q8qiLsFr0	O
=	O
vr0	O
=	O
vr0dc8meaabaqaciaaca	O
@	O
47C6	O
@	O

where	O
f	O
is	O
the	O
total	O
number	O
of	O
genes	O
with	O
the	O
same	O
category	O
(	O
in	O
the	O
matrix	O
)	O
and	O
g	O
is	O
the	O
total	O
number	O
of	O
genes	O
in	O
our	O
matrix	O
.	O

A	O
secondary	O
structural	O
common	O
core	O
in	O
the	O
ribosomal	O
ITS2	O
(	O
internal	O
transcribed	O
spacer	O
)	O
of	O

Culexspecies	O
from	O
diverse	O
geographical	O
locations	O

Abstract	O

In	O
the	O
present	O
study	O
,	O
sequence	O
and	O
structural	O
analysis	O
of	O
ITS2	O
region	O
(	O
the	O
spacer	O
segment	O
between	O
5	O
.	O
8S	O
and	O
28S	O
rRNA	O
of	O

mature	O
rRNA	O
sequences	O
)	O
of	O
7	O
Culex	O
species	O
belonging	O
to	O
5	O
different	O
geographical	O
locations	O
was	O
carried	O
out	O
.	O

Alignment	O
of	O
the	O

ITS2	O
sequence	O
from	O
the	O
7	O
species	O
revealed	O
8	O
homologous	O
domains	O
.	O

Four	O
species	O
namely	O
C	B
.	I
vishnui	I
,	O
C	B
.	I
annulus	I
,	O
C	B
.	I
pipiens	I
,	O

C	B
.	I
quiquefasciatusshowe	I
high	O
sequence	O
(	O
98	O
-	O
100	O
%	O
)	O
and	O
RNA	O
secondary	O
structure	O
similarity	O
.	O

The	O
ITS2	O
similarity	O
among	O
different	O

species	O
is	O
high	O
despite	O
their	O
varying	O
geographical	O
locations	O
.	O

Several	O
common	O
features	O
of	O
secondary	O
structure	O
are	O
shared	O
among	O

these	O
species	O
,	O
with	O
some	O
of	O
them	O
supported	O
by	O
compensatory	O
changes	O
,	O
suggesting	O
the	O
significant	O
role	O
by	O
ITS2	O
as	O
an	O
RNA	O
domain	O

during	O
ribosome	O
biogenesis	O
.	O

Background	O

Culex	O
mosquito	O
species	O
have	O
been	O
described	O
from	O
a	O
wide	O
range	O
of	O
environments	O
and	O
are	O
involved	O
in	O
pathogen	O
transmission	O
from	O

human	B
to	O
reservoirs	O
and	O
vice	O
-	O
versa	O
.	O

[	O
1	O
]	O
Sequence	O
similarity	O
have	O
been	O

reported	O
for	O
ITS2	O
(	O
the	O
spacer	O
segments	O
between	O
5	O
.	O
8S	O
and	O
28S	O
rRNA	O
of	O
mature	O
rRNA	O
sequences	O
)	O
from	O
5	O
Culex	O
species	O
of	O
diverse	O

geographic	O
locations	O
.	O

[	O
3	O
-	O
4	O
-	O

5	O
-	O
9	O
-	O

20	O
]	O
The	O
ITS	O
spacers	O
are	O
versatile	O
as	O
genetic	O
markers	O
and	O
have	O
been	O
used	O
for	O
the	O
determination	O
of	O
taxonomic	O

classification	O
.	O

[	O
17	O
]	O
Recent	O
functional	O
analyses	O
performed	O
on	O
yeast	B
ribosomal	O

RNA	O
genes	O
clearly	O
show	O
that	O
the	O
structural	O
integrity	O
of	O
the	O
transcribed	O
spacer	O
regions	O
is	O
an	O
essential	O
prerequisite	O
for	O
the	O
correct	O

processing	O
of	O
mature	O
rRNA	O
and	O
for	O
the	O
biogenesis	O
of	O
active	O
ribosomal	O
subunits	O
.	O

[	O
2	O
-	O

3	O
]	O
The	O
derivation	O
of	O
reliable	O
secondary	O
structure	O
models	O
for	O
each	O
transcribed	O
spacer	O

region	O
would	O
represent	O
a	O
major	O
step	O
towards	O
a	O
detailed	O
understanding	O
of	O
their	O
biological	O
roles	O
.	O

Comparative	O
sequence	O
analysis	O
provides	O
a	O
powerful	O
tool	O
for	O
identifying	O
biologically	O
relevant	O
folding	O
patterns	O
in	O
RNA	O
molecules	O
.	O

[	O
4	O
]	O
This	O
involves	O
collection	O
of	O
sequences	O
exhibiting	O
substantial	O
nucleotide	O

differences	O
while	O
retaining	O
unequivocal	O
sequence	O
similarity	O
.	O

However	O
,	O
a	O
high	O
degree	O
of	O
sequence	O
variation	O
in	O
the	O
transcribed	O

spacers	O
is	O
known	O
even	O
among	O
closely	O
related	O
species	O
.	O

[	O
5	O
-	O
6	O
-	O
7	O
]	O
Here	O
,	O
we	O
analyze	O
ITS2	O
from	O
7	O

Culex	O
species	O
characteristic	O
of	O
5	O
different	O
geographical	O
locations	O
to	O
assemble	O
common	O
RNA	O
structural	O
features	O
.	O

Methodology	O

Dataset	O

ITS2	O
nucleotide	O
sequences	O
from	O
7	O
Culex	O
mosquitoes	O
characteristic	O
of	O
5	O
geographical	O
locations	O
(	O
Italy	O
,	O
China	O
,	O
Africa	O
,	O

America	O
,	O
and	O
Japan	O
)	O
were	O
downloaded	O
from	O
GenBank	O
(	O
www	O
.	O
ncbi	O
.	O
nlm	O
.	O
nih	O
.	O
gov	O
/	O
genbank	O

)	O
.	O
The	O
GenBank	O
accession	O
numbers	O
for	O
ITS2	O
sequences	O

from	O
C	B
.	I
pipens	I
(	O
North	O
America	O
)	O
,	O
C	B
.	I
tritaeniorhynchus	I
(	O
China	O
)	O
,	O
C	B
.	I
quinquefasciatus	I

(	O
Africa	O
)	O
,	O
C	B
.	I
tarsalis	I
(	O
Italy	O
)	O
,	O
C	B
.	I
annulus	I
(	O
China	O
)	O
,	O
C	B
.	I
pseudovishnui	I

(	O
China	O
)	O
,	O
and	O
C	B
.	I
vishnui	I
(	O
Japan	O
)	O
were	O
X75817	O
,	O
AF305558	O
,	O
Z48468	O
,	O
U33031	O
,	O
AF453488	O
,	O
AF453498	O
and	O
AF165900	O
,	O

respectively	O
.	O

Sequence	O
alignments	O

Multiple	O
sequence	O
alignments	O
were	O
performed	O
using	O
CLUSTALW	O
with	O
a	O
gap	O
opening	O
penalty	O
of	O
15	O
and	O
gap	O
extension	O
penalty	O
of	O
6	O
.	O
66	O
.	O

[	O
8	O
]	O

Secondary	O
structure	O
prediction	O

The	O
RNA	O
secondary	O
structures	O
for	O
ITS2	O
were	O
predicted	O
using	O
RNADRAW	O
.	O

[	O
21	O
]	O

RNADRAW	O
predicts	O
RNA	O
structures	O
by	O
identifying	O
suboptimal	O
structures	O
using	O
the	O
free	O
energy	O
optimization	O
methodology	O
at	O
a	O
default	O

temperature	O
of	O
370	O
degrees	O
C	O
.	O

In	O
the	O
current	O
study	O
,	O
ITS2	O
and	O
5	O
.	O
8S	O
regions	O
(	O
the	O
first	O
170	O
nucleotides	O
)	O
were	O
used	O
for	O
RNA	O
structure	O

prediction	O
.	O

The	O
minimum	O
energy	O
structure	O
prediction	O
algorithm	O
in	O
RNADRAW	O
was	O
ported	O
from	O
the	O
RNAFOLD	O
program	O
included	O
in	O
the	O

Vienna	O
RNA	O
package	O
.	O

[	O
24	O
]	O
The	O
dynamic	O
programming	O
algorithm	O
employed	O
in	O

RNADRAW	O
was	O
based	O
on	O
the	O
work	O
of	O
Zuker	O
and	O
Stiegler	O
[	O
25	O
]	O
and	O
uses	O
energy	O

parameters	O
taken	O
from	O
Turner	O
[	O
26	O
]	O
,	O
Freier	O
[	O
27	O
]	O
and	O
Jaeger	O
.	O

[	O
28	O
]	O

Phylogenetic	O
analysis	O

The	O
phylogenetic	O
Genebee	O
service	O
was	O
used	O
for	O
phylogenetic	O
tree	O
construction	O
.	O

[	O
22	O

]	O

RNA	O
fold	O

The	O
Sribo	O
program	O
in	O
Sfold	O
(	O
Statistical	O
Folding	O
and	O
Rational	O
Design	O
of	O
Nucleic	O
Acids	O
)	O
was	O

used	O
to	O
predict	O
the	O
probable	O
target	O
accessibility	O
sites	O
(	O
loops	O
)	O
for	O
trans	O
-	O
cleaving	O
ribozymes	O
in	O
ITS2	O
.	O

[	O
24	O
]	O
The	O
prediction	O
of	O
accessibility	O
is	O
based	O
on	O
a	O
statistical	O
sample	O
of	O
the	O
Boltzmann	O

ensemble	O
for	O
secondary	O
structures	O
.	O

Here	O
,	O
we	O
assessed	O
the	O
likelihood	O
of	O
unpaired	O
sites	O
for	O
potential	O
ribozyme	O
target	O
.	O

Each	O
mRNA	O

exists	O
as	O
a	O
population	O
of	O
different	O
structures	O
.	O

Hence	O
,	O
stochastic	O
approach	O
to	O
the	O
evaluation	O
of	O
accessible	O
sites	O
was	O
found	O

appropriate	O
.	O

[	O
29	O
]	O
The	O
probability	O
profiling	O
approach	O
by	O
Ding	O
and	O
Lawrence	O

[	O
30	O
]	O
reveals	O
target	O
sites	O
that	O
are	O
commonly	O
accessible	O
for	O

a	O
large	O
number	O
of	O
statistically	O
representative	O
structures	O
in	O
the	O
target	O
RNA	O
.	O

This	O
novel	O
approach	O
bypasses	O
the	O
long	O
-	O
standing	O

difficulty	O
in	O
accessibility	O
evaluation	O
due	O
to	O
limited	O
representation	O
of	O
probable	O
structures	O
due	O
to	O
high	O
statistical	O
confidence	O

in	O
predictions	O
.	O

The	O
probability	O
profile	O
for	O
individual	O
bases	O
(	O
W	O
=	O
1	O
)	O
is	O
produced	O
for	O
the	O
region	O
that	O

includes	O
a	O
triplet	O
and	O
two	O
flanking	O
sequences	O
of	O
15	O
bases	O
each	O
in	O
every	O
site	O
of	O
the	O
selected	O
cleavage	O
triplet	O
(	O
e	O
.	O
g	O
.	O
,	O
GUC	O
)	O
.	O

Results	O
and	O
Discussion	O

ITS2	O
sequences	O
showed	O
a	O
taxonomic	O
trend	O
similar	O
to	O
that	O
in	O
phylogeny	O
construction	O
(	O
Figure	O
1A	O

)	O
.	O

A	O
multiple	O
sequence	O
alignment	O

of	O
5	O
.	O
8S	O
rDNA	O
and	O
ITS2	O
showed	O
in	O
Figure	O
1B	O
indicated	O
that	O
more	O
distantly	O
related	O
species	O
have	O

lower	O
sequence	O
similarity	O
in	O
the	O

ITS2	O
region	O
.	O

The	O
predicted	O
features	O
of	O
ITS2	O
using	O
RNADRAW	O
are	O
given	O
in	O
Table	O
1	O
.	O

The	O
stems	O

(	O
double	O
stranded	O
paired	O
regions	O
)	O

stabilize	O
RNA	O
secondary	O
structures	O
and	O
the	O
number	O
of	O
stems	O
present	O
in	O
each	O
ITS2	O
is	O
given	O
(	O
Table	O
1	O
)	O
.	O

ITS2	O
RNA	O
structures	O
from	O

C	B
.	I
pipiens	I
and	O
C	B
.	I
quinquefasciatus	I
have	O
the	O
highest	O
negative	O
free	O
energy	O
(	O
-	O
149	O
.	O
38	O
Kcal	O
and	O

-	O
148	O
.	O
23	O
Kcal	O
)	O
followed	O
by	O
C	B
.	I
tarsalis	I
(	O
-	O
129	O
.	O
2	O
)	O
,	O
C	B
.	I
annulus	I
and	O
then	O
by	O
C	B
.	I
vishnui	I

(	O
-	O
115	O
.	O
3	O
)	O
,	O
C	B
.	I
pseudovishnui	I
(	O
-	O
105	O
.	O
66	O
)	O
and	O
C	B
.	I
tritaeniorhyncus	I
(	O
-	O
82	O
.	O
57	O
)	O
.	O

Visual	O
comparison	O
shows	O

that	O
this	O
is	O
related	O
to	O
the	O
trend	O
in	O
the	O
cladogram	O
given	O
in	O
Figure	O
1A	O
.	O

A	O
high	O
degree	O
of	O
sequence	O
similarity	O
is	O
observed	O
at	O
the	O

5	O
'	O
end	O
compared	O
to	O
the	O
3	O
'	O
end	O
(	O
Figure	O
1A	O
)	O
.	O

This	O
is	O
due	O
to	O
factors	O
such	O
as	O
genetic	O
drift	O
,	O
the	O
relative	O
number	O
and	O
size	O
of	O
repeats	O
,	O

rates	O
of	O
unequal	O
crossover	O
,	O
gene	O
conversion	O
,	O
immigration	O
and	O
the	O
number	O
of	O
the	O
loci	O
influencing	O
the	O
length	O
.	O

[	O
10	O
]	O
Furthermore	O
,	O
a	O
high	O
level	O
of	O
sequence	O
similarity	O
is	O
found	O
between	O
C	O
.	O

annulus	O
and	O
C	B
.	I
vishnui	I
as	O
well	O
as	O
C	B
.	I
quinquefasciatus	I
and	O
C	B
.	I

pipiens	B
.	O

The	O
simple	O
tandem	O
repeats	O
shown	O
in	O
Figure	O
1B	O
as	O
bolded	O
regions	O
are	O
found	O
to	O
be	O
similar	O
.	O

This	O
similarity	O
is	O
seen	O
in	O
corresponding	O

RNA	O
structures	O
and	O
computed	O
energies	O
.	O

The	O
Culex	O
species	O
considered	O
in	O
this	O
study	O
were	O
then	O
grouped	O
into	O
three	O
classes	O
based	O
on	O
the	O
similarity	O
of	O

RNA	O
stems	O
and	O
loops	O
.	O

Despite	O
their	O
different	O
geographic	O
locations	O
with	O
varying	O
eco	O
-	O
climatic	O
conditions	O
,	O
class	O
I	O

(	O
C	B
.	I
annulus	I
,	O
C	B
.	I
pseudovishnui	I
and	O
C	B
.	I
vishnui	I
)	O
isolates	O
(	O
China	O
and	O
Japan	O
)	O
showed	O
high	O
similarity	O

in	O
secondary	O
structural	O
features	O
.	O

Similar	O
observations	O
were	O
seen	O
in	O
class	O
II	O
(	O
C	B
.	I
pipiens	I
,	O
C	B
.	I
quinquefasciatus	I
and	O

C	B
.	I
tarsalis	I
)	O
isolates	O
from	O
North	O
America	O
and	O
Africa	O
.	O

[	O
19	O
]	O

A	O
high	O
degree	O
of	O
similarity	O
in	O
the	O
5	O
.	O
8S	O
region	O
unlike	O
the	O
ITS2	O
is	O
shown	O
for	O
different	O
isolates	O
due	O
to	O
relative	O
evolutionary	O

selection	O
.	O

[	O
9	O
]	O
The	O
loops	O
11	O
and	O
12	O
having	O
sequences	O
UGUCG	O
and	O
CUUCGGUG	O
,	O

respectively	O
are	O
highly	O
conserved	O
in	O
all	O
classes	O
.	O

Figure	O
1C	O
shows	O
the	O
distribution	O
of	O
different	O
types	O
of	O
loops	O
(	O
hairpin	O
,	O
bulge	O
,	O
multi	O
branched	O
,	O
interior	O
and	O
exterior	O
)	O
among	O

different	O
isolates	O
.	O

The	O
segments	O
of	O
the	O
ITS2	O
having	O
score	O
>	O
=	O
50	O
are	O
further	O
probed	O
carefully	O
for	O
target	O
site	O
to	O
assess	O
the	O

likelihood	O
of	O
unpaired	O
segments	O
.	O

Interestingly	O
,	O
the	O
observed	O
phylogenetic	O
trend	O
was	O
identified	O
with	O
respect	O
to	O
the	O
target	O

accessibility	O
sites	O
for	O
the	O
seven	O
Culex	O
isolates	O
.	O

The	O
order	O
of	O
preference	O
is	O
interior	O
loop	O
,	O
bulge	O
loop	O
,	O
multiple	O

branched	O
loop	O
,	O
hairpin	O
loop	O
and	O
exterior	O
loops	O
in	O
all	O
the	O
isolates	O
.	O

Several	O
homologous	O
domains	O
were	O
observed	O
in	O
the	O
ITS	O
regions	O
of	O
Aedes	O
mosquito	O
species	O
by	O
Wesson	O

et	O
al	O
[	O
11	O
]	O
and	O
was	O
shown	O
that	O
these	O
domains	O
base	O
pair	O
to	O

form	O
a	O
core	O
region	O
central	O
to	O

several	O
stem	O
features	O
.	O

This	O
suggested	O
that	O
conserved	O
core	O
region	O
of	O
rDNA	O
is	O
more	O
important	O
for	O
a	O
functional	O
rRNA	O
folding	O

pattern	O
.	O

Barker	O
found	O
that	O
ITS2	O
is	O
unique	O
in	O
the	O
16	O
populations	O
of	O
Boophilus	B
microplus	I
,	O
Boophilus	B
decoloratus	I
,	O

Rhipicephalus	B
appendiculatus	I
,	O
Rhipicephalus	B
zambesiensis	I
,	O
Rhipicephalus	B
evertsi	I
,	O
Rhipicephalus	B
sanguineus	I
,	O
Rhipicephalus	O

turanicus	O
,	O
Rhipicephalus	B
pumilio	I
and	O
Rhipicephalus	B
camicasi	I
from	O
different	O
geographical	O
locations	O
.	O

[	O
12	O
]	O
These	O
results	O
suggest	O
that	O
the	O
differences	O
and	O
similarity	O
observed	O

in	O
the	O
ITS2	O
of	O
different	O
species	O
are	O
not	O
simply	O
accumulated	O
due	O
to	O
random	O
mutation	O
and	O
have	O
evolved	O
for	O
functional	O
selection	O

in	O
ribosome	O
biogenesis	O
.	O

However	O
,	O
it	O
was	O
shown	O
in	O
three	O
related	O
mosquito	O
genera	O
(	O
Aedes	O
,	O
Psorophora	O
and	O
Haemogogus	B
)	O

that	O
the	O
intra	O
-	O
spacer	O
variable	O
regions	O
appear	O
to	O
co	O
-	O
evolve	O
and	O
that	O
ITS2	O
variation	O
is	O
constrained	O
by	O
its	O
secondary	O
structure	O
.	O

[	O
11	O
]	O
Further	O
studies	O
have	O
demonstrated	O
that	O
the	O
ITS2	O
is	O
essential	O

for	O
the	O
correct	O
and	O
efficient	O
processing	O
and	O
maturation	O
of	O
26S	O
rRNA	O
ribosomal	O
units	O
.	O

[	O

13	O
]	O
Furthermore	O
,	O
the	O
information	O
required	O
for	O
the	O
efficient	O
removal	O
of	O
ITS2	O
from	O
its	O
RNA	O
precursor	O
is	O
not	O

localized	O
but	O
dispersed	O
throughout	O
the	O
ITS2	O
region	O
.	O

Thus	O
,	O
insertions	O
and	O
deletions	O
(	O
indels	O
)	O
that	O
affect	O
secondary	O
structures	O

alter	O
rRNA	O
processing	O
.	O

Critical	O
changes	O
in	O
the	O
rRNA	O
folding	O
pattern	O
due	O
to	O
evolutionary	O
sequence	O
variation	O
in	O
the	O
ITS	O
spacer	O

regions	O
may	O
thus	O
have	O
an	O
important	O
role	O
on	O
the	O
kinetics	O
of	O
precursor	O
rRNA	O
formation	O
for	O
the	O
efficient	O
functioning	O
of	O
rDNA	O
clusters	O
.	O

Conclusion	O

Comparison	O
of	O
ITS2	O
sequences	O
from	O
different	O
isolates	O
of	O
Culex	O
show	O
similarity	O
and	O
variations	O
.	O

Surprisingly	O
,	O
species	O
displaying	O

sequence	O
similarity	O
belong	O
to	O
different	O
geographical	O
locations	O
with	O
diverse	O
climatic	O
and	O
ecological	O
conditions	O
.	O

This	O
implies	O
that	O

the	O
ITS2	O
regions	O
have	O
less	O
selective	O
pressure	O
than	O
the	O
ribosomal	O
regions	O
.	O

Several	O
common	O
structural	O
folds	O
were	O
shared	O
among	O
the	O

selected	O
mosquitoes	O
for	O
maintaining	O
functional	O
equivalents	O
.	O

Construction	O
of	O
an	O
evolutionary	O
tree	O
using	O
more	O
isolates	O
of	O

Culex	O
will	O
provide	O
an	O
understanding	O
for	O
their	O
functional	O
selection	O
.	O

Integration	O
in	O
primary	O
community	O
care	O
networks	O
(	O
PCCNs	O
)	O
:	O
examination	O
of	O
governance	O
,	O
clinical	O
,	O
marketing	O
,	O
financial	O
,	O
and	O
information	O
infrastructures	O
in	O
a	O
national	O
demonstration	O
project	O
in	O
Taiwan	O

Abstract	O

Background	O

Taiwan	O
'	O
s	O
primary	O
community	O
care	O
network	O
(	O
PCCN	O
)	O
demonstration	O
project	O
,	O
funded	O
by	O
the	O
Bureau	O
of	O
National	O
Health	O
Insurance	O
on	O
March	O
2003	O
,	O
was	O
established	O
to	O
discourage	O
hospital	O
shopping	O
behavior	O
of	O
people	B
and	O
drive	O
the	O
traditional	O
fragmented	O
health	O
care	O
providers	O
into	O
cooperate	O
care	O
models	O
.	O

Between	O
2003	O
and	O
2005	O
,	O
268	O
PCCNs	O
were	O
established	O
.	O

This	O
study	O
profiled	O
the	O
individual	O
members	O
in	O
the	O
PCCNs	O
to	O
study	O
the	O
nature	O
and	O
extent	O
to	O
which	O
their	O
network	O
infrastructures	O
have	O
been	O
integrated	O
among	O
the	O
members	O
(	O
clinics	O
and	O
hospitals	O
)	O
within	O
individual	O
PCCNs	O
.	O

Methods	O

The	O
thorough	O
questionnaire	O
items	O
,	O
covering	O
the	O
network	O
working	O
infrastructures	O
-	O
governance	O
,	O
clinical	O
,	O
marketing	O
,	O
financial	O
,	O
and	O
information	O
integration	O
in	O
PCCNs	O
,	O
were	O
developed	O
with	O
validity	O
and	O
reliability	O
confirmed	O
.	O

One	O
thousand	O
five	O
hundred	O
and	O
fifty	O
-	O
seven	O
clinics	O
that	O
had	O
belonged	O
to	O
PCCNs	O
for	O
more	O
than	O
one	O
year	O
,	O
based	O
on	O
the	O
2003	O
-	O
2005	O
Taiwan	O
Primary	O
Community	O
Care	O
Network	O
List	O
,	O
were	O
surveyed	O
by	O
mail	O
.	O

Nine	O
hundred	O
and	O
twenty	O
-	O
eight	O
clinic	O
members	O
responded	O
to	O
the	O
surveys	O
giving	O
a	O
59	O
.	O
6	O
%	O
response	O
rate	O
.	O

Results	O

Overall	O
,	O
the	O
PCCNs	O
'	O
members	O
had	O
higher	O
involvement	O
in	O
the	O
governance	O
infrastructure	O
,	O
which	O
was	O
usually	O
viewed	O
as	O
the	O
most	O
important	O
for	O
establishment	O
of	O
core	O
values	O
in	O
PCCNs	O
'	O
organization	O
design	O
and	O
management	O
at	O
the	O
early	O
integration	O
stage	O
.	O

In	O
addition	O
,	O
it	O
found	O
that	O
there	O
existed	O
a	O
higher	O
extent	O
of	O
integration	O
of	O
clinical	O
,	O
marketing	O
,	O
and	O
information	O
infrastructures	O
among	O
the	O
hospital	O
-	O
clinic	O
member	O
relationship	O
than	O
those	O
among	O
clinic	O
members	O
within	O
individual	O
PCCNs	O
.	O

The	O
financial	O
infrastructure	O
was	O
shown	O
the	O
least	O
integrated	O
relative	O
to	O
other	O
functional	O
infrastructures	O
at	O
the	O
early	O
stage	O
of	O
PCCN	O
formation	O
.	O

Conclusion	O

There	O
was	O
still	O
room	O
for	O
better	O
integrated	O
partnerships	O
,	O
as	O
evidenced	O
by	O
the	O
great	O
variety	O
of	O
relationships	O
and	O
differences	O
in	O
extent	O
of	O
integration	O
in	O
this	O
study	O
.	O

In	O
addition	O
to	O
provide	O
how	O
the	O
network	O
members	O
have	O
done	O
for	O
their	O
initial	O
work	O
at	O
the	O
early	O
stage	O
of	O
network	O
forming	O
in	O
this	O
study	O
,	O
the	O
detailed	O
surveyed	O
items	O
,	O
the	O
concepts	O
proposed	O
by	O
the	O
managerial	O
and	O
theoretical	O
professionals	O
,	O
could	O
be	O
a	O
guide	O
for	O
those	O
health	O
care	O
providers	O
who	O
have	O
willingness	O
to	O
turn	O
their	O
business	O
into	O
multi	O
-	O
organizations	O
.	O

Background	O

Taiwan	O
'	O
s	O
National	O
Health	O
Insurance	O
(	O
NHI	O
)	O
under	O
the	O
control	O
of	O
the	O
Bureau	O
of	O
National	O
Health	O
Insurance	O
(	O
BNHI	O
)	O
,	O
was	O
launched	O
in	O
March	O
1995	O
to	O
replace	O
its	O
social	O
insurance	O
system	O
that	O
was	O
covering	O
59	O
%	O
of	O
its	O
population	O
:	O
government	O
employees	O
,	O
labourers	O
,	O
farmers	O
and	O
servicemen	O
[	O
1	O
]	O
.	O

By	O
June	O
2003	O
the	O
number	O
of	O
people	B
insured	O
had	O
reached	O
21	O
,	O
956	O
,	O
729	O
(	O
99	O
%	O
)	O
.	O

There	O
were	O
17	O
,	O
259	O
medical	O
providers	O
(	O
92	O
%	O
)	O
,	O
including	O
575	O
hospitals	O
and	O
16	O
,	O
684	O
clinics	O
contracted	O
with	O
the	O
BNHI	O
for	O
serving	O
the	O
enrolled	O
population	O
.	O

The	O
unique	O
phenomenon	O
characterized	O
in	O
Taiwan	O
health	O
care	O
industry	O
different	O
from	O
those	O
in	O
the	O
western	O
countries	O
is	O
the	O
freedom	O
of	O
patients	B
to	O
choose	O
the	O
health	O
care	O
providers	O
they	O
want	O
,	O
no	O
matter	O
what	O
their	O
disease	O
severity	O
is	O
.	O

Furthermore	O
,	O
Taiwan	O
people	B
favor	O
the	O
larger	O
scales	O
of	O
facilities	O
and	O
this	O
fallacy	O
leads	O
to	O
the	O
phenomenon	O
of	O
big	O
-	O
hospital	O
shopping	O
.	O

For	O
example	O
,	O
people	B
choose	O
the	O
medical	O
centers	O
which	O
are	O
accredited	O
as	O
the	O
highest	O
level	O
of	O
medical	O
science	O
in	O
Taiwan	O
when	O
they	O
only	O
suffer	O
from	O
a	O
common	O
cold	O
.	O

In	O
the	O
spring	O
of	O
2003	O
,	O
the	O
SARS	O
epidemic	O
viciously	O
attacked	O
the	O
health	O
of	O
Taiwan	O
'	O
s	O
people	B
.	O

The	O
people	B
'	O
s	O
freedom	O
to	O
choose	O
medical	O
providers	O
caused	O
the	O
national	O
health	O
authority	O
to	O
barely	O
control	O
and	O
traced	O
the	O
flow	O
of	O
epidemic	O
.	O

This	O
event	O
made	O
Taiwan	O
national	O
health	O
authorities	O
rethink	O
what	O
happened	O
and	O
how	O
it	O
damaged	O
under	O
the	O
traditional	O
fragmented	O
health	O
care	O
providers	O
in	O
Taiwan	O
.	O

One	O
health	O
reform	O
launched	O
was	O
named	O
the	O
"	O
Primary	O
Community	O
Care	O
Network	O
(	O
PCCN	O
)	O
demonstration	O
project	O
"	O
,	O
a	O
nationwide	O
health	O
care	O
financing	O
program	O
funded	O
by	O
the	O
Bureau	O
of	O
National	O
Health	O
Insurance	O
(	O
BNHI	O
)	O
in	O
March	O
2003	O
and	O
it	O
was	O
a	O
new	O
model	O
for	O
the	O
Taiwan	O
government	O
to	O
redefine	O
the	O
role	O
of	O
family	O
physicians	O
in	O
the	O
health	O
care	O
delivery	O
system	O
.	O

A	O
PCCN	O
in	O
Taiwan	O
consists	O
of	O
a	O
group	O
of	O
clinic	O
physicians	O
whose	O
medical	O
jobs	O
are	O
viewed	O
as	O
family	O
care	O
and	O
at	O
least	O
one	O
hospital	O
for	O
secondary	O
or	O
tertiary	O
care	O
.	O

The	O
idea	O
of	O
member	O
component	O
design	O
in	O
PCCNs	O
was	O
aimed	O
to	O
lead	O
the	O
Taiwan	O
citizens	O
to	O
choose	O
one	O
clinic	O
physician	O
as	O
their	O
personal	O
family	O
physician	O
for	O
health	O
maintenance	O
and	O
this	O
family	O
physician	O
also	O
would	O
have	O
the	O
responsibility	O
of	O
referring	O
the	O
patients	B
to	O
specialty	O
care	O
if	O
necessary	O
.	O

From	O
a	O
national	O
health	O
authority	O
perspective	O
,	O
they	O
expected	O
the	O
Taiwan	O
people	B
to	O
put	O
an	O
end	O
to	O
their	O
fallacy	O
that	O
"	O
bigger	O
is	O
better	O
"	O
for	O
health	O
care	O
organizations	O
and	O
establish	O
the	O
idea	O
of	O
"	O
human	B
health	O
"	O
,	O
starting	O
with	O
prevention	O
and	O
primary	O
care	O
,	O
followed	O
by	O
secondary	O
or	O
tertiary	O
care	O
,	O
emphasizing	O
health	O
promotion	O
and	O
maintenance	O
instead	O
of	O
disease	O
curing	O
.	O

Furthermore	O
,	O
it	O
could	O
decrease	O
the	O
inappropriateness	O
of	O
medical	O
usage	O
,	O
i	O
.	O
e	O
.	O
,	O
over	O
-	O
uses	O
of	O
secondary	O
and	O
tertiary	O
medical	O
services	O
in	O
the	O
high	O
-	O
tech	O
hospitals	O
.	O

In	O
addition	O
,	O
the	O
national	O
health	O
authority	O
was	O
expected	O
to	O
drive	O
the	O
traditional	O
fragmented	O
heath	O
care	O
providers	O
into	O
coordinated	O
medical	O
multidisciplinary	O
teams	O
and	O
share	O
the	O
limited	O
medical	O
resources	O
through	O
the	O
PCCN	O
demonstration	O
project	O
.	O

In	O
summary	O
,	O
the	O
PCCN	O
demonstration	O
project	O
was	O
aimed	O
to	O
:	O
1	O
)	O
change	O
the	O
traditional	O
patients	B
'	O
customs	O
of	O
freely	O
choosing	O
health	O
care	O
organizations	O
and	O
establish	O
referral	O
channels	O
along	O
the	O
continuum	O
of	O
care	O
,	O
and	O
2	O
)	O
establish	O
partnerships	O
among	O
the	O
primary	O
care	O
clinics	O
and	O
hospitals	O
to	O
provide	O
a	O
continuum	O
of	O
health	O
care	O
services	O
.	O

It	O
was	O
also	O
expected	O
to	O
establish	O
the	O
primary	O
care	O
system	O
of	O
family	O
physicians	O
to	O
provide	O
whole	O
-	O
people	B
health	O
care	O
and	O
improve	O
care	O
quality	O
[	O
1	O
]	O
.	O

Partnership	O
structures	O
in	O
the	O
PCCNs	O
represent	O
the	O
virtual	O
vertical	O
(	O
i	O
.	O
e	O
.	O
,	O
between	O
the	O
member	O
clinics	O
and	O
hospitals	O
)	O
and	O
virtual	O
horizontal	O
(	O
i	O
.	O
e	O
.	O
,	O
among	O
the	O
member	O
clinics	O
)	O
aspects	O
of	O
organizing	O
,	O
which	O
designate	O
the	O
formal	O
relationships	O
between	O
individuals	O
and	O
the	O
total	O
network	O
and	O
include	O
organizational	O
design	O
to	O
ensure	O
effective	O
communication	O
,	O
coordination	O
,	O
and	O
integration	O
across	O
the	O
total	O
network	O
.	O

Each	O
PCCN	O
consists	O
of	O
five	O
to	O
ten	O
clinics	O
:	O
half	O
of	O
them	O
should	O
offer	O
the	O
services	O
of	O
general	O
medicine	O
,	O
internal	O
medicine	O
,	O
surgery	O
,	O
obstetrics	O
and	O
gynecology	O
,	O
pediatric	O
,	O
or	O
family	O
medicine	O
.	O

And	O
each	O
PCCN	O
has	O
a	O
central	O
headquarters	O
,	O
usually	O
in	O
one	O
of	O
the	O
clinic	O
facilities	O
,	O
to	O
coordinate	O
and	O
integrate	O
the	O
network	O
.	O

All	O
the	O
clinic	O
physicians	O
in	O
a	O
PCCN	O
are	O
assigned	O
the	O
roles	O
of	O
"	O
family	O
physicians	O
"	O
or	O
"	O
gatekeepers	O
"	O
who	O
recruit	O
people	B
from	O
the	O
local	O
community	O
,	O
keep	O
background	O
and	O
medical	O
files	O
on	O
them	O
,	O
certify	O
family	O
physician	O
education	O
training	O
programs	O
,	O
and	O
hold	O
office	O
hours	O
in	O
the	O
member	O
hospital	O
,	O
where	O
they	O
serve	O
as	O
joint	O
faculty	O
members	O
for	O
further	O
medical	O
consultations	O
or	O
medical	O
utilizations	O
of	O
labs	O
and	O
tests	O
,	O
if	O
necessary	O
.	O

In	O
addition	O
,	O
the	O
hospital	O
member	O
is	O
asked	O
to	O
help	O
clinic	O
physicians	O
in	O
their	O
network	O
to	O
set	O
up	O
a	O
medical	O
information	O
system	O
,	O
share	O
hospital	O
resources	O
(	O
medical	O
equipment	O
and	O
library	O
literature	O
)	O
with	O
the	O
clinic	O
physicians	O
in	O
their	O
network	O
and	O
establish	O
referral	O
channels	O
among	O
the	O
network	O
members	O
.	O

Furthermore	O
,	O
this	O
new	O
demonstration	O
model	O
tries	O
to	O
minimize	O
the	O
barriers	O
to	O
patient	B
access	O
by	O
setting	O
up	O
24	O
-	O
hour	O
a	O
day	O
,	O
7	O
-	O
day	O
a	O
week	O
medical	O
consultation	O
telephone	O
lines	O
for	O
providing	O
urgent	O
services	O
onsite	O
and	O
for	O
taking	O
care	O
of	O
the	O
patients	B
whose	O
family	O
physicians	O
'	O
practices	O
are	O
closed	O
to	O
assure	O
seamless	O
care	O
channels	O
.	O

The	O
BNHI	O
funded	O
these	O
extra	O
demonstration	O
actions	O
,	O
at	O
around	O
one	O
hundred	O
thousand	O
US	O
dollars	O
(	O
i	O
.	O
e	O
.	O
,	O
NT	O
$	O
3	O
,	O
500	O
,	O
000	O
)	O
for	O
each	O
PCCN	O
under	O
the	O
current	O
fee	O
-	O
for	O
-	O
service	O
payment	O
system	O
[	O
1	O
]	O
.	O

Figure	O
1	O
describes	O
the	O
organizational	O
structure	O
of	O
individual	O
PCCNs	O
introduced	O
in	O
the	O
demonstration	O
project	O
in	O
Taiwan	O
.	O

To	O
date	O
,	O
the	O
PCCN	O
demonstration	O
project	O
has	O
been	O
in	O
operation	O
for	O
more	O
than	O
three	O
years	O
.	O

There	O
have	O
been	O
268	O
PCCNs	O
formed	O
in	O
the	O
period	O
of	O
2003	O
to	O
2005	O
around	O
Taiwan	O
.	O

The	O
geographical	O
distributions	O
of	O
PCCNs	O
and	O
their	O
members	O
were	O
described	O
in	O
Table	O
1	O
.	O

Analyzing	O
all	O
1	O
,	O
557	O
participating	O
clinic	O
members	O
in	O
the	O
demonstration	O
project	O
in	O
terms	O
of	O
medical	O
specialties	O
,	O
they	O
cover	O
general	O
medicine	O
,	O
internal	O
medicine	O
,	O
surgeries	O
,	O
obstetrics	O
and	O
gynecology	O
,	O
pediatrics	O
,	O
family	O
medicines	O
,	O
otolaryngology	O
,	O
ophthalmology	O
,	O
rehabilitation	O
medicine	O
,	O
dermatology	O
,	O
and	O
psychiatry	O
,	O
with	O
237	O
clinics	O
providing	O
more	O
than	O
two	O
specialties	O
.	O

On	O
the	O
other	O
hand	O
,	O
each	O
PCCN	O
recruits	O
at	O
least	O
one	O
district	O
or	O
regional	O
accredited	O
hospital	O
for	O
acute	O
care	O
demands	O
(	O
required	O
for	O
network	O
members	O
)	O
and	O
a	O
medical	O
center	O
for	O
tertiary	O
care	O
support	O
(	O
not	O
required	O
for	O
network	O
members	O
)	O
.	O

There	O
are	O
6	O
medical	O
centers	O
,	O
52	O
regional	O
hospitals	O
,	O
and	O
71	O
district	O
hospitals	O
joining	O
in	O
the	O
demonstration	O
project	O
.	O

See	O
Table	O
1	O
for	O
more	O
detailed	O
information	O
about	O
the	O
PCCN	O
members	O
.	O

To	O
date	O
,	O
there	O
have	O
been	O
few	O
empirical	O
studies	O
of	O
the	O
working	O
relationships	O
that	O
have	O
developed	O
between	O
members	O
of	O
the	O
PCCN	O
program	O
.	O

Partnership	O
needs	O
a	O
method	O
to	O
determine	O
at	O
an	O
early	O
stage	O
,	O
to	O
make	O
sure	O
whether	O
they	O
are	O
making	O
the	O
most	O
of	O
collaboration	O
[	O
2	O
]	O
and	O
the	O
acceptance	O
of	O
the	O
contracting	O
networks	O
in	O
Taiwan	O
as	O
an	O
organizational	O
innovation	O
worthy	O
of	O
greater	O
diffusion	O
deserves	O
to	O
be	O
explored	O
.	O

Therefore	O
,	O
this	O
study	O
used	O
a	O
structured	O
questionnaire	O
to	O
characterize	O
the	O
relationship	O
among	O
the	O
members	O
in	O
the	O
individual	O
PCCNs	O
,	O
with	O
regard	O
to	O
governance	O
,	O
clinical	O
,	O
marketing	O
,	O
financing	O
,	O
as	O
well	O
as	O
information	O
integration	O
infrastructures	O
.	O

The	O
results	O
of	O
this	O
study	O
provide	O
descriptive	O
analyses	O
in	O
detail	O
to	O
map	O
the	O
partnership	O
developments	O
,	O
to	O
enrich	O
the	O
body	O
of	O
knowledge	O
of	O
the	O
partner	O
relationships	O
and	O
to	O
help	O
policy	O
makers	O
understand	O
the	O
coordinated	O
efforts	O
of	O
these	O
health	O
care	O
providers	O
which	O
have	O
developed	O
under	O
this	O
system	O
.	O

It	O
also	O
provides	O
the	O
recommendations	O
for	O
heath	O
policy	O
decision	O
-	O
making	O
and	O
management	O
of	O
networks	O
of	O
health	O
care	O
providers	O
for	O
the	O
future	O
involvement	O
.	O

Methods	O

This	O
study	O
was	O
aimed	O
at	O
providing	O
descriptive	O
analyses	O
to	O
map	O
the	O
partnership	O
development	O
.	O

To	O
understand	O
the	O
actual	O
integration	O
actions	O
done	O
by	O
network	O
members	O
,	O
the	O
theoretical	O
concept	O
employed	O
by	O
network	O
partnerships	O
were	O
described	O
and	O
then	O
the	O
derived	O
survey	O
instrument	O
was	O
developed	O
.	O

Theoretical	O
framework	O
for	O
organization	O
design	O
of	O
network	O
integration	O

The	O
rapid	O
organizational	O
changes	O
in	O
the	O
health	O
care	O
industry	O
have	O
driven	O
theorists	O
from	O
every	O
discipline	O
and	O
across	O
the	O
world	O
to	O
seek	O
an	O
approach	O
that	O
allows	O
organizations	O
to	O
flourish	O
.	O

Organization	O
theory	O
allows	O
investigators	O
to	O
profile	O
an	O
organization	O
from	O
the	O
aspect	O
of	O
patterns	O
and	O
regularities	O
in	O
organizational	O
design	O
and	O
behavior	O
.	O

In	O
the	O
early	O
20th	O
century	O
,	O
classical	O
management	O
theorists	O
claimed	O
that	O
an	O
organization	O
has	O
"	O
a	O
best	O
way	O
"	O
to	O
be	O
organized	O
and	O
managed	O
[	O
3	O
]	O
.	O

That	O
implied	O
that	O
all	O
organizations	O
would	O
own	O
the	O
"	O
same	O
"	O
organizational	O
styles	O
or	O
structures	O
.	O

In	O
the	O
1960s	O
,	O
several	O
theorists	O
[	O
4	O
-	O
8	O
]	O
challenged	O
this	O
assumption	O
by	O
applying	O
a	O
"	O
contingency	O
approach	O
"	O
to	O
propose	O
that	O
there	O
is	O
no	O
best	O
way	O
to	O
organize	O
an	O
organization	O
,	O
and	O
that	O
the	O
effectiveness	O
of	O
an	O
organizational	O
structure	O
varies	O
with	O
the	O
situation	O
of	O
an	O
organization	O
.	O

Furthermore	O
,	O
it	O
is	O
proposed	O
that	O
the	O
best	O
way	O
to	O
organize	O
an	O
organization	O
depends	O
on	O
the	O
nature	O
of	O
the	O
environment	O
to	O
which	O
the	O
organization	O
relates	O
.	O

Contingency	O
theory	O
delineates	O
the	O
concepts	O
"	O
organization	O
'	O
s	O
internal	O
features	O
,	O
"	O
"	O
the	O
demands	O
of	O
organizational	O
environments	O
,	O
"	O
"	O
best	O
adaptation	O
,	O
"	O
and	O
,	O
the	O
most	O
important	O
and	O
difficult	O
of	O
all	O
,	O
"	O
best	O
match	O
"	O
[	O
9	O
]	O
.	O

Lawrence	O
&	O
Lorsch	O
[	O
7	O
]	O
argued	O
that	O
environments	O
characterized	O
by	O
uncertainty	O
and	O
rapid	O
rates	O
of	O
change	O
in	O
market	O
conditions	O
or	O
technology	O
impose	O
different	O
demands	O
,	O
including	O
constraints	O
and	O
opportunities	O
,	O
on	O
organizations	O
than	O
do	O
placid	O
and	O
stable	O
environments	O
.	O

Similarly	O
to	O
Lawrence	O
and	O
Lorsch	O
'	O
s	O
views	O
mentioned	O
above	O
,	O
Galbraith	O
[	O
10	O
,	O
11	O
]	O
stressed	O
the	O
contingency	O
perspective	O
on	O
information	O
processing	O
.	O

The	O
information	O
-	O
processing	O
approach	O
emphasizes	O
that	O
environment	O
,	O
size	O
,	O
and	O
technology	O
impose	O
different	O
information	O
-	O
processing	O
requirements	O
on	O
organizations	O
,	O
and	O
thus	O
an	O
organization	O
must	O
be	O
designed	O
to	O
encourage	O
information	O
flow	O
in	O
both	O
vertical	O
and	O
horizontal	O
directions	O
to	O
achieve	O
the	O
overall	O
tasks	O
of	O
the	O
organization	O
and	O
,	O
finally	O
,	O
organizational	O
effectiveness	O
[	O
11	O
-	O
14	O
]	O
.	O

Some	O
theorists	O
have	O
criticized	O
conventional	O
contingency	O
theorists	O
who	O
presume	O
that	O
organizational	O
structure	O
is	O
driven	O
by	O
the	O
environment	O
.	O

Child	O
[	O
15	O
]	O
,	O
Miller	O
[	O
16	O
]	O
,	O
Van	O
de	O
Ven	O
and	O
Drazin	O
[	O
17	O
]	O
,	O
and	O
Tushman	O
and	O
Romanelli	O
[	O
18	O
]	O
raised	O
such	O
criticisms	O
;	O
they	O
argued	O
that	O
organizations	O
become	O
what	O
they	O
are	O
not	O
only	O
because	O
of	O
the	O
environment	O
,	O
but	O
also	O
because	O
of	O
choices	O
made	O
by	O
members	O
,	O
especially	O
choices	O
about	O
strategy	O
and	O
organizational	O
design	O
.	O

As	O
Thompson	O
'	O
s	O
words	O
in	O
the	O
book	O
Organizations	O
in	O
Action	O
[	O
8	O
]	O
put	O
it	O
,	O
"	O
organizations	O
are	O
not	O
determined	O
simply	O
by	O
their	O
environments	O
(	O
p	O
.	O
27	O
)	O
.	O
"	O
He	O
also	O
pointed	O
out	O
that	O
"	O
administration	O
may	O
innovate	O
on	O
any	O
or	O
all	O
of	O
the	O
necessary	O
dimensions	O
,	O
but	O
only	O
to	O
the	O
extent	O
that	O
innovations	O
are	O
acceptable	O
to	O
those	O
on	O
whom	O
the	O
organization	O
can	O
and	O
must	O
depend	O
.	O
"	O
Instead	O
of	O
assuming	O
that	O
administrators	O
are	O
highly	O
constrained	O
in	O
their	O
decisions	O
,	O
strategic	O
contingency	O
theorists	O
emphasized	O
"	O
the	O
importance	O
of	O
choice	O
,	O
"	O
that	O
is	O
,	O
"	O
the	O
freedom	O
of	O
agency	O
"	O
[	O
15	O
]	O
.	O

Furthermore	O
,	O
Pfeffer	O
[	O
19	O
]	O
explicitly	O
pointed	O
out	O
that	O
"	O
organizational	O
structures	O
are	O
the	O
outcomes	O
of	O
political	O
contests	O
within	O
organizations	O
(	O
p	O
.	O
38	O
)	O
.	O
"	O

Daft	O
[	O
14	O
]	O
proposed	O
a	O
top	O
management	O
model	O
to	O
delineate	O
how	O
"	O
a	O
strategy	O
is	O
a	O
plan	O
for	O
interacting	O
with	O
the	O
competitive	O
environment	O
to	O
achieve	O
organizational	O
goals	O
.	O
"	O
He	O
stated	O
that	O
the	O
major	O
responsibility	O
of	O
top	O
management	O
is	O
to	O
determine	O
the	O
goals	O
,	O
strategy	O
,	O
and	O
design	O
of	O
an	O
organization	O
to	O
adapt	O
to	O
a	O
changing	O
environment	O
.	O

To	O
assess	O
the	O
external	O
and	O
internal	O
environments	O
of	O
an	O
organization	O
seems	O
to	O
be	O
the	O
first	O
task	O
for	O
top	O
managers	O
in	O
defining	O
an	O
organization	O
'	O
s	O
goals	O
and	O
missions	O
.	O

Then	O
,	O
guided	O
by	O
the	O
goals	O
and	O
missions	O
of	O
the	O
organization	O
,	O
top	O
managers	O
shape	O
the	O
design	O
of	O
the	O
organization	O
,	O
including	O
structural	O
forms	O
,	O
information	O
system	O
,	O
technology	O
,	O
human	B
resources	O
,	O
organizational	O
culture	O
,	O
and	O
inter	O
-	O
organizational	O
linkages	O
,	O
to	O
achieve	O
the	O
final	O
organizational	O
performance	O
.	O

Integration	O
refers	O
to	O
the	O
mechanisms	O
of	O
coordination	O
,	O
the	O
ways	O
guided	O
to	O
partnership	O
goals	O
to	O
fit	O
internal	O
and	O
external	O
conditions	O
[	O
7	O
,	O
20	O
,	O
21	O
]	O
.	O

In	O
the	O
early	O
1990s	O
,	O
proposals	O
for	O
US	O
national	O
health	O
care	O
reform	O
recognized	O
the	O
need	O
for	O
integrating	O
mechanisms	O
to	O
achieve	O
both	O
financial	O
success	O
and	O
quality	O
of	O
care	O
of	O
a	O
well	O
-	O
organized	O
system	O
of	O
care	O
[	O
22	O
,	O
23	O
]	O
.	O

Several	O
researchers	O
also	O
viewed	O
inter	O
-	O
organizational	O
cooperation	O
as	O
resource	O
exchanges	O
,	O
including	O
client	O
referrals	O
,	O
money	O
,	O
and	O
staff	O
[	O
24	O
-	O
27	O
]	O
.	O

From	O
practical	O
ways	O
of	O
viewing	O
integration	O
,	O
the	O
success	O
of	O
integration	O
lies	O
in	O
the	O
coordinative	O
mechanisms	O
and	O
partnership	O
working	O
that	O
support	O
it	O
[	O
28	O
]	O
,	O
including	O
an	O
administrative	O
organization	O
that	O
coordinates	O
the	O
operations	O
of	O
various	O
health	O
care	O
services	O
;	O
a	O
management	O
information	O
system	O
that	O
integrates	O
clinical	O
,	O
utilization	O
,	O
and	O
financial	O
data	O
and	O
follows	O
clients	O
across	O
different	O
settings	O
;	O
a	O
care	O
coordination	O
program	O
such	O
as	O
case	O
management	O
or	O
disease	O
management	O
that	O
works	O
with	O
clients	O
to	O
arrange	O
health	O
care	O
services	O
;	O
and	O
a	O
financial	O
mechanism	O
that	O
enables	O
pooling	O
of	O
funds	O
across	O
services	O
[	O
29	O
-	O
35	O
]	O
.	O

Fox	O
[	O
36	O
]	O
suggested	O
the	O
success	O
of	O
integrated	O
health	O
networks	O
should	O
ensure	O
that	O
the	O
new	O
business	O
link	O
such	O
aspects	O
as	O
technology	O
,	O
functional	O
skills	O
,	O
customer	O
access	O
,	O
management	O
,	O
or	O
products	O
that	O
can	O
be	O
shared	O
across	O
both	O
the	O
core	O
and	O
the	O
new	O
business	O
;	O
to	O
conduct	O
market	O
financial	O
evaluation	O
;	O
to	O
share	O
the	O
risk	O
of	O
vertical	O
integration	O
with	O
outside	O
entities	O
,	O
to	O
develop	O
the	O
management	O
structure	O
that	O
can	O
reflect	O
the	O
degree	O
of	O
coordination	O
necessary	O
to	O
support	O
the	O
core	O
business	O
activities	O
;	O
to	O
ensure	O
that	O
the	O
integration	O
strategy	O
meets	O
the	O
needs	O
of	O
customers	O
,	O
including	O
medical	O
treatment	O
,	O
the	O
use	O
of	O
medical	O
technology	O
,	O
and	O
the	O
preferred	O
methods	O
of	O
purchase	O
;	O
and	O
to	O
measure	O
the	O
new	O
business	O
by	O
its	O
value	O
to	O
the	O
enterprise	O
as	O
a	O
whole	O
,	O
rather	O
than	O
by	O
its	O
profitability	O
as	O
a	O
stand	O
-	O
alone	O
entity	O
.	O

In	O
summary	O
,	O
the	O
effects	O
that	O
integration	O
in	O
inter	O
-	O
organizational	O
designs	O
has	O
on	O
network	O
management	O
were	O
substantial	O
from	O
a	O
managerial	O
perspective	O
.	O

Borrowing	O
the	O
ideas	O
of	O
strategic	O
contingency	O
perspective	O
[	O
8	O
,	O
15	O
,	O
19	O
]	O
and	O
top	O
management	O
model	O
[	O
14	O
]	O
,	O
it	O
could	O
be	O
imply	O
that	O
success	O
(	O
organization	O
performance	O
)	O
in	O
reengineering	O
a	O
network	O
lies	O
in	O
the	O
integration	O
of	O
process	O
and	O
services	O
(	O
see	O
Figure	O
1	O
)	O
,	O
including	O
leadership	O
/	O
governing	O
structure	O
,	O
teamwork	O
between	O
disciplines	O
and	O
patient	B
care	O
,	O
financial	O
planning	O
,	O
and	O
information	O
systems	O
,	O
characterized	O
as	O
the	O
constructs	O
of	O
governance	O
,	O
clinical	O
,	O
financial	O
,	O
and	O
information	O
infrastructures	O
,	O
respectively	O
,	O
in	O
this	O
study	O
.	O

In	O
addition	O
,	O
another	O
construct	O
,	O
marketing	O
infrastructure	O
,	O
was	O
especially	O
important	O
and	O
designed	O
to	O
explore	O
for	O
PCCNs	O
in	O
this	O
study	O
because	O
of	O
patients	B
'	O
freedom	O
of	O
making	O
healthcare	O
choice	O
and	O
the	O
traditional	O
fragmented	O
health	O
care	O
systems	O
by	O
individual	O
health	O
care	O
organizations	O
in	O
Taiwan	O
.	O

One	O
major	O
reason	O
for	O
Taiwan	O
people	B
'	O
s	O
hospital	O
shopping	O
preferences	O
was	O
that	O
Taiwan	O
people	B
usually	O
believe	O
the	O
bigger	O
the	O
facility	O
,	O
the	O
better	O
capacities	O
a	O
facility	O
has	O
no	O
matter	O
on	O
any	O
aspect	O
from	O
medical	O
professionals	O
to	O
tangible	O
medical	O
equipment	O
and	O
plants	O
.	O

And	O
this	O
fallacy	O
made	O
the	O
public	O
want	O
to	O
overuse	O
the	O
facility	O
with	O
high	O
-	O
tech	O
medical	O
services	O
no	O
matter	O
if	O
it	O
fits	O
their	O
needs	O
.	O

From	O
the	O
health	O
policy	O
and	O
management	O
perspectives	O
,	O
therefore	O
,	O
the	O
health	O
care	O
providers	O
were	O
encouraged	O
to	O
market	O
their	O
services	O
as	O
a	O
new	O
corporate	O
identity	O
and	O
brand	O
strategy	O
[	O
37	O
]	O
,	O
including	O
offering	O
tangible	O
resources	O
such	O
as	O
books	O
,	O
libraries	O
,	O
medical	O
equipment	O
,	O
and	O
intangible	O
resources	O
such	O
as	O
knowledge	O
and	O
information	O
exchanges	O
(	O
education	O
)	O
and	O
reputation	O
sharing	O
one	O
another	O
among	O
PCCN	O
members	O
.	O

Furthermore	O
,	O
through	O
the	O
process	O
of	O
marketing	O
resource	O
exchanges	O
,	O
therefore	O
,	O
each	O
PCCN	O
could	O
establish	O
the	O
images	O
of	O
"	O
one	O
system	O
,	O
one	O
brand	O
and	O
quality	O
"	O
for	O
the	O
public	O
and	O
for	O
the	O
health	O
care	O
providers	O
.	O

It	O
also	O
makes	O
it	O
be	O
more	O
visible	O
to	O
the	O
public	O
.	O

The	O
five	O
integration	O
infrastructures	O
of	O
network	O
management	O
were	O
constructed	O
as	O
a	O
conceptual	O
framework	O
in	O
this	O
study	O
to	O
help	O
to	O
portray	O
how	O
the	O
PCCN	O
members	O
have	O
done	O
.	O

The	O
survey	O
instrument	O
development	O
was	O
described	O
in	O
the	O
following	O
.	O

Survey	O
instrument	O
development	O
:	O
integration	O
infrastructures	O
and	O
measurements	O
of	O
partnerships	O

Based	O
on	O
the	O
five	O
integration	O
infrastructures	O
of	O
network	O
management	O
,	O
the	O
structured	O
questionnaire	O
were	O
derived	O
from	O
extensive	O
literature	O
reviews	O
.	O

Governance	O
infrastructure	O

Governance	O
assumes	O
the	O
broad	O
responsibility	O
for	O
organizational	O
goals	O
and	O
survival	O
and	O
involves	O
the	O
series	O
process	O
of	O
setting	O
and	O
monitoring	O
organizational	O
goals	O
and	O
strategy	O
development	O
through	O
a	O
board	O
of	O
representatives	O
[	O
38	O
]	O
.	O

Governance	O
or	O
administrative	O
integration	O
infrastructure	O
in	O
establishing	O
network	O
partnerships	O
refers	O
to	O
administrative	O
structures	O
(	O
or	O
responsibilities	O
)	O
created	O
to	O
facilitate	O
communication	O
,	O
clear	O
lines	O
of	O
authority	O
,	O
accountability	O
,	O
and	O
responsibility	O
for	O
patient	B
care	O
services	O
;	O
to	O
negotiate	O
budgets	O
and	O
financial	O
trade	O
-	O
offs	O
;	O
and	O
to	O
present	O
a	O
cohesive	O
,	O
consistent	O
message	O
in	O
interactions	O
with	O
external	O
agencies	O
and	O
the	O
community	O
[	O
29	O
,	O
39	O
-	O
41	O
]	O
and	O
most	O
important	O
for	O
members	O
in	O
contract	O
agreements	O
,	O
to	O
manage	O
participation	O
[	O
33	O
]	O
.	O

From	O
a	O
multidisciplinary	O
perspective	O
,	O
Mitchell	O
and	O
Shortell	O
[	O
42	O
]	O
applied	O
the	O
concepts	O
of	O
governance	O
and	O
management	O
characteristics	O
in	O
effective	O
community	O
health	O
partnerships	O
.	O

The	O
construct	O
of	O
governance	O
involved	O
several	O
tasks	O
,	O
including	O
setting	O
priorities	O
for	O
strategic	O
goals	O
,	O
choosing	O
the	O
membership	O
composition	O
,	O
obtaining	O
the	O
necessary	O
financial	O
resources	O
,	O
and	O
setting	O
up	O
the	O
accountability	O
systems	O
,	O
and	O
so	O
on	O
.	O

The	O
construct	O
of	O
the	O
management	O
refers	O
to	O
the	O
tasks	O
of	O
engaging	O
and	O
maintaining	O
organizational	O
members	O
'	O
interest	O
in	O
a	O
shared	O
vision	O
and	O
mission	O
,	O
providing	O
appropriate	O
structures	O
and	O
coordination	O
mechanisms	O
for	O
the	O
specified	O
strategies	O
,	O
promoting	O
constructive	O
conflicts	O
and	O
managing	O
destructive	O
conflicts	O
,	O
implementing	O
information	O
systems	O
to	O
monitor	O
the	O
dynamics	O
,	O
adjusting	O
the	O
leadership	O
in	O
the	O
overall	O
membership	O
,	O
and	O
so	O
on	O
.	O

The	O
issues	O
of	O
governance	O
and	O
administrative	O
integration	O
in	O
the	O
PCCNs	O
could	O
include	O
[	O
2	O
,	O
38	O
,	O
40	O
,	O
41	O
,	O
43	O
-	O
47	O
]	O
:	O

*	O
planning	O
the	O
shared	O
visions	O
and	O
missions	O

*	O
determining	O
the	O
shared	O
service	O
strategies	O
,	O
cooperation	O
priorities	O
,	O
policies	O
and	O
principles	O

*	O
identifying	O
the	O
information	O
needed	O
and	O
how	O
to	O
get	O
it	O

*	O
organizing	O
the	O
network	O
dynamics	O
and	O
member	O
roles	O

*	O
leading	O
and	O
managing	O
the	O
conflicts	O
and	O
communication	O

*	O
designing	O
and	O
controlling	O
the	O
shared	O
network	O
performance	O
systems	O
,	O
including	O
indicator	O
settings	O
,	O
feedbacks	O
,	O
and	O
accountability	O
.	O

Clinical	O
infrastructure	O

The	O
idea	O
of	O
care	O
integration	O
begins	O
through	O
such	O
public	O
programs	O
that	O
include	O
social	O
workers	O
in	O
public	O
welfare	O
departments	O
,	O
caseworkers	O
in	O
mental	O
health	O
,	O
or	O
nurses	O
in	O
public	O
health	O
departments	O
.	O

In	O
the	O
late	O
1980s	O
,	O
care	O
integration	O
was	O
deemed	O
necessary	O
for	O
the	O
streamlining	O
of	O
care	O
and	O
negotiating	O
the	O
maze	O
of	O
long	O
-	O
term	O
care	O
services	O
.	O

At	O
that	O
time	O
,	O
it	O
was	O
referred	O
to	O
as	O
service	O
coordination	O
or	O
case	O
management	O
,	O
or	O
in	O
other	O
related	O
terms	O
[	O
29	O
]	O
.	O

The	O
purpose	O
of	O
care	O
integration	O
is	O
to	O
work	O
directly	O
with	O
patients	B
and	O
their	O
families	O
over	O
time	O
to	O
help	O
them	O
arrange	O
and	O
manage	O
the	O
complex	O
resources	O
that	O
patients	B
may	O
need	O
to	O
maintain	O
health	O
and	O
independent	O
functioning	O
.	O

At	O
the	O
same	O
time	O
,	O
care	O
integration	O
is	O
used	O
to	O
achieve	O
the	O
most	O
cost	O
-	O
effective	O
use	O
possible	O
of	O
scarce	O
resources	O
,	O
by	O
steering	O
patients	B
to	O
the	O
health	O
,	O
social	O
,	O
and	O
support	O
services	O
most	O
appropriate	O
for	O
them	O
at	O
a	O
given	O
time	O
[	O
29	O
]	O
.	O

Conrad	O
and	O
Dowling	O
[	O
33	O
]	O
pointed	O
out	O
that	O
to	O
coordinate	O
and	O
integrate	O
patient	B
care	O
relies	O
on	O
connecting	O
patient	B
services	O
at	O
the	O
different	O
stages	O
of	O
the	O
patient	B
care	O
processes	O
.	O

Care	O
coordination	O
in	O
integrated	O
networks	O
can	O
be	O
achieved	O
through	O
integration	O
of	O
training	O
programs	O
and	O
some	O
clinical	O
services	O
,	O
provision	O
of	O
complementary	O
clinical	O
capabilities	O
,	O
clinical	O
geographic	O
proximity	O
design	O
,	O
clear	O
role	O
definition	O
of	O
each	O
institution	O
,	O
commitment	O
and	O
flexibility	O
of	O
leaderships	O
and	O
medical	O
staffs	O
,	O
and	O
the	O
support	O
of	O
a	O
large	O
referring	O
physician	O
groups	O
embracing	O
the	O
affiliation	O
concepts	O
[	O
48	O
]	O
.	O

The	O
issues	O
of	O
clinical	O
integration	O
in	O
the	O
PCCNs	O
could	O
include	O
[	O
48	O
-	O
50	O
]	O
:	O

*	O
planning	O
and	O
differentiating	O
target	O
markets	O
based	O
on	O
the	O
clinical	O
services	O
of	O
the	O
network	O
members	O

*	O
uniting	O
individual	O
clinical	O
professionals	O
for	O
clinical	O
project	O
planning	O

*	O
designing	O
patient	B
-	O
centered	O
care	O
or	O
case	O
management	O
teams	O

*	O
establishing	O
committees	O
responsible	O
for	O
patient	B
-	O
centered	O
case	O
report	O
meetings	O
,	O
case	O
referral	O
,	O
transfer	O
,	O
and	O
tracing	O
,	O
file	O
management	O
(	O
record	O
and	O
information	O
exchanges	O
)	O
,	O
clinical	O
quality	O
management	O
(	O
quality	O
assurance	O
,	O
improvement	O
,	O
risk	O
and	O
malpractice	O
management	O
,	O
and	O
utilization	O
review	O
)	O
,	O
and	O
medical	O
continuing	O
education	O
and	O
on	O
-	O
job	O
education	O
.	O

Marketing	O
infrastructure	O

Marketing	O
integration	O
refers	O
to	O
how	O
to	O
work	O
together	O
as	O
a	O
whole	O
both	O
from	O
the	O
provider	O
and	O
patient	B
perspectives	O
.	O

One	O
of	O
the	O
case	O
reports	O
interviewing	O
developing	O
integrated	O
delivery	O
system	O
or	O
networks	O
realized	O
that	O
the	O
most	O
important	O
thing	O
is	O
how	O
an	O
integrated	O
system	O
or	O
network	O
is	O
promoted	O
and	O
what	O
is	O
promoted	O
for	O
the	O
consumers	O
[	O
51	O
]	O
,	O
including	O
focusing	O
on	O
product	O
development	O
,	O
making	O
sure	O
the	O
branding	O
holds	O
together	O
,	O
marketing	O
directly	O
to	O
consumers	O
,	O
demonstrating	O
values	O
to	O
consumers	O
,	O
and	O
even	O
conducting	O
marketing	O
research	O
to	O
make	O
efforts	O
for	O
the	O
long	O
term	O
.	O

In	O
a	O
health	O
care	O
network	O
with	O
several	O
organizational	O
members	O
and	O
target	O
patients	B
,	O
the	O
marketing	O
infrastructure	O
in	O
PCCNs	O
here	O
refers	O
to	O
provider	O
members	O
'	O
marketing	O
,	O
meaning	O
the	O
resource	O
sharing	O
and	O
market	O
development	O
in	O
a	O
PCCN	O
as	O
a	O
whole	O
.	O

The	O
issues	O
of	O
the	O
marketing	O
integration	O
in	O
the	O
PCCNs	O
could	O
include	O
[	O
37	O
,	O
52	O
-	O
54	O
]	O
:	O

*	O
sharing	O
the	O
literature	O
and	O
facility	O
publications	O
among	O
the	O
network	O
members	O

*	O
uniting	O
public	O
promotions	O
such	O
as	O
united	O
activities	O
,	O
electronic	O
and	O
paper	O
media	O
for	O
enhancing	O
the	O
network	O
reputation	O
as	O
"	O
one	O
system	O
,	O
one	O
brand	O
and	O
quality	O
"	O

*	O
differentiating	O
target	O
markets	O
of	O
the	O
network	O
for	O
competing	O
in	O
the	O
medical	O
industry	O
.	O

Financial	O
infrastructure	O

Comprehensive	O
,	O
flexible	O
,	O
and	O
adequate	O
financing	O
is	O
a	O
goal	O
of	O
the	O
ideal	O
continuum	O
of	O
care	O
.	O

That	O
component	O
is	O
the	O
most	O
critical	O
and	O
challenging	O
to	O
manage	O
under	O
the	O
changes	O
in	O
the	O
health	O
care	O
delivery	O
environment	O
.	O

Gillies	O
et	O
al	O
.	O

[	O
30	O
]	O
suggested	O
that	O
integrating	O
financial	O
management	O
across	O
operating	O
units	O
adds	O
the	O
greatest	O
value	O
to	O
systems	O
or	O
organizations	O
.	O

In	O
one	O
case	O
study	O
,	O
Bramson	O
et	O
al	O
.	O

[	O
55	O
]	O
also	O
showed	O
that	O
reducing	O
costs	O
through	O
joint	O
purchasing	O
by	O
the	O
radiology	O
departments	O
of	O
a	O
vertically	O
integrated	O
health	O
system	O
could	O
yield	O
substantial	O
savings	O
.	O

The	O
issues	O
of	O
the	O
financial	O
integration	O
in	O
the	O
PCCNs	O
could	O
include	O
:	O

*	O
budgeting	O

*	O
uniting	O
equipment	O
,	O
medical	O
materials	O
,	O
and	O
drug	O
purchasing	O
and	O
routine	O
administrative	O
stuff	O
management	O

*	O
pooling	O
recruitment	O
funds	O

*	O
designing	O
a	O
financial	O
risk	O
and	O
sharing	O
mechanism	O
.	O

Information	O
infrastructure	O

Information	O
is	O
an	O
essential	O
component	O
of	O
an	O
organization	O
.	O

A	O
complete	O
information	O
system	O
can	O
help	O
an	O
organization	O
to	O
integrate	O
its	O
individual	O
units	O
and	O
efficiently	O
manage	O
the	O
continuum	O
.	O

The	O
ideal	O
information	O
system	O
for	O
a	O
continuum	O
of	O
care	O
was	O
conceived	O
of	O
and	O
formed	O
in	O
the	O
mid	O
-	O
1980s	O
[	O
56	O
]	O
.	O

During	O
the	O
late	O
1980s	O
,	O
computer	O
technology	O
began	O
to	O
make	O
an	O
information	O
system	O
feasible	O
and	O
affordable	O
through	O
new	O
computer	O
chips	O
with	O
expanded	O
capability	O
and	O
networking	O
technology	O
.	O

In	O
the	O
1990s	O
,	O
the	O
individual	O
services	O
of	O
the	O
continuum	O
upgraded	O
their	O
information	O
systems	O
to	O
combine	O
clinical	O
,	O
financial	O
,	O
and	O
utilization	O
data	O
[	O
29	O
]	O
.	O

Some	O
studies	O
have	O
argued	O
that	O
the	O
quality	O
of	O
information	O
systems	O
can	O
drive	O
costs	O
down	O
,	O
because	O
a	O
good	O
information	O
system	O
can	O
give	O
physicians	O
easy	O
electronic	O
access	O
to	O
complete	O
the	O
documentation	O
of	O
the	O
patients	B
'	O
clinical	O
records	O
,	O
better	O
inform	O
them	O
about	O
reimbursement	O
and	O
capitation	O
issues	O
,	O
help	O
them	O
easily	O
associate	O
and	O
manage	O
cases	O
together	O
,	O
and	O
achieve	O
a	O
higher	O
level	O
of	O
professional	O
satisfaction	O
[	O
57	O
,	O
58	O
]	O
.	O

Using	O
Inova	O
Health	O
System	O
,	O
an	O
integrated	O
delivery	O
system	O
in	O
northern	O
Virginia	O
,	O
as	O
an	O
example	O
,	O
Wager	O
,	O
Heda	O
,	O
and	O
Austin	O
[	O
59	O
]	O
showed	O
that	O
by	O
developing	O
a	O
health	O
information	O
network	O
within	O
an	O
integrated	O
delivery	O
system	O
,	O
Inova	O
can	O
have	O
a	O
clinical	O
transaction	O
system	O
for	O
hospitals	O
and	O
other	O
entities	O
,	O
a	O
data	O
repository	O
for	O
decision	O
support	O
and	O
outcome	O
management	O
,	O
a	O
managed	O
care	O
information	O
system	O
to	O
support	O
managed	O
care	O
and	O
capitation	O
contracts	O
,	O
and	O
greater	O
capability	O
to	O
acquire	O
physicians	O
.	O

The	O
issues	O
of	O
information	O
coordination	O
include	O
[	O
60	O
-	O
68	O
]	O
:	O

*	O
establishing	O
an	O
electronic	O
medical	O
record	O
system	O
,	O
regional	O
information	O
network	O
for	O
patient	B
clinical	O
and	O
administrative	O
data	O
,	O
clinical	O
service	O
arrangements	O
and	O
administrative	O
work	O

*	O
uniting	O
the	O
system	O
information	O
management	O
and	O
web	O
pages	O
.	O

The	O
structured	O
questionnaire	O
was	O
developed	O
with	O
the	O
wording	O
of	O
practical	O
managerial	O
actions	O
based	O
on	O
the	O
five	O
concepts	O
just	O
mentioned	O
.	O

There	O
were	O
19	O
survey	O
items	O
on	O
governance	O
infrastructure	O
,	O
25	O
on	O
clinical	O
infrastructure	O
,	O
13	O
on	O
marketing	O
infrastructure	O
,	O
20	O
on	O
financial	O
infrastructure	O
,	O
and	O
7	O
on	O
information	O
infrastructure	O
.	O

All	O
84	O
items	O
were	O
,	O
simultaneously	O
,	O
applied	O
to	O
examine	O
the	O
relationships	O
of	O
the	O
clinic	O
'	O
s	O
peer	O
members	O
and	O
the	O
relationship	O
of	O
clinic	O
and	O
hospital	O
members	O
in	O
a	O
PCCN	O
,	O
and	O
it	O
resulted	O
in	O
a	O
total	O
of	O
168	O
survey	O
questions	O
.	O

The	O
detailed	O
information	O
of	O
the	O
item	O
questions	O
was	O
listed	O
in	O
Table	O
2	O
,	O
3	O
,	O
4	O
,	O
5	O
,	O
6	O
.	O

The	O
structured	O
questionnaires	O
were	O
drafted	O
from	O
previous	O
literatures	O
and	O
then	O
examined	O
by	O
two	O
academic	O
professors	O
for	O
theoretical	O
accuracy	O
.	O

Then	O
one	O
pilot	O
study	O
was	O
pre	O
-	O
tested	O
for	O
the	O
PCCN	O
pioneers	O
(	O
i	O
.	O
e	O
.	O
,	O
92	O
network	O
clinic	O
members	O
)	O
and	O
116	O
hospital	O
providers	O
which	O
have	O
partner	O
relationships	O
with	O
other	O
health	O
care	O
organizations	O
(	O
i	O
.	O
e	O
.	O
,	O
hospitals	O
,	O
clinics	O
,	O
long	O
-	O
term	O
care	O
facilities	O
)	O
.	O

The	O
wordings	O
and	O
meanings	O
of	O
each	O
question	O
item	O
were	O
revised	O
to	O
assure	O
content	O
validity	O
.	O

The	O
Cronbach	O
alpha	O
values	O
for	O
the	O
five	O
integration	O
constructs	O
-	O
governance	O
,	O
clinical	O
,	O
marketing	O
,	O
finance	O
,	O
and	O
information	O
infrastructure	O
were	O
0	O
.	O
946	O
,	O
0	O
.	O
958	O
,	O
0	O
.	O
932	O
,	O
0	O
.	O
944	O
,	O
and	O
0	O
.	O
898	O
for	O
the	O
measures	O
of	O
clinic	O
-	O
clinic	O
member	O
relationships	O
;	O
and	O
0	O
.	O
945	O
,	O
0	O
.	O
949	O
,	O
0	O
.	O
916	O
,	O
0	O
.	O
948	O
,	O
and	O
0	O
.	O
896	O
for	O
the	O
measures	O
of	O
clinic	O
-	O
hospital	O
member	O
relationships	O
.	O

Study	O
subjects	O

To	O
find	O
the	O
member	O
partnership	O
,	O
we	O
sent	O
questionnaires	O
to	O
1	O
,	O
557	O
individual	O
clinics	O
which	O
had	O
belonged	O
to	O
PCCNs	O
for	O
at	O
least	O
one	O
year	O
,	O
based	O
on	O
information	O
contained	O
in	O
the	O
Taiwan	O
Primary	O
Community	O
Care	O
Network	O
List	O
(	O
Bureau	O
of	O
National	O
Health	O
Insurance	O
2003	O
,	O
2004	O
and	O
2005	O
)	O
.	O

We	O
let	O
clinic	O
members	O
in	O
all	O
PCCNs	O
point	O
out	O
how	O
they	O
coordinate	O
with	O
their	O
peer	O
clinic	O
members	O
and	O
hospital	O
members	O
within	O
a	O
PCCN	O
because	O
individual	O
clinic	O
members	O
could	O
be	O
better	O
informants	O
than	O
hospital	O
members	O
,	O
which	O
need	O
to	O
deal	O
with	O
multiple	O
clinic	O
relationships	O
and	O
therefore	O
might	O
find	O
it	O
hard	O
to	O
describe	O
the	O
coordination	O
involvement	O
one	O
by	O
one	O
with	O
clinic	O
members	O
.	O

Moreover	O
,	O
networks	O
form	O
for	O
various	O
reasons	O
and	O
it	O
might	O
lead	O
to	O
the	O
various	O
involvements	O
by	O
individual	O
network	O
members	O
(	O
i	O
.	O
e	O
.	O
,	O
hospital	O
and	O
clinic	O
members	O
)	O
.	O

Therefore	O
,	O
using	O
the	O
participating	O
clinics	O
as	O
individual	O
survey	O
units	O
,	O
the	O
results	O
could	O
portray	O
the	O
overall	O
dynamics	O
and	O
processes	O
more	O
authentically	O
and	O
detailed	O
throughout	O
all	O
PCCNs	O
in	O
the	O
demonstration	O
project	O
.	O

Nine	O
hundred	O
and	O
twenty	O
-	O
eight	O
clinics	O
responded	O
(	O
59	O
.	O
6	O
%	O
)	O
,	O
with	O
239	O
clinics	O
in	O
the	O
Taipei	O
region	O
,	O
165	O
in	O
the	O
northern	O
region	O
,	O
241	O
in	O
the	O
central	O
region	O
,	O
108	O
in	O
the	O
southern	O
region	O
,	O
150	O
in	O
the	O
Kao	O
-	O
Ping	O
region	O
,	O
and	O
15	O
in	O
the	O
eastern	O
region	O
of	O
Taiwan	O
.	O

Ten	O
clinics	O
had	O
not	O
mentioned	O
their	O
practicing	O
locations	O
.	O

There	O
is	O
no	O
statistically	O
significant	O
difference	O
in	O
geographical	O
distribution	O
between	O
the	O
respondents	O
and	O
the	O
study	O
population	O
(	O
chi	O
2	O
=	O
4	O
.	O
208	O
,	O
p	O
>	O
0	O
.	O
05	O
)	O
.	O

Analytical	O
techniques	O

The	O
data	O
was	O
first	O
analyzed	O
descriptively	O
with	O
frequency	O
counts	O
(	O
percentage	O
)	O
for	O
each	O
survey	O
item	O
,	O
instead	O
of	O
using	O
mean	O
as	O
a	O
statistical	O
method	O
,	O
because	O
the	O
variation	O
among	O
the	O
respondents	O
may	O
not	O
represent	O
the	O
normal	O
distribution	O
and	O
it	O
might	O
ignore	O
the	O
extreme	O
values	O
for	O
the	O
respondents	O
'	O
answers	O
.	O

To	O
compare	O
how	O
the	O
respondents	O
perceived	O
the	O
strength	O
of	O
integration	O
existing	O
in	O
clinic	O
-	O
clinic	O
and	O
clinic	O
-	O
hospital	O
relationships	O
,	O
paired	O
t	O
-	O
tests	O
were	O
performed	O
for	O
individual	O
survey	O
items	O
,	O
using	O
the	O
original	O
numerical	O
scores	O
.	O

Results	O

Profiling	O
the	O
partnerships	O
in	O
Taiwan	O
PCCNs	O
:	O
governance	O
infrastructure	O

With	O
regard	O
to	O
the	O
governance	O
infrastructures	O
,	O
the	O
frequency	O
was	O
counted	O
for	O
each	O
survey	O
item	O
with	O
recalculated	O
scales	O
:	O
disagree	O
(	O
Likert	O
scale	O
1	O
and	O
2	O
)	O
,	O
fair	O
(	O
Likert	O
scale	O
3	O
)	O
,	O
and	O
agree	O
(	O
Likert	O
scale	O
4	O
and	O
5	O
)	O
with	O
individual	O
items	O
.	O

In	O
clinic	O
-	O
clinic	O
relationship	O
(	O
Table	O
2	O
)	O
,	O
the	O
majority	O
of	O
clinic	O
members	O
agree	O
that	O
the	O
determined	O
deals	O
were	O
obeyed	O
(	O
Table	O
2	O
,	O
item	O
1	O
:	O
88	O
.	O
69	O
%	O
)	O
,	O
the	O
goals	O
and	O
strategies	O
of	O
members	O
were	O
well	O
-	O
understood	O
(	O
Table	O
2	O
,	O
item	O
16	O
:	O
79	O
.	O
74	O
%	O
)	O
,	O
and	O
the	O
united	O
principals	O
for	O
individual	O
members	O
were	O
developed	O
(	O
Table	O
2	O
,	O
item	O
15	O
:	O
79	O
.	O
42	O
%	O
)	O
.	O

The	O
higher	O
percentages	O
were	O
also	O
found	O
in	O
clinic	O
-	O
hospital	O
relationship	O
in	O
the	O
same	O
items	O
(	O
Table	O
2	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
establishing	O
fair	O
coordination	O
mechanism	O
(	O
Table	O
2	O
,	O
item	O
11	O
:	O
27	O
.	O
91	O
%	O
)	O
,	O
designing	O
and	O
employing	O
the	O
network	O
performance	O
indicators	O
(	O
Table	O
2	O
,	O
item	O
3	O
:	O
21	O
.	O
23	O
%	O
)	O
,	O
and	O
establishing	O
communication	O
models	O
and	O
channels	O
(	O
Table	O
2	O
,	O
item	O
12	O
:	O
19	O
.	O
94	O
%	O
)	O
still	O
occupied	O
higher	O
percentages	O
not	O
developed	O
and	O
deserved	O
to	O
been	O
made	O
the	O
focus	O
of	O
more	O
efforts	O
in	O
the	O
future	O
.	O

Paired	O
t	O
-	O
test	O
analyses	O
for	O
all	O
individual	O
survey	O
items	O
of	O
governance	O
infrastructure	O
showed	O
that	O
the	O
deals	O
obeyed	O
(	O
Table	O
2	O
,	O
item1	O
)	O
and	O
plans	O
and	O
goals	O
controlled	O
(	O
Table	O
2	O
,	O
item	O
2	O
)	O
were	O
achieved	O
more	O
in	O
clinic	O
-	O
clinic	O
relationships	O
than	O
those	O
in	O
clinic	O
-	O
hospital	O
relationships	O
;	O
however	O
,	O
the	O
design	O
of	O
network	O
performance	O
indicators	O
(	O
Table	O
2	O
,	O
item	O
3	O
)	O
,	O
development	O
of	O
disintegration	O
policy	O
and	O
principals	O
(	O
Table	O
2	O
,	O
item	O
8	O
)	O
,	O
and	O
the	O
establishment	O
of	O
fair	O
coordination	O
mechanism	O
(	O
Table	O
2	O
,	O
item	O
11	O
)	O
were	O
reached	O
more	O
in	O
clinic	O
-	O
hospital	O
relationships	O
than	O
those	O
in	O
clinic	O
-	O
clinic	O
relationships	O
.	O

Profiling	O
the	O
partnerships	O
in	O
Taiwan	O
PCCNs	O
:	O
clinical	O
infrastructure	O

Examining	O
the	O
extent	O
of	O
clinical	O
infrastructure	O
for	O
network	O
members	O
,	O
establishing	O
two	O
-	O
directed	O
patient	B
referral	O
systems	O
and	O
patient	B
referral	O
information	O
files	O
(	O
Table	O
3	O
,	O
items	O
35	O
&	O
37	O
)	O
and	O
uniting	O
medical	O
continuing	O
education	O
and	O
on	O
-	O
job	O
education	O
(	O
Table	O
3	O
,	O
item	O
34	O
)	O
were	O
shown	O
at	O
a	O
highly	O
implemented	O
rate	O
in	O
clinic	O
-	O
clinic	O
(	O
more	O
than	O
70	O
%	O
)	O
and	O
clinic	O
-	O
hospital	O
(	O
more	O
than	O
80	O
%	O
)	O
relationships	O
.	O

On	O
the	O
other	O
hand	O
,	O
network	O
members	O
had	O
higher	O
percentages	O
(	O
more	O
than	O
40	O
%	O
)	O
not	O
to	O
think	O
about	O
the	O
possible	O
integration	O
mechanisms	O
including	O
establishing	O
committees	O
to	O
deal	O
with	O
medical	O
malpractice	O
(	O
Table	O
3	O
,	O
item	O
44	O
)	O
,	O
planning	O
and	O
differentiating	O
clinical	O
market	O
areas	O
(	O
Table	O
3	O
,	O
item	O
20	O
)	O
,	O
and	O
designing	O
patient	B
-	O
centered	O
case	O
management	O
teams	O
(	O
Table	O
3	O
,	O
item	O
22	O
)	O
.	O

Overall	O
,	O
there	O
was	O
better	O
clinical	O
integration	O
involvement	O
for	O
all	O
the	O
described	O
items	O
in	O
clinic	O
-	O
hospital	O
relationships	O
than	O
those	O
in	O
clinic	O
-	O
clinic	O
relationships	O
within	O
a	O
network	O
in	O
this	O
study	O
(	O
see	O
Table	O
3	O
,	O
paired	O
t	O
-	O
tests	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Profiling	O
the	O
partnerships	O
in	O
Taiwan	O
PCCNs	O
:	O
marketing	O
infrastructure	O

For	O
marketing	O
planning	O
,	O
the	O
clinics	O
had	O
better	O
integrated	O
marketing	O
activities	O
with	O
their	O
respective	O
hospitals	O
than	O
with	O
peer	O
clinic	O
members	O
within	O
PCCNs	O
for	O
all	O
studied	O
items	O
(	O
Table	O
4	O
,	O
paired	O
t	O
-	O
test	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Examining	O
the	O
clinic	O
-	O
clinic	O
relationships	O
,	O
uniting	O
social	O
activities	O
(	O
Table	O
4	O
,	O
item	O
53	O
)	O
,	O
sharing	O
the	O
individual	O
facility	O
reports	O
for	O
updated	O
services	O
(	O
Table	O
4	O
,	O
item	O
46	O
)	O
,	O
public	O
promotion	O
(	O
Table	O
4	O
,	O
item	O
54	O
)	O
,	O
and	O
uniting	O
and	O
joining	O
the	O
facility	O
activities	O
(	O
Table	O
4	O
,	O
item	O
51	O
)	O
were	O
the	O
top	O
four	O
marketing	O
works	O
done	O
among	O
clinic	O
members	O
(	O
more	O
than	O
60	O
%	O
implemented	O
rate	O
)	O
;	O
and	O
those	O
items	O
also	O
showed	O
a	O
higher	O
implemented	O
rate	O
(	O
more	O
than	O
70	O
%	O
)	O
between	O
clinic	O
and	O
hospital	O
members	O
.	O

On	O
the	O
other	O
hand	O
,	O
facility	O
assets	O
such	O
as	O
reports	O
(	O
Table	O
4	O
,	O
item	O
49	O
)	O
,	O
and	O
professional	O
literatures	O
and	O
books	O
(	O
Table	O
4	O
,	O
item	O
45	O
)	O
were	O
not	O
well	O
-	O
shared	O
among	O
clinic	O
members	O
(	O
"	O
never	O
-	O
thinking	O
"	O
rate	O
:	O
42	O
.	O
13	O
%	O
)	O
.	O

In	O
addition	O
,	O
uniting	O
the	O
network	O
publication	O
could	O
make	O
more	O
efforts	O
in	O
the	O
future	O
(	O
"	O
never	O
-	O
thinking	O
"	O
rate	O
in	O
item	O
50	O
:	O
39	O
.	O
98	O
%	O
)	O
.	O

The	O
room	O
for	O
clinic	O
-	O
hospital	O
partnership	O
to	O
think	O
about	O
acting	O
was	O
kind	O
of	O
different	O
from	O
those	O
in	O
the	O
clinic	O
-	O
clinic	O
relationship	O
.	O

In	O
addition	O
to	O
the	O
uniting	O
publication	O
that	O
can	O
be	O
encouraged	O
to	O
improve	O
the	O
clinic	O
-	O
hospital	O
relationship	O
(	O
Table	O
4	O
,	O
item	O
50	O
:	O
27	O
.	O
48	O
%	O
)	O
,	O
cooperating	O
in	O
research	O
projects	O
(	O
Table	O
4	O
,	O
item	O
52	O
:	O
25	O
.	O
00	O
%	O
)	O
and	O
identifying	O
and	O
differentiating	O
target	O
markets	O
(	O
Table	O
4	O
,	O
item	O
57	O
:	O
24	O
.	O
57	O
%	O
)	O
had	O
still	O
more	O
opportunities	O
to	O
be	O
focused	O
on	O
in	O
the	O
future	O
.	O

Profiling	O
the	O
partnerships	O
in	O
Taiwan	O
PCCNs	O
:	O
financial	O
infrastructure	O

The	O
PCCN	O
members	O
were	O
found	O
to	O
have	O
a	O
lower	O
extent	O
of	O
financial	O
integration	O
as	O
evidenced	O
by	O
higher	O
percentage	O
of	O
'	O
'	O
never	O
thinking	O
'	O
'	O
scale	O
about	O
the	O
survey	O
items	O
on	O
almost	O
all	O
items	O
(	O
see	O
Table	O
5	O
)	O
.	O

Slightly	O
more	O
integration	O
(	O
that	O
is	O
,	O
'	O
'	O
acting	O
'	O
'	O
rate	O
)	O
was	O
found	O
in	O
only	O
four	O
items	O
both	O
in	O
clinic	O
-	O
clinic	O
relationships	O
and	O
in	O
clinic	O
-	O
hospital	O
relationships	O
,	O
including	O
uniting	O
budget	O
planning	O
(	O
Table	O
5	O
:	O
item	O
58	O
)	O
,	O
sharing	O
places	O
,	O
materials	O
,	O
and	O
equipment	O
(	O
Table	O
5	O
:	O
item	O
68	O
)	O
,	O
uniting	O
budgeting	O
for	O
certain	O
services	O
(	O
Table	O
5	O
:	O
items	O
72	O
)	O
,	O
and	O
designing	O
the	O
resource	O
distribution	O
principals	O
based	O
on	O
the	O
whole	O
network	O
goals	O
(	O
Table	O
5	O
:	O
item	O
77	O
)	O
.	O

Further	O
examining	O
the	O
financial	O
infrastructure	O
in	O
clinic	O
-	O
clinic	O
relationship	O
and	O
clinic	O
-	O
hospital	O
relationship	O
,	O
paired	O
-	O
t	O
tests	O
revealed	O
that	O
clinic	O
-	O
hospital	O
partnerships	O
were	O
involved	O
more	O
in	O
places	O
,	O
materials	O
,	O
and	O
equipment	O
sharing	O
and	O
maintenance	O
(	O
Table	O
5	O
,	O
items	O
62	O
and	O
68	O
)	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
and	O
higher	O
financial	O
infrastructure	O
coordination	O
exists	O
in	O
clinic	O
-	O
clinic	O
relationships	O
(	O
Table	O
5	O
,	O
items	O
58	O
,	O
59	O
,	O
63	O
-	O
65	O
,	O
72	O
,	O
74	O
,	O
75	O
,	O
and	O
77	O
)	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Profiling	O
the	O
partnerships	O
in	O
Taiwan	O
PCCNs	O
:	O
information	O
infrastructure	O

There	O
was	O
significantly	O
greater	O
integration	O
of	O
information	O
in	O
clinic	O
-	O
hospital	O
than	O
clinic	O
-	O
clinic	O
relationships	O
in	O
all	O
items	O
in	O
this	O
category	O
(	O
Table	O
6	O
,	O
paired	O
t	O
-	O
tests	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

The	O
greatest	O
integration	O
was	O
found	O
in	O
electronic	O
patient	B
records	O
(	O
Table	O
6	O
:	O
item	O
78	O
)	O
,	O
followed	O
by	O
information	O
integration	O
for	O
patient	B
data	O
(	O
Table	O
6	O
:	O
item	O
79	O
)	O
and	O
clinical	O
service	O
arrangements	O
(	O
Table	O
6	O
:	O
item	O
81	O
)	O
.	O

The	O
lowest	O
level	O
of	O
integration	O
in	O
information	O
infrastructure	O
was	O
found	O
in	O
administrative	O
works	O
such	O
as	O
registration	O
,	O
billing	O
and	O
so	O
on	O
(	O
Table	O
6	O
:	O
item	O
82	O
,	O
'	O
'	O
never	O
-	O
thinking	O
'	O
'	O
rate	O
more	O
than	O
50	O
%	O
)	O
within	O
network	O
members	O
.	O

Discussion	O

In	O
this	O
study	O
,	O
we	O
surveyed	O
943	O
clinics	O
that	O
had	O
belonged	O
to	O
Taiwan	O
PCCNs	O
for	O
more	O
than	O
a	O
year	O
to	O
understand	O
the	O
nature	O
and	O
extent	O
of	O
integration	O
to	O
which	O
they	O
and	O
their	O
associated	O
PCCN	O
members	O
(	O
clinics	O
and	O
hospitals	O
)	O
had	O
in	O
governance	O
,	O
clinical	O
,	O
marketing	O
,	O
financial	O
,	O
and	O
information	O
infrastructures	O
.	O

It	O
was	O
found	O
a	O
wide	O
variance	O
in	O
the	O
kind	O
and	O
degree	O
of	O
integration	O
among	O
them	O
and	O
a	O
lot	O
of	O
room	O
for	O
better	O
integration	O
(	O
Table	O
2	O
,	O
3	O
,	O
4	O
,	O
5	O
,	O
6	O
)	O
.	O

From	O
the	O
governance	O
perspective	O
,	O
we	O
found	O
lower	O
integration	O
was	O
found	O
in	O
the	O
establishment	O
of	O
fair	O
coordination	O
mechanism	O
(	O
Table	O
2	O
:	O
item	O
11	O
)	O
among	O
member	O
clinics	O
and	O
member	O
hospitals	O
.	O

Coordination	O
could	O
be	O
viewed	O
from	O
different	O
perspectives	O
,	O
including	O
the	O
use	O
of	O
standardized	O
languages	O
and	O
forms	O
,	O
organizational	O
rules	O
and	O
procedures	O
,	O
the	O
establishment	O
of	O
common	O
rules	O
,	O
policies	O
,	O
and	O
procedures	O
,	O
and	O
the	O
monitoring	O
through	O
memos	O
,	O
reports	O
,	O
and	O
a	O
computerized	O
information	O
system	O
[	O
69	O
,	O
70	O
]	O
.	O

Facing	O
the	O
cumbersome	O
integration	O
processes	O
,	O
it	O
suggests	O
that	O
each	O
PCCN	O
'	O
s	O
headquarters	O
should	O
become	O
actively	O
involved	O
and	O
clarify	O
the	O
authority	O
,	O
responsibility	O
and	O
accountability	O
of	O
individual	O
members	O
,	O
identify	O
the	O
potential	O
conflict	O
sources	O
,	O
and	O
publicize	O
the	O
rules	O
and	O
regulation	O
of	O
network	O
integration	O
dynamics	O
covering	O
decision	O
making	O
processes	O
,	O
market	O
planning	O
,	O
clinical	O
teamwork	O
designs	O
,	O
and	O
financial	O
reports	O
of	O
individual	O
network	O
members	O
.	O

These	O
actions	O
could	O
enhance	O
the	O
trust	O
and	O
respect	O
of	O
network	O
members	O
one	O
another	O
and	O
could	O
improve	O
the	O
small	O
extent	O
of	O
integration	O
found	O
in	O
this	O
study	O
about	O
the	O
mechanisms	O
for	O
communication	O
models	O
and	O
channels	O
in	O
the	O
PCCNs	O
(	O
Table	O
2	O
:	O
item	O
12	O
)	O
.	O

From	O
the	O
network	O
management	O
perspective	O
,	O
communication	O
could	O
occur	O
between	O
the	O
various	O
entities	O
such	O
as	O
between	O
hospital	O
and	O
clinics	O
,	O
primary	O
care	O
physicians	O
and	O
specialists	O
,	O
managers	O
and	O
clinical	O
professionals	O
,	O
and	O
even	O
among	O
the	O
clinical	O
professionals	O
in	O
the	O
network	O
.	O

To	O
develop	O
effective	O
and	O
timely	O
communication	O
channels	O
was	O
the	O
key	O
for	O
the	O
management	O
of	O
integrated	O
organizations	O
[	O
30	O
-	O
32	O
]	O
and	O
could	O
alleviate	O
the	O
tensions	O
that	O
sometimes	O
occur	O
in	O
the	O
dynamics	O
of	O
the	O
multi	O
-	O
organizations	O
.	O

In	O
this	O
study	O
,	O
it	O
was	O
found	O
a	O
low	O
level	O
of	O
involvement	O
of	O
medical	O
teams	O
in	O
medical	O
projects	O
,	O
patient	B
-	O
centered	O
case	O
management	O
,	O
and	O
case	O
report	O
meetings	O
among	O
the	O
network	O
members	O
(	O
Table	O
3	O
:	O
item	O
21	O
,	O
22	O
,	O
and	O
23	O
)	O
from	O
a	O
clinical	O
integration	O
perspective	O
.	O

Several	O
researchers	O
have	O
addressed	O
that	O
clinical	O
integration	O
providing	O
a	O
process	O
of	O
medical	O
management	O
,	O
care	O
management	O
,	O
case	O
management	O
,	O
and	O
patient	B
management	O
designed	O
to	O
transform	O
the	O
traditionally	O
fragmented	O
delivery	O
system	O
into	O
a	O
more	O
cohesive	O
system	O
[	O
71	O
]	O
,	O
and	O
lead	O
to	O
higher	O
service	O
quality	O
and	O
assure	O
financial	O
objectives	O
[	O
72	O
,	O
73	O
]	O
.	O

More	O
attention	O
could	O
be	O
paid	O
to	O
these	O
activities	O
in	O
the	O
future	O
.	O

In	O
addition	O
,	O
it	O
was	O
also	O
found	O
less	O
integration	O
in	O
planning	O
and	O
differentiating	O
clinical	O
market	O
areas	O
(	O
Table	O
3	O
,	O
item	O
20	O
)	O
among	O
the	O
network	O
members	O
in	O
the	O
category	O
of	O
clinical	O
infrastructure	O
.	O

This	O
may	O
result	O
from	O
the	O
existing	O
specialty	O
diversities	O
in	O
individual	O
PCCNs	O
,	O
which	O
might	O
not	O
need	O
to	O
involve	O
planning	O
and	O
differentiating	O
market	O
area	O
based	O
on	O
the	O
members	O
'	O
clinical	O
services	O
at	O
the	O
early	O
stage	O
of	O
network	O
development	O
.	O

There	O
was	O
more	O
involvement	O
in	O
marketing	O
efforts	O
in	O
clinic	O
-	O
hospital	O
relationships	O
than	O
in	O
clinic	O
-	O
clinic	O
relationships	O
.	O

Generally	O
speaking	O
,	O
hospitals	O
have	O
more	O
resources	O
(	O
i	O
.	O
e	O
.	O
,	O
money	O
,	O
human	B
resources	O
,	O
materials	O
,	O
and	O
physical	O
assets	O
)	O
than	O
clinics	O
,	O
which	O
might	O
explain	O
the	O
stronger	O
marketing	O
involvements	O
between	O
the	O
clinic	O
and	O
hospital	O
members	O
,	O
including	O
the	O
library	O
sharing	O
(	O
books	O
and	O
literatures	O
)	O
,	O
facility	O
brochure	O
dissemination	O
,	O
public	O
promoting	O
,	O
and	O
medical	O
research	O
cooperation	O
.	O

These	O
integration	O
efforts	O
also	O
meet	O
the	O
expectation	O
of	O
the	O
national	O
health	O
authority	O
for	O
resource	O
sharing	O
and	O
medical	O
quality	O
image	O
enhancement	O
among	O
the	O
health	O
care	O
providers	O
.	O

Financial	O
infrastructure	O
was	O
found	O
to	O
be	O
the	O
least	O
integrated	O
,	O
with	O
most	O
items	O
never	O
considered	O
.	O

Perhaps	O
the	O
only	O
reason	O
for	O
the	O
higher	O
score	O
of	O
budget	O
planning	O
activities	O
(	O
Table	O
5	O
:	O
items	O
58	O
and	O
77	O
)	O
was	O
that	O
BHNI	O
required	O
each	O
PCCN	O
to	O
design	O
and	O
determine	O
its	O
budgeting	O
arrangement	O
in	O
advance	O
before	O
joining	O
the	O
demonstration	O
project	O
.	O

While	O
slightly	O
more	O
financial	O
involvement	O
was	O
made	O
among	O
network	O
members	O
(	O
Table	O
5	O
:	O
items	O
68	O
,	O
72	O
&	O
73	O
)	O
,	O
possibly	O
due	O
to	O
similar	O
needs	O
,	O
there	O
remains	O
a	O
lot	O
of	O
room	O
for	O
financial	O
integration	O
in	O
the	O
future	O
.	O

There	O
was	O
a	O
need	O
for	O
networks	O
to	O
develop	O
electronic	O
information	O
systems	O
,	O
though	O
creating	O
and	O
managing	O
an	O
integrated	O
information	O
system	O
involves	O
very	O
detailed	O
work	O
.	O

Most	O
of	O
the	O
clinics	O
surveyed	O
have	O
focused	O
more	O
on	O
the	O
individual	O
public	O
members	O
'	O
administrative	O
works	O
such	O
as	O
filing	O
patient	B
medical	O
records	O
,	O
collecting	O
and	O
managing	O
network	O
patient	B
clinical	O
data	O
,	O
and	O
scheduling	O
clinical	O
services	O
,	O
which	O
were	O
required	O
by	O
the	O
BNHI	O
.	O

The	O
factors	O
for	O
the	O
health	O
care	O
managers	O
to	O
adopt	O
the	O
integrated	O
clinical	O
information	O
systems	O
include	O
the	O
decision	O
of	O
make	O
or	O
buy	O
,	O
adoption	O
leadership	O
,	O
adoption	O
objectives	O
,	O
implementation	O
leadership	O
,	O
phased	O
versus	O
simultaneous	O
implementation	O
,	O
parallel	O
systems	O
,	O
information	O
technology	O
implementation	O
policies	O
and	O
practices	O
,	O
use	O
levels	O
and	O
resistance	O
,	O
and	O
realized	O
benefits	O
and	O
return	O
on	O
investment	O
calculation	O
[	O
66	O
]	O
,	O
which	O
might	O
be	O
very	O
cumbersome	O
and	O
time	O
-	O
consuming	O
.	O

It	O
suggests	O
that	O
the	O
network	O
partners	O
might	O
be	O
engaged	O
,	O
firstly	O
,	O
more	O
in	O
simpler	O
network	O
cooperation	O
such	O
as	O
the	O
administrative	O
systems	O
for	O
patient	B
admission	O
to	O
the	O
network	O
members	O
and	O
establishing	O
united	O
web	O
pages	O
for	O
patients	B
to	O
access	O
their	O
family	O
physicians	O
and	O
network	O
members	O
for	O
medical	O
and	O
public	O
promotion	O
purposes	O
.	O

And	O
for	O
further	O
integrated	O
information	O
investments	O
,	O
efforts	O
must	O
be	O
redirected	O
for	O
network	O
members	O
to	O
work	O
together	O
to	O
define	O
the	O
approach	O
to	O
specific	O
classes	O
of	O
integration	O
for	O
the	O
long	O
term	O
[	O
74	O
]	O
.	O

Conclusion	O

This	O
study	O
tried	O
to	O
portray	O
and	O
trace	O
how	O
the	O
facility	O
participants	B
were	O
involved	O
in	O
the	O
Taiwan	O
PCCNs	O
.	O

It	O
was	O
found	O
that	O
Taiwan	O
PCCNs	O
'	O
members	O
had	O
higher	O
involvement	O
in	O
the	O
governance	O
infrastructure	O
,	O
which	O
was	O
usually	O
viewed	O
as	O
the	O
most	O
important	O
for	O
establishment	O
of	O
core	O
values	O
in	O
PCCNs	O
'	O
organization	O
design	O
and	O
management	O
.	O

There	O
existed	O
a	O
higher	O
extent	O
of	O
integration	O
of	O
clinical	O
,	O
marketing	O
,	O
and	O
information	O
infrastructures	O
among	O
the	O
hospital	O
-	O
clinic	O
member	O
relationship	O
than	O
those	O
among	O
clinic	O
members	O
within	O
individual	O
PCCNs	O
.	O

The	O
financial	O
infrastructure	O
was	O
shown	O
the	O
least	O
integrated	O
relative	O
to	O
other	O
functional	O
infrastructures	O
at	O
the	O
early	O
stage	O
of	O
PCCN	O
formation	O
.	O

Page	O
[	O
43	O
]	O
argued	O
that	O
networks	O
form	O
and	O
grow	O
for	O
various	O
reasons	O
,	O
however	O
,	O
only	O
some	O
of	O
them	O
could	O
be	O
compatible	O
with	O
the	O
iterative	O
processes	O
of	O
collaboration	O
.	O

Some	O
participants	B
in	O
the	O
PCCNs	O
may	O
simply	O
seek	O
short	O
-	O
term	O
economic	O
gains	O
and	O
have	O
little	O
interest	O
in	O
joint	O
learning	O
and	O
continuous	O
improvement	O
.	O

From	O
an	O
organizational	O
design	O
perspective	O
,	O
the	O
old	O
phrase	O
proposed	O
by	O
the	O
wisdom	O
of	O
the	O
saying	O
about	O
developing	O
the	O
integrated	O
organizations	O
(	O
networks	O
)	O
should	O
be	O
-	O
"	O
coming	O
together	O
is	O
the	O
beginning	O
,	O
and	O
working	O
together	O
is	O
the	O
success	O
.	O
"	O
Page	O
[	O
43	O
]	O
examined	O
the	O
virtual	O
provider	O
organizations	O
such	O
as	O
physician	O
-	O
hospital	O
organizations	O
and	O
pointed	O
out	O
the	O
issue	O
of	O
the	O
provider	O
attitudes	O
and	O
behaviors	O
as	O
the	O
critically	O
successful	O
continuous	O
improvements	O
in	O
the	O
health	O
care	O
environments	O
.	O

A	O
wide	O
variance	O
of	O
degree	O
of	O
network	O
integration	O
in	O
Taiwan	O
PCCNs	O
still	O
leaves	O
room	O
to	O
improve	O
.	O

In	O
this	O
study	O
,	O
the	O
thoroughly	O
surveyed	O
items	O
,	O
that	O
is	O
,	O
the	O
potential	O
network	O
design	O
content	O
,	O
were	O
employed	O
.	O

In	O
addition	O
to	O
provide	O
how	O
the	O
network	O
members	O
have	O
done	O
their	O
initial	O
work	O
at	O
the	O
early	O
stage	O
of	O
network	O
forming	O
in	O
this	O
study	O
,	O
the	O
detailed	O
surveyed	O
items	O
,	O
the	O
concepts	O
proposed	O
by	O
the	O
managerial	O
and	O
theoretical	O
professionals	O
,	O
could	O
be	O
also	O
a	O
guide	O
for	O
those	O
health	O
care	O
providers	O
who	O
have	O
a	O
willingness	O
to	O
join	O
multi	O
-	O
organizations	O
.	O

It	O
suggests	O
that	O
health	O
care	O
providers	O
could	O
take	O
more	O
detailed	O
looks	O
about	O
those	O
surveyed	O
items	O
and	O
give	O
some	O
possible	O
opportunities	O
to	O
create	O
the	O
potential	O
actions	O
.	O

Further	O
research	O
could	O
be	O
empirically	O
done	O
to	O
explore	O
the	O
relative	O
influence	O
of	O
these	O
integration	O
mechanisms	O
on	O
the	O
effectiveness	O
of	O
organizational	O
partnerships	O
.	O

The	O
partnerships	O
within	O
each	O
PCCN	O
represent	O
various	O
relationships	O
that	O
depend	O
on	O
how	O
much	O
the	O
members	O
are	O
engaged	O
in	O
the	O
projects	O
.	O

In	O
addition	O
to	O
the	O
macro	O
concepts	O
including	O
governance	O
,	O
clinical	O
,	O
marketing	O
,	O
financial	O
,	O
and	O
information	O
infrastructures	O
explored	O
in	O
this	O
study	O
,	O
other	O
managerial	O
issues	O
for	O
integrated	O
organizations	O
were	O
also	O
suggested	O
such	O
as	O
formation	O
of	O
an	O
integrated	O
cultural	O
atmosphere	O
,	O
human	B
resources	O
management	O
,	O
physician	O
involvement	O
,	O
mission	O
and	O
commitment	O
establishment	O
,	O
from	O
micro	O
organizational	O
behavior	O
perspective	O
[	O
30	O
-	O
32	O
,	O
34	O
,	O
36	O
,	O
75	O
,	O
76	O
]	O
.	O

Micro	O
managerial	O
and	O
longitudinal	O
research	O
designs	O
could	O
be	O
employed	O
to	O
more	O
precisely	O
catch	O
the	O
never	O
completing	O
integration	O
efforts	O
in	O
the	O
future	O
.	O

Abbreviations	O

primary	O
community	O
care	O
network	O
(	O
PCCN	O
)	O
;	O
Bureau	O
of	O
National	O
Health	O
Insurance	O
(	O
BNHI	O
)	O

Competing	O
interests	O

The	O
author	O
(	O
s	O
)	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

BYJL	O
independently	O
designed	O
and	O
conducted	O
this	O
study	O
.	O

Pre	O
-	O
publication	O
history	O

The	O
pre	O
-	O
publication	O
history	O
for	O
this	O
paper	O
can	O
be	O
accessed	O
here	O
:	O

Recombinant	O
activated	O
protein	O
C	O
in	O
sepsis	O
:	O
endothelium	O
protection	O
or	O
endothelium	O
therapy	O
?	O

Abstract	O

Endothelium	O
dysfunction	O
is	O
one	O
of	O
the	O
hallmarks	O
of	O
sepsis	O
.	O

Looney	O
and	O
Mattay	O
,	O
in	O
the	O
previous	O
issue	O
of	O
Critical	O
Care	O
,	O
highlight	O
the	O
role	O
of	O
activated	O
protein	O
C	O
(	O
APC	O
)	O
as	O
a	O
protective	O
endothelial	O
drug	O
in	O
septic	O
situations	O
.	O

Nevertheless	O
,	O
the	O
results	O
of	O
in	O
vivo	O
studies	O
are	O
less	O
explicit	O
and	O
it	O
remains	O
uncertain	O
whether	O
these	O
properties	O
are	O
relevant	O
in	O
human	B
septic	O
shock	O
.	O

Before	O
considering	O
recombinant	O
APC	O
(	O
rAPC	O
)	O
as	O
a	O
therapeutic	O
drug	O
for	O
the	O
endothelium	O
,	O
we	O
have	O
to	O
demonstrate	O
its	O
efficiency	O
to	O
protect	O
or	O
to	O
reduce	O
endothelium	O
injury	O
when	O
infused	O
a	O
long	O
time	O
after	O
the	O
septic	O
challenge	O
.	O

Nevertheless	O
,	O
if	O
rAPC	O
is	O
efficient	O
when	O
infused	O
in	O
the	O
early	O
phase	O
of	O
septic	O
challenge	O
,	O
we	O
thus	O
need	O
to	O
treat	O
our	O
patients	B
earlier	O
.	O

At	O
the	O
least	O
,	O
genetically	O
engineered	O
variants	O
have	O
been	O
designed	O
with	O
greater	O
anti	O
-	O
apoptotic	O
activity	O
and	O
reduced	O
anticoagulant	O
activity	O
relative	O
to	O
wild	O
-	O
type	O
APC	O
.	O

Further	O
studies	O
are	O
needed	O
to	O
demonstrate	O
the	O
usefulness	O
of	O
these	O
variants	O
in	O
septic	O
shock	O
therapy	O
.	O

The	O
use	O
of	O
recombinant	O
activated	O
protein	O
C	O
(	O
rAPC	O
)	O
is	O
one	O
of	O
the	O
hottest	O
topics	O
in	O
septic	O
shock	O
therapy	O
.	O

The	O
pivotal	O
phase	O
3	O
placebo	O
-	O
controlled	O
Protein	O
C	O
Worldwide	O
Evaluation	O
in	O
Severe	O
Sepsis	O
(	O
PROWESS	O
)	O
clinical	O
trial	O
demonstrated	O
a	O
19	O
.	O
4	O
%	O
relative	O
risk	O
reduction	O
in	O
28	O
-	O
day	O
mortality	O
(	O
6	O
.	O
1	O
%	O
absolute	O
risk	O
reduction	O
)	O
with	O
an	O
increased	O
risk	O
(	O
3	O
.	O
5	O
%	O
versus	O
2	O
.	O
0	O
%	O
)	O
of	O
serious	O
bleeding	O
events	O
compared	O
with	O
placebo	O
.	O

Two	O
recent	O
and	O
important	O
articles	O
have	O
highlighted	O
the	O
role	O
of	O
APC	O
as	O
a	O
protective	O
endothelial	O
drug	O
[	O
1	O
]	O
and	O
as	O
a	O
cyto	O
-	O
protective	O
drug	O
[	O
2	O
]	O
.	O

Beneficial	O
effects	O
of	O
rAPC	O
in	O
the	O
PROWESS	O
study	O
were	O
thought	O
to	O
be	O
related	O
to	O
a	O
reduction	O
in	O
coagulation	O
and	O
,	O
to	O
a	O
lesser	O
extent	O
,	O
to	O
a	O
reduction	O
in	O
inflammatory	O
response	O
to	O
sepsis	O
[	O
3	O
]	O
.	O

Post	O
-	O
PROWESS	O
investigations	O
have	O
been	O
associated	O
with	O
a	O
myriad	O
of	O
cellular	O
or	O
animal	O
studies	O
demonstrating	O
that	O
rAPC	O
,	O
through	O
reactions	O
mediated	O
by	O
endothelial	O
protein	O
C	O
receptor	O
and	O
the	O
effector	O
receptor	O
,	O
protease	O
activated	O
receptor	O
-	O
1	O
,	O
acts	O
directly	O
on	O
cells	O
to	O
exert	O
multiple	O
cytoprotective	O
effects	O
including	O
:	O
down	O
regulation	O
of	O
pro	O
-	O
inflammatory	O
gene	O
expression	O
[	O
4	O
]	O
;	O
anti	O
-	O
inflammatory	O
activities	O
[	O
5	O
]	O
;	O
anti	O
-	O
apoptotic	O
activity	O
[	O
6	O
]	O
;	O
and	O
protection	O
of	O
endothelial	O
barrier	O
function	O
[	O
1	O
,	O
2	O
]	O
.	O

Endothelium	O
dysfunction	O
is	O
one	O
of	O
the	O
hallmarks	O
of	O
sepsis	O
[	O
7	O
]	O
.	O

Sepsis	O
,	O
per	O
se	O
,	O
may	O
induce	O
phenotypic	O
modulations	O
of	O
the	O
endothelium	O
through	O
direct	O
or	O
indirect	O
interaction	O
of	O
the	O
endothelial	O
layer	O
with	O
components	O
of	O
the	O
bacterial	O
wall	O
,	O
inducing	O
a	O
myriad	O
of	O
host	O
-	O
derived	O
factors	O
from	O
endothelial	O
cells	O
.	O

Phenotypic	O
modifications	O
include	O
changes	O
in	O
pro	O
-	O
coagulant	O
and	O
proadhesive	O
properties	O
,	O
increased	O
endothelial	O
permeability	O
,	O
endothelial	O
cell	O
apoptosis	O
and	O
changes	O
in	O
vasomotor	O
properties	O
;	O
the	O
last	O
of	O
these	O
is	O
crucial	O
since	O
vasoplegia	O
is	O
directly	O
related	O
to	O
septic	O
shock	O
mortality	O
.	O

Recent	O
animal	O
and	O
human	B
data	O
have	O
suggested	O
that	O
rAPC	O
may	O
improve	O
both	O
vascular	O
and	O
myocardial	O
dysfunction	O
and	O
vascular	O
reactivity	O
to	O
catecholamine	O
during	O
endotoxin	O
and	O
/	O
or	O
septic	O
challenge	O
[	O
8	O
,	O
9	O
]	O
.	O

From	O
bench	O
to	O
bedside	O

Experimental	O
evidence	O
supports	O
a	O
role	O
of	O
APC	O
in	O
maintaining	O
the	O
integrity	O
of	O
the	O
endothelium	O
through	O
both	O
direct	O
and	O
indirect	O
mechanisms	O
.	O

Nevertheless	O
,	O
the	O
results	O
of	O
in	O
vivo	O
studies	O
are	O
less	O
explicit	O
.	O

In	O
a	O
retrospective	O
study	O
of	O
septic	O
shock	O
in	O
humans	B
,	O
Monnet	O
and	O
colleagues	O
[	O
9	O
]	O
demonstrated	O
that	O
APC	O
infusion	O
was	O
associated	O
with	O
a	O
decrease	O
in	O
the	O
amount	O
of	O
delivered	O
norepinephrine	O
.	O

Wiel	O
and	O
colleagues	O
[	O
10	O
]	O
demonstrated	O
in	O
a	O
rabbit	B
model	O
of	O
endotoxin	O
induced	O
shock	O
that	O
APC	O
decreased	O
aorta	O
endothelial	O
injury	O
.	O

By	O
contrast	O
,	O
in	O
a	O
lung	O
model	O
of	O
endotoxin	O
induced	O
inflammation	O
,	O
Robriquet	O
and	O
colleagues	O
[	O
11	O
]	O
demonstrated	O
a	O
trend	O
to	O
an	O
increased	O
vascular	O
permeability	O
using	O
high	O
doses	O
of	O
human	B
APC	O
.	O

This	O
last	O
result	O
was	O
in	O
sharp	O
contrast	O
with	O
the	O
results	O
obtained	O
by	O
Nick	O
and	O
colleagues	O
[	O
12	O
]	O
in	O
a	O
human	B
model	O
of	O
pulmonary	O
endotoxin	O
administration	O
.	O

APC	O
appears	O
to	O
improve	O
mortality	O
in	O
septic	O
shock	O
with	O
a	O
high	O
APACHE	O
2	O
score	O
and	O
is	O
potentially	O
detrimental	O
in	O
severe	O
sepsis	O
.	O

In	O
rats	O
,	O
APC	O
markedly	O
decreased	O
tumour	O
necrosis	O
factor	O
concentrations	O
whereas	O
they	O
remained	O
unchanged	O
in	O
either	O
human	B
septic	O
shock	O
or	O
endotoxemia	O
.	O

The	O
question	O
arises	O
,	O
therefore	O
,	O
as	O
to	O
whether	O
it	O
is	O
truly	O
possible	O
to	O
reconcile	O
all	O
these	O
discrepancies	O
?	O

Moreover	O
,	O
can	O
these	O
stirring	O
laboratory	O
data	O
be	O
translated	O
into	O
clinical	O
practice	O
?	O

Limitations	O
of	O
experimental	O
studies	O
:	O
endothelium	O
protection	O
versus	O
endothelium	O
therapy	O

Clearly	O
,	O
in	O
cellular	O
and	O
animal	O
models	O
,	O
rAPC	O
has	O
been	O
given	O
either	O
as	O
a	O
pre	O
-	O
treatment	O
or	O
concurrent	O
with	O
septic	O
challenge	O
.	O

This	O
mode	O
of	O
administration	O
favours	O
the	O
anti	O
-	O
inflammatory	O
effects	O
of	O
rAPC	O
,	O
which	O
are	O
particularly	O
efficient	O
in	O
murine	B
models	O
in	O
protecting	O
the	O
endothelium	O
from	O
cytokine	O
-	O
mediated	O
apoptosis	O
or	O
upregulation	O
of	O
endothelial	O
adhesion	O
molecules	O
.	O

Thus	O
,	O
studies	O
using	O
post	O
-	O
injury	O
treatment	O
are	O
needed	O
in	O
models	O
that	O
mimic	O
septic	O
shock	O
,	O
such	O
as	O
experimental	O
pneumonia	O
or	O
peritonitis	O
treated	O
by	O
antibiotics	O
and	O
volume	O
resuscitation	O
,	O
and	O
where	O
the	O
effects	O
of	O
rAPC	O
would	O
be	O
investigated	O
16	O
to	O
24	O
hours	O
after	O
septic	O
challenge	O
.	O

If	O
we	O
can	O
demonstrate	O
the	O
efficiency	O
of	O
rAPC	O
to	O
protect	O
or	O
to	O
reduce	O
endothelium	O
injury	O
in	O
these	O
conditions	O
,	O
we	O
can	O
ultimately	O
postulate	O
that	O
rAPC	O
is	O
also	O
a	O
therapeutic	O
drug	O
for	O
the	O
endothelium	O
.	O

The	O
earlier	O
the	O
better	O

If	O
rAPC	O
is	O
efficient	O
when	O
infused	O
in	O
the	O
early	O
phase	O
of	O
septic	O
challenge	O
,	O
we	O
thus	O
need	O
to	O
treat	O
our	O
patients	B
earlier	O
.	O

At	O
least	O
two	O
studies	O
suggest	O
that	O
treatment	O
with	O
rAPC	O
within	O
24	O
hours	O
may	O
carry	O
a	O
larger	O
survival	O
advantage	O
for	O
patients	B
with	O
severe	O
sepsis	O
,	O
compared	O
with	O
those	O
treated	O
more	O
than	O
24	O
hours	O
after	O
organ	O
dysfunction	O
[	O
13	O
]	O
.	O

Interventions	O
directed	O
at	O
specific	O
endpoints	O
,	O
when	O
initiated	O
early	O
in	O
the	O
'	O
golden	O
hours	O
'	O
of	O
a	O
patient	O
'	O
s	O
condition	O
,	O
seem	O
to	O
be	O
promising	O
[	O
14	O
]	O
.	O

The	O
beneficial	O
effects	O
of	O
earlier	O
administration	O
of	O
rAPC	O
to	O
appropriate	O
patients	B
may	O
fit	O
into	O
this	O
paradigm	O
.	O

The	O
future	O

Extensive	O
in	O
vivo	O
and	O
in	O
vitro	O
studies	O
have	O
focused	O
on	O
the	O
cytoprotective	O
effects	O
of	O
APC	O
and	O
most	O
authors	O
agree	O
that	O
its	O
anticoagulant	O
and	O
cytoprotective	O
effects	O
are	O
mediated	O
by	O
distinct	O
APC	O
structural	O
features	O
.	O

Positively	O
charged	O
residues	O
in	O
surface	O
loops	O
in	O
the	O
APC	O
protease	O
domain	O
have	O
been	O
identified	O
as	O
participating	O
in	O
the	O
anticoagulant	O
activity	O
but	O
not	O
in	O
cellular	O
effects	O
.	O

Hence	O
,	O
variants	O
have	O
been	O
designed	O
with	O
greater	O
anti	O
-	O
apoptotic	O
activity	O
and	O
reduced	O
anticoagulant	O
activity	O
relative	O
to	O
wild	O
-	O
type	O
APC	O
[	O
2	O
]	O
.	O

Whether	O
these	O
genetically	O
engineered	O
variants	O
actually	O
provide	O
superior	O
pharmacological	O
properties	O
remains	O
to	O
be	O
elucidated	O
in	O
vivo	O
.	O

Such	O
investigations	O
may	O
allow	O
the	O
design	O
of	O
therapeutic	O
APC	O
variants	O
with	O
decreased	O
anticoagulant	O
activity	O
to	O
reduce	O
the	O
risk	O
of	O
bleeding	O
on	O
the	O
one	O
hand	O
,	O
but	O
also	O
with	O
normal	O
cytoprotective	O
properties	O
in	O
order	O
to	O
retain	O
full	O
beneficial	O
effects	O
on	O
sepsis	O
outcome	O
.	O

Abbreviations	O

PROWESS	O
=	O
Protein	O
C	O
Worldwide	O
Evaluation	O
in	O
Severe	O
Sepsis	O
;	O
rAPC	O
=	O
recombinant	O
activated	O
protein	O
C	O
.	O

Competing	O
interests	O

BL	O
has	O
received	O
reimbursements	O
and	O
funding	O
from	O
Eli	O
Lilly	O
,	O
France	O
.	O

Carbonic	O
Anhydrase	O
Inhibitors	O
.	O

Part	O
541	O
:	O
Metal	O
Complexes	O
of	O
Heterocyclic	O
Sulfonamides	O
:	O
A	O
New	O
Class	O
of	O
Antiglaucoma	O
Agents	O

Abstract	O

Metal	O
complexes	O
of	O
heterocyclic	O
sulfonamides	O
possessing	O
carbonic	O
anhydrase	O
(	O
CA	O
)	O
inhibitory	O
properties	O
were	O
recently	O
shown	O
to	O
be	O
useful	O
as	O
intraocular	O
pressure	O
(	O
IOP	O
)	O
lowering	O
agents	O
in	O
experimental	O
animals	O
,	O
and	O
might	O
be	O
developed	O
as	O
a	O
novel	O
class	O
of	O
antiglaucoma	O
drugs	O
.	O

Here	O
we	O
report	O
the	O
synthesis	O
of	O
a	O
heterocyclic	O
sulfonamide	O
CA	O
inhibitor	O
and	O
of	O
the	O
metal	O
complexes	O
containing	O
main	O
group	O
metal	O
ions	O
,	O
such	O
as	O
Be	O
(	O
II	O
)	O
,	O
Mg	O
(	O
II	O
)	O
,	O
Al	O
(	O
III	O
)	O
,	O
Zn	O
(	O
II	O
)	O
,	O
Cd	O
(	O
II	O
)	O
and	O
Hg	O
(	O
II	O
)	O
and	O
the	O
new	O
sulfonamide	O
as	O
well	O
as	O
5	O
-	O
amino	O
-	O
1	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
as	O
ligands	O
.	O

The	O
new	O
complexes	O
were	O
characterized	O
by	O
standard	O
physico	O
-	O
chemical	O
procedures	O
,	O
and	O
assayed	O
as	O
inhibitors	O
of	O
three	O
CA	O
isozymes	O
,	O
CA	O
I	O
,	O
II	O
and	O
IV	O
.	O

Some	O
of	O
them	O
(	O
but	O
not	O
the	O
parent	O
sulfonamides	O
)	O
strongly	O
lowered	O
IOP	O
in	O
rabbits	B
when	O
administered	O
as	O
a	O
2	O
%	O
solution	O
into	O
the	O
eye	O
.	O

CARBONIC	O
ANHYDRASE	O
INHIBITORS	O
.	O

Part	O
54	O
METAL	O
COMPLEXES	O
OF	O
HETEROCYCLIC	O
SULFONAMIDES	O
:	O
A	O
NEW	O
CLASS	O
OF	O
ANTIGLAUCOMA	O
AGENTS	O
Claudiu	O
T	O
.	O

Supuran	O
*	O
,	O
Andrea	O
Scozzafava	O

and	O
Andrei	O
Jitianu	O
2	O

Universit	O
&	O
degli	O
Studi	O
,	O
Dipartimento	O
di	O
Chimica	O
,	O
Laboratorio	O
di	O
Chimica	O
Inorganica	O
e	O
Bioinorganica	O
,	O
Via	O
Gino	O
Capponi	O
7	O
,	O
1	O
-	O
50121	O
,	O
Florence	O
,	O
Italy	O
2	O
"	O
I	O
.	O
G	O
.	O

Murgulescu	O
"	O
Institute	O
of	O
Physical	O
Chemistry	O
,	O
Academia	O
Romana	O
,	O
Spl	O
.	O

Independentei	O
202	O
,	O
R	O
-	O
77208	O
Bucharest	O
,	O
Roumania	O
Abstract	O
:	O
Metal	O
complexes	O
of	O
heterocyclic	O
sulfonamides	O
possessing	O
carbonic	O
anhydrase	O
(	O
CA	O
)	O
inhibitory	O
properties	O
were	O
recently	O
shown	O
to	O
be	O
useful	O
as	O
intraocular	O
pressure	O
(	O
IOP	O
)	O
lowering	O
agents	O
in	O
experimental	O
animals	O
,	O
and	O
might	O
be	O
developed	O
as	O
a	O
novel	O
class	O
of	O
antiglaucoma	O
drugs	O
.	O

Here	O
we	O
report	O
the	O
synthesis	O
of	O
a	O
heterocyclic	O
sulfonamide	O
CA	O
inhibitor	O
and	O
of	O
the	O
metal	O
complexes	O
containing	O
main	O
group	O
metal	O
ions	O
,	O
such	O
as	O
Be	O
(	O
II	O
)	O
,	O
Mg	O
(	O
II	O
)	O
,	O
AI	O
(	O
III	O
)	O
,	O
Zn	O
(	O
II	O
)	O
,	O
Cd	O
(	O
II	O
)	O
and	O
Hg	O
(	O
II	O
)	O
and	O
the	O
new	O
sulfonamide	O
as	O
well	O
as	O
5	O
-	O
amino	O
-	O
l	O
,	O
3	O
,	O
4thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
as	O
ligands	O
.	O

The	O
new	O
complexes	O
were	O
characterized	O
by	O
standard	O
physico	O
-	O
chemical	O
procedures	O
,	O
and	O
assayed	O
as	O
inhibitors	O
of	O
three	O
CA	O
isozymes	O
,	O
CA	O
I	O
,	O
II	O
and	O
IV	O
.	O

Some	O
of	O
them	O
(	O
but	O
not	O
the	O
parent	O
sulfonamides	O
)	O
strongly	O
lowered	O
IOP	O
in	O
rabbits	B
when	O
administered	O
as	O
a	O
2	O
%	O
solution	O
into	O
the	O
eye	O
.	O

Introduction	O
Sulfonamides	O
possessing	O
carbonic	O
anhydrase	O
(	O
CA	O
,	O
EC	O
4	O
.	O
2	O
.	O
1	O
.	O
1	O
)	O
inhibitory	O
properties	O
[	O
2	O
]	O
such	O
as	O
acetazolamide	O
1	O
,	O
methazolamide	O
2	O
,	O
ethoxzolamide	O
3	O
and	O
dichlorophenamide	O
4	O
have	O
been	O
used	O
for	O
more	O
than	O
40	O
years	O
as	O
pressure	O
lowering	O
systemic	O
drugs	O
in	O
the	O
treatment	O
of	O
open	O
-	O
angle	O
glaucoma	O
[	O
3	O
,	O
4	O
]	O
.	O

Their	O
effect	O
is	O
due	O
to	O
inhibition	O
of	O
at	O
least	O
two	O
CA	O
isozymes	O
present	O
within	O
cilliary	O
processes	O
of	O
the	O
eye	O
,	O
ie	O
,	O
CA	O
II	O
and	O
CA	O
IV	O
,	O
which	O
is	O
followed	O
by	O
lowered	O
bicarbonate	O
formation	O
and	O
reduction	O
of	O
aqueous	O
humor	O
secretion	O
[	O
5	O
-	O
7	O
]	O
.	O

Their	O
main	O
drawback	O
is	O
constituted	O
by	O
side	O
effects	O
such	O
as	O
fatigue	O
,	O
augmented	O
diuresis	O
,	O
or	O
paresthesias	O
,	O
due	O
to	O
CA	O
inhibition	O
in	O
other	O
tissues	O
/	O
organs	O
than	O
the	O
target	O
one	O
,	O
ie	O
,	O
the	O
eye	O
[	O
8	O
]	O
.	O

N	O
-	O
-	O
N	O

XN	O
-	O
-	O
N	O
EtO	O
S	O

NH	O
2	O

O	O

NH	O
O	O
:	O
S	O
-	O
-	O
-	O
-	O
O	O

NHEt	O

The	O
above	O
-	O
mentioned	O
side	O
effects	O
are	O
absent	O
in	O
the	O
case	O
in	O
which	O
the	O
inhibitor	O
has	O
topical	O
activity	O
,	O
and	O
is	O
applied	O
directly	O
into	O
the	O
eye	O
.	O

This	O
route	O
has	O
been	O
demonstrated	O
only	O
in	O
1983	O
by	O
Maren	O
'	O
s	O
group	O
[	O
9	O
]	O
and	O
was	O
followed	O
by	O
the	O
development	O
of	O
the	O
first	O
clinical	O
agent	O
of	O
this	O
type	O
,	O
dorzolamide	O
5	O
[	O
10	O
,	O
11	O
]	O
.	O

Dorzolamide	O
(	O
Trusopt	O
)	O
has	O
been	O
introduced	O
in	O
clinical	O
use	O
in	O
1995	O
in	O
USA	O
and	O
Europe	O
and	O
it	O
constituted	O
the	O
beginning	O
of	O
a	O
radically	O
new	O
treatment	O
of	O
glaucoma	O
,	O
devoid	O
of	O
the	O
severe	O
side	O
effects	O
observed	O
with	O
the	O
systemic	O
inhibitors	O
[	O
4	O
-	O
6	O
]	O
.	O

The	O
success	O
of	O
topical	O
antiglaucoma	O
CA	O
inhibitors	O
fostered	O
much	O
research	O
in	O
the	O
synthesis	O
and	O
clinical	O
evaluation	O
of	O
other	O
types	O
of	O
such	O
compounds	O
[	O
12	O
-	O
15	O
]	O
.	O

307	O

Vol	O
.	O

4	O
,	O
No	O
.	O
6	O
,	O
1997	O

Metal	O
Complexes	O
of	O
Heterocyclic	O
Sulfonamides	O
:	O
A	O
New	O
Class	O
ofAntiglaucoma	O
Agents	O

On	O
the	O
other	O
hand	O
,	O
metal	O
complexes	O
of	O
heterocyclic	O
sulfonamides	O
of	O
type	O
1	O
-	O
5	O
have	O
been	O
recently	O
prepared	O
by	O
two	O
groups	O
16	O
-	O
20	O
]	O
,	O
and	O
it	O
was	O
proved	O
that	O
they	O
possess	O
much	O
stronger	O
CA	O
inhibitory	O
properties	O
than	O
the	O
sulfonamides	O
from	O
which	O
they	O
were	O
prepared	O
18	O
-	O
22	O
]	O
.	O

Although	O
the	O
mechanism	O
of	O
CA	O
inhibition	O
of	O
the	O
metal	O
complexes	O
is	O
presently	O
unknown	O
,	O
it	O
was	O
hypothesized	O
that	O
their	O
increased	O
inhibitory	O
power	O
might	O
be	O
due	O
to	O
two	O
processes	O
,	O
occurring	O
separately	O
or	O
in	O
concert	O
,	O
ie	O
,	O
(	O
i	O
)	O
dissociation	O
of	O
the	O
complex	O
inhibitor	O
in	O
sulfonamide	O
anions	O
and	O
metal	O
ions	O
(	O
in	O
diluted	O
solution	O
)	O
,	O
which	O
in	O
turn	O
both	O
interact	O
thereafter	O
with	O
the	O
enzyme	O
,	O
at	O
different	O
binding	O
sites	O
,	O
and	O
(	O
ii	O
)	O
direct	O
interaction	O
of	O
the	O
undissociated	O
complex	O
with	O
the	O
enzyme	O
,	O
and	O
more	O
specifically	O
with	O
the	O
hydrophilic	O
patch	O
at	O
the	O
entrance	O
of	O
CA	O
II	O
active	O
site	O
[	O
23	O
]	O
,	O
this	O
being	O
the	O
isozyme	O
most	O
susceptible	O
to	O
inhibition	O
with	O
this	O
class	O
of	O
compounds	O
[	O
2	O
,	O
22	O
]	O
.	O

Whether	O
initially	O
the	O
first	O
mechanism	O
of	O
action	O
mentioned	O
above	O
was	O
favored	O
by	O
us	O
[	O
22	O
]	O
,	O
recent	O
evidences	O
suggested	O
that	O
the	O
undissociated	O
complex	O
might	O
be	O
the	O
inhibitory	O
species	O
,	O
at	O
least	O
for	O
some	O
isozymes	O
[	O
24	O
]	O
.	O

Since	O
metal	O
complexes	O
are	O
much	O
more	O
inhibitory	O
than	O
the	O
parent	O
sulfonamide	O
from	O
which	O
they	O
were	O
prepared	O
,	O
it	O
appeared	O
of	O
interest	O
to	O
test	O
whether	O
this	O
property	O
might	O
be	O
useful	O
for	O
their	O
use	O
in	O
lowering	O
IOP	O
in	O
experimental	O
animals	O
and	O
whence	O
as	O
a	O
possible	O
glaucoma	O
therapy	O
.	O

Recently	O
we	O
proved	O
[	O
25	O
,	O
26	O
]	O
that	O
some	O
metal	O
complexes	O
of	O
heterocyclic	O
sulfonamides	O
(	O
which	O
themselves	O
do	O
not	O
possess	O
IOP	O
lowering	O
properties	O
)	O
act	O
as	O
very	O
powerful	O
such	O
agents	O
when	O
administered	O
as	O
diluted	O
solutions	O
directly	O
into	O
the	O
eye	O
of	O
experimental	O
animals	O
,	O
and	O
would	O
thus	O
offer	O
the	O
possibility	O
of	O
developing	O
such	O
totally	O
novel	O
drugs	O
.	O

Here	O
we	O
report	O
the	O
synthesis	O
of	O
a	O
heterocyclic	O
sulfonamide	O
possessing	O
strong	O
CA	O
inhibitory	O
properties	O
,	O
ie	O
,	O
5	O
-	O
(	O
chloroacetamido	O
)	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
,	O
and	O
of	O
the	O
metal	O
complexes	O
of	O
this	O
sulfonamide	O
and	O
of	O
5	O
-	O
amino	O
-	O
1	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
,	O
containing	O
some	O
main	O
group	O
metal	O
ions	O
.	O

The	O
new	O
compounds	O
have	O
been	O
characterized	O
by	O
standard	O
physico	O
-	O
chemical	O
procedures	O
,	O
and	O
were	O
assayed	O
as	O
inhibitors	O
of	O
three	O
CA	O
isozymes	O
,	O
hCA	O
I	O
,	O
hCA	O
II	O
and	O
bCA	O
IV	O
(	O
h	O
human	B
;	O
b	O
bovine	B
;	O
these	O
are	O
the	O
isozymes	O
considered	O
to	O
play	O
a	O
critical	O
role	O
in	O
aqueous	O
humour	O
secretion	O
within	O
the	O
eye	O
of	O
higher	O
vertebrates	O
[	O
2	O
-	O
5	O
]	O
)	O
.	O

Materials	O
and	O
Methods	O

Melting	O
points	O
were	O
recorded	O
with	O
a	O
heating	O
plate	O
microscope	O
and	O
are	O
not	O
corrected	O
.	O

IR	O
spectra	O
were	O
recorded	O
in	O
KBr	O
pellets	O
with	O
a	O
Carl	O
Zeiss	O
IR	O
-	O
80	O
instrument	O
.	O

1H	O
-	O
NMR	O
spectra	O
were	O
recorded	O
in	O
DMSO	O
-	O
d6	O
as	O
solvent	O
,	O
with	O
a	O
Bruker	O
CPX200	O
instrument	O
.	O

Chemical	O
shifts	O
are	O
reported	O
as	O
values	O
,	O
relative	O
to	O
Me4Si	O
as	O
internal	O
standard	O
.	O

Conductimetric	O
measurements	O
were	O
done	O
at	O
room	O
temperature	O
(	O
1	O
mM	O
concentration	O
of	O
complex	O
)	O
in	O
DMSO	O
solution	O
with	O
a	O
Fisher	O
conductimeter	O
.	O

Elemental	O
analyses	O
were	O
done	O
by	O
combustion	O
for	O
C	O
,	O
H	O
,	O
N	O
with	O
an	O
automated	O
Carlo	O
Erba	O
analyzer	O
,	O
and	O
gravimetrically	O
for	O
the	O
metal	O
ions	O
,	O
and	O
were	O
0	O
.	O
4	O
%	O
of	O
the	O
theoretical	O
values	O
.	O

Thermogravimetric	O
measurements	O
were	O
done	O
in	O
air	O
,	O
at	O
a	O
heating	O
rate	O
of	O
10C	O
/	O
min	O
.	O
,	O
with	O
a	O
Perkin	O
Elmer	O
3600	O
thermobalance	O
.	O

Sulfonamides	O
used	O
as	O
standards	O
in	O
the	O
enzymatic	O
assay	O
(	O
except	O
for	O
5	O
)	O
,	O
acetazolamide	O
,	O
pyridine	O
,	O
and	O
chloroacetyl	O
chloride	O
used	O
for	O
the	O
preparation	O
of	O
compound	O
7	O
,	O
solvents	O
as	O
well	O
as	O
inorganic	O
reagents	O
were	O
from	O
Sigma	O
,	O
Merck	O
and	O
Carlo	O
Erba	O
.	O

5	O
-	O
Amino	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
6	O
was	O
prepared	O
from	O
acetazolamide	O
by	O
literature	O
procedures	O
[	O
27	O
]	O
,	O
by	O
desacetylation	O
with	O
concentrated	O
hydrochloric	O
acid	O
,	O
followed	O
by	O
neutralization	O
with	O
sodium	O
bicarbonate	O
of	O
the	O
corresponding	O
hydrochloride	O
(	O
Scheme	O
1	O
)	O
.	O

Dorzolamide	O
hydrochloride	O
5	O
was	O
from	O
Merck	O
,	O
Sharp	O
and	O
Dohme	O
or	O
was	O
prepared	O
as	O
described	O
by	O
Ponticello	O
et	O
al	O
10	O
,	O
11	O
]	O
.	O

Human	B
CA	O
and	O
CA	O
II	O
cDNAs	O
were	O
expressed	O
in	O
Escherichia	O
coli	O
strain	O
BL21	O
(	O
DE3	O
)	O
from	O
the	O
plasmids	O
pACA	O
/	O
hCA	O
I	O
and	O
pACAdaCA	O
II	O
described	O
by	O
Forsman	O
et	O
al	O
.	O

[	O
28	O
]	O
(	O
the	O
two	O
plasmids	O
were	O
a	O
gift	O
from	O
Prof	O
.	O
Sven	O
Lindskog	O
,	O
Umea	O
University	O
,	O
Sweden	O
)	O
.	O

Cell	O
growth	O
conditions	O
were	O
those	O
described	O
by	O
Lindskog	O
'	O
s	O
group	O
[	O
29	O
]	O
,	O
and	O
enzymes	O
were	O
purified	O
by	O
affinity	O
chromatography	O
according	O
to	O
the	O
method	O
of	O
Khalifah	O
et	O
al	O
[	O
30	O
]	O
.	O

Enzyme	O
concentrations	O
were	O
determined	O
spectrophotometrical	O
at	O
280	O
nm	O
,	O
utilizing	O
a	O
molar	O
absorptivity	O
of	O
49	O
mM	O
-	O
l	O
.	O
cm	O
-	O
1	O
for	O
hCA	O
and	O
54	O
mM	O
-	O
l	O
.	O
cm	O
-	O
1	O
for	O
hCA	O
II	O
,	O
respectively	O
,	O
based	O
on	O
M	O
28	O
.	O
85	O
kDa	O
for	O
hCA	O
I	O
,	O
and	O
29	O
.	O
3	O
kDa	O
for	O
hCA	O
II	O
,	O
respectively	O
[	O
31	O
,	O
32	O
]	O
.	O

bCA	O
IV	O
was	O
isolated	O
from	O
bovine	B
lung	O
microsomes	O
as	O
described	O
by	O
Maren	O
et	O
al	O
,	O
and	O
its	O
concentration	O
has	O
been	O
determined	O
by	O
titration	O
with	O
ethoxzolamide	O
[	O
33	O
]	O
.	O

Synthesis	O
of	O
5	O
-	O
(	O
chloroacetamido	O
)	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
7	O
An	O
amount	O
of	O
1	O
.	O
80	O
g	O
(	O
10	O
mmol	O
)	O
of	O
5	O
-	O
amino	O
-	O
1	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
6	O
was	O
suspended	O
in	O
20	O
mL	O
of	O
anhydrous	O
acetonitrile	O
and	O
0	O
.	O
9	O
mL	O
(	O
0	O
.	O
87g	O
,	O
11	O
mmol	O
)	O
of	O
pyridine	O
added	O
.	O

The	O
mixture	O
was	O
magnetically	O
stirred	O
at	O
4	O
C	O
for	O
10	O
minutes	O
,	O
then	O
10	O
.	O
5	O
mmol	O
of	O
monochloroacetyl	O
chloride	O
,	O
dissolved	O
in	O
3	O
mL	O
acetonitrile	O
,	O
were	O
added	O
dropwise	O
for	O
5	O
min	O
,	O
and	O
stirring	O
was	O
continued	O
for	O
other	O
2	O
hours	O
at	O
room	O
temperature	O
.	O

After	O
an	O
additional	O
30	O
min	O
of	O
refluxation	O
,	O
followed	O
by	O
cooling	O
,	O
the	O
precipitated	O
crystals	O
were	O
filtered	O
and	O
recrystallized	O
from	O
ethanol	O
.	O

Yield	O
of	O
62	O
%	O
white	O
crystals	O
,	O
mp	O
246	O
-	O
248	O
o	O
lit	O
[	O
34	O
]	O
mp	O
IR	O
(	O
KBr	O
)	O
,	O
cm	O
-	O
l	O
:	O
590	O
,	O
610	O
,	O
660	O
,	O
790	O
,	O
935	O
,	O
1090	O
,	O
1115	O
,	O
1170	O
,	O
1350	O
,	O
1400	O
,	O
1550	O
,	O
1650	O
,	O
1720	O
,	O
2870	O
,	O
3280	O
3370	O
(	O
broad	O
)	O
;	O
UV	O
spectrum	O
,	O
,	O
max	O
,	O
nm	O
(	O
lg	O
)	O
:	O
255	O
(	O
3	O
.	O
50	O
)	O
;	O
288	O
(	O
4	O
.	O
37	O
)	O
H	O
-	O
NMR	O
(	O
DMSO	O
-	O
d6	O
)	O
,	O
i	O
,	O
ppm	O
:	O
2	O
.	O
96	O
(	O
s	O
,	O
2H	O
,	O
CH2	O
)	O
;	O
8	O
.	O
20	O
(	O
s	O
,	O
2H	O
,	O
SOzNH2	O
)	O
;	O
12	O
.	O
22	O
(	O
s	O
,	O
1H	O
,	O
CONH	O
)	O
.	O

Analysis	O
,	O
found	O
:	O
C	O
,	O
18	O
.	O
56	O
;	O
H	O
,	O
1	O
.	O
88	O
;	O
N	O
,	O
21	O
.	O
76	O
;	O
S	O
,	O
24	O
.	O
62	O
%	O
;	O
C4HsC1N403S2	O
requires	O
"	O
C	O
,	O
18	O
.	O
72	O
;	O
H	O
,	O
1	O
.	O
96	O
;	O
N	O
,	O
21	O
.	O
83	O
;	O
S	O
,	O
24	O
.	O
98	O
%	O
.	O

General	O
procedure	O
for	O
the	O
preparation	O
of	O
compounds	O
8	O
-	O
20	O
An	O
amount	O
of	O
6	O
mmol	O
of	O
sodium	O
salt	O
of	O
sulfonamides	O
6	O
or	O
7	O
was	O
prepared	O
by	O
reacting	O
the	O
corresponding	O
sulfonamide	O
with	O
the	O
required	O
amount	O
of	O
an	O
alcoholic	O
1N	O
NaOH	O
solution	O
,	O
in	O
ethanol	O
as	O
solvent	O
.	O

To	O
this	O
308	O

Claudiu	O
T	O
.	O
Supuran	O
et	O
al	O
.	O

Metal	O
-	O
Based	O
Drugs	O

solution	O
was	O
added	O
the	O
aqueous	O
metal	O
salt	O
(	O
Zn	O
(	O
II	O
)	O
,	O
Mg	O
(	O
II	O
)	O
,	O
AI	O
(	O
III	O
)	O
,	O
Cd	O
(	O
II	O
)	O
chlorides	O
,	O
and	O
Be	O
(	O
II	O
)	O
,	O
Pb	O
(	O
II	O
)	O
and	O
Hg	O
(	O
II	O
)	O
nitrate	O
)	O
solution	O
,	O
working	O
in	O
molar	O
ratios	O
RSOzNH	O
-	O
Mn	O
+	O
of	O
2	O
:	O
1	O
for	O
the	O
divalent	O
cations	O
and	O
3	O
:	O
1	O
for	O
the	O
trivalent	O
cation	O
,	O
respectively	O
.	O

The	O
aqueous	O
-	O
alcoholic	O
reaction	O
mixture	O
was	O
heated	O
on	O
a	O
steam	O
bath	O
for	O
one	O
hour	O
,	O
adjusting	O
the	O
pH	O
at	O
7	O
if	O
necessary	O
,	O
and	O
after	O
being	O
cooled	O
at	O
0	O
C	O
the	O
precipitated	O
complexes	O
were	O
filtered	O
and	O
thoroughly	O
washed	O
with	O
alcohol	O
-	O
water	O
1	O
:	O
1	O
(	O
v	O
/	O
v	O
)	O
and	O
air	O
dried	O
.	O

Yields	O
were	O
in	O
the	O
range	O
of	O
85	O
-	O
90	O
%	O
.	O

The	O
obtained	O
white	O
powders	O
of	O
compounds	O
8	O
-	O
20	O
melted	O
with	O
decomposition	O
at	O
temperatures	O
higher	O
than	O
350	O
C	O
,	O
and	O
were	O
poorly	O
soluble	O
in	O
water	O
and	O
alcohol	O
,	O
but	O
had	O
good	O
solubilities	O
in	O
DMSO	O
,	O
DMF	O
as	O
well	O
as	O
mixtures	O
of	O
DMSO	O
-	O
water	O
,	O
DMF	O
-	O
water	O
.	O

Pharmacology	O
Carbonic	O
anhydrase	O
inhibition	O
Initial	O
rates	O
of	O
4	O
-	O
nitrophenyl	O
acetate	O
hydrolysis	O
catalysed	O
by	O
different	O
CA	O
isozymes	O
were	O
monitored	O
spectrophotometrical	O
,	O
at	O
400	O
rim	O
,	O
with	O
a	O
Cary	O
3	O
instrument	O
interfaced	O
with	O
an	O
IBM	O
compatible	O
PC	O
[	O
35	O
]	O
.	O

Solutions	O
of	O
substrate	O
were	O
prepared	O
in	O
anhydrous	O
acetonitrile	O
;	O
the	O
substrate	O
concentrations	O
varied	O
between	O
2	O
.	O
10	O
-	O
2	O
and	O
1	O
.	O
10	O
-	O
6	O
M	O
,	O
working	O
at	O
25C	O
.	O

A	O
molar	O
absorption	O
coefficient	O
of	O
18	O
,	O
400	O
M	O
-	O
l	O
.	O
cm	O
-	O
1	O
was	O
used	O
for	O
the	O
4	O
-	O
nitrophenolate	O
formed	O
by	O
hydrolysis	O
,	O
in	O
the	O
conditions	O
of	O
the	O
experiments	O
(	O
pH	O
7	O
.	O
40	O
)	O
,	O
as	O
reported	O
in	O
the	O
literature	O
[	O
35	O
]	O
.	O

Non	O
-	O
enzymatic	O
hydrolysis	O
rates	O
were	O
always	O
subtracted	O
from	O
the	O
observed	O
rates	O
.	O

Duplicate	O
experiments	O
were	O
done	O
for	O
each	O
inhibitor	O
concentration	O
,	O
and	O
the	O
values	O
reported	O
throughout	O
the	O
paper	O
are	O
the	O
mean	O
of	O
such	O
results	O
.	O

Stock	O
solutions	O
of	O
inhibitor	O
(	O
1	O
mM	O
)	O
were	O
prepared	O
in	O
distilled	O
-	O
deionized	O
water	O
with	O
1020	O
%	O
(	O
v	O
/	O
v	O
)	O
DMSO	O
(	O
which	O
is	O
not	O
inhibitory	O
at	O
these	O
concentrations	O
[	O
2	O
]	O
)	O
and	O
dilutions	O
up	O
to	O
0	O
.	O
01	O
nM	O
were	O
done	O
thereafter	O
with	O
distilled	O
-	O
deionized	O
water	O
.	O

Inhibitor	O
and	O
enzyme	O
solutions	O
were	O
preincubated	O
together	O
for	O
10	O
min	O
at	O
room	O
temperature	O
prior	O
to	O
assay	O
,	O
in	O
order	O
to	O
allow	O
for	O
the	O
formation	O
of	O
the	O
E	O
-	O
I	O
complex	O
.	O

The	O
inhibition	O
constant	O
KI	O
was	O
determined	O
as	O
described	O
by	O
Pocket	O
and	O
Stone	O
[	O
35	O
]	O
.	O

Enzyme	O
concentrations	O
were	O
3	O
.	O
3	O
nM	O
for	O
hCA	O
II	O
,	O
l0	O
nM	O
for	O
hCA	O
and	O
34	O
nM	O
for	O
bCA	O
IV	O
(	O
this	O
isozyme	O
has	O
a	O
decreased	O
esterase	O
activity	O
[	O
36	O
]	O
and	O
higher	O
concentrations	O
had	O
to	O
be	O
used	O
for	O
the	O
-	O
measurements	O
)	O
.	O

Measurement	O
of	O
tonometric	O
lOP	O
Adult	O
male	O
New	O
Zealand	O
albino	O
rabbits	B
weighing	O
2	O
-	O
3	O
kg	O
were	O
used	O
in	O
the	O
experiments	O
(	O
three	O
animals	O
were	O
used	O
for	O
each	O
inhibitor	O
studied	O
)	O
.	O

The	O
experimental	O
procedures	O
conform	O
to	O
the	O
Association	O
for	O
Research	O
in	O
Vision	O
and	O
Ophthalmology	O
Resolution	O
on	O
the	O
use	O
of	O
animals	O
.	O

The	O
rabbits	B
were	O
kept	O
in	O
individual	O
cages	O
with	O
food	O
and	O
water	O
provided	O
ad	O
libitum	O
.	O

The	O
animals	O
were	O
maintained	O
on	O
a	O
12	O
h	O
:	O
12	O
h	O
light	O
/	O
dark	O
cycle	O
in	O
a	O
temperature	O
controlled	O
room	O
,	O
at	O
22	O
-	O
26	O
C	O
.	O

Solutions	O
of	O
inhibitors	O
(	O
2	O
%	O
,	O
by	O
weight	O
)	O
were	O
obtained	O
in	O
DMSOwater	O
(	O
2	O
:	O
3	O
,	O
v	O
/	O
v	O
)	O
due	O
to	O
the	O
low	O
water	O
solubility	O
of	O
some	O
of	O
these	O
derivatives	O
.	O

Control	O
experiments	O
with	O
DMSO	O
(	O
at	O
the	O
same	O
concentration	O
as	O
that	O
used	O
for	O
obtaining	O
the	O
inhibitors	O
solutions	O
showed	O
that	O
it	O
does	O
not	O
possess	O
IOP	O
lowering	O
or	O
increasing	O
effects	O
.	O

IOP	O
was	O
measured	O
using	O
a	O
Digilab	O
30R	O
pneumatonometer	O
(	O
BioRad	O
,	O
Cambridge	O
,	O
MA	O
,	O
USA	O
)	O
as	O
described	O
by	O
Maren	O
'	O
s	O
group	O
[	O
37	O
-	O
39	O
]	O
.	O

The	O
pressure	O
readings	O
were	O
matched	O
with	O
two	O
-	O
point	O
standard	O
pressure	O
measurements	O
at	O
least	O
twice	O
each	O
day	O
using	O
a	O
Digilab	O
Calibration	O
verifier	O
.	O

All	O
IOP	O
measurements	O
were	O
done	O
by	O
the	O
same	O
investigator	O
with	O
the	O
same	O
tonometer	O
.	O

One	O
drop	O
of	O
0	O
.	O
2	O
%	O
oxybuprocaine	O
hydrochloride	O
(	O
novesine	O
,	O
Sandoz	O
)	O
diluted	O
1	O
"	O
1	O
with	O
saline	O
was	O
instilled	O
in	O
each	O
eye	O
immediately	O
before	O
each	O
set	O
of	O
pressure	O
measurements	O
.	O

IOP	O
was	O
measured	O
three	O
times	O
at	O
each	O
time	O
interval	O
,	O
and	O
the	O
means	O
reported	O
.	O

IOP	O
was	O
measured	O
first	O
immediately	O
before	O
drug	O
administration	O
,	O
then	O
at	O
30	O
min	O
after	O
the	O
instillation	O
of	O
the	O
pharmacological	O
agent	O
,	O
and	O
then	O
each	O
30	O
minutes	O
for	O
a	O
period	O
of	O
several	O
hours	O
.	O

For	O
all	O
IOP	O
experiments	O
drug	O
was	O
administered	O
to	O
only	O
one	O
eye	O
,	O
leaving	O
the	O
contralateral	O
eye	O
as	O
an	O
untreated	O
control	O
.	O

The	O
ocular	O
hypotensive	O
activity	O
is	O
expressed	O
as	O
the	O
average	O
difference	O
in	O
IOP	O
between	O
the	O
treated	O
and	O
control	O
eye	O
,	O
in	O
this	O
way	O
minimizing	O
the	O
diurnal	O
,	O
seasonal	O
and	O
interindividual	O
variations	O
commonly	O
observed	O
in	O
the	O
rabbit	B
[	O
37	O
-	O
39	O
]	O
.	O

All	O
data	O
are	O
expressed	O
as	O
mean	O
SE	O
,	O
using	O
a	O
one	O
-	O
tailed	O
test	O
.	O

Results	O
and	O
Discussion	O
Reaction	O
of	O
5	O
-	O
amino	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
6	O
[	O
19b	O
]	O
with	O
chloroacteyl	O
chloride	O
in	O
the	O
presence	O
of	O
pyridine	O
afforded	O
5	O
-	O
(	O
chloroacetamido	O
)	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
7	O
,	O
by	O
the	O
procedure	O
already	O
reported	O
by	O
Young	O
et	O
al	O
.	O

[	O
34	O
]	O
(	O
Scheme	O
1	O
)	O
.	O

The	O
sulfonamide	O
7	O
has	O
been	O
characterized	O
by	O
elemental	O
analysis	O
and	O
spectroscopic	O
methods	O
which	O
confirmed	O
its	O
structure	O
(	O
only	O
its	O
m	O
.	O
p	O
.	O
has	O
been	O
reported	O
in	O
ref	O
.	O
[	O
34	O
]	O
)	O
.	O

The	O
sodium	O
salt	O
of	O
sulfonamides	O
6	O
and	O
7	O
,	O
obtained	O
in	O
situ	O
from	O
the	O
corresponding	O
sulfonamide	O
and	O
sodium	O
hydroxide	O
,	O
were	O
then	O
used	O
for	O
the	O
preparation	O
of	O
coordination	O
compounds	O
,	O
containing	O
the	O
following	O
metal	O
ions	O
:	O
Be	O
(	O
II	O
)	O
,	O
Mg	O
(	O
II	O
)	O
,	O
Al	O
(	O
III	O
)	O
,	O
Zn	O
(	O
II	O
)	O
,	O
Cd	O
(	O
II	O
)	O
and	O
Hg	O
(	O
II	O
)	O
.	O

Mention	O
should	O
be	O
made	O
that	O
although	O
5	O
-	O
amino	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
6	O
is	O
the	O
parent	O
compound	O
of	O
important	O
sulfonamide	O
CA	O
inhibitors	O
,	O
such	O
as	O
acetazolamide	O
,	O
benzolamide	O
,	O
methazolamide	O
,	O
etc	O
.	O
,	O
its	O
coordination	O
chemistry	O
has	O
been	O
scarcely	O
investigated	O
up	O
to	O
now	O
[	O
22	O
,	O
40	O
]	O
.	O

The	O
new	O
complexes	O
prepared	O
in	O
this	O
work	O
are	O
shown	O
in	O
Table	O
I	O
.	O
Both	O
compounds	O
containing	O
the	O
sulfonamide	O
-	O
deprotonated	O
species	O
of	O
sulfonamide	O
7	O
(	O
LH	O
)	O
,	O
as	O
well	O
as	O
complexes	O
in	O
which	O
the	O
anion	O
of	O
5amino	O
-	O
1	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
(	O
tda	O
)	O
act	O
as	O
ligands	O
,	O
have	O
been	O
prepared	O
.	O

In	O
fact	O
in	O
another	O
work	O
[	O
40	O
]	O
it	O
was	O
documented	O
that	O
in	O
some	O
cases	O
,	O
sulfonamides	O
derived	O
from	O
this	O
ring	O
system	O
may	O
undergo	O
hydrolysis	O
to	O

309	O

Vol	O
.	O

4	O
,	O
No	O
.	O
6	O
,	O
1997	O

Metal	O
Complexes	O
of	O
Heterocyclic	O
Sulfonamides	O
.	O
"	O
A	O
New	O
Class	O
ofAntiglaucoma	O
Agents	O

the	O
moiety	O
substituting	O
the	O
5	O
position	O
,	O
with	O
the	O
formation	O
of	O
5	O
-	O
amino	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
6	O
,	O
which	O
thereafter	O
coordinates	O
metal	O
ions	O
present	O
in	O
solution	O
.	O

N	O
CIH	O
N	O

I	O

N	O
+	O
NaHCO	O
2	O

N	O
2	O

S	O
'	O

-	O
NaCl	O

I	O
S	O

N	O

II	O

SO2NH	O

1	O
_	O
12	O
O	O
Py	O
/	O
MeCN	O

6Htda	O
+	O
CIOCCH2CI	O

0	O
Cl	O
CH	O
2	O
Scheme	O
1	O

HN	O

.	O
I	O

N	O

N	O

S	O
7	O
:	O
LH	O

II	O

SqNH	O

Thus	O
,	O
the	O
X	O
-	O
ray	O
crystal	O
structure	O
of	O
the	O
complex	O
[	O
Zn	O
(	O
tda	O
)	O
2	O
(	O
NH3	O
)	O
]	O
.	O
H20	O
prepared	O
in	O
this	O
way	O
has	O
recently	O
been	O
reported	O
by	O
this	O
group	O
[	O
40	O
]	O
.	O

On	O
the	O
other	O
hand	O
,	O
when	O
the	O
ligand	O
7	O
has	O
not	O
been	O
hydrolyzed	O
(	O
during	O
the	O
preparation	O
of	O
the	O
coordination	O
compounds	O
)	O
in	O
the	O
presence	O
of	O
the	O
metal	O
ion	O
to	O
5	O
-	O
amino	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2sulfonamide	O
and	O
chloroacetate	O
,	O
the	O
metal	O
complexes	O
contining	O
6	O
as	O
ligand	O
have	O
been	O
prepared	O
from	O
the	O
last	O
(	O
pure	O
)	O
compound	O
(	O
as	O
sodium	O
salt	O
)	O
and	O
the	O
corresponding	O
metal	O
salt	O
,	O
by	O
the	O
general	O
procedure	O
described	O
in	O
the	O
Experimental	O
part	O
.	O

Table	O
I	O
:	O
Prepared	O
complexes	O
8	O
-	O
20	O
,	O
containing	O
the	O
conjugate	O
bases	O
of	O
sulfonamides	O
6	O
and	O
7	O
as	O
ligands	O
and	O
their	O
elemental	O
analysis	O
data	O
.	O

L	O
stands	O
for	O
the	O
sulfonamide	O
deprotonated	O
species	O
of	O
7	O
,	O
whereas	O
tda	O
for	O
the	O
sulfonamide	O
deprotonated	O
species	O
of	O
5	O
-	O
amino	O
-	O
1	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
6	O
.	O

No	O
.	O
8	O
9	O
10	O
11	O
12	O
13	O
14	O
15	O
16	O
17	O
18	O
19	O
20	O

Complex	O

Yield	O

(	O
%	O
)	O

%	O
Ma	O

Analysis	O
(	O
calculated	O
/	O
found	O
)	O
%	O
H	O
b	O
%	O
C	O
b	O
13	O
.	O
0	O
/	O
13	O
.	O
1	O
11	O
.	O
0	O
/	O
10	O
.	O
8	O
11	O
.	O
3	O
/	O
11	O
.	O
4	O
10	O
.	O
2	O
/	O
10	O
.	O
1	O
8	O
.	O
5	O
/	O
8	O
.	O
1	O
7	O
.	O
9	O
/	O
7	O
.	O
9	O
12	O
.	O
7	O
/	O
12	O
.	O
8	O
18	O
.	O
4	O
/	O
18	O
.	O
1	O
18	O
.	O
1	O
/	O
17	O
.	O
9	O
16	O
.	O
6	O
/	O
16	O
.	O
2	O
15	O
.	O
3	O
/	O
14	O
.	O
9	O
13	O
.	O
4	O
/	O
13	O
.	O
3	O
12	O
.	O
7	O
/	O
12	O
.	O
5	O
1	O
.	O
6	O
/	O
1	O
.	O
3	O
2	O
.	O
7	O
/	O
2	O
.	O
3	O
1	O
.	O
4	O
/	O
1	O
.	O
1	O
1	O
.	O
2	O
/	O
1	O
.	O
2	O
1	O
.	O
0	O
/	O
1	O
.	O
2	O
1	O
.	O
6	O
/	O
1	O
.	O
3	O
1	O
.	O
6	O
/	O
1	O
.	O
6	O
1	O
.	O
5	O
/	O
1	O
.	O
5	O
1	O
.	O
5	O
/	O
1	O
.	O
3	O
1	O
.	O
3	O
/	O
1	O
.	O
4	O
1	O
.	O
2	O
/	O
1	O
.	O
1	O
1	O
.	O
1	O
/	O
1	O
.	O
2	O
1	O
.	O
0	O
/	O
1	O
.	O
0	O

%	O
N	O
b	O
30	O
.	O
4	O
/	O
30	O
.	O
2	O
25	O
.	O
6	O
/	O
25	O
.	O
5	O
26	O
.	O
4	O
/	O
26	O
.	O
4	O
13	O
.	O
7	O
/	O
23	O
.	O
3	O
20	O
.	O
0	O
/	O
19	O
.	O
8	O
18	O
.	O
6	O
/	O
18	O
.	O
5	O
29	O
.	O
7	O
/	O
29	O
.	O
6	O
21	O
.	O
5	O
/	O
21	O
.	O
3	O
21	O
.	O
1	O
/	O
20	O
.	O
8	O
19	O
.	O
4	O
/	O
19	O
.	O
3	O
17	O
.	O
9	O
/	O
17	O
.	O
8	O
15	O
.	O
7	O
/	O
15	O
.	O
6	O
14	O
.	O
8	O
/	O
14	O
.	O
6	O

[	O
Be	O
(	O
tda	O
)	O
2	O
]	O
[	O
Mg	O
(	O
tda	O
)	O
2	O
]	O
.	O
3	O
H20	O
[	O
Zn	O
(	O
tda	O
)	O
2	O
]	O
[	O
Cd	O
(	O
tda	O
)	O
2	O
]	O
[	O
Hg	O
(	O
tda	O
)	O
2	O
]	O
[	O
Pb	O
(	O
tda	O
)	O
z	O
(	O
OH2	O
)	O
2	O
]	O
[	O
Al	O
(	O
tda	O
)	O
3	O
]	O
[	O
BeL2	O
]	O
[	O
ALL3	O
]	O
[	O
ZnL2	O
]	O
[	O
CdL2	O
]	O
[	O
HgL2	O
]	O
[	O
PbLz	O
(	O
OH2	O
)	O
2	O
]	O

78	O
76	O
83	O
90	O
95	O
84	O
72	O
75	O
59	O
87	O
88	O
92	O
95	O

2	O
.	O
4	O
/	O
2	O
.	O
5	O
5	O
.	O
5	O
/	O
5	O
.	O
1	O
15	O
.	O
4	O
/	O
15	O
.	O
0	O
23	O
.	O
8	O
/	O
24	O
.	O
1	O
35	O
.	O
8	O
/	O
35	O
.	O
7	O
34	O
.	O
4	O
/	O
34	O
.	O
7	O
4	O
.	O
7	O
/	O
4	O
.	O
4	O
1	O
.	O
7	O
/	O
1	O
.	O
6	O
3	O
.	O
4	O
/	O
3	O
.	O
5	O
11	O
.	O
3	O
/	O
11	O
.	O
5	O
18	O
.	O
0	O
/	O
18	O
.	O
1	O
28	O
.	O
1	O
/	O
28	O
.	O
3	O
27	O
.	O
4	O
/	O
27	O
.	O
2	O

aBy	O
gravimetry	O
;	O
bBy	O
combustion	O
.	O

The	O
new	O
complexes	O
have	O
also	O
been	O
characterized	O
by	O
spectroscopic	O
,	O
conductimetric	O
and	O
thermogravimetric	O
measurements	O
(	O
Table	O
II	O
)	O
.	O

By	O
comparing	O
the	O
IR	O
spectra	O
of	O
the	O
complexes	O
and	O
the	O
corresponding	O
ligands	O
,	O
the	O
following	O
observations	O
should	O
be	O
made	O
:	O
(	O
i	O
)	O
the	O
shift	O
of	O
the	O
two	O
sulfonamido	O
vibrations	O
(	O
both	O
the	O
symmetric	O
as	O
well	O
as	O
the	O
the	O
assymetric	O
one	O
)	O
,	O
towards	O
lower	O
wavenumbers	O
in	O
the	O
spectra	O
of	O
the	O
complexes	O
,	O
as	O
compared	O
to	O
the	O
spectra	O
of	O
the	O
corresponding	O
ligand	O
(	O
Table	O
II	O
)	O
,	O
as	O
already	O
documented	O
previously	O
for	O
similar	O
complexes	O
[	O
13	O
-	O
22	O
]	O
.	O

This	O
is	O
a	O
direct	O
indication	O
that	O
the	O
deprotonated	O
sulfonamido	O
310	O

Claudiu	O
T	O
.	O
Supuran	O
et	O
al	O
.	O

Metal	O
-	O
Based	O
Drugs	O

moieties	O
of	O
the	O
ligands	O
interacts	O
with	O
the	O
metal	O
ions	O
in	O
the	O
newly	O
prepared	O
coordination	O
compounds	O
;	O
(	O
ii	O
)	O
the	O
amide	O
vibrations	O
(	O
the	O
most	O
intense	O
such	O
bands	O
at	O
1670	O
-	O
1680	O
cm	O
-	O
1	O
)	O
of	O
ligand	O
7	O
appear	O
unchanged	O
in	O
the	O
IR	O
spectra	O
of	O
complexes	O
15	O
-	O
20	O
(	O
data	O
not	O
shown	O
)	O
,	O
suggesting	O
that	O
these	O
moieties	O
do	O
not	O
participate	O
in	O
coordination	O
of	O
the	O
metal	O
ions	O
;	O
(	O
iii	O
)	O
the	O
C	O
-	O
N	O
stretching	O
vibration	O
in	O
the	O
spectra	O
of	O
the	O
prepared	O
complexes	O
is	O
shifted	O
with	O
5	O
-	O
20	O
cm	O
-	O
1	O
towards	O
lower	O
wavenumbers	O
,	O
as	O
compared	O
to	O
the	O
same	O
vibration	O
in	O
the	O
spectra	O
of	O
sulfonamides	O
6	O
and	O
7	O
,	O
indicating	O
that	O
one	O
of	O
the	O
endocyclic	O
nitrogens	O
of	O
the	O
thiadiazolic	O
ring	O
(	O
presumably	O
N3	O
)	O
acts	O
as	O
donor	O
atom	O
,	O
as	O
already	O
documented	O
by	O
X	O
-	O
ray	O
crystallographic	O
and	O
spectroscopic	O
determinations	O
on	O
complexes	O
of	O
other	O
sulfonamides	O
(	O
such	O
as	O
1	O
-	O
3	O
)	O
with	O
divalent	O
metal	O
ions	O
[	O
13	O
-	O
22	O
]	O
(	O
Table	O
II	O
)	O
;	O
(	O
iv	O
)	O
changes	O
in	O
the	O
region	O
3100	O
-	O
3160	O
cm	O
-	O
,	O
as	O
the	O
bands	O
present	O
in	O
the	O
spectra	O
of	O
sulfonamides	O
6	O
,	O
7	O
are	O
present	O
in	O
the	O
spectra	O
of	O
complexes	O
8	O
-	O
20	O
too	O
,	O
but	O
they	O
are	O
not	O
well	O
resolved	O
,	O
and	O
have	O
a	O
smaller	O
intensity	O
.	O

This	O
is	O
probably	O
due	O
to	O
deprotonation	O
of	O
the	O
SO2NH2	O
moiety	O
and	O
participation	O
in	O
the	O
binding	O
of	O
cations	O
;	O
(	O
v	O
)	O
the	O
amino	O
vibrations	O
from	O
3320	O
cm	O
-	O
in	O
the	O
spectra	O
of	O
6	O
appear	O
unchanged	O
in	O
the	O
spectra	O
of	O
its	O
complexes	O
8	O
-	O
14	O
(	O
data	O
not	O
s	O
.	O
hown	O
)	O
.	O

In	O
the	O
1H	O
-	O
NMR	O
spectra	O
of	O
compound	O
6	O
and	O
its	O
metal	O
complexes	O
,	O
the	O
signal	O
of	O
the	O
amino	O
group	O
has	O
been	O
evidenced	O
as	O
a	O
broad	O
singlet	O
centered	O
at	O
4	O
.	O
54	O
ppm	O
(	O
Table	O
II	O
)	O
,	O
which	O
is	O
not	O
exchangeable	O
by	O
addition	O
of	O
D20	O
into	O
the	O
NMR	O
tube	O
,	O
in	O
contrast	O
to	O
the	O
sulfonamido	O
NH2	O
protons	O
(	O
which	O
readily	O
exchange	O
)	O
.	O

This	O
proves	O
that	O
the	O
5	O
-	O
amino	O
moiety	O
is	O
not	O
involved	O
in	O
binding	O
the	O
metal	O
ions	O
,	O
as	O
already	O
shown	O
in	O
the	O
X	O
-	O
ray	O
crystallographic	O
work	O
of	O
the	O
complex	O
[	O
Zn	O
(	O
tda	O
)	O
z	O
(	O
NH3	O
)	O
]	O
.	O
H20	O
previously	O
reported	O
[	O
40	O
]	O
.	O

For	O
sulfonamide	O
7	O
the	O
CONH	O
proton	O
resonates	O
as	O
a	O
singlet	O
at	O
12	O
.	O
22	O
ppm	O
.	O

In	O
complexes	O
15	O
-	O
20	O
only	O
very	O
minor	O
shifts	O
of	O
this	O
signal	O
were	O
evidenced	O
(	O
Table	O
II	O
)	O
,	O
proving	O
basically	O
that	O
the	O
CONH	O
moiety	O
does	O
not	O
interact	O
with	O
the	O
metal	O
ions	O
in	O
these	O
complexes	O
.	O

Table	O
II	O
:	O
Spectroscopic	O
,	O
thermogravimetric	O
and	O
conductimetric	O
data	O
for	O
compounds	O
6	O
-	O
20	O
.	O

1H	O
-	O
NMR	O
Spectrab	O
Comp	O
.	O

IR	O
Spectraa	O
,	O
cm	O
-	O
1	O
as	O
v	O
(	O
C	O
=	O
N	O
)	O
CONH	O
,	O
i	O
(	O
ppm	O
)	O
v	O
(	O
SO2	O
)	O
S	O
;	O
v	O
(	O
SO2	O
)	O
6	O
8	O
9	O
10	O
11	O

TG	O
analysisc	O
calc	O
.	O
/	O
found	O

Conductimetryd	O
AM	O
(	O
-	O
1	O
x	O
cm2x	O
mol	O
-	O
)	O
2	O
7	O
4	O
5	O
3	O
2	O
2	O
6	O
3	O
4	O
2	O
9	O
3	O
2	O
8	O

12	O
13	O
14	O
7	O
15	O
16	O
17	O
18	O
19	O
20	O

1170	O
;	O
1150	O
;	O
1150	O
;	O
1145	O
;	O
1145	O
;	O
1140	O
;	O
1145	O
;	O
1150	O
;	O
1170	O
;	O
1130	O
;	O
1140	O
;	O
1140	O
;	O
1150	O
;	O
1140	O
;	O
1145	O
;	O

1350	O
1300	O
1305	O
1300	O
1305	O
1300	O
1300	O
1300	O
1350	O
1335	O
1330	O
1330	O
1330	O
1335	O
1330	O

1610	O
1600	O
1600	O
1600	O
1600	O
1590	O
1605	O
1605	O
1610	O
1605	O
1610	O
1610	O
1605	O
1600	O
1600	O

A	O
A	O
A	O
A	O
A	O
A	O
A	O

e	O
e	O

12	O
.	O
3	O
/	O
12	O
.	O
1f	O
e	O
e	O
e	O
5	O
.	O
9	O
/	O
5	O
.	O
7g	O

A	O
12	O
.	O
22	O
(	O
1H	O
)	O
12	O
.	O
19	O
(	O
2H	O
)	O
12	O
.	O
18	O
(	O
3H	O
)	O
12	O
.	O
20	O
(	O
2H	O
)	O
12	O
.	O
18	O
(	O
2H	O
)	O
12	O
.	O
19	O
(	O
2H	O
)	O
12	O
.	O
21	O
(	O
2H	O
)	O

e	O
e	O
e	O
e	O
e	O
e	O
e	O
4	O
.	O
7	O
/	O
4	O
.	O
8g	O

a	O
In	O
KBr	O
;	O
bin	O
DMSO	O
-	O
d6	O
;	O
A	O
the	O
signal	O
of	O
the	O
5	O
-	O
amino	O
group	O
of	O
6	O
(	O
appearing	O
in	O
the	O
ligand	O
at	O
4	O
.	O
54	O
ppm	O
as	O
a	O
broad	O
singlet	O
)	O
appears	O
at	O
the	O
same	O
chemical	O
shift	O
(	O
4	O
.	O
50	O
4	O
.	O
55	O
ppm	O
)	O
in	O
complexes	O
8	O
-	O
14	O
;	O
cWeight	O
loss	O
between	O
70	O
-	O
250	O
C	O
;	O
d	O
mM	O
solution	O
,	O
in	O
DMF	O
,	O
at	O
25C	O
;	O
e	O
No	O
weight	O
loss	O
seen	O
under	O
250	O
C	O
;	O
fCorresponding	O
to	O
three	O
lattice	O
water	O
molecules	O
lost	O
at	O
70	O
-	O
110C	O
,	O
and	O
gCorresponding	O
to	O
two	O
coordinated	O
water	O
molecules	O
,	O
lost	O
at	O
160	O
-	O
180	O
C	O
.	O

Thermogravimetric	O
analysis	O
showed	O
the	O
presence	O
of	O
uncoordinated	O
water	O
molecules	O
in	O
the	O
molecule	O
of	O
complex	O
9	O
(	O
the	O
three	O
waters	O
were	O
lost	O
in	O
a	O
single	O
step	O
,	O
between	O
70	O
-	O
110	O
C	O
)	O
and	O
of	O
coordinated	O
water	O
in	O
the	O
molecules	O
of	O
the	O
lead	O
(	O
II	O
)	O
derivatives	O
13	O
and	O
20	O
.	O

All	O
these	O
compounds	O
behaved	O
as	O
non	O
-	O
electrolytes	O
in	O
DMF	O
as	O
solvent	O
(	O
Table	O
II	O
)	O
.	O

Mention	O
should	O
be	O
made	O
that	O
the	O
Mg	O
(	O
II	O
)	O
complex	O
of	O
sulfonamide	O
7	O
could	O
not	O
be	O
isolated	O
.	O

Instead	O
,	O
only	O
the	O
correponding	O
complex	O
of	O
5	O
-	O
amino	O
-	O
l	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
has	O
been	O
obtained	O
from	O
reaction	O
mixtures	O
containing	O
magnesium	O
salts	O
and	O
the	O
sodium	O
salt	O
of	O
7	O
,	O
probably	O
due	O
to	O
a	O
metal	O
ion	O
assisted	O
hydrolysis	O
of	O
7	O
to	O
6	O
and	O
chloroacetate	O
.	O

Generally	O
such	O
hydrolytic	O
processes	O
involve	O
highly	O
acidic	O
conditions	O
and	O
prolonged	O
heating	O
of	O
the	O
5	O
-	O
alkylamido	O
-	O
1	O
,	O
3	O
,	O
4	O
-	O
thiadiazole	O
-	O
2	O
-	O
sulfonamide	O
derivatives	O
[	O
41	O
]	O
,	O
but	O
they	O
might	O
become	O
milder	O
by	O
taking	O
into	O
account	O
the	O
putative	O
catalytic	O
effect	O
of	O
Mg2	O
+	O
ions	O
reported	O
here	O
.	O

The	O
data	O
shown	O
above	O
lead	O
to	O
the	O
conclusion	O
that	O
ligand	O
7	O
shares	O
a	O
common	O
coordination	O
chemistry	O
with	O
acetazolamide	O
1	O
with	O
which	O
it	O
is	O
structurally	O
related	O
,	O
whereas	O
6	O
probably	O
also	O
behaves	O
similarly	O
to	O
acetazolamide	O
in	O
the	O
sense	O
that	O
the	O
5	O
-	O
amino	O
group	O
seems	O
not	O
to	O
be	O
involved	O
in	O
coordinating	O
metal	O
ions	O
,	O
at	O
311	O

Vol	O
.	O

4	O
,	O
No	O
.	O
6	O
,	O
1997	O

Metal	O
Complexes	O
of	O
Heterocyclic	O
Sulfonamides	O
:	O
A	O
New	O
Class	O
ofAntiglaucoma	O
Agents	O

least	O
in	O
the	O
complexes	O
reported	O
by	O
us	O
here	O
(	O
and	O
also	O
in	O
the	O
compound	O
characterized	O
by	O
X	O
-	O
ray	O
crystallography	O
mentioned	O
above	O
[	O
40	O
]	O
)	O
.	O

Thus	O
,	O
in	O
all	O
complexes	O
reported	O
here	O
these	O
sulfonamides	O
(	O
as	O
monodeprotonated	O
species	O
at	O
the	O
SO2NH	O
2	O
moieties	O
)	O
act	O
as	O
bidentate	O
ligands	O
,	O
through	O
the	O
endocyclic	O
N	O
-	O
3	O
and	O
the	O
NH	O
-	O
groups	O
.	O

The	O
proposed	O
formulae	O
of	O
the	O
new	O
complxes	O
are	O
shown	O
below	O
.	O

Except	O
for	O
the	O
two	O
Pb	O
(	O
II	O
)	O
complexes	O
13	O
and	O
20	O
,	O
as	O
well	O
as	O
the	O
AI	O
(	O
III	O
)	O
derivatives	O
14	O
and	O
16	O
,	O
which	O
presumably	O
are	O
pseudo	O
-	O
octahedral	O
,	O
the	O
other	O
derivatives	O
are	O
supposed	O
to	O
contain	O
tetrahedral	O
M	O
(	O
II	O
)	O
ions	O
.	O

R	O

R	O
13	O
"	O
R	O
=	O
20	O
"	O
R	O
=	O

H2N	O

CICH2CONH	O

14	O
:	O
R	O
=	O
16	O
:	O
R	O
=	O

H2N	O
CICH2CONH	O

The	O
compounds	O
6	O
-	O
20	O
together	O
with	O
the	O
standard	O
CA	O
inhibitors	O
1	O
-	O
5	O
were	O
assayed	O
for	O
inhibition	O
against	O
three	O
isozymes	O
,	O
hCA	O
I	O
,	O
hCA	O
II	O
and	O
bCA	O
IV	O
(	O
Table	O
III	O
)	O
.	O

As	O
seen	O
from	O
the	O
above	O
data	O
,	O
the	O
chloracetamido	O
derivative	O
is	O
more	O
inhibitory	O
than	O
acetazolamide	O
,	O
methazolamide	O
and	O
dichlorophenamide	O
,	O
whereas	O
the	O
unacylated	O
compound	O
6	O
is	O
less	O
inhibitory	O
than	O
the	O
above	O
sulfonamides	O
.	O

The	O
metal	O
complexes	O
820	O
are	O
much	O
more	O
inhibitory	O
than	O
the	O
sulfonamides	O
from	O
which	O
they	O
derive	O
6	O
,	O
7	O
and	O
than	O
all	O
other	O
simple	O
sulfonamides	O
assayed	O
.	O

They	O
behave	O
similarly	O
to	O
the	O
metal	O
complexes	O
of	O
acetazolamide	O
,	O
methazolamide	O
or	O
dorzolamide	O
previously	O
reported	O
by	O
this	O
group	O
,	O
which	O
were	O
all	O
more	O
inhibitory	O
than	O
the	O
parent	O
sulfonamide	O
from	O
which	O
were	O
prepared	O
[	O
16	O
-	O
22	O
,	O
40	O
]	O
.	O

Particularly	O
strong	O
inhibition	O
was	O
observed	O
for	O
the	O
Zn	O
(	O
II	O
)	O
,	O
Hg	O
(	O
II	O
)	O
,	O
Pb	O
(	O
II	O
)	O
and	O
Cd	O
(	O
II	O
)	O
complexes	O
,	O
especially	O
against	O
CA	O
II	O
and	O
CA	O
IV	O
,	O
the	O
isozymes	O
critical	O
for	O
aqueous	O
humor	O
formation	O
.	O

In	O
vivo	O
IOP	O
lowering	O
experiments	O
were	O
done	O
in	O
rabbits	B
with	O
some	O
of	O
the	O
new	O
compounds	O
prepared	O
in	O
the	O
present	O
work	O
,	O
such	O
as	O
the	O
sulfonamides	O
6	O
and	O
7	O
,	O
and	O
their	O
Zn	O
(	O
II	O
)	O
complexes	O
,	O
which	O
were	O
among	O
the	O
strong	O
CA	O
II	O
and	O
CA	O
IV	O
inhibitors	O
in	O
the	O
obtained	O
series	O
.	O

Some	O
of	O
the	O
IOP	O
lowering	O
data	O
at	O
half	O
an	O
hour	O
and	O
one	O
hour	O
after	O
the	O
instillation	O
of	O
one	O
drop	O
of	O
2	O
%	O
solution	O
of	O
inhibitor	O
within	O
the	O
rabbit	B
eye	O
are	O
shown	O
in	O
312	O

Claudiu	O
T	O
.	O
Supuran	O
et	O
al	O
.	O

Metal	O
-	O
Based	O
Drugs	O

Table	O
IV	O
,	O
with	O
dorzolamide	O
(	O
at	O
the	O
same	O
concentration	O
)	O
as	O
standard	O
.	O

In	O
Fig	O
.	O
the	O
time	O
dependence	O
of	O
IOP	O
lowering	O
with	O
dorzolamide	O
5	O
and	O
the	O
two	O
Zn	O
(	O
II	O
)	O
complexes	O
10	O
and	O
17	O
is	O
presented	O
.	O

Table	O
III	O
.	O

CA	O
inhibition	O
data	O
with	O
the	O
standard	O
inhibitors	O
1	O
-	O
5	O
,	O
the	O
sulfonamides	O
6	O
and	O
7	O
,	O
and	O
their	O
metal	O
complexes	O
8	O
-	O
20	O
.	O

No	O
1	O
2	O
3	O
4	O
5	O
6	O
7	O
8	O
9	O
10	O
11	O
12	O
13	O
14	O
15	O
16	O
17	O
18	O
19	O
20	O
a	O

Inhibitor	O

KI	O
hCA	O
Ia	O
900	O
780	O
25	O
1200	O
>	O
50	O
,	O
000	O
1550	O
640	O
1050	O
350	O
50	O
40	O
12	O
80	O
240	O
120	O
80	O
40	O
40	O
9	O
15	O

(	O
nM	O
)	O
bCA	O
IVb	O
220	O
240	O
13	O
380	O
43	O
780	O
24	O
540	O
220	O
25	O
19	O
10	O
26	O
110	O
12	O
16	O
9	O
10	O
5	O
10	O

hCA	O
IIa	O
12	O
14	O
8	O
38	O
9	O
230	O
5	O
190	O
110	O
15	O
14	O
7	O
10	O
76	O
5	O
4	O
3	O
3	O
2	O
5	O

Acetazolamide	O
Methazolamide	O
Ethoxzolamide	O

Dichlorophenamide	O
Dorzolamide	O

Human	B
(	O
cloned	O
)	O
isozymes	O
;	O
b	O
From	O
bovine	B
lung	O
microsomes	O
.	O

Table	O
IV	O
:	O
IOP	O
lowering	O
following	O
topical	O
application	O
of	O
CA	O
inhibitors	O
,	O
half	O
an	O
hour	O
and	O
one	O
hour	O
after	O
instillation	O
into	O
the	O
eye	O
of	O
a	O
drop	O
(	O
50	O
L	O
)	O
of	O
2	O
%	O
solution	O
of	O
inhibitor	O
.	O

Inhibitor	O

lOP	O
SE	O
1	O
/	O
2	O
h	O

a	O

(	O
mm	O
Hg	O
)	O
lh	O
4	O
.	O
1	O
0	O
.	O
15	O
0	O
0	O
.	O
09	O
0	O
0	O
.	O
09	O
5	O
.	O
0	O
0	O
.	O
12	O
8	O
.	O
1	O
0	O
.	O
21	O
Dorzolamide	O
5	O
6	O
7	O
10	O
17	O
a	O

2	O
.	O
2	O
0	O
.	O
10	O
0	O
0	O
.	O
10	O
0	O
0	O
.	O
10	O
2	O
.	O
00	O
.	O
09	O
8	O
.	O
0	O
0	O
.	O
14	O

IOP	O

IOP	O
control	O
eye	O
"	O
IOP	O
treated	O
eye	O
(	O
N	O
3	O
)	O
.	O

As	O
seen	O
from	O
the	O
above	O
data	O
,	O
the	O
sulfonamides	O
6	O
and	O
7	O
are	O
totally	O
ineffective	O
as	O
lOP	O
lowering	O
agents	O
,	O
similarly	O
to	O
the	O
classical	O
clinically	O
used	O
inhibitors	O
of	O
type	O
1	O
-	O
5	O
[	O
2	O
,	O
3	O
]	O
.	O

On	O
the	O
other	O
hand	O
,	O
dorzolamide	O
,	O
the	O
first	O
topical	O
sulfonamide	O
used	O
clinically	O
in	O
the	O
treatment	O
of	O
glaucoma	O
is	O
an	O
effective	O
such	O
agent	O
,	O
with	O
a	O
decrease	O
of	O
lOP	O
of	O
around	O
4	O
mm	O
Hg	O
,	O
one	O
hour	O
after	O
administration	O
directly	O
into	O
the	O
eye	O
(	O
Table	O
IV	O
)	O
.	O

From	O
the	O
data	O
of	O
this	O
table	O
,	O
it	O
is	O
obvious	O
that	O
the	O
metal	O
complexes	O
of	O
heterocyclic	O
sulfonamides	O
investigated	O
by	O
us	O
behave	O
as	O
much	O
more	O
effective	O
IOP	O
lowering	O
agents	O
than	O
dorzolamide	O
,	O
and	O
their	O
effect	O
is	O
generally	O
longerlasting	O
(	O
Fig	O
.	O
1	O
)	O
.	O

A	O
last	O
remark	O
should	O
be	O
made	O
about	O
the	O
possible	O
mechanism	O
of	O
action	O
of	O
the	O
new	O
class	O
of	O
IOP	O
lowering	O
agents	O
.	O

Obviously	O
,	O
their	O
activity	O
is	O
due	O
to	O
inhibition	O
of	O
CA	O
isozymes	O
present	O
in	O
the	O
cilliary	O
processes	O
within	O
the	O
eye	O
,	O
similarly	O
to	O
other	O
topically	O
active	O
sulfonamides	O
[	O
2	O
-	O
6	O
]	O
.	O

The	O
fact	O
that	O
the	O
sulfonamide	O
per	O
se	O
is	O
inactive	O
via	O
the	O
topical	O
route	O
,	O
whereas	O
the	O
metal	O
complexes	O
result	O
much	O
better	O
than	O
the	O
drug	O

313	O

Vol	O
.	O

4	O
,	O
No	O
.	O
6	O
,	O
1997	O

Metal	O
Complexes	O
of	O
Heterocyclic	O
Sulfonamides	O
.	O
"	O
A	O
New	O
Class	O
ofAntiglaucoma	O
Agents	O

dorzolamide	O
,	O
indicates	O
that	O
the	O
presence	O
of	O
metal	O
ions	O
in	O
the	O
molecules	O
of	O
these	O
CA	O
inhibitors	O
is	O
essential	O
and	O
confers	O
them	O
completely	O
new	O
properties	O
.	O

Lowering	O
of	O
IOP	O
(	O
ram	O
Hg	O
)	O

"	O
|	O
|	O
,	O

/	O

"	O
,	O
,	O

'	O
"	O
,	O
.	O
,	O

,	O
<	O

.	O
7	O
,	O
/	O

/	O

.	O
6	O

-	O
0	O

-	O
10	O
0	O

2	O

Time	O
(	O
hours	O
)	O

Fig	O
l	O
"	O
Time	O
dependence	O
of	O
IOP	O
lowering	O
with	O
dorzolamide	O
(	O
curve	O
1	O
)	O
;	O
the	O
zinc	O
complex	O
10	O
(	O
curve	O
3	O
)	O
and	O
the	O
zinc	O
complex	O
17	O
(	O
curve	O
3	O
)	O
,	O
after	O
topical	O
administration	O
of	O
one	O
drop	O
of	O
2	O
%	O
solution	O
of	O
inhibitor	O
in	O
rabbit	B
.	O

Preliminary	O
results	O
from	O
this	O
laboratory	O
indicate	O
that	O
the	O
metal	O
complexes	O
of	O
topically	O
active	O
sulfonamides	O
show	O
also	O
increased	O
lOP	O
lowering	O
effects	O
with	O
respect	O
to	O
the	O
complexes	O
prepared	O
in	O
the	O
present	O
study	O
[	O
42	O
]	O
.	O

Our	O
hypothesis	O
is	O
that	O
the	O
presence	O
of	O
the	O
metal	O
ion	O
in	O
the	O
molecules	O
of	O
these	O
complex	O
inhibitors	O
induces	O
a	O
dramatic	O
change	O
in	O
their	O
physico	O
-	O
chemical	O
properties	O
as	O
compared	O
to	O
those	O
of	O
the	O
parent	O
sulfonamide	O
.	O

This	O
phenomenon	O
is	O
certainly	O
governed	O
by	O
the	O
strong	O
polarization	O
induced	O
by	O
the	O
metal	O
ions	O
.	O

In	O
this	O
way	O
,	O
it	O
is	O
quite	O
probable	O
that	O
the	O
right	O
balance	O
between	O
the	O
lipo	O
-	O
and	O
hydrosolubility	O
of	O
these	O
compounds	O
is	O
achieved	O
,	O
which	O
has	O
been	O
considered	O
to	O
be	O
the	O
critical	O
factor	O
for	O
not	O
observing	O
topical	O
activity	O
in	O
the	O
classical	O
CA	O
inhibitors	O
,	O
such	O
as	O
acetazolamide	O
,	O
methazolamide	O
and	O
ethoxzolamide	O
,	O
which	O
were	O
either	O
too	O
lipophilic	O
or	O
too	O
hy	O
.	O
drosoluble	O
[	O
2	O
,	O
3	O
]	O
.	O

So	O
,	O
by	O
choosing	O
different	O
metal	O
ions	O
and	O
diverse	O
sulfonamides	O
,	O
much	O
larger	O
possibilities	O
arise	O
to	O
finely	O
tune	O
the	O
pharmacological	O
properties	O
which	O
strongly	O
influence	O
the	O
value	O
of	O
a	O
drug	O
.	O

In	O
conclusion	O
we	O
describe	O
here	O
a	O
novel	O
class	O
of	O
lOP	O
lowering	O
agents	O
,	O
ie	O
,	O
the	O
metal	O
complexes	O
of	O
sulfonamide	O
CA	O
inhibitors	O
.	O

These	O
derivatives	O
appear	O
to	O
be	O
very	O
active	O
and	O
longer	O
lasting	O
than	O
the	O
drug	O
dorzolamide	O
,	O
and	O
might	O
constitute	O
the	O
premises	O
for	O
a	O
new	O
generation	O
of	O
antiglaucoma	O
drugs	O
.	O

Acknowledgments	O
.	O

We	O
are	O
grateful	O
to	O
Prof	O
.	O

S	O
.	O

Lindskog	O
(	O
Umea	O
Univ	O
.	O
,	O
Sweden	O
)	O
for	O
the	O
gift	O
of	O
the	O
hCA	O
and	O
II	O
plasmids	O
.	O

References	O
Preceding	O
part	O
of	O
this	O
series	O
"	O
Supuran	O
CT	O
,	O
Scozzafava	O
A	O
,	O
Ilies	O
MA	O
,	O
Iorga	O
B	O
,	O
Cristea	O
T	O
,	O
Chiraleu	O
F	O
,	O
Banciu	O
MD	O
(	O
1997	O
)	O
Eur	O
J	O
Med	O
Chem	O
,	O
submitted	O
.	O

2	O
Supuran	O
CT	O
(	O
1994	O
)	O
"	O
Carbonic	O
anhydrase	O
inhibitors	O
"	O
In	O
Carbonic	O
Anhydrase	O
and	O
Modulation	O
of	O
Physiologic	O
and	O
Pathologic	O
Processes	O
in	O
the	O
Organism	O
,	O
(	O
Puscas	O
I	O
,	O
Ed	O
)	O
Helicon	O
,	O
Timisoara	O
,	O
pp	O
.	O

29	O
-	O
111	O
.	O

3	O
Maren	O
TH	O
(	O
1991	O
)	O
"	O
The	O
links	O
among	O
biochemistry	O
,	O
physiology	O
and	O
pharmacology	O
in	O
carbonic	O
anhydrase	O
mediated	O
systems	O
"	O
.	O

In	O
Carbonic	O
Anhydrase	O
From	O
Biochemistry	O
and	O
Genetics	O
to	O
Physiology	O
and	O
Clinical	O
Medicine	O
,	O
(	O
Botr6	O
F	O
,	O
Gros	O
G	O
,	O
Storey	O
BT	O
Eds	O
)	O
VCH	O
,	O
Weinheim	O
,	O
pp	O
.	O

186	O
-	O
207	O
.	O

4	O
Bayer	O
A	O
,	O
Ferrari	O
F	O
,	O
Maren	O
TH	O
,	O
Erb	O
C	O
(	O
1996	O
)	O
dFr	O
Ophtalrnol	O
19	O
,	O
3	O
:	O
57	O
-	O
362	O
.	O

:	O
5	O
Maren	O
TH	O
,	O
Conroy	O
CW	O
,	O
Wynns	O
GC	O
,	O
Levy	O
NS	O
(	O
1997	O
)	O
d	O
Ocul	O
Pharrnacol	O
Therapeut	O
13	O
,	O
23	O
-	O
30	O
.	O

6	O
Sugrue	O
MF	O
(	O
1996	O
)	O
d	O
Ocul	O
Pharmacol	O
Ther	O
12	O
,	O
363	O
-	O
376	O
.	O

7	O
Bartlett	O
JD	O
,	O
Jaanus	O
SD	O
(	O
1989	O
)	O
"	O
Carbonic	O
anhydrase	O
inhibitors	O
"	O
.	O

In	O
Clinical	O
Ocular	O
Pharmacology	O
,	O
Second	O
Edition	O
,	O
Butterworths	O
Publishers	O
,	O
Boston	O
,	O
pp	O
.	O

2	O
:	O
54	O
-	O
263	O
.	O

8	O
Alward	O
PD	O
,	O
Wilensky	O
JT	O
(	O
1981	O
)	O
Arch	O
Ophthalmo199	O
,	O
1973	O
-	O
1976	O
.	O

314	O

Claudiu	O
T	O
.	O
Supuran	O
et	O
al	O
.	O

Metal	O
-	O
Based	O
Drugs	O

9	O
Maren	O
TH	O
,	O
Jankowska	O
L	O
,	O
Sanyal	O
G	O
,	O
Edelhauser	O
HF	O
(	O
1983	O
)	O
Exp	O
Eye	O
Res	O
36	O
,	O
457	O
-	O
480	O
.	O

10	O
a	O
)	O
Ponticello	O
GS	O
,	O
Freedman	O
MB	O
,	O
Habecker	O
CN	O
,	O
Lyle	O
PA	O
,	O
Schwam	O
H	O
,	O
Varga	O
SL	O
,	O
Christy	O
ME	O
,	O
Randall	O
WC	O
,	O
Baldwin	O
JJ	O
(	O
1987	O
)	O
J	O
Med	O
Chem	O
30	O
,	O
591	O
-	O
597	O
;	O
b	O
)	O
Greer	O
J	O
,	O
Erickson	O
JW	O
,	O
Baldwin	O
JJ	O
,	O
Varney	O
MD	O
(	O
1994	O
)	O
J	O
Med	O
Chem	O
37	O
,	O
1035	O
-	O
1054	O
.	O

11	O
Baldwin	O
JJ	O
,	O
Ponticello	O
GS	O
,	O
Anderson	O
GS	O
,	O
Christy	O
ME	O
,	O
Murcko	O
MA	O
,	O
Randall	O
WC	O
,	O
Schwam	O
H	O
,	O
Sugrue	O
MF	O
,	O
Springer	O
JP	O
,	O
Gautheron	O
P	O
,	O
Grove	O
J	O
,	O
Mallorga	O
P	O
,	O
Viader	O
MP	O
,	O
McKeever	O
BM	O
,	O
Navia	O
MA	O
(	O
1989	O
)	O
J	O
Med	O
Chem	O
32	O
,	O
2510	O
-	O
2513	O
.	O

12	O
Chow	O
K	O
,	O
Lai	O
R	O
,	O
Holmes	O
JM	O
,	O
Wijono	O
M	O
,	O
Wheeler	O
LA	O
,	O
Garst	O
ME	O
(	O
1996	O
)	O
EurJMed	O
Chem	O
31	O
,	O
175	O
-	O
186	O
.	O

13	O
Supuran	O
CT	O
,	O
Nicolae	O
A	O
,	O
Popescu	O
A	O
(	O
1996	O
)	O
Eur	O
JMed	O
Chem	O
31	O
,	O
431	O
-	O
438	O
.	O

14	O
Supuran	O
CT	O
,	O
Popescu	O
A	O
,	O
Ilisiu	O
M	O
,	O
Costandache	O
A	O
,	O
Banciu	O
MD	O
(	O
1996	O
)	O
Eur	O
JMed	O
Chem	O
31	O
,	O
439	O
-	O
448	O
.	O

15	O
Supuran	O
CT	O
,	O
Scozzafava	O
A	O
,	O
Popescu	O
A	O
,	O
Bobes	O
-	O
Tureac	O
R	O
,	O
Banciu	O
A	O
,	O
Creanga	O
A	O
,	O
Bobes	O
-	O
Tureac	O
G	O
,	O
Banciu	O
MD	O
(	O
1997	O
)	O
Eur	O
JMed	O
Chem	O
32	O
,	O
445	O
-	O
452	O
.	O

16	O
Alzuet	O
G	O
,	O
Casanova	O
J	O
,	O
Ramirez	O
JA	O
,	O
Borras	O
J	O
,	O
Carugo	O
O	O
(	O
1995	O
)	O
J	O
Inorg	O
Bioehem	O
57	O
,	O
219	O
-	O
234	O
.	O

17	O
Sumalan	O
SL	O
,	O
Casanova	O
J	O
,	O
Alzuet	O
G	O
,	O
Borras	O
J	O
,	O
Castifieiras	O
A	O
,	O
Supuran	O
CT	O
(	O
1996	O
)	O
J	O
Inorg	O
Biochem	O
62	O
,	O
3139	O
.	O

18	O
a	O
)	O
Supuran	O
CT	O
(	O
1995	O
)	O
Metal	O
Based	O
Drugs	O
2	O
,	O
327	O
-	O
330	O
;	O
b	O
)	O
Scozzafava	O
A	O
,	O
Supuran	O
CT	O
(	O
1997	O
)	O
Metal	O
Based	O
Drugs	O
4	O
,	O
19	O
-	O
26	O
.	O

19	O
a	O
)	O
Borras	O
J	O
,	O
Cristea	O
T	O
,	O
Supuran	O
CT	O
(	O
1996	O
)	O
,	O
Main	O
Group	O
Met	O
Chem	O
19	O
,	O
339	O
-	O
346	O
;	O
b	O
)	O
Jitianu	O
A	O
,	O
Ilies	O
MA	O
,	O
Briganti	O
F	O
,	O
Scozzafava	O
A	O
,	O
Supuran	O
CT	O
(	O
1997	O
)	O
Metal	O
Based	O
Drugs	O
4	O
,	O
1	O
-	O
7	O
.	O

20	O
a	O
)	O
Supuran	O
CT	O
,	O
Scozzafava	O
A	O
(	O
1997	O
)	O
J	O
Enzyme	O
Inhibition	O
12	O
,	O
37	O
-	O
51	O
;	O
b	O
)	O
Supuran	O
CT	O
,	O
Briganti	O
F	O
,	O
Scozzafava	O
A	O
(	O
1997	O
)	O
J	O
Enzyme	O
Inhibition	O
12	O
,	O
175	O
-	O
190	O
.	O

21	O
Mincione	O
G	O
,	O
Scozzafava	O
A	O
,	O
Supuran	O
CT	O
(	O
1997	O
)	O
Metal	O
Based	O
Drugs	O
4	O
,	O
27	O
-	O
34	O
.	O

22	O
Alzuet	O
G	O
,	O
Ferrer	O
S	O
,	O
Borras	O
J	O
,	O
Supuran	O
CT	O
(	O
1994	O
)	O
Roum	O
Chem	O
Quart	O
Rev	O
2	O
,	O
283	O
-	O
300	O
.	O

23	O
Briganti	O
F	O
,	O
Mangani	O
S	O
,	O
Orioli	O
P	O
,	O
Scozzafava	O
A	O
,	O
Vernaglione	O
G	O
,	O
Supuran	O
CT	O
(	O
1997	O
)	O
Biochemistry	O
36	O
,	O
10384	O
-	O
10392	O
.	O

24	O
Borras	O
J	O
,	O
Casanova	O
J	O
,	O
Cristea	O
T	O
,	O
Gheorghe	O
A	O
,	O
Scozzafava	O
A	O
,	O
Supuran	O
CT	O
,	O
Tudor	O
V	O
(	O
1996	O
)	O
Metal	O
Based	O
Drugs	O
3	O
,	O
143	O
-	O
148	O
.	O

25	O
Supuran	O
CT	O
,	O
Mincione	O
F	O
,	O
Scozzafava	O
A	O
,	O
Briganti	O
F	O
,	O
Mincione	O
G	O
,	O
Ilies	O
MA	O
(	O
1997	O
)	O
Eur	O
J	O
Med	O
Chem	O
,	O
in	O

press	O
.	O

26	O
Supuran	O
CT	O
,	O
Scozzafava	O
A	O
,	O
Saramet	O
I	O
,	O
Banciu	O
MD	O
(	O
1997	O
)	O
J	O
Enzyme	O
Inhibition	O
,	O
in	O
press	O
.	O

27	O
Jitianu	O
A	O
,	O
Ilies	O
MA	O
,	O
Scozzafava	O
A	O
,	O
Supuran	O
CT	O
(	O
1997	O
)	O
Main	O
Group	O
Met	O
Chem	O
20	O
,	O
151	O
-	O
156	O
.	O

28	O
Forsman	O
C	O
,	O
Behravan	O
G	O
,	O
Osterman	O
A	O
,	O
Jonsson	O
BH	O
(	O
1988	O
)	O
Acta	O
Chem	O
Scand	O
B42	O
,	O
314	O
-	O
318	O
.	O

29	O
Behravan	O
G	O
,	O
Jonasson	O
P	O
,	O
Jonsson	O
BH	O
,	O
Lindskog	O
S	O
(	O
1991	O
)	O
Eur	O
JBiochem	O
198	O
,	O
589	O
-	O
592	O
.	O

30	O
Khalifah	O
RG	O
,	O
Strader	O
DJ	O
,	O
Bryant	O
SH	O
,	O
Gibson	O
SM	O
(	O
1977	O
)	O
Biochemistry	O
16	O
,	O
2241	O
-	O
2247	O
.	O

31	O
Nyman	O
PO	O
,	O
Lindskog	O
S	O
(	O
1964	O
)	O
Biochim	O
Biophys	O
Acta	O
85	O
,	O
141	O
-	O
151	O
.	O

32	O
Henderson	O
LE	O
,	O
Henriksson	O
D	O
,	O
Nyman	O
PO	O
(	O
1976	O
)	O
JBiol	O
Chem	O
251	O
,	O
5457	O
-	O
5463	O
.	O

33	O
Maren	O
TH	O
,	O
Wynns	O
GC	O
,	O
Wistrand	O
PJ	O
(	O
1993	O
)	O
Mol	O
Pharmaco144	O
,	O
901	O
-	O
906	O
.	O

34	O
Young	O
RW	O
,	O
Wood	O
KH	O
,	O
Vaughan	O
JR	O
,	O
Anderson	O
GW	O
(	O
1956	O
)	O
J	O
Am	O
Chem	O
Soc	O
78	O
,	O
4649	O
-	O
4654	O
.	O

35	O
Pocker	O
Y	O
,	O
Stone	O
JT	O
(	O
1967	O
)	O
Biochemistry	O
6	O
,	O
668	O
-	O
678	O
.	O

36	O
Baird	O
TT	O
,	O
Waheed	O
A	O
,	O
Okuyama	O
T	O
,	O
Sly	O
WS	O
,	O
Fierke	O
CA	O
(	O
1997	O
)	O
Biochemistry	O
36	O
,	O
2669	O
-	O
2678	O
.	O

37	O
Maren	O
TH	O
,	O
Bar	O
-	O
Ilan	O
A	O
,	O
Conroy	O
CW	O
,	O
Brechue	O
WF	O
(	O
1990	O
)	O
Exp	O
Eye	O
Res	O
50	O
,	O
27	O
-	O
36	O
.	O

38	O
Maren	O
TH	O
,	O
Brechue	O
WF	O
,	O
Bar	O
-	O
Ilan	O
A	O
(	O
1992	O
)	O
Exp	O
Eye	O
Res	O
55	O
,	O
73	O
-	O
79	O
.	O

39	O
Brechue	O
WF	O
,	O
Maren	O
TH	O
(	O
1993	O
)	O
Invest	O
Ophthalmol	O
Vis	O
Sci	O
34	O
,	O
2581	O
-	O
2587	O
.	O

40	O
Borja	O
P	O
,	O
Alzuet	O
G	O
,	O
Server	O
-	O
Carri6	O
J	O
,	O
Borras	O
J	O
,	O
Supuran	O
CT	O
(	O
1997	O
)	O
J	O
Biol	O
Inorg	O
Chem	O
(	O
JBIC	O
)	O
,	O
in	O
press	O
.	O

41	O
Supuran	O
CT	O
,	O
Balaban	O
AT	O
,	O
Gheorghiu	O
MD	O
,	O
Schiketanz	O
A	O
,	O
Dinculescu	O
A	O
,	O
Puscas	O
I	O
(	O
1990	O
)	O
Rev	O
Roum	O
Chim	O
35	O
,	O
399	O
-	O
405	O
.	O

42	O
Supuran	O
CT	O
,	O
Scozzafava	O
A	O
(	O
1997	O
)	O
unpublished	O
results	O
.	O

Received	O
:	O
September	O
24	O
,	O
1997	O
Accepted	O
:	O
October	O
17	O
,	O
1997	O
Received	O
in	O
revised	O
camera	O
-	O
ready	O
format	O
"	O
October	O
23	O
,	O
1997	O

315	O

Synthesis	O
,	O
Characterization	O
and	O
Antitumour	O
Activity	O
of	O
Some	O
Butyltin	O
(	O
IV	O
)	O
Cysteaminates	O
and	O
N	O
,	O
N	O
-	O
Dimethylcysteaminate	O

Abstract	O

The	O
synthesis	O
and	O
characterization	O
of	O
four	O
di	O
-	O
and	O
tri	O
-	O
n	O
-	O
butyltin	O
cysteaminates	O
and	O
N	O
,	O
N	O
-	O
dimethylcysteaminate	O
and	O
three	O
protonated	O
/	O
quaternized	O
derivatives	O
are	O
reported	O
.	O

They	O
all	O
exhibit	O
moderate	O
or	O
high	O
in	O
vitro	O
cytotoxic	O
activity	O
.	O

Six	O
of	O
seven	O
compounds	O
presented	O
in	O
this	O
work	O
are	O
more	O
active	O
than	O
cisplatin	O
,	O
etoposide	O
and	O
5	O
-	O
fluorouracil	O
,	O
but	O
less	O
active	O
than	O
methotrexate	O
and	O
doxorubicin	O
.	O

Metal	O
Based	O
Drugs	O

Vol	O
.	O

7	O
,	O
Nr	O
.	O

5	O
,	O
2000	O

SYNTHESIS	O
,	O
CHARACTERIZATION	O
AND	O
ANTITUMOUR	O
ACTITY	O
OF	O
SOME	O
BUTYLTIN	O
(	O
IV	O
)	O
CYSTEAMINATES	O
AND	O
N	O
,	O
N	O
-	O
DIMETHYLCYSTEAMINATE	O
Marcel	O
Gielen	O
Karel	O
Handlir	O
.	O
2	O
,	O
Martin	O
Hollein	O
and	O
Dick	O
de	O
Vos	O
2	O
3	O

Departement	O
of	O
General	O
and	O
Organic	O
Chemistry	O
AOSC	O
,	O
Faculty	O
of	O
Applied	O
Sciences	O
,	O
Free	O
University	O
of	O
Brussels	O
VUV	O
,	O
Pleinlaan	O
2	O
,	O
B	O
-	O
1050	O
Brussels	O
,	O
Belgium	O
Departement	O
of	O
General	O
and	O
Inorganic	O
Chemistry	O
,	O
Faculty	O
of	O
Chemical	O
Technology	O
,	O
University	O
of	O
Pafdubice	O
,	O
Nam	O
.	O

Cs	O
.	O
legii	O
565	O
,	O
53210	O
Pardubice	O
,	O
Czech	O
Republic	O
Pharmachemie	O
B	O
.	O

V	O
.	O
,	O
Haarlem	O
,	O
the	O
Netherlands	O
Abstract	O
.	O

The	O
synthesis	O
and	O
characterization	O
of	O
four	O
di	O
-	O
and	O
tri	O
-	O
n	O
-	O
butyltin	O
cysteaminates	O
and	O
_	O
N	O
,	O
N	O
-	O
dimethylcysteaminate	O
and	O
three	O
protonated	O
/	O
quaternized	O
derivatives	O
are	O
reported	O
.	O

They	O
all	O
exhibit	O
moderate	O
or	O
high	O
in	O
vitro	O
cytotoxic	O
activity	O
.	O

Six	O
of	O
seven	O
compounds	O
presented	O
in	O
this	O
work	O
are	O
more	O
active	O
than	O
cisplatin	O
,	O
etoposide	O
and	O
5	O
-	O
fluorouracil	O
,	O
but	O
less	O
active	O
than	O
methotrexate	O
and	O
doxorubiein	O
.	O

Introduction	O
.	O

Several	O
organotin	O
cysteaminates	O
(	O
aminoethylthiolates	O
)	O
have	O
been	O
studied	O
1	O
-	O
4	O
as	O
compounds	O
with	O
potentially	O
high	O
biological	O
activity	O
,	O
but	O
little	O
is	O
known	O
about	O
their	O
cytotoxic	O
effect	O
.	O

The	O
present	O
paper	O
reports	O
the	O
synthesis	O
and	O
characterization	O
of	O
di	O
-	O
and	O
tri	O
-	O
n	O
-	O
butyltin	O
cysteaminates	O
and	O
their	O
N	O
,	O
N	O
-	O
dimethyl	O
analogues	O
and	O
their	O
in	O
vitro	O
cytotoxicity	O
.	O

It	O
is	O
shown	O
that	O
a	O
correct	O
evaluation	O
of	O
the	O
biological	O
activity	O
of	O
organotin	O
compounds	O
remains	O
5	O
often	O
hampered	O
by	O
their	O
low	O
water	O
solubility	O
.	O

Therefore	O
,	O
we	O
focused	O
on	O
the	O
synthesis	O
of	O
derivatives	O
with	O
potentially	O
higher	O
water	O
solubility	O
by	O
introducing	O
ionic	O
groups	O
into	O
the	O
molecule	O
by	O
protonation	O
or	O
quatemization	O
of	O
a	O
nitrogen	O
atom	O
.	O

Results	O
and	O
discussion	O
.	O

3	O

2	O

4	O

(	O
n	O
-	O
Bu	O
)	O
n	O
Sn	O
[	O
SCH2	O
-	O
CH2	O
-	O
NHm	O
(	O
CH3	O
)	O
2	O
-	O
m	O
]	O
4	O
-	O
n	O

n	O
=	O
3	O
,	O
n	O
=	O
3	O
,	O
n	O
=	O
2	O
,	O
n	O
=	O
2	O
,	O

m	O
=	O
2	O
m	O
=	O
O	O
m	O
=	O
2	O
m	O
=	O
O	O

(	O
1	O
)	O
(	O
2	O
)	O
(	O
3	O
)	O
(	O
4	O
)	O

3	O

2	O

4	O

(	O
n	O
-	O
Bu	O
)	O
3	O
Sn	O
S	O
-	O
CH2	O
-	O
CH2	O
-	O
NHm	O
(	O
CH3	O
)	O
3	O
.	O
m	O
X	O

m	O
=	O
3	O
,	O
x	O
=	O
cn3so3	O
(	O
5	O
)	O
m	O
1	O
,	O
X	O
=	O
CH3SO3	O
(	O
6	O
)	O
m	O
0	O
,	O
X	O
I	O
(	O
7	O
)	O

n	O
-	O
Bu	O
CH3	O
-	O
CH2	O
-	O
CH2	O
-	O
CH2	O

(	O
2	O
)	O
,	O
di	O
-	O
nTri	O
-	O
n	O
-	O
butyltin	O
cysteaminate	O
(	O
1	O
)	O
,	O
tri	O
-	O
n	O
-	O
butyltin	O
N	O
,	O
N	O
-	O
dimethylcysteaminate	O
butyltin	O
bis	O
(	O
cysteaminate	O
)	O
(	O
3	O
)	O
and	O
di	O
-	O
n	O
-	O
butyltin	O
bis	O
(	O
N	O
,	O
N	O
-	O
dimethylcysteaminate	O
)	O
(	O
4	O
)	O
were	O
prepared	O
by	O
the	O
reaction	O
of	O
the	O
sodium	O
cysteaminate	O
(	O
prepared	O
in	O
situ	O
by	O
the	O
reaction	O
of	O
sodium	O
methylate	O
with	O
the	O
hydrochloride	O
of	O
eysteamine	O
)	O
with	O
the	O
suitable	O
di	O
-	O
or	O
tri	O
-	O
n	O
-	O
butyltin	O
chloride	O
in	O
chloroform	O
following	O
reference	O
by	O
the	O
reactions	O
of	O
the	O
The	O
methanesulphonates	O
5	O
and	O
6	O
were	O
respectively	O
synthesized	O
equimolar	O
amount	O
of	O
methane	O
sulphonic	O
acid	O
in	O
unprotonated	O
analogs	O
1	O
and	O
2	O
with	O
an	O
chloroform	O
.	O

After	O
purification	O
on	O
a	O
short	O
column	O
of	O
alumina	O
and	O
evaporation	O
of	O
the	O
solvent	O
,	O
colourless	O
viscous	O
oils	O
were	O
obtained	O
.	O

The	O
quaternized	O
methyl	O
derivative	O
of	O
2	O
,	O
the	O
methiodide	O
(	O
7	O
)	O
,	O
was	O
prepared	O
by	O
its	O
reaction	O
with	O
methyl	O
iodide	O
in	O
benzene	O
and	O
purified	O
by	O
recrystalization	O
from	O
chloroform	O
.	O

233	O

M	O
.	O

Gielen	O
,	O
K	O
.	O

Handlir	O
,	O
M	O
.	O

Hollein	O
and	O
D	O
.	O

de	O
Vos	O
Synthesis	O
,	O
Characterization	O
and	O
Antitumor	O
Activity	O
ofSome	O
Butyltin	O
(	O
IV	O
)	O
Cysteaminates	O
and	O
N	O
,	O
N	O
-	O
Dimethylcysteaminate	O

86	O
77	O
85	O
3	O
(	O
C4H9	O
)	O
2Sn	O
(	O
SCH2CH2NH2	O
)	O
2	O
90	O
4	O
(	O
C4Hg	O
)	O
zSn	O
(	O
SCH2CHzN	O
(	O
CH3	O
)	O
2	O
)	O
2	O
92	O
oil	O
5	O
(	O
C4H9	O
)	O
3	O
SnSCH2CH2NH3	O
CH3SO3	O
94	O
6	O
oil	O
(	O
C4H9	O
)	O
3	O
SnSCH2CH2NH	O
(	O
CH3	O
)	O
2	O
CH3SO3	O
118	O
-	O
120	O
74	O
7	O
(	O
C4H9	O
)	O
.	O
SnSCH	O
.	O
CH	O
.	O
N	O
(	O
CH3	O
)	O
31	O
The	O
elemental	O
analyses	O
(	O
C	O
,	O
H	O
,	O
N	O
,	O
Sn	O
)	O
agree	O
satisfactorily	O
with	O
the	O
proposed	O
formul	O

Table	O
1	O
.	O

Melting	O
points	O
and	O
yields	O
for	O
.	O
.	O
c0mP0unds	O
1	O
(	O
)	O
rmula	O
,	O
2	O
comp	O
.	O

1	O
(	O
C4H9	O
)	O
3SnSCHzCH2NH2	O
2	O
(	O
C4H9	O
)	O
3SnSCHzCH2N	O
(	O
CH3	O
)	O
2	O

7	O
.	O

m	O
.	O
p	O
.	O
,	O
.	O
.	O
b	O
.	O
p	O
.	O
.	O
,	O
.	O
C	O
120	O
-	O
123	O
/	O
40	O
Pa	O
129	O
-	O
131	O
/	O
35	O
Pa	O
167	O
-	O
169	O
/	O
35	O
Pa	O
172	O
-	O
174	O
/	O
40	O
Pa	O

'	O
o	O
'	O

yield	O
,	O
.	O
%	O

Compounds	O
1	O
-	O
4	O
,	O
and	O
7	O
,	O
are	O
poorly	O
soluble	O
in	O
aqueous	O
solutions	O
(	O
<	O
mg	O
/	O
mL	O
)	O
.	O

Compounds	O
5	O
and	O
6	O
exhibit	O
higher	O
water	O
solubilities	O
(	O
ca	O
.	O
2	O
mg	O
/	O
mL	O
)	O
.	O

Compounds	O
1	O
7	O
are	O
soluble	O
in	O
a	O
therapeutic	O
solution	O
(	O
0	O
,	O
103	O
M	O
solution	O
of	O
NaCl	O
in	O
water	O
/	O
DMSO	O
1	O
/	O
9	O
)	O
.	O

A	O
white	O
turbidity	O
appears	O
in	O
these	O
solutions	O
only	O
after	O
several	O
hours	O
due	O
to	O
slow	O
hydrolysis	O
.	O

Compounds	O
1	O
7	O
were	O
characterized	O
by	O
multinuclear	O
NMR	O
spectroscopy	O
.	O

The	O
NMR	O
parameters	O
are	O
given	O
in	O
Table	O
2	O
.	O

Table	O
2	O
.	O

Resonances	O
of	O
13C	O
,	O
(	O
ca	O
20	O
%	O
sol	O
.	O
v	O
/	O
v	O
)	O
1	O
'	O
compound	O

SN	O
and	O
ll9Sn	O
NMR	O
spectra	O
of	O
2	O

the	O
compounds	O
1	O
-	O
7	O
in	O
CDCI3	O
5	O
86	O
.	O
3	O
13	O
.	O
45	O

6	O
'	O
'	O
S	O
'	O
n	O
)	O
,	O
"	O
ppm	O
6	O
(	O
3c	O
)	O
a	O
,	O
ppm	O

x	O

77	O
.	O
6	O
12	O
.	O
3	O

77	O
.	O
5	O
12	O
.	O
75	O

3	O
-	O
28	O
.	O
9	O
22	O
.	O
38	O

38	O
.	O
'	O
18	O
.	O
78	O

4	O

6	O
'	O
'	O
89	O
.	O
5	O
13	O
.	O
45	O

7	O
93	O
.	O
2	O
13	O
.	O
60	O

(	O
332	O
)	O
27	O
.	O
93	O

(	O
331	O
)	O
27	O
.	O
97	O

(	O
495	O
)	O
28	O
.	O
27	O

(	O
438	O
)	O
27	O
.	O
51	O

(	O
322	O
)	O
28	O
.	O
30	O

(	O
350	O
)	O
28	O
.	O
34	O

(	O
339	O
)	O
28	O
.	O
47	O

(	O
21	O
.	O
3	O
)	O
26	O
.	O
32	O

(	O
21	O
.	O
1	O
)	O
26	O
.	O
38	O

(	O
28	O
.	O
4	O
)	O
26	O
.	O
42	O

(	O
26	O
.	O
4	O
)	O
25	O
.	O
90	O

(	O
21	O
.	O
4	O
)	O
26	O
.	O
85	O

(	O
21	O
.	O
3	O
)	O
26	O
.	O
81	O

(	O
22	O
.	O
0	O
)	O
26	O
.	O
91	O

(	O
59	O
.	O
6	O
)	O
12	O
.	O
89	O

(	O
59	O
.	O
8	O
)	O
12	O
.	O
95	O

(	O
87	O
.	O
1	O
)	O
13	O
.	O
35	O

(	O
83	O
.	O
8	O
)	O
12	O
.	O
82	O

(	O
62	O
.	O
7	O
)	O
13	O
.	O
45	O

(	O
61	O
.	O
4	O
)	O
13	O
.	O
58	O

62	O
.	O
2	O
)	O
14	O
.	O
00	O

(	O
-	O
)	O
30	O
.	O
31	O
45	O
.	O
02	O

(	O
-	O
)	O
23	O
.	O
59	O
63	O
.	O
12	O
44	O
.	O
71	O

(	O
-	O
)	O
30	O
.	O
04	O
44	O
.	O
44	O

(	O
-	O
)	O
23	O
.	O
84	O
61	O
.	O
84	O
44	O
.	O
46	O

(	O
-	O
)	O
23	O
.	O
92	O
43	O
.	O
08	O

(	O
-	O
;	O

(	O
-	O
)	O

20	O
.	O
94	O
19	O
.	O
70	O
60	O
.	O
94	O
69	O
.	O
49	O
43	O
.	O
42	O
54	O
.	O
18	O
39	O
.	O
15	O
39	O
.	O
16	O
-	O
360	O
.	O
4	O
-	O
354	O
.	O
0	O
-	O
355	O
.	O
3	O
-	O
354	O
.	O
4	O
-	O
349	O
.	O
4	O
-	O
344	O
.	O
2	O
-	O
325	O
.	O
8	O
1	O
.	O
1	O
6	O
.	O
2	O
1	O
.	O
5	O
1	O
.	O
5	O
12	O
.	O
7	O
11	O
.	O
7	O
30	O
.	O
1	O
13	O
a	O
'	O
values	O
of	O
nJ	O
(	O
n	O
J	O
9	O
Sn	O
,	O
,	O
C	O
)	O
c0uplihg	O
constants	O
in	O
Hz	O
'	O
for	O
Carbon	O
ato	O
]	O
ns	O
in	O
parentlee	O
'	O
s	O
difference	O
btween	O
(	O
N	O
)	O
for	O
the	O
organo	O
.	O
i	O
compound	O
and	O
free	O
cysteamine	O
,	O
6	O
(	O
N	O
)	O
361	O
.	O
5	O
ppm	O
;	O
N	O
,	O
N	O
-	O
dimethylcysteamine	O
,	O
5	O
(	O
N	O
)	O
-	O
355	O
.	O
9	O
ppm	O
)	O
not	O
observed	O

C	O
resonances	O
were	O
assigned	O
on	O
the	O
basis	O
of	O
the	O
values	O
of	O
n	O
J	O
(	O
119	O
Sn	O
,	O
13	O
C	O
)	O
coupling	O
constants	O
and	O
standard	O
13	O
C	O
-	O
APT	O
techniques	O
utilization	O
in	O
agreement	O
with	O
ref	O
.	O
.	O

The	O
values	O
of	O
119	O
Sn	O
chemical	O
shifts	O
are	O
found	O
in	O
the	O
interval	O
characteristic	O
for	O
fourcoordinated	O
tin	O
6	O
,	O
7	O
.	O

The	O
values	O
of	O
the	O
coupling	O
constants	O
j	O
(	O
1	O
lqSn	O
,	O
13C	O
)	O
agree	O
with	O
the	O
structure	O
proposed	O
.	O

Compound	O
3	O
is	O
characterized	O
by	O
a	O
somewhat	O
larger	O
upfield	O
shift	O
,	O
close	O
to	O
the	O
upper	O
limit	O
of	O
the	O
above	O
mentioned	O
interval	O
,	O
together	O
with	O
a	O
high	O
value	O
of	O
1j	O
(	O
l	O
lqSn	O
,	O
13C	O
)	O
(	O
495	O
Hz	O
)	O
.	O

67	O
The	O
C	O
-	O
Sn	O
-	O
C	O
angle	O
,	O
est	O
'	O
mated	O
,	O
from	O
this	O
value	O
of	O
coupling	O
constant	O
is	O
124	O
According	O
to	O
ref	O
.	O
this	O
behaviour	O
can	O
be	O
due	O
to	O
intermolecular	O
association	O
increasing	O
the	O
coordinatitn	O
number	O
of	O
tin	O
in	O
concentrated	O
solutions	O
,	O
as	O
suggested	O
by	O
the	O
concentration	O
dependence	O
of	O
tS	O
(	O
Sn	O
)	O
and	O
cryoscopic	O
measurements	O
in	O
benzene	O
.	O

The	O
values	O
of	O
the	O
6	O
(	O
SN	O
)	O
chemical	O
shifts	O
of	O
compounds	O
1	O
,	O
2	O
and	O
4	O
only	O
slightly	O
differ	O
from	O
the	O
(	O
15N	O
)	O
values	O
of	O
the	O
free	O
cysteamine	O
.	O

The	O
significantly	O
larger	O
i	O
(	O
15N	O
)	O
chemical	O
shift	O
of	O
compound	O
3	O
is	O
however	O
much	O
lower	O
than	O
those	O
of	O
compounds	O
5	O
,	O
6	O
and	O
7	O
containing	O
a	O
N	O
interaction	O
in	O
compounds	O
1	O
tetracoordinated	O
nitrogen	O
atom	O
.	O

It	O
can	O
be	O
stated	O
that	O
the	O
Sn	O
4	O
is	O
negligible	O
or	O
only	O
very	O
weak	O
in	O
chlorofom	O
solutions	O
.	O

This	O
conclusion	O
is	O
not	O
in	O
contradiction	O
with	O
the	O
proved	O
Sn	O
N	O
interaction	O
found	O
in	O
the	O
solid	O
state	O
8	O
.	O

13	O

.	O

,	O

234	O

Metal	O
Based	O
Drugs	O

Vol	O
.	O

7	O
,	O
Nr	O
.	O

5	O
,	O
2000	O

Antitumour	O
activity	O
.	O

The	O
results	O
of	O
the	O
in	O
vitro	O
antitumour	O
tests	O
of	O
compounds	O
1	O
7	O
are	O
given	O
in	O
Table	O
3	O
as	O
the	O
inhibition	O
doses	O
IDs0	O
observed	O
against	O
a	O
panel	O
of	O
seven	O
human	O
tumour	O
cell	O
lines	O
,	O
MCF	O
-	O
7	O
and	O
EVSA	O
-	O
T	O
,	O
two	O
breast	O
cancers	O
,	O
WiDr	O
,	O
a	O
colon	O
cancer	O
,	O
IGROV	O
,	O
an	O
ovarian	O
cancer	O
,	O
M19	O
MEL	O
,	O
a	O
melanoma	O
,	O
A248	O
,	O
a	O
renal	O
cancer	O
,	O
and	O
H226	O
,	O
a	O
non	O
-	O
small	O
cell	O
lung	O
cancer	O
.	O

The	O
antitumour	O
tests	O
results	O
are	O
compared	O
with	O
those	O
obtained	O
for	O
clinically	O
used	O
reference	O
compounds9	O
like	O
cisplatin	O
,	O
doxorubicin	O
,	O
etoposide	O
,	O
5	O
-	O
fluorouracil	O
and	O
methotrexate	O
.	O

Table	O
3	O
.	O

Inhibition	O
doses	O

comp	O
.	O

1	O
2	O
3	O
4	O
5	O
6	O
7	O

MF	O
-	O
7	O
41	O
41	O
51	O
78	O
30	O
90	O
385	O
699	O
10	O
2	O
594	O
750	O
18	O

EVSA	O
-	O
T	O
33	O
35	O
45	O
65	O
<	O
3	O
57	O
367	O

IDs0	O
of	O
compounds	O
WiDr	O
39	O
39	O
211	O
331	O
19	O
40	O
339	O

1	O
-	O
7	O
and	O
of	O
five	O
reference	O
compounds	O
.	O

IGROV	O
M19MEL	O
A498	O
H226	O
67	O
44	O
85	O
39	O
46	O
78	O
88	O
39	O
68	O
70	O
118	O
72	O
110	O
129	O
108	O
112	O
31	O
29	O
36	O
42	O
83	O
133	O
77	O
111	O
327	O
758	O
576	O
411	O
169	O
60	O
580	O
297	O
7	O
558	O
16	O
505	O
442	O
23	O

cisplatin	O
doxorubicin	O

etoposide	O
5	O
-	O
fluorouracil	O

422	O
8	O
317	O
475	O
5	O

methotrexate	O

967	O
11	O
150	O
225	O
<	O
3	O

2	O
253	O
90	O
314	O
143	O
37	O

3	O
369	O
199	O
3	O
934	O
340	O
2	O
287	O

It	O
is	O
evident	O
from	O
Table	O
3	O
that	O
all	O
studied	O
compounds	O
exhibit	O
excellent	O
cytostatic	O
activities	O
,	O
except	O
compound	O
7	O
showing	O
only	O
moderate	O
activity	O
.	O

Compounds	O
1	O
6	O
are	O
more	O
active	O
than	O
cisplatin	O
and	O
,	O
in	O
most	O
cases	O
,	O
than	O
etoposide	O
and	O
5	O
-	O
fluorouracil	O
.	O

Their	O
activity	O
is	O
lower	O
than	O
that	O
of	O
doxorubicin	O
and	O
methotrexate	O
in	O
most	O
cases	O
for	O
the	O
studied	O
cancer	O
cell	O
lines	O
.	O

The	O
very	O
limited	O
set	O
of	O
acquired	O
activity	O
values	O
show	O
that	O
the	O
activity	O
of	O
tri	O
-	O
n	O
-	O
butyltin	O
are	O
higher	O
than	O
those	O
of	O
di	O
-	O
n	O
-	O
butyl	O
analogues	O
(	O
1	O
>	O
3	O
,	O
2	O
>	O
4	O
)	O
for	O
all	O
cell	O
lines	O
,	O
especially	O
compounds	O
against	O
WiDr	O
.	O

The	O
N	O
,	O
N	O
-	O
dimethyl	O
derivatives	O
exhibit	O
an	O
activity	O
comparable	O
to	O
or	O
somewhat	O
higher	O
than	O
that	O
of	O
unmethylated	O
compounds	O
.	O

Compound	O
8	O
,	O
with	O
a	O
quaternized	O
nitrogen	O
,	O
exhibits	O
the	O
lowest	O
cytotoxic	O
activities	O
,	O
approximatively	O
9	O
times	O
lower	O
than	O
compound	O
2	O
.	O

It	O
might	O
be	O
underlined	O
that	O
the	O
ionic	O
more	O
water	O
-	O
soluble	O
compounds	O
5	O
and	O
6	O
are	O
not	O
more	O
active	O
than	O
the	O
uncharged	O
analogs	O
1	O
-	O
4	O
,	O
whereas	O
the	O
hydrophilic	O
organotin	O
polyoxacarboxylates	O
exhibit	O
much	O
higher	O
in	O
vitro	O
activities	O
than	O
other	O
organotin	O
carxylates	O
51	O
Compounds	O
5	O
and	O
6	O
(	O
with	O
a	O
protonated	O
nitrogen	O
)	O
exhibit	O
activities	O
comparable	O
or	O
even	O
considerably	O
higher	O
(	O
compound	O
5	O
)	O
against	O
EVSA	O
-	O
T	O
than	O
the	O
corresponding	O
unprotonated	O
compounds	O
.	O

Compound	O
7	O
(	O
with	O
a	O
quaternized	O
nitrogen	O
)	O
exhibits	O
the	O
lowest	O
cytostatic	O
activities	O
,	O
approximately	O
9	O
times	O
should	O
however	O
be	O
mentioned	O
that	O
another	O
ionic	O
organotin	O
lower	O
than	O
compound	O
2	O
.	O

It	O
compound	O
,	O
bis	O
(	O
dicyclohexyl	O
)	O
ammonium	O
bis	O
(	O
2	O
,	O
6	O
-	O
pyridinecarboxyla	O
,	O
to	O
)	O
di	O
-	O
n	O
-	O
butylstannate	O
,	O
where	O
the	O
organotin	O
moiety	O
is	O
this	O
time	O
anionic	O
,	O
is	O
also	O
as	O
active	O
as	O
the	O
uncharged	O
analog	O
l	O
.	O

All	O
NMR	O
spectra	O
were	O
recorded	O
on	O
a	O
Bruker	O
AMX	O
360	O
instrument	O
using	O
a	O
5	O
mm	O
multinuclear	O
tuneable	O
probe	O
.	O

The	O
residual	O
CHCI3	O
resonance	O
at	O
7	O
.	O
24	O
ppm	O
was	O
used	O
as	O
reference	O
for	O
the	O
H	O
soectra	O
and	O
the	O
central	O
13CDCI3	O
resonance	O
at	O
77	O
.	O
0	O
ppm	O
,	O
for	O
the	O
13C	O
spectra	O
.	O

The	O
119	O
Sn	O
chemical	O
shifts	O
were	O
refered	O
to	O
the	O
external	O
tetramethyltin	O
[	O
6	O
(	O
119	O
Sn	O
)	O
0	O
.	O
0	O
]	O
.	O

The	O
15N	O
NMR	O
spectra	O
were	O
measur	O
;	O
l	O
using	O
the	O
INEPT	O
technique	O
or	O
in	O
inverse	O
-	O
gated	O
mode	O
.	O

(	O
reference	O
:	O
Instrumentation	O
.	O

external	O
nitromethane	O
,	O
[	O
5	O
(	O
'	O
N	O
)	O
0	O
.	O
0	O
]	O
)	O
.	O

The	O
protocol	O
followed	O
for	O
the	O
in	O
vitro	O
antitumour	O
screenings	O
has	O
been	O
already	O
reported	O
10	O
.	O

Acknowledgements	O
.	O

K	O
.	O

H	O
.	O
and	O
M	O
H	O
.	O
thank	O
the	O
Grant	O
Agency	O
of	O
the	O
Czech	O
Republic	O
(	O
Grant	O
No	O
.	O
203	O
/	O
00	O
/	O
0920	O
)	O
and	O
the	O
Ministry	O
o	O
"	O
Education	O
,	O
Youth	O
and	O
Sport	O
of	O
the	O
Czech	O
republic	O
,	O
associated	O
with	O
EU	O
in	O
the	O
COST	O
8	O
.	O
20	O
program	O
for	O
financial	O
support	O
of	O
this	O
work	O
.	O

We	O
are	O
grateful	O
to	O
Mr	O
.	O
R	O
.	O

G	O
.	O

Experimental	O
Oostrum	O
,	O
Dr	O
.	O
J	O
.	O
verweij	O
,	O
Prof	O
.	O

Dr	O
.	O
G	O
.	O

Stoter	O
,	O
r	O
.	O
K	O
.	O

Nooter	O
,	O
Laboratory	O
of	O
Chemotherapy	O
and	O
Pharmacology	O
,	O
Department	O
of	O
Medical	O
Oncology	O
,	O
Rotterdam	O
Cancer	O
235	O

M	O
.	O

Gielen	O
,	O
K	O
.	O

Handlir	O
,	O
M	O
.	O

HoHein	O
and	O
D	O
.	O

de	O
Vos	O
Synthesis	O
,	O
Characterization	O
and	O
Antitumor	O
Activity	O
ofSome	O
Butyltin	O
(	O
IV	O
)	O
Cysteaminates	O
and	O
N	O
,	O
N	O
-	O
Dimethylcysteaminate	O

Institute	O
,	O
NL	O
3008	O
AE	O
,	O
Rotterdam	O
,	O
The	O
Netherlands	O
,	O
for	O
performing	O
the	O
in	O
vitro	O
tests	O
.	O

This	O
research	O
was	O
supported	O
by	O
the	O
Fund	O
for	O
Scientific	O
Research	O
Flanders	O
(	O
Belgium	O
)	O
,	O
grant	O
nr	O
G	O
.	O
0074	O
.	O
00	O
,	O
M	O
.	O

G	O
.	O
)	O
.	O

References	O
.	O

1	O
.	O

B	O
.	O
S	O
.	O

Saraswat	O
,	O
J	O
.	O

Mason	O
,	O
Polyhedron	O
(	O
9	O
)	O
,	O
5	O
(	O
1986	O
)	O
,	O
1449	O
.	O

2	O
.	O

G	O
.	O

Domazetis	O
,	O
R	O
.	O

J	O
.	O

Magee	O
,	O
B	O
.	O

D	O
.	O

James	O
,	O
J	O
.	O

Organomet	O
.	O

Chem	O
,	O
162	O
(	O
1978	O
)	O
,	O
239	O
.	O

3	O
.	O

J	O
.	O
D	O
.	O

Cashion	O
,	O
G	O
.	O

Domazetis	O
,	O
B	O
.	O

D	O
.	O

James	O
,	O
J	O
.	O

Organomet	O
.	O

Chem	O
,	O
185	O
(	O
1980	O
)	O
,	O
433	O
.	O

4	O
.	O

G	O
.	O

Domazetis	O
,	O
R	O
.	O

J	O
.	O

Magee	O
,	O
B	O
.	O

D	O
.	O

James	O
,	O
J	O
.	O

Organomet	O
.	O

Chem	O
,	O
148	O
(	O
1978	O
)	O
,	O
339	O
.	O

5	O
.	O

G	O
.	O

Atassi	O
,	O
Rev	O
.	O

Si	O
Ge	O
Sn	O
Pb	O
Cpds	O
,	O
8	O
(	O
1985	O
)	O
,	O
219	O
;	O
M	O
.	O

Kemmer	O
,	O
M	O
.	O

Gielen	O
,	O
M	O
.	O

Biesemans	O
,	O
D	O
.	O

de	O
Vos	O
,	O
R	O
.	O

Willem	O
,	O
Metal	O
-	O
Based	O
Drugs	O
5	O
(	O
1998	O
)	O
,	O
189	O
;	O
M	O
.	O

Gielen	O
,	O
M	O
.	O

Biesemans	O
,	O
D	O
.	O

de	O
Vos	O
,	O
R	O
.	O

Willem	O
,	O
J	O
.	O

Inorg	O
.	O

Biochem	O
.	O
,	O
79	O
(	O
2000	O
)	O
,	O
139	O
.	O

6	O
.	O

J	O
.	O

Holecek	O
,	O
A	O
.	O

Lycka	O
,	O
Inorg	O
.	O

Chim	O
.	O

Acta	O
,	O
118	O
(	O
1986	O
)	O
,	O
L	O
15	O
.	O

7	O
.	O

J	O
.	O

Holecek	O
,	O
M	O
.	O

Nadvomik	O
,	O
K	O
.	O

Handlir	O
,	O
A	O
.	O

Lycka	O
,	O
J	O
.	O

Organomet	O
.	O

Chem	O
.	O
,	O
315	O
(	O
1986	O
)	O
,	O
299	O
.	O

8	O
.	O

B	O
.	O
D	O
.	O

James	O
,	O
R	O
.	O

J	O
.	O

Magee	O
,	O
W	O
.	O

C	O
.	O

Patalinghug	O
,	O
B	O
.	O

W	O
.	O

Skelton	O
,	O
A	O
.	O

H	O
.	O

White	O
,	O
J	O
.	O

Organomet	O
.	O

Chem	O
,	O
467	O
(	O
1994	O
)	O
,	O
51	O
9	O
.	O

P	O
.	O

Skehan	O
,	O
R	O
.	O

Storeng	O
,	O
D	O
.	O

Scudiero	O
,	O
A	O
.	O

Monks	O
,	O
J	O
.	O

McMahon	O
,	O
D	O
.	O

Vistica	O
,	O
J	O
.	O

T	O
.	O

Warren	O
,	O
H	O
.	O

Bokesh	O
,	O
S	O
.	O

Kenney	O
,	O
M	O
.	O

R	O
.	O

Boyd	O
,	O
J	O
.	O
.	O

Natl	O
.	O

Cancer	O
lnst	O
.	O
,	O
82	O
(	O
1990	O
)	O
,	O
1107	O
.	O

10	O
.	O

Y	O
.	O

P	O
.	O

Kepers	O
,	O
G	O
.	O

J	O
.	O

Peters	O
,	O
J	O
.	O

Van	O
Ark	O
-	O
Otte	O
,	O
B	O
.	O

Winograd	O
,	O
H	O
.	O

M	O
.	O

Pinedo	O
,	O
Eur	O
.	O

J	O
.	O

Cancer	O
,	O
27	O
(	O
1991	O
)	O
,	O
897	O
.	O

11	O
.	O

M	O
.	O

Kemmer	O
,	O
L	O
.	O

Ghys	O
,	O
M	O
.	O

Gielen	O
,	O
M	O
.	O

Biesemans	O
,	O
E	O
.	O

R	O
.	O

T	O
.	O

Tiekink	O
,	O
R	O
.	O

Willem	O
,	O
J	O
.	O

Organomet	O
.	O

Chem	O
.	O

582	O
(	O
1999	O
)	O
,	O
195	O
.	O

12	O
.	O

S	O
.	O

W	O
.	O

Ng	O
,	O
V	O
.	O

G	O
.	O

Kumar	O
Das	O
,	O
J	O
.	O

Holecek	O
,	O
A	O
.	O

Lycka	O
,	O
M	O
.	O

Gielen	O
,	O
M	O
.	O

G	O
.	O

B	O
.	O

Drew	O
,	O
Appl	O
.	O

Organomet	O
.	O

Chem	O
.	O

11	O
(	O
1997	O
)	O
,	O
3	O
9	O
.	O

Received	O
"	O
September	O
22	O
,	O
2000	O
Accepted	O
-	O
October	O
19	O
,	O
2000	O
Received	O
in	O
revised	O
camera	O
-	O
ready	O
format	O
-	O
October	O
20	O
,	O
2000	O

236	O

Genomic	O
-	O
Bioinformatic	O
Analysis	O
of	O
Transcripts	O
Enriched	O
in	O
the	O
Third	O
-	O
Stage	O
Larva	O
of	O
the	O
Parasitic	O
Nematode	O
Ascaris	B
suum	I

Abstract	O

Differential	O
transcription	O
in	O
Ascaris	B
suum	I
was	O
investigated	O
using	O
a	O
genomic	O
-	O
bioinformatic	O
approach	O
.	O

A	O
cDNA	O
archive	O
enriched	O
for	O
molecules	O
in	O
the	O
infective	O
third	O
-	O
stage	O
larva	O
(	O
L3	O
)	O
of	O
A	B
.	I
suum	I
was	O
constructed	O
by	O
suppressive	O
-	O
subtractive	O
hybridization	O
(	O
SSH	O
)	O
,	O
and	O
a	O
subset	O
of	O
cDNAs	O
from	O
3075	O
clones	O
subjected	O
to	O
microarray	O
analysis	O
using	O
cDNA	O
probes	O
derived	O
from	O
RNA	O
from	O
different	O
developmental	O
stages	O
of	O
A	B
.	I
suum	I
.	O

The	O
cDNAs	O
(	O
n	O
=	O
498	O
)	O
shown	O
by	O
microarray	O
analysis	O
to	O
be	O
enriched	O
in	O
the	O
L3	O
were	O
sequenced	O
and	O
subjected	O
to	O
bioinformatic	O
analyses	O
using	O
a	O
semi	O
-	O
automated	O
pipeline	O
(	O
ESTExplorer	O
)	O
.	O

Using	O
gene	O
ontology	O
(	O
GO	O
)	O
,	O
235	O
of	O
these	O
molecules	O
were	O
assigned	O
to	O
'	O
biological	O
process	O
'	O
(	O
n	O
=	O
68	O
)	O
,	O
'	O
cellular	O
component	O
'	O
(	O
n	O
=	O
50	O
)	O
,	O
or	O
'	O
molecular	O
function	O
'	O
(	O
n	O
=	O
117	O
)	O
.	O

Of	O
the	O
91	O
clusters	O
assembled	O
,	O
56	O
molecules	O
(	O
61	O
.	O
5	O
%	O
)	O
had	O
homologues	O
/	O
orthologues	O
in	O
the	O
free	O
-	O
living	O
nematodes	O
Caenorhabditis	B
elegans	I
and	O
C	B
.	I
briggsae	I
and	O
/	O
or	O
other	O
organisms	O
,	O
whereas	O
35	O
(	O
38	O
.	O
5	O
%	O
)	O
had	O
no	O
significant	O
similarity	O
to	O
any	O
sequences	O
available	O
in	O
current	O
gene	O
databases	O
.	O

Transcripts	O
encoding	O
protein	O
kinases	O
,	O
protein	O
phosphatases	O
(	O
and	O
their	O
precursors	O
)	O
,	O
and	O
enolases	O
were	O
abundantly	O
represented	O
in	O
the	O
L3	O
of	O
A	B
.	I
suum	I
,	O
as	O
were	O
molecules	O
involved	O
in	O
cellular	O
processes	O
,	O
such	O
as	O
ubiquitination	O
and	O
proteasome	O
function	O
,	O
gene	O
transcription	O
,	O
protein	O
-	O
protein	O
interactions	O
,	O
and	O
function	O
.	O

In	O
silico	O
analyses	O
inferred	O
the	O
C	B
.	I
elegans	I
orthologues	O
/	O
homologues	O
(	O
n	O
=	O
50	O
)	O
to	O
be	O
involved	O
in	O
apoptosis	O
and	O
insulin	O
signaling	O
(	O
2	O
%	O
)	O
,	O
ATP	O
synthesis	O
(	O
2	O
%	O
)	O
,	O
carbon	O
metabolism	O
(	O
6	O
%	O
)	O
,	O
fatty	O
acid	O
biosynthesis	O
(	O
2	O
%	O
)	O
,	O
gap	O
junction	O
(	O
2	O
%	O
)	O
,	O
glucose	O
metabolism	O
(	O
6	O
%	O
)	O
,	O
or	O
porphyrin	O
metabolism	O
(	O
2	O
%	O
)	O
,	O
although	O
34	O
(	O
68	O
%	O
)	O
of	O
them	O
could	O
not	O
be	O
mapped	O
to	O
a	O
specific	O
metabolic	O
pathway	O
.	O

Small	O
numbers	O
of	O
these	O
50	O
molecules	O
were	O
predicted	O
to	O
be	O
secreted	O
(	O
10	O
%	O
)	O
,	O
anchored	O
(	O
2	O
%	O
)	O
,	O
and	O
/	O
or	O
transmembrane	O
(	O
12	O
%	O
)	O
proteins	O
.	O

Functionally	O
,	O
17	O
(	O
34	O
%	O
)	O
of	O
them	O
were	O
predicted	O
to	O
be	O
associated	O
with	O
(	O
non	O
-	O
wild	O
-	O
type	O
)	O
RNAi	O
phenotypes	O
in	O
C	B
.	I
elegans	I
,	O
the	O
majority	O
being	O
embryonic	O
lethality	O
(	O
Emb	O
)	O
(	O
13	O
types	O
;	O
58	O
.	O
8	O
%	O
)	O
,	O
larval	O
arrest	O
(	O
Lva	O
)	O
(	O
23	O
.	O
5	O
%	O
)	O
and	O
larval	O
lethality	O
(	O
Lvl	O
)	O
(	O
47	O
%	O
)	O
.	O

A	O
genetic	O
interaction	O
network	O
was	O
predicted	O
for	O
these	O
17	O
C	B
.	I
elegans	I
orthologues	O
,	O
revealing	O
highly	O
significant	O
interactions	O
for	O
nine	O
molecules	O
associated	O
with	O
embryonic	O
and	O
larval	O
development	O
(	O
66	O
.	O
9	O
%	O
)	O
,	O
information	O
storage	O
and	O
processing	O
(	O
5	O
.	O
1	O
%	O
)	O
,	O
cellular	O
processing	O
and	O
signaling	O
(	O
15	O
.	O
2	O
%	O
)	O
,	O
metabolism	O
(	O
6	O
.	O
1	O
%	O
)	O
,	O
and	O
unknown	O
function	O
(	O
6	O
.	O
7	O
%	O
)	O
.	O

The	O
potential	O
roles	O
of	O
these	O
molecules	O
in	O
development	O
are	O
discussed	O
in	O
relation	O
to	O
the	O
known	O
roles	O
of	O
their	O
homologues	O
/	O
orthologues	O
in	O
C	B
.	I
elegans	I
and	O
some	O
other	O
nematodes	O
.	O

The	O
results	O
of	O
the	O
present	O
study	O
provide	O
a	O
basis	O
for	O
future	O
functional	O
genomic	O
studies	O
to	O
elucidate	O
molecular	O
aspects	O
governing	O
larval	O
developmental	O
processes	O
in	O
A	B
.	I
suum	I
and	O
/	O
or	O
the	O
transition	O
to	O
parasitism	O
.	O

Introduction	O

Parasitic	O
nematodes	O
are	O
of	O
major	O
socio	O
-	O
economic	O
importance	O
in	O
animals	O
.	O

For	O
example	O
,	O
hundreds	O
of	O
millions	O
of	O
people	B
are	O
infected	O
with	O
geohelminths	O
(	O
soil	O
-	O
transmitted	O
worms	O
)	O
,	O
such	O
as	O
blood	O
-	O
feeding	O
hookworms	O
Ancylostoma	B
duodenale	I
and	O
/	O
or	O
Necator	B
americanus	I
,	O
Trichuris	B
trichiura	I
and	O
Ascaris	O
spp	O
.	O

[	O
1	O
]	O
,	O
causing	O
serious	O
adverse	O
effects	O
on	O
human	B
health	O
,	O
particularly	O
in	O
children	B
.	O

Similarly	O
,	O
parasitic	O
nematodes	O
of	O
livestock	O
,	O
such	O
as	O
pigs	B
,	O
also	O
cause	O
substantial	O
economic	O
losses	O
due	O
to	O
subclinical	O
and	O
clinical	O
diseases	O
,	O
with	O
billions	O
of	O
dollars	O
spent	O
annually	O
on	O
the	O
treatment	O
and	O
control	O
of	O
gastro	O
-	O
intestinal	O
nematodes	O
.	O

In	O
addition	O
to	O
the	O
socioeconomic	O
impact	O
that	O
these	O
parasites	O
have	O
,	O
there	O
is	O
potential	O
for	O
the	O
emergence	O
of	O
resistance	O
in	O
them	O
against	O
all	O
of	O
the	O
main	O
classes	O
of	O
(	O
nematocidal	O
)	O
compounds	O
used	O
to	O
treat	O
the	O
diseases	O
they	O
cause	O
[	O
2	O
]	O
-	O
[	O
5	O
]	O
.	O

Therefore	O
,	O
there	O
is	O
a	O
significant	O
need	O
to	O
work	O
toward	O
discovering	O
new	O
compounds	O
to	O
control	O
these	O
parasites	O
.	O

Gaining	O
an	O
improved	O
understanding	O
of	O
the	O
molecular	O
basis	O
of	O
parasite	O
development	O
provides	O
such	O
an	O
avenue	O
.	O

Compared	O
with	O
the	O
free	O
-	O
living	O
nematode	O
Caenorhabditis	B
elegans	I
,	O
there	O
is	O
very	O
little	O
information	O
on	O
fundamental	O
molecular	O
aspects	O
of	O
development	O
in	O
parasitic	O
nematodes	O
[	O
6	O
]	O
-	O
[	O
8	O
]	O
.	O

Since	O
the	O
genome	O
sequence	O
of	O
C	B
.	I
elegans	I
was	O
published	O
in	O
1998	O
[	O
9	O
]	O
,	O
many	O
aspects	O
of	O
the	O
molecular	O
biology	O
of	O
this	O
nematode	O
have	O
been	O
elucidated	O
.	O

For	O
instance	O
,	O
microarray	O
analyses	O
have	O
been	O
used	O
to	O
examine	O
developmental	O
and	O
gender	O
-	O
enriched	O
gene	O
expression	O
[	O
10	O
]	O
,	O
[	O
11	O
]	O
,	O
and	O
the	O
functions	O
of	O
more	O
than	O
96	O
%	O
of	O
the	O
C	B
.	I
elegans	I
genes	O
have	O
been	O
assessed	O
by	O
double	O
-	O
stranded	O
RNA	O
interference	O
(	O
RNAi	O
,	O
or	O
gene	O
silencing	O
;	O
[	O
12	O
]	O
)	O
[	O
13	O
]	O
-	O
[	O
18	O
]	O
.	O

Comparative	O
analyses	O
of	O
genetic	O
data	O
sets	O
have	O
shown	O
that	O
parasitic	O
nematodes	O
usually	O
share	O
~	O
50	O
-	O
70	O
%	O
of	O
genes	O
with	O
C	B
.	I
elegans	I
(	O
e	O
.	O
g	O
.	O
,	O
[	O
19	O
]	O
,	O
[	O
20	O
]	O
)	O
.	O

There	O
is	O
similarity	O
in	O
other	O
features	O
(	O
such	O
as	O
basic	O
body	O
plan	O
and	O
moulting	O
)	O
between	O
C	B
.	I
elegans	I
and	O
parasitic	O
nematodes	O
,	O
suggesting	O
that	O
some	O
molecular	O
pathways	O
are	O
relatively	O
conserved	O
[	O
8	O
]	O
,	O
[	O
21	O
]	O
.	O

Understanding	O
the	O
pathways	O
linked	O
to	O
basic	O
nematode	O
biology	O
and	O
development	O
could	O
have	O
important	O
implications	O
for	O
finding	O
new	O
ways	O
of	O
disrupting	O
these	O
pathways	O
and	O
thus	O
facilitate	O
the	O
identification	O
of	O
new	O
drug	O
targets	O
.	O

Despite	O
the	O
advances	O
in	O
genomic	O
technologies	O
[	O
7	O
]	O
,	O
[	O
22	O
]	O
-	O
[	O
29	O
]	O
and	O
the	O
study	O
of	O
C	B
.	I
elegans	I
,	O
there	O
is	O
a	O
paucity	O
of	O
information	O
on	O
the	O
genomics	O
of	O
parasitic	O
nematodes	O
of	O
animals	O
,	O
particularly	O
in	O
relation	O
to	O
development	O
.	O

Also	O
considering	O
the	O
major	O
socioeconomic	O
impact	O
of	O
Ascaris	O
and	O
ascariasis	O
in	O
humans	B
and	O
pigs	B
[	O
30	O
]	O
-	O
[	O
32	O
]	O
,	O
several	O
characteristics	O
,	O
including	O
the	O
large	O
size	O
of	O
the	O
adult	O
worm	O
(	O
providing	O
the	O
opportunity	O
of	O
investigating	O
individual	O
organ	O
systems	O
and	O
tissues	O
)	O
,	O
the	O
ability	O
to	O
maintain	O
Ascaris	O
in	O
the	O
pig	B
,	O
store	O
eggs	O
and	O
culture	O
larvae	O
in	O
vitro	O
for	O
relatively	O
long	O
periods	O
of	O
time	O
(	O
months	O
to	O
years	O
)	O
[	O
32	O
]	O
as	O
well	O
as	O
the	O
discovery	O
that	O
RNAi	O
achieves	O
"	O
cross	O
-	O
species	O
"	O
gene	O
silencing	O
for	O
a	O
selected	O
number	O
of	O
genes	O
[	O
33	O
]	O
,	O
[	O
34	O
]	O
and	O
the	O
imminent	O
genome	O
sequence	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
sanger	O
.	O
ac	O
.	O
uk	O
/	O
Projects	O
/	O
Helminths	O
/	O
)	O
all	O
indicate	O
that	O
Ascaris	O
could	O
serve	O
as	O
a	O
powerful	O
model	O
system	O
for	O
investigating	O
reproductive	O
and	O
developmental	O
processes	O
in	O
nematodes	O
.	O

In	O
the	O
present	O
study	O
,	O
Ascaris	O
from	O
pigs	B
was	O
used	O
to	O
study	O
molecules	O
abundantly	O
transcribed	O
in	O
the	O
infective	O
third	O
-	O
stage	O
larva	O
(	O
L3	O
)	O
.	O

Following	O
the	O
oral	O
ingestion	O
of	O
Ascaris	O
eggs	O
by	O
the	O
host	O
(	O
human	B
or	O
pig	B
)	O
,	O
L3s	O
are	O
released	O
and	O
then	O
invade	O
/	O
penetrate	O
predominantly	O
the	O
caecal	O
wall	O
[	O
35	O
]	O
to	O
then	O
undergo	O
hepato	O
-	O
pulmonary	O
migration	O
,	O
after	O
which	O
ultimately	O
the	O
adult	O
females	O
and	O
males	O
establish	O
and	O
develop	O
in	O
the	O
small	O
intestine	O
[	O
36	O
]	O
,	O
[	O
37	O
]	O
.	O

The	O
molecular	O
mechanisms	O
linked	O
to	O
host	O
invasion	O
and	O
parasite	O
development	O
are	O
largely	O
unknown	O
.	O

Here	O
,	O
we	O
constructed	O
an	O
L3	O
-	O
enriched	O
cDNA	O
library	O
using	O
the	O
method	O
of	O
suppressive	O
-	O
subtractive	O
hybridization	O
(	O
SSH	O
)	O
,	O
explored	O
transcription	O
of	O
a	O
representative	O
subset	O
of	O
molecules	O
by	O
microarray	O
analysis	O
and	O
conducted	O
bioinformatic	O
analyses	O
to	O
characterize	O
these	O
molecules	O
,	O
map	O
them	O
to	O
biochemical	O
pathways	O
and	O
predict	O
genetic	O
interactions	O
based	O
on	O
comparisons	O
with	O
C	B
.	I
elegans	I
and	O
/	O
or	O
other	O
organisms	O
.	O

Materials	O
and	O
Methods	O

Production	O
of	O
Different	O
Developmental	O
Stages	O
of	O
Ascaris	O

Experimental	O
pigs	B
(	O
8	O
-	O
12	O
weeks	O
of	O
age	O
)	O
were	O
purchased	O
from	O
and	O
maintained	O
in	O
the	O
Experimental	O
Animal	O
Center	O
of	O
South	O
China	O
Agricultural	O
University	O
.	O

These	O
pigs	B
were	O
treated	O
humanely	O
,	O
according	O
to	O
the	O
Animal	O
Ethics	O
procedures	O
and	O
guidelines	O
of	O
the	O
People	O
'	O
s	O
Republic	O
of	O
China	O
.	O

Adult	O
worms	O
(	O
males	O
and	O
females	O
)	O
of	O
A	B
.	I
suum	I
were	O
collected	O
from	O
the	O
small	O
intestines	O
of	O
pigs	B
from	O
an	O
abattoir	O
in	O
Shenzhen	O
,	O
China	O
.	O

Infective	O
eggs	O
and	O
infective	O
L3s	O
of	O
A	B
.	I
suum	I
were	O
produced	O
according	O
to	O
the	O
methods	O
described	O
previously	O
[	O
38	O
]	O
.	O

In	O
brief	O
,	O
eggs	O
from	O
the	O
uteri	O
of	O
adult	O
females	O
of	O
A	B
.	I
suum	I
were	O
collected	O
and	O
incubated	O
at	O
28	O
degrees	O
C	O
for	O
28	O
days	O
to	O
allow	O
them	O
to	O
develop	O
to	O
infective	O
eggs	O
(	O
containing	O
infective	O
L3s	O
)	O
.	O

To	O
obtain	O
pure	O
infective	O
L3s	O
,	O
7	O
.	O
5	O
%	O
v	O
/	O
v	O
sodium	O
hypochlorite	O
was	O
used	O
to	O
treat	O
the	O
larvated	O
eggs	O
at	O
37	O
degrees	O
C	O
overnight	O
and	O
then	O
the	O
eggs	O
were	O
shaken	O
with	O
glass	O
-	O
beads	O
;	O
then	O
,	O
the	O
exsheathed	O
L3s	O
and	O
shells	O
were	O
separated	O
by	O
density	O
gradient	O
centrifugation	O
using	O
lymphocyte	O
separating	O
medium	O
(	O
LSM	O
)	O
[	O
38	O
]	O
.	O

Following	O
the	O
experimental	O
infection	O
of	O
helminth	O
-	O
free	O
pigs	B
with	O
infective	O
Ascaris	O
eggs	O
as	O
described	O
previously	O
[	O
39	O
]	O
,	O
the	O
L3s	O
from	O
livers	O
and	O
in	O
lungs	O
as	O
well	O
as	O
L4s	O
in	O
intestines	O
were	O
isolated	O
according	O
to	O
an	O
established	O
method	O
[	O
40	O
]	O
.	O

All	O
parasite	O
materials	O
were	O
snap	O
-	O
frozen	O
in	O
liquid	O
nitrogen	O
prior	O
to	O
storage	O
at	O
-	O
70	O
degrees	O
C	O
.	O

Construction	O
of	O
the	O
cDNA	O
Library	O
by	O
Subtractive	O
-	O
Suppressive	O
Hybridization	O
(	O
SSH	O
)	O

Total	O
RNA	O
was	O
isolated	O
from	O
adult	O
females	O
and	O
males	O
,	O
different	O
larval	O
stages	O
or	O
eggs	O
of	O
A	B
.	I
suum	I
using	O
TriPure	O
reagent	O
(	O
Roche	O
)	O
as	O
recommended	O
by	O
the	O
manufacturer	O
.	O

Equal	O
amounts	O
of	O
total	O
RNA	O
from	O
each	O
stage	O
or	O
sex	O
were	O
pooled	O
.	O

The	O
mRNA	O
was	O
isolated	O
using	O
the	O
Oligotex	O
mRNA	O
Kit	O
(	O
Qiagen	O
)	O
,	O
following	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

SSH	O
was	O
carried	O
out	O
using	O
the	O
PCR	O
-	O
Select	O
cDNA	O
Subtraction	O
kit	O
(	O
Clontech	O
)	O
,	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

In	O
brief	O
,	O
cDNA	O
synthesized	O
from	O
mRNAs	O
from	O
infective	O
L3s	O
was	O
subtracted	O
against	O
cDNA	O
synthesized	O
from	O
the	O
pooled	O
mRNA	O
from	O
all	O
other	O
stages	O
included	O
herein	O
.	O

The	O
SSH	O
library	O
was	O
constructed	O
using	O
infective	O
L3s	O
as	O
the	O
tester	O
and	O
pooled	O
cDNAs	O
from	O
all	O
other	O
stages	O
as	O
the	O
driver	O
.	O

The	O
effectiveness	O
of	O
this	O
subtraction	O
process	O
has	O
already	O
been	O
demonstrated	O
in	O
previous	O
studies	O
[	O
41	O
]	O
,	O
[	O
42	O
]	O
.	O

The	O
cDNA	O
obtained	O
following	O
SSH	O
was	O
cloned	O
into	O
the	O
pGEM	O
-	O
T	O
Easy	O
plasmid	O
vector	O
(	O
Promega	O
)	O
and	O
competent	O
Escherichia	B
coli	I
(	O
JM109	O
)	O
transformed	O
.	O

Positive	O
clones	O
,	O
picked	O
randomly	O
(	O
based	O
on	O
blue	O
/	O
white	O
selection	O
)	O
,	O
were	O
grown	O
overnight	O
in	O
Luria	O
Bertani	O
(	O
LB	O
)	O
medium	O
(	O
shaking	O
,	O
37	O
degrees	O
C	O
)	O
.	O

Individual	O
inserts	O
were	O
PCR	O
-	O
amplified	O
using	O
"	O
nested	O
primers	O
"	O
1	O
and	O
2R	O
from	O
the	O
Subtraction	O
kit	O
(	O
Clontech	O
)	O
and	O
examined	O
by	O
agarose	O
electrophoresis	O
.	O

Preparation	O
of	O
Microarray	O
Slides	O

Clones	O
(	O
n	O
=	O
3075	O
)	O
from	O
the	O
subtracted	O
library	O
were	O
picked	O
and	O
cultured	O
overnight	O
in	O
LB	O
containing	O
ampicillin	O
(	O
1000	O
IU	O
/	O
ml	O
)	O
in	O
sealed	O
96	O
-	O
well	O
blocks	O
.	O

Five	O
micro	O
l	O
of	O
culture	O
suspension	O
from	O
each	O
well	O
were	O
transferred	O
into	O
individual	O
wells	O
thermocycling	O
(	O
96	O
-	O
well	O
)	O
plates	O
and	O
the	O
inserts	O
PCR	O
-	O
amplified	O
using	O
primers	O
1	O
and	O
2R	O
.	O

Following	O
a	O
10	O
min	O
denaturation	O
step	O
at	O
94	O
degrees	O
C	O
,	O
the	O
amplification	O
proceeded	O
for	O
25	O
cycles	O
of	O
10	O
s	O
at	O
94	O
degrees	O
C	O
,	O
30	O
s	O
at	O
68	O
degrees	O
C	O
and	O
1	O
.	O
5	O
min	O
at	O
72	O
degrees	O
C	O
,	O
with	O
a	O
final	O
extension	O
for	O
5	O
min	O
at	O
72	O
degrees	O
C	O
.	O

Products	O
were	O
resolved	O
in	O
agarose	O
gels	O
,	O
ethanol	O
precipitated	O
,	O
re	O
-	O
suspended	O
in	O
16	O
micro	O
l	O
of	O
"	O
spotting	O
solution	O
"	O
(	O
Shanghai	O
BioStar	O
Genechip	O
,	O
Inc	O
)	O
to	O
a	O
final	O
concentration	O
of	O
~	O
500	O
ng	O
per	O
micro	O
l	O
,	O
before	O
being	O
printed	O
on	O
to	O
glass	O
slides	O
(	O
in	O
duplicate	O
)	O
using	O
a	O
robotic	O
arrayer	O
.	O

Sixteen	O
blanks	O
(	O
using	O
spotting	O
solution	O
only	O
)	O
and	O
the	O
same	O
number	O
of	O
negative	O
(	O
irrelevant	O
cDNAs	O
with	O
no	O
relationship	O
to	O
Ascaris	O
)	O
were	O
also	O
printed	O
on	O
to	O
slides	O
and	O
served	O
as	O
negative	O
controls	O
;	O
beta	O
-	O
actin	O
of	O
A	B
.	I
suum	I
served	O
as	O
a	O
positive	O
control	O
to	O
assess	O
the	O
efficiency	O
of	O
labeling	O
and	O
hybridization	O
.	O

The	O
slides	O
were	O
air	O
-	O
dried	O
for	O
2	O
h	O
,	O
and	O
cDNA	O
in	O
the	O
spots	O
were	O
cross	O
-	O
linked	O
at	O
254	O
mJ	O
.	O

The	O
printed	O
slides	O
were	O
stored	O
at	O
4	O
degrees	O
C	O
.	O

Labeling	O
of	O
cDNA	O
Probes	O
with	O
Fluorescent	O
Dyes	O
,	O
and	O
Microarray	O
Analysis	O

The	O
cDNAs	O
produced	O
from	O
total	O
RNA	O
from	O
A	B
.	I
suum	I
eggs	O
,	O
infective	O
L3s	O
,	O
L3s	O
isolated	O
from	O
pig	B
liver	O
or	O
lung	O
,	O
fourth	O
-	O
stage	O
larvae	O
(	O
L4s	O
)	O
,	O
adult	O
males	O
or	O
females	O
[	O
as	O
described	O
in	O
the	O
section	O
'	O
Construction	O
of	O
the	O
cDNA	O
Library	O
by	O
Subtractive	O
-	O
Suppressive	O
Hybridization	O
(	O
SSH	O
)	O
'	O
]	O
were	O
labeled	O
with	O
cyanine	O
dyes	O
.	O

Cy3	O
or	O
Cy5	O
-	O
dCTP	O
was	O
incorporated	O
into	O
cDNA	O
produced	O
from	O
30	O
micro	O
g	O
of	O
total	O
RNA	O
by	O
direct	O
labeling	O
in	O
a	O
reverse	O
transcription	O
reaction	O
using	O
an	O
oligo	O
(	O
dT	O
)	O
primer	O
.	O

Labeled	O
cDNA	O
was	O
purified	O
using	O
DyeEx	O
columns	O
(	O
Qiagen	O
)	O
.	O

Microarray	O
slides	O
were	O
incubated	O
with	O
a	O
pre	O
-	O
hybridization	O
solution	O
[	O
5	O
x	O
SSC	O
,	O
1	O
%	O
bovine	B
serum	O
albumin	O
(	O
BSA	O
)	O
,	O
0	O
.	O
1	O
%	O
sodium	O
dodecyl	O
-	O
sulphate	O
(	O
SDS	O
)	O
]	O
for	O
6	O
h	O
at	O
42	O
degrees	O
C	O
.	O

After	O
pre	O
-	O
hybridization	O
,	O
the	O
microarray	O
slides	O
were	O
incubated	O
with	O
'	O
pooled	O
'	O
Cy3	O
and	O
Cy5	O
-	O
labeled	O
probes	O
in	O
hybridization	O
solution	O
(	O
5	O
x	O
SSC	O
,	O
1	O
%	O
BSA	O
,	O
0	O
.	O
1	O
%	O
SDS	O
)	O
,	O
in	O
the	O
dark	O
at	O
42	O
degrees	O
C	O
for	O
18	O
h	O
,	O
and	O
then	O
washed	O
in	O
solution	O
I	O
(	O
1	O
x	O
SSC	O
,	O
0	O
.	O
2	O
%	O
SDS	O
)	O
for	O
10	O
min	O
,	O
followed	O
by	O
solution	O
II	O
(	O
0	O
.	O
1	O
x	O
SSC	O
,	O
0	O
.	O
2	O
%	O
SDS	O
)	O
for	O
10	O
min	O
at	O
60	O
degrees	O
C	O
,	O
according	O
to	O
the	O
protocols	O
provided	O
by	O
Shanghai	O
BioStar	O
Genechip	O
,	O
Inc	O
.	O

A	O
"	O
dye	O
flip	O
"	O
was	O
carried	O
out	O
to	O
control	O
for	O
any	O
bias	O
in	O
hybridization	O
signal	O
between	O
the	O
Cy	O
-	O
labeled	O
cDNA	O
probes	O
(	O
produced	O
for	O
two	O
distinct	O
mRNA	O
populations	O
)	O
.	O

The	O
slides	O
were	O
dried	O
and	O
scanned	O
(	O
ScanArray	O
4000	O
scanner	O
)	O
using	O
image	O
acquisition	O
software	O
(	O
Shanghai	O
BioStar	O
Genechip	O
Inc	O
.	O
)	O
and	O
a	O
range	O
of	O
laser	O
power	O
and	O
photo	O
-	O
multiplier	O
tube	O
intensities	O
.	O

The	O
mean	O
hybridization	O
signal	O
(	O
derived	O
from	O
four	O
replicates	O
of	O
the	O
same	O
array	O
)	O
were	O
corrected	O
for	O
background	O
,	O
normalized	O
[	O
43	O
]	O
,	O
log2	O
-	O
transformed	O
and	O
then	O
subjected	O
to	O
statistical	O
analysis	O
employing	O
the	O
students	O
t	O
-	O
test	O
in	O
a	O
spreadsheet	O
(	O
Excel	O
,	O
Microsoft	O
,	O
USA	O
)	O
.	O

The	O
microarray	O
data	O
were	O
analysed	O
for	O
differential	O
cDNA	O
hybridization	O
(	O
>	O
2	O
.	O
0	O
-	O
fold	O
to	O
114	O
.	O
3	O
-	O
fold	O
)	O
between	O
L3	O
and	O
each	O
of	O
the	O
other	O
stages	O
(	O
eggs	O
,	O
lung	O
and	O
liver	O
L3s	O
,	O
L4	O
,	O
adult	O
female	O
and	O
adult	O
male	O
)	O
.	O

Verification	O
of	O
Differential	O
Hybridization	O
by	O
Reverse	O
Transcription	O
-	O
Coupled	O
Polymerase	O
Chain	O
Reaction	O
(	O
RT	O
-	O
PCR	O
)	O
Analysis	O

For	O
a	O
subset	O
(	O
n	O
=	O
17	O
)	O
of	O
representative	O
ESTs	O
(	O
rESTs	O
)	O
,	O
RT	O
-	O
PCR	O
was	O
used	O
to	O
verify	O
the	O
differential	O
transcription	O
recorded	O
by	O
microarray	O
analysis	O
.	O

Double	O
-	O
stranded	O
cDNA	O
was	O
synthesized	O
from	O
total	O
RNA	O
(	O
separately	O
)	O
from	O
each	O
stage	O
or	O
sex	O
of	O
A	B
.	I
suum	I
using	O
reverse	O
transcriptase	O
(	O
Superscript	O
III	O
,	O
Invitrogen	O
)	O
.	O

Briefly	O
,	O
5	O
micro	O
g	O
of	O
total	O
RNA	O
were	O
added	O
to	O
14	O
micro	O
l	O
of	O
H2O	O
and	O
1	O
micro	O
l	O
of	O
oligo	O
d	O
(	O
T	O
)	O
n	O
=	O
12	O
-	O
18	O
primer	O
(	O
0	O
.	O
5	O
micro	O
g	O
/	O
micro	O
l	O
)	O
,	O
heated	O
to	O
70	O
degrees	O
C	O
for	O
10	O
min	O
and	O
chilled	O
on	O
ice	O
.	O

First	O
-	O
and	O
second	O
-	O
strand	O
cDNAs	O
were	O
synthesized	O
via	O
the	O
addition	O
of	O
4	O
micro	O
l	O
of	O
first	O
-	O
strand	O
cDNA	O
buffer	O
(	O
250	O
mM	O
Tris	O
-	O
HCl	O
,	O
pH	O
8	O
.	O
3	O
,	O
375	O
mM	O
KCl	O
and	O
15	O
mM	O
MgCl2	O
)	O
,	O
2	O
micro	O
l	O
of	O
0	O
.	O
1	O
M	O
dithiothreitol	O
,	O
and	O
1	O
micro	O
l	O
of	O
10	O
mM	O
of	O
each	O
dNTP	O
,	O
followed	O
by	O
an	O
incubation	O
at	O
25	O
degrees	O
C	O
(	O
10	O
min	O
)	O
,	O
42	O
degrees	O
C	O
(	O
50	O
min	O
)	O
and	O
70	O
degrees	O
C	O
(	O
15	O
min	O
)	O
.	O

One	O
-	O
tenth	O
of	O
each	O
double	O
-	O
stranded	O
cDNA	O
produced	O
was	O
then	O
used	O
as	O
a	O
template	O
in	O
the	O
PCR	O
.	O

The	O
transcripts	O
were	O
amplified	O
from	O
individual	O
cDNAs	O
by	O
PCR	O
using	O
oligonucleotide	O
primers	O
(	O
sequences	O
available	O
upon	O
request	O
)	O
designed	O
to	O
each	O
EST	O
.	O

The	O
PCR	O
amplification	O
of	O
a	O
portion	O
(	O
209	O
bp	O
)	O
of	O
the	O
beta	O
-	O
actin	O
gene	O
(	O
accession	O
no	O
.	O
BI594141	O
)	O
using	O
forward	O
primer	O
(	O
5	O
'	O
-	O
CTCGAAACAAGAATACGATG	O
-	O
3	O
'	O
)	O
and	O
reverse	O
primer	O
(	O
5	O
'	O
-	O
ACATGTGCCGTTGTATGATG	O
-	O
3	O
'	O
)	O
,	O
previously	O
determined	O
to	O
be	O
present	O
in	O
all	O
developmental	O
stages	O
and	O
both	O
sexes	O
of	O
A	B
.	I
suum	I
[	O
44	O
]	O
,	O
served	O
as	O
a	O
positive	O
control	O
.	O

Samples	O
without	O
template	O
(	O
no	O
-	O
DNA	O
controls	O
)	O
were	O
included	O
in	O
each	O
PCR	O
run	O
.	O

The	O
following	O
cycling	O
conditions	O
were	O
employed	O
:	O
one	O
cycle	O
at	O
94	O
degrees	O
C	O
(	O
5	O
min	O
)	O
,	O
94	O
degrees	O
C	O
(	O
30	O
s	O
)	O
,	O
60	O
degrees	O
C	O
(	O
30	O
s	O
)	O
and	O
72	O
degrees	O
C	O
(	O
30	O
s	O
)	O
for	O
30	O
cycles	O
,	O
followed	O
by	O
a	O
final	O
extension	O
of	O
70	O
degrees	O
C	O
(	O
7	O
min	O
)	O
.	O

Following	O
the	O
PCR	O
,	O
5	O
micro	O
l	O
of	O
individual	O
amplicons	O
were	O
resolved	O
in	O
ethidium	O
bromide	O
-	O
stained	O
agarose	O
gels	O
(	O
2	O
%	O
)	O
and	O
then	O
photographed	O
upon	O
transillumination	O
.	O

The	O
relative	O
band	O
intensities	O
were	O
analyzed	O
using	O
UVIsoft	O
Image	O
Acquisition	O
and	O
Analysis	O
software	O
(	O
UVITEC	O
)	O
.	O

The	O
specificity	O
and	O
identity	O
of	O
individual	O
amplicons	O
were	O
confirmed	O
by	O
direct	O
sequencing	O
using	O
the	O
same	O
primers	O
(	O
separately	O
)	O
as	O
employed	O
for	O
their	O
amplification	O
.	O

Sequencing	O
and	O
Bioinformatics	O
Analyses	O

Clones	O
from	O
the	O
SSH	O
cDNA	O
library	O
with	O
increased	O
hybridization	O
in	O
microarray	O
analysis	O
to	O
the	O
infective	O
L3	O
compared	O
with	O
other	O
stages	O
were	O
sequenced	O
using	O
standard	O
technology	O
[	O
45	O
]	O
.	O

The	O
nucleotide	O
sequences	O
have	O
been	O
deposited	O
in	O
the	O
GenBank	O
database	O
under	O
accession	O
numbers	O
ES290984	O
-	O
ES291074	O
.	O

Following	O
the	O
processing	O
of	O
the	O
sequences	O
(	O
i	O
.	O
e	O
.	O
,	O
removal	O
of	O
vector	O
sequences	O
,	O
quality	O
assurance	O
and	O
clustering	O
)	O
,	O
contigs	O
or	O
singletons	O
from	O
individual	O
clusters	O
were	O
subjected	O
to	O
BLASTx	O
(	O
NCBI	O
:	O
www	O
.	O
ncbi	O
.	O
nlm	O
.	O
nih	O
.	O
gov	O
)	O
and	O
BLASTn	O
(	O
EMBL	O
-	O
EBI	O
Parasite	O
Genome	O
Blast	O
Server	O
:	O
www	O
.	O
ebi	O
.	O
ac	O
.	O
uk	O
)	O
analysis	O
to	O
identify	O
putative	O
homologues	O
in	O
C	B
.	I
elegans	I
,	O
other	O
nematodes	O
and	O
other	O
organisms	O
(	O
e	O
-	O
value	O
of	O
<	O
=	O
1e	O
-	O
05	O
)	O
.	O

Peptides	O
inferred	O
from	O
ESTs	O
were	O
classified	O
functionally	O
using	O
Interproscan	O
(	O
available	O
at	O
http	O
:	O
/	O
/	O
www	O
.	O
ebi	O
.	O
ac	O
.	O
uk	O
/	O
InterProScan	O
/	O
)	O
employing	O
the	O
default	O
search	O
parameters	O
.	O

WormBase	O
(	O
www	O
.	O
wormbase	O
.	O
org	O
)	O
was	O
interrogated	O
extensively	O
for	O
relevant	O
information	O
on	O
C	B
.	I
elegans	I
homologues	O
/	O
orthologues	O
,	O
including	O
RNAi	O
phenotypic	O
,	O
transcriptomic	O
,	O
proteomic	O
and	O
interactomic	O
data	O
.	O

ESTs	O
with	O
homologues	O
/	O
orthologues	O
in	O
C	B
.	I
elegans	I
and	O
other	O
nematodes	O
were	O
also	O
subjected	O
to	O
analysis	O
employing	O
the	O
KEGG	O
Orthology	O
-	O
Based	O
Annotation	O
System	O
(	O
KOBAS	O
)	O
(	O
www	O
.	O
kobas	O
.	O
cbi	O
.	O
pku	O
.	O
edu	O
.	O
cn	O
)	O
,	O
which	O
predicts	O
the	O
biochemical	O
pathways	O
in	O
which	O
molecules	O
are	O
involved	O
.	O

The	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
inferred	O
from	O
selected	O
ESTs	O
with	O
orthologues	O
in	O
C	B
.	I
elegans	I
were	O
also	O
subjected	O
to	O
"	O
secretome	O
analysis	O
"	O
using	O
the	O
program	O
SignalP	O
v	O
.	O
2	O
.	O
0	O
www	O
.	O
cbs	O
.	O
dtu	O
.	O
dk	O
/	O
services	O
/	O
SignalP	O
/	O
)	O
,	O
employing	O
both	O
the	O
neural	O
network	O
and	O
hidden	O
Markov	O
models	O
to	O
predict	O
signal	O
peptides	O
and	O
/	O
or	O
anchors	O
[	O
46	O
]	O
-	O
[	O
48	O
]	O
.	O

Also	O
,	O
transmembrane	O
domains	O
were	O
predicted	O
using	O
the	O
program	O
TMHMM	O
(	O
www	O
.	O
cbs	O
.	O
dtu	O
.	O
dk	O
/	O
services	O
/	O
TMHMM	O
/	O
;	O
[	O
49	O
]	O
-	O
[	O
51	O
]	O
)	O
,	O
and	O
subcellular	O
localization	O
inferred	O
employing	O
the	O
program	O
WoLF	O
PSORT	O
(	O
http	O
:	O
/	O
/	O
wolfpsort	O
.	O
org	O
/	O
;	O
[	O
52	O
]	O
)	O
.	O

The	O
method	O
established	O
by	O
Zhong	O
and	O
Sternberg	O
[	O
53	O
]	O
was	O
used	O
to	O
predict	O
the	O
interactions	O
for	O
C	B
.	I
elegans	I
orthologues	O
of	O
the	O
L3	O
-	O
enriched	O
molecules	O
from	O
Ascaris	O
.	O

In	O
brief	O
,	O
interaction	O
,	O
phenotypic	O
,	O
expression	O
and	O
gene	O
ontology	O
data	O
from	O
fruitfly	B
,	O
yeast	B
,	O
mouse	B
and	O
human	B
were	O
integrated	O
using	O
a	O
na	O
i	O
ve	O
Bayesian	O
model	O
to	O
predict	O
genetic	O
interactions	O
among	O
C	B
.	I
elegans	I
genes	O
(	O
[	O
45	O
]	O
,	O
[	O
53	O
]	O
;	O
Zhong	O
and	O
Sternberg	O
,	O
unpublished	O
)	O
.	O

The	O
predicted	O
networks	O
resulting	O
from	O
the	O
analyses	O
were	O
saved	O
in	O
a	O
graphic	O
display	O
file	O
(	O
gdf	O
)	O
format	O
and	O
examined	O
using	O
the	O
graph	O
exploration	O
system	O
available	O
at	O
http	O
:	O
/	O
/	O
graphexploration	O
.	O
cond	O
.	O
org	O
/	O
.	O

Images	O
were	O
labeled	O
and	O
saved	O
in	O
the	O
joint	O
photographic	O
experts	O
group	O
(	O
jpeg	O
)	O
format	O
.	O

Results	O

To	O
identify	O
molecules	O
transcribed	O
abundantly	O
in	O
the	O
L3	O
of	O
A	B
.	I
suum	I
,	O
an	O
enriched	O
cDNA	O
library	O
was	O
constructed	O
by	O
SSH	O
.	O

From	O
a	O
total	O
of	O
3075	O
clones	O
from	O
this	O
library	O
,	O
2921	O
(	O
95	O
%	O
)	O
were	O
shown	O
to	O
contain	O
an	O
insert	O
(	O
which	O
could	O
be	O
amplified	O
by	O
PCR	O
)	O
.	O

From	O
2671	O
(	O
92	O
%	O
)	O
of	O
these	O
clones	O
,	O
amplicons	O
representing	O
single	O
bands	O
of	O
~	O
400	O
to	O
600	O
bp	O
in	O
size	O
were	O
produced	O
.	O

These	O
latter	O
amplicons	O
were	O
arrayed	O
(	O
in	O
duplicate	O
)	O
on	O
to	O
slides	O
and	O
then	O
hybridized	O
with	O
Cy3	O
-	O
labeled	O
L3	O
-	O
cDNA	O
or	O
with	O
Cy5	O
-	O
labeled	O
cDNA	O
from	O
eggs	O
,	O
liver	O
/	O
lung	O
L3s	O
,	O
L4s	O
,	O
adult	O
female	O
or	O
adult	O
male	O
of	O
Ascaris	O
.	O

Dye	O
flip	O
was	O
conducted	O
to	O
verify	O
the	O
hybridization	O
data	O
.	O

Of	O
the	O
2671	O
(	O
duplicate	O
)	O
spots	O
,	O
1526	O
had	O
a	O
significant	O
difference	O
in	O
hybridization	O
between	O
infective	O
L3	O
cDNA	O
and	O
cDNAs	O
from	O
all	O
other	O
stages	O
or	O
sexes	O
of	O
A	B
.	I
suum	I
,	O
of	O
which	O
515	O
had	O
a	O
>	O
2	O
.	O
0	O
-	O
fold	O
increased	O
hybridization	O
for	O
the	O
L3	O
.	O

In	O
order	O
to	O
independently	O
verify	O
the	O
hybridization	O
results	O
in	O
the	O
microarray	O
,	O
a	O
PCR	O
-	O
based	O
analysis	O
of	O
a	O
selected	O
subset	O
(	O
n	O
=	O
17	O
)	O
clones	O
was	O
conducted	O
using	O
specific	O
primer	O
pairs	O
.	O

Having	O
verified	O
the	O
specificity	O
and	O
identity	O
of	O
individual	O
amplicons	O
by	O
sequencing	O
,	O
PCR	O
results	O
were	O
reproducible	O
(	O
based	O
on	O
multiple	O
runs	O
on	O
different	O
days	O
)	O
and	O
~	O
94	O
%	O
(	O
16	O
of	O
17	O
)	O
concordant	O
with	O
those	O
of	O
the	O
microarray	O
analysis	O
(	O
not	O
shown	O
)	O
.	O

There	O
was	O
complete	O
concordance	O
for	O
representative	O
clones	O
associated	O
with	O
a	O
differential	O
signal	O
of	O
>	O
=	O
3	O
.	O
0	O
-	O
fold	O
in	O
the	O
microarray	O
.	O

The	O
clones	O
linked	O
to	O
the	O
515	O
spots	O
representing	O
increased	O
transcription	O
(	O
>	O
2	O
.	O
0	O
-	O
fold	O
)	O
in	O
infective	O
L3	O
compared	O
with	O
the	O
other	O
developmental	O
stages	O
or	O
sexes	O
included	O
were	O
subjected	O
to	O
sequencing	O
.	O

The	O
498	O
sequences	O
(	O
length	O
:	O
550	O
+	O
/	O
-	O
115	O
bp	O
)	O
determined	O
were	O
then	O
subjected	O
to	O
detailed	O
bioinformatic	O
analyses	O
.	O

There	O
were	O
91	O
unique	O
clusters	O
(	O
accession	O
numbers	O
ES290984	O
-	O
ES291074	O
)	O
,	O
of	O
which	O
55	O
were	O
singletons	O
(	O
sequences	O
determined	O
once	O
)	O
.	O

Of	O
56	O
molecules	O
(	O
61	O
.	O
5	O
%	O
)	O
with	O
significant	O
similarity	O
to	O
sequences	O
other	O
than	O
A	B
.	I
suum	I
in	O
the	O
databases	O
interrogated	O
,	O
50	O
(	O
54	O
.	O
9	O
%	O
)	O
had	O
C	B
.	I
elegans	I
or	O
C	B
.	I
briggsae	I
homologues	O
,	O
and	O
six	O
had	O
similarity	O
to	O
ESTs	O
already	O
sequenced	O
from	O
ascaridoid	O
and	O
/	O
or	O
other	O
parasitic	O
nematodes	O
,	O
and	O
/	O
or	O
other	O
organisms	O
(	O
Table	O
1	O
)	O
.	O

A	O
significant	O
proportion	O
(	O
38	O
.	O
4	O
%	O
)	O
did	O
not	O
have	O
any	O
similarity	O
in	O
sequence	O
to	O
any	O
organisms	O
for	O
which	O
data	O
are	O
presently	O
available	O
.	O

Comparative	O
analysis	O
specifically	O
against	O
A	B
.	I
suum	I
EST	O
data	O
sets	O
(	O
n	O
~	O
42	O
,	O
000	O
)	O
available	O
in	O
public	O
databases	O
confirmed	O
independently	O
that	O
the	O
majority	O
of	O
molecules	O
(	O
>	O
60	O
%	O
)	O
were	O
present	O
exclusively	O
in	O
the	O
infective	O
L3	O
stage	O
or	O
were	O
orphans	O
.	O

As	O
gene	O
ontology	O
(	O
GO	O
)	O
provides	O
a	O
hierarchy	O
that	O
unifies	O
the	O
descriptions	O
of	O
biological	O
,	O
cellular	O
and	O
molecular	O
functions	O
[	O
54	O
]	O
,	O
this	O
approach	O
was	O
employed	O
to	O
predict	O
the	O
classification	O
and	O
gene	O
function	O
of	O
molecules	O
enriched	O
in	O
infective	O
L3	O
of	O
A	B
.	I
suum	I
.	O

A	O
summary	O
of	O
the	O
GO	O
categories	O
of	O
these	O
molecules	O
is	O
displayed	O
in	O
Fig	O
.	O

1	O
.	O

Of	O
the	O
91	O
contigs	O
,	O
32	O
(	O
35	O
%	O
)	O
could	O
be	O
functionally	O
assigned	O
to	O
'	O
biological	O
process	O
'	O
(	O
n	O
=	O
38	O
)	O
,	O
'	O
cellular	O
component	O
'	O
(	O
n	O
=	O
17	O
)	O
and	O
'	O
molecular	O
function	O
'	O
(	O
n	O
=	O
64	O
)	O
.	O

The	O
most	O
common	O
subcategories	O
were	O
gluconeogenesis	O
(	O
13	O
%	O
)	O
and	O
metabolic	O
process	O
(	O
13	O
%	O
)	O
within	O
'	O
biological	O
process	O
'	O
,	O
extracellular	O
region	O
(	O
24	O
%	O
)	O
within	O
'	O
cellular	O
component	O
'	O
,	O
and	O
catalytic	O
activity	O
(	O
11	O
%	O
)	O
and	O
phosphoenolpyruvate	O
carboxykinase	O
activity	O
(	O
8	O
%	O
)	O
within	O
'	O
molecular	O
function	O
'	O
(	O
Table	O
S1	O
)	O
.	O

A	O
focused	O
KOBAS	O
analysis	O
inferred	O
the	O
50	O
C	B
.	I
elegans	I
orthologues	O
/	O
homologues	O
to	O
be	O
involved	O
in	O
apoptosis	O
and	O
insulin	O
signaling	O
(	O
2	O
%	O
)	O
,	O
ATP	O
synthesis	O
(	O
2	O
%	O
)	O
,	O
carbon	O
metabolism	O
(	O
6	O
%	O
)	O
,	O
fatty	O
acid	O
biosynthesis	O
(	O
2	O
%	O
)	O
,	O
gap	O
junction	O
(	O
2	O
%	O
)	O
,	O
glucose	O
metabolism	O
(	O
6	O
%	O
)	O
or	O
porphyrin	O
metabolism	O
(	O
2	O
%	O
)	O
,	O
although	O
34	O
(	O
68	O
%	O
)	O
of	O
them	O
could	O
not	O
be	O
mapped	O
to	O
a	O
specific	O
metabolic	O
pathway	O
(	O
Table	O
2	O
)	O
.	O

Of	O
these	O
50	O
molecules	O
,	O
small	O
numbers	O
were	O
predicted	O
to	O
be	O
secreted	O
(	O
10	O
%	O
)	O
,	O
anchored	O
(	O
2	O
%	O
)	O
and	O
/	O
or	O
transmembrane	O
(	O
12	O
%	O
)	O
proteins	O
(	O
Table	O
2	O
)	O
.	O

Functionally	O
,	O
17	O
(	O
34	O
%	O
)	O
of	O
the	O
50	O
molecules	O
were	O
associated	O
with	O
(	O
non	O
-	O
wild	O
-	O
type	O
)	O
RNAi	O
phenotypes	O
in	O
C	B
.	I
elegans	I
,	O
the	O
majority	O
displaying	O
embryonic	O
lethality	O
(	O
Emb	O
)	O
(	O
13	O
types	O
;	O
58	O
.	O
8	O
%	O
)	O
,	O
larval	O
arrest	O
(	O
Lva	O
)	O
(	O
23	O
.	O
5	O
%	O
)	O
and	O
larval	O
lethality	O
(	O
Lvl	O
)	O
(	O
47	O
%	O
)	O
(	O
Table	O
2	O
)	O
.	O

Extending	O
this	O
analysis	O
,	O
a	O
relatively	O
complex	O
genetic	O
interaction	O
network	O
was	O
predicted	O
for	O
the	O
17	O
C	B
.	I
elegans	I
orthologues	O
(	O
i	O
.	O
e	O
.	O
,	O
with	O
non	O
-	O
wild	O
-	O
type	O
RNAi	O
phenotypes	O
)	O
(	O
see	O
Table	O
S2	O
)	O
.	O

Statistically	O
highly	O
significant	O
interactions	O
were	O
predicted	O
for	O
nine	O
of	O
the	O
C	B
.	I
elegans	I
genes	O
;	O
the	O
top	O
five	O
interactors	O
are	O
displayed	O
in	O
Fig	O
.	O

2	O
.	O

The	O
gene	O
ontology	O
categories	O
for	O
eight	O
selected	O
C	B
.	I
elegans	I
genes	O
(	O
F33D11	O
.	O
10	O
,	O
F55A12	O
.	O
8	O
,	O
kin	O
-	O
2	O
,	O
mec	O
-	O
12	O
,	O
mup	O
-	O
2	O
,	O
pab	O
-	O
1	O
,	O
rpl	O
-	O
22	O
and	O
T21B10	O
.	O
2	O
)	O
included	O
:	O
embryonic	O
development	O
,	O
egg	O
hatching	O
,	O
larval	O
development	O
and	O
/	O
or	O
growth	O
.	O

The	O
other	O
categories	O
included	O
:	O
positive	O
regulation	O
of	O
growth	O
rate	O
(	O
F55A12	O
.	O
8	O
,	O
kin	O
-	O
2	O
,	O
mup	O
-	O
2	O
,	O
pab	O
-	O
1	O
,	O
rpl	O
-	O
22	O
and	O
T21B10	O
.	O
2	O
)	O
and	O
gamete	O
generation	O
and	O
locomotory	O
behaviour	O
(	O
kin	O
-	O
2	O
,	O
mup	O
-	O
2	O
,	O
pab	O
-	O
1	O
and	O
F55A12	O
.	O
8	O
,	O
kin	O
-	O
2	O
,	O
mup	O
-	O
2	O
,	O
respectively	O
)	O
.	O

The	O
C	B
.	I
elegans	I
homologue	O
egl	O
-	O
3	O
was	O
predicted	O
to	O
be	O
involved	O
in	O
proteolysis	O
(	O
see	O
www	O
.	O
wormbase	O
.	O
org	O
)	O
.	O

All	O
nine	O
C	B
.	I
elegans	I
orthologues	O
were	O
predicted	O
to	O
interact	O
directly	O
with	O
a	O
total	O
of	O
296	O
(	O
range	O
:	O
5	O
-	O
75	O
)	O
other	O
genes	O
and	O
,	O
in	O
particular	O
,	O
a	O
direct	O
genetic	O
interaction	O
was	O
predicted	O
between	O
pab	O
-	O
1	O
and	O
T21B10	O
.	O
2	O
(	O
Fig	O
.	O
2	O
)	O
.	O

The	O
296	O
interactors	O
were	O
associated	O
with	O
embryonic	O
and	O
larval	O
development	O
(	O
n	O
=	O
198	O
;	O
66	O
.	O
9	O
%	O
)	O
,	O
information	O
storage	O
and	O
processing	O
(	O
n	O
=	O
15	O
;	O
5	O
.	O
1	O
%	O
)	O
,	O
cellular	O
processes	O
and	O
signalling	O
(	O
n	O
=	O
45	O
;	O
15	O
.	O
2	O
%	O
)	O
and	O
metabolism	O
(	O
n	O
=	O
18	O
;	O
6	O
.	O
1	O
%	O
)	O
;	O
the	O
precise	O
function	O
of	O
some	O
of	O
the	O
interactors	O
(	O
n	O
=	O
20	O
;	O
6	O
.	O
7	O
%	O
)	O
is	O
presently	O
unknown	O
(	O
Table	O
S2	O
)	O
.	O

Discussion	O

The	O
present	O
study	O
investigated	O
transcripts	O
in	O
infective	O
L3s	O
of	O
A	B
.	I
suum	I
using	O
a	O
genomic	O
-	O
bioinformatic	O
platform	O
.	O

The	O
focus	O
was	O
on	O
comparisons	O
with	O
C	B
.	I
elegans	I
homologues	O
/	O
orthologues	O
,	O
because	O
the	O
entire	O
genome	O
sequence	O
of	O
this	O
nematode	O
is	O
known	O
[	O
9	O
]	O
and	O
because	O
there	O
is	O
a	O
wealth	O
of	O
information	O
on	O
the	O
localization	O
and	O
functionality	O
of	O
its	O
molecules	O
(	O
www	O
.	O
wormbase	O
.	O
org	O
;	O
http	O
:	O
/	O
/	O
elegans	O
.	O
bcgsc	O
.	O
bc	O
.	O
ca	O
/	O
knockout	O
.	O
shtml	O
)	O
.	O

The	O
functions	O
of	O
most	O
genes	O
in	O
C	B
.	I
elegans	I
have	O
been	O
assessed	O
using	O
RNAi	O
(	O
e	O
.	O
g	O
.	O
,	O
[	O
14	O
]	O
,	O
[	O
15	O
]	O
,	O
[	O
17	O
]	O
,	O
[	O
55	O
]	O
,	O
[	O
56	O
]	O
)	O
in	O
the	O
hermaphroditic	O
stage	O
,	O
whereas	O
there	O
is	O
a	O
paucity	O
of	O
functional	O
information	O
available	O
for	O
Ascaris	O
and	O
other	O
parasitic	O
nematodes	O
of	O
animals	O
[	O
57	O
]	O
,	O
[	O
58	O
]	O
.	O

Following	O
the	O
microarray	O
analysis	O
of	O
>	O
2500	O
ESTs	O
from	O
the	O
SSH	O
library	O
,	O
498	O
cDNAs	O
inferred	O
to	O
be	O
enriched	O
in	O
the	O
L3	O
,	O
based	O
on	O
hybridization	O
signal	O
,	O
were	O
sequenced	O
and	O
subjected	O
to	O
comprehensive	O
in	O
silico	O
analyses	O
.	O

Of	O
the	O
91	O
clusters	O
of	O
molecules	O
categorized	O
,	O
50	O
(	O
54	O
.	O
9	O
%	O
)	O
had	O
C	B
.	I
elegans	I
homologues	O
/	O
orthologues	O
with	O
loss	O
-	O
of	O
-	O
function	O
phenotypes	O
could	O
be	O
mapped	O
to	O
key	O
pathways	O
.	O

The	O
statistically	O
significant	O
genetic	O
interactions	O
predicted	O
for	O
9	O
of	O
the	O
50	O
C	B
.	I
elegans	I
orthologues	O
[	O
namely	O
egl	O
-	O
3	O
,	O
F33D11	O
.	O
10	O
,	O
F55A12	O
.	O
8	O
,	O
kin	O
-	O
2	O
,	O
mec	O
-	O
12	O
,	O
mup	O
-	O
2	O
,	O
pab	O
-	O
1	O
,	O
rpl	O
-	O
22	O
and	O
T21B10	O
.	O
2	O
(	O
=	O
enol	O
-	O
1	O
)	O
]	O
and	O
the	O
interaction	O
network	O
included	O
genes	O
encoding	O
kinases	O
,	O
alpha	O
-	O
tubulins	O
,	O
enolases	O
,	O
troponin	O
and	O
other	O
named	O
and	O
unnamed	O
proteins	O
.	O

Eight	O
of	O
these	O
molecules	O
(	O
enol	O
-	O
1	O
,	O
pab	O
-	O
1	O
,	O
F33D11	O
.	O
10	O
,	O
rpl	O
-	O
22	O
,	O
F55A12	O
.	O
8	O
mec	O
-	O
12	O
,	O
mup	O
-	O
2	O
and	O
kin	O
-	O
2	O
)	O
have	O
known	O
or	O
predicted	O
roles	O
in	O
embryonic	O
and	O
larval	O
growth	O
and	O
development	O
,	O
gamete	O
generation	O
,	O
locomotory	O
behaviour	O
or	O
other	O
biological	O
processes	O
in	O
C	B
.	I
elegans	I
(	O
see	O
www	O
.	O
wormbase	O
.	O
org	O
)	O
.	O

The	O
enolase	O
encoded	O
by	O
enol	O
-	O
1	O
is	O
predicted	O
to	O
play	O
a	O
role	O
in	O
glycolysis	O
,	O
gluconeogenesis	O
,	O
phenylalanine	O
,	O
tyrosine	O
and	O
tryptophan	O
biosynthesis	O
(	O
cf	O
.	O
[	O
59	O
]	O
)	O
.	O

Since	O
glucose	O
is	O
the	O
main	O
source	O
for	O
ATP	O
production	O
,	O
the	O
alteration	O
in	O
these	O
key	O
glycolytic	O
enzymes	O
may	O
lead	O
to	O
cellular	O
dysfunction	O
,	O
such	O
as	O
impaired	O
ion	O
-	O
motive	O
ATPase	O
required	O
to	O
maintain	O
potential	O
gradients	O
,	O
operate	O
pumps	O
and	O
maintain	O
membrane	O
lipid	O
asymmetry	O
[	O
60	O
]	O
.	O

Bioinformatic	O
analysis	O
for	O
transmembrane	O
helices	O
(	O
TMHMM	O
)	O
and	O
peptide	O
signal	O
sequences	O
(	O
SignalP	O
)	O
predicted	O
ENOL	O
-	O
1	O
to	O
be	O
a	O
non	O
-	O
secreted	O
protein	O
localized	O
to	O
the	O
cytoplasm	O
(	O
cf	O
.	O
Table	O
2	O
)	O
.	O

Nonetheless	O
,	O
enolases	O
are	O
often	O
detected	O
in	O
the	O
excretory	O
/	O
secretory	O
(	O
ES	O
)	O
products	O
of	O
parasitic	O
helminths	O
,	O
including	O
adult	O
A	B
.	I
suum	I
[	O
61	O
]	O
,	O
and	O
appear	O
to	O
play	O
a	O
role	O
in	O
the	O
triggering	O
of	O
nitric	O
oxide	O
production	O
by	O
host	O
cells	O
.	O

The	O
enol	O
-	O
1	O
orthologue	O
of	O
C	B
.	I
elegans	I
has	O
been	O
predicted	O
to	O
interact	O
specifically	O
with	O
the	O
polyadenylate	O
binding	O
protein	O
gene	O
,	O
pab	O
-	O
1	O
,	O
inferred	O
to	O
be	O
involved	O
in	O
coordinated	O
gene	O
transcription	O
and	O
expression	O
during	O
normal	O
larval	O
development	O
[	O
16	O
]	O
.	O

Poly	O
(	O
A	O
)	O
-	O
binding	O
proteins	O
(	O
PABPs	O
)	O
are	O
recognized	O
to	O
be	O
central	O
to	O
the	O
regulation	O
of	O
mRNA	O
translation	O
and	O
stability	O
[	O
62	O
]	O
.	O

Present	O
evidence	O
suggests	O
that	O
the	O
expression	O
of	O
PAB	O
-	O
1	O
is	O
regulated	O
by	O
an	O
oligo	O
-	O
pyrimidine	O
tract	O
in	O
response	O
to	O
cell	O
growth	O
and	O
relates	O
to	O
coordinated	O
growth	O
regulation	O
in	O
C	B
.	I
elegans	I
[	O
62	O
]	O
.	O

Furthermore	O
,	O
gene	O
silencing	O
of	O
pab	O
-	O
1	O
and	O
its	O
selected	O
interactors	O
(	O
see	O
Fig	O
.	O
2	O
)	O
leads	O
to	O
embryonic	O
lethal	O
(	O
Emb	O
)	O
,	O
slow	O
growth	O
(	O
Slo	O
)	O
and	O
sterile	O
progeny	O
(	O
Stp	O
)	O
phenotypes	O
(	O
see	O
www	O
.	O
wormbase	O
.	O
org	O
)	O
.	O

Another	O
gene	O
(	O
F33D11	O
.	O
10	O
;	O
EST	O
code	O
4F10	O
;	O
see	O
Table	O
2	O
)	O
which	O
encodes	O
an	O
ATP	O
-	O
dependent	O
RNA	O
helicase	O
and	O
is	O
associated	O
with	O
embryonic	O
lethal	O
(	O
Emb	O
)	O
and	O
larval	O
lethal	O
(	O
Lvl	O
)	O
RNAi	O
phenotypes	O
,	O
was	O
shown	O
to	O
be	O
highly	O
transcribed	O
in	O
infective	O
L3s	O
of	O
A	B
.	I
suum	I
.	O

Helicases	O
are	O
involved	O
in	O
a	O
variety	O
of	O
RNA	O
metabolic	O
processes	O
,	O
including	O
translation	O
initiation	O
,	O
pre	O
-	O
mRNA	O
splicing	O
,	O
pre	O
-	O
rRNA	O
processing	O
,	O
rRNA	O
maturation	O
and	O
RNA	O
degradation	O
[	O
63	O
]	O
,	O
and	O
are	O
crucial	O
for	O
life	O
cycle	O
progression	O
,	O
sex	O
determination	O
and	O
early	O
embryogenesis	O
in	O
C	B
.	I
elegans	I
[	O
60	O
]	O
.	O

The	O
high	O
transcription	O
levels	O
of	O
a	O
homologue	O
/	O
orthologue	O
in	O
the	O
L3	O
of	O
A	B
.	I
suum	I
might	O
suggest	O
a	O
similar	O
role	O
in	O
this	O
ascaridoid	O
.	O

Similarly	O
,	O
the	O
coordination	O
of	O
the	O
expression	O
of	O
a	O
large	O
number	O
of	O
genes	O
is	O
required	O
for	O
normal	O
growth	O
and	O
cell	O
proliferation	O
during	O
larval	O
development	O
.	O

The	O
high	O
transcription	O
level	O
for	O
the	O
ribosomal	O
protein	O
gene	O
homologue	O
rpl	O
-	O
22	O
(	O
large	O
subunit	O
family	O
member	O
;	O
EST	O
code	O
26G12	O
,	O
see	O
Table	O
2	O
)	O
in	O
the	O
infective	O
L3	O
of	O
A	B
.	I
suum	I
compared	O
with	O
other	O
developmental	O
stages	O
is	O
likely	O
to	O
reflect	O
the	O
substantial	O
rate	O
of	O
cell	O
growth	O
in	O
this	O
stage	O
[	O
64	O
]	O
.	O

The	O
gene	O
(	O
F55A12	O
.	O
8	O
,	O
EST	O
code	O
4G11	O
;	O
see	O
Table	O
2	O
)	O
encoding	O
an	O
acetyl	O
-	O
transferase	O
with	O
a	O
putative	O
ATPase	O
domain	O
,	O
shown	O
to	O
be	O
enriched	O
in	O
the	O
L3	O
of	O
A	B
.	I
suum	I
,	O
was	O
predicted	O
to	O
interact	O
with	O
75	O
other	O
genes	O
all	O
involved	O
in	O
energy	O
production	O
and	O
/	O
or	O
RNA	O
processing	O
(	O
see	O
Table	O
S2	O
)	O
.	O

Several	O
molecules	O
involved	O
in	O
ATP	O
synthesis	O
and	O
mitochondrial	O
pathways	O
(	O
e	O
.	O
g	O
.	O
,	O
cytochrome	O
oxidase	O
c	O
subunits	O
1	O
,	O
2	O
and	O
3	O
,	O
ADP	O
/	O
ATP	O
translocases	O
,	O
NADH	O
dehydrogenases	O
,	O
ATPases	O
and	O
ATP	O
synthetases	O
)	O
have	O
been	O
reported	O
previously	O
to	O
be	O
highly	O
represented	O
in	O
the	O
L3	O
stage	O
of	O
Anisakis	B
simplex	I
[	O
65	O
]	O
,	O
thus	O
supporting	O
the	O
proposal	O
that	O
substantial	O
energy	O
is	O
required	O
for	O
larval	O
development	O
as	O
well	O
as	O
the	O
transition	O
from	O
the	O
free	O
-	O
living	O
to	O
the	O
parasitic	O
stage	O
and	O
the	O
invasion	O
of	O
the	O
host	O
.	O

There	O
is	O
also	O
likely	O
to	O
be	O
a	O
substantial	O
energy	O
requirement	O
for	O
muscle	O
contraction	O
linked	O
to	O
larval	O
motility	O
in	O
A	B
.	I
suum	I
,	O
as	O
the	O
L3s	O
penetrate	O
the	O
caecal	O
wall	O
in	O
the	O
porcine	O
host	O
,	O
before	O
undergoing	O
hepato	O
-	O
pulmonary	O
migration	O
[	O
35	O
]	O
.	O

Accordingly	O
,	O
genes	O
encoding	O
a	O
specialized	O
tubulin	O
expressed	O
in	O
mechanoreceptors	O
(	O
mec	O
-	O
12	O
,	O
EST	O
code	O
13E09	O
)	O
and	O
a	O
troponin	O
(	O
mup	O
-	O
2	O
,	O
EST	O
code	O
01G03	O
;	O
see	O
Table	O
2	O
)	O
,	O
both	O
predicted	O
to	O
interact	O
with	O
a	O
total	O
number	O
of	O
32	O
tubulin	O
-	O
and	O
myosin	O
-	O
encoding	O
genes	O
,	O
also	O
supported	O
a	O
link	O
to	O
extensive	O
muscle	O
contraction	O
and	O
motility	O
in	O
A	B
.	I
suum	I
L3s	O
.	O

Also	O
,	O
neuroactive	O
peptides	O
are	O
required	O
to	O
regulate	O
the	O
responsiveness	O
of	O
nematode	O
larvae	O
to	O
mechanical	O
stimuli	O
[	O
66	O
]	O
.	O

A	O
homologue	O
encoded	O
by	O
egl	O
-	O
3	O
was	O
shown	O
to	O
be	O
highly	O
transcribed	O
in	O
the	O
L3	O
of	O
A	B
.	I
suum	I
;	O
EGL	O
-	O
3	O
is	O
predicted	O
to	O
be	O
a	O
pro	O
-	O
hormone	O
convertase	O
involved	O
in	O
the	O
maturation	O
of	O
neuropeptides	O
and	O
could	O
be	O
associated	O
with	O
mechano	O
-	O
sensory	O
responses	O
and	O
touch	O
sensitivity	O
linked	O
to	O
the	O
host	O
invasion	O
.	O

A	O
regulatory	O
subunit	O
of	O
a	O
cAMP	O
-	O
dependent	O
protein	O
kinase	O
(	O
kin	O
-	O
2	O
,	O
EST	O
code	O
22H01	O
;	O
see	O
Table	O
2	O
)	O
was	O
predicted	O
to	O
interact	O
with	O
72	O
other	O
genes	O
all	O
involved	O
in	O
diverse	O
cellular	O
processes	O
,	O
such	O
as	O
nuclear	O
trafficking	O
,	O
and	O
DNA	O
replication	O
and	O
repair	O
(	O
see	O
Table	O
S2	O
)	O
.	O

Based	O
on	O
gene	O
ontology	O
terms	O
,	O
kin	O
-	O
2	O
is	O
implicated	O
in	O
gamete	O
generation	O
,	O
growth	O
,	O
larval	O
development	O
,	O
post	O
-	O
embryonic	O
body	O
morphogenesis	O
,	O
signal	O
transduction	O
and	O
/	O
or	O
protein	O
amino	O
acid	O
phosphorylation	O
(	O
see	O
Table	O
S2	O
)	O
.	O

Gene	O
silencing	O
of	O
kin	O
-	O
2	O
in	O
C	B
.	I
elegans	I
leads	O
to	O
phenotypes	O
,	O
such	O
as	O
larval	O
lethal	O
(	O
Lvl	O
)	O
,	O
larval	O
arrest	O
(	O
Lva	O
)	O
,	O
body	O
morphology	O
defect	O
(	O
Bmd	O
)	O
,	O
dumpy	O
(	O
Dpy	O
)	O
,	O
uncoordinated	O
(	O
Unc	O
)	O
and	O
sterile	O
progeny	O
(	O
Stp	O
)	O
(	O
www	O
.	O
wormbase	O
.	O
org	O
)	O
,	O
suggesting	O
that	O
its	O
homologue	O
in	O
A	B
.	I
suum	I
is	O
central	O
to	O
larval	O
maturation	O
.	O

The	O
KOBAS	O
analysis	O
predicted	O
the	O
protein	O
KIN	O
-	O
2	O
to	O
be	O
involved	O
in	O
the	O
insulin	O
-	O
signaling	O
pathway	O
,	O
previously	O
implicated	O
in	O
controlling	O
the	O
exit	O
from	O
dauer	O
in	O
C	B
.	I
elegans	I
and	O
the	O
activation	O
of	O
L3s	O
of	O
the	O
canine	B
hookworm	I
,	O
Ancylostoma	B
caninum	I
,	O
following	O
exsheathment	O
[	O
67	O
]	O
.	O

In	O
a	O
recent	O
study	O
,	O
Brand	O
and	O
Hawdon	O
[	O
68	O
]	O
were	O
able	O
to	O
inhibit	O
(	O
with	O
a	O
phosphoinositide	O
-	O
3	O
-	O
OH	O
-	O
kinase	O
inhibitor	O
)	O
the	O
activation	O
of	O
infective	O
L3s	O
of	O
both	O
of	O
the	O
hookworms	O
Ancylostoma	B
caninum	I
and	O
Ancylostoma	B
ceylanicum	I
via	O
the	O
insulin	O
signaling	O
pathway	O
,	O
thus	O
lending	O
some	O
credence	O
to	O
the	O
hypothesis	O
that	O
this	O
pathway	O
plays	O
an	O
critical	O
role	O
in	O
regulating	O
the	O
transition	O
from	O
the	O
free	O
-	O
living	O
to	O
the	O
parasitic	O
stage	O
[	O
68	O
]	O
.	O

Recently	O
,	O
it	O
has	O
been	O
proposed	O
that	O
transcriptional	O
and	O
feeding	O
responses	O
to	O
serum	O
-	O
stimulation	O
in	O
Ancylostoma	B
caninum	I
are	O
regulated	O
by	O
parallel	O
systems	O
,	O
with	O
the	O
insulin	O
signaling	O
pathway	O
playing	O
a	O
significant	O
role	O
in	O
the	O
'	O
resumption	O
of	O
feeding	O
'	O
in	O
activated	O
larvae	O
[	O
69	O
]	O
.	O

Protein	O
kinases	O
are	O
also	O
likely	O
to	O
be	O
involved	O
in	O
pathways	O
linked	O
to	O
sexual	O
maturation	O
in	O
developing	O
larvae	O
.	O

As	O
already	O
proposed	O
for	O
adult	O
stages	O
of	O
H	B
.	I
contortus	I
[	O
45	O
]	O
,	O
the	O
protein	O
kinase	O
gene	O
cdk	O
-	O
1	O
is	O
predicted	O
to	O
play	O
a	O
pivotal	O
role	O
in	O
the	O
germline	O
,	O
oogenesis	O
and	O
spermiogenesis	O
pathways	O
of	O
this	O
parasitic	O
nematode	O
.	O

Other	O
protein	O
kinases	O
,	O
such	O
as	O
PEPCK	O
,	O
and	O
phosphatases	O
,	O
were	O
shown	O
herein	O
to	O
be	O
transcribed	O
at	O
high	O
levels	O
in	O
the	O
L3	O
stage	O
compared	O
with	O
other	O
developmental	O
stages	O
of	O
A	B
.	I
suum	I
(	O
see	O
Table	O
2	O
)	O
,	O
which	O
is	O
in	O
accordance	O
to	O
findings	O
reported	O
recently	O
for	O
Anisakis	B
simplex	I
[	O
65	O
]	O
.	O

Due	O
to	O
their	O
major	O
regulatory	O
effects	O
in	O
eukaryotic	O
signaling	O
events	O
and	O
regulatory	O
and	O
sensory	O
functions	O
,	O
protein	O
kinases	O
have	O
been	O
considered	O
interesting	O
targets	O
for	O
anti	O
-	O
parasitic	O
drugs	O
[	O
70	O
]	O
.	O

In	O
conclusion	O
,	O
this	O
study	O
has	O
given	O
some	O
interesting	O
insights	O
into	O
early	O
molecular	O
processes	O
in	O
the	O
L3	O
of	O
A	B
.	I
suum	I
.	O

Approximately	O
60	O
%	O
of	O
the	O
transcripts	O
enriched	O
in	O
the	O
L3	O
stage	O
of	O
A	B
.	I
suum	I
have	O
homologues	O
/	O
orthologues	O
in	O
C	B
.	I
elegans	I
.	O

The	O
bioinformatic	O
analyses	O
of	O
selected	O
molecules	O
suggest	O
that	O
a	O
complex	O
genetic	O
network	O
regulates	O
or	O
controls	O
larval	O
growth	O
and	O
development	O
in	O
A	B
.	I
suum	I
L3s	O
,	O
and	O
some	O
of	O
these	O
might	O
be	O
involved	O
in	O
or	O
regulate	O
the	O
switch	O
from	O
the	O
free	O
-	O
living	O
to	O
the	O
parasitic	O
stage	O
.	O

Some	O
caution	O
is	O
warranted	O
in	O
drawing	O
conclusions	O
regarding	O
molecular	O
mechanisms	O
regulating	O
the	O
transition	O
to	O
parasitism	O
in	O
parasitic	O
nematodes	O
from	O
information	O
on	O
C	B
.	I
elegans	I
,	O
as	O
latter	O
is	O
a	O
free	O
-	O
living	O
nematode	O
.	O

Also	O
,	O
while	O
the	O
method	O
of	O
data	O
integration	O
is	O
essential	O
for	O
the	O
reliable	O
prediction	O
of	O
genetic	O
interactions	O
,	O
it	O
might	O
limit	O
the	O
capacity	O
of	O
the	O
approach	O
somewhat	O
to	O
infer	O
nematode	O
-	O
specific	O
interactions	O
.	O

As	O
additional	O
datasets	O
of	O
genes	O
and	O
gene	O
functions	O
become	O
available	O
for	O
various	O
parasitic	O
nematodes	O
,	O
more	O
informed	O
inferences	O
can	O
be	O
made	O
regarding	O
the	O
functions	O
of	O
nematode	O
-	O
specific	O
genes	O
,	O
particularly	O
those	O
involved	O
in	O
the	O
transition	O
to	O
parasitism	O
.	O

The	O
imminent	O
genome	O
sequence	O
of	O
A	B
.	I
suum	I
(	O
http	O
:	O
/	O
/	O
www	O
.	O
sanger	O
.	O
ac	O
.	O
uk	O
/	O
Projects	O
/	O
Helminths	O
/	O
)	O
should	O
all	O
assist	O
in	O
this	O
endeavour	O
.	O

Also	O
,	O
functional	O
analysis	O
of	O
selected	O
molecules	O
representing	O
selected	O
ESTs	O
identified	O
herein	O
,	O
utilizing	O
gene	O
silencing	O
approaches	O
established	O
recently	O
[	O
33	O
]	O
,	O
[	O
34	O
]	O
,	O
could	O
provide	O
some	O
insights	O
into	O
developmental	O
processes	O
in	O
Ascaris	O
and	O
related	O
ascaridoid	O
nematodes	O
and	O
provide	O
avenues	O
for	O
the	O
development	O
of	O
novel	O
approaches	O
for	O
their	O
control	O
.	O

Supporting	O
Information	O

Minocycline	O
attenuates	O
lipopolysaccharide	O
(	O
LPS	O
)	O
-	O
induced	O
neuroinflammation	O
,	O
sickness	O
behavior	O
,	O
and	O
anhedonia	O

Abstract	O

Background	O

Activation	O
of	O
the	O
peripheral	O
innate	O
immune	O
system	O
stimulates	O
the	O
secretion	O
of	O
CNS	O
cytokines	O
that	O
modulate	O
the	O
behavioral	O
symptoms	O
of	O
sickness	O
.	O

Excessive	O
production	O
of	O
cytokines	O
by	O
microglia	O
,	O
however	O
,	O
may	O
cause	O
long	O
-	O
lasting	O
behavioral	O
and	O
cognitive	O
complications	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
determine	O
if	O
minocycline	O
,	O
an	O
anti	O
-	O
inflammatory	O
agent	O
and	O
purported	O
microglial	O
inhibitor	O
,	O
attenuates	O
lipopolysaccharide	O
(	O
LPS	O
)	O
-	O
induced	O
neuroinflammation	O
,	O
sickness	O
behavior	O
,	O
and	O
anhedonia	O
.	O

Methods	O

In	O
the	O
first	O
set	O
of	O
experiments	O
the	O
effect	O
of	O
minocycline	O
pretreatment	O
on	O
LPS	O
-	O
induced	O
microglia	O
activation	O
was	O
assessed	O
in	O
BV	O
-	O
2	O
microglia	O
cell	O
cultures	O
.	O

In	O
the	O
second	O
study	O
,	O
adult	O
(	O
3	O
-	O
6	O
m	O
)	O
BALB	O
/	O
c	O
mice	B
received	O
an	O
intraperitoneal	O
(	O
i	O
.	O
p	O
.	O
)	O
injection	O
of	O
vehicle	O
or	O
minocycline	O
(	O
50	O
mg	O
/	O
kg	O
)	O
for	O
three	O
consecutive	O
days	O
.	O

On	O
the	O
third	O
day	O
,	O
mice	B
were	O
also	O
injected	O
(	O
i	O
.	O
p	O
.	O
)	O
with	O
saline	O
or	O
Escherichia	B
coli	I
LPS	O
(	O
0	O
.	O
33	O
mg	O
/	O
kg	O
)	O
and	O
behavior	O
(	O
i	O
.	O
e	O
.	O
,	O
sickness	O
and	O
anhedonia	O
)	O
and	O
markers	O
of	O
neuroinflammation	O
(	O
i	O
.	O
e	O
.	O
,	O
microglia	O
activation	O
and	O
inflammatory	O
cytokines	O
)	O
were	O
determined	O
.	O

In	O
the	O
final	O
study	O
,	O
adult	O
and	O
aged	O
BALB	O
/	O
c	O
mice	B
were	O
treated	O
with	O
the	O
same	O
minocycline	O
and	O
LPS	O
injection	O
regimen	O
and	O
markers	O
of	O
neuroinflammation	O
were	O
determined	O
.	O

All	O
data	O
were	O
analyzed	O
using	O
Statistical	O
Analysis	O
Systems	O
General	O
Linear	O
Model	O
procedures	O
and	O
were	O
subjected	O
to	O
one	O
-	O
,	O
two	O
-	O
,	O
or	O
three	O
-	O
way	O
ANOVA	O
to	O
determine	O
significant	O
main	O
effects	O
and	O
interactions	O
.	O

Results	O

Minocycline	O
blocked	O
LPS	O
-	O
stimulated	O
inflammatory	O
cytokine	O
secretion	O
in	O
the	O
BV	O
-	O
2	O
microglia	O
-	O
derived	O
cell	O
line	O
and	O
reduced	O
LPS	O
-	O
induced	O
Toll	O
-	O
like	O
-	O
receptor	O
-	O
2	O
(	O
TLR2	O
)	O
surface	O
expression	O
on	O
brain	O
microglia	O
.	O

Moreover	O
,	O
minocycline	O
facilitated	O
the	O
recovery	O
from	O
sickness	O
behavior	O
(	O
i	O
.	O
e	O
.	O
,	O
anorexia	O
,	O
weight	O
loss	O
,	O
and	O
social	O
withdrawal	O
)	O
and	O
prevented	O
anhedonia	O
in	O
adult	O
mice	B
challenged	O
with	O
LPS	O
.	O

Furthermore	O
,	O
the	O
minocycline	O
associated	O
recovery	O
from	O
LPS	O
-	O
induced	O
sickness	O
behavior	O
was	O
paralleled	O
by	O
reduced	O
mRNA	O
levels	O
of	O
Interleukin	O
(	O
IL	O
)	O
-	O
1	O
beta	O
,	O
IL	O
-	O
6	O
,	O
and	O
indoleamine	O
2	O
,	O
3	O
dioxygenase	O
(	O
IDO	O
)	O
in	O
the	O
cortex	O
and	O
hippocampus	O
.	O

Finally	O
,	O
in	O
aged	O
mice	B
,	O
where	O
exaggerated	O
neuroinflammation	O
was	O
elicited	O
by	O
LPS	O
,	O
minocycline	O
pretreatment	O
was	O
still	O
effective	O
in	O
markedly	O
reducing	O
mRNA	O
levels	O
of	O
IL	O
-	O
1	O
beta	O
,	O
TLR2	O
and	O
IDO	O
in	O
the	O
hippocampus	O
.	O

Conclusion	O

These	O
data	O
indicate	O
that	O
minocycline	O
mitigates	O
neuroinflammation	O
in	O
the	O
adult	O
and	O
aged	O
brain	O
and	O
modulates	O
the	O
cytokine	O
-	O
associated	O
changes	O
in	O
motivation	O
and	O
behavior	O
.	O

Background	O

The	O
bi	O
-	O
directional	O
communication	O
between	O
the	O
immune	O
system	O
and	O
the	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
is	O
necessary	O
for	O
mounting	O
the	O
appropriate	O
immunological	O
,	O
physiological	O
,	O
and	O
behavioral	O
responses	O
to	O
immune	O
stimulation	O
[	O
1	O
]	O
.	O

CNS	O
innate	O
immune	O
cells	O
including	O
microglia	O
and	O
macrophages	O
play	O
integral	O
roles	O
in	O
receiving	O
and	O
propagating	O
inflammatory	O
signals	O
that	O
are	O
initiated	O
at	O
the	O
periphery	O
.	O

Activation	O
of	O
peripheral	O
innate	O
immune	O
cells	O
elicits	O
the	O
secretion	O
of	O
inflammatory	O
cytokines	O
,	O
including	O
interleukin	O
(	O
IL	O
)	O
-	O
1	O
,	O
IL	O
-	O
6	O
,	O
and	O
tumor	O
necrosis	O
factor	O
-	O
alpha	O
(	O
TNF	O
alpha	O
.	O
)	O
,	O
that	O
use	O
neural	O
[	O
2	O
,	O
3	O
]	O
,	O
humoral	O
[	O
4	O
]	O
and	O
blood	O
brain	O
barrier	O
pathways	O
[	O
5	O
]	O
to	O
relay	O
this	O
signal	O
to	O
the	O
CNS	O
.	O

This	O
inflammatory	O
signal	O
,	O
in	O
turn	O
,	O
induces	O
CNS	O
macrophages	O
and	O
microglia	O
to	O
produce	O
the	O
same	O
cytokines	O
[	O
6	O
]	O
,	O
which	O
target	O
neuronal	O
substrates	O
and	O
elicit	O
a	O
sickness	O
behavior	O
syndrome	O
that	O
is	O
normally	O
adaptive	O
and	O
beneficial	O
to	O
the	O
host	O
[	O
1	O
]	O
.	O

An	O
amplified	O
or	O
excessive	O
inflammatory	O
cytokine	O
response	O
in	O
the	O
brain	O
,	O
however	O
,	O
is	O
associated	O
with	O
a	O
myriad	O
of	O
complications	O
including	O
cognitive	O
dysfunction	O
[	O
7	O
-	O
10	O
]	O
,	O
prolonged	O
sickness	O
behavior	O
[	O
11	O
-	O
14	O
]	O
,	O
and	O
depressive	O
-	O
like	O
behavior	O
[	O
15	O
]	O
.	O

Microglia	O
are	O
primarily	O
involved	O
in	O
immune	O
surveillance	O
[	O
16	O
,	O
17	O
]	O
,	O
but	O
when	O
activated	O
have	O
macrophage	O
-	O
like	O
capabilities	O
including	O
phagocytosis	O
,	O
inflammatory	O
cytokine	O
production	O
,	O
and	O
antigen	O
presentation	O
[	O
18	O
]	O
.	O

Normally	O
these	O
neuroinflammatory	O
changes	O
are	O
transient	O
with	O
microglia	O
returning	O
to	O
a	O
resting	O
state	O
as	O
the	O
immune	O
stimulus	O
is	O
resolved	O
.	O

Aging	O
or	O
neurological	O
disease	O
,	O
however	O
,	O
may	O
provide	O
a	O
brain	O
environment	O
where	O
microglia	O
are	O
more	O
"	O
reactive	O
or	O
primed	O
"	O
to	O
a	O
peripheral	O
immune	O
challenge	O
[	O
19	O
]	O
.	O

Recent	O
findings	O
indicate	O
that	O
several	O
markers	O
of	O
glial	O
activation	O
such	O
as	O
major	O
histocompatibility	O
complex	O
(	O
MHC	O
)	O
class	O
II	O
,	O
complement	O
receptors	O
,	O
and	O
scavenger	O
receptors	O
are	O
increased	O
in	O
brain	O
during	O
normal	O
aging	O
[	O
13	O
,	O
20	O
-	O
26	O
]	O
.	O

Furthermore	O
,	O
we	O
and	O
others	O
have	O
reported	O
that	O
a	O
biological	O
consequence	O
of	O
this	O
reactive	O
glial	O
profile	O
is	O
an	O
exaggerated	O
neuroinflammatory	O
response	O
to	O
innate	O
immune	O
challenge	O
[	O
9	O
,	O
10	O
,	O
12	O
-	O
14	O
,	O
27	O
,	O
28	O
]	O
.	O

Active	O
microglia	O
and	O
CNS	O
macrophages	O
also	O
contribute	O
to	O
the	O
production	O
of	O
oxidative	O
and	O
neuroactive	O
mediators	O
that	O
may	O
influence	O
behavior	O
.	O

For	O
instance	O
,	O
inflammatory	O
cytokines	O
in	O
the	O
CNS	O
upregulate	O
the	O
enzyme	O
IDO	O
[	O
29	O
,	O
30	O
]	O
,	O
which	O
metabolizes	O
tryptophan	O
(	O
TRP	O
)	O
into	O
L	O
-	O
kynurenine	O
(	O
KYN	O
)	O
[	O
31	O
]	O
.	O

TRP	O
degradation	O
to	O
KYN	O
can	O
reduce	O
TRP	O
levels	O
that	O
are	O
required	O
for	O
serotonin	O
synthesis	O
[	O
32	O
]	O
and	O
can	O
lead	O
to	O
the	O
production	O
of	O
neuroactive	O
mediators	O
including	O
3	O
-	O
hydroxykynurenine	O
(	O
3HK	O
)	O
and	O
quinolinic	O
acid	O
(	O
QUIN	O
)	O
[	O
31	O
]	O
.	O

High	O
levels	O
of	O
3HK	O
and	O
QUIN	O
induce	O
neuronal	O
damage	O
through	O
oxidative	O
stress	O
[	O
33	O
]	O
and	O
over	O
stimulation	O
of	O
N	O
-	O
methyl	O
-	O
D	O
-	O
aspartate	O
(	O
NMDA	O
)	O
receptors	O
[	O
34	O
,	O
35	O
]	O
.	O

A	O
recent	O
study	O
indicates	O
that	O
while	O
several	O
cell	O
types	O
in	O
the	O
CNS	O
express	O
IDO	O
,	O
only	O
microglia	O
maintain	O
all	O
the	O
enzymes	O
required	O
to	O
produce	O
3HK	O
and	O
QUIN	O
[	O
36	O
]	O
.	O

Because	O
IDO	O
mediated	O
TRP	O
degradation	O
impacts	O
both	O
serotonergic	O
and	O
glutamatergic	O
pathways	O
,	O
this	O
may	O
be	O
an	O
important	O
mechanism	O
underlying	O
mood	O
and	O
behavior	O
complications	O
concomitant	O
with	O
inflammation	O
[	O
37	O
-	O
39	O
]	O
.	O

Because	O
activated	O
microglia	O
are	O
suspected	O
to	O
cause	O
or	O
exacerbate	O
several	O
neurodegenerative	O
diseases	O
,	O
pharmacological	O
strategies	O
to	O
suppress	O
microglial	O
activity	O
are	O
being	O
explored	O
as	O
therapies	O
.	O

Minocycline	O
is	O
a	O
tetracycline	O
derived	O
antibiotic	O
that	O
has	O
anti	O
-	O
inflammatory	O
properties	O
in	O
the	O
CNS	O
that	O
are	O
separate	O
from	O
its	O
antimicrobial	O
action	O
[	O
40	O
]	O
.	O

Minocycline	O
readily	O
crosses	O
the	O
blood	O
brain	O
barrier	O
and	O
attenuates	O
inflammation	O
associated	O
with	O
microglial	O
activation	O
.	O

For	O
example	O
,	O
minocycline	O
blocks	O
the	O
deleterious	O
effects	O
of	O
neuroinflammation	O
on	O
neurogenesis	O
,	O
long	O
-	O
term	O
potentiation	O
,	O
and	O
neuronal	O
survival	O
[	O
41	O
-	O
43	O
]	O
.	O

The	O
mechanism	O
of	O
action	O
is	O
unclear	O
,	O
but	O
recent	O
studies	O
indicate	O
that	O
minocycline	O
abrogates	O
MAPkinase	O
and	O
NF	O
kappa	O
B	O
dependent	O
signaling	O
pathways	O
in	O
primary	O
microglia	O
and	O
microglia	O
cell	O
cultures	O
[	O
44	O
]	O
.	O

Moreover	O
,	O
in	O
the	O
brain	O
of	O
rats	B
,	O
minocycline	O
abrogates	O
microglial	O
expression	O
of	O
CD11b	O
and	O
MHC	O
II	O
through	O
a	O
protein	O
kinase	O
-	O
c	O
dependent	O
mechanism	O
[	O
45	O
]	O
.	O

This	O
is	O
relevant	O
because	O
minocycline	O
attenuates	O
neuroinflammation	O
in	O
several	O
rodent	O
models	O
of	O
disease	O
including	O
Amyotrophic	O
Lateral	O
Sclerosis	O
[	O
46	O
]	O
,	O
Experimental	O
Autoimmune	O
Encephalomyelitis	O
(	O
EAE	O
)	O
[	O
45	O
]	O
and	O
MPTP	O
-	O
induced	O
Parkinson	O
'	O
s	O
disease	O
[	O
47	O
]	O
.	O

However	O
,	O
the	O
extent	O
to	O
which	O
minocycline	O
facilitates	O
the	O
recovery	O
from	O
cytokine	O
-	O
mediated	O
sickness	O
behavior	O
is	O
unknown	O
.	O

The	O
present	O
study	O
investigated	O
the	O
degree	O
to	O
which	O
minocycline	O
-	O
an	O
anti	O
-	O
inflammatory	O
agent	O
and	O
purported	O
microglial	O
inhibitor	O
-	O
reduced	O
LPS	O
-	O
induced	O
neuroinflammation	O
and	O
sickness	O
behavior	O
.	O

We	O
show	O
that	O
minocycline	O
blocked	O
LPS	O
-	O
stimulated	O
inflammatory	O
cytokine	O
secretion	O
in	O
the	O
BV	O
-	O
2	O
microglia	O
-	O
derived	O
cell	O
line	O
and	O
reduced	O
LPS	O
-	O
induced	O
Toll	O
-	O
like	O
-	O
receptor	O
-	O
2	O
(	O
TLR2	O
)	O
surface	O
expression	O
on	O
brain	O
microglia	O
.	O

Moreover	O
,	O
our	O
data	O
show	O
that	O
minocycline	O
pretreatment	O
attenuated	O
LPS	O
-	O
induced	O
weight	O
loss	O
,	O
social	O
withdrawal	O
,	O
and	O
anhedonia	O
in	O
adult	O
mice	B
.	O

The	O
attenuation	O
of	O
sickness	O
behavior	O
was	O
paralleled	O
with	O
minocycline	O
dependent	O
decrease	O
in	O
markers	O
of	O
neuroinflammation	O
(	O
IL	O
-	O
1	O
beta	O
,	O
TLR2	O
,	O
and	O
IDO	O
)	O
in	O
adult	O
and	O
aged	O
mice	B
.	O

These	O
findings	O
support	O
our	O
hypothesis	O
that	O
the	O
ability	O
to	O
mitigate	O
cytokine	O
expression	O
in	O
the	O
brain	O
during	O
systemic	O
inflammatory	O
events	O
may	O
be	O
useful	O
in	O
preventing	O
cognitive	O
and	O
behavioral	O
deficits	O
.	O

Methods	O

Animals	O

Male	O
BALB	O
/	O
c	O
mice	B
,	O
adults	O
(	O
3	O
month	O
old	O
)	O
and	O
juvenile	O
(	O
3	O
-	O
4	O
week	O
old	O
)	O
were	O
purchased	O
from	O
Harlan	O
(	O
Indianapolis	O
,	O
IN	O
)	O
.	O

For	O
age	O
comparisons	O
,	O
male	O
BALB	O
/	O
c	O
mice	B
(	O
3	O
-	O
4	O
and	O
20	O
-	O
22	O
month	O
old	O
)	O
were	O
purchased	O
from	O
the	O
National	O
Institute	O
on	O
Aging	O
specific	O
pathogen	O
free	O
colony	O
.	O

Upon	O
arrival	O
,	O
mice	B
were	O
individually	O
housed	O
in	O
polypropylene	O
cages	O
and	O
maintained	O
at	O
21	O
degrees	O
C	O
under	O
a	O
12	O
h	O
light	O
:	O
12	O
h	O
dark	O
cycle	O
with	O
ad	O
libitum	O
access	O
to	O
water	O
and	O
rodent	O
chow	O
.	O

At	O
the	O
end	O
of	O
each	O
study	O
,	O
mice	B
were	O
examined	O
postmortem	O
for	O
gross	O
signs	O
of	O
disease	O
(	O
e	O
.	O
g	O
.	O
,	O
splenomeglia	O
or	O
tumors	O
)	O
.	O

Data	O
from	O
mice	B
determined	O
to	O
be	O
unhealthy	O
were	O
excluded	O
from	O
analysis	O
(	O
<	O
5	O
%	O
)	O
.	O

All	O
procedures	O
were	O
in	O
accordance	O
with	O
the	O
National	O
Institute	O
of	O
Health	O
Guidelines	O
for	O
the	O
Care	O
and	O
Use	O
of	O
Laboratory	O
Animals	O
and	O
were	O
approved	O
by	O
The	O
Ohio	O
State	O
University	O
Institutional	O
Laboratory	O
Animal	O
Care	O
and	O
Use	O
Committee	O
.	O

Cell	O
culture	O

BV	O
-	O
2	O
microglia	O
cell	O
lines	O
were	O
cultured	O
in	O
growth	O
medium	O
(	O
DMEM	O
supplemented	O
with	O
10	O
%	O
FBS	O
,	O
sodium	O
bicarbonate	O
3	O
.	O
7	O
g	O
/	O
l	O
,	O
200	O
mM	O
glutamine	O
,	O
100	O
U	O
/	O
ml	O
penicillin	O
G	O
,	O
100	O
mu	O
g	O
/	O
ml	O
streptomycin	O
,	O
0	O
.	O
25	O
mu	O
g	O
/	O
ml	O
fungizone	O
)	O
as	O
previously	O
described	O
[	O
12	O
]	O
.	O

Cultures	O
were	O
maintained	O
at	O
37	O
degrees	O
C	O
with	O
95	O
%	O
humidity	O
and	O
5	O
%	O
CO2	O
and	O
growth	O
medium	O
was	O
replenished	O
every	O
third	O
day	O
until	O
confluence	O
.	O

Cultures	O
were	O
washed	O
twice	O
and	O
supplemented	O
with	O
warm	O
growth	O
medium	O
containing	O
experimental	O
treatments	O
.	O

Cell	O
viability	O
was	O
measured	O
by	O
the	O
MTS	O
cell	O
proliferation	O
assay	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
(	O
Promega	O
,	O
Madison	O
,	O
WI	O
)	O
.	O

CNS	O
macrophage	O
/	O
microglia	O
isolation	O

CNS	O
macrophages	O
and	O
microglia	O
were	O
collected	O
from	O
whole	O
brain	O
homogenates	O
as	O
described	O
previously	O
[	O
48	O
]	O
,	O
but	O
with	O
several	O
modifications	O
.	O

Mice	B
were	O
euthanized	O
by	O
CO2	O
asphyxiation	O
and	O
whole	O
brains	O
were	O
collected	O
.	O

Brains	O
were	O
homogenized	O
in	O
Hank	O
'	O
s	O
balanced	O
salt	O
solution	O
(	O
HBSS	O
)	O
pH	O
7	O
.	O
4	O
.	O

Brain	O
homogenates	O
were	O
passed	O
through	O
a	O
70	O
mu	O
m	O
nylon	O
cell	O
strainer	O
and	O
centrifuged	O
at	O
400	O
x	O
g	O
for	O
10	O
min	O
.	O

Supernatants	O
were	O
removed	O
and	O
cell	O
pellets	O
were	O
re	O
-	O
suspended	O
in	O
70	O
%	O
isotonic	O
Percoll	O
(	O
GE	O
-	O
healthcare	O
,	O
Uppsala	O
,	O
Sweden	O
)	O
at	O
room	O
temperature	O
.	O

A	O
discontinuous	O
Percoll	O
density	O
gradient	O
was	O
set	O
up	O
as	O
follows	O
:	O
70	O
%	O
,	O
35	O
%	O
,	O
and	O
0	O
%	O
isotonic	O
Percoll	O
.	O

This	O
suspension	O
was	O
centrifuged	O
for	O
30	O
minutes	O
at	O
400	O
x	O
g	O
.	O

A	O
mixed	O
population	O
of	O
CNS	O
macrophages	O
and	O
microglia	O
was	O
collected	O
from	O
the	O
interphase	O
between	O
the	O
70	O
%	O
and	O
35	O
%	O
Percoll	O
layers	O
.	O

Cells	O
were	O
washed	O
and	O
then	O
re	O
-	O
suspended	O
in	O
sterile	O
HBSS	O
.	O

The	O
number	O
of	O
viable	O
cells	O
was	O
determined	O
using	O
a	O
hemacytometer	O
and	O
0	O
.	O
2	O
%	O
trypan	O
blue	O
staining	O
.	O

Flow	O
cytometry	O

Flow	O
cytometric	O
analysis	O
of	O
microglial	O
cell	O
surface	O
markers	O
was	O
performed	O
as	O
described	O
previously	O
,	O
but	O
with	O
a	O
few	O
modifications	O
[	O
48	O
]	O
.	O

In	O
brief	O
,	O
Fc	O
receptors	O
on	O
macrophages	O
and	O
microglia	O
were	O
blocked	O
with	O
anti	O
-	O
CD16	O
/	O
CD32	O
antibody	O
(	O
eBiosciences	O
,	O
CA	O
)	O
.	O

Next	O
,	O
cells	O
were	O
incubated	O
with	O
either	O
Panel	O
-	O
1	O
(	O
anti	O
-	O
CD11b	O
APC	O
,	O
anti	O
-	O
CD45	O
FITC	O
,	O
and	O
anti	O
-	O
MHC	O
II	O
PE	O
from	O
eBiosciences	O
,	O
CA	O
)	O
or	O
Panel	O
-	O
2	O
antibodies	O
(	O
anti	O
-	O
CD11b	O
APC	O
,	O
anti	O
-	O
CD45	O
FITC	O
,	O
and	O
anti	O
-	O
TLR2	O
PE	O
from	O
eBiosciences	O
,	O
CA	O
)	O
.	O

Expression	O
of	O
these	O
surface	O
receptors	O
was	O
determined	O
by	O
flow	O
cytometry	O
using	O
a	O
Becton	O
-	O
Dickinson	O
FACSCaliber	O
four	O
color	O
Cytometer	O
.	O

Thirty	O
thousand	O
events	O
were	O
collected	O
and	O
microglia	O
were	O
differentiated	O
from	O
macrophages	O
based	O
on	O
the	O
levels	O
of	O
CD11b	O
and	O
CD45	O
surface	O
expression	O
.	O

Microglia	O
stain	O
CD11b	O
+	O
/	O
CD45low	O
and	O
macrophages	O
stain	O
CD11b	O
+	O
/	O
CD45high	O
[	O
48	O
,	O
49	O
]	O
.	O

Flow	O
data	O
were	O
analyzed	O
using	O
FlowJo	O
software	O
(	O
Tree	O
Star	O
,	O
San	O
Carlos	O
,	O
CA	O
)	O
.	O

Behavior	O
tests	O

Social	O
exploratory	O
behavior	O

To	O
assess	O
the	O
motivation	O
to	O
engage	O
in	O
social	O
exploratory	O
behavior	O
,	O
a	O
novel	O
juvenile	O
conspecific	O
was	O
introduced	O
into	O
the	O
test	O
subject	O
'	O
s	O
home	O
cage	O
for	O
a	O
10	O
-	O
min	O
period	O
.	O

Behavior	O
was	O
video	O
taped	O
and	O
the	O
cumulative	O
amount	O
of	O
time	O
the	O
subject	O
engaged	O
in	O
social	O
investigation	O
was	O
determined	O
from	O
the	O
video	O
records	O
by	O
a	O
trained	O
observer	O
who	O
was	O
blind	O
to	O
the	O
experimental	O
treatments	O
.	O

Baseline	O
social	O
behavior	O
was	O
measured	O
at	O
time	O
0	O
for	O
all	O
experimental	O
treatments	O
.	O

Social	O
behavior	O
was	O
determined	O
as	O
the	O
amount	O
of	O
time	O
that	O
the	O
experimental	O
subject	O
spent	O
investigating	O
(	O
e	O
.	O
g	O
.	O
,	O
anogenital	O
sniffing	O
,	O
trailing	O
)	O
the	O
juvenile	O
.	O

Results	O
are	O
expressed	O
as	O
percent	O
decrease	O
in	O
time	O
engaged	O
in	O
social	O
behavior	O
compared	O
to	O
respective	O
baseline	O
measures	O
.	O

Sucrose	O
preference	O

To	O
assess	O
sucrose	O
preference	O
,	O
mice	B
were	O
provided	O
two	O
solutions	O
,	O
water	O
or	O
water	O
supplemented	O
with	O
2	O
%	O
sucrose	O
,	O
in	O
50	O
ml	O
conical	O
tubes	O
with	O
stoppers	O
fitted	O
with	O
ball	O
-	O
type	O
sipper	O
tubes	O
.	O

Prior	O
to	O
testing	O
conditions	O
,	O
all	O
mice	B
were	O
acclimated	O
to	O
the	O
two	O
bottle	O
test	O
choice	O
.	O

All	O
mice	B
drank	O
both	O
the	O
water	O
and	O
the	O
2	O
%	O
sucrose	O
solution	O
,	O
but	O
preferred	O
drinking	O
the	O
sucrose	O
over	O
the	O
water	O
(	O
data	O
not	O
shown	O
)	O
.	O

On	O
the	O
day	O
of	O
testing	O
,	O
mice	B
were	O
fluid	O
and	O
food	O
deprived	O
for	O
2	O
h	O
prior	O
to	O
testing	O
[	O
50	O
]	O
.	O

At	O
the	O
start	O
of	O
the	O
dark	O
phase	O
of	O
the	O
photoperiod	O
,	O
drinking	O
water	O
and	O
the	O
2	O
%	O
sucrose	O
solution	O
were	O
placed	O
in	O
the	O
home	O
cage	O
overnight	O
(	O
15	O
h	O
)	O
.	O

At	O
the	O
end	O
of	O
each	O
testing	O
period	O
the	O
fluid	O
content	O
of	O
the	O
conical	O
tubes	O
was	O
measured	O
and	O
sucrose	O
preference	O
was	O
determined	O
using	O
the	O
equation	O
:	O
Sucrose	O
intake	O
/	O
Total	O
fluid	O
intake	O
(	O
water	O
+	O
sucrose	O
intake	O
)	O
x	O
100	O
[	O
51	O
]	O
.	O

Plasma	O
cytokine	O
measurement	O

IL	O
-	O
6	O
and	O
IL	O
-	O
1	O
beta	O
were	O
measured	O
in	O
the	O
plasma	O
as	O
previously	O
described	O
[	O
52	O
]	O
.	O

In	O
brief	O
,	O
mice	B
were	O
euthanized	O
by	O
CO2	O
asphyxiation	O
and	O
blood	O
was	O
collected	O
by	O
cardiac	O
puncture	O
into	O
EDTA	O
coated	O
syringes	O
.	O

Samples	O
were	O
centrifuged	O
(	O
6000	O
x	O
g	O
for	O
15	O
min	O
at	O
4	O
degrees	O
C	O
)	O
and	O
plasma	O
was	O
collected	O
and	O
stored	O
frozen	O
(	O
-	O
80	O
degrees	O
C	O
)	O
until	O
assaying	O
.	O

Plasma	O
samples	O
were	O
assayed	O
for	O
IL	O
-	O
6	O
using	O
a	O
customized	O
ELISA	O
that	O
we	O
have	O
described	O
in	O
detail	O
[	O
52	O
]	O
and	O
for	O
IL	O
-	O
1	O
beta	O
using	O
a	O
commercial	O
ELISA	O
kit	O
(	O
R	O
&	O
D	O
Systems	O
,	O
Minneapolis	O
,	O
MN	O
)	O
.	O

Assays	O
were	O
sensitive	O
to	O
8	O
pg	O
/	O
ml	O
of	O
IL	O
-	O
6	O
and	O
1	O
.	O
5	O
pg	O
/	O
ml	O
of	O
IL	O
-	O
1	O
beta	O
,	O
and	O
inter	O
-	O
and	O
intra	O
-	O
assay	O
coefficients	O
of	O
variation	O
were	O
less	O
than	O
10	O
%	O
.	O

Real	O
time	O
PCR	O

Total	O
RNA	O
was	O
isolated	O
from	O
brain	O
using	O
the	O
Tri	O
Reagent	O
protocol	O
(	O
Sigma	O
,	O
St	O
.	O
Louis	O
,	O
MO	O
)	O
.	O

RNA	O
samples	O
were	O
subjected	O
to	O
a	O
DNase	O
I	O
digestion	O
procedure	O
and	O
then	O
reverse	O
transcribed	O
to	O
cDNA	O
using	O
a	O
RT	O
RETROscript	O
kit	O
(	O
Ambion	O
,	O
Austin	O
,	O
TX	O
)	O
.	O

Quantitative	O
real	O
time	O
PCR	O
was	O
performed	O
using	O
the	O
Applied	O
Biosystems	O
(	O
Foster	O
,	O
CA	O
)	O
Assay	O
-	O
on	O
Demand	O
Gene	O
Expression	O
protocol	O
as	O
previously	O
described	O
[	O
13	O
]	O
.	O

In	O
brief	O
,	O
cDNA	O
was	O
amplified	O
by	O
real	O
time	O
PCR	O
where	O
a	O
target	O
cDNA	O
(	O
IL	O
-	O
1	O
beta	O
,	O
IL	O
-	O
6	O
,	O
MHC	O
II	O
,	O
TLR2	O
,	O
or	O
IDO	O
)	O
and	O
a	O
reference	O
cDNA	O
(	O
glyceraldehyde	O
-	O
3	O
-	O
phosphate	O
dehydrogenase	O
)	O
were	O
amplified	O
simultaneously	O
using	O
an	O
oligonucleotide	O
probe	O
with	O
a	O
5	O
'	O
fluorescent	O
reporter	O
dye	O
(	O
6	O
-	O
FAM	O
)	O
and	O
a	O
3	O
'	O
quencher	O
dye	O
(	O
NFQ	O
)	O
.	O

Fluorescence	O
was	O
determined	O
on	O
an	O
ABI	O
PRISM	O
7300	O
-	O
sequence	O
detection	O
system	O
(	O
Applied	O
Biosystems	O
,	O
CA	O
)	O
.	O

Data	O
were	O
analyzed	O
using	O
the	O
comparative	O
threshold	O
cycle	O
(	O
Ct	O
)	O
method	O
and	O
results	O
are	O
expressed	O
as	O
fold	O
difference	O
.	O

Experimental	O
protocols	O

For	O
the	O
cell	O
culture	O
studies	O
,	O
minocycline	O
was	O
prepared	O
in	O
dimethyl	O
sulfoxide	O
(	O
DMSO	O
)	O
and	O
BV	O
-	O
2	O
cells	O
were	O
washed	O
and	O
replenished	O
with	O
growth	O
mediumsupplemented	O
with	O
0	O
,	O
25	O
,	O
50	O
,	O
100	O
,	O
200	O
,	O
or	O
400	O
mu	O
g	O
/	O
ml	O
minocycline	O
.	O

After	O
30	O
min	O
,	O
LPS	O
at	O
10	O
ng	O
/	O
ml	O
was	O
added	O
to	O
the	O
culture	O
medium	O
.	O

Supernatants	O
were	O
collected	O
4	O
h	O
later	O
and	O
IL	O
-	O
6	O
and	O
IL	O
-	O
1	O
beta	O
concentrations	O
were	O
determined	O
by	O
ELISA	O
.	O

Total	O
proteins	O
were	O
determined	O
from	O
cell	O
culture	O
homogenates	O
by	O
the	O
Bio	O
-	O
Rad	O
Dc	O
protein	O
assay	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
(	O
Bio	O
-	O
Rad	O
Lboratories	O
,	O
Hercules	O
,	O
CA	O
)	O
.	O

Each	O
treatment	O
was	O
replicated	O
a	O
minimum	O
of	O
four	O
times	O
.	O

Cell	O
viability	O
was	O
confirmed	O
by	O
the	O
MTS	O
cell	O
proliferation	O
assay	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
(	O
Promega	O
,	O
Madison	O
,	O
WI	O
)	O
.	O

For	O
all	O
mouse	B
studies	O
,	O
minocycline	O
(	O
Sigma	O
,	O
St	O
.	O
Louis	O
,	O
MO	O
)	O
was	O
dissolved	O
in	O
sterile	O
water	O
and	O
sonicated	O
to	O
ensure	O
complete	O
solubilization	O
.	O

In	O
the	O
first	O
mouse	B
study	O
,	O
adult	O
male	O
BALB	O
/	O
c	O
mice	B
received	O
an	O
intraperitoneal	O
(	O
i	O
.	O
p	O
.	O
)	O
injection	O
of	O
vehicle	O
or	O
minocycline	O
(	O
50	O
mg	O
/	O
kg	O
)	O
for	O
three	O
consecutive	O
days	O
.	O

On	O
the	O
3rd	O
day	O
,	O
mice	B
were	O
also	O
injected	O
i	O
.	O
p	O
.	O
with	O
saline	O
or	O
Escherichia	B
coli	I
LPS	O
(	O
0	O
.	O
33	O
mg	O
/	O
kg	O
;	O
serotype	O
0127	O
:	O
B8	O
,	O
Sigma	O
,	O
St	O
.	O
Louis	O
,	O
MO	O
)	O
and	O
were	O
euthanized	O
by	O
CO2	O
asphyxiation	O
24	O
h	O
later	O
(	O
n	O
=	O
6	O
)	O
.	O

The	O
LPS	O
dosage	O
was	O
selected	O
because	O
it	O
elicits	O
a	O
proinflammatory	O
cytokine	O
response	O
in	O
the	O
brain	O
resulting	O
in	O
mild	O
transient	O
sickness	O
behavior	O
in	O
adult	O
mice	B
[	O
13	O
,	O
53	O
]	O
.	O

Macrophage	O
/	O
microglial	O
cells	O
were	O
isolated	O
from	O
whole	O
brain	O
homogenates	O
and	O
TLR2	O
and	O
MHC	O
II	O
surface	O
expression	O
were	O
determined	O
by	O
flow	O
cytometry	O
.	O

The	O
minocycline	O
injection	O
regimen	O
and	O
dosage	O
was	O
selected	O
because	O
a	O
repeated	O
pretreatment	O
course	O
with	O
minocycline	O
is	O
necessary	O
to	O
attenuate	O
neuroinflammation	O
[	O
41	O
-	O
43	O
,	O
45	O
]	O
.	O

In	O
the	O
second	O
study	O
,	O
adult	O
male	O
BALB	O
/	O
c	O
mice	B
received	O
an	O
i	O
.	O
p	O
.	O
injection	O
with	O
vehicle	O
or	O
minocycline	O
for	O
three	O
consecutive	O
days	O
.	O

On	O
the	O
third	O
day	O
,	O
motivation	O
to	O
engage	O
in	O
social	O
behavior	O
was	O
determined	O
immediately	O
before	O
i	O
.	O
p	O
.	O
injection	O
of	O
saline	O
or	O
LPS	O
(	O
0	O
.	O
33	O
mg	O
/	O
kg	O
)	O
and	O
again	O
2	O
,	O
4	O
,	O
8	O
,	O
12	O
,	O
and	O
24	O
h	O
later	O
(	O
n	O
=	O
8	O
)	O
.	O

Body	O
weight	O
and	O
food	O
intake	O
were	O
measured	O
at	O
each	O
time	O
point	O
over	O
the	O
24	O
h	O
period	O
.	O

In	O
a	O
related	O
,	O
but	O
separate	O
study	O
,	O
adult	O
mice	B
were	O
treated	O
with	O
minocycline	O
and	O
LPS	O
as	O
described	O
and	O
anhedonia	O
was	O
assessed	O
24	O
-	O
39	O
h	O
following	O
i	O
.	O
p	O
.	O
injection	O
of	O
saline	O
or	O
LPS	O
(	O
0	O
.	O
33	O
mg	O
/	O
kg	O
)	O
(	O
n	O
=	O
15	O
)	O
.	O

Body	O
weight	O
,	O
food	O
intake	O
,	O
water	O
intake	O
,	O
and	O
sucrose	O
intake	O
were	O
determined	O
over	O
the	O
testing	O
period	O
.	O

In	O
the	O
third	O
study	O
,	O
adult	O
BALB	O
/	O
c	O
mice	B
were	O
treated	O
with	O
minocycline	O
and	O
then	O
LPS	O
as	O
described	O
.	O

Mice	B
were	O
euthanized	O
by	O
CO2	O
asphyxiation	O
4	O
later	O
.	O

Brains	O
were	O
removed	O
and	O
dissected	O
to	O
collect	O
different	O
brain	O
regions	O
.	O

Brain	O
regions	O
were	O
stored	O
at	O
-	O
20	O
degrees	O
C	O
in	O
RNAlater	O
(	O
Qiagen	O
,	O
CA	O
)	O
.	O

Total	O
RNA	O
was	O
isolated	O
from	O
brain	O
samples	O
and	O
assayed	O
using	O
quantitative	O
PCR	O
(	O
n	O
=	O
8	O
)	O
.	O

Plasma	O
was	O
also	O
collected	O
and	O
stored	O
(	O
-	O
80	O
degrees	O
C	O
)	O
until	O
assaying	O
.	O

In	O
a	O
final	O
study	O
,	O
adult	O
(	O
3	O
-	O
4	O
month	O
old	O
)	O
or	O
aged	O
(	O
20	O
-	O
22	O
month	O
old	O
)	O
male	O
BALB	O
/	O
c	O
mice	B
were	O
treated	O
with	O
minocycline	O
and	O
LPS	O
as	O
described	O
and	O
euthanized	O
4	O
h	O
later	O
.	O

Brains	O
were	O
dissected	O
to	O
collect	O
different	O
brain	O
regions	O
and	O
were	O
stored	O
at	O
-	O
20	O
degrees	O
C	O
in	O
RNAlater	O
(	O
Qiagen	O
,	O
CA	O
)	O
.	O

Total	O
RNA	O
was	O
isolated	O
from	O
the	O
hippocampus	O
and	O
assayed	O
using	O
quantitative	O
PCR	O
(	O
n	O
=	O
8	O
)	O
.	O

Statistical	O
analysis	O

All	O
data	O
were	O
analyzed	O
using	O
Statistical	O
Analysis	O
Systems	O
(	O
SAS	O
)	O
General	O
Linear	O
Model	O
procedures	O
.	O

Data	O
were	O
subjected	O
to	O
one	O
,	O
two	O
-	O
(	O
Mino	O
x	O
LPS	O
,	O
Age	O
x	O
LPS	O
,	O
Mino	O
x	O
Age	O
)	O
or	O
three	O
-	O
way	O
(	O
Mino	O
x	O
LPS	O
x	O
Time	O
,	O
Mino	O
x	O
LPS	O
x	O
Age	O
)	O
ANOVA	O
to	O
determine	O
significant	O
main	O
effects	O
and	O
interactions	O
between	O
main	O
factors	O
.	O

When	O
appropriate	O
,	O
differences	O
between	O
treatment	O
means	O
were	O
evaluated	O
by	O
an	O
F	O
-	O
protected	O
t	O
-	O
test	O
using	O
the	O
Least	O
-	O
Significant	O
Difference	O
procedure	O
of	O
SAS	O
.	O

All	O
data	O
are	O
expressed	O
as	O
treatment	O
means	O
+	O
/	O
-	O
standard	O
error	O
of	O
the	O
mean	O
(	O
SEM	O
)	O
.	O

Results	O

Minocycline	O
attenuates	O
LPS	O
-	O
induced	O
cytokine	O
production	O
in	O
BV	O
-	O
2	O
microglia	O

Minocycline	O
is	O
a	O
tetracycline	O
-	O
type	O
antibiotic	O
that	O
has	O
anti	O
-	O
inflammatory	O
properties	O
in	O
the	O
CNS	O
[	O
41	O
-	O
43	O
,	O
45	O
]	O
.	O

To	O
determine	O
the	O
degree	O
to	O
which	O
minocycline	O
suppresses	O
microglia	O
activation	O
,	O
BV	O
-	O
2	O
microglia	O
-	O
derived	O
cell	O
lines	O
were	O
used	O
.	O

In	O
the	O
first	O
experiment	O
,	O
BV	O
-	O
2	O
cells	O
were	O
treated	O
with	O
LPS	O
and	O
IL	O
-	O
6	O
production	O
was	O
determined	O
4	O
h	O
later	O
.	O

Fig	O
.	O

1A	O
shows	O
that	O
LPS	O
increased	O
IL	O
-	O
6	O
production	O
in	O
a	O
dose	O
dependent	O
manner	O
F	O
(	O
5	O
,	O
23	O
)	O
=	O
101	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

In	O
the	O
second	O
experiment	O
,	O
BV	O
-	O
2	O
cells	O
were	O
incubated	O
with	O
DMSO	O
or	O
minocycline	O
and	O
then	O
stimulated	O
with	O
LPS	O
.	O

Minocycline	O
reduced	O
LPS	O
-	O
induced	O
IL	O
-	O
6	O
secretion	O
in	O
a	O
dose	O
dependent	O
manner	O
(	O
Mino	O
x	O
LPS	O
interaction	O
,	O
F	O
(	O
4	O
,	O
23	O
)	O
=	O
16	O
.	O
87	O
,	O
P	O
<	O
0	O
.	O
001	O
,	O
Fig	O
.	O
1B	O
)	O
.	O

Minocycline	O
pretreatment	O
had	O
a	O
similar	O
anti	O
-	O
inflammatory	O
effect	O
on	O
LPS	O
-	O
stimulated	O
IL	O
-	O
1	O
beta	O
secretion	O
(	O
Fig	O
.	O
1C	O
)	O
.	O

In	O
a	O
third	O
experiment	O
,	O
minocycline	O
suppressed	O
LPS	O
-	O
induced	O
MHC	O
II	O
,	O
TLR2	O
,	O
IL	O
-	O
1	O
beta	O
,	O
and	O
IL	O
-	O
6	O
mRNA	O
levels	O
(	O
P	O
<	O
0	O
.	O
05	O
,	O
for	O
each	O
,	O
Fig	O
.	O
1D	O
)	O
.	O

The	O
MTS	O
assay	O
verified	O
that	O
neither	O
cell	O
survival	O
nor	O
proliferation	O
was	O
affected	O
by	O
the	O
experimental	O
treatments	O
(	O
data	O
not	O
shown	O
)	O
.	O

LPS	O
-	O
induced	O
TLR2	O
surface	O
expression	O
on	O
microglia	O
is	O
reduced	O
by	O
minocycline	O

Because	O
minocycline	O
attenuated	O
LPS	O
-	O
induced	O
cytokine	O
secretion	O
and	O
TLR2	O
mRNA	O
expression	O
in	O
BV	O
-	O
2	O
cells	O
we	O
next	O
sought	O
to	O
determine	O
if	O
minocycline	O
suppresses	O
markers	O
of	O
microglial	O
activation	O
in	O
the	O
brain	O
of	O
mice	B
.	O

Mice	B
were	O
injected	O
i	O
.	O
p	O
.	O
with	O
vehicle	O
or	O
minocycline	O
for	O
3	O
consecutive	O
days	O
then	O
challenged	O
with	O
saline	O
or	O
LPS	O
i	O
.	O
p	O
.	O

Markers	O
of	O
activation	O
,	O
TLR2	O
and	O
MHC	O
II	O
,	O
were	O
determined	O
on	O
microglia	O
collected	O
24	O
h	O
later	O
.	O

The	O
representative	O
bivariate	O
density	O
plot	O
in	O
Fig	O
.	O

2A	O
shows	O
that	O
there	O
were	O
two	O
populations	O
of	O
CD11b	O
/	O
CD45	O
positive	O
cells	O
and	O
that	O
more	O
cells	O
stained	O
CD11b	O
+	O
/	O
CD45low	O
(	O
microglia	O
)	O
than	O
CD11b	O
+	O
/	O
CD45high	O
(	O
CNS	O
macrophages	O
)	O
.	O

ANOVA	O
revealed	O
that	O
LPS	O
injection	O
increased	O
TLR2	O
surface	O
expression	O
on	O
microglia	O
(	O
F	O
(	O
1	O
,	O
20	O
)	O
=	O
17	O
.	O
6	O
,	O
P	O
<	O
0	O
.	O
004	O
,	O
Fig	O
.	O
2B	O
&	O
D	O
)	O
,	O
but	O
this	O
induction	O
was	O
abrogated	O
by	O
minocycline	O
pretreatment	O
(	O
Tendency	O
for	O
Mino	O
x	O
LPS	O
interaction	O
,	O
F	O
(	O
1	O
,	O
20	O
)	O
=	O
2	O
.	O
66	O
,	O
P	O
=	O
0	O
.	O
10	O
,	O
Fig	O
.	O
2C	O
&	O
D	O
)	O
.	O

It	O
is	O
important	O
to	O
note	O
that	O
because	O
minocycline	O
and	O
saline	O
controls	O
did	O
not	O
differ	O
in	O
their	O
TLR2	O
expression	O
,	O
these	O
data	O
were	O
grouped	O
together	O
as	O
the	O
Control	O
group	O
(	O
Fig	O
.	O
2B	O
&	O
C	O
)	O
.	O

In	O
addition	O
,	O
neither	O
minocycline	O
nor	O
LPS	O
treatment	O
had	O
a	O
significant	O
main	O
effect	O
on	O
MHC	O
class	O
II	O
surface	O
expression	O
on	O
microglia	O
(	O
data	O
not	O
shown	O
)	O
.	O

These	O
data	O
indicate	O
that	O
minocycline	O
attenuated	O
LPS	O
-	O
induced	O
TLR2	O
expression	O
on	O
microglia	O
.	O

Minocycline	O
facilitates	O
the	O
recovery	O
from	O
LPS	O
-	O
induced	O
sickness	O
behavior	O

CNS	O
macrophages	O
and	O
microglia	O
produce	O
inflammatory	O
cytokines	O
and	O
secondary	O
messengers	O
that	O
modulate	O
behavioral	O
responses	O
.	O

Therefore	O
,	O
we	O
next	O
investigated	O
if	O
minocycline	O
reduced	O
the	O
sickness	O
response	O
associated	O
with	O
peripheral	O
LPS	O
injection	O
.	O

In	O
this	O
experiment	O
,	O
adult	O
mice	B
were	O
treated	O
with	O
minocycline	O
and	O
LPS	O
as	O
described	O
.	O

Social	O
exploratory	O
behavior	O
was	O
measured	O
before	O
i	O
.	O
p	O
.	O

LPS	O
injection	O
and	O
again	O
2	O
,	O
4	O
,	O
8	O
,	O
and	O
24	O
h	O
later	O
.	O

Fig	O
.	O

3A	O
shows	O
that	O
LPS	O
injection	O
caused	O
a	O
reduction	O
in	O
social	O
exploratory	O
behavior	O
(	O
F	O
(	O
1	O
,	O
57	O
)	O
=	O
218	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
that	O
was	O
time	O
dependent	O
(	O
F	O
(	O
4	O
,	O
57	O
)	O
=	O
66	O
.	O
5	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Moreover	O
,	O
the	O
LPS	O
-	O
associated	O
reduction	O
in	O
social	O
exploration	O
was	O
attenuated	O
by	O
minocycline	O
(	O
Mino	O
x	O
LPS	O
interaction	O
,	O
F	O
(	O
1	O
,	O
57	O
)	O
=	O
7	O
.	O
5	O
,	O
P	O
<	O
0	O
.	O
007	O
)	O
.	O

For	O
example	O
,	O
at	O
8	O
h	O
post	O
LPS	O
,	O
social	O
exploration	O
was	O
reduced	O
by	O
35	O
%	O
in	O
minocycline	O
pretreated	O
mice	B
given	O
LPS	O
compared	O
to	O
a	O
67	O
%	O
reduction	O
in	O
vehicle	O
pretreated	O
mice	B
given	O
LPS	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

While	O
minocycline	O
administration	O
alone	O
reduced	O
food	O
intake	O
and	O
body	O
weight	O
in	O
control	O
mice	B
(	O
P	O
<	O
0	O
.	O
05	O
,	O
for	O
each	O
)	O
,	O
it	O
also	O
protected	O
against	O
LPS	O
-	O
associated	O
anorexia	O
(	O
Mino	O
x	O
LPS	O
interaction	O
,	O
F	O
(	O
1	O
,	O
60	O
)	O
=	O
70	O
.	O
0	O
,	O
P	O
<	O
0	O
.	O
001	O
,	O
Fig	O
.	O
3B	O
)	O
and	O
weight	O
loss	O
(	O
Mino	O
x	O
LPS	O
interaction	O
,	O
F	O
(	O
1	O
,	O
60	O
)	O
=	O
29	O
.	O
7	O
,	O
P	O
<	O
0	O
.	O
001	O
,	O
Fig	O
.	O
3C	O
)	O
.	O

Because	O
sickness	O
can	O
also	O
be	O
associated	O
with	O
longer	O
lasting	O
changes	O
in	O
motivation	O
[	O
38	O
]	O
,	O
we	O
next	O
sought	O
to	O
determine	O
if	O
minocycline	O
abrogated	O
LPS	O
-	O
induced	O
anhedonia	O
[	O
54	O
,	O
55	O
]	O
.	O

In	O
this	O
experiment	O
,	O
mice	B
were	O
subjected	O
to	O
the	O
same	O
minocycline	O
injection	O
regimen	O
and	O
LPS	O
challenge	O
as	O
above	O
and	O
sucrose	O
preference	O
was	O
assessed	O
24	O
-	O
39	O
h	O
post	O
LPS	O
injection	O
.	O

By	O
24	O
h	O
post	O
LPS	O
injection	O
,	O
food	O
and	O
water	O
intake	O
returned	O
to	O
baseline	O
and	O
LPS	O
treated	O
mice	B
still	O
exhibited	O
a	O
marked	O
reduction	O
in	O
sucrose	O
preference	O
from	O
24	O
-	O
39	O
h	O
(	O
F	O
(	O
1	O
,	O
59	O
)	O
=	O
14	O
.	O
3	O
,	O
P	O
<	O
0	O
.	O
003	O
)	O
.	O

Moreover	O
,	O
this	O
LPS	O
-	O
dependent	O
reduction	O
in	O
sucrose	O
preference	O
was	O
prevented	O
by	O
minocycline	O
pretreatment	O
(	O
Mino	O
x	O
LPS	O
interaction	O
,	O
F	O
(	O
1	O
,	O
59	O
)	O
=	O
9	O
.	O
9	O
,	O
P	O
<	O
0	O
.	O
004	O
,	O
Fig	O
.	O
4	O
)	O
.	O

For	O
example	O
,	O
minocycline	O
pretreated	O
mice	B
injected	O
with	O
LPS	O
maintained	O
the	O
same	O
strong	O
preference	O
for	O
sucrose	O
as	O
saline	O
and	O
minocycline	O
controls	O
(	O
i	O
.	O
e	O
.	O
,	O
approximately	O
85	O
%	O
preference	O
)	O
.	O

These	O
data	O
can	O
be	O
interpreted	O
to	O
indicate	O
that	O
minocycline	O
blocks	O
anhedonia	O
associated	O
with	O
peripheral	O
LPS	O
challenge	O
.	O

Minocycline	O
reduces	O
LPS	O
-	O
induced	O
neuroinflammation	O

Pro	O
-	O
inflammatory	O
cytokines	O
in	O
the	O
CNS	O
are	O
partially	O
responsible	O
for	O
the	O
behavioral	O
symptoms	O
of	O
sickness	O
(	O
e	O
.	O
g	O
.	O
,	O
anorexia	O
,	O
social	O
withdrawal	O
,	O
and	O
anhedonia	O
)	O
[	O
1	O
]	O
.	O

Therefore	O
,	O
we	O
investigated	O
the	O
degree	O
to	O
which	O
minocycline	O
reduces	O
neuroinflammation	O
(	O
IL	O
-	O
1	O
beta	O
,	O
IL	O
-	O
6	O
,	O
and	O
IDO	O
)	O
after	O
peripheral	O
injection	O
of	O
LPS	O
.	O

In	O
this	O
experiment	O
,	O
mice	B
were	O
subjected	O
to	O
the	O
minocycline	O
injection	O
regimen	O
and	O
LPS	O
challenge	O
as	O
above	O
and	O
cytokine	O
mRNA	O
levels	O
were	O
determined	O
in	O
the	O
cortex	O
and	O
hippocampus	O
4	O
h	O
after	O
LPS	O
injection	O
.	O

In	O
mice	B
pretreated	O
with	O
vehicle	O
,	O
LPS	O
markedly	O
increased	O
IL	O
-	O
1	O
beta	O
mRNA	O
levels	O
in	O
the	O
hippocampus	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
62	O
,	O
P	O
<	O
0	O
.	O
0001	O
)	O
and	O
cortex	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
17	O
.	O
25	O
,	O
P	O
<	O
0	O
.	O
0003	O
)	O
.	O

The	O
LPS	O
-	O
induced	O
IL	O
-	O
1	O
beta	O
mRNA	O
expression	O
was	O
reduced	O
in	O
both	O
brain	O
regions	O
in	O
mice	B
receiving	O
minocycline	O
prior	O
to	O
LPS	O
injection	O
:	O
(	O
hippocampus	O
,	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
9	O
.	O
63	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
and	O
cortex	O
,	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
7	O
.	O
23	O
,	O
P	O
=	O
0	O
.	O
08	O
,	O
Fig	O
.	O

5A	O
)	O
.	O

LPS	O
caused	O
a	O
similar	O
induction	O
of	O
IL	O
-	O
6	O
mRNA	O
levels	O
in	O
the	O
hippocampus	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
37	O
.	O
2	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
and	O
cortex	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
22	O
.	O
5	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
but	O
minocycline	O
pretreatment	O
only	O
significantly	O
attenuated	O
LPS	O
-	O
induced	O
IL	O
-	O
6	O
mRNA	O
levels	O
in	O
the	O
hippocampus	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
10	O
.	O
27	O
,	O
P	O
<	O
0	O
.	O
004	O
,	O
Fig	O
.	O
5B	O
)	O
.	O

IDO	O
mRNA	O
levels	O
were	O
determined	O
from	O
the	O
same	O
RNA	O
pool	O
.	O

Fig	O
.	O

6D	O
shows	O
that	O
LPS	O
injection	O
increased	O
IDO	O
mRNA	O
expression	O
in	O
the	O
hippocampus	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
11	O
.	O
69	O
,	O
P	O
<	O
0	O
.	O
002	O
)	O
and	O
cortex	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
5	O
.	O
26	O
,	O
P	O
<	O
0	O
.	O
03	O
)	O
.	O

This	O
LPS	O
-	O
induced	O
IDO	O
mRNA	O
expression	O
was	O
attenuated	O
by	O
minocycline	O
in	O
the	O
hippocampus	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
11	O
.	O
69	O
,	O
P	O
<	O
0	O
.	O
002	O
)	O
and	O
cortex	O
(	O
F	O
(	O
1	O
,	O
31	O
)	O
=	O
5	O
.	O
26	O
,	O
P	O
<	O
0	O
.	O
03	O
)	O
.	O

It	O
is	O
important	O
to	O
note	O
that	O
IDO	O
mRNA	O
was	O
undetected	O
in	O
saline	O
treated	O
mice	B
.	O

Therefore	O
,	O
the	O
fold	O
IDO	O
change	O
was	O
relative	O
to	O
the	O
IDO	O
mRNA	O
levels	O
in	O
mice	B
receiving	O
minocycline	O
prior	O
to	O
LPS	O
.	O

Minocycline	O
reduces	O
LPS	O
-	O
induced	O
IL	O
-	O
6	O
,	O
but	O
not	O
IL	O
-	O
1	O
beta	O
,	O
in	O
the	O
plasma	O

Because	O
cytokine	O
signals	O
can	O
be	O
relayed	O
from	O
the	O
periphery	O
to	O
the	O
brain	O
by	O
humoral	O
pathways	O
[	O
56	O
]	O
,	O
plasma	O
cytokine	O
levels	O
of	O
IL	O
-	O
6	O
and	O
IL	O
-	O
1	O
beta	O
were	O
determined	O
4	O
h	O
post	O
LPS	O
injection	O
.	O

As	O
expected	O
,	O
LPS	O
injection	O
caused	O
a	O
marked	O
increase	O
in	O
plasma	O
IL	O
-	O
1	O
beta	O
(	O
F	O
(	O
1	O
,	O
36	O
)	O
=	O
52	O
.	O
5	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
and	O
IL	O
-	O
6	O
levels	O
(	O
F	O
(	O
1	O
,	O
36	O
)	O
34	O
.	O
01	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Minocycline	O
pretreatment	O
reduced	O
LPS	O
-	O
induced	O
IL	O
-	O
6	O
levels	O
in	O
the	O
plasma	O
(	O
F	O
(	O
1	O
,	O
36	O
)	O
6	O
.	O
68	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
but	O
had	O
no	O
significant	O
main	O
effect	O
on	O
LPS	O
-	O
induced	O
IL	O
-	O
1	O
beta	O
levels	O
(	O
Fig	O
.	O
6	O
)	O
.	O

Minocycline	O
attenuates	O
LPS	O
-	O
induced	O
exaggerated	O
neuroinflammation	O
in	O
aged	O
mice	B

Aged	O
BALB	O
/	O
c	O
mice	B
(	O
22	O
-	O
24	O
m	O
)	O
have	O
an	O
exaggerated	O
neuroinflammatory	O
response	O
to	O
LPS	O
injection	O
[	O
10	O
,	O
13	O
,	O
14	O
]	O
.	O

Therefore	O
,	O
we	O
next	O
sought	O
to	O
determine	O
if	O
the	O
heightened	O
inflammatory	O
response	O
in	O
the	O
brain	O
of	O
aged	O
mice	B
was	O
reduced	O
by	O
minocycline	O
.	O

In	O
this	O
experiment	O
,	O
adult	O
and	O
aged	O
mice	B
were	O
subjected	O
to	O
the	O
minocycline	O
injection	O
regimen	O
and	O
LPS	O
challenge	O
as	O
above	O
.	O

As	O
we	O
have	O
reported	O
previously	O
,	O
MHC	O
II	O
mRNA	O
expression	O
was	O
increased	O
by	O
age	O
(	O
P	O
<	O
0	O
.	O
03	O
,	O
Fig	O
.	O
7A	O
)	O
[	O
13	O
,	O
14	O
]	O
,	O
but	O
MHC	O
II	O
levels	O
were	O
unaffected	O
by	O
either	O
LPS	O
or	O
minocycline	O
treatment	O
(	O
not	O
shown	O
)	O
.	O

Consistent	O
with	O
the	O
data	O
presented	O
in	O
Fig	O
.	O

2	O
,	O
ANOVA	O
revealed	O
a	O
significant	O
main	O
effect	O
of	O
LPS	O
injection	O
on	O
TLR2	O
mRNA	O
expression	O
in	O
the	O
hippocampus	O
(	O
F	O
(	O
1	O
,	O
63	O
)	O
=	O
85	O
.	O
5	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Moreover	O
,	O
LPS	O
caused	O
a	O
greater	O
increase	O
in	O
TLR2	O
mRNA	O
in	O
the	O
hippocampus	O
of	O
aged	O
mice	B
compared	O
to	O
adults	O
(	O
LPS	O
x	O
Age	O
interaction	O
,	O
F	O
(	O
1	O
,	O
63	O
)	O
=	O
12	O
.	O
70	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Furthermore	O
,	O
minocycline	O
pretreatment	O
attenuated	O
LPS	O
-	O
induced	O
TLR2	O
mRNA	O
levels	O
in	O
both	O
adult	O
and	O
aged	O
mice	B
(	O
Mino	O
x	O
LPS	O
interaction	O
,	O
F	O
(	O
1	O
,	O
63	O
)	O
=	O
9	O
.	O
02	O
,	O
P	O
<	O
0	O
.	O
004	O
)	O
.	O

Parallel	O
to	O
the	O
results	O
for	O
TLR2	O
,	O
LPS	O
caused	O
a	O
greater	O
increase	O
in	O
IL	O
-	O
1	O
beta	O
and	O
IDO	O
mRNA	O
levels	O
in	O
hippocampus	O
of	O
aged	O
mice	B
compared	O
to	O
adults	O
(	O
Age	O
x	O
LPS	O
,	O
F	O
(	O
1	O
,	O
60	O
)	O
=	O
8	O
.	O
64	O
,	O
P	O
<	O
0	O
.	O
01	O
for	O
IL	O
-	O
1	O
beta	O
and	O
F	O
(	O
1	O
,	O
60	O
)	O
=	O
4	O
.	O
0	O
,	O
P	O
<	O
0	O
.	O
05	O
for	O
IDO	O
)	O
.	O

Minocycline	O
pretreatment	O
attenuated	O
LPS	O
-	O
induced	O
mRNA	O
levels	O
of	O
IL	O
-	O
1	O
beta	O
(	O
Mino	O
x	O
LPS	O
,	O
F	O
(	O
1	O
,	O
60	O
)	O
=	O
8	O
.	O
76	O
,	O
P	O
<	O
0	O
.	O
01	O
,	O
Fig	O
.	O
7C	O
)	O
and	O
IDO	O
(	O
Mino	O
x	O
LPS	O
,	O
F	O
(	O
1	O
,	O
60	O
)	O
=	O
9	O
.	O
7	O
,	O
P	O
<	O
0	O
.	O
003	O
,	O
Fig	O
.	O
7D	O
)	O
.	O

While	O
LPS	O
induced	O
higher	O
IL	O
-	O
6	O
mRNA	O
levels	O
in	O
the	O
hippocampus	O
of	O
both	O
adult	O
and	O
aged	O
mice	B
(	O
F	O
(	O
1	O
,	O
59	O
)	O
=	O
44	O
.	O
5	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
there	O
was	O
not	O
an	O
Age	O
x	O
LPS	O
interaction	O
.	O

Minocycline	O
pretreatment	O
attenuated	O
the	O
LPS	O
-	O
induced	O
increase	O
in	O
hippocampal	O
IL	O
-	O
6	O
mRNA	O
(	O
Mino	O
x	O
LPS	O
,	O
F	O
(	O
1	O
,	O
59	O
)	O
=	O
5	O
.	O
4	O
,	O
P	O
<	O
0	O
.	O
02	O
,	O
Fig	O
.	O
7E	O
)	O
.	O

Taken	O
together	O
these	O
data	O
indicate	O
that	O
minocycline	O
pretreatment	O
was	O
effective	O
in	O
attenuating	O
the	O
exaggerated	O
neuroinflammation	O
in	O
aged	O
mice	B
.	O

Discussion	O

In	O
the	O
elderly	O
,	O
systemic	O
infection	O
is	O
associated	O
with	O
an	O
increased	O
frequency	O
of	O
behavioral	O
and	O
cognitive	O
complications	O
[	O
57	O
,	O
58	O
]	O
.	O

We	O
have	O
reported	O
that	O
stimulation	O
of	O
the	O
peripheral	O
immune	O
system	O
in	O
older	O
(	O
20	O
-	O
24	O
m	O
)	O
BALB	O
/	O
c	O
mice	B
causes	O
exaggerated	O
neuroinflammation	O
that	O
is	O
paralleled	O
by	O
prolonged	O
sickness	O
[	O
13	O
]	O
,	O
impaired	O
working	O
memory	O
[	O
10	O
]	O
,	O
and	O
depressive	O
-	O
like	O
behaviors	O
[	O
15	O
]	O
.	O

Therefore	O
,	O
it	O
is	O
important	O
to	O
understand	O
the	O
mechanisms	O
that	O
can	O
modulate	O
cytokine	O
-	O
mediated	O
pathways	O
in	O
the	O
brain	O
.	O

Here	O
we	O
show	O
that	O
minocycline	O
treatment	O
reduced	O
LPS	O
-	O
induced	O
TLR2	O
expression	O
in	O
BV	O
-	O
2	O
cells	O
and	O
on	O
microglia	O
isolated	O
from	O
adult	O
mice	B
.	O

Moreover	O
,	O
we	O
demonstrate	O
that	O
minocycline	O
was	O
effective	O
in	O
facilitating	O
the	O
recovery	O
from	O
LPS	O
-	O
induced	O
sickness	O
and	O
preventing	O
anhedonia	O
in	O
adult	O
mice	B
.	O

Furthermore	O
,	O
we	O
show	O
that	O
minocycline	O
attenuated	O
LPS	O
-	O
induced	O
neuroinflammation	O
in	O
adults	O
and	O
normalized	O
the	O
exaggerated	O
neuroinflammation	O
in	O
aged	O
mice	B
.	O

Our	O
findings	O
,	O
using	O
cell	O
culture	O
and	O
animal	O
experiments	O
,	O
support	O
the	O
notion	O
that	O
minocycline	O
attenuates	O
microglial	O
activation	O
and	O
limits	O
production	O
of	O
inflammatory	O
mediators	O
.	O

For	O
instance	O
,	O
minocycline	O
pretreatment	O
of	O
BV	O
-	O
2	O
cultures	O
decreased	O
LPS	O
-	O
stimulated	O
cytokine	O
production	O
in	O
a	O
dose	O
dependent	O
manner	O
(	O
Fig	O
.	O
1A	O
)	O
.	O

In	O
BV	O
-	O
2	O
cells	O
,	O
minocycline	O
also	O
attenuated	O
mRNA	O
expression	O
of	O
inflammatory	O
genes	O
including	O
IL	O
-	O
6	O
,	O
IL	O
-	O
1	O
beta	O
,	O
MHC	O
II	O
,	O
and	O
TLR2	O
(	O
Fig	O
.	O
1D	O
)	O
.	O

These	O
data	O
are	O
consistent	O
with	O
other	O
studies	O
using	O
minocycline	O
and	O
LPS	O
in	O
BV	O
-	O
2	O
cells	O
[	O
44	O
,	O
59	O
]	O
.	O

Based	O
on	O
these	O
data	O
we	O
next	O
investigated	O
if	O
microglial	O
activation	O
could	O
be	O
attenuated	O
in	O
the	O
brain	O
.	O

Because	O
LPS	O
increases	O
brain	O
cytokine	O
production	O
we	O
expected	O
that	O
MHC	O
II	O
expression	O
would	O
also	O
be	O
increased	O
.	O

Contrary	O
to	O
our	O
predictions	O
,	O
neither	O
MHC	O
II	O
mRNA	O
levels	O
(	O
Fig	O
.	O
7	O
)	O
in	O
the	O
brain	O
nor	O
MHC	O
II	O
surface	O
expression	O
on	O
microglia	O
(	O
CD11b	O
+	O
/	O
CD45low	O
)	O
(	O
data	O
not	O
shown	O
)	O
were	O
increased	O
by	O
LPS	O
injection	O
.	O

In	O
an	O
EAE	O
model	O
,	O
minocycline	O
reduced	O
microglial	O
expression	O
of	O
MHC	O
II	O
[	O
45	O
]	O
,	O
but	O
one	O
key	O
difference	O
from	O
our	O
study	O
is	O
that	O
the	O
induction	O
of	O
EAE	O
pathology	O
requires	O
functional	O
antigen	O
presentation	O
on	O
MHC	O
II	O
[	O
60	O
]	O
.	O

It	O
is	O
postulated	O
that	O
microglia	O
have	O
several	O
activation	O
states	O
that	O
depend	O
on	O
the	O
specific	O
inflammatory	O
stimulus	O
[	O
61	O
]	O
.	O

Thus	O
,	O
in	O
situations	O
of	O
transient	O
peripheral	O
innate	O
immune	O
stimulation	O
,	O
markers	O
in	O
the	O
CNS	O
such	O
as	O
Toll	O
-	O
Like	O
receptors	O
[	O
6	O
]	O
may	O
be	O
indicative	O
of	O
microglia	O
activation	O
.	O

In	O
support	O
of	O
this	O
premise	O
,	O
our	O
data	O
show	O
that	O
LPS	O
injection	O
increases	O
TLR2	O
surface	O
expression	O
on	O
microglia	O
(	O
CD11b	O
+	O
/	O
CD45low	O
)	O
,	O
which	O
is	O
inhibited	O
by	O
minocycline	O
pretreatment	O
(	O
Fig	O
.	O
2	O
)	O
.	O

These	O
data	O
are	O
consistent	O
with	O
other	O
studies	O
showing	O
that	O
central	O
or	O
peripheral	O
LPS	O
challenge	O
increases	O
TLR2	O
mRNA	O
in	O
the	O
brain	O
[	O
6	O
,	O
14	O
]	O
.	O

Taken	O
together	O
our	O
findings	O
can	O
be	O
interpreted	O
to	O
suggest	O
that	O
minocycline	O
attenuates	O
pathways	O
associated	O
with	O
microglia	O
activation	O
following	O
peripheral	O
LPS	O
challenge	O
.	O

One	O
of	O
the	O
important	O
findings	O
of	O
this	O
study	O
was	O
that	O
reduction	O
of	O
neuroinflammation	O
by	O
minocycline	O
was	O
associated	O
with	O
facilitated	O
recovery	O
from	O
LPS	O
-	O
induced	O
sickness	O
behavior	O
.	O

These	O
results	O
are	O
akin	O
to	O
our	O
previous	O
work	O
with	O
the	O
anti	O
-	O
oxidant	O
,	O
alpha	O
-	O
tocopherol	O
[	O
52	O
]	O
,	O
and	O
an	O
NFKB	O
decoy	O
inhibitor	O
[	O
62	O
]	O
.	O

Consistent	O
with	O
our	O
previous	O
studies	O
[	O
52	O
,	O
53	O
,	O
62	O
,	O
63	O
]	O
,	O
reductions	O
in	O
neuroinflammatory	O
cytokines	O
(	O
Fig	O
.	O
5	O
)	O
did	O
not	O
prevent	O
the	O
induction	O
of	O
the	O
LPS	O
-	O
induced	O
sickness	O
response	O
(	O
2	O
-	O
4	O
h	O
)	O
,	O
but	O
rather	O
facilitated	O
the	O
recovery	O
from	O
sickness	O
(	O
8	O
-	O
24	O
h	O
)	O
(	O
Fig	O
.	O
3A	O
)	O
.	O

Recovery	O
may	O
be	O
a	O
critical	O
issue	O
because	O
brain	O
cytokines	O
and	O
the	O
corresponding	O
physiological	O
and	O
behavioral	O
responses	O
are	O
beneficial	O
to	O
the	O
host	O
[	O
1	O
]	O
.	O

The	O
potential	O
risk	O
for	O
a	O
maladaptive	O
response	O
occurs	O
when	O
the	O
normally	O
transient	O
neuroinflammatory	O
response	O
is	O
amplified	O
or	O
protracted	O
[	O
64	O
]	O
.	O

Therefore	O
pharmacological	O
agents	O
,	O
similar	O
to	O
minocycline	O
,	O
that	O
attenuate	O
neuroinflammatory	O
responses	O
,	O
but	O
do	O
not	O
completely	O
inhibit	O
them	O
,	O
may	O
be	O
important	O
in	O
preventing	O
the	O
development	O
of	O
more	O
severe	O
and	O
long	O
-	O
lasting	O
cognitive	O
and	O
behavioral	O
complications	O
.	O

The	O
results	O
of	O
the	O
sucrose	O
preference	O
experiments	O
support	O
the	O
idea	O
that	O
limiting	O
exposure	O
to	O
neuroinflammation	O
decreases	O
the	O
duration	O
of	O
behavioral	O
responses	O
.	O

For	O
example	O
,	O
while	O
minocycline	O
did	O
not	O
inhibit	O
cytokine	O
expression	O
(	O
Fig	O
.	O
5	O
)	O
or	O
the	O
induction	O
of	O
sickness	O
(	O
Fig	O
.	O
3A	O
)	O
,	O
minocycline	O
pretreatment	O
completely	O
reversed	O
the	O
reduction	O
in	O
sucrose	O
preference	O
(	O
i	O
.	O
e	O
.	O
,	O
anhedonia	O
)	O
associated	O
with	O
LPS	O
injection	O
(	O
Fig	O
.	O
4	O
)	O
.	O

It	O
is	O
also	O
important	O
to	O
mention	O
that	O
while	O
LPS	O
-	O
associated	O
sickness	O
and	O
anhedonia	O
are	O
interrelated	O
,	O
these	O
behaviors	O
can	O
be	O
differentiated	O
from	O
one	O
another	O
.	O

For	O
instance	O
,	O
reduced	O
social	O
exploration	O
was	O
evident	O
2	O
-	O
24	O
h	O
post	O
injection	O
(	O
Fig	O
.	O
3A	O
)	O
,	O
but	O
only	O
decreased	O
sucrose	O
preference	O
was	O
exhibited	O
24	O
to	O
39	O
h	O
later	O
(	O
Fig	O
.	O
4	O
)	O
.	O

This	O
separation	O
between	O
behaviors	O
is	O
consistent	O
with	O
other	O
studies	O
investigating	O
sickness	O
and	O
longer	O
-	O
lasting	O
changes	O
in	O
motivation	O
[	O
15	O
,	O
65	O
,	O
66	O
]	O
.	O

IDO	O
mediated	O
TRP	O
metabolism	O
represents	O
a	O
potential	O
connection	O
between	O
activation	O
of	O
CNS	O
innate	O
immune	O
cells	O
and	O
longer	O
lasting	O
behavioral	O
responses	O
.	O

IDO	O
mediated	O
TRP	O
metabolism	O
in	O
the	O
brain	O
may	O
affect	O
behavior	O
by	O
impacting	O
both	O
serotonin	O
and	O
glutamate	O
pathways	O
[	O
39	O
]	O
.	O

We	O
have	O
reported	O
that	O
IDO	O
induction	O
and	O
activity	O
is	O
amplified	O
in	O
the	O
brain	O
of	O
aged	O
mice	B
and	O
is	O
associated	O
with	O
prolonged	O
depressive	O
-	O
like	O
behavior	O
[	O
15	O
]	O
.	O

Here	O
we	O
show	O
that	O
IDO	O
mRNA	O
induction	O
is	O
blocked	O
by	O
minocycline	O
in	O
the	O
brain	O
of	O
both	O
adult	O
and	O
aged	O
mice	B
(	O
Figs	O
.	O
5	O
&	O
7	O
)	O
.	O

These	O
data	O
are	O
consistent	O
with	O
a	O
recent	O
report	O
showing	O
a	O
causal	O
relationship	O
between	O
IDO	O
activity	O
and	O
acute	O
depressive	O
effects	O
in	O
adult	O
CD	O
-	O
1	O
mice	B
.	O

In	O
this	O
study	O
,	O
O	O
'	O
Connor	O
et	O
al	O
.	O
report	O
that	O
both	O
1	O
-	O
methyl	O
tryptophan	O
(	O
a	O
competitive	O
inhibitor	O
of	O
IDO	O
)	O
and	O
minocycline	O
blocked	O
IDO	O
induction	O
and	O
prevented	O
depressive	O
-	O
like	O
immobility	O
in	O
the	O
tail	O
suspension	O
and	O
forced	O
swimming	O
tests	O
[	O
66	O
]	O
.	O

Thus	O
,	O
in	O
the	O
present	O
study	O
,	O
the	O
minocycline	O
blockade	O
of	O
IDO	O
induction	O
may	O
explain	O
the	O
abrogation	O
of	O
LPS	O
-	O
induced	O
anhedonia	O
.	O

Another	O
interesting	O
finding	O
was	O
that	O
while	O
minocycline	O
pretreatment	O
in	O
adult	O
mice	B
attenuated	O
LPS	O
-	O
induced	O
brain	O
IL	O
-	O
1	O
beta	O
at	O
4	O
h	O
(	O
Fig	O
.	O
5	O
)	O
,	O
it	O
had	O
no	O
effect	O
on	O
plasma	O
IL	O
-	O
1	O
beta	O
levels	O
(	O
Fig	O
.	O
6	O
)	O
.	O

Because	O
IL	O
-	O
1	O
beta	O
signals	O
can	O
be	O
relayed	O
from	O
the	O
periphery	O
to	O
the	O
brain	O
by	O
humoral	O
pathways	O
[	O
5	O
]	O
,	O
these	O
findings	O
suggest	O
that	O
minocycline	O
has	O
anti	O
-	O
inflammatory	O
properties	O
within	O
the	O
brain	O
.	O

These	O
data	O
are	O
consistent	O
with	O
related	O
findings	O
that	O
minocycline	O
readily	O
crosses	O
the	O
blood	O
brain	O
barrier	O
to	O
elicit	O
an	O
anti	O
-	O
inflammatory	O
effect	O
[	O
41	O
-	O
43	O
]	O
.	O

With	O
regard	O
to	O
IL	O
-	O
6	O
,	O
minocycline	O
pretreatment	O
attenuated	O
both	O
brain	O
and	O
plasma	O
levels	O
at	O
4	O
h	O
post	O
LPS	O
injection	O
.	O

Because	O
circulating	O
IL	O
-	O
6	O
levels	O
can	O
be	O
increased	O
by	O
CNS	O
mediated	O
pathways	O
including	O
activation	O
of	O
the	O
hypothalamus	O
-	O
pituitary	O
-	O
adrenal	O
(	O
HPA	O
)	O
axis	O
[	O
67	O
]	O
and	O
the	O
sympathetic	O
nervous	O
system	O
[	O
68	O
]	O
,	O
the	O
specific	O
reduction	O
in	O
plasma	O
IL	O
-	O
6	O
by	O
minocycline	O
may	O
reflect	O
the	O
reduction	O
in	O
brain	O
inflammation	O
at	O
4	O
h	O
(	O
Fig	O
.	O
5	O
)	O
.	O

In	O
support	O
of	O
this	O
notion	O
,	O
we	O
and	O
others	O
have	O
reported	O
that	O
i	O
.	O
c	O
.	O
v	O
.	O
injection	O
of	O
LPS	O
or	O
IL	O
-	O
1	O
beta	O
increase	O
plasma	O
IL	O
-	O
6	O
levels	O
,	O
but	O
not	O
IL	O
-	O
1	O
beta	O
levels	O
[	O
14	O
,	O
68	O
,	O
69	O
]	O
.	O

The	O
final	O
critical	O
finding	O
of	O
this	O
study	O
was	O
that	O
minocycline	O
was	O
effective	O
in	O
attenuating	O
neuroinflammation	O
independent	O
of	O
age	O
.	O

Consistent	O
with	O
other	O
aging	O
and	O
neuroinflammation	O
studies	O
,	O
our	O
data	O
show	O
that	O
LPS	O
caused	O
exaggerated	O
neuroinflammation	O
in	O
aged	O
mice	B
compared	O
to	O
adults	O
[	O
10	O
,	O
13	O
-	O
15	O
]	O
.	O

It	O
is	O
important	O
to	O
mention	O
that	O
while	O
there	O
was	O
an	O
age	O
-	O
related	O
difference	O
in	O
MHC	O
II	O
expression	O
in	O
the	O
hippocampus	O
of	O
saline	O
treated	O
mice	B
(	O
Fig	O
.	O
7A	O
)	O
there	O
was	O
not	O
an	O
age	O
-	O
related	O
difference	O
in	O
IL	O
-	O
1	O
beta	O
and	O
IL	O
-	O
6	O
mRNA	O
levels	O
.	O

These	O
data	O
differ	O
from	O
a	O
previous	O
report	O
using	O
BALB	O
/	O
c	O
mice	B
showing	O
an	O
increase	O
in	O
IL	O
-	O
6	O
in	O
older	O
mice	B
[	O
70	O
]	O
.	O

This	O
may	O
be	O
because	O
the	O
mice	B
used	O
in	O
the	O
present	O
study	O
were	O
approximately	O
4	O
months	O
younger	O
than	O
the	O
mice	B
used	O
previously	O
.	O

Nonetheless	O
,	O
microglia	O
can	O
be	O
primed	O
or	O
reactive	O
with	O
increased	O
MHC	O
II	O
expression	O
,	O
but	O
do	O
not	O
necessarily	O
produce	O
inflammatory	O
cytokines	O
in	O
this	O
state	O
[	O
19	O
]	O
.	O

The	O
key	O
results	O
are	O
that	O
peripheral	O
LPS	O
injection	O
causes	O
a	O
greater	O
induction	O
of	O
TLR2	O
,	O
IL	O
-	O
1	O
beta	O
,	O
and	O
IDO	O
mRNA	O
in	O
the	O
aged	O
brain	O
than	O
in	O
the	O
adult	O
brain	O
and	O
that	O
minocycline	O
pretreatment	O
normalizes	O
this	O
age	O
-	O
related	O
exaggerated	O
neuroinflammation	O
(	O
Fig	O
.	O
7	O
)	O
.	O

These	O
findings	O
are	O
also	O
important	O
because	O
an	O
amplified	O
neuroinflammatory	O
response	O
in	O
the	O
aged	O
brain	O
is	O
a	O
precursor	O
to	O
complications	O
including	O
deficits	O
in	O
working	O
memory	O
,	O
memory	O
consolidation	O
,	O
and	O
depressive	O
-	O
like	O
behavior	O
[	O
9	O
,	O
10	O
,	O
15	O
]	O
.	O

Based	O
on	O
the	O
biochemical	O
and	O
behavioral	O
data	O
obtained	O
from	O
this	O
study	O
,	O
we	O
predict	O
that	O
minocycline	O
will	O
abrogate	O
the	O
prolonged	O
LPS	O
-	O
induced	O
sickness	O
[	O
13	O
]	O
and	O
depressive	O
-	O
like	O
behavior	O
exhibited	O
by	O
aged	O
BALB	O
/	O
c	O
mice	B
[	O
15	O
]	O
.	O

We	O
acknowledge	O
,	O
however	O
,	O
that	O
future	O
studies	O
are	O
necessary	O
to	O
test	O
these	O
predictions	O
.	O

Conclusion	O

The	O
present	O
study	O
demonstrates	O
that	O
minocycline	O
reduces	O
LPS	O
-	O
induced	O
microglial	O
activation	O
,	O
CNS	O
cytokine	O
production	O
,	O
and	O
behavioral	O
symptoms	O
of	O
sickness	O
(	O
e	O
.	O
g	O
.	O
,	O
social	O
withdrawal	O
and	O
anhedonia	O
)	O
.	O

These	O
findings	O
are	O
potentially	O
important	O
because	O
they	O
indicate	O
that	O
minocycline	O
can	O
be	O
used	O
to	O
mitigate	O
cytokine	O
expression	O
in	O
the	O
brain	O
and	O
have	O
a	O
beneficial	O
affect	O
on	O
behavioral	O
responses	O
.	O

Taken	O
together	O
,	O
these	O
data	O
support	O
the	O
idea	O
that	O
pharmacological	O
strategies	O
aimed	O
at	O
decreasing	O
neuroinflammation	O
associated	O
with	O
microglial	O
activation	O
are	O
important	O
for	O
improving	O
recovery	O
from	O
sickness	O
and	O
reducing	O
the	O
frequency	O
of	O
neurobehavioral	O
complications	O
.	O

List	O
of	O
abbreviations	O

3	O
-	O
Hydroxy	O
-	O
L	O
-	O
Kynuriene	O
(	O
3HK	O
)	O
,	O
Allophycocyanin	O
(	O
APC	O
)	O
,	O
Analysis	O
of	O
variance	O
(	O
ANOVA	O
)	O
,	O
Central	O
Nervous	O
System	O
(	O
CNS	O
)	O
,	O
Dulbecco	O
'	O
s	O
Modified	O
Eagle	O
'	O
s	O
Medium	O
(	O
DMEM	O
)	O
,	O
Dimethyl	O
Sulfoxide	O
(	O
DMSO	O
)	O
,	O
Experimental	O
Autoimmune	O
Encephalomyelitis	O
(	O
EAE	O
)	O
,	O
Enzyme	O
Linked	O
Immmunosorbent	O
Assay	O
(	O
ELISA	O
)	O
,	O
Fluorescein	O
Isothiocyanate	O
(	O
FITC	O
)	O
,	O
Fetal	O
Bovine	B
Serum	O
(	O
FBS	O
)	O
,	O
Hank	O
'	O
s	O
Balanced	O
Salt	O
Solution	O
(	O
HBSS	O
)	O
,	O
Indoleamine	O
2	O
,	O
3	O
dioxygenase	O
(	O
IDO	O
)	O
,	O
Intraperitoneal	O
(	O
i	O
.	O
p	O
.	O
)	O
,	O
Intracerebroventricu	O
(	O
i	O
.	O
c	O
.	O
v	O
.	O
)	O
,	O
Interleukin	O
(	O
IL	O
)	O
,	O
Kynurenine	O
(	O
KYN	O
)	O
,	O
Lipopolysaccharide	O
(	O
LPS	O
)	O
,	O
Major	O
Histocompatibility	O
Complex	O
class	O
II	O
(	O
MHC	O
II	O
)	O
,	O
Mitogen	O
Activated	O
Protein	O
Kinase	O
(	O
MAP	O
-	O
kinase	O
)	O
,	O
Nuclear	O
factor	O
kappa	O
B	O
(	O
NF	O
kappa	O
B	O
)	O
,	O
N	O
-	O
methyl	O
-	O
D	O
-	O
aspartate	O
(	O
NMDA	O
)	O
,	O
R	O
-	O
Phycoerthrin	O
(	O
PE	O
)	O
,	O
Quinolinic	O
acid	O
(	O
QUIN	O
)	O
,	O
Statistical	O
Analysis	O
Systems	O
(	O
SAS	O
)	O
,	O
Standard	O
Error	O
of	O
the	O
Mean	O
(	O
SEM	O
)	O
,	O
Toll	O
-	O
like	O
Receptor	O
-	O
2	O
(	O
TLR2	O
)	O
,	O
and	O
Tryptophan	O
(	O
TRP	O
)	O
.	O

Competing	O
interests	O

The	O
authors	O
of	O
this	O
manuscript	O
declare	O
that	O
there	O
are	O
no	O
actual	O
or	O
potential	O
conflicts	O
of	O
interest	O
.	O

The	O
authors	O
affirm	O
that	O
there	O
are	O
no	O
financial	O
,	O
personal	O
or	O
other	O
relationships	O
with	O
other	O
people	B
or	O
organizations	O
that	O
have	O
inappropriately	O
influenced	O
or	O
biased	O
their	O
research	O
.	O

Authors	O
'	O
contributions	O

CJH	O
was	O
involved	O
in	O
research	O
experimentation	O
,	O
completion	O
of	O
statistical	O
analysis	O
,	O
and	O
writing	O
of	O
the	O
manuscript	O
.	O

YH	O
,	O
AW	O
,	O
MH	O
and	O
JH	O
assisted	O
with	O
experimentation	O
and	O
data	O
analysis	O
.	O

MB	O
and	O
JFS	O
contributed	O
to	O
the	O
design	O
of	O
the	O
experiments	O
and	O
assisted	O
in	O
editing	O
the	O
manuscript	O
.	O

JPG	O
directed	O
all	O
aspects	O
of	O
this	O
research	O
project	O
including	O
the	O
experimental	O
design	O
,	O
research	O
experimentation	O
,	O
completion	O
of	O
statistical	O
analysis	O
,	O
and	O
writing	O
of	O
the	O
manuscript	O
.	O

A	O
case	O
of	O
demand	O
ischemia	O
from	O
phendimetrazine	O

Abstract	O

Introduction	O

Phendimetrazine	O
is	O
a	O
medication	O
currently	O
being	O
used	O
to	O
help	O
patients	B
with	O
weight	O
loss	O
.	O

It	O
shares	O
a	O
chemical	O
structure	O
with	O
amphetamines	O
.	O

As	O
such	O
,	O
it	O
shares	O
some	O
of	O
the	O
same	O
toxicities	O
,	O
which	O
can	O
include	O
cardiac	O
toxicity	O
.	O

This	O
case	O
highlights	O
this	O
principle	O
.	O

Case	O
presentation	O

a	O
54	O
year	O
old	O
Caucasian	O
female	O
presented	O
to	O
our	O
urgent	O
care	O
facility	O
with	O
complaints	O
of	O
chest	O
pains	O
and	O
other	O
symptoms	O
suggestive	O
of	O
acute	O
coronary	O
syndrome	O
.	O

Ultimately	O
,	O
she	O
was	O
transferred	O
to	O
the	O
emergency	O
room	O
.	O

After	O
evaluation	O
there	O
,	O
it	O
appeared	O
she	O
was	O
having	O
demand	O
ischemia	O
from	O
prescription	O
diet	O
pills	O

Conclusion	O

This	O
case	O
report	O
demonstrates	O
the	O
potential	O
dangers	O
of	O
amphetamine	O
based	O
diet	O
pills	O
.	O

There	O
have	O
been	O
other	O
cases	O
of	O
cardiomyopathies	O
related	O
to	O
phendimetrazine	O
,	O
but	O
it	O
is	O
something	O
that	O
is	O
rarely	O
recognized	O
in	O
an	O
outpatient	O
setting	O
.	O

A	O
case	O
such	O
as	O
this	O
demonstrates	O
the	O
importance	O
of	O
obtaining	O
a	O
careful	O
medication	O
history	O
in	O
all	O
patients	B
and	O
in	O
recognizing	O
diet	O
pills	O
with	O
an	O
amphetamine	O
base	O
can	O
cause	O
cardiac	O
toxicity	O
.	O

Case	O
presentation	O

A	O
54	O
year	O
-	O
old	O
Caucasian	O
female	O
presented	O
to	O
our	O
urgent	O
care	O
facility	O
complaining	O
of	O
nausea	O
and	O
vomiting	O
,	O
sense	O
of	O
impending	O
doom	O
and	O
vague	O
chest	O
pain	O
radiating	O
toward	O
her	O
left	O
side	O
for	O
about	O
five	O
hours	O
.	O

She	O
never	O
had	O
similar	O
symptoms	O
in	O
the	O
past	O
.	O

She	O
also	O
denied	O
anything	O
that	O
could	O
have	O
precipitated	O
these	O
symptoms	O
.	O

Her	O
only	O
past	O
medical	O
history	O
was	O
significant	O
for	O
spina	O
bifida	O
.	O

Her	O
medications	O
included	O
occasional	O
Fiorinal	O
(	O
unknown	O
dose	O
)	O
,	O
Xanax	O
0	O
.	O
5	O
mg	O
as	O
needed	O
,	O
and	O
Phendimetrazine	O
(	O
unclear	O
dose	O
)	O
.	O

Her	O
social	O
history	O
was	O
significant	O
for	O
smoking	O
1	O
/	O
2	O
pack	O
per	O
day	O
cigarette	O
use	O
.	O

She	O
denied	O
alcohol	O
use	O
.	O

Family	O
history	O
was	O
non	O
contributory	O
.	O

She	O
worked	O
from	O
home	O
.	O

Her	O
physical	O
exam	O
showed	O
a	O
tachycardia	O
of	O
around	O
100	O
beats	O
per	O
minute	O
,	O
respiratory	O
rate	O
of	O
16	O
,	O
temperature	O
of	O
98	O
.	O
1	O
,	O
and	O
O2	O
saturation	O
of	O
100	O
%	O
on	O
room	O
air	O
.	O

She	O
was	O
approximately	O
5	O
'	O
7	O
"	O
and	O
145	O
pounds	O
.	O

In	O
general	O
,	O
she	O
was	O
an	O
anxious	O
appearing	O
,	O
diaphoretic	O
woman	B
in	O
moderate	O
distress	O
,	O
she	O
had	O
no	O
elevated	O
JVD	O
at	O
30	O
degrees	O
,	O
her	O
heart	O
was	O
tachycardic	O
,	O
but	O
otherwise	O
without	O
murmur	O
,	O
gallops	O
,	O
or	O
rubs	O
,	O
her	O
lungs	O
were	O
clear	O
,	O
abdomen	O
soft	O
,	O
and	O
she	O
had	O
no	O
peripheral	O
edema	O
.	O

An	O
EKG	O
was	O
checked	O
which	O
appears	O
below	O
(	O
figure	O
1	O
)	O
.	O

After	O
examination	O
,	O
there	O
was	O
concern	O
for	O
acute	O
coronary	O
syndrome	O
(	O
ACS	O
)	O
.	O

She	O
was	O
given	O
nitroglycerin	O
with	O
relief	O
of	O
her	O
chest	O
discomfort	O
.	O

She	O
was	O
also	O
given	O
aspirin	O
to	O
chew	O
.	O

EMS	O
was	O
called	O
and	O
she	O
was	O
transferred	O
to	O
a	O
local	O
emergency	O
room	O
.	O

She	O
was	O
hospitalized	O
there	O
for	O
three	O
days	O
and	O
after	O
her	O
discharge	O
,	O
we	O
got	O
permission	O
from	O
her	O
to	O
request	O
records	O
.	O

While	O
hospitalized	O
,	O
she	O
was	O
ruled	O
out	O
for	O
ACS	O
with	O
negative	O
troponins	O
.	O

She	O
was	O
also	O
given	O
beta	O
blockade	O
which	O
resolved	O
her	O
tachycardia	O
and	O
her	O
T	O
wave	O
changes	O
on	O
EKG	O
.	O

The	O
next	O
morning	O
,	O
she	O
had	O
an	O
adenosine	O
stress	O
test	O
which	O
revealed	O
normal	O
uptake	O
with	O
no	O
areas	O
of	O
ischemia	O
and	O
an	O
ejection	O
fraction	O
of	O
55	O
%	O
.	O

She	O
was	O
monitored	O
for	O
one	O
more	O
day	O
and	O
then	O
discharged	O
with	O
instructions	O
to	O
discontinue	O
her	O
diet	O
pills	O
.	O

Discussion	O

Phendimetrazine	O
is	O
a	O
medication	O
currently	O
being	O
used	O
for	O
weight	O
loss	O
,	O
with	O
potential	O
for	O
illicit	O
use	O
.	O

It	O
has	O
a	O
similar	O
chemical	O
composition	O
of	O
amphetamines	O
,	O
which	O
is	O
thought	O
to	O
account	O
for	O
its	O
clinical	O
actions	O
[	O
1	O
]	O
.	O

Amphetamines	O
are	O
well	O
recognized	O
as	O
an	O
etiology	O
of	O
cardiac	O
ischemia	O
,	O
however	O
phendimetrazine	O
is	O
more	O
rarely	O
described	O
in	O
the	O
literature	O
as	O
causing	O
cardiac	O
events	O
.	O

[	O
2	O
,	O
3	O
]	O
.	O

Acute	O
effects	O
include	O
hyperpyrexia	O
,	O
mydriasis	O
,	O
chest	O
pain	O
,	O
arrhytmias	O
,	O
delirium	O
,	O
and	O
,	O
rhabdomylosis	O
,	O
among	O
others	O
[	O
2	O
]	O
.	O

Long	O
term	O
use	O
has	O
been	O
associated	O
with	O
dilated	O
cardiomyopathies	O
,	O
some	O
of	O
which	O
have	O
resolved	O
with	O
discontinuation	O
of	O
the	O
medication	O
[	O
3	O
]	O
.	O

In	O
this	O
particular	O
case	O
,	O
it	O
appears	O
she	O
may	O
have	O
developed	O
a	O
demand	O
ischemia	O
from	O
the	O
medication	O
.	O

It	O
is	O
not	O
known	O
how	O
much	O
of	O
the	O
drug	O
she	O
was	O
taking	O
.	O

Initially	O
,	O
she	O
was	O
resistant	O
to	O
accepting	O
that	O
phendimetrazine	O
could	O
induce	O
side	O
effects	O
,	O
and	O
there	O
was	O
suspicion	O
that	O
she	O
could	O
have	O
been	O
taking	O
more	O
of	O
the	O
drug	O
that	O
recommended	O
.	O

In	O
addition	O
,	O
she	O
was	O
not	O
prescribed	O
the	O
medication	O
and	O
would	O
not	O
admit	O
to	O
where	O
she	O
obtained	O
it	O
.	O

As	O
the	O
public	O
seems	O
to	O
have	O
more	O
focus	O
on	O
using	O
medications	O
to	O
induce	O
weight	O
loss	O
,	O
this	O
may	O
be	O
a	O
more	O
recognized	O
complication	O
and	O
heart	O
conditions	O
should	O
likely	O
be	O
monitored	O
prior	O
to	O
starting	O
amphetamine	O
based	O
weight	O
loss	O
pills	O
.	O

Conclusion	O

Due	O
to	O
potentially	O
detrimental	O
effects	O
of	O
this	O
medication	O
,	O
phendimetrazine	O
should	O
be	O
used	O
cautiously	O
in	O
many	O
situations	O
.	O

As	O
it	O
shares	O
its	O
chemical	O
structure	O
with	O
amphetamines	O
,	O
it	O
also	O
shares	O
many	O
of	O
the	O
side	O
effects	O
and	O
the	O
potential	O
for	O
abuse	O
/	O
addiction	O
.	O

There	O
have	O
been	O
other	O
reports	O
in	O
literature	O
describing	O
adverse	O
outcomes	O
from	O
phendimetrazine	O
as	O
well	O
as	O
other	O
weight	O
loss	O
medications	O
.	O

Therefore	O
,	O
cautious	O
use	O
is	O
warranted	O
.	O

Abbreviations	O

ACS	O
:	O
Acute	O
Coronary	O
Syndrome	O
.	O

Competing	O
interests	O

The	O
authors	O
declare	O
that	O
they	O
have	O
no	O
competing	O
interests	O
.	O

Authors	O
'	O
contributions	O

DL	O
,	O
JJ	O
,	O
GG	O
have	O
all	O
been	O
involved	O
in	O
and	O
approve	O
of	O
the	O
writing	O
of	O
this	O
case	O
presentation	O
.	O

Consent	O

Written	O
informed	O
consent	O
was	O
obtained	O
from	O
the	O
patient	O
for	O
publication	O
purposes	O
.	O

A	O
copy	O
can	O
be	O
obtained	O
if	O
requested	O
by	O
the	O
Editor	O
in	O
Chief	O
of	O
this	O
journal	O
.	O

Advanced	O
software	O
concepts	O
for	O
employing	O
microcomputers	O
in	O
the	O

laboratory	O

Abstract	O

IIII	O

II	O

,	O
Advanced	O
software	O
concepts	O
for	O

employing	O
microcomputers	O
in	O
the	O
laboratory	O
Scott	O
B	O
.	O
Tilden	O
and	O
M	O
.	O
Bonner	O
Denton	O
,	O
Department	O
of	O
Chemistry	O
,	O
University	O
of	O
Arizona	O
,	O
Tucson	O
,	O
Arizona	O
85721	O
,	O
USA	O
.	O

Introduction	O
While	O
a	O
proliferation	O
of	O
commercial	O
chemical	O
instrumentation	O
is	O
appearing	O
today	O
employing	O
microprocessors	O
for	O
a	O
variety	O
of	O
control	O
and	O
data	O
reduction	O
applications	O
,	O
the	O
great	O
potential	O
of	O
microprocessors	O
has	O
not	O
been	O
exploited	O
extensively	O
for	O
individual	O
custom	O
applications	O
.	O

The	O
primary	O
reason	O
for	O
this	O
phenomenon	O
is	O
altogether	O
too	O
clear	O
microprocessor	O
software	O
is	O
either	O
difficult	O
to	O
develop	O
or	O
inefficient	O
in	O
memory	O
requirements	O
and	O
speed	O
.	O

This	O
problem	O
is	O
even	O
more	O
important	O
in	O
situations	O
requiring	O
constant	O
software	O

modification	O
.	O

Initially	O
,	O
most	O
instrument	O
manufacturers	O
utilized	O
cross	O
assemblers	O
supported	O
on	O
large	O
"	O
number	O
cruncher	O
"	O
computers	O
to	O
generate	O
the	O
required	O
machine	O
code	O
binary	O
program	O
.	O

More	O
recently	O
,	O
the	O
trend	O
has	O
been	O
toward	O
the	O
use	O
of	O
a	O
"	O
developmental	O
system	O
"	O
(	O
at	O
a	O
cost	O
comparable	O
to	O
a	O
moderate	O
minicomputer	O
-	O
the	O
authors	O
use	O
the	O
term	O
"	O
mini	O
"	O
in	O
contrast	O
to	O
"	O
micro	O
"	O
reluctantly	O
because	O
of	O
the	O
ever	O
increasing	O
overlap	O
in	O
computing	O
capability	O
)	O
to	O
write	O
and	O
debug	O
assembly	O
level	O
porgrams	O
which	O
are	O
subsequently	O
converted	O
to	O
binary	O
and	O
incorporated	O
into	O
an	O
instrument	O
in	O
the	O
form	O
of	O
"	O
read	O
only	O
memory	O
"	O
(	O
ROM	O
)	O
.	O

While	O
this	O
approach	O

Interpretative	O
Machine	O
Code	O

Source	O
Code	O
File	O

to	O
Execute	O
Command	O
A	O
Hachine	O
Code	O
Various	O

to	O
Execute	O
Comma	O
nd	O
B	O
ne	O
Code	O

'	O
commands	O
making	O
up	O

,	O
lachi	O

to	O
Execute	O
Command	O
C	O

users	O
source	O
program	O

i	O

Machine	O
Code	O

to	O
Execute	O
Command	O
D	O

etc	O
.	O

Figure	O
1	O
.	O

The	O
interpretative	O
cycle	O
of	O
common	O
types	O
of	O
languages	O
such	O
as	O
BASIC	O
.	O

After	O
examining	O
each	O
command	O
in	O
the	O
source	O
file	O
,	O
the	O
interpreter	O
searches	O
for	O
and	O
branches	O
to	O
the	O
corresponding	O
block	O
of	O
machine	O
code	O
;	O
thus	O
,	O
program	O
execution	O
always	O
remains	O
within	O
the	O
interpreter	O
.	O

128	O

The	O
Journal	O
of	O
Automatic	O
Chemistry	O

Tilden	O
&	O
Denton	O
IIII	O

Advanced	O
software	O
concepts	O

III	O

Users	O
Source	O
File	O

The	O
Compiler	O

Command	O
A	O

Comma	O
nd	O
B	O
Command	O
C	O
Command	O
D	O
etc	O
.	O

/	O
z	O
/	O
li	O
i	O

II	O

.	O
Machine	O
Code	O

etc	O
.	O

.	O
lachi	O
ne	O
Code	O

to	O
Execute	O
Command	O
A	O

etc	O
.	O
to	O
Execute	O

Machine	O
Code	O

to	O
Execute	O
Command	O
C	O

Machine	O
Code	O

etc	O
.	O

Figure	O
2	O
.	O

Note	O
that	O
the	O
compiler	O
transforms	O
each	O
source	O
"	O
command	O
"	O
into	O
executable	O
machine	O
code	O
.	O

This	O
code	O
will	O
,	O
subsequently	O
,	O
be	O
loaded	O
and	O
executed	O
independently	O
of	O
the	O
compiler	O
.	O

has	O
proven	O
cost	O
effective	O
for	O
high	O
volume	O
mass	O
produced	O
applications	O
,	O
it	O
possesses	O
serious	O
limitations	O
for	O
system	O
updates	O
and	O
custom	O
applications	O
.	O

Additionally	O
,	O
the	O
ability	O
to	O
program	O
efficiently	O
at	O
the	O
assembly	O
level	O
is	O
a	O
talent	O
requiring	O
a	O
significant	O
expenditure	O
of	O
time	O
to	O
develop	O
.	O

During	O
the	O
past	O
several	O
years	O
,	O
a	O
virtual	O
deluge	O
of	O
sophisticated	O
,	O
flexible	O
,	O
high	O
performance	O
computer	O
hardware	O
has	O
been	O
introduced	O
primarily	O
aimed	O
at	O
a	O
rapidly	O
growing	O
"	O
hobbyist	O
"	O
market	O
.	O

Manufacturers	O
quickly	O
realilsed	O
that	O
to	O
sell	O
the	O
public	O
hardware	O
,	O
some	O
form	O
of	O
reasonably	O
high	O
level	O
software	O
must	O
be	O
made	O
available	O
.	O

A	O
variety	O
of	O
BASIC	O
interpreters	O
,	O
ranging	O
from	O
rather	O
"	O
dumb	O
"	O
to	O
"	O
quite	O
intelligent	O
"	O
have	O
since	O
evolved	O
.	O

The	O
more	O
intelligent	O
BASIC	O
interpreters	O
have	O
several	O
highly	O
attractive	O
attributes	O
for	O
"	O
hobbyist	O
"	O
applications	O
.	O

The	O
language	O
is	O
both	O
easy	O
to	O
master	O
and	O
conversational	O
.	O

Error	O
and	O
caution	O
messages	O
are	O
provided	O
as	O
aids	O
during	O
programming	O
.	O

Why	O
not	O
apply	O
the	O
"	O
hobbyist	O
"	O
technology	O
toward	O
the	O
implementation	O
of	O
custom	O
laboratory	O
systems	O
?	O

Many	O
investigators	O
have	O
and	O
,	O
no	O
doubt	O
,	O
many	O
more	O
will	O
take	O
this	O
approach	O
.	O

However	O
,	O
BASIC	O
interpreters	O
possess	O
serious	O
limitations	O
in	O
terms	O
of	O
system	O
speed	O
,	O
flexibility	O
and	O
input	O
/	O
output	O
(	O
I	O
/	O
O	O
)	O
capabilities	O
.	O

In	O
BASIC	O
,	O
each	O
command	O
must	O
first	O
be	O
interpreted	O
and	O
then	O
executed	O
(	O
see	O
Figure	O
1	O
)	O
.	O

In	O
many	O
cases	O
,	O
the	O
interpretation	O
process	O
takes	O
much	O
more	O
time	O
than	O
the	O
actual	O
execution	O
.	O

This	O
problem	O
is	O
compounded	O
by	O
the	O
fact	O
that	O
commands	O
interpreted	O
in	O
the	O
past	O
must	O
be	O
re	O
-	O
interpreted	O
each	O
time	O
they	O
are	O
used	O
causing	O
iterative	O
programs	O
to	O
be	O
very	O
slow	O
.	O

While	O
speed	O
is	O
often	O
not	O
a	O
serious	O
limitation	O
in	O
playing	O
computer	O
games	O
,	O
laboratory	O
application	O
requiring	O
high	O
speed	O
data	O
acquisition	O
and	O
/	O
or	O
data	O
manipulation	O
are	O
common	O
.	O

Additionally	O
,	O
the	O
more	O
intelligent	O
BASICs	O
make	O
very	O
inefficient	O
use	O
of	O
memory	O
often	O
requiring	O
minimum	O
of	O
12	O
or	O
16	O
K	O
bytes	O
(	O
twelve	O
or	O
sixteen	O
thousand	O
eight	O
bit	O
words	O
)	O
'	O
Volume	O

cS	O

H	O

A	O

D	O

H	O
Figure	O
3	O
.	O

The	O
'	O
threaded	O
'	O
code	O
approach	O
used	O
in	O
CONVERS	O
.	O

In	O
'	O
threaded	O
'	O
code	O
programming	O
modules	O
for	O
sub	O
-	O
routines	O
are	O
used	O
repetitively	O
in	O
a	O
variety	O
of	O
combinations	O
to	O
allow	O
implementation	O
of	O
an	O
infinite	O
number	O
of	O
functions	O
.	O

Note	O
that	O
the	O
flow	O
of	O
logic	O
threads	O
its	O
way	O
in	O
a	O
very	O
non	O
.	O
linear	O
fashion	O
through	O
these	O
modules	O
.	O

No	O
.	O
3	O
April	O
1979	O

129	O

Tilden	O

&	O
Denton	O

Advanced	O
software	O
concepts	O
|	O
I	O

Stack	O

Upper	O
Memory	O
Bound	O

User	O
'	O
s	O
Application	O
Dictionaries	O

4	O
.	O
5k	O
Octal	O
CONVERS	O
-	O
Di	O
sk	O
Operating	O
System	O

3	O
.	O
7k	O
Octal	O
Standard	O
High	O

Level	O
Dictionary	O
1	O
.	O
2k	O
Octal	O
Initial	O
Machine	O

Code	O
Dictionary	O

I	O
@	O
@	O
Octal	O

Figure	O
4	O
.	O

Memory	O
map	O
of	O
the	O
CON	O
VERS	O
dictionary	O
.	O

The	O
stack	O
which	O
is	O
composed	O
of	O
data	O
parameters	O
etc	O
.	O
acts	O
as	O
a	O
constantly	O
expanding	O
or	O
contracting	O
memory	O
buffer	O
which	O
allows	O
one	O
subroutine	O
to	O
communicate	O
with	O
another	O
without	O
either	O
needing	O
to	O
know	O
the	O
other	O
'	O
s	O
location	O
.	O

In	O
contrast	O
to	O
interpreters	O
,	O
high	O
level	O
compilers	O
,	O
such	O
as	O
FORTRAN	O
,	O
offer	O
a	O
much	O
faster	O
"	O
run	O
time	O
"	O
execution	O
speed	O
.	O

This	O
is	O
accomplished	O
through	O
generation	O
of	O
the	O
required	O
machine	O
code	O
during	O
a	O
series	O
of	O
programming	O
operations	O
.	O

Compilers	O
using	O
FORTRAN	O
,	O
which	O
are	O
designed	O
to	O
run	O
on	O
many	O
minicomputers	O
and	O
some	O
micros	O
,	O
often	O
first	O
transform	O
user	O
symbolic	O
source	O
code	O
into	O
assembly	O
code	O
.	O

An	O
assembler	O
program	O
,	O
subsequently	O
,	O
transforms	O
this	O
into	O
the	O
required	O
machine	O
code	O
.	O

This	O
ready	O
-	O
to	O
-	O
run	O
machine	O
code	O
is	O
often	O
loaded	O
along	O
with	O
a	O
run	O
time	O
package	O
which	O
executes	O
in	O
the	O
manner	O
shown	O
in	O
Figure	O
2	O
.	O

While	O
this	O
approach	O
greatly	O
improves	O
execution	O
speed	O
,	O
the	O
need	O
for	O
loading	O
several	O
different	O
soft	O
-	O
ware	O
routines	O
increases	O
the	O
"	O
hassle	O
"	O
associated	O
with	O
editing	O
and	O
debugging	O
.	O

Thus	O
,	O
this	O
makes	O
some	O
form	O
of	O
mass	O
memory	O
,	O
such	O
as	O
a	O
disk	O
or	O
magnetic	O
tape	O
,	O
almost	O
mandatory	O
.	O

Additionally	O
,	O
I	O
/	O
O	O
algorithms	O
generally	O
must	O
be	O
implemented	O
in	O
assembly	O
level	O
code	O
!	O

One	O
obvious	O
question	O
immediately	O
arises	O
-	O
why	O
not	O
incorporate	O
the	O
most	O
desirable	O
characteristics	O
of	O
both	O
interpreters	O
and	O
compilers	O
into	O
a	O
single	O
language	O
?	O

Additionally	O
,	O
due	O
to	O
the	O
unique	O
requirements	O
found	O
in	O
many	O
applications	O
,	O
why	O
not	O
allow	O
the	O
programmer	O
additional	O
flexibility	O
by	O
providing	O
him	O
with	O
the	O
ability	O
to	O
actually	O
develop	O
his	O
own	O
individual	O
modifications	O
and	O
additions	O
to	O
the	O
language	O
itself	O
?	O

Other	O
desirable	O
features	O
would	O
include	O
high	O
memory	O
efficiency	O
,	O
high	O
level	O
I	O
]	O
O	O
programming	O
,	O
ease	O
of	O
understanding	O
the	O
language	O
'	O
s	O
"	O
inter	O
-	O
working	O
"	O
and	O
the	O
ability	O
to	O
be	O
transferred	O
from	O
one	O
CPU	O
to	O
another	O
with	O
minimum	O
effort	O
.	O

Type	O
"	O
ACQUIRE	O
"	O

ACQUIRE	O

#	O
of	O
characters	O

A	O
G	O

FORMAT	O
T	O
PLOT	O

START	O
SCAN	O
GALC	O
%	O
T	O

DISPLAY	O
RETURN	O

EXECUTIVE	O

Figure	O
5	O
.	O

If	O
a	O
previously	O
defined	O
program	O
name	O
(	O
A	O
CO	O
U	O
R	O
tQ	O
is	O
entered	O
when	O
in	O
EXECUTE	O
mode	O
,	O
a	O
dictionary	O
search	O
takes	O
place	O
locating	O
the	O
ACQUIRE	O
entry	O
.	O

Once	O
found	O
,	O
this	O
entry	O
contains	O
all	O
the	O
required	O
machine	O
code	O
and	O
/	O
or	O
calls	O
to	O
addresses	O
of	O
other	O
previously	O
compiled	O
machine	O
code	O
modules	O
to	O
completely	O
execute	O
the	O
desired	O
function	O
.	O

130	O

The	O
Journal	O
of	O
Automatic	O
Chemistry	O

Tilden	O
&	O
Denton	O

Advanced	O
software	O
concepts	O

2000	O

VARIABLE	O
VARIABLE	O

START	O
STOP	O

5000	O
20	O

VARIABLE	O
VARIABLE	O
7	O

INCREMENT	O

0	O

LOCATION	O

A	O
/	O
D7	O

INDEVICE	O
START	O

INITIALIZE	O
STEP	O

@	O

LOCATION	O

LOCATION	O

@	O

INCREMENT	O
5	O
INDEVICE	O

@	O

+	O
10	O

LOCATION	O

DELAY	O
MOVE	O
SCAN	O

BEGIN	O
-	O
HERE	O
LOCATION	O

AND	O

IF	O
DELAY	O

A	O
/	O
D7	O

ELSE	O

BEGIN	O

THEN	O

@	O

5	O

OUTDEVICE	O

STEP	O

INITIALIZE	O

BEGIN	O
-	O
HERE	O

MOVE	O

LOCATION	O

@	O

STOP	O

@	O

>	O

IF	O

END	O

ELSE	O

BEGIN	O

THEN	O

3000	O
6500	O
10	O

START	O
START	O

INCREMENT	O

SCAN	O

Figure	O
6	O
.	O

Ten	O
lines	O
of	O
typical	O
CONVERS	O
code	O
to	O
scan	O
wavelengths	O
between	O
two	O
easily	O
changed	O
limits	O
and	O
acquire	O
data	O
.	O

By	O
reference	O
to	O
notes	O
in	O
the	O
text	O
it	O
can	O
be	O
easily	O
understood	O
.	O

NOTE	O
:	O
a	O
number	O
or	O
name	O
pushes	O
the	O
number	O
of	O
address	O
occupied	O
by	O
the	O
name	O
on	O
the	O
stack	O
.	O

The	O
symbol	O
@	O
,	O
pips	O
the	O
top	O
number	O
from	O
the	O
stack	O
uses	O
it	O
as	O
the	O
address	O
from	O
which	O
to	O
obtain	O
a	O
number	O
and	O
pushes	O
that	O
number	O
on	O
the	O
stack	O
.	O

Development	O
of	O
CONVERS	O
During	O
the	O
past	O
two	O
years	O
,	O
a	O
different	O
approach	O
to	O
software	O
has	O
been	O
taking	O
place	O
at	O
the	O
University	O
of	O
Arizona	O
referred	O
to	O
as	O
an	O
"	O
Interpretive	O
Compiler	O
"	O
called	O
CONVERS	O
.	O

This	O
package	O
,	O
which	O
is	O
conceptually	O
similar	O
to	O
the	O
FORTH	O
language	O
currently	O
being	O
used	O
in	O
several	O
minicomputerastronom	O
applications	O
]	O
,	O
is	O
able	O
to	O
provide	O
many	O
of	O
the	O
desirable	O
features	O
found	O
in	O
both	O
interpreters	O
and	O
compilers	O
by	O
separating	O
the	O
compile	O
and	O
execute	O
states	O
(	O
as	O
a	O
compiler	O
does	O
)	O
while	O
maintaining	O
a	O
resident	O
user	O
interactive	O
and	O
conversational	O
executive	O
which	O
oversees	O
system	O
operation	O
.	O

The	O
ability	O
to	O
realise	O
such	O
advanced	O
software	O
capabilities	O
in	O
a	O
very	O
modest	O
amount	O
of	O
memory	O
(	O
less	O
than	O
4	O
K	O
bytes	O
on	O
an	O
8080	O
based	O
micro	O
)	O
is	O
the	O
direct	O
result	O
of	O
exploiting	O
threaded	O
code	O
programming	O
techniques	O
(	O
see	O
Figure	O
3	O
)	O
.	O

The	O
approach	O
involves	O
highly	O
efficient	O
use	O
of	O
simple	O
macroinstructions	O
to	O
build	O
more	O
complex	O
subroutines	O
which	O
are	O
recombined	O
with	O
additional	O
macroinstructions	O
to	O
form	O
super	O
subroutines	O
.	O

This	O
process	O
of	O
combining	O
previously	O
defined	O
modules	O
to	O
form	O
ever	O
increasingly	O
sophisticated	O
routines	O
for	O
performing	O
the	O
task	O
at	O
hand	O
is	O
the	O
essence	O
of	O
threaded	O
code	O
programming	O
.	O

When	O
initially	O
loaded	O
and	O
running	O
,	O
CONVERS	O
acts	O
much	O
like	O
an	O
interpreter	O
,	O
i	O
.	O
e	O
.	O
it	O
is	O
conversational	O
,	O
ready	O
to	O
either	O
execute	O
a	O
previously	O
programmed	O
algorithm	O
or	O
accept	O
a	O
new	O
one	O
.	O

However	O
,	O
in	O
contrast	O
to	O
BASIC	O
,	O
when	O
a	O
new	O
program	O
is	O
being	O
entered	O
under	O
CONVERS	O
,	O
it	O
is	O
immediately	O
transformed	O
into	O
binary	O
machine	O
code	O
or	O
to	O
the	O
binary	O
starting	O
addresses	O
of	O
other	O
previously	O
entered	O
and	O
compiled	O
machine	O
code	O
programs	O
.	O

During	O
this	O
process	O
,	O
the	O
operator	O
is	O
kept	O
informed	O
of	O
the	O
status	O
of	O
the	O
program	O
by	O
a	O
series	O
of	O
error	O
and	O
diagnostic	O
Volume	O

messages	O
.	O

When	O
the	O
new	O
program	O
has	O
been	O
completed	O
,	O
it	O
is	O
entered	O
in	O
a	O
program	O
library	O
or	O
dictionary	O
,	O
which	O
is	O
constantly	O
building	O
up	O
from	O
low	O
memory	O
(	O
see	O
Figure	O
4	O
)	O
.	O

If	O
the	O
operator	O
now	O
wants	O
to	O
execute	O
this	O
program	O
,	O
he	O
can	O
request	O
it	O
from	O
his	O
terminal	O
.	O

A	O
dictionary	O
search	O
will	O
begin	O
at	O
the	O
last	O
entry	O
and	O
progress	O
until	O
the	O
requested	O
program	O
is	O
located	O
.	O

Once	O
located	O
,	O
the	O
requested	O
program	O
will	O
run	O
in	O
its	O
entirety	O
without	O
need	O
for	O
any	O
additional	O
dictionary	O
searches	O
.	O

For	O
example	O
,	O
let	O
us	O
assume	O
an	O
algorithm	O
,	O
called	O
ACQUIRE	O
,	O
has	O
been	O
programmed	O
to	O
take	O
data	O
from	O
some	O
hypothetical	O
experimental	O
system	O
.	O

When	O
ACQUIRE	O
is	O
requested	O
from	O
the	O
terminal	O
,	O
a	O
dictionary	O
search	O
is	O
initiated	O
.	O

The	O
program	O
names	O
ACQUIRE	O
(	O
see	O
Figure	O
5	O
)	O
,	O
once	O
located	O
,	O
contains	O
the	O
starting	O
addresses	O
of	O
a	O
series	O
of	O
previously	O
defined	O
modules	O
which	O
implement	O
the	O
various	O
steps	O
necessary	O
to	O
perform	O
the	O
desired	O
experiment	O
.	O

For	O
example	O
,	O
the	O
module	O
SCAN	O
which	O
might	O
be	O
intended	O
to	O
scan	O
a	O
monochromator	O
'	O
s	O
wavelength	O
in	O
some	O
desired	O
manner	O
has	O
been	O
previously	O
defined	O
and	O
tested	O
.	O

This	O
ability	O
to	O
easily	O
test	O
each	O
module	O
separately	O
and	O
then	O
efficiently	O
combine	O
a	O
series	O
of	O
modules	O
to	O
perform	O
a	O
more	O
complex	O
function	O
,	O
test	O
this	O
function	O
,	O
and	O
then	O
employ	O
.	O
it	O
in	O
a	O
vastly	O
more	O
complex	O
function	O
,	O
etc	O
.	O
,	O
i	O
.	O
e	O
.	O
testing	O
each	O
step	O
as	O
the	O
threaded	O
code	O
is	O
made	O
increasingly	O
complex	O
,	O
is	O
a	O
major	O
factor	O
contributing	O
to	O
the	O
speed	O
with	O
which	O
software	O
can	O
be	O
developed	O
using	O
CONVERS	O
.	O

Use	O
of	O
a	O
software	O
stack	O
also	O
contributes	O
toward	O
improved	O
memory	O
efficiency	O
and	O
simplified	O
programming	O
.	O

The	O
stack	O
is	O
an	O
area	O
of	O
memory	O
set	O
aside	O
to	O
handle	O
parameters	O
,	O
data	O
numbers	O
,	O
etc	O
.	O

One	O
of	O
the	O
primary	O
advantages	O
of	O
the	O
stack	O
is	O
that	O
entries	O
can	O
leave	O
temporary	O
parameters	O
on	O
the	O
stack	O
without	O
having	O
to	O
assign	O
specific	O
131	O

No	O
.	O
3	O
April	O
1979	O

Tilden	O
&	O
Denton	O

Advanced	O
software	O
concepts	O

DUAL	O
REGULATED	O
POWER	O
SUPPLY	O
I0	O
KV	O
I00	O

GRATING	O

PIEZOELECTRIC	O
TRANSLATOR	O

OP	O
TOACOUS	O
TIC	O
CELL	O

,	O
.	O
.	O

C02He	O
,	O
N2	O

MIRROR	O
TRANSLATOR	O

CHOPPER	O

POWER	O
DE	O
TECTOR	O

STEPPER	O
MOTOR	O

DRIVER	O

ADC	O

LOCK	O
-	O
IN	O
AMP	O

CONTROLLER	O

LOCK	O
-	O
IN	O

AMP	O

MICROFLOPPY	O

DISK	O
24K	O
RAM	O

1	O

Figure	O
7	O
.	O

The	O
optoacoustic	O
experiment	O
in	O
which	O
a	O
microcomputer	O
is	O
used	O
to	O
control	O
laser	O
wavelength	O
and	O
to	O
monitor	O
laser	O
power	O
and	O
optoacoustic	O
signal	O
.	O

memory	O
locations	O
to	O
store	O
them	O
.	O

This	O
not	O
only	O
can	O
save	O
considerable	O
memory	O
,	O
but	O
also	O
allows	O
programs	O
to	O
be	O
easily	O
relocatable	O
since	O
one	O
algorithm	O
need	O
only	O
know	O
that	O
a	O
previous	O
routine	O
left	O
so	O
many	O
words	O
of	O
data	O
,	O
etc	O
.	O
on	O
the	O
stack	O
.	O

It	O
need	O
not	O
know	O
where	O
the	O
previous	O
routine	O
is	O
nor	O
even	O
where	O
the	O
stack	O
is	O
located	O
.	O

A	O
series	O
of	O
stack	O
handling	O
routines	O
,	O
which	O
should	O
appear	O
quite	O
familiar	O
to	O
many	O
small	O
calculator	O
users	O
,	O
provide	O
an	O
array	O
of	O
capabilities	O
,	O
including	O
the	O
ability	O
to	O
PUSH	O
a	O
number	O
on	O
the	O
stack	O
,	O
POP	O
,	O
it	O
off	O
,	O
duplicate	O
it	O
,	O
SWAP	O
the	O
top	O
two	O
numbers	O
,	O
locate	O
a	O
number	O
some	O
distance	O
into	O
the	O
stack	O
,	O
and	O
copy	O
it	O
on	O
top	O
of	O
the	O
stack	O
,	O
etc	O
.	O

Additionally	O
,	O
a	O
variety	O
of	O
logic	O
functions	O
familiar	O
to	O
the	O
minicomputer	O
user	O
are	O
provided	O
including	O
OR	O
,	O
AND	O
,	O
shift	O
left	O
,	O
shift	O
right	O
,	O
greater	O
than	O
,	O
less	O
than	O
,	O
etc	O
.	O

Input	O
/	O
output	O
(	O
I	O
/	O
O	O
)	O
is	O
normally	O
accomplished	O
using	O
the	O
stack	O
in	O
conjunction	O
with	O
the	O
INDEVICE	O
or	O
OUTDEVICE	O
commands	O
.	O

For	O
example	O
,	O
to	O
take	O
data	O
from	O
a	O
device	O
located	O
at	O
I	O
/	O
O	O
,	O
port	O
7	O
,	O
the	O
number	O
seven	O
is	O
"	O
pushed	O
"	O
onto	O
the	O
stack	O
(	O
7	O
)	O
,	O
goes	O
to	O
this	O
I	O
/	O
O	O
port	O
,	O
takes	O
in	O
a	O
number	O
and	O
"	O
pushes	O
"	O
the	O
number	O
on	O
the	O
stack	O
.	O

OUTDEVICE	O
functions	O
in	O
a	O
similar	O
manner	O
,	O
requiring	O
the	O
number	O
to	O
be	O
sent	O
to	O
the	O
desired	O
device	O
to	O
be	O
"	O
pushed	O
"	O
onto	O
the	O
stack	O
followed	O
by	O
the	O
device	O
'	O
s	O
I	O
/	O
O	O
port	O
address	O
.	O

Hence	O
,	O
to	O
send	O
the	O
number	O
131	O
to	O
device	O
11	O
,	O
the	O
number	O
131	O
is	O
pushed	O
on	O
the	O
stack	O
followed	O
by	O
11	O
and	O
then	O
OUTDEVICE	O
.	O

This	O
"	O
pops	O
"	O
the	O
top	O
number	O
(	O
11	O
)	O
from	O
the	O
stack	O
,	O
uses	O
it	O
as	O
the	O
output	O
port	O
and	O
then	O
sends	O
the	O
number	O
131	O
to	O
that	O
location	O
.	O

SOUND	O

BELL	O

BELL	O

BELL	O

The	O
colon	O
denotes	O
changing	O
from	O
EXECUTE	O
to	O
COMPILE	O
mode	O
.	O

After	O
typing	O
the	O
name	O
of	O
the	O
new	O
routine	O
,	O
in	O
this	O
case	O
to	O
be	O
called	O
SOUND	O
,	O
typing	O
the	O
name	O
of	O
the	O
earlier	O
defined	O
routine	O
(	O
BELL	O
a	O
previously	O
defined	O
simple	O
program	O
to	O
rng	O
the	O
terminal	O
bell	O
)	O
initiates	O
a	O
dictionary	O
search	O
to	O
locate	O
this	O
routine	O
'	O
s	O
starting	O
address	O
which	O
subsequentially	O
is	O
entered	O
three	O
times	O
.	O

The	O
resulting	O
SOUND	O
routine	O
contains	O
machine	O
code	O
calls	O
to	O
the	O
BE	O
LL	O
routine	O
which	O
,	O
itself	O
,	O
is	O
composed	O
of	O
machine	O
code	O
.	O

Of	O
course	O
,	O
SOUND	O
could	O
also	O
have	O
been	O
defined	O
using	O
a	O
DO	O
-	O
LOOP	O
,	O
i	O
.	O
e	O
.	O
SOUND	O
3	O

DO	O

BELL	O

LOOP	O

where	O
the	O
numbers	O
three	O
and	O
one	O
set	O
the	O
upper	O
and	O
lower	O
indices	O
.	O

If	O
it	O
were	O
desirable	O
to	O
change	O
the	O
actual	O
number	O
of	O
bell	O
rings	O
from	O
some	O
other	O
program	O
,	O
this	O
value	O
could	O
be	O
defined	O
as	O
a	O
VARIABLE	O
let	O
'	O
s	O
call	O
it	O
NOISE	O
.	O

3	O

VARIABLE	O
NOISE	O

In	O
this	O
case	O
,	O
the	O
number	O
three	O
is	O
first	O
pushed	O
on	O
the	O
stack	O
,	O
VARIABLE	O
transfers	O
the	O
top	O
number	O
on	O
the	O
stack	O
(	O
the	O
three	O
)	O
to	O
a	O
dictionary	O
location	O
named	O
NOISE	O
.	O

If	O
SOUND	O
were	O
now	O
defined	O
as	O
:	O
SOUND	O

NOISE	O

@	O

DO	O

BELL	O

LOOP	O

Applications	O
of	O
CONVERS	O
To	O
appreciate	O
the	O
ease	O
with	O
which	O
real	O
programs	O
can	O
be	O
written	O
,	O
a	O
few	O
examples	O
will	O
be	O
considered	O
.	O

A	O
trivial	O
program	O
,	O
called	O
SOUND	O
,	O
which	O
rings	O
the	O
terminal	O
bell	O
three	O
times	O
,	O
might	O
be	O
written	O
:	O
132	O

the	O
bell	O
would	O
again	O
ring	O
three	O
times	O
.	O

In	O
this	O
case	O
,	O
when	O
the	O
word	O
NOISE	O
iS	O
encountered	O
,	O
its	O
address	O
is	O
pushed	O
on	O
the	O
stack	O
,	O
the	O
@	O
is	O
a	O
simple	O
program	O
which	O
goes	O
to	O
the	O
address	O
indicated	O
on	O
the	O
top	O
of	O
the	O
stack	O
(	O
that	O
of	O
NOISE	O
)	O
and	O
replaces	O
it	O
with	O
the	O
actual	O
value	O
located	O
at	O
that	O
address	O
(	O
the	O
number	O
three	O
)	O
.	O

At	O
any	O
future	O
time	O
,	O
the	O
value	O
of	O
VARIABLE	O
can	O
be	O
changed	O
by	O
"	O
pushing	O
"	O
the	O
new	O
value	O
onto	O
the	O
stack	O
,	O
followed	O
by	O
the	O
address	O
of	O
the	O
variable	O
to	O
be	O
changed	O
,	O
generated	O
by	O
its	O
name	O
and	O
an	O
exclamation	O
mark	O
.	O

To	O
change	O
N	O
O	O
IS	O
E	O
to	O
5	O
,	O
The	O
Journal	O
of	O
Automatic	O
Chemistry	O

Tilden	O
&	O
Denton	O

Advanced	O
software	O
concepts	O

5	O
NOISE	O
a	O
number	O
five	O
is	O
pushed	O
onto	O
the	O
stack	O
,	O
NOISE	O
pushes	O
its	O
address	O
on	O
the	O
stack	O
,	O
and	O
goes	O
to	O
the	O
address	O
indicated	O
by	O
the	O
"	O
top	O
"	O
number	O
on	O
the	O
stack	O
and	O
deposits	O
the	O
next	O
number	O
.	O

Now	O
sound	O
would	O
ring	O
the	O
terminal	O
bell	O
five	O
times	O
.	O

A	O
much	O
less	O
trivial	O
program	O
which	O
could	O
be	O
written	O
to	O
scan	O
and	O
take	O
data	O
from	O
a	O
monochromator	O
equipped	O
with	O
a	O

DENCO	O
SM2A	O
stepper	O
motor	O
controller	O
[	O
2	O
]	O
(	O
the	O
SM2A	O
takes	O
a	O
parallel	O
number	O
as	O
an	O
address	O
,	O
sends	O
one	O
of	O
two	O
stepper	O
motors	O
to	O
this	O
location	O
and	O
outputs	O
an	O
arrival	O
flag	O
when	O
the	O
address	O
is	O
reached	O
)	O
is	O
given	O
in	O
Figure	O
6	O
.	O

Assume	O
that	O
the	O
experimental	O
system	O
is	O
configured	O
so	O
the	O
SM2A	O
is	O
at	O
I	O
/	O
O	O
,	O
port	O
5	O
and	O
an	O
analog	O
to	O
digital	O
converter	O
to	O
acquire	O
data	O
is	O
at	O
I	O
/	O
O	O
,	O
port	O
7	O
.	O

Let	O
us	O
assume	O
that	O
,	O
initially	O
,	O
a	O
scan	O
is	O
designed	O
from	O
a	O
starting	O
stepper	O
motor	O
location	O
of	O
2000	O
to	O
a	O
final	O
location	O
of	O
5000	O
,	O
taking	O
data	O
every	O
20	O
steps	O
.	O

The	O
program	O
illustrated	O
in	O
figure	O
6	O
acts	O
in	O
the	O
following	O
manner	O
.	O

Line	O
defines	O
a	O
variable	O
called	O
START	O
to	O
be	O
2000	O
,	O
which	O
is	O
the	O
starting	O
location	O
of	O
fhe	O
scan	O
.	O

The	O
end	O
of	O
the	O
scan	O
is	O
defined	O
as	O
5000	O
in	O
the	O
next	O
line	O
.	O

Line	O
3	O
defines	O
the	O
increment	O
between	O
data	O
points	O
.	O

A	O
variable	O
called	O
LOCATION	O
where	O
the	O
.	O
next	O
address	O
is	O
stored	O
is	O
defined	O
in	O
line	O
4	O
.	O
.	O

Colon	O
,	O
in	O
line	O
5	O
,	O
puts	O
the	O
system	O
in	O
the	O
compile	O
mode	O
,	O
A	O
/	O
D7	O
will	O
be	O
the	O
name	O
of	O
the	O
module	O
which	O
when	O
called	O
will	O
cause	O
a	O
7	O
to	O
be	O
pushed	O
onto	O
the	O
stack	O
.	O

INDEVICE	O
will	O
'	O
pop	O
'	O
it	O
back	O
off	O
and	O
use	O
it	O
as	O
a	O
device	O
address	O
to	O
go	O
and	O
take	O
a	O
data	O
point	O
and	O
push	O
the	O
data	O
onto	O
the	O
stack	O
.	O

Line	O
6	O
defines	O
a	O
module	O
INITIALIZE	O
,	O
START	O
puts	O
its	O
address	O
on	O
the	O
stack	O
,	O
@	O
replaces	O
the	O
address	O
with	O
the	O
value	O
at	O
that	O
address	O
,	O
LOCATION	O
puts	O
its	O
address	O
on	O
the	O
stack	O
,	O
'	O
!	O
'	O
goes	O
to	O
the	O
address	O
specified	O
by	O
the	O
number	O
on	O
the	O
stack	O
and	O
deposits	O
the	O
second	O
number	O
and	O
the	O
net	O
result	O
value	O
at	O
START	O
is	O
put	O
into	O
LOCATION	O
.	O

Line	O
7	O
defines	O
STEP	O
to	O
take	O
values	O
from	O

LOCATION	O
and	O
INCREMENT	O
adds	O
them	O
together	O
and	O
puts	O
the	O
result	O
into	O
LOCATION	O
,	O
i	O
.	O
e	O
.	O
LOCATION	O
puts	O
its	O
address	O
on	O
the	O
stack	O
,	O
@	O
replaces	O
the	O
top	O
value	O
on	O
the	O
stack	O
with	O
the	O
number	O
stored	O
at	O
the	O
address	O
,	O
INCREMENT	O
@	O
gets	O
the	O
value	O
at	O
INCREMENT	O
and	O
puts	O
it	O
in	O
to	O
the	O
stack	O
,	O
and	O
adds	O
the	O
top	O
two	O
stack	O
numbers	O
and	O
pushes	O
the	O
result	O
on	O
the	O
stack	O
.	O

LOCATION	O
puts	O
its	O
address	O
on	O
the	O
stack	O
and	O
goes	O
to	O
the	O
address	O
specified	O
by	O
the	O
top	O
number	O
on	O
the	O
stack	O
and	O
deposits	O
the	O
second	O
number	O
.	O

Themodule	O
defined	O
in	O
line	O
8	O
takes	O
a	O
number	O
from	O
the	O
stepper	O
motor	O
controller	O
(	O
assume	O
device	O
numbered	O
5	O
)	O
pushes	O
on	O
the	O
stack	O
,	O
and	O
pushes	O
the	O
value	O
10	O
on	O
the	O
stack	O
and	O
does	O
a	O
logical	O
AND	O
to	O
see	O
if	O
the	O
controllers	O
flag	O
is	O
set	O
,	O
if	O
this	O
is	O
true	O
the	O
A	O
/	O
D7	O
module	O
will	O
be	O
called	O
to	O
input	O
data	O
,	O
if	O
the	O
flag	O
is	O
not	O
set	O
,	O
the	O
program	O
is	O
returned	O
to	O
BEGIN	O
-	O
HERE	O
.	O

Therefore	O
the	O
DELAY	O
module	O
is	O
a	O
loop	O
waiting	O
for	O
the	O
stepper	O
motor	O
to	O
arrive	O
at	O
its	O
new	O
location	O
followed	O
by	O
a	O
call	O
to	O
A	O
/	O
D7	O
data	O
acquisition	O
module	O
.	O

MOVE	O
defined	O
in	O
line	O
9	O
gets	O
the	O
value	O
stored	O
at	O
LOCATION	O
pushes	O
the	O
device	O
code	O
onto	O
the	O
stack	O
performs	O
an	O
outdevice	O
(	O
which	O
uses	O
the	O
top	O
stack	O
number	O
as	O
a	O
1	O
/	O
0	O
port	O
address	O
to	O
send	O
the	O
next	O
value	O
to	O
call	O
the	O
STEP	O
module	O
(	O
ie	O
the	O
value	O
at	O
LOCATION	O
)	O
,	O
this	O
increments	O
LOCATION	O
by	O
the	O
INCREM	O
E	O
N	O
T	O
value	O
and	O
finally	O
calls	O
D	O
E	O
L	O
A	O
Y	O
and	O
waits	O
for	O
a	O
flag	O
from	O
the	O
stepper	O
motor	O
controller	O
to	O
signal	O
its	O
arrival	O
at	O
the	O
desired	O
address	O
and	O
then	O
takes	O
a	O
data	O
point	O
.	O

The	O
final	O
line	O
shown	O
in	O
the	O
example	O
Called	O
SCAN	O
itself	O
calls	O
the	O
INITIALIZE	O
module	O
(	O
which	O
sets	O
LOCATION	O
to	O
the	O
START	O
location	O
for	O
the	O
Scan	O
)	O
it	O
also	O
calls	O
MOVE	O
(	O
which	O
sends	O
this	O
value	O
to	O
the	O
motor	O
LOCATION	O
controller	O
,	O
increments	O
the	O
value	O
stored	O
in	O
LOCATION	O
by	O
INCREMENT	O
and	O
calls	O
DELAY	O
which	O
waits	O
for	O
the	O
motor	O
to	O
arrive	O
and	O
then	O
takes	O
a	O
data	O
point	O
)	O
.	O

Next	O
the	O
incremented	O
value	O
from	O
LOCATION	O
is	O
placed	O
on	O
the	O
stack	O
(	O
LOCATION	O
)	O
followed	O
by	O
the	O
STOP	O

I0	O
KW	O
AMPLIFIER	O
MATCHING	O

,	O
NETWORKIS	O
PREAMP	O

MOTOR	O
CON	O
TROL	O
ER	O

MICRODISK	O
90K	O
byte	O

INTEL	O
8080	O
based	O
MICROCOMPUTER	O
16K	O

RAM	O

Figure	O
8	O
.	O

A	O
schematic	O
of	O
the	O
inductively	O
coupled	O
plasma	O
emission	O
spectrometer	O
in	O
which	O
the	O
microcomputer	O
is	O
used	O
to	O
control	O
radio	O
frequency	O
power	O
and	O
'	O
flame	O
'	O
positioning	O
as	O
well	O
as	O
to	O
monitor	O
light	O
intensity	O
.	O

Volume	O

No	O
.	O
3	O
April	O
1979	O

133	O

Tilden	O
&	O
Denton	O

Advanced	O
software	O
concepts	O

value	O
(	O
STOP	O
@	O
)	O
,	O
the	O
two	O
are	O
compared	O
to	O
to	O
see	O
if	O
the	O
incremented	O
value	O
at	O
LOCATION	O
is	O
larger	O
then	O
the	O
STOP	O
value	O
,	O
if	O
it	O
is	O
the	O
program	O
ends	O
,	O
if	O
not	O
,	O
it	O
repeats	O
the	O
process	O
starting	O
at	O
BEGIN	O
-	O
-	O
HERE	O
.	O

It	O
should	O
be	O
noted	O
that	O
whilst	O
many	O
variables	O
have	O
been	O
pushed	O
on	O
the	O
stack	O
,	O
only	O
the	O
data	O
will	O
remain	O
,	O
since	O
each	O
time	O
a	O
value	O
is	O
used	O
it	O
is	O
'	O
popped	O
'	O
(	O
removed	O
)	O
from	O
the	O
stack	O
.	O

If	O
a	O
different	O
spectra	O
region	O
is	O
to	O
be	O
scanned	O
i	O
.	O
e	O
.	O
from	O
3000	O
to	O
6500	O
with	O
10	O
increments	O
the	O
variables	O
need	O
only	O
be	O

>	O

data	O
acquisition	O
programs	O
have	O
been	O
easily	O
implemented	O
.	O

Memory	O
requirements	O
and	O
operating	O
speed	O
have	O
been	O
found	O
to	O
be	O
far	O
superior	O
to	O
conventional	O
approaches	O
.	O

Additionally	O
,	O
new	O
system	O
users	O
have	O
encountered	O
a	O
difficulty	O
in	O
utilising	O
previously	O
developed	O
custom	O
software	O
for	O
a	O
particular	O
experiment	O
even	O
when	O
documentation	O
was	O
vague	O
.	O

Discussion	O
The	O
authors	O
hope	O
that	O
this	O
short	O
introduction	O
to	O
only	O
a	O
few	O
of	O
the	O
concepts	O
employed	O
in	O
CONVERS	O
will	O
generate	O
interest	O
in	O
its	O
capabilities	O
.	O

A	O
much	O
more	O
complete	O
discussion	O
is	O
available	O
in	O
the	O
form	O
of	O
a	O
user	O
'	O
s	O
manual	O
[	O
3	O
]	O
available	O
from	O
the	O
authors	O
.	O

changed	O
thus	O
3000	O
START	O
!	O

6500	O
STOP	O
10	O
INCREMENT	O
and	O
type	O
SCAN	O
,	O
system	O
will	O
now	O
scan	O
from	O
3000	O
to	O
6500	O
taking	O
data	O
every	O
10	O
steps	O
.	O

While	O
the	O
code	O
might	O
look	O
a	O
little	O
strange	O
at	O
first	O
,	O
it	O
quickly	O
becomes	O
very	O
easy	O
to	O
work	O
with	O
.	O

The	O
SCAN	O
program	O
of	O
Figure	O
6	O
could	O
be	O
combined	O
with	O
other	O
modules	O
as	O
shown	O
in	O
Figure	O
5	O
to	O
perform	O
some	O
more	O
complex	O
experimental	O
function	O
.	O

Each	O
module	O
of	O
the	O
program	O
can	O
be	O
easily	O
tried	O
out	O
to	O
ensure	O
that	O
it	O
is	O
operational	O
before	O
proceeding	O
with	O
the	O
next	O
.	O

Presently	O
,	O
CONVERS	O
is	O
being	O
used	O
in	O
the	O
authors	O
'	O
laboratories	O
for	O
a	O
variety	O
of	O
spectrochemical	O
investigations	O
,	O
including	O
laser	O
excited	O
optoacoustic	O
spectroscopy	O
(	O
Figure	O
7	O
)	O
and	O
inductively	O
coupled	O
plasma	O
optical	O
emission	O
spectroscopy	O
(	O
Figure	O
8	O
)	O
.	O

Rather	O
complex	O
interactive	O
control	O
and	O

ACKNOWLEDGEMENTS	O
The	O
development	O
of	O
the	O
CONVERS	O
system	O
was	O
partially	O
supported	O
by	O
the	O
Office	O
of	O
Naval	O
Research	O
and	O
a	O
Alfred	O
P	O
.	O
Cloan	O
Foundation	O
Research	O
Fellowship	O
to	O
M	O
.	O

Bonnet	O
Denton	O
.	O

REFERENCES	O
C	O
.	O

Moore	O
,	O
Astronomical	O
Astrophysics	O
Supplemental	O
,	O
15	O
,	O
(	O
1974	O
)	O
497	O
.	O

[	O
2	O
]	O
M	O
.	O
B	O
.	O

Denton	O
,	O
J	O
.	O
D	O
.	O

Mack	O
,	O
M	O
.	O
W	O
.	O

Routh	O
and	O
D	O
.	O
B	O
.	O

SwartzClmerican	O

[	O
3	O
]	O

Laboratory	O
,	O
8	O
,	O
69	O
(	O
1976	O
)	O
.	O

CONVERS	O
An	O
Interpretive	O
Compiler	O
,	O
developed	O
by	O
Scott	O
B	O
.	O
Tilden	O
and	O
M	O
.	O

Bonner	O
Denton	O
,	O
Department	O
of	O
Chemistry	O
,	O
University	O
of	O
Arizona	O
,	O
Tucson	O
,	O
Arizona	O
85721	O
,	O
USA	O
.	O

The	O
use	O
of	O
a	O
microcomputer	O
for	O
flexible	O
automation	O
of	O
a	O
liquid	O

chromatograph	O
A	O
.	O
D	O
.	O

Mills	O
,	O
i	O
.	O

Mackenzie	O
and	O
R	O
.	O
J	O
.	O

Dolphin	O
*	O
Philips	O
Research	O
Laboratories	O
,	O
Redhill	O
,	O
Surrey	O
,	O
RH1	O
5HA	O
,	O
U	O
.	O
K	O
.	O

Introduction	O
Microprocessors	O
are	O
being	O
used	O
to	O
add	O
inexpensive	O
automatic	O
control	O
and	O
data	O
handling	O
facilities	O
to	O
a	O
variety	O
of	O
chemical	O
instruments	O
.	O

With	O
a	O
microcomputer	O
it	O
is	O
now	O
possible	O
to	O
realise	O
the	O
flexibility	O
formerly	O
available	O
only	O
with	O
a	O
relatively	O
large	O
and	O
expensive	O
minicomputer	O
in	O
an	O
instrument	O
little	O
different	O
in	O
size	O
and	O
cost	O
from	O
one	O
controlled	O
by	O
inflexible	O
hardware	O
.	O

In	O
many	O
ways	O
chromatography	O
is	O
an	O
ideal	O
process	O
for	O
such	O
automation	O
.	O

Most	O
instruments	O
are	O
given	O
a	O
high	O
workload	O
and	O
,	O
although	O
many	O
applications	O
may	O
be	O
routine	O
and	O
repetitive	O
,	O
the	O
versatility	O
of	O
the	O
technique	O
requires	O
an	O
instrument	O
which	O
can	O
easily	O
be	O
used	O
in	O
a	O
variety	O
of	O
modes	O
.	O

In	O
addition	O
to	O
improving	O
the	O
convenience	O
to	O
the	O
user	O
,	O
automation	O
of	O
a	O
liquid	O
chromatrograph	O
should	O
enhance	O
the	O
performance	O
of	O
the	O
instrument	O
.	O

Some	O
aspects	O
of	O
high	O
performance	O
liquid	O
chromatography	O
(	O
HPLC	O
)	O
which	O
can	O
benefit	O
in	O
this	O
way	O
are	O
as	O
follows	O
:	O
(	O
1	O
)	O
Accurate	O
control	O
of	O
solvent	O
flow	O
rate	O
will	O
compensate	O
for	O
changes	O
in	O
pressure	O
drop	O
and	O
lead	O
to	O
more	O
reliable	O
retention	O
times	O
.	O

(	O
2	O
)	O
The	O
composition	O
of	O
the	O
mobile	O
phase	O
can	O
be	O
accurately	O
controlled	O
in	O
either	O
isocratic	O
or	O
gradient	O
elution	O
chromatography	O
using	O
,	O
for	O
example	O
,	O
a	O
proportioning	O
valve	O
on	O
the	O
low	O
pressure	O
side	O
of	O
the	O
pump	O
.	O

(	O
3	O
)	O
Automatic	O
sampling	O
can	O
be	O
operated	O
in	O
a	O
variety	O
of	O
modes	O
to	O
process	O
a	O
number	O
of	O
samples	O
without	O
supervision	O
.	O

It	O
is	O
also	O
more	O
precise	O
than	O
manual	O
injection	O
.	O

(	O
4	O
)	O
A	O
built	O
-	O
in	O
data	O
handling	O
facility	O
can	O
present	O
the	O
analyst	O
with	O
an	O
easily	O
read	O
post	O
-	O
run	O
report	O
of	O
the	O
analytical	O
results	O
with	O
accurate	O
peak	O
area	O
measurements	O
even	O
for	O
peaks	O
which	O
are	O
poorly	O
resolved	O
.	O

Although	O
liquid	O
chromatographs	O
incorporating	O
microprocessors	O
for	O
control	O
and	O
data	O
handling	O
purposes	O
are	O
commercially	O
available	O
,	O
these	O
instruments	O
are	O
,	O
so	O
far	O
,	O
This	O
paper	O
describes	O
,	O
in	O
detail	O
,	O
the	O
relatively	O
inflexible	O
.	O
automation	O
of	O
a	O
liquid	O
chromatograph	O
using	O
an	O
inexpensive	O
general	O
purpose	O
microcomputer	O
,	O
which	O
has	O
previously	O
been	O
applied	O
in	O
atomic	O
absorption	O
spectrophotometry	O
[	O
1	O
]	O
and	O
for	O
column	O
switching	O
in	O
HPLC	O
2	O
]	O
.	O

Figure	O
illustrates	O
the	O
interconnection	O
of	O
the	O
chromatograph	O
and	O
the	O
microcomputer	O
which	O
controls	O
the	O
mobile	O
phase	O
flow	O
rate	O
,	O
operates	O
an	O
automatic	O
sampler	O
and	O
analyses	O
data	O
from	O
the	O
detector	O
.	O

The	O
control	O
and	O
data	O
handling	O
functions	O
are	O
integrated	O
in	O
a	O
program	O
which	O
enables	O
the	O
user	O
to	O
communicate	O
with	O
the	O
instrument	O
,	O
in	O
plain	O
English	O
,	O
via	O
a	O
visual	O
display	O
unit	O
(	O
VDU	O
)	O
or	O
teletypewriter	O
keyboard	O
.	O

A	O
variety	O
of	O
operational	O
modes	O
is	O
offered	O
,	O
giving	O
the	O
analyst	O
an	O
opportunity	O
to	O
establish	O
the	O
best	O
conditions	O
for	O
a	O
particular	O
separation	O
before	O
leaving	O
the	O
instrument	O
to	O
perform	O
its	O
given	O
tasks	O
without	O
further	O
interaction	O
.	O

The	O
microcomputer	O
Hardware	O
The	O
computer	O
is	O
a	O
general	O
purpose	O
instrument	O
constructed	O
using	O
a	O
set	O
of	O
ready	O
made	O
circuit	O
cards	O
(	O
Philips	O
,	O
Science	O
and	O
The	O
Journal	O
of	O
Automatic	O
Chemistry	O

*	O
Present	O
address	O
:	O
lye	O
Unicam	O
Ltd	O
.	O
,	O
York	O
Street	O
,	O
Cambridge	O
,	O
CB1	O
2PX	O
,	O
U	O
.	O
K	O
.	O

134	O

TOPS	O
+	O
+	O
FATCAT	O
:	O
Fast	O
flexible	O
structural	O
alignment	O
using	O
constraints	O
derived	O
from	O
TOPS	O
+	O
Strings	O
Model	O

Abstract	O

Background	O

Protein	O
structure	O
analysis	O
and	O
comparison	O
are	O
major	O
challenges	O
in	O
structural	O
bioinformatics	O
.	O

Despite	O
the	O
existence	O
of	O
many	O
tools	O
and	O
algorithms	O
,	O
very	O
few	O
of	O
them	O
have	O
managed	O
to	O
capture	O
the	O
intuitive	O
understanding	O
of	O
protein	O
structures	O
developed	O
in	O
structural	O
biology	O
,	O
especially	O
in	O
the	O
context	O
of	O
rapid	O
database	O
searches	O
.	O

Such	O
intuitions	O
could	O
help	O
speed	O
up	O
similarity	O
searches	O
and	O
make	O
it	O
easier	O
to	O
understand	O
the	O
results	O
of	O
such	O
analyses	O
.	O

Results	O

We	O
developed	O
a	O
TOPS	O
+	O
+	O
FATCAT	O
algorithm	O
that	O
uses	O
an	O
intuitive	O
description	O
of	O
the	O
proteins	O
'	O
structures	O
as	O
captured	O
in	O
the	O
popular	O
TOPS	O
diagrams	O
to	O
limit	O
the	O
search	O
space	O
of	O
the	O
aligned	O
fragment	O
pairs	O
(	O
AFPs	O
)	O
in	O
the	O
flexible	O
alignment	O
of	O
protein	O
structures	O
performed	O
by	O
the	O
FATCAT	O
algorithm	O
.	O

The	O
TOPS	O
+	O
+	O
FATCAT	O
algorithm	O
is	O
faster	O
than	O
FATCAT	O
by	O
more	O
than	O
an	O
order	O
of	O
magnitude	O
with	O
a	O
minimal	O
cost	O
in	O
classification	O
and	O
alignment	O
accuracy	O
.	O

For	O
beta	O
-	O
rich	O
proteins	O
its	O
accuracy	O
is	O
better	O
than	O
FATCAT	O
,	O
because	O
the	O
TOPS	O
+	O
strings	O
models	O
contains	O
important	O
information	O
of	O
the	O
parallel	O
and	O
anti	O
-	O
parallel	O
hydrogen	O
-	O
bond	O
patterns	O
between	O
the	O
beta	O
-	O
strand	O
SSEs	O
(	O
Secondary	O
Structural	O
Elements	O
)	O
.	O

We	O
show	O
that	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
errors	O
,	O
rare	O
as	O
they	O
are	O
,	O
can	O
be	O
clearly	O
linked	O
to	O
oversimplifications	O
of	O
the	O
TOPS	O
diagrams	O
and	O
can	O
be	O
corrected	O
by	O
the	O
development	O
of	O
more	O
precise	O
secondary	O
structure	O
element	O
definitions	O
.	O

Software	O
Availability	O

The	O
benchmark	O
analysis	O
results	O
and	O
the	O
compressed	O
archive	O
of	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
program	O
for	O
Linux	O
platform	O
can	O
be	O
downloaded	O
from	O
the	O
following	O
web	O
site	O
:	O

Conclusion	O

TOPS	O
+	O
+	O
FATCAT	O
provides	O
FATCAT	O
accuracy	O
and	O
insights	O
into	O
protein	O
structural	O
changes	O
at	O
a	O
speed	O
comparable	O
to	O
sequence	O
alignments	O
,	O
opening	O
up	O
a	O
possibility	O
of	O
interactive	O
protein	O
structure	O
similarity	O
searches	O
.	O

Background	O

Structural	O
biology	O
is	O
one	O
of	O
the	O
most	O
successful	O
fields	O
of	O
modern	O
biology	O
.	O

Over	O
50	O
,	O
000	O
solved	O
protein	O
structures	O
illustrate	O
details	O
of	O
many	O
specific	O
biological	O
processes	O
.	O

The	O
same	O
data	O
also	O
provide	O
us	O
with	O
information	O
about	O
the	O
global	O
features	O
of	O
protein	O
structure	O
space	O
and	O
can	O
be	O
studied	O
to	O
discover	O
the	O
evolutionary	O
,	O
physical	O
,	O
and	O
mathematical	O
rules	O
governing	O
them	O
.	O

How	O
many	O
fundamentally	O
different	O
protein	O
shapes	O
(	O
folds	O
)	O
are	O
there	O
?	O

How	O
do	O
protein	O
structures	O
evolve	O
?	O

How	O
do	O
new	O
structural	O
features	O
appear	O
,	O
and	O
if	O
they	O
are	O
coupled	O
with	O
changes	O
in	O
function	O
,	O
how	O
does	O
this	O
process	O
occur	O
?	O

Such	O
questions	O
can	O
be	O
studied	O
by	O
classifying	O
,	O
comparing	O
and	O
analyzing	O
known	O
protein	O
structures	O
.	O

Two	O
different	O
,	O
but	O
synergistic	O
strategies	O
are	O
typically	O
used	O
for	O
this	O
purpose	O
.	O

In	O
classification	O
systems	O
such	O
as	O
SCOP	O
[	O
1	O
]	O
or	O
CATH	O
[	O
2	O
]	O
,	O
human	B
intuition	O
is	O
used	O
to	O
simplify	O
the	O
description	O
of	O
protein	O
structures	O
to	O
a	O
manageable	O
size	O
,	O
and	O
a	O
human	B
eye	O
,	O
sometimes	O
supported	O
by	O
automated	O
analysis	O
,	O
can	O
recognize	O
patterns	O
and	O
types	O
of	O
structures	O
.	O

In	O
the	O
second	O
approach	O
,	O
specialized	O
comparison	O
algorithms	O
,	O
such	O
as	O
DALI	O
[	O
3	O
]	O
,	O
CE	O
[	O
4	O
]	O
,	O
or	O
FATCAT	O
[	O
5	O
]	O
can	O
be	O
used	O
to	O
calculate	O
a	O
distance	O
-	O
like	O
metric	O
in	O
the	O
protein	O
structure	O
space	O
.	O

This	O
in	O
turn	O
can	O
be	O
used	O
to	O
cluster	O
proteins	O
into	O
groups	O
.	O

Many	O
such	O
algorithms	O
have	O
been	O
developed	O
over	O
the	O
past	O
few	O
decades	O
and	O
have	O
been	O
mostly	O
used	O
for	O
the	O
classification	O
of	O
protein	O
structures	O
into	O
families	O
.	O

An	O
exact	O
solution	O
of	O
an	O
alignment	O
between	O
two	O
structures	O
is	O
formally	O
equivalent	O
to	O
a	O
threading	O
problem	O
and	O
is	O
therefore	O
NP	O
-	O
complete	O
[	O
6	O
]	O
.	O

However	O
,	O
a	O
practical	O
solution	O
can	O
be	O
obtained	O
by	O
heuristics	O
reducing	O
the	O
problem	O
to	O
a	O
manageable	O
size	O
[	O
7	O
]	O
.	O

In	O
human	B
classification	O
systems	O
,	O
the	O
protein	O
is	O
usually	O
reduced	O
to	O
a	O
set	O
of	O
several	O
structural	O
elements	O
,	O
which	O
obviously	O
involve	O
many	O
arbitrary	O
thresholds	O
.	O

Automated	O
algorithms	O
have	O
the	O
same	O
problem	O
and	O
also	O
suffer	O
from	O
inconsistencies	O
between	O
different	O
numerical	O
measures	O
of	O
protein	O
structure	O
similarity	O
[	O
8	O
]	O
.	O

Interestingly	O
,	O
despite	O
these	O
problems	O
,	O
results	O
of	O
different	O
approaches	O
are	O
broadly	O
similar	O
.	O

They	O
all	O
identify	O
approximately	O
a	O
few	O
hundred	O
general	O
classes	O
of	O
protein	O
structures	O
,	O
usually	O
called	O
folds	O
[	O
1	O
]	O
or	O
topologies	O
[	O
2	O
]	O
,	O
distinguished	O
by	O
how	O
the	O
main	O
chain	O
of	O
the	O
protein	O
folds	O
around	O
itself	O
in	O
the	O
three	O
-	O
dimensional	O
space	O
.	O

At	O
the	O
same	O
time	O
,	O
the	O
comparison	O
of	O
different	O
approaches	O
,	O
both	O
between	O
and	O
within	O
the	O
two	O
classes	O
,	O
shows	O
that	O
fold	O
/	O
topologies	O
(	O
or	O
cluster	O
)	O
definitions	O
are	O
somewhat	O
fuzzy	O
,	O
with	O
some	O
proteins	O
being	O
occasionally	O
difficult	O
to	O
classify	O
and	O
joining	O
different	O
groups	O
depending	O
on	O
various	O
assumptions	O
.	O

This	O
lead	O
some	O
to	O
question	O
the	O
concept	O
of	O
the	O
fold	O
[	O
9	O
]	O
,	O
but	O
practical	O
application	O
of	O
protein	O
structure	O
comparison	O
leaves	O
little	O
doubt	O
that	O
protein	O
structure	O
space	O
has	O
some	O
natural	O
granularity	O
that	O
overlaps	O
well	O
with	O
the	O
traditional	O
fold	O
classification	O
.	O

Comparison	O
and	O
classification	O
of	O
protein	O
structures	O
is	O
significantly	O
simplified	O
by	O
the	O
fact	O
that	O
proteins	O
have	O
naturally	O
modular	O
structures	O
,	O
being	O
mostly	O
composed	O
of	O
locally	O
regular	O
structures	O
:	O
alpha	O
helices	O
and	O
beta	O
strands	O
.	O

These	O
two	O
types	O
of	O
secondary	O
structures	O
constitute	O
a	O
little	O
over	O
50	O
%	O
of	O
an	O
average	O
protein	O
'	O
s	O
length	O
.	O

With	O
the	O
average	O
length	O
of	O
a	O
secondary	O
structure	O
being	O
around	O
10	O
amino	O
acids	O
,	O
this	O
makes	O
it	O
possible	O
to	O
describe	O
protein	O
structure	O
as	O
an	O
arrangement	O
of	O
a	O
much	O
smaller	O
number	O
of	O
elements	O
.	O

Protein	O
structures	O
are	O
often	O
visualized	O
in	O
a	O
simplified	O
form	O
,	O
with	O
the	O
so	O
-	O
called	O
ribbon	O
diagram	O
with	O
secondary	O
structures	O
shown	O
as	O
helices	O
and	O
arrows	O
being	O
the	O
most	O
popular	O
(	O
see	O
Figure	O
1	O
)	O
.	O

This	O
picture	O
can	O
be	O
simplified	O
further	O
by	O
showing	O
individual	O
secondary	O
structure	O
elements	O
as	O
simple	O
symbols	O
(	O
circles	O
or	O
boxes	O
/	O
triangles	O
)	O
.	O

These	O
depictions	O
,	O
called	O
fold	O
diagrams	O
,	O
originally	O
proposed	O
in	O
the	O
70s	O
[	O
10	O
-	O
12	O
]	O
are	O
best	O
captured	O
by	O
a	O
TOPS	O
(	O
Topology	O
of	O
Protein	O
Structures	O
)	O
algorithm	O
,	O
which	O
attempts	O
to	O
automate	O
the	O
process	O
of	O
creation	O
of	O
the	O
topology	O
cartoon	O
[	O
13	O
]	O
.	O

While	O
useful	O
in	O
protein	O
classification	O
,	O
such	O
simplified	O
descriptions	O
are	O
not	O
used	O
in	O
the	O
most	O
popular	O
automated	O
protein	O
structure	O
comparison	O
algorithms	O
such	O
as	O
DALI	O
[	O
3	O
]	O
or	O
CE	O
[	O
4	O
]	O
.	O

Kleywegt	O
and	O
Jones	O
developed	O
a	O
method	O
for	O
finding	O
similar	O
motifs	O
based	O
on	O
comparing	O
distance	O
matrices	O
that	O
are	O
constructed	O
by	O
representing	O
protein	O
as	O
a	O
set	O
of	O
SSEs	O
with	O
their	O
directional	O
vectors	O
and	O
angle	O
between	O
those	O
vectors	O
[	O
14	O
]	O
.	O

Programs	O
that	O
used	O
SSEs	O
either	O
for	O
structure	O
comparison	O
based	O
on	O
hierarchical	O
superposition	O
of	O
both	O
SSEs	O
and	O
atomic	O
representation	O
[	O
15	O
]	O
or	O
for	O
finding	O
common	O
substructures	O
in	O
the	O
comparison	O
process	O
based	O
on	O
subgraph	O
isomorphism	O
,	O
such	O
as	O
[	O
16	O
,	O
17	O
]	O
and	O
recent	O
applications	O
of	O
the	O
TOPS	O
diagram	O
[	O
18	O
,	O
19	O
]	O
,	O
usually	O
struggle	O
with	O
translating	O
the	O
comparison	O
results	O
from	O
the	O
secondary	O
structure	O
to	O
the	O
individual	O
residue	O
level	O
.	O

Although	O
the	O
SSM	O
method	O
uses	O
graph	O
-	O
matching	O
procedures	O
at	O
the	O
SSE	O
level	O
followed	O
by	O
an	O
interactive	O
3D	O
alignment	O
of	O
the	O
protein	O
C	O
-	O
alpha	O
atom	O
[	O
20	O
]	O
,	O
it	O
lacks	O
the	O
topological	O
relationships	O
between	O
the	O
SSEs	O
,	O
which	O
are	O
essential	O
features	O
in	O
identifying	O
common	O
scaffolds	O
in	O
distantly	O
related	O
proteins	O
.	O

A	O
TOPS	O
pattern	O
was	O
used	O
to	O
guide	O
the	O
sequence	O
alignment	O
,	O
for	O
instance	O
,	O
to	O
build	O
multiple	O
structural	O
alignments	O
of	O
the	O
distantly	O
related	O
family	O
of	O
beta	O
-	O
rich	O
protein	O
domains	O
[	O
21	O
]	O
.	O

The	O
Multiple	O
Sequence	O
Alignment	O
Tool	O
(	O
MSAT	O
)	O
automates	O
this	O
approach	O
,	O
merging	O
it	O
with	O
a	O
popular	O
ClustalW	O
program	O
[	O
22	O
]	O
.	O

DALI	O
[	O
3	O
]	O
,	O
CE	O
[	O
4	O
]	O
or	O
FATCAT	O
[	O
5	O
]	O
introduce	O
their	O
own	O
methods	O
of	O
decomposing	O
the	O
protein	O
structure	O
into	O
smaller	O
units	O
,	O
such	O
as	O
7	O
x	O
7	O
dense	O
distance	O
map	O
fragments	O
(	O
DALIs	O
)	O
or	O
aligned	O
fragment	O
pairs	O
(	O
AFPs	O
)	O
(	O
CE	O
and	O
FATCAT	O
)	O
.	O

The	O
large	O
number	O
of	O
such	O
fragments	O
and	O
the	O
combinations	O
of	O
the	O
fragments	O
that	O
need	O
to	O
be	O
evaluated	O
by	O
structure	O
comparison	O
programs	O
is	O
the	O
main	O
reason	O
for	O
the	O
significant	O
computational	O
requirements	O
of	O
such	O
algorithms	O
.	O

However	O
,	O
more	O
importantly	O
,	O
TOPS	O
+	O
method	O
is	O
used	O
here	O
to	O
enable	O
a	O
structural	O
comparison	O
that	O
takes	O
into	O
account	O
flexibility	O
in	O
protein	O
structures	O
and	O
not	O
only	O
classifies	O
the	O
differences	O
,	O
but	O
also	O
can	O
recognize	O
such	O
rearrangements	O
-	O
which	O
is	O
a	O
first	O
such	O
application	O
using	O
the	O
SSEs	O
language	O
.	O

In	O
this	O
contribution	O
,	O
we	O
explore	O
the	O
question	O
of	O
whether	O
it	O
would	O
be	O
possible	O
to	O
combine	O
insights	O
provided	O
by	O
topology	O
diagrams	O
into	O
automated	O
protein	O
structure	O
alignment	O
algorithms	O
,	O
focusing	O
on	O
the	O
FATCAT	O
program	O
developed	O
previously	O
in	O
our	O
group	O
.	O

Methods	O

Flexible	O
structure	O
alignment	O
method	O
FATCAT	O

FATCAT	O
[	O
5	O
]	O
is	O
a	O
unique	O
structure	O
alignment	O
method	O
that	O
allows	O
for	O
flexibility	O
in	O
the	O
structures	O
being	O
compared	O
.	O

It	O
builds	O
the	O
alignment	O
by	O
chaining	O
aligned	O
fragment	O
pairs	O
(	O
AFPs	O
)	O
[	O
23	O
]	O
together	O
using	O
a	O
unified	O
scoring	O
function	O
where	O
AFP	O
extensions	O
,	O
gaps	O
,	O
and	O
twists	O
each	O
have	O
their	O
specific	O
scores	O
(	O
Figure	O
2	O
)	O
.	O

Introducing	O
a	O
twist	O
into	O
the	O
alignment	O
is	O
penalized	O
,	O
but	O
this	O
penalty	O
may	O
be	O
compensated	O
for	O
by	O
the	O
gain	O
in	O
the	O
score	O
of	O
the	O
resulting	O
alignment	O
(	O
i	O
.	O
e	O
.	O
,	O
longer	O
alignment	O
and	O
/	O
or	O
better	O
RMSD	O
)	O
.	O

Rigid	O
alignment	O
can	O
be	O
treated	O
as	O
a	O
special	O
case	O
,	O
in	O
which	O
no	O
twist	O
is	O
allowed	O
in	O
chaining	O
AFPs	O
.	O

FATCAT	O
program	O
provides	O
alignment	O
in	O
both	O
,	O
"	O
rigid	O
"	O
mode	O
and	O
"	O
flexible	O
"	O
(	O
default	O
)	O
mode	O
.	O

FATCAT	O
,	O
as	O
well	O
as	O
most	O
other	O
protein	O
structure	O
comparison	O
programs	O
,	O
is	O
very	O
slow	O
when	O
compared	O
to	O
sequence	O
alignments	O
.	O

The	O
computing	O
time	O
of	O
FATCAT	O
is	O
determined	O
by	O
the	O
size	O
of	O
the	O
collection	O
of	O
AFPs	O
detected	O
between	O
the	O
two	O
structures	O
being	O
compared	O
.	O

FATCAT	O
is	O
available	O
from	O
a	O
server	O
with	O
an	O
option	O
to	O
search	O
in	O
SCOP	O
or	O
PDB	O
databases	O
for	O
similar	O
structures	O
.	O

This	O
search	O
typically	O
takes	O
between	O
8	O
to	O
16	O
hours	O
of	O
CPU	O
time	O
,	O
and	O
this	O
is	O
the	O
main	O
obstacle	O
to	O
broader	O
use	O
of	O
this	O
option	O
.	O

FATCAT	O
has	O
been	O
used	O
to	O
construct	O
a	O
Flexible	O
Structure	O
Neighborhood	O
(	O
FSN	O
)	O
database	O
that	O
contains	O
pre	O
-	O
computed	O
results	O
of	O
structure	O
similarity	O
searches	O
and	O
it	O
takes	O
several	O
weeks	O
of	O
CPU	O
time	O
to	O
update	O
the	O
FSN	O
database	O
.	O

Other	O
protein	O
structure	O
comparison	O
resources	O
,	O
such	O
as	O
DALI	O
or	O
CE	O
have	O
very	O
similar	O
problems	O
.	O

TOPS	O
cartoons	O
and	O
TOPS	O
graph	O
models	O

As	O
discussed	O
in	O
the	O
Background	O
,	O
TOPS	O
cartoons	O
capture	O
the	O
simplified	O
,	O
fold	O
-	O
level	O
description	O
of	O
protein	O
structure	O
and	O
at	O
the	O
same	O
time	O
can	O
be	O
automated	O
[	O
24	O
]	O
.	O

The	O
TOPS	O
algorithm	O
uses	O
structural	O
features	O
such	O
as	O
hydrogen	O
bonds	O
and	O
chirality	O
of	O
the	O
beta	O
strands	O
to	O
provide	O
a	O
scoring	O
function	O
to	O
optimize	O
the	O
cartoon	O
(	O
see	O
Figure	O
1	O
(	O
b	O
)	O
)	O
.	O

In	O
TOPS	O
,	O
the	O
secondary	O
structural	O
elements	O
(	O
SSEs	O
)	O
are	O
derived	O
from	O
the	O
DSSP	O
program	O
[	O
25	O
]	O
.	O

Based	O
on	O
TOPS	O
cartoons	O
,	O
a	O
formal	O
graph	O
model	O
and	O
graph	O
-	O
based	O
definitions	O
of	O
protein	O
topology	O
and	O
pattern	O
discovery	O
and	O
comparison	O
methods	O
were	O
developed	O
[	O
26	O
,	O
27	O
]	O
.	O

The	O
TOPS	O
database	O
and	O
comparison	O
,	O
pattern	O
discovery	O
and	O
matching	O
programs	O
are	O
accessible	O
from	O
.	O

Novel	O
TOPS	O
+	O
and	O
TOPS	O
+	O
strings	O
models	O

The	O
TOPS	O
model	O
was	O
further	O
enhanced	O
to	O
incorporate	O
features	O
such	O
as	O
protein	O
-	O
ligand	O
interaction	O
information	O
and	O
more	O
detailed	O
secondary	O
structural	O
segment	O
information	O
.	O

This	O
enhanced	O
model	O
is	O
called	O
TOPS	O
+	O
model	O
(	O
see	O
Figure	O
3a	O
)	O
.	O

This	O
TOPS	O
+	O
model	O
can	O
be	O
described	O
formally	O
in	O
a	O
TOPS	O
+	O
strings	O
language	O
(	O
Figure	O
3b	O
)	O
at	O
a	O
reduced	O
linear	O
level	O
.	O

The	O
enhanced	O
TOPS	O
+	O
strings	O
models	O
can	O
be	O
used	O
in	O
fast	O
string	O
-	O
based	O
structure	O
matching	O
and	O
comparison	O
,	O
at	O
the	O
same	O
time	O
avoiding	O
issues	O
of	O
NP	O
-	O
completeness	O
associated	O
with	O
graph	O
alignments	O
.	O

In	O
detail	O
,	O
each	O
node	O
(	O
SSE	O
segment	O
)	O
of	O
the	O
TOPS	O
+	O
strings	O
is	O
described	O
by	O
its	O
type	O
,	O
orientation	O
,	O
PDB	O
start	O
number	O
,	O
segment	O
length	O
,	O
total	O
number	O
of	O
incoming	O
(	O
InArc	O
)	O
and	O
outgoing	O
(	O
OutArc	O
)	O
arcs	O
(	O
edges	O
)	O
,	O
total	O
number	O
of	O
ArcTypes	O
,	O
and	O
total	O
number	O
of	O
ligand	O
arcs	O
(	O
LigArc	O
)	O
.	O

The	O
type	O
of	O
the	O
segment	O
(	O
SSEType	O
)	O
could	O
be	O
one	O
of	O
[	O
E	O
,	O
e	O
,	O
H	O
,	O
h	O
,	O
U	O
,	O
u	O
]	O
,	O
where	O
,	O
"	O
E	O
"	O
and	O
"	O
e	O
"	O
represent	O
the	O
"	O
up	O
"	O
-	O
and	O
"	O
down	O
"	O
-	O
oriented	O
beta	O
strands	O
;	O
"	O
H	O
"	O
and	O
"	O
h	O
"	O
indicate	O
the	O
"	O
up	O
"	O
-	O
and	O
"	O
down	O
"	O
-	O
oriented	O
alpha	O
helices	O
;	O
and	O
"	O
U	O
"	O
and	O
"	O
u	O
"	O
represent	O
ligand	O
-	O
bound	O
and	O
ligand	O
-	O
free	O
loops	O
.	O

The	O
InArcType	O
can	O
be	O
classified	O
as	O
an	O
/	O
a	O
[	O
R	O
,	O
L	O
,	O
P	O
,	O
A	O
]	O
,	O
where	O
"	O
R	O
"	O
and	O
"	O
L	O
"	O
represent	O
right	O
and	O
left	O
chiralities	O
;	O
and	O
"	O
P	O
"	O
and	O
"	O
A	O
"	O
represent	O
parallel	O
and	O
anti	O
-	O
parallel	O
hydrogen	O
bonds	O
,	O
respectively	O
.	O

The	O
OutArcType	O
is	O
represented	O
in	O
a	O
similar	O
manner	O
by	O
[	O
R	O
'	O
,	O
L	O
'	O
,	O
P	O
'	O
,	O
A	O
'	O
]	O
.	O

Ligand	O
arcs	O
are	O
indicated	O
by	O
LT	O
=	O
AA	O
,	O
where	O
LT	O
is	O
the	O
ligand	O
type	O
and	O
AA	O
is	O
the	O
PDB	O
number	O
.	O

For	O
example	O
,	O
Figure	O
3	O
(	O
a	O
)	O
and	O
3	O
(	O
b	O
)	O
contain	O
visual	O
representations	O
of	O
TOPS	O
+	O
and	O
TOPS	O
+	O
strings	O
models	O
,	O
respectively	O
,	O
for	O
the	O
protein	O
domain	O
d1fnb	O
_	O
1	O
.	O

Here	O
the	O
triangles	O
represent	O
the	O
beta	O
strands	O
;	O
the	O
red	O
curve	O
represents	O
the	O
alpha	O
helix	O
;	O
gray	O
ellipsoids	O
indicate	O
loops	O
;	O
and	O
green	O
arcs	O
indicate	O
hydrogen	O
bonds	O
between	O
two	O
beta	O
strands	O
,	O
called	O
anti	O
-	O
parallel	O
beta	O
sheets	O
.	O

The	O
length	O
of	O
a	O
TOPS	O
+	O
strings	O
model	O
is	O
defined	O
by	O
number	O
of	O
SSEs	O
;	O
thus	O
,	O
the	O
length	O
of	O
d1fnb	O
_	O
1	O
is	O
19	O
.	O

For	O
further	O
details	O
,	O
see	O
[	O
28	O
]	O
.	O

TOPS	O
+	O
strings	O
comparison	O
method	O

TOPS	O
+	O
is	O
a	O
comparison	O
method	O
that	O
computes	O
a	O
distance	O
between	O
TOPS	O
+	O
strings	O
models	O
of	O
two	O
proteins	O
based	O
on	O
a	O
dynamic	O
programming	O
approach	O
and	O
identifies	O
the	O
longest	O
common	O
subsequence	O
(	O
LCS	O
)	O
,	O
consisting	O
of	O
the	O
list	O
of	O
the	O
topologically	O
equivalent	O
SSEs	O
between	O
two	O
proteins	O
.	O

For	O
example	O
,	O
Figure	O
3	O
(	O
c	O
)	O
shows	O
the	O
TOPS	O
+	O
strings	O
alignment	O
between	O
Dihydropteridine	O
reductase	O
proteins	O
from	O
rat	O
(	O
1dhr	O
)	O
and	O
human	B
(	O
1hdr	O
)	O
.	O

The	O
TOPS	O
+	O
strings	O
models	O
for	O
1dhr	O
and	O
1hdr	O
are	O
represented	O
by	O
a	O
linear	O
string	O
-	O
model	O
,	O
where	O
a	O
yellow	O
triangle	O
and	O
red	O
curves	O
indicate	O
the	O
beta	O
strands	O
and	O
alpha	O
helices	O
in	O
their	O
"	O
up	O
"	O
or	O
"	O
down	O
"	O
orientations	O
,	O
respectively	O
.	O

The	O
grey	O
line	O
and	O
purple	O
stubs	O
represent	O
the	O
loop	O
regions	O
and	O
the	O
NAD	O
ligand	O
interactions	O
,	O
respectively	O
.	O

Note	O
that	O
the	O
ligand	O
-	O
interaction	O
information	O
is	O
optional	O
and	O
in	O
this	O
work	O
we	O
have	O
not	O
used	O
it	O
.	O

The	O
incoming	O
and	O
outgoing	O
arcs	O
are	O
depicted	O
in	O
the	O
SSEs	O
(	O
top	O
and	O
bottom	O
of	O
the	O
beta	O
strands	O
)	O
,	O
where	O
red	O
and	O
green	O
arcs	O
represent	O
the	O
parallel	O
and	O
anti	O
-	O
parallel	O
hydrogen	O
-	O
bond	O
interactions	O
that	O
show	O
beta	O
-	O
sheet	O
information	O
,	O
while	O
yellow	O
and	O
blue	O
arcs	O
indicate	O
the	O
right	O
and	O
left	O
chirality	O
relationships	O
between	O
the	O
SSEs	O
.	O

A	O
pink	O
arrow	O
between	O
the	O
TOPS	O
+	O
strings	O
elements	O
indicates	O
the	O
conserved	O
SSE	O
.	O

The	O
dotted	O
arrows	O
indicate	O
the	O
conserved	O
alpha	O
helices	O
and	O
beta	O
strands	O
,	O
while	O
the	O
plain	O
arrows	O
indicate	O
the	O
conserved	O
loop	O
regions	O
.	O

TOPS	O
+	O
+	O
FATCAT	O
method	O

In	O
this	O
work	O
,	O
we	O
want	O
to	O
test	O
the	O
general	O
idea	O
of	O
pruning	O
the	O
search	O
space	O
of	O
the	O
FATCAT	O
comparison	O
process	O
using	O
topological	O
constraints	O
derived	O
from	O
the	O
TOPS	O
+	O
strings	O
alignment	O
.	O

Many	O
of	O
the	O
AFPs	O
considered	O
in	O
the	O
FATCAT	O
alignment	O
could	O
be	O
easily	O
eliminated	O
from	O
the	O
comparison	O
by	O
constraining	O
the	O
alignment	O
region	O
.	O

Here	O
we	O
explore	O
constraints	O
obtained	O
from	O
the	O
TOPS	O
+	O
strings	O
alignment	O
,	O
which	O
identifies	O
topologically	O
equivalent	O
secondary	O
structure	O
elements	O
(	O
alpha	O
helices	O
,	O
beta	O
strands	O
,	O
and	O
loops	O
)	O
for	O
this	O
purpose	O
.	O

Such	O
equivalences	O
define	O
blocks	O
that	O
restrict	O
the	O
alignment	O
region	O
;	O
AFPs	O
that	O
fall	O
outside	O
these	O
regions	O
are	O
simply	O
not	O
considered	O
(	O
see	O
Figure	O
4	O
(	O
b	O
)	O
)	O
.	O

We	O
introduce	O
a	O
parameter	O
r	O
to	O
control	O
the	O
strictness	O
of	O
constraints	O
by	O
TOPS	O
+	O
strings	O
alignments	O
;	O
r	O
equals	O
0	O
if	O
the	O
alignment	O
region	O
is	O
strictly	O
restrained	O
by	O
TOPS	O
+	O
strings	O
alignment	O
,	O
and	O
r	O
is	O
set	O
to	O
1	O
by	O
default	O
in	O
our	O
program	O
to	O
allow	O
certain	O
flexibility	O
to	O
the	O
constrained	O
alignment	O
region	O
(	O
Figure	O
4	O
(	O
c	O
)	O
)	O
.	O

We	O
then	O
can	O
speed	O
up	O
the	O
FATCAT	O
alignment	O
by	O
considering	O
only	O
the	O
AFPs	O
within	O
the	O
constrained	O
alignment	O
area	O
(	O
Figure	O
4	O
(	O
d	O
)	O
)	O
.	O

The	O
rigid	O
structural	O
alignment	O
can	O
be	O
treated	O
as	O
a	O
special	O
case	O
of	O
TOPS	O
+	O
+	O
FATCAT	O
,	O
in	O
which	O
no	O
twist	O
is	O
allowed	O
in	O
chaining	O
AFPs	O
.	O

However	O
,	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
program	O
provides	O
alignment	O
in	O
both	O
,	O
"	O
rigid	O
"	O
mode	O
and	O
"	O
flexible	O
"	O
mode	O
(	O
default	O
)	O
.	O

Benchmarking	O

For	O
benchmarking	O
and	O
comparison	O
,	O
we	O
have	O
used	O
the	O
PDB40	O
dataset	O
of	O
1	O
,	O
901	O
protein	O
domain	O
pairs	O
(	O
DP	O
)	O
corresponding	O
to	O
SCOP	O
version	O
1	O
.	O
61	O
from	O
the	O
ASTRAL	O
database	O
[	O
29	O
]	O
.	O

Table	O
1	O
provides	O
the	O
SCOP	O
superfamily	O
level	O
homolog	O
versus	O
non	O
-	O
homolog	O
statistics	O
for	O
the	O
four	O
main	O
SCOP	O
classes	O
i	O
.	O
e	O
.	O
,	O
all	O
-	O
alpha	O
,	O
all	O
-	O
beta	O
,	O
alpha	O
/	O
beta	O
,	O
alpha	O
+	O
beta	O
,	O
and	O
all	O
proteins	O
regardless	O
of	O
their	O
structural	O
classes	O
.	O

Evaluation	O
Analyses	O

We	O
performed	O
the	O
Receiver	O
Operating	O
Characteristics	O
(	O
ROC	O
)	O
curve	O
and	O
the	O
AUC	O
(	O
Area	O
Under	O
the	O
ROC	O
Curve	O
)	O
analyses	O
to	O
compare	O
the	O
performance	O
of	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
with	O
the	O
original	O
FATCAT	O
method	O
,	O
using	O
SCOP	O
classification	O
at	O
the	O
superfamily	O
level	O
as	O
a	O
standard	O
of	O
comparison	O
[	O
30	O
]	O
.	O

Results	O

ROC	O
and	O
AUC	O
Analyses	O

We	O
have	O
compared	O
the	O
performance	O
of	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
against	O
the	O
original	O
FATCAT	O
method	O
using	O
the	O
SCOP	O
classification	O
information	O
at	O
the	O
superfamily	O
level	O
.	O

We	O
have	O
plotted	O
the	O
ROC	O
curves	O
based	O
on	O
P	O
-	O
values	O
obtained	O
from	O
the	O
FATCAT	O
and	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
.	O

We	O
have	O
plotted	O
the	O
ROC	O
curves	O
separately	O
for	O
the	O
main	O
SCOP	O
classes	O
,	O
i	O
.	O
e	O
.	O
,	O
all	O
-	O
alpha	O
,	O
all	O
-	O
beta	O
,	O
alpha	O
/	O
beta	O
,	O
alpha	O
+	O
beta	O
,	O
and	O
all	O
proteins	O
regardless	O
of	O
the	O
class	O
they	O
belong	O
to	O
(	O
see	O
Figure	O
5	O
(	O
a	O
)	O
to	O
5	O
(	O
e	O
)	O
)	O
.	O

In	O
the	O
graph	O
,	O
the	O
x	O
-	O
and	O
y	O
-	O
axes	O
represent	O
the	O
false	O
positive	O
and	O
true	O
positive	O
rates	O
of	O
the	O
performance	O
of	O
the	O
comparison	O
methods	O
respectively	O
.	O

In	O
the	O
legend	O
,	O
rF	O
-	O
pvalue	O
and	O
fF	O
-	O
pvalue	O
indicate	O
results	O
from	O
the	O
rigid	O
and	O
flexible	O
FATCAT	O
methods	O
,	O
respectively	O
;	O
similarly	O
,	O
rT2F	O
-	O
pvalue	O
and	O
fT2F	O
-	O
pvalue	O
represent	O
the	O
rigid	O
and	O
flexible	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
,	O
respectively	O
.	O

We	O
have	O
calculated	O
the	O
AUC	O
values	O
for	O
all	O
the	O
SCOP	O
classes	O
based	O
on	O
ROC	O
curves	O
obtained	O
from	O
the	O
FATCAT	O
and	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
with	O
the	O
flexible	O
/	O
rigid	O
options	O
(	O
see	O
Table	O
2	O
)	O
.	O

For	O
all	O
protein	O
classes	O
,	O
the	O
rigid	O
FATCAT	O
performs	O
best	O
,	O
usually	O
followed	O
by	O
the	O
flexible	O
FATCAT	O
,	O
the	O
rigid	O
TOPS	O
+	O
+	O
FATCAT	O
,	O
and	O
the	O
flexible	O
TOPS	O
+	O
+	O
FATCAT	O
.	O

The	O
performance	O
of	O
all	O
four	O
methods	O
is	O
best	O
for	O
all	O
alpha	O
and	O
all	O
beta	O
proteins	O
,	O
and	O
all	O
four	O
perform	O
markedly	O
worse	O
(	O
but	O
similar	O
to	O
each	O
other	O
)	O
for	O
alpha	O
/	O
beta	O
proteins	O
.	O

Only	O
alpha	O
+	O
beta	O
proteins	O
show	O
a	O
clear	O
difference	O
between	O
the	O
FATCAT	O
and	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
.	O

It	O
is	O
important	O
to	O
note	O
that	O
the	O
TOPS	O
+	O
strings	O
models	O
consider	O
the	O
parallel	O
and	O
anti	O
-	O
parallel	O
properties	O
of	O
the	O
beta	O
-	O
sheet	O
information	O
in	O
the	O
form	O
of	O
total	O
number	O
of	O
incoming	O
and	O
outgoing	O
arcs	O
with	O
their	O
ArcTypes	O
.	O

Thus	O
,	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
discriminates	O
the	O
protein	O
domain	O
pairs	O
more	O
efficiently	O
compared	O
to	O
the	O
original	O
FATCAT	O
method	O
.	O

For	O
example	O
,	O
in	O
the	O
all	O
-	O
beta	O
protein	O
domain	O
pairs	O
,	O
both	O
the	O
flexible	O
and	O
the	O
rigid	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
perform	O
well	O
.	O

The	O
flexible	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
covers	O
nearly	O
84	O
%	O
of	O
protein	O
domains	O
with	O
0	O
%	O
false	O
positives	O
,	O
but	O
the	O
flexible	O
and	O
rigid	O
FATCAT	O
methods	O
cover	O
only	O
76	O
%	O
and	O
49	O
%	O
of	O
the	O
true	O
positives	O
,	O
respectively	O
,	O
with	O
0	O
%	O
false	O
positives	O
.	O

The	O
zoomed	O
-	O
in	O
version	O
of	O
the	O
ROC	O
curves	O
with	O
up	O
to	O
10	O
%	O
false	O
positives	O
for	O
all	O
-	O
beta	O
rich	O
protein	O
families	O
is	O
shown	O
in	O
Figure	O
5	O
(	O
f	O
)	O
;	O
where	O
both	O
the	O
rigid	O
TOPS	O
+	O
+	O
FATCAT	O
(	O
green	O
)	O
and	O
flexible	O
(	O
red	O
)	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
have	O
coverage	O
rates	O
of	O
82	O
%	O
and	O
84	O
%	O
true	O
positives	O
respectively	O
with	O
0	O
%	O
false	O
positives	O
.	O

The	O
overall	O
results	O
for	O
all	O
protein	O
classes	O
show	O
that	O
TOPS	O
+	O
+	O
FATCAT	O
performance	O
is	O
only	O
slightly	O
lower	O
(	O
3	O
%	O
-	O
7	O
%	O
AUC	O
value	O
difference	O
(	O
see	O
Table	O
2	O
)	O
)	O
as	O
compared	O
to	O
FATCAT	O
while	O
providing	O
a	O
significant	O
,	O
more	O
than	O
10	O
-	O
fold	O
speedup	O
(	O
see	O
next	O
section	O
)	O
.	O

AFP	O
and	O
Runtime	O
Analyses	O

We	O
tested	O
both	O
the	O
FATCAT	O
and	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
using	O
the	O
Mac	O
OS	O
X	O
version	O
10	O
.	O
4	O
.	O
10	O
computer	O
system	O
with	O
a	O
2	O
x	O
2	O
.	O
66	O
-	O
GHz	O
Dual	O
-	O
Core	O
Intel	O
Xeon	O
processor	O
and	O
1	O
-	O
GB	O
667	O
MHz	O
memory	O
.	O

We	O
have	O
performed	O
runtime	O
analysis	O
on	O
1	O
,	O
901	O
protein	O
domain	O
pairs	O
and	O
counted	O
the	O
total	O
number	O
of	O
AFPs	O
and	O
the	O
corresponding	O
runtime	O
from	O
both	O
the	O
FATCAT	O
and	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
.	O

The	O
results	O
show	O
an	O
exponential	O
increase	O
in	O
AFPs	O
(	O
Figure	O
6	O
(	O
b	O
)	O
)	O
and	O
corresponding	O
runtime	O
(	O
Figure	O
6	O
(	O
a	O
)	O
)	O
for	O
the	O
FATCAT	O
method	O
as	O
compared	O
to	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
(	O
see	O
Table	O
3	O
)	O
For	O
example	O
,	O
the	O
average	O
number	O
of	O
AFPs	O
for	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
is	O
530	O
,	O
but	O
the	O
average	O
number	O
of	O
AFPs	O
for	O
the	O
FATCAT	O
method	O
is	O
15	O
,	O
019	O
.	O

This	O
represents	O
the	O
number	O
of	O
average	O
AFPs	O
used	O
by	O
the	O
FATCAT	O
method	O
is	O
increased	O
by	O
a	O
factor	O
of	O
28	O
(	O
see	O
Table	O
3	O
)	O
.	O

This	O
result	O
leads	O
to	O
the	O
conclusion	O
that	O
TOPS	O
+	O
+	O
FATCAT	O
is	O
22	O
times	O
faster	O
compared	O
to	O
the	O
FATCAT	O
because	O
this	O
method	O
must	O
take	O
into	O
account	O
more	O
number	O
of	O
AFPs	O
in	O
the	O
comparison	O
process	O
(	O
see	O
Table	O
3	O
)	O
.	O

Case	O
Studies	O

While	O
the	O
overall	O
accuracy	O
of	O
both	O
rigid	O
and	O
flexible	O
FATCAT	O
methods	O
is	O
better	O
than	O
their	O
TOPS	O
+	O
+	O
FATCAT	O
equivalents	O
,	O
an	O
interesting	O
example	O
where	O
the	O
opposite	O
is	O
true	O
lies	O
in	O
the	O
comparison	O
of	O
two	O
proteins	O
,	O
d2trxa	O
_	O
(	O
108	O
aa	O
)	O
from	O
Escherichia	B
coli	I
and	O
d1kte	O
_	O
_	O
(	O
105	O
aa	O
)	O
from	O
Sus	B
scrofa	I
(	O
pig	B
)	O
from	O
the	O
thioredoxin	O
-	O
like	O
superfamily	O
.	O

For	O
this	O
pair	O
,	O
the	O
flexible	O
_	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
provides	O
an	O
alignment	O
with	O
88	O
equivalent	O
positions	O
with	O
1	O
.	O
67	O
A	O
chain	O
RMSD	O
and	O
3	O
.	O
06	O
A	O
of	O
optimal	O
RMSD	O
without	O
any	O
twist	O
,	O
giving	O
the	O
alignment	O
with	O
10	O
%	O
sequence	O
identity	O
(	O
see	O
Table	O
4	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
flexible	O
_	O
FATCAT	O
method	O
provides	O
an	O
alignment	O
with	O
86	O
aligned	O
positions	O
using	O
a	O
twist	O
in	O
the	O
C	O
-	O
terminal	O
region	O
;	O
it	O
has	O
a	O
higher	O
chain	O
RMSD	O
of	O
5	O
.	O
14	O
A	O
,	O
and	O
its	O
optimal	O
RMSD	O
is	O
3	O
.	O
48	O
A	O
.	O

For	O
more	O
information	O
regarding	O
the	O
chain	O
and	O
optimal	O
RMSDs	O
refer	O
[	O
5	O
]	O
.	O

The	O
flexible	O
_	O
FATCAT	O
method	O
uses	O
the	O
twist	O
to	O
align	O
a	O
helix	O
in	O
the	O
C	O
-	O
terminal	O
region	O
,	O
which	O
is	O
positioned	O
incorrectly	O
with	O
a	O
beta	O
-	O
sheet	O
core	O
(	O
see	O
Table	O
4	O
)	O
.	O

Figure	O
7	O
(	O
a	O
)	O
shows	O
the	O
superposition	O
of	O
d2trxa	O
_	O
(	O
gray	O
)	O
and	O
d1kte	O
_	O
_	O
(	O
orange	O
)	O
domains	O
from	O
the	O
flexible	O
_	O
FATCAT	O
method	O
,	O
where	O
the	O
blue	O
color	O
indicates	O
the	O
d1kte	O
_	O
_	O
protein	O
domain	O
from	O
the	O
flexible	O
_	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
.	O

The	O
incorrect	O
alignment	O
of	O
the	O
C	O
-	O
terminal	O
domain	O
alpha	O
helix	O
of	O
the	O
d1kte	O
_	O
_	O
domain	O
(	O
orange	O
)	O
is	O
visible	O
in	O
the	O
core	O
of	O
the	O
beta	O
-	O
sheet	O
region	O
.	O

Figure	O
7	O
(	O
b	O
)	O
and	O
7	O
(	O
c	O
)	O
shows	O
the	O
AFPs	O
from	O
the	O
flexible	O
_	O
FATCAT	O
and	O
flexible	O
_	O
TOPS	O
+	O
+	O
FATCAT	O
methods	O
,	O
respectively	O
.	O

The	O
hinge	O
region	O
provides	O
a	O
twist	O
in	O
the	O
flexible	O
_	O
FATCAT	O
method	O
indicated	O
by	O
an	O
arrow	O
and	O
the	O
AFPs	O
represented	O
by	O
a	O
different	O
color	O
(	O
see	O
Figure	O
7	O
(	O
b	O
)	O
)	O
.	O

In	O
this	O
case	O
,	O
the	O
alignment	O
constraints	O
from	O
the	O
TOPS	O
+	O
strings	O
alignment	O
allow	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
to	O
avoid	O
a	O
spurious	O
alignment	O
.	O

The	O
Erythrocruorin	O
protein	O
domain	O
d1eca	O
_	O
_	O
(	O
136	O
aa	O
)	O
from	O
Chironomus	B
thummi	I
and	O
the	O
Phycocyanin	O
alpha	O
subunit	O
protein	O
domain	O
d1cpca	O
_	O
(	O
162	O
aa	O
)	O
from	O
Fremyella	B
diplosiphon	I
(	O
Cyanobacterium	O
)	O
belong	O
to	O
the	O
Globin	O
-	O
like	O
superfamily	O
.	O

For	O
these	O
protein	O
domain	O
pairs	O
,	O
the	O
FATCAT	O
method	O
provides	O
a	O
better	O
alignment	O
with	O
120	O
and	O
118	O
aligned	O
positions	O
with	O
the	O
chain	O
RMSD	O
of	O
4	O
.	O
02	O
A	O
based	O
on	O
the	O
flexible	O
and	O
rigid	O
options	O
,	O
respectively	O
.	O

The	O
flexible	O
_	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
gives	O
an	O
alignment	O
of	O
63	O
aligned	O
positions	O
with	O
the	O
3	O
.	O
23	O
A	O
optimal	O
RMSD	O
and	O
the	O
6	O
.	O
28	O
A	O
chain	O
RMSD	O
.	O

In	O
this	O
case	O
,	O
the	O
flexible	O
_	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
misses	O
the	O
N	O
-	O
terminal	O
region	O
helix	O
and	O
misaligns	O
some	O
helices	O
.	O

For	O
example	O
,	O
Figure	O
8	O
(	O
a	O
)	O
shows	O
the	O
superposition	O
of	O
d1eca	O
_	O
_	O
(	O
gray	O
)	O
and	O
d1cpca	O
_	O
(	O
orange	O
)	O
domains	O
from	O
the	O
flexible	O
_	O
FATCAT	O
method	O
,	O
while	O
d1cpca	O
_	O
(	O
blue	O
)	O
domain	O
is	O
from	O
the	O
flexible	O
_	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
.	O

The	O
AFP	O
chaining	O
alignment	O
and	O
the	O
actual	O
alignment	O
from	O
FATCAT	O
are	O
shown	O
in	O
Figure	O
8	O
(	O
b	O
)	O
and	O
8	O
(	O
e	O
)	O
,	O
respectively	O
.	O

Figure	O
8	O
(	O
c	O
)	O
shows	O
the	O
AFP	O
alignment	O
from	O
TOPS	O
+	O
+	O
FATCAT	O
,	O
in	O
which	O
this	O
method	O
misses	O
the	O
N	O
-	O
terminal	O
region	O
and	O
incorrectly	O
aligns	O
some	O
of	O
the	O
C	O
-	O
terminal	O
regions	O
(	O
see	O
Figure	O
8	O
(	O
d	O
)	O
)	O
.	O

However	O
,	O
the	O
rigid	O
_	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
produces	O
an	O
alignment	O
of	O
108	O
aligned	O
positions	O
with	O
optimal	O
and	O
chain	O
RMSDs	O
of	O
3	O
.	O
22	O
A	O
and	O
6	O
.	O
28	O
A	O
respectively	O
.	O

In	O
general	O
,	O
TOPS	O
comparison	O
does	O
not	O
work	O
well	O
for	O
alpha	O
-	O
rich	O
proteins	O
due	O
to	O
the	O
lack	O
of	O
hydrogen	O
bonds	O
between	O
SSEs	O
[	O
26	O
]	O
.	O

The	O
same	O
is	O
true	O
for	O
TOPS	O
+	O
strings	O
comparison	O
to	O
some	O
extent	O
;	O
however	O
,	O
this	O
method	O
takes	O
advantage	O
of	O
ligand	O
-	O
interaction	O
information	O
to	O
compare	O
protein	O
domains	O
more	O
efficiently	O
;	O
for	O
example	O
the	O
DNA	O
binding	O
motifs	O
such	O
as	O
helix	O
-	O
turn	O
-	O
helix	O
and	O
helix	O
-	O
loop	O
-	O
helix	O
can	O
be	O
easily	O
recognized	O
[	O
28	O
]	O
.	O

However	O
,	O
we	O
have	O
not	O
explored	O
that	O
ligand	O
pattern	O
discovery	O
option	O
within	O
the	O
TOPS	O
+	O
strings	O
comparison	O
in	O
this	O
paper	O
.	O

In	O
addition	O
,	O
the	O
TOPS	O
+	O
strings	O
alignment	O
provides	O
only	O
a	O
basic	O
alignment	O
;	O
the	O
scoring	O
function	O
to	O
find	O
the	O
best	O
alignment	O
has	O
not	O
been	O
optimized	O
.	O

These	O
problems	O
can	O
be	O
addressed	O
in	O
future	O
development	O
by	O
considering	O
the	O
advanced	O
TOPS	O
+	O
and	O
TOPS	O
+	O
strings	O
models	O
based	O
on	O
helix	O
-	O
helix	O
packing	O
relationships	O
and	O
SSE	O
-	O
ligand	O
interaction	O
properties	O
together	O
with	O
the	O
right	O
and	O
left	O
chiralities	O
.	O

Furthermore	O
,	O
the	O
TOPS	O
+	O
strings	O
comparison	O
can	O
be	O
optimized	O
in	O
both	O
the	O
comparison	O
process	O
as	O
well	O
as	O
in	O
the	O
alignment	O
process	O
in	O
order	O
to	O
take	O
into	O
account	O
indels	O
(	O
insertion	O
/	O
deletion	O
)	O
of	O
SSEs	O
which	O
exist	O
in	O
nature	O
across	O
the	O
different	O
members	O
of	O
the	O
protein	O
superfamilies	O
[	O
31	O
]	O
.	O

Discussion	O
and	O
conclusion	O

The	O
overall	O
results	O
for	O
all	O
protein	O
classes	O
show	O
that	O
TOPS	O
+	O
+	O
FATCAT	O
performance	O
is	O
only	O
slightly	O
lower	O
(	O
3	O
%	O
-	O
7	O
%	O
AUC	O
value	O
difference	O
)	O
as	O
compared	O
to	O
FATCAT	O
while	O
providing	O
a	O
significant	O
,	O
more	O
than	O
10	O
-	O
fold	O
speedup	O
.	O

The	O
main	O
reason	O
for	O
the	O
discrepancies	O
is	O
that	O
TOPS	O
+	O
strings	O
alignments	O
occasionally	O
misalign	O
the	O
secondary	O
structure	O
elements	O
and	O
subsequent	O
FATCAT	O
alignment	O
,	O
constrained	O
by	O
the	O
TOPS	O
+	O
strings	O
alignment	O
,	O
cannot	O
overcome	O
the	O
earlier	O
errors	O
.	O

There	O
is	O
a	O
clear	O
trade	O
-	O
off	O
between	O
the	O
runtime	O
and	O
the	O
accuracy	O
;	O
limiting	O
the	O
pool	O
of	O
fragments	O
being	O
compared	O
speeds	O
up	O
the	O
algorithm	O
but	O
results	O
in	O
(	O
slightly	O
)	O
lower	O
accuracy	O
.	O

At	O
the	O
same	O
time	O
,	O
these	O
results	O
offer	O
clear	O
suggestions	O
for	O
future	O
development	O
.	O

Using	O
a	O
more	O
advanced	O
version	O
of	O
the	O
TOPS	O
+	O
strings	O
comparison	O
method	O
would	O
remove	O
some	O
of	O
the	O
false	O
positives	O
might	O
be	O
at	O
a	O
cost	O
of	O
significantly	O
slowing	O
the	O
total	O
performance	O
of	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
method	O
.	O

Authors	O
'	O
contributions	O

MV	O
developed	O
the	O
TOPS	O
+	O
+	O
FATCAT	O
algorithm	O
,	O
performed	O
the	O
calculations	O
and	O
prepared	O
the	O
figures	O
,	O
YY	O
provided	O
advice	O
and	O
oversight	O
in	O
the	O
project	O
,	O
verified	O
the	O
code	O
and	O
provided	O
FATCAT	O
results	O
for	O
comparison	O
,	O
AG	O
contributed	O
to	O
the	O
original	O
idea	O
and	O
to	O
writing	O
of	O
the	O
manuscript	O
.	O

Are	O
there	O
sensitive	O
subgroups	O
for	O
the	O
effects	O
of	O
airborne	O
particles	O
?	O

Abstract	O

Recent	O
studies	O
have	O
shown	O
that	O
particulate	O
air	O
pollution	O
is	O
a	O
risk	O
factor	O
for	O
hospitalization	O
for	O
heart	O
and	O
lung	O
disease	O
;	O
however	O
,	O
little	O
is	O
known	O
about	O
what	O
subpopulations	O
are	O
most	O
sensitive	O
to	O
this	O
pollutant	O
.	O

We	O
analyzed	O
Medicare	O
hospital	O
admissions	O
for	O
heart	O
disease	O
,	O
chronic	O
obstructive	O
pulmonary	O
disorders	O
(	O
COPD	O
)	O
and	O
pneumonia	O
in	O
Chicago	O
,	O
Cook	O
County	O
,	O
Illinois	O
,	O
between	O
1985	O
and	O
1994	O
.	O

We	O
examined	O
whether	O
previous	O
admissions	O
or	O
secondary	O
diagnoses	O
for	O
selected	O
conditions	O
predisposed	O
persons	B
to	O
having	O
a	O
greater	O
risk	O
from	O
air	O
pollution	O
.	O

We	O
also	O
considered	O
effect	O
modification	O
by	O
age	O
,	O
sex	O
,	O
and	O
race	O
.	O

We	O
found	O
that	O
the	O
air	O
-	O
pollution	O
-	O
associated	O
increase	O
in	O
hospital	O
admissions	O
for	O
cardiovascular	O
diseases	O
was	O
almost	O
doubled	O
in	O
subjects	O
with	O
concurrent	O
respiratory	O
infections	O
.	O

The	O
risk	O
was	O
also	O
increased	O
by	O
a	O
previous	O
admission	O
for	O
conduction	O
disorders	O
.	O

For	O
COPD	O
and	O
pneumonia	O
admissions	O
,	O
diagnosis	O
of	O
conduction	O
disorders	O
or	O
dysrhythmias	O
increased	O
the	O
risk	O
of	O
particulate	O
matter	O
<	O
10	O
microm	O
in	O
aerodynamic	O
diameter	O
(	O
PM	O
(	O
10	O
)	O
)	O
-	O
associated	O
admissions	O
.	O

Persons	B
with	O
asthma	O
had	O
twice	O
the	O
risk	O
of	O
a	O
PM	O
(	O
10	O
)	O
-	O
associated	O
pneumonia	O
admission	O
and	O
persons	B
with	O
heart	O
failure	O
had	O
twice	O
the	O
risk	O
of	O
PM	O
(	O
10	O
)	O
-	O
induced	O
COPD	O
admissions	O
.	O

The	O
PM	O
(	O
10	O
)	O
effect	O
did	O
not	O
vary	O
by	O
sex	O
,	O
age	O
,	O
and	O
race	O
.	O

These	O
results	O
suggest	O
that	O
patients	B
with	O
acute	O
respiratory	O
infections	O
or	O
defects	O
in	O
the	O
electrical	O
control	O
of	O
the	O
heart	O
are	O
a	O
risk	O
group	O
for	O
particulate	O
matter	O
effects	O
.	O

Articles	O

Are	O
There	O
Sensitive	O
Subgroups	O
for	O
the	O
Effects	O
of	O
Airborne	O
Particles	O
?	O

Antonella	O
Zanobetti	O
,	O
1	O
Joel	O
Schwartz	O
,	O
1	O
,	O
2	O
and	O
Diane	O
Gold1	O
,	O
2	O
1Environmental	O

Epidemiology	O
Program	O
,	O
Department	O
of	O
Environmental	O
Health	O
,	O
Harvard	O
School	O
of	O
Public	O
Health	O
,	O
Boston	O
,	O
Massachusetts	O
,	O
USA	O
;	O
2Channing	O
Laboratory	O
,	O
Department	O
of	O
Medicine	O
,	O
Harvard	O
Medical	O
School	O
and	O
Brigham	O
and	O
Women	B
'	O
s	O
Hospital	O
,	O
Boston	O
,	O
Massachusetts	O
,	O
USA	O

Recent	O
studies	O
have	O
shown	O
that	O
particulate	O
air	O
pollution	O
is	O
a	O
risk	O
factor	O
for	O
hospitalization	O
for	O
heart	O
and	O
lung	O
disease	O
;	O
however	O
,	O
little	O
is	O
known	O
about	O
what	O
subpopulations	O
are	O
most	O
sensitive	O
to	O
this	O
pollutant	O
.	O

We	O
analyzed	O
Medicare	O
hospital	O
admissions	O
for	O
heart	O
disease	O
,	O
chronic	O
obstructive	O
pulmonary	O
disorders	O
(	O
COPD	O
)	O
and	O
pneumonia	O
in	O
Chicago	O
,	O
Cook	O
County	O
,	O
Illinois	O
,	O
between	O
1985	O
and	O
1994	O
.	O

We	O
examined	O
whether	O
previous	O
admissions	O
or	O
secondary	O
diagnoses	O
for	O
selected	O
conditions	O
predisposed	O
persons	B
to	O
having	O
a	O
greater	O
risk	O
from	O
air	O
pollution	O
.	O

We	O
also	O
considered	O
effect	O
modification	O
by	O
age	O
,	O
sex	O
,	O
and	O
race	O
.	O

We	O
found	O
that	O
the	O
air	O
-	O
pollution	O
-	O
associated	O
increase	O
in	O
hospital	O
admissions	O
for	O
cardiovascular	O
diseases	O
was	O
almost	O
doubled	O
in	O
subjects	O
with	O
concurrent	O
respiratory	O
infections	O
.	O

The	O
risk	O
was	O
also	O
increased	O
by	O
a	O
previous	O
admission	O
for	O
conduction	O
disorders	O
.	O

For	O
COPD	O
and	O
pneumonia	O
admissions	O
,	O
diagnosis	O
of	O
conduction	O
disorders	O
or	O
dysrhythmias	O
increased	O
the	O
risk	O
of	O
particulate	O
matter	O
<	O
10	O
<	O
FFFD	O
>	O
m	O
in	O
aerodynamic	O
diameter	O
(	O
PM10	O
)	O
-	O
associated	O
admissions	O
.	O

Persons	B
with	O
asthma	O
had	O
twice	O
the	O
risk	O
of	O
a	O
PM10	O
-	O
associated	O
pneumonia	O
admission	O
and	O
persons	B
with	O
heart	O
failure	O
had	O
twice	O
the	O
risk	O
of	O
PM10	O
-	O
induced	O
COPD	O
admissions	O
.	O

The	O
PM10	O
effect	O
did	O
not	O
vary	O
by	O
sex	O
,	O
age	O
,	O
and	O
race	O
.	O

These	O
results	O
suggest	O
that	O
patients	B
with	O
acute	O
respiratory	O
infections	O
or	O
defects	O
in	O
the	O
electrical	O
control	O
of	O
the	O
heart	O
are	O
a	O
risk	O
group	O
for	O
particulate	O
matter	O
effects	O
.	O

Key	O
words	O
:	O
effect	O
modification	O
,	O
hospital	O
admissions	O
,	O
particulate	O
air	O
pollution	O
.	O

Environ	O
Health	O
Perspect	O
108	O
:	O
841	O
<	O
FFFD	O
>	O
845	O
(	O
2000	O
)	O
.	O

[	O
Online	O
28	O
July	O
2000	O
]	O
http	O
:	O
/	O
/	O
ehpnet1	O
.	O
niehs	O
.	O
nih	O
.	O
gov	O
/	O
docs	O
/	O
2000	O
/	O
108p841	O
-	O
845zanobetti	O
/	O
abstract	O
.	O
html	O

Particulate	O
air	O
pollution	O
has	O
been	O
associated	O
with	O
increases	O
in	O
daily	O
deaths	O
and	O
hospital	O
admissions	O
in	O
studies	O
all	O
over	O
the	O
world	O
(	O
1	O
<	O
FFFD	O
>	O
15	O
)	O
.	O

These	O
associations	O
are	O
now	O
well	O
documented	O
but	O
little	O
is	O
known	O
,	O
as	O
yet	O
,	O
of	O
the	O
characteristics	O
of	O
persons	B
that	O
put	O
them	O
at	O
increased	O
risk	O
of	O
adverse	O
events	O
related	O
to	O
particulate	O
air	O
pollution	O
.	O

This	O
has	O
been	O
identified	O
as	O
a	O
key	O
data	O
gap	O
(	O
16	O
)	O
.	O

Schwartz	O
and	O
Dockery	O
(	O
17	O
)	O
reported	O
that	O
persons	B
older	O
than	O
65	O
years	O
of	O
age	O
had	O
a	O
somewhat	O
increased	O
risk	O
of	O
death	O
,	O
and	O
this	O
has	O
been	O
confirmed	O
in	O
other	O
studies	O
(	O
18	O
)	O
.	O

A	O
more	O
detailed	O
examination	O
of	O
particulate	O
matter	O
-	O
related	O
risk	O
by	O
deciles	O
of	O
age	O
(	O
19	O
)	O
showed	O
the	O
risk	O
beginning	O
to	O
increase	O
at	O
approximately	O
40	O
years	O
of	O
age	O
and	O
reaching	O
its	O
maximum	O
for	O
those	O
75	O
years	O
of	O
age	O
and	O
older	O
.	O

In	O
addition	O
to	O
age	O
,	O
several	O
studies	O
suggest	O
that	O
persons	B
with	O
respiratory	O
illness	O
are	O
at	O
increased	O
risk	O
for	O
cardiovascular	O
effects	O
associated	O
with	O
air	O
pollution	O
.	O

An	O
examination	O
of	O
death	O
certificates	O
on	O
high	O
-	O
and	O
low	O
-	O
air	O
pollution	O
days	O
reported	O
a	O
substantial	O
difference	O
in	O
the	O
proportion	O
of	O
deaths	O
from	O
cardiovascular	O
causes	O
that	O
had	O
respiratory	O
disease	O
as	O
a	O
contributing	O
cause	O
of	O
death	O
(	O
19	O
)	O
.	O

A	O
recent	O
follow	O
-	O
up	O
study	O
of	O
a	O
cohort	O
of	O
persons	B
with	O
chronic	O
obstructive	O
pulmonary	O
disease	O
(	O
COPD	O
)	O
in	O
Barcelona	O
,	O
Spain	O
,	O
found	O
an	O
association	O
between	O
particulate	O
air	O
pollution	O
and	O
all	O
-	O
cause	O
mortality	O
in	O
the	O
cohort	O
(	O
20	O
)	O
.	O

The	O
magnitude	O
of	O
the	O
risk	O
per	O
microgram	O
per	O
cubic	O
meter	O
of	O
exposure	O
was	O
substantially	O
greater	O
than	O
that	O
for	O
the	O
general	O
population	O
.	O

Environmental	O
Health	O
Perspectives	O

Controlled	O
exposure	O
of	O
animals	O
with	O
chronic	O
bronchitis	O
and	O
control	O
animals	O
to	O
concentrated	O
air	O
particles	O
also	O
demonstrated	O
a	O
potentiating	O
effect	O
of	O
chronic	O
lung	O
disease	O
in	O
the	O
response	O
to	O
airborne	O
particles	O
(	O
21	O
)	O
.	O

This	O
has	O
led	O
to	O
the	O
hypothesis	O
that	O
the	O
cardiovascular	O
effects	O
of	O
air	O
pollution	O
are	O
predominantly	O
in	O
persons	B
with	O
chronic	O
lung	O
disease	O
.	O

There	O
has	O
been	O
even	O
less	O
done	O
to	O
examine	O
potential	O
modifiers	O
of	O
the	O
effects	O
of	O
airborne	O
particles	O
on	O
hospital	O
admissions	O
.	O

The	O
existing	O
literature	O
on	O
comorbidity	O
shows	O
that	O
comorbidity	O
per	O
se	O
seems	O
to	O
increase	O
the	O
risk	O
of	O
adverse	O
outcomes	O
(	O
22	O
<	O
FFFD	O
>	O
30	O
)	O
.	O

Little	O
is	O
known	O
about	O
the	O
role	O
of	O
these	O
comorbidities	O
as	O
effect	O
modifiers	O
for	O
the	O
effects	O
of	O
air	O
pollution	O
.	O

This	O
study	O
uses	O
data	O
from	O
the	O
Medicare	O
system	O
to	O
examine	O
potential	O
short	O
-	O
term	O
and	O
long	O
-	O
term	O
medical	O
conditions	O
that	O
may	O
increase	O
a	O
person	B
'	O
s	O
risk	O
of	O
hospital	O
admissions	O
associated	O
with	O
particulate	O
air	O
pollution	O
.	O

In	O
addition	O
,	O
we	O
examine	O
potential	O
effect	O
modification	O
by	O
age	O
,	O
race	O
,	O
and	O
sex	O
.	O

Materials	O
and	O
Methods	O
Health	O
data	O
.	O

The	O
Health	O
Care	O
Financing	O
Administration	O
(	O
Baltimore	O
,	O
MD	O
)	O
maintains	O
records	O
of	O
every	O
hospital	O
admission	O
for	O
Medicare	O
participants	B
in	O
the	O
United	O
States	O
.	O

Persons	B
in	O
this	O
database	O
have	O
a	O
unique	O
identifier	O
.	O

Using	O
this	O
identifier	O
,	O
we	O
traced	O
every	O
hospital	O
admission	O
for	O
heart	O
and	O
lung	O
disease	O
for	O
each	O
person	B
in	O
Cook	O
County	O
,	O
Illinois	O
,	O
between	O
1985	O
and	O
1994	O
.	O

We	O
chose	O
Cook	O
County	O
because	O
it	O
is	O
the	O
most	O
populous	O

county	O
in	O
the	O
United	O
States	O
with	O
daily	O
monitoring	O
for	O
particulate	O
matter	O
with	O
aerodynamic	O
diameter	O
<	O
10	O
<	O
FFFD	O
>	O
m	O
(	O
PM10	O
)	O
.	O

The	O
data	O
were	O
then	O
analyzed	O
to	O
look	O
at	O
effect	O
modification	O
by	O
concurrent	O
and	O
preexisting	O
conditions	O
as	O
well	O
as	O
by	O
age	O
,	O
race	O
,	O
and	O
sex	O
.	O

To	O
establish	O
a	O
baseline	O
risk	O
,	O
we	O
computed	O
daily	O
counts	O
of	O
hospital	O
admissions	O
for	O
cardiovascular	O
disease	O
(	O
CVD	O
)	O
[	O
International	O
Classification	O
of	O
Disease	O
,	O
9th	O
edition	O
,	O
World	O
Health	O
Organization	O
,	O
Geneva	O
(	O
ICD	O
-	O
9	O
)	O
code	O
390	O
<	O
FFFD	O
>	O
429	O
]	O
,	O
pneumonia	O
(	O
ICD	O
-	O
9	O
code	O
480	O
<	O
FFFD	O
>	O
487	O
)	O
,	O
and	O
COPD	O
(	O
ICD	O
-	O
9	O
code	O
490	O
<	O
FFFD	O
>	O
496	O
,	O
excluding	O
493	O
)	O
.	O

The	O
association	O
between	O
these	O
daily	O
counts	O
and	O
PM10	O
was	O
examined	O
for	O
the	O
years	O
1988	O
<	O
FFFD	O
>	O
1994	O
,	O
when	O
daily	O
PM10	O
monitoring	O
data	O
were	O
available	O
in	O
Chicago	O
.	O

Once	O
our	O
baseline	O
risks	O
were	O
established	O
,	O
we	O
examined	O
three	O
classes	O
of	O
potential	O
effect	O
modifiers	O
.	O

First	O
,	O
we	O
looked	O
at	O
whether	O
previous	O
admissions	O
for	O
selected	O
conditions	O
predisposed	O
persons	B
to	O
having	O
a	O
greater	O
risk	O
from	O
air	O
pollution	O
.	O

For	O
each	O
of	O
the	O
three	O
admission	O
categories	O
(	O
CVD	O
,	O
pneumonia	O
,	O
and	O
COPD	O
)	O
,	O
we	O
considered	O
10	O
causes	O
(	O
defined	O
by	O
a	O
previous	O
admission	O
)	O
as	O
effect	O
modifiers	O
:	O
COPD	O
(	O
ICD	O
-	O
9	O
code	O
490	O
<	O
FFFD	O
>	O
496	O
except	O
493	O
)	O
,	O
asthma	O
(	O
ICD	O
-	O
9	O
code	O
493	O
)	O
,	O
acute	O
bronchitis	O
(	O
ICD	O
-	O
9	O
code	O
466	O
)	O
,	O
acute	O
respiratory	O
illness	O
(	O
ICD	O
-	O
9	O
code	O
460	O
<	O
FFFD	O
>	O
466	O
)	O
,	O
pneumonia	O
(	O
ICD	O
-	O
9	O
code	O
480	O
<	O
FFFD	O
>	O
487	O
)	O
,	O
CVD	O
(	O
ICD	O
-	O
9	O
code	O
390	O
<	O
FFFD	O
>	O
429	O
)	O
,	O
myocardial	O
infarction	O
(	O
ICD	O
-	O
9	O
code	O
410	O
)	O
,	O
congestive	O
heart	O
failure	O
(	O
ICD	O
-	O
9	O
code	O
428	O
)	O
,	O
conduction	O
disorders	O
(	O
ICD	O
-	O
9	O
code	O
426	O
)	O
,	O
and	O
dysrhythmias	O
(	O
ICD9	O
code	O
427	O
)	O
.	O

To	O
test	O
the	O
hypothesis	O
that	O
persons	B
with	O
these	O
conditions	O
had	O
higher	O
risks	O
of	O
subsequent	O
PM10	O
-	O
related	O
admissions	O
,	O
we	O
computed	O
separate	O
daily	O
counts	O
of	O
admissions	O
for	O
our	O
three	O
target	O
causes	O
,	O
stratified	O
by	O
whether	O
or	O
not	O
the	O
person	B
admitted	O
had	O
been	O
previously	O
admitted	O
for	O
the	O
hypothesized	O
predisposing	O
condition	O
.	O

Separate	O
analyses	O
were	O
then	O
performed	O
within	O
each	O
strata	O
to	O
see	O
if	O
the	O
effects	O
of	O
PM10	O
differed	O
by	O
strata	O
.	O

Address	O
correspondence	O
to	O
A	O
.	O

Zanobetti	O
,	O
Department	O
of	O
Environmental	O
Health	O
,	O
Environmental	O
Epidemiology	O
Program	O
,	O
Harvard	O
School	O
of	O
Public	O
Health	O
,	O
665	O
Huntington	O
Avenue	O
,	O
Boston	O
,	O
MA	O
02115	O
USA	O
.	O

Telephone	O
:	O
(	O
617	O
)	O
4324642	O
.	O

Fax	O
:	O
(	O
617	O
)	O
277	O
-	O
2382	O
.	O

E	O
-	O
mail	O
:	O
azanob	O
@	O
sparc6a	O
.	O
harvard	O
.	O
edu	O
Supported	O
by	O
NIEHS	O
grant	O
ES07937	O
.	O

Received	O
18	O
January	O
2000	O
;	O
accepted	O
18	O
April	O
2000	O
.	O

<	O
FFFD	O
>	O
VOLUME	O
108	O
|	O
NUMBER	O
9	O
|	O
September	O
2000	O

841	O

Articles	O

<	O
FFFD	O
>	O

Zanobetti	O
et	O
al	O
.	O

The	O
second	O
set	O
of	O
potential	O
predisposing	O
conditions	O
included	O
secondary	O
diagnoses	O
associated	O
with	O
the	O
index	O
admission	O
.	O

These	O
could	O
represent	O
the	O
presence	O
of	O
a	O
chronic	O
condition	O
(	O
e	O
.	O
g	O
.	O
,	O
COPD	O
)	O
that	O
has	O
not	O
resulted	O
in	O
a	O
previous	O
hospital	O
admission	O
.	O

They	O
could	O
also	O
represent	O
acute	O
conditions	O
that	O
may	O
have	O
increased	O
the	O
subjects	O
'	O
sensitivity	O
to	O
air	O
pollution	O
.	O

For	O
example	O
,	O
if	O
respiratory	O
infections	O
modified	O
the	O
effect	O
of	O
particulate	O
matter	O
on	O
the	O
cardiovascular	O
health	O
of	O
persons	B
with	O
underlying	O
heart	O
disease	O
,	O
then	O
the	O
risk	O
of	O
a	O
hospital	O
admission	O
for	O
heart	O
disease	O
might	O
be	O
different	O
in	O
persons	B
with	O
infections	O
.	O

If	O
this	O
were	O
true	O
,	O
then	O
the	O
risk	O
ratio	O
of	O
a	O
10	O
-	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
increase	O
of	O
PM10	O
on	O
cardiovascular	O
admissions	O
of	O
persons	B
with	O
a	O
concurrent	O
respiratory	O
infection	O
would	O
be	O
different	O
from	O
the	O
ratio	O
in	O
persons	B
without	O
respiratory	O
infection	O
.	O

To	O
test	O
these	O
hypotheses	O
,	O
we	O
computed	O
separate	O
daily	O
counts	O
of	O
admissions	O
for	O
events	O
with	O
and	O
without	O
the	O
concurrent	O
conditions	O
hypothesized	O
to	O
increase	O
sensitivity	O
to	O
air	O
pollution	O
.	O

These	O
were	O
taken	O
as	O
the	O
same	O
10	O
conditions	O
in	O
the	O
first	O
analysis	O
with	O
certain	O
exclusions	O
for	O
pairing	O
that	O
would	O
be	O
illogical	O
.	O

That	O
is	O
,	O
the	O
concurrent	O
diagnosis	O
of	O
a	O
specific	O
cardiac	O
condition	O
was	O
not	O
treated	O
as	O
an	O
effect	O
modifier	O
for	O
admissions	O
for	O
any	O
cardiovascular	O
condition	O
.	O

Likewise	O
,	O
pneumonia	O
and	O
COPD	O
were	O
not	O
possible	O
concurrent	O
conditions	O
for	O
each	O
other	O
.	O

The	O
third	O
set	O
of	O
predisposing	O
conditions	O
considered	O
was	O
being	O
older	O
than	O
75	O
years	O
of	O
age	O
,	O
nonwhite	O
,	O
and	O
female	O
.	O

These	O
were	O
examined	O
for	O
all	O
three	O
outcomes	O
.	O

We	O
obtained	O
weather	O
data	O
for	O
O	O
'	O
Hare	O
Airport	O
from	O
the	O
EarthInfo	O
CD	O
-	O
ROM	O
(	O
EarthInfo	O
CD	O
NCDC	O
Surface	O
Airways	O
,	O
EarthInfo	O
Inc	O
.	O
,	O
Boulder	O
,	O
CO	O
)	O
,	O
and	O
we	O
obtained	O
air	O
pollution	O
data	O
from	O
the	O
U	O
.	O
S	O
.	O

Environmental	O
Protection	O
Agency	O
Aerometric	O
Information	O
Retrieval	O
System	O
network	O
(	O
31	O
)	O
.	O

running	O
-	O
line	O
smoother	O
,	O
loess	O
(	O
35	O
)	O
,	O
was	O
chosen	O
to	O
estimate	O
the	O
smooth	O
function	O
.	O

To	O
control	O
for	O
weather	O
variables	O
and	O
day	O
of	O
the	O
week	O
,	O
we	O
chose	O
the	O
smoothing	O
parameter	O
that	O
minimized	O
the	O
Akaike	O
'	O
s	O
information	O
criterion	O
(	O
36	O
)	O
.	O

To	O
model	O
seasonality	O
we	O
chose	O
the	O
smoothing	O
parameter	O
that	O
minimized	O
the	O
sum	O
of	O
the	O
autocorrelation	O
of	O
the	O
residuals	O
while	O
removing	O
seasonal	O
patterns	O
.	O

Two	O
autoregressive	O
terms	O
(	O
37	O
)	O
were	O
added	O
in	O
the	O
model	O
to	O
eliminate	O
the	O
remaining	O
serial	O
correlation	O
from	O
the	O
residuals	O
.	O

We	O
used	O
the	O
mean	O
of	O
PM10	O
on	O
the	O
day	O
of	O
the	O
admission	O
and	O
the	O
day	O
before	O
the	O
admission	O
as	O
our	O
exposure	O
variable	O
.	O

This	O
gives	O
results	O
that	O
are	O
similar	O
to	O
those	O
obtained	O
fitting	O
a	O
full	O
distributed	O
lag	O
model	O
(	O
38	O
)	O
.	O

PM10	O
was	O
treated	O
linearly	O
.	O

Our	O
baseline	O
models	O
used	O
the	O
daily	O
counts	O
of	O
CVD	O
,	O
pneumonia	O
,	O
and	O
COPD	O
admissions	O
as	O
outcomes	O
.	O

We	O
then	O
subdivided	O
those	O
counts	O
by	O
the	O
presence	O
or	O
absence	O
of	O
the	O
potential	O
effect	O
modifier	O
and	O
reestimated	O
our	O
regressions	O
on	O
those	O
subgroups	O
.	O

We	O
considered	O
effect	O
modification	O
to	O
be	O
indicated	O
when	O
the	O
estimates	O
of	O
PM10	O
in	O
the	O
group	O
with	O
the	O
condition	O
was	O
outside	O
of	O
the	O
95	O
%	O
confidence	O
interval	O
(	O
CI	O
)	O
of	O
the	O
effect	O
estimate	O
in	O
persons	B
without	O
the	O
condition	O
.	O

Results	O
Table	O
1	O
shows	O
the	O
mean	O
daily	O
admissions	O
for	O
COPD	O
,	O
cardiovascular	O
,	O
and	O
pneumonia	O
both	O
overall	O
and	O
in	O
the	O
presence	O
of	O
the	O
potential	O
effect	O
modifiers	O
.	O

For	O
some	O
effect	O
modifiers	O
such	O
as	O
conduction	O
disorders	O
or	O
myocardial	O
infarctions	O
,	O
the	O
counts	O
in	O
conjunction	O
with	O
our	O
respiratory	O
outcomes	O
are	O

low	O
,	O
which	O
limits	O
power	O
.	O

In	O
general	O
,	O
the	O
numbers	O
are	O
lower	O
for	O
examining	O
effect	O
modification	O
by	O
previous	O
admissions	O
than	O
for	O
effect	O
modification	O
by	O
concurrent	O
diagnosis	O
.	O

This	O
is	O
as	O
expected	O
because	O
many	O
clinically	O
relevant	O
comorbidities	O
may	O
never	O
have	O
resulted	O
in	O
a	O
hospital	O
admission	O
.	O

Table	O
2	O
shows	O
the	O
25th	O
,	O
50th	O
,	O
and	O
75th	O
percentile	O
values	O
for	O
the	O
environmental	O
variables	O
.	O

The	O
mean	O
value	O
for	O
PM10	O
is	O
33	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
.	O

The	O
daily	O
values	O
for	O
PM10	O
were	O
computed	O
as	O
the	O
average	O
of	O
10	O
monitors	O
,	O
two	O
of	O
which	O
measured	O
PM10	O
almost	O
every	O
day	O
and	O
the	O
others	O
less	O
frequently	O
(	O
38	O
)	O
.	O

Table	O
3	O
shows	O
the	O
mean	O
daily	O
counts	O
of	O
CVD	O
,	O
COPD	O
,	O
and	O
pneumonia	O
by	O
sex	O
,	O
age	O
groups	O
,	O
and	O
race	O
.	O

The	O
distribution	O
by	O
sex	O
is	O
almost	O
even	O
,	O
although	O
the	O
counts	O
of	O
admissions	O
for	O
males	O
are	O
generally	O
lower	O
(	O
approximately	O
10	O
%	O
)	O
than	O
for	O
females	O
,	O
particularly	O
for	O
cardiovascular	O
diseases	O
.	O

The	O
counts	O
of	O
CVD	O
,	O
COPD	O
,	O
and	O
pneumonia	O
admissions	O
were	O
similar	O
for	O
people	B
65	O
<	O
FFFD	O
>	O
75	O
or	O
75	O
years	O
of	O
age	O
and	O
older	O
.	O

Tables	O
4	O
<	O
FFFD	O
>	O
6	O
show	O
the	O
results	O
for	O
the	O
effect	O
PM10	O
overall	O
and	O
stratifying	O
by	O
concurrent	O
diagnosis	O
and	O
previous	O
admissions	O
.	O

These	O
are	O
expressed	O
as	O
the	O
percentage	O
increase	O
for	O
10	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
PM10	O
.	O

Table	O
4	O
shows	O
the	O
results	O
for	O
CVD	O
.	O

A	O
10	O
-	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
increase	O
in	O
PM10	O
was	O
associated	O
with	O
a	O
1	O
.	O
31	O
%	O
(	O
5	O
%	O
CI	O
,	O
0	O
.	O
97	O
%	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
66	O
%	O
)	O
increase	O
in	O
hospital	O
admissions	O
for	O
heart	O
disease	O
in	O
all	O
elderly	O
persons	B
.	O

A	O
concurrent	O
(	O
not	O
previous	O
)	O
diagnosis	O
of	O
COPD	O
modified	O
the	O
risk	O
of	O
PM10	O
-	O
associated	O
admissions	O
for	O
heart	O
disease	O
.	O

However	O
,	O
significant	O
associations	O
were	O
still	O
seen	O
between	O
PM10	O

Table	O
1	O
.	O

Mean	O
daily	O
counts	O
of	O
admissions	O
,	O
Chicago	O
1986	O
<	O
FFFD	O
>	O
1994	O
,	O
for	O
COPD	O
,	O
CVD	O
,	O
and	O
pneumonia	O
overall	O
and	O
by	O
concurrent	O
diagnosis	O
and	O
by	O
previous	O
admissions	O
.	O

By	O
concurrent	O
diagnosis	O
COPD	O
CVD	O
Pneumonia	O
Overall	O
Respiratory	O
disease	O
Acute	O
bronchitis	O
Acute	O
respiratory	O
infections	O
Pneumonia	O
Asthma	O
COPD	O
Cardiovascular	O
disease	O
CVD	O
Conduction	O
disorders	O
Cardiac	O
dysrhythmias	O
Congestive	O
heart	O
failure	O
Myocardial	O
infarction	O
NA	O
,	O
not	O
applicable	O
.	O

By	O
previous	O
admissions	O
COPD	O
CVD	O
Pneumonia	O
7	O
.	O
8	O
0	O
.	O
8	O
0	O
.	O
9	O
1	O
.	O
6	O
0	O
.	O
9	O
2	O
.	O
7	O
2	O
.	O
1	O
0	O
.	O
0	O
0	O
.	O
4	O
0	O
.	O
9	O
0	O
.	O
3	O
102	O
.	O
1	O
1	O
.	O
6	O
1	O
.	O
8	O
7	O
.	O
3	O
1	O
.	O
5	O
2	O
.	O
0	O
54	O
.	O
7	O
1	O
.	O
0	O
9	O
.	O
9	O
24	O
.	O
2	O
11	O
.	O
4	O
26	O
.	O
5	O
0	O
.	O
9	O
1	O
.	O
0	O
6	O
.	O
4	O
0	O
.	O
7	O
1	O
.	O
4	O
7	O
.	O
2	O
0	O
.	O
2	O
1	O
.	O
5	O
3	O
.	O
1	O
1	O
.	O
0	O

Methods	O
We	O
analyzed	O
the	O
data	O
with	O
a	O
generalized	O
additive	O
robust	O
Poisson	O
regression	O
model	O
(	O
32	O
)	O
.	O

This	O
approach	O
has	O
become	O
the	O
norm	O
in	O
such	O
studies	O
(	O
14	O
,	O
33	O
,	O
34	O
)	O
.	O

In	O
the	O
generalized	O
additive	O
model	O
the	O
outcome	O
is	O
assumed	O
to	O
depend	O
on	O
a	O
sum	O
of	O
nonparametric	O
smooth	O
functions	O
for	O
each	O
variable	O
that	O
models	O
the	O
potential	O
nonlinear	O
dependence	O
of	O
daily	O
admission	O
on	O
weather	O
and	O
season	O
.	O

The	O
model	O
is	O
of	O
the	O
form	O
:	O
log	O
[	O
E	O
(	O
Yt	O
)	O
]	O
=	O
0	O
+	O
S1	O
(	O
X1	O
)	O
+	O
.	O
.	O
.	O

+	O
Sp	O
(	O
Xp	O
)	O
where	O
E	O
(	O
Yt	O
)	O
is	O
the	O
expected	O
value	O
of	O
the	O
daily	O
count	O
of	O
admissions	O
Yt	O
and	O
Si	O
are	O
the	O
smooth	O
functions	O
of	O
the	O
covariates	O
Xi	O
.	O

We	O
examined	O
temperature	O
,	O
previous	O
day	O
'	O
s	O
temperature	O
,	O
relative	O
humidity	O
,	O
barometric	O
pressure	O
,	O
and	O
day	O
of	O
week	O
covariates	O
.	O

The	O
locally	O
weighted	O

7	O
.	O
8	O
0	O
.	O
1	O
0	O
.	O
3	O
0	O
.	O
4	O
0	O
.	O
1	O
NA	O
4	O
.	O
7	O
0	O
.	O
2	O
1	O
.	O
4	O
1	O
.	O
8	O
0	O
.	O
1	O

102	O
.	O
1	O
0	O
.	O
9	O
1	O
.	O
3	O
4	O
.	O
0	O
1	O
.	O
8	O
13	O
.	O
4	O
NA	O
NA	O
NA	O
NA	O
NA	O

26	O
.	O
5	O
0	O
.	O
3	O
0	O
.	O
3	O
NA	O
0	O
.	O
9	O
6	O
.	O
9	O
14	O
.	O
7	O
0	O
.	O
6	O
4	O
.	O
6	O
7	O
.	O
3	O
0	O
.	O
4	O

Table	O
2	O
.	O

25th	O
,	O
50th	O
,	O
and	O
75th	O
percentile	O
values	O
for	O
the	O
environmental	O
variables	O
in	O
Chicago	O
,	O
1988	O
<	O
FFFD	O
>	O
1994	O
.	O

Temperature	O
(	O
<	O
FFFD	O
>	O
F	O
)	O
35	O
51	O
67	O
Relative	O
humidity	O
62	O
70	O
79	O
Barometric	O
pressure	O
29	O
.	O
2	O
29	O
.	O
3	O
29	O
.	O
4	O
PM10	O
(	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
)	O
23	O
33	O
46	O

Table	O
3	O
.	O

Mean	O
daily	O
counts	O
of	O
admissions	O
by	O
sex	O
,	O
race	O
,	O
and	O
age	O
groups	O
,	O
Chicago	O
,	O
1986	O
<	O
FFFD	O
>	O
1994	O
.	O

Group	O
Overall	O
Female	O
Nonwhite	O
Age	O
>	O
75	O
years	O
COPD	O
7	O
.	O
8	O
4	O
.	O
2	O
1	O
.	O
6	O
3	O
.	O
7	O
CVD	O
102	O
.	O
1	O
59	O
.	O
4	O
21	O
.	O
0	O
55	O
.	O
1	O
Pneumonia	O
26	O
.	O
5	O
14	O
.	O
7	O
5	O
.	O
2	O
17	O
.	O
4	O

842	O

VOLUME	O

108	O
|	O
NUMBER	O
9	O
|	O
September	O
2000	O
<	O
FFFD	O
>	O
Environmental	O
Health	O
Perspectives	O

Articles	O

<	O
FFFD	O
>	O

Effects	O
of	O
particles	O
on	O
sensitive	O
subgroups	O

and	O
heart	O
disease	O
admissions	O
in	O
persons	B
without	O
COPD	O
listed	O
as	O
either	O
a	O
comorbidity	O
or	O
a	O
cause	O
of	O
previous	O
admission	O
(	O
Table	O
4	O
)	O
.	O

A	O
significant	O
association	O
was	O
also	O
seen	O
in	O
persons	B
without	O
any	O
respiratory	O
disease	O
as	O
a	O
concurrent	O
diagnosis	O
,	O
although	O
the	O
risk	O
is	O
much	O
lower	O
than	O
in	O
persons	B
with	O
respiratory	O
disease	O
.	O

However	O
,	O
the	O
risk	O
associated	O
with	O
PM10	O
was	O
roughly	O
doubled	O
in	O
subjects	O
with	O
concurrent	O
respiratory	O
infections	O
and	O
the	O
risk	O
estimates	O
in	O
those	O
subjects	O
were	O
outside	O
the	O
95	O
%	O
CI	O
of	O
the	O
risk	O
in	O
patients	B
without	O
concurrent	O
respiratory	O
infections	O
.	O

A	O
previous	O
admission	O
for	O
conduction	O
disorders	O
(	O
e	O
.	O
g	O
.	O
,	O
heart	O
block	O
)	O
increased	O
the	O
risk	O
of	O
a	O
PM10	O
-	O
related	O
subsequent	O
admission	O
for	O
any	O
heart	O
condition	O
,	O
and	O
a	O
weaker	O
indication	O
of	O
effect	O
modification	O
was	O
seen	O
for	O
persons	B
with	O
previous	O
admission	O
for	O
dysrhythmias	O
.	O

In	O
contrast	O
heart	O
failure	O
and	O
previous	O
myocardial	O
infarctions	O
were	O
highly	O
insignificant	O
as	O
effect	O
modifiers	O
.	O

Table	O
5	O
shows	O
the	O
results	O
for	O
COPD	O
.	O

Overall	O
,	O
there	O
is	O
a	O
1	O
.	O
89	O
%	O
(	O
95	O
%	O
CI	O
,	O
0	O
.	O
8	O
<	O
FFFD	O
>	O
3	O
.	O
0	O
)	O
increase	O
in	O
COPD	O
admissions	O
for	O
a	O
10	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
increase	O
in	O
PM10	O
.	O

The	O
results	O
of	O
the	O
stratified	O
analysis	O
suggest	O
that	O
preexisting	O
heart	O
disease	O
modifies	O
Table	O
4	O
.	O

Percentage	O
increase	O
in	O
hospital	O
admissions	O
for	O
CVD	O
in	O
all	O
persons	B
and	O
by	O
concurrent	O
diagnosis	O
and	O
previous	O
admissions	O
.	O

PM10	O
2	O
.	O
5	O
%	O
CI	O
97	O
.	O
5	O
%	O
CI	O
All	O
persons	B
1	O
.	O
31	O
By	O
concurrent	O
diagnosis	O
Respiratory	O
disease	O
All	O
respiratory	O
disease	O
With	O
1	O
.	O
65	O
Without	O
0	O
.	O
98	O
Acute	O
bronchitis	O
With	O
2	O
.	O
50	O
Without	O
1	O
.	O
07	O
Acute	O
respiratory	O
infections	O
With	O
2	O
.	O
71	O
Without	O
1	O
.	O
06	O
Pneumonia	O
With	O
1	O
.	O
95	O
Without	O
1	O
.	O
03	O
COPD	O
With	O
1	O
.	O
59	O
Without	O
1	O
.	O
08	O
By	O
previous	O
admissions	O
Respiratory	O
disease	O
All	O
respiratory	O
disease	O
With	O
1	O
.	O
18	O
Without	O
1	O
.	O
08	O
COPD	O
With	O
1	O
.	O
48	O
Without	O
1	O
.	O
09	O
Asthma	O
With	O
1	O
.	O
71	O
Without	O
1	O
.	O
08	O
Cardiovascular	O
disease	O
Conduction	O
disorders	O
With	O
2	O
.	O
89	O
Without	O
1	O
.	O
07	O
Cardiac	O
dyshrethmias	O
With	O
1	O
.	O
61	O
Without	O
1	O
.	O
04	O
0	O
.	O
97	O
1	O
.	O
66	O

the	O
risk	O
of	O
COPD	O
admissions	O
on	O
high	O
particle	O
days	O
.	O

Previous	O
admissions	O
for	O
any	O
cardiovascular	O
disease	O
increased	O
the	O
risk	O
of	O
a	O
PM10associated	O
COPD	O
admission	O
approximately	O
2	O
.	O
5	O
-	O
fold	O
.	O

A	O
previous	O
heart	O
failure	O
admission	O
caused	O
an	O
even	O
more	O
striking	O
increase	O
in	O
the	O
PM10	O
effect	O
.	O

Previous	O
admissions	O
for	O
dysrhythmias	O
and	O
conduction	O
defects	O
were	O
rare	O
(	O
Table	O
1	O
)	O
with	O
no	O
power	O
to	O
examine	O
effect	O
modifications	O
.	O

Listings	O
as	O
concurrent	O
diagnoses	O
were	O
more	O
common	O
and	O
here	O
they	O
joined	O
heart	O
failure	O
in	O
increasing	O
the	O
risk	O
of	O
PM	O
10	O
-	O
associated	O
COPD	O
admissions	O
.	O

For	O
COPD	O
there	O
was	O
also	O
some	O
indication	O
that	O
concurrent	O
pneumonia	O
or	O
an	O
acute	O
respiratory	O
infection	O
admission	O
in	O
the	O
last	O
year	O
increased	O
risk	O
.	O

The	O
low	O
numbers	O
made	O
these	O
estimates	O
less	O
precise	O
,	O
however	O
.	O

The	O
percentage	O
increase	O
in	O
pneumonia	O
admission	O
(	O
Table	O
6	O
)	O
for	O
10	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
PM10	O
is	O
higher	O
than	O
for	O
COPD	O
or	O
CVD	O
with	O
an	O
increase	O
of	O
2	O
.	O
34	O
%	O
(	O
95	O
%	O
CI	O
,	O
1	O
.	O
66	O
<	O
FFFD	O
>	O
3	O
.	O
0	O
)	O
.	O

As	O
with	O
COPD	O
,	O
persons	B
with	O
heart	O
disease	O
appeared	O
at	O
higher	O
risk	O
of	O
pneumonia	O
hospital	O
admissions	O
associated	O
with	O
particulate	O
air	O
pollution	O
.	O

Here	O
diagnoses	O
suggestive	O
of	O
impaired	O
autonomic	O
control	O
of	O
the	O
heart	O
,	O
such	O
as	O
conduction	O
disorders	O
or	O
dysrhythmias	O
,	O
were	O
associated	O
with	O
increased	O
risk	O
for	O
PM	O
10	O
effects	O
on	O
pneumonia	O
admissions	O
.	O

Unlike	O
COPD	O
,	O
no	O
difference	O
was	O
seen	O
for	O
congestive	O
heart	O
failure	O
.	O

Persons	B
with	O
asthma	O
Table	O
5	O
.	O

Percentage	O
increase	O
in	O
hospital	O
admissions	O
for	O
COPD	O
in	O
all	O
persons	B
and	O
by	O
concurrent	O
diagnosis	O
and	O
previous	O
admissions	O
.	O

PM10	O
2	O
.	O
5	O
%	O
CI	O
97	O
.	O
5	O
%	O
CI	O
All	O
persons	B
1	O
.	O
89	O
By	O
concurrent	O
diagnosis	O
Respiratory	O
disease	O
Pneumonia	O
With	O
4	O
.	O
00	O
Without	O
1	O
.	O
51	O
Cardiovascular	O
disease	O
Conduction	O
disorders	O
With	O
2	O
.	O
34	O
Without	O
1	O
.	O
60	O
Cardiac	O
dysrhythmias	O
With	O
3	O
.	O
09	O
Without	O
1	O
.	O
43	O
Congestive	O
heart	O
failure	O
With	O
2	O
.	O
90	O
Without	O
1	O
.	O
39	O
By	O
previous	O
admissions	O
Respiratory	O
disease	O
Acute	O
respiratory	O
infections	O
With	O
3	O
.	O
20	O
Without	O
1	O
.	O
70	O
Cardiovascular	O
disease	O
CVD	O
With	O
2	O
.	O
90	O
Without	O
1	O
.	O
18	O
Congestive	O
heart	O
failure	O
With	O
4	O
.	O
37	O
Without	O
1	O
.	O
14	O
Within	O
1	O
year	O
6	O
.	O
04	O
0	O
.	O
80	O
2	O
.	O
99	O

had	O
twice	O
the	O
risk	O
of	O
a	O
PM10	O
-	O
induced	O
pneumonia	O
admission	O
as	O
persons	B
without	O
asthma	O
.	O

Table	O
7	O
shows	O
the	O
results	O
by	O
sex	O
,	O
age	O
,	O
and	O
race	O
.	O

None	O
of	O
the	O
effect	O
size	O
estimates	O
for	O
any	O
of	O
the	O
stratification	O
variables	O
were	O
outside	O
of	O
the	O
95	O
%	O
CI	O
for	O
the	O
opposite	O
strata	O
.	O

There	O
was	O
a	O
tendency	O
for	O
the	O
effect	O
of	O
PM10	O
on	O
CVD	O
admissions	O
to	O
be	O
higher	O
for	O
females	O
,	O
whereas	O
the	O
effect	O
on	O
pneumonia	O
admissions	O
was	O
higher	O
for	O
males	O
.	O

In	O
general	O
,	O
we	O
found	O
somewhat	O
larger	O
effects	O
on	O
whites	O
compared	O
to	O
nonwhites	O
,	O
and	O
for	O
persons	B
older	O
than	O
75	O
years	O
of	O
age	O
compared	O
to	O
younger	O
persons	B
.	O

Discussion	O
In	O
this	O
analysis	O
we	O
examined	O
whether	O
the	O
effect	O
of	O
PM10	O
on	O
the	O
risk	O
of	O
hospital	O
admission	O
for	O
heart	O
and	O
lung	O
disease	O
was	O
different	O
depending	O
on	O
the	O
presence	O
of	O
comorbidities	O
.	O

We	O
found	O
that	O
PM10	O
was	O
associated	O
with	O
hospital	O
admissions	O
for	O
all	O
three	O
causes	O
(	O
CVD	O
,	O
COPD	O
,	O
and	O
pneumonia	O
)	O
and	O
we	O
found	O
not	O
a	O
general	O
increase	O
in	O
PM10	O
related	O
risk	O
with	O
comorbidities	O
,	O
but	O
a	O
specific	O
pattern	O
that	O
is	O
suggestive	O
of	O
potential	O
mechanisms	O
and	O
consistent	O
with	O
other	O
recent	O
epidemiologic	O
and	O
toxicologic	O
findings	O
.	O

One	O
major	O
finding	O
of	O
this	O
study	O
is	O
that	O
preexisting	O
cardiovascular	O
disease	O
,	O
particularly	O
impaired	O
autonomic	O
control	O
(	O
conduction	O
defects	O
and	O
dysrhythmias	O
)	O
and	O
heart	O
failure	O
,	O
substantially	O
increased	O
the	O
risk	O
of	O
respiratory	O
admissions	O
associated	O
with	O
airborne	O
particles	O
.	O

In	O
fact	O
,	O
recent	O
human	B
studies	O
have	O
shown	O
that	O
exposure	O
to	O
particulate	O
air	O
pollution	O
is	O
a	O
risk	O
factor	O
for	O
reduced	O
heart	O
rate	O
variability	O
(	O
39	O
<	O
FFFD	O
>	O
41	O
)	O
.	O

Reduced	O
heart	O
rate	O
variability	O
is	O
an	O
adverse	O
response	O
and	O
a	O
risk	O
factor	O
for	O
arrhythmia	O
.	O

A	O
new	O
study	O
of	O
defibrillator	O
discharges	O
in	O
patients	B
with	O
implanted	O
cardioverter	O
defibrillators	O
found	O
that	O
discharges	O
were	O
associated	O
with	O
air	O
pollution	O
(	O
42	O
)	O
.	O

Exposure	O
to	O
combustion	O
Table	O
6	O
.	O

Percentage	O
increase	O
in	O
hospital	O
admissions	O
for	O
pneumonia	O
in	O
all	O
persons	B
and	O
by	O
concurrent	O
diagnosis	O
and	O
previous	O
admissions	O
.	O

PM10	O
All	O
persons	B
By	O
concurrent	O
diagnosis	O
Respiratory	O
disease	O
Asthma	O
With	O
Without	O
Cardiovascular	O
disease	O
Conduction	O
disorders	O
With	O
Without	O
Cardiac	O
dysrhythmias	O
With	O
Without	O
By	O
previous	O
admissions	O
Cardiovascular	O
disease	O
Cardiac	O
dysrhythmias	O
With	O
Without	O
2	O
.	O
34	O
2	O
.	O
5	O
%	O
CI	O
97	O
.	O
5	O
%	O
CI	O
1	O
.	O
66	O
3	O
.	O
02	O

1	O
.	O
10	O
0	O
.	O
64	O
<	O
FFFD	O
>	O
0	O
.	O
47	O
0	O
.	O
76	O
0	O
.	O
18	O
0	O
.	O
76	O
0	O
.	O
55	O
0	O
.	O
72	O
0	O
.	O
85	O
0	O
.	O
75	O

2	O
.	O
20	O
1	O
.	O
33	O
5	O
.	O
55	O
1	O
.	O
37	O
5	O
.	O
30	O
1	O
.	O
37	O
3	O
.	O
36	O
1	O
.	O
35	O
2	O
.	O
34	O
1	O
.	O
41	O

<	O
FFFD	O
>	O
0	O
.	O
45	O
0	O
.	O
47	O
<	O
FFFD	O
>	O
4	O
.	O
42	O
0	O
.	O
58	O
0	O
.	O
64	O
0	O
.	O
33	O
0	O
.	O
77	O
0	O
.	O
24	O

8	O
.	O
65	O
2	O
.	O
57	O
9	O
.	O
59	O
2	O
.	O
64	O
5	O
.	O
60	O
2	O
.	O
55	O
5	O
.	O
08	O
2	O
.	O
55	O

0	O
.	O
45	O
0	O
.	O
76	O
<	O
FFFD	O
>	O
0	O
.	O
40	O
0	O
.	O
78	O
<	O
FFFD	O
>	O
0	O
.	O
43	O
0	O
.	O
77	O
0	O
.	O
22	O
0	O
.	O
76	O
0	O
.	O
75	O
0	O
.	O
72	O

1	O
.	O
91	O
1	O
.	O
41	O
3	O
.	O
40	O
1	O
.	O
40	O
3	O
.	O
89	O
1	O
.	O
39	O
5	O
.	O
63	O
1	O
.	O
38	O
2	O
.	O
48	O
1	O
.	O
36	O

4	O
.	O
18	O
2	O
.	O
07	O
7	O
.	O
92	O
1	O
.	O
99	O
<	O
FFFD	O
>	O
<	O
FFFD	O
>	O

1	O
.	O
01	O
1	O
.	O
46	O
4	O
.	O
28	O
1	O
.	O
37	O
<	O
FFFD	O
>	O
<	O
FFFD	O
>	O

7	O
.	O
46	O
2	O
.	O
69	O
11	O
.	O
69	O
2	O
.	O
61	O
<	O
FFFD	O
>	O
<	O
FFFD	O
>	O

<	O
FFFD	O
>	O
1	O
.	O
38	O
0	O
.	O
66	O
0	O
.	O
99	O
<	O
FFFD	O
>	O
0	O
.	O
01	O
1	O
.	O
43	O
0	O
.	O
05	O
2	O
.	O
10	O

8	O
.	O
01	O
2	O
.	O
76	O
4	O
.	O
85	O
2	O
.	O
39	O
7	O
.	O
40	O
2	O
.	O
24	O
10	O
.	O
14	O

3	O
.	O
47	O
2	O
.	O
08	O

1	O
.	O
21	O
1	O
.	O
45	O

5	O
.	O
79	O
2	O
.	O
71	O

Increases	O
are	O
for	O
a	O
10	O
-	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
increase	O
in	O
PM10	O
.	O

Increases	O
are	O
for	O
a	O
10	O
-	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
increase	O
in	O
PM10	O
.	O

Increases	O
are	O
for	O
a	O
10	O
-	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
increase	O
in	O
PM10	O
.	O

Environmental	O
Health	O
Perspectives	O

<	O
FFFD	O
>	O
VOLUME	O
108	O
|	O
NUMBER	O
9	O
|	O
September	O
2000	O

843	O

Articles	O

<	O
FFFD	O
>	O

Zanobetti	O
et	O
al	O
.	O

Table	O
7	O
.	O

Effect	O
modification	O
by	O
sex	O
,	O
race	O
,	O
and	O
age	O
groups	O
for	O
10	O
<	O
FFFD	O
>	O
g	O
/	O
m3	O
PM10	O
.	O

%	O
All	O
persons	B
Male	O
Female	O
White	O
Non	O
-	O
white	O
Age	O
>	O
75	O
Age	O
75	O
1	O
.	O
89	O
1	O
.	O
34	O
2	O
.	O
19	O
1	O
.	O
65	O
1	O
.	O
07	O
2	O
.	O
20	O
1	O
.	O
33	O
COPD	O
(	O
95	O
%	O
CI	O
)	O
(	O
0	O
.	O
80	O
,	O
2	O
.	O
99	O
)	O
(	O
<	O
FFFD	O
>	O
0	O
.	O
14	O
,	O
2	O
.	O
84	O
)	O
(	O
0	O
.	O
81	O
,	O
3	O
.	O
59	O
)	O
(	O
0	O
.	O
51	O
,	O
2	O
.	O
81	O
)	O
(	O
<	O
FFFD	O
>	O
1	O
.	O
11	O
,	O
3	O
.	O
3	O
)	O
(	O
0	O
.	O
72	O
,	O
3	O
.	O
69	O
)	O
(	O
0	O
.	O
03	O
,	O
2	O
.	O
65	O
)	O
%	O
1	O
.	O
31	O
1	O
.	O
07	O
1	O
.	O
21	O
1	O
.	O
20	O
0	O
.	O
70	O
1	O
.	O
28	O
0	O
.	O
93	O
CVD	O
(	O
95	O
%	O
CI	O
)	O
(	O
0	O
.	O
97	O
,	O
1	O
.	O
66	O
)	O
(	O
0	O
.	O
62	O
,	O
1	O
.	O
51	O
)	O
(	O
0	O
.	O
83	O
,	O
1	O
.	O
6	O
)	O
(	O
0	O
.	O
86	O
,	O
1	O
.	O
55	O
)	O
(	O
0	O
.	O
1	O
,	O
1	O
.	O
3	O
)	O
(	O
0	O
.	O
88	O
,	O
1	O
.	O
69	O
)	O
(	O
0	O
.	O
51	O
,	O
1	O
.	O
35	O
)	O
%	O
2	O
.	O
34	O
2	O
.	O
65	O
1	O
.	O
91	O
2	O
.	O
45	O
1	O
.	O
91	O
2	O
.	O
12	O
2	O
.	O
52	O
Pneumonia	O
(	O
95	O
%	O
CI	O
)	O
(	O
1	O
.	O
66	O
,	O
3	O
.	O
02	O
)	O
(	O
1	O
.	O
81	O
,	O
3	O
.	O
5	O
)	O
(	O
1	O
.	O
11	O
,	O
2	O
.	O
72	O
)	O
(	O
1	O
.	O
77	O
,	O
3	O
.	O
14	O
)	O
(	O
0	O
.	O
69	O
,	O
3	O
.	O
14	O
)	O
(	O
1	O
.	O
38	O
,	O
2	O
.	O
86	O
)	O
(	O
1	O
.	O
57	O
,	O
3	O
.	O
48	O
)	O

Figures	O
shown	O
are	O
the	O
percentage	O
increase	O
in	O
admissions	O
(	O
95	O
%	O
CI	O
)	O
.	O

particles	O
has	O
also	O
been	O
associated	O
with	O
arrhythmia	O
in	O
an	O
animal	O
model	O
(	O
43	O
)	O
and	O
changes	O
in	O
ST	O
segments	O
have	O
been	O
noted	O
as	O
well	O
(	O
44	O
)	O
.	O

This	O
is	O
the	O
first	O
study	O
to	O
suggest	O
persons	B
with	O
defects	O
in	O
the	O
electrical	O
control	O
of	O
the	O
heart	O
are	O
also	O
at	O
higher	O
risk	O
of	O
respiratory	O
illness	O
after	O
exposure	O
to	O
airborne	O
particles	O
.	O

These	O
data	O
also	O
suggest	O
that	O
persons	B
admitted	O
to	O
hospitals	O
for	O
pneumonia	O
during	O
an	O
air	O
pollution	O
episode	O
may	O
be	O
at	O
high	O
risk	O
for	O
clinically	O
significant	O
conduction	O
disorders	O
during	O
that	O
hospital	O
admission	O
.	O

Patients	B
with	O
congestive	O
heart	O
failure	O
were	O
at	O
greater	O
risk	O
of	O
hospital	O
admissions	O
for	O
COPD	O
in	O
association	O
with	O
airborne	O
particles	O
.	O

Heart	O
failure	O
and	O
COPD	O
is	O
not	O
an	O
uncommon	O
combination	O
.	O

The	O
finding	O
that	O
these	O
patients	B
are	O
at	O
higher	O
risk	O
for	O
admissions	O
associated	O
with	O
particulate	O
air	O
pollution	O
is	O
new	O
but	O
is	O
also	O
consistent	O
with	O
several	O
other	O
recent	O
reports	O
.	O

The	O
spontaneous	O
hypertensive	O
rat	B
develops	O
a	O
model	O
of	O
heart	O
failure	O
,	O
and	O
recent	O
studies	O
have	O
reported	O
greater	O
sensitivity	O
to	O
particulate	O
air	O
pollution	O
in	O
these	O
rats	B
.	O

These	O
include	O
both	O
electrocardiogram	O
abnormalities	O
(	O
44	O
)	O
and	O
pulmonary	O
toxicity	O
(	O
45	O
,	O
46	O
)	O
.	O

Similarly	O
,	O
in	O
an	O
epidemiologic	O
study	O
,	O
Hoek	O
et	O
al	O
.	O

(	O
47	O
)	O
,	O
found	O
a	O
higher	O
relative	O
risk	O
of	O
death	O
with	O
an	O
increase	O
in	O
PM10	O
for	O
congestive	O
heart	O
failure	O
deaths	O
than	O
other	O
deaths	O
.	O

The	O
potential	O
role	O
of	O
COPD	O
in	O
those	O
heart	O
failure	O
deaths	O
was	O
not	O
examined	O
.	O

Another	O
consistent	O
pattern	O
in	O
our	O
data	O
is	O
of	O
acute	O
respiratory	O
infections	O
increasing	O
susceptibility	O
to	O
airborne	O
particles	O
.	O

Acute	O
bronchitis	O
,	O
or	O
more	O
generally	O
acute	O
upper	O
respiratory	O
illnesses	O
,	O
as	O
well	O
as	O
pneumonia	O
,	O
increased	O
susceptibility	O
to	O
particle	O
-	O
associated	O
admissions	O
for	O
CVD	O
and	O
COPD	O
.	O

The	O
notion	O
that	O
air	O
pollution	O
exacerbates	O
acute	O
respiratory	O
infections	O
is	O
well	O
supported	O
by	O
studies	O
which	O
report	O
associations	O
between	O
airborne	O
particles	O
and	O
hospital	O
admissions	O
for	O
respiratory	O
infections	O
(	O
48	O
,	O
49	O
)	O
.	O

Zelikoff	O
et	O
al	O
.	O

(	O
50	O
)	O
exposed	O
rats	B
infected	O
with	O
streptococcus	O
to	O
concentrated	O
air	O
particles	O
and	O
reported	O
a	O
significant	O
increase	O
in	O
bacterial	O
burdens	O
and	O
in	O
the	O
extent	O
of	O
pneumonia	O
compared	O
to	O
animals	O
exposed	O
to	O
filtrated	O
air	O
.	O

This	O
suggests	O
an	O
impaired	O
immune	O
response	O
.	O

Similarly	O
,	O
exposure	O
to	O
combustion	O

particles	O
enhances	O
influenza	O
infections	O
in	O
mice	B
(	O
51	O
)	O
.	O

An	O
impaired	O
defense	O
to	O
respiratory	O
infection	O
is	O
a	O
major	O
reason	O
that	O
persons	B
with	O
COPD	O
require	O
hospital	O
admission	O
.	O

If	O
airborne	O
particles	O
result	O
in	O
further	O
impairment	O
the	O
effect	O
modification	O
we	O
observe	O
makes	O
good	O
sense	O
.	O

The	O
effect	O
modification	O
for	O
heart	O
disease	O
admissions	O
is	O
more	O
relevant	O
.	O

This	O
modification	O
is	O
consistent	O
with	O
the	O
earlier	O
report	O
of	O
Schwartz	O
(	O
19	O
)	O
,	O
who	O
found	O
greater	O
reports	O
of	O
respiratory	O
complications	O
on	O
death	O
certificates	O
with	O
an	O
underlying	O
cause	O
of	O
heart	O
disease	O
if	O
the	O
death	O
occurred	O
on	O
a	O
day	O
with	O
high	O
levels	O
of	O
airborne	O
particles	O
.	O

Although	O
airborne	O
particle	O
exposure	O
has	O
been	O
associated	O
with	O
increased	O
exacerbation	O
of	O
asthma	O
(	O
2	O
,	O
12	O
,	O
48	O
,	O
52	O
<	O
FFFD	O
>	O
59	O
)	O
,	O
this	O
paper	O
is	O
the	O
first	O
to	O
suggest	O
that	O
asthmatics	O
are	O
more	O
susceptible	O
to	O
PM10	O
-	O
induced	O
pneumonia	O
exacerbation	O
or	O
to	O
cardiovascular	O
effects	O
.	O

The	O
effects	O
on	O
pneumonia	O
admissions	O
are	O
plausible	O
,	O
given	O
the	O
impaired	O
ability	O
to	O
fight	O
off	O
infections	O
in	O
asthmatics	O
with	O
mucus	O
plugs	O
and	O
the	O
evidence	O
the	O
airborne	O
particles	O
impair	O
the	O
lungs	O
'	O
ability	O
to	O
fight	O
off	O
bacterial	O
and	O
viral	O
infections	O
,	O
as	O
noted	O
earlier	O
.	O

The	O
increased	O
cardiovascular	O
sensitivity	O
,	O
albeit	O
weaker	O
,	O
is	O
interesting	O
.	O

If	O
airborne	O
particles	O
affect	O
the	O
cardiovascular	O
system	O
via	O
the	O
role	O
of	O
the	O
lung	O
in	O
autonomic	O
control	O
,	O
it	O
is	O
possible	O
that	O
asthmatics	O
would	O
be	O
more	O
sensitive	O
to	O
those	O
effects	O
.	O

Animal	O
models	O
of	O
asthma	O
showed	O
that	O
combustion	O
particles	O
enhance	O
the	O
asthmatic	O
response	O
to	O
aeroallergen	O
challenges	O
(	O
59	O
)	O
.	O

This	O
suggests	O
an	O
enhancement	O
of	O
pulmonary	O
response	O
in	O
asthmatics	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
diagnosis	O
of	O
asthma	O
is	O
problematic	O
in	O
the	O
elderly	O
,	O
and	O
crossover	O
with	O
COPD	O
is	O
possible	O
.	O

The	O
possibility	O
that	O
this	O
explains	O
our	O
results	O
is	O
reduced	O
by	O
our	O
failure	O
to	O
find	O
previous	O
hospital	O
admission	O
for	O
COPD	O
was	O
an	O
effect	O
modifier	O
for	O
the	O
effect	O
of	O
particles	O
on	O
cardiovascular	O
admissions	O
.	O

We	O
must	O
acknowledge	O
several	O
potential	O
limitations	O
of	O
this	O
study	O
.	O

First	O
,	O
we	O
considered	O
only	O
previous	O
admissions	O
that	O
occurred	O
within	O
Cook	O
County	O
.	O

Hence	O
persons	B
with	O
previous	O
admissions	O
elsewhere	O
would	O
be	O
misclassified	O
to	O
our	O
reference	O
group	O
.	O

The	O
effect	O
of	O
this	O
would	O
be	O
to	O
reduce	O
the	O
difference	O
in	O
PM	O
10	O
effect	O
between	O
the	O
two	O
groups	O
.	O

VOLUME	O

Nevertheless	O
,	O
we	O
identified	O
some	O
interesting	O
interactions	O
.	O

We	O
cannot	O
exclude	O
the	O
possibility	O
that	O
there	O
are	O
areas	O
we	O
missed	O
for	O
this	O
reason	O
.	O

We	O
also	O
examined	O
interactions	O
in	O
a	O
log	O
relative	O
risk	O
model	O
,	O
which	O
is	O
inherently	O
multiplicative	O
.	O

Although	O
we	O
believe	O
this	O
is	O
justified	O
because	O
doubling	O
the	O
population	O
exposed	O
would	O
be	O
expected	O
to	O
double	O
the	O
pollution	O
associated	O
admissions	O
,	O
it	O
results	O
in	O
a	O
more	O
conservative	O
definition	O
of	O
interaction	O
than	O
would	O
an	O
additive	O
risk	O
model	O
.	O

Finally	O
,	O
our	O
exposure	O
is	O
clearly	O
measured	O
with	O
error	O
.	O

Most	O
of	O
this	O
error	O
is	O
Berkson	O
error	O
(	O
60	O
)	O
and	O
hence	O
will	O
introduce	O
no	O
bias	O
,	O
and	O
Zeger	O
et	O
al	O
.	O

(	O
60	O
)	O
showed	O
that	O
the	O
remaining	O
error	O
would	O
have	O
to	O
have	O
pathologic	O
correlations	O
with	O
other	O
variables	O
to	O
result	O
in	O
an	O
upward	O
bias	O
.	O

Another	O
important	O
result	O
from	O
this	O
study	O
,	O
of	O
course	O
,	O
is	O
an	O
estimate	O
of	O
the	O
magnitude	O
of	O
the	O
effect	O
of	O
airborne	O
particles	O
on	O
public	O
health	O
.	O

The	O
PM10	O
concentrations	O
in	O
Chicago	O
during	O
this	O
period	O
were	O
associated	O
with	O
approximately	O
1	O
,	O
600	O
additional	O
admissions	O
per	O
year	O
for	O
heart	O
disease	O
,	O
740	O
additional	O
admissions	O
per	O
year	O
for	O
pneumonia	O
,	O
and	O
170	O
additional	O
admissions	O
per	O
year	O
for	O
COPD	O
.	O

These	O
are	O
not	O
trivial	O
increases	O
in	O
serious	O
morbidity	O
.	O

The	O
results	O
of	O
our	O
study	O
should	O
be	O
replicated	O
in	O
additional	O
cities	O
,	O
although	O
they	O
do	O
begin	O
to	O
fill	O
in	O
some	O
missing	O
information	O
about	O
the	O
effects	O
of	O
airborne	O
particles	O
on	O
health	O
.	O

More	O
generally	O
airborne	O
particles	O
have	O
been	O
associated	O
with	O
a	O
broad	O
range	O
of	O
systemic	O
changes	O
including	O
heart	O
rate	O
variability	O
(	O
39	O
<	O
FFFD	O
>	O
41	O
)	O
,	O
increased	O
peripheral	O
neutrophils	O
(	O
61	O
<	O
FFFD	O
>	O
63	O
)	O
,	O
increased	O
plasma	O
viscosity	O
(	O
64	O
)	O
,	O
an	O
increase	O
in	O
blood	O
pressure	O
(	O
65	O
)	O
,	O
and	O
the	O
outcomes	O
mentioned	O
previously	O
.	O

The	O
role	O
of	O
these	O
systemic	O
changes	O
as	O
potential	O
sources	O
of	O
the	O
specific	O
effect	O
modifications	O
we	O
have	O
seen	O
should	O
be	O
an	O
area	O
of	O
fruitful	O
research	O
in	O
the	O
future	O
.	O

REFERENCES	O
AND	O
NOTES	O
1	O
.	O

Katsouyanni	O
K	O
,	O
Touloumi	O
G	O
,	O
Spix	O
C	O
,	O
Schwartz	O
J	O
,	O
Balducci	O
F	O
,	O
Medina	O
S	O
,	O
Rossi	O
G	O
,	O
Wojtyniak	O
D	O
,	O
Sunyer	O
J	O
,	O
Bacharova	O
L	O
,	O
et	O
al	O
.	O

Short	O
term	O
effects	O
of	O
ambient	O
sulphur	O
dioxide	O
and	O
particulate	O
matter	O
on	O
mortality	O
in	O
12	O
European	O
cities	O
:	O
results	O
from	O
time	O
series	O
data	O
from	O
the	O
APHEA	O
project	O
.	O

Br	O
Med	O
J	O
314	O
:	O
1658	O
<	O
FFFD	O
>	O
1663	O
(	O
1997	O
)	O
.	O

Pope	O
CA	O
,	O
Dockery	O
DW	O
,	O
Schwartz	O
J	O
.	O
Review	O
of	O
epidemiologic	O
evidence	O
of	O
health	O
effects	O
of	O
particulate	O
air	O
pollution	O
.	O

Inhal	O
Toxicol	O
7	O
:	O
1	O
<	O
FFFD	O
>	O
18	O
(	O
1995	O
)	O
.	O

Schwartz	O
J	O
.	O

Air	O
pollution	O
and	O
daily	O
mortality	O
:	O
a	O
review	O
and	O
meta	O
analysis	O
.	O

Environ	O
Res	O
64	O
:	O
36	O
<	O
FFFD	O
>	O
52	O
(	O
1994	O
)	O
.	O

Dominici	O
F	O
,	O
Samet	O
J	O
,	O
Zeger	O
SL	O
.	O

Combining	O
evidence	O
on	O
air	O
pollution	O
and	O
daily	O
mortality	O
from	O
the	O
largest	O
20	O
US	O
cities	O
:	O
a	O
hierarchical	O
modeling	O
strategy	O
.	O

R	O
Stat	O
Soc	O
Ser	O
A	O
,	O
in	O
press	O
.	O

Burnett	O
RT	O
,	O
Dales	O
RE	O
,	O
Raizenne	O
ME	O
,	O
Krewski	O
D	O
,	O
Summers	O
PW	O
,	O
Roberts	O
GR	O
,	O
Raad	O
-	O
Young	O
M	O
,	O
Dann	O
T	O
,	O
Brooke	O
T	O
.	O
Effects	O
of	O
low	O
ambient	O
levels	O
of	O
ozone	O
and	O
sulfates	O
on	O
the	O
frequency	O
of	O
respiratory	O
admissions	O
to	O
Ontario	O
hospitals	O
.	O

Environ	O
Res	O
65	O
:	O
172	O
<	O
FFFD	O
>	O
194	O
(	O
1994	O
)	O
.	O

Anderson	O
HR	O
,	O
Spix	O
C	O
,	O
Medina	O
S	O
,	O
Schouten	O
JP	O
,	O
Castellsague	O
J	O
,	O
Rossi	O
G	O
,	O
Zmirou	O
D	O
,	O
Touloumi	O
G	O
,	O
Wojtyniak	O
B	O
,	O
Ponka	O
A	O
,	O
et	O
al	O
.	O

Air	O
pollution	O
and	O
daily	O
admissions	O
for	O

2	O
.	O

3	O
.	O

4	O
.	O

5	O
.	O

6	O
.	O

844	O

108	O
|	O
NUMBER	O
9	O
|	O
September	O
2000	O
<	O
FFFD	O
>	O
Environmental	O
Health	O
Perspectives	O

Articles	O

<	O
FFFD	O
>	O

Effects	O
of	O
particles	O
on	O
sensitive	O
subgroups	O

7	O
.	O

8	O
.	O

9	O
.	O

10	O
.	O

11	O
.	O

12	O
.	O

13	O
.	O

14	O
.	O

15	O
.	O

16	O
.	O

17	O
.	O

18	O
.	O

19	O
.	O

20	O
.	O

21	O
.	O

22	O
.	O

23	O
.	O

24	O
.	O

25	O
.	O

26	O
.	O

27	O
.	O

28	O
.	O

29	O
.	O

30	O
.	O

chronic	O
obstructive	O
pulmonary	O
disease	O
in	O
6	O
European	O
cities	O
:	O
results	O
from	O
the	O
APHEA	O
project	O
.	O

Eur	O
Respir	O
J	O
10	O
:	O
1064	O
<	O
FFFD	O
>	O
1071	O
(	O
1997	O
)	O
.	O

Schwartz	O
J	O
.	O
Short	O
term	O
fluctuations	O
in	O
air	O
pollution	O
and	O
hospital	O
admissions	O
of	O
the	O
elderly	O
for	O
respiratory	O
disease	O
.	O

Thorax	O
50	O
:	O
531	O
<	O
FFFD	O
>	O
538	O
(	O
1995	O
)	O
.	O

Schwartz	O
J	O
.	O

Air	O
pollution	O
and	O
hospital	O
admissions	O
for	O
heart	O
disease	O
in	O
eight	O
U	O
.	O
S	O
.	O
counties	O
.	O

Epidemiology	O
10	O
:	O
17	O
<	O
FFFD	O
>	O
22	O
(	O
1999	O
)	O
.	O

Schwartz	O
J	O
.	O

Air	O
pollution	O
and	O
hospital	O
admissions	O
for	O
the	O
elderly	O
in	O
Minneapolis	O
.	O

Arch	O
Environ	O
Health	O
49	O
:	O
366	O
<	O
FFFD	O
>	O
374	O
(	O
1994	O
)	O
.	O

Schwartz	O
J	O
.	O

Air	O
pollution	O
and	O
hospital	O
admissions	O
for	O
the	O
elderly	O
in	O
Birmingham	O
,	O
Alabama	O
.	O

Am	O
J	O
Epidemiol	O
139	O
:	O
589	O
<	O
FFFD	O
>	O
598	O
(	O
1994	O
)	O
.	O

Schwartz	O
J	O
.	O

Air	O
pollution	O
and	O
hospital	O
admissions	O
for	O
the	O
elderly	O
in	O
Detroit	O
,	O
MI	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
150	O
:	O
648	O
<	O
FFFD	O
>	O
655	O
(	O
1994	O
)	O
.	O

Pope	O
CA	O
III	O
.	O

Respiratory	O
disease	O
associated	O
with	O
community	O
air	O
pollution	O
and	O
a	O
steel	O
mill	O
,	O
Utah	O
valley	O
.	O

Am	O
J	O
Public	O
Health	O
79	O
:	O
623	O
<	O
FFFD	O
>	O
628	O
(	O
1989	O
)	O
.	O

Saldiva	O
PH	O
,	O
Pope	O
CA	O
,	O
Schwartz	O
J	O
,	O
Dockery	O
DW	O
,	O
Lichtenfels	O
AJ	O
,	O
Salge	O
JM	O
,	O
Barone	O
I	O
,	O
Bohm	O
GM	O
.	O

Air	O
pollution	O
and	O
mortality	O
in	O
elderly	O
people	B
:	O
a	O
time	O
series	O
study	O
in	O
Sao	O
Paulo	O
,	O
Brazil	O
.	O

Arch	O
Environ	O
Health	O
50	O
:	O
159	O
<	O
FFFD	O
>	O
163	O
(	O
1995	O
)	O
.	O

Schwartz	O
,	O
J	O
.	O

Air	O
pollution	O
and	O
hospital	O
admissions	O
for	O
cardiovascular	O
disease	O
in	O
Tucson	O
.	O

Epidemiology	O
8	O
:	O
371	O
<	O
FFFD	O
>	O
177	O
(	O
1997	O
)	O
.	O

Delfino	O
RJ	O
,	O
Murphy	O
Moulton	O
AM	O
,	O
Becklake	O
MR	O
.	O

Emergency	O
room	O
visits	O
for	O
respiratory	O
illnesses	O
among	O
the	O
elderly	O
in	O
Montreal	O
:	O
association	O
with	O
low	O
level	O
ozone	O
exposure	O
.	O

Environ	O
Res	O
76	O
:	O
67	O
<	O
FFFD	O
>	O
77	O
(	O
1998	O
)	O
.	O

National	O
Research	O
Council	O
.	O

Research	O
Priorities	O
for	O
Airborne	O
Particulate	O
Matter	O
.	O

Washington	O
,	O
DC	O
:	O
National	O
Academy	O
Press	O
,	O
1998	O
.	O

Schwartz	O
J	O
,	O
Dockery	O
DW	O
.	O

Increased	O
mortality	O
in	O
Philadelphia	O
associated	O
with	O
daily	O
air	O
pollution	O
concentrations	O
.	O

Am	O
Rev	O
Respir	O
Dis	O
145	O
:	O
600	O
<	O
FFFD	O
>	O
604	O
(	O
1992	O
)	O
.	O

Samet	O
JM	O
,	O
Zeger	O
SL	O
,	O
Berhane	O
K	O
.	O

The	O
association	O
of	O
mortality	O
and	O
particulate	O
air	O
pollution	O
.	O

In	O
:	O
Particulate	O
Air	O
Pollution	O
and	O
Daily	O
Mortality	O
.	O

The	O
Phase	O
I	O
Report	O
of	O
the	O
Particle	O
Epidemiology	O
Evaluation	O
Project	O
.	O

Boston	O
,	O
MA	O
:	O
Health	O
Effects	O
Institute	O
,	O
1995	O
.	O

Schwartz	O
J	O
.	O
What	O
are	O
people	B
dying	O
of	O
on	O
high	O
air	O
pollution	O
days	O
?	O

Environ	O
Res	O
64	O
:	O
26	O
<	O
FFFD	O
>	O
35	O
(	O
1994	O
)	O
.	O

Sunyer	O
J	O
,	O
Schwartz	O
J	O
,	O
Tobias	O
A	O
,	O
MacFarlane	O
D	O
,	O
Garcia	O
J	O
,	O
Anto	O
JM	O
.	O

Patients	B
with	O
chronic	O
obstructive	O
pulmonary	O
disease	O
are	O
a	O
susceptible	O
population	O
of	O
dying	O
due	O
to	O
urban	O
particles	O
.	O

Am	O
J	O
Epidemiol	O
151	O
(	O
1	O
)	O
:	O
50	O
<	O
FFFD	O
>	O
56	O
(	O
2000	O
)	O
.	O

Godleski	O
JJ	O
,	O
Sioutas	O
C	O
,	O
Katler	O
M	O
,	O
Koutrakis	O
P	O
.	O
Death	O
from	O
inhalation	O
of	O
concentrated	O
air	O
particles	O
in	O
animal	O
models	O
of	O
pulmonary	O
disease	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
153	O
:	O
A15	O
(	O
1996	O
)	O
.	O

Matsui	O
K	O
,	O
Goldman	O
L	O
.	O
Comorbidity	O
as	O
a	O
correlate	O
of	O
length	O
of	O
stay	O
for	O
hospitalized	O
patients	B
with	O
acute	O
chest	O
pain	O
.	O

J	O
Gen	O
Intern	O
Med	O
11	O
:	O
262	O
<	O
FFFD	O
>	O
268	O
(	O
1996	O
)	O
.	O

Charlson	O
M	O
,	O
Szatrowshi	O
TP	O
,	O
Peterson	O
J	O
,	O
Gold	O
J	O
.	O
Validation	O
of	O
a	O
combined	O
comorbidity	O
index	O
.	O

J	O
Clin	O
Epidemiol	O
47	O
:	O
1245	O
<	O
FFFD	O
>	O
1251	O
(	O
1994	O
)	O
.	O

Monane	O
M	O
,	O
Kanter	O
DS	O
,	O
Glynn	O
RJ	O
,	O
Avorn	O
J	O
.	O
Variability	O
in	O
length	O
of	O
hospitalization	O
for	O
stroke	O
.	O

The	O
role	O
of	O
managed	O
care	O
in	O
an	O
elderly	O
population	O
.	O

Arch	O
Neurol	O
53	O
:	O
848	O
(	O
1996	O
)	O
.	O

Hallstrom	O
AP	O
,	O
Cobb	O
LA	O
,	O
Yu	O
BH	O
.	O

Influence	O
of	O
comorbidity	O
on	O
the	O
outcome	O
of	O
patients	B
treated	O
for	O
out	O
-	O
of	O
-	O
hospital	O
ventricular	O
fibrillation	O
.	O

Circulation	O
93	O
:	O
2019	O
<	O
FFFD	O
>	O
2022	O
(	O
1996	O
)	O
.	O

Malenka	O
DJ	O
,	O
Mclerran	O
D	O
,	O
Roos	O
N	O
,	O
Fisher	O
ES	O
,	O
Wennberg	O
JE	O
.	O

Using	O
administrative	O
data	O
to	O
describe	O
case	O
-	O
mix	O
:	O
a	O
comparison	O
with	O
the	O
medical	O
record	O
.	O

J	O
Clin	O
Epidemiol	O
47	O
:	O
1027	O
<	O
FFFD	O
>	O
1032	O
(	O
1994	O
)	O
.	O

Romano	O
PS	O
,	O
Roos	O
LL	O
,	O
Jollis	O
JG	O
.	O

Adapting	O
a	O
clinical	O
comorbidity	O
index	O
for	O
use	O
with	O
ICD	O
-	O
9	O
-	O
CM	O
administrative	O
data	O
:	O
differing	O
perspectives	O
.	O

J	O
Clin	O
Epidemiol	O
46	O
:	O
1075	O
<	O
FFFD	O
>	O
1079	O
(	O
1993	O
)	O
.	O

Deyo	O
RA	O
,	O
Cherkin	O
DC	O
,	O
Ciol	O
MA	O
.	O

Adapting	O
a	O
clinical	O
comorbidity	O
index	O
for	O
use	O
with	O
ICD	O
-	O
9CM	O
administrative	O
databases	O
.	O

J	O
Clin	O
Epidemiol	O
45	O
:	O
613	O
<	O
FFFD	O
>	O
619	O
(	O
1992	O
)	O
.	O

Charlson	O
ME	O
,	O
Pompei	O
P	O
,	O
Ales	O
KL	O
,	O
MacKenzie	O
CR	O
.	O

A	O
new	O
method	O
of	O
classifying	O
prognostic	O
comorbidity	O
in	O
longitudinal	O
studies	O
:	O
development	O
and	O
validation	O
.	O

J	O
Chronic	O
Dis	O
40	O
:	O
373	O
<	O
FFFD	O
>	O
383	O
(	O
1987	O
)	O
.	O

Librero	O
J	O
,	O
Peir	O
<	O
FFFD	O
>	O
S	O
,	O
Ordi	O
<	O
FFFD	O
>	O
ana	O
R	O
.	O

Chronic	O
comorbidity	O
and	O
outcomes	O
of	O
hospital	O
care	O
:	O
length	O
of	O
stay	O
,	O
mortality	O
,	O
and	O
readmission	O
at	O
30	O
and	O
365	O
days	O
.	O

J	O
Clin	O
Epidemiol	O
52	O
:	O
171	O
<	O
FFFD	O
>	O
179	O
(	O
1999	O
)	O
.	O

31	O
.	O

Nehls	O
GJ	O
,	O
Akland	O
GG	O
.	O

Procedures	O
for	O
handling	O
aerometric	O
data	O
.	O

J	O
Air	O
Pollut	O
Control	O
Assoc	O
23	O
:	O
180	O
<	O
FFFD	O
>	O
184	O
(	O
1973	O
)	O
.	O

32	O
.	O

Hastie	O
T	O
,	O
Tibshirani	O
R	O
.	O
Generalized	O
Additive	O
Models	O
.	O

London	O
:	O
Chapman	O
and	O
Hall	O
,	O
1990	O
.	O

33	O
.	O

Schwartz	O
J	O
.	O
Generalized	O
additive	O
models	O
in	O
epidemiology	O
.	O

In	O
:	O
International	O
Biometric	O
Society	O
,	O
Invited	O
Papers	O
.	O

17th	O
International	O
Biometric	O
Conference	O
,	O
8	O
<	O
FFFD	O
>	O
12	O
August	O
1994	O
,	O
Hamilton	O
,	O
Ontario	O
,	O
Canada	O
.	O

Washington	O
,	O
DC	O
:	O
International	O
Biometric	O
Society	O
,	O
1994	O
;	O
55	O
<	O
FFFD	O
>	O
80	O
.	O

34	O
.	O

Rossi	O
G	O
,	O
Vigotti	O
MA	O
,	O
Zanobetti	O
A	O
,	O
Repetto	O
F	O
,	O
Giannelle	O
V	O
,	O
Schwartz	O
J	O
.	O

Air	O
pollution	O
and	O
cause	O
specific	O
mortality	O
in	O
Milan	O
,	O
Italy	O
,	O
1980	O
<	O
FFFD	O
>	O
1989	O
.	O

Arch	O
Environ	O
Health	O
54	O
:	O
158	O
<	O
FFFD	O
>	O
164	O
(	O
1999	O
)	O
.	O

35	O
.	O

Cleveland	O
WS	O
,	O
Devlin	O
SJ	O
.	O

Robust	O
locally	O
-	O
weighted	O
regression	O
and	O
smoothing	O
scatterplots	O
.	O

J	O
Am	O
Stat	O
Assoc	O
74	O
:	O
829	O
<	O
FFFD	O
>	O
836	O
(	O
1988	O
)	O
.	O

36	O
.	O

Akaike	O
H	O
.	O
Information	O
theory	O
and	O
an	O
extension	O
of	O
the	O
maximum	O
likelihood	O
principal	O
.	O

In	O
:	O
2nd	O
International	O
Symposium	O
on	O
Information	O
Theory	O
(	O
Petrov	O
BN	O
,	O
Csaki	O
F	O
,	O
eds	O
)	O
.	O

Budapest	O
:	O
Akademiai	O
Kaiado	O
,	O
1973	O
;	O
267	O
<	O
FFFD	O
>	O
281	O
.	O

37	O
.	O

Brumback	O
BA	O
,	O
Ryan	O
LM	O
,	O
Schwartz	O
J	O
,	O
Neas	O
LM	O
,	O
Stark	O
PC	O
,	O
Burge	O
HA	O
.	O

Transitional	O
regression	O
models	O
with	O
application	O
to	O
environmental	O
time	O
series	O
.	O

J	O
Acoust	O
Soc	O
Am	O
95	O
(	O
449	O
)	O
:	O
16	O
<	O
FFFD	O
>	O
28	O
(	O
2000	O
)	O
.	O

38	O
.	O

Schwartz	O
J	O
.	O

The	O
distributed	O
lag	O
between	O
air	O
pollution	O
and	O
daily	O
deaths	O
.	O

Epidemiology	O
11	O
:	O
320	O
<	O
FFFD	O
>	O
326	O
(	O
2000	O
)	O
.	O

39	O
.	O

Pope	O
CA	O
III	O
,	O
Verrier	O
RL	O
,	O
Lovett	O
EG	O
,	O
Larson	O
AC	O
,	O
Raizenne	O
ME	O
,	O
Kanner	O
RE	O
,	O
Schwartz	O
J	O
,	O
Villegas	O
GM	O
,	O
Dockery	O
DW	O
.	O

Heart	O
rate	O
variability	O
associated	O
with	O
particulate	O
air	O
pollution	O
.	O

Am	O
Heart	O
J	O
138	O
:	O
890	O
<	O
FFFD	O
>	O
899	O
(	O
1999	O
)	O
.	O

40	O
.	O

Gold	O
DR	O
,	O
Litonjua	O
A	O
,	O
Schwartz	O
J	O
,	O
Lovett	O
E	O
,	O
Larson	O
A	O
,	O
Nearing	O
B	O
,	O
Allen	O
G	O
,	O
Verrier	O
M	O
,	O
Cherry	O
R	O
,	O
Verrier	O
R	O
.	O
Ambient	O
pollution	O
and	O
heart	O
rate	O
variability	O
.	O

Circulation	O
101	O
(	O
11	O
)	O
:	O
1267	O
<	O
FFFD	O
>	O
1273	O
(	O
2000	O
)	O
.	O

41	O
.	O

Liao	O
D	O
,	O
Creason	O
J	O
,	O
Shy	O
C	O
,	O
Williams	O
R	O
,	O
Watts	O
R	O
,	O
Zweidinger	O
R	O
.	O
Daily	O
variation	O
of	O
particulate	O
air	O
pollution	O
and	O
poor	O
cardiac	O
autonomic	O
control	O
in	O
the	O
elderly	O
.	O

Environ	O
Health	O
Perspect	O
107	O
:	O
521	O
<	O
FFFD	O
>	O
525	O
(	O
1999	O
)	O
.	O

42	O
.	O

Peters	O
A	O
,	O
Liu	O
E	O
,	O
Verrier	O
RL	O
,	O
Schwartz	O
J	O
,	O
Gold	O
DR	O
,	O
Mittelman	O
M	O
,	O
Baliff	O
J	O
,	O
Allen	O
G	O
,	O
Monahan	O
K	O
,	O
Dockery	O
DW	O
.	O

Air	O
pollution	O
and	O
incidences	O
of	O
cardiac	O
arrhythmia	O
.	O

Epidemiology	O
11	O
(	O
1	O
)	O
:	O
11	O
<	O
FFFD	O
>	O
17	O
(	O
2000	O
)	O
.	O

43	O
.	O

Godleski	O
JJ	O
,	O
Verrier	O
RL	O
,	O
Koutrakis	O
P	O
,	O
Catalano	O
P	O
.	O
Mechanisms	O
of	O
Morbidity	O
and	O
Mortality	O
from	O
Exposure	O
to	O
Ambient	O
Air	O
Particles	O
.	O

Health	O
Effects	O
Institute	O
Research	O
Report	O
91	O
.	O

Cambridge	O
,	O
MA	O
:	O
Health	O
Effects	O
Institute	O
,	O
2000	O
.	O

44	O
.	O

Watkinson	O
WP	O
,	O
Campen	O
MJ	O
,	O
Kodavanti	O
UP	O
,	O
Ledbetter	O
AD	O
,	O
Costa	O
DL	O
.	O

Effects	O
of	O
inhaled	O
residual	O
oil	O
fly	O
ash	O
particles	O
on	O
electrocardiographic	O
and	O
thermoregulatory	O
parameters	O
in	O
normal	O
and	O
compromised	O
rats	B
[	O
Abstract	O
]	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
157	O
:	O
A150	O
(	O
1998	O
)	O
.	O

45	O
.	O

Watkinson	O
WP	O
,	O
Campen	O
MJ	O
,	O
Costa	O
DL	O
.	O

Cardiac	O
arrhythmia	O
induction	O
after	O
exposure	O
to	O
residual	O
oil	O
fly	O
ash	O
particles	O
in	O
a	O
rodent	O
model	O
of	O
pulmonary	O
hypertension	O
.	O

Toxicol	O
Sci	O
41	O
:	O
209	O
<	O
FFFD	O
>	O
216	O
(	O
1998	O
)	O
.	O

46	O
.	O

Kodavanti	O
UP	O
,	O
Jackson	O
MC	O
,	O
Richards	O
J	O
,	O
Ledbetter	O
A	O
,	O
Costa	O
DL	O
.	O

Differential	O
pulmonary	O
responses	O
to	O
inhaled	O
emission	O
particulate	O
matter	O
(	O
PM	O
)	O
in	O
systemically	O
hypertensive	O
vs	O
.	O
normotensive	O
rats	B
[	O
Abstract	O
]	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
157	O
:	O
A260	O
(	O
1998	O
)	O
.	O

47	O
.	O

Hoek	O
G	O
,	O
Brunekreef	O
B	O
,	O
van	O
Wijnen	O
JH	O
.	O

Cardiovascular	O
mortality	O
response	O
to	O
air	O
pollution	O
is	O
strongest	O
for	O
heart	O
failure	O
and	O
thrombotic	O
causes	O
of	O
death	O
[	O
Abstract	O
]	O
.	O

Epidemiology	O
10	O
:	O
S177	O
(	O
1999	O
)	O
.	O

48	O
.	O

Bates	O
DV	O
,	O
Szito	O
R	O
.	O
Hospital	O
admissions	O
and	O
air	O
pollutants	O
in	O
southern	O
Ontario	O
:	O
the	O
acid	O
summer	O
haze	O
effect	O
.	O

Environ	O
Res	O
43	O
:	O
317	O
<	O
FFFD	O
>	O
331	O
(	O
1987	O
)	O
.	O

49	O
.	O

Pope	O
CA	O
III	O
.	O

Respiratory	O
disease	O
associated	O
with	O
community	O
air	O
pollution	O
and	O
a	O
steel	O
mill	O
,	O
Utah	O
valley	O
.	O

Am	O
J	O
Public	O
Health	O
79	O
:	O
623	O
<	O
FFFD	O
>	O
628	O
(	O
1989	O
)	O
.	O

50	O
.	O

Zelikoff	O
JT	O
,	O
Nadziejko	O
C	O
,	O
Fang	O
T	O
,	O
Gordon	O
C	O
,	O
Premdass	O
C	O
,	O
Cohen	O
MD	O
.	O

Short	O
term	O
,	O
low	O
-	O
dose	O
inhalation	O
of	O
ambient	O
particulate	O
matter	O
exacerbates	O
ongoing	O
pneumococcal	O
infections	O
in	O
Streptococcus	O
Pneumoniae	O
-	O
infected	O
rates	O
.	O

In	O
:	O
Proceedings	O
of	O
the	O
Third	O
Colloquium	O
on	O
Particulate	O
Air	O
Pollution	O
and	O
Human	B
Health	O
(	O
Phalen	O
RF	O
,	O
Bell	O
YM	O
,	O
eds	O
)	O
.	O

Irvine	O
,	O
CA	O
:	O
Air	O
Pollution	O
Health	O
Effects	O
Laboratory	O
,	O
University	O
of	O
California	O
,	O
1999	O
;	O
8	O
-	O
94	O
<	O
FFFD	O
>	O
8	O
-	O
101	O
.	O

51	O
.	O

Clarke	O
RW	O
,	O
Hemenway	O
DR	O
,	O
Frank	O
R	O
,	O
Kleeberger	O
SR	O
,	O
Longphre	O
MV	O
,	O
Jakab	O
GJ	O
.	O

Particle	O
associated	O
sulfate	O
exposure	O
enhances	O
murine	O
influenza	O
mortality	O
[	O
Abstract	O
]	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
155	O
:	O
A245	O
(	O
1997	O
)	O
.	O

52	O
.	O

Pope	O
CA	O
,	O
Dockery	O
DW	O
,	O
Spengler	O
JD	O
,	O
Raizenne	O
ME	O
.	O

Respiratory	O
health	O
and	O
PM10	O
pollution	O
:	O
a	O
daily	O
time	O
series	O
analysis	O
.	O

Am	O
Rev	O
Respir	O
Dis	O
144	O
:	O
668	O
<	O
FFFD	O
>	O
674	O
(	O
1991	O
)	O
.	O

53	O
.	O

Schwartz	O
J	O
,	O
Koenig	O
J	O
,	O
Slater	O
D	O
,	O
Larson	O
T	O
.	O
Particulate	O
air	O
pollution	O
and	O
hospital	O
emergency	O
visits	O
for	O
asthma	O
in	O
Seattle	O
.	O

Am	O
Rev	O
Respir	O
Dis	O
147	O
:	O
826	O
<	O
FFFD	O
>	O
831	O
(	O
1993	O
)	O
.	O

54	O
.	O

Thurston	O
GD	O
,	O
Ito	O
K	O
,	O
Lippman	O
M	O
,	O
Hayes	O
CG	O
,	O
Bates	O
DV	O
.	O

Respiratory	O
hospital	O
admissions	O
and	O
summertime	O
haze	O
air	O
pollution	O
in	O
Toronto	O
,	O
Ontario	O
:	O
consideration	O
of	O
the	O
role	O
of	O
acid	O
aerosols	O
.	O

Environ	O
Res	O
65	O
:	O
271	O
<	O
FFFD	O
>	O
290	O
(	O
1994	O
)	O
.	O

55	O
.	O

Norris	O
G	O
,	O
YoungPong	O
SN	O
,	O
Koenig	O
JQ	O
,	O
Larson	O
TV	O
,	O
Sheppard	O
L	O
,	O
Stout	O
JW	O
.	O

An	O
association	O
between	O
fine	O
particles	O
and	O
asthma	O
emergency	O
department	O
visits	O
for	O
children	B
in	O
Seattle	O
.	O

Environ	O
Health	O
Perspect	O
107	O
:	O
489	O
<	O
FFFD	O
>	O
493	O
(	O
1999	O
)	O
.	O

56	O
.	O

Hamada	O
K	O
,	O
Goldsmith	O
CW	O
,	O
Kobzik	O
L	O
.	O

Air	O
pollutant	O
aerosols	O
allow	O
airway	O
sensitization	O
to	O
allergen	O
in	O
juvenile	O
mice	B
.	O

Am	O
J	O
Resp	O
Crit	O
Care	O
Med	O
A28	O
(	O
1999	O
)	O
.	O

57	O
.	O

Lambert	O
AL	O
,	O
Selgrade	O
M	O
,	O
Dong	O
W	O
,	O
Winsett	O
D	O
,	O
Gilmour	O
M	O
.	O
Enhanced	O
allergic	O
sensitization	O
by	O
residual	O
oil	O
fly	O
ash	O
particles	O
is	O
mediated	O
by	O
soluble	O
metal	O
constituents	O
[	O
Abstract	O
]	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
159	O
:	O
A26	O
(	O
1999	O
)	O
.	O

58	O
.	O

Dailey	O
LA	O
,	O
Madden	O
MC	O
,	O
Devlin	O
RB	O
.	O

Do	O
airway	O
epithelial	O
cells	O
from	O
normal	O
and	O
asthmatic	O
donors	O
respond	O
differently	O
to	O
an	O
in	O
vitro	O
challenge	O
with	O
a	O
particulate	O
pollutant	O
?	O

[	O
Abstract	O
]	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
157	O
:	O
A598	O
(	O
1998	O
)	O
.	O

59	O
.	O

Gilmour	O
MI	O
,	O
Winsett	O
D	O
,	O
Selgrade	O
MJ	O
,	O
Costa	O
DL	O
.	O

Residual	O
oil	O
fly	O
ash	O
exposure	O
enhances	O
allergic	O
sensitization	O
to	O
house	O
dust	O
mite	O
in	O
rats	B
and	O
augments	O
immune	O
-	O
mediated	O
inflammation	O
[	O
Abstract	O
]	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
155	O
:	O
A244	O
(	O
1997	O
)	O
.	O

60	O
.	O

Zeger	O
SL	O
,	O
Thomas	O
D	O
,	O
Dominici	O
F	O
,	O
Samet	O
JM	O
,	O
Schwartz	O
JM	O
,	O
Dockery	O
D	O
,	O
Cohen	O
A	O
.	O
Exposure	O
measurement	O
error	O
in	O
time	O
<	O
FFFD	O
>	O
series	O
studies	O
of	O
air	O
pollution	O
:	O
concepts	O
and	O
consequences	O
.	O

Environ	O
Health	O
Perspect	O
108	O
:	O
419	O
<	O
FFFD	O
>	O
426	O
(	O
2000	O
)	O
.	O

61	O
.	O

Salvi	O
S	O
,	O
Blomberg	O
A	O
,	O
Rudell	O
B	O
,	O
Kelly	O
F	O
,	O
Sandstrom	O
T	O
,	O
Holgate	O
ST	O
,	O
Frew	O
A	O
.	O
Acute	O
inflammatory	O
responses	O
in	O
the	O
airways	O
and	O
peripheral	O
blood	O
after	O
short	O
-	O
term	O
exposure	O
to	O
diesel	O
exhaust	O
in	O
healthy	O
human	B
volunteers	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
159	O
:	O
702	O
<	O
FFFD	O
>	O
709	O
(	O
1999	O
)	O
.	O

62	O
.	O

Tan	O
WC	O
,	O
van	O
Eeden	O
S	O
,	O
Qiu	O
DW	O
,	O
Liam	O
BL	O
,	O
Dyachokova	O
Y	O
,	O
Hogg	O
JL	O
.	O

Particulate	O
air	O
pollution	O
,	O
bone	O
marrow	O
stimulation	O
and	O
the	O
pathogenesis	O
of	O
excess	O
cardiovascular	O
and	O
pulmonary	O
deaths	O
.	O

Am	O
J	O
Respir	O
Crit	O
Care	O
Med	O
155	O
:	O
1441	O
<	O
FFFD	O
>	O
1447	O
(	O
1997	O
)	O
.	O

63	O
.	O

Gordon	O
T	O
,	O
Nadziejko	O
C	O
,	O
Schlesinger	O
R	O
,	O
Chen	O
LC	O
.	O

Pulmonary	O
and	O
cardiovascular	O
effects	O
of	O
acute	O
exposure	O
to	O
concentrated	O
ambient	O
particulate	O
matter	O
in	O
rats	B
.	O

Toxicol	O
Lett	O
96	O
<	O
FFFD	O
>	O
97	O
:	O
285	O
<	O
FFFD	O
>	O
288	O
(	O
1998	O
)	O
.	O

64	O
.	O

Peters	O
A	O
,	O
Doering	O
A	O
,	O
Wichmann	O
HE	O
,	O
Koenig	O
W	O
.	O
Increased	O
plasma	O
viscosity	O
during	O
an	O
air	O
pollution	O
episode	O
:	O
a	O
link	O
to	O
mortality	O
?	O

Lancet	O
349	O
(	O
9065	O
)	O
:	O
1582	O
<	O
FFFD	O
>	O
1587	O
(	O
1997	O
)	O
.	O

65	O
.	O

Peters	O
A	O
,	O
Stieberv	O
J	O
,	O
Doering	O
A	O
,	O
Wichmann	O
HE	O
.	O

Is	O
systolic	O
blood	O
pressure	O
associated	O
with	O
air	O
pollution	O
?	O

[	O
Abstract	O
]	O
.	O

Epidemiology	O
10	O
(	O
4	O
)	O
:	O
S177	O
(	O
1999	O
)	O
.	O

Environmental	O
Health	O
Perspectives	O

<	O
FFFD	O
>	O
VOLUME	O
108	O
|	O
NUMBER	O
9	O
|	O
September	O
2000	O

845	O

Syndrome	O
of	O
arachnomelia	O
in	O
Simmental	O
cattle	B

Abstract	O

Background	O

The	O
syndrome	O
of	O
arachnomelia	O
is	O
an	O
inherited	O
malformation	O
mainly	O
of	O
limbs	O
,	O
back	O
and	O
head	O
in	O
cattle	B
.	O

At	O
present	O
the	O
arachnomelia	O
syndrome	O
has	O
been	O
well	O
known	O
mainly	O
in	O
Brown	O
Swiss	O
cattle	B
.	O

Nevertheless	O
,	O
the	O
arachnomelia	O
syndrome	O
had	O
been	O
observed	O
in	O
the	O
Hessian	O
Simmental	O
population	O
during	O
the	O
decade	O
1964	O
-	O
1974	O
.	O

Recently	O
,	O
stillborn	O
Simmental	O
calves	B
were	O
observed	O
having	O
a	O
morphology	O
similar	O
to	O
the	O
arachnomelia	O
syndrome	O
.	O

The	O
goal	O
of	O
this	O
work	O
was	O
the	O
characterization	O
of	O
the	O
morphology	O
and	O
genealogy	O
of	O
the	O
syndrome	O
in	O
Simmental	O
to	O
establish	O
the	O
basis	O
for	O
an	O
effective	O
management	O
of	O
the	O
disease	O
.	O

Results	O

The	O
first	O
pathologically	O
confirmed	O
arachnomelia	O
syndrome	O
-	O
cases	O
in	O
the	O
current	O
Simmental	O
population	O
appeared	O
in	O
the	O
year	O
2005	O
.	O

By	O
2007	O
,	O
an	O
additional	O
140	O
calves	B
with	O
the	O
arachnomelia	O
syndrome	O
were	O
identified	O
.	O

The	O
major	O
pathological	O
findings	O
were	O
malformed	O
bones	O
affecting	O
the	O
head	O
,	O
long	O
bones	O
of	O
the	O
legs	O
and	O
the	O
vertebral	O
column	O
.	O

It	O
could	O
be	O
shown	O
that	O
,	O
with	O
the	O
exception	O
of	O
two	O
cases	O
that	O
were	O
considered	O
as	O
phenocopies	O
,	O
all	O
of	O
the	O
paternal	O
and	O
about	O
two	O
-	O
third	O
of	O
the	O
maternal	O
pedigrees	O
of	O
the	O
affected	O
calves	B
could	O
be	O
traced	O
back	O
to	O
one	O
common	O
founder	O
.	O

Together	O
with	O
the	O
data	O
from	O
experimental	O
matings	O
,	O
the	O
pedigree	O
data	O
support	O
an	O
autosomal	O
recessive	O
mutation	O
being	O
the	O
etiology	O
of	O
the	O
arachnomelia	O
syndrome	O
.	O

The	O
frequency	O
of	O
the	O
mutation	O
in	O
the	O
current	O
population	O
was	O
estimated	O
to	O
be	O
3	O
.	O
32	O
%	O
.	O

Conclusion	O

We	O
describe	O
the	O
repeated	O
occurrence	O
of	O
the	O
arachnomelia	O
syndrome	O
in	O
Simmental	O
calves	B
.	O

It	O
resembles	O
completely	O
the	O
same	O
defect	O
occurring	O
in	O
the	O
Brown	O
Swiss	O
breed	O
.	O

The	O
mutation	O
became	O
relatively	O
widespread	O
amongst	O
the	O
current	O
population	O
.	O

Therefore	O
,	O
a	O
control	O
system	O
has	O
to	O
be	O
established	O
and	O
it	O
is	O
highly	O
desirable	O
to	O
map	O
the	O
disease	O
and	O
develop	O
a	O
genetic	O
test	O
system	O
.	O

Background	O

In	O
the	O
year	O
2006	O
a	O
syndrome	O
was	O
described	O
in	O
the	O
German	O
and	O
Austrian	O
Simmental	O
(	O
Fleckvieh	O
,	O
as	O
it	O
is	O
locally	O
called	O
,	O
is	O
the	O
main	O
dual	O
-	O
purpose	O
breed	O
in	O
Germany	O
,	O
in	O
short	O
called	O
Simmental	O
in	O
the	O
further	O
text	O
)	O
population	O
,	O
that	O
was	O
pathologically	O
similar	O
to	O
the	O
arachnomelia	O
syndrome	O
in	O
Brown	O
Swiss	O
cattle	B
[	O
1	O
]	O
.	O

The	O
congenital	O
arachnomelia	O
syndrome	O
(	O
AS	O
,	O
OMIA	O
Phene	O
ID	O
139	O
,	O
Group	O
000059	O
)	O
is	O
mainly	O
a	O
malformation	O
of	O
the	O
skeletal	O
system	O
in	O
cattle	B
that	O
was	O
initially	O
described	O
by	O
Rieck	O
and	O
Schade	O
[	O
2	O
]	O
in	O
Holstein	O
Friesian	O
,	O
Red	O
Holstein	O
and	O
Simmental	O
.	O

The	O
main	O
pathological	O
changes	O
are	O
skeletal	O
malformations	O
of	O
the	O
legs	O
,	O
the	O
spinal	O
column	O
and	O
the	O
skull	O
.	O

The	O
legs	O
are	O
thinner	O
and	O
appear	O
longer	O
than	O
normal	O
(	O
dolichostenomelia	O
,	O
arachnomelia	O
)	O
since	O
the	O
diameter	O
of	O
the	O
diaphyses	O
is	O
reduced	O
.	O

These	O
long	O
bones	O
are	O
more	O
fragile	O
and	O
,	O
in	O
combination	O
with	O
stiffened	O
joints	O
,	O
they	O
tend	O
to	O
fracture	O
during	O
calving	O
.	O

The	O
fetlock	O
joints	O
are	O
deformed	O
,	O
often	O
stiffened	O
and	O
show	O
hyperextension	O
.	O

The	O
malformation	O
of	O
the	O
spinal	O
column	O
leads	O
to	O
kyphosis	O
and	O
scoliosis	O
.	O

The	O
skull	O
malformations	O
are	O
characterized	O
by	O
a	O
shortened	O
lower	O
jaw	O
(	O
brachygnathia	O
inferior	O
)	O
,	O
convex	O
rounding	O
of	O
the	O
frontal	O
bone	O
leading	O
to	O
a	O
marked	O
stop	O
(	O
"	O
pointer	O
head	O
"	O
)	O
and	O
rotation	O
of	O
the	O
anterior	O
cranium	O
.	O

In	O
some	O
cases	O
,	O
additional	O
malformations	O
like	O
hydrocephalus	O
externus	O
develop	O
[	O
2	O
-	O
5	O
]	O
.	O

Since	O
the	O
report	O
of	O
Rieck	O
and	O
Schade	O
[	O
2	O
]	O
no	O
further	O
cases	O
were	O
reported	O
in	O
Simmental	O
cattle	B
,	O
but	O
in	O
the	O
1980s	O
the	O
syndrome	O
was	O
dispersed	O
in	O
another	O
breed	O
,	O
the	O
European	O
Brown	O
Swiss	O
cattle	B
,	O
by	O
the	O
use	O
of	O
American	O
Brown	O
Swiss	O
sires	O
[	O
4	O
,	O
6	O
]	O
.	O

In	O
Brown	O
Swiss	O
an	O
autosomal	O
recessive	O
mode	O
of	O
inheritance	O
was	O
supposed	O
and	O
a	O
control	O
program	O
based	O
on	O
the	O
identification	O
of	O
carriers	O
by	O
pedigree	O
analyses	O
was	O
established	O
[	O
5	O
]	O
.	O

Recently	O
,	O
four	O
cases	O
of	O
arachnomelia	O
syndrome	O
were	O
reported	O
in	O
Italy	O
[	O
3	O
]	O
.	O

In	O
this	O
study	O
,	O
we	O
present	O
the	O
data	O
of	O
152	O
pathologically	O
confirmed	O
cases	O
of	O
arachnomelia	O
syndrome	O
in	O
Simmental	O
that	O
were	O
collected	O
from	O
October	O
2005	O
to	O
March	O
2007	O
.	O

We	O
describe	O
the	O
pathological	O
findings	O
,	O
the	O
familial	O
occurrence	O
and	O
an	O
estimate	O
of	O
the	O
frequency	O
of	O
the	O
diseases	O
allele	O
in	O
Simmental	O
cattle	B
.	O

Additional	O
support	O
for	O
the	O
mode	O
of	O
inheritance	O
and	O
the	O
genetic	O
basis	O
of	O
the	O
arachnomelia	O
syndrome	O
is	O
given	O
by	O
the	O
result	O
of	O
experimental	O
matings	O
of	O
obligate	O
carriers	O
.	O

Results	O
and	O
discussion	O

AS	O
has	O
not	O
been	O
reported	O
again	O
in	O
Simmental	O
since	O
its	O
first	O
description	O
in	O
the	O
1970s	O
,	O
more	O
than	O
thirteen	O
years	O
ago	O
.	O

In	O
autumn	O
2004	O
a	O
number	O
of	O
stillborn	O
calves	B
with	O
similar	O
malformations	O
of	O
the	O
legs	O
and	O
head	O
were	O
recorded	O
within	O
the	O
monitoring	O
system	O
of	O
anomalies	O
in	O
Simmental	O
.	O

Some	O
of	O
these	O
calves	B
were	O
sent	O
to	O
the	O
veterinary	O
service	O
laboratory	O
for	O
examination	O
,	O
and	O
in	O
December	O
2005	O
the	O
first	O
15	O
cases	O
of	O
AS	O
were	O
pathologically	O
confirmed	O
.	O

Subsequently	O
,	O
farmers	O
and	O
veterinarians	O
had	O
been	O
encouraged	O
to	O
report	O
cases	O
by	O
an	O
information	O
leaflet	O
and	O
various	O
articles	O
in	O
local	O
trade	O
journals	O
.	O

An	O
increasing	O
number	O
of	O
suspected	O
cases	O
was	O
reported	O
and	O
an	O
additional	O
136	O
affected	O
calves	B
were	O
identified	O
by	O
pathological	O
examination	O
by	O
June	O
2007	O
.	O

Familial	O
occurrence	O
and	O
case	O
presentation	O
of	O
the	O
syndrome	O
of	O
arachnomelia	O

The	O
geographical	O
origins	O
of	O
the	O
cases	O
were	O
the	O
southern	O
part	O
of	O
Germany	O
and	O
Austria	O
,	O
reflecting	O
the	O
regional	O
distribution	O
of	O
the	O
Simmental	O
breed	O
.	O

Both	O
sexes	O
were	O
equally	O
represented	O
in	O
the	O
152	O
(	O
80	O
male	O
,	O
72	O
female	O
,	O
chi	O
2	O
=	O
0	O
.	O
21	O
,	O
p	O
=	O
0	O
.	O
64	O
)	O
affected	O
calves	B
.	O

The	O
largest	O
number	O
of	O
cases	O
was	O
registered	O
in	O
2006	O
(	O
Figure	O
1	O
)	O
.	O

In	O
retrospect	O
,	O
it	O
could	O
be	O
shown	O
that	O
the	O
main	O
reason	O
for	O
the	O
rapid	O
increase	O
of	O
cases	O
in	O
the	O
years	O
2005	O
and	O
2006	O
was	O
the	O
high	O
popularity	O
of	O
certain	O
sires	O
carrying	O
the	O
AS	O
mutation	O
(	O
ROMEL	O
,	O
ISO	O
-	O
Nr	O
.	O
276000911043667	O
,	O
born	O
in	O
1995	O
;	O
EGEL	O
,	O
276000915512806	O
,	O
1985	O
;	O
REXON	O
,	O
276000913008210	O
,	O
1989	O
)	O
.	O

The	O
latter	O
two	O
sires	O
represent	O
the	O
key	O
-	O
nodes	O
of	O
the	O
pedigree	O
pathways	O
of	O
the	O
mutation	O
from	O
the	O
founder	O
into	O
the	O
current	O
population	O
(	O
Figure	O
2	O
)	O
.	O

ROMEL	O
,	O
for	O
example	O
,	O
sired	O
more	O
than	O
40	O
,	O
000	O
cows	B
4	O
to	O
6	O
years	O
ago	O
.	O

Furthermore	O
,	O
115	O
sons	O
of	O
ROMEL	O
born	O
from	O
2001	O
to	O
2005	O
are	O
registered	O
and	O
listed	O
in	O
the	O
breeding	O
database	O
[	O
7	O
]	O
.	O

These	O
progeny	O
were	O
now	O
mated	O
to	O
ROMEL	O
and	O
sons	O
or	O
grandsons	O
of	O
EGEL	O
and	O
REXON	O
resulting	O
in	O
a	O
high	O
probability	O
for	O
the	O
occurrence	O
of	O
affected	O
calves	B
.	O

Increasing	O
awareness	O
of	O
the	O
disease	O
and	O
abandoning	O
of	O
selling	O
the	O
semen	O
from	O
carriers	O
led	O
to	O
a	O
sharp	O
drop	O
of	O
cases	O
in	O
2007	O
.	O

The	O
disease	O
was	O
successfully	O
managed	O
by	O
efficient	O
collaboration	O
of	O
the	O
Institute	O
for	O
Animal	O
Breeding	O
of	O
the	O
Bavarian	O
State	O
Research	O
Centre	O
for	O
Agriculture	O
(	O
LfL	O
)	O
,	O
the	O
Landeskuratorium	O
der	O
Erzeugerringe	O
f	O
u	O
r	O
tierische	O
Veredelung	O
in	O
Bayern	O
e	O
.	O
V	O
(	O
LKV	O
)	O
,	O
the	O
Bavarian	O
Animal	O
Health	O
Service	O
(	O
TGD	O
)	O
and	O
breeding	O
organizations	O
.	O

Pathological	O
findings	O

Calves	B
under	O
suspicion	O
of	O
the	O
arachnomelia	O
syndrome	O
were	O
sent	O
to	O
the	O
pathology	O
department	O
of	O
the	O
TGD	O
for	O
macroscopic	O
examination	O
.	O

The	O
observed	O
major	O
pathological	O
findings	O
were	O
(	O
1	O
)	O
facial	O
deformation	O
,	O
including	O
brachygnathia	O
inferior	O
and	O
concave	O
rounding	O
of	O
the	O
maxilla	O
forming	O
a	O
dent	O
(	O
'	O
pointer	O
-	O
head	O
'	O
)	O
;	O
(	O
2	O
)	O
abnormally	O
thin	O
diaphyses	O
of	O
the	O
long	O
bones	O
(	O
the	O
outer	O
diameter	O
of	O
the	O
diaphyses	O
is	O
diminished	O
,	O
whereas	O
the	O
width	O
of	O
the	O
substantia	O
compacta	O
is	O
normal	O
)	O
leading	O
to	O
frequent	O
fractures	O
of	O
the	O
metacarpus	O
and	O
metatarsus	O
in	O
the	O
course	O
of	O
forced	O
birth	O
assistance	O
(	O
'	O
spider	O
-	O
legs	O
'	O
,	O
dolichostenomelia	O
)	O
.	O

The	O
deformations	O
of	O
other	O
bones	O
of	O
the	O
legs	O
were	O
less	O
apparent	O
and	O
the	O
scapula	O
was	O
usually	O
unaffected	O
;	O
(	O
3	O
)	O
angular	O
deformations	O
of	O
the	O
distal	O
parts	O
of	O
the	O
legs	O
characterized	O
by	O
bilateral	O
stiff	O
and	O
hyperextended	O
fetlocks	O
with	O
the	O
extremity	O
of	O
the	O
toe	O
forward	O
and	O
parallel	O
to	O
the	O
trunk	O
of	O
the	O
body	O
;	O
and	O
(	O
4	O
)	O
defects	O
of	O
the	O
vertebral	O
column	O
(	O
kyphosis	O
and	O
scoliosis	O
)	O
,	O
but	O
not	O
of	O
the	O
ribs	O
(	O
Figure	O
3A	O
-	O
C	O
)	O
.	O

Additionally	O
,	O
inconsistent	O
pathological	O
findings	O
included	O
cerebral	O
herniation	O
combined	O
with	O
a	O
malformed	O
foramen	O
magnum	O
,	O
microphthalmia	O
,	O
and	O
external	O
and	O
internal	O
hydrocephalus	O
.	O

The	O
latter	O
seem	O
to	O
develop	O
secondarily	O
,	O
due	O
to	O
the	O
enlarged	O
foramen	O
magnum	O
.	O

Histological	O
examination	O
of	O
selected	O
cases	O
revealed	O
the	O
presence	O
of	O
hemorrhages	O
at	O
the	O
osteochondral	O
junction	O
of	O
the	O
epiphysis	O
and	O
an	O
abrupt	O
transmission	O
from	O
chondral	O
to	O
osteogenic	O
tissue	O
.	O

Cases	O
never	O
showed	O
isolated	O
malformations	O
,	O
e	O
.	O
g	O
.	O
of	O
the	O
head	O
or	O
legs	O
,	O
but	O
usually	O
a	O
combination	O
of	O
all	O
pathological	O
findings	O
that	O
are	O
characteristic	O
for	O
the	O
syndrome	O
.	O

Nevertheless	O
,	O
the	O
degree	O
of	O
the	O
lesions	O
ranged	O
from	O
obvious	O
spider	O
-	O
leg	O
cases	O
to	O
moderate	O
or	O
mild	O
changes	O
,	O
making	O
a	O
definite	O
diagnosis	O
difficult	O
.	O

The	O
latter	O
cases	O
(	O
3	O
)	O
were	O
excluded	O
from	O
the	O
initial	O
pedigree	O
analyses	O
.	O

Meanwhile	O
,	O
an	O
indirect	O
gene	O
test	O
is	O
available	O
that	O
has	O
been	O
developed	O
at	O
the	O
Institute	O
for	O
Animal	O
Breeding	O
of	O
the	O
Bavarian	O
State	O
Research	O
Centre	O
for	O
Agriculture	O
(	O
ITZ	O
)	O
and	O
it	O
could	O
be	O
shown	O
that	O
these	O
cases	O
are	O
most	O
probably	O
not	O
genetically	O
affected	O
(	O
Buitkamp	O
et	O
al	O
.	O
,	O
in	O
preparation	O
)	O
.	O

Carrier	O
identification	O

Two	O
criteria	O
were	O
used	O
for	O
carrier	O
identification	O
.	O

The	O
first	O
was	O
the	O
presence	O
of	O
a	O
calf	B
that	O
was	O
diagnosed	O
by	O
pathological	O
investigation	O
.	O

In	O
many	O
cases	O
more	O
than	O
one	O
affected	O
calf	B
per	O
sire	O
was	O
identified	O
[	O
8	O
]	O
.	O

Some	O
sires	O
had	O
only	O
one	O
affected	O
calf	B
,	O
but	O
a	O
large	O
number	O
of	O
risk	O
-	O
matings	O
.	O

In	O
these	O
cases	O
a	O
second	O
criterion	O
,	O
the	O
statistical	O
evaluation	O
of	O
risk	O
-	O
matings	O
,	O
was	O
used	O
to	O
identify	O
potential	O
phenocopies	O
.	O

For	O
this	O
purpose	O
,	O
the	O
probability	O
of	O
observing	O
only	O
a	O
single	O
affected	O
calf	B
among	O
a	O
certain	O
number	O
of	O
risk	O
-	O
matings	O
of	O
the	O
sire	O
in	O
question	O
was	O
calculated	O
.	O

Risk	O
-	O
matings	O
were	O
defined	O
as	O
matings	O
with	O
direct	O
progenies	O
of	O
identified	O
AS	O
carriers	O
.	O

The	O
probability	O
of	O
observing	O
an	O
affected	O
calf	B
depends	O
also	O
on	O
the	O
probability	O
that	O
such	O
a	O
calf	B
is	O
reported	O
to	O
the	O
LKV	O
.	O

We	O
assumed	O
this	O
probability	O
to	O
be	O
50	O
%	O
.	O

Under	O
these	O
conditions	O
,	O
the	O
probability	O
of	O
observing	O
only	O
one	O
affected	O
calf	B
is	O
lower	O
than	O
1	O
.	O
0	O
percent	O
,	O
if	O
at	O
least	O
104	O
risk	O
-	O
matings	O
are	O
given	O
for	O
a	O
single	O
sire	O
.	O

In	O
this	O
case	O
it	O
is	O
very	O
likely	O
that	O
the	O
single	O
affected	O
calf	B
is	O
a	O
phenocopy	O
.	O

In	O
2006	O
and	O
2007	O
this	O
was	O
the	O
case	O
for	O
two	O
sires	O
used	O
for	O
artificial	O
insemination	O
that	O
had	O
no	O
pedigree	O
connection	O
to	O
SEMPER	O
(	O
see	O
below	O
)	O
.	O

Experimental	O
matings	O
of	O
obligate	O
carriers	O

Four	O
out	O
of	O
seven	O
cows	B
that	O
were	O
known	O
AS	O
carriers	O
brought	O
to	O
the	O
facilities	O
of	O
the	O
ITZ	O
were	O
used	O
for	O
embryo	O
transfer	O
(	O
Table	O
1	O
)	O
.	O

33	O
of	O
the	O
60	O
recipients	O
(	O
55	O
%	O
)	O
were	O
confirmed	O
pregnant	O
on	O
day	O
35	O
.	O

Four	O
of	O
the	O
33	O
pregnant	O
heifers	O
(	O
12	O
%	O
)	O
aborted	O
between	O
days	O
36	O
and	O
49	O
of	O
pregnancy	O
.	O

Of	O
the	O
remaining	O
29	O
recipients	O
,	O
6	O
were	O
slaughtered	O
on	O
day	O
150	O
,	O
6	O
on	O
day	O
200	O
,	O
and	O
17	O
animals	O
on	O
day	O
225	O
of	O
pregnancy	O
(	O
Table	O
1	O
)	O
.	O

Four	O
fetuses	O
(	O
three	O
male	O
and	O
one	O
female	O
)	O
out	O
of	O
29	O
(	O
14	O
%	O
)	O
showed	O
the	O
typical	O
pathological	O
changes	O
of	O
the	O
arachnomelia	O
syndrome	O
as	O
described	O
above	O
(	O
Figure	O
4C	O
,	O
D	O
)	O
.	O

All	O
other	O
fetuses	O
showed	O
no	O
signs	O
of	O
AS	O
(	O
Figure	O
4A	O
,	O
B	O
)	O
.	O

Male	O
fetuses	O
represented	O
76	O
%	O
(	O
22	O
of	O
29	O
)	O
of	O
pregnancies	O
(	O
chi	O
2	O
=	O
3	O
.	O
123	O
,	O
p	O
=	O
0	O
.	O
077	O
,	O
Yates	O
corrected	O
for	O
sample	O
size	O
<	O
30	O
)	O
.	O

Female	O
weight	O
(	O
Table	O
2	O
)	O
,	O
crown	O
-	O
rump	O
length	O
at	O
day	O
225	O
and	O
chest	O
circumference	O
at	O
day	O
225	O
of	O
normal	O
fetuses	O
were	O
lower	O
than	O
that	O
of	O
male	O
fetuses	O
.	O

Fetuses	O
that	O
were	O
affected	O
by	O
the	O
arachnomelia	O
syndrome	O
showed	O
lower	O
weight	O
than	O
normal	O
fetuses	O
.	O

The	O
affected	O
and	O
the	O
normal	O
fetuses	O
had	O
similar	O
crown	O
-	O
rump	O
length	O
,	O
but	O
the	O
chest	O
circumference	O
of	O
affected	O
fetuses	O
was	O
higher	O
than	O
that	O
of	O
normal	O
fetuses	O
(	O
Table	O
2	O
)	O
.	O

Due	O
to	O
the	O
small	O
number	O
of	O
affected	O
female	O
fetuses	O
,	O
a	O
comparison	O
with	O
unaffected	O
animals	O
for	O
sex	O
was	O
not	O
possible	O
.	O

To	O
compare	O
unaffected	O
and	O
affected	O
animals	O
in	O
total	O
,	O
the	O
data	O
were	O
analyzed	O
for	O
statistical	O
differences	O
by	O
the	O
non	O
parametric	O
Mann	O
-	O
Whitney	O
-	O
Test	O
.	O

The	O
only	O
trait	O
that	O
was	O
significantly	O
different	O
between	O
unaffected	O
and	O
affected	O
fetuses	O
was	O
the	O
chest	O
circumference	O
(	O
p	O
=	O
0	O
.	O
004	O
,	O
Table	O
2	O
)	O
.	O

The	O
body	O
weight	O
of	O
AS	O
affected	O
calves	B
was	O
tendentially	O
lower	O
than	O
that	O
of	O
normal	O
calves	B
.	O

Since	O
affected	O
calves	B
did	O
not	O
have	O
different	O
crown	O
-	O
rump	O
-	O
length	O
and	O
their	O
chest	O
circumference	O
was	O
even	O
higher	O
,	O
this	O
can	O
best	O
be	O
explained	O
by	O
a	O
reduced	O
bone	O
mass	O
.	O

Pedigree	O
Analysis	O
and	O
mode	O
of	O
inheritance	O

Eight	O
-	O
generation	O
pedigrees	O
of	O
all	O
cases	O
were	O
extracted	O
from	O
the	O
joint	O
German	O
and	O
Austria	O
pedigree	O
data	O
and	O
screened	O
for	O
common	O
ancestors	O
.	O

The	O
pedigree	O
of	O
the	O
majority	O
of	O
affected	O
calves	B
(	O
paternal	O
line	O
150	O
,	O
maternal	O
line	O
106	O
out	O
of	O
152	O
,	O
Table	O
3	O
)	O
could	O
be	O
traced	O
back	O
to	O
one	O
founder	O
,	O
SEMPER	O
(	O
ISO	O
-	O
Nr	O
.	O
27000979299305	O
)	O
,	O
a	O
sire	O
born	O
in	O
1964	O
,	O
6	O
-	O
9	O
generations	O
before	O
the	O
affected	O
calves	B
were	O
born	O
(	O
Figure	O
2	O
)	O
.	O

Most	O
of	O
the	O
affected	O
calves	B
inherited	O
the	O
AS	O
mutation	O
via	O
REXON	O
or	O
EGEL	O
(	O
Table	O
3	O
,	O
Figure	O
2	O
)	O
.	O

In	O
44	O
cases	O
the	O
maternal	O
paths	O
were	O
not	O
linked	O
to	O
the	O
common	O
pedigree	O
(	O
Table	O
3	O
)	O
.	O

One	O
explanation	O
would	O
be	O
the	O
existence	O
of	O
additional	O
,	O
hereto	O
unknown	O
origins	O
of	O
the	O
mutation	O
.	O

This	O
could	O
happen	O
if	O
the	O
AS	O
mutation	O
is	O
much	O
more	O
ancient	O
and	O
additional	O
pedigree	O
paths	O
exist	O
or	O
if	O
an	O
independent	O
mutation	O
event	O
happened	O
leading	O
to	O
the	O
same	O
phenotype	O
.	O

An	O
alternative	O
,	O
more	O
plausible	O
explanation	O
could	O
be	O
the	O
occurrence	O
of	O
misparentages	O
.	O

It	O
is	O
well	O
known	O
that	O
in	O
the	O
pre	O
parentage	O
-	O
test	O
era	O
,	O
the	O
frequency	O
of	O
false	O
paternity	O
,	O
especially	O
of	O
the	O
cows	B
,	O
was	O
reasonable	O
high	O
(	O
up	O
to	O
23	O
%	O
[	O
9	O
]	O
)	O
.	O

Therefore	O
,	O
there	O
is	O
a	O
good	O
chance	O
of	O
a	O
false	O
registry	O
within	O
6	O
-	O
9	O
generations	O
.	O

There	O
is	O
strong	O
support	O
for	O
the	O
assumption	O
that	O
the	O
AS	O
is	O
regulated	O
by	O
a	O
single	O
autosomal	O
locus	O
acting	O
in	O
a	O
recessive	O
manner	O
.	O

First	O
of	O
all	O
,	O
the	O
pedigree	O
structure	O
of	O
the	O
affected	O
calves	B
in	O
Simmental	O
can	O
best	O
be	O
explained	O
by	O
a	O
recessive	O
mode	O
of	O
inheritance	O
.	O

The	O
paternal	O
branch	O
of	O
the	O
pedigree	O
could	O
be	O
traced	O
back	O
to	O
one	O
sire	O
,	O
SEMPER	O
,	O
for	O
all	O
affected	O
calves	B
,	O
the	O
maternal	O
branch	O
in	O
the	O
majority	O
of	O
the	O
cases	O
.	O

Inbreeding	O
loops	O
over	O
a	O
few	O
generations	O
are	O
present	O
in	O
several	O
pedigrees	O
of	O
affected	O
calves	B
,	O
e	O
.	O
g	O
.	O
cases	O
P3364	O
and	O
P1787	O
(	O
Figure	O
2	O
)	O
.	O

Sex	O
-	O
dependent	O
inheritance	O
can	O
obviously	O
be	O
excluded	O
and	O
a	O
dominant	O
mode	O
with	O
reduced	O
penetrance	O
seems	O
to	O
be	O
unlikely	O
.	O

Secondly	O
,	O
the	O
experimental	O
matings	O
resulted	O
in	O
4	O
affected	O
and	O
25	O
unaffected	O
fetuses	O
,	O
a	O
result	O
that	O
most	O
closely	O
resembles	O
the	O
expectation	O
of	O
a	O
recessive	O
mode	O
of	O
inheritance	O
.	O

Thirdly	O
,	O
the	O
occurrence	O
of	O
cases	O
corresponded	O
well	O
with	O
the	O
numbers	O
expected	O
under	O
the	O
assumption	O
of	O
a	O
recessively	O
acting	O
mutation	O
.	O

We	O
tested	O
this	O
on	O
the	O
progeny	O
of	O
ROMEL	O
,	O
the	O
largest	O
dataset	O
available	O
from	O
one	O
carrier	O
.	O

We	O
analyzed	O
the	O
period	O
from	O
the	O
beginning	O
of	O
the	O
recording	O
system	O
for	O
malformations	O
to	O
May	O
2007	O
.	O

In	O
that	O
period	O
44	O
,	O
170	O
calves	B
were	O
born	O
that	O
were	O
sired	O
by	O
ROMEL	O
.	O

From	O
these	O
,	O
662	O
were	O
considered	O
as	O
risk	O
pairings	O
,	O
i	O
.	O
e	O
.	O
the	O
mother	O
had	O
a	O
risk	O
of	O
0	O
.	O
5	O
to	O
be	O
a	O
carrier	O
(	O
i	O
.	O
e	O
.	O
one	O
of	O
the	O
grandparents	O
was	O
an	O
obligate	O
carrier	O
)	O
and	O
35	O
calves	B
out	O
of	O
these	O
were	O
diagnosed	O
as	O
affected	O
.	O

Since	O
it	O
is	O
expected	O
that	O
about	O
1	O
/	O
2	O
to	O
1	O
/	O
3	O
of	O
the	O
affected	O
calves	B
were	O
recorded	O
,	O
this	O
result	O
is	O
very	O
close	O
to	O
the	O
expected	O
1	O
:	O
7	O
ratio	O
of	O
affected	O
to	O
unaffected	O
calves	B
.	O

Moreover	O
,	O
these	O
findings	O
are	O
concordant	O
with	O
the	O
historical	O
description	O
of	O
the	O
arachnomelia	O
syndrome	O
in	O
Simmental	O
[	O
2	O
]	O
and	O
the	O
analyses	O
of	O
cases	O
in	O
Brown	O
Swiss	O
[	O
5	O
]	O
.	O

Finally	O
,	O
when	O
applying	O
linkage	O
analyses	O
using	O
microsatellite	O
markers	O
,	O
evaluations	O
with	O
a	O
model	O
assuming	O
recessive	O
autosomal	O
inheritance	O
gave	O
the	O
highest	O
lod	O
scores	O
(	O
Buitkamp	O
et	O
al	O
.	O
,	O
in	O
preparation	O
)	O
.	O

Allelic	O
frequency	O
of	O
carriers	O
in	O
the	O
present	O
Simmental	O
cow	B
population	O

Since	O
the	O
arachnomelia	O
syndrome	O
-	O
allele	O
was	O
passed	O
to	O
the	O
current	O
population	O
through	O
two	O
parental	O
lines	O
(	O
REXON	O
and	O
EGEL	O
)	O
and	O
the	O
main	O
carriers	O
are	O
known	O
,	O
it	O
is	O
possible	O
to	O
estimate	O
the	O
frequency	O
of	O
the	O
disease	O
allele	O
by	O
an	O
allele	O
-	O
counting	O
method	O
[	O
10	O
]	O
.	O

The	O
allelic	O
frequency	O
was	O
calculated	O
for	O
all	O
cows	B
from	O
the	O
breeding	O
population	O
who	O
were	O
alive	O
in	O
June	O
2007	O
.	O

In	O
10	O
.	O
4	O
percent	O
of	O
the	O
pedigrees	O
of	O
540	O
,	O
725	O
cows	B
an	O
identified	O
carrier	O
was	O
found	O
and	O
the	O
probability	O
that	O
individual	O
cows	B
were	O
carrier	O
of	O
the	O
arachnomelia	O
syndrome	O
-	O
allele	O
was	O
calculated	O
.	O

E	O
.	O
g	O
.	O
in	O
14	O
,	O
740	O
and	O
41	O
,	O
032	O
cases	O
a	O
known	O
carrier	O
appeared	O
as	O
sire	O
and	O
grandsire	O
,	O
respectively	O
.	O

In	O
these	O
cases	O
the	O
probability	O
of	O
transmitting	O
the	O
allele	O
is	O
50	O
and	O
25	O
percent	O
,	O
respectively	O
,	O
if	O
no	O
further	O
carrier	O
is	O
present	O
in	O
the	O
two	O
generation	O
pedigree	O
.	O

The	O
averaged	O
rate	O
of	O
the	O
arachnomelia	O
syndrome	O
carriers	O
based	O
on	O
known	O
carriers	O
over	O
all	O
cows	B
alive	O
in	O
Bavarian	O
Simmental	O
was	O
3	O
.	O
32	O
percent	O
.	O

Using	O
this	O
approach	O
,	O
the	O
frequency	O
of	O
carriers	O
was	O
calculated	O
for	O
each	O
year	O
(	O
always	O
based	O
on	O
the	O
actual	O
datasets	O
from	O
August	O
2008	O
)	O
from	O
2003	O
to	O
2008	O
(	O
Figure	O
1	O
)	O
.	O

The	O
calculations	O
were	O
done	O
twice	O
,	O
considering	O
all	O
known	O
carriers	O
together	O
,	O
and	O
also	O
by	O
using	O
only	O
ROMEL	O
as	O
a	O
carrier	O
to	O
show	O
the	O
numeric	O
contribution	O
of	O
his	O
progeny	O
(	O
Figure	O
1	O
)	O
.	O

For	O
these	O
analyses	O
,	O
the	O
sires	O
that	O
are	O
designated	O
to	O
be	O
non	O
-	O
carriers	O
by	O
the	O
number	O
of	O
risk	O
pairings	O
without	O
having	O
a	O
case	O
or	O
the	O
indirect	O
gene	O
test	O
are	O
set	O
as	O
non	O
-	O
carrier	O
.	O

Therefore	O
,	O
these	O
frequencies	O
are	O
slightly	O
lower	O
than	O
the	O
initial	O
frequency	O
estimate	O
of	O
3	O
.	O
32	O
percent	O
.	O

Conclusion	O

The	O
cases	O
of	O
malformed	O
Simmental	O
calves	B
presented	O
here	O
showed	O
the	O
same	O
morphology	O
described	O
in	O
the	O
arachnomelia	O
syndrome	O
in	O
Brown	O
Swiss	O
[	O
e	O
.	O
g	O
.	O
[	O
3	O
]	O
]	O
,	O
even	O
though	O
there	O
is	O
a	O
certain	O
morphological	O
variation	O
from	O
mild	O
to	O
severe	O
malformations	O
.	O

The	O
main	O
findings	O
,	O
brachygnathia	O
inferior	O
and	O
convex	O
frontal	O
bone	O
of	O
the	O
face	O
,	O
deformation	O
of	O
vertebrae	O
,	O
and	O
dysplasia	O
of	O
the	O
limbs	O
,	O
namely	O
the	O
diaphyses	O
of	O
metatarsus	O
and	O
-	O
carpus	O
and	O
the	O
fetlocks	O
,	O
can	O
best	O
be	O
explained	O
by	O
irregularly	O
developed	O
bone	O
structure	O
at	O
the	O
corresponding	O
locations	O
.	O

Without	O
pathological	O
examination	O
it	O
is	O
difficult	O
to	O
distinguish	O
the	O
arachnomelia	O
syndrome	O
from	O
other	O
malformations	O
of	O
the	O
limbs	O
.	O

Therefore	O
,	O
low	O
numbers	O
of	O
cases	O
in	O
Simmental	O
probably	O
passed	O
unrecognized	O
before	O
2005	O
.	O

In	O
that	O
year	O
the	O
allelic	O
frequency	O
of	O
the	O
disease	O
in	O
the	O
cow	B
population	O
increased	O
sharply	O
because	O
some	O
sires	O
that	O
had	O
been	O
carriers	O
of	O
the	O
mutation	O
had	O
become	O
very	O
popular	O
2	O
-	O
4	O
years	O
before	O
.	O

The	O
identification	O
of	O
a	O
common	O
ancestor	O
,	O
the	O
results	O
from	O
the	O
experimental	O
matings	O
and	O
the	O
analyses	O
of	O
numbers	O
of	O
cases	O
from	O
risk	O
matings	O
strongly	O
support	O
the	O
hypothesis	O
of	O
an	O
autosomal	O
recessively	O
inherited	O
disease	O
.	O

Furthermore	O
,	O
this	O
assumption	O
is	O
concordant	O
with	O
the	O
historical	O
description	O
of	O
the	O
syndrome	O
in	O
Simmental	O
and	O
Brown	O
Swiss	O
.	O

The	O
allelic	O
frequency	O
of	O
the	O
arachnomelia	O
syndrome	O
in	O
the	O
current	O
population	O
is	O
well	O
above	O
3	O
percent	O
and	O
a	O
substantial	O
number	O
of	O
progeny	O
from	O
known	O
carriers	O
with	O
superior	O
genetic	O
merit	O
shall	O
be	O
used	O
as	O
sires	O
during	O
the	O
next	O
years	O
.	O

Therefore	O
,	O
a	O
control	O
system	O
has	O
to	O
be	O
established	O
and	O
the	O
arachnomelia	O
syndrome	O
-	O
gene	O
should	O
be	O
mapped	O
as	O
a	O
prerequisite	O
for	O
the	O
development	O
of	O
an	O
indirect	O
gene	O
test	O
for	O
carrier	O
identification	O
.	O

The	O
availability	O
of	O
pathologically	O
well	O
characterized	O
cases	O
from	O
the	O
field	O
and	O
from	O
the	O
ET	O
-	O
generated	O
full	O
-	O
sib	O
families	O
will	O
be	O
an	O
excellent	O
material	O
for	O
a	O
genetic	O
mapping	O
procedure	O
.	O

Methods	O

Recording	O
system	O
for	O
congenital	O
malformations	O

A	O
system	O
for	O
monitoring	O
inherited	O
congenital	O
malformations	O
in	O
Bavarian	O
cattle	B
populations	O
was	O
established	O
by	O
the	O
Institute	O
for	O
Animal	O
Breeding	O
of	O
the	O
Bavarian	O
State	O
Research	O
Centre	O
for	O
Agriculture	O
(	O
ITZ	O
)	O
in	O
cooperation	O
with	O
the	O
Bavarian	O
milk	O
recording	O
organization	O
(	O
LKV	O
)	O
[	O
11	O
]	O
.	O

In	O
short	O
,	O
a	O
questionnaire	O
was	O
developed	O
for	O
detailed	O
recording	O
of	O
malformed	O
calves	B
.	O

The	O
malformation	O
was	O
described	O
according	O
to	O
its	O
location	O
(	O
e	O
.	O
g	O
.	O
head	O
,	O
legs	O
)	O
and	O
its	O
characteristics	O
(	O
e	O
.	O
g	O
.	O
hernia	O
)	O
.	O

The	O
standardized	O
data	O
were	O
stored	O
in	O
a	O
database	O
at	O
the	O
LKV	O
,	O
that	O
is	O
evaluated	O
monthly	O
for	O
a	O
potential	O
genetic	O
background	O
of	O
malformations	O
.	O

Sires	O
that	O
fit	O
into	O
the	O
pedigree	O
(	O
progeny	O
of	O
REXON	O
or	O
EGEL	O
)	O
with	O
at	O
least	O
one	O
affected	O
calf	B
with	O
confirmed	O
paternity	O
were	O
defined	O
as	O
obligate	O
carriers	O
and	O
marked	O
in	O
the	O
breeding	O
information	O
system	O
[	O
7	O
]	O
.	O

In	O
cases	O
without	O
connection	O
to	O
the	O
pedigree	O
and	O
only	O
one	O
recorded	O
calf	B
the	O
number	O
of	O
"	O
risk	O
pairings	O
"	O
(	O
matings	O
to	O
cows	B
where	O
at	O
least	O
one	O
parent	O
is	O
a	O
known	O
carrier	O
,	O
enabling	O
the	O
calculation	O
of	O
the	O
probability	O
for	O
the	O
occurrence	O
of	O
cases	O
)	O
was	O
calculated	O
.	O

When	O
the	O
probability	O
that	O
a	O
case	O
occurs	O
was	O
above	O
99	O
%	O
for	O
the	O
sire	O
in	O
question	O
the	O
case	O
was	O
considered	O
to	O
be	O
a	O
phenocopy	O
.	O

The	O
number	O
of	O
calves	B
affected	O
by	O
the	O
arachnomelia	O
syndrome	O
and	O
their	O
parentage	O
is	O
routinely	O
published	O
[	O
8	O
]	O
.	O

Pathological	O
examinations	O

Pathological	O
examinations	O
followed	O
standard	O
procedures	O
.	O

Calves	B
were	O
photographed	O
and	O
size	O
and	O
weight	O
measurements	O
were	O
recorded	O
.	O

Tissue	O
specimens	O
from	O
the	O
condyle	O
(	O
epiphysis	O
)	O
and	O
from	O
the	O
diaphysis	O
of	O
the	O
femur	O
were	O
collected	O
for	O
histological	O
examination	O
.	O

Specimens	O
were	O
fixed	O
in	O
10	O
%	O
formalin	O
and	O
kept	O
in	O
a	O
decalcifying	O
solution	O
(	O
Ossafixonafor	O
)	O
for	O
24	O
hours	O
.	O

Thereafter	O
,	O
specimens	O
were	O
processed	O
in	O
an	O
automated	O
embedding	O
system	O
,	O
sectioned	O
at	O
4	O
-	O
6	O
microns	O
and	O
finally	O
stained	O
with	O
haematoxyline	O
and	O
eosin	O
.	O

Experimental	O
matings	O
and	O
embryo	O
transfer	O

Known	O
carriers	O
of	O
the	O
arachnomelia	O
syndrome	O
(	O
seven	O
cows	B
that	O
had	O
produced	O
at	O
least	O
one	O
affected	O
calf	B
)	O
were	O
brought	O
to	O
the	O
facilities	O
of	O
the	O
ITZ	O
for	O
embryo	O
transfer	O
(	O
Table	O
1	O
)	O
.	O

Late	O
morulae	O
and	O
blastocysts	O
collected	O
on	O
day	O
7	O
(	O
day	O
0	O
=	O
estrus	O
)	O
from	O
superovulated	O
donor	O
cows	B
were	O
nonsurgically	O
transferred	O
to	O
heifers	O
[	O
12	O
]	O
.	O

Mode	O
of	O
inheritance	O
and	O
allele	O
frequency	O

The	O
pedigree	O
of	O
all	O
cases	O
was	O
constructed	O
from	O
the	O
pedigree	O
that	O
is	O
used	O
for	O
the	O
joint	O
breeding	O
evaluation	O
of	O
Germany	O
and	O
Austria	O
.	O

The	O
graphical	O
presentation	O
of	O
the	O
pedigree	O
was	O
performed	O
with	O
the	O
Pedigraph	O
TM	O
software	O
[	O
13	O
]	O
.	O

The	O
allelic	O
frequency	O
of	O
the	O
AS	O
mutation	O
in	O
the	O
current	O
cow	B
population	O
was	O
estimated	O
from	O
ancestors	O
with	O
known	O
genotypes	O
following	O
the	O
allele	O
-	O
counting	O
method	O
[	O
10	O
]	O
.	O

For	O
this	O
reason	O
two	O
generation	O
pedigrees	O
of	O
herd	O
book	O
cows	B
in	O
Bavarian	O
Simmental	O
were	O
analyzed	O
for	O
obligate	O
carriers	O
.	O

We	O
considered	O
all	O
cows	B
that	O
were	O
alive	O
in	O
June	O
2007	O
and	O
included	O
in	O
the	O
herd	O
book	O
.	O

All	O
animals	O
were	O
bred	O
by	O
the	O
use	O
of	O
artificial	O
insemination	O
.	O

Statistical	O
analyses	O

The	O
non	O
parametric	O
Mann	O
-	O
Whitney	O
-	O
Test	O
was	O
performed	O
using	O
SPSS	O
Version	O
14	O
.	O
0	O
,	O
the	O
Chi	O
-	O
square	O
test	O
was	O
performed	O
using	O
R	O
2	O
.	O
4	O
.	O
0	O
[	O
14	O
]	O
.	O

Authors	O
'	O
contributions	O

JB	O
drafted	O
the	O
manuscript	O
and	O
analyzed	O
the	O
pedigrees	O
.	O

BL	O
conceived	O
the	O
monitoring	O
system	O
for	O
inherited	O
diseases	O
.	O

RE	O
extracted	O
the	O
data	O
from	O
the	O
database	O
and	O
estimated	O
the	O
allelic	O
frequencies	O
of	O
the	O
arachnomelia	O
syndrome	O
.	O

HR	O
and	O
MW	O
performed	O
the	O
embryo	O
collection	O
,	O
transfer	O
and	O
recorded	O
the	O
morpho	O
-	O
metrical	O
data	O
of	O
the	O
experimental	O
matings	O
.	O

BS	O
examined	O
the	O
calves	B
pathologically	O
.	O

NM	O
and	O
KG	O
participated	O
in	O
study	O
design	O
and	O
coordination	O
and	O
critically	O
revised	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Suggestions	O
Concerning	O
the	O
Use	O
of	O
the	O
Subclavian	O
which	O
Arises	O
from	O
the	O
Aorta	O
in	O
the	O
Treatment	O
of	O
the	O
Tetralogy	O
of	O
Fallot	O
*	O

Abstract	O

Images	O

SUGGESTIONS	O
CONCERNING	O
THE	O
USE	O
OF	O
THE	O
SUBCLAVIAN	O

WHICH	O
ARISES	O
FROM	O
THE	O
AORTA	O
IN	O
THE	O
TREATMENT	O

OF	O
THE	O
TETRALOGY	O
OF	O
FALLOT	O
*	O

HARRIS	O
B	O
.	O

SHUMACKER	O
,	O
JR	O
.	O
*	O
*	O

In	O
Blalock	O
'	O
s	O
early	O
experience	O
with	O
the	O
operative	O
treatment	O
of	O
the	O
tetralogy	O
of	O
Fallot	O
,	O
the	O
two	O
subclavian	O
,	O
the	O
innominate	O
,	O
and	O
carotid	O
arteries	O
were	O
all	O
used	O
for	O
anastomosis	O
to	O
the	O
pulmonary	O
artery	O
.	O

Soon	O
,	O
however	O
,	O
it	O
became	O
evident	O
that	O
use	O
of	O
the	O
innominate	O
or	O
carotid	O
was	O
followed	O
by	O
a	O
relatively	O
high	O
incidence	O
of	O
complications	O
resulting	O
from	O
cerebral	O
ischemia	O
.	O

Blalock	O
suggested	O
,	O
therefore	O
,	O
that	O
the	O
subclavian	O
be	O
used	O
by	O
preference	O
.	O

The	O
subclavian	O
branch	O
of	O
the	O
innominate	O
does	O
not	O
become	O
kinked	O
or	O
badly	O
angulated	O
when	O
it	O
is	O
turned	O
down	O
for	O
the	O
anastomosis	O
,	O
and	O
a	O
good	O
functional	O
result	O
almost	O
invariably	O
follows	O
the	O
completion	O
of	O
a	O
satisfactory	O
anastomosis	O
.	O

The	O
subclavian	O
which	O
arises	O
directly	O
from	O
the	O
aorta	O
,	O
on	O
the	O
other	O
hand	O
,	O
tends	O
to	O
form	O
a	O
bad	O
angle	O
when	O
it	O
is	O
brought	O
down	O
for	O
the	O
anastomosis	O
,	O
and	O
,	O
indeed	O
,	O
near	O
its	O
point	O
of	O
origin	O
it	O
may	O
be	O
so	O
flattened	O
out	O
against	O
the	O
relatively	O
rigid	O
aortic	O
wall	O
as	O
to	O
obstruct	O
all	O
blood	O
flow	O
through	O
it	O
.	O

These	O
considerations	O
led	O
Blalock	O
to	O
recommend	O
the	O
use	O
of	O
the	O
former	O
except	O
in	O
infants	B
under	O
two	O
years	O
of	O
age	O
in	O
whom	O
this	O
artery	O
may	O
be	O
too	O
small	O
and	O
in	O
adults	O
or	O
children	B
over	O
twelve	O
years	O
old	O
or	O
five	O
feet	O
tall	O
with	O
a	O
left	O
aortic	O
arch	O
in	O
whom	O
it	O
is	O
often	O
too	O
short	O
to	O
permit	O
a	O
satisfactory	O
anastomosis	O
.	O
7	O
'	O

In	O
contrast	O
,	O
Paine	O
and	O
Varco	O
,	O
'	O
Lam	O
,	O
6	O
Holman	O
,	O
'	O
Olim	O
,	O
7	O
and	O
others	O
have	O
preferred	O
to	O
use	O
the	O
subclavian	O
which	O
arises	O
from	O
the	O
aorta	O
and	O
have	O
obtained	O
generally	O
excellent	O
results	O
.	O

They	O
point	O
out	O
that	O
the	O
tendency	O
to	O
kinking	O
of	O
the	O
artery	O
is	O
more	O
a	O
theoretical	O
than	O
a	O
practical	O
disadvantage	O
,	O
that	O
the	O
exposure	O
and	O
dissection	O
of	O
both	O
the	O
pulmonary	O
artery	O
and	O
the	O
subclavian	O
are	O
easier	O
on	O
the	O
side	O
of	O
the	O
aortic	O
arch	O
,	O
that	O
both	O
vessels	O
are	O
generally	O
longer	O
than	O
on	O
the	O
opposite	O
side	O
and	O
that	O
,	O
as	O
a	O
general	O
rule	O
,	O
the	O
anastomosis	O
can	O
be	O
accomplished	O
more	O
readily	O
.	O

The	O
practical	O
usefulness	O
of	O
a	O
third	O
systemic	O
vessel	O
,	O
namely	O
the	O
aorta	O
,	O
was	O
demonstrated	O
by	O
the	O
development	O
of	O
a	O
technique	O
for	O
side	O
-	O
to	O
-	O
side	O
aortic	O
pulmonary	O
anastomosis	O
by	O
Potts	O
and	O
his	O
associates	O
.	O
"	O
0	O
In	O
spite	O
of	O
the	O
preferences	O
held	O
by	O
individual	O
operators	O
for	O
use	O
of	O
one	O
vessel	O
or	O
another	O
,	O
the	O
fact	O
remains	O
,	O
as	O
Blalock	O
has	O
emphasized	O
,	O
that	O
there	O
is	O
always	O
present	O
a	O
usable	O
systemic	O
vessel	O
provided	O
a	O
suitable	O
pulmonary	O
artery	O
is	O
available	O
.	O

Nevertheless	O
,	O
the	O
choice	O
of	O
the	O
systemic	O
artery	O
in	O
each	O
individual	O
patient	B
is	O
important	O
since	O
in	O
certain	O
cases	O
one	O
or	O
another	O
is	O
unsuitable	O
.	O

*	O
From	O
the	O
Department	O
of	O
Surgery	O
,	O
the	O
Indiana	O
University	O
Medical	O
Center	O
,	O
Indianapolis	O
,	O
Indiana	O
.	O

Aided	O
by	O
a	O
contract	O
between	O
the	O
Office	O
of	O
Naval	O
Research	O
,	O
Department	O
of	O
the	O
Navy	O
,	O
and	O
Indiana	O
University	O
.	O

*	O
*	O
Resident	O
Surgeon	O
,	O
New	O
Haven	O
Hospital	O
,	O
1937	O
-	O
1938	O
.	O

Received	O
for	O
publication	O
April	O
26	O
,	O
1951	O
.	O

TREATMENT	O
OF	O
TETRALOGY	O
OF	O
FALLOT	O

It	O
has	O
been	O
my	O
custom	O
to	O
follow	O
a	O
policy	O
rather	O
similar	O
to	O
that	O
outlined	O
by	O
Blalock	O
.	O

The	O
subclavian	O
branch	O
of	O
the	O
innominate	O
has	O
generally	O
been	O
preferred	O
in	O
patients	B
ranging	O
between	O
two	O
and	O
twelve	O
years	O
of	O
age	O
and	O
in	O
older	O
individuals	O
in	O
whom	O
there	O
is	O
a	O
right	O
aortic	O
arch	O
.	O

In	O
others	O
the	O
thoracotomy	O
is	O
usually	O
made	O
on	O
the	O
side	O
of	O
the	O
aortic	O
arch	O
,	O
and	O
either	O
the	O
aorta	O
itself	O
or	O
the	O
subclavian	O
arising	O
from	O
the	O
aorta	O
is	O
used	O
for	O
the	O
anastomosis	O
.	O

My	O
experience	O
with	O
the	O
use	O
of	O
the	O
subclavian	O
originating	O
from	O
the	O
aorta	O
is	O
small	O
and	O
the	O
results	O
have	O
not	O
been	O
as	O
good	O
as	O
those	O
which	O
others	O
have	O
reported	O
.	O

One	O
eighteen	O
-	O
month	O
-	O
old	O
child	B
died	O
the	O
day	O
after	O
operation	O
and	O
was	O
found	O
at	O
post	O
-	O
mortem	O
examination	O
to	O
have	O
an	O
occluded	O
anastomosis	O
.	O

In	O
one	O
three	O
-	O
year	O
-	O
old	O
child	B
and	O
one	O
twenty	O
-	O
year	O
-	O
old	O
woman	B
a	O
poor	O
result	O
was	O
obtained	O
and	O
a	O
second	O
operation	O
upon	O
the	O
other	O
side	O
was	O
necessary	O
.	O

In	O
two	O
additional	O
cases	O
the	O
result	O
was	O
only	O
fair	O
.	O

Excluding	O
the	O
patients	B
mentioned	O
in	O
the	O
present	O
report	O
,	O
only	O
in	O
two	O
was	O
an	O
unquestionably	O
good	O
result	O
obtained	O
.	O

Recently	O
,	O
in	O
several	O
cases	O
in	O
which	O
failure	O
seemed	O
evident	O
a	O
modification	O
has	O
been	O
required	O
in	O
order	O
to	O
obtain	O
a	O
functioning	O
shunt	O
.	O

Since	O
these	O
modifications	O
proved	O
successful	O
and	O
since	O
these	O
threats	O
of	O
failure	O
tax	O
one	O
'	O
s	O
ingenuiity	O
at	O
the	O
time	O
of	O
operation	O
,	O
I	O
have	O
thought	O
it	O
might	O
be	O
helpful	O
to	O
describe	O
the	O
procedures	O
employed	O
and	O
to	O
illustrate	O
them	O
with	O
case	O
reports	O
.	O

One	O
is	O
a	O
method	O
which	O
obviously	O
has	O
very	O
limited	O
applicability	O
,	O
while	O
the	O
otlher	O
would	O
seem	O
to	O
be	O
rather	O
generally	O
applicable	O
.	O

The	O
first	O
consists	O
of	O
the	O
transplantation	O
of	O
the	O
origin	O
of	O
the	O
subclavian	O
to	O
a	O
more	O
suitable	O
portion	O
of	O
the	O
aorta	O
.	O

Case	O
report	O

The	O
patient	B
was	O
a	O
19	O
-	O
year	O
-	O
old	O
girl	B
who	O
had	O
been	O
cyanotic	O
since	O
the	O
age	O
of	O
six	O
months	O
.	O

She	O
had	O
developed	O
normally	O
but	O
was	O
always	O
limited	O
in	O
exercise	O
capacity	O
.	O

In	O
her	O
early	O
years	O
of	O
school	O
she	O
was	O
taken	O
to	O
school	O
by	O
her	O
parents	O
and	O
carried	O
to	O
and	O
from	O
her	O
seat	O
in	O
the	O
classroom	O
.	O

She	O
did	O
reasonably	O
well	O
in	O
high	O
school	O
,	O
being	O
driven	O
to	O
and	O
from	O
the	O
school	O
,	O
but	O
she	O
got	O
into	O
severe	O
difficulty	O
when	O
she	O
attempted	O
to	O
attend	O
college	O
.	O

The	O
longer	O
distances	O
between	O
classes	O
and	O
the	O
necessity	O
for	O
climbing	O
stairs	O
precipitated	O
a	O
downhill	O
course	O
,	O
with	O
increasing	O
dyspnea	O
,	O
more	O
marked	O
cyanosis	O
and	O
fatigue	O
,	O
and	O
the	O
onset	O
of	O
bouts	O
of	O
loss	O
of	O
consciousness	O
.	O

The	O
latter	O
occurred	O
several	O
times	O
daily	O
.	O

One	O
which	O
was	O
witnessed	O
by	O
her	O
physician	O
lasted	O
45	O
minutes	O
;	O
he	O
feared	O
it	O
would	O
prove	O
fatal	O
.	O

Ordinarily	O
,	O
she	O
could	O
not	O
walk	O
more	O
than	O
half	O
a	O
block	O
.	O

There	O
was	O
marked	O
cyanosis	O
of	O
the	O
nails	O
and	O
mucous	O
membranes	O
and	O
to	O
a	O
lesser	O
extent	O
of	O
the	O
skin	O
.	O

Clubbing	O
was	O
very	O
prominent	O
.	O

All	O
the	O
results	O
of	O
physical	O
and	O
laboratory	O
examination	O
fitted	O
in	O
with	O
a	O
diagnosis	O
of	O
tetralogy	O
of	O
Fallot	O
.	O

The	O
hematocrit	O
ranged	O
between	O
83	O
and	O
90	O
.	O

Oxygen	O
saturation	O
of	O
arterial	O
blood	O
was	O
65	O
per	O
cent	O
at	O
complete	O
rest	O
.	O

The	O
aortic	O
arch	O
was	O
on	O
the	O
left	O
side	O
.	O

On	O
October	O
26	O
,	O
1949	O
a	O
left	O
lateral	O
thoracotomy	O
was	O
performed	O
,	O
the	O
pleural	O
cavity	O
being	O
entered	O
through	O
the	O
bed	O
of	O
the	O
fifth	O
rib	O
.	O

There	O
was	O
evident	O
greatly	O
increased	O
collateral	O
circulation	O
in	O
the	O
mediastinum	O
and	O
hilum	O
.	O

The	O
pulmonary	O
artery	O
appeared	O
to	O
have	O
markedly	O
reduced	O
blood	O
flow	O
,	O
was	O
very	O
short	O
,	O
small	O
,	O
and	O
thin	O
-	O
walled	O
.	O

Its	O
diameter	O
was	O
less	O
than	O
5	O
mm	O
.	O

The	O
aorta	O
seemed	O
to	O
be	O
bowed	O
out	O
laterally	O
in	O
an	O
unusual	O
fashion	O
and	O
the	O
short	O
pulmonary	O
artery	O
could	O
not	O
possibly	O
be	O
brought	O
out	O
over	O
it	O
.	O

The	O
subclavian	O
artery	O
was	O
relatively	O
small	O
,	O
having	O

487	O

YALE	O
JOURNAL	O
OF	O
BIOLOGY	O
AND	O
MEDICINE	O

a	O
diameter	O
of	O
only	O
about	O
4	O
mm	O
.	O
but	O
it	O
seemed	O
rather	O
long	O
.	O

It	O
was	O
apparent	O
that	O
a	O
Pott	O
'	O
s	O
procedure	O
was	O
impossible	O
and	O
that	O
an	O
end	O
-	O
to	O
-	O
side	O
subclavian	O
pulmonary	O
artery	O
anastomosis	O
would	O
be	O
doomed	O
to	O
failure	O
.	O

Hence	O
,	O
the	O
subclavian	O
artery	O
was	O
divided	O
at	O
the	O
level	O
of	O
its	O
first	O
branch	O
,	O
the	O
pulmonary	O
artery	O
was	O
divided	O
proximally	O
,	O
and	O
an	O
end	O
-	O
to	O
-	O
end	O
subclavian	O
-	O
pulmonary	O
anastomosis	O
was	O
carried	O
out	O
.	O

This	O
was	O
done	O
with	O
ease	O
.	O

When	O
the	O
clamps	O
were	O
removed	O
,	O
however	O
,	O
no	O
blood	O
flowed	O
through	O
it	O
.	O

The	O
softwalled	O
subclavian	O
was	O
completely	O
flattened	O
out	O
against	O
the	O
relatively	O
rigid	O
aorta	O
(	O
Fig	O
.	O
1	O
)	O
.	O

When	O
the	O
hilar	O
structures	O
were	O
forcibly	O
elevated	O
in	O
a	O
cephalad	O
direction	O
the	O
subclavian	O
immediately	O
filled	O
and	O
pulsated	O
normally	O
and	O
a	O
thrill	O
could	O
be	O
felt	O
.	O

Simple	O
expansion	O
of	O
the	O
lungs	O
,	O
however	O
,	O
failed	O
to	O
achieve	O
this	O
result	O
and	O
I	O
could	O
conceive	O
of	O
no	O
way	O
in	O
which	O
the	O
hilar	O
region	O
could	O
be	O
held	O
in	O
a	O
more	O
cephalad	O
direction	O
.	O

The	O
subclavian	O
was	O
then	O
ligated	O
at	O
the	O
point	O
where	O
it	O
came	O
off	O
the	O
aorta	O
and	O
its	O
proximal	O
end	O
was	O
anastomosed	O
end	O
-	O
to	O
-	O
side	O
to	O
the	O
descending	O
aorta	O
.	O

It	O
now	O
pulsated	O
vigorously	O
as	O
did	O
the	O
pulmonary	O
artery	O
.	O

In	O
spite	O
of	O
the	O
good	O
pulsation	O
no	O
thrill	O
was	O
palpable	O
.	O

The	O
patient	B
had	O
an	O
uneventful	O
but	O
disappointing	O
convalescence	O
.	O

She	O
remained	O
markedly	O
cyanotic	O
and	O
no	O
continuous	O
bruit	O
was	O
audible	O
.	O

When	O
she	O
left	O
the	O
hospital	O
14	O
days	O
after	O
operation	O
there	O
was	O
no	O
improvement	O
in	O
her	O
appearance	O
,	O
hematocrit	O
,	O
or	O
arterial	O
oxygen	O
saturation	O
.	O

Surprisingly	O
enough	O
she	O
reported	O
progress	O
on	O
each	O
follow	O
-	O
up	O
examination	O
.	O

By	O
the	O
end	O
of	O
seven	O
weeks	O
she	O
was	O
obviously	O
less	O
cyanotic	O
,	O
her	O
hematocrit	O
was	O
77	O
,	O
and	O
she	O
was	O
able	O
to	O
walk	O
a	O
number	O
of	O
blocks	O
and	O
to	O
climb	O
a	O
flight	O
of	O
stairs	O
without	O
difficulty	O
.	O

She	O
reported	O
that	O
she	O
had	O
danced	O
and	O
roller	O
-	O
skated	O
without	O
much	O
trouble	O
.	O

Shortly	O
thereafter	O
a	O
continuous	O
murmur	O
was	O
audible	O
in	O
the	O
left	O
chest	O
.	O

She	O
continued	O
to	O
improve	O
and	O
in	O
January	O
entered	O
a	O
southern	O
college	O
.	O

She	O
did	O
well	O
.	O

At	O
least	O
once	O
a	O
day	O
,	O
often	O
twice	O
,	O
she	O
walked	O
without	O
difficulty	O
from	O
the	O
campus	O
into	O
town	O
and	O
back	O
,	O
a	O
distance	O
of	O
ten	O
blocks	O
each	O
way	O
.	O

She	O
played	O
a	O
little	O
tennis	O
,	O
learned	O
to	O
swim	O
,	O
and	O
began	O
to	O
dance	O
,	O
including	O
jitterbugging	O
.	O

When	O
she	O
xvas	O
seen	O
in	O
June	O
,	O
her	O
color	O
was	O
good	O
,	O
although	O
there	O
was	O
still	O
slight	O
cyanosis	O
of	O
lips	O
and	O
nail	O
beds	O
.	O

There	O
was	O
a	O
very	O
loud	O
,	O
continuous	O
murmur	O
in	O
the	O
left	O
chest	O
.	O

The	O
following	O
fall	O
she	O
transferred	O
to	O
a	O
midwestern	O
university	O
.	O

She	O
got	O
along	O
reasonably	O
well	O
but	O
not	O
as	O
well	O
as	O
she	O
had	O
in	O
a	O
warmer	O
climate	O
and	O
on	O
more	O
level	O
terrain	O
.	O

She	O
walked	O
four	O
or	O
five	O
blocks	O
up	O
and	O
down	O
hills	O
between	O
classes	O
without	O
difficulty	O
in	O
good	O
weather	O
but	O
complained	O
of	O
some	O
dyspnea	O
and	O
fatigue	O
on	O
cold	O
,	O
windy	O
days	O
.	O

She	O
attended	O
dances	O
and	O
often	O
danced	O
each	O
number	O
throughout	O
the	O
evening	O
without	O
trouble	O
.	O

When	O
seen	O
in	O
December	O
she	O
looked	O
well	O
.	O

Her	O
color	O
was	O
good	O
and	O
clubbing	O
was	O
definitely	O
less	O
marked	O
than	O
it	O
had	O
been	O
previously	O
.	O

She	O
had	O
a	O
severe	O
cold	O
at	O
the	O
time	O
.	O

Her	O
oxygen	O
saturation	O
of	O
arterial	O
blood	O
was	O
75	O
per	O
cent	O
at	O
rest	O
and	O
it	O
did	O
not	O
fall	O
when	O
she	O
stood	O
or	O
still	O
-	O
walked	O
.	O

The	O
hematocrit	O
was	O
69	O
.	O

There	O
was	O
audible	O
the	O
same	O
loud	O
continuous	O
murmur	O
in	O
the	O
left	O
chest	O
.	O

Though	O
the	O
patient	B
has	O
been	O
markedly	O
improved	O
,	O
it	O
is	O
recognized	O
that	O
the	O
result	O
is	O
not	O
as	O
good	O
as	O
is	O
commonly	O
obtained	O
when	O
patients	B
with	O
more	O
adequate	O
pulmonary	O
arteries	O
are	O
treated	O
by	O
the	O
conventional	O
anastomosis	O
of	O
a	O
systemic	O
artery	O
to	O
the	O
side	O
of	O
the	O
pulmonary	O
artery	O
.	O

Nevertheless	O
,	O
the	O
patient	B
has	O
thus	O
far	O
been	O
given	O
such	O
good	O
health	O
and	O
relatively	O
normal	O
capacity	O
for	O
ordinary	O
activity	O
that	O
further	O
operation	O
has	O
seemed	O
unwarranted	O
,	O
though	O
the	O
possibility	O
of	O
some	O
future	O
attempt	O
at	O
creation	O
of	O
an	O
additional	O
shunt	O
is	O
being	O
kept	O
in	O
mind	O
.	O

The	O
second	O
procedure	O
embodies	O
the	O
cephalad	O
transplantation	O
of	O
the	O
pulmonary	O
artery	O
by	O
a	O
plastic	O
repair	O
of	O
the	O
incision	O
in	O
the	O
hilar	O
and	O
mediastinal	O
pleural	O
structures	O
.	O

488	O

FIG	O
.	O

1	O
.	O

Drawing	O
illustrating	O
the	O
condition	O
which	O
existed	O
in	O
the	O
first	O
case	O
after	O
completion	O
of	O
the	O
anastomosis	O
(	O
A	O
)	O
and	O
its	O
correction	O
by	O
transplantation	O
of	O
the	O
origin	O
of	O
the	O
subclavian	O
(	O
B	O
)	O
.	O

FIG	O
.	O

2	O
.	O

Drawing	O
illustrating	O
correction	O
of	O
obstruction	O
to	O
blood	O
flow	O
through	O
the	O
subclavian	O
artery	O
by	O
inverted	O
T	O
or	O
L	O
plastic	O
closure	O
of	O
the	O
defect	O
in	O
the	O
hilar	O
and	O
mediastinal	O
structures	O
.	O

TREATMENT	O
OF	O
TETRALOGY	O
OF	O
FALLOT	O

Case	O
reports	O

The	O
first	O
patient	B
was	O
a	O
fully	O
grown	O
young	O
man	B
of	O
17	O
with	O
tetralogy	O
of	O
Fallot	O
which	O
caused	O
considerable	O
incapacity	O
.	O

He	O
was	O
admitted	O
to	O
the	O
hospital	O
on	O
July	O
18	O
,	O
1950	O
and	O
was	O
operated	O
upon	O
two	O
days	O
later	O
.	O

He	O
was	O
known	O
to	O
have	O
a	O
left	O
aortic	O
arch	O
,	O
and	O
a	O
left	O
lateral	O
thoracotomy	O
was	O
performed	O
.	O

The	O
aorta	O
was	O
freed	O
for	O
a	O
side	O
-	O
to	O
-	O
side	O
anastomosis	O
with	O
the	O
pulmonary	O
artery	O
.	O

So	O
much	O
difficulty	O
was	O
encountered	O
,	O
however	O
,	O
in	O
placing	O
the	O
aortic	O
clamp	O
in	O
proper	O
position	O
for	O
making	O
a	O
satisfactory	O
incision	O
in	O
the	O
aorta	O
that	O
the	O
procedure	O
was	O
abandoned	O
and	O
an	O
end	O
-	O
to	O
-	O
side	O
subclavian	O
-	O
pulmonary	O
artery	O
anastomosis	O
accomplished	O
instead	O
.	O

The	O
pulmonary	O
artery	O
was	O
of	O
fair	O
size	O
,	O
having	O
an	O
estimated	O
diameter	O
of	O
1	O
cm	O
.	O

The	O
subclavian	O
artery	O
appeared	O
to	O
be	O
quite	O
long	O
and	O
it	O
was	O
of	O
very	O
satisfactory	O
size	O
,	O
having	O
a	O
diameter	O
of	O
about	O
6	O
mm	O
.	O

To	O
my	O
dismay	O
,	O
the	O
first	O
portion	O
of	O
the	O
soft	O
-	O
walled	O
subclavian	O
artery	O
was	O
completely	O
flattened	O
out	O
against	O
the	O
rather	O
rigid	O
wall	O
of	O
the	O
aorta	O
and	O
no	O
blood	O
flow	O
through	O
it	O
could	O
be	O
demonstrated	O
,	O
there	O
being	O
no	O
subclavian	O
pulsation	O
nor	O
thrill	O
in	O
the	O
pulmonary	O
artery	O
.	O

If	O
one	O
forcefully	O
elevated	O
the	O
hilum	O
of	O
the	O
lung	O
in	O
a	O
cephalad	O
direction	O
,	O
the	O
obstruction	O
disappeared	O
,	O
the	O
subclavian	O
artery	O
began	O
to	O
pulsate	O
,	O
and	O
a	O
thrill	O
could	O
be	O
palpated	O
.	O

When	O
the	O
lung	O
was	O
allowed	O
to	O
assume	O
its	O
usual	O
position	O
,	O
the	O
subclavian	O
obstruction	O
was	O
again	O
evident	O
and	O
could	O
not	O
be	O
prevented	O
by	O
full	O
expansion	O
of	O
the	O
lung	O
.	O

It	O
was	O
found	O
that	O
the	O
hilar	O
region	O
and	O
the	O
pulmonary	O
artery	O
could	O
be	O
maintained	O
in	O
a	O
satisfactory	O
cephalad	O
position	O
by	O
traction	O
upward	O
upon	O
the	O
cuff	O
of	O
hilar	O
pleura	O
and	O
the	O
adjacent	O
vascular	O
sheath	O
and	O
that	O
these	O
structures	O
were	O
sufficiently	O
strong	O
so	O
that	O
traction	O
could	O
be	O
maintained	O
upon	O
them	O
with	O
a	O
small	O
hemostat	O
.	O

The	O
defect	O
in	O
the	O
mediastinal	O
and	O
hilar	O
tissues	O
was	O
then	O
repaired	O
using	O
a	O
sort	O
of	O
inverted	O
T	O
-	O
plastic	O
closure	O
.	O

By	O
this	O
maneuver	O
success	O
was	O
achieved	O
in	O
elevating	O
the	O
pulmonary	O
artery	O
in	O
a	O
cephalad	O
direction	O
so	O
that	O
the	O
subclavian	O
obstruction	O
was	O
relieved	O
and	O
excellent	O
pulsation	O
was	O
evident	O
(	O
Fig	O
.	O
2B	O
)	O
.	O

A	O
fairly	O
good	O
continuous	O
thrill	O
was	O
palpable	O
.	O

The	O
patient	B
had	O
an	O
uneventful	O
convalescence	O
.	O

When	O
last	O
seen	O
on	O
January	O
16	O
,	O
1951	O
he	O
had	O
excellent	O
color	O
without	O
any	O
visible	O
cyanosis	O
.	O

The	O
clubbing	O
seemed	O
to	O
have	O
decreased	O
somewhat	O
.	O

A	O
continuous	O
murmur	O
was	O
audible	O
.	O

He	O
stated	O
that	O
he	O
noted	O
no	O
limitation	O
of	O
exercise	O
capacity	O
.	O

In	O
outlining	O
his	O
activities	O
he	O
said	O
that	O
,	O
among	O
other	O
things	O
,	O
he	O
was	O
doing	O
a	O
great	O
deal	O
of	O
ice	O
-	O
skating	O
and	O
was	O
playing	O
ice	O
hockey	O
regularly	O
.	O

He	O
was	O
planning	O
to	O
start	O
college	O
work	O
the	O
following	O
month	O
.	O

The	O
second	O
patient	B
was	O
a	O
16	O
-	O
year	O
-	O
old	O
boy	B
who	O
had	O
been	O
cyanotic	O
since	O
birth	O
.	O

His	O
physical	O
development	O
was	O
somewhat	O
retarded	O
and	O
he	O
was	O
slow	O
in	O
learning	O
to	O
sit	O
and	O
walk	O
.	O

Until	O
he	O
had	O
grown	O
old	O
enough	O
to	O
be	O
self	O
-	O
conscious	O
about	O
it	O
he	O
had	O
always	O
squatted	O
when	O
he	O
was	O
tired	O
.	O

By	O
perseverance	O
he	O
had	O
managed	O
to	O
do	O
more	O
than	O
one	O
would	O
have	O
suspected	O
he	O
could	O
from	O
the	O
degree	O
of	O
his	O
cyanosis	O
.	O

He	O
could	O
walk	O
as	O
much	O
as	O
five	O
or	O
six	O
blocks	O
at	O
a	O
slow	O
pace	O
.	O

He	O
was	O
fond	O
of	O
drums	O
and	O
managed	O
to	O
play	O
occasionally	O
with	O
an	O
orchestra	O
in	O
a	O
somewhat	O
restricted	O
fashion	O
.	O

For	O
the	O
past	O
few	O
months	O
he	O
had	O
had	O
more	O
dyspnea	O
,	O
fatigability	O
,	O
and	O
seemed	O
to	O
be	O
going	O
downhill	O
generally	O
.	O

The	O
results	O
of	O
physical	O
and	O
laboratory	O
studies	O
were	O
rather	O
typical	O
of	O
the	O
tetralogy	O
of	O
Fallot	O
.	O

Clubbing	O
was	O
marked	O
,	O
the	O
nailbeds	O
and	O
mucous	O
membranes	O
were	O
a	O
rather	O
deep	O
purplish	O
-	O
blue	O
color	O
,	O
and	O
the	O
skin	O
had	O
a	O
dusky	O
cyanotic	O
tint	O
.	O

The	O
aortic	O
arch	O
was	O
determined	O
to	O
be	O
on	O
the	O
left	O
.	O

On	O
July	O
21	O
,	O
1950	O
a	O
left	O
lateral	O
thoracotomy	O
was	O
performed	O
,	O
the	O
pleural	O
cavity	O
being	O
entered	O
through	O
the	O
bed	O
of	O
the	O
fourth	O
rib	O
.	O

There	O
was	O
a	O
rather	O
marked	O
increase	O
in	O
the	O
collateral	O
circulation	O
in	O
the	O
mediastinum	O
and	O
the	O
hilar	O
region	O
.	O

The	O
pulmonary	O
artery	O
was	O
easily	O
dissected	O
free	O
.	O

It	O
was	O
fairly	O
long	O
and	O
was	O
about	O
1	O
cm	O
.	O
in	O
diameter	O
.	O

The	O
subclavian	O
artery	O
seemed	O
quite	O
long	O
and	O
was	O
of	O
adequate	O
size	O
,	O
having	O
a	O
diameter	O
of	O
about	O
5	O
mm	O
.	O

An	O
end	O
-	O
to	O
-	O
side	O
sub9lavian	O
pulmonary	O
anastomosis	O
was	O
performed	O
.	O

Again	O
in	O
this	O
case	O
,	O
however	O
,	O
the	O
first	O
part	O
of	O
the	O
subclavian	O
was	O
acutely	O
angulated	O
and	O
completely	O
flattened	O
out	O
against	O
the	O
aortic	O
wall	O
.	O

There	O
was	O
no	O

489	O

YALE	O
JOURNAL	O
OF	O
BIOLOGY	O
AND	O
MEDICINE	O

pulsation	O
in	O
the	O
subclavian	O
and	O
no	O
thrill	O
in	O
the	O
pulmonary	O
.	O

In	O
this	O
instance	O
also	O
,	O
good	O
blood	O
flow	O
through	O
the	O
subclavian	O
artery	O
was	O
evident	O
whenever	O
the	O
hilar	O
structures	O
were	O
elevated	O
in	O
a	O
cephalad	O
direction	O
but	O
no	O
pulsation	O
was	O
demonstrable	O
simply	O
by	O
expanding	O
fully	O
the	O
lung	O
.	O

Again	O
,	O
a	O
sort	O
of	O
inverted	O
T	O
-	O
plastic	O
closure	O
of	O
the	O
defect	O
in	O
the	O
hilum	O
and	O
mediastinum	O
brought	O
about	O
a	O
cephalad	O
elevation	O
of	O
the	O
pulmonary	O
artery	O
so	O
that	O
tension	O
was	O
released	O
and	O
there	O
was	O
excellent	O
pulsation	O
in	O
the	O
subclavian	O
artery	O
.	O

A	O
thrill	O
was	O
now	O
palpable	O
.	O

Convalescence	O
was	O
uneventful	O
.	O

Improvement	O
in	O
color	O
was	O
evident	O
within	O
a	O
few	O
days	O
and	O
his	O
color	O
was	O
excellent	O
by	O
the	O
time	O
he	O
was	O
discharged	O
from	O
the	O
hospital	O
on	O
the	O
thirteenth	O
postoperative	O
day	O
.	O

He	O
rapidly	O
found	O
that	O
he	O
was	O
now	O
able	O
to	O
lead	O
a	O
quite	O
normal	O
sort	O
of	O
life	O
.	O

When	O
he	O
was	O
seen	O
on	O
December	O
9	O
he	O
stated	O
that	O
he	O
had	O
no	O
limitation	O
in	O
exercise	O
capacity	O
.	O

He	O
could	O
walk	O
rapidly	O
without	O
fatigue	O
.	O

He	O
was	O
going	O
to	O
school	O
and	O
was	O
playing	O
the	O
drums	O
in	O
a	O
professional	O
orchestra	O
three	O
or	O
four	O
nights	O
each	O
week	O
.	O

There	O
was	O
some	O
diminution	O
in	O
the	O
clubbing	O
and	O
his	O
color	O
was	O
excellent	O
.	O

There	O
was	O
a	O
loud	O
continuous	O
bruit	O
audible	O
in	O
the	O
chest	O
.	O

On	O
March	O
27	O
the	O
arterial	O
oxygen	O
saturation	O
was	O
88	O
.	O
2	O
per	O
cent	O
.	O

When	O
I	O
first	O
used	O
this	O
procedure	O
I	O
was	O
rather	O
surprised	O
that	O
such	O
tissues	O
would	O
hold	O
sutures	O
and	O
serve	O
satisfactorily	O
to	O
elevate	O
the	O
hilum	O
.	O

On	O
occasions	O
I	O
had	O
previously	O
toyed	O
with	O
the	O
idea	O
of	O
suturing	O
hilar	O
pleura	O
to	O
the	O
mediastinal	O
pleura	O
but	O
had	O
abandoned	O
it	O
as	O
impractical	O
because	O
the	O
sutures	O
seemed	O
to	O
pull	O
out	O
whenever	O
there	O
was	O
any	O
tension	O
whatsoever	O
.	O

If	O
the	O
procedure	O
is	O
to	O
be	O
successful	O
,	O
it	O
is	O
essential	O
that	O
the	O
sutures	O
encompass	O
any	O
adjacent	O
areolar	O
and	O
fibrous	O
tissue	O
and	O
especially	O
the	O
so	O
-	O
called	O
vascular	O
sheath	O
which	O
surrounds	O
both	O
pulmonary	O
artery	O
and	O
aorta	O
and	O
is	O
dissected	O
free	O
during	O
the	O
course	O
of	O
the	O
operation	O
.	O

Fortunately	O
,	O
in	O
its	O
proximal	O
portion	O
the	O
sheath	O
about	O
the	O
pulmonary	O
artery	O
gains	O
added	O
strength	O
from	O
the	O
extension	O
into	O
it	O
of	O
a	O
reflection	O
of	O
the	O
fibrous	O
pericardium	O
.	O

Sutures	O
through	O
the	O
mediastinal	O
pleura	O
in	O
the	O
region	O
of	O
the	O
aortic	O
arch	O
purposely	O
include	O
the	O
perivascular	O
tissues	O
which	O
have	O
been	O
stripped	O
off	O
the	O
aorta	O
and	O
subclavian	O
artery	O
and	O
also	O
any	O
other	O
available	O
tissue	O
which	O
may	O
lend	O
strength	O
,	O
such	O
as	O
the	O
divided	O
ends	O
of	O
the	O
supreme	O
intercostal	O
vein	O
or	O
other	O
vessels	O
which	O
lhave	O
been	O
transected	O
and	O
ligated	O
.	O

The	O
exact	O
method	O
of	O
repair	O
will	O
vary	O
from	O
case	O
to	O
case	O
.	O

By	O
placing	O
the	O
sutures	O
properly	O
it	O
would	O
seem	O
possible	O
sometimes	O
to	O
displace	O
the	O
pulmonary	O
artery	O
laterally	O
as	O
well	O
as	O
in	O
a	O
cephalad	O
direction	O
if	O
such	O
a	O
maneuver	O
was	O
thought	O
to	O
be	O
desirable	O
(	O
Fig	O
.	O
2C	O
)	O
.	O

On	O
occasions	O
one	O
would	O
close	O
the	O
pleural	O
defect	O
fairly	O
snugly	O
,	O
on	O
others	O
leave	O
it	O
wide	O
open	O
in	O
places	O
.	O

Discussion	O

Though	O
there	O
is	O
always	O
available	O
some	O
suitable	O
systemic	O
vessel	O
and	O
though	O
the	O
major	O
concern	O
in	O
the	O
operative	O
treatment	O
of	O
the	O
tetralogy	O
of	O
Fallot	O
is	O
the	O
adequacy	O
of	O
the	O
pulmonary	O
artery	O
,	O
from	O
time	O
to	O
time	O
one	O
may	O
find	O
the	O
achievement	O
of	O
a	O
satisfactory	O
result	O
thwarted	O
by	O
the	O
local	O
anatomical	O
characteristics	O
regardless	O
of	O
one	O
'	O
s	O
choice	O
of	O
procedure	O
.	O

Consequently	O
,	O
those	O
modifications	O
which	O
may	O
add	O
to	O
the	O
likelihood	O
of	O
a	O
successful	O
outcome	O
are	O
important	O
.	O

Blalock	O
"	O
'	O
pointed	O
out	O
the	O
practicability	O
of	O
performing	O
an	O
end	O
-	O
toend	O
subclavian	O
-	O
pulmonary	O
artery	O
anastomosis	O
whenever	O
the	O
pulmonary	O
artery	O
is	O
judged	O
too	O
small	O
or	O
the	O
subclavian	O
too	O
short	O
for	O
a	O
satisfactory	O
end	O

490	O

TREATMENT	O
OF	O
TETRALOGY	O
OF	O
FALLOT	O
491	O

to	O
-	O
side	O
anastomosis	O
.	O

Holman	O
'	O
feels	O
that	O
a	O
poorly	O
functioning	O
shunt	O
after	O
end	O
-	O
to	O
-	O
side	O
anastomosis	O
can	O
usually	O
be	O
corrected	O
by	O
proximal	O
division	O
of	O
the	O
subclavian	O
artery	O
,	O
thus	O
in	O
effect	O
converting	O
the	O
procedure	O
into	O
an	O
end	O
-	O
to	O
-	O
end	O
anastomosis	O
.	O

If	O
a	O
satisfactory	O
end	O
-	O
to	O
-	O
side	O
suture	O
of	O
subclavian	O
and	O
pulmonary	O
arteries	O
or	O
side	O
-	O
to	O
-	O
side	O
aortic	O
pulmonary	O
anastomosis	O
seems	O
difficult	O
to	O
achieve	O
,	O
one	O
may	O
occasionally	O
find	O
it	O
useful	O
to	O
divide	O
the	O
upper	O
lobe	O
branch	O
of	O
the	O
pulmonary	O
artery	O
and	O
carry	O
out	O
an	O
end	O
-	O
to	O
-	O
end	O
suture	O
of	O
the	O
subclavian	O
and	O
the	O
proximal	O
end	O
of	O
the	O
upper	O
lobe	O
branch	O
.	O

Potts	O
and	O
Smith	O
'	O
performed	O
an	O
anastomosis	O
between	O
the	O
proximal	O
end	O
of	O
the	O
upper	O
lobe	O
branch	O
and	O
the	O
side	O
of	O
the	O
aorta	O
in	O
a	O
case	O
in	O
which	O
complete	O
temporary	O
occlusion	O
of	O
the	O
main	O
pulmonary	O
artery	O
was	O
withstood	O
poorly	O
.	O

I	O
have	O
found	O
this	O
principle	O
of	O
division	O
of	O
the	O
upper	O
lobe	O
branch	O
and	O
use	O
of	O
its	O
proximal	O
end	O
of	O
value	O
in	O
obtaining	O
a	O
suitable	O
subclavian	O
pulmonary	O
anastomosis	O
when	O
the	O
subclavian	O
seemed	O
to	O
have	O
inadequate	O
length	O
.	O

On	O
occasions	O
when	O
the	O
systemic	O
vessel	O
seems	O
too	O
short	O
,	O
one	O
may	O
elect	O
to	O
interpose	O
a	O
free	O
vascular	O
transplant	O
,	O
3	O
"	O
'	O
a	O
modification	O
I	O
first	O
employed	O
in	O
1946	O
though	O
unfortunately	O
not	O
with	O
success	O
in	O
this	O
instance	O
.	O

The	O
operation	O
performed	O
in	O
my	O
first	O
patient	B
constitutes	O
in	O
reality	O
the	O
use	O
of	O
the	O
subclavian	O
artery	O
as	O
an	O
autogenous	O
graft	O
between	O
the	O
aorta	O
and	O
pulmonary	O
artery	O
.	O

It	O
will	O
obviously	O
not	O
often	O
be	O
the	O
procedure	O
of	O
choice	O
but	O
sometimes	O
may	O
be	O
found	O
a	O
useful	O
measure	O
in	O
converting	O
an	O
apparently	O
inadequate	O
functional	O
shunt	O
into	O
a	O
good	O
one	O
.	O

If	O
my	O
initial	O
experiences	O
with	O
the	O
plastic	O
repair	O
of	O
the	O
defect	O
in	O
the	O
mediastinal	O
and	O
hilar	O
structures	O
are	O
characteristic	O
of	O
what	O
may	O
be	O
expected	O
of	O
this	O
procedure	O
,	O
it	O
would	O
seem	O
to	O
have	O
wide	O
applicability	O
whenever	O
a	O
poorly	O
functioning	O
subclavian	O
-	O
pulmonary	O
shunt	O
seems	O
correctable	O
by	O
cephalad	O
transplantation	O
of	O
the	O
hilar	O
structures	O
and	O
the	O
consequent	O
release	O
of	O
tension	O
.	O

I	O
was	O
unaware	O
of	O
any	O
reference	O
in	O
the	O
literature	O
to	O
its	O
use	O
until	O
belatedly	O
I	O
discovered	O
that	O
I	O
had	O
overlooked	O
a	O
statement	O
in	O
the	O
legend	O
of	O
one	O
of	O
the	O
excellent	O
drawings	O
in	O
Blalock	O
'	O
s	O
paper	O
on	O
surgical	O
procedures	O
in	O
pulmonic	O
stenosis	O
.	O
'	O
Here	O
he	O
states	O
that	O
suture	O
of	O
the	O
pleura	O
of	O
the	O
superior	O
aspect	O
of	O
the	O
hilum	O
to	O
the	O
mediastinal	O
pleura	O
may	O
effectively	O
elevate	O
a	O
little	O
the	O
pulmonary	O
artery	O
.	O

Perhaps	O
our	O
more	O
detailed	O
consideration	O
of	O
this	O
maneuver	O
may	O
add	O
to	O
its	O
general	O
usefulness	O
.	O

REFERENCES	O

1	O
Blalock	O
,	O
A	O
.	O
:	O
The	O
technique	O
of	O
creation	O
of	O
an	O
artificial	O
ductus	O
arteriosus	O
in	O
the	O

treatment	O
of	O
pulmonic	O
stenosis	O
.	O

J	O
.	O

Thorac	O
.	O

Surg	O
.	O
,	O
1947	O
,	O
16	O
,	O
244	O
.	O

2	O
Blalock	O
,	O
A	O
.	O
:	O
Surgical	O
procedures	O
employed	O
and	O
anatomical	O
variations	O
encountered	O

in	O
the	O
treatment	O
of	O
congenital	O
pulmonic	O
stenosis	O
.	O

Surg	O
.	O
,	O
Gyn	O
.	O

Obst	O
.	O
,	O
1948	O
,	O
87	O
,	O
385	O
.	O

3	O
Gross	O
,	O
R	O
.	O

E	O
.	O
,	O
Bill	O
,	O
A	O
.	O

H	O
.	O
,	O
Jr	O
.	O
,	O
and	O
Pierce	O
,	O
E	O
.	O

C	O
.	O
:	O
Methods	O
for	O
preservation	O
and	O

transplantation	O
of	O
aortic	O
grafts	O
.	O

Observation	O
on	O
arterial	O
grafts	O
in	O
dogs	B
.	O

Report	O
of	O
transplantation	O
of	O
preserved	O
arterial	O
grafts	O
in	O
nine	O
human	B
cases	O
.	O

Surg	O
.	O
,	O
Gyn	O
.	O

Obst	O
.	O
,	O
1949	O
,	O
88	O
,	O
689	O
.	O

4	O
Holman	O
,	O
E	O
.	O
:	O
The	O
surgery	O
of	O
pulmonary	O
stenosis	O
.	O

Experiences	O
with	O
left	O
subclavian	O

to	O
left	O
pulmonary	O
artery	O
anastomosis	O
.	O

J	O
.	O

Thorac	O
.	O

Surg	O
.	O
,	O
1949	O
,	O
18	O
,	O
827	O
.	O

5	O
Johnson	O
,	O
J	O
.	O
,	O
Kirby	O
,	O
C	O
.	O

K	O
.	O
,	O
Greifenstein	O
,	O
F	O
.	O

E	O
.	O
,	O
and	O
Costillo	O
,	O
A	O
.	O
:	O
The	O
experimental	O

and	O
clinical	O
use	O
of	O
vein	O
grafts	O
to	O
replace	O
defects	O
of	O
large	O
arteries	O
.	O

Surgery	O
,	O
1949	O
,	O
26	O
,	O
945	O
.	O

492	O
YALE	O
JOURNAL	O
OF	O
BIOLOGY	O
AND	O
MEDICINE	O

6	O
Lam	O
,	O
C	O
.	O

R	O
.	O
:	O
The	O
choice	O
of	O
the	O
side	O
for	O
approach	O
in	O
operations	O
for	O
pulmonary	O

stenosis	O
.	O

J	O
.	O

Thorac	O
.	O

Surg	O
.	O
,	O
1949	O
,	O
18	O
,	O
661	O
.	O

7	O
Olim	O
,	O
C	O
.	O

B	O
.	O
:	O
Experiences	O
in	O
the	O
surgical	O
treatment	O
of	O
congenital	O
pulmonary	O

stenosis	O
.	O

American	O
Surgeon	O
,	O
1951	O
,	O
17	O
,	O
245	O
.	O

8	O
Paine	O
,	O
J	O
.	O

R	O
.	O
and	O
Varco	O
,	O
R	O
.	O

C	O
.	O
:	O
Experiences	O
with	O
the	O
surgical	O
treatment	O
of	O
pul	O

monic	O
stenosis	O
.	O

Surgery	O
,	O
1948	O
,	O
24	O
,	O
355	O
.	O

9	O
Potts	O
,	O
W	O
.	O

J	O
.	O
and	O
Smith	O
,	O
S	O
.	O
:	O
New	O
surgical	O
procedures	O
in	O
certain	O
cases	O
of	O
congenital	O

pulmonary	O
stenosis	O
.	O

Arch	O
.	O

Surg	O
.	O
,	O
1949	O
,	O
59	O
,	O
491	O
.	O

10	O
Potts	O
,	O
W	O
.	O

J	O
.	O
,	O
Smith	O
S	O
.	O
,	O
and	O
Gibson	O
,	O
S	O
.	O
:	O
Anastomosis	O
of	O
the	O
aorta	O
to	O
a	O
pulmonary	O

artery	O
;	O
certain	O
types	O
in	O
congenital	O
heart	O
disease	O
.	O

J	O
.	O

Am	O
.	O

M	O
.	O

Ass	O
.	O
,	O
1946	O
,	O
132	O
,	O
627	O
.	O

Tissue	O
remodeling	O
:	O
a	O
mating	O
-	O
induced	O
differentiation	O
program	O
for	O
the	O
Drosophila	B
oviduct	O

Abstract	O

Background	O

In	O
both	O
vertebrates	O
and	O
invertebrates	O
,	O
the	O
oviduct	O
is	O
an	O
epithelial	O
tube	O
surrounded	O
by	O
visceral	O
muscles	O
that	O
serves	O
as	O
a	O
conduit	O
for	O
gamete	O
transport	O
between	O
the	O
ovary	O
and	O
uterus	O
.	O

While	O
Drosophila	O
is	O
a	O
model	O
system	O
for	O
tubular	O
organ	O
development	O
,	O
few	O
studies	O
have	O
addressed	O
the	O
development	O
of	O
the	O
fly	B
'	O
s	O
oviduct	O
.	O

Recent	O
studies	O
in	O
Drosophila	O
have	O
identified	O
mating	O
-	O
responsive	O
genes	O
and	O
proteins	O
whose	O
levels	O
in	O
the	O
oviduct	O
are	O
altered	O
by	O
mating	O
.	O

Since	O
many	O
of	O
these	O
molecules	O
(	O
e	O
.	O
g	O
.	O
Muscle	O
LIM	O
protein	O
84B	O
,	O
Coracle	O
,	O
Neuroglian	O
)	O
have	O
known	O
roles	O
in	O
the	O
differentiation	O
of	O
muscle	O
and	O
epithelia	O
of	O
other	O
organs	O
,	O
mating	O
may	O
trigger	O
similar	O
differentiation	O
events	O
in	O
the	O
oviduct	O
.	O

This	O
led	O
us	O
to	O
hypothesize	O
that	O
mating	O
mediates	O
the	O
last	O
stages	O
of	O
oviduct	O
differentiation	O
in	O
which	O
organ	O
-	O
specific	O
specializations	O
arise	O
.	O

Results	O

Using	O
electron	O
-	O
and	O
confocal	O
-	O
microscopy	O
we	O
identified	O
tissue	O
-	O
wide	O
post	O
-	O
mating	O
changes	O
in	O
the	O
oviduct	O
including	O
differentiation	O
of	O
cellular	O
junctions	O
,	O
remodeling	O
of	O
extracellular	O
matrix	O
,	O
increased	O
myofibril	O
formation	O
,	O
and	O
increased	O
innervation	O
.	O

Analysis	O
of	O
once	O
-	O
and	O
twice	O
-	O
mated	O
females	O
reveals	O
that	O
some	O
mating	O
-	O
responsive	O
proteins	O
respond	O
only	O
to	O
the	O
first	O
mating	O
,	O
while	O
others	O
respond	O
to	O
both	O
matings	O
.	O

Conclusion	O

We	O
uncovered	O
ultrastructural	O
changes	O
in	O
the	O
mated	O
oviduct	O
that	O
are	O
consistent	O
with	O
the	O
roles	O
that	O
mating	O
-	O
responsive	O
proteins	O
play	O
in	O
muscle	O
and	O
epithelial	O
differentiation	O
elsewhere	O
.	O

This	O
suggests	O
that	O
mating	O
triggers	O
the	O
late	O
differentiation	O
of	O
the	O
oviduct	O
.	O

Furthermore	O
,	O
we	O
suggest	O
that	O
mating	O
-	O
responsive	O
proteins	O
that	O
respond	O
only	O
to	O
the	O
first	O
mating	O
are	O
involved	O
in	O
the	O
final	O
maturation	O
of	O
the	O
oviduct	O
while	O
proteins	O
that	O
remain	O
responsive	O
to	O
later	O
matings	O
are	O
also	O
involved	O
in	O
maintenance	O
and	O
ongoing	O
function	O
of	O
the	O
oviduct	O
.	O

Taken	O
together	O
,	O
our	O
results	O
establish	O
the	O
oviduct	O
as	O
an	O
attractive	O
system	O
to	O
address	O
mechanisms	O
that	O
regulate	O
the	O
late	O
stages	O
of	O
differentiation	O
and	O
maintenance	O
of	O
a	O
tubular	O
organ	O
.	O

Background	O

Most	O
internal	O
organs	O
,	O
including	O
the	O
vascular	O
and	O
respiratory	O
systems	O
and	O
the	O
gastro	O
-	O
intestinal	O
and	O
urinary	O
-	O
genital	O
tracts	O
are	O
comprised	O
of	O
a	O
single	O
epithelial	O
tube	O
or	O
a	O
network	O
of	O
tubes	O
.	O

Tubular	O
organs	O
serve	O
as	O
conduits	O
for	O
the	O
transport	O
of	O
gases	O
,	O
liquids	O
,	O
or	O
solutes	O
,	O
and	O
serve	O
as	O
barriers	O
between	O
biological	O
compartments	O
.	O

To	O
create	O
tubes	O
with	O
specific	O
flow	O
and	O
barrier	O
properties	O
,	O
the	O
morphology	O
of	O
the	O
tube	O
must	O
be	O
precisely	O
specified	O
during	O
development	O
and	O
modulated	O
by	O
physiology	O
.	O

To	O
accommodate	O
specific	O
physiological	O
roles	O
,	O
tissue	O
-	O
specific	O
programs	O
for	O
differentiation	O
are	O
employed	O
at	O
the	O
last	O
stages	O
of	O
development	O
.	O

While	O
much	O
is	O
known	O
about	O
the	O
molecular	O
and	O
cellular	O
basis	O
of	O
tube	O
formation	O
[	O
1	O
-	O
6	O
]	O
,	O
little	O
is	O
known	O
about	O
the	O
mechanisms	O
that	O
regulate	O
the	O
late	O
stages	O
of	O
differentiation	O
in	O
which	O
organ	O
-	O
specific	O
specializations	O
arise	O
.	O

The	O
conservation	O
of	O
genes	O
and	O
similarity	O
in	O
tubular	O
organ	O
design	O
across	O
taxa	O
make	O
Drosophila	O
an	O
excellent	O
model	O
for	O
understanding	O
organogenesis	O
in	O
higher	O
animals	O
.	O

In	O
Drosophila	O
,	O
the	O
best	O
understood	O
tubular	O
organs	O
from	O
a	O
developmental	O
point	O
of	O
view	O
are	O
the	O
trachea	O
and	O
salivary	O
gland	O
.	O

Studies	O
of	O
these	O
organs	O
reveal	O
a	O
general	O
program	O
for	O
tubular	O
organ	O
development	O
,	O
in	O
which	O
combinatorial	O
expression	O
of	O
global	O
patterning	O
genes	O
specifies	O
positions	O
within	O
the	O
embryo	O
for	O
the	O
subsequent	O
activation	O
of	O
tissue	O
-	O
specific	O
early	O
genes	O
and	O
transcription	O
factors	O
.	O

This	O
program	O
results	O
in	O
the	O
activation	O
of	O
downstream	O
genes	O
involved	O
in	O
terminal	O
differentiation	O
of	O
organ	O
-	O
specific	O
specializations	O
such	O
as	O
the	O
cuticle	O
that	O
lines	O
the	O
tracheal	O
lumen	O
[	O
1	O
,	O
2	O
,	O
4	O
,	O
7	O
-	O
9	O
]	O
.	O

The	O
Drosophila	B
female	O
reproductive	O
tract	O
is	O
another	O
tubular	O
system	O
,	O
consisting	O
of	O
the	O
uterus	O
and	O
a	O
common	O
oviduct	O
(	O
the	O
main	O
tube	O
)	O
that	O
branches	O
into	O
two	O
lateral	O
oviducts	O
.	O

Regional	O
differences	O
in	O
function	O
are	O
observed	O
along	O
the	O
length	O
of	O
the	O
tract	O
,	O
with	O
egg	O
activation	O
occurring	O
largely	O
at	O
the	O
proximal	O
end	O
,	O
in	O
the	O
lateral	O
oviducts	O
,	O
and	O
fertilization	O
occurring	O
at	O
the	O
distal	O
end	O
,	O
in	O
the	O
uterus	O
[	O
10	O
,	O
11	O
]	O
.	O

Unlike	O
other	O
tubular	O
organs	O
,	O
little	O
is	O
known	O
about	O
the	O
development	O
of	O
the	O
female	O
reproductive	O
tract	O
.	O

However	O
,	O
regional	O
differences	O
in	O
function	O
suggest	O
the	O
presence	O
of	O
region	O
-	O
specific	O
differentiation	O
programs	O
within	O
the	O
female	O
reproductive	O
tract	O
.	O

In	O
Drosophila	O
,	O
mating	O
induces	O
changes	O
in	O
female	O
behavior	O
and	O
physiology	O
via	O
molecules	O
transmitted	O
in	O
the	O
seminal	O
fluid	O
.	O

These	O
changes	O
are	O
rapid	O
and	O
lead	O
to	O
a	O
mated	O
female	O
state	O
which	O
is	O
profoundly	O
different	O
from	O
the	O
unmated	O
female	O
state	O
.	O

While	O
an	O
unmated	O
female	O
lays	O
few	O
eggs	O
and	O
readily	O
accepts	O
the	O
courtship	O
efforts	O
of	O
a	O
male	O
,	O
a	O
mated	O
female	O
exhibits	O
increased	O
egg	O
-	O
laying	O
and	O
actively	O
rejects	O
males	O
[	O
12	O
-	O
19	O
]	O
.	O

Microarray	O
studies	O
of	O
whole	O
flies	B
reveal	O
that	O
the	O
changes	O
in	O
egg	O
-	O
laying	O
rate	O
are	O
accompanied	O
by	O
a	O
change	O
in	O
gene	O
expression	O
.	O

Within	O
three	O
hours	O
of	O
mating	O
there	O
is	O
an	O
increase	O
in	O
expression	O
of	O
a	O
small	O
number	O
of	O
genes	O
[	O
20	O
,	O
21	O
]	O
.	O

Rapid	O
changes	O
in	O
gene	O
expression	O
,	O
as	O
well	O
as	O
protein	O
abundance	O
,	O
have	O
also	O
been	O
observed	O
in	O
the	O
female	O
reproductive	O
tract	O
[	O
22	O
,	O
23	O
]	O
.	O

In	O
the	O
upper	O
reproductive	O
tract	O
(	O
lateral	O
and	O
common	O
oviducts	O
,	O
hereafter	O
,	O
oviduct	O
)	O
,	O
mating	O
induces	O
an	O
increase	O
in	O
immune	O
related	O
transcripts	O
and	O
down	O
regulates	O
transcription	O
factors	O
involved	O
in	O
cell	O
growth	O
and	O
differentiation	O
.	O

At	O
the	O
protein	O
level	O
mating	O
induces	O
increased	O
abundance	O
of	O
proteins	O
associated	O
with	O
muscle	O
assembly	O
and	O
function	O
and	O
cytoskeletal	O
proteins	O
associated	O
with	O
epithelial	O
morphogenesis	O
[	O
23	O
]	O
.	O

Since	O
many	O
of	O
these	O
mating	O
-	O
responsive	O
proteins	O
act	O
in	O
late	O
differentiation	O
pathways	O
of	O
muscle	O
and	O
epithelia	O
elsewhere	O
(	O
e	O
.	O
g	O
.	O
Bent	O
,	O
Muscle	O
LIM	O
protein	O
84B	O
(	O
Mlp84B	O
)	O
,	O
Neuroglian	O
(	O
Nrg	O
)	O
,	O
Coracle	O
(	O
Cora	O
)	O
)	O
,	O
we	O
hypothesize	O
that	O
mating	O
triggers	O
similar	O
differentiation	O
in	O
the	O
oviduct	O
.	O

To	O
test	O
our	O
hypothesis	O
we	O
characterized	O
the	O
ultrastructure	O
of	O
oviduct	O
epithelia	O
and	O
muscle	O
,	O
as	O
well	O
as	O
the	O
pattern	O
of	O
innervation	O
before	O
and	O
after	O
mating	O
.	O

We	O
then	O
examined	O
the	O
effect	O
of	O
different	O
mating	O
regimes	O
on	O
oviduct	O
mating	O
-	O
responsive	O
cytoskeletal	O
proteins	O
and	O
on	O
female	O
reproductive	O
output	O
.	O

Our	O
results	O
suggest	O
that	O
active	O
tissue	O
remodeling	O
takes	O
place	O
in	O
the	O
oviduct	O
epithelia	O
and	O
musculature	O
in	O
response	O
to	O
mating	O
.	O

Furthermore	O
,	O
we	O
found	O
a	O
striking	O
increase	O
in	O
innervation	O
of	O
the	O
oviduct	O
after	O
mating	O
.	O

Our	O
results	O
show	O
that	O
the	O
reproductive	O
tract	O
is	O
an	O
attractive	O
system	O
to	O
address	O
mechanisms	O
that	O
regulate	O
the	O
late	O
stages	O
of	O
tissue	O
differentiation	O
in	O
a	O
tubular	O
organ	O
.	O

Unlike	O
other	O
tubular	O
organs	O
,	O
the	O
last	O
differentiation	O
stage	O
of	O
the	O
oviduct	O
is	O
triggered	O
by	O
an	O
extrinsic	O
cue	O
(	O
mating	O
)	O
.	O

This	O
makes	O
it	O
possible	O
to	O
experimentally	O
control	O
the	O
onset	O
of	O
differentiation	O
,	O
with	O
an	O
opportunity	O
to	O
independently	O
examine	O
the	O
effects	O
of	O
mating	O
and	O
age	O
.	O

In	O
addition	O
,	O
it	O
allows	O
us	O
to	O
examine	O
processes	O
essential	O
for	O
reproduction	O
.	O

Results	O

Mating	O
induces	O
changes	O
in	O
oviduct	O
lumen	O

Our	O
previous	O
molecular	O
profiling	O
showed	O
that	O
mating	O
promotes	O
changes	O
in	O
actin	O
-	O
based	O
cytoskeletal	O
molecules	O
and	O
suggests	O
that	O
mating	O
triggers	O
molecular	O
changes	O
and	O
tissue	O
remodeling	O
in	O
the	O
female	O
reproductive	O
tract	O
that	O
mediate	O
its	O
progression	O
to	O
a	O
mature	O
functional	O
stage	O
[	O
23	O
]	O
.	O

To	O
gain	O
insight	O
into	O
the	O
mechanisms	O
that	O
underlie	O
this	O
progression	O
,	O
we	O
used	O
light	O
and	O
electron	O
microscopy	O
to	O
determine	O
the	O
morphological	O
status	O
of	O
the	O
oviduct	O
in	O
unmated	O
and	O
mated	O
3	O
-	O
day	O
old	O
females	O
.	O

In	O
nearly	O
all	O
mated	O
reproductive	O
tracts	O
processed	O
for	O
microscopy	O
(	O
8	O
/	O
9	O
)	O
,	O
an	O
egg	O
was	O
located	O
in	O
one	O
of	O
the	O
lateral	O
oviducts	O
,	O
whereas	O
an	O
egg	O
was	O
never	O
observed	O
in	O
the	O
oviduct	O
of	O
unmated	O
reproductive	O
tracts	O
(	O
5	O
/	O
5	O
)	O
(	O
Figure	O
1	O
)	O
.	O

This	O
observation	O
is	O
consistent	O
with	O
previous	O
studies	O
that	O
report	O
increased	O
ovulation	O
and	O
egg	O
-	O
laying	O
at	O
6	O
h	O
post	O
-	O
mating	O
[	O
24	O
]	O
.	O

In	O
all	O
unmated	O
reproductive	O
tracts	O
examined	O
,	O
the	O
region	O
between	O
the	O
lateral	O
oviducts	O
and	O
the	O
middle	O
of	O
the	O
common	O
oviduct	O
was	O
either	O
tapered	O
or	O
constricted	O
,	O
whereas	O
this	O
region	O
appeared	O
relaxed	O
in	O
the	O
mated	O
reproductive	O
tract	O
(	O
Figure	O
1A	O
and	O
1D	O
)	O
.	O

These	O
observations	O
raise	O
the	O
possibility	O
that	O
the	O
lumen	O
is	O
narrow	O
in	O
the	O
unmated	O
oviduct	O
and	O
larger	O
in	O
the	O
mated	O
oviduct	O
.	O

To	O
address	O
this	O
possibility	O
,	O
we	O
collected	O
serial	O
1	O
mu	O
m	O
longitudinal	O
sections	O
through	O
the	O
reproductive	O
tracts	O
of	O
unmated	O
and	O
mated	O
females	O
and	O
stained	O
these	O
sections	O
with	O
toluidine	O
blue	O
to	O
survey	O
the	O
appearance	O
of	O
the	O
lumen	O
along	O
the	O
entire	O
length	O
of	O
the	O
oviduct	O
(	O
Figure	O
1B	O
and	O
1E	O
)	O
.	O

Our	O
examination	O
reveals	O
that	O
,	O
in	O
unmated	O
reproductive	O
tracts	O
,	O
the	O
lateral	O
oviduct	O
lumen	O
has	O
an	O
irregular	O
shape	O
,	O
while	O
the	O
common	O
oviduct	O
lumen	O
appears	O
straight	O
.	O

Moreover	O
,	O
in	O
all	O
the	O
unmated	O
reproductive	O
tracts	O
sectioned	O
,	O
we	O
detected	O
patches	O
of	O
darkly	O
stained	O
material	O
in	O
the	O
lumen	O
of	O
the	O
lower	O
common	O
oviduct	O
.	O

In	O
the	O
mated	O
reproductive	O
tract	O
,	O
the	O
lumen	O
of	O
the	O
upper	O
oviduct	O
(	O
defined	O
as	O
the	O
lateral	O
oviduct	O
and	O
upper	O
part	O
of	O
the	O
common	O
oviduct	O
)	O
has	O
an	O
irregular	O
shape	O
,	O
and	O
the	O
lumen	O
of	O
the	O
lower	O
oviduct	O
(	O
defined	O
as	O
the	O
lower	O
part	O
of	O
common	O
oviduct	O
)	O
appears	O
straight	O
.	O

In	O
addition	O
,	O
the	O
lumen	O
of	O
the	O
lower	O
oviduct	O
appears	O
wider	O
in	O
mated	O
than	O
unmated	O
reproductive	O
tracts	O
(	O
Figure	O
1C	O
and	O
1F	O
)	O
.	O

Interestingly	O
,	O
darkly	O
stained	O
material	O
was	O
not	O
detected	O
in	O
the	O
oviduct	O
lumen	O
of	O
mated	O
females	O
.	O

This	O
observation	O
appears	O
to	O
be	O
consistent	O
with	O
the	O
description	O
made	O
by	O
Mahowald	O
et	O
al	O
.	O

[	O
25	O
]	O
,	O
who	O
reported	O
that	O
the	O
oviduct	O
lumen	O
of	O
unmated	O
females	O
is	O
nearly	O
filled	O
with	O
an	O
intima	O
-	O
like	O
matrix	O
and	O
that	O
this	O
matrix	O
is	O
reduced	O
after	O
mating	O
.	O

Because	O
3	O
-	O
day	O
-	O
old	O
mated	O
females	O
lay	O
eggs	O
,	O
it	O
is	O
unclear	O
whether	O
the	O
lack	O
of	O
lumenal	O
material	O
and	O
increase	O
in	O
lumen	O
size	O
in	O
mated	O
females	O
occurred	O
before	O
or	O
after	O
the	O
passage	O
of	O
eggs	O
.	O

We	O
suggest	O
that	O
mating	O
directly	O
or	O
indirectly	O
induces	O
morphological	O
changes	O
in	O
the	O
oviduct	O
that	O
facilitate	O
egg	O
passage	O
through	O
the	O
duct	O
.	O

Taken	O
together	O
,	O
our	O
observations	O
lead	O
us	O
to	O
propose	O
that	O
the	O
oviduct	O
lumen	O
is	O
closed	O
and	O
/	O
or	O
obstructed	O
in	O
the	O
unmated	O
reproductive	O
tract	O
,	O
and	O
that	O
mating	O
induces	O
changes	O
in	O
the	O
epithelia	O
and	O
/	O
or	O
muscle	O
that	O
"	O
open	O
"	O
the	O
oviduct	O
lumen	O
.	O

Initial	O
formation	O
of	O
cell	O
-	O
cell	O
junctions	O
in	O
oviduct	O
epithelia	O
is	O
mating	O
-	O
independent	O

To	O
determine	O
whether	O
mating	O
induces	O
specific	O
morphological	O
changes	O
in	O
the	O
oviduct	O
epithelia	O
post	O
-	O
mating	O
,	O
we	O
next	O
examined	O
the	O
ultrastructure	O
of	O
the	O
oviduct	O
epithelia	O
in	O
unmated	O
and	O
mated	O
reproductive	O
tracts	O
.	O

Since	O
molecular	O
profiling	O
demonstrates	O
that	O
proteins	O
associated	O
with	O
cellular	O
junctions	O
such	O
as	O
alpha	O
-	O
and	O
beta	O
-	O
Spectrin	O
(	O
Spec	O
)	O
,	O
Cora	O
,	O
and	O
Nrg	O
[	O
23	O
]	O
increase	O
post	O
-	O
mating	O
,	O
we	O
first	O
determined	O
the	O
status	O
of	O
the	O
cellular	O
junctions	O
in	O
the	O
oviduct	O
epithelia	O
of	O
unmated	O
females	O
,	O
and	O
whether	O
these	O
junctions	O
change	O
post	O
-	O
mating	O
.	O

In	O
Drosophila	O
,	O
most	O
ectodermally	O
derived	O
epithelia	O
(	O
such	O
as	O
the	O
epidermis	O
and	O
trachea	O
)	O
,	O
with	O
a	O
few	O
exceptions	O
,	O
are	O
joined	O
apically	O
by	O
a	O
belt	O
-	O
like	O
adherens	O
junction	O
called	O
the	O
zonal	O
adherens	O
junction	O
(	O
ZA	O
)	O
followed	O
basally	O
by	O
a	O
septate	O
junction	O
(	O
SJ	O
)	O
[	O
26	O
]	O
.	O

Our	O
analysis	O
reveals	O
that	O
the	O
oviduct	O
is	O
lined	O
,	O
along	O
its	O
entire	O
length	O
,	O
by	O
a	O
monolayered	O
epithelium	O
comprised	O
of	O
squamous	O
-	O
type	O
cells	O
.	O

Although	O
region	O
-	O
specific	O
differences	O
in	O
morphology	O
were	O
observed	O
,	O
all	O
oviduct	O
epithelia	O
examined	O
,	O
in	O
both	O
unmated	O
and	O
mated	O
females	O
,	O
are	O
joined	O
along	O
their	O
lateral	O
membranes	O
by	O
an	O
extensive	O
SJ	O
and	O
lack	O
an	O
apical	O
ZA	O
(	O
Figure	O
2	O
)	O
.	O

SJs	O
and	O
ZAs	O
form	O
complete	O
belts	O
that	O
surround	O
the	O
epithelial	O
cell	O
,	O
thus	O
making	O
these	O
junctions	O
easily	O
visible	O
in	O
transverse	O
sections	O
through	O
the	O
epithelium	O
.	O

Because	O
ZAs	O
were	O
not	O
detected	O
in	O
our	O
transverse	O
sections	O
through	O
the	O
oviduct	O
,	O
this	O
implies	O
that	O
ZAs	O
never	O
formed	O
,	O
or	O
developed	O
earlier	O
and	O
were	O
lost	O
(	O
Figure	O
2D	O
)	O
.	O

Interestingly	O
,	O
we	O
did	O
not	O
detect	O
any	O
ultrastructural	O
differences	O
in	O
the	O
SJs	O
at	O
6	O
h	O
post	O
-	O
mating	O
,	O
but	O
we	O
did	O
uncover	O
differences	O
in	O
SJ	O
ultrastructure	O
in	O
different	O
regions	O
of	O
the	O
oviduct	O
.	O

Based	O
on	O
their	O
ultrastructure	O
,	O
two	O
types	O
of	O
SJs	O
,	O
smooth	O
and	O
pleated	O
,	O
can	O
be	O
distinguished	O
in	O
Drosophila	O
[	O
26	O
]	O
.	O

Smooth	O
SJs	O
are	O
distinguished	O
by	O
the	O
lack	O
of	O
visible	O
septae	O
and	O
the	O
appearance	O
of	O
electron	O
dense	O
material	O
in	O
the	O
intercellular	O
space	O
,	O
while	O
pleated	O
SJs	O
are	O
distinguished	O
by	O
the	O
ladder	O
-	O
like	O
appearance	O
of	O
septae	O
.	O

In	O
the	O
lateral	O
oviducts	O
and	O
upper	O
common	O
oviduct	O
,	O
septa	O
were	O
not	O
detected	O
in	O
the	O
SJ	O
,	O
thus	O
these	O
SJs	O
represent	O
smooth	O
SJs	O
or	O
an	O
immature	O
stage	O
of	O
pleated	O
SJ	O
(	O
Figure	O
2A	O
,	O
2A	O
'	O
,	O
2A	O
"	O
)	O
.	O

In	O
contrast	O
,	O
a	O
ladder	O
-	O
like	O
arrangement	O
of	O
septae	O
was	O
often	O
visible	O
in	O
the	O
SJs	O
of	O
the	O
lower	O
common	O
oviduct	O
(	O
Figure	O
2C	O
'	O
)	O
,	O
thus	O
these	O
SJs	O
can	O
be	O
classified	O
as	O
pleated	O
.	O

Unlike	O
the	O
smooth	O
-	O
like	O
SJs	O
of	O
the	O
upper	O
oviduct	O
,	O
the	O
pleated	O
SJs	O
of	O
the	O
lower	O
oviduct	O
are	O
followed	O
basally	O
by	O
spot	O
type	O
adherens	O
junction	O
(	O
spot	O
AJs	O
)	O
(	O
Figure	O
2B	O
,	O
2B	O
'	O
;	O
additional	O
file	O
1	O
)	O
.	O

Further	O
analysis	O
is	O
necessary	O
to	O
determine	O
if	O
the	O
SJs	O
of	O
the	O
upper	O
and	O
lower	O
oviduct	O
represent	O
different	O
types	O
or	O
different	O
developmental	O
stages	O
.	O

Our	O
findings	O
demonstrate	O
that	O
the	O
initial	O
formation	O
of	O
SJs	O
,	O
as	O
well	O
as	O
spot	O
AJs	O
in	O
the	O
lower	O
oviduct	O
,	O
are	O
mating	O
-	O
independent	O
.	O

This	O
raises	O
an	O
interesting	O
question	O
.	O

Why	O
are	O
SJ	O
proteins	O
such	O
as	O
Cora	O
and	O
Nrg	O
up	O
-	O
regulated	O
post	O
-	O
mating	O
if	O
SJs	O
are	O
formed	O
prior	O
to	O
mating	O
?	O

It	O
is	O
possible	O
that	O
the	O
increased	O
expression	O
of	O
SJ	O
proteins	O
is	O
associated	O
with	O
functional	O
changes	O
in	O
polarized	O
secretion	O
post	O
-	O
mating	O
.	O

Recent	O
studies	O
have	O
shown	O
that	O
SJs	O
play	O
an	O
unexpected	O
role	O
in	O
regulating	O
the	O
apical	O
secretion	O
of	O
specialized	O
extracellular	O
matrix	O
molecules	O
in	O
the	O
trachea	O
[	O
27	O
,	O
28	O
]	O
,	O
and	O
that	O
these	O
molecules	O
are	O
important	O
regulators	O
of	O
lumen	O
size	O
.	O

Mating	O
modulates	O
apical	O
secretory	O
activity	O
in	O
the	O
oviduct	O

Given	O
the	O
presence	O
of	O
extensive	O
SJs	O
in	O
the	O
oviduct	O
and	O
the	O
role	O
of	O
SJs	O
in	O
regulating	O
apical	O
secretion	O
of	O
extracellular	O
matrix	O
molecules	O
in	O
other	O
epithelia	O
(	O
e	O
.	O
g	O
.	O
trachea	O
)	O
,	O
we	O
asked	O
if	O
mating	O
modulates	O
apical	O
secretion	O
in	O
the	O
oviduct	O
epithelia	O
.	O

Our	O
ultrastructural	O
analysis	O
reveals	O
that	O
different	O
regions	O
of	O
the	O
oviduct	O
display	O
different	O
apical	O
membrane	O
morphology	O
(	O
i	O
.	O
e	O
microvilli	O
or	O
pleats	O
)	O
(	O
see	O
Figures	O
2	O
and	O
additional	O
file	O
2A	O
and	O
2A	O
)	O
,	O
but	O
all	O
epithelia	O
are	O
covered	O
by	O
an	O
electron	O
dense	O
apical	O
extracellular	O
matrix	O
(	O
AECM	O
)	O
and	O
a	O
thin	O
layer	O
of	O
cuticle	O
.	O

We	O
found	O
that	O
mating	O
induces	O
ultrastructural	O
changes	O
in	O
the	O
AECM	O
and	O
cuticle	O
in	O
both	O
the	O
upper	O
and	O
lower	O
oviduct	O
.	O

In	O
the	O
upper	O
oviduct	O
of	O
the	O
unmated	O
female	O
,	O
the	O
AECM	O
varies	O
in	O
thickness	O
along	O
the	O
apical	O
surface	O
(	O
Figure	O
3A	O
)	O
.	O

Some	O
areas	O
have	O
little	O
AECM	O
,	O
while	O
other	O
areas	O
are	O
covered	O
by	O
a	O
distinct	O
layer	O
of	O
AECM	O
(	O
~	O
1	O
-	O
2	O
mu	O
m	O
in	O
thickness	O
;	O
Figure	O
3B	O
)	O
.	O

However	O
,	O
the	O
AECM	O
of	O
mated	O
females	O
is	O
more	O
evenly	O
distributed	O
along	O
the	O
apical	O
surface	O
,	O
(	O
~	O
2	O
mu	O
m	O
in	O
thickness	O
;	O
Figure	O
3E	O
)	O
.	O

Strikingly	O
,	O
the	O
AECM	O
and	O
cuticle	O
of	O
mated	O
females	O
have	O
a	O
ruffled	O
appearance	O
,	O
suggesting	O
that	O
the	O
AECM	O
and	O
cuticle	O
have	O
increased	O
in	O
surface	O
area	O
(	O
Figure	O
3F	O
)	O
.	O

Electron	O
dense	O
granules	O
up	O
to	O
~	O
1	O
.	O
5	O
mu	O
m	O
in	O
diameter	O
were	O
occasionally	O
observed	O
in	O
both	O
the	O
AECM	O
and	O
cell	O
cytoplasm	O
(	O
Figure	O
3F	O
)	O
.	O

Although	O
further	O
analysis	O
is	O
needed	O
to	O
determine	O
the	O
role	O
of	O
these	O
granules	O
in	O
the	O
oviduct	O
epithelia	O
,	O
it	O
is	O
possible	O
that	O
these	O
granules	O
participate	O
in	O
the	O
secretion	O
and	O
deposition	O
of	O
the	O
AECM	O
.	O

Taken	O
together	O
,	O
our	O
findings	O
suggest	O
that	O
polarized	O
secretion	O
via	O
the	O
AECM	O
,	O
while	O
ongoing	O
in	O
the	O
upper	O
oviduct	O
of	O
the	O
unmated	O
female	O
is	O
enhanced	O
and	O
/	O
or	O
modulated	O
post	O
-	O
mating	O
.	O

Post	O
-	O
mating	O
changes	O
in	O
AECM	O
ultrastructure	O
are	O
also	O
observed	O
in	O
the	O
lower	O
common	O
oviduct	O
.	O

However	O
,	O
unlike	O
the	O
AECM	O
of	O
the	O
upper	O
oviduct	O
,	O
the	O
AECM	O
of	O
the	O
lower	O
oviduct	O
is	O
well	O
developed	O
prior	O
to	O
mating	O
.	O

In	O
the	O
lower	O
oviduct	O
of	O
the	O
unmated	O
female	O
,	O
the	O
AECM	O
consists	O
of	O
an	O
amorphous	O
electron	O
dense	O
material	O
and	O
is	O
unevenly	O
distributed	O
,	O
forming	O
a	O
thick	O
,	O
bulbous	O
layer	O
above	O
the	O
plasma	O
membrane	O
in	O
some	O
regions	O
(	O
additional	O
file	O
2	O
)	O
.	O

Matrix	O
-	O
like	O
material	O
is	O
also	O
observed	O
in	O
the	O
lumen	O
,	O
but	O
this	O
material	O
is	O
more	O
electron	O
dense	O
than	O
the	O
AECM	O
(	O
additional	O
file	O
2A	O
and	O
2A	O
)	O
.	O

In	O
the	O
mated	O
female	O
,	O
the	O
AECM	O
is	O
flattened	O
against	O
the	O
plasma	O
membrane	O
and	O
is	O
uniformly	O
distributed	O
along	O
the	O
apical	O
surface	O
(	O
additional	O
file	O
2B	O
and	O
2B	O
)	O
.	O

Matrix	O
-	O
like	O
material	O
was	O
not	O
observed	O
in	O
the	O
center	O
of	O
the	O
lumen	O
,	O
but	O
small	O
pools	O
of	O
very	O
electron	O
dense	O
material	O
were	O
detected	O
in	O
the	O
spaces	O
between	O
the	O
epithelial	O
folds	O
(	O
additional	O
file	O
2C	O
and	O
2C	O
)	O
.	O

This	O
may	O
explain	O
why	O
lumenal	O
matrix	O
was	O
not	O
detected	O
at	O
the	O
light	O
microscopic	O
level	O
in	O
the	O
mated	O
female	O
oviduct	O
(	O
see	O
Figure	O
1E	O
and	O
1F	O
)	O
.	O

Taken	O
together	O
,	O
our	O
observations	O
suggest	O
that	O
the	O
lower	O
common	O
oviduct	O
is	O
a	O
site	O
of	O
active	O
apical	O
secretion	O
in	O
both	O
mated	O
and	O
unmated	O
females	O
,	O
and	O
that	O
matrix	O
secretion	O
,	O
particularly	O
in	O
the	O
lumen	O
,	O
is	O
reduced	O
post	O
-	O
mating	O
.	O

These	O
findings	O
raise	O
the	O
intriguing	O
possibility	O
that	O
the	O
AECM	O
and	O
lumenal	O
matrix	O
function	O
as	O
a	O
plug	O
in	O
the	O
lower	O
oviduct	O
,	O
and	O
that	O
mating	O
induces	O
the	O
breakdown	O
of	O
this	O
plug	O
.	O

Mating	O
induces	O
changes	O
in	O
hemi	O
-	O
adherens	O
junctions	O
in	O
upper	O
oviduct	O

In	O
addition	O
to	O
modulating	O
secretion	O
at	O
the	O
apical	O
membrane	O
,	O
mating	O
induces	O
changes	O
at	O
the	O
basolateral	O
membrane	O
.	O

In	O
many	O
epithelia	O
,	O
one	O
of	O
the	O
last	O
steps	O
of	O
differentiation	O
is	O
the	O
development	O
of	O
a	O
layer	O
of	O
extracellular	O
matrix	O
(	O
ECM	O
)	O
called	O
the	O
basal	O
lamina	O
that	O
covers	O
the	O
apical	O
and	O
/	O
or	O
basal	O
membranes	O
and	O
the	O
concomitant	O
development	O
of	O
hemi	O
-	O
adherens	O
junctions	O
(	O
HAJs	O
)	O
.	O

HAJs	O
connect	O
the	O
cell	O
cytoskeleton	O
with	O
the	O
ECM	O
and	O
are	O
formed	O
at	O
virtually	O
all	O
cell	O
surfaces	O
that	O
contact	O
an	O
ECM	O
.	O

HAJs	O
can	O
be	O
distinguished	O
at	O
the	O
ultrastructural	O
level	O
as	O
a	O
patch	O
-	O
like	O
,	O
electron	O
dense	O
undercoat	O
of	O
the	O
plasma	O
membrane	O
that	O
opposes	O
the	O
basal	O
lamina	O
(	O
[	O
26	O
]	O
;	O
Figure	O
3G	O
,	O
3H	O
)	O
.	O

In	O
the	O
Drosophila	B
embryo	O
,	O
the	O
HAJs	O
and	O
basal	O
lamina	O
are	O
formed	O
at	O
the	O
same	O
time	O
[	O
26	O
]	O
.	O

Because	O
the	O
basal	O
lamina	O
is	O
established	O
at	O
a	O
time	O
when	O
the	O
majority	O
of	O
extracellular	O
matrix	O
molecules	O
are	O
actively	O
secreted	O
[	O
26	O
,	O
29	O
]	O
,	O
this	O
suggests	O
that	O
the	O
formation	O
of	O
HAJs	O
is	O
tightly	O
coordinated	O
with	O
the	O
secretion	O
of	O
the	O
ECM	O
.	O

One	O
of	O
the	O
most	O
striking	O
post	O
-	O
mating	O
changes	O
observed	O
in	O
the	O
oviduct	O
epithelia	O
was	O
the	O
appearance	O
of	O
numerous	O
HAJs	O
along	O
the	O
basolateral	O
membrane	O
in	O
the	O
upper	O
oviduct	O
(	O
Figure	O
3	O
)	O
.	O

The	O
importance	O
of	O
HAJs	O
,	O
particularly	O
in	O
the	O
upper	O
oviduct	O
,	O
is	O
underscored	O
by	O
the	O
extensive	O
infolding	O
of	O
the	O
basolateral	O
membrane	O
that	O
is	O
observed	O
in	O
both	O
unmated	O
and	O
mated	O
females	O
(	O
Figure	O
3A	O
and	O
3E	O
)	O
.	O

The	O
infolded	O
membrane	O
gives	O
rise	O
to	O
a	O
highly	O
branched	O
intercellular	O
space	O
that	O
is	O
filled	O
with	O
an	O
ECM	O
(	O
Figure	O
3C	O
and	O
3G	O
)	O
.	O

This	O
ECM	O
is	O
contiguous	O
with	O
the	O
basal	O
lamina	O
that	O
surrounds	O
the	O
epithelia	O
.	O

Few	O
HAJs	O
were	O
observed	O
in	O
the	O
upper	O
oviduct	O
of	O
the	O
unmated	O
female	O
,	O
and	O
these	O
were	O
largely	O
restricted	O
to	O
the	O
basal	O
membrane	O
,	O
and	O
not	O
observed	O
along	O
the	O
basolateral	O
infolding	O
(	O
Figure	O
3C	O
)	O
.	O

In	O
contrast	O
,	O
numerous	O
HAJs	O
appear	O
along	O
the	O
basolateral	O
infolding	O
post	O
-	O
mating	O
in	O
this	O
region	O
of	O
the	O
oviduct	O
(	O
Figure	O
3F	O
-	O
3H	O
)	O
.	O

In	O
addition	O
,	O
the	O
intercellular	O
space	O
appears	O
wider	O
post	O
-	O
mating	O
(	O
Figure	O
3C	O
-	O
3D	O
and	O
3G	O
-	O
3H	O
)	O
,	O
suggesting	O
that	O
mating	O
induces	O
increased	O
secretion	O
and	O
/	O
or	O
deposition	O
of	O
the	O
ECM	O
in	O
this	O
cellular	O
compartment	O
and	O
brings	O
the	O
ECM	O
to	O
a	O
threshold	O
concentration	O
that	O
can	O
support	O
the	O
development	O
of	O
HAJs	O
.	O

HAJs	O
were	O
also	O
detected	O
along	O
the	O
basal	O
membrane	O
,	O
but	O
they	O
were	O
not	O
detected	O
along	O
the	O
apical	O
membrane	O
even	O
though	O
this	O
membrane	O
was	O
covered	O
by	O
an	O
ECM	O
.	O

Interestingly	O
,	O
while	O
the	O
basolateral	O
membrane	O
forms	O
very	O
shallow	O
folds	O
in	O
the	O
lower	O
oviduct	O
(	O
see	O
additional	O
file	O
2	O
)	O
,	O
HAJs	O
were	O
observed	O
along	O
this	O
membrane	O
in	O
unmated	O
reproductive	O
tracts	O
(	O
data	O
not	O
shown	O
)	O
,	O
thus	O
suggesting	O
that	O
the	O
epithelia	O
is	O
more	O
differentiated	O
in	O
this	O
region	O
of	O
the	O
oviduct	O
,	O
and	O
that	O
the	O
differentiation	O
of	O
the	O
upper	O
and	O
lower	O
oviduct	O
may	O
be	O
under	O
different	O
control	O
.	O

Muscle	O
differentiation	O
is	O
enhanced	O
post	O
-	O
mating	O

While	O
we	O
uncovered	O
post	O
-	O
mating	O
changes	O
in	O
the	O
oviduct	O
epithelia	O
that	O
might	O
facilitate	O
its	O
transition	O
to	O
a	O
high	O
egg	O
-	O
laying	O
state	O
,	O
this	O
transition	O
may	O
also	O
be	O
mediated	O
by	O
changes	O
in	O
oviduct	O
muscle	O
properties	O
and	O
/	O
or	O
activity	O
.	O

The	O
oviduct	O
is	O
lined	O
by	O
circular	O
muscle	O
fibers	O
with	O
supercontractile	O
characteristics	O
[	O
30	O
]	O
.	O

Our	O
previous	O
studies	O
showed	O
that	O
mef2	O
and	O
mlp84B	O
genes	O
that	O
regulate	O
muscle	O
differentiation	O
,	O
are	O
expressed	O
and	O
increased	O
post	O
-	O
mating	O
in	O
the	O
oviduct	O
,	O
as	O
well	O
as	O
in	O
the	O
sperm	O
storage	O
regions	O
of	O
the	O
reproductive	O
tract	O
[	O
22	O
,	O
23	O
]	O
.	O

This	O
suggests	O
that	O
mating	O
induces	O
muscle	O
differentiation	O
in	O
the	O
reproductive	O
tract	O
.	O

Muscle	O
differentiation	O
is	O
characterized	O
by	O
the	O
assembly	O
of	O
myofilaments	O
into	O
bundles	O
called	O
myofibrils	O
.	O

As	O
muscles	O
differentiate	O
,	O
myofibrils	O
and	O
z	O
-	O
bodies	O
appear	O
simultaneously	O
,	O
and	O
increase	O
in	O
number	O
until	O
the	O
cytoplasm	O
is	O
filled	O
with	O
myofibrils	O
[	O
31	O
]	O
.	O

Like	O
epithelia	O
,	O
one	O
of	O
the	O
last	O
steps	O
of	O
muscle	O
differentiation	O
is	O
the	O
secretion	O
of	O
a	O
basal	O
lamina	O
that	O
surrounds	O
the	O
muscle	O
fiber	O
.	O

To	O
determine	O
if	O
mating	O
induces	O
structural	O
changes	O
in	O
muscles	O
(	O
such	O
as	O
increased	O
myofibrils	O
)	O
we	O
examined	O
the	O
ultrastructure	O
of	O
muscle	O
fibers	O
in	O
the	O
upper	O
and	O
lower	O
parts	O
of	O
the	O
oviduct	O
.	O

Our	O
analysis	O
revealed	O
that	O
,	O
in	O
both	O
unmated	O
and	O
mated	O
reproductive	O
tracts	O
,	O
the	O
muscles	O
of	O
the	O
lower	O
oviduct	O
are	O
highly	O
differentiated	O
as	O
evidenced	O
by	O
the	O
high	O
density	O
of	O
myofibrils	O
,	O
well	O
developed	O
and	O
aligned	O
z	O
-	O
bodies	O
,	O
and	O
secretion	O
of	O
a	O
thick	O
,	O
electron	O
dense	O
basal	O
lamina	O
(	O
Figure	O
4E	O
and	O
4F	O
)	O
.	O

In	O
contrast	O
,	O
muscle	O
fibers	O
in	O
the	O
lateral	O
oviducts	O
and	O
upper	O
common	O
oviduct	O
appear	O
less	O
differentiated	O
than	O
muscles	O
in	O
the	O
lower	O
common	O
oviduct	O
,	O
as	O
evidenced	O
by	O
the	O
lesser	O
density	O
of	O
myofibrils	O
and	O
z	O
-	O
bodies	O
,	O
and	O
little	O
or	O
no	O
basal	O
lamina	O
(	O
Figure	O
4A	O
and	O
4B	O
)	O
.	O

Moreover	O
,	O
the	O
muscles	O
of	O
the	O
upper	O
oviduct	O
appear	O
more	O
differentiated	O
in	O
the	O
mated	O
than	O
in	O
unmated	O
reproductive	O
tracts	O
(	O
Figure	O
4A	O
-	O
4D	O
)	O
.	O

Interestingly	O
,	O
we	O
observed	O
neighboring	O
muscle	O
fibers	O
in	O
different	O
states	O
of	O
differentiation	O
in	O
the	O
lateral	O
oviducts	O
in	O
both	O
unmated	O
and	O
mated	O
reproductive	O
tracts	O
,	O
but	O
not	O
elsewhere	O
in	O
the	O
oviduct	O
(	O
Figure	O
4B	O
)	O
.	O

These	O
results	O
suggest	O
that	O
mating	O
enhances	O
the	O
rate	O
of	O
muscle	O
differentiation	O
in	O
the	O
upper	O
oviduct	O
,	O
and	O
that	O
muscle	O
differentiation	O
is	O
delayed	O
in	O
the	O
upper	O
as	O
compared	O
to	O
the	O
lower	O
oviduct	O
.	O

The	O
increased	O
muscle	O
differentiation	O
in	O
the	O
upper	O
oviduct	O
is	O
not	O
dramatic	O
and	O
likely	O
reflects	O
the	O
short	O
post	O
-	O
mating	O
period	O
examined	O
in	O
this	O
study	O
.	O

The	O
delayed	O
differentiation	O
of	O
the	O
upper	O
oviduct	O
muscles	O
resembles	O
the	O
delay	O
in	O
the	O
onset	O
of	O
development	O
between	O
the	O
adult	O
thoracic	O
muscles	O
and	O
abdominal	O
muscles	O
during	O
metamorphosis	O
[	O
32	O
]	O
.	O

Since	O
the	O
ovaries	O
and	O
the	O
other	O
parts	O
of	O
the	O
reproductive	O
tract	O
are	O
known	O
to	O
have	O
different	O
segmental	O
origins	O
[	O
33	O
]	O
,	O
we	O
hypothesize	O
that	O
different	O
parts	O
of	O
the	O
oviduct	O
develop	O
at	O
different	O
rates	O
or	O
begin	O
development	O
at	O
different	O
times	O
.	O

Increased	O
innervation	O
in	O
the	O
oviduct	O
post	O
-	O
mating	O

Nerve	O
-	O
muscle	O
interactions	O
play	O
an	O
important	O
role	O
in	O
regulating	O
adult	O
muscle	O
development	O
and	O
refining	O
the	O
final	O
pattern	O
of	O
innervation	O
[	O
34	O
,	O
35	O
]	O
.	O

Given	O
that	O
oviduct	O
muscle	O
differentiation	O
is	O
enhanced	O
post	O
-	O
mating	O
,	O
we	O
predicted	O
that	O
mating	O
either	O
directly	O
or	O
indirectly	O
induces	O
changes	O
in	O
innervation	O
.	O

To	O
address	O
this	O
prediction	O
,	O
we	O
quantified	O
the	O
number	O
of	O
nerve	O
terminals	O
or	O
boutons	O
innervating	O
the	O
lateral	O
oviducts	O
and	O
common	O
oviduct	O
in	O
unmated	O
and	O
mated	O
reproductive	O
tracts	O
.	O

Studies	O
of	O
oviduct	O
innervation	O
in	O
Drosophila	O
reveal	O
that	O
the	O
fly	B
'	O
s	O
oviduct	O
receives	O
aminergic	O
,	O
peptidergic	O
and	O
glutamatergic	O
input	O
[	O
30	O
,	O
36	O
-	O
39	O
]	O
.	O

In	O
both	O
larval	O
and	O
adult	O
Drosophila	O
,	O
different	O
types	O
of	O
boutons	O
are	O
formed	O
by	O
neurons	O
that	O
express	O
different	O
neurotransmitters	O
and	O
modulators	O
[	O
40	O
-	O
42	O
]	O
.	O

By	O
similarity	O
to	O
the	O
boutons	O
described	O
at	O
the	O
larval	O
and	O
adult	O
neuromuscular	O
junction	O
,	O
Middleton	O
et	O
al	O
.	O

[	O
30	O
]	O
report	O
that	O
the	O
fly	B
'	O
s	O
oviduct	O
is	O
innervated	O
by	O
glutamatergic	O
type	O
I	O
boutons	O
and	O
tyraminergic	O
/	O
octopaminergic	O
type	O
II	O
boutons	O
.	O

Rodgriguez	O
-	O
Valentin	O
et	O
al	O
.	O

[	O
43	O
]	O
further	O
report	O
that	O
the	O
oviduct	O
type	O
II	O
boutons	O
co	O
-	O
express	O
octopamine	O
and	O
glutamate	O
.	O

The	O
neurons	O
that	O
give	O
rise	O
to	O
the	O
type	O
I	O
innervation	O
have	O
not	O
been	O
identified	O
.	O

However	O
,	O
it	O
is	O
well	O
established	O
that	O
type	O
II	O
innervation	O
arises	O
from	O
octopaminergic	O
neurons	O
located	O
in	O
the	O
abdominal	O
ganglion	O
[	O
30	O
,	O
43	O
]	O
.	O

In	O
addition	O
,	O
it	O
has	O
been	O
shown	O
that	O
some	O
or	O
all	O
of	O
these	O
neurons	O
express	O
a	O
GAL4	O
insertion	O
line	O
for	O
the	O
bullwinkle	O
(	O
bwk	O
)	O
gene	O
[	O
43	O
]	O
.	O

Bwk	O
encodes	O
a	O
HMG	O
-	O
box	O
containing	O
putative	O
transcription	O
factor	O
[	O
44	O
]	O
.	O

To	O
determine	O
if	O
mating	O
induces	O
any	O
changes	O
in	O
the	O
number	O
of	O
type	O
I	O
and	O
II	O
boutons	O
innervating	O
the	O
oviduct	O
muscles	O
,	O
we	O
used	O
the	O
pan	O
-	O
neural	O
marker	O
,	O
anti	O
-	O
HRP	O
to	O
label	O
all	O
oviduct	O
boutons	O
in	O
unmated	O
and	O
mated	O
females	O
.	O

To	O
distinguish	O
between	O
type	O
I	O
and	O
II	O
boutons	O
we	O
used	O
an	O
antibody	O
against	O
the	O
Disc	O
Large	O
(	O
DLG	O
)	O
protein	O
[	O
45	O
]	O
.	O

Type	O
I	O
boutons	O
were	O
identified	O
by	O
their	O
DLG	O
postsynaptic	O
staining	O
and	O
large	O
size	O
(	O
>	O
8	O
mu	O
m	O
in	O
diameter	O
)	O
(	O
Figure	O
4G	O
)	O
,	O
while	O
type	O
II	O
boutons	O
were	O
distinguished	O
by	O
their	O
absence	O
of	O
DLG	O
staining	O
and	O
smaller	O
size	O
(	O
<	O
2	O
mu	O
m	O
)	O
(	O
Figure	O
4H	O
)	O
.	O

We	O
find	O
that	O
type	O
I	O
and	O
II	O
boutons	O
innervate	O
the	O
lateral	O
oviducts	O
and	O
common	O
oviduct	O
,	O
and	O
that	O
the	O
type	O
I	O
innervation	O
is	O
restricted	O
to	O
a	O
few	O
axons	O
that	O
run	O
parallel	O
to	O
the	O
length	O
of	O
the	O
oviduct	O
,	O
while	O
the	O
type	O
II	O
innervation	O
is	O
more	O
widespread	O
.	O

We	O
quantified	O
the	O
number	O
of	O
boutons	O
in	O
the	O
lateral	O
oviducts	O
and	O
common	O
oviduct	O
and	O
observed	O
a	O
74	O
%	O
increase	O
in	O
bouton	O
number	O
in	O
the	O
lateral	O
oviduct	O
and	O
a	O
66	O
%	O
increase	O
in	O
the	O
common	O
oviduct	O
post	O
-	O
mating	O
(	O
Figure	O
4I	O
)	O
.	O

More	O
over	O
,	O
we	O
observed	O
no	O
significant	O
change	O
in	O
the	O
number	O
of	O
type	O
I	O
boutons	O
in	O
the	O
lateral	O
oviduct	O
and	O
common	O
oviduct	O
.	O

However	O
,	O
we	O
detected	O
a	O
1	O
.	O
5	O
-	O
fold	O
increase	O
in	O
the	O
number	O
of	O
type	O
II	O
boutons	O
in	O
the	O
lateral	O
oviduct	O
and	O
a	O
1	O
.	O
8	O
-	O
fold	O
increase	O
in	O
type	O
II	O
innervation	O
in	O
the	O
common	O
oviduct	O
.	O

Dramatic	O
increases	O
in	O
bouton	O
growth	O
are	O
also	O
observed	O
during	O
development	O
.	O

For	O
example	O
,	O
a	O
ten	O
-	O
fold	O
increase	O
in	O
bouton	O
number	O
is	O
observed	O
at	O
the	O
neuromuscular	O
junction	O
during	O
the	O
larval	O
period	O
[	O
46	O
]	O
.	O

To	O
determine	O
if	O
the	O
increase	O
in	O
type	O
II	O
innervation	O
was	O
specific	O
to	O
mating	O
or	O
reflected	O
normal	O
growth	O
in	O
3	O
day	O
-	O
old	O
females	O
,	O
we	O
quantified	O
type	O
I	O
and	O
II	O
innervation	O
in	O
the	O
oviducts	O
of	O
5	O
day	O
-	O
old	O
unmated	O
females	O
.	O

We	O
found	O
no	O
significant	O
difference	O
in	O
type	O
I	O
and	O
II	O
innervation	O
in	O
unmated	O
3	O
day	O
-	O
old	O
and	O
5	O
-	O
day	O
-	O
old	O
females	O
,	O
indicating	O
that	O
mating	O
,	O
either	O
directly	O
or	O
indirectly	O
,	O
induces	O
a	O
dramatic	O
increase	O
in	O
type	O
II	O
innervation	O
(	O
Figure	O
4I	O
)	O
.	O

To	O
determine	O
if	O
the	O
post	O
-	O
mating	O
increase	O
in	O
innervation	O
is	O
unique	O
to	O
the	O
oviduct	O
,	O
we	O
asked	O
if	O
mating	O
induces	O
a	O
global	O
change	O
in	O
innervation	O
.	O

We	O
quantified	O
bouton	O
number	O
in	O
the	O
adult	O
ventral	O
midline	O
muscles	O
of	O
the	O
5th	O
abdominal	O
segment	O
.	O

These	O
muscles	O
are	O
innervated	O
by	O
boutons	O
that	O
increase	O
in	O
number	O
during	O
metamorphosis	O
[	O
47	O
]	O
.	O

No	O
significant	O
difference	O
in	O
bouton	O
number	O
was	O
detected	O
at	O
these	O
muscles	O
in	O
unmated	O
and	O
mated	O
females	O
(	O
additional	O
file	O
3	O
)	O
.	O

Though	O
further	O
analysis	O
is	O
needed	O
,	O
this	O
suggests	O
that	O
the	O
post	O
-	O
mating	O
increase	O
in	O
innervation	O
is	O
oviduct	O
-	O
specific	O
.	O

Because	O
the	O
type	O
II	O
boutons	O
are	O
octopaminergic	O
,	O
the	O
increased	O
type	O
II	O
innervation	O
may	O
result	O
in	O
increased	O
octopamine	O
(	O
OA	O
)	O
release	O
in	O
the	O
oviduct	O
.	O

In	O
support	O
of	O
this	O
possibility	O
,	O
we	O
have	O
preliminary	O
evidence	O
that	O
OA	O
is	O
released	O
in	O
the	O
oviduct	O
post	O
-	O
mating	O
(	O
Heifetz	O
and	O
Wolfner	O
,	O
in	O
preparation	O
)	O
.	O

Studies	O
in	O
locust	O
and	O
Drosophila	O
demonstrate	O
that	O
OA	O
inhibits	O
oviduct	O
contraction	O
,	O
while	O
glutamate	O
activates	O
oviduct	O
contraction	O
[	O
30	O
,	O
43	O
,	O
48	O
]	O
.	O

In	O
Drosophila	O
,	O
electrical	O
stimulation	O
of	O
the	O
posterior	O
abdominal	O
nerve	O
gives	O
rise	O
to	O
a	O
series	O
of	O
muscle	O
contractions	O
in	O
the	O
oviduct	O
followed	O
by	O
a	O
period	O
of	O
muscle	O
fatigue	O
or	O
relaxation	O
[	O
43	O
]	O
.	O

This	O
pattern	O
of	O
muscle	O
contraction	O
and	O
relaxation	O
may	O
facilitate	O
the	O
proper	O
movement	O
of	O
the	O
egg	O
through	O
the	O
oviduct	O
.	O

In	O
their	O
study	O
of	O
bwk	O
expressing	O
neurons	O
that	O
innervate	O
the	O
oviduct	O
,	O
Rodriguez	O
-	O
Valentin	O
et	O
al	O
.	O

[	O
43	O
]	O
show	O
that	O
OA	O
and	O
glutamate	O
interact	O
to	O
produce	O
the	O
pattern	O
of	O
oviduct	O
contraction	O
and	O
relaxation	O
described	O
above	O
.	O

It	O
is	O
therefore	O
possible	O
that	O
the	O
post	O
-	O
mating	O
increase	O
in	O
type	O
II	O
innervation	O
in	O
the	O
oviduct	O
plays	O
an	O
important	O
role	O
in	O
the	O
increased	O
rate	O
of	O
ovulation	O
and	O
egg	O
-	O
laying	O
observed	O
post	O
-	O
mating	O
.	O

Female	O
mating	O
history	O
affects	O
the	O
enrichment	O
of	O
cytosekeletal	O
proteins	O
in	O
the	O
oviduct	O

To	O
gain	O
insights	O
into	O
the	O
role	O
of	O
cytoskeletal	O
protein	O
enrichment	O
(	O
[	O
23	O
]	O
;	O
additional	O
file	O
4	O
)	O
in	O
mediating	O
the	O
morphological	O
changes	O
detected	O
in	O
this	O
study	O
,	O
we	O
examined	O
the	O
effect	O
of	O
different	O
mating	O
regimes	O
on	O
cytoskeletal	O
protein	O
abundance	O
.	O

We	O
focused	O
on	O
a	O
subset	O
of	O
mating	O
-	O
responsive	O
cytoskeletal	O
proteins	O
with	O
well	O
established	O
roles	O
in	O
the	O
differentiation	O
of	O
muscle	O
and	O
epithelia	O
.	O

These	O
include	O
:	O
(	O
i	O
)	O
Mlp84B	O
which	O
regulates	O
the	O
late	O
differentiation	O
pathway	O
of	O
muscle	O
[	O
49	O
]	O
;	O
(	O
ii	O
)	O
Cora	O
and	O
Nrg	O
which	O
are	O
required	O
for	O
the	O
formation	O
of	O
septate	O
junctions	O
in	O
epithelia	O
[	O
50	O
]	O
,	O
and	O
(	O
iii	O
)	O
Hu	O
-	O
li	O
tai	O
shao	O
(	O
Hts	O
)	O
,	O
also	O
known	O
as	O
adducin	O
-	O
like	O
protein	O
,	O
which	O
functions	O
in	O
assembly	O
of	O
the	O
cytoskeletal	O
network	O
.	O

Na	O
+	O
pump	O
alpha	O
subunit	O
(	O
ATP	O
alpha	O
)	O
,	O
another	O
protein	O
associated	O
with	O
septate	O
junctions	O
in	O
epithelia	O
,	O
is	O
not	O
a	O
mating	O
-	O
responsive	O
protein	O
and	O
was	O
used	O
as	O
a	O
control	O
.	O

Using	O
western	O
blots	O
,	O
we	O
first	O
determined	O
the	O
abundance	O
of	O
the	O
cytoskeletal	O
proteins	O
in	O
oviducts	O
of	O
3	O
-	O
day	O
-	O
old	O
unmated	O
and	O
mated	O
females	O
at	O
6	O
hrs	O
post	O
-	O
mating	O
.	O

We	O
confirmed	O
the	O
proteomic	O
results	O
of	O
Kalpenikov	O
et	O
al	O
.	O

[	O
23	O
]	O
and	O
found	O
that	O
mating	O
increases	O
the	O
abundance	O
of	O
all	O
proteins	O
,	O
except	O
ATP	O
alpha	O
in	O
mated	O
oviducts	O
relative	O
to	O
their	O
abundance	O
in	O
unmated	O
oviducts	O
(	O
Figure	O
5A	O
)	O
.	O

To	O
determine	O
whether	O
the	O
increased	O
abundance	O
of	O
mating	O
-	O
responsive	O
proteins	O
persists	O
for	O
longer	O
times	O
post	O
-	O
mating	O
,	O
we	O
examined	O
oviducts	O
of	O
10	O
-	O
day	O
-	O
old	O
females	O
that	O
mated	O
once	O
at	O
3	O
days	O
of	O
age	O
,	O
and	O
calculated	O
the	O
abundance	O
of	O
the	O
mating	O
-	O
responsive	O
proteins	O
relative	O
to	O
their	O
level	O
in	O
oviducts	O
of	O
3	O
-	O
day	O
-	O
old	O
unmated	O
females	O
.	O

We	O
found	O
no	O
change	O
or	O
a	O
slight	O
increase	O
in	O
the	O
relative	O
abundance	O
of	O
all	O
cytoskeletal	O
proteins	O
except	O
Mlp84B	O
at	O
7	O
days	O
post	O
-	O
mating	O
(	O
Figure	O
5A	O
)	O
.	O

Strikingly	O
,	O
the	O
level	O
of	O
Mlp84B	O
declines	O
by	O
7	O
days	O
post	O
-	O
mating	O
to	O
the	O
level	O
observed	O
prior	O
to	O
mating	O
.	O

Thus	O
Mlp84B	O
levels	O
rise	O
and	O
fall	O
after	O
mating	O
,	O
while	O
the	O
epithelial	O
-	O
related	O
proteins	O
rapidly	O
rise	O
and	O
are	O
maintained	O
at	O
a	O
high	O
level	O
after	O
mating	O
.	O

This	O
raises	O
the	O
possibility	O
that	O
a	O
second	O
mating	O
might	O
trigger	O
an	O
increase	O
in	O
Mlp84B	O
protein	O
expression	O
as	O
observed	O
in	O
3	O
-	O
day	O
-	O
old	O
females	O
at	O
6	O
h	O
post	O
-	O
mating	O
.	O

To	O
test	O
this	O
possibility	O
,	O
females	O
were	O
mated	O
twice	O
(	O
once	O
at	O
day	O
3	O
,	O
and	O
once	O
on	O
day	O
10	O
of	O
age	O
)	O
,	O
and	O
their	O
oviducts	O
were	O
examined	O
at	O
6	O
hrs	O
after	O
the	O
second	O
mating	O
.	O

We	O
calculated	O
the	O
abundance	O
of	O
the	O
cytoskeletal	O
proteins	O
in	O
the	O
twice	O
mated	O
oviducts	O
relative	O
to	O
their	O
abundance	O
in	O
oviducts	O
of	O
3	O
-	O
day	O
-	O
old	O
unmated	O
females	O
.	O

Our	O
results	O
show	O
that	O
a	O
second	O
mating	O
has	O
little	O
or	O
no	O
effect	O
on	O
Mlp84B	O
abundance	O
.	O

Thus	O
,	O
Mlp84B	O
may	O
represent	O
a	O
class	O
of	O
mating	O
-	O
responsive	O
proteins	O
that	O
is	O
only	O
needed	O
after	O
the	O
first	O
mating	O
.	O

Interestingly	O
,	O
the	O
effect	O
of	O
the	O
second	O
mating	O
on	O
the	O
epithelial	O
-	O
related	O
mating	O
-	O
responsive	O
proteins	O
appears	O
to	O
be	O
different	O
for	O
each	O
protein	O
.	O

While	O
Cora	O
levels	O
drop	O
to	O
the	O
level	O
observed	O
in	O
3	O
-	O
day	O
-	O
old	O
unmated	O
females	O
,	O
Nrg	O
and	O
Hts	O
are	O
maintained	O
at	O
a	O
high	O
level	O
.	O

To	O
determine	O
if	O
the	O
changes	O
in	O
cytoskeletal	O
protein	O
abundance	O
are	O
mating	O
-	O
dependent	O
we	O
measured	O
their	O
abundance	O
in	O
the	O
oviducts	O
of	O
unmated	O
5	O
-	O
and	O
10	O
-	O
day	O
-	O
old	O
females	O
.	O

We	O
calculated	O
their	O
abundance	O
relative	O
to	O
their	O
level	O
in	O
oviducts	O
of	O
unmated	O
3	O
-	O
day	O
-	O
old	O
females	O
(	O
Figure	O
5B	O
)	O
.	O

We	O
rationalized	O
that	O
if	O
the	O
change	O
in	O
cytoskeletal	O
protein	O
abundance	O
is	O
mating	O
-	O
dependent	O
we	O
will	O
not	O
see	O
similar	O
changes	O
in	O
unmated	O
females	O
.	O

We	O
observed	O
a	O
slow	O
increase	O
in	O
the	O
relative	O
abundance	O
of	O
all	O
mating	O
-	O
responsive	O
proteins	O
with	O
time	O
post	O
-	O
eclosion	O
(	O
Figure	O
5B	O
)	O
.	O

Because	O
unmated	O
females	O
lay	O
more	O
eggs	O
as	O
they	O
age	O
(	O
see	O
additional	O
file	O
5C	O
)	O
one	O
possible	O
interpretation	O
of	O
the	O
increased	O
level	O
of	O
cytoskeletal	O
proteins	O
in	O
unmated	O
females	O
is	O
that	O
these	O
proteins	O
are	O
associated	O
with	O
an	O
intrinsic	O
program	O
for	O
oviduct	O
maturation	O
and	O
that	O
mating	O
accelerates	O
this	O
process	O
to	O
maximize	O
egg	O
-	O
laying	O
efficacy	O
.	O

Alternatively	O
,	O
it	O
is	O
possible	O
that	O
the	O
slow	O
increase	O
in	O
protein	O
abundance	O
observed	O
in	O
unmated	O
females	O
is	O
due	O
to	O
the	O
passage	O
of	O
eggs	O
through	O
the	O
oviduct	O
.	O

Taken	O
together	O
,	O
our	O
results	O
suggest	O
that	O
mating	O
is	O
essential	O
to	O
fine	O
-	O
tune	O
the	O
levels	O
of	O
the	O
mating	O
-	O
responsive	O
proteins	O
examined	O
in	O
this	O
study	O
.	O

Because	O
the	O
changes	O
in	O
cytoskeletal	O
protein	O
abundance	O
are	O
different	O
in	O
unmated	O
and	O
mated	O
females	O
,	O
this	O
suggests	O
that	O
the	O
post	O
-	O
mating	O
changes	O
are	O
mating	O
-	O
dependent	O
.	O

Furthermore	O
,	O
we	O
suggest	O
that	O
these	O
post	O
-	O
mating	O
changes	O
are	O
linked	O
to	O
changes	O
in	O
oviduct	O
function	O
.	O

Early	O
or	O
prior	O
mating	O
increases	O
fecundity	O

In	O
Drosophila	O
,	O
female	O
fecundity	O
decreases	O
with	O
age	O
[	O
51	O
-	O
54	O
]	O
.	O

It	O
has	O
been	O
proposed	O
that	O
this	O
decrease	O
is	O
due	O
,	O
in	O
part	O
,	O
to	O
the	O
loss	O
of	O
germline	O
and	O
somatic	O
stem	O
cells	O
[	O
55	O
]	O
.	O

Since	O
the	O
expression	O
of	O
the	O
oviduct	O
cytoskeletal	O
proteins	O
examined	O
in	O
this	O
study	O
change	O
with	O
age	O
and	O
mating	O
experience	O
,	O
the	O
state	O
of	O
the	O
oviduct	O
may	O
also	O
play	O
a	O
role	O
in	O
fecundity	O
.	O

To	O
separate	O
the	O
effects	O
of	O
age	O
and	O
mating	O
,	O
we	O
measured	O
the	O
fecundity	O
of	O
females	O
that	O
mated	O
twice	O
,	O
first	O
at	O
3	O
days	O
post	O
-	O
eclosion	O
and	O
again	O
at	O
10	O
days	O
,	O
and	O
compared	O
that	O
to	O
the	O
fecundity	O
of	O
females	O
that	O
mated	O
once	O
at	O
3	O
days	O
and	O
females	O
that	O
mated	O
once	O
at	O
10	O
days	O
.	O

Fecundity	O
was	O
measured	O
as	O
the	O
number	O
of	O
eggs	O
laid	O
per	O
day	O
per	O
female	O
during	O
the	O
first	O
three	O
days	O
after	O
mating	O
.	O

Once	O
-	O
mated	O
3	O
-	O
day	O
-	O
old	O
females	O
laid	O
nearly	O
twice	O
as	O
many	O
eggs	O
as	O
once	O
-	O
mated	O
10	O
-	O
day	O
-	O
old	O
females	O
during	O
the	O
three	O
days	O
examined	O
(	O
24	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
7	O
versus	O
13	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
9	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
.	O

Twice	O
-	O
mated	O
10	O
-	O
day	O
-	O
old	O
females	O
also	O
laid	O
about	O
50	O
%	O
more	O
eggs	O
than	O
once	O
-	O
mated	O
females	O
of	O
the	O
same	O
age	O
(	O
19	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
9	O
versus	O
13	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
9	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
,	O
but	O
about	O
20	O
%	O
fewer	O
than	O
laid	O
by	O
once	O
-	O
mated	O
3	O
-	O
day	O
-	O
old	O
females	O
during	O
the	O
three	O
days	O
examined	O
(	O
19	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
9	O
versus	O
24	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
7	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
(	O
Figure	O
6A	O
,	O
see	O
also	O
additional	O
file	O
5A	O
and	O
5B	O
)	O
.	O

Thus	O
,	O
the	O
difference	O
in	O
fecundity	O
between	O
once	O
-	O
mated	O
10	O
-	O
day	O
-	O
old	O
and	O
once	O
-	O
mated	O
3	O
-	O
day	O
-	O
old	O
females	O
is	O
not	O
a	O
result	O
of	O
age	O
alone	O
.	O

Rather	O
the	O
main	O
determinant	O
of	O
fecundity	O
at	O
10	O
days	O
is	O
whether	O
there	O
had	O
been	O
a	O
prior	O
mating	O
at	O
3	O
days	O
.	O

We	O
also	O
calculated	O
the	O
fertility	O
(	O
number	O
of	O
adults	O
eclosed	O
)	O
of	O
once	O
-	O
and	O
twice	O
-	O
mated	O
females	O
.	O

Once	O
-	O
mated	O
3	O
-	O
day	O
-	O
old	O
females	O
are	O
more	O
fertile	O
than	O
once	O
-	O
mated	O
10	O
-	O
day	O
-	O
old	O
females	O
(	O
69	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
6	O
%	O
versus	O
56	O
.	O
1	O
+	O
/	O
-	O
3	O
.	O
0	O
%	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
and	O
slightly	O
more	O
fertile	O
than	O
twice	O
-	O
mated	O
10	O
-	O
day	O
-	O
old	O
females	O
(	O
69	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
6	O
%	O
versus	O
62	O
.	O
7	O
+	O
/	O
-	O
2	O
.	O
4	O
%	O
,	O
p	O
<	O
0	O
.	O
015	O
)	O
(	O
Figure	O
6B	O
,	O
see	O
also	O
additional	O
file	O
5D	O
)	O
.	O

Because	O
there	O
is	O
no	O
significant	O
difference	O
in	O
fertility	O
between	O
once	O
-	O
mated	O
and	O
twice	O
-	O
mated	O
10	O
-	O
day	O
-	O
old	O
females	O
,	O
this	O
suggests	O
that	O
(	O
1	O
)	O
a	O
prior	O
mating	O
has	O
no	O
significant	O
effect	O
on	O
the	O
fertility	O
of	O
10	O
-	O
day	O
-	O
old	O
mated	O
females	O
and	O
(	O
2	O
)	O
fertility	O
decreases	O
with	O
age	O
.	O

One	O
intriguing	O
interpretation	O
of	O
these	O
results	O
is	O
that	O
an	O
early	O
mating	O
increases	O
fecundity	O
which	O
partially	O
compensates	O
for	O
the	O
age	O
-	O
related	O
decrease	O
in	O
fertility	O
.	O

Thus	O
,	O
cytoskeletal	O
mating	O
-	O
responsive	O
protein	O
changes	O
may	O
be	O
associated	O
with	O
structural	O
changes	O
in	O
the	O
oviduct	O
that	O
result	O
in	O
increased	O
fecundity	O
.	O

This	O
may	O
counteract	O
the	O
effects	O
of	O
decreased	O
fertility	O
on	O
the	O
reproductive	O
output	O
.	O

Discussion	O

Despite	O
the	O
use	O
of	O
Drosophila	O
as	O
a	O
model	O
system	O
for	O
organ	O
-	O
level	O
biology	O
and	O
the	O
emerging	O
parallels	O
between	O
mammalian	O
and	O
Drosophila	B
reproductive	O
biology	O
[	O
56	O
]	O
,	O
this	O
is	O
the	O
first	O
integrative	O
tissue	O
-	O
wide	O
study	O
of	O
post	O
-	O
mating	O
changes	O
in	O
the	O
Drosophila	B
oviduct	O
.	O

Our	O
results	O
provide	O
several	O
lines	O
of	O
evidence	O
at	O
the	O
molecular	O
,	O
morphological	O
and	O
physiological	O
levels	O
suggesting	O
that	O
mating	O
induces	O
tissue	O
-	O
wide	O
differentiation	O
in	O
the	O
oviduct	O
.	O

Moreover	O
,	O
we	O
identify	O
ultrastructural	O
changes	O
in	O
the	O
mated	O
oviduct	O
that	O
are	O
consistent	O
with	O
the	O
roles	O
that	O
some	O
of	O
the	O
mating	O
-	O
responsive	O
proteins	O
examined	O
in	O
this	O
study	O
(	O
e	O
.	O
g	O
.	O
Mlp84B	O
,	O
Cora	O
,	O
Nrg	O
)	O
are	O
reported	O
to	O
play	O
in	O
muscle	O
and	O
epithelial	O
differentiation	O
elsewhere	O
.	O

For	O
example	O
,	O
the	O
increased	O
abundance	O
of	O
Mlp84B	O
,	O
a	O
major	O
regulator	O
of	O
the	O
late	O
differentiation	O
pathway	O
of	O
muscle	O
[	O
49	O
]	O
is	O
consistent	O
with	O
the	O
increased	O
muscle	O
differentiation	O
in	O
the	O
upper	O
oviduct	O
post	O
-	O
mating	O
(	O
Figure	O
4A	O
-	O
4F	O
)	O
.	O

Similarly	O
,	O
the	O
increased	O
abundance	O
of	O
Cora	O
and	O
Nrg	O
,	O
molecules	O
that	O
are	O
essential	O
for	O
SJ	O
development	O
and	O
function	O
[	O
50	O
]	O
is	O
consistent	O
with	O
the	O
observation	O
that	O
SJs	O
in	O
the	O
upper	O
oviduct	O
are	O
immature	O
and	O
/	O
or	O
that	O
mating	O
induces	O
changes	O
in	O
the	O
apical	O
extracellular	O
matrix	O
whose	O
secretion	O
may	O
be	O
regulated	O
,	O
in	O
part	O
,	O
by	O
SJs	O
as	O
occurs	O
in	O
the	O
trachea	O
[	O
27	O
,	O
28	O
]	O
.	O

Other	O
post	O
-	O
mating	O
changes	O
that	O
indicate	O
that	O
mating	O
induces	O
tissue	O
-	O
wide	O
differentiation	O
include	O
increased	O
HAJs	O
along	O
the	O
basolateral	O
membrane	O
and	O
increased	O
innervation	O
.	O

Analysis	O
of	O
protein	O
abundance	O
following	O
different	O
mating	O
regimes	O
(	O
unmated	O
,	O
once	O
-	O
mated	O
,	O
twice	O
-	O
mated	O
)	O
gave	O
us	O
further	O
insights	O
into	O
the	O
possible	O
roles	O
that	O
mating	O
-	O
responsive	O
proteins	O
play	O
in	O
the	O
oviduct	O
.	O

For	O
example	O
,	O
Mlp84B	O
is	O
only	O
responsive	O
to	O
the	O
first	O
mating	O
,	O
while	O
the	O
epithelial	O
proteins	O
examined	O
(	O
Cora	O
,	O
Nrg	O
and	O
Hts	O
)	O
are	O
responsive	O
to	O
the	O
first	O
and	O
second	O
mating	O
.	O

Furthermore	O
,	O
the	O
response	O
to	O
the	O
second	O
mating	O
is	O
different	O
from	O
the	O
response	O
to	O
the	O
first	O
mating	O
.	O

Taken	O
together	O
,	O
these	O
results	O
suggest	O
that	O
Mlp84B	O
is	O
required	O
for	O
the	O
final	O
maturation	O
of	O
the	O
oviduct	O
,	O
while	O
the	O
epithelial	O
proteins	O
examined	O
are	O
required	O
for	O
both	O
the	O
maturation	O
and	O
maintenance	O
of	O
the	O
oviduct	O
at	O
a	O
high	O
functional	O
state	O
.	O

Moreover	O
,	O
the	O
post	O
-	O
mating	O
pattern	O
of	O
Mlp84B	O
supports	O
the	O
idea	O
that	O
the	O
first	O
mating	O
induces	O
the	O
final	O
maturation	O
of	O
the	O
oviduct	O
.	O

The	O
rise	O
and	O
fall	O
of	O
Mlp84B	O
abundance	O
after	O
the	O
first	O
mating	O
(	O
Figure	O
5	O
)	O
parallels	O
the	O
expression	O
pattern	O
of	O
Mlp84B	O
during	O
development	O
where	O
peaks	O
in	O
Mlp84B	O
transcription	O
occur	O
during	O
periods	O
of	O
embryogenesis	O
and	O
metamorphosis	O
when	O
muscle	O
is	O
differentiating	O
[	O
49	O
]	O
.	O

Using	O
different	O
mating	O
regimes	O
we	O
tested	O
whether	O
the	O
first	O
/	O
early	O
mating	O
is	O
essential	O
for	O
maintenance	O
of	O
high	O
reproductive	O
output	O
in	O
the	O
second	O
mating	O
.	O

Our	O
results	O
suggest	O
that	O
mating	O
at	O
an	O
early	O
age	O
is	O
essential	O
to	O
achieve	O
maximum	O
reproductive	O
output	O
(	O
i	O
.	O
e	O
.	O
high	O
fecundity	O
and	O
fertility	O
)	O
.	O

Since	O
the	O
first	O
mating	O
increases	O
reproductive	O
output	O
(	O
evidence	O
from	O
our	O
mating	O
regime	O
experiments	O
)	O
,	O
it	O
is	O
likely	O
that	O
the	O
ultrastructural	O
changes	O
detected	O
in	O
mated	O
3	O
-	O
day	O
-	O
old	O
females	O
lead	O
to	O
a	O
highly	O
functional	O
oviduct	O
.	O

We	O
suggest	O
that	O
the	O
final	O
maturation	O
of	O
the	O
oviduct	O
includes	O
a	O
mating	O
-	O
dependent	O
stage	O
.	O

We	O
propose	O
that	O
during	O
the	O
first	O
few	O
days	O
post	O
-	O
eclosion	O
,	O
the	O
oviduct	O
undergoes	O
the	O
first	O
phase	O
of	O
differentiation	O
,	O
after	O
which	O
the	O
oviduct	O
is	O
developmentally	O
poised	O
for	O
a	O
rapid	O
response	O
to	O
an	O
extrinsic	O
cue	O
(	O
mating	O
)	O
.	O

Mating	O
then	O
triggers	O
the	O
second	O
phase	O
of	O
maturation	O
(	O
tissue	O
remodeling	O
and	O
modulation	O
)	O
which	O
is	O
essential	O
for	O
proper	O
oviduct	O
function	O
(	O
Figure	O
7	O
)	O
.	O

We	O
further	O
propose	O
that	O
the	O
second	O
phase	O
of	O
maturation	O
consists	O
of	O
processes	O
that	O
are	O
mating	O
-	O
independent	O
and	O
-	O
dependent	O
,	O
and	O
that	O
both	O
of	O
these	O
pathways	O
are	O
essential	O
to	O
produce	O
a	O
functional	O
oviduct	O
.	O

For	O
example	O
,	O
initial	O
formation	O
of	O
SJs	O
occurs	O
prior	O
to	O
mating	O
(	O
mating	O
-	O
independent	O
)	O
while	O
the	O
increased	O
apical	O
secretion	O
and	O
development	O
of	O
HAJs	O
are	O
mating	O
-	O
dependent	O
.	O

The	O
oviduct	O
musculature	O
is	O
an	O
example	O
where	O
both	O
mating	O
-	O
independent	O
and	O
-	O
dependent	O
processes	O
play	O
a	O
role	O
.	O

Muscles	O
are	O
highly	O
differentiated	O
in	O
the	O
lower	O
oviduct	O
prior	O
to	O
mating	O
,	O
while	O
muscle	O
differentiation	O
is	O
ongoing	O
in	O
the	O
upper	O
oviduct	O
and	O
increases	O
after	O
mating	O
.	O

Although	O
the	O
onset	O
of	O
muscle	O
differentiation	O
in	O
both	O
regions	O
is	O
mating	O
-	O
independent	O
,	O
the	O
further	O
differentiation	O
of	O
muscle	O
in	O
the	O
upper	O
oviduct	O
is	O
mating	O
-	O
dependent	O
.	O

Another	O
possible	O
interpretation	O
of	O
the	O
role	O
of	O
mating	O
on	O
oviduct	O
maturation	O
is	O
that	O
mating	O
accelerates	O
and	O
synchronizes	O
processes	O
that	O
are	O
essential	O
for	O
the	O
functional	O
maturation	O
of	O
the	O
oviduct	O
.	O

It	O
will	O
therefore	O
be	O
interesting	O
to	O
examine	O
the	O
oviducts	O
of	O
older	O
females	O
to	O
determine	O
the	O
status	O
of	O
oviduct	O
maturation	O
.	O

What	O
is	O
the	O
benefit	O
of	O
mating	O
-	O
induced	O
differentiation	O
of	O
the	O
oviduct	O
tissues	O
?	O

Unmated	O
females	O
are	O
capable	O
of	O
laying	O
eggs	O
,	O
albeit	O
at	O
a	O
reduced	O
rate	O
as	O
compared	O
to	O
mated	O
females	O
of	O
the	O
same	O
age	O
.	O

One	O
possible	O
interpretation	O
is	O
that	O
reproduction	O
is	O
energetically	O
costly	O
,	O
thus	O
delaying	O
oviduct	O
maturation	O
until	O
sperm	O
is	O
available	O
is	O
advantageous	O
to	O
the	O
female	O
.	O

This	O
may	O
reflect	O
the	O
evolution	O
of	O
a	O
mechanism	O
to	O
optimize	O
reproductive	O
capacity	O
in	O
early	O
adulthood	O
in	O
short	O
-	O
lived	O
animals	O
.	O

In	O
summary	O
,	O
we	O
have	O
identified	O
events	O
at	O
the	O
cellular	O
,	O
molecular	O
and	O
physiological	O
levels	O
that	O
are	O
part	O
of	O
an	O
efficient	O
and	O
specific	O
program	O
for	O
reproduction	O
.	O

Drosophila	O
affords	O
us	O
the	O
opportunity	O
to	O
uncover	O
the	O
signaling	O
pathways	O
that	O
coordinate	O
these	O
events	O
to	O
produce	O
a	O
physiologically	O
functional	O
organ	O
.	O

Methods	O

Flies	O

Wild	O
-	O
type	O
Canton	O
-	O
S	O
flies	B
were	O
used	O
for	O
the	O
fecundity	O
/	O
fertility	O
experiments	O
and	O
confocal	O
analysis	O
.	O

Wild	O
-	O
type	O
Canton	O
-	O
S5	O
[	O
57	O
]	O
flies	B
were	O
used	O
for	O
electron	O
microscopy	O
.	O

All	O
flies	B
were	O
kept	O
in	O
a	O
12	O
hrs	O
light	O
/	O
dark	O
cycle	O
at	O
23	O
+	O
/	O
-	O
2	O
degrees	O
C	O
.	O

Upon	O
eclosion	O
,	O
females	O
and	O
males	O
were	O
collected	O
on	O
ice	O
and	O
held	O
separately	O
until	O
3	O
(	O
females	O
and	O
males	O
)	O
or	O
10	O
(	O
females	O
)	O
days	O
of	O
age	O
.	O

Sample	O
preparation	O

For	O
all	O
assays	O
(	O
unless	O
described	O
differently	O
)	O
unmated	O
females	O
were	O
placed	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
and	O
observed	O
until	O
mating	O
initiated	O
.	O

At	O
the	O
end	O
of	O
mating	O
,	O
females	O
were	O
aspirated	O
into	O
fresh	O
vials	O
and	O
held	O
for	O
6	O
hrs	O
.	O

At	O
6	O
hrs	O
after	O
the	O
start	O
of	O
mating	O
,	O
females	O
were	O
placed	O
on	O
ice	O
for	O
dissection	O
.	O

Previous	O
molecular	O
studies	O
indicate	O
changes	O
in	O
protein	O
abundance	O
at	O
3	O
hrs	O
post	O
-	O
mating	O
.	O

We	O
hypothesize	O
that	O
these	O
molecular	O
changes	O
will	O
translate	O
into	O
morphological	O
changes	O
in	O
the	O
next	O
few	O
hours	O
.	O

We	O
chose	O
to	O
analyze	O
the	O
morphology	O
of	O
mated	O
females	O
at	O
6	O
h	O
post	O
-	O
mating	O
as	O
opposed	O
to	O
later	O
times	O
post	O
-	O
mating	O
because	O
the	O
changes	O
observed	O
at	O
later	O
times	O
may	O
be	O
due	O
,	O
in	O
part	O
,	O
to	O
the	O
high	O
rate	O
of	O
eggs	O
passing	O
through	O
the	O
oviduct	O
.	O

Electron	O
microscopy	O

Reproductive	O
tracts	O
were	O
dissected	O
in	O
Schneider	O
'	O
s	O
Drosophila	B
medium	O
(	O
Sigma	O
)	O
on	O
ice	O
and	O
processed	O
for	O
electron	O
microscopy	O
as	O
described	O
in	O
[	O
42	O
]	O
.	O

Tracts	O
were	O
flat	O
-	O
embedded	O
between	O
two	O
sheets	O
of	O
Aclar	O
(	O
Electron	O
Microscopy	O
Sciences	O
)	O
,	O
which	O
allowed	O
us	O
to	O
image	O
the	O
entire	O
tract	O
at	O
the	O
light	O
microscopic	O
level	O
prior	O
to	O
sectioning	O
.	O

Sections	O
were	O
cut	O
on	O
a	O
Reichart	O
Ultracut	O
microtome	O
.	O

One	O
-	O
mu	O
m	O
thick	O
sections	O
were	O
stained	O
with	O
1	O
%	O
toluidine	O
blue	O
,	O
and	O
viewed	O
with	O
a	O
Zeiss	O
Axoplan	O
microscope	O
.	O

Ultrathin	O
sections	O
(	O
~	O
100	O
nm	O
)	O
were	O
mounted	O
on	O
formvar	O
grids	O
,	O
stained	O
with	O
lead	O
citrate	O
,	O
and	O
viewed	O
with	O
a	O
Philips	O
/	O
FEI	O
Morgagni	O
268	O
TEM	O
at	O
80	O
kV	O
.	O

Our	O
analysis	O
is	O
based	O
on	O
4	O
unmated	O
samples	O
and	O
3	O
mated	O
samples	O
.	O

Two	O
unmated	O
samples	O
were	O
cut	O
in	O
the	O
longitudinal	O
plane	O
and	O
two	O
additional	O
unmated	O
samples	O
were	O
cut	O
in	O
the	O
transverse	O
plane	O
,	O
while	O
one	O
mated	O
sample	O
was	O
cut	O
in	O
the	O
longitudinal	O
plane	O
and	O
two	O
additional	O
mated	O
samples	O
were	O
cut	O
in	O
the	O
transverse	O
plane	O
.	O

For	O
longitudinal	O
sections	O
,	O
the	O
entire	O
tract	O
was	O
re	O
-	O
embedded	O
and	O
cut	O
.	O

For	O
samples	O
cut	O
in	O
the	O
transverse	O
plane	O
,	O
the	O
flat	O
-	O
embedded	O
reproductive	O
tract	O
was	O
divided	O
into	O
three	O
regions	O
:	O
(	O
1	O
)	O
lateral	O
oviducts	O
and	O
upper	O
common	O
oviducts	O
,	O
(	O
2	O
)	O
middle	O
common	O
oviduct	O
,	O
and	O
(	O
3	O
)	O
lower	O
common	O
oviduct	O
.	O

Each	O
region	O
was	O
re	O
-	O
embedded	O
and	O
sectioned	O
.	O

It	O
is	O
beyond	O
the	O
scope	O
of	O
this	O
paper	O
to	O
describe	O
all	O
three	O
regions	O
,	O
and	O
our	O
analysis	O
focuses	O
on	O
the	O
uppermost	O
and	O
lowermost	O
regions	O
.	O

Immunocytochemistry	O

Reproductive	O
tracts	O
were	O
dissected	O
in	O
Yamamoto	O
'	O
s	O
Ringer	O
(	O
10	O
mM	O
MOPS	O
;	O
80	O
mM	O
NaCl	O
;	O
10	O
mM	O
KCL	O
;	O
0	O
.	O
2	O
mM	O
MgCl2	O
;	O
0	O
.	O
1	O
mM	O
CaCl2	O
)	O
with	O
5	O
%	O
(	O
w	O
/	O
v	O
)	O
sucrose	O
on	O
ice	O
,	O
fixed	O
in	O
4	O
%	O
paraphormaldehyde	O
in	O
PBS	O
(	O
phosphate	O
-	O
buffered	O
saline	O
;	O
0	O
.	O
85	O
%	O
NaCl	O
,	O
1	O
.	O
4	O
mM	O
KH2	O
PO4	O
,	O
8	O
mM	O
Na2	O
HPO4	O
,	O
pH	O
7	O
.	O
4	O
)	O
for	O
45	O
min	O
and	O
then	O
washed	O
in	O
PBS	O
.	O

The	O
reproductive	O
tracts	O
were	O
then	O
incubated	O
in	O
blocking	O
solution	O
(	O
0	O
.	O
5	O
%	O
Triton	O
x	O
-	O
100	O
,	O
3	O
%	O
NGS	O
,	O
0	O
.	O
1	O
%	O
BSA	O
)	O
for	O
2	O
hrs	O
at	O
room	O
temperature	O
.	O

The	O
following	O
primary	O
antibodies	O
,	O
reagents	O
,	O
and	O
dilutions	O
were	O
used	O
:	O
Cy3	O
-	O
conjugated	O
goat	B
anti	O
-	O
HRP	O
,	O
1	O
:	O
200	O
(	O
Jackson	O
Immunochemicals	O
,	O
West	O
Grove	O
,	O
PA	O
)	O
;	O
mouse	B
anti	O
-	O
Disc	O
Large	O
(	O
DLG	O
)	O
,	O
1	O
:	O
1000	O
(	O
Developmental	O
Hybridoma	O
Bank	O
)	O
,	O
Alexa	O
Fluor	O
488	O
-	O
phalloidin	O
,	O
1	O
:	O
200	O
(	O
Invitrogen	O
,	O
Molecular	O
Probes	O
,	O
Scotland	O
)	O
.	O

Secondary	O
antibodies	O
were	O
Alexa	O
Flour	O
488	O
-	O
conjugated	O
Goat	B
anti	O
-	O
mouse	B
,	O
1	O
:	O
200	O
and	O
Alexa	O
Flour	O
546	O
-	O
conjugated	O
Goat	B
anti	O
-	O
rabbit	B
,	O
1	O
:	O
200	O
(	O
Invitrogen	O
,	O
Molecular	O
Probes	O
,	O
Scotland	O
)	O
.	O

Reproductive	O
tracts	O
were	O
incubated	O
with	O
the	O
different	O
primary	O
antibodies	O
(	O
diluted	O
in	O
PBS	O
+	O
0	O
.	O
2	O
%	O
Triton	O
x	O
-	O
100	O
)	O
for	O
2	O
hr	O
at	O
room	O
temperature	O
,	O
washed	O
with	O
PBST	O
,	O
incubated	O
with	O
secondary	O
antibodies	O
for	O
2	O
hrs	O
at	O
room	O
temperature	O
and	O
washed	O
with	O
PBS	O
.	O

Reproductive	O
tracts	O
of	O
the	O
different	O
treatments	O
were	O
mounted	O
with	O
Antifade	O
media	O
[	O
58	O
]	O
on	O
a	O
multi	O
-	O
well	O
glass	O
slide	O
(	O
Hendley	O
-	O
Essex	O
,	O
UK	O
)	O
.	O

For	O
each	O
treatment	O
(	O
unmated	O
,	O
mated	O
)	O
and	O
antibody	O
/	O
reagent	O
(	O
HRP	O
,	O
DLG	O
,	O
phalloidin	O
)	O
a	O
minimum	O
of	O
ten	O
reproductive	O
tracts	O
from	O
at	O
least	O
two	O
independent	O
biological	O
replicates	O
were	O
prepared	O
.	O

Confocal	O
microscopy	O

Reproductive	O
tracts	O
were	O
viewed	O
with	O
a	O
Zeiss	O
510	O
laser	O
scanning	O
confocal	O
microscope	O
using	O
20	O
x	O
and	O
60	O
x	O
objective	O
with	O
additional	O
zooming	O
.	O

Optical	O
sections	O
from	O
different	O
focal	O
plans	O
of	O
each	O
reproductive	O
tract	O
region	O
(	O
lateral	O
oviducts	O
,	O
common	O
oviduct	O
,	O
uterus	O
)	O
were	O
collected	O
and	O
projected	O
as	O
a	O
reconstructed	O
three	O
-	O
dimensional	O
image	O
using	O
LSM	O
image	O
browser	O
(	O
version	O
3	O
,	O
5	O
,	O
0	O
,	O
376	O
)	O
software	O
.	O

Image	O
collections	O
were	O
identical	O
for	O
each	O
of	O
the	O
different	O
reproductive	O
tract	O
regions	O
analyzed	O
.	O

Quantitation	O
of	O
bouton	O
number	O

To	O
quantify	O
the	O
number	O
of	O
boutons	O
in	O
the	O
lateral	O
and	O
common	O
oviducts	O
we	O
used	O
ImageJ	O
software	O
(	O
1	O
.	O
37b	O
,	O
National	O
Institutes	O
of	O
Health	O
)	O
to	O
analyze	O
confocal	O
images	O
of	O
anti	O
-	O
HRP	O
and	O
anti	O
-	O
DLG	O
labeled	O
boutons	O
in	O
the	O
oviduct	O
.	O

The	O
number	O
of	O
boutons	O
per	O
unit	O
area	O
was	O
quantified	O
with	O
the	O
Particle	O
Analysis	O
Tool	O
.	O

Briefly	O
,	O
to	O
differentiate	O
between	O
the	O
boutons	O
,	O
the	O
particle	O
analysis	O
tool	O
requires	O
the	O
image	O
to	O
be	O
a	O
"	O
binary	O
"	O
image	O
(	O
i	O
.	O
e	O
.	O
,	O
black	O
or	O
white	O
)	O
,	O
thus	O
we	O
first	O
converted	O
the	O
images	O
to	O
gray	O
scale	O
.	O

We	O
then	O
set	O
a	O
"	O
threshold	O
"	O
range	O
so	O
that	O
pixels	O
in	O
the	O
image	O
whose	O
value	O
lies	O
in	O
this	O
range	O
are	O
converted	O
to	O
black	O
;	O
pixels	O
with	O
values	O
outside	O
this	O
range	O
are	O
converted	O
to	O
white	O
.	O

We	O
next	O
defined	O
a	O
region	O
of	O
interest	O
(	O
ROI	O
)	O
within	O
the	O
oviduct	O
to	O
count	O
particles	O
(	O
i	O
.	O
e	O
.	O
count	O
boutons	O
)	O
.	O

This	O
ROI	O
was	O
saved	O
and	O
served	O
to	O
measure	O
the	O
number	O
of	O
boutons	O
per	O
unit	O
area	O
in	O
each	O
treatment	O
.	O

For	O
each	O
oviduct	O
we	O
counted	O
the	O
number	O
of	O
anti	O
-	O
HRP	O
and	O
anti	O
-	O
DLG	O
labeled	O
boutons	O
in	O
two	O
ROIs	O
within	O
the	O
lateral	O
oviducts	O
and	O
two	O
ROIs	O
in	O
the	O
common	O
oviduct	O
.	O

One	O
-	O
way	O
ANOVA	O
(	O
SPSS	O
15	O
.	O
0	O
)	O
was	O
used	O
to	O
measure	O
the	O
difference	O
in	O
bouton	O
number	O
per	O
unit	O
area	O
in	O
different	O
regions	O
of	O
the	O
oviducts	O
,	O
in	O
both	O
unmated	O
and	O
mated	O
females	O
.	O

Quantitation	O
of	O
cytoskeleton	O
proteins	O

Sample	O
preparation	O

To	O
evaluate	O
the	O
effect	O
of	O
mating	O
on	O
the	O
abundance	O
of	O
the	O
cytoskeleton	O
proteins	O
tested	O
,	O
females	O
were	O
:	O
(	O
i	O
)	O
aged	O
for	O
3	O
days	O
,	O
mated	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
and	O
their	O
oviducts	O
were	O
dissected	O
after	O
6	O
hrs	O
post	O
-	O
mating	O
(	O
Once3	O
)	O
;	O
(	O
ii	O
)	O
aged	O
for	O
3	O
days	O
,	O
mated	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
and	O
their	O
oviducts	O
were	O
dissected	O
after	O
7	O
days	O
(	O
Once3	O
day10	O
)	O
;	O
(	O
iii	O
)	O
aged	O
for	O
3	O
days	O
,	O
mated	O
first	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
and	O
held	O
singly	O
for	O
7	O
days	O
.	O

At	O
10	O
days	O
of	O
age	O
,	O
female	O
were	O
mated	O
again	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
.	O

Oviducts	O
were	O
dissected	O
at	O
6	O
hrs	O
post	O
-	O
second	O
mating	O
(	O
Twice3	O
&	O
10	O
)	O
.	O

We	O
also	O
examined	O
5	O
-	O
day	O
-	O
old	O
and	O
10	O
-	O
day	O
-	O
old	O
unmated	O
females	O
(	O
UM5	O
,	O
UM10	O
respectively	O
)	O
.	O

SDS	O
polyacrylamide	O
gel	O
electrophoresis	O
(	O
SDS	O
-	O
PAGE	O
)	O
and	O
Western	O
blotting	O

For	O
each	O
mating	O
regime	O
,	O
sixty	O
oviducts	O
were	O
pooled	O
and	O
30	O
mu	O
l	O
of	O
SDS	O
-	O
PAGE	O
sample	O
buffer	O
was	O
added	O
as	O
described	O
in	O
[	O
59	O
]	O
.	O

Samples	O
were	O
boiled	O
,	O
and	O
then	O
frozen	O
at	O
-	O
20	O
degrees	O
C	O
until	O
loading	O
.	O

SDS	O
-	O
PAGE	O
was	O
performed	O
on	O
12	O
%	O
polyacrylamide	O
gels	O
and	O
western	O
blotted	O
as	O
in	O
[	O
60	O
]	O
.	O

Proteins	O
were	O
cross	O
-	O
linked	O
to	O
the	O
filter	O
.	O

The	O
following	O
primary	O
antibodies	O
and	O
dilutions	O
were	O
used	O
:	O
mouse	B
anti	O
-	O
Neuroglian	O
(	O
kindly	O
provided	O
by	O
M	O
.	O
Hortsch	O
)	O
1	O
:	O
250	O
;	O
Guinea	B
pig	I
anti	O
-	O
Coracle	O
(	O
kindly	O
provided	O
by	O
R	O
.	O
G	O
.	O
Fehon	O
)	O
1	O
:	O
2500	O
;	O
rabbit	B
anti	O
-	O
Mlp84B	O
(	O
kindly	O
provided	O
by	O
M	O
.	O
Beckerle	O
)	O
1	O
:	O
1000	O
;	O
mouse	B
anti	O
-	O
hts	O
(	O
1B1	O
,	O
Developmental	O
Studies	O
Hybridoma	O
Bank	O
,	O
DSHB	O
)	O
1	O
:	O
75	O
;	O
mouse	B
anti	O
-	O
Na	O
,	O
K	O
-	O
ATPase	O
(	O
alpha	O
5	O
,	O
DSHB	O
)	O
1	O
:	O
100	O
.	O

Secondary	O
antibodies	O
included	O
:	O
anti	O
-	O
Guinea	B
pig	I
IgG	O
(	O
peroxidase	O
conjugated	O
)	O
,	O
anti	O
-	O
Rabbit	B
IgG	O
and	O
anti	O
-	O
Mouse	B
IgG	O
(	O
developed	O
in	O
goat	B
,	O
Sigma	O
,	O
Israel	O
)	O
1	O
:	O
10	O
,	O
000	O
.	O

Proteins	O
were	O
visualized	O
using	O
an	O
enhanced	O
chemiluminescence	O
(	O
ECL	O
)	O
detection	O
system	O
(	O
Amersham	O
Piscataway	O
,	O
NJ	O
)	O
.	O

Analysis	O

The	O
developed	O
film	O
was	O
scanned	O
and	O
the	O
signal	O
intensity	O
(	O
protein	O
abundance	O
)	O
of	O
each	O
band	O
was	O
determined	O
using	O
ImageJ	O
software	O
(	O
1	O
.	O
37d	O
,	O
National	O
Institutes	O
of	O
Health	O
)	O
.	O

We	O
evaluated	O
protein	O
abundance	O
by	O
measuring	O
the	O
mean	O
gray	O
value	O
of	O
a	O
specific	O
band	O
and	O
the	O
background	O
.	O

The	O
mean	O
gray	O
value	O
of	O
the	O
background	O
was	O
then	O
subtracted	O
from	O
that	O
of	O
the	O
measured	O
band	O
.	O

Relative	O
protein	O
abundance	O
in	O
mated	O
oviduct	O
vs	O
.	O
3	O
-	O
day	O
-	O
old	O
unmated	O
oviduct	O
was	O
then	O
calculated	O
.	O

Four	O
independent	O
biological	O
replicates	O
were	O
prepared	O
for	O
each	O
mating	O
status	O
.	O

The	O
reported	O
abundance	O
(	O
see	O
Figure	O
5	O
)	O
is	O
the	O
relative	O
ratio	O
(	O
mated	O
/	O
unmated	O
or	O
unmated	O
/	O
unmated	O
)	O
of	O
at	O
least	O
three	O
replicates	O
that	O
showed	O
the	O
same	O
trend	O
.	O

Examination	O
of	O
female	O
reproductive	O
output	O

Mating	O
regimes	O

To	O
evaluate	O
the	O
effect	O
of	O
mating	O
on	O
reproductive	O
output	O
females	O
were	O
treated	O
as	O
follows	O
:	O
(	O
i	O
)	O
aged	O
for	O
3	O
days	O
and	O
mated	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
(	O
Once3	O
)	O
;	O
(	O
ii	O
)	O
aged	O
for	O
10	O
days	O
and	O
mated	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
(	O
Once10	O
)	O
;	O
(	O
iii	O
)	O
aged	O
for	O
3	O
days	O
,	O
mated	O
first	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
,	O
held	O
for	O
7	O
days	O
and	O
mated	O
again	O
with	O
3	O
-	O
day	O
-	O
old	O
unmated	O
males	O
(	O
Twice3	O
&	O
10	O
)	O
.	O

In	O
all	O
cases	O
male	O
and	O
female	O
pairs	O
were	O
observed	O
to	O
record	O
mating	O
initiation	O
and	O
termination	O
.	O

Analysis	O

Following	O
mating	O
,	O
females	O
were	O
aspirated	O
into	O
fresh	O
vials	O
,	O
held	O
singly	O
and	O
allowed	O
to	O
lay	O
eggs	O
for	O
6	O
hrs	O
,	O
then	O
transferred	O
daily	O
(	O
each	O
24	O
hrs	O
)	O
to	O
fresh	O
vials	O
.	O

The	O
number	O
of	O
eggs	O
laid	O
and	O
the	O
number	O
of	O
eclosed	O
adults	O
were	O
counted	O
from	O
vials	O
created	O
at	O
6	O
hrs	O
,	O
1	O
,	O
2	O
and	O
3	O
days	O
post	O
-	O
mating	O
.	O

To	O
ascertain	O
the	O
baseline	O
of	O
female	O
egg	O
-	O
laying	O
,	O
we	O
also	O
included	O
in	O
our	O
experiment	O
unmated	O
females	O
that	O
were	O
kept	O
in	O
the	O
same	O
conditions	O
as	O
mated	O
females	O
.	O

The	O
number	O
of	O
eggs	O
laid	O
by	O
unmated	O
females	O
was	O
counted	O
from	O
vials	O
created	O
at	O
6	O
hrs	O
,	O
1	O
,	O
2	O
and	O
3	O
days	O
after	O
placing	O
the	O
females	O
in	O
the	O
holding	O
vials	O
.	O

In	O
addition	O
,	O
we	O
also	O
recorded	O
the	O
pattern	O
of	O
unmated	O
female	O
egg	O
-	O
laying	O
for	O
10	O
days	O
.	O

To	O
determine	O
the	O
effect	O
of	O
different	O
mating	O
regimes	O
on	O
female	O
reproductive	O
output	O
(	O
i	O
.	O
e	O
.	O
fecundity	O
and	O
fertility	O
)	O
,	O
we	O
used	O
One	O
-	O
way	O
ANOVA	O
(	O
SPSS	O
15	O
.	O
0	O
)	O
.	O

Abbreviations	O

Nrg	O
:	O
Neuroglian	O
;	O
Cora	O
:	O
Coracle	O
;	O
Spec	O
:	O
alpha	O
-	O
and	O
beta	O
-	O
Spectrin	O
;	O
SJ	O
:	O
septate	O
junction	O
;	O
SSJ	O
:	O
smooth	O
septate	O
junction	O
;	O
PSJ	O
:	O
pleated	O
septate	O
junction	O
;	O
ZA	O
:	O
zonal	O
adherens	O
junction	O
;	O
AJ	O
:	O
adherens	O
junction	O
;	O
AECM	O
:	O
apical	O
extracellular	O
matrix	O
;	O
ECM	O
:	O
extracellular	O
matrix	O
;	O
HAJ	O
:	O
hemi	O
-	O
adherens	O
junction	O
;	O
SAJ	O
:	O
spot	O
adherens	O
junction	O
;	O
OA	O
:	O
Octopamine	O
;	O
Hts	O
:	O
Hu	O
-	O
li	O
tai	O
shao	O
;	O
ATP	O
alpha	O
:	O
Na	O
+	O
pump	O
alpha	O
subunit	O
;	O
Mlp84B	O
:	O
Muscle	O
LIM	O
protein	O
at	O
84B	O
;	O
DLG	O
:	O
Disc	O
Large	O
;	O
HRP	O
:	O
horseradish	B
peroxidas	O
;	O
UM	O
:	O
unmated	O
;	O
M	O
:	O
mated	O
.	O

Authors	O
'	O
contributions	O

AK	O
and	O
PKR	O
contributed	O
equally	O
to	O
this	O
manuscript	O
.	O

AK	O
,	O
PKR	O
and	O
YH	O
conceived	O
and	O
designed	O
the	O
project	O
and	O
analyzed	O
the	O
data	O
.	O

AK	O
performed	O
the	O
confocal	O
,	O
Western	O
blots	O
and	O
fertility	O
assays	O
.	O

PKR	O
and	O
AK	O
performed	O
the	O
light	O
microscopy	O
.	O

PKR	O
conducted	O
the	O
electron	O
microscopy	O
.	O

AK	O
,	O
PKR	O
and	O
YH	O
wrote	O
the	O
manuscript	O
.	O

RRH	O
contributed	O
to	O
design	O
of	O
the	O
study	O
and	O
revision	O
of	O
the	O
manuscript	O
.	O

All	O
authors	O
participated	O
in	O
the	O
discussion	O
and	O
approval	O
of	O
the	O
final	O
manuscript	O
.	O

Supplementary	O
Material	O

Efficacy	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
(	O
Synvisc	O
(	O
R	O
)	O
)	O
for	O
the	O
treatment	O
of	O
osteoarthritis	O
affecting	O
the	O
first	O
metatarsophalangeal	O
joint	O
of	O
the	O
foot	O
(	O
hallux	O
limitus	O
)	O
:	O
study	O
protocol	O
for	O
a	O
randomised	O
placebo	O
controlled	O
trial	O

Abstract	O

Background	O

Osteoarthritis	O
of	O
the	O
first	O
metatarsophalangeal	O
joint	O
(	O
MPJ	O
)	O
of	O
the	O
foot	O
,	O
termed	O
hallux	O
limitus	O
,	O
is	O
common	O
and	O
painful	O
.	O

Numerous	O
non	O
-	O
surgical	O
interventions	O
have	O
been	O
proposed	O
for	O
this	O
disorder	O
,	O
however	O
there	O
is	O
limited	O
evidence	O
for	O
their	O
efficacy	O
.	O

Intra	O
-	O
articular	O
injections	O
of	O
hyaluronan	O
have	O
shown	O
beneficial	O
effects	O
in	O
case	O
-	O
series	O
and	O
clinical	O
trials	O
for	O
the	O
treatment	O
of	O
osteoarthritis	O
of	O
the	O
first	O
metatarsophalangeal	O
joint	O
.	O

However	O
,	O
no	O
study	O
has	O
evaluated	O
the	O
efficacy	O
of	O
this	O
form	O
of	O
treatment	O
using	O
a	O
randomised	O
placebo	O
controlled	O
trial	O
.	O

This	O
article	O
describes	O
the	O
design	O
of	O
a	O
randomised	O
placebo	O
controlled	O
trial	O
to	O
evaluate	O
the	O
efficacy	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
(	O
Synvisc	O
(	O
R	O
)	O
)	O
to	O
reduce	O
pain	O
and	O
improve	O
function	O
in	O
people	B
with	O
hallux	O
limitus	O
.	O

Methods	O

One	O
hundred	O
and	O
fifty	O
community	O
-	O
dwelling	O
men	B
and	O
women	B
aged	O
18	O
years	O
and	O
over	O
with	O
hallux	O
limitus	O
(	O
who	O
satisfy	O
inclusion	O
and	O
exclusion	O
criteria	O
)	O
will	O
be	O
recruited	O
.	O

Participants	B
will	O
be	O
randomised	O
,	O
using	O
a	O
computer	O
-	O
generated	O
random	O
number	O
sequence	O
,	O
to	O
receive	O
a	O
single	O
intra	O
-	O
articular	O
injection	O
of	O
up	O
to	O
1	O
ml	O
hyaluronan	O
(	O
Synvisc	O
(	O
R	O
)	O
)	O
or	O
sterile	O
saline	O
(	O
placebo	O
)	O
into	O
the	O
first	O
MPJ	O
.	O

The	O
injections	O
will	O
be	O
performed	O
by	O
an	O
interventional	O
radiologist	O
using	O
fluoroscopy	O
to	O
ensure	O
accurate	O
deposition	O
of	O
the	O
hyaluronan	O
in	O
the	O
joint	O
.	O

Participants	B
will	O
be	O
given	O
the	O
option	O
of	O
a	O
second	O
and	O
final	O
intra	O
-	O
articular	O
injection	O
(	O
of	O
Synvisc	O
(	O
R	O
)	O
or	O
sterile	O
saline	O
according	O
to	O
the	O
treatment	O
group	O
they	O
are	O
in	O
)	O
either	O
1	O
or	O
3	O
months	O
post	O
-	O
treatment	O
if	O
there	O
is	O
no	O
improvement	O
in	O
pain	O
and	O
the	O
participant	B
has	O
not	O
experienced	O
severe	O
adverse	O
effects	O
after	O
the	O
first	O
injection	O
.	O

The	O
primary	O
outcome	O
measures	O
will	O
be	O
the	O
pain	O
and	O
function	O
subscales	O
of	O
the	O
Foot	O
Health	O
Status	O
Questionnaire	O
.	O

The	O
secondary	O
outcome	O
measures	O
will	O
be	O
pain	O
at	O
the	O
first	O
MPJ	O
(	O
during	O
walking	O
and	O
at	O
rest	O
)	O
,	O
stiffness	O
at	O
the	O
first	O
MPJ	O
,	O
passive	O
non	O
-	O
weightbearing	O
dorsiflexion	O
of	O
the	O
first	O
MPJ	O
,	O
plantar	O
flexion	O
strength	O
of	O
the	O
toe	O
-	O
flexors	O
of	O
the	O
hallux	O
,	O
global	O
satisfaction	O
with	O
the	O
treatment	O
,	O
health	O
-	O
related	O
quality	O
of	O
life	O
(	O
assessed	O
using	O
the	O
Short	O
-	O
Form	O
-	O
36	O
version	O
two	O
questionnaire	O
)	O
,	O
magnitude	O
of	O
symptom	O
change	O
,	O
use	O
of	O
pain	O
-	O
relieving	O
medication	O
and	O
changes	O
in	O
dynamic	O
plantar	O
pressure	O
distribution	O
(	O
maximum	O
force	O
and	O
peak	O
pressure	O
)	O
during	O
walking	O
.	O

Data	O
will	O
be	O
collected	O
at	O
baseline	O
,	O
then	O
1	O
,	O
3	O
and	O
6	O
months	O
post	O
-	O
treatment	O
.	O

Data	O
will	O
be	O
analysed	O
using	O
the	O
intention	O
to	O
treat	O
principle	O
.	O

Discussion	O

This	O
study	O
is	O
the	O
first	O
randomised	O
placebo	O
controlled	O
trial	O
to	O
evaluate	O
the	O
efficacy	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
(	O
Synvisc	O
(	O
R	O
)	O
)	O
for	O
the	O
treatment	O
of	O
osteoarthritis	O
of	O
the	O
first	O
MPJ	O
(	O
hallux	O
limitus	O
)	O
.	O

The	O
study	O
has	O
been	O
pragmatically	O
designed	O
to	O
ensure	O
that	O
the	O
study	O
findings	O
can	O
be	O
implemented	O
into	O
clinical	O
practice	O
if	O
this	O
form	O
of	O
treatment	O
is	O
found	O
to	O
be	O
an	O
effective	O
treatment	O
strategy	O
.	O

Trial	O
registration	O

Australian	O
New	O
Zealand	O
Clinical	O
Trials	O
Registry	O
:	O
ACTRN12607000654459	O

Background	O

Osteoarthritis	O
(	O
OA	O
)	O
is	O
a	O
degenerative	O
joint	O
disease	O
that	O
commonly	O
presents	O
within	O
the	O
first	O
metatarsophalangeal	O
joint	O
(	O
MPJ	O
)	O
of	O
the	O
foot	O
.	O

The	O
terms	O
hallux	O
limitus	O
and	O
hallux	O
rigidus	O
have	O
frequently	O
been	O
used	O
interchangeably	O
to	O
describe	O
differing	O
severities	O
of	O
pain	O
and	O
limitation	O
of	O
motion	O
associated	O
with	O
OA	O
at	O
the	O
first	O
MPJ	O
[	O
1	O
]	O
.	O

Hallux	O
limitus	O
is	O
a	O
progressive	O
osteoarthritic	O
condition	O
of	O
the	O
first	O
MPJ	O
that	O
may	O
advance	O
to	O
an	O
end	O
-	O
stage	O
presentation	O
of	O
hallux	O
rigidus	O
where	O
the	O
joint	O
fuses	O
and	O
there	O
is	O
a	O
complete	O
restriction	O
of	O
motion	O
[	O
1	O
]	O
.	O

First	O
MPJ	O
OA	O
is	O
the	O
second	O
most	O
common	O
disorder	O
affecting	O
the	O
foot	O
after	O
hallux	O
valgus	O
[	O
2	O
]	O
.	O

The	O
prevalence	O
of	O
the	O
condition	O
increases	O
with	O
age	O
,	O
and	O
it	O
has	O
been	O
reported	O
that	O
radiographic	O
changes	O
in	O
the	O
first	O
MPJ	O
affect	O
are	O
evident	O
in	O
approximately	O
46	O
%	O
of	O
women	B
and	O
32	O
%	O
of	O
men	B
at	O
60	O
years	O
of	O
age	O
[	O
3	O
]	O
.	O

Osteoarthritis	O
at	O
the	O
first	O
MPJ	O
is	O
characterised	O
by	O
the	O
symptoms	O
of	O
pain	O
and	O
stiffness	O
at	O
the	O
joint	O
[	O
1	O
]	O
.	O

Secondary	O
painful	O
symptoms	O
relate	O
to	O
compensations	O
during	O
gait	O
that	O
may	O
occur	O
due	O
to	O
the	O
reduced	O
motion	O
of	O
the	O
first	O
MPJ	O
[	O
1	O
]	O
.	O

The	O
presence	O
of	O
pain	O
associated	O
with	O
first	O
MPJ	O
OA	O
impacts	O
on	O
normal	O
walking	O
and	O
quality	O
of	O
life	O
[	O
4	O
]	O
.	O

Treatment	O
of	O
hallux	O
limitus	O
involves	O
conservative	O
measures	O
(	O
such	O
as	O
physical	O
therapy	O
,	O
foot	O
orthoses	O
,	O
footwear	O
modification	O
,	O
joint	O
manipulation	O
and	O
injection	O
with	O
corticosteroid	O
)	O
[	O
5	O
]	O
,	O
or	O
surgical	O
intervention	O
(	O
either	O
joint	O
-	O
salvage	O
or	O
joint	O
-	O
destructive	O
procedures	O
)	O
[	O
6	O
]	O
.	O

Pharmacological	O
treatment	O
is	O
also	O
often	O
undertaken	O
as	O
an	O
adjunct	O
for	O
pain	O
relief	O
in	O
the	O
management	O
of	O
hallux	O
limitus	O
[	O
6	O
]	O
.	O

However	O
,	O
although	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
drugs	O
(	O
NSAIDs	O
)	O
and	O
cyclooxygenase	O
-	O
2	O
inhibitors	O
have	O
been	O
found	O
to	O
be	O
effective	O
in	O
the	O
management	O
of	O
various	O
forms	O
of	O
OA	O
,	O
gastrointestinal	O
complications	O
remain	O
a	O
concern	O
[	O
7	O
]	O
.	O

In	O
light	O
of	O
these	O
limitations	O
with	O
existing	O
treatments	O
,	O
an	O
alternative	O
treatment	O
termed	O
'	O
viscosupplementation	O
'	O
-	O
the	O
intra	O
-	O
articular	O
injection	O
of	O
hyaluronan	O
into	O
arthritic	O
joints	O
with	O
the	O
aim	O
of	O
restoring	O
the	O
viscoelasticity	O
of	O
the	O
synovial	O
fluid	O
[	O
8	O
]	O
-	O
has	O
been	O
proposed	O
and	O
has	O
attracted	O
considerable	O
attention	O
in	O
the	O
medical	O
literature	O
as	O
a	O
treatment	O
for	O
OA	O
[	O
9	O
]	O
.	O

In	O
particular	O
,	O
both	O
the	O
American	O
College	O
of	O
Rheumatology	O
(	O
ACR	O
)	O
and	O
European	O
League	O
Against	O
Rheumatism	O
(	O
EULAR	O
)	O
recommend	O
hyaluronan	O
in	O
the	O
management	O
of	O
OA	O
of	O
the	O
knee	O
[	O
10	O
,	O
11	O
]	O
.	O

Although	O
the	O
results	O
of	O
systematic	O
reviews	O
investigating	O
the	O
effectiveness	O
of	O
this	O
type	O
of	O
treatment	O
for	O
knee	O
OA	O
are	O
controversial	O
,	O
the	O
most	O
recent	O
update	O
of	O
the	O
Cochrane	O
systematic	O
review	O
evaluating	O
viscosupplementation	O
for	O
the	O
treatment	O
of	O
knee	O
OA	O
concluded	O
that	O
viscosupplementation	O
was	O
both	O
safe	O
and	O
effective	O
for	O
the	O
treatment	O
of	O
OA	O
and	O
was	O
superior	O
or	O
equivalent	O
to	O
any	O
form	O
of	O
systemic	O
intervention	O
or	O
intra	O
-	O
articular	O
corticosteroids	O
[	O
9	O
,	O
12	O
]	O
.	O

Despite	O
there	O
being	O
a	O
large	O
number	O
of	O
studies	O
investigating	O
the	O
effectiveness	O
of	O
hyaluronan	O
for	O
knee	O
OA	O
,	O
few	O
studies	O
have	O
investigated	O
the	O
effects	O
of	O
this	O
form	O
of	O
treatment	O
for	O
OA	O
at	O
the	O
first	O
MPJ	O
[	O
13	O
]	O
.	O

In	O
a	O
case	O
-	O
series	O
retrospective	O
study	O
,	O
14	O
patients	B
with	O
radiographically	O
confirmed	O
OA	O
at	O
the	O
first	O
MPJ	O
that	O
received	O
up	O
to	O
3	O
intra	O
-	O
articular	O
injections	O
of	O
1	O
ml	O
hyaluronan	O
(	O
Ostenil	O
(	O
R	O
)	O
Mini	O
)	O
(	O
sodium	O
hyaluronate	O
)	O
reported	O
a	O
statistically	O
significant	O
reduction	O
in	O
pain	O
(	O
reported	O
using	O
a	O
visual	O
analogue	O
scale	O
)	O
after	O
6	O
months	O
[	O
14	O
]	O
.	O

The	O
treatment	O
was	O
well	O
tolerated	O
,	O
with	O
3	O
/	O
14	O
(	O
21	O
%	O
)	O
participants	B
reporting	O
mild	O
adverse	O
reactions	O
at	O
the	O
injection	O
site	O
.	O

In	O
another	O
study	O
,	O
Pons	O
et	O
al	O
[	O
13	O
]	O
compared	O
a	O
single	O
intra	O
-	O
articular	O
injection	O
of	O
1	O
ml	O
Ostenil	O
(	O
R	O
)	O
Mini	O
(	O
sodium	O
hyaluronate	O
)	O
with	O
1	O
ml	O
Trigon	O
depot	O
(	O
R	O
)	O
(	O
triamcinolone	O
acetonide	O
,	O
a	O
corticosteroid	O
)	O
for	O
the	O
treatment	O
of	O
painful	O
,	O
grade	O
1	O
hallux	O
limitus	O
(	O
Karasick	O
and	O
Wapner	O
[	O
15	O
]	O
scale	O
)	O
in	O
37	O
participants	B
(	O
40	O
feet	O
)	O
[	O
13	O
]	O
.	O

Both	O
treatment	O
groups	O
showed	O
statistically	O
significant	O
reductions	O
in	O
pain	O
at	O
rest	O
or	O
on	O
palpation	O
for	O
up	O
to	O
12	O
weeks	O
post	O
-	O
injection	O
.	O

However	O
,	O
hyaluronan	O
treatment	O
resulted	O
in	O
a	O
statistically	O
significant	O
greater	O
reduction	O
in	O
pain	O
during	O
walking	O
and	O
greater	O
improvement	O
in	O
the	O
American	O
Orthopaedic	O
Foot	O
and	O
Ankle	O
Society	O
(	O
AOFAS	O
)	O
hallux	O
MPJ	O
score	O
compared	O
to	O
treatment	O
with	O
triamcinolone	O
acetonide	O
.	O

The	O
treatment	O
with	O
hyaluronan	O
was	O
well	O
tolerated	O
,	O
with	O
2	O
/	O
20	O
(	O
10	O
%	O
)	O
participants	B
reporting	O
mild	O
adverse	O
reactions	O
at	O
the	O
injection	O
site	O
.	O

Although	O
both	O
of	O
these	O
studies	O
suggest	O
that	O
intra	O
-	O
articular	O
hyaluronan	O
is	O
safe	O
and	O
effective	O
for	O
the	O
treatment	O
of	O
hallux	O
limitus	O
,	O
neither	O
used	O
a	O
placebo	O
control	O
group	O
[	O
13	O
,	O
14	O
]	O
.	O

This	O
limitation	O
is	O
significant	O
as	O
a	O
placebo	O
effect	O
can	O
account	O
for	O
79	O
%	O
of	O
the	O
efficacy	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
treatment	O
[	O
16	O
]	O
.	O

Further	O
,	O
both	O
studies	O
are	O
limited	O
in	O
that	O
neither	O
of	O
the	O
studies	O
used	O
blinding	O
of	O
both	O
the	O
participants	B
and	O
assessors	O
in	O
their	O
protocols	O
.	O

It	O
is	O
therefore	O
possible	O
that	O
the	O
positive	O
effects	O
of	O
hyaluronan	O
may	O
have	O
been	O
overestimated	O
.	O

Accordingly	O
,	O
the	O
aims	O
of	O
this	O
project	O
are	O
to	O
conduct	O
a	O
double	O
blind	O
randomised	O
controlled	O
trial	O
to	O
determine	O
the	O
effectiveness	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
(	O
Synvisc	O
(	O
R	O
)	O
)	O
on	O
(	O
i	O
)	O
foot	O
pain	O
and	O
function	O
;	O
(	O
ii	O
)	O
the	O
range	O
of	O
motion	O
of	O
the	O
first	O
MPJ	O
;	O
(	O
iii	O
)	O
the	O
strength	O
of	O
the	O
plantarflexor	O
muscles	O
of	O
the	O
first	O
MPJ	O
;	O
(	O
iv	O
)	O
the	O
health	O
related	O
quality	O
of	O
life	O
;	O
and	O
(	O
v	O
)	O
the	O
use	O
of	O
pain	O
-	O
relieving	O
medications	O
in	O
people	B
with	O
hallux	O
limitus	O
.	O

The	O
study	O
protocol	O
is	O
presented	O
in	O
this	O
paper	O
,	O
consistent	O
with	O
the	O
recommendations	O
of	O
Editorial	O
Board	O
of	O
BioMed	O
Central	O
[	O
17	O
]	O
.	O

Methods	O

Design	O

This	O
study	O
is	O
a	O
parallel	O
group	O
,	O
participant	B
and	O
assessor	O
blinded	O
,	O
randomised	O
controlled	O
trial	O
with	O
a	O
6	O
month	O
follow	O
-	O
up	O
(	O
Figure	O
1	O
)	O
.	O

It	O
has	O
been	O
developed	O
using	O
the	O
principles	O
described	O
by	O
Osteoarthritis	O
Research	O
Society	O
International	O
(	O
OARSI	O
)	O
Clinical	O
Trials	O
Task	O
Force	O
guidelines	O
[	O
18	O
]	O
.	O

Participants	B
will	O
be	O
randomised	O
to	O
receive	O
a	O
single	O
intra	O
-	O
articular	O
injection	O
of	O
up	O
to	O
1	O
ml	O
hyaluronan	O
(	O
Synvisc	O
(	O
R	O
)	O
)	O
or	O
sterile	O
saline	O
(	O
placebo	O
)	O
into	O
the	O
first	O
MPJ	O
.	O

Allocation	O
to	O
either	O
the	O
Synvisc	O
(	O
R	O
)	O
or	O
placebo	O
groups	O
will	O
be	O
achieved	O
using	O
a	O
computer	O
-	O
generated	O
random	O
number	O
sequence	O
.	O

The	O
allocation	O
sequence	O
will	O
be	O
generated	O
and	O
held	O
by	O
an	O
external	O
person	B
not	O
directly	O
involved	O
in	O
the	O
trial	O
.	O

Concealment	O
of	O
the	O
allocation	O
sequence	O
will	O
be	O
ensured	O
as	O
each	O
participant	B
'	O
s	O
allocation	O
will	O
be	O
contained	O
in	O
a	O
sealed	O
opaque	O
envelope	O
.	O

Envelopes	O
will	O
be	O
made	O
opaque	O
by	O
using	O
a	O
sheet	O
of	O
aluminium	O
foil	O
inside	O
the	O
envelope	O
.	O

In	O
addition	O
,	O
a	O
system	O
using	O
carbon	O
paper	O
will	O
be	O
employed	O
so	O
the	O
details	O
(	O
name	O
and	O
date	O
of	O
recruitment	O
)	O
are	O
transferred	O
from	O
the	O
outside	O
of	O
the	O
envelope	O
to	O
the	O
paper	O
inside	O
the	O
envelope	O
containing	O
the	O
allocation	O
prior	O
to	O
opening	O
the	O
seal	O
.	O

Assessors	O
and	O
participants	B
will	O
be	O
blinded	O
to	O
group	O
allocation	O
.	O

Participants	B
will	O
be	O
given	O
the	O
option	O
of	O
a	O
second	O
and	O
final	O
intra	O
-	O
articular	O
injection	O
(	O
of	O
Synvisc	O
(	O
R	O
)	O
or	O
sterile	O
saline	O
according	O
to	O
the	O
treatment	O
group	O
they	O
are	O
in	O
)	O
on	O
days	O
30	O
or	O
90	O
if	O
there	O
is	O
no	O
improvement	O
in	O
pain	O
and	O
the	O
participant	B
has	O
not	O
experienced	O
severe	O
adverse	O
effects	O
after	O
the	O
first	O
injection	O
)	O
.	O

Participants	B

The	O
Human	O
Studies	O
Ethics	O
Committee	O
at	O
La	O
Trobe	O
University	O
(	O
Human	O
Ethics	O
Committee	O
Application	O
No	O
.	O
07	O
-	O
45	O
)	O
and	O
the	O
Radiation	O
Advisory	O
Committee	O
of	O
the	O
Victorian	O
Department	O
of	O
Human	O
Services	O
have	O
given	O
approval	O
for	O
the	O
study	O
.	O

Written	O
informed	O
consent	O
will	O
be	O
obtained	O
from	O
all	O
participants	B
prior	O
to	O
their	O
participation	O
.	O

People	B
with	O
hallux	O
limitus	O
will	O
be	O
recruited	O
from	O
a	O
number	O
of	O
sources	O
:	O

(	O
i	O
)	O
advertisements	O
in	O
relevant	O
Melbourne	O
(	O
Australia	O
)	O
newspapers	O
;	O

(	O
ii	O
)	O
mail	O
-	O
out	O
advertisements	O
to	O
health	O
-	O
care	O
practitioners	O
in	O
Melbourne	O
;	O

(	O
iii	O
)	O
advertisements	O
using	O
relevant	O
internet	O
web	O
-	O
sites	O
(	O
including	O
)	O
;	O

(	O
iv	O
)	O
posters	O
displayed	O
in	O
local	O
retirement	O
villages	O
,	O
community	O
centres	O
and	O
universities	O
located	O
in	O
Melbourne	O
.	O

Respondents	O
will	O
initially	O
be	O
screened	O
by	O
telephone	O
interview	O
to	O
ensure	O
they	O
are	O
suitable	O
for	O
the	O
study	O
.	O

Suitable	O
individuals	O
will	O
then	O
be	O
invited	O
to	O
participate	O
in	O
the	O
study	O
and	O
attend	O
an	O
initial	O
assessment	O
.	O

To	O
be	O
included	O
in	O
the	O
study	O
,	O
participants	B
must	O
meet	O
the	O
following	O
inclusion	O
criteria	O
:	O

(	O
i	O
)	O
be	O
aged	O
at	O
least	O
18	O
years	O
;	O

(	O
ii	O
)	O
report	O
having	O
symptoms	O
of	O
pain	O
,	O
during	O
walking	O
or	O
rest	O
,	O
in	O
the	O
first	O
MPJ	O
for	O
at	O
least	O
3	O
months	O
;	O

(	O
iii	O
)	O
report	O
having	O
pain	O
rated	O
at	O
least	O
20	O
mm	O
on	O
a	O
100	O
mm	O
visual	O
analogue	O
pain	O
scale	O
(	O
VAPS	O
)	O
;	O

(	O
iv	O
)	O
have	O
pain	O
upon	O
palpation	O
of	O
the	O
dorsal	O
aspect	O
of	O
the	O
first	O
MPJ	O
;	O

(	O
v	O
)	O
radiographic	O
evidence	O
of	O
OA	O
(	O
score	O
1	O
or	O
2	O
for	O
either	O
osteophytes	O
or	O
joint	O
space	O
narrowing	O
using	O
a	O
previously	O
published	O
radiographic	O
classification	O
)	O
[	O
19	O
]	O
at	O
the	O
first	O
MPJ	O
.	O

(	O
vi	O
)	O
able	O
to	O
walk	O
household	O
distances	O
(	O
>	O
50	O
meters	O
)	O
without	O
the	O
aid	O
of	O
a	O
walker	O
,	O
crutches	O
or	O
cane	O
;	O

(	O
vii	O
)	O
be	O
willing	O
to	O
attend	O
the	O
La	O
Trobe	O
University	O
Medical	O
Centre	O
(	O
Melbourne	O
,	O
Australia	O
)	O
for	O
treatment	O
with	O
either	O
Synvisc	O
(	O
R	O
)	O
or	O
placebo	O
(	O
single	O
intra	O
-	O
articular	O
injection	O
)	O
and	O
attend	O
the	O
Health	O
Sciences	O
Clinic	O
at	O
La	O
Trobe	O
University	O
(	O
Melbourne	O
,	O
Australia	O
)	O
for	O
the	O
initial	O
assessment	O
and	O
the	O
outcome	O
measurements	O
(	O
at	O
baseline	O
and	O
1	O
,	O
3	O
and	O
6	O
months	O
post	O
-	O
treatment	O
)	O
;	O

(	O
viii	O
)	O
not	O
receive	O
other	O
intra	O
-	O
articular	O
injections	O
into	O
the	O
first	O
MPJ	O
during	O
the	O
course	O
of	O
the	O
study	O
,	O
apart	O
from	O
those	O
dictated	O
by	O
the	O
study	O
;	O

(	O
ix	O
)	O
be	O
willing	O
to	O
discontinue	O
taking	O
all	O
pain	O
-	O
relieving	O
medications	O
(	O
analgesics	O
and	O
non	O
-	O
steroidal	O
anti	O
-	O
inflammatory	O
medications	O
(	O
NSAIDs	O
)	O
,	O
except	O
paracetamol	O
up	O
to	O
4	O
g	O
/	O
day	O
,	O
taken	O
by	O
mouth	O
or	O
applied	O
topically	O
)	O
:	O

-	O
for	O
at	O
least	O
14	O
days	O
prior	O
to	O
the	O
baseline	O
assessment	O
;	O

-	O
during	O
the	O
study	O
period	O
(	O
6	O
months	O
after	O
the	O
final	O
treatment	O
with	O
Synvisc	O
(	O
R	O
)	O
)	O
.	O

Participants	B
who	O
do	O
take	O
paracetamol	O
need	O
to	O
discontinue	O
its	O
use	O
at	O
least	O
24	O
hours	O
prior	O
to	O
the	O
baseline	O
assessment	O
and	O
follow	O
-	O
up	O
assessments	O
at	O
1	O
,	O
3	O
and	O
6	O
months	O
after	O
the	O
treatment	O
;	O

(	O
x	O
)	O
be	O
willing	O
to	O
not	O
receive	O
any	O
physical	O
therapy	O
on	O
the	O
involved	O
MPJ	O
or	O
trial	O
of	O
shoe	O
modifications	O
or	O
foot	O
orthoses	O
during	O
the	O
study	O
period	O
.	O

Exclusion	O
criteria	O
for	O
participants	B
in	O
this	O
study	O
will	O
be	O
:	O

(	O
i	O
)	O
Severe	O
radiographic	O
evidence	O
of	O
OA	O
(	O
score	O
3	O
for	O
either	O
osteophytes	O
or	O
joint	O
space	O
narrowing	O
)	O
at	O
the	O
first	O
MPJ	O
using	O
a	O
previously	O
published	O
radiographic	O
classification	O
[	O
19	O
]	O
;	O

(	O
ii	O
)	O
previous	O
surgery	O
on	O
the	O
first	O
MPJ	O
;	O

(	O
iii	O
)	O
intra	O
-	O
articular	O
steroid	O
,	O
or	O
any	O
other	O
intra	O
-	O
articular	O
injection	O
at	O
the	O
first	O
MPJ	O
in	O
the	O
previous	O
6	O
months	O
;	O

(	O
iv	O
)	O
treatment	O
with	O
systemic	O
steroid	O
(	O
excluding	O
inhalation	O
or	O
topical	O
steroids	O
)	O
,	O
immunosuppressives	O
or	O
anticoagulants	O
(	O
except	O
for	O
acetylsalicylic	O
acid	O
at	O
dosages	O
of	O
up	O
to	O
325	O
mg	O
/	O
day	O
)	O
;	O

(	O
v	O
)	O
presence	O
of	O
joint	O
infection	O
(	O
s	O
)	O
of	O
the	O
foot	O
;	O

(	O
vi	O
)	O
significant	O
deformity	O
of	O
the	O
first	O
MPJ	O
including	O
hallux	O
abducto	O
valgus	O
(	O
grade	O
of	O
3	O
or	O
4	O
scored	O
using	O
the	O
Manchester	O
Scale	O
[	O
20	O
]	O
;	O

(	O
vii	O
)	O
presence	O
of	O
peripheral	O
vascular	O
disease	O
.	O

Peripheral	O
vascular	O
disease	O
will	O
be	O
considered	O
to	O
be	O
present	O
if	O
any	O
of	O
the	O
following	O
are	O
present	O
[	O
21	O
]	O
;	O

*	O
past	O
history	O
of	O
,	O
vascular	O
surgery	O
,	O
Raynaud	O
'	O
s	O
phenomenon	O
,	O
vasculitis	O
associated	O
with	O
connective	O
tissue	O
diseases	O
,	O
Buerger	O
'	O
s	O
disease	O
,	O
arterial	O
emboli	O
,	O
deep	O
vein	O
thrombosis	O
or	O
lower	O
limb	O
ulcers	O
;	O

*	O
history	O
of	O
intermittent	O
claudication	O
or	O
rest	O
pain	O
;	O

*	O
presence	O
of	O
atrophy	O
,	O
ulcers	O
or	O
significant	O
oedema	O
;	O

*	O
inability	O
to	O
palpate	O
at	O
least	O
one	O
pedal	O
pulse	O
;	O

*	O
Ankle	O
Brachial	O
Pressure	O
Index	O
<	O
0	O
.	O
9	O
;	O

(	O
viii	O
)	O
presence	O
of	O
one	O
or	O
more	O
conditions	O
that	O
can	O
confound	O
pain	O
and	O
functional	O
assessments	O
of	O
the	O
first	O
MPJ	O
,	O
such	O
as	O
metatarsalgia	O
,	O
plantar	O
fasciitis	O
,	O
pre	O
-	O
dislocation	O
syndrome	O
,	O
sprains	O
of	O
the	O
foot	O
,	O
Achilles	O
tendinopathy	O
,	O
degenerative	O
joint	O
disease	O
of	O
the	O
foot	O
(	O
other	O
than	O
the	O
first	O
MPJ	O
)	O
or	O
painful	O
corns	O
and	O
callus	O
;	O

(	O
ix	O
)	O
planning	O
to	O
undergo	O
any	O
surgical	O
procedure	O
or	O
receive	O
any	O
injections	O
,	O
apart	O
from	O
those	O
dictated	O
by	O
the	O
study	O
,	O
at	O
the	O
involved	O
first	O
MPJ	O
during	O
the	O
study	O
period	O
;	O

(	O
x	O
)	O
presence	O
of	O
systemic	O
inflammatory	O
condition	O
or	O
infection	O
,	O
such	O
as	O
inflammatory	O
arthritis	O
,	O
diagnosed	O
with	O
rheumatoid	O
arthritis	O
,	O
ankylosing	O
spondylitis	O
,	O
psoriatic	O
arthritis	O
,	O
reactive	O
arthritis	O
,	O
septic	O
arthritis	O
,	O
acute	O
pseudogout	O
,	O
or	O
any	O
other	O
connective	O
tissue	O
disease	O
;	O

(	O
xi	O
)	O
evidence	O
of	O
gout	O
or	O
other	O
musculoskeletal	O
disease	O
other	O
than	O
OA	O
within	O
the	O
feet	O
.	O

Gout	O
will	O
be	O
screened	O
for	O
using	O
clinical	O
history	O
and	O
physical	O
assessment	O
(	O
painful	O
joint	O
,	O
abrupt	O
onset	O
,	O
swelling	O
)	O
,	O
radiographic	O
assessment	O
(	O
asymmetrical	O
joint	O
swelling	O
,	O
subcortical	O
cysts	O
without	O
erosion	O
and	O
tophi	O
)	O
as	O
well	O
as	O
serum	O
uric	O
acid	O
levels	O
(	O
hyperuricaemia	O
=	O
serum	O
uric	O
acid	O
>	O
mean	O
+	O
2	O
SD	O
from	O
normal	O
population	O
)	O
[	O
22	O
]	O
;	O

(	O
xii	O
)	O
active	O
skin	O
disease	O
or	O
infection	O
in	O
the	O
area	O
of	O
the	O
injection	O
site	O
;	O

(	O
xiii	O
)	O
any	O
medical	O
condition	O
that	O
,	O
in	O
the	O
opinion	O
of	O
the	O
investigators	O
,	O
makes	O
the	O
participant	B
unsuitable	O
for	O
inclusion	O
(	O
e	O
.	O
g	O
.	O
,	O
severe	O
progressive	O
chronic	O
disease	O
,	O
malignancy	O
,	O
bleeding	O
disorder	O
,	O
clinically	O
important	O
pain	O
in	O
a	O
part	O
of	O
the	O
musculoskeletal	O
system	O
other	O
than	O
the	O
first	O
MPJ	O
,	O
or	O
fibromyalgia	O
)	O
;	O

(	O
xiv	O
)	O
pregnant	O
or	O
lactating	O
women	B
,	O
or	O
women	B
who	O
are	O
of	O
child	B
bearing	O
age	O
or	O
have	O
not	O
undergone	O
menopause	O
(	O
Synvisc	O
(	O
R	O
)	O
has	O
not	O
been	O
tested	O
in	O
pregnant	O
women	B
or	O
women	B
who	O
are	O
nursing	O
)	O
;	O

(	O
xv	O
)	O
cognitive	O
impairment	O
(	O
defined	O
as	O
a	O
score	O
of	O
<	O
7	O
on	O
the	O
Short	O
Portable	O
Mental	O
Status	O
Questionnaire	O
)	O
[	O
23	O
]	O
;	O

(	O
xvi	O
)	O
known	O
hypersensitivity	O
(	O
allergy	O
)	O
to	O
hyaluronan	O
preparations	O
,	O
or	O
to	O
avian	O
proteins	O
,	O
feathers	O
or	O
egg	O
products	O
;	O

(	O
xvii	O
)	O
involvement	O
in	O
any	O
clinical	O
research	O
study	O
in	O
the	O
previous	O
3	O
months	O
that	O
could	O
be	O
considered	O
to	O
affect	O
the	O
results	O
of	O
this	O
study	O
.	O

Intra	O
-	O
articular	O
injections	O
for	O
the	O
treatment	O
groups	O

Participants	B
will	O
be	O
randomised	O
to	O
receive	O
a	O
single	O
intra	O
-	O
articular	O
injection	O
of	O
up	O
to	O
1	O
ml	O
of	O
hyaluronan	O
(	O
Synvisc	O
(	O
R	O
)	O
;	O
Genzyme	O
Biosurgery	O
,	O
Genzyme	O
Corporation	O
,	O
NJ	O
,	O
USA	O
)	O
or	O
sterile	O
saline	O
(	O
placebo	O
)	O
into	O
the	O
first	O
MPJ	O
.	O

Each	O
2	O
ml	O
ampoule	O
of	O
Synvisc	O
(	O
R	O
)	O
contains	O
16	O
mg	O
of	O
hylan	O
G	O
-	O
F	O
20	O
(	O
cross	O
-	O
linked	O
hylan	O
polymers	O
;	O
hylan	O
A	O
and	O
B	O
)	O
,	O
17	O
mg	O
sodium	O
chloride	O
,	O
0	O
.	O
32	O
mg	O
disodium	O
hydrogen	O
phosphate	O
,	O
0	O
.	O
08	O
mg	O
sodium	O
dihydrogen	O
phosphate	O
monohydrate	O
.	O

The	O
hyaluronan	O
is	O
extracted	O
from	O
chicken	B
combs	O
and	O
the	O
purified	O
material	O
has	O
an	O
average	O
molecular	O
weight	O
of	O
6	O
,	O
000	O
kDa	O
.	O

The	O
injections	O
will	O
be	O
performed	O
by	O
the	O
same	O
experienced	O
interventional	O
radiologist	O
(	O
AEZ	O
)	O
using	O
fluoroscopic	O
imaging	O
to	O
ensure	O
accurate	O
deposition	O
of	O
the	O
hyaluronan	O
within	O
the	O
joint	O
.	O

As	O
the	O
Synvisc	O
(	O
R	O
)	O
is	O
provided	O
in	O
ampoules	O
that	O
are	O
labelled	O
with	O
the	O
product	O
name	O
,	O
it	O
will	O
not	O
be	O
possible	O
to	O
blind	O
the	O
injector	O
,	O
however	O
this	O
person	B
is	O
not	O
involved	O
in	O
generation	O
of	O
the	O
allocation	O
order	O
,	O
recruitment	O
,	O
assessment	O
or	O
data	O
analysis	O
.	O

The	O
intra	O
-	O
articular	O
injection	O
will	O
be	O
performed	O
using	O
a	O
21	O
gauge	O
(	O
0	O
.	O
80	O
x	O
19	O
mm	O
)	O
Surflo	O
(	O
R	O
)	O
(	O
Terumo	O
(	O
R	O
)	O
Corp	O
.	O
,	O
Tokyo	O
,	O
Japan	O
)	O
winged	O
infusion	O
set	O
under	O
aseptic	O
procedures	O
.	O

Either	O
a	O
dorso	O
-	O
lateral	O
or	O
dorso	O
-	O
medial	O
approach	O
for	O
injection	O
will	O
be	O
used	O
at	O
the	O
discretion	O
of	O
the	O
injector	O
(	O
depending	O
on	O
which	O
approach	O
provides	O
minimum	O
interference	O
from	O
the	O
osteophytes	O
at	O
the	O
first	O
MPJ	O
joint	O
margins	O
)	O
.	O

No	O
anaesthetic	O
will	O
be	O
used	O
.	O

If	O
the	O
participant	B
has	O
bilateral	O
painful	O
first	O
MPJs	O
,	O
only	O
one	O
side	O
(	O
the	O
most	O
painful	O
side	O
)	O
will	O
be	O
treated	O
and	O
used	O
for	O
data	O
collection	O
.	O

The	O
injector	O
will	O
record	O
the	O
volume	O
of	O
the	O
agent	O
that	O
is	O
injected	O
.	O

Participants	B
will	O
be	O
given	O
the	O
option	O
of	O
a	O
second	O
and	O
final	O
intra	O
-	O
articular	O
injection	O
(	O
of	O
Synvisc	O
(	O
R	O
)	O
or	O
sterile	O
saline	O
according	O
to	O
the	O
treatment	O
group	O
they	O
are	O
in	O
)	O
on	O
days	O
30	O
or	O
90	O
if	O
there	O
is	O
no	O
improvement	O
in	O
pain	O
(	O
assessed	O
using	O
the	O
VAPS	O
for	O
pain	O
during	O
walking	O
or	O
at	O
rest	O
)	O
and	O
the	O
participant	B
has	O
not	O
experienced	O
severe	O
adverse	O
effects	O
after	O
the	O
first	O
injection	O
)	O
.	O

Assessments	O

Initial	O
assessments	O

An	O
initial	O
assessment	O
will	O
be	O
performed	O
to	O
determine	O
the	O
eligibility	O
of	O
participants	B
for	O
this	O
study	O
.	O

Demographic	O
data	O
will	O
be	O
collected	O
including	O
the	O
age	O
,	O
gender	O
,	O
height	O
and	O
weight	O
of	O
participants	B
.	O

Data	O
will	O
also	O
be	O
obtained	O
concerning	O
the	O
presentation	O
of	O
symptoms	O
(	O
foot	O
affected	O
,	O
duration	O
of	O
symptoms	O
)	O
.	O

If	O
the	O
participant	B
has	O
bilateral	O
painful	O
first	O
MPJs	O
,	O
the	O
most	O
painful	O
side	O
will	O
be	O
used	O
for	O
data	O
collection	O
and	O
subsequent	O
treatment	O
.	O

To	O
establish	O
eligibility	O
for	O
the	O
study	O
,	O
participants	B
will	O
undergo	O
a	O
clinical	O
assessment	O
,	O
have	O
one	O
set	O
of	O
dorso	O
-	O
plantar	O
and	O
lateral	O
weight	O
-	O
bearing	O
x	O
-	O
rays	O
taken	O
of	O
their	O
feet	O
to	O
grade	O
the	O
severity	O
of	O
first	O
MPJ	O
OA	O
as	O
well	O
as	O
undergo	O
a	O
blood	O
test	O
to	O
assess	O
serum	O
uric	O
acid	O
levels	O
(	O
to	O
exclude	O
gout	O
)	O
.	O

Weightbearing	O
dorso	O
-	O
plantar	O
and	O
lateral	O
radiographic	O
views	O
will	O
be	O
obtained	O
from	O
both	O
feet	O
with	O
the	O
participant	B
standing	O
in	O
a	O
relaxed	O
bipedal	O
stance	O
position	O
.	O

All	O
x	O
-	O
rays	O
will	O
be	O
taken	O
by	O
the	O
same	O
medical	O
imaging	O
department	O
using	O
a	O
Shimadzu	O
UD150LRII	O
50	O
kw	O
/	O
30	O
kHz	O
Generator	O
and	O
0	O
.	O
6	O
/	O
1	O
.	O
2	O
P18DE	O
-	O
80S	O
high	O
speed	O
x	O
-	O
ray	O
tube	O
from	O
a	O
ceiling	O
suspended	O
tube	O
mount	O
.	O

AGFA	O
MD40	O
CR	O
digital	O
phosphor	O
plates	O
in	O
a	O
24	O
cm	O
x	O
30	O
cm	O
cassette	O
will	O
be	O
used	O
.	O

For	O
dorso	O
-	O
plantar	O
projections	O
,	O
the	O
x	O
-	O
ray	O
tube	O
will	O
be	O
angled	O
15	O
degrees	O
cephalad	O
and	O
centered	O
at	O
the	O
base	O
of	O
the	O
third	O
metatarsal	O
.	O

For	O
lateral	O
projections	O
,	O
the	O
tube	O
will	O
be	O
angled	O
90	O
degrees	O
and	O
centered	O
at	O
the	O
base	O
of	O
the	O
third	O
metatarsal	O
.	O

The	O
film	O
focus	O
distance	O
will	O
be	O
set	O
at	O
100	O
cm	O
[	O
19	O
]	O
.	O

Baseline	O
assessments	O
and	O
outcome	O
measures	O

Participants	B
who	O
are	O
eligible	O
for	O
the	O
study	O
will	O
be	O
invited	O
to	O
attend	O
a	O
baseline	O
assessment	O
.	O

During	O
the	O
baseline	O
assessment	O
,	O
participants	B
will	O
undergo	O
primary	O
and	O
secondary	O
outcome	O
measurements	O
prior	O
to	O
receiving	O
their	O
injection	O
.	O

The	O
outcome	O
measurements	O
have	O
been	O
developed	O
in	O
accordance	O
of	O
the	O
recommendations	O
of	O
the	O
OARSI	O
Clinical	O
Trials	O
Task	O
Force	O
guidelines	O
[	O
18	O
]	O
.	O

Primary	O
outcome	O
measures	O

Outcome	O
measurements	O
(	O
primary	O
and	O
secondary	O
)	O
will	O
occur	O
at	O
four	O
time	O
-	O
points	O
at	O
baseline	O
,	O
1	O
,	O
3	O
and	O
6	O
months	O
post	O
-	O
treatment	O
(	O
after	O
the	O
intra	O
-	O
articular	O
injection	O
of	O
Synvisc	O
(	O
R	O
)	O
or	O
placebo	O
)	O
.	O

The	O
assessor	O
performing	O
the	O
measurements	O
will	O
be	O
blinded	O
as	O
to	O
which	O
treatment	O
group	O
participants	B
have	O
been	O
allocated	O
to	O
.	O

Participants	B
who	O
receive	O
a	O
second	O
treatment	O
at	O
day	O
30	O
or	O
90	O
will	O
be	O
followed	O
for	O
a	O
further	O
30	O
days	O
or	O
90	O
days	O
respectively	O
and	O
undergo	O
outcome	O
measurements	O
at	O
7	O
or	O
9	O
months	O
respectively	O
.	O

The	O
primary	O
outcome	O
measures	O
will	O
be	O
the	O
Pain	O
and	O
Function	O
subscales	O
of	O
the	O
Foot	O
Health	O
Status	O
Questionnaire	O
(	O
FHSQ	O
)	O
[	O
24	O
]	O
.	O

The	O
FHSQ	O
includes	O
13	O
questions	O
that	O
assess	O
four	O
domains	O
of	O
foot	O
health	O
,	O
Foot	O
pain	O
,	O
Foot	O
function	O
,	O
Footwear	O
and	O
General	O
foot	O
health	O
.	O

The	O
FHSQ	O
has	O
been	O
subjected	O
to	O
an	O
extensive	O
validation	O
(	O
content	O
,	O
criterion	O
and	O
construct	O
validity	O
)	O
process	O
.	O

It	O
has	O
a	O
high	O
test	O
-	O
retest	O
reliability	O
(	O
intraclass	O
correlation	O
coefficients	O
ranging	O
from	O
0	O
.	O
74	O
to	O
0	O
.	O
92	O
)	O
and	O
a	O
high	O
degree	O
of	O
internal	O
consistency	O
(	O
Cronbach	O
'	O
s	O
alpha	O
ranging	O
from	O
0	O
.	O
85	O
to	O
0	O
.	O
88	O
)	O
[	O
24	O
]	O
.	O

Rigorous	O
reviews	O
have	O
rated	O
it	O
as	O
one	O
of	O
the	O
highest	O
quality	O
foot	O
health	O
status	O
measures	O
currently	O
available	O
[	O
25	O
-	O
27	O
]	O
.	O

Secondary	O
outcome	O
measures	O

The	O
secondary	O
outcome	O
measures	O
will	O
be	O
:	O

(	O
i	O
)	O
Severity	O
of	O
pain	O

Severity	O
of	O
pain	O
at	O
the	O
first	O
MPJ	O
during	O
walking	O
,	O
and	O
during	O
rest	O
,	O
over	O
the	O
past	O
week	O
will	O
be	O
assessed	O
using	O
a	O
100	O
mm	O
visual	O
analogue	O
pain	O
scale	O
.	O

The	O
left	O
side	O
of	O
the	O
scale	O
(	O
0	O
mm	O
)	O
will	O
be	O
labelled	O
"	O
no	O
pain	O
"	O
and	O
the	O
right	O
side	O
of	O
the	O
scale	O
(	O
100	O
mm	O
)	O
will	O
be	O
labelled	O
"	O
worst	O
pain	O
possible	O
"	O
for	O
each	O
question	O
[	O
25	O
,	O
28	O
]	O
.	O

(	O
ii	O
)	O
Severity	O
and	O
duration	O
of	O
stiffness	O
at	O
the	O
first	O
metatarsophalangeal	O
joint	O

The	O
severity	O
of	O
stiffness	O
at	O
the	O
first	O
MPJ	O
during	O
walking	O
over	O
the	O
past	O
week	O
will	O
be	O
assessed	O
using	O
a	O
100	O
mm	O
visual	O
analogue	O
scale	O
.	O

The	O
left	O
side	O
of	O
the	O
scale	O
(	O
0	O
mm	O
)	O
will	O
be	O
labelled	O
"	O
not	O
stiff	O
at	O
all	O
"	O
and	O
the	O
right	O
side	O
of	O
the	O
scale	O
(	O
100	O
mm	O
)	O
will	O
be	O
labelled	O
"	O
most	O
stiff	O
possible	O
"	O
.	O

The	O
average	O
duration	O
of	O
stiffness	O
at	O
the	O
first	O
MPJ	O
over	O
the	O
past	O
week	O
will	O
be	O
assessed	O
using	O
a	O
four	O
category	O
scale	O
response	O
.	O

The	O
responses	O
are	O
:	O
"	O
none	O
"	O
,	O
"	O
1	O
-	O
15	O
minutes	O
"	O
,	O
"	O
16	O
-	O
30	O
minutes	O
"	O
and	O
"	O
greater	O
than	O
30	O
minutes	O
"	O
[	O
29	O
]	O
.	O

(	O
iii	O
)	O
Passive	O
,	O
non	O
-	O
weightbearing	O
dorsiflexion	O
range	O
of	O
motion	O
of	O
the	O
first	O
metatarsophalangeal	O
joint	O

First	O
MPJ	O
dorsiflexion	O
range	O
of	O
motion	O
will	O
be	O
measured	O
using	O
a	O
goniometer	O
as	O
the	O
maximum	O
angle	O
at	O
which	O
the	O
hallux	O
cannot	O
be	O
passively	O
moved	O
into	O
further	O
extension	O
in	O
a	O
non	O
-	O
weightbearing	O
position	O
(	O
Figure	O
2	O
)	O
[	O
30	O
]	O
.	O

The	O
test	O
will	O
be	O
performed	O
two	O
times	O
and	O
the	O
average	O
will	O
be	O
used	O
for	O
analysis	O
.	O

This	O
measurement	O
technique	O
shows	O
high	O
intra	O
-	O
reliability	O
(	O
ICC	O
=	O
0	O
.	O
95	O
,	O
standard	O
error	O
of	O
mean	O
=	O
1	O
.	O
3	O
degrees	O
)	O
[	O
30	O
]	O
.	O

(	O
iv	O
)	O
Plantar	O
flexion	O
strength	O
of	O
the	O
toe	O
-	O
flexors	O
of	O
the	O
hallux	O

Plantar	O
flexion	O
strength	O
of	O
the	O
toe	O
-	O
flexors	O
of	O
the	O
hallux	O
will	O
be	O
measured	O
using	O
the	O
Mat	O
Scan	O
(	O
R	O
)	O
plantar	O
pressure	O
measurement	O
device	O
[	O
31	O
]	O
.	O

Participants	B
will	O
be	O
seated	O
with	O
the	O
hip	O
,	O
knee	O
,	O
and	O
ankle	O
at	O
90	O
degrees	O
and	O
their	O
foot	O
placed	O
over	O
the	O
Mat	O
Scan	O
(	O
R	O
)	O
plantar	O
pressure	O
measurement	O
device	O
(	O
Tekscan	O
,	O
Boston	O
,	O
MA	O
,	O
USA	O
)	O
(	O
Figure	O
3a	O
)	O
.	O

This	O
system	O
consists	O
of	O
a	O
5	O
-	O
mm	O
thick	O
floor	O
mat	O
(	O
432	O
x	O
368	O
mm	O
)	O
incorporating	O
2288	O
resistive	O
sensors	O
(	O
1	O
.	O
4	O
sensors	O
/	O
cm2	O
)	O
sampling	O
at	O
a	O
rate	O
of	O
40	O
Hz	O
.	O

The	O
mat	O
will	O
be	O
calibrated	O
for	O
each	O
participant	B
using	O
his	O
or	O
her	O
own	O
bodyweight	O
before	O
each	O
testing	O
session	O
.	O

Participants	B
will	O
be	O
instructed	O
to	O
use	O
their	O
toe	O
-	O
flexor	O
muscles	O
to	O
maximally	O
push	O
their	O
hallux	O
down	O
on	O
the	O
MatScan	O
(	O
R	O
)	O
device	O
and	O
forces	O
under	O
the	O
hallux	O
will	O
be	O
recorded	O
(	O
Figure	O
3b	O
)	O
.	O

The	O
test	O
will	O
be	O
performed	O
three	O
times	O
for	O
the	O
hallux	O
and	O
the	O
maximal	O
force	O
will	O
be	O
used	O
for	O
analysis	O
.	O

The	O
test	O
-	O
retest	O
reliability	O
of	O
this	O
measurement	O
technique	O
has	O
previously	O
been	O
shown	O
to	O
be	O
high	O
,	O
with	O
intraclass	O
correlation	O
coefficients	O
(	O
ICCs	O
)	O
=	O
0	O
.	O
88	O
(	O
95	O
%	O
CI	O
0	O
.	O
81	O
-	O
0	O
.	O
93	O
)	O
[	O
31	O
]	O
.	O

(	O
vi	O
)	O
Plantar	O
pressure	O
measurement	O

Plantar	O
pressures	O
will	O
be	O
recorded	O
during	O
level	O
barefoot	O
walking	O
using	O
the	O
MatScan	O
(	O
R	O
)	O
system	O
(	O
Tekscan	O
(	O
R	O
)	O
,	O
Boston	O
,	O
MA	O
,	O
USA	O
)	O
.	O

The	O
two	O
-	O
step	O
gait	O
initiation	O
protocol	O
will	O
be	O
used	O
to	O
obtain	O
foot	O
pressure	O
data	O
,	O
as	O
it	O
requires	O
fewer	O
trials	O
than	O
the	O
mid	O
-	O
gait	O
protocol	O
and	O
has	O
similar	O
re	O
-	O
test	O
reliability	O
[	O
32	O
]	O
.	O

Three	O
trials	O
will	O
be	O
recorded	O
,	O
which	O
has	O
been	O
found	O
to	O
be	O
sufficient	O
to	O
ensure	O
adequate	O
reliability	O
of	O
pressure	O
data	O
[	O
32	O
,	O
33	O
]	O
.	O

Following	O
data	O
collection	O
,	O
the	O
Research	O
Foot	O
(	O
R	O
)	O
software	O
(	O
version	O
5	O
.	O
24	O
)	O
will	O
be	O
used	O
to	O
construct	O
individual	O
"	O
masks	O
"	O
to	O
determine	O
maximum	O
force	O
(	O
kg	O
)	O
and	O
peak	O
pressure	O
(	O
kg	O
/	O
cm2	O
)	O
under	O
seven	O
regions	O
of	O
the	O
foot	O
:	O
hallux	O
,	O
lesser	O
toes	O
,	O
1st	O
MPJ	O
,	O
2nd	O
MPJ	O
,	O
3rd	O
to	O
5th	O
MPJs	O
,	O
midfoot	O
and	O
heel	O
(	O
Figure	O
4a	O
)	O
.	O

For	O
each	O
region	O
,	O
the	O
median	O
of	O
the	O
three	O
trials	O
will	O
be	O
used	O
for	O
analysis	O
.	O

Typical	O
plantar	O
pressure	O
recordings	O
from	O
a	O
participant	B
are	O
shown	O
in	O
Figure	O
4b	O
.	O

(	O
vi	O
)	O
Global	O
satisfaction	O
with	O
the	O
treatment	O

Global	O
satisfaction	O
with	O
the	O
treatment	O
will	O
be	O
assessed	O
using	O
a	O
5	O
-	O
point	O
Likert	O
scale	O
,	O
as	O
well	O
as	O
a	O
dichotomous	O
(	O
yes	O
/	O
no	O
)	O
scale	O
.	O

The	O
five	O
point	O
-	O
Likert	O
scale	O
will	O
ask	O
"	O
How	O
satisfied	O
are	O
you	O
with	O
the	O
treatment	O
you	O
received	O
for	O
your	O
big	O
-	O
toe	O
joint	O
pain	O
?	O
"	O
,	O
and	O
will	O
have	O
the	O
following	O
five	O
responses	O
:	O
"	O
Dissatisfied	O
"	O
,	O
"	O
Only	O
moderately	O
satisfied	O
"	O
,	O
"	O
Fairly	O
satisfied	O
"	O
,	O
"	O
Clearly	O
satisfied	O
"	O
and	O
"	O
Very	O
satisfied	O
"	O
.	O

The	O
dichotomous	O
scale	O
of	O
satisfaction	O
will	O
be	O
answered	O
as	O
"	O
Yes	O
"	O
'	O
or	O
"	O
No	O
"	O
in	O
response	O
to	O
the	O
question	O
:	O
"	O
Would	O
you	O
recommend	O
the	O
treatment	O
that	O
you	O
received	O
to	O
someone	O
else	O
with	O
big	O
-	O
toe	O
joint	O
pain	O
"	O
.	O

(	O
vii	O
)	O
Health	O
related	O
quality	O
of	O
life	O

The	O
Short	O
-	O
Form	O
-	O
36	O
(	O
version	O
two	O
)	O
(	O
SF	O
-	O
36	O
)	O
questionnaire	O
will	O
be	O
used	O
to	O
assess	O
health	O
related	O
quality	O
of	O
life	O
.	O

The	O
SF	O
-	O
36	O
is	O
a	O
36	O
question	O
survey	O
that	O
measures	O
eight	O
health	O
concepts	O
most	O
affected	O
by	O
disease	O
and	O
treatment	O
.	O

The	O
eight	O
health	O
concepts	O
can	O
then	O
be	O
used	O
to	O
form	O
two	O
summary	O
measures	O
:	O
Physical	O
health	O
and	O
Mental	O
health	O
.	O

The	O
Short	O
Form	O
-	O
36	O
(	O
SF	O
-	O
36	O
)	O
has	O
been	O
extensively	O
validated	O
and	O
is	O
one	O
of	O
the	O
most	O
widely	O
used	O
instruments	O
to	O
measure	O
health	O
status	O
.	O

The	O
SF	O
-	O
36	O
shows	O
content	O
,	O
concurrent	O
,	O
criterion	O
,	O
construct	O
,	O
and	O
predictive	O
evidence	O
of	O
validity	O
.	O

The	O
reliability	O
of	O
the	O
eight	O
concepts	O
and	O
two	O
summary	O
measures	O
has	O
been	O
assessed	O
using	O
both	O
internal	O
consistency	O
and	O
test	O
-	O
retest	O
methods	O
.	O

Reliability	O
statistics	O
have	O
exceeded	O
0	O
.	O
80	O
[	O
34	O
-	O
37	O
]	O
.	O

(	O
viii	O
)	O
Self	O
-	O
reported	O
magnitude	O
of	O
symptom	O
change	O

Self	O
-	O
reported	O
magnitude	O
of	O
symptom	O
change	O
will	O
be	O
measured	O
using	O
a	O
15	O
-	O
point	O
Likert	O
scale	O
.	O

The	O
scale	O
will	O
ask	O
participants	B
"	O
how	O
much	O
have	O
your	O
symptoms	O
in	O
your	O
big	O
-	O
toe	O
joint	O
have	O
changed	O
from	O
the	O
beginning	O
of	O
the	O
study	O
to	O
now	O
?	O
"	O
.	O

The	O
fifteen	O
responses	O
will	O
range	O
from	O
"	O
A	O
very	O
great	O
deal	O
better	O
"	O
to	O
"	O
A	O
very	O
great	O
deal	O
worse	O
"	O
.	O

(	O
ix	O
)	O
Use	O
of	O
rescue	O
medications	O
to	O
relieve	O
pain	O
at	O
the	O
first	O
metatarsophalangeal	O
joint	O

The	O
number	O
of	O
participants	B
who	O
consumed	O
rescue	O
medication	O
(	O
e	O
.	O
g	O
.	O
,	O
paracetamol	O
)	O
and	O
mean	O
consumption	O
of	O
rescue	O
medication	O
to	O
relieve	O
pain	O
at	O
the	O
first	O
MPJ	O
(	O
mean	O
grams	O
of	O
paracetamol	O
/	O
participant	B
/	O
month	O
]	O
will	O
be	O
assessed	O
using	O
a	O
medications	O
diary	O
that	O
participants	B
will	O
self	O
-	O
complete	O
[	O
38	O
,	O
39	O
]	O
.	O

The	O
diary	O
will	O
be	O
returned	O
to	O
the	O
assessor	O
at	O
monthly	O
intervals	O
for	O
analysis	O
.	O

(	O
x	O
)	O
Frequency	O
and	O
severity	O
of	O
adverse	O
events	O
as	O
safety	O
variables	O

The	O
frequency	O
(	O
number	O
of	O
participants	B
affected	O
and	O
number	O
of	O
cases	O
)	O
and	O
types	O
of	O
adverse	O
events	O
(	O
including	O
adverse	O
drug	O
reactions	O
)	O
in	O
each	O
treatment	O
group	O
during	O
the	O
trial	O
will	O
be	O
recorded	O
using	O
a	O
questionnaire	O
that	O
participants	B
will	O
complete	O
during	O
the	O
follow	O
-	O
up	O
appointments	O
at	O
1	O
,	O
3	O
and	O
6	O
months	O
post	O
-	O
treatment	O
[	O
40	O
]	O
.	O

To	O
classify	O
the	O
'	O
type	O
'	O
of	O
adverse	O
event	O
,	O
a	O
blinded	O
assessor	O
will	O
classify	O
the	O
adverse	O
event	O
as	O
being	O
serious	O
or	O
non	O
-	O
serious	O
[	O
40	O
]	O
.	O

Any	O
serious	O
adverse	O
events	O
,	O
defined	O
as	O
adverse	O
events	O
leading	O
to	O
serious	O
disability	O
,	O
hospital	O
admission	O
,	O
or	O
prolongation	O
of	O
hospitalisation	O
,	O
life	O
-	O
threatening	O
events	O
;	O
or	O
death	O
)	O
will	O
be	O
further	O
classified	O
using	O
the	O
International	O
Classification	O
of	O
Diseases	O
(	O
ICD	O
)	O
codes	O
[	O
41	O
]	O
.	O

Non	O
-	O
serious	O
adverse	O
events	O
will	O
include	O
both	O
local	O
(	O
pain	O
,	O
effusion	O
and	O
heat	O
,	O
with	O
each	O
classified	O
as	O
mild	O
,	O
moderate	O
,	O
severe	O
)	O
and	O
systemic	O
adverse	O
events	O
.	O

An	O
open	O
-	O
response	O
type	O
format	O
will	O
also	O
be	O
available	O
for	O
participant	B
responses	O
.	O

Sample	O
size	O

The	O
sample	O
size	O
for	O
the	O
study	O
has	O
been	O
pre	O
-	O
specified	O
using	O
an	O
a	O
priori	O
power	O
analysis	O
using	O
the	O
primary	O
outcome	O
measure	O
of	O
the	O
pain	O
domain	O
of	O
the	O
FHSQ	O
[	O
42	O
]	O
.	O

One	O
hundred	O
and	O
forty	O
two	O
participants	B
(	O
i	O
.	O
e	O
.	O
71	O
per	O
group	O
)	O
will	O
provide	O
power	O
of	O
90	O
%	O
to	O
detect	O
a	O
minimally	O
important	O
difference	O
in	O
the	O
pain	O
domain	O
of	O
the	O
FHSQ	O
(	O
i	O
.	O
e	O
.	O
14	O
points	O
on	O
the	O
FHSQ	O
questionnaire	O
)	O
with	O
the	O
significance	O
level	O
set	O
at	O
p	O
<	O
0	O
.	O
05	O
.	O

A	O
difference	O
of	O
14	O
points	O
was	O
determined	O
to	O
be	O
a	O
clinically	O
significant	O
difference	O
worth	O
detecting	O
[	O
43	O
]	O
and	O
a	O
standard	O
deviation	O
of	O
25	O
was	O
derived	O
from	O
a	O
previous	O
report	O
[	O
44	O
]	O
.	O

This	O
calculation	O
included	O
a	O
5	O
%	O
drop	O
-	O
out	O
rate	O
[	O
13	O
]	O
.	O

However	O
,	O
we	O
will	O
aim	O
to	O
recruit	O
150	O
participants	B
(	O
~	O
75	O
participants	B
per	O
intervention	O
group	O
)	O
.	O

Further	O
,	O
we	O
have	O
conservatively	O
ignored	O
the	O
extra	O
precision	O
provided	O
by	O
covariate	O
analysis	O
when	O
estimating	O
the	O
sample	O
size	O
.	O

Statistical	O
analysis	O

Statistical	O
analysis	O
will	O
be	O
undertaken	O
using	O
SPSS	O
version	O
14	O
.	O
0	O
(	O
SPSS	O
Corp	O
,	O
Chicago	O
,	O
Ill	O
,	O
USA	O
)	O
and	O
STATA	O
8	O
(	O
Stata	O
Corp	O
,	O
College	O
Station	O
,	O
Tex	O
.	O
,	O
USA	O
)	O
statistical	O
software	O
.	O

All	O
analyses	O
will	O
be	O
conducted	O
on	O
an	O
intention	O
-	O
to	O
-	O
treat	O
principle	O
using	O
all	O
randomised	O
participants	B
[	O
45	O
-	O
47	O
]	O
.	O

Missing	O
data	O
will	O
be	O
replaced	O
with	O
the	O
last	O
score	O
carried	O
forward	O
[	O
48	O
]	O
.	O

Standard	O
tests	O
for	O
normal	O
distribution	O
will	O
be	O
used	O
and	O
transformation	O
carried	O
out	O
if	O
required	O
.	O

Demographic	O
characteristics	O
(	O
gender	O
,	O
age	O
,	O
weight	O
,	O
height	O
,	O
body	O
mass	O
index	O
)	O
will	O
be	O
determined	O
for	O
the	O
baseline	O
visit	O
for	O
each	O
treatment	O
group	O
.	O

Summary	O
statistics	O
will	O
be	O
calculated	O
for	O
duration	O
of	O
symptoms	O
,	O
side	O
affected	O
(	O
left	O
,	O
right	O
,	O
bilateral	O
)	O
,	O
grade	O
of	O
OA	O
at	O
the	O
first	O
MPJ	O
[	O
19	O
]	O
as	O
well	O
as	O
all	O
primary	O
and	O
secondary	O
outcome	O
measurements	O
for	O
each	O
treatment	O
group	O
.	O

Analyses	O
will	O
be	O
conducted	O
on	O
1	O
,	O
3	O
and	O
6	O
month	O
outcome	O
measures	O
.	O

The	O
continuously	O
-	O
scored	O
outcome	O
measures	O
at	O
1	O
,	O
3	O
and	O
6	O
months	O
will	O
be	O
compared	O
using	O
analysis	O
of	O
covariance	O
with	O
baseline	O
scores	O
and	O
intervention	O
group	O
entered	O
as	O
independent	O
variables	O
[	O
49	O
,	O
50	O
]	O
.	O

The	O
exception	O
to	O
this	O
will	O
be	O
the	O
plantar	O
pressure	O
measurements	O
which	O
will	O
be	O
analysed	O
at	O
baseline	O
,	O
1	O
,	O
3	O
and	O
6	O
months	O
using	O
two	O
-	O
way	O
repeated	O
measures	O
analysis	O
of	O
variance	O
statistics	O
.	O

Post	O
-	O
hoc	O
comparisons	O
will	O
be	O
performed	O
using	O
Bonferroni	O
-	O
adjusted	O
t	O
-	O
tests	O
.	O

Nominal	O
and	O
ordinal	O
scaled	O
data	O
will	O
be	O
compared	O
at	O
1	O
,	O
3	O
and	O
6	O
months	O
using	O
Mann	O
-	O
Whitney	O
U	O
-	O
tests	O
and	O
chi	O
-	O
square	O
analyses	O
(	O
or	O
Fisher	O
'	O
s	O
exact	O
test	O
where	O
appropriate	O
)	O
respectively	O
.	O

Effect	O
sizes	O
will	O
be	O
determined	O
using	O
Cohen	O
'	O
s	O
d	O
(	O
continuous	O
scaled	O
data	O
)	O
or	O
odds	O
ratios	O
(	O
nominal	O
scaled	O
data	O
and	O
ordinal	O
scaled	O
data	O
)	O
as	O
appropriate	O
.	O

The	O
outcome	O
measurements	O
obtained	O
at	O
7	O
or	O
9	O
months	O
for	O
participants	B
that	O
receive	O
a	O
second	O
and	O
final	O
intra	O
-	O
articular	O
injection	O
(	O
of	O
Synvisc	O
(	O
R	O
)	O
or	O
sterile	O
saline	O
according	O
to	O
the	O
treatment	O
group	O
they	O
are	O
in	O
)	O
on	O
days	O
30	O
or	O
90	O
respectively	O
,	O
will	O
also	O
be	O
analysed	O
as	O
described	O
above	O
.	O

These	O
analyses	O
will	O
be	O
classified	O
as	O
secondary	O
outcomes	O
.	O

Discussion	O

This	O
study	O
is	O
a	O
randomised	O
placebo	O
controlled	O
trial	O
designed	O
to	O
investigate	O
the	O
efficacy	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
(	O
Synvisc	O
(	O
R	O
)	O
)	O
to	O
reduce	O
pain	O
and	O
improve	O
function	O
in	O
people	B
with	O
OA	O
of	O
the	O
first	O
MPJ	O
(	O
hallux	O
limitus	O
)	O
.	O

Two	O
studies	O
have	O
previously	O
investigated	O
the	O
efficacy	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
for	O
the	O
treatment	O
of	O
first	O
MPJ	O
OA	O
[	O
13	O
,	O
14	O
]	O
.	O

However	O
,	O
neither	O
of	O
these	O
studies	O
used	O
a	O
placebo	O
control	O
group	O
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
randomised	O
controlled	O
trial	O
using	O
intra	O
-	O
articular	O
hyaluronan	O
for	O
OA	O
of	O
the	O
first	O
MPJ	O
.	O

The	O
use	O
of	O
a	O
placebo	O
control	O
group	O
is	O
essential	O
for	O
studies	O
evaluating	O
the	O
effects	O
of	O
intra	O
-	O
articular	O
therapies	O
as	O
there	O
is	O
likely	O
to	O
be	O
a	O
large	O
placebo	O
response	O
related	O
to	O
the	O
injection	O
procedure	O
and	O
this	O
may	O
inflate	O
the	O
results	O
in	O
uncontrolled	O
evaluations	O
[	O
51	O
]	O
.	O

Indeed	O
,	O
a	O
recent	O
meta	O
-	O
analysis	O
of	O
hyaluronan	O
for	O
knee	O
OA	O
concluded	O
that	O
a	O
placebo	O
effect	O
accounted	O
for	O
79	O
%	O
of	O
the	O
efficacy	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
[	O
16	O
]	O
.	O

The	O
study	O
protocol	O
and	O
outcome	O
measures	O
have	O
been	O
developed	O
in	O
accordance	O
of	O
the	O
recommendations	O
of	O
the	O
OARSI	O
Clinical	O
Trials	O
Task	O
Force	O
guidelines	O
[	O
18	O
]	O
.	O

The	O
outcome	O
measures	O
are	O
pain	O
and	O
function	O
subscales	O
of	O
the	O
FHSQ	O
,	O
pain	O
and	O
stiffness	O
at	O
the	O
first	O
MPJ	O
,	O
range	O
of	O
motion	O
(	O
dorsiflexion	O
)	O
of	O
the	O
first	O
MPJ	O
,	O
plantar	O
flexion	O
strength	O
of	O
muscles	O
of	O
the	O
first	O
MPJ	O
,	O
generic	O
health	O
related	O
quality	O
of	O
life	O
(	O
SF	O
-	O
36	O
)	O
,	O
patient	B
satisfaction	O
with	O
treatment	O
,	O
consumption	O
of	O
rescue	O
medication	O
as	O
well	O
as	O
frequency	O
and	O
nature	O
of	O
adverse	O
effects	O
.	O

These	O
outcomes	O
will	O
be	O
measured	O
at	O
baseline	O
then	O
at	O
1	O
,	O
3	O
and	O
6	O
months	O
after	O
treatment	O
.	O

Previous	O
research	O
suggests	O
that	O
the	O
effects	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
persist	O
for	O
up	O
to	O
12	O
months	O
following	O
treatment	O
[	O
9	O
,	O
38	O
]	O
.	O

Thus	O
,	O
the	O
use	O
of	O
follow	O
-	O
up	O
assessments	O
at	O
6	O
month	O
post	O
-	O
treatment	O
will	O
allow	O
us	O
to	O
determine	O
if	O
the	O
effects	O
,	O
if	O
any	O
,	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
persist	O
in	O
the	O
longer	O
term	O
.	O

Participants	B
will	O
be	O
given	O
the	O
option	O
of	O
a	O
second	O
and	O
final	O
intra	O
-	O
articular	O
injection	O
(	O
of	O
Synvisc	O
(	O
R	O
)	O
or	O
sterile	O
saline	O
according	O
to	O
the	O
treatment	O
group	O
they	O
are	O
in	O
)	O
on	O
days	O
30	O
or	O
90	O
if	O
there	O
is	O
no	O
improvement	O
in	O
their	O
symptoms	O
.	O

Although	O
this	O
has	O
the	O
potential	O
to	O
complicate	O
the	O
interpretation	O
of	O
the	O
results	O
of	O
the	O
study	O
,	O
this	O
protocol	O
was	O
included	O
as	O
it	O
is	O
likely	O
to	O
be	O
more	O
reflective	O
of	O
clinical	O
practice	O
[	O
14	O
]	O
,	O
and	O
this	O
is	O
in	O
keeping	O
with	O
the	O
pragmatic	O
nature	O
of	O
this	O
trial	O
.	O

In	O
summary	O
,	O
this	O
project	O
is	O
the	O
first	O
randomised	O
controlled	O
trial	O
to	O
be	O
conducted	O
to	O
evaluate	O
the	O
efficacy	O
of	O
intra	O
-	O
articular	O
hyaluronan	O
for	O
reducing	O
pain	O
and	O
improving	O
function	O
in	O
people	B
with	O
hallux	O
limitus	O
.	O

The	O
study	O
protocol	O
,	O
including	O
interventions	O
,	O
have	O
been	O
pragmatically	O
designed	O
to	O
ensure	O
that	O
the	O
study	O
findings	O
are	O
generaliseable	O
to	O
clinical	O
practice	O
.	O

Recruitment	O
for	O
the	O
study	O
will	O
commence	O
in	O
June	O
2008	O
,	O
and	O
we	O
expect	O
final	O
results	O
to	O
be	O
available	O
in	O
mid	O
-	O
2010	O
.	O

Competing	O
interests	O

HBM	O
and	O
KBL	O
are	O
Editor	O
-	O
in	O
-	O
Chief	O
and	O
Deputy	O
Editor	O
-	O
in	O
-	O
Chief	O
,	O
respectively	O
,	O
of	O
Journal	O
of	O
Foot	O
and	O
Ankle	O
Research	O
.	O

It	O
is	O
journal	O
policy	O
that	O
editors	O
are	O
removed	O
from	O
the	O
peer	O
review	O
and	O
editorial	O
decision	O
making	O
processes	O
for	O
papers	O
they	O
have	O
co	O
-	O
authored	O
.	O

Authors	O
'	O
contributions	O

SEM	O
,	O
HBM	O
,	O
KBL	O
and	O
CJH	O
conceived	O
the	O
idea	O
and	O
obtained	O
funding	O
for	O
the	O
study	O
.	O

SEM	O
,	O
HBM	O
,	O
KBL	O
,	O
AEZ	O
and	O
JDL	O
designed	O
the	O
trial	O
protocol	O
.	O

SEM	O
,	O
HBM	O
,	O
KBL	O
and	O
GVZ	O
drafted	O
the	O
manuscript	O
.	O

All	O
authors	O
have	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

p8	O
inhibits	O
the	O
growth	O
of	O
human	B
pancreatic	O
cancer	O
cells	O
and	O
its	O
expression	O
is	O
induced	O
through	O
pathways	O
involved	O
in	O
growth	O
inhibition	O
and	O
repressed	O
by	O
factors	O
promoting	O
cell	O
growth	O

Abstract	O

Background	O

p8	O
is	O
a	O
stress	O
-	O
induced	O
protein	O
with	O
multiple	O
functions	O
and	O
biochemically	O
related	O
to	O
the	O
architectural	O
factor	O
HMG	O
-	O
I	O
/	O
Y	O
.	O

We	O
analyzed	O
the	O
expression	O
and	O
function	O
of	O
p8	O
in	O
pancreatic	O
cancer	O
-	O
derived	O
cells	O
.	O

Methods	O

Expression	O
of	O
p8	O
was	O
silenced	O
in	O
the	O
human	B
pancreatic	O
cancer	O
cell	O
lines	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
by	O
infection	O
with	O
a	O
retrovirus	O
expressing	O
p8	O
RNA	O
in	O
the	O
antisense	O
orientation	O
.	O

Cell	O
growth	O
was	O
measured	O
in	O
control	O
and	O
p8	O
-	O
silenced	O
cells	O
.	O

Influence	O
on	O
p8	O
expression	O
of	O
the	O
induction	O
of	O
intracellular	O
pathways	O
promoting	O
cellular	O
growth	O
or	O
growth	O
arrest	O
was	O
monitored	O
.	O

Results	O

p8	O
-	O
silenced	O
cells	O
grew	O
more	O
rapidly	O
than	O
control	O
cells	O
transfected	O
with	O
the	O
empty	O
retrovirus	O
.	O

Activation	O
of	O
the	O
Ras	O
-	O
-	O
>	O
Raf	O
-	O
-	O
>	O
MEK	O
-	O
-	O
>	O
ERK	O
and	O
JNK	O
intracellular	O
pathways	O
down	O
-	O
regulated	O
p8	O
expression	O
.	O

In	O
addition	O
,	O
the	O
MEK1	O
/	O
2	O
inhibitor	O
U0126	O
and	O
the	O
JNK	O
inhibitor	O
SP600125	O
up	O
-	O
regulates	O
expression	O
of	O
p8	O
.	O

Conversely	O
,	O
p38	O
or	O
TGF	O
beta	O
-	O
1	O
induced	O
p8	O
expression	O
whereas	O
the	O
specific	O
p38	O
inhibitor	O
SB203580	O
down	O
-	O
regulated	O
p8	O
expression	O
.	O

Finally	O
,	O
TGF	O
beta	O
-	O
1	O
induction	O
was	O
in	O
part	O
mediated	O
through	O
p38	O
.	O

Conclusions	O

p8	O
inhibits	O
the	O
growth	O
of	O
human	B
pancreatic	O
cancer	O
cells	O
.	O

p8	O
expression	O
is	O
induced	O
through	O
pathways	O
involved	O
in	O
growth	O
inhibition	O
and	O
repressed	O
by	O
factors	O
that	O
promote	O
cell	O
growth	O
.	O

These	O
results	O
suggest	O
that	O
p8	O
belongs	O
to	O
a	O
pathway	O
regulating	O
the	O
growth	O
of	O
pancreatic	O
cancer	O
cells	O
.	O

Background	O

While	O
studying	O
the	O
molecular	O
response	O
of	O
the	O
injured	O
pancreas	O
,	O
we	O
identified	O
a	O
new	O
gene	O
,	O
called	O
p8	O
,	O
whose	O
expression	O
is	O
strongly	O
induced	O
during	O
the	O
acute	O
phase	O
of	O
pancreatitis	O
[	O
1	O
]	O
.	O

Further	O
experiments	O
have	O
shown	O
that	O
p8	O
mRNA	O
is	O
activated	O
in	O
almost	O
all	O
cells	O
in	O
response	O
to	O
several	O
stresses	O
[	O
2	O
]	O
,	O
including	O
minimal	O
stresses	O
such	O
as	O
after	O
routine	O
change	O
of	O
the	O
culture	O
medium	O
in	O
the	O
absence	O
of	O
any	O
added	O
substance	O
[	O
3	O
]	O
,	O
indicating	O
that	O
p8	O
is	O
a	O
ubiquitous	O
protein	O
induced	O
by	O
cellular	O
stress	O
.	O

The	O
p8	O
gene	O
was	O
cloned	O
in	O
human	B
,	O
rat	B
,	O
mouse	B
,	O
and	O
Xenopus	B
laevis	I
[	O
1	O
,	O
4	O
-	O
6	O
]	O
,	O
conceptually	O
translated	O
from	O
the	O
Drosophila	B
melanogaster	I
genome	O
or	O
deduced	O
from	O
EST	O
libraries	O
(	O
Bos	B
taurus	I
,	O
Xenopus	B
tropicalis	I
,	O
Zebrafish	B
,	O
Orzzias	B
latipes	I
,	O
Bombyx	B
mori	I
and	O
Paralichthys	B
olivaceous	I
)	O
.	O

The	O
overall	O
degree	O
of	O
homology	O
with	O
human	B
p8	O
ranged	O
from	O
81	O
to	O
40	O
%	O
.	O

Secondary	O
structure	O
prediction	O
methods	O
indicated	O
that	O
within	O
the	O
homologous	O
region	O
of	O
the	O
eleven	O
proteins	O
,	O
there	O
is	O
a	O
basic	O
Helix	O
-	O
Loop	O
-	O
Helix	O
secondary	O
structure	O
motif	O
,	O
characteristic	O
of	O
some	O
classes	O
of	O
transcription	O
factors	O
[	O
1	O
]	O
.	O

Even	O
though	O
a	O
small	O
protein	O
such	O
as	O
p8	O
would	O
not	O
need	O
a	O
nuclear	O
localization	O
signal	O
(	O
NLS	O
)	O
to	O
be	O
transported	O
to	O
the	O
nucleus	O
,	O
a	O
clear	O
NLS	O
can	O
be	O
predicted	O
for	O
the	O
eleven	O
proteins	O
comprising	O
a	O
bipartite	O
domain	O
of	O
positively	O
charged	O
aminoacids	O
.	O

In	O
addition	O
,	O
a	O
nuclear	O
/	O
cytoplasmic	O
location	O
has	O
been	O
demonstrated	O
for	O
human	B
p8	O
upon	O
overexpression	O
of	O
the	O
recombinant	O
protein	O
and	O
immunohistochemistry	O
[	O
4	O
]	O
,	O
and	O
for	O
recombinant	O
Xenopus	B
laevis	I
p8	O
fused	O
to	O
green	O
fluorescent	O
protein	O
[	O
6	O
]	O
.	O

Homology	O
searching	O
in	O
databases	O
did	O
not	O
reveal	O
significant	O
similarity	O
of	O
p8	O
with	O
other	O
proteins	O
of	O
known	O
function	O
.	O

However	O
,	O
biochemical	O
properties	O
of	O
the	O
mammalian	O
p8	O
proteins	O
are	O
shared	O
by	O
some	O
high	O
mobility	O
group	O
proteins	O
(	O
HMG	O
)	O
[	O
7	O
]	O
,	O
particularly	O
by	O
the	O
HMG	O
-	O
I	O
/	O
Y	O
family	O
.	O

The	O
overall	O
identity	O
of	O
human	B
p8	O
with	O
human	B
HMG	O
-	O
I	O
/	O
Y	O
is	O
only	O
about	O
35	O
%	O
,	O
but	O
the	O
molecular	O
mass	O
,	O
isoelectric	O
point	O
,	O
hydrophilicity	O
plot	O
,	O
the	O
resistance	O
to	O
denaturation	O
after	O
heating	O
at	O
100	O
degrees	O
C	O
and	O
the	O
charge	O
separation	O
are	O
very	O
similar	O
[	O
8	O
]	O
.	O

The	O
p8	O
protein	O
seems	O
to	O
bind	O
DNA	O
weakly	O
,	O
as	O
shown	O
by	O
electrophoretic	O
mobility	O
shift	O
assay	O
,	O
without	O
preference	O
for	O
DNA	O
sequences	O
.	O

Finally	O
,	O
human	B
p8	O
has	O
also	O
been	O
shown	O
to	O
be	O
a	O
substrate	O
for	O
protein	O
kinase	O
A	O
in	O
vitro	O
and	O
phosphorylated	O
p8	O
has	O
a	O
higher	O
content	O
of	O
secondary	O
structure	O
and	O
binding	O
to	O
DNA	O
is	O
highly	O
increased	O
[	O
8	O
]	O
.	O

An	O
architectural	O
role	O
in	O
transcription	O
has	O
been	O
proposed	O
for	O
this	O
protein	O
,	O
in	O
analogy	O
with	O
the	O
HMG	O
-	O
I	O
/	O
Y	O
proteins	O
,	O
and	O
a	O
recent	O
work	O
seems	O
to	O
confirm	O
this	O
hypothesis	O
[	O
9	O
]	O
.	O

Functions	O
of	O
p8	O
appear	O
to	O
be	O
multiple	O
and	O
complex	O
.	O

For	O
example	O
,	O
p8	O
mRNA	O
expression	O
was	O
strongly	O
induced	O
in	O
3T3	O
cells	O
upon	O
TGF	O
beta	O
-	O
1	O
treatment	O
which	O
in	O
turn	O
enhances	O
the	O
Smad	O
-	O
transactivating	O
function	O
responsible	O
for	O
TGF	O
beta	O
-	O
1	O
activity	O
[	O
10	O
]	O
.	O

We	O
also	O
found	O
that	O
p8	O
is	O
involved	O
in	O
cell	O
cycle	O
regulation	O
since	O
p8	O
-	O
deficient	O
embryonic	O
fibroblasts	O
grew	O
more	O
rapidly	O
and	O
incorporated	O
more	O
[	O
3H	O
]	O
thymidine	O
and	O
BrdU	O
than	O
p8	O
-	O
expressing	O
cells	O
[	O
11	O
]	O
.	O

Moreover	O
,	O
expression	O
of	O
p8	O
in	O
breast	O
cancer	O
-	O
derived	O
cells	O
seems	O
to	O
mediate	O
the	O
inhibition	O
of	O
cell	O
growth	O
induced	O
by	O
1	O
,	O
25	O
-	O
Dihydroxyvitamin	O
D3	O
[	O
12	O
]	O
.	O

On	O
the	O
contrary	O
,	O
we	O
also	O
reported	O
that	O
p8	O
may	O
promote	O
cell	O
growth	O
when	O
overexpressed	O
in	O
Cos	O
-	O
7	O
,	O
AR42J	O
and	O
HeLa	O
cells	O
[	O
1	O
,	O
4	O
]	O
.	O

In	O
addition	O
,	O
p8	O
seems	O
to	O
be	O
involved	O
in	O
other	O
intracellular	O
functions	O
such	O
as	O
apoptosis	O
since	O
p8	O
-	O
expressing	O
fibroblasts	O
are	O
more	O
sensitive	O
than	O
p8	O
-	O
deficient	O
fibroblasts	O
to	O
the	O
apoptosis	O
induced	O
by	O
DNA	O
damage	O
.	O

Also	O
,	O
p8	O
is	O
required	O
for	O
endothelin	O
-	O
induced	O
mesangial	O
cell	O
hypertrophy	O
in	O
diabetic	O
kidney	O
,	O
in	O
a	O
mechanism	O
involving	O
ERK	O
,	O
JNK	O
and	O
PI3	O
kinase	O
[	O
13	O
]	O
.	O

p8	O
seems	O
to	O
play	O
a	O
functional	O
role	O
in	O
the	O
initiation	O
of	O
LH	O
beta	O
gene	O
expression	O
during	O
embryonic	O
cell	O
differentiation	O
[	O
14	O
]	O
.	O

Moreover	O
,	O
the	O
Drosophila	B
melanogaster	I
p8	O
homologue	O
is	O
involved	O
in	O
response	O
to	O
starvation	O
and	O
might	O
be	O
activated	O
to	O
stop	O
cell	O
growth	O
in	O
case	O
of	O
nutrient	O
deprivation	O
[	O
15	O
]	O
.	O

Finally	O
,	O
a	O
particularly	O
attractive	O
role	O
in	O
tumour	O
progression	O
was	O
recently	O
proposed	O
for	O
p8	O
[	O
16	O
]	O
.	O

Fibroblasts	O
obtained	O
from	O
p8	O
-	O
expressing	O
or	O
p8	O
-	O
deficient	O
animals	O
were	O
transformed	O
with	O
a	O
retroviral	O
vector	O
expressing	O
both	O
the	O
rasV12	O
mutated	O
protein	O
and	O
the	O
E1A	O
adenoviral	O
oncogene	O
.	O

In	O
soft	O
-	O
agar	O
assays	O
,	O
transformed	O
p8	O
-	O
expressing	O
cells	O
formed	O
colonies	O
at	O
high	O
frequency	O
,	O
as	O
expected	O
,	O
but	O
p8	O
-	O
deficient	O
transformed	O
fibroblasts	O
were	O
unable	O
to	O
form	O
colonies	O
.	O

Similarly	O
,	O
transformed	O
p8	O
-	O
expressing	O
cells	O
produced	O
tumours	O
in	O
all	O
athymic	O
nude	B
mice	I
when	O
injected	O
subcutaneously	O
or	O
intraperitoneally	O
,	O
whereas	O
transformed	O
p8	O
-	O
deficient	O
fibroblasts	O
did	O
not	O
.	O

On	O
the	O
other	O
hand	O
,	O
studies	O
by	O
another	O
laboratory	O
revealed	O
that	O
expression	O
of	O
the	O
Com1	O
protein	O
[	O
17	O
]	O
,	O
which	O
is	O
identical	O
to	O
human	B
p8	O
,	O
mediates	O
the	O
growth	O
of	O
tumour	O
cells	O
after	O
metastatic	O
establishment	O
in	O
a	O
secondary	O
organ	O
,	O
indicating	O
that	O
activated	O
expression	O
of	O
Com1	O
/	O
p8	O
in	O
metastatic	O
cells	O
is	O
required	O
for	O
tumour	O
progression	O
.	O

These	O
results	O
strongly	O
suggest	O
that	O
p8	O
is	O
involved	O
in	O
the	O
cellular	O
pathway	O
(	O
s	O
)	O
required	O
for	O
tumour	O
progression	O
and	O
metastasis	O
.	O

Our	O
aim	O
is	O
to	O
check	O
the	O
relevance	O
of	O
p8	O
to	O
cancer	O
progression	O
in	O
human	B
.	O

As	O
a	O
first	O
step	O
,	O
we	O
investigated	O
in	O
the	O
present	O
study	O
the	O
function	O
of	O
p8	O
in	O
two	O
cell	O
lines	O
derived	O
from	O
human	B
pancreatic	O
cancer	O
.	O

We	O
observed	O
that	O
inhibition	O
of	O
p8	O
expression	O
increased	O
the	O
cells	O
growth	O
rate	O
.	O

In	O
addition	O
,	O
activations	O
of	O
the	O
Ras	O
-	O
-	O
>	O
Raf	O
-	O
-	O
>	O
MEK	O
-	O
-	O
>	O
ERK	O
and	O
JNK	O
intracellular	O
pathways	O
,	O
which	O
promote	O
the	O
growth	O
of	O
pancreatic	O
cells	O
,	O
down	O
-	O
regulated	O
p8	O
expression	O
,	O
whereas	O
activation	O
of	O
p38	O
or	O
TGF	O
beta	O
-	O
1	O
,	O
which	O
inhibit	O
cell	O
growth	O
,	O
induced	O
its	O
expression	O
.	O

It	O
was	O
concluded	O
that	O
i	O
/	O
p8	O
inhibits	O
the	O
growth	O
of	O
human	B
pancreatic	O
cancer	O
cell	O
lines	O
,	O
ii	O
/	O
p8	O
expression	O
is	O
induced	O
through	O
pathways	O
involved	O
in	O
growth	O
inhibition	O
and	O
,	O
conversely	O
,	O
repressed	O
by	O
factors	O
that	O
promote	O
cell	O
growth	O
.	O

Results	O

p8	O
is	O
silenced	O
in	O
pancreatic	O
cancer	O
cells	O
by	O
infection	O
with	O
a	O
retrovirus	O
expressing	O
p8	O
RNA	O
in	O
the	O
antisense	O
orientation	O

Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
pancreatic	O
cells	O
were	O
chosen	O
for	O
this	O
study	O
because	O
,	O
on	O
the	O
one	O
hand	O
,	O
both	O
cells	O
express	O
higher	O
level	O
of	O
p8	O
(	O
Figure	O
1	O
)	O
and	O
,	O
on	O
the	O
other	O
hand	O
,	O
because	O
Panc	O
-	O
1	O
is	O
wild	O
-	O
type	O
for	O
Smad4	O
/	O
DPC4	O
and	O
mutated	O
for	O
K	O
-	O
ras	O
,	O
while	O
BxPc	O
-	O
3	O
is	O
Smad4	O
/	O
DPC4	O
mutated	O
and	O
K	O
-	O
ras	O
wild	O
-	O
type	O
[	O
18	O
,	O
19	O
]	O
,	O
therefore	O
representing	O
different	O
mechanisms	O
of	O
transformation	O
and	O
different	O
genetic	O
backgrounds	O
.	O

K	O
-	O
ras	O
and	O
Smad4	O
/	O
DPC4	O
mutations	O
are	O
the	O
major	O
mechanisms	O
involved	O
in	O
pancreatic	O
cancer	O
development	O
.	O

We	O
inhibited	O
p8	O
expression	O
in	O
both	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
pancreatic	O
cells	O
by	O
infecting	O
cells	O
with	O
a	O
retrovirus	O
expressing	O
the	O
p8	O
asRNA	O
(	O
antisense	O
RNA	O
)	O
and	O
carrying	O
the	O
puromycin	O
resistance	O
.	O

The	O
antibiotic	O
-	O
selected	O
cells	O
were	O
analyzed	O
by	O
Western	O
blotting	O
to	O
evaluate	O
the	O
intracellular	O
amounts	O
of	O
p8	O
protein	O
.	O

As	O
shown	O
in	O
Figure	O
2	O
,	O
the	O
p8	O
protein	O
was	O
clearly	O
visible	O
in	O
both	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
pancreatic	O
cells	O
infected	O
with	O
the	O
empty	O
retrovirus	O
but	O
almost	O
undetectable	O
in	O
cells	O
infected	O
with	O
the	O
retrovirus	O
encoding	O
the	O
p8	O
asRNA	O
showed	O
,	O
indicating	O
that	O
our	O
anti	O
-	O
sense	O
strategy	O
is	O
efficient	O
to	O
silence	O
p8	O
gene	O
expression	O
in	O
pancreatic	O
cancer	O
cells	O
.	O

Preliminary	O
studies	O
had	O
been	O
conducted	O
to	O
select	O
the	O
best	O
strategy	O
to	O
inhibit	O
p8	O
expression	O
.	O

We	O
compared	O
the	O
efficacy	O
of	O
the	O
stable	O
transfection	O
of	O
a	O
siRNA	O
,	O
using	O
a	O
retroviral	O
expression	O
vector	O
to	O
the	O
asRNA	O
strategy	O
described	O
above	O
.	O

In	O
our	O
hands	O
,	O
the	O
antisense	O
strategy	O
worked	O
best	O
,	O
as	O
judged	O
from	O
Western	O
blot	O
assessment	O
of	O
p8	O
protein	O
expression	O
(	O
data	O
not	O
shown	O
)	O
.	O

p8	O
-	O
silenced	O
pancreatic	O
cells	O
grow	O
more	O
rapidly	O

We	O
compared	O
in	O
the	O
two	O
cell	O
lines	O
the	O
influence	O
on	O
growth	O
parameters	O
of	O
blocking	O
p8	O
expression	O
with	O
the	O
p8	O
asRNA	O
.	O

Figure	O
3	O
shows	O
that	O
both	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
cells	O
in	O
which	O
p8	O
has	O
been	O
silenced	O
grew	O
more	O
rapidly	O
than	O
cells	O
infected	O
with	O
the	O
empty	O
vector	O
suggesting	O
that	O
inhibition	O
by	O
p8	O
of	O
pancreatic	O
cancer	O
cell	O
growth	O
is	O
independent	O
from	O
the	O
mechanism	O
of	O
transformation	O
and	O
genetic	O
background	O
.	O

Serum	O
-	O
stimulated	O
cellular	O
growth	O
down	O
-	O
regulates	O
p8	O
expression	O

Fetal	O
calf	B
serum	O
,	O
which	O
contains	O
a	O
complex	O
mix	O
of	O
growth	O
factors	O
,	O
can	O
be	O
used	O
as	O
inductor	O
of	O
cell	O
growth	O
.	O

As	O
shown	O
in	O
Figure	O
4	O
expression	O
of	O
p8	O
mRNA	O
was	O
down	O
-	O
regulated	O
in	O
both	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
when	O
the	O
cells	O
were	O
shifted	O
from	O
culture	O
media	O
containing	O
0	O
.	O
1	O
%	O
fetal	O
calf	B
serum	O
to	O
media	O
containing	O
10	O
%	O
FCS	O
.	O

p8	O
protein	O
showed	O
a	O
similar	O
behavior	O
.	O

These	O
results	O
show	O
that	O
p8	O
expression	O
is	O
down	O
-	O
regulated	O
in	O
growing	O
pancreatic	O
cells	O
.	O

The	O
Ras	O
-	O
-	O
>	O
Raf	O
-	O
-	O
>	O
MEK	O
-	O
-	O
>	O
ERK	O
pathway	O
down	O
-	O
regulates	O
p8	O
expression	O
in	O
pancreatic	O
cancer	O
cells	O

Most	O
human	B
pancreatic	O
cancers	O
harbor	O
mutations	O
in	O
the	O
K	O
-	O
ras	O
oncogene	O
,	O
which	O
happens	O
relatively	O
early	O
in	O
pancreatic	O
tumorigenesis	O
[	O
20	O
]	O
.	O

The	O
oncogenic	O
mutation	O
of	O
the	O
K	O
-	O
ras	O
gene	O
stabilizes	O
the	O
Ras	O
protein	O
in	O
a	O
GTP	O
-	O
bound	O
form	O
,	O
which	O
is	O
constitutively	O
active	O
and	O
make	O
the	O
cells	O
grow	O
more	O
rapidly	O
.	O

Contrary	O
to	O
the	O
activated	O
Ras	O
protein	O
,	O
p8	O
inhibits	O
cell	O
growth	O
(	O
Figure	O
3	O
)	O
.	O

We	O
looked	O
whether	O
the	O
Ras	O
-	O
-	O
>	O
Raf	O
-	O
-	O
>	O
MEK	O
-	O
-	O
>	O
ERK	O
pathway	O
was	O
also	O
involved	O
in	O
the	O
regulation	O
of	O
p8	O
expression	O
,	O
and	O
which	O
step	O
(	O
s	O
)	O
were	O
critical	O
.	O

Figure	O
5	O
shown	O
that	O
expression	O
of	O
a	O
mutated	O
form	O
of	O
the	O
Ras	O
protein	O
(	O
rasV12	O
)	O
in	O
BxPc	O
-	O
3	O
cells	O
,	O
which	O
are	O
wild	O
-	O
type	O
for	O
ras	O
,	O
resulted	O
in	O
decreased	O
p8	O
mRNA	O
concentration	O
and	O
protein	O
level	O
suggesting	O
that	O
the	O
activated	O
ras	O
inhibits	O
p8	O
expression	O
.	O

Figure	O
6	O
shows	O
that	O
overexpression	O
of	O
Raf	O
,	O
but	O
not	O
of	O
Raf301	O
(	O
a	O
negative	O
mutant	O
of	O
Raf	O
)	O
,	O
and	O
of	O
ERK	O
also	O
inhibited	O
the	O
expression	O
of	O
the	O
p8	O
-	O
CAT	O
construct	O
in	O
Panc	O
-	O
1	O
as	O
well	O
as	O
in	O
BxPc	O
-	O
3	O
.	O

Finally	O
,	O
the	O
MEK1	O
/	O
2	O
specific	O
inhibitor	O
U0126	O
[	O
21	O
]	O
activated	O
p8	O
mRNA	O
expression	O
in	O
pancreatic	O
cells	O
whether	O
they	O
carry	O
mutated	O
ras	O
(	O
Panc	O
-	O
1	O
)	O
or	O
wild	O
-	O
type	O
(	O
BxPc	O
-	O
3	O
)	O
.	O

Similar	O
results	O
were	O
observed	O
when	O
expression	O
of	O
the	O
p8	O
protein	O
was	O
monitored	O
by	O
Western	O
blotting	O
(	O
Figure	O
7	O
)	O
.	O

Activation	O
of	O
the	O
JNK	O
pathway	O
down	O
-	O
regulates	O
p8	O
expression	O
in	O
pancreatic	O
cancer	O
cells	O

c	O
-	O
Jun	O
NH2	O
-	O
terminal	O
kinase	O
(	O
JNK	O
)	O
is	O
another	O
major	O
MAPK	O
pathway	O
which	O
converts	O
extracellular	O
signals	O
into	O
expression	O
of	O
specific	O
target	O
genes	O
through	O
phosphorylation	O
and	O
activation	O
of	O
transcription	O
factors	O
.	O

JNK	O
activation	O
has	O
been	O
implicated	O
in	O
various	O
,	O
often	O
opposite	O
cellular	O
responses	O
,	O
such	O
as	O
cell	O
proliferation	O
,	O
transformation	O
and	O
apoptosis	O
.	O

As	O
shown	O
in	O
Figure	O
8	O
,	O
overexpression	O
of	O
JNK	O
down	O
-	O
regulates	O
the	O
gene	O
reporter	O
activity	O
of	O
the	O
p8	O
-	O
CAT	O
construct	O
in	O
Panc	O
-	O
1	O
cells	O
.	O

Similar	O
results	O
were	O
found	O
in	O
BxPc	O
-	O
3	O
cells	O
.	O

Treatment	O
of	O
these	O
cells	O
with	O
the	O
JNK	O
specific	O
inhibitor	O
SP600125	O
[	O
22	O
]	O
up	O
-	O
regulates	O
expression	O
of	O
the	O
p8	O
mRNA	O
and	O
p8	O
protein	O
(	O
Figure	O
9	O
)	O
.	O

These	O
results	O
show	O
that	O
the	O
JNK	O
pathway	O
is	O
involved	O
in	O
the	O
regulation	O
of	O
p8	O
expression	O
.	O

The	O
p38	O
pathway	O
up	O
-	O
regulates	O
p8	O
expression	O
in	O
pancreatic	O
cancer	O
cells	O

The	O
p38	O
signal	O
transduction	O
pathway	O
also	O
plays	O
an	O
essential	O
role	O
in	O
regulating	O
several	O
cell	O
functions	O
including	O
growth	O
,	O
response	O
to	O
inflammation	O
,	O
differentiation	O
and	O
apoptosis	O
.	O

In	O
fact	O
,	O
in	O
pancreatic	O
cancer	O
cells	O
,	O
p38	O
is	O
a	O
strong	O
inhibitor	O
of	O
proliferation	O
[	O
23	O
]	O
contrary	O
to	O
the	O
Ras	O
-	O
-	O
>	O
Raf	O
-	O
-	O
>	O
MEK	O
-	O
-	O
>	O
ERK	O
and	O
JNK	O
pathways	O
.	O

We	O
therefore	O
analyzed	O
the	O
putative	O
role	O
of	O
the	O
p38	O
pathway	O
in	O
regulating	O
p8	O
expression	O
in	O
pancreatic	O
cancer	O
cells	O
.	O

Figure	O
10	O
shows	O
that	O
over	O
-	O
expression	O
of	O
the	O
plasmid	O
encoding	O
p38	O
significantly	O
increases	O
p8	O
-	O
CAT	O
activity	O
in	O
Panc	O
-	O
1	O
as	O
well	O
as	O
in	O
BxPc	O
-	O
3	O
cells	O
.	O

Then	O
,	O
cells	O
were	O
treated	O
with	O
SB203580	O
,	O
a	O
specific	O
inhibitor	O
of	O
p38	O
[	O
24	O
]	O
,	O
and	O
p8	O
expression	O
was	O
measured	O
.	O

p8	O
mRNA	O
as	O
well	O
as	O
the	O
encoded	O
protein	O
were	O
down	O
-	O
regulated	O
after	O
inhibition	O
of	O
the	O
p38	O
activity	O
(	O
Figure	O
11	O
)	O
.	O

These	O
results	O
indicate	O
that	O
the	O
p38	O
pathway	O
is	O
a	O
positive	O
regulator	O
of	O
p8	O
expression	O
in	O
pancreatic	O
cancer	O
cells	O
.	O

TGF	O
beta	O
-	O
1	O
up	O
-	O
regulates	O
p8	O
expression	O
in	O
pancreatic	O
cancer	O
cells	O

The	O
most	O
prominent	O
biological	O
activity	O
of	O
TGF	O
beta	O
-	O
1	O
is	O
its	O
potent	O
inhibition	O
of	O
cell	O
growth	O
in	O
a	O
wide	O
variety	O
of	O
cell	O
types	O
including	O
pancreatic	O
cells	O
.	O

TGF	O
beta	O
-	O
1	O
signals	O
are	O
sent	O
through	O
two	O
types	O
of	O
transmembrane	O
serine	O
/	O
threonine	O
kinase	O
receptors	O
.	O

In	O
fact	O
,	O
TGF	O
beta	O
-	O
1	O
binds	O
and	O
brings	O
together	O
the	O
type	O
I	O
and	O
type	O
II	O
receptors	O
.	O

In	O
the	O
resulting	O
complex	O
,	O
the	O
constitutively	O
active	O
TGF	O
beta	O
-	O
1	O
type	O
II	O
receptor	O
phosphorylates	O
the	O
type	O
I	O
receptor	O
,	O
which	O
then	O
plays	O
a	O
major	O
role	O
in	O
transducing	O
the	O
signal	O
to	O
downstream	O
components	O
to	O
affect	O
gene	O
expression	O
through	O
phosphorylation	O
of	O
SMAD	O
proteins	O
.	O

Phosphorylated	O
receptor	O
-	O
regulated	O
SMADs	O
then	O
form	O
heteromeric	O
complexes	O
with	O
the	O
common	O
partner	O
SMAD4	O
.	O

These	O
heteromeric	O
complexes	O
then	O
move	O
to	O
the	O
nucleus	O
,	O
where	O
SMAD4	O
will	O
bind	O
DNA	O
and	O
contribute	O
to	O
transcriptional	O
activation	O
.	O

In	O
general	O
,	O
pancreatic	O
cancer	O
cells	O
present	O
with	O
defects	O
in	O
TGF	O
beta	O
-	O
1	O
signaling	O
and	O
are	O
resistant	O
to	O
TGF	O
beta	O
-	O
1	O
-	O
mediated	O
growth	O
suppression	O
.	O

Since	O
TGF	O
beta	O
-	O
1	O
and	O
p8	O
are	O
inhibitors	O
of	O
pancreatic	O
cell	O
growth	O
we	O
analyzed	O
whether	O
p8	O
could	O
mediate	O
,	O
at	O
least	O
in	O
part	O
,	O
the	O
effect	O
of	O
TGF	O
beta	O
-	O
1	O
.	O

First	O
,	O
we	O
found	O
that	O
treatment	O
of	O
Panc	O
-	O
1	O
cells	O
with	O
TGF	O
beta	O
-	O
1	O
increased	O
p8	O
mRNA	O
levels	O
and	O
p8	O
protein	O
as	O
judged	O
by	O
Western	O
blot	O
(	O
Figure	O
12	O
)	O
.	O

Then	O
,	O
to	O
confirm	O
that	O
overexpression	O
is	O
regulated	O
at	O
the	O
transcriptional	O
level	O
,	O
we	O
analyzed	O
the	O
effect	O
of	O
some	O
constructs	O
expressing	O
constitutively	O
activated	O
type	O
I	O
TGF	O
beta	O
receptor	O
,	O
dominant	O
negative	O
type	O
II	O
TGF	O
beta	O
receptor	O
,	O
a	O
dominant	O
negative	O
of	O
Smad4	O
and	O
the	O
wild	O
-	O
type	O
Smad4	O
on	O
the	O
p8	O
-	O
CAT	O
activity	O
.	O

As	O
expected	O
,	O
the	O
constitutively	O
activated	O
type	O
I	O
TGF	O
beta	O
receptor	O
but	O
not	O
the	O
dominant	O
negative	O
type	O
II	O
TGF	O
beta	O
receptor	O
increased	O
CAT	O
activity	O
.	O

Also	O
,	O
expression	O
of	O
the	O
Smad4	O
,	O
contrary	O
to	O
that	O
of	O
the	O
negative	O
mutant	O
,	O
induced	O
p8	O
transcription	O
(	O
Figure	O
13	O
)	O
.	O

Together	O
,	O
these	O
results	O
indicate	O
that	O
p8	O
is	O
positively	O
regulated	O
by	O
TGF	O
beta	O
-	O
1	O
.	O

Beside	O
the	O
Smad	O
proteins	O
,	O
TGF	O
beta	O
-	O
1	O
also	O
activates	O
the	O
p38	O
MAPK	O
pathway	O
in	O
pancreas	O
-	O
derived	O
cells	O
,	O
which	O
may	O
play	O
an	O
important	O
role	O
in	O
TGF	O
beta	O
-	O
1	O
induced	O
genes	O
[	O
25	O
]	O
.	O

Therefore	O
,	O
we	O
analyzed	O
the	O
p38	O
-	O
dependent	O
effect	O
of	O
TGF	O
beta	O
-	O
1	O
on	O
p8	O
transcription	O
.	O

As	O
shown	O
in	O
Figure	O
13	O
,	O
inhibition	O
of	O
p38	O
activity	O
with	O
the	O
SB203580	O
specific	O
inhibitor	O
decreased	O
about	O
40	O
%	O
the	O
activity	O
of	O
TGF	O
beta	O
-	O
1	O
on	O
the	O
p8	O
promoter	O
indicating	O
that	O
the	O
effect	O
of	O
TGF	O
beta	O
-	O
1	O
on	O
p8	O
promoter	O
is	O
mediated	O
by	O
both	O
p38	O
-	O
dependent	O
and	O
p38	O
-	O
independent	O
pathways	O
.	O

Discussion	O

Pancreatic	O
adenocarcinoma	O
is	O
the	O
fourth	O
leading	O
cause	O
of	O
death	O
from	O
malignant	O
diseases	O
[	O
26	O
]	O
.	O

The	O
aggressive	O
nature	O
of	O
the	O
neoplasia	O
,	O
the	O
lack	O
of	O
early	O
detection	O
,	O
and	O
the	O
limited	O
response	O
to	O
treatments	O
such	O
as	O
chemotherapy	O
and	O
radiotherapy	O
contribute	O
to	O
the	O
high	O
mortality	O
rate	O
of	O
the	O
disease	O
.	O

Therefore	O
,	O
a	O
better	O
understanding	O
of	O
the	O
molecular	O
mechanism	O
leading	O
to	O
pancreatic	O
cancer	O
remains	O
a	O
major	O
goal	O
because	O
it	O
may	O
help	O
proposing	O
strategies	O
for	O
earlier	O
diagnosis	O
and	O
better	O
treatment	O
.	O

The	O
most	O
commonly	O
altered	O
genes	O
in	O
pancreatic	O
adenocarcinoma	O
are	O
K	O
-	O
ras	O
(	O
75	O
to	O
100	O
%	O
)	O
,	O
p16INK4a	O
(	O
95	O
%	O
)	O
,	O
p53	O
(	O
50	O
to	O
75	O
%	O
)	O
and	O
DPC4	O
(	O
50	O
%	O
)	O
[	O
27	O
-	O
31	O
]	O
.	O

Whereas	O
K	O
-	O
ras	O
is	O
a	O
proto	O
-	O
oncogene	O
all	O
the	O
others	O
are	O
tumour	O
suppressor	O
genes	O
.	O

Additional	O
genes	O
have	O
been	O
found	O
altered	O
at	O
lower	O
frequency	O
.	O

Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
pancreatic	O
cells	O
were	O
chosen	O
for	O
this	O
study	O
because	O
they	O
both	O
express	O
high	O
levels	O
of	O
p8	O
(	O
Figure	O
1	O
)	O
and	O
because	O
they	O
present	O
with	O
different	O
mechanisms	O
of	O
transformation	O
and	O
genetic	O
backgrounds	O
,	O
Panc	O
-	O
1	O
being	O
wild	O
-	O
type	O
for	O
Smad4	O
/	O
DPC4	O
but	O
mutated	O
for	O
K	O
-	O
ras	O
and	O
BxPc	O
-	O
3	O
mutated	O
for	O
Smad4	O
/	O
DPC4	O
and	O
wild	O
-	O
type	O
for	O
K	O
-	O
ras	O
[	O
18	O
,	O
19	O
]	O
.	O

This	O
work	O
presents	O
evidences	O
that	O
p8	O
inhibits	O
the	O
growth	O
rate	O
of	O
pancreatic	O
cancer	O
-	O
derived	O
cells	O
and	O
that	O
the	O
intracellular	O
pathways	O
promoting	O
cell	O
growth	O
down	O
-	O
regulate	O
p8	O
expression	O
whereas	O
those	O
promoting	O
growth	O
arrest	O
up	O
-	O
regulate	O
its	O
expression	O
.	O

Together	O
,	O
these	O
results	O
suggest	O
that	O
p8	O
is	O
downstream	O
of	O
some	O
cell	O
growth	O
regulators	O
and	O
therefore	O
regulation	O
of	O
p8	O
expression	O
or	O
its	O
activity	O
could	O
be	O
used	O
as	O
a	O
target	O
for	O
treating	O
pancreatic	O
cancer	O
.	O

Silencing	O
p8	O
expression	O
was	O
able	O
to	O
strongly	O
promote	O
cell	O
growth	O
in	O
both	O
cell	O
types	O
,	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
,	O
suggesting	O
that	O
p8	O
may	O
act	O
downstream	O
of	O
the	O
ras	O
-	O
or	O
Smad4	O
/	O
DPC4	O
-	O
dependent	O
ways	O
.	O

Also	O
,	O
we	O
found	O
that	O
stimulating	O
cell	O
growth	O
by	O
the	O
complex	O
combination	O
of	O
growth	O
factors	O
contained	O
in	O
fetal	O
calf	B
serum	O
down	O
-	O
regulated	O
expression	O
of	O
p8	O
whereas	O
,	O
on	O
the	O
contrary	O
,	O
treating	O
the	O
cells	O
with	O
TGF	O
beta	O
-	O
1	O
,	O
which	O
promotes	O
cell	O
cycle	O
arrest	O
,	O
stimulates	O
p8	O
expression	O
.	O

Therefore	O
,	O
p8	O
gene	O
expression	O
seems	O
to	O
be	O
regulated	O
in	O
opposite	O
directions	O
by	O
mechanisms	O
promoting	O
cell	O
growth	O
or	O
cell	O
cycle	O
arrest	O
.	O

It	O
is	O
interesting	O
to	O
note	O
that	O
while	O
p8	O
expression	O
is	O
under	O
the	O
control	O
of	O
cell	O
growth	O
regulatory	O
pathways	O
such	O
as	O
Ras	O
-	O
-	O
>	O
Raf	O
-	O
-	O
>	O
MEK	O
-	O
-	O
>	O
ERK	O
,	O
JNK	O
,	O
p38	O
and	O
TGF	O
beta	O
-	O
1	O
,	O
p8	O
can	O
affect	O
cell	O
cycle	O
progression	O
,	O
suggesting	O
that	O
p8	O
is	O
a	O
target	O
for	O
factors	O
regulating	O
pancreatic	O
cell	O
growth	O
.	O

A	O
mechanism	O
by	O
which	O
p8	O
could	O
regulate	O
cell	O
cycle	O
progression	O
in	O
embryonic	O
fibroblasts	O
was	O
previously	O
proposed	O
[	O
11	O
]	O
.	O

In	O
fact	O
,	O
p8	O
seems	O
to	O
take	O
action	O
upstream	O
from	O
cyclin	O
-	O
dependent	O
kinases	O
because	O
the	O
intracellular	O
levels	O
and	O
activities	O
of	O
Cdk2	O
and	O
Cdk4	O
are	O
decreased	O
when	O
p8	O
is	O
expressed	O
.	O

Concomitantly	O
,	O
the	O
cyclin	O
-	O
dependent	O
kinase	O
inhibitor	O
p27	O
is	O
expressed	O
at	O
a	O
low	O
level	O
in	O
p8	O
-	O
deficient	O
cells	O
which	O
may	O
explain	O
the	O
increased	O
activity	O
of	O
Cdk2	O
and	O
Cdk4	O
.	O

The	O
mechanism	O
by	O
which	O
p8	O
regulates	O
the	O
intracellular	O
level	O
of	O
those	O
proteins	O
remains	O
to	O
be	O
determined	O
.	O

However	O
,	O
because	O
p8	O
is	O
a	O
transcriptional	O
cofactor	O
,	O
it	O
is	O
possible	O
that	O
regulation	O
of	O
expression	O
of	O
these	O
molecules	O
takes	O
place	O
,	O
at	O
least	O
in	O
part	O
,	O
at	O
the	O
transcription	O
level	O
.	O

Interestingly	O
,	O
expression	O
of	O
p8	O
mRNA	O
seems	O
to	O
be	O
regulated	O
in	O
a	O
cell	O
type	O
-	O
and	O
stimulus	O
-	O
specific	O
manner	O
since	O
,	O
for	O
example	O
,	O
p38	O
can	O
induce	O
p8	O
expression	O
in	O
response	O
to	O
stress	O
in	O
fibroblasts	O
[	O
3	O
]	O
but	O
not	O
in	O
renal	O
mesangial	O
cells	O
treated	O
with	O
endothelin	O
[	O
13	O
]	O
.	O

In	O
pancreatic	O
cancer	O
-	O
derived	O
cells	O
p38	O
seems	O
to	O
play	O
a	O
major	O
role	O
since	O
it	O
is	O
involved	O
in	O
p8	O
activation	O
as	O
judged	O
by	O
transient	O
transfection	O
assays	O
and	O
using	O
a	O
specific	O
p38	O
inhibitor	O
(	O
Figures	O
10	O
and	O
11	O
)	O
.	O

In	O
addition	O
,	O
p38	O
is	O
also	O
involved	O
in	O
TGF	O
beta	O
-	O
1	O
-	O
induced	O
p8	O
expression	O
because	O
about	O
40	O
%	O
of	O
the	O
TGF	O
beta	O
-	O
1	O
effect	O
was	O
abolished	O
when	O
p38	O
activity	O
was	O
specifically	O
blocked	O
(	O
Figure	O
13	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
ERK	O
and	O
JNK	O
are	O
inducers	O
of	O
p8	O
expression	O
in	O
mesangial	O
cells	O
treated	O
with	O
endothelin	O
,	O
but	O
not	O
involved	O
in	O
the	O
activation	O
of	O
p8	O
in	O
response	O
to	O
stress	O
in	O
fibroblasts	O
[	O
3	O
]	O
,	O
and	O
even	O
repressors	O
in	O
pancreatic	O
cells	O
(	O
Figures	O
5	O
,	O
6	O
,	O
7	O
,	O
8	O
and	O
9	O
)	O
.	O

Finally	O
,	O
PI3	O
kinase	O
is	O
an	O
inducer	O
of	O
p8	O
expression	O
in	O
both	O
endothelin	O
-	O
mediated	O
p8	O
activation	O
in	O
mesangial	O
cells	O
[	O
13	O
]	O
and	O
pancreatic	O
cells	O
(	O
data	O
not	O
shown	O
)	O
.	O

Based	O
on	O
these	O
observations	O
,	O
overexpression	O
of	O
p8	O
could	O
be	O
considered	O
a	O
possible	O
goal	O
for	O
treating	O
pancreatic	O
tumours	O
,	O
in	O
order	O
to	O
limit	O
their	O
growth	O
.	O

However	O
,	O
we	O
previously	O
reported	O
that	O
p8	O
repression	O
would	O
prevent	O
rasV12	O
/	O
E1A	O
transformed	O
fibroblasts	O
from	O
evolving	O
as	O
tumours	O
in	O
nude	B
mice	I
[	O
16	O
]	O
.	O

This	O
apparent	O
contradiction	O
needs	O
to	O
be	O
resolved	O
before	O
considering	O
p8	O
as	O
a	O
target	O
for	O
treating	O
cancer	O
progression	O
.	O

Conclusions	O

In	O
conclusion	O
(	O
see	O
Figure	O
14	O
)	O
,	O
we	O
report	O
in	O
this	O
paper	O
that	O
inhibition	O
of	O
p8	O
expression	O
by	O
an	O
anti	O
-	O
sense	O
strategy	O
increases	O
the	O
growth	O
rate	O
of	O
both	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
pancreatic	O
cancer	O
-	O
derived	O
cells	O
.	O

Moreover	O
,	O
ERK	O
-	O
and	O
JNK	O
-	O
mediated	O
pathways	O
down	O
-	O
regulate	O
p8	O
expression	O
,	O
whereas	O
p38	O
and	O
TGF	O
beta	O
-	O
1	O
pathways	O
induce	O
p8	O
expression	O
.	O

Also	O
,	O
cell	O
growth	O
triggered	O
by	O
expression	O
of	O
a	O
RAS	O
mutated	O
protein	O
or	O
by	O
10	O
%	O
fetal	O
calf	B
serum	O
induces	O
down	O
-	O
regulation	O
of	O
p8	O
expression	O
.	O

Together	O
,	O
these	O
results	O
indicate	O
that	O
p8	O
is	O
an	O
intracellular	O
cell	O
growth	O
inhibitor	O
and	O
that	O
it	O
is	O
oppositely	O
regulated	O
by	O
growth	O
-	O
promoting	O
or	O
growth	O
-	O
inhibiting	O
factors	O
in	O
pancreatic	O
cancer	O
-	O
derived	O
cells	O
.	O

Material	O
and	O
Methods	O

Cell	O
lines	O
and	O
cell	O
culture	O
conditions	O

The	O
human	B
pancreatic	O
cancer	O
cell	O
lines	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
were	O
a	O
kind	O
gift	O
of	O
Dr	O
C	O
.	O

Susini	O
(	O
INSERM	O
U	O
.	O
531	O
,	O
Toulouse	O
)	O
and	O
A	O
.	O

Hajri	O
(	O
IRCAD	O
,	O
Strasbourg	O
)	O
respectively	O
.	O

Panc	O
-	O
1	O
cells	O
were	O
grown	O
in	O
Dulbecco	O
'	O
s	O
modified	O
Eagle	O
'	O
s	O
medium	O
(	O
DMEM	O
)	O
supplemented	O
with	O
10	O
%	O
fetal	O
calf	B
serum	O
,	O
2	O
mM	O
L	O
-	O
glutamine	O
,	O
100	O
IU	O
/	O
ml	O
penicilin	O
G	O
and	O
100	O
mu	O
g	O
/	O
ml	O
streptomycin	O
.	O

BxPc	O
-	O
3	O
were	O
cultivated	O
in	O
RPMI	O
1640	O
medium	O
in	O
the	O
presence	O
of	O
2	O
mM	O
L	O
-	O
glutamine	O
,	O
4	O
.	O
5	O
g	O
/	O
L	O
glucose	O
,	O
10	O
mM	O
Hepes	O
,	O
1	O
.	O
0	O
mM	O
sodium	O
pyruvate	O
,	O
10	O
%	O
fetal	O
calf	B
serum	O
and	O
100	O
IU	O
/	O
ml	O
penicilin	O
G	O
and	O
100	O
mu	O
g	O
/	O
ml	O
streptomycin	O
.	O

Human	B
recombinant	O
TGF	O
beta	O
-	O
1	O
was	O
obtained	O
from	O
Sigma	O
,	O
and	O
specific	O
SB203580	O
,	O
U0126	O
and	O
SP600125	O
inhibitors	O
were	O
from	O
Calbiochem	O
and	O
utilized	O
at	O
10	O
mu	O
M	O
.	O

Expression	O
plasmids	O

Expression	O
plamids	O
encoding	O
p38	O
(	O
pCEFL	O
HA	O
p38	O
)	O
,	O
Erk2	O
(	O
pcDNAIII	O
HA	O
ERK2	O
)	O
,	O
JNK	O
(	O
pcDNAIIIB	O
HA	O
JNK	O
)	O
,	O
the	O
wild	O
-	O
type	O
Raf	O
(	O
pcDNA	O
RAF	O
BXB	O
)	O
and	O
the	O
Raf	O
dominant	O
negative	O
(	O
pcDNA	O
RAF	O
301	O
K375W	O
)	O
were	O
obtained	O
from	O
O	O
Coso	O
(	O
University	O
of	O
Buenos	O
Aires	O
)	O
.	O

Plamids	O
encoding	O
the	O
constitutively	O
activated	O
type	O
I	O
TGF	O
beta	O
receptor	O
(	O
RI	O
ACT	O
)	O
,	O
the	O
dominant	O
negative	O
type	O
II	O
TGF	O
beta	O
receptor	O
(	O
RII	O
DN	O
)	O
and	O
the	O
Smad4	O
dominant	O
negative	O
(	O
DPC4	O
1	O
-	O
514	O
a	O
.	O
a	O
.	O
)	O
were	O
obtained	O
from	O
R	O
Urrutia	O
(	O
Mayo	O
Clinic	O
,	O
Rochester	O
)	O
and	O
the	O
wild	O
type	O
Smad4	O
was	O
from	O
C	O
Heldin	O
(	O
Ludwig	O
Institute	O
,	O
Uppsala	O
)	O
.	O

Pancreatic	O
p8	O
-	O
deficient	O
cells	O

To	O
silence	O
p8	O
expression	O
in	O
pancreatic	O
cells	O
,	O
we	O
infected	O
these	O
cells	O
with	O
a	O
retrovirus	O
expressing	O
human	B
p8	O
in	O
the	O
antisense	O
orientation	O
.	O

The	O
retroviral	O
vector	O
was	O
constructed	O
as	O
follows	O
:	O
human	B
p8	O
cDNA	O
was	O
subcloned	O
in	O
HindIII	O
and	O
XhoI	O
restriction	O
sites	O
of	O
the	O
pLPC	O
plasmid	O
(	O
obtained	O
from	O
S	O
.	O
Lowe	O
)	O
in	O
the	O
antisense	O
orientation	O
.	O

Amphotrope	O
human	B
p8	O
expressing	O
retrovirus	O
was	O
then	O
generated	O
by	O
transient	O
transfection	O
using	O
Phoenix	O
amphotrope	O
packaging	O
cells	O
.	O

Viral	O
supernatant	O
was	O
used	O
to	O
infect	O
Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
pancreatic	O
cells	O
and	O
the	O
population	O
of	O
p8	O
-	O
silenced	O
cells	O
was	O
isolated	O
by	O
selection	O
in	O
presence	O
of	O
puromycin	O
(	O
1	O
mu	O
g	O
/	O
ml	O
)	O
.	O

As	O
control	O
,	O
cells	O
were	O
infected	O
with	O
the	O
pLPC	O
empty	O
vector	O
.	O

p8	O
expression	O
in	O
arrested	O
and	O
growing	O
cells	O

One	O
million	O
of	O
Panc	O
-	O
1	O
or	O
BxPc	O
-	O
3	O
cells	O
were	O
cultivated	O
on	O
10	O
-	O
cm	O
Petri	O
plates	O
in	O
standard	O
conditions	O
(	O
with	O
10	O
%	O
FCS	O
)	O
.	O

After	O
48	O
h	O
,	O
culture	O
media	O
were	O
changed	O
for	O
fresh	O
media	O
with	O
FCS	O
restricted	O
to	O
0	O
.	O
1	O
%	O
,	O
in	O
order	O
to	O
stop	O
growth	O
.	O

After	O
24	O
hours	O
of	O
growth	O
arrest	O
,	O
culture	O
medium	O
was	O
replaced	O
either	O
by	O
medium	O
with	O
10	O
%	O
fetal	O
calf	B
serum	O
to	O
resume	O
cell	O
growth	O
or	O
,	O
as	O
control	O
,	O
by	O
medium	O
with	O
0	O
.	O
1	O
%	O
fetal	O
calf	B
serum	O
.	O

Twenty	O
four	O
hours	O
later	O
cells	O
were	O
recovered	O
and	O
RNA	O
and	O
protein	O
extracted	O
.	O

p8	O
expression	O
in	O
TGF	O
beta	O
-	O
1	O
-	O
treated	O
Panc	O
-	O
1	O
cells	O

One	O
million	O
of	O
Panc	O
-	O
1	O
cells	O
were	O
cultivated	O
in	O
10	O
-	O
cm	O
culture	O
dishes	O
for	O
48	O
hours	O
under	O
standard	O
conditions	O
before	O
TGF	O
beta	O
-	O
1	O
treatment	O
.	O

Human	B
recombinant	O
TGF	O
beta	O
-	O
1	O
(	O
5	O
ng	O
/	O
ml	O
)	O
was	O
added	O
to	O
cells	O
,	O
without	O
changing	O
the	O
culture	O
medium	O
,	O
and	O
cells	O
were	O
collected	O
12	O
hours	O
later	O
for	O
RNA	O
and	O
protein	O
preparation	O
.	O

BxPc	O
-	O
3	O
rasV12	O
-	O
expressing	O
cells	O

pLPC	O
-	O
rasV12	O
and	O
pLPC	O
plasmids	O
were	O
obtained	O
from	O
S	O
.	O

Lowe	O
.	O

Phoenix	O
amphotrope	O
packaging	O
cells	O
(	O
106	O
)	O
were	O
plated	O
in	O
a	O
6	O
-	O
well	O
plate	O
,	O
incubated	O
for	O
24	O
hours	O
,	O
then	O
transfected	O
with	O
PEI	O
with	O
5	O
mu	O
g	O
of	O
retroviral	O
plasmid	O
.	O

After	O
48	O
hours	O
,	O
the	O
medium	O
containing	O
virus	O
was	O
filtered	O
(	O
0	O
.	O
45	O
mu	O
m	O
filter	O
,	O
Millipore	O
)	O
to	O
obtain	O
the	O
viral	O
supernatant	O
.	O

Target	O
BxPc	O
-	O
3	O
were	O
plated	O
at	O
2	O
x	O
105	O
cells	O
per	O
35	O
-	O
mm	O
dish	O
and	O
incubated	O
overnight	O
.	O

For	O
infections	O
,	O
the	O
culture	O
medium	O
was	O
replaced	O
by	O
an	O
appropriate	O
mix	O
of	O
the	O
viral	O
supernatant	O
and	O
culture	O
medium	O
(	O
V	O
/	O
V	O
)	O
,	O
supplemented	O
with	O
4	O
mu	O
g	O
/	O
ml	O
polybrene	O
(	O
Sigma	O
)	O
,	O
and	O
cells	O
were	O
incubated	O
at	O
37	O
degrees	O
C	O
.	O

BxPc	O
-	O
3	O
rasV12	O
-	O
expressing	O
cells	O
were	O
selected	O
with	O
puromycin	O
(	O
1	O
mu	O
g	O
/	O
ml	O
)	O
.	O

Cells	O
infected	O
with	O
the	O
pLPC	O
empty	O
vector	O
were	O
used	O
as	O
control	O
.	O

Western	O
-	O
blot	O
analyses	O

One	O
hundred	O
mu	O
g	O
of	O
total	O
protein	O
extracted	O
from	O
cells	O
was	O
separated	O
with	O
standard	O
procedures	O
on	O
15	O
.	O
0	O
%	O
SDS	O
-	O
PAGE	O
using	O
the	O
Mini	O
Protean	O
System	O
(	O
Bio	O
-	O
Rad	O
)	O
and	O
transferred	O
to	O
a	O
nitrocellulose	O
membrane	O
(	O
Sigma	O
)	O
.	O

The	O
intracellular	O
level	O
of	O
p8	O
was	O
estimated	O
by	O
Western	O
blot	O
using	O
a	O
polyclonal	O
antibody	O
(	O
1	O
:	O
1000	O
)	O
raised	O
against	O
human	B
p8	O
[	O
4	O
]	O
.	O

Growth	O
curves	O

One	O
hundred	O
thousand	O
cells	O
per	O
well	O
were	O
plated	O
in	O
a	O
series	O
of	O
35	O
-	O
mm	O
culture	O
dishes	O
.	O

The	O
cell	O
number	O
was	O
estimated	O
daily	O
in	O
triplicate	O
,	O
during	O
1	O
to	O
5	O
days	O
,	O
in	O
a	O
haemocytometer	O
.	O

Within	O
experiments	O
,	O
each	O
point	O
was	O
determined	O
at	O
least	O
two	O
times	O
.	O

Cell	O
transfection	O
and	O
gene	O
reporter	O
assays	O

Panc	O
-	O
1	O
and	O
BxPc	O
-	O
3	O
(	O
105	O
)	O
were	O
cultivated	O
in	O
30	O
mm	O
diameter	O
culture	O
dishes	O
for	O
24	O
hours	O
then	O
transiently	O
transfected	O
with	O
0	O
.	O
5	O
mu	O
g	O
of	O
p8	O
-	O
CAT	O
reporter	O
plasmid	O
and	O
0	O
.	O
5	O
mu	O
g	O
of	O
pCMV	O
/	O
beta	O
gal	O
plasmid	O
(	O
to	O
control	O
transfection	O
efficiency	O
)	O
using	O
the	O
Fugene	O
reagent	O
in	O
accordance	O
with	O
the	O
manufacturer	O
'	O
s	O
protocol	O
(	O
Roche	O
Molecular	O
Biochemicals	O
)	O
.	O

The	O
p8	O
-	O
CAT	O
plasmid	O
is	O
the	O
previously	O
reported	O
p	O
-	O
1471	O
/	O
+	O
37p8	O
-	O
CAT	O
promoter	O
construct	O
[	O
5	O
]	O
.	O

Reporter	O
activities	O
were	O
measured	O
as	O
previously	O
described	O
[	O
5	O
]	O
.	O

Briefly	O
,	O
cell	O
extracts	O
were	O
prepared	O
with	O
the	O
reporter	O
lysis	O
buffer	O
(	O
Promega	O
)	O
24	O
hours	O
after	O
transfection	O
and	O
CAT	O
activity	O
was	O
determined	O
by	O
the	O
phase	O
extraction	O
procedure	O
[	O
32	O
]	O
and	O
beta	O
-	O
galactosidase	O
assay	O
was	O
performed	O
essentially	O
as	O
described	O
in	O
Sambrook	O
et	O
al	O
.	O

[	O
33	O
]	O
.	O

CAT	O
activity	O
was	O
normalized	O
to	O
beta	O
-	O
galactosidase	O
activity	O
.	O

Experiments	O
were	O
carried	O
out	O
in	O
triplicate	O
and	O
repeated	O
at	O
least	O
two	O
times	O
.	O

Expression	O
plasmids	O
(	O
0	O
.	O
5	O
mu	O
g	O
)	O
were	O
co	O
-	O
transfected	O
with	O
p8	O
-	O
CAT	O
and	O
pCMV	O
/	O
beta	O
gal	O
plasmids	O
as	O
indicated	O
.	O

RT	O
-	O
PCR	O
analysis	O

RNA	O
was	O
extracted	O
using	O
the	O
Trizol	O
(	O
Life	O
Technologies	O
)	O
procedure	O
.	O

Total	O
RNA	O
(	O
1	O
mu	O
g	O
)	O
was	O
analyzed	O
by	O
RT	O
-	O
PCR	O
with	O
the	O
SuperScript	O
(	O
TM	O
)	O
One	O
-	O
step	O
RT	O
-	O
PCR	O
System	O
and	O
the	O
Platinum	O
Taq	O
kit	O
(	O
Life	O
Technologies	O
)	O
.	O

RT	O
-	O
PCR	O
was	O
performed	O
using	O
different	O
numbers	O
of	O
cycles	O
to	O
verify	O
that	O
the	O
conditions	O
chosen	O
were	O
within	O
the	O
linear	O
range	O
.	O

The	O
mRNA	O
coding	O
for	O
p8	O
was	O
specifically	O
amplified	O
with	O
sense	O
(	O
5	O
'	O
GAAGAGAGGCAGGGAAGACA	O
3	O
'	O
)	O
and	O
antisense	O
(	O
5	O
'	O
CTGCCGTGCGTGTCTATTTA	O
3	O
'	O
)	O
primers	O
,	O
in	O
positions	O
72	O
and	O
643	O
of	O
the	O
cDNA	O
(	O
accession	O
#	O
NM	O
_	O
012385	O
)	O
,	O
respectively	O
.	O

As	O
control	O
,	O
the	O
transcript	O
coding	O
for	O
the	O
ribosomal	O
protein	O
RL3	O
was	O
specifically	O
amplified	O
for	O
22	O
cycles	O
with	O
sense	O
(	O
5	O
'	O
GAAAGAAGTCGTGGAGGCTG	O
'	O
)	O
and	O
antisense	O
(	O
5	O
'	O
ATCTCATCCTGCCCAAACAC	O
'	O
)	O
primers	O
,	O
in	O
positions	O
216	O
and	O
637	O
of	O
the	O
cDNA	O
,	O
respectively	O
.	O

Author	O
'	O
s	O
contributions	O

CM	O
prepared	O
cells	O
and	O
retrovirus	O
,	O
carried	O
out	O
RNA	O
purification	O
,	O
RT	O
-	O
PCR	O
,	O
Western	O
blots	O
,	O
and	O
cell	O
growth	O
experiments	O
,	O
NL	O
carried	O
out	O
CAT	O
assays	O
,	O
SV	O
participated	O
in	O
the	O
design	O
of	O
the	O
study	O
and	O
analysis	O
of	O
data	O
,	O
JLI	O
participated	O
in	O
the	O
analysis	O
of	O
data	O
and	O
wrote	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Enzymatic	O
multiplex	O
DNA	O
sequencing	O
.	O

Abstract	O

The	O
problem	O
of	O
reading	O
DNA	O
sequence	O
films	O
has	O
been	O
reformulated	O
using	O
an	O
easily	O
implemented	O
,	O
multiplex	O
version	O
of	O
enzymatic	O
DNA	O
sequencing	O
.	O

By	O
utilizing	O
a	O
uniquely	O
tagged	O
primer	O
for	O
each	O
base	O
-	O
specific	O
sequencing	O
reaction	O
,	O
the	O
four	O
reactions	O
can	O
be	O
pooled	O
and	O
electrophoresed	O
in	O
a	O
single	O
lane	O
.	O

This	O
approach	O
has	O
been	O
previously	O
proposed	O
for	O
use	O
with	O
fluorescently	O
labelled	O
probes	O
(	O
1	O
)	O
,	O
and	O
is	O
analogous	O
to	O
the	O
principle	O
used	O
in	O
four	O
-	O
dye	O
fluorescence	O
sequencing	O
except	O
that	O
the	O
signals	O
are	O
resolved	O
following	O
electrophoresis	O
(	O
2	O
)	O
.	O

After	O
transfer	O
to	O
a	O
nylon	O
membrane	O
,	O
images	O
are	O
obtained	O
separately	O
for	O
each	O
of	O
the	O
four	O
reactions	O
by	O
hybridization	O
using	O
oligonucleotide	O
probes	O
.	O

The	O
images	O
can	O
then	O
be	O
superimposed	O
to	O
reconstitute	O
a	O
complete	O
sequence	O
pattern	O
.	O

In	O
this	O
way	O
the	O
correction	O
of	O
gel	O
distortion	O
effects	O
and	O
accurate	O
band	O
registration	O
are	O
considerably	O
simplified	O
,	O
as	O
each	O
of	O
the	O
four	O
base	O
-	O
specific	O
ladders	O
require	O
very	O
similar	O
corrections	O
.	O

The	O
methods	O
therefore	O
provide	O
the	O
basis	O
for	O
a	O
second	O
generation	O
of	O
more	O
accurate	O
and	O
reliable	O
film	O
reading	O
programs	O
,	O
as	O
well	O
as	O
being	O
useful	O
for	O
conventional	O
multiplex	O
sequencing	O
.	O

Unlike	O
the	O
original	O
multiplex	O
protocol	O
(	O
3	O
)	O
,	O
the	O
approach	O
described	O
is	O
suitable	O
for	O
small	O
projects	O
,	O
as	O
multiple	O
cloning	O
vectors	O
are	O
not	O
used	O
.	O

Although	O
more	O
than	O
one	O
vector	O
can	O
be	O
utilized	O
,	O
only	O
a	O
library	O
of	O
fragments	O
cloned	O
into	O
any	O
single	O
phage	O
,	O
phagemid	O
or	O
plasmid	O
vector	O
is	O
actually	O
required	O
,	O
together	O
with	O
a	O
set	O
of	O
tagged	O
oligonucleotide	O
primers	O
.	O
Images	O

Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O
3301	O

Enzymatic	O
multiplex	O
DNA	O
sequencing	O

Mark	O
Chee	O

Medical	O
Research	O
Council	O
Laboratory	O
of	O
Molecular	O
Biology	O
,	O
Hills	O
Road	O
,	O
Cambridge	O
CB2	O
20H	O
,	O
UK	O

Received	O
March	O
15	O
,	O
1991	O
;	O
Revised	O
and	O
Accepted	O
May	O
2	O
,	O
1991	O

ABSTRACT	O

The	O
problem	O
of	O
reading	O
DNA	O
sequence	O
films	O
has	O
been	O
reformulated	O
using	O
an	O
easily	O
implemented	O
,	O
multiplex	O
version	O
of	O
enzymatic	O
DNA	O
sequencing	O
.	O

By	O
utilizing	O
a	O
uniquely	O
tagged	O
primer	O
for	O
each	O
base	O
-	O
specific	O
sequencing	O
reaction	O
,	O
the	O
four	O
reactions	O
can	O
be	O
pooled	O
and	O
electrophoresed	O
in	O
a	O
single	O
lane	O
.	O

This	O
approach	O
has	O
been	O
previously	O
proposed	O
for	O
use	O
with	O
fluorescently	O
labelled	O
probes	O
(	O
1	O
)	O
,	O
and	O
is	O
analogous	O
to	O
the	O
principle	O
used	O
in	O
four	O
-	O
dye	O
fluorescence	O
sequencing	O
except	O
that	O
the	O
signals	O
are	O
resolved	O
following	O
electrophoresis	O
(	O
2	O
)	O
.	O

After	O
transfer	O
to	O
a	O
nylon	O
membrane	O
,	O
images	O
are	O
obtained	O
separately	O
for	O
each	O
of	O
the	O
four	O
reactions	O
by	O
hybridization	O
using	O
oligonucleotide	O
probes	O
.	O

The	O
images	O
can	O
then	O
be	O
superimposed	O
to	O
reconstitute	O
a	O
complete	O
sequence	O
pattern	O
.	O

In	O
this	O
way	O
the	O
correction	O
of	O
gel	O
distortion	O
effects	O
and	O
accurate	O
band	O
registration	O
are	O
considerably	O
simplified	O
,	O
as	O
each	O
of	O
the	O
four	O
basespecific	O
ladders	O
require	O
very	O
similar	O
corrections	O
.	O

The	O
methods	O
therefore	O
provide	O
the	O
basis	O
for	O
a	O
second	O
generation	O
of	O
more	O
accurate	O
and	O
reliable	O
film	O
reading	O
programs	O
,	O
as	O
well	O
as	O
being	O
useful	O
for	O
conventional	O
multiplex	O
sequencing	O
.	O

Unlike	O
the	O
original	O
multiplex	O
protocol	O
(	O
3	O
)	O
,	O
the	O
approach	O
described	O
is	O
suitable	O
for	O
small	O
projects	O
,	O
as	O
multiple	O
cloning	O
vectors	O
are	O
not	O
used	O
.	O

Although	O
more	O
than	O
one	O
vector	O
can	O
be	O
utilized	O
,	O
only	O
a	O
library	O
of	O
fragments	O
cloned	O
into	O
any	O
single	O
phage	O
.	O
phagemid	O
or	O
plasmid	O
vector	O
is	O
actually	O
required	O
,	O
together	O
with	O
a	O
set	O
of	O
tagged	O
oligonucleotide	O
primers	O
.	O

INTRODUCTION	O

The	O
community	O
of	O
biologists	O
is	O
undertaking	O
the	O
sequencing	O
of	O
representative	O
genomes	O
of	O
various	O
free	O
-	O
living	O
organisms	O
,	O
ranging	O
in	O
size	O
from	O
Mycoplasma	O
(	O
800kb	O
)	O
to	O
mammals	O
(	O
3	O
Gb	O
)	O
(	O
4	O
)	O
.	O

However	O
,	O
the	O
largest	O
contiguous	O
DNA	O
sequences	O
which	O
have	O
been	O
determined	O
so	O
far	O
are	O
the	O
genomes	O
of	O
several	O
dsDNA	O
eukaryotic	O
viruses	O
(	O
5	O
,	O
6	O
,	O
7	O
,	O
8	O
,	O
9	O
)	O
and	O
plant	O
chloroplasts	O
(	O
10	O
,	O
11	O
,	O
12	O
)	O
.	O

The	O
largest	O
of	O
these	O
is	O
the	O
229kb	O
genome	O
of	O
human	B
cytomegalovirus	I
(	O
8	O
)	O
.	O

The	O
difficulty	O
in	O
sequencing	O
millions	O
of	O
base	O
pairs	O
of	O
DNA	O
is	O
that	O
several	O
steps	O
in	O
the	O
methods	O
are	O
relatively	O
labour	O
intensive	O
,	O
although	O
the	O
sequencing	O
reactions	O
themselves	O
are	O
rapid	O
and	O
easily	O
performed	O
.	O

Two	O
limiting	O
steps	O
in	O
conventional	O
procedures	O
are	O
the	O
size	O
fractionation	O
of	O
sequencing	O
reaction	O
products	O
by	O
gel	O
electrophoresis	O
and	O
the	O
subsequent	O
reading	O
of	O
sequence	O
ladders	O
.	O

The	O
former	O
problem	O
can	O
be	O
overcome	O
by	O
multiplexing	O
,	O
which	O
theoretically	O
allows	O
an	O
enormous	O
amount	O
of	O

data	O
to	O
be	O
obtained	O
from	O
a	O
single	O
gel	O
by	O
processing	O
clones	O
as	O
mixtures	O
rather	O
than	O
individually	O
(	O
3	O
)	O
.	O

Each	O
sequence	O
in	O
the	O
mixture	O
is	O
labelled	O
by	O
a	O
unique	O
short	O
oligonucleotide	O
'	O
tag	O
'	O
sequence	O
.	O

This	O
allows	O
the	O
mixture	O
to	O
be	O
resolved	O
following	O
electrophoresis	O
:	O
the	O
superimposed	O
sequence	O
ladders	O
are	O
blotted	O
from	O
the	O
gel	O
to	O
a	O
nylon	O
membrane	O
,	O
and	O
detected	O
one	O
at	O
a	O
time	O
by	O
hybridization	O
using	O
tag	O
-	O
specific	O
oligonucleotide	O
probes	O
.	O

In	O
practice	O
,	O
at	O
least	O
50	O
sets	O
of	O
sequences	O
can	O
be	O
obtained	O
from	O
a	O
single	O
gel	O
(	O
3	O
)	O
.	O

Unfortunately	O
,	O
a	O
bottleneck	O
in	O
the	O
multiplex	O
procedure	O
is	O
the	O
reading	O
of	O
sequence	O
films	O
.	O

In	O
previous	O
large	O
-	O
scale	O
sequencing	O
projects	O
this	O
task	O
has	O
been	O
performed	O
with	O
the	O
aid	O
of	O
a	O
sonic	O
digitizer	O
(	O
13	O
,	O
14	O
)	O
.	O

Although	O
film	O
reading	O
programs	O
have	O
been	O
under	O
development	O
for	O
some	O
time	O
(	O
15	O
)	O
,	O
and	O
some	O
programs	O
are	O
commercially	O
available	O
,	O
their	O
error	O
rates	O
are	O
presently	O
more	O
variable	O
and	O
unpredictable	O
than	O
that	O
of	O
a	O
skilled	O
person	O
and	O
the	O
accurate	O
interpretation	O
of	O
film	O
-	O
imaged	O
sequence	O
ladders	O
by	O
computer	O
programs	O
is	O
difficult	O
to	O
achieve	O
in	O
routine	O
practice	O
.	O

Programs	O
specifically	O
designed	O
to	O
read	O
multiplex	O
films	O
have	O
an	O
advantage	O
.	O

This	O
is	O
because	O
a	O
sequence	O
image	O
can	O
be	O
used	O
as	O
an	O
'	O
internal	O
standard	O
'	O
to	O
help	O
interpret	O
other	O
images	O
derived	O
from	O
the	O
same	O
membrane	O
(	O
3	O
)	O
.	O

However	O
,	O
the	O
original	O
implementation	O
of	O
the	O
multiplex	O
strategy	O
used	O
chemical	O
sequencing	O
(	O
16	O
)	O
,	O
which	O
yields	O
a	O
more	O
complex	O
sequence	O
ladder	O
than	O
the	O
enzymatic	O
dideoxynucleotide	O
chain	O
-	O
termination	O
method	O
(	O
17	O
)	O
.	O

Most	O
successful	O
large	O
scale	O
sequencing	O
projects	O
have	O
used	O
the	O
chaintermination	O
method	O
and	O
bacteriophage	B
M13	I
vectors	O
,	O
which	O
allows	O
the	O
routine	O
production	O
of	O
clean	O
and	O
easily	O
interpretable	O
sequences	O
(	O
18	O
)	O
.	O

It	O
was	O
therefore	O
decided	O
to	O
adapt	O
the	O
original	O
multiplex	O
protocol	O
for	O
use	O
with	O
enzymatic	O
sequencing	O
,	O
using	O
tagged	O
primers	O
.	O

MATERIALS	O
AND	O
METHODS	O

Eight	O
oligonucleotide	O
sequencing	O
primers	O
were	O
synthesized	O
,	O
each	O
37	O
nucleotides	O
in	O
length	O
.	O

The	O
3	O
'	O
end	O
of	O
each	O
primer	O
consists	O
of	O
the	O
17	O
nucleotide	O
M13	O
universal	O
priming	O
sequence	O
[	O
GTAAAACGACGGCCAGT3	O
'	O
]	O
.	O

The	O
5	O
'	O
ends	O
of	O
the	O
primers	O
bear	O
different	O
20mer	O
tag	O
sequences	O
(	O
Figure	O
1	O
)	O
.	O

In	O
four	O
of	O
the	O
primers	O
,	O
UEO1C	O
,	O
UPOIC	O
,	O
UE02C	O
and	O
UP02C	O
,	O
these	O
tags	O
are	O
complementary	O
to	O
the	O
EO1	O
,	O
PO1	O
,	O
E02	O
and	O
P02	O
probe	O
sequences	O
respectively	O
(	O
copied	O
from	O
the	O
original	O
'	O
plex	O
'	O
vectors	O
(	O
3	O
)	O
)	O
.	O

A	O
second	O
set	O
of	O
four	O
primers	O
,	O
UJOL14C	O
,	O
UJOL15C	O
,	O
UJOL16C	O
and	O
UJOL17C	O
,	O
have	O
the	O
following	O
tag	O
sequences	O
:	O
5	O
'	O
CAAGTTTGAAGGTACTCATT	O
,	O
TATCAATTAAATTGTllTGA	O
,	O
GTGTTGCTACCCAAGAAGCA	O
,	O
and	O
TGTCACTAGAGCTGTCACTT	O
,	O
respectively	O
.	O

The	O

?	O
=	O
)	O
1991	O
Oxford	O
University	O
Press	O

3302	O
Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O

oligonucleotides	O
were	O
gel	O
-	O
purified	O
(	O
19	O
)	O
and	O
used	O
to	O
sequence	O
ssDNA	O
templates	O
prepared	O
by	O
phenol	O
extraction	O
(	O
20	O
)	O
or	O
SDS	O
denaturation	O
(	O
21	O
)	O
.	O

Conventional	O
sequencing	O
reactions	O
were	O
performed	O
as	O
previously	O
described	O
(	O
20	O
)	O
.	O

For	O
hybridization	O
experiments	O
,	O
radioactively	O
labelled	O
nucleotides	O
were	O
omitted	O
from	O
the	O
sequencing	O
reactions	O
.	O

Instead	O
,	O
the	O
21d	O
of	O
each	O
nucleotide	O
mix	O
added	O
to	O
the	O
reaction	O
mixture	O
consisted	O
of	O
the	O
following	O
:	O
'	O
A	O
'	O
mix	O
:	O
6	O
.	O
25MtM	O
dATP	O
,	O
62	O
.	O
5lM	O
ddATP	O
;	O
'	O
C	O
'	O
mix	O
:	O
6	O
.	O
25MM	O
dCTP	O
,	O
40MtM	O
ddCTP	O
;	O
'	O
G	O
'	O
mix	O
:	O
6	O
.	O
25MtM	O
dGTP	O
,	O
80MtM	O
ddGTP	O
;	O
'	O
T	O
'	O
mix	O
:	O
6	O
.	O
25MM	O
dTTP	O
,	O
250yM	O
ddTTP	O
;	O
as	O
well	O
as	O
125MM	O
of	O
each	O
of	O
the	O
three	O
other	O
dNTPs	O
in	O
each	O
mix	O
.	O

Apart	O
from	O
the	O
use	O
of	O
these	O
modified	O
mixes	O
,	O
no	O
changes	O
were	O
made	O
to	O
the	O
conventional	O
sequencing	O
procedure	O
(	O
20	O
)	O
.	O

Sequencing	O
reactions	O
were	O
pooled	O
and	O
ethanol	O
precipitated	O
as	O
appropriate	O
.	O

Precipitation	O
in	O
microtitre	O
trays	O
was	O
carried	O
out	O
as	O
follows	O
:	O
a	O
mixture	O
of	O
3	O
.	O
2M1	O
3M	O
NaAc	O
pH	O
5	O
.	O
0	O
and	O
112Mi1	O
EtOH	O
was	O
dispensed	O
to	O
individual	O
wells	O
of	O
a	O
microtitre	O
plate	O
(	O
Falcon	O
3911	O
or	O
Corning	O
25855	O
)	O
using	O
an	O
8	O
-	O
channel	O
pipettor	O
.	O

Each	O
set	O
of	O
four	O
reactions	O
was	O
added	O
to	O
the	O
EtOH	O
/	O
NaAc	O
mixture	O
,	O
and	O
the	O
tray	O
sealed	O
using	O
a	O
Falcon	O
3073	O
plate	O
sealer	O
.	O

The	O
samples	O
were	O
mixed	O
by	O
inversion	O
and	O
stored	O
at	O
-	O
20	O
?	O
C	O
for	O
30	O
minutes	O
.	O

The	O
DNA	O
was	O
collected	O
by	O
a	O
20	O
minute	O
centrifugation	O
at	O
4	O
000	O
rpm	O
in	O
an	O
IEC	O
Centra	O
3C	O
centrifuge	O
.	O

The	O
sealer	O
was	O
removed	O
,	O
and	O
the	O
plate	O
inverted	O
to	O
discard	O
the	O
supernatant	O
.	O

After	O
blotting	O
the	O
tray	O
on	O
tissue	O
paper	O
,	O
200MI	O
of	O
95	O
%	O
EtOH	O
was	O
added	O
to	O
each	O
well	O
.	O

The	O
plate	O
was	O
covered	O
with	O
a	O
plastic	O
lid	O
and	O
recentrifuged	O
for	O
2	O
minutes	O
.	O

The	O
EtOH	O
was	O
discarded	O
and	O
the	O
plate	O
inverted	O
for	O
several	O
minutes	O
on	O
tissue	O
paper	O
,	O
then	O
left	O
for	O
20	O
minutes	O
to	O
air	O
dry	O
.	O

Precipitated	O
samples	O
were	O
resuspended	O
in	O
6M1	O
deionized	O
water	O
by	O
vortexing	O
on	O
an	O
SMI	O
multi	O
-	O
tube	O
vortexer	O
for	O
1	O
minute	O
.	O

Samples	O
were	O
denatured	O
and	O
electrophoresed	O
on	O
6	O
%	O
polyacrylamide	O
buffer	O
gradient	O
gels	O
as	O
previously	O
described	O
(	O
20	O
)	O
.	O

Following	O
electrophoresis	O
,	O
the	O
gel	O
was	O
transferred	O
to	O
a	O
dry	O
piece	O
of	O
Whatman	O
3MM	O
blotting	O
paper	O
,	O
and	O
placed	O
on	O
a	O
second	O
sheet	O
of	O
blotting	O
paper	O
supported	O
on	O
a	O
glass	O
plate	O
and	O
saturated	O
in	O
4	O
x	O
SSC	O
(	O
SSC	O
:	O
150mM	O
NaCl	O
,	O
l5mM	O
trisodium	O
citrate	O
)	O
.	O

This	O
sheet	O
was	O
wicked	O
in	O
a	O
tray	O
containing	O
1	O
litre	O
of	O
4	O
x	O
SSC	O
.	O

The	O
DNA	O
was	O
transferred	O
to	O
a	O
nylon	O
membrane	O
(	O
Amersham	O
Hybond	O
N	O
)	O
by	O
capillary	O
blotting	O
overnight	O
(	O
22	O
)	O
.	O

DNA	O
was	O
fixed	O
to	O
the	O
membranes	O
by	O
U	O
.	O
V	O
.	O
crosslinking	O
(	O
23	O
)	O
.	O

Plex	O
oligonucleotide	O
probes	O
were	O
a	O
kind	O
gift	O
of	O
Dr	O
.	O
George	O
Church	O
.	O

Probes	O
were	O
tailed	O
at	O
their	O
3	O
'	O
ends	O
using	O
[	O
a	O
-	O
32p	O
]	O
dCTP	O
as	O
previously	O
described	O
(	O
3	O
)	O
.	O

For	O
the	O
preparation	O
of	O
digoxigenin	O
(	O
DIG	O
)	O
labelled	O
probes	O
,	O
identical	O
tailing	O
reactions	O
were	O
carried	O
out	O
substituting	O
I0pmols	O
of	O
DIG	O
-	O
II	O
dUTP	O
(	O
Boehringer	O
Mannheim	O
)	O
for	O
[	O
a	O
-	O
32P	O
]	O
dCTP	O
.	O

Membranes	O
were	O
prehybridized	O
for	O
at	O
least	O
10	O
minutes	O
in	O
4	O
x	O
SSC	O
,	O
5	O
x	O
Denhardts	O
'	O
(	O
0	O
.	O
1	O
%	O
(	O
w	O
/	O
v	O
)	O
each	O
of	O
BSA	O
(	O
heated	O
at	O
80	O
?	O
C	O
for	O
30	O
minutes	O
to	O
inactivate	O
any	O
alkaline	O
phosphatase	O
activity	O
)	O
,	O
Ficoll	O
(	O
Pharmacia	O
)	O
and	O
polyvinylpyrrolidone	O
)	O
,	O
0	O
.	O
5	O
%	O
(	O
w	O
/	O
v	O
)	O
SDS	O
,	O
5mM	O
NaHPO4	O
(	O
23	O
)	O
.	O

Hybridization	O
was	O
carried	O
out	O
in	O
25	O
-	O
50M1	O
of	O
prehybridization	O
buffer	O
per	O
cm2	O
of	O
membrane	O
.	O

The	O
probe	O
concentration	O
was	O
approximately	O
lnM	O
.	O

After	O
lh	O
at	O
42	O
?	O
C	O
,	O
unbound	O
probe	O
was	O
removed	O
by	O
five	O
1	O
minute	O
washes	O
at	O
room	O
temperature	O
in	O
1	O
x	O
SSC	O
,	O
0	O
.	O
5	O
%	O
SDS	O
(	O
200MI	O
/	O
cm2	O
membrane	O
)	O
.	O

Radioactive	O
blots	O
were	O
covered	O
in	O
Saran	O
wrap	O
and	O
exposed	O
to	O
film	O
immediately	O
.	O

Detection	O
of	O
DIG	O
labelled	O
probes	O
used	O
an	O
anti	O
-	O
DIG	O
antibodyalkaline	O
phosphatase	O
conjugate	O
(	O
Boehringer	O
Mannheim	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
,	O
except	O
that	O
all	O
volumes	O
were	O
reduced	O
by	O
70	O
%	O
and	O
the	O
conjugate	O
was	O
used	O
at	O
a	O
1	O
:	O
10	O
000	O
dilution	O
.	O

Blots	O
were	O
developed	O
in	O
25M1	O
of	O
100mM	O
Tris	O
.	O
Cl	O
pH9	O
.	O
5	O
,	O

mantane4	O
-	O
methoxy4	O
(	O
3	O
"	O
-	O
phosphoryloxy	O
)	O
phenyl	O
-	O
1	O
,	O
2	O
-	O
dioxetane	O
)	O
;	O
Tropix	O
)	O
/	O
cm2	O
for	O
30	O
minutes	O
at	O
37	O
?	O
C	O
,	O
prior	O
to	O
exposure	O
to	O
film	O
.	O

Probes	O
and	O
dioxetane	O
were	O
stripped	O
from	O
the	O
membranes	O
by	O
two	O
10	O
minute	O
washes	O
at	O
700C	O
with	O
0	O
.	O
2	O
%	O
SDS	O
,	O
2mM	O
EDTA	O
(	O
200	O
,	O
ul	O
/	O
cm2	O
membrane	O
)	O
.	O

The	O
hybridization	O
and	O
washing	O
procedures	O
were	O
carried	O
out	O
in	O
plastic	O
bags	O
.	O

However	O
,	O
washing	O
steps	O
have	O
also	O
been	O
performed	O
with	O
gentle	O
agitation	O
in	O
a	O
perspex	O
tub	O
(	O
43	O
x	O
27	O
x	O
15cm	O
)	O
mounted	O
on	O
a	O
reciprocal	O
shaker	O
,	O
with	O
equivalent	O
results	O
.	O

In	O
the	O
latter	O
case	O
a	O
minimum	O
wash	O
volume	O
of	O
500mls	O
was	O
used	O
.	O

The	O
use	O
of	O
a	O
tub	O
is	O
more	O
convenient	O
for	O
batch	O
processing	O
and	O
should	O
be	O
straightforward	O
to	O
automate	O
.	O

RESULTS	O

Autoradiograms	O
revealed	O
no	O
difference	O
in	O
sequence	O
quality	O
when	O
tagged	O
primers	O
were	O
used	O
instead	O
of	O
the	O
17mer	O
universal	O
primer	O
in	O
conventional	O
[	O
a	O
-	O
35S	O
]	O
dATP	O
labelled	O
sequencing	O
reactions	O
and	O
in	O
multiplex	O
hybridization	O
experiments	O
using	O
[	O
a	O
-	O
32P	O
]	O
dCTP	O
-	O
tailed	O
probes	O
(	O
results	O
not	O
shown	O
)	O
.	O

Experiments	O
were	O
then	O
conducted	O
to	O
determine	O
the	O
feasibility	O
of	O
pooling	O
the	O
four	O
base	O
reactions	O
for	O
each	O
clone	O
and	O
fractionating	O
them	O
in	O
a	O
single	O
lane	O
to	O
obtain	O
a	O
superimposed	O
but	O
interpretable	O
set	O
of	O
sequence	O
ladders	O
.	O

The	O
question	O
addressed	O
was	O
whether	O
or	O
not	O
difficulties	O
in	O
band	O
registration	O
might	O
arise	O
as	O
a	O
result	O
of	O
mobility	O
differences	O
between	O
the	O
different	O
primer	O
sequences	O
and	O
/	O
or	O
distortion	O
of	O
the	O
membrane	O
between	O
probings	O
.	O

It	O
is	O
relevant	O
that	O
an	O
automated	O
film	O
reader	O
employing	O
an	O
internal	O
standard	O
requires	O
that	O
the	O
nylon	O
membrane	O
does	O
not	O
undergo	O
significant	O
distortions	O
between	O
probings	O
(	O
George	O
Church	O
,	O
personal	O
communication	O
)	O
.	O

Clones	O
were	O
sequenced	O
using	O
the	O
four	O
tagged	O
primers	O
UEOlC	O
,	O
UPOIC	O
,	O
UE02C	O
,	O
and	O
UP02C	O
,	O
one	O
for	O
each	O
base	O
reaction	O
(	O
Figure	O
1	O
)	O
.	O

The	O
A	O
,	O
C	O
,	O
G	O
and	O
T	O
reactions	O
for	O
each	O
clone	O
were	O
pooled	O
,	O
and	O
processed	O
as	O
described	O
above	O
.	O

A	O
complete	O
set	O
of	O
sequence	O
autoradiograms	O
was	O
obtained	O
from	O
four	O
consecutive	O
rounds	O
of	O
probing	O
with	O
[	O
a	O
-	O
32P	O
]	O
dCTP	O
-	O
labelled	O
oligonucleotides	O
.	O

Alignment	O
of	O
the	O
films	O
showed	O
that	O
sequence	O
-	O
specific	O
mobility	O
effects	O
and	O
distortion	O
of	O
the	O
membrane	O
between	O
probings	O
were	O
sufficiently	O
minor	O
to	O
allow	O
accurate	O
registration	O
of	O
the	O
bands	O
,	O
and	O
hence	O
accurate	O
reading	O
of	O
the	O
sequence	O
.	O

At	O
least	O
200	O
nucleotides	O
of	O
sequence	O
could	O
be	O
read	O
accurately	O
from	O
a	O
single	O
clone	O
by	O
simply	O
tracing	O
the	O
four	O
sets	O
of	O
bands	O
using	O
different	O
colours	O
,	O
overlaying	O
the	O
tracings	O
,	O
and	O
reading	O
the	O
bands	O
sequentially	O
.	O

In	O
order	O
to	O
assess	O
the	O
practicality	O
of	O
reading	O
the	O
sequences	O
by	O
machine	O
,	O
the	O
images	O
were	O
scanned	O
to	O
provide	O
optical	O
density	O
profiles	O
(	O
Figure	O
2	O
)	O
.	O

These	O
profiles	O
were	O
overlaid	O
,	O
and	O
were	O
found	O
to	O
be	O
sufficiently	O
in	O
register	O
to	O
allow	O
accurate	O
interpretation	O
of	O
the	O
sequence	O
for	O
at	O
least	O
300	O
nucleotides	O
.	O

This	O
was	O
essentially	O
the	O
limit	O
of	O
resolution	O
of	O
the	O
gel	O
for	O
accurate	O
manual	O
reading	O
.	O

In	O
order	O
to	O
ensure	O
that	O
the	O
relatively	O
minor	O
mobility	O
differences	O
observed	O
between	O
the	O
four	O
primers	O
were	O
not	O
coincidental	O
to	O
the	O
oligonucleotides	O
used	O
,	O
a	O
second	O
set	O
of	O
four	O
tagged	O
M13	O
universal	O
primers	O
was	O
synthesised	O
,	O
this	O
time	O
incorporating	O
20mer	O
sequences	O
derived	O
from	O
the	O
genome	O
of	O
murine	O
herpesvirus	O
-	O
68	O
(	O
UJOL14C	O
,	O
15C	O
,	O
16C	O
,	O
17C	O
)	O
.	O

Sequencing	O
reactions	O
were	O
performed	O
using	O
[	O
cx	O
-	O
35S	O
]	O
dATP	O
to	O
label	O
the	O
DNA	O
directly	O
.	O

Various	O
templates	O
were	O
sequenced	O
,	O
and	O
in	O
all	O
cases	O
correctly	O
ordered	O
sequence	O
ladders	O
were	O
obtained	O
following	O
conventional	O
electrophoresis	O
in	O
which	O
the	O
four	O
reactions	O
were	O
run	O
side	O
-	O
by	O
-	O
side	O
(	O
results	O
not	O
shown	O
)	O
.	O

Initial	O
hybridization	O
experiments	O
were	O
conducted	O
using	O
[	O
f	O
-	O
32p	O
]	O

dCTP	O
tailed	O
oligonucleotide	O
probes	O
.	O

However	O
,	O
the	O
use	O
of	O

lOOmM	O
NaCl	O
,	O
5OmM	O
MgC12	O
,	O
0	O
.	O
15mM	O
AMPPD	O
(	O
[	O
3	O
-	O
(	O
2	O
'	O
-	O
ada	O

B	O

C	O

'	O
Ordinary	O
'	O
Plex	O
'	O
4	O
-	O
CJ3	O
4	O
-	O
rn	O
+	O

Primeir	O
Primer	O

"	O
All	O
"	O
C	O
"	O
"	O
G	O
"	O
"	O
T	O
"	O

'	O
Plex	O
'	O
'	O
Ordinary	O
'	O
Pool	O
and	O

Vector	O
Vector	O
fractionate	O

Resolve	O
by	O
sequential	O

hybridizations	O

Sequencing	O
reactions	O

SequencingreactIo	O
product	O

Sequencing	O
reaction	O
product	O

-	O
n	O
;	O

=	O
=	O

-	O
=	O

-	O
n	O
:	O
=	O

Figure	O
1	O
.	O
Approaches	O
to	O
enzymatic	O
multiplex	O
DNA	O
sequencing	O
.	O
a	O
)	O
A	O
set	O
of	O
sequence	O
-	O
tagged	O
vectors	O
can	O
be	O
used	O
.	O

The	O
tag	O
site	O
is	O
shown	O
in	O
red	O
,	O
and	O
the	O
insert	O
to	O
be	O
sequenced	O
in	O
blue	O
.	O

However	O
,	O
the	O
original	O
plex	O
vectors	O
(	O
3	O
)	O
are	O
plasmids	O
,	O
and	O
therefore	O
amenable	O
only	O
to	O
dsDNA	O
sequencing	O
.	O
Sets	O
of	O
bacteriophage	B
M13	I
vectors	O
have	O
been	O
constructed	O
bearing	O
either	O
one	O
(	O
32	O
)	O
or	O
two	O
[	O
Chee	O
,	O
unpublished	O
]	O
of	O
the	O
plex	O
tag	O
sites	O
flanking	O
the	O
polylinker	O
,	O
which	O
can	O
be	O
used	O
for	O
this	O
approach	O
.	O

b	O
)	O
The	O
strategy	O
used	O
in	O
this	O
paper	O
.	O

In	O
this	O
case	O
the	O
tag	O
site	O
is	O
carried	O
on	O
the	O
primer	O
.	O

c	O
)	O
If	O
tagged	O
primers	O
are	O
used	O
,	O
there	O
is	O
no	O
practical	O
impediment	O
to	O
performing	O
each	O
base	O
reaction	O
using	O
a	O
different	O
primer	O
,	O
as	O
depicted	O
.	O

The	O
reactions	O
can	O
then	O
be	O
pooled	O
in	O
any	O
combination	O
desired	O
.	O

The	O
configuration	O
shown	O
,	O
in	O
which	O
the	O
four	O
reactions	O
are	O
electrophoresed	O
in	O
a	O
single	O
lane	O
,	O
is	O
designed	O
to	O
facilitate	O
accurate	O
band	O
registration	O
and	O
reading	O
by	O
an	O
automatic	O
film	O
reader	O
.	O

In	O
order	O
to	O
read	O
the	O
sequence	O
manually	O
,	O
base	O
reactions	O
would	O
be	O
run	O
side	O
-	O
by	O
-	O
side	O
.	O

The	O
logistics	O
of	O
processing	O
the	O
reactions	O
are	O
essentially	O
the	O
same	O
with	O
either	O
configuration	O
;	O
the	O
same	O
number	O
of	O
probings	O
are	O
required	O
.	O

Figure	O
2	O
.	O

Four	O
overlaid	O
one	O
-	O
dimensional	O
optical	O
density	O
profiles	O
for	O
a	O
single	O
clone	O
shown	O
in	O
two	O
overlapping	O
sections	O
.	O

The	O
optical	O
density	O
profiles	O
are	O
unprocessed	O
,	O
except	O
for	O
a	O
simple	O
transform	O
to	O
correct	O
for	O
the	O
relative	O
displacement	O
(	O
translation	O
and	O
rotation	O
)	O
of	O
the	O
four	O
images	O
from	O
which	O
they	O
are	O
extracted	O
.	O

The	O
profiles	O
read	O
5	O
'	O
to	O
3	O
'	O
from	O
right	O
to	O
left	O
.	O

Nucleotides	O
positions	O
66	O
to	O
214	O
from	O
the	O
start	O
of	O
the	O
universal	O
priming	O
site	O
are	O
shown	O
.	O

The	O
sequence	O
is	O
that	O
of	O
Bluescribe	O
M13	O
+	O
(	O
template	O
DNA	O
obtained	O
by	O
rescue	O
with	O
M13K07	O
helper	O
phage	O
(	O
30	O
)	O
)	O
,	O
and	O
was	O
determined	O
using	O
the	O
primers	O
UEOIC	O
,	O
UPOIC	O
,	O
UE02C	O
,	O
and	O
UP02C	O
for	O
the	O
T	O
,	O
C	O
,	O
G	O
and	O
A	O

specific	O
reactions	O
respectively	O
.	O

Detection	O
was	O
by	O
autoradiography	O
following	O
hybridization	O
with	O
[	O
a	O
-	O
32p	O
]	O
dCTP	O
tailed	O
plex	O
probes	O
.	O

A	O

Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O
3303	O

I	O

3304	O
Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O

a	O
)	O

175	O
-	O
.	O
.	O
.	O

-	O
w	O

.	O
m	O
;	O

b	O
)	O

182	O

a	O
:	O
.	O
.	O
.	O
.	O
.	O
.	O

F	O
.	O
VW	O

an	O

-	O
w	O

-	O
1	O

S	O
-	O
K	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
~	O
i	O

'	O
F	O
C	O
C	O
;	O
A	O
I1	O
'	O
CG	O
A	O

Figure	O
3	O
.	O

Four	O
separate	O
base	O
-	O
specific	O
reactions	O
imaged	O
from	O
a	O
single	O
lane	O
using	O
chemiluminescent	O
detection	O
.	O

The	O
clones	O
sequenced	O
are	O
:	O
a	O
)	O
Bluescribe	O
M13	O
+	O
(	O
obtained	O
by	O
rescue	O
with	O
M13K07	O
helper	O
phage	O
(	O
30	O
)	O
)	O
and	O
b	O
)	O
an	O
M13	O
recombinant	O
clone	O
prepared	O
in	O
a	O
microtitre	O
tray	O
(	O
21	O
)	O
(	O
a	O
kind	O
gift	O
of	O
Victoria	O
Smith	O
)	O
.	O

Nucleotide	O
positions	O
shown	O
on	O
the	O
figure	O
are	O
numbered	O
from	O
the	O
start	O
of	O
the	O
universal	O
priming	O
site	O
.	O

The	O
clones	O
were	O
sequenced	O
using	O
UEOlC	O
,	O
UPOIC	O
,	O
UE02C	O
,	O
and	O
UP02C	O
for	O
the	O
T	O
,	O
C	O
,	O
G	O
and	O
A	O
specific	O
reactions	O
respectively	O
.	O

The	O
blot	O
was	O
probed	O
with	O
corresponding	O
DIG	O
-	O
11	O
-	O
dUTP	O
labelled	O
oligonucleotides	O
.	O

radioactivity	O
on	O
the	O
scale	O
envisioned	O
for	O
a	O
large	O
sequencing	O
project	O
is	O
undesirable	O
for	O
reasons	O
of	O
safety	O
.	O

The	O
relatively	O
long	O
exposure	O
times	O
required	O
(	O
6	O
to	O
24	O
hours	O
)	O
and	O
the	O
short	O
half	O
lives	O
of	O
the	O
probes	O
might	O
also	O
be	O
inconvenient	O
.	O

It	O
has	O
been	O
shown	O
that	O
a	O
biotin	O
/	O
streptavidin	O
/	O
alkaline	O
phosphatase	O
based	O
detection	O
system	O
used	O
in	O
conjunction	O
with	O
a	O
chemiluminescent	O
dioxetane	O
substrate	O
overcomes	O
these	O
disadvantages	O
(	O
24	O
,	O
25	O
,	O
26	O
)	O
.	O

We	O
utilized	O
a	O
different	O
bridging	O
system	O
with	O
similar	O
results	O
.	O

Digoxigenin	O
(	O
DIG	O
)	O
labelled	O
oligonucleotide	O
probes	O
were	O
detected	O
using	O
anti	O
-	O
DIG	O
antibody	O
-	O
alkaline	O
phosphatase	O
conjugates	O
and	O
a	O
chemiluminescent	O
dioxetane	O
substrate	O
.	O

Exposure	O
times	O
of	O
10	O
to	O
15	O
minutes	O
were	O
typically	O
required	O
,	O
following	O
a	O
one	O
hour	O
preincubation	O
period	O
(	O
Figure	O
3	O
)	O
.	O

In	O
our	O
hands	O
the	O
DIG	O
bridging	O
system	O
was	O
similar	O
in	O
sensitivity	O
to	O
the	O
streptavidin	O
based	O
system	O
(	O
24	O
)	O
,	O
and	O
the	O
practical	O
lower	O
limit	O
of	O
template	O
ssDNA	O
required	O
in	O
order	O
to	O
obtain	O
an	O
easily	O
interpretable	O
sequencing	O
ladder	O
was	O
estimated	O
to	O
be	O
in	O
the	O
range	O
of	O
20	O
to	O
50fmols	O
per	O
reaction	O
.	O

However	O
,	O
the	O
sensitivity	O
of	O
detection	O
was	O
limited	O
only	O
by	O
enzymaticallytrigger	O
background	O
luminescence	O
,	O
and	O
not	O
by	O
the	O
level	O
of	O
signal	O
obtained	O
.	O

The	O
nonradioactive	O
methods	O
described	O
have	O
been	O
used	O
successfully	O
in	O
an	O
8	O
-	O
plex	O
system	O
.	O

DISCUSSION	O

Although	O
the	O
original	O
multiplex	O
protocol	O
was	O
based	O
on	O
a	O
set	O
of	O
tagged	O
vectors	O
(	O
3	O
)	O
,	O
tagged	O
primers	O
have	O
also	O
been	O
used	O
or	O
proposed	O
for	O
various	O
forms	O
of	O
multiplex	O
DNA	O
sequencing	O
(	O
George	O
Church	O
,	O
personal	O
communication	O
;	O
2	O
,	O
27	O
)	O
.	O

For	O
example	O
,	O
a	O
proposal	O
was	O
recently	O
put	O
forward	O
for	O
multiplex	O
sequencing	O
using	O
sequence	O
-	O
labelled	O
primers	O
and	O
fluorophor	O
-	O
labelled	O
probes	O

(	O
1	O
)	O
,	O
similar	O
in	O
principle	O
to	O
the	O
methods	O
used	O
here	O
.	O

However	O
,	O
we	O
use	O
tagged	O
primers	O
and	O
the	O
superposition	O
of	O
the	O
four	O
sequencing	O
reactions	O
to	O
address	O
the	O
problem	O
of	O
reading	O
DNA	O
sequence	O
films	O
;	O
a	O
part	O
of	O
this	O
solution	O
is	O
to	O
utilize	O
M13	O
dideoxynucleotide	O
sequencing	O
,	O
thereby	O
improving	O
the	O
quality	O
of	O
the	O
data	O
to	O
be	O
analyzed	O
.	O

In	O
addition	O
,	O
the	O
proposal	O
for	O
fluorophor	O
-	O
labelled	O
probes	O
does	O
not	O
take	O
into	O
consideration	O
any	O
of	O
the	O
practical	O
sequencing	O
problems	O
addressed	O
here	O
,	O
and	O
,	O
in	O
the	O
version	O
described	O
,	O
remains	O
a	O
promising	O
but	O
unproven	O
scheme	O
for	O
large	O
scale	O
DNA	O
sequencing	O
.	O

There	O
are	O
several	O
advantages	O
to	O
tagging	O
primers	O
instead	O
of	O
vectors	O
.	O

Firstly	O
,	O
there	O
is	O
no	O
need	O
to	O
prepare	O
multiple	O
libraries	O
of	O
clones	O
in	O
special	O
vectors	O
.	O

This	O
means	O
that	O
workers	O
can	O
use	O
vector	O
/	O
host	O
combinations	O
that	O
yield	O
good	O
results	O
in	O
their	O
hands	O
,	O
and	O
an	O
increased	O
depth	O
of	O
multiplexing	O
can	O
easily	O
be	O
accomodated	O
by	O
synthesizing	O
more	O
primers	O
.	O

This	O
should	O
make	O
multiplexing	O
more	O
accessible	O
to	O
workers	O
undertaking	O
smaller	O
projects	O
.	O

A	O
theoretical	O
disadvantage	O
of	O
tagged	O
primers	O
is	O
that	O
the	O
procedure	O
can	O
only	O
be	O
multiplexed	O
following	O
primer	O
annealing	O
(	O
1	O
)	O
,	O
or	O
following	O
the	O
sequencing	O
reactions	O
(	O
this	O
paper	O
;	O
in	O
practice	O
,	O
pooling	O
immediately	O
after	O
the	O
annealing	O
step	O
might	O
lead	O
to	O
increased	O
backgrounds	O
if	O
one	O
or	O
more	O
primers	O
were	O
present	O
in	O
excess	O
over	O
their	O
template	O
DNAs	O
)	O
.	O

This	O
is	O
a	O
relatively	O
late	O
stage	O
.	O

In	O
the	O
original	O
procedure	O
(	O
3	O
)	O
,	O
clones	O
were	O
pooled	O
prior	O
to	O
amplification	O
by	O
growth	O
,	O
an	O
early	O
step	O
.	O

However	O
,	O
we	O
do	O
not	O
believe	O
the	O
sacrifice	O
to	O
be	O
of	O
practical	O
importance	O
when	O
using	O
phage	O
vectors	O
.	O

In	O
our	O
experience	O
,	O
recombinant	O
M13	O
phage	O
have	O
variable	O
growth	O
rates	O
and	O
the	O
effects	O
of	O
competition	O
are	O
likely	O
to	O
severely	O
limit	O
the	O
number	O
of	O
clones	O
that	O
can	O
usefully	O
be	O
pooled	O
for	O
growth	O
.	O

In	O
contrast	O
,	O
by	O
growing	O
clones	O
individually	O
,	O
the	O
depth	O
of	O
multiplexing	O
is	O
only	O
really	O
limited	O
by	O
probe	O
sensitivity	O
.	O

We	O
have	O
not	O
investigated	O
the	O
factors	O
influencing	O
variability	O
in	O
phage	O
growth	O
rates	O
.	O

It	O
is	O
worth	O
noting	O
that	O
reliable	O
protocols	O
have	O
been	O
developed	O
for	O
growing	O
large	O
numbers	O
of	O
individual	O
M13	O
clones	O
and	O
preparing	O
high	O
quality	O
ssDNA	O
templates	O
in	O
microtitre	O
trays	O
(	O
28	O
,	O
21	O
)	O
.	O

It	O
is	O
relatively	O
simple	O
to	O
prepare	O
manually	O
two	O
microtitre	O
trays	O
of	O
ssDNA	O
templates	O
(	O
192	O
clones	O
)	O
in	O
a	O
day	O
.	O

Sufficient	O
clones	O
can	O
be	O
prepared	O
in	O
a	O
week	O
to	O
sequence	O
a	O
20kb	O
fragment	O
to	O
a	O
redundancy	O
of	O
10	O
(	O
Victoria	O
Smith	O
,	O
personal	O
communication	O
)	O
.	O

In	O
this	O
laboratory	O
,	O
ssDNA	O
is	O
now	O
prepared	O
with	O
the	O
aid	O
of	O
a	O
commercially	O
available	O
robotic	O
workstation	O
(	O
21	O
)	O
.	O

As	O
sequencing	O
reactions	O
are	O
also	O
carried	O
out	O
in	O
microtitre	O
trays	O
,	O
manually	O
or	O
robotically	O
(	O
20	O
,	O
29	O
)	O
,	O
the	O
entire	O
M13	O
-	O
based	O
dideoxynucleotide	O
sequencing	O
procedure	O
is	O
amenable	O
to	O
automation	O
(	O
29	O
)	O
.	O

For	O
these	O
reasons	O
we	O
see	O
little	O
practical	O
advantage	O
in	O
pooling	O
clones	O
early	O
.	O

Finally	O
,	O
by	O
not	O
pooling	O
clones	O
early	O
,	O
the	O
ability	O
to	O
easily	O
retrieve	O
individual	O
clones	O
is	O
retained	O
,	O
which	O
may	O
facilitate	O
directed	O
sequencing	O
later	O
in	O
a	O
project	O
should	O
this	O
become	O
necessary	O
.	O

Multiplex	O
DNA	O
sequencing	O
is	O
currently	O
limited	O
by	O
the	O
lack	O
of	O
a	O
robust	O
computer	O
program	O
which	O
can	O
correct	O
for	O
the	O
large	O
variety	O
of	O
gel	O
and	O
sequencing	O
artefacts	O
that	O
are	O
normally	O
encountered	O
.	O

The	O
foundation	O
of	O
a	O
film	O
reading	O
program	O
is	O
the	O
ability	O
to	O
bring	O
into	O
register	O
precisely	O
vertical	O
arrays	O
of	O
base	O
-	O
specific	O
bands	O
.	O

This	O
requires	O
the	O
ability	O
to	O
track	O
lanes	O
,	O
correct	O
for	O
distortions	O
,	O
and	O
order	O
bands	O
based	O
on	O
their	O
relative	O
spacing	O
.	O

A	O
method	O
of	O
sequencing	O
which	O
has	O
successfully	O
overcome	O
the	O
problem	O
of	O
sequence	O
reading	O
uses	O
real	O
-	O
time	O
detection	O
of	O
fluorescently	O
labelled	O
DNA	O
samples	O
migrating	O
through	O
the	O
gel	O
(	O
2	O
)	O
.	O

This	O
system	O
also	O
utilizes	O
the	O
principle	O
of	O
running	O
the	O
four	O
base	O
reactions	O
down	O
the	O
same	O
lane	O
(	O
2	O
)	O
.	O

However	O
,	O
bands	O
are	O
detected	O
at	O
a	O
fixed	O
location	O

in	O
space	O
,	O
and	O
their	O
detection	O
is	O
separated	O
in	O
time	O
.	O

Hence	O
the	O

Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O
3305	O

problem	O
of	O
gel	O
distortion	O
is	O
essentially	O
avoided	O
,	O
although	O
corrections	O
for	O
the	O
different	O
mobilities	O
of	O
the	O
four	O
dyes	O
must	O
be	O
carried	O
out	O
.	O

In	O
contrast	O
,	O
we	O
utilize	O
the	O
advantages	O
of	O
single	O
lane	O
electrophoresis	O
to	O
address	O
the	O
problem	O
of	O
superimposing	O
four	O
relatively	O
large	O
and	O
complex	O
two	O
-	O
dimensional	O
images	O
.	O

Furthermore	O
,	O
by	O
using	O
sequence	O
-	O
tagged	O
oligonucleotides	O
which	O
are	O
detected	O
by	O
hybridization	O
,	O
a	O
much	O
greater	O
depth	O
of	O
multiplexing	O
can	O
realistically	O
be	O
achieved	O
than	O
by	O
real	O
-	O
time	O
detection	O
.	O

The	O
use	O
of	O
two	O
-	O
dimensional	O
colour	O
traces	O
to	O
depict	O
the	O
processed	O
output	O
of	O
a	O
film	O
reader	O
is	O
consistent	O
with	O
the	O
method	O
of	O
displaying	O
fluorescence	O
traces	O
,	O
and	O
should	O
facilitate	O
the	O
checking	O
and	O
editing	O
of	O
sequence	O
databases	O
in	O
which	O
both	O
kinds	O
of	O
data	O
have	O
been	O
entered	O
.	O

The	O
sequence	O
compilation	O
programs	O
used	O
in	O
this	O
laboratory	O
,	O
which	O
are	O
already	O
capable	O
of	O
handling	O
large	O
shotgun	O
databases	O
(	O
8	O
,	O
31	O
)	O
,	O
have	O
recently	O
undergone	O
extensive	O
improvements	O
(	O
Rodger	O
Staden	O
,	O
personal	O
communication	O
)	O
.	O

There	O
is	O
now	O
an	O
interactive	O
database	O
editor	O
which	O
allows	O
the	O
graphical	O
display	O
of	O
fluorescence	O
traces	O
,	O
and	O
it	O
is	O
envisaged	O
that	O
this	O
feature	O
could	O
be	O
extended	O
to	O
allow	O
the	O
handling	O
of	O
data	O
from	O
a	O
film	O
reader	O
when	O
a	O
suitable	O
machine	O
is	O
developed	O
.	O

ACKNOWLEDGEMENTS	O

I	O
am	O
particularly	O
grateful	O
to	O
George	O
Church	O
for	O
thought	O
-	O
provoking	O
discussions	O
and	O
gifts	O
of	O
vectors	O
and	O
oligonucleotide	O
probes	O
and	O
to	O
John	O
Sulston	O
for	O
advice	O
.	O

I	O
also	O
thank	O
Victoria	O
Smith	O
for	O
the	O
gift	O
of	O
DNA	O
samples	O
,	O
Bart	O
Barrell	O
for	O
long	O
-	O
term	O
support	O
,	O
Tom	O
O	O
'	O
Keefe	O
of	O
Milligen	O
/	O
Biosearch	O
for	O
lessons	O
in	O
multiplexing	O
and	O
Amersham	O
International	O
for	O
the	O
optical	O
density	O
overlays	O
shown	O
in	O
Figure	O
2	O
.	O

M	O
.	O
C	O
.	O

is	O
supported	O
by	O
a	O
fellowship	O
from	O
Applied	O
Biosystems	O
.	O

12	O
.	O

Hiratsuka	O
,	O
J	O
.	O
,	O
Shimada	O
,	O
H	O
.	O
,	O
Whittier	O
,	O
R	O
.	O
,	O
Ishibashi	O
,	O
T	O
.	O
,	O
Sakamoto	O
,	O
M	O
.	O
,	O
Mori	O
,	O

M	O
.	O
,	O
Kondo	O
,	O
C	O
.	O
,	O
Honju	O
,	O
Y	O
.	O
,	O
Sun	O
,	O
C	O
.	O

-	O
R	O
,	O
Meng	O
,	O
B	O
.	O

-	O
Y	O
,	O
Li	O
,	O
Y	O
.	O

-	O
Q	O
,	O
Kanno	O
,	O
A	O
.	O
,	O
Nisizawa	O
,	O
Y	O
.	O
,	O
Hirai	O
,	O
A	O
.	O
,	O
Shinozaki	O
,	O
K	O
.	O
and	O
Sugiura	O
,	O
M	O
.	O

(	O
1989	O
)	O
Molecular	O
and	O
General	O
Genetics	O
,	O
217	O
,	O
185	O
-	O
194	O
.	O

13	O
.	O

Komaromy	O
,	O
M	O
.	O
and	O
Govan	O
,	O
H	O
.	O

(	O
1984	O
)	O
Nucleic	O
Acids	O
Research	O
,	O
12	O
,	O
675	O
-	O
678	O
.	O

14	O
.	O

Staden	O
,	O
R	O
.	O

(	O
1984	O
)	O
Nucleic	O
Acids	O
Research	O
,	O
12	O
,	O
499	O
-	O
503	O
.	O

15	O
.	O

Elder	O
,	O
J	O
.	O

K	O
.	O
,	O
Green	O
,	O
D	O
.	O

K	O
.	O
and	O
Southern	O
,	O
E	O
.	O

M	O
.	O

(	O
1986	O
)	O
Nucleic	O
Acids	O

Research	O
,	O
14	O
,	O
417	O
-	O
424	O
.	O

16	O
.	O

Maxam	O
,	O
A	O
.	O

M	O
.	O
and	O
Gilbert	O
,	O
W	O
.	O

(	O
1977	O
)	O
Proceedings	O
of	O
the	O
National	O
Academy	O

of	O
Sciences	O
,	O
U	O
.	O
S	O
.	O
A	O
.	O
,	O
74	O
,	O
560	O
-	O
564	O
.	O

17	O
.	O

Sanger	O
,	O
F	O
.	O
,	O
Nicklen	O
,	O
S	O
.	O
and	O
Coulson	O
,	O
A	O
.	O

R	O
.	O

(	O
1977	O
)	O
Proceedings	O
of	O
the	O
National	O

Academy	O
of	O
Sciences	O
,	O
U	O
.	O
S	O
.	O
A	O
.	O
,	O
74	O
,	O
5463	O
-	O
5467	O
.	O

18	O
.	O

Sanger	O
,	O
F	O
.	O
,	O
Coulson	O
,	O
A	O
.	O

R	O
.	O
,	O
Barrell	O
,	O
B	O
.	O

G	O
.	O
,	O
Smith	O
,	O
A	O
.	O

J	O
.	O

H	O
.	O
and	O
Roe	O
,	O
B	O
.	O

A	O
.	O

(	O
1980	O
)	O
Journal	O
of	O
Molecular	O
Biology	O
,	O
143	O
,	O
161	O
-	O
178	O
.	O

19	O
.	O

Applied	O
Biosystems	O
User	O
Bulletin	O
(	O
1987	O
)	O
13	O
,	O
11	O
-	O
16	O
.	O

20	O
.	O

Bankier	O
,	O
A	O
.	O

T	O
.	O
,	O
Weston	O
,	O
K	O
.	O

M	O
.	O
and	O
Barrell	O
,	O
B	O
.	O

G	O
.	O

(	O
1987	O
)	O
Methods	O
in	O

Enzymology	O
,	O
155	O
,	O
51	O
-	O
93	O
.	O

21	O
.	O

Smith	O
,	O
V	O
.	O
,	O
Brown	O
,	O
C	O
.	O

M	O
.	O
,	O
Bankier	O
,	O
A	O
.	O

T	O
.	O
and	O
Barrell	O
,	O
B	O
.	O

G	O
.	O

(	O
1990	O
)	O
DNA	O

Sequence	O
,	O
1	O
,	O
73	O
-	O
78	O
.	O

22	O
.	O

Southern	O
,	O
E	O
.	O

M	O
.	O

(	O
1975	O
)	O
Journal	O
of	O
Molecular	O
Biology	O
,	O
98	O
,	O
503	O
-	O
517	O
.	O

23	O
.	O

Church	O
,	O
G	O
.	O

M	O
.	O
and	O
Gilbert	O
,	O
W	O
.	O

(	O
1984	O
)	O
Proceedings	O
of	O
the	O
National	O
Academy	O

of	O
Sciences	O
,	O
U	O
.	O
S	O
.	O
A	O
.	O
,	O
81	O
,	O
1991	O
-	O
1995	O
.	O

24	O
.	O

Beck	O
,	O
S	O
.	O
,	O
O	O
'	O
Keefe	O
,	O
T	O
.	O
,	O
Coull	O
,	O
J	O
.	O

M	O
.	O
and	O
Koster	O
,	O
H	O
.	O

(	O
1989	O
)	O
Nucleic	O
Acids	O

Research	O
,	O
17	O
,	O
5115	O
-	O
5123	O
.	O

25	O
.	O

Tizard	O
,	O
R	O
.	O
,	O
Cate	O
,	O
R	O
.	O

L	O
.	O
,	O
Ramachandran	O
,	O
K	O
.	O

L	O
.	O
,	O
Wysk	O
,	O
M	O
.	O
,	O
Voyta	O
,	O
J	O
.	O

C	O
.	O
,	O

Murphy	O
,	O
0	O
.	O

J	O
.	O
and	O
Bronstein	O
,	O
I	O
.	O

(	O
1990	O
)	O
Proceedings	O
of	O
the	O
National	O
Academy	O
of	O
Sciences	O
,	O
U	O
.	O
S	O
.	O
A	O
.	O
,	O
87	O
,	O
4514	O
-	O
4518	O
.	O

26	O
.	O

Beck	O
,	O
S	O
.	O
and	O
Koster	O
,	O
H	O
.	O

(	O
1990	O
)	O
Analytical	O
Chemistry	O
,	O
62	O
,	O
2558	O
-	O
2570	O
.	O

27	O
.	O

Jacobson	O
,	O
K	O
.	O

B	O
.	O
,	O
Arlinghaus	O
,	O
H	O
.	O

F	O
.	O
,	O
Schmitt	O
,	O
H	O
.	O

W	O
.	O
,	O
Sachleben	O
,	O
R	O
.	O

A	O
.	O
,	O

Brown	O
,	O
G	O
.	O

M	O
.	O
,	O
Thonnard	O
,	O
N	O
.	O
,	O
Sloop	O
,	O
F	O
.	O

V	O
.	O
,	O
Foote	O
,	O
R	O
.	O

S	O
.	O
,	O
Larimer	O
,	O
F	O
.	O

W	O
.	O
,	O
Woychik	O
,	O
R	O
.	O

P	O
.	O
,	O
England	O
,	O
M	O
.	O

W	O
.	O
,	O
Burchett	O
,	O
K	O
.	O

L	O
.	O
and	O
Jacobson	O
,	O
D	O
.	O

A	O
.	O

(	O
1991	O
)	O
Genomics	O
,	O
9	O
,	O
51	O
-	O
59	O
.	O

28	O
.	O

Eperon	O
,	O
I	O
.	O

C	O
.	O

(	O
1986	O
)	O
Analytical	O
Biochemistry	O
,	O
56	O
,	O
406	O
-	O
412	O
.	O

29	O
.	O

Bankier	O
,	O
A	O
.	O

T	O
.	O
and	O
Barrell	O
,	O
B	O
.	O

G	O
.	O

(	O
1989	O
)	O
In	O
Howe	O
,	O
C	O
.	O

J	O
.	O
and	O
Ward	O
,	O
E	O
.	O

S	O
.	O

(	O
ed	O
)	O
,	O
Nucleic	O
acids	O
sequencing	O
:	O
a	O
practical	O
approach	O
.	O

IRL	O
Press	O
,	O
Oxford	O
,	O
Vol	O
.	O

1	O
,	O
pp	O
.	O

37	O
-	O
78	O
.	O

30	O
.	O

Vieira	O
,	O
J	O
.	O
and	O
Messing	O
,	O
J	O
.	O

(	O
1987	O
)	O
Methods	O
in	O
Enzymology	O
,	O
153	O
,	O
3	O
-	O
11	O
.	O

31	O
.	O

Davison	O
,	O
A	O
.	O

DNA	O
Sequence	O
,	O
in	O
press	O
.	O

32	O
.	O

Heller	O
,	O
C	O
.	O
,	O
Radley	O
,	O
E	O
.	O
,	O
Khurshid	O
,	O
F	O
.	O

A	O
.	O
and	O
Beck	O
,	O
S	O
.	O

Gene	O
,	O
in	O
press	O
.	O

REFERENCES	O

1	O
.	O

Yang	O
,	O
M	O
.	O

M	O
.	O
and	O
Youvan	O
,	O
D	O
.	O

C	O
.	O

(	O
1989	O
)	O
Biotechnology	O
,	O
7	O
,	O
576	O
-	O
580	O
.	O

2	O
.	O

Smith	O
,	O
L	O
.	O

M	O
.	O
,	O
Sanders	O
,	O
J	O
.	O

Z	O
.	O
,	O
Kaiser	O
,	O
R	O
.	O

J	O
.	O
,	O
Hughes	O
,	O
P	O
.	O
,	O
Dodd	O
,	O
C	O
.	O
,	O
Connell	O
,	O

C	O
.	O

R	O
.	O
,	O
Heiner	O
,	O
C	O
.	O
,	O
Kent	O
,	O
S	O
.	O

B	O
.	O

H	O
.	O
and	O
Hood	O
,	O
L	O
.	O

E	O
.	O

(	O
1986	O
)	O
Nature	O
,	O
321	O
,	O
674	O
-	O
679	O
.	O

3	O
.	O

Church	O
,	O
G	O
.	O

M	O
.	O
and	O
Kieffer	O
-	O
Higgins	O
,	O
S	O
.	O

(	O
1988	O
)	O
Science	O
,	O
240	O
,	O
185	O
-	O
188	O
.	O

4	O
.	O

Watson	O
,	O
J	O
.	O

D	O
.	O

(	O
1990	O
)	O
Science	O
,	O
248	O
,	O
44	O
-	O
49	O
.	O

5	O
.	O

Baer	O
,	O
R	O
.	O
,	O
Bankier	O
,	O
A	O
.	O

T	O
.	O
,	O
Biggin	O
,	O
M	O
.	O

D	O
.	O
,	O
Deininger	O
,	O
P	O
.	O

L	O
.	O
,	O
Farrell	O
,	O
P	O
.	O

J	O
.	O
,	O

Gibson	O
,	O
T	O
.	O

J	O
.	O
,	O
Hatfull	O
,	O
G	O
.	O
,	O
Hudson	O
,	O
G	O
.	O

S	O
.	O
,	O
Satchwell	O
,	O
S	O
.	O

C	O
.	O
,	O
Seguin	O
,	O
C	O
.	O
,	O
Tuffnell	O
,	O
P	O
.	O

S	O
.	O
and	O
Barrell	O
,	O
B	O
.	O

G	O
.	O

(	O
1984	O
)	O
Nature	O
,	O
310	O
,	O
207	O
-	O
211	O
.	O

6	O
.	O

Davison	O
,	O
A	O
.	O

J	O
.	O
and	O
Scott	O
,	O
J	O
.	O

E	O
.	O

(	O
1986	O
)	O
Journal	O
of	O
General	O
Virology	O
,	O
67	O
,	O

1759	O
-	O
1816	O
.	O

7	O
.	O

McGeoch	O
,	O
D	O
.	O

J	O
.	O
,	O
Dalrymple	O
,	O
M	O
.	O

A	O
.	O
,	O
Davison	O
,	O
A	O
.	O

J	O
.	O
,	O
Dolan	O
,	O
A	O
.	O
,	O
Frame	O
,	O

M	O
.	O

C	O
.	O
,	O
McNab	O
,	O
D	O
.	O
,	O
Perry	O
,	O
L	O
.	O

J	O
.	O
,	O
Scott	O
,	O
J	O
.	O

E	O
.	O
and	O
Taylor	O
,	O
P	O
.	O

(	O
1988	O
)	O
Journal	O
of	O
General	O
Virology	O
,	O
69	O
,	O
1531	O
-	O
1574	O
.	O

8	O
.	O

Chee	O
,	O
M	O
.	O

S	O
.	O
,	O
Bankier	O
,	O
A	O
.	O

T	O
.	O
,	O
Beck	O
,	O
S	O
.	O
,	O
Bohni	O
,	O
R	O
.	O
,	O
Brown	O
,	O
C	O
.	O

M	O
.	O
,	O
Cerny	O
,	O

R	O
.	O
,	O
Horsnell	O
,	O
T	O
.	O
,	O
Hutchison	O
III	O
,	O
C	O
.	O

A	O
.	O
,	O
Kouzarides	O
,	O
T	O
.	O
,	O
Martignetti	O
,	O
J	O
.	O

A	O
.	O
,	O
Satchwell	O
,	O
S	O
.	O

C	O
.	O
,	O
Tomlinson	O
,	O
P	O
.	O
,	O
Weston	O
,	O
K	O
.	O

M	O
.	O
and	O
Barrell	O
,	O
B	O
.	O

G	O
.	O

(	O
1990	O
)	O
Current	O
Topics	O
in	O
Microbiology	O
and	O
Immunology	O
,	O
154	O
,	O
125	O
-	O
169	O
.	O

9	O
.	O

Goebel	O
,	O
S	O
.	O

J	O
.	O
,	O
Johnson	O
,	O
G	O
.	O

P	O
.	O
,	O
Perkus	O
,	O
M	O
.	O

E	O
.	O
,	O
Davis	O
,	O
S	O
.	O

W	O
.	O
,	O
Winslow	O
,	O
J	O
.	O

P	O
.	O
and	O
Paoletti	O
,	O
E	O
.	O

(	O
1990	O
)	O
Virology	O
,	O
179	O
,	O
247	O
-	O
266	O
.	O

10	O
.	O

Ohyama	O
,	O
K	O
.	O
,	O
Fukuzawa	O
,	O
H	O
.	O
,	O
Kohchi	O
,	O
T	O
.	O
,	O
Shirai	O
,	O
H	O
.	O
,	O
Sano	O
,	O
T	O
.	O
,	O
Sano	O
,	O
S	O
.	O
,	O

Umesono	O
,	O
K	O
.	O
,	O
Shiki	O
,	O
Y	O
.	O
,	O
Takeuchi	O
,	O
M	O
.	O
,	O
Chang	O
,	O
Z	O
.	O
,	O
Aota	O
,	O
S	O
.	O

-	O
I	O
,	O
Inokuchi	O
,	O
H	O
.	O
and	O
Ozeki	O
,	O
H	O
.	O

(	O
1986	O
)	O
Nature	O
,	O
322	O
,	O
572	O
-	O
574	O
.	O

11	O
.	O

Shinozaki	O
,	O
K	O
.	O
,	O
Ohme	O
,	O
M	O
.	O
,	O
Tanaka	O
,	O
M	O
.	O
,	O
Wakasugi	O
,	O
T	O
.	O
,	O
Hayashida	O
,	O
N	O
.	O
,	O

Matsubayashi	O
,	O
T	O
.	O
,	O
Zaita	O
,	O
N	O
.	O
,	O
Chunwongse	O
,	O
J	O
.	O
,	O
Obokata	O
,	O
J	O
.	O
,	O
YamaguchiShinozaki	O
,	O
K	O
.	O
,	O
Ohto	O
,	O
C	O
.	O
,	O
Torazawa	O
,	O
K	O
.	O
,	O
Meng	O
,	O
B	O
.	O

Y	O
.	O
,	O
Sugita	O
,	O
M	O
.	O
,	O
Deno	O
,	O
H	O
.	O
,	O
Kamogashira	O
,	O
T	O
.	O
,	O
Yamada	O
,	O
K	O
.	O
,	O
Kusuda	O
,	O
J	O
.	O
,	O
Takaiwa	O
,	O
F	O
.	O
,	O
Kato	O
,	O
A	O
.	O
,	O
Tohdoh	O
,	O
N	O
.	O
,	O
Shimada	O
,	O
H	O
.	O
and	O
Sugiura	O
,	O
M	O
.	O

(	O
1986	O
)	O
EMBO	O
Journal	O
,	O
5	O
,	O
2043	O
-	O
2049	O
.	O

Mapping	O
irradiation	O
hybrids	O
to	O
cosmid	O
and	O
yeast	B
artificial	O
chromosome	O
libraries	O
by	O
direct	O
hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
.	O

Abstract	O

A	O
direct	O
hybridization	O
protocol	O
is	O
described	O
for	O
screening	O
cosmid	O
and	O
yeast	B
artificial	O
chromosome	O
libraries	O
with	O
pools	O
of	O
Alu	O
-	O
PCR	O
products	O
from	O
somatic	O
cell	O
or	O
irradiation	O
hybrids	O
.	O

This	O
method	O
eliminates	O
purification	O
,	O
cloning	O
and	O
analysis	O
of	O
each	O
individual	O
Alu	O
-	O
PCR	O
product	O
before	O
library	O
screening	O
.	O

A	O
series	O
of	O
human	B
X	O
chromosome	O
irradiation	O
hybrids	O
were	O
mapped	O
by	O
this	O
method	O
,	O
using	O
a	O
cosmid	O
reference	O
library	O
for	O
comparisons	O
between	O
overlapping	O
hybrids	O
to	O
identify	O
interesting	O
clones	O
for	O
further	O
analysis	O
.	O
Images	O

Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O
3315	O

Mapping	O
irradiation	O
hybrids	O
to	O
cosmid	O
and	O
yeast	B
artificial	O
chromosome	O
libraries	O
by	O
direct	O
hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O

Anthony	O
P	O
.	O
Monaco	O
*	O
,	O
Veronica	O
M	O
.	O
S	O
.	O
Lam2	O
,	O
Gunther	O
Zehetner	O
,	O
Gregory	O
G	O
.	O
Lennon	O
,	O
Christal	O
Douglas	O
,	O
Dean	O
Nizetic	O
,	O
Peter	O
N	O
.	O
Goodfellow1	O
and	O
Hans	O
Lehrach	O

Genome	O
Analysis	O
Laboratory	O
and	O
'	O
Molecular	O
Human	O
Genetics	O
Laboratory	O
,	O
Imperial	O
Cancer	O
Research	O
Fund	O
,	O
44	O
Lincoln	O
'	O
s	O
Inn	O
Fields	O
,	O
London	O
WC2A	O
3PX	O
,	O
UK	O
and	O
2Department	O
of	O
Biochemistry	O
,	O
Li	O
Shu	O
Fan	O
Building	O
,	O
Sassoon	O
Road	O
,	O
University	O
of	O
Hong	O
Kong	O
,	O
Hong	O
Kong	O

Received	O
March	O
12	O
,	O
1991	O
;	O
Revised	O
and	O
Accepted	O
May	O
16	O
,	O
1991	O

ABSTRACT	O

A	O
direct	O
hybridization	O
protocol	O
is	O
described	O
for	O
screening	O
cosmid	O
and	O
yeast	B
artificial	O
chromosome	O
libraries	O
with	O
pools	O
of	O
Alu	O
-	O
PCR	O
products	O
from	O
somatic	O
cell	O
or	O
irradiation	O
hybrids	O
.	O

This	O
method	O
eliminates	O
purification	O
,	O
cloning	O
and	O
analysis	O
of	O
each	O
individual	O
AluPCR	O
product	O
before	O
library	O
screening	O
.	O

A	O
series	O
of	O
human	B
X	O
chromosome	O
irradiation	O
hybrids	O
were	O
mapped	O
by	O
this	O
method	O
,	O
using	O
a	O
cosmid	O
reference	O
library	O
for	O
comparisons	O
between	O
overlapping	O
hybrids	O
to	O
identify	O
interesting	O
clones	O
for	O
further	O
analysis	O
.	O

INTRODUCTION	O

The	O
generation	O
of	O
human	B
DNA	O
probes	O
specific	O
for	O
individual	O
chromosomes	O
and	O
subregions	O
of	O
chromosomes	O
has	O
been	O
advanced	O
with	O
Alu	O
-	O
sequence	O
primed	O
polymerase	O
chain	O
reaction	O
amplification	O
(	O
Alu	O
-	O
PCR	O
,	O
1	O
-	O
3	O
)	O
.	O

This	O
method	O
specifically	O
amplifies	O
sequences	O
between	O
Alu	O
repeats	O
from	O
human	B
DNA	O
in	O
somatic	O
cell	O
hybrids	O
and	O
yeast	B
artificial	O
chromosomes	O
(	O
YACs	O
,	O
4	O
)	O
.	O

Individual	O
Alu	O
-	O
PCR	O
products	O
can	O
be	O
purified	O
from	O
agarose	O
gels	O
or	O
ligated	O
into	O
plasmid	O
vectors	O
to	O
screen	O
for	O
single	O
copy	O
sequences	O
.	O

Unique	O
Alu	O
-	O
PCR	O
products	O
are	O
then	O
localized	O
to	O
certain	O
chromosome	O
regions	O
using	O
DNA	O
blots	O
of	O
somatic	O
cell	O
hybrid	O
panels	O
.	O

Once	O
localized	O
,	O
Alu	O
-	O
PCR	O
fragments	O
can	O
be	O
screened	O
against	O
genomic	O
libraries	O
to	O
isolate	O
longer	O
DNA	O
fragments	O
from	O
the	O
region	O
of	O
interest	O
.	O

As	O
an	O
alternative	O
to	O
this	O
multistep	O
process	O
we	O
have	O
developed	O
a	O
hybridization	O
protocol	O
for	O
screening	O
of	O
cosmid	O
and	O
YAC	O
libraries	O
directly	O
with	O
pools	O
of	O
Alu	O
-	O
PCR	O
products	O
.	O

Two	O
new	O
human	B
specific	O
Alu	O
primers	O
were	O
used	O
to	O
generate	O
DNA	O
probes	O
from	O
a	O
series	O
of	O
irradiation	O
-	O
reduced	O
hybrids	O
containing	O
multiple	O
human	B
X	O
chromosome	O
fragments	O
of	O
1	O
-	O
2000	O
kb	O
on	O
a	O
hamster	O
chromosome	O
background	O
(	O
5	O
;	O
P	O
.	O
N	O
.	O
G	O
.	O
,	O
unpublished	O
)	O
.	O

The	O
Alu	O
-	O
PCR	O
products	O
were	O
hybridized	O
as	O
a	O
pool	O
of	O
probes	O
to	O
X	O
-	O
specific	O
cosmid	O
and	O
YAC	O
libraries	O
,	O
after	O

competitive	O
reassociation	O
with	O
an	O
excess	O
of	O
human	B
DNA	O
to	O
both	O
the	O
library	O
filters	O
and	O
radioactively	O
labelled	O
Alu	O
-	O
PCR	O
products	O
.	O

Comparisons	O
were	O
made	O
between	O
clones	O
identified	O
by	O
overlapping	O
irradiation	O
hybrids	O
and	O
single	O
copy	O
DNA	O
probes	O
hybridized	O
to	O
the	O
cosmid	O
and	O
YAC	O
libraries	O
.	O

METHODS	O

Two	O
human	B
Alu	O
sequence	O
primers	O
were	O
generated	O
which	O
were	O
shown	O
to	O
be	O
human	B
specific	O
;	O
3144	O
from	O
the	O
3	O
'	O
end	O
of	O
Alu	O
:	O
5	O
'	O
-	O
GAGCGAGACTCCGTCTCAAA	O
-	O
3	O
'	O
and	O
2729	O
from	O
the	O
5	O
'	O
end	O
of	O
Alu	O
:	O
5	O
'	O
-	O
GTGGATCACCTGAGGTCAGG	O
-	O
3	O
'	O
.	O

All	O
PCR	O
reactions	O
were	O
carried	O
out	O
with	O
100	O
ng	O
of	O
hybrid	O
DNA	O
and	O
0	O
.	O
7	O
,	O
^	O
g	O
of	O
a	O
single	O
Alu	O
primer	O
in	O
100	O
d41	O
of	O
0	O
.	O
01	O
M	O
Tris	O
-	O
HCl	O
pH	O
8	O
.	O
3	O
,	O
0	O
.	O
0015	O
M	O
MgCl2	O
,	O
0	O
.	O
05	O
M	O
KCI	O
,	O
200	O
AtM	O
each	O
of	O
dNTPs	O
,	O
10	O
%	O
dimethlysulfoxide	O
,	O
and	O
2	O
.	O
5	O
units	O
of	O
Cetus	O
Taq	O
polymerase	O
.	O

Reactions	O
were	O
30	O
cycles	O
of	O
94	O
?	O
C	O
for	O
2	O
min	O
,	O
57	O
?	O
C	O
for	O
2	O
min	O
,	O
and	O
74	O
?	O
C	O
for	O
4	O
min	O
followed	O
by	O
a	O
final	O
extension	O
time	O
at	O
74	O
?	O
C	O
for	O
9	O
min	O
.	O

Reactions	O
products	O
were	O
analyzed	O
on	O
1	O
%	O
agarose	O
gels	O
and	O
shown	O
to	O
contain	O
between	O
five	O
and	O
twenty	O
fragments	O
,	O
with	O
sizes	O
ranging	O
from	O
0	O
.	O
1	O
to	O
2	O
.	O
0	O
kb	O
.	O

Chinese	B
hamster	I
DNA	O
and	O
no	O
DNA	O
PCR	O
reactions	O
were	O
done	O
to	O
control	O
for	O
non	O
-	O
human	B
products	O
(	O
data	O
not	O
shown	O
)	O
.	O

Alu	O
-	O
PCR	O
products	O
were	O
separated	O
from	O
Alu	O
oligomers	O
over	O
Qiagen	O
columns	O
,	O
and	O
approximately	O
50	O
-	O
100	O
ng	O
were	O
labelled	O
by	O
random	O
hexamer	O
priming	O
(	O
6	O
)	O
.	O

The	O
radioactively	O
labelled	O
pool	O
of	O
fragments	O
was	O
prehybridized	O
with	O
37	O
.	O
5	O
,	O
^	O
g	O
of	O
total	O
human	B
DNA	O
and	O
12	O
.	O
5	O
tsg	O
of	O
hamster	O
DNA	O
immobilized	O
on	O
a	O
cellulose	O
support	O
matrix	O
,	O
prepared	O
as	O
previously	O
described	O
(	O
7	O
)	O
.	O

Reactions	O
were	O
at	O
65	O
?	O
C	O
in	O
1	O
ml	O
of	O
0	O
.	O
75M	O
NaCl	O
,	O
0	O
.	O
05M	O
sodium	O
phosphate	O
pH	O
7	O
.	O
2	O
,	O
0	O
.	O
005M	O
EDTA	O
,	O
0	O
.	O
1	O
%	O
sodium	O
dodecyl	O
sulphate	O
(	O
SDS	O
)	O
,	O
0	O
.	O
5	O
mg	O
/	O
ml	O
heparin	O
,	O
and	O
100	O
jig	O
/	O
ml	O
denatured	O
salmon	O
sperm	O
DNA	O
.	O

The	O
cellulose	O
was	O
pelleted	O
and	O
the	O
supernatant	O
boiled	O
for	O
2	O
min	O
every	O
12	O
-	O
16	O
hours	O
(	O
three	O
times	O
in	O
two	O
days	O
)	O
.	O

Cosmid	O
and	O
YAC	O
library	O
filters	O
(	O
Hybond	O
N	O
+	O
,	O
Amersham	O
)	O
were	O
prehybridized	O
at	O
42	O
?	O
C	O
for	O
16	O
hours	O
with	O
100	O
jig	O
/	O
ml	O

*	O
To	O
whom	O
correspondence	O
should	O
be	O
addressed	O
at	O
Human	O
Genetics	O
Laboratory	O
,	O
Imperial	O
Cancer	O
Research	O
Fund	O
,	O
Institute	O
of	O
Molecular	O
Medicine	O
,	O
John	O
Radcliffe	O
Hospital	O
,	O
Headington	O
,	O
Oxford	O
OX3	O
9DU	O
,	O
UK	O

1991	O
Oxford	O
University	O
Press	O

3316	O
Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O

Chromosome	O
X	O

.	O
,	O
.	O
.	O
,	O
.	O
,	O
<	O

_	O
.	O
,	O
.	O

<	O
.	O
,	O

*	O
2	O
.	O
'	O
1	O
-	O
7	O
-	O
_	O

_	O
-	O
_	O
1	O
.	O

J	O

,	O
.	O
1	O
.	O
.	O

-	O
1	O
,	O
_	O
i	O
-	O
_	O
1	O
.	O

1	O

1	O
'	O
4	O
-	O
-	O
1	O
+	O

1	O
1	O
L	O
L	O
.	O

i	O

.	O
1	O
.	O

_	O
1	O

1	O
1	O
s	O
.	O

1	O
i	O

1	O
i	O
;	O
.	O

-	O
-	O
r	O
'	O
F	O
1	O
-	O

1	O
-	O
1	O
-	O
l	O

j	O
i	O
-	O
_	O
1	O
.	O

1	O

-	O
_	O
1	O
.	O
.	O

s	O
-	O
S	O
.	O

i	O
n	O
-	O
.	O

.	O
.	O

:	O
,	O
1	O
'	O
,	O
.	O

-	O
1	O
_	O
E	O
I	O
i	O
?	O

,	O
.	O

.	O
_	O
_	O
_	O

G	O
-	O

.	O

*	O
.	O
-	O
.	O
,	O
.	O
,	O
z	O

_	O

_	O
,	O

z	O
;	O
-	O
[	O
X1	O

21	O
,	O
In	O

27	O
38	O
45	O
48	O
54	O
74	O
86	O

I	O
1	O
I	O

I	O

I	O

107	O

MD	O

I	O

:	O
I	O
I	O

I	O
I	O

I	O
I	O

Figur	O
2a	O
and	O
2b	O
:	O
Hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
generated	O
with	O
Alu	O
primer	O
3144	O
from	O
irradiation	O
hybrid	O
48	O
to	O
duplicate	O
copies	O
of	O
22	O
x22cm	O
filters	O
containing	O
9216	O
human	B
X	O
chromosome	O
cosmids	O
(	O
8	O
)	O
.	O

2c	O
:	O
Hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
generated	O
with	O
Alu	O
primer	O
3144	O
from	O
an	O
independent	O
hybrid	O
(	O
54	O
)	O
to	O
a	O
third	O
identical	O
cosmid	O
filter	O
.	O

Figure	O
1	O
:	O
A	O
schematic	O
diagram	O
of	O
the	O
human	B
X	O
chromosome	O
alongside	O
the	O
approximate	O
cytogenetic	O
location	O
of	O
fragments	O
identified	O
in	O
nine	O
irradiation	O
hybrids	O
(	O
numbers	O
across	O
the	O
top	O
)	O
.	O

The	O
human	B
X	O
fragments	O
were	O
identified	O
by	O
hybridization	O
of	O
27	O
known	O
DNA	O
markers	O
(	O
indicated	O
by	O
a	O
black	O
line	O
;	O
P	O
.	O
N	O
.	O
G	O
,	O
unpublished	O
)	O
or	O
by	O
cosmids	O
in	O
common	O
with	O
unique	O
X	O
chromosome	O
probes	O
in	O
the	O
reference	O
library	O
database	O
(	O
open	O
boxes	O
and	O
Table	O
1	O
)	O
.	O

The	O
size	O
of	O
the	O
lines	O
and	O
boxes	O
relate	O
to	O
the	O
best	O
cytogenetic	O
location	O
of	O
the	O
probes	O
used	O
according	O
to	O
Human	O
Gene	O
Mapping	O
10	O
.	O
5	O
(	O
14	O
)	O
and	O
does	O
not	O
indicate	O
the	O
physical	O
extent	O
of	O
the	O
irradiation	O
hybrid	O
fragments	O
.	O

denatured	O
and	O
sheared	O
total	O
human	B
DNA	O
in	O
50	O
%	O
formamide	O
,	O
4XSSC	O
,	O
0	O
.	O
05	O
M	O
sodium	O
phosphate	O
pH	O
7	O
.	O
2	O
,	O
0	O
.	O
001	O
M	O
EDTA	O
,	O
10	O
%	O
dextran	O
sulphate	O
,	O
1	O
.	O
0	O
%	O
SDS	O
,	O
50	O
isg	O
/	O
ml	O
denatured	O
salmon	O
sperm	O
DNA	O
and	O
OxDenhardt	O
'	O
s	O
solution	O
.	O

The	O
radioactively	O
labelled	O
Alu	O
-	O
PCR	O
products	O
were	O
denatured	O
and	O
added	O
to	O
fresh	O

hybridization	O
solution	O
without	O
human	B
DNA	O
competitor	O
at	O
1	O
x	O
106	O

cpm	O
/	O
ml	O
and	O
hybridized	O
at	O
42	O
?	O
C	O
for	O
16	O
hours	O
.	O

Filters	O
were	O
washed	O
in	O
0	O
.	O
1	O
xSSC	O
and	O
1	O
.	O
0	O
%	O
SDS	O
,	O
twice	O
at	O
room	O
temperature	O
and	O
twice	O
at	O
65	O
?	O
C	O
for	O
30	O
min	O
each	O
and	O
exposed	O
to	O
Kodak	O
X	O
-	O
OMAT	O
film	O
for	O
2	O
-	O
3	O
days	O
at	O
-	O
70	O
?	O
C	O
with	O
an	O
intensifying	O
screen	O
.	O

For	O
each	O
hybridization	O
,	O
two	O
sets	O
of	O
duplicate	O
cosmid	O
filters	O
were	O
used	O
from	O
the	O
ICRF	O
reference	O
library	O
system	O
(	O
8	O
)	O
,	O
each	O
containing	O
9216	O
flow	O
-	O
sorted	O
human	B
X	O
chromosome	O
cosmid	O
clones	O
or	O
approximately	O
2	O
chromosome	O
equivalents	O
on	O
a	O
22	O
x	O
22	O
cm	O
filter	O
(	O
9	O
)	O
.	O

The	O
coordinates	O
of	O
signals	O
positive	O
on	O
duplicate	O
cosmid	O
filters	O
were	O
entered	O
into	O
the	O
reference	O
library	O
database	O
(	O
G	O
.	O
Z	O
,	O
unpublished	O
)	O
using	O
a	O
digitizing	O
tablet	O
.	O

For	O
the	O
X	O
chromosome	O
specific	O
YAC	O
library	O
(	O
A	O
.	O
P	O
.	O
M	O
.	O
and	O
H	O
.	O
L	O
.	O
,	O
unpublished	O
)	O
,	O
about	O
420	O
YAC	O
colonies	O
were	O
spotted	O
manually	O
onto	O
filters	O
from	O
96	O
well	O
microtiter	O
dishes	O
using	O
a	O
96	O
prong	O
device	O
.	O

After	O
growth	O
on	O
selective	O
media	O
for	O
3	O
days	O
,	O
YAC	O
filters	O
were	O
processed	O
for	O
hybridization	O
as	O
previously	O
described	O
(	O
10	O
)	O
.	O

RESULTS	O

A	O
panel	O
of	O
195	O
X	O
chromosome	O
irradiation	O
hybrids	O
was	O
constructed	O
(	O
50	O
,	O
000	O
rads	O
)	O
and	O
characterized	O
by	O
DNA	O
hybridization	O
using	O
27	O
X	O
chromosome	O
markers	O
and	O
flourescence	O
in	O
situ	O
hybridization	O
using	O
total	O
human	B
DNA	O
as	O
probe	O
(	O
Benham	O
et	O
al	O
.	O
,	O
1989	O
;	O
P	O
.	O
N	O
.	O
G	O
.	O
,	O
unpublished	O
)	O
.	O

This	O
analysis	O
indicated	O
that	O
the	O
hybrids	O
contained	O
multiple	O
small	O
fragments	O
(	O
4	O
-	O
10	O
fragments	O
of	O
1000	O
-	O
5000	O
kb	O
each	O
)	O
with	O
a	O
preferential	O
retaining	O
of	O
centromere	O
sequences	O
(	O
90	O
%	O
)	O
.	O

From	O
this	O
panel	O
,	O
nine	O
irradiation	O
hybrids	O
were	O
chosen	O
that	O
contained	O
less	O
than	O
five	O
different	O
regions	O
by	O
DNA	O
probe	O
hybridizations	O
,	O
mostly	O
from	O
the	O
short	O
arm	O
of	O
the	O
X	O
chromosome	O
(	O
Fig	O
1	O
)	O
.	O

All	O
nine	O
hybrids	O
were	O
used	O
in	O
PCR	O
reactions	O
with	O
3	O
'	O
-	O
Alu	O
primer	O
3144	O
and	O
two	O
were	O
used	O
with	O
5	O
'	O
-	O
Alu	O

Figure	O
3	O
:	O
Hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
generated	O
with	O
Alu	O
primer	O
3144	O
from	O
irradiation	O
hybrid	O
54	O
to	O
a	O
filter	O
containing	O
420	O
YAC	O
clones	O
from	O
the	O
human	B
X	O
chromosome	O
.	O

The	O
positive	O
YAC	O
was	O
also	O
identified	O
in	O
a	O
separate	O
hybridization	O
with	O
the	O
DMD	O
probe	O
P20	O
(	O
12	O
)	O
.	O

primer	O
2729	O
.	O

Example	O
hybridizations	O
to	O
a	O
human	B
X	O
chromosome	O
cosmid	O
filter	O
in	O
Fig	O
2	O
shows	O
the	O
intensity	O
and	O
reliability	O
of	O
positive	O
clones	O
identified	O
on	O
duplicate	O
filters	O
with	O
Alu	O
-	O
PCR	O
products	O
from	O
the	O
same	O
irradiation	O
hybrid	O
(	O
48	O
)	O
and	O
the	O
independence	O
of	O
clones	O
identified	O
with	O
Alu	O
-	O
PCR	O
products	O
from	O
a	O
different	O
hybrid	O
(	O
54	O
)	O
.	O

Fig	O
3	O
shows	O
a	O
single	O
positive	O
YAC	O
clone	O
after	O
hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
from	O
irradiation	O
hybrid	O
54	O
to	O
a	O
filter	O
containing	O
about	O
420	O
YAC	O
clones	O
specific	O
for	O
the	O
human	B
X	O
chromosome	O
.	O

The	O
total	O
number	O
of	O
cosmids	O
identified	O
with	O
each	O
pool	O
of	O
AluPCR	O
products	O
for	O
each	O
hybrid	O
is	O
shown	O
in	O
Table	O
1	O
.	O

From	O
the	O
average	O
number	O
of	O
cosmids	O
identified	O
(	O
24	O
)	O
in	O
four	O
chromosome	O
equivalents	O
screened	O
and	O
the	O
estimated	O
average	O
DNA	O
content	O
in	O
each	O
hybrid	O
(	O
3000	O
-	O
15000	O
kb	O
)	O
,	O
the	O
Alu	O
-	O
PCR	O
products	O
generated	O
by	O
a	O
single	O
primer	O
were	O
calculated	O
on	O
average	O
to	O
be	O
300	O
-	O
1500	O
kb	O
apart	O
,	O
similar	O
to	O
published	O
estimates	O
for	O
this	O
method	O
(	O
1	O
,	O
2	O
)	O
.	O

Only	O
3	O
-	O
4	O
cosmids	O
were	O
identified	O
in	O
common	O
using	O
Alu	O
-	O
PCR	O
products	O
generated	O
with	O
either	O
3	O
'	O
or	O
5	O
'	O
Alu	O
primers	O
(	O
3144	O
or	O
2729	O
)	O
from	O
two	O
hybrids	O
(	O
38	O
and	O
45	O
)	O
.	O

This	O
shows	O
that	O
separate	O
products	O
were	O
amplified	O
with	O
the	O
two	O
Alu	O
primers	O
since	O
they	O
prime	O
synthesis	O
from	O
opposite	O
ends	O
of	O
the	O
Alu	O
consensus	O
sequence	O
and	O
Alu	O
sequences	O
are	O
oriented	O
in	O
the	O
genome	O
either	O
head	O
to	O
head	O
,	O

A	O

B	O

C	O

El	O

I0	O

Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O
3317	O

Table	O
1	O
.	O

Cosmids	O
identified	O
by	O
hybrids	O
and	O
unique	O
probes	O

hybrids	O
21	O
27	O
38	O
38	O
45	O
45	O
48	O
54	O
74	O
86	O
107	O
unique	O

primer	O
3144	O
3144	O
3144	O
2729	O
3144	O
2729	O
3144	O
3144	O
3144	O
33144	O
3144	O
probes	O

21	O
3144	O
59	O
1	O
27	O
3144	O
7	O
14	O
2	O
38	O
3144	O
3	O
1	O
28	O
2	O
38	O
2729	O
0	O
0	O
4	O
25	O
0	O
45	O
3144	O
13	O
2	O
2	O
0	O
32	O
3	O
45	O
2729	O
1	O
0	O
0	O
0	O
3	O
31	O
0	O
48	O
3144	O
10	O
2	O
4	O
0	O
2	O
0	O
28	O
3	O
54	O
3144	O
11	O
3	O
0	O
0	O
5	O
0	O
5	O
30	O
2	O
74	O
3144	O
5	O
0	O
0	O
0	O
4	O
0	O
5	O
12	O
20	O
3	O
86	O
3144	O
3	O
1	O
0	O
0	O
4	O
1	O
3	O
4	O
3	O
17	O
0	O
107	O
3144	O
1	O
0	O
1	O
1	O
0	O
0	O
3	O
0	O
0	O
0	O
13	O
0	O

tail	O
to	O
tail	O
or	O
head	O
to	O
tail	O
relative	O
to	O
each	O
other	O
.	O

Therefore	O
,	O
by	O
using	O
the	O
3	O
'	O
-	O
and	O
5	O
'	O
-	O
Alu	O
primers	O
in	O
separate	O
PCR	O
reactions	O
with	O
the	O
same	O
hybrid	O
DNA	O
,	O
the	O
total	O
number	O
of	O
products	O
and	O
cosmid	O
clones	O
identified	O
was	O
almost	O
doubled	O
.	O

Table	O
1	O
also	O
indicates	O
how	O
many	O
cosmids	O
were	O
identified	O
by	O
Alu	O
-	O
PCR	O
products	O
from	O
other	O
hybrids	O
,	O
and	O
16	O
cosmids	O
previously	O
identified	O
with	O
unique	O
DNA	O
probes	O
in	O
the	O
reference	O
library	O
database	O
.	O

As	O
can	O
be	O
seen	O
in	O
Fig	O
1	O
and	O
previous	O
irradiation	O
hybrid	O
analysis	O
,	O
there	O
is	O
a	O
preferential	O
retention	O
of	O
centromere	O
sequences	O
(	O
2	O
,	O
11	O
)	O
.	O

However	O
,	O
there	O
were	O
no	O
cosmids	O
identified	O
in	O
common	O
from	O
all	O
the	O
hybrids	O
positive	O
with	O
centromere	O
sequences	O
.	O

This	O
is	O
probably	O
due	O
to	O
a	O
paucity	O
of	O
Alu	O
repeats	O
in	O
the	O
correct	O
orientation	O
in	O
alphoid	O
centromere	O
sequences	O
and	O
thus	O
few	O
or	O
no	O
Alu	O
-	O
PCR	O
products	O
would	O
be	O
amplified	O
from	O
the	O
centromere	O
.	O

Cosmids	O
identified	O
in	O
common	O
by	O
several	O
irradiation	O
hybrids	O
(	O
Table	O
1	O
)	O
were	O
most	O
likely	O
from	O
regions	O
of	O
overlap	O
outside	O
the	O
centromere	O
area	O
as	O
shown	O
by	O
the	O
previous	O
DNA	O
probe	O
characterization	O
(	O
Fig	O
1	O
)	O
.	O

The	O
overlap	O
regions	O
between	O
hybrids	O
were	O
also	O
seen	O
by	O
16	O
cosmids	O
(	O
Table	O
1	O
,	O
Fig	O
1	O
)	O
that	O
were	O
hybridization	O
targets	O
of	O
unique	O
DNA	O
markers	O
in	O
the	O
reference	O
library	O
database	O
that	O
mapped	O
in	O
independent	O
experiments	O
to	O
the	O
overlap	O
region	O
.	O

At	O
least	O
for	O
several	O
cosmids	O
this	O
showed	O
that	O
the	O
Alu	O
-	O
PCR	O
products	O
identified	O
target	O
cosmids	O
that	O
were	O
definitely	O
from	O
the	O
expected	O
region	O
contained	O
in	O
the	O
hybrids	O
.	O

For	O
example	O
,	O
hybrids	O
21	O
and	O
54	O
were	O
both	O
shown	O
to	O
contain	O
part	O
of	O
the	O
Duchenne	O
muscular	O
dystrophy	O
(	O
DMD	O
)	O
locus	O
(	O
Fig	O
1	O
;	O
P	O
.	O
N	O
.	O
G	O
.	O
,	O
unpublished	O
)	O
and	O
had	O
11	O
cosmids	O
in	O
common	O
,	O
including	O
one	O
identified	O
by	O
the	O
probe	O
P20	O
from	O
the	O
deletion	O
hotspot	O
region	O
of	O
the	O
DMD	O
gene	O
(	O
12	O
)	O
.	O

In	O
Fig	O
3	O
the	O
hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
from	O
hybrid	O
54	O
identified	O
a	O
YAC	O
clone	O
which	O
was	O
also	O
positive	O
for	O
the	O
DMD	O
probe	O
P20	O
(	O
data	O
not	O
shown	O
)	O
.	O

This	O
method	O
also	O
identified	O
fragments	O
in	O
the	O
hybrids	O
that	O
were	O
not	O
seen	O
in	O
the	O
initial	O
DNA	O
characterization	O
(	O
Fig	O
1	O
and	O
Table	O
1	O
)	O
.	O

Since	O
the	O
27	O
DNA	O
probes	O
were	O
not	O
close	O
enough	O
to	O
each	O
other	O
along	O
the	O
chromosome	O
to	O
detect	O
all	O
possible	O
hybrid	O
fragments	O
(	O
1000	O
-	O
5000	O
kb	O
)	O
,	O
many	O
regions	O
would	O
have	O
been	O
untested	O
.	O

For	O
example	O
,	O
AluPCR	O
products	O
from	O
hybrids	O
45	O
and	O
48	O
identified	O
several	O
cosmids	O
,	O
also	O
seen	O
by	O
the	O
cDNA	O
for	O
chronic	O
granulomatous	O
disease	O
gene	O
(	O
CYBB	O
,	O
13	O
)	O
in	O
Xp2	O
1	O
.	O
1	O
,	O
although	O
this	O
region	O
was	O
not	O
tested	O
in	O
the	O
original	O
hybrid	O
characterization	O
.	O

DISCUSSION	O

The	O
direct	O
hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
from	O
somatic	O
cell	O
hybrids	O
to	O
genomic	O
libraries	O
can	O
bypass	O
gel	O
purification	O
or	O
ligation	O
of	O
fragments	O
into	O
plasmid	O
vectors	O
and	O
individual	O
analysis	O
for	O
single	O
copy	O
sequences	O
.	O

Hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
as	O

a	O
pool	O
to	O
ordered	O
array	O
libraries	O
such	O
as	O
the	O
flow	O
-	O
sorted	O
X	O
chromosome	O
cosmid	O
library	O
(	O
9	O
)	O
,	O
allows	O
the	O
direct	O
comparison	O
of	O
overlapping	O
hybrids	O
to	O
pinpoint	O
cosmids	O
most	O
likely	O
to	O
be	O
from	O
the	O
region	O
of	O
interest	O
.	O

In	O
conjunction	O
with	O
the	O
reference	O
library	O
database	O
(	O
G	O
.	O
Z	O
,	O
unpublished	O
)	O
with	O
183	O
X	O
chromosome	O
probe	O
hybridization	O
entries	O
,	O
cosmids	O
identified	O
with	O
both	O
Alu	O
-	O
PCR	O
products	O
and	O
uniquely	O
mapped	O
X	O
probes	O
immediately	O
map	O
them	O
to	O
the	O
region	O
of	O
interest	O
and	O
proove	O
that	O
the	O
method	O
has	O
worked	O
.	O

Similar	O
hybridization	O
experiments	O
using	O
Alu	O
-	O
PCR	O
products	O
from	O
four	O
overlapping	O
irradiation	O
hybrids	O
identified	O
four	O
cosmids	O
in	O
common	O
that	O
mapped	O
to	O
the	O
region	O
of	O
overlap	O
by	O
independent	O
experiments	O
(	O
F	O
.	O
Muscatelli	O
,	O
A	O
.	O
P	O
.	O
M	O
.	O
,	O
P	O
.	O
N	O
.	O
G	O
.	O
,	O
H	O
.	O
L	O
.	O
and	O
M	O
.	O
Fontes	O
,	O
in	O
preparation	O
)	O
.	O

Since	O
only	O
27	O
probes	O
from	O
the	O
X	O
chromosome	O
were	O
used	O
to	O
initially	O
characterize	O
the	O
hybrids	O
and	O
the	O
length	O
of	O
individual	O
human	B
fragments	O
in	O
the	O
irradiation	O
hybrids	O
is	O
about	O
1000	O
-	O
5000	O
kb	O
,	O
many	O
regions	O
could	O
have	O
been	O
undetected	O
in	O
the	O
original	O
analysis	O
.	O

The	O
direct	O
hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
to	O
the	O
cosmid	O
reference	O
library	O
detected	O
such	O
fragments	O
since	O
they	O
identified	O
cosmids	O
in	O
common	O
with	O
uniquely	O
mapped	O
probes	O
in	O
regions	O
not	O
tested	O
originally	O
(	O
Table	O
1	O
and	O
Fig	O
1	O
)	O
.	O

This	O
should	O
prove	O
to	O
be	O
a	O
sensitive	O
and	O
efficient	O
method	O
to	O
determine	O
content	O
and	O
overlap	O
of	O
irradiation	O
hybrids	O
in	O
conjunction	O
with	O
DNA	O
blot	O
hybridization	O
.	O

However	O
,	O
since	O
the	O
exact	O
length	O
of	O
the	O
human	B
DNA	O
fragments	O
for	O
each	O
hybrid	O
and	O
the	O
spacing	O
of	O
Alu	O
-	O
PCR	O
products	O
along	O
the	O
chromosome	O
is	O
not	O
known	O
,	O
it	O
is	O
difficult	O
to	O
directly	O
correlate	O
the	O
number	O
of	O
target	O
cosmids	O
to	O
the	O
DNA	O
content	O
of	O
the	O
hybrids	O
.	O

The	O
direct	O
hybridization	O
of	O
Alu	O
-	O
PCR	O
products	O
from	O
irradiation	O
or	O
somatic	O
cell	O
hybrids	O
to	O
total	O
genomic	O
YAC	O
libraries	O
will	O
be	O
especially	O
useful	O
to	O
construct	O
long	O
range	O
YAC	O
contigs	O
from	O
specific	O
subregions	O
of	O
chromosomes	O
.	O

The	O
dissection	O
of	O
a	O
total	O
genomic	O
YAC	O
library	O
by	O
this	O
method	O
may	O
be	O
more	O
efficient	O
than	O
generating	O
chromosome	O
specific	O
YAC	O
libraries	O
from	O
somatic	O
cell	O
hybrids	O
(	O
usually	O
a	O
haploid	O
human	B
chromosome	O
on	O
a	O
diploid	O
or	O
greater	O
rodent	O
background	O
)	O
or	O
flow	O
-	O
sorted	O
chromosomes	O
,	O
because	O
of	O
the	O
low	O
transformation	O
efficiency	O
of	O
yeast	B
.	O

ACKNOWLEDGEMENTS	O

We	O
would	O
like	O
to	O
thank	O
Gert	O
-	O
Jan	O
Van	O
Ommen	O
for	O
the	O
probe	O
P20	O
and	O
Stuart	O
Orkin	O
for	O
the	O
CYBB	O
cDNA	O
probe	O
.	O

A	O
.	O
P	O
.	O
M	O
is	O
supported	O
in	O
part	O
by	O
a	O
research	O
fellowship	O
from	O
the	O
Muscular	O
Dystrophy	O
Association	O
of	O
America	O
.	O

V	O
.	O
M	O
.	O
S	O
.	O
L	O
.	O

is	O
supported	O
in	O
part	O
by	O
the	O
Medical	O
Research	O
Grant	O
of	O
the	O
University	O
of	O
Hong	O
Kong	O
.	O

Reference	O
library	O
filters	O
and	O
cosmids	O
identified	O
by	O
Alu	O
-	O
PCR	O
products	O
can	O
be	O
requested	O
from	O
the	O
Reference	O
Library	O
Database	O
,	O
ICRF	O
,	O
44	O
Lincoln	O
'	O
s	O
Inn	O
Fields	O
,	O
London	O
WC2A	O
3PX	O
,	O
U	O
.	O
K	O
.	O

3318	O
Nucleic	O
Acids	O
Research	O
,	O
Vol	O
.	O

19	O
,	O
No	O
.	O
12	O

REFERENCES	O

1	O
.	O

Nelson	O
,	O
D	O
.	O
L	O
.	O
,	O
Ledbetter	O
,	O
S	O
.	O
A	O
.	O
,	O
Corbo	O
,	O
L	O
.	O
,	O
Victoria	O
,	O
M	O
.	O
F	O
.	O
,	O
Ramirez	O
-	O
Solis	O
,	O

R	O
.	O
,	O
Webster	O
,	O
T	O
.	O
D	O
.	O
,	O
Ledbetter	O
,	O
D	O
.	O
H	O
.	O
,	O
and	O
Caskey	O
,	O
C	O
.	O
T	O
.	O

(	O
1989	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
,	O
86	O
:	O
6686	O
-	O
6690	O
.	O

2	O
.	O

Ledbetter	O
,	O
S	O
.	O
A	O
.	O
,	O
Nelson	O
,	O
D	O
.	O
L	O
.	O
,	O
Warren	O
,	O
S	O
.	O
T	O
.	O
,	O
and	O
Ledbetter	O
,	O
D	O
.	O
H	O
.	O

(	O
1990	O
)	O

Genomics	O
,	O
6	O
:	O
475	O
-	O
481	O
.	O

3	O
.	O

Cotter	O
,	O
F	O
.	O
E	O
.	O
,	O
Hampton	O
,	O
G	O
.	O
M	O
.	O
,	O
Nasipuri	O
,	O
S	O
.	O
,	O
Bodmer	O
,	O
W	O
.	O
F	O
.	O
,	O
and	O
Young	O

B	O
.	O
D	O
.	O

(	O
1990	O
)	O
Genomics	O
,	O
7	O
:	O
257	O
-	O
263	O
.	O

4	O
.	O

Burke	O
,	O
D	O
.	O
T	O
.	O
,	O
Carle	O
,	O
G	O
.	O
F	O
.	O
,	O
and	O
Olson	O
,	O
M	O
.	O
V	O
.	O

(	O
1987	O
)	O
Science	O
,	O
236	O
:	O
806	O
-	O
812	O
.	O

5	O
.	O

Benham	O
,	O
F	O
.	O
,	O
Hart	O
,	O
K	O
.	O
,	O
Crolla	O
,	O
J	O
.	O
,	O
Bobrow	O
,	O
M	O
.	O
,	O
Francavilla	O
,	O
M	O
.	O
,	O
and	O

Goodfellow	O
,	O
P	O
.	O
N	O
.	O

(	O
1989	O
)	O
Genomics	O
,	O
4	O
:	O
509	O
-	O
517	O
.	O

6	O
.	O

Feinberg	O
,	O
A	O
.	O
P	O
.	O
,	O
and	O
Vogelstein	O
,	O
B	O
.	O

(	O
1984	O
)	O
Anal	O
.	O

Biochem	O
.	O
,	O
137	O
:	O
266	O
-	O
267	O
.	O

7	O
.	O

Hochgeschwender	O
,	O
U	O
.	O
,	O
Sutciffe	O
,	O
J	O
.	O
G	O
.	O
,	O
and	O
Brennan	O
,	O
M	O
.	O
B	O
.	O

(	O
1989	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
,	O
86	O
:	O
8482	O
-	O
8486	O
.	O

8	O
.	O

Lehrach	O
,	O
H	O
.	O
,	O
Drmanac	O
,	O
R	O
.	O
,	O
Hoheisel	O
,	O
J	O
.	O
,	O
Larin	O
,	O
Z	O
.	O
,	O
Lennon	O
,	O
G	O
.	O
,	O
Monaco	O
,	O

A	O
.	O
P	O
.	O
,	O
Nizetic	O
,	O
D	O
.	O
,	O
Zehetner	O
,	O
G	O
.	O
,	O
and	O
Poustka	O
,	O
A	O
.	O

(	O
1990	O
)	O
In	O
Davies	O
,	O
K	O
.	O
E	O
.	O

&	O
Tilghman	O
,	O
S	O
.	O
M	O
.	O

(	O
eds	O
.	O
)	O
,	O
Genome	O
Analysis	O
Volume	O
1	O
:	O
Genetic	O
and	O
Physical	O
Mapping	O
.	O

Cold	O
Spring	O
Harbor	O
Laboratory	O
Press	O
,	O
Cold	O
Spring	O
Harbor	O
,	O
pp	O
.	O

39	O
-	O
81	O
.	O

9	O
.	O

Nizetic	O
,	O
D	O
.	O
,	O
Zehetner	O
,	O
G	O
.	O
,	O
Monaco	O
,	O
A	O
.	O
P	O
.	O
,	O
Gellen	O
,	O
L	O
.	O
,	O
Young	O
,	O
B	O
.	O
D	O
.	O
,	O
and	O

Lehrach	O
,	O
H	O
.	O

(	O
1991	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

USA	O
,	O
88	O
:	O
3233	O
-	O
3237	O
.	O

10	O
.	O

Larin	O
,	O
Z	O
.	O
and	O
Lehrach	O
,	O
H	O
.	O

(	O
1990	O
)	O
Genet	O
.	O

Res	O
.	O

Camb	O
.	O
,	O
56	O
:	O
203	O
-	O
208	O
.	O

11	O
.	O

Cox	O
,	O
D	O
,	O
R	O
.	O
,	O
Pritchard	O
,	O
C	O
.	O
A	O
.	O
,	O
Uglum	O
,	O
E	O
.	O
,	O
Casher	O
,	O
D	O
.	O
,	O
Koborl	O
.	O

J	O
.	O
and	O
Myers	O
,	O

R	O
.	O
M	O
.	O

(	O
1989	O
)	O
Genomics	O
,	O
4	O
:	O
397	O
-	O
407	O
.	O

12	O
.	O

Wapenaar	O
,	O
M	O
.	O
C	O
.	O
,	O
Kievits	O
,	O
T	O
.	O
,	O
Hart	O
,	O
K	O
.	O
A	O
.	O
,	O
Abbs	O
S	O
.	O
,	O
Blonden	O
,	O
L	O
.	O
A	O
.	O
J	O
.	O
,	O

denDunnen	O
,	O
J	O
.	O
T	O
.	O
,	O
Grootscholten	O
,	O
P	O
.	O
M	O
.	O
,	O
Bakker	O
,	O
E	O
.	O
,	O
Verellen	O
-	O
Dumoulin	O
,	O
C	O
.	O
,	O
Bobrow	O
,	O
M	O
.	O
,	O
vanOmmen	O
,	O
G	O
.	O
J	O
.	O
B	O
.	O
,	O
and	O
Pearson	O
,	O
P	O
.	O
L	O
.	O

(	O
1988	O
)	O
Genomics	O
,	O
2	O
:	O
101	O
-	O
108	O
.	O

13	O
.	O

Royer	O
-	O
Pokora	O
,	O
B	O
.	O
,	O
Kunkel	O
,	O
L	O
.	O
M	O
.	O
,	O
Monaco	O
,	O
A	O
.	O
P	O
.	O
,	O
Goff	O
,	O
S	O
.	O
C	O
.	O
,	O
Newburger	O
,	O

P	O
.	O
E	O
.	O
,	O
Baehner	O
,	O
R	O
.	O
L	O
.	O
,	O
Cole	O
F	O
.	O
S	O
.	O
,	O
Curnette	O
J	O
.	O
T	O
.	O
,	O
and	O
Orkin	O
,	O
S	O
.	O
A	O
.	O

(	O
1986	O
)	O
Nature	O
,	O
322	O
:	O
32	O
-	O
38	O
.	O

14	O
.	O

Davies	O
,	O
K	O
.	O
E	O
.	O
,	O
Mandel	O
,	O
J	O
.	O
L	O
.	O
,	O
Monaco	O
,	O
A	O
.	O
P	O
.	O
,	O
Nussbaum	O
,	O
R	O
.	O
L	O
.	O
and	O
Willard	O
,	O

H	O
.	O
F	O
.	O

(	O
1990	O
)	O
Cytogenet	O
.	O

Cell	O
Genet	O
.	O

55	O
:	O
254	O
-	O
313	O
.	O

The	O
Caenorhabditis	B
elegans	I
genome	O
contains	O
monomorphic	O
minisatellites	O
and	O
simple	O
sequences	O
.	O

Abstract	O

Many	O
species	O
have	O
been	O
shown	O
to	O
contain	O
tandemly	O
repeated	O
short	O
sequence	O
DNA	O
known	O
as	O
minisatellites	O
and	O
simple	O
sequence	O
motifs	O
.	O

Due	O
to	O
allelic	O
variation	O
in	O
the	O
copy	O
number	O
of	O
the	O
repeat	O
unit	O
these	O
loci	O
are	O
usually	O
highly	O
polymorphic	O
.	O

Here	O
we	O
demonstrate	O
the	O
presence	O
of	O
sequences	O
in	O
the	O
genome	O
of	O
the	O
nematode	O
Caenorhabditis	B
elegans	I
which	O
are	O
homologous	O
to	O
two	O
sets	O
of	O
short	O
sequence	O
DNA	O
.	O

However	O
,	O
when	O
two	O
independent	O
strains	O
were	O
compared	O
no	O
polymorphism	O
for	O
these	O
sequences	O
could	O
be	O
detected	O
.	O
Images	O

Volume	O
17	O
Number	O
23	O
1989	O
Nucleic	O
Acids	O
Research	O

The	O
Caenorhabds	B
elegans	I
genome	O
contains	O
monomorphic	O
minisatellites	O
and	O
simple	O
sequences	O
Andrd	O
G	O
.	O
Uitterlinden	O
,	O
P	O
.	O
Eline	O
Slagboom	O
,	O
Thomas	O
E	O
.	O
Johnsonl	O
and	O
Jan	O
Vijg	O

Department	O
of	O
Molecular	O
Biology	O
,	O
TNO	O
Institute	O
for	O
Experimental	O
Gerontology	O
,	O
PO	O
Box	O
5815	O
,	O
2280	O
HV	O
Rijswijk	O
,	O
The	O
Netherlands	O
and	O
lInstitute	O
for	O
Behavioral	O
Genetics	O
,	O
University	O
of	O
Colorado	O
,	O
Boulder	O
,	O
CO	O
80309	O
,	O
USA	O

Received	O
October	O
27	O
,	O
1989	O
;	O
Accepted	O
November	O
3	O
,	O
1989	O

ABSTRACT	O

Many	O
species	O
have	O
been	O
shown	O
to	O
contain	O
tandemly	O
repeated	O
short	O
sequence	O
DNA	O
kinown	O
as	O
minisatellites	O
and	O
simple	O
sequence	O
motifs	O
.	O

Due	O
to	O
allelic	O
variation	O
in	O
the	O
copy	O
number	O
of	O
the	O
repeat	O
unit	O
these	O
loci	O
are	O
usually	O
highly	O
polymorphic	O
.	O

Here	O
we	O
demonstrate	O
the	O
presence	O
of	O
sequences	O
in	O
the	O
genome	O
of	O
the	O
nematode	O
Caenorhabditis	B
elegans	I
which	O
are	O
homologous	O
to	O
two	O
sets	O
of	O
short	O
sequence	O
DNA	O
.	O

However	O
,	O
when	O
two	O
independent	O
strains	O
were	O
compared	O
no	O
polymorphism	O
for	O
these	O
sequences	O
could	O
be	O
detected	O
.	O

INTRODUCTION	O

The	O
genome	O
of	O
many	O
species	O
,	O
including	O
lower	O
organisms	O
,	O
contain	O
minisatellite	O
sequences	O
and	O
so	O
-	O
called	O
simple	O
sequence	O
motifs	O
(	O
1	O
,	O
2	O
,	O
3	O
)	O
.	O

Due	O
to	O
extensive	O
variation	O
in	O
the	O
number	O
of	O
repeat	O
units	O
,	O
many	O
of	O
these	O
loci	O
have	O
been	O
shown	O
useful	O
as	O
polymorphic	O
markers	O
,	O
e	O
.	O
g	O
.	O
for	O
genetic	O
linkage	O
studies	O
and	O
identification	O
purposes	O
.	O

Here	O
we	O
demonstrate	O
that	O
the	O
genome	O
of	O
the	O
nematode	O
Caenorhabditis	B
elegans	I
contains	O
sequences	O
that	O
are	O
homologous	O
to	O
the	O
minisatellite	O
core	O
sequence	O
33	O
.	O
6	O
(	O
1	O
)	O
and	O
to	O
the	O
simple	O
sequence	O
motif	O
(	O
AGC	O
)	O
n	O
.	O

Surprisingly	O
,	O
these	O
sequences	O
did	O
not	O
display	O
polymorphism	O
when	O
two	O
independent	O
C	B
.	I
elegans	I
strains	O
,	O
Bristol	O
and	O
Bergerac	O
,	O
were	O
compared	O
.	O

MATERIALS	O
AND	O
METHODS	O
Genomic	O
DNA	O
from	O
nematodes	O

Genomic	O
DNA	O
was	O
isolated	O
according	O
to	O
standard	O
procedures	O
from	O
the	O
two	O
strains	O
Bergerac	O
(	O
BO	O
)	O
and	O
Bristol	O
(	O
strain	O
N2	O
)	O
.	O

These	O
strains	O
are	O
derived	O
from	O
two	O
different	O
individual	O
worms	O
isolated	O
in	O
France	O
and	O
England	O
,	O
respectively	O
.	O

Southern	O
blotting	O

Genomic	O
DNA	O
digests	O
(	O
5	O
Ag	O
)	O
were	O
separated	O
in	O
a	O
1	O
%	O
agarose	O
gel	O
in	O
1	O
x	O
TAE	O
(	O
40	O
mM	O
Tris	O
.	O
HCl	O
,	O
pH	O
7	O
.	O
4	O
/	O
20	O
mM	O
sodium	O
acetate	O
/	O
I	O
mM	O
NaEDTA	O
)	O
by	O
electrophoresis	O
at	O
75	O
V	O
for	O
16	O
h	O
.	O

Separation	O
patterns	O
were	O
transferred	O
to	O
Zetaprobe	O
membrane	O
(	O
BIORAD	O
)	O
in	O
0	O
.	O
4	O
N	O
NaOH	O
,	O
0	O
.	O
6	O
M	O
NaCl	O
in	O
a	O
vacu	O
-	O
blot	O
apparatus	O
(	O
LKB	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
.	O

The	O
minisatellite	O
and	O
simple	O
sequence	O
probes	O
used	O
were	O
prepared	O
essentially	O
as	O
described	O
(	O
5	O
)	O
.	O

The	O
Tcl	O
probe	O
is	O
a	O
plasmid	O
containing	O
an	O
insert	O
of	O
the	O
transposable	O
element	O
Tcl	O
(	O
4	O
)	O
.	O

All	O
probes	O
were	O
labelled	O
by	O
random	O
-	O
priming	O
.	O

Hybridization	O
was	O
performed	O
for	O
12	O
h	O
in	O
7	O
%	O
SDS	O
,	O
0	O
.	O
5	O
M	O
phosphate	O
buffer	O
,	O
1	O
mM	O
Na2EDTA	O
at	O
650C	O
.	O

Blots	O
were	O
washed	O
twice	O
in	O
2	O
.	O
5	O
x	O
SSC	O
at	O
650C	O
and	O
exposed	O
to	O
Kodak	O
XAR	O
-	O
5	O
film	O
with	O
intensifying	O
screens	O
.	O

Exposure	O
times	O
are	O
indicated	O
in	O
Fig	O
.	O

1	O
.	O

(	O
IRL	O
Press	O

Nucleic	O
Acids	O
Research	O

Volume	O
17	O
Number	O
23	O
1989	O

9527	O

Nucleic	O
Acids	O
Research	O

C	B
.	I
elegans	I

N	O
0	O
$	O
8	O

_	O
_	O

:	O
,	O
s	O
,	O
.	O
.	O
e	O
:	O
*	O
.	O

,	O
~	O
:	O
:	O
:	O
:	O
:	O

.	O
4i	O

.	O
t	O
_	O
:	O
-	O
:	O
:	O
?	O
J	O
?	O
.	O
:	O

i	O
-	O

.	O
a	O

E	O
?	O
:	O
<	O
.	O

:	O
:	O
y	O
:	O

*	O
01	O

4	O
?	O
j	O
*	O

.	O
-	O
I	O

kb	O
-	O
27	O

-	O
9A	O
-	O

:	O
.	O
:	O
:	O
.	O
.	O
.	O
.	O
.	O
.	O
.	O

Mi	O
.	O
.	O
.	O
.	O

-	O
4v3	O

IC	O
.	O
3	O

If	O
.	O
0r	O

MW	O

!	O
5	O
c6	O

I	O

"	O
R	O
1d	O
~	O
!	O

;	O
,	O

Figure	O
1	O
.	O

Southern	O
hybridization	O
analysis	O
of	O
Hae	O
III	O
,	O
Rsa	O
I	O
and	O
Eco	O
RI	O
digested	O
genomic	O
DNA	O
isolated	O
from	O
the	O
two	O
C	B
.	I
elegans	I
strains	O
Bristol	O
(	O
N	O
)	O
and	O
Bergerac	O
(	O
B	O
)	O
.	O

The	O
probes	O
used	O
and	O
the	O
exposure	O
times	O
of	O
the	O
autoradiograph	O
are	O
indicated	O
below	O
the	O
figure	O
.	O

kb	O
=	O
kilo	O
basepairs	O
.	O

9528	O

*	O
:	O
.	O
.	O
?	O
.	O
;	O
.	O

.	O
*	O
.	O

i	O
.	O
.	O
.	O

:	O
"	O
.	O

ANN	O
&	O

'	O
ROW	O
:	O
.	O
lwmwww	O
.	O

.	O
Ammkw	O
.	O
l	O

4w	O
,	O

9	O

_	O
i	O
ob	O

Ill	O
a	O

Nucleic	O
Acids	O
Research	O

RESULTS	O

In	O
Figure	O
1	O
the	O
hybridization	O
patterns	O
are	O
shown	O
of	O
C	B
.	I
elegans	I
genomic	O
DNA	O
digested	O
with	O
Hae	O
II	O
,	O
Rsa	O
I	O
and	O
Eco	O
RI	O
,	O
and	O
subsequently	O
hybridized	O
to	O
minisatellite	O
core	O
probe	O
33	O
.	O
6	O
,	O
the	O
simple	O
sequence	O
probe	O
(	O
AGC	O
)	O
n	O
and	O
Tcl	O
.	O

The	O
latter	O
probe	O
contains	O
a	O
member	O
of	O
the	O
Tcl	O
family	O
of	O
transposable	O
elements	O
which	O
is	O
present	O
in	O
different	O
copy	O
numbers	O
in	O
the	O
two	O
different	O
strains	O
(	O
4	O
)	O
.	O

The	O
hybridization	O
patterns	O
of	O
probes	O
33	O
.	O
6	O
and	O
(	O
AGC	O
)	O
n	O
obtained	O
after	O
Hae	O
Im	O
and	O
Rsa	O
I	O
digestion	O
and	O
the	O
differences	O
in	O
intensities	O
of	O
the	O
hybridizing	O
bands	O
is	O
reminiscent	O
of	O
DNA	O
-	O
fingerprint	O
patterns	O
obtained	O
with	O
these	O
probes	O
in	O
other	O
species	O
(	O
1	O
,	O
2	O
,	O
3	O
)	O
.	O

However	O
,	O
identical	O
hybridization	O
patterns	O
for	O
the	O
two	O
strains	O
with	O
the	O
three	O
enzymes	O
tested	O
indicated	O
that	O
in	O
C	B
.	I
elegans	I
these	O
sequences	O
are	O
monomorphic	O
(	O
Fig	O
.	O
1	O
)	O
.	O

Based	O
on	O
the	O
number	O
of	O
hybridizing	O
bands	O
we	O
estimate	O
the	O
C	B
.	I
elegans	I
genome	O
to	O
contain	O
about	O
30	O
33	O
.	O
6	O
homologous	O
loci	O
and	O
about	O
20	O
(	O
AGC	O
)	O
n	O
homologous	O
loci	O
.	O

Rehybridization	O
of	O
the	O
same	O
blot	O
with	O
a	O
Tcl	O
probe	O
revealed	O
extensive	O
RFLPs	O
due	O
to	O
the	O
different	O
copy	O
number	O
of	O
the	O
transposon	O
in	O
the	O
two	O
strains	O
,	O
a	O
phenomenon	O
which	O
has	O
been	O
described	O
previously	O
by	O
others	O
(	O
4	O
)	O
.	O

DISCUSSION	O

The	O
findings	O
presented	O
in	O
this	O
paper	O
indicate	O
that	O
polymorphism	O
of	O
minisatellite	O
sequences	O
and	O
simple	O
sequence	O
motifs	O
,	O
is	O
not	O
a	O
general	O
phenomenon	O
in	O
animal	O
species	O
.	O

So	O
far	O
,	O
only	O
some	O
species	O
of	O
whales	O
have	O
displayed	O
similar	O
high	O
levels	O
of	O
monomorphism	O
(	O
6	O
)	O
.	O

In	O
other	O
species	O
thus	O
far	O
tested	O
both	O
minisatellites	O
and	O
simple	O
sequences	O
display	O
high	O
to	O
very	O
high	O
levels	O
of	O
polymorphism	O
.	O

It	O
should	O
be	O
noted	O
,	O
however	O
,	O
that	O
at	O
least	O
in	O
humans	B
,	O
a	O
substantial	O
part	O
of	O
the	O
minisatellites	O
detected	O
by	O
core	O
probes	O
also	O
displays	O
high	O
levels	O
of	O
monomorphism	O
as	O
analysed	O
by	O
cloning	O
(	O
1	O
)	O
or	O
by	O
two	O
-	O
dimensional	O
DNA	O
fingerprinting	O
(	O
5	O
)	O
.	O

The	O
fact	O
that	O
nematodes	O
are	O
hermaphrodites	O
,	O
and	O
thus	O
inbred	O
,	O
might	O
be	O
a	O
contributing	O
factor	O
to	O
the	O
observed	O
lack	O
of	O
polymorphism	O
.	O

However	O
,	O
the	O
high	O
levels	O
of	O
polymorphism	O
detected	O
by	O
the	O
Tcl	O
probe	O
do	O
not	O
indicate	O
a	O
general	O
absence	O
of	O
events	O
causing	O
genetic	O
variation	O
.	O

Indeed	O
,	O
Eide	O
and	O
Anderson	O
(	O
7	O
)	O
showed	O
that	O
tandemly	O
repeated	O
duplications	O
in	O
the	O
unc	O
-	O
54	O
gene	O
of	O
C	B
.	I
elegans	I
revert	O
at	O
high	O
frequencies	O
.	O

Since	O
in	O
all	O
cases	O
the	O
revertants	O
had	O
the	O
normal	O
genomic	O
configuration	O
this	O
suggests	O
that	O
unequal	O
crossing	O
-	O
over	O
does	O
occur	O
in	O
the	O
nematode	O
.	O

A	O
more	O
likely	O
explanation	O
for	O
the	O
monomorphic	O
nature	O
of	O
the	O
sequences	O
detected	O
with	O
33	O
.	O
6	O
and	O
(	O
AGC	O
)	O
n	O
in	O
C	B
.	I
elegans	I
is	O
selection	O
against	O
sequence	O
variants	O
at	O
these	O
loci	O
.	O

This	O
might	O
be	O
the	O
result	O
of	O
the	O
presence	O
of	O
a	O
particular	O
subset	O
of	O
minisatellites	O
and	O
/	O
or	O
simple	O
sequences	O
at	O
sites	O
in	O
the	O
genome	O
of	O
this	O
organism	O
,	O
e	O
.	O
g	O
.	O
in	O
coding	O
sequences	O
,	O
in	O
which	O
variation	O
in	O
copy	O
number	O
of	O
repeat	O
units	O
cannot	O
be	O
tolerated	O
.	O

An	O
example	O
of	O
such	O
a	O
coding	O
sequence	O
could	O
be	O
the	O
High	O
Mobility	O
Group	O
proteins	O
which	O
usually	O
have	O
stretches	O
of	O
identical	O
(	O
acidic	O
)	O
amino	O
acids	O
(	O
2	O
,	O
8	O
)	O
.	O

An	O
interesting	O
observation	O
in	O
this	O
respect	O
is	O
the	O
demonstration	O
of	O
the	O
absence	O
of	O
any	O
protein	O
polymorphisms	O
in	O
electrophoretic	O
comparisons	O
for	O
24	O
different	O
enzymes	O
between	O
the	O
Bristol	O
and	O
Bergerac	O
strains	O
(	O
9	O
)	O
.	O

An	O
important	O
step	O
in	O
understanding	O
this	O
phenomenon	O
will	O
therefore	O
be	O
the	O
isolation	O
and	O
analysis	O
of	O
individual	O
homologous	O
minisatellite	O
and	O
simple	O
sequence	O
loci	O
from	O
a	O
genomic	O
library	O
of	O
C	B
.	I
elegans	I
.	O

REFERENCES	O

1	O
.	O

Jeffreys	O
,	O
A	O
.	O
J	O
.	O
,	O
Wilson	O
,	O
V	O
.	O
,	O
and	O
Thein	O
,	O
S	O
.	O
L	O
.	O

(	O
1985	O
)	O
Nature	O
314	O
,	O
67	O
-	O
73	O
.	O

2	O
.	O

Tautz	O
,	O
D	O
.	O
,	O
Trick	O
M	O
.	O
,	O
and	O
Dover	O
,	O
G	O
.	O
A	O
.	O

(	O
1986	O
)	O
Nature	O
322	O
,	O
652	O
-	O
656	O
.	O

3	O
.	O

Rogstad	O
,	O
S	O
.	O
H	O
.	O
,	O
Herwaldt	O
,	O
B	O
.	O
L	O
.	O
,	O
Schlesinger	O
,	O
P	O
.	O
H	O
.	O
,	O
and	O
Krogstad	O
,	O
D	O
.	O
J	O
.	O

(	O
1989	O
)	O
Nucleic	O
Acids	O
Res	O
.	O

17	O
,	O
9	O
,	O
3610	O
.	O

4	O
.	O

Emmons	O
,	O
S	O
.	O
W	O
.	O
,	O
Yesner	O
,	O
L	O
.	O
,	O
Ruan	O
,	O
K	O
.	O
and	O
Katzenberg	O
,	O
D	O
.	O

(	O
1983	O
)	O
Cell	O
32	O
,	O
55	O
-	O
65	O
.	O

9529	O

Nucleic	O
Acids	O
Research	O

5	O
.	O

Uitterlinden	O
,	O
A	O
.	O
G	O
.	O
,	O
Slagboom	O
,	O
P	O
.	O
E	O
.	O
,	O
Knook	O
,	O
D	O
.	O
L	O
.	O
,	O
and	O
Vijg	O
,	O
J	O
.	O

(	O
1989	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

USA	O
86	O
,	O
2742	O
-	O
2746	O
.	O

6	O
.	O

Rus	O
Hoelzel	O
,	O
A	O
.	O
,	O
and	O
Amos	O
,	O
W	O
.	O

(	O
1988	O
)	O
Nature	O
333	O
,	O
305	O
.	O

7	O
.	O

Eide	O
,	O
D	O
.	O
,	O
and	O
Anderson	O
,	O
P	O
.	O

(	O
1985	O
)	O
Genetics	O
109	O
,	O
67	O
-	O
79	O
.	O

8	O
.	O

Pentecost	O
,	O
B	O
.	O
T	O
.	O
,	O
Wright	O
,	O
J	O
.	O
M	O
.	O
,	O
and	O
Dixon	O
,	O
G	O
.	O
H	O
.	O

(	O
1985	O
)	O
Nucleic	O
Acids	O
Res	O
.	O

13	O
,	O
4871	O
-	O
4888	O
.	O

9	O
.	O

Butler	O
et	O
al	O
.	O

(	O
1981	O
)	O
J	O
.	O

Molec	O
.	O

Evolution	O
18	O
,	O
18	O
-	O
23	O
.	O

9530	O

This	O
article	O
,	O
submitted	O
on	O
disc	O
,	O
has	O
been	O
automatically	O

converted	O
into	O
this	O
typeset	O
format	O
by	O
the	O
publisher	O
.	O

How	O
can	O
Health	O
Behavior	O
Theory	O
be	O
made	O
more	O
useful	O
for	O
intervention	O
research	O
?	O

Abstract	O

Background	O

The	O
present	O
paper	O
expresses	O
the	O
author	O
'	O
s	O
views	O
about	O
the	O
practical	O
utility	O
of	O
Health	O
Behavior	O
Theory	O
for	O
health	O
behavior	O
intervention	O
research	O
.	O

The	O
views	O
are	O
skeptical	O
and	O
perhaps	O
even	O
a	O
bit	O
exaggerated	O
.	O

They	O
are	O
,	O
however	O
,	O
also	O
based	O
on	O
20	O
-	O
plus	O
years	O
of	O
in	O
-	O
the	O
-	O
trenches	O
research	O
focused	O
on	O
improving	O
health	O
behavior	O
practice	O
through	O
research	O
.	O

Discussion	O

The	O
author	O
'	O
s	O
research	O
has	O
been	O
theoretically	O
driven	O
and	O
has	O
involved	O
measurement	O
of	O
varying	O
variables	O
considered	O
to	O
be	O
important	O
theoretical	O
mediators	O
and	O
moderators	O
of	O
health	O
behavior	O
.	O

Regretfully	O
,	O
much	O
of	O
this	O
work	O
has	O
found	O
these	O
variables	O
wanting	O
in	O
basic	O
scientific	O
merit	O
.	O

Health	O
Behavior	O
Theory	O
as	O
we	O
have	O
known	O
it	O
over	O
the	O
last	O
25	O
years	O
or	O
so	O
has	O
been	O
dominated	O
by	O
conceptualizations	O
of	O
behavior	O
change	O
processes	O
that	O
highlight	O
cognitive	O
decision	O
-	O
making	O
.	O

Although	O
much	O
of	O
health	O
behavior	O
practice	O
targets	O
what	O
people	B
do	O
rather	O
than	O
what	O
they	O
think	O
,	O
the	O
logic	O
of	O
focusing	O
on	O
thoughts	O
is	O
that	O
what	O
people	B
think	O
about	O
is	O
the	O
key	O
to	O
what	O
they	O
will	O
do	O
in	O
the	O
future	O
,	O
and	O
that	O
interventions	O
that	O
can	O
measure	O
and	O
harness	O
those	O
processes	O
will	O
succeed	O
to	O
a	O
greater	O
extent	O
than	O
those	O
that	O
do	O
not	O
.	O

Unfortunately	O
,	O
in	O
the	O
author	O
'	O
s	O
experience	O
,	O
the	O
premise	O
of	O
cognitive	O
theories	O
has	O
fallen	O
short	O
empirically	O
in	O
a	O
number	O
of	O
ways	O
.	O

The	O
cognitive	O
schemata	O
favored	O
by	O
most	O
health	O
behavior	O
theories	O
are	O
difficult	O
to	O
measure	O
,	O
they	O
do	O
not	O
predict	O
behavioral	O
outcomes	O
very	O
well	O
,	O
there	O
is	O
little	O
evidence	O
that	O
they	O
cause	O
behavior	O
,	O
and	O
they	O
are	O
hard	O
to	O
change	O
directly	O
.	O

Summary	O

It	O
is	O
suggested	O
that	O
health	O
behavior	O
researchers	O
reconsider	O
their	O
use	O
of	O
these	O
theories	O
in	O
favor	O
of	O
models	O
whose	O
variables	O
are	O
more	O
accessible	O
to	O
observation	O
and	O
experimental	O
manipulation	O
and	O
that	O
most	O
importantly	O
have	O
strong	O
empirical	O
support	O
.	O

Background	O

The	O
author	O
has	O
been	O
conducting	O
research	O
on	O
behavioral	O
treatment	O
of	O
obesity	O
for	O
about	O
25	O
years	O
.	O

During	O
that	O
time	O
,	O
the	O
dominant	O
conceptual	O
models	O
guiding	O
intervention	O
development	O
have	O
been	O
cognitive	O
behavior	O
models	O
that	O
have	O
their	O
origin	O
in	O
psychological	O
theory	O
.	O

Those	O
most	O
often	O
cited	O
include	O
the	O
Health	O
Belief	O
Model	O
[	O
1	O
]	O
,	O
Protection	O
Motivation	O
Theory	O
[	O
2	O
]	O
,	O
Subjective	O
Expected	O
Utility	O
Theory	O
[	O
3	O
]	O
,	O
the	O
Theory	O
of	O
Reasoned	O
Action	O
[	O
4	O
]	O
,	O
Social	O
Cognitive	O
Theory	O
[	O
5	O
]	O
,	O
and	O
the	O
Transtheoretical	O
Model	O
[	O
6	O
]	O
.	O

All	O
of	O
these	O
theories	O
are	O
concerned	O
with	O
how	O
people	B
make	O
behavioral	O
choices	O
and	O
the	O
general	O
idea	O
is	O
that	O
people	B
decide	O
what	O
to	O
do	O
based	O
on	O
the	O
extent	O
to	O
which	O
they	O
expect	O
that	O
their	O
choices	O
will	O
produce	O
results	O
that	O
they	O
value	O
.	O

Much	O
of	O
the	O
content	O
of	O
the	O
theories	O
is	O
concerned	O
with	O
factors	O
that	O
may	O
affect	O
value	O
/	O
expectancy	O
calculations	O
.	O

As	O
summarized	O
by	O
Weinstein	O
in	O
a	O
comparative	O
review	O
of	O
four	O
social	O
psychological	O
theories	O
[	O
7	O
]	O
,	O
variables	O
thought	O
to	O
influence	O
value	O
/	O
expectancy	O
judgments	O
include	O
such	O
factors	O
as	O
perceived	O
rewards	O
of	O
current	O
behavior	O
,	O
self	O
-	O
efficacy	O
,	O
normative	O
beliefs	O
,	O
motivation	O
,	O
and	O
the	O
perceived	O
consequences	O
of	O
not	O
changing	O
behavior	O
.	O

Weinstein	O
'	O
s	O
summary	O
is	O
illustrative	O
of	O
the	O
fact	O
that	O
Health	O
Behavior	O
Theory	O
has	O
tended	O
to	O
be	O
particularly	O
interested	O
in	O
understanding	O
people	B
'	O
s	O
motivation	O
to	O
change	O
behavior	O
rather	O
than	O
ability	O
to	O
change	O
.	O

Moreover	O
,	O
motivation	O
is	O
thought	O
to	O
be	O
the	O
result	O
of	O
a	O
relatively	O
complex	O
,	O
but	O
logical	O
,	O
interpretation	O
of	O
large	O
quantities	O
of	O
information	O
about	O
self	O
and	O
environment	O
.	O

The	O
theories	O
that	O
Weinstein	O
reviewed	O
deal	O
almost	O
exclusively	O
with	O
behavioral	O
decision	O
processes	O
in	O
people	B
'	O
s	O
minds	O
.	O

They	O
have	O
few	O
if	O
any	O
terms	O
relating	O
to	O
how	O
information	O
gets	O
into	O
peoples	O
minds	O
or	O
how	O
subsets	O
of	O
it	O
receive	O
more	O
or	O
less	O
attention	O
.	O

Broader	O
health	O
behavior	O
theories	O
such	O
as	O
Social	O
Cognitive	O
Theory	O
or	O
the	O
Transtheoretical	O
model	O
have	O
addressed	O
issues	O
and	O
variables	O
outside	O
the	O
person	B
to	O
a	O
greater	O
extent	O
,	O
but	O
the	O
fundamental	O
interest	O
in	O
and	O
belief	O
in	O
psychological	O
variables	O
as	O
the	O
key	O
force	O
in	O
determining	O
health	O
behavior	O
remains	O
.	O

The	O
implications	O
of	O
the	O
focus	O
of	O
health	O
behavior	O
theory	O
on	O
psychological	O
determinants	O
of	O
behavioral	O
decision	O
-	O
making	O
for	O
my	O
own	O
research	O
area	O
of	O
interest	O
,	O
obesity	O
treatment	O
,	O
are	O
several	O
.	O

One	O
is	O
the	O
inclusion	O
of	O
measures	O
of	O
psychological	O
characteristics	O
in	O
most	O
research	O
protocols	O
(	O
e	O
.	O
g	O
.	O
,	O
assessment	O
of	O
behavioral	O
intentions	O
,	O
self	O
-	O
efficacy	O
,	O
perception	O
of	O
barriers	O
to	O
change	O
,	O
perception	O
of	O
social	O
support	O
,	O
and	O
outcome	O
expectations	O
)	O
.	O

A	O
second	O
is	O
the	O
inclusion	O
of	O
treatment	O
elements	O
that	O
specifically	O
target	O
psychological	O
perceptions	O
and	O
processes	O
independent	O
of	O
the	O
diet	O
and	O
physical	O
activity	O
behaviors	O
that	O
actually	O
produce	O
weight	O
change	O
(	O
e	O
.	O
g	O
.	O
,	O
how	O
to	O
deal	O
with	O
emotional	O
eating	O
,	O
how	O
to	O
deal	O
with	O
the	O
frustration	O
of	O
lapses	O
and	O
relapses	O
,	O
and	O
how	O
to	O
talk	O
to	O
yourself	O
to	O
increase	O
self	O
-	O
motivation	O
)	O
.	O

A	O
third	O
is	O
the	O
belief	O
that	O
psychological	O
reactions	O
to	O
treatment	O
experiences	O
themselves	O
are	O
very	O
important	O
and	O
deserve	O
independent	O
attention	O
.	O

Common	O
behavioral	O
prescriptions	O
for	O
weight	O
-	O
loss	O
goals	O
and	O
frequency	O
of	O
self	O
-	O
weighing	O
are	O
exemplary	O
(	O
i	O
.	O
e	O
.	O
,	O
recommending	O
infrequent	O
weighing	O
to	O
prevent	O
discouraging	O
feedback	O
about	O
progress	O
and	O
encouraging	O
smaller	O
and	O
thus	O
"	O
more	O
attainable	O
"	O
behavior	O
and	O
weight	O
-	O
loss	O
goals	O
in	O
the	O
belief	O
that	O
they	O
will	O
be	O
more	O
motivating	O
)	O
.	O

The	O
problem	O
with	O
the	O
emphasis	O
on	O
cognitive	O
variables	O
in	O
weight	O
-	O
control	O
research	O
is	O
that	O
they	O
have	O
so	O
far	O
failed	O
to	O
meet	O
fundamental	O
scientific	O
criteria	O
for	O
empirical	O
verification	O
.	O

Thus	O
,	O
they	O
also	O
have	O
not	O
led	O
to	O
a	O
better	O
understanding	O
of	O
the	O
weight	O
-	O
loss	O
process	O
,	O
have	O
not	O
improved	O
our	O
ability	O
to	O
predict	O
weight	O
-	O
loss	O
outcomes	O
,	O
and	O
have	O
not	O
led	O
to	O
improvement	O
in	O
treatment	O
methods	O
.	O

In	O
some	O
cases	O
it	O
is	O
even	O
arguable	O
that	O
they	O
have	O
made	O
treatment	O
worse	O
.	O

I	O
will	O
illustrate	O
these	O
problems	O
with	O
results	O
from	O
my	O
own	O
research	O
.	O

Discussion	O

Like	O
most	O
behavioral	O
researchers	O
in	O
the	O
obesity	O
area	O
,	O
I	O
have	O
attempted	O
to	O
measure	O
elements	O
of	O
health	O
behavior	O
theory	O
in	O
every	O
obesity	O
intervention	O
project	O
I	O
have	O
ever	O
conducted	O
.	O

I	O
have	O
assessed	O
weight	O
-	O
loss	O
goals	O
,	O
behavioral	O
and	O
weight	O
-	O
loss	O
self	O
-	O
efficacy	O
,	O
psychological	O
well	O
-	O
being	O
,	O
perceived	O
barriers	O
to	O
diet	O
and	O
physical	O
activity	O
change	O
,	O
stages	O
-	O
of	O
-	O
change	O
,	O
and	O
perceived	O
social	O
support	O
.	O

How	O
well	O
have	O
empirical	O
examinations	O
of	O
these	O
factors	O
fared	O
as	O
predictors	O
of	O
success	O
in	O
weight	O
control	O
?	O

Self	O
-	O
efficacy	O

We	O
have	O
examined	O
the	O
predictive	O
value	O
of	O
self	O
-	O
efficacy	O
assessments	O
in	O
several	O
of	O
our	O
studies	O
and	O
describe	O
the	O
results	O
from	O
three	O
of	O
these	O
here	O
in	O
more	O
detail	O
[	O
8	O
-	O
10	O
]	O
.	O

In	O
the	O
first	O
study	O
,	O
self	O
-	O
efficacy	O
was	O
assessed	O
at	O
baseline	O
,	O
posttreatment	O
,	O
and	O
one	O
year	O
later	O
in	O
85	O
men	B
participating	O
in	O
a	O
15	O
-	O
week	O
weight	O
-	O
loss	O
program	O
[	O
8	O
]	O
.	O

The	O
self	O
-	O
efficacy	O
instrument	O
had	O
subscales	O
for	O
emotional	O
states	O
(	O
e	O
.	O
g	O
.	O
,	O
anxiety	O
)	O
and	O
situations	O
(	O
e	O
.	O
g	O
.	O
,	O
eating	O
away	O
from	O
home	O
)	O
.	O

Higher	O
baseline	O
self	O
-	O
efficacy	O
on	O
both	O
subscales	O
was	O
associated	O
with	O
greater	O
weight	O
loss	O
in	O
treatment	O
and	O
at	O
1	O
-	O
and	O
2	O
-	O
year	O
follow	O
-	O
up	O
.	O

Emotional	O
self	O
-	O
efficacy	O
at	O
posttreatment	O
did	O
not	O
predict	O
weight	O
loss	O
at	O
1	O
-	O
or	O
2	O
-	O
year	O
follow	O
-	O
up	O
.	O

Situational	O
self	O
-	O
efficacy	O
at	O
posttreatment	O
predicted	O
weight	O
loss	O
at	O
1	O
-	O
year	O
but	O
not	O
2	O
-	O
year	O
follow	O
-	O
up	O
.	O

The	O
second	O
study	O
examined	O
mood	O
and	O
situational	O
self	O
-	O
efficacy	O
in	O
55	O
men	B
and	O
58	O
women	B
before	O
and	O
after	O
a	O
16	O
-	O
week	O
weight	O
-	O
loss	O
treatment	O
with	O
a	O
1	O
-	O
year	O
follow	O
-	O
up	O
[	O
9	O
]	O
.	O

Women	B
had	O
lower	O
pretreatment	O
self	O
-	O
efficacy	O
than	O
men	B
.	O

Self	O
-	O
efficacy	O
was	O
predictive	O
of	O
weight	O
loss	O
and	O
maintenance	O
in	O
men	B
but	O
not	O
in	O
women	B
.	O

Change	O
in	O
self	O
-	O
efficacy	O
over	O
time	O
was	O
positively	O
related	O
to	O
weight	O
change	O
in	O
women	B
but	O
not	O
in	O
men	B
.	O

The	O
third	O
study	O
examined	O
predictors	O
of	O
weight	O
change	O
over	O
a	O
2	O
-	O
year	O
period	O
in	O
460	O
men	B
and	O
1172	O
women	B
who	O
received	O
a	O
low	O
-	O
intensity	O
weight	O
-	O
loss	O
intervention	O
delivered	O
through	O
their	O
HMO	O
[	O
10	O
]	O
.	O

The	O
self	O
-	O
efficacy	O
measure	O
was	O
the	O
WEL	O
questionnaire	O
.	O

Men	B
again	O
were	O
found	O
to	O
have	O
higher	O
baseline	O
self	O
-	O
efficacy	O
than	O
women	B
.	O

Self	O
-	O
efficacy	O
did	O
not	O
predict	O
weight	O
change	O
in	O
men	B
but	O
was	O
positively	O
,	O
though	O
weakly	O
,	O
related	O
to	O
weight	O
change	O
at	O
6	O
months	O
only	O
in	O
women	B
.	O

Our	O
overall	O
conclusion	O
from	O
the	O
analyses	O
described	O
above	O
,	O
as	O
well	O
as	O
others	O
not	O
pursued	O
in	O
as	O
great	O
detail	O
,	O
is	O
that	O
self	O
-	O
efficacy	O
is	O
a	O
weak	O
predictor	O
of	O
weight	O
loss	O
and	O
is	O
inconsistent	O
across	O
study	O
populations	O
and	O
gender	O
.	O

It	O
tends	O
to	O
increase	O
with	O
weight	O
loss	O
.	O

However	O
,	O
treatment	O
-	O
induced	O
increases	O
in	O
efficacy	O
are	O
not	O
predictive	O
of	O
longer	O
-	O
term	O
weight	O
-	O
loss	O
success	O
.	O

Barriers	O
to	O
Adherence	O

We	O
have	O
also	O
attempted	O
to	O
measure	O
barriers	O
to	O
adherence	O
to	O
weight	O
-	O
control	O
behaviors	O
in	O
many	O
of	O
our	O
studies	O
[	O
11	O
-	O
14	O
]	O
.	O

The	O
instruments	O
used	O
for	O
this	O
have	O
typically	O
been	O
formatted	O
similarly	O
to	O
efficacy	O
questionnaires	O
in	O
that	O
people	B
are	O
asked	O
to	O
indicate	O
how	O
difficult	O
they	O
find	O
situational	O
,	O
knowledge	O
,	O
and	O
motivational	O
challenges	O
to	O
achieving	O
diet	O
and	O
exercise	O
changes	O
.	O

The	O
findings	O
in	O
these	O
studies	O
have	O
been	O
quite	O
consistent	O
.	O

Baseline	O
assessments	O
of	O
perceived	O
barriers	O
to	O
behavior	O
change	O
are	O
not	O
predictive	O
of	O
weight	O
change	O
.	O

Weight	O
loss	O
is	O
associated	O
with	O
reported	O
decreases	O
in	O
perceived	O
barriers	O
.	O

Treatment	O
-	O
induced	O
change	O
in	O
perceived	O
barriers	O
are	O
not	O
predictive	O
of	O
future	O
weight	O
change	O
.	O

In	O
other	O
words	O
,	O
barrier	O
perceptions	O
as	O
we	O
have	O
measured	O
them	O
do	O
not	O
appear	O
to	O
have	O
pragmatic	O
significance	O
.	O

Weight	O
Goals	O

Goal	O
-	O
setting	O
has	O
long	O
been	O
of	O
interest	O
to	O
health	O
behavior	O
theory	O
and	O
in	O
recent	O
years	O
has	O
attracted	O
attention	O
in	O
weight	O
-	O
loss	O
research	O
when	O
it	O
was	O
realized	O
that	O
most	O
people	B
who	O
enter	O
weight	O
-	O
loss	O
treatments	O
want	O
to	O
lose	O
a	O
lot	O
more	O
weight	O
than	O
is	O
realistic	O
given	O
the	O
potency	O
of	O
current	O
weight	O
-	O
loss	O
methodologies	O
[	O
15	O
]	O
.	O

When	O
asked	O
to	O
describe	O
weight	O
losses	O
they	O
deem	O
to	O
represent	O
"	O
dream	O
,	O
happy	O
,	O
acceptable	O
,	O
and	O
disappointing	O
,	O
"	O
many	O
individuals	O
in	O
treatment	O
fail	O
to	O
reach	O
even	O
"	O
disappointing	O
"	O
weight	O
losses	O
even	O
though	O
in	O
objective	O
medical	O
terms	O
the	O
results	O
are	O
positive	O
.	O

Based	O
on	O
the	O
argument	O
that	O
failure	O
to	O
reach	O
gratifying	O
weight	O
-	O
loss	O
goals	O
leads	O
to	O
psychological	O
distress	O
that	O
lowers	O
weight	O
self	O
-	O
efficacy	O
and	O
undermines	O
weight	O
-	O
loss	O
efforts	O
,	O
it	O
has	O
become	O
popular	O
to	O
recommend	O
counseling	O
in	O
weight	O
-	O
loss	O
treatments	O
specifically	O
targeting	O
the	O
lowering	O
of	O
weight	O
-	O
loss	O
goals	O
.	O

The	O
theoretical	O
argument	O
is	O
that	O
excessive	O
outcome	O
expectations	O
undermine	O
behavioral	O
efforts	O
.	O

We	O
have	O
now	O
completed	O
three	O
sets	O
of	O
formal	O
analyses	O
examining	O
whether	O
weight	O
goals	O
are	O
predictive	O
of	O
weight	O
-	O
loss	O
success	O
.	O

In	O
one	O
of	O
these	O
analyses	O
the	O
relationship	O
between	O
weight	O
-	O
loss	O
goals	O
,	O
weight	O
-	O
loss	O
goal	O
attainment	O
,	O
and	O
long	O
-	O
term	O
(	O
30	O
months	O
)	O
weight	O
-	O
loss	O
attainment	O
and	O
psychological	O
well	O
-	O
being	O
were	O
assessed	O
in	O
69	O
men	B
and	O
61	O
women	B
participating	O
in	O
an	O
intensive	O
behavioral	O
treatment	O
program	O
[	O
16	O
]	O
.	O

Results	O
indicated	O
that	O
weight	O
-	O
loss	O
goals	O
were	O
unrealistically	O
high	O
on	O
average	O
and	O
that	O
lower	O
goals	O
were	O
more	O
likely	O
to	O
be	O
reached	O
.	O

Nevertheless	O
,	O
weight	O
-	O
loss	O
goals	O
did	O
not	O
predict	O
either	O
short	O
-	O
or	O
long	O
-	O
term	O
weight	O
losses	O
and	O
were	O
not	O
associated	O
with	O
elevated	O
psychological	O
distress	O
.	O

Two	O
more	O
recent	O
analyses	O
we	O
have	O
conducted	O
looking	O
at	O
weight	O
-	O
loss	O
goals	O
as	O
predictors	O
of	O
success	O
have	O
produced	O
similar	O
results	O
[	O
Linde	O
JA	O
,	O
Jeffery	O
RW	O
,	O
Levy	O
RL	O
,	O
Pronk	O
NP	O
and	O
Boyle	O
RG	O
,	O
unpublished	O
data	O
[	O
17	O
]	O
]	O
.	O

Weight	O
-	O
loss	O
goals	O
either	O
did	O
not	O
predict	O
weight	O
loss	O
at	O
all	O
or	O
were	O
slightly	O
positively	O
related	O
to	O
weight	O
-	O
loss	O
success	O
.	O

Perceived	O
Social	O
Support	O

Perceived	O
social	O
support	O
is	O
another	O
psychological	O
factor	O
thought	O
to	O
influence	O
health	O
behavior	O
decision	O
-	O
making	O
.	O

We	O
have	O
measured	O
social	O
support	O
in	O
a	O
variety	O
of	O
ways	O
in	O
our	O
studies	O
,	O
ranging	O
from	O
single	O
-	O
item	O
questions	O
to	O
multipaged	O
assessments	O
attempting	O
to	O
differentiate	O
among	O
informational	O
,	O
instrumental	O
,	O
and	O
emotional	O
support	O
.	O

The	O
results	O
,	O
unfortunately	O
,	O
have	O
closely	O
paralleled	O
those	O
we	O
have	O
seen	O
with	O
other	O
assessments	O
of	O
barriers	O
to	O
adherence	O
.	O

Assessments	O
of	O
social	O
support	O
prior	O
to	O
treatment	O
do	O
not	O
predict	O
weight	O
loss	O
.	O

Average	O
reports	O
of	O
social	O
support	O
tend	O
to	O
parallel	O
weight	O
loss	O
itself	O
.	O

When	O
people	B
lose	O
weight	O
they	O
report	O
more	O
social	O
support	O
.	O

When	O
they	O
regain	O
,	O
they	O
report	O
less	O
.	O

In	O
other	O
words	O
,	O
perceptions	O
of	O
social	O
support	O
are	O
not	O
predictive	O
of	O
success	O
in	O
weight	O
-	O
loss	O
treatments	O
.	O

Frequency	O
Weight	O
Self	O
-	O
monitoring	O

Self	O
-	O
monitoring	O
of	O
health	O
behavior	O
is	O
incorporated	O
into	O
many	O
health	O
behavior	O
theories	O
,	O
usually	O
as	O
part	O
of	O
a	O
person	B
'	O
s	O
assessment	O
of	O
achieved	O
outcomes	O
.	O

Although	O
self	O
-	O
monitoring	O
is	O
usually	O
considered	O
a	O
positive	O
element	O
in	O
the	O
adoption	O
of	O
health	O
behavior	O
,	O
in	O
obesity	O
treatment	O
frequent	O
self	O
-	O
monitoring	O
of	O
weight	O
has	O
tended	O
to	O
be	O
down	O
-	O
played	O
or	O
even	O
discouraged	O
on	O
the	O
grounds	O
that	O
disappointing	O
results	O
(	O
i	O
.	O
e	O
.	O
,	O
less	O
than	O
desired	O
weight	O
change	O
)	O
may	O
undermine	O
motivation	O
.	O

This	O
is	O
another	O
example	O
in	O
which	O
health	O
behavior	O
theory	O
may	O
have	O
indirectly	O
led	O
to	O
incorrect	O
treatment	O
recommendations	O
.	O

In	O
weight	O
-	O
loss	O
treatments	O
,	O
active	O
discouragement	O
of	O
frequent	O
self	O
-	O
observation	O
of	O
weight	O
has	O
become	O
popular	O
based	O
on	O
the	O
premise	O
that	O
more	O
frequent	O
weighting	O
will	O
cause	O
psychological	O
stress	O
and	O
lower	O
self	O
-	O
efficacy	O
.	O

Recently	O
,	O
we	O
have	O
examined	O
the	O
relationship	O
between	O
frequency	O
of	O
self	O
-	O
weighing	O
and	O
body	O
weight	O
in	O
both	O
clinical	O
and	O
population	O
samples	O
and	O
have	O
found	O
,	O
somewhat	O
to	O
our	O
surprise	O
,	O
that	O
frequency	O
of	O
self	O
-	O
weighing	O
is	O
one	O
of	O
the	O
strongest	O
single	O
predictors	O
of	O
body	O
weight	O
cross	O
-	O
sectionally	O
,	O
and	O
change	O
in	O
the	O
frequency	O
of	O
self	O
-	O
weighing	O
is	O
one	O
of	O
the	O
strongest	O
predictors	O
of	O
weight	O
change	O
[	O
Linde	O
JA	O
,	O
Jeffery	O
RW	O
and	O
French	O
SA	O
,	O
unpublished	O
data	O
]	O
.	O

The	O
direction	O
of	O
predictions	O
,	O
however	O
,	O
is	O
opposite	O
that	O
derived	O
from	O
theory	O
.	O

People	B
who	O
weigh	O
themselves	O
more	O
weigh	O
less	O
and	O
are	O
more	O
successful	O
in	O
losing	O
weight	O
.	O

Stage	O
-	O
of	O
-	O
Change	O

A	O
final	O
failure	O
of	O
current	O
health	O
behavior	O
theory	O
to	O
prove	O
useful	O
in	O
weight	O
-	O
control	O
research	O
is	O
a	O
recent	O
examination	O
of	O
the	O
relationship	O
between	O
a	O
stage	O
-	O
of	O
-	O
change	O
measure	O
adopted	O
from	O
Prochaska	O
and	O
short	O
-	O
and	O
long	O
-	O
term	O
weight	O
loss	O
[	O
18	O
]	O
.	O

Categories	O
of	O
precontemplation	O
,	O
contemplation	O
,	O
preparation	O
,	O
and	O
action	O
were	O
defined	O
based	O
on	O
questions	O
about	O
weight	O
-	O
loss	O
intentions	O
and	O
recent	O
weight	O
-	O
loss	O
attempts	O
.	O

Despite	O
a	O
large	O
sample	O
size	O
,	O
excellent	O
follow	O
-	O
up	O
rates	O
,	O
and	O
well	O
-	O
measured	O
objective	O
outcomes	O
,	O
we	O
were	O
unable	O
to	O
demonstrate	O
that	O
staging	O
algorithms	O
recommended	O
by	O
proponents	O
of	O
the	O
Transtheoretical	O
Model	O
could	O
predict	O
weight	O
-	O
loss	O
outcomes	O
.	O

Experimental	O
Modification	O
of	O
Expectations	O

Our	O
most	O
recent	O
effort	O
to	O
utilize	O
health	O
behavior	O
theory	O
in	O
obesity	O
intervention	O
research	O
is	O
a	O
study	O
that	O
attempted	O
to	O
examine	O
the	O
effectiveness	O
of	O
experimentally	O
-	O
induced	O
outcome	O
expectancies	O
on	O
weight	O
loss	O
[	O
Finch	O
EA	O
,	O
Linde	O
JA	O
,	O
Jeffery	O
RW	O
,	O
Rothman	O
AJ	O
and	O
King	O
CM	O
,	O
unpublished	O
data	O
]	O
.	O

Obese	O
men	B
and	O
women	B
participated	O
in	O
an	O
8	O
-	O
week	O
weight	O
-	O
loss	O
program	O
with	O
18	O
-	O
month	O
follow	O
-	O
up	O
in	O
which	O
they	O
were	O
assigned	O
to	O
one	O
of	O
two	O
expectancy	O
groups	O
.	O

The	O
optimistic	O
group	O
was	O
told	O
that	O
focusing	O
exclusively	O
on	O
the	O
positive	O
benefits	O
of	O
weight	O
loss	O
would	O
be	O
valuable	O
in	O
ensuring	O
that	O
they	O
remained	O
motivated	O
in	O
their	O
weight	O
-	O
loss	O
efforts	O
and	O
was	O
given	O
assignments	O
during	O
weekly	O
group	O
sessions	O
and	O
homework	O
between	O
sessions	O
to	O
reinforce	O
this	O
optimistic	O
mindset	O
.	O

A	O
"	O
balanced	O
"	O
expectancy	O
group	O
received	O
the	O
instructions	O
that	O
focusing	O
on	O
both	O
the	O
positive	O
and	O
negative	O
aspects	O
of	O
weight	O
loss	O
,	O
a	O
balanced	O
approach	O
,	O
would	O
be	O
most	O
conducive	O
to	O
maintaining	O
weight	O
-	O
loss	O
motivation	O
.	O

This	O
group	O
also	O
received	O
assignments	O
to	O
reinforce	O
their	O
message	O
.	O

Results	O
of	O
this	O
study	O
indicated	O
that	O
the	O
expectation	O
induction	O
was	O
successful	O
initially	O
but	O
difficult	O
to	O
maintain	O
in	O
the	O
face	O
of	O
real	O
weight	O
-	O
loss	O
experience	O
.	O

We	O
were	O
also	O
unable	O
to	O
show	O
that	O
experimentally	O
-	O
induced	O
expectations	O
influenced	O
weight	O
-	O
loss	O
success	O
.	O

Summary	O
and	O
Conclusion	O

To	O
summarize	O
the	O
findings	O
described	O
above	O
,	O
I	O
have	O
had	O
considerable	O
difficulty	O
over	O
the	O
last	O
25	O
years	O
in	O
confirming	O
that	O
the	O
psychosocial	O
variables	O
favored	O
by	O
health	O
behavior	O
theory	O
are	O
of	O
much	O
value	O
for	O
obesity	O
intervention	O
research	O
.	O

They	O
do	O
not	O
predict	O
weight	O
loss	O
well	O
,	O
either	O
as	O
mediators	O
or	O
moderators	O
.	O

There	O
is	O
little	O
evidence	O
to	O
support	O
the	O
idea	O
that	O
targeting	O
them	O
for	O
intervention	O
improves	O
weight	O
-	O
loss	O
outcomes	O
.	O

It	O
is	O
,	O
of	O
course	O
,	O
arguable	O
that	O
the	O
weak	O
findings	O
relating	O
to	O
health	O
behavior	O
theory	O
variables	O
are	O
due	O
in	O
large	O
part	O
to	O
methodological	O
weaknesses	O
,	O
either	O
in	O
measurement	O
tools	O
and	O
/	O
or	O
their	O
frequency	O
of	O
measurement	O
.	O

I	O
would	O
argue	O
,	O
however	O
,	O
that	O
25	O
years	O
is	O
long	O
enough	O
to	O
wait	O
for	O
improved	O
methods	O
and	O
that	O
it	O
is	O
time	O
to	O
look	O
elsewhere	O
for	O
variables	O
that	O
better	O
predict	O
weight	O
-	O
change	O
outcomes	O
and	O
that	O
,	O
therefore	O
,	O
may	O
form	O
a	O
better	O
basis	O
for	O
improving	O
future	O
treatments	O
.	O

Implication	O
for	O
Weight	O
-	O
Loss	O
Treatment	O

Given	O
the	O
lack	O
of	O
success	O
finding	O
support	O
for	O
cognitive	O
mediators	O
of	O
behavior	O
change	O
in	O
weight	O
loss	O
,	O
one	O
might	O
surmise	O
that	O
progress	O
in	O
improving	O
weight	O
-	O
loss	O
interventions	O
over	O
the	O
last	O
20	O
years	O
must	O
have	O
been	O
dreary	O
indeed	O
.	O

Somewhat	O
surprisingly	O
,	O
however	O
,	O
that	O
is	O
not	O
the	O
case	O
.	O

In	O
fact	O
,	O
the	O
short	O
-	O
term	O
(	O
6	O
to	O
12	O
months	O
)	O
success	O
of	O
weight	O
-	O
loss	O
treatments	O
has	O
approximately	O
doubled	O
over	O
that	O
time	O
and	O
several	O
variables	O
have	O
been	O
identified	O
that	O
reliably	O
enhance	O
treatment	O
outcomes	O
.	O

It	O
has	O
been	O
clearly	O
shown	O
experimentally	O
that	O
increasing	O
treatment	O
length	O
[	O
19	O
]	O
,	O
prescribing	O
low	O
-	O
energy	O
intakes	O
[	O
20	O
]	O
,	O
prescribing	O
high	O
-	O
energy	O
expenditure	O
[	O
21	O
]	O
,	O
using	O
a	O
deposit	O
contract	O
and	O
group	O
-	O
based	O
reward	O
systems	O
[	O
22	O
]	O
,	O
and	O
simplifying	O
adherence	O
to	O
diet	O
through	O
meal	O
substitutes	O
[	O
23	O
]	O
and	O
exercise	O
by	O
providing	O
exercise	O
equipment	O
[	O
24	O
]	O
all	O
improve	O
initial	O
weight	O
loss	O
.	O

From	O
a	O
theoretical	O
perspective	O
,	O
however	O
,	O
one	O
thing	O
is	O
noteworthy	O
about	O
these	O
successful	O
innovations	O
.	O

Although	O
not	O
incompatible	O
with	O
health	O
behavior	O
theory	O
,	O
none	O
of	O
them	O
are	O
specifically	O
derived	O
from	O
cognitive	O
decision	O
-	O
making	O
models	O
.	O

Indeed	O
,	O
health	O
behavior	O
theory	O
does	O
not	O
include	O
variables	O
like	O
these	O
in	O
its	O
models	O
.	O

Where	O
Do	O
We	O
Go	O
From	O
Here	O
?	O

The	O
argument	O
above	O
about	O
the	O
practical	O
limitations	O
of	O
many	O
popular	O
theories	O
of	O
health	O
behavior	O
is	O
not	O
meant	O
to	O
be	O
a	O
call	O
to	O
abandon	O
theory	O
.	O

Behavior	O
scientists	O
have	O
amassed	O
much	O
useful	O
information	O
about	O
the	O
principles	O
underlying	O
human	B
behavior	O
that	O
should	O
be	O
valuable	O
for	O
health	O
behavior	O
interventions	O
.	O

Much	O
is	O
known	O
about	O
human	B
perception	O
,	O
learning	O
,	O
motivation	O
,	O
and	O
responsiveness	O
to	O
environmental	O
opportunities	O
and	O
contingencies	O
.	O

Health	O
behavior	O
intervention	O
lies	O
at	O
the	O
interface	O
between	O
people	B
and	O
their	O
environment	O
.	O

Interventionists	O
change	O
aspects	O
of	O
the	O
environment	O
(	O
cues	O
,	O
information	O
,	O
behavioral	O
contingencies	O
)	O
with	O
the	O
intention	O
of	O
producing	O
changes	O
in	O
how	O
people	B
behave	O
.	O

What	O
is	O
needed	O
to	O
advance	O
health	O
behavior	O
intervention	O
is	O
theory	O
that	O
addresses	O
relationships	O
between	O
modifiable	O
aspects	O
of	O
the	O
environment	O
and	O
behavior	O
.	O

There	O
is	O
no	O
doubt	O
that	O
cognitive	O
processes	O
are	O
involved	O
in	O
these	O
relationships	O
.	O

However	O
,	O
the	O
extent	O
to	O
which	O
current	O
theories	O
capture	O
this	O
is	O
questionable	O
.	O

Data	O
now	O
available	O
suggest	O
that	O
easily	O
obtainable	O
information	O
about	O
people	B
'	O
s	O
cognitive	O
processes	O
adds	O
little	O
to	O
our	O
ability	O
to	O
predict	O
the	O
results	O
of	O
interventions	O
.	O

Thus	O
,	O
it	O
may	O
be	O
wise	O
to	O
pay	O
more	O
attention	O
to	O
applied	O
theories	O
like	O
classical	O
behavior	O
theory	O
[	O
25	O
]	O
,	O
communications	O
theory	O
[	O
26	O
]	O
,	O
and	O
learning	O
theory	O
[	O
27	O
]	O
than	O
to	O
those	O
coming	O
out	O
of	O
the	O
social	O
cognitive	O
traditions	O
.	O

Competing	O
interests	O

None	O
declared	O
.	O