In	O
the	O
8	O
patients	O
the	O
difference	O
betweent	O
he	O
mean	O
diastolic	O
values	O
of	O
delta	O
PU	O
and	O
delta	O
PM	O
was	O
-	O
0	O
.	O
54	O
+	O
/	O
-	O
1	O
.	O
0	O
(	O
SD	O
)	O
mmHg	O
.	O

The	O
biochemistry	O
of	O
amniotic	O
fluid	O
with	O
poor	O
fetal	O
growth	O
.	O

Resistance	O
to	O
the	O
simulated	O
physiologic	O
environment	O
was	O
tested	O
by	O
measured	O
retention	O
of	O
mechanical	O
properties	O
after	O
immersion	O
times	O
in	O
pseudo	O
-	O
extracellular	O
fluid	O
(	O
PECF	O
)	O
at	O
37	O
degrees	O
C	O
for	O
as	O
long	O
as	O
three	O
years	O
.	O

This	O
expression	O
assumes	O
:	O
(	O
1	O
)	O
a	O
laminar	O
flow	O
regimen	O
during	O
expiration	O
,	O
and	O
(	O
2	O
)	O
a	O
constant	O
CT	O
value	O
over	O
the	O
range	O
of	O
VT	O
.	O

Their	O
conduction	O
velocity	O
ranged	O
from	O
0	O
.	O
23	O
to	O
0	O
.	O
98	O
m	O
/	O
sec	O
(	O
group	O
C	O
)	O
.	O

The	O
major	O
urinary	O
metabolites	O
were	O
3	O
-	O
(	O
3	O
-	O
carboxyphenyl	O
)	O
-	O
5	O
-	O
hydroxymethyl	O
-	O
2	O
-	O
oxazolidinone	O
and	O
a	O
glucuronide	O
of	O
toloxatone	O
.	O

The	O
ventilation	O
did	O
not	O
increase	O
when	O
PACO2	O
was	O
increased	O
.	O

Changes	O
of	O
thirtynine	O
serum	O
protein	O
components	O
following	O
surgical	O
stress	O
.	O

These	O
differences	O
are	O
smaller	O
than	O
those	O
described	O
in	O
standard	O
textbooks	O
.	O

The	O
present	O
study	O
examined	O
the	O
dependence	O
of	O
difference	O
tone	O
level	O
[	O
L	O
(	O
f2	O
-	O
f1	O
)	O
]	O
on	O
the	O
following	O
parameters	O
of	O
the	O
two	O
-	O
tone	O
input	O
:	O
f1	O
,	O
f2	O
/	O
f1	O
(	O
f2	O
greater	O
than	O
f1	O
)	O
,	O
L1	O
,	O
L2	O
,	O
and	O
L1	O
=	O
L2	O
.	O

With	O
certain	O
exceptions	O
the	O
method	O
was	O
considered	O
suitable	O
in	O
the	O
routine	O
intravenous	O
cholangiography	O
.	O

Delayed	O
mortality	O
of	O
mice	O
following	O
inhalation	O
of	O
acute	O
doses	O
of	O
CH2O	O
,	O
SO2Cl2	O
,	O
and	O
Br2	O
.	O

Guinea	O
pigs	O
weighing	O
300	O
approximately	O
350	O
g	O
were	O
used	O
.	O

None	O
of	O
the	O
cystometrograms	O
showed	O
uninhibited	O
detrusor	O
contractions	O
.	O

Treatment	O
of	O
Graves	O
'	O
disease	O
.	O

Allergic	O
reaction	O
to	O
Patent	O
Blue	O
Violet	O
during	O
lymphography	O
.	O

One	O
-	O
third	O
of	O
the	O
men	O
with	O
azoospermia	O
and	O
with	O
sperm	O
density	O
of	O
less	O
than	O
10	O
million	O
had	O
marked	O
FSH	B-GENE
elevation	O
and	O
our	O
experience	O
confirms	O
the	O
work	O
of	O
others	O
that	O
this	O
indicates	O
a	O
poor	O
prognosis	O
.	O

It	O
was	O
concluded	O
that	O
both	O
of	O
these	O
surgical	O
procedures	O
were	O
as	O
effective	O
as	O
pinealectomy	O
in	O
reversing	O
the	O
pineal	O
-	O
induced	O
alterations	O
in	O
the	O
reproductive	O
physiology	O
of	O
the	O
blind	O
-	O
anosmic	O
female	O
rat	O
.	O

This	O
implies	O
that	O
the	O
groups	O
do	O
not	O
just	O
differ	O
along	O
one	O
dimension	O
,	O
but	O
along	O
three	O
dimensions	O
.	O

Deep	O
tans	O
were	O
induced	O
over	O
the	O
backs	O
of	O
volunteers	O
with	O
repeated	O
exposure	O
to	O
longwave	O
ultraviolet	O
radiation	O
(	O
UV	O
-	O
A	O
)	O
.	O

Elimination	O
of	O
bagassosis	O
in	O
Louisiana	O
paper	O
manufacturing	O
plant	O
workers	O
.	O

Evaluation	O
of	O
the	O
Du	O
Pont	O
aca	O
ammonia	O
procedure	O
.	O

2	O
)	O
The	O
time	O
-	O
sharing	O
principle	O
was	O
applied	O
to	O
gain	O
high	O
stability	O
.	O

In	O
three	O
of	O
the	O
seven	O
,	O
inhalation	O
of	O
2	O
ml	O
normal	O
saline	O
produced	O
FEV1	O
falls	O
of	O
25	O
%	O
to	O
30	O
%	O
,	O
but	O
these	O
falls	O
were	O
not	O
as	O
great	O
as	O
each	O
subject	O
'	O
s	O
reactions	O
to	O
the	O
test	O
solutions	O
.	O

Potency	O
of	O
enflurane	O
in	O
dogs	O
:	O
comparison	O
with	O
halothane	O
and	O
isoflurane	O
.	O

Measurement	O
of	O
magnesium	O
absorption	O
in	O
man	O
using	O
stable	O
26Mg	O
as	O
a	O
tracer	O
.	O

Female	O
mice	O
were	O
significantly	O
more	O
resistant	O
to	O
infection	O
than	O
males	O
.	O

During	O
the	O
following	O
9	O
1	O
/	O
2	O
years	O
three	O
sequential	O
liver	O
biopsies	O
were	O
performed	O
.	O

Thromboplastic	O
and	O
fibrynolytic	O
activity	O
of	O
the	O
blood	O
after	O
administration	O
of	O
intralipid	O
in	O
men	O
with	O
history	O
of	O
myocardial	O
infarction	O
up	O
to	O
45	O
year	O
of	O
life	O

The	O
authors	O
report	O
the	O
clinicopathologic	O
findings	O
in	O
four	O
cases	O
of	O
adult	O
women	O
with	O
rhabdomyosarcomas	O
that	O
originated	O
in	O
the	O
endometrium	O
or	O
cervix	O
,	O
or	O
both	O
.	O

Urine	O
antibodies	O
could	O
not	O
be	O
demonstrated	O
in	O
any	O
other	O
cases	O
.	O

99mTc	O
phytate	O
,	O
198Au	O
colloid	O
,	O
and	O
99mTc	O
antimony	O
sulfide	O
have	O
been	O
used	O
;	O
the	O
last	O
appears	O
to	O
have	O
been	O
the	O
most	O
satisfactory	O
.	O

A	O
suspected	O
hypothalamic	O
dysfunction	O
and	O
a	O
slightly	O
impaired	O
pituitary	O
function	O
manifested	O
as	O
GH	B-GENE
deficiency	O
were	O
their	O
common	O
endocrinological	O
features	O
.	O

A	O
one	O
-	O
way	O
analysis	O
of	O
variance	O
,	O
performed	O
separately	O
for	O
men	O
and	O
women	O
for	O
differences	O
among	O
the	O
three	O
phobic	O
groups	O
on	O
field	O
dependence	O
,	O
showed	O
significance	O
(	O
rho	O
less	O
than	O
.	O
05	O
)	O
for	O
the	O
females	O
,	O
with	O
the	O
famale	O
agoraphobic	O
being	O
more	O
field	O
dependent	O
than	O
the	O
female	O
simple	O
phobic	O
groups	O
,	O
but	O
not	O
for	O
the	O
males	O
.	O

Residues	O
removed	O
from	O
transcripts	O
by	O
splicing	O
were	O
identified	O
.	O

The	O
histochemistry	O
and	O
ultrastructure	O
of	O
calcified	O
cerebellar	O
deposits	O
described	O
by	O
Tonge	O
et	O
al	O
.	O

A	O
36	O
year	O
-	O
old	O
woman	O
was	O
given	O
Ergotamine	O
Tartrate	O
4	O
.	O
5	O
mg	O
p	O
.	O
d	O
.	O
during	O
seven	O
days	O
,	O
after	O
an	O
abortion	O
(	O
a	O
still	O
birth	O
)	O
.	O

As	O
expected	O
,	O
the	O
heparin	O
did	O
produce	O
increased	O
recalcification	O
times	O
and	O
the	O
development	O
of	O
occasional	O
subcutaneous	O
hematomas	O
.	O

The	O
overall	O
incidence	O
of	O
SIDS	O
was	O
1	O
.	O
43	O
per	O
1	O
,	O
000	O
live	O
births	O
.	O

Significant	O
increases	O
in	O
mean	O
serum	O
E2	O
concentration	O
(	O
100	O
to	O
150	O
pg	O
/	O
ml	O
)	O
were	O
noted	O
at	O
6	O
and	O
8	O
hours	O
after	O
administration	O
on	O
day	O
1	O
and	O
at	O
8	O
hours	O
on	O
day	O
4	O
.	O

We	O
remain	O
convinced	O
that	O
antilymphocyte	B-GENE
globulin	I-GENE
(	O
ALG	B-GENE
)	O
is	O
a	O
potent	O
immunosuppressive	O
agent	O
in	O
humans	O
.	O

Patients	O
were	O
subclassified	O
into	O
age	O
-	O
matched	O
groups	O
of	O
primary	O
untreated	O
cancer	O
(	O
21	O
)	O
,	O
recurrent	O
cancer	O
(	O
18	O
)	O
,	O
and	O
"	O
cured	O
"	O
patients	O
who	O
had	O
been	O
free	O
of	O
disease	O
for	O
at	O
least	O
9	O
months	O
(	O
16	O
)	O
.	O

Bacteriostatic	O
and	O
bacteriacidal	O
activity	O
of	O
hydroxy	O
-	O
9	O
ellipticine	O
in	O
vitro	O

Personal	O
satisfaction	O
in	O
nursing	O
:	O
an	O
encounter	O
with	O
extremely	O
hostile	O
patients	O

The	O
effect	O
of	O
hydrostatic	O
pressure	O
on	O
the	O
swimming	O
activity	O
of	O
three	O
hyponeustonic	O
crustacea	O
,	O
Anomalocera	O
patersoni	O
,	O
Pontella	O
mediterranea	O
,	O
Labidocera	O
wollastoni	O

Abnormal	O
calcium	O
metabolism	O
in	O
normocalcaemic	O
sarcoidosis	O
.	O

A	O
five	O
-	O
phase	O
experiment	O
was	O
designed	O
to	O
investigate	O
(	O
a	O
)	O
whether	O
contingent	O
music	O
-	O
listening	O
would	O
act	O
as	O
a	O
reinforcer	O
to	O
increase	O
arithmetic	O
performance	O
of	O
EMR	O
children	O
and	O
(	O
b	O
)	O
whether	O
this	O
contingent	O
reinforcement	O
would	O
affect	O
preference	O
for	O
that	O
reinforcer	O
.	O

The	O
responsiveness	O
of	O
visual	O
cortex	O
(	O
VC	O
)	O
and	O
superior	O
colliculus	O
(	O
SC	O
)	O
was	O
simultaneously	O
compared	O
following	O
conditioning	O
"	O
ON	O
"	O
or	O
"	O
OFF	O
"	O
stimulation	O
,	O
in	O
the	O
rabbit	O
.	O

During	O
activity	O
III	O
,	O
one	O
patient	O
developed	O
angina	O
.	O

Estimation	O
of	O
L	O
-	O
alanine	O
in	O
serum	O
or	O
plasma	O
using	O
the	O
LKB	O
reaction	O
rate	O
analyser	O
.	O

Infants	O
who	O
died	O
in	O
the	O
first	O
12	O
hours	O
from	O
'	O
IVH	O
only	O
'	O
had	O
suffered	O
severe	O
birth	O
asphyxia	O
but	O
in	O
those	O
who	O
died	O
later	O
the	O
main	O
symptom	O
was	O
recurrent	O
apnoea	O
.	O

Wherever	O
the	O
site	O
of	O
the	O
conditioning	O
stimulation	O
,	O
these	O
modifications	O
disappeared	O
after	O
ischaemia	O
of	O
the	O
leg	O
.	O

Near	O
term	O
,	O
under	O
experimental	O
conditions	O
,	O
maternal	O
and	O
fetal	O
blood	O
gases	O
,	O
pH	O
,	O
uterine	O
and	O
umbilical	O
blood	O
flows	O
were	O
measured	O
or	O
calculated	O
.	O

It	O
was	O
concluded	O
that	O
patients	O
with	O
acute	O
respiratory	O
failure	O
requiring	O
artificial	O
ventilation	O
have	O
two	O
componenents	O
of	O
the	O
pulmonary	O
shunt	O
,	O
one	O
parallel	O
with	O
and	O
the	O
other	O
inversely	O
related	O
with	O
the	O
PAO2	O
.	O

The	O
most	O
common	O
cause	O
of	O
renal	O
deterioration	O
in	O
the	O
spinal	O
cord	O
injured	O
patient	O
is	O
irreversible	O
vesicoureteral	O
reflux	O
.	O

Circulatory	O
arrest	O
in	O
the	O
operating	O
room	O
.	O

Iodine	O
-	O
123	O
was	O
satisfactorily	O
imaged	O
only	O
with	O
the	O
MEC	O
and	O
pinhole	O
collimators	O
,	O
which	O
in	O
turn	O
yielded	O
MTF	O
values	O
comparable	O
to	O
those	O
measured	O
for	O
99mTc	O
.	O

Petrous	O
meningioma	O
en	O
plaque	O
presenting	O
as	O
a	O
right	O
middle	O
ear	O
tumor	O
.	O

The	O
difficulties	O
to	O
analyse	O
prostaglandins	O
(	O
PG	O
)	O
by	O
gas	O
-	O
liquid	O
chromatography	O
are	O
mainly	O
due	O
to	O
the	O
lack	O
of	O
sensitivity	O
of	O
the	O
gas	O
-	O
chromatograph	O
itself	O
(	O
higher	O
than	O
200	O
ng	O
)	O
and	O
to	O
the	O
poor	O
resolution	O
of	O
the	O
packed	O
columns	O
.	O

Also	O
,	O
samples	O
of	O
serum	O
were	O
absorbed	O
with	O
the	O
various	O
solid	O
-	O
phase	O
allergens	O
and	O
the	O
reactivity	O
of	O
the	O
remaining	O
IgE	B-GENE
antibodies	I-GENE
was	O
determined	O
.	O

Extramedullary	O
plasmacytoma	O
of	O
the	O
parotid	O
gland	O

The	O
recovered	O
calves	O
were	O
tested	O
for	O
immunity	O
to	O
homologous	O
severe	O
challenge	O
,	O
50	O
or	O
73	O
days	O
after	O
the	O
first	O
infection	O
.	O

Oxygen	O
tension	O
of	O
the	O
small	O
lymph	O
vessels	O
(	O
PLO2	O
)	O
of	O
the	O
rabbit	O
hind	O
limb	O
was	O
measured	O
with	O
both	O
a	O
flow	O
-	O
through	O
micro	O
chamber	O
and	O
a	O
polarographic	O
catheter	O
-	O
tip	O
oxygen	O
electrode	O
to	O
obtain	O
experimental	O
data	O
on	O
the	O
source	O
of	O
oxygen	O
in	O
the	O
lymph	O
.	O

I	O
.	O

Since	O
1968	O
,	O
a	O
steep	O
decrease	O
in	O
the	O
number	O
of	O
strains	O
resistant	O
to	O
three	O
or	O
more	O
antibiotics	O
(	O
multiple	O
-	O
resistant	O
)	O
and	O
in	O
strains	O
of	O
the	O
83A	O
complex	O
was	O
noticed	O
.	O

The	O
contraceptive	O
pattern	O
of	O
157	O
women	O
was	O
analysed	O
and	O
13	O
.	O
8	O
percent	O
were	O
using	O
inefficient	O
methods	O
.	O

I	O
.	O

Nerve	O
stimulation	O
(	O
1	O
.	O
5	O
-	O
12	O
cycles	O
/	O
s	O
)	O
produced	O
frequency	O
-	O
dependent	O
reductions	O
in	O
CBF	O
,	O
a	O
decrease	O
of	O
50	O
percent	O
occurring	O
with	O
the	O
highest	O
frequency	O
.	O

Risk	O
of	O
infection	O
in	O
the	O
treatment	O
of	O
fractures	O

Prolonged	O
heavy	O
work	O
effected	O
an	O
increase	O
of	O
10	O
.	O
3	O
plus	O
or	O
minus	O
0	O
.	O
9	O
mmHg	O
in	O
in	O
vivo	O
P50	O
(	O
7	O
.	O
30	O
PH	O
-	O
v	O
,	O
41	O
degrees	O
C	O
-	O
v	O
,	O
and	O
45	O
Pv	O
-	O
CO2	O
)	O
;	O
due	O
entirely	O
to	O
the	O
additive	O
effects	O
of	O
increased	O
venous	O
temperature	O
and	O
[	O
H	O
+	O
]	O
.	O

This	O
sequence	O
is	O
almost	O
identical	O
with	O
that	O
of	O
human	B-GENE
luteinizing	I-GENE
hormone	I-GENE
(	O
Sairam	O
,	O
M	O
.	O

At	O
the	O
very	O
high	O
dose	O
levels	O
used	O
,	O
sodium	O
saccharin	O
and	O
sodium	O
cyclamate	O
were	O
weak	O
solitary	O
carcinogens	O
producing	O
4	O
/	O
253	O
and	O
3	O
/	O
228	O
bladder	O
tumours	O
respectively	O
,	O
and	O
the	O
first	O
of	O
these	O
tumours	O
did	O
not	O
appear	O
for	O
more	O
than	O
80	O
weeks	O
.	O

However	O
,	O
a	O
10	O
-	O
-	O
15	O
%	O
lengthening	O
of	O
the	O
partial	O
thromboplastin	B-GENE
time	O
is	O
evident	O
after	O
24	O
hours	O
of	O
storage	O
.	O

No	O
evidence	O
of	O
either	O
positive	O
or	O
negative	O
chemography	O
was	O
found	O
.	O

A	O
study	O
of	O
chromosomes	O
of	O
lymphocytes	O
from	O
patients	O
treated	O
with	O
hycanthone	O
.	O

Study	O
of	O
the	O
physico	O
-	O
chemical	O
state	O
of	O
plutonium	O
-	O
239	O
in	O
a	O
citrate	O
solution	O
-	O
blood	O
system	O

Maternal	O
lactation	O

In	O
both	O
cases	O
,	O
at	O
the	O
end	O
of	O
exposure	O
the	O
same	O
level	O
of	O
blood	B-GENE
carboxyhemoglobin	I-GENE
(	O
COHb	B-GENE
)	O
(	O
about	O
50	O
%	O
)	O
was	O
reached	O
.	O

The	O
results	O
indicate	O
that	O
increased	O
pulmonary	O
blood	O
flow	O
and	O
decreased	O
pulmonary	O
vascular	O
resistance	O
with	O
advancing	O
gestation	O
are	O
due	O
to	O
an	O
increase	O
in	O
the	O
total	O
number	O
of	O
vessels	O
and	O
increased	O
vasomotor	O
reactivity	O
is	O
related	O
to	O
an	O
increase	O
in	O
the	O
total	O
amount	O
of	O
smooth	O
muscle	O
while	O
the	O
thickness	O
of	O
muscle	O
in	O
individual	O
vessels	O
remains	O
constant	O
.	O

Reduction	O
in	O
dosage	O
restored	O
normal	O
taste	O
sense	O
in	O
all	O
three	O
,	O
but	O
in	O
two	O
the	O
drug	O
had	O
to	O
be	O
discontinued	O
because	O
of	O
persisting	O
high	O
transaminase	O
levels	O
.	O

A	O
late	O
diagnosis	O
of	O
retinoblastoma	O
is	O
an	O
unquestionable	O
fact	O
that	O
allows	O
its	O
growth	O
and	O
leads	O
to	O
a	O
deterioration	O
in	O
the	O
outlook	O
.	O

The	O
concept	O
of	O
"	O
structural	O
identifiability	O
"	O
is	O
employed	O
in	O
this	O
analysis	O
to	O
determine	O
which	O
model	O
parameters	O
can	O
be	O
and	O
which	O
cannot	O
be	O
determined	O
"	O
uniquely	O
"	O
from	O
given	O
input	O
-	O
output	O
data	O
;	O
a	O
step	O
-	O
by	O
-	O
step	O
procedure	O
based	O
on	O
an	O
extension	O
of	O
this	O
concept	O
is	O
presented	O
for	O
adapting	O
the	O
overall	O
approach	O
to	O
the	O
experimental	O
design	O
problem	O
.	O

Acquired	O
factor	B-GENE
VIII	I-GENE
inhibitor	O
in	O
non	O
-	O
hemophilic	O
patients	O

The	O
study	O
of	O
calcium	O
metabolism	O
in	O
ten	O
thalassaemic	O
children	O
comperatively	O
with	O
controls	O
after	O
oral	O
administration	O
of	O
47Ca	O
has	O
shown	O
diminished	O
intestinal	O
absorption	O
.	O

AP	O
was	O
induced	O
by	O
intraductal	O
infusion	O
of	O
two	O
different	O
concentrations	O
of	O
glycodeoxycholic	O
acid	O
(	O
GDOC	O
17	O
mmol	O
and	O
34	O
mmol	O
)	O
.	O

Tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
,	O
its	O
inhibitor	O
and	O
other	O
parameters	O
of	O
fibrinolysis	O
in	O
blood	O
of	O
patients	O
operated	O
for	O
mild	O
hypertrophy	O
of	O
the	O
prostate	O

The	O
mean	O
(	O
+	O
/	O
-	O
SD	O
)	O
PaO2	O
increased	O
from	O
80	O
.	O
8	O
+	O
/	O
-	O
26	O
.	O
9	O
mmHg	O
before	O
to	O
89	O
.	O
8	O
+	O
/	O
-	O
27	O
.	O
3	O
mmHg	O
after	O
the	O
infusion	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
and	O
the	O
PaCO2	O
decreased	O
from	O
42	O
.	O
4	O
+	O
/	O
-	O
8	O
.	O
3	O
to	O
39	O
.	O
6	O
+	O
/	O
-	O
7	O
.	O
9	O
mmHg	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
two	O
drugs	O
increase	O
the	O
rate	O
of	O
early	O
diastolic	O
filling	O
.	O

We	O
cloned	O
the	O
third	O
human	O
gene	O
for	O
the	O
LD78	B-GENE
,	O
termed	O
LD78	B-GENE
gamma	I-GENE
and	O
the	O
sequence	O
analysis	O
showed	O
that	O
it	O
is	O
a	O
5	O
'	O
-	O
truncated	O
pseudogene	O
.	O

In	O
the	O
absence	O
of	O
histological	O
criteria	O
,	O
which	O
it	O
is	O
difficult	O
to	O
demand	O
in	O
view	O
of	O
the	O
variability	O
of	O
results	O
and	O
potential	O
dangers	O
of	O
endomyocardial	O
biopsy	O
involving	O
such	O
thin	O
and	O
fragile	O
ventricular	O
walls	O
,	O
the	O
diagnosis	O
of	O
ACRV	O
is	O
based	O
upon	O
the	O
concomitant	O
existence	O
of	O
:	O
(	O
1	O
)	O
electrophysiological	O
criteria	O
:	O
ventricular	O
arrhythmias	O
,	O
in	O
particular	O
sustained	O
monomorphous	O
VT	O
,	O
with	O
the	O
particular	O
feature	O
of	O
a	O
very	O
high	O
degree	O
of	O
sensitivity	O
to	O
adrenergic	O
stimulation	O
(	O
exercise	O
)	O
,	O
the	O
existence	O
of	O
late	O
potentials	O
on	O
the	O
high	O
amplification	O
ECG	O
,	O
a	O
highly	O
specific	O
sign	O
,	O
though	O
unfortunately	O
of	O
poor	O
sensitivity	O
in	O
localized	O
froms	O
,	O
those	O
which	O
are	O
most	O
difficult	O
to	O
identify	O
(	O
2	O
)	O
;	O
segmentary	O
morphological	O
and	O
kinetic	O
RV	O
abnormalities	O
,	O
most	O
often	O
resulting	O
in	O
localized	O
akinetic	O
or	O
dyskinetic	O
parietal	O
vaulting	O
,	O
with	O
stasis	O
"	O
in	O
situ	O
"	O
.	O

66	O
:	O
469	O
-	O
479	O
,	O
1992	O
)	O
.	O

Possibly	O
,	O
the	O
scr1	B-GENE
-	I-GENE
1	I-GENE
mutation	I-GENE
does	O
not	O
affect	O
signal	O
recognition	O
or	O
translational	O
arrest	O
but	O
instead	O
results	O
in	O
maintenance	O
of	O
translational	O
arrest	O
of	O
AEP	B-GENE
synthesis	O
.	O

Both	O
Rep78	B-GENE
and	O
Rep68	B-GENE
cut	O
the	O
terminal	O
AAV	O
sequence	O
at	O
the	O
same	O
site	O
(	O
nucleotide	O
124	O
)	O
.	O

Nucleotide	O
sequence	O
analysis	O
revealed	O
that	O
TAR	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
is	O
very	O
similar	O
to	O
the	O
CREB2	B-GENE
protein	I-GENE
.	O

A	O
patient	O
suffering	O
from	O
heparin	O
-	O
associated	O
thrombocytopenia	O
(	O
HAT	O
)	O
,	O
recurrent	O
arteriothromboses	O
,	O
and	O
acute	O
renal	O
failure	O
after	O
treatment	O
with	O
standard	O
heparin	O
is	O
described	O
.	O

Comparison	O
with	O
the	O
sequence	O
databanks	O
show	O
that	O
Tactile	B-GENE
is	O
a	O
member	O
of	O
the	O
immunoglobulin	B-GENE
gene	I-GENE
superfamily	I-GENE
,	O
with	O
similarity	O
to	O
Drosophila	B-GENE
amalgam	I-GENE
,	O
the	O
melanoma	B-GENE
Ag	I-GENE
MUC	I-GENE
-	I-GENE
18	I-GENE
,	O
members	O
of	O
the	O
carcinoembryonic	B-GENE
Ag	I-GENE
family	I-GENE
,	O
the	O
poliovirus	B-GENE
receptor	I-GENE
,	O
and	O
the	O
neural	B-GENE
cell	I-GENE
adhesion	I-GENE
molecule	I-GENE
.	O

The	O
phenotypes	O
of	O
the	O
ICP0	B-GENE
nonsense	O
mutants	O
were	O
intermediate	O
between	O
those	O
of	O
the	O
wild	O
-	O
type	O
virus	O
and	O
7134	O
in	O
that	O
the	O
more	O
ICP0	B-GENE
-	I-GENE
coding	I-GENE
sequence	I-GENE
expressed	O
by	O
a	O
given	O
nonsense	O
mutant	O
,	O
the	O
more	O
wild	O
type	O
-	O
like	O
was	O
its	O
phenotype	O
.	O

In	O
contrast	O
,	O
gel	O
mobility	O
shift	O
experiments	O
have	O
failed	O
to	O
reveal	O
that	O
HAP2	B-GENE
or	O
HAP3	B-GENE
binds	O
to	O
domain	O
1	O
or	O
that	O
hap3	B-GENE
mutations	O
affect	O
the	O
complexes	O
bound	O
to	O
it	O
.	O

The	O
experiment	O
results	O
showed	O
:	O
(	O
i	O
)	O
not	O
only	O
1O2	O
,	O
but	O
also	O
free	O
radicals	O
(	O
O2	O
-	O
.	O
.	O
OH	O
and	O
YHPD	O
-	O
.	O
)	O
can	O
be	O
formed	O
by	O
the	O
aid	O
of	O
YHPD	O
;	O
and	O
(	O
ii	O
)	O
as	O
to	O
the	O
ability	O
of	O
producing	O
1O2	O
,	O
YHPD	O
less	O
than	O
BHPD	O
,	O
while	O
for	O
generating	O
O2	O
-	O
.	O
and	O
.	O
OH	O
,	O
YHPD	O
greater	O
than	O
BHPD	O
.	O

Two	O
points	O
are	O
indicated	O
:	O
first	O
,	O
the	O
photosensitized	O
damage	O
of	O
YHPD	O
is	O
interrelated	O
to	O
not	O
only	O
1O2	O
,	O
but	O
also	O
free	O
radicals	O
(	O
O2	O
-	O
.	O
.	O
OH	O
and	O
YHPD	O
-	O
.	O
)	O
;	O
second	O
,	O
although	O
the	O
photosensitized	O
damage	O
of	O
YHPD	O
is	O
stronger	O
than	O
that	O
of	O
BHPD	O
,	O
yet	O
the	O
photosensitized	O
damage	O
is	O
negatively	O
correlated	O
to	O
the	O
yield	O
of	O
1O2	O
but	O
positively	O
correlated	O
to	O
those	O
of	O
O2	O
-	O
.	O
and	O
OH	O
.	O

The	O
unphosphorylated	O
form	O
of	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
is	O
designated	O
IIA	O
,	O
whereas	O
the	O
phosphorylated	O
form	O
is	O
designated	O
IIO	O
.	O

RNA	B-GENE
polymerase	I-GENE
IIA	I-GENE
was	O
recovered	O
in	O
transcriptionally	O
active	O
complexes	O
in	O
reactions	O
in	O
which	O
the	O
input	O
enzyme	O
was	O
RNA	B-GENE
polymerase	I-GENE
IIA	I-GENE
.	O

Fructokinase	B-GENE
activity	O
is	O
elevated	O
up	O
to	O
twofold	O
when	O
Z	O
.	O
mobilis	O
was	O
grown	O
on	O
fructose	O
instead	O
of	O
glucose	O
,	O
and	O
there	O
was	O
a	O
parallel	O
increase	O
in	O
frk	B-GENE
mRNA	I-GENE
levels	O
.	O

The	O
enhancer	O
region	O
of	O
Akv	O
murine	O
leukemia	O
virus	O
contains	O
the	O
sequence	O
motif	O
ACAGATGG	O
.	O

Two	O
splice	O
variants	O
of	O
ALF1	B-GENE
cDNA	I-GENE
have	O
been	O
found	O
,	O
differing	O
by	O
a	O
72	O
-	O
bp	O
insertion	O
,	O
coding	O
for	O
putative	O
proteins	O
of	O
682	O
and	O
706	O
amino	O
acids	O
.	O

Cloning	O
and	O
primary	O
structure	O
of	O
neurocan	O
,	O
a	O
developmentally	O
regulated	O
,	O
aggregating	O
chondroitin	O
sulfate	O
proteoglycan	O
of	O
brain	O
.	O

The	O
-	O
64	O
/	O
-	O
37	O
region	O
interacted	O
with	O
purified	O
Sp1	B-GENE
and	O
an	O
unidentified	O
protein	O
(	O
s	O
)	O
,	O
proximal	B-GENE
regulatory	I-GENE
factor	I-GENE
(	I-GENE
s	I-GENE
)	I-GENE
I	I-GENE
(	O
PRF	B-GENE
-	I-GENE
I	I-GENE
)	O
.	O

This	O
soluble	O
form	O
of	O
the	O
HGFr	B-GENE
(	O
sHGFr	B-GENE
)	O
bound	O
HGF	B-GENE
with	O
an	O
affinity	O
similar	O
to	O
that	O
of	O
the	O
authentic	O
,	O
membrane	O
-	O
associated	O
receptor	O
.	O

Also	O
,	O
the	O
human	B-GENE
glycoprotein	I-GENE
alpha	I-GENE
-	I-GENE
subunit	I-GENE
promoter	I-GENE
was	O
induced	O
10	O
-	O
fold	O
by	O
FSK	B-GENE
in	O
GH4	O
rat	O
pituitary	O
cells	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Some	O
research	O
studies	O
have	O
related	O
this	O
kind	O
of	O
tumors	O
with	O
prolonged	O
ingestion	O
of	O
H2	O
inhibitors	O
and	O
others	O
antacid	O
.	O

The	O
rationale	O
for	O
continuous	O
dopaminergic	O
stimulation	O
in	O
patients	O
with	O
Parkinson	O
'	O
s	O
disease	O
.	O

Amino	O
acid	O
sequence	O
comparison	O
revealed	O
significant	O
homology	O
between	O
the	O
yeast	B-GENE
and	I-GENE
Escherichia	I-GENE
coli	I-GENE
gamma	I-GENE
-	I-GENE
glutamyl	I-GENE
kinases	I-GENE
throughout	O
their	O
lengths	O
.	O

This	O
computation	O
is	O
performed	O
by	O
a	O
parallel	O
network	O
of	O
locally	O
connected	O
neuron	O
-	O
like	O
elements	O
.	O

Neither	O
gene	O
possesses	O
a	O
distinct	O
transcriptional	O
start	O
site	O
as	O
shown	O
by	O
nuclease	B-GENE
S1	I-GENE
analysis	O
.	O

Gene	O
and	O
pseudogene	O
of	O
the	O
mouse	O
cation	O
-	O
dependent	O
mannose	B-GENE
6	I-GENE
-	I-GENE
phosphate	I-GENE
receptor	I-GENE
.	O

The	O
chick	O
axon	O
-	O
associated	O
surface	O
glycoprotein	O
neurofascin	B-GENE
is	O
implicated	O
in	O
axonal	O
growth	O
and	O
fasciculation	O
as	O
revealed	O
by	O
antibody	O
perturbation	O
experiments	O
.	O

Entry	O
of	O
yeast	O
cells	O
into	O
the	O
mitotic	O
cell	O
cycle	O
(	O
Start	O
)	O
involves	O
a	O
form	O
of	O
the	O
CDC28	B-GENE
kinase	I-GENE
that	O
associates	O
with	O
G1	O
-	O
specific	O
cyclins	B-GENE
encoded	O
by	O
CLN1	B-GENE
and	O
CLN2	B-GENE
(	O
ref	O
.	O

From	O
all	O
clinically	O
important	O
yeasts	O
species	O
,	O
a	O
total	O
of	O
96	O
%	O
were	O
identified	O
by	O
ATB	O
method	O
according	O
to	O
conventional	O
methods	O
.	O

Consequently	O
,	O
significant	O
differences	O
between	O
the	O
measured	O
and	O
calculated	O
methods	O
were	O
noted	O
in	O
oxygen	O
uptake	O
(	O
213	O
+	O
/	O
-	O
41	O
ml	O
/	O
min	O
vs	O
193	O
+	O
/	O
-	O
25	O
ml	O
/	O
min	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
oxygen	O
delivery	O
(	O
780	O
+	O
/	O
-	O
297	O
ml	O
/	O
min	O
vs	O
716	O
+	O
/	O
-	O
296	O
ml	O
/	O
min	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
,	O
and	O
cardiac	O
output	O
(	O
5	O
.	O
8	O
+	O
/	O
-	O
2	O
.	O
2	O
L	O
/	O
min	O
vs	O
5	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
8	O
L	O
/	O
min	O
,	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Negatively	O
supercoiled	O
plasmid	O
pUC19	O
did	O
not	O
compete	O
,	O
whereas	O
an	O
otherwise	O
identical	O
plasmid	O
pUC19	O
(	O
CG	O
)	O
,	O
which	O
contained	O
a	O
(	O
dG	O
-	O
dC	O
)	O
7	O
segment	O
in	O
the	O
Z	O
-	O
form	O
was	O
an	O
excellent	O
competitor	O
.	O

In	O
contrast	O
,	O
the	O
lumenal	O
domains	O
of	O
Sec12p	B-GENE
,	O
Stl1p	B-GENE
and	O
Stl2p	B-GENE
are	O
very	O
different	O
in	O
size	O
and	O
do	O
not	O
show	O
any	O
appreciable	O
homology	O
.	O

The	O
gene	O
sequence	O
also	O
identified	O
a	O
340	O
-	O
nucleotide	O
RNA	O
in	O
total	O
yeast	O
RNA	O
and	O
in	O
purified	O
RNase	B-GENE
MRP	I-GENE
enzyme	I-GENE
preparations	O
.	O

The	O
RNase	B-GENE
MRP	I-GENE
RNA	I-GENE
gene	I-GENE
was	O
deleted	O
by	O
insertional	O
replacement	O
and	O
found	O
to	O
be	O
essential	O
for	O
cellular	O
viability	O
,	O
indicating	O
a	O
critical	O
nuclear	O
role	O
for	O
RNase	B-GENE
MRP	I-GENE
.	O

Mutational	O
analysis	O
of	O
essential	O
IncP	O
alpha	O
plasmid	O
transfer	O
genes	O
traF	B-GENE
and	O
traG	B-GENE
and	O
involvement	O
of	O
traF	B-GENE
in	O
phage	O
sensitivity	O
.	O

The	O
promoter	O
was	O
stimulated	O
8	O
-	O
20	O
-	O
fold	O
by	O
phorbol	O
esters	O
accounting	O
for	O
the	O
previously	O
observed	O
transcriptional	O
activation	O
of	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
beta	I-GENE
.	O

In	O
the	O
eight	O
patients	O
with	O
persistent	O
generalized	O
lymph	O
-	O
adenopathy	O
(	O
PGL	O
)	O
and	O
nontender	O
,	O
nonenlarging	O
nodes	O
,	O
pathologic	O
analysis	O
revealed	O
lymphoid	O
hyperplasia	O
.	O

We	O
found	O
that	O
both	O
the	O
E26	O
virus	O
-	O
encoded	O
v	B-GENE
-	I-GENE
ets	I-GENE
and	O
the	O
myeloid	B-GENE
/	I-GENE
B	I-GENE
-	I-GENE
cell	I-GENE
-	I-GENE
specific	I-GENE
factor	I-GENE
PU	I-GENE
.	I-GENE
1	I-GENE
bind	O
efficiently	O
to	O
this	O
site	O
in	O
vitro	O
.	O

Localization	O
of	O
the	O
brachial	O
plexus	O
with	O
the	O
nerve	O
stimulator	O
is	O
equally	O
effective	O
at	O
the	O
interscalene	O
,	O
supraclavicular	O
,	O
and	O
axillary	O
sites	O
.	O

The	O
second	O
method	O
,	O
the	O
"	O
macro	O
"	O
assay	O
,	O
has	O
a	O
sensitivity	O
range	O
of	O
0	O
.	O
03	O
-	O
5	O
.	O
0	O
micrograms	O
phosphorus	O
with	O
100	O
-	O
500	O
microliters	O
HClO4	O
.	O

Anti	B-GENE
-	I-GENE
CRK	I-GENE
antibodies	I-GENE
detect	O
a	O
53kDa	O
protein	O
in	O
extracts	O
of	O
C	O
.	O
fasciculata	O
in	O
agreement	O
with	O
the	O
size	O
predicted	O
from	O
the	O
nucleotide	O
sequence	O
of	O
the	O
cloned	O
gene	O
.	O

Use	O
of	O
free	O
-	O
access	O
minerals	O
.	O

Respiratory	O
interaction	O
after	O
spinal	O
anesthesia	O
and	O
sedation	O
with	O
midazolam	O
.	O

V	O
.	O

Rice	B-GENE
dwarf	I-GENE
phytoreovirus	I-GENE
segment	I-GENE
S12	I-GENE
transcript	I-GENE
is	O
tricistronic	O
in	O
vitro	O
.	O

Cold	O
cardioplegia	O
was	O
administered	O
at	O
45	O
mm	O
Hg	O
every	O
20	O
minutes	O
for	O
2	O
hours	O
.	O

Comparable	O
amounts	O
of	O
alpha	B-GENE
5	I-GENE
beta	I-GENE
1	I-GENE
integrin	I-GENE
were	O
isolated	O
from	O
these	O
cells	O
by	O
chromatography	O
of	O
detergent	O
extracts	O
on	O
a	O
fibronectin	B-GENE
cell	O
-	O
binding	O
fragment	O
affinity	O
column	O
and	O
elution	O
with	O
EDTA	O
.	O

From	O
this	O
library	O
,	O
LEU2	B-GENE
and	O
HIS3	B-GENE
cDNAs	O
were	O
recovered	O
at	O
a	O
frequency	O
of	O
about	O
1	O
in	O
10	O
(	O
4	O
)	O
and	O
in	O
12	O
out	O
of	O
13	O
cases	O
these	O
were	O
expressed	O
in	O
a	O
galactose	O
-	O
dependent	O
manner	O
.	O

Among	O
these	O
,	O
ACT1	B-GENE
was	O
isolated	O
four	O
times	O
,	O
and	O
NSR1	B-GENE
three	O
times	O
.	O

BiP670	B-GENE
retains	O
basal	O
and	O
Ca2	O
+	O
ionophore	O
A23187	O
-	O
inducible	O
activities	O
.	O

As	O
a	O
part	O
of	O
a	O
large	O
examination	O
,	O
total	O
and	O
free	O
serum	O
cholesterol	O
,	O
total	O
lipid	O
and	O
triglyceride	O
levels	O
were	O
determined	O
.	O

DIBA	O
was	O
more	O
sensitive	O
and	O
had	O
a	O
better	O
negative	O
predictive	O
value	O
and	O
a	O
lower	O
false	O
negative	O
percentage	O
than	O
DFAT	O
.	O

Caries	O
and	O
parodontitis	O
have	O
been	O
one	O
of	O
the	O
most	O
spread	O
diseases	O
of	O
mankind	O
.	O

ME1a1	B-GENE
,	O
a	O
16	O
-	O
base	O
-	O
pair	O
nuclear	O
factor	O
binding	O
site	O
residing	O
between	O
the	O
c	B-GENE
-	I-GENE
MYC	I-GENE
P1	I-GENE
and	I-GENE
P2	I-GENE
transcription	I-GENE
initiation	I-GENE
sites	I-GENE
,	O
is	O
required	O
for	O
P2	O
activity	O
.	O

The	O
next	O
twenty	O
years	O
of	O
prevention	O
in	O
Indian	O
country	O
:	O
visionary	O
,	O
complex	O
,	O
and	O
practical	O
.	O

The	O
cDNA	O
has	O
an	O
open	O
reading	O
frame	O
of	O
900	O
amino	O
acids	O
capable	O
of	O
encoding	O
a	O
97	O
-	O
kDa	O
protein	O
.	O

The	O
gene	O
encoding	O
TRP	B-GENE
-	I-GENE
2	I-GENE
maps	O
to	O
mouse	O
chromosome	O
14	O
,	O
in	O
the	O
region	O
of	O
the	O
coat	B-GENE
colour	I-GENE
mutation	I-GENE
slaty	I-GENE
.	O

A	O
comparison	O
of	O
the	O
amino	O
acid	O
sequence	O
of	O
the	O
T	O
.	O
thermophilus	O
enzyme	O
with	O
that	O
of	O
the	O
Escherichia	O
coli	O
enzyme	O
showed	O
(	O
i	O
)	O
a	O
37	O
%	O
overall	O
similarity	O
;	O
(	O
ii	O
)	O
the	O
conservation	O
of	O
the	O
Ser	O
residue	O
,	O
which	O
is	O
known	O
to	O
be	O
phosphorylated	O
in	O
the	O
E	O
.	O
coli	O
enzyme	O
,	O
and	O
of	O
the	O
surrounding	O
sequence	O
;	O
and	O
(	O
iii	O
)	O
the	O
presence	O
of	O
141	O
extra	O
residues	O
at	O
the	O
C	O
terminus	O
of	O
the	O
T	O
.	O
thermophilus	O
enzyme	O
.	O

Because	O
single	O
-	O
chamber	O
rate	O
-	O
adaptive	O
atrial	O
pacing	O
leaves	O
the	O
patient	O
exposed	O
to	O
the	O
risk	O
of	O
future	O
development	O
of	O
AV	O
block	O
and	O
DDD	O
pacing	O
does	O
not	O
provide	O
chronotropic	O
support	O
,	O
it	O
is	O
likely	O
that	O
the	O
new	O
rate	O
-	O
adaptive	O
dual	O
-	O
chamber	O
(	O
DDDR	O
)	O
devices	O
will	O
be	O
used	O
in	O
a	O
significant	O
number	O
of	O
these	O
patients	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

When	O
transiently	O
transfected	O
into	O
K562	O
cells	O
,	O
this	O
Lg	B-GENE
genomic	O
clone	O
is	O
actively	O
transcribed	O
,	O
suggesting	O
that	O
,	O
although	O
it	O
possesses	O
the	O
characteristics	O
of	O
a	O
processed	O
pseudogene	O
,	O
it	O
is	O
likely	O
to	O
correspond	O
to	O
the	O
gene	O
encoding	O
this	O
new	O
ferritin	B-GENE
subunit	I-GENE
.	O

The	O
p130	B-GENE
and	O
p62	B-GENE
tyrosine	O
-	O
phosphorylated	O
proteins	O
that	O
complexed	O
v	B-GENE
-	I-GENE
Src	I-GENE
SH2	B-GENE
in	O
vitro	O
also	O
associated	O
with	O
v	B-GENE
-	I-GENE
Src	I-GENE
in	O
v	B-GENE
-	I-GENE
src	I-GENE
-	O
transformed	O
Rat	O
-	O
2	O
cells	O
;	O
this	O
in	O
vivo	O
binding	O
was	O
dependent	O
on	O
the	O
v	B-GENE
-	I-GENE
Src	I-GENE
SH2	B-GENE
domain	O
.	O

These	O
data	O
support	O
a	O
possible	O
biological	O
significance	O
of	O
the	O
frameshift	O
to	O
occur	O
at	O
this	O
position	O
of	O
the	O
large	O
overlap	O
by	O
including	O
the	O
putative	O
RNA	O
template	O
-	O
binding	O
site	O
of	O
the	O
PLRV	B-GENE
replicase	I-GENE
in	O
the	O
ORF2a	B-GENE
/	I-GENE
ORF2b	I-GENE
transframe	I-GENE
protein	I-GENE
.	O

The	O
MET4	B-GENE
gene	O
was	O
cloned	O
,	O
and	O
its	O
sequence	O
reveals	O
that	O
it	O
encodes	O
a	O
protein	O
related	O
to	O
the	O
family	O
of	O
the	O
bZIP	B-GENE
transcriptional	I-GENE
activators	I-GENE
.	O

It	O
is	O
believed	O
that	O
these	O
domains	O
are	O
important	O
for	O
directing	O
specific	O
protein	O
-	O
protein	O
interactions	O
necessary	O
for	O
the	O
proper	O
functioning	O
of	O
Src	B-GENE
.	O

The	O
recently	O
developed	O
gamma	B-GENE
-	I-GENE
interferon	I-GENE
(	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
)	O
assay	O
system	O
for	O
the	O
diagnosis	O
of	O
bovine	O
tuberculosis	O
in	O
cattle	O
has	O
been	O
accredited	O
by	O
the	O
Standing	O
Committee	O
on	O
Agriculture	O
for	O
use	O
in	O
Australia	O
.	O

Control	O
Tmuscle	O
was	O
35	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
7	O
degrees	O
C	O
,	O
with	O
control	O
Wi	O
,	O
max	O
being	O
51	O
.	O
6	O
(	O
SD	O
8	O
.	O
7	O
)	O
W	O
.	O
kg	O
-	O
1	O
.	O

However	O
,	O
other	O
regions	O
of	O
the	O
plasmid	O
are	O
also	O
efficiently	O
repaired	O
.	O

Thus	O
,	O
the	O
human	B-GENE
D1A	I-GENE
gene	I-GENE
belongs	O
to	O
the	O
category	O
of	O
tissue	O
-	O
specific	O
,	O
regulated	O
genes	O
that	O
have	O
housekeeping	O
-	O
type	O
promoters	O
.	O

Computer	O
-	O
aided	O
"	O
FRAME	O
"	O
analysis	O
revealed	O
four	O
possible	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
,	O
three	O
in	O
one	O
direction	O
and	O
one	O
in	O
the	O
opposite	O
direction	O
.	O

Domain	O
II	O
is	O
highly	O
homologous	O
to	O
the	O
LDL	B-GENE
receptor	I-GENE
and	O
contains	O
four	O
repeats	O
with	O
perfect	O
conservation	O
of	O
all	O
6	O
consecutive	O
cysteines	O
.	O

Here	O
,	O
we	O
present	O
evidence	O
for	O
a	O
model	O
in	O
which	O
mRNA	O
sequences	O
up	O
to	O
around	O
100	O
nucleotides	O
downstream	O
from	O
the	O
start	O
codon	O
of	O
21K	O
fold	O
back	O
and	O
base	O
-	O
pair	O
to	O
the	O
21K	O
translation	O
initiation	O
region	O
,	O
thereby	O
decreasing	O
the	O
translation	O
initiation	O
frequency	O
.	O

In	O
the	O
last	O
20	O
years	O
,	O
the	O
therapeutic	O
uses	O
of	O
botulinum	B-GENE
toxin	I-GENE
,	O
a	O
potent	O
neurotoxin	O
,	O
have	O
been	O
investigated	O
.	O

At	O
the	O
C	O
-	O
terminus	O
of	O
the	O
protein	O
is	O
a	O
domain	O
that	O
contains	O
sequences	O
very	O
similar	O
to	O
those	O
found	O
in	O
the	O
breakpoint	O
cluster	O
region	O
gene	O
product	O
,	O
n	B-GENE
-	I-GENE
chimerin	I-GENE
,	O
and	O
rho	B-GENE
GAP	I-GENE
,	O
all	O
of	O
which	O
have	O
been	O
shown	O
to	O
possess	O
intrinsic	O
GAP	B-GENE
activity	O
on	O
small	B-GENE
GTPases	I-GENE
.	O

The	O
circadian	O
rhythmicity	O
of	O
sleep	O
was	O
pronounced	O
.	O

The	O
sequence	O
data	O
now	O
permit	O
a	O
detailed	O
interpretation	O
of	O
the	O
X	O
-	O
ray	O
crystallographic	O
structure	O
of	O
the	O
enzyme	O
and	O
the	O
cloning	O
and	O
expression	O
of	O
the	O
clostridial	O
gene	O
will	O
facilitate	O
site	O
-	O
directed	O
mutagenesis	O
.	O

AgMNPV	O
and	O
Orgyia	O
pseudotsugata	O
MNPV	O
(	O
OpMNPV	O
)	O
are	O
similar	O
in	O
terms	O
of	O
promoter	O
structure	O
and	O
polyhedrin	B-GENE
primary	I-GENE
sequence	I-GENE
,	O
and	O
the	O
polyhedrin	B-GENE
gene	I-GENE
of	O
both	O
viruses	O
is	O
transcribed	O
in	O
the	O
anti	O
-	O
clockwise	O
direction	O
in	O
relation	O
to	O
their	O
physical	O
maps	O
.	O

These	O
results	O
are	O
consistent	O
with	O
the	O
roles	O
that	O
CCK	B-GENE
and	O
trypsin	B-GENE
inhibitors	O
are	O
believed	O
to	O
play	O
in	O
the	O
negative	O
feedback	O
control	O
of	O
pancreatic	O
exocrine	O
function	O
.	O

A	O
724	O
-	O
bp	O
segment	O
of	O
the	O
5	O
'	O
-	O
flanking	O
region	O
consisting	O
of	O
the	O
proximal	O
E	O
-	O
box	O
flanked	O
upstream	O
by	O
a	O
mammalian	O
-	O
specific	O
352	O
-	O
bp	O
region	O
was	O
sufficient	O
for	O
maximal	O
transcriptional	O
activation	O
in	O
postconfluent	O
BC3H1	O
myoblasts	O
.	O

These	O
results	O
indicate	O
that	O
baculovirus	O
-	O
expressed	O
TR	B-GENE
mediates	O
transcriptional	O
activation	O
and	O
repression	O
in	O
a	O
promoter	O
-	O
specific	O
manner	O
in	O
vitro	O
.	O

The	O
serum	O
erythropoietin	B-GENE
(	O
EPO	B-GENE
)	O
concentrations	O
of	O
15	O
male	O
triathletes	O
(	O
26	O
.	O
3	O
U	O
.	O
ml	O
-	O
1	O
)	O
were	O
significantly	O
lower	O
than	O
those	O
of	O
45	O
male	O
distance	O
runners	O
(	O
31	O
.	O
6	O
U	O
.	O
ml	O
-	O
1	O
;	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

These	O
results	O
support	O
the	O
diagnostic	O
validity	O
of	O
NFPD	O
in	O
CP	O
/	O
NCA	O
patients	O
,	O
because	O
such	O
patients	O
had	O
a	O
family	O
history	O
of	O
panic	O
disorder	O
similar	O
to	O
patients	O
with	O
a	O
more	O
classical	O
panic	O
disorder	O
presentation	O
.	O

FDA	O
regulations	O
for	O
growth	O
factors	O
and	O
related	O
products	O
.	O

DESIGN	O
:	O
Serum	O
aldosterone	O
and	O
plasma	B-GENE
renin	I-GENE
activity	O
were	O
measured	O
supine	O
prior	O
to	O
and	O
60	O
,	O
90	O
,	O
120	O
minutes	O
after	O
oral	O
captopril	O
,	O
25	O
mg	O
.	O

Both	O
parents	O
are	O
clinically	O
normal	O
and	O
unrelated	O
.	O

UF	O
-	O
021	O
ophthalmic	O
solution	O
(	O
0	O
.	O
03	O
to	O
0	O
.	O
24	O
%	O
)	O
,	O
when	O
topically	O
applied	O
to	O
the	O
eyes	O
of	O
rabbits	O
,	O
caused	O
dose	O
-	O
dependent	O
IOP	O
reduction	O
(	O
2	O
.	O
8	O
to	O
5	O
.	O
2	O
mmHg	O
)	O
,	O
without	O
transient	O
IOP	O
rise	O
.	O

This	O
is	O
in	O
contrast	O
with	O
the	O
classical	O
'	O
oxygen	O
debt	O
hypothesis	O
'	O
,	O
which	O
states	O
that	O
the	O
oxygen	O
debt	O
and	O
lactate	O
clearance	O
are	O
linked	O
.	O

In	O
addition	O
a	O
greater	O
proportion	O
of	O
women	O
in	O
the	O
sweeping	O
group	O
had	O
a	O
cervical	O
dilatation	O
of	O
4	O
cm	O
or	O
more	O
at	O
the	O
first	O
vaginal	O
examination	O
in	O
the	O
labour	O
ward	O
(	O
16	O
/	O
33	O
(	O
49	O
%	O
)	O
vs	O
5	O
/	O
32	O
(	O
16	O
%	O
)	O
;	O
OR	O
4	O
.	O
39	O
;	O
95	O
%	O
CI	O
1	O
.	O
56	O
to	O
12	O
.	O
32	O
;	O
P	O
=	O
0	O
.	O
005	O
)	O
.	O

A	O
control	O
group	O
of	O
nine	O
women	O
(	O
age	O
23	O
-	O
40	O
years	O
)	O
on	O
oral	O
contraceptives	O
(	O
Nordette	O
-	O
28	O
)	O
was	O
also	O
studied	O
four	O
times	O
during	O
a	O
pill	O
cycle	O
.	O

Patients	O
with	O
an	O
enzymatic	O
activity	O
below	O
X	O
-	O
-	O
1	O
manifested	O
a	O
decrease	O
of	O
the	O
content	O
of	O
IgA	B-GENE
,	O
IgG	B-GENE
,	O
IgM	B-GENE
,	O
T	O
and	O
B	O
lymphocytes	O
,	O
and	O
of	O
phagocytic	O
activity	O
of	O
neutrophils	O
as	O
compared	O
to	O
patients	O
exhibiting	O
a	O
high	O
enzymatic	O
activity	O
.	O

The	O
relation	O
between	O
myocardial	B-GENE
beta	I-GENE
-	I-GENE
adrenergic	I-GENE
receptor	I-GENE
and	O
left	O
ventricular	O
(	O
LV	O
)	O
function	O
was	O
studied	O
in	O
10	O
patients	O
,	O
aged	O
41	O
to	O
61	O
years	O
(	O
average	O
51	O
)	O
,	O
with	O
LV	O
volume	O
overload	O
mainly	O
due	O
to	O
chronic	O
mitral	O
regurgitation	O
.	O

axl	O
,	O
a	O
transforming	O
gene	O
isolated	O
from	O
primary	O
human	O
myeloid	O
leukemia	O
cells	O
,	O
encodes	O
a	O
novel	O
receptor	B-GENE
tyrosine	I-GENE
kinase	I-GENE
.	O

The	O
single	O
most	O
important	O
element	O
,	O
by	O
linker	O
-	O
scanning	O
analysis	O
,	O
is	O
a	O
10	O
-	O
bp	O
region	O
that	O
contains	O
a	O
CCAAT	O
motif	O
.	O

Capnography	O
curves	O
of	O
40	O
HVS	O
patients	O
,	O
40	O
non	O
-	O
HVS	O
patients	O
with	O
psycho	O
-	O
somatic	O
complaints	O
and	O
26	O
healthy	O
controls	O
were	O
analyzed	O
.	O

However	O
,	O
alterations	O
in	O
electrostatic	O
and	O
hydrophobic	O
interactions	O
created	O
by	O
the	O
three	O
amino	O
acid	O
substitutions	O
prevent	O
the	O
conformational	O
change	O
in	O
the	O
enzyme	O
usually	O
produced	O
by	O
calmodulin	B-GENE
binding	O
.	O

Transfer	O
RNA	O
genes	O
from	O
Dictyostelium	O
discoideum	O
are	O
frequently	O
associated	O
with	O
repetitive	O
elements	O
and	O
contain	O
consensus	O
boxes	O
in	O
their	O
5	O
'	O
and	O
3	O
'	O
-	O
flanking	O
regions	O
.	O

Histamine	O
-	O
2	O
blockade	O
in	O
psoriasis	O

A	O
third	O
is	O
a	O
partial	O
element	O
terminating	O
at	O
a	O
probable	O
internal	O
restriction	O
site	O
used	O
for	O
cloning	O
.	O

No	O
such	O
benefits	O
were	O
seen	O
for	O
children	O
with	O
CD4	B-GENE
+	I-GENE
counts	O
below	O
0	O
.	O
2	O
x	O
10	O
(	O
9	O
)	O
per	O
liter	O
at	O
entry	O
.	O

Because	O
the	O
human	B-GENE
Antp	I-GENE
TATAA	I-GENE
binding	I-GENE
protein	I-GENE
is	O
expressed	O
in	O
both	O
lymphoid	O
and	O
non	O
-	O
lymphoid	O
cells	O
,	O
we	O
suggest	O
that	O
this	O
homeobox	B-GENE
gene	I-GENE
has	O
evolved	O
a	O
more	O
general	O
transcriptional	O
regulatory	O
function	O
in	O
higher	O
eukaryotic	O
cells	O
.	O

Venkatesan	O
,	O
and	O
D	O
.	O

Stable	O
expression	O
of	O
the	O
chimeric	O
alpha	B-GENE
i	I-GENE
(	I-GENE
54	I-GENE
)	I-GENE
/	I-GENE
s	I-GENE
polypeptide	O
in	O
Chinese	O
hamster	O
ovary	O
(	O
CHO	O
)	O
cells	O
constitutively	O
increased	O
both	O
cAMP	O
synthesis	O
and	O
cAMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
activity	O
.	O

Surprisingly	O
,	O
there	O
is	O
no	O
sequence	O
homology	O
between	O
this	O
region	O
of	O
Ly	B-GENE
-	I-GENE
6E	I-GENE
and	O
the	O
established	O
consensus	O
for	O
the	O
interferon	B-GENE
-	I-GENE
stimulated	I-GENE
response	I-GENE
element	I-GENE
,	O
which	O
has	O
been	O
shown	O
functionally	O
important	O
to	O
all	O
previously	O
characterized	O
alpha	B-GENE
/	I-GENE
beta	I-GENE
interferon	I-GENE
-	O
inducible	O
promoters	O
.	O

Relatively	O
large	O
DNA	O
rearrangements	O
spanning	O
the	O
region	O
with	O
tandem	O
direct	O
repeats	O
encoding	O
the	O
carboxy	O
-	O
terminal	O
histone	B-GENE
H1	I-GENE
-	I-GENE
like	I-GENE
structure	O
of	O
AlgP	B-GENE
were	O
detected	O
in	O
several	O
strains	O
upon	O
conversion	O
from	O
the	O
mucoid	O
to	O
the	O
nonmucoid	O
phenotype	O
.	O

It	O
is	O
,	O
however	O
,	O
extremely	O
homologous	O
to	O
a	O
third	O
'	O
non	O
-	O
classical	O
'	O
gene	O
,	O
HLA	B-GENE
-	I-GENE
5	I-GENE
.	I-GENE
4	I-GENE
,	O
and	O
to	O
the	O
chimpanzee	O
gene	O
,	O
Ch28	B-GENE
.	O

Although	O
the	O
N13	O
-	O
N20	O
interpeak	O
interval	O
remained	O
stable	O
because	O
of	O
the	O
parallel	O
shift	O
of	O
the	O
2	O
peaks	O
,	O
the	O
central	O
conduction	O
time	O
measured	O
from	O
onset	O
latencies	O
of	O
N11	O
and	O
N20	O
significantly	O
increased	O
.	O

Isolation	O
and	O
characterization	O
of	O
the	O
rat	O
chromosomal	O
gene	O
for	O
a	O
polypeptide	O
(	O
pS1	B-GENE
)	O
antigenically	O
related	O
to	O
statin	B-GENE
.	O

Chem	O
.	O

This	O
report	O
substantiates	O
that	O
at	O
least	O
two	O
of	O
the	O
18	O
kDa	O
hsps	B-GENE
in	O
maize	O
are	O
products	O
of	O
different	O
but	O
related	O
genes	O
.	O

Finally	O
,	O
some	O
point	O
mutations	O
in	O
the	O
Gag	B-GENE
-	O
Pol	B-GENE
PR	O
domain	O
inhibited	O
activation	O
of	O
RT	B-GENE
in	O
trans	O
by	O
a	O
wild	O
-	O
type	O
PR	B-GENE
,	O
suggesting	O
that	O
the	O
correct	O
conformation	O
of	O
the	O
PR	B-GENE
domain	O
in	O
Gag	B-GENE
-	O
Pol	B-GENE
is	O
prerequisite	O
for	O
activation	O
of	O
RT	B-GENE
.	O

Cloning	O
of	O
a	O
human	O
cDNA	O
encoding	O
a	O
CDC2	B-GENE
-	I-GENE
related	I-GENE
kinase	I-GENE
by	O
complementation	O
of	O
a	O
budding	B-GENE
yeast	I-GENE
cdc28	I-GENE
mutation	O
.	O

E	O
.	O
,	O
Hession	O
,	O
C	O
.	O
,	O
Goff	O
,	O
D	O
.	O
,	O
Griffiths	O
,	O
B	O
.	O
,	O
Tizard	O
,	O
R	O
.	O
,	O
Newman	O
,	O
B	O
.	O
,	O
Chi	O
-	O
Rosso	O
,	O
G	O
.	O
,	O
and	O
Lobb	O
,	O
R	O
.	O
,	O
(	O
1990	O
)	O
Cell	O
63	O
,	O
1349	O
-	O
1356	O
)	O
.	O

The	O
above	O
results	O
mean	O
that	O
the	O
increase	O
in	O
alpha	B-GENE
-	I-GENE
adrenergic	I-GENE
receptors	I-GENE
makes	O
the	O
prostate	O
,	O
which	O
has	O
been	O
already	O
hypertrophied	O
,	O
less	O
elastic	O
,	O
inhibiting	O
external	O
urinary	O
sphincter	O
function	O
.	O

An	O
approximately	O
2	B-GENE
-	I-GENE
kilobase	I-GENE
B2	I-GENE
transcript	I-GENE
was	O
expressed	O
in	O
all	O
alfalfa	O
organs	O
tested	O
.	O

In	O
some	O
early	O
B	O
cells	O
and	O
Abelson	O
murine	O
leukemia	O
virus	O
-	O
transformed	O
pre	O
-	O
B	O
-	O
cell	O
lines	O
,	O
LT	B-GENE
mRNA	I-GENE
is	O
constitutively	O
expressed	O
.	O

Testosterone	O
,	O
free	O
testosterone	O
,	O
non	B-GENE
-	I-GENE
sex	I-GENE
hormone	I-GENE
-	I-GENE
binding	I-GENE
globulin	I-GENE
-	O
bound	O
testosterone	O
,	O
and	O
free	O
androgen	O
index	O
:	O
which	O
testosterone	O
measurement	O
is	O
most	O
relevant	O
to	O
reproductive	O
and	O
sexual	O
function	O
in	O
men	O
with	O
epilepsy	O
?	O

One	O
patients	O
had	O
plasma	B-GENE
C	I-GENE
-	I-GENE
peptide	I-GENE
greater	O
than	O
3	O
pM	O
and	O
was	O
therefore	O
excluded	O
from	O
analysis	O
.	O

Complex	O
repetitive	O
discharges	O
were	O
observed	O
in	O
muscles	O
of	O
mdx	O
mice	O
but	O
no	O
complex	O
repetitive	O
discharges	O
or	O
other	O
abnormalities	O
were	O
observed	O
in	O
muscles	O
of	O
normal	O
control	O
mice	O
.	O

W	O
.	O
G	O
.	O

A	O
mouse	B-GENE
brain	I-GENE
beta	I-GENE
-	I-GENE
spectrin	I-GENE
of	O
cDNA	O
was	O
identified	O
within	O
a	O
lambda	O
Gt11	O
expression	O
library	O
using	O
an	O
antibody	O
which	O
specifically	O
binds	O
with	O
the	O
235	B-GENE
kDa	I-GENE
spectrin	I-GENE
beta	I-GENE
-	I-GENE
subunit	I-GENE
.	O

We	O
obtained	O
quantitative	O
evidence	O
on	O
the	O
coding	O
of	O
interaural	O
time	O
differences	O
(	O
ITDs	O
)	O
of	O
click	O
stimuli	O
by	O
40	O
single	O
neurons	O
in	O
the	O
auditory	O
cortex	O
of	O
anesthetized	O
albino	O
rats	O
.	O

Pulmonary	O
hypertension	O
,	O
with	O
or	O
without	O
coronary	O
arterial	O
narrowing	O
,	O
is	O
the	O
major	O
condition	O
leading	O
to	O
isolated	O
atrial	O
infarction	O
.	O

Diltiazem	O
decreased	O
the	O
total	O
body	O
clearance	O
from	O
34	O
.	O
0	O
+	O
/	O
-	O
8	O
.	O
0	O
to	O
28	O
.	O
6	O
+	O
/	O
-	O
6	O
.	O
1	O
mL	O
/	O
min	O
(	O
P	O
less	O
than	O
.	O
01	O
)	O
,	O
and	O
prolonged	O
the	O
elimination	O
half	O
-	O
life	O
from	O
12	O
.	O
6	O
+	O
/	O
-	O
3	O
.	O
0	O
to	O
14	O
.	O
3	O
+	O
/	O
-	O
2	O
.	O
5	O
hours	O
(	O
P	O
less	O
than	O
.	O
01	O
)	O
of	O
antipyrine	O
without	O
any	O
changes	O
in	O
volume	O
of	O
distribution	O
.	O

The	O
model	O
is	O
able	O
to	O
anticipate	O
why	O
the	O
effect	O
of	O
water	O
fluoridation	O
on	O
caries	O
prevalence	O
is	O
most	O
pronounced	O
when	O
caries	O
is	O
diagnosed	O
at	O
cavity	O
level	O
.	O

An	O
8	O
-	O
h	O
exposure	O
to	O
10	O
mg	O
DMEA	O
/	O
m3	O
corresponds	O
to	O
a	O
postexposure	O
plasma	O
concentration	O
and	O
2	O
-	O
h	O
postexposure	O
urinary	O
excretion	O
of	O
4	O
.	O
9	O
mumol	O
/	O
l	O
and	O
75	O
mmol	O
/	O
mol	O
creatinine	O
,	O
respectively	O
.	O

Marked	O
thrombocytopenia	O
,	O
depletion	O
of	O
serum	B-GENE
fibrinogen	I-GENE
and	O
prolonged	O
prothrombin	B-GENE
and	O
activated	O
partial	O
thromboplastin	B-GENE
time	O
,	O
were	O
recorded	O
at	O
5	O
to	O
10	O
and	O
30	O
to	O
40	O
minutes	O
after	O
intravenous	O
envenomation	O
.	O

Auditory	O
threshold	O
shifts	O
,	O
as	O
measured	O
by	O
the	O
auditory	O
evoked	O
brainstem	O
response	O
,	O
were	O
measured	O
at	O
2	O
,	O
4	O
,	O
8	O
,	O
12	O
,	O
16	O
,	O
20	O
and	O
24	O
kHz	O
.	O

Interspecific	O
backcross	O
analysis	O
using	O
progeny	O
derived	O
from	O
matings	O
of	O
(	O
C57BL	O
/	O
6J	O
x	O
Mus	O
spretus	O
)	O
F1	O
x	O
C57BL	O
/	O
6J	O
mice	O
indicates	O
that	O
the	O
thrombospondin	B-GENE
gene	I-GENE
is	O
tightly	O
linked	O
to	O
the	O
Fshb	B-GENE
,	O
Actcl	B-GENE
,	O
Ltk	B-GENE
,	O
and	O
B2M	B-GENE
loci	I-GENE
on	O
murine	O
chromosome	O
2	O
.	O

If	O
delay	O
has	O
occurred	O
between	O
centrifugation	O
and	O
the	O
measurement	O
,	O
causing	O
substantial	O
loss	O
of	O
CO2	O
,	O
equilibration	O
of	O
the	O
sample	O
with	O
a	O
gas	O
mixture	O
corresponding	O
to	O
PCO2	O
=	O
5	O
.	O
3	O
kPa	O
prior	O
to	O
the	O
measurement	O
is	O
recommended	O
.	O

The	O
EPO	B-GENE
levels	O
were	O
distinctly	O
increased	O
before	O
transfusion	O
;	O
they	O
did	O
not	O
significantly	O
change	O
just	O
after	O
transfusion	O
,	O
but	O
subsequently	O
decreased	O
.	O

Felodipine	O
did	O
not	O
alter	O
the	O
baseline	O
FEV1	O
,	O
but	O
showed	O
a	O
small	O
significant	O
inhibitory	O
effect	O
upon	O
histamine	O
and	O
AMP	O
induced	O
bronchoconstriction	O
.	O

Relatively	O
little	O
is	O
known	O
regarding	O
the	O
role	O
of	O
5	B-GENE
-	I-GENE
HT2	I-GENE
receptor	I-GENE
activity	O
in	O
male	O
rat	O
sexual	O
behavior	O
.	O

The	O
present	O
study	O
reports	O
visual	O
evoked	O
potential	O
responses	O
to	O
pattern	O
reversal	O
(	O
VEP	O
-	O
P	O
)	O
in	O
ten	O
third	O
trimester	O
pregnant	O
women	O
and	O
changes	O
in	O
latency	O
of	O
NPN	O
complex	O
when	O
compared	O
with	O
these	O
responses	O
in	O
the	O
non	O
pregnant	O
state	O
.	O

In	O
all	O
instances	O
the	O
apparent	O
alcohol	O
responses	O
were	O
very	O
small	O
and	O
never	O
exceeded	O
a	O
reading	O
of	O
1	O
microgram	O
/	O
100ml	O
for	O
breath	O
samples	O
more	O
than	O
10min	O
post	O
-	O
exposure	O
.	O

The	O
gene	O
is	O
1	O
,	O
139	O
base	O
pairs	O
(	O
bp	O
)	O
long	O
,	O
and	O
,	O
like	O
other	O
members	O
of	O
the	O
SIG	B-GENE
family	I-GENE
,	O
the	O
beta	B-GENE
TG	I-GENE
gene	I-GENE
is	O
divided	O
into	O
3	O
exons	O
.	O

Thus	O
,	O
the	O
positive	O
effect	O
of	O
NS1	B-GENE
on	O
the	O
steady	O
-	O
state	O
levels	O
of	O
P4	B-GENE
transcripts	I-GENE
depends	O
on	O
the	O
amplification	O
of	O
gene	O
copy	O
number	O
and	O
the	O
integrity	O
of	O
the	O
terminal	O
repeats	O
.	O

It	O
is	O
transparent	O
,	O
cheap	O
to	O
be	O
made	O
,	O
and	O
easy	O
to	O
empty	O
and	O
was	O
tested	O
in	O
118	O
animals	O
for	O
two	O
and	O
four	O
weeks	O
.	O

The	O
Thr161Val	O
mutation	O
causes	O
a	O
lethal	O
phenotype	O
in	O
the	O
fission	O
yeast	O
Schizosaccharomyces	O
pombe	O
,	O
while	O
replacement	O
of	O
Thr161	O
with	O
glutamic	O
acid	O
,	O
potentially	O
mimicking	O
phosphorylation	O
,	O
causes	O
uncoordination	O
of	O
mitosis	O
and	O
multiple	O
cytokinesis	O
.	O

Deregulation	O
of	O
their	O
expression	O
may	O
contribute	O
to	O
malignant	O
transformation	O
associated	O
with	O
HTLV	O
-	O
1	O
infection	O
.	O

In	O
conclusion	O
,	O
we	O
observed	O
a	O
great	O
regeneration	O
ability	O
following	O
mechanical	O
injury	O
in	O
the	O
nasal	O
mucosa	O
.	O

There	O
occurred	O
a	O
linear	O
relationship	O
between	O
the	O
drop	O
in	O
glucose	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
phosphatase	I-GENE
dehydrogenase	I-GENE
activity	O
and	O
in	O
vitamin	O
E	O
level	O
,	O
on	O
one	O
hand	O
,	O
and	O
the	O
duration	O
of	O
poisoning	O
with	O
sodium	O
nitrite	O
.	O

A	O
vector	O
containing	O
a	O
transcriptionally	O
inactive	O
neomycin	B-GENE
phosphotransferase	I-GENE
II	I-GENE
gene	I-GENE
was	O
used	O
to	O
select	O
promoter	O
sequences	O
from	O
a	O
pool	O
of	O
random	O
genomic	O
DNA	O
fragments	O
.	O

Previous	O
analysis	O
of	O
the	O
98	O
-	O
bp	O
sequence	O
has	O
delineated	O
several	O
protein	O
-	O
binding	O
domains	O
that	O
are	O
recognized	O
by	O
nuclear	O
factors	O
present	O
in	O
human	O
brain	O
cells	O
.	O

Naturally	O
acquired	O
antibodies	O
were	O
demonstrated	O
in	O
some	O
rabbits	O
kept	O
on	O
commercial	O
farms	O
.	O

Biol	O
.	O

Nucleotide	O
sequences	O
between	O
the	O
env	B-GENE
gene	I-GENE
and	O
the	O
LTR	B-GENE
of	I-GENE
SFV	I-GENE
-	I-GENE
1	I-GENE
were	O
determined	O
.	O

The	O
human	O
cDNA	O
was	O
used	O
to	O
demonstrate	O
that	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
could	O
rapidly	O
stimulate	O
MARCKS	B-GENE
gene	I-GENE
transcription	O
in	O
the	O
human	O
promyelocytic	O
leukemia	O
cell	O
line	O
HL60	O
.	O

Dd	B-GENE
PK1	I-GENE
RNA	I-GENE
decreases	O
after	O
6	O
h	O
of	O
starvation	O
to	O
re	O
-	O
accumulate	O
once	O
the	O
cells	O
have	O
aggregated	O
.	O

Young	O
CD	O
-	O
1	O
mice	O
,	O
4	O
days	O
old	O
,	O
exposed	O
to	O
0	O
.	O
1	O
%	O
nicotine	O
sulfate	O
on	O
gestational	O
days	O
6	O
-	O
20	O
were	O
compared	O
with	O
untreated	O
pups	O
of	O
the	O
same	O
age	O
to	O
determine	O
its	O
effect	O
on	O
the	O
development	O
of	O
mandibular	O
first	O
molars	O
.	O

USF	B-GENE
synthesized	O
in	O
an	O
in	O
vitro	O
transcription	O
and	O
translation	O
system	O
also	O
binds	O
to	O
the	O
ADH	B-GENE
promoter	I-GENE
as	O
well	O
as	O
to	O
the	O
MLP	O
.	O

Arterial	O
radioactivity	O
content	O
after	O
the	O
intravenous	O
administration	O
of	O
HMPAO	O
in	O
seven	O
human	O
subjects	O
was	O
analyzed	O
.	O

Linear	O
regression	O
analysis	O
was	O
performed	O
and	O
the	O
following	O
result	O
was	O
obtained	O
:	O
clearance	O
(	O
HMPAO	O
)	O
=	O
0	O
.	O
07	O
+	O
0	O
.	O
43	O
.	O
rCBF	O
with	O
a	O
high	O
significance	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Saccharomyces	O
cerevisiae	O
has	O
been	O
used	O
widely	O
both	O
as	O
a	O
model	O
system	O
for	O
unraveling	O
the	O
biochemical	O
,	O
genetic	O
,	O
and	O
molecular	O
details	O
of	O
gene	O
expression	O
and	O
the	O
secretion	O
process	O
,	O
and	O
as	O
a	O
host	O
for	O
the	O
production	O
of	O
heterologous	O
proteins	O
of	O
biotechnological	O
interest	O
.	O

Formalin	O
activated	O
both	O
SNO	O
NS	O
and	O
NnS	O
neurones	O
,	O
but	O
,	O
when	O
they	O
responded	O
,	O
NS	O
neurones	O
(	O
n	O
=	O
5	O
)	O
showed	O
only	O
the	O
first	O
phase	O
of	O
activity	O
while	O
NnS	O
neurones	O
showed	O
either	O
one	O
(	O
n	O
=	O
13	O
)	O
or	O
two	O
phases	O
(	O
n	O
=	O
6	O
)	O
.	O

Uptake	O
of	O
ofloxacin	O
by	O
Escherichia	O
coli	O

A	O
deletion	O
series	O
of	O
the	O
5	O
'	O
flanking	O
region	O
was	O
created	O
from	O
position	O
-	O
1329	O
to	O
-	O
74	O
relative	O
to	O
the	O
transcriptional	O
initiation	O
site	O
and	O
similarly	O
examined	O
in	O
transgenic	O
tobacco	O
.	O

Toxicity	O
was	O
very	O
mild	O
with	O
both	O
regimens	O
,	O
although	O
sedation	O
was	O
significantly	O
higher	O
in	O
arm	O
B	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Limits	O
of	O
energy	O
turnover	O
in	O
relation	O
to	O
physical	O
performance	O
were	O
addressed	O
in	O
terms	O
of	O
upper	O
and	O
lower	O
limit	O
,	O
changes	O
during	O
a	O
training	O
programme	O
and	O
how	O
to	O
regulate	O
energy	O
balance	O
at	O
a	O
changing	O
energy	O
turnover	O
.	O

Moreover	O
,	O
promoters	O
containing	O
a	O
TATA	O
box	O
in	O
the	O
absence	O
of	O
Sp1	B-GENE
sites	I-GENE
or	O
Sp1	B-GENE
sites	I-GENE
in	O
the	O
absence	O
of	O
a	O
TATA	O
box	O
were	O
equally	O
inducible	O
in	O
vitro	O
,	O
as	O
was	O
an	O
RNA	B-GENE
polymerase	I-GENE
III	I-GENE
promoter	I-GENE
.	O

Ivermectin	O
uptake	O
and	O
distribution	O
in	O
the	O
plasma	O
and	O
tissue	O
of	O
Sudanese	O
and	O
Mexican	O
patients	O
infected	O
with	O
Onchocerca	O
volvulus	O
.	O

The	O
currently	O
proposed	O
extended	O
arch	O
repair	O
should	O
be	O
reserved	O
for	O
the	O
small	O
group	O
of	O
infants	O
with	O
transverse	O
aortic	O
arch	O
to	O
ascending	O
aorta	O
diameter	O
ratios	O
(	O
arch	O
indices	O
)	O
of	O
less	O
than	O
0	O
.	O
25	O
.	O

DNA	O
hybridization	O
analysis	O
revealed	O
that	O
both	O
pigmented	O
and	O
nonpigmented	O
cells	O
of	O
Y	O
.	O
pestis	O
possess	O
a	O
DNA	O
locus	O
homologous	O
to	O
the	O
Escherichia	B-GENE
coli	I-GENE
fur	I-GENE
gene	I-GENE
.	O

We	O
report	O
two	O
patients	O
receiving	O
maintenance	O
valproate	O
,	O
one	O
with	O
resolving	O
acute	O
hepatitis	O
C	O
and	O
the	O
other	O
with	O
chronic	O
persistent	O
hepatitis	O
C	O
,	O
with	O
incidental	O
microvesicular	O
steatosis	O
demonstrated	O
on	O
oil	O
-	O
red	O
O	O
stains	O
.	O

UDP	B-GENE
-	I-GENE
Gal	I-GENE
:	I-GENE
Gal	I-GENE
beta	I-GENE
1	I-GENE
-	I-GENE
-	I-GENE
-	I-GENE
-	I-GENE
4GlcNAc	I-GENE
alpha	I-GENE
1	I-GENE
-	I-GENE
-	I-GENE
-	I-GENE
-	I-GENE
3	I-GENE
-	I-GENE
galactosyltransferase	I-GENE
is	O
a	O
terminal	B-GENE
glycosyltransferase	I-GENE
that	O
is	O
widely	O
expressed	O
in	O
a	O
variety	O
of	O
mammalian	O
species	O
,	O
with	O
the	O
notable	O
exception	O
of	O
man	O
,	O
apes	O
,	O
and	O
Old	O
World	O
monkeys	O
.	O

A	O
synthetic	O
oligonucleotide	O
containing	O
the	O
SRE	O
sequence	O
from	O
the	O
mouse	B-GENE
c	I-GENE
-	I-GENE
fos	I-GENE
gene	I-GENE
promoter	I-GENE
(	O
-	O
299	O
to	O
-	O
322	O
)	O
was	O
radioactively	O
labeled	O
,	O
used	O
as	O
a	O
probe	O
for	O
the	O
mobility	O
shift	O
assay	O
and	O
Southwestern	O
(	O
DNA	O
-	O
protein	O
)	O
blotting	O
,	O
and	O
also	O
used	O
for	O
sequence	O
-	O
specific	O
affinity	O
chromatography	O
.	O

This	O
study	O
indicates	O
that	O
this	O
dose	O
-	O
intense	O
regimen	O
can	O
be	O
safely	O
administered	O
,	O
even	O
with	O
the	O
use	O
of	O
purged	O
marrow	O
,	O
with	O
an	O
acceptable	O
toxicity	O
profile	O
.	O

INTERVENTIONS	O
:	O
Patients	O
received	O
rt	B-GENE
-	I-GENE
PA	I-GENE
,	O
heparin	O
,	O
and	O
aspirin	O
.	O

Sequence	O
analysis	O
of	O
the	O
sMtCK	B-GENE
genomic	I-GENE
upstream	I-GENE
sequences	I-GENE
reveals	O
a	O
typical	O
TATAA	O
box	O
within	O
the	O
80	O
base	O
pairs	O
(	O
bp	O
)	O
that	O
,	O
by	O
transfection	O
experiments	O
,	O
are	O
sufficient	O
to	O
promote	O
expression	O
of	O
chimeric	O
plasmids	O
with	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	I-GENE
.	O

Sequence	O
analysis	O
of	O
the	O
sMtCK	B-GENE
genomic	I-GENE
upstream	I-GENE
sequences	I-GENE
reveals	O
a	O
typical	O
TATAA	O
box	O
within	O
the	O
80	O
base	O
pairs	O
(	O
bp	O
)	O
that	O
,	O
by	O
transfection	O
experiments	O
,	O
are	O
sufficient	O
to	O
promote	O
expression	O
of	O
chimeric	O
plasmids	O
with	O
the	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	I-GENE
.	O

The	O
cDNA	O
segment	O
is	O
flanked	O
by	O
the	O
immunoglobulin	B-GENE
gene	I-GENE
recombination	I-GENE
signal	I-GENE
sequences	I-GENE
so	O
that	O
the	O
cDNA	O
segment	O
can	O
invert	O
and	O
the	O
human	B-GENE
IL	I-GENE
-	I-GENE
2R	I-GENE
L	I-GENE
chain	I-GENE
is	O
subsequently	O
expressed	O
under	O
the	O
control	O
of	O
the	O
SV40	B-GENE
promoter	I-GENE
.	O

Habituation	O
of	O
completely	O
isolated	O
neurons	O
of	O
the	O
edible	O
snail	O
to	O
electrical	O
stimulation	O
.	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
in	O
burn	O
patients	O
.	O

The	O
suppression	O
was	O
also	O
demonstrated	O
in	O
a	O
transient	O
expression	O
assay	O
in	O
vivo	O
using	O
isolated	O
barley	O
endosperms	O
.	O

RNA	O
gel	O
retardation	O
and	O
competition	O
analyses	O
indicate	O
that	O
TRP	B-GENE
-	I-GENE
185	I-GENE
binding	O
is	O
strongly	O
dependent	O
on	O
the	O
TAR	O
RNA	O
loop	O
sequences	O
.	O

This	O
generalization	O
of	O
MFP	O
involves	O
defining	O
an	O
appropriate	O
high	O
-	O
resolution	O
cost	O
function	O
,	O
parametrizing	O
the	O
search	O
space	O
of	O
the	O
environment	O
and	O
source	O
,	O
constructing	O
solutions	O
of	O
the	O
wave	O
equation	O
,	O
and	O
utilizing	O
a	O
nonlinear	O
optimization	O
method	O
to	O
search	O
the	O
parameter	O
landscape	O
for	O
the	O
global	O
minimum	O
of	O
the	O
cost	O
function	O
.	O

The	O
original	O
technique	O
was	O
developed	O
in	O
the	O
1960	O
'	O
s	O
to	O
analyze	O
the	O
inner	O
ear	O
fluid	O
as	O
a	O
diagnostic	O
procedure	O
(	O
i	O
.	O
e	O
.	O
,	O
diagnostic	O
labyrinthotomy	O
)	O
in	O
acoustic	O
neuroma	O
suspects	O
.	O

Evolution	O
of	O
lesions	O
did	O
not	O
necessarily	O
follow	O
a	O
regular	O
progression	O
through	O
the	O
later	O
stages	O
of	O
the	O
vitelliform	O
classification	O
.	O

Urine	O
specimens	O
containing	O
either	O
phencyclidine	O
(	O
PCP	O
)	O
or	O
11	O
-	O
nor	O
-	O
delta	O
9	O
-	O
tetrahydrocannabinol	O
-	O
9	O
-	O
carboxylic	O
acid	O
(	O
9	O
-	O
THC	O
-	O
COOH	O
)	O
were	O
adulterated	O
with	O
sodium	O
chloride	O
,	O
bleach	O
,	O
vinegar	O
,	O
potassium	O
hydroxide	O
,	O
liquid	O
soap	O
,	O
2	O
-	O
propanol	O
,	O
and	O
ammonia	O
.	O

Along	O
with	O
previously	O
mapped	O
genes	O
including	O
Ly	B-GENE
-	I-GENE
1	I-GENE
and	O
CD20	B-GENE
,	O
OSBP	B-GENE
defines	O
a	O
new	O
conserved	O
syntenic	O
group	O
on	O
the	O
long	O
arm	O
of	O
chromosome	O
11	O
in	O
the	O
human	O
and	O
the	O
proximal	O
end	O
of	O
chromosome	O
19	O
in	O
the	O
mouse	O
.	O

Here	O
we	O
show	O
that	O
these	O
synthetic	O
binding	O
sites	O
have	O
a	O
more	O
restricted	O
and	O
specific	O
ability	O
to	O
enhance	O
transcription	O
when	O
assayed	O
in	O
transformed	O
embryos	O
.	O

After	O
base	O
-	O
line	O
CBF	O
was	O
established	O
,	O
hexamethonium	O
bromide	O
(	O
2	O
mg	O
/	O
kg	O
iv	O
)	O
,	O
ipratropium	O
bromide	O
(	O
0	O
.	O
5	O
microgram	O
/	O
kg	O
iv	O
)	O
,	O
indomethacin	O
(	O
2	O
mg	O
/	O
kg	O
iv	O
)	O
,	O
or	O
intravenous	O
0	O
.	O
9	O
%	O
saline	O
was	O
administered	O
.	O

This	O
study	O
suggests	O
that	O
BSPMs	O
are	O
useful	O
in	O
the	O
assessment	O
of	O
AMI	O
in	O
terms	O
of	O
diagnosis	O
,	O
location	O
and	O
extent	O
of	O
myocardial	O
infarct	O
.	O

Examination	O
of	O
immediate	B-GENE
-	I-GENE
early	I-GENE
transcription	I-GENE
factor	I-GENE
expression	O
during	O
the	O
MDI	O
regimen	O
revealed	O
that	O
RA	O
mediated	O
an	O
elevated	O
,	O
prolonged	O
expression	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
mRNA	I-GENE
accompanied	O
by	O
diminished	O
expression	O
of	O
c	B-GENE
-	I-GENE
Fos	I-GENE
and	O
Jun	B-GENE
-	I-GENE
B	I-GENE
mRNAs	I-GENE
.	O

Although	O
heart	O
rate	O
and	O
diastolic	O
pressure	O
rose	O
in	O
some	O
degree	O
1	O
min	O
after	O
intubation	O
,	O
free	O
and	O
total	O
CA	O
concentrations	O
did	O
not	O
increase	O
during	O
study	O
period	O
.	O

Processing	O
,	O
secretion	O
,	O
and	O
immunoreactivity	O
of	O
carboxy	B-GENE
terminally	I-GENE
truncated	I-GENE
dengue	I-GENE
-	I-GENE
2	I-GENE
virus	I-GENE
envelope	I-GENE
proteins	I-GENE
expressed	O
in	O
insect	O
cells	O
by	O
recombinant	O
baculoviruses	O
.	O

Seven	O
clones	O
encoding	O
interferon	B-GENE
response	I-GENE
element	I-GENE
binding	I-GENE
factors	I-GENE
have	O
been	O
isolated	O
from	O
a	O
mouse	O
fibroblast	O
lambda	O
gt11	O
cDNA	O
library	O
by	O
using	O
a	O
32P	O
end	O
-	O
labeled	O
tandem	O
trimer	O
of	O
the	O
mouse	B-GENE
(	I-GENE
2	I-GENE
'	I-GENE
-	I-GENE
5	I-GENE
'	I-GENE
)	I-GENE
oligoadenylate	I-GENE
synthetase	I-GENE
gene	I-GENE
interferon	O
response	O
element	O
as	O
a	O
probe	O
.	O

DNA	O
-	O
protein	O
UV	O
cross	O
-	O
linking	O
studies	O
indicated	O
that	O
UHF	B-GENE
-	I-GENE
1	I-GENE
has	O
an	O
electrophoretic	O
mobility	O
on	O
sodium	O
dodecyl	O
sulfate	O
-	O
acrylamide	O
gels	O
of	O
approximately	O
85	O
kDa	O
and	O
suggested	O
that	O
additional	O
proteins	O
,	O
specific	O
to	O
each	O
promoter	O
,	O
bind	O
to	O
each	O
site	O
.	O

The	O
specific	O
interaction	O
between	O
a	O
defined	O
structural	O
element	O
of	O
the	O
human	O
immunodeficiency	O
virus	O
mRNA	O
(	O
RRE	B-GENE
,	O
the	O
Rev	B-GENE
response	I-GENE
element	I-GENE
)	O
and	O
the	O
virus	B-GENE
-	I-GENE
encoded	I-GENE
protein	I-GENE
Rev	I-GENE
has	O
been	O
implicated	O
in	O
the	O
regulation	O
of	O
the	O
export	O
of	O
unspliced	O
or	O
singly	O
spliced	O
mRNA	O
from	O
the	O
nucleus	O
to	O
the	O
cytoplasm	O
.	O

Radiation	O
-	O
induced	O
changes	O
in	O
the	O
area	O
of	O
alveoli	O
and	O
septa	O
as	O
well	O
as	O
collagen	B-GENE
content	O
were	O
seen	O
11	O
weeks	O
after	O
irradiation	O
.	O

The	O
first	O
follow	O
-	O
up	O
was	O
at	O
a	O
nearly	O
constant	O
interval	O
of	O
5	O
.	O
1	O
years	O
in	O
Caerphilly	O
and	O
3	O
.	O
2	O
years	O
in	O
Speedwell	O
;	O
251	O
major	O
IHD	O
events	O
had	O
occurred	O
.	O

Once	O
the	O
proliferation	O
of	O
fibroblasts	O
and	O
collagen	B-GENE
synthesis	O
had	O
led	O
to	O
an	O
increase	O
of	O
mechanical	O
strength	O
,	O
no	O
negative	O
effect	O
on	O
wound	O
healing	O
could	O
be	O
detected	O
applying	O
the	O
same	O
chemotherapeutic	O
agents	O
.	O

During	O
the	O
years	O
1980	O
-	O
87	O
a	O
total	O
of	O
287	O
persons	O
received	O
disability	O
pensions	O
in	O
the	O
municipality	O
of	O
Nordreisa	O
in	O
northern	O
Norway	O
.	O

HeLa	O
and	O
Jurkat	O
cell	O
lines	O
carrying	O
the	O
nef	B-GENE
gene	I-GENE
linked	O
to	O
the	O
CMV	O
promoter	O
or	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
were	O
isolated	O
by	O
coselection	O
for	O
neomycin	O
resistance	O
.	O

Two	O
patients	O
had	O
immediate	O
adverse	O
effects	O
from	O
NMF	O
;	O
one	O
had	O
a	O
grand	O
mal	O
seizure	O
and	O
the	O
other	O
developed	O
severe	O
abdominal	O
pain	O
.	O

The	O
muscles	O
from	O
the	O
ischemic	O
group	O
had	O
significantly	O
lower	O
(	O
P	O
less	O
than	O
.	O
05	O
)	O
values	O
for	O
capillary	O
density	O
and	O
capillary	O
to	O
fiber	O
ratio	O
and	O
significantly	O
higher	O
intercapillary	O
distance	O
than	O
those	O
from	O
the	O
normal	O
group	O
.	O

Serum	B-GENE
TNF	I-GENE
concentrations	O
were	O
elevated	O
at	O
diagnosis	O
and	O
gradually	O
decreased	O
toward	O
the	O
reference	O
limits	O
by	O
week	O
16	O
.	O

Conclusion	O
:	O
inlet	O
type	O
VSD	O
and	O
perimembranous	O
type	O
TOF	O
have	O
anatomic	O
features	O
in	O
which	O
the	O
proximal	O
His	O
bundle	O
tends	O
to	O
be	O
jeopardized	O
by	O
suturing	O
for	O
VSD	O
closure	O
.	O

The	O
remainder	O
(	O
18	O
.	O
4	O
%	O
)	O
was	O
with	O
IgA	B-GENE
nephropathy	O
,	O
which	O
was	O
histologically	O
mild	O
.	O

Grossly	O
,	O
the	O
experimental	O
vulvitis	O
was	O
identical	O
to	O
the	O
field	O
condition	O
,	O
and	O
bacteria	O
indistinguishable	O
from	O
the	O
inoculated	O
strains	O
were	O
reisolated	O
.	O

3	O
.	O

Hemorrhagic	O
shock	O
and	O
bacterial	O
translocation	O
in	O
a	O
swine	O
model	O
.	O

A	O
method	O
for	O
establishing	O
stimulus	O
control	O
of	O
ethanol	O
responding	O
was	O
developed	O
.	O

In	O
all	O
cases	O
,	O
high	O
-	O
level	O
expression	O
of	O
the	O
truncated	B-GENE
avian	I-GENE
integrins	I-GENE
was	O
obtained	O
.	O

In	O
adulthood	O
these	O
rats	O
were	O
hyperactive	O
and	O
learned	O
the	O
active	O
avoidance	O
response	O
later	O
than	O
the	O
controls	O
.	O

The	O
N	O
-	O
terminal	O
115	O
amino	O
acids	O
correspond	O
to	O
a	O
putative	O
DNA	O
-	O
binding	O
domain	O
and	O
show	O
significant	O
sequence	O
similarity	O
with	O
other	O
cloned	O
IFN	B-GENE
response	I-GENE
factors	I-GENE
(	O
IRF	B-GENE
-	I-GENE
1	I-GENE
and	O
IRF	B-GENE
-	I-GENE
2	I-GENE
)	O
.	O

The	O
patients	O
were	O
divided	O
into	O
3	O
subgroups	O
:	O
1	O
)	O
13	O
N	O
+	O
patients	O
with	O
multiple	O
hot	O
spots	O
(	O
greater	O
than	O
2	O
)	O
(	O
N	O
+	O
IM	O
)	O
;	O
2	O
)	O
24	O
N	O
+	O
patients	O
with	O
single	O
hot	O
spots	O
(	O
less	O
than	O
or	O
equal	O
to	O
2	O
)	O
(	O
N	O
+	O
IS	O
)	O
;	O
3	O
)	O
12	O
N	O
-	O
patients	O
with	O
single	O
hot	O
spots	O
(	O
less	O
than	O
or	O
equal	O
to	O
2	O
)	O
(	O
N	O
-	O
IS	O
)	O
.	O

Further	O
,	O
they	O
are	O
consistent	O
with	O
the	O
suggestion	O
that	O
sites	O
homologous	O
to	O
the	O
CAR1	B-GENE
URS	I-GENE
may	O
be	O
situated	O
in	O
the	O
5	O
'	O
-	O
flanking	O
regions	O
of	O
multiple	O
unrelated	O
yeast	O
genes	O
.	O

Uses	O
of	O
orthoclone	O
OKT3	B-GENE
for	O
prophylaxis	O
of	O
rejection	O
and	O
induction	O
in	O
initial	O
nonfunction	O
in	O
kidney	O
transplantation	O
.	O

Uses	O
of	O
orthoclone	O
OKT3	O
for	O
prophylaxis	O
of	O
rejection	O
and	O
induction	O
in	O
initial	O
nonfunction	O
in	O
kidney	O
transplantation	O
.	O

In	O
Denmark	O
only	O
1	O
-	O
3	O
cases	O
of	O
transfusion	O
-	O
associated	O
hepatitis	O
NANB	O
(	O
TAH	O
-	O
NANB	O
)	O
are	O
registered	O
annually	O
or	O
about	O
1	O
case	O
per	O
100	O
,	O
000	O
units	O
transfused	O
.	O

Hence	O
,	O
the	O
replacement	O
of	O
Phe	O
-	O
62	O
with	O
Ser	O
specifically	O
affects	O
a	O
determinant	O
on	O
the	O
lambda	B-GENE
I	I-GENE
light	I-GENE
chain	I-GENE
that	O
is	O
necessary	O
for	O
the	O
intracellular	O
transport	O
of	O
this	O
molecule	O
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
has	O
the	O
greatest	O
homology	O
(	O
61	O
%	O
)	O
to	O
the	O
green	B-GENE
alga	I-GENE
Scenedemus	I-GENE
obliquus	I-GENE
plastocyanin	I-GENE
.	O

Higher	O
fasting	O
serum	O
gastrin	B-GENE
concentration	O
(	O
102	O
.	O
0	O
+	O
/	O
-	O
21	O
.	O
1	O
vs	O
63	O
.	O
3	O
+	O
/	O
-	O
8	O
.	O
3	O
ng	O
.	O
l	O
-	O
1	O
)	O
,	O
and	O
greater	O
postprandial	O
gastrin	B-GENE
release	O
(	O
AUC0	O
-	O
120	O
:	O
16690	O
+	O
/	O
-	O
2648	O
vs	O
10654	O
+	O
/	O
-	O
1283	O
ng	O
.	O
l	O
-	O
1	O
min	O
)	O
were	O
observed	O
after	O
VTP	O
-	O
HM	O
than	O
after	O
VTP	O
-	O
Cas	O
.	O

The	O
experimental	O
group	O
consisted	O
of	O
61	O
examinees	O
class	O
II	O
/	O
2	O
orthodontic	O
anomalies	O
.	O

Subjects	O
were	O
16	O
male	O
chronic	O
schizophrenics	O
consisting	O
of	O
8	O
DST	O
suppressors	O
and	O
8	O
nonsuppressors	O
.	O

In	O
this	O
article	O
we	O
propose	O
to	O
find	O
out	O
the	O
percentage	O
of	O
normal	O
occlusion	O
and	O
the	O
distribution	O
of	O
maloclusions	O
,	O
according	O
to	O
the	O
anteroposterior	O
relationship	O
between	O
the	O
dental	O
archs	O
(	O
following	O
the	O
ANGLE3	O
classification	O
)	O
.	O

We	O
have	O
previously	O
identified	O
,	O
by	O
screening	O
a	O
lambda	O
gt11	O
expression	O
library	O
,	O
murine	B-GENE
protein	I-GENE
mXBP	I-GENE
,	O
which	O
binds	O
to	O
a	O
sequence	O
which	O
overlaps	O
the	O
3	O
'	O
end	O
of	O
the	O
murine	B-GENE
class	I-GENE
II	I-GENE
major	I-GENE
histocompatibility	I-GENE
complex	I-GENE
A	I-GENE
alpha	I-GENE
gene	I-GENE
X	I-GENE
box	I-GENE
,	O
a	O
conserved	O
transcription	O
element	O
found	O
upstream	O
of	O
all	O
class	O
II	O
genes	O
.	O

A	O
contiguous	O
and	O
sequentially	O
occupied	O
secondary	O
Fur	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
in	O
entC	B-GENE
was	O
protected	O
at	O
higher	O
Fur	B-GENE
concentrations	O
,	O
extending	O
the	O
protected	O
region	O
to	O
+	O
49	O
,	O
and	O
sequestering	O
the	O
putative	O
Shine	O
-	O
Dalgarno	O
sequence	O
.	O

The	O
major	O
promoter	O
responds	O
strongly	O
to	O
virus	O
-	O
encoded	O
trans	O
activators	O
EIA	B-GENE
and	O
EIV	B-GENE
and	O
contains	O
four	O
elements	O
:	O
a	O
TAGA	O
motif	O
analogous	O
to	O
the	O
TATA	O
box	O
,	O
two	O
EIIF	B-GENE
sites	I-GENE
present	O
in	O
an	O
inverted	O
orientation	O
,	O
and	O
an	O
ATF	B-GENE
/	O
CREB	B-GENE
site	O
.	O

Luteinizing	B-GENE
hormone	I-GENE
-	I-GENE
releasing	I-GENE
hormone	I-GENE
analog	O
therapy	O
of	O
uterine	O
fibroid	O
:	O
analysis	O
of	O
results	O
obtained	O
with	O
buserelin	O
administered	O
intranasally	O
and	O
goserelin	O
administered	O
subcutaneously	O
as	O
a	O
monthly	O
depot	O
.	O

Although	O
there	O
are	O
no	O
octamer	O
elements	O
in	O
the	O
adenovirus	O
genome	O
that	O
are	O
known	O
to	O
be	O
important	O
for	O
transcription	O
,	O
there	O
are	O
octamer	O
elements	O
in	O
the	O
viral	O
terminal	O
repeat	O
sequences	O
.	O

A	O
4	O
.	O
8	O
-	O
kilobase	O
BamHI	B-GENE
-	O
HindIII	B-GENE
fragment	O
encoding	O
the	O
entire	B-GENE
Neurospora	I-GENE
crassa	I-GENE
CuZn	I-GENE
superoxide	I-GENE
dismutase	I-GENE
gene	I-GENE
(	O
herein	O
designated	O
sod	B-GENE
-	I-GENE
1	I-GENE
)	O
was	O
isolated	O
from	O
a	O
genomic	O
library	O
using	O
two	O
60	O
-	O
base	O
deoxyoligonucleotide	O
probes	O
corresponding	O
to	O
the	O
published	O
N	O
.	O
crassa	O
amino	O
acid	O
sequence	O
.	O

Using	O
appropriate	O
synthetic	O
HSE	O
oligonucleotides	O
,	O
three	O
types	O
of	O
clones	O
with	O
potential	O
HSE	O
binding	O
domains	O
were	O
isolated	O
from	O
a	O
tomato	O
lambda	O
gt11	O
expression	O
library	O
by	O
DNA	O
-	O
ligand	O
screening	O
.	O

This	O
result	O
indicates	O
that	O
separate	O
complexes	O
exist	O
containing	O
ankyrin	B-GENE
and	O
fodrin	B-GENE
with	O
either	O
uvomorulin	B-GENE
or	O
Na	B-GENE
+	I-GENE
,	I-GENE
K	I-GENE
+	I-GENE
-	I-GENE
ATPase	I-GENE
.	O

These	O
genes	O
are	O
expressed	O
within	O
a	O
few	O
hours	O
of	O
the	O
initiation	O
of	O
development	O
;	O
their	O
mRNAs	O
accumulate	O
to	O
a	O
peak	O
at	O
12	O
hr	O
and	O
persist	O
until	O
culmination	O
.	O

In	O
transient	O
cotransfection	O
assays	O
using	O
Chang	O
liver	O
cells	O
(	O
CCL	O
13	O
)	O
,	O
pM1	O
DNA	O
exerts	O
a	O
6	O
-	O
to	O
10	O
-	O
fold	O
trans	O
-	O
activating	O
effect	O
on	O
the	O
expression	O
of	O
the	O
pSV2CAT	O
reporter	O
plasmid	O
.	O

We	O
have	O
determined	O
the	O
nucleotide	O
(	O
nt	O
)	O
sequence	O
of	O
the	O
7	B-GENE
.	I-GENE
5	I-GENE
-	I-GENE
kb	I-GENE
COR	I-GENE
segment	I-GENE
that	O
encompasses	O
a	O
cluster	O
of	O
six	O
genes	O
(	O
CYC1	B-GENE
,	O
UTR1	B-GENE
,	O
UTR3	B-GENE
,	O
OSM1	B-GENE
,	O
tRNA	B-GENE
(	I-GENE
Gly	I-GENE
)	I-GENE
and	O
RAD7	B-GENE
)	O
located	O
on	O
chromosome	O
X	O
of	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
.	O

No	O
recombination	O
signal	O
sequences	O
have	O
been	O
found	O
contiguous	O
to	O
the	O
recombination	O
point	O
.	O

The	O
antinociceptive	O
properties	O
,	O
as	O
measured	O
by	O
the	O
tail	O
-	O
flick	O
and	O
hot	O
-	O
plate	O
tests	O
,	O
and	O
the	O
motor	O
effects	O
of	O
an	O
intrathecally	O
-	O
administered	O
benzodiazepine	O
agonist	O
midazolam	O
,	O
alone	O
,	O
and	O
in	O
combination	O
with	O
morphine	O
,	O
was	O
examined	O
in	O
rats	O
.	O

To	O
identify	O
these	O
sites	O
,	O
the	O
deduced	O
amino	O
acid	O
sequence	O
of	O
the	O
3T3	O
-	O
L1	O
adipocyte	B-GENE
insulin	I-GENE
receptor	I-GENE
of	O
the	O
mouse	O
was	O
determined	O
.	O

PAO	O
blocks	O
turnover	O
of	O
the	O
phosphoryl	O
group	O
of	O
pp15	B-GENE
,	O
causing	O
its	O
accumulation	O
,	O
and	O
thereby	O
appears	O
to	O
interrupt	O
signal	O
transmission	O
from	O
the	O
receptor	O
to	O
the	O
glucose	O
-	O
transport	O
system	O
.	O

It	O
is	O
likely	O
that	O
the	O
sequence	O
similarities	O
reflect	O
a	O
common	O
molecular	O
architecture	O
of	O
the	O
two	O
heme	O
binding	O
sites	O
and	O
of	O
a	O
copper	O
binding	O
site	O
in	O
these	O
enzymes	O
.	O

The	O
TraD	B-GENE
protein	I-GENE
(	I-GENE
83	I-GENE
,	I-GENE
899	I-GENE
Da	I-GENE
)	I-GENE
contains	O
three	O
hydrophobic	O
regions	O
,	O
of	O
which	O
two	O
are	O
located	O
near	O
the	O
amino	O
-	O
terminal	O
region	O
.	O

The	O
protein	O
product	O
of	O
orfD	B-GENE
,	O
which	O
is	O
probably	O
a	O
new	O
tra	B-GENE
gene	I-GENE
(	O
named	O
traX	B-GENE
)	O
,	O
contains	O
65	O
%	O
hydrophobic	O
amino	O
acids	O
,	O
especially	O
rich	O
in	O
alanine	O
and	O
leucine	O
.	O

A	O
gene	O
in	O
Drosophila	O
melanogaster	O
that	O
maps	O
cytologically	O
to	O
2C1	O
-	O
3	O
on	O
the	O
distal	O
portion	O
of	O
the	O
X	O
-	O
chromosome	O
encodes	O
a	O
member	O
of	O
the	O
steroid	B-GENE
/	I-GENE
thyroid	I-GENE
hormone	I-GENE
receptor	I-GENE
superfamily	I-GENE
.	O

A	O
portion	O
of	O
Region	O
II	O
also	O
resembles	O
part	O
of	O
the	O
human	O
c	B-GENE
-	I-GENE
jun	I-GENE
oncoprotein	O
'	O
s	O
leucine	O
zipper	O
,	O
which	O
in	O
turn	O
,	O
has	O
been	O
demonstrated	O
to	O
be	O
the	O
heterodimerization	O
site	O
between	O
the	O
jun	B-GENE
and	O
fos	B-GENE
oncoproteins	I-GENE
.	O

To	O
determine	O
whether	O
vanadate	O
could	O
inhibit	O
PEPCK	B-GENE
gene	I-GENE
transcription	O
,	O
a	O
series	O
of	O
chimeric	O
genes	O
containing	O
several	O
deletions	O
in	O
the	O
P	B-GENE
-	I-GENE
enolypyruvate	I-GENE
carboxykinase	I-GENE
promoter	I-GENE
between	O
-	O
550	O
and	O
-	O
68	O
was	O
linked	O
to	O
the	O
structural	O
genes	O
for	O
either	O
amino	B-GENE
-	I-GENE
3	I-GENE
-	I-GENE
glycosyl	I-GENE
phosphotransferase	I-GENE
(	O
neo	B-GENE
)	O
or	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
and	O
introduced	O
into	O
hepatoma	O
cells	O
using	O
three	O
methods	O
:	O
(	O
a	O
)	O
infection	O
with	O
a	O
Moloney	O
murine	O
leukemia	O
virus	O
-	O
based	O
retrovirus	O
,	O
(	O
b	O
)	O
transfection	O
and	O
stable	O
selection	O
for	O
neo	B-GENE
expression	O
,	O
or	O
(	O
c	O
)	O
transient	O
expression	O
of	O
chloroamphenicol	B-GENE
acetyltransferase	I-GENE
.	O

Significant	O
correlations	O
were	O
obtained	O
between	O
changes	O
in	O
SSEP	O
in	O
response	O
to	O
AS	O
and	O
the	O
presence	O
of	O
not	O
deep	O
residual	O
-	O
organic	O
disturbances	O
,	O
so	O
-	O
called	O
"	O
ground	O
"	O
in	O
psychogenic	O
disorders	O
.	O

Both	O
strains	O
grew	O
very	O
poorly	O
,	O
or	O
not	O
at	O
all	O
,	O
on	O
nonfermentable	O
carbon	O
sources	O
and	O
exhibited	O
,	O
at	O
most	O
,	O
only	O
5	O
%	O
of	O
wild	B-GENE
-	I-GENE
type	I-GENE
ubiquinol	I-GENE
-	I-GENE
cytochrome	I-GENE
c	I-GENE
oxidoreductase	I-GENE
activity	O
.	O

Regulation	O
of	O
irgA	B-GENE
by	O
iron	O
in	O
V	O
.	O
cholerae	O
occurs	O
at	O
the	O
transcriptional	O
level	O
,	O
and	O
there	O
is	O
an	O
interrupted	O
dyad	O
symmetric	O
sequence	O
in	O
the	O
vicinity	O
of	O
the	O
promoter	O
that	O
is	O
homologous	O
to	O
Fur	B-GENE
binding	I-GENE
sites	I-GENE
of	O
E	O
.	O
coli	O
.	O

The	O
recombinant	O
contains	O
the	O
normal	O
beta	B-GENE
A	I-GENE
-	I-GENE
globin	I-GENE
gene	I-GENE
,	O
the	O
mutant	O
gene	O
and	O
Ylp	O
vector	O
sequences	O
between	O
the	O
two	O
copies	O
.	O

The	O
characterized	O
Y	B-GENE
'	I-GENE
repeated	I-GENE
sequence	I-GENE
families	I-GENE
provide	O
an	O
experimental	O
system	O
in	O
which	O
repeated	O
sequence	O
interactions	O
and	O
subsequent	O
evolution	O
can	O
be	O
studied	O
.	O

However	O
,	O
primary	O
transcripts	O
of	O
a	O
variant	B-GENE
tRNA	I-GENE
(	I-GENE
Val	I-GENE
)	I-GENE
(	I-GENE
UAC	I-GENE
)	I-GENE
gene	I-GENE
are	O
processing	O
deficient	O
under	O
standard	O
growth	O
conditions	O
(	O
30	O
degrees	O
C	O
)	O
,	O
due	O
to	O
a	O
slightly	O
altered	O
5	O
'	O
flanking	O
region	O
.	O

Three	O
of	O
the	O
short	O
ORFs	O
in	O
the	O
central	O
region	O
of	O
BIV	O
have	O
been	O
identified	O
by	O
location	O
and	O
structural	O
similarity	O
to	O
the	O
nonstructural	O
/	O
regulatory	O
genes	O
(	O
vif	B-GENE
,	O
tat	B-GENE
,	O
and	O
rev	B-GENE
)	O
of	O
other	O
lentiviruses	O
;	O
we	O
also	O
discovered	O
two	O
unique	O
ORFs	O
,	O
termed	O
W	O
and	O
Y	O
,	O
which	O
may	O
serve	O
as	O
exons	O
for	O
novel	O
genes	O
.	O

The	O
contribution	O
that	O
alternative	O
splicing	O
events	O
in	O
c	B-GENE
-	I-GENE
myb	I-GENE
expression	O
may	O
make	O
on	O
c	B-GENE
-	I-GENE
myb	I-GENE
function	O
remains	O
to	O
be	O
elucidated	O
.	O

IgG	B-GENE
and	O
IgM	B-GENE
antibody	O
activity	O
was	O
determined	O
by	O
adding	O
a	O
1	O
:	O
100	O
dilution	O
of	O
serum	O
to	O
plates	O
coated	O
with	O
A60	B-GENE
antigen	I-GENE
.	O

1	O
,	O
among	O
which	O
nine	O
have	O
been	O
cloned	O
and	O
two	O
(	O
potentially	O
functional	O
)	O
sequenced	O
.	O

The	O
urinary	O
protein	O
,	O
serum	O
albumin	B-GENE
,	O
BUN	O
and	O
SCr	O
all	O
had	O
very	O
significant	O
improvement	O
.	O

Patients	O
with	O
detectable	O
serum	O
TNF	B-GENE
levels	O
had	O
significantly	O
lower	O
serum	O
T3	O
concentrations	O
compared	O
to	O
those	O
with	O
undetectable	O
levels	O
[	O
1	O
.	O
072	O
+	O
/	O
-	O
0	O
.	O
588	O
vs	O
.	O

Rats	O
with	O
one	O
olfactory	O
bulb	O
removed	O
and	O
the	O
contralateral	O
naris	O
closed	O
can	O
detect	O
odors	O
.	O

Expression	O
of	O
the	O
human	O
T	B-GENE
cell	I-GENE
receptor	I-GENE
(	I-GENE
TCR	I-GENE
)	I-GENE
alpha	I-GENE
gene	I-GENE
is	O
regulated	O
by	O
a	O
T	O
cell	O
-	O
specific	O
transcriptional	O
enhancer	O
that	O
is	O
located	O
4	O
.	O
5	O
kilobases	O
(	O
kb	O
)	O
3	O
'	O
to	O
the	O
C	B-GENE
alpha	I-GENE
gene	I-GENE
segment	I-GENE
.	O

The	O
Ets	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
site	I-GENE
was	O
localized	O
to	O
a	O
17	O
-	O
base	O
pair	O
(	O
bp	O
)	O
region	O
from	O
the	O
3	O
'	O
end	O
of	O
T	B-GENE
alpha	I-GENE
2	I-GENE
.	O

Human	O
T	O
-	O
cell	O
leukemia	O
virus	O
type	O
I	O
(	O
HTLV	O
-	O
I	O
)	O
encodes	O
a	O
40	O
-	O
kDa	O
nuclear	O
protein	O
,	O
Tax	B-GENE
,	O
which	O
stimulates	O
transcription	O
from	O
three	O
21	O
-	O
base	O
pair	O
(	O
bp	O
)	O
repeats	O
in	O
its	O
U3	O
region	O
.	O

We	O
have	O
now	O
identified	O
,	O
after	O
21	O
serial	O
undiluted	O
passages	O
of	O
MHV	O
,	O
a	O
small	B-GENE
DI	I-GENE
RNA	I-GENE
,	O
DIssF	B-GENE
,	O
which	O
is	O
efficiently	O
packaged	O
into	O
virions	O
.	O

This	O
,	O
together	O
with	O
the	O
data	O
obtained	O
with	O
haloperidol	O
,	O
suggests	O
that	O
a	O
minimal	O
increase	O
in	O
the	O
firing	O
rate	O
of	O
LC	O
cells	O
(	O
+	O
140	O
%	O
)	O
is	O
required	O
before	O
it	O
could	O
influence	O
the	O
turnover	O
of	O
NA	O
,	O
as	O
measured	O
by	O
DOPAC	O
changes	O
.	O

The	O
Mauriceville	O
and	O
Varkud	O
mitochondrial	O
plasmids	O
are	O
closely	O
related	O
,	O
closed	O
-	O
circular	O
DNAs	O
(	O
3	O
.	O
6	O
and	O
3	O
.	O
7	O
kb	O
,	O
respectively	O
)	O
that	O
have	O
characteristics	O
of	O
mtDNA	O
introns	O
and	O
retroid	O
elements	O
.	O

The	O
circadian	O
rhythm	O
,	O
however	O
,	O
was	O
not	O
affected	O
and	O
the	O
difference	O
between	O
minimum	O
(	O
12	O
.	O
00	O
h	O
)	O
and	O
maximum	O
(	O
18	O
.	O
50	O
h	O
)	O
serum	O
concentrations	O
was	O
31	O
.	O
3	O
%	O
.	O

Most	O
strains	O
(	O
95	O
%	O
)	O
of	O
S	O
.	O
lugdunensis	O
produced	O
a	O
delta	B-GENE
hemolysin	I-GENE
like	O
that	O
seen	O
with	O
nine	O
other	O
species	O
of	O
CNS	O
.	O

Experiments	O
showed	O
that	O
temporary	O
arrest	O
of	O
pulmonary	O
circulation	O
under	O
conditions	O
of	O
extracorporeal	O
circulation	O
is	O
attended	O
by	O
the	O
development	O
of	O
ischemia	O
of	O
the	O
respiratory	O
pulmonary	O
tissue	O
.	O

Taste	O
reactivity	O
tests	O
were	O
used	O
to	O
examine	O
the	O
orofacial	O
responses	O
of	O
alcohol	O
preferring	O
(	O
P	O
)	O
rats	O
and	O
alcohol	O
nonpreferring	O
(	O
NP	O
)	O
rats	O
to	O
the	O
taste	O
of	O
alcohol	O
.	O

1	O
(	O
"	O
long	O
method	O
"	O
)	O
and	O
the	O
HML	O
method	O
.	O

No	O
causal	O
relations	O
may	O
be	O
inferred	O
from	O
the	O
correlation	O
between	O
the	O
level	O
of	O
trapezius	O
activity	O
and	O
complaints	O
,	O
though	O
it	O
indicates	O
that	O
individual	O
,	O
inexpedient	O
muscle	O
activity	O
patterns	O
may	O
constitute	O
an	O
important	O
risk	O
factor	O
for	O
development	O
of	O
musculo	O
-	O
skeletal	O
complaints	O
.	O

Analysis	O
with	O
additional	O
anti	O
-	O
peptide	O
antibodies	O
specific	O
for	O
alpha	B-GENE
,	I-GENE
beta	I-GENE
,	I-GENE
or	I-GENE
gamma	I-GENE
PKC	I-GENE
indicated	O
that	O
all	O
three	O
types	O
of	O
PKC	B-GENE
are	O
expressed	O
in	O
JK	O
cells	O
;	O
however	O
,	O
JKPE	O
cells	O
lost	O
a	O
major	O
approximately	O
82	O
kDa	O
immunoreactive	O
cytosolic	O
protein	O
detectable	O
with	O
anti	B-GENE
-	I-GENE
PKC	I-GENE
alpha	I-GENE
antibody	I-GENE
.	O

Erythrocyte	O
protoporphyrin	O
concentration	O
increased	O
significantly	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
by	O
14	O
days	O
in	O
dogs	O
fed	O
the	O
basal	O
diet	O
,	O
and	O
remained	O
significantly	O
high	O
relative	O
to	O
that	O
in	O
dogs	O
of	O
the	O
other	O
dietary	O
groups	O
for	O
the	O
remainder	O
of	O
the	O
study	O
.	O

The	O
coding	O
sequences	O
of	O
the	O
Crry	B-GENE
gene	I-GENE
encompass	O
over	O
25	O
kb	O
of	O
DNA	O
,	O
whereas	O
the	O
Crry	B-GENE
-	O
ps	B-GENE
sequences	O
are	O
included	O
within	O
a	O
single	O
5	B-GENE
.	I-GENE
6	I-GENE
-	I-GENE
kb	I-GENE
Eco	I-GENE
-	I-GENE
R1	I-GENE
fragment	I-GENE
.	O

The	O
genomic	O
and	O
transcriptional	O
complexity	O
of	O
the	O
Crry	B-GENE
and	O
Crry	B-GENE
-	O
ps	B-GENE
genes	O
.	O

Determination	O
of	O
three	O
-	O
dimensional	O
imaging	O
properties	O
of	O
a	O
light	O
microscope	O
system	O
.	O

Methods	O
used	O
include	O
Cobb	O
angle	O
and	O
a	O
segmental	O
evaluation	O
(	O
T7	O
-	O
T12	O
)	O
of	O
each	O
of	O
convex	O
and	O
concave	O
rib	O
-	O
vertebra	O
angles	O
(	O
RVAs	O
)	O
,	O
rib	O
-	O
vertebra	O
angle	O
differences	O
(	O
RVADs	O
)	O
,	O
vertebral	O
rotation	O
,	O
tilt	O
and	O
displacement	O
.	O

Lars	O
has	O
AIDS	O
-	O
-	O
a	O
more	O
dignified	O
life	O
with	O
care	O
at	O
home	O
.	O

Accumulations	O
of	O
Tl	O
+	O
1	O
(	O
202Tl	O
label	O
)	O
were	O
6	O
times	O
those	O
for	O
Ga	O
or	O
In	O
in	O
the	O
brain	O
and	O
muscles	O
,	O
and	O
.	O
1	O
times	O
in	O
plasma	O
.	O

A	O
poor	O
correlation	O
was	O
also	O
observed	O
between	O
PbB	O
and	O
ALAD	B-GENE
activity	O
of	O
the	O
stearate	O
workers	O
.	O

Since	O
the	O
UfAP	B-GENE
and	O
UTMP	B-GENE
share	O
many	O
biosynthetic	O
and	O
structural	O
features	O
that	O
include	O
site	O
of	O
biosynthesis	O
in	O
the	O
endometrium	O
,	O
P4	O
-	O
responsiveness	O
,	O
the	O
presence	O
of	O
the	O
mannose	O
6	O
-	O
phosphate	O
lysosomal	O
recognition	O
marker	O
,	O
and	O
considerable	O
sequence	O
similarity	O
,	O
the	O
UfAP	B-GENE
and	O
the	O
UTMP	B-GENE
may	O
have	O
homologous	O
function	O
which	O
for	O
both	O
still	O
remains	O
obscure	O
.	O

Fifteen	O
light	O
for	O
dates	O
infants	O
and	O
their	O
placentae	O
were	O
compared	O
to	O
15	O
well	O
-	O
grown	O
infants	O
and	O
their	O
placentae	O
.	O

Treating	O
renal	O
anaemia	O
with	O
recombinant	O
human	O
erythropoietin	B-GENE
.	O

Basing	O
on	O
experimental	O
toxicity	O
research	O
it	O
was	O
established	O
that	O
,	O
out	O
of	O
50	O
atmosphere	O
metal	O
corrosion	O
inhibitors	O
,	O
some	O
14	O
per	O
cent	O
were	O
found	O
extremely	O
hazardous	O
,	O
42	O
per	O
cent	O
-	O
-	O
of	O
high	O
level	O
hazardous	O
,	O
33	O
percent	O
-	O
-	O
of	O
moderate	O
and	O
11	O
per	O
cent	O
-	O
-	O
of	O
low	O
hazardous	O
.	O

The	O
effects	O
on	O
reflex	O
latencies	O
but	O
not	O
on	O
paCO2	O
or	O
pHa	O
were	O
blocked	O
by	O
naloxone	O
(	O
2	O
mg	O
/	O
kg	O
)	O
,	O
and	O
were	O
not	O
present	O
in	O
morphine	O
-	O
tolerant	O
animals	O
.	O

Of	O
the	O
remaining	O
seven	O
,	O
five	O
reacted	O
either	O
with	O
immediate	O
and	O
strong	O
symptoms	O
or	O
had	O
spontaneously	O
reduced	O
gluten	B-GENE
intake	O
,	O
or	O
had	O
an	O
acquired	O
IgA	B-GENE
deficiency	O
.	O

In	O
addition	O
serum	B-GENE
IgE	I-GENE
concentrations	O
were	O
not	O
statistically	O
different	O
.	O

The	O
findings	O
suggest	O
that	O
,	O
although	O
iodine	O
deficiency	O
is	O
the	O
most	O
probable	O
cause	O
of	O
goiter	O
among	O
immigrants	O
of	O
the	O
1928	O
cohort	O
,	O
where	O
the	O
native	O
population	O
is	O
concerned	O
(	O
both	O
men	O
and	O
women	O
)	O
,	O
some	O
other	O
goitrogenic	O
factor	O
(	O
s	O
)	O
must	O
be	O
involved	O
.	O

Co	O
-	O
administration	O
of	O
5FU	O
,	O
angiotensin	B-GENE
II	I-GENE
and	O
microspheres	O
via	O
the	O
hepatic	O
artery	O
may	O
reduce	O
drug	O
exposure	O
in	O
the	O
systemic	O
compartment	O
and	O
therefore	O
may	O
increase	O
the	O
therapeutic	O
ratio	O
of	O
5FU	O
administration	O
via	O
the	O
hepatic	O
artery	O
.	O

In	O
contrast	O
,	O
2	O
,	O
397	O
(	O
74	O
%	O
)	O
had	O
one	O
or	O
more	O
risk	O
factors	O
(	O
not	O
low	O
risk	O
)	O
;	O
of	O
these	O
,	O
5	O
.	O
3	O
%	O
died	O
in	O
6	O
weeks	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Comparison	O
of	O
propofol	O
and	O
thiopentone	O
as	O
anaesthetic	O
agents	O
for	O
electroconvulsive	O
therapy	O
.	O

Nonvascular	O
ophthalmic	O
and	O
neurologic	O
disorders	O
that	O
can	O
be	O
confused	O
with	O
amaurosis	O
fugax	O
are	O
listed	O
,	O
and	O
an	O
algorithm	O
for	O
evaluation	O
(	O
which	O
includes	O
ophthalmic	O
examination	O
,	O
laboratory	O
studies	O
,	O
and	O
noninvasive	O
carotid	O
artery	O
studies	O
)	O
is	O
given	O
.	O

These	O
characteristics	O
of	O
N22	O
/	O
P22	O
indicate	O
that	O
it	O
is	O
a	O
localized	O
synaptically	O
dependent	O
event	O
conforming	O
to	O
a	O
transverse	O
dipole	O
with	O
dorsal	O
negativity	O
and	O
a	O
simultaneous	O
anterior	O
positivity	O
.	O

We	O
evaluated	O
the	O
likelihood	O
of	O
tissues	O
to	O
be	O
positive	O
for	O
carcinoembryonic	B-GENE
antigen	I-GENE
and	O
the	O
intensity	O
of	O
carcinoembryonic	B-GENE
antigen	I-GENE
staining	O
in	O
specimens	O
of	O
villous	O
adenomas	O
,	O
mixed	O
polypoid	O
villous	O
adenomas	O
,	O
polypoid	O
adenomas	O
,	O
and	O
diverticulitis	O
using	O
the	O
peroxidase	B-GENE
-	O
antiperoxidase	B-GENE
technique	O
.	O

These	O
results	O
support	O
the	O
view	O
that	O
clonidine	O
and	O
6	O
-	O
OHDA	O
,	O
but	O
not	O
alpha	O
-	O
MD	O
,	O
have	O
central	O
pressor	O
actions	O
in	O
the	O
rat	O
that	O
oppose	O
their	O
antihypertensive	O
action	O
.	O

We	O
conclude	O
that	O
Hansel	O
'	O
s	O
stain	O
substantially	O
improves	O
the	O
recognition	O
of	O
eosinophiluria	O
as	O
compared	O
with	O
Wright	O
'	O
s	O
stain	O
.	O

The	O
study	O
included	O
139	O
eyes	O
with	O
presumed	O
ocular	O
histoplasmosis	O
syndrome	O
(	O
POHS	O
)	O
and	O
age	O
-	O
related	O
macular	O
degeneration	O
(	O
AMD	O
)	O
.	O

Rarely	O
,	O
patients	O
with	O
locally	O
advanced	O
,	O
uncontrollable	O
,	O
non	O
-	O
metastatic	O
prostatic	O
cancer	O
enjoy	O
prolonged	O
survival	O
.	O

ATP	O
gamma	O
S	O
inhibition	O
can	O
be	O
overcome	O
by	O
high	O
concentrations	O
of	O
ATP	O
,	O
dATP	O
,	O
araATP	O
,	O
or	O
ddATP	O
.	O

Enhancer	O
and	O
promoter	O
elements	O
directing	O
activation	O
and	O
glucocorticoid	O
repression	O
of	O
the	O
alpha	B-GENE
1	I-GENE
-	I-GENE
fetoprotein	I-GENE
gene	I-GENE
in	O
hepatocytes	O
.	O

The	O
gene	O
is	O
contained	O
within	O
a	O
1	O
.	O
8	O
-	O
kilobase	O
AccI	B-GENE
-	O
EcoRI	B-GENE
restriction	O
fragment	O
mapping	O
at	O
map	O
coordinates	O
0	O
.	O
136	O
to	O
0	O
.	O
148	O
in	O
the	O
UL	O
region	O
of	O
the	O
EHV	O
-	O
1	O
genome	O
and	O
is	O
transcribed	O
from	O
right	O
to	O
left	O
.	O

Spontaneous	O
sensitization	O
to	O
cross	O
-	O
reacting	O
chemicals	O
in	O
a	O
proportion	O
of	O
control	O
animals	O
is	O
strongly	O
suggested	O
,	O
somewhat	O
akin	O
to	O
spontaneous	O
sensitization	O
in	O
patients	O
with	O
anaphylactoid	O
reactions	O
to	O
neuromuscular	O
blockers	O
on	O
first	O
exposure	O
,	O
and	O
in	O
whom	O
IgE	B-GENE
antibodies	I-GENE
are	O
detected	O
.	O

The	O
84	B-GENE
.	I-GENE
1C	I-GENE
mAb	I-GENE
recognizes	O
a	O
site	O
on	O
IgE	B-GENE
which	O
is	O
identical	O
or	O
very	O
close	O
to	O
the	O
Fc	B-GENE
epsilon	I-GENE
R	I-GENE
binding	I-GENE
site	I-GENE
,	O
and	O
95	O
.	O
3	O
recognizes	O
a	O
site	O
on	O
IgE	B-GENE
which	O
is	O
related	O
,	O
but	O
not	O
identical	O
to	O
the	O
Fc	B-GENE
epsilon	I-GENE
R	I-GENE
binding	I-GENE
site	I-GENE
.	O

Endocrine	O
cells	O
were	O
studied	O
by	O
means	O
of	O
Grimelius	O
'	O
silver	O
staining	O
and	O
immunostaining	O
for	O
chromogranin	B-GENE
,	O
a	O
general	O
marker	O
of	O
endocrine	O
cells	O
.	O

A	O
potential	O
TATA	O
box	O
is	O
located	O
29	O
base	O
pairs	O
upstream	O
of	O
the	O
first	O
transcription	O
initiation	O
site	O
.	O

In	O
76	O
%	O
of	O
59	O
lead	O
-	O
toxic	O
children	O
,	O
bone	O
lead	O
values	O
measured	O
by	O
LXRF	O
were	O
equal	O
to	O
or	O
greater	O
than	O
those	O
measured	O
in	O
normal	O
and	O
industrially	O
exposed	O
adults	O
.	O

When	O
considered	O
with	O
the	O
known	O
neurotoxic	O
effects	O
on	O
children	O
of	O
"	O
low	O
levels	O
"	O
of	O
exposure	O
to	O
lead	O
,	O
these	O
results	O
also	O
suggest	O
that	O
either	O
an	O
excessively	O
narrow	O
margin	O
of	O
safety	O
or	O
insufficient	O
safety	O
is	O
provided	O
by	O
present	O
U	O
.	O
S	O
.	O
guidelines	O
,	O
which	O
classify	O
an	O
elevated	O
blood	O
lead	O
concentration	O
as	O
25	O
micrograms	O
/	O
dl	O
or	O
greater	O
.	O

In	O
resting	O
3T3	O
cells	O
,	O
jun	B-GENE
-	I-GENE
D	I-GENE
is	O
expressed	O
at	O
a	O
higher	O
level	O
compared	O
to	O
c	B-GENE
-	I-GENE
jun	I-GENE
and	O
jun	B-GENE
-	I-GENE
B	I-GENE
,	O
and	O
its	O
transcription	O
is	O
stimulated	O
only	O
slightly	O
by	O
serum	O
growth	O
factors	O
.	O

Functional	O
rearranged	O
antibody	O
genes	O
were	O
detected	O
with	O
JH	B-GENE
and	O
VH	B-GENE
heavy	I-GENE
chain	I-GENE
probes	O
and	O
with	O
Jk	B-GENE
and	O
Vk	B-GENE
light	I-GENE
chain	I-GENE
probes	O
.	O

Isolation	O
of	O
Weeksella	O
virosa	O
(	O
formerly	O
CDC	O
group	O
IIf	O
)	O
from	O
a	O
vaginal	O
sample	O
.	O

Growth	O
of	O
tracheal	O
anastomoses	O
in	O
growing	O
animals	O

The	O
ORF1	O
product	O
was	O
required	O
for	O
competence	O
,	O
while	O
ORF2	O
,	O
which	O
was	O
cotranscribed	O
with	O
ORF1	O
and	O
encoded	O
a	O
predicted	O
protein	O
of	O
126	O
amino	O
acids	O
,	O
was	O
not	O
.	O

In	O
all	O
sessions	O
under	O
IFN	B-GENE
,	O
the	O
latency	O
of	O
the	O
P100	O
component	O
of	O
the	O
VEP	O
was	O
shortened	O
as	O
compared	O
to	O
baseline	O
conditions	O
.	O

This	O
paper	O
presents	O
the	O
reasons	O
why	O
countries	O
to	O
which	O
Chagas	O
disease	O
is	O
endemic	O
should	O
carry	O
out	O
the	O
relevant	O
research	O
themselves	O
.	O

The	O
PETCO2	O
measurement	O
during	O
precordial	O
compression	O
predicted	O
the	O
success	O
of	O
defibrillation	O
with	O
return	O
of	O
spontaneous	O
circulation	O
.	O

Gastric	O
CO2	O
/	O
HCO3	O
was	O
determined	O
in	O
absence	O
of	O
simultaneous	O
inhibition	O
of	O
acid	O
secretion	O
by	O
intra	O
-	O
and	O
extragastric	O
pCO2	O
/	O
pH	O
measurements	O
in	O
23	O
persons	O
and	O
calculated	O
using	O
the	O
equation	O
of	O
Henderson	O
-	O
Hasselbalch	O
.	O
pCO2	O
was	O
measured	O
with	O
use	O
of	O
a	O
new	O
electrode	O
.	O

Inefficacy	O
of	O
phosphine	O
fumigation	O
against	O
ticks	O
.	O

According	O
to	O
the	O
published	O
sequence	O
of	O
the	O
CHS1	B-GENE
gene	I-GENE
,	O
this	O
fragment	O
contains	O
four	O
repeats	O
of	O
a	O
TGAAACA	O
consensus	O
sequence	O
previously	O
identified	O
in	O
the	O
alpha	B-GENE
-	I-GENE
factor	I-GENE
-	O
inducible	O
BAR1	B-GENE
promoter	I-GENE
[	O
Kronstad	O
,	O
J	O
.	O

Xenopus	B-GENE
homolog	I-GENE
of	I-GENE
the	I-GENE
mos	I-GENE
protooncogene	I-GENE
transforms	O
mammalian	O
fibroblasts	O
and	O
induces	O
maturation	O
of	O
Xenopus	O
oocytes	O
.	O

Southern	O
blot	O
analyses	O
demonstrated	O
a	O
low	O
,	O
if	O
not	O
single	O
,	O
copy	O
number	O
for	O
this	O
gene	O
and	O
conservation	O
of	O
this	O
domain	O
in	O
other	O
vertebrates	O
.	O

We	O
conclude	O
that	O
(	O
a	O
)	O
the	O
likelihood	O
of	O
detecting	O
carcinoma	O
or	O
atypical	O
hyperplasia	O
exclusively	O
in	O
the	O
adipose	O
tissue	O
component	O
of	O
grossly	O
benign	O
breast	O
biopsies	O
is	O
extremely	O
low	O
,	O
and	O
(	O
b	O
)	O
a	O
possible	O
cost	O
-	O
effective	O
method	O
of	O
sampling	O
grossly	O
benign	O
breast	O
biopsies	O
consists	O
of	O
initially	O
submitting	O
a	O
maximum	O
of	O
10	O
blocks	O
of	O
fibrous	O
parenchyma	O
for	O
each	O
case	O
,	O
then	O
examining	O
the	O
remaining	O
tissue	O
histologically	O
only	O
if	O
carcinoma	O
or	O
atypical	O
hyperplasia	O
is	O
found	O
among	O
these	O
blocks	O
.	O

A	O
brief	O
account	O
of	O
the	O
1988	O
seminar	O
in	O
Shanghai	O
on	O
viral	O
hepatitis	O
A	O

Erythrocytic	O
stages	O
of	O
mammalian	O
malarial	O
parasites	O
contain	O
acristate	O
mitochondria	O
whose	O
functions	O
are	O
not	O
well	O
understood	O
.	O

Restriction	O
maps	O
of	O
the	O
cloned	O
plasmids	O
revealed	O
that	O
their	O
chromosomal	O
inserts	O
consisted	O
of	O
overlapping	O
fragments	O
.	O

In	O
contrast	O
,	O
a	O
similar	O
fragment	O
lacking	O
the	O
38	O
-	O
base	O
-	O
pair	O
region	O
had	O
no	O
such	O
stabilizing	O
effect	O
.	O

This	O
TC	B-GENE
-	I-GENE
II	I-GENE
enhanson	I-GENE
,	O
which	O
is	O
identical	O
to	O
the	O
kappa	B-GENE
B	I-GENE
motif	I-GENE
from	O
the	O
kappa	B-GENE
chain	I-GENE
enhancer	I-GENE
,	O
was	O
active	O
in	O
both	O
lymphoid	O
and	O
non	O
-	O
lymphoid	O
cells	O
,	O
which	O
contrasts	O
with	O
the	O
previously	O
reported	O
lymphoid	O
cell	O
specificity	O
of	O
the	O
kappa	B-GENE
B	I-GENE
motif	I-GENE
.	O

The	O
DNA	O
sequences	O
predict	O
proteins	O
for	O
SRP54sc	B-GENE
and	O
SRP54sp	B-GENE
that	O
are	O
47	O
%	O
and	O
52	O
%	O
identical	O
to	O
SRP54mam	B-GENE
,	O
respectively	O
.	O

Antihistamines	O
in	O
asthma	O
.	O

We	O
have	O
therefore	O
evaluated	O
the	O
efficacy	O
and	O
safety	O
of	O
doxazosin	O
,	O
a	O
new	O
orally	O
active	O
selective	O
alpha	B-GENE
1	I-GENE
blocker	O
,	O
in	O
patients	O
with	O
systemic	O
hypertension	O
with	O
concomitant	O
airflow	O
limitation	O
.	O

The	O
discussion	O
focuses	O
primarily	O
on	O
the	O
newer	O
drugs	O
like	O
angiotensin	B-GENE
converting	I-GENE
enzyme	I-GENE
inhibitors	O
,	O
alpha	B-GENE
-	I-GENE
adrenergic	I-GENE
receptor	I-GENE
blockers	O
,	O
and	O
calcium	O
antagonists	O
.	O

A	O
736	O
-	O
bp	O
sequence	O
of	O
the	O
5	O
'	O
flanking	O
region	O
adjacent	O
to	O
the	O
cap	O
site	O
of	O
the	O
human	B-GENE
AFP	I-GENE
gene	I-GENE
shows	O
a	O
61	O
%	O
similarity	O
with	O
the	O
corresponding	O
region	O
of	O
the	O
mouse	B-GENE
AFP	I-GENE
gene	I-GENE
.	O

Nodular	O
involvement	O
of	O
the	O
left	O
lung	O
and	O
infiltration	O
of	O
the	O
mucosa	O
of	O
the	O
left	O
lower	O
lobe	O
bronchus	O
followed	O
very	O
gradually	O
and	O
a	O
monoclonal	O
gammopathy	O
(	O
IgA	B-GENE
-	I-GENE
-	I-GENE
Type	I-GENE
Kappa	I-GENE
)	O
was	O
demonstrated	O
.	O

These	O
data	O
locate	O
the	O
aniridia	B-GENE
gene	I-GENE
(	O
AN2	B-GENE
)	O
and	O
a	O
recurrent	O
T	B-GENE
-	I-GENE
cell	I-GENE
leukemia	I-GENE
breakpoint	I-GENE
(	O
TCL2	B-GENE
)	O
in	O
the	O
marker	O
sequence	O
,	O
on	O
opposite	O
sides	O
of	O
MIC1	B-GENE
.	O

A	O
fine	O
-	O
structure	O
deletion	O
map	O
of	O
human	O
chromosome	O
11p	O
:	O
analysis	O
of	O
J1	O
series	O
hybrids	O
.	O

Most	O
of	O
them	O
were	O
situated	O
at	O
Sylvius	O
fissure	O
(	O
13	O
cases	O
)	O
.	O

Intracellular	O
activity	O
studies	O
indicated	O
that	O
,	O
at	O
ten	O
times	O
MBC	O
,	O
only	O
penicillin	O
had	O
any	O
significant	O
activity	O
against	O
intracellular	O
staphylococci	O
,	O
reducing	O
survival	O
by	O
28	O
%	O
.	O

The	O
lowest	O
detectable	O
concentration	O
was	O
1	O
.	O
0	O
ng	O
/	O
ml	O
in	O
the	O
serum	O
.	O

The	O
antigen	B-GENE
-	I-GENE
specific	I-GENE
IgG4	I-GENE
antibody	I-GENE
seems	O
to	O
be	O
an	O
index	O
in	O
evaluating	O
immunotherapy	O
objectively	O
.	O

The	O
differential	O
diagnosis	O
of	O
both	O
affections	O
is	O
based	O
on	O
the	O
clinical	O
course	O
,	O
sialography	O
and	O
CT	O
examination	O
which	O
along	O
with	O
modern	O
ATB	O
treatment	O
significantly	O
modify	O
hitherto	O
used	O
surgical	O
therapy	O
.	O

An	O
FP	B-GENE
mutant	I-GENE
,	O
AcFP875	B-GENE
-	I-GENE
2	I-GENE
,	O
had	O
a	O
1	O
.	O
6	O
-	O
kbp	O
insertion	O
of	O
S	O
.	O
frugiperda	O
DNA	O
near	O
the	O
5	O
'	O
end	O
of	O
these	O
transcripts	O
which	O
by	O
S1	B-GENE
analysis	O
were	O
shown	O
to	O
initiate	O
within	O
the	O
host	O
cell	O
sequence	O
.	O

Postcoital	O
contraception	O
:	O
a	O
family	O
planning	O
study	O
.	O

A	O
0	O
.	O
5	O
rating	O
was	O
intended	O
to	O
characterize	O
subjects	O
in	O
whom	O
mild	O
cognitive	O
impairment	O
due	O
to	O
senile	O
dementia	O
of	O
the	O
Alzheimer	O
type	O
was	O
suspected	O
but	O
was	O
insufficient	O
in	O
degree	O
to	O
warrant	O
a	O
diagnosis	O
of	O
definite	O
dementia	O
.	O

An	O
implant	O
may	O
release	O
a	O
drug	O
either	O
by	O
diffusion	O
concurrent	O
with	O
dissolution	O
of	O
the	O
polymeric	O
implant	O
material	O
without	O
depolymerization	O
(	O
Type	O
A	O
)	O
or	O
by	O
bioerosion	O
involving	O
depolymerization	O
(	O
Type	O
B	O
)	O
.	O

Improved	O
cosmesis	O
,	O
extension	O
of	O
the	O
scope	O
of	O
the	O
problems	O
that	O
can	O
be	O
addressed	O
with	O
this	O
repair	O
(	O
including	O
treatment	O
of	O
a	O
distal	O
urethrocutaneous	O
fistula	O
)	O
and	O
the	O
ease	O
with	O
which	O
the	O
Arap	O
procedure	O
can	O
be	O
performed	O
are	O
the	O
advantages	O
that	O
this	O
operation	O
has	O
over	O
other	O
1	O
-	O
stage	O
distal	O
hypospadias	O
repairs	O
.	O

The	O
galactose	B-GENE
transporter	I-GENE
shows	O
both	O
sequence	O
and	O
structural	O
homology	O
with	O
a	O
superfamily	O
of	O
sugar	B-GENE
transporters	I-GENE
which	O
includes	O
the	O
human	B-GENE
HepG2	I-GENE
-	I-GENE
erythrocyte	I-GENE
and	I-GENE
fetal	I-GENE
muscle	I-GENE
glucose	I-GENE
transporters	I-GENE
,	O
the	O
rat	B-GENE
brain	I-GENE
and	I-GENE
liver	I-GENE
glucose	I-GENE
transporters	I-GENE
,	O
the	O
Escherichia	B-GENE
coli	I-GENE
xylose	I-GENE
and	I-GENE
arabinose	I-GENE
permeases	I-GENE
,	O
and	O
the	O
S	B-GENE
.	I-GENE
cerevisiae	I-GENE
glucose	I-GENE
,	I-GENE
maltose	I-GENE
,	I-GENE
and	I-GENE
galactose	I-GENE
transporters	I-GENE
.	O

The	O
calcium	O
requirement	O
for	O
hypothermic	O
storage	O
of	O
the	O
cardiac	O
explant	O
.	O

The	O
seventh	O
cysteine	O
residue	O
of	O
CTSE	B-GENE
is	O
located	O
within	O
the	O
activation	O
peptide	O
region	O
of	O
the	O
proenzyme	O
.	O

With	O
both	O
wild	O
-	O
type	O
and	O
the	O
mutant	O
enzymes	O
,	O
ATP	O
activates	O
both	O
[	O
14C	O
]	O
Asp	O
in	O
equilibrium	O
N	O
-	O
carbamyl	O
-	O
L	O
-	O
aspartate	O
(	O
C	O
-	O
Asp	O
)	O
and	O
the	O
[	O
32P	O
]	O
carbamyl	O
phosphate	O
(	O
C	O
-	O
P	O
)	O
in	O
equilibrium	O
Pi	O
exchanges	O
.	O

Mapping	O
results	O
suggested	O
that	O
the	O
complementation	O
group	O
identified	O
by	O
these	O
mutants	O
is	O
allelic	O
to	O
the	O
ag	B-GENE
alpha	I-GENE
1	I-GENE
mutation	O
identified	O
previously	O
.	O

Recently	O
,	O
an	O
alternatively	O
spliced	O
form	O
of	O
c	B-GENE
-	I-GENE
myb	I-GENE
-	I-GENE
encoded	I-GENE
mRNA	I-GENE
has	O
been	O
identified	O
in	O
murine	O
cells	O
containing	O
either	O
normal	O
or	O
rearranged	O
c	B-GENE
-	I-GENE
myb	I-GENE
genes	I-GENE
.	O

Metformin	O
plasma	O
concentrations	O
remained	O
unchanged	O
except	O
for	O
patients	O
transferred	O
from	O
1	O
.	O
5	O
to	O
2	O
.	O
0	O
g	O
daily	O
to	O
850	O
mg	O
twice	O
daily	O
;	O
in	O
these	O
patients	O
plasma	O
concentrations	O
increased	O
from	O
1	O
.	O
83	O
+	O
/	O
-	O
0	O
.	O
87	O
to	O
2	O
.	O
50	O
+	O
/	O
-	O
0	O
.	O
89	O
micrograms	O
/	O
l	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

A	O
significant	O
relationship	O
existed	O
during	O
the	O
evolution	O
of	O
the	O
disease	O
between	O
CRS	O
/	O
BW	O
and	O
gas	O
exchange	O
parameters	O
(	O
FIO2	O
and	O
a	O
/	O
AO2	O
ratio	O
)	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
but	O
gas	O
exchange	O
improved	O
earlier	O
than	O
lung	O
mechanics	O
.	O

Liquid	O
chromatography	O
with	O
amperometric	O
detection	O
(	O
LC	O
/	O
AD	O
)	O
is	O
used	O
to	O
determine	O
fluazifop	O
acid	O
produced	O
from	O
the	O
metabolism	O
or	O
base	O
hydrolysis	O
of	O
fluazifop	O
-	O
butyl	O
in	O
soybeans	O
and	O
soybean	O
oil	O
.	O

The	O
dichloromethane	O
is	O
removed	O
,	O
mobile	O
phase	O
solvent	O
is	O
added	O
,	O
and	O
aliquots	O
are	O
injected	O
onto	O
a	O
PRP	O
-	O
1	O
liquid	O
chromatographic	O
column	O
;	O
fluazifop	O
acid	O
is	O
separated	O
from	O
coextracted	O
compounds	O
and	O
detected	O
at	O
an	O
applied	O
potential	O
of	O
+	O
1	O
.	O
25	O
V	O
,	O
using	O
an	O
amperometric	O
electrochemical	O
detector	O
in	O
the	O
oxidation	O
mode	O
.	O

The	O
titer	O
of	O
anti	B-GENE
HSV	I-GENE
type	I-GENE
1	I-GENE
and	O
anti	B-GENE
HSV	I-GENE
type	I-GENE
2	I-GENE
antibodies	I-GENE
in	O
the	O
mothers	O
'	O
and	O
cord	O
blood	O
was	O
determined	O
and	O
compared	O
.	O

Kidney	O
weight	O
and	O
kidney	O
-	O
to	O
-	O
body	O
weight	O
ratio	O
were	O
significantly	O
elevated	O
at	O
the	O
highest	O
dose	O
level	O
after	O
10	O
weeks	O
and	O
at	O
the	O
two	O
higher	O
dose	O
levels	O
after	O
15	O
weeks	O
of	O
exposure	O
.	O

Swim	O
-	O
over	O
:	O
an	O
alternative	O
method	O
for	O
harvesting	O
motile	O
spermatozoa	O
.	O

A	O
raised	O
amplitude	O
of	O
the	O
aggregation	O
of	O
plates	O
and	O
a	O
decrease	O
in	O
the	O
threshold	O
of	O
their	O
sensitivity	O
to	O
ADP	O
were	O
established	O
in	O
the	O
persons	O
with	O
types	O
IIa	O
and	O
IIb	O
HLP	O
and	O
in	O
CHD	O
without	O
HLP	O
.	O

In	O
Experiment	O
2	O
,	O
we	O
again	O
used	O
classification	O
,	O
but	O
the	O
fixed	O
standard	O
75	O
was	O
not	O
at	O
the	O
center	O
of	O
the	O
range	O
of	O
target	O
numbers	O
(	O
20	O
,	O
21	O
,	O
.	O
.	O
.	O

Among	O
booked	O
patients	O
the	O
maternal	O
mortality	O
rate	O
was	O
0	O
.	O
32	O
and	O
among	O
unbooked	O
patients	O
11	O
.	O
13	O
per	O
1000	O
deliveries	O
.	O

Evidence	O
from	O
the	O
structure	O
of	O
a	O
number	O
of	O
cDNA	O
clones	O
,	O
as	O
well	O
as	O
S1	B-GENE
nuclease	I-GENE
and	O
primer	O
extension	O
studies	O
supports	O
the	O
hypothesis	O
that	O
the	O
PTHrP	B-GENE
gene	I-GENE
contains	O
at	O
least	O
two	O
mRNA	O
transcription	O
start	O
points	O
that	O
define	O
two	O
putative	O
regulatory	O
domains	O
.	O

The	O
transcription	O
initiation	O
site	O
was	O
determined	O
by	O
S1	B-GENE
nuclease	I-GENE
mapping	O
.	O

A	O
larval	B-GENE
albumin	I-GENE
-	I-GENE
like	I-GENE
protein	I-GENE
was	O
not	O
detectable	O
by	O
silver	O
staining	O
in	O
serum	O
of	O
tadpoles	O
before	O
the	O
beginning	O
of	O
metamorphosis	O
at	O
stage	O
48	O
.	O

Behaviorally	O
,	O
a	O
pain	O
-	O
tolerant	O
group	O
(	O
PT	O
=	O
29	O
Ss	O
)	O
tolerated	O
the	O
entire	O
3	O
-	O
min	O
test	O
(	O
means	O
=	O
180	O
+	O
/	O
-	O
0	O
sec	O
)	O
,	O
while	O
a	O
pain	O
-	O
sensitive	O
group	O
(	O
PS	O
=	O
13	O
Ss	O
)	O
averaged	O
only	O
50	O
.	O
31	O
+	O
/	O
-	O
20	O
.	O
81	O
sec	O
of	O
the	O
cold	O
-	O
pressor	O
test	O
(	O
t	O
=	O
16	O
.	O
75	O
,	O
P	O
less	O
than	O
0	O
.	O
0001	O
)	O
,	O
replicating	O
our	O
earlier	O
studies	O
.	O

Isolated	O
proteinuria	O
(	O
i	O
.	O
e	O
.	O
without	O
hematuria	O
and	O
/	O
or	O
pyuria	O
)	O
is	O
a	O
frequent	O
finding	O
.	O

Lithium	O
delays	O
the	O
circadian	O
rhythm	O
of	O
wheel	O
-	O
running	O
in	O
Syrian	O
hamsters	O
at	O
plasma	O
concentrations	O
(	O
0	O
.	O
59	O
-	O
0	O
.	O
74	O
mM	O
)	O
that	O
also	O
cause	O
toxic	O
weight	O
loss	O
.	O

When	O
two	O
-	O
dimensional	O
polyacrylamide	O
gel	O
electrophoretic	O
patterns	O
of	O
[	O
35S	O
]	O
methionine	O
-	O
labeled	O
proteins	O
secreted	O
from	O
cells	O
infected	O
with	O
parental	O
and	O
recombinant	O
viruses	O
were	O
compared	O
,	O
a	O
spot	O
missing	O
from	O
the	O
latter	O
corresponded	O
in	O
molecular	O
weigh	O
and	O
isoelectric	O
point	O
with	O
that	O
predicted	O
from	O
the	O
N1L	B-GENE
ORF	I-GENE
.	O

Buflomedil	O
(	O
i	O
.	O
v	O
.	O
)	O
induced	O
a	O
dose	O
-	O
dependent	O
increase	O
of	O
cardiac	O
output	O
at	O
0	O
.	O
16	O
-	O
0	O
.	O
64	O
mg	O
/	O
kg	O
,	O
biphasic	O
changes	O
at	O
1	O
.	O
28	O
and	O
2	O
.	O
56	O
mg	O
/	O
kg	O
and	O
a	O
marked	O
decrease	O
and	O
subsequent	O
slight	O
increase	O
at	O
a	O
large	O
dose	O
of	O
5	O
.	O
12	O
mg	O
/	O
kg	O
.	O

We	O
use	O
the	O
term	O
corticosteroid	O
-	O
dependent	O
IA	O
to	O
refer	O
to	O
the	O
serious	O
problem	O
of	O
chronic	O
IA	O
requiring	O
maintenance	O
prednisone	O
therapy	O
.	O

The	O
two	O
IL6	B-GENE
mRNA	I-GENE
species	O
are	O
generated	O
by	O
alternative	O
polyadenylation	O
at	O
sites	O
separated	O
by	O
a	O
distance	O
of	O
1	O
.	O
2	O
kilobases	O
.	O

In	O
one	O
acromegalic	O
patient	O
visual	O
improvement	O
was	O
obtained	O
while	O
the	O
abnormal	O
GH	B-GENE
secretion	O
remained	O
unaltered	O
.	O

In	O
contrast	O
,	O
the	O
PPSF	O
+	O
DBP	O
side	O
showed	O
large	O
amounts	O
of	O
bone	O
formation	O
,	O
and	O
bone	O
almost	O
covered	O
the	O
implant	O
.	O

In	O
44	O
evaluable	O
patients	O
the	O
response	O
rate	O
was	O
50	O
%	O
,	O
with	O
one	O
complete	O
response	O
.	O

Thus	O
,	O
multiple	O
myogenic	O
factors	O
that	O
vary	O
qualitatively	O
and	O
quantitatively	O
may	O
be	O
responsible	O
for	O
the	O
different	O
and	O
complex	O
modulatory	O
programs	O
of	O
actin	B-GENE
gene	I-GENE
expression	O
observed	O
during	O
in	O
vivo	O
muscle	O
differentiation	O
.	O

The	O
effect	O
of	O
acetazolamide	O
(	O
ACZ	O
)	O
on	O
HCO3	O
-	O
and	O
Cl	O
-	O
activities	O
in	O
inner	O
ear	O
fluid	O
was	O
investigated	O
by	O
ion	O
-	O
selective	O
microelectrode	O
methods	O
.	O

The	O
predicted	O
L	B-GENE
mRNA	I-GENE
was	O
6398	O
nucleotides	O
long	O
and	O
contained	O
a	O
single	O
open	O
reading	O
frame	O
corresponding	O
to	O
an	O
L	B-GENE
protein	I-GENE
encompassing	I-GENE
2109	I-GENE
amino	I-GENE
acids	I-GENE
with	O
a	O
MW	O
of	O
241	O
,	O
546	O
.	O

Aplastic	O
crisis	O
in	O
sickle	O
cell	O
disorders	O
:	O
bone	O
marrow	O
necrosis	O
and	O
human	O
parvovirus	O
infection	O
.	O

The	O
bactericidal	O
activity	O
of	O
six	O
new	O
rifamycin	O
derivatives	O
-	O
-	O
rifabutin	O
(	O
RBU	O
)	O
,	O
FCE	O
22250	O
(	O
F22	O
)	O
,	O
rifapentine	O
(	O
RPE	O
)	O
,	O
CGP	O
29861	O
(	O
C29	O
)	O
,	O
CGP	O
7040	O
(	O
C70	O
)	O
and	O
CGP	O
27557	O
(	O
C27	O
)	O
and	O
rifampicin	O
(	O
RMP	O
)	O
-	O
-	O
have	O
been	O
measured	O
against	O
log	O
phase	O
and	O
,	O
as	O
a	O
better	O
test	O
of	O
sterilising	O
activity	O
,	O
against	O
stationary	O
phase	O
cultures	O
of	O
Mycobacterium	O
tuberculosis	O
,	O
H37Rv	O
.	O

Mo	O
+	O
SV	O
M	O
-	O
MuLV	O
-	O
inoculated	O
animals	O
became	O
moribund	O
at	O
3	O
to	O
13	O
months	O
postinoculation	O
,	O
whereas	O
delta	O
Mo	O
+	O
SV	O
M	O
-	O
MuLV	O
-	O
inoculated	O
animals	O
became	O
moribund	O
at	O
6	O
to	O
24	O
months	O
postinoculation	O
.	O

RVEF	O
and	O
LVEF	O
both	O
increased	O
by	O
about	O
14	O
%	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
and	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

The	O
levels	O
of	O
NPY	B-GENE
-	O
ir	O
in	O
the	O
rat	O
vas	O
deferens	O
were	O
not	O
affected	O
by	O
either	O
surgical	O
or	O
pharmacological	O
treatment	O
.	O

The	O
primary	O
structure	O
and	O
cotranscription	O
of	O
the	O
petCA	B-GENE
genes	I-GENE
encoding	O
the	O
Rieske	B-GENE
-	I-GENE
FeS	I-GENE
(	O
nuclear	B-GENE
encoded	I-GENE
in	I-GENE
plants	I-GENE
)	O
and	O
apocytochrome	B-GENE
f	I-GENE
proteins	I-GENE
has	O
been	O
described	O
previously	O
(	O
Kallas	O
,	O
T	O
.	O
,	O
Spiller	O
,	O
S	O
.	O
,	O
and	O
Malkin	O
,	O
R	O
.	O

The	O
Nostoc	O
petBD	B-GENE
genes	I-GENE
are	O
not	O
closely	O
linked	O
to	O
the	O
psbB	B-GENE
gene	I-GENE
(	O
encoding	O
the	O
51	O
-	O
kDa	O
photosystem	B-GENE
II	I-GENE
polypeptide	I-GENE
)	O
and	O
do	O
not	O
contain	O
introns	O
as	O
do	O
the	O
closely	O
related	O
chloroplast	O
genes	O
.	O

RNA	O
blot	O
hybridizations	O
identified	O
an	O
1	O
.	O
8	O
-	O
kb	O
mRNA	O
common	O
to	O
cytochrome	B-GENE
b6	I-GENE
and	O
subunit	O
IV	O
,	O
and	O
an	O
intensely	O
hybridizing	O
0	O
.	O
8	O
-	O
kb	O
mRNA	O
specific	O
to	O
the	O
subunit	O
IV	O
gene	O
probe	O
.	O

All	O
of	O
the	O
indigo	O
-	O
producing	O
bacteria	O
had	O
an	O
indoxyl	B-GENE
phosphatase	I-GENE
with	O
a	O
pI	O
of	O
6	O
.	O
4	O
.	O

The	O
number	O
of	O
polymerases	O
active	O
in	O
vitro	O
at	O
the	O
E	O
strand	O
promoter	O
was	O
similar	O
to	O
the	O
number	O
of	O
polymerases	O
at	O
the	O
L	O
strand	O
promoter	O
.	O

A	O
family	O
of	O
RNA	O
molecules	O
in	O
the	O
2	O
.	O
0	O
-	O
2	O
.	O
2	O
-	O
kilobase	O
range	O
identified	O
with	O
a	O
probe	O
from	O
this	O
gene	O
was	O
overexpressed	O
in	O
the	O
resistant	O
cells	O
.	O

Intravesical	O
chemotherapy	O
.	O

Studies	O
were	O
performed	O
on	O
several	O
superficial	O
veins	O
from	O
the	O
rabbit	O
face	O
to	O
examine	O
the	O
relationship	O
between	O
beta	B-GENE
adrenoceptor	I-GENE
subtype	I-GENE
distribution	O
,	O
intrinsic	O
myogenic	O
tone	O
and	O
sympathetic	O
nerve	O
innervation	O
.	O

Two	O
polyadenylation	O
sites	O
were	O
used	O
,	O
one	O
at	O
the	O
end	O
of	O
the	O
early	B-GENE
(	I-GENE
E	I-GENE
)	I-GENE
region	I-GENE
of	O
the	O
viral	O
DNA	O
,	O
the	O
other	O
at	O
the	O
end	O
of	O
the	O
late	B-GENE
(	I-GENE
L	I-GENE
)	I-GENE
region	I-GENE
.	O

We	O
propose	O
that	O
the	O
technique	O
of	O
low	O
-	O
frequency	O
kindling	O
is	O
a	O
useful	O
experimental	O
model	O
in	O
assessing	O
the	O
effects	O
of	O
antipsychotic	O
or	O
antiepileptic	O
drugs	O
on	O
the	O
excitability	O
of	O
the	O
limbic	O
regions	O
.	O

The	O
biosynthesis	O
and	O
stability	O
of	O
the	O
three	O
mutant	O
proteins	O
were	O
similar	O
to	O
those	O
of	O
the	O
wild	B-GENE
-	I-GENE
type	I-GENE
erbB	I-GENE
protein	I-GENE
,	O
and	O
all	O
three	O
retained	O
the	O
ability	O
to	O
transform	O
chicken	O
embryo	O
fibroblasts	O
.	O

Codon	O
usage	O
in	O
C	O
.	O
reinhardtii	O
mitochondria	O
is	O
highly	O
biased	O
,	O
with	O
eight	O
codons	O
entirely	O
absent	O
from	O
all	O
protein	O
-	O
coding	O
genes	O
;	O
however	O
,	O
even	O
though	O
codon	O
usage	O
is	O
restricted	O
,	O
it	O
appears	O
that	O
C	O
.	O
reinhardtii	O
mtDNA	O
cannot	O
encode	O
the	O
minimum	O
number	O
of	O
tRNAs	O
needed	O
to	O
support	O
mitochondrial	O
protein	O
synthesis	O
.	O

Like	O
scrotal	O
testes	O
,	O
undescended	O
testes	O
were	O
hypointense	O
to	O
fat	O
on	O
sequences	O
with	O
a	O
short	O
repetition	O
time	O
(	O
TR	O
)	O
and	O
echo	O
time	O
(	O
TE	O
)	O
in	O
all	O
cases	O
,	O
and	O
hyperintense	O
or	O
isointense	O
to	O
fat	O
on	O
long	O
TR	O
/	O
TE	O
sequences	O
in	O
all	O
but	O
two	O
cases	O
.	O

The	O
East	O
African	O
dik	O
-	O
dik	O
antelope	O
represents	O
a	O
miniature	O
model	O
ruminant	O
for	O
comparative	O
studies	O
.	O

Efficacy	O
and	O
field	O
evaluation	O
of	O
Bacillus	O
thuringiensis	O
(	O
H	O
-	O
14	O
)	O
and	O
B	O
.	O
sphaericus	O
against	O
floodwater	O
mosquitoes	O
in	O
California	O
.	O

2	O
cases	O
of	O
type	O
II	O
tyrosinosis	O
(	O
Richner	O
-	O
Hanhart	O
syndrome	O
)	O

This	O
loss	O
was	O
independent	O
of	O
drug	O
concentration	O
and	O
a	O
correction	O
factor	O
was	O
employed	O
to	O
calculate	O
the	O
true	O
free	O
diazepam	O
concentration	O
.	O

Effects	O
of	O
a	O
perfluorochemical	O
blood	O
substitute	O
on	O
diazepam	O
binding	O
by	O
human	B-GENE
albumin	I-GENE
.	O

A	O
second	O
promoter	O
activity	O
was	O
identified	O
in	O
the	O
region	O
between	O
the	O
two	O
major	O
transcriptional	O
start	O
sites	O
.	O

Computer	O
analysis	O
included	O
digital	O
averaging	O
,	O
followed	O
by	O
digital	O
filtering	O
in	O
different	O
frequency	O
bands	O
in	O
order	O
to	O
determine	O
the	O
frequency	O
range	O
corresponding	O
to	O
notches	O
and	O
slurs	O
.	O

We	O
also	O
examined	O
the	O
relationship	O
between	O
the	O
side	O
of	O
sinusitis	O
and	O
the	O
cleft	O
side	O
in	O
patients	O
with	O
unilateral	O
cleft	O
palate	O
.	O

Successful	O
use	O
of	O
transureteroureterostomy	O
to	O
salvage	O
ureterosigmoidostomy	O
after	O
anastomotic	O
failure	O
.	O

We	O
have	O
identified	O
and	O
characterized	O
the	O
structure	O
of	O
the	O
Spec1	B-GENE
gene	I-GENE
in	O
the	O
sea	O
urchin	O
Strongylocentrotus	O
purpuratus	O
.	O

Functional	O
flow	O
was	O
evaluated	O
using	O
laser	O
Doppler	O
flowmetry	O
(	O
LDF	O
)	O
,	O
for	O
which	O
the	O
output	O
signal	O
,	O
blood	O
cell	O
flux	O
(	O
BCF	O
)	O
,	O
is	O
expressed	O
in	O
terms	O
of	O
volts	O
.	O

Our	O
data	O
,	O
however	O
,	O
did	O
not	O
suggest	O
the	O
existence	O
of	O
a	O
conversion	O
factor	O
for	O
LDF	O
signal	O
to	O
absolute	O
flow	O
values	O
from	O
experiment	O
to	O
experiment	O
.	O

Quantitative	O
analysis	O
of	O
the	O
coronary	O
stenosis	O
was	O
assessed	O
before	O
and	O
after	O
PTCA	O
,	O
and	O
the	O
dilatation	O
resulted	O
in	O
an	O
increase	O
in	O
minimal	O
luminal	O
cross	O
-	O
sectional	O
area	O
from	O
1	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
8	O
to	O
2	O
.	O
7	O
+	O
/	O
-	O
1	O
.	O
2	O
mm2	O
.	O

In	O
a	O
previous	O
study	O
(	O
Brandl	O
,	O
C	O
.	O

The	O
seco	O
-	O
steroid	O
hormone	O
1	O
,	O
25	O
-	O
dihydroxyvitamin	O
D3	O
is	O
known	O
to	O
induce	O
the	O
expression	O
of	O
a	O
calcium	O
binding	O
protein	O
termed	O
calbindin	B-GENE
-	I-GENE
D28K	I-GENE
in	O
a	O
variety	O
of	O
target	O
tissues	O
.	O

In	O
addition	O
,	O
the	O
calbindin	B-GENE
-	I-GENE
D28K	I-GENE
promoter	I-GENE
is	O
composed	O
of	O
a	O
variety	O
of	O
simple	O
repeated	O
sequences	O
,	O
some	O
of	O
which	O
are	O
components	O
of	O
putative	O
regulatory	O
signals	O
.	O

Organ	O
transplantation	O
in	O
Denmark	O
.	O

A	O
114	O
-	O
base	O
pair	O
sequence	O
of	O
predominantly	O
repeating	O
purine	O
-	O
pyrimidine	O
nucleotides	O
separates	O
these	O
two	O
d	O
(	O
AC	O
)	O
repeats	O
.	O

Evidence	O
for	O
a	O
role	O
of	O
endogenous	B-GENE
corticotropin	I-GENE
-	I-GENE
releasing	I-GENE
factor	I-GENE
in	O
cold	O
,	O
ether	O
,	O
immobilization	O
,	O
and	O
traumatic	O
stress	O
.	O

The	O
210	O
kDa	O
precursor	O
is	O
converted	O
slowly	O
(	O
t	O
1	O
/	O
2	O
=	O
2	O
h	O
)	O
by	O
proteolytic	O
processing	O
into	O
a	O
125	O
kDa	O
(	O
alpha	O
'	O
)	O
and	O
83	O
kDa	O
(	O
beta	O
'	O
)	O
species	O
.	O

Its	O
predicted	O
amino	O
acid	O
sequence	O
shows	O
extensive	O
homology	O
to	O
those	O
of	O
Drosophila	B-GENE
hsp70	I-GENE
,	O
trout	B-GENE
hsp70	I-GENE
,	O
Xenopus	B-GENE
hsp70	I-GENE
,	O
yeast	B-GENE
hsp70	I-GENE
,	O
and	O
some	O
homology	O
to	O
the	O
heat	B-GENE
-	I-GENE
inducible	I-GENE
dnaK	I-GENE
gene	I-GENE
product	I-GENE
of	O
Escherichia	O
coli	O
.	O

At	O
temperatures	O
permissive	O
for	O
transformation	O
,	O
6m2	O
cells	O
contain	O
P58gag	B-GENE
produced	O
from	O
the	O
4	O
.	O
0	O
-	O
kilobase	O
(	O
kb	O
)	O
viral	O
RNA	O
genome	O
and	O
P85gag	B-GENE
-	O
mos	B-GENE
translated	O
from	O
a	O
3	O
.	O
5	O
-	O
kb	O
spliced	O
mRNA	O
.	O

Multistep	O
transformation	O
by	O
defined	O
fragments	O
of	O
herpes	O
simplex	O
virus	O
type	O
2	O
DNA	O
:	O
oncogenic	O
region	O
and	O
its	O
gene	O
product	O
.	O

One	O
group	O
(	O
n	O
=	O
9	O
)	O
was	O
premedicated	O
with	O
midazolam	O
,	O
0	O
.	O
1	O
mg	O
kg	O
-	O
1	O
,	O
and	O
atropine	O
0	O
.	O
2	O
-	O
0	O
.	O
4	O
mg	O
i	O
.	O
m	O
.	O

In	O
order	O
to	O
study	O
the	O
influence	O
of	O
iron	O
overload	O
on	O
the	O
polymorphonuclear	O
leucocyte	O
(	O
PMN	O
)	O
metabolism	O
of	O
patients	O
on	O
chronic	O
hemodialysis	O
,	O
generation	O
of	O
superoxide	O
anion	O
(	O
O2	O
-	O
)	O
by	O
PMN	O
in	O
whole	O
blood	O
was	O
compared	O
in	O
two	O
groups	O
of	O
hemodialyzed	O
patients	O
:	O
group	O
A	O
consisted	O
of	O
twenty	O
-	O
one	O
individuals	O
with	O
serum	O
ferritin	B-GENE
levels	O
above	O
1000	O
ng	O
/	O
ml	O
and	O
group	O
B	O
of	O
nineteen	O
individuals	O
with	O
serum	O
ferritin	B-GENE
levels	O
below	O
1000	O
ng	O
/	O
ml	O
.	O

Diazepam	O
(	O
3	O
mg	O
/	O
kg	O
)	O
generalized	O
to	O
Ro	O
11	O
-	O
6896	O
whereas	O
the	O
structurally	O
related	O
Ro	O
5	O
-	O
4864	O
(	O
3	O
mg	O
/	O
kg	O
and	O
30	O
mg	O
/	O
kg	O
)	O
did	O
not	O
.	O

Five	O
patients	O
developed	O
metastatic	O
spread	O
,	O
and	O
all	O
of	O
them	O
died	O
of	O
tumor	O
.	O

There	O
were	O
no	O
interfering	O
peaks	O
in	O
the	O
quantitation	O
of	O
sulbactam	O
.	O

Translation	O
of	O
specific	O
cellular	O
genes	O
from	O
the	O
chimeric	O
viral	O
-	O
cellular	O
transcripts	O
seems	O
to	O
be	O
unlikely	O
.	O

Two	O
mutants	O
,	O
each	O
representative	O
of	O
a	O
separate	O
pet	B-GENE
complementation	O
group	O
,	O
have	O
been	O
analyzed	O
.	O

A	O
centromere	O
in	O
S	O
.	O
cerevisiae	O
consists	O
of	O
a	O
region	O
of	O
DNA	O
,	O
approximately	O
150	O
bp	O
in	O
length	O
,	O
containing	O
three	O
important	O
sequence	O
elements	O
,	O
which	O
are	O
folded	O
with	O
proteins	O
into	O
a	O
specific	O
conformation	O
in	O
the	O
chromatin	O
(	O
the	O
yeast	O
kinetochore	O
)	O
.	O

Two	O
separate	O
NF1	B-GENE
-	I-GENE
binding	I-GENE
loci	I-GENE
were	O
also	O
found	O
in	O
the	O
equivalent	O
IE68	B-GENE
gene	I-GENE
of	O
HCMV	O
(	O
Towne	O
)	O
DNA	O
,	O
but	O
in	O
this	O
case	O
the	O
DNA	O
sequence	O
and	O
competition	O
filter	O
binding	O
experiments	O
indicated	O
a	O
maximum	O
of	O
only	O
four	O
to	O
five	O
consensus	O
binding	O
sites	O
encompassing	O
the	O
promoter	O
-	O
enhancer	O
region	O
.	O

The	O
previously	O
described	O
four	O
sets	O
of	O
13	O
-	O
to	O
18	O
-	O
base	O
-	O
pair	O
interspersed	O
repeat	O
elements	O
between	O
-	O
55	O
and	O
-	O
580	O
provide	O
most	O
of	O
the	O
high	O
basal	O
transcriptional	O
strength	O
,	O
whereas	O
the	O
arrangement	O
of	O
further	O
upstream	O
tandemly	O
repeated	O
NF1	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
may	O
contribute	O
significantly	O
to	O
the	O
expanded	O
biological	O
host	O
range	O
for	O
expression	O
of	O
SCMV	B-GENE
IE94	I-GENE
compared	O
with	O
HCMV	B-GENE
IE68	I-GENE
.	O

Active	O
lambda	B-GENE
and	I-GENE
kappa	I-GENE
antibody	I-GENE
gene	I-GENE
rearrangement	O
in	O
Abelson	O
murine	O
leukemia	O
virus	O
-	O
transformed	O
pre	O
-	O
B	O
cell	O
lines	O
.	O

Influence	O
of	O
cyclo	B-GENE
-	I-GENE
oxygenase	I-GENE
inhibition	O
and	O
of	O
leukotriene	B-GENE
receptor	I-GENE
blockade	O
on	O
pulmonary	O
vascular	O
pressure	O
/	O
cardiac	O
index	O
relationships	O
in	O
hyperoxic	O
and	O
in	O
hypoxic	O
dogs	O
.	O

Northern	O
analyses	O
of	O
RNAs	O
from	O
mouse	O
tissues	O
and	O
cell	O
lines	O
indicated	O
that	O
p11	B-GENE
mRNA	I-GENE
levels	O
vary	O
widely	O
.	O

Morphine	O
produced	O
a	O
dose	O
-	O
dependent	O
bradycardia	O
followed	O
by	O
tachycardia	O
.	O

The	O
PSS	B-GENE
gene	I-GENE
was	O
subcloned	O
into	O
a	O
1	O
.	O
1	O
-	O
kb	O
fragment	O
of	O
the	O
yeast	O
DNA	O
on	O
the	O
YEp13	O
vector	O
.	O

The	O
gene	O
is	O
essential	O
for	O
yeast	O
vegetative	O
growth	O
.	O

Bacteriologic	O
culture	O
of	O
pancreatic	O
tissue	O
was	O
positive	O
in	O
6	O
/	O
8	O
IB	O
and	O
3	O
/	O
17	O
NIB	O
rats	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

These	O
similarities	O
suggest	O
that	O
these	O
E2	B-GENE
proteins	I-GENE
are	O
structurally	O
and	O
evolutionarily	O
related	O
.	O

Histological	O
examination	O
revealed	O
a	O
small	O
simple	O
renal	O
cyst	O
associated	O
with	O
renal	O
cell	O
carcinoma	O
.	O

Thus	O
,	O
prostacyclin	O
enhanced	O
the	O
autoregulative	O
property	O
of	O
the	O
inner	O
ear	O
vessels	O
.	O

The	O
method	O
is	O
accurate	O
,	O
with	O
good	O
precision	O
and	O
adequate	O
sensitivity	O
.	O

Factors	O
influencing	O
the	O
bond	O
strength	O
between	O
glass	O
polyalkenoate	O
(	O
ionomer	O
)	O
cements	O
and	O
dentine	O
.	O

Van	O
der	O
Ende	O
,	O
R	O
.	O

Clinical	O
findings	O
were	O
:	O
height	O
183	O
cm	O
,	O
weight	O
62	O
kg	O
,	O
increased	O
length	O
of	O
lower	O
limbs	O
,	O
P2	O
-	O
A2	O
pilosity	O
and	O
micropenis	O
.	O

The	O
8	O
patients	O
receiving	O
Ir192	O
implant	O
in	O
addition	O
to	O
external	O
radiation	O
showed	O
improved	O
(	O
p	O
=	O
0	O
.	O
06	O
)	O
survival	O
compared	O
to	O
the	O
9	O
receiving	O
external	O
only	O
:	O
median	O
15	O
months	O
(	O
range	O
1	O
.	O
5	O
-	O
34	O
+	O
months	O
)	O
versus	O
7	O
months	O
(	O
range	O
2	O
.	O
5	O
-	O
21	O
months	O
)	O
.	O

No	O
effect	O
was	O
found	O
on	O
grooming	O
behavior	O
.	O

Clinical	O
and	O
biological	O
correlates	O
of	O
panic	O
states	O
.	O

Effects	O
of	O
long	O
-	O
term	O
parenteral	O
nutrition	O
on	O
gastrin	B-GENE
release	O
in	O
dogs	O
.	O

The	O
mean	O
weight	O
and	O
height	O
velocities	O
were	O
148	O
%	O
and	O
122	O
%	O
of	O
the	O
standard	O
,	O
respectively	O
.	O

In	O
64	O
%	O
a	O
small	O
cardiac	O
vein	O
does	O
not	O
exist	O
,	O
but	O
its	O
origin	O
,	O
the	O
right	O
marginal	O
vein	O
,	O
joins	O
the	O
system	O
of	O
anterior	O
cardiac	O
veins	O
.	O

The	O
results	O
of	O
these	O
experiments	O
indicate	O
that	O
at	O
least	O
two	O
upstream	O
activator	O
sequences	O
(	O
UAS	O
)	O
mediate	O
maximum	O
induction	O
by	O
galactose	O
.	O

Reversal	O
of	O
the	O
increase	O
in	O
apomorphine	O
-	O
induced	O
stereotypy	O
and	O
aggression	O
in	O
REM	O
sleep	O
deprived	O
rats	O
by	O
dopamine	O
agonist	O
pretreatments	O
.	O

The	O
genetic	O
basis	O
for	O
the	O
expression	O
of	O
a	O
latent	O
VH	B-GENE
allotype	I-GENE
in	O
the	O
rabbit	O
was	O
investigated	O
.	O

Potentiation	O
of	O
the	O
thrombolytic	O
efficacy	O
of	O
single	B-GENE
-	I-GENE
chain	I-GENE
urokinase	I-GENE
(	O
Pro	B-GENE
-	I-GENE
urokinase	I-GENE
)	O
by	O
heparin	O
.	O

The	O
variability	O
is	O
most	O
likely	O
a	O
result	O
of	O
alternative	O
splicing	O
of	O
exons	O
from	O
the	O
primary	O
elastin	B-GENE
transcripts	I-GENE
.	O

This	O
led	O
to	O
the	O
conclusion	O
that	O
the	O
metatarsal	O
artery	O
should	O
be	O
used	O
for	O
toe	O
MP	O
joint	O
grafts	O
,	O
while	O
the	O
unilateral	O
proper	O
digital	O
artery	O
is	O
suitable	O
for	O
toe	O
PIP	O
joint	O
grafts	O
,	O
together	O
with	O
concomitant	O
or	O
dorsal	O
cutaneous	O
vein	O
.	O

Factors	O
involved	O
in	O
specific	O
transcription	O
by	O
mammalian	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
:	O
purification	O
,	O
genetic	O
specificity	O
,	O
and	O
TATA	O
box	O
-	O
promoter	O
interactions	O
of	O
TFIID	B-GENE
.	O

You	O
make	O
the	O
diagnosis	O
.	O

Conservative	O
treatment	O
of	O
bladder	O
carcinoma	O
by	O
partial	O
cystectomy	O
and	O
interstitial	O
iridium	O
192	O
.	O

The	O
results	O
presented	O
suggest	O
that	O
TIQ	O
reduces	O
the	O
turnover	O
rate	O
of	O
the	O
nigrostriatal	O
dopamine	O
neurons	O
after	O
repeated	O
administration	O
for	O
a	O
long	O
period	O
in	O
mice	O
.	O

During	O
a	O
28	O
-	O
week	O
promotion	O
bioassay	O
,	O
groups	O
of	O
30	O
male	O
CD	O
-	O
1	O
mice	O
were	O
treated	O
once	O
with	O
50	O
microliter	O
of	O
either	O
DMBA	O
(	O
1	O
.	O
0	O
mg	O
/	O
ml	O
)	O
or	O
acetone	O
,	O
rested	O
for	O
2	O
weeks	O
,	O
and	O
then	O
treated	O
twice	O
per	O
week	O
with	O
test	O
material	O
for	O
the	O
remaining	O
25	O
weeks	O
.	O

An	O
11	O
-	O
month	O
-	O
old	O
girl	O
suffering	O
from	O
Dandy	O
-	O
Walker	O
malformation	O
(	O
DWM	O
)	O
associated	O
with	O
tetralogy	O
of	O
Fallot	O
(	O
TOF	O
)	O
is	O
presented	O
.	O

The	O
median	O
survival	O
is	O
not	O
reached	O
with	O
a	O
median	O
follow	O
-	O
up	O
time	O
of	O
9	O
.	O
6	O
years	O
.	O

Critical	O
evaluation	O
of	O
various	O
methods	O
of	O
determining	O
markers	O
of	O
fetal	O
maturity	O
in	O
amniotic	O
fluid	O

Neuromyelitis	O
optica	O
(	O
Devic	O
'	O
s	O
syndrome	O
)	O
:	O
not	O
always	O
multiple	O
sclerosis	O
.	O

Effect	O
of	O
the	O
methods	O
of	O
cutaneous	O
administration	O
of	O
methyl	O
isobutyl	O
ketone	O
on	O
its	O
toxicity	O

The	O
temporal	O
and	O
static	O
plasma	O
concentration	O
-	O
effect	O
relationships	O
were	O
evaluated	O
by	O
pharmacodynamic	O
modeling	O
and	O
linear	O
regression	O
.	O

Fourteen	O
patients	O
were	O
in	O
the	O
multifocal	O
disease	O
group	O
;	O
13	O
were	O
detected	O
by	O
SPECT	O
and	O
10	O
by	O
TCT	O
.	O

The	O
SSB	B-GENE
-	O
poly	O
(	O
dT	O
)	O
affinity	O
is	O
too	O
high	O
to	O
measure	O
in	O
buffers	O
containing	O
even	O
5	O
M	O
NaCl	O
;	O
however	O
,	O
in	O
1	O
.	O
8	O
-	O
2	O
.	O
5	O
M	O
NaBr	O
,	O
we	O
measure	O
alpha	O
log	O
Kobsd	O
/	O
alpha	O
log	O
[	O
NaBr	O
]	O
=	O
-	O
5	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
7	O
,	O
with	O
a	O
lower	O
value	O
of	O
omega	O
T	O
/	O
O	O
=	O
130	O
+	O
/	O
-	O
70	O
.	O

Minor	O
differences	O
were	O
noted	O
with	O
latamoxef	O
producing	O
mild	O
persistant	O
elevation	O
of	O
prothrombin	B-GENE
time	O
(	O
0	O
.	O
7	O
second	O
)	O
associated	O
with	O
depression	O
of	O
factor	B-GENE
II	I-GENE
and	O
factor	B-GENE
VII	I-GENE
.	O

Plasma	B-GENE
renin	I-GENE
activity	O
does	O
not	O
predict	O
the	O
antihypertensive	O
efficacy	O
of	O
chlorthalidone	O
.	O

Cephradine	O
250	O
mg	O
at	O
night	O
for	O
12	O
months	O
was	O
given	O
as	O
a	O
prophylactic	O
measure	O
to	O
33	O
female	O
patients	O
of	O
mean	O
age	O
41	O
.	O
6	O
years	O
,	O
who	O
had	O
a	O
history	O
in	O
the	O
preceding	O
12	O
months	O
of	O
between	O
three	O
and	O
24	O
(	O
median	O
=	O
7	O
)	O
episodes	O
of	O
frequency	O
and	O
/	O
or	O
dysuria	O
.	O

The	O
activity	O
of	O
the	O
EGF	B-GENE
receptor	I-GENE
promoter	I-GENE
can	O
be	O
modulated	O
by	O
E1A	B-GENE
protein	I-GENE
and	O
receptor	O
RNA	O
levels	O
increased	O
by	O
stimulation	O
with	O
phorbol	O
ester	O
or	O
fetal	O
calf	O
serum	O
.	O

By	O
Felix	O
Lagrange	O
,	O
1918	O
.	O

The	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
(	I-GENE
EGF	I-GENE
)	I-GENE
receptor	I-GENE
,	O
which	O
exhibits	O
intrinsic	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
activity	O
,	O
undergoes	O
a	O
rapid	O
,	O
intramolecular	O
self	O
-	O
phosphorylation	O
reaction	O
following	O
EGF	B-GENE
activation	O
.	O

A	O
case	O
of	O
AIDS	O
-	O
related	O
complex	O
(	O
ARC	O
/	O
LAS	O
)	O
in	O
a	O
health	O
worker	O

Vimentin	B-GENE
positivity	O
was	O
noted	O
in	O
the	O
undifferentiated	O
and	O
fibroblastic	O
components	O
.	O

The	O
spermicide	O
nonoxynol	O
-	O
9	O
is	O
a	O
member	O
of	O
a	O
homologous	O
series	O
of	O
alkylphenol	O
-	O
ethoxylates	O
(	O
polyethoxyethanols	O
)	O
of	O
general	O
formula	O
C9H19	O
-	O
C6H6	O
-	O
O	O
-	O
(	O
CH2CH2O	O
)	O
n	O
-	O
1	O
CH2CH2OH	O
.	O

Depending	O
on	O
the	O
location	O
and	O
size	O
of	O
the	O
mass	O
,	O
a	O
wide	O
range	O
of	O
clinical	O
presentations	O
is	O
associated	O
with	O
the	O
lesion	O
.	O

The	O
development	O
and	O
distribution	O
of	O
Trypanosoma	O
congolense	O
,	O
T	O
vivax	O
and	O
T	O
brucei	O
in	O
the	O
skin	O
of	O
goats	O
was	O
examined	O
after	O
the	O
animals	O
were	O
bitten	O
by	O
infected	O
Glossina	O
morsitans	O
centralis	O
.	O

During	O
the	O
observation	O
period	O
of	O
0	O
.	O
4	O
-	O
30	O
weeks	O
,	O
cardiac	O
white	O
spots	O
on	O
the	O
right	O
ventricle	O
of	O
BALB	O
/	O
c	O
mice	O
were	O
first	O
detected	O
at	O
three	O
weeks	O
(	O
6	O
of	O
20	O
mice	O
;	O
30	O
%	O
)	O
,	O
and	O
the	O
maximal	O
incidence	O
of	O
cardiac	O
white	O
spots	O
was	O
obtained	O
at	O
nine	O
weeks	O
(	O
39	O
of	O
44	O
mice	O
;	O
88	O
%	O
)	O
.	O

Increasing	O
the	O
RH	O
beyond	O
32	O
%	O
resulted	O
in	O
solvation	O
of	O
the	O
peroxy	O
radical	O
,	O
sterically	O
hindering	O
the	O
radical	O
from	O
entering	O
the	O
propagation	O
transition	O
state	O
.	O

PATIENTS	O
and	O
METHODS	O
:	O
Thallium	O
-	O
201	O
myocardial	O
scintigraphy	O
was	O
performed	O
at	O
rest	O
and	O
after	O
0	O
.	O
56	O
mg	O
/	O
kg	O
intravenous	O
dipyridamole	O
during	O
four	O
minutes	O
in	O
16	O
patients	O
with	O
sarcoidosis	O
.	O

Which	O
cineangiographically	O
assessed	O
anatomic	O
variable	O
correlates	O
best	O
with	O
functional	O
measurements	O
of	O
stenosis	O
severity	O
?	O
A	O
comparison	O
of	O
quantitative	O
analysis	O
of	O
the	O
coronary	O
cineangiogram	O
with	O
measured	O
coronary	O
flow	O
reserve	O
and	O
exercise	O
/	O
redistribution	O
thallium	O
-	O
201	O
scintigraphy	O
.	O

Water	O
content	O
and	O
equilibrium	O
water	O
partition	O
in	O
immature	O
cartilage	O
.	O

Ischemic	O
heart	O
disease	O
,	O
age	O
of	O
more	O
than	O
75	O
years	O
,	O
and	O
the	O
fact	O
that	O
the	O
patient	O
was	O
a	O
woman	O
were	O
independent	O
predictors	O
of	O
poor	O
cardiac	O
function	O
.	O

Liquid	O
chromatographic	O
method	O
for	O
determination	O
of	O
citreoviridin	O
in	O
corn	O
and	O
rice	O
.	O

The	O
incidence	O
of	O
cryptosporidiosis	O
in	O
young	O
children	O
was	O
determined	O
by	O
staining	O
of	O
faecal	O
specimens	O
with	O
a	O
modified	O
Kinyoun	O
stain	O
.	O

The	O
4	O
degrees	O
stimuli	O
were	O
found	O
to	O
elicit	O
scalp	O
distributions	O
for	O
the	O
pattern	O
reversal	O
P100	O
and	O
the	O
pattern	O
onset	O
C1	O
consistent	O
with	O
striate	O
and	O
extrastriate	O
visual	O
cortical	O
origins	O
respectively	O
.	O

A	O
Golgi	O
study	O
of	O
the	O
sixth	O
layer	O
of	O
the	O
cerebral	O
cortex	O
.	O

Man	O
and	O
insect	O
,	O
past	O
,	O
present	O
,	O
future	O

Mean	O
fluorosis	O
scores	O
,	O
however	O
,	O
were	O
similar	O
.	O

Autonomic	O
dysfunctions	O
were	O
restricted	O
to	O
tonic	O
pupils	O
.	O

On	O
the	O
other	O
hand	O
,	O
if	O
the	O
measured	O
angle	O
ANB	O
is	O
smaller	O
than	O
the	O
calculated	O
angle	O
,	O
the	O
skeletal	O
relation	O
is	O
Class	O
III	O
.	O

These	O
data	O
should	O
be	O
useful	O
in	O
developing	O
reagents	O
for	O
heterozygote	O
detection	O
and	O
prenatal	O
diagnosis	O
of	O
11	B-GENE
beta	I-GENE
-	I-GENE
hydroxylase	I-GENE
deficiency	O
,	O
the	O
second	O
most	O
frequent	O
cause	O
of	O
congenital	O
adrenal	O
hyperplasia	O
.	O

Neither	O
ethanol	O
nor	O
estrogen	O
has	O
been	O
shown	O
to	O
cause	O
UROD	B-GENE
-	O
deficiency	O
in	O
animals	O
.	O

Although	O
not	O
common	O
,	O
the	O
disorder	O
is	O
the	O
most	O
frequently	O
diagnosed	O
disturbance	O
of	O
porphyrin	O
metabolism	O
in	O
many	O
countries	O
,	O
and	O
further	O
insight	O
into	O
its	O
unusual	O
pathogenesis	O
may	O
clarify	O
the	O
hepatotoxic	O
effects	O
of	O
the	O
4	O
etiologic	O
agents	O
.	O

This	O
means	O
that	O
the	O
loss	O
of	O
recessives	O
must	O
be	O
calculated	O
by	O
using	O
a	O
hypergeometric	O
and	O
not	O
a	O
binomial	O
model	O
as	O
Fisher	O
did	O
.	O

The	O
poly	O
(	O
A	O
)	O
segment	O
of	O
the	O
RNA	O
was	O
selectively	O
cross	O
-	O
linked	O
to	O
the	O
72	O
,	O
000	O
-	O
molecular	O
-	O
weight	O
protein	O
(	O
72K	O
protein	O
)	O
.	O

Possible	O
pathogenetic	O
mechanisms	O
of	O
hemopoietic	O
changes	O
in	O
response	O
to	O
space	O
flight	O
effects	O
are	O
described	O
.	O

Development	O
of	O
a	O
yeast	O
system	O
to	O
assay	O
mutational	O
specificity	O
.	O

As	O
a	O
last	O
resort	O
,	O
it	O
may	O
be	O
possible	O
to	O
maintain	O
a	O
patient	O
on	O
dialysis	O
in	O
reasonable	O
health	O
with	O
a	O
DiaTAP	O
button	O
graft	O
complex	O
infected	O
with	O
Staphylococcus	O
epidermidis	O
and	O
intermittent	O
positive	O
blood	O
cultures	O
using	O
long	O
term	O
vancomycin	O
therapy	O
.	O

Reward	O
value	O
of	O
prosodic	O
features	O
of	O
language	O
for	O
autistic	O
,	O
mentally	O
retarded	O
,	O
and	O
normal	O
children	O
.	O

Due	O
to	O
its	O
relatively	O
soluble	O
chemical	O
form	O
,	O
90Sr	O
was	O
rapidly	O
translocated	O
from	O
lung	O
to	O
bone	O
where	O
a	O
substantial	O
portion	O
was	O
retained	O
for	O
a	O
long	O
period	O
of	O
time	O
.	O

Artificial	O
ventilation	O
was	O
conducted	O
using	O
a	O
tidal	O
volume	O
of	O
10	O
ml	O
X	O
kg	O
-	O
1	O
and	O
a	O
rate	O
of	O
10	O
to	O
12	O
c	O
X	O
min	O
-	O
1	O
.	O

Significantly	O
lower	O
heart	O
rate	O
reactivity	O
and	O
significantly	O
less	O
pronounced	O
left	O
temporal	O
artery	O
pulse	O
amplitude	O
responses	O
were	O
found	O
in	O
non	O
-	O
medicated	O
TH	O
subjects	O
than	O
in	O
controls	O
.	O

An	O
epidemiological	O
survey	O
of	O
rheumatic	O
valve	O
disease	O
and	O
rheumatic	O
fever	O
in	O
primary	O
and	O
secondary	O
school	O
students	O
in	O
Jiangxi	O
Province	O

Heat	O
-	O
labile	O
-	O
like	O
enterotoxin	O
(	O
LT	B-GENE
)	O
was	O
produced	O
by	O
26	O
of	O
42	O
stool	O
isolates	O
(	O
62	O
%	O
)	O
,	O
while	O
only	O
1	O
of	O
the	O
42	O
isolates	O
(	O
2	O
%	O
)	O
produced	O
enterotoxinlike	O
activity	O
in	O
suckling	O
mice	O
;	O
65	O
%	O
of	O
the	O
cytotoxin	O
-	O
producing	O
strains	O
also	O
produced	O
an	O
LT	B-GENE
-	I-GENE
like	I-GENE
material	O
.	O

The	O
nucleotide	O
sequences	O
of	O
the	O
human	B-GENE
and	I-GENE
murine	I-GENE
ornithine	I-GENE
decarboxylase	I-GENE
mRNAs	I-GENE
share	O
an	O
85	O
%	O
homology	O
,	O
even	O
in	O
their	O
3	O
'	O
-	O
noncoding	O
regions	O
.	O

The	O
absolute	O
concentrations	O
of	O
alpha	B-GENE
2	I-GENE
-	I-GENE
plasmin	I-GENE
inhibitor	O
,	O
alpha	B-GENE
2	I-GENE
-	I-GENE
macroglobulin	I-GENE
,	O
and	O
antithrombin	B-GENE
III	I-GENE
increased	O
with	O
exercise	O
(	O
all	O
P	O
less	O
than	O
0	O
.	O
005	O
)	O
,	O
but	O
when	O
concentrations	O
were	O
corrected	O
for	O
acute	O
shifts	O
of	O
plasma	O
water	O
during	O
exercise	O
,	O
the	O
quantity	O
of	O
these	O
inhibitors	O
actually	O
decreased	O
(	O
all	O
P	O
less	O
than	O
0	O
.	O
005	O
)	O
.	O

In	O
the	O
normal	O
,	O
basal	O
(	O
unstimulated	O
)	O
condition	O
there	O
were	O
no	O
significant	O
correlations	O
(	O
p	O
greater	O
than	O
0	O
.	O
05	O
)	O
between	O
the	O
systolic	O
blood	O
pressure	O
and	O
dopamine	O
(	O
r	O
=	O
0	O
.	O
09	O
)	O
,	O
norepinephrine	O
(	O
r	O
=	O
0	O
.	O
26	O
)	O
,	O
or	O
epinephrine	O
(	O
r	O
=	O
0	O
.	O
27	O
)	O
,	O
nor	O
were	O
there	O
significant	O
correlations	O
between	O
melatonin	O
and	O
dopamine	O
(	O
r	O
=	O
-	O
0	O
.	O
01	O
)	O
,	O
norepinephrine	O
(	O
r	O
=	O
-	O
0	O
.	O
26	O
)	O
,	O
or	O
growth	B-GENE
hormone	I-GENE
(	O
r	O
=	O
0	O
.	O
17	O
)	O
.	O

In	O
cases	O
of	O
1	O
degrees	O
HPT	O
,	O
the	O
plasma	O
1	O
,	O
25	O
-	O
(	O
OH	O
)	O
2D	O
level	O
rose	O
significantly	O
in	O
all	O
cases	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
,	O
although	O
the	O
pattern	O
of	O
the	O
increase	O
was	O
not	O
uniform	O
.	O

It	O
is	O
largely	O
predicted	O
by	O
lupus	O
anticoagulant	O
(	O
estimated	O
by	O
activated	O
partial	O
thromboplastin	B-GENE
time	O
)	O
and	O
/	O
or	O
antibody	O
to	O
cardiolipin	O
.	O

Data	O
from	O
119	O
men	O
and	O
40	O
women	O
undergoing	O
coronary	O
angiography	O
provide	O
an	O
opportunity	O
to	O
compare	O
these	O
associations	O
in	O
relation	O
to	O
a	O
direct	O
and	O
continuous	O
measure	O
of	O
atherosclerosis	O
while	O
controlling	O
for	O
age	O
,	O
sex	O
,	O
income	O
,	O
hypertension	O
,	O
serum	O
cholesterol	O
,	O
smoking	O
,	O
angina	O
,	O
diabetes	O
,	O
family	O
history	O
of	O
heart	O
disease	O
,	O
Type	O
A	O
behavior	O
pattern	O
,	O
and	O
hostility	O
.	O

The	O
presence	O
in	O
such	O
patients	O
of	O
antibodies	O
to	O
adrenaline	O
and	O
noradrenaline	O
is	O
indicative	O
of	O
considerable	O
disruption	O
of	O
catecholamine	O
biotransformation	O
.	O

Effects	O
of	O
a	O
low	O
-	O
energy	O
laser	O
beam	O
on	O
the	O
cells	O
of	O
the	O
newt	O
embryo	O

Samples	O
from	O
1415	O
neurological	O
patients	O
were	O
used	O
to	O
study	O
the	O
diagnostic	O
value	O
of	O
acid	B-GENE
alpha	I-GENE
1	I-GENE
-	I-GENE
glycoprotein	I-GENE
in	O
the	O
lumbar	O
cerebrospinal	O
fluid	O
.	O

Comparison	O
of	O
the	O
amino	O
acid	O
sequence	O
of	O
the	O
M	B-GENE
RNA	I-GENE
product	I-GENE
of	I-GENE
Uukuniemi	I-GENE
virus	I-GENE
with	O
that	O
of	O
Punta	O
Toro	O
and	O
Rift	O
Valley	O
fever	O
viruses	O
showed	O
in	O
both	O
cases	O
a	O
weak	O
homology	O
that	O
was	O
more	O
pronounced	O
for	O
the	O
proteins	O
located	O
at	O
the	O
COOH	O
-	O
terminal	O
end	O
of	O
the	O
precursor	O
.	O

The	O
purpose	O
of	O
this	O
study	O
is	O
twofold	O
:	O
(	O
1	O
)	O
to	O
present	O
a	O
parallel	O
form	O
of	O
the	O
Gudjonsson	O
Suggestibility	O
Scale	O
(	O
GSS	O
,	O
Form	O
1	O
)	O
;	O
(	O
2	O
)	O
to	O
study	O
test	O
-	O
retest	O
reliabilities	O
of	O
interrogative	O
suggestibility	O
.	O

The	O
average	O
deviations	O
in	O
the	O
X	O
-	O
ray	O
counts	O
of	O
the	O
constant	O
elements	O
from	O
the	O
series	O
means	O
were	O
used	O
to	O
correct	O
the	O
recorded	O
count	O
of	O
the	O
variable	O
element	O
in	O
each	O
block	O
.	O

To	O
evaluate	O
the	O
relative	O
accuracy	O
of	O
continuous	O
wave	O
(	O
CW	O
)	O
and	O
high	O
pulse	O
repetition	O
frequency	O
(	O
HPRF	O
)	O
Doppler	O
for	O
estimating	O
aortic	O
transvalvular	O
pressure	O
gradients	O
,	O
Doppler	O
examinations	O
with	O
both	O
devices	O
were	O
obtained	O
in	O
87	O
consecutive	O
patients	O
with	O
aortic	O
valve	O
disease	O
.	O

The	O
number	O
of	O
fecal	O
pellets	O
ingested	O
peaked	O
at	O
5	O
to	O
6	O
weeks	O
old	O
(	O
13	O
pellets	O
/	O
day	O
)	O
and	O
gradually	O
decreased	O
,	O
thereafter	O
(	O
2	O
.	O
1	O
pellets	O
at	O
78	O
weeks	O
old	O
,	O
1	O
.	O
5	O
pellets	O
at	O
104	O
weeks	O
old	O
)	O
.	O

Two	O
of	O
these	O
six	O
cases	O
showed	O
mucosal	O
spread	O
without	O
stromal	O
invasion	O
(	O
type	O
A	O
)	O
;	O
the	O
remaining	O
four	O
cases	O
presented	O
a	O
direct	O
extension	O
(	O
type	O
B	O
)	O
from	O
muscle	O
-	O
invasive	O
carcinomas	O
of	O
the	O
bladder	O
.	O

The	O
development	O
of	O
a	O
data	O
base	O
is	O
described	O
which	O
can	O
be	O
used	O
as	O
common	O
reference	O
for	O
ECG	O
computer	O
programs	O
analyzing	O
12	O
or	O
15	O
simultaneously	O
recorded	O
leads	O
.	O

Contraction	O
of	O
the	O
tracheal	O
muscle	O
and	O
the	O
activity	O
of	O
stretch	O
receptors	O
in	O
the	O
trachea	O

The	O
selenium	O
level	O
and	O
glutathione	B-GENE
peroxidase	I-GENE
activity	O
in	O
the	O
blood	O
,	O
liver	O
,	O
and	O
stomach	O
mucosa	O
were	O
significantly	O
higher	O
in	O
the	O
high	O
-	O
selenium	O
diet	O
group	O
than	O
in	O
the	O
low	O
-	O
selenium	O
diet	O
group	O
.	O

Amikacin	O
was	O
the	O
most	O
stable	O
and	O
tobramycin	O
was	O
the	O
least	O
stable	O
aminoglycoside	O
under	O
the	O
conditions	O
tested	O
.	O

This	O
may	O
explain	O
in	O
part	O
a	O
secular	O
trend	O
towards	O
reduced	O
birthweight	O
for	O
gestation	O
in	O
preterm	O
infants	O
.	O

Nickel	O
is	O
the	O
most	O
common	O
cause	O
of	O
allergic	O
contact	O
dermatitis	O
in	O
Singapore	O
,	O
resulting	O
in	O
positive	O
reactions	O
in	O
patch	O
tests	O
between	O
7	O
and	O
14	O
%	O
.	O

Findings	O
of	O
positive	O
potentials	O
showed	O
that	O
N1	O
originated	O
in	O
the	O
area	O
of	O
ventral	O
gray	O
matter	O
through	O
the	O
ventro	O
-	O
lateral	O
column	O
and	O
N2	O
through	O
the	O
dorsal	O
column	O
.	O

Splenectomized	O
patients	O
are	O
predisposed	O
toward	O
developing	O
overwhelming	O
bacterial	O
infections	O
.	O

The	O
rats	O
were	O
used	O
for	O
the	O
study	O
of	O
the	O
effects	O
of	O
sepsis	O
on	O
the	O
utilization	O
of	O
exogenous	O
fat	O
emulsion	O
.	O

The	O
possibility	O
of	O
a	O
hereditary	O
disorder	O
leading	O
to	O
a	O
minor	O
defect	O
in	O
elastic	O
fibre	O
structure	O
which	O
could	O
be	O
responsible	O
for	O
the	O
spontaneous	O
lesions	O
is	O
discussed	O
.	O

N	O
-	O
Substituted	O
trimethylsilylcarbamates	O
were	O
tested	O
as	O
derivatizing	O
reagents	O
for	O
gas	O
chromatographic	O
analysis	O
.	O

The	O
growing	O
drug	O
problem	O
is	O
also	O
reflected	O
in	O
the	O
increasing	O
number	O
of	O
cases	O
of	O
hepatitis	O
B	O
and	O
of	O
drug	O
-	O
related	O
deaths	O
.	O

Under	O
the	O
same	O
hematocrit	O
and	O
flow	O
conditions	O
,	O
the	O
rate	O
of	O
oxygen	O
saturation	O
decrease	O
was	O
significantly	O
higher	O
for	O
the	O
sickle	O
cells	O
than	O
for	O
normal	O
cells	O
.	O

The	O
risk	O
for	O
these	O
complications	O
is	O
increased	O
by	O
the	O
following	O
factors	O
:	O
multiple	O
gestation	O
,	O
the	O
combination	O
of	O
magnesium	O
sulfate	O
and	O
beta	O
-	O
adrenergic	O
agonist	O
,	O
and	O
the	O
use	O
of	O
adrenocortico	O
-	O
steroids	O
to	O
hasten	O
fetal	O
pulmonary	O
maturity	O
.	O

Intensification	O
of	O
human	O
myocardial	O
contractile	O
activity	O
as	O
affected	O
by	O
blood	O
serum	O

Inhibition	O
of	O
histalog	O
-	O
stimulated	O
gastric	O
secretion	O
by	O
40	O
749	O
RP	O
,	O
a	O
new	O
long	O
-	O
acting	O
gastric	O
antisecretory	O
agent	O
.	O

Five	O
-	O
year	O
prospective	O
study	O
of	O
peripheral	O
white	O
blood	O
cells	O
in	O
infectious	O
mononucleosis	O
.	O

Novel	O
multigene	O
families	O
encoding	O
highly	O
repetitive	O
peptide	O
sequences	O
.	O

The	O
M	O
-	O
3	O
subtype	O
was	O
an	O
adverse	O
prognostic	O
factor	O
.	O

In	O
addition	O
,	O
marked	O
hypertension	O
accompanied	O
this	O
disorder	O
and	O
all	O
abnormalities	O
,	O
including	O
the	O
hypertension	O
,	O
responded	O
to	O
1	B-GENE
-	I-GENE
desamino	I-GENE
-	I-GENE
8	I-GENE
-	I-GENE
D	I-GENE
-	I-GENE
arginine	I-GENE
vasopressin	I-GENE
therapy	O
.	O

In	O
19	O
patients	O
vagotomy	O
not	O
only	O
curbed	O
the	O
bleeding	O
but	O
provided	O
definitive	O
therapy	O
(	O
Visick	O
I	O
-	O
II	O
)	O
;	O
4	O
patients	O
died	O
(	O
mortality	O
rate	O
16	O
%	O
)	O
.	O

A	O
yeast	O
DNA	O
fragment	O
carrying	O
the	O
gene	B-GENE
CP	I-GENE
A1	I-GENE
encoding	O
the	O
small	O
subunit	O
of	O
the	O
arginine	O
pathway	O
carbamoyl	B-GENE
-	I-GENE
phosphate	I-GENE
synthetase	I-GENE
has	O
been	O
sequenced	O
.	O

The	O
H2	B-GENE
receptor	I-GENE
antagonists	O
and	O
sucralfate	O
cost	O
about	O
the	O
same	O
and	O
have	O
few	O
side	O
effects	O
.	O

Such	O
studied	O
acquired	O
with	O
low	O
energy	O
or	O
medium	O
energy	O
collimation	O
and	O
a	O
window	O
centered	O
on	O
the	O
159	O
keV	O
123I	O
photopeak	O
contain	O
appreciable	O
septal	O
breakthrough	O
signals	O
originating	O
from	O
Compton	O
scatter	O
of	O
high	O
energy	O
photons	O
primarily	O
from	O
124I	O
.	O

The	O
concentrations	O
of	O
apo	B-GENE
A	I-GENE
-	I-GENE
I	I-GENE
and	O
apo	B-GENE
A	I-GENE
-	I-GENE
II	I-GENE
of	O
abstainers	O
decreased	O
significantly	O
compared	O
with	O
the	O
corresponding	O
changes	O
in	O
controls	O
.	O

Thyrotropin	B-GENE
-	I-GENE
releasing	I-GENE
hormone	I-GENE
-	O
induced	O
contraction	O
of	O
urethral	O
and	O
vaginal	O
muscle	O
.	O

Results	O
of	O
this	O
study	O
indicate	O
that	O
GLC	O
of	O
short	O
chain	O
fatty	O
acids	O
produced	O
on	O
agar	O
medium	O
by	O
anaerobes	O
,	O
combined	O
with	O
simple	O
tests	O
such	O
as	O
Gram	O
'	O
s	O
stain	O
and	O
colonial	O
morphology	O
,	O
may	O
allow	O
fir	O
direct	O
presumptive	O
genus	O
identification	O
from	O
an	O
initial	O
pure	O
agar	O
culture	O
.	O

Tissue	O
pressure	O
,	O
rCBF	O
,	O
and	O
water	O
content	O
were	O
measured	O
from	O
gray	O
matter	O
in	O
the	O
central	O
core	O
and	O
the	O
peripheral	O
margin	O
of	O
the	O
MCA	O
territory	O
over	O
6	O
h	O
after	O
MCAO	O
.	O

Dissolution	O
of	O
the	O
Pt	O
-	O
30	O
%	O
Ir	O
microelectrode	O
tip	O
was	O
observed	O
by	O
scanning	O
electron	O
microscopy	O
at	O
charge	O
densities	O
as	O
low	O
as	O
200	O
microC	O
/	O
cm2	O
X	O
ph	O
(	O
1	O
A	O
/	O
cm2	O
)	O
,	O
whereas	O
erosion	O
of	O
activated	O
iridium	O
microelectrodes	O
occurred	O
only	O
at	O
the	O
highest	O
charge	O
and	O
current	O
densities	O
(	O
3200	O
microC	O
/	O
cm2	O
X	O
ph	O
,	O
16	O
A	O
/	O
cm2	O
)	O
.	O

The	O
results	O
from	O
the	O
first	O
five	O
years	O
of	O
follow	O
up	O
in	O
1972	O
showed	O
a	O
4	O
.	O
7	O
-	O
fold	O
excess	O
mortality	O
for	O
ischaemic	O
and	O
other	O
heart	O
diseases	O
(	O
ICD	O
A83	O
-	O
A84	O
)	O
compared	O
with	O
a	O
comparable	O
reference	O
cohort	O
of	O
paper	O
mill	O
workers	O
.	O

The	O
primary	O
CT	O
findings	O
were	O
misinterpreted	O
as	O
a	O
brain	O
infarct	O
or	O
possibly	O
a	O
tumour	O
.	O

However	O
,	O
kidneys	O
perfused	O
for	O
72	O
hr	O
demonstrated	O
more	O
similar	O
renal	O
functions	O
when	O
tested	O
by	O
either	O
IMPK	O
or	O
IBPK	O
.	O

It	O
has	O
been	O
reported	O
that	O
rat	O
blood	O
chloroform	O
levels	O
were	O
significantly	O
decreased	O
after	O
treatment	O
with	O
ClO2	O
.	O

For	O
this	O
purpose	O
,	O
a	O
simple	O
respiration	O
-	O
control	O
device	O
has	O
been	O
developed	O
that	O
enables	O
the	O
patient	O
to	O
monitor	O
breath	O
-	O
holding	O
during	O
successive	O
scans	O
.	O

In	O
the	O
10	O
patients	O
with	O
a	O
more	O
severe	O
degree	O
of	O
steatorrhea	O
the	O
decrease	O
in	O
fat	O
loss	O
approached	O
20	O
%	O
and	O
a	O
close	O
relationship	O
was	O
found	O
(	O
r	O
=	O
0	O
.	O
84	O
,	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
between	O
the	O
extent	O
of	O
the	O
fatty	O
acid	O
loss	O
on	O
placebo	O
and	O
the	O
decrease	O
of	O
this	O
loss	O
on	O
taurine	O
.	O

Polysorbate	O
80	O
did	O
not	O
have	O
a	O
direct	O
stimulant	O
or	O
relaxant	O
effect	O
on	O
either	O
guinea	O
pig	O
ileum	O
or	O
rat	O
uterus	O
,	O
however	O
,	O
it	O
antagonised	O
the	O
contractions	O
induced	O
by	O
acetylcholine	O
,	O
histamine	O
,	O
barium	O
,	O
5	O
-	O
hydroxytryptamine	O
and	O
carbachol	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

Either	O
a	O
UV	O
detector	O
set	O
at	O
268	O
nm	O
or	O
an	O
electrochemical	O
(	O
EC	O
)	O
detector	O
set	O
at	O
a	O
potential	O
of	O
+	O
0	O
.	O
9	O
V	O
(	O
versus	O
Ag	O
/	O
AgCl	O
/	O
3	O
M	O
NaCl	O
)	O
was	O
used	O
to	O
monitor	O
the	O
drug	O
.	O

The	O
mean	O
transfer	O
ratios	O
of	O
the	O
drug	O
into	O
the	O
genital	O
tissues	O
to	O
the	O
concentration	O
in	O
the	O
uterine	O
arterial	O
blood	O
were	O
such	O
that	O
the	O
transfer	O
ratio	O
into	O
the	O
portio	O
vaginalis	O
was	O
the	O
highest	O
,	O
followed	O
by	O
the	O
uterine	O
cervix	O
and	O
the	O
myometrium	O
,	O
and	O
that	O
into	O
the	O
oviduct	O
was	O
the	O
lowest	O
with	O
about	O
1	O
/	O
2	O
that	O
into	O
the	O
portio	O
vaginalis	O
.	O

Lower	O
extremity	O
weight	O
bearing	O
under	O
various	O
standing	O
conditions	O
in	O
independently	O
ambulatory	O
patients	O
with	O
hemiparesis	O
.	O

These	O
results	O
were	O
compared	O
with	O
those	O
obtained	O
in	O
-	O
D	O
mothers	O
and	O
pups	O
,	O
after	O
giving	O
the	O
mothers	O
an	O
oral	O
supplement	O
(	O
10	O
i	O
.	O
u	O
.	O
vitamin	O
D3	O
/	O
day	O
)	O
during	O
the	O
period	O
of	O
lactation	O
(	O
20	O
days	O
)	O
.	O

Treatment	O
with	O
oxyphenylbutazone	O
and	O
hydrocortisone	O
failed	O
to	O
inhibit	O
the	O
raised	O
serum	B-GENE
CPN	I-GENE
levels	O
.	O

40	O
,	O
000	O
)	O
.	O

Duration	O
of	O
remission	O
in	O
advanced	O
gastric	O
cancer	O
patients	O
responding	O
to	O
sequential	O
dose	O
of	O
MTX	O
and	O
5	O
-	O
FU	O

The	O
fast	O
real	O
-	O
time	O
digital	O
processing	O
of	O
the	O
N2	O
and	O
flow	O
signals	O
incorporated	O
filtering	O
,	O
delay	O
compensation	O
,	O
and	O
corrections	O
for	O
the	O
effects	O
of	O
changes	O
in	O
gas	O
composition	O
and	O
temperature	O
.	O

National	O
Institutes	O
of	O
Health	O
Consensus	O
Development	O
Conference	O
Statement	O
.	O

Diagnosis	O
:	O
progressive	O
multifocal	O
leukoencephalopathy	O
.	O

The	O
imino	O
proton	O
of	O
T3	O
in	O
the	O
O6meG	O
.	O
T	O
12	O
-	O
mer	O
and	O
G3	O
in	O
the	O
O6meG	O
.	O
N	O
12	O
-	O
mer	O
helix	O
,	O
which	O
are	O
associated	O
with	O
the	O
modification	O
site	O
,	O
resonate	O
at	O
unusually	O
high	O
field	O
(	O
8	O
.	O
5	O
to	O
9	O
.	O
0	O
ppm	O
)	O
compared	O
to	O
imino	O
protons	O
in	O
Watson	O
-	O
Crick	O
base	O
pairs	O
(	O
12	O
.	O
5	O
to	O
14	O
.	O
5	O
ppm	O
)	O
.	O

Postnatal	O
volumetric	O
development	O
of	O
the	O
prefrontal	O
cortex	O
in	O
the	O
rat	O
.	O

We	O
also	O
observed	O
that	O
the	O
predictive	O
ability	O
of	O
the	O
selected	O
attitudes	O
and	O
orientations	O
increased	O
considerably	O
from	O
1975	O
to	O
1982	O
.	O

They	O
also	O
discuss	O
the	O
existing	O
nomenclature	O
.	O

Estral	O
cycle	O
in	O
white	O
rats	O
in	O
the	O
low	O
and	O
high	O
mountains	O
of	O
Kirghizia	O

Studies	O
on	O
the	O
organic	O
matrix	O
of	O
human	O
ear	O
ossicles	O

Sensitization	O
to	O
hyperlactatemia	O
induced	O
by	O
phenformin	O
after	O
subtotal	O
ablation	O
of	O
the	O
pancreas	O
.	O

Effect	O
of	O
variations	O
in	O
time	O
interval	O
between	O
treatment	O
with	O
BCG	O
and	O
quartz	O
dust	O
on	O
translocation	O
of	O
quartz	O
dust	O
from	O
the	O
lungs	O
to	O
their	O
regional	O
lymph	O
nodes	O
.	O

Metastasis	O
of	O
colon	O
carcinoma	O
to	O
the	O
lip	O
.	O

Pre	B-GENE
-	I-GENE
beta	I-GENE
-	I-GENE
1	I-GENE
lipoprotein	I-GENE
and	O
early	O
detection	O
of	O
risk	O
factors	O
for	O
coronary	O
heart	O
disease	O
.	O

I	O
.	O

A	O
study	O
in	O
vivo	O
of	O
adrenergic	B-GENE
receptors	I-GENE
in	O
the	O
rectum	O
and	O
in	O
the	O
internal	O
and	O
sphincter	O
of	O
the	O
cat	O
.	O

Problems	O
common	O
to	O
pediatrics	O
and	O
anesthesiology	O

Clinical	O
course	O
and	O
nursing	O
care	O
of	O
patients	O
with	O
decubitus	O
ulcer	O
-	O
-	O
use	O
of	O
pillows	O
stuffed	O
with	O
buckwheat	O
chaff	O

Re	O
-	O
examining	O
methylbenzene	O
(	O
toluene	O
)	O
as	O
a	O
treatment	O
for	O
Ancylostomum	O
caninum	O
.	O

Teratological	O
studies	O
on	O
SF	O
-	O
837	O
.	O

60th	O
birthday	O
of	O
colonel	O
prof	O
.	O
e	O
.	O
cerny	O
m	O
.	O
d	O
.	O

Morphology	O
of	O
bacteriophages	O
of	O
Klebsiella	O
bacilli	O
.	O

Benign	O
intramural	O
tumors	O
of	O
the	O
esophagus	O

Methyl	O
mercury	O
intoxication	O
in	O
rat	O
kidneys	O
.	O

Disability	O
insurance	O
under	O
social	O
security	O
.	O

Polycythemia	O
-	O
1973	O
.	O

Analysis	O
of	O
clearance	O
curve	O
of	O
rose	O
bengal	O
-	O
I	O
-	O
131	O

VII	O
.	O

Effect	O
of	O
a	O
high	O
-	O
intensity	O
SHF	O
field	O
on	O
the	O
blood	O
coagulation	O
system	O

Plastic	O
solution	O
of	O
elbow	O
joint	O
ankylosis	O
with	O
a	O
decorticated	O
cylindrical	O
flap	O

Effects	O
of	O
ionizing	O
radiation	O
in	O
the	O
human	O
oral	O
cavity	O
and	O
oropharynx	O
:	O
results	O
of	O
a	O
survey	O
.	O

The	O
Twentieth	O
Anniversary	O
of	O
the	O
Pomeranian	O
Medical	O
Academy	O
.	O

Study	O
of	O
antinuclear	O
autoantibodies	O
by	O
immunofluorescence	O
technic	O
in	O
collagen	B-GENE
diseases	O

Some	O
reflexions	O
apropos	O
of	O
a	O
personal	O
statistical	O
study	O
of	O
513	O
arterial	O
embolisms	O

Reactivities	O
to	O
horse	B-GENE
anti	I-GENE
-	I-GENE
lymphocyte	I-GENE
globulin	I-GENE
.	O

The	O
effect	O
of	O
osmotic	O
flow	O
on	O
the	O
distribution	O
of	O
horseradish	B-GENE
peroxidase	I-GENE
within	O
the	O
intercellular	O
spaces	O
of	O
toad	O
bladder	O
epithelium	O
.	O

Nitrogen	O
-	O
hydrogen	O
tautomerism	O
in	O
porphyrins	O
and	O
chlorins	O
.	O

A	O
possible	O
role	O
for	O
the	O
mixed	O
function	O
oxidase	B-GENE
enzyme	O
system	O
in	O
the	O
requirement	O
for	O
selenium	O
in	O
the	O
rat	O
.	O

Periodic	O
breathing	O
and	O
apnea	O
in	O
preterm	O
infants	O
.	O

Working	O
session	O
report	O
:	O
in	O
vivo	O
-	O
in	O
vitro	O
screening	O
.	O

Dynamics	O
of	O
hospital	O
stay	O
in	O
peptic	O
ulcer	O
patients	O

A	O
case	O
of	O
M	O
hemoglobinosis	O

Results	O
of	O
the	O
official	O
inspection	O
of	O
the	O
commercial	O
anti	O
-	O
inflammatory	O
enzyme	O
preparations	O
containing	O
chymotrypsin	B-GENE
and	O
trypsin	B-GENE
by	O
means	O
of	O
modified	O
NF	O
13	O
methods	O

The	O
content	O
of	O
glucosamine	O
and	O
galactosamine	O
in	O
tartar	O

The	O
non	O
-	O
role	O
of	O
fluoride	O
in	O
the	O
control	O
of	O
plasma	O
calcium	O
in	O
the	O
parathyroidectomized	O
rat	O
.	O

Modification	O
of	O
the	O
growth	O
of	O
Tetrahymena	O
by	O
compounds	O
which	O
affect	O
the	O
adrenergic	O
mechanism	O
.	O

Factors	O
influencing	O
in	O
vitro	O
skin	B-GENE
permeability	I-GENE
factor	I-GENE
production	O
by	O
Vibrio	O
cholerae	O
.	O

Midge	O
control	O
in	O
flood	O
channels	O
.	O

Tolerance	O
test	O
of	O
HB	O
419	O
in	O
animal	O
experiments	O

The	O
distribution	O
of	O
body	O
fluids	O
following	O
hemorrhage	O
and	O
resuscitation	O
in	O
combat	O
casualties	O
.	O

Once	O
more	O
Hong	O
Kong	O
influenza	O
in	O
the	O
Netherlands	O

Early	O
disagnosis	O
of	O
cancer	O
-	O
-	O
50	O
per	O
cent	O
of	O
all	O
patients	O
could	O
be	O
cured	O

Difficulties	O
bound	O
to	O
measuring	O
of	O
sputum	O
viscosity	O

The	O
absolute	O
configuration	O
at	O
C	O
-	O
2	O
in	O
monocrotalic	O
acid	O
.	O

CO2	O
assimilation	O
by	O
chloroplasts	O
illuminated	O
on	O
filter	O
paper	O
.	O

The	O
effect	O
of	O
low	O
dosage	O
radiation	O
on	O
metabolism	O
and	O
function	O
of	O
the	O
rat	O
kidney	O
damaged	O
by	O
ischemia	O

Quantitation	O
of	O
exocrine	B-GENE
IgA	I-GENE
in	O
human	O
serum	O
in	O
health	O
and	O
disease	O
.	O

Iodine	O
metabolism	O
in	O
chronic	O
thyroiditis	O
.	O

Propagation	O
and	O
hormone	O
production	O
by	O
human	O
normal	O
and	O
malignant	O
trophoblast	O
in	O
rats	O
.	O

Morphogenesis	O
of	O
the	O
trochanter	O
produced	O
by	O
femoral	O
regeneration	O
in	O
the	O
phasmid	O
Carausius	O
morosus	O
Br	O

3	O
.	O

Nephrectomy	O
applied	O
to	O
cattle	O

Evaluation	O
of	O
automatic	O
blood	O
cell	O
counters	O
.	O

The	O
effect	O
of	O
a	O
constant	O
magnetic	O
field	O
on	O
the	O
phagocytic	O
activity	O
of	O
Paramecia	O

Relations	O
between	O
adrenergic	O
mechanisms	O
and	O
analgesic	O
effects	O

The	O
bearing	O
of	O
season	O
and	O
sequence	O
of	O
calving	O
on	O
frequency	O
of	O
male	O
,	O
female	O
and	O
total	O
calvings	O
in	O
Hariana	O
cows	O
.	O

Effect	O
of	O
castration	O
on	O
pituitary	B-GENE
and	I-GENE
serum	I-GENE
LH	I-GENE
and	O
FSH	B-GENE
in	O
testosterone	O
-	O
sterilized	O
rats	O
.	O

The	O
significance	O
of	O
the	O
phenolphthalein	B-GENE
sulphatase	I-GENE
test	O
for	O
the	O
differentiation	O
and	O
identification	O
of	O
Nocardia	O
species	O
.	O

Effect	O
of	O
heparin	O
on	O
the	O
inactivation	O
of	O
serum	B-GENE
lipoprotein	I-GENE
lipase	I-GENE
by	O
the	O
liver	O
in	O
unanesthetized	O
dogs	O
.	O

Experimental	O
chlorpromazine	O
cataracts	O
.	O

The	O
need	O
in	O
the	O
small	O
hospital	O
.	O

Statistics	O
of	O
the	O
past	O
5	O
years	O

Naphthalene	O
and	O
paradichlorobenzene	O
in	O
clinical	O
toxicology	O

Story	O
of	O
a	O
hospital	O
that	O
filmed	O
its	O
employee	O
orientation	O
program	O
.	O

Value	O
of	O
the	O
method	O
of	O
passive	O
hemagglutination	O
with	O
polysaccharide	O
C	O
in	O
detecting	O
C	B-GENE
-	I-GENE
reactive	I-GENE
protein	I-GENE
as	O
compared	O
to	O
precipitation	O
in	O
capillaries	O
and	O
slide	O
latex	O
test	O
with	O
anti	B-GENE
-	I-GENE
CRP	I-GENE
serum	O

Antimicrobial	O
substance	O
isolated	O
from	O
an	O
acorn	O
extract	O
.	O

On	O
the	O
amount	O
and	O
significance	O
of	O
the	O
effective	O
glucose	O
level	O
in	O
tumors	O
.	O

The	O
immuno	O
-	O
purified	O
mRNA	O
in	O
the	O
polysome	O
complex	O
was	O
used	O
to	O
prepare	O
cDNA	O
with	O
which	O
to	O
probe	O
a	O
D	O
.	O
melanogaster	O
genomic	O
library	O
.	O

Eight	O
recombinant	O
DNA	O
clones	O
of	O
endogenous	O
murine	O
leukemia	O
virus	O
(	O
MuLV	O
)	O
-	O
related	O
DNA	O
sequences	O
have	O
been	O
isolated	O
from	O
a	O
lambdaphage	O
genomic	O
library	O
of	O
Balb	O
/	O
c	O
mouse	O
DNA	O
.	O

Mature	O
mRNA	O
for	O
cytosolic	B-GENE
phosphoenolpyruvate	I-GENE
carboxykinase	I-GENE
of	I-GENE
the	I-GENE
chicken	I-GENE
is	O
2	O
.	O
8	O
kilobases	O
in	O
length	O
,	O
similar	O
to	O
that	O
previously	O
noted	O
for	O
mRNA	O
coding	O
for	O
the	O
same	O
enzyme	O
in	O
the	O
rat	O
.	O

Upstream	O
activation	O
sites	O
of	O
the	O
CYC1	B-GENE
gene	I-GENE
of	O
Saccharomyces	O
cerevisiae	O
are	O
active	O
when	O
inverted	O
but	O
not	O
when	O
placed	O
downstream	O
of	O
the	O
"	O
TATA	O
box	O
"	O
.	O

Plasma	O
and	O
erthrocyte	O
lipid	O
profile	O
and	O
lipoprotein	B-GENE
lipase	I-GENE
activity	O
in	O
postheparin	O
plasma	O
on	O
vasectomized	O
rabbits	O
were	O
studied	O
and	O
also	O
the	O
incidence	O
of	O
atherosclerosis	O
in	O
different	O
arterial	O
beds	O
.	O

Propranolol	O
also	O
effectively	O
controlled	O
her	O
familial	O
tremor	O
.	O

The	O
distribution	O
phase	O
is	O
followed	O
by	O
an	O
elimination	O
phase	O
with	O
a	O
much	O
longer	O
half	O
-	O
life	O
(	O
mean	O
value	O
375	O
min	O
)	O
and	O
a	O
volume	O
of	O
distribution	O
of	O
approximately	O
200	O
-	O
400	O
l	O
.	O

Plasma	B-GENE
secretin	I-GENE
,	O
pancreozymin	B-GENE
,	O
and	O
somatostatin	B-GENE
-	I-GENE
like	I-GENE
hormone	I-GENE
in	O
chronic	O
renal	O
failure	O
patients	O
.	O

We	O
have	O
followed	O
37	O
phenytoin	O
-	O
treated	O
patients	O
with	O
reduced	O
serum	B-GENE
IgA	I-GENE
concentrations	O
for	O
2	O
-	O
7	O
years	O
.	O

Unusual	O
course	O
of	O
plasmocytosis	O
.	O

Toxicity	O
was	O
significant	O
in	O
selected	O
cases	O
;	O
three	O
patients	O
developed	O
WBC	O
counts	O
less	O
than	O
1	O
,	O
000	O
/	O
mm3	O
and	O
one	O
of	O
these	O
patients	O
died	O
with	O
sepsis	O
.	O

At	O
Cabras	O
(	O
Oristano	O
)	O
,	O
a	O
town	O
characterized	O
by	O
a	O
high	O
incidence	O
of	O
thalassaemia	O
and	O
G6PD	B-GENE
deficiency	O
less	O
than	O
half	O
the	O
people	O
between	O
18	O
and	O
35	O
have	O
a	O
fair	O
knowledge	O
of	O
genetic	O
diseases	O
and	O
of	O
their	O
prevention	O
.	O

Experience	O
with	O
the	O
tensor	O
fasciae	O
latae	O
free	O
flap	O
.	O

The	O
abluminal	O
surface	O
is	O
often	O
almost	O
entirely	O
encircled	O
by	O
a	O
thick	O
layer	O
of	O
fibrillary	O
connective	O
tissue	O
.	O

The	O
customary	O
coupling	O
reagent	O
sulfanilic	O
acid	O
has	O
been	O
replaced	O
by	O
1	O
,	O
3	O
-	O
dimethylbarbituric	O
acid	O
;	O
CNCl	O
is	O
produced	O
in	O
the	O
flow	O
through	O
system	O
directly	O
from	O
KCN	O
and	O
chloramine	O
T	O
.	O

Among	O
six	O
different	O
library	O
isolates	O
containing	O
6	B-GENE
.	I-GENE
5	I-GENE
-	I-GENE
to	I-GENE
7	I-GENE
-	I-GENE
kb	I-GENE
IAP	I-GENE
units	I-GENE
,	O
some	O
restriction	O
sites	O
were	O
highly	O
conserved	O
whereas	O
others	O
varied	O
in	O
both	O
occurrence	O
and	O
position	O
.	O

During	O
the	O
period	O
from	O
May	O
to	O
August	O
,	O
1978	O
,	O
an	O
epidemic	O
of	O
hand	O
,	O
foot	O
and	O
mouth	O
disease	O
(	O
HFMD	O
)	O
occurred	O
in	O
Gifu	O
prefecture	O
.	O

We	O
have	O
investigated	O
the	O
requirements	O
of	O
the	O
CH	B-GENE
gene	I-GENE
switch	O
by	O
characterizing	O
two	O
rearranged	B-GENE
gamma	I-GENE
2b	I-GENE
genes	I-GENE
from	O
a	O
gamma	B-GENE
2b	I-GENE
producing	O
mouse	O
myeloma	O
(	O
MPC	O
-	O
11	O
)	O
.	O

WR	O
-	O
2721	O
(	O
S	O
-	O
2	O
-	O
(	O
3	O
aminopropylamino	O
)	O
ethylphosphorothioic	O
acid	O
)	O
has	O
been	O
investigated	O
for	O
its	O
ability	O
to	O
protect	O
gut	O
,	O
lung	O
,	O
and	O
testis	O
,	O
as	O
well	O
as	O
fibrosarcoma	O
(	O
FSa	O
)	O
tumor	O
nodules	O
,	O
in	O
the	O
lungs	O
of	O
mice	O
from	O
gamma	O
-	O
radiation	O
injury	O
.	O

The	O
ensembles	O
are	O
considered	O
to	O
be	O
one	O
of	O
the	O
forms	O
of	O
activity	O
of	O
the	O
structured	O
morphofunctional	O
cortical	O
units	O
,	O
i	O
.	O
e	O
.	O
the	O
columns	O
.	O

The	O
strong	O
conservation	O
of	O
the	O
inverted	O
terminal	O
repeat	O
sequence	O
may	O
reflect	O
a	O
common	O
integration	O
mechanism	O
for	O
VL30	B-GENE
elements	I-GENE
and	O
MuLV	O
proviruses	O
.	O

In	O
conclusion	O
,	O
these	O
studies	O
indicate	O
that	O
LiCl	O
(	O
1	O
)	O
decreases	O
histamine	O
-	O
stimulated	O
gastric	O
acid	O
secretion	O
,	O
and	O
(	O
2	O
)	O
diminishes	O
bile	O
-	O
induced	O
disruption	O
of	O
the	O
gastric	O
mucosal	O
barrier	O
in	O
the	O
canine	O
Heidenhain	O
pouch	O
.	O

Gel	O
route	O
preparation	O
of	O
low	O
fusing	O
dental	O
porcelain	O
frit	O
.	O

The	O
dnaQ	B-GENE
-	O
lacZ	B-GENE
and	O
the	O
rnh	B-GENE
-	O
lacZ	B-GENE
fused	O
genes	O
were	O
constructed	O
and	O
hybrid	O
proteins	O
with	O
beta	B-GENE
-	I-GENE
galactosidase	I-GENE
activity	O
were	O
produced	O
.	O

The	O
primary	O
structure	O
of	O
the	O
GAL7	B-GENE
5	I-GENE
'	I-GENE
flanking	I-GENE
region	I-GENE
has	O
many	O
features	O
common	O
to	O
those	O
of	O
multicellular	O
eukaryotic	O
genes	O
.	O

Sweet	O
oranges	O
,	O
mandarin	O
,	O
grapefruit	O
,	O
lemon	O
,	O
and	O
lime	O
are	O
generally	O
used	O
for	O
processing	O
.	O

Bepridil	O
,	O
a	O
calcium	O
antagonist	O
with	O
a	O
half	O
-	O
life	O
of	O
approximately	O
42	O
hours	O
,	O
was	O
compared	O
with	O
placebo	O
in	O
a	O
double	O
-	O
blind	O
,	O
randomized	O
,	O
crossover	O
trial	O
.	O

Climatic	O
treatment	O
of	O
children	O
with	O
respiratory	O
allergy	O

The	O
susceptibility	O
of	O
the	O
PPNG	O
strains	O
to	O
clinically	O
relevant	O
antibiotics	O
varied	O
with	O
the	O
plasmid	O
pattern	O
;	O
this	O
stresses	O
the	O
necessity	O
of	O
permanent	O
surveillance	O
of	O
gonococcal	O
infections	O
and	O
of	O
regular	O
evaluation	O
of	O
the	O
recommendations	O
for	O
antimicrobial	O
treatment	O
.	O

If	O
facilities	O
for	O
measurements	O
of	O
O2	O
consumption	O
and	O
hence	O
metabolic	O
rate	O
are	O
available	O
,	O
these	O
should	O
be	O
utilized	O
.	O

This	O
generally	O
means	O
an	O
energy	O
intake	O
of	O
1	O
.	O
4	O
to	O
1	O
.	O
6	O
times	O
the	O
energy	O
expenditure	O
,	O
with	O
a	O
N	O
intake	O
of	O
250	O
to	O
400	O
mg	O
/	O
kg	O
/	O
day	O
.	O

The	O
statistical	O
analysis	O
of	O
data	O
of	O
TRH	B-GENE
test	O
on	O
a	O
sample	O
of	O
57	O
healthy	O
volunteers	O
has	O
permitted	O
an	O
evaluation	O
of	O
the	O
upper	O
limits	O
of	O
the	O
normal	O
thyrotropin	B-GENE
response	O
;	O
the	O
secretory	O
area	O
(	O
As	O
)	O
was	O
shown	O
to	O
be	O
more	O
discriminating	O
.	O

Transitory	O
subclinical	O
and	O
permanent	O
hypothyroidism	O
in	O
the	O
course	O
of	O
subacute	O
thyroiditis	O
(	O
de	O
Quervain	O
)	O
.	O

It	O
is	O
concluded	O
that	O
axillo	O
-	O
axillary	O
by	O
-	O
pass	O
is	O
a	O
simple	O
solution	O
for	O
a	O
complex	O
haemodynamic	O
,	O
clinical	O
and	O
therapeutic	O
problem	O
.	O

Endothelium	O
of	O
the	O
central	O
ear	O
artery	O
of	O
an	O
anesthetized	O
rabbit	O
is	O
damaged	O
by	O
placing	O
artery	O
forceps	O
on	O
the	O
ear	O
directly	O
over	O
the	O
vessel	O
.	O

Hydrocortisone	O
seems	O
to	O
be	O
unable	O
to	O
hinder	O
the	O
postdenervation	O
changes	O
in	O
the	O
muscle	O
membrane	O
whereas	O
high	O
doses	O
of	O
the	O
hormone	O
are	O
able	O
to	O
induce	O
changes	O
in	O
the	O
muscle	O
membrane	O
.	O

Significant	O
clinical	O
differences	O
between	O
the	O
patients	O
treated	O
with	O
and	O
without	O
AMB	O
were	O
longer	O
survival	O
time	O
following	O
diagnosis	O
of	O
illness	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
more	O
frequent	O
cranial	O
nerve	O
signs	O
in	O
the	O
treated	O
patients	O
(	O
P	O
=	O
0	O
.	O
089	O
)	O
.	O

Catch	O
-	O
up	O
growth	O
was	O
observed	O
only	O
for	O
a	O
12	O
-	O
month	O
period	O
in	O
4	O
children	O
with	O
a	O
bone	O
age	O
of	O
7	O
to	O
8	O
years	O
.	O

The	O
present	O
paper	O
elucidates	O
the	O
existing	O
discrepancies	O
,	O
and	O
offers	O
a	O
consistent	O
terminology	O
incorporating	O
also	O
such	O
terms	O
as	O
"	O
additivity	O
"	O
,	O
"	O
potentiation	O
"	O
,	O
and	O
"	O
simple	O
similarity	O
"	O
.	O

Brainstem	O
auditory	O
evoked	O
responses	O
(	O
BAERs	O
)	O
and	O
quantitative	O
saccadic	O
eye	O
movement	O
studies	O
provide	O
information	O
on	O
the	O
integrity	O
of	O
pathways	O
traversing	O
the	O
brainstem	O
.	O

The	O
salient	O
clinical	O
features	O
,	O
the	O
problems	O
of	O
management	O
and	O
the	O
modern	O
approaches	O
to	O
the	O
reconstruction	O
of	O
facial	O
deformities	O
seen	O
in	O
this	O
disease	O
are	O
described	O
.	O

The	O
rational	O
for	O
the	O
prophylactic	O
treatment	O
,	O
the	O
therapy	O
of	O
the	O
meningopathy	O
and	O
AIL	O
-	O
AIEOP	O
protocols	O
are	O
exposed	O
.	O

Hepatitis	O
B	O
vaccine	O

The	O
Sarns	O
51F	O
cavoatrial	O
cannula	O
decompressed	O
the	O
venous	O
system	O
as	O
efficiently	O
as	O
the	O
double	O
caval	O
cannulas	O
.	O

Three	O
experiments	O
contrasted	O
the	O
effects	O
of	O
6	O
-	O
hydroxydopamine	O
-	O
induced	O
lesions	O
of	O
the	O
ventral	O
noradrenergic	O
and	O
dorsal	O
noradrenergic	O
projections	O
,	O
predominantly	O
to	O
hypothalamus	O
and	O
cortex	O
,	O
respectively	O
,	O
upon	O
body	O
weight	O
changes	O
and	O
food	O
-	O
related	O
behaviour	O
in	O
the	O
rat	O
.	O

Female	O
Wistar	O
rats	O
were	O
fed	O
a	O
liquid	O
diet	O
,	O
Sustacal	O
,	O
which	O
contained	O
ethanol	O
(	O
40	O
%	O
of	O
calories	O
)	O
or	O
isocaloric	O
sucrose	O
.	O

Introductory	O
remarks	O
.	O

Combination	O
of	O
a	O
Shwachman	O
syndrome	O
and	O
a	O
complex	O
granulocyte	O
function	O
disorder	O
in	O
a	O
girl	O

Trial	O
3	O
broiler	O
chickens	O
were	O
maintained	O
on	O
control	O
feed	O
until	O
they	O
reached	O
3	O
weeks	O
of	O
age	O
at	O
which	O
time	O
they	O
were	O
taken	O
off	O
of	O
feed	O
for	O
2	O
.	O
5	O
hr	O
and	O
then	O
placed	O
on	O
either	O
control	O
feed	O
or	O
feed	O
containing	O
4	O
.	O
0	O
ppm	O
ochratoxin	O
A	O
,	O
and	O
heart	O
rate	O
and	O
blood	O
pressure	O
were	O
measured	O
every	O
half	O
hour	O
through	O
7	O
hr	O
.	O

While	O
these	O
findings	O
may	O
reflect	O
the	O
sensitivity	O
of	O
a	O
thick	O
myocardial	O
wall	O
to	O
ischaemia	O
during	O
surgery	O
,	O
the	O
postoperative	O
recovery	O
was	O
not	O
related	O
to	O
the	O
serum	B-GENE
CK	I-GENE
-	I-GENE
MB	I-GENE
level	O
.	O

Using	O
a	O
MOS	O
-	O
Hypersil	O
reversed	O
-	O
phase	O
column	O
with	O
a	O
phosphate	O
buffer	O
-	O
-	O
acetonitrile	O
mobile	O
phase	O
,	O
baseline	O
separation	O
of	O
antipyrine	O
,	O
its	O
metabolites	O
3	O
-	O
hydroxymethylantipyrine	O
,	O
norantipyrine	O
and	O
4	O
-	O
hydroxyantipyrine	O
,	O
and	O
the	O
internal	O
standard	O
,	O
phenacetin	O
,	O
was	O
achieved	O
within	O
6	O
min	O
.	O

Serum	O
lipids	O
and	O
lipoproteins	O
of	O
29	O
insulin	B-GENE
dependent	O
diabetic	O
children	O
have	O
been	O
determined	O
and	O
related	O
to	O
the	O
metabolic	O
status	O
of	O
the	O
patients	O
.	O

The	O
AD	O
components	O
were	O
markedly	O
more	O
dependent	O
on	O
the	O
affective	O
state	O
of	O
the	O
rat	O
then	O
was	O
the	O
V1	O
component	O
.	O

HBB	O
concentration	O
in	O
the	O
fetuses	O
indicated	O
little	O
,	O
if	O
any	O
accumulation	O
.	O

All	O
samples	O
exhibited	O
a	O
decline	O
in	O
ethanol	O
concentration	O
,	O
with	O
most	O
losses	O
falling	O
within	O
the	O
expected	O
20	O
to	O
40	O
mg	O
%	O
range	O
.	O

Pilot	O
study	O
of	O
blood	O
coagulation	O
in	O
gout	O
patients	O
.	O

Further	O
,	O
the	O
reduction	O
in	O
5	O
-	O
hydroxytryptophan	O
(	O
5	O
-	O
HTP	O
)	O
accumulation	O
by	O
LSD	O
showed	O
regional	O
differences	O
in	O
inhibition	O
by	O
methiothepin	O
(	O
hypothalamus	O
greater	O
than	O
cortex	O
greater	O
than	O
striatum	O
)	O
which	O
paralleled	O
the	O
autoreceptor	O
antagonist	O
activity	O
of	O
methiothepin	O
in	O
vitro	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Effects	O
of	O
methiothepin	O
and	O
lysergic	O
acid	O
diethylamide	O
on	O
serotonin	O
release	O
in	O
vitro	O
and	O
serotonin	O
synthesis	O
in	O
vivo	O
:	O
possible	O
relation	O
to	O
serotonin	B-GENE
autoreceptor	I-GENE
function	O
.	O

In	O
a	O
recent	O
measles	O
epidemic	O
in	O
El	O
Paso	O
,	O
TX	O
,	O
120	O
,	O
000	O
records	O
were	O
screened	O
using	O
these	O
criteria	O
,	O
and	O
as	O
a	O
result	O
13	O
,	O
000	O
students	O
were	O
vaccinated	O
.	O

Twenty	O
-	O
one	O
percent	O
of	O
these	O
patients	O
had	O
neurologic	O
disease	O
that	O
appeared	O
to	O
be	O
responsible	O
for	O
the	O
tinnitus	O
.	O

Bullous	O
angiolymphoid	O
hyperplasia	O
with	O
eosinophilia	O

The	O
hypertension	O
with	O
elevated	O
PRA	O
,	O
however	O
,	O
was	O
resistant	O
to	O
the	O
angiotensin	B-GENE
II	I-GENE
(	O
AII	B-GENE
)	O
analog	O
[	O
Sar1	O
,	O
Ile8	O
]	O
ALL	O
.	O

Volume	O
of	O
distribution	O
of	O
total	O
DMDZ	O
(	O
range	O
,	O
1	O
.	O
33	O
to	O
6	O
.	O
30	O
l	O
/	O
kg	O
)	O
and	O
of	O
unbound	O
DMDZ	O
after	O
correction	O
for	O
protein	O
binding	O
(	O
range	O
,	O
43	O
to	O
243	O
l	O
/	O
kg	O
)	O
was	O
larger	O
in	O
women	O
than	O
in	O
men	O
of	O
all	O
ages	O
,	O
and	O
in	O
the	O
elderly	O
as	O
opposed	O
to	O
the	O
young	O
.	O

Effects	O
of	O
dopamine	O
and	O
of	O
a	O
dopaminergic	O
blocker	O
,	O
haloperidol	O
,	O
on	O
the	O
responses	O
of	O
carotid	O
body	O
chemoreceptors	O
to	O
hypoxia	O
and	O
hypercapnia	O
were	O
investigated	O
in	O
16	O
anesthetized	O
cats	O
.	O

1	O
.	O

The	O
alterations	O
in	O
differentiation	O
of	O
osteoprogenitor	O
cells	O
,	O
together	O
with	O
the	O
failure	O
of	O
mineralization	O
,	O
resulted	O
in	O
significantly	O
lower	O
rates	O
of	O
bone	O
formation	O
(	O
as	O
measured	O
by	O
fluorochrome	O
labeling	O
)	O
in	O
the	O
magnesium	O
-	O
deficient	O
rats	O
.	O

The	O
role	O
of	O
DNA	O
rearrangement	O
and	O
alternative	O
RNA	O
processing	O
in	O
the	O
expression	O
of	O
immunoglobulin	B-GENE
delta	I-GENE
genes	I-GENE
.	O

There	O
is	O
now	O
a	O
significative	O
difference	O
between	O
age	O
group	O
1	O
-	O
5	O
and	O
the	O
others	O
(	O
p	O
Less	O
Than	O
0	O
,	O
02	O
)	O
.	O

Factor	B-GENE
VIII	I-GENE
procoagulant	O
activity	O
,	O
antigen	O
concentration	O
and	O
von	B-GENE
Willebrand	I-GENE
activity	O
as	O
ristocetin	B-GENE
cofactor	I-GENE
were	O
determined	O
several	O
times	O
in	O
10	O
patients	O
with	O
DIC	O
.	O

In	O
silicosis	O
,	O
significant	O
relationships	O
between	O
patients	O
and	O
sons	O
were	O
not	O
seen	O
with	O
respect	O
to	O
arterial	O
blood	O
gas	O
determinations	O
and	O
ventilatory	O
responses	O
except	O
for	O
Paco2	O
of	O
patients	O
and	O
hypercapnic	O
ventilatory	O
responses	O
of	O
sons	O
.	O

For	O
steers	O
the	O
urinary	O
N	O
values	O
were	O
403	O
and	O
295	O
mg	O
/	O
kg	O
W0	O
.	O
75	O
at	O
200	O
and	O
350	O
kg	O
live	O
weight	O
respectively	O
and	O
total	O
N	O
excretion	O
including	O
faecal	O
N	O
was	O
408	O
and	O
320	O
mg	O
/	O
kg	O
W0	O
.	O
75	O
.	O

TEMTU	O
and	O
DPTU	O
were	O
the	O
most	O
potent	O
teratogens	O
.	O

Similar	O
observations	O
were	O
made	O
with	O
unilateral	O
pneumothorax	O
of	O
15	O
cmH2O	O
for	O
30	O
min	O
.	O

Fibromuscular	O
intimal	O
thickening	O
was	O
seen	O
in	O
the	O
ascending	O
and	O
thoracic	O
aorta	O
of	O
the	O
swine	O
fed	O
62	O
,	O
500	O
IU	O
of	O
vitamin	O
D3	O
/	O
kg	O
of	O
diet	O
for	O
three	O
months	O
duration	O
;	O
and	O
after	O
3	O
months	O
of	O
vitamin	O
D3	O
withdrawal	O
,	O
atherosclerotic	O
lesions	O
were	O
found	O
.	O

Detection	O
of	O
exercise	O
-	O
induced	O
asynergy	O
by	O
M	O
-	O
mode	O
echocardiography	O
.	O

Both	O
groups	O
were	O
subjected	O
to	O
tests	O
of	O
delayed	O
hypersensitivity	O
with	O
Candidin	B-GENE
,	O
Trycophytin	B-GENE
and	O
Tuberculin	B-GENE
.	O

Efficacy	O
of	O
cervical	O
spine	O
immobilization	O
methods	O
.	O

Circulating	O
platelets	O
may	O
be	O
activated	O
by	O
exposed	O
triple	O
-	O
helical	O
collagen	B-GENE
in	O
atherosclerotic	O
lesions	O
in	O
Mg	O
-	O
deficient	O
ruminants	O
.	O

In	O
the	O
ultramarathon	O
runner	O
the	O
testosterone	O
levels	O
sharply	O
rose	O
at	O
the	O
beginning	O
of	O
the	O
training	O
session	O
(	O
from	O
the	O
7	O
,	O
20	O
ng	O
/	O
ml	O
to	O
11	O
,	O
50	O
ng	O
/	O
ml	O
after	O
20	O
'	O
training	O
)	O
,	O
and	O
subsequently	O
decrease	O
after	O
3	O
hours	O
(	O
9	O
,	O
20	O
ng	O
/	O
ml	O
)	O
and	O
at	O
the	O
end	O
of	O
the	O
6	O
hours	O
training	O
(	O
4	O
,	O
60	O
ng	O
/	O
ml	O
)	O
.	O

Terbutaline	O
;	O
a	O
beta2	O
-	O
adrenergic	O
agonist	O
,	O
and	O
aminophyllin	O
,	O
a	O
phosphodiesterase	O
inhibitor	O
,	O
were	O
given	O
separately	O
,	O
or	O
in	O
combination	O
,	O
to	O
rabbit	O
fetuses	O
on	O
the	O
28th	O
day	O
of	O
gestation	O
.	O

The	O
hyperacute	O
phase	O
of	O
posterolateral	O
myocardial	O
infarction	O
.	O

After	O
a	O
year	O
of	O
planning	O
in	O
the	O
Laboratory	O
Assistants	O
'	O
School	O
in	O
Stockholm	O
:	O
new	O
education	O
for	O
laboratory	O
assistants	O
is	O
now	O
arranged	O

The	O
electrocardiogram	O
.	O

The	O
Authors	O
have	O
proposed	O
to	O
develop	O
this	O
research	O
employing	O
a	O
preparation	O
containing	O
exclusively	O
a	O
cortisonic	O
,	O
the	O
desametazone	O
,	O
in	O
order	O
to	O
evaluate	O
the	O
alterations	O
of	O
the	O
dentinogenesis	O
to	O
be	O
attributed	O
to	O
such	O
component	O
.	O

Secretory	B-GENE
IgA	I-GENE
and	O
serum	B-GENE
immunoglobulins	I-GENE
as	O
indices	O
of	O
the	O
local	O
immunity	O
of	O
the	O
intestinal	O
mucosa	O
in	O
acute	O
leukemias	O

Fluorometric	O
methods	O
can	O
also	O
provide	O
information	O
about	O
porphyrin	O
binding	O
sites	O
that	O
is	O
useful	O
in	O
understanding	O
porphyrin	O
transport	O
and	O
clearance	O
.	O

The	O
monoexponential	O
rate	O
of	O
clearance	O
of	O
tracer	O
-	O
-	O
obtained	O
from	O
the	O
portion	O
of	O
the	O
residue	O
-	O
detection	O
curve	O
reflecting	O
metabolism	O
of	O
fatty	O
acid	O
incorporated	O
into	O
neutral	O
lipids	O
-	O
-	O
correlated	O
directly	O
with	O
induced	O
changes	O
in	O
tension	O
-	O
time	O
index	O
after	O
injections	O
into	O
the	O
left	O
atrium	O
(	O
r	O
=	O
0	O
.	O
96	O
,	O
n	O
=	O
12	O
)	O
,	O
right	O
atrium	O
(	O
r	O
=	O
0	O
.	O
86	O
,	O
n	O
=	O
14	O
)	O
,	O
and	O
ear	O
vein	O
(	O
r	O
=	O
0	O
.	O
93	O
,	O
n	O
=	O
14	O
)	O
.	O

Specific	O
IgE	B-GENE
levels	O
decreased	O
slightly	O
,	O
but	O
always	O
remained	O
within	O
the	O
pathological	O
range	O
.	O

Correlation	O
between	O
intraocular	O
involvement	O
and	O
systemic	O
outcome	O
was	O
poor	O
.	O

The	O
results	O
indicate	O
that	O
folate	O
compounds	O
decrease	O
formate	O
accumulation	O
after	O
methanol	O
by	O
stimulating	O
formate	O
oxidation	O
or	O
utilization	O
and	O
suggest	O
a	O
possible	O
use	O
for	O
folates	O
in	O
the	O
treatment	O
of	O
certain	O
cases	O
of	O
human	O
methanol	O
poisoning	O
.	O

The	O
"	O
cracked	O
-	O
tooth	O
"	O
syndrome	O
.	O

The	O
foregoing	O
results	O
show	O
that	O
CXD	O
has	O
high	O
efficacy	O
and	O
safety	O
and	O
it	O
can	O
be	O
said	O
that	O
it	O
is	O
a	O
drug	O
required	O
in	O
the	O
pediatric	O
field	O
.	O

Based	O
on	O
peptide	O
map	O
similarities	O
,	O
partial	O
amino	O
-	O
terminal	O
sequence	O
data	O
,	O
and	O
common	O
genetic	O
origin	O
,	O
it	O
is	O
suggested	O
that	O
p60	B-GENE
and	O
p62	B-GENE
have	O
identical	O
amino	O
acid	O
sequences	O
carboxy	O
-	O
terminal	O
to	O
the	O
p60	B-GENE
initiator	O
methionine	O
(	O
residue	O
21	O
of	O
p62	B-GENE
)	O
.	O

Diagnosis	O
of	O
phenylalanine	B-GENE
hydroxylase	I-GENE
deficiency	O
(	O
phenylketonuria	O
)	O
.	O

The	O
uncomplicated	O
cases	O
of	O
typhoid	O
fever	O
were	O
found	O
to	O
have	O
an	O
intact	O
CMIR	O
as	O
compared	O
to	O
the	O
complicated	O
cases	O
.	O

There	O
was	O
a	O
significant	O
correlation	O
between	O
tubular	O
diameter	O
and	O
spg	O
(	O
r	O
=	O
0	O
.	O
68	O
,	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
suggesting	O
that	O
tubular	O
diameter	O
measurements	O
in	O
histological	O
sections	O
could	O
be	O
used	O
to	O
predict	O
sperm	O
production	O
.	O

The	O
differential	O
investigation	O
of	O
lipoproteins	O
,	O
however	O
,	O
showed	O
that	O
the	O
high	B-GENE
-	I-GENE
density	I-GENE
lipoprotein	I-GENE
(	O
HDL	B-GENE
)	O
fractions	O
are	O
absolutely	O
or	O
relatively	O
decreased	O
with	O
respect	O
to	O
low	B-GENE
-	I-GENE
density	I-GENE
lipoproteins	I-GENE
(	O
LDL	B-GENE
)	O
in	O
cerebral	O
infarcts	O
and	O
in	O
transient	O
ischaemic	O
attacks	O
.	O

A	O
note	O
on	O
some	O
consequences	O
of	O
UV	O
vision	O
in	O
birds	O
.	O

Parasitological	O
and	O
pathological	O
findings	O
in	O
capuchin	O
monkeys	O
infected	O
with	O
Schistosoma	O
japonicum	O
or	O
Schistosoma	O
mansoni	O
.	O

In	O
the	O
past	O
,	O
immunology	O
in	O
Singapore	O
was	O
mainly	O
confined	O
to	O
serology	O
for	O
the	O
diagnosis	O
of	O
certain	O
infectious	O
diseases	O
.	O

Modification	O
of	O
enteral	O
resorption	O
by	O
cytostatic	O
therapy	O

In	O
vitro	O
penetration	O
tests	O
of	O
human	O
sperm	O
into	O
cervical	O
mucus	O
were	O
introduced	O
in	O
order	O
to	O
study	O
the	O
interaction	O
between	O
sperm	O
and	O
cervical	O
mucus	O
.	O

Vibrio	O
fluvialis	O
(	O
group	O
F	O
vibrio	O
)	O
in	O
Maharashtra	O
.	O

The	O
hormonal	O
response	O
to	O
a	O
standardized	O
bicycle	O
exercise	O
test	O
was	O
studied	O
in	O
11	O
male	O
cadets	O
exposed	O
to	O
a	O
course	O
of	O
107	O
h	O
of	O
continuous	O
activity	O
with	O
less	O
than	O
2	O
h	O
sleep	O
.	O

At	O
an	O
ambient	O
temperature	O
of	O
25	O
degrees	O
C	O
,	O
the	O
responses	O
to	O
spinal	O
cooling	O
are	O
reduced	O
during	O
the	O
dark	O
phase	O
.	O

Ulcer	O
appeared	O
on	O
the	O
angulus	O
of	O
the	O
stomach	O
at	O
the	O
28th	O
week	O
and	O
resulted	O
in	O
ulcer	O
scar	O
at	O
the	O
42nd	O
week	O
.	O

Results	O
of	O
the	O
recognition	O
task	O
revealed	O
significant	O
effects	O
of	O
consonant	O
voicing	O
,	O
position	O
and	O
vowel	O
context	O
on	O
syllable	O
recognition	O
.	O

Visual	O
response	O
properties	O
of	O
neurons	O
in	O
four	O
extrastriate	O
visual	O
areas	O
of	O
the	O
owl	O
monkey	O
(	O
Aotus	O
trivirgatus	O
)	O
:	O
a	O
quantitative	O
comparison	O
of	O
medial	O
,	O
dorsomedial	O
,	O
dorsolateral	O
,	O
and	O
middle	O
temporal	O
areas	O
.	O

A	O
unified	O
approach	O
to	O
the	O
standardization	O
of	O
allergens	O
.	O

A	O
dose	O
-	O
dependent	O
fall	O
in	O
GABA	O
content	O
was	O
observed	O
;	O
GABA	O
decrease	O
was	O
evident	O
15	O
min	O
after	O
the	O
administration	O
,	O
reached	O
its	O
nadir	O
at	O
60	O
min	O
and	O
disappeared	O
at	O
120	O
minutes	O
.	O

For	O
monocytes	O
,	O
as	O
measured	O
on	O
the	O
Hematrak	O
,	O
it	O
was	O
13	O
.	O
4	O
%	O
.	O

Evoked	O
potential	O
and	O
single	O
unit	O
responses	O
to	O
olfactory	O
nerve	O
volleys	O
in	O
the	O
isolated	O
turtle	O
olfactory	O
bulb	O
.	O

While	O
all	O
deletions	O
within	O
the	O
sequence	O
coding	O
for	O
the	O
mature	O
tRNA	O
led	O
to	O
inactivity	O
of	O
the	O
mutated	O
genes	O
,	O
substitution	O
of	O
the	O
central	O
portion	O
by	O
concatenated	B-GENE
Hind	I-GENE
III	I-GENE
linkers	I-GENE
produced	O
gene	O
units	O
active	O
in	O
transcription	O
.	O

Survival	O
was	O
calculated	O
both	O
from	O
the	O
date	O
of	O
onset	O
and	O
from	O
the	O
date	O
of	O
diagnosis	O
.	O

With	O
Sair	O
and	O
So2	O
,	O
mean	O
vital	O
capacity	O
was	O
reduced	O
by	O
44	O
%	O
from	O
control	O
.	O

Of	O
the	O
117	O
patients	O
(	O
out	O
of	O
the	O
136	O
)	O
with	O
serologic	O
evidence	O
of	O
chronic	O
thyroiditis	O
who	O
could	O
be	O
studied	O
,	O
eight	O
(	O
7	O
%	O
)	O
had	O
hyperthyroidism	O
and	O
45	O
(	O
38	O
%	O
)	O
were	O
hypothyroid	O
.	O

The	O
new	O
semi	O
-	O
synthetic	O
oral	O
cephalosporin	O
,	O
CGP	O
9	O
,	O
000	O
,	O
has	O
been	O
evaluated	O
in	O
a	O
large	O
number	O
of	O
hospitalized	O
patients	O
with	O
urinary	O
infections	O
.	O

Current	O
status	O
of	O
chemotherapy	O
for	O
Hodgkin	O
'	O
s	O
disease	O

Over	O
a	O
period	O
of	O
15	O
days	O
16	O
%	O
of	O
the	O
dose	O
administered	O
was	O
excreted	O
with	O
faeces	O
and	O
0	O
.	O
9	O
%	O
in	O
the	O
urine	O
.	O

Electron	O
microscopic	O
picture	O
of	O
the	O
cerebral	O
cortex	O
in	O
rats	O
cooled	O
to	O
22	O
degrees	O
C	O

Thirty	O
-	O
one	O
age	O
-	O
matched	O
,	O
conscious	O
,	O
virgin	O
,	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
and	O
spontaneously	O
hypertensive	O
rats	O
(	O
SHRs	O
)	O
were	O
individually	O
injected	O
with	O
a	O
single	O
subcutaneous	O
dose	O
of	O
85	O
mg	O
/	O
kg	O
dl	O
-	O
isoproterenol	O
to	O
determine	O
the	O
degree	O
and	O
time	O
course	O
of	O
drug	O
-	O
induced	O
cardiac	O
failure	O
and	O
functional	O
recovery	O
.	O

Prevention	O
of	O
transfusion	O
reactions	O
by	O
the	O
use	O
of	O
saline	O
washed	O
red	O
blood	O
cells	O
.	O

The	O
geometric	O
mean	O
hemagglutination	O
-	O
inhibition	O
antibody	O
titers	O
(	O
GMT	O
)	O
of	O
non	O
-	O
immunized	O
,	O
once	O
-	O
immunized	O
,	O
and	O
twice	O
-	O
immunized	O
chickens	O
were	O
compared	O
at	O
2	O
-	O
week	O
intervals	O
following	O
primary	O
immunization	O
,	O
secondary	O
immunization	O
,	O
and	O
challenge	O
.	O

100	O
more	O
than	O
in	O
the	O
summer	O
coat	O
)	O
.	O

Two	O
new	O
artifacts	O
in	O
automated	O
coagulation	O
testing	O
.	O

This	O
relatively	O
simple	O
and	O
easily	O
performed	O
technique	O
of	O
measuring	O
deep	O
muscle	O
temperature	O
appears	O
to	O
be	O
a	O
useful	O
adjunct	O
in	O
choosing	O
the	O
amputation	O
level	O
.	O

Changes	O
in	O
immunologic	O
reactivity	O
in	O
subjects	O
receiving	O
transfer	B-GENE
factor	I-GENE
could	O
not	O
be	O
distinguished	O
from	O
those	O
in	O
subjects	O
receiving	O
placebo	O
.	O

Charcoal	O
-	O
facilitated	O
dialysis	O
.	O

Retinal	O
changes	O
in	O
pigmentary	O
retinopathy	O
in	O
children	O

As	O
a	O
result	O
,	O
beta	O
-	O
apo	O
-	O
8	O
'	O
-	O
carotenoic	O
acid	O
ethyl	O
ester	O
(	O
apo	O
-	O
EE	O
)	O
was	O
used	O
as	O
a	O
reference	O
standard	O
in	O
Experiments	O
4	O
to	O
6	O
.	O

Six	O
hours	O
after	O
the	O
last	O
administration	O
,	O
uterus	O
of	O
Gf	O
and	O
Cv	O
mice	O
were	O
weight	O
337	O
.	O
6	O
mg	O
%	O
and	O
423	O
.	O
5	O
mg	O
%	O
respectively	O
,	O
the	O
difference	O
was	O
statistically	O
significant	O
(	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Analysis	O
of	O
an	O
autopsy	O
population	O
.	O

Autoradiographic	O
localisation	O
of	O
its	O
cellular	O
distribution	O
in	O
the	O
kidney	O
.	O

Microscopic	O
anatomy	O
and	O
cell	O
population	O
dynamics	O
.	O

In	O
11	O
patients	O
with	O
Horton	O
'	O
s	O
headache	O
morphological	O
investigations	O
(	O
differential	O
white	O
blood	O
cell	O
count	O
)	O
,	O
cytoenzymatic	O
determinations	O
(	O
alkaline	B-GENE
and	I-GENE
acid	I-GENE
phosphatase	I-GENE
,	O
non	B-GENE
-	I-GENE
specific	I-GENE
esterase	I-GENE
)	O
and	O
cytoimmunological	O
tests	O
(	O
IgM	B-GENE
and	O
IgG	B-GENE
binding	O
)	O
were	O
carried	O
out	O
on	O
capillary	O
blood	O
neutrophils	O
obtained	O
from	O
the	O
area	O
of	O
pain	O
,	O
non	O
-	O
painful	O
area	O
of	O
the	O
skin	O
on	O
the	O
head	O
on	O
the	O
contralateral	O
side	O
,	O
and	O
from	O
the	O
finger	O
.	O

The	O
resulting	O
R	B-GENE
protein	I-GENE
terminates	O
five	O
codons	O
downstream	O
of	O
the	O
frameshift	O
site	O
at	O
the	O
V	B-GENE
protein	I-GENE
stop	O
codon	O
.	O

BSE	O
and	O
farmworkers	O
.	O

Peroxisome	B-GENE
proliferator	I-GENE
-	I-GENE
activated	I-GENE
receptors	I-GENE
(	O
PPARs	B-GENE
)	O
and	O
retinoid	B-GENE
X	I-GENE
receptors	I-GENE
(	O
RXRs	B-GENE
)	O
are	O
nuclear	B-GENE
hormone	I-GENE
receptors	I-GENE
that	O
are	O
activated	O
by	O
fatty	O
acids	O
and	O
9	O
-	O
cis	O
-	O
retinoic	O
acid	O
,	O
respectively	O
.	O

The	O
number	O
of	O
lactotropes	O
,	O
somatotropes	O
,	O
thyrotropes	O
,	O
and	O
gonadotropes	O
was	O
not	O
altered	O
compared	O
with	O
controls	O
,	O
indicating	O
that	O
in	O
the	O
adult	O
pituitary	O
,	O
POMC	B-GENE
products	I-GENE
are	O
not	O
required	O
to	O
maintain	O
the	O
distribution	O
of	O
cell	O
types	O
.	O

In	O
electrophoretic	O
mobility	O
shift	O
assays	O
,	O
the	O
PERE	B-GENE
formed	O
three	O
major	O
complexes	O
(	O
P1	O
,	O
P2	O
and	O
P3	O
)	O
with	O
proteins	O
in	O
nuclear	O
extracts	O
from	O
HeLa	O
or	O
293	O
cells	O
.	O

That	O
sequence	O
strongly	O
promoted	O
the	O
transcription	O
of	O
the	O
promotorless	O
chloramphenicol	B-GENE
acetyltranferase	I-GENE
(	O
CAT	B-GENE
)	O
gene	O
in	O
cells	O
of	O
pancreatic	O
origin	O
(	O
AR	O
-	O
42J	O
)	O
but	O
not	O
in	O
cells	O
of	O
non	O
-	O
pancreatic	O
origin	O
(	O
Rat	O
2	O
and	O
IEC	O
6	O
)	O
.	O

In	O
the	O
absence	O
of	O
E1A243	B-GENE
,	O
YY1	B-GENE
represses	O
CRE	O
-	O
dependent	O
transcription	O
of	O
c	B-GENE
-	I-GENE
fos	I-GENE
by	O
physically	O
interacting	O
with	O
ATF	B-GENE
/	O
CREB	B-GENE
proteins	O
bound	O
to	O
the	O
-	O
67	O
CRE	O
.	O

TPBF	B-GENE
has	O
two	O
potential	O
coiled	O
-	O
coil	O
regions	O
,	O
a	O
basic	O
region	O
,	O
a	O
proline	O
-	O
rich	O
region	O
,	O
a	O
histidine	O
-	O
rich	O
N	O
terminus	O
,	O
and	O
a	O
nuclear	O
targeting	O
sequence	O
.	O

To	O
confirm	O
the	O
GapIII	B-GENE
protein	I-GENE
activity	O
,	O
constructs	O
containing	O
different	O
GapIII	B-GENE
-	O
GRD	B-GENE
domains	O
were	O
transformed	O
into	O
iral	B-GENE
mutant	O
yeast	O
to	O
determine	O
their	O
relative	O
ability	O
to	O
replace	O
IRA1	B-GENE
functionally	O
.	O

A	O
water	O
-	O
vapour	O
giga	O
-	O
maser	O
in	O
the	O
active	O
galaxy	O
TXFS2226	O
-	O
184	O
.	O

These	O
incisors	O
were	O
studied	O
by	O
scanning	O
electron	O
microscopy	O
-	O
energy	O
dispersive	O
spectroscopy	O
analysis	O
(	O
SEM	O
-	O
EDS	O
)	O
and	O
light	O
microscopy	O
to	O
examine	O
the	O
calciotraumatic	O
lines	O
of	O
strontium	O
in	O
the	O
rat	O
incisor	O
labial	O
dentin	O
.	O

Mechanism	O
of	O
enhancement	O
of	O
DNA	O
expression	O
consequent	O
to	O
cointernalization	O
of	O
a	O
replication	O
-	O
deficient	O
adenovirus	O
and	O
unmodified	O
plasmid	O
DNA	O
.	O

Hepatitis	B-GENE
B	I-GENE
surface	I-GENE
antigen	I-GENE
was	O
detected	O
in	O
2	O
patients	O
,	O
with	O
negative	O
hepatitis	B-GENE
C	I-GENE
virus	I-GENE
antibody	I-GENE
.	O

Liver	O
transplantation	O
in	O
one	O
patient	O
resolved	O
metabolic	O
complications	O
but	O
did	O
not	O
improve	O
PMN	O
count	O
or	O
the	O
infectious	O
status	O
,	O
while	O
neutropenia	O
was	O
corrected	O
by	O
G	B-GENE
-	I-GENE
CSF	I-GENE
.	O

Joys	O
and	O
F	O
.	O

Tyrosine	O
phosphorylation	O
of	O
cellular	O
proteins	O
is	O
the	O
earliest	O
identifiable	O
event	O
following	O
T	B-GENE
-	I-GENE
cell	I-GENE
antigen	I-GENE
receptor	I-GENE
(	O
TCR	B-GENE
)	O
stimulation	O
and	O
is	O
essential	O
for	O
activating	O
downstream	O
signaling	O
machinery	O
.	O

The	O
interferon	B-GENE
-	O
induced	O
RNA	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
PKR	B-GENE
)	O
is	O
considered	O
to	O
play	O
an	O
important	O
role	O
in	O
the	O
cellular	O
defense	O
against	O
viral	O
infection	O
and	O
,	O
in	O
addition	O
,	O
has	O
been	O
suggested	O
to	O
be	O
a	O
tumor	O
suppressor	O
gene	O
because	O
of	O
its	O
growth	O
-	O
suppressive	O
properties	O
.	O

Moreover	O
,	O
Lck	B-GENE
was	O
reversibly	O
co	O
-	O
immunoprecipitated	O
with	O
p95Vav	B-GENE
,	O
and	O
the	O
stoichiometry	O
of	O
binding	O
increased	O
in	O
anti	B-GENE
-	I-GENE
CD3	I-GENE
-	O
treated	O
Jurkat	O
cells	O
.	O

Interleukin	B-GENE
-	I-GENE
8	I-GENE
(	O
IL	B-GENE
-	I-GENE
8	I-GENE
)	O
is	O
a	O
potent	O
inflammatory	O
mediator	O
that	O
belongs	O
to	O
the	O
family	O
of	O
C	B-GENE
-	I-GENE
X	I-GENE
-	I-GENE
C	I-GENE
chemokines	I-GENE
.	O

Three	O
mutants	O
(	O
pms1	B-GENE
,	O
pms2	B-GENE
and	O
pms3	B-GENE
)	O
isolated	O
earlier	O
from	O
MW104	O
-	O
1B	O
were	O
shown	O
to	O
correct	O
in	O
vitro	O
constructed	O
plasmids	O
with	O
defined	O
DNA	O
mismatches	O
(	O
G	O
/	O
T	O
,	O
A	O
/	O
C	O
,	O
G	O
/	O
G	O
,	O
etc	O
.	O
)	O
poorly	O
(	O
Kramer	O
et	O
al	O
.	O
,	O
1989a	O
)	O
.	O

Hematopoietic	B-GENE
growth	I-GENE
factors	I-GENE
are	O
being	O
used	O
to	O
accelerate	O
the	O
recovery	O
of	O
myelopoiesis	O
following	O
high	O
-	O
dose	O
chemotherapy	O
in	O
cancer	O
patients	O
.	O

A	O
particularly	O
striking	O
HpaII	B-GENE
tiny	O
fragment	O
island	O
,	O
extending	O
over	O
nearly	O
2	O
,	O
000	O
base	O
pairs	O
,	O
surrounds	O
the	O
USF2	B-GENE
translation	I-GENE
initiation	I-GENE
site	I-GENE
.	O

Dilutions	O
of	O
H	B-GENE
-	I-GENE
2b	I-GENE
or	I-GENE
H	I-GENE
-	I-GENE
2d	I-GENE
NP	I-GENE
peptides	I-GENE
indicated	O
that	O
3	O
-	O
4	O
logs	O
less	O
H	B-GENE
-	I-GENE
2b	I-GENE
NP	I-GENE
peptide	I-GENE
was	O
required	O
to	O
sensitize	O
syngeneic	O
target	O
cells	O
for	O
CTL	O
-	O
specific	O
lysis	O
,	O
suggesting	O
that	O
the	O
differing	O
affinities	O
of	O
H	O
-	O
2b	O
and	O
H	O
-	O
2d	O
major	B-GENE
histocompatibility	I-GENE
complex	I-GENE
molecules	I-GENE
for	O
their	O
peptides	O
likely	O
account	O
for	O
the	O
total	O
removal	O
of	O
NP	O
CTL	O
in	O
the	O
H	O
-	O
2b	O
mice	O
but	O
only	O
partial	O
removal	O
in	O
H	O
-	O
2d	O
mice	O
made	O
to	O
express	O
thymic	O
NP	O
.	O

Although	O
both	O
transfected	O
cell	O
lines	O
contain	O
FGF	B-GENE
-	I-GENE
1	I-GENE
cell	I-GENE
surface	I-GENE
receptors	I-GENE
as	O
judged	O
by	O
crosslinking	O
studies	O
,	O
the	O
wild	O
-	O
type	O
transfectants	O
are	O
refractory	O
to	O
exogenous	O
FGF	B-GENE
-	I-GENE
1	I-GENE
,	O
whereas	O
the	O
mutant	O
transfectants	O
respond	O
normally	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

The	O
median	O
post	O
-	O
treatment	O
,	O
pre	O
-	O
operative	O
serum	B-GENE
PSA	I-GENE
was	O
0	O
.	O
4	O
ng	O
/	O
ml	O
.	O

The	O
amino	O
acid	O
sequences	O
of	O
the	O
predicted	O
RfbA	B-GENE
and	O
RfbB	B-GENE
homologs	I-GENE
showed	O
identities	O
of	O
75	O
.	O
7	O
%	O
(	O
87	O
.	O
9	O
%	O
total	O
similarity	O
)	O
and	O
78	O
.	O
0	O
%	O
(	O
86	O
.	O
5	O
%	O
total	O
similarity	O
)	O
,	O
respectively	O
.	O

In	O
this	O
paper	O
we	O
report	O
that	O
ligand	O
binding	O
induced	O
tyrosine	O
phosphorylation	O
in	O
BaF3	O
cells	O
engineered	O
to	O
express	O
the	O
murine	B-GENE
Mpl	I-GENE
receptor	I-GENE
(	O
BaF3	O
/	O
mMpl	B-GENE
)	O
.	O

A	O
chicken	B-GENE
paxillin	I-GENE
cDNA	I-GENE
was	O
also	O
cloned	O
and	O
is	O
predicted	O
to	O
encode	O
a	O
protein	O
approximately	O
90	O
%	O
identical	O
to	O
human	B-GENE
paxil	I-GENE
-	I-GENE
lin	I-GENE
.	O

In	O
vivo	O
association	O
between	O
Shb	B-GENE
-	O
SH3	B-GENE
domain	O
proteins	O
v	B-GENE
-	I-GENE
Src	I-GENE
and	O
Eps8	B-GENE
was	O
detected	O
by	O
coimmunoprecipitation	O
.	O

As	O
expected	O
,	O
the	O
insulin	B-GENE
effect	O
to	O
increase	O
ras	B-GENE
GTP	I-GENE
formation	O
and	O
MAP	B-GENE
kinase	I-GENE
activity	O
was	O
negligible	O
in	O
A	O
/	O
K1018	O
cells	O
but	O
normal	O
,	O
or	O
supernormal	O
,	O
in	O
Y	O
/	O
F2	O
cells	O
.	O

Appropriate	O
restriction	O
sites	O
allow	O
one	O
to	O
insert	O
virtually	O
any	O
desired	O
cDNA	O
fragment	O
directly	O
behind	O
the	O
epitope	O
-	O
specific	O
sequence	O
and	O
before	O
a	O
long	O
poly	O
(	O
A	O
)	O
tail	O
.	O

The	O
gene	O
product	O
of	O
cotS	B-GENE
was	O
confirmed	O
to	O
be	O
identical	O
to	O
Cot40	B-GENE
-	I-GENE
2	I-GENE
by	O
SDS	O
-	O
PAGE	O
and	O
immunoblotting	O
from	O
Escherichia	O
coli	O
transformed	O
with	O
a	O
plasmid	O
containing	O
the	O
cotS	B-GENE
region	I-GENE
.	O

The	O
optimal	O
care	O
of	O
CHF	O
patient	O
includes	O
the	O
recognition	O
and	O
management	O
of	O
these	O
electrolyte	O
disturbances	O
.	O

METHODS	O
:	O
rHb1	B-GENE
.	I-GENE
1	I-GENE
or	O
human	B-GENE
serum	I-GENE
albumin	I-GENE
was	O
administered	O
intravenously	O
to	O
fasting	O
male	O
volunteers	O
.	O

A	O
mutant	O
(	O
residues	O
1	O
-	O
332	O
)	O
showed	O
complete	O
Ca2	O
+	O
/	O
CaM	B-GENE
-	O
dependent	O
activity	O
.	O

The	O
two	O
bases	O
immediately	O
flanking	O
the	O
5	O
'	O
end	O
of	O
the	O
element	O
proved	O
to	O
be	O
very	O
important	O
to	O
its	O
function	O
as	O
a	O
UAS	O
element	O
as	O
did	O
the	O
two	O
bases	O
immediately	O
3	O
'	O
of	O
the	O
bHLH	O
core	O
motif	O
.	O

These	O
results	O
indicate	O
that	O
the	O
PCNA	B-GENE
gene	I-GENE
is	O
a	O
likely	O
target	O
gene	O
of	O
E2F	B-GENE
.	O

Differential	O
sensitivity	O
of	O
the	O
MMPI	O
-	O
2	O
depression	O
scales	O
and	O
subscales	O
.	O

The	O
chloramphenicol	B-GENE
-	I-GENE
resistance	I-GENE
transposon	I-GENE
Tn4451	B-GENE
undergoes	O
precise	O
conjugative	O
deletion	O
from	O
its	O
parent	O
plasmid	O
plP401	O
in	O
Clostridium	O
perfringens	O
and	O
precise	O
spontaneous	O
excision	O
from	O
multicopy	O
plasmids	O
in	O
Escherichia	O
coli	O
.	O

A	O
general	O
model	O
for	O
ARE	O
-	O
mediated	O
mRNA	O
degradation	O
involving	O
a	O
potential	O
role	O
for	O
certain	O
heterogeneous	O
nuclear	O
ribonucleoproteins	O
and	O
ARE	B-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
is	O
proposed	O
.	O

Individual	O
mutations	O
in	O
motifs	O
III	O
,	O
IV	O
,	O
and	O
V	O
had	O
distinctive	O
effects	O
on	O
the	O
affinity	O
of	O
enzyme	O
for	O
GTP	O
,	O
the	O
rate	O
of	O
covalent	O
catalysis	O
(	O
EpG	O
formation	O
)	O
,	O
or	O
the	O
transfer	O
of	O
GMP	O
from	O
enzyme	O
to	O
RNA	O
.	O

Mutational	O
analysis	O
of	O
mRNA	B-GENE
capping	I-GENE
enzyme	I-GENE
identifies	O
amino	O
acids	O
involved	O
in	O
GTP	O
binding	O
,	O
enzyme	O
-	O
guanylate	O
formation	O
,	O
and	O
GMP	O
transfer	O
to	O
RNA	O
.	O

Staphylococcal	B-GENE
enterotoxin	I-GENE
A	I-GENE
involvement	O
in	O
the	O
illness	O
of	O
a	O
20	O
-	O
month	O
-	O
old	O
burn	O
patient	O
.	O

These	O
results	O
suggest	O
that	O
G	B-GENE
beta	I-GENE
gamma	I-GENE
-	O
stimulated	O
Shc	B-GENE
phosphorylation	O
represents	O
an	O
early	O
step	O
in	O
the	O
pathway	O
leading	O
to	O
p21ras	B-GENE
activation	O
,	O
similar	O
to	O
the	O
mechanism	O
utilized	O
by	O
growth	B-GENE
factor	I-GENE
tyrosine	I-GENE
kinase	I-GENE
receptors	I-GENE
.	O

Negative	O
-	O
staining	O
,	O
refractile	O
mycobacteria	O
in	O
Romanowsky	O
-	O
stained	O
smears	O
.	O

Here	O
we	O
focused	O
on	O
the	O
role	O
of	O
the	O
5	O
'	O
proximal	O
regulatory	O
cassette	O
(	O
-	O
190	O
;	O
+	O
53	O
bp	O
)	O
of	O
the	O
rat	B-GENE
enkephalin	I-GENE
(	O
rENK	B-GENE
)	O
gene	O
in	O
the	O
developmental	O
regulation	O
of	O
the	O
enkephalin	B-GENE
phenotype	O
.	O

Unexpectedly	O
,	O
all	O
ENK	B-GENE
-	I-GENE
specific	I-GENE
motifs	I-GENE
formed	O
specific	O
and	O
highly	O
abundant	O
protein	O
-	O
DNA	O
complexes	O
when	O
nuclear	O
extracts	O
from	O
the	O
human	O
tumor	O
cell	O
line	O
(	O
HeLa	O
)	O
,	O
which	O
does	O
not	O
express	O
ENK	B-GENE
,	O
were	O
used	O
.	O

Infant	O
aged	O
3	O
.	O
5	O
years	O
presents	O
persistence	O
of	O
primordial	O
vitreous	O
body	O
with	O
crystalline	O
dislocation	O
in	O
the	O
camera	O
aquosa	O
and	O
secondary	O
buphthalmos	O
of	O
the	O
left	O
eye	O
and	O
microphthalmos	O
with	O
dislocation	O
of	O
the	O
crystalline	O
in	O
the	O
vitreous	O
body	O
of	O
the	O
right	O
eye	O
.	O

Imaging	O
features	O
of	O
splenic	O
epidermoid	O
cyst	O
with	O
pathologic	O
correlation	O
.	O

SL1	B-GENE
trans	O
-	O
splicing	O
specified	O
by	O
AU	O
-	O
rich	O
synthetic	O
RNA	O
inserted	O
at	O
the	O
5	O
'	O
end	O
of	O
Caenorhabditis	O
elegans	O
pre	O
-	O
mRNA	O
.	O

Overexpression	O
of	O
wild	B-GENE
-	I-GENE
type	I-GENE
p53	I-GENE
also	O
induces	O
apoptosis	O
in	O
an	O
LCL	O
.	O

These	O
observations	O
lead	O
to	O
the	O
proposal	O
that	O
the	O
RNAP	B-GENE
II	I-GENE
CTD	I-GENE
might	O
be	O
an	O
in	O
vivo	O
target	O
for	O
the	O
activated	O
p42mapk	B-GENE
and	O
p44mapk	B-GENE
MAP	I-GENE
kinases	I-GENE
.	O

We	O
also	O
isolated	O
two	O
alternatively	O
spliced	O
forms	O
of	O
human	B-GENE
CD6	I-GENE
cDNA	I-GENE
lacking	O
sequences	O
encoding	O
membrane	O
-	O
proximal	O
regions	O
of	O
the	O
cytoplasmic	O
domain	O
which	O
maintain	O
the	O
same	O
reading	O
frame	O
as	O
CD6	B-GENE
-	O
PB1	B-GENE
.	O

We	O
have	O
isolated	O
a	O
Drosophila	O
melanogaster	O
(	O
Dm	O
)	O
cDNA	O
encoding	O
a	O
polypeptide	O
that	O
has	O
extensive	O
sequence	O
similarity	O
to	O
the	O
mammalian	B-GENE
MAPKAPK	I-GENE
-	I-GENE
2	I-GENE
.	O

A	O
2	B-GENE
.	I-GENE
4	I-GENE
-	I-GENE
kb	I-GENE
MAPKAPK	I-GENE
-	I-GENE
2	I-GENE
message	I-GENE
is	O
expressed	O
throughout	O
development	O
,	O
while	O
two	O
shorter	O
transcripts	O
of	O
2	O
.	O
3	O
and	O
1	O
.	O
8	O
kb	O
appear	O
to	O
be	O
specifically	O
expressed	O
in	O
the	O
germline	O
.	O

The	O
integrity	O
of	O
the	O
cDNA	O
sequence	O
was	O
confirmed	O
by	O
analysis	O
of	O
several	O
overlapping	O
genomic	O
clones	O
that	O
span	O
the	O
GAR1	B-GENE
gene	I-GENE
.	O

Phorbol	O
esters	O
stimulated	O
phosphorylation	O
of	O
CSK	B-GENE
35H	I-GENE
proteins	I-GENE
,	O
thus	O
emphasizing	O
that	O
sequences	O
isolated	O
according	O
to	O
PKC	B-GENE
binding	O
activity	O
in	O
vitro	O
are	O
also	O
PKC	B-GENE
substrates	O
in	O
vivo	O
.	O

One	O
of	O
these	O
is	O
surrounded	O
by	O
an	O
adenine	O
-	O
uridine	O
rich	O
region	O
that	O
can	O
form	O
an	O
11	O
-	O
base	O
pair	O
stem	O
structure	O
.	O

Additionally	O
,	O
the	O
enzyme	O
shows	O
activity	O
towards	O
triglycerides	O
such	O
as	O
olive	O
oil	O
and	O
tributyrin	O
and	O
towards	O
egg	O
-	O
yolk	O
emulsions	O
.	O

The	O
nucleotide	O
sequence	O
directly	O
upstream	O
of	O
fimA	B-GENE
contains	O
two	O
open	O
reading	O
frames	O
,	O
ORF5	O
and	O
ORF1	O
,	O
whose	O
deduced	O
protein	O
products	O
are	O
homologous	O
to	O
members	O
of	O
a	O
superfamily	O
of	O
ATP	B-GENE
-	I-GENE
binding	I-GENE
cassette	I-GENE
membrane	I-GENE
transport	I-GENE
proteins	I-GENE
,	O
including	O
both	O
prokaryotic	O
and	O
eukaryotic	O
uptake	O
and	O
export	O
systems	O
.	O

The	O
ORF3	O
probe	O
also	O
hybridized	O
to	O
a	O
540	O
bp	O
transcript	O
consistent	O
with	O
the	O
size	O
of	O
ORF3	O
alone	O
and	O
supportive	O
of	O
the	O
mutagenesis	O
data	O
of	O
non	O
-	O
linkage	O
.	O

Mean	O
growth	O
changes	O
in	O
this	O
Class	O
II	O
sample	O
were	O
comparable	O
to	O
those	O
previously	O
reported	O
for	O
male	O
subjects	O
with	O
Class	O
I	O
malocclusions	O
over	O
the	O
same	O
age	O
period	O
,	O
suggesting	O
a	O
similarity	O
in	O
postpubertal	O
development	O
between	O
these	O
two	O
groups	O
.	O

By	O
in	O
vitro	O
immunoprecipitations	O
and	O
gel	O
shift	O
assays	O
,	O
we	O
identified	O
two	O
classes	O
of	O
high	O
affinity	O
Engrailed	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
upstream	O
of	O
each	O
of	O
the	O
two	O
polyhomeotic	O
transcription	O
units	O
.	O

Subjects	O
with	O
a	O
short	O
postexposure	O
time	O
and	O
a	O
dioxin	O
burden	O
>	O
0	O
.	O
6	O
pg	O
/	O
m3	O
had	O
a	O
significantly	O
higher	O
risk	O
of	O
hypoergy	O
than	O
unexposed	O
subjects	O
(	O
hypoergy	O
I	O
:	O
OR	O
=	O
9	O
.	O
51	O
,	O
95	O
%	O
CI	O
=	O
1	O
.	O
96	O
-	O
42	O
.	O
02	O
;	O
hypoergy	O
II	O
:	O
OR	O
=	O
2	O
.	O
92	O
,	O
95	O
%	O
CI	O
=	O
1	O
.	O
14	O
-	O
7	O
.	O
5	O
)	O
.	O

Analysis	O
of	O
this	O
sequence	O
combined	O
with	O
that	O
previously	O
reported	O
for	O
the	O
5	O
'	O
-	O
flanking	O
region	O
directly	O
proximal	O
to	O
the	O
start	O
of	O
transcription	O
revealed	O
several	O
putative	O
regulatory	O
sequences	O
.	O

The	O
experimental	O
design	O
represents	O
a	O
2	O
x	O
3	O
factorial	O
arrangement	O
of	O
treatments	O
with	O
three	O
dietary	O
levels	O
of	O
incorporation	O
of	O
RSB	O
(	O
0	O
,	O
50	O
,	O
and	O
100	O
%	O
)	O
,	O
and	O
chickens	O
either	O
infected	O
or	O
uninfected	O
.	O

A	O
cDNA	O
clone	O
corresponding	O
to	O
the	O
putative	O
GA	B-GENE
20	I-GENE
-	O
oxidase	B-GENE
genomic	O
sequence	O
was	O
constructed	O
with	O
the	O
reverse	O
transcription	O
-	O
PCR	O
method	O
,	O
and	O
the	O
identity	O
of	O
the	O
cDNA	O
clone	O
was	O
confirmed	O
by	O
analyzing	O
the	O
capability	O
of	O
the	O
fusion	O
protein	O
expressed	O
in	O
Escherichia	O
coli	O
to	O
convert	O
GA53	B-GENE
to	O
GA44	B-GENE
and	O
GA19	B-GENE
to	O
GA20	B-GENE
.	O

Total	O
cholesterol	O
was	O
also	O
reduced	O
at	O
week	O
12	O
by	O
17	O
.	O
0	O
%	O
(	O
20	O
mg	O
/	O
day	O
)	O
and	O
15	O
.	O
7	O
%	O
(	O
20	O
-	O
30	O
mg	O
/	O
day	O
)	O
,	O
and	O
at	O
week	O
52	O
by	O
20	O
.	O
4	O
%	O
(	O
<	O
or	O
=	O
20	O
mg	O
/	O
day	O
)	O
and	O
19	O
.	O
2	O
%	O
(	O
>	O
or	O
=	O
30	O
mg	O
/	O
day	O
)	O
.	O

Piperacillin	O
-	O
tazobactam	O
can	O
be	O
used	O
for	O
the	O
treatment	O
of	O
infections	O
caused	O
by	O
gram	O
-	O
negative	O
,	O
gram	O
-	O
positive	O
,	O
aerobic	O
,	O
and	O
anaerobic	O
bacteria	O
.	O

This	O
apparently	O
anomalous	O
structure	O
/	O
activity	O
relationship	O
raises	O
important	O
issues	O
for	O
understanding	O
the	O
evolution	O
of	O
regulatory	O
peptides	O
and	O
the	O
mechanisms	O
that	O
control	O
their	O
expression	O
.	O

This	O
paper	O
summarises	O
the	O
experimental	O
evidence	O
upon	O
which	O
the	O
clinical	O
trials	O
of	O
aldose	B-GENE
reductase	I-GENE
inhibitors	O
in	O
diabetic	O
patients	O
have	O
been	O
initiated	O
and	O
the	O
results	O
of	O
published	O
drug	O
trials	O
in	O
these	O
patients	O
.	O

Increase	O
in	O
urinary	O
calcium	O
and	O
oxalate	O
after	O
fructose	O
infusion	O
.	O

The	O
Babcock	O
Surgical	O
Clinic	O
.	O

Histopathological	O
features	O
of	O
relapsed	O
leprosy	O
.	O

One	O
of	O
these	O
factors	O
,	O
HRF	B-GENE
-	I-GENE
1	I-GENE
,	O
recognizes	O
a	O
cis	O
element	O
consisting	O
of	O
an	O
inverted	O
palindromic	O
motif	O
.	O

Regulation	O
of	O
Gax	B-GENE
homeobox	B-GENE
gene	I-GENE
transcription	O
by	O
a	O
combination	O
of	O
positive	O
factors	O
including	O
myocyte	B-GENE
-	I-GENE
specific	I-GENE
enhancer	I-GENE
factor	I-GENE
2	I-GENE
.	O

The	O
carboxyl	O
-	O
terminal	O
transactivation	O
domain	O
of	O
heat	B-GENE
shock	I-GENE
factor	I-GENE
1	I-GENE
is	O
negatively	O
regulated	O
and	O
stress	O
responsive	O
.	O

The	O
RAT3	B-GENE
gene	I-GENE
encodes	O
an	O
1157	O
-	O
amino	O
acid	O
protein	O
without	O
similarity	O
to	O
other	O
known	O
proteins	O
.	O

CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
isoforms	I-GENE
beta	I-GENE
and	I-GENE
delta	I-GENE
are	O
expressed	O
in	O
mammary	O
epithelial	O
cells	O
and	O
bind	O
to	O
multiple	O
sites	O
in	O
the	O
beta	B-GENE
-	I-GENE
casein	I-GENE
gene	I-GENE
promoter	I-GENE
.	O

We	O
have	O
found	O
that	O
the	O
expression	O
of	O
GTPase	B-GENE
-	O
deficient	O
mutants	O
of	O
alpha	B-GENE
12	I-GENE
(	O
alpha	B-GENE
12Q229L	I-GENE
)	O
or	O
alpha	B-GENE
13	I-GENE
(	O
alpha	B-GENE
13Q226L	I-GENE
)	O
leads	O
to	O
robust	O
activation	O
of	O
the	O
Jun	B-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

Using	O
mutagenesis	O
,	O
we	O
have	O
identified	O
two	O
mutations	O
of	O
the	O
second	O
actin	B-GENE
-	I-GENE
binding	I-GENE
domain	I-GENE
that	O
can	O
also	O
suppress	O
the	O
act1	B-GENE
mutations	O
of	O
interest	O
.	O

The	O
normal	O
cell	O
cycle	O
is	O
regulated	O
by	O
several	O
molecules	O
,	O
such	O
as	O
the	O
tumor	B-GENE
-	I-GENE
suppressor	I-GENE
protein	I-GENE
pRb	I-GENE
,	O
the	O
G1	B-GENE
cyclins	I-GENE
,	O
the	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
,	O
and	O
their	O
inhibitors	O
.	O

These	O
results	O
are	O
very	O
useful	O
for	O
deciding	O
on	O
the	O
doses	O
of	O
hormones	O
and	O
the	O
expected	O
serum	O
estradiol	O
level	O
in	O
HRT	O
for	O
Japanese	O
women	O
.	O

Comparison	O
of	O
1	O
.	O
5	O
Tesla	O
and	O
0	O
.	O
35	O
Tesla	O
field	O
strength	O
magnetic	O
resonance	O
imaging	O
scans	O
in	O
the	O
morphometric	O
evaluation	O
of	O
the	O
lumbar	O
intervertebral	O
foramina	O
.	O

A	O
new	O
vector	O
,	O
pHBK280	O
,	O
was	O
designed	O
to	O
facilitate	O
this	O
analysis	O
.	O

Here	O
we	O
describe	O
an	O
in	O
vitro	O
assay	O
where	O
the	O
NS3	B-GENE
-	I-GENE
4A	I-GENE
polyprotein	I-GENE
,	O
NS3	B-GENE
,	O
the	O
serine	B-GENE
proteinase	I-GENE
domain	I-GENE
(	I-GENE
the	I-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
181	I-GENE
residues	I-GENE
of	I-GENE
NS3	I-GENE
)	I-GENE
,	O
and	O
the	O
NS4A	B-GENE
cofactor	I-GENE
were	O
produced	O
by	O
cell	O
-	O
free	O
translation	O
and	O
tested	O
for	O
trans	O
-	O
processing	O
of	O
radiolabeled	O
substrates	O
.	O

In	O
contrast	O
,	O
over	O
-	O
expression	O
of	O
RAR	B-GENE
beta	I-GENE
only	O
poorly	O
restored	O
differentiation	O
,	O
although	O
it	O
could	O
replace	O
RAR	B-GENE
gamma	I-GENE
for	O
the	O
activation	O
of	O
target	O
genes	O
.	O

The	O
5	O
'	O
-	O
terminus	O
of	O
the	O
p	B-GENE
-	I-GENE
gvpF	I-GENE
-	I-GENE
M	I-GENE
mRNA	I-GENE
was	O
located	O
169	O
nucleotides	O
upstream	O
of	O
p	B-GENE
-	I-GENE
gvpF	I-GENE
within	O
p	B-GENE
-	I-GENE
gvpE	I-GENE
.	O

However	O
,	O
the	O
relative	O
binding	O
affinity	O
for	O
the	O
motifs	O
is	O
different	O
.	O

The	O
transport	O
of	O
a	O
genetically	O
engineered	O
chimeric	O
transmembrane	O
protein	O
connected	O
to	O
this	O
ER	O
leader	O
sequence	O
was	O
as	O
efficient	O
as	O
that	O
of	O
the	O
original	O
protein	O
from	O
which	O
the	O
ER	O
sequence	O
has	O
been	O
derived	O
.	O

A	O
polymorphic	O
bipartite	O
motif	O
signals	O
nuclear	O
targeting	O
of	O
early	O
auxin	O
-	O
inducible	O
proteins	O
related	O
to	O
PS	B-GENE
-	I-GENE
IAA4	I-GENE
from	I-GENE
pea	I-GENE
(	I-GENE
Pisum	I-GENE
sativum	I-GENE
)	I-GENE
.	O

The	O
plant	O
hormone	O
auxin	O
transcriptionally	O
activates	O
early	B-GENE
genes	I-GENE
.	O

A	O
new	O
non	O
-	O
LTR	O
retrotransposon	O
provides	O
evidence	O
for	O
multiple	O
distinct	O
site	O
-	O
specific	O
elements	O
in	O
Crithidia	O
fasciculata	O
miniexon	O
arrays	O
.	O

The	O
CVA16	B-GENE
.	I-GENE
4	I-GENE
proteolipid	I-GENE
transcript	I-GENE
is	O
the	O
most	O
prevalent	O
of	O
the	O
two	O
proteolipid	O
messages	O
in	O
expanding	O
ovules	O
harvested	O
10	O
d	O
post	O
-	O
anthesis	O
.	O

The	O
synthetic	O
DNA	O
sequence	O
was	O
constructed	O
to	O
achieve	O
efficient	O
base	O
pairing	O
with	O
Escherichia	B-GENE
coli	I-GENE
16S	I-GENE
ribosomal	I-GENE
RNA	I-GENE
,	O
avoidance	O
of	O
internal	O
secondary	O
structure	O
,	O
and	O
optimal	O
codon	O
usage	O
for	O
high	O
-	O
level	O
protein	O
expression	O
in	O
accord	O
with	O
the	O
known	O
preferences	O
in	O
E	O
.	O
coli	O
.	O

Transcription	O
factors	O
containing	O
a	O
basic	O
helix	O
-	O
loop	O
-	O
helix	O
(	O
bHLH	O
)	O
motif	O
regulate	O
the	O
expression	O
of	O
tissue	O
-	O
specific	O
genes	O
in	O
a	O
number	O
of	O
mammalian	O
and	O
insect	O
systems	O
.	O

EsaR	B-GENE
can	O
repress	O
its	O
own	O
expression	O
but	O
seems	O
not	O
to	O
regulate	O
the	O
expression	O
of	O
esaI	B-GENE
.	O

We	O
conclude	O
that	O
,	O
in	O
comparison	O
to	O
reports	O
from	O
other	O
regions	O
,	O
Scandinavian	O
renal	O
transplant	O
recipients	O
are	O
at	O
high	O
risk	O
of	O
dying	O
of	O
IHD	O
.	O

Veterinary	O
certification	O
for	O
livestock	O
export	O
.	O

Diffuse	O
white	O
matter	O
injury	O
can	O
be	O
attributed	O
to	O
radiation	O
and	O
associated	O
with	O
neurological	O
deficits	O
,	O
but	O
leukoencephalopathy	O
is	O
rarely	O
observed	O
in	O
the	O
absence	O
of	O
chemotherapy	O
.	O

The	O
ectopic	O
expression	O
of	O
Oct	B-GENE
-	I-GENE
3	I-GENE
/	I-GENE
4	I-GENE
in	O
hybrid	O
cells	O
under	O
a	O
constitutive	O
promoter	O
is	O
sufficient	O
for	O
transcriptional	O
activation	O
of	O
an	O
octamer	O
-	O
dependent	O
promoter	O
.	O

We	O
here	O
demonstrate	O
that	O
a	O
temperature	O
-	O
sensitive	O
fission	O
yeast	O
mutant	O
which	O
has	O
a	O
mutation	O
in	O
a	O
homologous	O
gene	O
,	O
and	O
two	O
of	O
three	O
additional	O
(	O
mtr1	B-GENE
/	O
prp20	B-GENE
/	O
srm1	B-GENE
)	O
mutants	O
accumulate	O
nuclear	O
poly	O
(	O
A	O
)	O
+	O
RNA	O
at	O
37	O
degrees	O
C	O
.	O

Since	O
RCC1p	B-GENE
acts	O
as	O
GNRP	B-GENE
for	O
Ran	B-GENE
,	O
a	O
small	B-GENE
nuclear	I-GENE
GTPase	I-GENE
of	O
the	O
ras	B-GENE
superfamily	I-GENE
,	O
we	O
have	O
identified	O
two	O
homologs	O
of	O
Ran	B-GENE
in	O
S	O
.	O
cerevisiae	O
(	O
CNR1	B-GENE
and	O
CNR2	B-GENE
)	O
.	O

Prostate	B-GENE
specific	I-GENE
antigen	I-GENE
shows	O
the	O
metastatic	O
cases	O
better	O
[	O
correction	O
of	O
worse	O
]	O
than	O
prostatic	B-GENE
acid	I-GENE
phosphatase	I-GENE
.	O

Of	O
these	O
carriers	O
149	O
were	O
diagnosed	O
to	O
be	O
asymptomatic	O
clinically	O
,	O
biochemically	O
and	O
echographically	O
.	O

Identification	O
of	O
mutations	O
in	O
the	O
coding	O
sequence	O
of	O
the	O
proto	B-GENE
-	I-GENE
oncogene	I-GENE
c	I-GENE
-	I-GENE
kit	I-GENE
in	O
a	O
human	O
mast	O
cell	O
leukemia	O
cell	O
line	O
causing	O
ligand	O
-	O
independent	O
activation	O
of	O
c	B-GENE
-	I-GENE
kit	I-GENE
product	I-GENE
.	O

Insulin	B-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
-	I-GENE
2	I-GENE
(	O
IGF	B-GENE
-	I-GENE
BP	I-GENE
-	I-GENE
2	I-GENE
)	O
transcription	O
in	O
rat	O
liver	O
varies	O
with	O
developmental	O
age	O
and	O
fasting	O
.	O

The	O
presence	O
of	O
the	O
RV	O
5	O
'	O
(	O
+	O
)	O
SL	O
sequence	O
had	O
the	O
primary	O
enhancing	O
effect	O
on	O
translation	O
.	O

By	O
contrast	O
,	O
all	O
proteins	O
initiated	O
with	O
a	O
methionine	O
placed	O
one	O
residue	O
upstream	O
of	O
the	O
natural	O
N	O
terminus	O
of	O
PR	B-GENE
failed	O
to	O
show	O
specific	O
proteolysis	O
.	O

Reverse	B-GENE
transcriptase	I-GENE
and	O
protease	O
activities	O
of	O
avian	O
leukosis	O
virus	O
Gag	B-GENE
-	O
Pol	B-GENE
fusion	O
proteins	O
expressed	O
in	O
insect	O
cells	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
We	O
report	O
our	O
experience	O
with	O
seven	O
children	O
with	O
active	O
small	O
bowel	O
Crohn	O
'	O
s	O
disease	O
given	O
a	O
casein	B-GENE
-	O
based	O
,	O
polymeric	O
feed	O
rich	O
in	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
2	I-GENE
(	O
Specific	O
Polymeric	O
Diet	O
;	O
Nestle	O
-	O
Clintec	O
;	O
Vevey	O
,	O
Switzerland	O
)	O
as	O
complete	O
nutrition	O
for	O
8	O
weeks	O
.	O

The	O
leader	O
sequence	O
of	O
the	O
isolated	O
cDNA	O
clone	O
contains	O
several	O
small	O
open	O
reading	O
frames	O
upstream	O
of	O
the	O
initiation	O
codon	O
of	O
the	O
largest	O
open	O
reading	O
frame	O
coding	O
for	O
the	O
homeodomain	B-GENE
protein	I-GENE
.	O

Experimental	O
adhesion	O
prophylaxis	O
with	O
recombinant	B-GENE
tissue	I-GENE
plasminogen	I-GENE
activator	I-GENE
.	O

To	O
determine	O
which	O
sequences	O
in	O
the	O
rat	B-GENE
P450c17	I-GENE
promoter	I-GENE
may	O
be	O
responsible	O
for	O
basal	O
and	O
cAMP	O
-	O
stimulated	O
gene	O
transcription	O
,	O
deletion	O
constructs	O
containing	O
between	O
-	O
1	O
,	O
560	O
and	O
-	O
53	O
base	O
pairs	O
of	O
5	O
'	O
-	O
flanking	O
DNA	O
from	O
the	O
rat	B-GENE
P450c17	I-GENE
gene	I-GENE
were	O
ligated	O
to	O
plasmids	O
expressing	O
the	O
reporter	O
gene	O
luciferase	B-GENE
and	O
transfected	O
into	O
two	O
mouse	O
cell	O
lines	O
,	O
adrenal	O
Y	O
-	O
1	O
cells	O
,	O
and	O
testicular	O
Leydig	O
MA	O
-	O
10	O
cells	O
.	O

We	O
have	O
cloned	O
and	O
sequenced	O
the	O
mouse	B-GENE
NMO1	I-GENE
cDNA	I-GENE
,	O
which	O
encodes	O
the	O
NAD	B-GENE
(	I-GENE
P	I-GENE
)	I-GENE
H	I-GENE
:	I-GENE
menadione	I-GENE
oxidoreductase	I-GENE
[	O
also	O
called	O
NAD	B-GENE
(	I-GENE
P	I-GENE
)	I-GENE
H	I-GENE
:	I-GENE
(	I-GENE
quinone	I-GENE
acceptor	I-GENE
)	I-GENE
oxidoreductase	I-GENE
;	O
quinone	B-GENE
reductase	I-GENE
;	O
azo	B-GENE
dye	I-GENE
reductase	I-GENE
;	O
DT	B-GENE
diaphorase	I-GENE
;	O
EC	B-GENE
1	I-GENE
.	I-GENE
6	I-GENE
.	I-GENE
99	I-GENE
.	I-GENE
2	I-GENE
]	O
.	O

Mutations	O
in	O
the	O
VPS45	B-GENE
gene	I-GENE
,	O
a	O
SEC1	B-GENE
homologue	O
,	O
result	O
in	O
vacuolar	O
protein	O
sorting	O
defects	O
and	O
accumulation	O
of	O
membrane	O
vesicles	O
.	O

In	O
293	O
cells	O
,	O
expression	O
of	O
the	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
inhibitor	O
,	O
I	B-GENE
kappa	I-GENE
B	I-GENE
-	I-GENE
alpha	I-GENE
,	O
reduced	O
the	O
stimulatory	O
activity	O
of	O
LMP	B-GENE
.	O

Binding	O
of	O
meAda	B-GENE
is	O
necessary	O
to	O
activate	O
transcription	O
of	O
the	O
adaptive	O
response	O
genes	O
;	O
accordingly	O
,	O
in	O
vitro	O
transcription	O
of	O
aidB	B-GENE
is	O
dependent	O
on	O
the	O
presence	O
of	O
meAda	B-GENE
.	O

No	O
significant	O
differences	O
were	O
identified	O
between	O
groups	O
for	O
pH	O
,	O
PaCO2	O
,	O
intracranial	O
pressure	O
,	O
heart	O
rate	O
,	O
brain	O
temperature	O
,	O
or	O
glucose	O
levels	O
.	O

Weak	O
allergenicity	O
of	O
recombinant	B-GENE
hirudin	I-GENE
CGP	I-GENE
39393	I-GENE
(	O
REVASC	O
)	O
in	O
immunocompetent	O
volunteers	O
.	O

Each	O
dietary	O
treatment	O
was	O
fed	O
to	O
six	O
pen	O
replicates	O
of	O
five	O
chicks	O
per	O
pen	O
for	O
21	O
d	O
.	O

The	O
NarX	B-GENE
and	O
NarQ	B-GENE
proteins	I-GENE
with	O
amino	O
acid	O
substitutions	O
at	O
the	O
first	O
conserved	O
histidine	O
position	O
were	O
also	O
unable	O
to	O
dephosphorylate	O
NarL	B-GENE
-	O
phosphate	O
in	O
vitro	O
.	O

The	O
Ng	B-GENE
/	I-GENE
RC3	I-GENE
and	O
PKC	B-GENE
-	I-GENE
gamma	I-GENE
genes	I-GENE
have	O
a	O
similar	O
expression	O
pattern	O
in	O
the	O
brain	O
during	O
development	O
.	O

Structure	O
and	O
regulation	O
of	O
the	O
gene	O
encoding	O
the	O
neuron	O
-	O
specific	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
substrate	O
neurogranin	B-GENE
(	O
RC3	B-GENE
protein	I-GENE
)	O
.	O

As	O
in	O
Tb	O
,	O
U6	B-GENE
is	O
a	O
single	O
-	O
copy	O
gene	O
and	O
two	O
tRNA	O
genes	O
,	O
tRNAGln	B-GENE
and	O
tRNAIle	B-GENE
,	O
are	O
found	O
upstream	O
to	O
the	O
gene	O
.	O

2	O
.	O

Two	O
mammalian	O
enzymes	O
,	O
the	O
haem	B-GENE
-	I-GENE
controlled	I-GENE
repressor	I-GENE
(	O
HCR	B-GENE
)	O
and	O
the	O
double	B-GENE
-	I-GENE
stranded	I-GENE
RNA	I-GENE
-	I-GENE
activated	I-GENE
inhibitor	I-GENE
(	O
dsI	B-GENE
)	O
,	O
phosphorylate	O
Ser	O
-	O
51	O
of	O
the	O
alpha	O
subunit	O
,	O
thereby	O
inhibiting	O
the	O
exchange	O
of	O
bound	O
nucleotides	O
on	O
,	O
and	O
thus	O
the	O
recycling	O
of	O
,	O
eIF	B-GENE
-	I-GENE
2	I-GENE
.	O

A	O
triple	O
Ser	O
-	O
-	O
>	O
Ala	O
mutant	O
form	O
of	O
yeast	O
eIF	B-GENE
-	I-GENE
2	I-GENE
alpha	I-GENE
was	O
found	O
to	O
be	O
no	O
longer	O
phosphorylated	O
by	O
either	O
of	O
the	O
yeast	O
(	O
or	O
mammalian	O
)	O
casein	B-GENE
kinase	I-GENE
activities	O
in	O
vitro	O
.	O

Binding	O
activity	O
in	O
rat	O
liver	O
nuclear	O
extracts	O
includes	O
these	O
orphan	O
receptors	O
as	O
judged	O
from	O
electromobility	O
supershift	O
experiments	O
and	O
from	O
results	O
obtained	O
with	O
expressed	O
receptors	O
,	O
although	O
the	O
element	O
in	O
CYP2C11	B-GENE
did	O
not	O
bind	O
HNF	B-GENE
-	I-GENE
4	I-GENE
.	O

Transcript	O
analysis	O
reveals	O
that	O
lethal	O
B	B-GENE
block	I-GENE
substitutions	O
reduce	O
U6	B-GENE
RNA	I-GENE
synthesis	O
at	O
least	O
10	O
-	O
fold	O
in	O
vivo	O
and	O
20	O
-	O
fold	O
in	O
vitro	O
.	O

Lung	O
function	O
tests	O
(	O
EFR	O
)	O
were	O
performed	O
on	O
these	O
patients	O
for	O
a	O
period	O
of	O
19	O
.	O
2	O
+	O
/	O
-	O
3	O
.	O
4	O
months	O
.	O

Staphylococcus	O
aureus	O
and	O
CNS	O
showed	O
high	O
or	O
moderate	O
resistance	O
rates	O
to	O
methicillin	O
(	O
DMPPC	O
)	O
.	O

Hybridization	O
signals	O
were	O
also	O
detected	O
with	O
total	O
DNAs	O
of	O
Rhizobium	O
leguminosarum	O
bv	O
.	O
phaseoli	O
,	O
Rhodobacter	O
capsulatus	O
and	O
Escherichia	O
coli	O
,	O
but	O
not	O
those	O
of	O
Xanthomonas	O
campestris	O
pv	O
.	O
campestris	O
and	O
Pseudomonas	O
putida	O
.	O

Serum	O
induction	O
of	O
a	O
MEF2	B-GENE
reporter	I-GENE
gene	I-GENE
was	O
not	O
observed	O
in	O
a	O
line	O
of	O
NIH	O
3T3	O
cells	O
which	O
contain	O
low	O
MEF2	B-GENE
site	I-GENE
binding	O
activity	O
.	O

Since	O
AP	B-GENE
-	I-GENE
1	I-GENE
is	O
an	O
important	O
mediator	O
of	O
tumor	O
promoter	O
action	O
,	O
these	O
findings	O
may	O
explain	O
the	O
anti	O
-	O
tumor	O
-	O
promoting	O
activity	O
of	O
phenolic	O
antioxidants	O
.	O

The	O
second	O
complex	O
,	O
when	O
purified	O
,	O
contained	O
four	O
protein	O
components	O
including	O
the	O
36	O
-	O
kDa	O
protein	O
.	O

The	O
study	O
was	O
repeated	O
after	O
administration	O
of	O
oral	O
amiodarone	O
,	O
50	O
mg	O
/	O
kg	O
/	O
day	O
for	O
2	O
days	O
in	O
8	O
divided	O
doses	O
(	O
mean	O
dose	O
6	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
4	O
g	O
)	O
.	O

The	O
other	O
two	O
clones	O
,	O
Ash	B-GENE
-	I-GENE
m	I-GENE
and	I-GENE
-	I-GENE
s	I-GENE
,	O
had	O
nucleotide	O
sequences	O
identical	O
with	O
Ash	B-GENE
-	I-GENE
l	I-GENE
cDNA	O
in	O
the	O
amino	O
-	O
terminal	O
region	O
.	O

MATERIAL	O
AND	O
METHODS	O
:	O
Of	O
the	O
17	O
men	O
and	O
17	O
women	O
,	O
who	O
were	O
21	O
to	O
80	O
years	O
of	O
age	O
,	O
27	O
had	O
hereditary	O
motor	O
and	O
sensory	O
neuropathy	O
type	O
I	O
and	O
7	O
had	O
acquired	O
demyelinating	O
polyneuropathy	O
.	O

Muscle	B-GENE
GSH	I-GENE
-	I-GENE
Px	I-GENE
activity	O
after	O
prolonged	O
exercise	O
,	O
training	O
,	O
and	O
selenium	O
supplementation	O
.	O

We	O
found	O
that	O
PML	B-GENE
was	O
expressed	O
at	O
a	O
lower	O
level	O
in	O
S	O
,	O
G2	O
,	O
and	O
M	O
phases	O
and	O
at	O
a	O
significantly	O
higher	O
level	O
in	O
G1	O
phase	O
.	O

The	O
roxithromycin	O
doses	O
that	O
were	O
chosen	O
for	O
these	O
studies	O
were	O
less	O
than	O
achievable	O
blood	O
levels	O
.	O

We	O
demonstrate	O
here	O
that	O
the	O
-	O
DEDDDL	O
sequence	O
stabilizes	O
GDP	O
binding	O
to	O
Ran	B-GENE
,	O
and	O
that	O
the	O
domain	O
is	O
required	O
for	O
high	O
affinity	O
interaction	O
with	O
a	O
Ran	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
,	O
HTF9A	B-GENE
/	O
RanBP1	B-GENE
.	O

Serial	O
followup	O
strength	O
data	O
for	O
2	O
patients	O
were	O
compared	O
to	O
change	O
in	O
creatinine	B-GENE
kinase	I-GENE
(	O
CK	B-GENE
)	O
levels	O
.	O

Transfection	O
of	O
non	O
-	O
deleted	O
expression	O
vector	O
into	O
NIH3T3	O
cells	O
results	O
in	O
acquisition	O
of	O
focus	O
-	O
forming	O
activity	O
while	O
a	O
deleted	O
form	O
of	O
expression	O
vector	O
fails	O
to	O
show	O
this	O
activity	O
even	O
in	O
the	O
presence	O
of	O
basic	B-GENE
FGF	I-GENE
.	O

All	O
ribosomal	B-GENE
protein	I-GENE
(	O
rp	B-GENE
)	O
gene	O
promoters	O
from	O
Saccharomyces	O
cerevisiae	O
studied	O
so	O
far	O
contain	O
either	O
(	O
usually	O
two	O
)	O
binding	O
sites	O
for	O
the	O
global	O
gene	O
regulator	O
Rap1p	B-GENE
or	O
one	O
binding	O
site	O
for	O
another	O
global	O
factor	O
,	O
Abf1p	B-GENE
.	O

CONCLUSION	O
:	O
The	O
MTD	O
for	O
CPT	O
-	O
11	O
administered	O
in	O
a	O
3	O
consecutive	O
-	O
days	O
-	O
every	O
-	O
3	O
weeks	O
schedule	O
in	O
this	O
patient	O
population	O
is	O
115	O
mg	O
/	O
m2	O
/	O
day	O
.	O

Otte	O
,	O
Mol	O
.	O

A	O
secondary	O
phosphorylation	O
of	O
CREB341	B-GENE
at	O
Ser129	O
is	O
required	O
for	O
the	O
cAMP	O
-	O
mediated	O
control	O
of	O
gene	O
expression	O
.	O

A	O
role	O
for	O
glycogen	B-GENE
synthase	I-GENE
kinase	I-GENE
-	I-GENE
3	I-GENE
in	O
the	O
control	O
of	O
gene	O
expression	O
.	O

Reconstitution	O
of	O
complexes	O
containing	O
p62	B-GENE
and	O
the	O
src	B-GENE
family	I-GENE
kinase	I-GENE
p59fyn	B-GENE
in	O
HeLa	O
cells	O
demonstrated	O
that	O
complex	O
formation	O
resulted	O
in	O
tyrosine	O
phosphorylation	O
of	O
p62	B-GENE
and	O
was	O
mediated	O
by	O
both	O
the	O
SH3	B-GENE
and	O
SH2	B-GENE
domains	I-GENE
of	O
p59fyn	B-GENE
.	O

Protein	B-GENE
cHMGI	I-GENE
binds	O
preferentially	O
to	O
AT	O
-	O
rich	O
DNA	O
with	O
a	O
half	O
-	O
saturation	O
value	O
of	O
1	O
.	O
1	O
nM	O
.	O

The	O
U14	B-GENE
genes	I-GENE
of	O
mouse	O
as	O
well	O
as	O
rat	O
,	O
hamster	O
,	O
human	O
,	O
Xenopus	O
and	O
trout	O
are	O
encoded	O
within	O
introns	O
of	O
the	O
constitutively	O
expressed	O
70	B-GENE
-	I-GENE
kDa	I-GENE
-	I-GENE
cognate	I-GENE
-	I-GENE
heat	I-GENE
-	I-GENE
shock	I-GENE
protein	I-GENE
gene	I-GENE
(	O
hsc70	B-GENE
)	O
.	O

Inclusion	O
in	O
this	O
family	O
of	O
proteins	O
suggests	O
that	O
FliQ	B-GENE
and	O
FliR	B-GENE
may	O
participate	O
in	O
an	O
export	O
pathway	O
required	O
for	O
flagellum	O
assembly	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

Atcys1	B-GENE
,	O
Athyp1	B-GENE
,	O
AKin10	B-GENE
and	O
the	O
ORF	O
are	O
very	O
close	O
to	O
each	O
other	O
and	O
organized	O
in	O
the	O
same	O
polarity	O
;	O
hence	O
,	O
the	O
intergenic	O
regions	O
probably	O
contain	O
,	O
within	O
less	O
than	O
0	O
.	O
5	O
kb	O
,	O
all	O
the	O
regulatory	O
elements	O
necessary	O
to	O
govern	O
initiation	O
and	O
termination	O
of	O
transcription	O
.	O

Southern	O
blot	O
hybridization	O
experiments	O
suggest	O
the	O
presence	O
of	O
one	O
copy	O
of	O
Atcys1	B-GENE
,	O
Athyp1	B-GENE
and	O
AKin10	B-GENE
per	O
haploid	O
genome	O
,	O
and	O
Northern	O
blot	O
analysis	O
demonstrates	O
that	O
the	O
three	O
genes	O
are	O
differentially	O
expressed	O
in	O
roots	O
,	O
shoots	O
and	O
leaves	O
.	O

Between	O
the	O
subgroups	O
of	O
dementia	O
disorders	O
there	O
were	O
no	O
significant	O
differences	O
in	O
basal	O
cortisol	O
levels	O
.	O

Basal	O
components	O
of	O
the	O
transcription	O
apparatus	O
(	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
,	O
TATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
)	O
contain	O
activation	O
domains	O
:	O
is	O
the	O
repetitive	O
C	O
-	O
terminal	O
domain	O
(	O
CTD	O
)	O
of	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
a	O
"	O
portable	O
enhancer	O
domain	O
"	O
?	O
Regions	O
rich	O
in	O
serine	O
,	O
threonine	O
,	O
and	O
proline	O
residues	O
can	O
be	O
found	O
in	O
transcriptional	O
activation	O
domains	O
,	O
as	O
well	O
as	O
in	O
the	O
N	O
-	O
terminal	O
parts	O
of	O
mammalian	B-GENE
TATA	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
,	O
where	O
they	O
are	O
interrupted	O
by	O
polyglutamine	O
stretches	O
.	O

Mutagenesis	O
of	O
IM1	B-GENE
enhances	O
the	O
ability	O
of	O
c	B-GENE
-	I-GENE
Fos	I-GENE
to	O
activate	O
an	O
AP1	B-GENE
bearing	I-GENE
promoter	I-GENE
.	O

Self	O
or	O
foreign	O
cellular	O
proteins	O
provide	O
peptides	O
for	O
presentation	O
by	O
major	B-GENE
histocompatibility	I-GENE
complex	I-GENE
(	I-GENE
MHC	I-GENE
)	I-GENE
class	I-GENE
I	I-GENE
molecules	I-GENE
on	O
the	O
surface	O
of	O
antigen	O
presenting	O
cells	O
(	O
APC	O
)	O
.	O

However	O
,	O
cotransfection	O
studies	O
indicate	O
that	O
RVR	B-GENE
does	O
not	O
activate	O
transcription	O
when	O
this	O
hormone	O
response	O
element	O
is	O
linked	O
to	O
a	O
reporter	O
gene	O
but	O
rather	O
acts	O
as	O
a	O
potent	O
competitive	O
repressor	O
of	O
ROR	B-GENE
alpha	I-GENE
function	O
.	O

Molecular	O
cloning	O
and	O
sequencing	O
of	O
a	O
cDNA	O
encoding	O
SR	B-GENE
beta	I-GENE
revealed	O
that	O
SR	B-GENE
beta	I-GENE
is	O
a	O
transmembrane	O
protein	O
and	O
,	O
like	O
SR	B-GENE
alpha	I-GENE
and	O
SRP54	B-GENE
,	O
is	O
a	O
member	O
of	O
the	O
GTPase	B-GENE
superfamily	I-GENE
.	O

To	O
understand	O
the	O
function	O
of	O
receptor	B-GENE
-	I-GENE
linked	I-GENE
tyrosine	I-GENE
phosphatases	I-GENE
in	O
neural	O
development	O
,	O
we	O
sought	O
to	O
identify	O
LAR	B-GENE
isoforms	I-GENE
preferentially	O
expressed	O
in	O
the	O
nervous	O
system	O
and	O
cellular	O
processes	O
regulating	O
LAR	B-GENE
alternative	O
splicing	O
.	O

135	O
students	O
had	O
a	O
count	O
of	O
less	O
than	O
50	O
eggs	O
/	O
10	O
ml	O
.	O
urine	O
and	O
56	O
had	O
more	O
than	O
50	O
eggs	O
/	O
10ml	O
.	O

Chrispeels	O
[	O
1993	O
]	O
EMBO	O
J	O
12	O
:	O
2241	O
-	O
2247	O
)	O
.	O

The	O
mRNAs	O
of	O
the	O
GRF	B-GENE
genes	I-GENE
are	O
encoded	O
by	O
six	O
exons	O
interrupted	O
by	O
five	O
introns	O
.	O

A	O
major	O
task	O
for	O
sports	O
scientists	O
may	O
be	O
to	O
verify	O
empirically	O
the	O
nature	O
of	O
an	O
integrated	O
model	O
of	O
the	O
sport	O
performer	O
.	O

Removal	O
of	O
the	O
GST	B-GENE
domain	I-GENE
from	O
GST	B-GENE
-	O
Tax	B-GENE
by	O
thrombin	B-GENE
restores	O
Tax	B-GENE
'	O
s	O
ability	O
to	O
assemble	O
a	O
ternary	O
Tax	B-GENE
-	O
CREB	B-GENE
-	O
21	O
-	O
bp	O
-	O
repeat	O
complex	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Specific	O
binding	O
was	O
not	O
observed	O
with	O
either	O
the	O
orthologous	O
rat	O
or	O
mouse	O
fragments	O
using	O
human	O
or	O
rodent	O
extracts	O
.	O

We	O
have	O
attempted	O
to	O
clone	O
two	O
recessive	O
extragenic	O
suppressors	O
of	O
such	O
ts	O
mutants	O
(	O
sdp1	B-GENE
for	O
mutation	B-GENE
pol3	I-GENE
-	I-GENE
14	I-GENE
and	O
sdp5	B-GENE
-	I-GENE
1	I-GENE
for	O
mutation	B-GENE
pol3	I-GENE
-	I-GENE
11	I-GENE
)	O
by	O
transforming	O
thermoresistant	O
haploid	O
strains	O
pol3	B-GENE
-	I-GENE
14	I-GENE
sdp1	I-GENE
and	O
pol3	B-GENE
-	I-GENE
11	I-GENE
sdp5	I-GENE
-	I-GENE
1	I-GENE
with	O
wild	O
-	O
type	O
genomic	O
libraries	O
in	O
singlecopy	O
or	O
multicopy	O
vectors	O
.	O

In	O
acute	O
-	O
phase	O
livers	O
,	O
we	O
observed	O
a	O
dramatic	O
reduction	O
in	O
HNF	B-GENE
-	I-GENE
3	I-GENE
alpha	I-GENE
expression	O
which	O
correlates	O
with	O
a	O
decrease	O
in	O
the	O
expression	O
of	O
its	O
target	O
gene	O
,	O
the	O
TTR	B-GENE
gene	I-GENE
.	O

Similarly	O
,	O
in	O
mammalian	O
cells	O
PBP74	B-GENE
is	O
synthesized	O
as	O
a	O
pre	O
-	O
protein	O
that	O
requires	O
membrane	O
potential	O
-	O
dependent	O
import	O
into	O
mitochondria	O
for	O
its	O
maturation	O
.	O

The	O
first	O
open	O
reading	O
frame	O
of	O
the	O
blueberry	O
scorch	O
carlavirus	O
(	O
BBScV	O
)	O
genome	O
encodes	O
a	O
putative	O
replication	O
-	O
associated	O
protein	O
of	O
223	O
kDa	O
(	O
p223	B-GENE
)	O
.	O

From	O
sequence	O
alignments	O
with	O
phylogenetically	O
related	O
viruses	O
,	O
including	O
tymoviruses	O
,	O
we	O
predicted	O
that	O
p223	B-GENE
contained	O
a	O
papain	B-GENE
-	I-GENE
like	I-GENE
proteinase	I-GENE
domain	I-GENE
with	O
a	O
putative	O
catalytic	O
cysteine994	O
and	O
histidine1075	O
.	O

The	O
p97	B-GENE
-	O
depleted	O
nuclei	O
remained	O
largely	O
competent	O
for	O
nuclear	O
protein	O
import	O
.	O

Using	O
gel	O
retardation	O
assays	O
with	O
HepG2	O
nuclear	O
extract	O
,	O
we	O
demonstrated	O
the	O
presence	O
of	O
a	O
specific	O
protein	O
which	O
bound	O
to	O
the	O
NRE	O
fragment	O
.	O

Twenty	O
-	O
two	O
consecutive	O
patients	O
with	O
ischaemic	O
ulcers	O
had	O
tcPO2	O
measured	O
and	O
the	O
ankle	O
/	O
brachial	O
(	O
ABI	O
)	O
and	O
toe	O
/	O
brachial	O
(	O
TBI	O
)	O
indices	O
calculated	O
.	O

TcPO2	O
measurement	O
appears	O
to	O
be	O
a	O
reliable	O
technique	O
that	O
can	O
influence	O
ischaemic	O
ulcer	O
management	O
.	O

Expression	O
of	O
h6	O
.	O
1	O
in	O
COS	O
-	O
1	O
cells	O
led	O
to	O
the	O
production	O
of	O
a	O
typical	O
type	B-GENE
IV	I-GENE
PDE	I-GENE
activity	O
in	O
that	O
cAMP	O
,	O
but	O
not	O
cGMP	O
,	O
served	O
as	O
substrate	O
and	O
its	O
activity	O
was	O
insensitive	O
to	O
either	O
Ca2	O
+	O
/	O
CaM	B-GENE
or	O
cGMP	O
but	O
was	O
inhibited	O
by	O
low	O
concentrations	O
of	O
rolipram	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

The	O
PSD2	B-GENE
gene	I-GENE
was	O
heterologously	O
expressed	O
by	O
infection	O
of	O
Sf	O
-	O
9	O
insect	O
cells	O
with	O
recombinant	O
baculovirus	O
,	O
resulting	O
in	O
a	O
10	O
-	O
fold	O
increase	O
in	O
PSD	B-GENE
activity	O
.	O

Like	O
Epo	B-GENE
,	O
HNF	B-GENE
-	I-GENE
4	I-GENE
is	O
expressed	O
in	O
kidney	O
,	O
liver	O
,	O
and	O
Hep3B	O
cells	O
but	O
not	O
in	O
HeLa	O
cells	O
.	O

Moreover	O
,	O
the	O
hypoxia	O
-	O
induced	O
expression	O
of	O
the	O
endogenous	O
Epo	B-GENE
gene	I-GENE
was	O
significantly	O
inhibited	O
in	O
Hep3B	O
cells	O
stably	O
transfected	O
with	O
HNF	B-GENE
-	I-GENE
4	I-GENE
delta	I-GENE
C	I-GENE
.	O

These	O
observations	O
indicate	O
that	O
there	O
are	O
multiple	O
mechanisms	O
by	O
which	O
an	O
individual	O
transcript	O
can	O
be	O
degraded	O
following	O
deadenylation	O
.	O

Small	B-GENE
Maf	I-GENE
proteins	I-GENE
heterodimerize	O
with	O
Fos	B-GENE
and	O
may	O
act	O
as	O
competitive	O
repressors	O
of	O
the	O
NF	B-GENE
-	I-GENE
E2	I-GENE
transcription	I-GENE
factor	I-GENE
.	O

Both	O
factors	O
demonstrated	O
significant	O
correlations	O
with	O
rCBF	O
in	O
the	O
medial	O
prefrontal	O
cortex	O
and	O
frontal	O
polar	O
cortex	O
while	O
for	O
each	O
factor	O
there	O
were	O
also	O
unique	O
patterns	O
of	O
correlations	O
with	O
posterior	O
brain	O
regions	O
.	O

The	O
resulting	O
integrated	O
physical	O
,	O
genetic	O
,	O
and	O
cytogenetic	O
map	O
constitutes	O
a	O
resource	O
for	O
the	O
characterization	O
of	O
genes	O
that	O
may	O
be	O
involved	O
in	O
the	O
WAGR	O
syndrome	O
.	O

Three	O
classes	O
of	O
test	O
objects	O
were	O
considered	O
:	O
(	O
1	O
)	O
a	O
multicompartment	O
test	O
object	O
for	O
31P	O
MRS	O
measurements	O
performed	O
with	O
slice	O
-	O
selective	O
sequences	O
;	O
(	O
2	O
)	O
a	O
two	O
-	O
compartment	O
test	O
object	O
for	O
volume	O
-	O
selection	O
1H	O
MRS	O
;	O
and	O
(	O
3	O
)	O
two	O
-	O
compartment	O
test	O
objects	O
for	O
assessing	O
the	O
performance	O
of	O
experimental	O
systems	O
using	O
ISIS	O
as	O
volume	O
localization	O
sequence	O
in	O
31P	O
MRS	O
.	O

Pregnancy	O
screening	O
by	O
uterine	O
artery	O
Doppler	O
velocimetry	O
-	O
-	O
which	O
criterion	O
performs	O
best	O
?	O
OBJECTIVE	O
:	O
To	O
test	O
whether	O
repeating	O
Doppler	O
studies	O
of	O
the	O
uteroplacental	O
circulation	O
late	O
in	O
gestation	O
will	O
improve	O
the	O
test	O
'	O
s	O
power	O
for	O
predicting	O
pregnancy	O
-	O
induced	O
hypertension	O
and	O
fetal	O
growth	O
restriction	O
(	O
FGR	O
)	O
,	O
and	O
whether	O
analysis	O
based	O
on	O
a	O
combination	O
of	O
quantitative	O
and	O
qualitative	O
assessments	O
of	O
the	O
uterine	O
arterial	O
waveforms	O
will	O
yield	O
better	O
results	O
than	O
analysis	O
based	O
on	O
either	O
alone	O
.	O

Analysis	O
of	O
disassociation	O
rates	O
indicates	O
that	O
the	O
Grf10	B-GENE
-	O
Swi5	B-GENE
-	O
DNA	O
complex	O
has	O
a	O
longer	O
half	O
-	O
life	O
than	O
protein	O
-	O
DNA	O
complexes	O
that	O
contain	O
only	O
Swi5	B-GENE
or	O
Grf10	B-GENE
.	O

The	O
mutant	O
allele	O
of	O
the	O
alpha	B-GENE
1	I-GENE
-	I-GENE
tubulin	I-GENE
gene	I-GENE
was	O
designated	O
tua1	B-GENE
-	I-GENE
1	I-GENE
.	O

Analysis	O
of	O
a	O
set	O
of	O
deletion	O
constructs	O
in	O
transient	O
transfection	O
assays	O
measuring	O
heterologous	O
reporter	O
gene	O
(	O
luciferase	B-GENE
)	O
activity	O
demonstrated	O
that	O
the	O
182	O
-	O
bp	O
5	O
'	O
-	O
flanking	O
region	O
provides	O
full	O
promoter	O
activity	O
in	O
IL	B-GENE
-	I-GENE
2	I-GENE
-	O
stimulated	O
L2	O
cells	O
.	O

Northern	O
analysis	O
of	O
RNA	O
samples	O
isolated	O
from	O
ammonium	O
-	O
grown	O
cultures	O
of	O
the	O
ntcA	B-GENE
mutant	I-GENE
showed	O
reduced	O
amounts	O
of	O
glnA	B-GENE
message	I-GENE
and	O
the	O
absence	O
of	O
a	O
1	O
.	O
7	O
-	O
kb	O
transcript	O
.	O

In	O
order	O
to	O
define	O
potential	O
candidate	O
genes	O
for	O
inherited	O
disorders	O
characterized	O
by	O
aberrant	O
gene	O
expression	O
,	O
we	O
utilized	O
Kruppel	B-GENE
-	I-GENE
related	I-GENE
sequences	I-GENE
to	O
isolate	O
zinc	O
finger	O
-	O
containing	O
cDNAs	O
.	O

The	O
isolated	O
POT1	B-GENE
clones	O
hybridized	O
to	O
a	O
1	O
.	O
4	O
kb	O
RNA	O
species	O
,	O
which	O
was	O
induced	O
approximately	O
30	O
-	O
fold	O
when	O
oleate	O
was	O
the	O
carbon	O
source	O
.	O

The	O
Y	O
.	O
lipolytica	O
genomic	O
POT1	B-GENE
gene	O
was	O
disrupted	O
by	O
replacing	O
120	O
bp	O
of	O
its	O
coding	O
sequence	O
with	O
2	O
.	O
7	O
kbp	O
of	O
DNA	O
including	O
the	O
Y	O
.	O
lipolytica	O
LEU2	B-GENE
gene	I-GENE
.	O

The	O
novel	O
Notch	B-GENE
homologue	I-GENE
mouse	B-GENE
Notch	I-GENE
3	I-GENE
lacks	O
specific	O
epidermal	B-GENE
growth	I-GENE
factor	I-GENE
-	I-GENE
repeats	I-GENE
and	O
is	O
expressed	O
in	O
proliferating	O
neuroepithelium	O
.	O

Immunoreactive	O
AR	B-GENE
content	O
in	O
transfected	O
COS	O
-	O
1	O
cells	O
was	O
not	O
influenced	O
by	O
exposure	O
to	O
8	O
-	O
Br	O
-	O
cAMP	O
.	O

Internal	O
biliary	O
drainage	O
,	O
unlike	O
external	O
drainage	O
,	O
does	O
not	O
suppress	O
the	O
regeneration	O
of	O
cholestatic	O
rat	O
liver	O
after	O
partial	O
hepatectomy	O
.	O

ORF	O
2	O
potentially	O
encoded	O
a	O
hydrophobic	O
protein	O
of	O
29	O
,	O
705	O
Da	O
with	O
six	O
potential	O
membrane	O
-	O
spanning	O
regions	O
.	O

Plasmids	O
were	O
constructed	O
with	O
the	O
mouse	O
promoter	O
region	O
linked	O
to	O
the	O
reporter	B-GENE
gene	I-GENE
chloramphenicol	I-GENE
acetyltransferase	I-GENE
(	O
CAT	B-GENE
)	O
,	O
and	O
transiently	O
and	O
stably	O
transfected	O
in	O
the	O
INS	O
-	O
1	O
cells	O
.	O

Specifically	O
,	O
this	O
study	O
determined	O
the	O
influence	O
of	O
:	O
(	O
1	O
)	O
an	O
awareness	O
strategy	O
,	O
(	O
2	O
)	O
a	O
non	O
-	O
awareness	O
strategy	O
,	O
(	O
3	O
)	O
a	O
Five	O
-	O
Step	O
Approach	O
strategy	O
and	O
(	O
4	O
)	O
a	O
control	O
condition	O
.	O

Mutually	O
exclusive	O
interaction	O
of	O
the	O
adenovirus	B-GENE
E4	I-GENE
-	I-GENE
6	I-GENE
/	I-GENE
7	I-GENE
protein	I-GENE
and	O
the	O
retinoblastoma	B-GENE
gene	I-GENE
product	I-GENE
with	O
internal	O
domains	O
of	O
E2F	B-GENE
-	I-GENE
1	I-GENE
and	O
DP	B-GENE
-	I-GENE
1	I-GENE
.	O

The	O
transverse	O
magnetization	O
decays	O
mentioned	O
above	O
exhibited	O
two	O
components	O
,	O
a	O
T2	O
fast	O
(	O
T2f	O
)	O
and	O
a	O
T2	O
slow	O
(	O
T2s	O
)	O
component	O
.	O

Expression	O
of	O
a	O
dominant	B-GENE
-	I-GENE
negative	I-GENE
ras	I-GENE
gene	I-GENE
also	O
blocks	O
TIS10	B-GENE
/	O
PGS2	B-GENE
induction	O
by	O
v	B-GENE
-	I-GENE
src	I-GENE
.	O

Human	O
T	O
-	O
cell	O
leukemia	O
virus	O
type	O
I	O
Tax	B-GENE
activation	O
of	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
/	O
Rel	B-GENE
involves	O
phosphorylation	O
and	O
degradation	O
of	O
I	B-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
and	O
RelA	B-GENE
(	I-GENE
p65	I-GENE
)	I-GENE
-	O
mediated	O
induction	O
of	O
the	O
c	B-GENE
-	I-GENE
rel	I-GENE
gene	I-GENE
.	O

These	O
RZR	B-GENE
subtypes	O
represent	O
members	O
of	O
a	O
new	O
family	O
of	O
orphan	B-GENE
nuclear	I-GENE
receptors	I-GENE
that	O
most	O
likely	O
regulate	O
specific	O
gene	O
expression	O
.	O

Interestingly	O
,	O
these	O
response	O
elements	O
display	O
dramatically	O
reduced	O
affinity	O
for	O
retinoic	B-GENE
acid	I-GENE
receptor	I-GENE
-	O
retinoid	B-GENE
-	I-GENE
X	I-GENE
receptor	I-GENE
heterodimers	O
.	O

Remarkably	O
,	O
U21	B-GENE
contains	O
a	O
long	O
stretch	O
(	O
13	O
nt	O
.	O
)	O
of	O
complementarity	O
to	O
a	O
highly	O
conserved	O
sequence	O
in	O
28S	B-GENE
rRNA	I-GENE
.	O

These	O
results	O
provide	O
evidence	O
of	O
a	O
bypass	O
of	O
p53	B-GENE
-	O
induced	O
Waf1	B-GENE
/	O
Cip1	B-GENE
-	O
mediated	O
cell	O
cycle	O
regulatory	O
pathways	O
by	O
a	O
member	O
of	O
the	O
myb	B-GENE
oncogene	I-GENE
family	I-GENE
.	O

All	O
groups	O
were	O
challenged	O
subsequently	O
with	O
naloxone	O
(	O
0	O
.	O
4	O
mg	O
/	O
kg	O
)	O
in	O
the	O
distinctive	O
environment	O
and	O
then	O
observed	O
for	O
signs	O
of	O
opiate	O
withdrawal	O
.	O

There	O
were	O
9	O
patients	O
in	O
NYHA	O
class	O
III	O
and	O
8	O
in	O
class	O
IV	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

TG	O
-	O
day	O
and	O
TG	O
-	O
night	O
were	O
19	O
.	O
4	O
+	O
/	O
-	O
6	O
.	O
1	O
%	O
,	O
26	O
.	O
6	O
+	O
/	O
-	O
5	O
.	O
3	O
%	O
,	O
(	O
750	O
mm3	O
<	O
T	O
.	O

Ten	O
volunteers	O
were	O
tested	O
at	O
18	O
,	O
000	O
ft	O
(	O
5	O
,	O
486	O
m	O
)	O
,	O
and	O
through	O
12	O
,	O
000	O
,	O
8	O
,	O
000	O
,	O
and	O
5	O
,	O
000	O
ft	O
(	O
3	O
,	O
657	O
,	O
2	O
,	O
438	O
,	O
and	O
1	O
,	O
524	O
m	O
)	O
with	O
directional	O
sounds	O
recorded	O
via	O
a	O
dummy	O
head	O
microphone	O
and	O
presented	O
binaurally	O
.	O

Upon	O
differentiation	O
with	O
retinoic	O
acid	O
(	O
RA	O
)	O
,	O
transcription	O
of	O
the	O
Rex	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
decreases	O
rapidly	O
.	O

In	O
general	O
,	O
the	O
filtration	O
rate	O
in	O
relevant	O
areas	O
appears	O
to	O
be	O
an	O
integrative	O
and	O
easily	O
determined	O
parameter	O
,	O
reflecting	O
hormonal	O
and	O
neurogenic	O
vascular	O
as	O
well	O
as	O
local	O
interstitial	O
control	O
of	O
the	O
Starling	O
forces	O
.	O

Homozygous	O
null	O
embryos	O
also	O
displayed	O
abnormalities	O
in	O
heart	O
development	O
,	O
consistent	O
with	O
the	O
conclusion	O
that	O
Tek	B-GENE
is	O
necessary	O
for	O
endocardial	O
/	O
myocardial	O
interactions	O
during	O
development	O
.	O

A	O
strong	O
trithorax	B-GENE
binding	I-GENE
site	I-GENE
was	O
found	O
at	O
the	O
cytological	O
location	O
of	O
the	O
fork	B-GENE
head	I-GENE
gene	I-GENE
,	O
a	O
region	O
-	O
specific	O
homeotic	B-GENE
gene	I-GENE
not	O
located	O
within	O
a	O
homeotic	B-GENE
complex	I-GENE
.	O

C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
also	O
activates	O
the	O
promoter	O
of	O
the	O
rat	B-GENE
class	I-GENE
-	I-GENE
I	I-GENE
ADH	I-GENE
gene	I-GENE
in	O
a	O
sequence	O
-	O
specific	O
manner	O
[	O
Potter	O
et	O
al	O
.	O
,	O
Arch	O
.	O

C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
also	O
activates	O
the	O
promoter	O
of	O
the	O
rat	B-GENE
class	I-GENE
-	I-GENE
I	I-GENE
ADH	I-GENE
gene	I-GENE
in	O
a	O
sequence	O
-	O
specific	O
manner	O
[	O
Potter	O
et	O
al	O
.	O
,	O
Arch	O
.	O

Segments	O
with	O
more	O
reduced	O
BMIPP	O
uptake	O
than	O
MIBI	O
uptake	O
(	O
mismatching	O
)	O
showed	O
either	O
normal	O
wall	O
motion	O
or	O
demonstrated	O
inotropic	O
reserve	O
during	O
dobutamine	O
stimulation	O
.	O

The	O
present	O
data	O
also	O
indicate	O
that	O
patients	O
with	O
TGBM	O
nephropathy	O
often	O
have	O
concomitant	O
IgA	B-GENE
nephropathy	O
and	O
mesangial	O
proliferative	O
glomerulonephritis	O
.	O

A	O
full	O
-	O
length	O
cDNA	O
clone	O
isolated	O
from	O
a	O
rat	O
lung	O
library	O
was	O
predicted	O
to	O
encode	O
a	O
55	O
-	O
kDa	O
protein	O
containing	O
at	O
its	O
amino	O
terminus	O
a	O
targeting	O
domain	O
that	O
binds	O
to	O
the	O
ANP	B-GENE
-	I-GENE
receptor	I-GENE
kinase	I-GENE
-	I-GENE
like	I-GENE
domain	I-GENE
and	O
containing	O
at	O
its	O
carboxyl	O
terminus	O
a	O
putative	O
protein	B-GENE
-	I-GENE
serine	I-GENE
phosphatase	I-GENE
domain	O
.	O

A	O
high	O
-	O
resolution	O
restriction	O
map	O
of	O
over	O
200	O
kb	O
of	O
contiguous	O
DNA	O
containing	O
N	B-GENE
-	I-GENE
myc	I-GENE
has	O
been	O
generated	O
by	O
subcloning	O
YACs	O
into	O
cosmids	O
.	O

In	O
the	O
present	O
article	O
,	O
the	O
causes	O
of	O
death	O
or	O
ill	O
-	O
being	O
as	O
found	O
in	O
10	O
consecutive	O
carcinogenicity	O
studies	O
-	O
-	O
5	O
studies	O
with	O
2400	O
OFA	O
(	O
Sprague	O
-	O
Dawley	O
-	O
derived	O
)	O
and	O
Wistar	O
rats	O
and	O
5	O
studies	O
with	O
2400	O
OF1	O
and	O
NMRI	O
mice	O
-	O
-	O
were	O
re	O
-	O
examined	O
.	O

Surprisingly	O
,	O
Northern	O
(	O
RNA	O
)	O
blot	O
analysis	O
and	O
reverse	B-GENE
transcriptase	I-GENE
-	O
PCRs	O
performed	O
after	O
transfection	O
of	O
COS	O
-	O
7	O
or	O
HeLa	O
cells	O
with	O
these	O
viral	O
RNAs	O
revealed	O
that	O
Y88S	B-GENE
and	O
Y88L	B-GENE
RNAs	I-GENE
replicated	O
at	O
only	O
very	O
low	O
levels	O
.	O

Moreover	O
,	O
the	O
ability	O
to	O
selectivity	O
arrest	O
elongation	O
by	O
polIII	B-GENE
at	O
defined	O
positions	O
within	O
the	O
tRNA	O
gene	O
transcription	O
unit	O
has	O
permitted	O
the	O
identification	O
of	O
discrete	O
functional	O
properties	O
of	O
paused	O
mammalian	B-GENE
polIII	I-GENE
ternary	I-GENE
complexes	I-GENE
.	O

A	O
recent	O
index	O
(	O
Fluorosis	O
Risk	O
Index	O
)	O
developed	O
by	O
Pendrys	O
(	O
1990	O
)	O
is	O
also	O
included	O
in	O
this	O
review	O
.	O

The	O
role	O
of	O
HIV	B-GENE
tat	I-GENE
,	O
which	O
is	O
the	O
main	O
enhancing	O
factor	O
for	O
viral	B-GENE
LTR	I-GENE
,	O
in	O
the	O
regulation	O
of	O
IL	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
transcription	O
has	O
been	O
studied	O
following	O
transient	O
expression	O
of	O
the	O
tat	B-GENE
gene	I-GENE
in	O
phorbol	O
ester	O
and	O
calcium	O
ionophore	O
-	O
activated	O
Jurkat	O
cells	O
transfected	O
with	O
IL	B-GENE
-	I-GENE
2	I-GENE
promoter	O
-	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	O
constructs	O
.	O

Splice	O
variations	O
in	O
genes	O
coding	O
for	O
the	O
transmembrane	B-GENE
FGF	I-GENE
receptor	I-GENE
(	O
FGFR	B-GENE
)	O
result	O
in	O
isoforms	O
that	O
vary	O
in	O
the	O
ectodomain	O
,	O
intracellular	O
juxtamembrane	O
domain	O
,	O
and	O
the	O
intracellular	O
kinase	O
domain	O
.	O

The	O
git1	B-GENE
,	O
git3	B-GENE
,	O
git5	B-GENE
,	O
git7	B-GENE
,	O
git8	B-GENE
and	O
git10	B-GENE
genes	I-GENE
act	O
upstream	O
of	O
adenylate	B-GENE
cyclase	I-GENE
,	O
presumably	O
encoding	O
an	O
adenylate	B-GENE
cyclase	I-GENE
activation	O
pathway	O
.	O

Deletion	O
studies	O
identified	O
a	O
distal	O
response	O
element	O
that	O
is	O
responsible	O
for	O
the	O
cytokine	O
response	O
and	O
has	O
properties	O
of	O
an	O
inducible	O
transcriptional	O
enhancer	O
.	O

No	O
drop	O
in	O
oxygen	O
saturation	O
(	O
SaO2	O
)	O
or	O
visual	O
evidence	O
of	O
transient	O
electroencephalographic	O
(	O
EEG	O
)	O
arousals	O
can	O
be	O
found	O
at	O
repeat	O
polysomnography	O
.	O

This	O
sequenced	O
region	O
of	O
the	O
V	O
beta	O
locus	O
contains	O
an	O
average	O
number	O
of	O
repetitive	O
DNA	O
elements	O
(	O
21	O
Alu	B-GENE
,	O
three	O
L1	B-GENE
,	O
three	O
MER	O
,	O
and	O
three	O
retrovirus	O
-	O
related	O
elements	O
.	O

However	O
,	O
by	O
an	O
NS35	B-GENE
-	I-GENE
specific	I-GENE
RNA	I-GENE
capture	O
assay	O
,	O
the	O
multimers	O
were	O
shown	O
to	O
possess	O
the	O
RNA	O
-	O
binding	O
activity	O
previously	O
demonstrated	O
for	O
NS35	B-GENE
.	O

Ketamine	O
in	O
the	O
treatment	O
of	O
bronchospasm	O
during	O
mechanical	O
ventilation	O
.	O

The	O
molecular	O
basis	O
for	O
commitment	O
of	O
progenitors	O
to	O
the	O
eosinophil	O
lineage	O
and	O
mechanisms	O
by	O
which	O
eosinophil	O
-	O
specific	O
genes	O
are	O
expressed	O
and	O
regulated	O
during	O
differentiation	O
is	O
unknown	O
.	O

Thus	O
,	O
YMIP	B-GENE
is	O
a	O
functional	O
homolog	O
of	O
RMIP	B-GENE
and	O
represents	O
a	O
new	O
component	O
of	O
the	O
yeast	O
mitochondrial	O
import	O
machinery	O
.	O

Tryptic	O
cleavage	O
and	O
peptide	O
sequence	O
analysis	O
demonstrated	O
that	O
the	O
98	O
-	O
kD	O
protein	O
is	O
identical	O
to	O
a	O
recently	O
cloned	O
protein	O
,	O
special	B-GENE
A	I-GENE
-	I-GENE
T	I-GENE
-	I-GENE
rich	I-GENE
binding	I-GENE
protein	I-GENE
1	I-GENE
(	O
SATB1	B-GENE
)	O
,	O
that	O
binds	O
selectively	O
to	O
nuclear	O
matrix	O
/	O
scaffold	O
-	O
associated	O
regions	O
of	O
DNA	O
(	O
MARs	O
/	O
SARs	O
)	O
.	O

Heparin	O
had	O
no	O
effect	O
on	O
rAC	B-GENE
-	I-GENE
st	I-GENE
myosin	I-GENE
light	I-GENE
chain	I-GENE
phosphatase	I-GENE
activity	O
,	O
while	O
the	O
B	O
subunit	O
-	O
containing	O
forms	O
were	O
stimulated	O
2	O
-	O
3	O
-	O
fold	O
.	O

BACKGROUND	O
AND	O
DESIGN	O
:	O
Fifty	O
-	O
nine	O
melanocytic	O
nevi	O
with	O
eccentric	O
foci	O
of	O
hyperpigmentation	O
(	O
"	O
small	O
dark	O
dots	O
"	O
)	O
that	O
measured	O
primarily	O
1	O
to	O
2	O
mm	O
in	O
diameter	O
were	O
prospectively	O
examined	O
to	O
determine	O
the	O
histologic	O
correlates	O
of	O
the	O
dark	O
dots	O
.	O

A	O
single	O
NMSC	O
was	O
present	O
in	O
69	O
.	O
4	O
%	O
,	O
two	O
in	O
16	O
%	O
,	O
three	O
in	O
6	O
.	O
4	O
%	O
,	O
four	O
in	O
3	O
.	O
5	O
%	O
,	O
five	O
to	O
nine	O
in	O
4	O
.	O
2	O
%	O
,	O
and	O
0	O
.	O
5	O
%	O
had	O
ten	O
or	O
more	O
.	O

The	O
two	O
ParA	B-GENE
proteins	I-GENE
that	O
are	O
produced	O
as	O
a	O
result	O
of	O
independent	O
translation	O
initiation	O
at	O
two	O
different	O
start	O
codons	O
within	O
the	O
same	O
open	O
reading	O
frame	O
were	O
overexpressed	O
in	O
Escherichia	O
coli	O
and	O
partially	O
purified	O
.	O

To	O
get	O
further	O
insights	O
into	O
the	O
molecular	O
mechanisms	O
that	O
control	O
tal	B-GENE
-	I-GENE
1	I-GENE
expression	O
,	O
we	O
have	O
isolated	O
5	O
'	O
sequences	O
of	O
the	O
murine	O
gene	O
and	O
compared	O
them	O
to	O
their	O
human	O
counterparts	O
.	O

These	O
results	O
demonstrate	O
that	O
a	O
diverse	O
set	O
of	O
carboxyl	O
-	O
terminal	O
sequence	O
motifs	O
and	O
posttranslational	O
modifications	O
lead	O
to	O
functional	O
Ras	B-GENE
proteins	I-GENE
in	O
yeast	O
.	O

Binding	O
of	O
U2	B-GENE
small	I-GENE
nuclear	I-GENE
ribonucleoprotein	I-GENE
(	O
snRNP	O
)	O
to	O
the	O
pre	O
-	O
mRNA	O
is	O
an	O
early	O
and	O
important	O
step	O
in	O
spliceosome	O
assembly	O
.	O

Our	O
results	O
indicate	O
that	O
the	O
KRAB	B-GENE
domain	I-GENE
present	O
in	O
the	O
non	O
-	O
finger	O
region	O
of	O
many	O
ZFP	B-GENE
genes	I-GENE
quenches	O
transcription	O
possibly	O
due	O
to	O
specific	O
protein	O
-	O
protein	O
interactions	O
between	O
the	O
KRAB	B-GENE
-	I-GENE
A	I-GENE
domain	I-GENE
and	O
components	O
of	O
the	O
proximal	O
transcriptional	O
apparatus	O
.	O

Marine	O
oils	O
and	O
cardiovascular	O
reactivity	O
.	O

Significant	O
alterations	O
in	O
CBC	O
results	O
and	O
serum	B-GENE
CRP	I-GENE
concentration	O
,	O
compared	O
with	O
baseline	O
values	O
,	O
were	O
lacking	O
in	O
dogs	O
of	O
the	O
control	O
group	O
.	O

The	O
newly	O
recognised	O
skeletogenital	O
syndrome	O
.	O

Ras	B-GENE
-	I-GENE
and	I-GENE
ultra	I-GENE
-	I-GENE
violet	I-GENE
-	I-GENE
responsive	I-GENE
protein	I-GENE
kinases	I-GENE
that	O
phosphorylate	O
c	B-GENE
-	I-GENE
Jun	I-GENE
on	O
serine	O
residues	O
at	O
positions	O
63	O
and	O
73	O
and	O
stimulate	O
its	O
transcriptional	O
activity	O
have	O
been	O
identified	O
.	O

A	O
short	O
sequence	O
surrounding	O
the	O
major	O
JNK	B-GENE
phosphorylation	O
site	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
is	O
conserved	O
in	O
c	B-GENE
-	I-GENE
Fos	I-GENE
and	O
is	O
part	O
of	O
its	O
activation	O
domain	O
,	O
suggesting	O
that	O
c	B-GENE
-	I-GENE
Fos	I-GENE
may	O
be	O
similarly	O
regulated	O
.	O

c	B-GENE
-	I-GENE
Fos	I-GENE
transcriptional	O
activity	O
stimulated	O
by	O
H	B-GENE
-	I-GENE
Ras	I-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
distinct	O
from	O
JNK	B-GENE
and	O
ERK	B-GENE
.	O

Essential	O
features	O
of	O
this	O
model	O
are	O
bending	O
of	O
the	O
DNA	O
double	O
helix	O
and	O
contact	O
of	O
operator	O
sites	O
with	O
repressor	O
domains	O
bearing	O
sequence	O
homologies	O
with	O
the	O
helix	O
-	O
turn	O
-	O
helix	O
(	O
HTH	O
)	O
motifs	O
of	O
other	O
DNA	O
-	O
binding	O
proteins	O
.	O

The	O
binding	O
of	O
transcription	O
factor	O
AP	B-GENE
-	I-GENE
1	I-GENE
and	O
vitamin	B-GENE
D	I-GENE
receptor	I-GENE
(	O
VDR	B-GENE
)	O
to	O
the	O
composite	O
AP	B-GENE
-	I-GENE
1	I-GENE
plus	I-GENE
vitamin	I-GENE
-	I-GENE
D	I-GENE
-	I-GENE
responsive	I-GENE
promoter	I-GENE
region	O
(	O
AP	B-GENE
-	I-GENE
1	I-GENE
+	I-GENE
VDRE	I-GENE
)	O
of	O
the	O
human	B-GENE
osteocalcin	I-GENE
gene	I-GENE
was	O
characterized	O
in	O
osteocalcin	B-GENE
-	O
producing	O
(	O
MG	O
-	O
63	O
)	O
and	O
non	O
-	O
producing	O
(	O
U2	O
-	O
Os	O
,	O
SaOs	O
-	O
2	O
)	O
human	O
osteosarcoma	O
cell	O
lines	O
.	O

2	O
.	O

The	O
LTR	O
-	O
binding	O
activities	O
of	O
VBP	B-GENE
,	O
a1	B-GENE
/	I-GENE
EBP	I-GENE
,	O
and	O
B	B-GENE
-	I-GENE
cell	I-GENE
nuclear	I-GENE
extract	I-GENE
protein	I-GENE
were	O
compared	O
and	O
mapped	O
by	O
gel	O
shift	O
,	O
DNase	B-GENE
I	I-GENE
footprinting	O
,	O
and	O
methylation	O
interference	O
assays	O
.	O

These	O
results	O
suggest	O
that	O
leader	O
-	O
mRNA	O
fusion	O
in	O
coronavirus	O
transcription	O
does	O
not	O
require	O
direct	O
RNA	O
-	O
RNA	O
interaction	O
between	O
complementary	O
sequences	O
.	O

These	O
results	O
suggest	O
that	O
leader	O
-	O
mRNA	O
fusion	O
in	O
coronavirus	O
transcription	O
does	O
not	O
require	O
direct	O
RNA	O
-	O
RNA	O
interaction	O
between	O
complementary	O
sequences	O
.	O

To	O
determine	O
whether	O
P35	B-GENE
could	O
activate	O
the	O
39k	O
promoter	O
in	O
the	O
absence	O
of	O
IE1	B-GENE
,	O
the	O
p35	B-GENE
open	O
reading	O
frame	O
was	O
cloned	O
under	O
the	O
control	O
of	O
the	O
ie1	B-GENE
promoter	I-GENE
.	O

In	O
addition	O
,	O
a	O
microsatellite	O
repeat	O
polymorphism	O
with	O
a	O
heterozygosity	O
of	O
71	O
%	O
at	O
the	O
RET	B-GENE
locus	I-GENE
and	O
a	O
restriction	O
fragment	O
length	O
polymorphism	O
with	O
a	O
heterozygosity	O
of	O
42	O
%	O
detected	O
by	O
a	O
lambda	O
clone	O
from	O
the	O
D10S94	B-GENE
locus	I-GENE
have	O
been	O
developed	O
for	O
high	O
-	O
resolution	O
genetic	O
linkage	O
mapping	O
and	O
predictive	O
diagnostic	O
testing	O
.	O

However	O
,	O
tyrA	B-GENE
can	O
be	O
expressed	O
efficiently	O
from	O
an	O
internal	O
promoter	O
which	O
appears	O
to	O
lie	O
within	O
the	O
3	O
'	O
portion	O
of	O
aroF	B-GENE
.	O

Within	O
the	O
span	O
of	O
attenuator	O
region	O
encoding	O
the	O
three	O
stem	O
-	O
loop	O
structures	O
of	O
mRNA	O
secondary	O
configuration	O
,	O
hot	O
spots	O
of	O
base	O
-	O
residue	O
divergence	O
were	O
localized	O
to	O
looped	O
-	O
out	O
regions	O
.	O

Previous	O
studies	O
showed	O
that	O
mutations	O
in	O
the	O
6K	O
protein	O
led	O
to	O
the	O
slow	O
release	O
of	O
aberrant	O
,	O
multi	O
-	O
cored	O
infectious	O
virions	O
.	O

The	O
RFLP	O
patterns	O
of	O
the	O
isolates	O
from	O
six	O
of	O
these	O
patients	O
remained	O
essentially	O
unchanged	O
(	O
two	O
strains	O
showed	O
one	O
additional	O
band	O
)	O
despite	O
the	O
development	O
of	O
drug	O
resistance	O
.	O

Southern	O
analysis	O
on	O
genomic	O
DNA	O
isolated	O
from	O
tissues	O
and	O
cell	O
lines	O
from	O
several	O
mouse	O
strains	O
using	O
mCD22	B-GENE
cDNA	I-GENE
demonstrated	O
that	O
the	O
Cd22	B-GENE
locus	I-GENE
encoding	O
mCD22	B-GENE
is	O
a	O
single	O
copy	O
gene	O
of	O
<	O
or	O
=	O
30	O
kb	O
.	O

The	O
tyrosine	B-GENE
hydroxylase	I-GENE
gene	I-GENE
(	O
TH	B-GENE
)	O
contains	O
a	O
single	O
copy	O
of	O
a	O
consensus	O
CRE	O
at	O
-	O
45	O
to	O
-	O
38	O
base	O
pair	O
(	O
bp	O
)	O
upstream	O
of	O
the	O
transcription	O
initiation	O
site	O
.	O

Fenoldopam	O
,	O
a	O
dopamine	B-GENE
receptor	I-GENE
agonist	O
,	O
has	O
been	O
shown	O
,	O
in	O
animal	O
experiments	O
,	O
to	O
improve	O
renal	O
perfusion	O
.	O

The	O
results	O
indicate	O
that	O
hrpRS	B-GENE
and	O
hrpL	B-GENE
are	O
part	O
of	O
a	O
regulatory	O
cascade	O
in	O
which	O
HrpR	B-GENE
and	O
HrpS	B-GENE
activate	O
expression	O
of	O
hrpL	B-GENE
and	O
HrpL	B-GENE
,	O
a	O
putative	O
sigma	B-GENE
factor	I-GENE
,	O
induces	O
expression	O
of	O
HrpL	B-GENE
-	I-GENE
responsive	I-GENE
genes	I-GENE
.	O

All	O
other	O
normal	O
and	O
transformed	O
lymphoid	O
and	O
nonlymphoid	O
cell	O
lines	O
and	O
normal	O
tissues	O
were	O
negative	O
for	O
PANG	B-GENE
expression	O
except	O
for	O
the	O
brain	O
,	O
wherein	O
unique	O
4	O
.	O
0	O
-	O
and	O
6	O
.	O
1	O
-	O
kb	O
transcripts	O
were	O
detected	O
.	O

L	O
.	O
,	O
Greer	O
,	O
J	O
.	O
&	O
Carter	O
,	O
G	O
.	O

Western	O
blotting	O
(	O
immunoblotting	O
)	O
with	O
an	O
antiserum	O
to	O
a	O
partial	O
SOD	B-GENE
expressed	O
in	O
Escherichia	O
coli	O
revealed	O
two	O
proteins	O
with	O
estimated	O
molecular	O
masses	O
of	O
19	O
and	O
29	O
kDa	O
.	O

Members	O
of	O
the	O
myocyte	B-GENE
-	I-GENE
specific	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
factor	I-GENE
2	I-GENE
(	O
MEF2	B-GENE
)	O
family	O
of	O
transcription	O
factors	O
bind	O
a	O
conserved	O
A	O
/	O
T	O
-	O
rich	O
sequence	O
in	O
the	O
control	O
regions	O
of	O
numerous	O
muscle	O
-	O
specific	O
genes	O
.	O

Seven	O
of	O
these	O
had	O
counterparts	O
in	O
the	O
US	O
of	O
herpes	O
simplex	O
type	O
1	O
(	O
HSV	O
-	O
1	O
)	O
,	O
pseudorabies	O
virus	O
(	O
PRV	O
)	O
,	O
and	O
equine	O
herpesvirus	O
type	O
1	O
(	O
EHV	O
-	O
1	O
)	O
.	O

The	O
previously	O
described	O
enhanced	O
translation	O
of	O
spinach	O
L12	B-GENE
mRNA	I-GENE
from	O
its	O
two	O
tandem	O
AUG	O
codons	O
and	O
the	O
two	O
functional	O
rpl12	B-GENE
genes	I-GENE
in	O
Arabidopsis	O
probably	O
provide	O
two	O
mechanisms	O
for	O
generating	O
the	O
four	O
copies	O
of	O
L12	B-GENE
/	I-GENE
chloroplast	I-GENE
ribosome	I-GENE
,	O
qualitatively	O
different	O
from	O
those	O
attempted	O
in	O
eubacteria	O
.	O

Genomic	O
DNA	O
clones	O
containing	O
the	O
T	B-GENE
-	I-GENE
cell	I-GENE
-	I-GENE
specific	I-GENE
human	I-GENE
MAL	I-GENE
gene	I-GENE
were	O
isolated	O
.	O

Expression	O
of	O
the	O
dibasic	O
proprotein	O
processing	O
enzyme	O
furin	B-GENE
is	O
directed	O
by	O
multiple	O
promoters	O
.	O

Certain	O
spt10	B-GENE
spontaneous	O
alleles	O
are	O
good	O
suppressors	O
but	O
have	O
a	O
normal	O
growth	O
rate	O
,	O
suggesting	O
that	O
the	O
SPT10	B-GENE
protein	I-GENE
may	O
have	O
two	O
distinct	O
functions	O
.	O

In	O
Rat	O
1a	O
cells	O
,	O
m1R	B-GENE
stimulation	O
of	O
phospholipase	B-GENE
C	I-GENE
beta	I-GENE
and	O
the	O
marked	O
rise	O
in	O
intracellular	O
calcium	O
stimulated	O
cyclic	O
AMP	O
(	O
cAMP	O
)	O
synthesis	O
,	O
resulting	O
in	O
the	O
activation	O
of	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
.	O

The	O
mutations	O
did	O
not	O
affect	O
the	O
repression	O
of	O
CPA1	B-GENE
by	O
arginine	O
.	O

A	O
segment	O
of	O
mRNA	O
encoding	O
the	O
leader	O
peptide	O
of	O
the	O
CPA1	B-GENE
gene	I-GENE
confers	O
repression	O
by	O
arginine	O
on	O
a	O
heterologous	O
yeast	O
gene	O
transcript	O
.	O

Structure	O
and	O
expression	O
of	O
the	O
alternative	O
sigma	B-GENE
factor	I-GENE
,	O
RpoN	B-GENE
,	O
in	O
Rhodobacter	O
capsulatus	O
;	O
physiological	O
relevance	O
of	O
an	O
autoactivated	O
nifU2	B-GENE
-	O
rpoN	B-GENE
superoperon	O
.	O

Insertion	O
of	O
short	O
oligonucleotides	O
encoding	O
the	O
basic	O
amino	O
acid	O
motifs	O
726	O
-	O
GRKRKSP	O
-	O
732	O
from	O
IE175	B-GENE
and	O
500	O
-	O
VRPRKRR	O
-	O
506	O
from	O
IE110	B-GENE
into	O
deleted	O
cytoplasmic	O
forms	O
of	O
the	O
two	O
proteins	O
restored	O
the	O
karyophilic	O
phenotype	O
and	O
confirmed	O
that	O
these	O
motifs	O
are	O
both	O
necessary	O
and	O
sufficient	O
for	O
proper	O
nuclear	O
localization	O
.	O

Mapping	O
of	O
intracellular	O
localization	O
domains	O
and	O
evidence	O
for	O
colocalization	O
interactions	O
between	O
the	O
IE110	B-GENE
and	O
IE175	B-GENE
nuclear	O
transactivator	O
proteins	O
of	O
herpes	O
simplex	O
virus	O
.	O

The	O
revertant	O
TATA	O
boxes	O
accelerated	O
the	O
kinetics	O
of	O
HIV	O
replication	O
when	O
present	O
in	O
the	O
context	O
of	O
an	O
LTR	O
containing	O
a	O
Sp1	B-GENE
mutation	O
(	O
deletion	O
or	O
site	O
specific	O
)	O
;	O
no	O
effect	O
was	O
observed	O
on	O
the	O
infectivity	O
of	O
wild	O
-	O
type	O
HIV	O
.	O

Mitochondrial	B-GENE
Mas70p	I-GENE
signal	I-GENE
anchor	I-GENE
sequence	I-GENE
.	O

Response	O
to	O
treatment	O
was	O
better	O
in	O
patients	O
with	O
less	O
pretreatment	O
(	O
one	O
-	O
two	O
prior	O
treatments	O
)	O
than	O
in	O
heavily	O
pretreated	O
ones	O
(	O
more	O
than	O
three	O
)	O
and	O
this	O
relation	O
was	O
found	O
to	O
be	O
statistically	O
significant	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
class	B-GENE
II	I-GENE
Escherichia	I-GENE
coli	I-GENE
alanine	I-GENE
tRNA	I-GENE
synthetase	I-GENE
aminoacylates	I-GENE
RNA	I-GENE
miniduplexes	I-GENE
,	O
which	O
reconstruct	O
the	O
acceptor	O
end	O
of	O
alanine	B-GENE
tRNA	I-GENE
with	O
the	O
critical	O
G3	O
:	O
U70	O
base	O
pair	O
.	O

A	O
second	O
study	O
group	O
,	O
with	O
intact	O
cardiac	O
innervation	O
,	O
consisted	O
of	O
19	O
patients	O
with	O
stable	O
angina	O
pectoris	O
class	O
I	O
to	O
III	O
.	O

Thus	O
,	O
we	O
have	O
separated	O
the	O
signal	O
function	O
from	O
the	O
anchor	O
function	O
of	O
the	O
6	O
.	O
7K	O
SA	O
domain	O
.	O

Exposure	O
to	O
higher	O
TPA	O
concentrations	O
decreased	O
the	O
content	O
of	O
these	O
transcripts	O
.	O

Our	O
results	O
indicate	O
that	O
the	O
minimal	O
requirements	O
for	O
induction	O
of	O
PEPCK	B-GENE
by	O
PKA	B-GENE
and	O
inhibition	O
by	O
insulin	B-GENE
include	O
:	O
1	O
)	O
the	O
CREB	B-GENE
activation	I-GENE
domain	I-GENE
,	O
2	O
)	O
the	O
PEPCK	B-GENE
TATA	I-GENE
sequence	I-GENE
,	O
and	O
3	O
)	O
insulin	B-GENE
-	O
responsive	O
hepatoma	O
cells	O
.	O

Topical	O
L	O
-	O
NNA	O
attenuated	O
the	O
hypercapnic	O
increase	O
of	O
CoBF	O
by	O
52	O
+	O
/	O
-	O
6	O
%	O
and	O
CeBF	O
by	O
29	O
+	O
/	O
-	O
5	O
%	O
after	O
45	O
-	O
min	O
exposure	O
.	O

Restriction	O
analysis	O
and	O
Southern	O
hybridization	O
revealed	O
the	O
presence	O
of	O
Tn5422	B-GENE
in	O
all	O
the	O
plasmid	O
-	O
mediated	O
cadmium	O
-	O
resistant	O
L	O
.	O
monocytogenes	O
strains	O
tested	O
but	O
not	O
in	O
strains	O
encoding	O
cadmium	O
resistance	O
on	O
the	O
chromosome	O
.	O

The	O
7	O
-	O
day	O
treatment	O
resulted	O
in	O
a	O
decrease	O
in	O
mitochondrial	O
uptake	O
of	O
Rh123	O
and	O
an	O
increase	O
in	O
NAO	O
uptake	O
.	O

Thrombotic	O
thrombocytopenic	O
purpura	O
in	O
systemic	O
lupus	O
erythematosus	O
.	O

Women	O
'	O
s	O
opportunities	O
for	O
paid	O
work	O
outside	O
the	O
home	O
are	O
constrained	O
by	O
their	O
role	O
as	O
primary	O
carer	O
within	O
the	O
family	O
,	O
writes	O
Trudy	O
Wynne	O
.	O

Interestingly	O
,	O
the	O
interaction	O
of	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
with	O
the	O
motif	O
was	O
dependent	O
on	O
the	O
presence	O
of	O
both	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
SH2	B-GENE
domains	I-GENE
and	O
both	O
of	O
the	O
tyrosine	O
residues	O
in	O
the	O
motif	O
,	O
suggesting	O
that	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
interacts	O
with	O
two	O
phosphotyrosine	O
residues	O
and	O
that	O
the	O
binding	O
of	O
the	O
two	O
SH2	B-GENE
domains	I-GENE
is	O
cooperative	O
.	O

PRL	B-GENE
-	I-GENE
1	I-GENE
is	O
able	O
to	O
dephosphorylate	O
phosphotyrosine	O
substrates	O
,	O
and	O
mutation	O
of	O
the	O
active	O
-	O
site	O
cysteine	O
residue	O
abolishes	O
this	O
activity	O
.	O

50	O
kDa	O
and	O
130	O
-	O
170	O
kDa	O
were	O
detected	O
.	O

This	O
strategy	O
was	O
used	O
to	O
place	O
both	O
the	O
Tn903	B-GENE
neo	I-GENE
gene	I-GENE
and	O
the	O
Rhodosporidium	B-GENE
toruloides	I-GENE
phenylalanine	I-GENE
ammonia	I-GENE
lyase	I-GENE
(	O
PAL	B-GENE
)	O
-	O
encoding	O
gene	O
under	O
the	O
transcriptional	O
control	O
of	O
pPGK	B-GENE
:	O
:	O
REP2	B-GENE
.	O

In	O
the	O
case	O
of	O
congenital	O
protein	B-GENE
C	I-GENE
deficiency	O
,	O
vitamin	O
K	O
antagonists	O
must	O
be	O
started	O
cautiously	O
due	O
to	O
the	O
risk	O
of	O
skin	O
necrosis	O
.	O

In	O
addition	O
,	O
we	O
observe	O
that	O
the	O
hUBF	B-GENE
-	I-GENE
promoter	I-GENE
interaction	O
is	O
highly	O
sensitive	O
to	O
the	O
antagonistic	O
effects	O
of	O
cisplatin	O
-	O
DNA	O
adducts	O
.	O

Simultaneous	O
,	O
bilateral	O
and	O
permanent	O
ventilation	O
with	O
a	O
diaphragm	O
pacing	O
in	O
childhood	O
:	O
the	O
implantation	O
technique	O
and	O
indications	O

The	O
pyrR	B-GENE
and	O
pyrP	B-GENE
genes	I-GENE
encoded	O
polypeptides	O
with	O
calculated	O
molecular	O
masses	O
of	O
19	O
.	O
9	O
and	O
45	O
.	O
2	O
kDa	O
,	O
respectively	O
.	O

To	O
identify	O
the	O
precise	O
location	O
of	O
the	O
phosphorylation	O
site	O
on	O
the	O
64	O
-	O
kDa	O
protein	O
,	O
a	O
step	O
-	O
by	O
-	O
step	O
mutagenesis	O
procedures	O
was	O
followed	O
.	O

Co	O
-	O
transfection	O
of	O
a	O
tat	B-GENE
expressing	O
plasmid	O
with	O
these	O
viruses	O
containing	O
the	O
tat	B-GENE
ORF	I-GENE
mutations	O
resulted	O
in	O
higher	O
levels	O
of	O
virus	O
production	O
demonstrating	O
that	O
the	O
effects	O
of	O
both	O
mutants	O
are	O
tat	B-GENE
specific	O
.	O

Analysis	O
of	O
the	O
gag	B-GENE
and	O
rev	B-GENE
proteins	I-GENE
in	O
the	O
transfected	O
cells	O
demonstrated	O
that	O
these	O
proteins	O
were	O
not	O
detectable	O
in	O
cells	O
transfected	O
with	O
the	O
tat	B-GENE
mutants	I-GENE
but	O
could	O
be	O
readily	O
detected	O
when	O
the	O
mutations	O
were	O
complemented	O
in	O
trans	O
with	O
a	O
tat	B-GENE
expression	O
vector	O
.	O

SIN	O
-	O
1	O
had	O
no	O
influence	O
on	O
either	O
the	O
ischemic	O
parameters	O
in	O
the	O
surface	O
electrocardiogram	O
(	O
ECG	O
)	O
or	O
the	O
intracoronary	O
ECG	O
.	O

Stimulation	O
of	O
[	O
3H	O
]	O
PA	O
production	O
upon	O
CD3	B-GENE
cross	O
-	O
linking	O
was	O
77	O
%	O
lower	O
in	O
permeabilized	O
CD45	B-GENE
-	I-GENE
cells	O
than	O
in	O
CD45	B-GENE
+	I-GENE
cells	O
,	O
consistent	O
with	O
the	O
reduced	O
activity	O
of	O
p59fyn	B-GENE
in	O
CD45	B-GENE
-	I-GENE
cells	O
.	O

A	O
Dictyostelium	O
transformant	O
overexpressing	O
DdPTPa	B-GENE
does	O
not	O
develop	O
normally	O
.	O

We	O
postulate	O
that	O
CaM	B-GENE
binding	O
by	O
HIV	B-GENE
envelope	I-GENE
proteins	I-GENE
is	O
likely	O
to	O
exert	O
diverse	O
modulatory	O
effects	O
,	O
and	O
the	O
mechanism	O
for	O
HIV	O
-	O
induced	O
cytotoxicity	O
may	O
involve	O
,	O
in	O
part	O
,	O
inhibition	O
of	O
CaM	B-GENE
-	O
regulated	O
cellular	O
functions	O
.	O

There	O
was	O
no	O
apparent	O
effect	O
of	O
growth	O
temperature	O
on	O
the	O
steady	O
-	O
state	O
levels	O
of	O
fad7	B-GENE
mRNA	I-GENE
in	O
wild	O
type	O
plants	O
.	O

A	O
second	O
important	O
molecule	O
in	O
TCR	B-GENE
signal	O
transduction	O
is	O
the	O
guanine	B-GENE
nucleotide	I-GENE
binding	I-GENE
protein	I-GENE
,	O
p21ras	B-GENE
,	O
which	O
is	O
coupled	O
to	O
the	O
TCR	B-GENE
by	O
a	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
dependent	O
mechanism	O
.	O

A	O
series	O
of	O
5	O
'	O
-	O
deletions	O
revealed	O
that	O
the	O
fragment	O
-	O
218	O
to	O
+	O
4	O
from	O
the	O
TSS	O
had	O
the	O
highest	O
promoter	O
activity	O
,	O
nearly	O
1000	O
-	O
fold	O
greater	O
than	O
the	O
promoterless	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
construct	I-GENE
.	O

The	O
lemdr1	B-GENE
gene	I-GENE
was	O
cloned	O
in	O
the	O
expression	O
vector	O
pALTNEO	O
and	O
transfected	O
into	O
wild	O
-	O
type	O
L	O
.	O
enriettii	O
and	O
the	O
resulting	O
transfected	O
cells	O
were	O
resistant	O
to	O
vinblastine	O
but	O
at	O
lower	O
levels	O
than	O
in	O
the	O
selected	O
mutant	O
cells	O
.	O

The	O
bioavailability	O
of	O
etodolac	O
from	O
capsules	O
exposed	O
to	O
stressed	O
conditions	O
was	O
compared	O
in	O
both	O
dogs	O
and	O
humans	O
to	O
capsules	O
stored	O
at	O
RT	O
conditions	O
.	O

As	O
regards	O
lipid	O
metabolism	O
,	O
the	O
mean	O
values	O
for	O
total	O
triglycerides	O
,	O
cholesterol	O
,	O
LDL	B-GENE
-	I-GENE
cholesterol	I-GENE
and	O
HDL	B-GENE
-	I-GENE
cholesterol	I-GENE
seen	O
at	O
the	O
end	O
of	O
five	O
years	O
of	O
Norplant	O
-	O
2	O
rod	O
use	O
and	O
six	O
months	O
postremoval	O
were	O
similar	O
to	O
the	O
preinsertion	O
mean	O
.	O

To	O
our	O
knowledge	O
this	O
is	O
the	O
first	O
case	O
in	O
which	O
a	O
probable	O
association	O
between	O
cholelithiasis	O
and	O
Wildervanck	O
'	O
s	O
syndrome	O
has	O
been	O
recorded	O
.	O

Addition	O
of	O
phalloidin	O
-	O
stabilized	O
F	B-GENE
-	I-GENE
actin	I-GENE
nuclei	O
and	O
phalloidin	O
restored	O
L266D	O
actin	B-GENE
'	O
s	O
ability	O
to	O
polymerize	O
at	O
4	O
degrees	O
C	O
.	O

Northern	O
(	O
RNA	O
)	O
analysis	O
demonstrated	O
expression	O
of	O
human	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
in	O
all	O
tissues	O
and	O
cell	O
lines	O
tested	O
.	O

These	O
results	O
demonstrate	O
the	O
existence	O
of	O
different	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
isoforms	I-GENE
and	O
define	O
a	O
family	O
of	O
genes	O
encoding	O
distinct	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
catalytic	I-GENE
subunits	I-GENE
that	O
can	O
associate	O
with	O
p85	B-GENE
.	O

One	O
complex	O
most	O
likely	O
contained	O
Sp1	B-GENE
,	O
and	O
another	O
complex	O
showed	O
S	O
-	O
phase	O
-	O
specific	O
binding	O
,	O
suggesting	O
a	O
direct	O
role	O
in	O
the	O
cell	O
-	O
cycle	O
-	O
dependent	O
R1	B-GENE
gene	I-GENE
expression	O
.	O

The	O
rate	O
of	O
enzymic	O
stimulation	O
induced	O
by	O
a	O
given	O
nitrate	O
correlates	O
closely	O
with	O
the	O
rate	O
of	O
measured	O
NO	O
production	O
from	O
the	O
nitrate	O
molecule	O
.	O

Two	O
patients	O
were	O
treated	O
successfully	O
with	O
a	O
combination	O
of	O
metronidazole	O
(	O
a	O
tissue	O
amoebicide	O
)	O
and	O
diloxanide	O
(	O
a	O
lumenal	O
amoebicide	O
)	O
.	O

We	O
have	O
identified	O
in	O
the	O
5	O
'	O
untranslated	O
region	O
of	O
the	O
Drosophila	B-GENE
copia	I-GENE
retrotransposon	I-GENE
,	O
3	O
'	O
to	O
the	O
left	O
LTR	O
,	O
a	O
sequence	O
for	O
transcriptional	O
regulation	O
by	O
homeoproteins	O
.	O

By	O
using	O
the	O
full	O
-	O
length	O
cytoplasmic	O
domain	O
and	O
mutants	O
with	O
progressive	O
carboxy	O
-	O
terminal	O
deletions	O
,	O
internal	O
deletions	O
,	O
or	O
point	O
mutations	O
,	O
we	O
identified	O
the	O
first	O
150	O
amino	O
acid	O
residues	O
of	O
LIFR	B-GENE
as	O
the	O
minimal	O
region	O
necessary	O
for	O
signaling	O
.	O

Oligonucleotide	O
competitors	O
were	O
used	O
to	O
evaluate	O
the	O
accessibility	O
of	O
the	O
TATA	O
-	O
binding	O
site	O
in	O
TIF	B-GENE
-	I-GENE
IB	I-GENE
,	O
TFIID	B-GENE
,	O
and	O
TFIIIB	B-GENE
.	O

The	O
227	O
-	O
to	O
-	O
239	O
region	O
blocked	O
ADR1	B-GENE
activity	O
independently	O
of	O
the	O
TAD	B-GENE
present	O
on	O
ADR1	B-GENE
,	O
ADR1	B-GENE
DNA	O
binding	O
,	O
and	O
specific	O
ADH2	B-GENE
promoter	I-GENE
sequences	I-GENE
.	O

TGF	B-GENE
beta	I-GENE
1	I-GENE
expression	O
is	O
largely	O
governed	O
by	O
three	O
AP	B-GENE
-	I-GENE
1	I-GENE
binding	I-GENE
sites	I-GENE
located	O
in	O
two	O
different	O
promoters	O
of	O
this	O
gene	O
.	O

Repeated	O
administration	O
of	O
GRg2	O
20	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
significantly	O
improved	O
the	O
CYP	O
-	O
induced	O
recognitional	O
deficits	O
by	O
increasing	O
the	O
CYP	O
-	O
decreased	O
rate	O
from	O
55	O
.	O
8	O
+	O
/	O
-	O
9	O
.	O
6	O
to	O
80	O
.	O
8	O
+	O
/	O
-	O
4	O
.	O
2	O
in	O
d	O
3	O
learning	O
acquisition	O
(	O
F	O
(	O
1	O
,	O
14	O
)	O
=	O
5	O
.	O
6	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
from	O
53	O
.	O
4	O
+	O
/	O
-	O
8	O
.	O
4	O
to	O
60	O
.	O
0	O
+	O
/	O
-	O
8	O
.	O
2	O
in	O
48	O
h	O
memory	O
acquisition	O
(	O
F	O
(	O
1	O
,	O
14	O
)	O
=	O
7	O
.	O
5	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
and	O
from	O
55	O
.	O
0	O
+	O
/	O
-	O
5	O
.	O
5	O
to	O
88	O
.	O
3	O
+	O
/	O
-	O
2	O
.	O
5	O
in	O
24	O
h	O
memory	O
retention	O
(	O
F	O
(	O
1	O
,	O
12	O
)	O
27	O
.	O
5	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
as	O
well	O
as	O
from	O
60	O
.	O
0	O
+	O
/	O
-	O
6	O
.	O
8	O
to	O
85	O
.	O
6	O
+	O
/	O
-	O
6	O
.	O
9	O
in	O
48	O
h	O
memory	O
retrieval	O
(	O
F	O
(	O
1	O
,	O
12	O
)	O
=	O
5	O
.	O
2	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
respectively	O
.	O

The	O
therapeutic	O
action	O
of	O
cyclosporin	O
A	O
(	O
Sandimmun	O
)	O
:	O
its	O
application	O
in	O
rheumatoid	O
arthritis	O
.	O

Pentazocine	O
analgesia	O
:	O
is	O
there	O
a	O
niche	O
for	O
Talwin	O
Nx	O
?	O
Pentazocine	O
can	O
be	O
a	O
useful	O
analgesic	O
agent	O
for	O
the	O
management	O
of	O
acute	O
dental	O
pain	O
.	O

In	O
addition	O
,	O
REP21	O
plants	O
were	O
resistant	O
to	O
an	O
unusually	O
broad	O
range	O
of	O
tobamoviruses	O
including	O
tomato	O
mosaic	O
virus	O
,	O
tobacco	O
mild	O
green	O
mosaic	O
virus	O
,	O
TMV	O
-	O
U5	O
,	O
green	O
tomato	O
atypical	O
mosaic	O
virus	O
,	O
and	O
ribgrass	O
mosaic	O
virus	O
.	O

In	O
our	O
studies	O
,	O
we	O
utilized	O
HIV	O
-	O
1	O
HXB2	B-GENE
and	O
HIV	O
-	O
1	O
Z2Z6	B-GENE
core	I-GENE
enhancers	I-GENE
because	O
the	O
Z2Z6	B-GENE
strain	O
has	O
a	O
single	O
point	O
mutation	O
flanking	O
the	O
right	O
ETS	B-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
.	O

Because	O
of	O
the	O
small	O
number	O
of	O
visceral	O
angiography	O
procedures	O
performed	O
(	O
38	O
)	O
,	O
no	O
definitive	O
conclusions	O
could	O
be	O
drawn	O
as	O
to	O
the	O
differences	O
between	O
ionic	O
and	O
nonionic	O
agents	O
regarding	O
grade	O
-	O
2	O
and	O
grade	O
-	O
3	O
adverse	O
events	O
.	O

The	O
Stryker	O
frame	O
modification	O
to	O
the	O
standard	O
Dornier	O
HM3	O
lithotriptor	O
allows	O
for	O
improved	O
visualization	O
and	O
easier	O
localization	O
of	O
distal	O
ureteral	O
calculi	O
compared	O
to	O
the	O
standard	O
gantry	O
.	O

Glomerular	O
mesangial	O
cells	O
expressed	O
an	O
abundant	O
1	O
.	O
1	O
kb	O
mRNA	O
transcript	O
for	O
Id1	B-GENE
,	O
but	O
in	O
contrast	O
to	O
other	O
cell	O
types	O
Id1	B-GENE
mRNA	I-GENE
was	O
expressed	O
in	O
both	O
randomly	O
cycling	O
cells	O
and	O
in	O
serum	O
-	O
deprived	O
,	O
quiescent	O
cultures	O
.	O

A	O
single	O
1	O
.	O
8	O
-	O
kb	O
transcript	O
mRNA	O
was	O
detected	O
by	O
Northern	O
(	O
RNA	O
)	O
blot	O
analysis	O
,	O
and	O
its	O
5	O
'	O
end	O
maps	O
to	O
a	O
position	O
51	O
bp	O
upstream	O
from	O
the	O
site	O
of	O
initiation	O
of	O
protein	O
synthesis	O
.	O

The	O
sequence	O
similarity	O
has	O
suggested	O
that	O
SCG10	B-GENE
and	O
stathmin	B-GENE
have	O
been	O
derived	O
from	O
structurally	O
and	O
evolutionarily	O
related	O
genes	O
.	O

These	O
data	O
are	O
consistent	O
with	O
the	O
idea	O
that	O
the	O
neuron	B-GENE
-	I-GENE
specific	I-GENE
SCG10	I-GENE
gene	I-GENE
evolved	O
by	O
duplication	O
and	O
modification	O
of	O
the	O
more	O
broadly	O
expressed	O
stathmin	B-GENE
/	O
Lap18	B-GENE
gene	O
.	O

We	O
found	O
that	O
T3	O
(	O
10	O
(	O
-	O
8	O
)	O
M	O
)	O
selectively	O
stimulates	O
transcription	O
from	O
rGH	B-GENE
-	O
TRE	O
-	O
and	O
TREpal	O
-	O
,	O
but	O
not	O
ME	O
-	O
TRE	O
-	O
and	O
F2	O
-	O
TRE	O
-	O
,	O
containing	O
templates	O
in	O
which	O
these	O
TREs	O
are	O
linked	O
in	O
front	O
of	O
the	O
rGH	B-GENE
minimal	I-GENE
promoter	I-GENE
containing	O
only	O
the	O
TATA	B-GENE
box	I-GENE
binding	I-GENE
protein	I-GENE
,	O
but	O
not	O
any	O
other	O
proximal	O
binding	O
protein	O
,	O
sequence	O
.	O

However	O
,	O
artificially	O
ventilated	O
rats	O
,	O
pretreated	O
with	O
MK	O
-	O
801	O
,	O
were	O
more	O
sensitive	O
(	O
lethal	O
cocaine	O
dose	O
,	O
76	O
.	O
6	O
+	O
/	O
-	O
8	O
.	O
0	O
mg	O
/	O
kg	O
,	O
n	O
=	O
5	O
)	O
than	O
vehicle	O
pretreated	O
rats	O
(	O
129	O
.	O
4	O
+	O
/	O
-	O
15	O
.	O
8	O
mg	O
/	O
kg	O
,	O
n	O
=	O
6	O
)	O
,	O
indicating	O
that	O
MK	O
-	O
801	O
may	O
increase	O
both	O
the	O
respiratory	O
and	O
the	O
cardiac	O
toxicity	O
of	O
cocaine	O
in	O
urethane	O
anesthetized	O
rats	O
.	O

ENV	B-GENE
also	O
was	O
secreted	O
from	O
P	O
.	O
pastoris	O
using	O
the	O
S	B-GENE
.	I-GENE
cerevisiae	I-GENE
alpha	I-GENE
-	I-GENE
factor	I-GENE
prepro	I-GENE
secretion	I-GENE
leader	I-GENE
and	O
the	O
S	B-GENE
.	I-GENE
cerevisiae	I-GENE
invertase	I-GENE
signal	I-GENE
sequence	I-GENE
.	O

The	O
following	O
evidence	O
indicates	O
that	O
the	O
69	O
-	O
kD	O
protein	O
is	O
a	O
common	O
,	O
rather	O
than	O
a	O
U1	B-GENE
-	O
specific	O
,	O
protein	O
,	O
possibly	O
associating	O
with	O
the	O
snRNP	O
core	O
particles	O
by	O
protein	O
-	O
protein	O
interaction	O
.	O

Praziquantel	O
and	O
Albendazole	O
were	O
found	O
effective	O
in	O
the	O
treatment	O
of	O
neurocysticercosis	O
,	O
but	O
because	O
of	O
serious	O
side	O
effects	O
encountered	O
in	O
some	O
cases	O
,	O
the	O
drugs	O
should	O
be	O
used	O
cautiously	O
in	O
selected	O
cases	O
only	O
.	O

Transcriptional	O
analysis	O
of	O
a	O
series	O
of	O
deletion	O
mutants	O
of	O
the	O
gene	O
in	O
the	O
nuclear	O
extracts	O
prepared	O
from	O
the	O
middle	O
silk	O
gland	O
of	O
2	O
-	O
day	O
-	O
old	O
fifth	O
instar	O
larvae	O
revealed	O
the	O
presence	O
of	O
multiple	O
cis	O
-	O
regulatory	O
elements	O
located	O
both	O
upstream	O
and	O
downstream	O
of	O
the	O
initiation	O
site	O
.	O

One	O
of	O
these	O
elements	O
,	O
the	O
homeodomain	B-GENE
-	I-GENE
binding	I-GENE
element	I-GENE
,	O
was	O
identified	O
to	O
mediate	O
negative	O
regulation	O
.	O

Monospecific	O
antibodies	O
raised	O
against	O
rat	B-GENE
cytochrome	I-GENE
P	I-GENE
-	I-GENE
450	I-GENE
1A1	I-GENE
recognized	O
a	O
protein	O
in	O
the	O
hepatic	O
microsomes	O
of	O
the	O
double	O
-	O
crested	O
cormorant	O
,	O
and	O
also	O
in	O
those	O
of	O
the	O
great	O
blue	O
heron	O
(	O
Ardea	O
herodias	O
)	O
,	O
using	O
immunoblotting	O
.	O

Mutations	O
in	O
the	O
nuclear	B-GENE
gene	I-GENE
CBP1	I-GENE
of	I-GENE
Saccharomyces	I-GENE
cerevisiae	I-GENE
result	O
in	O
degradation	O
of	O
mitochondrially	B-GENE
encoded	I-GENE
cytochrome	I-GENE
b	I-GENE
(	O
cob	B-GENE
)	O
RNA	O
;	O
thus	O
,	O
the	O
cells	O
are	O
unable	O
to	O
respire	O
.	O

The	O
5	O
'	O
ends	O
of	O
F3R	B-GENE
late	O
transcripts	O
were	O
located	O
to	O
an	O
A	O
within	O
the	O
sequence	O
5	O
'	O
-	O
TAAAG	O
,	O
41	O
nt	O
downstream	O
from	O
the	O
early	O
promoter	O
and	O
17	O
nt	O
upstream	O
from	O
the	O
initiation	O
codon	O
.	O

NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
p65	B-GENE
,	O
p50	B-GENE
,	O
and	O
Rel	B-GENE
functionally	O
synergize	O
with	O
C	B-GENE
/	I-GENE
EBP	I-GENE
alpha	I-GENE
,	O
C	B-GENE
/	I-GENE
EBP	I-GENE
beta	I-GENE
,	O
and	O
C	B-GENE
/	I-GENE
EBP	I-GENE
delta	I-GENE
.	O

It	O
could	O
be	O
detected	O
exclusively	O
in	O
the	O
culture	O
medium	O
of	O
cDNA	O
-	O
transfected	O
COS	O
cells	O
.	O

The	O
first	O
group	O
of	O
sequential	O
BMB	O
showed	O
a	O
significant	O
progress	O
to	O
myelofibrosis	O
in	O
so	O
-	O
called	O
"	O
Chronic	O
Megakaryocytic	O
-	O
Granulocytic	O
Myelosis	O
"	O
-	O
-	O
CMGM	O
-	O
,	O
which	O
corresponds	O
to	O
Agnogenic	O
Myeloid	O
Metaplasia	O
-	O
AMM	O
-	O
in	O
72	O
.	O
4	O
%	O
(	O
21	O
/	O
29	O
patients	O
)	O
,	O
as	O
well	O
as	O
in	O
CML	O
with	O
megakaryocytic	O
increase	O
-	O
CML	O
.	O
MI	O
-	O
in	O
39	O
.	O
2	O
%	O
(	O
20	O
/	O
51	O
)	O
.	O

These	O
lesions	O
were	O
asymptomatic	O
,	O
but	O
both	O
were	O
characterized	O
clinically	O
by	O
central	O
ulceration	O
.	O

Release	O
of	O
this	O
selective	O
pressure	O
,	O
however	O
,	O
gave	O
way	O
to	O
homologous	O
resolution	O
of	O
the	O
cointegrate	O
structures	O
.	O

The	O
equivalent	O
of	O
the	O
third	O
ligand	O
,	O
H	O
-	O
87	O
,	O
is	O
T	O
-	O
47	O
in	O
the	O
PSTAIRE	O
sequence	O
motif	O
.	O

Botulinum	B-GENE
toxin	I-GENE
:	O
preferred	O
treatment	O
for	O
hemifacial	O
spasm	O
.	O

2	O
-	O
AP	O
induced	O
marked	O
,	O
steady	O
rises	O
in	O
mRNA	O
accumulation	O
from	O
both	O
transfected	O
and	O
chromosomally	O
integrated	O
HIV	O
-	O
1	O
constructs	O
but	O
no	O
increases	O
from	O
an	O
endogenous	O
gene	O
encoding	O
gamma	B-GENE
-	I-GENE
actin	I-GENE
or	O
glucose	B-GENE
6	I-GENE
-	I-GENE
phosphate	I-GENE
dehydrogenase	I-GENE
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
structures	O
of	O
the	O
b	O
-	O
Zip	O
domain	O
are	O
well	O
conserved	O
among	O
these	O
Maf	B-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
.	O

The	O
Functional	O
Independence	O
Measure	O
:	O
a	O
comparative	O
study	O
of	O
clinician	O
and	O
self	O
ratings	O
.	O

Polymyxin	O
B	O
was	O
given	O
intravenously	O
for	O
1	O
week	O
postburn	O
in	O
doses	O
designed	O
to	O
neutralize	O
circulating	O
endotoxemia	O
.	O

SvO2	O
can	O
be	O
determined	O
in	O
vitro	O
and	O
in	O
vivo	O
.	O

The	O
transverse	O
relaxation	O
time	O
(	O
T2	O
)	O
and	O
apparent	O
diffusion	O
coefficient	O
of	O
water	O
were	O
determined	O
.	O

These	O
findings	O
suggest	O
a	O
functional	O
cross	O
-	O
talk	O
between	O
RB	B-GENE
protein	I-GENE
and	O
p21ras	B-GENE
,	O
which	O
balances	O
the	O
cell	O
phenotype	O
between	O
normal	O
and	O
transformed	O
states	O
.	O

The	O
other	O
transmembrane	O
regions	O
as	O
well	O
as	O
the	O
nucleoplasmic	O
domain	O
are	O
not	O
required	O
for	O
sorting	O
.	O

These	O
cell	O
lines	O
,	O
selected	O
for	O
the	O
ability	O
to	O
support	O
the	O
replication	O
of	O
a	O
temperature	O
-	O
sensitive	O
VP5	B-GENE
mutant	I-GENE
,	O
were	O
used	O
to	O
isolate	O
VP5	B-GENE
and	O
VP23	B-GENE
null	O
mutants	O
.	O

The	O
E1	B-GENE
nuclear	I-GENE
transport	I-GENE
motif	I-GENE
is	O
highly	O
conserved	O
in	O
the	O
animal	O
and	O
human	O
papillomaviruses	O
and	O
is	O
encoded	O
in	O
a	O
similar	O
region	O
in	O
the	O
related	O
E1	B-GENE
genes	I-GENE
.	O

The	O
E1	B-GENE
replication	I-GENE
protein	I-GENE
of	O
bovine	O
papillomavirus	O
type	O
1	O
contains	O
an	O
extended	O
nuclear	O
localization	O
signal	O
that	O
includes	O
a	O
p34cdc2	B-GENE
phosphorylation	O
site	O
.	O

In	O
the	O
present	O
study	O
,	O
beta	O
-	O
funaltrexamine	O
(	O
beta	O
-	O
FNA	O
)	O
and	O
naltrindole	O
(	O
NTI	O
)	O
(	O
nonequilibrium	O
mu	O
-	O
and	O
delta	O
-	O
antagonist	O
,	O
respectively	O
)	O
were	O
used	O
to	O
precipitate	O
withdrawal	O
in	O
butorphanol	O
-	O
dependent	O
rats	O
.	O

Mutations	O
at	O
the	O
extreme	O
C	O
-	O
terminus	O
of	O
EIAV	B-GENE
Tat	I-GENE
impaired	O
both	O
RNA	O
binding	O
and	O
activation	O
domain	O
functions	O
,	O
suggesting	O
effects	O
on	O
secondary	O
or	O
tertiary	O
structure	O
.	O

This	O
observation	O
suggests	O
that	O
the	O
methyl	O
-	O
directed	O
repair	O
system	O
utilizes	O
the	O
proximal	O
d	O
(	O
GATC	O
)	O
sequence	O
to	O
direct	O
correction	O
.	O

Lithium	O
phthalocyanine	O
(	O
LiPc	O
)	O
is	O
a	O
prototype	O
of	O
another	O
generation	O
of	O
synthetic	O
,	O
metallic	O
-	O
organic	O
,	O
paramagnetic	O
crystallites	O
that	O
appear	O
very	O
useful	O
for	O
in	O
vitro	O
and	O
in	O
vivo	O
electron	O
paramagnetic	O
resonance	O
oximetry	O
.	O

IE2	B-GENE
-	O
IE2	B-GENE
interactions	O
were	O
mapped	O
to	O
a	O
domain	O
containing	O
a	O
putative	O
helix	O
-	O
turn	O
-	O
helix	O
motif	O
located	O
near	O
the	O
C	O
terminus	O
of	O
IE2	B-GENE
,	O
between	O
amino	O
acids	O
456	O
and	O
539	O
.	O

Precipitation	O
using	O
GST	B-GENE
fusion	I-GENE
proteins	I-GENE
containing	O
Fyn	B-GENE
SH2	B-GENE
,	O
SH3	B-GENE
,	O
and	O
SH2	B-GENE
/	O
SH3	B-GENE
domains	O
revealed	O
that	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
bound	O
principally	O
to	O
the	O
SH3	B-GENE
domain	I-GENE
of	O
Fyn	B-GENE
.	O

A	O
sheep	O
testicular	O
cDNA	O
library	O
constructed	O
in	O
pcDNA1	O
vector	O
was	O
screened	O
with	O
a	O
probe	O
generated	O
by	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
and	O
corresponding	O
to	O
a	O
1	O
.	O
6	O
kb	O
fragment	O
of	O
the	O
rat	B-GENE
luteinizing	I-GENE
hormone	I-GENE
receptor	I-GENE
cDNA	I-GENE
.	O

Two	O
putative	O
Rev	B-GENE
proteins	I-GENE
with	O
apparent	O
molecular	O
masses	O
of	O
18	O
and	O
16	O
kDa	O
were	O
expressed	O
by	O
p2	B-GENE
/	I-GENE
2	I-GENE
and	O
p176	B-GENE
,	O
while	O
p20	B-GENE
expressed	O
only	O
a	O
16	O
-	O
kDa	O
species	O
.	O

Defects	O
of	O
fibrillin	B-GENE
(	O
FBN1	B-GENE
)	O
,	O
a	O
glycoprotein	O
component	O
of	O
the	O
extracellular	O
microfibril	O
,	O
cause	O
Marfan	O
syndrome	O
.	O

A	O
region	O
approximately	O
100	O
bp	O
upstream	O
from	O
the	O
transcription	O
start	O
point	O
of	O
virB	B-GENE
was	O
identified	O
as	O
being	O
necessary	O
for	O
full	O
activation	O
of	O
this	O
promoter	O
by	O
VirF	B-GENE
.	O

METHODS	O
:	O
Fifty	O
-	O
one	O
healthy	O
eyes	O
,	O
169	O
ocular	O
hypertensive	O
eyes	O
with	O
normal	O
visual	O
fields	O
,	O
and	O
132	O
glaucomatous	O
eyes	O
with	O
early	O
visual	O
field	O
defects	O
were	O
evaluated	O
with	O
qualitative	O
and	O
quantitative	O
measures	O
of	O
structural	O
damage	O
to	O
the	O
optic	O
nerve	O
and	O
nerve	O
fiber	O
layer	O
.	O

Consistent	O
with	O
the	O
hypothesis	O
that	O
it	O
acts	O
as	O
transcriptional	O
regulator	O
,	O
wild	B-GENE
-	I-GENE
type	I-GENE
p53	I-GENE
protein	I-GENE
binds	O
DNA	O
and	O
activates	O
transcription	O
of	O
several	O
promoters	O
.	O

Instead	O
,	O
mRNA	O
of	O
2	O
.	O
0	O
and	O
2	O
.	O
8	O
kb	O
are	O
detected	O
in	O
varying	O
abundance	O
.	O

The	O
sequence	O
of	O
the	O
HIR1	B-GENE
gene	I-GENE
predicts	O
an	O
88	O
-	O
kDa	O
protein	O
with	O
three	O
repeats	O
of	O
a	O
motif	O
found	O
in	O
the	O
G	B-GENE
beta	I-GENE
subunit	I-GENE
of	O
retinal	B-GENE
transducin	I-GENE
and	O
in	O
a	O
yeast	O
transcriptional	O
repressor	O
,	O
Tup1	B-GENE
.	O

All	O
of	O
these	O
data	O
suggest	O
that	O
replication	O
of	O
UV	O
-	O
damaged	O
templates	O
occurs	O
in	O
vitro	O
as	O
it	O
does	O
in	O
vivo	O
and	O
that	O
this	O
replication	O
results	O
in	O
mutation	O
fixation	O
.	O

Biol	O
.	O

265	O
,	O
1102	O
-	O
1110	O
)	O
.	O

The	O
use	O
of	O
this	O
model	O
for	O
investigating	O
pathophysiologically	O
significant	O
issues	O
in	O
denervating	O
diseases	O
is	O
illustrated	O
with	O
five	O
different	O
sets	O
of	O
parameters	O
.	O

We	O
describe	O
a	O
novel	O
cytoplasmic	B-GENE
tyrosine	I-GENE
kinase	I-GENE
,	O
termed	O
BPK	B-GENE
(	O
B	B-GENE
cell	I-GENE
progenitor	I-GENE
kinase	I-GENE
)	O
,	O
which	O
is	O
expressed	O
in	O
all	O
stages	O
of	O
the	O
B	O
lineage	O
and	O
in	O
myeloid	O
cells	O
.	O

However	O
,	O
L	B-GENE
-	I-GENE
plastin	I-GENE
has	O
been	O
found	O
in	O
many	O
types	O
of	O
malignant	O
human	O
cells	O
of	O
non	O
-	O
hemopoietic	O
origin	O
suggesting	O
that	O
its	O
expression	O
is	O
induced	O
accompanying	O
tumorigenesis	O
in	O
solid	O
tissues	O
.	O

Finally	O
,	O
we	O
present	O
evidence	O
that	O
fimbrin	B-GENE
is	O
a	O
third	O
distinct	O
plastin	B-GENE
isoform	I-GENE
which	O
is	O
specifically	O
expressed	O
at	O
high	O
levels	O
in	O
the	O
small	O
intestine	O
.	O

The	O
DNase	B-GENE
I	I-GENE
footprint	O
extended	O
5	O
'	O
in	O
the	O
silencer	O
region	O
to	O
include	O
an	O
inverted	O
repeat	O
of	O
a	O
six	O
-	O
nucleotide	O
motif	O
(	O
epsilon	O
-	O
267	O
to	O
-	O
278	O
bp	O
)	O
which	O
shares	O
5	O
of	O
6	O
bases	O
with	O
the	O
GATA	B-GENE
-	I-GENE
1	I-GENE
consensus	I-GENE
sequence	I-GENE
.	O

Furthermore	O
,	O
competitor	O
containing	O
the	O
YY1	B-GENE
consensus	I-GENE
sequence	I-GENE
competed	O
for	O
protein	B-GENE
B	I-GENE
binding	O
,	O
whereas	O
competitor	O
containing	O
a	O
perfect	O
yeast	B-GENE
ABF	I-GENE
-	I-GENE
1	I-GENE
consensus	I-GENE
sequence	I-GENE
did	O
not	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Naval	O
personnel	O
who	O
exceed	O
standards	O
for	O
%	O
BF	O
can	O
be	O
separated	O
from	O
active	O
duty	O
.	O

Weak	O
promoter	O
activity	O
was	O
observed	O
for	O
the	O
promoter	O
of	O
the	O
C1	B-GENE
and	O
C2	B-GENE
ORFs	O
(	O
C1	B-GENE
-	O
C2	B-GENE
gene	O
)	O
and	O
for	O
the	O
promoter	O
of	O
the	O
V1	B-GENE
ORF	I-GENE
.	O

The	O
activity	O
of	O
the	O
coat	B-GENE
protein	I-GENE
promoter	I-GENE
of	O
chloris	O
striate	O
mosaic	O
virus	O
is	O
enhanced	O
by	O
its	O
own	O
and	O
C1	B-GENE
-	O
C2	B-GENE
gene	O
products	O
.	O

The	O
amino	O
acid	O
sequence	O
alignment	O
of	O
TC	B-GENE
II	I-GENE
with	O
that	O
of	O
other	O
Cbl	B-GENE
binding	I-GENE
proteins	I-GENE
(	O
rat	B-GENE
intrinsic	I-GENE
factor	I-GENE
,	O
human	B-GENE
transcobalamin	I-GENE
I	I-GENE
and	O
porcine	B-GENE
haptocorrin	I-GENE
)	O
revealed	O
only	O
33	O
%	O
overall	O
homology	O
.	O

This	O
short	O
communication	O
compares	O
a	O
novel	O
fluorimetric	O
microplate	O
enzyme	O
immunoassay	O
(	O
FEIA	O
)	O
with	O
a	O
commercial	O
time	O
-	O
resolved	O
fluoroimmunoassay	O
for	O
the	O
determination	O
of	O
thyrotropin	B-GENE
in	O
dried	O
blood	O
spots	O
.	O

The	O
evaluation	O
was	O
performed	O
using	O
a	O
retrospective	O
study	O
design	O
with	O
newborn	O
blood	O
samples	O
from	O
three	O
screening	O
centres	O
.	O

When	O
ligated	O
to	O
the	O
proIL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
cap	I-GENE
site	I-GENE
-	I-GENE
proximal	I-GENE
region	I-GENE
(	O
located	O
between	O
-	O
131	O
to	O
+	O
12	O
)	O
,	O
both	O
the	O
proIL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
and	O
the	O
simian	B-GENE
virus	I-GENE
40	I-GENE
enhancer	I-GENE
elements	I-GENE
functioned	O
more	O
efficiently	O
in	O
monocytes	O
than	O
in	O
HeLa	O
cells	O
,	O
which	O
are	O
not	O
normally	O
competent	O
for	O
IL	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
expression	O
.	O

Therefore	O
,	O
PC	B-GENE
-	I-GENE
PLC	I-GENE
is	O
a	O
component	O
of	O
a	O
signal	O
transduction	O
pathway	O
leading	O
to	O
transcription	O
of	O
c	B-GENE
-	I-GENE
fos	I-GENE
and	O
junB	B-GENE
that	O
collaborates	O
with	O
c	B-GENE
-	I-GENE
myc	I-GENE
and	O
is	O
independent	O
of	O
PKC	B-GENE
-	I-GENE
delta	I-GENE
and	O
Ras	B-GENE
activation	O
.	O

Southern	O
blot	O
analysis	O
using	O
probes	O
from	O
the	O
3	O
'	O
portions	O
of	O
the	O
genomic	O
and	O
B	B-GENE
.	I-GENE
napus	I-GENE
MA	I-GENE
and	O
MB	B-GENE
cDNA	I-GENE
clones	O
showed	O
that	O
MA	B-GENE
type	I-GENE
myrosinases	B-GENE
are	O
encoded	O
by	O
approximately	O
4	O
genes	O
,	O
while	O
MB	B-GENE
type	I-GENE
myrosinases	B-GENE
are	O
encoded	O
by	O
more	O
than	O
10	O
genes	O
in	O
B	O
.	O
napus	O
.	O

Type	O
II	O
could	O
be	O
divided	O
further	O
into	O
two	O
forms	O
(	O
IIA	O
and	O
IIB	O
)	O
that	O
may	O
represent	O
two	O
underscribed	O
species	O
or	O
developmental	O
stages	O
of	O
the	O
same	O
species	O
.	O

In	O
the	O
present	O
study	O
we	O
demonstrated	O
a	O
unique	O
mechanism	O
of	O
action	O
of	O
8	O
-	O
Cl	O
-	O
cAMP	O
in	O
the	O
regulation	O
of	O
these	O
kinase	O
isozymes	O
in	O
HL	O
-	O
60	O
human	O
promyelocytic	O
leukemia	O
cells	O
.	O

There	O
are	O
,	O
however	O
,	O
several	O
differences	O
between	O
the	O
two	O
new	O
ars	O
sequences	O
.	O

Pokeweed	B-GENE
mitogen	I-GENE
(	O
PWM	B-GENE
)	O
or	O
anti	B-GENE
-	I-GENE
CD3	I-GENE
significantly	O
increases	O
c	B-GENE
-	I-GENE
jun	I-GENE
messenger	I-GENE
RNA	I-GENE
(	I-GENE
mRNA	I-GENE
)	I-GENE
levels	O
in	O
T	O
cells	O
.	O

Following	O
seizure	O
induction	O
,	O
MABP	O
increased	O
to	O
105	O
mm	O
Hg	O
and	O
brain	O
pHi	O
fell	O
to	O
6	O
.	O
79	O
+	O
/	O
-	O
0	O
.	O
03	O
within	O
15	O
min	O
and	O
remained	O
at	O
this	O
level	O
for	O
1	O
h	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Sterile	O
mutants	O
of	O
Saccharomyces	O
cerevisiae	O
were	O
isolated	O
from	O
alpha	O
*	O
cells	O
having	O
the	O
a	B-GENE
/	I-GENE
alpha	I-GENE
aar1	I-GENE
-	I-GENE
6	I-GENE
genotype	O
(	O
exhibiting	O
alpha	O
mating	O
ability	O
and	O
weak	O
a	O
mating	O
ability	O
as	O
a	O
result	O
of	O
a	O
defect	O
in	O
a1	B-GENE
-	I-GENE
alpha	I-GENE
2	I-GENE
repression	O
)	O
.	O

OBJECTIVE	O
:	O
Our	O
purpose	O
was	O
to	O
determine	O
the	O
simultaneous	O
concentrations	O
of	O
serum	O
cotinine	O
in	O
both	O
fetal	O
and	O
maternal	O
blood	O
.	O

5	O
micrograms	O
/	O
l	O
was	O
detected	O
in	O
urine	O
from	O
some	O
non	O
-	O
occupationally	O
exposed	O
persons	O
.	O

Finger	B-GENE
associated	I-GENE
box	I-GENE
-	I-GENE
zinc	I-GENE
finger	I-GENE
proteins	I-GENE
(	O
FAX	B-GENE
-	I-GENE
ZFPs	I-GENE
)	O
constitute	O
a	O
subfamily	O
of	O
the	O
many	O
C2H2	B-GENE
type	I-GENE
ZFPs	I-GENE
in	O
Xenopus	O
laevis	O
.	O

Further	O
evidence	O
for	O
a	O
clustered	O
organization	O
of	O
FAX	B-GENE
-	O
ZFP	B-GENE
transcription	O
units	O
is	O
provided	O
by	O
Southern	O
blot	O
analysis	O
of	O
large	O
genomic	O
restriction	O
fragments	O
separated	O
by	O
transverse	O
field	O
gel	O
electrophoresis	O
,	O
and	O
by	O
in	O
situ	O
hybridization	O
on	O
intact	O
chromosomes	O
.	O

Mutational	O
analyses	O
have	O
demonstrated	O
the	O
importance	O
of	O
sequences	O
within	O
the	O
327	O
bp	O
segment	O
that	O
contain	O
a	O
putative	O
cyclic	B-GENE
AMP	I-GENE
responsive	I-GENE
element	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CREB	B-GENE
)	O
binding	O
site	O
for	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
1	I-GENE
and	O
PMA	O
responsiveness	O
and	O
putative	O
PU	B-GENE
-	I-GENE
1	I-GENE
and	O
Sp1	B-GENE
binding	I-GENE
sites	I-GENE
for	O
basal	O
promoter	O
activity	O
.	O

(	O
1992	O
)	O
J	O
.	O

We	O
obtained	O
the	O
prevalence	O
of	O
IgG	B-GENE
antibodies	I-GENE
against	O
Trypanosoma	O
cruzi	O
among	O
1076	O
blood	O
donors	O
at	O
the	O
Instituto	O
Nacional	O
de	O
Cardiologia	O
"	O
Ignacio	O
Chavez	O
"	O
in	O
Mexico	O
City	O
.	O

Examination	O
of	O
the	O
immediate	O
sequence	O
5	O
'	O
to	O
the	O
mRNA	O
start	O
site	O
reveals	O
no	O
TATA	O
box	O
and	O
multiple	O
known	O
enhancer	O
sequences	O
.	O

Pseudosubstrate	O
(	O
19	O
-	O
36	O
)	O
,	O
derived	O
from	O
the	O
C	O
-	O
terminus	O
of	O
Ca	B-GENE
-	I-GENE
dependent	I-GENE
PKC	I-GENE
isotypes	I-GENE
,	O
inhibited	O
beta	B-GENE
-	I-GENE
PKC	I-GENE
but	O
not	O
nPKC	B-GENE
activity	O
using	O
either	O
Histone	B-GENE
IIIS	I-GENE
or	O
peptide	O
(	O
19	O
-	O
31	O
)	O
as	O
substrate	O
.	O

This	O
may	O
account	O
,	O
at	O
least	O
in	O
part	O
,	O
for	O
the	O
ability	O
of	O
excess	O
wt	B-GENE
p53	I-GENE
to	O
inhibit	O
cell	O
proliferation	O
and	O
to	O
interfere	O
with	O
neoplastic	O
processes	O
.	O

Northern	O
blot	O
analysis	O
of	O
total	O
cellular	O
RNA	O
indicated	O
that	O
xylP	B-GENE
encodes	O
a	O
1	O
.	O
3	O
-	O
kb	O
transcript	O
which	O
is	O
induced	O
by	O
xylan	O
.	O

These	O
data	O
show	O
that	O
PTH	B-GENE
and	O
cAMP	O
can	O
repress	O
collagen	B-GENE
promoter	I-GENE
activity	O
in	O
calvariae	O
from	O
transgenic	O
mice	O
,	O
suggesting	O
that	O
the	O
alpha	B-GENE
1	I-GENE
(	I-GENE
I	I-GENE
)	I-GENE
collagen	I-GENE
promoter	I-GENE
may	O
contain	O
cis	O
elements	O
down	O
-	O
stream	O
of	O
-	O
2	O
.	O
3	O
kilobases	O
that	O
mediate	O
PTH	B-GENE
and	O
cAMP	O
repression	O
of	O
collagen	B-GENE
gene	I-GENE
expression	O
in	O
bone	O
.	O

The	O
yeast	O
gene	O
that	O
encodes	O
eIF	B-GENE
-	I-GENE
5	I-GENE
,	O
designated	O
TIF5	B-GENE
,	O
has	O
been	O
isolated	O
and	O
expressed	O
in	O
Escherichia	O
coli	O
to	O
yield	O
a	O
catalytically	O
active	O
eIF	B-GENE
-	I-GENE
5	I-GENE
protein	I-GENE
.	O

Xylose	O
-	O
and	O
arabinose	O
-	O
containing	O
polymers	O
were	O
better	O
digested	O
than	O
was	O
cellulose	O
for	O
both	O
breads	O
.	O

The	O
alpha	O
-	O
subunit	O
by	O
itself	O
binds	O
to	O
telomeric	O
DNA	O
.	O

We	O
conclude	O
that	O
the	O
alpha	O
-	O
subunit	O
of	O
the	O
telomere	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
,	O
like	O
many	O
transcription	O
factors	O
,	O
has	O
separable	O
DNA	O
-	O
binding	O
and	O
protein	O
-	O
protein	O
interaction	O
domains	O
.	O

Calcification	O
of	O
a	O
cariogenic	O
Streptococcus	O
and	O
of	O
Corynebacterium	O
(	O
Bacterionema	O
)	O
matruchotii	O
.	O

A	O
comparison	O
of	O
the	O
promoters	O
for	O
muMIP	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
and	O
muMIP	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
reveals	O
a	O
conserved	O
CK	O
-	O
1	O
element	O
,	O
but	O
transient	O
expression	O
studies	O
in	O
RAW	O
264	O
.	O
7	O
macrophages	O
with	O
proximal	O
fragments	O
of	O
either	O
the	O
muMIP	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
or	O
the	O
muMIP	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
5	I-GENE
'	I-GENE
promoter	I-GENE
fused	O
to	O
a	O
human	B-GENE
growth	I-GENE
hormone	I-GENE
reporter	I-GENE
gene	I-GENE
link	O
LPS	O
-	O
inducibility	O
in	O
both	O
to	O
promoter	O
segments	O
near	O
to	O
,	O
but	O
not	O
identical	O
with	O
,	O
the	O
consensus	O
CK	O
-	O
1	O
sequence	O
.	O

Sequence	O
analysis	O
and	O
identification	O
of	O
two	O
hyp	B-GENE
regulatory	I-GENE
mutants	I-GENE
.	O

The	O
gene	O
encoding	O
the	O
receptor	O
for	O
macrophage	B-GENE
colony	I-GENE
-	I-GENE
stimulating	I-GENE
factor	I-GENE
1	I-GENE
(	O
CSF	B-GENE
-	I-GENE
1	I-GENE
)	O
,	O
the	O
c	B-GENE
-	I-GENE
fms	I-GENE
protooncogene	I-GENE
,	O
is	O
selectively	O
expressed	O
in	O
immature	O
and	O
mature	O
mononuclear	O
phagocytes	O
and	O
trophoblasts	O
.	O

Since	O
the	O
regulation	O
of	O
SWI4	B-GENE
is	O
required	O
for	O
normal	O
cell	O
cycle	O
progression	O
,	O
we	O
have	O
characterized	O
cis	O
-	O
and	O
trans	O
-	O
acting	O
regulators	O
of	O
SWI4	B-GENE
transcription	O
.	O

It	O
also	O
suggests	O
that	O
there	O
is	O
another	O
pathway	O
which	O
can	O
activate	O
SWI4	B-GENE
transcription	O
in	O
the	O
absence	O
of	O
SWI6	B-GENE
.	O

Multiple	O
SWI6	B-GENE
-	O
dependent	O
cis	O
-	O
acting	O
elements	O
control	O
SWI4	B-GENE
transcription	O
through	O
the	O
cell	O
cycle	O
.	O

Biol	O
.	O

Patient	O
characteristics	O
associated	O
with	O
deep	O
wounds	O
as	O
well	O
as	O
patient	O
and	O
wound	O
characteristics	O
predictive	O
of	O
the	O
extent	O
of	O
healing	O
and	O
time	O
required	O
for	O
healing	O
were	O
identified	O
.	O

Yeast	O
mutants	O
lacking	O
a	O
functional	O
NOP1	B-GENE
gene	I-GENE
can	O
be	O
complemented	O
by	O
human	B-GENE
fibrillarin	I-GENE
but	O
are	O
temperature	O
sensitive	O
for	O
growth	O
and	O
impaired	O
in	O
pre	O
-	O
rRNA	O
processing	O
.	O

The	O
patients	O
were	O
divided	O
into	O
ischaemia	O
and	O
non	O
-	O
ischaemia	O
groups	O
on	O
the	O
basis	O
of	O
the	O
change	O
in	O
lactate	O
extraction	O
ratio	O
during	O
balloon	O
inflation	O
.	O

Both	O
immunophilins	B-GENE
may	O
have	O
important	O
roles	O
in	O
receptor	O
assembly	O
and	O
may	O
represent	O
a	O
new	O
category	O
of	O
ligand	O
-	O
and	O
calcium	O
-	O
dependent	O
modulators	O
of	O
protein	O
function	O
.	O

Umweltchem	O
.	O

Contrary	O
to	O
expectations	O
,	O
we	O
find	O
a	O
relatively	O
high	O
level	O
of	O
variation	O
in	O
the	O
stripe	B-GENE
2	I-GENE
enhancer	O
region	O
,	O
including	O
point	O
substitutions	O
and	O
insertion	O
/	O
deletions	O
in	O
binding	O
sites	O
,	O
and	O
a	O
comparable	O
level	O
of	O
variation	O
in	O
the	O
other	O
noncoding	O
regions	O
.	O

I	O
report	O
here	O
that	O
induction	O
of	O
HSP82	B-GENE
is	O
regulated	O
by	O
the	O
early	O
meiotic	O
IME1	B-GENE
-	O
IME2	B-GENE
transcriptional	O
cascade	O
.	O

Refugees	O
living	O
in	O
Lund	O
and	O
repatriated	O
to	O
Chile	O
considered	O
their	O
health	O
as	O
bad	O
in	O
a	O
higher	O
proportion	O
than	O
their	O
Swedish	O
counterparts	O
,	O
with	O
an	O
odds	O
ratio	O
of	O
3	O
.	O
48	O
(	O
2	O
.	O
03	O
-	O
5	O
.	O
66	O
)	O
and	O
4	O
.	O
78	O
(	O
2	O
.	O
1	O
-	O
10	O
.	O
25	O
)	O
respectively	O
.	O

This	O
study	O
underlines	O
the	O
importance	O
of	O
terminal	O
SC5b	B-GENE
-	I-GENE
9	I-GENE
complement	I-GENE
complex	I-GENE
as	O
a	O
suitable	O
marker	O
in	O
the	O
evaluation	O
of	O
complement	O
activation	O
during	O
cardiopulmonary	O
bypass	O
.	O

Striking	O
sequence	O
similarities	O
(	O
57	O
and	O
53	O
%	O
)	O
were	O
observed	O
with	O
yeast	O
mitochondrial	O
proteins	O
,	O
SMF1	B-GENE
and	O
SMF2	B-GENE
,	O
especially	O
within	O
putative	O
functional	O
domains	O
:	O
exon	O
6	O
encoding	O
the	O
second	O
transmembrane	O
spanning	O
domain	O
,	O
site	O
of	O
the	O
murine	B-GENE
susceptibility	I-GENE
mutation	O
;	O
and	O
exon	O
11	O
encoding	O
a	O
conserved	O
transport	O
motif	O
.	O

Furthermore	O
,	O
we	O
have	O
identified	O
a	O
soluble	O
form	O
of	O
ERp57	B-GENE
/	O
GRP58	B-GENE
by	O
Western	O
blotting	O
and	O
biosynthetic	O
labeling	O
.	O

Consistent	O
with	O
the	O
hepatic	O
and	O
epidermal	O
expression	O
of	O
histidase	B-GENE
,	O
this	O
finding	O
suggests	O
that	O
histidase	B-GENE
transcription	O
may	O
be	O
regulated	O
by	O
these	O
factors	O
.	O

Unlike	O
ARF	B-GENE
,	O
the	O
ARP	B-GENE
immunoreactivity	O
was	O
detected	O
in	O
plasma	O
membranes	O
but	O
not	O
in	O
cytosol	O
of	O
fractionated	O
3T3	O
-	O
L1	O
cells	O
.	O

An	O
infectious	O
origin	O
should	O
always	O
be	O
excluded	O
since	O
specific	O
etiologic	O
therapy	O
may	O
be	O
implemented	O
.	O

All	O
three	O
NR	B-GENE
isoforms	I-GENE
are	O
expressed	O
in	O
cv	O
.	O

All	O
three	O
NR	B-GENE
isoforms	O
are	O
expressed	O
in	O
cv	O
.	O

The	O
Arabidopsis	B-GENE
FAD7	I-GENE
gene	I-GENE
encodes	O
a	O
chloroplast	B-GENE
omega	I-GENE
-	I-GENE
3	I-GENE
fatty	I-GENE
acid	I-GENE
desaturase	I-GENE
that	O
catalyzes	O
the	O
desaturation	O
of	O
lipid	O
-	O
linked	O
dienoic	O
fatty	O
acids	O
(	O
18	O
:	O
2	O
and	O
16	O
:	O
2	O
)	O
.	O

Certain	O
transcript	O
patterns	O
in	O
Epifagus	O
plastids	O
are	O
highly	O
complex	O
and	O
similar	O
to	O
those	O
of	O
tobacco	O
operons	O
.	O

The	O
XS2	B-GENE
gene	I-GENE
down	O
-	O
regulates	O
but	O
does	O
not	O
abolish	O
expression	O
of	O
LU	B-GENE
genes	I-GENE
and	O
does	O
not	O
affect	O
expression	O
of	O
CD44	B-GENE
.	O

Diabetes	O
care	O
:	O
a	O
guideline	O
to	O
the	O
facilities	O
needed	O
to	O
support	O
internationally	O
endorsed	O
standards	O
.	O

The	O
gene	O
was	O
uniquely	O
mapped	O
with	O
odds	O
>	O
1	O
,	O
000	O
:	O
1	O
on	O
chromosome	O
3p	O
in	O
Centre	O
d	O
'	O
Etude	O
du	O
Polymorphisme	O
Humain	O
pedigrees	O
.	O

Human	B-GENE
LAF	I-GENE
-	I-GENE
4	I-GENE
readily	O
hybridized	O
with	O
genes	O
in	O
mouse	O
and	O
chicken	O
,	O
thus	O
showing	O
that	O
this	O
gene	O
family	O
has	O
been	O
highly	O
conserved	O
during	O
vertebrate	O
evolution	O
.	O

Cycles	O
were	O
repeated	O
every	O
3	O
weeks	O
.	O

Upstream	O
of	O
-	O
37	O
,	O
the	O
5	O
'	O
untranslated	O
sequences	O
of	O
the	O
isolates	O
differ	O
in	O
both	O
length	O
and	O
sequence	O
.	O

SBF	B-GENE
binds	O
to	O
the	O
promoter	O
prior	O
to	O
the	O
activation	O
of	O
transcription	O
in	O
late	O
G1	O
,	O
suggesting	O
that	O
Cln	B-GENE
/	O
Cdc28	B-GENE
kinase	O
regulates	O
the	O
ability	O
of	O
previously	O
bound	O
SBF	B-GENE
to	O
activate	O
transcription	O
.	O

However	O
,	O
it	O
remains	O
an	O
open	O
question	O
whether	O
vertebrate	B-GENE
Hox	I-GENE
genes	I-GENE
expressed	O
under	O
the	O
control	O
of	O
Drosophila	O
regulatory	O
sequences	O
can	O
substitute	O
the	O
function	O
of	O
Drosophila	B-GENE
Hox	I-GENE
genes	I-GENE
.	O

This	O
approach	O
places	O
gHoxb	B-GENE
-	I-GENE
1	I-GENE
into	O
the	O
normal	O
embryonic	O
spatiotemporal	O
context	O
in	O
which	O
lab	O
acts	O
.	O

We	O
propose	O
that	O
CTS1	B-GENE
and	I-GENE
CTS2	I-GENE
of	I-GENE
Ci	I-GENE
are	O
members	O
of	O
two	O
distinct	O
classes	O
of	O
fungal	B-GENE
chitinases	I-GENE
,	O
an	O
observation	O
not	O
previously	O
reported	O
for	O
a	O
single	O
fungus	O
.	O

The	O
purpose	O
of	O
the	O
study	O
reported	O
here	O
was	O
to	O
investigate	O
whether	O
differences	O
in	O
T1	O
and	O
T2	O
between	O
tumors	O
are	O
mainly	O
a	O
consequence	O
of	O
differences	O
in	O
the	O
fractional	O
volume	O
of	O
the	O
extracellular	O
compartment	O
.	O

A	O
mutant	B-GENE
areA	I-GENE
product	I-GENE
truncated	O
immediately	O
after	O
the	O
last	O
residue	O
of	O
the	O
highly	O
conserved	O
GATA	B-GENE
(	I-GENE
DNA	I-GENE
-	I-GENE
binding	I-GENE
)	I-GENE
domain	I-GENE
retains	O
partial	O
function	O
.	O

This	O
region	O
contains	O
a	O
motif	O
with	O
partial	O
identity	O
with	O
the	O
binding	O
site	O
for	O
the	O
ubiquitous	O
transcription	O
factor	O
upstream	B-GENE
stimulatory	I-GENE
factor	I-GENE
(	O
USF	B-GENE
)	O
,	O
which	O
binds	O
to	O
the	O
human	B-GENE
insulin	I-GENE
promoter	I-GENE
.	O

The	O
Clb5	B-GENE
kinase	I-GENE
,	O
which	O
promotes	O
S	O
phase	O
,	O
remains	O
active	O
during	O
the	O
G2	O
-	O
phase	O
arrest	O
of	O
cells	O
of	O
the	O
parental	O
strain	O
,	O
but	O
its	O
activity	O
declines	O
rapidly	O
in	O
sim	B-GENE
mutants	I-GENE
.	O

The	O
C	O
/	O
D	O
ratio	O
was	O
equal	O
to	O
or	O
over	O
0	O
.	O
6	O
in	O
9	O
cases	O
(	O
16	O
eyes	O
)	O
,	O
and	O
the	O
values	O
were	O
inconsistent	O
between	O
both	O
eyes	O
in	O
55	O
%	O
of	O
the	O
patients	O
.	O

(	O
1989	O
)	O
,	O
which	O
is	O
identical	O
to	O
the	O
SSC1	B-GENE
gene	I-GENE
(	O
Smith	O
et	O
al	O
.	O
,	O
1988	O
)	O
.	O

This	O
region	O
also	O
contains	O
a	O
gene	O
specifying	O
a	O
Leu	B-GENE
-	I-GENE
tRNA	I-GENE
precursor	I-GENE
and	O
a	O
remnant	O
of	O
a	O
tau	O
element	O
.	O

Occupational	O
exposure	O
to	O
hepatitis	O
B	O
virus	O
and	O
human	O
immunodeficiency	O
virus	O
:	O
a	O
comparative	O
risk	O
analysis	O
.	O

In	O
these	O
constructs	O
,	O
GUS	B-GENE
expression	O
was	O
driven	O
by	O
promoter	O
regions	O
derived	O
from	O
the	O
Arabidopsis	B-GENE
alcohol	I-GENE
dehydrogenase	I-GENE
(	O
Adh1	B-GENE
)	O
,	O
maize	B-GENE
ubiquitin	I-GENE
(	O
Ubi1	B-GENE
)	O
,	O
rice	B-GENE
actin	I-GENE
(	O
Act1	B-GENE
)	O
and	O
CaMV	B-GENE
35S	I-GENE
genes	I-GENE
.	O

Its	O
organization	O
and	O
regulation	O
indicate	O
that	O
the	O
S	B-GENE
.	I-GENE
pombe	I-GENE
URA1	I-GENE
gene	I-GENE
product	I-GENE
appears	O
very	O
similar	O
to	O
the	O
S	B-GENE
.	I-GENE
cerevisiae	I-GENE
URA2	I-GENE
gene	I-GENE
product	I-GENE
.	O

(	O
ii	O
)	O
opening	O
of	O
KATP	O
attenuates	O
,	O
inhibition	O
of	O
the	O
channel	O
exacerbates	O
functional	O
consequences	O
of	O
coronary	O
occlusion	O
,	O
and	O
(	O
iii	O
)	O
KATP	O
opening	O
attenuates	O
reperfusion	O
-	O
induced	O
VF	O
,	O
but	O
it	O
triggers	O
ischemia	O
-	O
induced	O
VF	O
.	O

Effects	O
of	O
repeated	O
exposures	O
of	O
hydrogen	O
sulphide	O
on	O
rat	O
hippocampal	O
EEG	O
.	O

Pseudomembranous	O
conjunctivitis	O
following	O
bone	O
marrow	O
transplantation	O
:	O
immunopathological	O
and	O
ultrastructural	O
study	O
of	O
one	O
case	O
.	O

In	O
view	O
of	O
the	O
presence	O
of	O
SECIS	O
elements	O
in	O
the	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
of	O
bacterial	B-GENE
selenoproteins	I-GENE
,	O
we	O
examine	O
the	O
effects	O
in	O
the	O
type	B-GENE
1	I-GENE
deiodinase	I-GENE
of	O
extending	O
the	O
ORF	O
into	O
the	O
SECIS	O
element	O
,	O
and	O
find	O
that	O
this	O
dramatically	O
inhibits	O
SECIS	O
function	O
.	O

This	O
spindle	O
defect	O
of	O
pds1	B-GENE
mutants	I-GENE
results	O
from	O
a	O
temperature	O
-	O
sensitive	O
step	O
that	O
occurs	O
around	O
the	O
G1	O
/	O
S	O
boundary	O
about	O
the	O
time	O
of	O
spindle	O
assembly	O
.	O

In	O
the	O
point	O
mutant	O
we	O
observed	O
normal	O
repair	O
of	O
endonuclease	B-GENE
III	I-GENE
site	I-GENE
(	O
i	O
.	O
e	O
.	O
as	O
wild	O
type	O
)	O
,	O
but	O
no	O
removal	O
of	O
CPDs	O
at	O
the	O
MAT	B-GENE
alpha	I-GENE
and	O
HML	B-GENE
alpha	I-GENE
loci	I-GENE
.	O

However	O
,	O
for	O
the	O
evaluable	O
cases	O
,	O
the	O
performances	O
of	O
the	O
CD3500	O
and	O
the	O
STKS	O
were	O
broadly	O
similar	O
and	O
generally	O
correlated	O
well	O
with	O
the	O
manual	O
reference	O
procedure	O
.	O

In	O
conclusion	O
,	O
IgM	B-GENE
class	O
CIC	O
is	O
the	O
predominant	O
CIC	O
in	O
acute	O
hepatitis	O
A	O
and	O
correlated	O
with	O
disease	O
activity	O
.	O

Left	O
atrial	O
volumes	O
were	O
greater	O
in	O
old	O
compared	O
with	O
young	O
subjects	O
(	O
maximal	O
:	O
31	O
+	O
/	O
-	O
10	O
cm3	O
/	O
m2	O
vs	O
24	O
+	O
/	O
-	O
8	O
cm3	O
/	O
m2	O
,	O
p	O
=	O
0	O
.	O
02	O
;	O
at	O
onset	O
of	O
atrial	O
systole	O
:	O
23	O
+	O
/	O
-	O
8	O
cm3	O
/	O
m2	O
vs	O
15	O
+	O
/	O
-	O
5	O
cm3	O
/	O
m2	O
,	O
p	O
=	O
0	O
.	O
0002	O
;	O
minimal	O
:	O
13	O
+	O
/	O
-	O
5	O
cm3	O
/	O
m2	O
vs	O
9	O
+	O
/	O
-	O
4	O
cm3	O
/	O
m2	O
,	O
p	O
=	O
0	O
.	O
001	O
)	O
.	O

We	O
observed	O
abundant	O
levels	O
of	O
Rev	B-GENE
-	O
erbA	B-GENE
alpha	I-GENE
mRNA	O
in	O
dividing	O
C2C12	O
myoblasts	O
,	O
which	O
were	O
suppressed	O
when	O
the	O
cells	O
differentiated	O
into	O
postmitotic	O
multinucleated	O
myotubes	O
.	O

We	O
then	O
demonstrated	O
that	O
1	O
)	O
GAL4	B-GENE
-	O
REV	B-GENE
-	O
erbA	B-GENE
alpha	I-GENE
chimeras	O
that	O
contain	O
the	O
'	O
AB	O
'	O
region	O
and	O
lack	O
the	O
'	O
E	O
'	O
region	O
activated	O
transcription	O
of	O
GAL4	B-GENE
response	I-GENE
elements	I-GENE
in	O
the	O
presence	O
of	O
8	O
-	O
Br	O
-	O
cAMP	O
and	O
2	O
)	O
the	O
ligand	O
-	O
binding	O
domain	O
(	O
LBD	O
)	O
contains	O
an	O
active	O
transcriptional	O
silencer	O
.	O

TNF	B-GENE
Treatment	O
of	O
cell	O
activated	O
the	O
p38	B-GENE
MAP	I-GENE
kinase	I-GENE
pathway	O
,	O
as	O
revealed	O
by	O
increased	O
phosphorylation	O
of	O
p38	B-GENE
MAP	I-GENE
kinase	I-GENE
itself	O
,	O
activation	O
of	O
the	O
substrate	O
protein	O
MAPKAP	B-GENE
kinase	I-GENE
-	I-GENE
2	I-GENE
,	O
and	O
culminating	O
in	O
the	O
phosphorylation	O
of	O
the	O
heat	B-GENE
shock	I-GENE
protein	I-GENE
27	I-GENE
(	O
hsp27	B-GENE
)	O
.	O

However	O
,	O
while	O
the	O
sequence	O
similarity	O
between	O
the	O
membrane	O
exons	O
of	O
avian	B-GENE
mIgY	I-GENE
and	O
mammalian	B-GENE
mIgG	I-GENE
and	I-GENE
IgE	I-GENE
is	O
striking	O
,	O
the	O
overall	O
similarity	O
with	O
Xenopus	B-GENE
mIgY	I-GENE
is	O
very	O
low	O
.	O

The	O
novel	O
hematopoietic	B-GENE
growth	I-GENE
factor	I-GENE
FLT3	I-GENE
ligand	I-GENE
(	O
FL	B-GENE
)	O
is	O
the	O
cognate	O
ligand	O
for	O
the	O
FLT3	B-GENE
,	O
tyrosine	B-GENE
kinase	I-GENE
receptor	I-GENE
(	O
R	B-GENE
)	O
,	O
also	O
referred	O
to	O
as	O
FLK	B-GENE
-	I-GENE
2	I-GENE
and	O
STK	B-GENE
-	I-GENE
1	I-GENE
.	O

In	O
contrast	O
to	O
the	O
selective	O
expression	O
of	O
the	O
receptor	O
,	O
FL	B-GENE
expression	O
was	O
detected	O
in	O
90	O
-	O
100	O
%	O
of	O
the	O
various	O
cell	O
types	O
of	O
leukemia	O
cell	O
lines	O
from	O
all	O
hematopoietic	O
cell	O
lineages	O
.	O

LY290181	O
appears	O
to	O
inhibit	O
uPA	B-GENE
promoter	I-GENE
activation	O
by	O
blocking	O
phorbol	O
ester	O
-	O
stimulated	O
binding	O
of	O
nuclear	O
proteins	O
to	O
the	O
uPA	B-GENE
PEA3	B-GENE
/	O
12	O
-	O
0	O
-	O
tetradecanoylphorbol	O
13	O
-	O
acetate	O
responsive	O
element	O
(	O
TRE	O
)	O
.	O

The	O
protein	O
folds	O
correctly	O
with	O
two	O
disulfide	O
bonds	O
and	O
a	O
free	O
thiol	O
group	O
at	O
Cys25	O
.	O

No	O
significant	O
differences	O
existed	O
between	O
the	O
two	O
age	O
groups	O
in	O
baseline	O
characteristics	O
,	O
including	O
treatment	O
protocol	O
,	O
performance	O
status	O
,	O
and	O
serum	B-GENE
lactate	I-GENE
dehydrogenase	I-GENE
(	O
LDH	B-GENE
)	O
level	O
.	O

Conversely	O
,	O
when	O
VDR	B-GENE
is	O
overexpressed	O
,	O
vitamin	O
D3	O
attenuates	O
9	O
-	O
cis	O
RA	O
induction	O
from	O
an	O
RXR	B-GENE
-	O
responsive	O
element	O
.	O

Mutations	O
within	O
conserved	O
region	O
2	O
(	O
CR2	O
)	O
of	O
E1A	B-GENE
that	O
inhibit	O
the	O
binding	O
of	O
E1A	B-GENE
to	O
the	O
retinoblastoma	B-GENE
gene	I-GENE
product	I-GENE
(	O
pRb	B-GENE
)	O
further	O
enhanced	O
the	O
stimulation	O
of	O
transcription	O
from	O
the	O
PEPCK	B-GENE
promoter	I-GENE
by	O
2	O
3	O
-	O
fold	O
compared	O
with	O
wild	B-GENE
type	I-GENE
E1A	I-GENE
.	O

Using	O
autoantibodies	O
from	O
a	O
Sjogren	O
'	O
s	O
syndrome	O
patient	O
,	O
we	O
have	O
previously	O
identified	O
a	O
230	O
-	O
kDa	O
peripheral	O
membrane	O
protein	O
associated	O
with	O
the	O
cytosolic	O
face	O
of	O
the	O
trans	O
-	O
Golgi	O
(	O
Kooy	O
,	O
J	O
.	O
,	O
Toh	O
,	O
B	O
.	O

Apart	O
from	O
two	O
proline	O
-	O
rich	O
regions	O
(	O
amino	O
acids	O
1	O
-	O
117	O
and	O
239	O
-	O
270	O
)	O
,	O
p230	B-GENE
contains	O
a	O
very	O
high	O
frequency	O
of	O
heptad	O
repeats	O
,	O
characteristic	O
of	O
alpha	O
-	O
helices	O
that	O
form	O
dimeric	O
coiled	O
-	O
coil	O
structures	O
.	O
p230	B-GENE
also	O
includes	O
the	O
sequence	O
ESLALEELEL	O
(	O
amino	O
acids	O
538	O
-	O
546	O
)	O
,	O
a	O
motif	O
found	O
in	O
the	O
granin	B-GENE
family	I-GENE
of	O
acidic	O
proteins	O
present	O
in	O
secretory	O
granules	O
of	O
neuroendocrine	O
cells	O
.	O

They	O
were	O
found	O
to	O
stimulate	O
at	O
nanomolar	O
concentrations	O
the	O
turnover	O
of	O
biosynthetically	O
labeled	O
ceramide	O
,	O
glucosylceramide	O
,	O
and	O
lactosylceramide	O
.	O

These	O
findings	O
suggest	O
that	O
the	O
increase	O
in	O
V	O
O2	O
may	O
have	O
been	O
a	O
consequence	O
of	O
the	O
increase	O
in	O
Q	O
O2	O
rather	O
than	O
a	O
response	O
to	O
the	O
procedure	O
itself	O
.	O

Consistent	O
with	O
ErbB	B-GENE
-	I-GENE
2	I-GENE
being	O
a	O
shared	O
receptor	O
subunit	O
,	O
its	O
tyrosine	O
phosphorylation	O
was	O
increased	O
by	O
both	O
heterologous	O
ligands	O
and	O
it	O
mediated	O
a	O
trans	O
-	O
inhibitory	O
effect	O
of	O
NDF	B-GENE
on	O
EGF	B-GENE
binding	O
.	O

Identification	O
of	O
a	O
consensus	O
cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
phosphorylation	I-GENE
site	I-GENE
unique	O
to	O
the	O
nuclear	O
form	O
of	O
human	B-GENE
deoxyuridine	I-GENE
triphosphate	I-GENE
nucleotidohydrolase	I-GENE
.	O

VDR	B-GENE
/	O
RXR	B-GENE
bound	O
well	O
to	O
the	O
VDREs	O
and	O
to	O
DR4	O
and	O
DR5	O
using	O
the	O
electrophoretic	O
mobility	O
shift	O
assay	O
.	O

The	O
sequence	O
and	O
isolated	O
cDNAs	O
will	O
provide	O
useful	O
reagents	O
for	O
studying	O
the	O
expression	O
of	O
Brca1	B-GENE
in	O
the	O
mouse	O
,	O
and	O
for	O
testing	O
the	O
importance	O
of	O
the	O
evolutionarily	O
conserved	O
domains	O
.	O

A	O
study	O
was	O
performed	O
to	O
compare	O
the	O
ONLINE	O
and	O
EMIT	O
II	O
immunoassays	O
with	O
gas	O
chromatographic	O
/	O
mass	O
spectrometric	O
(	O
GC	O
/	O
MS	O
)	O
analysis	O
of	O
methaqualone	O
metabolites	O
on	O
urine	O
using	O
samples	O
obtained	O
from	O
a	O
clinical	O
study	O
.	O

Isolation	O
by	O
PCR	O
of	O
a	O
cDNA	O
clone	O
from	O
pea	O
petals	O
with	O
similarity	O
to	O
petunia	O
and	O
wheat	B-GENE
zinc	I-GENE
finger	I-GENE
proteins	I-GENE
.	O

Exposure	O
of	O
peripheral	O
blood	O
T	O
cells	O
from	O
young	O
subjects	O
to	O
PHA	B-GENE
or	O
cross	O
-	O
linked	O
anti	B-GENE
-	I-GENE
CD3	I-GENE
monoclonal	I-GENE
antibodies	I-GENE
stimulated	O
rapid	O
increases	O
in	O
MAPK	B-GENE
and	O
MEK	B-GENE
enzymatic	O
activity	O
.	O

Deletion	O
analysis	O
of	O
rOC	B-GENE
promoter	I-GENE
-	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
constructs	O
demonstrates	O
that	O
an	O
AML	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
binding	I-GENE
sequence	I-GENE
within	O
the	O
proximal	O
promoter	O
(	O
-	O
138	O
to	O
-	O
130	O
nt	O
)	O
contributes	O
to	O
75	O
%	O
of	O
the	O
level	O
of	O
osteocalcin	B-GENE
gene	I-GENE
expression	O
.	O

Escherichia	O
coli	O
BL21	O
(	O
DE3	O
)	O
plysS	O
,	O
harbouring	O
a	O
recombinant	O
plasmid	O
containing	O
the	O
catalase	B-GENE
-	O
peroxidase	B-GENE
gene	O
,	O
produced	O
a	O
large	O
amount	O
of	O
proteins	O
that	O
co	O
-	O
migrated	O
on	O
SDS	O
/	O
PAGE	O
with	O
the	O
native	O
enzyme	O
.	O

Cdk2	B-GENE
formed	O
a	O
complex	O
with	O
cyclin	B-GENE
D1	I-GENE
in	O
this	O
system	O
.	O

The	O
Cdk2	B-GENE
-	O
cyclin	B-GENE
-	I-GENE
D1	I-GENE
complex	O
did	O
not	O
phosphorylate	O
any	O
tested	O
substrates	O
,	O
such	O
as	O
H1	B-GENE
histone	I-GENE
,	O
pRB	B-GENE
,	O
SV40	B-GENE
large	I-GENE
T	I-GENE
antigen	I-GENE
,	O
p53	B-GENE
,	O
E2F	B-GENE
-	I-GENE
1	I-GENE
or	O
a	O
preparation	O
of	O
nuclear	O
proteins	O
from	O
HeLa	O
cells	O
;	O
in	O
contrast	O
,	O
Cdk2	B-GENE
-	O
cyclin	B-GENE
-	I-GENE
E	I-GENE
and	O
Cdk2	B-GENE
-	O
cyclin	B-GENE
-	I-GENE
A	I-GENE
phosphorylated	O
these	O
proteins	O
.	O

Cyclin	B-GENE
-	I-GENE
dependent	I-GENE
kinase	I-GENE
-	I-GENE
2	I-GENE
(	O
Cdk2	B-GENE
)	O
forms	O
an	O
inactive	O
complex	O
with	O
cyclin	B-GENE
D1	I-GENE
since	O
Cdk2	B-GENE
associated	O
with	O
cyclin	B-GENE
D1	I-GENE
is	O
not	O
phosphorylated	O
by	O
Cdk7	B-GENE
-	O
cyclin	B-GENE
-	I-GENE
H	I-GENE
.	O

A	O
human	O
cytoplasmic	O
signaling	O
protein	O
has	O
been	O
cloned	O
that	O
possesses	O
the	O
same	O
structural	O
arrangement	O
of	O
SH3	B-GENE
-	O
SH2	B-GENE
-	O
SH3	B-GENE
domains	O
as	O
Grb2	B-GENE
.	O

Cloning	O
of	O
individual	O
ZI	O
domains	O
upstream	O
of	O
a	O
minimal	O
promoter	O
demonstrated	O
that	O
the	O
ZIA	O
,	O
ZIC	O
,	O
and	O
ZID	O
domains	O
,	O
but	O
not	O
the	O
ZIB	O
domain	O
,	O
are	O
TPA	O
responsive	O
.	O

Sp1	B-GENE
binds	O
two	O
sites	O
in	O
the	O
CD11c	B-GENE
promoter	I-GENE
in	O
vivo	O
specifically	O
in	O
myeloid	O
cells	O
and	O
cooperates	O
with	O
AP1	B-GENE
to	O
activate	O
transcription	O
.	O

We	O
found	O
that	O
120	O
bp	O
of	O
the	O
enhancer	O
'	O
s	O
transcriptional	O
core	O
becomes	O
DNase	B-GENE
I	I-GENE
hypersensitive	O
early	O
in	O
B	O
-	O
cell	O
development	O
.	O

A	O
developmentally	O
modulated	O
chromatin	O
structure	O
at	O
the	O
mouse	B-GENE
immunoglobulin	I-GENE
kappa	I-GENE
3	I-GENE
'	I-GENE
enhancer	I-GENE
.	O

Heme	B-GENE
oxygenase	I-GENE
1	I-GENE
is	O
an	O
essential	O
enzyme	O
in	O
heme	O
catabolism	O
that	O
cleaves	O
heme	O
to	O
form	O
biliverdin	O
,	O
iron	O
,	O
and	O
carbon	O
monoxide	O
.	O

An	O
inactive	O
analog	O
of	O
wortmannin	O
,	O
WM12	O
,	O
did	O
not	O
affect	O
TCR	B-GENE
/	O
CD3	B-GENE
-	O
induced	O
Erk2	B-GENE
activation	O
,	O
and	O
wortmannin	O
had	O
no	O
effect	O
on	O
the	O
activity	O
of	O
Erk2	B-GENE
when	O
added	O
directly	O
to	O
the	O
in	O
vitro	O
assays	O
.	O

Defects	O
in	O
the	O
Schizosaccharomyces	O
pombe	O
(	O
Sp	O
)	O
cell	O
cycle	O
-	O
controlling	O
genes	O
prevent	O
the	O
cell	O
cycle	O
progression	O
.	O

To	O
determine	O
the	O
signal	B-GENE
recognition	I-GENE
particle	I-GENE
(	O
SRP	B-GENE
)	O
-	O
SRP	B-GENE
receptor	I-GENE
(	O
Srb	B-GENE
)	O
system	O
in	O
Bacillus	O
subtilis	O
(	O
Bs	O
)	O
,	O
we	O
cloned	O
the	O
Bs	B-GENE
srb	I-GENE
gene	I-GENE
,	O
which	O
encodes	O
a	O
homologue	O
of	O
the	O
mammalian	B-GENE
SRP	I-GENE
receptor	I-GENE
alpha	I-GENE
-	I-GENE
subunit	I-GENE
[	O
Oguro	O
et	O
al	O
.	O
,	O
DNA	O
Res	O
.	O

Promoter	O
activity	O
was	O
high	O
in	O
cell	O
lines	O
that	O
expressed	O
high	O
levels	O
of	O
endogenous	O
D3	B-GENE
mRNA	I-GENE
,	O
as	O
indicated	O
by	O
Northern	O
blot	O
analyses	O
,	O
and	O
was	O
significantly	O
reduced	O
when	O
the	O
promoter	O
was	O
truncated	O
to	O
-	O
122	O
bp	O
.	O

This	O
phenomenon	O
did	O
not	O
require	O
DNA	O
binding	O
by	O
the	O
"	O
interfering	O
"	O
receptor	O
but	O
required	O
it	O
to	O
be	O
hormone	O
-	O
bound	O
,	O
indicating	O
that	O
a	O
transcriptionally	O
active	O
form	O
of	O
the	O
interfering	O
receptor	O
is	O
essential	O
for	O
the	O
interfering	O
effect	O
.	O

A	O
cis	O
-	O
acting	O
DNA	O
element	O
located	O
between	O
TATA	O
box	O
and	O
transcription	O
initiation	O
site	O
is	O
critical	O
in	O
response	O
to	O
regulatory	O
sequences	O
in	O
human	O
angiotensinogen	B-GENE
gene	I-GENE
.	O

The	O
promoter	O
of	O
the	O
rat	B-GENE
PGS	I-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
contains	O
a	O
CAAT	B-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
consensus	I-GENE
site	I-GENE
(	I-GENE
CAAT	I-GENE
box	I-GENE
)	I-GENE
which	O
can	O
confer	O
hormone	O
inducibility	O
to	O
a	O
PGS	B-GENE
-	I-GENE
2	I-GENE
.	O
CAT	B-GENE
reporter	O
gene	O
,	O
as	O
well	O
as	O
a	O
putative	O
E	O
-	O
box	O
region	O
.	O

SETTING	O
-	O
-	O
Delhi	O
,	O
urban	O
India	O
,	O
1985	O
-	O
6	O
.	O

Selective	O
translation	O
initiation	O
by	O
ribosome	O
jumping	O
in	O
adenovirus	O
-	O
infected	O
and	O
heat	O
-	O
shocked	O
cells	O
.	O

Furthermore	O
,	O
we	O
have	O
identified	O
a	O
43	O
-	O
bp	O
region	O
of	O
the	O
24p3	B-GENE
promoter	I-GENE
required	O
for	O
the	O
Dex	O
responsiveness	O
.	O

Our	O
data	O
demonstrate	O
directly	O
that	O
Rpm1r	B-GENE
is	O
transcribed	O
with	O
its	O
substrates	O
,	O
tRNA	B-GENE
met	I-GENE
f	I-GENE
and	O
tRNAPro	B-GENE
,	O
from	O
a	O
promoter	O
located	O
upstream	O
of	O
the	O
tRNA	B-GENE
met	I-GENE
f	I-GENE
gene	I-GENE
and	O
suggest	O
that	O
a	O
portion	O
also	O
originates	O
from	O
a	O
second	O
promoter	O
,	O
located	O
between	O
the	O
tRNA	B-GENE
met	I-GENE
f	I-GENE
gene	I-GENE
and	O
RPM1	B-GENE
.	O

Furthermore	O
,	O
strains	O
with	O
mutant	B-GENE
RPM1	I-GENE
genes	I-GENE
also	O
accumulate	O
precursor	B-GENE
Rpm1r	I-GENE
,	O
suggesting	O
that	O
mutations	O
in	O
either	O
gene	O
can	O
lead	O
to	O
similar	O
biogenesis	O
defects	O
.	O

Merlie	O
,	O
Cold	O
Spring	O
Harbor	O
Symp	O
.	O

Substantial	O
evidence	O
supports	O
a	O
critical	O
role	O
for	O
the	O
activation	O
of	O
the	O
Raf	B-GENE
-	I-GENE
1	I-GENE
/	O
MEK	B-GENE
/	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
pathway	O
in	O
oncogenic	O
Ras	B-GENE
-	O
mediated	O
transformation	O
.	O

Stylohyoid	O
chain	O
ossification	O
:	O
choice	O
of	O
the	O
surgical	O
approach	O
.	O

63	O
.	O
3	O
micromol	O
/	O
1	O
,	O
p	O
<	O
0	O
.	O
01	O
)	O
and	O
area	O
under	O
the	O
plasma	O
concentration	O
-	O
time	O
curve	O
extrapolated	O
to	O
infinity	O
AUC	O
9	O
(	O
0	O
-	O
infinity	O
)	O
(	O
518	O
.	O
7	O
vs	O
.	O

Mean	O
increase	O
of	O
milk	O
protein	O
yield	O
was	O
46	O
g	O
/	O
d	O
with	O
Met	O
plus	O
Lys	O
,	O
and	O
mean	O
increase	O
of	O
true	O
protein	O
content	O
was	O
1	O
.	O
1	O
g	O
/	O
kg	O
of	O
milk	O
.	O

A	O
chimeric	O
VP16	B-GENE
-	O
Tat	B-GENE
construct	O
containing	O
the	O
leucine	O
mutations	O
showed	O
no	O
increased	O
AP	B-GENE
-	I-GENE
1	I-GENE
responsiveness	O
in	O
comparison	O
with	O
that	O
of	O
the	O
VP16	B-GENE
activation	I-GENE
domain	I-GENE
alone	O
.	O

Despite	O
significant	O
lethality	O
and	O
cardiovascular	O
dysfunction	O
,	O
in	O
the	O
septic	O
group	O
on	O
Days	O
1	O
and	O
2	O
,	O
septic	O
versus	O
control	O
animals	O
had	O
no	O
significant	O
differences	O
in	O
mean	O
metabolic	O
cart	O
measured	O
(	O
Vo2DIR	O
,	O
ml	O
/	O
kg	O
/	O
min	O
;	O
Day	O
1	O
:	O
11	O
.	O
9	O
versus	O
12	O
.	O
4	O
,	O
p	O
=	O
0	O
.	O
81	O
;	O
Day	O
2	O
:	O
14	O
.	O
2	O
versus	O
13	O
.	O
5	O
,	O
p	O
=	O
0	O
.	O
72	O
,	O
respectively	O
)	O
and	O
intravascular	O
catheter	O
calculated	O
(	O
Vo2INDIR	O
,	O
ml	O
/	O
kg	O
/	O
min	O
;	O
Day	O
1	O
:	O
11	O
.	O
2	O
versus	O
11	O
.	O
2	O
,	O
p	O
=	O
0	O
.	O
99	O
;	O
Day	O
2	O
:	O
12	O
.	O
8	O
versus	O
15	O
.	O
4	O
,	O
p	O
=	O
0	O
.	O
49	O
,	O
respectively	O
)	O
.	O

Although	O
IL	B-GENE
-	I-GENE
2	I-GENE
and	O
IFN	B-GENE
-	I-GENE
alpha	I-GENE
activated	O
STAT1	B-GENE
alpha	I-GENE
and	O
STAT5	B-GENE
,	O
IL	B-GENE
-	I-GENE
2	I-GENE
predominantly	O
activated	O
STAT5	B-GENE
,	O
while	O
IFN	B-GENE
-	I-GENE
alpha	I-GENE
predominantly	O
activated	O
STAT1	B-GENE
alpha	I-GENE
.	O

One	O
complex	O
containing	O
a	O
70	O
D	O
protein	O
was	O
found	O
to	O
be	O
associated	O
specifically	O
with	O
transcriptionally	O
active	O
leukemia	O
cells	O
.	O

Our	O
results	O
confirm	O
the	O
participation	O
of	O
intron	O
1	O
in	O
transcriptional	O
regulation	O
of	O
the	O
c	B-GENE
-	I-GENE
myb	I-GENE
gene	I-GENE
(	O
in	O
mouse	O
and	O
human	O
)	O
and	O
implicate	O
multiple	O
and	O
complex	O
regulatory	O
mechanisms	O
of	O
activation	O
during	O
myelomonocytic	O
differentiation	O
and	O
leukemic	O
cell	O
growth	O
control	O
.	O

Limited	O
role	O
for	O
PCR	O
-	O
based	O
diagnosis	O
of	O
Whipple	O
'	O
s	O
disease	O
from	O
peripheral	O
blood	O
mononuclear	O
cells	O
.	O

The	O
Pro	O
-	O
258	O
-	O
-	O
>	O
Leu	O
(	O
P258L	O
)	O
mutation	O
caused	O
constitutive	O
receptor	O
signaling	O
that	O
was	O
equivalent	O
to	O
about	O
45	O
%	O
of	O
the	O
maximum	O
level	O
observed	O
in	O
wild	O
-	O
type	O
cells	O
stimulated	O
with	O
alpha	B-GENE
-	I-GENE
factor	I-GENE
.	O

CONCLUSIONS	O
:	O
Our	O
findings	O
suggest	O
that	O
pre	O
-	O
treatment	O
with	O
coenzyme	O
Q10	O
may	O
play	O
a	O
protective	O
role	O
during	O
routine	O
vascular	O
procedures	O
requiring	O
abdominal	O
aortic	O
cross	O
clamping	O
by	O
attenuating	O
the	O
degree	O
of	O
peroxidative	O
damage	O
.	O

In	O
a	O
screen	O
for	O
genes	O
with	O
oncogenic	O
potential	O
expressed	O
by	O
the	O
murine	O
B6SUtA1	O
myeloid	O
progenitor	O
cell	O
line	O
,	O
we	O
isolated	O
a	O
2	O
.	O

The	O
mechanism	O
involves	O
Gbetagamma	B-GENE
subunit	O
-	O
mediated	O
increases	O
in	O
tyrosine	O
phosphorylation	O
of	O
the	O
Shc	B-GENE
adapter	I-GENE
protein	I-GENE
,	O
Shc	B-GENE
*	O
Grb2	B-GENE
complex	O
formation	O
,	O
and	O
recruitment	O
of	O
Ras	B-GENE
guanine	I-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
activity	O
.	O

The	O
cis	O
-	O
acting	O
elements	O
that	O
control	O
promoter	O
activity	O
include	O
binding	O
sites	O
for	O
transcription	O
factors	O
Sp1	B-GENE
and	O
alphaCbf	B-GENE
,	O
a	O
60	B-GENE
-	I-GENE
kDa	I-GENE
CCAAT	I-GENE
box	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
.	O

There	O
was	O
a	O
general	O
broadening	O
of	O
proton	O
resonances	O
for	O
a	O
three	O
-	O
nucleotide	O
segment	O
centered	O
about	O
the	O
lesion	O
site	O
which	O
resulted	O
in	O
a	O
tentative	O
assignment	O
for	O
the	O
sugar	O
protons	O
of	O
the	O
C7	O
residue	O
in	O
the	O
spectrum	O
of	O
the	O
adduct	O
duplex	O
.	O

Using	O
immunogold	O
electron	O
microscopy	O
,	O
we	O
found	O
that	O
p58	B-GENE
/	O
p45	B-GENE
and	O
p54	B-GENE
are	O
localized	O
on	O
both	O
sides	O
of	O
the	O
nuclear	O
pore	O
complex	O
,	O
like	O
p62	B-GENE
.	O

Transcription	O
initiation	O
sites	O
of	O
the	O
rat	O
II	B-GENE
beta	I-GENE
-	I-GENE
,	I-GENE
III	I-GENE
beta	I-GENE
,	I-GENE
and	I-GENE
O	I-GENE
beta	I-GENE
-	I-GENE
globin	I-GENE
genes	O
were	O
determined	O
to	O
be	O
52	O
base	O
pairs	O
(	O
bp	O
)	O
5	O
'	O
-	O
upstream	O
of	O
the	O
translation	O
initiation	O
codon	O
(	O
ATG	O
)	O
,	O
in	O
each	O
gene	O
by	O
primer	O
extension	O
analysis	O
.	O

Aggravating	O
process	O
induced	O
by	O
indomethacin	O
on	O
chronic	O
gastric	O
lesion	O
in	O
rat	O
.	O

We	O
have	O
been	O
studying	O
the	O
interaction	O
of	O
the	O
oncogenic	O
human	O
polyomavirus	O
BK	O
(	O
BKV	O
)	O
with	O
the	O
tumor	B-GENE
-	I-GENE
suppressor	I-GENE
protein	I-GENE
p53	I-GENE
to	O
understand	O
the	O
biology	O
of	O
this	O
virus	O
as	O
well	O
as	O
to	O
understand	O
the	O
basic	O
mechanisms	O
of	O
p53	B-GENE
transactivation	O
.	O

Site	O
S	O
-	O
II	O
also	O
spans	O
a	O
23	O
bp	O
sequence	O
containing	O
two	O
tandem	O
consensus	O
binding	O
sites	O
with	O
three	O
base	O
pair	O
mismatches	O
in	O
each	O
and	O
a	O
one	O
base	O
pair	O
deletion	O
.	O

Unaided	O
attempts	O
to	O
quit	O
smoking	O
are	O
generally	O
unsuccessful	O
.	O

The	O
experience	O
of	O
the	O
lateral	O
rhinotomy	O
approach	O
in	O
transsphenoidal	O
surgery	O
of	O
acromegaly	O
has	O
been	O
favourable	O
.	O

Possible	O
relationship	O
between	O
hyperinsulinemia	O
and	O
glomerular	O
hypertrophy	O
in	O
nephrosclerosis	O
.	O

Blood	O
GSH	B-GENE
-	I-GENE
Px	I-GENE
activity	O
was	O
measured	O
with	O
a	O
spectrophotometer	O
,	O
using	O
a	O
modification	O
of	O
a	O
previously	O
described	O
assay	O
.	O

The	O
concentrations	O
of	O
vitamin	O
A	O
precursors	O
and	O
vitamin	O
E	O
in	O
the	O
hay	O
were	O
below	O
currently	O
recommended	O
dietary	O
levels	O
for	O
llamas	O
,	O
and	O
alfalfa	O
hay	O
appears	O
to	O
provide	O
an	O
unreliable	O
source	O
of	O
vitamins	O
A	O
and	O
E	O
in	O
this	O
species	O
.	O

Eight	O
cats	O
infected	O
with	O
H	O
.	O
pylori	O
were	O
used	O
in	O
the	O
study	O
.	O

However	O
,	O
as	O
determined	O
by	O
PCR	O
with	O
primers	O
specific	O
for	O
the	O
26	O
-	O
kDa	O
product	O
,	O
the	O
majority	O
of	O
cats	O
at	O
2	O
and	O
4	O
weeks	O
p	O
.	O
t	O
.	O
had	O
gastric	O
fluid	O
samples	O
which	O
were	O
positive	O
for	O
H	O
.	O
pylori	O
and	O
three	O
of	O
three	O
cats	O
at	O
2	O
weeks	O
p	O
.	O
t	O
.	O
had	O
dental	O
plaque	O
which	O
was	O
positive	O
for	O
H	O
.	O
pylori	O
.	O

The	O
most	O
frequent	O
causes	O
of	O
the	O
meningitis	O
was	O
the	O
external	O
ventricular	O
drainage	O
(	O
14	O
.	O
8	O
%	O
)	O
,	O
post	O
-	O
neurosurgical	O
(	O
0	O
.	O
8	O
%	O
)	O
and	O
head	O
injury	O
(	O
0	O
.	O
0007	O
%	O
)	O
.	O

In	O
vitro	O
interaction	O
studies	O
,	O
using	O
proteins	O
fused	O
to	O
glutathione	B-GENE
-	I-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
,	O
showed	O
that	O
RBP	B-GENE
-	I-GENE
J	I-GENE
kappa	I-GENE
and	O
Su	B-GENE
(	I-GENE
H	I-GENE
)	I-GENE
bind	O
directly	O
to	O
the	O
RAM23	B-GENE
regions	I-GENE
of	O
mouse	B-GENE
Notch1	I-GENE
and	O
Drosophila	B-GENE
Notch	I-GENE
,	O
respectively	O
.	O

Twelve	O
genomic	O
fragments	O
containing	O
novel	O
response	O
elements	O
are	O
described	O
,	O
and	O
the	O
transcription	O
unit	O
associated	O
with	O
one	O
of	O
them	O
,	O
NN	B-GENE
-	I-GENE
84AG	I-GENE
,	O
was	O
characterized	O
in	O
detail	O
.	O

Members	O
of	O
the	O
Ras	B-GENE
subfamily	I-GENE
of	O
small	B-GENE
GTP	I-GENE
-	I-GENE
binding	I-GENE
proteins	I-GENE
have	O
been	O
shown	O
to	O
be	O
promiscuous	O
towards	O
a	O
variety	O
of	O
putative	O
effector	O
molecules	O
such	O
as	O
the	O
protein	B-GENE
kinase	I-GENE
c	I-GENE
-	I-GENE
Raf	I-GENE
and	O
the	O
Ral	B-GENE
-	I-GENE
specific	I-GENE
guanine	I-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
(	O
Ral	B-GENE
-	I-GENE
GEF	I-GENE
)	O
.	O

The	O
cDNA	O
encoded	O
a	O
mature	O
protein	O
of	O
240	O
amino	O
acids	O
,	O
including	O
a	O
29	O
-	O
amino	O
acid	O
signal	O
sequence	O
.	O

Biol	O
.	O

The	O
effect	O
of	O
ligustrazine	O
hydrochloride	O
(	O
LTH	O
)	O
on	O
depressing	O
pulmonary	O
artery	O
hypertension	O
has	O
been	O
proved	O
in	O
recent	O
studies	O
.	O

In	O
the	O
same	O
period	O
we	O
pointed	O
out	O
an	O
increase	O
of	O
hematocrit	O
(	O
from	O
29	O
%	O
to	O
35	O
%	O
)	O
and	O
of	O
the	O
Hb	B-GENE
(	O
from	O
9	O
.	O
3	O
to	O
11	O
.	O
2	O
g	O
/	O
dl	O
)	O
.	O

The	O
structure	O
of	O
these	O
genes	O
suggests	O
a	O
common	O
ancestor	O
for	O
all	O
viperid	B-GENE
PLA2	I-GENE
genes	I-GENE
.	O

Chloroplast	B-GENE
mutator	I-GENE
(	O
chm	B-GENE
)	O
of	O
Arabidopsis	O
is	O
a	O
recessive	O
nuclear	O
mutation	O
that	O
causes	O
green	O
and	O
white	O
variegation	O
in	O
leaves	O
and	O
is	O
inherited	O
in	O
a	O
non	O
-	O
Mendelian	O
fashion	O
.	O

Also	O
like	O
the	O
thrombin	B-GENE
receptor	I-GENE
,	O
PAR2	B-GENE
can	O
be	O
activated	O
by	O
the	O
hexapeptide	O
corresponding	O
to	O
its	O
tethered	O
ligand	O
sequence	O
independent	O
of	O
receptor	O
cleavage	O
.	O

Such	O
an	O
increase	O
in	O
the	O
steady	O
-	O
state	O
testicular	B-GENE
TIMP	I-GENE
-	I-GENE
2	I-GENE
mRNA	I-GENE
level	O
apparently	O
is	O
not	O
the	O
result	O
of	O
an	O
up	O
-	O
regulation	O
by	O
germ	O
cells	O
because	O
germ	O
cells	O
cocultured	O
with	O
Sertoli	O
cells	O
failed	O
to	O
elicit	O
an	O
increase	O
in	O
the	O
Sertoli	O
cell	O
steady	O
-	O
state	O
TIMP	B-GENE
-	I-GENE
2	I-GENE
mRNA	I-GENE
level	O
.	O

In	O
the	O
SPK	O
and	O
PTA	O
category	O
,	O
anti	O
-	O
T	O
-	O
cell	O
therapy	O
significantly	O
lowered	O
the	O
risk	O
of	O
graft	O
loss	O
.	O

Five	O
-	O
year	O
survivals	O
amounted	O
to	O
100	O
%	O
,	O
86	O
.	O
2	O
%	O
,	O
59	O
.	O
4	O
%	O
,	O
29	O
.	O
8	O
%	O
,	O
and	O
20	O
%	O
for	O
stages	O
I	O
,	O
II	O
,	O
III	O
,	O
IVA	O
and	O
IVB	O
respectively	O
.	O

Targeted	O
disruption	O
of	O
the	O
OGG1	B-GENE
gene	I-GENE
in	O
yeast	O
revealed	O
a	O
second	O
OG	B-GENE
glycosylase	I-GENE
/	I-GENE
lyase	I-GENE
protein	I-GENE
,	O
tentatively	O
named	O
Ogg2	B-GENE
,	O
which	O
differs	O
from	O
Ogg1	B-GENE
in	O
that	O
it	O
preferentially	O
acts	O
on	O
OG	O
:	O
G	O
.	O

Sequence	O
analysis	O
of	O
the	O
isolated	O
genomic	O
clone	O
revealed	O
that	O
the	O
DNA	O
binding	O
domain	O
of	O
this	O
orphan	O
receptor	O
is	O
most	O
homologous	O
to	O
the	O
human	B-GENE
TR2	I-GENE
receptor	I-GENE
.	O

Genomic	O
DNA	O
hybridization	O
suggests	O
that	O
SpSHR2	B-GENE
is	O
a	O
single	O
-	O
copy	O
gene	O
in	O
the	O
S	O
.	O
purpuratus	O
genome	O
.	O

Its	O
hydropathy	O
profile	O
predicts	O
seven	O
transmembrane	O
spans	O
and	O
a	O
hydrophilic	O
amino	O
terminus	O
of	O
approximately	O
100	O
residues	O
,	O
and	O
it	O
suggests	O
the	O
presence	O
of	O
an	O
amphiphilic	O
alpha	O
-	O
helix	O
(	O
L	O
-	O
61	O
to	O
F	O
-	O
97	O
)	O
in	O
close	O
proximity	O
to	O
the	O
first	O
strongly	O
hydrophobic	O
segment	O
of	O
ProW	B-GENE
.	O

There	O
are	O
four	O
polyglutamine	O
motifs	O
interspersed	O
with	O
histidine	O
-	O
rich	O
regions	O
.	O

Quantitative	O
analysis	O
of	O
plasmid	O
loss	O
rates	O
in	O
cdc28	B-GENE
-	I-GENE
1N	I-GENE
strains	O
carrying	O
plasmids	O
with	O
multiple	O
replication	O
origins	O
suggests	O
that	O
a	O
defect	O
in	O
initiating	O
DNA	O
replication	O
probably	O
causes	O
this	O
plasmid	O
loss	O
phenotype	O
.	O

Platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
-	O
dependent	O
activation	O
of	O
phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
is	O
regulated	O
by	O
receptor	O
binding	O
of	O
SH2	B-GENE
-	I-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
proteins	I-GENE
which	O
influence	O
Ras	B-GENE
activity	O
.	O

Almost	O
complete	O
sequence	O
identity	O
was	O
found	O
between	O
the	O
3	O
'	O
end	O
of	O
the	O
DXS6673E	B-GENE
gene	I-GENE
and	O
two	O
expressed	O
sequence	O
tags	O
(	O
ESTs	O
)	O
and	O
between	O
the	O
5	O
'	O
end	O
of	O
the	O
DXS6673E	B-GENE
gene	I-GENE
and	O
a	O
third	O
EST	O
.	O

Several	O
of	O
the	O
exon	O
boundaries	O
correspond	O
to	O
the	O
boundaries	O
of	O
functional	O
domains	O
in	O
the	O
p55	B-GENE
protein	I-GENE
.	O

Tristetraprolin	B-GENE
(	O
TTP	B-GENE
)	O
is	O
the	O
prototype	O
of	O
a	O
group	O
of	O
potential	O
transcription	O
factors	O
that	O
contain	O
two	O
or	O
more	O
unusual	O
CCCH	O
zinc	O
fingers	O
.	O

The	O
ewes	O
were	O
returned	O
to	O
normoxia	O
,	O
and	O
monitoring	O
was	O
continued	O
for	O
1	O
h	O
.	O

Feline	O
leukemia	O
viruses	O
(	O
FeLVs	O
)	O
,	O
which	O
are	O
replication	O
-	O
competent	O
oncoretroviruses	O
of	O
the	O
domestic	O
cat	O
species	O
,	O
are	O
contagiously	O
transmitted	O
in	O
natural	O
environments	O
.	O

Both	O
verapamil	O
and	O
propranolol	O
can	O
exhibit	O
additive	O
effects	O
with	O
adenosine	O
in	O
prolonging	O
AV	O
nodal	O
conduction	O
time	O
;	O
however	O
,	O
only	O
verapamil	O
can	O
reduce	O
the	O
dose	O
of	O
adenosine	O
required	O
to	O
produce	O
AV	O
nodal	O
block	O
.	O

RVR	B-GENE
'	O
loss	O
of	O
function	O
'	O
studies	O
by	O
constitutive	O
over	O
-	O
expression	O
of	O
a	O
dominant	O
negative	O
RVR	B-GENE
delta	I-GENE
E	I-GENE
resulted	O
in	O
increased	O
levels	O
of	O
p21Cip1	B-GENE
/	O
Waf1	B-GENE
and	O
myogenin	B-GENE
mRNAs	I-GENE
after	O
serum	O
withdrawal	O
.	O

These	O
two	O
repeat	O
motifs	O
are	O
organized	O
in	O
an	O
extremely	O
well	O
-	O
ordered	O
pattern	O
in	O
each	O
domain	O
,	O
which	O
suggests	O
that	O
SbHRGP3	B-GENE
belongs	O
to	O
a	O
new	O
group	O
of	O
proteins	O
having	O
the	O
repeat	O
motifs	O
of	O
two	O
distinct	O
groups	O
of	O
dicot	B-GENE
extensins	I-GENE
.	O

Two	O
classes	O
of	O
inactive	O
receptors	O
were	O
identified	O
:	O
one	O
in	O
which	O
both	O
transcriptional	O
activation	O
and	O
dimerization	O
were	O
compromised	O
and	O
a	O
second	O
in	O
which	O
only	O
transcriptional	O
activation	O
was	O
abolished	O
.	O

Here	O
we	O
localize	O
a	O
transferable	O
40	O
-	O
amino	O
acid	O
region	O
within	O
the	O
LBDs	B-GENE
of	O
RXR	B-GENE
,	O
RAR	B-GENE
,	O
TR	B-GENE
,	O
and	O
chicken	B-GENE
ovalbumin	I-GENE
upstream	I-GENE
promoter	I-GENE
transcription	I-GENE
factor	I-GENE
that	O
is	O
critical	O
for	O
determining	O
identity	O
in	O
the	O
heterodimeric	O
interaction	O
and	O
for	O
high	O
-	O
affinity	O
DNA	O
binding	O
.	O

OKA	O
and	O
calyculin	O
A	O
do	O
not	O
decrease	O
OCFRE	B-GENE
DNA	O
-	O
protein	O
interactions	O
,	O
suggesting	O
that	O
important	O
protein	O
-	O
protein	O
interactions	O
are	O
phosphatase	O
regulated	O
.	O

IMPLICATIONS	O
:	O
Given	O
the	O
small	O
size	O
of	O
this	O
study	O
and	O
the	O
inconsistency	O
of	O
results	O
among	O
the	O
few	O
prospective	O
studies	O
of	O
ovarian	O
cancer	O
conducted	O
to	O
test	O
these	O
associations	O
,	O
replications	O
of	O
these	O
findings	O
are	O
highly	O
desirable	O
.	O

We	O
have	O
performed	O
toeprinting	O
analyses	O
on	O
repA	B-GENE
mRNA	I-GENE
of	O
plasmid	O
R1	O
,	O
both	O
free	O
and	O
in	O
duplex	O
with	O
the	O
antisense	O
RNA	O
,	O
CopA	B-GENE
.	O

Previous	O
work	O
showed	O
that	O
repA	B-GENE
(	O
initiator	O
protein	O
)	O
expression	O
requires	O
tap	B-GENE
(	O
leader	O
peptide	O
)	O
translation	O
.	O

Tonsillectomy	O
is	O
an	O
effective	O
means	O
of	O
prophylaxis	O
for	O
upper	O
respiratory	O
infection	O
in	O
habitual	O
angina	O
patients	O
.	O

These	O
results	O
were	O
corroborated	O
in	O
a	O
subsequent	O
study	O
in	O
which	O
30	O
hypogonadal	O
men	O
were	O
supplemented	O
with	O
SLT	O
5	O
mg	O
three	O
times	O
daily	O
for	O
6	O
months	O
.	O

The	O
elevations	O
achieved	O
by	O
LDEE	O
given	O
s	O
.	O
c	O
.	O
were	O
higher	O
than	O
those	O
achieved	O
after	O
i	O
.	O
p	O
.	O
administration	O
and	O
lasted	O
for	O
longer	O
periods	O
.	O

Many	O
human	O
viruses	O
are	O
able	O
to	O
develop	O
suitable	O
strategies	O
for	O
modifying	O
apoptosis	O
in	O
virus	O
-	O
infected	O
cells	O
and	O
in	O
virus	O
-	O
primed	O
T	O
cells	O
.	O

Taken	O
together	O
,	O
these	O
observations	O
indicate	O
that	O
the	O
C	O
-	O
terminal	O
24	O
amino	O
acids	O
are	O
sufficient	O
for	O
NodO	B-GENE
secretion	O
although	O
the	O
region	O
adjacent	O
to	O
this	O
domain	O
appears	O
to	O
affect	O
secretion	O
efficiency	O
.	O

The	O
model	O
also	O
predicts	O
that	O
blood	O
flow	O
shunt	O
fraction	O
(	O
Qs	O
/	O
QT	O
)	O
is	O
directly	O
related	O
to	O
the	O
oxygen	O
sine	O
-	O
wave	O
amplitude	O
perturbations	O
transmitted	O
to	O
end	O
-	O
expired	O
air	O
and	O
arterial	O
and	O
mixed	O
-	O
venous	O
blood	O
through	O
two	O
simple	O
equations	O
.	O

Discrimination	O
between	O
HIV	O
-	O
1	O
and	O
HIV	O
-	O
2	O
showed	O
evidence	O
for	O
the	O
presence	O
of	O
HIV	O
-	O
1	O
only	O
.	O

However	O
,	O
an	O
intrinsic	O
DNA	O
-	O
binding	O
subunit	O
for	O
HiNF	B-GENE
-	I-GENE
D	I-GENE
was	O
not	O
identified	O
.	O

The	O
HiNF	B-GENE
-	I-GENE
D	I-GENE
(	O
CDP	B-GENE
/	O
cut	B-GENE
)	O
complex	O
with	O
the	O
H4	B-GENE
promoter	I-GENE
is	O
immunoreactive	O
with	O
antibodies	O
against	O
CDP	B-GENE
/	O
cut	B-GENE
and	O
pRB	B-GENE
but	O
not	O
p107	B-GENE
,	O
whereas	O
the	O
CDP	B-GENE
/	O
cut	B-GENE
complex	O
with	O
a	O
nonhistone	O
promoter	O
(	O
gp91	B-GENE
-	O
phox	B-GENE
)	O
reacts	O
only	O
with	O
CDP	B-GENE
and	O
p107	B-GENE
antibodies	O
.	O

Eight	O
-	O
four	O
ACOAs	O
were	O
tested	O
in	O
order	O
to	O
examine	O
the	O
fit	O
of	O
the	O
model	O
to	O
the	O
data	O
by	O
path	O
analysis	O
with	O
LISREL	O
VII	O
.	O

Using	O
anchored	O
PCR	O
,	O
a	O
VL	B-GENE
element	I-GENE
rearranged	O
to	O
CL2	B-GENE
was	O
isolated	O
.	O

A	O
subset	O
of	O
these	O
DMP1	B-GENE
recognition	I-GENE
sequences	I-GENE
containing	O
a	O
GGA	O
trinucleotide	O
core	O
can	O
also	O
function	O
as	O
Ets	B-GENE
-	I-GENE
responsive	I-GENE
elements	I-GENE
.	O

In	O
both	O
settings	O
,	O
it	O
can	O
be	O
phosphorylated	O
by	O
cyclin	B-GENE
D	I-GENE
-	I-GENE
dependent	I-GENE
kinases	I-GENE
,	O
suggesting	O
that	O
its	O
transcriptional	O
activity	O
may	O
normally	O
be	O
regulated	O
through	O
such	O
mechanisms	O
.	O

Enterococcus	O
faecium	O
strains	O
with	O
vanA	O
-	O
mediated	O
glycopeptide	O
resistance	O
were	O
isolated	O
by	O
enrichment	O
culture	O
from	O
the	O
intestines	O
and	O
feces	O
of	O
several	O
animal	O
species	O
,	O
mainly	O
horses	O
and	O
dogs	O
(	O
8	O
%	O
positive	O
)	O
,	O
chickens	O
(	O
7	O
%	O
positive	O
)	O
,	O
and	O
pigs	O
(	O
6	O
%	O
positive	O
)	O
.	O

Oncogenic	O
activation	O
of	O
the	O
tyrosine	B-GENE
kinase	I-GENE
domain	I-GENE
of	O
the	O
human	B-GENE
trk	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
by	O
fusion	O
to	O
a	O
cell	O
adhesion	O
molecule	O
.	O

Physiol	O
.	O

They	O
suggest	O
that	O
decreased	O
steady	O
-	O
state	O
levels	O
of	O
IME1	B-GENE
and	O
IME2	B-GENE
mRNA	I-GENE
were	O
not	O
merely	O
the	O
result	O
of	O
non	O
-	O
specific	O
adverse	O
affects	O
on	O
nucleic	O
acid	O
metabolism	O
caused	O
by	O
the	O
yvh1	B-GENE
disruption	O
.	O

RNase	B-GENE
protection	O
analysis	O
of	O
two	O
rRNA	O
fragments	O
whose	O
genes	O
are	O
adjacent	O
provided	O
evidence	O
for	O
a	O
polycistronic	O
transcript	O
containing	O
sequences	O
from	O
both	O
,	O
as	O
well	O
as	O
separate	O
small	O
RNAs	O
.	O

These	O
two	O
contigs	O
contain	O
a	O
total	O
of	O
163	O
open	O
reading	O
frames	O
(	O
ORFs	O
)	O
in	O
26	O
-	O
29	O
putative	O
operons	O
;	O
56	O
ORFs	O
could	O
be	O
identified	O
with	O
reasonable	O
certainty	O
.	O

The	O
evidence	O
in	O
support	O
of	O
this	O
was	O
derived	O
from	O
the	O
fact	O
that	O
the	O
affinity	O
or	O
interaction	O
between	O
the	O
two	O
subunits	O
was	O
impaired	O
as	O
indicated	O
by	O
the	O
first	O
order	O
rate	O
constant	O
of	O
hCG	B-GENE
alpha	I-GENE
1	I-GENE
beta	I-GENE
(	O
km	O
=	O
4	O
.	O
1	O
x	O
10	O
(	O
-	O
2	O
)	O
min	O
-	O
1	O
)	O
at	O
pH	O
3	O
.	O
0	O
at	O
23	O
degrees	O
C	O
which	O
is	O
one	O
order	O
of	O
magnitude	O
greater	O
relative	O
to	O
rehCG	B-GENE
(	O
kw	O
=	O
4	O
.	O
6	O
x	O
10	O
(	O
-	O
3	O
)	O
min	O
-	O
1	O
)	O
.	O

Rifabutin	O
has	O
substantial	O
efficacy	O
when	O
combined	O
with	O
other	O
agents	O
.	O

Leukemia	B-GENE
-	I-GENE
inhibitory	I-GENE
factor	I-GENE
(	O
LIF	B-GENE
)	O
is	O
a	O
neuropoietin	B-GENE
able	O
to	O
regulate	O
the	O
differentiation	O
and	O
the	O
survival	O
of	O
many	O
cell	O
types	O
,	O
which	O
include	O
some	O
neuronal	O
populations	O
.	O

Paracrine	O
activation	O
of	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
LTR	I-GENE
promoter	I-GENE
by	O
the	O
viral	B-GENE
Tat	I-GENE
protein	I-GENE
is	O
mechanistically	O
similar	O
to	O
trans	O
-	O
activation	O
within	O
a	O
cell	O
.	O

RUSH	B-GENE
-	I-GENE
1	I-GENE
beta	I-GENE
is	O
a	O
95	O
-	O
kDa	O
truncated	O
version	O
of	O
RUSH	B-GENE
-	I-GENE
1	I-GENE
alpha	I-GENE
that	O
results	O
from	O
alternative	O
splicing	O
of	O
a	O
57	O
-	O
bp	O
exon	O
as	O
confirmed	O
by	O
genomic	O
cloning	O
.	O

The	O
mobility	O
shift	O
assay	O
of	O
the	O
65	O
bp	O
(	O
-	O
318	O
/	O
-	O
254	O
)	O
fragment	O
with	O
nuclear	O
extract	O
from	O
the	O
dark	O
-	O
adapted	O
sample	O
showed	O
an	O
additional	O
band	O
,	O
not	O
seen	O
with	O
the	O
light	O
-	O
grown	O
sample	O
.	O

Moreover	O
,	O
the	O
same	O
mutations	O
alter	O
the	O
structure	O
of	O
junB	B-GENE
5	O
'	O
flanking	O
DNA	O
within	O
chromatin	O
.	O

RESULTS	O
:	O
The	O
age	O
distribution	O
was	O
28	O
to	O
83	O
years	O
old	O
(	O
mean	O
was	O
54	O
.	O
1	O
years	O
)	O
.	O

The	O
ERH	B-GENE
expression	O
profile	O
is	O
similar	O
,	O
to	O
that	O
of	O
An3	B-GENE
,	O
which	O
localizes	O
to	O
the	O
animal	O
hemisphere	O
of	O
oocytes	O
and	O
is	O
abundantly	O
expressed	O
in	O
the	O
embryo	O
.	O

When	O
the	O
degree	O
of	O
exercise	O
was	O
maximal	O
,	O
mPAP	O
was	O
maintained	O
,	O
SVI	O
decreased	O
,	O
HR	O
was	O
unchanged	O
,	O
and	O
CO	O
and	O
VO2	O
decreased	O
.	O

327	O
and	O
736	O
protocols	O
of	O
postmortem	O
examinations	O
from	O
Moscow	O
hospitals	O
N	O
31	O
and	O
57	O
,	O
respectively	O
,	O
were	O
evaluated	O
statistically	O
.	O

The	O
effect	O
of	O
six	O
arginine	O
mutations	O
of	O
oxidative	O
phosphorylation	O
and	O
AAC	B-GENE
expression	O
.	O

The	O
RI	B-GENE
alpha	I-GENE
gene	I-GENE
is	O
composed	O
of	O
nine	O
coding	O
exons	O
of	O
varying	O
lengths	O
,	O
separated	O
by	O
introns	O
,	O
giving	O
the	O
gene	O
a	O
total	O
length	O
of	O
at	O
least	O
21	O
kb	O
.	O
our	O
recent	O
cloning	O
of	O
a	O
processed	O
RI	B-GENE
alpha	I-GENE
pseudogene	I-GENE
with	O
a	O
5	O
'	O
-	O
noncoding	O
region	O
different	O
from	O
the	O
previously	O
reported	O
RI	B-GENE
alpha	I-GENE
complementary	I-GENE
RNA	I-GENE
indicated	O
that	O
the	O
RI	B-GENE
alpha	I-GENE
gene	I-GENE
may	O
have	O
multiple	O
leader	O
exons	O
giving	O
rise	O
to	O
alternately	O
spliced	O
messenger	O
RNAs	O
(	O
mRNAs	O
)	O
.	O

This	O
establishes	O
Rad3	B-GENE
/	O
Mec1	B-GENE
as	O
the	O
only	O
conserved	O
protein	O
which	O
is	O
required	O
for	O
all	O
the	O
DNA	O
structure	O
checkpoints	O
in	O
both	O
yeast	O
model	O
systems	O
.	O

The	O
identification	O
of	O
the	O
hepatitis	O
C	O
virus	O
as	O
the	O
major	O
cause	O
of	O
liver	O
disease	O
both	O
in	O
dialysis	O
patients	O
and	O
in	O
transplant	O
patients	O
has	O
focused	O
attention	O
on	O
the	O
epidemiology	O
and	O
the	O
impact	O
of	O
continuing	O
infection	O
in	O
these	O
patient	O
groups	O
.	O

Stable	O
transfection	O
of	O
the	O
BL	O
cell	O
line	O
Raji	O
with	O
constructs	O
containing	O
core	O
promoter	O
mutations	O
confirmed	O
that	O
the	O
proximal	O
Sp1	B-GENE
site	I-GENE
and	O
the	O
TATA	O
box	O
are	O
essential	O
for	O
the	O
activation	O
of	O
promoter	O
P1	O
by	O
the	O
Ig	B-GENE
kappa	I-GENE
enhancers	I-GENE
.	O

The	O
first	O
identification	O
of	O
the	O
active	O
37LRP	B-GENE
/	O
p40	B-GENE
gene	O
presented	O
in	O
this	O
study	O
is	O
a	O
critical	O
step	O
toward	O
the	O
isolation	O
of	O
the	O
corresponding	O
human	O
gene	O
and	O
the	O
understanding	O
of	O
the	O
molecular	O
mechanisms	O
involved	O
in	O
the	O
up	O
-	O
regulation	O
of	O
its	O
expression	O
during	O
tumor	O
invasion	O
and	O
metastasis	O
.	O

The	O
promoter	O
region	O
(	O
P1	O
)	O
corresponding	O
to	O
the	O
main	O
group	O
of	O
transcription	O
initiation	O
sites	O
is	O
devoid	O
of	O
TATA	O
and	O
CAAT	O
boxes	O
but	O
has	O
putative	O
binding	O
sites	O
for	O
the	O
transcription	B-GENE
factor	I-GENE
SP1	I-GENE
and	O
is	O
embedded	O
in	O
a	O
large	O
G	O
+	O
C	O
-	O
rich	O
domain	O
of	O
a	O
CpG	O
island	O
,	O
features	O
shared	O
by	O
the	O
promoters	O
of	O
constitutively	O
expressed	O
housekeeping	O
genes	O
.	O

The	O
STAT	B-GENE
-	I-GENE
1	I-GENE
signaling	O
pathway	O
provides	O
at	O
least	O
one	O
mechanism	O
for	O
activation	O
of	O
the	O
CAEV	B-GENE
LTR	I-GENE
by	O
IFN	B-GENE
-	I-GENE
gamma	I-GENE
in	O
monocytes	O
.	O

Unlike	O
wild	B-GENE
-	I-GENE
type	I-GENE
p53	I-GENE
,	O
the	O
delta	B-GENE
proAE	I-GENE
mutant	I-GENE
cDNA	I-GENE
can	O
be	O
stably	O
expressed	O
in	O
tumor	O
derived	O
cell	O
lines	O
with	O
few	O
immediate	O
detrimental	O
effects	O
.	O

Several	O
artifacts	O
occurred	O
that	O
interfered	O
with	O
visualization	O
of	O
the	O
diaphragm	O
.	O

During	O
skeletal	O
muscle	O
development	O
,	O
different	O
types	O
of	O
muscle	O
fibers	O
are	O
generated	O
,	O
which	O
express	O
different	O
combinations	O
of	O
muscle	O
-	O
specific	O
gene	O
products	O
.	O

Its	O
transcription	O
product	O
,	O
a	O
1	O
.	O
3	O
kb	O
mRNA	O
,	O
is	O
polyadenylated	O
at	O
a	O
site	O
containing	O
consensus	O
eukaryotic	O
polyadenylation	O
signals	O
and	O
mapping	O
87	O
bp	O
downstream	O
of	O
the	O
translation	O
termination	O
codon	O
for	O
CG30	B-GENE
.	O

BCL	B-GENE
-	I-GENE
2	I-GENE
,	O
an	O
inhibitor	O
of	O
apoptosis	O
in	O
a	O
wide	O
variety	O
of	O
cell	O
types	O
,	O
has	O
been	O
reported	O
to	O
prevent	O
oxidative	O
stress	O
-	O
induced	O
cell	O
death	O
.	O

Full	B-GENE
-	I-GENE
length	I-GENE
AT	I-GENE
-	I-GENE
PHH1	I-GENE
,	O
and	O
both	O
AT	B-GENE
-	I-GENE
PHH1	I-GENE
and	O
AT	B-GENE
-	I-GENE
PHH1	I-GENE
delta	I-GENE
C	I-GENE
-	I-GENE
513	I-GENE
(	O
truncated	O
to	O
be	O
approximately	O
the	O
size	O
of	O
microbial	B-GENE
photolyase	I-GENE
genes	I-GENE
)	O
cDNAs	O
,	O
were	O
overexpressed	O
,	O
respectively	O
,	O
in	O
yeast	O
and	O
Escherichia	O
coli	O
mutants	O
hypersensitive	O
to	O
ultraviolet	O
light	O
.	O

Serotonin	O
concentration	O
in	O
the	O
blood	O
of	O
patients	O
with	O
hemorrhagic	O
fever	O
with	O
renal	O
syndrome	O

Control	O
examination	O
was	O
performed	O
at	O
the	O
end	O
of	O
each	O
period	O
.	O

The	O
total	O
number	O
of	O
specimens	O
was	O
131	O
with	O
78	O
nonsmokers	O
and	O
53	O
smokers	O
.	O

In	O
Experiment	O
1	O
,	O
pups	O
that	O
had	O
received	O
an	O
injection	O
of	O
the	O
noncompetitive	O
N	B-GENE
-	I-GENE
methyl	I-GENE
-	I-GENE
D	I-GENE
-	I-GENE
aspartate	I-GENE
receptor	I-GENE
antagonist	O
MK	O
-	O
801	O
(	O
0	O
.	O
1	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
either	O
30	O
min	O
before	O
or	O
immediately	O
after	O
conditioning	O
spent	O
less	O
time	O
over	O
the	O
conditioned	O
odor	O
than	O
saline	O
-	O
treated	O
controls	O
.	O

Serotonin	B-GENE
receptors	I-GENE
in	O
suicide	O
victims	O
with	O
major	O
depression	O
.	O

Experimental	O
data	O
showed	O
that	O
these	O
abnormal	O
proteins	O
are	O
constitutively	O
localized	O
in	O
the	O
nucleus	O
,	O
have	O
lost	O
the	O
transcriptional	O
repressor	O
functions	O
typical	O
of	O
normal	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B2p52	I-GENE
and	O
may	O
be	O
capable	O
of	O
transactivation	O
activity	O
.	O

Because	O
L	B-GENE
-	I-GENE
plastin	I-GENE
expression	O
in	O
tissue	O
-	O
specifically	O
regulated	O
in	O
both	O
humans	O
and	O
rodents	O
,	O
it	O
is	O
likely	O
that	O
similar	O
mechanisms	O
regulate	O
L	B-GENE
-	I-GENE
plastin	I-GENE
gene	I-GENE
expression	O
in	O
human	O
and	O
rodent	O
cells	O
and	O
that	O
they	O
could	O
be	O
identified	O
by	O
comparing	O
the	O
function	O
and	O
nucleotide	O
sequences	O
of	O
the	O
human	O
and	O
murine	O
L	B-GENE
-	I-GENE
plastin	I-GENE
gene	O
promoters	O
.	O

How	O
does	O
a	O
nurse	O
go	O
about	O
maintaining	O
her	O
level	O
of	O
competence	O
when	O
she	O
is	O
one	O
of	O
the	O
few	O
local	O
practitioners	O
in	O
her	O
field	O
?	O
Vancouver	O
sex	O
therapist	O
Bianca	O
Rucker	O
is	O
doing	O
it	O
by	O
cultivating	O
a	O
network	O
of	O
colleagues	O
and	O
mentors	O
in	O
related	O
fields	O
both	O
at	O
home	O
and	O
across	O
the	O
continent	O
.	O

Finally	O
,	O
antibody	O
binding	O
to	O
site	O
IIIa	O
on	O
the	O
hCG	B-GENE
-	I-GENE
ectodomain	I-GENE
complex	I-GENE
was	O
also	O
hindered	O
by	O
an	O
anti	O
-	O
peptide	O
mAb	O
directed	O
against	O
a	O
peptide	O
encoded	O
by	O
the	O
eighth	O
exon	O
(	O
pE	O
x	O
8	O
)	O
of	O
the	O
LHR	B-GENE
.	O

In	O
rlf2	B-GENE
mutants	I-GENE
,	O
telomeric	O
chromatin	O
is	O
perturbed	O
:	O
Telomeric	O
silencing	O
is	O
reduced	O
and	O
Rap1p	B-GENE
localization	O
is	O
altered	O
.	O

This	O
0	O
.	O
74	O
kb	O
cDNA	O
contains	O
an	O
open	O
reading	O
frame	O
(	O
ORF	O
)	O
of	O
477	O
bp	O
encoding	O
a	O
polypeptide	O
of	O
159	O
amino	O
acids	O
(	O
aa	O
)	O
which	O
differs	O
at	O
only	O
one	O
position	O
(	O
position	O
65	O
)	O
from	O
the	O
human	B-GENE
U1	I-GENE
-	I-GENE
C	I-GENE
protein	I-GENE
.	O

However	O
,	O
the	O
action	O
of	O
each	O
cognate	O
ligand	O
and	O
the	O
accessory	O
cellular	O
factors	O
that	O
can	O
differentially	O
regulate	O
the	O
transcriptional	O
responses	O
of	O
a	O
heterodimer	O
-	O
DNA	O
complex	O
are	O
not	O
well	O
understood	O
.	O

We	O
have	O
measured	O
the	O
MBF	O
on	O
incisors	O
and	O
its	O
direction	O
in	O
three	O
dimensions	O
for	O
different	O
jaw	O
openings	O
in	O
ten	O
subjects	O
.	O

Clinically	O
meaningful	O
decreases	O
due	O
to	O
alkalinization	O
alone	O
within	O
30	O
minutes	O
are	O
unlikely	O
.	O

In	O
co	O
-	O
transfection	O
studies	O
,	O
an	O
AP	B-GENE
-	I-GENE
2	I-GENE
but	O
not	O
an	O
Egr	B-GENE
-	I-GENE
1	I-GENE
expression	O
vector	O
activated	O
VPF	B-GENE
/	O
VEGF	B-GENE
transcription	O
,	O
thus	O
indicating	O
that	O
AP	B-GENE
-	I-GENE
2	I-GENE
protein	I-GENE
is	O
functionally	O
important	O
in	O
TGF	B-GENE
alpha	I-GENE
-	O
induced	O
VPF	B-GENE
/	O
VEGF	B-GENE
gene	O
expression	O
.	O

Cytohesin	B-GENE
-	I-GENE
1	I-GENE
,	O
a	O
protein	O
abundant	O
in	O
cells	O
of	O
the	O
immune	O
system	O
,	O
has	O
been	O
proposed	O
to	O
be	O
a	O
human	O
homolog	O
of	O
the	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
Sec7	I-GENE
gene	I-GENE
product	I-GENE
,	O
which	O
is	O
crucial	O
in	O
protein	O
transport	O
.	O

In	O
this	O
regard	O
,	O
it	O
differs	O
from	O
a	O
recently	O
reported	O
BFA	O
-	O
sensitive	O
ARF	B-GENE
-	O
GEP	B-GENE
that	O
contains	O
a	O
Sec7	B-GENE
domain	I-GENE
.	O

The	O
recombinant	O
protein	O
was	O
purified	O
to	O
homogeneity	O
by	O
(	O
NH4	O
)	O
2SO4	O
-	O
precipitation	O
and	O
affinity	O
chromatography	O
on	O
5	O
'	O
AMP	O
-	O
Sepharose	O
.	O

Derepression	O
of	O
gene	O
expression	O
mediated	O
by	O
the	O
5	O
'	O
upstream	O
region	O
of	O
the	O
isocitrate	B-GENE
lyase	I-GENE
gene	I-GENE
of	I-GENE
Candida	I-GENE
tropicalis	I-GENE
is	O
controlled	O
by	O
two	O
distinct	O
regulatory	O
pathways	O
in	O
Saccharomyces	O
cerevisiae	O
.	O

99mTc	O
-	O
HMPAO	O
was	O
distributed	O
in	O
the	O
territories	O
of	O
the	O
ACA	O
and	O
MCA	O
in	O
the	O
two	O
patients	O
who	O
were	O
treated	O
with	O
intraarterial	O
infusion	O
of	O
papaverine	O
from	O
the	O
C4	O
segment	O
,	O
but	O
was	O
distributed	O
only	O
to	O
the	O
territory	O
of	O
the	O
ACA	O
in	O
four	O
patients	O
who	O
were	O
treated	O
with	O
intraarterial	O
infusion	O
of	O
papaverine	O
from	O
the	O
C1	O
segment	O
at	O
1	O
ml	O
/	O
min	O
.	O

This	O
brief	O
review	O
analyses	O
these	O
interactions	O
and	O
defines	O
clinical	O
settings	O
where	O
antibiotic	O
-	O
induced	O
endotoxin	O
release	O
may	O
prove	O
to	O
be	O
clinically	O
relevant	O
.	O

These	O
changes	O
in	O
virus	O
entry	O
features	O
may	O
result	O
in	O
coronaviruses	O
with	O
novel	O
pathogenic	O
properties	O
.	O

Effect	O
of	O
Azadirachta	O
indica	O
hydroalcoholic	O
leaf	O
extract	O
on	O
the	O
cardiovascular	O
system	O
.	O

In	O
cellular	O
supernatant	O
fraction	O
,	O
SHRSP	O
showed	O
a	O
decrease	O
of	O
magnesium	O
in	O
many	O
tissues	O
and	O
an	O
elevation	O
of	O
the	O
calcium	O
to	O
magnesium	O
ratio	O
when	O
compared	O
to	O
age	O
-	O
matched	O
WKY	O
and	O
SHRSR	O
.	O

The	O
reduced	O
NO	O
production	O
in	O
these	O
cells	O
was	O
associated	O
with	O
low	O
levels	O
of	O
mRNA	O
of	O
inducible	B-GENE
NO	I-GENE
synthetase	I-GENE
.	O

Apart	O
from	O
iron	O
regulation	O
,	O
sodA	B-GENE
expression	O
was	O
affected	O
by	O
changes	O
in	O
DNA	O
topology	O
induced	O
by	O
coumermycin	O
A	O
but	O
not	O
by	O
the	O
global	O
virulence	O
regulatory	O
Bvg	B-GENE
system	I-GENE
.	O

In	O
the	O
present	O
study	O
,	O
we	O
have	O
isolated	O
and	O
sequenced	O
several	O
p15E	B-GENE
cDNA	I-GENE
gene	I-GENE
fragments	I-GENE
amplified	O
by	O
means	O
of	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
from	O
parental	O
(	O
P815	O
)	O
and	O
xenogenized	O
(	O
P815	O
/	O
DTIC	O
)	O
tumour	O
cells	O
.	O

Transcriptional	O
activity	O
was	O
measured	O
by	O
slot	O
-	O
blot	O
hybridization	O
with	O
steady	O
-	O
state	O
RNA	O
isolated	O
from	O
lacZ	B-GENE
+	I-GENE
M	I-GENE
.	I-GENE
smegmatis	I-GENE
clones	O
.	O

Movement	O
time	O
and	O
kinematic	O
characteristics	O
were	O
analyzed	O
together	O
with	O
the	O
magnitude	O
of	O
cerebral	O
blood	O
flow	O
to	O
identify	O
areas	O
of	O
brain	O
activity	O
proportionate	O
to	O
task	O
and	O
movement	O
variables	O
.	O

Areas	O
with	O
significantly	O
greater	O
rCBF	O
for	O
targeting	O
were	O
the	O
left	O
motor	O
cortex	O
,	O
left	O
intraparietal	O
sulcus	O
,	O
and	O
left	O
caudate	O
.	O

Recent	O
studies	O
have	O
demonstrated	O
that	O
the	O
U1	B-GENE
snRNP	I-GENE
is	O
recruited	O
to	O
the	O
5	O
'	O
splice	O
site	O
by	O
protein	O
/	O
protein	O
interactions	O
involving	O
the	O
SR	B-GENE
domains	O
of	O
the	O
U1	B-GENE
-	I-GENE
70K	I-GENE
protein	I-GENE
and	O
SF2	B-GENE
/	O
ASF	B-GENE
.	O

Thus	O
,	O
the	O
tri	O
-	O
snRNP	O
-	O
specific	O
27K	O
protein	O
could	O
potentially	O
be	O
involved	O
in	O
SR	B-GENE
protein	O
-	O
mediated	O
protein	O
/	O
protein	O
interactions	O
and	O
,	O
additionally	O
,	O
its	O
phosphorylation	O
state	O
could	O
modulate	O
pre	O
-	O
mRNA	O
splicing	O
.	O

Although	O
methods	O
to	O
align	O
the	O
control	O
and	O
activation	O
fMR	O
images	O
may	O
correct	O
for	O
some	O
of	O
this	O
motional	O
error	O
,	O
they	O
will	O
be	O
incomplete	O
in	O
correcting	O
for	O
those	O
that	O
depend	O
on	O
spatial	O
orientation	O
.	O

Three	O
women	O
have	O
had	O
abnormal	O
endocervical	O
follow	O
up	O
cytology	O
suggestive	O
of	O
residual	O
disease	O
.	O

This	O
site	O
is	O
upstream	O
from	O
the	O
TATA	O
box	O
used	O
in	O
somatic	O
cells	O
.	O

An	O
aromatic	O
stacking	O
interaction	O
between	O
subunits	O
helps	O
mediate	O
DNA	O
sequence	O
specificity	O
:	O
operator	O
site	O
discrimination	O
by	O
phage	B-GENE
lambda	I-GENE
cI	I-GENE
repressor	I-GENE
.	O

We	O
have	O
characterized	O
a	O
panel	O
of	O
6	O
monoclonal	O
antibodies	O
raised	O
against	O
human	B-GENE
platelet	I-GENE
talin	I-GENE
by	O
Western	O
blotting	O
,	O
immune	O
precipitation	O
,	O
and	O
immunofluorescence	O
,	O
and	O
shown	O
that	O
antibodies	B-GENE
TA205	I-GENE
and	O
TD77	B-GENE
disrupt	O
actin	B-GENE
stress	O
fibers	O
and	O
focal	O
adhesions	O
,	O
and	O
inhibit	O
cell	O
motility	O
when	O
microinjected	O
into	O
human	O
fibroblasts	O
.	O

Here	O
we	O
report	O
the	O
purification	O
of	O
this	O
larger	O
form	O
as	O
an	O
approximately	O
320	O
-	O
kDa	O
particle	O
that	O
contains	O
mRNP3	B-GENE
+	I-GENE
4	I-GENE
and	O
nine	O
additional	O
polypeptides	O
,	O
including	O
mRNA	O
-	O
binding	O
polypeptides	O
of	O
34	O
and	O
36	O
kDa	O
and	O
a	O
doublet	O
of	O
110	O
/	O
105	O
kDa	O
that	O
proved	O
to	O
be	O
nucleolin	B-GENE
.	O

This	O
study	O
indicates	O
that	O
the	O
phenotype	O
of	O
myofibrillar	O
disarray	O
seen	O
in	O
HCM	O
patients	O
which	O
harbor	O
either	O
of	O
these	O
two	O
mutations	O
may	O
not	O
be	O
directly	O
due	O
to	O
the	O
failure	O
of	O
the	O
mutant	B-GENE
myosin	I-GENE
heavy	I-GENE
chain	I-GENE
protein	I-GENE
to	O
assemble	O
and	O
form	O
normal	O
sarcomeres	O
,	O
but	O
may	O
rather	O
be	O
a	O
secondary	O
effect	O
possibly	O
resulting	O
from	O
the	O
chronic	O
stress	O
of	O
decreased	O
beta	B-GENE
MHC	I-GENE
function	O
.	O

A	O
method	O
for	O
the	O
simultaneous	O
determination	O
of	O
de	O
(	O
N	O
-	O
methyl	O
)	O
-	O
N	O
-	O
ethyl	O
-	O
8	O
,	O
9	O
-	O
anhydroerythromycin	O
A	O
6	O
,	O
9	O
-	O
hemiacetal	O
(	O
EM523	O
,	O
I	O
)	O
and	O
its	O
three	O
metabolites	O
in	O
human	O
plasma	O
and	O
urine	O
has	O
been	O
developed	O
using	O
high	O
-	O
performance	O
liquid	O
chromatography	O
(	O
HPLC	O
)	O
with	O
chemiluminescence	O
(	O
CL	O
)	O
detection	O
.	O

Cotransfection	O
of	O
Ets	B-GENE
-	I-GENE
2	I-GENE
and	O
p44	B-GENE
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
(	I-GENE
MAP	I-GENE
)	I-GENE
kinase	I-GENE
expression	O
vectors	O
strongly	O
potentiated	O
HB	B-GENE
-	O
EGF	B-GENE
promoter	O
activation	O
in	O
response	O
to	O
deltaRaf	B-GENE
-	I-GENE
1	I-GENE
:	O
ER	B-GENE
.	O

The	O
Rlm1	B-GENE
protein	I-GENE
,	O
a	O
member	O
of	O
the	O
MADS	B-GENE
box	I-GENE
family	I-GENE
of	O
transcription	O
factors	O
,	O
functions	O
downstream	O
of	O
Mpk1	B-GENE
in	O
the	O
pathway	O
.	O

The	O
likelihood	O
that	O
a	O
common	O
region	O
of	O
deletions	O
would	O
contain	O
a	O
tumor	O
suppressor	O
is	O
strongly	O
enhanced	O
by	O
coincidence	O
of	O
that	O
region	O
with	O
a	O
chromosome	O
fragment	O
suppressing	O
tumorigenicity	O
upon	O
introduction	O
in	O
tumor	O
cells	O
.	O

The	O
carboxyl	O
-	O
terminal	O
CCCC	O
module	O
is	O
structurally	O
related	O
to	O
the	O
DNA	O
-	O
binding	O
domain	O
of	O
the	O
erythroid	B-GENE
transcription	I-GENE
factor	I-GENE
GATA	I-GENE
-	I-GENE
1	I-GENE
.	O

The	O
different	O
holoenzyme	B-GENE
RNA	I-GENE
polymerases	I-GENE
generated	O
upon	O
reconstituting	O
these	O
mutants	O
independently	O
with	O
core	B-GENE
RNA	I-GENE
polymerase	I-GENE
(	O
alpha2beta	B-GENE
beta	I-GENE
'	I-GENE
)	O
have	O
shown	O
reduced	O
transcriptional	O
activity	O
in	O
comparison	O
to	O
the	O
enzyme	O
containing	O
wild	B-GENE
-	I-GENE
type	I-GENE
sigma	I-GENE
factor	I-GENE
.	O

These	O
data	O
are	O
consistent	O
with	O
a	O
model	O
in	O
which	O
GATA	B-GENE
-	I-GENE
5	I-GENE
performs	O
a	O
unique	O
temporally	O
and	O
spatially	O
restricted	O
function	O
in	O
the	O
embryonic	O
heart	O
and	O
lung	O
.	O

The	O
similar	O
phenotypes	O
of	O
bur6	B-GENE
and	O
bur3	B-GENE
(	O
mot1	B-GENE
)	O
mutations	O
suggest	O
that	O
Bur6p	B-GENE
and	O
Mot1p	B-GENE
have	O
related	O
,	O
but	O
not	O
identical	O
,	O
functions	O
in	O
modulating	O
the	O
activity	O
of	O
the	O
general	O
transcription	O
machinery	O
in	O
vivo	O
.	O

A	O
genetic	O
screen	O
applied	O
to	O
mutants	O
in	O
the	O
branch	O
site	O
region	O
shows	O
that	O
all	O
positions	O
in	O
the	O
conserved	O
TACTAAC	O
sequence	O
are	O
important	O
for	O
intron	O
recognition	O
.	O

Implication	O
of	O
PAF	B-GENE
and	O
acetylhydrolase	B-GENE
(	O
PAF	B-GENE
-	I-GENE
AH	I-GENE
)	O
activity	O
in	O
periodontal	O
disease	O
.	O

A	O
polypeptide	O
encoded	O
by	O
the	O
NTS	O
16	O
open	O
reading	O
frame	O
has	O
sequence	O
similarity	O
to	O
the	O
catalytic	O
domain	O
of	O
several	O
receptor	B-GENE
protein	I-GENE
kinases	I-GENE
from	I-GENE
plants	I-GENE
including	O
the	O
S	B-GENE
-	I-GENE
receptor	I-GENE
kinases	I-GENE
implicated	O
in	O
the	O
rejection	O
of	O
self	O
-	O
pollen	O
in	O
Brassica	O
species	O
and	O
the	O
Pto	B-GENE
gene	I-GENE
product	I-GENE
of	I-GENE
tomato	I-GENE
which	O
confers	O
resistance	O
to	O
a	O
bacterial	O
pathogen	O
.	O

The	O
atp	B-GENE
1	I-GENE
and	O
atp	B-GENE
2	I-GENE
types	O
of	O
cDNA	O
sequences	O
were	O
the	O
most	O
redundant	O
among	O
the	O
28	O
different	O
isoperoxidases	B-GENE
identified	O
among	O
about	O
200	O
peroxidase	B-GENE
encoding	I-GENE
ESTs	I-GENE
.	O

Glycemic	O
response	O
to	O
malted	O
,	O
popped	O
and	O
roller	O
dried	O
wheat	O
-	O
legume	O
based	O
foods	O
in	O
normal	O
subjects	O
.	O

4	O
.	O
26	O
+	O
/	O
-	O
1	O
.	O
54	O
mmol	O
/	O
l	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
,	O
and	O
systolic	O
BP	O
responses	O
to	O
intravenous	O
norepinephrine	O
and	O
angiotensin	B-GENE
II	I-GENE
were	O
significantly	O
higher	O
on	O
glibenclamide	O
than	O
on	O
metformin	O
(	O
P	O
<	O
0	O
.	O
02	O
and	O
P	O
<	O
0	O
.	O
05	O
,	O
respectively	O
)	O
.	O

Is	O
leishmaniasis	O
endemic	O
on	O
the	O
island	O
of	O
Minorca	O
(	O
Spain	O
)	O
?	O
A	O
human	O
visceral	O
case	O
after	O
living	O
13	O
years	O
in	O
Minorca	O
.	O

RESULTS	O
:	O
Surprisingly	O
,	O
PAF	B-GENE
blockade	O
increased	O
mortality	O
after	O
trauma	O
(	O
5	O
of	O
11	O
WEB	O
-	O
2086	O
animals	O
versus	O
1	O
of	O
9	O
vehicle	O
animals	O
;	O
p	O
=	O
0	O
.	O
15	O
)	O
and	O
depressed	O
cardiac	O
index	O
and	O
O2	O
delivery	O
at	O
72	O
hours	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

This	O
finding	O
is	O
the	O
first	O
example	O
of	O
utilization	O
of	O
noncomplementary	O
dinucleotide	O
primer	O
by	O
an	O
RNA	B-GENE
polymerase	I-GENE
.	O

Pure	O
T1	O
and	O
dual	O
-	O
T1	O
images	O
were	O
visually	O
evaluated	O
for	O
image	O
quality	O
(	O
IQ	O
)	O
on	O
a	O
five	O
-	O
point	O
scale	O
(	O
0	O
=	O
unacceptable	O
to	O
4	O
=	O
excellent	O
)	O
.	O

This	O
conformer	O
features	O
a	O
Type	O
I	O
beta	O
-	O
turn	O
and	O
has	O
extensive	O
hydrophobic	O
contacts	O
with	O
the	O
FKBP12	B-GENE
binding	O
surface	O
.	O

Children	O
'	O
s	O
temperament	O
and	O
maternal	O
socialization	O
at	O
Time	O
1	O
(	O
n	O
=	O
103	O
,	O
aged	O
2	O
-	O
3	O
years	O
)	O
were	O
considered	O
predictors	O
of	O
future	O
conscience	O
,	O
assessed	O
using	O
new	O
observational	O
and	O
narrative	O
measures	O
.	O

One	O
P1	O
genomic	O
clone	O
and	O
six	O
subsequent	O
plasmid	O
subclones	O
were	O
isolated	O
and	O
analyzed	O
for	O
the	O
exon	O
-	O
intron	O
organization	O
of	O
the	O
Ctpct	B-GENE
gene	I-GENE
.	O

Congruent	O
with	O
empirical	O
predictions	O
,	O
the	O
most	O
homesick	O
children	O
perceived	O
low	O
control	O
over	O
homesickness	O
and	O
separation	O
,	O
and	O
coped	O
by	O
relinquishing	O
control	O
.	O

We	O
also	O
review	O
the	O
role	O
of	O
grains	O
in	O
the	O
formation	O
of	O
complex	O
molecules	O
in	O
interstellar	O
molecular	O
clouds	O
.	O

The	O
C	O
-	O
LIP	O
also	O
was	O
compared	O
with	O
transcather	O
arterial	O
embolization	O
(	O
TAE	O
;	O
C	O
-	O
LIP	O
followed	O
by	O
gelatin	O
sponge	O
)	O
and	O
percutaneous	O
ethanol	O
injection	O
therapy	O
(	O
PEIT	O
)	O
.	O

We	O
also	O
demonstrate	O
that	O
preformed	O
triplexes	O
are	O
quite	O
stable	O
when	O
precipitated	O
with	O
ethanol	O
and	O
resuspended	O
in	O
water	O
.	O

Transfection	O
experiments	O
using	O
preformed	O
triplexes	O
with	O
a	O
reporter	O
plasmid	O
containing	O
the	O
collagen	B-GENE
promoter	I-GENE
sequence	I-GENE
showed	O
significant	O
inhibition	O
of	O
transcription	O
when	O
compared	O
with	O
a	O
control	O
phosphorothioate	O
ODN	O
.	O

Thus	O
,	O
an	O
increase	O
in	O
plasma	B-GENE
TBG	I-GENE
and	O
a	O
shift	O
from	O
adrenal	O
androgen	O
and	O
mineralocorticoid	O
steroid	O
secretion	O
towards	O
cortisol	O
secretion	O
may	O
be	O
endocrine	O
markers	O
for	O
progression	O
of	O
the	O
disease	O
in	O
patients	O
with	O
HIV	O
-	O
infection	O
.	O

Latanoprost	O
produces	O
an	O
additional	O
reduction	O
of	O
intraocular	O
pressure	O
(	O
IOP	O
)	O
when	O
used	O
in	O
combination	O
with	O
timolol	O
,	O
pilocarpine	O
,	O
acetazolamide	O
and	O
dipivefrin	O
.	O

Transient	O
overexpression	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
induced	O
tenascin	B-GENE
-	I-GENE
C	I-GENE
expression	O
in	O
primary	O
REF	O
and	O
in	O
FR3T3	O
,	O
an	O
established	O
fibroblast	O
cell	O
line	O
.	O

Selected	O
parameters	O
:	O
heart	O
rate	O
(	O
HR	O
)	O
,	O
arterial	O
blood	O
pressure	O
(	O
ABP	O
)	O
and	O
arterial	O
O2	O
saturation	O
(	O
SaO2	O
)	O
monitored	O
by	O
pulsoximetry	O
were	O
measured	O
during	O
the	O
procedure	O
.	O

We	O
have	O
tested	O
this	O
proposal	O
by	O
carrying	O
out	O
circular	O
dichroism	O
(	O
CD	O
)	O
and	O
NMR	O
experiments	O
on	O
the	O
Skn	B-GENE
domain	I-GENE
and	O
five	O
truncated	O
proteins	O
.	O

Genes	O
for	O
ocs	B-GENE
element	I-GENE
binding	I-GENE
factors	I-GENE
(	O
OBFs	B-GENE
)	O
,	O
belonging	O
to	O
a	O
specific	O
class	O
of	O
basic	B-GENE
-	I-GENE
region	I-GENE
leucine	I-GENE
zipper	I-GENE
(	I-GENE
bZIP	I-GENE
)	I-GENE
transcription	I-GENE
factors	I-GENE
,	O
have	O
been	O
isolated	O
in	O
a	O
number	O
of	O
plants	O
.	O

SRE	O
activity	O
is	O
dependent	O
upon	O
the	O
activation	O
by	O
phosphorylation	O
of	O
a	O
ternary	O
complex	O
factor	O
;	O
included	O
among	O
the	O
ternary	O
complex	O
factors	O
is	O
Elk	B-GENE
-	I-GENE
1	I-GENE
.	O

A	O
xylE	B-GENE
transcriptional	I-GENE
fusion	I-GENE
to	O
the	O
putative	O
mxbD	B-GENE
promoter	I-GENE
showed	O
low	O
-	O
level	O
expression	O
in	O
wild	O
-	O
type	O
cells	O
grown	O
on	O
one	O
-	O
carbon	O
(	O
C1	O
)	O
compounds	O
and	O
no	O
detectable	O
expression	O
in	O
cells	O
grown	O
on	O
succinate	O
.	O

Pax	B-GENE
-	I-GENE
3	I-GENE
is	O
a	O
paired	B-GENE
-	I-GENE
type	I-GENE
homeobox	I-GENE
gene	I-GENE
that	O
is	O
specifically	O
expressed	O
in	O
the	O
dorsal	O
and	O
posterior	O
neural	O
tube	O
.	O

Instead	O
,	O
they	O
contained	O
dendritic	O
cells	O
that	O
express	O
melanogenic	O
marker	O
proteins	O
such	O
as	O
tyrosinase	B-GENE
and	O
tyrosinase	B-GENE
-	I-GENE
related	I-GENE
protein	I-GENE
1	I-GENE
.	O

These	O
mutations	O
create	O
stop	O
codons	O
in	O
exon	O
7	O
and	O
8	O
,	O
respectively	O
,	O
and	O
probably	O
result	O
in	O
truncated	O
proteins	O
lacking	O
HLH	O
-	O
Zip	O
or	O
Zip	O
structure	O
.	O

These	O
six	O
amino	O
acids	O
are	O
part	O
of	O
an	O
amphipathic	O
helix	O
that	O
is	O
highly	O
conserved	O
among	O
nuclear	B-GENE
hormone	I-GENE
receptors	I-GENE
and	O
contains	O
the	O
core	O
domain	O
of	O
the	O
ligand	O
-	O
dependent	O
transactivation	O
function	O
,	O
AF	O
-	O
2	O
.	O

Surprisingly	O
,	O
the	O
RXR	B-GENE
-	O
specific	O
ligand	O
9	O
-	O
cis	O
-	O
retinoic	O
acid	O
induced	O
binding	O
of	O
SRC	B-GENE
-	I-GENE
1	I-GENE
to	O
the	O
RXR	B-GENE
component	I-GENE
of	O
the	O
TRE	O
-	O
bound	O
heterodimer	O
.	O

Using	O
PRL	B-GENE
-	I-GENE
R	I-GENE
tagged	O
both	O
in	O
the	O
N	O
-	O
terminal	O
or	O
C	O
-	O
terminal	O
regions	O
of	O
the	O
mature	O
receptor	O
excludes	O
the	O
possibility	O
of	O
a	O
cleaved	O
fragment	O
which	O
could	O
have	O
been	O
subsequently	O
imported	O
into	O
the	O
nucleus	O
.	O

Transcription	O
of	O
these	O
genes	O
was	O
also	O
elevated	O
in	O
gut	O
and	O
lung	O
during	O
freezing	O
,	O
but	O
mRNA	O
levels	O
in	O
these	O
tissues	O
were	O
lower	O
than	O
in	O
liver	O
.	O

The	O
most	O
important	O
one	O
among	O
them	O
is	O
Cyclosporin	O
A	O
,	O
which	O
is	O
a	O
selective	O
immunosuppressive	O
drug	O
.	O

Using	O
a	O
conditional	O
-	O
lethal	O
mutant	O
allele	O
of	O
SUP45	B-GENE
(	O
sup45	B-GENE
-	I-GENE
2	I-GENE
)	O
and	O
a	O
combination	O
of	O
in	O
vivo	O
and	O
in	O
vitro	O
approaches	O
,	O
we	O
demonstrate	O
that	O
the	O
product	O
of	O
the	O
SUP45	B-GENE
gene	I-GENE
(	O
Sup45p	B-GENE
or	O
eRF1	B-GENE
)	O
is	O
a	O
factor	O
required	O
for	O
translation	O
termination	O
in	O
yeast	O
.	O

She	O
was	O
able	O
to	O
stand	O
unaided	O
by	O
3	O
years	O
of	O
age	O
with	O
then	O
progressive	O
worsening	O
of	O
motor	O
abilities	O
.	O

Merosin	B-GENE
positive	O
congenital	O
muscular	O
dystrophy	O
with	O
mental	O
deficiency	O
,	O
epilepsy	O
and	O
MRI	O
changes	O
in	O
the	O
cerebral	O
white	O
matter	O
.	O

Also	O
,	O
transient	O
overexpression	O
of	O
this	O
protein	O
in	O
C2C12	O
cells	O
reduced	O
the	O
transcription	O
of	O
a	O
CAT	B-GENE
-	O
reporter	O
regulated	O
by	O
an	O
E12	B-GENE
/	O
MyoD	B-GENE
driven	O
enhancer	O
.	O

Type	O
I	O
position	O
-	O
vestibular	O
-	O
pause	O
(	O
PVP	O
I	O
)	O
and	O
vestibular	O
-	O
only	O
(	O
V	O
I	O
)	O
neurons	O
,	O
as	O
well	O
as	O
a	O
smaller	O
number	O
of	O
other	O
type	O
I	O
and	O
type	O
II	O
eye	O
-	O
plus	O
-	O
vestibular	O
neurons	O
were	O
studied	O
.	O

Using	O
mouse	O
-	O
human	O
somatic	O
hybrids	O
and	O
FISH	O
analysis	O
,	O
the	O
PE	B-GENE
-	I-GENE
2	I-GENE
gene	I-GENE
is	O
localized	O
to	O
human	O
chromosome	O
19q13	O
.	O
2	O
,	O
a	O
region	O
involved	O
in	O
translocations	O
and	O
deletions	O
in	O
leukemias	O
and	O
several	O
solid	O
tumors	O
,	O
suggesting	O
that	O
this	O
novel	O
ETS	B-GENE
factor	I-GENE
may	O
play	O
a	O
role	O
in	O
carcinogenesis	O
.	O

Sequence	O
divergence	O
is	O
observed	O
in	O
untranslated	O
regions	O
which	O
allows	O
the	O
definition	O
of	O
gene	O
-	O
specific	O
probes	O
.	O

In	O
adherent	O
macrophages	O
,	O
absence	O
of	O
CD45	B-GENE
led	O
to	O
the	O
hyperphosphorylation	O
and	O
hyperactivation	O
of	O
p56	B-GENE
/	I-GENE
59	I-GENE
(	O
hck	B-GENE
)	O
and	O
p53	B-GENE
/	I-GENE
56	I-GENE
(	O
lyn	B-GENE
)	O
,	O
but	O
not	O
of	O
p58	B-GENE
(	O
c	B-GENE
-	I-GENE
fgr	I-GENE
)	O
.	O

Secretion	O
in	O
milk	O
and	O
transplacental	O
transfer	O
of	O
two	O
iodized	O
oils	O
,	O
Lipiodol	O
UF	O
and	O
Oriodol	O
,	O
in	O
rabbits	O
.	O

The	O
RNA	O
-	O
binding	O
and	O
RNA	B-GENE
-	I-GENE
DNA	I-GENE
helicase	I-GENE
activities	O
of	O
the	O
Escherichia	B-GENE
coli	I-GENE
transcription	I-GENE
termination	I-GENE
factor	I-GENE
rho	I-GENE
have	O
been	O
investigated	O
using	O
natural	O
RNA	O
molecules	O
that	O
are	O
255	O
and	O
391	O
nucleotide	O
residues	O
in	O
length	O
and	O
that	O
contain	O
the	O
trp	B-GENE
t	I-GENE
'	I-GENE
rho	I-GENE
-	I-GENE
dependent	I-GENE
termination	I-GENE
sequence	I-GENE
of	O
E	O
.	O
coli	O
.	O

The	O
serum	O
levels	O
of	O
beta	B-GENE
-	I-GENE
human	I-GENE
chorionic	I-GENE
gonadotropin	I-GENE
(	O
HCG	B-GENE
)	O
and	O
placental	B-GENE
alkaline	I-GENE
phosphatase	I-GENE
(	O
PLAP	B-GENE
)	O
were	O
not	O
elevated	O
.	O

Thus	O
E14	O
.	O
1TG3B1	O
is	O
a	O
useful	O
ES	O
cell	O
line	O
for	O
modifying	O
the	O
mouse	O
genome	O
using	O
the	O
HPRT	B-GENE
gene	I-GENE
as	O
a	O
selection	O
marker	O
and	O
for	O
transmission	O
at	O
a	O
high	O
frequency	O
into	O
the	O
mouse	O
germ	O
line	O
.	O

OBJECTIVE	O
:	O
This	O
study	O
was	O
designed	O
to	O
analyze	O
the	O
common	O
cause	O
of	O
asthenopia	O
,	O
mixed	O
astigmatism	O
.	O

One	O
RNA	O
construct	O
which	O
consisted	O
of	O
112	O
nucleotides	O
(	O
nt	O
)	O
from	O
nt	O
639	O
to	O
nt	O
750	O
formed	O
a	O
heterodimeric	O
complex	O
with	O
the	O
RNA	O
which	O
consisted	O
of	O
200	O
nucleotides	O
from	O
nt	O
551	O
to	O
nt	O
750	O
.	O

However	O
,	O
we	O
could	O
not	O
find	O
the	O
homologous	O
regions	O
with	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factors	I-GENE
or	O
GTPase	B-GENE
-	I-GENE
activating	I-GENE
proteins	I-GENE
in	O
the	O
c	B-GENE
-	I-GENE
cbl	I-GENE
gene	I-GENE
.	O

Aryl	B-GENE
hydrocarbon	I-GENE
receptor	I-GENE
nuclear	I-GENE
translocator	I-GENE
(	O
ARNT	B-GENE
)	O
is	O
a	O
component	O
of	O
the	O
transcription	O
factors	O
,	O
aryl	B-GENE
hydrocarbon	I-GENE
receptor	I-GENE
(	O
AhR	B-GENE
)	O
and	O
hypoxia	B-GENE
-	I-GENE
inducible	I-GENE
factor	I-GENE
1	I-GENE
,	O
which	O
transactivate	O
their	O
target	O
genes	O
,	O
such	O
as	O
CYP1A1	B-GENE
and	O
erythropoietin	B-GENE
,	O
in	O
response	O
to	O
xenobiotic	O
aromatic	O
hydrocarbons	O
and	O
to	O
low	O
O2	O
concentration	O
,	O
respectively	O
.	O

We	O
also	O
provide	O
evidence	O
that	O
gar2	B-GENE
is	O
phosphorylated	O
in	O
vitro	O
by	O
a	O
p13	B-GENE
(	O
suc1	B-GENE
)	O
-	O
Sepharose	O
-	O
bound	O
kinase	O
from	O
Schizosaccharomyces	O
pombe	O
extracts	O
that	O
displays	O
cell	O
cycle	O
-	O
regulated	O
activity	O
similar	O
to	O
that	O
of	O
the	O
p34	B-GENE
(	O
cdc2	B-GENE
(	O
kinase	O
.	O

However	O
,	O
by	O
immobilized	O
metal	O
affinity	O
chromatography	O
assay	O
,	O
self	O
-	O
association	O
of	O
PR	B-GENE
-	I-GENE
A	I-GENE
was	O
3	O
.	O
5	O
-	O
fold	O
more	O
efficient	O
than	O
that	O
of	O
either	O
the	O
DhLBD	O
or	O
hLBD	O
constructs	O
.	O

The	O
overall	O
results	O
of	O
this	O
paper	O
are	O
consistent	O
with	O
the	O
conclusion	O
that	O
the	O
carboxyl	O
-	O
terminal	O
LBD	O
is	O
not	O
sufficient	O
for	O
mediating	O
PR	B-GENE
dimerization	O
and	O
that	O
multiple	O
regions	O
,	O
including	O
the	O
hinge	O
and	O
amino	O
-	O
terminal	O
sequences	O
,	O
contribute	O
either	O
directly	O
or	O
indirectly	O
to	O
homodimerization	O
of	O
PR	B-GENE
.	O

Colorectal	O
carcinoma	O
:	O
therapeutic	O
approach	O
in	O
patients	O
already	O
treated	O
with	O
metastasis	O
resection	O

Alternative	O
splicing	O
of	O
ClC	B-GENE
-	I-GENE
6	I-GENE
(	O
a	O
member	O
of	O
the	O
CIC	B-GENE
chloride	I-GENE
-	I-GENE
channel	I-GENE
family	I-GENE
)	O
transcripts	O
generates	O
three	O
truncated	O
isoforms	O
one	O
of	O
which	O
,	O
ClC	B-GENE
-	I-GENE
6c	I-GENE
,	O
is	O
kidney	O
-	O
specific	O
.	O

The	O
frequency	O
of	O
positive	O
anti	B-GENE
-	I-GENE
GM1	I-GENE
antibody	I-GENE
titers	O
in	O
the	O
Guillain	O
-	O
Barre	O
syndrome	O
patients	O
with	O
PEN	O
19	O
isolates	O
was	O
higher	O
than	O
that	O
in	O
the	O
Guillain	O
-	O
Barre	O
syndrome	O
and	O
Fisher	O
'	O
s	O
syndrome	O
patients	O
without	O
PEN	O
19	O
isolates	O
.	O

NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
/	O
Rel	B-GENE
transcription	O
factors	O
participate	O
in	O
the	O
activation	O
of	O
numerous	O
genes	O
involved	O
in	O
immune	O
regulation	O
/	O
inflammation	O
including	O
cytokines	O
,	O
cell	O
surface	O
receptors	O
,	O
adhesion	O
molecules	O
,	O
and	O
acute	O
phase	O
proteins	O
.	O

However	O
,	O
mean	O
food	O
intake	O
in	O
the	O
40	O
%	O
group	O
was	O
half	O
that	O
of	O
the	O
ACT	O
group	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
and	O
significantly	O
less	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
than	O
the	O
SEP	O
group	O
,	O
which	O
consumed	O
amounts	O
equivalent	O
to	O
65	O
%	O
of	O
daily	O
requirement	O
.	O

We	O
have	O
separated	O
a	O
dermatan	O
sulfate	O
proteoglycan	O
,	O
epiphycan	O
,	O
from	O
decorin	B-GENE
and	O
biglycan	O
by	O
using	O
dissociative	O
extraction	O
of	O
bovine	O
fetal	O
epiphyseal	O
cartilage	O
,	O
followed	O
by	O
sequential	O
ion	O
-	O
exchange	O
,	O
gel	O
permeation	O
,	O
hydrophobic	O
,	O
and	O
Zn2	O
+	O
chelate	O
chromatographic	O
steps	O
.	O

The	O
mean	O
times	O
to	O
detection	O
of	O
all	O
mycobacteria	O
with	O
BACTEC	O
9000	O
MB	O
and	O
BACTEC	O
460	O
TB	O
were	O
similar	O
(	O
10	O
.	O
3	O
and	O
10	O
.	O
0	O
days	O
,	O
respectively	O
)	O
.	O

Though	O
the	O
BACTEC	O
9000	O
MB	O
system	O
is	O
recommended	O
for	O
respiratory	O
specimens	O
,	O
we	O
demonstrated	O
that	O
it	O
can	O
be	O
successfully	O
used	O
also	O
for	O
recovery	O
of	O
mycobacteria	O
from	O
clinical	O
specimens	O
from	O
various	O
extrapulmonary	O
sites	O
.	O

A	O
pre	O
-	O
boutonniere	O
deformity	O
was	O
simulated	O
by	O
dividing	O
the	O
central	O
slip	O
.	O

This	O
regulation	O
requires	O
two	O
HMG	B-GENE
-	I-GENE
box	I-GENE
proteins	I-GENE
:	O
the	O
ubiquitous	O
Ste11	B-GENE
transcription	I-GENE
factor	I-GENE
and	O
the	O
M	O
cell	O
-	O
controlling	O
protein	O
Mat1	B-GENE
-	I-GENE
Mc	I-GENE
.	O

Neither	O
of	O
these	O
proteins	O
,	O
individually	O
or	O
as	O
a	O
pair	O
,	O
can	O
bind	O
the	O
alpha	B-GENE
-	I-GENE
globin	I-GENE
3	I-GENE
'	I-GENE
UTR	I-GENE
unless	O
they	O
are	O
complexed	O
with	O
the	O
remaining	O
non	O
-	O
poly	O
(	O
C	O
)	O
binding	O
proteins	O
of	O
the	O
alpha	B-GENE
-	I-GENE
complex	I-GENE
.	O

(	O
1996a	O
)	O
Biochemistry	O
35	O
,	O
1589	O
-	O
1598	O
]	O
.	O

A	O
prospective	O
observational	O
study	O
was	O
conducted	O
to	O
identify	O
early	O
indicators	O
of	O
acute	O
dengue	O
virus	O
infection	O
.	O

It	O
is	O
present	O
in	O
the	O
nucleus	O
of	O
the	O
cells	O
in	O
which	O
it	O
is	O
expressed	O
and	O
can	O
phosphorylate	O
and	O
activate	O
the	O
cyclic	B-GENE
AMP	I-GENE
response	I-GENE
element	I-GENE
binding	I-GENE
proteins	I-GENE
CREB	B-GENE
and	O
CREM	B-GENE
tau	I-GENE
in	O
a	O
manner	O
analogous	O
to	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
.	O

These	O
cells	O
fail	O
to	O
generate	O
the	O
signals	O
to	O
phosphorylate	O
CREB	B-GENE
and	O
produce	O
significantly	O
less	O
of	O
the	O
cytokine	O
Interleukin	B-GENE
-	I-GENE
2	I-GENE
(	O
IL	B-GENE
-	I-GENE
2	I-GENE
)	O
in	O
response	O
to	O
agents	O
that	O
either	O
increase	O
intracellular	O
Ca2	O
+	O
and	O
/	O
or	O
activate	O
protein	B-GENE
kinase	I-GENE
C	I-GENE
.	O

Both	O
of	O
these	O
dogs	O
had	O
low	O
serum	O
IgG	B-GENE
(	O
3	O
.	O
5	O
to	O
7	O
.	O
2	O
mg	O
/	O
ml	O
)	O
and	O
the	O
second	O
littermate	O
also	O
had	O
reduced	O
serum	O
IgA	B-GENE
(	O
<	O
0	O
.	O
1	O
to	O
0	O
.	O
15	O
mg	O
/	O
ml	O
)	O
.	O

CONCLUSIONS	O
:	O
Valproate	O
appears	O
to	O
inhibit	O
the	O
glucuronidation	O
of	O
carbamazepine	O
-	O
10	O
,	O
11	O
-	O
trans	O
-	O
diol	O
,	O
and	O
probably	O
also	O
inhibits	O
the	O
conversion	O
of	O
carbamazepine	O
-	O
10	O
,	O
11	O
-	O
epoxide	O
to	O
this	O
trans	O
-	O
diol	O
derivative	O
,	O
rather	O
than	O
simply	O
inhibiting	O
the	O
latter	O
reaction	O
only	O
.	O

Proteinuria	O
in	O
a	O
young	O
man	O
.	O

Neural	O
blockade	O
in	O
chronic	O
and	O
cancer	O
pain	O
.	O

Five	O
cell	O
strains	O
of	O
human	O
dermal	O
fibroblasts	O
were	O
each	O
treated	O
with	O
three	O
samples	O
of	O
burn	O
blister	O
fluid	O
and	O
the	O
effect	O
compared	O
with	O
the	O
rate	O
of	O
contraction	O
of	O
free	O
floating	O
fibroblast	O
populated	O
collagen	B-GENE
lattices	O
(	O
FPCL	O
)	O
.	O

It	O
is	O
thus	O
one	O
of	O
the	O
key	O
enzymes	O
involved	O
in	O
the	O
triiodothyronine	O
-	O
mediated	O
control	O
of	O
growth	O
,	O
differentiation	O
and	O
basal	O
metabolism	O
in	O
vertebrates	O
.	O

We	O
had	O
previously	O
analyzed	O
repair	O
rates	O
of	O
cyclobutane	O
pyrimidine	O
dimers	O
at	O
nucleotide	O
resolution	O
along	O
the	O
human	B-GENE
JUN	I-GENE
gene	I-GENE
in	O
normal	O
fibroblasts	O
and	O
found	O
very	O
efficient	O
repair	O
of	O
sequences	O
near	O
the	O
transcription	O
initiation	O
site	O
but	O
slow	O
repair	O
along	O
the	O
promoter	O
.	O

The	O
used	O
expression	O
system	O
could	O
allow	O
to	O
produce	O
mutated	O
forms	O
of	O
SsEF	B-GENE
-	I-GENE
2	I-GENE
obtained	O
by	O
mutagenesis	O
of	O
the	O
corresponding	O
gene	O
.	O

Crosstalk	O
among	O
the	O
pathways	O
may	O
explain	O
how	O
some	O
forms	O
of	O
stress	O
can	O
contribute	O
to	O
the	O
development	O
of	O
a	O
malignancy	O
.	O

MEASUREMENTS	O
AND	O
MAIN	O
RESULTS	O
:	O
Lung	O
elastance	O
(	O
EL	O
)	O
and	O
resistance	O
(	O
RL	O
)	O
were	O
calculated	O
from	O
measurements	O
of	O
airway	O
pressure	O
,	O
esophageal	O
pressure	O
,	O
and	O
airway	O
flow	O
in	O
five	O
anesthetized	O
,	O
paralyzed	O
dogs	O
during	O
sinusoidal	O
forcing	O
at	O
a	O
constant	O
mean	O
airway	O
pressure	O
of	O
10	O
cmH2O	O
in	O
a	O
wide	O
range	O
of	O
breathing	O
frequencies	O
(	O
0	O
.	O
2	O
to	O
1	O
.	O
0	O
Hz	O
in	O
intervals	O
of	O
0	O
.	O
2	O
)	O
and	O
tidal	O
volumes	O
(	O
50	O
,	O
100	O
,	O
200	O
,	O
and	O
to	O
300	O
mL	O
)	O
.	O

Because	O
the	O
biosynthetic	O
pathway	O
to	O
the	O
vacuole	O
intersects	O
with	O
the	O
endocytic	O
pathway	O
,	O
internalization	O
of	O
a	O
bulk	O
membrane	O
endocytic	O
marker	O
FM	O
4	O
-	O
64	O
was	O
assayed	O
in	O
the	O
sop	B-GENE
mutants	I-GENE
.	O

Naltrexone	O
has	O
been	O
recently	O
approved	O
by	O
the	O
Food	O
and	O
Drug	O
Administration	O
for	O
the	O
treatment	O
of	O
alcohol	O
dependence	O
.	O

Consistent	O
with	O
this	O
model	O
,	O
a	O
synthetic	O
construct	O
containing	O
three	O
tandem	O
copies	O
of	O
the	O
native	O
LDL	B-GENE
receptor	I-GENE
SREBP	B-GENE
site	O
linked	O
to	O
a	O
single	O
Sp1	B-GENE
site	I-GENE
was	O
also	O
significantly	O
activated	O
in	O
a	O
buttonhead	B-GENE
-	O
independent	O
fashion	O
.	O

Analysis	O
of	O
the	O
5	O
'	O
flanking	O
region	O
of	O
the	O
gene	O
also	O
revealed	O
the	O
presence	O
of	O
multiple	O
TATA	O
and	O
CAAT	O
sequences	O
.	O

Analysis	O
of	O
the	O
5	O
'	O
flanking	O
region	O
of	O
the	O
gene	O
also	O
revealed	O
the	O
presence	O
of	O
multiple	O
TATA	O
and	O
CAAT	O
sequences	O
.	O

The	O
m7GpppN	O
cap	O
structure	O
of	O
eukaryotic	O
mRNA	O
is	O
formed	O
cotranscriptionally	O
by	O
the	O
sequential	O
action	O
of	O
three	O
enzymes	O
:	O
RNA	B-GENE
triphosphatase	I-GENE
,	O
RNA	B-GENE
guanylyltransferase	I-GENE
,	O
and	O
RNA	B-GENE
(	I-GENE
guanine	I-GENE
-	I-GENE
7	I-GENE
)	I-GENE
-	I-GENE
methyltransferase	I-GENE
.	O

CONCLUSION	O
:	O
Patients	O
wit	O
clinically	O
palpable	O
neck	O
disease	O
(	O
N1	O
-	O
3	O
)	O
,	O
histological	O
evidence	O
of	O
metastatic	O
nodal	O
disease	O
,	O
extracapsular	O
spread	O
,	O
and	O
three	O
or	O
more	O
positive	O
lymph	O
nodes	O
are	O
at	O
greater	O
risk	O
of	O
developing	O
failure	O
at	O
distant	O
sites	O
.	O

4	O
.	O

Area	O
under	O
the	O
drug	O
concentration	O
-	O
time	O
curves	O
(	O
AUC0	O
-	O
24	O
hr	O
)	O
for	O
MTX	O
were	O
2379	O
and	O
3534	O
ng	O
*	O
hr	O
/	O
ml	O
from	O
PG	O
-	O
2	O
.	O
5	O
%	O
Azone	O
and	O
PG	O
-	O
7	O
.	O
5	O
%	O
Azone	O
systems	O
respectively	O
.	O

There	O
were	O
differences	O
between	O
males	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
for	O
most	O
of	O
the	O
characteristics	O
studied	O
.	O

Although	O
previous	O
data	O
have	O
suggested	O
that	O
Rev	B-GENE
uses	O
the	O
same	O
export	O
pathway	O
as	O
uracil	O
-	O
rich	O
small	O
nuclear	O
RNAs	O
and	O
5S	B-GENE
ribosomal	I-GENE
RNA	I-GENE
,	O
the	O
CTE	O
seems	O
to	O
interact	O
with	O
evolutionarily	O
conserved	O
factors	O
that	O
are	O
essential	O
for	O
cellular	O
mRNA	O
export	O
.	O

S2F	B-GENE
,	O
a	O
leaf	O
-	O
specific	O
trans	O
-	O
acting	O
factor	O
,	O
binds	O
to	O
a	O
novel	O
cis	O
-	O
acting	O
element	O
and	O
differentially	O
activates	O
the	O
RPL21	B-GENE
gene	I-GENE
.	O

Polarised	O
expression	O
of	O
human	O
intestinal	O
N	B-GENE
-	I-GENE
benzoyl	I-GENE
-	I-GENE
L	I-GENE
-	I-GENE
tyrosyl	I-GENE
-	I-GENE
p	I-GENE
-	I-GENE
aminobenzoic	I-GENE
acid	I-GENE
hydrolase	I-GENE
(	O
human	B-GENE
meprin	I-GENE
)	O
alpha	O
and	O
beta	O
subunits	O
in	O
Madin	O
-	O
Darby	O
canine	O
kidney	O
cells	O
.	O

Neither	O
mutant	O
exhibited	O
derepression	O
of	O
the	O
silent	B-GENE
mating	I-GENE
type	I-GENE
loci	I-GENE
.	O

In	O
contrast	O
to	O
the	O
wild	O
-	O
type	O
protein	O
,	O
expression	O
of	O
p45	B-GENE
NF	B-GENE
-	I-GENE
E2	I-GENE
lacking	O
this	O
activation	O
domain	O
in	O
an	O
NF	B-GENE
-	I-GENE
E2	I-GENE
null	O
cell	O
line	O
fails	O
to	O
support	O
enhancer	O
-	O
dependent	O
transcription	O
in	O
transient	O
assays	O
.	O

These	O
findings	O
suggest	O
one	O
potential	O
mechanism	O
for	O
direct	O
recruitment	O
of	O
distal	O
regulatory	O
regions	O
of	O
the	O
globin	B-GENE
loci	I-GENE
to	O
the	O
individual	O
promoters	O
.	O

The	O
promoter	O
region	O
showed	O
no	O
consensus	O
TATA	O
box	O
but	O
it	O
contains	O
CCAAT	O
and	O
CreA	B-GENE
boxes	O
known	O
to	O
be	O
involved	O
in	O
both	O
stress	O
and	O
carbon	O
-	O
catabolite	O
regulation	O
of	O
fungal	O
promoters	O
.	O

In	O
support	O
of	O
this	O
interpretation	O
we	O
demonstrate	O
that	O
MQ9b	B-GENE
binds	O
strongly	O
5	O
of	O
17	O
motif	O
-	O
positive	O
,	O
pathogen	O
-	O
derived	O
synthetic	O
peptides	O
.	O

These	O
discoloration	O
'	O
s	O
can	O
be	O
treated	O
in	O
several	O
ways	O
but	O
up	O
to	O
lately	O
tooth	O
structure	O
had	O
to	O
be	O
removed	O
in	O
an	O
irreversible	O
manner	O
in	O
order	O
to	O
provide	O
sufficient	O
bulk	O
for	O
the	O
new	O
restorative	O
material	O
.	O

Overexpression	O
of	O
BAG	B-GENE
-	I-GENE
1	I-GENE
also	O
protected	O
certain	O
cell	O
lines	O
from	O
heat	O
shock	O
-	O
induced	O
cell	O
death	O
.	O

The	O
5	O
'	O
flanking	O
region	O
contains	O
potential	O
binding	O
sites	O
for	O
TATA	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
,	O
Sp1	B-GENE
,	O
nuclear	B-GENE
factor	I-GENE
1	I-GENE
(	O
NF1	B-GENE
)	O
,	O
CAAT	B-GENE
-	I-GENE
box	I-GENE
binding	I-GENE
protein	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
)	O
,	O
hepatocyte	B-GENE
nuclear	I-GENE
factors	I-GENE
1	I-GENE
and	I-GENE
5	I-GENE
(	O
HNF1	B-GENE
,	O
HNF5	B-GENE
)	O
and	O
activator	B-GENE
proteins	I-GENE
1	I-GENE
and	I-GENE
2	I-GENE
(	O
AP1	B-GENE
,	O
AP2	B-GENE
)	O
.	O

The	O
recognition	O
specificity	O
of	O
the	O
p55	B-GENE
PDZ	B-GENE
domain	I-GENE
appears	O
to	O
be	O
unique	O
,	O
since	O
the	O
three	O
PDZ	B-GENE
domains	I-GENE
of	O
hDlg	B-GENE
(	O
human	O
lymphocyte	O
homologue	O
of	O
the	O
Drosophila	B-GENE
discs	I-GENE
large	I-GENE
tumor	I-GENE
suppressor	I-GENE
)	O
do	O
not	O
bind	O
the	O
cytoplasmic	O
domain	O
of	O
glycophorin	B-GENE
C	I-GENE
.	O

In	O
the	O
United	O
States	O
high	O
-	O
MW	O
HES	O
480	O
which	O
is	O
difficult	O
to	O
degrade	O
is	O
most	O
frequently	O
used	O
and	O
results	O
in	O
a	O
larger	O
in	O
vivo	O
MW	O
and	O
subsequent	O
decrease	O
in	O
factor	B-GENE
VIII	I-GENE
/	O
von	B-GENE
Willebrand	I-GENE
factor	I-GENE
levels	O
.	O

In	O
our	O
previous	O
studies	O
,	O
transcriptional	O
activation	O
was	O
shown	O
to	O
correlate	O
with	O
IEP86	B-GENE
binding	O
to	O
both	O
the	O
TATA	B-GENE
-	I-GENE
box	I-GENE
binding	I-GENE
protein	I-GENE
(	O
TBP	B-GENE
)	O
and	O
the	O
transcription	O
factor	O
bound	O
upstream	O
.	O

Previously	O
,	O
we	O
reported	O
that	O
scanthrough	O
translation	O
,	O
where	O
the	O
initiating	O
AUG	O
of	O
a	O
primary	O
open	O
reading	O
frame	O
is	O
bypassed	O
,	O
is	O
most	O
likely	O
to	O
account	O
for	O
the	O
presentation	O
of	O
cryptic	O
epitopes	O
from	O
alternative	O
reading	O
frames	O
within	O
the	O
influenza	B-GENE
A	I-GENE
PR	I-GENE
/	I-GENE
8	I-GENE
/	I-GENE
34	I-GENE
nucleoprotein	I-GENE
gene	I-GENE
.	O

The	O
deduced	O
amino	O
acid	O
sequence	O
of	O
the	O
gene	O
has	O
significant	O
homology	O
to	O
the	O
interferon	B-GENE
regulatory	I-GENE
factors	I-GENE
(	O
IRFs	B-GENE
)	O
.	O

The	O
pheromone	O
response	O
pathway	O
activates	O
transcription	O
of	O
Ty5	B-GENE
retrotransposons	I-GENE
located	O
within	O
silent	O
chromatin	O
of	O
Saccharomyces	O
cerevisiae	O
.	O

The	O
malate	B-GENE
synthase	I-GENE
gene	I-GENE
,	O
MLS1	B-GENE
,	O
of	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
is	O
transcriptionally	O
regulated	O
by	O
the	O
carbon	O
source	O
in	O
the	O
growth	O
medium	O
.	O

By	O
deletion	O
analysis	O
of	O
the	O
MLS1	B-GENE
control	O
region	O
,	O
we	O
identified	O
two	O
sites	O
,	O
UAS1	O
and	O
UAS2	O
,	O
as	O
important	O
for	O
efficient	O
derepression	O
of	O
the	O
gene	O
.	O

Prior	O
to	O
meals	O
2	O
to	O
3	O
times	O
daily	O
,	O
1	O
-	O
2	O
tablespoons	O
of	O
Alzoon	O
are	O
recommended	O
.	O

These	O
results	O
suggest	O
that	O
UBP41	B-GENE
may	O
play	O
an	O
important	O
role	O
in	O
the	O
recycling	O
of	O
ubiquitin	B-GENE
by	O
hydrolysis	O
of	O
branched	B-GENE
poly	I-GENE
-	I-GENE
ubiquitin	I-GENE
chains	I-GENE
generated	O
by	O
the	O
action	O
of	O
26	B-GENE
S	I-GENE
proteasome	I-GENE
on	O
poly	O
-	O
ubiquitinated	O
protein	O
substrates	O
,	O
as	O
well	O
as	O
in	O
the	O
production	O
of	O
free	O
ubiquitin	B-GENE
from	O
linear	B-GENE
poly	I-GENE
-	I-GENE
ubiquitin	I-GENE
chains	I-GENE
and	O
of	O
certain	O
ribosomal	O
proteins	O
from	O
ubiquitin	B-GENE
fusion	I-GENE
proteins	I-GENE
.	O

The	O
regurgitation	O
of	O
large	O
vitreous	O
injections	O
.	O

Attenuation	O
from	O
the	O
vit	B-GENE
A2	I-GENE
consensus	O
ERE	O
is	O
not	O
necessarily	O
dependent	O
on	O
DNA	O
binding	O
as	O
the	O
TR	B-GENE
alpha	I-GENE
DNA	O
binding	O
mutant	O
was	O
still	O
able	O
to	O
inhibit	O
E	O
-	O
dependent	O
transactivation	O
.	O

Null	O
mutations	O
in	O
daf	B-GENE
-	I-GENE
3	I-GENE
suppress	O
mutations	O
in	O
genes	O
encoding	O
this	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
signal	O
,	O
its	O
receptors	O
,	O
and	O
associated	O
Smad	B-GENE
signal	I-GENE
transduction	I-GENE
proteins	I-GENE
.	O
daf	B-GENE
-	I-GENE
3	I-GENE
encodes	O
a	O
Smad	B-GENE
protein	I-GENE
that	O
is	O
most	O
closely	O
related	O
to	O
mammalian	B-GENE
DPC4	I-GENE
,	O
and	O
is	O
expressed	O
throughout	O
development	O
in	O
many	O
of	O
the	O
tissues	O
that	O
are	O
remodeled	O
during	O
dauer	O
development	O
.	O

We	O
have	O
overexpressed	O
,	O
purified	O
,	O
characterized	O
,	O
and	O
crystallized	O
the	O
BTB	B-GENE
/	O
POZ	O
domain	O
from	O
PLZF	B-GENE
(	O
PLZF	B-GENE
-	O
BTB	B-GENE
/	O
POZ	O
)	O
.	O

Furthermore	O
,	O
deletion	O
and	O
mutation	O
analyses	O
of	O
the	O
VCAM	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
performed	O
with	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
constructs	I-GENE
revealed	O
that	O
Tax	B-GENE
was	O
trans	O
activating	O
the	O
VCAM	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
via	O
two	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
sites	I-GENE
present	O
at	O
bp	O
-	O
72	O
and	O
-	O
57	O
in	O
the	O
VCAM	B-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
promoter	I-GENE
,	O
with	O
both	O
of	O
them	O
being	O
required	O
for	O
the	O
Tax	B-GENE
-	O
induced	O
expression	O
of	O
this	O
adhesion	O
molecule	O
.	O

The	O
AGM	B-GENE
and	I-GENE
NIH	I-GENE
/	I-GENE
Swiss	I-GENE
mouse	I-GENE
CCR5	I-GENE
proteins	I-GENE
are	O
97	O
.	O
7	O
to	O
98	O
.	O
3	O
%	O
and	O
79	O
.	O
8	O
%	O
identical	O
to	O
the	O
human	O
protein	O
,	O
respectively	O
.	O

Recently	O
,	O
roles	O
also	O
have	O
been	O
suggested	O
for	O
the	O
nuclear	O
trans	O
-	O
factor	O
GATA	B-GENE
-	I-GENE
1	I-GENE
in	O
regulating	O
progenitor	O
cell	O
proliferation	O
.	O

(	O
ii	O
)	O
An	O
AF	O
G	B-GENE
-	I-GENE
CSF	I-GENE
level	O
>	O
2000	O
pg	O
/	O
ml	O
is	O
a	O
strong	O
positive	O
predictor	O
of	O
CAM	O
.	O

[	O
Pulmonary	O
vascular	O
resistance	O
(	O
PVR	O
)	O
during	O
10	O
%	O
O2	O
-	O
PVR	O
during	O
21	O
%	O
O2	O
/	O
PVR	O
during	O
21	O
%	O
O2	O
]	O
x	O
100	O
was	O
termed	O
as	O
hypoxic	O
pulmonary	O
vasoconstriction	O
(	O
HPV	O
)	O
.	O

An	O
unusual	O
cysteine	O
triplet	O
conserved	O
in	O
the	O
sequences	O
of	O
TB	B-GENE
domains	I-GENE
is	O
localized	O
to	O
the	O
hydrophobic	O
core	O
,	O
at	O
the	O
C	O
-	O
terminus	O
of	O
an	O
alpha	O
-	O
helix	O
.	O

Protein	O
phosphatases	O
play	O
a	O
critical	O
role	O
in	O
the	O
regulation	O
of	O
the	O
eukaryotic	O
cell	O
cycle	O
and	O
signal	O
transduction	O
.	O

Re	O
:	O
"	O
Assessing	O
the	O
direction	O
of	O
causality	O
in	O
cross	O
-	O
sectional	O
studies	O
"	O
.	O

Restriction	O
enzyme	O
mapping	O
,	O
subcloning	O
,	O
and	O
DNA	O
sequencing	O
analysis	O
of	O
recombinant	O
phage	O
lambda	O
and	O
P1	O
clones	O
revealed	O
that	O
exons	O
encoding	O
the	O
1	O
.	O
9	O
-	O
kb	O
mouse	B-GENE
TS	I-GENE
mRNA	I-GENE
are	O
dispersed	O
over	O
>	O
150	O
kb	O
genomic	O
DNA	O
.	O

Transfection	O
analyses	O
indicated	O
that	O
the	O
expression	O
of	O
Tbxas1	B-GENE
is	O
controlled	O
by	O
a	O
short	O
(	O
70	O
-	O
bp	O
)	O
positive	O
regulatory	O
sequence	O
and	O
several	O
upstream	O
repressive	O
elements	O
.	O

Electromobility	O
shift	O
and	O
cotransfection	O
assays	O
demonstrated	O
that	O
HNF1alpha	B-GENE
,	O
but	O
not	O
HNF4	B-GENE
,	O
bound	O
to	O
its	O
cognate	O
site	O
and	O
transactivated	O
G6Pase	B-GENE
gene	I-GENE
expression	O
.	O

Differential	O
regulation	O
of	O
the	O
pre	B-GENE
-	I-GENE
C	I-GENE
and	O
pregenomic	O
promoters	O
of	O
human	O
hepatitis	O
B	O
virus	O
by	O
members	O
of	O
the	O
nuclear	B-GENE
receptor	I-GENE
superfamily	I-GENE
.	O

These	O
results	O
implicate	O
a	O
precursor	O
-	O
specific	O
base	O
-	O
paired	O
structure	O
involving	O
sequences	O
on	O
both	O
sides	O
of	O
the	O
mature	O
cleavage	O
site	O
in	O
the	O
3	O
'	O
processing	O
of	O
human	B-GENE
U2	I-GENE
RNA	I-GENE
.	O

The	O
mouse	B-GENE
M	I-GENE
-	I-GENE
lysozyme	I-GENE
downstream	I-GENE
enhancer	I-GENE
has	O
been	O
previously	O
characterized	O
on	O
several	O
levels	O
of	O
gene	O
regulation	O
.	O

Bitter	O
cassava	O
contains	O
cyanogenic	O
glycosides	O
;	O
processing	O
breaks	O
them	O
down	O
to	O
acetone	O
cyanohydrin	O
and	O
hydrogen	O
cyanide	O
.	O

First	O
,	O
two	O
MCTs	O
using	O
a	O
long	O
electrode	O
,	O
3	O
cm	O
in	O
size	O
,	O
were	O
performed	O
in	O
the	O
central	O
area	O
of	O
the	O
tumor	O
,	O
and	O
eight	O
MCTs	O
by	O
a	O
short	O
electrode	O
,	O
2	O
cm	O
in	O
size	O
,	O
were	O
done	O
in	O
the	O
peripheral	O
and	O
surrounding	O
area	O
of	O
the	O
tumor	O
.	O

We	O
also	O
show	O
by	O
immunogold	O
electron	O
microscopy	O
immunocytochemistry	O
that	O
amphiphysin	B-GENE
I	I-GENE
is	O
localized	O
in	O
the	O
nerve	O
terminal	O
cytomatrix	O
and	O
is	O
partially	O
associated	O
with	O
endocytic	O
intermediates	O
.	O

The	O
prescription	O
for	O
apoplexy	O
includes	O
C1	O
-	O
7	O
,	O
T1	O
-	O
9	O
and	O
L2	O
-	O
4	O
.	O

Thus	O
,	O
dpp	B-GENE
and	O
omb	B-GENE
promote	O
both	O
dorsal	O
leg	O
cell	O
fate	O
as	O
well	O
as	O
transdetermination	O
-	O
competent	O
leg	O
disc	O
cells	O
.	O

These	O
observations	O
provide	O
strong	O
support	O
for	O
the	O
idea	O
that	O
expression	O
of	O
mutant	O
tRNA	O
can	O
confer	O
a	O
mutator	O
phenotype	O
,	O
including	O
the	O
UVM	O
-	O
constitutive	O
phenotype	O
observed	O
in	O
mutA	B-GENE
and	O
mutC	B-GENE
cells	O
.	O

We	O
now	O
demonstrate	O
that	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	I-GENE
C	I-GENE
/	I-GENE
EBP	I-GENE
)	I-GENE
delta	I-GENE
is	O
a	O
major	O
component	O
of	O
a	O
PGE2	O
-	O
stimulated	O
DNA	O
-	O
protein	O
complex	O
involving	O
HS3D	B-GENE
and	O
find	O
that	O
C	B-GENE
/	I-GENE
EBPdelta	I-GENE
transactivates	O
IGF	B-GENE
-	I-GENE
I	I-GENE
promoter	I-GENE
1	I-GENE
through	O
this	O
site	O
.	O

Interleukin	B-GENE
-	I-GENE
1	I-GENE
levels	O
remained	O
low	O
throughout	O
the	O
course	O
.	O

Southern	O
blot	O
analysis	O
of	O
endonuclease	O
-	O
digested	O
genomic	O
DNA	O
from	O
primary	O
chick	O
embryo	O
fibroblasts	O
(	O
CEF	O
)	O
suggested	O
that	O
MEK2	B-GENE
is	O
a	O
single	O
-	O
copy	O
gene	O
in	O
this	O
vertebrate	O
species	O
.	O

SCID	O
V	B-GENE
(	O
D	B-GENE
)	O
J	B-GENE
recombination	O
can	O
be	O
partly	O
rescued	O
in	O
T	O
-	O
lymphocytes	O
by	O
either	O
DNA	O
-	O
damaging	O
agents	O
(	O
gamma	O
-	O
irradiation	O
and	O
bieomycin	O
)	O
or	O
a	O
null	O
mutation	O
of	O
the	O
p53	B-GENE
gene	I-GENE
,	O
possibly	O
because	O
of	O
transiently	O
elevated	O
DNA	O
repair	O
activity	O
in	O
response	O
to	O
DNA	O
damage	O
or	O
to	O
delayed	O
apoptosis	O
in	O
the	O
absence	O
of	O
p53	B-GENE
.	O

The	O
existence	O
of	O
these	O
two	O
categories	O
of	O
strains	O
offers	O
a	O
new	O
genetic	O
system	O
in	O
which	O
the	O
properties	O
of	O
a	O
potential	O
invertebrate	O
retrovirus	O
can	O
be	O
tested	O
.	O

TSA	O
treatment	O
,	O
however	O
,	O
did	O
not	O
detectably	O
alter	O
enhancer	O
factor	O
binding	O
or	O
the	O
positioning	O
of	O
nuc	B-GENE
-	I-GENE
1	I-GENE
on	O
the	O
majority	O
of	O
the	O
chromatin	O
templates	O
indicating	O
that	O
protein	O
acetylation	O
and	O
chromatin	O
remodeling	O
may	O
be	O
limiting	O
steps	O
that	O
occur	O
only	O
on	O
transcriptionally	O
competent	O
templates	O
,	O
or	O
that	O
remodeling	O
of	O
nuc	B-GENE
-	I-GENE
1	I-GENE
requires	O
additional	O
factors	O
.	O

Y15170	B-GENE
(	O
Surf	B-GENE
-	I-GENE
2	I-GENE
,	O
Surf	B-GENE
-	I-GENE
4	I-GENE
)	O
,	O
Y15171	B-GENE
(	O
Surf	B-GENE
-	I-GENE
3	I-GENE
,	O
Surf	B-GENE
-	I-GENE
1	I-GENE
,	O
Surf	B-GENE
-	I-GENE
6	I-GENE
)	O
,	O
and	O
Y15172	B-GENE
(	O
Surf	B-GENE
-	I-GENE
5	I-GENE
.	O
)	O
]	O

The	O
mean	O
values	O
of	O
the	O
first	O
three	O
components	O
were	O
not	O
significantly	O
different	O
in	O
ARVD	O
patients	O
and	O
control	O
subjects	O
.	O

However	O
,	O
the	O
signaling	O
cascade	O
utilized	O
by	O
the	O
urokinase	B-GENE
receptor	I-GENE
is	O
only	O
incompletely	O
understood	O
.	O

The	O
interaction	O
between	O
DDB	B-GENE
and	O
E2F1	B-GENE
can	O
also	O
be	O
detected	O
by	O
coimmunoprecipitation	O
experiments	O
.	O

Lysine	B-GENE
-	I-GENE
ketoglutarate	I-GENE
reductase	I-GENE
and	O
saccharopine	B-GENE
dehydrogenase	I-GENE
from	O
Arabidopsis	O
thaliana	O
:	O
nucleotide	O
sequence	O
and	O
characterization	O
.	O

The	O
pel	B-GENE
gene	I-GENE
from	O
an	O
Amycolata	O
sp	O
.	O
encoding	O
a	O
pectate	B-GENE
lyase	I-GENE
(	O
EC	B-GENE
4	I-GENE
.	I-GENE
2	I-GENE
.	I-GENE
2	I-GENE
.	I-GENE
2	I-GENE
)	O
was	O
isolated	O
by	O
activity	O
screening	O
a	O
genomic	O
DNA	O
library	O
in	O
Streptomyces	O
lividans	O
TK24	O
.	O

In	O
the	O
clinical	O
study	O
,	O
the	O
defect	O
size	O
shown	O
by	O
BMIPP	O
imaging	O
was	O
greater	O
in	O
anterior	O
than	O
in	O
inferior	O
infarcts	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
and	O
correlated	O
well	O
with	O
the	O
risk	O
area	O
revealed	O
by	O
contrast	O
ventriculography	O
(	O
r	O
=	O
0	O
.	O
80	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
CONCLUSION	O
:	O
The	O
above	O
preliminary	O
data	O
,	O
admittedly	O
from	O
a	O
small	O
group	O
of	O
patients	O
,	O
suggest	O
that	O
tomographic	O
BMIPP	O
imaging	O
provides	O
an	O
accurate	O
quantification	O
of	O
defect	O
size	O
by	O
means	O
of	O
a	O
simple	O
threshold	O
technique	O
and	O
,	O
in	O
the	O
subacute	O
phase	O
,	O
permits	O
determination	O
of	O
the	O
amount	O
of	O
myocardium	O
at	O
risk	O
after	O
acute	O
myocardial	O
infarction	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

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

Protein	B-GENE
C	I-GENE
deficiency	O
or	O
protein	B-GENE
S	I-GENE
deficiency	O
was	O
the	O
only	O
identified	O
risk	O
factor	O
for	O
5	O
.	O
4	O
%	O
(	O
2	O
patients	O
)	O
and	O
13	O
.	O
5	O
%	O
(	O
5	O
patients	O
)	O
,	O
respectively	O
,	O
of	O
these	O
37	O
children	O
.	O

A	O
reciprocal	O
binding	O
assay	O
using	O
IM	O
-	O
9	O
cells	O
as	O
a	O
source	O
of	O
SHP	B-GENE
-	I-GENE
1	I-GENE
and	O
SHP	B-GENE
-	I-GENE
2	I-GENE
revealed	O
specific	O
association	O
of	O
SHP	B-GENE
-	I-GENE
2	I-GENE
(	O
but	O
not	O
SHP	B-GENE
-	I-GENE
1	I-GENE
)	O
with	O
a	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
fusion	I-GENE
incorporating	O
GHR	B-GENE
cytoplasmic	I-GENE
domain	I-GENE
residues	I-GENE
485	I-GENE
-	I-GENE
620	I-GENE
,	O
but	O
only	O
if	O
the	O
fusion	O
was	O
first	O
rendered	O
tyrosine	O
-	O
phosphorylated	O
.	O

We	O
have	O
used	O
mutation	O
-	O
directed	O
chemical	O
cross	O
-	O
linking	O
with	O
bis	O
(	O
sulfosuccinimidyl	O
)	O
suberate	O
(	O
BS3	O
)	O
to	O
investigate	O
the	O
architecture	O
of	O
the	O
gp41	B-GENE
oligomer	I-GENE
.	O

Consistent	O
with	O
previous	O
reports	O
,	O
addition	O
of	O
a	O
myristoylation	O
signal	O
to	O
mSos1	B-GENE
(	O
MyrSos1	B-GENE
)	O
rendered	O
it	O
transforming	O
for	O
NIH	O
3T3	O
cells	O
and	O
deletion	O
of	O
the	O
mSos	B-GENE
C	I-GENE
terminus	I-GENE
(	O
MyrSos1	B-GENE
-	I-GENE
deltaC	I-GENE
)	O
did	O
not	O
interfere	O
with	O
this	O
activity	O
.	O

Demonstration	O
of	O
tissue	O
lesions	O
after	O
intramuscular	O
injection	O
by	O
determination	O
of	O
creatine	B-GENE
kinase	I-GENE
in	O
blood	O

Levels	O
of	O
the	O
MEK	B-GENE
inhibitor	O
PD98059	O
that	O
block	O
EGF	B-GENE
-	O
induced	O
mitogenesis	O
and	O
MAP	B-GENE
kinase	I-GENE
phosphorylation	O
also	O
abrogate	O
EGF	B-GENE
-	O
induced	O
focal	O
adhesion	O
disassembly	O
and	O
cell	O
motility	O
.	O

Surprisingly	O
,	O
the	O
COOH	O
-	O
terminal	O
domain	O
of	O
RanGAP1	B-GENE
was	O
also	O
found	O
to	O
harbor	O
a	O
nuclear	O
localization	O
signal	O
.	O

Here	O
,	O
we	O
present	O
evidence	O
that	O
exposure	O
of	O
DT40	O
lymphoma	O
B	O
cells	O
to	O
low	O
energy	O
electromagnetic	O
field	O
(	O
EMF	O
)	O
results	O
in	O
a	O
tyrosine	B-GENE
kinase	I-GENE
-	O
dependent	O
activation	O
of	O
phospholipase	B-GENE
Cgamma2	I-GENE
(	O
PLC	B-GENE
-	I-GENE
gamma2	I-GENE
)	O
leading	O
to	O
increased	O
inositol	O
phospholipid	O
turnover	O
.	O

PATIENTS	O
AND	O
METHOD	O
:	O
Since	O
1986	O
,	O
62	O
patients	O
were	O
irradiated	O
stereotactically	O
.	O

Training	O
for	O
audit	O
.	O

Cytoskeletal	O
polarization	O
of	O
T	O
cells	O
is	O
regulated	O
by	O
an	O
immunoreceptor	O
tyrosine	O
-	O
based	O
activation	O
motif	O
-	O
dependent	O
mechanism	O
.	O

Here	O
we	O
have	O
examined	O
the	O
ability	O
of	O
the	O
cellular	O
protein	O
YB	B-GENE
-	I-GENE
1	I-GENE
to	O
modulate	O
transcription	O
of	O
the	O
HIV	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
in	O
a	O
human	O
astrocytic	O
cell	O
line	O
(	O
U	O
-	O
87MG	O
)	O
,	O
a	O
neuronal	O
cell	O
line	O
(	O
SK	O
-	O
N	O
-	O
MC	O
)	O
and	O
lymphoid	O
cells	O
(	O
Jurkat	O
)	O
by	O
transfection	O
assay	O
.	O

Substrates	O
for	O
p210	B-GENE
(	O
bcr	B-GENE
-	O
abl	B-GENE
)	O
are	O
likely	O
to	O
be	O
involved	O
in	O
the	O
pathogenesis	O
of	O
CML	O
.	O

The	O
COOH	O
-	O
terminal	O
region	O
of	O
the	O
transcripts	O
contained	O
fifteen	O
triplet	O
repeats	O
(	O
GCT	O
;	O
alanine	O
)	O
at	O
nucleotide	O
465	O
to	O
509	O
,	O
which	O
is	O
significantly	O
expanded	O
compared	O
to	O
the	O
rat	B-GENE
RL14	I-GENE
.	O

Control	O
of	O
fatty	O
liver	O
syndrome	O
in	O
a	O
Jersey	O
herd	O
by	O
a	O
change	O
of	O
diet	O
and	O
the	O
use	O
of	O
recombinant	O
bovine	O
somatotrophin	B-GENE
.	O

During	O
organogenesis	O
,	O
HFH	B-GENE
-	I-GENE
8	I-GENE
expression	O
is	O
found	O
in	O
the	O
splanchnic	O
mesoderm	O
in	O
close	O
apposition	O
of	O
the	O
gut	O
endoderm	O
,	O
suggesting	O
a	O
role	O
in	O
mesenchymal	O
-	O
epithelial	O
induction	O
of	O
lung	O
and	O
gut	O
morphogenesis	O
.	O

However	O
,	O
laparoscopy	O
failed	O
to	O
establish	O
inoperability	O
in	O
any	O
cases	O
of	O
carcinoma	O
spread	O
to	O
areas	O
not	O
accessible	O
to	O
laparoscopic	O
visualization	O
.	O

No	O
difference	O
in	O
telomere	O
length	O
was	O
seen	O
in	O
mutants	O
affected	O
in	O
the	O
regulation	O
of	O
Cdc2	B-GENE
,	O
whereas	O
some	O
of	O
the	O
DNA	O
repair	O
mutants	O
examined	O
had	O
slightly	O
longer	O
telomeres	O
than	O
did	O
the	O
wild	O
type	O
.	O

Sp1	B-GENE
can	O
activate	O
transcription	O
through	O
immunoglobulin	B-GENE
kappa	I-GENE
-	I-GENE
chain	I-GENE
enhancer	I-GENE
or	O
P	B-GENE
-	I-GENE
selectin	I-GENE
promoter	I-GENE
NF	B-GENE
-	I-GENE
kappaB	I-GENE
sites	I-GENE
.	O
p50	B-GENE
homodimers	I-GENE
replace	O
Sp1	B-GENE
from	O
the	O
P	B-GENE
-	I-GENE
selectin	I-GENE
promoter	I-GENE
by	O
binding	O
site	O
competition	O
and	O
thereby	O
either	O
inhibit	O
basal	O
Sp1	B-GENE
-	O
driven	O
expression	O
or	O
,	O
in	O
concert	O
with	O
Bcl	B-GENE
-	I-GENE
3	I-GENE
,	O
stimulate	O
expression	O
.	O

For	O
the	O
5HT5A	B-GENE
receptor	I-GENE
the	O
addition	O
of	O
yohimbine	O
resulted	O
in	O
a	O
similar	O
but	O
smaller	O
effect	O
.	O

CONCLUSIONS	O
:	O
XCoe2	B-GENE
may	O
play	O
a	O
pivotal	O
role	O
in	O
the	O
transcriptional	O
cascade	O
that	O
specifies	O
primary	O
neurons	O
in	O
Xenopus	O
embryos	O
:	O
by	O
maintaining	O
Delta	B-GENE
-	O
Notch	B-GENE
signalling	O
,	O
XCoe2	B-GENE
stabilises	O
the	O
higher	O
neural	O
potential	O
of	O
selected	O
progenitor	O
cells	O
that	O
express	O
X	B-GENE
-	I-GENE
ngnr	I-GENE
-	I-GENE
1	I-GENE
,	O
ensuring	O
the	O
transition	O
between	O
neural	O
competence	O
and	O
irreversible	O
commitment	O
to	O
a	O
neural	O
fate	O
;	O
and	O
it	O
promotes	O
neuronal	O
differentiation	O
by	O
activating	O
XNeuroD	B-GENE
expression	O
,	O
directly	O
or	O
indirectly	O
.	O

RESULTS	O
:	O
Patients	O
in	O
Group	O
A	O
had	O
a	O
higher	O
incidence	O
of	O
posterolateral	O
wall	O
motion	O
abnormalities	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
on	O
radionuclide	O
ventriculography	O
,	O
a	O
larger	O
infarct	O
area	O
(	O
as	O
evidenced	O
by	O
higher	O
peak	O
creatine	B-GENE
kinase	I-GENE
levels	O
)	O
(	O
p	O
<	O
0	O
.	O
02	O
)	O
and	O
a	O
lower	O
left	O
ventricular	O
ejection	O
fraction	O
(	O
LVEF	O
)	O
at	O
hospital	O
discharge	O
(	O
p	O
<	O
0	O
.	O
008	O
)	O
than	O
those	O
in	O
Group	O
B	O
.	O

In	O
all	O
cells	O
,	O
the	O
accumulation	O
of	O
high	O
Dsg	B-GENE
protein	I-GENE
levels	O
required	O
calcium	O
and	O
was	O
not	O
observed	O
in	O
low	O
calcium	O
(	O
0	O
.	O
05	O
-	O
0	O
.	O
07	O
mM	O
)	O
media	O
.	O

RESULTS	O
:	O
Using	O
information	O
in	O
the	O
dbEST	O
database	O
of	O
expressed	O
sequence	O
tags	O
,	O
we	O
isolated	O
an	O
Arabidopsis	O
thaliana	O
gene	O
(	O
GCR1	B-GENE
)	O
that	O
encodes	O
a	O
protein	O
with	O
seven	O
predicted	O
membrane	O
-	O
spanning	O
domains	O
and	O
other	O
features	O
characteristic	O
of	O
7TM	B-GENE
receptors	I-GENE
.	O

E1A	B-GENE
represses	O
apolipoprotein	B-GENE
AI	I-GENE
enhancer	I-GENE
activity	O
in	O
liver	O
cells	O
through	O
a	O
pRb	B-GENE
-	O
and	O
CBP	B-GENE
-	O
independent	O
pathway	O
.	O

M	B-GENE
-	I-GENE
66	I-GENE
identified	O
the	O
14	O
-	O
kDa	O
protein	O
in	O
another	O
MMTV	O
bearing	O
T	O
-	O
cell	O
lymphoma	O
,	O
EL	O
-	O
4	O
.	O

RT	O
-	O
PCR	O
indicated	O
that	O
p21	B-GENE
mRNA	I-GENE
was	O
induced	O
1	O
.	O
4	O
-	O
,	O
2	O
.	O
0	O
-	O
,	O
and	O
3	O
.	O
1	O
-	O
fold	O
in	O
the	O
2	O
-	O
day	O
neonatal	O
,	O
7	O
-	O
day	O
neonatal	O
,	O
and	O
adult	O
stages	O
,	O
respectively	O
,	O
compared	O
to	O
the	O
17	O
-	O
day	O
fetal	O
stage	O
.	O

Ganciclovir	O
and	O
foscarnet	O
efficacy	O
in	O
AIDS	O
-	O
related	O
CMV	O
polyradiculopathy	O
.	O

BACKGROUND	O
AND	O
OBJECTIVES	O
:	O
The	O
sexually	O
transmitted	O
diseases	O
(	O
STD	O
)	O
control	O
program	O
for	O
female	O
sex	O
workers	O
(	O
FSW	O
)	O
in	O
Lima	O
,	O
Peru	O
,	O
provided	O
periodic	O
serological	O
tests	O
for	O
syphilis	O
and	O
cervical	O
smears	O
for	O
gonococci	O
,	O
but	O
not	O
medication	O
for	O
STD	O
or	O
condoms	O
.	O

In	O
order	O
to	O
examine	O
the	O
potential	O
role	O
of	O
transcriptional	O
silencing	O
during	O
productive	O
HSV	O
-	O
1	O
infection	O
,	O
recombinant	O
viruses	O
were	O
generated	O
in	O
which	O
wild	B-GENE
-	I-GENE
type	I-GENE
or	I-GENE
mutant	I-GENE
ICP34	I-GENE
.	I-GENE
5	I-GENE
promoters	I-GENE
controlling	O
the	O
expression	O
of	O
a	O
chloramphenicol	B-GENE
acetyltransferase	I-GENE
reporter	I-GENE
gene	I-GENE
were	O
inserted	O
into	O
the	O
thymidine	B-GENE
kinase	I-GENE
gene	I-GENE
of	O
the	O
viral	O
genome	O
.	O

Members	O
of	O
the	O
meis1	B-GENE
and	O
pbx	B-GENE
homeodomain	I-GENE
protein	I-GENE
families	I-GENE
cooperatively	O
bind	O
a	O
cAMP	O
-	O
responsive	O
sequence	O
(	O
CRS1	O
)	O
from	O
bovine	B-GENE
CYP17	I-GENE
.	O

The	O
RAS	B-GENE
-	O
cyclic	B-GENE
AMP	I-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
cAPK	B-GENE
pathway	O
prevents	O
the	O
UAS	O
activity	O
of	O
IREu	B-GENE
in	O
the	O
presence	O
of	O
glucose	O
as	O
the	O
sole	O
carbon	O
source	O
,	O
while	O
the	O
transcriptional	O
activators	O
Msn2p	B-GENE
and	O
Msn4p	B-GENE
promote	O
the	O
UAS	O
activity	O
of	O
this	O
repeat	O
in	O
the	O
presence	O
of	O
acetate	O
.	O

Alternative	O
splicing	O
of	O
fibroblast	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
2	I-GENE
(	O
FGF	B-GENE
-	I-GENE
R2	I-GENE
)	O
is	O
an	O
example	O
of	O
highly	O
regulated	O
alternative	O
splicing	O
in	O
which	O
exons	O
IIIb	O
and	O
IIIc	O
are	O
utilized	O
in	O
a	O
mutually	O
exclusive	O
manner	O
in	O
different	O
cell	O
types	O
.	O

SNAC	O
or	O
PBS	O
was	O
infused	O
for	O
6	O
.	O
5	O
h	O
,	O
beginning	O
30	O
min	O
before	O
ischemia	O
and	O
continuing	O
throughout	O
the	O
duration	O
of	O
reperfusion	O
.	O

Moreover	O
,	O
it	O
is	O
the	O
assumptions	O
behind	O
steady	O
-	O
state	O
O2	O
uptake	O
that	O
do	O
not	O
permit	O
proper	O
interpretation	O
of	O
energy	O
expenditure	O
during	O
EPOC	O
;	O
1	O
l	O
O2	O
not	O
=	O
20	O
.	O
9	O
kJ	O
.	O

The	O
predicted	O
amino	O
acid	O
sequence	O
of	O
m	B-GENE
-	I-GENE
Staf	I-GENE
is	O
highly	O
homologous	O
to	O
that	O
of	O
Staf	B-GENE
,	O
another	O
selenocysteine	B-GENE
tRNA	I-GENE
gene	I-GENE
transcription	I-GENE
activating	I-GENE
factor	I-GENE
of	O
Xenopus	O
laevis	O
.	O

Recent	O
studies	O
have	O
revealed	O
unconventional	O
myosin	B-GENE
V	I-GENE
to	O
be	O
an	O
important	O
actin	B-GENE
-	O
based	O
molecular	O
motor	O
involved	O
in	O
vesicular	O
movement	O
.	O

Furthermore	O
,	O
a	O
minor	O
start	O
site	O
was	O
localized	O
179	O
bp	O
upstream	O
of	O
the	O
major	O
site	O
using	O
reverse	B-GENE
transcriptase	I-GENE
-	O
polymerase	O
chain	O
reaction	O
with	O
various	O
P1	O
primers	O
(	O
primer	O
walking	O
)	O
,	O
primer	O
extension	O
,	O
and	O
cDNA	O
cloning	O
.	O

Analysis	O
of	O
promoter	O
and	O
androgen	O
regulatory	O
sequences	O
required	O
for	O
optimal	O
transcription	O
of	O
the	O
rat	O
androgen	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
gene	O
.	O

In	O
a	O
gntR	B-GENE
deletion	I-GENE
mutant	I-GENE
,	O
the	O
expression	O
of	O
a	O
chromosomal	O
gntT	B-GENE
:	O
:	O
lacZ	B-GENE
fusion	O
is	O
both	O
high	O
and	O
constitutive	O
,	O
confirming	O
that	O
GntR	B-GENE
is	O
the	O
negative	O
regulator	O
of	O
gntT	B-GENE
.	O

Therefore	O
,	O
we	O
conclude	O
that	O
DnaA	B-GENE
may	O
contact	O
the	O
beta	O
subunit	O
of	O
RNA	B-GENE
polymerase	I-GENE
during	O
activation	O
of	O
the	O
pR	B-GENE
promoter	I-GENE
.	O

Expression	O
of	O
Bcl	B-GENE
-	I-GENE
XL	I-GENE
inhibited	O
the	O
association	O
of	O
Apaf	B-GENE
-	I-GENE
1	I-GENE
with	O
caspase	B-GENE
-	I-GENE
9	I-GENE
in	O
mammalian	O
cells	O
.	O

Whole	O
-	O
mount	O
in	O
situ	O
hybridization	O
to	O
early	O
mouse	O
embryos	O
of	O
9	O
.	O
5	O
-	O
10	O
.	O
5	O
days	O
indicated	O
a	O
complex	O
pattern	O
of	O
Arp1	B-GENE
expression	O
spatially	O
overlapping	O
with	O
the	O
expression	O
of	O
All1	B-GENE
.	O

Creatine	B-GENE
kinase	I-GENE
release	O
after	O
hepatic	O
artery	O
embolization	O
in	O
patients	O
with	O
carcinoid	O
tumors	O
.	O

Our	O
observations	O
suggest	O
that	O
members	O
of	O
the	O
HMG	B-GENE
-	I-GENE
I	I-GENE
family	I-GENE
play	O
an	O
important	O
role	O
in	O
SRF	B-GENE
-	O
dependent	O
transcription	O
and	O
that	O
their	O
effect	O
is	O
mediated	O
primarily	O
by	O
a	O
protein	O
-	O
protein	O
interaction	O
.	O

We	O
recently	O
characterized	O
a	O
single	O
yeast	B-GENE
hnRNP	I-GENE
methyltransferase	I-GENE
(	O
HMT1	B-GENE
)	O
.	O

We	O
recently	O
characterized	O
a	O
single	O
yeast	B-GENE
hnRNP	I-GENE
methyltransferase	I-GENE
(	O
HMT1	B-GENE
)	O
.	O

Recombinant	B-GENE
HRMT1L2	I-GENE
protein	I-GENE
encoded	O
by	O
the	O
most	O
common	O
5	O
'	O
-	O
variant	O
exhibited	O
methyltransferase	O
activity	O
in	O
vitro	O
.	O

The	O
possible	O
roles	O
of	O
HRMT1L1	B-GENE
and	O
HRMT1L2	B-GENE
in	O
human	O
disease	O
are	O
currently	O
unknown	O
.	O

Identification	O
and	O
characterization	O
of	O
two	O
putative	O
human	B-GENE
arginine	I-GENE
methyltransferases	I-GENE
(	O
HRMT1L1	B-GENE
and	O
HRMT1L2	B-GENE
)	O
.	O

To	O
identify	O
nuclear	O
regulatory	O
factors	O
,	O
we	O
have	O
located	O
and	O
functionally	O
characterized	O
the	O
CCR5	B-GENE
gene	I-GENE
promoter	I-GENE
.	O

The	O
interaction	O
between	O
piroxicam	O
and	O
poloxamer	O
was	O
studied	O
by	O
x	O
-	O
ray	O
diffractometry	O
(	O
XRD	O
)	O
,	O
infrared	O
(	O
IR	O
)	O
spectroscopy	O
and	O
differential	O
thermal	O
analysis	O
(	O
DTA	O
)	O
with	O
a	O
solid	O
dispersion	O
,	O
coprecipitate	O
,	O
or	O
physical	O
mixture	O
.	O

The	O
results	O
confirm	O
that	O
a	O
single	O
base	O
change	O
in	O
the	O
branchpoint	O
consensus	O
sequence	O
of	O
an	O
intron	O
can	O
cause	O
human	O
disease	O
although	O
this	O
sequence	O
is	O
poorly	O
conserved	O
in	O
mammals	O
.	O

It	O
bound	O
to	O
vitamin	B-GENE
D	I-GENE
receptor	I-GENE
(	O
VDR	B-GENE
)	O
but	O
not	O
retinoic	B-GENE
acid	I-GENE
Xalpha	I-GENE
receptor	I-GENE
(	O
RXRalpha	B-GENE
)	O
in	O
the	O
human	O
T	O
cell	O
line	O
MT2	O
cells	O
.	O

Based	O
on	O
the	O
current	O
literature	O
,	O
the	O
mechanisms	O
involved	O
in	O
the	O
toxicity	O
of	O
OA	B-GENE
indicate	O
three	O
major	O
effects	O
:	O
(	O
1	O
)	O
inhibition	O
of	O
mitochondrial	O
respiration	O
correlated	O
with	O
a	O
depletion	O
of	O
ATP	O
;	O
(	O
2	O
)	O
inhibition	O
of	O
tRNA	B-GENE
-	I-GENE
synthetase	I-GENE
accompanied	O
by	O
a	O
reduced	O
protein	O
synthesis	O
;	O
and	O
(	O
3	O
)	O
enhanced	O
lipid	O
peroxidation	O
.	O

Another	O
stem	O
-	O
loop	O
called	O
structure	O
III	O
near	O
the	O
3	O
'	O
-	O
end	O
of	O
repY	B-GENE
sequesters	O
both	O
the	O
5	O
'	O
-	O
rCGCC	O
-	O
3	O
'	O
sequence	O
and	O
the	O
repZ	B-GENE
ribosome	I-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
.	O

The	O
general	O
transcription	B-GENE
factor	I-GENE
IIA	I-GENE
(	O
TFIIA	B-GENE
)	O
interacts	O
with	O
the	O
TATA	B-GENE
binding	I-GENE
protein	I-GENE
(	O
TBP	B-GENE
)	O
and	O
promoter	O
DNA	O
to	O
mediate	O
transcription	O
activation	O
in	O
vitro	O
.	O

Localization	O
of	O
67	O
exons	O
on	O
a	O
YAC	O
contig	O
spanning	O
1	O
.	O
5	O
Mb	O
around	O
the	O
multidrug	B-GENE
resistance	I-GENE
gene	I-GENE
region	I-GENE
of	O
human	O
chromosome	O
7q21	O
.	O
1	O
.	O

Using	O
Southern	O
blot	O
analysis	O
and	O
restriction	O
mapping	O
of	O
genomic	O
YAC	O
(	O
yeast	O
artificial	O
chromosome	O
)	O
and	O
cosmid	O
clones	O
,	O
we	O
located	O
the	O
human	B-GENE
RIL	I-GENE
gene	I-GENE
240	O
-	O
260	O
kb	O
telomeric	O
to	O
the	O
IRF1	B-GENE
gene	I-GENE
and	O
characterized	O
its	O
genomic	O
structure	O
.	O

U73	B-GENE
contains	O
C	O
,	O
D	O
and	O
D	O
'	O
boxes	O
and	O
a	O
12	O
-	O
nucleotide	O
antisense	O
complementarity	O
to	O
the	O
28S	B-GENE
ribosomal	I-GENE
RNA	I-GENE
.	O

However	O
,	O
mandibular	O
position	O
(	O
S	O
-	O
N	O
-	O
B	O
and	O
S	O
-	O
N	O
-	O
Pog	O
)	O
was	O
found	O
to	O
be	O
significantly	O
more	O
retrusive	O
in	O
Class	O
II	O
when	O
compared	O
with	O
Class	O
I	O
subjects	O
.	O

Echinostomiasis	O
is	O
aggravated	O
by	O
socioeconomic	O
factors	O
such	O
as	O
poverty	O
,	O
malnutrition	O
,	O
an	O
explosively	O
growing	O
free	O
-	O
food	O
market	O
,	O
a	O
lack	O
of	O
supervised	O
food	O
inspection	O
,	O
poor	O
or	O
insufficient	O
sanitation	O
,	O
other	O
helminthiases	O
,	O
and	O
declining	O
economic	O
conditions	O
.	O

The	O
localization	O
of	O
ZAP	B-GENE
-	I-GENE
70	I-GENE
to	O
the	O
cell	O
cortex	O
is	O
,	O
therefore	O
,	O
regulated	O
by	O
the	O
activity	O
of	O
SRC	B-GENE
-	I-GENE
family	I-GENE
kinases	I-GENE
,	O
independently	O
of	O
their	O
ability	O
to	O
phosphorylate	O
immunoreceptor	O
tyrosine	O
-	O
based	O
activation	O
motifs	O
of	O
the	O
TCR	B-GENE
.	O

The	O
effect	O
of	O
nitric	B-GENE
oxide	I-GENE
synthase	I-GENE
inhibitor	O
on	O
reperfusion	O
injury	O
of	O
the	O
brain	O
under	O
hypothermic	O
circulatory	O
arrest	O
.	O

UDP	B-GENE
-	I-GENE
GlcNAc	I-GENE
:	O
alpha	B-GENE
-	I-GENE
6	I-GENE
-	I-GENE
D	I-GENE
-	I-GENE
mannoside	I-GENE
beta	I-GENE
-	I-GENE
1	I-GENE
,	I-GENE
2	I-GENE
-	I-GENE
N	I-GENE
-	I-GENE
acetylglucosaminyltransferase	I-GENE
II	I-GENE
(	O
GnT	B-GENE
II	I-GENE
;	O
EC	B-GENE
2	I-GENE
.	I-GENE
4	I-GENE
.	I-GENE
1	I-GENE
.	I-GENE
143	I-GENE
)	O
is	O
essential	O
for	O
the	O
normal	O
assembly	O
of	O
complex	O
Asn	O
-	O
linked	O
glycans	O
.	O

Taken	O
together	O
,	O
these	O
results	O
suggest	O
that	O
silymarin	O
may	O
exert	O
a	O
strong	O
anticarcinogenic	O
effect	O
against	O
PCA	O
and	O
that	O
this	O
effect	O
is	O
likely	O
to	O
involve	O
impairment	O
of	O
erbB1	B-GENE
-	O
SHC	B-GENE
-	O
mediated	O
signaling	O
pathway	O
,	O
induction	O
of	O
CDKIs	B-GENE
,	O
and	O
a	O
resultant	O
G1	O
arrest	O
.	O

In	O
connective	O
tissue	O
,	O
cell	O
structure	O
contributes	O
to	O
type	B-GENE
I	I-GENE
collagen	I-GENE
expression	O
.	O

A	O
point	O
mutation	O
in	O
Galphao	B-GENE
and	O
Galphai1	B-GENE
blocks	O
interaction	O
with	O
regulator	O
of	O
G	B-GENE
protein	I-GENE
signaling	O
proteins	O
.	O

Indeed	O
,	O
it	O
is	O
shown	O
that	O
it	O
mediates	O
the	O
formation	O
of	O
disulfide	O
-	O
linked	O
homodimers	O
and	O
that	O
the	O
formation	O
of	O
homo	O
-	O
and	O
heterodimers	O
are	O
mutually	O
excluded	O
.	O

N	O
.	O
,	O
and	O
Fanning	O
,	O
E	O
.	O

In	O
patients	O
with	O
type	O
IA	O
maple	O
syrup	O
urine	O
disease	O
,	O
the	O
E1alpha	B-GENE
subunit	I-GENE
is	O
affected	O
,	O
resulting	O
in	O
the	O
loss	O
of	O
E1	B-GENE
and	O
branched	B-GENE
-	I-GENE
chain	I-GENE
ketoacid	I-GENE
dehydrogenase	I-GENE
catalytic	O
activities	O
.	O

All	O
patients	O
diagnosed	O
of	O
H	O
.	O
influenza	O
type	O
b	O
meningitis	O
were	O
less	O
than	O
3	O
years	O
old	O
.	O

Immunohistochemically	O
,	O
anticytokeratin	B-GENE
19	I-GENE
antibody	I-GENE
revealed	O
strong	O
staining	O
in	O
both	O
epithelial	O
and	O
sarcomatous	O
MPM	O
tissues	O
.	O

Combined	O
expression	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
and	O
p65	B-GENE
induced	O
vigorous	O
transcription	O
of	O
IL	B-GENE
-	I-GENE
2	I-GENE
promoter	O
-	O
and	O
CD28RE	B-GENE
-	I-GENE
driven	I-GENE
reporter	I-GENE
constructs	I-GENE
in	O
both	O
LFA	B-GENE
-	I-GENE
3	I-GENE
-	O
and	O
B7	B-GENE
-	I-GENE
1	I-GENE
-	O
costimulated	O
Jurkat	O
cells	O
.	O

Liquid	O
chromatographic	O
method	O
for	O
analysis	O
of	O
all	O
-	O
rac	O
-	O
alpha	O
-	O
tocopheryl	O
acetate	O
and	O
retinyl	O
palmitate	O
in	O
milk	O
-	O
based	O
infant	O
formula	O
using	O
matrix	O
solid	O
-	O
phase	O
dispersion	O
.	O

The	O
ability	O
to	O
maintain	O
expression	O
of	O
FAS1	B-GENE
in	O
nmt1	B-GENE
-	O
451Dino2	B-GENE
Delta	O
cells	O
suggests	O
the	O
existence	O
of	O
another	O
transcription	O
factor	O
,	O
or	O
factors	O
,	O
whose	O
expression	O
/	O
activity	O
is	O
inversely	O
related	O
to	O
overall	O
levels	O
of	O
cellular	O
protein	O
N	O
-	O
myristoy	O
-	O
lation	O
.	O

The	O
identified	O
isolates	O
of	O
CSF	O
(	O
20	O
of	O
29	O
)	O
were	O
:	O
ECHO	O
30	O
(	O
9	O
)	O
,	O
ECHO	O
11	O
(	O
7	O
)	O
,	O
ECHO	O
9	O
(	O
3	O
)	O
and	O
ECHO	O
7	O
(	O
1	O
)	O
.	O

There	O
was	O
no	O
evidence	O
of	O
any	O
persistent	O
oscillation	O
within	O
the	O
ULF	O
band	O
.	O

A	O
large	O
deletion	O
in	O
the	O
CTD	B-GENE
-	I-GENE
binding	I-GENE
motif	I-GENE
blocks	O
down	O
-	O
regulation	O
but	O
does	O
not	O
affect	O
the	O
essential	O
function	O
of	O
Nrd1	B-GENE
.	O

Thus	O
,	O
included	O
in	O
the	O
KG1a	O
EST	O
dataset	O
are	O
candidates	O
for	O
new	O
human	O
genes	O
that	O
may	O
play	O
roles	O
in	O
hematopoietic	O
differentiative	O
progression	O
and	O
lineage	O
commitment	O
.	O

Sp1	B-GENE
and	O
two	O
Sp3	B-GENE
isoforms	I-GENE
were	O
detected	O
as	O
the	O
primary	O
cellular	O
constituents	O
of	O
DNA	O
-	O
protein	O
complexes	O
formed	O
with	O
the	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
-	I-GENE
proximal	I-GENE
site	I-GENE
.	O

The	O
second	O
patient	O
had	O
received	O
pituitary	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
hormone	I-GENE
for	O
treatment	O
of	O
growth	B-GENE
hormone	I-GENE
deficiency	O
,	O
secondary	O
to	O
a	O
third	O
ventricle	O
teratoma	O
,	O
exised	O
13	O
yr	O
earlier	O
.	O

Binding	O
affinities	O
of	O
different	O
nucleotide	O
mono	O
-	O
,	O
di	O
-	O
and	O
triphosphates	O
and	O
non	O
-	O
hydrolyzable	O
analogs	O
indicate	O
that	O
the	O
beta	O
-	O
phosphate	O
moiety	O
is	O
required	O
for	O
substrate	O
binding	O
.	O

[	O
Treatment	O
of	O
early	O
T1	O
small	O
T2N	O
breast	O
cancers	O
.	O

Malaria	O
had	O
diminished	O
significantly	O
by	O
the	O
early	O
1940s	O
,	O
and	O
this	O
paper	O
queries	O
whether	O
that	O
reduction	O
was	O
due	O
to	O
the	O
control	O
projects	O
of	O
the	O
thirties	O
,	O
and	O
,	O
if	O
so	O
,	O
whether	O
such	O
projects	O
should	O
be	O
a	O
model	O
for	O
the	O
current	O
developing	O
world	O
,	O
where	O
malaria	O
is	O
a	O
growing	O
problem	O
today	O
.	O

Fowlpox	O
virus	O
encodes	O
nonessential	O
homologs	O
of	O
cellular	B-GENE
alpha	I-GENE
-	I-GENE
SNAP	I-GENE
,	O
PC	B-GENE
-	I-GENE
1	I-GENE
,	O
and	O
an	O
orphan	O
human	O
homolog	O
of	O
a	O
secreted	O
nematode	O
protein	O
.	O

Further	O
,	O
Ser	O
/	O
Thr	O
phosphorylation	O
of	O
downstream	O
molecules	O
Akt	B-GENE
and	O
p70	B-GENE
S6	I-GENE
kinase	I-GENE
was	O
inhibited	O
.	O

Quantitative	O
evaluation	O
of	O
the	O
steady	O
state	O
kinetics	O
of	O
MEK	B-GENE
inhibition	O
by	O
these	O
compounds	O
reveals	O
that	O
U0126	O
has	O
approximately	O
100	O
-	O
fold	O
higher	O
affinity	O
for	O
deltaN3	B-GENE
-	I-GENE
S218E	I-GENE
/	I-GENE
S222D	I-GENE
MEK	I-GENE
than	O
does	O
PD098059	O
.	O

However	O
,	O
little	O
is	O
known	O
regarding	O
the	O
genomic	O
organization	O
and	O
developmental	O
expression	O
of	O
the	O
caveolin	B-GENE
gene	I-GENE
family	I-GENE
.	O

Tensile	O
bond	O
strengths	O
between	O
resin	O
composite	O
and	O
bovine	O
dentin	O
using	O
dentin	O
adhesive	O
systems	O
(	O
Clearfil	O
Liner	O
Bond	O
II	O
:	O
LB	O
II	O
;	O
Scotchbond	O
Multi	O
-	O
Purpose	O
:	O
MP	O
)	O
bonding	O
systems	O
showed	O
a	O
large	O
scatter	O
among	O
students	O
and	O
dentists	O
.	O

To	O
better	O
understand	O
the	O
role	O
of	O
Ets	B-GENE
proteins	I-GENE
in	O
Ras	B-GENE
transformation	O
,	O
we	O
have	O
now	O
analyzed	O
the	O
effects	O
of	O
stably	O
expressing	O
a	O
variety	O
of	O
Ets2	B-GENE
constructs	I-GENE
in	O
Ras	B-GENE
-	O
transformed	O
NIH3T3	O
(	O
DT	O
)	O
cells	O
.	O

Manipulation	O
of	O
the	O
checkpoint	O
regulators	O
involved	O
in	O
cell	O
cycle	O
arrest	O
and	O
apoptosis	O
may	O
thus	O
provide	O
a	O
novel	O
strategy	O
to	O
cancer	O
therapy	O
.	O

The	O
diagnostic	O
accuracy	O
of	O
serum	O
PE	B-GENE
-	I-GENE
1	I-GENE
was	O
0	O
.	O
80	O
,	O
and	O
that	O
of	O
amylase	B-GENE
0	O
.	O
97	O
.	O

We	O
demonstrate	O
that	O
Ddc1p	B-GENE
interacts	O
physically	O
in	O
vivo	O
with	O
Mec3p	B-GENE
,	O
and	O
this	O
interaction	O
requires	O
Rad17p	B-GENE
.	O

Deleting	O
SNF1	B-GENE
repressed	O
meiosis	O
at	O
the	O
same	O
three	O
steps	O
that	O
were	O
inhibited	O
by	O
glucose	O
,	O
suggesting	O
that	O
glucose	O
blocks	O
meiosis	O
by	O
inhibiting	O
Snf1	B-GENE
.	O

Ligand	O
-	O
independent	O
activation	O
of	O
platelet	B-GENE
-	I-GENE
derived	I-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
is	O
a	O
necessary	O
intermediate	O
in	O
lysophosphatidic	O
,	O
acid	O
-	O
stimulated	O
mitogenic	O
activity	O
in	O
L	O
cells	O
.	O

In	O
canrenoate	O
-	O
treated	O
rats	O
,	O
ANP	B-GENE
infusion	O
caused	O
greater	O
increases	O
in	O
sodium	O
excretion	O
(	O
FENA	O
from	O
3	O
.	O
05	O
+	O
/	O
-	O
0	O
.	O
71	O
to	O
7	O
.	O
21	O
+	O
/	O
-	O
0	O
.	O
45	O
%	O
;	O
P	O
<	O
0	O
.	O
05	O
;	O
n	O
=	O
8	O
)	O
than	O
saline	O
infusion	O
(	O
FENA	O
from	O
4	O
.	O
16	O
+	O
/	O
-	O
1	O
.	O
11	O
to	O
5	O
.	O
47	O
+	O
/	O
-	O
0	O
.	O
66	O
%	O
;	O
n	O
=	O
6	O
)	O
,	O
despite	O
the	O
hypocapnia	O
.	O

Identical	O
c	B-GENE
-	I-GENE
erbB3	I-GENE
transcripts	I-GENE
are	O
expressed	O
in	O
normal	O
human	O
placental	O
tissues	O
.	O

Downregulation	O
of	O
FUS	B-GENE
expression	O
in	O
BCR	B-GENE
/	O
ABL	B-GENE
-	O
expressing	O
32Dcl3	O
cells	O
was	O
associated	O
with	O
suppression	O
of	O
growth	O
factor	O
-	O
independent	O
colony	O
formation	O
,	O
restoration	O
of	O
G	B-GENE
-	I-GENE
CSF	I-GENE
-	O
induced	O
granulocytic	O
differentiation	O
and	O
reduced	O
tumorigenic	O
potential	O
in	O
vivo	O
.	O

We	O
propose	O
a	O
model	O
in	O
which	O
Sro7	B-GENE
function	O
is	O
involved	O
in	O
the	O
targeting	O
of	O
the	O
myosin	B-GENE
proteins	I-GENE
to	O
their	O
intrinsic	O
pathways	O
.	O

In	O
experiments	O
with	O
the	O
D1	O
antagonist	O
SCH	O
23390	O
,	O
buprenorphine	O
-	O
induced	O
depression	O
was	O
consistently	O
blocked	O
,	O
but	O
facilitation	O
was	O
unaffected	O
.	O

Acute	O
idiopathic	O
thrombocytopenic	O
purpura	O
presenting	O
a	O
high	O
serum	O
level	O
of	O
immunoglobulin	B-GENE
E	I-GENE
and	O
eosinophilia	O
in	O
an	O
elderly	O
patient	O
.	O

The	O
purpose	O
of	O
this	O
article	O
is	O
to	O
discuss	O
the	O
factors	O
involved	O
in	O
the	O
selection	O
of	O
antibodies	O
,	O
radionuclides	O
and	O
labeling	O
methods	O
in	O
the	O
development	O
of	O
radioimmunotherapy	O
(	O
RIT	O
)	O
for	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphoma	O
(	O
NHL	O
)	O
from	O
a	O
single	O
clinical	O
study	O
site	O
through	O
multicenter	O
trials	O
and	O
commercialization	O
.	O

Transcriptional	O
regulation	O
of	O
the	O
GluR2	B-GENE
gene	I-GENE
:	O
neural	O
-	O
specific	O
expression	O
,	O
multiple	O
promoters	O
,	O
and	O
regulatory	O
elements	O
.	O

The	O
binding	O
of	O
NF	B-GENE
-	I-GENE
ATp	I-GENE
,	O
although	O
not	O
NF	B-GENE
-	I-GENE
AT4	I-GENE
,	O
to	O
this	O
enhancer	O
also	O
occurs	O
along	O
with	O
HTLV	O
-	O
I	O
-	O
mediated	O
infection	O
of	O
human	O
peripheral	O
blood	O
T	O
-	O
cells	O
.	O

Thus	O
,	O
TRAF2	B-GENE
initiates	O
SAPK	B-GENE
and	O
p38	B-GENE
activation	O
by	O
binding	O
two	O
proximal	O
protein	O
kinases	O
:	O
GCK	B-GENE
and	O
RIP	B-GENE
.	O

Tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
signaling	O
to	O
stress	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
SAPK	B-GENE
)	O
/	O
Jun	B-GENE
NH2	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
(	O
JNK	B-GENE
)	O
and	O
p38	B-GENE
.	O

The	O
activity	O
of	O
the	O
minimal	O
promoter	O
was	O
found	O
to	O
be	O
controlled	O
by	O
a	O
combination	O
of	O
the	O
activities	O
of	O
the	O
transcription	O
factors	O
Sp1	B-GENE
,	O
Sp3	B-GENE
,	O
and	O
NF	B-GENE
-	I-GENE
Y	I-GENE
.	O

Pressure	O
ulcers	O
.	O

TBP	B-GENE
can	O
be	O
phosphorylated	O
in	O
vitro	O
by	O
extracts	O
of	O
U937	O
cells	O
or	O
by	O
bacterially	O
expressed	O
activated	O
ERK2	B-GENE
;	O
the	O
phosphorylation	O
sites	O
were	O
mapped	O
to	O
ERK	B-GENE
kinase	I-GENE
consensus	I-GENE
sites	I-GENE
in	O
the	O
TBP	B-GENE
amino	I-GENE
-	I-GENE
terminal	I-GENE
domain	I-GENE
.	O

During	O
the	O
CR	O
/	O
PP	O
diet	O
only	O
the	O
HS	O
subjects	O
did	O
not	O
show	O
the	O
stress	O
-	O
induced	O
rise	O
in	O
depression	O
,	O
decline	O
in	O
vigour	O
and	O
cortisol	O
elevation	O
that	O
they	O
showed	O
after	O
the	O
PR	O
/	O
CP	O
diet	O
.	O

Evidence	O
for	O
a	O
novel	O
MAPKKK	B-GENE
-	O
independent	O
pathway	O
controlling	O
the	O
stress	O
activated	O
Sty1	B-GENE
/	O
Spc1	B-GENE
MAP	O
kinase	O
in	O
fission	O
yeast	O
.	O

Furthermore	O
,	O
we	O
demonstrated	O
that	O
Galpha11	B-GENE
Q209L	I-GENE
stimulated	O
Src	B-GENE
family	I-GENE
kinase	O
activity	O
and	O
induced	O
tyrosine	O
phosphorylation	O
of	O
several	O
proteins	O
in	O
HEK	O
-	O
293	O
cells	O
.	O

The	O
micturition	O
pressure	O
was	O
significantly	O
decreased	O
only	O
after	O
injection	O
with	O
BUP	O
-	O
4	O
in	O
both	O
normal	O
and	O
obstructed	O
rats	O
.	O

Peroxisome	B-GENE
proliferator	I-GENE
-	I-GENE
activated	I-GENE
receptors	I-GENE
(	O
PPAR	B-GENE
)	O
modulate	O
transcription	O
by	O
binding	O
to	O
specific	O
peroxisome	O
proliferator	O
-	O
response	O
elements	O
(	O
PPRE	O
)	O
through	O
heterodimerization	O
with	O
the	O
9	B-GENE
-	I-GENE
cis	I-GENE
retinoic	I-GENE
acid	I-GENE
receptor	I-GENE
(	O
RXR	B-GENE
)	O
.	O

Molecular	O
cloning	O
and	O
functional	O
characterization	O
of	O
murine	B-GENE
sphingosine	I-GENE
kinase	I-GENE
.	O

Our	O
results	O
show	O
that	O
,	O
from	O
a	O
thermodynamical	O
standpoint	O
,	O
melatonin	O
may	O
directly	O
scavenge	O
hydroxyl	O
radicals	O
both	O
in	O
vacuum	O
and	O
in	O
aqueous	O
solution	O
.	O

This	O
sequence	O
,	O
Thr	O
-	O
Gly	O
-	O
X	O
-	O
X	O
-	O
Gly	O
-	O
Asp	O
-	O
Gly	O
-	O
Lys	O
-	O
Ile	O
-	O
Phe	O
,	O
forms	O
part	O
of	O
the	O
B	O
-	O
loop	O
and	O
is	O
conserved	O
in	O
a	O
wide	O
variety	O
of	O
organisms	O
that	O
include	O
bacteria	O
,	O
algae	O
and	O
archeabacteria	O
.	O

The	O
only	O
abundant	O
viral	O
transcript	O
expressed	O
during	O
latency	O
is	O
the	O
latency	B-GENE
-	I-GENE
related	I-GENE
(	O
LR	B-GENE
)	O
RNA	O
.	O

Expression	O
of	O
constitutively	O
active	O
MEK1	B-GENE
,	O
the	O
kinase	O
that	O
activates	O
ERKs	B-GENE
,	O
or	O
overexpression	O
of	O
ERK2	B-GENE
,	O
but	O
not	O
JNK1	B-GENE
,	O
inhibited	O
Stat3	B-GENE
activation	O
.	O

MEKs	B-GENE
and	O
ERKs	B-GENE
inhibited	O
IL	B-GENE
-	I-GENE
6	I-GENE
activation	O
of	O
Stat3	B-GENE
harboring	O
a	O
mutation	O
at	O
serine	O
-	O
727	O
,	O
the	O
major	O
site	O
for	O
serine	O
phosphorylation	O
,	O
similar	O
to	O
inhibition	O
of	O
wild	B-GENE
-	I-GENE
type	I-GENE
Stat3	I-GENE
,	O
and	O
inhibited	O
Janus	B-GENE
kinases	I-GENE
Jak1	B-GENE
and	O
Jak2	B-GENE
upstream	O
of	O
Stat3	B-GENE
in	O
the	O
Jak	B-GENE
-	O
STAT	B-GENE
-	O
signaling	O
pathway	O
.	O

Genome	O
plasticity	O
in	O
the	O
distal	O
tail	O
fiber	O
locus	O
of	O
the	O
T	O
-	O
even	O
bacteriophage	O
:	O
recombination	O
between	O
conserved	O
motifs	O
swaps	O
adhesin	B-GENE
specificity	O
.	O

Whereas	O
,	O
in	O
the	O
single	O
-	O
chambered	O
body	O
box	O
,	O
PenH	O
units	O
(	O
Enhanced	O
Pause	O
)	O
reflect	O
"	O
effort	O
of	O
breathing	O
.	O
"	O
This	O
is	O
measured	O
as	O
the	O
pause	O
between	O
inspiration	O
and	O
expiration	O
.	O

This	O
suggests	O
that	O
while	O
underpredictions	O
of	O
pain	O
do	O
not	O
hurt	O
more	O
,	O
disruption	O
on	O
primary	O
tasks	O
and	O
physiological	O
impact	O
are	O
higher	O
.	O

Badcock	O
and	O
Westheimer	O
(	O
Spatial	O
Vision	O
1	O
(	O
1	O
)	O
,	O
3	O
-	O
11	O
,	O
1985	O
)	O
showed	O
that	O
a	O
thin	O
vertical	O
line	O
induces	O
nearby	O
zones	O
of	O
attraction	O
and	O
repulsion	O
;	O
this	O
study	O
extends	O
those	O
results	O
by	O
more	O
closely	O
examining	O
the	O
horizontal	O
and	O
vertical	O
extents	O
of	O
the	O
repulsion	O
zone	O
and	O
by	O
using	O
an	O
illusory	O
contour	O
to	O
induce	O
repulsion	O
.	O

desmethyltrimebutine	O
was	O
inactive	O
.	O

A	O
5	O
.	O
0	O
-	O
kb	O
transcript	O
detected	O
by	O
the	O
differential	O
display	O
amplicon	O
3G1	O
was	O
found	O
to	O
correlate	O
strongly	O
with	O
RAG1	B-GENE
mRNA	I-GENE
expression	O
in	O
various	O
human	O
cell	O
lines	O
.	O

The	O
hBRAG	B-GENE
gene	I-GENE
was	O
localized	O
to	O
the	O
long	O
arm	O
of	O
chromosome	O
10	O
(	O
10q26	O
)	O
.	O

Genomic	O
locus	O
of	O
chCTCF	B-GENE
contains	O
a	O
GC	O
-	O
rich	O
untranslated	O
exon	O
separated	O
from	O
seven	O
coding	O
exons	O
by	O
a	O
long	O
intron	O
.	O

Small	B-GENE
GTPases	I-GENE
of	O
the	O
Ypt	B-GENE
/	O
Rab	B-GENE
family	O
are	O
involved	O
in	O
the	O
regulation	O
of	O
vesicular	O
transport	O
.	O

The	O
GEF	B-GENE
and	O
GAP	B-GENE
activities	O
for	O
Ypt1p	B-GENE
localize	O
to	O
particulate	O
cellular	O
fractions	O
.	O

Dopamine	B-GENE
beta	I-GENE
-	I-GENE
hydroxylase	I-GENE
(	O
DBH	B-GENE
)	O
catalyzes	O
the	O
conversion	O
of	O
dopamine	O
to	O
noradrenaline	O
and	O
is	O
selectively	O
expressed	O
in	O
noradrenergic	O
and	O
adrenergic	O
neurons	O
and	O
neuroendocrine	O
cells	O
.	O

Collectively	O
,	O
this	O
study	O
emphasizes	O
a	O
critical	O
role	O
of	O
Phox2a	B-GENE
as	O
well	O
as	O
its	O
functional	O
synergism	O
with	O
other	O
transcription	O
factors	O
(	O
e	O
.	O
g	O
.	O
,	O
CREB	B-GENE
,	O
AP2	B-GENE
,	O
and	O
Sp1	B-GENE
)	O
in	O
transcriptional	O
activation	O
of	O
the	O
DBH	B-GENE
gene	I-GENE
.	O

Sequence	O
comparisons	O
strongly	O
suggest	O
that	O
the	O
S27a	B-GENE
and	O
the	O
ubiquitin	B-GENE
coding	O
sequences	O
found	O
in	O
the	O
genome	O
of	O
CP	O
Rit	O
were	O
both	O
derived	O
from	O
a	O
bovine	O
mRNA	O
encoding	O
a	O
hybrid	O
protein	O
with	O
the	O
structure	O
NH2	O
-	O
ubiquitin	B-GENE
-	O
S27a	B-GENE
-	O
COOH	O
.	O

J	O
.	O

There	O
was	O
a	O
trend	O
in	O
all	O
studies	O
favouring	O
PVI	O
.	O

This	O
domain	O
,	O
although	O
adjacent	O
to	O
the	O
5	O
'	O
edge	O
of	O
the	O
SD	O
sequence	O
,	O
does	O
not	O
inhibit	O
ribosome	O
binding	O
as	O
long	O
as	O
the	O
single	O
-	O
stranded	O
region	O
of	O
domain	O
3	O
is	O
present	O
.	O

Previous	O
genetic	O
studies	O
led	O
to	O
the	O
conclusion	O
that	O
nitrate	O
and	O
nitrite	O
induction	O
of	O
nasF	B-GENE
operon	I-GENE
expression	O
is	O
determined	O
by	O
a	O
transcriptional	O
antitermination	O
mechanism	O
.	O

EGFR	B-GENE
levels	O
were	O
found	O
to	O
be	O
elevated	O
5	O
-	O
,	O
3	O
.	O

Furthermore	O
,	O
LB1	B-GENE
gene	I-GENE
mapped	O
to	O
chromosome	O
13q14	O
,	O
a	O
region	O
that	O
has	O
been	O
involved	O
as	O
a	O
chromosomal	O
breakpoint	O
in	O
DLBL	O
.	O

Wild	B-GENE
-	I-GENE
type	I-GENE
AT1A	I-GENE
receptors	I-GENE
,	O
expressed	O
in	O
Chinese	O
hamster	O
ovary	O
cells	O
,	O
rapidly	O
internalized	O
after	O
Ang	B-GENE
II	I-GENE
stimulation	O
[	O
t1	O
/	O
2	O
2	O
.	O
3	O
min	O
;	O
maximal	O
level	O
of	O
internalization	O
(	O
Ymax	O
)	O
78	O
.	O
2	O
%	O
]	O
,	O
as	O
did	O
mutant	O
receptors	O
carrying	O
single	O
acidic	O
substitutions	O
(	O
T332E	O
,	O
t1	O
/	O
2	O
2	O
.	O
7	O
min	O
,	O
Ymax	O
76	O
.	O
3	O
%	O
;	O
S335D	O
,	O
t1	O
/	O
2	O
2	O
.	O
4	O
min	O
,	O
Ymax	O
76	O
.	O
7	O
%	O
;	O
T336E	O
,	O
t1	O
/	O
2	O
2	O
.	O
5	O
min	O
,	O
Ymax	O
78	O
.	O
2	O
%	O
;	O
S338D	O
,	O
t1	O
/	O
2	O
2	O
.	O
6	O
min	O
,	O
Ymax	O
78	O
.	O
4	O
%	O
)	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

T	O
.	O
,	O
Mahasneh	O
,	O
A	O
.	O
,	O
and	O
Cote	O
,	O
G	O
.	O

RESULTS	O
:	O
The	O
binding	O
of	O
99mTc	O
d	O
,	O
1	O
-	O
HMPAO	O
to	O
human	O
placenta	O
ranged	O
from	O
2	O
.	O
95	O
%	O
+	O
/	O
-	O
1	O
.	O
5	O
%	O
to	O
5	O
.	O
82	O
%	O
+	O
/	O
-	O
0	O
.	O
3	O
%	O
per	O
1	O
ml	O
standard	O
solution	O
.	O

CM	O
reduced	O
the	O
nuclear	O
binding	O
activity	O
of	O
transcription	B-GENE
factor	I-GENE
AP	I-GENE
-	I-GENE
1	I-GENE
.	O

NF	B-GENE
-	I-GENE
kappaB	I-GENE
,	O
which	O
is	O
probably	O
important	O
for	O
basal	O
activity	O
of	O
the	O
human	B-GENE
NOS	I-GENE
II	I-GENE
promoter	I-GENE
,	O
is	O
unlikely	O
to	O
function	O
as	O
a	O
major	O
effector	O
of	O
CM	O
in	O
DLD	O
-	O
1	O
cells	O
.	O

RESULTS	O
:	O
The	O
cardiac	O
index	O
significantly	O
changed	O
with	O
varying	O
PaCO2	O
levels	O
(	O
hypocapnia	O
,	O
-	O
9	O
%	O
;	O
hypercapnia	O
,	O
13	O
%	O
)	O
.	O

Sequencing	O
of	O
a	O
40	O
-	O
kb	O
DNA	O
segment	O
of	O
the	O
FK506	O
gene	O
cluster	O
from	O
Streptomyces	O
sp	O
.	O

The	O
predicted	O
domain	O
structures	O
of	O
FkbB	B-GENE
and	O
FkbC	B-GENE
are	O
analogous	O
to	O
that	O
of	O
FkbA	B-GENE
and	O
comprise	O
30	O
fatty	B-GENE
-	I-GENE
acid	I-GENE
-	I-GENE
synthase	I-GENE
(	O
FAS	B-GENE
)	O
-	O
like	O
domains	O
arranged	O
in	O
6	O
modules	O
.	O

The	O
cwg2	B-GENE
-	I-GENE
1	I-GENE
mutation	I-GENE
was	O
identified	O
as	O
a	O
guanine	O
to	O
adenine	O
substitution	O
at	O
nucleotide	O
604	O
of	O
the	O
coding	O
region	O
,	O
originating	O
the	O
change	O
A202T	O
in	O
the	O
cwg2p	B-GENE
.	O

Handling	O
on	O
PND	O
9	O
did	O
not	O
result	O
in	O
elevated	O
CORT	O
levels	O
in	O
any	O
of	O
the	O
groups	O
.	O

633	O
+	O
/	O
-	O
258	O
aggregates	O
/	O
ml	O
at	O
0	O
rpm	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

These	O
results	O
indicate	O
that	O
the	O
total	O
number	O
of	O
subunit	O
c	O
in	O
F0	B-GENE
should	O
be	O
a	O
multiple	O
of	O
2	O
and	O
3	O
.	O

BACKGROUND	O
:	O
The	O
c	B-GENE
-	I-GENE
myc	I-GENE
proto	I-GENE
-	I-GENE
oncogene	I-GENE
has	O
been	O
suggested	O
to	O
play	O
key	O
roles	O
in	O
cell	O
proliferation	O
,	O
differentiation	O
,	O
transformation	O
and	O
apoptosis	O
.	O

AMY	B-GENE
-	I-GENE
1	I-GENE
was	O
localized	O
in	O
the	O
cytoplasm	O
in	O
cells	O
expressing	O
c	B-GENE
-	I-GENE
myc	I-GENE
at	O
low	O
levels	O
,	O
but	O
in	O
the	O
nucleus	O
in	O
the	O
cells	O
of	O
a	O
high	O
c	B-GENE
-	I-GENE
myc	I-GENE
expression	O
in	O
transiently	O
transfected	O
cells	O
.	O

Antidepressant	O
-	O
like	O
properties	O
of	O
some	O
serotonin	B-GENE
receptor	I-GENE
ligands	O
and	O
calcium	O
channel	O
antagonists	O
measured	O
with	O
the	O
forced	O
swimming	O
test	O
in	O
mice	O
.	O

The	O
various	O
available	O
data	O
strongly	O
suggesting	O
an	O
environmental	O
toxic	O
origin	O
for	O
the	O
"	O
sperm	O
fall	O
"	O
will	O
be	O
presented	O
as	O
well	O
as	O
the	O
most	O
frequently	O
suspected	O
class	O
of	O
substances	O
,	O
the	O
xenoestrogens	O
.	O

Examination	O
of	O
DNA	O
:	O
protein	O
binding	O
complexes	O
by	O
gel	O
-	O
shift	O
analysis	O
indicated	O
that	O
nuclear	O
factors	O
from	O
both	O
proliferative	O
and	O
growth	O
-	O
arrested	O
cells	O
bound	O
to	O
the	O
DNA	O
fragment	O
spanning	O
-	O
949	O
-	O
-	O
722	O
bp	O
.	O

RESULTS	O
:	O
An	O
herpetic	O
seroconversion	O
is	O
observed	O
with	O
presence	O
of	O
type	O
I	O
herpes	O
simplex	O
virus	O
(	O
HSV	O
I	O
)	O
nucleic	O
acids	O
in	O
the	O
recipient	O
'	O
s	O
aqueous	O
humor	O
.	O

GH	B-GENE
failed	O
to	O
stimulate	O
phosphorylation	O
or	O
activation	O
of	O
Jun	B-GENE
N	I-GENE
-	I-GENE
terminal	I-GENE
kinase	I-GENE
under	O
the	O
conditions	O
used	O
.	O

CD4	B-GENE
lymphocyte	O
and	O
viral	O
load	O
levels	O
suggested	O
an	O
optimal	O
response	O
to	O
ARV	O
therapy	O
at	O
the	O
time	O
LD	O
developed	O
.	O

By	O
DNase	B-GENE
I	I-GENE
footprint	O
analysis	O
of	O
the	O
PNR	O
element	O
,	O
a	O
palindrome	O
of	O
two	O
high	O
-	O
affinity	O
Ets	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
(	O
CTTCCCTGGAAG	O
)	O
was	O
identified	O
.	O

No	O
mutations	O
were	O
found	O
in	O
follicular	O
adenomas	O
.	O

Expression	O
of	O
lacZ	B-GENE
from	O
the	O
promoter	O
of	O
the	O
Escherichia	B-GENE
coli	I-GENE
spc	I-GENE
operon	I-GENE
cloned	O
into	O
vectors	O
carrying	O
the	O
W205	O
trp	B-GENE
-	O
lac	B-GENE
fusion	O
.	O

RT	O
-	O
PCR	O
analysis	O
showed	O
that	O
PLP	B-GENE
-	I-GENE
H	I-GENE
as	O
well	O
as	O
PLP	B-GENE
-	I-GENE
C	I-GENE
and	O
PLP	B-GENE
-	I-GENE
D	I-GENE
are	O
expressed	O
in	O
all	O
rat	O
strains	O
examined	O
,	O
confirming	O
that	O
PLP	B-GENE
diversity	O
is	O
not	O
due	O
to	O
strain	O
differences	O
.	O

Molecular	O
cloning	O
and	O
characterization	O
of	O
a	O
new	O
member	O
of	O
the	O
rat	B-GENE
placental	I-GENE
prolactin	I-GENE
(	O
PRL	B-GENE
)	O
family	O
,	O
PRL	B-GENE
-	O
like	O
protein	B-GENE
H	I-GENE
.	O

Thus	O
,	O
we	O
have	O
identified	O
an	O
activation	O
target	O
of	O
a	O
human	O
activator	O
,	O
Oct	B-GENE
-	I-GENE
1	I-GENE
,	O
within	O
its	O
cognate	O
basal	O
transcription	O
complex	O
.	O

The	O
results	O
raise	O
the	O
possibility	O
that	O
pH	O
induced	O
post	O
-	O
translational	O
modifications	O
of	O
DdRPA	B-GENE
are	O
involved	O
in	O
events	O
that	O
halt	O
cell	O
proliferation	O
and	O
induce	O
differentiation	O
in	O
Dictyostelium	O
.	O

P	B-GENE
-	I-GENE
CIP1	I-GENE
,	O
a	O
novel	O
protein	O
that	O
interacts	O
with	O
the	O
cytosolic	O
domain	O
of	O
peptidylglycine	B-GENE
alpha	I-GENE
-	I-GENE
amidating	I-GENE
monooxygenase	I-GENE
,	O
is	O
associated	O
with	O
endosomes	O
.	O

In	O
this	O
study	O
we	O
provide	O
evidence	O
that	O
B	B-GENE
-	I-GENE
Myb	I-GENE
is	O
a	O
direct	O
physiological	O
target	O
for	O
cyclin	B-GENE
A	I-GENE
/	O
Cdk2	B-GENE
.	O

The	O
highly	O
amyloidogenic	O
42	O
-	O
residue	O
form	O
of	O
Abeta	B-GENE
(	O
Abeta42	B-GENE
)	O
is	O
the	O
first	O
species	O
to	O
be	O
deposited	O
in	O
both	O
sporadic	O
and	O
familial	O
AD	O
.	O

This	O
model	O
is	O
supported	O
by	O
experiments	O
showing	O
that	O
Cdr2	B-GENE
associates	O
with	O
the	O
N	B-GENE
-	I-GENE
terminal	I-GENE
regulatory	I-GENE
domain	I-GENE
of	I-GENE
Wee1	I-GENE
in	O
cell	O
lysates	O
and	O
phosphorylates	O
Wee1	B-GENE
in	O
vitro	O
.	O

RESULTS	O
:	O
Significant	O
changes	O
from	O
pretreatment	O
to	O
posttreatment	O
were	O
observed	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

The	O
tip	O
of	O
the	O
button	O
caused	O
a	O
perforation	O
of	O
the	O
posterior	O
stomach	O
wall	O
,	O
leading	O
to	O
death	O
.	O

Also	O
,	O
the	O
amplitude	O
of	O
the	O
oscillatory	O
potentials	O
(	O
O1	O
+	O
O2	O
+	O
O3	O
+	O
O4	O
)	O
was	O
significantly	O
reduced	O
in	O
the	O
early	O
postoperative	O
period	O
.	O

Both	O
NUP98	B-GENE
-	O
HOXA9	B-GENE
chimeras	O
transformed	O
NIH	O
3T3	O
fibroblasts	O
,	O
and	O
this	O
transformation	O
required	O
the	O
HOXA9	B-GENE
domains	I-GENE
for	O
DNA	O
binding	O
and	O
PBX	B-GENE
interaction	O
.	O

Ethylene	O
is	O
involved	O
in	O
endosperm	O
rupture	O
and	O
high	O
-	O
level	O
betaGLU	B-GENE
I	I-GENE
expression	O
;	O
but	O
,	O
it	O
does	O
not	O
affect	O
the	O
spatial	O
and	O
temporal	O
pattern	O
of	O
betaGLU	B-GENE
I	I-GENE
expression	O
.	O

The	O
divergence	O
in	O
primary	O
structure	O
between	O
the	O
sheep	O
CRF1	B-GENE
and	O
the	O
other	O
mammalian	B-GENE
CRF1s	I-GENE
is	O
primarily	O
localized	O
to	O
the	O
extracellular	O
amino	O
terminal	O
domain	O
of	O
the	O
receptor	O
(	O
18	O
of	O
22	O
divergent	O
residues	O
,	O
ovine	O
vs	O
human	B-GENE
CRF1	I-GENE
)	O
.	O

Agonist	O
-	O
induced	O
receptor	O
internalization	O
,	O
determined	O
as	O
the	O
percent	O
of	O
total	O
[	O
125I	O
]	O
Tyr0	B-GENE
-	I-GENE
oCRF	I-GENE
bound	O
located	O
in	O
the	O
acid	O
-	O
resistant	O
fraction	O
of	O
transfected	O
Cos	O
7	O
cells	O
,	O
increased	O
with	O
time	O
(	O
0	O
-	O
60	O
min	O
at	O
37	O
degrees	O
C	O
)	O
for	O
both	O
wild	O
-	O
type	O
and	O
variant	O
oCRF1	B-GENE
.	O

This	O
c	B-GENE
-	I-GENE
Jun	I-GENE
activity	O
is	O
inhibited	O
by	O
c	B-GENE
-	I-GENE
Fos	I-GENE
,	O
another	O
protooncoprotein	O
that	O
can	O
dimerize	O
with	O
c	B-GENE
-	I-GENE
Jun	I-GENE
to	O
form	O
the	O
transcription	O
factor	O
AP	B-GENE
-	I-GENE
1	I-GENE
.	O

CONCLUSION	O
:	O
Our	O
study	O
shows	O
that	O
(	O
1	O
)	O
total	O
body	O
BMD	O
and	O
femoral	O
neck	O
BMD	O
were	O
significantly	O
higher	O
in	O
the	O
study	O
group	O
that	O
performed	O
weight	O
-	O
bearing	O
exercises	O
than	O
in	O
control	O
subjects	O
,	O
(	O
2	O
)	O
swimming	O
exercise	O
had	O
no	O
effect	O
on	O
BMD	O
,	O
and	O
(	O
3	O
)	O
although	O
swimming	O
is	O
not	O
a	O
bone	O
-	O
building	O
exercise	O
,	O
it	O
can	O
significantly	O
improve	O
shoulder	O
,	O
back	O
,	O
and	O
grip	O
muscle	O
strength	O
.	O

Comparisons	O
with	O
other	O
known	O
germins	B-GENE
and	O
germin	B-GENE
-	I-GENE
like	I-GENE
proteins	I-GENE
indicate	O
that	O
these	O
Arabidopsis	O
GLP	B-GENE
subfamilies	O
are	O
unique	O
from	O
wheat	O
germin	B-GENE
.	O

However	O
,	O
there	O
has	O
not	O
been	O
any	O
evidence	O
of	O
A	O
.	O
salmonicida	O
infections	O
,	O
specifically	O
furunculosis	O
,	O
associated	O
with	O
the	O
fish	O
in	O
this	O
loch	O
.	O

Improving	O
the	O
evidence	O
base	O
for	O
anaesthesia	O
.	O

Plasma	O
CCK	B-GENE
levels	O
were	O
determined	O
at	O
regular	O
intervals	O
.	O

Consistent	O
with	O
these	O
findings	O
,	O
relatively	O
weak	O
transcriptional	O
silencing	O
by	O
the	O
native	O
VDR	B-GENE
was	O
observed	O
using	O
the	O
osteopontin	B-GENE
VDRE	O
.	O

A	O
motif	O
(	O
TGATGTCA	O
)	O
which	O
matches	O
a	O
CREB	B-GENE
site	I-GENE
and	O
is	O
similar	O
to	O
an	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
is	O
embedded	O
within	O
ER2	B-GENE
.	O

Conventionally	O
,	O
four	O
nominal	O
allotypic	O
variants	O
,	O
b4	O
,	O
b5	O
,	O
b6	O
and	O
b9	O
have	O
been	O
shown	O
to	O
be	O
co	O
-	O
dominantly	O
expressed	O
at	O
the	O
Ckappa1	B-GENE
gene	I-GENE
locus	I-GENE
.	O

Therefore	O
,	O
in	O
order	O
to	O
search	O
for	O
the	O
latent	O
genes	O
,	O
we	O
used	O
allotype	O
-	O
specific	O
oligonucleotides	O
for	O
b5	O
,	O
b6	O
and	O
b9	O
to	O
probe	O
DNAs	O
from	O
both	O
normal	O
and	O
T	O
.	O
brucei	O
-	O
infected	O
rabbits	O
by	O
Southern	O
blotting	O
.	O

TRAF2	B-GENE
is	O
known	O
to	O
associate	O
with	O
TRADD	B-GENE
,	O
and	O
expression	O
of	O
a	O
dominant	O
-	O
negative	O
N	O
-	O
terminal	O
deletion	O
TRAF2	B-GENE
mutant	I-GENE
was	O
found	O
to	O
partially	O
inhibit	O
LMP1	B-GENE
-	O
induced	O
JNK	B-GENE
activation	O
in	O
293	O
cells	O
.	O

These	O
data	O
further	O
define	O
a	O
role	O
for	O
TRADD	B-GENE
and	O
TRAF2	B-GENE
in	O
JNK	B-GENE
activation	O
and	O
confirm	O
that	O
LMP1	B-GENE
utilizes	O
signalling	O
mechanisms	O
used	O
by	O
the	O
TNF	B-GENE
receptor	I-GENE
/	O
CD40	B-GENE
family	O
to	O
elicit	O
its	O
pleiotropic	O
activities	O
.	O

Epstein	B-GENE
-	I-GENE
Barr	I-GENE
virus	I-GENE
-	I-GENE
encoded	I-GENE
latent	I-GENE
membrane	I-GENE
protein	I-GENE
1	I-GENE
activates	O
the	O
JNK	B-GENE
pathway	O
through	O
its	O
extreme	O
C	O
terminus	O
via	O
a	O
mechanism	O
involving	O
TRADD	B-GENE
and	O
TRAF2	B-GENE
.	O

In	O
contrast	O
,	O
transiently	O
transfected	O
cells	O
expressing	O
EBNA	B-GENE
-	I-GENE
3	I-GENE
revealed	O
a	O
sixfold	O
increase	O
in	O
EBNA	B-GENE
-	I-GENE
3	I-GENE
protein	I-GENE
expression	O
from	O
the	O
genomic	O
EBNA	B-GENE
-	I-GENE
3	I-GENE
gene	I-GENE
compared	O
to	O
EBNA	B-GENE
-	I-GENE
3	I-GENE
cDNA	I-GENE
.	O

However	O
,	O
serial	O
passages	O
of	O
fetal	O
lamb	O
kidney	O
(	O
FLK	O
)	O
cells	O
,	O
which	O
are	O
sensitive	O
to	O
infection	O
with	O
BLV	O
,	O
after	O
transient	O
transfection	O
revealed	O
that	O
mutation	O
of	O
a	O
second	O
tyrosine	O
residue	O
in	O
the	O
N	O
-	O
terminal	O
motif	O
completely	O
prevented	O
the	O
propagation	O
of	O
the	O
virus	O
.	O

To	O
search	O
for	O
transcriptional	O
regulators	O
,	O
we	O
used	O
a	O
fragment	O
of	O
the	O
SpHE	B-GENE
promoter	I-GENE
containing	O
several	O
individual	O
elements	O
instead	O
of	O
the	O
conventional	O
bait	O
that	O
contains	O
a	O
multimerized	O
cis	O
element	O
.	O

As	O
expected	O
for	O
a	O
positive	O
SpHE	B-GENE
transcriptional	I-GENE
regulator	I-GENE
,	O
the	O
timing	O
of	O
SpEts4	B-GENE
gene	I-GENE
expression	O
precedes	O
the	O
transient	O
expression	O
of	O
SpHE	B-GENE
in	O
the	O
very	O
early	O
sea	O
urchin	O
blastula	O
.	O

Induction	O
of	O
anaesthesia	O
was	O
standardised	O
:	O
fentanyl	O
(	O
3	O
micrograms	O
/	O
kg	O
)	O
,	O
thiopentone	O
(	O
5	O
mg	O
/	O
kg	O
)	O
,	O
atracurium	O
(	O
0	O
.	O
4	O
mg	O
/	O
kg	O
)	O
.	O

Conserved	O
and	O
distinct	O
roles	O
of	O
kreisler	B-GENE
in	O
regulation	O
of	O
the	O
paralogous	O
Hoxa3	B-GENE
and	O
Hoxb3	B-GENE
genes	I-GENE
.	O

Moreover	O
,	O
this	O
enhancement	O
of	O
transcriptional	O
activation	O
by	O
COUP	B-GENE
-	I-GENE
TFI	I-GENE
requires	O
specifically	O
the	O
AF	O
-	O
1	O
transactivation	O
function	O
of	O
ER	B-GENE
and	O
can	O
be	O
observed	O
in	O
the	O
presence	O
of	O
E2	O
or	O
4	O
-	O
hydroxytamoxifen	O
but	O
not	O
ICI	O
164384	O
.	O

Recombinant	B-GENE
Ffh	I-GENE
has	O
a	O
melting	O
point	O
of	O
tm	O
=	O
89	O
degreesC	O
.	O

This	O
region	O
of	O
hsp90	B-GENE
mediates	O
ATP	O
-	O
independent	O
chaperone	O
activity	O
,	O
overlaps	O
the	O
hsp90	B-GENE
dimerization	I-GENE
domain	I-GENE
,	O
and	O
includes	O
structural	O
elements	O
important	O
for	O
steroid	B-GENE
receptor	I-GENE
interaction	O
.	O

The	O
RNA	B-GENE
polymerase	I-GENE
III	I-GENE
-	I-GENE
recruiting	I-GENE
factor	I-GENE
TFIIIB	I-GENE
induces	O
a	O
DNA	O
bend	O
between	O
the	O
TATA	O
box	O
and	O
the	O
transcriptional	O
start	O
site	O
.	O

Analysis	O
of	O
hematopoietic	B-GENE
growth	I-GENE
factor	I-GENE
prescriptions	O
in	O
19	O
french	O
cancer	O
centers	O

Chem	O
.	O

These	O
results	O
suggest	O
that	O
the	O
c	B-GENE
-	I-GENE
met	I-GENE
gene	I-GENE
is	O
also	O
a	O
target	O
of	O
p53	B-GENE
gene	I-GENE
regulation	O
.	O

Pokeweed	B-GENE
antiviral	I-GENE
protein	I-GENE
(	O
PAP	B-GENE
)	O
from	O
Phytolacca	O
americana	O
is	O
a	O
highly	O
specific	O
N	B-GENE
-	I-GENE
glycosidase	I-GENE
removing	O
adenine	O
residues	O
(	O
A4324	O
in	O
28S	B-GENE
rRNA	I-GENE
and	O
A2660	O
in	O
23S	B-GENE
rRNA	I-GENE
)	O
from	O
intact	O
ribosomes	O
of	O
both	O
eukaryotes	O
and	O
prokaryotes	O
.	O

Among	O
these	O
360	O
ZFPs	B-GENE
,	O
a	O
novel	O
ZFP	B-GENE
cDNA	I-GENE
named	O
HFHZ	B-GENE
(	O
human	B-GENE
fetal	I-GENE
heart	I-GENE
ZFP	I-GENE
)	O
with	O
sequence	O
homology	O
to	O
a	O
Kruppel	B-GENE
-	I-GENE
associated	I-GENE
box	I-GENE
(	O
KRAB	B-GENE
)	O
was	O
identified	O
.	O

The	O
3	O
.	O
3	O
-	O
fold	O
higher	O
expression	O
in	O
the	O
fetal	O
heart	O
than	O
in	O
the	O
adult	O
heart	O
suggests	O
that	O
HFHZ	B-GENE
mRNA	I-GENE
is	O
downregulated	O
in	O
the	O
process	O
of	O
development	O
.	O

CONTEXT	O
:	O
ThinPrep	O
,	O
AutoPap	O
,	O
and	O
Papnet	O
are	O
3	O
new	O
technologies	O
that	O
increase	O
the	O
sensitivity	O
and	O
cost	O
of	O
cervical	O
cancer	O
screening	O
.	O

Experiments	O
on	O
narcotized	O
cats	O
demonstrated	O
that	O
the	O
derivatives	O
of	O
2	O
-	O
mercaptobenzimidazole	O
possessing	O
the	O
properties	O
of	O
specific	O
bradycardic	O
agents	O
and	O
coded	O
as	O
CM	O
-	O
251	O
,	O
CM	O
-	O
266	O
,	O
and	O
CM	O
-	O
345	O
,	O
reduce	O
the	O
mean	O
rise	O
of	O
segment	O
ST	O
on	O
numerous	O
leads	O
of	O
the	O
epicardial	O
electrogram	O
during	O
5	O
-	O
min	O
occlusion	O
of	O
the	O
anterior	O
descending	O
branch	O
of	O
the	O
left	O
coronary	O
artery	O
.	O

Expression	O
of	O
the	O
second	O
gene	O
(	O
XT3	B-GENE
)	O
was	O
found	O
to	O
be	O
conserved	O
in	O
human	O
kidney	O
,	O
and	O
partial	O
sequence	O
was	O
obtained	O
from	O
a	O
human	O
cDNA	O
library	O
.	O

Internal	O
modes	O
of	O
a	O
soliton	O
.	O

(	O
2	O
)	O
Erythroid	O
32D	O
Epo1	B-GENE
cells	O
showed	O
a	O
lower	O
level	O
of	O
bulk	O
PKC	B-GENE
catalytic	O
activity	O
,	O
lacked	O
the	O
expression	O
of	O
epsilon	B-GENE
and	I-GENE
eta	I-GENE
PKC	I-GENE
isoforms	I-GENE
,	O
and	O
showed	O
a	O
weak	O
or	O
absent	O
upregulation	O
of	O
the	O
remaining	O
isoforms	O
,	O
except	O
betaI	B-GENE
,	O
upon	O
readdition	O
of	O
Epo	B-GENE
to	O
growth	O
factor	O
-	O
starved	O
cells	O
.	O

We	O
used	O
expression	O
cloning	O
to	O
identify	O
interleukin	B-GENE
-	I-GENE
6	I-GENE
(	O
IL	B-GENE
-	I-GENE
6	I-GENE
)	O
as	O
one	O
factor	O
that	O
suppressed	O
growth	O
of	O
a	O
pre	O
-	O
B	O
-	O
cell	O
variant	O
line	O
,	O
1A9	O
-	O
M	O
.	O

Airflow	O
through	O
the	O
dust	O
trap	O
was	O
controlled	O
with	O
a	O
vacuum	O
pump	O
.	O

Several	O
mutations	O
disrupted	O
the	O
endonuclease	O
and	O
helicase	B-GENE
activities	O
;	O
however	O
,	O
only	O
one	O
amino	B-GENE
-	I-GENE
terminal	I-GENE
-	I-GENE
charge	I-GENE
cluster	I-GENE
mutant	I-GENE
protein	I-GENE
(	O
D40A	O
-	O
D42A	O
-	O
D44A	O
)	O
completely	O
lost	O
AAV	O
hairpin	O
DNA	O
binding	O
activity	O
.	O

Here	O
we	O
describe	O
the	O
identification	O
and	O
characterization	O
of	O
several	O
Sp100	B-GENE
splice	I-GENE
variant	I-GENE
proteins	I-GENE
and	O
support	O
their	O
existence	O
by	O
elucidation	O
of	O
the	O
3	O
'	O
-	O
end	O
of	O
the	O
Sp100	B-GENE
gene	I-GENE
.	O

It	O
was	O
demonstrated	O
that	O
the	O
processing	O
signals	O
in	O
the	O
transcript	O
,	O
i	O
.	O
e	O
.	O
both	O
donor	O
splice	O
sites	O
and	O
the	O
polyadenylation	O
site	O
located	O
in	O
the	O
muscle	O
-	O
specific	O
intron	O
,	O
have	O
to	O
be	O
weak	O
.	O

Chirality	O
-	O
glass	O
and	O
spin	O
-	O
glass	O
correlations	O
in	O
the	O
two	O
-	O
dimensional	O
random	O
-	O
bond	O
XY	O
model	O
.	O

Echo	O
modulation	O
in	O
Pr3	O
+	O
:	O
YAlO3	O
.	O

Mechanisms	O
of	O
visible	O
-	O
light	O
emission	O
from	O
electro	O
-	O
oxidized	O
porous	O
silicon	O
.	O

Optically	O
detected	O
librons	O
and	O
phonons	O
in	O
crystalline	O
C60	O
.	O

Factors	O
influencing	O
direct	O
-	O
immersion	O
(	O
DI	O
)	O
-	O
SPME	O
process	O
were	O
also	O
checked	O
and	O
chosen	O
experimentally	O
.	O

In	O
contrast	O
,	O
an	O
amino	O
-	O
terminal	O
fragment	O
containing	O
the	O
C	O
/	O
H1	O
domain	O
was	O
sufficient	O
for	O
coactivation	O
of	O
Zta	B-GENE
transcription	O
and	O
viral	O
reactivation	O
function	O
.	O

In	O
addition	O
,	O
a	O
potent	O
splicing	O
enhancer	O
sequence	O
isolated	O
in	O
the	O
selection	O
specifically	O
binds	O
a	O
20	B-GENE
-	I-GENE
kDa	I-GENE
SR	I-GENE
protein	I-GENE
.	O

These	O
data	O
suggest	O
that	O
other	O
Ras	B-GENE
effectors	I-GENE
can	O
collaborate	O
with	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
and	O
with	O
each	O
other	O
to	O
activate	O
Pak	B-GENE
.	O

Electrophoretic	O
mobility	O
-	O
shift	O
assays	O
performed	O
with	O
the	O
HNF	B-GENE
-	I-GENE
3	I-GENE
X	O
and	O
Y	O
sites	O
demonstrated	O
that	O
both	O
sites	O
are	O
capable	O
of	O
binding	O
HNF	B-GENE
-	I-GENE
3alpha	I-GENE
and	O
HNF	B-GENE
-	I-GENE
3beta	I-GENE
.	O

Proteins	O
known	O
to	O
bind	O
the	O
PEPCK	B-GENE
CRE	O
include	O
the	O
CRE	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
CREB	B-GENE
)	O
and	O
members	O
of	O
the	O
CCAAT	B-GENE
/	I-GENE
enhancer	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	O
C	B-GENE
/	I-GENE
EBP	I-GENE
)	O
family	O
.	O

This	O
construct	O
,	O
termed	O
pDeltaCREC	B-GENE
/	O
EBP	B-GENE
,	O
binds	O
C	B-GENE
/	I-GENE
EBPalpha	I-GENE
and	I-GENE
beta	I-GENE
but	O
not	O
CREB	B-GENE
,	O
yet	O
it	O
confers	O
a	O
nearly	O
complete	O
glucocorticoid	O
response	O
when	O
transiently	O
transfected	O
into	O
H4IIE	O
rat	O
hepatoma	O
cells	O
.	O

Systematic	O
functional	O
analysis	O
of	O
V1a	B-GENE
/	I-GENE
V2	I-GENE
hybrid	I-GENE
receptors	I-GENE
showed	O
that	O
the	O
second	O
intracellular	O
loop	O
of	O
the	O
V1a	B-GENE
receptor	I-GENE
is	O
required	O
and	O
sufficient	O
for	O
efficient	O
coupling	O
to	O
Gq	B-GENE
/	I-GENE
11	I-GENE
,	O
whereas	O
the	O
third	O
intracellular	O
loop	O
of	O
the	O
V2	B-GENE
receptor	I-GENE
is	O
required	O
and	O
sufficient	O
for	O
coupling	O
to	O
Gs	B-GENE
.	O

The	O
fatigue	O
exercise	O
showed	O
relatively	O
high	O
blood	O
lactate	O
concentration	O
[	O
12	O
.	O
5	O
(	O
SD	O
2	O
.	O
6	O
)	O
mmol	O
x	O
l	O
(	O
-	O
1	O
)	O
]	O
and	O
an	O
increase	O
of	O
serum	B-GENE
creatine	I-GENE
kinase	I-GENE
(	O
CK	B-GENE
)	O
activity	O
delayed	O
by	O
2	O
days	O
[	O
540	O
(	O
SD	O
407	O
)	O
U	O
x	O
l	O
(	O
-	O
1	O
)	O
]	O
.	O

New	O
Langevin	O
equations	O
for	O
a	O
translating	O
and	O
simultaneously	O
rotating	O
asymmetric	O
top	O
.	O

In	O
the	O
brain	O
,	O
muscarinic	B-GENE
receptors	I-GENE
mediate	O
motor	O
and	O
memory	O
function	O
by	O
interaction	O
with	O
their	O
ligand	O
acetylcholine	O
.	O

In	O
this	O
study	O
,	O
we	O
investigated	O
the	O
signal	O
transduction	O
pathways	O
that	O
are	O
involved	O
in	O
OM	B-GENE
-	O
induced	O
LDLR	B-GENE
transcription	O
.	O

The	O
Lp	B-GENE
mouse	I-GENE
mutant	I-GENE
provides	O
a	O
model	O
for	O
the	O
severe	O
human	O
neural	O
tube	O
defect	O
(	O
NTD	O
)	O
,	O
cranio	O
-	O
rachischisis	O
.	O

Therefore	O
,	O
high	O
set	O
-	O
up	O
accuracy	O
and	O
reproducibility	O
are	O
mandatory	O
.	O

CPDs	O
at	O
these	O
three	O
sites	O
may	O
partially	O
displace	O
TFIIIA	B-GENE
,	O
thereby	O
enabling	O
rapid	O
repair	O
.	O

There	O
was	O
no	O
difference	O
in	O
the	O
hormone	O
receptor	O
status	O
between	O
the	O
cases	O
without	O
lymph	O
node	O
metastases	O
and	O
with	O
lymph	O
node	O
metastases	O
,	O
'	O
clandestine	O
'	O
or	O
macrometastases	O
.	O

Gel	O
filtration	O
,	O
sedimentation	O
velocity	O
,	O
and	O
immunoprecipitation	O
experiments	O
revealed	O
that	O
beta4	O
is	O
a	O
component	O
of	O
a	O
multisubunit	O
complex	O
(	O
AP	B-GENE
-	I-GENE
4	I-GENE
)	O
that	O
also	O
contains	O
the	O
sigma4	O
polypeptide	O
and	O
two	O
additional	O
adaptor	O
subunit	O
homologs	O
named	O
mu4	O
(	O
mu	O
-	O
ARP2	O
)	O
and	O
epsilon	O
.	O

We	O
show	O
that	O
the	O
mouse	O
genome	O
contains	O
four	O
copies	O
of	O
the	O
ubc	B-GENE
-	I-GENE
9	I-GENE
gene	I-GENE
.	O

Independent	O
splicing	O
events	O
involve	O
three	O
previously	O
described	O
cassette	O
exons	O
,	O
which	O
are	O
predicted	O
to	O
encode	O
most	O
of	O
the	O
second	O
transmembrane	O
domain	O
.	O

Each	O
of	O
these	O
genes	O
contains	O
a	O
putative	O
upstream	O
ORF	O
,	O
while	O
STA2	B-GENE
has	O
two	O
additional	O
in	O
-	O
frame	O
AUG	O
codons	O
5	O
'	O
to	O
the	O
major	O
cistron	O
.	O

Primary	O
and	O
secondary	O
structural	O
elements	O
required	O
for	O
synthesis	O
of	O
barley	O
yellow	O
dwarf	O
virus	O
subgenomic	O
RNA1	O
.	O

The	O
H	O
-	O
reflex	O
recovery	O
curve	O
was	O
obtained	O
after	O
stimulation	O
of	O
the	O
median	O
nerve	O
at	O
the	O
elbow	O
and	O
recording	O
from	O
the	O
flexor	O
carpi	O
radialis	O
.	O

To	O
identify	O
additional	O
non	O
-	O
Sir	B-GENE
factors	I-GENE
that	O
affect	O
rDNA	O
silencing	O
,	O
we	O
performed	O
a	O
genetic	O
screen	O
designed	O
to	O
isolate	O
mutations	O
which	O
alter	O
the	O
expression	O
of	O
reporter	O
genes	O
integrated	O
within	O
the	O
rDNA	O
.	O

In	O
this	O
study	O
,	O
we	O
elucidate	O
signaling	O
pathways	O
induced	O
by	O
photodynamic	O
therapy	O
(	O
PDT	O
)	O
with	O
hypericin	O
.	O

These	O
results	O
indicate	O
that	O
ATF	B-GENE
-	I-GENE
2	I-GENE
plays	O
a	O
central	O
role	O
in	O
TGF	B-GENE
-	I-GENE
beta	I-GENE
signaling	O
by	O
acting	O
as	O
a	O
common	O
nuclear	O
target	O
of	O
both	O
Smad	B-GENE
and	O
TAK1	B-GENE
pathways	O
.	O

FASEB	O
Federal	O
Funding	O
Consensus	O
Conference	O
FY	O
2000	O
.	O

Analysis	O
of	O
the	O
protein	O
sequences	O
of	O
these	O
two	O
replicases	B-GENE
,	O
together	O
with	O
previously	O
characterized	O
H	B-GENE
.	I-GENE
pylori	I-GENE
plasmid	I-GENE
replication	I-GENE
proteins	I-GENE
,	O
supports	O
the	O
formation	O
of	O
a	O
distinct	O
class	O
of	O
H	B-GENE
.	I-GENE
pylori	I-GENE
plasmid	I-GENE
proteins	I-GENE
.	O

The	O
algorithm	O
also	O
limited	O
TG	O
to	O
20	O
and	O
64	O
%	O
,	O
apoB	B-GENE
to	O
6	O
and	O
20	O
%	O
,	O
and	O
Lp	B-GENE
(	I-GENE
a	I-GENE
)	I-GENE
to	O
15	O
and	O
56	O
%	O
,	O
of	O
low	O
-	O
and	O
high	O
-	O
risk	O
groups	O
,	O
respectively	O
.	O

Conformational	O
studies	O
combining	O
secondary	O
structure	O
predictions	O
,	O
CD	O
and	O
NMR	O
spectroscopy	O
together	O
with	O
ELISA	O
assays	O
,	O
showed	O
that	O
the	O
greater	O
is	O
the	O
propensity	O
of	O
the	O
epitope	O
for	O
helix	O
formation	O
the	O
higher	O
is	O
the	O
recognition	O
by	O
anti	B-GENE
-	I-GENE
K159	I-GENE
.	O

Schwab	O
and	O
England	O
ADL	O
scores	O
in	O
the	O
"	O
off	O
"	O
state	O
were	O
improved	O
by	O
18	O
%	O
and	O
in	O
the	O
"	O
on	O
"	O
state	O
the	O
scores	O
declined	O
by	O
2	O
%	O
.	O

Sequence	O
analysis	O
revealed	O
that	O
the	O
MEMA	B-GENE
protein	I-GENE
is	O
identical	O
with	O
a	O
160	B-GENE
kDa	I-GENE
nuclear	I-GENE
'	I-GENE
domain	I-GENE
rich	I-GENE
in	I-GENE
serines	I-GENE
'	I-GENE
(	I-GENE
DRS	I-GENE
)	I-GENE
protein	I-GENE
occurring	O
free	O
in	O
the	O
nucleoplasm	O
and	O
in	O
U2	B-GENE
-	I-GENE
ribonucleoprotein	I-GENE
structures	I-GENE
.	O

Dopaminergic	O
modulation	O
of	O
transcallosal	O
activity	O
of	O
cat	O
motor	O
cortical	O
neurons	O
.	O

The	O
induced	O
respiratory	O
burst	O
was	O
investigated	O
by	O
the	O
intracellular	O
oxidative	O
transformation	O
of	O
dihydrorhodamine	O
123	O
to	O
the	O
fluorescent	O
dye	O
rhodamine	O
123	O
via	O
flow	O
cytometry	O
.	O

JCAHO	O
asks	O
for	O
hospitals	O
'	O
patience	O
.	O

25	O
-	O
OH	O
-	O
D3	O
did	O
not	O
adversely	O
affect	O
animal	O
health	O
at	O
the	O
proposed	O
use	O
level	O
of	O
99	O
micrograms	O
/	O
kg	O
feed	O
when	O
replacing	O
vitamin	O
D3	O
in	O
turkey	O
rations	O
.	O

As	O
such	O
the	O
findings	O
support	O
existing	O
studies	O
that	O
have	O
identified	O
given	O
social	O
characteristics	O
of	O
drink	O
drivers	O
.	O

Analysis	O
of	O
lacZ	B-GENE
transcriptional	I-GENE
fusions	I-GENE
shows	O
that	O
the	O
KdgR	B-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
negatively	O
affect	O
the	O
expression	O
of	O
rsmB	B-GENE
.	O

In	O
the	O
cell	O
-	O
free	O
import	O
assay	O
,	O
beta	B-GENE
-	I-GENE
catenin	I-GENE
rapidly	O
migrates	O
into	O
the	O
nucleus	O
without	O
the	O
exogenous	O
addition	O
of	O
cytosol	O
,	O
Ran	B-GENE
,	O
or	O
ATP	O
/	O
GTP	O
.	O

In	O
ischemic	O
and	O
hypoxic	O
hypoxia	O
,	O
a	O
strong	O
correlation	O
was	O
found	O
between	O
cyt	O
a	O
,	O
a3	O
oxidation	O
level	O
and	O
VO2	O
in	O
both	O
ischemic	O
and	O
hypoxic	O
hypoxia	O
(	O
r2	O
=	O
.	O
90	O
and	O
.	O
87	O
,	O
respectively	O
)	O
.	O

Each	O
recombinant	O
product	O
was	O
a	O
fusion	O
protein	O
with	O
a	O
B	O
domain	O
of	O
Staphylococcal	B-GENE
protein	I-GENE
A	I-GENE
(	O
SPA	B-GENE
)	O
.	O

Polypyrimidine	O
and	O
ssDNA	O
binding	O
by	O
the	O
isolated	O
VH	B-GENE
domain	I-GENE
of	O
immunization	O
-	O
induced	O
anti	O
-	O
Z	O
-	O
DNA	O
Ab	O
resembles	O
the	O
activity	O
of	O
natural	O
autoantibodies	O
and	O
suggests	O
that	O
VH	B-GENE
-	O
dependent	O
binding	O
to	O
a	O
ligand	O
mimicked	O
by	O
polypyrimidines	O
may	O
play	O
a	O
role	O
in	O
B	O
cell	O
selection	O
before	O
immunization	O
with	O
Z	O
-	O
DNA	O
.	O

INTERVENTIONS	O
:	O
Study	O
patients	O
were	O
randomly	O
divided	O
into	O
four	O
parallel	O
groups	O
to	O
receive	O
either	O
terbinafine	O
250	O
mg	O
a	O
day	O
for	O
12	O
or	O
16	O
weeks	O
(	O
groups	O
T12	O
and	O
T16	O
)	O
or	O
itraconazole	O
400	O
mg	O
a	O
day	O
for	O
1	O
week	O
in	O
every	O
4	O
weeks	O
for	O
12	O
or	O
16	O
weeks	O
(	O
groups	O
I3	O
and	O
I4	O
)	O
.	O

Bacteria	O
can	O
also	O
cause	O
a	O
labyrinthitis	O
acting	O
directly	O
on	O
the	O
inner	O
ear	O
:	O
among	O
these	O
,	O
Treponemas	O
Pallidum	O
,	O
a	O
spirochaete	O
which	O
causes	O
syphilis	O
and	O
Borrelia	O
Burgdorferi	O
,	O
a	O
spirochaete	O
that	O
causes	O
Lyme	O
Disease	O
,	O
must	O
be	O
mentioned	O
.	O

Initial	O
control	O
of	O
bleeding	O
is	O
similar	O
,	O
but	O
eradication	O
is	O
achieved	O
in	O
fewer	O
sessions	O
with	O
EVL	O
.	O

Canalith	O
repositioning	O
is	O
the	O
mainstay	O
of	O
treatment	O
.	O

Solution	O
structure	O
and	O
mechanism	O
of	O
the	O
MutT	B-GENE
pyrophosphohydrolase	I-GENE
.	O

The	O
binding	O
of	O
PH	B-GENE
domains	I-GENE
to	O
Gbetagamma	B-GENE
was	O
inhibited	O
by	O
preincubation	O
of	O
Gbetagamma	B-GENE
with	O
the	O
GDP	O
-	O
bound	O
but	O
not	O
the	O
GTP	O
-	O
bound	O
form	O
of	O
Gialpha	B-GENE
.	O

Two	O
-	O
dimensional	O
gel	O
electrophoresis	O
of	O
anti	B-GENE
-	I-GENE
p59fyn	I-GENE
immunoprecipitates	O
obtained	O
from	O
non	O
-	O
transformed	O
resting	O
human	O
T	O
lymphocytes	O
resulted	O
in	O
the	O
identification	O
of	O
an	O
oligomeric	O
protein	O
complex	O
which	O
is	O
constitutively	O
formed	O
between	O
Fyn	B-GENE
and	O
several	O
additional	O
phosphoproteins	O
(	O
pp43	B-GENE
,	O
pp72	B-GENE
,	O
pp85	B-GENE
,	O
the	O
protein	B-GENE
tyrosine	I-GENE
kinase	I-GENE
Pyk2	B-GENE
,	O
as	O
well	O
as	O
the	O
two	O
recently	O
cloned	O
adaptor	O
proteins	O
,	O
SKAP55	B-GENE
and	O
SLAP	B-GENE
-	I-GENE
130	I-GENE
)	O
.	O

The	O
gene	O
structure	O
of	O
Elk1	B-GENE
spans	O
15	O
.	O
2	O
kb	O
and	O
consists	O
of	O
seven	O
exons	O
and	O
six	O
introns	O
.	O

Sequence	O
analysis	O
suggests	O
that	O
TtrA	B-GENE
contains	O
a	O
molybdopterin	O
guanine	O
dinucleotide	O
cofactor	O
and	O
a	O
[	O
4Fe	O
-	O
4S	O
]	O
cluster	O
,	O
that	O
TtrB	B-GENE
binds	O
four	O
[	O
4Fe	O
-	O
4S	O
]	O
clusters	O
,	O
and	O
that	O
TtrC	B-GENE
is	O
an	O
integral	O
membrane	O
protein	O
containing	O
a	O
quinol	O
oxidation	O
site	O
.	O

Previous	O
work	O
has	O
shown	O
that	O
spleen	B-GENE
necrosis	I-GENE
virus	I-GENE
(	I-GENE
SNV	I-GENE
)	I-GENE
long	I-GENE
terminal	I-GENE
repeats	I-GENE
(	O
LTRs	O
)	O
are	O
associated	O
with	O
Rex	B-GENE
/	O
Rex	B-GENE
-	O
responsive	O
element	O
-	O
independent	O
expression	O
of	O
bovine	O
leukemia	O
virus	O
RNA	O
and	O
supports	O
the	O
hypothesis	O
that	O
SNV	O
RNA	O
contains	O
a	O
cis	O
-	O
acting	O
element	O
that	O
interacts	O
with	O
cellular	B-GENE
Rex	I-GENE
-	I-GENE
like	I-GENE
proteins	I-GENE
.	O

Online	O
LATCH	O
demonstrates	O
a	O
shift	O
in	O
identification	O
of	O
the	O
library	O
as	O
an	O
isolated	O
unit	O
to	O
an	O
interactive	O
resource	O
center	O
.	O

We	O
calculated	O
differences	O
in	O
late	O
occlusion	O
rates	O
by	O
the	O
chi2	O
(	O
chi	O
-	O
square	O
)	O
test	O
,	O
and	O
found	O
these	O
differences	O
were	O
significant	O
(	O
P	O
=	O
.	O
04	O
)	O
.	O

We	O
describe	O
a	O
genetic	O
system	O
for	O
further	O
characterizing	O
the	O
role	O
of	O
the	O
extreme	O
C	O
-	O
terminus	O
of	O
the	O
beta	O
subunit	O
of	O
E	B-GENE
.	I-GENE
coli	I-GENE
RNA	I-GENE
polymerase	I-GENE
.	O

The	O
enhanced	O
binding	O
of	O
c	B-GENE
-	I-GENE
Abl	I-GENE
to	O
DNA	O
containing	O
5	O
-	O
methylcytosine	O
residues	O
may	O
result	O
from	O
an	O
increased	O
propensity	O
of	O
the	O
double	O
helix	O
to	O
denature	O
locally	O
coupled	O
with	O
a	O
protein	O
-	O
induced	O
reduction	O
in	O
the	O
base	O
stacking	O
interaction	O
.	O

We	O
further	O
demonstrate	O
that	O
the	O
Stress	B-GENE
-	I-GENE
Activated	I-GENE
-	I-GENE
Protein	I-GENE
-	I-GENE
Kinase	I-GENE
(	O
SAPK	B-GENE
)	O
target	O
sites	O
of	O
ATF2	B-GENE
,	O
Thr69	O
and	O
Thr71	O
are	O
not	O
required	O
for	O
the	O
formation	O
of	O
the	O
p300	B-GENE
/	O
CBP	B-GENE
-	O
ATF2	B-GENE
multiprotein	O
complex	O
.	O

O	B-GENE
.	I-GENE
novo	I-GENE
-	I-GENE
ulmi	I-GENE
RNA	I-GENE
-	I-GENE
7	I-GENE
,	O
previously	O
believed	O
to	O
be	O
a	O
satellite	O
-	O
like	O
RNA	O
,	O
is	O
shown	O
to	O
be	O
a	O
defective	O
RNA	O
,	O
derived	O
from	O
OnuMV4	B-GENE
-	I-GENE
Ld	I-GENE
RNA	I-GENE
by	O
multiple	O
internal	O
deletions	O
.	O

The	O
paramyxovirus	B-GENE
fusion	I-GENE
(	I-GENE
F	I-GENE
)	I-GENE
protein	I-GENE
mediates	O
membrane	O
fusion	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
show	O
that	O
SRm160	B-GENE
/	I-GENE
300	I-GENE
is	O
required	O
for	O
a	O
purine	O
-	O
rich	O
ESE	B-GENE
to	O
promote	O
the	O
splicing	O
of	O
a	O
pre	O
-	O
mRNA	O
derived	O
from	O
the	O
Drosophila	B-GENE
doublesex	I-GENE
gene	I-GENE
.	O

The	O
coefficient	O
of	O
determination	O
,	O
r2	O
,	O
of	O
the	O
other	O
scores	O
ranged	O
from	O
0	O
.	O
56	O
to	O
0	O
.	O
61	O
.	O

While	O
determination	O
of	O
the	O
protein	O
content	O
of	O
the	O
formulae	O
gave	O
no	O
valid	O
information	O
,	O
RAST	O
/	O
EAST	O
inhibition	O
was	O
highest	O
for	O
cow	O
'	O
s	O
milk	O
,	O
followed	O
by	O
the	O
partially	O
hydrolysed	O
whey	O
formula	O
,	O
partially	O
hydrolysed	O
whey	O
/	O
casein	B-GENE
formula	O
,	O
soy	B-GENE
/	I-GENE
pork	I-GENE
collagen	I-GENE
formula	O
,	O
and	O
the	O
amino	O
acid	O
formula	O
.	O

In	O
light	O
of	O
the	O
importance	O
of	O
GnRHR	B-GENE
,	O
the	O
molecular	O
mechanisms	O
underlying	O
the	O
transcriptional	O
regulation	O
of	O
the	O
human	B-GENE
GnRHR	I-GENE
(	O
hGnRHR	B-GENE
)	O
gene	O
become	O
a	O
key	O
issue	O
in	O
understanding	O
human	O
reproduction	O
.	O

Competitive	O
mobility	O
shift	O
assays	O
using	O
either	O
alphaT3	O
-	O
1	O
nuclear	O
extract	O
or	O
recombinant	B-GENE
SF	I-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
clearly	O
indicated	O
that	O
SF	B-GENE
-	I-GENE
1	I-GENE
is	O
able	O
to	O
interact	O
specifically	O
with	O
this	O
GSE	B-GENE
element	I-GENE
positioned	O
at	O
-	O
134	O
.	O

Grade	O
3	O
mucositis	O
was	O
reported	O
in	O
1	O
patient	O
.	O

In	O
a	O
heterologous	O
transcriptional	O
system	O
in	O
which	O
the	O
upstream	O
regions	O
of	O
oIFNtau	B-GENE
were	O
inserted	O
in	O
front	O
of	O
simian	B-GENE
virus	I-GENE
40	I-GENE
(	I-GENE
SV40	I-GENE
)	I-GENE
promoter	I-GENE
,	O
the	O
regions	O
between	O
bases	O
-	O
654	O
and	O
-	O
555	O
were	O
determined	O
as	O
being	O
the	O
enhancer	O
region	O
required	O
for	O
oIFNtau	B-GENE
-	O
SV40	O
-	O
CAT	B-GENE
transactivation	O
.	O

In	O
co	O
-	O
transfection	O
studies	O
,	O
the	O
expression	O
of	O
c	B-GENE
-	I-GENE
Jun	I-GENE
plus	O
c	B-GENE
-	I-GENE
Fos	I-GENE
enhanced	O
the	O
transactivation	O
of	O
oIFNtau	B-GENE
-	O
CAT	B-GENE
but	O
the	O
expression	O
of	O
GATA	B-GENE
-	I-GENE
1	I-GENE
,	O
GATA	B-GENE
-	I-GENE
2	I-GENE
or	O
GATA	B-GENE
-	I-GENE
3	I-GENE
did	O
not	O
.	O

The	O
relatively	O
mild	O
defects	O
observed	O
in	O
Rpd3	B-GENE
mutants	I-GENE
suggest	O
that	O
the	O
recently	O
identified	O
Groucho	B-GENE
and	O
dCtBP	B-GENE
corepressor	I-GENE
proteins	I-GENE
do	O
not	O
function	O
solely	O
through	O
the	O
recruitment	O
of	O
histone	B-GENE
deacetylases	I-GENE
.	O

Both	O
carbachol	O
(	O
100	O
microM	O
)	O
and	O
EGF	B-GENE
(	O
10	O
nM	O
)	O
induced	O
Ras	B-GENE
activation	O
.	O

Dominant	O
negative	O
Sos	B-GENE
did	O
not	O
affect	O
carbachol	O
stimulation	O
of	O
HA	B-GENE
-	O
ERK2	B-GENE
but	O
inhibited	O
the	O
stimulatory	O
effect	O
of	O
EGF	B-GENE
by	O
60	O
%	O
.	O

Hrs	B-GENE
has	O
a	O
FYVE	O
double	O
zinc	O
finger	O
domain	O
,	O
which	O
specifically	O
binds	O
phosphatidylinositol	O
(	O
3	O
)	O
-	O
phosphate	O
and	O
is	O
conserved	O
in	O
several	O
proteins	O
involved	O
in	O
vesicular	O
traffic	O
.	O

Three	O
subgenomes	O
also	O
comprised	O
15	O
to	O
75	O
nucleotides	O
derived	O
from	O
the	O
5	O
'	O
part	O
of	O
the	O
NS2	B-GENE
gene	I-GENE
.	O

The	O
hybrid	O
viruses	O
were	O
found	O
to	O
accumulate	O
to	O
high	O
levels	O
in	O
infected	O
plants	O
,	O
to	O
form	O
stable	O
virions	O
,	O
and	O
to	O
be	O
mechanically	O
transmissible	O
.	O

Nevertheless	O
cryopreservation	O
of	O
spermatozoa	O
in	O
a	O
medium	O
containing	O
neither	O
SP	O
nor	O
biological	O
substances	O
could	O
offer	O
an	O
acceptable	O
cryoprotection	O
of	O
spermatozoa	O
to	O
be	O
used	O
in	O
assisted	O
fertilization	O
procedures	O
,	O
especially	O
for	O
intracytoplasmic	O
sperm	O
injection	O
.	O

EMSA	O
with	O
crude	O
nuclear	O
extracts	O
demonstrated	O
that	O
stimulation	O
with	O
CD40L	B-GENE
results	O
in	O
the	O
induction	O
of	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
complexes	I-GENE
that	O
bind	O
to	O
each	O
of	O
the	O
three	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
sites	I-GENE
and	O
are	O
composed	O
mainly	O
of	O
p50	B-GENE
and	O
RelB	B-GENE
,	O
but	O
also	O
include	O
c	B-GENE
-	I-GENE
Rel	I-GENE
and	O
p65	B-GENE
.	O

The	O
major	O
transcription	O
factors	O
controlling	O
arginine	O
metabolism	O
in	O
Escherichia	O
coli	O
and	O
Bacillus	O
subtilis	O
,	O
ArgR	B-GENE
and	O
AhrC	B-GENE
,	O
respectively	O
,	O
are	O
homologous	O
multimeric	O
proteins	O
that	O
form	O
l	O
-	O
arginine	O
-	O
dependent	O
DNA	O
-	O
binding	O
complexes	O
capable	O
of	O
repressing	O
transcription	O
of	O
the	O
biosynthetic	O
genes	O
(	O
both	O
)	O
,	O
activating	O
transcription	O
of	O
catabolic	O
genes	O
(	O
AhrC	B-GENE
only	O
)	O
or	O
facilitating	O
plasmid	O
dimer	O
resolution	O
(	O
both	O
)	O
.	O

The	O
studied	O
protein	O
fragments	O
consist	O
of	O
residues	O
Arg183	O
-	O
His267	O
of	O
the	O
human	B-GENE
ER	I-GENE
and	O
residues	O
Lys438	O
-	O
Gln520	O
of	O
the	O
rat	O
GR	B-GENE
.	O

CONCLUSIONS	O
:	O
Turbutest	O
is	O
a	O
valuable	O
tool	O
in	O
asthmatic	O
patients	O
'	O
training	O
,	O
allowing	O
identification	O
and	O
improvement	O
of	O
an	O
inadequate	O
inhalation	O
technique	O
with	O
Turbuhaler	O
.	O

The	O
potency	O
of	O
the	O
effect	O
of	O
Nim	O
(	O
0	O
.	O
5	O
mg	O
.	O
kg	O
-	O
1	O
i	O
.	O
p	O
.	O
)	O
was	O
similar	O
to	O
that	O
of	O
NBP	O
(	O
10	O
mg	O
.	O
kg	O
-	O
1	O
i	O
.	O
p	O
.	O
)	O
.	O

CONCLUSION	O
:	O
NBP	O
pre	O
-	O
treatment	O
or	O
post	O
-	O
treatment	O
markedly	O
enhanced	O
the	O
rCBF	O
to	O
striatum	O
in	O
RMCAO	O
rats	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
investigate	O
the	O
spontaneous	O
reports	O
of	O
suspected	O
adverse	O
drug	O
reactions	O
,	O
observed	O
in	O
elderly	O
patients	O
(	O
over	O
65	O
years	O
of	O
age	O
)	O
in	O
Sicily	O
(	O
Italy	O
)	O
during	O
the	O
period	O
from	O
1	O
January	O
1995	O
to	O
31	O
December	O
1997	O
.	O

The	O
high	B-GENE
density	I-GENE
lipoprotein	I-GENE
(	I-GENE
HDL	I-GENE
)	I-GENE
receptor	I-GENE
mediates	O
the	O
uptake	O
of	O
cholesterol	O
and	O
cholesteryl	O
esters	O
,	O
substrates	O
for	O
steroidogenesis	O
,	O
from	O
an	O
HDL	B-GENE
particle	O
in	O
the	O
adrenal	O
gland	O
and	O
gonads	O
.	O

Ozagrel	O
,	O
ifenprodil	O
,	O
cinnarizine	O
and	O
dilazep	O
were	O
more	O
effective	O
than	O
pentoxifylline	O
in	O
increasing	O
rCBF	O
at	O
the	O
HPC	O
.	O

Using	O
sequence	O
information	O
from	O
human	B-GENE
BMAL1	I-GENE
(	O
hBMAL1	B-GENE
)	O
cDNAs	O
previously	O
reported	O
by	O
our	O
laboratory	O
,	O
we	O
have	O
isolated	O
and	O
characterized	O
cDNAs	O
encoding	O
three	O
splice	O
variants	O
of	O
the	O
mouse	B-GENE
BMAL1	I-GENE
(	O
mBMAL1	B-GENE
)	O
gene	O
.	O

Comparison	O
with	O
the	O
bHLH	B-GENE
/	O
PAS	B-GENE
family	O
genes	O
revealed	O
that	O
the	O
intron	O
/	O
exon	O
splice	O
pattern	O
of	O
mBMAL1	B-GENE
most	O
closely	O
matches	O
that	O
of	O
the	O
mAhr	B-GENE
,	O
which	O
suggests	O
that	O
BMAL1	B-GENE
and	O
Ahr	B-GENE
belong	O
to	O
the	O
same	O
subclass	O
and	O
may	O
be	O
derived	O
from	O
a	O
common	O
primordial	O
gene	O
.	O

We	O
were	O
able	O
to	O
detect	O
significant	O
differences	O
in	O
functional	O
residual	O
capacity	O
adjusted	O
for	O
weight	O
or	O
height	O
,	O
and	O
compliance	O
of	O
the	O
respiratory	O
system	O
adjusted	O
for	O
weight	O
or	O
lung	O
volume	O
in	O
the	O
ILD	O
infants	O
compared	O
to	O
the	O
healthy	O
controls	O
or	O
infants	O
who	O
had	O
PPHN	O
,	O
indicating	O
that	O
these	O
PFTs	O
were	O
sensitive	O
enough	O
to	O
determine	O
abnormal	O
lung	O
function	O
in	O
this	O
age	O
group	O
.	O

Classical	O
ligand	O
-	O
activated	O
nuclear	O
receptors	O
(	O
e	O
.	O
g	O
.	O
thyroid	B-GENE
hormone	I-GENE
receptor	I-GENE
,	O
retinoic	B-GENE
acid	I-GENE
receptor	I-GENE
)	O
,	O
orphan	B-GENE
nuclear	I-GENE
receptors	I-GENE
(	O
e	O
.	O
g	O
.	O

We	O
have	O
shown	O
previously	O
that	O
in	O
contrast	O
to	O
other	O
extracellular	O
matrix	O
molecules	O
pepsin	B-GENE
-	O
solubilized	O
collagen	B-GENE
VI	I-GENE
(	O
CVI	B-GENE
)	O
can	O
stimulate	O
DNA	O
synthesis	O
of	O
various	O
mesenchymal	O
cell	O
types	O
,	O
apparently	O
independent	O
of	O
integrin	B-GENE
-	O
mediated	O
signal	O
transduction	O
.	O

The	O
enzyme	O
displays	O
optimal	O
activity	O
at	O
about	O
0	O
.	O
5	O
mM	O
pantoate	O
(	O
k	O
(	O
cat	O
)	O
0	O
.	O
63	O
s	O
(	O
-	O
1	O
)	O
)	O
and	O
at	O
pH	O
7	O
.	O
8	O
.	O

Taken	O
together	O
,	O
these	O
results	O
demonstrate	O
that	O
the	O
RP	B-GENE
,	O
like	O
the	O
20S	B-GENE
proteasome	I-GENE
,	O
is	O
functionally	O
and	O
structurally	O
conserved	O
among	O
eukaryotes	O
and	O
indicate	O
that	O
the	O
plant	B-GENE
RPT	I-GENE
subunits	I-GENE
,	O
like	O
their	O
yeast	O
counterparts	O
,	O
have	O
non	O
-	O
redundant	O
functions	O
.	O

Structure	O
and	O
expression	O
of	O
the	O
mouse	B-GENE
growth	I-GENE
hormone	I-GENE
receptor	I-GENE
/	O
growth	B-GENE
hormone	I-GENE
binding	I-GENE
protein	I-GENE
gene	I-GENE
.	O

Repair	O
of	O
double	O
-	O
strand	O
breaks	O
(	O
DSBs	O
)	O
in	O
chromosomal	O
DNA	O
by	O
nonhomologous	O
end	O
-	O
joining	O
(	O
NHEJ	O
)	O
is	O
not	O
well	O
characterized	O
in	O
the	O
yeast	O
Saccharomyces	O
cerevisiae	O
.	O

Thus	O
,	O
elongin	B-GENE
C	I-GENE
is	O
found	O
to	O
oligomerize	O
in	O
solution	O
and	O
to	O
undergo	O
significant	O
structural	O
rearrangements	O
upon	O
binding	O
of	O
two	O
different	O
partner	O
proteins	O
.	O

Gel	O
filtration	O
and	O
co	O
-	O
immunoprecipitation	O
analyses	O
reveal	O
that	O
Mad2p	B-GENE
tightly	O
associates	O
with	O
another	O
spindle	O
checkpoint	O
component	O
,	O
Mad1p	B-GENE
.	O

John	O
leonard	O
dawson	O

Microcirculatory	O
oxygenation	O
and	O
shunting	O
in	O
sepsis	O
and	O
shock	O
.	O

The	O
present	O
investigation	O
conducted	O
in	O
a	O
population	O
of	O
258	O
dentally	O
aware	O
individuals	O
in	O
the	O
age	O
range	O
20	O
-	O
69	O
years	O
,	O
was	O
initiated	O
to	O
elucidate	O
the	O
relationship	O
between	O
tobacco	O
smoking	O
and	O
supragingival	O
calculus	O
,	O
taking	O
into	O
account	O
possible	O
confounding	O
factors	O
such	O
as	O
age	O
,	O
gender	O
,	O
oral	O
hygiene	O
and	O
gingival	O
inflammation	O
.	O

Interaction	O
of	O
HRI	B-GENE
with	O
Hsc70	B-GENE
was	O
required	O
for	O
the	O
transformation	O
of	O
HRI	B-GENE
,	O
as	O
the	O
Hsc70	B-GENE
antagonist	O
clofibric	O
acid	O
inhibited	O
the	O
folding	O
of	O
HRI	B-GENE
into	O
a	O
mature	O
-	O
competent	O
conformation	O
.	O

In	O
the	O
budding	O
yeast	O
,	O
Saccharomyces	O
cerevisiae	O
,	O
replicators	O
can	O
function	O
outside	O
the	O
chromosome	O
as	O
autonomously	O
replicating	O
sequence	O
(	O
ARS	O
)	O
elements	O
;	O
however	O
,	O
within	O
chromosome	O
III	O
,	O
certain	O
ARSs	O
near	O
the	O
transcriptionally	O
silent	O
HML	B-GENE
locus	I-GENE
show	O
no	O
replication	O
origin	O
activity	O
.	O

These	O
results	O
suggest	O
that	O
,	O
for	O
the	O
HML	B-GENE
ARS	O
cluster	O
(	O
ARS303	B-GENE
,	O
ARS320	B-GENE
,	O
and	O
ARS302	B-GENE
)	O
,	O
inactivity	O
of	O
origins	O
is	O
independent	O
of	O
local	O
transcriptional	O
silencing	O
,	O
even	O
though	O
origins	O
and	O
silencers	O
share	O
key	O
cis	O
-	O
and	O
trans	O
-	O
acting	O
components	O
.	O

We	O
report	O
the	O
construction	O
of	O
an	O
approximately	O
1	O
.	O
7	O
-	O
Mb	O
sequence	O
-	O
ready	O
YAC	O
/	O
BAC	O
clone	O
contig	O
of	O
8p22	O
-	O
p23	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

ECG	O
-	O
gated	O
myocardial	O
Technetium	O
-	O
99m	O
sestamibi	O
SPECT	O
is	O
a	O
useful	O
technique	O
to	O
measure	O
myocardial	O
perfusion	O
and	O
function	O
simultaneously	O
.	O

The	O
controversy	O
of	O
significance	O
testing	O
:	O
misconceptions	O
and	O
alternatives	O
.	O

The	O
arrangement	O
of	O
these	O
cutoff	O
-	O
levels	O
leads	O
to	O
a	O
sensitivity	O
of	O
85	O
%	O
at	O
a	O
specificity	O
of	O
55	O
%	O
for	O
Protein	B-GENE
S100	I-GENE
when	O
measured	O
by	O
RIA	O
,	O
and	O
to	O
a	O
sensitivity	O
of	O
77	O
%	O
at	O
a	O
specificity	O
of	O
61	O
%	O
when	O
measured	O
by	O
LIA	O
.	O

Null	O
alleles	O
of	O
SAS4	B-GENE
and	O
SAS5	B-GENE
bypassed	O
the	O
role	O
of	O
the	O
Abf1p	B-GENE
binding	I-GENE
site	I-GENE
of	O
the	O
HMR	B-GENE
-	I-GENE
E	I-GENE
silencer	I-GENE
but	O
not	O
the	O
role	O
of	O
the	O
ACS	B-GENE
or	O
Rap1p	B-GENE
binding	I-GENE
site	I-GENE
.	O

RESULTS	O
:	O
256	O
Periods	O
of	O
TTP	O
or	O
PUNP	O
were	O
reported	O
by	O
men	O
and	O
174	O
by	O
women	O
.	O

Cytokine	O
-	O
induced	O
NF	B-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
DNA	O
binding	O
activity	O
,	O
RelA	B-GENE
nuclear	O
translocation	O
,	O
I	B-GENE
kappa	I-GENE
B	I-GENE
alpha	I-GENE
degradation	O
,	O
I	B-GENE
kappa	I-GENE
B	I-GENE
serine	O
32	O
phosphorylation	O
,	O
and	O
I	B-GENE
kappa	I-GENE
B	I-GENE
kinase	I-GENE
(	O
IKK	B-GENE
)	O
activity	O
were	O
blocked	O
by	O
curcumin	O
treatment	O
.	O

To	O
estimate	O
the	O
locations	O
of	O
sources	O
with	O
the	O
TF	O
-	O
MUSIC	O
algorithm	O
,	O
we	O
first	O
set	O
the	O
target	O
region	O
on	O
the	O
spectrogram	O
of	O
the	O
somatosensory	O
responses	O
.	O

Immunohistochemical	O
staining	O
with	O
MIB	B-GENE
-	I-GENE
1	I-GENE
and	O
p53	B-GENE
antibodies	I-GENE
showed	O
low	O
(	O
<	O
1	O
%	O
)	O
and	O
negative	O
reaction	O
.	O

Two	O
patients	O
with	O
recurrent	O
tumors	O
had	O
high	O
S	O
-	O
phase	O
fractions	O
both	O
on	O
the	O
first	O
resected	O
specimens	O
and	O
at	O
the	O
time	O
of	O
the	O
second	O
operation	O
.	O

Treatment	O
of	O
unstable	O
angina	O
:	O
role	O
of	O
antithrombotic	O
therapy	O
.	O

Mutations	O
of	O
the	O
RET	B-GENE
gene	I-GENE
,	O
encoding	O
a	O
receptor	B-GENE
tyrosine	I-GENE
kinase	I-GENE
,	O
have	O
been	O
associated	O
with	O
the	O
inherited	O
cancer	O
syndromes	O
MEN	O
2A	O
and	O
MEN	O
2B	O
.	O

Protein	B-GENE
kinase	I-GENE
A	I-GENE
-	I-GENE
Ialpha	I-GENE
subunit	O
-	O
directed	O
antisense	O
inhibition	O
of	O
ovarian	O
cancer	O
cell	O
growth	O
:	O
crosstalk	O
with	O
tyrosine	B-GENE
kinase	I-GENE
signaling	O
pathway	O
.	O

During	O
both	O
encephalopathy	O
episodes	O
,	O
CSF	O
protein	O
and	O
immunoglobulin	B-GENE
G	I-GENE
(	O
IgG	B-GENE
)	O
levels	O
were	O
elevated	O
without	O
an	O
increased	O
IgG	B-GENE
index	O
or	O
IgG	B-GENE
synthesis	O
rate	O
.	O

SCOB	O
testing	O
of	O
food	O
-	O
restricted	O
animals	O
,	O
using	O
a	O
multiple	O
fixed	O
ratio	O
(	O
FR	O
)	O
/	O
fixed	O
interval	O
(	O
FI	O
)	O
schedule	O
(	O
FR20	O
:	O
FI120	O
)	O
,	O
was	O
conducted	O
prior	O
to	O
each	O
exposure	O
to	O
maintain	O
the	O
operant	O
behavior	O
;	O
the	O
data	O
from	O
Weeks	O
-	O
1	O
,	O
4	O
,	O
8	O
,	O
and	O
13	O
were	O
evaluated	O
for	O
evidence	O
of	O
neurotoxicity	O
.	O

Differential	O
expression	O
was	O
confirmed	O
by	O
Northern	O
blot	O
analysis	O
employing	O
multiple	O
normal	O
and	O
tumor	O
cell	O
lines	O
.	O

Several	O
genes	O
or	O
transcriptional	O
units	O
were	O
identified	O
,	O
including	O
the	O
3	O
'	O
end	O
of	O
ribosomal	B-GENE
s6	I-GENE
kinase	I-GENE
(	O
Rsk3	B-GENE
)	O
;	O
two	O
apparently	O
intronless	O
and	O
ORF	O
-	O
less	O
genes	O
;	O
and	O
Gpr31	B-GENE
,	O
an	O
intronless	O
,	O
putative	O
G	B-GENE
-	I-GENE
protein	I-GENE
coupled	I-GENE
receptor	I-GENE
.	O

The	O
results	O
suggest	O
that	O
GATA	B-GENE
-	I-GENE
5	I-GENE
may	O
have	O
specific	O
downstream	O
targets	O
and	O
that	O
GATA	B-GENE
-	I-GENE
4	I-GENE
,	I-GENE
-	I-GENE
5	I-GENE
,	I-GENE
and	I-GENE
-	I-GENE
6	I-GENE
can	O
only	O
partially	O
substitute	O
for	O
each	O
other	O
in	O
cardiogenesis	O
.	O

This	O
study	O
was	O
designed	O
to	O
compare	O
the	O
efficacy	O
of	O
efegatran	O
plus	O
streptokinase	B-GENE
versus	O
heparin	O
plus	O
accelerated	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
(	O
TPA	B-GENE
)	O
in	O
coronary	O
reperfusion	O
in	O
acute	O
MI	O
.	O

From	O
February	O
1991	O
to	O
August	O
1997	O
,	O
124	O
patients	O
with	O
endometrial	O
carcinoma	O
were	O
treated	O
postoperatively	O
with	O
high	O
-	O
dose	O
-	O
rate	O
vaginal	O
vault	O
brachytherapy	O
as	O
the	O
only	O
adjuvant	O
treatment	O
.	O

Twelve	O
patients	O
had	O
stage	O
IBG3	O
,	O
14	O
had	O
ICG1	O
,	O
9	O
had	O
ICG2	O
,	O
and	O
3	O
had	O
ICG3	O
disease	O
.	O

For	O
EPV	O
3	O
,	O
10	O
,	O
or	O
40	O
,	O
the	O
bias	O
exceeded	O
25	O
%	O
for	O
7	O
,	O
3	O
,	O
and	O
1	O
in	O
the	O
8	O
-	O
predictor	O
model	O
respectively	O
,	O
when	O
a	O
conventional	O
selection	O
criterion	O
was	O
used	O
(	O
alpha	O
=	O
0	O
.	O
05	O
)	O
.	O

Me	O
(	O
2	O
)	O
SO	O
-	O
induced	O
neuronal	O
differentiation	O
of	O
N1E	O
-	O
115	O
neuroblastoma	O
cells	O
increased	O
both	O
the	O
expression	O
of	O
the	O
endogenous	B-GENE
Ntr	I-GENE
-	I-GENE
1	I-GENE
gene	I-GENE
and	O
reporter	O
genes	O
driven	O
by	O
NTR	B-GENE
-	I-GENE
1	I-GENE
promoter	I-GENE
sequences	I-GENE
by	O
3	O
-	O
4	O
-	O
fold	O
.	O

Although	O
the	O
Src	B-GENE
tyrosine	I-GENE
kinase	I-GENE
induces	O
constitutive	O
Stat3	B-GENE
phosphorylation	O
on	O
tyrosine	O
,	O
activation	O
of	O
Stat3	B-GENE
-	O
mediated	O
gene	O
regulation	O
requires	O
both	O
tyrosine	O
and	O
serine	O
phosphorylation	O
of	O
Stat3	B-GENE
.	O

RESULTS	O
:	O
Factors	O
associated	O
with	O
significantly	O
(	O
P	O
<	O
.	O
05	O
)	O
increased	O
risk	O
of	O
treatment	O
failure	O
in	O
a	O
Cox	O
multivariate	O
analysis	O
included	O
age	O
older	O
than	O
45	O
years	O
(	O
relative	O
hazard	O
,	O
1	O
.	O
17	O
;	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
,	O
1	O
.	O
02	O
-	O
1	O
.	O
33	O
)	O
,	O
Karnofsky	O
performance	O
score	O
less	O
than	O
90	O
%	O
(	O
1	O
.	O
27	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
07	O
-	O
1	O
.	O
51	O
)	O
,	O
absence	O
of	O
hormone	O
receptors	O
(	O
1	O
.	O
31	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
15	O
-	O
1	O
.	O
51	O
)	O
,	O
prior	O
use	O
of	O
adjuvant	O
chemotherapy	O
(	O
1	O
.	O
31	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
10	O
-	O
1	O
.	O
56	O
)	O
,	O
initial	O
disease	O
-	O
free	O
survival	O
interval	O
after	O
adjuvant	O
treatment	O
of	O
no	O
more	O
than	O
18	O
months	O
(	O
1	O
.	O
99	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
62	O
-	O
2	O
.	O
43	O
)	O
,	O
metastases	O
in	O
the	O
liver	O
(	O
1	O
.	O
47	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
20	O
-	O
1	O
.	O
80	O
)	O
or	O
central	O
nervous	O
system	O
(	O
1	O
.	O
56	O
;	O
95	O
%	O
CI	O
,	O
0	O
.	O
99	O
-	O
2	O
.	O
46	O
[	O
approaches	O
significance	O
]	O
)	O
vs	O
soft	O
tissue	O
,	O
bone	O
,	O
or	O
lung	O
,	O
3	O
or	O
more	O
sites	O
of	O
metastatic	O
disease	O
(	O
1	O
.	O
32	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
13	O
-	O
1	O
.	O
54	O
)	O
,	O
and	O
incomplete	O
response	O
vs	O
complete	O
response	O
to	O
standard	O
-	O
dose	O
chemotherapy	O
(	O
1	O
.	O
65	O
;	O
95	O
%	O
CI	O
,	O
1	O
.	O
36	O
-	O
1	O
.	O
99	O
)	O
.	O

The	O
proteasome	O
is	O
a	O
large	O
complex	O
consisting	O
of	O
two	O
multisubunit	O
structures	O
,	O
the	O
20S	B-GENE
and	O
19S	B-GENE
(	O
PA700	B-GENE
)	O
or	O
P28	B-GENE
complexes	I-GENE
,	O
that	O
combine	O
to	O
form	O
the	O
26S	B-GENE
particles	I-GENE
.	O

We	O
have	O
cloned	O
cDNA	O
and	O
genomic	O
DNA	O
for	O
a	O
mouse	O
gene	O
encoding	O
a	O
protein	O
with	O
significant	O
sequence	O
similarity	O
to	O
conserved	O
domains	O
found	O
in	O
proteins	O
of	O
the	O
Spo11p	B-GENE
family	I-GENE
.	O

RT	O
-	O
PCR	O
and	O
in	O
situ	O
hybridization	O
analyses	O
of	O
a	O
time	O
course	O
of	O
juvenile	O
testis	O
development	O
indicate	O
that	O
Spo11	B-GENE
expression	O
begins	O
in	O
early	O
meiotic	O
Prophase	O
I	O
,	O
prior	O
to	O
the	O
pachytene	O
stage	O
,	O
with	O
increasing	O
accumulation	O
of	O
mRNA	O
through	O
the	O
pachytene	O
stage	O
.	O

Animals	O
were	O
put	O
to	O
death	O
8	O
weeks	O
later	O
and	O
the	O
grafts	O
were	O
sterilely	O
explanted	O
and	O
analyzed	O
via	O
microbiologic	O
culture	O
and	O
standard	O
histologic	O
procedures	O
for	O
evidence	O
of	O
infection	O
.	O

Oseltamivir	O
(	O
GS4104	O
)	O
,	O
which	O
can	O
be	O
administered	O
orally	O
,	O
is	O
the	O
prodrug	O
of	O
GS4071	O
,	O
a	O
potent	O
and	O
selective	O
inhibitor	O
of	O
influenzavirus	B-GENE
neuraminidases	I-GENE
.	O

We	O
also	O
show	O
that	O
activation	O
of	O
protein	B-GENE
kinase	I-GENE
A	I-GENE
(	O
PKA	B-GENE
)	O
signaling	O
is	O
sufficient	O
to	O
down	O
-	O
regulate	O
caveolin	B-GENE
-	I-GENE
1	I-GENE
protein	I-GENE
expression	O
and	O
promoter	O
activity	O
.	O

Phosphatidylinositol	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
requirement	O
in	O
activation	O
of	O
the	O
ras	B-GENE
/	O
C	B-GENE
-	I-GENE
raf	I-GENE
-	I-GENE
1	I-GENE
/	O
MEK	B-GENE
/	O
ERK	B-GENE
and	O
p70	B-GENE
(	O
s6k	B-GENE
)	O
signaling	O
cascade	O
by	O
the	O
insulinomimetic	O
agent	O
vanadyl	O
sulfate	O
.	O

For	O
example	O
,	O
introduction	O
of	O
immunogenic	O
and	O
purification	O
tag	O
sequences	O
into	O
the	O
C	O
-	O
terminal	O
coding	O
region	O
significantly	O
decreased	O
bop	B-GENE
gene	I-GENE
mRNA	I-GENE
and	O
protein	O
accumulation	O
.	O

We	O
recommend	O
that	O
paracervical	O
block	O
with	O
lignocaine	O
should	O
be	O
used	O
in	O
conjunction	O
with	O
i	O
.	O
v	O
.	O
sedation	O
/	O
analgesia	O
during	O
egg	O
collection	O
performed	O
through	O
the	O
transvaginal	O
route	O
under	O
ultrasound	O
guidance	O
(	O
TUGOR	O
)	O
to	O
reduce	O
the	O
pain	O
of	O
the	O
procedure	O
.	O

This	O
report	O
describes	O
a	O
patient	O
with	O
a	O
previous	O
inferior	O
acute	O
myocardial	O
infarction	O
who	O
developed	O
right	O
ventricular	O
infarction	O
with	O
significant	O
anterior	O
lead	O
ST	O
segment	O
elevation	O
(	O
V1	O
-	O
V4	O
)	O
caused	O
by	O
the	O
loss	O
of	O
two	O
large	O
right	O
ventricular	O
branches	O
during	O
a	O
coronary	O
angioplasty	O
of	O
the	O
right	O
coronary	O
artery	O
.	O

PURPOSE	O
:	O
Previous	O
WR	O
-	O
2721	O
human	O
pharmacokinetic	O
studies	O
were	O
limited	O
to	O
plasma	O
levels	O
in	O
patients	O
receiving	O
platinum	O
-	O
based	O
compounds	O
,	O
and	O
none	O
includes	O
the	O
effects	O
of	O
WR	O
-	O
2721	O
on	O
endogenous	O
thiols	O
.	O

CONCLUSIONS	O
:	O
In	O
addition	O
to	O
the	O
superiority	O
of	O
octafluoropropane	O
-	O
filled	O
microspheres	O
to	O
air	O
-	O
filled	O
microspheres	O
for	O
LV	O
opacification	O
,	O
the	O
efficacy	O
of	O
OCTA	O
is	O
relatively	O
unaffected	O
by	O
impaired	O
LV	O
function	O
and	O
is	O
less	O
susceptible	O
to	O
the	O
effects	O
of	O
poor	O
echogenicity	O
than	O
AIR	O
.	O

These	O
kinases	O
belong	O
to	O
a	O
new	O
subfamily	O
related	O
to	O
the	O
Trk	B-GENE
subfamily	I-GENE
.	O

The	O
data	O
indicate	O
that	O
etr	B-GENE
-	I-GENE
1	I-GENE
is	O
essential	O
for	O
muscle	O
development	O
in	O
C	O
.	O
elegans	O
,	O
perhaps	O
by	O
playing	O
a	O
role	O
in	O
post	O
-	O
transcriptional	O
processing	O
of	O
some	O
muscle	O
component	O
,	O
and	O
thus	O
suggesting	O
a	O
possible	O
conservation	O
of	O
gene	O
function	O
with	O
human	B-GENE
CUG	I-GENE
-	I-GENE
bp	I-GENE
.	O

Detection	O
of	O
poisoning	O
by	O
Impila	O
(	O
Callilepis	O
laureola	O
)	O
in	O
a	O
mother	O
and	O
child	O
.	O

In	O
HCMV	O
(	O
Towne	O
)	O
-	O
infected	O
HF	O
cells	O
at	O
24	O
to	O
48	O
h	O
,	O
IE2	B-GENE
also	O
accumulated	O
in	O
newly	O
formed	O
viral	O
DNA	O
replication	O
compartments	O
containing	O
the	O
polymerase	B-GENE
processivity	I-GENE
factor	I-GENE
(	O
UL44	B-GENE
)	O
,	O
the	O
single	B-GENE
-	I-GENE
stranded	I-GENE
DNA	I-GENE
binding	I-GENE
protein	I-GENE
(	O
SSB	B-GENE
;	O
UL57	B-GENE
)	O
,	O
the	O
UL112	B-GENE
-	I-GENE
113	I-GENE
accessory	I-GENE
protein	I-GENE
,	O
and	O
newly	O
incorporated	O
bromodeoxyuridine	O
(	O
BrdU	O
)	O
.	O

Macroscopic	O
researches	O
on	O
heart	O
vascularization	O
have	O
indicated	O
that	O
the	O
angioarchitecture	O
of	O
the	O
conducting	O
system	O
differs	O
from	O
that	O
of	O
the	O
normal	O
myocardium	O
.	O

However	O
,	O
reoperation	O
for	O
bulky	O
cervical	O
disease	O
(	O
group	O
3	O
)	O
rarely	O
results	O
in	O
normal	O
calcitonin	B-GENE
levels	O
and	O
is	O
associated	O
with	O
a	O
high	O
incidence	O
of	O
permanent	O
hypoparathyroidism	O
.	O

We	O
present	O
a	O
case	O
of	O
carcinoma	O
of	O
the	O
breast	O
presenting	O
concurrently	O
with	O
SSc	O
that	O
subsequently	O
progressed	O
to	O
dialysis	O
-	O
dependent	O
renal	O
failure	O
in	O
just	O
1	O
month	O
.	O

The	O
GPI	O
anchor	O
moiety	O
is	O
either	O
absent	O
or	O
present	O
at	O
a	O
very	O
low	O
level	O
in	O
the	O
polypeptide	O
expressed	O
from	O
the	O
cDNA	O
that	O
contained	O
both	O
the	O
signal	O
peptide	O
and	O
GPI	O
signal	O
sequences	O
.	O

They	O
self	O
-	O
completed	O
the	O
SF	O
-	O
36	O
questionnaire	O
and	O
their	O
QoL	O
was	O
described	O
and	O
retrospectively	O
compared	O
to	O
that	O
of	O
historical	O
controls	O
.	O

There	O
was	O
a	O
trend	O
toward	O
an	O
association	O
between	O
IENF	O
and	O
sural	O
nerve	O
unmyelinated	O
fiber	O
densities	O
(	O
r	O
=	O
0	O
.	O
32	O
,	O
p	O
=	O
0	O
.	O
054	O
)	O
.	O

FISH	O
using	O
a	O
whole	O
chromosome	O
4	O
paint	O
demonstrated	O
multiple	O
rearrangements	O
involving	O
chromosome	O
4	O
in	O
MCF	O
-	O
7	O
AdVp3000	O
and	O
MCF	O
-	O
7	O
MX	O
,	O
while	O
S1	O
-	O
M1	O
-	O
80	O
contained	O
only	O
a	O
simple	O
reciprocal	O
translocation	O
.	O

The	O
MXR	B-GENE
gene	I-GENE
encodes	O
a	O
half	O
-	O
transporter	O
and	O
the	O
absence	O
of	O
cytogenetic	O
evidence	O
of	O
coamplification	O
of	O
other	O
regions	O
suggests	O
that	O
a	O
partner	O
may	O
not	O
be	O
overexpressed	O
,	O
and	O
instead	O
the	O
MXR	B-GENE
half	I-GENE
-	I-GENE
transporter	I-GENE
homodimerizes	O
to	O
mediate	O
drug	O
transport	O
.	O

Serum	B-GENE
insulin	I-GENE
-	I-GENE
like	I-GENE
growth	I-GENE
factor	I-GENE
I	I-GENE
(	O
IGF	B-GENE
-	I-GENE
I	I-GENE
)	O
SD	O
score	O
increased	O
from	O
-	O
2	O
.	O
2	O
and	O
-	O
4	O
.	O
2	O
in	O
men	O
and	O
women	O
,	O
respectively	O
,	O
to	O
1	O
.	O
8	O
and	O
-	O
0	O
.	O
9	O
at	O
6	O
months	O
and	O
0	O
.	O
8	O
and	O
-	O
0	O
.	O
7	O
at	O
12	O
months	O
.	O

The	O
level	O
of	O
serum	B-GENE
creatine	I-GENE
kinase	I-GENE
was	O
significantly	O
high	O
2	O
days	O
after	O
ESWIB	O
,	O
but	O
it	O
recovered	O
in	O
a	O
week	O
.	O

Several	O
7SL	B-GENE
RNA	I-GENE
-	I-GENE
encoding	I-GENE
sequences	I-GENE
and	O
various	O
intergenic	O
spacers	O
were	O
amplified	O
from	O
the	O
individual	O
HindIII	B-GENE
fragments	I-GENE
of	O
about	O
1	O
.	O
3	O
and	O
2	O
.	O
8	O
kb	O
.	O

Analysis	O
of	O
its	O
genomic	O
region	O
revealed	O
that	O
the	O
13	O
-	O
kb	O
Cdc6	B-GENE
gene	I-GENE
is	O
divided	O
into	O
12	O
exons	O
by	O
11	O
introns	O
.	O

Phosphorylation	O
of	O
myosin	B-GENE
-	I-GENE
binding	I-GENE
subunit	I-GENE
(	O
MBS	B-GENE
)	O
of	O
myosin	B-GENE
phosphatase	I-GENE
by	O
Rho	B-GENE
-	I-GENE
kinase	I-GENE
in	O
vivo	O
.	O

Because	O
the	O
Pit	B-GENE
-	I-GENE
1	I-GENE
sites	I-GENE
in	O
the	O
hGH	B-GENE
-	I-GENE
N	I-GENE
gene	I-GENE
promoter	I-GENE
are	O
insufficient	O
for	O
such	O
gene	O
activation	O
in	O
vivo	O
,	O
these	O
data	O
suggested	O
a	O
unique	O
chromatin	O
-	O
mediated	O
developmental	O
role	O
for	O
Pit	B-GENE
-	I-GENE
1	I-GENE
in	O
the	O
hGH	B-GENE
LCR	I-GENE
.	O

Recombinant	B-GENE
prenylcysteine	I-GENE
lyase	I-GENE
was	O
produced	O
in	O
a	O
baculovirus	O
-	O
Sf9	O
expression	O
system	O
.	O

Mycoplasma	O
hominis	O
infections	O
are	O
easily	O
missed	O
because	O
conventional	O
methods	O
for	O
bacterial	O
detection	O
may	O
fail	O
.	O

For	O
this	O
purpose	O
,	O
we	O
used	O
a	O
series	O
of	O
plasmid	O
constructs	O
encoding	O
different	O
forms	O
of	O
the	O
envelope	B-GENE
glycoprotein	I-GENE
E	I-GENE
of	I-GENE
the	I-GENE
flavivirus	I-GENE
tick	I-GENE
-	I-GENE
borne	I-GENE
encephalitis	I-GENE
virus	I-GENE
.	O

By	O
an	O
induced	O
-	O
fit	O
mechanism	O
,	O
contacts	O
with	O
the	O
anticodon	O
can	O
activate	O
formation	O
of	O
a	O
robust	O
transition	O
state	O
at	O
a	O
site	O
over	O
70	O
A	O
away	O
.	O

This	O
revealed	O
a	O
minimum	O
of	O
six	O
novel	O
OSBP	B-GENE
-	I-GENE
related	I-GENE
proteins	I-GENE
,	O
designated	O
ORP	B-GENE
-	I-GENE
1	I-GENE
to	O
ORP	B-GENE
-	I-GENE
6	I-GENE
.	O

In	O
conclusion	O
:	O
(	O
i	O
)	O
TECRA	O
kit	O
is	O
suggested	O
to	O
be	O
used	O
for	O
screening	O
SE	O
producing	O
strains	O
;	O
(	O
ii	O
)	O
SET	O
-	O
RPLA	O
and	O
RIDASCREEN	O
kits	O
are	O
suitable	O
for	O
epidemiological	O
investigation	O
of	O
SE	O
types	O
,	O
but	O
the	O
lack	O
of	O
ability	O
for	O
detecting	O
SEE	O
,	O
long	O
time	O
required	O
for	O
testing	O
with	O
SET	O
-	O
RPLA	O
kit	O
and	O
high	O
background	O
when	O
using	O
RIDASCREEN	O
kit	O
must	O
be	O
overcome	O
;	O
and	O
(	O
iii	O
)	O
because	O
of	O
the	O
complicated	O
test	O
procedures	O
and	O
the	O
lack	O
of	O
ability	O
for	O
detecting	O
SEE	O
,	O
the	O
practicality	O
of	O
SET	O
-	O
EIA	O
kit	O
in	O
screening	O
and	O
epidemiological	O
research	O
purposes	O
is	O
low	O
.	O

Comparison	O
of	O
immunoassay	O
kits	O
for	O
detection	O
of	O
staphylococcal	B-GENE
enterotoxins	I-GENE
produced	O
by	O
Staphylococcus	O
aureus	O

Sequence	O
analysis	O
of	O
the	O
promoter	O
region	O
showed	O
no	O
TATA	O
box	O
but	O
identified	O
consensus	O
binding	O
motifs	O
for	O
Sp1	B-GENE
,	O
CREB	B-GENE
,	O
and	O
half	O
sites	O
of	O
the	O
estrogen	B-GENE
receptor	I-GENE
binding	I-GENE
site	I-GENE
.	O

Sak	B-GENE
kinase	I-GENE
gene	O
structure	O
and	O
transcriptional	O
regulation	O
.	O

Based	O
on	O
a	O
type	O
I	O
error	O
of	O
0	O
.	O
05	O
,	O
our	O
study	O
had	O
a	O
power	O
greater	O
than	O
or	O
equal	O
to	O
75	O
%	O
to	O
detect	O
group	O
differences	O
in	O
treatment	O
effect	O
of	O
greater	O
than	O
or	O
equal	O
to	O
15	O
%	O
to	O
20	O
%	O
.	O

However	O
,	O
no	O
genetic	O
alteration	O
was	O
detected	O
in	O
any	O
of	O
the	O
cancers	O
examined	O
.	O

Statins	B-GENE
:	O
lower	O
lipids	O
and	O
better	O
bones	O
?	O
Although	O
statins	O
are	O
widely	O
used	O
as	O
cholesterol	O
-	O
lowering	O
drugs	O
,	O
a	O
recent	O
study	O
suggests	O
that	O
these	O
compounds	O
have	O
anabolic	O
effects	O
on	O
bone	O
and	O
could	O
be	O
developed	O
into	O
new	O
treatments	O
for	O
common	O
metabolic	O
bone	O
diseases	O
such	O
as	O
osteoporosis	O

Leukocyte	O
cultures	O
,	O
prepared	O
from	O
blood	O
drawn	O
from	O
these	O
18	O
children	O
at	O
6	O
months	O
of	O
age	O
,	O
produced	O
lower	O
yields	O
of	O
IFN	B-GENE
than	O
those	O
of	O
the	O
remaining	O
53	O
children	O
,	O
when	O
stimulated	O
with	O
adenovirus	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
coronavirus	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
or	O
rhinovirus	O
(	O
P	O
=	O
0	O
.	O
002	O
)	O
.	O

In	O
the	O
BF	O
ECT	O
group	O
the	O
-	O
age	O
based	O
dose	O
would	O
have	O
been	O
similarly	O
dependent	O
on	O
the	O
initial	O
seizure	O
threshold	O
level	O
.	O

Haycocknema	O
perplexum	O
n	O
.	O
g	O
.	O
,	O
n	O
.	O
sp	O
.	O

Hypothermia	O
After	O
Cardiac	O
Arrest	O
(	O
HACA	O
)	O
Study	O
Group	O
.	O

Two	O
US	O
commercial	O
cultivars	O
(	O
Tehama	O
and	O
Vina	O
)	O
,	O
three	O
European	O
commercial	O
cultivars	O
(	O
Esterhazy	O
,	O
139	O
,	O
G120	O
)	O
and	O
five	O
New	O
Zealand	O
selections	O
(	O
Rex	O
,	O
Dublin	O
'	O
s	O
Glory	O
,	O
Meyric	O
,	O
McKinster	O
,	O
Stanley	O
)	O
were	O
evaluated	O
.	O

Previously	O
,	O
we	O
showed	O
that	O
the	O
APRE	O
is	O
a	O
cytokine	O
[	O
tumor	B-GENE
necrosis	I-GENE
factor	I-GENE
-	I-GENE
alpha	I-GENE
(	O
TNFalpha	B-GENE
)	O
]	O
-	O
inducible	O
enhancer	O
by	O
binding	O
the	O
heterodimeric	B-GENE
nuclear	I-GENE
factor	I-GENE
-	I-GENE
kappaB	I-GENE
(	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
)	O
complex	O
Rel	B-GENE
A	I-GENE
x	O
NF	B-GENE
-	I-GENE
kappaB1	I-GENE
.	O

Angiotensin	B-GENE
II	I-GENE
induces	O
nuclear	B-GENE
factor	I-GENE
(	I-GENE
NF	I-GENE
)	I-GENE
-	I-GENE
kappaB1	I-GENE
isoforms	I-GENE
to	O
bind	O
the	O
angiotensinogen	B-GENE
gene	I-GENE
acute	O
-	O
phase	O
response	O
element	O
:	O
a	O
stimulus	O
-	O
specific	O
pathway	O
for	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
activation	O
.	O

Arhythmacanthus	O
Yamaguti	O
,	O
1935	O
is	O
maintained	O
as	O
a	O
synonym	O
of	O
Heterosentis	O
because	O
the	O
distinction	O
between	O
two	O
and	O
three	O
hook	O
types	O
is	O
made	O
equivocal	O
when	O
the	O
transition	O
between	O
the	O
apical	O
and	O
subapical	O
hooks	O
is	O
gradual	O
.	O

We	O
describe	O
a	O
case	O
of	O
acetaminophen	O
overdose	O
that	O
was	O
treated	O
with	O
both	O
hemodialysis	O
(	O
HD	O
)	O
and	O
NAC	O
due	O
to	O
severe	O
intoxication	O
and	O
slow	O
drug	O
clearance	O
.	O

Following	O
conditioning	O
,	O
a	O
single	O
coat	O
of	O
adhesive	O
was	O
applied	O
and	O
light	O
-	O
cured	O
.	O

Upon	O
tyrosine	O
phosphorylation	O
at	O
the	O
ITIMs	O
,	O
these	O
molecules	O
recruit	O
SH2	B-GENE
domain	O
-	O
containing	O
phosphatases	O
such	O
as	O
SH2	B-GENE
-	O
containing	O
tyrosine	B-GENE
phosphatase	I-GENE
-	I-GENE
1	I-GENE
and	O
negatively	O
regulate	O
cell	O
activity	O
.	O

These	O
results	O
suggest	O
that	O
VP1	B-GENE
was	O
efficiently	O
transported	O
to	O
the	O
nucleus	O
and	O
localized	O
in	O
the	O
discrete	O
subnuclear	O
regions	O
,	O
possibly	O
with	O
VP2	B-GENE
and	O
VP3	B-GENE
.	O

The	O
case	O
for	O
completing	O
the	O
lymphadenectomy	O
when	O
positive	O
lymph	O
nodes	O
are	O
found	O
during	O
radical	O
hysterectomy	O
for	O
cervical	O
carcinoma	O
.	O

Isolation	O
of	O
cDNAs	B-GENE
encoding	I-GENE
gibbon	I-GENE
and	I-GENE
monkey	I-GENE
platelet	I-GENE
and	I-GENE
T	I-GENE
cell	I-GENE
activation	I-GENE
antigen	I-GENE
1	I-GENE
(	O
PTA1	B-GENE
)	O
.	O

All	O
clones	O
and	O
strains	O
produced	O
have	O
been	O
deposited	O
in	O
the	O
EUROFAN	O
genetic	O
stock	O
centre	O
(	O
EUROSCARF	O
,	O
Frankfurt	O
)	O
.	O

High	O
resolution	O
computed	O
tomography	O
of	O
the	O
lungs	O
in	O
patients	O
with	O
rheumatoid	O
arthritis	O
.	O

Actins	B-GENE
show	O
two	O
different	O
forms	O
of	O
N	O
-	O
terminal	O
processing	O
dependent	O
on	O
their	O
N	O
-	O
terminal	O
sequence	O
.	O

All	O
four	O
domains	O
were	O
linked	O
via	O
proline	O
-	O
threonine	O
-	O
rich	O
peptides	O
.	O

METHODS	O
:	O
The	O
former	O
group	O
included	O
patients	O
who	O
had	O
been	O
treated	O
with	O
at	O
least	O
four	O
PGE1	O
alpha	O
-	O
ciclodestrina	O
,	O
short	O
-	O
term	O
treatment	O
cycles	O
per	O
year	O
while	O
the	O
latter	O
was	O
a	O
historical	O
reference	O
group	O
managed	O
without	O
prostaglandins	O
.	O

Zebrafish	O
cyclops	B-GENE
(	O
cyc	B-GENE
)	O
encodes	O
a	O
Transforming	B-GENE
Growth	I-GENE
Factor	I-GENE
beta	I-GENE
(	O
TGFbeta	B-GENE
)	O
signaling	O
factor	O
closely	O
related	O
to	O
mouse	O
Nodal	B-GENE
.	O

The	O
genome	O
organization	O
of	O
the	O
mite	O
-	O
transmitted	O
wheat	O
streak	O
mosaic	O
virus	O
(	O
WSMV	O
)	O
appears	O
to	O
parallel	O
that	O
of	O
members	O
of	O
the	O
Potyviridae	O
with	O
monopartite	O
genomes	O
,	O
but	O
there	O
are	O
substantial	O
amino	O
acid	O
dissimilarities	O
with	O
other	O
potyviral	O
polyproteins	O
.	O

The	O
two	O
-	O
hybrid	O
assay	O
was	O
then	O
performed	O
using	O
full	O
-	O
length	O
genes	O
of	O
CI	B-GENE
,	O
HC	B-GENE
-	I-GENE
Pro	I-GENE
,	O
P1	B-GENE
,	O
P3	B-GENE
,	O
and	O
CP	B-GENE
,	O
but	O
no	O
heterologous	O
interactions	O
were	O
detected	O
.	O

Diverse	O
endogenous	O
light	O
chains	O
contribute	O
to	O
basement	O
membrane	O
reactivity	O
in	O
nonautoimmune	O
mice	O
transgenic	O
for	O
an	O
anti	B-GENE
-	I-GENE
laminin	I-GENE
Ig	B-GENE
heavy	I-GENE
chain	I-GENE
.	O

Mechanisms	O
of	O
tachyphylaxis	O
in	O
regional	O
anesthesia	O
of	O
long	O
duration	O

Dermatology	O
is	O
no	O
exception	O
.	O

Molecular	O
cloning	O
of	O
a	O
novel	O
human	B-GENE
I	I-GENE
-	I-GENE
mfa	I-GENE
domain	I-GENE
-	I-GENE
containing	I-GENE
protein	I-GENE
that	O
differently	O
regulates	O
human	O
T	O
-	O
cell	O
leukemia	O
virus	O
type	O
I	O
and	O
HIV	O
-	O
1	O
expression	O
.	O

The	O
central	O
(	O
R	O
)	O
domain	O
is	O
responsible	O
for	O
receptor	O
-	O
binding	O
activity	O
whereas	O
the	O
N	O
-	O
terminal	O
(	O
T	O
)	O
domain	O
mediates	O
translocation	O
,	O
the	O
process	O
by	O
which	O
the	O
C	O
-	O
terminal	O
cytotoxic	O
domain	O
is	O
transported	O
from	O
the	O
receptor	O
to	O
the	O
site	O
of	O
its	O
cytotoxicity	O
.	O

We	O
have	O
previously	O
demonstrated	O
that	O
expression	O
of	O
the	O
gene	O
for	O
the	O
reproductive	O
neuropeptide	O
,	O
GnRH	B-GENE
,	O
is	O
repressed	O
by	O
the	O
glutamate	O
/	O
NO	O
/	O
cyclic	O
GMP	O
(	O
cGMP	O
)	O
signal	O
transduction	O
pathway	O
through	O
cGMP	B-GENE
-	I-GENE
dependent	I-GENE
protein	I-GENE
kinase	I-GENE
in	O
the	O
hypothalamic	O
GnRH	B-GENE
-	O
secreting	O
neuronal	O
cell	O
line	O
GT1	O
-	O
7	O
.	O

MSSPs	B-GENE
are	O
believed	O
to	O
regulate	O
DNA	O
replication	O
,	O
transcription	O
,	O
apopotosis	O
and	O
cell	O
cycle	O
progression	O
by	O
interacting	O
with	O
the	O
C	B-GENE
-	I-GENE
MYC	I-GENE
protein	I-GENE
.	O

As	O
no	O
complete	O
PPARgamma	B-GENE
antagonists	O
have	O
been	O
described	O
hitherto	O
,	O
we	O
have	O
constructed	O
a	O
dominant	O
-	O
negative	O
mutant	O
receptor	O
to	O
inhibit	O
wild	O
-	O
type	O
PPARgamma	B-GENE
action	O
.	O

Forty	O
4	O
-	O
month	O
old	O
SD	O
female	O
rats	O
were	O
randomly	O
divided	O
into	O
four	O
groups	O
,	O
namely	O
sham	O
operation	O
,	O
bilateral	O
ovariectomy	O
,	O
ovariectomy	O
plus	O
supplementary	O
ethinyl	O
estradiol	O
(	O
0	O
.	O
2	O
microgram	O
/	O
100	O
g	O
B	O
.	O

The	O
requirement	O
of	O
3	O
'	O
complementarity	O
for	O
a	O
ligation	O
reaction	O
is	O
reaffirmed	O
by	O
results	O
from	O
1	O
nt	O
insertions	O
on	O
either	O
the	O
3	O
'	O
-	O
or	O
5	O
'	O
-	O
side	O
of	O
the	O
nick	O
.	O

Expression	O
in	O
early	O
postnatal	O
pituitary	O
and	O
in	O
pre	O
-	O
somatotrophic	O
cells	O
suggests	O
that	O
Zn	B-GENE
-	I-GENE
16	I-GENE
could	O
play	O
a	O
role	O
in	O
pituitary	O
development	O
prior	O
to	O
somatotroph	O
differentiation	O
.	O

Mouse	B-GENE
growth	I-GENE
hormone	I-GENE
transcription	I-GENE
factor	I-GENE
Zn	I-GENE
-	I-GENE
16	I-GENE
:	O
unique	O
bipartite	O
structure	O
containing	O
tandemly	O
repeated	O
zinc	O
finger	O
domains	O
not	O
reported	O
in	O
rat	B-GENE
Zn	I-GENE
-	I-GENE
15	I-GENE
.	O

The	O
CCAAT	O
core	O
sequence	O
mutants	O
in	O
which	O
both	O
CIII	O
and	O
CI	O
/	O
CII	O
were	O
abolished	O
,	O
also	O
increased	O
the	O
promoter	O
activity	O
.	O

Finally	O
,	O
the	O
mechanism	O
of	O
ASK1	B-GENE
activation	O
involves	O
,	O
in	O
part	O
,	O
homo	O
-	O
oligomerization	O
.	O

Two	O
other	O
patients	O
underwent	O
PRFR	O
.	O

The	O
variations	O
were	O
caused	O
by	O
opposite	O
shifts	O
in	O
TSH	B-GENE
frequency	O
distribution	O
in	O
mothers	O
and	O
neonates	O
.	O

However	O
,	O
such	O
a	O
mechanism	O
was	O
not	O
detected	O
in	O
preliminary	O
observations	O
on	O
M	O
.	O
synoviae	O
.	O

The	O
expression	O
of	O
the	O
yam8	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
cDNA	I-GENE
in	O
the	O
mid1	B-GENE
mutant	I-GENE
cells	O
partially	O
remediated	O
the	O
mid	O
phenotype	O
and	O
resulted	O
in	O
a	O
slight	O
increase	O
in	O
Ca	O
(	O
2	O
+	O
)	O
uptake	O
activity	O
.	O

TIP30	B-GENE
has	O
an	O
intrinsic	O
kinase	O
activity	O
required	O
for	O
up	O
-	O
regulation	O
of	O
a	O
subset	O
of	O
apoptotic	O
genes	O
.	O

Alternatively	O
,	O
PC12	O
-	O
E2	O
cells	O
were	O
submitted	O
to	O
treatment	O
with	O
antibodies	O
to	O
the	O
fibroblast	B-GENE
growth	I-GENE
factor	I-GENE
(	I-GENE
FGF	I-GENE
)	I-GENE
receptor	I-GENE
,	O
inhibitors	O
of	O
the	O
nonreceptor	B-GENE
tyrosine	I-GENE
kinase	I-GENE
p59	B-GENE
(	O
fyn	B-GENE
)	O
,	O
PLC	B-GENE
,	O
PKC	B-GENE
and	O
MEK	B-GENE
and	O
an	O
activator	O
of	O
PKC	B-GENE
,	O
phorbol	O
-	O
12	O
-	O
myristate	O
-	O
13	O
-	O
acetate	O
(	O
PMA	O
)	O
.	O

Approximately	O
20	O
%	O
of	O
ALCLs	O
that	O
express	O
ALK	B-GENE
do	O
not	O
contain	O
the	O
t	O
(	O
2	O
;	O
5	O
)	O
,	O
suggesting	O
that	O
other	O
genetic	O
abnormalities	O
can	O
result	O
in	O
aberrant	O
ALK	B-GENE
expression	O
.	O

In	O
addition	O
,	O
expected	O
decreases	O
in	O
ATIC	B-GENE
enzymatic	O
function	O
in	O
ATIC	B-GENE
-	O
ALK	B-GENE
-	O
containing	O
lymphomas	O
may	O
render	O
these	O
tumors	O
more	O
sensitive	O
to	O
antifolate	O
drugs	O
such	O
as	O
methotrexate	O
.	O

Manganese	O
ions	O
were	O
found	O
to	O
be	O
essential	O
for	O
autophosphorylation	O
of	O
BGLF4	B-GENE
,	O
and	O
magnesium	O
can	O
stimulate	O
the	O
activity	O
.	O

An	O
amino	O
-	O
acid	O
sequence	O
comparison	O
revealed	O
that	O
Bacillus	B-GENE
YM55	I-GENE
-	I-GENE
1	I-GENE
aspartase	I-GENE
shared	O
71	O
%	O
homology	O
with	O
Bacillus	B-GENE
subtilis	I-GENE
aspartase	I-GENE
and	O
49	O
%	O
with	O
Escherichia	O
coli	O
and	O
Pseudomonas	B-GENE
fluorescens	I-GENE
aspartases	I-GENE
.	O

Unique	O
to	O
this	O
system	O
,	O
the	O
activity	O
of	O
TraR	B-GENE
is	O
negatively	O
modulated	O
by	O
an	O
antiactivator	O
called	O
TraM	B-GENE
.	O

As	O
assessed	O
by	O
a	O
genetic	O
assay	O
that	O
measures	O
AAI	O
-	O
dependent	O
DNA	O
binding	O
,	O
TraM	B-GENE
inhibited	O
TraR	B-GENE
function	O
before	O
and	O
after	O
the	O
transcription	O
factor	O
had	O
bound	O
to	O
its	O
DNA	O
recognition	O
site	O
.	O

Collectively	O
,	O
the	O
results	O
suggest	O
that	O
ARF	B-GENE
binding	O
to	O
Mdm2	B-GENE
induces	O
a	O
conformational	O
change	O
that	O
facilitates	O
nucleolar	O
import	O
of	O
the	O
ARF	B-GENE
-	O
Mdm2	B-GENE
complex	O
and	O
p53	B-GENE
-	O
dependent	O
cell	O
cycle	O
arrest	O
.	O

The	O
AtERF	B-GENE
genes	I-GENE
were	O
differentially	O
regulated	O
by	O
ethylene	O
and	O
by	O
abiotic	O
stress	O
conditions	O
,	O
such	O
as	O
wounding	O
,	O
cold	O
,	O
high	O
salinity	O
,	O
or	O
drought	O
,	O
via	O
ETHYLENE	B-GENE
-	I-GENE
INSENSITIVE2	I-GENE
(	O
EIN2	B-GENE
)	O
-	O
dependent	O
or	O
-	O
independent	O
pathways	O
.	O

Electrophoretic	O
mobility	O
shift	O
assays	O
revealed	O
that	O
Sp1	B-GENE
binds	O
to	O
two	O
different	O
regions	O
in	O
the	O
proximal	O
promoter	O
,	O
a	O
typical	O
Sp1	B-GENE
site	I-GENE
located	O
at	O
(	O
-	O
38	O
;	O
-	O
33	O
)	O
and	O
a	O
G	O
/	O
C	O
-	O
rich	O
region	O
between	O
(	O
-	O
67	O
;	O
-	O
62	O
)	O
.	O

Eight	O
patients	O
received	O
1	O
.	O
5	O
mg	O
of	O
adefovir	O
dipivoxil	O
per	O
kg	O
of	O
body	O
weight	O
,	O
and	O
six	O
patients	O
received	O
3	O
.	O
0	O
mg	O
of	O
adefovir	O
dipivoxil	O
per	O
kg	O
.	O

Most	O
likely	O
they	O
might	O
represent	O
regulatory	O
RNAs	O
or	O
transcribed	O
transposable	O
elements	O
.	O

Here	O
we	O
describe	O
the	O
cloning	O
,	O
tissue	O
-	O
specific	O
expression	O
pattern	O
,	O
and	O
functional	O
characterization	O
of	O
two	O
novel	O
TEF	B-GENE
-	I-GENE
1	I-GENE
isoforms	I-GENE
,	O
TEF	B-GENE
-	I-GENE
1beta	I-GENE
and	O
TEF	B-GENE
-	I-GENE
1gamma	I-GENE
.	O

The	O
comparison	O
of	O
the	O
expression	O
patterns	O
of	O
the	O
known	O
Kv4	B-GENE
family	I-GENE
members	I-GENE
shows	O
subtype	O
specificity	O
with	O
significant	O
overlaps	O
.	O

Preliminary	O
use	O
of	O
the	O
Nottingham	O
Eczema	O
Severity	O
Score	O
would	O
support	O
further	O
development	O
as	O
a	O
research	O
tool	O
for	O
a	O
simple	O
assessment	O
of	O
disease	O
severity	O
that	O
could	O
be	O
used	O
in	O
epidemiological	O
studies	O
.	O

Advanced	O
adenoma	O
was	O
defined	O
as	O
an	O
adenoma	O
larger	O
than	O
10	O
mm	O
or	O
an	O
adenoma	O
of	O
any	O
size	O
with	O
villous	O
component	O
,	O
high	O
-	O
grade	O
dysplasia	O
or	O
invasive	O
carcinoma	O
.	O

To	O
understand	O
whether	O
Shc	B-GENE
localization	O
in	O
membrane	O
rafts	O
is	O
sufficient	O
to	O
regulate	O
Shc	B-GENE
function	O
,	O
we	O
constructed	O
a	O
Shc	B-GENE
chimera	I-GENE
containing	O
the	O
Ras	B-GENE
membrane	I-GENE
localization	I-GENE
motif	I-GENE
at	O
the	O
C	O
-	O
terminus	O
.	O

RegA	B-GENE
is	O
a	O
positive	O
yet	O
nonessential	O
regulator	O
of	O
tol	B-GENE
-	O
oprL	B-GENE
expression	O
.	O

Schlegel	O
,	O
J	O
.	O

The	O
early	O
dg	O
.	O
of	O
rejection	O
and	O
especially	O
acute	O
rejection	O
,	O
it	O
'	O
s	O
adequate	O
management	O
,	O
decreased	O
risk	O
for	O
the	O
future	O
chronic	O
rejection	O
nephropathy	O
.	O

Extracellular	B-GENE
-	I-GENE
regulated	I-GENE
kinase	I-GENE
(	O
ERK	B-GENE
)	O
activation	O
and	O
molecular	O
coupling	O
of	O
the	O
adaptor	O
proteins	O
p130	B-GENE
Crk	B-GENE
-	I-GENE
associated	I-GENE
substrate	I-GENE
(	O
CAS	B-GENE
)	O
and	O
c	B-GENE
-	I-GENE
CrkII	I-GENE
(	O
Crk	B-GENE
)	O
represent	O
two	O
distinct	O
pathways	O
that	O
induce	O
cell	O
invasion	O
and	O
protect	O
cells	O
from	O
apoptosis	O
in	O
a	O
three	O
-	O
dimensional	O
collagen	B-GENE
matrix	O
.	O

The	O
evolution	O
of	O
the	O
CCR5	B-GENE
cis	I-GENE
-	I-GENE
regulatory	I-GENE
region	I-GENE
versus	O
the	O
open	O
reading	O
frame	O
as	O
well	O
as	O
among	O
different	O
domains	O
of	O
the	O
open	O
reading	O
frame	O
differed	O
from	O
one	O
another	O
.	O

Scanning	O
mutations	O
throughout	O
the	O
AC	O
element	O
interfered	O
with	O
induction	O
but	O
allowed	O
us	O
to	O
define	O
five	O
overlapping	O
sites	O
for	O
regulatory	O
factors	O
in	O
AC	O
and	O
to	O
design	O
probes	O
binding	O
just	O
one	O
or	O
two	O
factors	O
.	O

Bites	O
by	O
two	O
species	O
of	O
adders	O
(	O
Vipera	O
aspis	O
and	O
Vipera	O
berus	O
)	O
can	O
lead	O
to	O
extensive	O
swelling	O
with	O
multiorgan	O
failure	O
.	O

CONCLUSION	O
:	O
Treatment	O
of	O
sepsis	O
with	O
the	O
platelet	B-GENE
-	I-GENE
activating	I-GENE
factor	I-GENE
antagonist	O
BB	O
-	O
882	O
offers	O
no	O
advantage	O
over	O
placebo	O
on	O
survival	O
,	O
hemodynamic	O
status	O
,	O
respiratory	O
function	O
,	O
or	O
organ	O
failure	O
scores	O
.	O

In	O
vivo	O
dimethyl	O
sulfate	O
footprinting	O
of	O
the	O
cyclin	B-GENE
E	I-GENE
promoter	I-GENE
revealed	O
several	O
regions	O
of	O
protection	O
and	O
hypersensitivity	O
that	O
were	O
unique	O
to	O
infected	O
cells	O
.	O

A	O
total	O
of	O
194	O
STSs	O
map	O
to	O
this	O
interval	O
of	O
3	O
Mb	O
,	O
giving	O
an	O
average	O
marker	O
resolution	O
of	O
approximately	O
one	O
per	O
15	O
kb	O
.	O

Recently	O
,	O
a	O
mutation	O
in	O
the	O
amino	O
-	O
terminus	O
of	O
IB1	B-GENE
was	O
associated	O
with	O
diabetes	O
.	O

Biol	O
.	O

These	O
data	O
show	O
that	O
the	O
alpha	O
-	O
helix	O
domain	O
of	O
p57	B-GENE
(	O
Kip2	B-GENE
)	O
,	O
which	O
is	O
conserved	O
in	O
the	O
Cip	B-GENE
/	O
Kip	B-GENE
proteins	O
,	O
is	O
implicated	O
in	O
protein	O
-	O
protein	O
interaction	O
and	O
confers	O
a	O
specific	O
regulatory	O
mechanism	O
,	O
outside	O
of	O
their	O
Cdk	B-GENE
-	O
inhibitory	O
activity	O
,	O
by	O
which	O
the	O
p57	B-GENE
(	O
Kip2	B-GENE
)	O
family	O
members	O
positively	O
act	O
on	O
myogenic	O
differentiation	O
.	O

The	O
somatoform	O
conundrum	O
:	O
a	O
question	O
of	O
nosological	O
valves	O
.	O

Intra	O
-	O
operative	O
ultrasound	O
(	O
IOUS	O
)	O
has	O
been	O
widely	O
used	O
in	O
an	O
attempt	O
to	O
overcome	O
these	O
difficulties	O
,	O
but	O
is	O
limited	O
by	O
its	O
two	O
-	O
dimensional	O
nature	O
,	O
inter	O
-	O
user	O
variability	O
,	O
and	O
image	O
obliteration	O
with	O
ablative	O
or	O
resectional	O
techniques	O
.	O

CONCLUSIONS	O
:	O
This	O
randomized	O
study	O
shows	O
that	O
Vivostat	O
fibrin	B-GENE
sealant	O
is	O
effective	O
in	O
preventing	O
air	O
leakage	O
after	O
small	O
lung	O
resections	O
in	O
pigs	O
,	O
even	O
at	O
high	O
inspiratory	O
pressures	O
.	O

Hailey	O
-	O
Hailey	O
disease	O
is	O
caused	O
by	O
mutations	O
in	O
ATP2C1	B-GENE
encoding	O
a	O
novel	O
Ca	O
(	O
2	O
+	O
)	O
pump	O
.	O

A	O
cause	O
of	O
increase	O
of	O
alkaline	B-GENE
phosphatase	I-GENE
in	O
children	O

Significantly	O
,	O
two	O
proximal	O
GATA	B-GENE
-	I-GENE
1	I-GENE
-	I-GENE
binding	I-GENE
sites	I-GENE
(	O
-	O
118	O
/	O
-	O
113	O
and	O
-	O
98	O
/	O
-	O
93	O
)	O
and	O
a	O
region	O
located	O
within	O
-	O
518	O
to	O
-	O
315bp	O
of	O
the	O
mouse	B-GENE
ALAS2	I-GENE
promoter	I-GENE
were	O
essential	O
for	O
transcriptional	O
activation	O
during	O
chemically	O
induced	O
differentiation	O
of	O
MEL	O
cells	O
,	O
implying	O
their	O
importance	O
in	O
conferring	O
erythroid	O
specificity	O
to	O
the	O
ALAS2	B-GENE
transcriptional	O
activation	O
.	O

The	O
HMG	B-GENE
domain	I-GENE
of	O
both	O
HMG20	B-GENE
proteins	I-GENE
is	O
most	O
similar	O
to	O
that	O
of	O
yeast	B-GENE
NHP6A	I-GENE
(	O
38	O
%	O
to	O
42	O
%	O
)	O
.	O

IgM	B-GENE
and	O
IgG	B-GENE
anti	I-GENE
A	I-GENE
and	O
anti	B-GENE
B	I-GENE
antibody	I-GENE
status	O
of	O
100	O
antenatal	O
O	O
group	O
mothers	O
(	O
who	O
had	O
non	O
O	O
group	O
husbands	O
)	O
were	O
studied	O
.	O

In	O
an	O
attempt	O
to	O
understand	O
Wee1	B-GENE
regulation	O
during	O
cell	O
cycle	O
,	O
yeast	O
two	O
-	O
hybrid	O
screening	O
was	O
used	O
to	O
identify	O
Wee1	B-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
(	I-GENE
s	I-GENE
)	I-GENE
.	O

Retroviral	O
transduction	O
of	O
T	B-GENE
/	I-GENE
T	I-GENE
(	I-GENE
L	I-GENE
)	I-GENE
causes	O
a	O
rapidly	O
fatal	O
myeloproliferative	O
disease	O
in	O
a	O
murine	O
bone	O
marrow	O
transplant	O
(	O
BMT	O
)	O
model	O
,	O
whereas	O
T	B-GENE
/	I-GENE
T	I-GENE
(	I-GENE
F	I-GENE
)	I-GENE
causes	O
a	O
long	O
-	O
latency	O
,	O
pre	O
-	O
B	O
-	O
cell	O
lymphoblastic	O
lymphoma	O
.	O

The	O
codon	O
usage	O
is	O
particularly	O
marked	O
for	O
the	O
gag	B-GENE
,	O
pol	B-GENE
,	O
and	O
env	B-GENE
genes	I-GENE
.	O

Slap	B-GENE
negatively	O
regulates	O
Src	B-GENE
mitogenic	O
function	O
but	O
does	O
not	O
revert	O
Src	B-GENE
-	O
induced	O
cell	O
morphology	O
changes	O
.	O

We	O
examine	O
current	O
models	O
of	O
the	O
effects	O
of	O
aging	O
on	O
mean	O
response	O
time	O
and	O
show	O
how	O
they	O
might	O
be	O
reinterpreted	O
.	O

The	O
effects	O
of	O
these	O
mutations	O
on	O
protein	O
function	O
require	O
further	O
examination	O
.	O

Kaposi	O
'	O
s	O
sarcoma	O
-	O
associated	O
herpesvirus	O
viral	B-GENE
interferon	I-GENE
regulatory	I-GENE
factor	I-GENE
confers	O
resistance	O
to	O
the	O
antiproliferative	O
effect	O
of	O
interferon	B-GENE
-	I-GENE
alpha	I-GENE
.	O

AMDA	O
white	O
paper	O
identifies	O
ways	O
to	O
improve	O
pharmaceutical	O
care	O
in	O
SNFs	O
.	O

Because	O
the	O
mutant	O
defective	O
in	O
DNA	O
binding	O
also	O
fails	O
to	O
stimulate	O
Abf1	B-GENE
ARS1	O
DNA	O
-	O
binding	O
activity	O
,	O
our	O
results	O
suggest	O
that	O
Cdc6	B-GENE
DNA	O
-	O
binding	O
activity	O
may	O
play	O
a	O
pivotal	O
role	O
in	O
the	O
initiation	O
of	O
DNA	O
replication	O
.	O

The	O
structural	O
study	O
of	O
peptides	O
belonging	O
to	O
the	O
terminal	O
domains	O
of	O
histone	B-GENE
H1	I-GENE
can	O
be	O
considered	O
as	O
a	O
step	O
toward	O
the	O
understanding	O
of	O
the	O
function	O
of	O
H1	B-GENE
in	O
chromatin	O
.	O

The	O
recovery	O
rates	O
for	O
the	O
MB	O
/	O
BacT	O
,	O
MGIT	O
960	O
,	O
and	O
solid	O
media	O
were	O
91	O
.	O
6	O
,	O
87	O
.	O
4	O
,	O
and	O
54	O
.	O
7	O
%	O
,	O
respectively	O
,	O
for	O
all	O
mycobacteria	O
;	O
the	O
recovery	O
rates	O
were	O
93	O
.	O
6	O
,	O
88	O
.	O
9	O
,	O
and	O
63	O
.	O
4	O
%	O
,	O
respectively	O
,	O
for	O
M	O
.	O
tuberculosis	O
complex	O
alone	O
,	O
and	O
87	O
.	O
5	O
,	O
84	O
.	O
4	O
,	O
and	O
37	O
.	O
5	O
%	O
,	O
respectively	O
,	O
for	O
all	O
nontuberculous	O
mycobacteria	O
.	O

SELECTION	O
CRITERIA	O
:	O
Randomised	O
and	O
possibly	O
randomised	O
trials	O
using	O
acupuncture	O
to	O
treat	O
asthma	O
and	O
asthma	O
-	O
like	O
symptoms	O
.	O

SELECTION	O
CRITERIA	O
:	O
Randomised	O
trials	O
comparing	O
children	O
undergoing	O
systematic	O
therapy	O
focusing	O
on	O
the	O
family	O
in	O
conjunction	O
with	O
asthma	O
medication	O
,	O
with	O
children	O
taking	O
asthma	O
medication	O
only	O
.	O

The	O
models	O
were	O
tested	O
by	O
studying	O
their	O
response	O
to	O
disturbances	O
of	O
the	O
afferent	O
signal	O
from	O
the	O
bladder	O
.	O

We	O
also	O
show	O
that	O
p65	B-GENE
binds	O
to	O
these	O
targets	O
with	O
almost	O
equal	O
affinity	O
and	O
that	O
different	O
residues	O
have	O
variable	O
roles	O
in	O
binding	O
different	O
kappaB	B-GENE
targets	I-GENE
.	O

To	O
illustrate	O
its	O
performance	O
,	O
measurements	O
of	O
photoluminescence	O
in	O
GaAs	O
/	O
AlGaAs	O
heterostructures	O
are	O
presented	O
.	O

D5	B-GENE
/	I-GENE
D1	I-GENE
(	I-GENE
CT	I-GENE
)	I-GENE
or	O
D5	B-GENE
/	I-GENE
D1D	I-GENE
(	I-GENE
CT	I-GENE
)	I-GENE
tail	O
substitution	O
mutants	O
displayed	O
a	O
rank	O
order	O
of	O
potency	O
and	O
agonist	O
affinities	O
virtually	O
mimicking	O
wild	B-GENE
-	I-GENE
type	I-GENE
(	I-GENE
wt	I-GENE
)	I-GENE
D1	I-GENE
receptors	I-GENE
,	O
as	O
indexed	O
by	O
both	O
ligand	O
binding	O
and	O
dopamine	O
-	O
stimulated	O
cAMP	O
accumulation	O
assays	O
,	O
and	O
,	O
similar	O
to	O
wt	O
D1	B-GENE
receptors	I-GENE
,	O
did	O
not	O
exhibit	O
receptor	O
constitutive	O
activity	O
or	O
responsiveness	O
to	O
inverse	O
agonists	O
.	O

Modeling	O
also	O
revealed	O
a	O
very	O
hydrophobic	O
surface	O
due	O
to	O
the	O
absence	O
of	O
H12	O
,	O
exposing	O
residues	O
from	O
H3	O
,	O
loop	O
3	O
-	O
4	O
,	O
H4	O
,	O
and	O
H11	O
.	O

The	O
immune	O
system	O
is	O
closely	O
integrated	O
with	O
the	O
neuroendocrine	O
system	O
,	O
and	O
infection	O
-	O
induced	O
increases	O
in	O
cytokines	O
such	O
as	O
IL	B-GENE
-	I-GENE
1	I-GENE
,	O
IL	B-GENE
-	I-GENE
6	I-GENE
and	O
TNF	B-GENE
have	O
numerous	O
effects	O
on	O
the	O
central	O
nervous	O
system	O
.	O

Flavonoids	O
from	O
Brosimum	O
acutifolium	O
.	O

Although	O
the	O
OC	B-GENE
promoter	I-GENE
is	O
activated	O
in	O
a	O
C	O
terminus	O
dependent	O
manner	O
,	O
the	O
MDR	B-GENE
,	O
LTR	O
and	O
BSP	B-GENE
promoters	I-GENE
are	O
repressed	O
by	O
three	O
distinct	O
mechanisms	O
,	O
either	O
independent	O
of	O
or	O
involving	O
the	O
AML	B-GENE
C	I-GENE
terminus	I-GENE
,	O
or	O
requiring	O
only	O
the	O
conserved	O
C	O
-	O
terminal	O
pentapeptide	O
VWRPY	O
.	O

Therefore	O
,	O
analogs	O
of	O
vitamin	O
D3	O
have	O
been	O
investigated	O
in	O
a	O
number	O
of	O
trials	O
showing	O
improvement	O
of	O
psoriasis	O
.	O

The	O
network	O
evolution	O
was	O
interpreted	O
by	O
an	O
approach	O
based	O
on	O
the	O
Flory	O
model	O
.	O

Biologically	O
significant	O
amounts	O
of	O
platelet	B-GENE
activating	I-GENE
factor	I-GENE
were	O
eluted	O
from	O
the	O
sorbent	O
during	O
the	O
entire	O
treatment	O
time	O
.	O

Mucin	B-GENE
gene	I-GENE
expression	O
has	O
been	O
shown	O
to	O
be	O
altered	O
in	O
many	O
intestinal	O
diseases	O
and	O
especially	O
cancers	O
of	O
the	O
gastrointestinal	O
tract	O
.	O

E2F	B-GENE
-	I-GENE
1	I-GENE
is	O
a	O
transcription	O
factor	O
that	O
regulates	O
cell	O
cycle	O
progression	O
into	O
S	O
-	O
phase	O
.	O

Taken	O
together	O
,	O
these	O
results	O
indicate	O
that	O
MAP	B-GENE
kinase	I-GENE
stimulates	O
the	O
hPL	B-GENE
-	I-GENE
B	I-GENE
enhancer	I-GENE
by	O
an	O
NF	B-GENE
-	I-GENE
IL	I-GENE
-	I-GENE
6	I-GENE
-	O
dependent	O
pathway	O
.	O

Using	O
adenoviral	O
transfer	O
of	O
IkappaBalpha	B-GENE
(	O
IkappaBalpha	B-GENE
overexpression	O
)	O
,	O
the	O
production	O
of	O
TNF	B-GENE
-	I-GENE
alpha	I-GENE
induced	O
by	O
whole	O
GBS	O
was	O
inhibited	O
by	O
only	O
20	O
%	O
.	O

The	O
delta	B-GENE
srb10	I-GENE
mutation	I-GENE
also	O
influenced	O
on	O
the	O
transcript	O
levels	O
of	O
meiosis	O
-	O
inducing	O
genes	O
called	O
IME1	B-GENE
and	O
IME2	B-GENE
:	O
the	O
mutation	O
elevated	O
the	O
transcript	O
level	O
of	O
IME1	B-GENE
but	O
reduced	O
that	O
of	O
IME2	B-GENE
,	O
resulting	O
in	O
partial	O
defects	O
in	O
premeiotic	O
DNA	O
synthesis	O
and	O
meiosis	O
.	O

We	O
also	O
found	O
that	O
environmental	O
conditions	O
for	O
meiosis	O
finely	O
regulate	O
the	O
transcript	O
levels	O
of	O
KIN28	B-GENE
and	O
CCL1	B-GENE
,	O
such	O
that	O
nitrogen	O
starvation	O
first	O
elevates	O
them	O
but	O
subsequent	O
alkalization	O
of	O
medium	O
decreases	O
them	O
.	O

The	O
effect	O
of	O
acute	O
,	O
mid	O
-	O
cervical	O
spinal	O
cord	O
lesions	O
on	O
neuronal	O
and	O
reflex	O
activity	O
evoked	O
by	O
the	O
noxious	O
visceral	O
stimulus	O
,	O
colorectal	O
distension	O
(	O
CRD	O
;	O
80	O
mmHg	O
,	O
20	O
s	O
)	O
,	O
was	O
determined	O
in	O
halothane	O
-	O
anesthetized	O
rats	O
.	O

The	O
results	O
suggest	O
that	O
the	O
role	O
of	O
S	O
.	O
argyrostoma	O
in	O
the	O
dissemination	O
of	O
Trichinella	O
larvae	O
in	O
nature	O
is	O
limited	O
in	O
comparison	O
to	O
the	O
role	O
played	O
by	O
mammals	O
with	O
scavenger	O
and	O
cannibalistic	O
behavior	O
.	O

The	O
equilibrium	O
dissociation	O
binding	O
constant	O
for	O
the	O
interaction	O
of	O
TnrA	B-GENE
with	O
the	O
nrgAB	B-GENE
promoter	I-GENE
fragment	I-GENE
was	O
7	O
.	O
7	O
nM	O
under	O
the	O
conditions	O
used	O
here	O
.	O

Phd	B-GENE
antibody	O
-	O
immunoreactive	O
peptides	O
are	O
seen	O
in	O
light	O
-	O
adapted	O
mouse	O
retinal	O
cytosolic	O
and	O
nuclear	O
extracts	O
.	O

In	O
contrast	O
to	O
the	O
morphological	O
criteria	O
,	O
the	O
few	O
data	O
available	O
from	O
recent	O
studies	O
at	O
the	O
genetic	O
level	O
have	O
suggested	O
that	O
EPVs	O
infecting	O
different	O
insect	O
orders	O
are	O
phylogenetically	O
distant	O
.	O

Prevention	O
,	O
differential	O
diagnosis	O
and	O
therapy	O
of	O
travel	O
diarrhea	O

Mutation	O
analysis	O
demonstrates	O
that	O
the	O
motif	O
TCCCCT	O
is	O
critical	O
for	O
PyRo1	B-GENE
interaction	O
.	O

Our	O
results	O
suggest	O
that	O
proteasome	O
inhibition	O
leads	O
to	O
upregulation	O
of	O
specific	O
members	O
of	O
transcription	O
factor	O
families	O
controlling	O
cellular	O
stress	O
response	O
and	O
proliferation	O
.	O

In	O
hemodialyzed	O
patients	O
(	O
Epo	B-GENE
and	O
Non	O
-	O
Epo	B-GENE
group	O
)	O
leptin	B-GENE
levels	O
were	O
significantly	O
higher	O
when	O
compared	O
to	O
CAPD	O
patients	O
(	O
Epo	B-GENE
and	O
Non	O
-	O
Epo	B-GENE
group	O
,	O
respectively	O
)	O
.	O

ID	O
-	O
PaGIA	O
diphtheria	B-GENE
toxin	I-GENE
polymer	O
particle	O
diagnostic	O
agent	O
manufactured	O
by	O
DiaMed	O
AG	O
,	O
Switzerland	O
,	O
was	O
tried	O
at	O
bacteriological	O
laboratory	O
of	O
Institute	O
of	O
Childhood	O
Infections	O
in	O
St	O
.	O

Topics	O
reviewed	O
here	O
include	O
:	O
data	O
supporting	O
the	O
association	O
of	O
myositis	O
with	O
cancer	O
and	O
the	O
appropriate	O
evaluations	O
for	O
malignancy	O
in	O
a	O
myositis	O
patient	O
;	O
an	O
approach	O
to	O
the	O
assessment	O
of	O
patients	O
with	O
dermatomyositis	O
sine	O
myositis	O
;	O
the	O
usefulness	O
of	O
the	O
clinicopathological	O
and	O
serological	O
classifications	O
;	O
a	O
discussion	O
of	O
whether	O
childhood	O
and	O
adult	O
myositis	O
are	O
the	O
same	O
or	O
different	O
entities	O
;	O
a	O
review	O
of	O
those	O
prognostic	O
factors	O
to	O
consider	O
in	O
the	O
clinical	O
management	O
of	O
myositis	O
patients	O
;	O
current	O
approaches	O
and	O
their	O
limitations	O
for	O
assessing	O
disease	O
activity	O
and	O
damage	O
.	O

The	O
outer	O
diameter	O
and	O
the	O
thickness	O
of	O
the	O
rotor	O
are	O
60	O
mm	O
and	O
8	O
mm	O
,	O
respectively	O
.	O

CONCLUSIONS	O
:	O
There	O
is	O
a	O
relation	O
in	O
the	O
topography	O
of	O
some	O
visual	O
field	O
areas	O
assessed	O
by	O
SWAP	O
and	O
the	O
inferotemporal	O
neuroretinal	O
rim	O
area	O
,	O
which	O
may	O
play	O
a	O
role	O
in	O
the	O
diagnosis	O
and	O
follow	O
-	O
up	O
of	O
suspected	O
glaucoma	O
.	O

ACE	B-GENE
-	I-GENE
2	I-GENE
has	O
a	O
hydrophobic	O
C	O
terminus	O
of	O
H	O
type	O
.	O

We	O
concluded	O
that	O
activation	O
of	O
c	B-GENE
-	I-GENE
fosER	I-GENE
mediated	O
transcriptional	O
inhibition	O
of	O
p21	B-GENE
(	O
Cip1	B-GENE
/	O
WAF1	B-GENE
)	O
through	O
a	O
previously	O
uncharacterized	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
,	O
revealing	O
an	O
important	O
role	O
for	O
c	B-GENE
-	I-GENE
fos	I-GENE
in	O
negative	O
control	O
of	O
cell	O
cycle	O
regulatory	O
genes	O
.	O

The	O
first	O
symptoms	O
of	O
enzootic	O
calcinosis	O
were	O
noted	O
in	O
March	O
1998	O
,	O
when	O
some	O
of	O
the	O
cows	O
developed	O
locomotor	O
abnormalities	O
.	O

Screening	O
,	O
counseling	O
,	O
and	O
treatment	O
for	O
alcohol	O
and	O
illicit	O
drug	O
use	O
should	O
be	O
essential	O
components	O
in	O
comprehensive	O
HBP	O
care	O
.	O

Transcriptional	O
regulation	O
of	O
the	O
mouse	B-GENE
cytosolic	I-GENE
chaperonin	I-GENE
subunit	I-GENE
gene	I-GENE
Ccta	B-GENE
/	I-GENE
t	I-GENE
-	I-GENE
complex	I-GENE
polypeptide	I-GENE
1	I-GENE
by	O
selenocysteine	B-GENE
tRNA	I-GENE
gene	I-GENE
transcription	I-GENE
activating	I-GENE
factor	I-GENE
family	I-GENE
zinc	I-GENE
finger	I-GENE
proteins	I-GENE
.	O

We	O
have	O
shown	O
that	O
the	O
epidural	O
(	O
EPI	O
)	O
delivery	O
of	O
morphine	O
encapsulated	O
in	O
multivesicular	O
liposomes	O
(	O
DepoFoam	O
drug	O
delivery	O
system	O
)	O
produces	O
a	O
sustained	O
clearance	O
of	O
morphine	O
and	O
a	O
prolonged	O
analgesia	O
.	O

Following	O
EPI	O
-	O
C0401	O
,	O
but	O
not	O
saline	O
or	O
DepoFoam	O
vehicle	O
,	O
there	O
were	O
transient	O
(	O
<	O
72	O
hr	O
)	O
decreases	O
in	O
food	O
consumption	O
,	O
arousal	O
,	O
hindlimb	O
muscle	O
tone	O
,	O
and	O
body	O
temperature	O
.	O

Resistance	O
ratios	O
for	O
the	O
other	O
field	O
strains	O
obtained	O
by	O
comparison	O
with	O
the	O
R5	O
strain	O
ranged	O
from	O
24	O
.	O
5	O
to	O
239	O
for	O
topical	O
application	O
and	O
from	O
1	O
.	O
2	O
to	O
9	O
.	O
8	O
for	O
the	O
glass	O
jar	O
method	O
.	O

Reliability	O
of	O
cervical	O
range	O
of	O
motion	O
using	O
the	O
OSI	O
CA	O
6000	O
spine	O
motion	O
analyser	O
on	O
asymptomatic	O
and	O
symptomatic	O
subjects	O
.	O

Activation	O
of	O
PKA	B-GENE
by	O
8	O
-	O
bromo	O
-	O
cyclic	O
AMP	O
or	O
forskolin	O
,	O
and	O
inhibition	O
of	O
PKC	B-GENE
by	O
calphostin	O
C	O
,	O
resulted	O
in	O
a	O
significant	O
decrease	O
in	O
3TP	B-GENE
activity	O
as	O
well	O
as	O
in	O
vitro	O
ERK	B-GENE
kinase	I-GENE
activity	O
in	O
CRAC	O
.	O

Mus81p	B-GENE
also	O
shares	O
homology	O
with	O
motifs	O
found	O
in	O
the	O
XPF	B-GENE
endonuclease	I-GENE
superfamily	I-GENE
.	O

Double	O
mutant	O
analysis	O
suggests	O
that	O
Rad54p	B-GENE
and	O
Mus81p	B-GENE
act	O
in	O
one	O
pathway	O
for	O
the	O
repair	O
of	O
,	O
or	O
tolerance	O
to	O
,	O
UV	O
-	O
induced	O
DNA	O
damage	O
.	O

SELECTION	O
CRITERIA	O
:	O
All	O
controlled	O
trials	O
where	O
adults	O
with	O
schizophrenia	O
or	O
similar	O
illnesses	O
were	O
randomised	O
to	O
quetiapine	O
,	O
placebo	O
or	O
other	O
neuroleptic	O
drugs	O
and	O
where	O
clinically	O
relevant	O
outcomes	O
were	O
reported	O
.	O

Six	O
distinct	O
Ets	B-GENE
mRNAs	I-GENE
were	O
identified	O
:	O
Ets2	B-GENE
,	O
Fli1	B-GENE
,	O
GABPalpha	B-GENE
,	O
SAP1	B-GENE
,	O
Elk1	B-GENE
,	O
and	O
PE1	B-GENE
.	O

A	O
2	O
kb	O
transcript	O
was	O
isolated	O
from	O
brain	O
that	O
encodes	O
a	O
approximately	O
57	O
kDa	O
protein	O
;	O
the	O
predicted	O
protein	O
contains	O
the	O
known	O
N	B-GENE
-	I-GENE
terminal	I-GENE
Ets	I-GENE
domain	I-GENE
of	O
PE1	B-GENE
and	O
a	O
novel	O
C	O
-	O
terminal	O
domain	O
with	O
signficant	O
homology	O
to	O
murine	B-GENE
ERF	I-GENE
.	O

Twenty	O
eligible	O
patients	O
with	O
cirrhosis	O
were	O
randomized	O
into	O
two	O
groups	O
:	O
10	O
patients	O
treated	O
with	O
6	O
million	O
units	O
of	O
natural	O
IFN	B-GENE
-	I-GENE
beta	I-GENE
twice	O
a	O
week	O
for	O
36	O
months	O
and	O
10	O
patients	O
without	O
IFN	B-GENE
therapy	O
.	O

It	O
is	O
now	O
well	O
accepted	O
that	O
the	O
p53	B-GENE
C	I-GENE
-	I-GENE
terminus	I-GENE
plays	O
a	O
central	O
role	O
in	O
controlling	O
the	O
activity	O
of	O
the	O
wild	O
-	O
type	O
molecule	O
.	O

The	O
transcription	O
factor	O
Jun	B-GENE
(	O
c	B-GENE
-	I-GENE
Jun	I-GENE
)	O
functions	O
as	O
a	O
recipient	O
of	O
extracellular	O
growth	O
signals	O
and	O
converts	O
them	O
into	O
patterns	O
of	O
gene	O
expression	O
.	O

This	O
compound	O
is	O
the	O
main	O
bioactive	O
metabolite	O
of	O
trimebutine	O
II	O
(	O
Debridat	O
,	O
CAS	O
39133	O
-	O
31	O
-	O
8	O
)	O
,	O
an	O
antispasmodic	O
widely	O
used	O
for	O
intestinal	O
diseases	O
since	O
1969	O
.	O

This	O
enabled	O
the	O
formation	O
of	O
stem	O
-	O
loop	O
templates	O
with	O
the	O
fusion	O
point	O
of	O
the	O
chimeric	O
transcript	O
in	O
the	O
loop	O
and	O
the	O
use	O
of	O
MLL	B-GENE
primers	O
in	O
two	O
-	O
sided	O
PCR	O
.	O

It	O
contains	O
25	O
exons	O
coding	O
for	O
a	O
4	O
.	O
7kb	O
transcript	O
including	O
large	O
5	O
'	O
-	O
and	O
3	O
'	O
-	O
(	O
1218bp	O
and	O
701bp	O
,	O
respectively	O
)	O
untranslated	O
regions	O
(	O
UTRs	O
)	O
.	O

The	O
limit	O
between	O
the	O
cecum	O
and	O
the	O
ascending	O
colon	O
was	O
externally	O
marked	O
by	O
the	O
sulcus	O
cecocolicus	O
dorsalis	O
and	O
ventralis	O
.	O

These	O
results	O
further	O
support	O
an	O
important	O
role	O
for	O
CBF2	B-GENE
in	O
mediating	O
EBNA2	B-GENE
transactivation	O
;	O
they	O
identify	O
the	O
hnRNP	B-GENE
protein	I-GENE
AUF1	I-GENE
as	O
a	O
major	O
component	O
of	O
CBF2	B-GENE
and	O
are	O
also	O
the	O
first	O
evidence	O
of	O
a	O
cis	O
-	O
acting	O
sequence	O
other	O
than	O
a	O
CBF1	B-GENE
binding	I-GENE
element	I-GENE
that	O
is	O
able	O
to	O
confer	O
responsiveness	O
to	O
EBNA2	B-GENE
.	O

Viruses	O
were	O
isolated	O
from	O
9	O
lungs	O
:	O
7	O
with	O
PI	O
-	O
3V	O
,	O
1	O
with	O
NCP	O
BVDV	O
type	O
1	O
,	O
and	O
1	O
with	O
both	O
BVHV	O
-	O
1	O
and	O
BVDV	O
.	O

Splicing	O
of	O
the	O
K	B-GENE
-	I-GENE
SAM	I-GENE
alternative	O
exon	O
of	O
the	O
fibroblast	B-GENE
growth	I-GENE
factor	I-GENE
receptor	I-GENE
2	I-GENE
gene	I-GENE
is	O
heavily	O
dependent	O
on	O
the	O
U	O
-	O
rich	O
sequence	O
IAS1	B-GENE
lying	O
immediately	O
downstream	O
from	O
its	O
5	O
'	O
splice	O
site	O
.	O

During	O
treatment	O
,	O
the	O
phosphorylation	O
state	O
of	O
Rb	B-GENE
shifted	O
to	O
a	O
hypophosphorylated	O
form	O
.	O
mRNA	O
for	O
the	O
HPV	O
E6	B-GENE
/	O
E7	B-GENE
genes	O
decreased	O
;	O
however	O
,	O
significant	O
changes	O
in	O
the	O
E7	B-GENE
protein	I-GENE
were	O
not	O
observed	O
,	O
while	O
increased	O
levels	O
of	O
Rb	B-GENE
immunoprecipitated	O
with	O
anti	B-GENE
-	I-GENE
E7	I-GENE
antibodies	I-GENE
were	O
observed	O
.	O

Five	O
of	O
the	O
Aeromonas	O
strains	O
and	O
one	O
of	O
V	O
cholerae	O
non	O
-	O
O1	O
were	O
positive	O
for	O
enterotoxin	O
activity	O
.	O

The	O
2	O
cDNAs	O
differed	O
in	O
the	O
length	O
of	O
their	O
respective	O
3	O
'	O
untranslated	O
regions	O
,	O
of	O
577	O
bp	O
in	O
Cp	B-GENE
.	I-GENE
F6	I-GENE
and	O
72	O
bp	O
in	O
Cp	B-GENE
.	I-GENE
F10	I-GENE
,	O
in	O
both	O
of	O
which	O
a	O
putative	O
polyadenylation	O
signal	O
was	O
identified	O
.	O

Platelet	O
counts	O
and	O
function	O
as	O
well	O
as	O
fibrinogen	B-GENE
and	O
von	B-GENE
Willebrand	I-GENE
factor	I-GENE
(	O
vWF	B-GENE
)	O
levels	O
were	O
determined	O
in	O
each	O
sample	O
.	O

The	O
aim	O
of	O
our	O
study	O
was	O
to	O
evaluate	O
the	O
level	O
of	O
oxidative	O
stress	O
in	O
healthy	O
controls	O
(	O
CTL	O
)	O
compared	O
with	O
CRF	O
and	O
HD	O
patients	O
before	O
(	O
pre	O
-	O
HD	O
)	O
and	O
after	O
(	O
post	O
-	O
HD	O
)	O
the	O
dialysis	O
session	O
,	O
carried	O
out	O
on	O
a	O
high	O
biocompatible	O
polyacrylonitrile	O
membrane	O
AN69	O
.	O

Indirect	O
plasma	O
parameters	O
such	O
as	O
vitamin	O
E	O
,	O
thiol	O
and	O
uric	O
acid	O
levels	O
were	O
also	O
quantified	O
.	O

The	O
results	O
indicate	O
that	O
the	O
relationship	O
between	O
comprehension	O
and	O
production	O
is	O
different	O
at	O
different	O
stages	O
in	O
development	O
.	O

On	O
long	O
-	O
term	O
follow	O
-	O
up	O
,	O
there	O
was	O
no	O
significant	O
difference	O
in	O
the	O
incidence	O
of	O
hospitalizations	O
(	O
1	O
per	O
2	O
.	O
1	O
vs	O
.	O

The	O
tumor	B-GENE
-	I-GENE
suppressor	I-GENE
protein	I-GENE
p53	I-GENE
is	O
involved	O
in	O
maintaining	O
genomic	O
stability	O
.	O

Abrogation	O
of	O
p53	B-GENE
function	O
by	O
E6	B-GENE
resulted	O
in	O
an	O
increase	O
in	O
the	O
spontaneous	O
mutation	O
frequencies	O
at	O
the	O
heterozygous	O
thymidine	B-GENE
kinase	I-GENE
(	O
TK	B-GENE
)	O
locus	O
but	O
not	O
at	O
the	O
hemizygous	O
hypoxanthine	B-GENE
phosphoribosyl	I-GENE
transferase	I-GENE
(	O
HPRT	B-GENE
)	O
locus	O
.	O

Cytogenetic	O
analysis	O
of	O
LOH	O
mutants	O
by	O
chromosome	O
painting	O
indicated	O
a	O
mosaic	O
of	O
chromosomal	O
aberrations	O
involving	O
chromosome	O
17	O
,	O
in	O
which	O
partial	O
chromosome	O
deletions	O
,	O
amplifications	O
,	O
and	O
multiple	O
translocations	O
appeared	O
heterogeneously	O
in	O
a	O
single	O
mutant	O
.	O

These	O
results	O
support	O
a	O
model	O
in	O
which	O
p53	B-GENE
protein	I-GENE
contributes	O
to	O
the	O
maintenance	O
of	O
genomic	O
integrity	O
through	O
recombinational	O
repair	O
.	O

In	O
patients	O
with	O
type	O
II	O
tumors	O
,	O
the	O
pattern	O
of	O
lymphatic	O
spread	O
was	O
primarily	O
directed	O
toward	O
the	O
paracardial	O
,	O
lesser	O
curvature	O
,	O
and	O
left	O
gastric	O
artery	O
nodes	O
;	O
esophagectomy	O
offered	O
no	O
survival	O
benefit	O
over	O
extended	O
gastrectomy	O
in	O
these	O
patients	O
.	O

The	O
muskox	O
is	O
a	O
new	O
host	O
record	O
for	O
T	O
.	O
gondii	O
.	O

Mucosal	O
application	O
of	O
NCX	O
-	O
4016	O
,	O
however	O
,	O
did	O
not	O
cause	O
PD	O
reduction	O
and	O
luminal	O
H	O
+	O
loss	O
,	O
but	O
produced	O
a	O
marked	O
hyperemia	O
,	O
resulting	O
in	O
no	O
damage	O
in	O
the	O
stomach	O
of	O
both	O
normal	O
and	O
STZ	O
-	O
diabetic	O
rats	O
.	O

The	O
amino	O
acid	O
sequence	O
of	O
matrilysin	B-GENE
-	I-GENE
2	I-GENE
also	O
contains	O
a	O
threonine	O
residue	O
adjacent	O
to	O
the	O
Zn	O
-	O
binding	O
site	O
that	O
has	O
been	O
defined	O
as	O
a	O
specific	O
feature	O
of	O
matrilysin	B-GENE
.	O

Regarding	O
"	O
the	O
relation	O
between	O
sexual	O
orientation	O
and	O
penile	O
size	O
,	O
"	O
by	O
A	O
.	O

Analysis	O
of	O
Standard	O
Reference	O
Material	O
1846	O
,	O
Infant	O
Formula	O
,	O
gave	O
a	O
mean	O
value	O
of	O
0	O
.	O
95	O
+	O
/	O
-	O
0	O
.	O
088	O
mg	O
vitamin	O
K	O
/	O
kg	O
(	O
K	O
or	O
K1	O
?	O
)	O
(	O
n	O
=	O
31	O
)	O
with	O
a	O
coefficient	O
of	O
variation	O
of	O
9	O
.	O
26	O
.	O

The	O
Spo0F	B-GENE
residues	I-GENE
making	O
up	O
the	O
hydrophobic	O
patch	O
are	O
very	O
similar	O
in	O
all	O
response	O
regulators	O
suggesting	O
that	O
the	O
binding	O
is	O
initiated	O
through	O
the	O
same	O
residues	O
in	O
all	O
interacting	O
response	O
regulator	O
-	O
kinase	O
pairs	O
.	O

While	O
mutations	O
in	O
K	B-GENE
-	I-GENE
Rev	I-GENE
that	O
inactivate	O
any	O
one	O
of	O
these	O
properties	O
also	O
blocked	O
K	B-GENE
-	I-GENE
Rev	I-GENE
-	O
dependent	O
nuclear	O
RNA	O
export	O
,	O
several	O
K	B-GENE
-	I-GENE
Rev	I-GENE
mutants	I-GENE
were	O
comparable	O
to	O
wild	O
type	O
when	O
assayed	O
for	O
any	O
of	O
these	O
individual	O
activities	O
yet	O
nevertheless	O
defective	O
for	O
RNA	O
export	O
.	O

These	O
results	O
suggest	O
that	O
Cdc42p	B-GENE
is	O
in	O
fact	O
required	O
for	O
pheromone	O
response	O
and	O
that	O
interaction	O
with	O
the	O
PAK	B-GENE
Ste20p	B-GENE
is	O
critical	O
for	O
that	O
role	O
.	O

Symptoms	O
,	O
however	O
,	O
appear	O
to	O
correlate	O
poorly	O
with	O
oesophagitis	O
;	O
hence	O
,	O
severe	O
symptoms	O
do	O
not	O
indicate	O
there	O
is	O
greater	O
oesophageal	O
damage	O
.	O

The	O
variable	O
phenotype	O
of	O
the	O
allotetraploids	O
could	O
not	O
be	O
explained	O
by	O
cytological	O
abnormalities	O
.	O

It	O
is	O
now	O
estimated	O
that	O
inactivation	O
mutants	O
of	O
PTEN	B-GENE
exist	O
in	O
60	O
%	O
of	O
all	O
forms	O
of	O
solid	O
tumors	O
.	O

We	O
have	O
demonstrated	O
that	O
the	O
activity	O
of	O
ILK	B-GENE
is	O
constitutively	O
elevated	O
in	O
PTEN	B-GENE
mutant	I-GENE
cells	O
.	O

The	O
detector	O
has	O
the	O
advantage	O
of	O
finding	O
both	O
ST	O
segment	O
deviations	O
and	O
entire	O
ST	O
-	O
T	O
complex	O
changes	O
thereby	O
providing	O
a	O
wider	O
characterization	O
of	O
the	O
potential	O
ischemic	O
events	O
.	O

Primary	O
adrenal	O
hypersensitivity	O
to	O
ACTH	B-GENE
drive	O
in	O
obesity	O
has	O
also	O
been	O
suggested	O
.	O

In	O
addition	O
,	O
a	O
noncanonical	O
C	B-GENE
/	I-GENE
EBP	I-GENE
-	I-GENE
binding	I-GENE
site	I-GENE
within	O
the	O
Gadd45gamma	B-GENE
promoter	I-GENE
where	O
C	B-GENE
/	I-GENE
EBPbeta	I-GENE
and	O
C	B-GENE
/	I-GENE
EBPdelta	I-GENE
could	O
bind	O
,	O
was	O
identified	O
by	O
electrophoretic	O
mobility	O
shift	O
assay	O
(	O
EMSA	O
)	O
and	O
reporter	O
gene	O
analysis	O
.	O

From	O
two	O
inhibitor	O
scaffolds	O
,	O
we	O
have	O
identified	O
potent	O
and	O
selective	O
inhibitors	O
for	O
sensitized	O
kinases	O
from	O
five	O
distinct	O
subfamilies	O
.	O

By	O
progressive	O
5	O
'	O
-	O
deletion	O
studies	O
,	O
we	O
have	O
identified	O
a	O
248	O
-	O
bp	O
DNA	O
fragment	O
(	O
-	O
1018	O
to	O
-	O
771	O
,	O
relative	O
to	O
the	O
translation	O
start	O
site	O
)	O
at	O
the	O
5	O
'	O
-	O
flanking	O
region	O
of	O
the	O
human	B-GENE
GnRHR	I-GENE
gene	I-GENE
that	O
is	O
responsible	O
for	O
the	O
GnRHa	O
-	O
mediated	O
down	O
-	O
regulation	O
of	O
human	B-GENE
GnRHR	I-GENE
promoter	I-GENE
activity	O
.	O

Intracellular	O
localization	O
studies	O
using	O
the	O
mDAP	B-GENE
-	I-GENE
3	I-GENE
/	O
EGFP	B-GENE
fusion	O
protein	O
,	O
cell	O
fractionation	O
and	O
protease	O
protection	O
experiments	O
localized	O
mDAP	B-GENE
-	I-GENE
3	I-GENE
to	O
the	O
mitochondrial	O
matrix	O
.	O

Reporter	O
gene	O
expression	O
analyses	O
indicate	O
that	O
both	O
WASP	B-GENE
promoters	I-GENE
show	O
high	O
levels	O
of	O
expression	O
in	O
different	O
hematopoietic	O
cell	O
lines	O
.	O

Altogether	O
these	O
results	O
suggest	O
that	O
,	O
in	O
KG1a	O
cells	O
,	O
TNFalpha	B-GENE
can	O
stimulate	O
in	O
parallel	O
PC	B-GENE
-	I-GENE
PLC	I-GENE
and	O
PLD	B-GENE
,	O
whose	O
lipid	O
products	O
activate	O
in	O
turn	O
mitogen	B-GENE
-	I-GENE
activated	I-GENE
protein	I-GENE
kinase	I-GENE
(	O
MAP	B-GENE
kinase	I-GENE
)	O
and	O
NF	B-GENE
-	I-GENE
kappaB	I-GENE
signalling	O
respectively	O
.	O

Polysome	O
and	O
40S	B-GENE
ribosome	I-GENE
fractions	O
were	O
severely	O
decreased	O
in	O
the	O
krr1	B-GENE
mutant	I-GENE
and	O
Kri1p	B-GENE
-	O
depleted	O
cells	O
.	O

They	O
also	O
negatively	O
modulate	O
the	O
PI	B-GENE
3	I-GENE
-	I-GENE
kinase	I-GENE
catalytic	O
activity	O
but	O
to	O
different	O
extents	O
,	O
dependent	O
on	O
the	O
unique	O
N	O
-	O
terminal	O
structure	O
of	O
each	O
isoform	O
.	O

The	O
Drosophila	B-GENE
melanogaster	I-GENE
suppressor	I-GENE
of	I-GENE
sable	I-GENE
gene	I-GENE
,	O
su	B-GENE
(	I-GENE
s	I-GENE
)	I-GENE
,	O
encodes	O
a	O
novel	O
,	O
150	O
-	O
kDa	O
nuclear	O
RNA	O
binding	O
protein	O
,	O
SU	B-GENE
(	I-GENE
S	I-GENE
)	I-GENE
,	O
that	O
negatively	O
regulates	O
RNA	O
accumulation	O
from	O
mutant	O
alleles	O
of	O
other	O
genes	O
that	O
have	O
transposon	O
insertions	O
in	O
the	O
5	O
'	O
transcribed	O
region	O
.	O

As	O
a	O
result	O
,	O
we	O
have	O
defined	O
two	O
arginine	O
-	O
rich	O
motifs	O
(	O
ARM1	O
and	O
ARM2	O
)	O
that	O
mediate	O
the	O
RNA	O
binding	O
activity	O
of	O
SU	B-GENE
(	I-GENE
S	I-GENE
)	I-GENE
.	O

Vasoactive	B-GENE
intestinal	I-GENE
peptide	I-GENE
and	O
pituitary	B-GENE
adenylate	I-GENE
cyclase	I-GENE
-	I-GENE
activating	I-GENE
polypeptide	I-GENE
inhibit	O
nuclear	B-GENE
factor	I-GENE
-	I-GENE
kappa	I-GENE
B	I-GENE
-	I-GENE
dependent	I-GENE
gene	I-GENE
activation	O
at	O
multiple	O
levels	O
in	O
the	O
human	O
monocytic	O
cell	O
line	O
THP	O
-	O
1	O
.	O

Overexpression	O
of	O
Trdpm1	B-GENE
in	O
a	O
dpm1	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
:	O
:	O
his7	B-GENE
/	I-GENE
dpm1	I-GENE
(	I-GENE
+	I-GENE
)	I-GENE
S	O
.	O
pombe	O
diploid	O
resulted	O
in	O
a	O
4	O
-	O
fold	O
increase	O
in	O
specific	O
DPM	B-GENE
synthase	I-GENE
activity	O
.	O

The	O
N	O
-	O
terminal	O
small	O
segment	O
of	O
yeast	B-GENE
TAF145	I-GENE
(	O
yTAF145	B-GENE
)	O
binds	O
to	O
TBP	B-GENE
and	O
thereby	O
inhibits	O
TBP	B-GENE
function	O
.	O

These	O
probable	O
border	O
sequences	O
are	O
closely	O
related	O
to	O
those	O
of	O
other	O
known	O
T	O
-	O
regions	O
and	O
define	O
a	O
second	O
T	O
-	O
region	O
of	O
pTiChry5	O
,	O
called	O
T	O
-	O
right	O
(	O
TR	O
)	O
,	O
that	O
confers	O
production	O
of	O
the	O
Amadoriopines	O
.	O

Another	O
cis	O
-	O
acting	O
element	O
,	O
exonic	O
splicing	O
suppressor	O
1	O
(	O
ESS1	O
)	O
,	O
represses	O
use	O
of	O
the	O
nt	O
3225	O
3	O
'	O
splice	O
site	O
.	O

5	O
'	O
-	O
RACE	O
analysis	O
suggested	O
a	O
single	O
transcription	O
initiation	O
site	O
187	O
bp	O
upstream	O
from	O
the	O
translational	O
start	O
site	O
.	O

Thromboelastography	O
is	O
a	O
test	O
that	O
could	O
potentially	O
correlate	O
with	O
the	O
degree	O
of	O
anticoagulation	O
produced	O
by	O
low	O
molecular	O
weight	O
heparin	O
.	O

Expression	O
of	O
a	O
hybrid	O
protein	O
containing	O
the	O
cytoplasmic	O
C	O
-	O
terminal	O
half	O
of	O
UhpB	B-GENE
fused	O
to	O
glutathione	B-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
(	O
GST	B-GENE
)	O
also	O
interfered	O
with	O
Uhp	B-GENE
signaling	O
.	O

RESULTS	O
:	O
Glaucoma	O
suspects	O
were	O
divided	O
into	O
two	O
groups	O
according	O
to	O
their	O
SWAP	O
results	O
:	O
high	O
risk	O
(	O
with	O
SWAP	O
abnormalities	O
)	O
and	O
low	O
risk	O
(	O
with	O
normal	O
SWAP	O
result	O
)	O
.	O

To	O
begin	O
to	O
understand	O
this	O
role	O
,	O
we	O
overexpressed	O
ATF	B-GENE
-	I-GENE
2	I-GENE
in	O
a	O
human	O
cancer	O
cell	O
line	O
.	O

Botulinum	B-GENE
toxin	I-GENE
A	I-GENE
in	O
the	O
treatment	O
of	O
hemiplegic	O
spastic	O
foot	O
drop	O
-	O
-	O
clinical	O
and	O
functional	O
outcomes	O
.	O

The	O
U17	B-GENE
/	O
U16	B-GENE
and	O
the	O
U16	B-GENE
+	I-GENE
gene	I-GENE
products	I-GENE
transactivated	O
the	O
HIV	B-GENE
LTR	I-GENE
.	O

The	O
Cili	B-GENE
-	I-GENE
2	I-GENE
sequences	I-GENE
possess	O
similarity	O
to	O
the	O
RNaseH	B-GENE
domain	I-GENE
of	O
Lian	B-GENE
-	O
Aa1	B-GENE
,	O
a	O
mosquito	B-GENE
non	I-GENE
-	I-GENE
LTR	I-GENE
retrotransposon	I-GENE
.	O

This	O
dynamic	O
response	O
strongly	O
suggests	O
that	O
the	O
p53	B-GENE
and	O
Rb	B-GENE
tumor	O
suppressor	O
pathways	O
are	O
intact	O
in	O
HeLa	O
cells	O
and	O
that	O
repression	O
of	O
HPV	B-GENE
E6	I-GENE
and	O
E7	B-GENE
mobilizes	O
these	O
pathways	O
in	O
an	O
orderly	O
fashion	O
to	O
deliver	O
growth	O
inhibitory	O
signals	O
to	O
the	O
cells	O
.	O

Effects	O
of	O
spatial	O
and	O
temporal	O
smoothing	O
on	O
stimulated	O
brillouin	O
scattering	O
in	O
the	O
independent	O
-	O
hot	O
-	O
spot	O
model	O
limit	O
The	O
influence	O
of	O
laser	O
beam	O
smoothing	O
on	O
stimulated	O
Brillouin	O
backscattering	O
(	O
SBBS	O
)	O
is	O
studied	O
analytically	O
in	O
the	O
limit	O
of	O
the	O
independent	O
hot	O
spot	O
model	O
.	O

Association	O
of	O
stress	O
during	O
delivery	O
with	O
increased	O
numbers	O
of	O
nucleated	O
cells	O
and	O
hematopoietic	O
progenitor	O
cells	O
in	O
umbilical	O
cord	O
blood	O
.	O

Transformation	O
of	O
the	O
sconC3	B-GENE
mutant	I-GENE
with	O
sconB	B-GENE
+	I-GENE
restores	O
the	O
wild	O
-	O
type	O
phenotype	O
.	O

RESULTS	O
:	O
The	O
main	O
effect	O
of	O
muscle	O
pain	O
,	O
compared	O
to	O
non	O
-	O
painful	O
stimulation	O
,	O
was	O
a	O
significant	O
and	O
long	O
-	O
lasting	O
increase	O
of	O
delta	O
(	O
1	O
-	O
3	O
Hz	O
)	O
power	O
and	O
an	O
alpha	O
-	O
1	O
(	O
9	O
-	O
11	O
Hz	O
)	O
power	O
increase	O
over	O
the	O
contralateral	O
parietal	O
locus	O
.	O

Based	O
on	O
16S	B-GENE
rRNA	I-GENE
gene	I-GENE
sequence	I-GENE
analysis	O
,	O
the	O
11	O
species	O
having	O
two	O
tuf	B-GENE
genes	I-GENE
all	O
have	O
a	O
common	O
ancestor	O
,	O
while	O
the	O
six	O
species	O
having	O
only	O
one	O
copy	O
diverged	O
from	O
the	O
enterococcal	O
lineage	O
before	O
that	O
common	O
ancestor	O
.	O

This	O
transcriptional	O
regulation	O
occurs	O
through	O
modulation	O
of	O
the	O
forkhead	B-GENE
transcription	I-GENE
factor	I-GENE
FKHR	B-GENE
-	I-GENE
L1	I-GENE
,	O
and	O
IL	B-GENE
-	I-GENE
3	I-GENE
inhibited	O
FKHR	B-GENE
-	I-GENE
L1	I-GENE
activity	O
in	O
a	O
PI3K	B-GENE
-	O
dependent	O
manner	O
.	O

Taken	O
together	O
,	O
these	O
observations	O
indicate	O
that	O
inhibition	O
of	O
p27	B-GENE
(	O
KIP1	B-GENE
)	O
transcription	O
through	O
PI3K	B-GENE
-	O
induced	O
FKHR	B-GENE
-	I-GENE
L1	I-GENE
phosphorylation	O
provides	O
a	O
novel	O
mechanism	O
of	O
regulating	O
cytokine	O
-	O
mediated	O
survival	O
and	O
proliferation	O
.	O

DNase	B-GENE
I	I-GENE
genomic	O
footprinting	O
revealed	O
that	O
the	O
c	B-GENE
-	I-GENE
Myb	I-GENE
site	I-GENE
is	O
occupied	O
in	O
a	O
tissue	O
-	O
specific	O
fashion	O
in	O
vivo	O
.	O

We	O
conclude	O
that	O
c	B-GENE
-	I-GENE
Myb	I-GENE
regulates	O
the	O
RAG	B-GENE
-	I-GENE
2	I-GENE
promoter	I-GENE
in	O
T	O
cells	O
by	O
binding	O
to	O
this	O
consensus	B-GENE
c	I-GENE
-	I-GENE
Myb	I-GENE
binding	I-GENE
site	I-GENE
.	O

RESULTS	O
:	O
Average	O
age	O
at	O
symptom	O
onset	O
was	O
41	O
.	O
2	O
years	O
.	O

Unlike	O
the	O
mammalian	O
proteins	O
,	O
XFGF3	B-GENE
is	O
efficiently	O
secreted	O
as	O
a	O
Mr	O
31	O
,	O
000	O
glycoprotein	O
,	O
gp31	B-GENE
,	O
which	O
undergoes	O
proteolytic	O
cleavage	O
to	O
produce	O
an	O
NH2	O
-	O
terminally	O
truncated	O
product	O
,	O
gp27	B-GENE
.	O

NH2	O
-	O
terminal	O
trimming	O
of	O
Xenopus	O
and	O
mammalian	B-GENE
FGF3s	I-GENE
may	O
therefore	O
be	O
a	O
prerequisite	O
of	O
optimal	O
biological	O
activity	O
.	O

Here	O
,	O
we	O
identified	O
three	O
cis	O
-	O
elements	O
required	O
for	O
replication	O
within	O
the	O
200	O
bp	O
promoter	O
,	O
using	O
autonomously	O
replicating	O
plasmids	O
carrying	O
various	O
mutations	O
and	O
deletions	O
.	O

The	O
objectives	O
of	O
the	O
present	O
study	O
were	O
to	O
evaluate	O
the	O
effects	O
of	O
adding	O
Equex	O
to	O
a	O
TRIS	O
-	O
extender	O
,	O
diluting	O
the	O
semen	O
in	O
1	O
or	O
2	O
steps	O
,	O
freezing	O
according	O
to	O
2	O
methods	O
,	O
thawing	O
at	O
2	O
rates	O
,	O
and	O
the	O
interactions	O
between	O
these	O
treatments	O
,	O
on	O
the	O
post	O
-	O
thaw	O
survival	O
of	O
dog	O
spermatozoa	O
at	O
38	O
degrees	O
C	O
.	O

Molecular	O
cloning	O
and	O
expression	O
of	O
human	B-GENE
UDP	I-GENE
-	I-GENE
d	I-GENE
-	I-GENE
Xylose	I-GENE
:	I-GENE
proteoglycan	I-GENE
core	I-GENE
protein	I-GENE
beta	B-GENE
-	I-GENE
d	I-GENE
-	I-GENE
xylosyltransferase	I-GENE
and	O
its	O
first	O
isoform	B-GENE
XT	I-GENE
-	I-GENE
II	I-GENE
.	O

Oncogenic	O
signalling	O
by	O
E2F1	B-GENE
has	O
recently	O
been	O
linked	O
to	O
stabilization	O
and	O
activation	O
of	O
the	O
tumour	O
suppressor	O
p53	B-GENE
(	O
refs	O
1	O
,	O
3	O
,	O
4	O
)	O
.	O

We	O
describe	O
the	O
identification	O
and	O
initial	O
characterization	O
of	O
neurobeachin	B-GENE
,	O
a	O
neuron	O
-	O
specific	O
multidomain	O
protein	O
of	O
327	O
kDa	O
with	O
a	O
high	O
-	O
affinity	O
binding	O
site	O
(	O
K	O
(	O
d	O
)	O
,	O
10	O
nm	O
)	O
for	O
the	O
type	B-GENE
II	I-GENE
regulatory	I-GENE
subunit	I-GENE
of	I-GENE
protein	I-GENE
kinase	I-GENE
A	I-GENE
(	O
PKA	B-GENE
RII	I-GENE
)	O
.	O

Antimicrobial	O
Susceptibility	O
of	O
Klebsiella	O
pneumoniae	O
Producing	O
Extended	B-GENE
-	I-GENE
Spectrum	I-GENE
beta	I-GENE
-	I-GENE
lactamase	I-GENE
(	O
ESBL	B-GENE
)	O
Isolated	O
in	O
Hospitals	O
in	O
Brazil	O
.	O

CONCLUSION	O
:	O
Our	O
results	O
suggest	O
that	O
AIF	O
peak	O
saturation	O
leads	O
to	O
a	O
significant	O
systematic	O
error	O
in	O
the	O
determination	O
of	O
CBV	O
and	O
CBF	O
values	O
and	O
has	O
necessarily	O
to	O
be	O
taken	O
into	O
account	O
for	O
dynamic	O
contrast	O
-	O
enhanced	O
MR	O
perfusion	O
studies	O
.	O

Toward	O
this	O
end	O
,	O
we	O
prepared	O
synthetic	O
proteins	O
with	O
either	O
the	O
catalytic	O
domain	O
of	O
FAP	B-GENE
-	I-GENE
1	I-GENE
(	I-GENE
C	I-GENE
-	I-GENE
terminal	I-GENE
399	I-GENE
amino	I-GENE
acids	I-GENE
)	I-GENE
or	O
its	O
inactive	O
form	O
(	O
Cys2408	O
-	O
-	O
>	O
Ser	O
)	O
fused	O
to	O
glutathione	B-GENE
-	I-GENE
S	I-GENE
-	I-GENE
transferase	I-GENE
(	O
GST	B-GENE
)	O
.	O

Furthermore	O
,	O
transfection	O
of	O
cells	O
with	O
the	O
spacer	O
-	O
RING	O
domain	O
alone	O
suppressed	O
the	O
antiapoptotic	O
function	O
of	O
the	O
N	O
-	O
terminal	O
BIR	B-GENE
domain	O
of	O
c	B-GENE
-	I-GENE
IAP1	I-GENE
and	O
induced	O
apoptosis	O
.	O

MS	O
characteristics	O
of	O
coumarins	O
,	O
psoralens	O
and	O
polymethoxylated	O
flavones	O
with	O
different	O
substitution	O
patterns	O
were	O
determined	O
on	O
the	O
basis	O
of	O
the	O
response	O
obtained	O
with	O
the	O
APcI	O
interface	O
.	O

Copyright	O
2000	O
Academic	O
Press	O
.	O

Plectin	B-GENE
and	O
desmoplakin	B-GENE
have	O
GSR	O
-	O
containing	O
domains	O
at	O
their	O
C	O
-	O
termini	O
and	O
we	O
further	O
demonstrate	O
that	O
the	O
GSR	O
-	O
containing	O
domain	O
of	O
plectin	B-GENE
,	O
but	O
not	O
desmoplakin	B-GENE
,	O
can	O
bind	O
to	O
MTs	O
in	O
vivo	O
.	O

Characterization	O
of	O
the	O
microtubule	O
binding	O
domain	O
of	O
microtubule	B-GENE
actin	I-GENE
crosslinking	I-GENE
factor	I-GENE
(	O
MACF	B-GENE
)	O
:	O
identification	O
of	O
a	O
novel	O
group	O
of	O
microtubule	B-GENE
associated	I-GENE
proteins	I-GENE
.	O

Fecal	O
samples	O
were	O
collected	O
at	O
the	O
beginning	O
and	O
end	O
of	O
each	O
trial	O
period	O
and	O
were	O
analyzed	O
for	O
gastrointestinal	O
nematode	O
eggs	O
and	O
Giardia	O
cyst	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
risk	O
factors	O
for	O
background	O
diabetic	O
retinopathy	O
(	O
BDR	O
)	O
and	O
PDR	O
by	O
following	O
394	O
Japanese	O
patients	O
with	O
early	O
-	O
onset	O
type	O
2	O
diabetes	O
diagnosed	O
before	O
30	O
years	O
of	O
age	O
(	O
mean	O
age	O
27	O
,	O
mean	O
blood	O
pressure	O
at	O
entry	O
116	O
/	O
73	O
mm	O
Hg	O
)	O
.	O

These	O
cells	O
produced	O
P2Y	B-GENE
(	I-GENE
11	I-GENE
)	I-GENE
mRNA	I-GENE
during	O
culture	O
.	O

Differential	O
association	O
of	O
products	O
of	O
alternative	O
transcripts	O
of	O
the	O
candidate	O
tumor	B-GENE
suppressor	I-GENE
ING1	I-GENE
with	O
the	O
mSin3	B-GENE
/	O
HDAC1	B-GENE
transcriptional	O
corepressor	O
complex	O
.	O

As	O
hypothesized	O
,	O
believers	O
showed	O
relatively	O
higher	O
right	O
hemispheric	O
activation	O
and	O
reduced	O
hemispheric	O
asymmetry	O
of	O
functional	O
complexity	O
.	O

Nucleotide	O
sequence	O
,	O
genome	O
organization	O
and	O
phylogenetic	O
analysis	O
of	O
pineapple	O
mealybug	O
wilt	O
-	O
associated	O
virus	O
-	O
2	O
.	O

Adjuvant	O
therapy	O
for	O
colon	O
cancer	O
]	O
Surgery	O
alone	O
may	O
fail	O
to	O
cure	O
a	O
considerable	O
number	O
of	O
locally	O
advanced	O
colon	O
cancers	O
.	O

Effects	O
of	O
Trypanosoma	O
vivax	O
on	O
pregnancy	O
of	O
Yankasa	O
sheep	O
and	O
the	O
results	O
of	O
homidum	O
chloride	O
chemotherapy	O
.	O

NF	B-GENE
kappa	I-GENE
B	I-GENE
was	O
activated	O
to	O
a	O
much	O
greater	O
extent	O
by	O
roscovitine	O
in	O
the	O
WT	O
cells	O
than	O
in	O
Y8	O
cells	O
.	O

Additionally	O
,	O
MIP	B-GENE
-	I-GENE
2A	I-GENE
antagonizes	O
cell	O
growth	O
regulatory	O
role	O
of	O
MBP	B-GENE
-	I-GENE
1	I-GENE
.	O

3	O
.	O
04	O
+	O
/	O
-	O
1	O
.	O
2	O
,	O
P	O
<	O
0	O
.	O
0001	O
)	O
,	O
large	O
accelerations	O
/	O
30	O
min	O
(	O
1	O
.	O
46	O
+	O
/	O
-	O
1	O
.	O
96	O
vs	O
.	O

In	O
addition	O
,	O
we	O
identified	O
two	O
mutations	O
,	O
Delta	O
M1281	O
and	O
IVS51	O
+	O
5G	O
-	O
-	O
>	O
A	O
,	O
in	O
a	O
German	O
USH1	B-GENE
patient	O
.	O

Nuclease	O
probing	O
and	O
structure	O
-	O
directed	O
mutagenesis	O
revealed	O
that	O
the	O
105	O
-	O
nt	O
TE	O
(	O
TE105	O
)	O
forms	O
a	O
cruciform	O
secondary	O
structure	O
containing	O
four	O
helices	O
connected	O
by	O
single	O
-	O
stranded	O
regions	O
.	O

Tele	O
-	O
Talk	O
has	O
the	O
extra	O
capability	O
of	O
operating	O
in	O
live	O
conference	O
situations	O
using	O
microphone	O
input	O
.	O

Perfusion	O
technique	O
for	O
perfusion	O
-	O
assisted	O
direct	O
coronary	O
artery	O
bypass	O
(	O
PADCAB	O
)	O
.	O

As	O
well	O
,	O
mixtures	O
of	O
(	O
LA	O
)	O
(	O
12	O
)	O
with	O
the	O
longer	O
chain	O
PEs	O
exhibit	O
unusual	O
biomodal	O
enthalpy	O
variations	O
,	O
suggesting	O
peptide	O
immiscibility	O
in	O
thicker	O
gel	O
state	O
bilayers	O
.	O

Energy	O
expenditure	O
was	O
obtained	O
using	O
a	O
primed	O
,	O
3	O
-	O
hour	O
infusion	O
of	O
NaH	O
(	O
13	O
)	O
CO	O
(	O
3	O
'	O
)	O
,	O
breath	O
(	O
13	O
)	O
CO	O
(	O
2	O
)	O
enrichment	O
determination	O
by	O
isotope	O
ratio	O
mass	O
spectroscopy	O
,	O
and	O
the	O
application	O
of	O
a	O
standard	O
regression	O
equation	O
.	O

Workload	O
,	O
UAPs	O
,	O
and	O
you	O
.	O

Naltrexone	O
hydrochloride	O
is	O
a	O
synthetic	O
opioid	B-GENE
receptor	I-GENE
antagonist	O
recently	O
used	O
in	O
efforts	O
to	O
provide	O
rapid	O
opioid	O
detoxification	O
.	O

Derivation	O
and	O
initial	O
characterization	O
of	O
a	O
mouse	O
mammary	O
tumor	O
cell	O
line	O
carrying	O
the	O
polyomavirus	B-GENE
middle	I-GENE
T	I-GENE
antigen	I-GENE
:	O
utility	O
in	O
the	O
development	O
of	O
novel	O
cancer	O
therapeutics	O
.	O

Hypomorphic	O
dSLBP	B-GENE
alleles	I-GENE
support	O
zygotic	O
development	O
but	O
cause	O
female	O
sterility	O
.	O

We	O
mapped	O
the	O
DGCR6	B-GENE
gene	I-GENE
to	O
chromosome	O
22q11	O
within	O
a	O
low	O
copy	O
repeat	O
,	O
termed	O
sc11	O
.	O
1a	O
,	O
and	O
identified	O
a	O
second	O
copy	O
of	O
the	O
gene	O
,	O
DGCR6L	B-GENE
,	O
within	O
the	O
duplicate	O
locus	O
,	O
termed	O
sc11	O
.	O
1b	O
.	O

Recruitment	O
of	O
an	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
complex	I-GENE
is	O
mediated	O
by	O
the	O
constitutive	O
activation	O
domain	O
in	O
CREB	B-GENE
,	O
independently	O
of	O
CREB	B-GENE
phosphorylation	O
.	O

The	O
observed	O
phenotypes	O
may	O
be	O
explained	O
by	O
(	O
i	O
)	O
a	O
selective	O
disruption	O
of	O
very	B-GENE
-	I-GENE
low	I-GENE
-	I-GENE
density	I-GENE
lipoprotein	I-GENE
secretion	O
due	O
to	O
decreased	O
expression	O
of	O
genes	O
encoding	O
apolipoprotein	B-GENE
B	I-GENE
and	O
microsomal	B-GENE
triglyceride	I-GENE
transfer	I-GENE
protein	I-GENE
,	O
(	O
ii	O
)	O
an	O
increase	O
in	O
hepatic	O
cholesterol	O
uptake	O
due	O
to	O
increased	O
expression	O
of	O
the	O
major	O
high	B-GENE
-	I-GENE
density	I-GENE
lipoprotein	I-GENE
receptor	I-GENE
,	O
scavenger	B-GENE
receptor	I-GENE
BI	I-GENE
,	O
and	O
(	O
iii	O
)	O
a	O
decrease	O
in	O
bile	O
acid	O
uptake	O
to	O
the	O
liver	O
due	O
to	O
down	O
-	O
regulation	O
of	O
the	O
major	O
basolateral	B-GENE
bile	I-GENE
acid	I-GENE
transporters	I-GENE
sodium	I-GENE
taurocholate	I-GENE
cotransporter	I-GENE
protein	I-GENE
and	O
organic	B-GENE
anion	I-GENE
transporter	I-GENE
protein	I-GENE
1	I-GENE
.	O

Inactivity	O
of	O
the	O
human	B-GENE
cytomegalovirus	I-GENE
(	I-GENE
HCMV	I-GENE
)	I-GENE
major	I-GENE
immediate	I-GENE
-	I-GENE
early	I-GENE
regulatory	I-GENE
region	I-GENE
(	O
MIERR	B-GENE
)	O
,	O
which	O
is	O
composed	O
of	O
promoter	O
,	O
enhancer	O
,	O
unique	O
region	O
,	O
and	O
modulator	O
,	O
is	O
linked	O
to	O
lack	O
of	O
HCMV	O
replication	O
in	O
latently	O
infected	O
cells	O
and	O
in	O
other	O
nonpermissive	O
cell	O
types	O
,	O
including	O
human	O
embryonal	O
NTera2	O
carcinoma	O
(	O
NT2	O
)	O
cells	O
.	O

Both	O
Z	B-GENE
and	O
R	B-GENE
expression	O
resulted	O
in	O
PML	O
dispersion	O
in	O
EBV	O
-	O
positive	O
cells	O
.	O

Immunofluorescence	O
studies	O
in	O
C2C12	O
myotubes	O
show	O
that	O
Smad2	B-GENE
and	O
MEF2A	B-GENE
co	O
-	O
localise	O
in	O
the	O
nucleus	O
of	O
multinuclear	O
myotubes	O
during	O
differentiation	O
.	O

Southern	O
blot	O
analysis	O
of	O
genomic	O
DNA	O
from	O
somatic	O
cell	O
hybrids	O
showed	O
that	O
endothelial	B-GENE
-	I-GENE
TACC	I-GENE
-	I-GENE
related	I-GENE
cDNA	I-GENE
maps	O
to	O
chromosome	O
10	O
.	O

The	O
presence	O
of	O
truncated	O
receptor	O
isoforms	O
in	O
diverse	O
species	O
suggests	O
that	O
these	O
proteins	O
may	O
have	O
important	O
functional	O
roles	O
in	O
regulating	O
EGFR	B-GENE
activity	O
.	O

The	O
continuing	O
development	O
of	O
ligands	O
that	O
function	O
as	O
selective	O
estrogens	O
or	O
antiestrogens	O
for	O
ERalpha	B-GENE
or	O
ERbeta	B-GENE
should	O
allow	O
optimized	O
tissue	O
selectivity	O
of	O
these	O
agents	O
for	O
menopausal	O
hormone	O
replacement	O
therapy	O
and	O
the	O
treatment	O
and	O
prevention	O
of	O
breast	O
cancer	O
.	O

Behavioural	O
tests	O
with	O
192	O
specimen	O
of	O
the	O
roman	O
garden	O
snail	O
Helix	O
pomatia	O
L	O
.	O
were	O
performed	O
in	O
order	O
to	O
clarify	O
whether	O
the	O
thermopreferendum	O
of	O
this	O
pulmonate	O
is	O
influenced	O
not	O
only	O
by	O
the	O
temperature	O
of	O
the	O
substratum	O
but	O
also	O
by	O
air	O
temperature	O
.	O

Increased	O
erythropoietin	B-GENE
synthesis	O
in	O
patients	O
with	O
COLD	O
or	O
left	O
heart	O
failure	O
is	O
related	O
to	O
alterations	O
in	O
renal	O
haemodynamics	O
.	O

Using	O
immunochemical	O
co	O
-	O
precipitation	O
methods	O
,	O
we	O
also	O
found	O
that	O
the	O
two	O
proteins	O
are	O
bound	O
in	O
vivo	O
.	O

An	O
additional	O
9	O
patients	O
achieved	O
normal	O
levels	O
with	O
adjunctive	O
drug	O
therapy	O
.	O

For	O
immunological	O
methods	O
,	O
identification	O
of	O
such	O
antigens	O
with	O
intermolecular	O
variability	O
,	O
e	O
.	O
g	O
.	O
,	O
the	O
structural	O
aescin	O
analogs	O
,	O
is	O
of	O
unknown	O
validity	O
.	O

Blood	O
from	O
dams	O
was	O
collected	O
prior	O
to	O
inoculation	O
and	O
at	O
time	O
of	O
necropsy	O
for	O
measurement	O
of	O
IgM	B-GENE
and	O
IgG	B-GENE
antibodies	I-GENE
to	O
M	O
.	O
pulmonis	O
.	O

Single	O
amino	O
acid	O
substitutions	O
at	O
the	O
acyl	O
-	O
CoA	O
-	O
binding	O
domain	O
interrupt	O
14	O
[	O
C	O
]	O
palmitoyl	O
-	O
CoA	O
binding	O
of	O
ACBP2	B-GENE
,	O
an	O
Arabidopsis	O
acyl	B-GENE
-	I-GENE
CoA	I-GENE
-	I-GENE
binding	I-GENE
protein	I-GENE
with	O
ankyrin	B-GENE
repeats	O
.	O

The	O
bovine	B-GENE
PGHS	I-GENE
-	I-GENE
2	I-GENE
cDNA	I-GENE
was	O
cloned	O
by	O
a	O
combination	O
of	O
reverse	O
transcription	O
-	O
polymerase	O
chain	O
reaction	O
and	O
cDNA	O
library	O
screening	O
.	O

The	O
regulation	O
of	O
PGHS	B-GENE
-	I-GENE
2	I-GENE
mRNA	I-GENE
and	O
protein	O
was	O
studied	O
in	O
primary	O
cultures	O
of	O
bovine	O
uterine	O
stromal	O
cells	O
stimulated	O
with	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
(	O
PMA	O
;	O
100	O
nM	O
)	O
.	O

Anti	B-GENE
-	I-GENE
nucleolin	I-GENE
mAb	I-GENE
was	O
used	O
to	O
confirm	O
the	O
antigenic	O
properties	O
of	O
this	O
p95	B-GENE
component	I-GENE
.	O

Furthermore	O
,	O
stable	O
expression	O
of	O
a	O
constitutively	O
active	O
form	O
of	O
chicken	O
Notch1	B-GENE
or	O
Notch2	B-GENE
in	O
a	O
B	O
cell	O
line	O
results	O
in	O
a	O
down	O
-	O
regulation	O
of	O
surface	O
IgM	B-GENE
expression	O
,	O
which	O
is	O
accompanied	O
by	O
the	O
reduction	O
of	O
IgH	B-GENE
gene	I-GENE
transcripts	I-GENE
.	O

The	O
effects	O
of	O
the	O
transfected	O
receptors	O
were	O
associated	O
with	O
antagonism	O
of	O
activator	B-GENE
protein	I-GENE
1	I-GENE
(	O
AP	B-GENE
-	I-GENE
1	I-GENE
)	O
activity	O
.	O

Recent	O
studies	O
using	O
isolated	O
rat	O
adipocytes	O
and	O
chemically	O
synthesized	O
PIG	O
compounds	O
point	O
to	O
IRS1	B-GENE
/	I-GENE
3	I-GENE
tyrosine	O
phosphorylation	O
by	O
p59Lyn	B-GENE
kinase	I-GENE
as	O
the	O
site	O
of	O
cross	O
-	O
talk	O
,	O
the	O
negative	O
regulation	O
of	O
which	O
by	O
interaction	O
with	O
caveolin	B-GENE
is	O
apparently	O
abrogated	O
by	O
PIG	O
.	O

As	O
an	O
oral	O
,	O
nontoxic	O
compound	O
with	O
a	O
mechanism	O
of	O
action	O
distinct	O
from	O
that	O
of	O
ABL	B-GENE
tyrosine	I-GENE
kinase	I-GENE
inhibition	O
,	O
FTI	O
SCH66336	O
shows	O
promise	O
for	O
the	O
treatment	O
of	O
BCR	B-GENE
/	O
ABL	B-GENE
-	O
induced	O
leukemia	O
.	O

We	O
conclude	O
that	O
RPMS	B-GENE
acts	O
as	O
a	O
negative	O
regulator	O
of	O
EBNA2	B-GENE
and	O
Notch	B-GENE
activity	O
through	O
its	O
interactions	O
with	O
the	O
CBF1	B-GENE
-	I-GENE
associated	I-GENE
corepressor	I-GENE
complex	I-GENE
.	O

Transactivation	O
of	O
oIFNtau	B-GENE
enhancer	O
-	O
reporter	O
constructs	O
was	O
primarily	O
regulated	O
by	O
three	O
regions	O
containing	O
AP	B-GENE
-	I-GENE
1	I-GENE
site	I-GENE
,	O
GATA	B-GENE
like	I-GENE
sequence	I-GENE
and	O
site	O
(	O
s	O
)	O
unidentified	O
.	O

Copyright	O
2000	O
John	O
Wiley	O
&	O
Sons	O
,	O
Ltd	O
.	O

Fluorimetric	O
determination	O
of	O
methylmercury	O
as	O
an	O
ion	O
-	O
association	O
complex	O
with	O
rhodamine	O
B	O
in	O
the	O
presence	O
of	O
iodide	O
.	O

Cells	O
containing	O
alpha	O
subunits	O
that	O
lacked	O
a	O
distal	O
domain	O
(	O
term	O
-	O
3	O
)	O
or	O
had	O
the	O
alternatively	O
spliced	O
alpha	O
-	O
2	O
distal	O
domain	O
showed	O
markedly	O
decreased	O
ability	O
to	O
support	O
tyrosine	O
phosphorylation	O
of	O
Jak	B-GENE
-	I-GENE
2	I-GENE
and	O
its	O
substrates	O
or	O
to	O
up	O
-	O
regulate	O
CD86	B-GENE
.	O

In	O
Saccharomyces	O
cerevisiae	O
,	O
eIF6	B-GENE
is	O
encoded	O
by	O
a	O
single	O
-	O
copy	O
essential	O
gene	O
.	O

TaqMan	O
analysis	O
of	O
gene	O
expression	O
following	O
chronic	O
FA	O
treatment	O
showed	O
neither	O
a	O
decrease	O
in	O
the	O
amount	O
of	O
leptin	B-GENE
receptor	I-GENE
(	O
Ob	B-GENE
-	I-GENE
R	I-GENE
)	O
mRNA	O
,	O
nor	O
an	O
increase	O
in	O
the	O
negative	O
regulators	O
of	O
STAT	B-GENE
signalling	O
,	O
SOCS3	B-GENE
(	O
suppressors	B-GENE
of	I-GENE
cytokine	I-GENE
signalling	I-GENE
)	O
or	O
cytokine	B-GENE
inducible	I-GENE
sequence	I-GENE
(	O
CIS	B-GENE
)	O
.	O

The	O
blood	O
levels	O
of	O
lactate	O
,	O
pyruvate	O
and	O
amino	O
acids	O
were	O
not	O
elevated	O
.	O

The	O
expression	O
of	O
alpha	B-GENE
-	I-GENE
amylase	I-GENE
can	O
be	O
transactivated	O
by	O
the	O
transcription	O
factor	O
GAMyb	B-GENE
,	O
which	O
is	O
itself	O
induced	O
by	O
GA	O
.	O

Only	O
nine	O
patients	O
were	O
offered	O
surgery	O
(	O
six	O
were	O
resected	O
and	O
three	O
were	O
found	O
inoperable	O
)	O
.	O

Adjuvant	O
and	O
neoadjuvant	O
treatment	O
of	O
breast	O
cancer	O
.	O

Sequence	O
analysis	O
revealed	O
significant	O
differences	O
between	O
the	O
5	O
'	O
region	O
of	O
the	O
beta	O
subunit	O
gene	O
and	O
the	O
corresponding	O
regions	O
of	O
the	O
homologous	B-GENE
GlyR	I-GENE
alpha	I-GENE
subunit	I-GENE
genes	I-GENE
;	O
it	O
also	O
identified	O
a	O
novel	O
exon	O
(	O
exon	O
0	O
)	O
that	O
encodes	O
most	O
of	O
the	O
5	O
'	O
-	O
untranslated	O
portion	O
of	O
the	O
GlyR	B-GENE
beta	I-GENE
mRNA	I-GENE
.	O

Anecdotal	O
observations	O
scattered	O
throughout	O
the	O
literature	O
have	O
often	O
provided	O
clues	O
to	O
underlying	O
variations	O
in	O
humans	O
'	O
ability	O
to	O
handle	O
dietary	O
chemicals	O
.	O

The	O
human	B-GENE
cytomegalovirus	I-GENE
(	I-GENE
HCMV	I-GENE
)	I-GENE
major	I-GENE
immediate	I-GENE
-	I-GENE
early	I-GENE
protein	I-GENE
IE2	I-GENE
is	O
a	O
nuclear	O
phosphoprotein	O
that	O
is	O
believed	O
to	O
be	O
a	O
key	O
regulator	O
in	O
both	O
lytic	O
and	O
latent	O
infections	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
whether	O
RSTD	O
predicts	O
coronary	O
anatomy	O
during	O
acute	O
coronary	O
occlusion	O
.	O

We	O
have	O
now	O
tested	O
all	O
known	O
mammalian	B-GENE
Groucho	I-GENE
family	I-GENE
members	I-GENE
for	O
their	O
ability	O
to	O
interact	O
specifically	O
with	O
individual	O
Tcf	B-GENE
/	O
Lef	B-GENE
family	O
members	O
.	O

We	O
show	O
here	O
that	O
the	O
in	O
vitro	O
transcription	O
extract	O
contains	O
a	O
binding	O
activity	O
that	O
is	O
specific	O
for	O
the	O
initiator	O
element	O
and	O
thus	O
may	O
participate	O
in	O
recruiting	O
RNA	B-GENE
polymerase	I-GENE
II	I-GENE
to	O
the	O
SL	O
RNA	O
gene	O
promoter	O
.	O

The	O
438	B-GENE
bp	I-GENE
EcoRI	I-GENE
fragment	I-GENE
,	O
which	O
was	O
detected	O
by	O
Southern	O
hybridization	O
,	O
reveals	O
an	O
open	O
reading	O
frame	O
which	O
encodes	O
a	O
protein	O
of	O
103	O
amino	O
acids	O
.	O

Furthermore	O
,	O
this	O
kinase	O
-	O
deficient	O
mutant	O
inhibited	O
2	O
-	O
MeSADP	O
-	O
induced	O
caspase	B-GENE
-	I-GENE
3	I-GENE
stimulation	O
and	O
the	O
associated	O
decrease	O
in	O
cell	O
number	O
.	O

A	O
20	O
-	O
base	O
pair	O
oligonucleotide	O
containing	O
this	O
nonamer	O
confers	O
up	O
-	O
regulation	O
by	O
hypoxia	O
and	O
inhibition	O
by	O
unsaturated	O
fatty	O
acids	O
when	O
placed	O
upstream	O
of	O
a	O
heterologous	O
promoter	O
in	O
a	O
lacZ	B-GENE
reporter	I-GENE
construct	I-GENE
.	O

Deletion	O
analyses	O
implicate	O
the	O
N	O
-	O
terminal	O
110	O
amino	O
acids	O
of	O
Grb14	B-GENE
and	O
ankyrin	B-GENE
repeats	O
10	O
-	O
19	O
of	O
tankyrase	B-GENE
2	I-GENE
in	O
mediating	O
this	O
interaction	O
.	O

Finally	O
a	O
10	O
-	O
nucleotide	O
region	O
flanking	O
the	O
exon	O
4	O
protein	O
-	O
binding	O
site	O
is	O
homologous	O
to	O
instability	O
elements	O
within	O
five	O
other	O
transcripts	O
,	O
suggesting	O
that	O
a	O
common	O
coding	O
region	O
determinant	O
may	O
exist	O
.	O

Analysis	O
of	O
regulatory	O
regions	O
in	O
the	O
promoter	O
of	O
the	O
ctr4	B-GENE
(	I-GENE
+	I-GENE
)	I-GENE
copper	I-GENE
transporter	I-GENE
gene	I-GENE
in	O
fission	O
yeast	O
Schizosaccharomyces	O
pombe	O
reveals	O
the	O
identity	O
of	O
a	O
conserved	O
copper	O
-	O
signaling	O
element	O
(	O
CuSE	O
)	O
,	O
which	O
is	O
recognized	O
by	O
the	O
transcription	B-GENE
factor	I-GENE
Cuf1	I-GENE
.	O

WRN	B-GENE
helicase	I-GENE
resolves	O
alternate	O
DNA	O
structures	O
including	O
tetraplex	O
and	O
triplex	O
DNA	O
,	O
and	O
Holliday	O
junctions	O
.	O

These	O
data	O
suggest	O
that	O
ADAM	B-GENE
-	I-GENE
TS12	I-GENE
may	O
play	O
roles	O
in	O
pulmonary	O
cells	O
during	O
fetal	O
development	O
or	O
in	O
tumor	O
processes	O
through	O
its	O
proteolytic	O
activity	O
or	O
as	O
a	O
molecule	O
potentially	O
involved	O
in	O
regulation	O
of	O
cell	O
adhesion	O
.	O

Biol	O
.	O

CONCLUSIONS	O
:	O
Using	O
icodextrin	O
-	O
based	O
instead	O
of	O
glucose	O
-	O
based	O
PD	O
fluids	O
can	O
largely	O
reduce	O
the	O
formation	O
of	O
Amadori	O
albumin	B-GENE
and	O
AGEs	O
.	O

In	O
contrast	O
,	O
exogenous	B-GENE
PTHrP1	I-GENE
-	I-GENE
34	I-GENE
and	I-GENE
1	I-GENE
-	I-GENE
86	I-GENE
peptides	I-GENE
did	O
not	O
significantly	O
affect	O
IL	B-GENE
-	I-GENE
8	I-GENE
production	O
;	O
moreover	O
,	O
PTHrP	B-GENE
-	I-GENE
neutralizing	I-GENE
antibodies	I-GENE
did	O
not	O
inhibit	O
the	O
production	O
of	O
IL	B-GENE
-	I-GENE
8	I-GENE
by	O
transfected	O
PTHrP	B-GENE
.	O

Our	O
results	O
suggest	O
that	O
WASP	B-GENE
activates	O
transcription	O
following	O
TCR	B-GENE
stimulation	O
in	O
a	O
manner	O
that	O
is	O
independent	O
of	O
its	O
role	O
in	O
Arp2	B-GENE
/	I-GENE
3	I-GENE
-	O
directed	O
actin	B-GENE
polymerization	O
.	O

These	O
data	O
define	O
a	O
conserved	O
pathway	O
wherein	O
sequential	O
histone	B-GENE
modifications	O
establish	O
a	O
"	O
histone	B-GENE
code	O
"	O
essential	O
for	O
the	O
epigenetic	O
inheritance	O
of	O
heterochromatin	O
assembly	O
.	O

The	O
Delta6CCI	O
virus	O
was	O
extremely	O
attenuated	O
in	O
replication	O
capacity	O
yet	O
retained	O
infectiousness	O
for	O
CEMx174	O
and	O
MT4	O
cells	O
.	O

PABP	B-GENE
is	O
a	O
modular	O
protein	O
,	O
with	O
four	O
N	O
-	O
terminal	O
RNA	O
-	O
binding	O
domains	O
and	O
an	O
extensive	O
C	O
terminus	O
.	O

In	O
addition	O
,	O
another	O
derivative	O
of	O
pCMVJS21	O
(	O
pCMVJS21DeltaGP	O
)	O
in	O
which	O
the	O
gag	B-GENE
,	O
pol	B-GENE
(	O
and	O
orf	B-GENE
-	I-GENE
x	I-GENE
)	O
coding	O
sequences	O
were	O
deleted	O
also	O
gave	O
transformed	O
foci	O
.	O

In	O
contrast	O
,	O
neither	O
I	O
.	O
argentina	O
nor	O
I	O
.	O
theezans	O
exerted	O
any	O
effect	O
on	O
BF	O
or	O
intestinal	O
propulsion	O
.	O

These	O
data	O
reveal	O
a	O
complex	O
network	O
of	O
interactions	O
between	O
GTPases	B-GENE
in	O
the	O
ARF	B-GENE
family	I-GENE
and	O
their	O
effectors	O
and	O
reveal	O
a	O
potential	O
for	O
cross	O
-	O
talk	O
not	O
demonstrated	O
previously	O
.	O

A	O
mutation	O
in	O
the	O
C	O
domain	O
of	O
Rb	B-GENE
,	O
L901Q	O
,	O
has	O
been	O
identified	O
that	O
completely	O
abolishes	O
cdk4	B-GENE
/	O
D1	B-GENE
phosphorylation	O
of	O
the	O
isolated	O
C	O
domain	O
.	O

We	O
previously	O
showed	O
that	O
this	O
proteolysis	O
1	O
)	O
can	O
be	O
acutely	O
promoted	O
by	O
the	O
phorbol	O
ester	O
phorbol	O
12	O
-	O
myristate	O
13	O
-	O
acetate	O
(	O
PMA	O
)	O
,	O
2	O
)	O
requires	O
a	O
metalloprotease	B-GENE
activity	O
,	O
3	O
)	O
generates	O
both	O
shed	O
GHBP	B-GENE
and	O
a	O
membrane	B-GENE
-	I-GENE
associated	I-GENE
GHR	I-GENE
transmembrane	I-GENE
/	I-GENE
cytoplasmic	I-GENE
domain	I-GENE
remnant	O
,	O
and	O
4	O
)	O
results	O
in	O
down	O
-	O
regulation	O
of	O
GHR	B-GENE
abundance	O
and	O
GH	B-GENE
signaling	O
.	O

These	O
disorders	O
include	O
low	O
-	O
back	O
pain	O
,	O
saddle	O
anesthesia	O
,	O
bilateral	O
sciatica	O
,	O
then	O
motor	O
weakness	O
of	O
the	O
lower	O
extremities	O
or	O
chronic	O
paraplegia	O
and	O
,	O
bladder	O
dysfunction	O
.	O

Sural	O
nerve	O
biopsy	O
showed	O
mild	O
thickening	O
of	O
the	O
perineurium	O
,	O
vascular	O
alterations	O
with	O
inflammatory	O
cell	O
infiltration	O
in	O
the	O
perineurium	O
,	O
and	O
remarkable	O
loss	O
of	O
large	O
and	O
small	O
myelinated	O
fibers	O
.	O

When	O
this	O
CCAAT	O
box	O
was	O
inserted	O
into	O
a	O
heterologous	O
promoter	O
construct	O
,	O
OA	O
induction	O
was	O
dependent	O
on	O
an	O
intact	O
CCAAT	O
box	O
.	O

The	O
JHRLSS	O
has	O
been	O
used	O
in	O
prior	O
studies	O
to	O
assess	O
RLS	O
severity	O
,	O
but	O
has	O
not	O
previously	O
been	O
validated	O
in	O
relation	O
to	O
direct	O
measures	O
of	O
the	O
morbidity	O
associated	O
with	O
RLS	O
.	O

Our	O
results	O
suggest	O
that	O
the	O
C	O
-	O
terminal	O
region	O
of	O
Crk	B-GENE
contains	O
negative	O
regulatory	O
elements	O
important	O
for	O
both	O
Abl	B-GENE
and	O
FAK	B-GENE
dependent	O
signal	O
pathways	O
,	O
and	O
offers	O
a	O
paradigm	O
for	O
an	O
autoinhibitory	O
region	O
in	O
the	O
SH3	B-GENE
linker	O
/	O
C	O
-	O
terminal	O
SH3	B-GENE
domain	O
.	O

This	O
unique	O
location	O
of	O
cavernous	O
malformation	O
is	O
associated	O
with	O
a	O
risk	O
of	O
permanent	O
loss	O
of	O
the	O
vision	O
.	O

The	O
MSL	B-GENE
complex	I-GENE
is	O
specifically	O
localized	O
on	O
the	O
male	O
X	O
chromosome	O
to	O
increase	O
its	O
expression	O
approximately	O
2	O
-	O
fold	O
.	O

Consistent	O
effects	O
on	O
pVHL	B-GENE
function	O
were	O
observed	O
for	O
all	O
mutations	O
within	O
each	O
subclass	O
.	O

Here	O
,	O
we	O
identify	O
Rsc3	B-GENE
and	O
Rsc30	B-GENE
as	O
novel	O
components	O
of	O
the	O
essential	O
yeast	B-GENE
remodeler	I-GENE
RSC	I-GENE
complex	I-GENE
.	O

Early	O
indicators	O
of	O
the	O
effect	O
of	O
a	O
breast	O
cancer	O
screening	O
program	O
for	O
low	O
-	O
income	O
women	O
.	O

Linear	O
eight	O
-	O
or	O
nine	O
-	O
residue	O
D	O
-	O
peptides	O
derived	O
from	O
the	O
pocket	O
-	O
binding	O
domain	O
of	O
the	O
cyclic	O
molecules	O
also	O
bind	O
specifically	O
.	O

Here	O
we	O
present	O
evidence	O
that	O
the	O
distal	O
half	O
(	O
Stem	O
2	O
)	O
of	O
the	O
conserved	O
base	O
-	O
paired	O
stem	O
structure	O
found	O
in	O
all	O
hY	B-GENE
RNAs	I-GENE
also	O
plays	O
a	O
critical	O
role	O
in	O
the	O
export	O
process	O
.	O

Here	O
we	O
provide	O
the	O
first	O
evidence	O
for	O
the	O
involvement	O
of	O
GCN1	B-GENE
-	O
GCN2	B-GENE
interaction	O
in	O
activation	O
of	O
GCN2	B-GENE
per	O
se	O
.	O

Expression	O
of	O
human	B-GENE
RACK1	I-GENE
efficiently	O
relieves	O
E1A	B-GENE
-	O
mediated	O
growth	O
inhibition	O
in	O
HF7c	O
and	O
protects	O
human	O
tumor	O
cells	O
from	O
E1A	B-GENE
-	O
induced	O
apoptosis	O
.	O

Molecular	O
analysis	O
of	O
the	O
pRA2	O
partitioning	O
region	O
:	O
ParB	B-GENE
autoregulates	O
parAB	B-GENE
transcription	O
and	O
forms	O
a	O
nucleoprotein	O
complex	O
with	O
the	O
plasmid	O
partition	O
site	O
,	O
parS	B-GENE
.	O

SERS	O
spectra	O
were	O
obtained	O
by	O
vacuum	O
evaporation	O
and	O
casting	O
of	O
p	O
-	O
NTP	O
onto	O
silver	O
island	O
films	O
,	O
and	O
also	O
from	O
colloidal	O
silver	O
solutions	O
.	O

Copyright	O
2001	O
Academic	O
Press	O
.	O

These	O
corrections	O
do	O
not	O
involve	O
sequences	O
predicted	O
to	O
function	O
as	O
transcription	O
factor	O
binding	O
sites	O
.	O

A	O
patient	O
is	O
described	O
with	O
skin	O
lesions	O
resembling	O
Kaposi	O
'	O
s	O
sarcoma	O
(	O
KS	O
)	O
.	O

The	O
images	O
showed	O
rapid	O
,	O
predominantly	O
urinary	O
excretion	O
of	O
99mTc	O
ciprofloxacin	O
,	O
with	O
low	O
to	O
absent	O
brain	O
,	O
lung	O
and	O
bone	O
marrow	O
uptake	O
and	O
low	O
liver	O
uptake	O
and	O
excretion	O
.	O

To	O
this	O
end	O
,	O
an	O
expression	O
cassette	O
consisting	O
of	O
the	O
gene	O
for	O
a	O
green	B-GENE
fluorescent	I-GENE
protein	I-GENE
(	O
GFP	B-GENE
)	O
flanked	O
at	O
its	O
3	O
'	O
end	O
by	O
EAV	O
-	O
specific	O
transcription	O
-	O
regulating	O
sequences	O
was	O
constructed	O
.	O

In	O
addition	O
,	O
severe	O
vision	O
loss	O
can	O
be	O
seen	O
with	O
interferon	B-GENE
alfa	I-GENE
-	I-GENE
2b	I-GENE
-	O
associated	O
retinopathy	O
.	O

The	O
mechanism	O
of	O
the	O
induction	O
of	O
3beta	B-GENE
-	I-GENE
HSD	I-GENE
type	I-GENE
1	I-GENE
gene	I-GENE
expression	O
was	O
further	O
characterized	O
in	O
ZR	O
-	O
75	O
-	O
1	O
human	O
breast	O
cancer	O
cells	O
.	O

The	O
application	O
of	O
the	O
biotechnology	O
at	O
the	O
plants	O
for	O
treatment	O
of	O
the	O
surface	O
storm	O
waters	O
from	O
the	O
industrial	O
zone	O
Telychka	O
of	O
the	O
city	O
of	O
Kyiv	O
has	O
allowed	O
the	O
content	O
of	O
petroleum	O
in	O
water	O
dropped	O
to	O
the	O
Dnieper	O
to	O
be	O
constantly	O
reduced	O
50	O
-	O
100	O
times	O
.	O

Fans	O
in	O
tunnels	O
and	O
open	O
windows	O
at	O
aboveground	O
locations	O
appeared	O
to	O
greatly	O
reduce	O
the	O
likelihood	O
of	O
high	O
PH3	O
concentrations	O
in	O
enclosed	O
areas	O
.	O

The	O
first	O
case	O
of	O
HCV	O
seroconversion	O
in	O
Portugal	O
after	O
the	O
introduction	O
of	O
HCV	O
NAT	O
screening	O
.	O

The	O
observed	O
triplexes	O
depend	O
on	O
the	O
length	O
of	O
the	O
repeat	O
.	O

We	O
used	O
stored	O
plasma	O
samples	O
from	O
409	O
patients	O
in	O
the	O
National	O
Institute	O
of	O
Neurological	O
Diseases	O
and	O
Stroke	O
(	O
NINDS	O
)	O
tissue	B-GENE
plasminogen	I-GENE
activator	I-GENE
(	O
t	B-GENE
-	I-GENE
PA	I-GENE
)	O
Stroke	O
Trial	O
to	O
examine	O
the	O
relationship	O
between	O
an	O
apolipoprotein	B-GENE
(	I-GENE
Apo	I-GENE
)	I-GENE
E2	I-GENE
or	O
an	O
Apo	B-GENE
E4	I-GENE
phenotype	O
and	O
a	O
favorable	O
outcome	O
3	O
months	O
after	O
stroke	O
,	O
the	O
risk	O
of	O
intracerebral	O
hemorrhage	O
,	O
and	O
the	O
response	O
to	O
intravenous	O
t	B-GENE
-	I-GENE
PA	I-GENE
therapy	O
.	O

Colorectal	O
cancer	O
was	O
shown	O
to	O
disproportionately	O
overburden	O
Ashkenazi	O
Jews	O
,	O
who	O
may	O
also	O
be	O
at	O
increased	O
risk	O
for	O
ovarian	O
,	O
pancreatic	O
and	O
stomach	O
cancer	O
,	O
and	O
non	O
-	O
Hodgkin	O
'	O
s	O
lymphoma	O
.	O

RANTES	B-GENE
(	O
regulated	B-GENE
upon	I-GENE
activation	I-GENE
,	I-GENE
normally	I-GENE
T	I-GENE
-	I-GENE
cell	I-GENE
expressed	I-GENE
and	I-GENE
presumably	I-GENE
secreted	I-GENE
)	O
is	O
a	O
CC	O
chemokine	O
which	O
recruits	O
and	O
activates	O
monocytes	O
,	O
lymphocytes	O
,	O
and	O
eosinophils	O
,	O
all	O
cell	O
types	O
present	O
in	O
the	O
lung	O
inflammatory	O
infiltrate	O
induced	O
by	O
RSV	O
infection	O
.	O

Five	O
modalities	O
of	O
nonpharmacologic	O
approaches	O
are	O
recommended	O
at	O
present	O
for	O
lifestyle	O
modification	O
and	O
control	O
of	O
arterial	O
blood	O
pressure	O
elevation	O
:	O
1	O
)	O
weight	O
reduction	O
to	O
ideal	O
body	O
weight	O
,	O
since	O
it	O
reduces	O
risk	O
of	O
hypertension	O
as	O
well	O
as	O
overall	O
cardiovascular	O
morbidity	O
and	O
mortality	O
;	O
2	O
)	O
dietary	O
sodium	O
restriction	O
to	O
less	O
than	O
2	O
g	O
a	O
day	O
,	O
without	O
assurance	O
that	O
it	O
will	O
normalize	O
arterial	O
pressure	O
although	O
it	O
may	O
help	O
reduce	O
dosage	O
and	O
numbers	O
of	O
prescribed	O
antihypertensive	O
drugs	O
;	O
3	O
)	O
moderation	O
of	O
alcohol	O
consumption	O
to	O
less	O
than	O
1	O
ounce	O
a	O
day	O
;	O
4	O
)	O
a	O
regular	O
isotonic	O
exercise	O
program	O
;	O
and	O
5	O
)	O
cessation	O
of	O
tobacco	O
consumption	O
.	O

Ga	O
-	O
67	O
and	O
Tl	O
-	O
201	O
scintigraphy	O
in	O
extramedullary	O
plasmacytoma	O
:	O
a	O
case	O
report	O
.	O

Arterial	O
blood	O
gas	O
tensions	O
were	O
similar	O
across	O
all	O
ventilation	O
modes	O
.	O

As	O
expected	O
,	O
homologous	B-GENE
loxP	I-GENE
sequences	I-GENE
efficiently	O
underwent	O
Cre	B-GENE
-	O
mediated	O
recombination	O
.	O

The	O
Van	O
der	O
Hoeve	O
'	O
s	O
syndrome	O
lesions	O
as	O
poorly	O
mineralized	O
,	O
with	O
low	O
calcium	O
salt	O
and	O
apparent	O
increase	O
of	O
phosphates	O
.	O

A	O
5	O
-	O
month	O
-	O
old	O
infant	O
with	O
persistent	O
congenital	O
stridor	O
and	O
acute	O
respiratory	O
distress	O
is	O
presented	O
.	O

PURPOSE	O
:	O
The	O
objective	O
of	O
this	O
study	O
was	O
to	O
assess	O
first	O
embryo	O
cleavage	O
(	O
FEC	O
)	O
25	O
-	O
27	O
h	O
after	O
intracytoplasmic	O
sperm	O
injection	O
(	O
ICSI	O
)	O
as	O
a	O
parameter	O
for	O
the	O
embryo	O
selection	O
process	O
.	O

In	O
35	O
of	O
those	O
patients	O
DD	O
was	O
measured	O
also	O
with	O
microlatex	O
tests	O
-	O
-	O
Tinaquant	O
and	O
BC	O
d	O
-	O
dimer	O
.	O

Cytosolic	B-GENE
acetyl	I-GENE
-	I-GENE
CoA	I-GENE
synthetase	I-GENE
(	O
AceCS1	B-GENE
)	O
activates	O
acetate	O
to	O
supply	O
the	O
cells	O
with	O
acetyl	O
-	O
CoA	O
for	O
lipid	O
synthesis	O
.	O

Tolerance	O
in	O
renal	O
transplantation	O
after	O
allogeneic	O
bone	O
marrow	O
transplantation	O
-	O
6	O
-	O
year	O
follow	O
-	O
up	O
.	O

Foreigners	O
return	O
.	O

The	O
present	O
chemotherapy	O
of	O
AE	O
is	O
based	O
on	O
the	O
administration	O
of	O
benzimidazole	O
carbamate	O
derivatives	O
,	O
such	O
as	O
mebendazole	O
and	O
albendazole	O
.	O

Topological	O
and	O
mutational	O
analysis	O
of	O
Saccharomyces	B-GENE
cerevisiae	I-GENE
Ste14p	I-GENE
,	O
founding	O
member	O
of	O
the	O
isoprenylcysteine	B-GENE
carboxyl	I-GENE
methyltransferase	I-GENE
family	I-GENE
.	O

Hormonal	O
regulation	O
of	O
multiple	O
promoters	O
of	O
the	O
rat	B-GENE
mitochondrial	I-GENE
glycerol	I-GENE
-	I-GENE
3	I-GENE
-	I-GENE
phosphate	I-GENE
dehydrogenase	I-GENE
gene	I-GENE
:	O
identification	O
of	O
a	O
complex	O
hormone	O
-	O
response	O
element	O
in	O
the	O
ubiquitous	O
promoter	O
B	O
.	O

The	O
telomerase	B-GENE
RNA	I-GENE
-	I-GENE
protein	I-GENE
complex	I-GENE
responsible	O
for	O
maintenance	O
of	O
telomeric	O
DNA	O
at	O
chromosome	O
ends	O
,	O
is	O
usually	O
inactive	O
in	O
most	O
primary	O
somatic	O
human	O
cells	O
,	O
but	O
is	O
specifically	O
activated	O
with	O
in	O
vitro	O
immortalization	O
and	O
during	O
tumorigenesis	O
.	O

Our	O
results	O
show	O
that	O
CVN	B-GENE
specifically	O
recognizes	O
with	O
nanomolar	O
affinity	O
Man	O
(	O
9	O
)	O
GlcNAc	O
(	O
2	O
)	O
and	O
the	O
D1D3	O
isomer	O
of	O
Man	O
(	O
8	O
)	O
GlcNAc	O
(	O
2	O
)	O
.	O

Zhu	O
,	O
V	O
.	O

The	O
novel	O
approach	O
to	O
insulin	B-GENE
administration	O
known	O
as	O
chronic	O
intermittent	O
intravenous	O
insulin	B-GENE
therapy	O
(	O
CIIIT	O
)	O
delivers	O
insulin	B-GENE
in	O
a	O
pulsatile	O
fashion	O
and	O
achieves	O
physiological	O
insulin	B-GENE
concentration	O
in	O
the	O
portal	O
vein	O
.	O

The	O
activity	O
of	O
Rac1	B-GENE
leads	O
to	O
STAT3	B-GENE
translocation	O
to	O
the	O
nucleus	O
coincident	O
with	O
STAT3	B-GENE
-	O
dependent	O
gene	O
expression	O
.	O

Mss4	B-GENE
also	O
acts	O
as	O
a	O
relatively	O
inefficient	O
guanine	B-GENE
nucleotide	I-GENE
exchange	I-GENE
factor	I-GENE
(	O
GEF	B-GENE
)	O
.	O

She	O
has	O
since	O
developed	O
a	O
positive	O
anti	B-GENE
-	I-GENE
cardiolipin	I-GENE
antibody	I-GENE
but	O
does	O
not	O
meet	O
diagnostic	O
criteria	O
for	O
systemic	O
lupus	O
erythematosis	O
.	O
CONCLUSION	O
:	O
The	O
presence	O
of	O
known	O
autoimmune	O
disease	O
in	O
a	O
woman	O
with	O
POF	O
should	O
not	O
dissuade	O
the	O
clinician	O
from	O
evaluating	O
for	O
a	O
potential	O
genetic	O
cause	O
.	O

Effects	O
of	O
aerosol	O
-	O
vapor	O
JP	O
-	O
8	O
jet	O
fuel	O
on	O
the	O
functional	O
observational	O
battery	O
,	O
and	O
learning	O
and	O
memory	O
in	O
the	O
rat	O
.	O

CONCLUSION	O
:	O
There	O
are	O
no	O
differences	O
in	O
the	O
measurement	O
data	O
derived	O
from	O
this	O
method	O
and	O
actual	O
measurement	O
data	O
from	O
an	O
object	O
created	O
by	O
the	O
computer	O
-	O
aided	O
dental	O
design	O
program	O
.	O

Many	O
factors	O
do	O
influence	O
the	O
educational	O
outcome	O
in	O
students	O
and	O
large	O
statistical	O
power	O
(	O
such	O
as	O
meta	O
analysis	O
)	O
should	O
be	O
helpful	O
to	O
eliminate	O
many	O
sources	O
of	O
error	O
.	O

Our	O
results	O
demonstrated	O
that	O
50	O
%	O
of	O
the	O
hepatic	O
artery	O
-	O
alone	O
ALT	O
graft	O
showed	O
almost	O
normal	O
structure	O
histologically	O
at	O
1	O
month	O
after	O
grafting	O
,	O
with	O
bile	O
secretion	O
preserved	O
.	O

The	O
human	B-GENE
ABCG1	I-GENE
gene	I-GENE
encodes	O
a	O
member	O
of	O
the	O
ATP	B-GENE
-	I-GENE
binding	I-GENE
cassette	I-GENE
(	O
ABC	B-GENE
)	O
superfamily	O
of	O
transporter	B-GENE
proteins	I-GENE
and	O
is	O
highly	O
induced	O
when	O
macrophages	O
are	O
incubated	O
with	O
oxysterols	O
.	O

C	B-GENE
/	I-GENE
EBPbeta	I-GENE
LIP	I-GENE
overexpressing	O
HC11	O
cells	O
did	O
not	O
express	O
beta	B-GENE
-	I-GENE
casein	I-GENE
mRNA	I-GENE
(	O
mammary	O
epithelial	O
cell	O
differentiation	O
marker	O
)	O
in	O
response	O
to	O
lactogenic	O
hormones	O
.	O

EXAFS	O
measurements	O
around	O
the	O
Ge	O
-	O
K	O
edge	O
have	O
been	O
carried	O
out	O
for	O
liquid	O
Ge	O
-	O
Si	O
alloys	O
for	O
the	O
first	O
time	O
to	O
investigate	O
the	O
local	O
structure	O
around	O
a	O
Ge	O
atom	O
.	O

Although	O
metabolized	O
by	O
the	O
cytochrome	B-GENE
P	I-GENE
-	I-GENE
450	I-GENE
(	O
CYP	B-GENE
)	O
system	O
,	O
venlafaxine	O
inhibits	O
CYP	B-GENE
2D6	I-GENE
and	I-GENE
3A4	I-GENE
to	O
a	O
far	O
lesser	O
extent	O
than	O
do	O
the	O
SSRIs	O
.	O

Analysis	O
of	O
the	O
promoter	O
sequence	O
revealed	O
the	O
presence	O
of	O
a	O
major	O
transcriptional	O
start	O
site	O
,	O
a	O
canonical	O
TATA	O
box	O
and	O
putative	O
cis	O
regulatory	O
elements	O
for	O
pituitary	O
specific	O
expression	O
as	O
well	O
as	O
an	O
E	O
-	O
responsive	O
element	O
.	O

Novel	O
intronic	O
promoter	O
in	O
the	O
rat	B-GENE
ER	I-GENE
alpha	I-GENE
gene	I-GENE
responsible	O
for	O
the	O
transient	O
transcription	O
of	O
a	O
variant	O
receptor	O
.	O

Pitx2	B-GENE
rescues	O
the	O
GABAergic	O
differentiation	O
defect	O
and	O
partially	O
rescues	O
the	O
axon	O
guidance	O
and	O
behavioral	O
phenotypes	O
of	O
unc	B-GENE
-	I-GENE
30	I-GENE
mutants	I-GENE
,	O
indicating	O
a	O
high	O
degree	O
of	O
functional	O
conservation	O
between	O
these	O
evolutionarily	O
related	O
genes	O
.	O

We	O
have	O
previously	O
shown	O
that	O
the	O
adenoviral	B-GENE
12S	I-GENE
E1A	I-GENE
protein	I-GENE
modulates	O
the	O
phosphorylation	O
status	O
of	O
p130	B-GENE
and	O
p107	B-GENE
without	O
apparent	O
changes	O
in	O
the	O
cell	O
cycle	O
dependent	O
phosphorylation	O
of	O
the	O
retinoblastoma	B-GENE
protein	I-GENE
.	O

The	O
prevalence	O
of	O
tobacco	O
dependence	O
diagnosed	O
according	O
to	O
the	O
ICD	O
-	O
10	O
criteria	O
was	O
higher	O
in	O
alcohol	O
-	O
dependent	O
individuals	O
(	O
58	O
.	O
1	O
%	O
)	O
than	O
in	O
nondrinkers	O
or	O
social	O
drinkers	O
(	O
12	O
.	O
8	O
%	O
)	O
.	O

Diffuse	O
myalgias	O
were	O
more	O
frequent	O
in	O
patients	O
with	O
than	O
without	O
an	O
MMF	O
lesion	O
at	O
deltoid	O
muscle	O
biopsy	O
(	O
P	O
<	O
0	O
.	O
0001	O
)	O
.	O

Additionally	O
,	O
a	O
CaCO3	O
-	O
CO2	O
/	O
N2	O
buffered	O
solution	O
was	O
necessary	O
to	O
maintain	O
a	O
pH	O
of	O
8	O
.	O

Copyright	O
2001	O
S	O
.	O

NF	B-GENE
-	I-GENE
kappaB	I-GENE
is	O
involved	O
in	O
the	O
regulation	O
of	O
CD154	B-GENE
(	O
CD40	B-GENE
ligand	I-GENE
)	O
expression	O
in	O
primary	O
human	O
T	O
cells	O
.	O

Mutation	O
of	O
the	O
octamer	O
element	O
also	O
significantly	O
reduced	O
the	O
ability	O
of	O
HDAC1	B-GENE
to	O
confer	O
repression	O
of	O
inducible	O
HLA	B-GENE
-	I-GENE
DRA	I-GENE
promoter	I-GENE
activation	O
.	O

In	O
such	O
conditions	O
,	O
the	O
following	O
kinetic	O
reactions	O
have	O
been	O
studied	O
:	O
N2	O
(	O
A	O
)	O
+	O
N2	O
(	O
A	O
)	O
-	O
-	O
>	O
N2	O
(	O
C	O
,	O
B	O
,	O
V	O
'	O
)	O
+	O
N2	O
(	O
X	O
)	O
,	O
N2	O
(	O
A	O
)	O
+	O
N2	O
(	O
X	O
,	O
V	O
>	O
5	O
)	O
-	O
-	O
>	O
N2	O
(	O
X	O
)	O
+	O
N2	O
(	O
B	O
,	O
V	O
'	O
)	O
in	O
pure	O
N2	O
post	O
-	O
discharges	O
and	O
N2	O
(	O
A	O
)	O
+	O
CH4	O
-	O
-	O
>	O
products	O
,	O
C	O
+	O
N	O
+	O
M2	O
-	O
-	O
>	O
CN	O
(	O
B	O
,	O
V	O
'	O
)	O
+	O
M2	O
,	O
N2	O
(	O
X	O
,	O
V	O
>	O
4	O
)	O
+	O
CN	O
-	O
-	O
>	O
N2	O
(	O
X	O
)	O
+	O
CN	O
(	O
B	O
,	O
A	O
,	O
V	O
'	O
)	O
,	O
in	O
N2	O
-	O
1	O
%	O
CH4	O
post	O
-	O
discharges	O
.	O

Six	O
of	O
the	O
gstC	B-GENE
'	I-GENE
mutants	I-GENE
,	O
primarily	O
in	O
the	O
C	O
-	O
terminal	O
half	O
of	O
C	B-GENE
'	I-GENE
,	O
exhibited	O
a	O
defect	O
in	O
the	O
ability	O
to	O
bind	O
L	B-GENE
protein	I-GENE
.	O

A	O
proposal	O
of	O
50	O
performance	O
indicators	O
divided	O
into	O
five	O
different	O
groups	O
is	O
presented	O
here	O
,	O
namely	O
structural	O
indicators	O
,	O
operational	O
indicators	O
,	O
water	O
and	O
service	O
quality	O
indicators	O
,	O
personnel	O
indicators	O
and	O
economic	O
indicators	O
.	O

CONCLUSIONS	O
:	O
ChromaFlo	O
-	O
enhanced	O
IVUS	O
demonstrates	O
colorized	O
blood	O
flow	O
inside	O
the	O
vessel	O
lumen	O
,	O
which	O
is	O
helpful	O
in	O
distinguishing	O
echolucent	O
disease	O
from	O
luminal	O
blood	O
flow	O
and	O
can	O
also	O
be	O
used	O
to	O
perform	O
peripheral	O
interventions	O
in	O
patients	O
with	O
renal	O
failure	O
or	O
allergy	O
,	O
avoiding	O
the	O
use	O
of	O
contrast	O
media	O
.	O

The	O
hatcher	O
incubators	O
of	O
both	O
companies	O
were	O
also	O
persistently	O
contaminated	O
with	O
Salmonella	O
livingstone	O
and	O
Salmonella	O
thomasville	O
in	O
company	O
A	O
and	O
with	O
Salmonella	O
senftenberg	O
in	O
company	O
B	O
.	O

At	O
both	O
companies	O
sites	O
Salmonella	O
enteritidis	O
and	O
Salmonella	O
typhimurium	O
Tr104	O
were	O
also	O
isolated	O
occasionally	O
from	O
various	O
locations	O
.	O

E2F1	B-GENE
-	O
mediated	O
transcriptional	O
inhibition	O
of	O
the	O
plasminogen	B-GENE
activator	I-GENE
inhibitor	I-GENE
type	I-GENE
1	I-GENE
gene	I-GENE
.	O

The	O
small	O
copepod	O
Pseudonychocamptus	O
proximus	O
progressively	O
replaced	O
the	O
large	O
Tisbe	O
furcata	O
in	O
sand	O
filters	O
during	O
the	O
fall	O
of	O
1995	O
and	O
was	O
responsible	O
for	O
the	O
large	O
increase	O
in	O
meiofaunal	O
biomass	O
observed	O
after	O
spring	O
1996	O
.	O

The	O
probability	O
of	O
treatment	O
with	O
lamotrigine	O
being	O
maintained	O
for	O
six	O
months	O
was	O
86	O
%	O
,	O
for	O
twelve	O
months	O
61	O
%	O
and	O
for	O
three	O
years	O
31	O
%	O
.	O

Data	O
from	O
in	O
vitro	O
splicing	O
assays	O
,	O
UV	O
crosslinking	O
and	O
RNA	O
-	O
binding	O
competition	O
experiments	O
indicates	O
a	O
strong	O
correlation	O
between	O
the	O
binding	O
affinities	O
of	O
PSI	B-GENE
for	O
the	O
SELEX	O
sequences	O
and	O
their	O
ability	O
to	O
modulate	O
splicing	O
of	O
P	B-GENE
element	I-GENE
IVS3	B-GENE
in	O
vitro	O
.	O

This	O
paper	O
describes	O
the	O
results	O
of	O
an	O
initial	O
study	O
on	O
the	O
application	O
of	O
linear	O
solvation	O
energy	O
relationships	O
(	O
LSERs	O
)	O
to	O
the	O
prediction	O
of	O
internal	O
standard	O
compounds	O
in	O
reversed	O
-	O
phase	O
liquid	O
chromatographic	O
(	O
RPLC	O
)	O
method	O
development	O
.	O

ICAM	B-GENE
-	I-GENE
1	I-GENE
has	O
been	O
suggested	O
a	O
predictor	O
of	O
the	O
onset	O
of	O
GO	O
.	O

Northern	O
blot	O
analysis	O
with	O
one	O
of	O
the	O
PARNAs	B-GENE
revealed	O
a	O
highly	O
abundant	O
signal	O
of	O
approximately	O
2	O
.	O
0	O
kilobases	O
(	O
kb	O
)	O
present	O
in	O
all	O
cell	O
lines	O
tested	O
.	O

The	O
corresponding	O
orifice	O
voltages	O
for	O
the	O
three	O
instruments	O
were	O
20	O
/	O
50	O
/	O
80	O
V	O
(	O
API	O
365	O
)	O
,	O
30	O
/	O
90	O
/	O
130	O
V	O
(	O
API	O
2000	O
)	O
and	O
40	O
/	O
80	O
/	O
120	O
V	O
(	O
API	O
3000	O
)	O
.	O

The	O
LA	O
50s	O
derived	O
from	O
this	O
combined	O
data	O
when	O
compared	O
with	O
our	O
earlier	O
series	O
from	O
1965	O
to	O
1970	O
also	O
did	O
not	O
show	O
a	O
significant	O
change	O
in	O
mortality	O
.	O

Treatment	O
of	O
ischemic	O
heart	O
disease	O
in	O
the	O
elderly	O

A	O
peculiar	O
people	O
:	O
"	O
the	O
physiological	O
aspects	O
of	O
Mormonism	O
1850	O
-	O
1975	O
.	O
"	O

She	O
drank	O
alcohol	O
once	O
or	O
twice	O
a	O
week	O
and	O
regularly	O
took	O
an	O
analgesic	O
preparation	O
,	O
containing	O
aspirin	O
and	O
acetaminophen	O
,	O
for	O
alleviation	O
of	O
headaches	O
.	O

The	O
most	O
important	O
risk	O
factors	O
are	O
:	O
1	O
)	O
genetic	O
;	O
2	O
)	O
Epstein	O
-	O
Barr	O
virus	O
(	O
infectious	O
mononucleosis	O
)	O
;	O
3	O
)	O
congenital	O
and	O
acquired	O
immunodeficiency	O
;	O
4	O
)	O
occupational	O
exposure	O
(	O
the	O
wood	O
industry	O
)	O
.	O

OBJECTIVES	O
:	O
The	O
objective	O
of	O
this	O
review	O
was	O
to	O
assess	O
the	O
effects	O
of	O
prophylactic	O
prostaglandin	O
use	O
in	O
the	O
third	O
stage	O
of	O
labour	O
.	O

Under	O
our	O
conditions	O
,	O
the	O
combination	O
O3	O
/	O
UV	O
did	O
not	O
improve	O
the	O
degradation	O
rate	O
obtained	O
by	O
ozonation	O
.	O

On	O
the	O
other	O
hand	O
,	O
hepatic	O
arterial	O
infusion	O
therapy	O
prolongs	O
the	O
survival	O
of	O
H3	O
patients	O
only	O
.	O

Finally	O
,	O
there	O
are	O
a	O
growing	O
number	O
of	O
arguments	O
favouring	O
the	O
use	O
of	O
ACE	B-GENE
inhibitors	O
very	O
early	O
in	O
patients	O
with	O
diabetes	O
mellitus	O
.	O

Is	O
clopidogrel	O
superior	O
to	O
aspirin	O
in	O
secondary	O
prevention	O
of	O
vascular	O
disease	O
?	O
The	O
cornerstone	O
in	O
clinical	O
evidence	O
of	O
the	O
relative	O
efficacy	O
of	O
thienopyridines	O
(	O
clopidogrel	O
,	O
ticlopidine	O
)	O
versus	O
aspirin	O
in	O
the	O
secondary	O
prevention	O
of	O
vascular	O
disease	O
is	O
the	O
Clopidogrel	O
versus	O
Aspirin	O
in	O
Patients	O
at	O
Risk	O
of	O
Ischaemic	O
Events	O
trial	O
.	O

We	O
hypothesize	O
that	O
proprioception	O
may	O
be	O
used	O
to	O
calibrate	O
the	O
efference	O
copy	O
during	O
development	O
and	O
in	O
response	O
to	O
perturbations	O
by	O
signaling	O
potential	O
mismatches	O
between	O
eye	O
movement	O
information	O
derived	O
from	O
the	O
efferent	O
command	O
and	O
the	O
actual	O
motion	O
of	O
the	O
eye	O
transduced	O
by	O
the	O
proprioceptive	O
organs	O
.	O

The	O
severity	O
of	O
clinical	O
course	O
was	O
expressed	O
by	O
means	O
of	O
SOFA	O
score	O
(	O
group	O
A	O
0	O
.	O
3	O
-	O
1	O
-	O
1	O
.	O
3	O
point	O
,	O
group	O
B	O
2	O
.	O
2	O
-	O
2	O
.	O
9	O
-	O
2	O
.	O
6	O
point	O
,	O
group	O
C	O
7	O
.	O
4	O
-	O
8	O
.	O
3	O
-	O
7	O
.	O
7	O
point	O
)	O
and	O
APACHE	O
II	O
score	O
(	O
group	O
A	O
3	O
.	O
7	O
-	O
7	O
.	O
6	O
-	O
8	O
.	O
1	O
point	O
,	O
group	O
B	O
8	O
.	O
6	O
-	O
11	O
.	O
1	O
-	O
10	O
.	O
5	O
point	O
,	O
group	O
C	O
16	O
.	O
3	O
-	O
15	O
.	O
2	O
-	O
14	O
.	O
3	O
point	O
)	O
.	O

These	O
results	O
were	O
compared	O
with	O
the	O
estimates	O
of	O
penetration	O
from	O
steady	O
-	O
state	O
calculations	O
,	O
square	O
root	O
of	O
time	O
calculations	O
,	O
and	O
a	O
biologically	O
based	O
mathematical	O
model	O
.	O

Treadmill	O
training	O
at	O
least	O
for	O
2	O
weeks	O
can	O
reduce	O
the	O
infarction	O
size	O
and	O
edema	O
caused	O
by	O
MCA	O
occlusion	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Modality	O
-	O
specific	O
areas	O
(	O
e	O
.	O
g	O
.	O
,	O
right	O
Wernicke	O
,	O
left	O
fusiform	O
gyrus	O
,	O
Broca	O
BA44	O
,	O
supramarginal	O
gyrus	O
)	O
,	O
appear	O
to	O
cope	O
with	O
the	O
computations	O
relevant	O
to	O
making	O
contact	O
with	O
these	O
more	O
abstract	O
dimensions	O
.	O

We	O
found	O
no	O
correlation	O
between	O
plasma	O
COP	O
and	O
body	O
weight	O
at	O
the	O
same	O
age	O
(	O
r2	O
=	O
0	O
.	O
05	O
,	O
P	O
=	O
0	O
.	O
155	O
)	O
.	O

Both	O
toxins	O
in	O
a	O
dose	O
10	O
-	O
fold	O
surpassing	O
the	O
maximum	O
permissible	O
concentration	O
increased	O
activity	O
of	O
glutathione	B-GENE
peroxidase	I-GENE
in	O
brain	O
tissue	O
;	O
moreover	O
,	O
toluene	O
increased	O
chemiluminescence	O
intensity	O
,	O
which	O
attested	O
to	O
activation	O
of	O
free	O
radical	O
processes	O
.	O

The	O
performance	O
of	O
pH	O
-	O
sensitive	O
particles	O
is	O
attributed	O
to	O
their	O
ability	O
to	O
release	O
the	O
drug	O
selectively	O
in	O
the	O
upper	O
part	O
of	O
the	O
intestine	O
in	O
a	O
molecular	O
or	O
amorphous	O
form	O
.	O

Comparison	O
of	O
remnant	O
-	O
like	O
lipoprotein	O
particles	O
in	O
postmenopausal	O
women	O
with	O
and	O
without	O
coronary	O
artery	O
disease	O
and	O
in	O
men	O
with	O
coronary	O
artery	O
disease	O
.	O

Because	O
results	O
of	O
recent	O
randomized	O
trials	O
indicate	O
minimal	O
efficacy	O
of	O
continuing	O
MAC	O
prophylaxis	O
in	O
patients	O
who	O
respond	O
to	O
potent	O
combination	O
antiretroviral	O
therapy	O
,	O
the	O
observed	O
high	O
incidence	O
of	O
macrolide	O
-	O
resistant	O
bacterial	O
colonization	O
of	O
the	O
respiratory	O
tract	O
in	O
this	O
trial	O
supports	O
the	O
discontinuation	O
of	O
macrolide	O
prophylaxis	O
in	O
all	O
AIDS	O
patients	O
whose	O
CD4	B-GENE
counts	O
have	O
risen	O
above	O
100	O
cells	O
/	O
microL	O
.	O

METHODS	O
:	O
302	O
consecutive	O
patients	O
with	O
BS	O
and	O
438	O
patients	O
with	O
other	O
rheumatological	O
conditions	O
were	O
surveyed	O
for	O
the	O
presence	O
or	O
absence	O
of	O
the	O
features	O
of	O
BS	O
by	O
means	O
of	O
a	O
standard	O
form	O
which	O
had	O
been	O
prepared	O
according	O
to	O
ISG	O
criteria	O
.	O

A	O
computer	O
program	O
,	O
ACCESS	O
-	O
IAQ	O
,	O
is	O
developed	O
to	O
simulate	O
the	O
airflow	O
pattern	O
,	O
the	O
time	O
history	O
of	O
the	O
contaminant	O
concentrations	O
in	O
the	O
occupied	O
zone	O
,	O
and	O
the	O
inhalation	O
exposures	O
.	O

Classification	O
according	O
to	O
the	O
ILAR	O
criteria	O
was	O
possible	O
in	O
321	O
patients	O
;	O
290	O
patients	O
had	O
a	O
disease	O
duration	O
>	O
or	O
=	O
3	O
months	O
and	O
were	O
classified	O
according	O
to	O
the	O
EULAR	O
criteria	O
.	O

We	O
conducted	O
a	O
clinical	O
and	O
pathologic	O
review	O
of	O
nine	O
patients	O
with	O
immature	O
ovarian	O
teratoma	O
.	O

The	O
results	O
are	O
discussed	O
in	O
relation	O
to	O
acoustical	O
models	O
of	O
sound	O
propagation	O
and	O
physiology	O
,	O
and	O
it	O
is	O
suggested	O
that	O
height	O
-	O
dependent	O
degradation	O
within	O
a	O
forest	O
is	O
an	O
important	O
selection	O
pressure	O
for	O
transmissibility	O
in	O
avian	O
communication	O
.	O

In	O
sterilized	O
milk	O
there	O
was	O
a	O
slight	O
decrease	O
of	O
linoleic	O
acid	O
(	O
C18	O
:	O
2n6	O
;	O
-	O
0	O
.	O
7	O
%	O
vs	O
.	O
fresh	O
;	O
P	O
=	O
0	O
.	O
006	O
)	O
and	O
arachidonic	O
acid	O
(	O
C20	O
:	O
4n6	O
;	O
-	O
2	O
.	O
5	O
%	O
;	O
P	O
=	O
0	O
.	O
045	O
)	O
.	O

The	O
electrodes	O
themselves	O
do	O
not	O
need	O
to	O
be	O
polished	O
prior	O
to	O
their	O
use	O
but	O
are	O
observed	O
to	O
be	O
slightly	O
recessed	O
from	O
the	O
surrounding	O
insulating	O
surface	O
.	O

Because	O
the	O
DPPD	B-GENE
gene	I-GENE
is	O
not	O
present	O
in	O
non	O
-	O
tuberculous	O
bacilli	O
,	O
these	O
results	O
suggest	O
that	O
this	O
molecule	O
can	O
be	O
an	O
additional	O
tool	O
for	O
a	O
more	O
specific	O
diagnosis	O
of	O
tuberculosis	O
.	O

Patients	O
with	O
a	O
secondary	O
cardiac	O
event	O
had	O
more	O
common	O
Type	O
A	O
behavior	O
patterns	O
and	O
higher	O
Bortner	O
scores	O
than	O
patients	O
without	O
a	O
secondary	O
cardiac	O
event	O
.	O

Interestingly	O
,	O
continuation	O
of	O
the	O
interferon	B-GENE
therapy	O
in	O
the	O
presence	O
of	O
a	O
mild	O
-	O
to	O
-	O
moderate	O
exacerbation	O
of	O
sarcoidosis	O
may	O
be	O
safe	O
in	O
a	O
minority	O
of	O
patients	O
with	O
noncritical	O
organ	O
involvement	O
.	O

There	O
was	O
no	O
difference	O
in	O
apnea	O
duration	O
between	O
the	O
supine	O
and	O
prone	O
positions	O
.	O

TNFalpha	B-GENE
and	O
IL	B-GENE
-	I-GENE
6	I-GENE
levels	O
were	O
determined	O
in	O
the	O
culture	O
supernatants	O
.	O

Therefore	O
,	O
this	O
study	O
has	O
demonstrated	O
that	O
prenatal	O
disturbance	O
can	O
induce	O
a	O
lasting	O
change	O
in	O
cytokine	O
biology	O
,	O
which	O
persists	O
well	O
beyond	O
the	O
fetal	O
and	O
infant	O
stage	O
.	O

Based	O
on	O
analytic	O
precisions	O
,	O
a	O
+	O
/	O
-	O
2	O
%	O
urine	O
-	O
plasma	O
difference	O
was	O
set	O
as	O
the	O
cut	O
-	O
off	O
value	O
.	O

Schistosoma	O
mansoni	O
schistosomiasis	O
]	O
Schistosomosis	O
are	O
parasitic	O
diseases	O
caused	O
by	O
blood	O
flukes	O
of	O
the	O
Schistosoma	O
genus	O
.	O

Emphysematous	O
cholecystitis	O
:	O
sonographic	O
findings	O
.	O

Age	O
was	O
categorized	O
into	O
four	O
groups	O
:	O
20	O
-	O
44	O
,	O
45	O
-	O
64	O
,	O
65	O
-	O
74	O
,	O
and	O
75	O
+	O
.	O
RESULTS	O
:	O
At	O
the	O
initiation	O
of	O
dialysis	O
PD	O
patients	O
were	O
approximately	O
6	O
years	O
younger	O
(	O
P	O
<	O
0	O
.	O
0001	O
)	O
than	O
HD	O
patients	O
.	O

The	O
utility	O
of	O
such	O
analyses	O
in	O
the	O
design	O
of	O
ceramic	O
/	O
substrate	O
bilayer	O
systems	O
for	O
optimal	O
resistance	O
to	O
lifetime	O
-	O
threatening	O
damage	O
is	O
discussed	O
.	O

Adjacent	O
to	O
those	O
lesions	O
,	O
and	O
in	O
homologous	O
contralateral	O
structures	O
,	O
FMZ	O
binding	O
was	O
analysed	O
in	O
four	O
pairs	O
of	O
cortical	O
9	O
x	O
9	O
-	O
mm	O
regions	O
of	O
interest	O
(	O
ROIs	O
)	O
placed	O
on	O
transaxial	O
and	O
coronal	O
slices	O
,	O
respectively	O
,	O
as	O
well	O
as	O
in	O
the	O
lesion	O
volume	O
and	O
its	O
mirror	O
region	O
.	O

Because	O
a	O
close	O
correlation	O
between	O
regional	O
decreases	O
in	O
FMZ	O
binding	O
and	O
spiking	O
activity	O
was	O
recently	O
demonstrated	O
in	O
neocortical	O
epilepsies	O
,	O
abnormal	O
peri	O
-	O
lesional	O
FMZ	O
binding	O
may	O
bear	O
some	O
relation	O
to	O
the	O
mechanisms	O
of	O
epileptogenesis	O
in	O
symptomatic	O
epilepsies	O
.	O

We	O
found	O
three	O
out	O
of	O
four	O
original	O
(	O
Volkan	O
'	O
s	O
)	O
groups	O
of	O
linking	O
objects	O
,	O
but	O
also	O
an	O
additional	O
one	O
,	O
hitherto	O
undescribed	O
,	O
comprising	O
objects	O
used	O
for	O
designing	O
a	O
memorial	O
shrine	O
to	O
the	O
deceased	O
.	O

One	O
CKD	O
patient	O
'	O
s	O
journey	O
.	O

In	O
patients	O
who	O
respond	O
to	O
quetiapine	O
,	O
therapy	O
should	O
be	O
continued	O
at	O
the	O
optimal	O
dose	O
that	O
maintains	O
remission	O
,	O
within	O
the	O
range	O
of	O
150	O
to	O
750	O
mg	O
/	O
d	O
.	O

With	O
such	O
analysis	O
,	O
one	O
can	O
test	O
hypotheses	O
about	O
the	O
structure	O
of	O
latent	O
variability	O
within	O
a	O
given	O
data	O
set	O
.	O

In	O
this	O
study	O
we	O
wanted	O
to	O
assess	O
the	O
DR	O
using	O
the	O
'	O
combined	O
test	O
'	O
in	O
an	O
unselected	O
population	O
of	O
self	O
-	O
referred	O
pregnant	O
women	O
at	O
a	O
false	O
-	O
positive	O
rate	O
(	O
FPR	O
)	O
of	O
about	O
5	O
%	O
.	O

22	B-Chemical
-	I-Chemical
oxacalcitriol	I-Chemical
suppresses	O
secondary	B-Disease
hyperparathyroidism	I-Disease
without	O
inducing	O
low	B-Disease
bone	I-Disease
turnover	I-Disease
in	O
dogs	O
with	O
renal	B-Disease
failure	I-Disease
.	O

BACKGROUND	O
:	O
Calcitriol	B-Chemical
therapy	O
suppresses	O
serum	O
levels	O
of	O
parathyroid	O
hormone	O
(	O
PTH	O
)	O
in	O
patients	O
with	O
renal	B-Disease
failure	I-Disease
but	O
has	O
several	O
drawbacks	O
,	O
including	O
hypercalcemia	B-Disease
and	O
/	O
or	O
marked	O
suppression	B-Disease
of	I-Disease
bone	I-Disease
turnover	I-Disease
,	O
which	O
may	O
lead	O
to	O
adynamic	B-Disease
bone	I-Disease
disease	I-Disease
.	O

A	O
new	O
vitamin	B-Chemical
D	I-Chemical
analogue	O
,	O
22	B-Chemical
-	I-Chemical
oxacalcitriol	I-Chemical
(	O
OCT	B-Chemical
)	O
,	O
has	O
been	O
shown	O
to	O
have	O
promising	O
characteristics	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
determine	O
the	O
effects	O
of	O
OCT	B-Chemical
on	O
serum	O
PTH	O
levels	O
and	O
bone	O
turnover	O
in	O
states	O
of	O
normal	O
or	O
impaired	B-Disease
renal	I-Disease
function	I-Disease
.	O

METHODS	O
:	O
Sixty	O
dogs	O
were	O
either	O
nephrectomized	O
(	O
Nx	O
,	O
N	O
=	O
38	O
)	O
or	O
sham	O
-	O
operated	O
(	O
Sham	O
,	O
N	O
=	O
22	O
)	O
.	O

The	O
animals	O
received	O
supplemental	O
phosphate	B-Chemical
to	O
enhance	O
PTH	O
secretion	O
.	O

Fourteen	O
weeks	O
after	O
the	O
start	O
of	O
phosphate	B-Chemical
supplementation	O
,	O
half	O
of	O
the	O
Nx	O
and	O
Sham	O
dogs	O
received	O
doses	O
of	O
OCT	B-Chemical
(	O
three	O
times	O
per	O
week	O
)	O
;	O
the	O
other	O
half	O
were	O
given	O
vehicle	O
for	O
60	O
weeks	O
.	O

Thereafter	O
,	O
the	O
treatment	O
modalities	O
for	O
a	O
subset	O
of	O
animals	O
were	O
crossed	O
over	O
for	O
an	O
additional	O
eight	O
months	O
.	O

Biochemical	O
and	O
hormonal	O
indices	O
of	O
calcium	B-Chemical
and	O
bone	O
metabolism	O
were	O
measured	O
throughout	O
the	O
study	O
,	O
and	O
bone	O
biopsies	O
were	O
done	O
at	O
baseline	O
,	O
60	O
weeks	O
after	O
OCT	B-Chemical
or	O
vehicle	O
treatment	O
,	O
and	O
at	O
the	O
end	O
of	O
the	O
crossover	O
period	O
.	O

RESULTS	O
:	O
In	O
Nx	O
dogs	O
,	O
OCT	B-Chemical
significantly	O
decreased	O
serum	O
PTH	O
levels	O
soon	O
after	O
the	O
induction	O
of	O
renal	B-Disease
insufficiency	I-Disease
.	O

In	O
long	O
-	O
standing	O
secondary	B-Disease
hyperparathyroidism	I-Disease
,	O
OCT	B-Chemical
(	O
0	O
.	O
03	O
microg	O
/	O
kg	O
)	O
stabilized	O
serum	O
PTH	O
levels	O
during	O
the	O
first	O
months	O
.	O

Serum	O
PTH	O
levels	O
rose	O
thereafter	O
,	O
but	O
the	O
rise	O
was	O
less	O
pronounced	O
compared	O
with	O
baseline	O
than	O
the	O
rise	O
seen	O
in	O
Nx	O
control	O
.	O

These	O
effects	O
were	O
accompanied	O
by	O
episodes	O
of	O
hypercalcemia	B-Disease
and	O
hyperphosphatemia	B-Disease
.	O

In	O
animals	O
with	O
normal	O
renal	O
function	O
,	O
OCT	B-Chemical
induced	O
a	O
transient	O
decrease	O
in	O
serum	O
PTH	O
levels	O
at	O
a	O
dose	O
of	O
0	O
.	O
1	O
microg	O
/	O
kg	O
,	O
which	O
was	O
not	O
sustained	O
with	O
lowering	O
of	O
the	O
doses	O
.	O

In	O
Nx	O
dogs	O
,	O
OCT	B-Chemical
reversed	O
abnormal	O
bone	O
formation	O
,	O
such	O
as	O
woven	B-Disease
osteoid	I-Disease
and	O
fibrosis	B-Disease
,	O
but	O
did	O
not	O
significantly	O
alter	O
the	O
level	O
of	O
bone	O
turnover	O
.	O

In	O
addition	O
,	O
OCT	B-Chemical
improved	O
mineralization	O
lag	O
time	O
,	O
(	O
that	O
is	O
,	O
the	O
rate	O
at	O
which	O
osteoid	O
mineralizes	O
)	O
in	O
both	O
Nx	O
and	O
Sham	O
dogs	O
.	O

CONCLUSIONS	O
:	O
These	O
results	O
indicate	O
that	O
even	O
though	O
OCT	B-Chemical
does	O
not	O
completely	O
prevent	O
the	O
occurrence	O
of	O
hypercalcemia	B-Disease
in	O
experimental	O
dogs	O
with	O
renal	B-Disease
insufficiency	I-Disease
,	O
it	O
may	O
be	O
of	O
use	O
in	O
the	O
management	O
of	O
secondary	B-Disease
hyperparathyroidism	I-Disease
because	O
it	O
does	O
not	O
induce	O
low	B-Disease
bone	I-Disease
turnover	I-Disease
and	O
,	O
therefore	O
,	O
does	O
not	O
increase	O
the	O
risk	O
of	O
adynamic	B-Disease
bone	I-Disease
disease	I-Disease
.	O

Hypotension	B-Disease
,	O
bradycardia	B-Disease
,	O
and	O
asystole	B-Disease
after	O
high	O
-	O
dose	O
intravenous	O
methylprednisolone	B-Chemical
in	O
a	O
monitored	O
patient	O
.	O

We	O
report	O
a	O
case	O
of	O
hypotension	B-Disease
,	O
bradycardia	B-Disease
,	O
and	O
asystole	B-Disease
after	O
intravenous	O
administration	O
of	O
high	O
-	O
dose	O
methylprednisolone	B-Chemical
in	O
a	O
73	O
-	O
year	O
-	O
old	O
patient	O
who	O
underwent	O
electrocardiographic	O
(	O
ECG	O
)	O
monitoring	O
throughout	O
the	O
episode	O
.	O

There	O
was	O
a	O
history	O
of	O
ischemic	B-Disease
cardiac	B-Disease
disease	I-Disease
9	O
years	O
earlier	O
.	O

The	O
patient	O
was	O
admitted	O
with	O
a	O
pulmonary	B-Disease
-	I-Disease
renal	I-Disease
syndrome	I-Disease
with	O
hemoptysis	B-Disease
,	O
rapidly	O
progressive	O
renal	B-Disease
failure	I-Disease
,	O
and	O
hypoxemia	B-Disease
that	O
required	O
mechanical	O
ventilation	O
in	O
the	O
intensive	O
care	O
unit	O
.	O

After	O
receiving	O
advanced	O
cardiopulmonary	O
resuscitation	O
,	O
the	O
patient	O
recovered	O
cardiac	O
rhythm	O
.	O

The	O
ECG	O
showed	O
a	O
junctional	O
rhythm	O
without	O
ventricular	B-Disease
arrhythmia	I-Disease
.	O

This	O
study	O
reviews	O
the	O
current	O
proposed	O
mechanisms	O
of	O
sudden	B-Disease
death	I-Disease
after	O
a	O
high	O
dose	O
of	O
intravenous	O
methylprednisolone	B-Chemical
(	O
IVMP	B-Chemical
)	O
.	O

These	O
mechanisms	O
are	O
not	O
well	O
understood	O
because	O
,	O
in	O
most	O
cases	O
,	O
the	O
patients	O
were	O
not	O
monitored	O
at	O
the	O
moment	O
of	O
the	O
event	O
.	O

Rapid	O
infusion	O
and	O
underlying	O
cardiac	B-Disease
disease	I-Disease
were	O
important	O
risk	O
factors	O
in	O
the	O
case	O
reported	O
here	O
,	O
and	O
the	O
authors	O
discount	O
ventricular	B-Disease
arrhythmia	I-Disease
as	O
the	O
main	O
mechanism	O
.	O

Worsening	O
of	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
by	O
motor	O
and	O
mental	O
tasks	O
.	O

Ten	O
patients	O
who	O
had	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
with	O
disabling	O
dyskinesia	B-Disease
were	O
included	O
in	O
this	O
study	O
to	O
evaluate	O
the	O
role	O
of	O
mental	O
(	O
mental	O
calculation	O
)	O
and	O
motor	O
(	O
flexion	O
/	O
extension	O
of	O
right	O
fingers	O
,	O
flexion	O
/	O
extension	O
of	O
left	O
fingers	O
,	O
flexion	O
/	O
extension	O
of	O
the	O
neck	O
,	O
speaking	O
aloud	O
)	O
tasks	O
on	O
the	O
worsening	O
of	O
peak	O
-	O
dose	O
dyskinesia	B-Disease
following	O
administration	O
of	O
an	O
effective	O
single	O
dose	O
of	O
apomorphine	B-Chemical
.	O

Compared	O
with	O
the	O
score	O
at	O
rest	O
(	O
1	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
3	O
)	O
,	O
a	O
significant	O
aggravation	O
of	O
the	O
dyskinesia	B-Disease
score	O
was	O
observed	O
during	O
speaking	O
aloud	O
(	O
5	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
1	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
movements	O
of	O
right	O
(	O
4	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
0	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
and	O
left	O
(	O
3	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
8	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
fingers	O
,	O
movements	O
of	O
the	O
neck	O
(	O
5	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
0	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
,	O
and	O
mental	O
calculation	O
(	O
3	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
0	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

These	O
results	O
suggest	O
that	O
activation	O
tasks	O
such	O
as	O
"	O
speaking	O
aloud	O
"	O
could	O
be	O
used	O
for	O
objective	O
assessment	O
of	O
dyskinesia	B-Disease
severity	O
.	O

Urine	O
N	O
-	O
acetyl	O
-	O
beta	O
-	O
D	O
-	O
glucosaminidase	O
-	O
-	O
a	O
marker	O
of	O
tubular	O
damage	O
?	O

BACKGROUND	O
:	O
Although	O
an	O
indicator	O
of	O
renal	B-Disease
tubular	I-Disease
dysfunction	I-Disease
,	O
an	O
increased	O
urinary	O
N	O
-	O
acetyl	O
-	O
beta	O
-	O
D	O
-	O
glucosaminidase	O
(	O
NAG	O
)	O
activity	O
might	O
reflect	O
increased	O
lysosomal	O
activity	O
in	O
renal	O
tubular	O
cells	O
.	O

METHODS	O
:	O
Puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
)	O
was	O
administered	O
to	O
Sprague	O
Dawley	O
rats	O
to	O
induce	O
proteinuria	B-Disease
.	O

Total	O
protein	O
,	O
albumin	O
,	O
NAG	O
activity	O
and	O
protein	O
electrophoretic	O
pattern	O
were	O
assessed	O
in	O
daily	O
urine	O
samples	O
for	O
33	O
days	O
.	O

The	O
morphological	O
appearance	O
of	O
the	O
kidneys	O
was	O
examined	O
on	O
days	O
three	O
,	O
four	O
,	O
six	O
,	O
eight	O
and	O
thirty	O
three	O
and	O
the	O
NAG	O
isoenzyme	O
patterns	O
on	O
days	O
zero	O
,	O
four	O
,	O
eight	O
and	O
thirty	O
three	O
.	O

RESULTS	O
:	O
Following	O
intravenous	O
PAN	B-Chemical
urine	O
volume	O
and	O
urine	O
NAG	O
activity	O
increased	O
significantly	O
by	O
day	O
two	O
,	O
but	O
returned	O
to	O
normal	O
by	O
day	O
four	O
.	O

After	O
day	O
four	O
all	O
treated	O
animals	O
exhibited	O
a	O
marked	O
rise	O
in	O
urine	O
albumin	O
,	O
total	O
protein	O
excretion	O
and	O
NAG	O
activity	O
.	O

Electrophoresis	O
showed	O
a	O
generalised	O
increase	O
in	O
middle	O
and	O
high	O
molecular	O
weight	O
urine	O
proteins	O
from	O
day	O
four	O
onwards	O
.	O

Protein	O
droplets	O
first	O
appeared	O
prominent	O
in	O
tubular	O
cells	O
on	O
day	O
four	O
.	O

Peak	O
urine	O
NAG	O
activity	O
and	O
a	O
change	O
in	O
NAG	O
isoenzyme	O
pattern	O
coincided	O
with	O
both	O
the	O
peak	O
proteinuria	B-Disease
and	O
the	O
reduction	O
in	O
intracellular	O
protein	O
and	O
NAG	O
droplets	O
(	O
day	O
six	O
onwards	O
)	O
.	O

CONCLUSIONS	O
:	O
This	O
animal	O
model	O
demonstrates	O
that	O
an	O
increase	O
in	O
lysosomal	O
turnover	O
and	O
hence	O
urine	O
NAG	O
activity	O
,	O
occurs	O
when	O
increased	O
protein	O
is	O
presented	O
to	O
the	O
tubular	O
cells	O
.	O

Urine	O
NAG	O
activity	O
is	O
thus	O
a	O
measure	O
of	O
altered	O
function	O
in	O
the	O
renal	O
tubules	O
and	O
not	O
simply	O
an	O
indicator	O
of	O
damage	O
.	O

Cauda	B-Disease
equina	I-Disease
syndrome	I-Disease
after	O
spinal	O
anaesthesia	O
with	O
hyperbaric	O
5	O
%	O
lignocaine	B-Chemical
:	O
a	O
review	O
of	O
six	O
cases	O
of	O
cauda	B-Disease
equina	I-Disease
syndrome	I-Disease
reported	O
to	O
the	O
Swedish	O
Pharmaceutical	O
Insurance	O
1993	O
-	O
1997	O
.	O

Six	O
cases	O
of	O
cauda	B-Disease
equina	I-Disease
syndrome	I-Disease
with	O
varying	O
severity	O
were	O
reported	O
to	O
the	O
Swedish	O
Pharmaceutical	O
Insurance	O
during	O
the	O
period	O
1993	O
-	O
1997	O
.	O

All	O
were	O
associated	O
with	O
spinal	O
anaesthesia	O
using	O
hyperbaric	O
5	O
%	O
lignocaine	B-Chemical
.	O

Five	O
cases	O
had	O
single	O
-	O
shot	O
spinal	O
anaesthesia	O
and	O
one	O
had	O
a	O
repeat	O
spinal	O
anaesthetic	O
due	O
to	O
inadequate	O
block	O
.	O

The	O
dose	O
of	O
hyperbaric	O
5	O
%	O
lignocaine	B-Chemical
administered	O
ranged	O
from	O
60	O
to	O
120	O
mg	O
.	O

Three	O
of	O
the	O
cases	O
were	O
most	O
likely	O
caused	O
by	O
direct	O
neurotoxicity	B-Disease
of	O
hyperbaric	O
5	O
%	O
lignocaine	B-Chemical
.	O

In	O
the	O
other	O
3	O
cases	O
,	O
direct	O
neurotoxicity	B-Disease
was	O
also	O
probable	O
,	O
but	O
unfortunately	O
radiological	O
investigations	O
were	O
not	O
done	O
to	O
definitely	O
exclude	O
a	O
compressive	O
aetiology	O
.	O

All	O
cases	O
sustained	O
permanent	O
neurological	B-Disease
deficits	I-Disease
.	O

We	O
recommend	O
that	O
hyperbaric	O
lignocaine	B-Chemical
should	O
be	O
administered	O
in	O
concentrations	O
not	O
greater	O
than	O
2	O
%	O
and	O
at	O
a	O
total	O
dose	O
preferably	O
not	O
exceeding	O
60	O
mg	O
.	O

Systemic	O
toxicity	B-Disease
following	O
administration	O
of	O
sirolimus	B-Chemical
(	O
formerly	O
rapamycin	B-Chemical
)	O
for	O
psoriasis	B-Disease
:	O
association	O
of	O
capillary	B-Disease
leak	I-Disease
syndrome	I-Disease
with	O
apoptosis	O
of	O
lesional	O
lymphocytes	O
.	O

BACKGROUND	O
:	O
Sirolimus	B-Chemical
(	O
formerly	O
rapamycin	B-Chemical
)	O
is	O
an	O
immunosuppressive	O
agent	O
that	O
interferes	O
with	O
T	O
-	O
cell	O
activation	O
.	O

After	O
2	O
individuals	O
with	O
psoriasis	B-Disease
developed	O
a	O
capillary	B-Disease
leak	I-Disease
syndrome	I-Disease
following	O
treatment	O
with	O
oral	O
sirolimus	B-Chemical
lesional	O
skin	O
cells	O
and	O
activated	O
peripheral	O
blood	O
cells	O
were	O
analyzed	O
for	O
induction	O
of	O
apoptosis	O
.	O

OBSERVATIONS	O
:	O
A	O
keratome	O
skin	O
specimen	O
from	O
1	O
patient	O
with	O
sirolimus	B-Chemical
-	O
induced	O
capillary	B-Disease
leak	I-Disease
syndrome	I-Disease
had	O
a	O
2	O
.	O
3	O
-	O
fold	O
increase	O
in	O
percentage	O
of	O
apoptotic	O
cells	O
(	O
to	O
48	O
%	O
)	O
compared	O
with	O
an	O
unaffected	O
sirolimus	B-Chemical
-	O
treated	O
patient	O
with	O
psoriasis	B-Disease
(	O
21	O
%	O
)	O
.	O

Activated	O
peripheral	O
blood	O
T	O
cells	O
from	O
patients	O
with	O
psoriasis	B-Disease
tended	O
to	O
exhibit	O
greater	O
spontaneous	O
or	O
dexamethasone	B-Chemical
-	O
induced	O
apoptosis	O
than	O
did	O
normal	O
T	O
cells	O
,	O
particularly	O
in	O
the	O
presence	O
of	O
sirolimus	B-Chemical
.	O

CONCLUSIONS	O
:	O
Severe	O
adverse	O
effects	O
of	O
sirolimus	B-Chemical
include	O
fever	B-Disease
,	O
anemia	B-Disease
,	O
and	O
capillary	B-Disease
leak	I-Disease
syndrome	I-Disease
.	O

These	O
symptoms	O
may	O
be	O
the	O
result	O
of	O
drug	O
-	O
induced	O
apoptosis	O
of	O
lesional	O
leukocytes	O
,	O
especially	O
activated	O
T	O
lymphocytes	O
,	O
and	O
possibly	O
release	O
of	O
inflammatory	O
mediators	O
.	O

Because	O
patients	O
with	O
severe	O
psoriasis	B-Disease
may	O
develop	O
capillary	B-Disease
leak	I-Disease
from	O
various	O
systemic	O
therapies	O
,	O
clinical	O
monitoring	O
is	O
advisable	O
for	O
patients	O
with	O
inflammatory	B-Disease
diseases	I-Disease
who	O
are	O
treated	O
with	O
immune	O
modulators	O
.	O

Effect	O
of	O
lithium	B-Chemical
maintenance	O
therapy	O
on	O
thyroid	O
and	O
parathyroid	O
function	O
.	O

OBJECTIVES	O
:	O
To	O
assess	O
changes	O
induced	O
by	O
lithium	B-Chemical
maintenance	O
therapy	O
on	O
the	O
incidence	O
of	O
thyroid	O
,	O
parathyroid	O
and	O
ion	O
alterations	O
.	O

These	O
were	O
evaluated	O
with	O
respect	O
to	O
the	O
duration	O
of	O
lithium	B-Chemical
therapy	O
,	O
age	O
,	O
sex	O
,	O
and	O
family	O
history	O
(	O
whether	O
or	O
not	O
the	O
patient	O
had	O
a	O
first	O
-	O
degree	O
relative	O
with	O
thyroid	B-Disease
disease	I-Disease
)	O
.	O

DESIGN	O
:	O
Prospective	O
study	O
.	O

SETTING	O
:	O
Affective	O
Disorders	O
Clinic	O
at	O
St	O
.	O

Mary	O
'	O
s	O
Hospital	O
,	O
Montreal	O
.	O

PATIENTS	O
:	O
One	O
hundred	O
and	O
one	O
patients	O
(	O
28	O
men	O
and	O
73	O
women	O
)	O
with	O
bipolar	B-Disease
disorder	I-Disease
receiving	O
lithium	B-Chemical
maintenance	O
therapy	O
ranging	O
from	O
1	O
year	O
'	O
s	O
to	O
32	O
years	O
'	O
duration	O
.	O

The	O
control	O
group	O
consisted	O
of	O
82	O
patients	O
with	O
no	O
psychiatric	B-Disease
or	O
endocrinological	O
diagnoses	O
from	O
the	O
hospital	O
'	O
s	O
out	O
-	O
patient	O
clinics	O
.	O

OUTCOME	O
MEASURES	O
:	O
Laboratory	O
analyses	O
of	O
calcium	B-Chemical
,	O
magnesium	B-Chemical
and	O
thyroid	O
-	O
stimulating	O
hormone	O
levels	O
performed	O
before	O
beginning	O
lithium	B-Chemical
therapy	O
and	O
at	O
biannual	O
follow	O
-	O
up	O
.	O

RESULTS	O
:	O
Hypothyroidism	B-Disease
developed	O
in	O
40	O
patients	O
,	O
excluding	O
8	O
patients	O
who	O
were	O
hypothyroid	B-Disease
at	O
baseline	O
.	O

All	O
patients	O
having	O
first	O
-	O
degree	O
relatives	O
affected	O
by	O
thyroid	B-Disease
illness	I-Disease
had	O
accelerated	O
onset	O
of	O
hypothyroidism	B-Disease
(	O
3	O
.	O
7	O
years	O
after	O
onset	O
of	O
lithium	B-Chemical
therapy	O
)	O
compared	O
with	O
patients	O
without	O
a	O
family	O
history	O
(	O
8	O
.	O
6	O
years	O
after	O
onset	O
of	O
lithium	B-Chemical
therapy	O
)	O
.	O

Women	O
over	O
60	O
years	O
of	O
age	O
were	O
more	O
often	O
affected	O
by	O
hypothyroidism	B-Disease
than	O
women	O
under	O
60	O
years	O
of	O
age	O
(	O
34	O
.	O
6	O
%	O
versus	O
31	O
.	O
9	O
%	O
)	O
.	O

Magnesium	B-Chemical
levels	O
in	O
patients	O
on	O
lithium	B-Chemical
treatment	O
were	O
unchanged	O
from	O
baseline	O
levels	O
.	O

After	O
lithium	B-Chemical
treatment	O
,	O
calcium	B-Chemical
levels	O
were	O
higher	O
than	O
either	O
baseline	O
levels	O
or	O
control	O
levels	O
.	O

Thus	O
,	O
lithium	B-Chemical
treatment	O
counteracted	O
the	O
decrease	O
in	O
plasma	O
calcium	B-Chemical
levels	O
associated	O
with	O
aging	O
.	O

CONCLUSIONS	O
:	O
Familial	O
thyroid	B-Disease
illness	I-Disease
is	O
a	O
risk	O
factor	O
for	O
hypothyroidism	B-Disease
and	O
hypercalcemia	B-Disease
during	O
lithium	B-Chemical
therapy	O
.	O

Severe	O
immune	O
hemolytic	B-Disease
anemia	I-Disease
associated	O
with	O
prophylactic	O
use	O
of	O
cefotetan	B-Chemical
in	O
obstetric	O
and	O
gynecologic	O
procedures	O
.	O

Second	O
-	O
and	O
third	O
-	O
generation	O
cephalosporins	B-Chemical
,	O
especially	O
cefotetan	B-Chemical
,	O
are	O
increasingly	O
associated	O
with	O
severe	O
,	O
sometimes	O
fatal	O
immune	O
hemolytic	B-Disease
anemia	I-Disease
.	O

We	O
noticed	O
that	O
10	O
of	O
our	O
35	O
cases	O
of	O
cefotetan	B-Chemical
-	O
induced	O
hemolytic	B-Disease
anemias	I-Disease
were	O
in	O
patients	O
who	O
had	O
received	O
cefotetan	B-Chemical
prophylactically	O
for	O
obstetric	O
and	O
gynecologic	O
procedures	O
.	O

Eight	O
of	O
these	O
cases	O
of	O
severe	O
immune	O
hemolytic	B-Disease
anemia	I-Disease
are	O
described	O
.	O

Effects	O
of	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drugs	O
on	O
hemostasis	O
in	O
patients	O
with	O
aneurysmal	B-Disease
subarachnoid	I-Disease
hemorrhage	I-Disease
.	O

Platelet	O
function	O
is	O
impaired	O
by	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drugs	O
(	O
NSAIDs	O
)	O
with	O
prominent	O
anti	O
-	O
inflammatory	O
properties	O
.	O

Their	O
safety	O
in	O
patients	O
undergoing	O
intracranial	O
surgery	O
is	O
under	O
debate	O
.	O

Patients	O
with	O
aneurysmal	B-Disease
subarachnoid	I-Disease
hemorrhage	I-Disease
(	O
SAH	B-Disease
)	O
were	O
randomized	O
to	O
receive	O
either	O
ketoprofen	B-Chemical
,	O
100	O
mg	O
,	O
three	O
times	O
a	O
day	O
(	O
ketoprofen	B-Chemical
group	O
,	O
n	O
=	O
9	O
)	O
or	O
a	O
weak	O
NSAID	O
,	O
acetaminophen	B-Chemical
,	O
1	O
g	O
,	O
three	O
times	O
a	O
day	O
(	O
acetaminophen	B-Chemical
group	O
,	O
n	O
=	O
9	O
)	O
starting	O
immediately	O
after	O
the	O
diagnosis	O
of	O
aneurysmal	B-Disease
SAH	B-Disease
.	O

Treatment	O
was	O
continued	O
for	O
3	O
days	O
postoperatively	O
.	O

Test	O
blood	O
samples	O
were	O
taken	O
before	O
treatment	O
and	O
surgery	O
as	O
well	O
as	O
on	O
the	O
first	O
,	O
third	O
,	O
and	O
fifth	O
postoperative	O
mornings	O
.	O

Maximal	O
platelet	B-Disease
aggregation	I-Disease
induced	O
by	O
6	O
microM	O
of	O
adenosine	B-Chemical
diphosphate	I-Chemical
decreased	O
after	O
administration	O
of	O
ketoprofen	B-Chemical
.	O

Aggregation	O
was	O
lower	O
(	O
P	O
<	O
.	O
05	O
)	O
in	O
the	O
ketoprofen	B-Chemical
group	O
than	O
in	O
the	O
acetaminophen	B-Chemical
group	O
just	O
before	O
surgery	O
and	O
on	O
the	O
third	O
postoperative	O
day	O
.	O

In	O
contrast	O
,	O
maximal	O
platelet	B-Disease
aggregation	I-Disease
increased	O
in	O
the	O
acetaminophen	B-Chemical
group	O
on	O
the	O
third	O
postoperative	O
day	O
as	O
compared	O
with	O
the	O
pretreatment	O
platelet	B-Disease
aggregation	I-Disease
results	O
(	O
P	O
<	O
.	O
05	O
)	O
.	O

One	O
patient	O
in	O
the	O
ketoprofen	B-Chemical
group	O
developed	O
a	O
postoperative	O
intracranial	O
hematoma	B-Disease
.	O

Coagulation	O
(	O
prothrombin	O
time	O
[	O
PT	O
]	O
,	O
activated	O
partial	O
thromboplastin	O
time	O
[	O
APPT	O
]	O
,	O
fibrinogen	O
concentration	O
,	O
and	O
antithrombin	O
III	O
[	O
AT	O
III	O
]	O
)	O
was	O
comparable	O
between	O
the	O
two	O
groups	O
.	O

Ketoprofen	B-Chemical
but	O
not	O
acetaminophen	B-Chemical
impaired	O
platelet	O
function	O
in	O
patients	O
with	O
SAH	B-Disease
.	O

If	O
ketoprofen	B-Chemical
is	O
used	O
before	O
surgery	O
on	O
cerebral	O
artery	B-Disease
aneurysms	I-Disease
,	O
it	O
may	O
pose	O
an	O
additional	O
risk	O
factor	O
for	O
hemorrhage	B-Disease
.	O

Nitric	B-Chemical
oxide	I-Chemical
synthase	O
expression	O
in	O
the	O
course	O
of	O
lead	B-Chemical
-	O
induced	O
hypertension	B-Disease
.	O

We	O
recently	O
showed	O
elevated	O
reactive	O
oxygen	B-Chemical
species	O
(	O
ROS	O
)	O
,	O
reduced	O
urinary	O
excretion	O
of	O
NO	B-Chemical
metabolites	O
(	O
NOx	O
)	O
,	O
and	O
increased	O
NO	B-Chemical
sequestration	O
as	O
nitrotyrosine	B-Chemical
in	O
various	O
tissues	O
in	O
rats	O
with	O
lead	B-Chemical
-	O
induced	O
hypertension	B-Disease
.	O

This	O
study	O
was	O
designed	O
to	O
discern	O
whether	O
the	O
reduction	O
in	O
urinary	O
NOx	O
in	O
lead	B-Chemical
-	O
induced	O
hypertension	B-Disease
is	O
,	O
in	O
part	O
,	O
due	O
to	O
depressed	O
NO	B-Chemical
synthase	O
(	O
NOS	O
)	O
expression	O
.	O

Male	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
randomly	O
assigned	O
to	O
a	O
lead	B-Chemical
-	O
treated	O
group	O
(	O
given	O
lead	B-Chemical
acetate	I-Chemical
,	O
100	O
ppm	O
,	O
in	O
drinking	O
water	O
and	O
regular	O
rat	O
chow	O
)	O
,	O
a	O
group	O
given	O
lead	B-Chemical
and	O
vitamin	B-Chemical
E	I-Chemical
-	O
fortified	O
chow	O
,	O
or	O
a	O
normal	O
control	O
group	O
given	O
either	O
regular	O
food	O
and	O
water	O
or	O
vitamin	B-Chemical
E	I-Chemical
-	O
fortified	O
food	O
for	O
12	O
weeks	O
.	O

Tail	O
blood	O
pressure	O
,	O
urinary	O
NOx	O
excretion	O
,	O
plasma	O
malondialdehyde	B-Chemical
(	O
MDA	B-Chemical
)	O
,	O
and	O
endothelial	O
and	O
inducible	O
NOS	O
(	O
eNOS	O
and	O
iNOS	O
)	O
isotypes	O
in	O
the	O
aorta	O
and	O
kidney	O
were	O
measured	O
.	O

The	O
lead	B-Chemical
-	O
treated	O
group	O
exhibited	O
a	O
rise	O
in	O
blood	O
pressure	O
and	O
plasma	O
MDA	B-Chemical
concentration	O
,	O
a	O
fall	O
in	O
urinary	O
NOx	O
excretion	O
,	O
and	O
a	O
paradoxical	O
rise	O
in	O
vascular	O
and	O
renal	O
tissue	O
eNOS	O
and	O
iNOS	O
expression	O
.	O

Vitamin	B-Chemical
E	I-Chemical
supplementation	O
ameliorated	O
hypertension	B-Disease
,	O
lowered	O
plasma	O
MDA	B-Chemical
concentration	O
,	O
and	O
raised	O
urinary	O
NOx	O
excretion	O
while	O
significantly	O
lowering	O
vascular	O
,	O
but	O
not	O
renal	O
,	O
tissue	O
eNOS	O
and	O
iNOS	O
expression	O
.	O

Vitamin	B-Chemical
E	I-Chemical
supplementation	O
had	O
no	O
effect	O
on	O
either	O
blood	O
pressure	O
,	O
plasma	O
MDA	B-Chemical
,	O
or	O
NOS	O
expression	O
in	O
the	O
control	O
group	O
.	O

The	O
study	O
also	O
revealed	O
significant	O
inhibition	O
of	O
NOS	O
enzymatic	O
activity	O
by	O
lead	B-Chemical
in	O
cell	O
-	O
free	O
preparations	O
.	O

In	O
conclusion	O
,	O
lead	B-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
this	O
model	O
was	O
associated	O
with	O
a	O
compensatory	O
upregulation	O
of	O
renal	O
and	O
vascular	O
eNOS	O
and	O
iNOS	O
expression	O
.	O

This	O
is	O
,	O
in	O
part	O
,	O
due	O
to	O
ROS	O
-	O
mediated	O
NO	B-Chemical
inactivation	O
,	O
lead	B-Chemical
-	O
associated	O
inhibition	O
of	O
NOS	O
activity	O
,	O
and	O
perhaps	O
stimulatory	O
actions	O
of	O
increased	O
shear	O
stress	O
associated	O
with	O
hypertension	B-Disease
.	O

Glyceryl	B-Chemical
trinitrate	I-Chemical
induces	O
attacks	O
of	O
migraine	B-Disease
without	I-Disease
aura	I-Disease
in	O
sufferers	O
of	O
migraine	B-Disease
with	I-Disease
aura	I-Disease
.	O

Migraine	B-Disease
with	I-Disease
aura	I-Disease
and	O
migraine	B-Disease
without	I-Disease
aura	I-Disease
have	O
the	O
same	O
pain	B-Disease
phase	O
,	O
thus	O
indicating	O
that	O
migraine	B-Disease
with	I-Disease
aura	I-Disease
and	O
migraine	B-Disease
without	I-Disease
aura	I-Disease
share	O
a	O
common	O
pathway	O
of	O
nociception	O
.	O

In	O
recent	O
years	O
,	O
increasing	O
evidence	O
has	O
suggested	O
that	O
the	O
messenger	O
molecule	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
is	O
involved	O
in	O
pain	B-Disease
mechanisms	O
of	O
migraine	B-Disease
without	I-Disease
aura	I-Disease
.	O

In	O
order	O
to	O
clarify	O
whether	O
the	O
same	O
is	O
true	O
for	O
migraine	B-Disease
with	I-Disease
aura	I-Disease
,	O
in	O
the	O
present	O
study	O
we	O
examined	O
the	O
headache	B-Disease
response	O
to	O
intravenous	O
infusion	O
of	O
glyceryl	B-Chemical
trinitrate	I-Chemical
(	O
GTN	B-Chemical
)	O
(	O
0	O
.	O
5	O
microg	O
/	O
kg	O
/	O
min	O
for	O
20	O
min	O
)	O
in	O
12	O
sufferers	O
of	O
migraine	B-Disease
with	I-Disease
aura	I-Disease
.	O

The	O
specific	O
aim	O
was	O
to	O
elucidate	O
whether	O
an	O
aura	O
and	O
/	O
or	O
an	O
attack	O
of	O
migraine	B-Disease
without	I-Disease
aura	I-Disease
could	O
be	O
induced	O
.	O

Fourteen	O
healthy	O
subjects	O
served	O
as	O
controls	O
.	O

Aura	O
symptoms	O
were	O
not	O
elicited	O
in	O
any	O
subject	O
.	O

Headache	B-Disease
was	O
more	O
severe	O
in	O
migraineurs	B-Disease
than	O
in	O
the	O
controls	O
during	O
and	O
immediately	O
after	O
GTN	B-Chemical
infusion	O
(	O
p	O
=	O
0	O
.	O
037	O
)	O
as	O
well	O
as	O
during	O
the	O
following	O
11	O
h	O
(	O
p	O
=	O
0	O
.	O
008	O
)	O
.	O

In	O
the	O
controls	O
,	O
the	O
GTN	B-Chemical
-	O
induced	O
headache	B-Disease
gradually	O
disappeared	O
,	O
whereas	O
in	O
migraineurs	B-Disease
peak	O
headache	B-Disease
intensity	O
occurred	O
at	O
a	O
mean	O
time	O
of	O
240	O
min	O
post	O
-	O
infusion	O
.	O

At	O
this	O
time	O
the	O
induced	O
headache	B-Disease
in	O
6	O
of	O
12	O
migraineurs	B-Disease
fulfilled	O
the	O
diagnostic	O
criteria	O
for	O
migraine	B-Disease
without	I-Disease
aura	I-Disease
of	O
the	O
International	O
Headache	B-Disease
Society	O
.	O

The	O
results	O
therefore	O
suggest	O
that	O
NO	B-Chemical
is	O
involved	O
in	O
the	O
pain	B-Disease
mechanisms	O
of	O
migraine	B-Disease
with	I-Disease
aura	I-Disease
.	O

Since	O
cortical	O
spreading	O
depression	B-Disease
has	O
been	O
shown	O
to	O
liberate	O
NO	B-Chemical
in	O
animals	O
,	O
this	O
finding	O
may	O
help	O
our	O
understanding	O
of	O
the	O
coupling	O
between	O
cortical	O
spreading	O
depression	B-Disease
and	O
headache	B-Disease
in	O
migraine	B-Disease
with	I-Disease
aura	I-Disease
.	O

Rapid	O
reversal	O
of	O
life	O
-	O
threatening	O
diltiazem	B-Chemical
-	O
induced	O
tetany	B-Disease
with	O
calcium	B-Chemical
chloride	I-Chemical
.	O

We	O
describe	O
a	O
patient	O
who	O
developed	O
tetany	B-Disease
with	O
sudden	O
respiratory	B-Disease
arrest	I-Disease
after	O
the	O
infusion	O
of	O
intravenous	O
diltiazem	B-Chemical
.	O

The	O
administration	O
of	O
calcium	B-Chemical
chloride	I-Chemical
rapidly	O
resolved	O
the	O
patient	O
'	O
s	O
tetany	B-Disease
with	O
prompt	O
recovery	O
of	O
respiratory	O
function	O
,	O
averting	O
the	O
need	O
for	O
more	O
aggressive	O
airway	O
management	O
and	O
ventilatory	O
support	O
.	O

The	O
emergency	O
physician	O
should	O
be	O
aware	O
that	O
life	O
-	O
threatening	O
tetany	B-Disease
may	O
accompany	O
the	O
administration	O
of	O
intravenous	O
diltiazem	B-Chemical
and	O
that	O
calcium	B-Chemical
chloride	I-Chemical
may	O
be	O
a	O
rapid	O
and	O
effective	O
remedy	O
.	O

Predictors	O
of	O
decreased	B-Disease
renal	I-Disease
function	I-Disease
in	O
patients	O
with	O
heart	B-Disease
failure	I-Disease
during	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
inhibitor	O
therapy	O
:	O
results	O
from	O
the	O
studies	O
of	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
(	O
SOLVD	O
)	O

BACKGROUND	O
:	O
Although	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
inhibitor	O
therapy	O
reduces	O
mortality	O
rates	O
in	O
patients	O
with	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
(	O
CHF	B-Disease
)	O
,	O
it	O
may	O
also	O
cause	O
decreased	B-Disease
renal	I-Disease
function	I-Disease
.	O

Little	O
information	O
is	O
available	O
to	O
predict	O
which	O
patients	O
are	O
at	O
highest	O
risk	O
for	O
this	O
complication	O
.	O

OBJECTIVE	O
:	O
To	O
quantify	O
specific	O
clinical	O
predictors	O
of	O
reduction	B-Disease
in	I-Disease
renal	I-Disease
function	I-Disease
in	O
patients	O
with	O
CHF	B-Disease
who	O
are	O
prescribed	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
inhibitor	O
therapy	O
.	O

METHOD	O
:	O
We	O
analyzed	O
data	O
from	O
the	O
Studies	O
of	O
Left	B-Disease
Ventricular	I-Disease
Dysfunction	I-Disease
(	O
SOLVD	O
)	O
,	O
a	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
trial	O
of	O
enalapril	B-Chemical
for	O
the	O
treatment	O
of	O
CHF	B-Disease
.	O

There	O
were	O
3379	O
patients	O
randomly	O
assigned	O
to	O
enalapril	B-Chemical
with	O
a	O
median	O
follow	O
-	O
up	O
of	O
974	O
days	O
and	O
3379	O
patients	O
randomly	O
assigned	O
to	O
placebo	O
with	O
a	O
mean	O
follow	O
-	O
up	O
of	O
967	O
days	O
.	O

Decreased	B-Disease
renal	I-Disease
function	I-Disease
was	O
defined	O
as	O
a	O
rise	O
in	O
serum	O
creatinine	B-Chemical
>	O
/	O
=	O
0	O
.	O
5	O
mg	O
/	O
dL	O
(	O
44	O
micromol	O
/	O
L	O
)	O
from	O
baseline	O
.	O

We	O
used	O
time	O
-	O
to	O
-	O
event	O
analysis	O
to	O
identify	O
potential	O
predictors	O
of	O
decrease	O
in	O
renal	O
function	O
including	O
age	O
,	O
baseline	O
ejection	O
fraction	O
,	O
baseline	O
creatinine	B-Chemical
,	O
low	O
systolic	O
blood	O
pressure	O
(	O
<	O
100	O
mm	O
Hg	O
)	O
,	O
history	O
of	O
hypertension	B-Disease
,	O
diabetes	B-Disease
,	O
and	O
use	O
of	O
antiplatelet	O
,	O
diuretic	B-Chemical
,	O
and	O
beta	O
-	O
blocker	O
therapy	O
.	O

RESULTS	O
:	O
Patients	O
randomly	O
assigned	O
to	O
enalapril	B-Chemical
had	O
a	O
33	O
%	O
greater	O
likelihood	O
of	O
decreased	B-Disease
renal	I-Disease
function	I-Disease
than	O
controls	O
(	O
P	O
=	O
.	O
003	O
)	O
.	O

By	O
multivariate	O
analysis	O
,	O
in	O
both	O
the	O
placebo	O
and	O
enalapril	B-Chemical
groups	O
older	O
age	O
,	O
diuretic	B-Chemical
therapy	O
,	O
and	O
diabetes	B-Disease
were	O
associated	O
with	O
decreased	B-Disease
renal	I-Disease
function	I-Disease
,	O
whereas	O
beta	O
-	O
blocker	O
therapy	O
and	O
higher	O
ejection	O
fraction	O
were	O
renoprotective	O
.	O

Older	O
age	O
was	O
associated	O
with	O
a	O
greater	O
risk	O
of	O
developing	O
decreased	B-Disease
renal	I-Disease
function	I-Disease
in	O
both	O
groups	O
,	O
but	O
significantly	O
more	O
so	O
in	O
the	O
enalapril	B-Chemical
group	O
(	O
enalapril	B-Chemical
:	O
risk	O
ratio	O
[	O
RR	O
]	O
1	O
.	O
42	O
per	O
10	O
years	O
,	O
95	O
%	O
confidence	O
interval	O
[	O
CI	O
]	O
1	O
.	O
32	O
-	O
1	O
.	O
52	O
with	O
enalapril	B-Chemical
;	O
placebo	O
:	O
RR	O
1	O
.	O
18	O
,	O
95	O
%	O
CI	O
1	O
.	O
12	O
-	O
1	O
.	O
25	O
)	O
.	O

Diuretic	B-Chemical
therapy	O
was	O
likewise	O
associated	O
with	O
a	O
greater	O
risk	O
of	O
decreased	B-Disease
renal	I-Disease
function	I-Disease
in	O
the	O
enalapril	B-Chemical
group	O
(	O
RR	O
1	O
.	O
89	O
,	O
95	O
%	O
CI	O
1	O
.	O
70	O
-	O
2	O
.	O
08	O
)	O
than	O
in	O
the	O
placebo	O
group	O
(	O
RR	O
1	O
.	O
35	O
,	O
95	O
%	O
CI	O
1	O
.	O
09	O
-	O
1	O
.	O
66	O
)	O
.	O

Conversely	O
,	O
enalapril	B-Chemical
had	O
a	O
relative	O
renoprotective	O
effect	O
(	O
RR	O
1	O
.	O
33	O
,	O
95	O
%	O
CI	O
1	O
.	O
13	O
-	O
1	O
.	O
53	O
)	O
compared	O
with	O
placebo	O
(	O
RR	O
1	O
.	O
96	O
,	O
95	O
%	O
CI	O
1	O
.	O
57	O
-	O
2	O
.	O
44	O
)	O
in	O
patients	O
with	O
diabetes	B-Disease
.	O

A	O
lower	O
risk	O
of	O
renal	B-Disease
impairment	I-Disease
was	O
seen	O
in	O
both	O
groups	O
with	O
beta	O
-	O
blocker	O
therapy	O
(	O
RR	O
0	O
.	O
70	O
,	O
95	O
%	O
CI	O
0	O
.	O
57	O
-	O
0	O
.	O
85	O
)	O
and	O
higher	O
baseline	O
ejection	O
fraction	O
(	O
RR	O
0	O
.	O
93	O
per	O
5	O
%	O
increment	O
,	O
95	O
%	O
CI	O
0	O
.	O
91	O
-	O
0	O
.	O
96	O
)	O
.	O

CONCLUSIONS	O
:	O
Enalapril	B-Chemical
use	O
caused	O
a	O
33	O
%	O
increase	O
in	O
the	O
risk	O
of	O
decreased	B-Disease
renal	I-Disease
function	I-Disease
in	O
patients	O
with	O
CHF	B-Disease
.	O

Diuretic	B-Chemical
use	O
and	O
advanced	O
age	O
increased	O
this	O
risk	O
.	O

Diabetes	B-Disease
was	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
renal	B-Disease
impairment	I-Disease
in	O
all	O
patients	O
with	O
CHF	B-Disease
,	O
but	O
this	O
risk	O
was	O
reduced	O
in	O
the	O
enalapril	B-Chemical
group	O
compared	O
with	O
the	O
placebo	O
group	O
.	O

beta	O
-	O
Blocker	O
therapy	O
and	O
higher	O
ejection	O
fraction	O
were	O
renoprotective	O
in	O
all	O
patients	O
regardless	O
of	O
therapy	O
.	O

Hypomania	B-Disease
-	O
like	O
syndrome	O
induced	O
by	O
olanzapine	B-Chemical
.	O

We	O
report	O
a	O
female	O
patient	O
with	O
a	O
diagnosis	O
of	O
a	O
not	O
otherwise	O
specified	O
psychotic	B-Disease
disorder	I-Disease
(	O
DSM	O
-	O
IV	O
)	O
who	O
developed	O
hypomania	B-Disease
shortly	O
after	O
the	O
introduction	O
of	O
olanzapine	B-Chemical
treatment	O
.	O

Acetazolamide	B-Chemical
-	O
induced	O
Gerstmann	B-Disease
syndrome	I-Disease
.	O

Acute	O
confusion	B-Disease
induced	O
by	O
acetazolamide	B-Chemical
is	O
a	O
well	O
known	O
adverse	O
drug	O
reaction	O
in	O
patients	O
with	O
renal	B-Disease
impairment	I-Disease
.	O

We	O
report	O
a	O
case	O
of	O
acetazolamide	B-Chemical
-	O
induced	O
Gerstmann	B-Disease
syndrome	I-Disease
in	O
a	O
patient	O
with	O
normal	O
renal	O
function	O
,	O
to	O
highlight	O
predisposing	O
factors	O
that	O
are	O
frequently	O
overlooked	O
.	O

Vasopressin	B-Chemical
in	O
the	O
treatment	O
of	O
milrinone	B-Chemical
-	O
induced	O
hypotension	B-Disease
in	O
severe	O
heart	B-Disease
failure	I-Disease
.	O

The	O
use	O
of	O
phosphodiesterase	O
inhibitors	O
such	O
as	O
milrinone	B-Chemical
in	O
the	O
treatment	O
of	O
severe	O
heart	B-Disease
failure	I-Disease
is	O
frequently	O
restricted	O
because	O
they	O
cause	O
vasodilation	O
and	O
hypotension	B-Disease
.	O

In	O
patients	O
with	O
decompensated	O
heart	B-Disease
failure	I-Disease
with	O
hypotension	B-Disease
after	O
treatment	O
with	O
milrinone	B-Chemical
,	O
low	O
doses	O
of	O
vasopressin	B-Chemical
restored	O
blood	O
pressure	O
without	O
inhibiting	O
the	O
inotropic	O
effect	O
of	O
milrinone	B-Chemical
.	O

Treatment	O
of	O
tacrolimus	B-Chemical
-	O
related	O
adverse	O
effects	O
by	O
conversion	O
to	O
cyclosporine	B-Chemical
in	O
liver	O
transplant	O
recipients	O
.	O

When	O
tacrolimus	B-Chemical
side	O
effects	O
persist	O
despite	O
dose	O
reduction	O
,	O
conversion	O
to	O
cyclosporine	B-Chemical
-	O
based	O
immunosuppression	O
(	O
CyA	O
)	O
is	O
necessary	O
.	O

We	O
characterized	O
tacrolimus	B-Chemical
side	O
effects	O
that	O
warranted	O
discontinuation	O
of	O
the	O
drug	O
,	O
and	O
outcomes	O
after	O
conversion	O
.	O

Of	O
388	O
liver	O
recipients	O
who	O
received	O
tacrolimus	B-Chemical
as	O
primary	O
immunosuppression	O
,	O
70	O
required	O
conversion	O
to	O
CyA	O
.	O

We	O
recorded	O
indication	O
for	O
conversion	O
,	O
whether	O
conversion	O
was	O
early	O
or	O
late	O
after	O
transplantation	O
,	O
tacrolimus	B-Chemical
dose	O
and	O
trough	O
blood	O
level	O
at	O
conversion	O
,	O
and	O
incidence	O
of	O
rejection	O
after	O
conversion	O
.	O

Conversion	O
was	O
early	O
in	O
29	O
patients	O
(	O
41	O
.	O
4	O
%	O
)	O
and	O
late	O
in	O
41	O
(	O
58	O
.	O
6	O
%	O
)	O
.	O

Indications	O
for	O
early	O
conversion	O
were	O
neurotoxicity	B-Disease
(	O
20	O
)	O
,	O
(	B-Disease
insulin	I-Disease
-	I-Disease
dependent	I-Disease
)	I-Disease
diabetes	I-Disease
mellitus	I-Disease
(	O
IDDM	B-Disease
)	O
(	O
5	O
)	O
,	O
nephrotoxicity	B-Disease
(	O
3	O
)	O
,	O
gastrointestinal	B-Disease
(	I-Disease
GI	I-Disease
)	I-Disease
toxicity	I-Disease
(	O
6	O
)	O
,	O
and	O
cardiomyopathy	B-Disease
(	O
1	O
)	O
,	O
and	O
for	O
late	O
conversion	O
were	O
neurotoxicity	B-Disease
(	O
15	O
)	O
,	O
IDDM	B-Disease
(	O
12	O
)	O
,	O
nephrotoxicity	B-Disease
(	O
3	O
)	O
,	O
GI	B-Disease
toxicity	I-Disease
(	O
5	O
)	O
,	O
hepatotoxicity	B-Disease
(	O
6	O
)	O
,	O
post	B-Disease
-	I-Disease
transplant	I-Disease
lmphoproliferate	I-Disease
disease	I-Disease
(	O
PTLD	B-Disease
)	O
(	O
2	O
)	O
,	O
cardiomyopathy	B-Disease
(	O
1	O
)	O
,	O
hemolytic	B-Disease
anemia	I-Disease
(	O
1	O
)	O
,	O
and	O
pruritus	B-Disease
(	O
1	O
)	O
.	O

All	O
early	O
-	O
conversion	O
patients	O
showed	O
improvement	O
/	O
resolution	O
of	O
symptoms	O
.	O

Among	O
late	O
-	O
conversion	O
patients	O
,	O
37	O
(	O
90	O
.	O
2	O
%	O
)	O
had	O
improvement	O
/	O
resolution	O
;	O
in	O
4	O
(	O
9	O
.	O
8	O
%	O
)	O
,	O
adverse	O
effects	O
persisted	O
.	O

The	O
overall	O
rejection	O
rate	O
was	O
30	O
%	O
.	O

Sixty	O
-	O
two	O
patients	O
(	O
88	O
.	O
6	O
%	O
)	O
are	O
alive	O
with	O
functioning	O
grafts	O
686	O
+	O
/	O
-	O
362	O
days	O
(	O
range	O
,	O
154	O
-	O
1433	O
days	O
)	O
after	O
conversion	O
.	O

When	O
tacrolimus	B-Chemical
side	O
effects	O
are	O
unresponsive	O
to	O
dose	O
reduction	O
,	O
conversion	O
to	O
CyA	O
can	O
be	O
accomplished	O
safely	O
,	O
with	O
no	O
increased	O
risk	O
of	O
rejection	O
and	O
excellent	O
long	O
-	O
term	O
outcome	O
.	O

Ocular	O
manifestations	O
of	O
juvenile	B-Disease
rheumatoid	I-Disease
arthritis	I-Disease
.	O

We	O
followed	O
210	O
cases	O
of	O
juvenile	B-Disease
rheumatoid	I-Disease
arthritis	I-Disease
closely	O
for	O
eleven	O
years	O
.	O

Thirty	O
-	O
six	O
of	O
the	O
210	O
patients	O
(	O
17	O
.	O
2	O
%	O
)	O
developed	O
iridocyclitis	B-Disease
.	O

Iridocyclitis	B-Disease
was	O
seen	O
most	O
frequently	O
in	O
young	O
female	O
patients	O
(	O
0	O
to	O
4	O
years	O
)	O
with	O
the	O
monoarticular	O
or	O
pauciatricular	O
form	O
of	O
the	O
arthritis	B-Disease
.	O

However	O
,	O
30	O
%	O
of	O
the	O
patients	O
developed	O
uveitis	B-Disease
after	O
16	O
years	O
of	O
age	O
.	O

Although	O
61	O
%	O
of	O
patients	O
had	O
a	O
noncontributory	O
ocular	O
history	O
on	O
entry	O
,	O
42	O
%	O
had	O
active	O
uveitis	B-Disease
on	O
entry	O
.	O

Our	O
approach	O
was	O
effective	O
in	O
detecting	O
uveitis	B-Disease
in	O
new	O
cases	O
and	O
exacerbations	O
of	O
uveitis	B-Disease
in	O
established	O
cases	O
.	O

Forty	O
-	O
four	O
percent	O
of	O
patients	O
with	O
uveitis	B-Disease
had	O
one	O
or	O
more	O
identifiable	O
signs	O
or	O
symptoms	O
,	O
such	O
as	O
red	O
eye	O
,	O
ocular	B-Disease
pain	I-Disease
,	O
decreased	B-Disease
visual	I-Disease
acuity	I-Disease
,	O
or	O
photophobia	B-Disease
,	O
in	O
order	O
of	O
decreasing	O
frequency	O
.	O

Even	O
after	O
early	O
detection	O
and	O
prompt	O
treatment	O
,	O
41	O
%	O
of	O
cases	O
of	O
uveitis	B-Disease
did	O
not	O
respond	O
to	O
more	O
than	O
six	O
months	O
of	O
intensive	O
topical	O
treatment	O
with	O
corticosteroids	B-Chemical
and	O
mydriatics	O
.	O

Despite	O
this	O
,	O
there	O
was	O
a	O
dramatic	O
decrease	O
in	O
the	O
50	O
%	O
incidence	O
of	O
blinding	O
complications	O
of	O
uveitis	B-Disease
cited	O
in	O
earlier	O
studies	O
.	O

Cataract	B-Disease
and	O
band	B-Disease
keratopathy	I-Disease
occurred	O
in	O
only	O
22	O
and	O
13	O
%	O
of	O
our	O
group	O
,	O
respectively	O
.	O

We	O
used	O
chloroquine	B-Chemical
or	O
hydroxychloroquine	B-Chemical
in	O
173	O
of	O
210	O
cases	O
and	O
found	O
only	O
one	O
case	O
of	O
chorioretinopathy	B-Disease
attributable	O
to	O
these	O
drugs	O
.	O

Systemically	O
administered	O
corticosteroids	B-Chemical
were	O
used	O
in	O
75	O
of	O
210	O
cases	O
;	O
a	O
significant	O
number	O
of	O
posterior	O
subcapsular	O
cataracts	B-Disease
was	O
found	O
.	O

Typical	O
keratoconjunctivitis	B-Disease
sicca	O
developed	O
in	O
three	O
of	O
the	O
uveitis	B-Disease
cases	O
.	O

This	O
association	O
with	O
uveitis	B-Disease
and	O
JRA	O
was	O
not	O
noted	O
previously	O
.	O

Surgical	O
treatment	O
of	O
cataracts	B-Disease
,	O
band	B-Disease
keratopathy	I-Disease
,	O
and	O
glaucoma	B-Disease
achieved	O
uniformly	O
discouraging	O
results	O
.	O

Cyclophosphamide	B-Chemical
-	O
induced	O
cystitis	B-Disease
in	O
freely	O
-	O
moving	O
conscious	O
rats	O
:	O
behavioral	O
approach	O
to	O
a	O
new	O
model	O
of	O
visceral	B-Disease
pain	I-Disease
.	O

PURPOSE	O
:	O
To	O
develop	O
a	O
model	O
of	O
visceral	B-Disease
pain	I-Disease
in	O
rats	O
using	O
a	O
behavioral	O
approach	O
.	O

Cyclophosphamide	B-Chemical
(	O
CP	B-Chemical
)	O
,	O
an	O
antitumoral	O
agent	O
known	O
to	O
produce	O
toxic	O
effects	O
on	O
the	O
bladder	O
wall	O
through	O
its	O
main	O
toxic	O
metabolite	O
acrolein	B-Chemical
,	O
was	O
used	O
to	O
induce	O
cystitis	B-Disease
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
CP	B-Chemical
was	O
administered	O
at	O
doses	O
of	O
50	O
,	O
100	O
and	O
200	O
mg	O
.	O
/	O
kg	O
.	O

i	O
.	O
p	O
.	O
to	O
male	O
rats	O
,	O
and	O
their	O
behavior	O
observed	O
and	O
scored	O
.	O

The	O
effects	O
of	O
morphine	B-Chemical
(	O
0	O
.	O
5	O
to	O
4	O
mg	O
.	O
/	O
kg	O
.	O
i	O
.	O
v	O
.	O
)	O
on	O
CP	B-Chemical
-	O
induced	O
behavioral	O
modifications	O
were	O
tested	O
administered	O
alone	O
and	O
after	O
naloxone	B-Chemical
(	O
1	O
mg	O
.	O
/	O
kg	O
.	O
s	O
.	O
c	O
.	O
)	O
.	O

In	O
addition	O
,	O
90	O
minutes	O
after	O
CP	B-Chemical
injection	O
,	O
that	O
is	O
,	O
at	O
the	O
time	O
of	O
administration	O
of	O
morphine	B-Chemical
,	O
the	O
bladder	O
was	O
removed	O
in	O
some	O
rats	O
for	O
histological	O
examination	O
.	O

Finally	O
,	O
to	O
show	O
that	O
the	O
bladder	O
is	O
essential	O
for	O
the	O
CP	B-Chemical
-	O
induced	O
behavioral	O
modifications	O
,	O
female	O
rats	O
also	O
received	O
CP	B-Chemical
at	O
doses	O
of	O
200	O
mg	O
.	O
/	O
kg	O
.	O

i	O
.	O
p	O
.	O
and	O
of	O
20	O
mg	O
.	O
by	O
the	O
intravesical	O
route	O
,	O
and	O
acrolein	B-Chemical
at	O
doses	O
of	O
0	O
.	O
5	O
mg	O
.	O
by	O
the	O
intravesical	O
route	O
and	O
of	O
5	O
mg	O
.	O
/	O
kg	O
.	O

i	O
.	O
v	O
.	O
RESULTS	O
:	O
CP	B-Chemical
dose	O
-	O
relatedly	O
induced	O
marked	O
behavioral	O
modifications	O
in	O
male	O
rats	O
:	O
breathing	O
rate	O
decrease	O
,	O
closing	O
of	O
the	O
eyes	O
and	O
occurrence	O
of	O
specific	O
postures	O
.	O

Morphine	B-Chemical
dose	O
-	O
dependently	O
reversed	O
these	O
behavioral	B-Disease
disorders	I-Disease
.	O

A	O
dose	O
of	O
0	O
.	O
5	O
mg	O
.	O
/	O
kg	O
.	O
produced	O
a	O
reduction	O
of	O
almost	O
50	O
%	O
of	O
the	O
behavioral	O
score	O
induced	O
by	O
CP	B-Chemical
200	O
mg	O
.	O
/	O
kg	O
.	O

This	O
effect	O
was	O
completely	O
prevented	O
by	O
pretreatment	O
with	O
naloxone	B-Chemical
.	O

At	O
the	O
time	O
of	O
administration	O
of	O
morphine	B-Chemical
,	O
histological	O
modifications	O
of	O
the	O
bladder	O
wall	O
,	O
such	O
as	O
chorionic	O
and	O
muscle	O
layer	O
edema	B-Disease
,	O
were	O
observed	O
.	O

In	O
female	O
rats	O
,	O
CP	B-Chemical
200	O
mg	O
.	O
/	O
kg	O
.	O

i	O
.	O
p	O
.	O
produced	O
the	O
same	O
marked	O
behavioral	O
modifications	O
as	O
those	O
observed	O
in	O
male	O
rats	O
.	O

Administered	O
at	O
the	O
dose	O
of	O
20	O
mg	O
.	O
intravesically	O
,	O
CP	B-Chemical
did	O
not	O
produce	O
any	O
behavioral	O
effects	O
,	O
whereas	O
acrolein	B-Chemical
at	O
0	O
.	O
5	O
mg	O
.	O
intravesically	O
induced	O
behavioral	O
modifications	O
identical	O
to	O
those	O
under	O
CP	B-Chemical
200	O
mg	O
.	O
/	O
kg	O
.	O

i	O
.	O
p	O
.	O
,	O
with	O
the	O
same	O
maximal	O
levels	O
.	O

Conversely	O
,	O
acrolein	B-Chemical
5	O
mg	O
.	O
/	O
kg	O
.	O

i	O
.	O
v	O
.	O
did	O
not	O
produce	O
any	O
behavioral	O
effects	O
at	O
all	O
.	O

CONCLUSIONS	O
:	O
Overall	O
,	O
these	O
results	O
indicate	O
that	O
this	O
experimental	O
model	O
of	O
CP	B-Chemical
-	O
induced	O
cystitis	B-Disease
may	O
be	O
an	O
interesting	O
new	O
behavioral	O
model	O
of	O
inflammatory	O
visceral	B-Disease
pain	I-Disease
,	O
allowing	O
a	O
better	O
understanding	O
of	O
these	O
painful	B-Disease
syndromes	I-Disease
and	O
thus	O
a	O
better	O
therapeutic	O
approach	O
to	O
them	O
.	O

Prednisolone	B-Chemical
-	O
induced	O
muscle	B-Disease
dysfunction	I-Disease
is	O
caused	O
more	O
by	O
atrophy	B-Disease
than	O
by	O
altered	O
acetylcholine	B-Chemical
receptor	O
expression	O
.	O

Large	O
doses	O
of	O
glucocorticoids	O
can	O
alter	O
muscle	O
physiology	O
and	O
susceptibility	O
to	O
neuromuscular	O
blocking	O
drugs	O
by	O
mechanisms	O
not	O
clearly	O
understood	O
.	O

We	O
investigated	O
the	O
effects	O
of	O
moderate	O
and	O
large	O
doses	O
of	O
prednisolone	B-Chemical
on	O
muscle	O
function	O
and	O
pharmacology	O
,	O
and	O
their	O
relationship	O
to	O
changes	O
in	O
muscle	O
size	O
and	O
acetylcholine	B-Chemical
receptor	O
(	O
AChR	O
)	O
expression	O
.	O

With	O
institutional	O
approval	O
,	O
35	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
randomly	O
allocated	O
to	O
receive	O
daily	O
subcutaneous	O
doses	O
of	O
10	O
mg	O
/	O
kg	O
prednisolone	B-Chemical
(	O
P10	O
group	O
)	O
,	O
100	O
mg	O
/	O
kg	O
prednisolone	B-Chemical
(	O
P100	O
group	O
)	O
,	O
or	O
an	O
equal	O
volume	O
of	O
saline	O
(	O
S	O
group	O
)	O
for	O
7	O
days	O
.	O

A	O
fourth	O
group	O
of	O
rats	O
was	O
pair	O
fed	O
(	O
food	O
restricted	O
)	O
with	O
the	O
P100	O
rats	O
for	O
7	O
days	O
(	O
FR	O
group	O
)	O
.	O

On	O
Day	O
8	O
,	O
the	O
nerve	O
-	O
evoked	O
peak	O
twitch	O
tensions	O
,	O
tetanic	B-Disease
tensions	O
,	O
and	O
fatigability	O
,	O
and	O
the	O
dose	O
-	O
response	O
curves	O
of	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
in	O
the	O
tibialis	O
cranialis	O
muscle	O
were	O
measured	O
in	O
vivo	O
and	O
related	O
to	O
muscle	O
mass	O
or	O
expression	O
of	O
AChRs	O
.	O

Rate	O
of	O
body	O
weight	O
gain	O
was	O
depressed	O
in	O
the	O
P100	O
,	O
FR	O
,	O
and	O
P10	O
groups	O
compared	O
with	O
the	O
S	O
group	O
.	O

Tibialis	O
muscle	O
mass	O
was	O
smaller	O
in	O
the	O
P100	O
group	O
than	O
in	O
the	O
P10	O
or	O
S	O
groups	O
.	O

The	O
evoked	O
peak	O
twitch	O
and	O
tetanic	B-Disease
tensions	O
were	O
less	O
in	O
the	O
P100	O
group	O
than	O
in	O
the	O
P10	O
or	O
S	O
groups	O
,	O
however	O
,	O
tension	O
per	O
milligram	O
of	O
muscle	O
mass	O
was	O
greater	O
in	O
the	O
P100	O
group	O
than	O
in	O
the	O
S	O
group	O
.	O

The	O
50	O
%	O
effective	O
dose	O
of	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
(	O
microg	O
/	O
kg	O
)	O
in	O
the	O
tibialis	O
muscle	O
was	O
smaller	O
in	O
the	O
P10	O
(	O
33	O
.	O
6	O
+	O
/	O
-	O
5	O
.	O
4	O
)	O
than	O
in	O
the	O
S	O
(	O
61	O
.	O
9	O
+	O
/	O
-	O
5	O
.	O
0	O
)	O
or	O
the	O
P100	O
(	O
71	O
.	O
3	O
+	O
/	O
-	O
9	O
.	O
6	O
)	O
groups	O
.	O

AChR	O
expression	O
was	O
less	O
in	O
the	O
P10	O
group	O
than	O
in	O
the	O
S	O
group	O
.	O

The	O
evoked	O
tensions	O
correlated	O
with	O
muscle	O
mass	O
(	O
r	O
(	O
2	O
)	O
=	O
0	O
.	O
32	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
,	O
however	O
,	O
not	O
with	O
expression	O
of	O
AChR	O
.	O

The	O
50	O
%	O
effective	O
dose	O
of	O
d	B-Chemical
-	I-Chemical
tubocurarine	I-Chemical
did	O
not	O
correlate	O
with	O
muscle	O
mass	O
or	O
AChR	O
expression	O
.	O

Our	O
results	O
suggest	O
that	O
the	O
neuromuscular	B-Disease
dysfunction	I-Disease
after	O
prednisolone	B-Chemical
is	O
dose	O
-	O
dependent	O
,	O
and	O
derives	O
primarily	O
from	O
muscle	B-Disease
atrophy	I-Disease
and	O
derives	O
less	O
so	O
from	O
changes	O
in	O
AChR	O
expression	O
.	O

IMPLICATIONS	O
:	O
The	O
mechanisms	O
by	O
which	O
chronic	O
glucocorticoid	O
therapy	O
alters	O
neuromuscular	O
physiology	O
and	O
pharmacology	O
are	O
unclear	O
.	O

We	O
suggest	O
that	O
the	O
observed	O
effects	O
are	O
dose	O
-	O
dependent	O
and	O
derive	O
primarily	O
from	O
muscle	B-Disease
atrophy	I-Disease
and	O
derive	O
less	O
from	O
changes	O
in	O
acetylcholine	B-Chemical
receptor	O
expression	O
.	O

Apomorphine	B-Chemical
:	O
an	O
underutilized	O
therapy	O
for	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Apomorphine	B-Chemical
was	O
the	O
first	O
dopaminergic	O
drug	O
ever	O
used	O
to	O
treat	O
symptoms	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

While	O
powerful	O
antiparkinsonian	O
effects	O
had	O
been	O
observed	O
as	O
early	O
as	O
1951	O
,	O
the	O
potential	O
of	O
treating	O
fluctuating	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
by	O
subcutaneous	O
administration	O
of	O
apomorphine	B-Chemical
has	O
only	O
recently	O
become	O
the	O
subject	O
of	O
systematic	O
study	O
.	O

A	O
number	O
of	O
small	O
scale	O
clinical	O
trials	O
have	O
unequivocally	O
shown	O
that	O
intermittent	O
subcutaneous	O
apomorphine	B-Chemical
injections	O
produce	O
antiparkinsonian	O
benefit	O
close	O
if	O
not	O
identical	O
to	O
that	O
seen	O
with	O
levodopa	B-Chemical
and	O
that	O
apomorphine	B-Chemical
rescue	O
injections	O
can	O
reliably	O
revert	O
off	O
-	O
periods	O
even	O
in	O
patients	O
with	O
complex	O
on	O
-	O
off	O
motor	O
swings	O
.	O

Continuous	O
subcutaneous	O
apomorphine	B-Chemical
infusions	O
can	O
reduce	O
daily	O
off	O
-	O
time	O
by	O
more	O
than	O
50	O
%	O
in	O
this	O
group	O
of	O
patients	O
,	O
which	O
appears	O
to	O
be	O
a	O
stronger	O
effect	O
than	O
that	O
generally	O
seen	O
with	O
add	O
-	O
on	O
therapy	O
with	O
oral	O
dopamine	B-Chemical
agonists	O
or	O
COMT	O
inhibitors	O
.	O

Extended	O
follow	O
-	O
up	O
studies	O
of	O
up	O
to	O
8	O
years	O
have	O
demonstrated	O
long	O
-	O
term	O
persistence	O
of	O
apomorphine	B-Chemical
efficacy	O
.	O

In	O
addition	O
,	O
there	O
is	O
convincing	O
clinical	O
evidence	O
that	O
monotherapy	O
with	O
continuous	O
subcutaneous	O
apomorphine	B-Chemical
infusions	O
is	O
associated	O
with	O
marked	O
reductions	O
of	O
preexisting	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
.	O

The	O
main	O
side	O
effects	O
of	O
subcutaneous	O
apomorphine	B-Chemical
treatment	O
are	O
related	O
to	O
cutaneous	O
tolerability	O
problems	O
,	O
whereas	O
sedation	O
and	O
psychiatric	B-Disease
complications	O
play	O
a	O
lesser	O
role	O
.	O

Given	O
the	O
marked	O
degree	O
of	O
efficacy	O
of	O
subcutaneous	O
apomorphine	B-Chemical
treatment	O
in	O
fluctuating	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
,	O
this	O
approach	O
seems	O
to	O
deserve	O
more	O
widespread	O
clinical	O
use	O
.	O

Probing	O
peripheral	O
and	O
central	O
cholinergic	O
system	O
responses	O
.	O

OBJECTIVE	O
:	O
The	O
pharmacological	O
response	O
to	O
drugs	O
that	O
act	O
on	O
the	O
cholinergic	O
system	O
of	O
the	O
iris	O
has	O
been	O
used	O
to	O
predict	O
deficits	O
in	O
central	O
cholinergic	O
functioning	O
due	O
to	O
diseases	O
such	O
as	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
,	O
yet	O
correlations	O
between	O
central	O
and	O
peripheral	O
responses	O
have	O
not	O
been	O
properly	O
studied	O
.	O

This	O
study	O
assessed	O
the	O
effect	O
of	O
normal	O
aging	O
on	O
(	O
1	O
)	O
the	O
tropicamide	B-Chemical
-	O
induced	O
increase	O
in	O
pupil	O
diameter	O
,	O
and	O
(	O
2	O
)	O
the	O
reversal	O
of	O
this	O
effect	O
with	O
pilocarpine	B-Chemical
.	O

Scopolamine	B-Chemical
was	O
used	O
as	O
a	O
positive	O
control	O
to	O
detect	O
age	O
-	O
dependent	O
changes	O
in	O
central	O
cholinergic	O
functioning	O
in	O
the	O
elderly	O
.	O

DESIGN	O
:	O
Randomized	O
double	O
-	O
blind	O
controlled	O
trial	O
.	O

PARTICIPANTS	O
:	O
Ten	O
healthy	O
elderly	O
(	O
mean	O
age	O
70	O
)	O
and	O
9	O
young	O
(	O
mean	O
age	O
33	O
)	O
volunteers	O
.	O

INTERVENTIONS	O
:	O
Pupil	O
diameter	O
was	O
monitored	O
using	O
a	O
computerized	O
infrared	O
pupillometer	O
over	O
4	O
hours	O
.	O

The	O
study	O
involved	O
4	O
sessions	O
.	O

In	O
1	O
session	O
,	O
tropicamide	B-Chemical
(	O
20	O
microL	O
,	O
0	O
.	O
01	O
%	O
)	O
was	O
administered	O
to	O
one	O
eye	O
and	O
placebo	O
to	O
the	O
other	O
.	O

In	O
another	O
session	O
,	O
tropicamide	B-Chemical
(	O
20	O
microL	O
,	O
0	O
.	O
01	O
%	O
)	O
was	O
administered	O
to	O
both	O
eyes	O
,	O
followed	O
23	O
minutes	O
later	O
by	O
the	O
application	O
of	O
pilocarpine	B-Chemical
(	O
20	O
microL	O
,	O
0	O
.	O
1	O
%	O
)	O
to	O
one	O
eye	O
and	O
placebo	O
to	O
the	O
other	O
.	O

All	O
eye	O
drops	O
were	O
given	O
in	O
a	O
randomized	O
order	O
.	O

In	O
2	O
separate	O
sessions	O
,	O
a	O
single	O
dose	O
of	O
scopolamine	B-Chemical
(	O
0	O
.	O
5	O
mg	O
,	O
intravenously	O
)	O
or	O
placebo	O
was	O
administered	O
,	O
and	O
the	O
effects	O
on	O
word	O
recall	O
were	O
measured	O
using	O
the	O
Buschke	O
Selective	O
Reminding	O
Test	O
over	O
2	O
hours	O
.	O

OUTCOME	O
MEASURES	O
:	O
Pupil	O
size	O
at	O
time	O
points	O
after	O
administration	O
of	O
tropicamide	B-Chemical
and	O
pilocarpine	B-Chemical
;	O
scopolamine	B-Chemical
-	O
induced	O
impairment	B-Disease
in	I-Disease
word	I-Disease
recall	I-Disease
.	O

RESULTS	O
:	O
There	O
was	O
no	O
significant	O
difference	O
between	O
elderly	O
and	O
young	O
volunteers	O
in	O
pupillary	O
response	O
to	O
tropicamide	B-Chemical
at	O
any	O
time	O
point	O
(	O
p	O
>	O
0	O
.	O
05	O
)	O
.	O

The	O
elderly	O
group	O
had	O
a	O
significantly	O
greater	O
pilocarpine	B-Chemical
-	O
induced	O
net	O
decrease	O
in	O
pupil	O
size	O
85	O
,	O
125	O
,	O
165	O
and	O
215	O
minutes	O
after	O
administration	O
,	O
compared	O
with	O
the	O
young	O
group	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Compared	O
with	O
the	O
young	O
group	O
,	O
the	O
elderly	O
group	O
had	O
greater	O
scopolamine	B-Chemical
-	O
induced	O
impairment	B-Disease
in	I-Disease
word	I-Disease
recall	I-Disease
60	O
,	O
90	O
and	O
120	O
minutes	O
after	O
administration	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

CONCLUSION	O
:	O
There	O
is	O
an	O
age	O
-	O
related	O
pupillary	O
response	O
to	O
pilocarpine	B-Chemical
that	O
is	O
not	O
found	O
with	O
tropicamide	B-Chemical
.	O

Thus	O
,	O
pilocarpine	B-Chemical
may	O
be	O
useful	O
to	O
assess	O
variations	O
in	O
central	O
cholinergic	O
function	O
in	O
elderly	O
patients	O
.	O

Pain	B-Disease
responses	O
in	O
methadone	B-Chemical
-	O
maintained	O
opioid	O
abusers	O
.	O

Providing	O
pain	B-Disease
management	O
for	O
known	O
opioid	O
abusers	O
is	O
a	O
challenging	O
clinical	O
task	O
,	O
in	O
part	O
because	O
little	O
is	O
known	O
about	O
their	O
pain	B-Disease
experience	O
and	O
analgesic	O
requirements	O
.	O

This	O
study	O
was	O
designed	O
to	O
describe	O
pain	B-Disease
tolerance	O
and	O
analgesic	O
response	O
in	O
a	O
sample	O
of	O
opioid	B-Disease
addicts	I-Disease
stabilized	O
in	O
methadone	B-Chemical
-	O
maintenance	O
(	O
MM	O
)	O
treatment	O
(	O
n	O
=	O
60	O
)	O
in	O
comparison	O
to	O
matched	O
nondependent	O
control	O
subjects	O
(	O
n	O
=	O
60	O
)	O
.	O

By	O
using	O
a	O
placebo	O
-	O
controlled	O
,	O
two	O
-	O
way	O
factorial	O
design	O
,	O
tolerance	O
to	O
cold	O
-	O
pressor	O
(	O
CP	O
)	O
pain	B-Disease
was	O
examined	O
,	O
both	O
before	O
and	O
after	O
oral	O
administration	O
of	O
therapeutic	O
doses	O
of	O
common	O
opioid	O
(	O
hydromorphone	B-Chemical
2	O
mg	O
)	O
and	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
(	O
ketorolac	B-Chemical
10	O
mg	O
)	O
analgesic	O
agents	O
.	O

Results	O
showed	O
that	O
MM	O
individuals	O
were	O
significantly	O
less	O
tolerant	O
of	O
CP	O
pain	B-Disease
than	O
control	O
subjects	O
,	O
replicating	O
previous	O
work	O
.	O

Analgesic	O
effects	O
were	O
significant	O
neither	O
for	O
medication	O
nor	O
group	O
.	O

These	O
data	O
indicate	O
that	O
MM	O
opioid	O
abusers	O
represent	O
a	O
pain	B-Disease
-	I-Disease
intolerant	I-Disease
subset	O
of	O
clinical	O
patients	O
.	O

Their	O
complaints	O
of	O
pain	B-Disease
should	O
be	O
evaluated	O
seriously	O
and	O
managed	O
aggressively	O
.	O

High	O
-	O
dose	O
methylprednisolone	B-Chemical
may	O
do	O
more	O
harm	O
for	O
spinal	B-Disease
cord	I-Disease
injury	I-Disease
.	O

Because	O
of	O
the	O
National	O
Acute	O
Spinal	B-Disease
Cord	I-Disease
Injury	I-Disease
Studies	O
(	O
NASCIS	O
)	O
,	O
high	O
-	O
dose	O
methylprednisolone	B-Chemical
became	O
the	O
standard	O
of	O
care	O
for	O
the	O
acute	O
spinal	B-Disease
cord	I-Disease
injury	I-Disease
.	O

In	O
the	O
NASCIS	O
,	O
there	O
was	O
no	O
mention	O
regarding	O
the	O
possibility	O
of	O
acute	O
corticosteroid	B-Chemical
myopathy	B-Disease
that	O
high	O
-	O
dose	O
methylprednisolone	B-Chemical
may	O
cause	O
.	O

The	O
dosage	O
of	O
methylprednisolone	B-Chemical
recommended	O
by	O
the	O
NASCIS	O
3	O
is	O
the	O
highest	O
dose	O
of	O
steroids	B-Chemical
ever	O
being	O
used	O
during	O
a	O
2	O
-	O
day	O
period	O
for	O
any	O
clinical	O
condition	O
.	O

We	O
hypothesize	O
that	O
it	O
may	O
cause	O
some	O
damage	B-Disease
to	I-Disease
the	I-Disease
muscle	I-Disease
of	O
spinal	B-Disease
cord	I-Disease
injury	I-Disease
patients	O
.	O

Further	O
,	O
steroid	B-Chemical
myopathy	B-Disease
recovers	O
naturally	O
and	O
the	O
neurological	O
improvement	O
shown	O
in	O
the	O
NASCIS	O
may	O
be	O
just	O
a	O
recording	O
of	O
this	O
natural	O
motor	O
recovery	O
from	O
the	O
steroid	B-Chemical
myopathy	B-Disease
,	O
instead	O
of	O
any	O
protection	O
that	O
methylprednisolone	B-Chemical
offers	O
to	O
the	O
spinal	B-Disease
cord	I-Disease
injury	I-Disease
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
discussion	O
considering	O
the	O
possibility	O
that	O
the	O
methylprednisolone	B-Chemical
recommended	O
by	O
NASCIS	O
may	O
cause	O
acute	O
corticosteroid	B-Chemical
myopathy	B-Disease
.	O

Conversion	O
to	O
rapamycin	B-Chemical
immunosuppression	O
in	O
renal	O
transplant	O
recipients	O
:	O
report	O
of	O
an	O
initial	O
experience	O
.	O

BACKGROUND	O
:	O
The	O
aim	O
of	O
this	O
study	O
is	O
to	O
evaluate	O
the	O
effects	O
of	O
RAPA	B-Chemical
conversion	O
in	O
patients	O
undergoing	O
cyclosporine	B-Chemical
(	O
CsA	B-Chemical
)	O
or	O
tacrolimus	B-Chemical
(	O
Tac	B-Chemical
)	O
toxicity	B-Disease
.	O

METHODS	O
:	O
Twenty	O
renal	O
transplant	O
recipients	O
were	O
switched	O
to	O
fixed	O
dose	O
rapamycin	B-Chemical
(	O
RAPA	B-Chemical
)	O
(	O
5	O
mg	O
/	O
day	O
)	O
0	O
to	O
204	O
months	O
posttransplant	O
.	O

Drug	O
monitoring	O
was	O
not	O
initially	O
used	O
to	O
adjust	O
doses	O
.	O

The	O
indications	O
for	O
switch	O
were	O
chronic	O
CsA	B-Chemical
or	O
Tac	B-Chemical
nephrotoxicity	B-Disease
(	O
12	O
)	O
,	O
acute	O
CsA	B-Chemical
or	O
Tac	B-Chemical
toxicity	B-Disease
(	O
3	O
)	O
,	O
severe	O
facial	B-Disease
dysmorphism	I-Disease
(	O
2	O
)	O
,	O
posttransplant	B-Disease
lymphoproliferative	I-Disease
disorder	I-Disease
(	O
PTLD	B-Disease
)	O
in	O
remission	O
(	O
2	O
)	O
,	O
and	O
hepatotoxicity	B-Disease
in	O
1	O
.	O

Follow	O
-	O
up	O
is	O
7	O
to	O
24	O
months	O
.	O

RESULTS	O
:	O
In	O
the	O
12	O
patients	O
switched	O
because	O
of	O
chronic	O
nephrotoxicity	B-Disease
there	O
was	O
a	O
significant	O
decrease	O
in	O
serum	O
creatinine	B-Chemical
[	O
233	O
+	O
/	O
-	O
34	O
to	O
210	O
+	O
/	O
-	O
56	O
micromol	O
/	O
liter	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
at	O
6	O
months	O
]	O
.	O

Facial	B-Disease
dysmorphism	I-Disease
improved	O
in	O
two	O
patients	O
.	O

No	O
relapse	O
of	O
PTLD	B-Disease
was	O
observed	O
.	O

Five	O
patients	O
developed	O
pneumonia	B-Disease
(	O
two	O
Pneumocystis	B-Disease
carinii	I-Disease
pneumonia	I-Disease
,	O
one	O
infectious	B-Disease
mononucleosis	I-Disease
with	O
polyclonal	O
PTLD	B-Disease
lung	O
infiltrate	O
)	O
and	O
two	O
had	O
bronchiolitis	B-Disease
obliterans	I-Disease
.	O

There	O
were	O
no	O
deaths	O
.	O

RAPA	B-Chemical
was	O
discontinued	O
in	O
four	O
patients	O
,	O
because	O
of	O
pneumonia	B-Disease
in	O
two	O
,	O
PTLD	B-Disease
in	O
one	O
,	O
and	O
oral	O
aphtous	B-Disease
ulcers	I-Disease
in	O
one	O
.	O

RAPA	B-Chemical
levels	O
were	O
high	O
(	O
>	O
15	O
ng	O
/	O
ml	O
)	O
in	O
7	O
of	O
13	O
(	O
54	O
%	O
)	O
patients	O
.	O

CONCLUSIONS	O
:	O
RAPA	B-Chemical
conversion	O
provides	O
adequate	O
immunosuppression	O
to	O
enable	O
CsA	B-Chemical
withdrawal	O
.	O

However	O
,	O
when	O
converting	O
patients	O
to	O
RAPA	B-Chemical
drug	O
levels	O
should	O
be	O
monitored	O
to	O
avoid	O
over	O
-	O
immunosuppression	O
and	O
adequate	O
antiviral	O
and	O
Pneumocystis	B-Disease
carinii	I-Disease
pneumonia	I-Disease
prophylaxis	O
should	O
be	O
given	O
.	O

Electro	O
-	O
oculography	O
,	O
electroretinography	O
,	O
visual	O
evoked	O
potentials	O
,	O
and	O
multifocal	O
electroretinography	O
in	O
patients	O
with	O
vigabatrin	B-Chemical
-	O
attributed	O
visual	B-Disease
field	I-Disease
constriction	I-Disease
.	O

PURPOSE	O
:	O
Symptomatic	O
visual	B-Disease
field	I-Disease
constriction	I-Disease
thought	O
to	O
be	O
associated	O
with	O
vigabatrin	B-Chemical
has	O
been	O
reported	O
.	O

The	O
current	O
study	O
investigated	O
the	O
visual	O
fields	O
and	O
visual	O
electrophysiology	O
of	O
eight	O
patients	O
with	O
known	O
vigabatrin	B-Chemical
-	O
attributed	O
visual	B-Disease
field	I-Disease
loss	I-Disease
,	O
three	O
of	O
whom	O
were	O
reported	O
previously	O
.	O

Six	O
of	O
the	O
patients	O
were	O
no	O
longer	O
receiving	O
vigabatrin	B-Chemical
.	O

METHODS	O
:	O
The	O
central	O
and	O
peripheral	O
fields	O
were	O
examined	O
with	O
the	O
Humphrey	O
Visual	O
Field	O
Analyzer	O
.	O

Full	O
visual	O
electrophysiology	O
,	O
including	O
flash	O
electroretinography	O
(	O
ERG	O
)	O
,	O
pattern	O
electroretinography	O
,	O
multifocal	O
ERG	O
using	O
the	O
VERIS	O
system	O
,	O
electro	O
-	O
oculography	O
,	O
and	O
flash	O
and	O
pattern	O
visual	O
evoked	O
potentials	O
,	O
was	O
undertaken	O
.	O

RESULTS	O
:	O
Seven	O
patients	O
showed	O
marked	O
visual	B-Disease
field	I-Disease
constriction	I-Disease
with	O
some	O
sparing	O
of	O
the	O
temporal	O
visual	O
field	O
.	O

The	O
eighth	O
exhibited	O
concentric	O
constriction	O
.	O

Most	O
electrophysiological	O
responses	O
were	O
usually	O
just	O
within	O
normal	O
limits	O
;	O
two	O
patients	O
had	O
subnormal	O
Arden	O
electro	O
-	O
oculography	O
indices	O
;	O
and	O
one	O
patient	O
showed	O
an	O
abnormally	O
delayed	O
photopic	O
b	O
wave	O
.	O

However	O
,	O
five	O
patients	O
showed	O
delayed	O
30	O
-	O
Hz	O
flicker	O
b	O
waves	O
,	O
and	O
seven	O
patients	O
showed	O
delayed	O
oscillatory	O
potentials	O
.	O

Multifocal	O
ERG	O
showed	O
abnormalities	O
that	O
sometimes	O
correlated	O
with	O
the	O
visual	O
field	O
appearance	O
and	O
confirmed	O
that	O
the	O
deficit	O
occurs	O
at	O
the	O
retinal	O
level	O
.	O

CONCLUSION	O
:	O
Marked	O
visual	B-Disease
field	I-Disease
constriction	I-Disease
appears	O
to	O
be	O
associated	O
with	O
vigabatrin	B-Chemical
therapy	O
.	O

The	O
field	O
defects	O
and	O
some	O
electrophysiological	O
abnormalities	O
persist	O
when	O
vigabatrin	B-Chemical
therapy	O
is	O
withdrawn	O
.	O

Myocardial	B-Disease
ischemia	I-Disease
due	O
to	O
coronary	B-Disease
artery	I-Disease
spasm	I-Disease
during	O
dobutamine	B-Chemical
stress	O
echocardiography	O
.	O

Dobutamine	B-Chemical
stress	O
echocardiography	O
(	O
DSE	O
)	O
is	O
a	O
useful	O
and	O
safe	O
provocation	O
test	O
for	O
myocardial	B-Disease
ischemia	I-Disease
.	O

Until	O
now	O
,	O
the	O
test	O
has	O
been	O
focused	O
only	O
on	O
the	O
organic	O
lesion	O
in	O
the	O
coronary	O
artery	O
,	O
and	O
positive	O
DSE	O
has	O
indicated	O
the	O
presence	O
of	O
significant	O
fixed	O
coronary	B-Disease
artery	I-Disease
stenosis	I-Disease
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
is	O
to	O
examine	O
whether	O
myocardial	B-Disease
ischemia	I-Disease
due	O
to	O
coronary	B-Disease
spasm	I-Disease
is	O
induced	O
by	O
dobutamine	B-Chemical
.	O

We	O
performed	O
DSE	O
on	O
51	O
patients	O
with	O
coronary	B-Disease
spastic	I-Disease
angina	I-Disease
but	O
without	O
significant	O
fixed	O
coronary	B-Disease
artery	I-Disease
stenosis	I-Disease
.	O

All	O
patients	O
had	O
anginal	B-Disease
attacks	O
at	O
rest	O
with	O
ST	O
elevation	O
on	O
the	O
electrocardiogram	O
(	O
variant	B-Disease
angina	I-Disease
)	O
.	O

Coronary	O
spasm	O
was	O
induced	O
by	O
intracoronary	O
injection	O
of	O
acetylcholine	B-Chemical
,	O
and	O
no	O
fixed	O
coronary	B-Disease
artery	I-Disease
stenosis	I-Disease
was	O
documented	O
on	O
angiograms	O
in	O
all	O
patients	O
.	O

DSE	O
was	O
performed	O
with	O
intravenous	O
dobutamine	B-Chemical
infusion	O
with	O
an	O
incremental	O
doses	O
of	O
5	O
,	O
10	O
,	O
20	O
,	O
30	O
,	O
and	O
40	O
microg	O
/	O
kg	O
/	O
min	O
every	O
5	O
minutes	O
.	O

Of	O
the	O
51	O
patients	O
,	O
7	O
patients	O
showed	O
asynergy	O
with	O
ST	O
elevation	O
.	O

All	O
7	O
patients	O
(	O
13	O
.	O
7	O
%	O
)	O
had	O
chest	B-Disease
pain	I-Disease
during	O
asynergy	O
,	O
and	O
both	O
chest	B-Disease
pain	I-Disease
and	O
electrocardiographic	O
changes	O
were	O
preceded	O
by	O
asynergy	O
.	O

These	O
findings	O
indicate	O
that	O
dobutamine	B-Chemical
can	O
provoke	O
coronary	B-Disease
spasm	I-Disease
in	O
some	O
patients	O
with	O
coronary	B-Disease
spastic	I-Disease
angina	I-Disease
.	O

When	O
DSE	O
is	O
performed	O
to	O
evaluate	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
,	O
not	O
only	O
fixed	O
coronary	B-Disease
stenosis	I-Disease
,	O
but	O
also	O
coronary	B-Disease
spasm	I-Disease
should	O
be	O
considered	O
as	O
a	O
genesis	O
of	O
asynergy	O
.	O

Effect	O
of	O
intravenous	O
metoprolol	B-Chemical
or	O
intravenous	O
metoprolol	B-Chemical
plus	O
glucagon	O
on	O
dobutamine	B-Chemical
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
.	O

STUDY	O
OBJECTIVE	O
:	O
To	O
determine	O
the	O
effect	O
of	O
metoprolol	B-Chemical
on	O
dobutamine	B-Chemical
stress	O
testing	O
with	O
technetium	B-Chemical
-	I-Chemical
99m	I-Chemical
sestamibi	I-Chemical
single	O
-	O
photon	O
emission	O
computed	O
tomography	O
imaging	O
and	O
ST	O
-	O
segment	O
monitoring	O
,	O
and	O
to	O
assess	O
the	O
impact	O
of	O
intravenous	O
glucagon	O
on	O
metoprolol	B-Chemical
'	O
s	O
effects	O
.	O

DESIGN	O
:	O
Randomized	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
trial	O
.	O

SETTING	O
:	O
Community	O
hospital	O
.	O

PATIENTS	O
:	O
Twenty	O
-	O
two	O
patients	O
with	O
known	O
reversible	O
perfusion	O
defects	O
.	O

INTERVENTION	O
:	O
Patients	O
underwent	O
dobutamine	B-Chemical
stress	O
tests	O
per	O
standard	O
protocol	O
.	O

Before	O
dobutamine	B-Chemical
was	O
begun	O
,	O
no	O
therapy	O
was	O
given	O
during	O
the	O
first	O
visit	O
,	O
and	O
patients	O
were	O
randomized	O
on	O
subsequent	O
visits	O
to	O
receive	O
metoprolol	B-Chemical
or	O
metoprolol	B-Chemical
plus	O
glucagon	O
1	O
mg	O
.	O

Metoprolol	B-Chemical
was	O
dosed	O
to	O
achieve	O
a	O
resting	O
predobutamine	B-Chemical
heart	O
rate	O
below	O
65	O
beats	O
/	O
minute	O
or	O
a	O
total	O
intravenous	O
dose	O
of	O
20	O
mg	O
.	O

MEASUREMENTS	O
AND	O
MAIN	O
RESULTS	O
:	O
Metoprolol	B-Chemical
reduced	O
maximum	O
heart	O
rate	O
31	O
%	O
,	O
summed	O
stress	O
scores	O
29	O
%	O
,	O
and	O
summed	O
difference	O
scores	O
43	O
%	O
versus	O
control	O
.	O

Metoprolol	B-Chemical
plus	O
glucagon	O
also	O
reduced	O
the	O
maximum	O
heart	O
rate	O
29	O
%	O
versus	O
control	O
.	O

Summed	O
stress	O
and	O
summed	O
difference	O
scores	O
were	O
not	O
significantly	O
reduced	O
,	O
although	O
they	O
were	O
18	O
%	O
and	O
30	O
%	O
lower	O
,	O
respectively	O
,	O
than	O
control	O
.	O

No	O
significant	O
differences	O
were	O
found	O
in	O
any	O
parameter	O
between	O
metoprolol	B-Chemical
and	O
metoprolol	B-Chemical
-	O
glucagon	O
.	O

CONCLUSION	O
:	O
During	O
dobutamine	B-Chemical
stress	O
testing	O
,	O
metoprolol	B-Chemical
attenuates	O
or	O
eliminates	O
evidence	O
of	O
myocardial	B-Disease
ischemia	I-Disease
.	O

Glucagon	O
1	O
mg	O
,	O
although	O
somewhat	O
effective	O
,	O
does	O
not	O
correct	O
this	O
effect	O
to	O
the	O
extent	O
that	O
it	O
can	O
be	O
administered	O
clinically	O
.	O

Evidence	O
of	O
functional	O
somatotopy	O
in	O
GPi	O
from	O
results	O
of	O
pallidotomy	O
.	O

The	O
objective	O
of	O
this	O
study	O
was	O
to	O
explore	O
the	O
functional	O
anatomy	O
of	O
the	O
globus	O
pallidus	O
internus	O
(	O
GPi	O
)	O
by	O
studying	O
the	O
effects	O
of	O
unilateral	O
pallidotomy	O
on	O
parkinsonian	B-Disease
'	O
off	O
'	O
signs	O
and	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
(	O
LID	B-Disease
)	O
.	O

We	O
found	O
significant	O
positive	O
correlations	O
between	O
the	O
preoperative	O
levodopa	B-Chemical
responsiveness	O
of	O
motor	O
signs	O
and	O
the	O
levodopa	B-Chemical
responsiveness	O
of	O
scores	O
in	O
timed	O
tests	O
(	O
Core	O
Assessment	O
Program	O
for	O
Intracerebral	O
Transplantations	O
)	O
in	O
the	O
contralateral	O
limbs	O
and	O
the	O
improvement	O
in	O
these	O
scores	O
after	O
surgery	O
,	O
whereas	O
there	O
was	O
no	O
correlation	O
with	O
the	O
improvement	O
in	O
LID	B-Disease
.	O

We	O
also	O
found	O
a	O
highly	O
significant	O
correlation	O
(	O
P	O
:	O
<	O
0	O
.	O
0001	O
,	O
r	O
=	O
0	O
.	O
8	O
)	O
between	O
the	O
volume	O
of	O
the	O
ventral	O
lesion	O
in	O
the	O
GPi	O
and	O
the	O
improvement	O
in	O
LID	B-Disease
in	O
the	O
contralateral	O
limbs	O
,	O
whereas	O
there	O
was	O
no	O
correlation	O
between	O
the	O
ventral	O
volume	O
and	O
the	O
improvement	O
in	O
parkinsonian	B-Disease
'	O
off	O
'	O
signs	O
.	O

The	O
volumes	O
of	O
the	O
total	O
lesion	O
cylinder	O
and	O
the	O
dorsal	O
lesion	O
did	O
not	O
correlate	O
with	O
the	O
outcome	O
of	O
either	O
dyskinesias	B-Disease
or	O
parkinsonian	B-Disease
'	O
off	O
'	O
signs	O
.	O

The	O
differential	O
predictive	O
value	O
of	O
levodopa	B-Chemical
responsiveness	O
for	O
the	O
outcome	O
of	O
parkinsonian	B-Disease
'	O
off	O
'	O
signs	O
and	O
LID	B-Disease
and	O
the	O
different	O
correlations	O
of	O
ventral	O
lesion	O
volume	O
with	O
dyskinesias	B-Disease
and	O
parkinsonian	B-Disease
'	O
off	O
'	O
signs	O
indicate	O
that	O
different	O
anatomical	O
or	O
pathophysiological	O
substrates	O
may	O
be	O
responsible	O
for	O
the	O
generation	O
of	O
parkinsonian	B-Disease
'	O
off	O
'	O
signs	O
and	O
dyskinesias	B-Disease
.	O

Whereas	O
cells	O
in	O
a	O
wider	O
area	O
of	O
the	O
GPi	O
may	O
be	O
implicated	O
in	O
parkinsonism	B-Disease
,	O
the	O
ventral	O
GPi	O
seems	O
to	O
be	O
crucial	O
for	O
the	O
manifestation	O
of	O
LID	B-Disease
.	O

We	O
suggest	O
that	O
our	O
observations	O
are	O
additional	O
proof	O
of	O
the	O
functional	O
somatotopy	O
of	O
the	O
systems	O
within	O
the	O
GPi	O
that	O
mediate	O
parkinsonism	B-Disease
and	O
dyskinesias	B-Disease
,	O
especially	O
along	O
the	O
dorsoventral	O
trajectory	O
used	O
in	O
pallidotomy	O
.	O

The	O
outcome	O
of	O
pallidotomy	O
in	O
which	O
the	O
lesion	O
involves	O
the	O
ventral	O
and	O
dorsal	O
GPi	O
could	O
be	O
the	O
net	O
effect	O
of	O
alteration	O
in	O
the	O
activity	O
of	O
pathways	O
which	O
mediate	O
different	O
symptoms	O
,	O
and	O
hence	O
could	O
be	O
variable	O
.	O

Screening	O
for	O
stimulant	O
use	O
in	O
adult	O
emergency	O
department	O
seizure	B-Disease
patients	O
.	O

OBJECTIVE	O
:	O
The	O
objective	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
prevalence	O
of	O
positive	O
plasma	O
drug	O
screening	O
for	O
cocaine	B-Chemical
or	O
amphetamine	B-Chemical
in	O
adult	O
emergency	O
department	O
seizure	B-Disease
patients	O
.	O

METHODS	O
:	O
This	O
prospective	O
study	O
evaluated	O
consecutive	O
eligible	O
seizure	B-Disease
patients	O
who	O
had	O
a	O
plasma	O
sample	O
collected	O
as	O
part	O
of	O
their	O
clinical	O
evaluation	O
.	O

Plasma	O
was	O
tested	O
for	O
amphetamine	B-Chemical
and	O
the	O
cocaine	B-Chemical
metabolite	O
benzoylecgonine	B-Chemical
using	O
enzyme	O
-	O
mediated	O
immunoassay	O
methodology	O
.	O

Plasma	O
samples	O
with	O
benzoylecgonine	B-Chemical
greater	O
than	O
150	O
ng	O
/	O
mL	O
or	O
an	O
amphetamine	B-Chemical
greater	O
than	O
500	O
ng	O
/	O
mL	O
were	O
defined	O
as	O
positive	O
.	O

Patient	O
demographics	O
,	O
history	O
of	O
underlying	O
drug	O
or	O
alcohol	B-Chemical
-	O
related	O
seizure	B-Disease
disorder	O
,	O
estimated	O
time	O
from	O
seizure	B-Disease
to	O
sample	O
collection	O
,	O
history	O
or	O
suspicion	O
of	O
cocaine	B-Disease
or	I-Disease
amphetamine	I-Disease
abuse	I-Disease
,	O
results	O
of	O
clinical	O
urine	O
testing	O
for	O
drugs	O
of	O
abuse	O
,	O
and	O
assay	O
results	O
were	O
recorded	O
without	O
patient	O
identifiers	O
.	O

RESULTS	O
:	O
Fourteen	O
of	O
248	O
(	O
5	O
.	O
6	O
%	O
,	O
95	O
%	O
CI	O
2	O
.	O
7	O
%	O
-	O
8	O
.	O
5	O
%	O
)	O
plasma	O
samples	O
were	O
positive	O
by	O
immunoassay	O
testing	O
for	O
benzoylecgonine	B-Chemical
and	O
no	O
samples	O
(	O
0	O
%	O
,	O
95	O
%	O
CI	O
0	O
-	O
1	O
.	O
2	O
%	O
)	O
were	O
positive	O
for	O
amphetamine	B-Chemical
.	O

Positive	O
test	O
results	O
were	O
more	O
common	O
in	O
patient	O
visits	O
where	O
there	O
was	O
a	O
history	O
or	O
suspicion	O
of	O
cocaine	B-Disease
or	I-Disease
amphetamine	I-Disease
abuse	I-Disease
(	O
p	O
<	O
0	O
.	O
0005	O
)	O
.	O

CONCLUSIONS	O
:	O
During	O
this	O
study	O
period	O
,	O
routine	O
plasma	O
screening	O
for	O
cocaine	B-Chemical
and	O
amphetamines	B-Chemical
in	O
adult	O
seizure	B-Disease
patients	O
had	O
a	O
low	O
yield	O
.	O

As	O
a	O
result	O
,	O
routine	O
plasma	O
screening	O
would	O
yield	O
few	O
cases	O
of	O
stimulant	O
drug	O
in	O
which	O
there	O
was	O
neither	O
a	O
history	O
nor	O
suspicion	O
of	O
drug	B-Disease
abuse	I-Disease
in	O
this	O
population	O
.	O

Contribution	O
of	O
sodium	B-Chemical
valproate	I-Chemical
to	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

We	O
report	O
the	O
case	O
of	O
a	O
62	O
-	O
year	O
-	O
old	O
man	O
who	O
was	O
administered	O
sodium	B-Chemical
valproate	I-Chemical
(	O
VPA	B-Chemical
)	O
and	O
who	O
subsequently	O
developed	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
SIADH	B-Disease
)	O
.	O

He	O
had	O
been	O
taking	O
VPA	B-Chemical
for	O
treatment	O
of	O
idiopathic	O
generalized	O
tonic	B-Disease
-	I-Disease
clonic	I-Disease
convulsions	I-Disease
since	O
he	O
was	O
56	O
years	O
old	O
.	O

After	O
substituting	O
VPA	B-Chemical
with	O
zonisamide	B-Chemical
,	O
the	O
serum	O
sodium	B-Chemical
level	O
returned	O
to	O
normal	O
.	O

We	O
consider	O
this	O
episode	O
of	O
SIADH	B-Disease
to	O
be	O
the	O
result	O
of	O
a	O
combination	O
of	O
factors	O
including	O
a	O
weakness	B-Disease
of	I-Disease
the	I-Disease
central	I-Disease
nervous	I-Disease
system	I-Disease
and	O
the	O
long	O
-	O
term	O
administration	O
of	O
VPA	B-Chemical
.	O

Association	O
of	O
nitric	B-Chemical
oxide	I-Chemical
production	O
and	O
apoptosis	O
in	O
a	O
model	O
of	O
experimental	O
nephropathy	B-Disease
.	O

BACKGROUND	O
:	O
In	O
recent	O
studies	O
increased	O
amounts	O
of	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
and	O
apoptosis	O
have	O
been	O
implicated	O
in	O
various	O
pathological	O
conditions	O
in	O
the	O
kidney	O
.	O

We	O
have	O
studied	O
the	O
role	O
of	O
NO	B-Chemical
and	O
its	O
association	O
with	O
apoptosis	O
in	O
an	O
experimental	O
model	O
of	O
nephrotic	B-Disease
syndrome	I-Disease
induced	O
by	O
a	O
single	O
injection	O
of	O
adriamycin	B-Chemical
(	O
ADR	B-Chemical
)	O
.	O

METHODS	O
:	O
The	O
alteration	O
in	O
the	O
NO	B-Chemical
pathway	O
was	O
assessed	O
by	O
measuring	O
nitrite	B-Chemical
levels	O
in	O
serum	O
/	O
urine	O
and	O
by	O
evaluating	O
the	O
changes	O
in	O
vascular	O
reactivity	O
of	O
the	O
isolated	O
perfused	O
rat	O
kidney	O
(	O
IPRK	O
)	O
system	O
.	O

Rats	O
were	O
stratified	O
into	O
control	O
groups	O
and	O
ADR	B-Chemical
-	O
induced	O
nephropathy	B-Disease
groups	O
.	O

These	O
two	O
groups	O
were	O
then	O
divided	O
into	O
:	O
group	O
1	O
,	O
animals	O
receiving	O
saline	O
;	O
and	O
group	O
2	O
,	O
animals	O
receiving	O
aminoguanidine	B-Chemical
(	O
AG	B-Chemical
)	O
which	O
is	O
a	O
specific	O
inhibitor	O
of	O
inducible	O
-	O
NO	B-Chemical
synthase	O
.	O

On	O
day	O
21	O
,	O
rats	O
were	O
sacrificed	O
after	O
obtaining	O
material	O
for	O
biochemical	O
analysis	O
.	O

RESULTS	O
:	O
Histopathological	O
examination	O
of	O
the	O
kidneys	O
of	O
rats	O
treated	O
with	O
ADR	B-Chemical
revealed	O
focal	O
areas	O
of	O
mesangial	B-Disease
proliferation	I-Disease
and	O
mild	O
tubulointerstitial	B-Disease
inflammation	I-Disease
.	O

They	O
also	O
had	O
significantly	O
higher	O
levels	O
of	O
proteinuria	B-Disease
compared	O
with	O
control	O
and	O
treatment	O
groups	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Urine	O
nitrite	B-Chemical
levels	O
were	O
significantly	O
increased	O
in	O
the	O
ADR	B-Chemical
-	O
nephropathy	B-Disease
group	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

In	O
the	O
IPRK	O
phenylephrine	B-Chemical
and	O
acetylcholine	B-Chemical
related	O
responses	O
were	O
significantly	O
impaired	O
in	O
the	O
ADR	B-Chemical
-	O
nephropathy	B-Disease
group	O
.	O

Apoptosis	O
was	O
not	O
detected	O
in	O
controls	O
.	O

However	O
,	O
in	O
the	O
ADR	B-Chemical
-	O
nephropathy	B-Disease
group	O
,	O
numerous	O
apoptotic	O
cells	O
were	O
identified	O
in	O
the	O
tubulointerstitial	O
areas	O
.	O

Double	O
staining	O
revealed	O
numerous	O
interstitial	O
apoptotic	O
cells	O
to	O
stain	O
for	O
ED1	O
,	O
a	O
marker	O
for	O
monocytes	O
/	O
macrophages	O
.	O

Treatment	O
with	O
AG	B-Chemical
prevented	O
the	O
impairment	O
of	O
renal	O
vascular	O
bed	O
responses	O
and	O
reduced	O
both	O
urine	O
nitrite	B-Chemical
levels	O
and	O
apoptosis	O
to	O
control	O
levels	O
.	O

CONCLUSION	O
:	O
We	O
suggest	O
that	O
interactions	O
between	O
NO	B-Chemical
and	O
apoptosis	O
are	O
important	O
in	O
the	O
pathogenesis	O
of	O
the	O
ADR	B-Chemical
-	O
induced	O
nephrosis	B-Disease
.	O

Dual	O
effects	O
of	O
melatonin	B-Chemical
on	O
barbiturate	B-Chemical
-	O
induced	O
narcosis	B-Disease
in	O
rats	O
.	O

Melatonin	B-Chemical
affects	O
the	O
circadian	O
sleep	O
/	O
wake	O
cycle	O
,	O
but	O
it	O
is	O
not	O
clear	O
whether	O
it	O
may	O
influence	O
drug	O
-	O
induced	O
narcosis	B-Disease
.	O

Sodium	B-Chemical
thiopenthal	I-Chemical
was	O
administered	O
intraperitoneally	O
into	O
male	O
rats	O
pre	O
-	O
treated	O
with	O
melatonin	B-Chemical
(	O
0	O
.	O
05	O
,	O
0	O
.	O
5	O
,	O
5	O
and	O
50	O
mg	O
/	O
kg	O
)	O
.	O

Melatonin	B-Chemical
pre	O
-	O
treatment	O
affected	O
in	O
a	O
dual	O
manner	O
barbiturate	B-Chemical
narcosis	B-Disease
,	O
however	O
,	O
no	O
dose	O
-	O
effect	O
correlation	O
was	O
found	O
.	O

In	O
particular	O
,	O
low	O
doses	O
reduced	O
the	O
latency	O
to	O
and	O
prolonged	O
the	O
duration	O
of	O
barbiturate	B-Chemical
narcosis	B-Disease
.	O

In	O
contrast	O
,	O
the	O
highest	O
dose	O
of	O
melatonin	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
)	O
caused	O
a	O
paradoxical	O
increase	O
in	O
the	O
latency	O
and	O
produced	O
a	O
sustained	O
reduction	O
of	O
the	O
duration	O
of	O
narcosis	B-Disease
,	O
and	O
a	O
reduction	O
in	O
mortality	O
rate	O
.	O

Melatonin	B-Chemical
0	O
.	O
5	O
and	O
5	O
mg	O
/	O
kg	O
influenced	O
the	O
duration	O
but	O
not	O
the	O
latency	O
of	O
ketamine	B-Chemical
-	O
or	O
diazepam	B-Chemical
-	O
induced	O
narcosis	B-Disease
.	O

Thus	O
,	O
the	O
dual	O
action	O
of	O
melatonin	B-Chemical
on	O
pharmacological	O
narcosis	B-Disease
seems	O
to	O
be	O
specific	O
for	O
the	O
barbiturate	B-Chemical
mechanism	O
of	O
action	O
.	O

Reduced	O
cardiotoxicity	B-Disease
and	O
preserved	O
antitumor	O
efficacy	O
of	O
liposome	O
-	O
encapsulated	O
doxorubicin	B-Chemical
and	O
cyclophosphamide	B-Chemical
compared	O
with	O
conventional	O
doxorubicin	B-Chemical
and	O
cyclophosphamide	B-Chemical
in	O
a	O
randomized	O
,	O
multicenter	O
trial	O
of	O
metastatic	O
breast	B-Disease
cancer	I-Disease
.	O

PURPOSE	O
:	O
To	O
determine	O
whether	O
Myocet	B-Chemical
(	O
liposome	O
-	O
encapsulated	O
doxorubicin	B-Chemical
;	O
The	O
Liposome	O
Company	O
,	O
Elan	O
Corporation	O
,	O
Princeton	O
,	O
NJ	O
)	O
in	O
combination	O
with	O
cyclophosphamide	B-Chemical
significantly	O
reduces	O
doxorubicin	B-Chemical
cardiotoxicity	B-Disease
while	O
providing	O
comparable	O
antitumor	O
efficacy	O
in	O
first	O
-	O
line	O
treatment	O
of	O
metastatic	O
breast	B-Disease
cancer	I-Disease
(	O
MBC	B-Disease
)	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Two	O
hundred	O
ninety	O
-	O
seven	O
patients	O
with	O
MBC	B-Disease
and	O
no	O
prior	O
chemotherapy	O
for	O
metastatic	O
disease	O
were	O
randomized	O
to	O
receive	O
either	O
60	O
mg	O
/	O
m	O
(	O
2	O
)	O
of	O
Myocet	B-Chemical
(	O
M	O
)	O
or	O
conventional	O
doxorubicin	B-Chemical
(	O
A	O
)	O
,	O
in	O
combination	O
with	O
600	O
mg	O
/	O
m	O
(	O
2	O
)	O
of	O
cyclophosphamide	B-Chemical
(	O
C	O
)	O
,	O
every	O
3	O
weeks	O
until	O
disease	O
progression	O
or	O
unacceptable	O
toxicity	B-Disease
.	O

Cardiotoxicity	B-Disease
was	O
defined	O
by	O
reductions	O
in	O
left	O
-	O
ventricular	O
ejection	O
fraction	O
,	O
assessed	O
by	O
serial	O
multigated	O
radionuclide	O
angiography	O
scans	O
,	O
or	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
(	O
CHF	B-Disease
)	O
.	O

Antitumor	O
efficacy	O
was	O
assessed	O
by	O
objective	O
tumor	B-Disease
response	O
rates	O
(	O
World	O
Health	O
Organization	O
criteria	O
)	O
,	O
time	O
to	O
progression	O
,	O
and	O
survival	O
.	O

RESULTS	O
:	O
Six	O
percent	O
of	O
MC	O
patients	O
versus	O
21	O
%	O
(	O
including	O
five	O
cases	O
of	O
CHF	B-Disease
)	O
of	O
AC	O
patients	O
developed	O
cardiotoxicity	B-Disease
(	O
P	O
=	O
.	O
0002	O
)	O
.	O

Median	O
cumulative	O
doxorubicin	B-Chemical
dose	O
at	O
onset	O
was	O
more	O
than	O
2	O
,	O
220	O
mg	O
/	O
m	O
(	O
2	O
)	O
for	O
MC	O
versus	O
480	O
mg	O
/	O
m	O
(	O
2	O
)	O
for	O
AC	O
(	O
P	O
=	O
.	O
0001	O
,	O
hazard	O
ratio	O
,	O
5	O
.	O
04	O
)	O
.	O

MC	O
patients	O
also	O
experienced	O
less	O
grade	O
4	O
neutropenia	B-Disease
.	O

Antitumor	O
efficacy	O
of	O
MC	O
versus	O
AC	O
was	O
comparable	O
:	O
objective	O
response	O
rates	O
,	O
43	O
%	O
versus	O
43	O
%	O
;	O
median	O
time	O
to	O
progression	O
,	O
5	O
.	O
1	O
%	O
versus	O
5	O
.	O
5	O
months	O
;	O
median	O
time	O
to	O
treatment	O
failure	O
,	O
4	O
.	O
6	O
versus	O
4	O
.	O
4	O
months	O
;	O
and	O
median	O
survival	O
,	O
19	O
versus	O
16	O
months	O
.	O

CONCLUSION	O
:	O
Myocet	B-Chemical
improves	O
the	O
therapeutic	O
index	O
of	O
doxorubicin	B-Chemical
by	O
significantly	O
reducing	O
cardiotoxicity	B-Disease
and	O
grade	O
4	O
neutropenia	B-Disease
and	O
provides	O
comparable	O
antitumor	O
efficacy	O
,	O
when	O
used	O
in	O
combination	O
with	O
cyclophosphamide	B-Chemical
as	O
first	O
-	O
line	O
therapy	O
for	O
MBC	B-Disease
.	O

The	O
role	O
of	O
nitrergic	O
system	O
in	O
lidocaine	B-Chemical
-	O
induced	O
convulsion	B-Disease
in	O
the	O
mouse	O
.	O

The	O
effects	O
of	O
N	B-Chemical
-	I-Chemical
nitro	I-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
arginine	I-Chemical
-	I-Chemical
methyl	I-Chemical
ester	I-Chemical
(	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
)	O
a	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
synthase	O
inhibitor	O
and	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
,	O
a	O
NO	B-Chemical
precursor	O
,	O
were	O
investigated	O
on	O
lidocaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
.	O

In	O
the	O
first	O
experiment	O
,	O
four	O
groups	O
of	O
mice	O
received	O
physiological	O
saline	O
(	O
0	O
.	O
9	O
%	O
)	O
,	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
(	O
300	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
,	O
L	B-Chemical
-	I-Chemical
NAME	I-Chemical
(	O
100	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
and	O
diazepam	B-Chemical
(	O
2	O
mg	O
/	O
kg	O
)	O
,	O
respectively	O
.	O

Thirty	O
minutes	O
after	O
these	O
injections	O
,	O
all	O
mice	O
received	O
lidocaine	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
.	O

In	O
the	O
second	O
experiment	O
,	O
four	O
groups	O
of	O
mice	O
received	O
similar	O
treatment	O
in	O
the	O
first	O
experiment	O
,	O
and	O
30	O
min	O
after	O
these	O
injections	O
,	O
all	O
mice	O
received	O
a	O
higher	O
dose	O
of	O
lidocaine	B-Chemical
(	O
80	O
mg	O
/	O
kg	O
)	O
.	O

L	B-Chemical
-	I-Chemical
NAME	I-Chemical
(	O
100	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
and	O
diazepam	B-Chemical
(	O
2	O
mg	O
/	O
kg	O
)	O
significantly	O
decreased	O
the	O
incidence	O
of	O
lidocaine	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
)	O
-	O
induced	O
convulsions	B-Disease
.	O

In	O
contrast	O
,	O
the	O
L	B-Chemical
-	I-Chemical
arginine	I-Chemical
treatment	O
increased	O
the	O
incidence	O
of	O
lidocaine	B-Chemical
(	O
80	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
-	O
induced	O
convulsions	B-Disease
significantly	O
.	O

These	O
results	O
may	O
suggest	O
that	O
NO	B-Chemical
is	O
a	O
proconvulsant	O
mediator	O
in	O
lidocaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
.	O

Erythropoietin	O
restores	O
the	O
anemia	B-Disease
-	O
induced	O
reduction	O
in	O
cyclophosphamide	B-Chemical
cytotoxicity	B-Disease
in	O
rat	O
tumors	B-Disease
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
examine	O
the	O
impact	O
of	O
anemia	B-Disease
prevention	O
by	O
recombinant	O
human	O
erythropoietin	O
(	O
rHuEPO	O
)	O
treatment	O
on	O
the	O
cytotoxicity	B-Disease
of	O
cyclophosphamide	B-Chemical
in	O
solid	O
experimental	O
tumors	B-Disease
.	O

Anemia	B-Disease
was	O
induced	O
using	O
a	O
single	O
dose	O
of	O
carboplatin	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
resulting	O
in	O
a	O
long	O
-	O
lasting	O
reduction	O
(	O
30	O
%	O
)	O
of	O
the	O
hemoglobin	O
concentration	O
.	O

In	O
a	O
second	O
group	O
,	O
the	O
development	O
of	O
anemia	B-Disease
was	O
prevented	O
by	O
rHuEPO	O
(	O
1000	O
IU	O
/	O
kg	O
)	O
administered	O
s	O
.	O
c	O
.	O
three	O
times	O
/	O
week	O
starting	O
7	O
days	O
before	O
carboplatin	B-Chemical
application	O
.	O

Four	O
days	O
after	O
carboplatin	B-Chemical
treatment	O
,	O
tumors	B-Disease
(	O
DS	O
-	O
sarcoma	B-Disease
of	O
the	O
rat	O
)	O
were	O
implanted	O
s	O
.	O
c	O
.	O
onto	O
the	O
hind	O
food	O
dorsum	O
.	O

Neither	O
carboplatin	B-Chemical
nor	O
rHuEPO	O
treatment	O
influenced	O
tumor	B-Disease
growth	O
rate	O
per	O
se	O
.	O

When	O
tumors	B-Disease
were	O
treated	O
with	O
a	O
single	O
dose	O
of	O
cyclophosphamide	B-Chemical
(	O
60	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
5	O
days	O
after	O
implantation	O
,	O
a	O
growth	O
delay	O
with	O
a	O
subsequent	O
regrowth	O
of	O
the	O
tumors	B-Disease
was	O
observed	O
.	O

In	O
the	O
anemia	B-Disease
group	O
,	O
the	O
growth	O
delay	O
was	O
significantly	O
shorter	O
compared	O
with	O
nonanemic	O
controls	O
(	O
13	O
.	O
3	O
days	O
versus	O
8	O
.	O
6	O
days	O
)	O
.	O

In	O
the	O
group	O
where	O
anemia	B-Disease
was	O
prevented	O
by	O
rHuEPO	O
treatment	O
,	O
growth	O
delay	O
was	O
comparable	O
with	O
that	O
of	O
nonanemic	O
controls	O
(	O
13	O
.	O
3	O
days	O
)	O
.	O

These	O
results	O
suggest	O
that	O
chemotherapy	O
-	O
induced	O
anemia	B-Disease
reduces	O
cytotoxicity	B-Disease
of	O
cyclophosphamide	B-Chemical
in	O
tumors	B-Disease
,	O
whereas	O
correction	O
of	O
anemia	B-Disease
by	O
rHuEPO	O
treatment	O
(	O
epoetin	O
alpha	O
)	O
increases	O
the	O
sensitivity	O
,	O
probably	O
as	O
a	O
result	O
of	O
an	O
improved	O
oxygen	B-Chemical
supply	O
to	O
tumor	B-Disease
tissue	O
.	O

Fatal	O
haemorrhagic	B-Disease
myocarditis	I-Disease
secondary	O
to	O
cyclophosphamide	B-Chemical
therapy	O
.	O

Haemorrhagic	B-Disease
myocarditis	I-Disease
is	O
a	O
rare	O
but	O
important	O
complication	O
of	O
cyclophosphamide	B-Chemical
therapy	O
.	O

Echocardiographic	O
identification	O
of	O
the	O
disorder	O
can	O
be	O
made	O
.	O

We	O
believe	O
that	O
the	O
ultrasound	O
features	O
of	O
this	O
disorder	O
have	O
not	O
been	O
previously	O
reported	O
.	O

Effects	O
of	O
verapamil	B-Chemical
on	O
atrial	B-Disease
fibrillation	I-Disease
and	O
its	O
electrophysiological	O
determinants	O
in	O
dogs	O
.	O

BACKGROUND	O
:	O
Atrial	B-Disease
tachycardia	I-Disease
-	O
induced	O
remodeling	O
promotes	O
the	O
occurrence	O
and	O
maintenance	O
of	O
atrial	B-Disease
fibrillation	I-Disease
(	O
AF	B-Disease
)	O
and	O
decreases	O
L	O
-	O
type	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
current	O
.	O

There	O
is	O
also	O
a	O
clinical	O
suggestion	O
that	O
acute	O
L	O
-	O
type	O
Ca	B-Chemical
(	O
2	O
)	O
channel	O
blockade	O
can	O
promote	O
AF	B-Disease
,	O
consistent	O
with	O
an	O
AF	B-Disease
promoting	O
effect	O
of	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
channel	O
inhibition	O
.	O

METHODS	O
:	O
To	O
evaluate	O
the	O
potential	O
mechanisms	O
of	O
AF	B-Disease
promotion	O
by	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
channel	O
blockers	O
,	O
we	O
administered	O
verapamil	B-Chemical
to	O
morphine	B-Chemical
-	O
chloralose	B-Chemical
anesthetized	O
dogs	O
.	O

Diltiazem	B-Chemical
was	O
used	O
as	O
a	O
comparison	O
drug	O
and	O
autonomic	O
blockade	O
with	O
atropine	B-Chemical
and	O
nadolol	B-Chemical
was	O
applied	O
in	O
some	O
experiments	O
.	O

Epicardial	O
mapping	O
with	O
240	O
epicardial	O
electrodes	O
was	O
used	O
to	O
evaluate	O
activation	O
during	O
AF	B-Disease
.	O

RESULTS	O
:	O
Verapamil	B-Chemical
caused	O
AF	B-Disease
promotion	O
in	O
six	O
dogs	O
,	O
increasing	O
mean	O
duration	O
of	O
AF	B-Disease
induced	O
by	O
burst	O
pacing	O
,	O
from	O
8	O
+	O
/	O
-	O
4	O
s	O
(	O
mean	O
+	O
/	O
-	O
S	O
.	O
E	O
.	O
)	O
to	O
95	O
+	O
/	O
-	O
39	O
s	O
(	O
P	O
<	O
0	O
.	O
01	O
vs	O
.	O
control	O
)	O
at	O
a	O
loading	O
dose	O
of	O
0	O
.	O
1	O
mg	O
/	O
kg	O
and	O
228	O
+	O
/	O
-	O
101	O
s	O
(	O
P	O
<	O
0	O
.	O
0005	O
vs	O
.	O
control	O
)	O
at	O
a	O
dose	O
of	O
0	O
.	O
2	O
mg	O
/	O
kg	O
.	O

Underlying	O
electrophysiological	O
mechanisms	O
were	O
studied	O
in	O
detail	O
in	O
five	O
additional	O
dogs	O
under	O
control	O
conditions	O
and	O
in	O
the	O
presence	O
of	O
the	O
higher	O
dose	O
of	O
verapamil	B-Chemical
.	O

In	O
these	O
experiments	O
,	O
verapamil	B-Chemical
shortened	O
mean	O
effective	O
refractory	O
period	O
(	O
ERP	O
)	O
from	O
122	O
+	O
/	O
-	O
5	O
to	O
114	O
+	O
/	O
-	O
4	O
ms	O
(	O
P	O
<	O
0	O
.	O
02	O
)	O
at	O
a	O
cycle	O
length	O
of	O
300	O
ms	O
,	O
decreased	O
ERP	O
heterogeneity	O
(	O
from	O
15	O
+	O
/	O
-	O
1	O
to	O
10	O
+	O
/	O
-	O
1	O
%	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
,	O
heterogeneously	O
accelerated	O
atrial	O
conduction	O
and	O
decreased	O
the	O
cycle	O
length	O
of	O
AF	B-Disease
(	O
94	O
+	O
/	O
-	O
4	O
to	O
84	O
+	O
/	O
-	O
3	O
ms	O
,	O
P	O
<	O
0	O
.	O
005	O
)	O
.	O

Diltiazem	B-Chemical
did	O
not	O
affect	O
ERP	O
,	O
AF	B-Disease
cycle	O
length	O
or	O
AF	B-Disease
duration	O
,	O
but	O
produced	O
conduction	O
acceleration	O
similar	O
to	O
that	O
caused	O
by	O
verapamil	B-Chemical
(	O
n	O
=	O
5	O
)	O
.	O

In	O
the	O
presence	O
of	O
autonomic	O
blockade	O
,	O
verapamil	B-Chemical
failed	O
to	O
promote	O
AF	B-Disease
and	O
increased	O
,	O
rather	O
than	O
decreasing	O
,	O
refractoriness	O
.	O

Neither	O
verapamil	B-Chemical
nor	O
diltiazem	B-Chemical
affected	O
atrial	O
conduction	O
in	O
the	O
presence	O
of	O
autonomic	O
blockade	O
.	O

Epicardial	O
mapping	O
suggested	O
that	O
verapamil	B-Chemical
promoted	O
AF	B-Disease
by	O
increasing	O
the	O
number	O
of	O
simultaneous	O
wavefronts	O
reflected	O
by	O
separate	O
zones	O
of	O
reactivation	O
in	O
each	O
cycle	O
.	O

CONCLUSIONS	O
:	O
Verapamil	B-Chemical
promotes	O
AF	B-Disease
in	O
normal	O
dogs	O
by	O
promoting	O
multiple	O
circuit	O
reentry	O
,	O
an	O
effect	O
dependent	O
on	O
intact	O
autonomic	O
tone	O
and	O
not	O
shared	O
by	O
diltiazem	B-Chemical
.	O

Calcitonin	O
gene	O
-	O
related	O
peptide	O
levels	O
during	O
nitric	B-Chemical
oxide	I-Chemical
-	O
induced	O
headache	B-Disease
in	O
patients	O
with	O
chronic	O
tension	B-Disease
-	I-Disease
type	I-Disease
headache	I-Disease
.	O

It	O
has	O
been	O
proposed	O
that	O
nitric	B-Chemical
oxide	I-Chemical
(	O
NO	B-Chemical
)	O
induced	O
headache	B-Disease
in	O
primary	B-Disease
headaches	I-Disease
may	O
be	O
associated	O
with	O
release	O
of	O
calcitonin	O
gene	O
-	O
related	O
peptide	O
(	O
CGRP	O
)	O
.	O

In	O
the	O
present	O
study	O
we	O
aimed	O
to	O
investigate	O
plasma	O
levels	O
of	O
CGRP	O
during	O
headache	B-Disease
induced	O
by	O
the	O
NO	B-Chemical
donor	O
glyceryl	B-Chemical
trinitrate	I-Chemical
(	O
GTN	B-Chemical
)	O
in	O
16	O
patients	O
with	O
chronic	O
tension	B-Disease
-	I-Disease
type	I-Disease
headache	I-Disease
and	O
16	O
healthy	O
controls	O
.	O

The	O
subjects	O
were	O
randomly	O
allocated	O
to	O
receive	O
0	O
.	O
5	O
microg	O
/	O
kg	O
/	O
min	O
GTN	B-Chemical
or	O
placebo	O
over	O
20	O
min	O
on	O
two	O
headache	B-Disease
-	O
free	O
days	O
.	O

Blood	O
samples	O
were	O
collected	O
at	O
baseline	O
,	O
10	O
,	O
20	O
and	O
60	O
min	O
after	O
start	O
of	O
infusion	O
.	O

Both	O
patients	O
and	O
controls	O
developed	O
significantly	O
stronger	O
immediate	O
headache	B-Disease
on	O
the	O
GTN	B-Chemical
day	O
than	O
on	O
the	O
placebo	O
day	O
and	O
the	O
headache	B-Disease
was	O
significantly	O
more	O
pronounced	O
in	O
patients	O
than	O
in	O
controls	O
.	O

There	O
was	O
no	O
difference	O
between	O
the	O
area	O
under	O
the	O
CGRP	O
curve	O
(	O
AUCCGRP	O
)	O
on	O
GTN	B-Chemical
vs	O
.	O
placebo	O
day	O
in	O
either	O
patients	O
(	O
P	O
=	O
0	O
.	O
65	O
)	O
or	O
controls	O
(	O
P	O
=	O
0	O
.	O
48	O
)	O
.	O

The	O
AUCCGRP	O
recorded	O
on	O
the	O
GTN	B-Chemical
day	O
did	O
not	O
differ	O
between	O
patients	O
and	O
controls	O
(	O
P	O
=	O
0	O
.	O
36	O
)	O
.	O

Both	O
in	O
patients	O
and	O
controls	O
,	O
CGRP	O
levels	O
changed	O
significantly	O
over	O
time	O
,	O
on	O
both	O
the	O
GTN	B-Chemical
and	O
placebo	O
days	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
present	O
study	O
indicates	O
that	O
NO	B-Chemical
-	O
induced	O
immediate	O
headache	B-Disease
is	O
not	O
associated	O
with	O
release	O
of	O
CGRP	O
.	O

Fluconazole	B-Chemical
-	O
induced	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
.	O

OBJECTIVE	O
:	O
To	O
present	O
a	O
case	O
of	O
fluconazole	B-Chemical
-	O
associated	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
(	O
TDP	B-Disease
)	O
and	O
discuss	O
fluconazole	B-Chemical
'	O
s	O
role	O
in	O
causing	O
TDP	B-Disease
.	O

CASE	O
SUMMARY	O
:	O
A	O
68	O
-	O
year	O
-	O
old	O
white	O
woman	O
with	O
Candida	O
glabrata	O
isolated	O
from	O
a	O
presacral	O
abscess	O
developed	O
TDP	B-Disease
eight	O
days	O
after	O
commencing	O
oral	O
fluconazole	B-Chemical
The	O
patient	O
had	O
no	O
other	O
risk	O
factors	O
for	O
TDP	B-Disease
,	O
including	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
,	O
cardiomyopathy	B-Disease
,	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
,	O
and	O
electrolyte	O
abnormalities	O
There	O
was	O
a	O
temporal	O
association	O
between	O
the	O
initiation	O
of	O
fluconazole	B-Chemical
and	O
TDP	B-Disease
.	O

The	O
TDP	B-Disease
resolved	O
when	O
fluconazole	B-Chemical
was	O
discontinued	O
;	O
however	O
,	O
the	O
patient	O
continued	O
to	O
have	O
premature	B-Disease
ventricular	I-Disease
contractions	I-Disease
and	O
nonsustained	O
ventricular	B-Disease
tachycardia	I-Disease
(	O
NSVT	B-Disease
)	O
until	O
six	O
days	O
after	O
drug	O
cessation	O
DISCUSSION	O
:	O
Use	O
of	O
the	O
Naranjo	O
probability	O
scale	O
indicates	O
a	O
probable	O
relationship	O
between	O
the	O
use	O
of	O
fluconazole	B-Chemical
and	O
the	O
development	O
of	O
TDP	B-Disease
.	O

The	O
possible	O
mechanism	O
is	O
depression	B-Disease
of	O
rapidly	O
activating	O
delayed	O
rectifier	O
potassium	B-Chemical
currents	O
.	O

In	O
our	O
patient	O
,	O
there	O
was	O
no	O
other	O
etiology	O
identified	O
that	O
could	O
explain	O
QT	B-Disease
prolongation	I-Disease
or	O
TDP	B-Disease
The	O
complete	O
disappearance	O
of	O
NSVT	B-Disease
and	O
premature	B-Disease
ventricular	I-Disease
contractions	I-Disease
followed	O
by	O
normalization	O
of	O
QT	O
interval	O
after	O
the	O
drug	O
was	O
stopped	O
strongly	O
suggests	O
fluconazole	B-Chemical
as	O
the	O
etiology	O
.	O

CONCLUSIONS	O
:	O
Clinicians	O
should	O
be	O
aware	O
that	O
fluconazole	B-Chemical
,	O
even	O
at	O
low	O
doses	O
,	O
may	O
cause	O
prolongation	B-Disease
of	I-Disease
the	I-Disease
QT	I-Disease
interval	I-Disease
,	O
leading	O
to	O
TDP	B-Disease
.	O

Serial	O
electrocardiographic	O
monitoring	O
may	O
be	O
considered	O
when	O
fluconazole	B-Chemical
is	O
administered	O
in	O
patients	O
who	O
are	O
at	O
risk	O
for	O
ventricular	B-Disease
arrhythmias	I-Disease
.	O

Cutaneous	B-Disease
leucocytoclastic	I-Disease
vasculitis	I-Disease
associated	O
with	O
oxacillin	B-Chemical
.	O

A	O
67	O
-	O
year	O
-	O
old	O
man	O
who	O
was	O
treated	O
with	O
oxacillin	B-Chemical
for	O
one	O
week	O
because	O
of	O
Staphylococcus	B-Disease
aureus	I-Disease
bacteremia	I-Disease
,	O
developed	O
renal	B-Disease
failure	I-Disease
and	O
diffuse	O
,	O
symmetric	O
,	O
palpable	O
purpuric	B-Disease
lesions	I-Disease
on	O
his	O
feet	O
.	O

Necrotic	B-Disease
blisters	I-Disease
were	O
noted	O
on	O
his	O
fingers	O
.	O

Skin	O
biopsies	O
showed	O
findings	O
diagnostic	O
of	O
leucocytoclastic	B-Disease
vasculitis	I-Disease
.	O

Oxacillin	B-Chemical
was	O
discontinued	O
and	O
patient	O
was	O
treated	O
with	O
corticosteroids	B-Chemical
.	O

The	O
rash	B-Disease
disappeared	O
after	O
three	O
weeks	O
and	O
renal	O
function	O
returned	O
to	O
normal	O
.	O

Leucocytoclastic	B-Disease
vasculitis	I-Disease
presents	O
as	O
palpable	O
purpura	B-Disease
of	O
the	O
lower	O
extremities	O
often	O
accompanied	O
by	O
abdominal	B-Disease
pain	I-Disease
,	O
arthralgia	B-Disease
,	O
and	O
renal	B-Disease
involvement	I-Disease
.	O

Etiologic	O
factors	O
or	O
associated	O
disorders	O
include	O
infections	B-Disease
,	O
medications	O
,	O
collagen	B-Disease
vascular	I-Disease
disease	I-Disease
and	O
neoplasia	B-Disease
.	O

However	O
,	O
in	O
half	O
of	O
the	O
cases	O
no	O
etiologic	O
factor	O
is	O
identified	O
.	O

Usually	O
it	O
is	O
a	O
self	O
-	O
limited	O
disorder	O
,	O
but	O
corticosteroid	B-Chemical
therapy	O
may	O
be	O
needed	O
in	O
life	O
-	O
threatening	O
cases	O
since	O
early	O
treatment	O
with	O
corticosteroids	B-Chemical
in	O
severe	O
cases	O
can	O
prevent	O
complications	O
.	O

Oxacillin	B-Chemical
should	O
be	O
included	O
among	O
the	O
drugs	O
that	O
can	O
cause	O
leucocytoclastic	B-Disease
vasculitis	I-Disease
.	O

The	O
renal	O
pathology	O
in	O
a	O
case	O
of	O
lithium	B-Chemical
-	O
induced	O
diabetes	B-Disease
insipidus	I-Disease
.	O

A	O
case	O
of	O
lithium	B-Chemical
-	O
induced	O
diabetes	B-Disease
insipidus	I-Disease
is	O
reported	O
.	O

At	O
necropsy	O
microscopy	O
shoed	O
unique	O
and	O
extensive	O
damage	O
to	O
cells	O
lining	O
the	O
distal	O
nephron	O
.	O

It	O
is	O
suggested	O
that	O
these	O
changes	O
represent	O
a	O
specific	O
toxic	O
effect	O
of	O
lithium	B-Chemical
,	O
reported	O
here	O
for	O
the	O
first	O
time	O
in	O
man	O
.	O

Cholestatic	B-Disease
jaundice	I-Disease
associated	O
with	O
the	O
use	O
of	O
metformin	B-Chemical
.	O

We	O
report	O
a	O
patient	O
who	O
developed	O
cholestatic	B-Disease
jaundice	I-Disease
shortly	O
after	O
initiation	O
of	O
treatment	O
with	O
metformin	B-Chemical
hydrochloride	I-Chemical
.	O

Ultrasound	O
of	O
the	O
liver	O
and	O
abdominal	O
CT	O
were	O
normal	O
.	O

An	O
ERCP	O
showed	O
normal	O
biliary	O
anatomy	O
.	O

A	O
percutaneous	O
liver	O
biopsy	O
was	O
obtained	O
showing	O
marked	O
cholestasis	B-Disease
,	O
with	O
portal	O
edema	B-Disease
,	O
ductular	O
proliferation	O
,	O
and	O
acute	O
inflammation	B-Disease
.	O

Metformin	B-Chemical
hydrochloride	I-Chemical
was	O
discontinued	O
,	O
and	O
the	O
patient	O
'	O
s	O
jaundice	B-Disease
resolved	O
slowly	O
over	O
a	O
period	O
of	O
several	O
months	O
.	O

Given	O
the	O
onset	O
of	O
his	O
jaundice	B-Disease
2	O
wk	O
after	O
the	O
initiation	O
of	O
metformin	B-Chemical
,	O
we	O
believe	O
that	O
this	O
case	O
represents	O
an	O
example	O
of	O
metformin	B-Chemical
-	O
associated	O
hepatotoxicity	B-Disease
,	O
the	O
first	O
such	O
case	O
reported	O
.	O

Systemic	O
toxicity	B-Disease
and	O
resuscitation	O
in	O
bupivacaine	B-Chemical
-	O
,	O
levobupivacaine	B-Chemical
-	O
,	O
or	O
ropivacaine	B-Chemical
-	O
infused	O
rats	O
.	O

We	O
compared	O
the	O
systemic	O
toxicity	B-Disease
of	O
bupivacaine	B-Chemical
,	O
levobupivacaine	B-Chemical
,	O
and	O
ropivacaine	B-Chemical
in	O
anesthetized	O
rats	O
.	O

We	O
also	O
compared	O
the	O
ability	O
to	O
resuscitate	O
rats	O
after	O
lethal	O
doses	O
of	O
these	O
local	O
anesthetics	O
.	O

Bupivacaine	B-Chemical
,	O
levobupivacaine	B-Chemical
,	O
or	O
ropivacaine	B-Chemical
was	O
infused	O
at	O
a	O
rate	O
of	O
2	O
mg	O
.	O

kg	O
(	O
-	O
1	O
)	O
.	O

min	O
(	O
-	O
1	O
)	O
while	O
electrocardiogram	O
,	O
electroencephalogram	O
,	O
and	O
arterial	O
pressure	O
were	O
continuously	O
monitored	O
.	O

When	O
asystole	B-Disease
was	O
recorded	O
,	O
drug	O
infusion	O
was	O
stopped	O
and	O
a	O
resuscitation	O
sequence	O
was	O
begun	O
.	O

Epinephrine	B-Chemical
0	O
.	O
01	O
mg	O
/	O
kg	O
was	O
administered	O
at	O
1	O
-	O
min	O
intervals	O
while	O
external	O
cardiac	O
compressions	O
were	O
applied	O
.	O

Resuscitation	O
was	O
considered	O
successful	O
when	O
a	O
systolic	O
arterial	O
pressure	O
>	O
or	O
=	O
100	O
mm	O
Hg	O
was	O
achieved	O
within	O
5	O
min	O
.	O

The	O
cumulative	O
doses	O
of	O
levobupivacaine	B-Chemical
and	O
ropivacaine	B-Chemical
that	O
produced	O
seizures	B-Disease
were	O
similar	O
and	O
were	O
larger	O
than	O
those	O
of	O
bupivacaine	B-Chemical
.	O

The	O
cumulative	O
doses	O
of	O
levobupivacaine	B-Chemical
that	O
produced	O
dysrhythmias	B-Disease
and	O
asystole	B-Disease
were	O
smaller	O
than	O
the	O
corresponding	O
doses	O
of	O
ropivacaine	B-Chemical
,	O
but	O
they	O
were	O
larger	O
than	O
those	O
of	O
bupivacaine	B-Chemical
.	O

The	O
number	O
of	O
successful	O
resuscitations	O
did	O
not	O
differ	O
among	O
groups	O
.	O

However	O
,	O
a	O
smaller	O
dose	O
of	O
epinephrine	B-Chemical
was	O
required	O
in	O
the	O
Ropivacaine	B-Chemical
group	O
than	O
in	O
the	O
other	O
groups	O
.	O

We	O
conclude	O
that	O
the	O
systemic	O
toxicity	B-Disease
of	O
levobupivacaine	B-Chemical
is	O
intermediate	O
between	O
that	O
of	O
ropivacaine	B-Chemical
and	O
bupivacaine	B-Chemical
when	O
administered	O
at	O
the	O
same	O
rate	O
and	O
that	O
ropivacaine	B-Chemical
-	O
induced	O
cardiac	B-Disease
arrest	I-Disease
appears	O
to	O
be	O
more	O
susceptible	O
to	O
treatment	O
than	O
that	O
induced	O
by	O
bupivacaine	B-Chemical
or	O
levobupivacaine	B-Chemical
.	O

Amphotericin	B-Chemical
B	I-Chemical
-	O
induced	O
seizures	B-Disease
in	O
a	O
patient	O
with	O
AIDS	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
multiple	O
episodes	O
of	O
seizure	B-Disease
activity	O
in	O
an	O
AIDS	B-Disease
patent	O
following	O
amphotericin	B-Chemical
B	I-Chemical
infusion	O
.	O

CASE	O
SUMMARY	O
:	O
A	O
46	O
-	O
year	O
-	O
old	O
African	O
-	O
American	O
man	O
experienced	O
recurrent	O
grand	B-Disease
mal	I-Disease
seizures	I-Disease
during	O
intravenous	O
infusion	O
of	O
amphotericin	B-Chemical
B	I-Chemical
,	O
then	O
petit	O
mal	O
seizures	B-Disease
as	O
the	O
infusion	O
was	O
stopped	O
and	O
the	O
drug	O
concentrations	O
decreased	O
with	O
time	O
.	O

The	O
patients	O
concurrent	O
medications	O
included	O
didanosine	B-Chemical
,	O
hydroxyzine	B-Chemical
,	O
promethazine	B-Chemical
,	O
hydrocortisone	B-Chemical
,	O
and	O
prochlorperazine	B-Chemical
.	O

Despite	O
administration	O
of	O
phenytoin	B-Chemical
and	O
lorazepam	B-Chemical
,	O
the	O
seizures	B-Disease
persisted	O
and	O
occurred	O
only	O
during	O
amphotercin	B-Chemical
B	I-Chemical
administration	O
.	O

DISCUSSION	O
:	O
AIDS	B-Disease
and	O
cryptococcal	B-Disease
meningitis	I-Disease
,	O
both	O
of	O
which	O
the	O
patient	O
had	O
,	O
can	O
potentially	O
cause	O
seizures	B-Disease
.	O

The	O
patient	O
had	O
a	O
history	O
of	O
alcohol	B-Disease
abuse	I-Disease
;	O
alcohol	B-Chemical
intake	O
as	O
well	O
as	O
withdrawal	O
can	O
also	O
cause	O
seizures	B-Disease
.	O

Didanosine	B-Chemical
also	O
has	O
a	O
potential	O
for	O
inducing	O
seizures	B-Disease
.	O

However	O
,	O
these	O
other	O
potential	O
causes	O
of	O
seizure	B-Disease
were	O
ruled	O
out	O
.	O

The	O
time	O
course	O
of	O
events	O
suggested	O
that	O
amphotericin	B-Chemical
B	I-Chemical
was	O
the	O
cause	O
of	O
the	O
seizures	B-Disease
in	O
this	O
AIDS	B-Disease
patient	O
.	O

CONCLUSIONS	O
:	O
Amphotericin	B-Chemical
B	I-Chemical
seems	O
to	O
be	O
the	O
probable	O
cause	O
of	O
the	O
seizures	B-Disease
.	O

To	O
date	O
,	O
only	O
three	O
cases	O
of	O
seizures	B-Disease
associated	O
with	O
amphotericin	B-Chemical
B	I-Chemical
have	O
been	O
reported	O
in	O
the	O
literature	O
,	O
but	O
healthcare	O
providers	O
should	O
be	O
aware	O
of	O
the	O
potential	O
for	O
this	O
rare	O
adverse	O
effect	O
.	O

Sirolimus	B-Chemical
and	O
mycophenolate	B-Chemical
mofetil	I-Chemical
for	O
calcineurin	O
-	O
free	O
immunosuppression	O
in	O
renal	O
transplant	O
recipients	O
.	O

Calcineurin	O
inhibitors	O
,	O
such	O
as	O
cyclosporine	B-Chemical
and	O
tacrolimus	B-Chemical
,	O
have	O
been	O
available	O
for	O
almost	O
20	O
years	O
.	O

Although	O
these	O
drugs	O
are	O
highly	O
effective	O
and	O
represent	O
the	O
mainstay	O
of	O
transplant	O
immunosuppression	O
,	O
they	O
are	O
associated	O
with	O
acute	O
and	O
chronic	O
nephrotoxicity	B-Disease
.	O

Acute	O
nephrotoxicity	B-Disease
,	O
which	O
occurs	O
in	O
the	O
early	O
period	O
after	O
transplantation	O
,	O
leads	O
to	O
a	O
higher	O
rate	O
of	O
dialysis	O
,	O
and	O
chronic	O
nephrotoxicity	B-Disease
may	O
eventually	O
result	O
in	O
graft	O
loss	O
.	O

Acute	O
and	O
chronic	O
nephrotoxicity	B-Disease
is	O
becoming	O
more	O
common	O
as	O
the	O
use	O
of	O
marginal	O
kidneys	O
for	O
transplantation	O
increases	O
.	O

Two	O
recently	O
available	O
immunosuppressive	O
agents	O
,	O
mycophenolate	B-Chemical
mofetil	I-Chemical
and	O
sirolimus	B-Chemical
(	O
rapamycin	B-Chemical
)	O
,	O
have	O
no	O
nephrotoxicity	B-Disease
.	O

The	O
use	O
of	O
these	O
drugs	O
in	O
combination	O
with	O
other	O
agents	O
has	O
led	O
to	O
the	O
development	O
of	O
new	O
paradigms	O
of	O
immunosuppressive	O
therapy	O
.	O

This	O
paper	O
reviews	O
the	O
results	O
of	O
clinical	O
trials	O
that	O
have	O
investigated	O
these	O
new	O
approaches	O
to	O
immunosuppression	O
in	O
renal	O
transplant	O
recipients	O
.	O

Tolerability	O
of	O
nimesulide	B-Chemical
and	O
paracetamol	B-Chemical
in	O
patients	O
with	O
NSAID	B-Chemical
-	O
induced	O
urticaria	B-Disease
/	O
angioedema	B-Disease
.	O

Previous	O
studies	O
evaluated	O
the	O
tolerance	O
of	O
nimesulide	B-Chemical
and	O
paracetamol	B-Chemical
in	O
subjects	O
with	O
cutaneous	O
,	O
respiratory	O
and	O
anaphylactoid	O
reactions	O
induced	O
by	O
nonsteroidal	B-Chemical
anti	I-Chemical
-	I-Chemical
inflammatory	I-Chemical
drugs	I-Chemical
(	O
NSAIDs	B-Chemical
)	O
.	O

In	O
this	O
study	O
we	O
investigated	O
tolerability	O
and	O
reliability	O
of	O
nimesulide	B-Chemical
and	O
paracetamol	B-Chemical
in	O
a	O
very	O
large	O
number	O
of	O
patients	O
with	O
an	O
exclusive	O
well	O
-	O
documented	O
history	O
of	O
NSAID	B-Chemical
-	O
induced	O
urticaria	B-Disease
/	O
angioedema	B-Disease
.	O

Furthermore	O
,	O
we	O
evaluated	O
whether	O
some	O
factors	O
have	O
the	O
potential	O
to	O
increase	O
the	O
risk	O
of	O
reaction	O
to	O
paracetamol	B-Chemical
and	O
nimesulide	B-Chemical
.	O

A	O
single	O
-	O
placebo	O
-	O
controlled	O
oral	O
challenge	O
procedure	O
with	O
nimesulide	B-Chemical
or	O
paracetamol	B-Chemical
was	O
applied	O
to	O
829	O
patients	O
with	O
a	O
history	O
of	O
NSAID	B-Chemical
-	O
induced	O
urticaria	B-Disease
/	O
angioedema	B-Disease
.	O

A	O
total	O
of	O
75	O
/	O
829	O
(	O
9	O
.	O
4	O
%	O
)	O
patients	O
experienced	O
reactions	O
to	O
nimesulide	B-Chemical
or	O
paracetamol	B-Chemical
.	O

Of	O
the	O
715	O
patients	O
tested	O
with	O
nimesulide	B-Chemical
62	O
(	O
8	O
.	O
6	O
%	O
)	O
showed	O
a	O
positive	O
test	O
,	O
while	O
of	O
114	O
subjects	O
submitted	O
to	O
the	O
challenge	O
with	O
paracetamol	B-Chemical
,	O
13	O
(	O
9	O
.	O
6	O
%	O
)	O
did	O
not	O
tolerate	O
this	O
drug	O
.	O

Furthermore	O
,	O
18	O
.	O
28	O
%	O
of	O
patients	O
with	O
a	O
history	O
of	O
chronic	O
urticaria	B-Disease
and	O
11	O
.	O
8	O
%	O
of	O
subjects	O
with	O
an	O
history	O
of	O
NSAID	B-Chemical
-	O
induced	O
urticaria	B-Disease
/	O
angioedema	B-Disease
or	O
angioedema	B-Disease
alone	O
(	O
with	O
or	O
without	O
chronic	O
urticaria	B-Disease
)	O
resulted	O
to	O
be	O
intolerant	O
to	O
alternative	O
drugs	O
.	O

Taken	O
together	O
,	O
our	O
results	O
confirm	O
the	O
good	O
tolerability	O
of	O
nimesulide	B-Chemical
and	O
paracetamol	B-Chemical
in	O
patients	O
who	O
experienced	O
urticaria	B-Disease
/	O
angioedema	B-Disease
caused	O
by	O
NSAIDs	B-Chemical
.	O

However	O
,	O
the	O
risk	O
of	O
reaction	O
to	O
these	O
alternative	O
study	O
drugs	O
is	O
statistically	O
increased	O
by	O
a	O
history	O
of	O
chronic	O
urticaria	B-Disease
and	O
,	O
above	O
all	O
,	O
by	O
a	O
history	O
of	O
NSAID	B-Chemical
-	O
induced	O
angioedema	B-Disease
.	O

Comparison	O
of	O
aqueous	O
and	O
gellan	O
ophthalmic	O
timolol	B-Chemical
with	O
placebo	O
on	O
the	O
24	O
-	O
hour	O
heart	O
rate	O
response	O
in	O
patients	O
on	O
treatment	O
for	O
glaucoma	B-Disease
.	O

PURPOSE	O
:	O
Topical	O
beta	O
-	O
blocker	O
treatment	O
is	O
routine	O
therapy	O
in	O
the	O
management	O
of	O
patients	O
with	O
glaucoma	B-Disease
.	O

Therapy	O
results	O
in	O
systemic	O
absorption	O
,	O
however	O
,	O
the	O
degree	O
of	O
reduction	O
of	O
resting	O
and	O
peak	O
heart	O
rate	O
has	O
not	O
been	O
quantified	O
.	O

DESIGN	O
:	O
This	O
trial	O
evaluated	O
the	O
effect	O
of	O
placebo	O
,	O
0	O
.	O
5	O
%	O
aqueous	O
timolol	B-Chemical
(	O
timolol	B-Chemical
solution	O
)	O
and	O
a	O
0	O
.	O
5	O
%	O
timolol	B-Chemical
suspension	O
that	O
forms	O
a	O
gel	O
on	O
application	O
to	O
the	O
conjunctiva	O
(	O
timolol	B-Chemical
gellan	O
)	O
on	O
the	O
24	O
-	O
hour	O
heart	O
rate	O
in	O
patients	O
currently	O
being	O
treated	O
for	O
glaucoma	B-Disease
to	O
quantify	O
the	O
reduction	O
in	O
mean	O
heart	O
rate	O
.	O

METHODS	O
:	O
Forty	O
-	O
three	O
Caucasian	O
patients	O
with	O
primary	O
open	B-Disease
-	I-Disease
angle	I-Disease
glaucoma	I-Disease
or	O
ocular	B-Disease
hypertension	I-Disease
with	O
a	O
mean	O
(	O
+	O
/	O
-	O
SD	O
)	O
age	O
of	O
63	O
(	O
+	O
/	O
-	O
8	O
)	O
years	O
were	O
randomized	O
and	O
crossed	O
over	O
in	O
a	O
double	O
-	O
masked	O
manner	O
to	O
14	O
days	O
of	O
treatment	O
with	O
placebo	O
(	O
morning	O
and	O
evening	O
in	O
both	O
eyes	O
)	O
,	O
timolol	B-Chemical
solution	O
(	O
morning	O
and	O
evening	O
in	O
both	O
eyes	O
)	O
,	O
or	O
timolol	B-Chemical
gellan	O
(	O
morning	O
in	O
both	O
eyes	O
with	O
placebo	O
in	O
the	O
evening	O
)	O
.	O

On	O
the	O
13th	O
day	O
of	O
each	O
period	O
,	O
heart	O
rate	O
was	O
recorded	O
continuously	O
during	O
a	O
typical	O
,	O
ambulant	O
24	O
-	O
hour	O
period	O
.	O

RESULTS	O
:	O
Both	O
timolol	B-Chemical
solution	O
and	O
timolol	B-Chemical
gellan	O
reduced	O
the	O
mean	O
24	O
-	O
hour	O
heart	O
rate	O
compared	O
with	O
placebo	O
(	O
P	O
<	O
or	O
=	O
.	O
001	O
)	O
,	O
and	O
this	O
reduction	O
was	O
most	O
pronounced	O
during	O
the	O
daytime	O
(	O
-	O
7	O
.	O
5	O
%	O
change	O
in	O
mean	O
heart	O
rate	O
,	O
-	O
5	O
.	O
7	O
beats	O
/	O
min	O
)	O
.	O

Timolol	B-Chemical
gellan	O
showed	O
a	O
numerically	O
but	O
not	O
significantly	O
smaller	O
reduction	O
in	O
24	O
-	O
hour	O
heart	O
rate	O
,	O
compared	O
with	O
timolol	B-Chemical
solution	O
.	O

During	O
the	O
night	O
,	O
the	O
mean	O
12	O
-	O
hour	O
heart	O
rate	O
on	O
placebo	O
and	O
timolol	B-Chemical
gellan	O
were	O
both	O
significantly	O
less	O
than	O
on	O
timolol	B-Chemical
solution	O
;	O
the	O
difference	O
between	O
solution	O
and	O
gellan	O
treatments	O
was	O
statistically	O
significant	O
(	O
P	O
=	O
.	O
01	O
)	O
.	O

CONCLUSIONS	O
:	O
Both	O
timolol	B-Chemical
solution	O
and	O
timolol	B-Chemical
gellan	O
decrease	O
the	O
mean	O
24	O
-	O
hour	O
heart	O
rate	O
compared	O
with	O
placebo	O
.	O

This	O
response	O
was	O
most	O
pronounced	O
during	O
the	O
active	O
daytime	O
period	O
.	O

These	O
data	O
quantify	O
the	O
modest	O
bradycardia	B-Disease
associated	O
with	O
ophthalmic	O
beta	O
-	O
blocker	O
therapy	O
in	O
a	O
typical	O
patient	O
population	O
on	O
therapy	O
for	O
glaucoma	B-Disease
.	O

Although	O
exercise	O
performance	O
was	O
not	O
assessed	O
in	O
this	O
trial	O
,	O
reductions	O
of	O
this	O
magnitude	O
should	O
not	O
have	O
substantial	O
clinical	O
consequences	O
.	O

Management	O
strategies	O
for	O
ribavirin	B-Chemical
-	O
induced	O
hemolytic	B-Disease
anemia	I-Disease
in	O
the	O
treatment	O
of	O
hepatitis	B-Disease
C	I-Disease
:	O
clinical	O
and	O
economic	O
implications	O
.	O

OBJECTIVES	O
:	O
Recently	O
published	O
studies	O
have	O
demonstrated	O
increased	O
efficacy	O
and	O
cost	O
-	O
effectiveness	O
of	O
combination	O
therapy	O
with	O
interferon	O
and	O
alpha	O
-	O
2b	O
/	O
ribavirin	B-Chemical
compared	O
with	O
interferon	B-Chemical
-	I-Chemical
alpha	I-Chemical
monotherapy	O
in	O
the	O
treatment	O
of	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
(	O
CHC	B-Disease
)	O
.	O

Combination	O
therapy	O
is	O
associated	O
with	O
a	O
clinically	O
important	O
adverse	O
effect	O
:	O
ribavirin	B-Chemical
-	O
induced	O
hemolytic	B-Disease
anemia	I-Disease
(	O
RIHA	B-Disease
)	O
.	O

The	O
objective	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
the	O
direct	O
health	O
-	O
care	O
costs	O
and	O
management	O
of	O
RIHA	B-Disease
during	O
treatment	O
of	O
CHC	B-Disease
in	O
a	O
clinical	O
trial	O
setting	O
.	O

METHODS	O
:	O
A	O
systematic	O
literature	O
review	O
was	O
conducted	O
to	O
synthesize	O
information	O
on	O
the	O
incidence	O
and	O
management	O
of	O
RIHA	B-Disease
.	O

Decision	O
-	O
analytic	O
techniques	O
were	O
used	O
to	O
estimate	O
the	O
cost	O
of	O
treating	O
RIHA	B-Disease
.	O

Uncertainty	O
was	O
evaluated	O
using	O
sensitivity	O
analyses	O
.	O

RESULTS	O
:	O
RIHA	B-Disease
,	O
defined	O
as	O
a	O
reduction	O
in	O
hemoglobin	O
to	O
less	O
than	O
100	O
g	O
/	O
L	O
,	O
occurs	O
in	O
approximately	O
7	O
%	O
to	O
9	O
%	O
of	O
patients	O
treated	O
with	O
combination	O
therapy	O
.	O

The	O
standard	O
of	O
care	O
for	O
management	O
of	O
RIHA	B-Disease
is	O
reduction	O
or	O
discontinuation	O
of	O
the	O
ribavirin	B-Chemical
dosage	O
.	O

We	O
estimated	O
the	O
direct	O
cost	O
of	O
treating	O
clinically	O
significant	O
RIHA	B-Disease
to	O
be	O
170	O
per	O
patient	O
receiving	O
combination	O
therapy	O
per	O
48	O
-	O
week	O
treatment	O
course	O
(	O
range	O
68	O
-	O
692	O
)	O
.	O

The	O
results	O
of	O
the	O
one	O
-	O
way	O
sensitivity	O
analyses	O
ranged	O
from	O
57	O
to	O
317	O
.	O

In	O
comparison	O
,	O
the	O
cost	O
of	O
48	O
weeks	O
of	O
combination	O
therapy	O
is	O
16	O
,	O
459	O
.	O

CONCLUSIONS	O
:	O
The	O
direct	O
cost	O
of	O
treating	O
clinically	O
significant	O
RIHA	B-Disease
is	O
1	O
%	O
(	O
170	O
/	O
16	O
,	O
459	O
)	O
of	O
drug	O
treatment	O
costs	O
.	O

Questions	O
remain	O
about	O
the	O
optimal	O
dose	O
of	O
ribavirin	B-Chemical
and	O
the	O
incidence	O
of	O
RIHA	B-Disease
in	O
a	O
real	O
-	O
world	O
population	O
.	O

Despite	O
these	O
uncertainties	O
,	O
this	O
initial	O
evaluation	O
of	O
the	O
direct	O
cost	O
of	O
treating	O
RIHA	B-Disease
provides	O
an	O
estimate	O
of	O
the	O
cost	O
and	O
management	O
implications	O
of	O
this	O
clinically	O
important	O
adverse	O
effect	O
.	O

Preliminary	O
efficacy	O
assessment	O
of	O
intrathecal	O
injection	O
of	O
an	O
American	O
formulation	O
of	O
adenosine	B-Chemical
in	O
humans	O
.	O

BACKGROUND	O
:	O
Preclinical	O
studies	O
of	O
intrathecal	O
adenosine	B-Chemical
suggest	O
it	O
may	O
be	O
effective	O
in	O
the	O
treatment	O
of	O
acute	B-Disease
and	I-Disease
chronic	I-Disease
pain	I-Disease
in	O
humans	O
,	O
and	O
preliminary	O
studies	O
in	O
volunteers	O
and	O
patients	O
with	O
a	O
Swedish	O
formulation	O
of	O
adenosine	B-Chemical
suggests	O
it	O
may	O
be	O
effective	O
in	O
hypersensitivity	B-Disease
states	O
but	O
not	O
with	O
acute	O
noxious	O
stimulation	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
screen	O
for	O
efficacy	O
of	O
a	O
different	O
formulation	O
of	O
adenosine	B-Chemical
marketed	O
in	O
the	O
US	O
,	O
using	O
both	O
acute	O
noxious	O
stimulation	O
and	O
capsaicin	B-Chemical
-	O
evoked	O
mechanical	O
hypersensitivity	B-Disease
.	O

METHODS	O
:	O
Following	O
Food	O
and	O
Drug	O
Administration	O
and	O
institutional	O
review	O
board	O
approval	O
and	O
written	O
informed	O
consent	O
,	O
65	O
volunteers	O
were	O
studied	O
in	O
two	O
trials	O
:	O
an	O
open	O
-	O
label	O
,	O
dose	O
-	O
escalating	O
trial	O
with	O
intrathecal	O
adenosine	B-Chemical
doses	O
of	O
0	O
.	O
25	O
-	O
2	O
.	O
0	O
mg	O
and	O
a	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
trial	O
of	O
adenosine	B-Chemical
,	O
2	O
mg	O
.	O

Cerebrospinal	O
fluid	O
was	O
obtained	O
for	O
pharmacokinetic	O
analysis	O
,	O
and	O
pain	B-Disease
ratings	O
in	O
response	O
to	O
acute	O
heat	O
stimuli	O
and	O
areas	O
of	O
mechanical	B-Disease
hyperalgesia	I-Disease
and	O
allodynia	B-Disease
after	O
intradermal	O
capsaicin	B-Chemical
injection	O
were	O
determined	O
.	O

RESULTS	O
:	O
Adenosine	B-Chemical
produced	O
no	O
effect	O
on	O
pain	B-Disease
report	O
to	O
acute	O
noxious	O
thermal	O
or	O
chemical	O
stimulation	O
but	O
reduced	O
mechanical	B-Disease
hyperalgesia	I-Disease
and	O
allodynia	B-Disease
from	O
intradermal	O
capsaicin	B-Chemical
injection	O
for	O
at	O
least	O
24	O
h	O
.	O

In	O
contrast	O
,	O
residence	O
time	O
of	O
adenosine	B-Chemical
in	O
cerebrospinal	O
fluid	O
was	O
short	O
(	O
<	O
4	O
h	O
)	O
.	O

CONCLUSIONS	O
:	O
These	O
results	O
show	O
selective	O
inhibition	O
by	O
intrathecal	O
adenosine	B-Chemical
of	O
hypersensitivity	B-Disease
,	O
presumed	O
to	O
reflect	O
central	O
sensitization	O
in	O
humans	O
after	O
peripheral	O
capsaicin	B-Chemical
injection	O
.	O

The	O
long	O
-	O
lasting	O
effect	O
is	O
consistent	O
with	O
that	O
observed	O
in	O
preliminary	O
reports	O
of	O
patients	O
with	O
chronic	O
neuropathic	B-Disease
pain	I-Disease
and	O
is	O
not	O
due	O
to	O
prolonged	O
residence	O
of	O
adenosine	B-Chemical
in	O
cerebrospinal	O
fluid	O
.	O

Delayed	O
-	O
onset	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
.	O

BACKGROUND	O
:	O
Heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
presents	O
5	O
to	O
12	O
days	O
after	O
heparin	B-Chemical
exposure	O
,	O
with	O
or	O
without	O
arterial	B-Disease
or	I-Disease
venous	I-Disease
thromboemboli	I-Disease
.	O

Delayed	O
recognition	O
and	O
treatment	O
of	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
contribute	O
to	O
poor	O
patient	O
outcomes	O
.	O

OBJECTIVE	O
:	O
To	O
describe	O
and	O
increase	O
awareness	O
of	O
a	O
clinical	O
scenario	O
in	O
which	O
the	O
onset	O
or	O
manifestations	O
of	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
are	O
delayed	O
.	O

DESIGN	O
:	O
Retrospective	O
case	O
series	O
.	O

SETTING	O
:	O
Three	O
large	O
urban	O
hospitals	O
(	O
with	O
active	O
cardiovascular	O
surgery	O
programs	O
)	O
.	O

PATIENTS	O
:	O
14	O
patients	O
seen	O
over	O
a	O
3	O
-	O
year	O
period	O
in	O
whom	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
became	O
apparent	O
on	O
delayed	O
presentation	O
with	O
thromboembolic	B-Disease
complications	O
.	O

MEASUREMENTS	O
:	O
Platelet	O
counts	O
,	O
onset	O
of	O
objectively	O
determined	O
thromboembolism	B-Disease
,	O
results	O
of	O
heparin	B-Chemical
-	O
induced	O
platelet	O
factor	O
4	O
antibody	O
tests	O
,	O
and	O
outcomes	O
.	O

RESULTS	O
:	O
Patients	O
went	O
home	O
after	O
hospitalizations	O
that	O
had	O
included	O
heparin	B-Chemical
exposure	O
-	O
-	O
in	O
most	O
cases	O
,	O
with	O
no	O
thrombocytopenia	B-Disease
recognized	O
-	O
-	O
only	O
to	O
return	O
to	O
the	O
hospital	O
(	O
median	O
,	O
day	O
14	O
)	O
with	O
thromboembolic	B-Disease
complications	O
.	O

Thromboemboli	B-Disease
were	O
venous	O
(	O
12	O
patients	O
,	O
7	O
with	O
pulmonary	B-Disease
emboli	I-Disease
)	O
or	O
arterial	O
(	O
4	O
patients	O
)	O
or	O
both	O
.	O

Platelet	O
counts	O
were	O
mildly	O
decreased	O
in	O
all	O
but	O
2	O
patients	O
on	O
second	O
presentation	O
.	O

On	O
readmission	O
,	O
11	O
patients	O
received	O
therapeutic	O
heparin	B-Chemical
,	O
which	O
worsened	O
the	O
patients	O
'	O
clinical	O
condition	O
and	O
,	O
in	O
all	O
11	O
cases	O
,	O
decreased	O
the	O
platelet	O
count	O
(	O
mean	O
at	O
readmission	O
,	O
143	O
x	O
10	O
(	O
9	O
)	O
cells	O
/	O
L	O
;	O
mean	O
nadir	O
after	O
heparin	B-Chemical
re	O
-	O
exposure	O
,	O
39	O
x	O
10	O
(	O
9	O
)	O
cells	O
/	O
L	O
)	O
.	O

Results	O
of	O
serologic	O
tests	O
for	O
heparin	B-Chemical
-	O
induced	O
antibodies	O
were	O
positive	O
in	O
all	O
patients	O
.	O

Subsequent	O
treatments	O
included	O
alternative	O
anticoagulants	O
(	O
11	O
patients	O
)	O
,	O
thrombolytic	O
drugs	O
(	O
3	O
patients	O
)	O
,	O
inferior	O
vena	O
cava	O
filters	O
(	O
3	O
patients	O
)	O
and	O
,	O
eventually	O
,	O
warfarin	B-Chemical
(	O
11	O
patients	O
)	O
.	O

Three	O
patients	O
died	O
.	O

CONCLUSIONS	O
:	O
Delayed	O
-	O
onset	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
is	O
increasingly	O
being	O
recognized	O
.	O

To	O
avoid	O
disastrous	O
outcomes	O
,	O
physicians	O
must	O
consider	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
whenever	O
a	O
recently	O
hospitalized	O
patient	O
returns	O
with	O
thromboembolism	B-Disease
;	O
therapy	O
with	O
alternative	O
anticoagulants	O
,	O
not	O
heparin	B-Chemical
,	O
should	O
be	O
initiated	O
.	O

Treatment	O
of	O
risperidone	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
with	O
a	O
dopamine	B-Chemical
agonist	O
in	O
children	O
.	O

BACKGROUND	O
:	O
Risperidone	B-Chemical
,	O
a	O
potent	O
antagonist	O
of	O
both	O
serotonergic	O
(	O
5HT2A	O
)	O
and	O
dopaminergic	O
D2	O
receptors	O
is	O
associated	O
with	O
hyperprolactinemia	B-Disease
in	O
adults	O
and	O
children	O
.	O

Chronically	O
elevated	O
prolactin	O
levels	O
in	O
children	O
with	O
prolactinomas	B-Disease
may	O
be	O
associated	O
with	O
arrested	O
growth	O
and	O
development	O
resulting	O
in	O
either	O
delayed	B-Disease
puberty	I-Disease
or	O
short	O
stature	O
.	O

These	O
possibilities	O
stress	O
the	O
importance	O
of	O
developing	O
a	O
safe	O
and	O
effective	O
approach	O
to	O
drug	O
-	O
induced	O
hyperprolactinemia	B-Disease
in	O
youth	O
.	O

We	O
report	O
the	O
successful	O
treatment	O
of	O
risperidone	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
with	O
cabergoline	B-Chemical
in	O
youth	O
.	O

METHODS	O
:	O
We	O
undertook	O
a	O
retrospective	O
case	O
review	O
of	O
four	O
children	O
with	O
risperidone	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
treated	O
with	O
cabergoline	B-Chemical
.	O

RESULTS	O
:	O
Four	O
males	O
(	O
age	O
6	O
-	O
11	O
years	O
)	O
with	O
Diagnostic	O
and	O
Statistical	O
Manual	O
of	O
Mental	B-Disease
Disorders	I-Disease
(	O
fourth	O
edition	O
)	O
bipolar	B-Disease
disorder	I-Disease
or	O
psychoses	B-Disease
,	O
with	O
risperidone	B-Chemical
-	O
induced	O
elevations	O
in	O
serum	O
prolactin	O
levels	O
(	O
57	O
.	O
5	O
-	O
129	O
ng	O
/	O
mL	O
,	O
normal	O
5	O
-	O
15	O
ng	O
/	O
mL	O
)	O
,	O
were	O
treated	O
with	O
cabergoline	B-Chemical
(	O
mean	O
dose	O
2	O
.	O
13	O
+	O
/	O
-	O
0	O
.	O
09	O
mg	O
/	O
week	O
)	O
.	O

When	O
serum	O
prolactin	O
levels	O
normalized	O
in	O
all	O
four	O
subjects	O
(	O
mean	O
11	O
.	O
2	O
+	O
/	O
-	O
10	O
.	O
9	O
ng	O
/	O
mL	O
)	O
,	O
the	O
cabergoline	B-Chemical
dose	O
was	O
reduced	O
to	O
1	O
mg	O
/	O
week	O
in	O
three	O
of	O
four	O
subjects	O
.	O

The	O
mean	O
duration	O
of	O
therapy	O
with	O
cabergoline	B-Chemical
was	O
523	O
.	O
5	O
+	O
/	O
-	O
129	O
.	O
7	O
days	O
,	O
and	O
the	O
mean	O
duration	O
of	O
therapy	O
with	O
risperidone	B-Chemical
was	O
788	O
.	O
5	O
+	O
/	O
-	O
162	O
.	O
5	O
days	O
.	O

Cabergoline	B-Chemical
was	O
well	O
tolerated	O
without	O
adverse	O
effects	O
.	O

CONCLUSIONS	O
:	O
Cabergoline	B-Chemical
may	O
be	O
useful	O
for	O
the	O
treatment	O
of	O
risperidone	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
in	O
youth	O
;	O
however	O
,	O
further	O
research	O
is	O
needed	O
.	O

Acute	O
cholestatic	B-Disease
hepatitis	I-Disease
after	O
exposure	O
to	O
isoflurane	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
acute	O
cholestatic	B-Disease
hepatitis	I-Disease
following	O
exposure	O
to	O
the	O
inhalational	O
anesthetic	O
isoflurane	B-Chemical
.	O

CASE	O
SUMMARY	O
:	O
A	O
70	O
-	O
year	O
-	O
old	O
healthy	O
woman	O
from	O
Iraq	O
developed	O
acute	O
cholestatic	B-Disease
hepatitis	I-Disease
3	O
weeks	O
following	O
repair	O
of	O
the	O
right	O
rotator	O
cuff	O
under	O
general	O
anesthesia	O
.	O

There	O
was	O
no	O
evidence	O
for	O
viral	O
,	O
autoimmune	O
,	O
or	O
metabolic	O
causes	O
of	O
hepatitis	B-Disease
.	O

No	O
other	O
medications	O
were	O
involved	O
except	O
for	O
dipyrone	B-Chemical
for	O
analgesia	B-Disease
.	O

The	O
alanine	B-Chemical
aminotransferase	O
was	O
elevated	O
to	O
a	O
peak	O
concentration	O
of	O
1533	O
U	O
/	O
L	O
and	O
the	O
serum	O
bilirubin	B-Chemical
reached	O
a	O
peak	O
of	O
17	O
.	O
0	O
mg	O
/	O
dL	O
.	O

There	O
was	O
slow	O
improvement	O
over	O
4	O
months	O
.	O

Accidental	O
reexposure	O
by	O
the	O
patient	O
to	O
dipyrone	B-Chemical
was	O
uneventful	O
.	O

DISCUSSION	O
:	O
The	O
clinical	O
and	O
histologic	O
picture	O
of	O
this	O
case	O
resembles	O
halothane	B-Disease
hepatitis	I-Disease
,	O
which	O
has	O
a	O
significant	O
mortality	O
rate	O
.	O

CONCLUSIONS	O
:	O
Isoflurane	B-Chemical
,	O
a	O
common	O
anesthetic	O
agent	O
,	O
can	O
cause	O
severe	O
cholestatic	B-Disease
hepatitis	I-Disease
.	O

Torsade	B-Disease
de	I-Disease
pointes	I-Disease
induced	O
by	O
metoclopramide	B-Chemical
in	O
an	O
elderly	O
woman	O
with	O
preexisting	O
complete	O
left	B-Disease
bundle	I-Disease
branch	I-Disease
block	I-Disease
.	O

There	O
is	O
a	O
growing	O
list	O
of	O
drugs	O
implicated	O
in	O
acquired	O
long	B-Disease
QT	I-Disease
syndrome	I-Disease
and	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
.	O

However	O
,	O
the	O
torsadogenic	O
potential	O
of	O
metoclopramide	B-Chemical
,	O
a	O
commonly	O
used	O
antiemetic	O
and	O
prokinetic	O
drug	O
,	O
has	O
not	O
been	O
reported	O
in	O
the	O
literature	O
,	O
despite	O
its	O
chemical	O
similarity	O
to	O
procainamide	B-Chemical
.	O

We	O
report	O
on	O
a	O
92	O
-	O
year	O
-	O
old	O
woman	O
with	O
preexisting	O
complete	O
left	B-Disease
bundle	I-Disease
branch	I-Disease
block	I-Disease
who	O
developed	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
after	O
intravenous	O
and	O
oral	O
administration	O
of	O
metoclopramide	B-Chemical
.	O

This	O
patient	O
also	O
developed	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
when	O
cisapride	B-Chemical
and	O
erythromycin	B-Chemical
were	O
given	O
simultaneously	O
.	O

These	O
two	O
episodes	O
were	O
suppressed	O
successfully	O
after	O
discontinuing	O
the	O
offending	O
drugs	O
and	O
administering	O
class	O
IB	O
drugs	O
.	O

This	O
is	O
the	O
first	O
documentation	O
that	O
metoclopramide	B-Chemical
provokes	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
clinically	O
.	O

Metoclopramide	B-Chemical
should	O
be	O
used	O
cautiously	O
in	O
patients	O
with	O
a	O
risk	O
of	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
.	O

Dopamine	B-Chemical
D2	O
receptor	O
signaling	O
controls	O
neuronal	O
cell	O
death	O
induced	O
by	O
muscarinic	O
and	O
glutamatergic	O
drugs	O
.	O

Dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
,	O
through	O
D1	O
/	O
D2	O
receptor	O
-	O
mediated	O
signaling	O
,	O
plays	O
a	O
major	O
role	O
in	O
the	O
control	O
of	O
epileptic	B-Disease
seizures	I-Disease
arising	O
in	O
the	O
limbic	O
system	O
.	O

Excitotoxicity	B-Disease
leading	O
to	O
neuronal	O
cell	O
death	O
in	O
the	O
affected	O
areas	O
is	O
a	O
major	O
consequence	O
of	O
seizures	B-Disease
at	O
the	O
cellular	O
level	O
.	O

In	O
this	O
respect	O
,	O
little	O
is	O
known	O
about	O
the	O
role	O
of	O
DA	B-Chemical
receptors	O
in	O
the	O
occurrence	O
of	O
epilepsy	B-Disease
-	O
induced	O
neuronal	O
cell	O
death	O
.	O

Here	O
we	O
analyze	O
the	O
occurrence	O
of	O
seizures	B-Disease
and	O
neurotoxicity	B-Disease
in	O
D2R	O
-	O
/	O
-	O
mice	O
treated	O
with	O
the	O
cholinergic	O
agonist	O
pilocarpine	B-Chemical
.	O

We	O
compared	O
these	O
results	O
with	O
those	O
previously	O
obtained	O
with	O
kainic	B-Chemical
acid	I-Chemical
(	O
KA	B-Chemical
)	O
,	O
a	O
potent	O
glutamate	B-Chemical
agonist	O
.	O

Importantly	O
,	O
D2R	O
-	O
/	O
-	O
mice	O
develop	O
seizures	B-Disease
at	O
doses	O
of	O
both	O
drugs	O
that	O
are	O
not	O
epileptogenic	O
for	O
WT	O
littermates	O
and	O
show	O
greater	O
neurotoxicity	B-Disease
.	O

However	O
,	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
result	O
in	O
a	O
more	O
widespread	O
neuronal	O
death	O
in	O
both	O
WT	O
and	O
D2R	O
-	O
/	O
-	O
brains	O
in	O
comparison	O
to	O
KA	B-Chemical
.	O

Thus	O
,	O
the	O
absence	O
of	O
D2R	O
lowers	O
the	O
threshold	O
for	O
seizures	B-Disease
induced	O
by	O
both	O
glutamate	B-Chemical
and	O
acetylcholine	B-Chemical
.	O

Moreover	O
,	O
the	O
dopaminergic	O
control	O
of	O
epilepsy	B-Disease
-	O
induced	O
neurodegeneration	B-Disease
seems	O
to	O
be	O
mediated	O
by	O
distinct	O
interactions	O
of	O
D2R	O
signaling	O
with	O
these	O
two	O
neurotransmitters	O
.	O

Steroid	B-Chemical
structure	O
and	O
pharmacological	O
properties	O
determine	O
the	O
anti	O
-	O
amnesic	B-Disease
effects	O
of	O
pregnenolone	B-Chemical
sulphate	I-Chemical
in	O
the	O
passive	O
avoidance	O
task	O
in	O
rats	O
.	O

Pregnenolone	B-Chemical
sulphate	I-Chemical
(	O
PREGS	B-Chemical
)	O
has	O
generated	O
interest	O
as	O
one	O
of	O
the	O
most	O
potent	O
memory	O
-	O
enhancing	O
neurosteroids	O
to	O
be	O
examined	O
in	O
rodent	O
learning	O
studies	O
,	O
with	O
particular	O
importance	O
in	O
the	O
ageing	O
process	O
.	O

The	O
mechanism	O
by	O
which	O
this	O
endogenous	O
steroid	B-Chemical
enhances	O
memory	O
formation	O
is	O
hypothesized	O
to	O
involve	O
actions	O
on	O
glutamatergic	O
and	O
GABAergic	O
systems	O
.	O

This	O
hypothesis	O
stems	O
from	O
findings	O
that	O
PREGS	B-Chemical
is	O
a	O
potent	O
positive	O
modulator	O
of	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
d	I-Chemical
-	I-Chemical
aspartate	I-Chemical
receptors	O
(	O
NMDARs	O
)	O
and	O
a	O
negative	O
modulator	O
of	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
(	O
A	O
)	O
receptors	O
(	O
GABA	B-Chemical
(	O
A	O
)	O
Rs	O
)	O
.	O

Moreover	O
,	O
PREGS	B-Chemical
is	O
able	O
to	O
reverse	O
the	O
amnesic	B-Disease
-	O
like	O
effects	O
of	O
NMDAR	O
and	O
GABA	B-Chemical
(	O
A	O
)	O
R	O
ligands	O
.	O

To	O
investigate	O
this	O
hypothesis	O
,	O
the	O
present	O
study	O
in	O
rats	O
examined	O
the	O
memory	O
-	O
altering	O
abilities	O
of	O
structural	O
analogs	O
of	O
PREGS	B-Chemical
,	O
which	O
differ	O
in	O
their	O
modulation	O
of	O
NMDAR	O
and	O
/	O
or	O
GABA	B-Chemical
(	O
A	O
)	O
R	O
function	O
.	O

The	O
analogs	O
tested	O
were	O
:	O
11	B-Chemical
-	I-Chemical
ketopregnenolone	I-Chemical
sulphate	I-Chemical
(	O
an	O
agent	O
that	O
is	O
inactive	O
at	O
GABA	B-Chemical
(	O
A	O
)	O
Rs	O
and	O
NMDARs	O
)	O
,	O
epipregnanolone	B-Chemical
(	I-Chemical
[	I-Chemical
3beta	I-Chemical
-	I-Chemical
hydroxy	I-Chemical
-	I-Chemical
5beta	I-Chemical
-	I-Chemical
pregnan	I-Chemical
-	I-Chemical
20	I-Chemical
-	I-Chemical
one	I-Chemical
]	I-Chemical
sulphate	I-Chemical
,	O
an	O
inhibitor	O
of	O
both	O
GABA	B-Chemical
(	O
A	O
)	O
Rs	O
and	O
NMDARs	O
)	O
,	O
and	O
a	O
newly	O
synthesized	O
(	O
-	O
)	O
PREGS	B-Chemical
enantiomer	O
(	O
which	O
is	O
identical	O
to	O
PREGS	B-Chemical
in	O
effects	O
on	O
GABA	B-Chemical
(	O
A	O
)	O
Rs	O
and	O
NMDARs	O
)	O
.	O

The	O
memory	O
-	O
enhancing	O
effects	O
of	O
PREGS	B-Chemical
and	O
its	O
analogs	O
were	O
tested	O
in	O
the	O
passive	O
avoidance	O
task	O
using	O
the	O
model	O
of	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
.	O

Both	O
PREGS	B-Chemical
and	O
its	O
(	O
-	O
)	O
enantiomer	O
blocked	O
the	O
effects	O
of	O
scopolamine	B-Chemical
.	O

The	O
results	O
show	O
that	O
,	O
unlike	O
PREGS	B-Chemical
,	O
11	B-Chemical
-	I-Chemical
ketopregnenolone	I-Chemical
sulphate	I-Chemical
and	O
epipregnanolone	B-Chemical
sulphate	I-Chemical
failed	O
to	O
block	O
the	O
effect	O
of	O
scopolamine	B-Chemical
,	O
suggesting	O
that	O
altering	O
the	O
modulation	O
of	O
NMDA	B-Chemical
receptors	O
diminishes	O
the	O
memory	O
-	O
enhancing	O
effects	O
of	O
PREGS	B-Chemical
.	O

Moreover	O
,	O
enantioselectivity	O
was	O
demonstrated	O
by	O
the	O
ability	O
of	O
natural	O
PREGS	B-Chemical
to	O
be	O
an	O
order	O
of	O
magnitude	O
more	O
effective	O
than	O
its	O
synthetic	O
enantiomer	O
in	O
reversing	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
.	O

These	O
results	O
identify	O
a	O
novel	O
neuropharmacological	O
site	O
for	O
the	O
modulation	O
of	O
memory	O
processes	O
by	O
neuroactive	O
steroids	B-Chemical
.	O

Activation	O
of	O
poly	B-Chemical
(	I-Chemical
ADP	I-Chemical
-	I-Chemical
ribose	I-Chemical
)	I-Chemical
polymerase	O
contributes	O
to	O
development	O
of	O
doxorubicin	B-Chemical
-	O
induced	O
heart	B-Disease
failure	I-Disease
.	O

Activation	O
of	O
the	O
nuclear	O
enzyme	O
poly	B-Chemical
(	I-Chemical
ADP	I-Chemical
-	I-Chemical
ribose	I-Chemical
)	I-Chemical
polymerase	O
(	O
PARP	O
)	O
by	O
oxidant	O
-	O
mediated	O
DNA	O
damage	O
is	O
an	O
important	O
pathway	O
of	O
cell	O
dysfunction	O
and	O
tissue	O
injury	O
in	O
conditions	O
associated	O
with	O
oxidative	O
stress	O
.	O

Increased	O
oxidative	O
stress	O
is	O
a	O
major	O
factor	O
implicated	O
in	O
the	O
cardiotoxicity	B-Disease
of	O
doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
,	O
a	O
widely	O
used	O
antitumor	O
anthracycline	B-Chemical
antibiotic	O
.	O

Thus	O
,	O
we	O
hypothesized	O
that	O
the	O
activation	O
of	O
PARP	O
may	O
contribute	O
to	O
the	O
DOX	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

Using	O
a	O
dual	O
approach	O
of	O
PARP	O
-	O
1	O
suppression	O
,	O
by	O
genetic	O
deletion	O
or	O
pharmacological	O
inhibition	O
with	O
the	O
phenanthridinone	O
PARP	O
inhibitor	O
PJ34	B-Chemical
,	O
we	O
now	O
demonstrate	O
the	O
role	O
of	O
PARP	O
in	O
the	O
development	O
of	O
cardiac	B-Disease
dysfunction	I-Disease
induced	O
by	O
DOX	B-Chemical
.	O

PARP	O
-	O
1	O
+	O
/	O
+	O
and	O
PARP	O
-	O
1	O
-	O
/	O
-	O
mice	O
received	O
a	O
single	O
injection	O
of	O
DOX	B-Chemical
(	O
25	O
mg	O
/	O
kg	O
i	O
.	O
p	O
)	O
.	O

Five	O
days	O
after	O
DOX	B-Chemical
administration	O
,	O
left	O
ventricular	O
performance	O
was	O
significantly	O
depressed	O
in	O
PARP	O
-	O
1	O
+	O
/	O
+	O
mice	O
,	O
but	O
only	O
to	O
a	O
smaller	O
extent	O
in	O
PARP	O
-	O
1	O
-	O
/	O
-	O
ones	O
.	O

Similar	O
experiments	O
were	O
conducted	O
in	O
BALB	O
/	O
c	O
mice	O
treated	O
with	O
PJ34	B-Chemical
or	O
vehicle	O
.	O

Treatment	O
with	O
a	O
PJ34	B-Chemical
significantly	O
improved	O
cardiac	B-Disease
dysfunction	I-Disease
and	O
increased	O
the	O
survival	O
of	O
the	O
animals	O
.	O

In	O
addition	O
PJ34	B-Chemical
significantly	O
reduced	O
the	O
DOX	B-Chemical
-	O
induced	O
increase	O
in	O
the	O
serum	O
lactate	B-Chemical
dehydrogenase	O
and	O
creatine	B-Chemical
kinase	O
activities	O
but	O
not	O
metalloproteinase	O
activation	O
in	O
the	O
heart	O
.	O

Thus	O
,	O
PARP	O
activation	O
contributes	O
to	O
the	O
cardiotoxicity	B-Disease
of	O
DOX	B-Chemical
.	O

PARP	O
inhibitors	O
may	O
exert	O
protective	O
effects	O
against	O
the	O
development	O
of	O
severe	O
cardiac	B-Disease
complications	I-Disease
associated	O
with	O
the	O
DOX	B-Chemical
treatment	O
.	O

Spironolactone	B-Chemical
:	O
is	O
it	O
a	O
novel	O
drug	O
for	O
the	O
prevention	O
of	O
amphotericin	B-Chemical
B	I-Chemical
-	O
related	O
hypokalemia	B-Disease
in	O
cancer	B-Disease
patients	O
?	O

OBJECTIVE	O
:	O
Nephrotoxicity	B-Disease
is	O
the	O
major	O
adverse	O
effect	O
of	O
amphotericin	B-Chemical
B	I-Chemical
(	O
AmB	B-Chemical
)	O
,	O
often	O
limiting	O
administration	O
of	O
full	O
dosage	O
.	O

Selective	O
distal	O
tubular	O
epithelial	O
toxicity	B-Disease
seems	O
to	O
be	O
responsible	O
for	O
the	O
profound	O
potassium	B-Chemical
wasting	O
that	O
is	O
a	O
major	O
clinical	O
side	O
effect	O
of	O
treatment	O
with	O
AmB	B-Chemical
.	O

Potassium	B-Chemical
depletion	O
also	O
potentiates	O
the	O
tubular	O
toxicity	B-Disease
of	O
AmB	B-Chemical
.	O

This	O
study	O
was	O
designed	O
to	O
assess	O
the	O
ability	O
of	O
spironolactone	B-Chemical
to	O
reduce	O
potassium	B-Chemical
requirements	O
and	O
to	O
prevent	O
hypokalemia	B-Disease
in	O
neutropenic	B-Disease
patients	O
on	O
AmB	B-Chemical
treatment	O
.	O

METHODS	O
:	O
In	O
this	O
study	O
26	O
patients	O
with	O
various	O
hematological	B-Disease
disorders	I-Disease
were	O
randomized	O
to	O
receive	O
either	O
intravenous	O
AmB	B-Chemical
alone	O
or	O
AmB	B-Chemical
and	O
oral	O
spironolactone	B-Chemical
100	O
mg	O
twice	O
daily	O
when	O
developing	O
a	O
proven	O
or	O
suspected	O
fungal	B-Disease
infection	I-Disease
.	O

RESULTS	O
:	O
Patients	O
receiving	O
concomitant	O
AmB	B-Chemical
and	O
spironolactone	B-Chemical
had	O
significantly	O
higher	O
plasma	O
potassium	B-Chemical
levels	O
than	O
those	O
receiving	O
AmB	B-Chemical
alone	O
(	O
P	O
=	O
0	O
.	O
0027	O
)	O
.	O

Those	O
patients	O
receiving	O
AmB	B-Chemical
and	O
spironolactone	B-Chemical
required	O
significantly	O
less	O
potassium	B-Chemical
supplementation	O
to	O
maintain	O
their	O
plasma	O
potassium	B-Chemical
within	O
the	O
normal	O
range	O
(	O
P	O
=	O
0	O
.	O
022	O
)	O
.	O

Moreover	O
,	O
urinary	O
potassium	B-Chemical
losses	O
were	O
significantly	O
less	O
in	O
patients	O
receiving	O
AmB	B-Chemical
and	O
spironolactone	B-Chemical
than	O
those	O
receiving	O
AmB	B-Chemical
alone	O
(	O
P	O
=	O
0	O
.	O
040	O
)	O
.	O

CONCLUSION	O
:	O
This	O
study	O
showed	O
that	O
spironolactone	B-Chemical
can	O
reduce	O
potassium	B-Chemical
requirements	O
and	O
prevent	O
hypokalemia	B-Disease
by	O
reducing	O
urinary	O
potassium	B-Chemical
loss	O
in	O
neutropenic	B-Disease
patients	O
on	O
AmB	B-Chemical
treatment	O
.	O

Erectile	B-Disease
dysfunction	I-Disease
occurs	O
following	O
substantia	O
nigra	O
lesions	O
in	O
the	O
rat	O
.	O

Erectile	O
function	O
was	O
assessed	O
6	O
weeks	O
following	O
uni	O
-	O
and	O
bilateral	O
injections	O
of	O
6	B-Chemical
-	I-Chemical
hydroxydopamine	I-Chemical
in	O
the	O
substantia	O
nigra	O
nucleus	O
of	O
the	O
brain	O
.	O

Behavioral	O
apomorphine	B-Chemical
-	O
induced	O
penile	O
erections	O
were	O
reduced	O
(	O
5	O
/	O
8	O
)	O
and	O
increased	O
(	O
3	O
/	O
8	O
)	O
in	O
uni	O
-	O
and	O
bilateral	O
lesioned	O
animals	O
.	O

Intracavernous	O
pressures	O
,	O
following	O
electrical	O
stimulation	O
of	O
the	O
cavernous	O
nerve	O
,	O
decreased	O
in	O
lesioned	O
animals	O
.	O

Lesions	O
of	O
the	O
substantia	O
nigra	O
were	O
confirmed	O
by	O
histology	O
.	O

Concentration	O
of	O
dopamine	B-Chemical
and	O
its	O
metabolites	O
were	O
decreased	O
in	O
the	O
striatum	O
of	O
substantia	O
nigra	O
lesioned	O
rats	O
.	O

Lesions	O
of	O
the	O
substantia	O
nigra	O
are	O
therefore	O
associated	O
with	O
erectile	B-Disease
dysfunction	I-Disease
in	O
rats	O
and	O
may	O
serve	O
as	O
a	O
model	O
to	O
study	O
erectile	B-Disease
dysfunction	I-Disease
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Nicotine	B-Chemical
potentiation	O
of	O
morphine	B-Chemical
-	O
induced	O
catalepsy	B-Disease
in	O
mice	O
.	O

In	O
the	O
present	O
study	O
,	O
effects	O
of	O
nicotine	B-Chemical
on	O
catalepsy	B-Disease
induced	O
by	O
morphine	B-Chemical
in	O
mice	O
have	O
been	O
investigated	O
.	O

Morphine	B-Chemical
but	O
not	O
nicotine	B-Chemical
induced	O
a	O
dose	O
-	O
dependent	O
catalepsy	B-Disease
.	O

The	O
response	O
of	O
morphine	B-Chemical
was	O
potentiated	O
by	O
nicotine	B-Chemical
.	O

Intraperitoneal	O
administration	O
of	O
atropine	B-Chemical
,	O
naloxone	B-Chemical
,	O
mecamylamine	B-Chemical
,	O
and	O
hexamethonium	B-Chemical
to	O
mice	O
reduced	O
catalepsy	B-Disease
induced	O
by	O
a	O
combination	O
of	O
morphine	B-Chemical
with	O
nicotine	B-Chemical
.	O

Intracerebroventricular	O
injection	O
of	O
atropine	B-Chemical
,	O
hexamethonium	B-Chemical
,	O
and	O
naloxone	B-Chemical
also	O
decreased	O
catalepsy	B-Disease
induced	O
by	O
morphine	B-Chemical
plus	O
nicotine	B-Chemical
.	O

Intraperitoneal	O
administration	O
of	O
atropine	B-Chemical
,	O
but	O
not	O
intraperitoneal	O
or	O
intracerebroventricular	O
injection	O
of	O
hexamethonium	B-Chemical
,	O
decreased	O
the	O
effect	O
of	O
a	O
single	O
dose	O
of	O
morphine	B-Chemical
.	O

It	O
was	O
concluded	O
that	O
morphine	B-Chemical
catalepsy	B-Disease
can	O
be	O
elicited	O
by	O
opioid	O
and	O
cholinergic	O
receptors	O
,	O
and	O
the	O
potentiation	O
of	O
morphine	B-Chemical
induced	O
by	O
nicotine	B-Chemical
may	O
also	O
be	O
mediated	O
through	O
cholinergic	O
receptor	O
mechanisms	O
.	O

Force	O
overflow	O
and	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

We	O
assessed	O
force	O
coordination	O
of	O
the	O
hand	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
and	O
its	O
relationship	O
to	O
motor	O
complications	O
of	O
levodopa	B-Chemical
therapy	O
,	O
particularly	O
to	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
(	O
LID	B-Disease
)	O
.	O

We	O
studied	O
two	O
groups	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
patients	O
with	O
(	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
+	O
LID	B-Disease
,	O
n	O
=	O
23	O
)	O
and	O
without	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
(	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
-	O
LID	B-Disease
,	O
n	O
=	O
10	O
)	O
,	O
and	O
age	O
-	O
matched	O
healthy	O
controls	O
.	O

The	O
motor	O
score	O
of	O
the	O
Unified	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
Disease	I-Disease
Rating	O
Scale	O
,	O
a	O
dyskinesia	B-Disease
score	O
and	O
force	O
in	O
a	O
grip	O
-	O
lift	O
paradigm	O
were	O
assessed	O
ON	O
and	O
OFF	O
levodopa	B-Chemical
.	O

A	O
pathological	O
increase	O
of	O
forces	O
was	O
seen	O
in	O
ON	O
-	O
state	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
+	O
LID	B-Disease
only	O
.	O

In	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
+	O
LID	B-Disease
,	O
the	O
force	O
involved	O
in	O
pressing	O
down	O
the	O
object	O
before	O
lifting	O
was	O
significantly	O
increased	O
by	O
levodopa	B-Chemical
(	O
by	O
61	O
%	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

An	O
overshooting	O
of	O
peak	O
grip	O
force	O
by	O
51	O
%	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
and	O
of	O
static	O
grip	O
force	O
by	O
45	O
%	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
was	O
observed	O
in	O
the	O
ON	O
-	O
compared	O
with	O
the	O
OFF	O
-	O
drug	O
condition	O
.	O

In	O
contrast	O
,	O
no	O
excessive	O
force	O
was	O
found	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
-	O
LID	B-Disease
.	O

Peak	O
grip	O
force	O
in	O
ON	O
-	O
state	O
was	O
140	O
%	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
higher	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
+	O
LID	B-Disease
than	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
-	O
LID	B-Disease
,	O
while	O
static	O
grip	O
force	O
was	O
increased	O
by	O
138	O
%	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
between	O
groups	O
.	O

Severity	O
of	O
peak	O
-	O
dose	O
dyskinesias	B-Disease
was	O
strongly	O
correlated	O
with	O
grip	O
force	O
in	O
ON	O
-	O
state	O
(	O
r	O
=	O
0	O
.	O
79	O
with	O
peak	O
force	O
,	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

No	O
correlation	O
was	O
observed	O
between	O
forces	O
and	O
the	O
motor	O
score	O
as	O
well	O
as	O
with	O
the	O
daily	O
dose	O
of	O
dopaminergic	O
medication	O
.	O

Force	O
excess	O
was	O
only	O
observed	O
in	O
patients	O
with	O
LID	B-Disease
and	O
motor	O
fluctuations	O
.	O

A	O
close	O
relationship	O
was	O
seen	O
between	O
the	O
overshooting	O
of	O
forces	O
and	O
dyskinesias	B-Disease
in	O
the	O
ON	O
-	O
drug	O
condition	O
.	O

We	O
postulate	O
that	O
both	O
LID	B-Disease
and	O
grip	O
force	O
excess	O
share	O
common	O
pathophysiological	O
mechanisms	O
related	O
to	O
motor	O
fluctuations	O
.	O

Behavioral	O
effects	O
of	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
on	O
reserpine	B-Chemical
-	O
treated	O
mice	O
.	O

The	O
effects	O
of	O
dizocilpine	B-Chemical
(	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
)	O
,	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
were	O
studied	O
on	O
dopamine	B-Chemical
-	O
related	O
behaviors	O
induced	O
by	O
reserpine	B-Chemical
treatments	O
.	O

This	O
study	O
focuses	O
on	O
behavioral	O
syndromes	O
that	O
may	O
used	O
as	O
models	O
for	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
,	O
or	O
tardive	B-Disease
dyskinesia	I-Disease
,	O
and	O
its	O
response	O
after	O
glutamatergic	O
blockage	O
.	O

Reserpine	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
)	O
,	O
administered	O
once	O
every	O
other	O
day	O
for	O
4	O
days	O
,	O
produced	O
increases	O
in	O
orofacial	B-Disease
dyskinesia	I-Disease
,	O
tongue	O
protrusion	O
and	O
vacuous	O
chewing	O
in	O
mice	O
,	O
which	O
are	O
signs	O
indicative	O
of	O
tardive	B-Disease
dyskinesia	I-Disease
.	O

Reserpine	B-Chemical
also	O
produced	O
tremor	B-Disease
and	O
catalepsy	B-Disease
,	O
which	O
are	O
signs	O
suggestive	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

MK	B-Chemical
-	I-Chemical
801	I-Chemical
(	O
0	O
.	O
1	O
mg	O
/	O
kg	O
)	O
,	O
administered	O
30	O
min	O
before	O
the	O
observation	O
test	O
,	O
prevented	O
the	O
vacuous	O
chewing	O
movements	O
,	O
tongue	O
protrusions	O
and	O
catalepsy	B-Disease
induced	O
by	O
reserpine	B-Chemical
.	O

However	O
,	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
injection	O
produced	O
a	O
significant	O
increase	O
of	O
tremor	B-Disease
in	O
reserpine	B-Chemical
-	O
treated	O
mice	O
.	O

Reserpine	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
)	O
,	O
administered	O
90	O
min	O
before	O
the	O
test	O
and	O
followed	O
by	O
apomophine	B-Chemical
injection	O
(	O
0	O
.	O
1	O
mg	O
/	O
kg	O
)	O
5	O
min	O
before	O
the	O
test	O
,	O
did	O
not	O
produce	O
oral	B-Disease
dyskinesia	I-Disease
in	O
mice	O
.	O

On	O
the	O
other	O
hand	O
,	O
reserpine	B-Chemical
induced	O
increases	O
in	O
tremor	B-Disease
and	O
catalepsy	B-Disease
compared	O
to	O
control	O
mice	O
.	O

MK	B-Chemical
-	I-Chemical
801	I-Chemical
(	O
0	O
.	O
1	O
mg	O
/	O
kg	O
)	O
administration	O
attenuated	O
the	O
catalepsy	B-Disease
and	O
tremor	B-Disease
induced	O
by	O
reserpine	B-Chemical
.	O

Pretreatment	O
with	O
reserpine	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
)	O
24	O
h	O
before	O
the	O
observation	O
test	O
produced	O
increases	O
in	O
vacuous	O
chewing	O
movements	O
and	O
tongue	O
protrusion	O
,	O
as	O
well	O
as	O
increases	O
in	O
tremor	B-Disease
and	O
catalepsy	B-Disease
,	O
whereas	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
(	O
0	O
.	O
1	O
mg	O
/	O
kg	O
)	O
injection	O
90	O
min	O
before	O
the	O
test	O
reversed	O
the	O
effects	O
of	O
reserpine	B-Chemical
.	O

These	O
results	O
show	O
that	O
reserpine	B-Chemical
produces	O
different	O
and	O
abnormal	B-Disease
movements	I-Disease
,	O
which	O
are	O
related	O
to	O
dose	O
and	O
schedule	O
employed	O
and	O
can	O
be	O
considered	O
as	O
parkinsonian	B-Disease
-	O
like	O
and	O
tardive	B-Disease
dsykinesia	I-Disease
signs	O
.	O

The	O
glutamatergic	O
blockage	O
produced	O
by	O
NMDA	B-Chemical
can	O
restore	O
these	O
signs	O
,	O
such	O
as	O
vacuous	O
chewing	O
movements	O
,	O
tongue	O
protrusions	O
,	O
catalepsy	B-Disease
and	O
tremor	B-Disease
according	O
to	O
the	O
employed	O
model	O
.	O

Risperidone	B-Chemical
-	O
associated	O
,	O
benign	O
transient	O
visual	B-Disease
disturbances	I-Disease
in	O
schizophrenic	B-Disease
patients	O
with	O
a	O
past	O
history	O
of	O
LSD	B-Chemical
abuse	O
.	O

Two	O
schizophrenic	B-Disease
patients	O
,	O
who	O
had	O
a	O
prior	O
history	O
of	O
LSD	B-Chemical
abuse	O
and	O
who	O
had	O
previously	O
developed	O
EPS	B-Disease
with	O
classic	O
antipsychotics	O
,	O
were	O
successfully	O
treated	O
with	O
risperidone	B-Chemical
.	O

They	O
both	O
reported	O
short	O
episodes	O
of	O
transient	O
visual	B-Disease
disturbances	I-Disease
,	O
which	O
appeared	O
immediately	O
after	O
starting	O
treatment	O
with	O
risperidone	B-Chemical
.	O

This	O
imagery	O
resembled	O
visual	B-Disease
disturbances	I-Disease
previously	O
experienced	O
as	O
"	O
flashbacks	O
"	O
related	O
to	O
prior	O
LSD	B-Chemical
consumption	O
.	O

Risperidone	B-Chemical
administration	O
was	O
continued	O
and	O
the	O
visual	B-Disease
disturbances	I-Disease
gradually	O
wore	O
off	O
.	O

During	O
a	O
six	O
-	O
month	O
follow	O
-	O
up	O
period	O
,	O
there	O
was	O
no	O
recurrence	O
of	O
visual	B-Disease
disturbances	I-Disease
.	O

This	O
phenomenon	O
may	O
be	O
interpreted	O
as	O
a	O
benign	O
,	O
short	O
-	O
term	O
and	O
self	O
-	O
limiting	O
side	O
effect	O
which	O
does	O
not	O
contraindicate	O
the	O
use	O
of	O
risperidone	B-Chemical
or	O
interfere	O
with	O
treatment	O
.	O

Conclusions	O
based	O
on	O
two	O
case	O
reports	O
should	O
be	O
taken	O
with	O
appropriate	O
caution	O
.	O

Topiramate	B-Chemical
-	O
induced	O
nephrolithiasis	B-Disease
.	O

Topiramate	B-Chemical
is	O
a	O
recently	O
developed	O
antiepileptic	O
medication	O
that	O
is	O
becoming	O
more	O
widely	O
prescribed	O
because	O
of	O
its	O
efficacy	O
in	O
treating	O
refractory	B-Disease
seizures	I-Disease
.	O

Urologists	O
should	O
be	O
aware	O
that	O
this	O
medication	O
can	O
cause	O
metabolic	B-Disease
acidosis	I-Disease
in	O
patients	O
secondary	O
to	O
inhibition	O
of	O
carbonic	O
anhydrase	O
.	O

In	O
addition	O
,	O
a	O
distal	O
tubular	O
acidification	O
defect	O
may	O
result	O
,	O
thus	O
impairing	O
the	O
normal	O
compensatory	O
drop	O
in	O
urine	O
pH	O
.	O

These	O
factors	O
can	O
lead	O
to	O
the	O
development	O
of	O
calcium	B-Chemical
phosphate	I-Chemical
nephrolithiasis	B-Disease
.	O

We	O
report	O
the	O
first	O
two	O
cases	O
of	O
topiramate	B-Chemical
-	O
induced	O
nephrolithiasis	B-Disease
in	O
the	O
urologic	O
literature	O
.	O

Ketamine	B-Chemical
in	O
war	O
/	O
tropical	O
surgery	O
(	O
a	O
final	O
tribute	O
to	O
the	O
racemic	O
mixture	O
)	O
.	O

A	O
technique	O
of	O
continuous	O
intravenous	O
anaesthesia	O
with	O
ketamine	B-Chemical
was	O
used	O
successfully	O
during	O
the	O
Somalia	O
civil	O
war	O
in	O
1994	O
and	O
in	O
north	O
Uganda	O
in	O
1999	O
for	O
64	O
operations	O
in	O
62	O
patients	O
,	O
aged	O
from	O
6	O
weeks	O
to	O
70	O
years	O
,	O
undergoing	O
limb	O
and	O
abdominal	O
surgery	O
including	O
caesarian	O
sections	O
and	O
interventions	O
in	O
neonates	O
.	O

Operations	O
lasting	O
up	O
to	O
2h	O
could	O
be	O
performed	O
in	O
the	O
absence	O
of	O
sophisticated	O
equipment	O
such	O
as	O
pulse	O
oximeters	O
or	O
ventilators	O
in	O
patients	O
on	O
spontaneous	O
ventilation	O
breathing	O
air	O
/	O
oxygen	B-Chemical
only	O
.	O

After	O
premedication	O
with	O
diazepam	B-Chemical
,	O
glycopyrrolate	B-Chemical
and	O
local	O
anaesthesia	O
,	O
and	O
induction	O
with	O
standard	O
doses	O
of	O
ketamine	B-Chemical
,	O
a	O
maintenance	O
dose	O
of	O
10	O
-	O
20	O
microg	O
/	O
kg	O
/	O
min	O
of	O
ketamine	B-Chemical
proved	O
safe	O
and	O
effective	O
.	O

Emphasis	O
was	O
placed	O
on	O
bedside	O
clinical	O
monitoring	O
,	O
relying	O
heavily	O
on	O
the	O
heart	O
rate	O
.	O

Diazepam	B-Chemical
,	O
unless	O
contraindicated	O
or	O
risky	O
,	O
remains	O
the	O
only	O
necessary	O
complementary	O
drug	O
to	O
ketamine	B-Chemical
as	O
it	O
buffers	O
its	O
cardiovascular	O
response	O
and	O
decreases	O
the	O
duration	O
and	O
intensity	O
of	O
operative	O
and	O
postoperative	O
hallucinations	B-Disease
.	O

Local	O
anaesthetic	O
blocks	O
were	O
useful	O
in	O
decreasing	O
the	O
requirement	O
for	O
postoperative	O
analgesia	B-Disease
.	O

An	O
antisialogue	O
was	O
usually	O
unnecessary	O
in	O
operations	O
lasting	O
up	O
to	O
2	O
h	O
,	O
glycopyrrolate	B-Chemical
being	O
the	O
best	O
choice	O
for	O
its	O
lowest	O
psychotropic	O
and	O
chronotropic	O
effects	O
,	O
especially	O
in	O
a	O
hot	O
climate	O
.	O

Experience	O
in	O
war	O
/	O
tropical	O
settings	O
suggests	O
this	O
technique	O
could	O
be	O
useful	O
in	O
civilian	O
contexts	O
such	O
as	O
outdoor	O
life	O
-	O
saving	O
emergency	O
surgery	O
or	O
in	O
mass	O
casualties	O
where	O
,	O
e	O
.	O
g	O
.	O
amputation	O
and	O
rapid	O
extrication	O
were	O
required	O
.	O

Intravenous	O
ribavirin	B-Chemical
treatment	O
for	O
severe	O
adenovirus	B-Disease
disease	I-Disease
in	O
immunocompromised	O
children	O
.	O

BACKGROUND	O
:	O
Adenovirus	O
is	O
an	O
important	O
cause	O
of	O
morbidity	O
and	O
mortality	O
in	O
the	O
immunocompromised	O
host	O
.	O

The	O
incidence	O
of	O
severe	O
adenovirus	B-Disease
disease	I-Disease
in	O
pediatrics	O
is	O
increasing	O
in	O
association	O
with	O
growing	O
numbers	O
of	O
immunocompromised	O
children	O
,	O
where	O
case	O
fatality	O
rates	O
as	O
high	O
as	O
50	O
%	O
to	O
80	O
%	O
have	O
been	O
reported	O
.	O

There	O
are	O
no	O
approved	O
antiviral	O
agents	O
with	O
proven	O
efficacy	O
for	O
the	O
treatment	O
of	O
severe	O
adenovirus	B-Disease
disease	I-Disease
,	O
nor	O
are	O
there	O
any	O
prospective	O
randomized	O
,	O
controlled	O
trials	O
of	O
potentially	O
useful	O
anti	O
-	O
adenovirus	O
therapies	O
.	O

Apparent	O
clinical	O
success	O
in	O
the	O
treatment	O
of	O
severe	O
adenovirus	B-Disease
disease	I-Disease
is	O
limited	O
to	O
a	O
few	O
case	O
reports	O
and	O
small	O
series	O
.	O

Experience	O
is	O
greatest	O
with	O
intravenous	O
ribavirin	B-Chemical
and	O
cidofovir	B-Chemical
.	O

Ribavirin	B-Chemical
,	O
a	O
guanosine	B-Chemical
analogue	O
,	O
has	O
broad	O
antiviral	O
activity	O
against	O
both	O
RNA	O
and	O
DNA	O
viruses	O
,	O
including	O
documented	O
activity	O
against	O
adenovirus	O
in	O
vitro	O
.	O

Ribavirin	B-Chemical
is	O
licensed	O
in	O
aerosol	O
form	O
for	O
the	O
treatment	O
of	O
respiratory	B-Disease
syncytial	I-Disease
virus	I-Disease
infection	I-Disease
,	O
and	O
orally	O
in	O
combination	O
with	O
interferon	O
to	O
treat	O
hepatitis	B-Disease
C	I-Disease
.	O

Intravenous	O
ribavirin	B-Chemical
is	O
the	O
treatment	O
of	O
choice	O
for	O
infection	B-Disease
with	I-Disease
hemorrhagic	I-Disease
fever	I-Disease
viruses	I-Disease
.	O

The	O
most	O
common	O
adverse	O
effect	O
of	O
intravenous	O
ribavirin	B-Chemical
is	O
reversible	O
mild	O
anemia	B-Disease
.	O

The	O
use	O
of	O
cidofovir	B-Chemical
in	O
severe	O
adenovirus	B-Disease
infection	I-Disease
has	O
been	O
limited	O
by	O
adverse	O
effects	O
,	O
the	O
most	O
significant	O
of	O
which	O
is	O
nephrotoxicity	B-Disease
.	O

OBJECTIVE	O
:	O
We	O
report	O
our	O
experience	O
with	O
intravenous	O
ribavirin	B-Chemical
therapy	O
for	O
severe	O
adenovirus	B-Disease
disease	I-Disease
in	O
a	O
series	O
of	O
immunocompromised	O
children	O
and	O
review	O
the	O
literature	O
.	O

DESIGN	O
/	O
METHODS	O
:	O
We	O
retrospectively	O
reviewed	O
the	O
medical	O
records	O
of	O
5	O
children	O
treated	O
with	O
intravenous	O
ribavirin	B-Chemical
for	O
documented	O
severe	O
adenovirus	B-Disease
disease	I-Disease
.	O

Two	O
patients	O
developed	O
adenovirus	O
hemorrhagic	B-Disease
cystitis	I-Disease
after	O
cardiac	O
and	O
bone	O
marrow	O
transplants	O
,	O
respectively	O
.	O

The	O
bone	O
marrow	O
transplant	O
patient	O
also	O
received	O
intravenous	O
cidofovir	B-Chemical
for	O
progressive	O
disseminated	O
disease	O
.	O

An	O
additional	O
3	O
children	O
developed	O
adenovirus	B-Disease
pneumonia	I-Disease
;	O
2	O
were	O
neonates	O
,	O
1	O
of	O
whom	O
had	O
partial	O
DiGeorge	B-Disease
syndrome	I-Disease
.	O

The	O
remaining	O
infant	O
had	O
recently	O
undergone	O
a	O
cardiac	O
transplant	O
.	O

Intravenous	O
ribavirin	B-Chemical
was	O
administered	O
on	O
a	O
compassionate	O
-	O
use	O
protocol	O
.	O

RESULTS	O
:	O
Complete	O
clinical	O
recovery	O
followed	O
later	O
by	O
viral	O
clearance	O
was	O
observed	O
in	O
2	O
children	O
:	O
the	O
cardiac	O
transplant	O
recipient	O
with	O
adenovirus	O
hemorrhagic	B-Disease
cystitis	I-Disease
and	O
the	O
immunocompetent	O
neonate	O
with	O
adenovirus	B-Disease
pneumonia	I-Disease
.	O

The	O
remaining	O
3	O
children	O
died	O
of	O
adenovirus	B-Disease
disease	I-Disease
.	O

Intravenous	O
ribavirin	B-Chemical
therapy	O
was	O
well	O
tolerated	O
.	O

Use	O
of	O
cidofovir	B-Chemical
in	O
1	O
child	O
was	O
associated	O
with	O
progressive	B-Disease
renal	I-Disease
failure	I-Disease
and	O
neutropenia	B-Disease
.	O

DISCUSSION	O
:	O
Our	O
series	O
of	O
patients	O
is	O
representative	O
of	O
the	O
spectrum	O
of	O
immunocompromised	O
children	O
at	O
greatest	O
risk	O
for	O
severe	O
adenovirus	B-Disease
disease	I-Disease
,	O
namely	O
solid	O
-	O
organ	O
and	O
bone	O
marrow	O
transplant	O
recipients	O
,	O
neonates	O
,	O
and	O
children	O
with	O
immunodeficiency	B-Disease
.	O

Although	O
intravenous	O
ribavirin	B-Chemical
was	O
not	O
effective	O
for	O
all	O
children	O
with	O
severe	O
adenovirus	B-Disease
disease	I-Disease
in	O
this	O
series	O
or	O
in	O
the	O
literature	O
,	O
therapy	O
is	O
unlikely	O
to	O
be	O
of	O
benefit	O
if	O
begun	O
late	O
in	O
the	O
course	O
of	O
the	O
infection	B-Disease
.	O

Early	O
identification	O
,	O
eg	O
by	O
polymerase	O
chain	O
reaction	O
of	O
those	O
patients	O
at	O
risk	O
of	O
disseminated	O
adenovirus	B-Disease
disease	I-Disease
may	O
permit	O
earlier	O
antiviral	O
treatment	O
and	O
better	O
evaluation	O
of	O
therapeutic	O
response	O
.	O

CONCLUSIONS	O
:	O
Two	O
of	O
5	O
children	O
with	O
severe	O
adenovirus	B-Disease
disease	I-Disease
treated	O
with	O
intravenous	O
ribavirin	B-Chemical
recovered	O
.	O

The	O
availability	O
of	O
newer	O
rapid	O
diagnostic	O
techniques	O
,	O
such	O
as	O
polymerase	O
chain	O
reaction	O
,	O
may	O
make	O
earlier	O
,	O
more	O
effective	O
treatment	O
of	O
adenovirus	B-Disease
infection	I-Disease
possible	O
.	O

Given	O
the	O
seriousness	O
and	O
increasing	O
prevalence	O
of	O
adenovirus	B-Disease
disease	I-Disease
in	O
certain	O
hosts	O
,	O
especially	O
children	O
,	O
a	O
large	O
,	O
multicenter	O
clinical	O
trial	O
of	O
potentially	O
useful	O
anti	O
-	O
adenoviral	O
therapies	O
,	O
such	O
as	O
intravenous	O
ribavirin	B-Chemical
,	O
is	O
clearly	O
required	O
to	O
demonstrate	O
the	O
most	O
effective	O
and	O
least	O
toxic	O
therapy	O
.	O

Delayed	O
asystolic	B-Disease
cardiac	B-Disease
arrest	I-Disease
after	O
diltiazem	B-Chemical
overdose	B-Disease
;	O
resuscitation	O
with	O
high	O
dose	O
intravenous	O
calcium	B-Chemical
.	O

A	O
51	O
year	O
old	O
man	O
took	O
a	O
mixed	O
overdose	B-Disease
including	O
1	O
.	O
8	O
-	O
3	O
.	O
6	O
g	O
of	O
diltiazem	B-Chemical
,	O
paracetamol	B-Chemical
,	O
aspirin	B-Chemical
,	O
isosorbide	B-Chemical
nitrate	B-Chemical
,	O
and	O
alcohol	B-Chemical
.	O

He	O
initially	O
presented	O
to	O
hospital	O
after	O
six	O
hours	O
with	O
mild	O
hypotension	B-Disease
and	O
was	O
treated	O
with	O
activated	O
charcoal	O
and	O
intravenous	O
fluids	O
.	O

Eighteen	O
hours	O
after	O
the	O
overdose	B-Disease
he	O
had	O
two	O
generalised	O
tonic	B-Disease
-	I-Disease
clonic	I-Disease
seizures	I-Disease
.	O

The	O
patient	O
remained	O
unresponsive	O
with	O
junctional	O
bradycardia	B-Disease
,	O
unrecordable	O
blood	O
pressure	O
,	O
and	O
then	O
became	O
asystolic	B-Disease
.	O

He	O
was	O
resuscitated	O
with	O
high	O
dose	O
(	O
13	O
.	O
5	O
g	O
)	O
intravenous	O
calcium	B-Chemical
and	O
adrenaline	B-Chemical
(	O
epinephrine	B-Chemical
)	O
.	O

He	O
required	O
inotropic	O
support	O
and	O
temporary	O
pacing	O
over	O
the	O
next	O
48	O
hours	O
.	O

This	O
case	O
suggests	O
there	O
is	O
a	O
role	O
for	O
aggressive	O
high	O
dose	O
intravenous	O
calcium	B-Chemical
therapy	O
in	O
severe	O
diltiazem	B-Chemical
overdose	B-Disease
,	O
particularly	O
with	O
the	O
onset	O
of	O
asystole	B-Disease
.	O

It	O
should	O
be	O
considered	O
early	O
in	O
cases	O
of	O
cardiac	B-Disease
arrest	I-Disease
after	O
diltiazem	B-Chemical
overdose	B-Disease
.	O

The	O
case	O
also	O
highlights	O
the	O
problems	O
with	O
delayed	O
toxicity	B-Disease
when	O
whole	O
bowel	O
irrigation	O
is	O
not	O
administered	O
.	O

Low	B-Chemical
-	I-Chemical
molecular	I-Chemical
-	I-Chemical
weight	I-Chemical
heparin	I-Chemical
for	O
the	O
treatment	O
of	O
patients	O
with	O
mechanical	O
heart	O
valves	O
.	O

BACKGROUND	O
:	O
The	O
interruption	O
of	O
oral	O
anticoagulant	O
(	O
OAC	O
)	O
administration	O
is	O
sometimes	O
indicated	O
in	O
patients	O
with	O
mechanical	O
heart	O
valves	O
,	O
mainly	O
before	O
noncardiac	O
surgery	O
,	O
non	O
-	O
surgical	O
interventions	O
,	O
and	O
pregnancy	O
.	O

Unfractionated	B-Chemical
heparin	I-Chemical
(	O
UH	B-Chemical
)	O
is	O
currently	O
the	O
substitute	O
for	O
selected	O
patients	O
.	O

Low	B-Chemical
-	I-Chemical
molecular	I-Chemical
-	I-Chemical
weight	I-Chemical
heparin	I-Chemical
(	O
LMWH	B-Chemical
)	O
offers	O
theoretical	O
advantages	O
over	O
UH	B-Chemical
,	O
but	O
is	O
not	O
currently	O
considered	O
in	O
clinical	O
guidelines	O
as	O
an	O
alternative	O
to	O
UH	B-Chemical
in	O
patients	O
with	O
prosthetic	O
valves	O
.	O

HYPOTHESIS	O
:	O
The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
review	O
the	O
data	O
accumulated	O
so	O
far	O
on	O
the	O
use	O
of	O
LMWH	B-Chemical
in	O
this	O
patient	O
population	O
and	O
to	O
discuss	O
its	O
applicability	O
in	O
common	O
practice	O
.	O

METHODS	O
:	O
For	O
this	O
paper	O
,	O
the	O
current	O
medical	O
literature	O
on	O
LMWH	B-Chemical
in	O
patients	O
with	O
mechanical	O
heart	O
valves	O
was	O
extensively	O
reviewed	O
.	O

RESULTS	O
:	O
There	O
were	O
eight	O
series	O
and	O
six	O
case	O
reports	O
.	O

None	O
of	O
the	O
studies	O
was	O
randomized	O
,	O
and	O
only	O
one	O
was	O
prospective	O
.	O

Data	O
to	O
establish	O
the	O
thromboembolic	B-Disease
risk	O
were	O
incomplete	O
.	O

After	O
excluding	O
case	O
reports	O
,	O
the	O
following	O
groups	O
were	O
constructed	O
:	O
(	O
a	O
)	O
short	O
-	O
term	O
administration	O
,	O
after	O
valve	O
insertion	O
(	O
n	O
=	O
212	O
)	O
;	O
(	O
b	O
)	O
short	O
-	O
term	O
,	O
perioperative	O
(	O
noncardiac	O
)	O
/	O
periprocedural	O
(	O
n	O
=	O
114	O
)	O
;	O
(	O
c	O
)	O
long	O
-	O
term	O
,	O
due	O
to	O
intolerance	O
to	O
OAC	O
(	O
n	O
=	O
16	O
)	O
;	O
(	O
d	O
)	O
long	O
-	O
term	O
,	O
in	O
pregnancy	O
(	O
n	O
=	O
10	O
)	O
.	O

The	O
incidence	O
rate	O
of	O
thromboembolism	B-Disease
was	O
0	O
.	O
9	O
%	O
for	O
all	O
the	O
studies	O
and	O
0	O
.	O
5	O
,	O
0	O
,	O
20	O
,	O
and	O
0	O
%	O
in	O
groups	O
a	O
,	O
b	O
,	O
c	O
,	O
and	O
d	O
,	O
respectively	O
;	O
for	O
hemorrhage	B-Disease
,	O
the	O
overall	O
rate	O
was	O
3	O
.	O
4	O
%	O
(	O
3	O
.	O
8	O
,	O
2	O
.	O
6	O
,	O
10	O
,	O
and	O
0	O
%	O
for	O
the	O
respective	O
groups	O
)	O
.	O

CONCLUSIONS	O
:	O
In	O
patients	O
with	O
mechanical	O
heart	O
valves	O
,	O
short	O
-	O
term	O
LMWH	B-Chemical
therapy	O
compares	O
favorably	O
with	O
UH	B-Chemical
.	O

Data	O
on	O
mid	O
-	O
and	O
long	O
-	O
term	O
LMWH	B-Chemical
administration	O
in	O
these	O
patients	O
are	O
sparse	O
.	O

Further	O
randomized	O
studies	O
are	O
needed	O
to	O
confirm	O
the	O
safety	O
and	O
precise	O
indications	O
for	O
the	O
use	O
of	O
LMWH	B-Chemical
in	O
patients	O
with	O
mechanical	O
heart	O
valves	O
.	O

Cardiac	B-Disease
arrest	I-Disease
after	O
intravenous	O
metoclopramide	B-Chemical
-	O
a	O
case	O
of	O
five	O
repeated	O
injections	O
of	O
metoclopramide	B-Chemical
causing	O
five	O
episodes	O
of	O
cardiac	B-Disease
arrest	I-Disease
.	O

We	O
describe	O
a	O
patient	O
where	O
intravenous	O
injection	O
of	O
metoclopramide	B-Chemical
was	O
immediately	O
followed	O
by	O
asystole	B-Disease
repeatedly	O
.	O

The	O
patient	O
received	O
metoclopramide	B-Chemical
10	O
mg	O
i	O
.	O
v	O
.	O
five	O
times	O
during	O
48	O
h	O
.	O

After	O
interviewing	O
the	O
attending	O
nurses	O
and	O
reviewing	O
the	O
written	O
documentation	O
,	O
it	O
is	O
clear	O
that	O
every	O
administration	O
of	O
metoclopramide	B-Chemical
was	O
immediately	O
(	O
within	O
s	O
)	O
followed	O
by	O
asystole	B-Disease
.	O

The	O
asystole	B-Disease
lasted	O
15	O
-	O
30	O
s	O
on	O
four	O
occasions	O
,	O
on	O
one	O
occasion	O
it	O
lasted	O
2	O
min	O
.	O

The	O
patient	O
received	O
atropine	B-Chemical
0	O
.	O
5	O
-	O
1	O
mg	O
and	O
chest	O
compressions	O
,	O
before	O
sinus	O
rhythm	O
again	O
took	O
over	O
.	O

We	O
interpret	O
this	O
as	O
episodes	O
of	O
cardiac	B-Disease
arrest	I-Disease
caused	O
by	O
metoclopramide	B-Chemical
.	O

The	O
rapid	O
injection	O
via	O
the	O
central	O
venous	O
route	O
and	O
the	O
concomitant	O
tapering	O
of	O
dopamine	B-Chemical
infusion	O
might	O
have	O
contributed	O
in	O
precipitating	O
the	O
adverse	O
drug	O
reaction	O
.	O

Immunohistochemical	O
study	O
on	O
inducible	O
type	O
of	O
nitric	B-Chemical
oxide	I-Chemical
(	O
iNOS	O
)	O
,	O
basic	O
fibroblast	O
growth	O
factor	O
(	O
bFGF	O
)	O
and	O
tumor	B-Disease
growth	O
factor	O
-	O
beta1	O
(	O
TGF	O
-	O
beta1	O
)	O
in	O
arteritis	B-Disease
induced	O
in	O
rats	O
by	O
fenoldopam	B-Chemical
and	O
theophylline	B-Chemical
,	O
vasodilators	O
.	O

Arteritis	B-Disease
induced	O
in	O
rats	O
by	O
vasodilators	O
,	O
fenoldopam	B-Chemical
and	O
theophylline	B-Chemical
,	O
was	O
examined	O
immunohistochemically	O
for	O
expressions	O
of	O
inducible	O
type	O
of	O
nitric	B-Chemical
oxide	I-Chemical
synthase	O
(	O
iNOS	O
)	O
,	O
basic	O
fibroblast	O
growth	O
factor	O
(	O
bFGF	O
)	O
and	O
tumor	B-Disease
growth	O
factor	O
-	O
beta1	O
(	O
TGF	O
-	O
beta1	O
)	O
.	O

Rats	O
were	O
administered	O
fenoldopam	B-Chemical
for	O
24	O
hours	O
by	O
intravenous	O
infusion	O
with	O
or	O
without	O
following	O
repeated	O
daily	O
oral	O
administrations	O
of	O
theophylline	B-Chemical
.	O

Irrespective	O
of	O
theophylline	B-Chemical
administration	O
,	O
iNOS	O
antigens	O
were	O
remarkably	O
abundant	O
in	O
ED	O
-	O
1	O
-	O
positive	O
cells	O
on	O
day	O
5	O
and	O
8	O
post	O
-	O
fenoldopam	B-Chemical
-	O
infusion	O
(	O
DPI	O
)	O
;	O
bFGF	O
antigens	O
were	O
remarkably	O
abundant	O
in	O
ED	O
-	O
1	O
-	O
positive	O
cells	O
on	O
1	O
and	O
3	O
DPI	O
;	O
TGF	O
-	O
beta1	O
antigens	O
were	O
observed	O
in	O
ED	O
-	O
1	O
-	O
positive	O
cells	O
on	O
and	O
after	O
5	O
DPI	O
.	O

These	O
results	O
suggest	O
that	O
the	O
peak	O
expression	O
of	O
iNOS	O
antigen	O
was	O
followed	O
by	O
that	O
of	O
bFGF	O
antigen	O
,	O
and	O
bFGF	O
may	O
have	O
a	O
suppressive	O
effect	O
on	O
iNOS	O
expression	O
in	O
these	O
rat	O
arteritis	B-Disease
models	O
.	O

On	O
the	O
other	O
hand	O
,	O
TGF	O
-	O
beta1	O
was	O
not	O
considered	O
to	O
have	O
a	O
suppressive	O
effect	O
on	O
iNOS	O
expression	O
in	O
these	O
models	O
.	O

The	O
striatum	O
as	O
a	O
target	O
for	O
anti	O
-	O
rigor	O
effects	O
of	O
an	O
antagonist	O
of	O
mGluR1	O
,	O
but	O
not	O
an	O
agonist	O
of	O
group	O
II	O
metabotropic	O
glutamate	B-Chemical
receptors	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
find	O
out	O
whether	O
the	O
metabotropic	O
receptor	O
1	O
(	O
mGluR1	O
)	O
and	O
group	O
II	O
mGluRs	O
,	O
localized	O
in	O
the	O
striatum	O
,	O
are	O
involved	O
in	O
antiparkinsonian	O
-	O
like	O
effects	O
in	O
rats	O
.	O

Haloperidol	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
ip	O
)	O
induced	O
parkinsonian	B-Disease
-	O
like	O
muscle	B-Disease
rigidity	I-Disease
,	O
measured	O
as	O
an	O
increased	O
resistance	O
of	O
a	O
rat	O
'	O
s	O
hind	O
foot	O
to	O
passive	O
flexion	O
and	O
extension	O
at	O
the	O
ankle	O
joint	O
.	O

(	B-Chemical
RS	I-Chemical
)	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
aminoindan	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
dicarboxylic	I-Chemical
acid	I-Chemical
(	O
AIDA	B-Chemical
;	O
0	O
.	O
5	O
-	O
15	O
microg	O
/	O
0	O
.	O
5	O
microl	O
)	O
,	O
a	O
potent	O
and	O
selective	O
mGluR1	O
antagonist	O
,	O
or	O
(	B-Chemical
2R	I-Chemical
,	I-Chemical
4R	I-Chemical
)	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
aminopyrrolidine	I-Chemical
-	I-Chemical
2	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dicarboxylate	I-Chemical
(	O
2R	B-Chemical
,	I-Chemical
4R	I-Chemical
-	I-Chemical
APDC	I-Chemical
;	O
7	O
.	O
5	O
-	O
15	O
microg	O
/	O
0	O
.	O
5	O
microl	O
)	O
,	O
a	O
selective	O
group	O
II	O
agonist	O
,	O
was	O
injected	O
bilaterally	O
into	O
the	O
striatum	O
of	O
haloperidol	B-Chemical
-	O
treated	O
animals	O
.	O

AIDA	B-Chemical
in	O
doses	O
of	O
7	O
.	O
5	O
-	O
15	O
microg	O
/	O
0	O
.	O
5	O
microl	O
diminished	O
the	O
haloperidol	B-Chemical
-	O
induced	O
muscle	B-Disease
rigidity	I-Disease
.	O

In	O
contrast	O
,	O
2R	B-Chemical
,	I-Chemical
4R	I-Chemical
-	I-Chemical
APDC	I-Chemical
injections	O
were	O
ineffective	O
.	O

The	O
present	O
results	O
may	O
suggest	O
that	O
the	O
blockade	O
of	O
striatal	O
mGluR1	O
,	O
but	O
not	O
the	O
stimulation	O
of	O
group	O
II	O
mGluRs	O
,	O
may	O
ameliorate	O
parkinsonian	B-Disease
muscle	B-Disease
rigidity	I-Disease
.	O

A	O
phase	O
II	O
study	O
of	O
thalidomide	B-Chemical
in	O
advanced	O
metastatic	O
renal	B-Disease
cell	I-Disease
carcinoma	I-Disease
.	O

OBJECTIVES	O
:	O
To	O
evaluate	O
the	O
toxicity	B-Disease
and	O
activity	O
of	O
thalidomide	B-Chemical
in	O
patients	O
with	O
advanced	O
metastatic	O
renal	B-Disease
cell	I-Disease
cancer	I-Disease
and	O
to	O
measure	O
changes	O
of	O
one	O
angiogenic	O
factor	O
,	O
vascular	O
endothelial	O
growth	O
factor	O
(	O
VEGF	O
)	O
165	O
,	O
with	O
therapy	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
29	O
patients	O
were	O
enrolled	O
on	O
a	O
study	O
of	O
thalidomide	B-Chemical
using	O
an	O
intra	O
-	O
patient	O
dose	O
escalation	O
schedule	O
.	O

Patients	O
began	O
thalidomide	B-Chemical
at	O
400	O
mg	O
/	O
d	O
and	O
escalated	O
as	O
tolerated	O
to	O
1200	O
mg	O
/	O
d	O
by	O
day	O
54	O
.	O

Fifty	O
-	O
nine	O
per	O
cent	O
of	O
patients	O
had	O
had	O
previous	O
therapy	O
with	O
IL	O
-	O
2	O
and	O
52	O
%	O
were	O
performance	O
status	O
2	O
or	O
3	O
.	O

Systemic	O
plasma	O
VEGF165	O
levels	O
were	O
measured	O
by	O
dual	O
monoclonal	O
ELISA	O
in	O
8	O
patients	O
.	O

RESULTS	O
:	O
24	O
patients	O
were	O
evaluable	O
for	O
response	O
with	O
one	O
partial	O
response	O
of	O
11	O
months	O
duration	O
of	O
a	O
patient	O
with	O
hepatic	O
and	O
pulmonary	O
metastases	B-Disease
(	O
4	O
%	O
)	O
,	O
one	O
minor	O
response	O
,	O
and	O
2	O
patients	O
stable	O
for	O
over	O
6	O
months	O
.	O

Somnolence	B-Disease
and	O
constipation	B-Disease
were	O
prominent	O
toxicities	B-Disease
and	O
most	O
patients	O
could	O
not	O
tolerate	O
the	O
1200	O
mg	O
/	O
day	O
dose	O
level	O
.	O

Systemic	O
plasma	O
VEGF165	O
levels	O
did	O
not	O
change	O
with	O
therapy	O
.	O

CONCLUSION	O
:	O
These	O
results	O
are	O
consistent	O
with	O
a	O
low	O
level	O
of	O
activity	O
of	O
thalidomide	B-Chemical
in	O
renal	B-Disease
cell	I-Disease
carcinoma	I-Disease
.	O

Administration	O
of	O
doses	O
over	O
800	O
mg	O
/	O
day	O
was	O
difficult	O
to	O
achieve	O
in	O
this	O
patient	O
population	O
,	O
however	O
lower	O
doses	O
were	O
practical	O
.	O

The	O
dose	O
-	O
response	O
relationship	O
,	O
if	O
any	O
,	O
of	O
thalidomide	B-Chemical
for	O
renal	B-Disease
cell	I-Disease
carcinoma	I-Disease
is	O
unclear	O
.	O

Can	O
lidocaine	B-Chemical
reduce	O
succinylcholine	B-Chemical
induced	O
postoperative	B-Disease
myalgia	I-Disease
?	O

This	O
study	O
was	O
undertaken	O
to	O
determine	O
the	O
effect	O
of	O
lidocaine	B-Chemical
pretreatment	O
on	O
reduction	O
of	O
succinylcholine	B-Chemical
-	O
induced	O
myalgia	B-Disease
in	O
patients	O
undergoing	O
general	O
anesthesia	O
for	O
gynecological	O
surgery	O
.	O

One	O
hundred	O
and	O
thirty	O
-	O
five	O
patients	O
were	O
assigned	O
to	O
one	O
of	O
three	O
groups	O
in	O
a	O
prospective	O
,	O
double	O
blind	O
,	O
randomized	O
manner	O
.	O

Group	O
PS	O
,	O
the	O
control	O
group	O
,	O
received	O
normal	O
saline	O
and	O
succinylcholine	B-Chemical
1	O
.	O
5	O
mg	O
x	O
kg	O
(	O
-	O
1	O
)	O
;	O
Group	O
LS	O
,	O
lidocaine	B-Chemical
1	O
.	O
5	O
mg	O
x	O
kg	O
(	O
-	O
1	O
)	O
and	O
succinylcholine	B-Chemical
1	O
.	O
5	O
mg	O
x	O
kg	O
(	O
-	O
1	O
)	O
;	O
Group	O
PR	O
,	O
normal	O
saline	O
and	O
rocuronium	B-Chemical
0	O
.	O
6	O
mg	O
x	O
kg	O
(	O
-	O
1	O
)	O
.	O

Morphine	B-Chemical
0	O
.	O
1	O
mg	O
x	O
kg	O
(	O
-	O
1	O
)	O
iv	O
was	O
given	O
for	O
premedication	O
and	O
all	O
patients	O
were	O
monitored	O
with	O
a	O
noninvasive	O
blood	O
pressure	O
monitor	O
,	O
ECG	O
and	O
pulse	O
oximetry	O
.	O

Anesthesia	O
was	O
induced	O
with	O
5	O
mg	O
.	O
kg	O
(	O
-	O
1	O
)	O
thiopental	B-Chemical
iv	O
.	O
followed	O
by	O
succinylcholine	B-Chemical
(	O
Group	O
PS	O
,	O
LS	O
)	O
or	O
rocuronium	B-Chemical
(	O
Group	O
PR	O
)	O
for	O
tracheal	O
intubation	O
.	O

Following	O
administration	O
of	O
these	O
agents	O
,	O
the	O
presence	O
,	O
and	O
degree	O
of	O
fasciculation	B-Disease
were	O
assessed	O
visually	O
on	O
a	O
four	O
point	O
scale	O
by	O
one	O
investigator	O
who	O
was	O
blinded	O
to	O
the	O
drug	O
administered	O
.	O

The	O
blood	O
pressure	O
and	O
heart	O
rate	O
of	O
each	O
patient	O
were	O
monitored	O
on	O
nine	O
occasions	O
.	O

Twenty	O
-	O
four	O
hours	O
later	O
,	O
any	O
myalgia	B-Disease
experienced	O
was	O
assessed	O
according	O
to	O
a	O
structured	O
questionaire	O
and	O
graded	O
by	O
a	O
four	O
point	O
scale	O
by	O
one	O
investigator	O
blinded	O
to	O
the	O
intraoperative	O
management	O
.	O

The	O
results	O
indicate	O
that	O
muscle	B-Disease
fasciculation	I-Disease
was	O
not	O
found	O
in	O
Group	O
PR	O
while	O
the	O
patients	O
in	O
Group	O
LS	O
had	O
a	O
lower	O
incidence	O
of	O
muscle	B-Disease
fasciculation	I-Disease
than	O
those	O
in	O
Group	O
PS	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

At	O
24	O
h	O
,	O
the	O
incidence	O
of	O
myalgia	B-Disease
was	O
higher	O
in	O
Group	O
PS	O
than	O
in	O
Group	O
LS	O
and	O
PR	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

A	O
correlation	O
was	O
not	O
found	O
between	O
the	O
incidence	O
of	O
myalgia	B-Disease
and	O
the	O
occurrence	O
of	O
muscle	B-Disease
fasciculation	I-Disease
.	O

The	O
changes	O
in	O
systolic	O
and	O
diastolic	O
blood	O
pressure	O
and	O
heart	O
rate	O
were	O
not	O
significant	O
among	O
the	O
three	O
groups	O
.	O

In	O
conclusion	O
,	O
where	O
succinylcholine	B-Chemical
is	O
used	O
,	O
lidocaine	B-Chemical
is	O
proven	O
to	O
be	O
the	O
useful	O
pretreatment	O
agent	O
for	O
the	O
reduction	O
of	O
postoperative	B-Disease
myalgia	I-Disease
.	O

Reduced	O
sodium	B-Chemical
channel	O
density	O
,	O
altered	O
voltage	O
dependence	O
of	O
inactivation	O
,	O
and	O
increased	O
susceptibility	O
to	O
seizures	B-Disease
in	O
mice	O
lacking	O
sodium	B-Chemical
channel	O
beta	O
2	O
-	O
subunits	O
.	O

Sodium	B-Chemical
channel	O
beta	O
-	O
subunits	O
modulate	O
channel	O
gating	O
,	O
assembly	O
,	O
and	O
cell	O
surface	O
expression	O
in	O
heterologous	O
cell	O
systems	O
.	O

We	O
generated	O
beta2	O
(	O
-	O
/	O
-	O
)	O
mice	O
to	O
investigate	O
the	O
role	O
of	O
beta2	O
in	O
control	O
of	O
sodium	B-Chemical
channel	O
density	O
,	O
localization	O
,	O
and	O
function	O
in	O
neurons	O
in	O
vivo	O
.	O

Measurements	O
of	O
[	O
(	O
3	O
)	O
H	O
]	O
saxitoxin	B-Chemical
(	O
STX	B-Chemical
)	O
binding	O
showed	O
a	O
significant	O
reduction	O
in	O
the	O
level	O
of	O
plasma	O
membrane	O
sodium	B-Chemical
channels	O
in	O
beta2	O
(	O
-	O
/	O
-	O
)	O
neurons	O
.	O

The	O
loss	O
of	O
beta2	O
resulted	O
in	O
negative	O
shifts	O
in	O
the	O
voltage	O
dependence	O
of	O
inactivation	O
as	O
well	O
as	O
significant	O
decreases	O
in	O
sodium	B-Chemical
current	O
density	O
in	O
acutely	O
dissociated	O
hippocampal	O
neurons	O
.	O

The	O
integral	O
of	O
the	O
compound	O
action	O
potential	O
in	O
optic	O
nerve	O
was	O
significantly	O
reduced	O
,	O
and	O
the	O
threshold	O
for	O
action	O
potential	O
generation	O
was	O
increased	O
,	O
indicating	O
a	O
reduction	O
in	O
the	O
level	O
of	O
functional	O
plasma	O
membrane	O
sodium	B-Chemical
channels	O
.	O

In	O
contrast	O
,	O
the	O
conduction	O
velocity	O
,	O
the	O
number	O
and	O
size	O
of	O
axons	O
in	O
the	O
optic	O
nerve	O
,	O
and	O
the	O
specific	O
localization	O
of	O
Na	B-Chemical
(	O
v	O
)	O
1	O
.	O
6	O
channels	O
in	O
the	O
nodes	O
of	O
Ranvier	O
were	O
unchanged	O
.	O

beta2	O
(	O
-	O
/	O
-	O
)	O
mice	O
displayed	O
increased	O
susceptibility	O
to	O
seizures	B-Disease
,	O
as	O
indicated	O
by	O
reduced	O
latency	O
and	O
threshold	O
for	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
,	O
but	O
seemed	O
normal	O
in	O
other	O
neurological	O
tests	O
.	O

Our	O
observations	O
show	O
that	O
beta2	O
-	O
subunits	O
play	O
an	O
important	O
role	O
in	O
the	O
regulation	O
of	O
sodium	B-Chemical
channel	O
density	O
and	O
function	O
in	O
neurons	O
in	O
vivo	O
and	O
are	O
required	O
for	O
normal	O
action	O
potential	O
generation	O
and	O
control	O
of	O
excitability	O
.	O

Acute	B-Disease
liver	I-Disease
failure	I-Disease
with	O
concurrent	O
bupropion	B-Chemical
and	O
carbimazole	B-Chemical
therapy	O
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
fatal	O
liver	B-Disease
failure	I-Disease
possibly	O
associated	O
with	O
concurrent	O
use	O
of	O
bupropion	B-Chemical
and	O
carbimazole	B-Chemical
.	O

CASE	O
SUMMARY	O
:	O
A	O
41	O
-	O
year	O
-	O
old	O
Chinese	O
man	O
with	O
a	O
history	O
of	O
hyperthyroidism	B-Disease
had	O
been	O
treated	O
with	O
carbimazole	B-Chemical
and	O
propranolol	B-Chemical
for	O
the	O
past	O
5	O
years	O
.	O

He	O
received	O
a	O
10	O
-	O
day	O
course	O
of	O
bupropion	B-Chemical
as	O
an	O
aid	O
for	O
smoking	O
cessation	O
10	O
weeks	O
prior	O
to	O
presentation	O
.	O

He	O
developed	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
with	O
rapid	O
deterioration	O
of	O
renal	O
function	O
.	O

Liver	O
biopsy	O
showed	O
evidence	O
of	O
nonspecific	O
drug	B-Disease
-	I-Disease
induced	I-Disease
acute	I-Disease
liver	I-Disease
injury	I-Disease
.	O

His	O
condition	O
was	O
further	O
complicated	O
by	O
sepsis	B-Disease
and	O
coagulopathy	B-Disease
.	O

Death	O
resulted	O
19	O
days	O
after	O
the	O
onset	O
of	O
symptoms	O
.	O

The	O
likelihood	O
that	O
bupropion	B-Chemical
induced	O
hepatotoxicity	B-Disease
in	O
our	O
patient	O
was	O
possible	O
,	O
based	O
on	O
the	O
Naranjo	O
probability	O
scale	O
.	O

DISCUSSION	O
:	O
Although	O
there	O
is	O
increasing	O
evidence	O
of	O
hepatotoxicity	B-Disease
induced	O
by	O
bupropion	B-Chemical
,	O
this	O
is	O
the	O
first	O
case	O
of	O
fatality	O
that	O
could	O
have	O
resulted	O
from	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
in	O
a	O
patient	O
receiving	O
bupropion	B-Chemical
while	O
on	O
concomitant	O
treatment	O
with	O
carbimazole	B-Chemical
.	O

CONCLUSIONS	O
:	O
Clinicians	O
should	O
be	O
aware	O
of	O
the	O
possibility	O
of	O
acute	B-Disease
liver	I-Disease
insult	I-Disease
induced	O
by	O
bupropion	B-Chemical
given	O
concurrently	O
with	O
other	O
hepatotoxic	B-Disease
drugs	O
.	O

Pyeloureteral	O
filling	O
defects	O
associated	O
with	O
systemic	O
anticoagulation	O
:	O
a	O
case	O
report	O
.	O

The	O
etiology	O
of	O
pyeloureteritis	B-Disease
cystica	I-Disease
has	O
long	O
been	O
attributed	O
to	O
chronic	O
infection	B-Disease
and	O
inflammation	B-Disease
.	O

A	O
case	O
is	O
presented	O
that	O
is	O
unique	O
in	O
that	O
the	O
acute	O
onset	O
and	O
the	O
rapid	O
resolution	O
of	O
pyeloureteral	O
filling	O
defects	O
in	O
this	O
patient	O
were	O
documented	O
by	O
radiography	O
.	O

There	O
is	O
no	O
evidence	O
of	O
antecedent	O
or	O
concurrent	O
infection	B-Disease
in	O
this	O
patient	O
.	O

The	O
disease	O
occurred	O
subsequent	O
to	O
the	O
initiation	O
of	O
heparin	B-Chemical
therapy	O
for	O
suspected	O
pelvic	O
thrombophlebitis	B-Disease
and	O
cleared	O
rapidly	O
subsequent	O
to	O
its	O
discontinuation	O
.	O

The	O
rate	O
of	O
resolution	O
of	O
the	O
radiographic	O
findings	O
may	O
be	O
helpful	O
in	O
distinguishing	O
between	O
true	O
pyeloureteritis	B-Disease
cystica	I-Disease
and	O
submucosal	B-Disease
hemorrhage	I-Disease
.	O

Nephrotoxic	B-Disease
effects	O
in	O
high	O
-	O
risk	O
patients	O
undergoing	O
angiography	O
.	O

BACKGROUND	O
:	O
The	O
use	O
of	O
iodinated	O
contrast	O
medium	O
can	O
result	O
in	O
nephropathy	B-Disease
.	O

Whether	O
iso	O
-	O
osmolar	O
contrast	O
medium	O
is	O
less	O
nephrotoxic	B-Disease
than	O
low	O
-	O
osmolar	O
contrast	O
medium	O
in	O
high	O
-	O
risk	O
patients	O
is	O
uncertain	O
.	O

METHODS	O
:	O
We	O
conducted	O
a	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
prospective	O
,	O
multicenter	O
study	O
comparing	O
the	O
nephrotoxic	B-Disease
effects	O
of	O
an	O
iso	O
-	O
osmolar	O
,	O
dimeric	O
,	O
nonionic	O
contrast	O
medium	O
,	O
iodixanol	B-Chemical
,	O
with	O
those	O
of	O
a	O
low	O
-	O
osmolar	O
,	O
nonionic	O
,	O
monomeric	O
contrast	O
medium	O
,	O
iohexol	B-Chemical
.	O

The	O
study	O
involved	O
129	O
patients	O
with	O
diabetes	B-Disease
with	O
serum	O
creatinine	B-Chemical
concentrations	O
of	O
1	O
.	O
5	O
to	O
3	O
.	O
5	O
mg	O
per	O
deciliter	O
who	O
underwent	O
coronary	O
or	O
aortofemoral	O
angiography	O
.	O

The	O
primary	O
end	O
point	O
was	O
the	O
peak	O
increase	O
from	O
base	O
line	O
in	O
the	O
creatinine	B-Chemical
concentration	O
during	O
the	O
three	O
days	O
after	O
angiography	O
.	O

Other	O
end	O
points	O
were	O
an	O
increase	O
in	O
the	O
creatinine	B-Chemical
concentration	O
of	O
0	O
.	O
5	O
mg	O
per	O
deciliter	O
or	O
more	O
,	O
an	O
increase	O
of	O
1	O
.	O
0	O
mg	O
per	O
deciliter	O
or	O
more	O
,	O
and	O
a	O
change	O
in	O
the	O
creatinine	B-Chemical
concentration	O
from	O
day	O
0	O
to	O
day	O
7	O
.	O

RESULTS	O
:	O
The	O
creatinine	B-Chemical
concentration	O
increased	O
significantly	O
less	O
in	O
patients	O
who	O
received	O
iodixanol	B-Chemical
.	O

From	O
day	O
0	O
to	O
day	O
3	O
,	O
the	O
mean	O
peak	O
increase	O
in	O
creatinine	B-Chemical
was	O
0	O
.	O
13	O
mg	O
per	O
deciliter	O
in	O
the	O
iodixanol	B-Chemical
group	O
and	O
0	O
.	O
55	O
mg	O
per	O
deciliter	O
in	O
the	O
iohexol	B-Chemical
group	O
(	O
P	O
=	O
0	O
.	O
001	O
;	O
the	O
increase	O
with	O
iodixanol	B-Chemical
minus	O
the	O
increase	O
with	O
iohexol	B-Chemical
,	O
-	O
0	O
.	O
42	O
mg	O
per	O
deciliter	O
[	O
95	O
percent	O
confidence	O
interval	O
,	O
-	O
0	O
.	O
73	O
to	O
-	O
0	O
.	O
22	O
]	O
)	O
.	O

Two	O
of	O
the	O
64	O
patients	O
in	O
the	O
iodixanol	B-Chemical
group	O
(	O
3	O
percent	O
)	O
had	O
an	O
increase	O
in	O
the	O
creatinine	B-Chemical
concentration	O
of	O
0	O
.	O
5	O
mg	O
per	O
deciliter	O
or	O
more	O
,	O
as	O
compared	O
with	O
17	O
of	O
the	O
65	O
patients	O
in	O
the	O
iohexol	B-Chemical
group	O
(	O
26	O
percent	O
)	O
(	O
P	O
=	O
0	O
.	O
002	O
;	O
odds	O
ratio	O
for	O
such	O
an	O
increase	O
in	O
the	O
iodixanol	B-Chemical
group	O
,	O
0	O
.	O
09	O
[	O
95	O
percent	O
confidence	O
interval	O
,	O
0	O
.	O
02	O
to	O
0	O
.	O
41	O
]	O
)	O
.	O

No	O
patient	O
receiving	O
iodixanol	B-Chemical
had	O
an	O
increase	O
of	O
1	O
.	O
0	O
mg	O
per	O
deciliter	O
or	O
more	O
,	O
but	O
10	O
patients	O
in	O
the	O
iohexol	B-Chemical
group	O
(	O
15	O
percent	O
)	O
did	O
.	O

The	O
mean	O
change	O
in	O
the	O
creatinine	B-Chemical
concentration	O
from	O
day	O
0	O
to	O
day	O
7	O
was	O
0	O
.	O
07	O
mg	O
per	O
deciliter	O
in	O
the	O
iodixanol	B-Chemical
group	O
and	O
0	O
.	O
24	O
mg	O
per	O
deciliter	O
in	O
the	O
iohexol	B-Chemical
group	O
(	O
P	O
=	O
0	O
.	O
003	O
;	O
value	O
in	O
the	O
iodixanol	B-Chemical
group	O
minus	O
the	O
value	O
in	O
the	O
iohexol	B-Chemical
group	O
,	O
-	O
0	O
.	O
17	O
mg	O
per	O
deciliter	O
[	O
95	O
percent	O
confidence	O
interval	O
,	O
-	O
0	O
.	O
34	O
to	O
-	O
0	O
.	O
07	O
]	O
)	O
.	O

CONCLUSIONS	O
:	O
Nephropathy	B-Disease
induced	O
by	O
contrast	O
medium	O
may	O
be	O
less	O
likely	O
to	O
develop	O
in	O
high	O
-	O
risk	O
patients	O
when	O
iodixanol	B-Chemical
is	O
used	O
rather	O
than	O
a	O
low	O
-	O
osmolar	O
,	O
nonionic	O
contrast	O
medium	O
.	O

Protective	O
effect	O
of	O
edaravone	B-Chemical
against	O
streptomycin	B-Chemical
-	O
induced	O
vestibulotoxicity	B-Disease
in	O
the	O
guinea	O
pig	O
.	O

This	O
study	O
investigated	O
alleviation	O
of	O
streptomycin	B-Chemical
-	O
induced	O
vestibulotoxicity	B-Disease
by	O
edaravone	B-Chemical
in	O
guinea	O
pigs	O
.	O

Edaravone	B-Chemical
,	O
a	O
free	O
radical	O
scavenger	O
,	O
has	O
potent	O
free	O
radical	O
quenching	O
action	O
and	O
is	O
used	O
in	O
clinical	O
practice	O
to	O
treat	O
cerebral	B-Disease
infarction	I-Disease
.	O

Streptomycin	B-Chemical
was	O
administered	O
to	O
the	O
inner	O
ear	O
by	O
osmotic	O
pump	O
for	O
24	O
h	O
,	O
and	O
edaravone	B-Chemical
(	O
n	O
=	O
8	O
)	O
or	O
saline	O
(	O
n	O
=	O
6	O
)	O
was	O
intraperitoneally	O
injected	O
once	O
a	O
day	O
for	O
7	O
days	O
.	O

We	O
observed	O
horizontal	O
vestibulo	O
-	O
ocular	O
reflex	O
as	O
a	O
marker	O
of	O
postoperative	O
vestibular	O
function	O
.	O

Animals	O
injected	O
with	O
saline	O
showed	O
statistically	O
smaller	O
gains	O
than	O
those	O
injected	O
with	O
edaravone	B-Chemical
.	O

These	O
results	O
suggest	O
that	O
edaravone	B-Chemical
suppresses	O
streptomycin	B-Chemical
-	O
induced	O
vestibulotoxicity	B-Disease
.	O

Levodopa	B-Chemical
-	O
induced	O
oromandibular	O
dystonia	B-Disease
in	O
progressive	B-Disease
supranuclear	I-Disease
palsy	I-Disease
.	O

Levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
have	O
been	O
reported	O
in	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
and	O
multiple	B-Disease
system	I-Disease
atrophy	I-Disease
.	O

Cranial	O
dystonias	B-Disease
are	O
rare	O
in	O
patients	O
with	O
progressive	B-Disease
supranuclear	I-Disease
palsy	I-Disease
(	O
PSP	B-Disease
)	O
.	O

In	O
this	O
report	O
we	O
describe	O
an	O
unusual	O
case	O
of	O
reversible	O
levodopa	B-Chemical
-	O
induced	O
Oromandibular	B-Disease
dystonia	I-Disease
(	O
OMD	B-Disease
)	O
in	O
a	O
PSP	B-Disease
patient	O
to	O
highlight	O
the	O
importance	O
of	O
recognizing	O
this	O
drug	O
related	O
complication	O
in	O
the	O
management	O
of	O
PSP	B-Disease
,	O
and	O
discuss	O
the	O
possible	O
underlying	O
pathophysiology	O
.	O

Case	O
report	O
:	O
Dexatrim	B-Chemical
(	O
Phenylpropanolamine	B-Chemical
)	O
as	O
a	O
cause	O
of	O
myocardial	B-Disease
infarction	I-Disease
.	O

Phenylpropanolamine	B-Chemical
(	O
PPA	B-Chemical
)	O
is	O
a	O
sympathetic	O
amine	B-Chemical
used	O
in	O
over	O
-	O
the	O
-	O
counter	O
cold	O
remedies	O
and	O
weight	O
-	O
control	O
preparations	O
worldwide	O
.	O

Its	O
use	O
has	O
been	O
associated	O
with	O
hypertensive	B-Disease
episodes	O
and	O
hemorrhagic	B-Disease
strokes	I-Disease
in	O
younger	O
women	O
.	O

Several	O
reports	O
have	O
linked	O
the	O
abuse	O
of	O
PPA	B-Chemical
with	O
myocardial	B-Disease
injury	I-Disease
,	O
especially	O
when	O
overdose	B-Disease
is	O
involved	O
.	O

We	O
report	O
here	O
the	O
first	O
case	O
of	O
Dexatrim	B-Chemical
(	O
PPA	B-Chemical
)	O
-	O
induced	O
myocardial	B-Disease
injury	I-Disease
in	O
a	O
young	O
woman	O
who	O
was	O
using	O
it	O
at	O
recommended	O
doses	O
for	O
weight	O
control	O
.	O

In	O
addition	O
,	O
we	O
review	O
the	O
7	O
other	O
cases	O
of	O
PPA	B-Chemical
related	O
myocardial	B-Disease
injury	I-Disease
that	O
have	O
been	O
reported	O
so	O
far	O
.	O

Physicians	O
and	O
patients	O
should	O
be	O
alert	O
to	O
the	O
potential	O
cardiac	O
risk	O
associated	O
with	O
the	O
use	O
of	O
PPA	B-Chemical
,	O
even	O
at	O
doses	O
generally	O
considered	O
to	O
be	O
safe	O
.	O

Differential	O
diagnosis	O
of	O
high	O
serum	O
creatine	B-Chemical
kinase	O
levels	O
in	O
systemic	B-Disease
lupus	I-Disease
erythematosus	I-Disease
.	O

We	O
report	O
the	O
clinical	O
and	O
bioptic	O
findings	O
for	O
a	O
57	O
-	O
year	O
-	O
old	O
woman	O
with	O
severe	O
chloroquine	B-Chemical
-	O
induced	O
myopathy	B-Disease
.	O

Since	O
1989	O
,	O
she	O
had	O
been	O
suffering	O
from	O
systemic	B-Disease
lupus	I-Disease
erythematosus	I-Disease
(	O
SLE	B-Disease
)	O
with	O
renal	B-Disease
involvement	I-Disease
and	O
undergone	O
periods	O
of	O
treatment	O
with	O
azathioprine	B-Chemical
and	O
cyclophosphamide	B-Chemical
.	O

Additional	O
therapy	O
with	O
chloroquine	B-Chemical
(	O
CQ	B-Chemical
)	O
was	O
started	O
because	O
of	O
arthralgia	B-Disease
.	O

At	O
the	O
same	O
time	O
,	O
slightly	O
increased	O
creatine	B-Chemical
kinase	O
(	O
CK	O
)	O
levels	O
were	O
noted	O
.	O

Myositis	B-Disease
was	O
suspected	O
,	O
and	O
the	O
patient	O
was	O
treated	O
with	O
steroids	B-Chemical
.	O

The	O
CK	O
increase	O
persisted	O
,	O
however	O
,	O
and	O
she	O
developed	O
progressive	O
muscular	B-Disease
weakness	I-Disease
and	O
muscular	B-Disease
atrophy	I-Disease
.	O

Routine	O
controls	O
revealed	O
markedly	O
elevated	O
CK	O
levels	O
of	O
1	O
,	O
700	O
U	O
/	O
l	O
.	O

The	O
neurological	O
and	O
electrophysiological	O
findings	O
were	O
not	O
typical	O
of	O
myositis	B-Disease
.	O

Thus	O
,	O
muscle	O
biopsy	O
of	O
the	O
deltoid	O
muscle	O
was	O
performed	O
in	O
order	O
to	O
exclude	O
polymyositis	B-Disease
or	O
toxic	O
myopathy	B-Disease
.	O

As	O
it	O
revealed	O
chloroquine	B-Chemical
-	O
induced	O
myopathy	B-Disease
,	O
medication	O
was	O
stopped	O
.	O

Discriminating	O
between	O
primary	O
SLE	B-Disease
-	O
induced	O
affection	B-Disease
of	I-Disease
the	I-Disease
musculoskeletal	I-Disease
system	I-Disease
and	O
drug	O
-	O
induced	O
side	O
effects	O
is	O
important	O
for	O
appropriate	O
treatment	O
of	O
SLE	B-Disease
patients	O
.	O

Seizure	B-Disease
associated	O
with	O
sleep	B-Disease
deprivation	I-Disease
and	O
sustained	O
-	O
release	O
bupropion	B-Chemical
.	O

This	O
case	O
report	O
describes	O
a	O
generalized	O
seizure	B-Disease
associated	O
with	O
sustained	O
-	O
release	O
bupropion	B-Chemical
use	O
and	O
sleep	B-Disease
deprivation	I-Disease
.	O

The	O
subject	O
,	O
a	O
31	O
-	O
year	O
-	O
old	O
female	O
smoker	O
,	O
was	O
participating	O
in	O
a	O
clinical	O
trial	O
evaluating	O
an	O
investigational	O
medication	O
for	O
smoking	O
cessation	O
that	O
used	O
sustained	O
-	O
release	O
bupropion	B-Chemical
as	O
an	O
active	O
control	O
.	O

After	O
5	O
weeks	O
of	O
bupropion	B-Chemical
use	O
,	O
the	O
subject	O
experienced	O
a	O
generalized	O
tonic	O
clonic	O
seizure	B-Disease
after	O
staying	O
up	O
nearly	O
all	O
night	O
packing	O
and	O
moving	O
to	O
a	O
new	O
residence	O
.	O

The	O
patient	O
had	O
no	O
other	O
risk	O
factors	O
for	O
seizures	B-Disease
.	O

We	O
suggest	O
that	O
sleep	B-Disease
deprivation	I-Disease
may	O
add	O
to	O
the	O
risk	O
of	O
bupropion	B-Chemical
-	O
associated	O
seizures	B-Disease
.	O

Postoperative	B-Disease
myalgia	I-Disease
after	O
succinylcholine	B-Chemical
:	O
no	O
evidence	O
for	O
an	O
inflammatory	O
origin	O
.	O

A	O
common	O
side	O
effect	O
associated	O
with	O
succinylcholine	B-Chemical
is	O
postoperative	B-Disease
myalgia	I-Disease
.	O

The	O
pathogenesis	O
of	O
this	O
myalgia	B-Disease
is	O
still	O
unclear	O
;	O
inflammation	B-Disease
has	O
been	O
suggested	O
but	O
without	O
convincing	O
evidence	O
.	O

We	O
designed	O
the	O
present	O
study	O
to	O
investigate	O
whether	O
an	O
inflammatory	O
reaction	O
contributes	O
to	O
this	O
myalgia	B-Disease
.	O

The	O
incidence	O
and	O
severity	O
of	O
succinylcholine	B-Chemical
-	O
associated	O
myalgia	B-Disease
was	O
determined	O
in	O
64	O
patients	O
pretreated	O
with	O
saline	O
or	O
dexamethasone	B-Chemical
before	O
succinylcholine	B-Chemical
(	O
n	O
=	O
32	O
for	O
each	O
)	O
.	O

Incidence	O
and	O
severity	O
of	O
myalgia	B-Disease
did	O
not	O
differ	O
significantly	O
between	O
the	O
two	O
groups	O
:	O
15	O
patients	O
in	O
the	O
dexamethasone	B-Chemical
group	O
complained	O
of	O
myalgia	B-Disease
compared	O
with	O
18	O
patients	O
in	O
the	O
saline	O
group	O
,	O
and	O
severe	O
myalgia	B-Disease
was	O
reported	O
by	O
five	O
patients	O
and	O
three	O
patients	O
,	O
respectively	O
(	O
not	O
significant	O
)	O
.	O

At	O
48	O
h	O
after	O
surgery	O
,	O
12	O
patients	O
in	O
both	O
groups	O
still	O
suffered	O
from	O
myalgia	B-Disease
(	O
not	O
significant	O
)	O
.	O

In	O
addition	O
,	O
interleukin	O
-	O
6	O
(	O
IL	O
-	O
6	O
)	O
as	O
an	O
early	O
marker	O
of	O
inflammation	B-Disease
was	O
assessed	O
in	O
a	O
subgroup	O
of	O
10	O
patients	O
pretreated	O
with	O
saline	O
.	O

We	O
found	O
an	O
increase	O
of	O
IL	O
-	O
6	O
for	O
only	O
three	O
patients	O
,	O
but	O
only	O
one	O
patient	O
reported	O
myalgia	B-Disease
;	O
no	O
relationship	O
between	O
myalgia	B-Disease
and	O
the	O
increase	O
of	O
IL	O
-	O
6	O
was	O
found	O
.	O

In	O
conclusion	O
,	O
there	O
is	O
no	O
evidence	O
for	O
an	O
inflammatory	O
origin	O
of	O
succinylcholine	B-Chemical
-	O
associated	O
myalgia	B-Disease
.	O

IMPLICATIONS	O
:	O
Administration	O
of	O
dexamethasone	B-Chemical
before	O
succinylcholine	B-Chemical
was	O
not	O
effective	O
in	O
decreasing	O
the	O
incidence	O
or	O
the	O
severity	O
of	O
succinylcholine	B-Chemical
-	O
induced	O
postoperative	B-Disease
myalgia	I-Disease
.	O

Furthermore	O
,	O
there	O
was	O
no	O
significant	O
relationship	O
between	O
postoperative	B-Disease
myalgia	I-Disease
and	O
time	O
course	O
of	O
interleukin	O
-	O
6	O
concentrations	O
,	O
a	O
marker	O
of	O
inflammation	B-Disease
.	O

Pretreatment	O
with	O
dexamethasone	B-Chemical
is	O
not	O
justified	O
to	O
prevent	O
postoperative	B-Disease
myalgia	I-Disease
after	O
succinylcholine	B-Chemical
.	O

Effect	O
of	O
lindane	B-Chemical
on	O
hepatic	O
and	O
brain	O
cytochrome	O
P450s	O
and	O
influence	O
of	O
P450	O
modulation	O
in	O
lindane	B-Chemical
induced	O
neurotoxicity	B-Disease
.	O

Oral	O
administration	O
of	O
lindane	B-Chemical
(	O
2	O
.	O
5	O
,	O
5	O
,	O
10	O
and	O
15	O
mg	O
/	O
kg	O
,	O
body	O
weight	O
)	O
for	O
5	O
days	O
was	O
found	O
to	O
produce	O
a	O
dose	O
-	O
dependent	O
increase	O
in	O
the	O
activity	O
of	O
P450	O
dependent	O
7	O
-	O
ethoxyresorufin	O
-	O
O	O
-	O
deethylase	O
(	O
EROD	O
)	O
,	O
7	O
-	O
pentoxyresorufin	O
-	O
O	O
-	O
dealkylase	O
(	O
PROD	O
)	O
and	O
N	B-Chemical
-	I-Chemical
nitrosodimethylamine	I-Chemical
demethylase	O
(	O
NDMA	B-Chemical
-	O
d	O
)	O
in	O
rat	O
brain	O
and	O
liver	O
.	O

A	O
significant	O
increase	O
in	O
the	O
hepatic	O
and	O
brain	O
P450	O
monooxygenases	O
was	O
also	O
observed	O
when	O
the	O
duration	O
of	O
exposure	O
of	O
low	O
dose	O
(	O
2	O
.	O
5	O
mg	O
/	O
kg	O
)	O
of	O
lindane	B-Chemical
was	O
increased	O
from	O
5	O
days	O
to	O
15	O
or	O
21	O
days	O
.	O

As	O
observed	O
with	O
different	O
doses	O
,	O
the	O
magnitude	O
of	O
induction	O
in	O
the	O
activity	O
of	O
P450	O
monooxygenases	O
was	O
several	O
fold	O
higher	O
in	O
liver	O
microsomes	O
when	O
compared	O
with	O
the	O
brain	O
.	O

Western	O
blotting	O
studies	O
have	O
indicated	O
that	O
the	O
increase	O
in	O
the	O
P450	O
enzymes	O
could	O
be	O
due	O
to	O
the	O
increase	O
in	O
the	O
expression	O
of	O
P450	O
1A1	O
/	O
1A2	O
,	O
2B1	O
/	O
2B2	O
and	O
2E1	O
isoenzymes	O
.	O

In	O
vitro	O
studies	O
using	O
organic	O
inhibitors	O
specific	O
for	O
individual	O
P450	O
isoenzymes	O
and	O
antibody	O
inhibition	O
experiments	O
have	O
further	O
demonstrated	O
that	O
the	O
increase	O
in	O
the	O
activity	O
of	O
PROD	O
,	O
EROD	O
and	O
NDMA	B-Chemical
-	O
d	O
are	O
due	O
to	O
the	O
increase	O
in	O
the	O
levels	O
of	O
P450	O
2B1	O
/	O
2B2	O
,	O
1A1	O
/	O
1A2	O
and	O
2E1	O
isoenzymes	O
,	O
respectively	O
.	O

Induction	O
studies	O
have	O
further	O
shown	O
that	O
while	O
pretreatment	O
of	O
3	B-Chemical
-	I-Chemical
methylcholanthrene	I-Chemical
(	O
MC	B-Chemical
)	O
,	O
an	O
inducer	O
of	O
P4501A1	O
/	O
1A2	O
,	O
did	O
not	O
produce	O
any	O
significant	O
effect	O
in	O
the	O
incidence	O
of	O
lindane	B-Chemical
induced	O
convulsions	B-Disease
,	O
pretreatment	O
with	O
phenobarbital	B-Chemical
(	O
PB	O
)	O
,	O
an	O
inducer	O
of	O
P450	O
2B1	O
/	O
2B2	O
or	O
ethanol	B-Chemical
,	O
an	O
inducer	O
of	O
P450	O
2E1	O
catalysed	O
reactions	O
,	O
significantly	O
increased	O
the	O
incidence	O
of	O
lindane	B-Chemical
induced	O
convulsions	B-Disease
.	O

Similarly	O
,	O
when	O
the	O
P450	O
-	O
mediated	O
metabolism	O
of	O
lindane	B-Chemical
was	O
blocked	O
by	O
cobalt	B-Chemical
chloride	I-Chemical
incidence	O
of	O
convulsions	B-Disease
was	O
increased	O
in	O
animals	O
treated	O
with	O
lindane	B-Chemical
indicating	O
that	O
lindane	B-Chemical
per	O
se	O
or	O
its	O
metabolites	O
formed	O
by	O
PB	O
or	O
ethanol	B-Chemical
inducible	O
P450	O
isoenzymes	O
are	O
involved	O
in	O
its	O
neurobehavioral	O
toxicity	B-Disease
.	O

Absolute	O
and	O
attributable	O
risk	O
of	O
venous	B-Disease
thromboembolism	I-Disease
in	O
women	O
on	O
combined	O
cyproterone	B-Chemical
acetate	I-Chemical
and	O
ethinylestradiol	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
achieve	O
absolute	O
risk	O
estimates	O
of	O
venous	B-Disease
thromboembolism	I-Disease
(	O
VTE	B-Disease
)	O
among	O
women	O
on	O
cyproterone	B-Chemical
acetate	I-Chemical
plus	O
ethinylestradiol	B-Chemical
(	O
CPA	B-Chemical
/	O
EE	B-Chemical
)	O
,	O
and	O
among	O
women	O
on	O
combined	B-Chemical
oral	I-Chemical
contraceptives	I-Chemical
(	O
COCs	B-Chemical
)	O
.	O

METHODS	O
:	O
From	O
the	O
Danish	O
National	O
Register	O
of	O
Patients	O
(	O
NRP	O
)	O
,	O
1996	O
to	O
1998	O
,	O
the	O
records	O
of	O
1	O
.	O
1	O
million	O
Danish	O
women	O
,	O
ages	O
15	O
to	O
44	O
years	O
,	O
were	O
searched	O
for	O
evidence	O
of	O
VTE	B-Disease
.	O

COC	B-Chemical
use	O
was	O
ascertained	O
through	O
mailed	O
questionnaires	O
.	O

Sales	O
statistics	O
of	O
COCs	B-Chemical
and	O
CPA	B-Chemical
/	O
EE	B-Chemical
were	O
provided	O
through	O
Danish	O
Drug	O
Statistics	O
.	O

RESULTS	O
:	O
During	O
the	O
time	O
frame	O
of	O
the	O
study	O
,	O
330	O
women	O
were	O
found	O
to	O
have	O
had	O
VTE	B-Disease
while	O
on	O
COCs	B-Chemical
.	O

Of	O
these	O
women	O
,	O
67	O
were	O
on	O
levonorgestrel	B-Chemical
-	O
containing	O
COCs	B-Chemical
.	O

Eleven	O
were	O
on	O
CPA	B-Chemical
/	O
EE	B-Chemical
.	O

The	O
corresponding	O
absolute	O
risk	O
of	O
VTE	B-Disease
was	O
3	O
.	O
4	O
(	O
range	O
,	O
3	O
.	O
1	O
-	O
3	O
.	O
8	O
)	O
per	O
10	O
000	O
women	O
years	O
among	O
the	O
women	O
on	O
COCs	B-Chemical
,	O
4	O
.	O
2	O
(	O
range	O
,	O
3	O
.	O
2	O
-	O
5	O
.	O
2	O
)	O
per	O
10	O
000	O
women	O
years	O
among	O
women	O
on	O
levonorgestrel	B-Chemical
-	O
containing	O
COCs	B-Chemical
,	O
and	O
3	O
.	O
1	O
(	O
range	O
,	O
1	O
.	O
3	O
-	O
4	O
.	O
9	O
)	O
per	O
10	O
000	O
women	O
years	O
among	O
the	O
women	O
on	O
CPA	B-Chemical
/	O
EE	B-Chemical
.	O

CONCLUSION	O
:	O
Our	O
results	O
suggest	O
the	O
absolute	O
risk	O
of	O
VTE	B-Disease
among	O
Danish	O
women	O
on	O
COCs	B-Chemical
is	O
similar	O
to	O
that	O
among	O
women	O
taking	O
CPA	B-Chemical
/	O
EE	B-Chemical
.	O

Comparison	O
of	O
developmental	O
toxicology	O
of	O
aspirin	B-Chemical
(	O
acetylsalicylic	B-Chemical
acid	I-Chemical
)	O
in	O
rats	O
using	O
selected	O
dosing	O
paradigms	O
.	O

BACKGROUND	O
:	O
Analysis	O
of	O
the	O
literature	O
for	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drugs	O
(	O
NSAIDs	O
)	O
suggests	O
that	O
a	O
low	O
incidence	O
of	O
developmental	B-Disease
anomalies	I-Disease
occurs	O
in	O
rats	O
given	O
NSAIDs	O
on	O
specific	O
days	O
during	O
organogenesis	O
.	O

Aspirin	B-Chemical
(	O
acetylsalicylic	B-Chemical
acid	I-Chemical
[	O
ASA	B-Chemical
]	O
)	O
,	O
an	O
irreversible	O
cyclooxygenase	O
1	O
and	O
2	O
inhibitor	O
,	O
induces	O
developmental	B-Disease
anomalies	I-Disease
when	O
administered	O
to	O
Wistar	O
rats	O
on	O
gestational	O
day	O
(	O
GD	O
)	O
9	O
,	O
10	O
,	O
or	O
11	O
(	O
Kimmel	O
CA	O
,	O
Wilson	O
JG	O
,	O
Schumacher	O
HJ	O
.	O
Teratology	O
4	O
:	O
15	O
-	O
24	O
,	O
1971	O
)	O
.	O

There	O
are	O
no	O
published	O
ASA	B-Chemical
studies	O
using	O
the	O
multiple	O
dosing	O
paradigm	O
of	O
GDs	O
6	O
to	O
17	O
.	O

Objectives	O
of	O
the	O
current	O
study	O
were	O
to	O
compare	O
results	O
between	O
Sprague	O
-	O
Dawley	O
(	O
SD	O
)	O
and	O
Wistar	O
strains	O
when	O
ASA	B-Chemical
is	O
administered	O
on	O
GD	O
9	O
,	O
10	O
,	O
or	O
11	O
;	O
to	O
compare	O
the	O
malformation	O
patterns	O
following	O
single	O
and	O
multiple	O
dosings	O
during	O
organogenesis	O
in	O
SD	O
rats	O
;	O
and	O
to	O
test	O
the	O
hypothesis	O
that	O
maternal	O
gastrointestinal	B-Disease
toxicity	I-Disease
confounds	O
the	O
detection	O
of	O
low	O
incidence	O
malformations	B-Disease
with	O
ASA	B-Chemical
when	O
a	O
multiple	O
dosing	O
paradigm	O
is	O
used	O
.	O

METHODS	O
:	O
ASA	B-Chemical
was	O
administered	O
as	O
a	O
single	O
dose	O
on	O
GD	O
9	O
(	O
0	O
,	O
250	O
,	O
500	O
,	O
or	O
625	O
mg	O
/	O
kg	O
)	O
,	O
10	O
(	O
0	O
,	O
500	O
,	O
625	O
,	O
or	O
750	O
mg	O
/	O
kg	O
)	O
,	O
or	O
11	O
(	O
0	O
,	O
500	O
,	O
750	O
,	O
or	O
1000	O
mg	O
/	O
kg	O
)	O
and	O
from	O
GD	O
6	O
to	O
GD	O
17	O
(	O
0	O
,	O
50	O
,	O
125	O
,	O
or	O
250	O
mg	O
/	O
kg	O
a	O
day	O
)	O
in	O
the	O
multiple	O
dose	O
study	O
to	O
SD	O
rats	O
.	O

Animals	O
were	O
killed	O
on	O
GD	O
21	O
,	O
and	O
fetuses	O
were	O
examined	O
viscerally	O
.	O

RESULTS	O
:	O
The	O
literature	O
evaluation	O
suggested	O
that	O
NSAIDs	O
induce	O
ventricular	B-Disease
septal	I-Disease
defects	I-Disease
(	O
VSDs	B-Disease
)	O
and	O
midline	B-Disease
defects	I-Disease
(	O
MDs	B-Disease
)	O
in	O
rats	O
and	O
diaphragmatic	B-Disease
hernia	I-Disease
(	O
DH	B-Disease
)	O
,	O
MDs	B-Disease
,	O
and	O
VSDs	B-Disease
in	O
rabbits	O
(	O
Cook	O
JC	O
et	O
al	O
.	O
,	O
2003	O
)	O
;	O
hence	O
,	O
the	O
present	O
study	O
focused	O
on	O
these	O
malformations	B-Disease
,	O
even	O
though	O
ASA	B-Chemical
induces	O
several	O
other	O
low	O
-	O
incidence	O
malformations	B-Disease
.	O

In	O
single	O
dose	O
studies	O
,	O
DH	B-Disease
,	O
MD	B-Disease
,	O
and	O
VSD	B-Disease
were	O
induced	O
on	O
GDs	O
9	O
and	O
10	O
.	O

VSD	B-Disease
also	O
was	O
noted	O
following	O
treatment	O
on	O
GD	O
11	O
.	O

In	O
contrast	O
,	O
DH	B-Disease
and	O
MD	B-Disease
were	O
noted	O
in	O
the	O
multiple	O
dose	O
study	O
design	O
only	O
in	O
the	O
high	O
-	O
dose	O
group	O
,	O
and	O
VSD	B-Disease
was	O
noted	O
across	O
all	O
dose	O
groups	O
.	O

CONCLUSIONS	O
:	O
High	O
concordance	O
in	O
major	O
developmental	B-Disease
anomalies	I-Disease
between	O
Wistar	O
and	O
SD	O
rats	O
were	O
noted	O
with	O
the	O
exception	O
of	O
VSD	B-Disease
in	O
the	O
SD	O
rats	O
and	O
hydrocephalus	B-Disease
in	O
the	O
Wistar	O
rats	O
.	O

Variations	O
and	O
malformations	B-Disease
were	O
similar	O
when	O
ASA	B-Chemical
was	O
administered	O
as	O
a	O
single	O
dose	O
or	O
during	O
the	O
period	O
of	O
organogenesis	O
(	O
GDs	O
6	O
to	O
17	O
)	O
.	O

It	O
was	O
also	O
evident	O
that	O
,	O
by	O
titrating	O
the	O
dose	O
to	O
achieve	O
a	O
maximum	O
tolerated	O
dose	O
,	O
malformations	B-Disease
that	O
normally	O
occur	O
at	O
low	O
incidence	O
,	O
as	O
reported	O
from	O
previous	O
single	O
dose	O
studies	O
,	O
could	O
also	O
be	O
induced	O
with	O
ASA	B-Chemical
given	O
at	O
multiple	O
doses	O
.	O

Reversal	O
of	O
central	O
benzodiazepine	B-Chemical
effects	O
by	O
flumazenil	B-Chemical
after	O
intravenous	O
conscious	O
sedation	O
with	O
diazepam	B-Chemical
and	O
opioids	O
:	O
report	O
of	O
a	O
double	O
-	O
blind	O
multicenter	O
study	O
.	O

The	O
Flumazenil	B-Chemical
in	O
Intravenous	O
Conscious	O
Sedation	O
with	O
Diazepam	B-Chemical
Multicenter	O
Study	O
Group	O
II	O
.	O

The	O
efficacy	O
and	O
safety	O
of	O
a	O
new	O
benzodiazepine	B-Chemical
antagonist	O
,	O
flumazenil	B-Chemical
,	O
were	O
assessed	O
in	O
a	O
double	O
-	O
blind	O
multicenter	O
study	O
.	O

Flumazenil	B-Chemical
(	O
mean	O
dose	O
,	O
0	O
.	O
76	O
mg	O
)	O
or	O
placebo	O
(	O
mean	O
dose	O
,	O
8	O
.	O
9	O
ml	O
)	O
was	O
administered	O
intravenously	O
to	O
130	O
and	O
67	O
patients	O
,	O
respectively	O
,	O
who	O
had	O
been	O
given	O
diazepam	B-Chemical
in	O
conjunction	O
with	O
an	O
opioid	O
(	O
fentanyl	B-Chemical
,	O
meperidine	B-Chemical
,	O
or	O
morphine	B-Chemical
)	O
for	O
the	O
induction	O
and	O
maintenance	O
of	O
intravenous	O
conscious	O
sedation	O
for	O
diagnostic	O
or	O
therapeutic	O
surgical	O
procedures	O
.	O

The	O
group	O
assessable	O
for	O
efficacy	O
comprised	O
122	O
patients	O
treated	O
with	O
flumazenil	B-Chemical
and	O
64	O
patients	O
given	O
placebo	O
.	O

After	O
5	O
minutes	O
,	O
80	O
/	O
115	O
(	O
70	O
%	O
)	O
flumazenil	B-Chemical
-	O
treated	O
patients	O
,	O
compared	O
with	O
21	O
/	O
63	O
(	O
33	O
%	O
)	O
placebo	O
-	O
treated	O
patients	O
,	O
were	O
completely	O
awake	O
and	O
alert	O
,	O
as	O
indicated	O
by	O
a	O
score	O
of	O
5	O
on	O
the	O
Observer	O
'	O
s	O
Assessment	O
of	O
Alertness	O
/	O
Sedation	O
Scale	O
.	O

Ninety	O
-	O
five	O
percent	O
of	O
patients	O
in	O
each	O
group	O
who	O
attained	O
a	O
score	O
of	O
5	O
at	O
the	O
5	O
-	O
minute	O
assessment	O
showed	O
no	O
loss	O
of	O
alertness	O
throughout	O
the	O
180	O
-	O
minute	O
assessment	O
period	O
.	O

Flumazenil	B-Chemical
-	O
treated	O
patients	O
also	O
performed	O
significantly	O
better	O
on	O
the	O
Finger	O
-	O
to	O
-	O
Nose	O
Test	O
and	O
the	O
recall	O
of	O
pictures	O
shown	O
at	O
the	O
5	O
-	O
minute	O
assessment	O
.	O

Flumazenil	B-Chemical
was	O
well	O
tolerated	O
,	O
with	O
no	O
serious	O
adverse	O
effects	O
reported	O
.	O

Thirty	O
-	O
nine	O
(	O
30	O
%	O
)	O
of	O
flumazenil	B-Chemical
-	O
treated	O
patients	O
,	O
compared	O
with	O
17	O
(	O
25	O
%	O
)	O
of	O
placebo	O
-	O
treated	O
patients	O
had	O
one	O
or	O
more	O
drug	O
-	O
related	O
adverse	O
experiences	O
.	O

The	O
most	O
common	O
adverse	O
effects	O
were	O
nausea	B-Disease
and	O
vomiting	B-Disease
in	O
the	O
flumazenil	B-Chemical
group	O
and	O
nausea	B-Disease
and	O
injection	O
-	O
site	O
pain	B-Disease
in	O
the	O
placebo	O
group	O
.	O

Flumazenil	B-Chemical
was	O
found	O
to	O
promptly	O
reverse	O
sedation	O
induced	O
by	O
diazepam	B-Chemical
in	O
the	O
presence	O
of	O
opioids	O
.	O

Methylphenidate	B-Chemical
-	O
induced	O
obsessive	B-Disease
-	I-Disease
compulsive	I-Disease
symptoms	I-Disease
in	O
an	O
elderly	O
man	O
.	O

An	O
82	O
-	O
year	O
-	O
old	O
man	O
with	O
treatment	B-Disease
-	I-Disease
resistant	I-Disease
depression	I-Disease
and	O
early	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
was	O
started	O
on	O
methylphenidate	B-Chemical
.	O

Significant	O
obsessive	B-Disease
-	I-Disease
compulsive	I-Disease
behavior	I-Disease
ensued	O
but	O
diminished	O
over	O
several	O
weeks	O
when	O
methylphenidate	B-Chemical
was	O
replaced	O
by	O
fluvoxamine	B-Chemical
.	O

The	O
patient	O
had	O
no	O
prior	O
psychiatric	B-Disease
history	O
,	O
but	O
he	O
had	O
a	O
sister	O
with	O
obsessive	B-Disease
-	I-Disease
compulsive	I-Disease
disorder	I-Disease
.	O

It	O
appears	O
that	O
methylphenidate	B-Chemical
precipitated	O
the	O
patient	O
'	O
s	O
pathological	O
behavior	O
.	O

Ciprofloxacin	B-Chemical
-	O
induced	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
and	O
autoimmune	B-Disease
hemolytic	I-Disease
anemia	I-Disease
.	O

Ciprofloxacin	B-Chemical
has	O
been	O
associated	O
with	O
several	O
side	O
effects	O
including	O
interstitial	B-Disease
nephritis	I-Disease
and	O
hemolytic	B-Disease
anemia	I-Disease
.	O

The	O
combination	O
of	O
both	O
side	O
effects	O
is	O
extremely	O
rare	O
.	O

In	O
this	O
report	O
,	O
we	O
describe	O
a	O
case	O
of	O
ciprofloxacin	B-Chemical
-	O
induced	O
interstitial	B-Disease
nephritis	I-Disease
and	O
autoimmune	B-Disease
hemolytic	I-Disease
anemia	I-Disease
.	O

Hemolytic	B-Disease
anemia	I-Disease
improved	O
after	O
stopping	O
the	O
drug	O
and	O
initiation	O
of	O
steroid	B-Chemical
therapy	O
.	O

Unfortunately	O
,	O
acute	O
interstitial	B-Disease
nephritis	I-Disease
was	O
irreversible	O
and	O
the	O
patient	O
developed	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
.	O

Potential	O
deleterious	O
effect	O
of	O
furosemide	B-Chemical
in	O
radiocontrast	O
nephropathy	B-Disease
.	O

The	O
purpose	O
of	O
the	O
study	O
was	O
to	O
determine	O
the	O
efficacy	O
of	O
furosemide	B-Chemical
in	O
addition	O
to	O
intravenous	O
fluids	O
in	O
the	O
prevention	O
of	O
radiocontrast	O
nephropathy	B-Disease
.	O

18	O
patients	O
,	O
referred	O
to	O
a	O
radiocontrast	O
study	O
,	O
considered	O
at	O
risk	O
because	O
of	O
preexisting	O
renal	B-Disease
insufficiency	I-Disease
,	O
were	O
enrolled	O
in	O
a	O
prospective	O
,	O
randomized	O
,	O
controlled	O
trial	O
,	O
performed	O
at	O
the	O
secondary	O
care	O
center	O
of	O
a	O
1	O
,	O
100	O
-	O
bed	O
private	O
university	O
hospital	O
.	O

In	O
addition	O
to	O
fluids	O
,	O
the	O
treatment	O
group	O
received	O
furosemide	B-Chemical
(	O
mean	O
dose	O
110	O
mg	O
)	O
intravenously	O
30	O
min	O
prior	O
to	O
the	O
injection	O
of	O
contrast	O
material	O
.	O

The	O
control	O
group	O
received	O
fluids	O
(	O
mean	O
3	O
liters	O
)	O
.	O

Radiological	O
studies	O
were	O
mostly	O
angiographies	O
performed	O
with	O
both	O
ionic	O
and	O
non	O
-	O
ionic	O
contrast	O
material	O
,	O
at	O
an	O
average	O
dose	O
of	O
245	O
ml	O
.	O

Renal	B-Disease
function	I-Disease
significantly	I-Disease
deteriorated	I-Disease
in	O
the	O
group	O
pretreated	O
with	O
furosemide	B-Chemical
(	O
p	O
<	O
0	O
.	O
005	O
by	O
ANOVA	O
)	O
,	O
with	O
a	O
rise	O
in	O
serum	O
creatinine	B-Chemical
from	O
145	O
+	O
/	O
-	O
13	O
to	O
182	O
+	O
/	O
-	O
16	O
mumol	O
/	O
l	O
at	O
24	O
h	O
,	O
while	O
no	O
change	O
occurred	O
in	O
the	O
control	O
group	O
(	O
from	O
141	O
+	O
/	O
-	O
6	O
to	O
142	O
+	O
/	O
-	O
7	O
mumol	O
/	O
l	O
)	O
.	O

Renal	B-Disease
failure	I-Disease
was	O
associated	O
with	O
weight	B-Disease
loss	I-Disease
in	O
the	O
furosemide	B-Chemical
-	O
treated	O
group	O
.	O

Furosemide	B-Chemical
may	O
be	O
deleterious	O
in	O
the	O
prevention	O
of	O
radiocontrast	O
nephropathy	B-Disease
.	O

Progestational	O
agents	O
and	O
blood	B-Disease
coagulation	I-Disease
.	O

VII	O
.	O

Thromboembolic	B-Disease
and	O
other	O
complications	O
of	O
oral	B-Chemical
contraceptive	I-Chemical
therapy	O
in	O
relationship	O
to	O
pretreatment	O
levels	O
of	O
blood	B-Disease
coagulation	I-Disease
factors	O
:	O
summary	O
report	O
of	O
a	O
ten	O
-	O
year	O
study	O
.	O

During	O
a	O
ten	O
-	O
year	O
period	O
,	O
348	O
women	O
were	O
studied	O
for	O
a	O
total	O
of	O
5	O
,	O
877	O
patient	O
months	O
in	O
four	O
separate	O
studies	O
relating	O
oral	B-Chemical
contraceptives	I-Chemical
to	O
changes	O
in	O
hematologic	O
parameters	O
.	O

Significant	O
increases	O
in	O
certain	O
factors	O
of	O
the	O
blood	B-Disease
coagulation	I-Disease
and	O
fibrinolysin	O
systems	O
(	O
factors	O
I	O
,	O
II	O
,	O
VII	O
,	O
VIII	O
,	O
IX	O
,	O
and	O
X	O
and	O
plasminogen	O
)	O
were	O
observed	O
in	O
the	O
treated	O
groups	O
.	O

Severe	O
complications	O
developed	O
in	O
four	O
patients	O
.	O

All	O
four	O
had	O
an	O
abnormal	O
blood	B-Disease
coagulation	I-Disease
profile	O
,	O
suggesting	O
"	O
hypercoagulability	B-Disease
"	O
before	O
initiation	O
of	O
therapy	O
.	O

Some	O
of	O
these	O
findings	O
represented	O
the	O
most	O
extreme	O
abnormalities	O
seen	O
in	O
the	O
entire	O
group	O
of	O
patients	O
;	O
some	O
increased	O
further	O
during	O
therapy	O
.	O

One	O
of	O
these	O
patients	O
developed	O
a	O
myocardial	B-Disease
infarction	I-Disease
before	O
receiving	O
any	O
medication	O
,	O
shortly	O
after	O
the	O
base	O
-	O
line	O
values	O
were	O
obtained	O
.	O

One	O
patient	O
developed	O
retinopathy	B-Disease
19	O
months	O
after	O
she	O
began	O
therapy	O
,	O
and	O
another	O
developed	O
thrombophlebitis	B-Disease
after	O
27	O
months	O
of	O
therapy	O
.	O

The	O
fourth	O
patient	O
developed	O
thrombophlebitis	B-Disease
14	O
days	O
after	O
initiation	O
of	O
contraceptive	O
therapy	O
.	O

All	O
four	O
patients	O
were	O
of	O
the	O
A	O
or	O
AB	O
blood	O
group	O
.	O

Previous	O
studies	O
suggested	O
the	O
possiblility	O
of	O
increased	O
propensity	O
for	O
thromboembolic	B-Disease
episodes	I-Disease
in	O
patients	O
possessing	O
the	O
A	O
antigen	O
.	O

It	O
appears	O
from	O
these	O
data	O
that	O
hematologic	O
work	O
-	O
ups	O
may	O
be	O
useful	O
in	O
women	O
who	O
are	O
about	O
to	O
start	O
long	O
-	O
term	O
oral	B-Chemical
contraceptive	I-Chemical
therapy	O
.	O

Orthostatic	B-Disease
hypotension	I-Disease
occurs	O
following	O
alpha	O
2	O
-	O
adrenoceptor	O
blockade	O
in	O
chronic	O
prazosin	B-Chemical
-	O
pretreated	O
conscious	O
spontaneously	O
hypertensive	B-Disease
rats	O
.	O

1	O
.	O

Studies	O
were	O
performed	O
to	O
evaluate	O
whether	O
chronic	O
prazosin	B-Chemical
treatment	O
alters	O
the	O
alpha	O
2	O
-	O
adrenoceptor	O
function	O
for	O
orthostatic	O
control	O
of	O
arterial	O
blood	O
pressure	O
in	O
conscious	O
spontaneously	O
hypertensive	B-Disease
rats	O
(	O
SHR	O
)	O
.	O

2	O
.	O

Conscious	O
SHR	O
(	O
male	O
300	O
-	O
350	O
g	O
)	O
were	O
subjected	O
to	O
90	O
degrees	O
head	O
-	O
up	O
tilts	O
for	O
60	O
s	O
following	O
acute	O
administration	O
of	O
prazosin	B-Chemical
(	O
0	O
.	O
1	O
mg	O
kg	O
-	O
1	O
i	O
.	O
p	O
.	O
)	O
or	O
rauwolscine	B-Chemical
(	O
3	O
mg	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
)	O
.	O

Orthostatic	B-Disease
hypotension	I-Disease
was	O
determined	O
by	O
the	O
average	O
decrease	O
(	O
%	O
)	O
in	O
mean	O
arterial	O
pressure	O
(	O
MAP	O
femoral	O
)	O
over	O
the	O
60	O
-	O
s	O
tilt	O
period	O
.	O

The	O
basal	O
MAP	O
of	O
conscious	O
SHR	O
was	O
reduced	O
to	O
a	O
similar	O
extent	O
by	O
prazosin	B-Chemical
(	O
-	O
23	O
%	O
(	O
-	O
)	O
-	O
26	O
%	O
MAP	O
)	O
and	O
rauwolscine	B-Chemical
(	O
-	O
16	O
%	O
(	O
-	O
)	O
-	O
33	O
%	O
MAP	O
)	O
.	O

However	O
,	O
the	O
head	O
-	O
up	O
tilt	O
induced	O
orthostatic	B-Disease
hypotension	I-Disease
in	O
the	O
SHR	O
treated	O
with	O
prazosin	B-Chemical
(	O
-	O
16	O
%	O
MAP	O
,	O
n	O
=	O
6	O
)	O
,	O
but	O
not	O
in	O
the	O
SHR	O
treated	O
with	O
rauwolscine	B-Chemical
(	O
less	O
than	O
+	O
2	O
%	O
MAP	O
,	O
n	O
=	O
6	O
)	O
.	O

3	O
.	O

Conscious	O
SHR	O
were	O
treated	O
for	O
4	O
days	O
with	O
prazosin	B-Chemical
at	O
2	O
mg	O
kg	O
-	O
1	O
day	O
-	O
1	O
i	O
.	O
p	O
.	O
for	O
chronic	O
alpha	O
1	O
-	O
adrenoceptor	O
blockade	O
.	O

MAP	O
in	O
conscious	O
SHR	O
after	O
chronic	O
prazosin	B-Chemical
treatment	O
was	O
14	O
%	O
lower	O
than	O
in	O
the	O
untreated	O
SHR	O
(	O
n	O
=	O
8	O
)	O
.	O

Head	O
-	O
up	O
tilts	O
in	O
these	O
rats	O
did	O
not	O
produce	O
orthostatic	B-Disease
hypotension	I-Disease
when	O
performed	O
either	O
prior	O
to	O
or	O
after	O
acute	O
dosing	O
of	O
prazosin	B-Chemical
(	O
0	O
.	O
1	O
mg	O
kg	O
-	O
1	O
i	O
.	O
p	O
.	O
)	O
.	O

Conversely	O
,	O
administration	O
of	O
rauwolscine	B-Chemical
(	O
3	O
mg	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
)	O
in	O
chronic	O
prazosin	B-Chemical
treated	O
SHR	O
decreased	O
the	O
basal	O
MAP	O
by	O
12	O
-	O
31	O
%	O
(	O
n	O
=	O
4	O
)	O
,	O
and	O
subsequent	O
tilts	O
induced	O
further	O
drops	O
of	O
MAP	O
by	O
19	O
-	O
23	O
%	O
in	O
these	O
rats	O
.	O

4	O
.	O

The	O
pressor	O
responses	O
and	O
bradycardia	B-Disease
to	O
the	O
alpha	O
1	O
-	O
agonist	O
cirazoline	B-Chemical
(	O
0	O
.	O
6	O
and	O
2	O
micrograms	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
)	O
,	O
the	O
alpha	O
2	O
-	O
agonist	O
Abbott	B-Chemical
-	I-Chemical
53693	I-Chemical
(	O
1	O
and	O
3	O
micrograms	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
)	O
,	O
and	O
noradrenaline	B-Chemical
(	O
0	O
.	O
1	O
and	O
1	O
.	O
0	O
micrograms	O
kg	O
-	O
1	O
i	O
.	O
v	O
.	O
)	O
were	O
determined	O
in	O
conscious	O
SHR	O
with	O
and	O
without	O
chronic	O
prazosin	B-Chemical
pretreatment	O
.	O

Both	O
the	O
pressor	O
and	O
bradycardia	B-Disease
effects	O
of	O
cirazoline	B-Chemical
were	O
abolished	O
in	O
chronic	O
prazosin	B-Chemical
treated	O
SHR	O
(	O
n	O
=	O
4	O
)	O
as	O
compared	O
to	O
the	O
untreated	O
SHR	O
(	O
n	O
=	O
4	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
pressor	O
effects	O
of	O
Abbott	B-Chemical
-	I-Chemical
53693	I-Chemical
were	O
similar	O
in	O
both	O
groups	O
of	O
SHR	O
,	O
but	O
the	O
accompanying	O
bradycardia	B-Disease
was	O
greater	O
in	O
SHR	O
with	O
chronic	O
prazosin	B-Chemical
treatment	O
than	O
without	O
such	O
treatment	O
.	O

Furthermore	O
,	O
the	O
bradycardia	B-Disease
that	O
accompanied	O
the	O
noradrenaline	B-Chemical
-	O
induced	O
pressor	O
effect	O
in	O
SHR	O
was	O
similar	O
with	O
and	O
without	O
chronic	O
prazosin	B-Chemical
treatment	O
despite	O
a	O
47	O
-	O
71	O
%	O
reduction	O
of	O
the	O
pressor	O
effect	O
in	O
chronic	O
alpha	O
1	O
-	O
receptor	O
blocked	O
SHR	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
400	O
WORDS	O
)	O

Hemolytic	B-Disease
-	I-Disease
uremic	I-Disease
syndrome	I-Disease
associated	O
with	O
ingestion	O
of	O
quinine	B-Chemical
.	O

Hemolytic	B-Disease
-	I-Disease
uremic	I-Disease
syndrome	I-Disease
following	O
quinine	B-Chemical
ingestion	O
is	O
a	O
newly	O
described	O
phenomenon	O
,	O
with	O
just	O
two	O
previous	O
descriptions	O
of	O
4	O
cases	O
in	O
the	O
literature	O
.	O

We	O
describe	O
a	O
5th	O
case	O
.	O

The	O
reaction	O
may	O
be	O
mediated	O
by	O
the	O
presence	O
of	O
antibodies	O
reactive	O
against	O
platelets	O
in	O
the	O
presence	O
of	O
quinine	B-Chemical
.	O

Treatment	O
has	O
included	O
use	O
of	O
plasma	O
exchange	O
,	O
prednisone	B-Chemical
,	O
aspirin	B-Chemical
,	O
and	O
dipyridamole	B-Chemical
.	O

The	O
patients	O
have	O
all	O
regained	O
some	O
degree	O
of	O
renal	O
function	O
.	O

However	O
,	O
it	O
is	O
unclear	O
whether	O
pharmacological	O
treatment	O
or	O
spontaneous	O
resolution	O
is	O
responsible	O
for	O
the	O
improvement	O
.	O

Quinine	B-Chemical
-	O
associated	O
hemolytic	B-Disease
-	I-Disease
uremic	I-Disease
syndrome	I-Disease
probably	O
occurs	O
more	O
often	O
than	O
is	O
recognized	O
.	O

It	O
is	O
important	O
to	O
recognize	O
this	O
reaction	O
when	O
it	O
occurs	O
and	O
to	O
avoid	O
further	O
quinine	B-Chemical
exposure	O
,	O
since	O
the	O
reaction	O
seems	O
to	O
be	O
recurrent	O
.	O

Amnestic	B-Disease
syndrome	I-Disease
associated	O
with	O
propranolol	B-Chemical
toxicity	B-Disease
:	O
a	O
case	O
report	O
.	O

An	O
elderly	O
woman	O
developed	O
an	O
Alzheimer	B-Disease
-	O
like	O
subacute	O
dementia	B-Disease
as	O
a	O
result	O
of	O
propranolol	B-Chemical
toxicity	B-Disease
.	O

Analysis	O
of	O
the	O
manifestations	O
showed	O
that	O
severe	O
impairment	O
of	O
memory	O
accounted	O
for	O
virtually	O
all	O
of	O
the	O
abnormalities	O
.	O

There	O
is	O
evidence	O
that	O
cerebral	O
reactions	O
to	O
drug	O
toxicity	B-Disease
can	O
exhibit	O
patterns	O
that	O
suggest	O
highly	O
selective	O
involvement	O
of	O
functional	O
subdivisions	O
of	O
the	O
brain	O
.	O

Cefotetan	B-Chemical
-	O
induced	O
immune	O
hemolytic	B-Disease
anemia	I-Disease
.	O

Immune	O
hemolytic	B-Disease
anemia	I-Disease
due	O
to	O
a	O
drug	O
-	O
adsorption	O
mechanism	O
has	O
been	O
described	O
primarily	O
in	O
patients	O
receiving	O
penicillins	B-Chemical
and	O
first	O
-	O
generation	O
cephalosporins	B-Chemical
.	O

We	O
describe	O
a	O
patient	O
who	O
developed	O
anemia	B-Disease
while	O
receiving	O
intravenous	O
cefotetan	B-Chemical
.	O

Cefotetan	B-Chemical
-	O
dependent	O
antibodies	O
were	O
detected	O
in	O
the	O
patient	O
'	O
s	O
serum	O
and	O
in	O
an	O
eluate	O
prepared	O
from	O
his	O
red	O
blood	O
cells	O
.	O

The	O
eluate	O
also	O
reacted	O
weakly	O
with	O
red	O
blood	O
cells	O
in	O
the	O
absence	O
of	O
cefotetan	B-Chemical
,	O
suggesting	O
the	O
concomitant	O
formation	O
of	O
warm	O
-	O
reactive	O
autoantibodies	O
.	O

These	O
observations	O
,	O
in	O
conjunction	O
with	O
clinical	O
and	O
laboratory	O
evidence	O
of	O
extravascular	O
hemolysis	B-Disease
,	O
are	O
consistent	O
with	O
drug	O
-	O
induced	O
hemolytic	B-Disease
anemia	I-Disease
,	O
possibly	O
involving	O
both	O
drug	O
-	O
adsorption	O
and	O
autoantibody	O
formation	O
mechanisms	O
.	O

This	O
case	O
emphasizes	O
the	O
need	O
for	O
increased	O
awareness	O
of	O
hemolytic	O
reactions	O
to	O
all	O
cephalosporins	B-Chemical
.	O

Use	O
of	O
dexamethasone	B-Chemical
with	O
mesna	B-Chemical
for	O
the	O
prevention	O
of	O
ifosfamide	B-Chemical
-	O
induced	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

AIM	O
:	O
Hemorrhagic	B-Disease
cystitis	I-Disease
(	O
HC	B-Disease
)	O
is	O
a	O
limiting	O
side	O
-	O
effect	O
of	O
chemotherapy	O
with	O
ifosfamide	B-Chemical
(	O
IFS	B-Chemical
)	O
.	O

In	O
the	O
study	O
presented	O
here	O
,	O
we	O
investigated	O
the	O
use	O
of	O
dexamethasone	B-Chemical
in	O
combination	O
with	O
mesna	B-Chemical
for	O
the	O
prevention	O
of	O
IFS	B-Chemical
-	O
induced	O
HC	B-Disease
.	O

METHODS	O
:	O
Male	O
Wistar	O
rats	O
(	O
150	O
-	O
200	O
g	O
;	O
6	O
rats	O
per	O
group	O
)	O
were	O
treated	O
with	O
saline	O
or	O
mesna	B-Chemical
5	O
min	O
(	O
i	O
.	O
p	O
.	O
)	O
before	O
and	O
2	O
and	O
6	O
h	O
after	O
(	O
v	O
.	O
o	O
.	O
)	O
administration	O
of	O
IFS	B-Chemical
.	O

One	O
,	O
two	O
or	O
three	O
doses	O
of	O
mesna	B-Chemical
were	O
replaced	O
with	O
dexamethasone	B-Chemical
alone	O
or	O
with	O
dexamethasone	B-Chemical
plus	O
mesna	B-Chemical
.	O

Cystitis	B-Disease
was	O
evaluated	O
24	O
h	O
after	O
its	O
induction	O
by	O
the	O
changes	O
in	O
bladder	O
wet	O
weight	O
and	O
by	O
macroscopic	O
and	O
microscopic	O
analysis	O
.	O

RESULTS	O
:	O
The	O
replacement	O
of	O
the	O
last	O
dose	O
or	O
the	O
last	O
two	O
doses	O
of	O
mesna	B-Chemical
with	O
dexamethasone	B-Chemical
reduced	O
the	O
increase	O
in	O
bladder	O
wet	O
weight	O
induced	O
by	O
IFS	B-Chemical
by	O
84	O
.	O
79	O
%	O
and	O
89	O
.	O
13	O
%	O
,	O
respectively	O
.	O

In	O
addition	O
,	O
it	O
almost	O
abolished	O
the	O
macroscopic	O
and	O
microscopic	O
alterations	O
induced	O
by	O
IFS	B-Chemical
.	O

Moreover	O
,	O
the	O
addition	O
of	O
dexamethasone	B-Chemical
to	O
the	O
last	O
two	O
doses	O
of	O
mesna	B-Chemical
was	O
more	O
efficient	O
than	O
three	O
doses	O
of	O
mesna	B-Chemical
alone	O
when	O
evaluated	O
microscopically	O
.	O

CONCLUSION	O
:	O
Dexamethasone	B-Chemical
in	O
combination	O
with	O
mesna	B-Chemical
was	O
efficient	O
in	O
blocking	O
IFS	B-Chemical
-	O
induced	O
HC	B-Disease
.	O

However	O
,	O
the	O
replacement	O
of	O
last	O
two	O
doses	O
of	O
mesna	B-Chemical
with	O
saline	O
or	O
all	O
of	O
the	O
mesna	B-Chemical
doses	O
with	O
dexamethasone	B-Chemical
did	O
not	O
prevent	O
HC	B-Disease
.	O

All	B-Chemical
-	I-Chemical
trans	I-Chemical
-	I-Chemical
retinoic	I-Chemical
acid	I-Chemical
-	O
induced	O
erythema	B-Disease
nodosum	I-Disease
in	O
patients	O
with	O
acute	B-Disease
promyelocytic	I-Disease
leukemia	I-Disease
.	O

Erythema	B-Disease
nodosum	I-Disease
associated	O
with	O
all	B-Chemical
-	I-Chemical
trans	I-Chemical
-	I-Chemical
retinoic	I-Chemical
acid	I-Chemical
(	O
ATRA	B-Chemical
)	O
for	O
acute	B-Disease
promyelocytic	I-Disease
leukemia	I-Disease
(	O
APL	B-Disease
)	O
is	O
very	O
rare	O
.	O

We	O
describe	O
four	O
patients	O
with	O
classic	O
APL	B-Disease
who	O
developed	O
erythema	B-Disease
nodosum	I-Disease
during	O
ATRA	B-Chemical
therapy	O
.	O

Fever	B-Disease
and	O
subsequent	O
multiple	O
painful	B-Disease
erythematous	B-Disease
nodules	I-Disease
over	O
extremities	O
developed	O
on	O
D11	O
,	O
D16	O
,	O
D17	O
,	O
and	O
D19	O
,	O
respectively	O
,	O
after	O
ATRA	B-Chemical
therapy	O
.	O

The	O
skin	O
biopsy	O
taken	O
from	O
each	O
patient	O
was	O
consistent	O
with	O
erythema	B-Disease
nodosum	I-Disease
.	O

All	O
patients	O
received	O
short	O
course	O
of	O
steroids	B-Chemical
.	O

Fever	B-Disease
subsided	O
rapidly	O
and	O
the	O
skin	O
lesions	O
regressed	O
completely	O
.	O

All	O
patients	O
achieved	O
complete	O
remission	O
without	O
withdrawal	O
of	O
ATRA	B-Chemical
.	O

ATRA	B-Chemical
seemed	O
to	O
be	O
the	O
most	O
possible	O
etiology	O
of	O
erythema	B-Disease
nodosum	I-Disease
in	O
our	O
patients	O
.	O

Short	O
-	O
term	O
use	O
of	O
steroid	B-Chemical
is	O
very	O
effective	O
in	O
ATRA	B-Chemical
-	O
induced	O
erythema	B-Disease
nodosum	I-Disease
.	O

Effect	O
of	O
some	O
convulsants	O
on	O
the	O
protective	O
activity	O
of	O
loreclezole	B-Chemical
and	O
its	O
combinations	O
with	O
valproate	B-Chemical
or	O
clonazepam	B-Chemical
in	O
amygdala	O
-	O
kindled	O
rats	O
.	O

Loreclezole	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
)	O
exerted	O
a	O
significant	O
protective	O
action	O
in	O
amygdala	O
-	O
kindled	O
rats	O
,	O
reducing	O
both	O
seizure	B-Disease
and	O
afterdischarge	O
durations	O
.	O

The	O
combinations	O
of	O
loreclezole	B-Chemical
(	O
2	O
.	O
5	O
mg	O
/	O
kg	O
)	O
with	O
valproate	B-Chemical
,	O
clonazepam	B-Chemical
,	O
or	O
carbamazepine	B-Chemical
(	O
applied	O
at	O
their	O
subprotective	O
doses	O
)	O
also	O
exhibited	O
antiseizure	O
effect	O
in	O
this	O
test	O
.	O

However	O
,	O
only	O
two	O
first	O
combinations	O
occurred	O
to	O
be	O
of	O
pharmacodynamic	O
nature	O
.	O

Among	O
several	O
chemoconvulsants	O
,	O
bicuculline	B-Chemical
,	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartic	I-Chemical
acid	I-Chemical
and	O
BAY	B-Chemical
k	I-Chemical
-	I-Chemical
8644	I-Chemical
(	O
the	O
opener	O
of	O
L	O
-	O
type	O
calcium	B-Chemical
channels	O
)	O
reversed	O
the	O
protective	O
activity	O
of	O
loreclezole	B-Chemical
alone	O
and	O
its	O
combination	O
with	O
valproate	B-Chemical
.	O

On	O
the	O
other	O
hand	O
,	O
bicuculline	B-Chemical
,	O
aminophylline	B-Chemical
and	O
BAY	B-Chemical
k	I-Chemical
-	I-Chemical
8644	I-Chemical
inhibited	O
the	O
anticonvulsive	O
action	O
of	O
loreclezole	B-Chemical
combined	O
with	O
clonazepam	B-Chemical
.	O

The	O
results	O
support	O
the	O
hypothesis	O
that	O
the	O
protective	O
activity	O
of	O
loreclezole	B-Chemical
and	O
its	O
combinations	O
with	O
other	O
antiepileptics	O
may	O
involve	O
potentiation	O
of	O
GABAergic	O
neurotransmission	O
and	O
blockade	O
of	O
L	O
-	O
type	O
of	O
calcium	B-Chemical
channels	O
.	O

Mitochondrial	O
DNA	O
and	O
its	O
respiratory	O
chain	O
products	O
are	O
defective	O
in	O
doxorubicin	B-Chemical
nephrosis	B-Disease
.	O

BACKGROUND	O
:	O
Doxorubicin	B-Chemical
induces	O
a	O
self	O
-	O
perpetuating	O
nephropathy	B-Disease
characterized	O
by	O
early	O
glomerular	B-Disease
and	I-Disease
late	I-Disease
-	I-Disease
onset	I-Disease
tubular	I-Disease
lesions	I-Disease
in	O
rats	O
.	O

We	O
investigated	O
the	O
potential	O
role	O
of	O
mitochondrial	B-Disease
injury	I-Disease
in	O
the	O
onset	O
of	O
these	O
lesions	O
.	O

METHODS	O
:	O
Rats	O
were	O
treated	O
with	O
intravenous	O
doxorubicin	B-Chemical
(	O
1	O
mg	O
kg	O
(	O
-	O
1	O
)	O
week	O
(	O
-	O
1	O
)	O
)	O
for	O
7	O
weeks	O
and	O
were	O
sacrificed	O
either	O
1	O
week	O
(	O
'	O
short	O
-	O
term	O
'	O
)	O
or	O
30	O
weeks	O
(	O
'	O
long	O
-	O
term	O
'	O
)	O
following	O
the	O
last	O
dose	O
.	O

Additional	O
rats	O
received	O
a	O
single	O
dose	O
either	O
6	O
days	O
or	O
2	O
h	O
prior	O
to	O
euthanasia	O
.	O

All	O
rats	O
were	O
killed	O
at	O
48	O
weeks	O
of	O
age	O
.	O

Glomerular	B-Disease
and	I-Disease
tubular	I-Disease
injury	I-Disease
was	O
monitored	O
and	O
correlated	O
to	O
the	O
activity	O
or	O
expression	O
of	O
respiratory	O
chain	O
components	O
.	O

Finally	O
,	O
we	O
quantified	O
both	O
nuclear	O
and	O
mitochondrial	O
DNA	O
(	O
mtDNA	O
)	O
as	O
well	O
as	O
superoxide	B-Chemical
production	O
and	O
the	O
4834	O
base	O
pair	O
'	O
common	O
'	O
mtDNA	O
deletion	O
.	O

RESULTS	O
:	O
The	O
'	O
long	O
-	O
term	O
'	O
group	O
had	O
significant	O
glomerular	B-Disease
and	I-Disease
tubular	I-Disease
lesions	I-Disease
,	O
depressed	O
activities	O
of	O
mtDNA	O
-	O
encoded	O
NADH	O
dehydrogenase	O
and	O
cytochrome	O
-	O
c	O
oxidase	O
(	O
COX	O
)	O
and	O
increased	O
citrate	B-Chemical
synthase	O
activity	O
.	O

In	O
addition	O
,	O
expression	O
of	O
the	O
mtDNA	O
-	O
encoded	O
COX	O
subunit	O
I	O
was	O
reduced	O
and	O
mtDNA	O
levels	O
were	O
decreased	O
.	O

In	O
'	O
short	O
-	O
term	O
'	O
rats	O
,	O
there	O
were	O
fewer	O
tubular	B-Disease
lesions	I-Disease
,	O
but	O
similar	O
numbers	O
of	O
glomerular	B-Disease
lesions	I-Disease
activity	O
.	O

Among	O
all	O
animals	O
,	O
glomerular	B-Disease
and	I-Disease
tubular	I-Disease
injury	I-Disease
were	O
inversely	O
correlated	O
with	O
mtDNA	O
levels	O
,	O
mtDNA	O
-	O
encoded	O
respiratory	O
chain	O
activities	O
and	O
with	O
the	O
expression	O
of	O
the	O
mtDNA	O
-	O
encoded	O
respiratory	O
chain	O
subunit	O
COX	O
-	O
I	O
.	O

Injury	O
was	O
positively	O
correlated	O
with	O
superoxide	B-Chemical
production	O
and	O
the	O
activities	O
of	O
nucleus	O
-	O
encoded	O
mitochondrial	O
or	O
cytoplasmic	O
enzymes	O
.	O

Kidneys	O
from	O
the	O
'	O
long	O
-	O
term	O
'	O
group	O
showed	O
more	O
mtDNA	O
deletions	O
than	O
in	O
'	O
short	O
-	O
term	O
'	O
animals	O
and	O
these	O
were	O
not	O
observed	O
in	O
the	O
other	O
groups	O
.	O

CONCLUSIONS	O
:	O
These	O
results	O
suggest	O
an	O
important	O
role	O
for	O
quantitative	O
and	O
qualitative	O
mtDNA	O
alterations	O
through	O
the	O
reduction	O
of	O
mtDNA	O
-	O
encoded	O
respiratory	O
chain	O
function	O
and	O
induction	O
of	O
superoxide	B-Chemical
in	O
doxorubicin	B-Chemical
-	O
induced	O
renal	B-Disease
lesions	I-Disease
.	O

A	O
randomized	O
,	O
placebo	O
-	O
controlled	O
,	O
crossover	O
study	O
of	O
ephedrine	B-Chemical
for	O
SSRI	O
-	O
induced	O
female	O
sexual	B-Disease
dysfunction	I-Disease
.	O

The	O
objective	O
of	O
this	O
study	O
was	O
to	O
determine	O
whether	O
ephedrine	B-Chemical
,	O
an	O
alpha	O
-	O
and	O
beta	O
-	O
adrenergic	O
agonist	O
previously	O
shown	O
to	O
enhance	O
genital	O
blood	O
flow	O
in	O
women	O
,	O
has	O
beneficial	O
effects	O
in	O
reversing	O
antidepressant	O
-	O
induced	O
sexual	B-Disease
dysfunction	I-Disease
.	O

Nineteen	O
sexually	B-Disease
dysfunctional	I-Disease
women	O
receiving	O
either	O
fluoxetine	B-Chemical
,	O
sertraline	B-Chemical
,	O
or	O
paroxetine	B-Chemical
participated	O
in	O
an	O
eight	O
-	O
week	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
,	O
cross	O
-	O
over	O
study	O
of	O
the	O
effects	O
of	O
ephedrine	B-Chemical
(	O
50	O
mg	O
)	O
on	O
self	O
-	O
report	O
measures	O
of	O
sexual	O
desire	O
,	O
arousal	O
,	O
orgasm	O
,	O
and	O
sexual	O
satisfaction	O
.	O

Although	O
there	O
were	O
significant	O
improvements	O
relative	O
to	O
baseline	O
in	O
sexual	O
desire	O
and	O
orgasm	O
intensity	O
/	O
pleasure	O
on	O
50	O
mg	O
ephedrine	B-Chemical
1	O
-	O
hr	O
prior	O
to	O
sexual	O
activity	O
,	O
significant	O
improvements	O
in	O
these	O
measures	O
,	O
as	O
well	O
as	O
in	O
sexual	O
arousal	O
and	O
orgasmic	O
ability	O
also	O
were	O
noted	O
with	O
placebo	O
.	O

These	O
findings	O
highlight	O
the	O
importance	O
of	O
conducting	O
placebo	O
-	O
controlled	O
trials	O
for	O
this	O
condition	O
.	O

Does	O
hormone	O
therapy	O
for	O
the	O
treatment	O
of	O
breast	B-Disease
cancer	I-Disease
have	O
a	O
detrimental	B-Disease
effect	I-Disease
on	I-Disease
memory	I-Disease
and	I-Disease
cognition	I-Disease
?	O

A	O
pilot	O
study	O
.	O

This	O
pilot	O
study	O
examines	O
whether	O
hormone	O
therapy	O
for	O
breast	B-Disease
cancer	I-Disease
affects	O
cognition	O
.	O

Patients	O
participating	O
in	O
a	O
randomised	O
trial	O
of	O
anastrozole	B-Chemical
,	O
tamoxifen	B-Chemical
alone	O
or	O
combined	O
(	O
ATAC	O
)	O
(	O
n	O
=	O
94	O
)	O
and	O
a	O
group	O
of	O
women	O
without	O
breast	B-Disease
cancer	I-Disease
(	O
n	O
=	O
35	O
)	O
completed	O
a	O
battery	O
of	O
neuropsychological	O
measures	O
.	O

Compared	O
with	O
the	O
control	O
group	O
,	O
the	O
patients	O
were	O
impaired	O
on	O
a	O
processing	O
speed	O
task	O
(	O
p	O
=	O
0	O
.	O
032	O
)	O
and	O
on	O
a	O
measure	O
of	O
immediate	O
verbal	O
memory	O
(	O
p	O
=	O
0	O
.	O
026	O
)	O
after	O
controlling	O
for	O
the	O
use	O
of	O
hormone	O
replacement	O
therapy	O
in	O
both	O
groups	O
.	O

Patient	O
group	O
performance	O
was	O
not	O
significantly	O
related	O
to	O
length	O
of	O
treatment	O
or	O
measures	O
of	O
psychological	O
morbidity	O
.	O

The	O
results	O
showed	O
specific	O
impairments	O
in	O
processing	O
speed	O
and	O
verbal	O
memory	O
in	O
women	O
receiving	O
hormonal	O
therapy	O
for	O
the	O
treatment	O
of	O
breast	B-Disease
cancer	I-Disease
.	O

Verbal	O
memory	O
may	O
be	O
especially	O
sensitive	O
to	O
changes	O
in	O
oestrogen	B-Chemical
levels	O
,	O
a	O
finding	O
commonly	O
reported	O
in	O
studies	O
of	O
hormone	O
replacement	O
therapy	O
in	O
healthy	O
women	O
.	O

In	O
view	O
of	O
the	O
increased	O
use	O
of	O
hormone	O
therapies	O
in	O
an	O
adjuvant	O
and	O
preventative	O
setting	O
their	O
impact	O
on	O
cognitive	O
functioning	O
should	O
be	O
investigated	O
more	O
thoroughly	O
.	O

Expression	O
of	O
p300	O
protects	O
cardiac	O
myocytes	O
from	O
apoptosis	O
in	O
vivo	O
.	O

Doxorubicin	B-Chemical
is	O
an	O
anti	O
-	O
tumor	B-Disease
agent	O
that	O
represses	O
cardiac	O
-	O
specific	O
gene	O
expression	O
and	O
induces	O
myocardial	O
cell	O
apoptosis	O
.	O

Doxorubicin	B-Chemical
depletes	O
cardiac	O
p300	O
,	O
a	O
transcriptional	O
coactivator	O
that	O
is	O
required	O
for	O
the	O
maintenance	O
of	O
the	O
differentiated	O
phenotype	O
of	O
cardiac	O
myocytes	O
.	O

However	O
,	O
the	O
role	O
of	O
p300	O
in	O
protection	O
against	O
doxorubicin	B-Chemical
-	O
induced	O
apoptosis	O
is	O
unknown	O
.	O

Transgenic	O
mice	O
overexpressing	O
p300	O
in	O
the	O
heart	O
and	O
wild	O
-	O
type	O
mice	O
were	O
subjected	O
to	O
doxorubicin	B-Chemical
treatment	O
.	O

Compared	O
with	O
wild	O
-	O
type	O
mice	O
,	O
transgenic	O
mice	O
exhibited	O
higher	O
survival	O
rate	O
as	O
well	O
as	O
more	O
preserved	O
left	O
ventricular	O
function	O
and	O
cardiac	O
expression	O
of	O
alpha	O
-	O
sarcomeric	O
actin	O
.	O

Doxorubicin	B-Chemical
induced	O
myocardial	O
cell	O
apoptosis	O
in	O
wild	O
-	O
type	O
mice	O
but	O
not	O
in	O
transgenic	O
mice	O
.	O

Expression	O
of	O
p300	O
increased	O
the	O
cardiac	O
level	O
of	O
bcl	O
-	O
2	O
and	O
mdm	O
-	O
2	O
,	O
but	O
not	O
that	O
of	O
p53	O
or	O
other	O
members	O
of	O
the	O
bcl	O
-	O
2	O
family	O
.	O

These	O
findings	O
demonstrate	O
that	O
overexpression	O
of	O
p300	O
protects	O
cardiac	O
myocytes	O
from	O
doxorubicin	B-Chemical
-	O
induced	O
apoptosis	O
and	O
reduces	O
the	O
extent	O
of	O
acute	O
heart	B-Disease
failure	I-Disease
in	O
adult	O
mice	O
in	O
vivo	O
.	O

Methimazole	B-Chemical
-	O
induced	O
cholestatic	B-Disease
jaundice	I-Disease
.	O

Methimazole	B-Chemical
is	O
a	O
widely	O
used	O
and	O
generally	O
well	O
-	O
tolerated	O
antithyroid	O
agent	O
.	O

A	O
43	O
-	O
year	O
-	O
old	O
woman	O
had	O
severe	O
jaundice	B-Disease
and	O
itching	B-Disease
1	O
month	O
after	O
receiving	O
methimazole	B-Chemical
(	O
10	O
mg	O
tid	O
)	O
and	O
propranolol	B-Chemical
(	O
20	O
mg	O
tid	O
)	O
for	O
treatment	O
of	O
hyperthyroidism	B-Disease
.	O

The	O
patient	O
continued	O
treatment	O
for	O
another	O
4	O
days	O
after	O
the	O
appearance	O
of	O
jaundice	B-Disease
until	O
she	O
finished	O
both	O
medications	O
.	O

When	O
seen	O
at	O
the	O
emergency	O
department	O
2	O
weeks	O
later	O
,	O
she	O
still	O
had	O
severe	O
icterus	B-Disease
,	O
pruritus	B-Disease
,	O
and	O
hyperbilirubinemia	B-Disease
,	O
formed	O
mainly	O
of	O
the	O
conjugated	O
fraction	O
.	O

Methimazole	B-Chemical
-	O
induced	O
cholestasis	B-Disease
was	O
diagnosed	O
,	O
and	O
propranolol	B-Chemical
therapy	O
was	O
resumed	O
.	O

Over	O
the	O
following	O
9	O
days	O
,	O
the	O
symptoms	O
improved	O
and	O
plasma	O
bilirubin	B-Chemical
levels	O
were	O
normal	O
after	O
12	O
weeks	O
without	O
methimazole	B-Chemical
.	O

In	O
rare	O
cases	O
within	O
the	O
first	O
few	O
weeks	O
of	O
therapy	O
,	O
this	O
drug	O
can	O
cause	O
severe	O
and	O
reversible	O
cholestatic	B-Disease
jaundice	I-Disease
.	O

Physicians	O
and	O
patients	O
should	O
be	O
aware	O
of	O
this	O
adverse	O
effect	O
so	O
that	O
,	O
upon	O
occurrence	O
,	O
they	O
can	O
discontinue	O
methimazole	B-Chemical
therapy	O
and	O
avoid	O
unnecessary	O
invasive	O
procedures	O
.	O

Atrial	B-Disease
fibrillation	I-Disease
following	O
chemotherapy	O
for	O
stage	O
IIIE	O
diffuse	O
large	O
B	O
-	O
cell	O
gastric	B-Disease
lymphoma	I-Disease
in	O
a	O
patient	O
with	O
myotonic	B-Disease
dystrophy	I-Disease
(	O
Steinert	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
)	O
.	O

The	O
authors	O
describe	O
the	O
unusual	O
association	O
between	O
diffuse	O
B	O
-	O
cell	O
gastric	B-Disease
lymphoma	I-Disease
and	O
myotonic	B-Disease
dystrophy	I-Disease
,	O
the	O
most	O
common	O
form	O
of	O
adult	O
muscular	B-Disease
dystrophy	I-Disease
,	O
and	O
sudden	O
atrial	B-Disease
fibrillation	I-Disease
following	O
one	O
cycle	O
of	O
doxorubicin	B-Chemical
-	O
based	O
chemotherapy	O
in	O
the	O
same	O
patient	O
.	O

Atrial	B-Disease
fibrillation	I-Disease
or	O
other	O
cardiac	B-Disease
arrhythmias	I-Disease
are	O
unusual	O
complications	O
in	O
patients	O
treated	O
with	O
chemotherapy	O
.	O

The	O
cardiac	B-Disease
toxicity	I-Disease
intrinsically	O
associated	O
with	O
the	O
aggressive	O
chemotherapy	O
employed	O
could	O
function	O
as	O
a	O
triggering	O
factor	O
for	O
the	O
arrhythmia	B-Disease
in	O
the	O
predisposed	O
myocardium	O
of	O
this	O
patient	O
.	O

Hypersensitivity	B-Disease
immune	O
reaction	O
as	O
a	O
mechanism	O
for	O
dilevalol	B-Chemical
-	O
associated	O
hepatitis	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
assess	O
lymphocyte	O
reactivity	O
to	O
dilevalol	B-Chemical
and	O
to	O
serum	O
containing	O
putative	O
ex	O
vivo	O
dilevalol	B-Chemical
antigens	O
or	O
metabolites	O
in	O
a	O
case	O
of	O
dilevalol	B-Chemical
-	O
induced	O
liver	B-Disease
injury	I-Disease
.	O

PATIENT	O
:	O
A	O
58	O
-	O
year	O
-	O
old	O
woman	O
with	O
a	O
clinical	O
diagnosis	O
of	O
dilevalol	B-Chemical
-	O
induced	O
liver	B-Disease
injury	I-Disease
.	O

METHODS	O
:	O
Peripheral	O
blood	O
mononuclear	O
cells	O
collected	O
from	O
the	O
patient	O
were	O
cultured	O
in	O
the	O
presence	O
of	O
a	O
solution	O
of	O
dilevalol	B-Chemical
and	O
also	O
with	O
sera	O
collected	O
from	O
a	O
volunteer	O
before	O
and	O
after	O
dilevalol	B-Chemical
intake	O
.	O

A	O
similar	O
protocol	O
was	O
performed	O
with	O
lymphocytes	O
from	O
a	O
healthy	O
subject	O
.	O

RESULTS	O
:	O
No	O
lymphocyte	O
proliferation	O
was	O
observed	O
either	O
in	O
the	O
patient	O
or	O
in	O
the	O
healthy	O
volunteer	O
in	O
the	O
presence	O
of	O
dilevalol	B-Chemical
solutions	O
.	O

A	O
significant	O
proliferative	O
response	O
to	O
serum	O
collected	O
after	O
dilevalol	B-Chemical
intake	O
was	O
observed	O
in	O
the	O
case	O
of	O
the	O
patient	O
compared	O
with	O
the	O
proliferative	O
response	O
to	O
the	O
serum	O
collected	O
before	O
the	O
drug	O
intake	O
.	O

No	O
reactivity	O
was	O
found	O
when	O
lymphocytes	O
from	O
the	O
healthy	O
subject	O
were	O
tested	O
under	O
similar	O
conditions	O
.	O

CONCLUSIONS	O
:	O
The	O
methodology	O
used	O
allowed	O
the	O
detection	O
of	O
lymphocyte	O
sensitization	O
to	O
sera	O
containing	O
ex	O
vivo	O
-	O
prepared	O
dilevalol	B-Chemical
antigens	O
,	O
suggesting	O
the	O
involvement	O
of	O
an	O
immunologic	O
mechanism	O
in	O
dilevalol	B-Chemical
-	O
induced	O
liver	B-Disease
injury	I-Disease
.	O

Increased	O
expression	O
and	O
apical	O
targeting	O
of	O
renal	O
ENaC	O
subunits	O
in	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
nephrotic	B-Disease
syndrome	I-Disease
in	O
rats	O
.	O

Nephrotic	B-Disease
syndrome	I-Disease
is	O
often	O
accompanied	O
by	O
sodium	B-Chemical
retention	O
and	O
generalized	O
edema	B-Disease
.	O

However	O
,	O
the	O
molecular	O
basis	O
for	O
the	O
decreased	O
renal	O
sodium	B-Chemical
excretion	O
remains	O
undefined	O
.	O

We	O
hypothesized	O
that	O
epithelial	O
Na	B-Chemical
channel	O
(	O
ENaC	O
)	O
subunit	O
dysregulation	O
may	O
be	O
responsible	O
for	O
the	O
increased	O
sodium	B-Chemical
retention	O
.	O

An	O
experimental	O
group	O
of	O
rats	O
was	O
treated	O
with	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
;	O
180	O
mg	O
/	O
kg	O
iv	O
)	O
,	O
whereas	O
the	O
control	O
group	O
received	O
only	O
vehicle	O
.	O

After	O
7	O
days	O
,	O
PAN	B-Chemical
treatment	O
induced	O
significant	O
proteinuria	B-Disease
,	O
hypoalbuminemia	B-Disease
,	O
decreased	O
urinary	O
sodium	B-Chemical
excretion	O
,	O
and	O
extensive	O
ascites	B-Disease
.	O

The	O
protein	O
abundance	O
of	O
alpha	O
-	O
ENaC	O
and	O
beta	O
-	O
ENaC	O
was	O
increased	O
in	O
the	O
inner	O
stripe	O
of	O
the	O
outer	O
medulla	O
(	O
ISOM	O
)	O
and	O
in	O
the	O
inner	O
medulla	O
(	O
IM	O
)	O
but	O
was	O
not	O
altered	O
in	O
the	O
cortex	O
.	O

gamma	O
-	O
ENaC	O
abundance	O
was	O
increased	O
in	O
the	O
cortex	O
,	O
ISOM	O
,	O
and	O
IM	O
.	O

Immunoperoxidase	O
brightfield	O
-	O
and	O
laser	O
-	O
scanning	O
confocal	O
fluorescence	O
microscopy	O
demonstrated	O
increased	O
targeting	O
of	O
alpha	O
-	O
ENaC	O
,	O
beta	O
-	O
ENaC	O
,	O
and	O
gamma	O
-	O
ENaC	O
subunits	O
to	O
the	O
apical	O
plasma	O
membrane	O
in	O
the	O
distal	O
convoluted	O
tubule	O
(	O
DCT2	O
)	O
,	O
connecting	O
tubule	O
,	O
and	O
cortical	O
and	O
medullary	O
collecting	O
duct	O
segments	O
.	O

Immunoelectron	O
microscopy	O
further	O
revealed	O
an	O
increased	O
labeling	O
of	O
alpha	O
-	O
ENaC	O
in	O
the	O
apical	O
plasma	O
membrane	O
of	O
cortical	O
collecting	O
duct	O
principal	O
cells	O
of	O
PAN	B-Chemical
-	O
treated	O
rats	O
,	O
indicating	O
enhanced	O
apical	O
targeting	O
of	O
alpha	O
-	O
ENaC	O
subunits	O
.	O

In	O
contrast	O
,	O
the	O
protein	O
abundances	O
of	O
Na	B-Chemical
(	O
+	O
)	O
/	O
H	B-Chemical
(	O
+	O
)	O
exchanger	O
type	O
3	O
(	O
NHE3	O
)	O
,	O
Na	B-Chemical
(	O
+	O
)	O
-	O
K	B-Chemical
(	O
+	O
)	O
-	O
2Cl	B-Chemical
(	O
-	O
)	O
cotransporter	O
(	O
BSC	O
-	O
1	O
)	O
,	O
and	O
thiazide	B-Chemical
-	O
sensitive	O
Na	B-Chemical
(	O
+	O
)	O
-	O
Cl	B-Chemical
(	O
-	O
)	O
cotransporter	O
(	O
TSC	O
)	O
were	O
decreased	O
.	O

Moreover	O
,	O
the	O
abundance	O
of	O
the	O
alpha	O
(	O
1	O
)	O
-	O
subunit	O
of	O
the	O
Na	B-Chemical
-	O
K	B-Chemical
-	O
ATPase	O
was	O
decreased	O
in	O
the	O
cortex	O
and	O
ISOM	O
,	O
but	O
it	O
remained	O
unchanged	O
in	O
the	O
IM	O
.	O

In	O
conclusion	O
,	O
the	O
increased	O
or	O
sustained	O
expression	O
of	O
ENaC	O
subunits	O
combined	O
with	O
increased	O
apical	O
targeting	O
in	O
the	O
DCT2	O
,	O
connecting	O
tubule	O
,	O
and	O
collecting	O
duct	O
are	O
likely	O
to	O
play	O
a	O
role	O
in	O
the	O
sodium	B-Chemical
retention	O
associated	O
with	O
PAN	B-Chemical
-	O
induced	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

The	O
decreased	O
abundance	O
of	O
NHE3	O
,	O
BSC	O
-	O
1	O
,	O
TSC	O
,	O
and	O
Na	B-Chemical
-	O
K	B-Chemical
-	O
ATPase	O
may	O
play	O
a	O
compensatory	O
role	O
to	O
promote	O
sodium	B-Chemical
excretion	O
.	O

Pallidal	O
stimulation	O
:	O
an	O
alternative	O
to	O
pallidotomy	O
?	O

A	O
resurgence	O
of	O
interest	O
in	O
the	O
surgical	O
treatment	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
came	O
with	O
the	O
rediscovery	O
of	O
posteroventral	O
pallidotomy	O
by	O
Laitinen	O
in	O
1985	O
.	O

Laitinen	O
'	O
s	O
procedure	O
improved	O
most	O
symptoms	O
in	O
drug	O
-	O
resistant	O
PD	B-Disease
,	O
which	O
engendered	O
wide	O
interest	O
in	O
the	O
neurosurgical	O
community	O
.	O

Another	O
lesioning	O
procedure	O
,	O
ventrolateral	O
thalamotomy	O
,	O
has	O
become	O
a	O
powerful	O
alternative	O
to	O
stimulate	O
the	O
nucleus	O
ventralis	O
intermedius	O
,	O
producing	O
high	O
long	O
-	O
term	O
success	O
rates	O
and	O
low	O
morbidity	O
rates	O
.	O

Pallidal	O
stimulation	O
has	O
not	O
met	O
with	O
the	O
same	O
success	O
.	O

According	O
to	O
the	O
literature	O
pallidotomy	O
improves	O
the	O
"	O
on	O
"	O
symptoms	O
of	O
PD	B-Disease
,	O
such	O
as	O
dyskinesias	B-Disease
,	O
as	O
well	O
as	O
the	O
"	O
off	O
"	O
symptoms	O
,	O
such	O
as	O
rigidity	B-Disease
,	O
bradykinesia	B-Disease
,	O
and	O
on	O
-	O
off	O
fluctuations	O
.	O

Pallidal	O
stimulation	O
improves	O
bradykinesia	B-Disease
and	O
rigidity	B-Disease
to	O
a	O
minor	O
extent	O
;	O
however	O
,	O
its	O
strength	O
seems	O
to	O
be	O
in	O
improving	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
.	O

Stimulation	O
often	O
produces	O
an	O
improvement	O
in	O
the	O
hyper	B-Disease
-	I-Disease
or	I-Disease
dyskinetic	I-Disease
upper	O
limbs	O
,	O
but	O
increases	O
the	O
"	O
freezing	O
"	O
phenomenon	O
in	O
the	O
lower	O
limbs	O
at	O
the	O
same	O
time	O
.	O

Considering	O
the	O
small	O
increase	O
in	O
the	O
patient	O
'	O
s	O
independence	O
,	O
the	O
high	O
costs	O
of	O
bilateral	O
implants	O
,	O
and	O
the	O
difficulty	O
most	O
patients	O
experience	O
in	O
handling	O
the	O
devices	O
,	O
the	O
question	O
arises	O
as	O
to	O
whether	O
bilateral	O
pallidal	O
stimulation	O
is	O
a	O
real	O
alternative	O
to	O
pallidotomy	O
.	O

Effects	O
of	O
the	O
cyclooxygenase	O
-	O
2	O
specific	O
inhibitor	O
valdecoxib	B-Chemical
versus	O
nonsteroidal	O
antiinflammatory	O
agents	O
and	O
placebo	O
on	O
cardiovascular	O
thrombotic	B-Disease
events	O
in	O
patients	O
with	O
arthritis	B-Disease
.	O

There	O
have	O
been	O
concerns	O
that	O
the	O
risk	O
of	O
cardiovascular	O
thrombotic	B-Disease
events	O
may	O
be	O
higher	O
with	O
cyclooxygenase	O
(	O
COX	O
)	O
-	O
2	O
-	O
specific	O
inhibitors	O
than	O
nonselective	O
nonsteroidal	O
antiinflammatory	O
drugs	O
(	O
NSAIDs	O
)	O
.	O

We	O
evaluated	O
cardiovascular	O
event	O
data	O
for	O
valdecoxib	B-Chemical
,	O
a	O
new	O
COX	O
-	O
2	O
-	O
specific	O
inhibitor	O
in	O
approximately	O
8000	O
patients	O
with	O
osteoarthritis	B-Disease
and	O
rheumatoid	B-Disease
arthritis	I-Disease
treated	O
with	O
this	O
agent	O
in	O
randomized	O
clinical	O
trials	O
.	O

The	O
incidence	O
of	O
cardiovascular	O
thrombotic	B-Disease
events	O
(	O
cardiac	O
,	O
cerebrovascular	O
and	O
peripheral	O
vascular	O
,	O
or	O
arterial	O
thrombotic	B-Disease
)	O
was	O
determined	O
by	O
analyzing	O
pooled	O
valdecoxib	B-Chemical
(	O
10	O
-	O
80	O
mg	O
daily	O
)	O
,	O
nonselective	O
NSAID	O
(	O
diclofenac	B-Chemical
75	O
mg	O
bid	O
,	O
ibuprofen	B-Chemical
800	O
mg	O
tid	O
,	O
or	O
naproxen	B-Chemical
500	O
mg	O
bid	O
)	O
and	O
placebo	O
data	O
from	O
10	O
randomized	O
osteoarthritis	B-Disease
and	O
rheumatoid	B-Disease
arthritis	I-Disease
trials	O
that	O
were	O
6	O
-	O
52	O
weeks	O
in	O
duration	O
.	O

The	O
incidence	O
rates	O
of	O
events	O
were	O
determined	O
in	O
all	O
patients	O
(	O
n	O
=	O
7934	O
)	O
and	O
in	O
users	O
of	O
low	O
-	O
dose	O
(	O
<	O
or	O
=	O
325	O
mg	O
daily	O
)	O
aspirin	B-Chemical
(	O
n	O
=	O
1051	O
)	O
and	O
nonusers	O
of	O
aspirin	B-Chemical
(	O
n	O
=	O
6883	O
)	O
.	O

Crude	O
and	O
exposure	O
-	O
adjusted	O
incidences	O
of	O
thrombotic	B-Disease
events	O
were	O
similar	O
for	O
valdecoxib	B-Chemical
,	O
NSAIDs	O
,	O
and	O
placebo	O
.	O

The	O
risk	O
of	O
serious	O
thrombotic	B-Disease
events	O
was	O
also	O
similar	O
for	O
each	O
valdecoxib	B-Chemical
dose	O
.	O

Thrombotic	B-Disease
risk	O
was	O
consistently	O
higher	O
for	O
users	O
of	O
aspirin	B-Chemical
users	O
than	O
nonusers	O
of	O
aspirin	B-Chemical
(	O
placebo	O
,	O
1	O
.	O
4	O
%	O
vs	O
.	O
0	O
%	O
;	O
valdecoxib	B-Chemical
,	O
1	O
.	O
7	O
%	O
vs	O
.	O
0	O
.	O
2	O
%	O
;	O
NSAIDs	O
,	O
1	O
.	O
9	O
%	O
vs	O
.	O
0	O
.	O
5	O
%	O
)	O
.	O

The	O
rates	O
of	O
events	O
in	O
users	O
of	O
aspirin	B-Chemical
were	O
similar	O
for	O
all	O
3	O
treatment	O
groups	O
and	O
across	O
valdecoxib	B-Chemical
doses	O
.	O

Short	O
-	O
and	O
intermediate	O
-	O
term	O
treatment	O
with	O
therapeutic	O
(	O
10	O
or	O
20	O
mg	O
daily	O
)	O
and	O
supratherapeutic	O
(	O
40	O
or	O
80	O
mg	O
daily	O
)	O
valdecoxib	B-Chemical
doses	O
was	O
not	O
associated	O
with	O
an	O
increased	O
incidence	O
of	O
thrombotic	B-Disease
events	O
relative	O
to	O
nonselective	O
NSAIDs	O
or	O
placebo	O
in	O
osteoarthritis	B-Disease
and	O
rheumatoid	B-Disease
arthritis	I-Disease
patients	O
in	O
controlled	O
clinical	O
trials	O
.	O

Hypersensitivity	B-Disease
myocarditis	B-Disease
complicating	O
hypertrophic	B-Disease
cardiomyopathy	I-Disease
heart	O
.	O

The	O
present	O
report	O
describes	O
a	O
case	O
of	O
eosinophilic	B-Disease
myocarditis	I-Disease
complicating	O
hypertrophic	B-Disease
cardiomyopathy	I-Disease
.	O

The	O
47	O
-	O
year	O
-	O
old	O
female	O
patient	O
,	O
known	O
to	O
have	O
hypertrophic	B-Disease
cardiomyopathy	I-Disease
,	O
was	O
admitted	O
with	O
biventricular	B-Disease
failure	I-Disease
and	O
managed	O
aggressively	O
with	O
dobutamine	B-Chemical
infusion	O
and	O
other	O
drugs	O
while	O
being	O
assessed	O
for	O
heart	O
transplantation	O
.	O

On	O
transthoracic	O
echocardiogram	O
,	O
she	O
had	O
moderate	O
left	B-Disease
ventricular	I-Disease
dysfunction	I-Disease
with	O
regional	O
variability	O
and	O
moderate	O
mitral	B-Disease
regurgitation	I-Disease
.	O

The	O
recipient	O
'	O
s	O
heart	O
showed	O
the	O
features	O
of	O
apical	O
hypertrophic	B-Disease
cardiomyopathy	I-Disease
and	O
myocarditis	B-Disease
with	O
abundant	O
eosinophils	O
.	O

Myocarditis	B-Disease
is	O
rare	O
and	O
eosinophilic	B-Disease
myocarditis	I-Disease
is	O
rarer	O
.	O

It	O
is	O
likely	O
that	O
the	O
hypersensitivity	B-Disease
(	O
eosinophilic	B-Disease
)	O
myocarditis	B-Disease
was	O
related	O
to	O
dobutamine	B-Chemical
infusion	O
therapy	O
.	O

Eosinophilic	B-Disease
myocarditis	I-Disease
has	O
been	O
reported	O
with	O
an	O
incidence	O
of	O
2	O
.	O
4	O
%	O
to	O
7	O
.	O
2	O
%	O
in	O
explanted	O
hearts	O
and	O
may	O
be	O
related	O
to	O
multidrug	O
therapy	O
.	O

Time	O
trends	O
in	O
warfarin	B-Chemical
-	O
associated	O
hemorrhage	B-Disease
.	O

The	O
annual	O
incidence	O
of	O
warfarin	B-Chemical
-	O
related	O
bleeding	B-Disease
at	O
Brigham	O
and	O
Women	O
'	O
s	O
Hospital	O
increased	O
from	O
0	O
.	O
97	O
/	O
1	O
,	O
000	O
patient	O
admissions	O
in	O
the	O
first	O
time	O
period	O
(	O
January	O
1995	O
to	O
October	O
1998	O
)	O
to	O
1	O
.	O
19	O
/	O
1	O
,	O
000	O
patient	O
admissions	O
in	O
the	O
second	O
time	O
period	O
(	O
November	O
1998	O
to	O
August	O
2002	O
)	O
of	O
this	O
study	O
.	O

The	O
proportion	O
of	O
patients	O
with	O
major	O
and	O
intracranial	B-Disease
bleeding	I-Disease
increased	O
from	O
20	O
.	O
2	O
%	O
and	O
1	O
.	O
9	O
%	O
,	O
respectively	O
,	O
in	O
the	O
first	O
time	O
period	O
,	O
to	O
33	O
.	O
3	O
%	O
and	O
7	O
.	O
8	O
%	O
,	O
respectively	O
,	O
in	O
the	O
second	O
.	O

Yohimbine	B-Chemical
treatment	O
of	O
sexual	B-Disease
side	I-Disease
effects	I-Disease
induced	O
by	O
serotonin	B-Chemical
reuptake	O
blockers	O
.	O

BACKGROUND	O
:	O
Preclinical	O
and	O
clinical	O
studies	O
suggest	O
that	O
yohimbine	B-Chemical
facilitates	O
sexual	O
behavior	O
and	O
may	O
be	O
helpful	O
in	O
the	O
treatment	O
of	O
male	B-Disease
impotence	I-Disease
.	O

A	O
single	O
case	O
report	O
suggests	O
that	O
yohimbine	B-Chemical
may	O
be	O
used	O
to	O
treat	O
the	O
sexual	B-Disease
side	I-Disease
effects	I-Disease
of	O
clomipramine	B-Chemical
.	O

This	O
study	O
evaluated	O
yohimbine	B-Chemical
as	O
a	O
treatment	O
for	O
the	O
sexual	B-Disease
side	I-Disease
effects	I-Disease
caused	O
by	O
serotonin	B-Chemical
reuptake	O
blockers	O
.	O

METHOD	O
:	O
Six	O
patients	O
with	O
either	O
obsessive	B-Disease
compulsive	I-Disease
disorder	I-Disease
,	O
trichotillomania	B-Disease
,	O
anxiety	B-Disease
,	O
or	O
affective	B-Disease
disorders	I-Disease
who	O
suffered	O
sexual	B-Disease
side	I-Disease
effects	I-Disease
after	O
treatment	O
with	O
serotonin	B-Chemical
reuptake	O
blockers	O
were	O
given	O
yohimbine	B-Chemical
on	O
a	O
p	O
.	O
r	O
.	O
n	O
.	O
basis	O
in	O
an	O
open	O
clinical	O
trial	O
.	O

Various	O
doses	O
of	O
yohimbine	B-Chemical
were	O
used	O
to	O
determine	O
the	O
ideal	O
dose	O
for	O
each	O
patient	O
.	O

RESULTS	O
:	O
Five	O
of	O
the	O
six	O
patients	O
experienced	O
improved	O
sexual	O
functioning	O
after	O
taking	O
yohimbine	B-Chemical
.	O

One	O
patient	O
who	O
failed	O
to	O
comply	O
with	O
yohimbine	B-Chemical
treatment	O
had	O
no	O
therapeutic	O
effects	O
.	O

Side	O
effects	O
of	O
yohimbine	B-Chemical
included	O
excessive	O
sweating	O
,	O
increased	O
anxiety	B-Disease
,	O
and	O
a	O
wound	O
-	O
up	O
feeling	O
in	O
some	O
patients	O
.	O

CONCLUSION	O
:	O
The	O
results	O
of	O
this	O
study	O
indicate	O
that	O
yohimbine	B-Chemical
may	O
be	O
an	O
effective	O
treatment	O
for	O
the	O
sexual	B-Disease
side	I-Disease
effects	I-Disease
caused	O
by	O
serotonin	B-Chemical
reuptake	O
blockers	O
.	O

Future	O
controlled	O
studies	O
are	O
needed	O
to	O
further	O
investigate	O
the	O
effectiveness	O
and	O
safety	O
of	O
yohimbine	B-Chemical
for	O
this	O
indication	O
.	O

Hemorrhagic	B-Disease
cystitis	I-Disease
complicating	O
bone	O
marrow	O
transplantation	O
.	O

Hemorrhagic	B-Disease
cystitis	I-Disease
is	O
a	O
potentially	O
serious	O
complication	O
of	O
high	O
-	O
dose	O
cyclophosphamide	B-Chemical
therapy	O
administered	O
before	O
bone	O
marrow	O
transplantation	O
.	O

As	O
standard	O
practice	O
at	O
our	O
institution	O
,	O
patients	O
who	O
are	O
scheduled	O
to	O
receive	O
a	O
bone	O
marrow	O
transplant	O
are	O
treated	O
prophylactically	O
with	O
forced	O
hydration	O
and	O
bladder	O
irrigation	O
.	O

In	O
an	O
attempt	O
to	O
obviate	O
the	O
inconvenience	O
of	O
bladder	O
irrigation	O
,	O
we	O
conducted	O
a	O
feasibility	O
trial	O
of	O
uroprophylaxis	O
with	O
mesna	B-Chemical
,	O
which	O
neutralizes	O
the	O
hepatic	O
metabolite	O
of	O
cyclophosphamide	B-Chemical
that	O
causes	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

Of	O
97	O
patients	O
who	O
received	O
standard	O
prophylaxis	O
,	O
4	O
had	O
symptomatic	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

In	O
contrast	O
,	O
two	O
of	O
four	O
consecutive	O
patients	O
who	O
received	O
mesna	B-Chemical
uroprophylaxis	O
before	O
allogeneic	O
bone	O
marrow	O
transplantation	O
had	O
severe	O
hemorrhagic	B-Disease
cystitis	I-Disease
for	O
at	O
least	O
2	O
weeks	O
.	O

Because	O
of	O
this	O
suboptimal	O
result	O
,	O
we	O
resumed	O
the	O
use	O
of	O
bladder	O
irrigation	O
and	O
forced	O
hydration	O
to	O
minimize	O
the	O
risk	O
of	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

Consensus	O
statement	O
concerning	O
cardiotoxicity	B-Disease
occurring	O
during	O
haematopoietic	O
stem	O
cell	O
transplantation	O
in	O
the	O
treatment	O
of	O
autoimmune	B-Disease
diseases	I-Disease
,	O
with	O
special	O
reference	O
to	O
systemic	B-Disease
sclerosis	I-Disease
and	O
multiple	B-Disease
sclerosis	I-Disease
.	O

Autologous	O
haematopoietic	O
stem	O
cell	O
transplantation	O
is	O
now	O
a	O
feasible	O
and	O
effective	O
treatment	O
for	O
selected	O
patients	O
with	O
severe	O
autoimmune	B-Disease
diseases	I-Disease
.	O

Worldwide	O
,	O
over	O
650	O
patients	O
have	O
been	O
transplanted	O
in	O
the	O
context	O
of	O
phase	O
I	O
and	O
II	O
clinical	O
trials	O
.	O

The	O
results	O
are	O
encouraging	O
enough	O
to	O
begin	O
randomised	O
phase	O
III	O
trials	O
.	O

However	O
,	O
as	O
predicted	O
,	O
significant	O
transplant	O
-	O
related	O
morbidity	O
and	O
mortality	O
have	O
been	O
observed	O
.	O

This	O
is	O
primarily	O
due	O
to	O
complications	O
related	O
to	O
either	O
the	O
stage	O
of	O
the	O
disease	O
at	O
transplant	O
or	O
due	O
to	O
infections	B-Disease
.	O

The	O
number	O
of	O
deaths	O
related	O
to	O
cardiac	B-Disease
toxicity	I-Disease
is	O
low	O
.	O

However	O
,	O
caution	O
is	O
required	O
when	O
cyclophosphamide	B-Chemical
or	O
anthracyclines	B-Chemical
such	O
as	O
mitoxantrone	B-Chemical
are	O
used	O
in	O
patients	O
with	O
a	O
possible	O
underlying	O
heart	B-Disease
damage	I-Disease
,	O
for	O
example	O
,	O
systemic	B-Disease
sclerosis	I-Disease
patients	O
.	O

In	O
November	O
2002	O
,	O
a	O
meeting	O
was	O
held	O
in	O
Florence	O
,	O
bringing	O
together	O
a	O
number	O
of	O
experts	O
in	O
various	O
fields	O
,	O
including	O
rheumatology	O
,	O
cardiology	O
,	O
neurology	O
,	O
pharmacology	O
and	O
transplantation	O
medicine	O
.	O

The	O
object	O
of	O
the	O
meeting	O
was	O
to	O
analyse	O
existing	O
data	O
,	O
both	O
published	O
or	O
available	O
,	O
in	O
the	O
European	O
Group	O
for	O
Blood	O
and	O
Marrow	O
Transplantation	O
autoimmune	B-Disease
disease	I-Disease
database	O
,	O
and	O
to	O
propose	O
a	O
safe	O
approach	O
to	O
such	O
patients	O
.	O

A	O
full	O
cardiological	O
assessment	O
before	O
and	O
during	O
the	O
transplant	O
emerged	O
as	O
the	O
major	O
recommendation	O
.	O

Does	O
supplemental	O
vitamin	B-Chemical
C	I-Chemical
increase	O
cardiovascular	B-Disease
disease	I-Disease
risk	O
in	O
women	O
with	O
diabetes	B-Disease
?	O

BACKGROUND	O
:	O
Vitamin	B-Chemical
C	I-Chemical
acts	O
as	O
a	O
potent	O
antioxidant	O
;	O
however	O
,	O
it	O
can	O
also	O
be	O
a	O
prooxidant	O
and	O
glycate	O
protein	O
under	O
certain	O
circumstances	O
in	O
vitro	O
.	O

These	O
observations	O
led	O
us	O
to	O
hypothesize	O
that	O
a	O
high	O
intake	O
of	O
vitamin	B-Chemical
C	I-Chemical
in	O
diabetic	B-Disease
persons	O
might	O
promote	O
atherosclerosis	B-Disease
.	O

OBJECTIVE	O
:	O
The	O
objective	O
was	O
to	O
examine	O
the	O
relation	O
between	O
vitamin	B-Chemical
C	I-Chemical
intake	O
and	O
mortality	O
from	O
cardiovascular	B-Disease
disease	I-Disease
.	O

DESIGN	O
:	O
We	O
studied	O
the	O
relation	O
between	O
vitamin	B-Chemical
C	I-Chemical
intake	O
and	O
mortality	O
from	O
total	O
cardiovascular	B-Disease
disease	I-Disease
(	O
n	O
=	O
281	O
)	O
,	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
(	O
n	O
=	O
175	O
)	O
,	O
and	O
stroke	B-Disease
(	O
n	O
=	O
57	O
)	O
in	O
1923	O
postmenopausal	O
women	O
who	O
reported	O
being	O
diabetic	B-Disease
at	O
baseline	O
.	O

Diet	O
was	O
assessed	O
with	O
a	O
food	O
-	O
frequency	O
questionnaire	O
at	O
baseline	O
,	O
and	O
subjects	O
initially	O
free	O
of	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
were	O
prospectively	O
followed	O
for	O
15	O
y	O
.	O

RESULTS	O
:	O
After	O
adjustment	O
for	O
cardiovascular	B-Disease
disease	I-Disease
risk	O
factors	O
,	O
type	O
of	O
diabetes	B-Disease
medication	O
used	O
,	O
duration	O
of	O
diabetes	B-Disease
,	O
and	O
intakes	O
of	O
folate	B-Chemical
,	O
vitamin	B-Chemical
E	I-Chemical
,	O
and	O
beta	B-Chemical
-	I-Chemical
carotene	I-Chemical
,	O
the	O
adjusted	O
relative	O
risks	O
of	O
total	O
cardiovascular	B-Disease
disease	I-Disease
mortality	O
were	O
1	O
.	O
0	O
,	O
0	O
.	O
97	O
,	O
1	O
.	O
11	O
,	O
1	O
.	O
47	O
,	O
and	O
1	O
.	O
84	O
(	O
P	O
for	O
trend	O
<	O
0	O
.	O
01	O
)	O
across	O
quintiles	O
of	O
total	O
vitamin	B-Chemical
C	I-Chemical
intake	O
from	O
food	O
and	O
supplements	O
.	O

Adjusted	O
relative	O
risks	O
of	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
were	O
1	O
.	O
0	O
,	O
0	O
.	O
81	O
,	O
0	O
.	O
99	O
,	O
1	O
.	O
26	O
,	O
and	O
1	O
.	O
91	O
(	O
P	O
for	O
trend	O
=	O
0	O
.	O
01	O
)	O
and	O
of	O
stroke	B-Disease
were	O
1	O
.	O
0	O
,	O
0	O
.	O
52	O
,	O
1	O
.	O
23	O
,	O
2	O
.	O
22	O
,	O
and	O
2	O
.	O
57	O
(	O
P	O
for	O
trend	O
<	O
0	O
.	O
01	O
)	O
.	O

When	O
dietary	O
and	O
supplemental	O
vitamin	B-Chemical
C	I-Chemical
were	O
analyzed	O
separately	O
,	O
only	O
supplemental	O
vitamin	B-Chemical
C	I-Chemical
showed	O
a	O
positive	O
association	O
with	O
mortality	O
endpoints	O
.	O

Vitamin	B-Chemical
C	I-Chemical
intake	O
was	O
unrelated	O
to	O
mortality	O
from	O
cardiovascular	B-Disease
disease	I-Disease
in	O
the	O
nondiabetic	O
subjects	O
at	O
baseline	O
.	O

CONCLUSION	O
:	O
A	O
high	O
vitamin	B-Chemical
C	I-Chemical
intake	O
from	O
supplements	O
is	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
cardiovascular	B-Disease
disease	I-Disease
mortality	O
in	O
postmenopausal	O
women	O
with	O
diabetes	B-Disease
.	O

Optical	O
coherence	O
tomography	O
can	O
measure	O
axonal	O
loss	O
in	O
patients	O
with	O
ethambutol	B-Chemical
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
.	O

PURPOSE	O
:	O
To	O
map	O
and	O
identify	O
the	O
pattern	O
,	O
in	O
vivo	O
,	O
of	O
axonal	B-Disease
degeneration	I-Disease
in	O
ethambutol	B-Chemical
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
using	O
optical	O
coherence	O
tomography	O
(	O
OCT	O
)	O
.	O

Ethambutol	B-Chemical
is	O
an	O
antimycobacterial	O
agent	O
often	O
used	O
to	O
treat	O
tuberculosis	B-Disease
.	O

A	O
serious	O
complication	O
of	O
ethambutol	B-Chemical
is	O
an	O
optic	B-Disease
neuropathy	I-Disease
that	O
impairs	O
visual	O
acuity	O
,	O
contrast	O
sensitivity	O
,	O
and	O
color	O
vision	O
.	O

However	O
,	O
early	O
on	O
,	O
when	O
the	O
toxic	O
optic	B-Disease
neuropathy	I-Disease
is	O
mild	O
and	O
partly	O
reversible	O
,	O
the	O
funduscopic	O
findings	O
are	O
often	O
subtle	O
and	O
easy	O
to	O
miss	O
.	O

METHODS	O
:	O
Three	O
subjects	O
with	O
a	O
history	O
of	O
ethambutol	B-Chemical
(	O
EMB	B-Chemical
)	O
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
of	O
short	O
-	O
,	O
intermediate	O
-	O
,	O
and	O
long	O
-	O
term	O
visual	B-Disease
deficits	I-Disease
were	O
administered	O
a	O
full	O
neuro	O
-	O
ophthalmologic	O
examination	O
including	O
visual	O
acuity	O
,	O
color	O
vision	O
,	O
contrast	O
sensitivity	O
,	O
and	O
fundus	O
examination	O
.	O

In	O
addition	O
,	O
OCT	O
(	O
OCT	O
3000	O
,	O
Humphrey	O
-	O
Zeiss	O
,	O
Dublin	O
,	O
CA	O
)	O
was	O
performed	O
on	O
both	O
eyes	O
of	O
each	O
subject	O
using	O
the	O
retinal	O
nerve	O
fiber	O
layer	O
(	O
RNFL	O
)	O
analysis	O
protocol	O
.	O

OCT	O
interpolates	O
data	O
from	O
100	O
points	O
around	O
the	O
optic	O
nerve	O
to	O
effectively	O
map	O
out	O
the	O
RNFL	O
.	O

RESULTS	O
:	O
The	O
results	O
were	O
compared	O
to	O
the	O
calculated	O
average	O
RNFL	O
of	O
normal	O
eyes	O
accumulated	O
from	O
four	O
prior	O
studies	O
using	O
OCT	O
,	O
n	O
=	O
661	O
.	O

In	O
all	O
subjects	O
with	O
history	O
of	O
EMB	B-Chemical
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
,	O
there	O
was	O
a	O
mean	O
loss	O
of	O
72	O
%	O
nerve	O
fiber	O
layer	O
thickness	O
in	O
the	O
temporal	O
quadrant	O
(	O
patient	O
A	O
,	O
with	O
eventual	O
recovery	O
of	O
visual	O
acuity	O
and	O
fields	O
,	O
58	O
%	O
loss	O
;	O
patient	O
B	O
,	O
with	O
intermediate	O
visual	B-Disease
deficits	I-Disease
,	O
68	O
%	O
loss	O
;	O
patient	O
C	O
,	O
with	O
chronic	O
visual	B-Disease
deficits	I-Disease
,	O
90	O
%	O
loss	O
)	O
,	O
with	O
an	O
average	O
mean	O
optic	O
nerve	O
thickness	O
of	O
26	O
+	O
/	O
-	O
16	O
microm	O
.	O

There	O
was	O
a	O
combined	O
mean	O
loss	O
of	O
46	O
%	O
of	O
fibers	O
from	O
the	O
superior	O
,	O
inferior	O
,	O
and	O
nasal	O
quadrants	O
in	O
the	O
(	O
six	O
)	O
eyes	O
of	O
all	O
three	O
subjects	O
(	O
mean	O
average	O
thickness	O
of	O
55	O
+	O
/	O
-	O
29	O
microm	O
)	O
.	O

In	O
both	O
sets	O
(	O
four	O
)	O
of	O
eyes	O
of	O
the	O
subjects	O
with	O
persistent	O
visual	B-Disease
deficits	I-Disease
(	O
patients	O
B	O
and	O
C	O
)	O
,	O
there	O
was	O
an	O
average	O
loss	O
of	O
79	O
%	O
of	O
nerve	O
fiber	O
thickness	O
in	O
the	O
temporal	O
quadrant	O
.	O

CONCLUSIONS	O
:	O
The	O
OCT	O
results	O
in	O
these	O
patients	O
with	O
EMB	B-Chemical
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
show	O
considerable	O
loss	O
especially	O
of	O
the	O
temporal	O
fibers	O
.	O

This	O
is	O
consistent	O
with	O
prior	O
histopathological	O
studies	O
that	O
show	O
predominant	O
loss	O
of	O
parvo	O
-	O
cellular	O
axons	O
(	O
or	O
small	O
-	O
caliber	O
axons	O
)	O
within	O
the	O
papillo	O
-	O
macular	O
bundle	O
in	O
toxic	O
or	O
hereditary	O
optic	B-Disease
neuropathies	I-Disease
.	O

OCT	O
can	O
be	O
a	O
valuable	O
tool	O
in	O
the	O
quantitative	O
analysis	O
of	O
optic	B-Disease
neuropathies	I-Disease
.	O

Additionally	O
,	O
in	O
terms	O
of	O
management	O
of	O
EMB	B-Chemical
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
,	O
it	O
is	O
important	O
to	O
properly	O
manage	O
ethambutol	B-Chemical
dosing	O
in	O
patients	O
with	O
renal	B-Disease
impairment	I-Disease
and	O
to	O
achieve	O
proper	O
transition	O
to	O
a	O
maintenance	O
dose	O
once	O
an	O
appropriate	O
loading	O
dose	O
has	O
been	O
reached	O
.	O

Hypoxia	B-Disease
in	O
renal	B-Disease
disease	I-Disease
with	O
proteinuria	B-Disease
and	O
/	O
or	O
glomerular	O
hypertension	B-Disease
.	O

Despite	O
the	O
increasing	O
need	O
to	O
identify	O
and	O
quantify	O
tissue	O
oxygenation	O
at	O
the	O
cellular	O
level	O
,	O
relatively	O
few	O
methods	O
have	O
been	O
available	O
.	O

In	O
this	O
study	O
,	O
we	O
developed	O
a	O
new	O
hypoxia	B-Disease
-	O
responsive	O
reporter	O
vector	O
using	O
a	O
hypoxia	B-Disease
-	O
responsive	O
element	O
of	O
the	O
5	O
'	O
vascular	O
endothelial	O
growth	O
factor	O
untranslated	O
region	O
and	O
generated	O
a	O
novel	O
hypoxia	B-Disease
-	O
sensing	O
transgenic	O
rat	O
.	O

We	O
then	O
applied	O
this	O
animal	O
model	O
to	O
the	O
detection	O
of	O
tubulointerstitial	O
hypoxia	B-Disease
in	O
the	O
diseased	B-Disease
kidney	I-Disease
.	O

With	O
this	O
model	O
,	O
we	O
were	O
able	O
to	O
identify	O
diffuse	O
cortical	O
hypoxia	B-Disease
in	O
the	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
nephrotic	B-Disease
syndrome	I-Disease
and	O
focal	O
and	O
segmental	O
hypoxia	B-Disease
in	O
the	O
remnant	O
kidney	O
model	O
.	O

Expression	O
of	O
the	O
hypoxia	B-Disease
-	O
responsive	O
transgene	O
increased	O
throughout	O
the	O
observation	O
period	O
,	O
reaching	O
2	O
.	O
2	O
-	O
fold	O
at	O
2	O
weeks	O
in	O
the	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
model	O
and	O
2	O
.	O
6	O
-	O
fold	O
at	O
4	O
weeks	O
in	O
the	O
remnant	O
kidney	O
model	O
,	O
whereas	O
that	O
of	O
vascular	O
endothelial	O
growth	O
factor	O
showed	O
a	O
mild	O
decrease	O
,	O
reflecting	O
distinct	O
behaviors	O
of	O
the	O
two	O
genes	O
.	O

The	O
degree	O
of	O
hypoxia	B-Disease
showed	O
a	O
positive	O
correlation	O
with	O
microscopic	O
tubulointerstitial	B-Disease
injury	I-Disease
in	O
both	O
models	O
.	O

Finally	O
,	O
we	O
identified	O
the	O
localization	O
of	O
proliferating	O
cell	O
nuclear	O
antigen	O
-	O
positive	O
,	O
ED	O
-	O
1	O
-	O
positive	O
,	O
and	O
terminal	O
dUTP	O
nick	O
-	O
end	O
labeled	O
-	O
positive	O
cells	O
in	O
the	O
hypoxic	B-Disease
cortical	O
area	O
in	O
the	O
remnant	O
kidney	O
model	O
.	O

We	O
propose	O
here	O
a	O
possible	O
pathological	O
tie	O
between	O
chronic	O
tubulointerstitial	O
hypoxia	B-Disease
and	O
progressive	O
glomerular	B-Disease
diseases	I-Disease
.	O

Adequate	O
timing	O
of	O
ribavirin	B-Chemical
reduction	O
in	O
patients	O
with	O
hemolysis	B-Disease
during	O
combination	O
therapy	O
of	O
interferon	B-Chemical
and	O
ribavirin	B-Chemical
for	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
.	O

BACKGROUND	O
:	O
Hemolytic	B-Disease
anemia	I-Disease
is	O
one	O
of	O
the	O
major	O
adverse	O
events	O
of	O
the	O
combination	O
therapy	O
of	O
interferon	B-Chemical
and	O
ribavirin	B-Chemical
.	O

Because	O
of	O
ribavirin	B-Chemical
-	O
related	O
hemolytic	B-Disease
anemia	I-Disease
,	O
dose	O
reduction	O
is	O
a	O
common	O
event	O
in	O
this	O
therapy	O
.	O

In	O
this	O
clinical	O
retrospective	O
cohort	O
study	O
we	O
have	O
examined	O
the	O
suitable	O
timing	O
of	O
ribavirin	B-Chemical
reduction	O
in	O
patients	O
with	O
hemolysis	B-Disease
during	O
combination	O
therapy	O
.	O

METHODS	O
:	O
Thirty	O
-	O
seven	O
of	O
160	O
patients	O
who	O
had	O
HCV	O
-	O
genotype	O
1b	O
,	O
had	O
high	O
virus	O
load	O
,	O
and	O
received	O
24	O
-	O
week	O
combination	O
therapy	O
developed	O
anemia	B-Disease
with	O
hemoglobin	O
level	O
<	O
10	O
g	O
/	O
dl	O
or	O
anemia	B-Disease
-	O
related	O
signs	O
during	O
therapy	O
.	O

After	O
that	O
,	O
these	O
37	O
patients	O
were	O
reduced	O
one	O
tablet	O
of	O
ribavirin	B-Chemical
(	O
200	O
mg	O
)	O
per	O
day	O
.	O

After	O
reduction	O
of	O
ribavirin	B-Chemical
,	O
27	O
of	O
37	O
patients	O
could	O
continue	O
combination	O
therapy	O
for	O
a	O
total	O
of	O
24	O
weeks	O
(	O
group	O
A	O
)	O
.	O

However	O
,	O
10	O
of	O
37	O
patients	O
with	O
reduction	O
of	O
ribavirin	B-Chemical
could	O
not	O
continue	O
combination	O
therapy	O
because	O
their	O
<	O
8	O
.	O
5	O
g	O
/	O
dl	O
hemoglobin	O
values	O
decreased	O
to	O
or	O
anemia	B-Disease
-	O
related	O
severe	O
side	O
effects	O
occurred	O
(	O
group	O
B	O
)	O
.	O

We	O
assessed	O
the	O
final	O
efficacy	O
and	O
safety	O
after	O
reduction	O
of	O
ribavirin	B-Chemical
in	O
groups	O
A	O
and	O
B	O
.	O

RESULTS	O
:	O
A	O
sustained	O
virological	O
response	O
(	O
SVR	O
)	O
was	O
29	O
.	O
6	O
%	O
(	O
8	O
/	O
27	O
)	O
in	O
group	O
A	O
and	O
10	O
%	O
(	O
1	O
/	O
10	O
)	O
in	O
group	O
B	O
,	O
respectively	O
.	O

A	O
34	O
.	O
4	O
%	O
(	O
12	O
/	O
27	O
)	O
of	O
SVR	O
+	O
biological	O
response	O
in	O
group	O
A	O
was	O
higher	O
than	O
10	O
%	O
(	O
1	O
/	O
10	O
)	O
in	O
group	O
B	O
(	O
P	O
=	O
0	O
.	O
051	O
)	O
,	O
with	O
slight	O
significance	O
.	O

With	O
respect	O
to	O
hemoglobin	O
level	O
at	O
the	O
time	O
of	O
ribavirin	B-Chemical
reduction	O
,	O
a	O
rate	O
of	O
continuation	O
of	O
therapy	O
in	O
patients	O
with	O
>	O
or	O
=	O
10	O
g	O
/	O
dl	O
hemoglobin	O
was	O
higher	O
than	O
that	O
in	O
patients	O
with	O
<	O
10	O
g	O
/	O
dl	O
(	O
P	O
=	O
0	O
.	O
036	O
)	O
.	O

CONCLUSIONS	O
:	O
Reduction	O
of	O
ribavirin	B-Chemical
at	O
hemoglobin	O
level	O
>	O
or	O
=	O
10	O
g	O
/	O
dl	O
is	O
suitable	O
in	O
terms	O
of	O
efficacy	O
and	O
side	O
effects	O
.	O

Aging	O
process	O
of	O
epithelial	O
cells	O
of	O
the	O
rat	O
prostate	O
lateral	O
lobe	O
in	O
experimental	O
hyperprolactinemia	B-Disease
induced	O
by	O
haloperidol	B-Chemical
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
examine	O
the	O
influence	O
of	O
hyperprolactinemia	B-Disease
,	O
induced	O
by	O
haloperidol	B-Chemical
(	O
HAL	B-Chemical
)	O
on	O
age	O
related	O
morphology	O
and	O
function	O
changes	O
of	O
epithelial	O
cells	O
in	O
rat	O
prostate	O
lateral	O
lobe	O
.	O

The	O
study	O
was	O
performed	O
on	O
sexually	O
mature	O
male	O
rats	O
.	O

Serum	O
concentrations	O
of	O
prolactin	O
(	O
PRL	B-Chemical
)	O
and	O
testosterone	B-Chemical
(	O
T	B-Chemical
)	O
were	O
measured	O
.	O

Tissue	O
sections	O
were	O
evaluated	O
with	O
light	O
and	O
electron	O
microscopy	O
.	O

Immunohistochemical	O
reactions	O
for	O
Anti	O
-	O
Proliferating	O
Cell	O
Nuclear	O
Antigen	O
(	O
PCNA	O
)	O
were	O
performed	O
.	O

In	O
rats	O
of	O
the	O
experimental	O
group	O
,	O
the	O
mean	O
concentration	O
of	O
:	O
PRL	B-Chemical
was	O
more	O
than	O
twice	O
higher	O
,	O
whereas	O
T	B-Chemical
concentration	O
was	O
almost	O
twice	O
lower	O
than	O
that	O
in	O
the	O
control	O
group	O
.	O

Light	O
microscopy	O
visualized	O
the	O
following	O
:	O
hypertrophy	B-Disease
and	O
epithelium	O
hyperplasia	B-Disease
of	O
the	O
glandular	O
ducts	O
,	O
associated	O
with	O
increased	O
PCNA	O
expression	O
.	O

Electron	O
microscopy	O
revealed	O
changes	O
in	O
columnar	O
epithelial	O
cells	O
,	O
concerning	O
organelles	O
,	O
engaged	O
in	O
protein	O
synthesis	O
and	O
secretion	O
.	O

Relation	O
of	O
perfusion	O
defects	O
observed	O
with	O
myocardial	O
contrast	O
echocardiography	O
to	O
the	O
severity	O
of	O
coronary	B-Disease
stenosis	I-Disease
:	O
correlation	O
with	O
thallium	B-Chemical
-	O
201	O
single	O
-	O
photon	O
emission	O
tomography	O
.	O

It	O
has	O
been	O
previously	O
shown	O
that	O
myocardial	O
contrast	O
echocardiography	O
is	O
a	O
valuable	O
technique	O
for	O
delineating	O
regions	O
of	O
myocardial	O
underperfusion	O
secondary	O
to	O
coronary	B-Disease
occlusion	I-Disease
and	O
to	O
critical	O
coronary	B-Disease
stenoses	I-Disease
in	O
the	O
presence	O
of	O
hyperemic	B-Disease
stimulation	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
determine	O
whether	O
myocardial	O
contrast	O
echocardiography	O
performed	O
with	O
a	O
stable	O
solution	O
of	O
sonicated	O
albumin	O
could	O
detect	O
regions	O
of	O
myocardial	O
underperfusion	O
resulting	O
from	O
various	O
degrees	O
of	O
coronary	B-Disease
stenosis	I-Disease
.	O

The	O
perfusion	O
defect	O
produced	O
in	O
16	O
open	O
chest	O
dogs	O
was	O
compared	O
with	O
the	O
anatomic	O
area	O
at	O
risk	O
measured	O
by	O
the	O
postmortem	O
dual	O
-	O
perfusion	O
technique	O
and	O
with	O
thallium	B-Chemical
-	O
201	O
single	O
-	O
photon	O
emission	O
tomography	O
(	O
SPECT	O
)	O
.	O

During	O
a	O
transient	O
(	O
20	O
-	O
s	O
)	O
coronary	B-Disease
occlusion	I-Disease
,	O
a	O
perfusion	O
defect	O
was	O
observed	O
with	O
contrast	O
echocardiography	O
in	O
14	O
of	O
the	O
15	O
dogs	O
in	O
which	O
the	O
occlusion	O
was	O
produced	O
.	O

The	O
perfusion	O
defect	O
correlated	O
significantly	O
with	O
the	O
anatomic	O
area	O
at	O
risk	O
(	O
r	O
=	O
0	O
.	O
74	O
;	O
p	O
less	O
than	O
0	O
.	O
002	O
)	O
.	O

During	O
dipyridamole	B-Chemical
-	O
induced	O
hyperemia	B-Disease
,	O
12	O
of	O
the	O
16	O
dogs	O
with	O
a	O
partial	O
coronary	B-Disease
stenosis	I-Disease
had	O
a	O
visible	O
area	O
of	O
hypoperfusion	O
by	O
contrast	O
echocardiography	O
.	O

The	O
four	O
dogs	O
without	O
a	O
perfusion	O
defect	O
had	O
a	O
stenosis	O
that	O
resulted	O
in	O
a	O
mild	O
(	O
0	O
%	O
to	O
50	O
%	O
)	O
reduction	O
in	O
dipyridamole	B-Chemical
-	O
induced	O
hyperemia	B-Disease
.	O

The	O
size	O
of	O
the	O
perfusion	O
defect	O
during	O
stenosis	O
correlated	O
significantly	O
with	O
the	O
anatomic	O
area	O
at	O
risk	O
(	O
r	O
=	O
0	O
.	O
61	O
;	O
p	O
=	O
0	O
.	O
02	O
)	O
.	O

Thallium	B-Chemical
-	O
201	O
SPECT	O
demonstrated	O
a	O
perfusion	O
defect	O
in	O
all	O
14	O
dogs	O
analyzed	O
during	O
dipyridamole	B-Chemical
-	O
induced	O
hyperemia	B-Disease
;	O
the	O
size	O
of	O
the	O
perfusion	O
defect	O
correlated	O
with	O
the	O
anatomic	O
area	O
at	O
risk	O
(	O
r	O
=	O
0	O
.	O
58	O
;	O
p	O
less	O
than	O
0	O
.	O
03	O
)	O
and	O
with	O
the	O
perfusion	O
defect	O
by	O
contrast	O
echocardiography	O
(	O
r	O
=	O
0	O
.	O
58	O
;	O
p	O
less	O
than	O
0	O
.	O
03	O
)	O
.	O

Thus	O
,	O
myocardial	O
contrast	O
echocardiography	O
can	O
be	O
used	O
to	O
visualize	O
and	O
quantitate	O
the	O
amount	O
of	O
jeopardized	O
myocardium	O
during	O
moderate	O
to	O
severe	O
degrees	O
of	O
coronary	B-Disease
stenosis	I-Disease
.	O

The	O
results	O
obtained	O
show	O
a	O
correlation	O
with	O
the	O
anatomic	O
area	O
at	O
risk	O
similar	O
to	O
that	O
obtained	O
with	O
thallium	B-Chemical
-	O
201	O
SPECT	O
.	O

The	O
activation	O
of	O
spinal	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
receptors	O
may	O
contribute	O
to	O
degeneration	O
of	O
spinal	O
motor	O
neurons	O
induced	O
by	O
neuraxial	O
morphine	B-Chemical
after	O
a	O
noninjurious	O
interval	O
of	O
spinal	B-Disease
cord	I-Disease
ischemia	I-Disease
.	O

We	O
investigated	O
the	O
relationship	O
between	O
the	O
degeneration	O
of	O
spinal	O
motor	O
neurons	O
and	O
activation	O
of	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
d	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
receptors	O
after	O
neuraxial	O
morphine	B-Chemical
following	O
a	O
noninjurious	O
interval	O
of	O
aortic	B-Disease
occlusion	I-Disease
in	O
rats	O
.	O

Spinal	B-Disease
cord	I-Disease
ischemia	I-Disease
was	O
induced	O
by	O
aortic	B-Disease
occlusion	I-Disease
for	O
6	O
min	O
with	O
a	O
balloon	O
catheter	O
.	O

In	O
a	O
microdialysis	O
study	O
,	O
10	O
muL	O
of	O
saline	O
(	O
group	O
C	O
;	O
n	O
=	O
8	O
)	O
or	O
30	O
mug	O
of	O
morphine	B-Chemical
(	O
group	O
M	O
;	O
n	O
=	O
8	O
)	O
was	O
injected	O
intrathecally	O
(	O
IT	O
)	O
0	O
.	O
5	O
h	O
after	O
reflow	O
,	O
and	O
30	O
mug	O
of	O
morphine	B-Chemical
(	O
group	O
SM	O
;	O
n	O
=	O
8	O
)	O
or	O
10	O
muL	O
of	O
saline	O
(	O
group	O
SC	O
;	O
n	O
=	O
8	O
)	O
was	O
injected	O
IT	O
0	O
.	O
5	O
h	O
after	O
sham	O
operation	O
.	O

Microdialysis	O
samples	O
were	O
collected	O
preischemia	O
,	O
before	O
IT	O
injection	O
,	O
and	O
at	O
2	O
,	O
4	O
,	O
8	O
,	O
24	O
,	O
and	O
48	O
h	O
of	O
reperfusion	O
(	O
after	O
IT	O
injection	O
)	O
.	O

Second	O
,	O
we	O
investigated	O
the	O
effect	O
of	O
IT	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
(	O
30	O
mug	O
)	O
on	O
the	O
histopathologic	O
changes	O
in	O
the	O
spinal	O
cord	O
after	O
morphine	B-Chemical
-	O
induced	O
spastic	B-Disease
paraparesis	I-Disease
.	O

After	O
IT	O
morphine	B-Chemical
,	O
the	O
cerebrospinal	O
fluid	O
(	O
CSF	O
)	O
glutamate	B-Chemical
concentration	O
was	O
increased	O
in	O
group	O
M	O
relative	O
to	O
both	O
baseline	O
and	O
group	O
C	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

This	O
increase	O
persisted	O
for	O
8	O
hrs	O
.	O

IT	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
significantly	O
reduced	O
the	O
number	O
of	O
dark	O
-	O
stained	O
alpha	O
-	O
motoneurons	O
after	O
morphine	B-Chemical
-	O
induced	O
spastic	B-Disease
paraparesis	I-Disease
compared	O
with	O
the	O
saline	O
group	O
.	O

These	O
data	O
indicate	O
that	O
IT	O
morphine	B-Chemical
induces	O
spastic	B-Disease
paraparesis	I-Disease
with	O
a	O
concomitant	O
increase	O
in	O
CSF	O
glutamate	B-Chemical
,	O
which	O
is	O
involved	O
in	O
NMDA	B-Chemical
receptor	O
activation	O
.	O

We	O
suggest	O
that	O
opioids	O
may	O
be	O
neurotoxic	B-Disease
in	O
the	O
setting	O
of	O
spinal	B-Disease
cord	I-Disease
ischemia	I-Disease
via	O
NMDA	B-Chemical
receptor	O
activation	O
.	O

Acute	O
low	B-Disease
back	I-Disease
pain	I-Disease
during	O
intravenous	O
administration	O
of	O
amiodarone	B-Chemical
:	O
a	O
report	O
of	O
two	O
cases	O
.	O

Amiodarone	B-Chemical
represents	O
an	O
effective	O
antiarrhythmic	O
drug	O
for	O
cardioversion	O
of	O
recent	O
-	O
onset	O
atrial	B-Disease
fibrillation	I-Disease
(	O
AF	B-Disease
)	O
and	O
maintenance	O
of	O
sinus	O
rhythm	O
.	O

We	O
briefly	O
describe	O
two	O
patients	O
suffering	O
from	O
recent	O
-	O
onset	O
atrial	B-Disease
fibrillation	I-Disease
,	O
who	O
experienced	O
an	O
acute	O
devastating	O
low	B-Disease
back	I-Disease
pain	I-Disease
a	O
few	O
minutes	O
after	O
initiation	O
of	O
intravenous	O
amiodarone	B-Chemical
loading	O
.	O

Notably	O
,	O
this	O
side	O
effect	O
has	O
not	O
been	O
ever	O
reported	O
in	O
the	O
medical	O
literature	O
.	O

Clinicians	O
should	O
be	O
aware	O
of	O
this	O
reaction	O
since	O
prompt	O
termination	O
of	O
parenteral	O
administration	O
leads	O
to	O
complete	O
resolution	O
.	O

Quantitative	O
drug	O
levels	O
in	O
stimulant	O
psychosis	B-Disease
:	O
relationship	O
to	O
symptom	O
severity	O
,	O
catecholamines	B-Chemical
and	O
hyperkinesia	B-Disease
.	O

To	O
examine	O
the	O
relationship	O
between	O
quantitative	O
stimulant	O
drug	O
levels	O
,	O
catecholamines	B-Chemical
,	O
and	O
psychotic	B-Disease
symptoms	I-Disease
,	O
nineteen	O
patients	O
in	O
a	O
psychiatric	B-Disease
emergency	O
service	O
with	O
a	O
diagnosis	O
of	O
amphetamine	B-Chemical
-	O
or	O
cocaine	B-Chemical
-	O
induced	O
psychosis	B-Disease
were	O
interviewed	O
,	O
and	O
plasma	O
and	O
urine	O
were	O
collected	O
for	O
quantitative	O
assays	O
of	O
stimulant	O
drug	O
and	O
catecholamine	B-Chemical
metabolite	O
levels	O
.	O

Methamphetamine	B-Chemical
or	O
amphetamine	B-Chemical
levels	O
were	O
related	O
to	O
several	O
psychopathology	O
scores	O
and	O
the	O
global	O
hyperkinesia	B-Disease
rating	O
.	O

HVA	O
levels	O
were	O
related	O
to	O
global	O
hyperkinesia	B-Disease
but	O
not	O
to	O
psychopathology	O
ratings	O
.	O

Although	O
many	O
other	O
factors	O
such	O
as	O
sensitization	O
may	O
play	O
a	O
role	O
,	O
intensity	O
of	O
stimulant	O
-	O
induced	O
psychotic	B-Disease
symptoms	I-Disease
and	O
stereotypies	B-Disease
appears	O
to	O
be	O
at	O
least	O
in	O
part	O
dose	O
-	O
related	O
.	O

Pheochromocytoma	B-Disease
unmasked	O
by	O
amisulpride	B-Chemical
and	O
tiapride	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
describe	O
the	O
unmasking	O
of	O
pheochromocytoma	B-Disease
in	O
a	O
patient	O
treated	O
with	O
amisulpride	B-Chemical
and	O
tiapride	B-Chemical
.	O

CASE	O
SUMMARY	O
:	O
A	O
42	O
-	O
year	O
-	O
old	O
white	O
man	O
developed	O
acute	O
hypertension	B-Disease
with	O
severe	O
headache	B-Disease
and	O
vomiting	B-Disease
2	O
hours	O
after	O
the	O
first	O
doses	O
of	O
amisulpride	B-Chemical
100	O
mg	O
and	O
tiapride	B-Chemical
100	O
mg	O
.	O

Both	O
drugs	O
were	O
immediately	O
discontinued	O
,	O
and	O
the	O
patient	O
recovered	O
after	O
subsequent	O
nicardipine	B-Chemical
and	O
verapamil	B-Chemical
treatment	O
.	O

Abdominal	O
ultrasound	O
showed	O
an	O
adrenal	O
mass	O
,	O
and	O
postoperative	O
histologic	O
examination	O
confirmed	O
the	O
diagnosis	O
of	O
pheochromocytoma	B-Disease
.	O

DISCUSSION	O
:	O
Drug	O
-	O
induced	O
symptoms	O
of	O
pheochromocytoma	B-Disease
are	O
often	O
associated	O
with	O
the	O
use	O
of	O
substituted	O
benzamide	B-Chemical
drugs	O
,	O
but	O
the	O
underlying	O
mechanism	O
is	O
unknown	O
.	O

In	O
our	O
case	O
,	O
use	O
of	O
the	O
Naranjo	O
probability	O
scale	O
indicated	O
a	O
possible	O
relationship	O
between	O
the	O
hypertensive	B-Disease
crisis	O
and	O
amisulpride	B-Chemical
and	O
tiapride	B-Chemical
therapy	O
.	O

CONCLUSIONS	O
:	O
As	O
of	O
March	O
24	O
,	O
2005	O
,	O
this	O
is	O
the	O
first	O
reported	O
case	O
of	O
amisulpride	B-Chemical
-	O
and	O
tiapride	B-Chemical
-	O
induced	O
hypertensive	B-Disease
crisis	O
in	O
a	O
patient	O
with	O
pheochromocytoma	B-Disease
.	O

Physicians	O
and	O
other	O
healthcare	O
professionals	O
should	O
be	O
aware	O
of	O
this	O
potential	O
adverse	O
effect	O
of	O
tiapride	B-Chemical
and	O
amisulpride	B-Chemical
.	O

Minor	O
neurological	B-Disease
dysfunction	I-Disease
,	O
cognitive	O
development	O
,	O
and	O
somatic	O
development	O
at	O
the	O
age	O
of	O
3	O
to	O
7	O
years	O
after	O
dexamethasone	B-Chemical
treatment	O
in	O
very	O
-	O
low	O
birth	O
-	O
weight	O
infants	O
.	O

The	O
objective	O
of	O
this	O
study	O
was	O
to	O
assess	O
minor	O
neurological	B-Disease
dysfunction	I-Disease
,	O
cognitive	O
development	O
,	O
and	O
somatic	O
development	O
after	O
dexamethasone	B-Chemical
therapy	O
in	O
very	O
-	O
low	O
-	O
birthweight	O
infants	O
.	O

Thirty	O
-	O
three	O
children	O
after	O
dexamethasone	B-Chemical
treatment	O
were	O
matched	O
to	O
33	O
children	O
without	O
dexamethasone	B-Chemical
treatment	O
.	O

Data	O
were	O
assessed	O
at	O
the	O
age	O
of	O
3	O
-	O
7	O
years	O
.	O

Dexamethasone	B-Chemical
was	O
started	O
between	O
the	O
7th	O
and	O
the	O
28th	O
day	O
of	O
life	O
over	O
7	O
days	O
with	O
a	O
total	O
dose	O
of	O
2	O
.	O
35	O
mg	O
/	O
kg	O
/	O
day	O
.	O

Exclusion	O
criteria	O
were	O
asphyxia	B-Disease
,	O
malformations	B-Disease
,	O
major	O
surgical	O
interventions	O
,	O
small	O
for	O
gestational	O
age	O
,	O
intraventricular	O
haemorrhage	B-Disease
grades	O
III	O
and	O
IV	O
,	O
periventricular	B-Disease
leukomalacia	I-Disease
,	O
and	O
severe	O
psychomotor	B-Disease
retardation	I-Disease
.	O

Each	O
child	O
was	O
examined	O
by	O
a	O
neuropediatrician	O
for	O
minor	O
neurological	B-Disease
dysfunctions	I-Disease
and	O
tested	O
by	O
a	O
psychologist	O
for	O
cognitive	O
development	O
with	O
a	O
Kaufman	O
Assessment	O
Battery	O
for	O
Children	O
and	O
a	O
Draw	O
-	O
a	O
-	O
Man	O
Test	O
.	O

There	O
were	O
no	O
differences	O
in	O
demographic	O
data	O
,	O
growth	O
,	O
and	O
socio	O
-	O
economic	O
status	O
between	O
the	O
two	O
groups	O
.	O

Fine	O
motor	O
skills	O
and	O
gross	O
motor	O
function	O
were	O
significantly	O
better	O
in	O
the	O
control	O
group	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
.	O

In	O
the	O
Draw	O
-	O
a	O
-	O
Man	O
Test	O
,	O
the	O
control	O
group	O
showed	O
better	O
results	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

There	O
were	O
no	O
differences	O
in	O
development	O
of	O
speech	O
,	O
social	O
development	O
,	O
and	O
the	O
Kaufman	O
Assessment	O
Battery	O
for	O
Children	O
.	O

After	O
dexamethasone	B-Chemical
treatment	O
,	O
children	O
showed	O
a	O
higher	O
rate	O
of	O
minor	O
neurological	B-Disease
dysfunctions	I-Disease
.	O

Neurological	O
development	O
was	O
affected	O
even	O
without	O
neurological	O
diagnosis	O
.	O

Further	O
long	O
-	O
term	O
follow	O
-	O
up	O
studies	O
will	O
be	O
necessary	O
to	O
fully	O
evaluate	O
the	O
impact	O
of	O
dexamethasone	B-Chemical
on	O
neurological	O
and	O
cognitive	O
development	O
.	O

Valproic	B-Chemical
acid	I-Chemical
I	O
:	O
time	O
course	O
of	O
lipid	O
peroxidation	O
biomarkers	O
,	O
liver	B-Disease
toxicity	I-Disease
,	O
and	O
valproic	B-Chemical
acid	I-Chemical
metabolite	O
levels	O
in	O
rats	O
.	O

A	O
single	O
dose	O
of	O
valproic	B-Chemical
acid	I-Chemical
(	O
VPA	B-Chemical
)	O
,	O
which	O
is	O
a	O
widely	O
used	O
antiepileptic	O
drug	O
,	O
is	O
associated	O
with	O
oxidative	O
stress	O
in	O
rats	O
,	O
as	O
recently	O
demonstrated	O
by	O
elevated	O
levels	O
of	O
15	B-Chemical
-	I-Chemical
F	I-Chemical
(	I-Chemical
2t	I-Chemical
)	I-Chemical
-	I-Chemical
isoprostane	I-Chemical
(	O
15	B-Chemical
-	I-Chemical
F	I-Chemical
(	I-Chemical
2t	I-Chemical
)	I-Chemical
-	I-Chemical
IsoP	I-Chemical
)	O
.	O

To	O
determine	O
whether	O
there	O
was	O
a	O
temporal	O
relationship	O
between	O
VPA	B-Chemical
-	O
associated	O
oxidative	O
stress	O
and	O
hepatotoxicity	B-Disease
,	O
adult	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
treated	O
ip	O
with	O
VPA	B-Chemical
(	O
500	O
mg	O
/	O
kg	O
)	O
or	O
0	O
.	O
9	O
%	O
saline	O
(	O
vehicle	O
)	O
once	O
daily	O
for	O
2	O
,	O
4	O
,	O
7	O
,	O
10	O
,	O
or	O
14	O
days	O
.	O

Oxidative	O
stress	O
was	O
assessed	O
by	O
determining	O
plasma	O
and	O
liver	O
levels	O
of	O
15	B-Chemical
-	I-Chemical
F	I-Chemical
(	I-Chemical
2t	I-Chemical
)	I-Chemical
-	I-Chemical
IsoP	I-Chemical
,	O
lipid	B-Chemical
hydroperoxides	I-Chemical
(	O
LPO	B-Chemical
)	O
,	O
and	O
thiobarbituric	B-Chemical
acid	I-Chemical
reactive	I-Chemical
substances	I-Chemical
(	O
TBARs	B-Chemical
)	O
.	O

Plasma	O
and	O
liver	O
15	B-Chemical
-	I-Chemical
F	I-Chemical
(	I-Chemical
2t	I-Chemical
)	I-Chemical
-	I-Chemical
IsoP	I-Chemical
were	O
elevated	O
and	O
reached	O
a	O
plateau	O
after	O
day	O
2	O
of	O
VPA	B-Chemical
treatment	O
compared	O
to	O
control	O
.	O

Liver	O
LPO	B-Chemical
levels	O
were	O
not	O
elevated	O
until	O
day	O
7	O
of	O
treatment	O
(	O
1	O
.	O
8	O
-	O
fold	O
versus	O
control	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Liver	O
and	O
plasma	O
TBARs	B-Chemical
were	O
not	O
increased	O
until	O
14	O
days	O
(	O
2	O
-	O
fold	O
vs	O
.	O
control	O
,	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Liver	B-Disease
toxicity	I-Disease
was	O
evaluated	O
based	O
on	O
serum	O
levels	O
of	O
alpha	O
-	O
glutathione	B-Chemical
S	O
-	O
transferase	O
(	O
alpha	O
-	O
GST	O
)	O
and	O
by	O
histology	O
.	O

Serum	O
alpha	O
-	O
GST	O
levels	O
were	O
significantly	O
elevated	O
by	O
day	O
4	O
,	O
which	O
corresponded	O
to	O
hepatotoxicity	B-Disease
as	O
shown	O
by	O
the	O
increasing	O
incidence	O
of	O
inflammation	B-Disease
of	O
the	O
liver	O
capsule	O
,	O
necrosis	B-Disease
,	O
and	O
steatosis	B-Disease
throughout	O
the	O
study	O
.	O

The	O
liver	O
levels	O
of	O
beta	O
-	O
oxidation	O
metabolites	O
of	O
VPA	B-Chemical
were	O
decreased	O
by	O
day	O
14	O
,	O
while	O
the	O
levels	O
of	O
4	B-Chemical
-	I-Chemical
ene	I-Chemical
-	I-Chemical
VPA	I-Chemical
and	O
(	O
E	O
)	O
-	O
2	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
diene	I-Chemical
-	I-Chemical
VPA	I-Chemical
were	O
not	O
elevated	O
throughout	O
the	O
study	O
.	O

Overall	O
,	O
these	O
findings	O
indicate	O
that	O
VPA	B-Chemical
treatment	O
results	O
in	O
oxidative	O
stress	O
,	O
as	O
measured	O
by	O
levels	O
of	O
15	B-Chemical
-	I-Chemical
F	I-Chemical
(	I-Chemical
2t	I-Chemical
)	I-Chemical
-	I-Chemical
IsoP	I-Chemical
,	O
which	O
precedes	O
the	O
onset	O
of	O
necrosis	B-Disease
,	O
steatosis	B-Disease
,	O
and	O
elevated	O
levels	O
of	O
serum	O
alpha	O
-	O
GST	O
.	O

Assessment	O
of	O
perinatal	O
hepatitis	B-Disease
B	I-Disease
and	O
rubella	B-Disease
prevention	O
in	O
New	O
Hampshire	O
delivery	O
hospitals	O
.	O

OBJECTIVE	O
:	O
To	O
evaluate	O
current	O
performance	O
on	O
recommended	O
perinatal	O
hepatitis	B-Disease
B	I-Disease
and	O
rubella	B-Disease
prevention	O
practices	O
in	O
New	O
Hampshire	O
.	O

METHODS	O
:	O
Data	O
were	O
extracted	O
from	O
2021	O
paired	O
mother	O
-	O
infant	O
records	O
for	O
the	O
year	O
2000	O
birth	O
cohort	O
in	O
New	O
Hampshire	O
'	O
s	O
25	O
delivery	O
hospitals	O
.	O

Assessment	O
was	O
done	O
on	O
the	O
following	O
:	O
prenatal	O
screening	O
for	O
hepatitis	B-Disease
B	I-Disease
and	O
rubella	B-Disease
,	O
administration	O
of	O
the	O
hepatitis	B-Disease
B	I-Disease
vaccine	O
birth	O
dose	O
to	O
all	O
infants	O
,	O
administration	O
of	O
hepatitis	B-Disease
B	I-Disease
immune	O
globulin	O
to	O
infants	O
who	O
were	O
born	O
to	O
hepatitis	B-Chemical
B	I-Chemical
surface	I-Chemical
antigen	I-Chemical
-	O
positive	O
mothers	O
,	O
rubella	B-Disease
immunity	O
,	O
and	O
administration	O
of	O
in	O
-	O
hospital	O
postpartum	O
rubella	B-Disease
vaccine	O
to	O
rubella	B-Disease
nonimmune	O
women	O
.	O

RESULTS	O
:	O
Prenatal	O
screening	O
rates	O
for	O
hepatitis	B-Disease
B	I-Disease
(	O
98	O
.	O
8	O
%	O
)	O
and	O
rubella	B-Disease
(	O
99	O
.	O
4	O
%	O
)	O
were	O
high	O
.	O

Hepatitis	B-Disease
B	I-Disease
vaccine	O
birth	O
dose	O
was	O
administered	O
to	O
76	O
.	O
2	O
%	O
of	O
all	O
infants	O
.	O

All	O
infants	O
who	O
were	O
born	O
to	O
hepatitis	B-Chemical
B	I-Chemical
surface	I-Chemical
antigen	I-Chemical
-	O
positive	O
mothers	O
also	O
received	O
hepatitis	B-Disease
B	I-Disease
immune	O
globulin	O
.	O

Multivariate	O
logistic	O
regression	O
showed	O
that	O
the	O
month	O
of	O
delivery	O
and	O
infant	O
birth	O
weight	O
were	O
independent	O
predictors	O
of	O
hepatitis	B-Disease
B	I-Disease
vaccination	O
.	O

The	O
proportion	O
of	O
infants	O
who	O
were	O
vaccinated	O
in	O
January	O
and	O
February	O
2000	O
(	O
48	O
.	O
5	O
%	O
and	O
67	O
.	O
5	O
%	O
,	O
respectively	O
)	O
was	O
less	O
than	O
any	O
other	O
months	O
,	O
whereas	O
the	O
proportion	O
who	O
were	O
vaccinated	O
in	O
December	O
2000	O
(	O
88	O
.	O
2	O
%	O
)	O
was	O
the	O
highest	O
.	O

Women	O
who	O
were	O
born	O
between	O
1971	O
and	O
1975	O
had	O
the	O
highest	O
rate	O
of	O
rubella	B-Disease
nonimmunity	O
(	O
9	O
.	O
5	O
%	O
)	O
.	O

In	O
-	O
hospital	O
postpartum	O
rubella	B-Disease
vaccine	O
administration	O
was	O
documented	O
for	O
75	O
.	O
6	O
%	O
of	O
nonimmune	O
women	O
.	O

CONCLUSION	O
:	O
This	O
study	O
documents	O
good	O
compliance	O
in	O
New	O
Hampshire	O
'	O
s	O
birthing	O
hospitals	O
with	O
national	O
guidelines	O
for	O
perinatal	O
hepatitis	B-Disease
B	I-Disease
and	O
rubella	B-Disease
prevention	O
and	O
highlights	O
potential	O
areas	O
for	O
improvement	O
.	O

Succinylcholine	B-Chemical
-	O
induced	O
masseter	B-Disease
muscle	I-Disease
rigidity	I-Disease
during	O
bronchoscopic	O
removal	O
of	O
a	O
tracheal	O
foreign	O
body	O
.	O

Masseter	B-Disease
muscle	I-Disease
rigidity	I-Disease
during	O
general	O
anesthesia	O
is	O
considered	O
an	O
early	O
warning	O
sign	O
of	O
a	O
possible	O
episode	O
of	O
malignant	B-Disease
hyperthermia	I-Disease
.	O

The	O
decision	O
whether	O
to	O
continue	O
or	O
discontinue	O
the	O
procedure	O
depends	O
on	O
the	O
urgency	O
of	O
the	O
surgery	O
and	O
severity	O
of	O
masseter	B-Disease
muscle	I-Disease
rigidity	I-Disease
.	O

Here	O
,	O
we	O
describe	O
a	O
case	O
of	O
severe	O
masseter	B-Disease
muscle	I-Disease
rigidity	I-Disease
(	O
jaw	B-Disease
of	I-Disease
steel	I-Disease
)	O
after	O
succinylcholine	B-Chemical
(	O
Sch	B-Chemical
)	O
administration	O
during	O
general	O
anesthetic	O
management	O
for	O
rigid	O
bronchoscopic	O
removal	O
of	O
a	O
tracheal	O
foreign	O
body	O
.	O

Anesthesia	O
was	O
continued	O
uneventfully	O
with	O
propofol	B-Chemical
infusion	O
while	O
all	O
facilities	O
were	O
available	O
to	O
detect	O
and	O
treat	O
malignant	B-Disease
hyperthermia	I-Disease
.	O

Dexrazoxane	B-Chemical
protects	O
against	O
myelosuppression	B-Disease
from	O
the	O
DNA	O
cleavage	O
-	O
enhancing	O
drugs	O
etoposide	B-Chemical
and	O
daunorubicin	B-Chemical
but	O
not	O
doxorubicin	B-Chemical
.	O

PURPOSE	O
:	O
The	O
anthracyclines	B-Chemical
daunorubicin	B-Chemical
and	O
doxorubicin	B-Chemical
and	O
the	O
epipodophyllotoxin	B-Chemical
etoposide	B-Chemical
are	O
potent	O
DNA	O
cleavage	O
-	O
enhancing	O
drugs	O
that	O
are	O
widely	O
used	O
in	O
clinical	O
oncology	O
;	O
however	O
,	O
myelosuppression	B-Disease
and	O
cardiac	B-Disease
toxicity	I-Disease
limit	O
their	O
use	O
.	O

Dexrazoxane	B-Chemical
(	O
ICRF	B-Chemical
-	I-Chemical
187	I-Chemical
)	O
is	O
recommended	O
for	O
protection	O
against	O
anthracycline	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

EXPERIMENTAL	O
DESIGN	O
:	O
Because	O
of	O
their	O
widespread	O
use	O
,	O
the	O
hematologic	B-Disease
toxicity	I-Disease
following	O
coadministration	O
of	O
dexrazoxane	B-Chemical
and	O
these	O
three	O
structurally	O
different	O
DNA	O
cleavage	O
enhancers	O
was	O
investigated	O
:	O
Sensitivity	O
of	O
human	O
and	O
murine	O
blood	O
progenitor	O
cells	O
to	O
etoposide	B-Chemical
,	O
daunorubicin	B-Chemical
,	O
and	O
doxorubicin	B-Chemical
+	O
/	O
-	O
dexrazoxane	B-Chemical
was	O
determined	O
in	O
granulocyte	O
-	O
macrophage	O
colony	O
forming	O
assays	O
.	O

Likewise	O
,	O
in	O
vivo	O
,	O
B6D2F1	O
mice	O
were	O
treated	O
with	O
etoposide	B-Chemical
,	O
daunorubicin	B-Chemical
,	O
and	O
doxorubicin	B-Chemical
,	O
with	O
or	O
without	O
dexrazoxane	B-Chemical
over	O
a	O
wide	O
range	O
of	O
doses	O
:	O
posttreatment	O
,	O
a	O
full	O
hematologic	O
evaluation	O
was	O
done	O
.	O

RESULTS	O
:	O
Nontoxic	O
doses	O
of	O
dexrazoxane	B-Chemical
reduced	O
myelosuppression	B-Disease
and	O
weight	B-Disease
loss	I-Disease
from	O
daunorubicin	B-Chemical
and	O
etoposide	B-Chemical
in	O
mice	O
and	O
antagonized	O
their	O
antiproliferative	O
effects	O
in	O
the	O
colony	O
assay	O
;	O
however	O
,	O
dexrazoxane	B-Chemical
neither	O
reduced	O
myelosuppression	B-Disease
,	O
weight	B-Disease
loss	I-Disease
,	O
nor	O
the	O
in	O
vitro	O
cytotoxicity	B-Disease
from	O
doxorubicin	B-Chemical
.	O

CONCLUSION	O
:	O
Although	O
our	O
findings	O
support	O
the	O
observation	O
that	O
dexrazoxane	B-Chemical
reduces	O
neither	O
hematologic	O
activity	O
nor	O
antitumor	O
activity	O
from	O
doxorubicin	B-Chemical
clinically	O
,	O
the	O
potent	O
antagonism	O
of	O
daunorubicin	B-Chemical
activity	O
raises	O
concern	O
;	O
a	O
possible	O
interference	O
with	O
anticancer	O
efficacy	O
certainly	O
would	O
call	O
for	O
renewed	O
attention	O
.	O

Our	O
data	O
also	O
suggest	O
that	O
significant	O
etoposide	B-Chemical
dose	O
escalation	O
is	O
perhaps	O
possible	O
by	O
the	O
use	O
of	O
dexrazoxane	B-Chemical
.	O

Clinical	O
trials	O
in	O
patients	O
with	O
brain	O
metastases	B-Disease
combining	O
dexrazoxane	B-Chemical
and	O
high	O
doses	O
of	O
etoposide	B-Chemical
is	O
ongoing	O
with	O
the	O
aim	O
of	O
improving	O
efficacy	O
without	O
aggravating	O
hematologic	B-Disease
toxicity	I-Disease
.	O

If	O
successful	O
,	O
this	O
represents	O
an	O
exciting	O
mechanism	O
for	O
pharmacologic	O
regulation	O
of	O
side	O
effects	O
from	O
cytotoxic	O
chemotherapy	O
.	O

Assessment	O
of	O
the	O
onset	O
and	O
persistence	O
of	O
amnesia	B-Disease
during	O
procedural	O
sedation	O
with	O
propofol	B-Chemical
.	O

OBJECTIVES	O
:	O
To	O
assess	O
patients	O
'	O
ability	O
to	O
repeat	O
and	O
recall	O
words	O
presented	O
to	O
them	O
while	O
undergoing	O
procedural	O
sedation	O
with	O
propofol	B-Chemical
,	O
and	O
correlate	O
their	O
recall	O
with	O
their	O
level	O
of	O
awareness	O
as	O
measured	O
by	O
bispectral	O
index	O
(	O
BIS	O
)	O
monitoring	O
.	O

METHODS	O
:	O
This	O
was	O
a	O
prospective	O
,	O
single	O
-	O
intervention	O
study	O
of	O
consenting	O
adult	O
patients	O
undergoing	O
procedural	O
sedation	O
with	O
propofol	B-Chemical
between	O
December	O
28	O
,	O
2002	O
,	O
and	O
October	O
31	O
,	O
2003	O
.	O

BIS	O
monitoring	O
was	O
initiated	O
starting	O
3	O
minutes	O
before	O
the	O
procedure	O
and	O
continuing	O
until	O
the	O
patient	O
had	O
regained	O
baseline	O
mental	O
status	O
.	O

At	O
1	O
-	O
minute	O
intervals	O
during	O
the	O
procedural	O
sedation	O
,	O
until	O
the	O
patient	O
regained	O
baseline	O
mental	O
status	O
at	O
the	O
end	O
of	O
the	O
procedure	O
,	O
a	O
word	O
from	O
a	O
standardized	O
list	O
was	O
read	O
aloud	O
,	O
and	O
the	O
patient	O
was	O
asked	O
to	O
immediately	O
repeat	O
the	O
word	O
to	O
the	O
investigator	O
.	O

The	O
BIS	O
score	O
at	O
the	O
time	O
the	O
word	O
was	O
read	O
and	O
the	O
patient	O
'	O
s	O
ability	O
to	O
repeat	O
the	O
word	O
were	O
recorded	O
.	O

After	O
the	O
procedure	O
,	O
the	O
patient	O
was	O
asked	O
to	O
state	O
all	O
of	O
the	O
words	O
from	O
the	O
list	O
that	O
he	O
or	O
she	O
could	O
recall	O
,	O
and	O
to	O
identify	O
the	O
last	O
word	O
recalled	O
from	O
prior	O
to	O
the	O
start	O
of	O
the	O
procedure	O
and	O
the	O
first	O
word	O
recalled	O
from	O
after	O
the	O
procedure	O
was	O
completed	O
.	O

RESULTS	O
:	O
Seventy	O
-	O
five	O
consenting	O
patients	O
were	O
enrolled	O
;	O
one	O
patient	O
was	O
excluded	O
from	O
data	O
analysis	O
for	O
a	O
protocol	O
violation	O
.	O

No	O
serious	O
adverse	O
events	O
were	O
noted	O
during	O
the	O
procedural	O
sedations	O
.	O

The	O
mean	O
(	O
+	O
/	O
-	O
standard	O
deviation	O
)	O
time	O
of	O
data	O
collection	O
was	O
16	O
.	O
4	O
minutes	O
(	O
+	O
/	O
-	O
7	O
.	O
1	O
;	O
range	O
5	O
to	O
34	O
minutes	O
)	O
.	O

The	O
mean	O
initial	O
(	O
preprocedure	O
)	O
BIS	O
score	O
was	O
97	O
.	O
1	O
(	O
+	O
/	O
-	O
2	O
.	O
3	O
;	O
range	O
92	O
to	O
99	O
)	O
.	O

The	O
mean	O
lowest	O
BIS	O
score	O
occurring	O
during	O
these	O
procedural	O
sedations	O
was	O
66	O
.	O
9	O
(	O
+	O
/	O
-	O
14	O
.	O
4	O
;	O
range	O
33	O
to	O
91	O
)	O
.	O

The	O
mean	O
lowest	O
BIS	O
score	O
corresponding	O
to	O
the	O
ability	O
of	O
the	O
patient	O
to	O
immediately	O
repeat	O
words	O
read	O
from	O
the	O
list	O
was	O
77	O
.	O
1	O
(	O
95	O
%	O
CI	O
=	O
74	O
.	O
3	O
to	O
80	O
.	O
0	O
)	O
.	O

The	O
mean	O
highest	O
BIS	O
score	O
corresponding	O
to	O
the	O
inability	B-Disease
to	I-Disease
repeat	I-Disease
words	I-Disease
was	O
81	O
.	O
5	O
(	O
95	O
%	O
CI	O
=	O
78	O
.	O
1	O
to	O
84	O
.	O
8	O
)	O
.	O

The	O
mean	O
BIS	O
score	O
corresponding	O
to	O
the	O
last	O
word	O
recalled	O
from	O
prior	O
to	O
the	O
initiation	O
of	O
the	O
sedation	O
was	O
96	O
.	O
7	O
(	O
+	O
/	O
-	O
2	O
.	O
4	O
;	O
range	O
84	O
to	O
98	O
)	O
.	O

The	O
mean	O
BIS	O
score	O
corresponding	O
to	O
the	O
first	O
word	O
recalled	O
after	O
the	O
procedure	O
was	O
completed	O
was	O
91	O
.	O
2	O
(	O
95	O
%	O
CI	O
=	O
88	O
.	O
1	O
to	O
94	O
.	O
3	O
)	O
.	O

All	O
patients	O
recalled	O
at	O
least	O
one	O
word	O
that	O
had	O
been	O
read	O
to	O
them	O
during	O
the	O
protocol	O
.	O

The	O
mean	O
lowest	O
BIS	O
score	O
for	O
any	O
recalled	O
word	O
was	O
91	O
.	O
5	O
(	O
+	O
/	O
-	O
11	O
.	O
1	O
;	O
range	O
79	O
to	O
98	O
)	O
,	O
and	O
no	O
words	O
were	O
recalled	O
when	O
the	O
corresponding	O
BIS	O
score	O
was	O
less	O
than	O
90	O
.	O

CONCLUSIONS	O
:	O
There	O
is	O
a	O
range	O
of	O
BIS	O
scores	O
during	O
which	O
sedated	O
patients	O
are	O
able	O
to	O
repeat	O
words	O
read	O
to	O
them	O
but	O
are	O
not	O
able	O
to	O
subsequently	O
recall	O
these	O
words	O
.	O

Furthermore	O
,	O
patients	O
had	O
no	O
recall	O
of	O
words	O
repeated	O
prior	O
to	O
procedural	O
sedation	O
in	O
BIS	O
ranges	O
associated	O
with	O
recall	O
after	O
procedural	O
sedation	O
,	O
suggestive	O
of	O
retrograde	B-Disease
amnesia	I-Disease
.	O

Amiodarone	B-Chemical
pulmonary	B-Disease
toxicity	I-Disease
.	O

Amiodarone	B-Chemical
is	O
an	O
effective	O
antiarrhythmic	O
agent	O
whose	O
utility	O
is	O
limited	O
by	O
many	O
side	O
-	O
effects	O
,	O
the	O
most	O
problematic	O
being	O
pneumonitis	B-Disease
.	O

The	O
pulmonary	B-Disease
toxicity	I-Disease
of	O
amiodarone	B-Chemical
is	O
thought	O
to	O
result	O
from	O
direct	O
injury	O
related	O
to	O
the	O
intracellular	O
accumulation	O
of	O
phospholipid	O
and	O
T	O
cell	O
-	O
mediated	O
hypersensitivity	B-Disease
pneumonitis	I-Disease
.	O

The	O
clinical	O
and	O
radiographic	O
features	O
of	O
amiodarone	B-Chemical
-	O
induced	O
pulmonary	B-Disease
toxicity	I-Disease
are	O
characteristic	O
but	O
nonspecific	O
.	O

The	O
diagnosis	O
depends	O
on	O
exclusion	O
of	O
other	O
entities	O
,	O
such	O
as	O
heart	B-Disease
failure	I-Disease
,	O
infection	B-Disease
,	O
and	O
malignancy	B-Disease
.	O

While	O
withdrawal	O
of	O
amiodarone	B-Chemical
leads	O
to	O
clinical	O
improvement	O
in	O
majority	O
of	O
cases	O
,	O
this	O
is	O
not	O
always	O
possible	O
or	O
advisable	O
.	O

Dose	O
reduction	O
or	O
concomitant	O
steroid	B-Chemical
therapy	O
may	O
have	O
a	O
role	O
in	O
selected	O
patients	O
.	O

Two	O
prodrugs	O
of	O
potent	O
and	O
selective	O
GluR5	O
kainate	B-Chemical
receptor	O
antagonists	O
actives	O
in	O
three	O
animal	O
models	O
of	O
pain	B-Disease
.	O

Amino	O
acids	O
5	O
and	O
7	O
,	O
two	O
potent	O
and	O
selective	O
competitive	O
GluR5	O
KA	B-Chemical
receptor	O
antagonists	O
,	O
exhibited	O
high	O
GluR5	O
receptor	O
affinity	O
over	O
other	O
glutamate	B-Chemical
receptors	O
.	O

Their	O
ester	O
prodrugs	O
6	O
and	O
8	O
were	O
orally	O
active	O
in	O
three	O
models	O
of	O
pain	B-Disease
:	O
reversal	O
of	O
formalin	B-Chemical
-	O
induced	O
paw	O
licking	O
,	O
carrageenan	B-Chemical
-	O
induced	O
thermal	B-Disease
hyperalgesia	I-Disease
,	O
and	O
capsaicin	B-Chemical
-	O
induced	O
mechanical	B-Disease
hyperalgesia	I-Disease
.	O

Possible	O
azithromycin	B-Chemical
-	O
associated	O
hiccups	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
report	O
a	O
case	O
of	O
persistent	O
hiccups	B-Disease
associated	O
by	O
azithromycin	B-Chemical
therapy	O
.	O

CASE	O
SUMMARY	O
:	O
A	O
76	O
-	O
year	O
-	O
old	O
man	O
presented	O
with	O
persistent	O
hiccups	B-Disease
after	O
beginning	O
azithromycin	B-Chemical
for	O
the	O
treatment	O
of	O
pharyngitis	B-Disease
.	O

Hiccups	B-Disease
were	O
persistent	O
and	O
exhausting	O
.	O

Discontinuation	O
of	O
azithromycin	B-Chemical
and	O
therapy	O
with	O
baclofen	B-Chemical
finally	O
resolved	O
hiccups	B-Disease
.	O

No	O
organic	O
cause	O
of	O
hiccups	B-Disease
was	O
identified	O
despite	O
extensive	O
investigation	O
.	O

DISCUSSION	O
:	O
Pharmacotherapeutic	O
agents	O
have	O
been	O
uncommonly	O
associated	O
with	O
hiccups	B-Disease
.	O

Corticosteroids	O
(	O
dexamethasone	B-Chemical
and	O
methylprednisolone	B-Chemical
)	O
,	O
benzodiazepines	B-Chemical
(	O
midazolam	B-Chemical
)	O
and	O
general	O
anaesthesia	O
have	O
been	O
the	O
specific	O
agents	O
mentioned	O
most	O
frequently	O
in	O
the	O
literature	O
as	O
being	O
associated	O
with	O
the	O
development	O
of	O
hiccups	B-Disease
.	O

Few	O
cases	O
of	O
drug	O
-	O
induced	O
hiccups	B-Disease
have	O
been	O
reported	O
related	O
to	O
macrolide	B-Chemical
antimicrobials	O
.	O

Using	O
the	O
Naranjo	O
adverse	O
effect	O
reaction	O
probability	O
scale	O
this	O
event	O
could	O
be	O
classified	O
as	O
possible	O
(	O
score	O
5	O
points	O
)	O
,	O
mostly	O
because	O
of	O
the	O
close	O
temporal	O
sequence	O
,	O
previous	O
reports	O
on	O
this	O
reaction	O
with	O
other	O
macrolides	B-Chemical
and	O
the	O
absence	O
of	O
any	O
alternative	O
explanation	O
for	O
hiccups	B-Disease
.	O

Our	O
hypothesis	O
is	O
that	O
a	O
vagal	O
mechanism	O
mediated	O
by	O
azithromycin	B-Chemical
could	O
be	O
the	O
pathogenesis	O
of	O
hiccups	B-Disease
in	O
our	O
patient	O
.	O

CONCLUSIONS	O
:	O
Diagnosis	O
of	O
drug	O
-	O
induced	O
hiccups	B-Disease
is	O
difficult	O
and	O
often	O
achieved	O
only	O
by	O
a	O
process	O
of	O
elimination	O
.	O

However	O
,	O
macrolide	B-Chemical
antimicrobials	O
have	O
been	O
reported	O
to	O
be	O
associated	O
with	O
hiccups	B-Disease
and	O
vagal	O
mechanism	O
could	O
explain	O
the	O
development	O
of	O
this	O
side	O
-	O
effect	O
.	O

Calcium	B-Chemical
carbonate	I-Chemical
toxicity	B-Disease
:	O
the	O
updated	O
milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
;	O
report	O
of	O
3	O
cases	O
and	O
review	O
of	O
the	O
literature	O
.	O

OBJECTIVE	O
:	O
To	O
describe	O
3	O
patients	O
with	O
calcium	B-Chemical
carbonate	I-Chemical
-	O
induced	O
hypercalcemia	B-Disease
and	O
gain	O
insights	O
into	O
the	O
cause	O
and	O
management	O
of	O
the	O
milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
.	O

METHODS	O
:	O
We	O
report	O
the	O
clinical	O
and	O
laboratory	O
data	O
in	O
3	O
patients	O
who	O
presented	O
with	O
severe	O
hypercalcemia	B-Disease
(	O
corrected	O
serum	O
calcium	B-Chemical
>	O
or	O
=	O
14	O
mg	O
/	O
dL	O
)	O
and	O
review	O
the	O
pertinent	O
literature	O
on	O
milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
.	O

RESULTS	O
:	O
The	O
3	O
patients	O
had	O
acute	B-Disease
renal	I-Disease
insufficiency	I-Disease
,	O
relative	O
metabolic	B-Disease
alkalosis	I-Disease
,	O
and	O
low	O
parathyroid	O
hormone	O
(	O
PTH	O
)	O
,	O
PTH	O
-	O
related	O
peptide	O
,	O
and	O
1	B-Chemical
,	I-Chemical
25	I-Chemical
-	I-Chemical
dihydroxyvitamin	I-Chemical
D	I-Chemical
concentrations	O
.	O

No	O
malignant	O
lesion	O
was	O
found	O
.	O

Treatment	O
included	O
aggressive	O
hydration	O
and	O
varied	O
amounts	O
of	O
furosemide	B-Chemical
.	O

The	O
2	O
patients	O
with	O
the	O
higher	O
serum	O
calcium	B-Chemical
concentrations	O
received	O
pamidronate	B-Chemical
intravenously	O
(	O
60	O
and	O
30	O
mg	O
,	O
respectively	O
)	O
,	O
which	O
caused	O
severe	O
hypocalcemia	B-Disease
.	O

Of	O
the	O
3	O
patients	O
,	O
2	O
were	O
ingesting	O
acceptable	O
doses	O
of	O
elemental	O
calcium	B-Chemical
(	O
1	O
g	O
and	O
2	O
g	O
daily	O
,	O
respectively	O
)	O
in	O
the	O
form	O
of	O
calcium	B-Chemical
carbonate	I-Chemical
.	O

In	O
addition	O
to	O
our	O
highlighted	O
cases	O
,	O
we	O
review	O
the	O
history	O
,	O
classification	O
,	O
pathophysiologic	O
features	O
,	O
and	O
treatment	O
of	O
milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
and	O
summarize	O
the	O
cases	O
reported	O
from	O
early	O
1995	O
to	O
November	O
2003	O
.	O

CONCLUSION	O
:	O
Milk	B-Disease
-	I-Disease
alkali	I-Disease
syndrome	I-Disease
may	O
be	O
a	O
common	O
cause	O
of	O
unexplained	O
hypercalcemia	B-Disease
and	O
can	O
be	O
precipitated	O
by	O
small	O
amounts	O
of	O
orally	O
ingested	O
calcium	B-Chemical
carbonate	I-Chemical
in	O
susceptible	O
persons	O
.	O

Treatment	O
with	O
hydration	O
,	O
furosemide	B-Chemical
,	O
and	O
discontinuation	O
of	O
the	O
calcium	B-Chemical
and	O
vitamin	B-Chemical
D	I-Chemical
source	O
is	O
adequate	O
.	O

Pamidronate	B-Chemical
treatment	O
is	O
associated	O
with	O
considerable	O
risk	O
for	O
hypocalcemia	B-Disease
,	O
even	O
in	O
cases	O
of	O
initially	O
severe	O
hypercalcemia	B-Disease
.	O

Warfarin	B-Chemical
-	O
induced	O
leukocytoclastic	B-Disease
vasculitis	I-Disease
.	O

Skin	O
reactions	O
associated	O
with	O
oral	O
coumarin	B-Chemical
-	O
derived	O
anticoagulants	O
are	O
an	O
uncommon	O
occurrence	O
.	O

Leukocytoclastic	B-Disease
vasculitis	I-Disease
(	O
LV	B-Disease
)	O
is	O
primarily	O
a	O
cutaneous	B-Disease
small	I-Disease
vessel	I-Disease
vasculitis	I-Disease
,	O
though	O
systemic	O
involvement	O
may	O
be	O
encountered	O
.	O

We	O
report	O
4	O
patients	O
with	O
late	O
-	O
onset	O
LV	B-Disease
probably	O
due	O
to	O
warfarin	B-Chemical
.	O

All	O
4	O
patients	O
presented	O
with	O
skin	B-Disease
eruptions	I-Disease
that	O
developed	O
after	O
receiving	O
warfarin	B-Chemical
for	O
several	O
years	O
.	O

The	O
results	O
of	O
skin	B-Disease
lesion	I-Disease
biopsies	O
were	O
available	O
in	O
3	O
patients	O
,	O
confirming	O
LV	B-Disease
Cutaneous	I-Disease
lesions	I-Disease
resolved	O
in	O
all	O
patients	O
after	O
warfarin	B-Chemical
was	O
discontinued	O
.	O

In	O
2	O
of	O
the	O
4	O
patients	O
,	O
rechallenge	O
with	O
warfarin	B-Chemical
led	O
to	O
recurrence	O
of	O
the	O
lesions	O
.	O

LV	B-Disease
may	O
be	O
a	O
late	O
-	O
onset	O
adverse	O
reaction	O
associated	O
with	O
warfarin	B-Chemical
therapy	O
.	O

Cocaine	B-Chemical
-	O
induced	O
brainstem	O
seizures	B-Disease
and	O
behavior	O
.	O

A	O
variety	O
of	O
abnormal	O
sensory	O
/	O
motor	O
behaviors	O
associated	O
with	O
electrical	O
discharges	O
recorded	O
from	O
the	O
bilateral	O
brainstem	O
were	O
induced	O
in	O
adult	O
WKY	O
rats	O
by	O
mechanical	O
(	O
electrode	O
implants	O
)	O
and	O
DC	O
electrical	O
current	O
stimulations	O
and	O
by	O
acute	O
and	O
chronic	O
administration	O
of	O
cocaine	B-Chemical
.	O

The	O
electrode	O
implant	O
implicated	O
one	O
side	O
or	O
the	O
other	O
of	O
the	O
reticular	O
system	O
of	O
the	O
brainstem	O
but	O
subjects	O
were	O
not	O
incapacitated	O
by	O
the	O
stimulations	O
.	O

Cocaine	B-Chemical
(	O
40	O
mg	O
/	O
kg	O
)	O
was	O
injected	O
subcutaneously	O
for	O
an	O
acute	O
experiment	O
and	O
subsequent	O
20	O
mg	O
/	O
kg	O
doses	O
twice	O
daily	O
for	O
3	O
days	O
in	O
a	O
chronic	O
study	O
.	O

Cocaine	B-Chemical
generated	O
more	O
abnormal	O
behaviors	O
in	O
the	O
brainstem	O
perturbation	O
group	O
,	O
especially	O
the	O
electrically	O
perturbated	O
subjects	O
.	O

The	O
abnormal	O
behaviors	O
were	O
yawning	O
,	O
retrocollis	O
,	O
hyperactivity	B-Disease
,	O
hypersensitivity	B-Disease
,	O
"	O
beating	O
drum	O
"	O
behavior	O
,	O
squealing	O
,	O
head	O
bobbing	O
,	O
circling	O
,	O
sniffing	O
,	O
abnormal	O
posturing	O
,	O
and	O
facial	O
twitching	O
.	O

Shifts	O
in	O
the	O
power	O
frequency	O
spectra	O
of	O
the	O
discharge	O
patterns	O
were	O
noted	O
between	O
quiet	O
and	O
pacing	O
behavioral	O
states	O
.	O

Hypersensitivity	B-Disease
to	O
various	O
auditory	O
,	O
tactile	O
,	O
and	O
visual	O
stimulation	O
was	O
present	O
and	O
shifts	O
in	O
the	O
brainstem	O
ambient	O
power	O
spectral	O
frequency	O
occurred	O
in	O
response	O
to	O
tactile	O
stimulation	O
.	O

These	O
findings	O
suggest	O
that	O
the	O
brainstem	O
generates	O
and	O
propagates	O
pathological	O
discharges	O
that	O
can	O
be	O
elicited	O
by	O
mechanical	O
and	O
DC	O
electrical	O
perturbation	O
.	O

Cocaine	B-Chemical
was	O
found	O
to	O
activate	O
the	O
discharge	O
system	O
and	O
thus	O
induce	O
abnormal	O
behaviors	O
that	O
are	O
generated	O
at	O
the	O
discharge	O
site	O
and	O
at	O
distant	O
sites	O
to	O
which	O
the	O
discharge	O
propagates	O
.	O

Cognitive	O
functions	O
may	O
also	O
be	O
involved	O
since	O
dopaminergic	O
and	O
serotonergic	O
cellular	O
elements	O
at	O
the	O
brainstem	O
level	O
are	O
also	O
implicated	O
.	O

rTMS	O
of	O
supplementary	O
motor	O
area	O
modulates	O
therapy	O
-	O
induced	O
dyskinesias	B-Disease
in	O
Parkinson	B-Disease
disease	I-Disease
.	O

The	O
neural	O
mechanisms	O
and	O
circuitry	O
involved	O
in	O
levodopa	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
are	O
unclear	O
.	O

Using	O
repetitive	O
transcranial	O
magnetic	O
stimulation	O
(	O
rTMS	O
)	O
over	O
the	O
supplementary	O
motor	O
area	O
(	O
SMA	O
)	O
in	O
a	O
group	O
of	O
patients	O
with	O
advanced	O
Parkinson	B-Disease
disease	I-Disease
,	O
the	O
authors	O
investigated	O
whether	O
modulation	O
of	O
SMA	O
excitability	O
may	O
result	O
in	O
a	O
modification	O
of	O
a	O
dyskinetic	B-Disease
state	O
induced	O
by	O
continuous	O
apomorphine	B-Chemical
infusion	O
.	O

rTMS	O
at	O
1	O
Hz	O
was	O
observed	O
to	O
markedly	O
reduce	O
drug	B-Disease
-	I-Disease
induced	I-Disease
dyskinesias	I-Disease
,	O
whereas	O
5	O
-	O
Hz	O
rTMS	O
induced	O
a	O
slight	O
but	O
not	O
significant	O
increase	O
.	O

Intracavitary	O
chemotherapy	O
(	O
paclitaxel	B-Chemical
/	O
carboplatin	B-Chemical
liquid	O
crystalline	O
cubic	O
phases	O
)	O
for	O
recurrent	O
glioblastoma	B-Disease
-	O
-	O
clinical	O
observations	O
.	O

Human	O
malignant	O
brain	B-Disease
tumors	I-Disease
have	O
a	O
poor	O
prognosis	O
in	O
spite	O
of	O
surgery	O
and	O
radiation	O
therapy	O
.	O

Cubic	O
phases	O
consist	O
of	O
curved	O
biocontinuous	O
lipid	O
bilayers	O
,	O
separating	O
two	O
congruent	O
networks	O
of	O
water	O
channels	O
.	O

Used	O
as	O
a	O
host	O
for	O
cytotoxic	O
drugs	O
,	O
the	O
gel	O
-	O
like	O
matrix	O
can	O
easily	O
be	O
applied	O
to	O
the	O
walls	O
of	O
a	O
surgical	O
resection	O
cavity	O
.	O

For	O
human	O
glioblastoma	B-Disease
recurrences	O
,	O
the	O
feasibility	O
,	O
safety	O
,	O
and	O
short	O
-	O
term	O
effects	O
of	O
a	O
surgical	O
intracavitary	O
application	O
of	O
paclitaxel	B-Chemical
and	O
carboplatin	B-Chemical
encapsulated	O
by	O
liquid	O
crystalline	O
cubic	O
phases	O
are	O
examined	O
in	O
a	O
pilot	O
study	O
.	O

A	O
total	O
of	O
12	O
patients	O
with	O
a	O
recurrence	O
of	O
a	O
glioblastoma	B-Disease
multiforme	O
underwent	O
re	O
-	O
resection	O
and	O
received	O
an	O
intracavitary	O
application	O
of	O
paclitaxel	B-Chemical
and	O
carboplatin	B-Chemical
cubic	O
phases	O
in	O
different	O
dosages	O
.	O

Six	O
of	O
the	O
patients	O
received	O
more	O
than	O
15	O
mg	O
paclitaxel	B-Chemical
and	O
suffered	O
from	O
moderate	O
to	O
severe	O
brain	B-Disease
edema	I-Disease
,	O
while	O
the	O
remaining	O
patients	O
received	O
only	O
a	O
total	O
of	O
15	O
mg	O
paclitaxel	B-Chemical
.	O

In	O
the	O
latter	O
group	O
,	O
brain	B-Disease
edema	I-Disease
was	O
markedly	O
reduced	O
and	O
dealt	O
medically	O
.	O

Intracavitary	O
chemotherapy	O
in	O
recurrent	O
glioblastoma	B-Disease
using	O
cubic	O
phases	O
is	O
feasible	O
and	O
safe	O
,	O
yet	O
the	O
clinical	O
benefit	O
remains	O
to	O
be	O
examined	O
in	O
a	O
clinical	O
phase	O
II	O
study	O
.	O

Lamotrigine	B-Chemical
associated	O
with	O
exacerbation	O
or	O
de	O
novo	O
myoclonus	B-Disease
in	O
idiopathic	B-Disease
generalized	I-Disease
epilepsies	I-Disease
.	O

Five	O
patients	O
with	O
idiopathic	B-Disease
generalized	I-Disease
epilepsies	I-Disease
(	O
IGE	B-Disease
)	O
treated	O
with	O
lamotrigine	B-Chemical
(	O
LTG	B-Chemical
)	O
experienced	O
exacerbation	O
or	O
de	O
novo	O
appearance	O
of	O
myoclonic	B-Disease
jerks	I-Disease
(	O
MJ	B-Disease
)	O
.	O

In	O
three	O
patients	O
,	O
LTG	B-Chemical
exacerbated	O
MJ	B-Disease
in	O
a	O
dose	O
-	O
dependent	O
manner	O
with	O
early	O
aggravation	O
during	O
titration	O
.	O

MJ	B-Disease
disappeared	O
when	O
LTG	B-Chemical
dose	O
was	O
decreased	O
by	O
25	O
to	O
50	O
%	O
.	O

In	O
two	O
patients	O
,	O
LTG	B-Chemical
exacerbated	O
MJ	B-Disease
in	O
a	O
delayed	O
but	O
more	O
severe	O
manner	O
,	O
with	O
myoclonic	B-Disease
status	I-Disease
that	O
only	O
ceased	O
after	O
LTG	B-Chemical
withdrawal	O
.	O

Absence	O
of	O
acute	O
cerebral	O
vasoconstriction	O
after	O
cocaine	B-Chemical
-	O
associated	O
subarachnoid	B-Disease
hemorrhage	I-Disease
.	O

INTRODUCTION	O
:	O
Cocaine	B-Chemical
use	O
has	O
been	O
associated	O
with	O
neurovascular	B-Disease
complications	I-Disease
,	O
including	O
arterial	O
vasoconstriction	O
and	O
vasculitis	B-Disease
.	O

However	O
,	O
there	O
are	O
few	O
studies	O
of	O
angiographic	O
effects	O
of	O
cocaine	B-Chemical
on	O
human	O
cerebral	O
arteries	O
.	O

Information	O
on	O
these	O
effects	O
could	O
be	O
obtained	O
from	O
angiograms	O
of	O
patients	O
with	O
cocaine	B-Chemical
-	O
associated	O
subarachnoid	B-Disease
hemorrhage	I-Disease
(	O
SAH	B-Disease
)	O
who	O
underwent	O
angiography	O
shortly	O
after	O
cocaine	B-Chemical
use	O
.	O

METHODS	O
:	O
We	O
screened	O
patients	O
with	O
SAH	B-Disease
retrospectively	O
and	O
identified	O
those	O
with	O
positive	O
urine	O
toxicology	O
for	O
cocaine	B-Chemical
or	O
its	O
metabolites	O
.	O

Quantitative	O
arterial	O
diameter	O
measurements	O
from	O
angiograms	O
of	O
these	O
patients	O
were	O
compared	O
to	O
measurements	O
from	O
control	O
patients	O
with	O
SAH	B-Disease
who	O
were	O
matched	O
for	O
factors	O
known	O
to	O
influence	O
arterial	O
diameter	O
.	O

Qualitative	O
comparisons	O
of	O
small	O
artery	O
changes	O
also	O
were	O
made	O
.	O

RESULTS	O
:	O
Thirteen	O
patients	O
with	O
positive	O
cocaine	B-Chemical
toxicology	O
were	O
compared	O
to	O
26	O
controls	O
.	O

There	O
were	O
no	O
significant	O
differences	O
between	O
groups	O
in	O
the	O
mean	O
diameters	O
of	O
the	O
intradural	O
internal	O
carotid	O
,	O
sphenoidal	O
segment	O
of	O
the	O
middle	O
cerebral	O
,	O
precommunicating	O
segment	O
of	O
the	O
anterior	O
cerebral	O
,	O
or	O
basilar	O
arteries	O
(	O
p	O
greater	O
than	O
0	O
.	O
05	O
for	O
all	O
comparisons	O
,	O
unpaired	O
t	O
-	O
tests	O
)	O
.	O

There	O
also	O
were	O
no	O
significant	O
differences	O
between	O
groups	O
when	O
expressing	O
diameters	O
as	O
the	O
sum	O
of	O
the	O
precommunicating	O
segment	O
of	O
the	O
anterior	O
cerebral	O
+	O
sphenoidal	O
segment	O
of	O
the	O
middle	O
cerebral	O
+	O
supraclinoid	O
internal	O
carotid	O
artery	O
+	O
basilar	O
artery	O
divided	O
by	O
the	O
diameter	O
of	O
the	O
petrous	O
internal	O
carotid	O
artery	O
(	O
p	O
greater	O
than	O
0	O
.	O
05	O
,	O
unpaired	O
t	O
-	O
tests	O
)	O
.	O

Qualitative	O
assessments	O
showed	O
two	O
arterial	O
irregularities	O
in	O
the	O
distal	O
vasculature	O
in	O
each	O
group	O
.	O

CONCLUSION	O
:	O
No	O
quantitative	O
evidence	O
for	O
narrowing	O
of	O
large	O
cerebral	O
arteries	O
or	O
qualitative	O
angiographic	O
evidence	O
for	O
distal	O
narrowing	O
or	O
vasculitis	B-Disease
could	O
be	O
found	O
in	O
patients	O
who	O
underwent	O
angiography	O
after	O
aneurysmal	B-Disease
SAH	B-Disease
associated	O
with	O
cocaine	B-Chemical
use	O
.	O

Methamphetamine	B-Chemical
causes	O
alterations	O
in	O
the	O
MAP	O
kinase	O
-	O
related	O
pathways	O
in	O
the	O
brains	O
of	O
mice	O
that	O
display	O
increased	O
aggressiveness	B-Disease
.	O

Aggressive	B-Disease
behaviors	I-Disease
have	O
been	O
reported	O
in	O
patients	O
who	O
suffer	O
from	O
some	O
psychiatric	B-Disease
disorders	I-Disease
,	O
and	O
are	O
common	O
in	O
methamphetamine	B-Chemical
(	O
METH	B-Chemical
)	O
abusers	O
.	O

Herein	O
,	O
we	O
report	O
that	O
multiple	O
(	O
but	O
not	O
single	O
)	O
injections	O
of	O
METH	B-Chemical
significantly	O
increased	O
aggressiveness	B-Disease
in	O
male	O
CD	O
-	O
1	O
mice	O
.	O

This	O
increase	O
in	O
aggressiveness	B-Disease
was	O
not	O
secondary	O
to	O
METH	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
.	O

Analysis	O
of	O
protein	O
expression	O
using	O
antibody	O
microarrays	O
and	O
Western	O
blotting	O
revealed	O
differential	O
changes	O
in	O
MAP	O
kinase	O
-	O
related	O
pathways	O
after	O
multiple	O
and	O
single	O
METH	B-Chemical
injections	O
.	O

There	O
were	O
statistically	O
significant	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
decreases	O
in	O
MEK1	O
,	O
Erk2p	O
,	O
GSK3alpha	O
,	O
14	O
-	O
3	O
-	O
3e	O
,	O
and	O
MEK7	O
in	O
the	O
striata	O
of	O
mice	O
after	O
multiple	O
injections	O
of	O
METH	B-Chemical
.	O

MEK1	O
was	O
significantly	O
decreased	O
also	O
after	O
a	O
single	O
injection	O
of	O
METH	B-Chemical
,	O
but	O
to	O
a	O
much	O
lesser	O
degree	O
than	O
after	O
multiple	O
injections	O
of	O
METH	B-Chemical
.	O

In	O
the	O
frontal	O
cortex	O
,	O
there	O
was	O
a	O
statistically	O
significant	O
decrease	O
in	O
GSK3alpha	O
after	O
multiple	O
(	O
but	O
not	O
single	O
)	O
injections	O
of	O
METH	B-Chemical
.	O

These	O
findings	O
suggest	O
that	O
alterations	O
in	O
MAP	O
kinase	O
-	O
related	O
pathways	O
in	O
the	O
prefronto	O
-	O
striatal	O
circuitries	O
might	O
be	O
involved	O
in	O
the	O
manifestation	O
of	O
aggressive	B-Disease
behaviors	I-Disease
in	O
mice	O
.	O

Amisulpride	B-Chemical
related	O
tic	B-Disease
-	I-Disease
like	I-Disease
symptoms	I-Disease
in	O
an	O
adolescent	O
schizophrenic	B-Disease
.	O

Tic	B-Disease
disorders	I-Disease
can	O
be	O
effectively	O
treated	O
by	O
atypical	O
antipsychotics	O
such	O
as	O
risperidone	B-Chemical
,	O
olanzapine	B-Chemical
and	O
ziprasidone	B-Chemical
.	O

However	O
,	O
there	O
are	O
two	O
case	O
reports	O
that	O
show	O
tic	B-Disease
-	I-Disease
like	I-Disease
symptoms	I-Disease
,	O
including	O
motor	O
and	O
phonic	O
variants	O
,	O
occurring	O
during	O
treatment	O
with	O
quetiapine	B-Chemical
or	O
clozapine	B-Chemical
.	O

We	O
present	O
a	O
15	O
-	O
year	O
-	O
old	O
girl	O
schizophrenic	B-Disease
who	O
developed	O
frequent	O
involuntary	B-Disease
eye	I-Disease
-	I-Disease
blinking	I-Disease
movements	I-Disease
after	O
5	O
months	O
of	O
amisulpride	B-Chemical
treatment	O
(	O
1000	O
mg	O
per	O
day	O
)	O
.	O

The	O
tic	B-Disease
-	I-Disease
like	I-Disease
symptoms	I-Disease
resolved	O
completely	O
after	O
we	O
reduced	O
the	O
dose	O
of	O
amisulpride	B-Chemical
down	O
to	O
800	O
mg	O
per	O
day	O
.	O

However	O
,	O
her	O
psychosis	B-Disease
recurred	O
after	O
the	O
dose	O
reduction	O
.	O

We	O
then	O
placed	O
her	O
on	O
an	O
additional	O
100	O
mg	O
per	O
day	O
of	O
quetiapine	B-Chemical
.	O

She	O
has	O
been	O
in	O
complete	O
remission	O
under	O
the	O
combined	O
medications	O
for	O
more	O
than	O
one	O
year	O
and	O
maintains	O
a	O
fair	O
role	O
function	O
.	O

No	O
more	O
tic	B-Disease
-	I-Disease
like	I-Disease
symptoms	I-Disease
or	O
other	O
side	O
effects	O
have	O
been	O
reported	O
.	O

Together	O
with	O
previously	O
reported	O
cases	O
,	O
our	O
patient	O
suggests	O
that	O
tic	B-Disease
-	I-Disease
like	I-Disease
symptoms	I-Disease
might	O
occur	O
in	O
certain	O
vulnerable	O
individuals	O
during	O
treatment	O
with	O
atypical	O
antipsychotics	O
such	O
as	O
quetiapine	B-Chemical
,	O
clozapine	B-Chemical
,	O
or	O
amisulpride	B-Chemical
.	O

Chloroquine	B-Chemical
related	O
complete	O
heart	B-Disease
block	I-Disease
with	O
blindness	B-Disease
:	O
case	O
report	O
.	O

A	O
27	O
-	O
year	O
old	O
African	O
woman	O
with	O
history	O
of	O
regular	O
chloroquine	B-Chemical
ingestion	O
presented	O
with	O
progressive	O
deterioration	B-Disease
of	I-Disease
vision	I-Disease
,	O
easy	O
fatiguability	B-Disease
,	O
dyspnoea	B-Disease
,	O
dizziness	B-Disease
progressing	O
to	O
syncopal	B-Disease
attacks	I-Disease
.	O

Ophthalmological	O
assessment	O
revealed	O
features	O
of	O
chloroquine	B-Chemical
retinopathy	B-Disease
,	O
cardiac	O
assessment	O
revealed	O
features	O
of	O
heart	B-Disease
failure	I-Disease
and	O
a	O
complete	O
heart	B-Disease
block	I-Disease
with	O
right	B-Disease
bundle	I-Disease
branch	I-Disease
block	I-Disease
pattern	O
.	O

The	O
heart	B-Disease
block	I-Disease
was	O
treated	O
by	O
pacemaker	O
insertion	O
and	O
the	O
heart	B-Disease
failure	I-Disease
resolved	O
spontaneously	O
following	O
chloroquine	B-Chemical
discontinuation	O
.	O

She	O
however	O
remains	O
blind	B-Disease
.	O

Effects	O
of	O
suprofen	B-Chemical
on	O
the	O
isolated	O
perfused	O
rat	O
kidney	O
.	O

Although	O
suprofen	B-Chemical
has	O
been	O
associated	O
with	O
the	O
development	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
in	O
greater	O
than	O
100	O
subjects	O
,	O
the	O
mechanism	O
of	O
damage	O
remains	O
unclear	O
.	O

The	O
direct	O
nephrotoxic	B-Disease
effects	O
of	O
a	O
single	O
dose	O
of	O
15	O
mg	O
of	O
suprofen	B-Chemical
were	O
compared	O
in	O
the	O
recirculating	O
isolated	O
rat	O
kidney	O
perfused	O
with	O
cell	O
-	O
free	O
buffer	O
with	O
or	O
without	O
the	O
addition	O
of	O
5	O
mg	O
/	O
dL	O
of	O
uric	B-Chemical
acid	I-Chemical
.	O

There	O
were	O
no	O
significant	O
differences	O
in	O
renal	O
sodium	B-Chemical
excretion	O
,	O
oxygen	B-Chemical
consumption	O
,	O
or	O
urinary	O
flow	O
rates	O
in	O
kidneys	O
perfused	O
with	O
suprofen	B-Chemical
compared	O
with	O
the	O
drug	O
-	O
free	O
control	O
groups	O
.	O

In	O
contrast	O
,	O
a	O
significant	O
decline	O
in	O
glomerular	O
filtration	O
rate	O
was	O
found	O
after	O
the	O
introduction	O
of	O
suprofen	B-Chemical
to	O
the	O
kidney	O
perfused	O
with	O
uric	B-Chemical
acid	I-Chemical
;	O
no	O
changes	O
were	O
found	O
with	O
suprofen	B-Chemical
in	O
the	O
absence	O
of	O
uric	B-Chemical
acid	I-Chemical
.	O

A	O
significant	O
decrease	O
in	O
the	O
baseline	O
excretion	O
rate	O
of	O
uric	B-Chemical
acid	I-Chemical
was	O
found	O
in	O
rats	O
given	O
suprofen	B-Chemical
,	O
compared	O
with	O
drug	O
-	O
free	O
controls	O
.	O

However	O
,	O
the	O
fractional	O
excretion	O
of	O
uric	B-Chemical
acid	I-Chemical
was	O
unchanged	O
between	O
the	O
groups	O
over	O
the	O
experimental	O
period	O
.	O

In	O
summary	O
,	O
suprofen	B-Chemical
causes	O
acute	B-Disease
declines	I-Disease
in	I-Disease
renal	I-Disease
function	I-Disease
,	O
most	O
likely	O
by	O
directly	O
altering	O
the	O
intrarenal	O
distribution	O
of	O
uric	B-Chemical
acid	I-Chemical
.	O

Microinjection	O
of	O
ritanserin	B-Chemical
into	O
the	O
CA1	O
region	O
of	O
hippocampus	O
improves	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
in	O
adult	O
male	O
rats	O
.	O

The	O
effect	O
of	O
ritanserin	B-Chemical
(	O
5	O
-	O
HT2	O
antagonist	O
)	O
on	O
scopolamine	B-Chemical
(	O
muscarinic	O
cholinergic	O
antagonist	O
)	O
-	O
induced	O
amnesia	B-Disease
in	O
Morris	O
water	O
maze	O
(	O
MWM	O
)	O
was	O
investigated	O
.	O

Rats	O
were	O
divided	O
into	O
eight	O
groups	O
and	O
bilaterally	O
cannulated	O
into	O
CA1	O
region	O
of	O
the	O
hippocampus	O
.	O

One	O
week	O
later	O
,	O
they	O
received	O
repeatedly	O
vehicles	O
(	O
saline	O
,	O
DMSO	B-Chemical
,	O
saline	O
+	O
DMSO	B-Chemical
)	O
,	O
scopolamine	B-Chemical
(	O
2	O
microg	O
/	O
0	O
.	O
5	O
microl	O
saline	O
/	O
side	O
;	O
30	O
min	O
before	O
training	O
)	O
,	O
ritanserin	B-Chemical
(	O
2	O
,	O
4	O
and	O
8	O
microg	O
/	O
0	O
.	O
5	O
microl	O
DMSO	B-Chemical
/	O
side	O
;	O
20	O
min	O
before	O
training	O
)	O
and	O
scopolamine	B-Chemical
(	O
2	O
microg	O
/	O
0	O
.	O
5	O
microl	O
;	O
30	O
min	O
before	O
ritanserin	B-Chemical
injection	O
)	O
+	O
ritanserin	B-Chemical
(	O
4	O
microg	O
/	O
0	O
.	O
5	O
microl	O
DMSO	B-Chemical
)	O
through	O
cannulae	O
each	O
day	O
.	O

Animals	O
were	O
tested	O
for	O
four	O
consecutive	O
days	O
(	O
4	O
trial	O
/	O
day	O
)	O
in	O
MWM	O
during	O
which	O
the	O
position	O
of	O
hidden	O
platform	O
was	O
unchanged	O
.	O

In	O
the	O
fifth	O
day	O
,	O
the	O
platform	O
was	O
elevated	O
above	O
the	O
water	O
surface	O
in	O
another	O
position	O
to	O
evaluate	O
the	O
function	O
of	O
motor	O
,	O
motivational	O
and	O
visual	O
systems	O
.	O

The	O
results	O
showed	O
a	O
significant	O
increase	O
in	O
escape	O
latencies	O
and	O
traveled	O
distances	O
to	O
find	O
platform	O
in	O
scopolamine	B-Chemical
-	O
treated	O
group	O
as	O
compared	O
to	O
saline	O
group	O
.	O

Ritanserin	B-Chemical
-	O
treated	O
rats	O
(	O
4	O
microg	O
/	O
0	O
.	O
5	O
microl	O
/	O
side	O
)	O
showed	O
a	O
significant	O
decrease	O
in	O
the	O
mentioned	O
parameters	O
as	O
compared	O
to	O
DMSO	B-Chemical
-	O
treated	O
group	O
.	O

However	O
,	O
scopolamine	B-Chemical
and	O
ritanserin	B-Chemical
co	O
-	O
administration	O
resulted	O
in	O
a	O
significant	O
decrease	O
in	O
escape	O
latencies	O
and	O
traveled	O
distances	O
as	O
compared	O
to	O
the	O
scopolamine	B-Chemical
-	O
treated	O
rats	O
.	O

Our	O
findings	O
show	O
that	O
microinjection	O
of	O
ritanserin	B-Chemical
into	O
the	O
CA1	O
region	O
of	O
the	O
hippocampus	O
improves	O
the	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
.	O

PTU	B-Chemical
-	O
associated	O
vasculitis	B-Disease
in	O
a	O
girl	O
with	O
Turner	B-Disease
Syndrome	I-Disease
and	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
.	O

Palpable	O
purpura	B-Disease
is	O
a	O
concerning	O
clinical	O
finding	O
in	O
pediatric	O
patients	O
and	O
can	O
have	O
many	O
causes	O
,	O
including	O
infectious	O
and	O
autoimmune	O
processes	O
.	O

A	O
rare	O
cause	O
,	O
drug	O
-	O
induced	O
vasculitis	B-Disease
,	O
may	O
result	O
from	O
the	O
production	O
of	O
antineutrophil	O
cytoplasmic	O
antibodies	O
(	O
ANCAs	O
)	O
in	O
response	O
to	O
a	O
medication	O
.	O

We	O
report	O
a	O
girl	O
with	O
Turner	B-Disease
syndrome	I-Disease
and	O
Graves	B-Disease
'	I-Disease
disease	I-Disease
who	O
presented	O
with	O
palpable	O
purpuric	B-Disease
lesions	I-Disease
.	O

The	O
diagnosis	O
of	O
propylthiouracil	B-Chemical
(	O
PTU	B-Chemical
)	O
-	O
associated	O
vasculitis	B-Disease
was	O
made	O
by	O
observation	O
of	O
consistent	O
clinical	O
features	O
,	O
the	O
detection	O
of	O
elevated	O
ANA	O
and	O
ANCA	O
in	O
the	O
blood	O
,	O
and	O
the	O
observed	O
clinical	O
resolution	O
of	O
symptoms	O
following	O
withdrawal	O
of	O
PTU	B-Chemical
.	O

Subsequent	O
treatment	O
of	O
persistent	O
hyperthyroidism	B-Disease
with	O
radioablation	O
did	O
not	O
result	O
in	O
an	O
exacerbation	O
of	O
the	O
vasculitis	B-Disease
,	O
a	O
complication	O
described	O
in	O
prior	O
case	O
reports	O
.	O

Daidzein	B-Chemical
activates	O
choline	B-Chemical
acetyltransferase	O
from	O
MC	O
-	O
IXC	O
cells	O
and	O
improves	O
drug	O
-	O
induced	O
amnesia	B-Disease
.	O

The	O
choline	B-Chemical
acetyltransferase	O
(	O
ChAT	O
)	O
activator	O
,	O
which	O
enhances	O
cholinergic	O
transmission	O
via	O
an	O
augmentation	O
of	O
the	O
enzymatic	O
production	O
of	O
acetylcholine	B-Chemical
(	O
ACh	B-Chemical
)	O
,	O
is	O
an	O
important	O
factor	O
in	O
the	O
treatment	O
of	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
AD	B-Disease
)	O
.	O

Methanolic	O
extracts	O
from	O
Pueraria	O
thunbergiana	O
exhibited	O
an	O
activation	O
effect	O
(	O
46	O
%	O
)	O
on	O
ChAT	O
in	O
vitro	O
.	O

Via	O
the	O
sequential	O
isolation	O
of	O
Pueraria	O
thunbergiana	O
,	O
the	O
active	O
component	O
was	O
ultimately	O
identified	O
as	O
daidzein	B-Chemical
(	O
4	B-Chemical
'	I-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
dihydroxy	I-Chemical
-	I-Chemical
isoflavone	I-Chemical
)	O
.	O

In	O
order	O
to	O
investigate	O
the	O
effects	O
of	O
daidzein	B-Chemical
from	O
Pueraria	O
thunbergiana	O
on	O
scopolamine	B-Chemical
-	O
induced	O
impairments	B-Disease
of	I-Disease
learning	I-Disease
and	I-Disease
memory	I-Disease
,	O
we	O
conducted	O
a	O
series	O
of	O
in	O
vivo	O
tests	O
.	O

Administration	O
of	O
daidzein	B-Chemical
(	O
4	O
.	O
5	O
mg	O
/	O
kg	O
body	O
weight	O
)	O
to	O
mice	O
was	O
shown	O
significantly	O
to	O
reverse	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
,	O
according	O
to	O
the	O
results	O
of	O
a	O
Y	O
-	O
maze	O
test	O
.	O

Injections	O
of	O
scopolamine	B-Chemical
into	O
mice	O
resulted	O
in	O
impaired	O
performance	O
on	O
Y	O
-	O
maze	O
tests	O
(	O
a	O
37	O
%	O
decreases	O
in	O
alternation	O
behavior	O
)	O
.	O

By	O
way	O
of	O
contrast	O
,	O
mice	O
treated	O
with	O
daidzein	B-Chemical
prior	O
to	O
the	O
scopolamine	B-Chemical
injections	O
were	O
noticeably	O
protected	O
from	O
this	O
performance	O
impairment	O
(	O
an	O
approximately	O
12	O
%	O
-	O
21	O
%	O
decrease	O
in	O
alternation	O
behavior	O
)	O
.	O

These	O
results	O
indicate	O
that	O
daidzein	B-Chemical
might	O
play	O
a	O
role	O
in	O
acetylcholine	B-Chemical
biosynthesis	O
as	O
a	O
ChAT	O
activator	O
,	O
and	O
that	O
it	O
also	O
ameliorates	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
.	O

Urinary	O
symptoms	O
and	O
quality	O
of	O
life	O
changes	O
in	O
Thai	O
women	O
with	O
overactive	B-Disease
bladder	I-Disease
after	O
tolterodine	B-Chemical
treatment	O
.	O

OBJECTIVES	O
:	O
To	O
study	O
the	O
urinary	O
symptoms	O
and	O
quality	O
of	O
life	O
changes	O
in	O
Thai	O
women	O
with	O
overactive	B-Disease
bladder	I-Disease
(	O
OAB	B-Disease
)	O
after	O
tolterodine	B-Chemical
treatment	O
.	O

MATERIAL	O
AND	O
METHOD	O
:	O
Thirty	O
women	O
(	O
aged	O
30	O
-	O
77	O
years	O
)	O
diagnosed	O
as	O
having	O
OAB	B-Disease
at	O
the	O
Gynecology	O
Clinic	O
,	O
King	O
Chulalongkorn	O
Memorial	O
Hospital	O
from	O
January	O
to	O
April	O
2004	O
were	O
included	O
in	O
the	O
present	O
study	O
.	O

Tolterodine	B-Chemical
2	O
mg	O
,	O
twice	O
daily	O
was	O
given	O
.	O

After	O
8	O
weeks	O
treatment	O
,	O
changes	O
in	O
micturition	O
diary	O
variables	O
and	O
tolerability	O
were	O
determined	O
.	O

Short	O
form	O
36	O
(	O
SF36	O
)	O
questionaires	O
(	O
Thai	O
version	O
)	O
were	O
given	O
before	O
and	O
after	O
8	O
weeks	O
of	O
treatment	O
.	O

RESULTS	O
:	O
At	O
8	O
weeks	O
,	O
all	O
micturition	O
per	O
day	O
decreased	O
from	O
16	O
.	O

7	O
+	O
/	O
-	O
5	O
.	O

3	O
to	O
6	O
.	O

7	O
+	O
/	O
-	O
2	O
.	O
4	O
times	O
per	O
day	O
.	O

The	O
number	O
of	O
nocturia	B-Disease
episodes	O
decreased	O
from	O
5	O
.	O
4	O
+	O
/	O
-	O
4	O
.	O
2	O
to	O
1	O
.	O
1	O
+	O
/	O
-	O
1	O
.	O
0	O
times	O
per	O
night	O
.	O

The	O
most	O
common	O
side	O
effect	O
was	O
dry	B-Disease
month	I-Disease
in	O
5	O
cases	O
(	O
16	O
.	O
7	O
%	O
)	O
with	O
2	O
cases	O
reporting	O
a	O
moderate	O
degree	O
and	O
1	O
case	O
with	O
severe	O
degree	O
.	O

Only	O
one	O
case	O
(	O
3	O
.	O
3	O
%	O
)	O
withdrew	O
from	O
the	O
present	O
study	O
due	O
to	O
a	O
severe	O
dry	B-Disease
mouth	I-Disease
.	O

The	O
SF	O
-	O
36	O
scores	O
changed	O
significantly	O
in	O
the	O
domains	O
of	O
physical	O
functioning	O
,	O
role	O
function	O
emotional	O
,	O
social	O
function	O
and	O
mental	O
heath	O
.	O

CONCLUSION	O
:	O
Tolterodine	B-Chemical
was	O
well	O
tolerated	O
and	O
its	O
effects	O
improved	O
the	O
quality	O
of	O
life	O
in	O
Thai	O
women	O
with	O
OAB	B-Disease
.	O

Remifentanil	B-Chemical
pretreatment	O
reduces	O
myoclonus	B-Disease
after	O
etomidate	B-Chemical
.	O

STUDY	O
OBJECTIVE	O
:	O
The	O
aim	O
of	O
the	O
study	O
was	O
to	O
compare	O
the	O
effect	O
of	O
pretreatment	O
with	O
remifentanil	B-Chemical
1	O
microg	O
/	O
kg	O
and	O
the	O
effect	O
of	O
gender	O
on	O
the	O
incidence	O
of	O
myoclonus	B-Disease
after	O
anesthesia	O
induction	O
with	O
etomidate	B-Chemical
.	O

DESIGN	O
:	O
This	O
was	O
a	O
randomized	O
,	O
double	O
-	O
blind	O
study	O
.	O

SETTING	O
:	O
The	O
study	O
was	O
conducted	O
at	O
a	O
university	O
hospital	O
.	O

PATIENTS	O
:	O
Sixty	O
patients	O
were	O
pretreated	O
in	O
a	O
randomized	O
double	O
-	O
blinded	O
fashion	O
with	O
remifentanil	B-Chemical
1	O
microg	O
/	O
kg	O
or	O
placebo	O
.	O

Two	O
minutes	O
after	O
remifentanil	B-Chemical
or	O
placebo	O
injection	O
,	O
etomidate	B-Chemical
0	O
.	O
3	O
mg	O
/	O
kg	O
was	O
given	O
.	O

MEASUREMENTS	O
:	O
Myoclonus	B-Disease
was	O
recorded	O
with	O
a	O
scale	O
of	O
0	O
to	O
3	O
.	O

The	O
grade	O
of	O
sedation	O
(	O
none	O
,	O
mild	O
,	O
moderate	O
,	O
severe	O
)	O
,	O
nausea	B-Disease
,	O
pruritus	B-Disease
,	O
and	O
apnea	B-Disease
were	O
recorded	O
after	O
injection	O
of	O
both	O
drugs	O
.	O

MAIN	O
RESULTS	O
:	O
The	O
incidence	O
of	O
myoclonus	B-Disease
was	O
significantly	O
lower	O
in	O
the	O
remifentanil	B-Chemical
group	O
(	O
6	O
.	O
7	O
%	O
)	O
than	O
in	O
the	O
placebo	O
group	O
(	O
70	O
%	O
)	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

None	O
of	O
the	O
patients	O
experienced	O
sedation	O
,	O
apnea	B-Disease
,	O
nausea	B-Disease
,	O
or	O
pruritus	B-Disease
after	O
injection	O
of	O
both	O
drugs	O
.	O

In	O
the	O
placebo	O
group	O
,	O
male	O
patients	O
were	O
associated	O
with	O
significantly	O
increased	O
incidence	O
of	O
myoclonus	B-Disease
after	O
etomidate	B-Chemical
administration	O
.	O

CONCLUSION	O
:	O
Pretreatment	O
with	O
remifentanil	B-Chemical
1	O
microg	O
/	O
kg	O
reduced	O
myoclonus	B-Disease
after	O
etomidate	B-Chemical
induction	O
without	O
side	O
effects	O
such	O
as	O
sedation	O
,	O
apnea	B-Disease
,	O
nausea	B-Disease
,	O
or	O
pruritus	B-Disease
.	O

Men	O
experience	O
increased	O
incidence	O
of	O
myoclonus	B-Disease
than	O
women	O
after	O
etomidate	B-Chemical
administration	O
.	O

Memory	O
function	O
and	O
serotonin	B-Chemical
transporter	O
promoter	O
gene	O
polymorphism	O
in	O
ecstasy	B-Chemical
(	O
MDMA	B-Chemical
)	O
users	O
.	O

Although	O
3	B-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
methylenedioxymethamphetamine	I-Chemical
(	O
MDMA	B-Chemical
or	O
ecstasy	B-Chemical
)	O
has	O
been	O
shown	O
to	O
damage	O
brain	O
serotonin	B-Chemical
(	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
)	O
neurons	O
in	O
animals	O
and	O
possibly	O
humans	O
,	O
little	O
is	O
known	O
about	O
the	O
long	O
-	O
term	O
consequences	O
of	O
MDMA	B-Chemical
-	O
induced	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
neurotoxic	B-Disease
lesions	I-Disease
on	O
functions	O
in	O
which	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
is	O
involved	O
,	O
such	O
as	O
cognitive	O
function	O
.	O

Because	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
transporters	O
play	O
a	O
key	O
element	O
in	O
the	O
regulation	O
of	O
synaptic	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
transmission	O
it	O
may	O
be	O
important	O
to	O
control	O
for	O
the	O
potential	O
covariance	O
effect	O
of	O
a	O
polymorphism	O
in	O
the	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
transporter	O
promoter	O
gene	O
region	O
(	O
5	O
-	O
HTTLPR	O
)	O
when	O
studying	O
the	O
effects	O
of	O
MDMA	B-Chemical
as	O
well	O
as	O
cognitive	O
functioning	O
.	O

The	O
aim	O
of	O
the	O
study	O
was	O
to	O
investigate	O
the	O
effects	O
of	O
moderate	O
and	O
heavy	O
MDMA	B-Chemical
use	O
on	O
cognitive	O
function	O
,	O
as	O
well	O
as	O
the	O
effects	O
of	O
long	O
-	O
term	O
abstention	O
from	O
MDMA	B-Chemical
,	O
in	O
subjects	O
genotyped	O
for	O
5	O
-	O
HTTLPR	O
.	O

A	O
second	O
aim	O
of	O
the	O
study	O
was	O
to	O
determine	O
whether	O
these	O
effects	O
differ	O
for	O
females	O
and	O
males	O
.	O

Fifteen	O
moderate	O
MDMA	B-Chemical
users	O
(	O
<	O
55	O
lifetime	O
tablets	O
)	O
,	O
22	O
heavy	O
MDMA	B-Chemical
+	O
users	O
(	O
>	O
55	O
lifetime	O
tablets	O
)	O
,	O
16	O
ex	O
-	O
MDMA	B-Chemical
+	O
users	O
(	O
last	O
tablet	O
>	O
1	O
year	O
ago	O
)	O
and	O
13	O
controls	O
were	O
compared	O
on	O
a	O
battery	O
of	O
neuropsychological	O
tests	O
.	O

DNA	O
from	O
peripheral	O
nuclear	O
blood	O
cells	O
was	O
genotyped	O
for	O
5	O
-	O
HTTLPR	O
using	O
standard	O
polymerase	O
chain	O
reaction	O
methods	O
.	O
A	O
significant	O
group	O
effect	O
was	O
observed	O
only	O
on	O
memory	O
function	O
tasks	O
(	O
p	O
=	O
0	O
.	O
04	O
)	O
but	O
not	O
on	O
reaction	O
times	O
(	O
p	O
=	O
0	O
.	O
61	O
)	O
or	O
attention	O
/	O
executive	O
functioning	O
(	O
p	O
=	O
0	O
.	O
59	O
)	O
.	O

Heavy	O
and	O
ex	O
-	O
MDMA	B-Chemical
+	O
users	O
performed	O
significantly	O
poorer	O
on	O
memory	O
tasks	O
than	O
controls	O
.	O

In	O
contrast	O
,	O
no	O
evidence	O
of	O
memory	B-Disease
impairment	I-Disease
was	O
observed	O
in	O
moderate	O
MDMA	B-Chemical
users	O
.	O

No	O
significant	O
effect	O
of	O
5	O
-	O
HTTLPR	O
or	O
gender	O
was	O
observed	O
.	O

While	O
the	O
use	O
of	O
MDMA	B-Chemical
in	O
quantities	O
that	O
may	O
be	O
considered	O
"	O
moderate	O
"	O
is	O
not	O
associated	O
with	O
impaired	B-Disease
memory	I-Disease
functioning	I-Disease
,	O
heavy	O
use	O
of	O
MDMA	B-Chemical
use	O
may	O
lead	O
to	O
long	O
lasting	O
memory	B-Disease
impairments	I-Disease
.	O

No	O
effect	O
of	O
5	O
-	O
HTTLPR	O
or	O
gender	O
on	O
memory	O
function	O
or	O
MDMA	B-Chemical
use	O
was	O
observed	O
.	O

Role	O
of	O
mangiferin	B-Chemical
on	O
biochemical	O
alterations	O
and	O
antioxidant	O
status	O
in	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
in	O
rats	O
.	O

The	O
current	O
study	O
dealt	O
with	O
the	O
protective	O
role	O
of	O
mangiferin	B-Chemical
,	O
a	O
polyphenol	B-Chemical
from	O
Mangifera	O
indica	O
Linn	O
.	O

(	O
Anacardiaceae	O
)	O
,	O
on	O
isoproterenol	B-Chemical
(	O
ISPH	B-Chemical
)	O
-	O
induced	O
myocardial	B-Disease
infarction	I-Disease
(	O
MI	B-Disease
)	O
in	O
rats	O
through	O
its	O
antioxidative	O
mechanism	O
.	O

Subcutaneous	O
injection	O
of	O
ISPH	B-Chemical
(	O
200	O
mg	O
/	O
kg	O
body	O
weight	O
in	O
1	O
ml	O
saline	O
)	O
to	O
rats	O
for	O
2	O
consecutive	O
days	O
caused	O
myocardial	B-Disease
damage	I-Disease
in	O
rat	O
heart	O
,	O
which	O
was	O
determined	O
by	O
the	O
increased	O
activity	O
of	O
serum	O
lactate	B-Chemical
dehydrogenase	O
(	O
LDH	O
)	O
and	O
creatine	B-Chemical
phosphokinase	O
isoenzymes	O
(	O
CK	O
-	O
MB	O
)	O
,	O
increased	O
uric	B-Chemical
acid	I-Chemical
level	O
and	O
reduced	O
plasma	O
iron	B-Chemical
binding	O
capacity	O
.	O

The	O
protective	O
role	O
of	O
mangiferin	B-Chemical
was	O
analyzed	O
by	O
triphenyl	B-Chemical
tetrazolium	I-Chemical
chloride	I-Chemical
(	O
TTC	B-Chemical
)	O
test	O
used	O
for	O
macroscopic	O
enzyme	O
mapping	O
assay	O
of	O
the	O
ischemic	B-Disease
myocardium	I-Disease
.	O

The	O
heart	O
tissue	O
antioxidant	O
enzymes	O
such	O
as	O
superoxide	B-Chemical
dismutase	O
,	O
catalase	O
,	O
glutathione	B-Chemical
peroxidase	O
,	O
glutathione	B-Chemical
transferase	O
and	O
glutathione	B-Chemical
reductase	O
activities	O
,	O
non	O
-	O
enzymic	O
antioxidants	O
such	O
as	O
cerruloplasmin	O
,	O
Vitamin	B-Chemical
C	I-Chemical
,	O
Vitamin	B-Chemical
E	I-Chemical
and	O
glutathione	B-Chemical
levels	O
were	O
altered	O
in	O
MI	B-Disease
rats	O
.	O

Upon	O
pretreatment	O
with	O
mangiferin	B-Chemical
(	O
100	O
mg	O
/	O
kg	O
body	O
weight	O
suspended	O
in	O
2	O
ml	O
of	O
dimethyl	B-Chemical
sulphoxide	I-Chemical
)	O
given	O
intraperitoneally	O
for	O
28	O
days	O
to	O
MI	B-Disease
rats	O
protected	O
the	O
above	O
-	O
mentioned	O
parameters	O
to	O
fall	O
from	O
the	O
normal	O
levels	O
.	O

Activities	O
of	O
heart	O
tissue	O
enzymic	O
antioxidants	O
and	O
serum	O
non	O
-	O
enzymic	O
antioxidants	O
levels	O
rose	O
significantly	O
upon	O
mangiferin	B-Chemical
administration	O
as	O
compared	O
to	O
ISPH	B-Chemical
-	O
induced	O
MI	B-Disease
rats	O
.	O

From	O
the	O
present	O
study	O
it	O
is	O
concluded	O
that	O
mangiferin	B-Chemical
exerts	O
a	O
beneficial	O
effect	O
against	O
ISPH	B-Chemical
-	O
induced	O
MI	B-Disease
due	O
to	O
its	O
antioxidant	O
potential	O
,	O
which	O
regulated	O
the	O
tissues	O
defense	O
system	O
against	O
cardiac	B-Disease
damage	I-Disease
.	O

Cardiovascular	O
risk	O
with	O
cyclooxygenase	B-Chemical
inhibitors	I-Chemical
:	O
general	O
problem	O
with	O
substance	O
specific	O
differences	O
?	O

Randomised	O
clinical	O
trials	O
and	O
observational	O
studies	O
have	O
shown	O
an	O
increased	O
risk	O
of	O
myocardial	B-Disease
infarction	I-Disease
,	O
stroke	B-Disease
,	O
hypertension	B-Disease
and	O
heart	B-Disease
failure	I-Disease
during	O
treatment	O
with	O
cyclooxygenase	B-Chemical
inhibitors	I-Chemical
.	O

Adverse	O
cardiovascular	O
effects	O
occurred	O
mainly	O
,	O
but	O
not	O
exclusively	O
,	O
in	O
patients	O
with	O
concomitant	O
risk	O
factors	O
.	O

Cyclooxygenase	B-Chemical
inhibitors	I-Chemical
cause	O
complex	O
changes	O
in	O
renal	O
,	O
vascular	O
and	O
cardiac	O
prostanoid	O
profiles	O
thereby	O
increasing	O
vascular	O
resistance	O
and	O
fluid	O
retention	O
.	O

The	O
incidence	O
of	O
cardiovascular	O
adverse	O
events	O
tends	O
to	O
increase	O
with	O
the	O
daily	O
dose	O
and	O
total	O
exposure	O
time	O
.	O

A	O
comparison	O
of	O
individual	O
selective	O
and	O
unselective	O
cyclooxygenase	B-Chemical
inhibitors	I-Chemical
suggests	O
substance	O
-	O
specific	O
differences	O
,	O
which	O
may	O
depend	O
on	O
differences	O
in	O
pharmacokinetic	O
parameters	O
or	O
inhibitory	O
potency	O
and	O
may	O
be	O
contributed	O
by	O
prostaglandin	B-Chemical
-	O
independent	O
effects	O
.	O

Diagnostic	O
markers	O
such	O
as	O
N	B-Chemical
-	I-Chemical
terminal	I-Chemical
pro	I-Chemical
brain	I-Chemical
natriuretic	I-Chemical
peptide	I-Chemical
(	O
NT	B-Chemical
-	I-Chemical
proBNP	I-Chemical
)	O
or	O
high	O
-	O
sensitive	O
C	O
-	O
reactive	O
protein	O
might	O
help	O
in	O
the	O
early	O
identification	O
of	O
patients	O
at	O
risk	O
,	O
thus	O
avoiding	O
the	O
occurrence	O
of	O
serious	O
cardiovascular	B-Disease
toxicity	I-Disease
.	O

Pilocarpine	B-Chemical
seizures	B-Disease
cause	O
age	O
-	O
dependent	O
impairment	B-Disease
in	I-Disease
auditory	I-Disease
location	I-Disease
discrimination	I-Disease
.	O

Children	O
who	O
have	O
status	B-Disease
epilepticus	I-Disease
have	O
continuous	O
or	O
rapidly	O
repeating	O
seizures	B-Disease
that	O
may	O
be	O
life	O
-	O
threatening	O
and	O
may	O
cause	O
life	O
-	O
long	O
changes	O
in	O
brain	O
and	O
behavior	O
.	O

The	O
extent	O
to	O
which	O
status	B-Disease
epilepticus	I-Disease
causes	O
deficits	B-Disease
in	I-Disease
auditory	I-Disease
discrimination	I-Disease
is	O
unknown	O
.	O

A	O
naturalistic	O
auditory	O
location	O
discrimination	O
method	O
was	O
used	O
to	O
evaluate	O
this	O
question	O
using	O
an	O
animal	O
model	O
of	O
status	B-Disease
epilepticus	I-Disease
.	O

Male	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
injected	O
with	O
saline	O
on	O
postnatal	O
day	O
(	O
P	O
)	O
20	O
,	O
or	O
a	O
convulsant	O
dose	O
of	O
pilocarpine	B-Chemical
on	O
P20	O
or	O
P45	O
.	O

Pilocarpine	B-Chemical
on	O
either	O
day	O
induced	O
status	B-Disease
epilepticus	I-Disease
;	O
status	B-Disease
epilepticus	I-Disease
at	O
P45	O
resulted	O
in	O
CA3	O
cell	O
loss	O
and	O
spontaneous	O
seizures	B-Disease
,	O
whereas	O
P20	O
rats	O
had	O
no	O
cell	O
loss	O
or	O
spontaneous	O
seizures	B-Disease
.	O

Mature	O
rats	O
were	O
trained	O
with	O
sound	O
-	O
source	O
location	O
and	O
sound	O
-	O
silence	O
discriminations	O
.	O

Control	O
(	O
saline	O
P20	O
)	O
rats	O
acquired	O
both	O
discriminations	O
immediately	O
.	O

In	O
status	B-Disease
epilepticus	I-Disease
(	O
P20	O
)	O
rats	O
,	O
acquisition	O
of	O
the	O
sound	O
-	O
source	O
location	O
discrimination	O
was	O
moderately	O
impaired	O
.	O

Status	B-Disease
epilepticus	I-Disease
(	O
P45	O
)	O
rats	O
failed	O
to	O
acquire	O
either	O
sound	O
-	O
source	O
location	O
or	O
sound	O
-	O
silence	O
discriminations	O
.	O

Status	B-Disease
epilepticus	I-Disease
in	O
rat	O
causes	O
an	O
age	O
-	O
dependent	O
,	O
long	O
-	O
term	O
impairment	B-Disease
in	I-Disease
auditory	I-Disease
discrimination	I-Disease
.	O

This	O
impairment	O
may	O
explain	O
one	O
cause	O
of	O
impaired	B-Disease
auditory	I-Disease
location	I-Disease
discrimination	I-Disease
in	O
humans	O
.	O

Nerve	O
growth	O
factor	O
and	O
prostaglandins	B-Chemical
in	O
the	O
urine	O
of	O
female	O
patients	O
with	O
overactive	B-Disease
bladder	I-Disease
.	O

PURPOSE	O
:	O
NGF	O
and	O
PGs	B-Chemical
in	O
the	O
bladder	O
can	O
be	O
affected	O
by	O
pathological	O
changes	O
in	O
the	O
bladder	O
and	O
these	O
changes	O
can	O
be	O
detected	O
in	O
urine	O
.	O

We	O
investigated	O
changes	O
in	O
urinary	O
NGF	O
and	O
PGs	B-Chemical
in	O
women	O
with	O
OAB	B-Disease
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
The	O
study	O
groups	O
included	O
65	O
women	O
with	O
OAB	B-Disease
and	O
20	O
without	O
bladder	O
symptoms	O
who	O
served	O
as	O
controls	O
.	O

Evaluation	O
included	O
patient	O
history	O
,	O
urinalysis	O
,	O
a	O
voiding	O
diary	O
and	O
urodynamic	O
studies	O
.	O

Urine	O
samples	O
were	O
collected	O
.	O

NGF	O
,	O
PGE2	B-Chemical
,	O
PGF2alpha	B-Chemical
and	O
PGI2	B-Chemical
were	O
measured	O
using	O
enzyme	O
-	O
linked	O
immunosorbent	O
assay	O
and	O
compared	O
between	O
the	O
groups	O
.	O

In	O
addition	O
,	O
correlations	O
between	O
urinary	O
NGF	O
and	O
PG	B-Chemical
,	O
and	O
urodynamic	O
parameters	O
in	O
patients	O
with	O
OAB	B-Disease
were	O
examined	O
.	O

RESULTS	O
:	O
Urinary	O
NGF	O
,	O
PGE2	B-Chemical
and	O
PGF2alpha	B-Chemical
were	O
significantly	O
increased	O
in	O
patients	O
with	O
OAB	B-Disease
compared	O
with	O
controls	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

However	O
,	O
urinary	O
PGI2	B-Chemical
was	O
not	O
different	O
between	O
controls	O
and	O
patients	O
with	O
OAB	B-Disease
.	O

In	O
patients	O
with	O
OAB	B-Disease
urinary	O
PGE2	B-Chemical
positively	O
correlated	O
with	O
volume	O
at	O
first	O
desire	O
to	O
void	O
and	O
maximum	O
cystometric	O
capacity	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Urinary	O
NGF	O
,	O
PGF2alpha	B-Chemical
and	O
PGI2	B-Chemical
did	O
not	O
correlate	O
with	O
urodynamic	O
parameters	O
in	O
patients	O
with	O
OAB	B-Disease
.	O

CONCLUSIONS	O
:	O
NGF	O
and	O
PGs	B-Chemical
have	O
important	O
roles	O
in	O
the	O
development	O
of	O
OAB	B-Disease
symptoms	O
in	O
female	O
patients	O
.	O

Urinary	O
levels	O
of	O
these	O
factors	O
may	O
be	O
used	O
as	O
markers	O
to	O
evaluate	O
OAB	B-Disease
symptoms	O
.	O

Definition	O
and	O
management	O
of	O
anemia	B-Disease
in	O
patients	O
infected	B-Disease
with	I-Disease
hepatitis	I-Disease
C	I-Disease
virus	I-Disease
.	O

Chronic	B-Disease
infection	I-Disease
with	I-Disease
hepatitis	I-Disease
C	I-Disease
virus	I-Disease
(	O
HCV	O
)	O
can	O
progress	O
to	O
cirrhosis	B-Disease
,	O
hepatocellular	B-Disease
carcinoma	I-Disease
,	O
and	O
end	B-Disease
-	I-Disease
stage	I-Disease
liver	I-Disease
disease	I-Disease
.	O

The	O
current	O
best	O
treatment	O
for	O
HCV	B-Disease
infection	I-Disease
is	O
combination	O
therapy	O
with	O
pegylated	O
interferon	B-Chemical
and	O
ribavirin	B-Chemical
.	O

Although	O
this	O
regimen	O
produces	O
sustained	O
virologic	O
responses	O
(	O
SVRs	O
)	O
in	O
approximately	O
50	O
%	O
of	O
patients	O
,	O
it	O
can	O
be	O
associated	O
with	O
a	O
potentially	O
dose	O
-	O
limiting	O
hemolytic	B-Disease
anemia	I-Disease
.	O

Hemoglobin	O
concentrations	O
decrease	O
mainly	O
as	O
a	O
result	O
of	O
ribavirin	B-Chemical
-	O
induced	O
hemolysis	B-Disease
,	O
and	O
this	O
anemia	B-Disease
can	O
be	O
problematic	O
in	O
patients	O
with	O
HCV	B-Disease
infection	I-Disease
,	O
especially	O
those	O
who	O
have	O
comorbid	O
renal	B-Disease
or	I-Disease
cardiovascular	I-Disease
disorders	I-Disease
.	O

In	O
general	O
,	O
anemia	B-Disease
can	O
increase	O
the	O
risk	O
of	O
morbidity	O
and	O
mortality	O
,	O
and	O
may	O
have	O
negative	O
effects	O
on	O
cerebral	O
function	O
and	O
quality	O
of	O
life	O
.	O

Although	O
ribavirin	B-Chemical
-	O
associated	O
anemia	B-Disease
can	O
be	O
reversed	O
by	O
dose	O
reduction	O
or	O
discontinuation	O
,	O
this	O
approach	O
compromises	O
outcomes	O
by	O
significantly	O
decreasing	O
SVR	O
rates	O
.	O

Recombinant	O
human	O
erythropoietin	O
has	O
been	O
used	O
to	O
manage	O
ribavirin	B-Chemical
-	O
associated	O
anemia	B-Disease
but	O
has	O
other	O
potential	O
disadvantages	O
.	O

Viramidine	B-Chemical
,	O
a	O
liver	O
-	O
targeting	O
prodrug	O
of	O
ribavirin	B-Chemical
,	O
has	O
the	O
potential	O
to	O
maintain	O
the	O
virologic	O
efficacy	O
of	O
ribavirin	B-Chemical
while	O
decreasing	O
the	O
risk	O
of	O
hemolytic	B-Disease
anemia	I-Disease
in	O
patients	O
with	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
.	O

Impact	O
of	O
alcohol	B-Chemical
exposure	O
after	O
pregnancy	O
recognition	O
on	O
ultrasonographic	O
fetal	O
growth	O
measures	O
.	O

BACKGROUND	O
:	O
More	O
than	O
3	O
decades	O
after	O
Jones	O
and	O
Smith	O
(	O
1973	O
)	O
reported	O
on	O
the	O
devastation	O
caused	O
by	O
alcohol	B-Chemical
exposure	O
on	O
fetal	O
development	O
,	O
the	O
rates	O
of	O
heavy	O
drinking	O
during	O
pregnancy	O
remain	O
relatively	O
unchanged	O
.	O

Early	O
identification	O
of	O
fetal	O
alcohol	B-Chemical
exposure	O
and	O
maternal	O
abstinence	O
led	O
to	O
better	O
infant	O
outcomes	O
.	O

This	O
study	O
examined	O
the	O
utility	O
of	O
biometry	O
for	O
detecting	O
alcohol	B-Chemical
-	O
related	O
fetal	O
growth	B-Disease
impairment	I-Disease
.	O

METHODS	O
:	O
We	O
obtained	O
fetal	O
ultrasound	O
measures	O
from	O
routine	O
ultrasound	O
examinations	O
for	O
167	O
pregnant	O
hazardous	O
drinkers	O
who	O
were	O
enrolled	O
in	O
a	O
brief	O
alcohol	B-Chemical
intervention	O
study	O
.	O

The	O
fetal	O
measures	O
for	O
women	O
who	O
quit	O
after	O
learning	O
of	O
their	O
pregnancies	O
were	O
compared	O
with	O
measures	O
for	O
women	O
who	O
continued	O
some	O
drinking	O
throughout	O
the	O
course	O
of	O
their	O
pregnancies	O
.	O

Because	O
intensity	O
of	O
alcohol	B-Chemical
consumption	O
is	O
associated	O
with	O
poorer	O
fetal	O
outcomes	O
,	O
separate	O
analyses	O
were	O
conducted	O
for	O
the	O
heavy	O
(	O
average	O
of	O
>	O
or	O
=	O
5	O
drinks	O
per	O
drinking	O
day	O
)	O
alcohol	B-Chemical
consumers	O
.	O

Fetal	O
measures	O
from	O
the	O
heavy	O
-	O
exposed	O
fetuses	O
were	O
also	O
compared	O
with	O
measures	O
from	O
a	O
nondrinking	O
group	O
that	O
was	O
representative	O
of	O
normal	O
,	O
uncomplicated	O
pregnancies	O
from	O
our	O
clinics	O
.	O

Analyses	O
of	O
covariance	O
were	O
used	O
to	O
determine	O
whether	O
there	O
were	O
differences	O
between	O
groups	O
after	O
controlling	O
for	O
influences	O
of	O
gestational	O
age	O
and	O
drug	B-Disease
abuse	I-Disease
.	O

RESULTS	O
:	O
Nearly	O
half	O
of	O
the	O
pregnant	O
drinkers	O
abstained	O
after	O
learning	O
of	O
their	O
pregnancies	O
.	O

When	O
women	O
reportedly	O
quit	O
drinking	O
early	O
in	O
their	O
pregnancies	O
,	O
fetal	O
growth	O
measures	O
were	O
not	O
significantly	O
different	O
from	O
a	O
non	O
-	O
alcohol	B-Chemical
-	O
exposed	O
group	O
,	O
regardless	O
of	O
prior	O
drinking	O
patterns	O
.	O

Any	O
alcohol	B-Chemical
consumption	O
postpregnancy	O
recognition	O
among	O
the	O
heavy	O
drinkers	O
resulted	O
in	O
reduced	B-Disease
cerebellar	I-Disease
growth	I-Disease
as	O
well	O
as	O
decreased	B-Disease
cranial	I-Disease
to	I-Disease
body	I-Disease
growth	I-Disease
in	O
comparison	O
with	O
women	O
who	O
either	O
quit	O
drinking	O
or	O
who	O
were	O
nondrinkers	O
.	O

Amphetamine	B-Chemical
abuse	O
was	O
predictive	O
of	O
larger	O
cranial	O
to	O
body	O
growth	O
ratios	O
.	O

CONCLUSIONS	O
:	O
Alterations	O
in	O
fetal	O
biometric	O
measurements	O
were	O
observed	O
among	O
the	O
heavy	O
drinkers	O
only	O
when	O
they	O
continued	O
drinking	O
after	O
becoming	O
aware	O
of	O
their	O
pregnancies	O
.	O

Although	O
the	O
reliance	O
on	O
self	O
-	O
reported	O
drinking	O
is	O
a	O
limitation	O
in	O
this	O
study	O
,	O
these	O
findings	O
support	O
the	O
benefits	O
of	O
early	O
abstinence	O
and	O
the	O
potential	O
for	O
ultrasound	O
examinations	O
in	O
the	O
detection	O
of	O
fetal	O
alcohol	B-Chemical
effects	O
.	O

Ethambutol	B-Chemical
-	O
associated	O
optic	B-Disease
neuropathy	I-Disease
.	O

INTRODUCTION	O
:	O
Ethambutol	B-Chemical
is	O
used	O
in	O
the	O
treatment	O
of	O
tuberculosis	B-Disease
,	O
which	O
is	O
still	O
prevalent	O
in	O
Southeast	O
Asia	O
,	O
and	O
can	O
be	O
associated	O
with	O
permanent	O
visual	B-Disease
loss	I-Disease
.	O

We	O
report	O
3	O
cases	O
which	O
presented	O
with	O
bitemporal	B-Disease
hemianopia	I-Disease
.	O

CLINICAL	O
PICTURE	O
:	O
Three	O
patients	O
with	O
ethambutol	B-Chemical
-	O
associated	O
toxic	O
optic	B-Disease
neuropathy	I-Disease
are	O
described	O
.	O

All	O
3	O
patients	O
had	O
loss	B-Disease
of	I-Disease
central	I-Disease
visual	I-Disease
acuity	I-Disease
,	I-Disease
colour	I-Disease
vision	I-Disease
(	I-Disease
Ishihara	I-Disease
)	I-Disease
and	I-Disease
visual	I-Disease
field	I-Disease
.	O

The	O
visual	B-Disease
field	I-Disease
loss	I-Disease
had	O
a	O
bitemporal	O
flavour	O
,	O
suggesting	O
involvement	O
of	O
the	O
optic	O
chiasm	O
.	O

TREATMENT	O
:	O
Despite	O
stopping	O
ethambutol	B-Chemical
on	O
diagnosis	O
,	O
visual	O
function	O
continued	O
to	O
deteriorate	O
for	O
a	O
few	O
months	O
.	O

Subsequent	O
improvement	O
was	O
mild	O
in	O
2	O
cases	O
.	O

In	O
the	O
third	O
case	O
,	O
visual	O
acuity	O
and	O
colour	O
vision	O
normalised	O
but	O
the	O
optic	O
discs	O
were	O
pale	O
.	O

OUTCOME	O
:	O
All	O
3	O
patients	O
had	O
some	O
permanent	O
loss	B-Disease
of	I-Disease
visual	I-Disease
function	I-Disease
.	O

CONCLUSIONS	O
:	O
Ethambutol	B-Chemical
usage	O
is	O
associated	O
with	O
permanent	O
visual	B-Disease
loss	I-Disease
and	O
should	O
be	O
avoided	O
if	O
possible	O
or	O
used	O
with	O
caution	O
and	O
proper	O
ophthalmological	O
follow	O
-	O
up	O
.	O

The	O
author	O
postulates	O
that	O
in	O
cases	O
of	O
ethambutol	B-Chemical
associated	O
chiasmopathy	O
,	O
ethambutol	B-Chemical
may	O
initially	O
affect	O
the	O
optic	O
nerves	O
and	O
subsequently	O
progress	O
to	O
involve	O
the	O
optic	O
chiasm	O
.	O

Possible	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
related	O
to	O
concomitant	O
treatment	O
with	O
paroxetine	B-Chemical
and	O
alprazolam	B-Chemical
.	O

A	O
74	O
-	O
year	O
-	O
old	O
man	O
with	O
depressive	B-Disease
symptoms	I-Disease
was	O
admitted	O
to	O
a	O
psychiatric	B-Disease
hospital	O
due	O
to	O
insomnia	B-Disease
,	O
loss	B-Disease
of	I-Disease
appetite	I-Disease
,	O
exhaustion	O
,	O
and	O
agitation	B-Disease
.	O

Medical	O
treatment	O
was	O
initiated	O
at	O
a	O
daily	O
dose	O
of	O
20	O
mg	O
paroxetine	B-Chemical
and	O
1	O
.	O
2	O
mg	O
alprazolam	B-Chemical
.	O

On	O
the	O
10th	O
day	O
of	O
paroxetine	B-Chemical
and	O
alprazolam	B-Chemical
treatment	O
,	O
the	O
patient	O
exhibited	O
marked	O
psychomotor	B-Disease
retardation	I-Disease
,	O
disorientation	O
,	O
and	O
severe	O
muscle	B-Disease
rigidity	I-Disease
with	O
tremors	B-Disease
.	O

The	O
patient	O
had	O
a	O
fever	B-Disease
(	O
38	O
.	O
2	O
degrees	O
C	O
)	O
,	O
fluctuating	O
blood	O
pressure	O
(	O
between	O
165	O
/	O
90	O
and	O
130	O
/	O
70	O
mg	O
mm	O
Hg	O
)	O
,	O
and	O
severe	O
extrapyramidal	B-Disease
symptoms	I-Disease
.	O

Laboratory	O
tests	O
showed	O
an	O
elevation	O
of	O
creatine	B-Chemical
phosphokinase	O
(	O
2218	O
IU	O
/	O
L	O
)	O
,	O
aspartate	B-Chemical
aminotransferase	O
(	O
134	O
IU	O
/	O
L	O
)	O
,	O
alanine	B-Chemical
aminotransferase	O
(	O
78	O
IU	O
/	O
L	O
)	O
,	O
and	O
BUN	O
(	O
27	O
.	O
9	O
mg	O
/	O
ml	O
)	O
levels	O
.	O

The	O
patient	O
received	O
bromocriptine	B-Chemical
and	O
diazepam	B-Chemical
to	O
treat	O
his	O
symptoms	O
.	O

7	O
days	O
later	O
,	O
the	O
fever	B-Disease
disappeared	O
and	O
the	O
patient	O
'	O
s	O
serum	O
CPK	O
levels	O
were	O
normalized	O
(	O
175	O
IU	O
/	O
L	O
)	O
.	O

This	O
patient	O
presented	O
with	O
symptoms	O
of	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
(	O
NMS	B-Disease
)	O
,	O
thus	O
demonstrating	O
that	O
NMS	B-Disease
-	O
like	O
symptoms	O
can	O
occur	O
after	O
combined	O
paroxetine	B-Chemical
and	O
alprazolam	B-Chemical
treatment	O
.	O

The	O
adverse	O
drug	O
reaction	O
score	O
obtained	O
by	O
the	O
Naranjo	O
algorithm	O
was	O
6	O
in	O
our	O
case	O
,	O
indicating	O
a	O
probable	O
relationship	O
between	O
the	O
patient	O
'	O
s	O
NMS	B-Disease
-	O
like	O
adverse	O
symptoms	O
and	O
the	O
combined	O
treatment	O
used	O
in	O
this	O
case	O
.	O

The	O
involvement	O
of	O
physiologic	O
and	O
environmental	O
aspects	O
specific	O
to	O
this	O
patient	O
was	O
suspected	O
.	O

Several	O
risk	O
factors	O
for	O
NMS	B-Disease
should	O
be	O
noted	O
in	O
elderly	O
depressive	B-Disease
patients	O
whose	O
symptoms	O
often	O
include	O
dehydration	B-Disease
,	O
agitation	B-Disease
,	O
malnutrition	B-Disease
,	O
and	O
exhaustion	O
.	O

Careful	O
therapeutic	O
intervention	O
is	O
necessary	O
in	O
cases	O
involving	O
elderly	O
patients	O
who	O
suffer	O
from	O
depression	B-Disease
.	O

Down	O
-	O
regulation	O
of	O
norepinephrine	B-Chemical
transporter	O
function	O
induced	O
by	O
chronic	O
administration	O
of	O
desipramine	B-Chemical
linking	O
to	O
the	O
alteration	O
of	O
sensitivity	O
of	O
local	O
-	O
anesthetics	O
-	O
induced	O
convulsions	B-Disease
and	O
the	O
counteraction	O
by	O
co	O
-	O
administration	O
with	O
local	O
anesthetics	O
.	O

Alterations	O
of	O
norepinephrine	B-Chemical
transporter	O
(	O
NET	O
)	O
function	O
by	O
chronic	O
inhibition	O
of	O
NET	O
in	O
relation	O
to	O
sensitization	O
to	O
seizures	B-Disease
induce	O
by	O
cocaine	B-Chemical
and	O
local	O
anesthetics	O
were	O
studied	O
in	O
mice	O
.	O

Daily	O
administration	O
of	O
desipramine	B-Chemical
,	O
an	O
inhibitor	O
of	O
the	O
NET	O
,	O
for	O
5	O
days	O
decreased	O
[	O
(	O
3	O
)	O
H	O
]	O
norepinephrine	B-Chemical
uptake	O
in	O
the	O
P2	O
fractions	O
of	O
hippocampus	O
but	O
not	O
cortex	O
,	O
striatum	O
or	O
amygdalae	O
.	O

Co	O
-	O
administration	O
of	O
lidocaine	B-Chemical
,	O
bupivacaine	B-Chemical
or	O
tricaine	B-Chemical
with	O
desipramine	B-Chemical
reversed	O
this	O
effect	O
.	O

Daily	O
treatment	O
of	O
cocaine	B-Chemical
increased	O
[	O
(	O
3	O
)	O
H	O
]	O
norepinephrine	B-Chemical
uptake	O
into	O
the	O
hippocampus	O
.	O

Daily	O
administration	O
of	O
desipramine	B-Chemical
increased	O
the	O
incidence	O
of	O
appearance	O
of	O
lidocaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
and	O
decreased	O
that	O
of	O
cocaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
.	O

Co	O
-	O
administration	O
of	O
lidocaine	B-Chemical
with	O
desipramine	B-Chemical
reversed	O
the	O
changes	O
of	O
convulsive	B-Disease
activity	O
of	O
lidocaine	B-Chemical
and	O
cocaine	B-Chemical
induced	O
by	O
repeated	O
administration	O
of	O
desipramine	B-Chemical
.	O

These	O
results	O
suggest	O
that	O
down	O
-	O
regulation	O
of	O
hippocampal	O
NET	O
induced	O
by	O
chronic	O
administration	O
of	O
desipramine	B-Chemical
may	O
be	O
relevant	O
to	O
desipramine	B-Chemical
-	O
induced	O
sensitization	O
of	O
lidocaine	B-Chemical
convulsions	B-Disease
.	O

Inhibition	O
of	O
Na	B-Chemical
(	O
+	O
)	O
channels	O
by	O
local	O
anesthetics	O
may	O
regulate	O
desipramine	B-Chemical
-	O
induced	O
down	O
-	O
regulation	O
of	O
NET	O
function	O
.	O

Repeated	O
administration	O
of	O
cocaine	B-Chemical
induces	O
up	O
-	O
regulation	O
of	O
hippocampal	O
NET	O
function	O
.	O

Desipramine	B-Chemical
-	O
induced	O
sensitization	O
of	O
lidocaine	B-Chemical
seizures	B-Disease
may	O
have	O
a	O
mechanism	O
distinct	O
from	O
kindling	O
resulting	O
from	O
repeated	O
administration	O
of	O
cocaine	B-Chemical
.	O

Atorvastatin	B-Chemical
prevented	O
and	O
reversed	O
dexamethasone	B-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
the	O
rat	O
.	O

To	O
assess	O
the	O
antioxidant	O
effects	O
of	O
atorvastatin	B-Chemical
(	O
atorva	B-Chemical
)	O
on	O
dexamethasone	B-Chemical
(	O
dex	B-Chemical
)	O
-	O
induced	O
hypertension	B-Disease
,	O
60	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
treated	O
with	O
atorva	B-Chemical
30	O
mg	O
/	O
kg	O
/	O
day	O
or	O
tap	O
water	O
for	O
15	O
days	O
.	O

Dex	B-Chemical
increased	O
systolic	O
blood	O
pressure	O
(	O
SBP	O
)	O
from	O
109	O
+	O
/	O
-	O
1	O
.	O
8	O
to	O
135	O
+	O
/	O
-	O
0	O
.	O
6	O
mmHg	O
and	O
plasma	O
superoxide	B-Chemical
(	O
5711	O
+	O
/	O
-	O
284	O
.	O
9	O
saline	O
,	O
7931	O
+	O
/	O
-	O
392	O
.	O
8	O
U	O
/	O
ml	O
dex	B-Chemical
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

In	O
this	O
prevention	O
study	O
,	O
SBP	O
in	O
the	O
atorva	B-Chemical
+	O
dex	B-Chemical
group	O
was	O
increased	O
from	O
115	O
+	O
/	O
-	O
0	O
.	O
4	O
to	O
124	O
+	O
/	O
-	O
1	O
.	O
5	O
mmHg	O
,	O
but	O
this	O
was	O
significantly	O
lower	O
than	O
in	O
the	O
dex	B-Chemical
-	O
only	O
group	O
(	O
P	O
'	O
<	O
0	O
.	O
05	O
)	O
.	O

Atorva	B-Chemical
reversed	O
dex	B-Chemical
-	O
induced	O
hypertension	B-Disease
(	O
129	O
+	O
/	O
-	O
0	O
.	O
6	O
mmHg	O
,	O
vs	O
.	O
135	O
+	O
/	O
-	O
0	O
.	O
6	O
mmHg	O
P	O
'	O
<	O
0	O
.	O
05	O
)	O
and	O
decreased	O
plasma	O
superoxide	B-Chemical
(	O
7931	O
+	O
/	O
-	O
392	O
.	O
8	O
dex	B-Chemical
,	O
1187	O
+	O
/	O
-	O
441	O
.	O
2	O
atorva	B-Chemical
+	O
dex	B-Chemical
,	O
P	O
<	O
0	O
.	O
0001	O
)	O
.	O

Plasma	O
nitrate	B-Chemical
/	O
nitrite	B-Chemical
(	O
NOx	O
)	O
was	O
decreased	O
in	O
dex	B-Chemical
-	O
treated	O
rats	O
compared	O
to	O
saline	O
-	O
treated	O
rats	O
(	O
11	O
.	O
2	O
+	O
/	O
-	O
1	O
.	O
08	O
microm	O
,	O
15	O
.	O
3	O
+	O
/	O
-	O
1	O
.	O
17	O
microm	O
,	O
respectively	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Atorva	B-Chemical
affected	O
neither	O
plasma	O
NOx	O
nor	O
thymus	O
weight	O
.	O

Thus	O
,	O
atorvastatin	B-Chemical
prevented	O
and	O
reversed	O
dexamethasone	B-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
the	O
rat	O
.	O

Peripheral	B-Disease
neuropathy	I-Disease
caused	O
by	O
high	O
-	O
dose	O
cytosine	B-Chemical
arabinoside	I-Chemical
treatment	O
in	O
a	O
patient	O
with	O
acute	B-Disease
myeloid	I-Disease
leukemia	I-Disease
.	O

The	O
central	O
nervous	O
system	O
toxicity	B-Disease
of	O
high	O
-	O
dose	O
cytosine	B-Chemical
arabinoside	I-Chemical
is	O
well	O
recognized	O
,	O
but	O
the	O
toxicity	B-Disease
of	O
cytosine	B-Chemical
arabinoside	I-Chemical
in	O
the	O
peripheral	O
nervous	O
system	O
has	O
been	O
infrequently	O
reported	O
.	O

A	O
49	O
-	O
year	O
-	O
old	O
Japanese	O
man	O
was	O
diagnosed	O
with	O
acute	B-Disease
myeloid	I-Disease
leukemia	I-Disease
.	O

After	O
he	O
achieved	O
complete	O
remission	O
,	O
he	O
received	O
high	O
-	O
dose	O
cytosine	B-Chemical
arabinoside	I-Chemical
treatment	O
(	O
2	O
g	O
/	O
m2	O
twice	O
a	O
day	O
for	O
5	O
days	O
;	O
total	O
,	O
20	O
g	O
/	O
m2	O
)	O
as	O
consolidation	O
therapy	O
.	O

The	O
first	O
course	O
of	O
high	O
-	O
dose	O
cytosine	B-Chemical
arabinoside	I-Chemical
resulted	O
in	O
no	O
unusual	O
symptoms	O
,	O
but	O
on	O
day	O
21	O
of	O
the	O
second	O
course	O
of	O
treatment	O
,	O
the	O
patient	O
complained	O
of	O
numbness	B-Disease
in	O
his	O
right	O
foot	O
.	O

Electromyogram	O
and	O
nerve	O
-	O
conduction	O
studies	O
showed	O
peripheral	B-Disease
neuropathy	I-Disease
in	O
both	O
peroneal	O
nerves	O
.	O

This	O
neuropathy	B-Disease
was	O
gradually	O
resolving	O
;	O
however	O
,	O
after	O
the	O
patient	O
received	O
allogeneic	O
bone	O
marrow	O
transplantation	O
,	O
the	O
symptoms	O
worsened	O
,	O
with	O
the	O
development	O
of	O
graft	B-Disease
-	I-Disease
versus	I-Disease
-	I-Disease
host	I-Disease
disease	I-Disease
,	O
and	O
the	O
symptoms	O
subsequently	O
responded	O
to	O
methylprednisolone	B-Chemical
.	O

Although	O
the	O
mechanisms	O
of	O
peripheral	B-Disease
neuropathy	I-Disease
are	O
still	O
unclear	O
,	O
high	O
-	O
dose	O
cytosine	B-Chemical
arabinoside	I-Chemical
is	O
a	O
therapy	O
that	O
is	O
potentially	O
toxic	O
to	O
the	O
peripheral	O
nervous	O
system	O
,	O
and	O
auto	O
/	O
alloimmunity	O
may	O
play	O
an	O
important	O
role	O
in	O
these	O
mechanisms	O
.	O

Effect	O
of	O
alpha	B-Chemical
-	I-Chemical
tocopherol	I-Chemical
and	O
deferoxamine	B-Chemical
on	O
methamphetamine	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
.	O

Methamphetamine	B-Chemical
(	O
MA	B-Chemical
)	O
-	O
induced	O
dopaminergic	O
neurotoxicity	B-Disease
is	O
believed	O
to	O
be	O
associated	O
with	O
the	O
increased	O
formation	O
of	O
free	O
radicals	O
.	O

This	O
study	O
examined	O
the	O
effect	O
of	O
alpha	B-Chemical
-	I-Chemical
tocopherol	I-Chemical
(	O
alpha	B-Chemical
-	I-Chemical
TC	I-Chemical
)	O
,	O
a	O
scavenger	O
of	O
reactive	O
oxygen	B-Chemical
species	O
,	O
and	O
deferoxamine	B-Chemical
(	O
DFO	B-Chemical
)	O
,	O
an	O
iron	B-Chemical
chelator	O
,	O
on	O
the	O
MA	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
.	O

Male	O
rats	O
were	O
treated	O
with	O
MA	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
,	O
every	O
2	O
h	O
for	O
four	O
injections	O
)	O
.	O

The	O
rat	O
received	O
either	O
alpha	B-Chemical
-	I-Chemical
TC	I-Chemical
(	O
20	O
mg	O
/	O
kg	O
)	O
intraperitoneally	O
for	O
3	O
days	O
and	O
30	O
min	O
prior	O
to	O
MA	B-Chemical
administration	O
or	O
DFO	B-Chemical
(	O
50	O
mg	O
/	O
kg	O
)	O
subcutaneously	O
30	O
min	O
before	O
MA	B-Chemical
administration	O
.	O

The	O
concentrations	O
of	O
dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
,	O
serotonin	B-Chemical
and	O
their	O
metabolites	O
decreased	O
significantly	O
after	O
MA	B-Chemical
administration	O
,	O
which	O
was	O
inhibited	O
by	O
the	O
alpha	B-Chemical
-	I-Chemical
TC	I-Chemical
and	O
DFO	B-Chemical
pretreatment	O
.	O

alpha	B-Chemical
-	I-Chemical
TC	I-Chemical
and	O
DFO	B-Chemical
attenuated	O
the	O
MA	B-Chemical
-	O
induced	O
hyperthermia	B-Disease
as	O
well	O
as	O
the	O
alterations	O
in	O
the	O
locomotor	O
activity	O
.	O

The	O
level	O
of	O
lipid	O
peroxidation	O
was	O
higher	O
and	O
the	O
reduced	O
glutathione	B-Chemical
concentration	O
was	O
lower	O
in	O
the	O
MA	B-Chemical
-	O
treated	O
rats	O
.	O

These	O
changes	O
were	O
significantly	O
attenuated	O
by	O
alpha	B-Chemical
-	I-Chemical
TC	I-Chemical
and	O
DFO	B-Chemical
.	O

This	O
suggests	O
that	O
alpha	B-Chemical
-	I-Chemical
TC	I-Chemical
and	O
DFO	B-Chemical
ameliorate	O
the	O
MA	B-Chemical
-	O
induced	O
neuronal	B-Disease
damage	I-Disease
by	O
decreasing	O
the	O
level	O
of	O
oxidative	O
stress	O
.	O

Blockade	O
of	O
both	O
D	O
-	O
1	O
and	O
D	O
-	O
2	O
dopamine	B-Chemical
receptors	O
may	O
induce	O
catalepsy	B-Disease
in	O
mice	O
.	O

1	O
.	O

The	O
catalepsy	B-Disease
induced	O
by	O
dopamine	B-Chemical
antagonists	O
has	O
been	O
tested	O
and	O
the	O
possible	O
dopamine	B-Chemical
subtypes	O
involved	O
in	O
catalepsy	B-Disease
was	O
determined	O
.	O

2	O
.	O

Dopamine	B-Chemical
antagonist	O
fluphenazine	B-Chemical
,	O
D	O
-	O
1	O
antagonist	O
SCH	B-Chemical
23390	I-Chemical
or	O
D	O
-	O
2	O
antagonist	O
sulpiride	B-Chemical
induced	O
catalepsy	B-Disease
.	O

The	O
effect	O
of	O
fluphenazine	B-Chemical
and	O
sulpiride	B-Chemical
was	O
dose	O
-	O
dependent	O
.	O

Combination	O
of	O
SCH	B-Chemical
23390	I-Chemical
with	O
sulpiride	B-Chemical
did	O
not	O
induce	O
catalepsy	B-Disease
potentiation	O
.	O

3	O
.	O

D	O
-	O
1	O
agonist	O
SKF	B-Chemical
38393	I-Chemical
or	O
D	O
-	O
2	O
agonist	O
quinpirole	B-Chemical
decreased	O
the	O
catalepsy	B-Disease
induced	O
by	O
fluphenazine	B-Chemical
,	O
SCH	B-Chemical
23390	I-Chemical
or	O
sulpiride	B-Chemical
.	O

4	O
.	O

Combination	O
of	O
SKF	B-Chemical
38393	I-Chemical
with	O
quinpirole	B-Chemical
did	O
not	O
cause	O
potentiated	O
inhibitory	O
effect	O
on	O
catalepsy	B-Disease
induced	O
by	O
dopamine	B-Chemical
antagonists	O
.	O

5	O
.	O

The	O
data	O
may	O
indicate	O
that	O
although	O
D	O
-	O
2	O
receptor	O
blockade	O
is	O
involved	O
in	O
catalepsy	B-Disease
,	O
the	O
D	O
-	O
1	O
receptor	O
may	O
plan	O
a	O
role	O
.	O

Sustained	O
clinical	O
improvement	O
of	O
a	O
patient	O
with	O
decompensated	O
hepatitis	B-Disease
B	I-Disease
virus	O
-	O
related	O
cirrhosis	B-Disease
after	O
treatment	O
with	O
lamivudine	B-Chemical
monotherapy	O
.	O

Hepatitis	B-Disease
B	I-Disease
virus	I-Disease
(	I-Disease
HBV	I-Disease
)	I-Disease
infection	I-Disease
,	O
which	O
causes	O
liver	B-Disease
cirrhosis	I-Disease
and	O
hepatocellular	B-Disease
carcinoma	I-Disease
,	O
remains	O
a	O
major	O
health	O
problem	O
in	O
Asian	O
countries	O
.	O

Recent	O
development	O
of	O
vaccine	O
for	O
prevention	O
is	O
reported	O
to	O
be	O
successful	O
in	O
reducing	O
the	O
size	O
of	O
chronically	O
infected	O
carriers	O
,	O
although	O
the	O
standard	O
medical	O
therapies	O
have	O
not	O
been	O
established	O
up	O
to	O
now	O
.	O

In	O
this	O
report	O
,	O
we	O
encountered	O
a	O
patient	O
with	O
decompensated	O
HBV	O
-	O
related	O
cirrhosis	B-Disease
who	O
exhibited	O
the	O
dramatic	O
improvements	O
after	O
antiviral	O
therapy	O
.	O

The	O
patient	O
was	O
a	O
50	O
-	O
year	O
-	O
old	O
woman	O
.	O

Previous	O
conventional	O
medical	O
treatments	O
were	O
not	O
effective	O
for	O
this	O
patient	O
,	O
thus	O
this	O
patient	O
had	O
been	O
referred	O
to	O
our	O
hospital	O
.	O

However	O
,	O
the	O
administration	O
of	O
lamivudine	B-Chemical
,	O
a	O
reverse	O
transcriptase	O
inhibitor	O
,	O
for	O
23	O
months	O
dramatically	O
improved	O
her	O
liver	O
severity	O
.	O

During	O
this	O
period	O
,	O
no	O
drug	O
resistant	O
mutant	O
HBV	O
emerged	O
,	O
and	O
the	O
serum	O
HBV	O
-	O
DNA	O
level	O
was	O
continuously	O
suppressed	O
.	O

These	O
virological	O
responses	O
were	O
also	O
maintained	O
even	O
after	O
the	O
antiviral	O
therapy	O
was	O
discontinued	O
.	O

Moreover	O
,	O
both	O
hepatitis	B-Chemical
B	I-Chemical
surface	I-Chemical
antigen	I-Chemical
and	I-Chemical
e	I-Chemical
antigen	I-Chemical
were	O
observed	O
to	O
have	O
disappeared	O
in	O
this	O
patient	O
.	O

The	O
administration	O
of	O
lamivudine	B-Chemical
to	O
patients	O
with	O
HBV	O
-	O
related	O
cirrhosis	B-Disease
,	O
like	O
our	O
present	O
case	O
,	O
should	O
be	O
considered	O
as	O
an	O
initial	O
medical	O
therapeutic	O
option	O
,	O
especially	O
in	O
countries	O
where	O
liver	O
transplantation	O
is	O
not	O
reliably	O
available	O
.	O

Antiarrhythmic	O
effects	O
of	O
optical	O
isomers	O
of	O
cibenzoline	B-Chemical
on	O
canine	O
ventricular	B-Disease
arrhythmias	I-Disease
.	O

Antiarrhythmic	O
effects	O
of	O
(	O
+	O
)	O
-	O
cibenzoline	B-Chemical
and	O
(	O
-	O
)	O
-	O
cibenzoline	B-Chemical
were	O
examined	O
using	O
two	O
canine	O
ventricular	B-Disease
arrhythmia	I-Disease
models	O
.	O

Digitalis	B-Chemical
arrhythmia	B-Disease
,	O
which	O
is	O
suppressed	O
by	O
Na	B-Chemical
channel	O
blockers	O
,	O
was	O
induced	O
by	O
intermittent	O
intravenous	O
(	O
i	O
.	O
v	O
.	O
)	O
injection	O
of	O
ouabain	B-Chemical
in	O
pentobarbital	B-Chemical
-	O
anesthetized	O
dogs	O
.	O

Adrenaline	B-Disease
arrhythmia	I-Disease
,	O
which	O
is	O
suppressed	O
by	O
Ca	B-Chemical
channel	O
blockers	O
,	O
was	O
induced	O
by	O
adrenaline	B-Chemical
infusion	O
in	O
halothane	B-Chemical
-	O
anesthetized	O
dogs	O
.	O

Ten	O
and	O
5	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
(	O
+	O
)	O
-	O
cibenzoline	B-Chemical
suppressed	O
digitalis	B-Chemical
-	O
and	O
adrenaline	B-Chemical
-	O
induced	O
arrhythmias	B-Disease
,	O
respectively	O
.	O

The	O
minimum	O
effective	O
plasma	O
concentrations	O
of	O
(	O
+	O
)	O
-	O
cibenzoline	B-Chemical
for	O
digitalis	B-Chemical
-	O
and	O
adrenaline	B-Chemical
-	O
induced	O
arrhythmias	B-Disease
were	O
1	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
4	O
and	O
2	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
6	O
micrograms	O
/	O
ml	O
,	O
respectively	O
(	O
mean	O
+	O
/	O
-	O
SD	O
,	O
n	O
=	O
6	O
)	O
.	O

A	O
lower	O
dose	O
of	O
1	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
of	O
(	O
-	O
)	O
-	O
cibenzoline	B-Chemical
suppressed	O
the	O
digitalis	B-Chemical
-	O
induced	O
arrhythmia	B-Disease
,	O
whereas	O
5	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
was	O
needed	O
to	O
suppress	O
adrenaline	B-Chemical
-	O
induced	O
arrhythmias	B-Disease
.	O

The	O
minimum	O
effective	O
plasma	O
concentrations	O
of	O
(	O
-	O
)	O
-	O
cibenzoline	B-Chemical
for	O
digitalis	B-Chemical
-	O
and	O
adrenaline	B-Chemical
-	O
induced	O
arrhythmia	B-Disease
were	O
0	O
.	O
06	O
+	O
/	O
-	O
0	O
.	O
04	O
and	O
0	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
1	O
micrograms	O
/	O
ml	O
,	O
respectively	O
(	O
mean	O
+	O
/	O
-	O
SD	O
,	O
n	O
=	O
6	O
)	O
.	O

The	O
stronger	O
antiarrhythmic	O
effect	O
of	O
(	O
-	O
)	O
-	O
cibenzoline	B-Chemical
indicates	O
that	O
(	O
-	O
)	O
-	O
isomer	O
may	O
have	O
an	O
effect	O
nearly	O
5	O
-	O
20	O
times	O
stronger	O
in	O
suppressing	O
Na	B-Chemical
channels	O
,	O
but	O
effects	O
of	O
both	O
drugs	O
on	O
Ca	B-Chemical
channels	O
may	O
be	O
almost	O
equipotent	O
.	O

Passage	O
of	O
mannitol	B-Chemical
into	O
the	O
brain	O
around	O
gliomas	B-Disease
:	O
a	O
potential	O
cause	O
of	O
rebound	O
phenomenon	O
.	O

A	O
study	O
on	O
21	O
patients	O
.	O

AIM	O
:	O
Widespread	O
use	O
of	O
mannitol	B-Chemical
to	O
reduce	O
brain	B-Disease
edema	I-Disease
and	O
lower	O
elevated	B-Disease
ICP	I-Disease
in	O
brain	B-Disease
tumor	I-Disease
patients	O
continues	O
to	O
be	O
afflicted	O
by	O
the	O
so	O
-	O
called	O
rebound	O
phenomenon	O
.	O

Leakage	O
of	O
mannitol	B-Chemical
into	O
the	O
brain	O
parenchyma	O
through	O
an	O
altered	O
BBB	O
and	O
secondary	O
reversal	O
of	O
osmotic	O
gradient	O
is	O
considered	O
the	O
major	O
cause	O
of	O
rebound	O
.	O

This	O
has	O
only	O
been	O
demonstrated	O
experimentally	O
in	O
animals	O
.	O

As	O
a	O
contribution	O
to	O
this	O
issue	O
we	O
decided	O
to	O
research	O
the	O
possible	O
passage	O
of	O
mannitol	B-Chemical
into	O
the	O
brain	O
after	O
administration	O
to	O
21	O
brain	B-Disease
tumor	I-Disease
patients	O
.	O

METHODS	O
:	O
Mannitol	B-Chemical
(	O
18	O
%	O
solution	O
;	O
1	O
g	O
/	O
kg	O
)	O
was	O
administered	O
as	O
a	O
bolus	O
to	O
patients	O
(	O
ten	O
had	O
malignant	B-Disease
glioma	I-Disease
,	O
seven	O
brain	O
metastases	B-Disease
and	O
four	O
meningioma	B-Disease
)	O
about	O
30	O
minutes	O
before	O
craniotomy	O
.	O

During	O
resection	O
,	O
a	O
sample	O
of	O
the	O
surrounding	O
edematous	B-Disease
white	O
matter	O
was	O
taken	O
at	O
the	O
same	O
time	O
as	O
a	O
10	O
ml	O
venous	O
blood	O
sample	O
.	O

Mannitol	B-Chemical
concentrations	O
were	O
measured	O
in	O
plasma	O
and	O
white	O
matter	O
by	O
a	O
modified	O
version	O
of	O
the	O
enzyme	O
assay	O
of	O
Blonquist	O
et	O
al	O
.	O

RESULTS	O
:	O
In	O
most	O
glioma	B-Disease
patients	O
,	O
mannitol	B-Chemical
concentrations	O
in	O
white	O
matter	O
were	O
2	O
to	O
6	O
times	O
higher	O
than	O
in	O
plasma	O
(	O
mean	O
3	O
.	O
5	O
times	O
)	O
.	O

In	O
meningioma	B-Disease
and	O
metastases	B-Disease
patients	O
plasma	O
concentrations	O
of	O
mannitol	B-Chemical
were	O
higher	O
than	O
white	O
matter	O
concentrations	O
except	O
in	O
three	O
cases	O
with	O
infiltration	O
by	O
neoplastic	O
cells	O
.	O

CONCLUSIONS	O
:	O
The	O
results	O
of	O
our	O
study	O
show	O
that	O
even	O
after	O
a	O
single	O
bolus	O
,	O
mannitol	B-Chemical
may	O
leak	O
through	O
the	O
altered	O
BBB	O
near	O
gliomas	B-Disease
,	O
reversing	O
the	O
initial	O
plasma	O
-	O
to	O
-	O
blood	O
osmotic	O
gradient	O
,	O
aggravating	O
peritumoral	O
edema	B-Disease
and	O
promoting	O
rebound	O
of	O
ICP	O
.	O

Placebo	O
-	O
level	O
incidence	O
of	O
extrapyramidal	B-Disease
symptoms	I-Disease
(	O
EPS	B-Disease
)	O
with	O
quetiapine	B-Chemical
in	O
controlled	O
studies	O
of	O
patients	O
with	O
bipolar	B-Disease
mania	I-Disease
.	O

OBJECTIVES	O
:	O
To	O
evaluate	O
extrapyramidal	B-Disease
symptoms	I-Disease
(	O
EPS	B-Disease
)	O
,	O
including	O
akathisia	B-Disease
,	O
with	O
quetiapine	B-Chemical
in	O
patients	O
with	O
bipolar	B-Disease
mania	I-Disease
.	O

METHODS	O
:	O
Data	O
were	O
analyzed	O
from	O
four	O
similarly	O
designed	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
3	O
-	O
to	O
12	O
-	O
week	O
studies	O
.	O

Two	O
studies	O
evaluated	O
quetiapine	B-Chemical
monotherapy	O
(	O
up	O
to	O
800	O
mg	O
/	O
day	O
)	O
(	O
n	O
=	O
209	O
)	O
versus	O
placebo	O
(	O
n	O
=	O
198	O
)	O
,	O
with	O
lithium	B-Chemical
or	O
haloperidol	B-Chemical
monotherapy	O
as	O
respective	O
active	O
controls	O
.	O

Two	O
studies	O
evaluated	O
quetiapine	B-Chemical
(	O
up	O
to	O
800	O
mg	O
/	O
day	O
)	O
in	O
combination	O
with	O
a	O
mood	O
stabilizer	O
(	O
lithium	B-Chemical
or	O
divalproex	B-Chemical
,	O
QTP	B-Chemical
+	O
Li	B-Chemical
/	O
DVP	B-Chemical
)	O
(	O
n	O
=	O
196	O
)	O
compared	O
to	O
placebo	O
and	O
mood	O
stabilizer	O
(	O
PBO	O
+	O
Li	B-Chemical
/	O
DVP	B-Chemical
)	O
(	O
n	O
=	O
203	O
)	O
.	O

Extrapyramidal	B-Disease
symptoms	I-Disease
were	O
evaluated	O
using	O
the	O
Simpson	O
-	O
Angus	O
Scale	O
(	O
SAS	O
)	O
,	O
the	O
Barnes	O
Akathisia	O
Rating	O
Scale	O
(	O
BARS	O
)	O
,	O
adverse	O
event	O
reports	O
and	O
anticholinergic	O
drug	O
usage	O
.	O

RESULTS	O
:	O
The	O
incidence	O
of	O
EPS	B-Disease
-	O
related	O
adverse	O
events	O
,	O
including	O
akathisia	B-Disease
,	O
was	O
no	O
different	O
with	O
quetiapine	B-Chemical
monotherapy	O
(	O
12	O
.	O
9	O
%	O
)	O
than	O
with	O
placebo	O
(	O
13	O
.	O
1	O
%	O
)	O
.	O

Similarly	O
,	O
EPS	B-Disease
-	O
related	O
adverse	O
events	O
with	O
QTP	B-Chemical
+	O
Li	B-Chemical
/	O
DVP	B-Chemical
(	O
21	O
.	O
4	O
%	O
)	O
were	O
no	O
different	O
than	O
with	O
PBO	O
+	O
Li	B-Chemical
/	O
DVP	B-Chemical
(	O
19	O
.	O
2	O
%	O
)	O
.	O

Adverse	O
events	O
related	O
to	O
EPS	B-Disease
occurred	O
in	O
59	O
.	O
6	O
%	O
of	O
patients	O
treated	O
with	O
haloperidol	B-Chemical
(	O
n	O
=	O
99	O
)	O
monotherapy	O
,	O
whereas	O
26	O
.	O
5	O
%	O
of	O
patients	O
treated	O
with	O
lithium	B-Chemical
(	O
n	O
=	O
98	O
)	O
monotherapy	O
experienced	O
adverse	O
events	O
related	O
to	O
EPS	B-Disease
.	O

The	O
incidence	O
of	O
akathisia	B-Disease
was	O
low	O
and	O
similar	O
with	O
quetiapine	B-Chemical
monotherapy	O
(	O
3	O
.	O
3	O
%	O
)	O
and	O
placebo	O
(	O
6	O
.	O
1	O
%	O
)	O
,	O
and	O
with	O
QTP	B-Chemical
+	O
Li	B-Chemical
/	O
DVP	B-Chemical
(	O
3	O
.	O
6	O
%	O
)	O
and	O
PBO	O
+	O
Li	B-Chemical
/	O
DVP	B-Chemical
(	O
4	O
.	O
9	O
%	O
)	O
.	O

Lithium	B-Chemical
was	O
associated	O
with	O
a	O
significantly	O
higher	O
incidence	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
of	O
tremor	B-Disease
(	O
18	O
.	O
4	O
%	O
)	O
than	O
quetiapine	B-Chemical
(	O
5	O
.	O
6	O
%	O
)	O
;	O
cerebellar	O
tremor	B-Disease
,	O
which	O
is	O
a	O
known	O
adverse	O
effect	O
of	O
lithium	B-Chemical
,	O
may	O
have	O
contributed	O
to	O
the	O
elevated	O
rate	O
of	O
tremor	B-Disease
in	O
patients	O
receiving	O
lithium	B-Chemical
therapy	O
.	O

Haloperidol	B-Chemical
induced	O
a	O
significantly	O
higher	O
incidence	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
of	O
akathisia	B-Disease
(	O
33	O
.	O
3	O
%	O
versus	O
5	O
.	O
9	O
%	O
)	O
,	O
tremor	B-Disease
(	O
30	O
.	O
3	O
%	O
versus	O
7	O
.	O
8	O
%	O
)	O
,	O
and	O
extrapyramidal	B-Disease
syndrome	I-Disease
(	O
35	O
.	O
4	O
%	O
versus	O
5	O
.	O
9	O
%	O
)	O
than	O
quetiapine	B-Chemical
.	O

No	O
significant	O
differences	O
were	O
observed	O
between	O
quetiapine	B-Chemical
and	O
placebo	O
on	O
SAS	O
and	O
BARS	O
scores	O
.	O

Anticholinergic	O
use	O
was	O
low	O
and	O
similar	O
with	O
quetiapine	B-Chemical
or	O
placebo	O
.	O

CONCLUSIONS	O
:	O
In	O
bipolar	B-Disease
mania	I-Disease
,	O
the	O
incidence	O
of	O
EPS	B-Disease
,	O
including	O
akathisia	B-Disease
,	O
with	O
quetiapine	B-Chemical
therapy	O
is	O
similar	O
to	O
that	O
with	O
placebo	O
.	O

Is	O
phenytoin	B-Chemical
administration	O
safe	O
in	O
a	O
hypothermic	B-Disease
child	O
?	O

A	O
male	O
neonate	O
with	O
a	O
Chiari	B-Disease
malformation	I-Disease
and	O
a	O
leaking	O
myelomeningocoele	O
underwent	O
ventriculoperitoneal	O
shunt	O
insertion	O
followed	O
by	O
repair	O
of	O
myelomeningocoele	O
.	O

During	O
anaesthesia	O
and	O
surgery	O
,	O
he	O
inadvertently	O
became	O
moderately	O
hypothermic	B-Disease
.	O

Intravenous	O
phenytoin	B-Chemical
was	O
administered	O
during	O
the	O
later	O
part	O
of	O
the	O
surgery	O
for	O
seizure	B-Disease
prophylaxis	O
.	O

Following	O
phenytoin	B-Chemical
administration	O
,	O
the	O
patient	O
developed	O
acute	O
severe	O
bradycardia	B-Disease
,	O
refractory	O
to	O
atropine	B-Chemical
and	O
adrenaline	B-Chemical
.	O

The	O
cardiac	O
depressant	O
actions	O
of	O
phenytoin	B-Chemical
and	O
hypothermia	B-Disease
can	O
be	O
additive	O
.	O

Administration	O
of	O
phenytoin	B-Chemical
in	O
the	O
presence	O
of	O
hypothermia	B-Disease
may	O
lead	O
to	O
an	O
adverse	O
cardiac	O
event	O
in	O
children	O
.	O

As	O
phenytoin	B-Chemical
is	O
a	O
commonly	O
used	O
drug	O
,	O
clinicians	O
need	O
to	O
be	O
aware	O
of	O
this	O
interaction	O
.	O

Valproate	B-Chemical
-	O
induced	O
chorea	B-Disease
and	O
encephalopathy	B-Disease
in	O
atypical	O
nonketotic	B-Disease
hyperglycinemia	I-Disease
.	O

Nonketotic	B-Disease
hyperglycinemia	I-Disease
is	O
a	O
disorder	B-Disease
of	I-Disease
amino	I-Disease
acid	I-Disease
metabolism	I-Disease
in	O
which	O
a	O
defect	O
in	O
the	O
glycine	B-Chemical
cleavage	O
system	O
leads	O
to	O
an	O
accumulation	O
of	O
glycine	B-Chemical
in	O
the	O
brain	O
and	O
other	O
body	O
compartments	O
.	O

In	O
the	O
classical	O
form	O
it	O
presents	O
as	O
neonatal	O
apnea	B-Disease
,	O
intractable	O
seizures	B-Disease
,	O
and	O
hypotonia	B-Disease
,	O
followed	O
by	O
significant	O
psychomotor	B-Disease
retardation	I-Disease
.	O

An	O
important	O
subset	O
of	O
children	O
with	O
nonketotic	B-Disease
hyperglycinemia	I-Disease
are	O
atypical	O
variants	O
who	O
present	O
in	O
a	O
heterogeneous	O
manner	O
.	O

This	O
report	O
describes	O
a	O
patient	O
with	O
mild	O
language	B-Disease
delay	I-Disease
and	O
mental	B-Disease
retardation	I-Disease
,	O
who	O
was	O
found	O
to	O
have	O
nonketotic	B-Disease
hyperglycinemia	I-Disease
following	O
her	O
presentation	O
with	O
acute	O
encephalopathy	B-Disease
and	O
chorea	B-Disease
shortly	O
after	O
initiation	O
of	O
valproate	B-Chemical
therapy	O
.	O

Delayed	O
institution	O
of	O
hypertension	B-Disease
during	O
focal	O
cerebral	B-Disease
ischemia	I-Disease
:	O
effect	O
on	O
brain	B-Disease
edema	I-Disease
.	O

The	O
effect	O
of	O
induced	O
hypertension	B-Disease
instituted	O
after	O
a	O
2	O
-	O
h	O
delay	O
following	O
middle	B-Disease
cerebral	I-Disease
artery	I-Disease
occlusion	I-Disease
(	O
MCAO	B-Disease
)	O
on	O
brain	B-Disease
edema	I-Disease
formation	O
and	O
histochemical	O
injury	O
was	O
studied	O
.	O

Under	O
isoflurane	B-Chemical
anesthesia	O
,	O
the	O
MCA	O
of	O
14	O
spontaneously	O
hypertensive	B-Disease
rats	O
was	O
occluded	O
.	O

In	O
the	O
control	O
group	O
(	O
n	O
=	O
7	O
)	O
,	O
the	O
mean	O
arterial	O
pressure	O
(	O
MAP	O
)	O
was	O
not	O
manipulated	O
.	O

In	O
the	O
hypertensive	B-Disease
group	O
(	O
n	O
=	O
7	O
)	O
,	O
the	O
MAP	O
was	O
elevated	O
by	O
25	O
-	O
30	O
mm	O
Hg	O
beginning	O
2	O
h	O
after	O
MCAO	B-Disease
.	O

Four	O
hours	O
after	O
MCAO	B-Disease
,	O
the	O
rats	O
were	O
killed	O
and	O
the	O
brains	O
harvested	O
.	O

The	O
brains	O
were	O
sectioned	O
along	O
coronal	O
planes	O
spanning	O
the	O
distribution	O
of	O
ischemia	B-Disease
produced	O
by	O
MCAO	B-Disease
.	O

Specific	O
gravity	O
(	O
SG	O
)	O
was	O
determined	O
in	O
the	O
subcortex	O
and	O
in	O
two	O
sites	O
in	O
the	O
cortex	O
(	O
core	O
and	O
periphery	O
of	O
the	O
ischemic	B-Disease
territory	O
)	O
.	O

The	O
extent	O
of	O
neuronal	B-Disease
injury	I-Disease
was	O
determined	O
by	O
2	B-Chemical
,	I-Chemical
3	I-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
triphenyltetrazolium	I-Chemical
staining	O
.	O

In	O
the	O
ischemic	B-Disease
core	O
,	O
there	O
was	O
no	O
difference	O
in	O
SG	O
in	O
the	O
subcortex	O
and	O
cortex	O
in	O
the	O
two	O
groups	O
.	O

In	O
the	O
periphery	O
of	O
the	O
ischemic	B-Disease
territory	O
,	O
SG	O
in	O
the	O
cortex	O
was	O
greater	O
(	O
less	O
edema	B-Disease
accumulation	O
)	O
in	O
the	O
hypertensive	B-Disease
group	O
(	O
1	O
.	O
041	O
+	O
/	O
-	O
0	O
.	O
001	O
vs	O
1	O
.	O
039	O
+	O
/	O
-	O
0	O
.	O
001	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
area	O
of	O
histochemical	O
injury	O
(	O
as	O
a	O
percent	O
of	O
the	O
cross	O
-	O
sectional	O
area	O
of	O
the	O
hemisphere	O
)	O
was	O
less	O
in	O
the	O
hypertensive	B-Disease
group	O
(	O
33	O
+	O
/	O
-	O
3	O
%	O
vs	O
21	O
+	O
/	O
-	O
2	O
%	O
,	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

The	O
data	O
indicate	O
that	O
phenylephrine	B-Chemical
-	O
induced	O
hypertension	B-Disease
instituted	O
2	O
h	O
after	O
MCAO	B-Disease
does	O
not	O
aggravate	O
edema	B-Disease
in	O
the	O
ischemic	B-Disease
core	O
,	O
that	O
it	O
improves	O
edema	B-Disease
in	O
the	O
periphery	O
of	O
the	O
ischemic	B-Disease
territory	O
,	O
and	O
that	O
it	O
reduces	O
the	O
area	O
of	O
histochemical	O
neuronal	B-Disease
dysfunction	I-Disease
.	O

Behavioral	O
effects	O
of	O
pubertal	O
anabolic	O
androgenic	O
steroid	B-Chemical
exposure	O
in	O
male	O
rats	O
with	O
low	O
serotonin	B-Chemical
.	O

The	O
goal	O
of	O
this	O
study	O
was	O
to	O
assess	O
the	O
interactive	O
effects	O
of	O
chronic	O
anabolic	O
androgenic	O
steroid	B-Chemical
(	O
AAS	O
)	O
exposure	O
and	O
brain	O
serotonin	B-Chemical
(	O
5	B-Chemical
-	I-Chemical
hydroxytryptamine	I-Chemical
,	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
)	O
depletion	O
on	O
behavior	O
of	O
pubertal	O
male	O
rats	O
.	O

Serotonin	B-Chemical
was	O
depleted	O
beginning	O
on	O
postnatal	O
day	O
26	O
with	O
parachlorophenylalanine	B-Chemical
(	O
PCPA	B-Chemical
100	O
mg	O
/	O
kg	O
,	O
every	O
other	O
day	O
)	O
;	O
controls	O
received	O
saline	O
.	O

At	O
puberty	O
(	O
P40	O
)	O
,	O
half	O
the	O
PCPA	B-Chemical
-	O
treated	O
rats	O
and	O
half	O
the	O
saline	O
-	O
treated	O
rats	O
began	O
treatment	O
with	O
testosterone	B-Chemical
(	O
T	B-Chemical
,	O
5	O
mg	O
/	O
kg	O
,	O
5	O
days	O
/	O
week	O
)	O
.	O

Behavioral	O
measures	O
included	O
locomotion	O
,	O
irritability	B-Disease
,	O
copulation	O
,	O
partner	O
preference	O
,	O
and	O
aggression	B-Disease
.	O

Animals	O
were	O
tested	O
for	O
aggression	B-Disease
in	O
their	O
home	O
cage	O
,	O
both	O
with	O
and	O
without	O
physical	O
provocation	O
(	O
mild	O
tail	O
pinch	O
)	O
.	O

Brain	O
levels	O
of	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
and	O
its	O
metabolite	O
,	O
5	B-Chemical
-	I-Chemical
hydroxyindoleacetic	I-Chemical
acid	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
HIAA	I-Chemical
)	O
,	O
were	O
determined	O
using	O
HPLC	O
.	O

PCPA	B-Chemical
significantly	O
and	O
substantially	O
depleted	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
and	O
5	B-Chemical
-	I-Chemical
HIAA	I-Chemical
in	O
all	O
brain	O
regions	O
examined	O
.	O

Chronic	O
T	B-Chemical
treatment	O
significantly	O
decreased	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
and	O
5	B-Chemical
-	I-Chemical
HIAA	I-Chemical
in	O
certain	O
brain	O
areas	O
,	O
but	O
to	O
a	O
much	O
lesser	O
extent	O
than	O
PCPA	B-Chemical
.	O

Chronic	O
exposure	O
to	O
PCPA	B-Chemical
alone	O
significantly	O
decreased	O
locomotor	O
activity	O
and	O
increased	O
irritability	B-Disease
but	O
had	O
no	O
effect	O
on	O
sexual	O
behavior	O
,	O
partner	O
preference	O
,	O
or	O
aggression	B-Disease
.	O

T	B-Chemical
alone	O
had	O
no	O
effect	O
on	O
locomotion	O
,	O
irritability	B-Disease
,	O
or	O
sexual	O
behavior	O
but	O
increased	O
partner	O
preference	O
and	O
aggression	B-Disease
.	O

The	O
most	O
striking	O
effect	O
of	O
combining	O
T	B-Chemical
+	O
PCPA	B-Chemical
was	O
a	O
significant	O
increase	O
in	O
attack	O
frequency	O
as	O
well	O
as	O
a	O
significant	O
decrease	O
in	O
the	O
latency	O
to	O
attack	O
,	O
particularly	O
following	O
physical	O
provocation	O
.	O

Based	O
on	O
these	O
data	O
,	O
it	O
can	O
be	O
speculated	O
that	O
pubertal	O
AAS	O
users	O
with	O
low	O
central	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
may	O
be	O
especially	O
prone	O
to	O
exhibit	O
aggressive	B-Disease
behavior	I-Disease
.	O

Effects	O
of	O
UMB24	B-Chemical
and	O
(	O
+	O
/	O
-	O
)	O
-	O
SM	B-Chemical
21	I-Chemical
,	O
putative	O
sigma2	O
-	O
preferring	O
antagonists	O
,	O
on	O
behavioral	O
toxic	O
and	O
stimulant	O
effects	O
of	O
cocaine	B-Chemical
in	O
mice	O
.	O

Earlier	O
studies	O
have	O
demonstrated	O
that	O
antagonism	O
of	O
sigma1	O
receptors	O
attenuates	O
the	O
convulsive	B-Disease
,	O
lethal	O
,	O
locomotor	O
stimulatory	O
and	O
rewarding	O
actions	O
of	O
cocaine	B-Chemical
in	O
mice	O
.	O

In	O
contrast	O
,	O
the	O
contribution	O
of	O
sigma2	O
receptors	O
is	O
unclear	O
because	O
experimental	O
tools	O
to	O
selectively	O
target	O
this	O
subtype	O
are	O
unavailable	O
.	O

To	O
begin	O
addressing	O
this	O
need	O
,	O
we	O
characterized	O
UMB24	B-Chemical
(	O
1	B-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
phenethyl	I-Chemical
)	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
pyridyl	I-Chemical
)	I-Chemical
-	I-Chemical
piperazine	I-Chemical
)	O
and	O
(	O
+	O
/	O
-	O
)	O
-	O
SM	B-Chemical
21	I-Chemical
(	O
3alpha	B-Chemical
-	I-Chemical
tropanyl	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
4	I-Chemical
-	I-Chemical
chorophenoxy	I-Chemical
)	I-Chemical
butyrate	I-Chemical
)	O
in	O
receptor	O
binding	O
and	O
behavioral	O
studies	O
.	O

Receptor	O
binding	O
studies	O
confirmed	O
that	O
UMB24	B-Chemical
and	O
(	O
+	O
/	O
-	O
)	O
-	O
SM	B-Chemical
21	I-Chemical
display	O
preferential	O
affinity	O
for	O
sigma2	O
over	O
sigma1	O
receptors	O
.	O

In	O
behavioral	O
studies	O
,	O
pretreatment	O
of	O
Swiss	O
Webster	O
mice	O
with	O
UMB24	B-Chemical
or	O
(	O
+	O
/	O
-	O
)	O
-	O
SM	B-Chemical
21	I-Chemical
significantly	O
attenuated	O
cocaine	B-Chemical
-	O
induced	O
convulsions	B-Disease
and	O
locomotor	O
activity	O
,	O
but	O
not	O
lethality	O
.	O

When	O
administered	O
alone	O
,	O
(	O
+	O
/	O
-	O
)	O
-	O
SM	B-Chemical
21	I-Chemical
produced	O
no	O
significant	O
effects	O
compared	O
to	O
control	O
injections	O
of	O
saline	O
,	O
but	O
UMB24	B-Chemical
had	O
locomotor	O
depressant	O
actions	O
.	O

Together	O
,	O
the	O
data	O
suggest	O
that	O
sigma2	O
receptor	O
antagonists	O
have	O
the	O
potential	O
to	O
attenuate	O
some	O
of	O
the	O
behavioral	O
effects	O
of	O
cocaine	B-Chemical
,	O
and	O
further	O
development	O
of	O
more	O
selective	O
,	O
high	O
affinity	O
ligands	O
are	O
warranted	O
.	O

Cardiac	B-Disease
arrest	I-Disease
in	O
a	O
child	O
with	O
cerebral	B-Disease
palsy	I-Disease
undergoing	O
sevoflurane	B-Chemical
induction	O
of	O
anesthesia	O
after	O
preoperative	O
clonidine	B-Chemical
.	O

Clonidine	B-Chemical
is	O
a	O
frequently	O
administered	O
alpha2	O
-	O
adrenergic	O
agonist	O
which	O
can	O
decrease	O
heart	O
rate	O
and	O
blood	O
pressure	O
.	O

We	O
present	O
a	O
case	O
of	O
a	O
5	O
-	O
year	O
-	O
old	O
child	O
with	O
cerebral	B-Disease
palsy	I-Disease
and	O
seizure	B-Disease
disorder	I-Disease
,	O
receiving	O
clonidine	B-Chemical
for	O
restlessness	B-Disease
,	O
who	O
presented	O
for	O
placement	O
of	O
a	O
baclofen	B-Chemical
pump	O
.	O

Without	O
the	O
knowledge	O
of	O
the	O
medical	O
personnel	O
,	O
the	O
patient	O
'	O
s	O
mother	O
administered	O
three	O
doses	O
of	O
clonidine	B-Chemical
during	O
the	O
evening	O
before	O
and	O
morning	O
of	O
surgery	O
to	O
reduce	O
anxiety	B-Disease
.	O

During	O
induction	O
of	O
anesthesia	O
,	O
the	O
patient	O
developed	O
bradycardia	B-Disease
and	O
hypotension	B-Disease
requiring	O
cardiac	O
resuscitation	O
.	O

There	O
are	O
no	O
previous	O
reports	O
of	O
clonidine	B-Chemical
-	O
associated	O
cardiac	B-Disease
arrest	I-Disease
in	O
a	O
child	O
undergoing	O
induction	O
of	O
anesthesia	O
.	O

Angiotensin	O
-	O
converting	O
enzyme	O
(	O
ACE	O
)	O
inhibitor	O
-	O
associated	O
angioedema	B-Disease
of	O
the	O
stomach	O
and	O
small	O
intestine	O
:	O
a	O
case	O
report	O
.	O

This	O
is	O
a	O
case	O
report	O
on	O
a	O
45	O
-	O
year	O
old	O
African	O
-	O
American	O
female	O
with	O
newly	O
diagnosed	O
hypertension	B-Disease
,	O
who	O
was	O
started	O
on	O
a	O
combination	O
pill	O
of	O
amlodipine	B-Chemical
/	O
benazapril	B-Chemical
10	O
/	O
5	O
mg	O
.	O

The	O
very	O
next	O
day	O
,	O
she	O
presented	O
at	O
the	O
emergency	O
room	O
(	O
ER	O
)	O
with	O
abdominal	B-Disease
pain	I-Disease
,	O
nausea	B-Disease
and	O
vomiting	B-Disease
.	O

Physical	O
exam	O
,	O
complete	O
metabolic	O
panel	O
,	O
and	O
hemogram	O
were	O
in	O
the	O
normal	O
range	O
.	O

She	O
was	O
discharged	O
from	O
the	O
ER	O
after	O
a	O
few	O
hours	O
of	O
treatment	O
with	O
fluid	O
and	O
analgesics	O
.	O

However	O
,	O
she	O
returned	O
to	O
the	O
ER	O
the	O
next	O
day	O
with	O
the	O
same	O
complaints	O
.	O

This	O
time	O
the	O
physical	O
exam	O
was	O
significant	O
for	O
a	O
distended	O
abdomen	O
with	O
dullness	O
to	O
percussion	O
.	O

CT	O
scan	O
of	O
the	O
abdomen	O
revealed	O
markedly	O
thickened	O
antrum	O
of	O
the	O
stomach	O
,	O
duodenum	O
and	O
jejunum	O
,	O
along	O
with	O
fluid	O
in	O
the	O
abdominal	O
and	O
pelvic	O
cavity	O
.	O

Angiotensin	O
-	O
converting	O
enzyme	O
inhibitor	O
(	O
ACEI	O
)	O
-	O
induced	O
angioedema	B-Disease
was	O
suspected	O
,	O
and	O
anti	O
-	O
hypertensive	B-Disease
medications	O
were	O
discontinued	O
.	O

Her	O
symptoms	O
improved	O
within	O
the	O
next	O
24	O
hours	O
,	O
and	O
repeat	O
CT	O
after	O
72	O
hours	O
revealed	O
marked	O
improvement	O
in	O
stomach	O
and	O
small	O
bowel	O
thickening	O
and	O
resolution	O
of	O
ascites	B-Disease
.	O

The	O
recognition	O
of	O
angiotensin	B-Chemical
-	O
converting	O
enzyme	O
(	O
ACE	O
)	O
and	O
angiotensin	B-Chemical
receptor	O
blocker	O
(	O
ARB	O
)	O
intestinal	B-Disease
angioedema	I-Disease
constitutes	O
a	O
challenge	O
to	O
primary	O
care	O
physicians	O
,	O
internists	O
,	O
emergency	O
room	O
personal	O
and	O
surgeons	O
.	O

Carbamazepine	B-Chemical
-	O
induced	O
cardiac	B-Disease
dysfunction	I-Disease
.	O

Characterization	O
of	O
two	O
distinct	O
clinical	O
syndromes	O
.	O

A	O
patient	O
with	O
sinus	O
bradycardia	B-Disease
and	O
atrioventricular	B-Disease
block	I-Disease
,	O
induced	O
by	O
carbamazepine	B-Chemical
,	O
prompted	O
an	O
extensive	O
literature	O
review	O
of	O
all	O
previously	O
reported	O
cases	O
.	O

From	O
the	O
analysis	O
of	O
these	O
cases	O
,	O
two	O
distinct	O
forms	O
of	O
carbamazepine	B-Chemical
-	O
associated	O
cardiac	B-Disease
dysfunction	I-Disease
emerged	O
.	O

One	O
patient	O
group	O
developed	O
sinus	B-Disease
tachycardias	I-Disease
in	O
the	O
setting	O
of	O
a	O
massive	O
carbamazepine	B-Chemical
overdose	B-Disease
.	O

The	O
second	O
group	O
consisted	O
almost	O
exclusively	O
of	O
elderly	O
women	O
who	O
developed	O
potentially	O
life	O
-	O
threatening	O
bradyarrhythmias	B-Disease
or	O
atrioventricular	B-Disease
conduction	I-Disease
delay	I-Disease
,	O
associated	O
with	O
either	O
therapeutic	O
or	O
modestly	O
elevated	O
carbamazepine	B-Chemical
serum	O
levels	O
.	O

Because	O
carbamazepine	B-Chemical
is	O
widely	O
used	O
in	O
the	O
treatment	O
of	O
many	O
neurologic	O
and	O
psychiatric	B-Disease
conditions	O
,	O
the	O
recognition	O
of	O
the	O
latter	O
syndrome	O
has	O
important	O
implications	O
for	O
the	O
use	O
of	O
this	O
drug	O
in	O
elderly	O
patients	O
.	O

Detection	O
of	O
abnormal	O
cardiac	O
adrenergic	O
neuron	O
activity	O
in	O
adriamycin	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
with	O
iodine	B-Chemical
-	I-Chemical
125	I-Chemical
-	I-Chemical
metaiodobenzylguanidine	I-Chemical
.	O

Radiolabeled	B-Chemical
metaiodobenzylguanidine	I-Chemical
(	O
MIBG	B-Chemical
)	O
,	O
an	O
analog	O
of	O
norepinephrine	B-Chemical
(	O
NE	B-Chemical
)	O
,	O
serves	O
as	O
an	O
index	O
of	O
adrenergic	O
neuron	O
integrity	O
and	O
function	O
.	O

Using	O
a	O
rat	O
model	O
of	O
adriamycin	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
,	O
we	O
tested	O
the	O
hypothesis	O
that	O
abnormal	O
cardiac	O
adrenergic	O
neuron	O
activity	O
may	O
appear	O
and	O
be	O
exacerbated	O
dose	O
-	O
dependently	O
in	O
adriamycin	B-Chemical
cardiomyopathy	B-Disease
.	O

The	O
degree	O
of	O
vacuolar	B-Disease
degeneration	I-Disease
of	I-Disease
myocardial	I-Disease
cells	I-Disease
was	O
analyzed	O
in	O
relation	O
to	O
the	O
duration	O
of	O
adriamycin	B-Chemical
treatment	O
(	O
2	O
mg	O
/	O
kg	O
,	O
once	O
a	O
week	O
)	O
.	O

There	O
were	O
no	O
abnormalities	O
or	O
only	O
isolated	O
degeneration	O
in	O
the	O
1	O
-	O
or	O
2	O
-	O
wk	O
treatment	O
groups	O
,	O
isolated	O
or	O
scattered	O
degeneration	O
in	O
half	O
of	O
the	O
3	O
-	O
wk	O
group	O
,	O
frequent	O
scattered	O
degeneration	O
in	O
the	O
4	O
-	O
wk	O
group	O
,	O
scattered	O
or	O
focal	O
degeneration	O
in	O
the	O
5	O
-	O
wk	O
group	O
,	O
and	O
extensive	O
degeneration	O
in	O
the	O
8	O
-	O
wk	O
group	O
.	O

Myocardial	O
accumulation	O
of	O
[	O
125I	O
]	O
MIBG	B-Chemical
4	O
hr	O
after	O
intravenous	O
injection	O
did	O
not	O
differ	O
between	O
the	O
controls	O
and	O
the	O
groups	O
treated	O
3	O
wk	O
or	O
less	O
.	O

However	O
,	O
the	O
4	O
-	O
wk	O
group	O
had	O
a	O
slightly	O
lower	O
accumulation	O
in	O
the	O
right	O
ventricular	O
wall	O
(	O
82	O
%	O
of	O
the	O
control	O
)	O
and	O
significantly	O
lower	O
accumulation	O
in	O
the	O
left	O
ventricular	O
wall	O
(	O
about	O
66	O
%	O
of	O
the	O
control	O
:	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

In	O
the	O
5	O
-	O
wk	O
group	O
,	O
MIBG	B-Chemical
accumulation	O
in	O
the	O
right	O
and	O
left	O
ventricular	O
wall	O
was	O
35	O
%	O
and	O
27	O
%	O
of	O
that	O
in	O
controls	O
,	O
respectively	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

In	O
the	O
8	O
-	O
wk	O
group	O
,	O
MIBG	B-Chemical
accumulation	O
in	O
the	O
right	O
and	O
left	O
ventricular	O
wall	O
was	O
18	O
%	O
and	O
14	O
%	O
of	O
that	O
in	O
controls	O
,	O
respectively	O
(	O
p	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Thus	O
,	O
MIBG	B-Chemical
accumulation	O
in	O
the	O
myocardium	O
decreased	O
in	O
an	O
adriamycin	B-Chemical
dose	O
-	O
dependent	O
manner	O
.	O

The	O
appearance	O
of	O
impaired	O
cardiac	O
adrenergic	O
neuron	O
activity	O
in	O
the	O
presence	O
of	O
slight	O
myocardial	B-Disease
impairment	I-Disease
(	O
scattered	O
or	O
focal	O
vacuolar	B-Disease
degeneration	I-Disease
)	O
indicates	O
that	O
MIBG	B-Chemical
scintigraphy	O
may	O
be	O
a	O
useful	O
method	O
for	O
detection	O
of	O
adriamycin	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
.	O

Syncope	B-Disease
and	O
QT	B-Disease
prolongation	I-Disease
among	O
patients	O
treated	O
with	O
methadone	B-Chemical
for	O
heroin	B-Chemical
dependence	O
in	O
the	O
city	O
of	O
Copenhagen	O
.	O

BACKGROUND	O
:	O
Methadone	B-Chemical
is	O
prescribed	O
to	O
heroin	B-Chemical
addicts	O
to	O
decrease	O
illicit	O
opioid	O
use	O
.	O

Prolongation	O
of	O
the	O
QT	O
interval	O
in	O
the	O
ECG	O
of	O
patients	O
with	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
(	O
TdP	B-Disease
)	O
has	O
been	O
reported	O
in	O
methadone	B-Chemical
users	O
.	O

As	O
heroin	B-Chemical
addicts	O
sometimes	O
faint	O
while	O
using	O
illicit	O
drugs	O
,	O
doctors	O
might	O
attribute	O
too	O
many	O
episodes	O
of	O
syncope	B-Disease
to	O
illicit	O
drug	O
use	O
and	O
thereby	O
underestimate	O
the	O
incidence	O
of	O
TdP	B-Disease
in	O
this	O
special	O
population	O
,	O
and	O
the	O
high	O
mortality	O
in	O
this	O
population	O
may	O
,	O
in	O
part	O
,	O
be	O
caused	O
by	O
the	O
proarrhythmic	O
effect	O
of	O
methadone	B-Chemical
.	O

METHODS	O
:	O
In	O
this	O
cross	O
-	O
sectional	O
study	O
interview	O
,	O
ECGs	O
and	O
blood	O
samples	O
were	O
collected	O
in	O
a	O
population	O
of	O
adult	O
heroin	B-Chemical
addicts	O
treated	O
with	O
methadone	B-Chemical
or	O
buprenorphine	B-Chemical
on	O
a	O
daily	O
basis	O
.	O

Of	O
the	O
patients	O
at	O
the	O
Drug	O
Addiction	O
Service	O
in	O
the	O
municipal	O
of	O
Copenhagen	O
,	O
450	O
(	O
approximately	O
52	O
%	O
)	O
were	O
included	O
.	O

The	O
QT	O
interval	O
was	O
estimated	O
from	O
12	O
lead	O
ECGs	O
.	O

All	O
participants	O
were	O
interviewed	O
about	O
any	O
experience	O
of	O
syncope	B-Disease
.	O

The	O
association	O
between	O
opioid	O
dose	O
and	O
QT	O
,	O
and	O
methadone	B-Chemical
dose	O
and	O
reporting	O
of	O
syncope	B-Disease
was	O
assessed	O
using	O
multivariate	O
linear	O
regression	O
and	O
logistic	O
regression	O
,	O
respectively	O
.	O

RESULTS	O
:	O
Methadone	B-Chemical
dose	O
was	O
associated	O
with	O
longer	O
QT	O
interval	O
of	O
0	O
.	O
140	O
ms	O
/	O
mg	O
(	O
p	O
=	O
0	O
.	O
002	O
)	O
.	O

No	O
association	O
between	O
buprenorphine	B-Chemical
and	O
QTc	O
was	O
found	O
.	O

Among	O
the	O
subjects	O
treated	O
with	O
methadone	B-Chemical
,	O
28	O
%	O
men	O
and	O
32	O
%	O
women	O
had	O
prolonged	B-Disease
QTc	I-Disease
interval	I-Disease
.	O

None	O
of	O
the	O
subjects	O
treated	O
with	O
buprenorphine	B-Chemical
had	O
QTc	O
interval	O
>	O
0	O
.	O
440	O
s	O
(	O
(	O
1	O
/	O
2	O
)	O
)	O
.	O

A	O
50	O
mg	O
higher	O
methadone	B-Chemical
dose	O
was	O
associated	O
with	O
a	O
1	O
.	O
2	O
(	O
95	O
%	O
CI	O
1	O
.	O
1	O
to	O
1	O
.	O
4	O
)	O
times	O
higher	O
odds	O
for	O
syncope	B-Disease
.	O

CONCLUSIONS	O
:	O
Methadone	B-Chemical
is	O
associated	O
with	O
QT	B-Disease
prolongation	I-Disease
and	O
higher	O
reporting	O
of	O
syncope	B-Disease
in	O
a	O
population	O
of	O
heroin	B-Chemical
addicts	O
.	O

Neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
induced	O
by	O
ziprasidone	B-Chemical
on	O
the	O
second	O
day	O
of	O
treatment	O
.	O

Neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
(	O
NMS	B-Disease
)	O
is	O
the	O
rarest	O
and	O
most	O
serious	O
of	O
the	O
neuroleptic	O
-	O
induced	O
movement	B-Disease
disorders	I-Disease
.	O

We	O
describe	O
a	O
case	O
of	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
(	O
NMS	B-Disease
)	O
associated	O
with	O
the	O
use	O
of	O
ziprasidone	B-Chemical
.	O

Although	O
conventional	O
neuroleptics	O
are	O
more	O
frequently	O
associated	O
with	O
NMS	B-Disease
,	O
atypical	O
antipsychotic	O
drugs	O
like	O
ziprasidone	B-Chemical
may	O
also	O
be	O
a	O
cause	O
.	O

The	O
patient	O
is	O
a	O
24	O
-	O
year	O
-	O
old	O
male	O
with	O
a	O
history	O
of	O
schizophrenia	B-Disease
who	O
developed	O
signs	O
and	O
symptoms	O
of	O
NMS	B-Disease
after	O
2	O
days	O
of	O
treatment	O
with	O
an	O
80	O
-	O
mg	O
/	O
day	O
dose	O
of	O
orally	O
administrated	O
ziprasidone	B-Chemical
.	O

This	O
case	O
is	O
the	O
earliest	O
(	O
second	O
day	O
of	O
treatment	O
)	O
NMS	B-Disease
due	O
to	O
ziprasidone	B-Chemical
reported	O
in	O
the	O
literature	O
.	O

Peripheral	O
iron	B-Chemical
dextran	I-Chemical
induced	O
degeneration	B-Disease
of	I-Disease
dopaminergic	I-Disease
neurons	I-Disease
in	O
rat	O
substantia	O
nigra	O
.	O

Iron	B-Chemical
accumulation	O
is	O
considered	O
to	O
be	O
involved	O
in	O
the	O
pathogenesis	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

To	O
demonstrate	O
the	O
relationship	O
between	O
peripheral	O
iron	B-Chemical
overload	O
and	O
dopaminergic	O
neuron	O
loss	O
in	O
rat	O
substantia	O
nigra	O
(	O
SN	O
)	O
,	O
in	O
the	O
present	O
study	O
we	O
used	O
fast	O
cyclic	O
voltammetry	O
,	O
tyrosine	B-Chemical
hydroxylase	O
(	O
TH	O
)	O
immunohistochemistry	O
,	O
Perls	O
'	O
iron	B-Chemical
staining	O
,	O
and	O
high	O
performance	O
liquid	O
chromatography	O
-	O
electrochemical	O
detection	O
to	O
study	O
the	O
degeneration	B-Disease
of	I-Disease
dopaminergic	I-Disease
neurons	I-Disease
and	O
increased	O
iron	B-Chemical
content	O
in	O
the	O
SN	O
of	O
iron	B-Chemical
dextran	I-Chemical
overloaded	O
animals	O
.	O

The	O
findings	O
showed	O
that	O
peripheral	O
iron	B-Chemical
dextran	I-Chemical
overload	O
increased	O
the	O
iron	B-Chemical
staining	O
positive	O
cells	O
and	O
reduced	O
the	O
number	O
of	O
TH	O
-	O
immunoreactive	O
neurons	O
in	O
the	O
SN	O
.	O

As	O
a	O
result	O
,	O
dopamine	B-Chemical
release	O
and	O
content	O
,	O
as	O
well	O
as	O
its	O
metabolites	O
contents	O
were	O
decreased	O
in	O
caudate	O
putamen	O
.	O

Even	O
more	O
dramatic	O
changes	O
were	O
found	O
in	O
chronic	O
overload	O
group	O
.	O

These	O
results	O
suggest	O
that	O
peripheral	O
iron	B-Chemical
dextran	I-Chemical
can	O
increase	O
the	O
iron	B-Chemical
level	O
in	O
the	O
SN	O
,	O
where	O
excessive	O
iron	B-Chemical
causes	O
the	O
degeneration	B-Disease
of	I-Disease
dopaminergic	I-Disease
neurons	I-Disease
.	O

The	O
chronic	O
iron	B-Chemical
overload	O
may	O
be	O
more	O
destructive	O
to	O
dopaminergic	O
neurons	O
than	O
the	O
acute	O
iron	B-Chemical
overload	O
.	O

Attenuated	O
disruption	O
of	O
prepulse	O
inhibition	O
by	O
dopaminergic	O
stimulation	O
after	O
maternal	O
deprivation	O
and	O
adolescent	O
corticosterone	B-Chemical
treatment	O
in	O
rats	O
.	O

The	O
development	O
of	O
schizophrenia	B-Disease
may	O
include	O
an	O
early	O
neurodevelopmental	O
stress	O
component	O
which	O
increases	O
vulnerability	O
to	O
later	O
stressful	O
life	O
events	O
,	O
in	O
combination	O
leading	O
to	O
overt	O
disease	O
.	O

We	O
investigated	O
the	O
effect	O
of	O
an	O
early	O
stress	O
,	O
in	O
the	O
form	O
of	O
maternal	O
deprivation	O
,	O
combined	O
with	O
a	O
later	O
stress	O
,	O
simulated	O
by	O
chronic	O
periadolescent	O
corticosterone	B-Chemical
treatment	O
,	O
on	O
behaviour	O
in	O
rats	O
.	O

Acute	O
treatment	O
with	O
apomorphine	B-Chemical
caused	O
disruption	O
of	O
prepulse	O
inhibition	O
(	O
PPI	O
)	O
in	O
controls	O
and	O
in	O
rats	O
that	O
had	O
undergone	O
either	O
maternal	O
deprivation	O
or	O
corticosterone	B-Chemical
treatment	O
,	O
but	O
was	O
surprisingly	O
absent	O
in	O
rats	O
that	O
had	O
undergone	O
the	O
combined	O
early	O
and	O
late	O
stress	O
.	O

Amphetamine	B-Chemical
treatment	O
significantly	O
disrupted	O
PPI	O
in	O
both	O
non	O
-	O
deprived	O
groups	O
,	O
but	O
was	O
absent	O
in	O
both	O
maternally	O
deprived	O
groups	O
.	O

The	O
serotonin	B-Chemical
-	O
1A	O
receptor	O
agonist	O
,	O
8	B-Chemical
-	I-Chemical
OH	I-Chemical
-	I-Chemical
DPAT	I-Chemical
,	O
induced	O
a	O
significant	O
disruption	O
of	O
PPI	O
in	O
all	O
groups	O
.	O

Amphetamine	B-Chemical
-	O
induced	O
locomotor	B-Disease
hyperactivity	I-Disease
was	O
similar	O
in	O
all	O
groups	O
.	O

These	O
results	O
show	O
an	O
inhibitory	O
interaction	O
of	O
early	O
stress	O
,	O
caused	O
by	O
maternal	O
deprivation	O
,	O
combined	O
with	O
'	O
adolescent	O
'	O
stress	O
,	O
simulated	O
by	O
corticosterone	B-Chemical
treatment	O
,	O
on	O
dopaminergic	O
regulation	O
of	O
PPI	O
.	O

The	O
altered	O
effects	O
of	O
apomorphine	B-Chemical
and	O
amphetamine	B-Chemical
could	O
indicate	O
differential	O
changes	O
in	O
dopamine	B-Chemical
receptor	O
signalling	O
leading	O
to	O
functional	O
desensitisation	O
,	O
or	O
altered	O
modulation	O
of	O
sensory	O
gating	O
in	O
the	O
nucleus	O
accumbens	O
by	O
limbic	O
structures	O
such	O
as	O
the	O
hippocampus	O
.	O

An	O
extremely	O
rare	O
case	O
of	O
delusional	B-Disease
parasitosis	I-Disease
in	O
a	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
patient	O
during	O
pegylated	B-Chemical
interferon	I-Chemical
alpha	I-Chemical
-	I-Chemical
2b	I-Chemical
and	O
ribavirin	B-Chemical
treatment	O
.	O

During	O
treatment	O
of	O
chronic	B-Disease
hepatitis	I-Disease
C	I-Disease
patients	O
with	O
interferon	O
and	O
ribavirin	B-Chemical
,	O
a	O
lot	O
of	O
side	O
effects	O
are	O
described	O
.	O

Twenty	O
-	O
three	O
percent	O
to	O
44	O
%	O
of	O
patients	O
develop	O
depression	B-Disease
.	O

A	O
minority	O
of	O
patients	O
evolve	O
to	O
psychosis	B-Disease
.	O

To	O
the	O
best	O
of	O
our	O
knowledge	O
,	O
no	O
cases	O
of	O
psychogenic	B-Disease
parasitosis	I-Disease
occurring	O
during	O
interferon	O
therapy	O
have	O
been	O
described	O
in	O
the	O
literature	O
.	O

We	O
present	O
a	O
49	O
-	O
year	O
-	O
old	O
woman	O
who	O
developed	O
a	O
delusional	B-Disease
parasitosis	I-Disease
during	O
treatment	O
with	O
pegylated	B-Chemical
interferon	I-Chemical
alpha	I-Chemical
-	I-Chemical
2b	I-Chemical
weekly	O
and	O
ribavirin	B-Chemical
.	O

She	O
complained	O
of	O
seeing	O
parasites	O
and	O
the	O
larvae	O
of	O
fleas	O
in	O
her	O
stools	O
.	O

This	O
could	O
not	O
be	O
confirmed	O
by	O
any	O
technical	O
examination	O
.	O

All	O
the	O
complaints	O
disappeared	O
after	O
stopping	O
pegylated	B-Chemical
interferon	I-Chemical
alpha	I-Chemical
-	I-Chemical
2b	I-Chemical
and	O
reappeared	O
after	O
restarting	O
it	O
.	O

She	O
had	O
a	O
complete	O
sustained	O
viral	O
response	O
.	O

Hepatonecrosis	B-Disease
and	O
cholangitis	B-Disease
related	O
to	O
long	O
-	O
term	O
phenobarbital	B-Chemical
therapy	O
:	O
an	O
autopsy	O
report	O
of	O
two	O
patients	O
.	O

Phenobarbital	B-Chemical
(	O
PB	B-Chemical
)	O
has	O
a	O
reputation	O
for	O
safety	O
,	O
and	O
it	O
is	O
commonly	O
believed	O
that	O
PB	B-Chemical
-	O
related	O
increases	O
in	O
serum	O
aminotransferase	O
levels	O
do	O
not	O
indicate	O
or	O
predict	O
the	O
development	O
of	O
significant	O
chronic	O
liver	B-Disease
disease	I-Disease
.	O

Here	O
we	O
report	O
of	O
two	O
adult	O
patients	O
with	O
a	O
long	O
history	O
of	O
epilepsy	B-Disease
treated	O
with	O
PB	B-Chemical
who	O
died	O
suddenly	O
:	O
one	O
as	O
consequence	O
of	O
cardiac	B-Disease
arrest	I-Disease
,	O
the	O
other	O
of	O
acute	O
bronchopneumonia	B-Disease
.	O

At	O
autopsy	O
,	O
analysis	O
of	O
liver	O
parenchyma	O
revealed	O
rich	O
portal	O
inflammatory	O
infiltrate	O
,	O
which	O
consisted	O
of	O
mixed	O
eosinophil	O
and	O
monocyte	O
cells	O
,	O
associated	O
with	O
several	O
foci	O
of	O
necrosis	B-Disease
surrounded	O
by	O
a	O
hard	O
ring	O
of	O
non	O
-	O
specific	O
granulomatous	O
tissue	O
.	O

Inflammatory	O
reactions	O
of	O
internal	O
and	O
external	O
hepatic	O
biliary	O
ducts	O
were	O
also	O
seen	O
.	O

Our	O
findings	O
illustrate	O
that	O
PB	B-Chemical
may	O
be	O
associated	O
with	O
chronic	O
liver	B-Disease
damage	I-Disease
,	O
which	O
may	O
lead	O
to	O
more	O
serious	O
and	O
deleterious	O
consequences	O
.	O

For	O
this	O
reason	O
,	O
each	O
clinician	O
should	O
recognize	O
this	O
entity	O
in	O
the	O
differential	O
diagnosis	O
of	O
PB	B-Chemical
-	O
related	O
asymptomatic	O
chronic	B-Disease
hepatic	I-Disease
enzyme	I-Disease
dysfunction	I-Disease
.	O

Delayed	O
leukoencephalopathy	B-Disease
with	O
stroke	B-Disease
-	O
like	O
presentation	O
in	O
chemotherapy	O
recipients	O
.	O

BACKGROUND	O
:	O
A	O
transient	O
leukoencephalopathy	B-Disease
mimicking	O
cerebrovascular	B-Disease
accident	I-Disease
has	O
been	O
described	O
as	O
a	O
complication	O
of	O
chemotherapy	O
,	O
most	O
commonly	O
in	O
recipients	O
of	O
intrathecal	O
methotrexate	B-Chemical
for	O
childhood	O
leukaemia	B-Disease
.	O

Recently	O
published	O
neuroimaging	O
data	O
suggest	O
a	O
common	O
pathophysiology	O
associated	O
with	O
a	O
variety	O
of	O
chemotherapy	O
agents	O
and	O
modes	O
of	O
administration	O
.	O

METHODS	O
:	O
We	O
reviewed	O
the	O
medical	O
literature	O
for	O
single	O
reports	O
and	O
case	O
series	O
of	O
patients	O
presenting	O
with	O
stroke	B-Disease
-	O
like	O
episodes	O
while	O
receiving	O
systemic	O
or	O
intrathecal	O
chemotherapy	O
.	O

We	O
only	O
included	O
studies	O
providing	O
detailed	O
neuroimaging	O
data	O
.	O

Patients	O
with	O
cerebrovascular	B-Disease
accidents	I-Disease
were	O
excluded	O
.	O

RESULTS	O
:	O
We	O
identified	O
27	O
reports	O
of	O
toxic	O
leukoencephalopathy	B-Disease
in	O
patients	O
treated	O
with	O
methotrexate	B-Chemical
(	O
intrathecal	O
,	O
systemic	O
)	O
,	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
and	O
its	O
derivative	O
carmofur	B-Chemical
,	O
and	O
capecitabine	B-Chemical
.	O

Diffusion	O
weighted	O
imaging	O
(	O
DWI	O
)	O
of	O
all	O
patients	O
revealed	O
well	O
demarcated	O
hyperintense	O
lesions	B-Disease
within	I-Disease
the	I-Disease
subcortical	I-Disease
white	I-Disease
matter	I-Disease
of	O
the	O
cerebral	O
hemispheres	O
and	O
the	O
corpus	O
callosum	O
,	O
corresponding	O
to	O
areas	O
of	O
decreased	O
proton	O
diffusion	O
on	O
apparent	O
diffusion	O
coefficient	O
(	O
ADC	O
)	O
maps	O
(	O
available	O
in	O
21	O
/	O
27	O
patients	O
)	O
.	O

Lesions	O
exceeded	O
the	O
confines	O
of	O
adjacent	O
vascular	O
territories	O
.	O

Complete	O
resolution	O
of	O
symptoms	O
within	O
1	O
-	O
4	O
days	O
was	O
accompanied	O
by	O
normalisation	O
of	O
ADC	O
abnormalities	O
.	O

However	O
,	O
fluid	O
attenuated	O
inversion	O
recovery	O
(	O
FLAIR	O
)	O
sequences	O
frequently	O
revealed	O
persistent	O
white	B-Disease
matter	I-Disease
abnormalities	I-Disease
.	O

CONCLUSIONS	O
:	O
Several	O
pathophysiological	O
models	O
of	O
delayed	O
leukoencephalopathy	B-Disease
after	O
exposure	O
to	O
intrathecal	O
or	O
systemic	O
chemotherapy	O
have	O
been	O
proposed	O
.	O

DWI	O
findings	O
in	O
this	O
cohort	O
are	O
indicative	O
of	O
cytotoxic	B-Disease
oedema	I-Disease
within	I-Disease
cerebral	I-Disease
white	I-Disease
matter	I-Disease
and	O
lend	O
support	O
to	O
an	O
at	O
least	O
partially	O
reversible	O
metabolic	O
derangement	O
as	O
the	O
basis	O
for	O
this	O
syndrome	O
.	O

Prenatal	O
exposure	O
to	O
fluoxetine	B-Chemical
induces	O
fetal	B-Disease
pulmonary	I-Disease
hypertension	I-Disease
in	O
the	O
rat	O
.	O

RATIONALE	O
:	O
Fluoxetine	B-Chemical
is	O
a	O
selective	O
serotonin	B-Chemical
reuptake	O
inhibitor	O
antidepressant	O
widely	O
used	O
by	O
pregnant	O
women	O
.	O

Epidemiological	O
data	O
suggest	O
that	O
fluoxetine	B-Chemical
exposure	O
prenatally	O
increases	O
the	O
prevalence	O
of	O
persistent	O
pulmonary	B-Disease
hypertension	I-Disease
syndrome	I-Disease
of	O
the	O
newborn	O
.	O

The	O
mechanism	O
responsible	O
for	O
this	O
effect	O
is	O
unclear	O
and	O
paradoxical	O
,	O
considering	O
the	O
current	O
evidence	O
of	O
a	O
pulmonary	B-Disease
hypertension	I-Disease
protective	O
fluoxetine	B-Chemical
effect	O
in	O
adult	O
rodents	O
.	O

OBJECTIVES	O
:	O
To	O
evaluate	O
the	O
fluoxetine	B-Chemical
effect	O
on	O
fetal	O
rat	O
pulmonary	O
vascular	O
smooth	O
muscle	O
mechanical	O
properties	O
and	O
cell	O
proliferation	O
rate	O
.	O

METHODS	O
:	O
Pregnant	O
rats	O
were	O
treated	O
with	O
fluoxetine	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
)	O
from	O
Day	O
11	O
through	O
Day	O
21	O
of	O
gestation	O
.	O

MEASUREMENTS	O
AND	O
MAIN	O
RESULTS	O
:	O
Fetuses	O
were	O
delivered	O
by	O
cesarean	O
section	O
.	O

As	O
compared	O
with	O
controls	O
,	O
fluoxetine	B-Chemical
exposure	O
resulted	O
in	O
fetal	B-Disease
pulmonary	I-Disease
hypertension	I-Disease
as	O
evidenced	O
by	O
an	O
increase	O
in	O
the	O
weight	O
ratio	O
of	O
the	O
right	O
ventricle	O
to	O
the	O
left	O
ventricle	O
plus	O
septum	O
(	O
P	O
=	O
0	O
.	O
02	O
)	O
and	O
by	O
an	O
increase	O
in	O
pulmonary	O
arterial	O
medial	O
thickness	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Postnatal	O
mortality	O
was	O
increased	O
among	O
experimental	O
animals	O
,	O
and	O
arterial	O
oxygen	B-Chemical
saturation	O
was	O
96	O
+	O
/	O
-	O
1	O
%	O
in	O
1	O
-	O
day	O
-	O
old	O
control	O
animals	O
and	O
significantly	O
lower	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
in	O
fluoxetine	B-Chemical
-	O
exposed	O
pups	O
(	O
79	O
+	O
/	O
-	O
2	O
%	O
)	O
.	O

In	O
vitro	O
,	O
fluoxetine	B-Chemical
induced	O
pulmonary	O
arterial	O
muscle	O
contraction	O
in	O
fetal	O
,	O
but	O
not	O
adult	O
,	O
animals	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
and	O
reduced	O
serotonin	B-Chemical
-	O
induced	O
contraction	O
at	O
both	O
ages	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

After	O
in	O
utero	O
exposure	O
to	O
a	O
low	O
fluoxetine	B-Chemical
concentration	O
the	O
pulmonary	O
arterial	O
smooth	O
muscle	O
cell	O
proliferation	O
rate	O
was	O
significantly	O
increased	O
in	O
fetal	O
,	O
but	O
not	O
adult	O
,	O
cells	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

CONCLUSIONS	O
:	O
In	O
contrast	O
to	O
the	O
adult	O
,	O
fluoxetine	B-Chemical
exposure	O
in	O
utero	O
induces	O
pulmonary	B-Disease
hypertension	I-Disease
in	O
the	O
fetal	O
rat	O
as	O
a	O
result	O
of	O
a	O
developmentally	O
regulated	O
increase	O
in	O
pulmonary	O
vascular	O
smooth	O
muscle	O
proliferation	O
.	O

Disulfiram	B-Chemical
-	O
induced	O
transient	O
optic	B-Disease
and	I-Disease
peripheral	I-Disease
neuropathy	I-Disease
:	O
a	O
case	O
report	O
.	O

AIM	O
:	O
To	O
report	O
a	O
case	O
of	O
optic	B-Disease
and	I-Disease
peripheral	I-Disease
neuropathy	I-Disease
after	O
chronic	O
use	O
of	O
disulfiram	B-Chemical
for	O
alcohol	B-Disease
dependence	I-Disease
management	O
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
A	O
case	O
report	O
.	O

RESULTS	O
:	O
A	O
57	O
-	O
year	O
-	O
old	O
male	O
presented	O
with	O
gradual	O
loss	B-Disease
of	I-Disease
vision	I-Disease
in	O
both	O
eyes	O
with	O
intermittent	O
headaches	B-Disease
for	O
2	O
months	O
.	O

He	O
also	O
complained	O
of	O
paraesthesia	B-Disease
with	O
numbness	B-Disease
in	O
both	O
feet	O
.	O

His	O
vision	O
was	O
6	O
/	O
15	O
and	O
2	O
/	O
60	O
in	O
the	O
right	O
and	O
left	O
eyes	O
,	O
respectively	O
.	O

Fundoscopy	O
revealed	O
bilaterally	O
swollen	O
optic	O
nerve	O
heads	O
.	O

Visual	O
field	O
testing	O
confirmed	O
bilateral	O
central	O
-	O
caecal	O
scotomata	B-Disease
.	O

He	O
had	O
been	O
taking	O
disulfiram	B-Chemical
for	O
alcohol	B-Disease
dependence	I-Disease
for	O
the	O
preceding	O
3	O
years	O
.	O

Disulfiram	B-Chemical
discontinuation	O
lead	O
to	O
an	O
immediate	O
symptomatic	O
improvement	O
.	O

CONCLUSION	O
:	O
Physicians	O
initiating	O
long	O
-	O
term	O
disulfiram	B-Chemical
therapy	O
should	O
be	O
aware	O
of	O
these	O
adverse	O
effects	O
.	O

They	O
should	O
recommend	O
annual	O
ophthalmic	O
reviews	O
with	O
visual	O
field	O
testing	O
.	O

Patients	O
should	O
be	O
reassured	O
with	O
respect	O
to	O
the	O
reversibility	O
of	O
these	O
adverse	O
effects	O
.	O

Intraocular	O
pressure	O
in	O
patients	O
with	O
uveitis	B-Disease
treated	O
with	O
fluocinolone	B-Chemical
acetonide	I-Chemical
implants	O
.	O

OBJECTIVE	O
:	O
To	O
report	O
the	O
incidence	O
and	O
management	O
of	O
elevated	B-Disease
intraocular	I-Disease
pressure	I-Disease
(	O
IOP	O
)	O
in	O
patients	O
with	O
uveitis	B-Disease
treated	O
with	O
the	O
fluocinolone	B-Chemical
acetonide	I-Chemical
(	O
FA	B-Chemical
)	O
intravitreal	O
implant	O
.	O

DESIGN	O
:	O
Pooled	O
data	O
from	O
3	O
multicenter	O
,	O
double	O
-	O
masked	O
,	O
randomized	O
,	O
controlled	O
,	O
phase	O
2b	O
/	O
3	O
clinical	O
trials	O
evaluating	O
the	O
safety	O
and	O
efficacy	O
of	O
the	O
0	O
.	O
59	O
-	O
mg	O
or	O
2	O
.	O
1	O
-	O
mg	O
FA	B-Chemical
intravitreal	O
implant	O
or	O
standard	O
therapy	O
were	O
analyzed	O
.	O

RESULTS	O
:	O
During	O
the	O
3	O
-	O
year	O
follow	O
-	O
up	O
,	O
71	O
.	O
0	O
%	O
of	O
implanted	O
eyes	O
had	O
an	O
IOP	O
increase	O
of	O
10	O
mm	O
Hg	O
or	O
more	O
than	O
baseline	O
and	O
55	O
.	O
1	O
%	O
,	O
24	O
.	O
7	O
%	O
,	O
and	O
6	O
.	O
2	O
%	O
of	O
eyes	O
reached	O
an	O
IOP	O
of	O
30	O
mm	O
Hg	O
or	O
more	O
,	O
40	O
mm	O
Hg	O
or	O
more	O
,	O
and	O
50	O
mm	O
Hg	O
or	O
more	O
,	O
respectively	O
.	O

Topical	O
IOP	O
-	O
lowering	O
medication	O
was	O
administered	O
in	O
74	O
.	O
8	O
%	O
of	O
implanted	O
eyes	O
,	O
and	O
IOP	O
-	O
lowering	O
surgeries	O
,	O
most	O
of	O
which	O
were	O
trabeculectomies	O
(	O
76	O
.	O
2	O
%	O
)	O
,	O
were	O
performed	O
on	O
36	O
.	O
6	O
%	O
of	O
implanted	O
eyes	O
.	O

Intraocular	O
pressure	O
-	O
lowering	O
surgeries	O
were	O
considered	O
a	O
success	O
(	O
postoperative	O
IOP	O
of	O
6	O
-	O
21	O
mm	O
Hg	O
with	O
or	O
without	O
additional	O
IOP	O
-	O
lowering	O
medication	O
)	O
in	O
85	O
.	O
1	O
%	O
of	O
eyes	O
at	O
1	O
year	O
.	O

The	O
rate	O
of	O
hypotony	B-Disease
(	O
IOP	O
<	O
/	O
=	O
5	O
mm	O
Hg	O
)	O
following	O
IOP	O
-	O
lowering	O
surgery	O
(	O
42	O
.	O
5	O
%	O
)	O
was	O
not	O
different	O
from	O
that	O
of	O
implanted	O
eyes	O
not	O
subjected	O
to	O
surgery	O
(	O
35	O
.	O
4	O
%	O
)	O
(	O
P	O
=	O
.	O
09	O
)	O
.	O

CONCLUSION	O
:	O
Elevated	O
IOP	O
is	O
a	O
significant	O
complication	O
with	O
the	O
FA	O
intravitreal	O
implant	O
but	O
may	O
be	O
controlled	O
with	O
medication	O
and	O
surgery	O
.	O

Myocardial	O
Fas	O
ligand	O
expression	O
increases	O
susceptibility	O
to	O
AZT	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
.	O

BACKGROUND	O
:	O
Dilated	B-Disease
cardiomyopathy	I-Disease
(	O
DCM	B-Disease
)	O
and	O
myocarditis	B-Disease
occur	O
in	O
many	O
HIV	B-Disease
-	I-Disease
infected	I-Disease
individuals	O
,	O
resulting	O
in	O
symptomatic	O
heart	B-Disease
failure	I-Disease
in	O
up	O
to	O
5	O
%	O
of	O
patients	O
.	O

Highly	O
active	O
antiretroviral	O
therapy	O
(	O
HAART	O
)	O
has	O
significantly	O
reduced	O
morbidity	O
and	O
mortality	O
of	O
acquired	B-Disease
immunodeficiency	I-Disease
syndrome	I-Disease
(	O
AIDS	B-Disease
)	O
,	O
but	O
has	O
resulted	O
in	O
an	O
increase	O
in	O
cardiac	B-Disease
and	I-Disease
skeletal	I-Disease
myopathies	I-Disease
.	O

METHODS	O
AND	O
RESULTS	O
:	O
In	O
order	O
to	O
investigate	O
whether	O
the	O
HAART	O
component	O
zidovudine	B-Chemical
(	O
3	B-Chemical
'	I-Chemical
-	I-Chemical
azido	I-Chemical
-	I-Chemical
2	I-Chemical
'	I-Chemical
,	I-Chemical
3	I-Chemical
'	I-Chemical
-	I-Chemical
deoxythymidine	I-Chemical
;	O
AZT	B-Chemical
)	O
triggers	O
the	O
Fas	O
-	O
dependent	O
cell	O
-	O
death	O
pathway	O
and	O
cause	O
cytoskeletal	O
disruption	O
in	O
a	O
murine	O
model	O
of	O
DCM	B-Disease
,	O
8	O
-	O
week	O
-	O
old	O
transgenic	O
(	O
expressing	O
Fas	O
ligand	O
in	O
the	O
myocardium	O
:	O
FasL	O
Tg	O
)	O
and	O
non	O
-	O
transgenic	O
(	O
NTg	O
)	O
mice	O
received	O
water	O
ad	O
libitum	O
containing	O
different	O
concentrations	O
of	O
AZT	B-Chemical
(	O
0	O
,	O
0	O
.	O
07	O
,	O
0	O
.	O
2	O
,	O
and	O
0	O
.	O
7	O
mg	O
/	O
ml	O
)	O
.	O

After	O
6	O
weeks	O
,	O
cardiac	O
function	O
was	O
assessed	O
by	O
echocardiography	O
and	O
morphology	O
was	O
assessed	O
by	O
histopathologic	O
and	O
immunohistochemical	O
methods	O
.	O

NTg	O
and	O
untreated	O
FasL	O
Tg	O
mice	O
showed	O
little	O
or	O
no	O
change	O
in	O
cardiac	O
structure	O
or	O
function	O
.	O

In	O
contrast	O
,	O
AZT	B-Chemical
-	O
treated	O
FasL	O
Tg	O
mice	O
developed	O
cardiac	B-Disease
dilation	I-Disease
and	O
depressed	O
cardiac	O
function	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
,	O
with	O
concomitant	O
inflammatory	O
infiltration	O
of	O
both	O
ventricles	O
.	O

These	O
changes	O
were	O
associated	O
with	O
an	O
increased	O
sarcolemmal	O
expression	O
of	O
Fas	O
and	O
FasL	O
,	O
as	O
well	O
as	O
increased	O
activation	O
of	O
caspase	O
3	O
,	O
translocation	O
of	O
calpain	O
1	O
to	O
the	O
sarcolemma	O
and	O
sarcomere	O
,	O
and	O
increased	O
numbers	O
of	O
cells	O
undergoing	O
apoptosis	O
.	O

These	O
were	O
associated	O
with	O
changes	O
in	O
dystrophin	O
and	O
cardiac	O
troponin	O
I	O
localization	O
,	O
as	O
well	O
as	O
loss	O
of	O
sarcolemmal	O
integrity	O
.	O

CONCLUSIONS	O
:	O
The	O
expression	O
of	O
Fas	O
ligand	O
in	O
the	O
myocardium	O
,	O
as	O
identified	O
in	O
HIV	O
-	O
positive	O
patients	O
,	O
might	O
increase	O
the	O
susceptibility	O
to	O
HAART	O
-	O
induced	O
cardiomyopathy	B-Disease
due	O
to	O
activation	O
of	O
apoptotic	O
pathways	O
,	O
resulting	O
in	O
cardiac	B-Disease
dilation	I-Disease
and	I-Disease
dysfunction	I-Disease
.	O

Gastrointestinal	O
tolerability	O
of	O
etoricoxib	B-Chemical
in	O
rheumatoid	B-Disease
arthritis	I-Disease
patients	O
:	O
results	O
of	O
the	O
etoricoxib	B-Chemical
vs	O
diclofenac	B-Chemical
sodium	I-Chemical
gastrointestinal	O
tolerability	O
and	O
effectiveness	O
trial	O
(	O
EDGE	O
-	O
II	O
)	O
.	O

OBJECTIVE	O
:	O
A	O
randomised	O
,	O
double	O
-	O
blind	O
study	O
to	O
compare	O
the	O
gastrointestinal	O
(	O
GI	O
)	O
tolerability	O
,	O
safety	O
and	O
efficacy	O
of	O
etoricoxib	B-Chemical
and	O
diclofenac	B-Chemical
in	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
(	O
RA	B-Disease
)	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
A	O
total	O
of	O
4086	O
patients	O
(	O
mean	O
age	O
60	O
.	O
8	O
years	O
)	O
diagnosed	O
with	O
RA	B-Disease
were	O
enrolled	O
and	O
received	O
etoricoxib	B-Chemical
90	O
mg	O
daily	O
(	O
n	O
=	O
2032	O
)	O
or	O
diclofenac	B-Chemical
75	O
mg	O
twice	O
daily	O
(	O
n	O
=	O
2054	O
)	O
.	O

Use	O
of	O
gastroprotective	O
agents	O
and	O
low	O
-	O
dose	O
aspirin	B-Chemical
was	O
allowed	O
.	O

The	O
prespecified	O
primary	O
end	O
point	O
consisted	O
of	O
the	O
cumulative	O
rate	O
of	O
patient	O
discontinuations	O
due	O
to	O
clinical	O
and	O
laboratory	O
GI	O
adverse	O
experiences	O
(	O
AEs	O
)	O
.	O

General	O
safety	O
was	O
also	O
assessed	O
,	O
including	O
adjudicated	O
thrombotic	B-Disease
cardiovascular	I-Disease
event	O
data	O
.	O

Efficacy	O
was	O
evaluated	O
using	O
the	O
Patient	O
Global	O
Assessment	O
of	O
Disease	O
Status	O
(	O
PGADS	O
;	O
0	O
-	O
4	O
point	O
scale	O
)	O
.	O

RESULTS	O
:	O
Mean	O
(	O
SD	O
;	O
maximum	O
)	O
duration	O
of	O
treatment	O
was	O
19	O
.	O
3	O
(	O
10	O
.	O
3	O
;	O
32	O
.	O
9	O
)	O
and	O
19	O
.	O
1	O
(	O
10	O
.	O
4	O
;	O
33	O
.	O
1	O
)	O
months	O
in	O
the	O
etoricoxib	B-Chemical
and	O
diclofenac	B-Chemical
groups	O
,	O
respectively	O
.	O

The	O
cumulative	O
discontinuation	O
rate	O
due	O
to	O
GI	B-Disease
AEs	I-Disease
was	O
significantly	O
lower	O
with	O
etoricoxib	B-Chemical
than	O
diclofenac	B-Chemical
(	O
5	O
.	O
2	O
vs	O
8	O
.	O
5	O
events	O
per	O
100	O
patient	O
-	O
years	O
,	O
respectively	O
;	O
hazard	O
ratio	O
0	O
.	O
62	O
(	O
95	O
%	O
CI	O
:	O
0	O
.	O
47	O
,	O
0	O
.	O
81	O
;	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
)	O
.	O

The	O
incidence	O
of	O
discontinuations	O
for	O
hypertension	B-Disease
-	O
related	O
and	O
oedema	B-Disease
-	O
related	O
AEs	O
were	O
significantly	O
higher	O
with	O
etoricoxib	B-Chemical
(	O
2	O
.	O
5	O
%	O
and	O
1	O
.	O
1	O
%	O
respectively	O
)	O
compared	O
with	O
diclofenac	B-Chemical
(	O
1	O
.	O
5	O
%	O
and	O
0	O
.	O
4	O
%	O
respectively	O
;	O
p	O
<	O
0	O
.	O
001	O
for	O
hypertension	B-Disease
and	O
p	O
<	O
0	O
.	O
01	O
for	O
oedema	B-Disease
)	O
.	O

Etoricoxib	B-Chemical
and	O
diclofenac	B-Chemical
treatment	O
resulted	O
in	O
similar	O
efficacy	O
(	O
PGADS	O
mean	O
changes	O
from	O
baseline	O
-	O
0	O
.	O
62	O
vs	O
-	O
0	O
.	O
58	O
,	O
respectively	O
)	O
.	O

CONCLUSIONS	O
:	O
Etoricoxib	B-Chemical
90	O
mg	O
demonstrated	O
a	O
significantly	O
lower	O
risk	O
for	O
discontinuing	O
treatment	O
due	O
to	O
GI	B-Disease
AEs	I-Disease
compared	O
with	O
diclofenac	B-Chemical
150	O
mg	O
.	O

Discontinuations	O
from	O
renovascular	O
AEs	O
,	O
although	O
less	O
common	O
than	O
discontinuations	O
from	O
GI	B-Disease
AEs	I-Disease
,	O
were	O
significantly	O
higher	O
with	O
etoricoxib	B-Chemical
.	O

Anxiogenic	O
potential	O
of	O
ciprofloxacin	B-Chemical
and	O
norfloxacin	B-Chemical
in	O
rats	O
.	O

INTRODUCTION	O
:	O
The	O
possible	O
anxiogenic	O
effects	O
of	O
fluoroquinolones	B-Chemical
,	O
namely	O
ciprofloxacin	B-Chemical
and	O
norfloxacin	B-Chemical
,	O
were	O
investigated	O
in	O
adult	O
Charles	O
Foster	O
albino	O
rats	O
of	O
either	O
sex	O
,	O
weighing	O
150	O
-	O
200	O
g	O
.	O

METHODS	O
:	O
The	O
drugs	O
were	O
given	O
orally	O
,	O
in	O
doses	O
of	O
50	O
mg	O
/	O
kg	O
for	O
five	O
consecutive	O
days	O
and	O
the	O
experiments	O
were	O
performed	O
on	O
the	O
fifth	O
day	O
.	O

The	O
tests	O
included	O
open	O
-	O
field	O
exploratory	O
behaviour	O
,	O
elevated	O
plus	O
maze	O
and	O
elevated	O
zero	O
maze	O
,	O
social	O
interaction	O
and	O
novelty	O
-	O
suppressed	O
feeding	O
latency	O
behaviour	O
.	O

RESULTS	O
:	O
The	O
results	O
indicate	O
that	O
ciprofloxacin	B-Chemical
-	O
and	O
norfloxacin	B-Chemical
-	O
treated	O
rats	O
showed	O
anxious	B-Disease
behaviour	I-Disease
in	O
comparison	O
to	O
control	O
rats	O
in	O
all	O
the	O
parameters	O
studied	O
.	O

However	O
,	O
ciprofloxacin	B-Chemical
-	O
and	O
norfloxacin	B-Chemical
-	O
treated	O
rats	O
did	O
not	O
differ	O
significantly	O
from	O
each	O
other	O
in	O
various	O
behavioural	O
parameters	O
.	O

CONCLUSION	O
:	O
The	O
present	O
experimental	O
findings	O
substantiate	O
the	O
clinically	O
observed	O
anxiogenic	O
potential	O
of	O
ciprofloxacin	B-Chemical
and	O
norfloxacin	B-Chemical
.	O

Reduction	O
of	O
pain	B-Disease
during	O
induction	O
with	O
target	O
-	O
controlled	O
propofol	B-Chemical
and	O
remifentanil	B-Chemical
.	O

BACKGROUND	O
:	O
Pain	B-Disease
on	O
injection	O
of	O
propofol	B-Chemical
is	O
unpleasant	O
.	O

We	O
hypothesized	O
that	O
propofol	B-Chemical
infusion	O
pain	B-Disease
might	O
be	O
prevented	O
by	O
infusing	O
remifentanil	B-Chemical
before	O
starting	O
the	O
propofol	B-Chemical
infusion	O
in	O
a	O
clinical	O
setting	O
where	O
target	O
-	O
controlled	O
infusions	O
(	O
TCI	O
)	O
of	O
both	O
drugs	O
were	O
used	O
.	O

A	O
prospective	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
placebo	O
-	O
controlled	O
trial	O
was	O
performed	O
to	O
determine	O
the	O
effect	O
-	O
site	O
concentration	O
(	O
Ce	O
)	O
of	O
remifentanil	B-Chemical
to	O
prevent	O
the	O
pain	B-Disease
without	O
producing	O
complications	O
.	O

METHODS	O
:	O
A	O
total	O
of	O
128	O
patients	O
undergoing	O
general	O
surgery	O
were	O
randomly	O
allocated	O
to	O
receive	O
normal	O
saline	O
(	O
control	O
)	O
or	O
remifentanil	B-Chemical
to	O
a	O
target	O
Ce	O
of	O
2	O
ng	O
ml	O
(	O
-	O
1	O
)	O
(	O
R2	O
)	O
,	O
4	O
ng	O
ml	O
(	O
-	O
1	O
)	O
(	O
R4	O
)	O
,	O
or	O
6	O
ng	O
ml	O
(	O
-	O
1	O
)	O
(	O
R6	O
)	O
administered	O
via	O
TCI	O
.	O

After	O
the	O
target	O
Ce	O
was	O
achieved	O
,	O
the	O
infusion	O
of	O
propofol	B-Chemical
was	O
started	O
.	O

Remifentanil	B-Chemical
-	O
related	O
complications	O
were	O
assessed	O
during	O
the	O
remifentanil	B-Chemical
infusion	O
,	O
and	O
pain	B-Disease
caused	O
by	O
propofol	B-Chemical
was	O
evaluated	O
using	O
a	O
four	O
-	O
point	O
scale	O
during	O
the	O
propofol	B-Chemical
infusion	O
.	O

RESULTS	O
:	O
The	O
incidence	O
of	O
pain	B-Disease
was	O
significantly	O
lower	O
in	O
Groups	O
R4	O
and	O
R6	O
than	O
in	O
the	O
control	O
and	O
R2	O
groups	O
(	O
12	O
/	O
32	O
and	O
6	O
/	O
31	O
vs	O
26	O
/	O
31	O
and	O
25	O
/	O
32	O
,	O
respectively	O
,	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Pain	B-Disease
was	O
less	O
severe	O
in	O
Groups	O
R4	O
and	O
R6	O
than	O
in	O
the	O
control	O
and	O
R2	O
groups	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

However	O
,	O
both	O
incidence	O
and	O
severity	O
of	O
pain	B-Disease
were	O
not	O
different	O
between	O
Groups	O
R4	O
and	O
R6	O
.	O

No	O
significant	O
complications	O
were	O
observed	O
during	O
the	O
study	O
.	O

CONCLUSIONS	O
:	O
During	O
induction	O
of	O
anaesthesia	O
with	O
TCI	O
of	O
propofol	B-Chemical
and	O
remifentanil	B-Chemical
,	O
a	O
significant	O
reduction	O
in	O
propofol	B-Chemical
infusion	O
pain	B-Disease
was	O
achieved	O
without	O
significant	O
complications	O
by	O
prior	O
administration	O
of	O
remifentanil	B-Chemical
at	O
a	O
target	O
Ce	O
of	O
4	O
ng	O
ml	O
(	O
-	O
1	O
)	O
.	O

Dexmedetomidine	B-Chemical
and	O
cardiac	O
protection	O
for	O
non	O
-	O
cardiac	O
surgery	O
:	O
a	O
meta	O
-	O
analysis	O
of	O
randomised	O
controlled	O
trials	O
.	O

We	O
conducted	O
a	O
systematic	O
review	O
of	O
the	O
effects	O
of	O
dexmedetomidine	B-Chemical
on	O
cardiac	O
outcomes	O
following	O
non	O
-	O
cardiac	O
surgery	O
.	O

We	O
included	O
prospective	O
,	O
randomised	O
peri	O
-	O
operative	O
studies	O
of	O
dexmedetomidine	B-Chemical
that	O
reported	O
mortality	O
,	O
cardiac	O
morbidity	O
or	O
adverse	O
drug	O
events	O
.	O

A	O
PubMed	O
Central	O
and	O
EMBASE	O
search	O
was	O
conducted	O
up	O
to	O
July	O
2007	O
.	O

The	O
reference	O
lists	O
of	O
identified	O
papers	O
were	O
examined	O
for	O
further	O
trials	O
.	O

Of	O
425	O
studies	O
identified	O
,	O
20	O
were	O
included	O
in	O
the	O
meta	O
-	O
analysis	O
(	O
840	O
patients	O
)	O
.	O

Dexmedetomidine	B-Chemical
was	O
associated	O
with	O
a	O
trend	O
towards	O
improved	O
cardiac	O
outcomes	O
;	O
all	O
-	O
cause	O
mortality	O
(	O
OR	O
0	O
.	O
27	O
,	O
95	O
%	O
CI	O
0	O
.	O
01	O
-	O
7	O
.	O
13	O
,	O
p	O
=	O
0	O
.	O
44	O
)	O
,	O
non	O
-	O
fatal	O
myocardial	B-Disease
infarction	I-Disease
(	O
OR	O
0	O
.	O
26	O
,	O
95	O
%	O
CI	O
0	O
.	O
04	O
-	O
1	O
.	O
60	O
,	O
p	O
=	O
0	O
.	O
14	O
)	O
,	O
and	O
myocardial	B-Disease
ischaemia	I-Disease
(	O
OR	O
0	O
.	O
65	O
,	O
95	O
%	O
CI	O
0	O
.	O
26	O
-	O
1	O
.	O
63	O
,	O
p	O
=	O
0	O
.	O
36	O
)	O
.	O

Peri	O
-	O
operative	O
hypotension	B-Disease
(	O
26	O
%	O
,	O
OR	O
3	O
.	O
80	O
,	O
95	O
%	O
CI	O
1	O
.	O
91	O
-	O
7	O
.	O
54	O
,	O
p	O
=	O
0	O
.	O
0001	O
)	O
and	O
bradycardia	B-Disease
(	O
17	O
%	O
,	O
OR	O
5	O
.	O
45	O
,	O
95	O
%	O
CI	O
2	O
.	O
98	O
-	O
9	O
.	O
95	O
,	O
p	O
<	O
0	O
.	O
00001	O
)	O
were	O
significantly	O
increased	O
.	O

An	O
anticholinergic	O
did	O
not	O
reduce	O
the	O
incidence	O
of	O
bradycardia	B-Disease
(	O
p	O
=	O
0	O
.	O
43	O
)	O
.	O

A	O
randomised	O
placebo	O
-	O
controlled	O
trial	O
of	O
dexmedetomidine	B-Chemical
is	O
warranted	O
.	O

Myocardial	B-Disease
infarction	I-Disease
in	O
pregnancy	O
associated	O
with	O
clomiphene	B-Chemical
citrate	I-Chemical
for	O
ovulation	O
induction	O
:	O
a	O
case	O
report	O
.	O

BACKGROUND	O
:	O
Clomiphene	B-Chemical
citrate	I-Chemical
(	O
CC	B-Chemical
)	O
is	O
commonly	O
prescribed	O
for	O
ovulation	O
induction	O
.	O

It	O
is	O
considered	O
safe	O
,	O
with	O
minimal	O
side	O
effects	O
.	O

Thromboembolism	B-Disease
is	O
a	O
rare	O
but	O
life	O
-	O
threatening	O
complication	O
that	O
has	O
been	O
reported	O
after	O
ovulation	O
induction	O
with	O
CC	B-Chemical
.	O

Spontaneous	O
coronary	B-Disease
thrombosis	I-Disease
or	O
thromboembolism	B-Disease
with	O
subsequent	O
clot	O
lysis	O
has	O
been	O
suggested	O
as	O
one	O
of	O
the	O
most	O
common	O
causes	O
of	O
myocardial	B-Disease
infarction	I-Disease
(	O
MI	B-Disease
)	O
during	O
pregnancy	O
,	O
with	O
a	O
subsequently	O
normal	O
coronary	O
angiogram	O
.	O

CASE	O
:	O
A	O
33	O
-	O
year	O
-	O
old	O
woman	O
with	O
a	O
5	O
-	O
week	O
gestation	O
had	O
recently	O
received	O
CC	B-Chemical
for	O
ovulation	O
induction	O
and	O
presented	O
with	O
chest	B-Disease
pain	I-Disease
.	O

An	O
electrocardiogram	O
showed	O
a	O
lateral	O
and	O
anterior	O
wall	O
myocardial	B-Disease
infarction	I-Disease
.	O

Cardiac	O
enzymes	O
showed	O
a	O
peak	O
rise	O
in	O
troponin	O
I	O
to	O
9	O
.	O
10	O
ng	O
/	O
mL	O
.	O

An	O
initial	O
exercise	O
stress	O
test	O
was	O
normal	O
.	O

At	O
the	O
time	O
of	O
admission	O
,	O
the	O
patient	O
was	O
at	O
high	O
risk	O
of	O
radiation	B-Disease
injury	I-Disease
to	O
the	O
fetus	O
,	O
so	O
a	O
coronary	O
angiogram	O
was	O
postponed	O
until	O
the	O
second	O
trimester	O
.	O

It	O
showed	O
normal	O
coronary	O
vessels	O
.	O

CONCLUSION	O
:	O
This	O
appears	O
to	O
be	O
the	O
first	O
reported	O
case	O
documenting	O
a	O
possible	O
association	O
between	O
CC	B-Chemical
and	O
myocardial	B-Disease
infarction	I-Disease
.	O

Thrombosis	B-Disease
might	O
be	O
a	O
rare	O
but	O
hazardous	O
complication	O
of	O
CC	B-Chemical
.	O

Given	O
this	O
life	O
-	O
threatening	O
complication	O
,	O
appropriate	O
prophylactic	O
measures	O
should	O
be	O
used	O
in	O
high	O
-	O
risk	O
woman	O
undergoing	O
ovarian	O
stimulation	O
.	O

Reverse	O
or	O
inverted	O
left	B-Disease
ventricular	I-Disease
apical	I-Disease
ballooning	I-Disease
syndrome	I-Disease
(	O
reverse	O
Takotsubo	B-Disease
cardiomyopathy	I-Disease
)	O
in	O
a	O
young	O
woman	O
in	O
the	O
setting	O
of	O
amphetamine	B-Chemical
use	O
.	O

Transient	O
left	B-Disease
ventricular	I-Disease
apical	I-Disease
ballooning	I-Disease
syndrome	I-Disease
was	O
first	O
described	O
in	O
Japan	O
as	O
"	O
Takotsubo	B-Disease
cardiomyopathy	I-Disease
.	O
"	O
This	O
syndrome	O
has	O
been	O
identified	O
in	O
many	O
other	O
countries	O
.	O

Many	O
variations	O
of	O
this	O
syndrome	O
have	O
been	O
recently	O
described	O
in	O
the	O
literature	O
.	O

One	O
of	O
the	O
rarest	O
is	O
the	O
reverse	O
type	O
of	O
this	O
syndrome	O
,	O
with	O
hyperdynamic	O
apex	O
and	O
complete	O
akinesia	B-Disease
of	O
the	O
base	O
(	O
as	O
opposed	O
to	O
the	O
classic	O
apical	B-Disease
ballooning	I-Disease
)	O
.	O

In	O
this	O
article	O
,	O
we	O
report	O
an	O
interesting	O
case	O
of	O
a	O
young	O
woman	O
who	O
presented	O
with	O
this	O
rare	O
type	O
of	O
reverse	O
apical	B-Disease
ballooning	I-Disease
syndrome	I-Disease
occurring	O
after	O
amphetamine	B-Chemical
use	O
.	O

This	O
report	O
is	O
followed	O
by	O
review	O
of	O
the	O
literature	O
.	O

Results	O
of	O
a	O
comparative	O
,	O
phase	O
III	O
,	O
12	O
-	O
week	O
,	O
multicenter	O
,	O
prospective	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
assessment	O
of	O
the	O
efficacy	O
and	O
tolerability	O
of	O
a	O
fixed	O
-	O
dose	O
combination	O
of	O
telmisartan	B-Chemical
and	O
amlodipine	B-Chemical
versus	O
amlodipine	B-Chemical
monotherapy	O
in	O
Indian	O
adults	O
with	O
stage	O
II	O
hypertension	B-Disease
.	O

OBJECTIVE	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
evaluate	O
the	O
efficacy	O
and	O
tolerability	O
of	O
a	O
new	O
fixed	O
-	O
dose	O
combination	O
(	O
FDC	O
)	O
of	O
telmisartan	B-Chemical
40	O
mg	O
+	O
amlodipine	B-Chemical
5	O
mg	O
(	O
T	O
+	O
A	O
)	O
compared	O
with	O
amlodipine	B-Chemical
5	O
-	O
mg	O
monotherapy	O
(	O
A	O
)	O
in	O
adult	O
Indian	O
patients	O
with	O
stage	O
II	O
hypertension	B-Disease
.	O

METHODS	O
:	O
This	O
comparative	O
,	O
Phase	O
III	O
,	O
12	O
-	O
week	O
,	O
multicenter	O
,	O
prospective	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
study	O
was	O
conducted	O
in	O
Indian	O
patients	O
aged	O
18	O
to	O
65	O
years	O
with	O
established	O
stage	O
II	O
hypertension	B-Disease
.	O

Patients	O
were	O
treated	O
with	O
oral	O
FDC	O
of	O
T	O
+	O
A	O
or	O
A	O
QD	O
before	O
breakfast	O
for	O
12	O
weeks	O
;	O
blood	O
pressure	O
(	O
BP	O
)	O
and	O
heart	O
rate	O
were	O
measured	O
in	O
the	O
sitting	O
position	O
.	O

Primary	O
efficacy	O
end	O
points	O
were	O
reduction	O
in	O
clinical	O
systolic	O
BP	O
(	O
SBP	O
)	O
/	O
diastolic	O
BP	O
(	O
DBP	O
)	O
from	O
baseline	O
to	O
study	O
end	O
and	O
number	O
of	O
responders	O
(	O
ie	O
,	O
patients	O
who	O
achieved	O
target	O
SBP	O
/	O
DBP	O
<	O
130	O
/	O
<	O
80	O
mm	O
Hg	O
)	O
at	O
end	O
of	O
study	O
.	O

Tolerability	O
was	O
assessed	O
by	O
treatment	O
-	O
emergent	O
adverse	O
events	O
,	O
identified	O
using	O
physical	O
examination	O
,	O
laboratory	O
analysis	O
,	O
and	O
electrocardiography	O
.	O

RESULTS	O
:	O
A	O
total	O
of	O
210	O
patients	O
were	O
enrolled	O
in	O
the	O
study	O
;	O
203	O
patients	O
(	O
143	O
men	O
,	O
60	O
women	O
)	O
completed	O
the	O
study	O
while	O
7	O
were	O
lost	O
to	O
follow	O
-	O
up	O
(	O
4	O
patients	O
in	O
the	O
T	O
+	O
A	O
group	O
and	O
3	O
in	O
the	O
A	O
group	O
)	O
and	O
considered	O
with	O
-	O
drawn	O
.	O

At	O
study	O
end	O
,	O
statistically	O
significant	O
percentage	O
reductions	O
from	O
baseline	O
within	O
groups	O
and	O
between	O
groups	O
were	O
observed	O
in	O
SBP	O
(	O
T	O
+	O
A	O
[	O
-	O
27	O
.	O
4	O
%	O
]	O
;	O
A	O
[	O
-	O
16	O
.	O
6	O
%	O
]	O
)	O
and	O
DBP	O
(	O
T	O
+	O
A	O
[	O
-	O
20	O
.	O
1	O
%	O
]	O
;	O
A	O
[	O
-	O
13	O
.	O
3	O
%	O
]	O
)	O
(	O
all	O
,	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Response	O
rates	O
were	O
87	O
.	O
3	O
%	O
(	O
89	O
/	O
102	O
)	O
in	O
the	O
T	O
+	O
A	O
group	O
and	O
69	O
.	O
3	O
%	O
(	O
70	O
/	O
101	O
)	O
in	O
the	O
A	O
group	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
prevalences	O
of	O
adverse	O
events	O
were	O
not	O
significantly	O
different	O
between	O
the	O
2	O
treatment	O
groups	O
(	O
T	O
+	O
A	O
,	O
16	O
.	O
0	O
%	O
[	O
17	O
/	O
106	O
]	O
;	O
A	O
,	O
15	O
.	O
4	O
%	O
[	O
16	O
/	O
104	O
]	O
)	O
.	O

Peripheral	O
edema	B-Disease
was	O
reported	O
in	O
8	O
.	O
5	O
%	O
patients	O
(	O
9	O
/	O
106	O
)	O
in	O
the	O
T	O
+	O
A	O
group	O
compared	O
with	O
13	O
.	O
5	O
%	O
(	O
14	O
/	O
104	O
)	O
in	O
the	O
A	O
group	O
,	O
and	O
cough	B-Disease
was	O
reported	O
in	O
3	O
.	O
8	O
%	O
patients	O
(	O
4	O
/	O
106	O
)	O
in	O
the	O
T	O
+	O
A	O
group	O
and	O
1	O
.	O
0	O
%	O
(	O
1	O
/	O
104	O
)	O
patients	O
in	O
the	O
A	O
group	O
;	O
these	O
differences	O
did	O
not	O
reach	O
statistical	O
significance	O
.	O

The	O
incidences	O
of	O
headache	B-Disease
,	O
dizziness	B-Disease
,	O
and	O
diarrhea	B-Disease
were	O
similar	O
between	O
the	O
2	O
groups	O
.	O

CONCLUSIONS	O
:	O
Among	O
these	O
Indian	O
patients	O
with	O
stage	O
II	O
hypertension	B-Disease
,	O
the	O
FDC	O
of	O
T	O
+	O
A	O
was	O
found	O
to	O
be	O
significantly	O
more	O
effective	O
,	O
with	O
regard	O
to	O
BP	O
reductions	O
,	O
than	O
A	O
,	O
and	O
both	O
treatments	O
were	O
well	O
tolerated	O
.	O

Increased	O
mental	B-Disease
slowing	I-Disease
associated	O
with	O
the	O
APOE	O
epsilon4	O
allele	O
after	O
trihexyphenidyl	B-Chemical
oral	O
anticholinergic	O
challenge	O
in	O
healthy	O
elderly	O
.	O

OBJECTIVES	O
:	O
The	O
objectives	O
of	O
this	O
study	O
were	O
to	O
examine	O
the	O
relationship	O
between	O
APOE	O
epsilon4	O
and	O
subjective	O
effects	O
of	O
trihexyphenidyl	B-Chemical
on	O
measures	O
reflecting	O
sedation	O
and	O
confusion	B-Disease
and	O
to	O
investigate	O
the	O
relationship	O
between	O
trihexyphenidyl	B-Chemical
-	O
induced	O
subjective	O
effects	O
and	O
objective	O
memory	O
performance	O
.	O

METHODS	O
:	O
This	O
study	O
comprised	O
24	O
cognitively	O
intact	O
,	O
health	O
elderly	O
adults	O
(	O
12	O
APOE	O
epsilon4	O
carriers	O
)	O
at	O
an	O
outpatient	O
geriatric	O
psychiatry	O
research	O
clinic	O
.	O

This	O
was	O
a	O
randomized	O
,	O
double	O
blind	O
,	O
placebo	O
-	O
controlled	O
,	O
three	O
-	O
way	O
,	O
crossover	O
experimental	O
design	O
.	O

All	O
participants	O
received	O
1	O
.	O
0	O
mg	O
or	O
2	O
.	O
0	O
mg	O
trihexyphenidyl	B-Chemical
or	O
placebo	O
administered	O
in	O
counterbalanced	O
sequences	O
over	O
a	O
period	O
of	O
three	O
consecutive	O
weeks	O
.	O

Bond	O
and	O
Lader	O
'	O
s	O
visual	O
analog	O
scales	O
and	O
alternate	O
versions	O
of	O
the	O
Buschke	O
Selective	O
Reminding	O
Test	O
were	O
administered	O
in	O
a	O
repeated	O
measures	O
design	O
at	O
baseline	O
,	O
1	O
,	O
2	O
.	O
5	O
,	O
and	O
5	O
hours	O
postdrug	O
administration	O
.	O

RESULTS	O
:	O
A	O
2	O
.	O
0	O
-	O
mg	O
oral	O
dose	O
of	O
trihexyphenidyl	B-Chemical
resulted	O
in	O
increased	O
subjective	O
ratings	O
of	O
mental	B-Disease
slowness	I-Disease
in	O
carriers	O
of	O
the	O
APOE	O
epsilon4	O
allele	O
only	O
.	O

Drug	O
effects	O
as	O
determined	O
by	O
difference	O
scores	O
between	O
2	O
.	O
0	O
mg	O
trihexyphenidyl	B-Chemical
and	O
placebo	O
on	O
ratings	O
of	O
mental	B-Disease
slowness	I-Disease
significantly	O
correlated	O
with	O
total	O
and	O
delayed	O
recall	O
on	O
the	O
Buschke	O
Selective	O
Reminding	O
Test	O
in	O
carriers	O
of	O
the	O
APOE	O
epsilon4	O
allele	O
only	O
.	O

However	O
,	O
no	O
significant	O
effects	O
were	O
found	O
with	O
other	O
visual	O
analog	O
scales	O
reflecting	O
subjective	O
sedation	O
and	O
clear	O
-	O
headedness	O
.	O

CONCLUSION	O
:	O
The	O
epsilon4	O
allele	O
in	O
healthy	O
elderly	O
was	O
associated	O
with	O
increased	O
subjective	O
mental	B-Disease
slowing	I-Disease
after	O
trihexyphenidyl	B-Chemical
anticholinergic	O
challenge	O
.	O

An	O
evaluation	O
of	O
amikacin	B-Chemical
nephrotoxicity	B-Disease
in	O
the	O
hematology	O
/	O
oncology	O
population	O
.	O

Amikacin	B-Chemical
is	O
an	O
aminoglycoside	B-Chemical
commonly	O
used	O
to	O
provide	O
empirical	O
double	O
gram	O
-	O
negative	O
treatment	O
for	O
febrile	B-Disease
neutropenia	I-Disease
and	O
other	O
suspected	O
infections	B-Disease
.	O

Strategies	O
of	O
extended	O
-	O
interval	O
and	O
conventional	O
dosing	O
have	O
been	O
utilized	O
extensively	O
in	O
the	O
general	O
medical	O
population	O
;	O
however	O
,	O
data	O
are	O
lacking	O
to	O
support	O
a	O
dosing	O
strategy	O
in	O
the	O
hematology	O
/	O
oncology	O
population	O
.	O

To	O
evaluate	O
amikacin	B-Chemical
-	O
associated	O
nephrotoxicity	B-Disease
in	O
an	O
adult	O
hematology	O
/	O
oncology	O
population	O
,	O
a	O
prospective	O
,	O
randomized	O
,	O
open	O
-	O
label	O
trial	O
was	O
conducted	O
at	O
a	O
university	O
-	O
affiliated	O
medical	O
center	O
.	O

Forty	O
patients	O
with	O
a	O
diagnosis	O
consistent	O
with	O
a	O
hematologic	B-Disease
/	I-Disease
oncologic	I-Disease
disorder	I-Disease
that	O
required	O
treatment	O
with	O
an	O
aminoglycoside	B-Chemical
were	O
randomized	O
to	O
either	O
conventional	O
or	O
extended	O
-	O
interval	O
amikacin	B-Chemical
.	O

The	O
occurrence	O
of	O
nephrotoxicity	B-Disease
by	O
means	O
of	O
an	O
increase	O
in	O
serum	O
creatinine	B-Chemical
and	O
evaluation	O
of	O
efficacy	O
via	O
amikacin	B-Chemical
serum	O
concentrations	O
with	O
respective	O
pathogens	O
were	O
assessed	O
.	O

The	O
occurrence	O
of	O
nephrotoxicity	B-Disease
was	O
similar	O
between	O
the	O
conventional	O
and	O
extended	O
-	O
interval	O
groups	O
,	O
at	O
10	O
%	O
and	O
5	O
%	O
,	O
respectively	O
(	O
P	O
=	O
1	O
.	O
00	O
)	O
.	O

Six	O
patients	O
in	O
the	O
conventional	O
group	O
had	O
a	O
positive	O
culture	O
,	O
compared	O
with	O
none	O
in	O
the	O
extended	O
-	O
interval	O
group	O
(	O
P	O
=	O
0	O
.	O
002	O
)	O
.	O

The	O
occurrence	O
of	O
nephrotoxicity	B-Disease
was	O
similar	O
between	O
the	O
two	O
dosing	O
regimens	O
,	O
but	O
the	O
distribution	O
of	O
risk	O
factors	O
was	O
variable	O
between	O
the	O
two	O
groups	O
.	O

Efficacy	O
could	O
not	O
be	O
assessed	O
.	O

High	O
dose	O
dexmedetomidine	B-Chemical
as	O
the	O
sole	O
sedative	O
for	O
pediatric	O
MRI	O
.	O

OBJECTIVE	O
:	O
This	O
large	O
-	O
scale	O
retrospective	O
review	O
evaluates	O
the	O
sedation	O
profile	O
of	O
dexmedetomidine	B-Chemical
.	O

AIM	O
:	O
To	O
determine	O
the	O
hemodynamic	O
responses	O
,	O
efficacy	O
and	O
adverse	O
events	O
associated	O
with	O
the	O
use	O
of	O
high	O
dose	O
dexmedetomidine	B-Chemical
as	O
the	O
sole	O
sedative	O
for	O
magnetic	O
resonance	O
imaging	O
(	O
MRI	O
)	O
studies	O
.	O

BACKGROUND	O
:	O
Dexmedetomidine	B-Chemical
has	O
been	O
used	O
at	O
our	O
institution	O
since	O
2005	O
to	O
provide	O
sedation	O
for	O
pediatric	O
radiological	O
imaging	O
studies	O
.	O

Over	O
time	O
,	O
an	O
effective	O
protocol	O
utilizing	O
high	O
dose	O
dexmedetomidine	B-Chemical
as	O
the	O
sole	O
sedative	O
agent	O
has	O
evolved	O
.	O

METHODS	O
/	O
MATERIALS	O
:	O
As	O
part	O
of	O
the	O
ongoing	O
Quality	O
Assurance	O
process	O
,	O
data	O
on	O
all	O
sedations	O
are	O
reviewed	O
monthly	O
and	O
protocols	O
modified	O
as	O
needed	O
.	O

Data	O
were	O
analyzed	O
from	O
all	O
747	O
consecutive	O
patients	O
who	O
received	O
dexmedetomidine	B-Chemical
for	O
MRI	O
sedation	O
from	O
April	O
2005	O
to	O
April	O
2007	O
.	O

RESULTS	O
:	O
Since	O
2005	O
,	O
the	O
10	O
-	O
min	O
loading	O
dose	O
of	O
our	O
dexmedetomidine	B-Chemical
protocol	O
increased	O
from	O
2	O
to	O
3	O
microg	O
.	O
kg	O
(	O
-	O
1	O
)	O
,	O
and	O
the	O
infusion	O
rate	O
increased	O
from	O
1	O
to	O
1	O
.	O
5	O
to	O
2	O
microg	O
.	O
kg	O
(	O
-	O
1	O
)	O
.	O
h	O
(	O
-	O
1	O
)	O
.	O

The	O
current	O
sedation	O
protocol	O
progressively	O
increased	O
the	O
rate	O
of	O
successful	O
sedation	O
(	O
able	O
to	O
complete	O
the	O
imaging	O
study	O
)	O
when	O
using	O
dexmedetomidine	B-Chemical
alone	O
from	O
91	O
.	O
8	O
%	O
to	O
97	O
.	O
6	O
%	O
(	O
P	O
=	O
0	O
.	O
009	O
)	O
,	O
reducing	O
the	O
requirement	O
for	O
adjuvant	O
pentobarbital	B-Chemical
in	O
the	O
event	O
of	O
sedation	O
failure	O
with	O
dexmedetomidine	B-Chemical
alone	O
and	O
decreased	O
the	O
mean	O
recovery	O
time	O
by	O
10	O
min	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Although	O
dexmedetomidine	B-Chemical
sedation	O
was	O
associated	O
with	O
a	O
16	O
%	O
incidence	O
of	O
bradycardia	B-Disease
,	O
all	O
concomitant	O
mean	O
arterial	O
blood	O
pressures	O
were	O
within	O
20	O
%	O
of	O
age	O
-	O
adjusted	O
normal	O
range	O
and	O
oxygen	B-Chemical
saturations	O
were	O
95	O
%	O
or	O
higher	O
.	O

CONCLUSION	O
:	O
Dexmedetomidine	B-Chemical
in	O
high	O
doses	O
provides	O
adequate	O
sedation	O
for	O
pediatric	O
MRI	O
studies	O
.	O

While	O
use	O
of	O
high	O
dose	O
dexmedetomidine	B-Chemical
is	O
associated	O
with	O
decreases	O
in	O
heart	O
rate	O
and	O
blood	O
pressure	O
outside	O
the	O
established	O
'	O
awake	O
'	O
norms	O
,	O
this	O
deviation	O
is	O
generally	O
within	O
20	O
%	O
of	O
norms	O
,	O
and	O
is	O
not	O
associated	O
with	O
adverse	O
sequelae	O
.	O

Dexmedetomidine	B-Chemical
is	O
useful	O
as	O
the	O
sole	O
sedative	O
for	O
pediatric	O
MRI	O
.	O

Hepatotoxicity	B-Disease
associated	O
with	O
sulfasalazine	B-Chemical
in	O
inflammatory	O
arthritis	B-Disease
:	O
A	O
case	O
series	O
from	O
a	O
local	O
surveillance	O
of	O
serious	O
adverse	O
events	O
.	O

BACKGROUND	O
:	O
Spontaneous	O
reporting	O
systems	O
for	O
adverse	O
drug	O
reactions	O
(	O
ADRs	O
)	O
are	O
handicapped	O
by	O
under	O
-	O
reporting	O
and	O
limited	O
detail	O
on	O
individual	O
cases	O
.	O

We	O
report	O
an	O
investigation	O
from	O
a	O
local	O
surveillance	O
for	O
serious	O
adverse	O
drug	O
reactions	O
associated	O
with	O
disease	O
modifying	O
anti	O
-	O
rheumatic	O
drugs	O
that	O
was	O
triggered	O
by	O
the	O
occurrence	O
of	O
liver	B-Disease
failure	I-Disease
in	O
two	O
of	O
our	O
patients	O
.	O

METHODS	O
:	O
Serious	O
ADR	O
reports	O
have	O
been	O
solicited	O
from	O
local	O
clinicians	O
by	O
regular	O
postcards	O
over	O
the	O
past	O
seven	O
years	O
.	O

Patients	O
'	O
,	O
who	O
had	O
hepatotoxicity	B-Disease
on	O
sulfasalazine	B-Chemical
and	O
met	O
a	O
definition	O
of	O
a	O
serious	O
ADR	O
,	O
were	O
identified	O
.	O

Two	O
clinicians	O
reviewed	O
structured	O
case	O
reports	O
and	O
assessed	O
causality	O
by	O
consensus	O
and	O
by	O
using	O
a	O
causality	O
assessment	O
instrument	O
.	O

The	O
likely	O
frequency	O
of	O
hepatotoxicity	B-Disease
with	O
sulfasalazine	B-Chemical
was	O
estimated	O
by	O
making	O
a	O
series	O
of	O
conservative	O
assumptions	O
.	O

RESULTS	O
:	O
Ten	O
cases	O
were	O
identified	O
:	O
eight	O
occurred	O
during	O
surveillance	O
.	O

Eight	O
patients	O
were	O
hospitalised	O
,	O
two	O
in	O
hepatic	B-Disease
failure	I-Disease
-	O
one	O
died	O
after	O
a	O
liver	O
transplant	O
.	O

All	O
but	O
one	O
event	O
occurred	O
within	O
6	O
weeks	O
of	O
treatment	O
.	O

Seven	O
patients	O
had	O
a	O
skin	B-Disease
rash	I-Disease
,	O
three	O
eosinophilia	B-Disease
and	O
one	O
interstitial	B-Disease
nephritis	I-Disease
.	O

Five	O
patients	O
were	O
of	O
Black	O
British	O
of	O
African	O
or	O
Caribbean	O
descent	O
.	O

Liver	O
enzymes	O
showed	O
a	O
hepatocellular	O
pattern	O
in	O
four	O
cases	O
and	O
a	O
mixed	O
pattern	O
in	O
six	O
.	O

Drug	O
-	O
related	O
hepatotoxicity	B-Disease
was	O
judged	O
probable	O
or	O
highly	O
probable	O
in	O
8	O
patients	O
.	O

The	O
likely	O
frequency	O
of	O
serious	O
hepatotoxicity	B-Disease
with	O
sulfasalazine	B-Chemical
was	O
estimated	O
at	O
0	O
.	O
4	O
%	O
of	O
treated	O
patients	O
.	O

CONCLUSION	O
:	O
Serious	O
hepatotoxicity	B-Disease
associated	O
with	O
sulfasalazine	B-Chemical
appears	O
to	O
be	O
under	O
-	O
appreciated	O
and	O
intensive	O
monitoring	O
and	O
vigilance	O
in	O
the	O
first	O
6	O
weeks	O
of	O
treatment	O
is	O
especially	O
important	O
.	O

Complete	O
atrioventricular	B-Disease
block	I-Disease
secondary	O
to	O
lithium	B-Chemical
therapy	O
.	O

Sinus	B-Disease
node	I-Disease
dysfunction	I-Disease
has	O
been	O
reported	O
most	O
frequently	O
among	O
the	O
adverse	O
cardiovascular	O
effects	O
of	O
lithium	B-Chemical
.	O

In	O
the	O
present	O
case	O
,	O
complete	O
atrioventricular	B-Disease
(	I-Disease
AV	I-Disease
)	I-Disease
block	I-Disease
with	O
syncopal	B-Disease
attacks	I-Disease
developed	O
secondary	O
to	O
lithium	B-Chemical
therapy	O
,	O
necessitating	O
permanent	O
pacemaker	O
implantation	O
.	O

Serum	O
lithium	B-Chemical
levels	O
remained	O
under	O
or	O
within	O
the	O
therapeutic	O
range	O
during	O
the	O
syncopal	B-Disease
attacks	I-Disease
.	O

Lithium	B-Chemical
should	O
be	O
used	O
with	O
extreme	O
caution	O
,	O
especially	O
in	O
patients	O
with	O
mild	O
disturbance	O
of	O
AV	O
conduction	O
.	O

Exaggerated	O
expression	O
of	O
inflammatory	O
mediators	O
in	O
vasoactive	O
intestinal	O
polypeptide	O
knockout	O
(	O
VIP	O
-	O
/	O
-	O
)	O
mice	O
with	O
cyclophosphamide	B-Chemical
(	O
CYP	B-Chemical
)	O
-	O
induced	O
cystitis	B-Disease
.	O

Vasoactive	O
intestinal	O
polypeptide	O
(	O
VIP	O
)	O
is	O
an	O
immunomodulatory	O
neuropeptide	O
distributed	O
in	O
micturition	O
pathways	O
.	O

VIP	O
(	O
-	O
/	O
-	O
)	O
mice	O
exhibit	O
altered	O
bladder	O
function	O
and	O
neurochemical	O
properties	O
in	O
micturition	O
pathways	O
after	O
cyclophosphamide	B-Chemical
(	O
CYP	B-Chemical
)	O
-	O
induced	O
cystitis	B-Disease
.	O

Given	O
VIP	O
'	O
s	O
role	O
as	O
an	O
anti	O
-	O
inflammatory	O
mediator	O
,	O
we	O
hypothesized	O
that	O
VIP	O
(	O
-	O
/	O
-	O
)	O
mice	O
would	O
exhibit	O
enhanced	O
inflammatory	O
mediator	O
expression	O
after	O
cystitis	B-Disease
.	O

A	O
mouse	O
inflammatory	O
cytokine	O
and	O
receptor	O
RT2	O
profiler	O
array	O
was	O
used	O
to	O
determine	O
regulated	O
transcripts	O
in	O
the	O
urinary	O
bladder	O
of	O
wild	O
type	O
(	O
WT	O
)	O
and	O
VIP	O
(	O
-	O
/	O
-	O
)	O
mice	O
with	O
or	O
without	O
CYP	B-Chemical
-	O
induced	O
cystitis	B-Disease
(	O
150	O
mg	O
/	O
kg	O
;	O
i	O
.	O
p	O
.	O
;	O
48	O
h	O
)	O
.	O

Four	O
binary	O
comparisons	O
were	O
made	O
:	O
WT	O
control	O
versus	O
CYP	B-Chemical
treatment	O
(	O
48	O
h	O
)	O
,	O
VIP	O
(	O
-	O
/	O
-	O
)	O
control	O
versus	O
CYP	B-Chemical
treatment	O
(	O
48	O
h	O
)	O
,	O
WT	O
control	O
versus	O
VIP	O
(	O
-	O
/	O
-	O
)	O
control	O
,	O
and	O
WT	O
with	O
CYP	B-Chemical
treatment	O
(	O
48	O
h	O
)	O
versus	O
VIP	O
(	O
-	O
/	O
-	O
)	O
with	O
CYP	B-Chemical
treatment	O
(	O
48	O
h	O
)	O
.	O

The	O
genes	O
presented	O
represent	O
(	O
1	O
)	O
greater	O
than	O
1	O
.	O
5	O
-	O
fold	O
change	O
in	O
either	O
direction	O
and	O
(	O
2	O
)	O
the	O
p	O
value	O
is	O
less	O
than	O
0	O
.	O
05	O
for	O
the	O
comparison	O
being	O
made	O
.	O

Several	O
regulated	O
genes	O
were	O
validated	O
using	O
enzyme	O
-	O
linked	O
immunoassays	O
including	O
IL	O
-	O
1beta	O
and	O
CXCL1	O
.	O

CYP	B-Chemical
treatment	O
significantly	O
(	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
increased	O
expression	O
of	O
CXCL1	O
and	O
IL	O
-	O
1beta	O
in	O
the	O
urinary	O
bladder	O
of	O
WT	O
and	O
VIP	O
(	O
-	O
/	O
-	O
)	O
mice	O
,	O
but	O
expression	O
in	O
VIP	O
(	O
-	O
/	O
-	O
)	O
mice	O
with	O
CYP	B-Chemical
treatment	O
was	O
significantly	O
(	O
p	O
<	O
or	O
=	O
0	O
.	O
001	O
)	O
greater	O
(	O
4	O
.	O
2	O
-	O
to	O
13	O
-	O
fold	O
increase	O
)	O
than	O
that	O
observed	O
in	O
WT	O
urinary	O
bladder	O
(	O
3	O
.	O
6	O
-	O
to	O
5	O
-	O
fold	O
increase	O
)	O
.	O

The	O
data	O
suggest	O
that	O
in	O
VIP	O
(	O
-	O
/	O
-	O
)	O
mice	O
with	O
bladder	B-Disease
inflammation	I-Disease
,	O
inflammatory	O
mediators	O
are	O
increased	O
above	O
that	O
observed	O
in	O
WT	O
with	O
CYP	B-Chemical
.	O

This	O
shift	O
in	O
balance	O
may	O
contribute	O
to	O
increased	O
bladder	B-Disease
dysfunction	I-Disease
in	O
VIP	O
(	O
-	O
/	O
-	O
)	O
mice	O
with	O
bladder	B-Disease
inflammation	I-Disease
and	O
altered	O
neurochemical	O
expression	O
in	O
micturition	O
pathways	O
.	O

Debrisoquine	B-Chemical
phenotype	O
and	O
the	O
pharmacokinetics	O
and	O
beta	O
-	O
2	O
receptor	O
pharmacodynamics	O
of	O
metoprolol	B-Chemical
and	O
its	O
enantiomers	O
.	O

The	O
metabolism	O
of	O
the	O
cardioselective	O
beta	O
-	O
blocker	O
metoprolol	B-Chemical
is	O
under	O
genetic	O
control	O
of	O
the	O
debrisoquine	B-Chemical
/	O
sparteine	B-Chemical
type	O
.	O

The	O
two	O
metabolic	O
phenotypes	O
,	O
extensive	O
(	O
EM	O
)	O
and	O
poor	O
metabolizers	O
(	O
PM	O
)	O
,	O
show	O
different	O
stereoselective	O
metabolism	O
,	O
resulting	O
in	O
apparently	O
higher	O
beta	O
-	O
1	O
adrenoceptor	O
antagonistic	O
potency	O
of	O
racemic	O
metoprolol	B-Chemical
in	O
EMs	O
.	O

We	O
investigated	O
if	O
the	O
latter	O
also	O
applies	O
to	O
the	O
beta	O
-	O
2	O
adrenoceptor	O
antagonism	O
by	O
metoprolol	B-Chemical
.	O

The	O
drug	O
effect	O
studied	O
was	O
the	O
antagonism	O
by	O
metoprolol	B-Chemical
of	O
terbutaline	B-Chemical
-	O
induced	O
hypokalemia	B-Disease
.	O

By	O
using	O
pharmacokinetic	O
pharmacodynamic	O
modeling	O
the	O
pharmacodynamics	O
of	O
racemic	O
metoprolol	B-Chemical
and	O
the	O
active	O
S	O
-	O
isomer	O
,	O
were	O
quantitated	O
in	O
EMs	O
and	O
PMs	O
in	O
terms	O
of	O
IC50	O
values	O
,	O
representing	O
metoprolol	B-Chemical
plasma	O
concentrations	O
resulting	O
in	O
half	O
-	O
maximum	O
receptor	O
occupancy	O
.	O

Six	O
EMs	O
received	O
0	O
.	O
5	O
mg	O
of	O
terbutaline	B-Chemical
s	O
.	O
c	O
.	O
on	O
two	O
different	O
occasions	O
:	O
1	O
)	O
1	O
hr	O
after	O
administration	O
of	O
a	O
placebo	O
and	O
2	O
)	O
1	O
hr	O
after	O
150	O
mg	O
of	O
metoprolol	B-Chemical
p	O
.	O
o	O
.	O

Five	O
PMs	O
were	O
studied	O
according	O
to	O
the	O
same	O
protocol	O
,	O
except	O
for	O
a	O
higher	O
terbutaline	B-Chemical
dose	O
(	O
0	O
.	O
75	O
mg	O
)	O
on	O
day	O
2	O
.	O

Blood	O
samples	O
for	O
the	O
analysis	O
of	O
plasma	O
potassium	B-Chemical
,	O
terbutaline	B-Chemical
,	O
metoprolol	B-Chemical
(	O
racemic	O
,	O
R	O
-	O
and	O
S	O
-	O
isomer	O
)	O
,	O
and	O
alpha	B-Chemical
-	I-Chemical
hydroxymetoprolol	I-Chemical
concentrations	O
were	O
taken	O
at	O
regular	O
time	O
intervals	O
,	O
during	O
8	O
hr	O
after	O
metoprolol	B-Chemical
.	O

In	O
PMs	O
,	O
metoprolol	B-Chemical
increased	O
the	O
terbutaline	B-Chemical
area	O
under	O
the	O
plasma	O
concentration	O
vs	O
.	O
time	O
curve	O
(	O
+	O
67	O
%	O
)	O
.	O

Higher	O
metoprolol	B-Chemical
/	O
alpha	B-Chemical
-	I-Chemical
hydroxymetoprolol	I-Chemical
ratios	O
in	O
PMs	O
were	O
predictive	O
for	O
higher	O
R	O
-	O
/	O
S	O
-	O
isomer	O
ratios	O
of	O
unchanged	O
drug	O
.	O

There	O
was	O
a	O
difference	O
in	O
metoprolol	B-Chemical
potency	O
with	O
higher	O
racemic	O
metoprolol	B-Chemical
IC50	O
values	O
in	O
PMs	O
(	O
72	O
+	O
/	O
-	O
7	O
ng	O
.	O
ml	O
-	O
1	O
)	O
than	O
EMs	O
(	O
42	O
+	O
/	O
-	O
8	O
ng	O
.	O
ml	O
-	O
1	O
,	O
P	O
less	O
than	O
.	O
001	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

The	O
hemodynamics	O
of	O
oxytocin	B-Chemical
and	O
other	O
vasoactive	O
agents	O
during	O
neuraxial	O
anesthesia	O
for	O
cesarean	O
delivery	O
:	O
findings	O
in	O
six	O
cases	O
.	O

Oxytocin	B-Chemical
is	O
a	O
commonly	O
used	O
uterotonic	O
that	O
can	O
cause	O
significant	O
and	O
even	O
fatal	O
hypotension	B-Disease
,	O
particularly	O
when	O
given	O
as	O
a	O
bolus	O
.	O

The	O
resulting	O
hypotension	B-Disease
can	O
be	O
produced	O
by	O
a	O
decrease	O
in	O
systemic	O
vascular	O
resistance	O
or	O
cardiac	O
output	O
through	O
a	O
decrease	O
in	O
venous	O
return	O
.	O

Parturients	O
with	O
normal	O
volume	O
status	O
,	O
heart	O
valves	O
and	O
pulmonary	O
vasculature	O
most	O
often	O
respond	O
to	O
this	O
hypotension	B-Disease
with	O
a	O
compensatory	O
increase	O
in	O
heart	O
rate	O
and	O
stroke	B-Disease
volume	O
.	O

Oxytocin	B-Chemical
-	O
induced	O
hypotension	B-Disease
at	O
cesarean	O
delivery	O
may	O
be	O
incorrectly	O
attributed	O
to	O
blood	B-Disease
loss	I-Disease
.	O

Pulse	O
power	O
analysis	O
(	O
also	O
called	O
"	O
pulse	O
contour	O
analysis	O
"	O
)	O
of	O
an	O
arterial	O
pressure	O
wave	O
form	O
allows	O
continuous	O
evaluation	O
of	O
systemic	O
vascular	O
resistance	O
and	O
cardiac	O
output	O
in	O
real	O
time	O
,	O
thereby	O
elucidating	O
the	O
causative	O
factors	O
behind	O
changes	O
in	O
blood	O
pressure	O
.	O

Pulse	O
power	O
analysis	O
was	O
conducted	O
in	O
six	O
cases	O
of	O
cesarean	O
delivery	O
performed	O
under	O
neuraxial	O
anesthesia	O
.	O

Hypotension	B-Disease
in	O
response	O
to	O
oxytocin	B-Chemical
was	O
associated	O
with	O
a	O
decrease	O
in	O
systemic	O
vascular	O
resistance	O
and	O
a	O
compensatory	O
increase	O
in	O
stroke	B-Disease
volume	O
,	O
heart	O
rate	O
and	O
cardiac	O
output	O
.	O

Pulse	O
power	O
analysis	O
may	O
be	O
helpful	O
in	O
determining	O
the	O
etiology	O
of	O
and	O
treating	O
hypotension	B-Disease
during	O
cesarean	O
delivery	O
under	O
neuraxial	O
anesthesia	O
.	O

Protective	O
effects	O
of	O
antithrombin	O
on	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
nephrosis	B-Disease
in	O
rats	O
.	O

We	O
investigated	O
the	O
effects	O
of	O
antithrombin	O
,	O
a	O
plasma	O
inhibitor	O
of	O
coagulation	O
factors	O
,	O
in	O
rats	O
with	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
nephrosis	B-Disease
,	O
which	O
is	O
an	O
experimental	O
model	O
of	O
human	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

Antithrombin	O
(	O
50	O
or	O
500	O
IU	O
/	O
kg	O
/	O
i	O
.	O
v	O
.	O
)	O
was	O
administered	O
to	O
rats	O
once	O
a	O
day	O
for	O
10	O
days	O
immediately	O
after	O
the	O
injection	O
of	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
50	O
mg	O
/	O
kg	O
/	O
i	O
.	O
v	O
.	O
)	O
.	O

Treatment	O
with	O
antithrombin	O
attenuated	O
the	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
hematological	B-Disease
abnormalities	I-Disease
.	O

Puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
renal	B-Disease
dysfunction	I-Disease
and	O
hyperlipidemia	B-Disease
were	O
also	O
suppressed	O
.	O

Histopathological	O
examination	O
revealed	O
severe	O
renal	B-Disease
damage	I-Disease
such	O
as	O
proteinaceous	O
casts	O
in	O
tubuli	O
and	O
tubular	O
expansion	O
in	O
the	O
kidney	O
of	O
control	O
rats	O
,	O
while	O
an	O
improvement	O
of	O
the	O
damage	O
was	O
seen	O
in	O
antithrombin	O
-	O
treated	O
rats	O
.	O

In	O
addition	O
,	O
antithrombin	O
treatment	O
markedly	O
suppressed	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
apoptosis	O
of	O
renal	O
tubular	O
epithelial	O
cells	O
.	O

Furthermore	O
,	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
increases	O
in	O
renal	O
cytokine	O
content	O
were	O
also	O
decreased	O
.	O

These	O
findings	O
suggest	O
that	O
thrombin	O
plays	O
an	O
important	O
role	O
in	O
the	O
pathogenesis	O
of	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
-	O
induced	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

Treatment	O
with	O
antithrombin	O
may	O
be	O
clinically	O
effective	O
in	O
patients	O
with	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

Heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
after	O
liver	O
transplantation	O
.	O

BACKGROUND	O
:	O
Unfractionated	B-Chemical
heparin	I-Chemical
sodium	I-Chemical
(	O
UFH	B-Chemical
)	O
or	O
low	B-Chemical
-	I-Chemical
molecular	I-Chemical
weight	I-Chemical
heparin	I-Chemical
(	O
LMWH	O
)	O
is	O
used	O
in	O
anticoagulant	O
protocols	O
at	O
several	O
institutions	O
to	O
prevent	O
thrombosis	B-Disease
after	O
liver	O
transplantation	O
.	O

Heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
(	O
HIT	B-Disease
)	O
is	O
an	O
adverse	O
immune	O
-	O
mediated	O
reaction	O
to	O
heparin	B-Chemical
,	O
resulting	O
in	O
platelet	O
count	O
decreases	O
of	O
more	O
than	O
50	O
%	O
.	O

The	O
frequencies	O
of	O
HIT	B-Disease
after	O
liver	O
transplantation	O
and	O
platelet	O
factor	O
4	O
/	O
heparin	B-Chemical
-	O
reactive	O
antibody	O
(	O
HIT	B-Disease
antibody	O
)	O
positivity	O
in	O
liver	O
transplantation	O
patients	O
,	O
however	O
,	O
are	O
unknown	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
The	O
32	O
men	O
and	O
20	O
women	O
underwent	O
living	O
donor	O
liver	O
transplantation	O
.	O

We	O
started	O
LMWH	O
(	O
25	O
IU	O
/	O
kg	O
/	O
h	O
)	O
on	O
postoperative	O
day	O
(	O
POD	O
)	O
1	O
,	O
switching	O
to	O
UFH	B-Chemical
(	O
5000	O
U	O
/	O
d	O
)	O
on	O
POD	O
2	O
or	O
3	O
.	O

The	O
dose	O
of	O
UFH	B-Chemical
was	O
changed	O
according	O
to	O
the	O
activated	O
clotting	O
time	O
level	O
.	O

HIT	B-Disease
antibody	O
levels	O
were	O
measured	O
the	O
day	O
before	O
surgery	O
and	O
on	O
POD	O
7	O
and	O
14	O
.	O

Platelet	O
count	O
was	O
measured	O
daily	O
for	O
3	O
weeks	O
.	O

RESULTS	O
:	O
The	O
average	O
platelet	O
counts	O
preoperatively	O
,	O
and	O
on	O
POD	O
7	O
,	O
14	O
,	O
and	O
21	O
were	O
65	O
,	O
88	O
,	O
149	O
,	O
and	O
169	O
x	O
10	O
(	O
9	O
)	O
/	O
L	O
,	O
respectively	O
.	O

Two	O
patients	O
developed	O
hepatic	O
artery	O
thrombosis	B-Disease
on	O
POD	O
11	O
and	O
19	O
,	O
respectively	O
,	O
although	O
they	O
were	O
HIT	B-Disease
antibody	O
-	O
negative	O
and	O
their	O
platelet	O
counts	O
were	O
stable	O
.	O

In	O
2	O
other	O
patients	O
,	O
the	O
platelet	O
count	O
decreased	O
suddenly	O
from	O
107	O
x	O
10	O
(	O
9	O
)	O
/	O
L	O
on	O
POD	O
4	O
to	O
65	O
x	O
10	O
(	O
9	O
)	O
/	O
L	O
on	O
POD	O
6	O
and	O
from	O
76	O
x	O
10	O
(	O
9	O
)	O
/	O
L	O
on	O
POD	O
7	O
to	O
33	O
x	O
10	O
(	O
9	O
)	O
/	O
L	O
on	O
POD	O
9	O
,	O
respectively	O
.	O

The	O
heparin	B-Chemical
-	O
induced	O
platelet	B-Disease
aggregation	I-Disease
test	O
was	O
negative	O
in	O
these	O
patients	O
.	O

The	O
percentage	O
of	O
HIT	B-Disease
antibody	O
-	O
positive	O
patients	O
was	O
0	O
.	O
5	O
%	O
preoperatively	O
,	O
5	O
.	O
6	O
%	O
on	O
POD	O
7	O
,	O
and	O
5	O
.	O
6	O
%	O
on	O
POD	O
14	O
.	O

None	O
of	O
the	O
subjects	O
/	O
patients	O
developed	O
UFH	B-Chemical
-	O
related	O
HIT	B-Disease
.	O

CONCLUSIONS	O
:	O
In	O
our	O
series	O
,	O
the	O
occurrence	O
of	O
HIT	B-Disease
after	O
liver	O
transplantation	O
was	O
uncommon	O
.	O

Doxorubicin	B-Chemical
cardiomyopathy	B-Disease
-	O
induced	O
inflammation	B-Disease
and	O
apoptosis	O
are	O
attenuated	O
by	O
gene	O
deletion	O
of	O
the	O
kinin	O
B1	O
receptor	O
.	O

Clinical	O
use	O
of	O
the	O
anthracycline	B-Chemical
doxorubicin	B-Chemical
(	O
DOX	B-Chemical
)	O
is	O
limited	O
by	O
its	O
cardiotoxic	B-Disease
effects	O
,	O
which	O
are	O
attributed	O
to	O
the	O
induction	O
of	O
apoptosis	O
.	O

To	O
elucidate	O
the	O
possible	O
role	O
of	O
the	O
kinin	O
B1	O
receptor	O
(	O
B1R	O
)	O
during	O
the	O
development	O
of	O
DOX	B-Chemical
cardiomyopathy	B-Disease
,	O
we	O
studied	O
B1R	O
knockout	O
mice	O
(	O
B1R	O
(	O
-	O
/	O
-	O
)	O
)	O
by	O
investigating	O
cardiac	O
inflammation	B-Disease
and	O
apoptosis	O
after	O
induction	O
of	O
DOX	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
.	O

DOX	B-Chemical
control	O
mice	O
showed	O
cardiac	B-Disease
dysfunction	I-Disease
measured	O
by	O
pressure	O
-	O
volume	O
loops	O
in	O
vivo	O
.	O

This	O
was	O
associated	O
with	O
a	O
reduced	O
activation	O
state	O
of	O
AKT	O
,	O
as	O
well	O
as	O
an	O
increased	O
bax	O
/	O
bcl2	O
ratio	O
in	O
Western	O
blots	O
,	O
indicating	O
cardiac	B-Disease
apoptosis	I-Disease
.	O

Furthermore	O
,	O
mRNA	O
levels	O
of	O
the	O
proinflammatory	O
cytokine	O
interleukin	O
6	O
were	O
increased	O
in	O
the	O
cardiac	O
tissue	O
.	O

In	O
DOX	B-Chemical
B1R	O
(	O
-	O
/	O
-	O
)	O
mice	O
,	O
cardiac	B-Disease
dysfunction	I-Disease
was	O
improved	O
compared	O
to	O
DOX	B-Chemical
control	O
mice	O
,	O
which	O
was	O
associated	O
with	O
normalization	O
of	O
the	O
bax	O
/	O
bcl	O
-	O
2	O
ratio	O
and	O
interleukin	O
6	O
,	O
as	O
well	O
as	O
AKT	O
activation	O
state	O
.	O

These	O
findings	O
suggest	O
that	O
B1R	O
is	O
detrimental	O
in	O
DOX	B-Chemical
cardiomyopathy	B-Disease
in	O
that	O
it	O
mediates	O
the	O
inflammatory	O
response	O
and	O
apoptosis	O
.	O

These	O
insights	O
might	O
have	O
useful	O
implications	O
for	O
future	O
studies	O
utilizing	O
B1R	O
antagonists	O
for	O
treatment	O
of	O
human	O
DOX	B-Chemical
cardiomyopathy	B-Disease
.	O

Detailed	O
spectral	O
profile	O
analysis	O
of	O
penicillin	B-Chemical
-	O
induced	O
epileptiform	B-Disease
activity	I-Disease
in	O
anesthetized	O
rats	O
.	O

Penicillin	B-Chemical
model	O
is	O
a	O
widely	O
used	O
experimental	O
model	O
for	O
epilepsy	B-Disease
research	O
.	O

In	O
the	O
present	O
study	O
we	O
aimed	O
to	O
portray	O
a	O
detailed	O
spectral	O
analysis	O
of	O
penicillin	B-Chemical
-	O
induced	O
epileptiform	B-Disease
activity	I-Disease
in	O
comparison	O
with	O
basal	O
brain	O
activity	O
in	O
anesthetized	O
Wistar	O
rats	O
.	O

Male	O
Wistar	O
rats	O
were	O
anesthetized	O
with	O
i	O
.	O
p	O
.	O
urethane	B-Chemical
and	O
connected	O
to	O
an	O
electrocorticogram	O
setup	O
.	O

After	O
a	O
short	O
period	O
of	O
basal	O
activity	O
recording	O
,	O
epileptic	B-Disease
focus	O
was	O
induced	O
by	O
injecting	O
400IU	O
/	O
2	O
microl	O
penicillin	B-Chemical
-	I-Chemical
G	I-Chemical
potassium	I-Chemical
into	O
the	O
left	O
lateral	O
ventricle	O
while	O
the	O
cortical	O
activity	O
was	O
continuously	O
recorded	O
.	O

Basal	O
activity	O
,	O
latent	O
period	O
and	O
the	O
penicillin	B-Chemical
-	O
induced	O
epileptiform	B-Disease
activity	I-Disease
periods	O
were	O
then	O
analyzed	O
using	O
both	O
conventional	O
methods	O
and	O
spectral	O
analysis	O
.	O

Spectral	O
analyses	O
were	O
conducted	O
by	O
dividing	O
the	O
whole	O
spectrum	O
into	O
different	O
frequency	O
bands	O
including	O
delta	O
,	O
theta	O
(	O
slow	O
and	O
fast	O
)	O
,	O
alpha	O
-	O
sigma	O
,	O
beta	O
(	O
1	O
and	O
2	O
)	O
and	O
gamma	O
(	O
1	O
and	O
2	O
)	O
bands	O
.	O

Our	O
results	O
show	O
that	O
the	O
most	O
affected	O
frequency	O
bands	O
were	O
delta	O
,	O
theta	O
,	O
beta	O
-	O
2	O
and	O
gamma	O
-	O
2	O
bands	O
during	O
the	O
epileptiform	B-Disease
activity	I-Disease
and	O
there	O
were	O
marked	O
differences	O
in	O
terms	O
of	O
spectral	O
densities	O
between	O
three	O
investigated	O
episodes	O
(	O
basal	O
activity	O
,	O
latent	O
period	O
and	O
epileptiform	B-Disease
activity	I-Disease
)	O
.	O

Our	O
results	O
may	O
help	O
to	O
analyze	O
novel	O
data	O
obtained	O
using	O
similar	O
experimental	O
models	O
and	O
the	O
simple	O
analysis	O
method	O
described	O
here	O
can	O
be	O
used	O
in	O
similar	O
studies	O
to	O
investigate	O
the	O
basic	O
neuronal	O
mechanism	O
of	O
this	O
or	O
other	O
types	O
of	O
experimental	O
epilepsies	B-Disease
.	O

High	O
fat	B-Chemical
diet	O
-	O
fed	O
obese	B-Disease
rats	O
are	O
highly	O
sensitive	O
to	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

Often	O
,	O
chemotherapy	O
by	O
doxorubicin	B-Chemical
(	O
Adriamycin	B-Chemical
)	O
is	O
limited	O
due	O
to	O
life	O
threatening	O
cardiotoxicity	B-Disease
in	O
patients	O
during	O
and	O
posttherapy	O
.	O

Recently	O
,	O
we	O
have	O
shown	O
that	O
moderate	O
diet	O
restriction	O
remarkably	O
protects	O
against	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

This	O
cardioprotection	O
is	O
accompanied	O
by	O
decreased	O
cardiac	O
oxidative	O
stress	O
and	O
triglycerides	B-Chemical
and	O
increased	O
cardiac	O
fatty	O
-	O
acid	O
oxidation	O
,	O
ATP	B-Chemical
synthesis	O
,	O
and	O
upregulated	O
JAK	O
/	O
STAT3	O
pathway	O
.	O

In	O
the	O
current	O
study	O
,	O
we	O
investigated	O
whether	O
a	O
physiological	O
intervention	O
by	O
feeding	O
40	O
%	O
high	O
fat	B-Chemical
diet	O
(	O
HFD	O
)	O
,	O
which	O
induces	O
obesity	B-Disease
in	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
(	O
250	O
-	O
275	O
g	O
)	O
,	O
sensitizes	O
to	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
.	O

A	O
LD	O
(	O
10	O
)	O
dose	O
(	O
8	O
mg	O
doxorubicin	B-Chemical
/	O
kg	O
,	O
ip	O
)	O
administered	O
on	O
day	O
43	O
of	O
the	O
HFD	O
feeding	O
regimen	O
led	O
to	O
higher	O
cardiotoxicity	B-Disease
,	O
cardiac	B-Disease
dysfunction	I-Disease
,	O
lipid	O
peroxidation	O
,	O
and	O
80	O
%	O
mortality	O
in	O
the	O
obese	B-Disease
(	O
OB	B-Disease
)	O
rats	O
in	O
the	O
absence	O
of	O
any	O
significant	O
renal	B-Disease
or	I-Disease
hepatic	I-Disease
toxicity	I-Disease
.	O

Doxorubicin	B-Chemical
toxicokinetics	O
studies	O
revealed	O
no	O
change	O
in	O
accumulation	O
of	O
doxorubicin	B-Chemical
and	O
doxorubicinol	B-Chemical
(	O
toxic	O
metabolite	O
)	O
in	O
the	O
normal	O
diet	O
-	O
fed	O
(	O
ND	O
)	O
and	O
OB	B-Disease
hearts	O
.	O

Mechanistic	O
studies	O
revealed	O
that	O
OB	B-Disease
rats	O
are	O
sensitized	O
due	O
to	O
:	O
(	O
1	O
)	O
higher	O
oxyradical	O
stress	O
leading	O
to	O
upregulation	O
of	O
uncoupling	O
proteins	O
2	O
and	O
3	O
,	O
(	O
2	O
)	O
downregulation	O
of	O
cardiac	O
peroxisome	O
proliferators	O
activated	O
receptor	O
-	O
alpha	O
,	O
(	O
3	O
)	O
decreased	O
plasma	O
adiponectin	O
levels	O
,	O
(	O
4	O
)	O
decreased	O
cardiac	O
fatty	O
-	O
acid	O
oxidation	O
(	O
666	O
.	O
9	O
+	O
/	O
-	O
14	O
.	O
0	O
nmol	O
/	O
min	O
/	O
g	O
heart	O
in	O
ND	O
versus	O
400	O
.	O
2	O
+	O
/	O
-	O
11	O
.	O
8	O
nmol	O
/	O
min	O
/	O
g	O
heart	O
in	O
OB	B-Disease
)	O
,	O
(	O
5	O
)	O
decreased	O
mitochondrial	O
AMP	B-Chemical
-	O
alpha2	O
protein	O
kinase	O
,	O
and	O
(	O
6	O
)	O
86	O
%	O
drop	O
in	O
cardiac	O
ATP	B-Chemical
levels	O
accompanied	O
by	O
decreased	O
ATP	B-Chemical
/	O
ADP	B-Chemical
ratio	O
after	O
doxorubicin	B-Chemical
administration	O
.	O

Decreased	O
cardiac	O
erythropoietin	O
and	O
increased	O
SOCS3	O
further	O
downregulated	O
the	O
cardioprotective	O
JAK	O
/	O
STAT3	O
pathway	O
.	O

In	O
conclusion	O
,	O
HFD	O
-	O
induced	O
obese	B-Disease
rats	O
are	O
highly	O
sensitized	O
to	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
by	O
substantially	O
downregulating	O
cardiac	O
mitochondrial	O
ATP	B-Chemical
generation	O
,	O
increasing	O
oxidative	O
stress	O
and	O
downregulating	O
the	O
JAK	O
/	O
STAT3	O
pathway	O
.	O

Isoproterenol	B-Chemical
induces	O
primary	O
loss	O
of	O
dystrophin	O
in	O
rat	O
hearts	O
:	O
correlation	O
with	O
myocardial	B-Disease
injury	I-Disease
.	O

The	O
mechanism	O
of	O
isoproterenol	B-Chemical
-	O
induced	O
myocardial	B-Disease
damage	I-Disease
is	O
unknown	O
,	O
but	O
a	O
mismatch	O
of	O
oxygen	B-Chemical
supply	O
vs	O
.	O
demand	O
following	O
coronary	O
hypotension	B-Disease
and	O
myocardial	B-Disease
hyperactivity	I-Disease
is	O
the	O
best	O
explanation	O
for	O
the	O
complex	O
morphological	O
alterations	O
observed	O
.	O

Severe	O
alterations	O
in	O
the	O
structural	O
integrity	O
of	O
the	O
sarcolemma	O
of	O
cardiomyocytes	O
have	O
been	O
demonstrated	O
to	O
be	O
caused	O
by	O
isoproterenol	B-Chemical
.	O

Taking	O
into	O
account	O
that	O
the	O
sarcolemmal	O
integrity	O
is	O
stabilized	O
by	O
the	O
dystrophin	O
-	O
glycoprotein	O
complex	O
(	O
DGC	O
)	O
that	O
connects	O
actin	O
and	O
laminin	O
in	O
contractile	O
machinery	O
and	O
extracellular	O
matrix	O
and	O
by	O
integrins	O
,	O
this	O
study	O
tests	O
the	O
hypothesis	O
that	O
isoproterenol	B-Chemical
affects	O
sarcolemmal	O
stability	O
through	O
changes	O
in	O
the	O
DGC	O
and	O
integrins	O
.	O

We	O
found	O
different	O
sensitivity	O
of	O
the	O
DGC	O
and	O
integrin	O
to	O
isoproterenol	B-Chemical
subcutaneous	O
administration	O
.	O

Immunofluorescent	O
staining	O
revealed	O
that	O
dystrophin	O
is	O
the	O
most	O
sensitive	O
among	O
the	O
structures	O
connecting	O
the	O
actin	O
in	O
the	O
cardiomyocyte	O
cytoskeleton	O
and	O
the	O
extracellular	O
matrix	O
.	O

The	O
sarcomeric	O
actin	O
dissolution	O
occurred	O
after	O
the	O
reduction	O
or	O
loss	O
of	O
dystrophin	O
.	O

Subsequently	O
,	O
after	O
lysis	O
of	O
myofilaments	O
,	O
gamma	O
-	O
sarcoglycan	O
,	O
beta	O
-	O
dystroglycan	O
,	O
beta1	O
-	O
integrin	O
,	O
and	O
laminin	O
alpha	O
-	O
2	O
expressions	O
were	O
reduced	O
followed	O
by	O
their	O
breakdown	O
,	O
as	O
epiphenomena	O
of	O
the	O
myocytolytic	O
process	O
.	O

In	O
conclusion	O
,	O
administration	O
of	O
isoproterenol	B-Chemical
to	O
rats	O
results	O
in	O
primary	O
loss	O
of	O
dystrophin	O
,	O
the	O
most	O
sensitive	O
among	O
the	O
structural	O
proteins	O
that	O
form	O
the	O
DGC	O
that	O
connects	O
the	O
extracellular	O
matrix	O
and	O
the	O
cytoskeleton	O
in	O
cardiomyocyte	O
.	O

These	O
changes	O
,	O
related	O
to	O
ischaemic	B-Disease
injury	I-Disease
,	O
explain	O
the	O
severe	O
alterations	O
in	O
the	O
structural	O
integrity	O
of	O
the	O
sarcolemma	O
of	O
cardiomyocytes	O
and	O
hence	O
severe	O
and	O
irreversible	O
injury	O
induced	O
by	O
isoproterenol	B-Chemical
.	O

Etiologic	O
factors	O
in	O
the	O
pathogenesis	O
of	O
liver	B-Disease
tumors	I-Disease
associated	O
with	O
oral	B-Chemical
contraceptives	I-Chemical
.	O

Within	O
the	O
last	O
several	O
years	O
,	O
previously	O
rare	O
liver	B-Disease
tumors	I-Disease
have	O
been	O
seen	O
in	O
young	O
women	O
using	O
oral	B-Chemical
contraceptive	I-Chemical
steroids	B-Chemical
.	O

The	O
Registry	O
for	O
Liver	B-Disease
Tumors	I-Disease
Associated	O
with	O
Oral	B-Chemical
Contraceptives	I-Chemical
at	O
the	O
University	O
of	O
California	O
,	O
Irvine	O
,	O
has	O
clearly	O
identified	O
27	O
cases	O
.	O

The	O
recent	O
literature	O
contains	O
44	O
case	O
reports	O
.	O

Common	O
to	O
these	O
71	O
cases	O
has	O
been	O
a	O
histopathologic	O
diagnosis	O
of	O
focal	B-Disease
nodular	I-Disease
hyperplasia	I-Disease
,	O
adenoma	B-Disease
,	O
hamartoma	B-Disease
,	O
and	O
hepatoma	B-Disease
.	O

Significant	O
statistical	O
etiologic	O
factors	O
include	O
prolonged	O
uninterrupted	O
usage	O
of	O
oral	B-Chemical
contraceptive	I-Chemical
steroids	B-Chemical
.	O

Eight	O
deaths	O
and	O
liver	O
rupture	B-Disease
in	O
18	O
patients	O
attest	O
to	O
the	O
seriousness	O
of	O
this	O
new	O
potentially	O
lethal	O
adverse	O
phenomenon	O
.	O

Ifosfamide	B-Chemical
continuous	O
infusion	O
without	O
mesna	B-Chemical
.	O

A	O
phase	O
I	O
trial	O
of	O
a	O
14	O
-	O
day	O
cycle	O
.	O

Twenty	O
patients	O
received	O
27	O
courses	O
of	O
ifosfamide	B-Chemical
administered	O
as	O
a	O
24	O
-	O
hour	O
continuous	O
infusion	O
for	O
14	O
days	O
without	O
Mesna	B-Chemical
.	O

The	O
goal	O
of	O
the	O
study	O
was	O
to	O
deliver	O
a	O
dose	O
rate	O
and	O
total	O
cumulative	O
dose	O
of	O
ifosfamide	B-Chemical
that	O
would	O
be	O
comparable	O
to	O
standard	O
bolus	O
or	O
short	O
-	O
term	O
infusions	O
administered	O
with	O
Mesna	B-Chemical
.	O

Dose	O
escalations	O
proceeded	O
from	O
200	O
to	O
300	O
,	O
400	O
,	O
450	O
,	O
500	O
,	O
and	O
550	O
mg	O
/	O
m2	O
/	O
d	O
.	O

Four	O
patients	O
developed	O
transient	O
microscopic	O
hematuria	B-Disease
at	O
400	O
,	O
450	O
,	O
and	O
500	O
mg	O
/	O
m2	O
/	O
d	O
.	O

There	O
were	O
no	O
instances	O
of	O
macroscopic	O
hematuria	B-Disease
.	O

At	O
550	O
mg	O
/	O
m2	O
/	O
d	O
,	O
three	O
patients	O
experienced	O
nonurologic	O
toxicity	B-Disease
;	O
confusion	B-Disease
(	O
1	O
)	O
,	O
nausea	B-Disease
(	O
1	O
)	O
,	O
and	O
Grade	O
2	O
leukopenia	B-Disease
(	O
1	O
)	O
.	O

The	O
recommended	O
dose	O
of	O
500	O
mg	O
/	O
m2	O
/	O
d	O
delivers	O
a	O
total	O
dose	O
of	O
7	O
g	O
/	O
m2	O
per	O
cycle	O
,	O
which	O
is	O
comparable	O
to	O
that	O
delivered	O
in	O
clinical	O
practice	O
for	O
bolus	O
or	O
short	O
-	O
term	O
infusion	O
.	O

Because	O
few	O
patients	O
received	O
multiple	O
courses	O
over	O
time	O
,	O
the	O
cumulative	O
effects	O
are	O
indeterminate	O
in	O
the	O
present	O
trial	O
.	O

The	O
frequency	O
and	O
predictability	O
of	O
hematuria	B-Disease
are	O
not	O
precise	O
,	O
and	O
at	O
least	O
daily	O
monitoring	O
by	O
urine	O
Hematest	O
is	O
essential	O
,	O
adding	O
Mesna	B-Chemical
to	O
the	O
infusate	O
in	O
patients	O
with	O
persistent	O
hematuria	B-Disease
.	O

The	O
protracted	O
infusion	O
schedule	O
for	O
ifosfamide	B-Chemical
permits	O
convenient	O
outpatient	O
administration	O
without	O
Mesna	B-Chemical
and	O
reduces	O
the	O
drug	O
cost	O
of	O
clinical	O
usage	O
of	O
this	O
agent	O
by	O
up	O
to	O
890	O
per	O
cycle	O
.	O

Clinical	O
activity	O
was	O
demonstrated	O
in	O
a	O
single	O
patient	O
,	O
but	O
a	O
comparative	O
trial	O
of	O
standard	O
bolus	O
schedules	O
with	O
the	O
protracted	O
infusion	O
schedule	O
will	O
be	O
necessary	O
to	O
determine	O
if	O
the	O
clinical	O
effectiveness	O
of	O
the	O
drug	O
is	O
maintained	O
.	O

A	O
case	O
of	O
ventricular	B-Disease
tachycardia	I-Disease
related	O
to	O
caffeine	B-Chemical
pretreatment	O
.	O

Suboptimal	O
seizure	B-Disease
duration	O
is	O
commonly	O
encountered	O
in	O
electroconvulsive	O
therapy	O
practice	O
,	O
especially	O
in	O
older	O
patients	O
with	O
higher	O
seizure	B-Disease
thresholds	O
.	O

Intravenous	O
caffeine	B-Chemical
is	O
commonly	O
used	O
to	O
improve	O
seizure	B-Disease
duration	O
and	O
quality	O
in	O
such	O
patients	O
and	O
is	O
generally	O
well	O
tolerated	O
aside	O
from	O
occasional	O
reports	O
of	O
relatively	O
benign	O
ventricular	B-Disease
ectopy	I-Disease
.	O

We	O
describe	O
a	O
patient	O
with	O
no	O
previous	O
history	O
of	O
cardiac	B-Disease
disease	I-Disease
or	O
arrhythmia	B-Disease
who	O
developed	O
sustained	O
bigeminy	O
and	O
2	O
brief	O
runs	O
of	O
ventricular	B-Disease
tachycardia	I-Disease
after	O
caffeine	B-Chemical
administration	O
.	O

Although	O
intravenous	O
caffeine	B-Chemical
is	O
generally	O
well	O
tolerated	O
,	O
the	O
clinician	O
should	O
be	O
aware	O
of	O
the	O
potential	O
for	O
unpredictable	O
and	O
serious	O
ventricular	B-Disease
arrhythmias	I-Disease
.	O

Fatal	O
haemopericardium	B-Disease
and	O
gastrointestinal	B-Disease
haemorrhage	I-Disease
due	O
to	O
possible	O
interaction	O
of	O
cranberry	O
juice	O
with	O
warfarin	B-Chemical
.	O

We	O
report	O
a	O
case	O
of	O
fatal	O
internal	O
haemorrhage	B-Disease
in	O
an	O
elderly	O
man	O
who	O
consumed	O
only	O
cranberry	O
juice	O
for	O
two	O
weeks	O
while	O
maintaining	O
his	O
usual	O
dosage	O
of	O
warfarin	B-Chemical
.	O

We	O
propose	O
that	O
naturally	O
occurring	O
compounds	O
such	O
as	O
flavonoids	B-Chemical
,	O
which	O
are	O
present	O
in	O
fruit	O
juices	O
,	O
may	O
increase	O
the	O
potency	O
of	O
warfarin	B-Chemical
by	O
competing	O
for	O
the	O
enzymes	O
that	O
normally	O
inactivate	O
warfarin	B-Chemical
.	O

While	O
traditionally	O
regarded	O
as	O
foodstuffs	O
,	O
consumption	O
of	O
fruit	O
juices	O
should	O
be	O
considered	O
when	O
patients	O
develop	O
adverse	O
drug	O
reactions	O
.	O

Effect	O
of	O
increasing	O
intraperitoneal	O
infusion	O
rates	O
on	O
bupropion	B-Chemical
hydrochloride	I-Chemical
-	O
induced	O
seizures	B-Disease
in	O
mice	O
.	O

BACKGROUND	O
:	O
It	O
is	O
not	O
known	O
if	O
there	O
is	O
a	O
relationship	O
between	O
input	O
rate	O
and	O
incidence	O
of	O
bupropion	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

This	O
is	O
important	O
,	O
since	O
different	O
controlled	O
release	O
formulations	O
of	O
bupropion	B-Chemical
release	O
the	O
active	O
drug	O
at	O
different	O
rates	O
.	O

METHODS	O
:	O
We	O
investigated	O
the	O
effect	O
of	O
varying	O
the	O
intraperitoneal	O
infusion	O
rates	O
of	O
bupropion	B-Chemical
HCl	I-Chemical
120	O
mg	O
/	O
kg	O
,	O
a	O
known	O
convulsive	B-Disease
dose	O
50	O
(	O
CD50	O
)	O
,	O
on	O
the	O
incidence	O
and	O
severity	O
of	O
bupropion	B-Chemical
-	O
induced	O
convulsions	B-Disease
in	O
the	O
Swiss	O
albino	O
mice	O
.	O

A	O
total	O
of	O
69	O
mice	O
,	O
approximately	O
7	O
weeks	O
of	O
age	O
,	O
and	O
weighing	O
21	O
.	O
0	O
to	O
29	O
.	O
1	O
g	O
were	O
randomly	O
assigned	O
to	O
bupropion	B-Chemical
HCl	I-Chemical
120	O
mg	O
/	O
kg	O
treatment	O
by	O
intraperitoneal	O
(	O
IP	O
)	O
administration	O
in	O
7	O
groups	O
(	O
9	O
to	O
10	O
animals	O
per	O
group	O
)	O
.	O

Bupropion	B-Chemical
HCl	I-Chemical
was	O
infused	O
through	O
a	O
surgically	O
implanted	O
IP	O
dosing	O
catheter	O
with	O
infusions	O
in	O
each	O
group	O
of	O
0	O
min	O
,	O
15	O
min	O
,	O
30	O
min	O
,	O
60	O
min	O
,	O
90	O
min	O
,	O
120	O
min	O
,	O
and	O
240	O
min	O
.	O

The	O
number	O
,	O
time	O
of	O
onset	O
,	O
duration	O
and	O
the	O
intensity	O
of	O
the	O
convulsions	B-Disease
or	O
absence	O
of	O
convulsions	B-Disease
were	O
recorded	O
.	O

RESULTS	O
:	O
The	O
results	O
showed	O
that	O
IP	O
administration	O
of	O
bupropion	B-Chemical
HCl	I-Chemical
120	O
mg	O
/	O
kg	O
by	O
bolus	O
injection	O
induced	O
convulsions	B-Disease
in	O
6	O
out	O
of	O
10	O
mice	O
(	O
60	O
%	O
of	O
convulsing	O
mice	O
)	O
in	O
group	O
1	O
.	O

Logistic	O
regression	O
analysis	O
revealed	O
that	O
infusion	O
time	O
was	O
significant	O
(	O
p	O
=	O
0	O
.	O
0004	O
;	O
odds	O
ratio	O
=	O
0	O
.	O
974	O
)	O
and	O
increasing	O
the	O
IP	O
infusion	O
time	O
of	O
bupropion	B-Chemical
HCl	I-Chemical
120	O
mg	O
/	O
kg	O
was	O
associated	O
with	O
a	O
91	O
%	O
reduced	O
odds	O
of	O
convulsions	B-Disease
at	O
infusion	O
times	O
of	O
15	O
to	O
90	O
min	O
compared	O
to	O
bolus	O
injection	O
.	O

Further	O
increase	O
in	O
infusion	O
time	O
resulted	O
in	O
further	O
reduction	O
in	O
the	O
odds	O
of	O
convulsions	B-Disease
to	O
99	O
.	O
8	O
%	O
reduction	O
at	O
240	O
min	O
.	O

CONCLUSION	O
:	O
In	O
conclusion	O
,	O
the	O
demonstration	O
of	O
an	O
inverse	O
relationship	O
between	O
infusion	O
time	O
of	O
a	O
fixed	O
and	O
convulsive	B-Disease
dose	O
of	O
bupropion	B-Chemical
and	O
the	O
risk	O
of	O
convulsions	B-Disease
in	O
a	O
prospective	O
study	O
is	O
novel	O
.	O

Graft	B-Disease
-	I-Disease
versus	I-Disease
-	I-Disease
host	I-Disease
disease	I-Disease
prophylaxis	O
with	O
everolimus	B-Chemical
and	O
tacrolimus	B-Chemical
is	O
associated	O
with	O
a	O
high	O
incidence	O
of	O
sinusoidal	B-Disease
obstruction	I-Disease
syndrome	I-Disease
and	O
microangiopathy	B-Disease
:	O
results	O
of	O
the	O
EVTAC	O
trial	O
.	O

A	O
calcineurin	O
inhibitor	O
combined	O
with	O
methotrexate	B-Chemical
is	O
the	O
standard	O
prophylaxis	O
for	O
graft	B-Disease
-	I-Disease
versus	I-Disease
-	I-Disease
host	I-Disease
disease	I-Disease
(	O
GVHD	B-Disease
)	O
after	O
allogeneic	O
hematopoietic	O
stem	O
cell	O
transplantation	O
(	O
HSCT	O
)	O
.	O

Everolimus	B-Chemical
,	O
a	O
derivative	O
of	O
sirolimus	B-Chemical
,	O
seems	O
to	O
mediate	O
antileukemia	O
effects	O
.	O

We	O
report	O
on	O
a	O
combination	O
of	O
everolimus	B-Chemical
and	O
tacrolimus	B-Chemical
in	O
24	O
patients	O
(	O
median	O
age	O
,	O
62	O
years	O
)	O
with	O
either	O
myelodysplastic	B-Disease
syndrome	I-Disease
(	O
MDS	B-Disease
;	O
n	O
=	O
17	O
)	O
or	O
acute	B-Disease
myeloid	I-Disease
leukemia	I-Disease
(	O
AML	B-Disease
;	O
n	O
=	O
7	O
)	O
undergoing	O
intensive	O
conditioning	O
followed	O
by	O
HSCT	O
from	O
related	O
(	O
n	O
=	O
4	O
)	O
or	O
unrelated	O
(	O
n	O
=	O
20	O
)	O
donors	O
.	O

All	O
patients	O
engrafted	O
,	O
and	O
only	O
1	O
patient	O
experienced	O
grade	O
IV	O
mucositis	B-Disease
.	O

Nine	O
patients	O
(	O
37	O
%	O
)	O
developed	O
acute	O
grade	O
II	O
-	O
IV	O
GVHD	B-Disease
,	O
and	O
11	O
of	O
17	O
evaluable	O
patients	O
(	O
64	O
%	O
)	O
developed	O
chronic	O
extensive	O
GVHD	B-Disease
.	O

Transplantation	B-Disease
-	I-Disease
associated	I-Disease
microangiopathy	I-Disease
(	O
TMA	B-Disease
)	O
occurred	O
in	O
7	O
patients	O
(	O
29	O
%	O
)	O
,	O
with	O
2	O
cases	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

The	O
study	O
was	O
terminated	O
prematurely	O
because	O
an	O
additional	O
6	O
patients	O
(	O
25	O
%	O
)	O
developed	O
sinusoidal	B-Disease
obstruction	I-Disease
syndrome	I-Disease
(	O
SOS	B-Disease
)	O
,	O
which	O
was	O
fatal	O
in	O
2	O
cases	O
.	O

With	O
a	O
median	O
follow	O
-	O
up	O
of	O
26	O
months	O
,	O
the	O
2	O
-	O
year	O
overall	O
survival	O
rate	O
was	O
47	O
%	O
.	O

Although	O
this	O
new	O
combination	O
appears	O
to	O
be	O
effective	O
as	O
a	O
prophylactic	O
regimen	O
for	O
acute	O
GVHD	B-Disease
,	O
the	O
incidence	O
of	O
TMA	B-Disease
and	O
SOS	B-Disease
is	O
considerably	O
higher	O
than	O
seen	O
with	O
other	O
regimens	O
.	O

Longitudinal	O
assessment	O
of	O
air	O
conduction	O
audiograms	O
in	O
a	O
phase	O
III	O
clinical	O
trial	O
of	O
difluoromethylornithine	B-Chemical
and	O
sulindac	B-Chemical
for	O
prevention	O
of	O
sporadic	O
colorectal	B-Disease
adenomas	I-Disease
.	O

A	O
phase	O
III	O
clinical	O
trial	O
assessed	O
the	O
recurrence	O
of	O
adenomatous	B-Disease
polyps	I-Disease
after	O
treatment	O
for	O
36	O
months	O
with	O
difluoromethylornithine	B-Chemical
(	O
DFMO	B-Chemical
)	O
plus	O
sulindac	B-Chemical
or	O
matched	O
placebos	O
.	O

Temporary	O
hearing	B-Disease
loss	I-Disease
is	O
a	O
known	O
toxicity	B-Disease
of	O
treatment	O
with	O
DFMO	B-Chemical
,	O
thus	O
a	O
comprehensive	O
approach	O
was	O
developed	O
to	O
analyze	O
serial	O
air	O
conduction	O
audiograms	O
.	O

The	O
generalized	O
estimating	O
equation	O
method	O
estimated	O
the	O
mean	O
difference	O
between	O
treatment	O
arms	O
with	O
regard	O
to	O
change	O
in	O
air	O
conduction	O
pure	O
tone	O
thresholds	O
while	O
accounting	O
for	O
within	O
-	O
subject	O
correlation	O
due	O
to	O
repeated	O
measurements	O
at	O
frequencies	O
.	O

Based	O
on	O
290	O
subjects	O
,	O
there	O
was	O
an	O
average	O
difference	O
of	O
0	O
.	O
50	O
dB	O
between	O
subjects	O
treated	O
with	O
DFMO	B-Chemical
plus	O
sulindac	B-Chemical
compared	O
with	O
those	O
treated	O
with	O
placebo	O
(	O
95	O
%	O
confidence	O
interval	O
,	O
-	O
0	O
.	O
64	O
to	O
1	O
.	O
63	O
dB	O
;	O
P	O
=	O
0	O
.	O
39	O
)	O
,	O
adjusted	O
for	O
baseline	O
values	O
,	O
age	O
,	O
and	O
frequencies	O
.	O

In	O
the	O
normal	O
speech	O
range	O
of	O
500	O
to	O
3	O
,	O
000	O
Hz	O
,	O
an	O
estimated	O
difference	O
of	O
0	O
.	O
99	O
dB	O
(	O
-	O
0	O
.	O
17	O
to	O
2	O
.	O
14	O
dB	O
;	O
P	O
=	O
0	O
.	O
09	O
)	O
was	O
detected	O
.	O

Dose	O
intensity	O
did	O
not	O
add	O
information	O
to	O
models	O
.	O

There	O
were	O
14	O
of	O
151	O
(	O
9	O
.	O
3	O
%	O
)	O
in	O
the	O
DFMO	B-Chemical
plus	O
sulindac	B-Chemical
group	O
and	O
4	O
of	O
139	O
(	O
2	O
.	O
9	O
%	O
)	O
in	O
the	O
placebo	O
group	O
who	O
experienced	O
at	O
least	O
15	O
dB	O
hearing	O
reduction	O
from	O
baseline	O
in	O
2	O
or	O
more	O
consecutive	O
frequencies	O
across	O
the	O
entire	O
range	O
tested	O
(	O
P	O
=	O
0	O
.	O
02	O
)	O
.	O

Follow	O
-	O
up	O
air	O
conduction	O
done	O
at	O
least	O
6	O
months	O
after	O
end	O
of	O
treatment	O
showed	O
an	O
adjusted	O
mean	O
difference	O
in	O
hearing	O
thresholds	O
of	O
1	O
.	O
08	O
dB	O
(	O
-	O
0	O
.	O
81	O
to	O
2	O
.	O
96	O
dB	O
;	O
P	O
=	O
0	O
.	O
26	O
)	O
between	O
treatment	O
arms	O
.	O

There	O
was	O
no	O
significant	O
difference	O
in	O
the	O
proportion	O
of	O
subjects	O
in	O
the	O
DFMO	B-Chemical
plus	O
sulindac	B-Chemical
group	O
who	O
experienced	O
clinically	O
significant	O
hearing	B-Disease
loss	I-Disease
compared	O
with	O
the	O
placebo	O
group	O
.	O

The	O
estimated	O
attributable	O
risk	O
of	O
ototoxicity	B-Disease
from	O
exposure	O
to	O
the	O
drug	O
is	O
8	O
.	O
4	O
%	O
(	O
95	O
%	O
confidence	O
interval	O
,	O
-	O
2	O
.	O
0	O
%	O
to	O
18	O
.	O
8	O
%	O
;	O
P	O
=	O
0	O
.	O
12	O
)	O
.	O

There	O
is	O
a	O
<	O
2	O
dB	O
difference	O
in	O
mean	O
threshold	O
for	O
patients	O
treated	O
with	O
DFMO	B-Chemical
plus	O
sulindac	B-Chemical
compared	O
with	O
those	O
treated	O
with	O
placebo	O
.	O

Proteinase	O
3	O
-	O
antineutrophil	O
cytoplasmic	O
antibody	O
-	O
(	O
PR3	O
-	O
ANCA	O
)	O
positive	O
necrotizing	O
glomerulonephritis	B-Disease
after	O
restarting	O
sulphasalazine	B-Chemical
treatment	O
.	O

A	O
59	O
-	O
year	O
-	O
old	O
woman	O
with	O
ulcerative	B-Disease
colitis	I-Disease
developed	O
red	B-Disease
eyes	I-Disease
,	O
pleural	B-Disease
effusion	I-Disease
,	O
eosinophilia	B-Disease
and	O
urinary	B-Disease
abnormalities	I-Disease
after	O
restarting	O
of	O
sulphasalazine	B-Chemical
treatment	O
.	O

Light	O
microscopy	O
of	O
a	O
kidney	O
biopsy	O
revealed	O
segmental	B-Disease
necrotizing	I-Disease
glomerulonephritis	I-Disease
without	O
deposition	O
of	O
immunoglobulin	O
or	O
complement	O
.	O

Proteinase	O
3	O
-	O
antineutrophil	O
cytoplasmic	O
antibody	O
(	O
PR3	O
-	O
ANCA	O
)	O
titer	O
was	O
elevated	O
at	O
183	O
ELISA	O
units	O
(	O
EU	O
)	O
in	O
sera	O
(	O
normal	O
range	O
less	O
than	O
10	O
EU	O
)	O
,	O
myeloperoxidase	O
-	O
ANCA	O
was	O
negative	O
.	O

PR3	O
-	O
ANCA	O
titer	O
was	O
250	O
and	O
1	O
,	O
070	O
EU	O
in	O
pleural	B-Disease
effusions	I-Disease
on	O
right	O
and	O
left	O
side	O
,	O
respectively	O
.	O

Although	O
cessation	O
of	O
sulphasalazine	B-Chemical
treatment	O
resulted	O
in	O
improvements	O
in	O
fever	B-Disease
,	O
red	B-Disease
eyes	I-Disease
,	O
chest	B-Disease
pain	I-Disease
,	O
titer	O
of	O
C	O
-	O
reactive	O
protein	O
and	O
volume	O
of	O
the	O
pleural	B-Disease
effusions	I-Disease
,	O
we	O
initiated	O
steroid	B-Chemical
therapy	O
,	O
because	O
PR3	O
-	O
ANCA	O
titer	O
rose	O
to	O
320	O
EU	O
,	O
eosinophil	O
count	O
increased	O
to	O
1	O
,	O
100	O
cells	O
/	O
microl	O
,	O
and	O
the	O
pleural	B-Disease
effusion	I-Disease
remained	O
.	O

One	O
month	O
after	O
steroid	B-Chemical
therapy	O
,	O
the	O
pleural	B-Disease
effusion	I-Disease
disappeared	O
,	O
and	O
PR3	O
-	O
ANCA	O
titer	O
normalized	O
3	O
months	O
later	O
.	O

This	O
case	O
suggests	O
that	O
sulphasalazine	B-Chemical
can	O
induce	O
PR3	O
-	O
ANCA	O
-	O
positive	O
necrotizing	O
glomerulonephritis	B-Disease
.	O

Comparison	O
of	O
unilateral	O
pallidotomy	O
and	O
subthalamotomy	O
findings	O
in	O
advanced	O
idiopathic	B-Disease
Parkinson	I-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

A	O
prospective	O
,	O
randomized	O
,	O
double	O
-	O
blind	O
pilot	O
study	O
to	O
compare	O
the	O
results	O
of	O
stereotactic	O
unilateral	O
pallidotomy	O
and	O
subthalamotomy	O
in	O
advanced	O
idiopathic	B-Disease
Parkinson	I-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
refractory	O
to	O
medical	O
treatment	O
was	O
designed	O
.	O

Ten	O
consecutive	O
patients	O
(	O
mean	O
age	O
,	O
58	O
.	O
4	O
+	O
/	O
-	O
6	O
.	O
8	O
years	O
;	O
7	O
men	O
,	O
3	O
women	O
)	O
with	O
similar	O
characteristics	O
at	O
the	O
duration	O
of	O
disease	O
(	O
mean	O
disease	O
time	O
,	O
8	O
.	O
4	O
+	O
/	O
-	O
3	O
.	O
5	O
years	O
)	O
,	O
disabling	O
motor	O
fluctuations	O
(	O
Hoehn	O
_	O
Yahr	O
stage	O
3	O
-	O
5	O
in	O
off	O
-	O
drug	O
phases	O
)	O
and	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
were	O
selected	O
.	O

All	O
patients	O
had	O
bilateral	O
symptoms	O
and	O
their	O
levodopa	B-Chemical
equivalent	O
dosing	O
were	O
analysed	O
.	O

Six	O
patients	O
were	O
operated	O
on	O
in	O
the	O
globus	O
pallidus	O
interna	O
(	O
GPi	O
)	O
and	O
four	O
in	O
the	O
subthalamic	O
nucleus	O
(	O
STN	O
)	O
.	O

Clinical	O
evaluation	O
included	O
the	O
use	O
of	O
the	O
Unified	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
Disease	I-Disease
Rating	O
Scale	O
(	O
UPDRS	O
)	O
,	O
Hoehn	O
_	O
Yahr	O
score	O
and	O
Schwab	O
England	O
activities	O
of	O
daily	O
living	O
(	O
ADL	O
)	O
score	O
in	O
'	O
on	O
'	O
-	O
and	O
'	O
off	O
'	O
-	O
drug	O
conditions	O
before	O
surgery	O
and	O
6	O
months	O
after	O
surgery	O
.	O

There	O
was	O
statistically	O
significant	O
improvement	O
in	O
all	O
contralateral	O
major	O
parkinsonian	B-Disease
motor	O
signs	O
in	O
all	O
patients	O
followed	O
for	O
6	O
months	O
.	O

Levodopa	B-Chemical
equivalent	O
daily	O
intake	O
was	O
significantly	O
reduced	O
in	O
the	O
STN	O
group	O
.	O

Changes	O
in	O
UPDRS	O
,	O
Hoehn	O
_	O
Yahr	O
and	O
Schwab	O
England	O
ADL	O
scores	O
were	O
similar	O
in	O
both	O
groups	O
.	O

Cognitive	O
functions	O
were	O
unchanged	O
in	O
both	O
groups	O
.	O

Complications	O
were	O
observed	O
in	O
two	O
patients	O
:	O
one	O
had	O
a	O
left	O
homonymous	B-Disease
hemianopsia	I-Disease
after	O
pallidotomy	O
and	O
another	O
one	O
developed	O
left	O
hemiballistic	O
movements	O
3	O
days	O
after	O
subthalamotomy	O
which	O
partly	O
improved	O
within	O
1	O
month	O
with	O
Valproate	B-Chemical
1000	O
mg	O
/	O
day	O
.	O

The	O
findings	O
of	O
this	O
study	O
suggest	O
that	O
lesions	O
of	O
the	O
unilateral	O
STN	O
and	O
GPi	O
are	O
equally	O
effective	O
treatment	O
for	O
patients	O
with	O
advanced	O
PD	B-Disease
refractory	O
to	O
medical	O
treatment	O
.	O

DSMM	O
XI	O
study	O
:	O
dose	O
definition	O
for	O
intravenous	O
cyclophosphamide	B-Chemical
in	O
combination	O
with	O
bortezomib	B-Chemical
/	O
dexamethasone	B-Chemical
for	O
remission	O
induction	O
in	O
patients	O
with	O
newly	O
diagnosed	O
myeloma	B-Disease
.	O

A	O
clinical	O
trial	O
was	O
initiated	O
to	O
evaluate	O
the	O
recommended	O
dose	O
of	O
cyclophosphamide	B-Chemical
in	O
combination	O
with	O
bortezomib	B-Chemical
and	O
dexamethasone	B-Chemical
as	O
induction	O
treatment	O
before	O
stem	O
cell	O
transplantation	O
for	O
younger	O
patients	O
with	O
newly	O
diagnosed	O
multiple	B-Disease
myeloma	I-Disease
(	O
MM	B-Disease
)	O
.	O

Thirty	O
patients	O
were	O
treated	O
with	O
three	O
21	O
-	O
day	O
cycles	O
of	O
bortezomib	B-Chemical
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
plus	O
dexamethasone	B-Chemical
40	O
mg	O
on	O
the	O
day	O
of	O
bortezomib	B-Chemical
injection	O
and	O
the	O
day	O
after	O
plus	O
cyclophosphamide	B-Chemical
at	O
900	O
,	O
1	O
,	O
200	O
,	O
or	O
1	O
,	O
500	O
mg	O
/	O
m	O
(	O
2	O
)	O
on	O
day	O
1	O
.	O

The	O
maximum	O
tolerated	O
dose	O
of	O
cyclophosphamide	B-Chemical
was	O
defined	O
as	O
900	O
mg	O
/	O
m	O
(	O
2	O
)	O
.	O

At	O
this	O
dose	O
level	O
,	O
92	O
%	O
of	O
patients	O
achieved	O
at	O
least	O
a	O
partial	O
response	O
.	O

The	O
overall	O
response	O
rate	O
[	O
complete	O
response	O
(	O
CR	O
)	O
plus	O
partial	O
response	O
(	O
PR	O
)	O
]	O
across	O
all	O
dose	O
levels	O
was	O
77	O
%	O
,	O
with	O
a	O
10	O
%	O
CR	O
rate	O
.	O

No	O
patient	O
experienced	O
progressive	O
disease	O
.	O

The	O
most	O
frequent	O
adverse	O
events	O
were	O
hematological	B-Disease
and	I-Disease
gastrointestinal	I-Disease
toxicities	I-Disease
as	O
well	O
as	O
neuropathy	B-Disease
.	O

The	O
results	O
suggest	O
that	O
bortezomib	B-Chemical
in	O
combination	O
with	O
cyclophosphamide	B-Chemical
at	O
900	O
mg	O
/	O
m	O
(	O
2	O
)	O
and	O
dexamethasone	B-Chemical
is	O
an	O
effective	O
induction	O
treatment	O
for	O
patients	O
with	O
newly	O
diagnosed	O
MM	B-Disease
that	O
warrants	O
further	O
investigation	O
.	O

Naloxone	B-Chemical
reversal	O
of	O
hypotension	B-Disease
due	O
to	O
captopril	B-Chemical
overdose	B-Disease
.	O

The	O
hemodynamic	O
effects	O
of	O
captopril	B-Chemical
and	O
other	O
angiotensin	B-Chemical
-	I-Chemical
converting	I-Chemical
enzyme	I-Chemical
inhibitors	I-Chemical
may	O
be	O
mediated	O
by	O
the	O
endogenous	O
opioid	O
system	O
.	O

The	O
opioid	O
antagonist	O
naloxone	B-Chemical
has	O
been	O
shown	O
to	O
block	O
or	O
reverse	O
the	O
hypotensive	B-Disease
actions	O
of	O
captopril	B-Chemical
.	O

We	O
report	O
a	O
case	O
of	O
an	O
intentional	O
captopril	B-Chemical
overdose	B-Disease
,	O
manifested	O
by	O
marked	O
hypotension	B-Disease
,	O
that	O
resolved	O
promptly	O
with	O
the	O
administration	O
of	O
naloxone	B-Chemical
.	O

To	O
our	O
knowledge	O
,	O
this	O
is	O
the	O
first	O
reported	O
case	O
of	O
captopril	B-Chemical
-	O
induced	O
hypotension	B-Disease
treated	O
with	O
naloxone	B-Chemical
.	O

Our	O
experience	O
demonstrates	O
a	O
possible	O
role	O
of	O
naloxone	B-Chemical
in	O
the	O
reversal	O
of	O
hypotension	B-Disease
resulting	O
from	O
captopril	B-Chemical
.	O

Identification	O
of	O
a	O
simple	O
and	O
sensitive	O
microplate	O
method	O
for	O
the	O
detection	O
of	O
oversulfated	O
chondroitin	B-Chemical
sulfate	I-Chemical
in	O
heparin	B-Chemical
products	O
.	O

Heparin	B-Chemical
is	O
a	O
commonly	O
implemented	O
anticoagulant	O
used	O
to	O
treat	O
critically	O
ill	O
patients	O
.	O

Recently	O
,	O
a	O
number	O
of	O
commercial	O
lots	O
of	O
heparin	B-Chemical
products	O
were	O
found	O
to	O
be	O
contaminated	O
with	O
an	O
oversulfated	O
chondroitin	B-Chemical
sulfate	I-Chemical
(	O
OSCS	O
)	O
derivative	O
that	O
could	O
elicit	O
a	O
hypotensive	B-Disease
response	O
in	O
pigs	O
following	O
a	O
single	O
high	O
-	O
dose	O
infusion	O
.	O

Using	O
both	O
contaminated	O
heparin	B-Chemical
products	O
and	O
the	O
synthetically	O
produced	O
derivative	O
,	O
we	O
showed	O
that	O
the	O
OSCS	O
produces	O
dose	O
-	O
dependent	O
hypotension	B-Disease
in	O
pigs	O
.	O

The	O
no	O
observed	O
effect	O
level	O
(	O
NOEL	O
)	O
for	O
this	O
contaminant	O
appears	O
to	O
be	O
approximately	O
1mg	O
/	O
kg	O
,	O
corresponding	O
to	O
a	O
contamination	O
level	O
of	O
approximately	O
3	O
%	O
.	O

We	O
also	O
demonstrated	O
that	O
OSCS	O
can	O
be	O
identified	O
in	O
heparin	B-Chemical
products	O
using	O
a	O
simple	O
,	O
inexpensive	O
,	O
commercially	O
available	O
heparin	B-Chemical
enzyme	O
immunoassay	O
(	O
EIA	O
)	O
kit	O
that	O
has	O
a	O
limit	O
of	O
detection	O
of	O
approximately	O
0	O
.	O
1	O
%	O
,	O
well	O
below	O
the	O
NOEL	O
.	O

This	O
kit	O
may	O
provide	O
a	O
useful	O
method	O
to	O
test	O
heparin	B-Chemical
products	O
for	O
contamination	O
with	O
oversulfated	O
GAG	O
derivatives	O
.	O

5	B-Chemical
flourouracil	I-Chemical
-	O
induced	O
apical	B-Disease
ballooning	I-Disease
syndrome	I-Disease
:	O
a	O
case	O
report	O
.	O

The	O
apical	B-Disease
ballooning	I-Disease
syndrome	I-Disease
(	O
ABS	B-Disease
)	O
is	O
a	O
recently	O
described	O
stress	O
-	O
mediated	O
acute	B-Disease
cardiac	I-Disease
syndrome	I-Disease
characterized	O
by	O
transient	O
wall	O
-	O
motion	O
abnormalities	O
involving	O
the	O
apex	O
and	O
midventricle	O
with	O
hyperkinesis	B-Disease
of	O
the	O
basal	O
left	O
ventricular	O
(	O
LV	O
)	O
segments	O
without	O
obstructive	O
epicardial	B-Disease
coronary	I-Disease
disease	I-Disease
.	O

Cardiotoxicity	B-Disease
is	O
not	O
an	O
uncommon	O
adverse	O
effect	O
of	O
chemotherapeutic	O
agents	O
.	O

However	O
,	O
there	O
are	O
no	O
reports	O
of	O
ABS	B-Disease
secondary	O
to	O
chemotherapeutic	O
agents	O
.	O

We	O
describe	O
the	O
case	O
of	O
a	O
woman	O
who	O
developed	O
the	O
syndrome	O
after	O
chemotherapy	O
for	O
metastatic	O
cancer	B-Disease
.	O

A	O
79	O
-	O
year	O
-	O
old	O
woman	O
presented	O
with	O
typical	O
ischemic	B-Disease
chest	B-Disease
pain	I-Disease
,	O
elevated	O
cardiac	O
enzymes	O
with	O
significant	O
ST	O
-	O
segment	O
abnormalities	O
on	O
her	O
electrocardiogram	O
.	O

She	O
underwent	O
recent	O
chemotherapy	O
with	O
fluorouracil	B-Chemical
for	O
metastatic	O
colorectal	B-Disease
cancer	I-Disease
.	O

Echocardiography	O
revealed	O
a	O
wall	O
-	O
motion	O
abnormality	O
involving	O
the	O
apical	O
and	O
periapical	O
segments	O
which	O
appeared	O
akinetic	B-Disease
.	O

Coronary	O
angiography	O
revealed	O
no	O
obstructive	O
coronary	O
lesions	O
.	O

The	O
patient	O
was	O
stabilized	O
with	O
medical	O
therapy	O
.	O

Four	O
weeks	O
later	O
she	O
remained	O
completely	O
asymptomatic	O
.	O

Echocardiogram	O
revealed	O
a	O
normal	O
ejection	O
fraction	O
and	O
a	O
resolution	O
of	O
the	O
apical	O
akinesis	B-Disease
.	O

Pathogenetic	O
mechanisms	O
of	O
cardiac	B-Disease
complications	I-Disease
in	O
cancer	B-Disease
patients	O
undergoing	O
chemotherapy	O
include	O
coronary	B-Disease
vasospasm	I-Disease
,	O
endothelial	O
damage	O
and	O
consequent	O
thrombus	B-Disease
formation	O
.	O

In	O
our	O
patient	O
,	O
both	O
supraphysiologic	O
levels	O
of	O
plasma	O
catecholamines	B-Chemical
and	O
stress	O
related	O
neuropeptides	O
caused	O
by	O
cancer	B-Disease
diagnosis	O
as	O
well	O
as	O
chemotherapy	O
may	O
have	O
contributed	O
the	O
development	O
of	O
ABS	B-Disease
.	O

Rapid	O
reversal	O
of	O
anticoagulation	O
reduces	O
hemorrhage	B-Disease
volume	O
in	O
a	O
mouse	O
model	O
of	O
warfarin	B-Chemical
-	O
associated	O
intracerebral	B-Disease
hemorrhage	I-Disease
.	O

Warfarin	B-Chemical
-	O
associated	O
intracerebral	B-Disease
hemorrhage	I-Disease
(	O
W	O
-	O
ICH	B-Disease
)	O
is	O
a	O
severe	O
type	O
of	O
stroke	B-Disease
.	O

There	O
is	O
no	O
consensus	O
on	O
the	O
optimal	O
treatment	O
for	O
W	O
-	O
ICH	B-Disease
.	O

Using	O
a	O
mouse	O
model	O
,	O
we	O
tested	O
whether	O
the	O
rapid	O
reversal	O
of	O
anticoagulation	O
using	O
human	O
prothrombin	B-Chemical
complex	I-Chemical
concentrate	I-Chemical
(	O
PCC	B-Chemical
)	O
can	O
reduce	O
hemorrhagic	O
blood	O
volume	O
.	O

Male	O
CD	O
-	O
1	O
mice	O
were	O
treated	O
with	O
warfarin	B-Chemical
(	O
2	O
mg	O
/	O
kg	O
over	O
24	O
h	O
)	O
,	O
resulting	O
in	O
a	O
mean	O
(	O
+	O
/	O
-	O
s	O
.	O
d	O
.	O
)	O
International	O
Normalized	O
Ratio	O
of	O
3	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
9	O
.	O

First	O
,	O
we	O
showed	O
that	O
an	O
intravenous	O
administration	O
of	O
human	O
PCC	B-Chemical
rapidly	O
reversed	O
anticoagulation	O
in	O
mice	O
.	O

Second	O
,	O
a	O
stereotactic	O
injection	O
of	O
collagenase	O
was	O
administered	O
to	O
induce	O
hemorrhage	B-Disease
in	O
the	O
right	O
striatum	O
.	O

Forty	O
-	O
five	O
minutes	O
later	O
,	O
the	O
animals	O
were	O
randomly	O
treated	O
with	O
PCC	B-Chemical
(	O
100	O
U	O
/	O
kg	O
)	O
or	O
saline	O
i	O
.	O
v	O
.	O
(	O
n	O
=	O
12	O
per	O
group	O
)	O
.	O

Twenty	O
-	O
four	O
hours	O
after	O
hemorrhage	B-Disease
induction	O
,	O
hemorrhagic	O
blood	O
volume	O
was	O
quantified	O
using	O
a	O
photometric	O
hemoglobin	O
assay	O
.	O

The	O
mean	O
hemorrhagic	O
blood	O
volume	O
was	O
reduced	O
in	O
PCC	B-Chemical
-	O
treated	O
animals	O
(	O
6	O
.	O
5	O
+	O
/	O
-	O
3	O
.	O
1	O
microL	O
)	O
compared	O
with	O
saline	O
controls	O
(	O
15	O
.	O
3	O
+	O
/	O
-	O
11	O
.	O
2	O
microL	O
,	O
P	O
=	O
0	O
.	O
015	O
)	O
.	O

In	O
the	O
saline	O
group	O
,	O
45	O
%	O
of	O
the	O
mice	O
developed	O
large	O
hematomas	B-Disease
(	O
i	O
.	O
e	O
.	O
,	O
>	O
15	O
microL	O
)	O
.	O

In	O
contrast	O
,	O
such	O
extensive	O
lesions	O
were	O
never	O
found	O
in	O
the	O
PCC	B-Chemical
group	O
.	O

We	O
provide	O
experimental	O
data	O
suggesting	O
PCC	B-Chemical
to	O
be	O
an	O
effective	O
acute	O
treatment	O
for	O
W	O
-	O
ICH	B-Disease
in	O
terms	O
of	O
reducing	O
hemorrhagic	O
blood	O
volume	O
.	O

Future	O
studies	O
are	O
needed	O
to	O
assess	O
the	O
therapeutic	O
potential	O
emerging	O
from	O
our	O
finding	O
for	O
human	O
W	O
-	O
ICH	B-Disease
.	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	O
symptoms	O
and	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
.	O

This	O
is	O
an	O
updated	O
version	O
of	O
the	O
original	O
Cochrane	O
review	O
first	O
published	O
in	O
2005	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
cardiovascular	O
outcomes	O
,	O
cancer	B-Disease
,	O
gallbladder	B-Disease
disease	I-Disease
,	O
cognition	O
,	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
to	O
November	O
2007	O
:	O
Trials	O
Register	O
of	O
the	O
Cochrane	O
Menstrual	B-Disease
Disorders	I-Disease
and	O
Subfertility	O
Group	O
,	O
Cochrane	O
Central	O
Register	O
of	O
Controlled	O
Trials	O
,	O
MEDLINE	O
,	O
EMBASE	O
,	O
Biological	O
Abstracts	O
.	O

Also	O
relevant	O
non	O
-	O
indexed	O
journals	O
and	O
conference	O
abstracts	O
.	O

SELECTION	O
CRITERIA	O
:	O
Randomised	O
double	O
-	O
blind	O
trials	O
of	O
HT	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

HT	O
included	O
oestrogens	B-Chemical
,	O
with	O
or	O
without	O
progestogens	B-Chemical
,	O
via	O
oral	O
,	O
transdermal	O
,	O
subcutaneous	O
or	O
transnasal	O
routes	O
.	O

DATA	O
COLLECTION	O
AND	O
ANALYSIS	O
:	O
Two	O
authors	O
independently	O
assessed	O
trial	O
quality	O
and	O
extracted	O
data	O
.	O

MAIN	O
RESULTS	O
:	O
Nineteen	O
trials	O
involving	O
41	O
,	O
904	O
women	O
were	O
included	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
thrombo	I-Disease
-	I-Disease
embolism	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
three	O
years	O
)	O
,	O
breast	B-Disease
cancer	I-Disease
and	O
gallbladder	B-Disease
disease	I-Disease
.	O

Long	O
-	O
term	O
oestrogen	B-Chemical
-	O
only	O
HT	O
significantly	O
increased	O
the	O
risk	O
of	O
venous	B-Disease
thrombo	I-Disease
-	I-Disease
embolism	I-Disease
,	O
stroke	B-Disease
and	O
gallbladder	B-Disease
disease	I-Disease
(	O
after	O
one	O
to	O
two	O
years	O
,	O
three	O
years	O
and	O
seven	O
years	O
'	O
use	O
respectively	O
)	O
,	O
but	O
did	O
not	O
significantly	O
increase	O
the	O
risk	O
of	O
breast	B-Disease
cancer	I-Disease
.	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
(	O
for	O
combined	O
HT	O
)	O
colon	B-Disease
cancer	I-Disease
,	O
with	O
long	O
-	O
term	O
use	O
.	O

Among	O
women	O
aged	O
over	O
65	O
who	O
were	O
relatively	O
healthy	O
(	O
i	O
.	O
e	O
.	O
generally	O
fit	O
,	O
without	O
overt	O
disease	O
)	O
and	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
thrombo	I-Disease
-	I-Disease
embolism	I-Disease
.	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
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
thrombo	I-Disease
-	I-Disease
embolism	I-Disease
in	O
women	O
taking	O
combined	O
continuous	O
HT	O
:	O
their	O
absolute	O
risk	O
remained	O
low	O
,	O
at	O
less	O
than	O
1	O
/	O
500	O
.	O

However	O
,	O
this	O
study	O
was	O
not	O
powered	O
to	O
detect	O
differences	O
between	O
groups	O
of	O
younger	O
women	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	O
disease	O
.	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

Acute	B-Disease
renal	I-Disease
failure	I-Disease
in	O
patients	O
with	O
AIDS	B-Disease
on	O
tenofovir	B-Chemical
while	O
receiving	O
prolonged	O
vancomycin	B-Chemical
course	O
for	O
osteomyelitis	B-Disease
.	O

Renal	B-Disease
failure	I-Disease
developed	O
after	O
a	O
prolonged	O
course	O
of	O
vancomycin	B-Chemical
therapy	O
in	O
2	O
patients	O
who	O
were	O
receiving	O
tenofovir	B-Chemical
disoproxil	I-Chemical
fumarate	I-Chemical
as	O
part	O
of	O
an	O
antiretroviral	O
regimen	O
.	O

Tenofovir	B-Chemical
has	O
been	O
implicated	O
in	O
the	O
development	O
of	O
Fanconi	B-Disease
syndrome	I-Disease
and	O
renal	B-Disease
insufficiency	I-Disease
because	O
of	O
its	O
effects	O
on	O
the	O
proximal	O
renal	O
tubule	O
.	O

Vancomycin	B-Chemical
nephrotoxicity	B-Disease
is	O
infrequent	O
but	O
may	O
result	O
from	O
coadministration	O
with	O
a	O
nephrotoxic	B-Disease
agent	O
.	O

Clinicians	O
should	O
be	O
aware	O
that	O
tenofovir	B-Chemical
may	O
raise	O
the	O
risk	O
of	O
renal	B-Disease
failure	I-Disease
during	O
prolonged	O
administration	O
of	O
vancomycin	B-Chemical
.	O

Recurrent	O
dysosmia	B-Disease
induced	O
by	O
pyrazinamide	B-Chemical
.	O

Pyrazinamide	B-Chemical
can	O
have	O
adverse	O
effects	O
such	O
as	O
hepatic	B-Disease
toxicity	I-Disease
,	O
hyperuricemia	B-Disease
or	O
digestive	O
disorders	O
.	O

In	O
rare	O
cases	O
,	O
alterations	O
in	O
taste	O
and	O
smell	O
function	O
have	O
been	O
reported	O
for	O
pyrazinamide	B-Chemical
when	O
combined	O
with	O
other	O
drugs	O
.	O

We	O
report	O
a	O
case	O
of	O
reversible	O
olfactory	B-Disease
disorder	I-Disease
related	O
to	O
pyrazinamide	B-Chemical
in	O
a	O
woman	O
,	O
with	O
a	O
positive	O
rechallenge	O
.	O

The	O
patient	O
presented	O
every	O
day	O
a	O
sensation	O
of	O
smelling	O
something	O
burning	O
15	O
min	O
after	O
drug	O
intake	O
.	O

Dysosmia	B-Disease
disappeared	O
completely	O
after	O
pyrazinamide	B-Chemical
withdrawal	O
and	O
recurred	O
after	O
its	O
rechallenge	O
.	O

The	O
case	O
was	O
reported	O
to	O
the	O
Tunisian	O
Centre	O
of	O
Pharmacovigilance	O
.	O

Mice	O
lacking	O
mPGES	O
-	O
1	O
are	O
resistant	O
to	O
lithium	B-Chemical
-	O
induced	O
polyuria	B-Disease
.	O

Cyclooxygenase	O
-	O
2	O
activity	O
is	O
required	O
for	O
the	O
development	O
of	O
lithium	B-Chemical
-	O
induced	O
polyuria	B-Disease
.	O

However	O
,	O
the	O
involvement	O
of	O
a	O
specific	O
,	O
terminal	O
prostaglandin	B-Chemical
(	O
PG	B-Chemical
)	O
isomerase	O
has	O
not	O
been	O
evaluated	O
.	O

The	O
present	O
study	O
was	O
undertaken	O
to	O
assess	O
lithium	B-Chemical
-	O
induced	O
polyuria	B-Disease
in	O
mice	O
deficient	O
in	O
microsomal	O
prostaglandin	B-Chemical
E	I-Chemical
synthase	O
-	O
1	O
(	O
mPGES	O
-	O
1	O
)	O
.	O

A	O
2	O
-	O
wk	O
administration	O
of	O
LiCl	B-Chemical
(	O
4	O
mmol	O
.	O
kg	O
(	O
-	O
1	O
)	O
.	O
day	O
(	O
-	O
1	O
)	O
ip	O
)	O
in	O
mPGES	O
-	O
1	O
+	O
/	O
+	O
mice	O
led	O
to	O
a	O
marked	O
polyuria	B-Disease
with	O
hyposmotic	O
urine	O
.	O

This	O
was	O
associated	O
with	O
elevated	O
renal	O
mPGES	O
-	O
1	O
protein	O
expression	O
and	O
increased	O
urine	O
PGE	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
excretion	O
.	O

In	O
contrast	O
,	O
mPGES	O
-	O
1	O
-	O
/	O
-	O
mice	O
were	O
largely	O
resistant	O
to	O
lithium	B-Chemical
-	O
induced	O
polyuria	B-Disease
and	O
a	O
urine	O
concentrating	O
defect	O
,	O
accompanied	O
by	O
nearly	O
complete	O
blockade	O
of	O
high	O
urine	O
PGE	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
and	O
cAMP	O
output	O
.	O

Immunoblotting	O
,	O
immunohistochemistry	O
,	O
and	O
quantitative	O
(	O
q	O
)	O
RT	O
-	O
PCR	O
consistently	O
detected	O
a	O
significant	O
decrease	O
in	O
aquaporin	O
-	O
2	O
(	O
AQP2	O
)	O
protein	O
expression	O
in	O
both	O
the	O
renal	O
cortex	O
and	O
medulla	O
of	O
lithium	B-Chemical
-	O
treated	O
+	O
/	O
+	O
mice	O
.	O

This	O
decrease	O
was	O
significantly	O
attenuated	O
in	O
the	O
-	O
/	O
-	O
mice	O
.	O

qRT	O
-	O
PCR	O
detected	O
similar	O
patterns	O
of	O
changes	O
in	O
AQP2	O
mRNA	O
in	O
the	O
medulla	O
but	O
not	O
in	O
the	O
cortex	O
.	O

Similarly	O
,	O
the	O
total	O
protein	O
abundance	O
of	O
the	O
Na	B-Chemical
-	O
K	B-Chemical
-	O
2Cl	B-Chemical
cotransporter	O
(	O
NKCC2	O
)	O
in	O
the	O
medulla	O
but	O
not	O
in	O
the	O
cortex	O
of	O
the	O
+	O
/	O
+	O
mice	O
was	O
significantly	O
reduced	O
by	O
lithium	B-Chemical
treatment	O
.	O

In	O
contrast	O
,	O
the	O
dowregulation	O
of	O
renal	O
medullary	O
NKCC2	O
expression	O
was	O
significantly	O
attenuated	O
in	O
the	O
-	O
/	O
-	O
mice	O
.	O

We	O
conclude	O
that	O
mPGES	O
-	O
1	O
-	O
derived	O
PGE	B-Chemical
(	I-Chemical
2	I-Chemical
)	I-Chemical
mediates	O
lithium	B-Chemical
-	O
induced	O
polyuria	B-Disease
likely	O
via	O
inhibition	O
of	O
AQP2	O
and	O
NKCC2	O
expression	O
.	O

Preservation	O
of	O
renal	O
blood	O
flow	O
during	O
hypotension	B-Disease
induced	O
with	O
fenoldopam	B-Chemical
in	O
dogs	O
.	O

The	O
introduction	O
of	O
drugs	O
that	O
could	O
induce	O
hypotension	B-Disease
with	O
different	O
pharmacological	O
actions	O
would	O
be	O
advantageous	O
because	O
side	O
effects	O
unique	O
to	O
a	O
specific	O
drug	O
could	O
be	O
minimized	O
by	O
selecting	O
appropriate	O
therapy	O
.	O

Specific	O
dopamine	B-Chemical
-	O
1	O
,	O
(	O
DA1	B-Chemical
)	O
and	O
dopamine	B-Chemical
-	O
2	O
(	O
DA2	B-Chemical
)	O
receptor	O
agonists	O
are	O
now	O
under	O
clinical	O
investigation	O
.	O

Fenoldopam	B-Chemical
mesylate	I-Chemical
is	O
a	O
specific	O
DA1	O
receptor	O
agonist	O
that	O
lowers	O
blood	O
pressure	O
by	O
vasodilatation	O
.	O

The	O
hypothesis	O
that	O
fenoldopam	B-Chemical
could	O
be	O
used	O
to	O
induce	O
hypotension	B-Disease
and	O
preserve	O
blood	O
flow	O
to	O
the	O
kidney	O
was	O
tested	O
.	O

Systemic	O
aortic	O
blood	O
pressure	O
and	O
renal	O
blood	O
flow	O
were	O
measured	O
continuously	O
with	O
a	O
carotid	O
arterial	O
catheter	O
and	O
an	O
electromagnetic	O
flow	O
probe	O
respectively	O
,	O
in	O
order	O
to	O
compare	O
the	O
cardiovascular	O
and	O
renal	O
vascular	O
effects	O
of	O
fenoldopam	B-Chemical
and	O
sodium	B-Chemical
nitroprusside	B-Chemical
in	O
ten	O
dogs	O
under	O
halothane	B-Chemical
general	O
anaesthesia	O
.	O

Mean	O
arterial	O
pressure	O
was	O
decreased	O
30	O
+	O
/	O
-	O
8	O
per	O
cent	O
from	O
control	O
with	O
infusion	O
of	O
fenoldopam	B-Chemical
(	O
3	O
.	O
4	O
+	O
/	O
-	O
2	O
.	O
0	O
micrograms	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
)	O
and	O
34	O
+	O
/	O
-	O
4	O
per	O
cent	O
with	O
infusion	O
of	O
sodium	B-Chemical
nitroprusside	B-Chemical
(	O
5	O
.	O
9	O
micrograms	O
.	O
kg	O
-	O
1	O
.	O
min	O
-	O
1	O
)	O
(	O
NS	O
)	O
.	O

Renal	O
blood	O
flow	O
(	O
RBF	O
)	O
increased	O
during	O
fenoldopam	B-Chemical
-	O
induced	O
hypotension	B-Disease
11	O
+	O
/	O
-	O
7	O
per	O
cent	O
and	O
decreased	O
21	O
+	O
/	O
-	O
8	O
per	O
cent	O
during	O
sodium	B-Chemical
nitroprusside	B-Chemical
-	O
induced	O
hypotension	B-Disease
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Sodium	O
nitroprusside	B-Chemical
is	O
a	O
non	O
-	O
selective	O
arteriolar	O
and	O
venous	O
vasodilator	O
that	O
can	O
produce	O
redistribution	O
of	O
blood	O
flow	O
away	O
from	O
the	O
kidney	O
during	O
induced	O
hypotension	B-Disease
.	O

Fenoldopam	O
is	O
a	O
selective	O
dopamine	B-Chemical
-	O
1	O
(	O
DA1	O
)	O
receptor	O
agonist	O
that	O
causes	O
vasodilatation	O
to	O
the	O
kidney	O
and	O
other	O
organs	O
with	O
DA1	O
receptors	O
and	O
preserves	O
blood	O
flow	O
to	O
the	O
kidney	O
during	O
induced	O
hypotension	B-Disease
.	O

Seizures	B-Disease
associated	O
with	O
levofloxacin	B-Chemical
:	O
case	O
presentation	O
and	O
literature	O
review	O
.	O

PURPOSE	O
:	O
We	O
present	O
a	O
case	O
of	O
a	O
patient	O
who	O
developed	O
seizures	B-Disease
shortly	O
after	O
initiating	O
treatment	O
with	O
levofloxacin	B-Chemical
and	O
to	O
discuss	O
the	O
potential	O
drug	O
-	O
drug	O
interactions	O
related	O
to	O
the	O
inhibition	O
of	O
cytochrome	O
P450	O
(	O
CYP	O
)	O
1A2	O
in	O
this	O
case	O
,	O
as	O
well	O
as	O
in	O
other	O
cases	O
,	O
of	O
levofloxacin	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

METHODS	O
:	O
Several	O
biomedical	O
databases	O
were	O
searched	O
including	O
MEDLINE	O
,	O
Cochrane	O
and	O
Ovid	O
.	O

The	O
main	O
search	O
terms	O
utilized	O
were	O
case	O
report	O
and	O
levofloxacin	B-Chemical
.	O

The	O
search	O
was	O
limited	O
to	O
studies	O
published	O
in	O
English	O
.	O

RESULTS	O
:	O
Six	O
cases	O
of	O
levofloxacin	B-Chemical
-	O
induced	O
seizures	B-Disease
have	O
been	O
reported	O
in	O
the	O
literature	O
.	O

Drug	O
-	O
drug	O
interactions	O
related	O
to	O
the	O
inhibition	O
of	O
CYP1A2	O
by	O
levofloxacin	B-Chemical
are	O
likely	O
involved	O
in	O
the	O
clinical	O
outcome	O
of	O
these	O
cases	O
.	O

CONCLUSIONS	O
:	O
Clinicians	O
are	O
exhorted	O
to	O
pay	O
close	O
attention	O
when	O
initiating	O
levofloxacin	B-Chemical
therapy	O
in	O
patients	O
taking	O
medications	O
with	O
epileptogenic	O
properties	O
that	O
are	O
CYP1A2	O
substrates	O
.	O

Dextran	B-Chemical
-	O
etodolac	B-Chemical
conjugates	O
:	O
synthesis	O
,	O
in	O
vitro	O
and	O
in	O
vivo	O
evaluation	O
.	O

Etodolac	B-Chemical
(	O
E	B-Chemical
)	O
,	O
is	O
a	O
non	O
-	O
narcotic	O
analgesic	O
and	O
antiinflammatory	O
drug	O
.	O

A	O
biodegradable	O
polymer	O
dextran	B-Chemical
has	O
been	O
utilized	O
as	O
a	O
carrier	O
for	O
synthesis	O
of	O
etodolac	B-Chemical
-	O
dextran	B-Chemical
conjugates	O
(	O
ED	O
)	O
to	O
improve	O
its	O
aqueous	O
solubility	O
and	O
reduce	O
gastrointestinal	O
side	O
effects	O
.	O

An	O
activated	O
moiety	O
,	O
i	O
.	O
e	O
.	O
N	B-Chemical
-	I-Chemical
acylimidazole	I-Chemical
derivative	O
of	O
etodolac	B-Chemical
(	O
EAI	B-Chemical
)	O
,	O
was	O
condensed	O
with	O
the	O
polysaccharide	O
polymer	O
dextran	B-Chemical
of	O
different	O
molecular	O
weights	O
(	O
40000	O
,	O
60000	O
,	O
110000	O
and	O
200000	O
)	O
.	O

IR	O
spectral	O
data	O
confirmed	O
formation	O
of	O
ester	O
bonding	O
in	O
the	O
conjugates	O
.	O

Etodolac	B-Chemical
contents	O
were	O
evaluated	O
by	O
UV	O
-	O
spectrophotometric	O
analysis	O
.	O

The	O
molecular	O
weights	O
were	O
determined	O
by	O
measuring	O
viscosity	O
using	O
the	O
Mark	O
-	O
Howink	O
-	O
Sakurada	O
equation	O
.	O

In	O
vitro	O
hydrolysis	O
of	O
ED	O
was	O
done	O
in	O
aqueous	O
buffers	O
(	O
pH	O
1	O
.	O
2	O
,	O
7	O
.	O
4	O
,	O
9	O
)	O
and	O
in	O
80	O
%	O
(	O
v	O
/	O
v	O
)	O
human	O
plasma	O
(	O
pH	O
7	O
.	O
4	O
)	O
.	O

At	O
pH	O
9	O
,	O
a	O
higher	O
rate	O
of	O
etodolac	B-Chemical
release	O
from	O
ED	O
was	O
observed	O
as	O
compared	O
to	O
aqueous	O
buffer	O
of	O
pH	O
7	O
.	O
4	O
and	O
80	O
%	O
human	O
plasma	O
(	O
pH	O
7	O
.	O
4	O
)	O
,	O
following	O
first	O
-	O
order	O
kinetics	O
.	O

In	O
vivo	O
investigations	O
were	O
performed	O
in	O
animals	O
.	O

Acute	O
analgesic	O
and	O
antiinflammatory	O
activities	O
were	O
ascertained	O
using	O
acetic	B-Chemical
acid	I-Chemical
induced	O
writhing	B-Disease
model	O
(	O
mice	O
)	O
and	O
carrageenan	B-Chemical
-	O
induced	O
rat	O
paw	O
edema	B-Disease
model	O
,	O
respectively	O
.	O

In	O
comparison	O
to	O
control	O
,	O
E	B-Chemical
and	O
ED1	O
-	O
ED4	O
showed	O
highly	O
significant	O
analgesic	O
and	O
antiinflammatory	O
activities	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Biological	O
evaluation	O
suggested	O
that	O
conjugates	O
(	O
ED1	O
-	O
ED4	O
)	O
retained	O
comparable	O
analgesic	O
and	O
antiinflammatory	O
activities	O
with	O
remarkably	O
reduced	O
ulcerogenicity	O
as	O
compared	O
to	O
their	O
parent	O
drug	O
-	O
-	O
etodolac	B-Chemical
.	O

The	O
antiarrhythmic	O
effect	O
and	O
possible	O
ionic	O
mechanisms	O
of	O
pilocarpine	B-Chemical
on	O
animal	O
models	O
.	O

This	O
study	O
was	O
designed	O
to	O
evaluate	O
the	O
effects	O
of	O
pilocarpine	B-Chemical
and	O
explore	O
the	O
underlying	O
ionic	O
mechanism	O
,	O
using	O
both	O
aconitine	B-Chemical
-	O
induced	O
rat	O
and	O
ouabain	B-Chemical
-	O
induced	O
guinea	O
pig	O
arrhythmia	B-Disease
models	O
.	O

Confocal	O
microscopy	O
was	O
used	O
to	O
measure	O
intracellular	O
free	O
-	O
calcium	B-Chemical
concentrations	O
(	O
[	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
]	O
(	O
i	O
)	O
)	O
in	O
isolated	O
myocytes	O
.	O

The	O
current	O
data	O
showed	O
that	O
pilocarpine	B-Chemical
significantly	O
delayed	O
onset	O
of	O
arrhythmias	B-Disease
,	O
decreased	O
the	O
time	O
course	O
of	O
ventricular	B-Disease
tachycardia	I-Disease
and	I-Disease
fibrillation	I-Disease
,	O
reduced	O
arrhythmia	B-Disease
score	O
,	O
and	O
increased	O
the	O
survival	O
time	O
of	O
arrhythmic	B-Disease
rats	O
and	O
guinea	O
pigs	O
.	O

[	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
]	O
(	O
i	O
)	O
overload	O
induced	O
by	O
aconitine	B-Chemical
or	O
ouabain	B-Chemical
was	O
reduced	O
in	O
isolated	O
myocytes	O
pretreated	O
with	O
pilocarpine	B-Chemical
.	O

Moreover	O
,	O
M	O
(	O
3	O
)	O
-	O
muscarinic	O
acetylcholine	B-Chemical
receptor	O
(	O
mAChR	O
)	O
antagonist	O
4	B-Chemical
-	I-Chemical
DAMP	I-Chemical
(	O
4	B-Chemical
-	I-Chemical
diphenylacetoxy	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
methylpiperidine	I-Chemical
-	I-Chemical
methiodide	I-Chemical
)	O
partially	O
abolished	O
the	O
beneficial	O
effects	O
of	O
pilocarpine	B-Chemical
.	O

These	O
data	O
suggest	O
that	O
pilocarpine	B-Chemical
produced	O
antiarrhythmic	O
actions	O
on	O
arrhythmic	B-Disease
rat	O
and	O
guinea	O
pig	O
models	O
induced	O
by	O
aconitine	B-Chemical
or	O
ouabain	B-Chemical
via	O
stimulating	O
the	O
cardiac	O
M	O
(	O
3	O
)	O
-	O
mAChR	O
.	O

The	O
mechanism	O
may	O
be	O
related	O
to	O
the	O
improvement	O
of	O
Ca	B-Chemical
(	O
2	O
+	O
)	O
handling	O
.	O

Effect	O
of	O
Hibiscus	B-Chemical
rosa	I-Chemical
sinensis	I-Chemical
on	O
reserpine	B-Chemical
-	O
induced	O
neurobehavioral	O
and	O
biochemical	O
alterations	O
in	O
rats	O
.	O

Effect	O
of	O
methanolic	O
extract	O
of	O
Hibiscus	B-Chemical
rosa	I-Chemical
sinensis	I-Chemical
(	O
100	O
-	O
300	O
mg	O
/	O
kg	O
)	O
was	O
studied	O
on	O
reserpine	B-Chemical
-	O
induced	O
orofacial	O
dyskinesia	B-Disease
and	O
neurochemical	O
alterations	O
.	O

The	O
rats	O
were	O
treated	O
with	O
intraperitoneal	O
reserpine	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
,	O
ip	O
)	O
for	O
3	O
days	O
every	O
other	O
day	O
.	O

On	O
day	O
5	O
,	O
vacuous	O
chewing	O
movements	O
and	O
tongue	O
protrusions	O
were	O
counted	O
for	O
5	O
min	O
.	O

Reserpine	B-Chemical
treated	O
rats	O
significantly	O
developed	O
vacuous	O
chewing	O
movements	O
and	O
tongue	O
protrusions	O
however	O
,	O
coadministration	O
of	O
Hibiscus	B-Chemical
rosa	I-Chemical
sinensis	I-Chemical
roots	O
extract	O
(	O
100	O
,	O
200	O
and	O
300	O
mg	O
/	O
kg	O
,	O
per	O
orally	O
)	O
attenuated	O
the	O
effects	O
.	O

Biochemical	O
analysis	O
of	O
brain	O
revealed	O
that	O
the	O
reserpine	B-Chemical
treatment	O
significantly	O
increased	O
lipid	O
peroxidation	O
and	O
decreased	O
levels	O
of	O
superoxide	B-Chemical
dismutase	O
(	O
SOD	O
)	O
,	O
catalase	O
(	O
CAT	O
)	O
and	O
glutathione	B-Chemical
reductase	O
(	O
GSH	O
)	O
,	O
an	O
index	O
of	O
oxidative	O
stress	O
process	O
.	O

Coadministration	O
of	O
extract	O
significantly	O
reduced	O
the	O
lipid	O
peroxidation	O
and	O
reversed	O
the	O
decrease	O
in	O
brain	O
SOD	O
,	O
CAT	O
and	O
GSH	O
levels	O
.	O

The	O
results	O
of	O
the	O
present	O
study	O
suggested	O
that	O
Hibiscus	B-Chemical
rosa	I-Chemical
sinensis	I-Chemical
had	O
a	O
protective	O
role	O
against	O
reserpine	B-Chemical
-	O
induced	O
orofacial	O
dyskinesia	B-Disease
and	O
oxidative	O
stress	O
.	O

Dynamic	O
response	O
of	O
blood	O
vessel	O
in	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

In	O
this	O
study	O
we	O
postulated	O
that	O
during	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
induced	O
by	O
gentamicin	B-Chemical
the	O
transient	O
or	O
dynamic	O
response	O
of	O
blood	O
vessels	O
could	O
be	O
affected	O
,	O
and	O
that	O
antioxidants	O
can	O
prevent	O
the	O
changes	O
in	O
dynamic	O
responses	O
of	O
blood	O
vessels	O
.	O

The	O
new	O
approach	O
to	O
ex	O
vivo	O
blood	O
vessel	O
experiments	O
in	O
which	O
not	O
only	O
the	O
end	O
points	O
of	O
vessels	O
response	O
within	O
the	O
time	O
interval	O
is	O
considered	O
,	O
but	O
also	O
dynamics	O
of	O
this	O
response	O
,	O
was	O
used	O
in	O
this	O
paper	O
.	O

Our	O
results	O
confirm	O
the	O
alteration	O
in	O
dynamic	O
response	O
of	O
blood	O
vessels	O
during	O
the	O
change	O
of	O
pressure	O
in	O
gentamicin	B-Chemical
-	O
treated	O
animals	O
.	O

The	O
beneficial	O
effects	O
of	O
vitamin	B-Chemical
C	I-Chemical
administration	O
to	O
gentamicin	B-Chemical
-	O
treated	O
animals	O
are	O
also	O
confirmed	O
through	O
:	O
lower	O
level	O
of	O
blood	O
urea	B-Chemical
and	O
creatinine	B-Chemical
and	O
higher	O
level	O
of	O
potassium	B-Chemical
.	O

The	O
pressure	O
dynamic	O
responses	O
of	O
isolated	O
blood	O
vessels	O
show	O
a	O
faster	O
pressure	O
change	O
in	O
gentamicin	B-Chemical
-	O
treated	O
animals	O
(	O
8	O
.	O
07	O
+	O
/	O
-	O
1	O
.	O
7	O
s	O
vs	O
.	O
5	O
.	O
64	O
+	O
/	O
-	O
0	O
.	O
18	O
s	O
)	O
.	O

Vitamin	B-Chemical
C	I-Chemical
administration	O
induced	O
slowdown	O
of	O
pressure	O
change	O
back	O
to	O
the	O
control	O
values	O
.	O

The	O
pressure	O
dynamic	O
properties	O
,	O
quantitatively	O
defined	O
by	O
comparative	O
pressure	O
dynamic	O
and	O
total	O
pressure	O
dynamic	O
,	O
confirm	O
the	O
alteration	O
in	O
dynamic	O
response	O
of	O
blood	O
vessels	O
during	O
the	O
change	O
of	O
pressure	O
in	O
gentamicin	B-Chemical
-	O
treated	O
animals	O
and	O
beneficial	O
effects	O
of	O
vitamin	B-Chemical
C	I-Chemical
administration	O
.	O

Reversible	O
myocardial	B-Disease
hypertrophy	I-Disease
induced	O
by	O
tacrolimus	B-Chemical
in	O
a	O
pediatric	O
heart	O
transplant	O
recipient	O
:	O
case	O
report	O
.	O

Tacrolimus	B-Chemical
is	O
a	O
potent	O
immunosuppressant	O
that	O
is	O
frequently	O
used	O
in	O
organ	O
transplantation	O
.	O

However	O
,	O
adverse	O
effects	O
include	O
cardiac	B-Disease
toxicity	I-Disease
.	O

Herein	O
we	O
describe	O
transient	O
myocardial	B-Disease
hypertrophy	I-Disease
induced	O
by	O
tacrolimus	B-Chemical
after	O
heart	O
transplantation	O
.	O

The	O
hypertrophy	B-Disease
caused	O
no	O
clinical	O
symptoms	O
but	O
was	O
noted	O
because	O
of	O
elevation	O
of	O
plasma	O
brain	O
natriuretic	O
peptide	O
concentration	O
and	O
confirmed	O
at	O
echocardiography	O
.	O

Initially	O
,	O
allograft	O
rejection	O
was	O
feared	O
;	O
however	O
,	O
myocardial	O
biopsy	O
samples	O
revealed	O
only	O
interstitial	O
edema	B-Disease
and	O
mild	O
myocardial	B-Disease
hypertrophy	I-Disease
;	O
neither	O
cellular	O
nor	O
humoral	O
rejection	O
was	O
detected	O
.	O

The	O
blood	O
tacrolimus	B-Chemical
concentration	O
was	O
higher	O
than	O
usual	O
at	O
that	O
time	O
;	O
thus	O
,	O
tacrolimus	B-Chemical
dosage	O
was	O
reduced	O
.	O

Myocardial	B-Disease
hypertrophy	I-Disease
completely	O
resolved	O
upon	O
reducing	O
the	O
target	O
concentration	O
of	O
tacrolimus	B-Chemical
and	O
did	O
not	O
recur	O
,	O
as	O
confirmed	O
at	O
echocardiography	O
and	O
myocardial	O
biopsy	O
.	O

Thus	O
,	O
we	O
conclude	O
that	O
tacrolimus	B-Chemical
induces	O
reversible	O
myocardial	B-Disease
hypertrophy	I-Disease
.	O

In	O
patients	O
receiving	O
tacrolimus	B-Chemical
therapy	O
,	O
blood	O
concentration	O
should	O
be	O
carefully	O
controlled	O
and	O
extreme	O
attention	O
paid	O
to	O
cardiac	O
involvement	O
.	O

Nimodipine	B-Chemical
prevents	O
memory	B-Disease
impairment	I-Disease
caused	O
by	O
nitroglycerin	B-Chemical
-	O
induced	O
hypotension	B-Disease
in	O
adult	O
mice	O
.	O

BACKGROUND	O
:	O
Hypotension	B-Disease
and	O
a	O
resultant	O
decrease	O
in	O
cerebral	O
blood	O
flow	O
have	O
been	O
implicated	O
in	O
the	O
development	O
of	O
cognitive	B-Disease
dysfunction	I-Disease
.	O

We	O
tested	O
the	O
hypothesis	O
that	O
nimodipine	B-Chemical
(	O
NIMO	B-Chemical
)	O
administered	O
at	O
the	O
onset	O
of	O
nitroglycerin	B-Chemical
(	O
NTG	B-Chemical
)	O
-	O
induced	O
hypotension	B-Disease
would	O
preserve	O
long	O
-	O
term	O
associative	O
memory	O
.	O

METHODS	O
:	O
The	O
passive	O
avoidance	O
(	O
PA	O
)	O
paradigm	O
was	O
used	O
to	O
assess	O
memory	O
retention	O
.	O

For	O
PA	O
training	O
,	O
latencies	O
(	O
seconds	O
)	O
were	O
recorded	O
for	O
entry	O
from	O
a	O
suspended	O
platform	O
into	O
a	O
Plexiglas	O
tube	O
where	O
a	O
shock	O
was	O
automatically	O
delivered	O
.	O

Latencies	O
were	O
recorded	O
48	O
h	O
later	O
for	O
a	O
testing	O
trial	O
.	O

Ninety	O
-	O
six	O
Swiss	O
-	O
Webster	O
mice	O
(	O
30	O
-	O
35	O
g	O
,	O
6	O
-	O
8	O
wk	O
)	O
,	O
were	O
randomized	O
into	O
6	O
groups	O
1	O
)	O
saline	O
(	O
control	O
)	O
,	O
2	O
)	O
NTG	B-Chemical
immediately	O
after	O
learning	O
,	O
3	O
)	O
NTG	B-Chemical
3	O
h	O
after	O
learning	O
,	O
4	O
)	O
NTG	B-Chemical
and	O
NIMO	B-Chemical
,	O
5	O
)	O
vehicle	O
,	O
and	O
6	O
)	O
NIMO	B-Chemical
alone	O
.	O

The	O
extent	O
of	O
hypotension	B-Disease
and	O
changes	O
in	O
brain	O
tissue	O
oxygenation	O
(	O
PbtO	O
(	O
2	O
)	O
)	O
and	O
in	O
cerebral	O
blood	O
flow	O
were	O
studied	O
in	O
a	O
separate	O
group	O
of	O
animals	O
.	O

RESULTS	O
:	O
All	O
groups	O
exhibited	O
similar	O
training	O
latencies	O
(	O
17	O
.	O
0	O
+	O
/	O
-	O
4	O
.	O
6	O
s	O
)	O
.	O

Mice	O
subjected	O
to	O
hypotensive	B-Disease
episodes	O
showed	O
a	O
significant	O
decrease	O
in	O
latency	O
time	O
(	O
178	O
+	O
/	O
-	O
156	O
s	O
)	O
compared	O
with	O
those	O
injected	O
with	O
saline	O
,	O
NTG	B-Chemical
+	O
NIMO	B-Chemical
,	O
or	O
delayed	O
NTG	B-Chemical
(	O
580	O
+	O
/	O
-	O
81	O
s	O
,	O
557	O
+	O
/	O
-	O
67	O
s	O
,	O
and	O
493	O
+	O
/	O
-	O
146	O
s	O
,	O
respectively	O
)	O
.	O

A	O
Kruskal	O
-	O
Wallis	O
1	O
-	O
way	O
analysis	O
of	O
variance	O
indicated	O
a	O
significant	O
difference	O
among	O
the	O
4	O
treatment	O
groups	O
(	O
H	O
=	O
15	O
.	O
34	O
;	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

In	O
a	O
separate	O
group	O
of	O
mice	O
not	O
subjected	O
to	O
behavioral	O
studies	O
,	O
the	O
same	O
dose	O
of	O
NTG	B-Chemical
(	O
n	O
=	O
3	O
)	O
and	O
NTG	B-Chemical
+	O
NIMO	B-Chemical
(	O
n	O
=	O
3	O
)	O
caused	O
mean	O
arterial	O
blood	O
pressure	O
to	O
decrease	O
from	O
85	O
.	O
9	O
+	O
/	O
-	O
3	O
.	O
8	O
mm	O
Hg	O
sem	O
to	O
31	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
8	O
mm	O
Hg	O
sem	O
and	O
from	O
86	O
.	O
2	O
+	O
/	O
-	O
3	O
.	O
7	O
mm	O
Hg	O
sem	O
to	O
32	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
2	O
mm	O
Hg	O
sem	O
,	O
respectively	O
.	O

Mean	O
arterial	O
blood	O
pressure	O
in	O
mice	O
treated	O
with	O
NIMO	B-Chemical
alone	O
decreased	O
from	O
88	O
.	O
1	O
+	O
/	O
-	O
3	O
.	O
8	O
mm	O
Hg	O
to	O
80	O
.	O
0	O
+	O
/	O
-	O
2	O
.	O
9	O
mm	O
Hg	O
.	O

The	O
intergroup	O
difference	O
was	O
statistically	O
significant	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

PbtO	O
(	O
2	O
)	O
decreased	O
from	O
51	O
.	O
7	O
+	O
/	O
-	O
4	O
.	O
5	O
mm	O
Hg	O
sem	O
to	O
33	O
.	O
8	O
+	O
/	O
-	O
5	O
.	O
2	O
mm	O
Hg	O
sem	O
in	O
the	O
NTG	B-Chemical
group	O
and	O
from	O
38	O
.	O
6	O
+	O
/	O
-	O
6	O
.	O
1	O
mm	O
Hg	O
sem	O
to	O
25	O
.	O
4	O
+	O
/	O
-	O
2	O
.	O
0	O
mm	O
Hg	O
sem	O
in	O
the	O
NTG	B-Chemical
+	O
NIMO	B-Chemical
groups	O
,	O
respectively	O
.	O

There	O
were	O
no	O
significant	O
differences	O
among	O
groups	O
.	O

CONCLUSION	O
:	O
In	O
a	O
PA	O
retention	O
paradigm	O
,	O
the	O
injection	O
of	O
NTG	B-Chemical
immediately	O
after	O
learning	O
produced	O
a	O
significant	O
impairment	O
of	O
long	O
-	O
term	O
associative	O
memory	O
in	O
mice	O
,	O
whereas	O
delayed	O
induced	O
hypotension	B-Disease
had	O
no	O
effect	O
.	O

NIMO	B-Chemical
attenuated	O
the	O
disruption	O
in	O
consolidation	O
of	O
long	O
-	O
term	O
memory	O
caused	O
by	O
NTG	B-Chemical
but	O
did	O
not	O
improve	O
latency	O
in	O
the	O
absence	O
of	O
hypotension	B-Disease
.	O

The	O
observed	O
effect	O
of	O
NIMO	B-Chemical
may	O
have	O
been	O
attributable	O
to	O
the	O
preservation	O
of	O
calcium	B-Chemical
homeostasis	O
during	O
hypotension	B-Disease
,	O
because	O
there	O
were	O
no	O
differences	O
in	O
the	O
PbtO	O
(	O
2	O
)	O
indices	O
among	O
groups	O
.	O

Metabotropic	O
glutamate	B-Chemical
7	O
receptor	O
subtype	O
modulates	O
motor	O
symptoms	O
in	O
rodent	O
models	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Metabotropic	O
glutamate	B-Chemical
(	O
mGlu	O
)	O
receptors	O
modulate	O
synaptic	O
transmission	O
in	O
the	O
central	O
nervous	O
system	O
and	O
represent	O
promising	O
therapeutic	O
targets	O
for	O
symptomatic	O
treatment	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
.	O

Among	O
the	O
eight	O
mGlu	O
receptor	O
subtypes	O
,	O
mGlu7	O
receptor	O
is	O
prominently	O
expressed	O
in	O
the	O
basal	O
ganglia	O
,	O
but	O
its	O
role	O
in	O
restoring	O
motor	O
function	O
in	O
animal	O
models	O
of	O
PD	B-Disease
is	O
not	O
known	O
.	O

The	O
effects	O
of	O
N	B-Chemical
,	I-Chemical
N	I-Chemical
'	I-Chemical
-	I-Chemical
dibenzhydrylethane	I-Chemical
-	I-Chemical
1	I-Chemical
,	I-Chemical
2	I-Chemical
-	I-Chemical
diamine	I-Chemical
dihydrochloride	I-Chemical
(	O
AMN082	B-Chemical
)	O
,	O
the	O
first	O
selective	O
allosteric	O
activator	O
of	O
mGlu7	O
receptors	O
,	O
were	O
thus	O
tested	O
in	O
different	O
rodent	O
models	O
of	O
PD	B-Disease
.	O

Here	O
,	O
we	O
show	O
that	O
oral	O
(	O
5	O
mg	O
/	O
kg	O
)	O
or	O
intrastriatal	O
administration	O
(	O
0	O
.	O
1	O
and	O
0	O
.	O
5	O
nmol	O
)	O
of	O
AMN082	B-Chemical
reverses	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
in	O
rats	O
.	O

AMN082	B-Chemical
(	O
2	O
.	O
5	O
and	O
5	O
mg	O
/	O
kg	O
)	O
reduces	O
apomorphine	B-Chemical
-	O
induced	O
rotations	O
in	O
unilateral	O
6	B-Chemical
-	I-Chemical
hydroxydopamine	I-Chemical
(	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
)	O
-	O
lesioned	O
rats	O
.	O

In	O
a	O
more	O
complex	O
task	O
commonly	O
used	O
to	O
evaluate	O
major	O
akinetic	B-Disease
symptoms	O
of	O
PD	B-Disease
patients	O
,	O
5	O
mg	O
/	O
kg	O
AMN082	B-Chemical
reverses	O
the	O
increased	O
reaction	O
time	O
to	O
respond	O
to	O
a	O
cue	O
of	O
bilateral	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
-	O
lesioned	O
rats	O
.	O

In	O
addition	O
,	O
AMN082	B-Chemical
reduces	O
the	O
duration	O
of	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
in	O
a	O
mGlu7	O
receptor	O
-	O
dependent	O
manner	O
in	O
wild	O
-	O
type	O
but	O
not	O
mGlu7	O
receptor	O
knockout	O
mice	O
.	O

Higher	O
doses	O
of	O
AMN082	B-Chemical
(	O
10	O
and	O
20	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
)	O
have	O
no	O
effect	O
on	O
the	O
same	O
models	O
of	O
PD	B-Disease
.	O

Overall	O
these	O
findings	O
suggest	O
that	O
mGlu7	O
receptor	O
activation	O
can	O
reverse	O
motor	O
dysfunction	O
associated	O
with	O
reduced	O
dopamine	B-Chemical
activity	O
.	O

Selective	O
ligands	O
of	O
mGlu7	O
receptor	O
subtypes	O
may	O
thus	O
be	O
considered	O
as	O
promising	O
compounds	O
for	O
the	O
development	O
of	O
antiparkinsonian	O
therapeutic	O
strategies	O
.	O

Sorafenib	B-Chemical
-	O
induced	O
acute	O
myocardial	B-Disease
infarction	I-Disease
due	O
to	O
coronary	B-Disease
artery	I-Disease
spasm	I-Disease
.	O

A	O
65	O
-	O
year	O
-	O
old	O
man	O
with	O
advanced	O
renal	B-Disease
cell	I-Disease
carcinoma	I-Disease
was	O
admitted	O
due	O
to	O
continuing	O
chest	B-Disease
pain	I-Disease
at	O
rest	O
.	O

Two	O
weeks	O
before	O
his	O
admission	O
,	O
sorafenib	B-Chemical
had	O
been	O
started	O
.	O

He	O
was	O
diagnosed	O
with	O
non	O
-	O
ST	O
-	O
elevation	O
myocardial	B-Disease
infarction	I-Disease
by	O
laboratory	O
data	O
and	O
electrocardiogram	O
.	O

Enhanced	O
heart	O
magnetic	O
resonance	O
imaging	O
also	O
showed	O
subendocardial	B-Disease
infarction	I-Disease
.	O

However	O
,	O
there	O
was	O
no	O
stenosis	O
in	O
coronary	O
arteries	O
on	O
angiography	O
.	O

Coronary	B-Disease
artery	I-Disease
spasm	I-Disease
was	O
induced	O
by	O
a	O
provocative	O
test	O
.	O

Cessation	O
of	O
sorafenib	B-Chemical
and	O
administration	O
of	O
Ca	B-Chemical
-	O
channel	O
blocker	O
and	O
nitrates	B-Chemical
ameliorated	O
his	O
symptoms	O
,	O
but	O
relapse	O
occurred	O
after	O
resumption	O
of	O
sorafenib	B-Chemical
.	O

Addition	O
of	O
oral	O
nicorandil	B-Chemical
reduced	O
his	O
symptoms	O
and	O
maintained	O
stable	B-Disease
angina	I-Disease
status	O
.	O

We	O
report	O
the	O
first	O
case	O
of	O
sorafenib	B-Chemical
-	O
induced	O
coronary	B-Disease
artery	I-Disease
spasm	I-Disease
.	O

Sorafenib	B-Chemical
is	O
a	O
multikinase	O
inhibitor	O
that	O
targets	O
signaling	O
pathways	O
necessary	O
for	O
cellular	O
proliferation	O
and	O
survival	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
Rho	O
/	O
ROCK	O
pathway	O
has	O
an	O
important	O
role	O
in	O
the	O
pathogenesis	O
of	O
coronary	B-Disease
artery	I-Disease
spasm	I-Disease
.	O

Our	O
report	O
may	O
show	O
an	O
adverse	O
effect	O
on	O
the	O
Rho	O
/	O
ROCK	O
pathway	O
by	O
sorafenib	B-Chemical
use	O
.	O

A	O
novel	O
animal	O
model	O
to	O
evaluate	O
the	O
ability	O
of	O
a	O
drug	O
delivery	O
system	O
to	O
promote	O
the	O
passage	O
through	O
the	O
BBB	O
.	O

The	O
purpose	O
of	O
this	O
investigation	O
was	O
to	O
explore	O
the	O
potentiality	O
of	O
a	O
novel	O
animal	O
model	O
to	O
be	O
used	O
for	O
the	O
in	O
vivo	O
evaluation	O
of	O
the	O
ability	O
of	O
a	O
drug	O
delivery	O
system	O
to	O
promote	O
the	O
passage	O
through	O
the	O
blood	O
-	O
brain	O
barrier	O
(	O
BBB	O
)	O
and	O
/	O
or	O
to	O
improve	O
the	O
brain	O
localization	O
of	O
a	O
bioactive	O
compound	O
.	O

A	O
Tween	O
80	O
-	O
coated	O
poly	B-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
lactid	I-Chemical
acid	I-Chemical
nanoparticles	O
was	O
used	O
as	O
a	O
model	O
of	O
colloidal	O
drug	O
delivery	O
system	O
,	O
able	O
to	O
trespass	O
the	O
BBB	O
.	O

Tacrine	B-Chemical
,	O
administered	O
in	O
LiCl	B-Chemical
pre	O
-	O
treated	O
rats	O
,	O
induces	O
electrocorticographic	O
seizures	B-Disease
and	O
delayed	O
hippocampal	B-Disease
damage	I-Disease
.	O

The	O
toxic	O
effects	O
of	O
tacrine	B-Chemical
-	O
loaded	O
poly	B-Chemical
-	I-Chemical
L	I-Chemical
-	I-Chemical
lactid	I-Chemical
acid	I-Chemical
nanoparticles	O
(	O
5mg	O
/	O
kg	O
)	O
,	O
a	O
saline	O
solution	O
of	O
tacrine	B-Chemical
(	O
5mg	O
/	O
kg	O
)	O
and	O
an	O
empty	O
colloidal	O
nanoparticle	O
suspension	O
were	O
compared	O
following	O
i	O
.	O
p	O
.	O
administration	O
in	O
LiCl	B-Chemical
-	O
pre	O
-	O
treated	O
Wistar	O
rats	O
.	O

All	O
the	O
animals	O
treated	O
with	O
tacrine	B-Chemical
-	O
loaded	O
nanoparticles	O
showed	O
an	O
earlier	O
outcome	O
of	O
CNS	O
adverse	O
symptoms	O
,	O
i	O
.	O
e	O
.	O
epileptic	B-Disease
onset	O
,	O
with	O
respect	O
to	O
those	O
animals	O
treated	O
with	O
the	O
free	O
compound	O
(	O
10	O
min	O
vs	O
.	O
22	O
min	O
respectively	O
)	O
.	O

In	O
addition	O
,	O
tacrine	B-Chemical
-	O
loaded	O
nanoparticles	O
administration	O
induced	O
damage	B-Disease
of	I-Disease
neuronal	I-Disease
cells	I-Disease
in	O
CA1	O
field	O
of	O
the	O
hippocampus	O
in	O
all	O
treated	O
animals	O
,	O
while	O
the	O
saline	O
solution	O
of	O
tacrine	B-Chemical
only	O
in	O
60	O
%	O
of	O
animals	O
.	O

Empty	O
nanoparticles	O
provided	O
similar	O
results	O
to	O
control	O
(	O
saline	O
-	O
treated	O
)	O
group	O
of	O
animals	O
.	O

In	O
conclusion	O
,	O
the	O
evaluation	O
of	O
time	O
-	O
to	O
-	O
onset	O
of	O
symptoms	O
and	O
the	O
severity	O
of	O
neurodegenerative	O
processes	O
induced	O
by	O
the	O
tacrine	B-Chemical
-	O
lithium	B-Chemical
model	O
of	O
epilepsy	B-Disease
in	O
the	O
rat	O
,	O
could	O
be	O
used	O
to	O
evaluate	O
preliminarily	O
the	O
capability	O
of	O
a	O
drug	O
delivery	O
system	O
to	O
trespass	O
(	O
or	O
not	O
)	O
the	O
BBB	O
in	O
vivo	O
.	O

High	O
-	O
dose	O
tranexamic	B-Chemical
Acid	I-Chemical
is	O
associated	O
with	O
nonischemic	O
clinical	O
seizures	B-Disease
in	O
cardiac	O
surgical	O
patients	O
.	O

BACKGROUND	O
:	O
In	O
2	O
separate	O
centers	O
,	O
we	O
observed	O
a	O
notable	O
increase	O
in	O
the	O
incidence	O
of	O
postoperative	O
convulsive	B-Disease
seizures	B-Disease
from	O
1	O
.	O
3	O
%	O
to	O
3	O
.	O
8	O
%	O
in	O
patients	O
having	O
undergone	O
major	O
cardiac	O
surgical	O
procedures	O
.	O

These	O
events	O
were	O
temporally	O
coincident	O
with	O
the	O
initial	O
use	O
of	O
high	O
-	O
dose	O
tranexamic	B-Chemical
acid	I-Chemical
(	O
TXA	B-Chemical
)	O
therapy	O
after	O
withdrawal	O
of	O
aprotinin	O
from	O
general	O
clinical	O
usage	O
.	O

The	O
purpose	O
of	O
this	O
review	O
was	O
to	O
perform	O
a	O
retrospective	O
analysis	O
to	O
examine	O
whether	O
there	O
was	O
a	O
relation	O
between	O
TXA	B-Chemical
usage	O
and	O
seizures	B-Disease
after	O
cardiac	O
surgery	O
.	O

METHODS	O
:	O
An	O
in	O
-	O
depth	O
chart	O
review	O
was	O
undertaken	O
in	O
all	O
24	O
patients	O
who	O
developed	O
perioperative	O
seizures	B-Disease
.	O

Electroencephalographic	O
activity	O
was	O
recorded	O
in	O
11	O
of	O
these	O
patients	O
,	O
and	O
all	O
patients	O
had	O
a	O
formal	O
neurological	O
evaluation	O
and	O
brain	O
imaging	O
studies	O
.	O

RESULTS	O
:	O
Twenty	O
-	O
one	O
of	O
the	O
24	O
patients	O
did	O
not	O
have	O
evidence	O
of	O
new	O
cerebral	B-Disease
ischemic	I-Disease
injury	I-Disease
,	O
but	O
seizures	B-Disease
were	O
likely	O
due	O
to	O
ischemic	B-Disease
brain	I-Disease
injury	I-Disease
in	O
3	O
patients	O
.	O

All	O
patients	O
with	O
seizures	B-Disease
did	O
not	O
have	O
permanent	O
neurological	B-Disease
abnormalities	I-Disease
.	O

All	O
24	O
patients	O
with	O
seizures	B-Disease
received	O
high	O
doses	O
of	O
TXA	B-Chemical
intraoperatively	O
ranging	O
from	O
61	O
to	O
259	O
mg	O
/	O
kg	O
,	O
had	O
a	O
mean	O
age	O
of	O
69	O
.	O
9	O
years	O
,	O
and	O
21	O
of	O
24	O
had	O
undergone	O
open	O
chamber	O
rather	O
than	O
coronary	O
bypass	O
procedures	O
.	O

All	O
but	O
one	O
patient	O
were	O
managed	O
using	O
cardiopulmonary	O
bypass	O
.	O

No	O
evidence	O
of	O
brain	B-Disease
ischemic	I-Disease
,	O
metabolic	O
,	O
or	O
hyperthermia	B-Disease
-	O
induced	O
causes	O
for	O
their	O
seizures	B-Disease
was	O
apparent	O
.	O

CONCLUSION	O
:	O
Our	O
results	O
suggest	O
that	O
use	O
of	O
high	O
-	O
dose	O
TXA	B-Chemical
in	O
older	O
patients	O
in	O
conjunction	O
with	O
cardiopulmonary	O
bypass	O
and	O
open	O
-	O
chamber	O
cardiac	O
surgery	O
is	O
associated	O
with	O
clinical	O
seizures	B-Disease
in	O
susceptible	O
patients	O
.	O

Electrocardiographic	O
changes	O
and	O
cardiac	B-Disease
arrhythmias	I-Disease
in	O
patients	O
receiving	O
psychotropic	O
drugs	O
.	O

Eight	O
patients	O
had	O
cardiac	O
manifestations	O
that	O
were	O
life	O
-	O
threatening	O
in	O
five	O
while	O
taking	O
psychotropic	O
drugs	O
,	O
either	O
phenothiazines	B-Chemical
or	O
tricyclic	O
antidepressants	O
.	O

Although	O
most	O
patients	O
were	O
receiving	O
several	O
drugs	O
,	O
Mellaril	B-Chemical
(	O
thioridazine	B-Chemical
)	O
appeared	O
to	O
be	O
responsible	O
for	O
five	O
cases	O
of	O
ventricular	B-Disease
tachycardia	I-Disease
,	O
one	O
of	O
which	O
was	O
fatal	O
in	O
a	O
35	O
year	O
old	O
woman	O
.	O

Supraventricular	B-Disease
tachycardia	I-Disease
developed	O
in	O
one	O
patient	O
receiving	O
Thorazine	B-Chemical
(	O
chlorpromazine	B-Chemical
)	O
.	O

Aventyl	B-Chemical
(	O
nortriptyline	B-Chemical
)	O
and	O
Elavil	B-Chemical
(	O
amitriptyline	B-Chemical
)	O
each	O
produced	O
left	B-Disease
bundle	I-Disease
branch	I-Disease
block	I-Disease
in	O
a	O
73	O
year	O
old	O
woman	O
.	O

Electrocardiographic	O
T	O
and	O
U	O
wave	O
abnormalities	O
were	O
present	O
in	O
most	O
patients	O
.	O

The	O
ventricular	B-Disease
arrhythmias	I-Disease
responded	O
to	O
intravenous	O
administration	O
of	O
lidocaine	B-Chemical
and	O
to	O
direct	O
current	O
electric	O
shock	O
;	O
ventricular	O
pacing	O
was	O
required	O
in	O
some	O
instances	O
and	O
intravenous	O
administration	O
of	O
propranolol	B-Chemical
combined	O
with	O
ventricular	O
pacing	O
in	O
one	O
.	O

The	O
tachyarrhythmias	B-Disease
generally	O
subsided	O
within	O
48	O
hours	O
after	O
administration	O
of	O
the	O
drugs	O
was	O
stopped	O
.	O

Five	O
of	O
the	O
eight	O
patients	O
were	O
50	O
years	O
of	O
age	O
or	O
younger	O
;	O
only	O
one	O
clearly	O
had	O
antecedent	O
heart	B-Disease
disease	I-Disease
.	O

Major	O
cardiac	B-Disease
arrhythmias	I-Disease
are	O
a	O
potential	O
hazard	O
in	O
patients	O
without	O
heart	B-Disease
disease	I-Disease
who	O
are	O
receiving	O
customary	O
therapeutic	O
doses	O
of	O
psychotropic	O
drugs	O
.	O

A	O
prospective	O
clinical	O
trial	O
is	O
suggested	O
to	O
quantify	O
the	O
risk	O
of	O
cardiac	B-Disease
complications	I-Disease
to	O
patients	O
receiving	O
phenothiazines	B-Chemical
or	O
tricyclic	O
antidepressant	O
drugs	O
.	O

Sensitivity	O
of	O
erythroid	O
progenitor	O
colonies	O
to	O
erythropoietin	O
in	O
azidothymidine	B-Chemical
treated	O
immunodeficient	B-Disease
mice	O
.	O

The	O
anaemia	B-Disease
induced	O
by	O
3	B-Chemical
'	I-Chemical
-	I-Chemical
azido	I-Chemical
-	I-Chemical
3	I-Chemical
'	I-Chemical
dideoxythymidine	I-Chemical
(	O
AZT	B-Chemical
)	O
is	O
poorly	O
understood	O
.	O

We	O
have	O
used	O
a	O
murine	O
model	O
of	O
AIDS	B-Disease
,	O
infection	B-Disease
of	O
female	O
C57BL	O
/	O
6	O
mice	O
with	O
LP	O
-	O
BM5	O
murine	O
leukaemia	B-Disease
(	O
MuLV	O
)	O
virus	O
,	O
to	O
determine	O
if	O
AZT	B-Chemical
-	O
induced	O
anaemia	B-Disease
is	O
due	O
,	O
in	O
part	O
,	O
to	O
decreased	O
responsiveness	O
of	O
erythropoietic	O
precursors	O
(	O
BFU	O
-	O
e	O
)	O
to	O
erythropoietin	O
(	O
EPO	O
)	O
.	O

Mice	O
in	O
the	O
early	O
stage	O
of	O
LP	O
-	O
BM5	O
MuLV	O
disease	O
were	O
given	O
AZT	B-Chemical
in	O
their	O
drinking	O
water	O
at	O
1	O
.	O
0	O
and	O
2	O
.	O
5	O
mg	O
/	O
ml	O
.	O

AZT	B-Chemical
produced	O
anaemia	B-Disease
in	O
both	O
groups	O
,	O
in	O
a	O
dose	O
-	O
dependent	O
fashion	O
.	O

Despite	O
the	O
anaemia	B-Disease
,	O
the	O
number	O
of	O
splenic	O
and	O
bone	O
marrow	O
BFU	O
-	O
e	O
in	O
AZT	B-Chemical
treated	O
mice	O
increased	O
up	O
to	O
five	O
-	O
fold	O
over	O
levels	O
observed	O
in	O
infected	O
untreated	O
animals	O
after	O
15	O
d	O
of	O
treatment	O
.	O

Colony	O
formation	O
by	O
splenic	O
and	O
bone	O
marrow	O
BFUe	O
was	O
stimulated	O
at	O
lower	O
concentrations	O
of	O
EPO	O
in	O
mice	O
receiving	O
AZT	B-Chemical
for	O
15	O
d	O
than	O
for	O
infected	O
,	O
untreated	O
mice	O
.	O

By	O
day	O
30	O
,	O
sensitivity	O
of	O
both	O
splenic	O
and	O
bone	O
marrow	O
BFU	O
-	O
e	O
of	O
treated	O
animals	O
returned	O
to	O
that	O
observed	O
from	O
cells	O
of	O
infected	O
untreated	O
animals	O
.	O

The	O
mean	O
plasma	O
levels	O
of	O
EPO	O
observed	O
in	O
AZT	B-Chemical
treated	O
mice	O
were	O
appropriate	O
for	O
the	O
degree	O
of	O
anaemia	B-Disease
observed	O
when	O
compared	O
with	O
phenylhydrazine	B-Chemical
(	O
PHZ	B-Chemical
)	O
treated	O
mice	O
.	O

The	O
numbers	O
of	O
BFU	O
-	O
e	O
and	O
the	O
percentage	O
of	O
bone	O
marrow	O
erythroblasts	O
observed	O
were	O
comparable	O
in	O
AZT	B-Chemical
and	O
PHZ	B-Chemical
treated	O
mice	O
with	O
similar	O
degrees	O
of	O
anaemia	B-Disease
.	O

However	O
,	O
reticulocytosis	B-Disease
was	O
inappropriate	O
for	O
the	O
degree	O
of	O
anaemia	B-Disease
observed	O
in	O
AZT	B-Chemical
treated	O
infected	O
mice	O
.	O

AZT	B-Chemical
-	O
induced	O
peripheral	O
anaemia	B-Disease
in	O
the	O
face	O
of	O
increased	O
numbers	O
of	O
BFU	O
-	O
e	O
and	O
increased	O
levels	O
of	O
plasma	O
EPO	O
suggest	O
a	O
lesion	O
in	O
terminal	O
differentiation	O
.	O

Sedation	O
depth	O
during	O
spinal	O
anesthesia	O
and	O
the	O
development	O
of	O
postoperative	B-Disease
delirium	I-Disease
in	O
elderly	O
patients	O
undergoing	O
hip	B-Disease
fracture	I-Disease
repair	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
whether	O
limiting	O
intraoperative	O
sedation	O
depth	O
during	O
spinal	O
anesthesia	O
for	O
hip	B-Disease
fracture	I-Disease
repair	O
in	O
elderly	O
patients	O
can	O
decrease	O
the	O
prevalence	O
of	O
postoperative	B-Disease
delirium	I-Disease
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
We	O
performed	O
a	O
double	O
-	O
blind	O
,	O
randomized	O
controlled	O
trial	O
at	O
an	O
academic	O
medical	O
center	O
of	O
elderly	O
patients	O
(	O
>	O
or	O
=	O
65	O
years	O
)	O
without	O
preoperative	O
delirium	B-Disease
or	O
severe	O
dementia	B-Disease
who	O
underwent	O
hip	B-Disease
fracture	I-Disease
repair	O
under	O
spinal	O
anesthesia	O
with	O
propofol	B-Chemical
sedation	O
.	O

Sedation	O
depth	O
was	O
titrated	O
using	O
processed	O
electroencephalography	O
with	O
the	O
bispectral	O
index	O
(	O
BIS	O
)	O
,	O
and	O
patients	O
were	O
randomized	O
to	O
receive	O
either	O
deep	O
(	O
BIS	O
,	O
approximately	O
50	O
)	O
or	O
light	O
(	O
BIS	O
,	O
>	O
or	O
=	O
80	O
)	O
sedation	O
.	O

Postoperative	B-Disease
delirium	I-Disease
was	O
assessed	O
as	O
defined	O
by	O
Diagnostic	O
and	O
Statistical	O
Manual	O
of	O
Mental	B-Disease
Disorders	I-Disease
(	O
Third	O
Edition	O
Revised	O
)	O
criteria	O
using	O
the	O
Confusion	O
Assessment	O
Method	O
beginning	O
at	O
any	O
time	O
from	O
the	O
second	O
day	O
after	O
surgery	O
.	O

RESULTS	O
:	O
From	O
April	O
2	O
,	O
2005	O
,	O
through	O
October	O
30	O
,	O
2008	O
,	O
a	O
total	O
of	O
114	O
patients	O
were	O
randomized	O
.	O

The	O
prevalence	O
of	O
postoperative	B-Disease
delirium	I-Disease
was	O
significantly	O
lower	O
in	O
the	O
light	O
sedation	O
group	O
(	O
11	O
/	O
57	O
[	O
19	O
%	O
]	O
vs	O
23	O
/	O
57	O
[	O
40	O
%	O
]	O
in	O
the	O
deep	O
sedation	O
group	O
;	O
P	O
=	O
.	O
02	O
)	O
,	O
indicating	O
that	O
1	O
incident	O
of	O
delirium	B-Disease
will	O
be	O
prevented	O
for	O
every	O
4	O
.	O
7	O
patients	O
treated	O
with	O
light	O
sedation	O
.	O

The	O
mean	O
+	O
/	O
-	O
SD	O
number	O
of	O
days	O
of	O
delirium	B-Disease
during	O
hospitalization	O
was	O
lower	O
in	O
the	O
light	O
sedation	O
group	O
than	O
in	O
the	O
deep	O
sedation	O
group	O
(	O
0	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
5	O
days	O
vs	O
1	O
.	O
4	O
+	O
/	O
-	O
4	O
.	O
0	O
days	O
;	O
P	O
=	O
.	O
01	O
)	O
.	O

CONCLUSION	O
:	O
The	O
use	O
of	O
light	O
propofol	B-Chemical
sedation	O
decreased	O
the	O
prevalence	O
of	O
postoperative	B-Disease
delirium	I-Disease
by	O
50	O
%	O
compared	O
with	O
deep	O
sedation	O
.	O

Limiting	O
depth	O
of	O
sedation	O
during	O
spinal	O
anesthesia	O
is	O
a	O
simple	O
,	O
safe	O
,	O
and	O
cost	O
-	O
effective	O
intervention	O
for	O
preventing	O
postoperative	B-Disease
delirium	I-Disease
in	O
elderly	O
patients	O
that	O
could	O
be	O
widely	O
and	O
readily	O
adopted	O
.	O

The	O
protective	O
role	O
of	O
Nrf2	O
in	O
streptozotocin	B-Chemical
-	O
induced	O
diabetic	B-Disease
nephropathy	I-Disease
.	O

OBJECTIVE	O
:	O
Diabetic	B-Disease
nephropathy	I-Disease
is	O
one	O
of	O
the	O
major	O
causes	O
of	O
renal	B-Disease
failure	I-Disease
,	O
which	O
is	O
accompanied	O
by	O
the	O
production	O
of	O
reactive	O
oxygen	B-Chemical
species	O
(	O
ROS	O
)	O
.	O

Nrf2	O
is	O
the	O
primary	O
transcription	O
factor	O
that	O
controls	O
the	O
antioxidant	O
response	O
essential	O
for	O
maintaining	O
cellular	O
redox	O
homeostasis	O
.	O

Here	O
,	O
we	O
report	O
our	O
findings	O
demonstrating	O
a	O
protective	O
role	O
of	O
Nrf2	O
against	O
diabetic	B-Disease
nephropathy	I-Disease
.	O

RESEARCH	O
DESIGN	O
AND	O
METHODS	O
:	O
We	O
explore	O
the	O
protective	O
role	O
of	O
Nrf2	O
against	O
diabetic	B-Disease
nephropathy	I-Disease
using	O
human	O
kidney	O
biopsy	O
tissues	O
from	O
diabetic	B-Disease
nephropathy	I-Disease
patients	O
,	O
a	O
streptozotocin	B-Chemical
-	O
induced	O
diabetic	B-Disease
nephropathy	I-Disease
model	O
in	O
Nrf2	O
(	O
-	O
/	O
-	O
)	O
mice	O
,	O
and	O
cultured	O
human	O
mesangial	O
cells	O
.	O

RESULTS	O
:	O
The	O
glomeruli	O
of	O
human	O
diabetic	B-Disease
nephropathy	I-Disease
patients	O
were	O
under	O
oxidative	O
stress	O
and	O
had	O
elevated	O
Nrf2	O
levels	O
.	O

In	O
the	O
animal	O
study	O
,	O
Nrf2	O
was	O
demonstrated	O
to	O
be	O
crucial	O
in	O
ameliorating	O
streptozotocin	B-Chemical
-	O
induced	O
renal	B-Disease
damage	I-Disease
.	O

This	O
is	O
evident	O
by	O
Nrf2	O
(	O
-	O
/	O
-	O
)	O
mice	O
having	O
higher	O
ROS	O
production	O
and	O
suffering	O
from	O
greater	O
oxidative	O
DNA	O
damage	O
and	O
renal	B-Disease
injury	I-Disease
compared	O
with	O
Nrf2	O
(	O
+	O
/	O
+	O
)	O
mice	O
.	O

Mechanistic	O
studies	O
in	O
both	O
in	O
vivo	O
and	O
in	O
vitro	O
systems	O
showed	O
that	O
the	O
Nrf2	O
-	O
mediated	O
protection	O
against	O
diabetic	B-Disease
nephropathy	I-Disease
is	O
,	O
at	O
least	O
,	O
partially	O
through	O
inhibition	O
of	O
transforming	O
growth	O
factor	O
-	O
beta1	O
(	O
TGF	O
-	O
beta1	O
)	O
and	O
reduction	O
of	O
extracellular	O
matrix	O
production	O
.	O

In	O
human	O
renal	O
mesangial	O
cells	O
,	O
high	O
glucose	B-Chemical
induced	O
ROS	O
production	O
and	O
activated	O
expression	O
of	O
Nrf2	O
and	O
its	O
downstream	O
genes	O
.	O

Furthermore	O
,	O
activation	O
or	O
overexpression	O
of	O
Nrf2	O
inhibited	O
the	O
promoter	O
activity	O
of	O
TGF	O
-	O
beta1	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
,	O
whereas	O
knockdown	O
of	O
Nrf2	O
by	O
siRNA	O
enhanced	O
TGF	O
-	O
beta1	O
transcription	O
and	O
fibronectin	O
production	O
.	O

CONCLUSIONS	O
:	O
This	O
work	O
clearly	O
indicates	O
a	O
protective	O
role	O
of	O
Nrf2	O
in	O
diabetic	B-Disease
nephropathy	I-Disease
,	O
suggesting	O
that	O
dietary	O
or	O
therapeutic	O
activation	O
of	O
Nrf2	O
could	O
be	O
used	O
as	O
a	O
strategy	O
to	O
prevent	O
or	O
slow	O
down	O
the	O
progression	O
of	O
diabetic	B-Disease
nephropathy	I-Disease
.	O

Metformin	B-Chemical
prevents	O
experimental	O
gentamicin	B-Chemical
-	O
induced	O
nephropathy	B-Disease
by	O
a	O
mitochondria	O
-	O
dependent	O
pathway	O
.	O

The	O
antidiabetic	O
drug	O
metformin	B-Chemical
can	O
diminish	O
apoptosis	O
induced	O
by	O
oxidative	O
stress	O
in	O
endothelial	O
cells	O
and	O
prevent	O
vascular	B-Disease
dysfunction	I-Disease
even	O
in	O
nondiabetic	O
patients	O
.	O

Here	O
we	O
tested	O
whether	O
it	O
has	O
a	O
beneficial	O
effect	O
in	O
a	O
rat	O
model	O
of	O
gentamicin	B-Chemical
toxicity	B-Disease
.	O

Mitochondrial	O
analysis	O
,	O
respiration	O
intensity	O
,	O
levels	O
of	O
reactive	O
oxygen	B-Chemical
species	O
,	O
permeability	O
transition	O
,	O
and	O
cytochrome	O
c	O
release	O
were	O
assessed	O
3	O
and	O
6	O
days	O
after	O
gentamicin	B-Chemical
administration	O
.	O

Metformin	B-Chemical
treatment	O
fully	O
blocked	O
gentamicin	B-Chemical
-	O
mediated	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

This	O
was	O
accompanied	O
by	O
a	O
lower	O
activity	O
of	O
N	O
-	O
acetyl	O
-	O
beta	O
-	O
D	O
-	O
glucosaminidase	O
,	O
together	O
with	O
a	O
decrease	O
of	O
lipid	O
peroxidation	O
and	O
increase	O
of	O
antioxidant	O
systems	O
.	O

Metformin	B-Chemical
also	O
protected	O
the	O
kidney	O
from	O
histological	O
damage	O
6	O
days	O
after	O
gentamicin	B-Chemical
administration	O
.	O

These	O
in	O
vivo	O
markers	O
of	O
kidney	B-Disease
dysfunction	I-Disease
and	O
their	O
correction	O
by	O
metformin	B-Chemical
were	O
complemented	O
by	O
in	O
vitro	O
studies	O
of	O
mitochondrial	O
function	O
.	O

We	O
found	O
that	O
gentamicin	B-Chemical
treatment	O
depleted	O
respiratory	O
components	O
(	O
cytochrome	O
c	O
,	O
NADH	O
)	O
,	O
probably	O
due	O
to	O
the	O
opening	O
of	O
mitochondrial	O
transition	O
pores	O
.	O

These	O
injuries	O
,	O
partly	O
mediated	O
by	O
a	O
rise	O
in	O
reactive	O
oxygen	B-Chemical
species	O
from	O
the	O
electron	O
transfer	O
chain	O
,	O
were	O
significantly	O
decreased	O
by	O
metformin	B-Chemical
.	O

Thus	O
,	O
our	O
study	O
suggests	O
that	O
pleiotropic	O
effects	O
of	O
metformin	B-Chemical
can	O
lessen	O
gentamicin	B-Chemical
nephrotoxicity	B-Disease
and	O
improve	O
mitochondrial	O
homeostasis	O
.	O

Risk	O
of	O
nephropathy	B-Disease
after	O
consumption	O
of	O
nonionic	O
contrast	B-Chemical
media	I-Chemical
by	O
children	O
undergoing	O
cardiac	O
angiography	O
:	O
a	O
prospective	O
study	O
.	O

Despite	O
increasing	O
reports	O
on	O
nonionic	O
contrast	B-Chemical
media	I-Chemical
-	O
induced	O
nephropathy	B-Disease
(	O
CIN	B-Disease
)	O
in	O
hospitalized	O
adult	O
patients	O
during	O
cardiac	O
procedures	O
,	O
the	O
studies	O
in	O
pediatrics	O
are	O
limited	O
,	O
with	O
even	O
less	O
focus	O
on	O
possible	O
predisposing	O
factors	O
and	O
preventive	O
measures	O
for	O
patients	O
undergoing	O
cardiac	O
angiography	O
.	O

This	O
prospective	O
study	O
determined	O
the	O
incidence	O
of	O
CIN	B-Disease
for	O
two	O
nonionic	O
contrast	B-Chemical
media	I-Chemical
(	O
CM	B-Chemical
)	O
,	O
iopromide	B-Chemical
and	O
iohexol	B-Chemical
,	O
among	O
80	O
patients	O
younger	O
than	O
18	O
years	O
and	O
compared	O
the	O
rates	O
for	O
this	O
complication	O
in	O
relation	O
to	O
the	O
type	O
and	O
dosage	O
of	O
CM	B-Chemical
and	O
the	O
presence	O
of	O
cyanosis	B-Disease
.	O

The	O
80	O
patients	O
in	O
the	O
study	O
consecutively	O
received	O
either	O
iopromide	B-Chemical
(	O
group	O
A	O
,	O
n	O
=	O
40	O
)	O
or	O
iohexol	B-Chemical
(	O
group	O
B	O
,	O
n	O
=	O
40	O
)	O
.	O

Serum	O
sodium	B-Chemical
(	O
Na	B-Chemical
)	O
,	O
potassium	B-Chemical
(	O
K	B-Chemical
)	O
,	O
and	O
creatinine	B-Chemical
(	O
Cr	B-Chemical
)	O
were	O
measured	O
24	O
h	O
before	O
angiography	O
as	O
baseline	O
values	O
,	O
then	O
measured	O
again	O
at	O
12	O
-	O
,	O
24	O
-	O
,	O
and	O
48	O
-	O
h	O
intervals	O
after	O
CM	B-Chemical
use	O
.	O

Urine	O
samples	O
for	O
Na	B-Chemical
and	O
Cr	B-Chemical
also	O
were	O
checked	O
at	O
the	O
same	O
intervals	O
.	O

Risk	O
of	O
renal	B-Disease
failure	I-Disease
,	O
Injury	B-Disease
to	I-Disease
the	I-Disease
kidney	I-Disease
,	O
Failure	B-Disease
of	I-Disease
kidney	I-Disease
function	I-Disease
,	O
Loss	B-Disease
of	I-Disease
kidney	I-Disease
function	I-Disease
,	O
and	O
End	O
-	O
stage	O
renal	B-Disease
damage	I-Disease
(	O
RIFLE	O
criteria	O
)	O
were	O
used	O
to	O
define	O
CIN	B-Disease
and	O
its	O
incidence	O
in	O
the	O
study	O
population	O
.	O

Accordingly	O
,	O
among	O
the	O
15	O
CIN	B-Disease
patients	O
(	O
18	O
.	O
75	O
%	O
)	O
,	O
7	O
.	O
5	O
%	O
of	O
the	O
patients	O
in	O
group	O
A	O
had	O
increased	O
risk	O
and	O
3	O
.	O
75	O
%	O
had	O
renal	B-Disease
injury	I-Disease
,	O
whereas	O
5	O
%	O
of	O
group	O
B	O
had	O
increased	O
risk	O
and	O
2	O
.	O
5	O
%	O
had	O
renal	B-Disease
injury	I-Disease
.	O

Whereas	O
33	O
.	O
3	O
%	O
of	O
the	O
patients	O
with	O
CIN	B-Disease
were	O
among	O
those	O
who	O
received	O
the	O
proper	O
dosage	O
of	O
CM	B-Chemical
,	O
the	O
percentage	O
increased	O
to	O
66	O
.	O
6	O
%	O
among	O
those	O
who	O
received	O
larger	O
doses	O
,	O
with	O
a	O
significant	O
difference	O
in	O
the	O
incidence	O
of	O
CIN	B-Disease
related	O
to	O
the	O
different	O
dosages	O
of	O
CM	B-Chemical
(	O
p	O
=	O
0	O
.	O
014	O
)	O
.	O

Among	O
the	O
15	O
patients	O
with	O
CIN	B-Disease
,	O
6	O
had	O
cyanotic	O
congenital	B-Disease
heart	I-Disease
diseases	I-Disease
,	O
but	O
the	O
incidence	O
did	O
not	O
differ	O
significantly	O
from	O
that	O
for	O
the	O
noncyanotic	O
patients	O
(	O
p	O
=	O
0	O
.	O
243	O
)	O
.	O

Although	O
clinically	O
silent	O
,	O
CIN	B-Disease
is	O
not	O
rare	O
in	O
pediatrics	O
.	O

The	O
incidence	O
depends	O
on	O
dosage	O
but	O
not	O
on	O
the	O
type	O
of	O
consumed	O
nonionic	O
CM	B-Chemical
,	O
nor	O
on	O
the	O
presence	O
of	O
cyanosis	B-Disease
,	O
and	O
although	O
CIN	B-Disease
usually	O
is	O
reversible	O
,	O
more	O
concern	O
is	O
needed	O
for	O
the	O
prevention	O
of	O
such	O
a	O
complication	O
in	O
children	O
.	O

Renal	O
function	O
and	O
hemodynamics	O
during	O
prolonged	O
isoflurane	B-Chemical
-	O
induced	O
hypotension	B-Disease
in	O
humans	O
.	O

The	O
effect	O
of	O
isoflurane	B-Chemical
-	O
induced	O
hypotension	B-Disease
on	O
glomerular	O
function	O
and	O
renal	O
blood	O
flow	O
was	O
investigated	O
in	O
20	O
human	O
subjects	O
.	O

Glomerular	O
filtration	O
rate	O
(	O
GFR	O
)	O
and	O
effective	O
renal	O
plasma	O
flow	O
(	O
ERPF	O
)	O
were	O
measured	O
by	O
inulin	O
and	O
para	B-Chemical
-	I-Chemical
aminohippurate	I-Chemical
(	O
PAH	B-Chemical
)	O
clearance	O
,	O
respectively	O
.	O

Anesthesia	O
was	O
maintained	O
with	O
fentanyl	B-Chemical
,	O
nitrous	B-Chemical
oxide	I-Chemical
,	O
oxygen	B-Chemical
,	O
and	O
isoflurane	B-Chemical
.	O

Hypotension	B-Disease
was	O
induced	O
for	O
236	O
.	O
9	O
+	O
/	O
-	O
15	O
.	O
1	O
min	O
by	O
increasing	O
the	O
isoflurane	B-Chemical
inspired	O
concentration	O
to	O
maintain	O
a	O
mean	O
arterial	O
pressure	O
of	O
59	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
4	O
mmHg	O
.	O

GFR	O
and	O
ERPF	O
decreased	O
with	O
the	O
induction	O
of	O
anesthesia	O
but	O
not	O
significantly	O
more	O
during	O
hypotension	B-Disease
.	O

Postoperatively	O
,	O
ERPF	O
returned	O
to	O
preoperative	O
values	O
,	O
whereas	O
GFR	O
was	O
higher	O
than	O
preoperative	O
values	O
.	O

Renal	O
vascular	O
resistance	O
increased	O
during	O
anesthesia	O
but	O
decreased	O
when	O
hypotension	B-Disease
was	O
induced	O
,	O
allowing	O
the	O
maintenance	O
of	O
renal	O
blood	O
flow	O
.	O

We	O
conclude	O
that	O
renal	O
compensatory	O
mechanisms	O
are	O
preserved	O
during	O
isoflurane	B-Chemical
-	O
induced	O
hypotension	B-Disease
and	O
that	O
renal	O
function	O
and	O
hemodynamics	O
quickly	O
return	O
to	O
normal	O
when	O
normotension	O
is	O
resumed	O
.	O

Brainstem	B-Disease
dysgenesis	I-Disease
in	O
an	O
infant	O
prenatally	O
exposed	O
to	O
cocaine	B-Chemical
.	O

Many	O
authors	O
described	O
the	O
effects	O
on	O
the	O
fetus	O
of	O
maternal	O
cocaine	B-Disease
abuse	I-Disease
during	O
pregnancy	O
.	O

Vasoconstriction	O
appears	O
to	O
be	O
the	O
common	O
mechanism	O
of	O
action	O
leading	O
to	O
a	O
wide	O
range	O
of	O
fetal	B-Disease
anomalies	I-Disease
.	O

We	O
report	O
on	O
an	O
infant	O
with	O
multiple	B-Disease
cranial	I-Disease
-	I-Disease
nerve	I-Disease
involvement	I-Disease
attributable	O
to	O
brainstem	B-Disease
dysgenesis	I-Disease
,	O
born	O
to	O
a	O
cocaine	B-Disease
-	I-Disease
addicted	I-Disease
mother	O
.	O

A	O
cross	O
-	O
sectional	O
evaluation	O
of	O
the	O
effect	O
of	O
risperidone	B-Chemical
and	O
selective	O
serotonin	B-Chemical
reuptake	O
inhibitors	O
on	O
bone	O
mineral	O
density	O
in	O
boys	O
.	O

OBJECTIVE	O
:	O
The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
the	O
effect	O
of	O
risperidone	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
on	O
trabecular	O
bone	O
mineral	O
density	O
(	O
BMD	O
)	O
in	O
children	O
and	O
adolescents	O
.	O

METHOD	O
:	O
Medically	O
healthy	O
7	O
-	O
to	O
17	O
-	O
year	O
-	O
old	O
males	O
chronically	O
treated	O
,	O
in	O
a	O
naturalistic	O
setting	O
,	O
with	O
risperidone	B-Chemical
were	O
recruited	O
for	O
this	O
cross	O
-	O
sectional	O
study	O
through	O
child	O
psychiatry	O
outpatient	O
clinics	O
between	O
November	O
2005	O
and	O
June	O
2007	O
.	O

Anthropometric	O
measurements	O
and	O
laboratory	O
testing	O
were	O
conducted	O
.	O

The	O
clinical	O
diagnoses	O
were	O
based	O
on	O
chart	O
review	O
,	O
and	O
developmental	O
and	O
treatment	O
history	O
was	O
obtained	O
from	O
the	O
medical	O
record	O
.	O

Volumetric	O
BMD	O
of	O
the	O
ultradistal	O
radius	O
was	O
measured	O
using	O
peripheral	O
quantitative	O
computed	O
tomography	O
,	O
and	O
areal	O
BMD	O
of	O
the	O
lumbar	O
spine	O
was	O
estimated	O
using	O
dual	O
-	O
energy	O
x	O
-	O
ray	O
absorptiometry	O
.	O

RESULTS	O
:	O
Hyperprolactinemia	B-Disease
was	O
present	O
in	O
49	O
%	O
of	O
83	O
boys	O
(	O
n	O
=	O
41	O
)	O
treated	O
with	O
risperidone	B-Chemical
for	O
a	O
mean	O
of	O
2	O
.	O
9	O
years	O
.	O

Serum	O
testosterone	B-Chemical
concentration	O
increased	O
with	O
pubertal	O
status	O
but	O
was	O
not	O
affected	O
by	O
hyperprolactinemia	B-Disease
.	O

As	O
expected	O
,	O
bone	O
mineral	O
content	O
and	O
BMD	O
increased	O
with	O
sexual	O
maturity	O
.	O

After	O
adjusting	O
for	O
the	O
stage	O
of	O
sexual	O
development	O
and	O
height	O
and	O
BMI	O
z	O
scores	O
,	O
serum	O
prolactin	O
was	O
negatively	O
associated	O
with	O
trabecular	O
volumetric	O
BMD	O
at	O
the	O
ultradistal	O
radius	O
(	O
P	O
<	O
.	O
03	O
)	O
.	O

Controlling	O
for	O
relevant	O
covariates	O
,	O
we	O
also	O
found	O
treatment	O
with	O
selective	O
serotonin	B-Chemical
reuptake	O
inhibitors	O
(	O
SSRIs	O
)	O
to	O
be	O
associated	O
with	O
lower	O
trabecular	O
BMD	O
at	O
the	O
radius	O
(	O
P	O
=	O
.	O
03	O
)	O
and	O
BMD	O
z	O
score	O
at	O
the	O
lumbar	O
spine	O
(	O
P	O
<	O
.	O
05	O
)	O
.	O

These	O
findings	O
became	O
more	O
marked	O
when	O
the	O
analysis	O
was	O
restricted	O
to	O
non	O
-	O
Hispanic	O
white	O
patients	O
.	O

Of	O
13	O
documented	O
fractures	B-Disease
,	O
3	O
occurred	O
after	O
risperidone	B-Chemical
and	O
SSRIs	O
were	O
started	O
,	O
and	O
none	O
occurred	O
in	O
patients	O
with	O
hyperprolactinemia	B-Disease
.	O

CONCLUSIONS	O
:	O
This	O
is	O
the	O
first	O
study	O
to	O
link	O
risperidone	B-Chemical
-	O
induced	O
hyperprolactinemia	B-Disease
and	O
SSRI	O
treatment	O
to	O
lower	O
BMD	O
in	O
children	O
and	O
adolescents	O
.	O

Future	O
research	O
should	O
evaluate	O
the	O
longitudinal	O
course	O
of	O
this	O
adverse	O
event	O
to	O
determine	O
its	O
temporal	O
stability	O
and	O
whether	O
a	O
higher	O
fracture	O
rate	O
ensues	O
.	O

Fear	O
-	O
potentiated	O
startle	B-Disease
,	O
but	O
not	O
light	O
-	O
enhanced	O
startle	B-Disease
,	O
is	O
enhanced	O
by	O
anxiogenic	O
drugs	O
.	O

RATIONALE	O
AND	O
OBJECTIVES	O
:	O
The	O
light	O
-	O
enhanced	O
startle	B-Disease
paradigm	O
(	O
LES	O
)	O
is	O
suggested	O
to	O
model	O
anxiety	B-Disease
,	O
because	O
of	O
the	O
non	O
-	O
specific	O
cue	O
and	O
the	O
long	O
-	O
term	O
effect	O
.	O

In	O
contrast	O
,	O
the	O
fear	O
-	O
potentiated	O
startle	B-Disease
(	O
FPS	O
)	O
is	O
suggested	O
to	O
model	O
conditioned	O
fear	O
.	O

However	O
,	O
the	O
pharmacological	O
profiles	O
of	O
these	O
two	O
paradigms	O
are	O
very	O
similar	O
.	O

The	O
present	O
study	O
investigated	O
the	O
effects	O
of	O
putative	O
anxiogenic	O
drugs	O
on	O
LES	O
and	O
FPS	O
and	O
aimed	O
at	O
determining	O
the	O
sensitivity	O
of	O
LES	O
for	O
anxiogenic	O
drugs	O
and	O
to	O
potentially	O
showing	O
a	O
pharmacological	O
differentiation	O
between	O
these	O
two	O
paradigms	O
.	O

METHODS	O
:	O
Male	O
Wistar	O
rats	O
received	O
each	O
dose	O
of	O
the	O
alpha	O
(	O
2	O
)	O
-	O
adrenoceptor	O
antagonist	O
yohimbine	B-Chemical
(	O
0	O
.	O
25	O
-	O
1	O
.	O
0mg	O
/	O
kg	O
)	O
,	O
the	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
(	O
2C	O
)	O
receptor	O
agonist	O
m	B-Chemical
-	I-Chemical
chlorophenylpiperazine	I-Chemical
(	O
mCPP	B-Chemical
,	O
0	O
.	O
5	O
-	O
2	O
.	O
0mg	O
/	O
kg	O
)	O
or	O
the	O
GABA	B-Chemical
(	O
A	O
)	O
inverse	O
receptor	O
agonist	O
pentylenetetrazole	B-Chemical
(	O
PTZ	B-Chemical
,	O
3	O
-	O
30mg	O
/	O
kg	O
)	O
and	O
were	O
subsequently	O
tested	O
in	O
either	O
LES	O
or	O
FPS	O
.	O

RESULTS	O
:	O
None	O
of	O
the	O
drugs	O
enhanced	O
LES	O
,	O
whereas	O
mCPP	B-Chemical
increased	O
percentage	O
FPS	O
and	O
yohimbine	B-Chemical
increased	O
absolute	O
FPS	O
values	O
.	O

Furthermore	O
,	O
yohimbine	B-Chemical
increased	O
baseline	O
startle	B-Disease
amplitude	O
in	O
the	O
LES	O
,	O
while	O
mCPP	B-Chemical
suppressed	O
baseline	O
startle	B-Disease
in	O
both	O
the	O
LES	O
and	O
FPS	O
and	O
PTZ	B-Chemical
suppressed	O
baseline	O
startle	B-Disease
in	O
the	O
FPS	O
.	O

CONCLUSIONS	O
:	O
In	O
contrast	O
to	O
findings	O
in	O
the	O
FPS	O
paradigm	O
,	O
none	O
of	O
the	O
drugs	O
were	O
able	O
to	O
exacerbate	O
the	O
LES	O
response	O
.	O

Thus	O
,	O
a	O
clear	O
pharmacological	O
differentiation	O
was	O
found	O
between	O
LES	O
and	O
FPS	O
.	O

Rosaceiform	O
dermatitis	B-Disease
associated	O
with	O
topical	O
tacrolimus	B-Chemical
treatment	O
.	O

We	O
describe	O
herein	O
3	O
patients	O
who	O
developed	O
rosacea	B-Disease
-	O
like	O
dermatitis	B-Disease
eruptions	B-Disease
while	O
using	O
0	O
.	O
03	O
%	O
or	O
0	O
.	O
1	O
%	O
tacrolimus	B-Chemical
ointment	O
for	O
facial	B-Disease
dermatitis	I-Disease
.	O

Skin	O
biopsy	O
specimens	O
showed	O
telangiectasia	B-Disease
and	O
noncaseating	O
epithelioid	O
granulomatous	O
tissue	O
formation	O
in	O
the	O
papillary	O
to	O
mid	O
dermis	O
.	O

Continuous	O
topical	O
use	O
of	O
immunomodulators	O
such	O
as	O
tacrolimus	B-Chemical
or	O
pimecrolimus	B-Chemical
should	O
be	O
regarded	O
as	O
a	O
potential	O
cause	O
of	O
rosaceiform	O
dermatitis	B-Disease
,	O
although	O
many	O
cases	O
have	O
not	O
been	O
reported	O
.	O

Coenzyme	B-Chemical
Q10	I-Chemical
treatment	O
ameliorates	O
acute	O
cisplatin	B-Chemical
nephrotoxicity	B-Disease
in	O
mice	O
.	O

The	O
nephroprotective	O
effect	O
of	O
coenzyme	B-Chemical
Q10	I-Chemical
was	O
investigated	O
in	O
mice	O
with	O
acute	B-Disease
renal	I-Disease
injury	I-Disease
induced	O
by	O
a	O
single	O
i	O
.	O
p	O
.	O
injection	O
of	O
cisplatin	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
)	O
.	O

Coenzyme	B-Chemical
Q10	I-Chemical
treatment	O
(	O
10	O
mg	O
/	O
kg	O
/	O
day	O
,	O
i	O
.	O
p	O
.	O
)	O
was	O
applied	O
for	O
6	O
consecutive	O
days	O
,	O
starting	O
1	O
day	O
before	O
cisplatin	B-Chemical
administration	O
.	O

Coenzyme	B-Chemical
Q10	I-Chemical
significantly	O
reduced	O
blood	B-Chemical
urea	I-Chemical
nitrogen	I-Chemical
and	O
serum	O
creatinine	B-Chemical
levels	O
which	O
were	O
increased	O
by	O
cisplatin	B-Chemical
.	O

Coenzyme	B-Chemical
Q10	I-Chemical
significantly	O
compensated	O
deficits	O
in	O
the	O
antioxidant	O
defense	O
mechanisms	O
(	O
reduced	B-Chemical
glutathione	I-Chemical
level	O
and	O
superoxide	B-Chemical
dismutase	O
activity	O
)	O
,	O
suppressed	O
lipid	O
peroxidation	O
,	O
decreased	O
the	O
elevations	O
of	O
tumor	B-Disease
necrosis	B-Disease
factor	O
-	O
alpha	O
,	O
nitric	B-Chemical
oxide	I-Chemical
and	O
platinum	B-Chemical
ion	O
concentration	O
,	O
and	O
attenuated	O
the	O
reductions	O
of	O
selenium	B-Chemical
and	O
zinc	B-Chemical
ions	O
in	O
renal	O
tissue	O
resulted	O
from	O
cisplatin	B-Chemical
administration	O
.	O

Also	O
,	O
histopathological	O
renal	B-Disease
tissue	I-Disease
damage	I-Disease
mediated	O
by	O
cisplatin	B-Chemical
was	O
ameliorated	O
by	O
coenzyme	B-Chemical
Q10	I-Chemical
treatment	O
.	O

Immunohistochemical	O
analysis	O
revealed	O
that	O
coenzyme	B-Chemical
Q10	I-Chemical
significantly	O
decreased	O
the	O
cisplatin	B-Chemical
-	O
induced	O
overexpression	O
of	O
inducible	O
nitric	B-Chemical
oxide	I-Chemical
synthase	O
,	O
nuclear	O
factor	O
-	O
kappaB	O
,	O
caspase	O
-	O
3	O
and	O
p53	O
in	O
renal	O
tissue	O
.	O

It	O
was	O
concluded	O
that	O
coenzyme	B-Chemical
Q10	I-Chemical
represents	O
a	O
potential	O
therapeutic	O
option	O
to	O
protect	O
against	O
acute	O
cisplatin	B-Chemical
nephrotoxicity	B-Disease
commonly	O
encountered	O
in	O
clinical	O
practice	O
.	O

Reversible	O
cholestasis	B-Disease
with	O
bile	B-Disease
duct	I-Disease
injury	I-Disease
following	O
azathioprine	B-Chemical
therapy	O
.	O

A	O
case	O
report	O
.	O

A	O
67	O
-	O
year	O
-	O
old	O
patient	O
,	O
with	O
primary	O
polymyositis	B-Disease
and	O
without	O
previous	O
evidence	O
of	O
liver	B-Disease
disease	I-Disease
,	O
developed	O
clinical	O
and	O
biochemical	O
features	O
of	O
severe	O
cholestasis	B-Disease
3	O
months	O
after	O
initiation	O
of	O
azathioprine	B-Chemical
therapy	O
.	O

Liver	O
biopsy	O
showed	O
cholestasis	B-Disease
with	O
both	O
cytological	O
and	O
architectural	O
alterations	O
of	O
interlobular	O
bile	O
ducts	O
.	O

Azathioprine	B-Chemical
withdrawal	O
resulted	O
after	O
7	O
weeks	O
in	O
the	O
resolution	O
of	O
clinical	O
and	O
biochemical	O
abnormalities	O
.	O

It	O
is	O
believed	O
that	O
this	O
is	O
the	O
first	O
reported	O
case	O
of	O
reversible	O
azathioprine	B-Chemical
-	O
induced	O
cholestasis	B-Disease
associated	O
with	O
histological	O
evidence	O
of	O
bile	B-Disease
duct	I-Disease
injury	I-Disease
.	O

Dopamine	B-Chemical
is	O
not	O
essential	O
for	O
the	O
development	O
of	O
methamphetamine	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
.	O

It	O
is	O
widely	O
believed	O
that	O
dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
mediates	O
methamphetamine	B-Chemical
(	O
METH	B-Chemical
)	O
-	O
induced	O
toxicity	B-Disease
to	O
brain	O
dopaminergic	O
neurons	O
,	O
because	O
drugs	O
that	O
interfere	O
with	O
DA	B-Chemical
neurotransmission	O
decrease	O
toxicity	B-Disease
,	O
whereas	O
drugs	O
that	O
increase	O
DA	B-Chemical
neurotransmission	O
enhance	O
toxicity	B-Disease
.	O

However	O
,	O
temperature	O
effects	O
of	O
drugs	O
that	O
have	O
been	O
used	O
to	O
manipulate	O
brain	O
DA	B-Chemical
neurotransmission	O
confound	O
interpretation	O
of	O
the	O
data	O
.	O

Here	O
we	O
show	O
that	O
the	O
recently	O
reported	O
ability	O
of	O
L	B-Chemical
-	I-Chemical
dihydroxyphenylalanine	I-Chemical
to	O
reverse	O
the	O
protective	O
effect	O
of	O
alpha	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
para	I-Chemical
-	I-Chemical
tyrosine	I-Chemical
on	O
METH	B-Chemical
-	O
induced	O
DA	B-Chemical
neurotoxicity	B-Disease
is	O
also	O
confounded	O
by	O
drug	O
effects	O
on	O
body	O
temperature	O
.	O

Further	O
,	O
we	O
show	O
that	O
mice	O
genetically	O
engineered	O
to	O
be	O
deficient	O
in	O
brain	O
DA	B-Chemical
develop	O
METH	B-Chemical
neurotoxicity	B-Disease
,	O
as	O
long	O
as	O
the	O
thermic	O
effects	O
of	O
METH	B-Chemical
are	O
preserved	O
.	O

In	O
addition	O
,	O
we	O
demonstrate	O
that	O
mice	O
genetically	O
engineered	O
to	O
have	O
unilateral	O
brain	O
DA	B-Chemical
deficits	O
develop	O
METH	B-Chemical
-	O
induced	O
dopaminergic	B-Disease
deficits	I-Disease
that	O
are	O
of	O
comparable	O
magnitude	O
on	O
both	O
sides	O
of	O
the	O
brain	O
.	O

Taken	O
together	O
,	O
these	O
findings	O
demonstrate	O
that	O
DA	B-Chemical
is	O
not	O
essential	O
for	O
the	O
development	O
of	O
METH	B-Chemical
-	O
induced	O
dopaminergic	O
neurotoxicity	B-Disease
and	O
suggest	O
that	O
mechanisms	O
independent	O
of	O
DA	B-Chemical
warrant	O
more	O
intense	O
investigation	O
.	O

Swallowing	O
-	O
induced	O
atrial	B-Disease
tachyarrhythmia	I-Disease
triggered	O
by	O
salbutamol	B-Chemical
:	O
case	O
report	O
and	O
review	O
of	O
the	O
literature	O
.	O

CASE	O
:	O
A	O
49	O
-	O
year	O
-	O
old	O
patient	O
experienced	O
chest	O
discomfort	O
while	O
swallowing	O
.	O

On	O
electrocardiogram	O
,	O
episodes	O
of	O
atrial	B-Disease
tachyarrhythmia	I-Disease
were	O
recorded	O
immediately	O
after	O
swallowing	O
;	O
24	O
-	O
hour	O
Holter	O
monitoring	O
recorded	O
several	O
events	O
.	O

The	O
arrhythmia	B-Disease
resolved	O
after	O
therapy	O
with	O
atenolol	B-Chemical
,	O
but	O
recurred	O
a	O
year	O
later	O
.	O

The	O
patient	O
noticed	O
that	O
before	O
these	O
episodes	O
he	O
had	O
been	O
using	O
an	O
inhalator	O
of	O
salbutamol	B-Chemical
.	O

After	O
stopping	O
the	O
beta	O
-	O
agonist	O
,	O
and	O
after	O
a	O
week	O
with	O
the	O
atenolol	B-Chemical
,	O
the	O
arrhythmia	B-Disease
disappeared	O
.	O

DISCUSSION	O
:	O
Swallowing	O
-	O
induced	O
atrial	B-Disease
tachyarrhythmia	I-Disease
(	O
SIAT	B-Disease
)	O
is	O
a	O
rare	O
phenomenon	O
.	O

Fewer	O
than	O
50	O
cases	O
of	O
SIAT	B-Disease
have	O
been	O
described	O
in	O
the	O
literature	O
.	O

This	O
article	O
summarizes	O
all	O
the	O
cases	O
published	O
,	O
creating	O
a	O
comprehensive	O
review	O
of	O
the	O
current	O
knowledge	O
and	O
approach	O
to	O
SIAT	B-Disease
.	O

It	O
discusses	O
demographics	O
,	O
clinical	O
characteristics	O
and	O
types	O
of	O
arrhythmia	B-Disease
,	O
postulated	O
mechanisms	O
of	O
SIAT	B-Disease
,	O
and	O
different	O
treatment	O
possibilities	O
such	O
as	O
medications	O
,	O
surgery	O
,	O
and	O
radiofrequency	O
catheter	O
ablation	O
(	O
RFCA	O
)	O
.	O

CONCLUSION	O
:	O
Salbutamol	B-Chemical
is	O
presented	O
here	O
as	O
a	O
possible	O
trigger	O
for	O
SIAT	B-Disease
.	O

Although	O
it	O
is	O
difficult	O
to	O
define	O
causality	O
in	O
a	O
case	O
report	O
,	O
it	O
is	O
logical	O
to	O
think	O
that	O
a	O
beta	O
-	O
agonist	O
like	O
salbutamol	B-Chemical
(	O
known	O
to	O
induce	O
tachycardia	B-Disease
)	O
may	O
be	O
the	O
trigger	O
of	O
adrenergic	O
reflexes	O
originating	O
in	O
the	O
esophagus	O
while	O
swallowing	O
and	O
that	O
a	O
beta	O
-	O
blocker	O
such	O
as	O
atenolol	B-Chemical
(	O
that	O
blocks	O
the	O
adrenergic	O
activity	O
)	O
may	O
relieve	O
it	O
.	O

The	O
ability	O
of	O
insulin	O
treatment	O
to	O
reverse	O
or	O
prevent	O
the	O
changes	O
in	O
urinary	O
bladder	O
function	O
caused	O
by	O
streptozotocin	B-Chemical
-	O
induced	O
diabetes	B-Disease
mellitus	I-Disease
.	O

1	O
.	O

The	O
effects	O
of	O
insulin	O
treatment	O
on	O
in	O
vivo	O
and	O
in	O
vitro	O
urinary	O
bladder	O
function	O
in	O
streptozotocin	B-Chemical
-	O
diabetic	B-Disease
rats	O
were	O
investigated	O
.	O

2	O
.	O

Diabetes	B-Disease
of	O
2	O
months	O
duration	O
resulted	O
in	O
decreases	O
in	O
body	O
weight	O
and	O
increases	O
in	O
fluid	O
consumption	O
,	O
urine	O
volume	O
,	O
frequency	O
of	O
micturition	O
,	O
and	O
average	O
volume	O
per	O
micturition	O
;	O
effects	O
which	O
were	O
prevented	O
by	O
insulin	O
treatment	O
.	O

3	O
.	O

Insulin	O
treatment	O
also	O
prevented	O
the	O
increases	O
in	O
contractile	O
responses	O
of	O
bladder	O
body	O
strips	O
from	O
diabetic	B-Disease
rats	O
to	O
nerve	O
stimulation	O
,	O
ATP	B-Chemical
,	O
and	O
bethanechol	B-Chemical
.	O

4	O
.	O

Diabetes	B-Disease
of	O
4	O
months	O
duration	O
also	O
resulted	O
in	O
decreases	O
in	O
body	O
weight	O
,	O
and	O
increases	O
in	O
fluid	O
consumption	O
,	O
urine	O
volume	O
,	O
frequency	O
of	O
micturition	O
,	O
and	O
average	O
volume	O
per	O
micturition	O
,	O
effects	O
which	O
were	O
reversed	O
by	O
insulin	O
treatment	O
for	O
the	O
final	O
2	O
months	O
of	O
the	O
study	O
.	O

5	O
.	O

Insulin	O
treatment	O
reversed	O
the	O
increases	O
in	O
contractile	O
responses	O
of	O
bladder	O
body	O
strips	O
from	O
diabetic	B-Disease
rats	O
to	O
nerve	O
stimulation	O
,	O
ATP	B-Chemical
,	O
and	O
bethanechol	B-Chemical
.	O

6	O
.	O

The	O
data	O
indicate	O
that	O
the	O
effects	O
of	O
streptozotocin	B-Chemical
-	O
induced	O
diabetes	B-Disease
on	O
urinary	O
bladder	O
function	O
are	O
both	O
prevented	O
and	O
reversed	O
by	O
insulin	O
treatment	O
.	O

Glutamatergic	O
neurotransmission	O
mediated	O
by	O
NMDA	B-Chemical
receptors	O
in	O
the	O
inferior	O
colliculus	O
can	O
modulate	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
.	O

The	O
inferior	O
colliculus	O
(	O
IC	O
)	O
is	O
primarily	O
involved	O
in	O
the	O
processing	O
of	O
auditory	O
information	O
,	O
but	O
it	O
is	O
distinguished	O
from	O
other	O
auditory	O
nuclei	O
in	O
the	O
brainstem	O
by	O
its	O
connections	O
with	O
structures	O
of	O
the	O
motor	O
system	O
.	O

Functional	O
evidence	O
relating	O
the	O
IC	O
to	O
motor	O
behavior	O
derives	O
from	O
experiments	O
showing	O
that	O
activation	O
of	O
the	O
IC	O
by	O
electrical	O
stimulation	O
or	O
excitatory	O
amino	B-Chemical
acid	I-Chemical
microinjection	O
causes	O
freezing	O
,	O
escape	O
-	O
like	O
behavior	O
,	O
and	O
immobility	O
.	O

However	O
,	O
the	O
nature	O
of	O
this	O
immobility	O
is	O
still	O
unclear	O
.	O

The	O
present	O
study	O
examined	O
the	O
influence	O
of	O
excitatory	O
amino	B-Chemical
acid	I-Chemical
-	O
mediated	O
mechanisms	O
in	O
the	O
IC	O
on	O
the	O
catalepsy	B-Disease
induced	O
by	O
the	O
dopamine	B-Chemical
receptor	O
blocker	O
haloperidol	B-Chemical
administered	O
systemically	O
(	O
1	O
or	O
0	O
.	O
5	O
mg	O
/	O
kg	O
)	O
in	O
rats	O
.	O

Haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
was	O
challenged	O
with	O
prior	O
intracollicular	O
microinjections	O
of	O
glutamate	B-Chemical
NMDA	B-Chemical
receptor	O
antagonists	O
,	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
(	O
15	O
or	O
30	O
mmol	O
/	O
0	O
.	O
5	O
microl	O
)	O
and	O
AP7	B-Chemical
(	O
10	O
or	O
20	O
nmol	O
/	O
0	O
.	O
5	O
microl	O
)	O
,	O
or	O
of	O
the	O
NMDA	B-Chemical
receptor	O
agonist	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
d	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
,	O
20	O
or	O
30	O
nmol	O
/	O
0	O
.	O
5	O
microl	O
)	O
.	O

The	O
results	O
showed	O
that	O
intracollicular	O
microinjection	O
of	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
and	O
AP7	B-Chemical
previous	O
to	O
systemic	O
injections	O
of	O
haloperidol	B-Chemical
significantly	O
attenuated	O
the	O
catalepsy	B-Disease
,	O
as	O
indicated	O
by	O
a	O
reduced	O
latency	O
to	O
step	O
down	O
from	O
a	O
horizontal	O
bar	O
.	O

Accordingly	O
,	O
intracollicular	O
microinjection	O
of	O
NMDA	B-Chemical
increased	O
the	O
latency	O
to	O
step	O
down	O
the	O
bar	O
.	O

These	O
findings	O
suggest	O
that	O
glutamate	B-Chemical
-	O
mediated	O
mechanisms	O
in	O
the	O
neural	O
circuits	O
at	O
the	O
IC	O
level	O
influence	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
and	O
participate	O
in	O
the	O
regulation	O
of	O
motor	O
activity	O
.	O

Severe	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
patient	O
on	O
amiodarone	B-Chemical
presenting	O
with	O
myxedemic	B-Disease
coma	I-Disease
:	O
a	O
case	O
report	O
.	O

This	O
is	O
a	O
case	O
report	O
of	O
myxedema	B-Disease
coma	I-Disease
secondary	O
to	O
amiodarone	B-Chemical
-	O
induced	O
hypothyroidism	B-Disease
in	O
a	O
patient	O
with	O
severe	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
(	O
CHF	B-Disease
)	O
.	O

To	O
our	O
knowledge	O
and	O
after	O
reviewing	O
the	O
literature	O
there	O
is	O
one	O
case	O
report	O
of	O
myxedema	B-Disease
coma	I-Disease
during	O
long	O
term	O
amiodarone	B-Chemical
therapy	O
.	O

Myxedema	B-Disease
coma	I-Disease
is	O
a	O
life	O
threatening	O
condition	O
that	O
carries	O
a	O
mortality	O
reaching	O
as	O
high	O
as	O
20	O
%	O
with	O
treatment	O
.	O

The	O
condition	O
is	O
treated	O
with	O
intravenous	O
thyroxine	B-Chemical
(	O
T4	B-Chemical
)	O
or	O
intravenous	O
tri	B-Chemical
-	I-Chemical
iodo	I-Chemical
-	I-Chemical
thyronine	I-Chemical
(	O
T3	B-Chemical
)	O
.	O

Patients	O
with	O
CHF	B-Disease
on	O
amiodarone	B-Chemical
may	O
suffer	O
serious	O
morbidity	O
and	O
mortality	O
from	O
hypothyroidism	B-Disease
,	O
and	O
thus	O
may	O
deserve	O
closer	O
follow	O
up	O
for	O
thyroid	O
stimulating	O
hormone	O
(	O
TSH	O
)	O
levels	O
.	O

This	O
case	O
report	O
carries	O
an	O
important	O
clinical	O
application	O
given	O
the	O
frequent	O
usage	O
of	O
amiodarone	B-Chemical
among	O
CHF	B-Disease
patients	O
.	O

The	O
myriad	O
clinical	O
presentation	O
of	O
myxedema	B-Disease
coma	I-Disease
and	O
its	O
serious	O
morbidity	O
and	O
mortality	O
stresses	O
the	O
need	O
to	O
suspect	O
this	O
clinical	O
syndrome	O
among	O
CHF	B-Disease
patients	O
presenting	O
with	O
hypotension	B-Disease
,	O
weakness	B-Disease
or	O
other	O
unexplained	O
symptoms	O
.	O

Effects	O
of	O
active	O
constituents	O
of	O
Crocus	O
sativus	O
L	O
.	O
,	O
crocin	B-Chemical
on	O
streptozocin	B-Chemical
-	O
induced	O
model	O
of	O
sporadic	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
in	O
male	O
rats	O
.	O

BACKGROUND	O
:	O
The	O
involvement	O
of	O
water	O
-	O
soluble	O
carotenoids	B-Chemical
,	O
crocins	B-Chemical
,	O
as	O
the	O
main	O
and	O
active	O
components	O
of	O
Crocus	O
sativus	O
L	O
.	O
extract	O
in	O
learning	O
and	O
memory	O
processes	O
has	O
been	O
proposed	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
effect	O
of	O
crocins	B-Chemical
on	O
sporadic	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
induced	O
by	O
intracerebroventricular	O
(	O
icv	O
)	O
streptozocin	B-Chemical
(	O
STZ	B-Chemical
)	O
in	O
male	O
rats	O
was	O
investigated	O
.	O

METHODS	O
:	O
Male	O
adult	O
Wistar	O
rats	O
(	O
n	O
=	O
90	O
and	O
260	O
-	O
290	O
g	O
)	O
were	O
divided	O
into	O
1	O
,	O
control	O
;	O
2	O
and	O
3	O
,	O
crocins	B-Chemical
(	O
15	O
and	O
30	O
mg	O
/	O
kg	O
)	O
;	O
4	O
,	O
STZ	B-Chemical
;	O
5	O
and	O
6	O
,	O
STZ	B-Chemical
+	O
crocins	B-Chemical
(	O
15	O
and	O
30	O
mg	O
/	O
kg	O
)	O
groups	O
.	O

In	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
groups	O
,	O
rats	O
were	O
injected	O
with	O
STZ	B-Chemical
-	O
icv	O
bilaterally	O
(	O
3	O
mg	O
/	O
kg	O
)	O
in	O
first	O
day	O
and	O
3	O
days	O
later	O
,	O
a	O
similar	O
STZ	B-Chemical
-	O
icv	O
application	O
was	O
repeated	O
.	O

In	O
STZ	B-Chemical
+	O
crocin	B-Chemical
animal	O
groups	O
,	O
crocin	B-Chemical
was	O
applied	O
in	O
doses	O
of	O
15	O
and	O
30	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
,	O
one	O
day	O
pre	O
-	O
surgery	O
and	O
continued	O
for	O
three	O
weeks	O
.	O

Prescription	O
of	O
crocin	B-Chemical
in	O
each	O
dose	O
was	O
repeated	O
once	O
for	O
two	O
days	O
.	O

However	O
,	O
the	O
learning	O
and	O
memory	O
performance	O
was	O
assessed	O
using	O
passive	O
avoidance	O
paradigm	O
,	O
and	O
for	O
spatial	O
cognition	O
evaluation	O
,	O
Y	O
-	O
maze	O
task	O
was	O
used	O
.	O

RESULTS	O
:	O
It	O
was	O
found	O
out	O
that	O
crocin	B-Chemical
(	O
30	O
mg	O
/	O
kg	O
)	O
-	O
treated	O
STZ	B-Chemical
-	O
injected	O
rats	O
show	O
higher	O
correct	O
choices	O
and	O
lower	O
errors	O
in	O
Y	O
-	O
maze	O
than	O
vehicle	O
-	O
treated	O
STZ	B-Chemical
-	O
injected	O
rats	O
.	O

In	O
addition	O
,	O
crocin	B-Chemical
in	O
the	O
mentioned	O
dose	O
could	O
significantly	O
attenuated	O
learning	B-Disease
and	I-Disease
memory	I-Disease
impairment	I-Disease
in	O
treated	O
STZ	B-Chemical
-	O
injected	O
group	O
in	O
passive	O
avoidance	O
test	O
.	O

CONCLUSION	O
:	O
Therefore	O
,	O
these	O
results	O
demonstrate	O
the	O
effectiveness	O
of	O
crocin	B-Chemical
(	O
30	O
mg	O
/	O
kg	O
)	O
in	O
antagonizing	O
the	O
cognitive	B-Disease
deficits	I-Disease
caused	O
by	O
STZ	B-Chemical
-	O
icv	O
in	O
rats	O
and	O
its	O
potential	O
in	O
the	O
treatment	O
of	O
neurodegenerative	B-Disease
diseases	I-Disease
such	O
as	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Serotonin	B-Chemical
6	O
receptor	O
gene	O
is	O
associated	O
with	O
methamphetamine	B-Chemical
-	O
induced	O
psychosis	B-Disease
in	O
a	O
Japanese	O
population	O
.	O

BACKGROUND	O
:	O
Altered	O
serotonergic	O
neural	O
transmission	O
is	O
hypothesized	O
to	O
be	O
a	O
susceptibility	O
factor	O
for	O
psychotic	B-Disease
disorders	I-Disease
such	O
as	O
schizophrenia	B-Disease
.	O

The	O
serotonin	B-Chemical
6	O
(	O
5	B-Chemical
-	I-Chemical
HT6	I-Chemical
)	O
receptor	O
is	O
therapeutically	O
targeted	O
by	O
several	O
second	O
generation	O
antipsychotics	O
,	O
such	O
as	O
clozapine	B-Chemical
and	O
olanzapine	B-Chemical
,	O
and	O
d	B-Chemical
-	I-Chemical
amphetamine	I-Chemical
-	O
induced	O
hyperactivity	B-Disease
in	O
rats	O
is	O
corrected	O
with	O
the	O
use	O
of	O
a	O
selective	O
5	B-Chemical
-	I-Chemical
HT6	I-Chemical
receptor	O
antagonist	O
.	O

In	O
addition	O
,	O
the	O
disrupted	O
prepulse	O
inhibition	O
induced	O
by	O
d	B-Chemical
-	I-Chemical
amphetamine	I-Chemical
or	O
phencyclidine	B-Chemical
was	O
restored	O
by	O
5	B-Chemical
-	I-Chemical
HT6	I-Chemical
receptor	O
antagonist	O
in	O
an	O
animal	O
study	O
using	O
rats	O
.	O

These	O
animal	O
models	O
were	O
considered	O
to	O
reflect	O
the	O
positive	O
symptoms	O
of	O
schizophrenia	B-Disease
,	O
and	O
the	O
above	O
evidence	O
suggests	O
that	O
altered	O
5	B-Chemical
-	I-Chemical
HT6	I-Chemical
receptors	O
are	O
involved	O
in	O
the	O
pathophysiology	O
of	O
psychotic	B-Disease
disorders	I-Disease
.	O

The	O
symptoms	O
of	O
methamphetamine	B-Chemical
(	O
METH	B-Chemical
)	O
-	O
induced	O
psychosis	B-Disease
are	O
similar	O
to	O
those	O
of	O
paranoid	B-Disease
type	I-Disease
schizophrenia	I-Disease
.	O

Therefore	O
,	O
we	O
conducted	O
an	O
analysis	O
of	O
the	O
association	O
of	O
the	O
5	B-Chemical
-	I-Chemical
HT6	I-Chemical
gene	O
(	O
HTR6	O
)	O
with	O
METH	B-Chemical
-	O
induced	O
psychosis	B-Disease
.	O

METHOD	O
:	O
Using	O
five	O
tagging	O
SNPs	O
(	O
rs6693503	O
,	O
rs1805054	O
,	O
rs4912138	O
,	O
rs3790757	O
and	O
rs9659997	O
)	O
,	O
we	O
conducted	O
a	O
genetic	O
association	O
analysis	O
of	O
case	O
-	O
control	O
samples	O
(	O
197	O
METH	B-Chemical
-	O
induced	O
psychosis	B-Disease
patients	O
and	O
337	O
controls	O
)	O
in	O
the	O
Japanese	O
population	O
.	O

The	O
age	O
and	O
sex	O
of	O
the	O
control	O
subjects	O
did	O
not	O
differ	O
from	O
those	O
of	O
the	O
methamphetamine	B-Chemical
dependence	O
patients	O
.	O

RESULTS	O
:	O
rs6693503	O
was	O
associated	O
with	O
METH	B-Chemical
-	O
induced	O
psychosis	B-Disease
patients	O
in	O
the	O
allele	O
/	O
genotype	O
-	O
wise	O
analysis	O
.	O

Moreover	O
,	O
this	O
association	O
remained	O
significant	O
after	O
Bonferroni	O
correction	O
.	O

In	O
the	O
haplotype	O
-	O
wise	O
analysis	O
,	O
we	O
detected	O
an	O
association	O
between	O
two	O
markers	O
(	O
rs6693503	O
and	O
rs1805054	O
)	O
and	O
three	O
markers	O
(	O
rs6693503	O
,	O
rs1805054	O
and	O
rs4912138	O
)	O
in	O
HTR6	O
and	O
METH	B-Chemical
-	O
induced	O
psychosis	B-Disease
patients	O
,	O
respectively	O
.	O

CONCLUSION	O
:	O
HTR6	O
may	O
play	O
an	O
important	O
role	O
in	O
the	O
pathophysiology	O
of	O
METH	B-Chemical
-	O
induced	O
psychosis	B-Disease
in	O
the	O
Japanese	O
population	O
.	O

Neural	O
correlates	O
of	O
S	B-Chemical
-	I-Chemical
ketamine	I-Chemical
induced	O
psychosis	B-Disease
during	O
overt	O
continuous	O
verbal	O
fluency	O
.	O

The	O
glutamatergic	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
has	O
been	O
implicated	O
in	O
the	O
pathophysiology	O
of	O
schizophrenia	B-Disease
.	O

Administered	O
to	O
healthy	O
volunteers	O
,	O
a	O
subanesthetic	O
dose	O
of	O
the	O
non	O
-	O
competitive	O
NMDA	B-Chemical
receptor	O
antagonist	O
ketamine	B-Chemical
leads	O
to	O
psychopathological	O
symptoms	O
similar	O
to	O
those	O
observed	O
in	O
schizophrenia	B-Disease
.	O

In	O
patients	O
with	O
schizophrenia	B-Disease
,	O
ketamine	B-Chemical
exacerbates	O
the	O
core	O
symptoms	O
of	O
illness	O
,	O
supporting	O
the	O
hypothesis	O
of	O
a	O
glutamatergic	B-Disease
dysfunction	I-Disease
.	O

In	O
a	O
counterbalanced	O
,	O
placebo	O
-	O
controlled	O
,	O
double	O
-	O
blind	O
study	O
design	O
,	O
healthy	O
subjects	O
were	O
administered	O
a	O
continuous	O
subanesthetic	O
S	B-Chemical
-	I-Chemical
ketamine	I-Chemical
infusion	O
while	O
differences	O
in	O
BOLD	O
responses	O
measured	O
with	O
fMRI	O
were	O
detected	O
.	O

During	O
the	O
scanning	O
period	O
,	O
subjects	O
performed	O
continuous	O
overt	O
verbal	O
fluency	O
tasks	O
(	O
phonological	O
,	O
lexical	O
and	O
semantic	O
)	O
.	O

Ketamine	B-Chemical
-	O
induced	O
psychopathological	O
symptoms	O
were	O
assessed	O
with	O
the	O
Positive	O
and	O
Negative	O
Syndrome	O
Scale	O
(	O
PANSS	O
)	O
.	O

Ketamine	B-Chemical
elicited	O
psychosis	B-Disease
like	O
psychopathology	O
.	O

Post	O
-	O
hoc	O
t	O
-	O
tests	O
revealed	O
significant	O
differences	O
between	O
placebo	O
and	O
ketamine	B-Chemical
for	O
the	O
amounts	O
of	O
words	O
generated	O
during	O
lexical	O
and	O
semantic	O
verbal	O
fluency	O
,	O
while	O
the	O
phonological	O
domain	O
remained	O
unaffected	O
.	O

Ketamine	B-Chemical
led	O
to	O
enhanced	O
cortical	O
activations	O
in	O
supramarginal	O
and	O
frontal	O
brain	O
regions	O
for	O
phonological	O
and	O
lexical	O
verbal	O
fluency	O
,	O
but	O
not	O
for	O
semantic	O
verbal	O
fluency	O
.	O

Ketamine	B-Chemical
induces	O
activation	O
changes	O
in	O
healthy	O
subjects	O
similar	O
to	O
those	O
observed	O
in	O
patients	O
with	O
schizophrenia	B-Disease
,	O
particularly	O
in	O
frontal	O
and	O
temporal	O
brain	O
regions	O
.	O

Our	O
results	O
provide	O
further	O
support	O
for	O
the	O
hypothesis	O
of	O
an	O
NMDA	B-Chemical
receptor	O
dysfunction	O
in	O
the	O
pathophysiology	O
of	O
schizophrenia	B-Disease
.	O

Long	O
-	O
term	O
prognosis	O
for	O
transplant	O
-	O
free	O
survivors	O
of	O
paracetamol	B-Chemical
-	O
induced	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
.	O

BACKGROUND	O
:	O
The	O
prognosis	O
for	O
transplant	O
-	O
free	O
survivors	O
of	O
paracetamol	B-Chemical
-	O
induced	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
remains	O
unknown	O
.	O

AIM	O
:	O
To	O
examine	O
whether	O
paracetamol	B-Chemical
-	O
induced	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
increases	O
long	O
-	O
term	O
mortality	O
.	O

METHODS	O
:	O
We	O
followed	O
up	O
all	O
transplant	O
-	O
free	O
survivors	O
of	O
paracetamol	B-Chemical
-	O
induced	O
acute	B-Disease
liver	I-Disease
injury	I-Disease
,	O
hospitalized	O
in	O
a	O
Danish	O
national	O
referral	O
centre	O
during	O
1984	O
-	O
2004	O
.	O

We	O
compared	O
age	O
-	O
specific	O
mortality	O
rates	O
from	O
1	O
year	O
post	O
-	O
discharge	O
through	O
2008	O
between	O
those	O
in	O
whom	O
the	O
liver	B-Disease
injury	I-Disease
led	O
to	O
an	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
and	O
those	O
in	O
whom	O
it	O
did	O
not	O
.	O

RESULTS	O
:	O
We	O
included	O
641	O
patients	O
.	O

On	O
average	O
,	O
age	O
-	O
specific	O
mortality	O
rates	O
were	O
slightly	O
higher	O
for	O
the	O
101	O
patients	O
whose	O
paracetamol	B-Chemical
-	O
induced	O
liver	B-Disease
injury	I-Disease
had	O
caused	O
an	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
(	O
adjusted	O
mortality	O
rate	O
ratio	O
=	O
1	O
.	O
70	O
,	O
95	O
%	O
CI	O
1	O
.	O
02	O
-	O
2	O
.	O
85	O
)	O
,	O
but	O
the	O
association	O
was	O
age	O
-	O
dependent	O
,	O
and	O
no	O
survivors	O
of	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
died	O
of	O
liver	B-Disease
disease	I-Disease
,	O
whereas	O
suicides	O
were	O
frequent	O
in	O
both	O
groups	O
.	O

These	O
observations	O
speak	O
against	O
long	O
-	O
term	O
effects	O
of	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
.	O

More	O
likely	O
,	O
the	O
elevated	O
mortality	O
rate	O
ratio	O
resulted	O
from	O
incomplete	O
adjustment	O
for	O
the	O
greater	O
prevalence	O
of	O
substance	B-Disease
abuse	I-Disease
among	O
survivors	O
of	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
.	O

CONCLUSIONS	O
:	O
Paracetamol	B-Chemical
-	O
induced	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
did	O
not	O
affect	O
long	O
-	O
term	O
mortality	O
.	O

Clinical	O
follow	O
-	O
up	O
may	O
be	O
justified	O
by	O
the	O
cause	O
of	O
the	O
liver	B-Disease
failure	I-Disease
,	O
but	O
not	O
by	O
the	O
liver	B-Disease
failure	I-Disease
itself	O
.	O

In	O
vivo	O
characterization	O
of	O
a	O
dual	O
adenosine	B-Chemical
A2A	I-Chemical
/	I-Chemical
A1	I-Chemical
receptor	I-Chemical
antagonist	I-Chemical
in	O
animal	O
models	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

The	O
in	O
vivo	O
characterization	O
of	O
a	O
dual	O
adenosine	B-Chemical
A	I-Chemical
(	I-Chemical
2A	I-Chemical
)	I-Chemical
/	I-Chemical
A	I-Chemical
(	I-Chemical
1	I-Chemical
)	I-Chemical
receptor	I-Chemical
antagonist	I-Chemical
in	O
several	O
animal	O
models	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
is	O
described	O
.	O

Discovery	O
and	O
scale	O
-	O
up	O
syntheses	O
of	O
compound	O
1	O
are	O
described	O
in	O
detail	O
,	O
highlighting	O
optimization	O
steps	O
that	O
increased	O
the	O
overall	O
yield	O
of	O
1	O
from	O
10	O
.	O
0	O
%	O
to	O
30	O
.	O
5	O
%	O
.	O

Compound	O
1	O
is	O
a	O
potent	O
A	O
(	O
2A	O
)	O
/	O
A	O
(	O
1	O
)	O
receptor	O
antagonist	O
in	O
vitro	O
(	O
A	O
(	O
2A	O
)	O
K	O
(	O
i	O
)	O
=	O
4	O
.	O
1	O
nM	O
;	O
A	O
(	O
1	O
)	O
K	O
(	O
i	O
)	O
=	O
17	O
.	O
0	O
nM	O
)	O
that	O
has	O
excellent	O
activity	O
,	O
after	O
oral	O
administration	O
,	O
across	O
a	O
number	O
of	O
animal	O
models	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
including	O
mouse	O
and	O
rat	O
models	O
of	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
,	O
mouse	O
model	O
of	O
reserpine	B-Chemical
-	O
induced	O
akinesia	B-Disease
,	O
rat	O
6	B-Chemical
-	I-Chemical
hydroxydopamine	I-Chemical
(	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
)	O
lesion	O
model	O
of	O
drug	O
-	O
induced	O
rotation	O
,	O
and	O
MPTP	B-Chemical
-	O
treated	O
non	O
-	O
human	O
primate	O
model	O
.	O

Effects	O
of	O
the	O
hippocampal	O
deep	O
brain	O
stimulation	O
on	O
cortical	O
epileptic	B-Disease
discharges	O
in	O
penicillin	B-Chemical
-	O
induced	O
epilepsy	B-Disease
model	O
in	O
rats	O
.	O

AIM	O
:	O
Experimental	O
and	O
clinical	O
studies	O
have	O
revealed	O
that	O
hippocampal	O
DBS	O
can	O
control	O
epileptic	B-Disease
activity	O
,	O
but	O
the	O
mechanism	O
of	O
action	O
is	O
obscure	O
and	O
optimal	O
stimulation	O
parameters	O
are	O
not	O
clearly	O
defined	O
.	O

The	O
aim	O
was	O
to	O
evaluate	O
the	O
effects	O
of	O
high	O
frequency	O
hippocampal	O
stimulation	O
on	O
cortical	O
epileptic	B-Disease
activity	O
in	O
penicillin	B-Chemical
-	O
induced	O
epilepsy	B-Disease
model	O
.	O

MATERIAL	O
AND	O
METHODS	O
:	O
Twenty	O
-	O
five	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
implanted	O
DBS	O
electrodes	O
.	O

In	O
group	O
-	O
1	O
(	O
n	O
=	O
10	O
)	O
hippocampal	O
DBS	O
was	O
off	O
and	O
in	O
the	O
group	O
-	O
2	O
(	O
n	O
=	O
10	O
)	O
hippocampal	O
DBS	O
was	O
on	O
(	O
185	O
Hz	O
,	O
0	O
.	O
5V	O
,	O
1V	O
,	O
2V	O
,	O
and	O
5V	O
for	O
60	O
sec	O
)	O
following	O
penicillin	B-Chemical
G	I-Chemical
injection	O
intracortically	O
.	O

In	O
the	O
control	O
group	O
hippocampal	O
DBS	O
was	O
on	O
following	O
8	O
l	O
saline	O
injection	O
intracortically	O
.	O

EEG	O
recordings	O
were	O
obtained	O
before	O
and	O
15	O
minutes	O
following	O
penicillin	B-Chemical
-	I-Chemical
G	I-Chemical
injection	O
,	O
and	O
at	O
10th	O
minutes	O
following	O
each	O
stimulus	O
for	O
analysis	O
in	O
terms	O
of	O
frequency	O
,	O
amplitude	O
,	O
and	O
power	O
spectrum	O
.	O

RESULTS	O
:	O
High	O
frequency	O
hippocampal	O
DBS	O
suppressed	O
the	O
acute	O
penicillin	B-Chemical
-	O
induced	O
cortical	O
epileptic	B-Disease
activity	O
independent	O
from	O
stimulus	O
intensity	O
.	O

In	O
the	O
control	O
group	O
,	O
hippocampal	O
stimulation	O
alone	O
lead	O
only	O
to	O
diffuse	O
slowing	O
of	O
cerebral	O
bioelectrical	O
activity	O
at	O
5V	O
stimulation	O
.	O

CONCLUSION	O
:	O
Our	O
results	O
revealed	O
that	O
continuous	O
high	O
frequency	O
stimulation	O
of	O
the	O
hippocampus	O
suppressed	O
acute	O
cortical	O
epileptic	B-Disease
activity	O
effectively	O
without	O
causing	O
secondary	O
epileptic	B-Disease
discharges	O
.	O

These	O
results	O
are	O
important	O
in	O
terms	O
of	O
defining	O
the	O
optimal	O
parameters	O
of	O
hippocampal	O
DBS	O
in	O
patients	O
with	O
epilepsy	B-Disease
.	O

CCNU	B-Chemical
(	O
lomustine	B-Chemical
)	O
toxicity	B-Disease
in	O
dogs	O
:	O
a	O
retrospective	O
study	O
(	O
2002	O
-	O
07	O
)	O
.	O

OBJECTIVE	O
:	O
To	O
describe	O
the	O
incidence	O
of	O
haematological	B-Disease
,	I-Disease
renal	I-Disease
,	I-Disease
hepatic	I-Disease
and	I-Disease
gastrointestinal	I-Disease
toxicities	I-Disease
in	O
tumour	O
-	O
bearing	O
dogs	O
receiving	O
1	B-Chemical
-	I-Chemical
(	I-Chemical
2	I-Chemical
-	I-Chemical
chloroethyl	I-Chemical
)	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
cyclohexyl	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
nitrosourea	I-Chemical
(	O
CCNU	B-Chemical
)	O
.	O

DESIGN	O
:	O
The	O
medical	O
records	O
of	O
206	O
dogs	O
that	O
were	O
treated	O
with	O
CCNU	B-Chemical
at	O
the	O
Melbourne	O
Veterinary	O
Specialist	O
Centre	O
between	O
February	O
2002	O
and	O
December	O
2007	O
were	O
retrospectively	O
evaluated	O
.	O

RESULTS	O
:	O
Of	O
the	O
206	O
dogs	O
treated	O
with	O
CCNU	B-Chemical
,	O
185	O
met	O
the	O
inclusion	O
criteria	O
for	O
at	O
least	O
one	O
class	O
of	O
toxicity	B-Disease
.	O

CCNU	B-Chemical
was	O
used	O
most	O
commonly	O
in	O
the	O
treatment	O
of	O
lymphoma	B-Disease
,	O
mast	B-Disease
cell	I-Disease
tumour	I-Disease
,	O
brain	B-Disease
tumour	I-Disease
,	O
histiocytic	B-Disease
tumours	I-Disease
and	O
epitheliotropic	B-Disease
lymphoma	I-Disease
.	O

Throughout	O
treatment	O
,	O
56	O
.	O
9	O
%	O
of	O
dogs	O
experienced	O
neutropenia	B-Disease
,	O
34	O
.	O
2	O
%	O
experienced	O
anaemia	B-Disease
and	O
14	O
.	O
2	O
%	O
experienced	O
thrombocytopenia	B-Disease
.	O

Gastrointestinal	B-Disease
toxicosis	I-Disease
was	O
detected	O
in	O
37	O
.	O
8	O
%	O
of	O
dogs	O
,	O
the	O
most	O
common	O
sign	O
of	O
which	O
was	O
vomiting	B-Disease
(	O
24	O
.	O
3	O
%	O
)	O
.	O

Potential	O
renal	O
toxicity	B-Disease
and	O
elevated	O
alanine	B-Chemical
transaminase	O
(	O
ALT	O
)	O
concentration	O
were	O
reported	O
in	O
12	O
.	O
2	O
%	O
and	O
48	O
.	O
8	O
%	O
of	O
dogs	O
,	O
respectively	O
.	O

The	O
incidence	O
of	O
hepatic	B-Disease
failure	I-Disease
was	O
1	O
.	O
2	O
%	O
.	O

CONCLUSIONS	O
:	O
CCNU	B-Chemical
-	O
associated	O
toxicity	B-Disease
in	O
dogs	O
is	O
common	O
,	O
but	O
is	O
usually	O
not	O
life	O
threatening	O
.	O

Central	O
vein	B-Disease
thrombosis	I-Disease
and	O
topical	O
dipivalyl	B-Chemical
epinephrine	I-Chemical
.	O

A	O
report	O
is	O
given	O
on	O
an	O
83	O
-	O
year	O
-	O
old	O
female	O
who	O
acquired	O
central	O
vein	B-Disease
thrombosis	I-Disease
in	O
her	O
seeing	O
eye	O
one	O
day	O
after	O
having	O
started	O
topical	O
medication	O
with	O
dipivalyl	B-Chemical
epinephrine	I-Chemical
for	O
advanced	O
glaucoma	B-Disease
discovered	O
in	O
the	O
other	O
eye	O
.	O

From	O
present	O
knowledge	O
about	O
the	O
effects	O
of	O
adrenergic	O
eye	O
drops	O
on	O
ocular	O
blood	O
circulation	O
,	O
it	O
is	O
difficult	O
to	O
suggest	O
an	O
association	O
between	O
the	O
two	O
events	O
,	O
which	O
may	O
be	O
coincidental	O
only	O
.	O

Benzylacyclouridine	B-Chemical
reverses	O
azidothymidine	B-Chemical
-	O
induced	O
marrow	B-Disease
suppression	I-Disease
without	O
impairment	O
of	O
anti	O
-	O
human	O
immunodeficiency	B-Disease
virus	O
activity	O
.	O

Increased	O
extracellular	O
concentrations	O
of	O
uridine	B-Chemical
(	O
Urd	B-Chemical
)	O
have	O
been	O
reported	O
to	O
reduce	O
,	O
in	O
vitro	O
,	O
azidothymidine	B-Chemical
(	O
AZT	B-Chemical
)	O
-	O
induced	O
inhibition	O
of	O
human	O
granulocyte	O
-	O
macrophage	O
progenitor	O
cells	O
without	O
impairment	O
of	O
its	O
antihuman	O
immunodeficiency	B-Disease
virus	O
(	O
HIV	O
)	O
activity	O
.	O

Because	O
of	O
the	O
clinical	O
toxicities	B-Disease
associated	O
with	O
chronic	O
Urd	B-Chemical
administration	O
,	O
the	O
ability	O
of	O
benzylacyclouridine	B-Chemical
(	O
BAU	B-Chemical
)	O
to	O
effect	O
,	O
in	O
vivo	O
,	O
AZT	B-Chemical
-	O
induced	O
anemia	B-Disease
and	O
leukopenia	B-Disease
was	O
assessed	O
.	O

This	O
agent	O
inhibits	O
Urd	B-Chemical
catabolism	O
and	O
,	O
in	O
vivo	O
,	O
increases	O
the	O
plasma	O
concentration	O
of	O
Urd	B-Chemical
in	O
a	O
dose	O
-	O
dependent	O
manner	O
,	O
without	O
Urd	B-Chemical
-	O
related	O
toxicity	B-Disease
.	O

In	O
mice	O
rendered	O
anemic	B-Disease
and	O
leukopenic	B-Disease
by	O
the	O
administration	O
of	O
AZT	B-Chemical
for	O
28	O
days	O
in	O
drinking	O
water	O
(	O
1	O
.	O
5	O
mg	O
/	O
mL	O
)	O
,	O
the	O
continued	O
administration	O
of	O
AZT	B-Chemical
plus	O
daily	O
BAU	B-Chemical
(	O
300	O
mg	O
/	O
kg	O
,	O
orally	O
)	O
partially	O
reversed	O
AZT	B-Chemical
-	O
induced	O
anemia	B-Disease
and	O
leukopenia	B-Disease
(	O
P	O
less	O
than	O
.	O
05	O
)	O
,	O
increased	O
peripheral	O
reticulocytes	O
(	O
to	O
4	O
.	O
9	O
%	O
,	O
P	O
less	O
than	O
.	O
01	O
)	O
,	O
increased	O
cellularity	O
in	O
the	O
marrow	O
,	O
and	O
improved	O
megaloblastosis	B-Disease
.	O

When	O
coadministered	O
with	O
AZT	B-Chemical
from	O
the	O
onset	O
of	O
drug	O
administration	O
,	O
BAU	B-Chemical
reduced	O
AZT	B-Chemical
-	O
induced	O
marrow	B-Disease
toxicity	I-Disease
.	O

In	O
vitro	O
,	O
at	O
a	O
concentration	O
of	O
100	O
mumol	O
/	O
L	O
,	O
BAU	B-Chemical
possesses	O
minimal	O
anti	O
-	O
HIV	O
activity	O
and	O
has	O
no	O
effect	O
on	O
the	O
ability	O
of	O
AZT	B-Chemical
to	O
reverse	O
the	O
HIV	O
-	O
induced	O
cytopathic	O
effect	O
in	O
MT4	O
cells	O
.	O

The	O
clinical	O
and	O
biochemical	O
implications	O
of	O
these	O
findings	O
are	O
discussed	O
.	O

Lethal	O
anuria	B-Disease
complicating	O
high	O
dose	O
ifosfamide	B-Chemical
chemotherapy	O
in	O
a	O
breast	B-Disease
cancer	I-Disease
patient	O
with	O
an	O
impaired	B-Disease
renal	I-Disease
function	I-Disease
.	O

A	O
sixty	O
-	O
year	O
-	O
old	O
woman	O
with	O
advanced	O
breast	B-Disease
cancer	I-Disease
,	O
previously	O
treated	O
with	O
cisplatin	B-Chemical
,	O
developed	O
an	O
irreversible	O
lethal	O
renal	B-Disease
failure	I-Disease
with	O
anuria	B-Disease
,	O
the	O
day	O
after	O
5	O
g	O
/	O
m2	O
bolus	O
ifosfamide	B-Chemical
.	O

Postrenal	B-Disease
failure	I-Disease
was	O
excluded	O
by	O
echography	O
.	O

A	O
prerenal	O
component	O
could	O
have	O
contributed	O
to	O
renal	B-Disease
failure	I-Disease
because	O
of	O
a	O
transient	O
hypotension	B-Disease
,	O
due	O
to	O
an	O
increasing	O
ascitis	O
,	O
occurring	O
just	O
before	O
anuria	B-Disease
.	O

However	O
,	O
correction	O
of	O
the	O
hemodynamic	O
parameters	O
did	O
not	O
improve	O
renal	O
function	O
.	O

Ifosfamide	B-Chemical
is	O
a	O
known	O
nephrotoxic	B-Disease
drug	O
with	O
demonstrated	O
tubulopathies	B-Disease
.	O

We	O
strongly	O
suspect	O
that	O
this	O
lethal	O
anuria	B-Disease
was	O
mainly	O
due	O
to	O
ifosfamide	B-Chemical
,	O
occurring	O
in	O
a	O
patient	O
having	O
received	O
previous	O
cisplatin	B-Chemical
chemotherapy	O
and	O
with	O
poor	O
kidney	O
perfusion	O
due	O
to	O
transient	O
hypotension	B-Disease
.	O

We	O
recommend	O
careful	O
use	O
of	O
ifosfamide	B-Chemical
in	O
patients	O
pretreated	O
with	O
nephrotoxic	B-Disease
chemotherapy	O
and	O
inadequate	O
renal	O
perfusion	O
.	O

Nociceptive	O
effects	O
induced	O
by	O
intrathecal	O
administration	O
of	O
prostaglandin	B-Chemical
D2	I-Chemical
,	I-Chemical
E2	I-Chemical
,	I-Chemical
or	I-Chemical
F2	I-Chemical
alpha	I-Chemical
to	O
conscious	O
mice	O
.	O

The	O
effects	O
of	O
intrathecal	O
administration	O
of	O
prostaglandins	B-Chemical
on	O
pain	B-Disease
responses	O
in	O
conscious	O
mice	O
were	O
evaluated	O
by	O
using	O
hot	O
plate	O
and	O
acetic	B-Chemical
acid	I-Chemical
writhing	O
tests	O
.	O

Prostaglandin	B-Chemical
D2	I-Chemical
(	O
0	O
.	O
5	O
-	O
3	O
ng	O
/	O
mouse	O
)	O
had	O
a	O
hyperalgesic	B-Disease
action	O
on	O
the	O
response	O
to	O
a	O
hot	O
plate	O
during	O
a	O
3	O
-	O
60	O
min	O
period	O
after	O
injection	O
.	O

Prostaglandin	B-Chemical
E2	I-Chemical
showed	O
a	O
hyperalgesic	B-Disease
effect	O
at	O
doses	O
of	O
1	O
pg	B-Chemical
to	O
10	O
ng	O
/	O
mouse	O
,	O
but	O
the	O
effect	O
lasted	O
shorter	O
(	O
3	O
-	O
30	O
min	O
)	O
than	O
that	O
of	O
prostaglandin	B-Chemical
D2	I-Chemical
.	O

Similar	O
results	O
were	O
obtained	O
by	O
acetic	B-Chemical
acid	I-Chemical
writhing	O
tests	O
.	O

The	O
hyperalgesic	B-Disease
effect	O
of	O
prostaglandin	B-Chemical
D2	I-Chemical
was	O
blocked	O
by	O
simultaneous	O
injection	O
of	O
a	O
substance	O
P	O
antagonist	O
(	O
greater	O
than	O
or	O
equal	O
to	O
100	O
ng	O
)	O
but	O
not	O
by	O
AH6809	B-Chemical
,	O
a	O
prostanoid	O
EP1	O
-	O
receptor	O
antagonist	O
.	O

Conversely	O
,	O
prostaglandin	B-Chemical
E2	I-Chemical
-	O
induced	O
hyperalgesia	B-Disease
was	O
blocked	O
by	O
AH6809	B-Chemical
(	O
greater	O
than	O
or	O
equal	O
to	O
500	O
ng	O
)	O
but	O
not	O
by	O
the	O
substance	O
P	O
antagonist	O
.	O

Prostaglandin	B-Chemical
F2	I-Chemical
alpha	I-Chemical
had	O
little	O
effect	O
on	O
pain	B-Disease
responses	O
.	O

These	O
results	O
demonstrate	O
that	O
both	O
prostaglandin	B-Chemical
D2	I-Chemical
and	O
prostaglandin	B-Chemical
E2	I-Chemical
exert	O
hyperalgesia	B-Disease
in	O
the	O
spinal	O
cord	O
,	O
but	O
in	O
different	O
ways	O
.	O

D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
in	O
the	O
treatment	O
of	O
localized	B-Disease
scleroderma	I-Disease
.	O

Localized	B-Disease
scleroderma	I-Disease
has	O
no	O
recognized	O
internal	O
organ	O
involvement	O
but	O
may	O
be	O
disfiguring	O
and	O
disabling	O
when	O
the	O
cutaneous	O
lesions	O
are	O
extensive	O
or	O
affect	O
children	O
.	O

There	O
is	O
no	O
accepted	O
or	O
proven	O
treatment	O
for	O
localized	B-Disease
scleroderma	I-Disease
.	O

Case	O
reports	O
of	O
11	O
patients	O
with	O
severe	O
,	O
extensive	O
localized	B-Disease
scleroderma	I-Disease
who	O
were	O
treated	O
with	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
are	O
summarized	O
in	O
this	O
article	O
.	O

This	O
drug	O
was	O
judged	O
to	O
have	O
a	O
favorable	O
effect	O
on	O
the	O
disease	O
course	O
in	O
7	O
(	O
64	O
%	O
)	O
of	O
11	O
patients	O
.	O

Improvement	O
began	O
within	O
3	O
to	O
6	O
months	O
and	O
consisted	O
of	O
cessation	O
of	O
active	O
cutaneous	O
lesions	O
in	O
all	O
7	O
patients	O
,	O
skin	O
softening	O
in	O
5	O
,	O
and	O
more	O
normal	O
growth	O
of	O
the	O
affected	O
limb	O
in	O
2	O
of	O
3	O
children	O
.	O

Joint	O
stiffness	O
and	O
contractures	B-Disease
also	O
improved	O
.	O

The	O
dose	O
of	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
associated	O
with	O
a	O
favorable	O
response	O
was	O
as	O
low	O
as	O
2	O
to	O
5	O
mg	O
/	O
kg	O
per	O
day	O
given	O
over	O
a	O
period	O
ranging	O
from	O
15	O
to	O
53	O
months	O
.	O

D	B-Chemical
-	I-Chemical
Penicillamine	I-Chemical
caused	O
nephrotic	B-Disease
syndrome	I-Disease
in	O
1	O
patient	O
and	O
milder	O
reversible	O
proteinuria	B-Disease
in	O
3	O
other	O
patients	O
;	O
none	O
developed	O
renal	B-Disease
insufficiency	I-Disease
.	O

These	O
data	O
suggest	O
that	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
may	O
be	O
effective	O
in	O
severe	O
cases	O
of	O
localized	B-Disease
scleroderma	I-Disease
.	O

Cerebral	B-Disease
sinus	I-Disease
thrombosis	I-Disease
as	O
a	O
potential	O
hazard	O
of	O
antifibrinolytic	O
treatment	O
in	O
menorrhagia	B-Disease
.	O

We	O
describe	O
a	O
42	O
-	O
year	O
-	O
old	O
woman	O
who	O
developed	O
superior	O
sagittal	B-Disease
and	I-Disease
left	I-Disease
transverse	I-Disease
sinus	I-Disease
thrombosis	I-Disease
associated	O
with	O
prolonged	O
epsilon	B-Chemical
-	I-Chemical
aminocaproic	I-Chemical
acid	I-Chemical
therapy	O
for	O
menorrhagia	B-Disease
.	O

This	O
antifibrinolytic	O
agent	O
has	O
been	O
used	O
in	O
women	O
with	O
menorrhagia	B-Disease
to	O
promote	O
clotting	O
and	O
reduce	O
blood	B-Disease
loss	I-Disease
.	O

Although	O
increased	O
risk	O
of	O
thromboembolic	B-Disease
disease	I-Disease
has	O
been	O
reported	O
during	O
treatment	O
with	O
epsilon	B-Chemical
-	I-Chemical
aminocaproic	I-Chemical
acid	I-Chemical
,	O
cerebral	B-Disease
sinus	I-Disease
thrombosis	I-Disease
has	O
not	O
been	O
previously	O
described	O
.	O

Careful	O
use	O
of	O
epsilon	B-Chemical
-	I-Chemical
aminocaproic	I-Chemical
acid	I-Chemical
therapy	O
is	O
recommended	O
.	O

Seizure	B-Disease
activity	O
with	O
imipenem	B-Chemical
therapy	O
:	O
incidence	O
and	O
risk	O
factors	O
.	O

Two	O
elderly	O
patients	O
with	O
a	O
history	O
of	O
either	O
cerebral	B-Disease
vascular	I-Disease
accident	I-Disease
(	O
CVA	B-Disease
)	O
or	O
head	B-Disease
trauma	I-Disease
and	O
no	O
evidence	O
of	O
renal	B-Disease
disease	I-Disease
developed	O
seizures	B-Disease
while	O
receiving	O
maximum	O
doses	O
of	O
imipenem	B-Chemical
/	I-Chemical
cilastatin	I-Chemical
.	O

Neither	O
patient	O
had	O
reported	O
previous	O
seizures	B-Disease
or	O
seizure	B-Disease
-	O
like	O
activity	O
nor	O
was	O
receiving	O
anticonvulsant	O
agents	O
.	O

All	O
seizures	B-Disease
were	O
controlled	O
with	O
therapeutic	O
doses	O
of	O
phenytoin	B-Chemical
.	O

Both	O
patients	O
had	O
received	O
maximum	O
doses	O
of	O
other	O
beta	B-Chemical
-	I-Chemical
lactam	I-Chemical
antibiotics	O
without	O
evidence	O
of	O
seizure	B-Disease
activity	O
.	O

Midline	O
B3	O
serotonin	B-Chemical
nerves	O
in	O
rat	O
medulla	O
are	O
involved	O
in	O
hypotensive	B-Disease
effect	O
of	O
methyldopa	B-Chemical
.	O

Previous	O
experiments	O
in	O
this	O
laboratory	O
have	O
shown	O
that	O
microinjection	O
of	O
methyldopa	B-Chemical
onto	O
the	O
ventrolateral	O
cells	O
of	O
the	O
B3	O
serotonin	B-Chemical
neurons	O
in	O
the	O
medulla	O
elicits	O
a	O
hypotensive	B-Disease
response	O
mediated	O
by	O
a	O
projection	O
descending	O
into	O
the	O
spinal	O
cord	O
.	O

The	O
present	O
experiments	O
were	O
designed	O
to	O
investigate	O
the	O
role	O
of	O
the	O
midline	O
cells	O
of	O
the	O
B3	O
serotonin	B-Chemical
neurons	O
in	O
the	O
medulla	O
,	O
coinciding	O
with	O
the	O
raphe	O
magnus	O
.	O

In	O
spontaneously	O
hypertensive	B-Disease
,	O
stroke	B-Disease
-	O
prone	O
rats	O
,	O
microinjection	O
of	O
methyldopa	B-Chemical
into	O
the	O
area	O
of	O
the	O
midline	O
B3	O
serotonin	B-Chemical
cell	O
group	O
in	O
the	O
ventral	O
medulla	O
caused	O
a	O
potent	O
hypotension	B-Disease
of	O
30	O
-	O
40	O
mm	O
Hg	O
,	O
which	O
was	O
maximal	O
2	O
-	O
3	O
h	O
after	O
administration	O
and	O
was	O
abolished	O
by	O
the	O
serotonin	B-Chemical
neurotoxin	O
5	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
dihydroxytryptamine	I-Chemical
(	O
5	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
DHT	I-Chemical
)	O
injected	O
intracerebroventricularly	O
.	O

However	O
,	O
intraspinal	O
injection	O
of	O
5	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
DHT	I-Chemical
to	O
produce	O
a	O
more	O
selective	O
lesion	O
of	O
only	O
descending	O
serotonin	B-Chemical
projections	O
in	O
the	O
spinal	O
cord	O
did	O
not	O
affect	O
this	O
hypotension	B-Disease
.	O

Further	O
,	O
5	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
DHT	I-Chemical
lesion	O
of	O
serotonin	B-Chemical
nerves	O
travelling	O
in	O
the	O
median	O
forebrain	O
bundle	O
,	O
one	O
of	O
the	O
main	O
ascending	O
pathways	O
from	O
the	O
B3	O
serotonin	B-Chemical
cells	O
,	O
did	O
not	O
affect	O
the	O
fall	O
in	O
blood	O
pressure	O
associated	O
with	O
a	O
midline	O
B3	O
serotonin	B-Chemical
methyldopa	B-Chemical
injection	O
.	O

It	O
is	O
concluded	O
therefore	O
that	O
,	O
unlike	O
the	O
ventrolateral	O
B3	O
cells	O
which	O
mediate	O
a	O
methyldopa	B-Chemical
-	O
induced	O
hypotension	B-Disease
via	O
descending	O
projections	O
,	O
the	O
midline	O
serotonin	B-Chemical
B3	O
cells	O
in	O
the	O
medulla	O
contribute	O
to	O
the	O
hypotensive	B-Disease
action	O
of	O
methyldopa	B-Chemical
,	O
either	O
by	O
way	O
of	O
an	O
ascending	O
projection	O
which	O
does	O
not	O
pass	O
through	O
the	O
median	O
forebrain	O
bundle	O
,	O
or	O
through	O
a	O
projection	O
restricted	O
to	O
the	O
caudal	O
brainstem	O
.	O

Antiarrhythmic	O
plasma	O
concentrations	O
of	O
cibenzoline	B-Chemical
on	O
canine	O
ventricular	B-Disease
arrhythmias	I-Disease
.	O

Using	O
two	O
-	O
stage	O
coronary	O
ligation	O
-	O
,	O
digitalis	B-Chemical
-	O
,	O
and	O
adrenaline	B-Chemical
-	O
induced	O
canine	O
ventricular	B-Disease
arrhythmias	I-Disease
,	O
antiarrhythmic	O
effects	O
of	O
cibenzoline	B-Chemical
were	O
examined	O
and	O
the	O
minimum	O
effective	O
plasma	O
concentration	O
for	O
each	O
arrhythmia	B-Disease
model	O
was	O
determined	O
.	O

Cibenzoline	B-Chemical
suppressed	O
all	O
the	O
arrhythmias	B-Disease
,	O
and	O
the	O
minimum	O
effective	O
plasma	O
concentrations	O
for	O
arrhythmias	B-Disease
induced	O
by	O
24	O
-	O
h	O
coronary	O
ligation	O
,	O
48	O
-	O
h	O
coronary	O
ligation	O
,	O
digitalis	B-Chemical
,	O
and	O
adrenaline	B-Chemical
were	O
1	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
9	O
(	O
by	O
8	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
,	O
1	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
5	O
(	O
by	O
8	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
,	O
0	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
2	O
(	O
by	O
2	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
,	O
and	O
3	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
3	O
(	O
by	O
5	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
micrograms	O
/	O
ml	O
,	O
respectively	O
(	O
mean	O
+	O
/	O
-	O
SDM	O
,	O
n	O
=	O
6	O
-	O
7	O
)	O
.	O

The	O
concentration	O
for	O
adrenaline	B-Chemical
-	O
induced	O
arrhythmia	B-Disease
was	O
significantly	O
higher	O
than	O
those	O
for	O
the	O
other	O
types	O
of	O
arrhythmias	B-Disease
.	O

This	O
pharmacological	O
profile	O
is	O
similar	O
to	O
those	O
of	O
mexiletine	B-Chemical
and	O
tocainide	B-Chemical
,	O
and	O
all	O
three	O
drugs	O
have	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
stimulant	O
action	O
.	O

Because	O
cibenzoline	B-Chemical
had	O
only	O
weak	O
hypotensive	B-Disease
and	O
sinus	O
node	O
depressive	B-Disease
effects	O
and	O
was	O
found	O
to	O
be	O
orally	O
active	O
when	O
given	O
to	O
coronary	O
ligation	O
arrhythmia	B-Disease
dogs	O
,	O
its	O
clinical	O
usefulness	O
is	O
expected	O
.	O

Continuous	O
ambulatory	O
ECG	O
monitoring	O
during	O
fluorouracil	B-Chemical
therapy	O
:	O
a	O
prospective	O
study	O
.	O

Although	O
there	O
have	O
been	O
anecdotal	O
reports	O
of	O
cardiac	B-Disease
toxicity	I-Disease
associated	O
with	O
fluorouracil	B-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
therapy	O
,	O
this	O
phenomenon	O
has	O
not	O
been	O
studied	O
in	O
a	O
systematic	O
fashion	O
.	O

We	O
prospectively	O
performed	O
continuous	O
ambulatory	O
ECG	O
monitoring	O
on	O
25	O
patients	O
undergoing	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
for	O
treatment	O
of	O
solid	O
tumors	B-Disease
in	O
order	O
to	O
assess	O
the	O
incidence	O
of	O
ischemic	B-Disease
ST	O
changes	O
.	O

Patients	O
were	O
monitored	O
for	O
23	O
+	O
/	O
-	O
4	O
hours	O
before	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
,	O
and	O
98	O
+	O
/	O
-	O
9	O
hours	O
during	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
.	O

Anginal	B-Disease
episodes	O
were	O
rare	O
:	O
only	O
one	O
patient	O
had	O
angina	B-Disease
(	O
during	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
)	O
.	O

However	O
,	O
asymptomatic	O
ST	O
changes	O
(	O
greater	O
than	O
or	O
equal	O
to	O
1	O
mm	O
ST	O
deviation	O
)	O
were	O
common	O
:	O
six	O
of	O
25	O
patients	O
(	O
24	O
%	O
)	O
had	O
ST	O
changes	O
before	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
v	O
17	O
(	O
68	O
%	O
)	O
during	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
(	O
P	O
less	O
than	O
.	O
002	O
)	O
.	O

The	O
incidence	O
of	O
ischemic	B-Disease
episodes	O
per	O
patient	O
per	O
hour	O
was	O
0	O
.	O
05	O
+	O
/	O
-	O
0	O
.	O
02	O
prior	O
to	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
v	O
0	O
.	O
13	O
+	O
/	O
-	O
0	O
.	O
03	O
during	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
(	O
P	O
less	O
than	O
.	O
001	O
)	O
;	O
the	O
duration	O
of	O
ECG	O
changes	O
was	O
0	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
3	O
minutes	O
per	O
patient	O
per	O
hour	O
before	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
v	O
1	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
5	O
minutes	O
per	O
patient	O
per	O
hour	O
during	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
(	O
P	O
less	O
than	O
.	O
01	O
)	O
.	O

ECG	O
changes	O
were	O
more	O
common	O
among	O
patients	O
with	O
known	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
.	O

There	O
were	O
two	O
cases	O
of	O
sudden	B-Disease
death	I-Disease
,	O
both	O
of	O
which	O
occurred	O
at	O
the	O
end	O
of	O
the	O
chemotherapy	O
course	O
.	O

We	O
conclude	O
that	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
infusion	O
is	O
associated	O
with	O
a	O
significant	O
increase	O
in	O
silent	O
ST	O
segment	O
deviation	O
suggestive	O
of	O
ischemia	B-Disease
,	O
particularly	O
among	O
patients	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
.	O

The	O
mechanism	O
and	O
clinical	O
significance	O
of	O
these	O
ECG	O
changes	O
remain	O
to	O
be	O
determined	O
.	O

Nature	O
,	O
time	O
course	O
and	O
dose	O
dependence	O
of	O
zidovudine	B-Chemical
-	O
related	O
side	O
effects	O
:	O
results	O
from	O
the	O
Multicenter	O
Canadian	O
Azidothymidine	B-Chemical
Trial	O
.	O

To	O
characterize	O
the	O
nature	O
,	O
time	O
course	O
and	O
dose	O
dependency	O
of	O
zidovudine	B-Chemical
-	O
related	O
side	O
effects	O
,	O
we	O
undertook	O
a	O
multicenter	O
,	O
prospective	O
,	O
dose	O
-	O
range	O
finding	O
study	O
.	O

Our	O
study	O
group	O
consisted	O
of	O
74	O
HIV	O
-	O
positive	O
homosexual	O
men	O
belonging	O
to	O
groups	O
II	O
B	O
,	O
III	O
and	O
IV	O
C2	O
from	O
the	O
Centers	O
for	O
Disease	O
Control	O
(	O
CDC	O
)	O
classification	O
of	O
HIV	B-Disease
disease	I-Disease
.	O

Following	O
a	O
3	O
-	O
week	O
observation	O
period	O
,	O
volunteers	O
were	O
treated	O
with	O
zidovudine	B-Chemical
600	O
mg	O
/	O
day	O
for	O
18	O
weeks	O
,	O
900	O
mg	O
/	O
day	O
for	O
9	O
weeks	O
and	O
1200	O
mg	O
/	O
day	O
for	O
9	O
weeks	O
,	O
followed	O
by	O
a	O
washout	O
period	O
of	O
6	O
weeks	O
after	O
which	O
they	O
were	O
re	O
-	O
started	O
on	O
1200	O
mg	O
/	O
day	O
or	O
the	O
highest	O
tolerated	O
dose	O
at	O
8	O
-	O
hourly	O
intervals	O
.	O

Subjects	O
were	O
randomly	O
assigned	O
to	O
4	O
-	O
hourly	O
or	O
8	O
-	O
hourly	O
regimens	O
within	O
CDC	O
groups	O
while	O
taking	O
600	O
and	O
1200	O
mg	O
/	O
day	O
.	O

Clinical	O
and	O
laboratory	O
evaluations	O
were	O
performed	O
at	O
3	O
-	O
week	O
intervals	O
.	O

Symptomatic	O
adverse	O
effects	O
were	O
present	O
in	O
96	O
%	O
of	O
subjects	O
,	O
most	O
commonly	O
nausea	B-Disease
(	O
64	O
%	O
)	O
,	O
fatigue	B-Disease
(	O
55	O
%	O
)	O
and	O
headache	B-Disease
(	O
49	O
%	O
)	O
.	O

These	O
were	O
generally	O
self	O
-	O
limited	O
,	O
reappearing	O
briefly	O
at	O
each	O
dose	O
increment	O
.	O

A	O
decrease	O
in	O
hemoglobin	O
occurred	O
shortly	O
after	O
initiation	O
of	O
therapy	O
.	O

This	O
was	O
not	O
dose	O
dependent	O
and	O
reversed	O
rapidly	O
upon	O
discontinuation	O
of	O
treatment	O
.	O

A	O
red	O
blood	O
cell	O
count	O
decrease	O
,	O
a	O
mean	O
cell	O
volume	O
increase	O
and	O
a	O
granulocyte	O
count	O
decrease	O
developed	O
early	O
in	O
a	O
dose	O
-	O
independent	O
fashion	O
,	O
reverting	O
at	O
least	O
partially	O
during	O
the	O
washout	O
phase	O
.	O

The	O
decrease	O
in	O
reticulocyte	O
count	O
was	O
dose	O
related	O
between	O
600	O
and	O
900	O
mg	O
/	O
day	O
with	O
no	O
further	O
change	O
when	O
the	O
dose	O
was	O
escalated	O
to	O
1200	O
mg	O
/	O
day	O
.	O

Bone	O
marrow	O
changes	O
occurred	O
rapidly	O
as	O
demonstrated	O
by	O
megaloblastosis	B-Disease
in	O
95	O
%	O
of	O
65	O
specimens	O
at	O
week	O
18	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

National	O
project	O
on	O
the	O
prevention	O
of	O
mother	O
-	O
to	O
-	O
infant	O
infection	B-Disease
by	I-Disease
hepatitis	I-Disease
B	I-Disease
virus	I-Disease
in	O
Japan	O
.	O

In	O
Japan	O
,	O
a	O
nationwide	O
prevention	O
program	O
against	O
mother	O
-	O
to	O
-	O
infant	O
infection	B-Disease
by	I-Disease
hepatitis	I-Disease
B	I-Disease
virus	I-Disease
(	O
HBV	O
)	O
started	O
in	O
1985	O
.	O

This	O
program	O
consists	O
of	O
double	O
screenings	O
of	O
pregnant	O
women	O
and	O
prophylactic	O
treatment	O
to	O
the	O
infants	O
born	O
to	O
both	O
hepatitis	B-Chemical
B	I-Chemical
surface	I-Chemical
antigen	I-Chemical
(	O
HBsAg	B-Chemical
)	O
and	O
hepatitis	B-Chemical
B	I-Chemical
e	I-Chemical
antigen	I-Chemical
(	O
HBeAg	B-Chemical
)	O
positive	O
mothers	O
.	O

These	O
infants	O
are	O
treated	O
with	O
two	O
injections	O
of	O
hepatitis	B-Disease
B	I-Disease
immune	O
globulin	O
(	O
HBIG	O
)	O
and	O
at	O
least	O
three	O
injections	O
of	O
plasma	O
derived	O
hepatitis	B-Chemical
B	I-Chemical
vaccine	I-Chemical
.	O

We	O
sent	O
questionnaires	O
about	O
the	O
numbers	O
of	O
each	O
procedure	O
or	O
examination	O
during	O
nine	O
months	O
of	O
investigation	O
period	O
to	O
each	O
local	O
government	O
in	O
1986	O
and	O
1987	O
.	O

93	O
.	O
4	O
%	O
pregnant	O
women	O
had	O
the	O
chance	O
to	O
be	O
examined	O
for	O
HBsAg	B-Chemical
,	O
and	O
the	O
positive	O
rate	O
was	O
1	O
.	O
4	O
to	O
1	O
.	O
5	O
%	O
.	O

The	O
HBeAg	B-Chemical
positive	O
rate	O
in	O
HBsAg	B-Chemical
positive	O
was	O
23	O
to	O
26	O
%	O
.	O

The	O
HBsAg	B-Chemical
positive	O
rate	O
in	O
neonates	O
and	O
in	O
infants	O
before	O
two	O
months	O
were	O
3	O
%	O
and	O
2	O
%	O
respectively	O
.	O

Some	O
problems	O
may	O
arise	O
,	O
because	O
27	O
to	O
30	O
%	O
of	O
infants	O
need	O
the	O
fourth	O
vaccination	O
in	O
some	O
restricted	O
areas	O
.	O

Involvement	O
of	O
the	O
mu	O
-	O
opiate	O
receptor	O
in	O
peripheral	O
analgesia	B-Disease
.	O

The	O
intradermal	O
injection	O
of	O
mu	O
(	O
morphine	B-Chemical
,	O
Tyr	B-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
Ala	I-Chemical
-	I-Chemical
Gly	I-Chemical
-	I-Chemical
NMe	I-Chemical
-	I-Chemical
Phe	I-Chemical
-	I-Chemical
Gly	I-Chemical
-	I-Chemical
ol	I-Chemical
and	O
morphiceptin	B-Chemical
)	O
,	O
kappa	O
(	O
trans	B-Chemical
-	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dichloro	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
N	I-Chemical
[	I-Chemical
2	I-Chemical
-	I-Chemical
(	I-Chemical
1	I-Chemical
-	I-Chemical
pyrrolidinyl	I-Chemical
)	I-Chemical
cyclohexyl	I-Chemical
]	I-Chemical
benzeneactemide	I-Chemical
)	O
and	O
delta	O
(	O
[	B-Chemical
D	I-Chemical
-	I-Chemical
Pen2	I-Chemical
.	I-Chemical
5	I-Chemical
]	I-Chemical
-	I-Chemical
enkephalin	I-Chemical
and	O
[	B-Chemical
D	I-Chemical
-	I-Chemical
Ser2	I-Chemical
]	I-Chemical
-	I-Chemical
[	I-Chemical
Leu	I-Chemical
]	I-Chemical
enkephalin	I-Chemical
-	I-Chemical
Thr	I-Chemical
)	O
selective	O
opioid	O
-	O
agonists	O
,	O
by	O
themselves	O
,	O
did	O
not	O
significantly	O
affect	O
the	O
mechanical	O
nociceptive	O
threshold	O
in	O
the	O
hindpaw	O
of	O
the	O
rat	O
.	O

Intradermal	O
injection	O
of	O
mu	O
,	O
but	O
not	O
delta	O
or	O
kappa	O
opioid	O
-	O
agonists	O
,	O
however	O
,	O
produced	O
dose	O
-	O
dependent	O
inhibition	O
of	O
prostaglandin	B-Chemical
E2	I-Chemical
-	O
induced	O
hyperalgesia	B-Disease
.	O

The	O
analgesic	O
effect	O
of	O
the	O
mu	O
-	O
agonist	O
morphine	B-Chemical
was	O
dose	O
-	O
dependently	O
antagonized	O
by	O
naloxone	B-Chemical
and	O
prevented	O
by	O
co	O
-	O
injection	O
of	O
pertussis	O
toxin	O
.	O

Morphine	B-Chemical
did	O
not	O
,	O
however	O
,	O
alter	O
the	O
hyperalgesia	B-Disease
induced	O
by	O
8	B-Chemical
-	I-Chemical
bromo	I-Chemical
cyclic	I-Chemical
adenosine	I-Chemical
monophosphate	I-Chemical
.	O

We	O
conclude	O
that	O
the	O
analgesic	O
action	O
of	O
opioids	O
on	O
the	O
peripheral	O
terminals	O
of	O
primary	O
afferents	O
is	O
via	O
a	O
binding	O
site	O
with	O
characteristics	O
of	O
the	O
mu	O
-	O
opioid	O
receptor	O
and	O
that	O
this	O
action	O
is	O
mediated	O
by	O
inhibition	O
of	O
the	O
cyclic	B-Chemical
adenosine	I-Chemical
monophosphate	I-Chemical
second	O
messenger	O
system	O
.	O

Involvement	O
of	O
locus	O
coeruleus	O
and	O
noradrenergic	O
neurotransmission	O
in	O
fentanyl	B-Chemical
-	O
induced	O
muscular	B-Disease
rigidity	I-Disease
in	O
the	O
rat	O
.	O

Whereas	O
muscular	B-Disease
rigidity	I-Disease
is	O
a	O
well	O
-	O
known	O
side	O
effect	O
that	O
is	O
associated	O
with	O
high	O
-	O
dose	O
fentanyl	B-Chemical
anesthesia	O
,	O
a	O
paucity	O
of	O
information	O
exists	O
with	O
regard	O
to	O
its	O
underlying	O
mechanism	O
(	O
s	O
)	O
.	O

We	O
investigated	O
in	O
this	O
study	O
the	O
possible	O
engagement	O
of	O
locus	O
coeruleus	O
of	O
the	O
pons	O
in	O
this	O
phenomenon	O
,	O
using	O
male	O
Sprague	O
-	O
Dawley	O
rats	O
anesthetized	O
with	O
ketamine	B-Chemical
.	O

Under	O
proper	O
control	O
of	O
respiration	O
,	O
body	O
temperature	O
and	O
end	O
-	O
tidal	O
CO2	B-Chemical
,	O
intravenous	O
administration	O
of	O
fentanyl	B-Chemical
(	O
50	O
or	O
100	O
micrograms	O
/	O
kg	O
)	O
consistently	O
promoted	O
an	O
increase	O
in	O
electromyographic	O
activity	O
recorded	O
from	O
the	O
gastrocnemius	O
and	O
abdominal	O
rectus	O
muscles	O
.	O

Such	O
an	O
induced	O
muscular	B-Disease
rigidity	I-Disease
by	O
the	O
narcotic	O
agent	O
was	O
significantly	O
antagonized	O
or	O
even	O
reduced	O
by	O
prior	O
electrolytic	O
lesions	O
of	O
the	O
locus	O
coeruleus	O
or	O
pretreatment	O
with	O
the	O
alpha	O
-	O
adrenoceptor	O
blocker	O
,	O
prazosin	B-Chemical
.	O

Microinjection	O
of	O
fentanyl	B-Chemical
(	O
2	O
.	O
5	O
micrograms	O
/	O
50	O
nl	O
)	O
directly	O
into	O
this	O
pontine	O
nucleus	O
,	O
on	O
the	O
other	O
hand	O
,	O
elicited	O
discernible	O
electromyographic	O
excitation	O
.	O

It	O
is	O
speculated	O
that	O
the	O
induction	O
of	O
muscular	B-Disease
rigidity	I-Disease
by	O
fentanyl	B-Chemical
may	O
involve	O
the	O
coerulospinal	O
noradrenergic	O
fibers	O
to	O
the	O
spinal	O
motoneurons	O
.	O

Dexmedetomidine	B-Chemical
,	O
acting	O
through	O
central	O
alpha	O
-	O
2	O
adrenoceptors	O
,	O
prevents	O
opiate	O
-	O
induced	O
muscle	B-Disease
rigidity	I-Disease
in	O
the	O
rat	O
.	O

The	O
highly	O
-	O
selective	O
alpha	O
-	O
2	O
adrenergic	O
agonist	O
dexmedetomidine	B-Chemical
(	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
)	O
is	O
capable	O
of	O
inducing	O
muscle	B-Disease
flaccidity	I-Disease
and	O
anesthesia	O
in	O
rats	O
and	O
dogs	O
.	O

Intense	O
generalized	O
muscle	B-Disease
rigidity	I-Disease
is	O
an	O
undesirable	O
side	O
effect	O
of	O
potent	O
opiate	O
agonists	O
.	O

Although	O
the	O
neurochemistry	O
of	O
opiate	O
-	O
induced	O
rigidity	B-Disease
has	O
yet	O
to	O
be	O
fully	O
elucidated	O
,	O
recent	O
work	O
suggests	O
a	O
role	O
for	O
a	O
central	O
adrenergic	O
mechanism	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
authors	O
determined	O
if	O
treatment	O
with	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
prevents	O
the	O
muscle	B-Disease
rigidity	I-Disease
caused	O
by	O
high	O
-	O
dose	O
alfentanil	B-Chemical
anesthesia	O
in	O
the	O
rat	O
.	O

Animals	O
(	O
n	O
=	O
42	O
)	O
were	O
treated	O
intraperitoneally	O
with	O
one	O
of	O
the	O
following	O
six	O
regimens	O
:	O
1	O
)	O
L	O
-	O
MED	O
(	O
the	O
inactive	O
L	O
-	O
isomer	O
of	O
medetomidine	B-Chemical
)	O
,	O
30	O
micrograms	O
/	O
kg	O
;	O
2	O
)	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
,	O
10	O
micrograms	O
/	O
kg	O
;	O
3	O
)	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
,	O
30	O
micrograms	O
/	O
kg	O
;	O
4	O
)	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
[	O
30	O
micrograms	O
/	O
kg	O
]	O
and	O
the	O
central	O
-	O
acting	O
alpha	O
-	O
2	O
antagonist	O
,	O
idazoxan	B-Chemical
[	O
10	O
mg	O
/	O
kg	O
]	O
;	O
5	O
)	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
[	O
30	O
micrograms	O
/	O
kg	O
]	O
and	O
the	O
peripheral	O
-	O
acting	O
alpha	O
-	O
2	O
antagonist	O
DG	B-Chemical
-	I-Chemical
5128	I-Chemical
[	O
10	O
mg	O
/	O
kg	O
]	O
,	O
or	O
;	O
6	O
)	O
saline	O
.	O

Baseline	O
electromyographic	O
activity	O
was	O
recorded	O
from	O
the	O
gastrocnemius	O
muscle	O
before	O
and	O
after	O
drug	O
treatment	O
.	O

Each	O
rat	O
was	O
then	O
injected	O
with	O
alfentanil	B-Chemical
(	O
ALF	B-Chemical
,	O
0	O
.	O
5	O
mg	O
/	O
kg	O
sc	O
)	O
.	O

ALF	B-Chemical
injection	O
resulted	O
in	O
a	O
marked	O
increase	O
in	O
hindlimb	O
EMG	O
activity	O
in	O
the	O
L	O
-	O
MED	O
treatment	O
group	O
which	O
was	O
indistinguishable	O
from	O
that	O
seen	O
in	O
animals	O
treated	O
with	O
saline	O
.	O

In	O
contrast	O
,	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
prevented	O
alfentanil	B-Chemical
-	O
induced	O
muscle	B-Disease
rigidity	I-Disease
in	O
a	O
dose	O
-	O
dependent	O
fashion	O
.	O

The	O
small	O
EMG	O
values	O
obtained	O
in	O
the	O
high	O
-	O
dose	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
group	O
were	O
comparable	O
with	O
those	O
recorded	O
in	O
earlier	O
studies	O
from	O
control	O
animals	O
not	O
given	O
any	O
opiate	O
.	O

The	O
high	O
-	O
dose	O
D	B-Chemical
-	I-Chemical
MED	I-Chemical
animals	O
were	O
flaccid	O
,	O
akinetic	B-Disease
,	O
and	O
lacked	O
a	O
startle	B-Disease
response	O
during	O
the	O
entire	O
experimental	O
period	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Some	O
central	O
effects	O
of	O
repeated	O
treatment	O
with	O
fluvoxamine	B-Chemical
.	O

We	O
investigated	O
the	O
effect	O
of	O
repeated	O
treatment	O
with	O
fluvoxamine	B-Chemical
,	O
a	O
selective	O
serotonin	B-Chemical
uptake	O
inhibitor	O
,	O
on	O
behavioral	O
effects	O
of	O
dopaminomimetics	O
and	O
methoxamine	B-Chemical
and	O
on	O
the	O
animal	O
behavior	O
in	O
the	O
"	O
behavioral	O
despair	O
"	O
test	O
.	O

A	O
repeated	O
treatment	O
with	O
fluvoxamine	B-Chemical
(	O
twice	O
daily	O
for	O
14	O
days	O
)	O
potentiated	O
in	O
mice	O
and	O
in	O
rats	O
(	O
weaker	O
)	O
the	O
amphetamine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
.	O

The	O
hyperactivity	B-Disease
induced	O
by	O
nomifensine	B-Chemical
in	O
mice	O
remained	O
unaffected	O
by	O
fluvoxamine	B-Chemical
.	O

The	O
stimulation	O
of	O
locomotor	O
activity	O
by	O
intracerebroventricularly	O
administered	O
methoxamine	B-Chemical
was	O
not	O
affected	O
by	O
repeated	O
treatment	O
with	O
fluvoxamine	B-Chemical
.	O

Given	O
three	O
times	O
fluvoxamine	B-Chemical
had	O
no	O
effect	O
on	O
the	O
immobilization	O
time	O
in	O
the	O
"	O
behavioral	O
despair	O
"	O
test	O
in	O
rats	O
.	O

The	O
results	O
indicate	O
that	O
fluvoxamine	B-Chemical
given	O
repeatedly	O
acts	O
differently	O
than	O
citalopram	B-Chemical
,	O
another	O
selective	O
serotonin	B-Chemical
uptake	O
inhibitor	O
,	O
and	O
differs	O
also	O
from	O
other	O
antidepressant	O
drugs	O
.	O

Protective	O
effect	O
of	O
a	O
specific	O
platelet	O
-	O
activating	O
factor	O
antagonist	O
,	O
BN	B-Chemical
52021	I-Chemical
,	O
on	O
bupivacaine	B-Chemical
-	O
induced	O
cardiovascular	B-Disease
impairments	I-Disease
in	O
rats	O
.	O

Administration	O
of	O
the	O
local	O
anaesthetic	O
bupivacaine	B-Chemical
(	O
1	O
.	O
5	O
or	O
2	O
mg	O
/	O
kg	O
,	O
i	O
.	O
v	O
.	O
)	O
to	O
rats	O
elicited	O
a	O
marked	O
decrease	B-Disease
of	I-Disease
mean	I-Disease
arterial	I-Disease
blood	I-Disease
pressure	I-Disease
(	I-Disease
MBP	I-Disease
)	I-Disease
and	I-Disease
heart	I-Disease
rate	I-Disease
(	I-Disease
HR	I-Disease
)	I-Disease
leading	O
to	O
death	O
(	O
in	O
67	O
%	O
or	O
90	O
%	O
of	O
animals	O
respectively	O
)	O
.	O

Intravenous	O
injection	O
of	O
the	O
specific	O
platelet	O
-	O
activating	O
factor	O
(	O
PAF	O
)	O
antagonist	O
BN	B-Chemical
52021	I-Chemical
(	O
10	O
mg	O
/	O
kg	O
)	O
,	O
30	O
min	O
before	O
bupivacaine	B-Chemical
administration	O
(	O
2	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
suppressed	O
both	O
the	O
decrease	B-Disease
of	I-Disease
MBP	I-Disease
and	I-Disease
HR	I-Disease
.	O

In	O
contrast	O
,	O
doses	O
of	O
1	O
mg	O
/	O
kg	O
BN	B-Chemical
52021	I-Chemical
given	O
30	O
min	O
before	O
or	O
10	O
mg	O
/	O
kg	O
administered	O
5	O
min	O
before	O
i	O
.	O
v	O
.	O
injection	O
of	O
bupivacaine	B-Chemical
were	O
ineffective	O
.	O

When	O
BN	B-Chemical
52021	I-Chemical
(	O
20	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
)	O
was	O
injected	O
immediately	O
after	O
bupivacaine	B-Chemical
(	O
2	O
mg	O
/	O
kg	O
)	O
,	O
a	O
partial	O
reversion	O
of	O
the	O
decrease	B-Disease
of	I-Disease
MBP	I-Disease
and	I-Disease
HR	I-Disease
was	O
observed	O
,	O
whereas	O
the	O
dose	O
of	O
10	O
mg	O
/	O
kg	O
was	O
ineffective	O
.	O

A	O
partial	O
recovery	O
of	O
bupivacaine	B-Chemical
-	O
induced	O
ECG	O
alterations	O
was	O
observed	O
after	O
pretreatment	O
of	O
the	O
rats	O
with	O
BN	B-Chemical
52021	I-Chemical
.	O

Since	O
the	O
administration	O
of	O
BN	B-Chemical
52021	I-Chemical
,	O
at	O
all	O
doses	O
studied	O
,	O
did	O
not	O
alter	O
MBP	O
and	O
HR	O
at	O
the	O
doses	O
used	O
,	O
the	O
bulk	O
of	O
these	O
results	O
clearly	O
demonstrate	O
a	O
protective	O
action	O
of	O
BN	B-Chemical
52021	I-Chemical
,	O
a	O
specific	O
antagonist	O
of	O
PAF	O
,	O
against	O
bupivacaine	B-Chemical
-	O
induced	O
cardiovascular	B-Disease
toxicity	I-Disease
.	O

Thus	O
,	O
consistent	O
with	O
its	O
direct	O
effect	O
on	O
heart	O
,	O
PAF	O
appears	O
to	O
be	O
implicated	O
in	O
bupivacaine	B-Chemical
-	O
induced	O
cardiovascular	B-Disease
alterations	I-Disease
.	O

The	O
epidemiology	O
of	O
the	O
acute	O
flank	B-Disease
pain	I-Disease
syndrome	O
from	O
suprofen	B-Chemical
.	O

Suprofen	B-Chemical
,	O
a	O
new	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drug	O
,	O
was	O
marketed	O
in	O
early	O
1986	O
as	O
an	O
analgesic	O
agent	O
.	O

Until	O
physicians	O
began	O
reporting	O
an	O
unusual	O
acute	O
flank	B-Disease
pain	I-Disease
syndrome	O
to	O
the	O
spontaneous	O
reporting	O
system	O
,	O
700	O
,	O
000	O
persons	O
used	O
the	O
drug	O
in	O
the	O
United	O
States	O
.	O

Through	O
August	O
1986	O
,	O
a	O
total	O
of	O
163	O
cases	O
of	O
this	O
syndrome	O
were	O
reported	O
.	O

To	O
elucidate	O
the	O
epidemiology	O
of	O
the	O
syndrome	O
,	O
a	O
case	O
-	O
control	O
study	O
was	O
performed	O
,	O
comparing	O
62	O
of	O
the	O
case	O
patients	O
who	O
had	O
been	O
reported	O
to	O
the	O
spontaneous	O
reporting	O
system	O
to	O
185	O
suprofen	B-Chemical
-	O
exposed	O
control	O
subjects	O
who	O
did	O
not	O
have	O
the	O
syndrome	O
.	O

Case	O
patients	O
were	O
more	O
likely	O
to	O
be	O
men	O
(	O
odds	O
ratio	O
,	O
3	O
.	O
8	O
;	O
95	O
%	O
confidence	O
interval	O
,	O
1	O
.	O
2	O
-	O
12	O
.	O
1	O
)	O
,	O
suffer	O
from	O
hay	B-Disease
fever	I-Disease
and	O
asthma	B-Disease
(	O
odds	O
ratio	O
,	O
3	O
.	O
4	O
;	O
95	O
%	O
confidence	O
interval	O
,	O
1	O
.	O
0	O
-	O
11	O
.	O
9	O
)	O
;	O
to	O
participate	O
in	O
regular	O
exercise	O
(	O
odds	O
ratio	O
,	O
5	O
.	O
9	O
;	O
95	O
%	O
confidence	O
interval	O
,	O
1	O
.	O
1	O
-	O
30	O
.	O
7	O
)	O
,	O
especially	O
in	O
the	O
use	O
of	O
Nautilus	O
equipment	O
(	O
p	O
=	O
0	O
.	O
02	O
)	O
;	O
and	O
to	O
use	O
alcohol	B-Chemical
(	O
odds	O
ratio	O
,	O
4	O
.	O
4	O
;	O
95	O
%	O
confidence	O
interval	O
,	O
1	O
.	O
1	O
-	O
17	O
.	O
5	O
)	O
.	O

Possible	O
risk	O
factors	O
included	O
young	O
age	O
,	O
concurrent	O
use	O
of	O
other	O
analgesic	O
agents	O
(	O
especially	O
ibuprofen	B-Chemical
)	O
,	O
preexisting	O
renal	B-Disease
disease	I-Disease
,	O
a	O
history	O
of	O
kidney	B-Disease
stones	I-Disease
,	O
a	O
history	O
of	O
gout	B-Disease
,	O
a	O
recent	O
increase	O
in	O
activity	O
,	O
a	O
recent	O
increase	O
in	O
sun	O
exposure	O
,	O
and	O
residence	O
in	O
the	O
Sunbelt	O
.	O

These	O
were	O
findings	O
that	O
were	O
suggestive	O
but	O
did	O
not	O
reach	O
conventional	O
statistical	O
significance	O
.	O

These	O
findings	O
are	O
consistent	O
with	O
the	O
postulated	O
mechanism	O
for	O
this	O
unusual	O
syndrome	O
:	O
acute	O
diffuse	O
crystallization	O
of	O
uric	B-Chemical
acid	I-Chemical
in	O
renal	O
tubules	O
.	O

Phlorizin	B-Chemical
-	O
induced	O
glycosuria	B-Disease
does	O
not	O
prevent	O
gentamicin	B-Chemical
nephrotoxicity	B-Disease
in	O
rats	O
.	O

Because	O
rats	O
with	O
streptozotocin	B-Chemical
-	O
induced	O
diabetes	B-Disease
mellitus	I-Disease
(	O
DM	B-Disease
)	O
have	O
a	O
high	O
solute	O
diuresis	O
(	O
glycosuria	B-Disease
of	O
10	O
to	O
12	O
g	O
/	O
day	O
)	O
,	O
we	O
have	O
suggested	O
that	O
this	O
may	O
in	O
part	O
be	O
responsible	O
for	O
their	O
resistance	O
to	O
gentamicin	B-Chemical
-	O
induced	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
(	O
ARF	B-Disease
)	O
.	O

The	O
protection	O
from	O
gentamicin	B-Chemical
nephrotoxicity	B-Disease
was	O
studied	O
in	O
non	O
-	O
diabetic	B-Disease
rats	O
with	O
chronic	O
solute	O
diuresis	O
induced	O
by	O
blockage	O
of	O
tubular	O
glucose	B-Chemical
reabsorption	O
with	O
phlorizin	B-Chemical
(	O
P	B-Chemical
)	O
.	O

DM	B-Disease
rats	O
with	O
mild	O
glycosuria	B-Disease
(	O
similar	O
in	O
degree	O
to	O
that	O
of	O
the	O
P	B-Chemical
treated	O
animals	O
)	O
were	O
also	O
studied	O
.	O

Unanesthetized	O
adult	O
female	O
,	O
Sprague	O
-	O
Dawley	O
rats	O
were	O
divided	O
in	O
four	O
groups	O
and	O
studied	O
for	O
15	O
days	O
.	O

Group	O
1	O
(	O
P	B-Chemical
alone	O
)	O
received	O
P	B-Chemical
,	O
360	O
mg	O
/	O
day	O
,	O
for	O
15	O
days	O
;	O
Group	O
II	O
(	O
P	B-Chemical
+	O
gentamicin	B-Chemical
)	O
;	O
Group	O
III	O
(	O
gentamicin	B-Chemical
alone	O
)	O
and	O
Group	O
IV	O
(	O
mild	O
DM	B-Disease
+	O
gentamicin	B-Chemical
)	O
.	O

Nephrotoxic	B-Disease
doses	O
(	O
40	O
mg	O
/	O
kg	O
body	O
wt	O
/	O
day	O
)	O
of	O
gentamicin	B-Chemical
were	O
injected	O
during	O
the	O
last	O
nine	O
days	O
of	O
study	O
to	O
the	O
animals	O
of	O
groups	O
II	O
to	O
IV	O
.	O

In	O
Group	O
I	O
,	O
P	B-Chemical
induced	O
a	O
moderate	O
and	O
stable	O
glycosuria	B-Disease
(	O
3	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
1	O
g	O
/	O
day	O
,	O
SE	O
)	O
,	O
and	O
no	O
functional	O
or	O
morphologic	O
evidence	O
of	O
renal	B-Disease
dysfunction	I-Disease
(	O
baseline	O
CCr	O
2	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
1	O
ml	O
/	O
min	O
,	O
undetectable	O
lysozymuria	O
)	O
or	O
damage	O
(	O
tubular	B-Disease
necrosis	I-Disease
score	O
[	O
maximum	O
4	O
]	O
,	O
zero	O
)	O
.	O

In	O
Group	O
II	O
,	O
P	B-Chemical
did	O
not	O
prevent	O
gentamicin	B-Chemical
-	O
ARF	B-Disease
(	O
maximal	O
decrease	O
in	O
CCr	O
at	O
day	O
9	O
.	O
89	O
%	O
,	O
P	B-Chemical
less	O
than	O
0	O
.	O
001	O
;	O
peak	O
lysozymuria	O
,	O
1863	O
+	O
/	O
-	O
321	O
micrograms	O
/	O
day	O
;	O
and	O
tubular	B-Disease
necrosis	I-Disease
score	O
,	O
3	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
1	O
)	O
.	O

These	O
values	O
were	O
not	O
different	O
from	O
those	O
of	O
Group	O
III	O
:	O
maximal	O
decrease	O
in	O
CCr	O
73	O
%	O
(	O
P	B-Chemical
less	O
than	O
0	O
.	O
001	O
)	O
;	O
lysozymuria	O
,	O
2147	O
+	O
/	O
-	O
701	O
micrograms	O
/	O
day	O
;	O
tubular	B-Disease
necrosis	I-Disease
score	O
,	O
3	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
1	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Catalepsy	B-Disease
induced	O
by	O
combinations	O
of	O
ketamine	B-Chemical
and	O
morphine	B-Chemical
:	O
potentiation	O
,	O
antagonism	O
,	O
tolerance	O
and	O
cross	O
-	O
tolerance	O
in	O
the	O
rat	O
.	O

Previous	O
studies	O
demonstrated	O
that	O
both	O
ketamine	B-Chemical
and	O
morphine	B-Chemical
induced	O
analgesia	B-Disease
and	O
catalepsy	B-Disease
in	O
the	O
rat	O
.	O

Pre	O
-	O
treatment	O
with	O
ketamine	B-Chemical
produced	O
cross	O
-	O
tolerance	O
to	O
morphine	B-Chemical
,	O
whereas	O
pretreatment	O
with	O
morphine	B-Chemical
did	O
not	O
induce	O
cross	O
-	O
tolerance	O
to	O
ketamine	B-Chemical
but	O
rather	O
augmented	O
the	O
cataleptic	B-Disease
response	O
;	O
this	O
augmentation	O
was	O
attributed	O
to	O
residual	O
morphine	B-Chemical
in	O
the	O
brain	O
.	O

The	O
present	O
studies	O
explored	O
the	O
duration	O
of	O
the	O
loss	O
of	O
righting	O
reflex	O
induced	O
by	O
sub	O
-	O
effective	O
doses	O
of	O
ketamine	B-Chemical
and	O
morphine	B-Chemical
,	O
administered	O
simultaneously	O
.	O

There	O
was	O
mutual	O
potentiation	O
between	O
sub	O
-	O
effective	O
doses	O
of	O
ketamine	B-Chemical
and	O
morphine	B-Chemical
,	O
but	O
sub	O
-	O
effective	O
doses	O
of	O
ketamine	B-Chemical
partly	O
antagonized	O
fully	O
-	O
effective	O
doses	O
of	O
morphine	B-Chemical
.	O

Latency	O
to	O
the	O
loss	O
of	O
righting	O
reflex	O
,	O
rigidity	B-Disease
and	O
behavior	O
on	O
recovery	O
,	O
reflected	O
the	O
relative	O
predominance	O
of	O
ketamine	B-Chemical
or	O
morphine	B-Chemical
in	O
each	O
combination	O
.	O

Naloxone	B-Chemical
inhibited	O
the	O
induced	O
cataleptic	B-Disease
effects	O
.	O

The	O
degree	O
and	O
time	O
course	O
of	O
development	O
of	O
tolerance	O
to	O
daily	O
administration	O
of	O
sub	O
-	O
effective	O
dose	O
combinations	O
of	O
ketamine	B-Chemical
and	O
morphine	B-Chemical
were	O
similar	O
.	O

Rats	O
,	O
tolerant	O
to	O
ketamine	B-Chemical
-	O
dominant	O
combinations	O
,	O
were	O
cross	O
-	O
tolerant	O
to	O
both	O
drugs	O
,	O
while	O
those	O
tolerant	O
to	O
morphine	B-Chemical
-	O
dominant	O
combinations	O
were	O
cross	O
-	O
tolerant	O
to	O
morphine	B-Chemical
but	O
showed	O
either	O
no	O
cross	O
-	O
tolerance	O
or	O
an	O
augmented	O
response	O
to	O
ketamine	B-Chemical
.	O

While	O
the	O
mutual	O
potentiation	O
,	O
antagonism	O
and	O
tolerance	O
suggest	O
common	O
mechanisms	O
for	O
the	O
induced	O
catalepsy	B-Disease
,	O
differences	O
in	O
latency	O
,	O
rigidity	B-Disease
and	O
behavior	O
,	O
asymmetry	O
of	O
cross	O
-	O
tolerance	O
and	O
a	O
widely	O
-	O
different	O
ID50	O
for	O
naloxone	B-Chemical
would	O
argue	O
against	O
an	O
action	O
at	O
a	O
single	O
opioid	O
site	O
.	O

Hydrocortisone	B-Chemical
-	O
induced	O
hypertension	B-Disease
in	O
humans	O
:	O
pressor	O
responsiveness	O
and	O
sympathetic	O
function	O
.	O

Oral	O
hydrocortisone	B-Chemical
increases	O
blood	O
pressure	O
and	O
enhances	O
pressor	O
responsiveness	O
in	O
normal	O
human	O
subjects	O
.	O

We	O
studied	O
the	O
effects	O
of	O
1	O
week	O
of	O
oral	O
hydrocortisone	B-Chemical
(	O
200	O
mg	O
/	O
day	O
)	O
on	O
blood	O
pressure	O
,	O
cardiac	O
output	O
,	O
total	O
peripheral	O
resistance	O
,	O
forearm	O
vascular	O
resistance	O
,	O
and	O
norepinephrine	B-Chemical
spillover	O
to	O
plasma	O
in	O
eight	O
healthy	O
male	O
volunteers	O
.	O

Although	O
diastolic	O
blood	O
pressure	O
remained	O
unchanged	O
,	O
systolic	O
blood	O
pressure	O
increased	O
from	O
119	O
to	O
135	O
mm	O
Hg	O
(	O
SED	O
+	O
/	O
-	O
3	O
.	O
4	O
,	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
,	O
associated	O
with	O
an	O
increased	B-Disease
cardiac	I-Disease
output	I-Disease
(	O
5	O
.	O
85	O
-	O
7	O
.	O
73	O
l	O
/	O
min	O
,	O
SED	O
+	O
/	O
-	O
0	O
.	O
46	O
,	O
p	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

Total	O
peripheral	O
vascular	O
resistance	O
fell	O
from	O
15	O
.	O
1	O
to	O
12	O
.	O
2	O
mm	O
Hg	O
/	O
l	O
/	O
min	O
(	O
SED	O
+	O
/	O
-	O
1	O
.	O
03	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

Resting	O
forearm	O
vascular	O
resistance	O
remained	O
unchanged	O
,	O
but	O
the	O
reflex	O
response	O
to	O
the	O
cold	O
pressor	O
test	O
was	O
accentuated	O
,	O
the	O
rise	O
in	O
resistance	O
increasing	O
from	O
10	O
.	O
5	O
mm	O
Hg	O
/	O
ml	O
/	O
100	O
ml	O
/	O
min	O
(	O
R	O
units	O
)	O
before	O
treatment	O
to	O
32	O
.	O
6	O
R	O
units	O
after	O
treatment	O
(	O
SED	O
+	O
/	O
-	O
6	O
.	O
4	O
,	O
p	O
less	O
than	O
0	O
.	O
025	O
)	O
.	O

The	O
rise	O
in	O
forearm	O
vascular	O
resistance	O
accompanying	O
intra	O
-	O
arterial	O
norepinephrine	B-Chemical
(	O
25	O
,	O
50	O
,	O
and	O
100	O
ng	O
/	O
min	O
)	O
was	O
also	O
significantly	O
greater	O
after	O
hydrocortisone	B-Chemical
,	O
increasing	O
from	O
an	O
average	O
of	O
14	O
.	O
9	O
+	O
/	O
-	O
2	O
.	O
4	O
R	O
units	O
before	O
treatment	O
to	O
35	O
.	O
1	O
+	O
/	O
-	O
5	O
.	O
5	O
R	O
units	O
after	O
hydrocortisone	B-Chemical
(	O
SED	O
+	O
/	O
-	O
6	O
.	O
0	O
,	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
.	O

A	O
shift	O
to	O
the	O
left	O
in	O
the	O
dose	O
-	O
response	O
relation	O
and	O
fall	O
in	O
threshold	O
suggested	O
increased	O
sensitivity	O
to	O
norepinephrine	B-Chemical
after	O
treatment	O
.	O

Measurement	O
of	O
resting	O
norepinephrine	B-Chemical
spillover	O
rate	O
to	O
plasma	O
and	O
norepinephrine	B-Chemical
uptake	O
indicated	O
that	O
overall	O
resting	O
sympathetic	O
nervous	O
system	O
activity	O
was	O
not	O
increased	O
.	O

The	O
rise	B-Disease
in	I-Disease
resting	I-Disease
blood	I-Disease
pressure	I-Disease
with	O
hydrocortisone	B-Chemical
is	O
associated	O
with	O
an	O
increased	B-Disease
cardiac	I-Disease
output	I-Disease
(	O
presumably	O
due	O
to	O
increased	O
blood	O
volume	O
)	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Neuromuscular	B-Disease
blockade	I-Disease
with	O
magnesium	B-Chemical
sulfate	I-Chemical
and	O
nifedipine	B-Chemical
.	O

A	O
patient	O
who	O
received	O
tocolysis	O
with	O
nifedipine	B-Chemical
developed	O
neuromuscular	B-Disease
blockade	I-Disease
after	O
500	O
mg	O
of	O
magnesium	B-Chemical
sulfate	I-Chemical
was	O
administered	O
.	O

This	O
reaction	O
demonstrates	O
that	O
nifedipine	B-Chemical
can	O
seriously	O
potentiate	O
the	O
toxicity	B-Disease
of	O
magnesium	B-Chemical
.	O

Caution	O
should	O
be	O
exercised	O
when	O
these	O
two	O
tocolytics	O
are	O
combined	O
.	O

Chronic	O
carbamazepine	B-Chemical
inhibits	O
the	O
development	O
of	O
local	O
anesthetic	O
seizures	B-Disease
kindled	O
by	O
cocaine	B-Chemical
and	O
lidocaine	B-Chemical
.	O

The	O
effects	O
of	O
carbamazepine	B-Chemical
(	O
CBZ	B-Chemical
)	O
treatment	O
on	O
local	O
anesthetic	O
-	O
kindled	O
seizures	B-Disease
and	O
lethality	O
were	O
evaluated	O
in	O
different	O
stages	O
of	O
the	O
kindling	O
process	O
and	O
under	O
different	O
methods	O
of	O
CBZ	B-Chemical
administration	O
.	O

Chronic	O
oral	O
CBZ	B-Chemical
inhibited	O
the	O
development	O
of	O
both	O
lidocaine	B-Chemical
-	O
and	O
cocaine	B-Chemical
-	O
induced	O
seizures	B-Disease
,	O
but	O
had	O
little	O
effect	O
on	O
the	O
fully	O
developed	O
local	O
anesthetic	O
seizures	B-Disease
.	O

Chronic	O
CBZ	B-Chemical
also	O
decreased	O
the	O
incidence	O
of	O
seizure	B-Disease
-	O
related	O
mortality	O
in	O
the	O
cocaine	B-Chemical
-	O
injected	O
rats	O
.	O

Acute	O
CBZ	B-Chemical
over	O
a	O
range	O
of	O
doses	O
(	O
15	O
-	O
50	O
mg	O
/	O
kg	O
)	O
had	O
no	O
effect	O
on	O
completed	O
lidocaine	B-Chemical
-	O
kindled	O
or	O
acute	O
cocaine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

Repeated	O
i	O
.	O
p	O
.	O
injection	O
of	O
CBZ	B-Chemical
(	O
15	O
mg	O
/	O
kg	O
)	O
also	O
was	O
without	O
effect	O
on	O
the	O
development	O
of	O
lidocaine	B-Chemical
-	O
or	O
cocaine	B-Chemical
-	O
kindled	O
seizures	B-Disease
.	O

The	O
differential	O
effects	O
of	O
CBZ	B-Chemical
depending	O
upon	O
stage	O
of	O
seizure	B-Disease
development	O
suggest	O
that	O
distinct	O
mechanisms	O
underlie	O
the	O
development	O
versus	O
maintenance	O
of	O
local	O
anesthetic	O
-	O
kindled	O
seizures	B-Disease
.	O

The	O
effectiveness	O
of	O
chronic	O
but	O
not	O
repeated	O
,	O
intermittent	O
injections	O
of	O
CBZ	B-Chemical
suggests	O
that	O
different	O
biochemical	O
consequences	O
result	O
from	O
the	O
different	O
treatment	O
regimens	O
.	O

The	O
possible	O
utility	O
of	O
chronic	O
CBZ	B-Chemical
in	O
preventing	O
the	O
development	O
of	O
toxic	O
side	O
effects	O
in	O
human	O
cocaine	B-Chemical
users	O
is	O
suggested	O
by	O
these	O
data	O
,	O
but	O
remains	O
to	O
be	O
directly	O
evaluated	O
.	O

Magnetic	O
resonance	O
imaging	O
of	O
cerebral	O
venous	B-Disease
thrombosis	I-Disease
secondary	O
to	O
"	O
low	O
-	O
dose	O
"	O
birth	O
control	O
pills	O
.	O

The	O
clinical	O
and	O
radiographic	O
features	O
of	O
cerebral	O
deep	B-Disease
venous	I-Disease
thrombosis	I-Disease
in	O
a	O
21	O
-	O
year	O
-	O
old	O
white	O
woman	O
are	O
presented	O
.	O

This	O
nulliparous	O
patient	O
presented	O
with	O
relatively	O
mild	O
clinical	O
symptoms	O
and	O
progressing	O
mental	O
status	O
changes	O
.	O

The	O
only	O
known	O
risk	O
factor	O
was	O
"	O
low	O
-	O
dose	O
"	O
oral	B-Chemical
contraceptive	I-Chemical
pills	O
.	O

The	O
magnetic	O
resonance	O
image	O
(	O
MRI	O
)	O
showed	O
increased	O
signal	O
intensity	O
from	O
the	O
internal	O
cerebral	O
veins	O
,	O
vein	O
of	O
Galen	O
,	O
and	O
straight	O
sinus	O
.	O

The	O
diagnosis	O
was	O
confirmed	O
by	O
arterial	O
angiography	O
.	O

Beta	O
-	O
2	O
-	O
adrenoceptor	O
-	O
mediated	O
hypokalemia	B-Disease
and	O
its	O
abolishment	O
by	O
oxprenolol	B-Chemical
.	O

The	O
time	O
course	O
and	O
concentration	O
-	O
effect	O
relationship	O
of	O
terbutaline	B-Chemical
-	O
induced	O
hypokalemia	B-Disease
was	O
studied	O
,	O
using	O
computer	O
-	O
aided	O
pharmacokinetic	O
-	O
dynamic	O
modeling	O
.	O

Subsequently	O
we	O
investigated	O
the	O
efficacy	O
of	O
oxprenolol	B-Chemical
in	O
antagonizing	O
such	O
hypokalemia	B-Disease
,	O
together	O
with	O
the	O
pharmacokinetic	O
interaction	O
between	O
both	O
drugs	O
.	O

Six	O
healthy	O
subjects	O
were	O
given	O
a	O
0	O
.	O
5	O
mg	O
subcutaneous	O
dose	O
of	O
terbutaline	B-Chemical
on	O
two	O
occasions	O
:	O
1	O
hour	O
after	O
oral	O
administration	O
of	O
a	O
placebo	O
and	O
1	O
hour	O
after	O
80	O
mg	O
oxprenolol	B-Chemical
orally	O
.	O

In	O
the	O
7	O
-	O
hour	O
period	O
after	O
terbutaline	B-Chemical
administration	O
,	O
plasma	O
samples	O
were	O
taken	O
for	O
determination	O
of	O
plasma	O
potassium	B-Chemical
levels	O
and	O
drug	O
concentrations	O
.	O

The	O
sigmoid	O
Emax	O
model	O
offered	O
a	O
good	O
description	O
of	O
the	O
relation	O
between	O
terbutaline	B-Chemical
concentrations	O
and	O
potassium	B-Chemical
effects	O
.	O

Oxprenolol	B-Chemical
caused	O
decreases	O
of	O
65	O
%	O
and	O
56	O
%	O
of	O
terbutaline	B-Chemical
volume	O
of	O
distribution	O
and	O
clearance	O
,	O
respectively	O
,	O
and	O
an	O
increase	O
of	O
130	O
%	O
of	O
its	O
AUC	O
.	O

In	O
spite	O
of	O
higher	O
terbutaline	B-Chemical
concentrations	O
after	O
oxprenolol	B-Chemical
pretreatment	O
,	O
the	O
hypokalemia	B-Disease
was	O
almost	O
completely	O
antagonized	O
by	O
the	O
beta	O
2	O
-	O
blocking	O
action	O
.	O

A	O
dystonia	B-Disease
-	O
like	O
syndrome	O
after	O
neuropeptide	O
(	O
MSH	B-Chemical
/	O
ACTH	B-Chemical
)	O
stimulation	O
of	O
the	O
rat	O
locus	O
ceruleus	O
.	O

The	O
movement	B-Disease
disorder	I-Disease
investigated	O
in	O
these	O
studies	O
has	O
some	O
features	O
in	O
common	O
with	O
human	O
idiopathic	O
dystonia	B-Disease
,	O
and	O
information	O
obtained	O
in	O
these	O
studies	O
may	O
be	O
of	O
potential	O
clinical	O
benefit	O
.	O

The	O
present	O
experimental	O
results	O
indicated	O
that	O
peptidergic	O
stimulation	O
of	O
the	O
LC	O
resulted	O
in	O
a	O
NE	O
-	O
mediated	O
inhibition	O
of	O
cerebellar	O
Purkinje	O
cells	O
located	O
at	O
terminals	O
of	O
the	O
ceruleo	O
-	O
cerebellar	O
pathway	O
.	O

However	O
,	O
it	O
is	O
not	O
certain	O
as	O
to	O
the	O
following	O
:	O
(	O
a	O
)	O
what	O
receptors	O
were	O
stimulated	O
by	O
the	O
ACTH	B-Chemical
N	O
-	O
terminal	O
fragments	O
at	O
the	O
LC	O
that	O
resulted	O
in	O
this	O
disorder	O
;	O
(	O
b	O
)	O
whether	O
NE	O
,	O
released	O
onto	O
Purkinje	O
cell	O
synapses	O
located	O
at	O
terminals	O
of	O
the	O
ceruleo	O
-	O
cerebellar	O
pathway	O
,	O
did	O
indeed	O
cause	O
the	O
long	O
-	O
term	O
depression	B-Disease
at	O
Purkinje	O
cell	O
synapses	O
(	O
previously	O
described	O
by	O
others	O
)	O
that	O
resulted	O
in	O
the	O
long	O
duration	O
of	O
the	O
movement	B-Disease
disorder	I-Disease
;	O
(	O
c	O
)	O
whether	O
the	O
inhibition	O
of	O
inhibitory	O
Purkinje	O
cells	O
resulted	O
in	O
disinhibition	O
or	O
increased	O
excitability	O
of	O
the	O
unilateral	O
cerebellar	O
fastigial	O
or	O
interpositus	O
nuclei	O
,	O
the	O
output	O
targets	O
of	O
the	O
Purkinje	O
cell	O
axons	O
,	O
that	O
may	O
have	O
been	O
an	O
important	O
contributing	O
factor	O
to	O
this	O
disorder	O
.	O

These	O
questions	O
are	O
currently	O
being	O
investigated	O
.	O

Enhanced	O
stimulus	O
-	O
induced	O
neurotransmitter	O
overflow	O
in	O
epinephrine	B-Chemical
-	O
induced	O
hypertensive	B-Disease
rats	O
is	O
not	O
mediated	O
by	O
prejunctional	O
beta	O
-	O
adrenoceptor	O
activation	O
.	O

The	O
present	O
study	O
examines	O
the	O
effect	O
of	O
6	O
-	O
day	O
epinephrine	B-Chemical
treatment	O
(	O
100	O
micrograms	O
/	O
kg	O
per	O
h	O
,	O
s	O
.	O
c	O
.	O
)	O
on	O
stimulus	O
-	O
induced	O
(	O
1	O
Hz	O
)	O
endogenous	O
neurotransmitter	O
overflow	O
from	O
the	O
isolated	O
perfused	O
kidney	O
of	O
vehicle	O
-	O
and	O
epinephrine	B-Chemical
-	O
treated	O
rats	O
.	O

Renal	O
catecholamine	B-Chemical
stores	O
and	O
stimulus	O
-	O
induced	O
overflow	O
in	O
the	O
vehicle	O
-	O
treated	O
group	O
consisted	O
of	O
norepinephrine	B-Chemical
only	O
.	O

However	O
,	O
epinephrine	B-Chemical
treatment	O
resulted	O
in	O
the	O
incorporation	O
of	O
epinephrine	B-Chemical
into	O
renal	O
catecholamine	B-Chemical
stores	O
such	O
that	O
approximately	O
40	O
%	O
of	O
the	O
catecholamine	B-Chemical
present	O
was	O
epinephrine	B-Chemical
while	O
the	O
norepinephrine	B-Chemical
content	O
was	O
reduced	O
by	O
a	O
similar	O
degree	O
.	O

Total	O
tissue	O
catecholamine	B-Chemical
content	O
of	O
the	O
kidney	O
on	O
a	O
molar	O
basis	O
was	O
unchanged	O
.	O

Stimulus	O
-	O
induced	O
fractional	O
overflow	O
of	O
neurotransmitter	O
from	O
the	O
epinephrine	B-Chemical
-	O
treated	O
kidneys	O
was	O
approximately	O
twice	O
normal	O
and	O
consisted	O
of	O
both	O
norepinephrine	B-Chemical
and	O
epinephrine	B-Chemical
in	O
proportions	O
similar	O
to	O
those	O
found	O
in	O
the	O
kidney	O
.	O

This	O
difference	O
in	O
fractional	O
overflow	O
between	O
groups	O
was	O
not	O
affected	O
by	O
neuronal	O
and	O
extraneuronal	O
uptake	O
blockade	O
.	O

Propranolol	B-Chemical
had	O
no	O
effect	O
on	O
stimulus	O
-	O
induced	O
overflow	O
in	O
either	O
group	O
.	O

Phentolamine	B-Chemical
increased	O
stimulus	O
-	O
induced	O
overflow	O
in	O
both	O
groups	O
although	O
the	O
increment	O
in	O
overflow	O
was	O
greater	O
in	O
the	O
epinephrine	B-Chemical
-	O
treated	O
group	O
.	O

In	O
conclusion	O
,	O
chronic	O
epinephrine	B-Chemical
treatment	O
results	O
in	O
enhanced	O
fractional	O
neurotransmitter	O
overflow	O
.	O

However	O
,	O
neither	O
alterations	O
in	O
prejunctional	O
beta	O
-	O
adrenoceptor	O
influences	O
nor	O
alterations	O
in	O
neuronal	O
and	O
extraneuronal	O
uptake	O
mechanisms	O
appear	O
to	O
be	O
responsible	O
for	O
this	O
alteration	O
.	O

Furthermore	O
,	O
data	O
obtained	O
with	O
phentolamine	B-Chemical
alone	O
do	O
not	O
suggest	O
alpha	O
-	O
adrenoceptor	O
desensitization	O
as	O
the	O
cause	O
of	O
the	O
enhanced	O
neurotransmitter	O
overflow	O
after	O
epinephrine	B-Chemical
treatment	O
.	O

GABA	B-Chemical
involvement	O
in	O
naloxone	B-Chemical
induced	O
reversal	O
of	O
respiratory	B-Disease
paralysis	I-Disease
produced	O
by	O
thiopental	B-Chemical
.	O

No	O
agent	O
is	O
yet	O
available	O
to	O
reverse	O
respiratory	B-Disease
paralysis	I-Disease
produced	O
by	O
CNS	O
depressants	O
,	O
such	O
as	O
general	O
anesthetics	O
.	O

In	O
this	O
study	O
naloxone	B-Chemical
reversed	O
respiratory	B-Disease
paralysis	I-Disease
induced	O
by	O
thiopental	B-Chemical
in	O
rats	O
.	O

25	O
mg	O
/	O
kg	O
,	O
i	O
.	O
v	O
.	O
thiopental	B-Chemical
produced	O
anesthesia	O
without	O
altering	O
respiratory	O
rate	O
,	O
increased	O
GABA	B-Chemical
,	O
decreased	O
glutamate	B-Chemical
,	O
and	O
had	O
no	O
effect	O
on	O
aspartate	B-Chemical
or	O
glycine	B-Chemical
levels	O
compared	O
to	O
controls	O
in	O
rat	O
cortex	O
and	O
brain	O
stem	O
.	O

Pretreatment	O
of	O
rats	O
with	O
thiosemicarbazide	B-Chemical
for	O
30	O
minutes	O
abolished	O
the	O
anesthetic	O
action	O
as	O
well	O
as	O
the	O
respiratory	O
depressant	O
action	O
of	O
thiopental	B-Chemical
.	O

50	O
mg	O
/	O
kg	O
,	O
i	O
.	O
v	O
.	O
thiopental	B-Chemical
produced	O
respiratory	B-Disease
arrest	I-Disease
with	O
further	O
increase	O
in	O
GABA	B-Chemical
and	O
decrease	O
in	O
glutamate	B-Chemical
again	O
in	O
cortex	O
and	O
brain	O
stem	O
without	O
affecting	O
any	O
of	O
the	O
amino	B-Chemical
acids	I-Chemical
studied	O
in	O
four	O
regions	O
of	O
rat	O
brain	O
.	O

Naloxone	B-Chemical
(	O
2	O
.	O
5	O
mg	O
/	O
kg	O
,	O
i	O
.	O
v	O
.	O
)	O
reversed	O
respiratory	B-Disease
paralysis	I-Disease
,	O
glutamate	B-Chemical
and	O
GABA	B-Chemical
levels	O
to	O
control	O
values	O
in	O
brain	O
stem	O
and	O
cortex	O
with	O
no	O
changes	O
in	O
caudate	O
or	O
cerebellum	O
.	O

These	O
data	O
suggest	O
naloxone	B-Chemical
reverses	O
respiratory	B-Disease
paralysis	I-Disease
produced	O
by	O
thiopental	B-Chemical
and	O
involves	O
GABA	B-Chemical
in	O
its	O
action	O
.	O

Diazepam	B-Chemical
facilitates	O
reflex	O
bradycardia	B-Disease
in	O
conscious	O
rats	O
.	O

The	O
effects	O
of	O
diazepam	B-Chemical
on	O
cardiovascular	O
function	O
were	O
assessed	O
in	O
conscious	O
rats	O
.	O

Intravenous	O
administration	O
of	O
diazepam	B-Chemical
(	O
1	O
-	O
30	O
mg	O
kg	O
-	O
1	O
)	O
produced	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

Also	O
,	O
reflex	O
bradycardia	B-Disease
was	O
produced	O
in	O
rats	O
by	O
intravenous	O
infusion	O
of	O
adrenaline	B-Chemical
(	O
1	O
.	O
25	O
-	O
2	O
.	O
5	O
micrograms	O
kg	O
-	O
1	O
)	O
.	O

Intravenous	O
pretreatment	O
of	O
the	O
rats	O
with	O
diazepam	B-Chemical
,	O
although	O
causing	O
no	O
change	O
in	O
the	O
adrenaline	B-Chemical
-	O
induced	O
pressor	O
effect	O
,	O
did	O
enhance	O
the	O
adrenaline	B-Chemical
-	O
induced	O
reflex	O
bradycardia	B-Disease
.	O

However	O
,	O
the	O
diazepam	B-Chemical
enhancement	O
of	O
adrenaline	B-Chemical
-	O
induced	O
reflex	O
bradycardia	B-Disease
was	O
antagonized	O
by	O
pretreatment	O
of	O
rats	O
with	O
an	O
intravenous	O
dose	O
of	O
picrotoxin	B-Chemical
(	O
an	O
agent	O
blocks	O
chloride	B-Chemical
channels	O
by	O
binding	O
to	O
sites	O
associated	O
with	O
the	O
benzodiazepine	B-Chemical
-	O
GABA	B-Chemical
-	O
chloride	B-Chemical
channel	O
macromolecular	O
complex	O
)	O
.	O

The	O
data	O
indicate	O
that	O
diazepam	B-Chemical
acts	O
through	O
the	O
benzodiazepine	B-Chemical
-	O
GABA	B-Chemical
-	O
chloride	B-Chemical
channel	O
macromolecular	O
complex	O
within	O
the	O
central	O
nervous	O
system	O
to	O
facilitate	O
reflex	O
bradycardia	B-Disease
mediated	O
through	O
baroreceptor	O
reflexes	O
in	O
response	O
to	O
an	O
acute	O
increase	O
in	O
arterial	O
pressure	O
.	O

Initial	O
potassium	B-Chemical
loss	O
and	O
hypokalaemia	B-Disease
during	O
chlorthalidone	B-Chemical
administration	O
in	O
patients	O
with	O
essential	O
hypertension	B-Disease
:	O
the	O
influence	O
of	O
dietary	O
sodium	B-Chemical
restriction	O
.	O

To	O
investigate	O
the	O
initial	O
potassium	B-Chemical
loss	O
and	O
development	O
of	O
hypokalaemia	B-Disease
during	O
the	O
administration	O
of	O
an	O
oral	O
diuretic	O
,	O
metabolic	O
balance	O
studies	O
were	O
performed	O
in	O
ten	O
patients	O
with	O
essential	O
hypertension	B-Disease
who	O
had	O
shown	O
hypokalaemia	B-Disease
under	O
prior	O
oral	O
diuretic	O
treatment	O
.	O

Chlorthalidone	B-Chemical
(	O
50	O
mg	O
daily	O
)	O
was	O
given	O
for	O
14	O
days	O
.	O

Six	O
patients	O
received	O
a	O
normal	O
-	O
sodium	B-Chemical
diet	O
and	O
four	O
a	O
low	O
-	O
sodium	B-Chemical
(	O
17	O
mmol	O
/	O
day	O
)	O
diet	O
.	O

All	O
patients	O
had	O
a	O
normal	O
initial	O
total	O
body	O
potassium	B-Chemical
(	O
40K	O
)	O
.	O

The	O
electrolyte	O
balances	O
,	O
weight	O
,	O
bromide	O
space	O
,	O
plasma	O
renin	O
activity	O
,	O
and	O
aldosterone	B-Chemical
secretion	O
rate	O
were	O
measured	O
.	O

In	O
both	O
groups	O
a	O
potassium	B-Chemical
deficit	O
developed	O
,	O
with	O
proportionally	O
larger	O
losses	O
from	O
the	O
extracellular	O
than	O
from	O
the	O
intracellular	O
compartment	O
.	O

In	O
the	O
normal	O
-	O
sodium	B-Chemical
group	O
the	O
highest	O
mean	O
potassium	B-Chemical
deficit	O
was	O
176	O
mmol	O
on	O
day	O
9	O
,	O
after	O
which	O
some	O
potassium	B-Chemical
was	O
regained	O
;	O
in	O
the	O
low	O
-	O
sodium	B-Chemical
group	O
the	O
highest	O
deficit	O
was	O
276	O
mmol	O
on	O
day	O
13	O
.	O

The	O
normal	O
-	O
sodium	B-Chemical
group	O
showed	O
an	O
immediate	O
but	O
temporary	O
rise	O
of	O
the	O
renin	O
and	O
aldosterone	B-Chemical
levels	O
;	O
in	O
the	O
low	O
-	O
sodium	B-Chemical
group	O
renin	O
and	O
aldosterone	B-Chemical
increased	O
more	O
slowly	O
but	O
remained	O
elevated	O
.	O

It	O
is	O
concluded	O
that	O
dietary	O
sodium	B-Chemical
restriction	O
increases	O
diuretic	O
-	O
induced	O
potassium	B-Chemical
loss	O
,	O
presumably	O
by	O
an	O
increased	O
activity	O
of	O
the	O
renin	O
-	O
angiotensin	B-Chemical
-	O
aldosterone	B-Chemical
system	O
,	O
while	O
sodium	B-Chemical
delivery	O
to	O
the	O
distal	O
renal	O
tubules	O
remains	O
sufficiently	O
high	O
to	O
allow	O
increased	O
potassium	B-Chemical
secretion	O
.	O

Reversal	O
of	O
neuroleptic	O
-	O
induced	O
catalepsy	B-Disease
by	O
novel	O
aryl	B-Chemical
-	I-Chemical
piperazine	I-Chemical
anxiolytic	O
drugs	O
.	O

The	O
novel	O
anxiolytic	O
drug	O
,	O
buspirone	B-Chemical
,	O
reverses	O
catalepsy	B-Disease
induced	O
by	O
haloperidol	B-Chemical
.	O

A	O
series	O
of	O
aryl	B-Chemical
-	I-Chemical
piperazine	I-Chemical
analogues	O
of	O
buspirone	B-Chemical
and	O
other	O
5	B-Chemical
-	I-Chemical
hydroxytryptaminergic	I-Chemical
agonists	I-Chemical
were	O
tested	O
for	O
their	O
ability	O
to	O
reverse	O
haloperidol	B-Chemical
induced	O
catalepsy	B-Disease
.	O

Those	O
drugs	O
with	O
strong	O
affinity	O
for	O
5	B-Chemical
-	I-Chemical
hydroxytryptamine1a	I-Chemical
receptors	O
were	O
able	O
to	O
reverse	O
catalepsy	B-Disease
.	O

Drugs	O
with	O
affinity	O
for	O
other	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
receptors	O
or	O
weak	O
affinity	O
were	O
ineffective	O
.	O

However	O
,	O
inhibition	O
of	O
postsynaptic	O
5	B-Chemical
-	I-Chemical
HT	I-Chemical
receptors	O
neither	O
inhibited	O
nor	O
potentiated	O
reversal	O
of	O
catalepsy	B-Disease
and	O
leaves	O
open	O
the	O
question	O
as	O
to	O
the	O
site	O
or	O
mechanism	O
for	O
this	O
effect	O
.	O

Glycopyrronium	B-Chemical
requirements	O
for	O
antagonism	O
of	O
the	O
muscarinic	O
side	O
effects	O
of	O
edrophonium	B-Chemical
.	O

We	O
have	O
compared	O
,	O
in	O
60	O
adult	O
patients	O
,	O
the	O
cardiovascular	O
effects	O
of	O
glycopyrronium	B-Chemical
5	O
micrograms	O
kg	O
-	O
1	O
and	O
10	O
micrograms	O
kg	O
-	O
1	O
given	O
either	O
simultaneously	O
or	O
1	O
min	O
before	O
edrophonium	B-Chemical
1	O
mg	O
kg	O
-	O
1	O
.	O

Significant	O
differences	O
between	O
the	O
four	O
groups	O
were	O
detected	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Both	O
groups	O
receiving	O
10	O
micrograms	O
kg	O
-	O
1	O
showed	O
increases	O
in	O
heart	O
rate	O
of	O
up	O
to	O
30	O
beat	O
min	O
-	O
1	O
(	O
95	O
%	O
confidence	O
limits	O
28	O
-	O
32	O
beat	O
min	O
-	O
1	O
)	O
.	O

Use	O
of	O
glycopyrronium	B-Chemical
5	O
micrograms	O
kg	O
-	O
1	O
provided	O
greater	O
cardiovascular	O
stability	O
and	O
,	O
given	O
1	O
min	O
before	O
the	O
edrophonium	B-Chemical
,	O
was	O
sufficient	O
to	O
minimize	O
early	O
,	O
edrophonium	B-Chemical
-	O
induced	O
bradycardias	B-Disease
.	O

This	O
low	O
dose	O
of	O
glycopyrronium	B-Chemical
provided	O
good	O
control	O
of	O
oropharyngeal	O
secretions	O
.	O

Selective	O
injection	O
of	O
iopentol	B-Chemical
,	O
iohexol	B-Chemical
and	O
metrizoate	B-Chemical
into	O
the	O
left	O
coronary	O
artery	O
of	O
the	O
dog	O
.	O

Induction	O
of	O
ventricular	B-Disease
fibrillation	I-Disease
and	O
decrease	O
of	O
aortic	O
pressure	O
.	O

In	O
twenty	O
beagle	O
dogs	O
selective	O
injections	O
were	O
made	O
into	O
the	O
left	O
coronary	O
artery	O
with	O
iopentol	B-Chemical
,	O
iohexol	B-Chemical
and	O
metrizoate	B-Chemical
in	O
doses	O
of	O
4	O
ml	O
,	O
8	O
ml	O
and	O
16	O
ml	O
.	O

Thirty	O
-	O
six	O
iopentol	B-Chemical
injections	O
,	O
35	O
iohexol	B-Chemical
injections	O
and	O
37	O
metrizoate	B-Chemical
injections	O
were	O
made	O
.	O

Frequencies	O
of	O
ventricular	B-Disease
fibrillation	I-Disease
were	O
significantly	O
lower	O
(	O
p	O
less	O
than	O
0	O
.	O
05	O
)	O
after	O
iopentol	B-Chemical
(	O
0	O
%	O
)	O
and	O
iohexol	B-Chemical
(	O
3	O
%	O
)	O
than	O
after	O
metrizoate	B-Chemical
(	O
22	O
%	O
)	O
.	O

Iopentol	B-Chemical
and	O
iohexol	B-Chemical
also	O
produced	O
significantly	O
less	O
decrease	O
in	O
aortic	O
blood	O
pressure	O
than	O
metrizoate	B-Chemical
at	O
the	O
different	O
doses	O
.	O

Thyroid	O
function	O
and	O
urine	O
-	O
concentrating	O
ability	O
during	O
lithium	B-Chemical
treatment	O
.	O

It	O
has	O
been	O
suggested	O
that	O
adenylate	O
cyclase	O
inhibition	O
may	O
be	O
important	O
in	O
the	O
development	O
of	O
both	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
and	O
hypothyroidism	B-Disease
during	O
lithium	B-Chemical
treatment	O
.	O

We	O
measured	O
serum	O
thyroxine	B-Chemical
and	O
urine	O
-	O
concentrating	O
ability	O
(	O
Umax	O
)	O
in	O
response	O
to	O
desmopressin	O
(	O
DDAVP	O
)	O
in	O
85	O
patients	O
receiving	O
lithium	B-Chemical
.	O

Hypothyroidism	B-Disease
developed	O
in	O
eight	O
patients	O
while	O
they	O
were	O
taking	O
lithium	B-Chemical
.	O

Impaired	O
Umax	O
was	O
found	O
in	O
both	O
euthyroid	O
and	O
hypothyroid	B-Disease
patients	O
while	O
some	O
hypothyroid	B-Disease
patients	O
concentrated	O
their	O
urine	O
well	O
.	O

It	O
is	O
concluded	O
that	O
the	O
dominant	O
mechanisms	O
by	O
which	O
lithium	B-Chemical
exerts	O
these	O
two	O
effects	O
are	O
different	O
.	O

Remodelling	O
of	O
nerve	O
structure	O
in	O
experimental	O
isoniazid	B-Chemical
neuropathy	B-Disease
in	O
the	O
rat	O
.	O

The	O
neuropathy	B-Disease
caused	O
by	O
a	O
single	O
dose	O
of	O
isoniazid	B-Chemical
in	O
rats	O
was	O
studied	O
with	O
a	O
computer	O
-	O
assisted	O
morphometric	O
method	O
.	O

Scatter	O
diagrams	O
of	O
the	O
g	O
ratio	O
(	O
quotient	O
fibre	O
diameter	O
/	O
axon	O
diameter	O
)	O
define	O
regenerating	O
fibres	O
as	O
a	O
distinct	O
population	O
,	O
distinguishable	O
from	O
the	O
surviving	O
fibres	O
by	O
reduced	O
sheath	O
thickness	O
and	O
reduced	O
axon	O
calibre	O
.	O

There	O
was	O
also	O
evidence	O
of	O
a	O
subtle	O
direct	O
toxic	O
effect	O
on	O
the	O
entire	O
fibre	O
population	O
,	O
causing	O
axon	O
shrinkage	O
masked	O
by	O
readjustment	O
of	O
the	O
myelin	O
sheath	O
.	O

Multicenter	O
,	O
double	O
-	O
blind	O
,	O
multiple	O
-	O
dose	O
,	O
parallel	O
-	O
groups	O
efficacy	O
and	O
safety	O
trial	O
of	O
azelastine	B-Chemical
,	O
chlorpheniramine	B-Chemical
,	O
and	O
placebo	O
in	O
the	O
treatment	O
of	O
spring	B-Disease
allergic	I-Disease
rhinitis	I-Disease
.	O

Azelastine	B-Chemical
,	O
a	O
novel	O
antiallergic	O
medication	O
,	O
was	O
compared	O
with	O
chlorpheniramine	B-Chemical
maleate	I-Chemical
and	O
placebo	O
for	O
efficacy	O
and	O
safety	O
in	O
the	O
treatment	O
of	O
spring	B-Disease
allergic	I-Disease
rhinitis	I-Disease
in	O
a	O
multicenter	O
,	O
double	O
-	O
blind	O
,	O
multiple	O
-	O
dose	O
,	O
parallel	O
-	O
groups	O
study	O
.	O

One	O
hundred	O
fifty	O
-	O
five	O
subjects	O
participated	O
.	O

Subjects	O
ranged	O
in	O
age	O
from	O
18	O
to	O
60	O
years	O
of	O
age	O
and	O
had	O
at	O
least	O
a	O
2	O
-	O
year	O
history	O
of	O
spring	B-Disease
allergic	I-Disease
rhinitis	I-Disease
,	O
confirmed	O
by	O
positive	O
skin	O
test	O
to	O
spring	O
aeroallergens	O
.	O

Medications	O
were	O
given	O
four	O
times	O
daily	O
;	O
the	O
azelastine	B-Chemical
groups	O
received	O
0	O
.	O
5	O
,	O
1	O
.	O
0	O
,	O
or	O
2	O
.	O
0	O
mg	O
in	O
the	O
morning	O
and	O
evening	O
with	O
placebo	O
in	O
the	O
early	O
and	O
late	O
afternoon	O
;	O
the	O
chlorpheniramine	B-Chemical
group	O
received	O
4	O
.	O
0	O
mg	O
four	O
times	O
daily	O
.	O

Daily	O
subject	O
symptom	O
cards	O
were	O
completed	O
during	O
a	O
screening	O
period	O
to	O
assess	O
pretreatment	O
symptoms	O
and	O
during	O
a	O
4	O
-	O
week	O
treatment	O
period	O
while	O
subjects	O
received	O
study	O
medications	O
.	O

Individual	O
symptoms	O
,	O
total	O
symptoms	O
,	O
and	O
major	O
symptoms	O
were	O
compared	O
to	O
determine	O
efficacy	O
of	O
medication	O
.	O

Elicited	O
,	O
volunteered	O
,	O
and	O
observed	O
adverse	O
experiences	O
were	O
recorded	O
for	O
each	O
subject	O
and	O
compared	O
among	O
groups	O
.	O

Vital	O
signs	O
,	O
body	O
weights	O
,	O
serum	O
chemistry	O
values	O
,	O
complete	O
blood	O
cell	O
counts	O
,	O
urine	O
studies	O
,	O
and	O
electrocardiograms	O
were	O
obtained	O
for	O
each	O
subject	O
and	O
compared	O
among	O
groups	O
.	O

Symptoms	O
relief	O
in	O
the	O
group	O
receiving	O
the	O
highest	O
concentration	O
of	O
azelastine	B-Chemical
(	O
2	O
.	O
0	O
mg	O
twice	O
daily	O
)	O
was	O
statistically	O
greater	O
than	O
in	O
the	O
placebo	O
group	O
during	O
all	O
weeks	O
of	O
the	O
study	O
.	O

Lower	O
doses	O
of	O
azelastine	B-Chemical
were	O
statistically	O
more	O
effective	O
than	O
placebo	O
only	O
during	O
portions	O
of	O
the	O
first	O
3	O
weeks	O
of	O
the	O
study	O
.	O

In	O
contrast	O
,	O
although	O
the	O
chlorpheniramine	B-Chemical
group	O
did	O
have	O
fewer	O
symptoms	O
than	O
the	O
placebo	O
group	O
during	O
the	O
study	O
,	O
the	O
difference	O
never	O
reached	O
statistical	O
significance	O
during	O
any	O
week	O
of	O
the	O
study	O
.	O

There	O
were	O
no	O
serious	O
side	O
effects	O
in	O
any	O
of	O
the	O
treatment	O
groups	O
.	O

Drowsiness	B-Disease
and	O
altered	B-Disease
taste	I-Disease
perception	I-Disease
were	O
increased	O
significantly	O
over	O
placebo	O
only	O
in	O
the	O
high	O
-	O
dose	O
azelastine	B-Chemical
group	O
.	O

Azelastine	B-Chemical
appears	O
to	O
be	O
a	O
safe	O
,	O
efficacious	O
medication	O
for	O
seasonal	B-Disease
allergic	I-Disease
rhinitis	I-Disease
.	O

Toxicity	B-Disease
due	O
to	O
remission	O
inducing	O
drugs	O
in	O
rheumatoid	B-Disease
arthritis	I-Disease
.	O

Association	O
with	O
HLA	O
-	O
B35	O
and	O
Cw4	O
antigens	O
.	O

Twenty	O
-	O
five	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
(	O
RA	B-Disease
)	O
who	O
developed	O
toxicity	B-Disease
while	O
taking	O
remission	O
inducing	O
drugs	O
and	O
30	O
without	O
toxicity	B-Disease
were	O
studied	O
for	O
possible	O
associations	O
with	O
class	O
I	O
and	O
II	O
HLA	O
antigens	O
.	O

A	O
strong	O
association	O
has	O
been	O
found	O
between	O
nephritis	B-Disease
and	O
dermatitis	B-Disease
due	O
to	O
Tiopronin	B-Chemical
(	O
a	O
D	B-Chemical
-	I-Chemical
Penicillamine	I-Chemical
like	O
compound	O
)	O
and	O
class	O
I	O
antigens	O
B35	O
-	O
Cw4	O
,	O
and	O
between	O
dermatitis	B-Disease
due	O
to	O
gold	B-Chemical
thiosulphate	B-Chemical
and	O
B35	O
.	O

Compared	O
to	O
healthy	O
controls	O
a	O
lower	O
DR5	O
frequency	O
was	O
observed	O
in	O
patients	O
with	O
RA	B-Disease
except	O
for	O
the	O
Tiopronin	B-Chemical
related	O
nephritis	B-Disease
group	O
.	O

Transient	O
contralateral	B-Disease
rotation	I-Disease
following	O
unilateral	O
substantia	B-Disease
nigra	I-Disease
lesion	I-Disease
reflects	O
susceptibility	O
of	O
the	O
nigrostriatal	O
system	O
to	O
exhaustion	O
by	O
amphetamine	B-Chemical
.	O

Following	O
unilateral	O
6	B-Chemical
-	I-Chemical
OHDA	I-Chemical
induced	O
SN	B-Disease
lesion	I-Disease
,	O
a	O
transient	O
period	O
of	O
contralateral	B-Disease
rotation	I-Disease
has	O
been	O
reported	O
to	O
precede	O
the	O
predominant	O
ipsilateral	B-Disease
circling	I-Disease
.	O

In	O
order	O
to	O
clarify	O
the	O
nature	O
of	O
this	O
initial	O
contralateral	B-Disease
rotation	I-Disease
we	O
examined	O
the	O
effect	O
of	O
the	O
duration	O
of	O
recovery	O
period	O
after	O
the	O
lesion	O
,	O
on	O
amphetamine	B-Chemical
-	O
induced	O
rotational	B-Disease
behavior	I-Disease
.	O

Three	O
days	O
post	O
lesion	O
,	O
most	O
rats	O
circled	O
predominantly	O
contralaterally	O
to	O
the	O
lesion	O
.	O

Such	O
contralateral	B-Disease
rotation	I-Disease
may	O
result	O
from	O
either	O
degeneration	O
-	O
induced	O
breakdown	O
of	O
the	O
DA	O
pool	O
,	O
or	O
lesion	O
-	O
induced	O
increase	O
of	O
DA	O
turnover	O
in	O
the	O
spared	O
neurons	O
.	O

A	O
substantial	O
degree	O
of	O
contralateral	O
preference	O
was	O
still	O
evident	O
when	O
amphetamine	B-Chemical
was	O
administered	O
for	O
the	O
first	O
time	O
24	O
days	O
after	O
lesioning	O
,	O
indicating	O
involvement	O
of	O
spared	O
cells	O
in	O
the	O
contralateral	B-Disease
rotation	I-Disease
.	O

However	O
,	O
regardless	O
of	O
the	O
duration	O
of	O
recovery	O
(	O
and	O
irrespective	O
of	O
either	O
lesion	O
volume	O
,	O
amphetamine	B-Chemical
dose	O
,	O
or	O
post	O
-	O
lesion	O
motor	O
exercise	O
)	O
,	O
amphetamine	B-Chemical
-	O
induced	O
rotation	B-Disease
tended	O
to	O
become	O
gradually	O
more	O
ipsilateral	O
as	O
the	O
observation	O
session	O
progressed	O
,	O
and	O
all	O
rats	O
circled	O
ipsilaterally	O
to	O
the	O
lesion	O
in	O
response	O
to	O
further	O
amphetamine	B-Chemical
injections	O
.	O

These	O
findings	O
suggest	O
that	O
amphetamine	B-Chemical
has	O
an	O
irreversible	O
effect	O
on	O
the	O
post	O
-	O
lesion	O
DA	O
pool	O
contributing	O
to	O
contralateral	B-Disease
rotation	I-Disease
.	O

Mitomycin	B-Chemical
C	I-Chemical
associated	O
hemolytic	B-Disease
uremic	I-Disease
syndrome	I-Disease
.	O

Mitomycin	B-Chemical
C	I-Chemical
associated	O
Hemolytic	B-Disease
Uremic	I-Disease
Syndrome	I-Disease
(	O
HUS	B-Disease
)	O
is	O
a	O
potentially	O
fatal	O
but	O
uncommon	O
condition	O
that	O
is	O
not	O
yet	O
widely	O
recognised	O
.	O

It	O
consists	O
of	O
microangiopathic	O
hemolytic	B-Disease
anemia	I-Disease
,	O
thrombocytopenia	B-Disease
and	O
progressive	O
renal	B-Disease
failure	I-Disease
associated	O
with	O
mitomycin	B-Chemical
C	I-Chemical
treatment	O
and	O
affects	O
about	O
10	O
%	O
of	O
patients	O
treated	O
with	O
this	O
agent	O
.	O

The	O
renal	B-Disease
failure	I-Disease
usually	O
develops	O
about	O
8	O
-	O
10	O
mth	O
after	O
start	O
of	O
mitomycin	B-Chemical
C	I-Chemical
treatment	O
and	O
the	O
mortality	O
is	O
approximately	O
60	O
%	O
from	O
renal	B-Disease
failure	I-Disease
or	O
pulmonary	B-Disease
edema	I-Disease
.	O

Renal	B-Disease
lesions	I-Disease
are	O
similar	O
to	O
those	O
seen	O
in	O
idiopathic	O
HUS	B-Disease
and	O
include	O
arteriolar	O
fibrin	O
thrombi	B-Disease
,	O
expanded	O
subendothelial	O
zones	O
in	O
glomerular	O
capillary	O
walls	O
,	O
ischemic	B-Disease
wrinkling	O
of	O
glomerular	O
basement	O
membranes	O
and	O
mesangiolysis	O
.	O

The	O
mechanism	O
of	O
action	O
is	O
postulated	O
as	O
mitomycin	B-Chemical
C	I-Chemical
-	O
induced	O
endothelial	O
cell	O
damage	O
.	O

We	O
describe	O
the	O
clinical	O
course	O
and	O
pathological	O
findings	O
in	O
a	O
65	O
yr	O
-	O
old	O
man	O
with	O
gastric	B-Disease
adenocarcinoma	I-Disease
who	O
developed	O
renal	B-Disease
failure	I-Disease
and	O
thrombocytopenia	B-Disease
while	O
on	O
treatment	O
with	O
mitomycin	B-Chemical
C	I-Chemical
and	O
died	O
in	O
pulmonary	B-Disease
edema	I-Disease
.	O

Ketanserin	B-Chemical
pretreatment	O
reverses	O
alfentanil	B-Chemical
-	O
induced	O
muscle	B-Disease
rigidity	I-Disease
.	O

Systemic	O
pretreatment	O
with	O
ketanserin	B-Chemical
,	O
a	O
relatively	O
specific	O
type	O
-	O
2	O
serotonin	B-Chemical
receptor	O
antagonist	O
,	O
significantly	O
attenuated	O
the	O
muscle	B-Disease
rigidity	I-Disease
produced	O
in	O
rats	O
by	O
the	O
potent	O
short	O
-	O
acting	O
opiate	O
agonist	O
alfentanil	B-Chemical
.	O

Following	O
placement	O
of	O
subcutaneous	O
electrodes	O
in	O
each	O
animal	O
'	O
s	O
left	O
gastrocnemius	O
muscle	O
,	O
rigidity	B-Disease
was	O
assessed	O
by	O
analyzing	O
root	O
-	O
mean	O
-	O
square	O
electromyographic	O
activity	O
.	O

Intraperitoneal	O
ketanserin	B-Chemical
administration	O
at	O
doses	O
of	O
0	O
.	O
63	O
and	O
2	O
.	O
5	O
mg	O
/	O
kg	O
prevented	O
the	O
alfentanil	B-Chemical
-	O
induced	O
increase	O
in	O
electromyographic	O
activity	O
compared	O
with	O
animals	O
pretreated	O
with	O
saline	O
.	O

Chlordiazepoxide	B-Chemical
at	O
doses	O
up	O
to	O
10	O
mg	O
/	O
kg	O
failed	O
to	O
significantly	O
influence	O
the	O
rigidity	B-Disease
produced	O
by	O
alfentanil	B-Chemical
.	O

Despite	O
the	O
absence	O
of	O
rigidity	B-Disease
,	O
animals	O
that	O
received	O
ketanserin	B-Chemical
(	O
greater	O
than	O
0	O
.	O
31	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
followed	O
by	O
alfentanil	B-Chemical
were	O
motionless	O
,	O
flaccid	O
,	O
and	O
less	O
responsive	O
to	O
external	O
stimuli	O
than	O
were	O
animals	O
receiving	O
alfentanil	B-Chemical
alone	O
.	O

Rats	O
that	O
received	O
ketanserin	B-Chemical
and	O
alfentanil	B-Chemical
exhibited	O
less	O
rearing	O
and	O
exploratory	O
behavior	O
at	O
the	O
end	O
of	O
the	O
60	O
-	O
min	O
recording	O
period	O
than	O
did	O
animals	O
that	O
received	O
ketanserin	B-Chemical
alone	O
.	O

These	O
results	O
,	O
in	O
combination	O
with	O
previous	O
work	O
,	O
suggest	O
that	O
muscle	B-Disease
rigidity	I-Disease
,	O
a	O
clinically	O
relevant	O
side	O
-	O
effect	O
of	O
parenteral	O
narcotic	O
administration	O
,	O
may	O
be	O
partly	O
mediated	O
via	O
serotonergic	O
pathways	O
.	O

Pretreatment	O
with	O
type	O
-	O
2	O
serotonin	B-Chemical
antagonists	O
may	O
be	O
clinically	O
useful	O
in	O
attenuating	O
opiate	O
-	O
induced	O
rigidity	B-Disease
,	O
although	O
further	O
studies	O
will	O
be	O
necessary	O
to	O
assess	O
the	O
interaction	O
of	O
possibly	O
enhanced	O
CNS	O
,	O
cardiovascular	B-Disease
,	I-Disease
and	I-Disease
respiratory	I-Disease
depression	I-Disease
.	O

Antagonism	O
of	O
diazepam	B-Chemical
-	O
induced	O
sedative	O
effects	O
by	O
Ro15	B-Chemical
-	I-Chemical
1788	I-Chemical
in	O
patients	O
after	O
surgery	O
under	O
lumbar	O
epidural	O
block	O
.	O

A	O
double	O
-	O
blind	O
placebo	O
-	O
controlled	O
investigation	O
of	O
efficacy	O
and	O
safety	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
to	O
assess	O
the	O
efficacy	O
of	O
Ro15	B-Chemical
-	I-Chemical
1788	I-Chemical
and	O
a	O
placebo	O
in	O
reversing	O
diazepam	B-Chemical
-	O
induced	O
effects	O
after	O
surgery	O
under	O
epidural	O
block	O
,	O
and	O
to	O
evaluate	O
the	O
local	O
tolerance	O
and	O
general	O
safety	O
of	O
Ro15	B-Chemical
-	I-Chemical
1788	I-Chemical
.	O

Fifty	O
-	O
seven	O
patients	O
were	O
sedated	O
with	O
diazepam	B-Chemical
for	O
surgery	O
under	O
epidural	O
anaesthesia	O
.	O

Antagonism	O
of	O
diazepam	B-Chemical
-	O
induced	O
effects	O
by	O
Ro15	B-Chemical
-	I-Chemical
1788	I-Chemical
was	O
investigated	O
postoperatively	O
in	O
a	O
double	O
-	O
blind	O
placebo	O
-	O
controlled	O
trial	O
.	O

The	O
patient	O
'	O
s	O
subjective	O
assessment	O
of	O
mood	O
rating	O
,	O
an	O
objective	O
test	O
of	O
performance	O
,	O
a	O
test	O
for	O
amnesia	B-Disease
,	O
and	O
vital	O
signs	O
were	O
recorded	O
for	O
up	O
to	O
300	O
min	O
after	O
administration	O
of	O
the	O
trial	O
drug	O
.	O

No	O
significant	O
differences	O
between	O
the	O
two	O
groups	O
were	O
observed	O
for	O
mood	O
rating	O
,	O
amnesia	B-Disease
,	O
or	O
vital	O
signs	O
.	O

The	O
Ro15	B-Chemical
-	I-Chemical
1788	I-Chemical
group	O
showed	O
a	O
significant	O
improvement	O
in	O
the	O
performance	O
test	O
up	O
to	O
120	O
min	O
after	O
administration	O
of	O
the	O
drug	O
.	O

There	O
was	O
no	O
evidence	O
of	O
reaction	O
at	O
the	O
injection	O
site	O
.	O

Chorea	B-Disease
associated	O
with	O
oral	B-Chemical
contraception	I-Chemical
.	O

Three	O
patients	O
developed	O
chorea	B-Disease
while	O
receiving	O
oral	B-Chemical
contraceptives	I-Chemical
.	O

Two	O
were	O
young	O
patients	O
whose	O
chorea	B-Disease
developed	O
long	O
after	O
treatment	O
had	O
been	O
started	O
and	O
disappeared	O
soon	O
after	O
it	O
had	O
been	O
discontinued	O
.	O

The	O
third	O
patient	O
had	O
acute	O
amphetamine	B-Chemical
-	O
induced	O
chorea	B-Disease
after	O
prolonged	O
oral	B-Chemical
contraception	I-Chemical
.	O

Prolonged	O
administration	O
of	O
female	O
sex	O
hormones	O
is	O
a	O
possible	O
cause	O
of	O
chorea	B-Disease
in	O
women	O
who	O
have	O
not	O
previously	O
had	O
chorea	B-Disease
or	O
rheumatic	B-Disease
fever	I-Disease
.	O

Co	O
-	O
carcinogenic	B-Disease
effect	O
of	O
retinyl	B-Chemical
acetate	I-Chemical
on	O
forestomach	B-Disease
carcinogenesis	I-Disease
of	O
male	O
F344	O
rats	O
induced	O
with	O
butylated	B-Chemical
hydroxyanisole	I-Chemical
.	O

The	O
potential	O
modifying	O
effect	O
of	O
retinyl	B-Chemical
acetate	I-Chemical
(	O
RA	B-Chemical
)	O
on	O
butylated	B-Chemical
hydroxyanisole	I-Chemical
(	O
BHA	B-Chemical
)	O
-	O
induced	O
rat	O
forestomach	B-Disease
tumorigenesis	I-Disease
was	O
examined	O
.	O

Male	O
F344	O
rats	O
,	O
5	O
weeks	O
of	O
age	O
,	O
were	O
maintained	O
on	O
diet	O
containing	O
1	O
%	O
or	O
2	O
%	O
BHA	B-Chemical
by	O
weight	O
and	O
simultaneously	O
on	O
drinking	O
water	O
supplemented	O
with	O
RA	B-Chemical
at	O
various	O
concentrations	O
(	O
w	O
/	O
v	O
)	O
for	O
52	O
weeks	O
.	O

In	O
groups	O
given	O
2	O
%	O
BHA	B-Chemical
,	O
although	O
marked	O
hyperplastic	O
changes	O
of	O
the	O
forestomach	O
epithelium	O
were	O
observed	O
in	O
all	O
animals	O
,	O
co	O
-	O
administration	O
of	O
0	O
.	O
25	O
%	O
RA	B-Chemical
significantly	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
increased	O
the	O
incidence	O
of	O
forestomach	B-Disease
tumors	I-Disease
(	O
squamous	B-Disease
cell	I-Disease
papilloma	I-Disease
and	O
carcinoma	B-Disease
)	O
to	O
60	O
%	O
(	O
9	O
/	O
15	O
,	O
2	O
rats	O
with	O
carcinoma	B-Disease
)	O
from	O
15	O
%	O
(	O
3	O
/	O
20	O
,	O
one	O
rat	O
with	O
carcinoma	B-Disease
)	O
in	O
the	O
group	O
given	O
RA	B-Chemical
-	O
free	O
water	O
.	O

In	O
rats	O
given	O
1	O
%	O
BHA	B-Chemical
,	O
RA	B-Chemical
co	O
-	O
administered	O
at	O
a	O
dose	O
of	O
0	O
.	O
05	O
,	O
0	O
.	O
1	O
,	O
0	O
.	O
2	O
or	O
0	O
.	O
25	O
%	O
showed	O
a	O
dose	O
-	O
dependent	O
enhancing	O
effect	O
on	O
the	O
development	O
of	O
the	O
BHA	B-Chemical
-	O
induced	O
epithelial	B-Disease
hyperplasia	I-Disease
.	O

Tumors	B-Disease
,	O
all	O
papillomas	B-Disease
,	O
were	O
induced	O
in	O
3	O
rats	O
(	O
17	O
%	O
)	O
with	O
0	O
.	O
25	O
%	O
RA	B-Chemical
and	O
in	O
one	O
rat	O
(	O
10	O
%	O
)	O
with	O
0	O
.	O
05	O
%	O
RA	B-Chemical
co	O
-	O
administration	O
.	O

RA	B-Chemical
alone	O
did	O
not	O
induce	O
hyperplastic	O
changes	O
in	O
the	O
forestomach	O
.	O

These	O
findings	O
indicate	O
that	O
RA	B-Chemical
acted	O
as	O
a	O
co	O
-	O
carcinogen	O
in	O
the	O
BHA	B-Chemical
forestomach	B-Disease
carcinogenesis	I-Disease
of	O
the	O
rat	O
.	O

A	O
prospective	O
study	O
on	O
the	O
dose	O
dependency	O
of	O
cardiotoxicity	B-Disease
induced	O
by	O
mitomycin	B-Chemical
C	I-Chemical
.	O

Since	O
1975	O
mitomycin	B-Chemical
C	I-Chemical
(	O
MMC	B-Chemical
)	O
has	O
been	O
suggested	O
to	O
be	O
cardiotoxic	B-Disease
,	O
especially	O
when	O
combined	O
with	O
or	O
given	O
following	O
doxorubicin	B-Chemical
.	O

Data	O
on	O
dose	O
dependency	O
or	O
incidence	O
concerning	O
this	O
side	O
effect	O
were	O
not	O
known	O
.	O

We	O
have	O
initiated	O
a	O
prospective	O
study	O
to	O
obtain	O
some	O
more	O
data	O
on	O
these	O
subjects	O
.	O

Forty	O
-	O
four	O
MMC	B-Chemical
-	O
treated	O
patients	O
were	O
studied	O
,	O
37	O
of	O
them	O
could	O
be	O
evaluated	O
.	O

All	O
patients	O
were	O
studied	O
by	O
repeated	O
physical	O
examinations	O
,	O
chest	O
X	O
-	O
rays	O
,	O
electro	O
-	O
and	O
echocardiography	O
and	O
radionuclide	O
left	O
ventricular	O
ejection	O
fraction	O
(	O
EF	O
)	O
determinations	O
.	O

The	O
results	O
were	O
evaluated	O
per	O
cumulative	O
dose	O
level	O
.	O

One	O
of	O
the	O
patients	O
developed	O
cardiac	B-Disease
failure	I-Disease
after	O
30	O
mg	O
m	O
-	O
2	O
MMC	B-Chemical
and	O
only	O
150	O
mg	O
m	O
-	O
2	O
doxorubicin	B-Chemical
.	O

The	O
cardiac	B-Disease
failure	I-Disease
was	O
predicted	O
by	O
a	O
drop	O
in	O
EF	O
determined	O
during	O
a	O
cold	O
pressor	O
test	O
.	O

None	O
of	O
the	O
other	O
patients	O
developed	O
clinical	O
cardiotoxicity	B-Disease
,	O
nor	O
did	O
the	O
studied	O
parameters	O
change	O
.	O

The	O
literature	O
on	O
this	O
subject	O
was	O
also	O
reviewed	O
.	O

Based	O
on	O
the	O
combined	O
data	O
from	O
the	O
present	O
study	O
and	O
the	O
literature	O
,	O
we	O
suggest	O
that	O
MMC	B-Chemical
-	O
related	O
cardiotoxicity	B-Disease
is	O
dose	O
dependent	O
,	O
occurring	O
at	O
cumulative	O
dose	O
levels	O
of	O
30	O
mg	O
m	O
-	O
2	O
or	O
more	O
,	O
mainly	O
in	O
patients	O
also	O
(	O
previously	O
or	O
simultaneously	O
)	O
treated	O
with	O
doxorubicin	B-Chemical
.	O

The	O
incidence	O
is	O
likely	O
to	O
be	O
less	O
than	O
10	O
%	O
even	O
for	O
this	O
risk	O
group	O
.	O

Reversible	O
cerebral	B-Disease
lesions	I-Disease
associated	O
with	O
tiazofurin	B-Chemical
usage	O
:	O
MR	O
demonstration	O
.	O

Tiazofurin	B-Chemical
is	O
an	O
experimental	O
chemotherapeutic	O
agent	O
currently	O
undergoing	O
clinical	O
evaluation	O
.	O

We	O
report	O
our	O
results	O
with	O
magnetic	O
resonance	O
(	O
MR	O
)	O
in	O
demonstrating	O
reversible	O
cerebral	B-Disease
abnormalities	I-Disease
concurrent	O
with	O
the	O
use	O
of	O
this	O
drug	O
.	O

The	O
abnormalities	O
on	O
MR	O
were	O
correlated	O
with	O
findings	O
on	O
CT	O
as	O
well	O
as	O
with	O
cerebral	O
angiography	O
.	O

The	O
utility	O
of	O
MR	O
in	O
the	O
evaluation	O
of	O
patients	O
receiving	O
this	O
new	O
agent	O
is	O
illustrated	O
.	O

Receptor	O
mechanisms	O
of	O
nicotine	B-Chemical
-	O
induced	O
locomotor	B-Disease
hyperactivity	I-Disease
in	O
chronic	O
nicotine	B-Chemical
-	O
treated	O
rats	O
.	O

Rats	O
were	O
pretreated	O
with	O
saline	O
or	O
nicotine	B-Chemical
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
per	O
day	O
)	O
by	O
subcutaneously	O
implanting	O
each	O
animal	O
with	O
an	O
Alzet	O
osmotic	O
mini	O
-	O
pump	O
which	O
continuously	O
released	O
saline	O
or	O
nicotine	B-Chemical
for	O
1	O
,	O
5	O
and	O
14	O
days	O
.	O

At	O
the	O
end	O
of	O
each	O
pretreatment	O
period	O
,	O
animals	O
were	O
used	O
for	O
(	O
i	O
)	O
determining	O
their	O
locomotor	O
response	O
to	O
acutely	O
injected	O
nicotine	B-Chemical
(	O
0	O
.	O
2	O
mg	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
and	O
(	O
ii	O
)	O
measuring	O
the	O
density	O
of	O
L	O
-	O
[	O
3H	O
]	O
nicotine	B-Chemical
and	O
[	O
3H	O
]	O
spiperone	B-Chemical
binding	O
sites	O
in	O
the	O
striatum	O
.	O

We	O
observed	O
no	O
changes	O
in	O
nicotine	B-Chemical
-	O
induced	O
locomotor	O
response	O
,	O
striatal	O
L	O
-	O
[	O
3H	O
]	O
nicotine	B-Chemical
and	O
[	O
3H	O
]	O
spiperone	B-Chemical
binding	O
in	O
the	O
animals	O
pretreated	O
with	O
nicotine	B-Chemical
for	O
1	O
day	O
.	O

In	O
rats	O
which	O
were	O
pretreated	O
with	O
nicotine	B-Chemical
for	O
5	O
days	O
,	O
there	O
was	O
a	O
significant	O
increase	O
in	O
the	O
nicotine	B-Chemical
-	O
stimulated	O
locomotor	O
response	O
which	O
was	O
associated	O
with	O
an	O
increase	O
in	O
the	O
number	O
of	O
L	O
-	O
[	O
3H	O
]	O
nicotine	B-Chemical
binding	O
sites	O
and	O
also	O
with	O
an	O
elevated	O
dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
level	O
in	O
the	O
striatum	O
.	O

The	O
number	O
of	O
striatal	O
[	O
3H	O
]	O
spiperone	B-Chemical
binding	O
sites	O
was	O
not	O
affected	O
.	O

In	O
animals	O
pretreated	O
with	O
nicotine	B-Chemical
for	O
14	O
days	O
,	O
the	O
nicotine	B-Chemical
-	O
induced	O
locomotor	O
response	O
remained	O
to	O
be	O
potentiated	O
.	O

However	O
,	O
this	O
response	O
was	O
correlated	O
with	O
an	O
elevated	O
number	O
of	O
striatal	O
[	O
3H	O
]	O
spiperone	B-Chemical
binding	O
sites	O
,	O
whereas	O
the	O
number	O
of	O
striatal	O
L	O
-	O
[	O
3H	O
]	O
nicotine	B-Chemical
binding	O
sites	O
and	O
the	O
striatal	O
DA	B-Chemical
level	O
were	O
normal	O
.	O

These	O
results	O
suggest	O
that	O
chronic	O
nicotine	B-Chemical
-	O
treated	O
rats	O
develop	O
locomotor	B-Disease
hyperactivity	I-Disease
in	O
response	O
to	O
nicotine	B-Chemical
initially	O
due	O
to	O
increases	O
of	O
both	O
the	O
density	O
of	O
nicotinic	O
receptors	O
and	O
DA	B-Chemical
concentration	O
,	O
followed	O
by	O
inducing	O
DA	B-Chemical
receptor	O
supersensitivity	O
in	O
the	O
striatum	O
.	O

Amelioration	O
of	O
bendrofluazide	B-Chemical
-	O
induced	O
hypokalemia	B-Disease
by	O
timolol	B-Chemical
.	O

The	O
beta	O
adrenergic	O
blocking	O
drug	O
,	O
timolol	B-Chemical
,	O
tended	O
to	O
correct	O
the	O
hypokalemia	B-Disease
of	O
short	O
-	O
term	O
bendrofluazide	B-Chemical
treatment	O
in	O
6	O
healthy	O
male	O
subjects	O
and	O
although	O
the	O
effect	O
was	O
small	O
it	O
was	O
significant	O
.	O

Timolol	B-Chemical
also	O
reduced	O
the	O
rise	O
in	O
plasma	O
aldosterone	B-Chemical
and	O
urine	O
potassium	B-Chemical
excretion	O
following	O
bendrofluazide	B-Chemical
and	O
increased	O
the	O
urine	O
sodium	B-Chemical
/	O
potassium	B-Chemical
ratio	O
.	O

There	O
was	O
no	O
evidence	O
of	O
a	O
shift	O
of	O
potassium	B-Chemical
from	O
the	O
intracellular	O
to	O
the	O
extracellular	O
space	O
.	O

St	B-Disease
.	I-Disease

Anthony	B-Disease
'	I-Disease
s	I-Disease
fire	I-Disease
,	O
then	O
and	O
now	O
:	O
a	O
case	O
report	O
and	O
historical	O
review	O
.	O

A	O
rare	O
case	O
of	O
morbid	O
vasospasm	B-Disease
,	O
together	O
with	O
striking	O
angiographic	O
findings	O
,	O
is	O
described	O
secondary	O
to	O
the	O
ingestion	O
of	O
methysergide	B-Chemical
by	O
a	O
48	O
-	O
year	O
-	O
old	O
woman	O
.	O

A	O
brief	O
review	O
of	O
the	O
literature	O
on	O
similar	O
cases	O
is	O
presented	O
.	O

A	O
discussion	O
of	O
the	O
history	O
of	O
ergot	B-Chemical
includes	O
its	O
original	O
discovery	O
,	O
the	O
epidemics	O
of	O
gangrene	B-Disease
that	O
it	O
has	O
caused	O
through	O
the	O
ages	O
and	O
its	O
past	O
and	O
present	O
role	O
in	O
the	O
management	O
of	O
migraine	B-Disease
headache	I-Disease
.	O

Despite	O
the	O
advent	O
of	O
calcium	B-Chemical
channel	O
blockers	O
and	O
beta	O
-	O
adrenergic	O
antagonists	O
,	O
ergot	B-Chemical
preparations	O
continue	O
to	O
play	O
a	O
major	O
role	O
in	O
migraine	B-Disease
therapy	O
,	O
so	O
that	O
the	O
danger	O
of	O
St	B-Disease
.	I-Disease

Anthony	B-Disease
'	I-Disease
s	I-Disease
fire	I-Disease
persists	O
.	O

Cardiac	O
transplantation	O
:	O
improved	O
quality	O
of	O
survival	O
with	O
a	O
modified	O
immunosuppressive	O
protocol	O
.	O

The	O
effects	O
on	O
renal	O
function	O
on	O
two	O
different	O
immunosuppressive	O
protocols	O
were	O
evaluated	O
retrospectively	O
in	O
two	O
subsequent	O
groups	O
of	O
heart	O
transplant	O
recipients	O
.	O

In	O
group	O
I	O
,	O
cyclosporine	B-Chemical
was	O
given	O
before	O
the	O
procedure	O
at	O
a	O
loading	O
dose	O
of	O
17	O
.	O
5	O
mg	O
/	O
kg	O
and	O
then	O
continued	O
after	O
the	O
procedure	O
to	O
keep	O
a	O
whole	O
blood	O
level	O
about	O
1000	O
ng	O
/	O
ml	O
.	O

In	O
group	O
II	O
,	O
cyclosporine	B-Chemical
was	O
started	O
only	O
after	O
the	O
procedure	O
at	O
a	O
lower	O
dosage	O
and	O
was	O
complemented	O
by	O
azathioprine	B-Chemical
,	O
which	O
was	O
used	O
for	O
the	O
first	O
postoperative	O
week	O
.	O

Group	O
II	O
showed	O
a	O
better	O
perioperative	O
renal	O
function	O
as	O
determined	O
by	O
serum	O
blood	O
urea	B-Chemical
nitrogen	I-Chemical
and	O
serum	O
creatinine	B-Chemical
levels	O
.	O

Group	O
II	O
also	O
showed	O
a	O
significant	O
decrease	O
of	O
chronic	O
nephrotoxicity	B-Disease
secondary	O
to	O
long	O
-	O
term	O
therapy	O
with	O
cyclosporine	B-Chemical
.	O

Despite	O
this	O
improvement	O
in	O
late	O
renal	O
function	O
,	O
group	O
II	O
still	O
shows	O
a	O
slow	O
rise	O
in	O
serum	O
creatinine	B-Chemical
.	O

We	O
think	O
that	O
even	O
these	O
lower	O
dosages	O
of	O
cyclosporine	B-Chemical
can	O
cause	O
chronic	O
nephrotoxicity	B-Disease
and	O
that	O
further	O
modification	O
of	O
the	O
immunosuppressive	O
regimen	O
is	O
required	O
to	O
completely	O
abolish	O
this	O
toxic	O
side	O
effect	O
.	O

Ethopropazine	B-Chemical
and	O
benztropine	B-Chemical
in	O
neuroleptic	O
-	O
induced	O
parkinsonism	B-Disease
.	O

In	O
a	O
12	O
-	O
week	O
controlled	O
study	O
ethopropazine	B-Chemical
was	O
compared	O
to	O
benztropine	B-Chemical
in	O
the	O
treatment	O
of	O
parkinsonism	B-Disease
induced	O
by	O
fluphenazine	B-Chemical
enanthate	I-Chemical
in	O
60	O
schizophrenic	B-Disease
outpatients	O
.	O

Ethopropazine	B-Chemical
and	O
benztropine	B-Chemical
were	O
found	O
to	O
be	O
equally	O
effective	O
in	O
controlling	O
parkinsonian	B-Disease
symptoms	I-Disease
and	O
were	O
as	O
efficacious	O
as	O
procyclidine	B-Chemical
,	O
their	O
previous	O
antiparkinsonian	O
drug	O
.	O

However	O
,	O
benztropine	B-Chemical
treated	O
patients	O
had	O
a	O
significant	O
increase	O
in	O
tardive	B-Disease
dyskinesia	I-Disease
compared	O
to	O
their	O
condition	O
during	O
procyclindine	B-Chemical
treatment	O
,	O
and	O
significantly	O
more	O
anxiety	B-Disease
and	O
depression	B-Disease
than	O
ethopropazine	B-Chemical
treated	O
patients	O
.	O

This	O
suggests	O
that	O
benztropine	B-Chemical
is	O
not	O
the	O
anticholinergic	O
drug	O
of	O
choice	O
in	O
the	O
treatment	O
of	O
neuroleptic	O
-	O
induced	O
parkinsonian	B-Disease
symptoms	I-Disease
,	O
because	O
of	O
its	O
more	O
toxic	O
central	O
and	O
peripheral	O
atropinic	O
effect	O
.	O

Quinidine	B-Chemical
phenylethylbarbiturate	I-Chemical
-	O
induced	O
fulminant	O
hepatitis	B-Disease
in	O
a	O
pregnant	O
woman	O
.	O

A	O
case	O
report	O
.	O

We	O
report	O
the	O
case	O
of	O
a	O
19	O
-	O
year	O
-	O
old	O
Laotian	O
patient	O
affected	O
by	O
fulminant	O
hepatitis	B-Disease
during	O
the	O
third	O
trimester	O
of	O
her	O
pregnancy	O
after	O
a	O
1	O
-	O
month	O
administration	O
of	O
quinidine	B-Chemical
phenylethylbarbiturate	I-Chemical
.	O

After	O
delivery	O
,	O
the	O
patient	O
underwent	O
orthotopic	O
liver	O
transplantation	O
.	O

The	O
patient	O
was	O
in	O
good	O
condition	O
16	O
months	O
after	O
liver	O
transplantation	O
.	O

Quinidine	B-Chemical
itself	O
or	O
phenylethylbarbiturate	B-Chemical
may	O
be	O
responsible	O
for	O
fulminant	O
hepatitis	B-Disease
in	O
this	O
patient	O
.	O

Mechanisms	O
of	O
myocardial	B-Disease
ischemia	I-Disease
induced	O
by	O
epinephrine	B-Chemical
:	O
comparison	O
with	O
exercise	O
-	O
induced	O
ischemia	B-Disease
.	O

The	O
role	O
of	O
epinephrine	B-Chemical
in	O
eliciting	O
myocardial	B-Disease
ischemia	I-Disease
was	O
examined	O
in	O
patients	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
.	O

Objective	O
signs	O
of	O
ischemia	B-Disease
and	O
factors	O
increasing	O
myocardial	O
oxygen	B-Chemical
consumption	O
were	O
compared	O
during	O
epinephrine	B-Chemical
infusion	O
and	O
supine	O
bicycle	O
exercise	O
.	O

Both	O
epinephrine	B-Chemical
and	O
exercise	O
produced	O
myocardial	B-Disease
ischemia	I-Disease
as	O
evidenced	O
by	O
ST	O
segment	O
depression	B-Disease
and	O
angina	B-Disease
.	O

However	O
,	O
the	O
mechanisms	O
of	O
myocardial	B-Disease
ischemia	I-Disease
induced	O
by	O
epinephrine	B-Chemical
were	O
significantly	O
different	O
from	O
those	O
of	O
exercise	O
.	O

Exercise	O
-	O
induced	O
myocardial	B-Disease
ischemia	I-Disease
was	O
marked	O
predominantly	O
by	O
increased	O
heart	O
rate	O
and	O
rate	O
-	O
pressure	O
product	O
with	O
a	O
minor	O
contribution	O
of	O
end	O
-	O
diastolic	O
volume	O
,	O
while	O
epinephrine	B-Chemical
-	O
induced	O
ischemia	B-Disease
was	O
characterized	O
by	O
a	O
marked	O
increase	O
in	O
contractility	O
and	O
a	O
less	O
pronounced	O
increase	O
in	O
heart	O
rate	O
and	O
rate	O
-	O
pressure	O
product	O
.	O

These	O
findings	O
indicate	O
that	O
ischemia	B-Disease
produced	O
by	O
epinephrine	B-Chemical
,	O
as	O
may	O
occur	O
during	O
states	O
of	O
emotional	O
distress	O
,	O
has	O
a	O
mechanism	O
distinct	O
from	O
that	O
due	O
to	O
physical	O
exertion	O
.	O

Recent	O
preclinical	O
and	O
clinical	O
studies	O
with	O
the	O
thymidylate	O
synthase	O
inhibitor	O
N10	B-Chemical
-	I-Chemical
propargyl	I-Chemical
-	I-Chemical
5	I-Chemical
,	I-Chemical
8	I-Chemical
-	I-Chemical
dideazafolic	I-Chemical
acid	I-Chemical
(	O
CB	B-Chemical
3717	I-Chemical
)	O
.	O

CB	B-Chemical
3717	I-Chemical
,	O
N10	B-Chemical
-	I-Chemical
propargyl	I-Chemical
-	I-Chemical
5	I-Chemical
,	I-Chemical
8	I-Chemical
-	I-Chemical
dideazafolic	I-Chemical
acid	I-Chemical
,	O
is	O
a	O
tight	O
-	O
binding	O
inhibitor	O
of	O
thymidylate	O
synthase	O
(	O
TS	O
)	O
whose	O
cytotoxicity	B-Disease
is	O
mediated	O
solely	O
through	O
the	O
inhibition	O
of	O
this	O
enzyme	O
.	O

Recent	O
preclinical	O
studies	O
have	O
focused	O
on	O
the	O
intracellular	O
formation	O
of	O
CB	B-Chemical
3717	I-Chemical
polyglutamates	O
.	O

Following	O
a	O
12	O
-	O
hour	O
exposure	O
of	O
L1210	O
cells	O
to	O
50	O
microM	O
[	O
3H	O
]	O
CB	B-Chemical
3717	I-Chemical
,	O
30	O
%	O
of	O
the	O
extractable	O
radioactivity	O
could	O
be	O
accounted	O
for	O
as	O
CB	B-Chemical
3717	I-Chemical
tetra	O
-	O
and	O
pentaglutamate	O
,	O
as	O
determined	O
by	O
high	O
-	O
pressure	O
liquid	O
chromatography	O
(	O
HPLC	O
)	O
analyses	O
.	O

As	O
inhibitors	O
of	O
isolated	O
L1210	O
TS	O
,	O
CB	O
3717	O
di	O
-	O
,	O
tri	O
-	O
,	O
tetra	O
-	O
and	O
pentaglutamate	O
are	O
26	O
-	O
,	O
87	O
-	O
,	O
119	O
-	O
and	O
114	O
-	O
fold	O
more	O
potent	O
than	O
CB	B-Chemical
3717	I-Chemical
,	O
respectively	O
,	O
and	O
their	O
formation	O
may	O
,	O
therefore	O
,	O
be	O
an	O
important	O
determinant	O
of	O
CB	B-Chemical
3717	I-Chemical
cytotoxicity	B-Disease
.	O

In	O
early	O
clinical	O
studies	O
with	O
CB	B-Chemical
3717	I-Chemical
,	O
activity	O
has	O
been	O
seen	O
in	O
breast	B-Disease
cancer	I-Disease
,	O
ovarian	B-Disease
cancer	I-Disease
,	O
hepatoma	B-Disease
,	O
and	O
mesothelioma	B-Disease
.	O

Toxicities	B-Disease
included	O
hepatotoxicity	B-Disease
,	O
malaise	B-Disease
,	O
and	O
dose	O
-	O
limiting	O
nephrotoxicity	B-Disease
.	O

This	O
latter	O
effect	O
is	O
thought	O
to	O
be	O
due	O
to	O
drug	O
precipitation	O
within	O
the	O
renal	O
tubule	O
as	O
a	O
result	O
of	O
the	O
poor	O
solubility	O
of	O
CB	B-Chemical
3717	I-Chemical
under	O
acidic	O
conditions	O
.	O

In	O
an	O
attempt	O
to	O
overcome	O
this	O
problem	O
,	O
a	O
clinical	O
trial	O
of	O
CB	B-Chemical
3717	I-Chemical
administered	O
with	O
alkaline	O
diuresis	O
is	O
under	O
way	O
.	O

Preliminary	O
results	O
at	O
400	O
and	O
500	O
mg	O
/	O
m2	O
suggest	O
that	O
a	O
reduction	O
in	O
nephrotoxicity	B-Disease
may	O
have	O
been	O
achieved	O
with	O
only	O
1	O
instance	O
of	O
renal	B-Disease
toxicity	I-Disease
in	O
10	O
patients	O
.	O

Hepatotoxicity	B-Disease
and	O
malaise	B-Disease
are	O
again	O
the	O
most	O
frequent	O
side	O
effects	O
.	O

Evidence	O
of	O
antitumor	O
activity	O
has	O
been	O
seen	O
in	O
3	O
patients	O
.	O

Pharmacokinetic	O
investigations	O
have	O
shown	O
that	O
alkaline	O
diuresis	O
does	O
not	O
alter	O
CB	B-Chemical
3717	I-Chemical
plasma	O
levels	O
or	O
urinary	O
excretion	O
and	O
that	O
satisfactory	O
urinary	O
alkalinization	O
can	O
be	O
readily	O
achieved	O
.	O

Type	B-Disease
B	I-Disease
hepatitis	I-Disease
after	O
needle	O
-	O
stick	O
exposure	O
:	O
prevention	O
with	O
hepatitis	B-Disease
B	I-Disease
immune	O
globulin	O
.	O

Final	O
report	O
of	O
the	O
Veterans	O
Administration	O
Cooperative	O
Study	O
.	O

Hepatitis	B-Disease
B	I-Disease
immune	O
globulin	O
(	O
HBIG	O
)	O
and	O
immune	O
serum	O
globulin	O
(	O
ISG	O
)	O
were	O
examined	O
in	O
a	O
randomized	O
,	O
double	O
-	O
blind	O
trial	O
to	O
assess	O
their	O
relative	O
efficacies	O
in	O
preventing	O
type	B-Disease
B	I-Disease
hepatitis	I-Disease
after	O
needle	O
-	O
stick	O
exposure	O
to	O
hepatitis	B-Chemical
B	I-Chemical
surface	I-Chemical
antigen	I-Chemical
(	O
HBsAG	B-Chemical
)	O
-	O
positive	O
donors	O
.	O

Clinical	O
hepatitis	B-Disease
developed	O
in	O
1	O
.	O
4	O
%	O
of	O
HBIG	O
and	O
in	O
5	O
.	O
9	O
%	O
of	O
ISG	O
recipients	O
(	O
P	O
=	O
0	O
.	O
016	O
)	O
,	O
and	O
seroconversion	O
(	O
anti	O
-	O
HBs	O
)	O
occurred	O
in	O
5	O
.	O
6	O
%	O
and	O
20	O
.	O
7	O
%	O
of	O
them	O
respectively	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
.	O

Mild	O
and	O
transient	O
side	O
-	O
effects	O
were	O
noted	O
in	O
3	O
.	O
0	O
%	O
of	O
ISG	O
and	O
in	O
3	O
.	O
2	O
%	O
of	O
HBIG	O
recipients	O
.	O

Available	O
donor	O
sera	O
were	O
examined	O
for	O
DNA	O
polymerase	O
(	O
DNAP	O
)	O
and	O
e	O
antigen	O
and	O
antibody	O
(	O
HBeAg	B-Chemical
;	O
anti	O
-	O
HBE	O
)	O
.	O

Both	O
DNAP	O
and	O
HBeAg	B-Chemical
showed	O
a	O
highly	O
statistically	O
significant	O
correlation	O
with	O
the	O
infectivity	O
of	O
HBsAg	B-Chemical
-	O
positive	O
donors	O
.	O

Hepatitis	B-Disease
B	I-Disease
immune	O
globulin	O
remained	O
significantly	O
superior	O
to	O
ISG	O
in	O
preventing	O
type	B-Disease
B	I-Disease
hepatitis	I-Disease
even	O
when	O
the	O
analysis	O
was	O
confined	O
to	O
these	O
two	O
high	O
-	O
risk	O
subgroups	O
.	O

The	O
efficacy	O
of	O
ISG	O
in	O
preventing	O
type	B-Disease
B	I-Disease
hepatitis	I-Disease
cannot	O
be	O
ascertained	O
because	O
a	O
true	O
placebo	O
group	O
was	O
not	O
included	O
.	O

Production	O
of	O
autochthonous	O
prostate	B-Disease
cancer	I-Disease
in	O
Lobund	O
-	O
Wistar	O
rats	O
by	O
treatments	O
with	O
N	B-Chemical
-	I-Chemical
nitroso	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
methylurea	I-Chemical
and	O
testosterone	B-Chemical
.	O

More	O
than	O
50	O
%	O
of	O
Lobund	O
-	O
Wistar	O
(	O
L	O
-	O
W	O
)	O
strain	O
rats	O
developed	O
large	O
,	O
palpable	O
prostate	B-Disease
adenocarcinomas	I-Disease
(	O
PAs	B-Disease
)	O
following	O
treatments	O
with	O
N	B-Chemical
-	I-Chemical
nitroso	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
methylurea	I-Chemical
(	O
CAS	O
:	O
684	O
-	O
93	O
-	O
5	O
)	O
and	O
testosterone	B-Chemical
propionate	I-Chemical
[	O
(	O
TP	B-Chemical
)	O
CAS	O
:	O
57	O
-	O
85	O
-	O
2	O
]	O
,	O
and	O
most	O
of	O
the	O
tumor	B-Disease
-	O
bearing	O
rats	O
manifested	O
metastatic	O
lesions	O
.	O

The	O
incubation	O
periods	O
averaged	O
10	O
.	O
6	O
months	O
.	O

Within	O
the	O
same	O
timeframe	O
,	O
no	O
L	O
-	O
W	O
rat	O
developed	O
a	O
similar	O
palpable	O
PA	B-Disease
when	O
treated	O
only	O
with	O
TP	B-Chemical
.	O

In	O
L	O
-	O
W	O
rats	O
,	O
TP	B-Chemical
acted	O
as	O
a	O
tumor	B-Disease
enhancement	O
agent	O
,	O
with	O
primary	O
emphasis	O
on	O
the	O
development	O
of	O
prostate	B-Disease
cancer	I-Disease
.	O

Relative	O
efficacy	O
and	O
toxicity	B-Disease
of	O
netilmicin	B-Chemical
and	O
tobramycin	B-Chemical
in	O
oncology	O
patients	O
.	O

We	O
prospectively	O
compared	O
the	O
efficacy	O
and	O
safety	O
of	O
netilmicin	B-Chemical
sulfate	I-Chemical
or	O
tobramycin	B-Chemical
sulfate	I-Chemical
in	O
conjunction	O
with	O
piperacillin	B-Chemical
sodium	I-Chemical
in	O
118	O
immunocompromised	O
patients	O
with	O
presumed	O
severe	O
infections	B-Disease
.	O

The	O
two	O
treatment	O
regimens	O
were	O
equally	O
efficacious	O
.	O

Nephrotoxicity	B-Disease
occurred	O
in	O
a	O
similar	O
proportion	O
in	O
patients	O
treated	O
with	O
netilmicin	B-Chemical
and	O
tobramycin	B-Chemical
(	O
17	O
%	O
vs	O
11	O
%	O
)	O
.	O

Ototoxicity	B-Disease
occurred	O
in	O
four	O
(	O
9	O
.	O
5	O
%	O
)	O
of	O
42	O
netilmicin	B-Chemical
and	O
piperacillin	B-Chemical
and	O
in	O
12	O
(	O
22	O
%	O
)	O
of	O
54	O
tobramycin	B-Chemical
and	O
piperacillin	B-Chemical
-	O
treated	O
patients	O
.	O

Of	O
those	O
evaluated	O
with	O
posttherapy	O
audiograms	O
,	O
three	O
of	O
four	O
netilmicin	B-Chemical
and	O
piperacillin	B-Chemical
-	O
treated	O
patients	O
had	O
auditory	O
thresholds	O
return	O
to	O
baseline	O
compared	O
with	O
one	O
of	O
nine	O
tobramycin	B-Chemical
and	O
piperacillin	B-Chemical
-	O
treated	O
patients	O
.	O

The	O
number	O
of	O
greater	O
than	O
or	O
equal	O
to	O
15	O
-	O
dB	O
increases	O
in	O
auditory	O
threshold	O
as	O
a	O
proportion	O
of	O
total	O
greater	O
than	O
or	O
equal	O
to	O
15	O
-	O
dB	O
changes	O
(	O
increases	O
and	O
decreases	O
)	O
was	O
significantly	O
lower	O
in	O
netilmicin	B-Chemical
and	O
piperacillin	B-Chemical
-	O
vs	O
tobramycin	B-Chemical
and	O
piperacillin	B-Chemical
-	O
treated	O
patients	O
(	O
18	O
of	O
78	O
vs	O
67	O
of	O
115	O
)	O
.	O

We	O
conclude	O
that	O
aminoglycoside	B-Chemical
-	O
associated	O
ototoxicity	B-Disease
was	O
less	O
severe	O
and	O
more	O
often	O
reversible	O
with	O
netilmicin	B-Chemical
than	O
with	O
tobramycin	B-Chemical
.	O

Urinary	O
enzymes	O
and	O
protein	O
patterns	O
as	O
indicators	O
of	O
injury	B-Disease
to	I-Disease
different	I-Disease
regions	I-Disease
of	I-Disease
the	I-Disease
kidney	I-Disease
.	O

Acute	B-Disease
experimental	I-Disease
models	I-Disease
of	I-Disease
renal	I-Disease
damage	I-Disease
to	O
the	O
proximal	O
tubular	O
,	O
glomerular	O
,	O
and	O
papillary	O
regions	O
of	O
the	O
rat	O
were	O
produced	O
by	O
administration	O
of	O
hexachloro	B-Chemical
-	I-Chemical
1	I-Chemical
:	I-Chemical
3	I-Chemical
-	I-Chemical
butadiene	I-Chemical
(	O
HCBD	B-Chemical
)	O
,	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
PAN	B-Chemical
)	O
,	O
and	O
2	B-Chemical
-	I-Chemical
bromoethylamine	I-Chemical
(	O
BEA	B-Chemical
)	O
,	O
respectively	O
.	O

Several	O
routine	O
indicators	O
of	O
nephrotoxicity	B-Disease
,	O
the	O
enzymes	O
alkaline	O
phosphatase	O
and	O
N	O
-	O
acetyl	O
-	O
beta	O
-	O
glucosaminidase	O
,	O
and	O
the	O
molecular	O
weight	O
of	O
protein	B-Disease
excretion	I-Disease
were	O
determined	O
on	O
urine	O
samples	O
.	O

Tubular	O
damage	O
produced	O
by	O
HCBD	B-Chemical
or	O
BEA	B-Chemical
was	O
discriminated	O
both	O
quantitatively	O
and	O
qualitatively	O
from	O
glomerular	B-Disease
damage	I-Disease
produced	O
by	O
PAN	B-Chemical
.	O

The	O
latter	O
was	O
characterized	O
by	O
a	O
pronounced	O
increase	O
in	O
protein	B-Disease
excretion	I-Disease
,	O
especially	O
proteins	O
with	O
molecular	O
weight	O
greater	O
than	O
40	O
,	O
000	O
Da	O
.	O

In	O
contrast	O
,	O
protein	B-Disease
excretion	I-Disease
in	O
tubular	O
damage	O
was	O
raised	O
only	O
slightly	O
and	O
characterized	O
by	O
excretion	B-Disease
of	I-Disease
proteins	I-Disease
of	O
a	O
wide	O
range	O
of	O
molecular	O
weights	O
.	O

Proximal	O
tubular	O
damage	O
caused	O
by	O
HCBD	B-Chemical
and	O
papillary	O
damage	O
caused	O
by	O
BEA	B-Chemical
were	O
distinguished	O
both	O
by	O
conventional	O
urinalysis	O
(	O
volume	O
and	O
specific	O
gravity	O
)	O
and	O
by	O
measurement	O
of	O
the	O
two	O
urinary	O
enzymes	O
.	O

Alkaline	O
phosphatase	O
and	O
glucose	B-Chemical
were	O
markedly	O
and	O
transiently	O
elevated	O
in	O
proximal	O
tubular	O
damage	O
and	O
N	O
-	O
acetyl	O
-	O
beta	O
-	O
glucosaminidase	O
showed	O
a	O
sustained	O
elevation	O
in	O
papillary	O
damage	O
.	O

It	O
is	O
concluded	O
that	O
both	O
selective	O
urinary	O
enzymes	O
and	O
the	O
molecular	O
weight	O
pattern	O
of	O
urinary	O
proteins	O
can	O
be	O
used	O
to	O
provide	O
diagnostic	O
information	O
about	O
the	O
possible	O
site	O
of	O
renal	B-Disease
damage	I-Disease
.	O

A	O
catch	O
in	O
the	O
Reye	B-Disease
.	O

Twenty	O
-	O
six	O
cases	O
of	O
Reye	B-Disease
syndrome	I-Disease
from	O
The	O
Children	O
'	O
s	O
Hospital	O
,	O
Camperdown	O
,	O
Australia	O
,	O
occurring	O
between	O
1973	O
and	O
1982	O
were	O
reviewed	O
.	O

Of	O
these	O
,	O
20	O
cases	O
met	O
the	O
US	O
Public	O
Health	O
Service	O
Centers	O
for	O
Disease	O
Control	O
criteria	O
for	O
the	O
diagnosis	O
of	O
Reye	B-Disease
syndrome	I-Disease
.	O

Aspirin	B-Chemical
or	O
salicylate	B-Chemical
ingestion	O
had	O
occurred	O
in	O
only	O
one	O
of	O
the	O
20	O
cases	O
(	O
5	O
%	O
)	O
,	O
and	O
paracetamol	B-Chemical
(	O
acetaminophen	B-Chemical
)	O
had	O
been	O
administered	O
in	O
only	O
six	O
of	O
the	O
cases	O
(	O
30	O
%	O
)	O
.	O

Pathologic	O
confirmation	O
of	O
the	O
diagnosis	O
of	O
Reye	B-Disease
syndrome	I-Disease
was	O
accomplished	O
in	O
90	O
%	O
of	O
the	O
cases	O
.	O

The	O
incidence	O
of	O
Reye	B-Disease
syndrome	I-Disease
in	O
New	O
South	O
Wales	O
,	O
Australia	O
,	O
is	O
estimated	O
from	O
this	O
study	O
to	O
be	O
approximately	O
nine	O
cases	O
per	O
1	O
million	O
children	O
compared	O
with	O
recent	O
US	O
data	O
of	O
ten	O
to	O
20	O
cases	O
per	O
1	O
million	O
children	O
and	O
three	O
to	O
seven	O
cases	O
per	O
1	O
million	O
children	O
in	O
Great	O
Britain	O
.	O

The	O
mortality	O
for	O
these	O
Reye	B-Disease
syndrome	I-Disease
cases	O
in	O
Australia	O
was	O
45	O
%	O
as	O
compared	O
with	O
a	O
32	O
%	O
case	O
-	O
fatality	O
rate	O
in	O
the	O
United	O
States	O
.	O

In	O
Australia	O
,	O
the	O
pediatric	O
usage	O
of	O
aspirin	B-Chemical
has	O
been	O
extremely	O
low	O
for	O
the	O
past	O
25	O
years	O
(	O
less	O
than	O
1	O
%	O
of	O
total	O
dosage	O
units	O
sold	O
)	O
,	O
with	O
paracetamol	B-Chemical
(	O
acetaminophen	B-Chemical
)	O
dominating	O
the	O
pediatric	O
analgesic	O
and	O
antipyretic	O
market	O
.	O

Reye	B-Disease
syndrome	I-Disease
may	O
be	O
disappearing	O
from	O
Australia	O
despite	O
a	O
total	O
lack	O
of	O
association	O
with	O
salicylates	B-Chemical
or	O
aspirin	B-Chemical
ingestion	O
,	O
since	O
there	O
were	O
no	O
cases	O
found	O
at	O
The	O
Children	O
'	O
s	O
Hospital	O
in	O
1983	O
,	O
1984	O
,	O
or	O
1985	O
.	O

Postpartum	O
psychosis	B-Disease
induced	O
by	O
bromocriptine	B-Chemical
.	O

Two	O
multigravida	O
patients	O
with	O
no	O
prior	O
psychiatric	B-Disease
history	O
were	O
seen	O
with	O
postpartum	O
psychosis	B-Disease
,	O
having	O
received	O
bromocriptine	B-Chemical
for	O
inhibition	B-Disease
of	I-Disease
lactation	I-Disease
.	O

Bromocriptine	B-Chemical
given	O
in	O
high	O
doses	O
has	O
been	O
associated	O
with	O
psychosis	B-Disease
in	O
patients	O
receiving	O
the	O
drug	O
for	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

These	O
cases	O
demonstrate	O
that	O
bromocriptine	B-Chemical
may	O
cause	O
psychosis	B-Disease
even	O
when	O
given	O
in	O
low	O
doses	O
.	O

Hyperglycemic	B-Disease
acidotic	I-Disease
coma	I-Disease
and	O
death	O
in	O
Kearns	B-Disease
-	I-Disease
Sayre	I-Disease
syndrome	I-Disease
.	O

This	O
paper	O
presents	O
the	O
clinical	O
and	O
metabolic	O
findings	O
in	O
two	O
young	O
boys	O
with	O
long	O
-	O
standing	O
Kearns	B-Disease
-	I-Disease
Sayre	I-Disease
syndrome	I-Disease
.	O

Following	O
short	O
exposure	O
to	O
oral	O
prednisone	B-Chemical
,	O
both	O
boys	O
developed	O
lethargy	B-Disease
,	O
increasing	O
somnolence	B-Disease
,	O
polydipsia	B-Disease
,	O
polyphagia	B-Disease
,	O
and	O
polyuria	B-Disease
.	O

Both	O
presented	O
in	O
the	O
emergency	O
room	O
with	O
profound	O
coma	B-Disease
,	O
hypotension	B-Disease
,	O
severe	O
hyperglycemia	B-Disease
,	O
and	O
acidosis	B-Disease
.	O

Nonketotic	O
lactic	B-Disease
acidosis	I-Disease
was	O
present	O
in	O
one	O
and	O
ketosis	B-Disease
without	O
a	O
known	O
serum	O
lactate	B-Chemical
level	O
was	O
present	O
in	O
the	O
other	O
.	O

Respiratory	B-Disease
failure	I-Disease
rapidly	O
ensued	O
and	O
both	O
patients	O
expired	O
in	O
spite	O
of	O
efforts	O
at	O
resuscitation	O
.	O

We	O
believe	O
these	O
two	O
cases	O
represent	O
a	O
newly	O
described	O
and	O
catastrophic	O
metabolic	B-Disease
-	I-Disease
endocrine	I-Disease
failure	I-Disease
in	O
the	O
Kearns	B-Disease
-	I-Disease
Sayre	I-Disease
syndrome	I-Disease
.	O

Experimental	O
cyclosporine	B-Chemical
nephrotoxicity	B-Disease
:	O
risk	O
of	O
concomitant	O
chemotherapy	O
.	O

The	O
role	O
of	O
cyclosporine	B-Chemical
(	O
CSA	B-Chemical
)	O
alone	O
or	O
in	O
combination	O
with	O
various	O
chemotherapeutics	O
in	O
the	O
development	O
of	O
renal	B-Disease
toxicity	I-Disease
was	O
evaluated	O
in	O
rats	O
.	O

Administration	O
of	O
20	O
mg	O
/	O
kg	O
/	O
day	O
CSA	B-Chemical
for	O
4	O
weeks	O
caused	O
renal	O
functional	O
and	O
structural	O
changes	O
similar	O
to	O
those	O
reported	O
in	O
man	O
.	O

The	O
combined	O
administration	O
of	O
CSA	B-Chemical
and	O
various	O
chemotherapeutic	O
drugs	O
with	O
a	O
nephrotoxic	B-Disease
potential	O
,	O
such	O
as	O
gentamicin	B-Chemical
(	O
at	O
therapeutic	O
doses	O
)	O
,	O
amphothericin	B-Chemical
B	I-Chemical
and	O
ketoconazole	B-Chemical
,	O
which	O
are	O
frequently	O
used	O
in	O
immunosuppressed	O
patients	O
,	O
did	O
not	O
aggravate	O
the	O
CSA	B-Chemical
induced	O
toxicity	B-Disease
in	O
the	O
rat	O
model	O
.	O

Gentamicin	B-Chemical
at	O
toxic	O
doses	O
,	O
however	O
,	O
increased	O
CSA	B-Chemical
nephrotoxicity	B-Disease
.	O

Thus	O
,	O
the	O
nephrotoxicity	B-Disease
induced	O
by	O
CSA	B-Chemical
has	O
a	O
different	O
pathogenetic	O
mechanism	O
.	O

Diuretics	O
,	O
potassium	B-Chemical
and	O
arrhythmias	B-Disease
in	O
hypertensive	B-Disease
coronary	B-Disease
disease	I-Disease
.	O

It	O
has	O
been	O
proposed	O
that	O
modest	O
changes	O
in	O
plasma	O
potassium	B-Chemical
can	O
alter	O
the	O
tendency	O
towards	O
cardiac	B-Disease
arrhythmias	I-Disease
.	O

If	O
this	O
were	O
so	O
,	O
patients	O
with	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
might	O
be	O
especially	O
susceptible	O
.	O

Thus	O
,	O
myocardial	O
electrical	O
excitability	O
was	O
measured	O
in	O
patients	O
with	O
mild	O
essential	O
hypertension	B-Disease
and	O
known	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
after	O
8	O
weeks	O
of	O
treatment	O
with	O
a	O
potassium	B-Chemical
-	O
conserving	O
diuretic	O
(	O
amiloride	B-Chemical
)	O
and	O
a	O
similar	O
period	O
on	O
a	O
potassium	B-Chemical
-	O
losing	O
diuretic	O
(	O
chlorthalidone	B-Chemical
)	O
in	O
a	O
randomised	O
study	O
.	O

Plasma	O
potassium	B-Chemical
concentrations	O
were	O
on	O
average	O
1	O
mmol	O
/	O
L	O
lower	O
during	O
the	O
chlorthalidone	B-Chemical
phase	O
compared	O
to	O
amiloride	B-Chemical
therapy	O
.	O

Blood	O
pressure	O
and	O
volume	O
states	O
as	O
assessed	O
by	O
bodyweight	O
,	O
plasma	O
renin	O
and	O
noradrenaline	B-Chemical
(	O
norepinephrine	B-Chemical
)	O
concentrations	O
were	O
similar	O
on	O
the	O
2	O
regimens	O
.	O

Compared	O
to	O
amiloride	B-Chemical
treatment	O
,	O
the	O
chlorthalidone	B-Chemical
phase	O
was	O
associated	O
with	O
an	O
increased	O
frequency	O
of	O
ventricular	B-Disease
ectopic	I-Disease
beats	I-Disease
(	O
24	O
-	O
hour	O
Holter	O
monitoring	O
)	O
and	O
a	O
higher	O
Lown	O
grading	O
,	O
increased	O
upslope	O
and	O
duration	O
of	O
the	O
monophasic	O
action	O
potential	O
,	O
prolonged	O
ventricular	O
effective	O
refractory	O
period	O
,	O
and	O
increased	O
electrical	O
instability	O
during	O
programmed	O
ventricular	O
stimulation	O
.	O

The	O
above	O
results	O
indicate	O
that	O
because	O
potassium	B-Chemical
-	O
losing	O
diuretic	O
therapy	O
can	O
increase	O
myocardial	O
electrical	O
excitability	O
in	O
patients	O
with	O
ischaemic	B-Disease
heart	I-Disease
disease	I-Disease
,	O
even	O
minor	O
falls	O
in	O
plasma	O
potassium	B-Chemical
concentrations	O
are	O
probably	O
best	O
avoided	O
in	O
such	O
patients	O
.	O

Transketolase	O
abnormality	O
in	O
tolazamide	B-Chemical
-	O
induced	O
Wernicke	B-Disease
'	I-Disease
s	I-Disease
encephalopathy	I-Disease
.	O

We	O
studied	O
a	O
thiamine	B-Chemical
-	O
dependent	O
enzyme	O
,	O
transketolase	O
,	O
from	O
fibroblasts	O
of	O
a	O
diabetic	B-Disease
patient	O
who	O
developed	O
Wernicke	B-Disease
'	I-Disease
s	I-Disease
encephalopathy	I-Disease
when	O
treated	O
with	O
tolazamide	B-Chemical
,	O
in	O
order	O
to	O
delineate	O
if	O
this	O
patient	O
also	O
had	O
transketolase	O
abnormality	O
[	O
high	O
Km	O
for	O
thiamine	B-Chemical
pyrophosphate	I-Chemical
(	O
TPP	B-Chemical
)	O
]	O
,	O
as	O
previously	O
reported	O
in	O
postalcoholic	O
Wernicke	B-Disease
-	I-Disease
Korsakoff	I-Disease
syndrome	I-Disease
.	O

In	O
addition	O
to	O
this	O
patient	O
,	O
we	O
also	O
studied	O
this	O
enzyme	O
from	O
three	O
diabetic	B-Disease
kindreds	O
without	O
any	O
history	O
of	O
Wernicke	B-Disease
'	I-Disease
s	I-Disease
encephalopathy	I-Disease
and	O
from	O
four	O
normal	O
controls	O
.	O

We	O
found	O
that	O
the	O
above	O
-	O
mentioned	O
patient	O
and	O
one	O
of	O
the	O
diabetic	B-Disease
kindreds	O
with	O
no	O
history	O
of	O
Wernicke	B-Disease
'	I-Disease
s	I-Disease
encephalopathy	I-Disease
had	O
abnormal	O
transketolase	O
as	O
determined	O
by	O
its	O
Km	O
for	O
TPP	B-Chemical
.	O

These	O
data	O
suggest	O
a	O
similarity	O
between	O
postalcoholic	O
Wernicke	B-Disease
-	I-Disease
Korsakoff	I-Disease
syndrome	I-Disease
and	O
the	O
patient	O
with	O
tolazamide	B-Chemical
-	O
induced	O
Wernicke	B-Disease
'	I-Disease
s	I-Disease
encephalopathy	I-Disease
from	O
the	O
standpoint	O
of	O
transketolase	O
abnormality	O
.	O

Bradycardia	B-Disease
due	O
to	O
trihexyphenidyl	B-Chemical
hydrochloride	I-Chemical
.	O

A	O
chronic	O
schizophrenic	B-Disease
patient	O
was	O
treated	O
with	O
an	O
anticholinergic	O
drug	O
,	O
trihexyphenidyl	B-Chemical
hydrochloride	I-Chemical
.	O

The	O
patient	O
developed	O
,	O
paradoxically	O
,	O
sinus	O
bradycardia	B-Disease
.	O

The	O
reaction	O
was	O
specific	O
to	O
trihexyphenidyl	B-Chemical
and	O
not	O
to	O
other	O
anticholinergic	O
drugs	O
.	O

This	O
antidyskinetic	O
drug	O
is	O
widely	O
used	O
in	O
clinical	O
psychiatric	B-Disease
practice	O
and	O
physicians	O
should	O
be	O
aware	O
of	O
this	O
side	O
effect	O
.	O

Post	O
-	O
operative	O
rigidity	B-Disease
after	O
fentanyl	B-Chemical
administration	O
.	O

A	O
case	O
of	O
thoraco	O
-	O
abdominal	O
rigidity	B-Disease
leading	O
to	O
respiratory	B-Disease
failure	I-Disease
is	O
described	O
in	O
the	O
post	O
-	O
operative	O
period	O
in	O
an	O
elderly	O
patient	O
who	O
received	O
a	O
moderate	O
dose	O
of	O
fentanyl	B-Chemical
.	O

This	O
was	O
successfully	O
reversed	O
by	O
naloxone	B-Chemical
.	O

The	O
mechanisms	O
possibly	O
implicated	O
in	O
this	O
accident	O
are	O
discussed	O
.	O

Anti	O
-	O
carcinogenic	B-Disease
action	O
of	O
phenobarbital	B-Chemical
given	O
simultaneously	O
with	O
diethylnitrosamine	B-Chemical
in	O
the	O
rat	O
.	O

The	O
present	O
work	O
has	O
been	O
planned	O
in	O
order	O
to	O
elucidate	O
the	O
effect	O
of	O
phenobarbital	B-Chemical
(	O
PB	B-Chemical
:	O
15	O
mg	O
per	O
rat	O
of	O
ingested	O
dose	O
)	O
on	O
carcinogenesis	B-Disease
when	O
it	O
is	O
administered	O
simultaneously	O
with	O
diethylnitrosamine	B-Chemical
(	O
DEN	B-Chemical
:	O
10	O
mg	O
/	O
kg	O
/	O
day	O
)	O
.	O

Wistar	O
rats	O
(	O
180	O
g	O
)	O
were	O
treated	O
by	O
DEN	B-Chemical
alone	O
or	O
by	O
DEN	B-Chemical
+	O
PB	B-Chemical
during	O
2	O
,	O
4	O
and	O
6	O
weeks	O
according	O
to	O
our	O
schedule	O
for	O
hepatocarcinogenesis	B-Disease
.	O

After	O
the	O
end	O
of	O
the	O
treatment	O
,	O
the	O
number	O
and	O
the	O
size	O
of	O
induced	O
PAS	O
positive	O
preneoplastic	B-Disease
foci	I-Disease
was	O
significantly	O
reduced	O
when	O
PB	B-Chemical
was	O
given	O
simultaneously	O
with	O
DEN	B-Chemical
for	O
4	O
and	O
6	O
weeks	O
.	O

The	O
mitotic	O
inhibition	O
and	O
the	O
production	O
of	O
micronuclei	O
normally	O
observed	O
after	O
partial	O
hepatectomy	O
in	O
DEN	B-Chemical
treated	O
rats	O
were	O
also	O
significantly	O
decreased	O
in	O
DEN	B-Chemical
+	O
PB	B-Chemical
treated	O
rats	O
.	O

When	O
the	O
treatment	O
last	O
only	O
2	O
weeks	O
,	O
the	O
presence	O
of	O
PB	B-Chemical
did	O
not	O
change	O
significantly	O
the	O
last	O
parameters	O
.	O

In	O
DEN	B-Chemical
+	O
PB	B-Chemical
treated	O
rats	O
,	O
the	O
survival	O
was	O
prolonged	O
and	O
the	O
tumor	B-Disease
incidence	O
decreased	O
as	O
compared	O
with	O
the	O
results	O
obtained	O
by	O
DEN	B-Chemical
alone	O
.	O

It	O
is	O
concluded	O
that	O
PB	B-Chemical
,	O
which	O
promotes	O
carcinogenesis	B-Disease
when	O
administered	O
after	O
the	O
DEN	B-Chemical
treatment	O
,	O
reduces	O
the	O
carcinogen	O
effect	O
when	O
given	O
simultaneously	O
with	O
DEN	B-Chemical
.	O

This	O
'	O
anti	O
-	O
carcinogen	O
'	O
effect	O
acts	O
on	O
the	O
initiation	O
as	O
well	O
as	O
on	O
the	O
promotion	O
of	O
the	O
precancerous	B-Disease
lesions	I-Disease
.	O

Biochemical	O
investigations	O
are	O
in	O
progress	O
to	O
obtain	O
more	O
information	O
about	O
this	O
'	O
paradoxical	O
'	O
PB	B-Chemical
effect	O
.	O

Bilateral	B-Disease
optic	I-Disease
neuropathy	I-Disease
due	O
to	O
combined	O
ethambutol	B-Chemical
and	O
isoniazid	B-Chemical
treatment	O
.	O

The	O
case	O
of	O
a	O
40	O
-	O
year	O
-	O
old	O
patient	O
who	O
underwent	O
an	O
unsuccessful	O
cadaver	O
kidney	O
transplantation	O
and	O
was	O
treated	O
with	O
ethambutol	B-Chemical
and	O
isoniazid	B-Chemical
is	O
reported	O
.	O

A	O
bilateral	B-Disease
retrobulbar	I-Disease
neuropathy	I-Disease
with	O
an	O
unusual	O
central	O
bitemporal	O
hemianopic	O
scotoma	B-Disease
was	O
found	O
.	O

Ethambutol	B-Chemical
was	O
stopped	O
and	O
only	O
small	O
improvement	O
of	O
the	O
visual	O
acuity	O
followed	O
.	O

Isoniazid	B-Chemical
was	O
discontinued	O
later	O
,	O
followed	O
by	O
a	O
dramatic	O
improvement	O
in	O
the	O
visual	O
acuity	O
.	O

The	O
hazards	O
of	O
optic	O
nerve	O
toxicity	B-Disease
due	O
to	O
ethambutol	B-Chemical
are	O
known	O
.	O

We	O
emphasize	O
the	O
potential	O
danger	O
in	O
the	O
use	O
of	O
ethambutol	B-Chemical
and	O
isoniazid	B-Chemical
.	O

A	O
prospective	O
study	O
of	O
adverse	O
reactions	O
associated	O
with	O
vancomycin	B-Chemical
therapy	O
.	O

A	O
prospective	O
evaluation	O
of	O
the	O
efficacy	O
and	O
safety	O
of	O
vancomycin	B-Chemical
was	O
conducted	O
in	O
54	O
consecutive	O
patients	O
over	O
a	O
16	O
-	O
month	O
period	O
.	O

Vancomycin	B-Chemical
was	O
curative	O
in	O
95	O
%	O
of	O
43	O
patients	O
with	O
proven	O
infection	B-Disease
.	O

Drugs	O
were	O
ceased	O
in	O
six	O
patients	O
because	O
of	O
adverse	O
reactions	O
;	O
in	O
three	O
of	O
these	O
vancomycin	B-Chemical
was	O
considered	O
the	O
likely	O
cause	O
.	O

Reactions	O
included	O
thrombophlebitis	B-Disease
(	O
20	O
of	O
54	O
patients	O
)	O
,	O
rash	B-Disease
(	O
4	O
of	O
54	O
)	O
,	O
nephrotoxicity	B-Disease
(	O
4	O
of	O
50	O
)	O
,	O
proteinuria	B-Disease
(	O
1	O
of	O
50	O
)	O
and	O
ototoxicity	B-Disease
(	O
1	O
of	O
11	O
patients	O
tested	O
by	O
audiometry	O
)	O
.	O

Thrombophlebitis	B-Disease
occurred	O
only	O
with	O
infusion	O
through	O
peripheral	O
cannulae	O
;	O
nephrotoxicity	B-Disease
and	O
ototoxicity	B-Disease
were	O
confined	O
to	O
patients	O
receiving	O
an	O
aminoglycoside	B-Chemical
plus	O
vancomycin	B-Chemical
.	O

We	O
conclude	O
that	O
vancomycin	B-Chemical
,	O
administered	O
appropriately	O
,	O
constitutes	O
safe	O
,	O
effective	O
therapy	O
for	O
infections	B-Disease
caused	O
by	O
susceptible	O
bacteria	O
.	O

Factors	O
associated	O
with	O
nephrotoxicity	B-Disease
and	O
clinical	O
outcome	O
in	O
patients	O
receiving	O
amikacin	B-Chemical
.	O

Data	O
from	O
60	O
patients	O
treated	O
with	O
amikacin	B-Chemical
were	O
analyzed	O
for	O
factors	O
associated	O
with	O
nephrotoxicity	B-Disease
.	O

In	O
42	O
of	O
these	O
patients	O
,	O
data	O
were	O
examined	O
for	O
factors	O
associated	O
with	O
clinical	O
outcome	O
.	O

Variables	O
evaluated	O
included	O
patient	O
weight	O
,	O
age	O
,	O
sex	O
,	O
serum	O
creatinine	B-Chemical
level	O
,	O
creatinine	B-Chemical
clearance	O
,	O
duration	O
of	O
therapy	O
,	O
total	O
dose	O
,	O
mean	O
daily	O
dose	O
,	O
organism	O
minimum	O
inhibitory	O
concentration	O
(	O
MIC	O
)	O
,	O
mean	O
peak	O
levels	O
,	O
mean	O
trough	O
levels	O
,	O
mean	O
area	O
under	O
the	O
serum	O
concentration	O
-	O
time	O
curve	O
(	O
AUC	O
)	O
,	O
total	O
AUC	O
,	O
mean	O
AUC	O
greater	O
than	O
MIC	O
,	O
total	O
AUC	O
greater	O
than	O
MIC	O
,	O
mean	O
Schumacher	O
'	O
s	O
intensity	O
factor	O
(	O
IF	O
)	O
,	O
total	O
IF	O
,	O
In	O
(	O
mean	O
maximum	O
concentration	O
[	O
Cmax	O
]	O
/	O
MIC	O
)	O
.	O

Model	O
-	O
dependent	O
pharmacokinetic	O
parameters	O
were	O
calculated	O
by	O
computer	O
based	O
on	O
a	O
one	O
-	O
compartment	O
model	O
.	O

When	O
the	O
parameters	O
were	O
examined	O
individually	O
,	O
duration	O
of	O
therapy	O
and	O
total	O
AUC	O
correlated	O
significantly	O
(	O
P	O
less	O
than	O
.	O
05	O
)	O
with	O
nephrotoxicity	B-Disease
.	O

In	O
contrast	O
,	O
a	O
stepwise	O
discriminant	O
function	O
analysis	O
identified	O
only	O
duration	O
of	O
therapy	O
(	O
P	O
less	O
than	O
.	O
001	O
)	O
as	O
an	O
important	O
factor	O
.	O

Based	O
on	O
this	O
model	O
and	O
on	O
Bayes	O
'	O
theorem	O
,	O
the	O
predictive	O
accuracy	O
of	O
identifying	O
"	O
nephrotoxic	B-Disease
"	O
patients	O
increased	O
from	O
0	O
.	O
17	O
to	O
0	O
.	O
39	O
.	O

When	O
examined	O
individually	O
,	O
mean	O
IF	O
,	O
MIC	O
,	O
total	O
dose	O
,	O
mean	O
daily	O
dose	O
,	O
and	O
ln	O
(	O
mean	O
Cmax	O
/	O
MIC	O
)	O
correlated	O
significantly	O
(	O
P	O
less	O
than	O
.	O
05	O
)	O
with	O
cure	O
.	O

In	O
contrast	O
,	O
a	O
simultaneous	O
multivariable	O
analysis	O
identified	O
IF	O
,	O
MIC	O
,	O
and	O
total	O
dose	O
according	O
to	O
one	O
model	O
and	O
ln	O
(	O
mean	O
Cmax	O
/	O
MIC	O
)	O
according	O
to	O
a	O
second	O
statistical	O
model	O
of	O
parameters	O
selected	O
to	O
have	O
the	O
greatest	O
prospective	O
value	O
.	O

Based	O
on	O
Bayes	O
'	O
theorem	O
and	O
the	O
first	O
model	O
,	O
the	O
predictive	O
accuracy	O
of	O
identifying	O
patients	O
not	O
cured	O
increased	O
from	O
0	O
.	O
19	O
to	O
0	O
.	O
83	O
.	O

For	O
the	O
second	O
model	O
,	O
the	O
predictive	O
accuracy	O
increased	O
from	O
0	O
.	O
19	O
to	O
0	O
.	O
50	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Cardiac	B-Disease
toxicity	I-Disease
of	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
.	O

Report	O
of	O
a	O
case	O
of	O
spontaneous	O
angina	B-Disease
.	O

We	O
report	O
a	O
case	O
of	O
a	O
patient	O
with	O
colon	B-Disease
carcinoma	I-Disease
and	O
liver	O
metastasis	B-Disease
who	O
presented	O
chest	B-Disease
pain	I-Disease
after	O
5	B-Chemical
-	I-Chemical
fluorouracil	I-Chemical
(	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
)	O
administration	O
.	O

Clinical	O
electrocardiographic	O
evolution	O
was	O
similar	O
to	O
that	O
observed	O
in	O
Prinzmetal	B-Disease
'	I-Disease
s	I-Disease
angina	I-Disease
,	O
and	O
chest	B-Disease
pain	I-Disease
promptly	O
resolved	O
with	O
nifedipine	B-Chemical
.	O

These	O
data	O
suggest	O
that	O
coronary	B-Disease
spasm	I-Disease
may	O
be	O
the	O
cause	O
of	O
cardiotoxicity	B-Disease
due	O
to	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
,	O
and	O
that	O
calcium	B-Chemical
antagonists	O
may	O
probably	O
be	O
used	O
in	O
the	O
prevention	O
or	O
treatment	O
of	O
5	B-Chemical
-	I-Chemical
FU	I-Chemical
cardiotoxicity	B-Disease
.	O

Dose	O
-	O
related	O
beneficial	O
and	O
adverse	O
effects	O
of	O
dietary	O
corticosterone	B-Chemical
on	O
organophosphorus	B-Chemical
-	O
induced	O
delayed	O
neuropathy	B-Disease
in	O
chickens	O
.	O

Tri	B-Chemical
-	I-Chemical
ortho	I-Chemical
-	I-Chemical
tolyl	I-Chemical
phosphate	I-Chemical
(	O
TOTP	B-Chemical
)	O
,	O
360	O
mg	O
/	O
kg	O
,	O
po	O
,	O
and	O
0	B-Chemical
,	I-Chemical
0	I-Chemical
'	I-Chemical
-	I-Chemical
diisopropyl	I-Chemical
phosphorofluoridate	I-Chemical
(	O
DFP	B-Chemical
)	O
,	O
1	O
mg	O
/	O
kg	O
sc	O
,	O
were	O
administered	O
to	O
adult	O
White	O
Leghorn	O
chickens	O
24	O
hr	O
after	O
they	O
were	O
placed	O
on	O
diets	O
containing	O
0	O
to	O
300	O
ppm	O
corticosterone	B-Chemical
.	O

Supplemented	O
diets	O
were	O
continued	O
until	O
clinical	O
signs	O
and	O
lesions	O
of	O
delayed	O
neuropathy	B-Disease
appeared	O
.	O

Although	O
low	O
concentrations	O
(	O
less	O
than	O
or	O
equal	O
to	O
50	O
ppm	O
)	O
of	O
corticosterone	B-Chemical
had	O
beneficial	O
effects	O
on	O
TOTP	B-Chemical
-	O
induced	O
neuropathy	B-Disease
,	O
greater	O
than	O
or	O
equal	O
to	O
200	O
ppm	O
exacerbated	O
clinical	O
signs	O
in	O
chickens	O
given	O
either	O
TOTP	B-Chemical
or	O
DFP	B-Chemical
.	O

Neurotoxic	B-Disease
esterase	O
activities	O
24	O
hr	O
after	O
TOTP	B-Chemical
or	O
DFP	B-Chemical
were	O
less	O
than	O
20	O
%	O
of	O
values	O
measured	O
in	O
chickens	O
not	O
given	O
organophosphorous	B-Chemical
compounds	O
.	O

Chickens	O
given	O
200	O
ppm	O
corticosterone	B-Chemical
without	O
TOTP	B-Chemical
or	O
DFP	B-Chemical
had	O
significantly	O
elevated	O
activity	O
of	O
plasma	O
cholinesterase	O
and	O
significantly	O
inhibited	O
activity	O
of	O
liver	O
carboxylesterase	O
.	O

Degenerating	B-Disease
myelinated	I-Disease
fibers	I-Disease
were	O
also	O
evident	O
in	O
distal	O
levels	O
of	O
the	O
peripheral	O
nerves	O
of	O
chickens	O
given	O
TOTP	B-Chemical
or	O
DFP	B-Chemical
.	O

Hepatotoxicity	B-Disease
of	O
amiodarone	B-Chemical
.	O

Amiodarone	B-Chemical
has	O
proved	O
very	O
effective	O
in	O
the	O
treatment	O
of	O
otherwise	O
resistant	O
cardiac	O
tachyarrhythmias	B-Disease
.	O

The	O
use	O
of	O
amiodarone	B-Chemical
has	O
,	O
however	O
,	O
been	O
limited	O
due	O
to	O
its	O
serious	O
side	O
-	O
effects	O
.	O

A	O
patient	O
with	O
cholestatic	B-Disease
hepatitis	I-Disease
due	O
to	O
amiodarone	B-Chemical
treatment	O
is	O
presented	O
below	O
and	O
a	O
review	O
of	O
the	O
hepatotoxicity	B-Disease
of	O
amiodarone	B-Chemical
is	O
given	O
.	O

It	O
is	O
concluded	O
that	O
solid	O
evidence	O
exists	O
of	O
hepatic	B-Disease
injury	I-Disease
due	O
to	O
amiodarone	B-Chemical
treatment	O
,	O
including	O
steatosis	B-Disease
,	O
alterations	O
resembling	O
alcoholic	B-Disease
hepatitis	I-Disease
,	O
cholestatic	B-Disease
hepatitis	I-Disease
and	O
micronodular	O
cirrhosis	B-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
.	O

Patients	O
receiving	O
amiodarone	B-Chemical
should	O
be	O
regularly	O
screened	O
with	O
respect	O
to	O
hepatic	O
enzyme	O
levels	O
.	O

Therapy	O
should	O
be	O
discontinued	O
on	O
the	O
suspicion	O
of	O
cholestatic	B-Disease
injury	I-Disease
or	O
hepatomegaly	B-Disease
.	O

Promotional	O
effects	O
of	O
testosterone	B-Chemical
and	O
dietary	O
fat	O
on	O
prostate	O
carcinogenesis	B-Disease
in	O
genetically	O
susceptible	O
rats	O
.	O

Germfree	O
(	O
GF	O
)	O
Lobund	O
strain	O
Wistar	O
(	O
LW	O
)	O
rats	O
,	O
fed	O
vegetable	O
diet	O
L	O
-	O
485	O
,	O
have	O
developed	O
prostate	B-Disease
adenocarcinomas	I-Disease
spontaneously	O
(	O
10	O
%	O
incidence	O
)	O
at	O
average	O
age	O
34	O
months	O
.	O

Conventional	O
LW	O
rats	O
,	O
implanted	O
with	O
testosterone	B-Chemical
at	O
age	O
4	O
months	O
,	O
developed	O
a	O
higher	O
incidence	O
of	O
prostate	B-Disease
cancer	I-Disease
after	O
an	O
average	O
interval	O
of	O
14	O
months	O
:	O
24	O
%	O
had	O
developed	O
gross	O
tumors	B-Disease
,	O
and	O
40	O
%	O
when	O
it	O
included	O
microscopic	O
tumors	B-Disease
.	O

Preliminary	O
results	O
indicate	O
that	O
testosterone	B-Chemical
-	O
treated	O
LW	O
rats	O
that	O
were	O
fed	O
the	O
same	O
diet	O
,	O
which	O
was	O
supplemented	O
with	O
corn	O
oil	O
up	O
to	O
20	O
%	O
fat	O
,	O
developed	O
prostate	B-Disease
cancer	I-Disease
after	O
intervals	O
of	O
6	O
-	O
12	O
months	O
.	O

Aged	O
GF	O
Sprague	O
-	O
Dawley	O
(	O
SD	O
)	O
rats	O
have	O
not	O
developed	O
prostate	B-Disease
cancer	I-Disease
spontaneously	O
.	O

Conventional	O
SD	O
rats	O
fed	O
diet	O
L	O
-	O
485	O
and	O
treated	O
with	O
testosterone	B-Chemical
developed	O
only	O
prostatitis	B-Disease
.	O

Experimental	O
designs	O
should	O
consider	O
genetic	O
susceptibility	O
as	O
a	O
basic	O
prerequisite	O
for	O
studies	O
on	O
experimental	O
prostate	B-Disease
cancer	I-Disease
.	O

Time	O
course	O
alterations	O
of	O
QTC	O
interval	O
due	O
to	O
hypaque	B-Chemical
76	I-Chemical
.	O

Sequential	O
measurement	O
of	O
QT	O
interval	O
during	O
left	O
ventricular	O
angiography	O
was	O
made	O
30	O
seconds	O
and	O
one	O
,	O
three	O
,	O
five	O
and	O
ten	O
minutes	O
after	O
injection	O
of	O
hypaque	B-Chemical
76	I-Chemical
.	O

The	O
subjects	O
were	O
ten	O
patients	O
found	O
to	O
have	O
normal	O
left	O
ventricles	O
and	O
coronary	O
arteries	O
.	O

Significant	O
QTC	B-Disease
prolongation	I-Disease
occurred	O
in	O
30	O
seconds	O
to	O
one	O
minute	O
in	O
association	O
with	O
marked	O
hypotension	B-Disease
and	O
elevation	O
of	O
cardiac	O
output	O
.	O

Rat	O
extraocular	O
muscle	O
regeneration	O
.	O

Repair	O
of	O
local	O
anesthetic	O
-	O
induced	O
damage	O
.	O

Local	O
anesthetics	O
that	O
are	O
commonly	O
used	O
in	O
ophthalmic	O
surgery	O
(	O
0	O
.	O
75	O
%	O
bupivacaine	B-Chemical
hydrochloride	I-Chemical
,	O
2	O
.	O
0	O
%	O
mepivacaine	B-Chemical
hydrochloride	I-Chemical
,	O
and	O
2	O
.	O
0	O
%	O
lidocaine	B-Chemical
hydrochloride	I-Chemical
plus	O
1	O
:	O
100	O
,	O
000	O
epinephrine	B-Chemical
)	O
were	O
injected	O
into	O
the	O
retrobulbar	O
area	O
of	O
rat	O
eyes	O
.	O

Controls	O
were	O
injected	O
with	O
physiological	O
saline	O
.	O

All	O
three	O
anesthetics	O
produced	O
massive	O
degeneration	O
of	O
the	O
extraocular	O
muscles	O
.	O

Muscle	B-Disease
degeneration	I-Disease
is	O
followed	O
by	O
regeneration	O
of	O
the	O
damaged	O
muscle	O
fibers	O
.	O

In	O
addition	O
to	O
muscle	B-Disease
damage	I-Disease
,	O
severe	O
damage	O
was	O
also	O
seen	O
in	O
harderian	O
glands	O
,	O
especially	O
after	O
exposure	O
to	O
mepivacaine	B-Chemical
and	O
lidocaine	B-Chemical
plus	O
epinephrine	B-Chemical
.	O

With	O
these	O
findings	O
in	O
rats	O
,	O
it	O
is	O
hypothesized	O
that	O
the	O
temporary	O
diplopia	B-Disease
sometimes	O
seen	O
in	O
patients	O
after	O
ophthalmic	O
surgery	O
might	O
be	O
due	O
to	O
anesthetic	O
-	O
induced	O
damage	O
to	O
the	O
extraocular	O
muscles	O
.	O

Gentamicin	B-Chemical
nephropathy	B-Disease
in	O
a	O
neonate	O
.	O

The	O
clinical	O
and	O
autopsy	O
findings	O
in	O
a	O
premature	O
baby	O
who	O
died	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
after	O
therapy	O
with	O
gentamicin	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
/	O
day	O
)	O
and	O
penicillin	B-Chemical
are	O
presented	O
.	O

The	O
serum	O
gentamicin	B-Chemical
concentration	O
had	O
reached	O
toxic	O
levels	O
when	O
anuria	B-Disease
developed	O
.	O

Numerous	O
periodic	B-Chemical
acid	I-Chemical
Schiff	O
(	O
PAS	O
)	O
positive	O
,	O
diastase	O
resistant	O
cytoplasmic	O
inclusion	O
bodies	O
which	O
appeared	O
as	O
myelin	O
figures	O
in	O
cytosegresomes	O
under	O
the	O
electron	O
microscope	O
were	O
identified	O
in	O
the	O
proximal	O
convoluted	O
tubules	O
.	O

The	O
pathological	O
changes	O
induced	O
by	O
gentamicin	B-Chemical
in	O
the	O
human	O
neonatal	O
kidneys	O
have	O
not	O
been	O
previously	O
reported	O
.	O

Induction	O
by	O
paracetamol	B-Chemical
of	O
bladder	B-Disease
and	I-Disease
liver	I-Disease
tumours	I-Disease
in	O
the	O
rat	O
.	O

Effects	O
on	O
hepatocyte	O
fine	O
structure	O
.	O

Groups	O
of	O
male	O
and	O
female	O
inbred	O
Leeds	O
strain	O
rats	O
were	O
fed	O
diets	O
containing	O
either	O
0	O
.	O
5	O
%	O
or	O
1	O
.	O
0	O
%	O
paracetamol	B-Chemical
by	O
weight	O
for	O
up	O
to	O
18	O
months	O
.	O

At	O
the	O
1	O
.	O
0	O
%	O
dosage	O
level	O
,	O
20	O
%	O
of	O
rats	O
of	O
both	O
sexes	O
developed	O
neoplastic	O
nodules	O
of	O
the	O
liver	O
,	O
a	O
statistically	O
significant	O
incidence	O
.	O

These	O
rats	O
also	O
showed	O
gross	O
enlargement	O
of	O
their	O
livers	O
and	O
an	O
increase	O
in	O
foci	O
of	O
cellular	O
alteration	O
,	O
the	O
latter	O
also	O
being	O
observed	O
in	O
the	O
low	O
dosage	O
male	O
rats	O
.	O

Papillomas	B-Disease
of	O
the	O
transitional	O
epithelium	O
of	O
the	O
bladder	O
developed	O
in	O
all	O
paracetamol	B-Chemical
-	O
treated	O
groups	O
,	O
and	O
three	O
rats	O
bore	O
bladder	B-Disease
carcinomas	I-Disease
.	O

However	O
,	O
significant	O
yields	O
of	O
bladder	B-Disease
tumours	I-Disease
were	O
only	O
obtained	O
from	O
low	O
dosage	O
females	O
and	O
high	O
dosage	O
males	O
.	O

Additionally	O
,	O
20	O
to	O
25	O
%	O
of	O
paracetamol	B-Chemical
-	O
treated	O
rats	O
developed	O
hyperplasia	B-Disease
of	O
the	O
bladder	O
epithelium	O
,	O
which	O
was	O
not	O
coincident	O
with	O
the	O
presence	O
of	O
bladder	B-Disease
calculi	I-Disease
.	O

A	O
low	O
yield	O
of	O
tumours	B-Disease
at	O
various	O
other	O
sites	O
also	O
arose	O
following	O
paracetamol	B-Chemical
feeding	O
.	O

An	O
electron	O
microscope	O
study	O
of	O
the	O
livers	O
of	O
paracetamol	B-Chemical
-	O
treated	O
rats	O
revealed	O
ultrastructural	O
changes	O
in	O
the	O
hepatocytes	O
that	O
resemble	O
those	O
that	O
result	O
from	O
exposure	O
to	O
a	O
variety	O
of	O
known	O
hepatocarcinogens	B-Disease
.	O

Transient	O
hemiparesis	B-Disease
:	O
a	O
rare	O
manifestation	O
of	O
diphenylhydantoin	B-Chemical
toxicity	B-Disease
.	O

Report	O
of	O
two	O
cases	O
.	O

Among	O
the	O
common	O
side	O
effects	O
of	O
diphenylhydantoin	B-Chemical
(	O
DPH	B-Chemical
)	O
overdose	B-Disease
,	O
the	O
most	O
frequently	O
encountered	O
neurological	O
signs	O
are	O
those	O
of	O
cerebellar	B-Disease
dysfunction	I-Disease
.	O

Very	O
rarely	O
,	O
the	O
toxic	O
neurological	O
manifestations	O
of	O
this	O
drug	O
are	O
of	O
cerebral	O
origin	O
.	O

Two	O
patients	O
are	O
presented	O
who	O
suffered	O
progressive	O
hemiparesis	B-Disease
due	O
to	O
DPH	B-Chemical
overdose	B-Disease
.	O

Both	O
had	O
brain	O
surgery	O
before	O
DPH	B-Chemical
treatment	O
.	O

It	O
is	O
assumed	O
that	O
patients	O
with	O
some	O
cerebral	B-Disease
damage	I-Disease
are	O
liable	O
to	O
manifest	O
DPH	B-Chemical
toxicity	B-Disease
as	O
focal	O
neurological	O
signs	O
.	O

Tiapride	B-Chemical
in	O
levodopa	B-Chemical
-	O
induced	O
involuntary	B-Disease
movements	I-Disease
.	O

Tiapride	B-Chemical
,	O
a	O
substituted	O
benzamide	B-Chemical
derivative	O
closely	O
related	O
to	O
metoclopramide	B-Chemical
,	O
reduced	O
levodopa	B-Chemical
-	O
induced	O
peak	O
dose	O
involuntary	B-Disease
movements	I-Disease
in	O
16	O
patients	O
with	O
idiopathic	B-Disease
Parkinson	I-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

However	O
,	O
an	O
unacceptable	O
increase	O
in	O
disability	O
from	O
Parkinsonism	B-Disease
with	O
aggravation	O
of	O
end	O
-	O
of	O
-	O
dose	O
akinesia	B-Disease
led	O
to	O
its	O
cessation	O
in	O
14	O
patients	O
.	O

Tiapride	B-Chemical
had	O
no	O
effect	O
on	O
levodopa	B-Chemical
-	O
induced	O
early	O
morning	O
of	O
"	O
off	O
-	O
period	O
"	O
segmental	O
dystonia	B-Disease
.	O

These	O
results	O
fail	O
to	O
support	O
the	O
notion	O
that	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
are	O
caused	O
by	O
overstimulation	O
of	O
a	O
separate	O
group	O
of	O
dopamine	B-Chemical
receptors	O
.	O

Quinidine	B-Chemical
hepatitis	B-Disease
.	O

Long	O
-	O
term	O
administration	O
of	O
quinidine	B-Chemical
was	O
associated	O
with	O
persistent	O
elevation	O
of	O
serum	O
concentrations	O
of	O
SGOT	O
,	O
lactic	B-Chemical
acid	I-Chemical
dehydrogenase	O
,	O
and	O
alkaline	O
phosphatase	O
.	O

Liver	O
biopsy	O
showed	O
active	O
hepatitis	B-Disease
.	O

Discontinuance	O
of	O
quinidine	B-Chemical
therapy	O
led	O
to	O
normalization	O
of	O
liver	O
function	O
tests	O
.	O

A	O
challenge	O
dose	O
of	O
quinidine	B-Chemical
caused	O
clinical	O
symptoms	O
and	O
abrupt	O
elevation	O
of	O
SGOT	O
,	O
alkaline	O
phosphatase	O
,	O
and	O
lactic	B-Chemical
acid	I-Chemical
dehydrogenase	O
values	O
.	O

We	O
concluded	O
that	O
this	O
patient	O
had	O
quinidine	B-Chemical
hepatotoxicity	B-Disease
and	O
believe	O
that	O
this	O
is	O
the	O
first	O
case	O
reported	O
with	O
liver	O
biopsy	O
documentation	O
.	O

This	O
report	O
also	O
suggests	O
that	O
,	O
even	O
after	O
long	O
-	O
term	O
administration	O
,	O
the	O
hepatic	B-Disease
toxicity	I-Disease
is	O
reversible	O
.	O

Arterial	O
thromboembolism	B-Disease
in	O
patients	O
receiving	O
systemic	O
heparin	B-Chemical
therapy	O
:	O
a	O
complication	O
associated	O
with	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
.	O

Arterial	O
thromboembolism	B-Disease
is	O
a	O
recognized	O
complication	O
of	O
systemic	O
heparin	B-Chemical
therapy	O
.	O

Characteristic	O
of	O
the	O
entity	O
is	O
arterial	B-Disease
occlusion	I-Disease
by	O
platelet	O
-	O
fibrin	O
thrombi	B-Disease
with	O
distal	O
ischemia	B-Disease
occurring	O
four	O
to	O
twenty	O
days	O
after	O
the	O
initiation	O
of	O
heparin	B-Chemical
therapy	O
,	O
preceded	O
by	O
profound	O
thrombocytopenia	B-Disease
with	O
platelet	O
counts	O
in	O
the	O
range	O
of	O
30	O
,	O
000	O
to	O
40	O
,	O
000	O
per	O
cubic	O
millimeter	O
.	O

The	O
clinically	O
apparent	O
occlusion	O
may	O
be	O
preceded	O
by	O
gastrointestinal	B-Disease
and	I-Disease
musculoskeletal	I-Disease
symptoms	I-Disease
that	O
appear	O
to	O
be	O
ischemic	B-Disease
in	O
origin	O
,	O
and	O
might	O
serve	O
to	O
warn	O
the	O
clinician	O
of	O
these	O
complications	O
.	O

Previous	O
reports	O
of	O
these	O
phenomena	O
as	O
well	O
as	O
recent	O
studies	O
of	O
the	O
effect	O
of	O
heparin	B-Chemical
are	O
reviewed	O
.	O

The	O
common	O
factor	O
relating	O
thromboembolism	B-Disease
and	O
thrombocytopenia	B-Disease
is	O
heparin	B-Chemical
-	O
induced	O
platelet	B-Disease
aggregation	I-Disease
.	O

Appropriate	O
treatment	O
consists	O
of	O
discontinuation	O
of	O
heparin	B-Chemical
,	O
and	O
anticoagulation	O
with	O
sodium	B-Chemical
warfarin	I-Chemical
if	O
necessary	O
.	O

Vascular	O
procedures	O
are	O
performed	O
as	O
indicated	O
.	O

Pharmacology	O
of	O
GYKI	B-Chemical
-	I-Chemical
41	I-Chemical
099	I-Chemical
(	O
chlorpropanol	B-Chemical
,	O
Tobanum	B-Chemical
)	O
a	O
new	O
potent	O
beta	O
-	O
adrenergic	O
antagonist	O
.	O

The	O
compound	O
GYKI	B-Chemical
-	I-Chemical
41	I-Chemical
099	I-Chemical
,	O
as	O
a	O
beta	O
-	O
adrenergic	O
antagonist	O
,	O
is	O
3	O
-	O
8	O
times	O
more	O
potent	O
than	O
propranolol	B-Chemical
in	O
vitro	O
and	O
in	O
vivo	O
.	O

Its	O
antiarrhythmic	O
effectiveness	O
surpasses	O
that	O
of	O
propranolol	B-Chemical
and	O
pindolol	B-Chemical
inhibiting	O
the	O
ouabain	B-Chemical
arrhythmia	B-Disease
in	O
dogs	O
and	O
cats	O
.	O

GYKI	B-Chemical
-	I-Chemical
41	I-Chemical
900	I-Chemical
has	O
a	O
negligible	O
cardiodepressant	O
activity	O
;	O
it	O
is	O
not	O
cardioselective	O
.	O

The	O
compound	O
shows	O
a	O
rapid	O
and	O
long	O
lasting	O
effect	O
.	O

There	O
was	O
a	O
prolonged	O
elimination	O
of	O
the	O
radioactivity	O
after	O
the	O
injection	O
of	O
14C	B-Chemical
-	I-Chemical
41	I-Chemical
099	I-Chemical
to	O
rats	O
and	O
dogs	O
.	O

The	O
half	O
life	O
of	O
the	O
unlabeled	O
substance	O
in	O
humans	O
was	O
more	O
than	O
10	O
hours	O
.	O

Adverse	O
reactions	O
to	O
bendrofluazide	B-Chemical
and	O
propranolol	B-Chemical
for	O
the	O
treatment	O
of	O
mild	O
hypertension	B-Disease
.	O

Report	O
of	O
Medical	O
Research	O
Council	O
Working	O
Party	O
on	O
Mild	O
to	O
Moderate	O
Hypertension	B-Disease
.	O

Participants	O
in	O
the	O
Medical	O
Research	O
Council	O
treatment	O
trial	O
for	O
mild	O
hypertension	B-Disease
are	O
randomly	O
allocated	O
to	O
one	O
of	O
four	O
treatment	O
groups	O
:	O
bendrofluazide	B-Chemical
,	O
propranolol	B-Chemical
,	O
or	O
a	O
placebo	O
for	O
either	O
of	O
these	O
drugs	O
.	O

The	O
trial	O
is	O
single	O
-	O
blind	O
.	O

23	O
582	O
patient	O
-	O
years	O
of	O
observation	O
have	O
been	O
completed	O
so	O
far	O
,	O
10	O
684	O
on	O
active	O
drugs	O
and	O
12	O
898	O
on	O
placebos	O
.	O

The	O
results	O
show	O
an	O
association	O
between	O
bendrofluazide	B-Chemical
treatment	O
and	O
impotence	B-Disease
,	O
and	O
impotence	B-Disease
also	O
occurred	O
more	O
frequently	O
in	O
patients	O
taking	O
propranolol	B-Chemical
than	O
in	O
those	O
taking	O
placebos	O
.	O

Other	O
adverse	O
reactions	O
significantly	O
linked	O
with	O
active	O
drugs	O
include	O
impaired	B-Disease
glucose	I-Disease
tolerance	I-Disease
in	O
men	O
and	O
women	O
and	O
gout	B-Disease
in	O
men	O
,	O
associated	O
with	O
bendrofluazide	B-Chemical
treatment	O
,	O
and	O
Raynaud	B-Disease
'	I-Disease
s	I-Disease
phenomenon	I-Disease
and	O
dyspnoea	B-Disease
in	O
men	O
and	O
women	O
taking	O
propranolol	B-Chemical
.	O

No	O
corneal	B-Disease
disease	I-Disease
is	O
known	O
to	O
have	O
occurred	O
in	O
the	O
propranolol	B-Chemical
group	O
.	O

Mean	O
serum	O
potassium	B-Chemical
level	O
fell	O
,	O
and	O
urea	B-Chemical
and	O
uric	B-Chemical
acid	I-Chemical
levels	O
rose	O
,	O
in	O
men	O
and	O
women	O
taking	O
bendrofluazide	B-Chemical
.	O

In	O
the	O
propranolol	B-Chemical
group	O
,	O
serum	O
potassium	B-Chemical
and	O
uric	B-Chemical
acid	I-Chemical
levels	O
rose	O
in	O
both	O
sexes	O
,	O
but	O
the	O
urea	B-Chemical
level	O
rose	O
significantly	O
in	O
women	O
only	O
.	O

Serotonergic	O
drugs	O
,	O
benzodiazepines	B-Chemical
and	O
baclofen	B-Chemical
block	O
muscimol	B-Chemical
-	O
induced	O
myoclonic	B-Disease
jerks	I-Disease
in	O
a	O
strain	O
of	O
mice	O
.	O

In	O
male	O
Swiss	O
mice	O
,	O
muscimol	B-Chemical
produced	O
myoclonic	B-Disease
jerks	I-Disease
.	O

A	O
3	O
mg	O
/	O
kg	O
(	O
i	O
.	O
p	O
.	O
)	O
dose	O
induced	O
this	O
response	O
in	O
all	O
of	O
the	O
mice	O
tested	O
and	O
the	O
peak	O
response	O
of	O
73	O
jerks	O
per	O
min	O
was	O
observed	O
between	O
27	O
and	O
45	O
min	O
.	O

Increasing	O
the	O
brain	O
serotonin	B-Chemical
levels	O
by	O
the	O
administration	O
of	O
5	B-Chemical
-	I-Chemical
hydroxytryptophan	I-Chemical
(	O
80	O
-	O
160	O
mg	O
/	O
kg	O
)	O
in	O
combination	O
with	O
a	O
peripheral	O
decarboxylase	O
inhibitor	O
resulted	O
in	O
an	O
inhibition	O
of	O
the	O
muscimol	B-Chemical
effect	O
.	O

However	O
,	O
in	O
a	O
similar	O
experiment	O
l	B-Chemical
-	I-Chemical
dopa	I-Chemical
(	O
80	O
-	O
160	O
mg	O
/	O
kg	O
)	O
was	O
without	O
effect	O
.	O

In	O
doses	O
of	O
3	O
-	O
10	O
mg	O
/	O
kg	O
,	O
the	O
serotonin	B-Chemical
receptor	O
agonist	O
MK	B-Chemical
-	I-Chemical
212	I-Chemical
caused	O
a	O
dose	O
-	O
dependent	O
blockade	O
of	O
the	O
response	O
of	O
muscimol	B-Chemical
.	O

Of	O
the	O
benzodiazepines	B-Chemical
,	O
clonazepam	B-Chemical
(	O
0	O
.	O
1	O
-	O
0	O
.	O
3	O
mg	O
/	O
kg	O
)	O
was	O
found	O
to	O
be	O
several	O
fold	O
more	O
potent	O
than	O
diazepam	B-Chemical
(	O
0	O
.	O
3	O
-	O
3	O
mg	O
/	O
kg	O
)	O
in	O
blocking	O
the	O
myoclonic	B-Disease
jerks	I-Disease
.	O

While	O
(	O
-	O
)	O
-	O
baclofen	B-Chemical
(	O
1	O
-	O
3	O
mg	O
/	O
kg	O
)	O
proved	O
to	O
be	O
an	O
effective	O
antagonist	O
of	O
muscimol	B-Chemical
,	O
its	O
(	O
+	O
)	O
-	O
isomer	O
(	O
5	O
-	O
20	O
mg	O
/	O
kg	O
)	O
lacked	O
this	O
property	O
.	O

Considering	O
the	O
fact	O
that	O
5	B-Chemical
-	I-Chemical
HTP	I-Chemical
and	O
the	O
benzodiazepines	B-Chemical
have	O
been	O
found	O
to	O
be	O
beneficial	O
in	O
the	O
management	O
of	O
clinical	O
myoclonus	B-Disease
,	O
the	O
muscimol	B-Chemical
-	O
induced	O
myoclonus	B-Disease
seems	O
to	O
be	O
a	O
satisfactory	O
animal	O
model	O
that	O
may	O
prove	O
useful	O
for	O
the	O
development	O
of	O
new	O
drug	O
treatments	O
for	O
this	O
condition	O
.	O

Our	O
present	O
study	O
indicated	O
the	O
possible	O
value	O
of	O
MK	B-Chemical
-	I-Chemical
212	I-Chemical
and	O
(	O
-	O
)	O
-	O
baclofen	B-Chemical
in	O
the	O
management	O
of	O
clinical	O
myoclonus	B-Disease
.	O

Adverse	O
interaction	O
between	O
beta	B-Chemical
-	I-Chemical
adrenergic	I-Chemical
blocking	I-Chemical
drugs	I-Chemical
and	O
verapamil	B-Chemical
-	O
-	O
report	O
of	O
three	O
cases	O
.	O

Three	O
patients	O
with	O
ischaemic	B-Disease
heart	I-Disease
disease	I-Disease
developed	O
profound	O
cardiac	B-Disease
failure	I-Disease
,	O
hypotension	B-Disease
and	O
bradycardia	B-Disease
during	O
combined	O
therapy	O
with	O
verapamil	B-Chemical
and	O
beta	B-Chemical
-	I-Chemical
adrenergic	I-Chemical
blocking	I-Chemical
drugs	I-Chemical
.	O

This	O
clinical	O
picture	O
resolved	O
completely	O
with	O
cessation	O
of	O
the	O
combined	O
therapy	O
.	O

Baseline	O
left	O
ventricular	O
function	O
,	O
assessed	O
by	O
cardiac	O
catheterisation	O
or	O
nuclear	O
angiography	O
,	O
was	O
normal	O
in	O
two	O
patients	O
and	O
only	O
mildly	O
reduced	O
in	O
the	O
other	O
.	O

Simultaneously	O
administration	O
of	O
beta	B-Chemical
-	I-Chemical
adrenergic	I-Chemical
blocking	I-Chemical
drugs	I-Chemical
and	O
verapamil	B-Chemical
may	O
result	O
in	O
profound	O
adverse	O
interactions	O
and	O
should	O
only	O
be	O
administered	O
with	O
great	O
caution	O
.	O

Comparison	O
of	O
the	O
effectiveness	O
of	O
ranitidine	B-Chemical
and	O
cimetidine	B-Chemical
in	O
inhibiting	O
acid	O
secretion	O
in	O
patients	O
with	O
gastric	O
hypersecretory	O
states	O
.	O

The	O
H2	O
-	O
histamine	B-Chemical
receptor	O
antagonists	O
ranitidine	B-Chemical
and	O
cimetidine	B-Chemical
were	O
compared	O
for	O
their	O
abilities	O
to	O
control	O
gastric	O
acid	O
hypersecretion	O
on	O
a	O
short	O
-	O
and	O
long	O
-	O
term	O
basis	O
in	O
22	O
patients	O
with	O
gastric	O
acid	O
hypersecretory	O
states	O
.	O

Nineteen	O
patients	O
had	O
Zollinger	B-Disease
-	I-Disease
Ellison	I-Disease
syndrome	I-Disease
,	O
one	O
patient	O
had	O
systemic	B-Disease
mastocytosis	I-Disease
,	O
and	O
two	O
patients	O
had	O
idiopathic	O
hypersecretion	O
.	O

The	O
rates	O
of	O
onset	O
of	O
the	O
action	O
of	O
cimetidine	B-Chemical
and	O
ranitidine	B-Chemical
were	O
the	O
same	O
.	O

The	O
actions	O
of	O
both	O
drugs	O
were	O
increased	O
by	O
anticholinergic	O
agents	O
,	O
and	O
there	O
was	O
a	O
close	O
correlation	O
between	O
the	O
daily	O
maintenance	O
dose	O
of	O
each	O
drug	O
needed	O
to	O
control	O
acid	O
secretion	O
.	O

However	O
,	O
ranitidine	B-Chemical
was	O
threefold	O
more	O
potent	O
than	O
cimetidine	B-Chemical
both	O
in	O
acute	O
inhibition	O
studies	O
and	O
in	O
the	O
median	O
maintenance	O
dose	O
needed	O
(	O
1	O
.	O
2	O
g	O
per	O
day	O
for	O
ranitidine	B-Chemical
and	O
3	O
.	O
6	O
g	O
per	O
day	O
for	O
cimetidine	B-Chemical
)	O
.	O

Sixty	O
percent	O
of	O
the	O
males	O
developed	O
breast	O
changes	O
or	O
impotence	B-Disease
while	O
taking	O
cimetidine	B-Chemical
and	O
in	O
all	O
cases	O
these	O
changes	O
disappeared	O
when	O
cimetidine	B-Chemical
was	O
replaced	O
by	O
ranitidine	B-Chemical
.	O

Treatment	O
with	O
high	O
doses	O
of	O
cimetidine	B-Chemical
(	O
one	O
to	O
60	O
months	O
;	O
median	O
,	O
11	O
months	O
)	O
or	O
ranitidine	B-Chemical
(	O
two	O
to	O
31	O
months	O
;	O
median	O
,	O
14	O
months	O
)	O
was	O
not	O
associated	O
with	O
hepatic	B-Disease
or	I-Disease
hematologic	I-Disease
toxicity	I-Disease
or	O
alterations	O
of	O
serum	O
gastrin	O
concentrations	O
,	O
but	O
ranitidine	B-Chemical
therapy	O
was	O
associated	O
with	O
a	O
significantly	O
lower	O
serum	O
creatinine	B-Chemical
level	O
than	O
seen	O
with	O
cimetidine	B-Chemical
therapy	O
.	O

The	O
results	O
show	O
that	O
both	O
drugs	O
can	O
adequately	O
inhibit	O
acid	O
secretion	O
in	O
patients	O
with	O
gastric	O
hypersecretory	O
states	O
.	O

Both	O
are	O
safe	O
at	O
high	O
doses	O
,	O
but	O
ranitidine	B-Chemical
is	O
threefold	O
more	O
potent	O
and	O
does	O
not	O
cause	O
the	O
antiandrogen	O
side	O
effects	O
frequently	O
seen	O
with	O
high	O
doses	O
of	O
cimetidine	B-Chemical
.	O

Epileptogenic	O
properties	O
of	O
enflurane	B-Chemical
and	O
their	O
clinical	O
interpretation	O
.	O

Three	O
cases	O
of	O
EEG	O
changes	O
induced	O
by	O
single	O
exposure	O
to	O
enflurane	B-Chemical
anesthesia	O
are	O
reported	O
.	O

In	O
one	O
patient	O
,	O
enflurane	B-Chemical
administered	O
during	O
a	O
donor	O
nephrectomy	O
resulted	O
in	O
unexpected	O
partial	O
motor	O
seizures	B-Disease
.	O

Until	O
the	O
cause	O
of	O
the	O
seizures	B-Disease
was	O
correctly	O
identified	O
,	O
the	O
patient	O
was	O
inappropriately	O
treated	O
with	O
anticonvulsants	O
.	O

Two	O
other	O
patients	O
suffered	O
from	O
partial	O
,	O
complex	O
and	O
generalized	O
seizures	B-Disease
uncontrolled	O
by	O
medication	O
.	O

Epileptic	B-Disease
foci	O
delineated	O
and	O
activated	O
by	O
enflurane	B-Chemical
were	O
surgically	O
ablated	O
and	O
the	O
patients	O
are	O
now	O
seizure	B-Disease
-	O
free	O
.	O

Previous	O
exposures	O
to	O
enflurane	B-Chemical
have	O
to	O
be	O
disclosed	O
to	O
avoid	O
mistakes	O
in	O
clinical	O
interpretation	O
of	O
the	O
EEG	O
.	O

On	O
the	O
other	O
hand	O
,	O
enflurane	B-Chemical
may	O
prove	O
to	O
be	O
a	O
safe	O
fast	O
acting	O
activator	O
of	O
epileptic	B-Disease
foci	O
during	O
corticography	O
or	O
depth	O
electrode	O
intraoperative	O
recordings	O
.	O

Development	O
of	O
isoproterenol	B-Chemical
-	O
induced	O
cardiac	B-Disease
hypertrophy	I-Disease
.	O

The	O
development	O
of	O
cardiac	B-Disease
hypertrophy	I-Disease
was	O
studied	O
in	O
adult	O
female	O
Wistar	O
rats	O
following	O
daily	O
subcutaneous	O
injections	O
of	O
isoproterenol	B-Chemical
(	O
ISO	B-Chemical
)	O
(	O
0	O
.	O
3	O
mg	O
/	O
kg	O
body	O
weight	O
)	O
.	O

A	O
time	O
course	O
was	O
established	O
for	O
the	O
change	O
in	O
tissue	O
mass	O
,	O
RNA	O
and	O
DNA	O
content	O
,	O
as	O
well	O
as	O
hydroxyproline	B-Chemical
content	O
.	O

Heart	O
weight	O
increased	O
44	O
%	O
after	O
8	O
days	O
of	O
treatment	O
with	O
a	O
half	O
time	O
of	O
3	O
.	O
4	O
days	O
.	O

Ventricular	O
RNA	O
content	O
was	O
elevated	O
26	O
%	O
after	O
24	O
h	O
of	O
a	O
single	O
injection	O
and	O
reached	O
a	O
maximal	O
level	O
following	O
8	O
days	O
of	O
therapy	O
.	O

The	O
half	O
time	O
for	O
RNA	O
accumulation	O
was	O
2	O
.	O
0	O
days	O
.	O

The	O
total	O
content	O
of	O
hydroxyproline	B-Chemical
remained	O
stable	O
during	O
the	O
first	O
2	O
days	O
of	O
treatment	O
but	O
increased	O
46	O
%	O
after	O
4	O
days	O
of	O
therapy	O
.	O

Ventricular	O
DNA	O
content	O
was	O
unchanged	O
during	O
the	O
early	O
stage	O
(	O
1	O
-	O
4	O
days	O
)	O
of	O
hypertrophic	B-Disease
growth	O
but	O
increased	O
to	O
a	O
new	O
steady	O
-	O
state	O
level	O
19	O
%	O
above	O
the	O
controls	O
after	O
8	O
days	O
of	O
treatment	O
.	O

Intraventricular	O
pressures	O
and	O
coronary	O
flow	O
measures	O
were	O
similar	O
for	O
control	O
and	O
experimental	O
animals	O
following	O
4	O
days	O
of	O
developed	O
hypertrophy	B-Disease
.	O

However	O
,	O
dP	O
/	O
dt	O
in	O
the	O
ISO	B-Chemical
-	O
treated	O
hearts	O
was	O
slightly	O
but	O
significantly	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
elevated	O
.	O

These	O
data	O
indicate	O
that	O
the	O
adaptive	O
response	O
to	O
ISO	B-Chemical
shows	O
an	O
early	O
hypertrophic	B-Disease
phase	O
(	O
1	O
-	O
4	O
days	O
)	O
characterized	O
by	O
a	O
substantial	O
increase	O
in	O
RNA	O
content	O
and	O
cardiac	O
mass	O
in	O
the	O
absence	O
of	O
changes	O
in	O
DNA	O
.	O

However	O
,	O
prolonged	O
stimulation	O
(	O
8	O
-	O
12	O
days	O
)	O
appears	O
to	O
represent	O
a	O
complex	O
integration	O
of	O
both	O
cellular	O
hypertrophy	B-Disease
and	O
hyperplasia	B-Disease
within	O
the	O
heart	O
.	O

Multiple	O
side	O
effects	O
of	O
penicillamine	B-Chemical
therapy	O
in	O
one	O
patient	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
.	O

Skin	B-Disease
rashes	I-Disease
,	O
proteinuria	B-Disease
,	O
systemic	B-Disease
lupus	I-Disease
erythematosus	I-Disease
,	O
polymyositis	B-Disease
and	O
myasthenia	B-Disease
gravis	I-Disease
have	O
all	O
been	O
recorded	O
as	O
complications	O
of	O
penicillamine	B-Chemical
therapy	O
in	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
.	O

A	O
patient	O
who	O
had	O
developed	O
all	O
5	O
is	O
now	O
described	O
.	O

The	O
skin	B-Disease
lesion	I-Disease
resembled	O
elastosis	B-Disease
perforans	I-Disease
serpiginosa	I-Disease
,	O
which	O
has	O
been	O
reported	O
as	O
a	O
rare	O
side	O
effect	O
in	O
patients	O
with	O
Wilson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
but	O
not	O
in	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
treated	O
with	O
penicillamine	B-Chemical
.	O

Obsolete	O
but	O
dangerous	O
antacid	O
preparations	O
.	O

One	O
case	O
of	O
acute	O
hypercalcaemia	B-Disease
and	O
two	O
of	O
recurrent	O
nephrolithiasis	B-Disease
are	O
reported	O
in	O
patients	O
who	O
had	O
regularly	O
consumed	O
large	O
amounts	O
of	O
calcium	B-Chemical
carbon	I-Chemical
-	I-Chemical
ate	I-Chemical
-	O
sodium	B-Chemical
bicarbonate	I-Chemical
powders	O
for	O
more	O
than	O
20	O
years	O
.	O

The	O
powders	O
had	O
been	O
obtained	O
from	O
pharmacists	O
unknown	O
to	O
the	O
patients	O
'	O
medical	O
practitioners	O
.	O

It	O
is	O
suggested	O
that	O
these	O
preparations	O
were	O
responsible	O
for	O
the	O
patient	O
'	O
s	O
problems	O
,	O
and	O
that	O
such	O
powders	O
should	O
no	O
longer	O
be	O
freely	O
obtainable	O
.	O

Doxorubicin	B-Chemical
cardiomyopathy	B-Disease
in	O
children	O
with	O
left	O
-	O
sided	O
Wilms	B-Disease
tumor	I-Disease
.	O

Two	O
children	O
with	O
Wilms	B-Disease
tumor	I-Disease
of	O
the	O
left	O
kidney	O
experienced	O
severe	O
anthracycline	B-Chemical
cardiomyopathy	B-Disease
after	O
irradiation	O
to	O
the	O
tumor	B-Disease
bed	O
and	O
conventional	O
dosage	O
of	O
doxorubicin	B-Chemical
.	O

The	O
cardiomyopathy	B-Disease
is	O
attributed	O
1	O
)	O
to	O
the	O
fact	O
that	O
radiation	O
fields	O
for	O
left	O
Wilms	B-Disease
tumor	I-Disease
include	O
the	O
lower	O
portion	O
of	O
the	O
heart	O
and	O
2	O
)	O
to	O
the	O
interaction	O
of	O
doxorubicin	B-Chemical
and	O
irradiation	O
on	O
cardiac	O
muscle	O
.	O

It	O
is	O
recommended	O
that	O
doxorubicin	B-Chemical
dosage	O
be	O
sharply	O
restricted	O
in	O
children	O
with	O
Wilms	B-Disease
tumor	I-Disease
of	O
the	O
left	O
kidney	O
who	O
receive	O
postoperative	O
irradiation	O
.	O

Effects	O
of	O
calcitonin	O
on	O
rat	O
extrapyramidal	O
motor	O
system	O
:	O
behavioral	O
and	O
biochemical	O
data	O
.	O

The	O
effects	O
of	O
i	O
.	O
v	O
.	O
c	O
.	O
injection	O
of	O
human	O
and	O
salmon	O
calcitonin	O
on	O
biochemical	O
and	O
behavioral	O
parameters	O
related	O
to	O
the	O
extrapyramidal	O
motor	O
system	O
,	O
were	O
investigated	O
in	O
male	O
rats	O
.	O

Calcitonin	O
injection	O
resulted	O
in	O
a	O
potentiation	O
of	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
and	O
a	O
partial	O
prevention	O
of	O
apomorphine	B-Chemical
-	O
induced	O
hyperactivity	B-Disease
.	O

Moreover	O
calcitonin	O
induced	O
a	O
significant	O
decrease	O
in	O
nigral	O
GAD	O
activity	O
but	O
no	O
change	O
in	O
striatal	O
DA	B-Chemical
and	O
DOPAC	B-Chemical
concentration	O
or	O
GAD	O
activity	O
.	O

The	O
results	O
are	O
discussed	O
in	O
view	O
of	O
a	O
primary	O
action	O
of	O
calcitonin	O
on	O
the	O
striatonigral	O
GABAergic	O
pathway	O
mediating	O
the	O
DA	B-Chemical
-	O
related	O
behavioral	O
messages	O
of	O
striatal	O
origin	O
.	O

Naloxazone	B-Chemical
pretreatment	O
modifies	O
cardiorespiratory	O
,	O
temperature	O
,	O
and	O
behavioral	O
effects	O
of	O
morphine	B-Chemical
.	O

Behavioral	O
and	O
cardiorespiratory	O
responses	O
to	O
a	O
lethal	O
dose	O
of	O
morphine	B-Chemical
were	O
evaluated	O
in	O
rats	O
pretreated	O
with	O
saline	O
or	O
naloxazone	B-Chemical
,	O
an	O
antagonist	O
of	O
high	O
-	O
affinity	O
mu	O
1	O
opioid	O
receptors	O
.	O

Pretreatment	O
with	O
naloxazone	B-Chemical
significantly	O
blocked	O
morphine	B-Chemical
analgesia	B-Disease
,	O
catalepsy	B-Disease
and	O
hypothermia	B-Disease
at	O
a	O
dose	O
which	O
completely	O
eliminated	O
high	O
-	O
affinity	O
binding	O
in	O
brain	O
membranes	O
.	O

Moreover	O
,	O
naloxazone	B-Chemical
significantly	O
attenuated	O
the	O
morphine	B-Chemical
-	O
induced	O
hypotension	B-Disease
and	O
respiratory	B-Disease
depression	I-Disease
,	O
whereas	O
morphine	B-Chemical
-	O
induced	O
bradycardia	B-Disease
was	O
less	O
affected	O
.	O

Results	O
indicate	O
that	O
subpopulations	O
of	O
mu	O
receptors	O
may	O
mediate	O
selective	O
behavioral	O
and	O
cardiorespiratory	O
responses	O
to	O
morphine	B-Chemical
.	O

Modification	O
of	O
drug	O
action	O
by	O
hyperammonemia	B-Disease
.	O

Pretreatment	O
with	O
ammonium	B-Chemical
acetate	I-Chemical
(	O
NH4Ac	B-Chemical
)	O
(	O
6	O
mmol	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
approximately	O
doubled	O
the	O
time	O
morphine	B-Chemical
-	O
treated	O
mice	O
remained	O
on	O
a	O
hot	O
surface	O
and	O
similarly	O
increased	O
muscular	O
incoordination	B-Disease
by	O
diazepam	B-Chemical
,	O
but	O
NH4Ac	B-Chemical
treatment	O
alone	O
had	O
no	O
effect	O
.	O

Thus	O
,	O
hyperammonemia	B-Disease
is	O
capable	O
of	O
altering	O
drug	O
action	O
and	O
must	O
be	O
considered	O
along	O
with	O
impaired	O
drug	O
metabolism	O
in	O
enhanced	O
drug	O
responses	O
associated	O
with	O
liver	B-Disease
disease	I-Disease
.	O

Experiments	O
in	O
vitro	O
showed	O
that	O
acetylcholine	B-Chemical
-	O
induced	O
catecholamine	B-Chemical
release	O
from	O
bovine	O
adrenal	O
medulla	O
is	O
depressed	O
as	O
much	O
as	O
50	O
%	O
by	O
0	O
.	O
3	O
mM	O
NH4Ac	B-Chemical
and	O
KCl	B-Chemical
-	O
induced	O
contractions	O
of	O
guinea	O
-	O
pig	O
ileum	O
were	O
inhibited	O
20	O
%	O
by	O
5	O
mM	O
NH4Ac	B-Chemical
.	O

Addition	O
of	O
excess	O
calcium	B-Chemical
reversed	O
the	O
depression	B-Disease
in	O
both	O
tissues	O
,	O
but	O
calcium	B-Chemical
-	O
independent	O
catecholamine	B-Chemical
release	O
by	O
acetaldehyde	B-Chemical
was	O
not	O
blocked	O
by	O
NH4Ac	B-Chemical
.	O

These	O
results	O
suggested	O
that	O
ammonia	B-Chemical
blocks	O
calcium	B-Chemical
channels	O
.	O

Parallels	O
in	O
the	O
actions	O
of	O
NH4Ac	B-Chemical
and	O
the	O
calcium	B-Chemical
channel	O
blocker	O
verapamil	B-Chemical
support	O
this	O
concept	O
.	O

Both	O
verapamil	B-Chemical
(	O
10	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
and	O
NH4Ac	B-Chemical
pretreatment	O
enhanced	O
morphine	B-Chemical
analgesia	B-Disease
-	O
and	O
diazepam	B-Chemical
-	O
induced	O
muscular	O
incoordination	B-Disease
and	O
antagonized	O
amphetamine	B-Chemical
-	O
induced	O
motor	O
activity	O
,	O
and	O
neither	O
verapamil	B-Chemical
nor	O
NH4Ac	B-Chemical
affected	O
the	O
convulsant	O
action	O
of	O
metrazol	B-Chemical
.	O

The	O
data	O
suggest	O
that	O
hyperammonemia	B-Disease
exerts	O
a	O
calcium	B-Chemical
channel	O
blocking	O
action	O
which	O
enhances	O
the	O
effects	O
of	O
central	O
nervous	O
system	O
depressants	O
and	O
certain	O
opioid	O
analgesics	O
.	O

Levodopa	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
and	O
thalamotomy	O
.	O

Levodopa	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
of	O
the	O
limbs	O
in	O
thirteen	O
cases	O
of	O
Parkinsonism	B-Disease
,	O
which	O
was	O
choreic	O
,	O
ballistic	O
or	O
dystonic	B-Disease
in	O
type	O
,	O
was	O
alleviated	O
almost	O
completely	O
by	O
stereotaxic	O
surgery	O
using	O
a	O
microelectrode	O
technique	O
for	O
the	O
ventralis	O
oralis	O
anterior	O
and	O
posterior	O
nuclei	O
of	O
the	O
thalamus	O
,	O
but	O
much	O
less	O
by	O
the	O
ventralis	O
intermedius	O
nucleus	O
.	O

Control	O
of	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
by	O
thalamic	B-Disease
lesions	I-Disease
in	O
the	O
course	O
of	O
routine	O
treatment	O
of	O
Parkinsonism	B-Disease
is	O
discussed	O
.	O

Treatment	O
of	O
ifosfamide	B-Chemical
-	O
induced	O
urothelial	B-Disease
toxicity	I-Disease
by	O
oral	O
administration	O
of	O
sodium	B-Chemical
2	I-Chemical
-	I-Chemical
mercaptoethane	I-Chemical
sulphonate	I-Chemical
(	O
MESNA	B-Chemical
)	O
to	O
patients	O
with	O
inoperable	O
lung	B-Disease
cancer	I-Disease
.	O

The	O
protective	O
effect	O
of	O
oral	O
administration	O
of	O
the	O
thiol	B-Chemical
compound	O
sodium	B-Chemical
2	I-Chemical
-	I-Chemical
mercaptoethane	I-Chemical
sulphonate	I-Chemical
(	O
MESNA	B-Chemical
)	O
against	O
urothelial	B-Disease
toxicity	I-Disease
induced	O
by	O
ifosfamide	B-Chemical
(	O
IF	B-Chemical
)	O
was	O
tested	O
in	O
a	O
group	O
of	O
45	O
patients	O
with	O
inoperable	O
lung	B-Disease
cancer	I-Disease
under	O
treatment	O
with	O
IF	B-Chemical
(	O
2250	O
mg	O
/	O
m2	O
on	O
days	O
2	O
-	O
5	O
)	O
as	O
part	O
of	O
a	O
polychemotherapy	O
regimen	O
repeated	O
in	O
a	O
4	O
-	O
week	O
cycle	O
.	O

MESNA	B-Chemical
was	O
given	O
orally	O
on	O
the	O
days	O
of	O
treatment	O
with	O
IF	B-Chemical
in	O
3	O
doses	O
of	O
840	O
mg	O
/	O
m2	O
,	O
each	O
administered	O
at	O
0	O
hr	O
(	O
=	O
injection	O
of	O
IF	B-Chemical
)	O
,	O
4	O
hr	O
and	O
8	O
hr	O
p	O
.	O
i	O
.	O

Out	O
of	O
a	O
total	O
of	O
88	O
courses	O
of	O
this	O
treatment	O
we	O
observed	O
10	O
episodes	O
of	O
asymptomatic	O
microscopic	O
haematuria	B-Disease
and	O
no	O
episodes	O
of	O
gross	O
haematuria	B-Disease
.	O

In	O
this	O
group	O
of	O
45	O
patients	O
under	O
protection	O
with	O
MESNA	B-Chemical
there	O
were	O
5	O
complete	O
remissions	O
and	O
9	O
partial	O
remissions	O
(	O
total	O
31	O
%	O
)	O
.	O

A	O
further	O
group	O
of	O
25	O
patients	O
under	O
polychemotherapy	O
with	O
IF	B-Chemical
were	O
treated	O
by	O
conventional	O
prophylactic	O
measures	O
(	O
raised	O
fluid	O
intake	O
and	O
forced	O
diuresis	O
)	O
.	O

In	O
this	O
group	O
there	O
were	O
1	O
complete	O
and	O
5	O
partial	O
remissions	O
(	O
total	O
24	O
%	O
)	O
,	O
but	O
nearly	O
all	O
patients	O
developed	O
either	O
gross	O
haematuria	B-Disease
and	O
/	O
or	O
symptoms	O
of	O
bladder	B-Disease
irritation	I-Disease
(	O
cystitis	B-Disease
and	O
pollakisuria	B-Disease
)	O
.	O

There	O
were	O
no	O
appreciable	O
differences	O
between	O
the	O
MESNA	B-Chemical
series	O
and	O
the	O
conventional	O
prophylaxis	O
series	O
with	O
respect	O
to	O
either	O
haematological	O
or	O
systemic	O
toxicity	B-Disease
of	O
the	O
cytostatic	O
treatment	O
.	O

Our	O
results	O
support	O
the	O
view	O
that	O
MESNA	B-Chemical
,	O
given	O
orally	O
in	O
conjunction	O
with	O
combined	O
cytostatic	O
regimens	O
which	O
include	O
IF	B-Chemical
,	O
simplifies	O
the	O
treatment	O
and	O
provides	O
optimum	O
protection	O
for	O
the	O
urinary	O
epithelium	O
.	O

Protection	O
with	O
oral	O
MESNA	B-Chemical
is	O
particularly	O
suitable	O
for	O
outpatients	O
.	O

Myoclonic	B-Disease
,	I-Disease
atonic	I-Disease
,	I-Disease
and	I-Disease
absence	I-Disease
seizures	I-Disease
following	O
institution	O
of	O
carbamazepine	B-Chemical
therapy	O
in	O
children	O
.	O

Five	O
children	O
,	O
aged	O
3	O
to	O
11	O
years	O
,	O
treated	O
with	O
carbamazepine	B-Chemical
for	O
epilepsy	B-Disease
,	O
had	O
an	O
acute	O
aberrant	O
reaction	O
characterized	O
by	O
the	O
onset	O
of	O
myoclonic	B-Disease
,	I-Disease
atypical	I-Disease
absence	I-Disease
and	I-Disease
/	I-Disease
or	I-Disease
atonic	I-Disease
(	I-Disease
minor	I-Disease
motor	I-Disease
)	I-Disease
seizures	I-Disease
within	O
a	O
few	O
days	O
.	O

When	O
the	O
carbamazepine	B-Chemical
was	O
discontinued	O
,	O
two	O
of	O
the	O
children	O
returned	O
to	O
their	O
former	O
state	O
very	O
quickly	O
,	O
two	O
had	O
the	O
minor	O
motor	O
seizures	B-Disease
resolve	O
in	O
3	O
and	O
6	O
months	O
,	O
and	O
one	O
had	O
the	O
seizures	B-Disease
persist	O
.	O

The	O
child	O
in	O
whom	O
the	O
seizures	B-Disease
persisted	O
was	O
later	O
found	O
to	O
have	O
ceroid	B-Disease
lipofuscinosis	I-Disease
.	O

The	O
other	O
children	O
are	O
doing	O
well	O
on	O
other	O
anticonvulsants	O
.	O

Effect	O
of	O
prostaglandin	B-Chemical
synthetase	O
inhibitors	O
on	O
experimentally	O
induced	O
convulsions	B-Disease
in	O
rats	O
.	O

To	O
investigate	O
the	O
relationship	O
of	O
prostaglandins	B-Chemical
(	O
PGs	B-Chemical
)	O
to	O
seizure	B-Disease
induction	O
,	O
the	O
effects	O
of	O
six	O
PG	O
synthetase	O
inhibitors	O
on	O
convulsions	B-Disease
induced	O
by	O
flurothyl	B-Chemical
,	O
picrotoxin	B-Chemical
,	O
pentetrazol	B-Chemical
(	O
PTZ	B-Chemical
)	O
,	O
electroshock	O
or	O
bicuculline	B-Chemical
were	O
evaluated	O
.	O

Ibuprofen	B-Chemical
,	O
sulindac	B-Chemical
,	O
mefenamic	B-Chemical
acid	I-Chemical
,	O
and	O
low	O
dose	O
meclofenamic	B-Chemical
acid	I-Chemical
increased	O
the	O
latency	O
-	O
to	O
-	O
onset	O
in	O
the	O
flurothyl	B-Chemical
and	O
/	O
or	O
PTZ	B-Chemical
models	O
;	O
the	O
electroshock	O
,	O
picrotoxin	B-Chemical
and	O
bicuculline	B-Chemical
models	O
were	O
not	O
significantly	O
affected	O
by	O
any	O
of	O
the	O
pretreatment	O
agents	O
.	O

These	O
results	O
suggest	O
that	O
PGs	B-Chemical
are	O
involved	O
in	O
the	O
mechanism	O
(	O
s	O
)	O
underlying	O
fluorthyl	B-Chemical
-	O
and	O
PTZ	B-Chemical
-	O
induced	O
convulsions	B-Disease
,	O
but	O
not	O
picrotoxin	B-Chemical
-	O
,	O
electroshock	O
-	O
,	O
or	O
bicuculline	B-Chemical
-	O
induced	O
convulsions	B-Disease
.	O

Acute	O
changes	O
of	O
blood	O
ammonia	B-Chemical
may	O
predict	O
short	O
-	O
term	O
adverse	O
effects	O
of	O
valproic	B-Chemical
acid	I-Chemical
.	O

Valproic	B-Chemical
acid	I-Chemical
(	O
VPA	B-Chemical
)	O
was	O
given	O
to	O
24	O
epileptic	B-Disease
patients	O
who	O
were	O
already	O
being	O
treated	O
with	O
other	O
antiepileptic	O
drugs	O
.	O

A	O
standardized	O
loading	O
dose	O
of	O
VPA	B-Chemical
was	O
administered	O
,	O
and	O
venous	O
blood	O
was	O
sampled	O
at	O
0	O
,	O
1	O
,	O
2	O
,	O
3	O
,	O
and	O
4	O
hours	O
.	O

Ammonia	B-Chemical
(	O
NH3	B-Chemical
)	O
was	O
higher	O
in	O
patients	O
who	O
,	O
during	O
continuous	O
therapy	O
,	O
complained	O
of	O
drowsiness	B-Disease
(	O
7	O
patients	O
)	O
than	O
in	O
those	O
who	O
were	O
symptom	O
-	O
free	O
(	O
17	O
patients	O
)	O
,	O
although	O
VPA	B-Chemical
plasma	O
levels	O
were	O
similar	O
in	O
both	O
groups	O
.	O

By	O
measuring	O
VPA	B-Chemical
-	O
induced	O
changes	O
of	O
blood	O
NH3	B-Chemical
content	O
,	O
it	O
may	O
be	O
possible	O
to	O
identify	O
patients	O
at	O
higher	O
risk	O
of	O
obtundation	O
when	O
VPA	B-Chemical
is	O
given	O
chronically	O
.	O

Effect	O
of	O
captopril	B-Chemical
on	O
pre	O
-	O
existing	O
and	O
aminonucleoside	B-Chemical
-	O
induced	O
proteinuria	B-Disease
in	O
spontaneously	O
hypertensive	B-Disease
rats	O
.	O

Proteinuria	B-Disease
is	O
a	O
side	O
effect	O
of	O
captopril	B-Chemical
treatment	O
in	O
hypertensive	B-Disease
patients	O
.	O

The	O
possibility	O
of	O
reproducing	O
the	O
same	O
renal	B-Disease
abnormality	I-Disease
with	O
captopril	B-Chemical
was	O
examined	O
in	O
SHR	O
.	O

Oral	O
administration	O
of	O
captopril	B-Chemical
at	O
100	O
mg	O
/	O
kg	O
for	O
14	O
days	O
failed	O
to	O
aggravate	O
proteinuria	B-Disease
pre	O
-	O
existing	O
in	O
SHR	O
.	O

Also	O
,	O
captopril	B-Chemical
treatment	O
failed	O
to	O
potentiate	O
or	O
facilitate	O
development	O
of	O
massive	O
proteinuria	B-Disease
invoked	O
by	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
in	O
SHR	O
.	O

Captopril	B-Chemical
had	O
little	O
or	O
no	O
demonstrable	O
effects	O
on	O
serum	O
electrolyte	O
concentrations	O
,	O
excretion	O
of	O
urine	O
,	O
sodium	B-Chemical
and	O
potassium	B-Chemical
,	O
endogenous	O
creatinine	B-Chemical
clearance	O
,	O
body	O
weight	O
,	O
and	O
food	O
and	O
water	O
consumption	O
.	O

However	O
,	O
ketone	B-Chemical
bodies	O
were	O
consistently	O
present	O
in	O
urine	O
and	O
several	O
lethalities	O
occurred	O
during	O
multiple	O
dosing	O
of	O
captopril	B-Chemical
in	O
SHR	O
.	O

Complete	O
heart	B-Disease
block	I-Disease
following	O
a	O
single	O
dose	O
of	O
trazodone	B-Chemical
.	O

Forty	O
minutes	O
after	O
receiving	O
a	O
single	O
starting	O
dose	O
of	O
trazodone	B-Chemical
,	O
a	O
patient	O
developed	O
complete	O
heart	B-Disease
block	I-Disease
.	O

The	O
case	O
illustrates	O
that	O
,	O
despite	O
the	O
results	O
of	O
earlier	O
studies	O
,	O
trazodone	B-Chemical
'	O
s	O
effect	O
on	O
cardiac	O
conduction	O
may	O
be	O
severe	O
in	O
individuals	O
at	O
risk	O
for	O
conduction	O
delay	O
.	O

Phenobarbital	B-Chemical
-	O
induced	O
dyskinesia	B-Disease
in	O
a	O
neurologically	B-Disease
-	I-Disease
impaired	I-Disease
child	O
.	O

A	O
2	O
-	O
year	O
-	O
old	O
child	O
with	O
known	O
neurologic	B-Disease
impairment	I-Disease
developed	O
a	O
dyskinesia	B-Disease
soon	O
after	O
starting	O
phenobarbital	B-Chemical
therapy	O
for	O
seizures	B-Disease
.	O

Known	O
causes	O
of	O
movement	B-Disease
disorders	I-Disease
were	O
eliminated	O
after	O
evaluation	O
.	O

On	O
repeat	O
challenge	O
with	O
phenobarbital	B-Chemical
,	O
the	O
dyskinesia	B-Disease
recurred	O
.	O

Phenobarbital	B-Chemical
should	O
be	O
added	O
to	O
the	O
list	O
of	O
anticonvulsant	O
drugs	O
that	O
can	O
cause	O
movement	B-Disease
disorders	I-Disease
.	O

Effects	O
of	O
amine	B-Chemical
pretreatment	O
on	O
ketamine	B-Chemical
catatonia	B-Disease
in	O
pinealectomized	O
or	O
hypophysectomized	O
animals	O
.	O

The	O
present	O
studies	O
were	O
designed	O
to	O
clarify	O
the	O
role	O
of	O
catecholamines	B-Chemical
and	O
pineal	O
idolamines	O
on	O
ketamine	B-Chemical
-	O
induced	O
catatonia	B-Disease
in	O
the	O
intact	O
,	O
pinealectomized	O
or	O
hypophysectomized	O
chick	O
and	O
rat	O
.	O

In	O
the	O
pinealectomized	O
chick	O
,	O
pretreatment	O
with	O
dopamine	B-Chemical
increased	O
the	O
duration	O
of	O
catatonia	B-Disease
(	O
DOC	O
)	O
after	O
ketamine	B-Chemical
,	O
but	O
pretreatment	O
with	O
norepinephrine	B-Chemical
did	O
not	O
.	O

The	O
pineal	O
indolamines	O
exhibited	O
mixed	O
actions	O
.	O

Serotonin	B-Chemical
and	O
N	B-Chemical
-	I-Chemical
acetyl	I-Chemical
serotonin	I-Chemical
which	O
augmented	O
ketamine	B-Chemical
DOC	O
,	O
did	O
not	O
do	O
so	O
in	O
the	O
absence	O
of	O
the	O
pineal	O
gland	O
,	O
whereas	O
melatonin	B-Chemical
potentiated	O
the	O
ketamine	B-Chemical
DOC	O
in	O
both	O
the	O
intact	O
and	O
pinealectomized	O
chick	O
.	O

Ketamine	B-Chemical
was	O
more	O
potent	O
in	O
the	O
hypophysectomized	O
chick	O
and	O
the	O
circadian	O
rhythm	O
noted	O
in	O
the	O
intact	O
chick	O
was	O
absent	O
;	O
furthermore	O
,	O
melatonin	B-Chemical
did	O
not	O
augment	O
the	O
ketamine	B-Chemical
DOC	O
whereas	O
dopamine	B-Chemical
continued	O
to	O
do	O
so	O
.	O

This	O
study	O
did	O
not	O
demonstrate	O
a	O
species	O
difference	O
regarding	O
the	O
role	O
of	O
the	O
amines	B-Chemical
on	O
the	O
pineal	O
in	O
spite	O
of	O
the	O
immature	O
blood	O
-	O
brain	O
barrier	O
in	O
the	O
young	O
chick	O
and	O
the	O
intact	O
barrier	O
in	O
the	O
rat	O
.	O

In	O
addition	O
,	O
these	O
data	O
indicate	O
a	O
direct	O
role	O
of	O
the	O
pituitary	O
in	O
the	O
augmentation	O
of	O
ketamine	B-Chemical
DOC	O
induced	O
by	O
melatonin	B-Chemical
.	O

Furthermore	O
,	O
dopamine	B-Chemical
appeared	O
to	O
act	O
on	O
systems	O
more	O
closely	O
involved	O
with	O
the	O
induction	O
of	O
ketamine	B-Chemical
catatonia	B-Disease
rather	O
than	O
directly	O
on	O
the	O
pituitary	O
.	O

Heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
,	O
thrombosis	B-Disease
,	O
and	O
hemorrhage	B-Disease
.	O

Sixty	O
-	O
two	O
patients	O
with	O
a	O
heparin	B-Chemical
-	O
induced	O
thrombocytopenia	B-Disease
are	O
reported	O
.	O

Clinical	O
manifestations	O
of	O
this	O
disorder	O
include	O
hemorrhage	B-Disease
or	O
,	O
more	O
frequently	O
,	O
thromboembolic	B-Disease
events	O
in	O
patients	O
receiving	O
heparin	B-Chemical
.	O

Laboratory	O
testing	O
has	O
revealed	O
a	B-Disease
falling	I-Disease
platelet	I-Disease
count	I-Disease
,	O
increased	O
resistance	O
to	O
heparin	B-Chemical
,	O
and	O
aggregation	O
of	O
platelets	O
by	O
the	O
patient	O
'	O
s	O
plasma	O
when	O
heparin	B-Chemical
is	O
added	O
.	O

Immunologic	O
testing	O
has	O
demonstrated	O
the	O
presence	O
of	O
a	O
heparin	B-Chemical
-	O
dependent	O
platelet	O
membrane	O
antibody	O
.	O

The	O
20	O
deaths	O
,	O
52	O
hemorrhagic	B-Disease
and	I-Disease
thromboembolic	I-Disease
complications	I-Disease
,	O
and	O
21	O
surgical	O
procedures	O
to	O
manage	O
the	O
complications	O
confirm	O
the	O
seriousness	O
of	O
the	O
disorder	O
.	O

Specific	O
risk	O
factors	O
have	O
not	O
been	O
identified	O
;	O
therefore	O
,	O
all	O
patients	O
receiving	O
heparin	B-Chemical
should	O
be	O
monitored	O
.	O

If	O
the	O
platelet	O
count	O
falls	O
to	O
less	O
than	O
100	O
,	O
000	O
/	O
mm3	O
,	O
while	O
the	O
patient	O
is	O
receiving	O
heparin	B-Chemical
,	O
platelet	B-Disease
aggregation	I-Disease
testing	O
,	O
using	O
the	O
patient	O
'	O
s	O
plasma	O
,	O
is	O
indicated	O
.	O

Management	O
consists	O
of	O
cessation	O
of	O
heparin	B-Chemical
,	O
platelet	O
anti	O
-	O
aggregating	O
agents	O
,	O
and	O
alternate	O
forms	O
of	O
anticoagulation	O
when	O
indicated	O
.	O

Ventricular	B-Disease
fibrillation	I-Disease
from	O
diatrizoate	B-Chemical
with	O
and	O
without	O
chelating	O
agents	O
.	O

The	O
toxicity	B-Disease
of	O
Renografin	B-Chemical
76	I-Chemical
%	I-Chemical
was	O
compared	O
with	O
that	O
of	O
Hypaque	B-Chemical
76	I-Chemical
%	I-Chemical
by	O
selective	O
injection	O
of	O
each	O
into	O
the	O
right	O
coronary	O
artery	O
of	O
dogs	O
.	O

Renografin	B-Chemical
contains	O
the	O
chelating	O
agents	O
sodium	B-Chemical
citrate	I-Chemical
and	O
disodium	B-Chemical
edetate	I-Chemical
,	O
while	O
Hypaque	B-Chemical
contains	O
calcium	B-Chemical
disodium	I-Chemical
edetate	I-Chemical
and	O
no	O
sodium	B-Chemical
citrate	I-Chemical
.	O

Ventricular	B-Disease
fibrillation	I-Disease
occurred	O
significantly	O
more	O
often	O
with	O
Renografin	B-Chemical
,	O
suggesting	O
that	O
chelating	O
agents	O
contribute	O
to	O
toxicity	B-Disease
in	O
coronary	O
angiography	O
.	O

Long	O
-	O
term	O
efficacy	O
and	O
toxicity	B-Disease
of	O
high	O
-	O
dose	O
amiodarone	B-Chemical
therapy	O
for	O
ventricular	B-Disease
tachycardia	I-Disease
or	O
ventricular	B-Disease
fibrillation	I-Disease
.	O

Amiodarone	B-Chemical
was	O
administered	O
to	O
154	O
patients	O
who	O
had	O
sustained	O
,	O
symptomatic	O
ventricular	B-Disease
tachycardia	I-Disease
(	O
VT	B-Disease
)	O
(	O
n	O
=	O
118	O
)	O
or	O
a	O
cardiac	B-Disease
arrest	I-Disease
(	O
n	O
=	O
36	O
)	O
and	O
who	O
were	O
refractory	O
to	O
conventional	O
antiarrhythmic	O
drugs	O
.	O

The	O
loading	O
dose	O
was	O
800	O
mg	O
/	O
day	O
for	O
6	O
weeks	O
and	O
the	O
maintenance	O
dose	O
was	O
600	O
mg	O
/	O
day	O
.	O

Sixty	O
-	O
nine	O
percent	O
of	O
patients	O
continued	O
treatment	O
with	O
amiodarone	B-Chemical
and	O
had	O
no	O
recurrence	O
of	O
symptomatic	O
VT	B-Disease
or	O
ventricular	B-Disease
fibrillation	I-Disease
(	O
VF	B-Disease
)	O
over	O
a	O
follow	O
-	O
up	O
of	O
6	O
to	O
52	O
months	O
(	O
mean	O
+	O
/	O
-	O
standard	O
deviation	O
14	O
.	O
2	O
+	O
/	O
-	O
8	O
.	O
2	O
)	O
.	O

Six	O
percent	O
of	O
the	O
patients	O
had	O
a	O
nonfatal	O
recurrence	O
of	O
VT	B-Disease
and	O
were	O
successfully	O
managed	O
by	O
continuing	O
amiodarone	B-Chemical
at	O
a	O
higher	O
dose	O
or	O
by	O
the	O
addition	O
of	O
a	O
conventional	O
antiarrhythmic	O
drug	O
.	O

One	O
or	O
more	O
adverse	O
drug	O
reactions	O
occurred	O
in	O
51	O
%	O
of	O
patients	O
.	O

Adverse	O
effects	O
forced	O
a	O
reduction	O
in	O
the	O
dose	O
of	O
amiodarone	B-Chemical
in	O
41	O
%	O
and	O
discontinuation	O
of	O
amiodarone	B-Chemical
in	O
10	O
%	O
of	O
patients	O
.	O

The	O
most	O
common	O
symptomatic	O
adverse	O
reactions	O
were	O
tremor	B-Disease
or	O
ataxia	B-Disease
(	O
35	O
%	O
)	O
,	O
nausea	B-Disease
and	O
anorexia	B-Disease
(	O
8	O
%	O
)	O
,	O
visual	B-Disease
halos	I-Disease
or	I-Disease
blurring	I-Disease
(	O
6	O
%	O
)	O
,	O
thyroid	B-Disease
function	I-Disease
abnormalities	I-Disease
(	O
6	O
%	O
)	O
and	O
pulmonary	B-Disease
interstitial	I-Disease
infiltrates	I-Disease
(	O
5	O
%	O
)	O
.	O

Although	O
large	O
-	O
dose	O
amiodarone	B-Chemical
is	O
highly	O
effective	O
in	O
the	O
long	O
-	O
term	O
treatment	O
of	O
VT	B-Disease
or	O
VF	B-Disease
refractory	O
to	O
conventional	O
antiarrhythmic	O
drugs	O
,	O
it	O
causes	O
significant	O
toxicity	B-Disease
in	O
approximately	O
50	O
%	O
of	O
patients	O
.	O

However	O
,	O
when	O
the	O
dose	O
is	O
adjusted	O
based	O
on	O
clinical	O
response	O
or	O
the	O
development	O
of	O
adverse	O
effects	O
,	O
75	O
%	O
of	O
patients	O
with	O
VT	B-Disease
or	O
VF	B-Disease
can	O
be	O
successfully	O
managed	O
with	O
amiodarone	B-Chemical
.	O

Why	O
may	O
epsilon	B-Chemical
-	I-Chemical
aminocaproic	I-Chemical
acid	I-Chemical
(	O
EACA	B-Chemical
)	O
induce	O
myopathy	B-Disease
in	O
man	O
?	O

Report	O
of	O
a	O
case	O
and	O
literature	O
review	O
.	O

A	O
case	O
of	O
necrotizing	B-Disease
myopathy	I-Disease
due	O
to	O
a	O
short	O
epsilon	B-Chemical
-	I-Chemical
aminocaproic	I-Chemical
acid	I-Chemical
(	O
EACA	B-Chemical
)	O
treatment	O
in	O
a	O
72	O
year	O
-	O
old	O
patient	O
with	O
subarachnoid	B-Disease
haemorrhage	I-Disease
(	O
SAH	B-Disease
)	O
is	O
described	O
.	O

Pathogenetic	O
hypotheses	O
are	O
discussed	O
.	O

Cerebral	B-Disease
hemorrhage	I-Disease
associated	O
with	O
phenylpropanolamine	B-Chemical
in	O
combination	O
with	O
caffeine	B-Chemical
.	O

Phenylpropanolamine	B-Chemical
(	O
PPA	B-Chemical
)	O
is	O
a	O
drug	O
that	O
has	O
been	O
associated	O
with	O
serious	O
side	O
effects	O
including	O
stroke	B-Disease
.	O

It	O
is	O
often	O
combined	O
with	O
caffeine	B-Chemical
in	O
diet	O
preparations	O
and	O
"	O
look	O
-	O
alike	O
"	O
pills	O
.	O

In	O
order	O
to	O
determine	O
if	O
PPA	B-Chemical
/	O
caffeine	B-Chemical
can	O
lead	O
to	O
stroke	B-Disease
in	O
normotensive	O
and	O
/	O
or	O
hypertensive	B-Disease
rats	O
,	O
we	O
administered	O
the	O
combination	O
in	O
six	O
times	O
the	O
allowed	O
human	O
dose	O
calculated	O
on	O
a	O
per	O
weight	O
basis	O
for	O
the	O
rats	O
two	O
times	O
per	O
day	O
for	O
five	O
days	O
.	O

Subarachnoid	B-Disease
and	I-Disease
cerebral	I-Disease
hemorrhage	I-Disease
was	O
noted	O
in	O
18	O
%	O
of	O
the	O
hypertensive	B-Disease
rats	O
.	O

A	O
single	O
PPA	B-Chemical
/	O
caffeine	B-Chemical
administration	O
(	O
same	O
dose	O
)	O
lead	O
to	O
acute	O
hypertension	B-Disease
in	O
both	O
the	O
normotensive	O
and	O
hypertensive	B-Disease
animals	O
.	O

These	O
results	O
suggest	O
that	O
PPA	B-Chemical
/	O
caffeine	B-Chemical
can	O
lead	O
to	O
cerebral	B-Disease
hemorrhage	I-Disease
in	O
previously	O
hypertensive	B-Disease
animals	O
when	O
administered	O
in	O
greater	O
than	O
the	O
allowed	O
dosage	O
.	O

An	O
acute	O
elevation	O
in	O
blood	O
pressure	O
may	O
be	O
a	O
contributing	O
factor	O
.	O

Renal	B-Disease
papillary	I-Disease
necrosis	I-Disease
due	O
to	O
naproxen	B-Chemical
.	O

A	O
31	O
-	O
year	O
-	O
old	O
man	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
,	O
who	O
had	O
previously	O
been	O
treated	O
with	O
sulindac	B-Chemical
,	O
fenoprofen	B-Chemical
calcium	I-Chemical
,	O
high	O
dose	O
salicylates	B-Chemical
and	O
gold	B-Chemical
salts	O
,	O
developed	O
renal	B-Disease
papillary	I-Disease
necrosis	I-Disease
(	O
RPN	B-Disease
)	O
4	O
months	O
after	O
institution	O
of	O
naproxen	B-Chemical
therapy	O
.	O

No	O
other	O
factor	O
predisposing	O
to	O
RPN	B-Disease
could	O
be	O
discovered	O
.	O

Sulindac	B-Chemical
was	O
substituted	O
for	O
naproxen	B-Chemical
and	O
no	O
further	O
adverse	O
renal	O
effects	O
occurred	O
over	O
the	O
next	O
12	O
months	O
.	O

We	O
review	O
previous	O
reports	O
linking	O
RPN	B-Disease
to	O
antiinflammatory	O
drug	O
use	O
and	O
discuss	O
possible	O
advantages	O
of	O
sulindac	B-Chemical
in	O
patients	O
who	O
have	O
experienced	O
renal	B-Disease
toxicity	I-Disease
from	O
other	O
antiinflammatory	O
agents	O
.	O

Nephrotoxic	B-Disease
effects	O
of	O
aminoglycoside	B-Chemical
treatment	O
on	O
renal	O
protein	O
reabsorption	O
and	O
accumulation	O
.	O

To	O
quantify	O
the	O
effects	O
of	O
gentamicin	B-Chemical
,	O
kanamycin	B-Chemical
and	O
netilmicin	B-Chemical
on	O
renal	O
protein	O
reabsorption	O
and	O
accumulation	O
,	O
these	O
drugs	O
were	O
administered	O
to	O
rats	O
intraperitoneally	O
(	O
30	O
mg	O
/	O
kg	O
/	O
day	O
)	O
for	O
7	O
,	O
14	O
or	O
21	O
days	O
.	O

Scanning	O
electron	O
microscopy	O
of	O
the	O
glomerular	O
endothelia	O
,	O
urinary	O
measurements	O
of	O
sodium	B-Chemical
,	O
potassium	B-Chemical
,	O
endogenous	O
lysozyme	O
,	O
N	O
-	O
acetyl	O
-	O
beta	O
-	O
D	O
-	O
glucosaminidase	O
(	O
NAG	O
)	O
as	O
well	O
as	O
clearance	O
and	O
accumulation	O
experiments	O
after	O
i	O
.	O
v	O
.	O
administration	O
of	O
egg	O
-	O
white	O
lysozyme	O
and	O
measurements	O
of	O
inulin	O
clearance	O
(	O
GFR	O
)	O
were	O
done	O
in	O
each	O
treatment	O
group	O
.	O

Gentamicin	B-Chemical
administration	O
decreased	O
diameter	O
,	O
density	O
and	O
shape	O
of	O
endothelial	O
fenestrae	O
.	O

Kanamycin	B-Chemical
and	O
netilmicin	B-Chemical
appeared	O
to	O
have	O
no	O
effect	O
at	O
the	O
dose	O
used	O
.	O

All	O
three	O
aminoglycosides	B-Chemical
decreased	O
GFR	O
and	O
increased	O
urinary	O
excretion	O
of	O
sodium	B-Chemical
and	O
potassium	B-Chemical
.	O

While	O
gentamicin	B-Chemical
and	O
kanamycin	B-Chemical
decreased	O
the	O
percentage	O
reabsorption	O
and	O
accumulation	O
of	O
lysozyme	O
after	O
i	O
.	O
v	O
.	O
administration	O
of	O
egg	O
-	O
white	O
lysozyme	O
netilmicin	B-Chemical
had	O
no	O
effect	O
.	O

Daily	O
excretion	O
of	O
total	O
protein	O
,	O
endogenous	O
lysozyme	O
and	O
NAG	O
increased	O
only	O
after	O
treatment	O
with	O
kanamycin	B-Chemical
and	O
gentamicin	B-Chemical
.	O

Thus	O
,	O
aminoglycosides	B-Chemical
may	O
act	O
as	O
nephrotoxicants	O
at	O
glomerular	O
and	O
/	O
or	O
tubular	O
level	O
inducing	O
impairment	B-Disease
of	I-Disease
renal	I-Disease
reabsorption	I-Disease
and	O
accumulation	O
of	O
proteins	O
.	O

Induction	O
of	O
the	O
obstructive	B-Disease
sleep	I-Disease
apnea	I-Disease
syndrome	I-Disease
in	O
a	O
woman	O
by	O
exogenous	O
androgen	B-Chemical
administration	O
.	O

We	O
documented	O
airway	O
occlusion	O
during	O
sleep	O
and	O
an	O
abnormally	O
high	O
supraglottic	O
resistance	O
while	O
awake	O
in	O
a	O
54	O
-	O
yr	O
-	O
old	O
woman	O
who	O
had	O
developed	O
physical	O
changes	O
and	O
the	O
syndrome	B-Disease
of	I-Disease
obstructive	I-Disease
sleep	I-Disease
apnea	I-Disease
while	O
being	O
administered	O
exogenous	O
androgens	B-Chemical
.	O

When	O
the	O
androgens	B-Chemical
were	O
withdrawn	O
,	O
the	O
patient	O
'	O
s	O
physical	O
changes	O
,	O
symptoms	O
,	O
sleep	O
study	O
,	O
and	O
supraglottic	O
resistance	O
all	O
returned	O
to	O
normal	O
.	O

A	O
rechallenge	O
with	O
androgen	B-Chemical
produced	O
symptoms	O
of	O
obstructive	B-Disease
sleep	I-Disease
apnea	I-Disease
that	O
abated	O
upon	O
withdrawal	O
of	O
the	O
hormone	O
.	O

Previous	O
reports	O
have	O
favored	O
a	O
role	O
of	O
androgens	B-Chemical
in	O
the	O
pathogenesis	O
of	O
sleep	B-Disease
apnea	I-Disease
.	O

Our	O
report	O
provides	O
direct	O
evidence	O
for	O
this	O
role	O
.	O

Structural	O
and	O
functional	O
measurements	O
indicate	O
that	O
androgens	B-Chemical
exert	O
a	O
permissive	O
or	O
necessary	O
action	O
on	O
the	O
structural	O
configuration	O
of	O
the	O
oropharynx	O
that	O
predisposes	O
to	O
obstruction	O
during	O
sleep	O
.	O

Development	O
of	O
the	O
obstructive	B-Disease
sleep	I-Disease
apnea	I-Disease
syndrome	I-Disease
must	O
be	O
considered	O
a	O
possible	O
side	O
effect	O
of	O
androgen	B-Chemical
therapy	O
.	O

Cardiotoxic	B-Disease
and	O
possible	O
leukemogenic	O
effects	O
of	O
adriamycin	B-Chemical
in	O
nonhuman	O
primates	O
.	O

10	O
monkeys	O
(	O
macaques	O
)	O
received	O
adriamycin	B-Chemical
by	O
monthly	O
intravenous	O
injections	O
at	O
12	O
mg	O
/	O
m2	O
(	O
1	O
mg	O
/	O
kg	O
)	O
.	O

8	O
of	O
the	O
10	O
monkeys	O
developed	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
at	O
an	O
average	O
cumulative	O
adriamycin	B-Chemical
dose	O
(	O
310	O
mg	O
/	O
m2	O
)	O
well	O
below	O
that	O
considered	O
the	O
safe	O
upper	O
limit	O
(	O
550	O
mg	O
/	O
m2	O
)	O
in	O
man	O
.	O

Histologically	O
,	O
the	O
myocardial	B-Disease
lesions	I-Disease
resembled	O
those	O
found	O
in	O
human	O
anthracycline	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
.	O

1	O
of	O
the	O
10	O
monkeys	O
developed	O
acute	B-Disease
myeloblastic	I-Disease
leukemia	I-Disease
after	O
receiving	O
324	O
mg	O
/	O
m2	O
of	O
adriamycin	B-Chemical
;	O
the	O
10th	O
monkey	O
is	O
alive	O
and	O
well	O
26	O
months	O
after	O
the	O
last	O
dose	O
of	O
drug	O
.	O

Our	O
results	O
suggest	O
that	O
adriamycin	B-Chemical
is	O
a	O
more	O
potent	O
cardiotoxin	O
in	O
monkeys	O
than	O
in	O
man	O
,	O
and	O
that	O
leukemia	B-Disease
may	O
be	O
a	O
consequence	O
of	O
prolonged	O
treatment	O
with	O
this	O
drug	O
.	O

Tricuspid	B-Disease
valve	I-Disease
regurgitation	I-Disease
and	O
lithium	B-Chemical
carbonate	I-Chemical
toxicity	B-Disease
in	O
a	O
newborn	O
infant	O
.	O

A	O
newborn	O
with	O
massive	O
tricuspid	B-Disease
regurgitation	I-Disease
,	O
atrial	B-Disease
flutter	I-Disease
,	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
,	O
and	O
a	O
high	O
serum	O
lithium	B-Chemical
level	O
is	O
described	O
.	O

This	O
is	O
the	O
first	O
patient	O
to	O
initially	O
manifest	O
tricuspid	B-Disease
regurgitation	I-Disease
and	O
atrial	B-Disease
flutter	I-Disease
,	O
and	O
the	O
11th	O
described	O
patient	O
with	O
cardiac	B-Disease
disease	I-Disease
among	O
infants	O
exposed	O
to	O
lithium	B-Chemical
compounds	O
in	O
the	O
first	O
trimester	O
of	O
pregnancy	O
.	O

Sixty	O
-	O
three	O
percent	O
of	O
these	O
infants	O
had	O
tricuspid	O
valve	O
involvement	O
.	O

Lithium	B-Chemical
carbonate	I-Chemical
may	O
be	O
a	O
factor	O
in	O
the	O
increasing	O
incidence	O
of	O
congenital	B-Disease
heart	I-Disease
disease	I-Disease
when	O
taken	O
during	O
early	O
pregnancy	O
.	O

It	O
also	O
causes	O
neurologic	B-Disease
depression	I-Disease
,	O
cyanosis	B-Disease
,	O
and	O
cardiac	B-Disease
arrhythmia	I-Disease
when	O
consumed	O
prior	O
to	O
delivery	O
.	O

Effects	O
of	O
the	O
novel	O
compound	O
aniracetam	B-Chemical
(	O
Ro	B-Chemical
13	I-Chemical
-	I-Chemical
5057	I-Chemical
)	O
upon	O
impaired	B-Disease
learning	I-Disease
and	I-Disease
memory	I-Disease
in	O
rodents	O
.	O

The	O
effect	O
of	O
aniracetam	B-Chemical
(	O
Ro	B-Chemical
13	I-Chemical
-	I-Chemical
5057	I-Chemical
,	O
1	B-Chemical
-	I-Chemical
anisoyl	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
pyrrolidinone	I-Chemical
)	O
was	O
studied	O
on	O
various	O
forms	O
of	O
experimentally	O
impaired	B-Disease
cognitive	I-Disease
functions	I-Disease
(	O
learning	O
and	O
memory	O
)	O
in	O
rodents	O
and	O
produced	O
the	O
following	O
effects	O
:	O
(	O
1	O
)	O
almost	O
complete	O
prevention	O
of	O
the	O
incapacity	O
to	O
learn	O
a	O
discrete	O
escape	O
response	O
in	O
rats	O
exposed	O
to	O
sublethal	O
hypercapnia	B-Disease
immediately	O
before	O
the	O
acquisition	O
session	O
;	O
(	O
2	O
)	O
partial	O
(	O
rats	O
)	O
or	O
complete	O
(	O
mice	O
)	O
prevention	O
of	O
the	O
scopolamine	B-Chemical
-	O
induced	O
short	O
-	O
term	O
amnesia	B-Disease
for	O
a	O
passive	O
avoidance	O
task	O
;	O
(	O
3	O
)	O
complete	O
protection	O
against	O
amnesia	B-Disease
for	O
a	O
passive	O
avoidance	O
task	O
in	O
rats	O
submitted	O
to	O
electroconvulsive	O
shock	O
immediately	O
after	O
avoidance	O
acquisition	O
;	O
(	O
4	O
)	O
prevention	O
of	O
the	O
long	O
-	O
term	O
retention	O
-	O
or	O
retrieval	O
-	O
deficit	O
for	O
a	O
passive	O
avoidance	O
task	O
induced	O
in	O
rats	O
and	O
mice	O
by	O
chloramphenicol	B-Chemical
or	O
cycloheximide	B-Chemical
administered	O
immediately	O
after	O
acquisition	O
;	O
(	O
5	O
)	O
reversal	O
,	O
when	O
administered	O
as	O
late	O
as	O
1	O
h	O
before	O
the	O
retention	O
test	O
,	O
of	O
the	O
deficit	O
in	O
retention	O
or	O
retrieval	O
of	O
a	O
passive	O
avoidance	O
task	O
induced	O
by	O
cycloheximide	B-Chemical
injected	O
2	O
days	O
previously	O
;	O
(	O
6	O
)	O
prevention	O
of	O
the	O
deficit	O
in	O
the	O
retrieval	O
of	O
an	O
active	O
avoidance	O
task	O
induced	O
in	O
mice	O
by	O
subconvulsant	O
electroshock	O
or	O
hypercapnia	B-Disease
applied	O
immediately	O
before	O
retrieval	O
testing	O
(	O
24	O
h	O
after	O
acquisition	O
)	O
.	O

These	O
improvements	O
or	O
normalizations	O
of	O
impaired	B-Disease
cognitive	I-Disease
functions	I-Disease
were	O
seen	O
at	O
oral	O
aniracetam	B-Chemical
doses	O
of	O
10	O
-	O
100	O
mg	O
/	O
kg	O
.	O

Generally	O
,	O
the	O
dose	O
-	O
response	O
curves	O
were	O
bell	O
-	O
shaped	O
.	O

The	O
mechanisms	O
underlying	O
the	O
activity	O
of	O
aniracetam	B-Chemical
and	O
its	O
'	O
therapeutic	O
window	O
'	O
are	O
unknown	O
.	O

Piracetam	B-Chemical
,	O
another	O
pyrrolidinone	B-Chemical
derivative	O
was	O
used	O
for	O
comparison	O
.	O

It	O
was	O
active	O
only	O
in	O
six	O
of	O
nine	O
tests	O
and	O
had	O
about	O
one	O
-	O
tenth	O
the	O
potency	O
of	O
aniracetam	B-Chemical
.	O

The	O
results	O
indicate	O
that	O
aniracetam	B-Chemical
improves	O
cognitive	O
functions	O
which	O
are	O
impaired	O
by	O
different	O
procedure	O
and	O
in	O
different	O
phases	O
of	O
the	O
learning	O
and	O
memory	O
process	O
.	O

Effect	O
of	O
calcium	B-Chemical
chloride	I-Chemical
on	O
gross	O
behavioural	O
changes	O
produced	O
by	O
carbachol	B-Chemical
and	O
eserine	B-Chemical
in	O
cats	O
.	O

The	O
effect	O
of	O
calcium	B-Chemical
chloride	I-Chemical
injected	O
into	O
the	O
cerebral	O
ventricles	O
of	O
group	O
-	O
housed	O
unanaesthetized	O
cats	O
upon	O
vocalization	O
(	O
rage	O
,	O
hissing	O
and	O
snarling	O
)	O
,	O
fighting	O
(	O
attack	O
with	O
paws	O
and	O
claws	O
,	O
defense	O
with	O
paws	O
and	O
claws	O
and	O
biting	O
)	O
,	O
mydriasis	B-Disease
,	O
tremor	B-Disease
and	O
clonic	B-Disease
-	I-Disease
tonic	I-Disease
convulsions	I-Disease
produced	O
by	O
carbachol	B-Chemical
and	O
eserine	B-Chemical
injected	O
similarly	O
was	O
investigated	O
.	O

Calcium	B-Chemical
chloride	I-Chemical
depressed	O
or	O
almost	O
completely	O
abolished	O
the	O
vocalization	O
and	O
fighting	O
due	O
to	O
carbachol	B-Chemical
and	O
eserine	B-Chemical
.	O

On	O
the	O
other	O
hand	O
,	O
mydriasis	B-Disease
,	O
tremor	B-Disease
and	O
clonic	B-Disease
-	I-Disease
tonic	I-Disease
convulsions	I-Disease
evoked	O
by	O
carbachol	B-Chemical
and	O
eserine	B-Chemical
were	O
not	O
significantly	O
changed	O
by	O
calcium	B-Chemical
chloride	I-Chemical
.	O

It	O
is	O
apparent	O
that	O
calcium	B-Chemical
chloride	I-Chemical
can	O
"	O
dissociate	O
"	O
vocalization	O
and	O
fighting	O
from	O
autonomic	O
and	O
motor	O
phenomena	O
such	O
as	O
mydriasis	B-Disease
,	O
tremor	B-Disease
and	O
clonic	B-Disease
-	I-Disease
tonic	I-Disease
convulsions	I-Disease
caused	O
by	O
carbachol	B-Chemical
and	O
eserine	B-Chemical
.	O

Calcium	B-Chemical
chloride	I-Chemical
inhibited	O
the	O
vocalization	O
and	O
fighting	O
produced	O
by	O
carbachol	B-Chemical
and	O
eserine	B-Chemical
most	O
probably	O
by	O
a	O
nonspecific	O
stabilizing	O
action	O
on	O
central	O
muscarinic	O
cholinoceptive	O
sites	O
.	O

These	O
results	O
further	O
support	O
the	O
view	O
that	O
calcium	B-Chemical
ions	O
in	O
excess	O
have	O
an	O
atropine	B-Chemical
-	O
like	O
action	O
also	O
in	O
the	O
central	O
nervous	O
system	O
.	O

Thiazide	B-Chemical
diuretics	O
,	O
hypokalemia	B-Disease
and	O
cardiac	B-Disease
arrhythmias	I-Disease
.	O

Thiazide	B-Chemical
diuretics	O
are	O
widely	O
accepted	O
as	O
the	O
cornerstone	O
of	O
antihypertensive	O
treatment	O
programs	O
.	O

Hypokalemia	B-Disease
is	O
a	O
commonly	O
encountered	O
metabolic	O
consequence	O
of	O
chronic	O
thiazide	B-Chemical
therapy	O
.	O

We	O
treated	O
38	O
patients	O
(	O
22	O
low	O
renin	O
,	O
16	O
normal	O
renin	O
)	O
with	O
moderate	O
diastolic	B-Disease
hypertension	I-Disease
with	O
hydrochlorothiazide	B-Chemical
(	O
HCTC	B-Chemical
)	O
administered	O
on	O
a	O
twice	O
daily	O
schedule	O
.	O

Initial	O
dose	O
was	O
50	O
mg	O
and	O
the	O
dose	O
was	O
increased	O
at	O
monthly	O
intervals	O
to	O
100	O
mg	O
,	O
150	O
mg	O
and	O
200	O
mg	O
daily	O
until	O
blood	O
pressure	O
normalized	O
.	O

The	O
serum	O
K	B-Chemical
during	O
the	O
control	O
period	O
was	O
4	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
2	O
mEq	O
/	O
l	O
an	O
on	O
50	O
,	O
100	O
,	O
150	O
and	O
200	O
mg	O
HCTZ	B-Chemical
daily	O
3	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
3	O
,	O
3	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
2	O
,	O
2	O
.	O
9	O
+	O
/	O
-	O
0	O
.	O
2	O
,	O
and	O
2	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
3	O
mEq	O
/	O
l	O
,	O
respectively	O
.	O

Corresponding	O
figures	O
for	O
whole	O
body	O
K	B-Chemical
were	O
4107	O
+	O
/	O
-	O
208	O
,	O
3722	O
+	O
/	O
-	O
319	O
,	O
3628	O
+	O
/	O
-	O
257	O
,	O
3551	O
+	O
/	O
-	O
336	O
,	O
and	O
3269	O
+	O
/	O
-	O
380	O
mEq	O
,	O
respectively	O
.	O

In	O
13	O
patients	O
we	O
observed	O
the	O
effects	O
of	O
HCTZ	B-Chemical
therapy	O
(	O
100	O
mg	O
daily	O
)	O
on	O
the	O
occurrence	O
of	O
PVC	O
'	O
s	O
during	O
rest	O
as	O
well	O
as	O
during	O
static	O
and	O
dynamic	O
exercise	O
.	O

During	O
rest	O
we	O
observed	O
0	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
08	O
PVC	O
beats	O
/	O
min	O
+	O
/	O
-	O
SEM	O
and	O
during	O
static	O
and	O
dynamic	O
exercise	O
0	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
06	O
and	O
0	O
.	O
8	O
+	O
/	O
-	O
0	O
.	O
15	O
,	O
respectively	O
.	O

Corresponding	O
figures	O
during	O
HCTZ	B-Chemical
therapy	O
100	O
mg	O
daily	O
were	O
1	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
1	O
,	O
3	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
7	O
and	O
5	O
.	O
7	O
4	O
/	O
-	O
0	O
.	O
8	O
,	O
respectively	O
.	O

The	O
occurrence	O
of	O
PVC	O
'	O
s	O
correlated	O
significantly	O
with	O
the	O
fall	O
in	O
serum	O
K	B-Chemical
+	O
observed	O
r	O
=	O
0	O
.	O
72	O
,	O
p	O
less	O
than	O
0	O
.	O
001	O
.	O

In	O
conclusion	O
we	O
found	O
that	O
thiazide	B-Chemical
diuretics	O
cause	O
hypokalemia	B-Disease
and	O
depletion	O
of	O
body	O
potassium	B-Chemical
.	O

The	O
more	O
profound	O
hypokalemia	B-Disease
,	O
the	O
greater	O
the	O
propensity	O
for	O
the	O
occurrence	O
of	O
PVC	O
'	O
s	O
.	O

Circulating	O
lysosomal	O
enzymes	O
and	O
acute	B-Disease
hepatic	I-Disease
necrosis	I-Disease
.	O

The	O
activities	O
of	O
the	O
lysosomal	O
enzymes	O
acid	O
and	O
neutral	O
protease	O
,	O
N	O
-	O
acetylglucosaminidase	O
,	O
and	O
acid	O
phosphatase	O
were	O
measured	O
in	O
the	O
serum	O
of	O
patients	O
with	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
.	O

Acid	O
protease	O
(	O
cathepsin	O
D	O
)	O
activity	O
was	O
increased	O
about	O
tenfold	O
in	O
patients	O
who	O
died	O
and	O
nearly	O
fourfold	O
in	O
those	O
who	O
survived	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
after	O
paracetamol	B-Chemical
overdose	B-Disease
,	O
whereas	O
activities	O
were	O
increased	O
equally	O
in	O
patients	O
with	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
due	O
to	O
viral	B-Disease
hepatitis	I-Disease
whether	O
or	O
not	O
they	O
survived	O
.	O

A	O
correlation	O
was	O
found	O
between	O
serum	O
acid	O
protease	O
activity	O
and	O
prothrombin	O
time	O
,	O
and	O
the	O
increase	O
in	O
cathepsin	O
D	O
activity	O
was	O
sustained	O
over	O
several	O
days	O
compared	O
with	O
aspartate	B-Chemical
aminotransferase	O
,	O
which	O
showed	O
a	O
sharp	O
early	O
peak	O
and	O
then	O
a	O
fall	O
.	O

Circulating	O
lysosomal	O
proteases	O
can	O
damage	O
other	O
organs	O
,	O
and	O
measurement	O
of	O
their	O
activity	O
may	O
therefore	O
be	O
of	O
added	O
value	O
in	O
assessing	O
prognosis	O
in	O
this	O
condition	O
.	O

Hepatic	B-Disease
veno	I-Disease
-	I-Disease
occlusive	I-Disease
disease	I-Disease
caused	O
by	O
6	B-Chemical
-	I-Chemical
thioguanine	I-Chemical
.	O

Clinically	O
reversible	O
veno	B-Disease
-	I-Disease
occlusive	I-Disease
disease	I-Disease
of	I-Disease
the	I-Disease
liver	I-Disease
developed	O
in	O
a	O
23	O
-	O
year	O
-	O
old	O
man	O
with	O
acute	B-Disease
lymphocytic	I-Disease
leukemia	I-Disease
after	O
10	O
months	O
of	O
maintenance	O
therapy	O
with	O
6	B-Chemical
-	I-Chemical
thioguanine	I-Chemical
.	O

Serial	O
liver	O
biopsies	O
showed	O
the	O
development	O
and	O
resolution	O
of	O
intense	O
sinusoidal	O
engorgement	O
.	O

Although	O
this	O
disease	O
was	O
clinically	O
reversible	O
,	O
some	O
subintimal	O
fibrosis	B-Disease
about	O
the	O
terminal	O
hepatic	O
veins	O
persisted	O
.	O

This	O
case	O
presented	O
a	O
unique	O
opportunity	O
to	O
observe	O
the	O
histologic	O
features	O
of	O
clinically	O
reversible	O
hepatic	B-Disease
veno	I-Disease
-	I-Disease
occlusive	I-Disease
disease	I-Disease
over	O
time	O
,	O
and	O
may	O
be	O
the	O
first	O
case	O
of	O
veno	O
-	O
occlusive	O
related	O
solely	O
to	O
6	B-Chemical
-	I-Chemical
thioguanine	I-Chemical
.	O

Chlorpropamide	B-Chemical
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
.	O

A	O
65	O
-	O
year	O
-	O
old	O
woman	O
with	O
adult	B-Disease
-	I-Disease
onset	I-Disease
diabetes	I-Disease
treated	O
with	O
chlorpropamide	B-Chemical
(	O
Diabenese	B-Chemical
)	O
had	O
a	O
toxic	B-Disease
optic	I-Disease
neuropathy	I-Disease
that	O
resolved	O
with	O
discontinuation	O
of	O
chlorpropamide	B-Chemical
therapy	O
.	O

Visual	B-Disease
loss	I-Disease
occurs	O
in	O
diabetics	B-Disease
for	O
a	O
variety	O
of	O
reasons	O
,	O
and	O
accurate	O
diagnosis	O
is	O
necessary	O
to	O
institute	O
appropriate	O
therapy	O
.	O

The	O
possibility	O
of	O
a	O
drug	O
-	O
induced	O
optic	B-Disease
neuropathy	I-Disease
should	O
be	O
considered	O
in	O
the	O
differential	O
diagnosis	O
of	O
visual	B-Disease
loss	I-Disease
in	O
diabetics	B-Disease
.	O

Plasma	O
and	O
urinary	O
lipids	O
and	O
lipoproteins	O
during	O
the	O
development	O
of	O
nephrotic	B-Disease
syndrome	I-Disease
induced	O
in	O
the	O
rat	O
by	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
.	O

This	O
study	O
was	O
undertaken	O
to	O
ascertain	O
whether	O
the	O
alterations	O
of	O
plasma	O
lipoproteins	O
found	O
in	O
nephrotic	B-Disease
syndrome	I-Disease
induced	O
by	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
were	O
due	O
to	O
nephrotic	B-Disease
syndrome	I-Disease
per	O
se	O
,	O
or	O
,	O
at	O
least	O
in	O
part	O
,	O
to	O
the	O
aminonucleoside	B-Chemical
.	O

The	O
purpose	O
of	O
the	O
present	O
study	O
was	O
to	O
investigate	O
the	O
changes	O
in	O
plasma	O
and	O
urinary	O
lipoproteins	O
during	O
the	O
administration	O
of	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
(	O
20	O
mg	O
/	O
kg	O
for	O
7	O
days	O
)	O
and	O
the	O
subsequent	O
development	O
of	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

Since	O
massive	O
albuminuria	B-Disease
occurred	O
after	O
6	O
days	O
of	O
treatment	O
,	O
the	O
time	O
-	O
course	O
study	O
was	O
divided	O
into	O
two	O
stages	O
:	O
pre	O
-	O
nephrotic	B-Disease
stage	O
(	O
day	O
1	O
-	O
5	O
)	O
and	O
nephrotic	B-Disease
stage	O
(	O
day	O
6	O
-	O
11	O
)	O
.	O

In	O
pre	O
-	O
nephrotic	B-Disease
stage	O
the	O
plasma	O
level	O
of	O
fatty	B-Chemical
acids	I-Chemical
,	O
triacylglycerol	B-Chemical
and	O
VLDL	O
decreased	O
while	O
that	O
of	O
phospholipid	O
,	O
cholesteryl	B-Chemical
esters	I-Chemical
and	O
HDL	O
remained	O
constant	O
.	O

Plasma	O
apolipoprotein	O
A	O
-	O
I	O
tended	O
to	O
increase	O
(	O
40	O
%	O
increase	O
at	O
day	O
5	O
)	O
.	O

At	O
the	O
beginning	O
of	O
nephrotic	B-Disease
stage	O
(	O
day	O
6	O
)	O
the	O
concentration	O
of	O
plasma	O
albumin	O
dropped	O
to	O
a	O
very	O
low	O
level	O
,	O
while	O
that	O
of	O
apolipoprotein	O
A	O
-	O
I	O
increased	O
abruptly	O
(	O
4	O
-	O
fold	O
increase	O
)	O
and	O
continued	O
to	O
rise	O
,	O
although	O
less	O
steeply	O
,	O
in	O
the	O
following	O
days	O
.	O

The	O
plasma	O
concentration	O
of	O
HDL	O
followed	O
the	O
same	O
pattern	O
.	O

Plasma	O
VLDL	O
and	O
LDL	O
increased	O
at	O
a	O
later	O
stage	O
(	O
day	O
9	O
)	O
.	O

Plasma	O
apolipoprotein	O
A	O
-	O
I	O
was	O
found	O
not	O
only	O
in	O
HDL	O
(	O
1	O
.	O
063	O
-	O
1	O
.	O
210	O
g	O
/	O
ml	O
)	O
but	O
also	O
in	O
the	O
LDL	O
density	O
class	O
(	O
1	O
.	O
025	O
-	O
1	O
.	O
050	O
g	O
/	O
ml	O
)	O
.	O

In	O
the	O
pre	O
-	O
nephrotic	B-Disease
stage	O
lipoproteinuria	O
was	O
negligible	O
,	O
while	O
in	O
the	O
early	O
nephrotic	B-Disease
stage	O
the	O
urinary	O
loss	O
of	O
plasma	O
lipoproteins	O
consisted	O
mainly	O
of	O
HDL	O
.	O

These	O
observations	O
indicate	O
that	O
puromycin	B-Chemical
aminonucleoside	I-Chemical
alters	O
plasma	O
lipoproteins	O
by	O
lowering	O
VLDL	O
and	O
increasing	O
HDL	O
.	O

It	O
is	O
likely	O
that	O
the	O
early	O
and	O
striking	O
increase	O
of	O
plasma	O
HDL	O
found	O
in	O
nephrotic	B-Disease
rats	O
is	O
related	O
to	O
a	O
direct	O
effect	O
of	O
the	O
drug	O
on	O
HDL	O
metabolism	O
.	O

Fatal	O
aplastic	B-Disease
anemia	I-Disease
following	O
topical	O
administration	O
of	O
ophthalmic	O
chloramphenicol	B-Chemical
.	O

A	O
73	O
-	O
year	O
-	O
old	O
woman	O
died	O
of	O
aplastic	B-Disease
anemia	I-Disease
less	O
than	O
two	O
months	O
after	O
undergoing	O
cataract	B-Disease
extraction	O
and	O
beginning	O
topical	O
therapy	O
with	O
chloramphenicol	B-Chemical
.	O

The	O
first	O
signs	O
of	O
pancytopenia	B-Disease
began	O
within	O
one	O
month	O
of	O
the	O
surgery	O
.	O

The	O
pattern	O
of	O
the	O
aplastic	B-Disease
anemia	I-Disease
was	O
associated	O
with	O
an	O
idiosyncratic	O
response	O
to	O
chloramphenicol	B-Chemical
.	O

This	O
was	O
the	O
second	O
report	O
of	O
fatal	O
aplastic	B-Disease
anemia	I-Disease
after	O
topical	O
treatment	O
with	O
chloramphenicol	B-Chemical
for	O
ocular	O
conditions	O
,	O
although	O
two	O
cases	O
of	O
reversible	O
bone	B-Disease
marrow	I-Disease
hypoplasia	I-Disease
have	O
also	O
been	O
reported	O
.	O

Any	O
other	O
suspected	O
cases	O
of	O
ocular	B-Disease
toxicity	I-Disease
associated	O
with	O
topically	O
applied	O
chloramphenicol	B-Chemical
should	O
be	O
reported	O
to	O
the	O
National	O
Registry	O
of	O
Drug	O
-	O
Induced	O
Ocular	O
Side	O
Effects	O
,	O
Oregon	O
Health	O
Sciences	O
University	O
,	O
Portland	O
,	O
OR	O
97201	O
.	O

Midazolam	B-Chemical
compared	O
with	O
thiopentone	B-Chemical
as	O
an	O
induction	O
agent	O
.	O

In	O
patients	O
premedicated	O
with	O
scopolamine	B-Chemical
+	O
morphine	B-Chemical
(	O
+	O
5	O
mg	O
nitrazepam	B-Chemical
the	O
evening	O
before	O
surgery	O
)	O
,	O
the	O
sleep	O
-	O
inducing	O
effect	O
of	O
midazolam	B-Chemical
0	O
.	O
15	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
was	O
clearly	O
slower	O
in	O
onset	O
than	O
that	O
of	O
thiopentone	B-Chemical
4	O
.	O
67	O
mg	O
/	O
kg	O
i	O
.	O
v	O
.	O
Somewhat	O
fewer	O
cardiovascular	O
and	O
local	O
sequelae	O
were	O
found	O
in	O
the	O
midazolam	B-Chemical
group	O
,	O
but	O
,	O
although	O
apnoea	B-Disease
occurred	O
less	O
often	O
in	O
the	O
midazolam	B-Chemical
group	O
it	O
lasted	O
longer	O
.	O

On	O
the	O
whole	O
,	O
the	O
differences	O
between	O
midazolam	B-Chemical
and	O
thiopentone	B-Chemical
had	O
no	O
apparent	O
clinical	O
consequences	O
.	O

Midazolam	B-Chemical
is	O
a	O
new	O
alternative	O
agent	O
for	O
induction	O
in	O
combination	O
anaesthesia	O
.	O

Extrapyramidal	O
side	O
effects	O
and	O
oral	O
haloperidol	B-Chemical
:	O
an	O
analysis	O
of	O
explanatory	O
patient	O
and	O
treatment	O
characteristics	O
.	O

The	O
incidence	O
of	O
extrapyramidal	O
side	O
effects	O
(	O
EPS	O
)	O
was	O
evaluated	O
in	O
98	O
patients	O
treated	O
with	O
haloperidol	B-Chemical
.	O

The	O
incidence	O
of	O
parkinsonism	B-Disease
was	O
higher	O
at	O
higher	O
doses	O
of	O
haloperidol	B-Chemical
and	O
in	O
younger	O
patients	O
.	O

Prophylactic	O
antiparkinsonian	O
medication	O
was	O
effective	O
in	O
younger	O
but	O
not	O
in	O
older	O
patients	O
.	O

However	O
,	O
these	O
medications	O
were	O
more	O
effective	O
in	O
both	O
young	O
and	O
old	O
patients	O
when	O
given	O
after	O
parkinsonism	B-Disease
developed	O
.	O

Akathisia	B-Disease
was	O
controlled	O
by	O
the	O
benzodiazepine	B-Chemical
lorazepam	B-Chemical
in	O
14	O
out	O
of	O
16	O
patients	O
,	O
while	O
prophylactic	O
antiparkinsonians	O
were	O
ineffective	O
.	O

The	O
present	O
study	O
points	O
to	O
patient	O
characteristics	O
that	O
may	O
be	O
of	O
significance	O
in	O
the	O
development	O
of	O
EPS	O
due	O
to	O
haloperidol	B-Chemical
.	O

Deaths	O
from	O
local	O
anesthetic	O
-	O
induced	O
convulsions	B-Disease
in	O
mice	O
.	O

Median	O
convulsant	O
(	O
CD50	O
)	O
and	O
median	O
lethal	O
(	O
LD50	O
)	O
doses	O
of	O
three	O
representative	O
local	O
anesthetics	O
were	O
determined	O
in	O
adult	O
mice	O
to	O
evaluate	O
the	O
threat	O
to	O
life	O
of	O
local	O
anesthetic	O
-	O
induced	O
convulsions	B-Disease
.	O

The	O
CD50	O
and	O
LD50	O
,	O
respectively	O
,	O
were	O
57	O
.	O
7	O
and	O
58	O
.	O
7	O
mg	O
/	O
kg	O
for	O
bupivacaine	B-Chemical
,	O
111	O
.	O
0	O
and	O
133	O
.	O
1	O
mg	O
/	O
kg	O
for	O
lidocaine	B-Chemical
,	O
and	O
243	O
.	O
4	O
and	O
266	O
.	O
5	O
mg	O
/	O
kg	O
for	O
chloroprocaine	B-Chemical
.	O

When	O
given	O
intraperitoneally	O
,	O
bupivacaine	B-Chemical
thus	O
was	O
only	O
about	O
twice	O
as	O
toxic	O
as	O
lidocaine	B-Chemical
and	O
four	O
times	O
as	O
toxic	O
as	O
chloroprocaine	B-Chemical
.	O

Convulsions	B-Disease
always	O
preceded	O
death	O
,	O
except	O
after	O
precipitous	O
cardiopulmonary	B-Disease
arrest	I-Disease
from	O
extreme	O
doses	O
.	O

A	O
CD50	O
dose	O
of	O
local	O
anesthetic	O
(	O
causing	O
convulsions	B-Disease
in	O
50	O
%	O
of	O
mice	O
)	O
was	O
fatal	O
in	O
90	O
%	O
of	O
bupivacaine	B-Chemical
-	O
induced	O
seizures	B-Disease
,	O
in	O
57	O
%	O
of	O
the	O
chloroprocaine	B-Chemical
group	O
,	O
and	O
in	O
6	O
%	O
of	O
the	O
lidocaine	B-Chemical
group	O
.	O

The	O
narrow	O
gap	O
between	O
convulsant	O
and	O
lethal	O
doses	O
of	O
local	O
anesthetics	O
indicates	O
that	O
untreated	O
convulsions	B-Disease
present	O
much	O
more	O
of	O
a	O
threat	O
to	O
life	O
than	O
heretofore	O
appreciated	O
.	O

REM	B-Disease
sleep	I-Disease
deprivation	I-Disease
changes	O
behavioral	O
response	O
to	O
catecholaminergic	O
and	O
serotonergic	O
receptor	O
activation	O
in	O
rats	O
.	O

The	O
effects	O
of	O
REM	B-Disease
sleep	I-Disease
deprivation	I-Disease
(	O
REMD	B-Disease
)	O
on	O
apomorphine	B-Chemical
-	O
induced	O
aggressiveness	B-Disease
and	O
quipazine	B-Chemical
-	O
induced	O
head	B-Disease
twitches	I-Disease
in	O
rats	O
were	O
determined	O
.	O

Forty	O
-	O
eight	O
hr	O
of	O
REMD	B-Disease
increased	O
apomorphine	B-Chemical
-	O
induced	O
aggressiveness	B-Disease
,	O
and	O
reduced	O
(	O
immediately	O
after	O
completing	O
of	O
REMD	B-Disease
)	O
or	O
increased	O
(	O
96	O
hr	O
after	O
completing	O
of	O
REMD	B-Disease
)	O
quipazine	B-Chemical
-	O
induced	O
head	B-Disease
twitches	I-Disease
.	O

Results	O
are	O
discussed	O
in	O
terms	O
of	O
similarity	O
to	O
pharmacological	O
effects	O
of	O
other	O
antidepressive	O
treatments	O
.	O

Fatal	O
aplastic	B-Disease
anemia	I-Disease
due	O
to	O
indomethacin	B-Chemical
-	O
-	O
lymphocyte	O
transformation	O
tests	O
in	O
vitro	O
.	O

Although	O
indomethacin	B-Chemical
has	O
been	O
implicated	O
as	O
a	O
possible	O
cause	O
of	O
aplastic	B-Disease
anemia	I-Disease
on	O
the	O
basis	O
of	O
a	O
few	O
clinical	O
observations	O
,	O
its	O
role	O
has	O
not	O
been	O
definitely	O
established	O
.	O

A	O
case	O
of	O
fatal	O
aplastic	B-Disease
anemia	I-Disease
is	O
described	O
in	O
which	O
no	O
drugs	O
other	O
than	O
allopurinol	B-Chemical
and	O
indomethacin	B-Chemical
were	O
given	O
.	O

Indomethacin	B-Chemical
was	O
first	O
given	O
four	O
weeks	O
prior	O
to	O
the	O
onset	O
of	O
symptoms	O
.	O

A	O
positive	O
lymphocyte	O
transformation	O
test	O
with	O
indomethacin	B-Chemical
in	O
vitro	O
further	O
substantiates	O
the	O
potential	O
role	O
of	O
this	O
drug	O
in	O
causing	O
aplastic	B-Disease
anemia	I-Disease
in	O
a	O
susceptible	O
patient	O
.	O

Fortunately	O
,	O
this	O
seems	O
to	O
be	O
a	O
very	O
rare	O
complication	O
.	O

Dose	O
-	O
effect	O
and	O
structure	O
-	O
function	O
relationships	O
in	O
doxorubicin	B-Chemical
cardiomyopathy	B-Disease
.	O

The	O
cardiomyopathy	B-Disease
(	O
CM	B-Disease
)	O
produced	O
by	O
the	O
anticancer	O
drug	O
doxorubicin	B-Chemical
(	O
DXR	B-Chemical
)	O
(	O
Adriamycin	B-Chemical
)	O
provides	O
a	O
unique	O
opportunity	O
to	O
analyze	O
dose	O
-	O
effect	O
and	O
structure	O
-	O
function	O
relationships	O
during	O
development	O
of	O
myocardial	B-Disease
disease	I-Disease
.	O

We	O
measured	O
the	O
degree	O
of	O
morphologic	O
damage	O
by	O
ultrastructural	O
examination	O
of	O
endomyocardial	O
biopsy	O
and	O
the	O
degree	O
of	O
performance	O
abnormally	O
by	O
right	O
heart	O
catheterization	O
in	O
patients	O
receiving	O
DXR	B-Chemical
.	O

Morphologic	O
damage	O
was	O
variable	O
but	O
was	O
proportional	O
to	O
the	O
total	O
cumulative	O
DXR	B-Chemical
dose	O
between	O
100	O
and	O
600	O
mg	O
/	O
m2	O
.	O

Performance	O
abnormalities	O
correlated	O
weakly	O
with	O
dose	O
,	O
exhibited	O
a	O
curvilinear	O
relationship	O
,	O
and	O
had	O
a	O
"	O
threshold	O
"	O
for	O
expression	O
.	O

Catheterization	O
abnormalities	O
correlated	O
well	O
with	O
morphologic	O
damage	O
(	O
r	O
=	O
0	O
.	O
57	O
to	O
0	O
.	O
78	O
)	O
in	O
a	O
subgroup	O
of	O
patients	O
in	O
whom	O
exercise	O
hemodynamics	O
were	O
measured	O
,	O
and	O
this	O
relationship	O
also	O
exhibited	O
a	O
curvilinear	O
,	O
threshold	O
configuration	O
.	O

In	O
DXR	B-Chemical
-	O
CM	B-Disease
myocardial	B-Disease
damage	I-Disease
is	O
proportional	O
to	O
the	O
degree	O
of	O
cytotoxic	O
insult	O
(	O
DXR	B-Chemical
dose	O
)	O
while	O
myocardial	O
function	O
is	O
preserved	O
until	O
a	O
critical	O
dose	O
or	O
degree	O
of	O
damage	O
is	O
reached	O
,	O
after	O
which	O
myocardial	O
performance	O
deteriorates	O
rapidly	O
.	O

Massive	O
cerebral	B-Disease
edema	I-Disease
associated	O
with	O
fulminant	O
hepatic	B-Disease
failure	I-Disease
in	O
acetaminophen	B-Chemical
overdose	B-Disease
:	O
possible	O
role	O
of	O
cranial	O
decompression	O
.	O

Cerebral	B-Disease
edema	I-Disease
may	O
complicate	O
the	O
course	O
of	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
.	O

Response	O
to	O
conventional	O
therapy	O
has	O
been	O
disappointing	O
.	O

We	O
present	O
a	O
patient	O
with	O
fatal	O
acetaminophen	B-Chemical
-	O
induced	O
fulminant	B-Disease
hepatic	I-Disease
failure	I-Disease
,	O
with	O
signs	O
and	O
symptoms	O
of	O
cerebral	B-Disease
edema	I-Disease
,	O
unresponsive	O
to	O
conventional	O
medical	O
therapy	O
.	O

Cranial	O
decompression	O
was	O
carried	O
out	O
.	O

A	O
justification	O
of	O
the	O
need	O
for	O
further	O
evaluation	O
of	O
cranial	O
decompression	O
in	O
such	O
patients	O
is	O
presented	O
.	O

Subjective	O
assessment	O
of	O
sexual	B-Disease
dysfunction	I-Disease
of	O
patients	O
on	O
long	O
-	O
term	O
administration	O
of	O
digoxin	B-Chemical
.	O

Various	O
data	O
suggest	O
that	O
male	O
patients	O
who	O
have	O
received	O
digoxin	B-Chemical
on	O
a	O
longterm	O
basis	O
have	O
increased	O
levels	O
of	O
serum	O
estrogen	B-Chemical
and	O
decreased	O
levels	O
of	O
plasma	O
testosterone	B-Chemical
and	O
luteinizing	O
hormone	O
(	O
LH	O
)	O
.	O

This	O
study	O
was	O
undertaken	O
to	O
investigate	O
the	O
links	O
between	O
the	O
long	O
-	O
term	O
administration	O
of	O
digoxin	B-Chemical
therapy	O
and	O
sexual	O
behavior	O
,	O
and	O
the	O
effect	O
of	O
digoxin	B-Chemical
on	O
plasma	O
levels	O
of	O
estradiol	B-Chemical
,	O
testosterone	B-Chemical
,	O
and	O
LH	O
.	O

The	O
patients	O
of	O
the	O
study	O
and	O
control	O
group	O
(	O
without	O
digoxin	B-Chemical
)	O
were	O
of	O
similar	O
cardiac	O
functional	O
capacity	O
and	O
age	O
(	O
25	O
-	O
40	O
years	O
)	O
and	O
were	O
randomly	O
selected	O
from	O
the	O
rheumatic	B-Disease
heart	I-Disease
disease	I-Disease
patients	O
.	O

A	O
subjective	O
assessment	O
of	O
sexual	O
behavior	O
in	O
the	O
study	O
and	O
control	O
groups	O
was	O
carried	O
out	O
,	O
using	O
parameters	O
such	O
as	O
sexual	O
desire	O
,	O
sexual	O
excitement	O
,	O
and	O
frequency	O
of	O
sexual	O
relations	O
.	O

Personal	O
interviews	O
and	O
a	O
questionnaire	O
were	O
also	O
used	O
for	O
the	O
evaluation	O
of	O
sexual	O
behavior	O
.	O

The	O
findings	O
support	O
the	O
reports	O
concerning	O
digoxin	B-Chemical
effect	O
on	O
plasma	O
estradiol	B-Chemical
,	O
testosterone	B-Chemical
,	O
and	O
LH	O
.	O

The	O
differences	O
in	O
the	O
means	O
were	O
significant	O
.	O

Tests	O
used	O
to	O
evaluate	O
the	O
changes	O
in	O
sexual	O
behavior	O
showed	O
a	O
significant	O
decrease	B-Disease
in	I-Disease
sexual	I-Disease
desire	I-Disease
,	O
sexual	O
excitement	O
phase	O
(	O
erection	O
)	O
,	O
and	O
frequency	O
of	O
sexual	O
relations	O
in	O
the	O
study	O
group	O
.	O

Endometrial	B-Disease
carcinoma	I-Disease
after	O
Hodgkin	B-Disease
disease	I-Disease
in	O
childhood	O
.	O

A	O
34	O
-	O
year	O
-	O
old	O
patient	O
developed	O
metastic	O
endometrial	B-Disease
carcinoma	I-Disease
after	O
Hodgkin	B-Disease
disease	I-Disease
in	O
childhood	O
.	O

She	O
had	O
ovarian	B-Disease
failure	I-Disease
after	O
abdominal	O
irradiation	O
and	O
chemotherapy	O
for	O
Hodgkin	B-Disease
disease	I-Disease
,	O
and	O
received	O
exogenous	O
estrogens	B-Chemical
,	O
a	O
treatment	O
implicated	O
in	O
the	O
development	O
of	O
endometrial	B-Disease
cancer	I-Disease
in	O
menopausal	O
women	O
.	O

Young	O
women	O
on	O
replacement	O
estrogens	B-Chemical
for	O
ovarian	B-Disease
failure	I-Disease
after	O
cancer	B-Disease
therapy	O
may	O
also	O
have	O
increased	O
risk	O
of	O
endometrial	B-Disease
carcinoma	I-Disease
and	O
should	O
be	O
examined	O
periodically	O
.	O

Long	O
-	O
term	O
lithium	B-Chemical
treatment	O
and	O
the	O
kidney	O
.	O

Interim	O
report	O
on	O
fifty	O
patients	O
.	O

This	O
is	O
a	O
report	O
on	O
the	O
first	O
part	O
of	O
our	O
study	O
of	O
the	O
effects	O
of	O
long	O
-	O
term	O
lithium	B-Chemical
treatment	O
on	O
the	O
kidney	O
.	O

Creatinine	B-Chemical
clearance	O
,	O
maximum	O
urinary	O
osmolality	O
and	O
24	O
hour	O
urine	O
volume	O
have	O
been	O
tested	O
in	O
50	O
affectively	O
ill	O
patients	O
who	O
have	O
been	O
on	O
long	O
-	O
term	O
lithium	B-Chemical
for	O
more	O
than	O
one	O
year	O
.	O

These	O
findings	O
have	O
been	O
compared	O
with	O
norms	O
and	O
with	O
values	O
of	O
the	O
same	O
tests	O
from	O
screening	O
prior	O
to	O
lithium	B-Chemical
,	O
available	O
for	O
most	O
of	O
our	O
patients	O
.	O

No	O
evidence	O
was	O
found	O
for	O
any	O
reduction	O
of	O
glomerular	O
filtration	O
during	O
lithium	B-Chemical
treatment	O
.	O

Low	O
clearance	O
values	O
found	O
in	O
several	O
patients	O
could	O
be	O
accounted	O
for	O
by	O
their	O
age	O
and	O
their	O
pre	O
-	O
lithium	B-Chemical
values	O
.	O

Urinary	O
concentration	O
defect	O
appeared	O
frequent	O
but	O
the	O
extent	O
of	O
the	O
impairment	O
is	O
difficult	O
to	O
assess	O
because	O
of	O
the	O
uncertainty	O
about	O
the	O
norms	O
applicable	O
to	O
this	O
group	O
of	O
patients	O
.	O

The	O
concentration	O
defect	O
appeared	O
reversible	O
,	O
at	O
least	O
in	O
part	O
.	O

Polyuria	B-Disease
above	O
3	O
litres	O
/	O
24	O
hours	O
was	O
found	O
in	O
10	O
%	O
of	O
patients	O
.	O

An	O
attempt	O
is	O
made	O
to	O
draw	O
practical	O
conclusions	O
from	O
the	O
preliminary	O
findings	O
.	O

Nephrotoxicity	B-Disease
of	O
cyclosporin	B-Chemical
A	I-Chemical
and	O
FK506	B-Chemical
:	O
inhibition	O
of	O
calcineurin	O
phosphatase	O
.	O

Cyclosporin	B-Chemical
A	I-Chemical
(	O
CsA	B-Chemical
;	O
50	O
mg	O
/	O
kg	O
)	O
and	O
Fujimycine	B-Chemical
(	O
FK506	B-Chemical
;	O
5	O
mg	O
/	O
kg	O
)	O
,	O
but	O
not	O
the	O
related	O
macrolide	B-Chemical
immunosuppressant	O
rapamycin	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
)	O
,	O
caused	O
a	O
reduction	O
of	O
glomerular	O
filtration	O
rate	O
,	O
degenerative	O
changes	O
of	O
proximal	O
tubular	O
epithelium	O
,	O
and	O
hypertrophy	B-Disease
of	O
the	O
juxtaglomerular	O
apparatus	O
in	O
male	O
Wistar	O
rats	O
when	O
given	O
for	O
10	O
days	O
.	O

The	O
molecular	O
mechanisms	O
of	O
CsA	B-Chemical
and	O
FK506	B-Chemical
toxicity	B-Disease
were	O
investigated	O
.	O

Cyclophilin	O
A	O
and	O
FK506	B-Chemical
-	O
binding	O
protein	O
,	O
the	O
main	O
intracytoplasmic	O
receptors	O
for	O
CsA	B-Chemical
and	O
FK506	B-Chemical
,	O
respectively	O
,	O
were	O
each	O
detected	O
in	O
renal	O
tissue	O
extract	O
.	O

In	O
the	O
kidney	O
,	O
high	O
levels	O
of	O
immunoreactive	O
and	O
enzymatically	O
active	O
calcineurin	O
were	O
found	O
which	O
were	O
inhibited	O
by	O
the	O
immunosuppressants	O
CsA	B-Chemical
and	O
FK506	B-Chemical
,	O
but	O
not	O
by	O
rapamycin	B-Chemical
.	O

Finally	O
,	O
specific	O
immunophilin	O
-	O
drug	O
-	O
calcineurin	O
complexes	O
formed	O
only	O
in	O
the	O
presence	O
of	O
CsA	B-Chemical
and	O
FK506	B-Chemical
,	O
but	O
not	O
rapamycin	B-Chemical
.	O

These	O
results	O
suggest	O
that	O
the	O
nephrotoxic	B-Disease
effects	O
of	O
CsA	B-Chemical
and	O
FK506	B-Chemical
is	O
likely	O
mediated	O
through	O
binding	O
to	O
renal	O
immunophilin	O
and	O
inhibiting	O
calcineurin	O
phosphatase	O
.	O

Acute	B-Disease
renal	I-Disease
failure	I-Disease
in	O
high	O
dose	O
carboplatin	B-Chemical
chemotherapy	O
.	O

Carboplatin	B-Chemical
has	O
been	O
reported	O
to	O
cause	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
when	O
administered	O
in	O
high	O
doses	O
to	O
adult	O
patients	O
.	O

We	O
report	O
a	O
4	O
1	O
/	O
2	O
-	O
year	O
-	O
old	O
girl	O
who	O
was	O
treated	O
with	O
high	O
-	O
dose	O
carboplatin	B-Chemical
for	O
metastatic	O
parameningeal	O
embryonal	B-Disease
rhabdomyosarcoma	I-Disease
.	O

Acute	B-Disease
renal	I-Disease
failure	I-Disease
developed	O
followed	O
by	O
a	O
slow	O
partial	O
recovery	O
of	O
renal	O
function	O
.	O

Possible	O
contributing	O
factors	O
are	O
discussed	O
.	O

Clinical	O
evaluation	O
on	O
combined	O
administration	O
of	O
oral	O
prostacyclin	B-Chemical
analogue	O
beraprost	B-Chemical
and	O
phosphodiesterase	O
inhibitor	O
cilostazol	B-Chemical
.	O

Among	O
various	O
oral	O
antiplatelets	O
,	O
a	O
combination	O
of	O
a	O
novel	O
prostacyclin	B-Chemical
analogue	O
beraprost	B-Chemical
(	O
BPT	B-Chemical
)	O
and	O
a	O
potent	O
phosphodiesterase	O
inhibitor	O
cilostazol	B-Chemical
(	O
CLZ	B-Chemical
)	O
may	O
result	O
in	O
untoward	O
clinical	O
effects	O
due	O
to	O
possible	O
synergistic	O
elevation	O
of	O
intracellular	O
cAMP	B-Chemical
(	O
cyclic	B-Chemical
adenosine	I-Chemical
3	I-Chemical
'	I-Chemical
,	I-Chemical
5	I-Chemical
'	I-Chemical
-	I-Chemical
monophosphate	I-Chemical
)	O
.	O

Thereby	O
,	O
a	O
clinical	O
study	O
of	O
the	O
combined	O
administration	O
of	O
the	O
two	O
agents	O
was	O
attempted	O
.	O

Twelve	O
healthy	O
volunteers	O
were	O
assigned	O
to	O
take	O
BPT	B-Chemical
/	O
CLZ	B-Chemical
in	O
the	O
following	O
schedule	O
;	O
BPT	B-Chemical
:	O
40	O
micrograms	O
at	O
day	O
1	O
and	O
120	O
micrograms	O
t	O
.	O
i	O
.	O
d	O
.	O
from	O
day	O
7	O
to	O
14	O
,	O
CLZ	B-Chemical
:	O
200	O
mg	O
t	O
.	O
i	O
.	O
d	O
.	O
from	O
day	O
3	O
to	O
14	O
.	O

At	O
various	O
time	O
intervals	O
,	O
physical	O
examination	O
and	O
blood	O
collection	O
for	O
ex	O
vivo	O
platelet	B-Disease
aggregation	I-Disease
and	O
determination	O
of	O
intraplatelet	O
cAMP	B-Chemical
were	O
performed	O
.	O

Throughout	O
the	O
observation	O
period	O
,	O
no	O
significant	O
alteration	O
in	O
vital	O
signs	O
was	O
observed	O
.	O

Seven	O
out	O
of	O
12	O
subjects	O
experienced	O
headache	B-Disease
of	O
a	O
short	O
duration	O
accompanying	O
facial	B-Disease
flush	I-Disease
in	O
one	O
and	O
nausea	B-Disease
in	O
one	O
,	O
especially	O
after	O
ingestion	O
of	O
CLZ	B-Chemical
.	O

All	O
of	O
these	O
symptoms	O
,	O
probably	O
caused	O
by	O
the	O
vasodilating	O
effect	O
of	O
the	O
two	O
agents	O
,	O
were	O
of	O
mild	O
degree	O
and	O
no	O
special	O
treatment	O
was	O
required	O
.	O

Intraplatelet	O
cAMP	B-Chemical
content	O
was	O
gradually	O
but	O
significantly	O
increased	O
to	O
9	O
.	O
84	O
+	O
/	O
-	O
4	O
.	O
59	O
pmol	O
per	O
10	O
(	O
9	O
)	O
platelets	O
at	O
day	O
14	O
in	O
comparison	O
with	O
the	O
initial	O
value	O
(	O
6	O
.	O
87	O
+	O
/	O
-	O
2	O
.	O
25	O
pmol	O
)	O
.	O

The	O
platelet	O
aggregability	O
was	O
significantly	O
suppressed	O
at	O
various	O
time	O
intervals	O
but	O
no	O
additive	O
or	O
synergistic	O
inhibitory	O
effect	O
by	O
the	O
combined	O
administration	O
was	O
noted	O
.	O

In	O
conclusion	O
,	O
the	O
combined	O
administration	O
of	O
BPT	B-Chemical
/	O
CLZ	B-Chemical
is	O
safe	O
at	O
doses	O
used	O
in	O
the	O
study	O
,	O
though	O
the	O
beneficial	O
clinical	O
effect	O
of	O
the	O
combined	O
administration	O
has	O
yet	O
to	O
be	O
elucidated	O
.	O

Pravastatin	B-Chemical
-	O
associated	O
myopathy	B-Disease
.	O

Report	O
of	O
a	O
case	O
.	O

A	O
case	O
of	O
acute	O
inflammatory	B-Disease
myopathy	I-Disease
associated	O
with	O
the	O
use	O
of	O
pravastatin	B-Chemical
,	O
a	O
new	O
hydrophilic	O
3	O
-	O
hydroxy	O
-	O
3	O
methylglutaril	O
coenzyme	O
A	O
reductase	O
inhibitor	O
,	O
is	O
reported	O
.	O

The	O
patient	O
,	O
a	O
69	O
-	O
year	O
-	O
old	O
man	O
was	O
affected	O
by	O
non	B-Disease
-	I-Disease
insulin	I-Disease
-	I-Disease
dependent	I-Disease
diabetes	I-Disease
mellitus	I-Disease
and	O
hypertension	B-Disease
.	O

He	O
assumed	O
pravastatin	B-Chemical
(	O
20	O
mg	O
/	O
day	O
)	O
because	O
of	O
hypercholesterolemia	B-Disease
.	O

He	O
was	O
admitted	O
with	O
acute	O
myopathy	B-Disease
of	O
the	O
lower	O
limbs	O
which	O
resolved	O
in	O
a	O
few	O
days	O
after	O
pravastatin	B-Chemical
discontinuation	O
.	O

A	O
previously	O
unknown	O
hypothyroidism	B-Disease
,	O
probably	O
due	O
to	O
chronic	O
autoimmune	B-Disease
thyroiditis	I-Disease
,	O
was	O
evidenced	O
.	O

Muscle	O
biopsy	O
(	O
left	O
gastrocnemius	O
)	O
revealed	O
a	O
perimysial	O
and	O
endomysial	O
inflammatory	O
infiltrate	O
with	O
a	O
prevalence	O
of	O
CD4	O
+	O
lymphocytes	O
.	O

While	O
lovastatin	B-Chemical
and	O
simvastatin	B-Chemical
have	O
been	O
associated	O
with	O
toxic	O
myopathy	B-Disease
,	O
pravastatin	B-Chemical
-	O
associated	O
myopathy	B-Disease
could	O
represent	O
a	O
distinct	O
,	O
inflammatory	O
entity	O
.	O

Reversal	O
of	O
ammonia	B-Chemical
coma	B-Disease
in	O
rats	O
by	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
:	O
a	O
peripheral	O
effect	O
.	O

Ammonia	B-Chemical
coma	B-Disease
was	O
produced	O
in	O
rats	O
within	O
10	O
to	O
15	O
minutes	O
of	O
an	O
intraperitonealinjection	O
of	O
1	O
.	O
7	O
mmol	O
NH4CL	B-Chemical
.	O

This	O
coma	B-Disease
was	O
prevented	O
with	O
1	O
.	O
68	O
mmol	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
given	O
by	O
gastric	O
intubation	O
15	O
minutes	O
before	O
the	O
ammonium	B-Chemical
salt	I-Chemical
injection	O
.	O

The	O
effect	O
of	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
was	O
correlated	O
with	O
a	O
decrease	O
in	O
blood	O
and	O
brain	O
ammonia	B-Chemical
,	O
an	O
increase	O
in	O
brain	O
dopamine	B-Chemical
,	O
and	O
an	O
increase	O
in	O
renal	O
excretion	O
of	O
ammonia	B-Chemical
and	O
urea	B-Chemical
.	O

Intraventricular	O
infusion	O
of	O
dopamine	B-Chemical
sufficient	O
to	O
raise	O
the	O
brain	O
dopamine	B-Chemical
to	O
the	O
same	O
extent	O
did	O
not	O
prevent	O
the	O
ammonia	B-Chemical
coma	B-Disease
nor	O
affect	O
the	O
blood	O
and	O
brain	O
ammonia	B-Chemical
concentrations	O
.	O

Bilateral	O
nephrectomy	O
eliminated	O
the	O
beneficial	O
effect	O
of	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
on	O
blood	O
and	O
brain	O
ammonia	B-Chemical
and	O
the	O
ammonia	B-Chemical
coma	B-Disease
was	O
not	O
prevented	O
.	O

Thus	O
,	O
the	O
reduction	O
in	O
blood	O
and	O
brain	O
ammonia	B-Chemical
and	O
the	O
prevention	O
of	O
ammonia	B-Chemical
coma	B-Disease
after	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
,	O
can	O
be	O
accounted	O
for	O
by	O
the	O
peripheral	O
effect	O
of	O
dopamine	B-Chemical
on	O
renal	O
function	O
rather	O
than	O
its	O
central	O
action	O
.	O

These	O
results	O
provide	O
a	O
reasonable	O
explanation	O
for	O
the	O
beneficial	O
effects	O
observed	O
in	O
some	O
encephalopathic	B-Disease
patients	O
receiving	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
.	O

Etoposide	B-Chemical
-	O
related	O
myocardial	B-Disease
infarction	I-Disease
.	O

The	O
occurrence	O
of	O
a	O
myocardial	B-Disease
infarction	I-Disease
is	O
reported	O
after	O
chemotherapy	O
containing	O
etoposide	B-Chemical
,	O
in	O
a	O
man	O
with	O
no	O
risk	O
factors	O
for	O
coronary	B-Disease
heart	I-Disease
disease	I-Disease
.	O

Possible	O
causal	O
mechanisms	O
are	O
discussed	O
.	O

Halogenated	O
anesthetics	O
form	O
liver	O
adducts	O
and	O
antigens	O
that	O
cross	O
-	O
react	O
with	O
halothane	B-Chemical
-	O
induced	O
antibodies	O
.	O

Two	O
halogenated	O
anesthetics	O
,	O
enflurane	B-Chemical
and	O
isoflurane	B-Chemical
,	O
have	O
been	O
associated	O
with	O
an	O
allergic	O
-	O
type	O
hepatic	B-Disease
injury	I-Disease
both	O
alone	O
and	O
following	O
previous	O
exposure	O
to	O
halothane	B-Chemical
.	O

Halothane	B-Chemical
hepatitis	B-Disease
appears	O
to	O
involve	O
an	O
aberrant	O
immune	O
response	O
.	O

An	O
antibody	O
response	O
to	O
a	O
protein	O
-	O
bound	O
biotransformation	O
product	O
(	O
trifluoroacetyl	B-Chemical
adduct	O
)	O
has	O
been	O
detected	O
on	O
halothane	B-Chemical
hepatitis	B-Disease
patients	O
.	O

This	O
study	O
was	O
performed	O
to	O
determine	O
cross	O
-	O
reactivity	O
between	O
enflurane	B-Chemical
and	O
isoflurane	B-Chemical
with	O
the	O
hypersensitivity	B-Disease
induced	O
by	O
halothane	B-Chemical
.	O

The	O
subcellular	O
and	O
lobular	O
production	O
of	O
hepatic	O
neoantigens	O
recognized	O
by	O
halothane	B-Chemical
-	O
induced	O
antibodies	O
following	O
enflurane	B-Chemical
and	O
isoflurane	B-Chemical
,	O
and	O
the	O
biochemical	O
nature	O
of	O
these	O
neoantigens	O
was	O
investigated	O
in	O
two	O
animal	O
models	O
.	O

Enflurane	B-Chemical
administration	O
resulted	O
in	O
neoantigens	O
detected	O
in	O
both	O
the	O
microsomal	O
and	O
cytosolic	O
fraction	O
of	O
liver	O
homogenates	O
and	O
in	O
the	O
centrilobular	O
region	O
of	O
the	O
liver	O
.	O

In	O
the	O
same	O
liver	O
,	O
biochemical	O
analysis	O
detected	O
fluorinated	O
liver	O
adducts	O
that	O
were	O
up	O
to	O
20	O
-	O
fold	O
greater	O
in	O
guinea	O
pigs	O
than	O
in	O
rats	O
.	O

This	O
supports	O
and	O
extends	O
previous	O
evidence	O
for	O
a	O
mechanism	O
by	O
which	O
enflurane	B-Chemical
and	O
/	O
or	O
isoflurane	B-Chemical
could	O
produce	O
a	O
hypersensitivity	B-Disease
condition	O
similar	O
to	O
that	O
of	O
halothane	B-Chemical
hepatitis	B-Disease
either	O
alone	O
or	O
subsequent	O
to	O
halothane	B-Chemical
administration	O
.	O

The	O
guinea	O
pig	O
would	O
appear	O
to	O
be	O
a	O
useful	O
model	O
for	O
further	O
investigations	O
of	O
the	O
immunological	O
response	O
to	O
these	O
antigens	O
.	O

Cholinergic	O
toxicity	B-Disease
resulting	O
from	O
ocular	O
instillation	O
of	O
echothiophate	B-Chemical
iodide	I-Chemical
eye	O
drops	O
.	O

A	O
patient	O
developed	O
a	O
severe	O
cholinergic	O
syndrome	O
from	O
the	O
use	O
of	O
echothiophate	B-Chemical
iodide	I-Chemical
ophthalmic	O
drops	O
,	O
presented	O
with	O
profound	O
muscle	B-Disease
weakness	I-Disease
and	O
was	O
initially	O
given	O
the	O
diagnosis	O
of	O
myasthenia	B-Disease
gravis	I-Disease
.	O

Red	O
blood	O
cell	O
and	O
serum	O
cholinesterase	O
levels	O
were	O
severely	O
depressed	O
and	O
symptoms	O
resolved	O
spontaneously	O
following	O
discontinuation	O
of	O
the	O
eye	O
drops	O
.	O

Seizure	B-Disease
after	O
flumazenil	B-Chemical
administration	O
in	O
a	O
pediatric	O
patient	O
.	O

Flumazenil	B-Chemical
is	O
a	O
benzodiazepine	B-Chemical
receptor	O
antagonist	O
used	O
to	O
reverse	O
sedation	O
and	O
respiratory	B-Disease
depression	I-Disease
induced	O
by	O
benzodiazepines	B-Chemical
.	O

Seizures	B-Disease
and	O
cardiac	B-Disease
arrhythmias	I-Disease
have	O
complicated	O
its	O
use	O
in	O
adult	O
patients	O
.	O

Overdose	B-Disease
patients	O
who	O
have	O
coingested	O
tricyclic	O
antidepressants	O
have	O
a	O
higher	O
risk	O
of	O
these	O
complications	O
.	O

Little	O
information	O
exists	O
concerning	O
adverse	O
effects	O
of	O
flumazenil	B-Chemical
in	O
children	O
.	O

We	O
report	O
the	O
occurrence	O
of	O
a	O
generalized	O
tonic	B-Disease
-	I-Disease
clonic	I-Disease
seizure	I-Disease
in	O
a	O
pediatric	O
patient	O
following	O
the	O
administration	O
of	O
flumazenil	B-Chemical
.	O

Phase	O
I	O
trial	O
of	O
13	B-Chemical
-	I-Chemical
cis	I-Chemical
-	I-Chemical
retinoic	I-Chemical
acid	I-Chemical
in	O
children	O
with	O
neuroblastoma	B-Disease
following	O
bone	O
marrow	O
transplantation	O
.	O

PURPOSE	O
:	O
Treatment	O
of	O
neuroblastoma	B-Disease
cell	O
lines	O
with	O
13	B-Chemical
-	I-Chemical
cis	I-Chemical
-	I-Chemical
retinoic	I-Chemical
acid	I-Chemical
(	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
)	O
can	O
cause	O
sustained	O
inhibition	O
of	O
proliferation	O
.	O

Since	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
has	O
demonstrated	O
clinical	O
responses	O
in	O
neuroblastoma	B-Disease
patients	O
,	O
it	O
may	O
be	O
effective	O
in	O
preventing	O
relapse	O
after	O
cytotoxic	O
therapy	O
.	O

This	O
phase	O
I	O
trial	O
was	O
designed	O
to	O
determine	O
the	O
maximal	O
-	O
tolerated	O
dosage	O
(	O
MTD	O
)	O
,	O
toxicities	B-Disease
,	O
and	O
pharmacokinetics	O
of	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
administered	O
on	O
an	O
intermittent	O
schedule	O
in	O
children	O
with	O
neuroblastoma	B-Disease
following	O
bone	O
marrow	O
transplantation	O
(	O
BMT	O
)	O
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
Fifty	O
-	O
one	O
assessable	O
patients	O
,	O
2	O
to	O
12	O
years	O
of	O
age	O
,	O
were	O
treated	O
with	O
oral	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
administered	O
in	O
two	O
equally	O
divided	O
doses	O
daily	O
for	O
2	O
weeks	O
,	O
followed	O
by	O
a	O
2	O
-	O
week	O
rest	O
period	O
,	O
for	O
up	O
to	O
12	O
courses	O
.	O

The	O
dose	O
was	O
escalated	O
from	O
100	O
to	O
200	O
mg	O
/	O
m2	O
/	O
d	O
until	O
dose	O
-	O
limiting	O
toxicity	B-Disease
(	O
DLT	O
)	O
was	O
observed	O
.	O

A	O
single	O
intrapatient	O
dose	O
escalation	O
was	O
permitted	O
.	O

RESULTS	O
:	O
The	O
MTD	O
of	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
was	O
160	O
mg	O
/	O
m2	O
/	O
d	O
.	O

Dose	O
-	O
limiting	O
toxicities	B-Disease
in	O
six	O
of	O
nine	O
patients	O
at	O
200	O
mg	O
/	O
m2	O
/	O
d	O
included	O
hypercalcemia	B-Disease
(	O
n	O
=	O
3	O
)	O
,	O
rash	B-Disease
(	O
n	O
=	O
2	O
)	O
,	O
and	O
anemia	B-Disease
/	O
thrombocytopenia	B-Disease
/	O
emesis	B-Disease
/	O
rash	B-Disease
(	O
n	O
=	O
1	O
)	O
.	O

All	O
toxicities	B-Disease
resolved	O
after	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
was	O
discontinued	O
.	O

Three	O
complete	O
responses	O
were	O
observed	O
in	O
marrow	O
metastases	B-Disease
.	O

Serum	O
levels	O
of	O
7	O
.	O
4	O
+	O
/	O
-	O
3	O
.	O
0	O
mumol	O
/	O
L	O
(	O
peak	O
)	O
and	O
4	O
.	O
0	O
+	O
/	O
-	O
2	O
.	O
8	O
mumol	O
/	O
L	O
(	O
trough	O
)	O
at	O
the	O
MTD	O
were	O
maintained	O
during	O
14	O
days	O
of	O
therapy	O
.	O

The	O
DLT	O
correlated	O
with	O
serum	O
levels	O
>	O
or	O
=	O
10	O
mumol	O
/	O
L	O
.	O

CONCLUSION	O
:	O
The	O
MTD	O
of	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
given	O
on	O
this	O
intermittent	O
schedule	O
was	O
160	O
mg	O
/	O
m2	O
/	O
d	O
.	O

Serum	O
levels	O
known	O
to	O
be	O
effective	O
against	O
neuroblastoma	B-Disease
in	O
vitro	O
were	O
achieved	O
at	O
this	O
dose	O
.	O

The	O
DLT	O
included	O
hypercalcemia	B-Disease
,	O
and	O
may	O
be	O
predicted	O
by	O
serum	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
levels	O
.	O

Monitoring	O
of	O
serum	O
calcium	B-Chemical
and	O
cis	B-Chemical
-	I-Chemical
RA	I-Chemical
levels	O
is	O
indicated	O
in	O
future	O
trials	O
.	O

Time	O
dependence	O
of	O
plasma	O
malondialdehyde	B-Chemical
,	O
oxypurines	B-Chemical
,	O
and	O
nucleosides	B-Chemical
during	O
incomplete	O
cerebral	B-Disease
ischemia	I-Disease
in	O
the	O
rat	O
.	O

Incomplete	O
cerebral	B-Disease
ischemia	I-Disease
(	O
30	O
min	O
)	O
was	O
induced	O
in	O
the	O
rat	O
by	O
bilaterally	O
clamping	O
the	O
common	O
carotid	O
arteries	O
.	O

Peripheral	O
venous	O
blood	O
samples	O
were	O
withdrawn	O
from	O
the	O
femoral	O
vein	O
four	O
times	O
(	O
once	O
every	O
5	O
min	O
)	O
before	O
ischemia	B-Disease
(	O
0	O
time	O
)	O
and	O
5	O
,	O
15	O
,	O
and	O
30	O
min	O
after	O
ischemia	B-Disease
.	O

Plasma	O
extracts	O
were	O
analyzed	O
by	O
a	O
highly	O
sensitive	O
high	O
-	O
performance	O
liquid	O
chromatographic	O
method	O
for	O
the	O
direct	O
determination	O
of	O
malondialdehyde	B-Chemical
,	O
oxypurines	B-Chemical
,	O
and	O
nucleosides	B-Chemical
.	O

During	O
ischemia	B-Disease
,	O
a	O
time	O
-	O
dependent	O
increase	O
of	O
plasma	O
oxypurines	B-Chemical
and	O
nucleosides	B-Chemical
was	O
observed	O
.	O

Plasma	O
malondialdehyde	B-Chemical
,	O
which	O
was	O
present	O
in	O
minimal	O
amount	O
at	O
zero	O
time	O
(	O
0	O
.	O
058	O
mumol	O
/	O
liter	O
plasma	O
;	O
SD	O
0	O
.	O
015	O
)	O
,	O
increased	O
after	O
5	O
min	O
of	O
ischemia	B-Disease
,	O
resulting	O
in	O
a	O
fivefold	O
increase	O
after	O
30	O
min	O
of	O
carotid	O
occlusion	O
(	O
0	O
.	O
298	O
mumol	O
/	O
liter	O
plasma	O
;	O
SD	O
0	O
.	O
078	O
)	O
.	O

Increased	O
plasma	O
malondialdehyde	B-Chemical
was	O
also	O
recorded	O
in	O
two	O
other	O
groups	O
of	O
animals	O
subjected	O
to	O
the	O
same	O
experimental	O
model	O
,	O
one	O
receiving	O
20	O
mg	O
/	O
kg	O
b	O
.	O
w	O
.	O
of	O
the	O
cyclooxygenase	O
inhibitor	O
acetylsalicylate	B-Chemical
intravenously	O
immediately	O
before	O
ischemia	B-Disease
,	O
the	O
other	O
receiving	O
650	O
micrograms	O
/	O
kg	O
b	O
.	O
w	O
.	O
of	O
the	O
hypotensive	B-Disease
drug	O
nitroprusside	B-Chemical
at	O
a	O
flow	O
rate	O
of	O
103	O
microliters	O
/	O
min	O
intravenously	O
during	O
ischemia	B-Disease
,	O
although	O
in	O
this	O
latter	O
group	O
malondialdehyde	B-Chemical
was	O
significantly	O
higher	O
.	O

The	O
present	O
data	O
indicate	O
that	O
the	O
determination	O
of	O
malondialdehyde	B-Chemical
,	O
oxypurines	B-Chemical
,	O
and	O
nucleosides	B-Chemical
in	O
peripheral	O
blood	O
,	O
may	O
be	O
used	O
to	O
monitor	O
the	O
metabolic	O
alterations	O
of	O
tissues	O
occurring	O
during	O
ischemic	B-Disease
phenomena	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Acute	O
renal	B-Disease
toxicity	I-Disease
of	O
doxorubicin	B-Chemical
(	O
adriamycin	B-Chemical
)	O
-	O
loaded	O
cyanoacrylate	B-Chemical
nanoparticles	O
.	O

Acute	O
doxorubicin	B-Chemical
-	O
loaded	O
nanoparticle	O
(	O
DXNP	O
)	O
renal	B-Disease
toxicity	I-Disease
was	O
explored	O
in	O
both	O
normal	O
rats	O
and	O
rats	O
with	O
experimental	O
glomerulonephritis	B-Disease
.	O

In	O
normal	O
rats	O
,	O
2	O
/	O
6	O
rats	O
given	O
free	O
doxorubicin	B-Chemical
(	O
DX	B-Chemical
)	O
(	O
5	O
mg	O
/	O
kg	O
)	O
died	O
within	O
one	O
week	O
,	O
whereas	O
all	O
control	O
animals	O
and	O
all	O
rats	O
having	O
received	O
free	O
NP	O
or	O
DXNP	O
survived	O
.	O

A	O
3	O
times	O
higher	O
proteinuria	B-Disease
appeared	O
in	O
animals	O
treated	O
with	O
DXNP	O
than	O
in	O
those	O
treated	O
with	O
DX	B-Chemical
.	O

Free	O
NP	O
did	O
not	O
provoke	O
any	O
proteinuria	B-Disease
.	O

Two	O
hr	O
post	O
-	O
injection	O
,	O
DXNP	O
was	O
2	O
.	O
7	O
times	O
more	O
concentrated	O
in	O
kidneys	O
than	O
free	O
DX	B-Chemical
(	O
p	O
<	O
0	O
.	O
025	O
)	O
.	O

In	O
rats	O
with	O
immune	O
experimental	O
glomerulonephritis	B-Disease
,	O
5	O
/	O
6	O
rats	O
given	O
DX	B-Chemical
died	O
within	O
7	O
days	O
,	O
in	O
contrast	O
to	O
animals	O
treated	O
by	O
DXNP	O
,	O
NP	O
,	O
or	O
untreated	O
,	O
which	O
all	O
survived	O
.	O

Proteinuria	B-Disease
appeared	O
in	O
all	O
series	O
,	O
but	O
was	O
2	O
-	O
5	O
times	O
more	O
intense	O
(	O
p	O
>	O
0	O
.	O
001	O
)	O
and	O
prolonged	O
after	O
doxorubicin	B-Chemical
treatment	O
(	O
400	O
-	O
700	O
mg	O
/	O
day	O
)	O
,	O
without	O
significant	O
difference	O
between	O
DXNP	O
and	O
DX	B-Chemical
.	O

Rats	O
treated	O
by	O
unloaded	O
NP	O
behaved	O
as	O
controls	O
.	O

These	O
results	O
demonstrate	O
that	O
,	O
in	O
these	O
experimental	O
conditions	O
,	O
DXNP	O
killed	O
less	O
animals	O
than	O
free	O
DX	B-Chemical
,	O
despite	O
of	O
an	O
enhanced	O
renal	B-Disease
toxicity	I-Disease
of	O
the	O
former	O
.	O

Both	O
effects	O
(	O
better	O
survival	O
and	O
nephrosis	B-Disease
)	O
are	O
most	O
probably	O
related	O
to	O
an	O
enhanced	O
capture	O
of	O
DXNP	O
by	O
cells	O
of	O
the	O
mononuclear	O
phagocyte	O
system	O
,	O
including	O
mesangial	O
cells	O
.	O

Prostaglandin	B-Chemical
E2	I-Chemical
-	O
induced	O
bladder	B-Disease
hyperactivity	I-Disease
in	O
normal	O
,	O
conscious	O
rats	O
:	O
involvement	O
of	O
tachykinins	B-Chemical
?	O

In	O
normal	O
conscious	O
rats	O
investigated	O
by	O
continuous	O
cystometry	O
,	O
intravesically	O
instilled	O
prostaglandin	B-Chemical
(	I-Chemical
PG	I-Chemical
)	I-Chemical
E2	I-Chemical
facilitated	O
micturition	O
and	O
increased	O
basal	O
intravesical	O
pressure	O
.	O

The	O
effect	O
was	O
attenuated	O
by	O
both	O
the	O
NK1	O
receptor	O
selective	O
antagonist	O
RP	B-Chemical
67	I-Chemical
,	I-Chemical
580	I-Chemical
and	O
the	O
NK2	O
receptor	O
selective	O
antagonist	O
SR	B-Chemical
48	I-Chemical
,	I-Chemical
968	I-Chemical
,	O
given	O
intra	O
-	O
arterially	O
,	O
suggesting	O
that	O
it	O
was	O
mediated	O
by	O
stimulation	O
of	O
both	O
NK1	O
and	O
NK2	O
receptors	O
.	O

Intra	O
-	O
arterially	O
given	O
PGE2	B-Chemical
produced	O
a	O
distinct	O
increase	O
in	O
bladder	O
pressure	O
before	O
initiating	O
a	O
micturition	O
reflex	O
,	O
indicating	O
that	O
the	O
PG	B-Chemical
had	O
a	O
direct	O
contractant	O
effect	O
on	O
the	O
detrusor	O
smooth	O
muscle	O
.	O

The	O
effect	O
of	O
intra	O
-	O
arterial	O
PGE2	B-Chemical
could	O
not	O
be	O
blocked	O
by	O
intra	O
-	O
arterial	O
RP	B-Chemical
67	I-Chemical
,	I-Chemical
580	I-Chemical
or	O
SR	B-Chemical
48	I-Chemical
,	I-Chemical
968	I-Chemical
,	O
which	O
opens	O
the	O
possibility	O
that	O
the	O
micturition	O
reflex	O
elicited	O
by	O
intra	O
-	O
arterial	O
PGE2	B-Chemical
was	O
mediated	O
by	O
pathways	O
other	O
than	O
the	O
reflex	O
initiated	O
when	O
the	O
PG	B-Chemical
was	O
given	O
intravesically	O
.	O

The	O
present	O
results	O
thus	O
suggest	O
that	O
intra	O
-	O
arterial	O
PGE2	B-Chemical
,	O
given	O
near	O
the	O
bladder	O
,	O
may	O
initiate	O
micturition	O
in	O
the	O
normal	O
rat	O
chiefly	O
by	O
directly	O
contracting	O
the	O
smooth	O
muscle	O
of	O
the	O
detrusor	O
.	O

However	O
,	O
when	O
given	O
intravesically	O
,	O
PGE2	B-Chemical
may	O
stimulate	O
micturition	O
by	O
releasing	O
tachykinins	B-Chemical
from	O
nerves	O
in	O
and	O
/	O
or	O
immediately	O
below	O
the	O
urothelium	O
.	O

These	O
tachykinins	B-Chemical
,	O
in	O
turn	O
,	O
initiate	O
a	O
micturition	O
reflex	O
by	O
stimulating	O
NK1	O
and	O
NK2	O
receptors	O
.	O

Prostanoids	B-Chemical
may	O
,	O
via	O
release	O
of	O
tachykinins	B-Chemical
,	O
contribute	O
to	O
both	O
urge	O
and	O
bladder	B-Disease
hyperactivity	I-Disease
seen	O
in	O
inflammatory	O
conditions	O
of	O
the	O
lower	O
urinary	O
tract	O
.	O

Refractory	O
cardiogenic	B-Disease
shock	I-Disease
and	O
complete	O
heart	B-Disease
block	I-Disease
after	O
verapamil	B-Chemical
SR	O
and	O
metoprolol	B-Chemical
treatment	O
.	O

A	O
case	O
report	O
.	O

A	O
seventy	O
-	O
eight	O
-	O
year	O
-	O
old	O
woman	O
presented	O
with	O
complete	O
heart	B-Disease
block	I-Disease
and	O
refractory	O
hypotension	B-Disease
two	O
days	O
after	O
a	O
therapeutic	O
dose	O
of	O
sustained	O
-	O
release	O
verapamil	B-Chemical
with	O
concomitant	O
use	O
of	O
metoprolol	B-Chemical
.	O

The	O
patient	O
continued	O
to	O
remain	O
hypotensive	B-Disease
with	O
complete	O
heart	B-Disease
block	I-Disease
,	O
even	O
with	O
multiple	O
uses	O
of	O
intravenous	O
atropine	B-Chemical
as	O
well	O
as	O
high	O
doses	O
of	O
pressor	O
agents	O
such	O
as	O
dopamine	B-Chemical
and	O
dobutamine	B-Chemical
.	O

However	O
,	O
shortly	O
after	O
the	O
use	O
of	O
intravenous	O
calcium	B-Chemical
chloride	I-Chemical
,	O
the	O
refractory	O
hypotension	B-Disease
and	O
complete	O
heart	B-Disease
block	I-Disease
resolved	O
.	O

Protective	O
effect	O
of	O
misoprostol	B-Chemical
on	O
indomethacin	B-Chemical
induced	O
renal	B-Disease
dysfunction	I-Disease
in	O
elderly	O
patients	O
.	O

OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
possible	O
protective	O
effects	O
of	O
misoprostol	B-Chemical
on	O
renal	O
function	O
in	O
hospitalized	O
elderly	O
patients	O
treated	O
with	O
indomethacin	B-Chemical
.	O

METHODS	O
:	O
Forty	O
-	O
five	O
hospitalized	O
elderly	O
patients	O
(	O
>	O
65	O
years	O
old	O
)	O
who	O
required	O
therapy	O
with	O
nonsteroidal	O
antiinflammatory	O
drugs	O
(	O
NSAID	O
)	O
were	O
randomly	O
assigned	O
to	O
receive	O
either	O
indomethacin	B-Chemical
,	O
150	O
mg	O
/	O
day	O
(	O
Group	O
A	O
)	O
,	O
or	O
indomethacin	B-Chemical
150	O
mg	O
/	O
day	O
plus	O
misoprostol	B-Chemical
at	O
0	O
.	O
6	O
mg	O
/	O
day	O
(	O
Group	O
B	O
)	O
.	O

Laboratory	O
variables	O
of	O
renal	O
function	O
[	O
serum	O
creatinine	B-Chemical
,	O
blood	B-Chemical
urea	I-Chemical
nitrogen	I-Chemical
(	O
BUN	B-Chemical
)	O
and	O
electrolytes	O
]	O
were	O
evaluated	O
before	O
initiation	O
of	O
therapy	O
and	O
every	O
2	O
days	O
,	O
until	O
termination	O
of	O
the	O
study	O
(	O
a	O
period	O
of	O
at	O
least	O
6	O
days	O
)	O
.	O

Response	O
to	O
treatment	O
was	O
estimated	O
by	O
the	O
visual	O
analog	O
scale	O
for	O
severity	O
of	O
pain	B-Disease
.	O

RESULTS	O
:	O
Forty	O
-	O
two	O
patients	O
completed	O
the	O
study	O
,	O
22	O
in	O
Group	O
A	O
and	O
20	O
in	O
Group	O
B	O
.	O

BUN	B-Chemical
and	O
creatinine	B-Chemical
increased	O
by	O
>	O
50	O
%	O
of	O
baseline	O
levels	O
in	O
54	O
and	O
45	O
%	O
of	O
Group	O
A	O
patients	O
,	O
respectively	O
,	O
compared	O
to	O
only	O
20	O
and	O
10	O
%	O
of	O
Group	O
B	O
patients	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

Potassium	B-Chemical
(	O
K	B-Chemical
)	O
increment	O
of	O
0	O
.	O
6	O
mEq	O
/	O
l	O
or	O
more	O
was	O
observed	O
in	O
50	O
%	O
of	O
Group	O
A	O
,	O
but	O
in	O
only	O
15	O
%	O
of	O
Group	O
B	O
patients	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

The	O
mean	O
increments	O
in	O
BUN	B-Chemical
,	O
creatinine	B-Chemical
,	O
and	O
K	B-Chemical
were	O
reduced	O
by	O
63	O
,	O
80	O
,	O
and	O
42	O
%	O
,	O
respectively	O
,	O
in	O
Group	O
B	O
patients	O
compared	O
to	O
Group	O
A	O
.	O
Response	O
to	O
treatment	O
did	O
not	O
differ	O
significantly	O
between	O
the	O
2	O
groups	O
.	O

CONCLUSION	O
:	O
Hospitalized	O
elderly	O
patients	O
are	O
at	O
risk	O
for	O
developing	O
indomethacin	B-Chemical
related	O
renal	B-Disease
dysfunction	I-Disease
.	O

Addition	O
of	O
misoprostol	B-Chemical
can	O
minimize	O
this	O
renal	B-Disease
impairment	I-Disease
without	O
affecting	O
pain	B-Disease
control	O
.	O

Cognitive	B-Disease
deterioration	I-Disease
from	O
long	O
-	O
term	O
abuse	O
of	O
dextromethorphan	B-Chemical
:	O
a	O
case	O
report	O
.	O

Dextromethorphan	B-Chemical
(	O
DM	B-Chemical
)	O
,	O
the	O
dextrorotatory	O
isomer	O
of	O
3	B-Chemical
-	I-Chemical
hydroxy	I-Chemical
-	I-Chemical
N	I-Chemical
-	I-Chemical
methylmorphinan	I-Chemical
,	O
is	O
the	O
main	O
ingredient	O
in	O
a	O
number	O
of	O
widely	O
available	O
,	O
over	O
-	O
the	O
-	O
counter	O
antitussives	O
.	O

Initial	O
studies	O
(	O
Bornstein	O
1968	O
)	O
showed	O
that	O
it	O
possessed	O
no	O
respiratory	O
suppressant	O
effects	O
and	O
no	O
addiction	O
liability	O
.	O

Subsequently	O
,	O
however	O
,	O
several	O
articles	O
reporting	O
abuse	O
of	O
this	O
drug	O
have	O
appeared	O
in	O
the	O
literature	O
.	O

The	O
drug	O
is	O
known	O
to	O
cause	O
a	O
variety	O
of	O
acute	O
toxic	O
effects	O
,	O
ranging	O
from	O
nausea	B-Disease
,	O
restlessness	B-Disease
,	O
insomnia	B-Disease
,	O
ataxia	B-Disease
,	O
slurred	O
speech	O
and	O
nystagmus	B-Disease
to	O
mood	O
changes	O
,	O
perceptual	O
alterations	O
,	O
inattention	O
,	O
disorientation	O
and	O
aggressive	B-Disease
behavior	I-Disease
(	O
Rammer	O
et	O
al	O
1988	O
;	O
Katona	O
and	O
Watson	O
1986	O
;	O
Isbell	O
and	O
Fraser	O
1953	O
;	O
Devlin	O
et	O
al	O
1985	O
;	O
McCarthy	O
1971	O
;	O
Dodds	O
and	O
Revai	O
1967	O
;	O
Degkwitz	O
1964	O
;	O
Hildebrand	O
et	O
al	O
1989	O
)	O
.	O

There	O
have	O
also	O
been	O
two	O
reported	O
fatalities	O
from	O
DM	B-Chemical
overdoses	O
(	O
Fleming	O
1986	O
)	O
.	O

However	O
,	O
there	O
are	O
no	O
reports	O
describing	O
the	O
effects	O
of	O
chronic	O
abuse	O
.	O

This	O
report	O
describes	O
a	O
case	O
of	O
cognitive	B-Disease
deterioration	I-Disease
resulting	O
from	O
prolonged	O
use	O
of	O
DM	B-Chemical
.	O

Effects	O
of	O
ouabain	B-Chemical
on	O
myocardial	O
oxygen	B-Chemical
supply	O
and	O
demand	O
in	O
patients	O
with	O
chronic	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
.	O

A	O
hemodynamic	O
,	O
volumetric	O
,	O
and	O
metabolic	O
study	O
in	O
patients	O
without	O
heart	B-Disease
failure	I-Disease
.	O

The	O
effects	O
of	O
digitalis	B-Chemical
glycosides	I-Chemical
on	O
myocardial	O
oxygen	B-Chemical
supply	O
and	O
demand	O
are	O
of	O
particular	O
interest	O
in	O
the	O
presence	O
of	O
obstructive	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
,	O
but	O
have	O
not	O
been	O
measured	O
previously	O
in	O
man	O
.	O

We	O
assessed	O
the	O
effects	O
of	O
ouabain	B-Chemical
(	O
0	O
.	O
015	O
mg	O
/	O
kg	O
body	O
weight	O
)	O
on	O
hemodynamic	O
,	O
volumetric	O
,	O
and	O
metabolic	O
parameters	O
in	O
11	O
patients	O
with	O
severe	O
chronic	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
without	O
clinical	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
.	O

Because	O
the	O
protocol	O
was	O
long	O
and	O
involved	O
interventions	O
which	O
might	O
affect	O
the	O
determinations	O
,	O
we	O
also	O
studied	O
in	O
nine	O
patients	O
using	O
an	O
identical	O
protocol	O
except	O
that	O
ouabain	B-Chemical
administration	O
was	O
omitted	O
.	O

Left	O
ventricular	O
end	O
-	O
diastolic	O
pressure	O
and	O
left	O
ventricular	O
end	O
-	O
diastolic	O
volume	O
fell	O
in	O
each	O
patient	O
given	O
ouabain	B-Chemical
,	O
even	O
though	O
they	O
were	O
initially	O
elevated	O
in	O
only	O
two	O
patients	O
.	O

Left	O
ventricular	O
end	O
-	O
diastolic	O
pressure	O
fell	O
from	O
11	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
4	O
(	O
mean	O
+	O
/	O
-	O
SE	O
)	O
to	O
5	O
.	O
6	O
+	O
/	O
-	O
0	O
.	O
9	O
mm	O
Hg	O
(	O
P	O
less	O
than	O
0	O
.	O
001	O
)	O
and	O
left	O
ventricular	O
end	O
-	O
diastolic	O
volume	O
fell	O
from	O
100	O
+	O
/	O
-	O
17	O
to	O
82	O
+	O
/	O
-	O
12	O
ml	O
/	O
m2	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
1	O
h	O
after	O
ouabain	B-Chemical
infusion	O
was	O
completed	O
.	O

The	O
maximum	O
velocity	O
of	O
contractile	O
element	O
shortening	O
increased	O
from	O
1	O
.	O
68	O
+	O
/	O
-	O
0	O
.	O
11	O
ml	O
/	O
s	O
to	O
2	O
.	O
18	O
+	O
/	O
-	O
0	O
.	O
21	O
muscle	O
-	O
lengths	O
/	O
s	O
(	O
P	O
less	O
than	O
0	O
.	O
05	O
)	O
and	O
is	O
consistent	O
with	O
an	O
increase	O
in	O
contractility	O
.	O

No	O
significant	O
change	O
in	O
these	O
parameters	O
occurred	O
in	O
the	O
control	O
patients	O
.	O

No	O
significant	O
change	O
in	O
myocardial	O
oxygen	B-Chemical
consumption	O
occurred	O
after	O
ouabain	B-Chemical
administration	O
but	O
this	O
may	O
be	O
related	O
to	O
a	O
greater	O
decrease	O
in	O
mean	O
arterial	O
pressure	O
in	O
the	O
ouabain	B-Chemical
patients	O
than	O
in	O
the	O
control	O
patients	O
.	O

We	O
conclude	O
that	O
in	O
patients	O
with	O
chronic	O
coronary	B-Disease
artery	I-Disease
disease	I-Disease
who	O
are	O
not	O
in	O
clinical	O
congestive	B-Disease
heart	I-Disease
failure	I-Disease
left	B-Disease
ventricular	I-Disease
end	I-Disease
-	I-Disease
diastolic	I-Disease
volume	I-Disease
falls	I-Disease
after	O
ouabain	B-Chemical
administration	O
even	O
when	O
it	O
is	O
initially	O
normal	O
.	O

Though	O
this	O
fall	O
would	O
be	O
associated	O
with	O
a	O
decrease	O
in	O
wall	O
tension	O
,	O
and	O
,	O
therefore	O
,	O
of	O
myocardial	O
oxygen	B-Chemical
consumption	O
,	O
it	O
may	O
not	O
be	O
of	O
sufficient	O
magnitude	O
to	O
prevent	O
a	O
net	O
increase	O
in	O
myocardial	O
oxygen	B-Chemical
consumption	O
.	O

Nevertheless	O
,	O
compensatory	O
mechanisms	O
prevent	O
a	O
deterioration	O
of	O
resting	O
myocardial	O
metabolism	O
.	O

Dexamethasone	B-Chemical
-	O
induced	O
ocular	B-Disease
hypertension	I-Disease
in	O
perfusion	O
-	O
cultured	O
human	O
eyes	O
.	O

PURPOSE	O
:	O
Glucocorticoid	O
administration	O
can	O
lead	O
to	O
the	O
development	O
of	O
ocular	B-Disease
hypertension	I-Disease
and	O
corticosteroid	B-Disease
glaucoma	I-Disease
in	O
a	O
subset	O
of	O
the	O
population	O
through	O
a	O
decrease	O
in	O
the	O
aqueous	O
humor	O
outflow	O
facility	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
determine	O
whether	O
glucocorticoid	O
treatment	O
can	O
directly	O
affect	O
the	O
outflow	O
facility	O
of	O
isolated	O
,	O
perfusion	O
-	O
cultured	O
human	O
eyes	O
.	O

METHODS	O
:	O
The	O
anterior	O
segments	O
of	O
human	O
donor	O
eyes	O
from	O
regional	O
eye	O
banks	O
were	O
placed	O
in	O
a	O
constant	O
flow	O
,	O
variable	O
pressure	O
perfusion	O
culture	O
system	O
.	O

Paired	O
eyes	O
were	O
perfused	O
in	O
serum	O
-	O
free	O
media	O
with	O
or	O
without	O
10	O
(	O
-	O
7	O
)	O
M	O
dexamethasone	B-Chemical
for	O
12	O
days	O
.	O

Intraocular	O
pressure	O
was	O
monitored	O
daily	O
.	O

After	O
incubation	O
,	O
the	O
eyes	O
were	O
morphologically	O
characterized	O
by	O
light	O
microscopy	O
,	O
transmission	O
and	O
scanning	O
electron	O
microscopy	O
,	O
and	O
scanning	O
laser	O
confocal	O
microscopy	O
.	O

RESULTS	O
:	O
A	O
significant	O
increase	O
in	O
intraocular	O
pressure	O
developed	O
in	O
13	O
of	O
the	O
44	O
pairs	O
of	O
eyes	O
perfused	O
with	O
dexamethasone	B-Chemical
with	O
an	O
average	O
pressure	O
rise	O
of	O
17	O
.	O
5	O
+	O
/	O
-	O
3	O
.	O
8	O
mm	O
Hg	O
after	O
12	O
days	O
of	O
dexamethasone	B-Chemical
exposure	O
.	O

The	O
contralateral	O
control	O
eyes	O
,	O
which	O
did	O
not	O
receive	O
dexamethasone	B-Chemical
,	O
maintained	O
a	O
stable	O
intraocular	O
pressure	O
during	O
the	O
same	O
period	O
.	O

The	O
outflow	O
pathway	O
of	O
the	O
untreated	O
eyes	O
appeared	O
morphologically	O
normal	O
.	O

In	O
contrast	O
,	O
the	O
dexamethasone	B-Chemical
-	O
treated	O
hypertensive	B-Disease
eyes	I-Disease
had	O
thickened	O
trabecular	O
beams	O
,	O
decreased	O
intertrabecular	O
spaces	O
,	O
thickened	O
juxtacanalicular	O
tissue	O
,	O
activated	O
trabecular	O
meshwork	O
cells	O
,	O
and	O
increased	O
amounts	O
of	O
amorphogranular	O
extracellular	O
material	O
,	O
especially	O
in	O
the	O
juxtacanalicular	O
tissue	O
and	O
beneath	O
the	O
endothelial	O
lining	O
of	O
the	O
canal	O
of	O
Schlemm	O
.	O

The	O
dexamethasone	B-Chemical
-	O
treated	O
nonresponder	O
eyes	O
appeared	O
to	O
be	O
morphologically	O
similar	O
to	O
the	O
untreated	O
eyes	O
,	O
although	O
several	O
subtle	O
dexamethasone	B-Chemical
-	O
induced	O
morphologic	O
changes	O
were	O
evident	O
.	O

CONCLUSION	O
:	O
Dexamethasone	B-Chemical
treatment	O
of	O
isolated	O
,	O
perfusion	O
-	O
cultured	O
human	O
eyes	O
led	O
to	O
the	O
generation	O
of	O
ocular	B-Disease
hypertension	I-Disease
in	O
approximately	O
30	O
%	O
of	O
the	O
dexamethasone	B-Chemical
-	O
treated	O
eyes	O
.	O

Steroid	B-Chemical
treatment	O
resulted	O
in	O
morphologic	O
changes	O
in	O
the	O
trabecular	O
meshwork	O
similar	O
to	O
those	O
reported	O
for	O
corticosteroid	B-Disease
glaucoma	I-Disease
and	O
open	B-Disease
angle	I-Disease
glaucoma	I-Disease
.	O

This	O
system	O
may	O
provide	O
an	O
acute	O
model	O
in	O
which	O
to	O
study	O
the	O
pathogenic	O
mechanisms	O
involved	O
in	O
steroid	B-Disease
glaucoma	I-Disease
and	O
primary	B-Disease
open	I-Disease
angle	I-Disease
glaucoma	I-Disease
.	O

Auditory	O
disturbance	O
associated	O
with	O
interscalene	O
brachial	O
plexus	O
block	O
.	O

We	O
performed	O
an	O
audiometric	O
study	O
in	O
20	O
patients	O
who	O
underwent	O
surgery	O
of	O
the	O
shoulder	O
region	O
under	O
an	O
interscalene	O
brachial	O
plexus	O
block	O
(	O
IBPB	O
)	O
.	O

Bupivacaine	B-Chemical
0	O
.	O
75	O
%	O
with	O
adrenaline	B-Chemical
was	O
given	O
followed	O
by	O
a	O
24	O
-	O
hr	O
continuous	O
infusion	O
of	O
0	O
.	O
25	O
%	O
bupivacaine	B-Chemical
.	O

Three	O
audiometric	O
threshold	O
measurements	O
(	O
0	O
.	O
25	O
-	O
18	O
kHz	O
)	O
were	O
made	O
:	O
the	O
first	O
before	O
IBPB	O
,	O
the	O
second	O
2	O
-	O
6	O
h	O
after	O
surgery	O
and	O
the	O
third	O
on	O
the	O
first	O
day	O
after	O
operation	O
.	O

In	O
four	O
patients	O
hearing	B-Disease
impairment	I-Disease
on	O
the	O
side	O
of	O
the	O
block	O
was	O
demonstrated	O
after	O
operation	O
,	O
in	O
three	O
measurements	O
on	O
the	O
day	O
of	O
surgery	O
and	O
in	O
one	O
on	O
the	O
following	O
day	O
.	O

The	O
frequencies	O
at	O
which	O
the	O
impairment	O
occurred	O
varied	O
between	O
patients	O
;	O
in	O
one	O
only	O
low	O
frequencies	O
(	O
0	O
.	O
25	O
-	O
0	O
.	O
5	O
kHz	O
)	O
were	O
involved	O
.	O

The	O
maximum	O
change	O
in	O
threshold	O
was	O
35	O
dB	O
at	O
6	O
kHz	O
measured	O
at	O
the	O
end	O
of	O
the	O
continuous	O
infusion	O
of	O
bupivacaine	B-Chemical
.	O

This	O
patient	O
had	O
hearing	O
threshold	O
changes	O
(	O
15	O
-	O
20	O
dB	O
)	O
at	O
6	O
-	O
10	O
kHz	O
on	O
the	O
opposite	O
side	O
also	O
.	O

IBPB	O
may	O
cause	O
transient	O
auditory	B-Disease
dysfunction	I-Disease
in	O
the	O
ipsilateral	O
ear	O
,	O
possibly	O
via	O
an	O
effect	O
on	O
sympathetic	O
innervation	O
.	O

The	O
safety	O
and	O
efficacy	O
of	O
combination	O
N	B-Chemical
-	I-Chemical
butyl	I-Chemical
-	I-Chemical
deoxynojirimycin	I-Chemical
(	O
SC	B-Chemical
-	I-Chemical
48334	I-Chemical
)	O
and	O
zidovudine	B-Chemical
in	O
patients	O
with	O
HIV	B-Disease
-	I-Disease
1	I-Disease
infection	I-Disease
and	O
200	O
-	O
500	O
CD4	O
cells	O
/	O
mm3	O
.	O

We	O
conducted	O
a	O
double	O
-	O
blind	O
,	O
randomized	O
phase	O
II	O
study	O
to	O
evaluate	O
the	O
safety	O
and	O
activity	O
of	O
combination	O
therapy	O
with	O
N	B-Chemical
-	I-Chemical
butyl	I-Chemical
-	I-Chemical
deoxynojirimycin	I-Chemical
(	O
SC	B-Chemical
-	I-Chemical
48334	I-Chemical
)	O
(	O
an	O
alpha	O
-	O
glucosidase	O
I	O
inhibitor	O
)	O
and	O
zidovudine	B-Chemical
versus	O
zidovudine	B-Chemical
alone	O
.	O

Patients	O
with	O
200	O
to	O
500	O
CD4	O
cells	O
/	O
mm3	O
who	O
tolerated	O
<	O
or	O
=	O
12	O
weeks	O
of	O
prior	O
zidovudine	B-Chemical
therapy	O
received	O
SC	B-Chemical
-	I-Chemical
48334	I-Chemical
(	O
1000	O
mg	O
every	O
8	O
h	O
)	O
and	O
zidovudine	B-Chemical
(	O
100	O
mg	O
every	O
8	O
h	O
)	O
or	O
zidovudine	B-Chemical
and	O
placebo	O
.	O

Sixty	O
patients	O
received	O
combination	O
therapy	O
and	O
58	O
,	O
zidovudine	B-Chemical
and	O
placebo	O
.	O

Twenty	O
-	O
three	O
patients	O
(	O
38	O
%	O
)	O
and	O
15	O
(	O
26	O
%	O
)	O
,	O
in	O
the	O
combination	O
and	O
zidovudine	B-Chemical
groups	O
,	O
respectively	O
,	O
discontinued	O
therapy	O
(	O
p	O
=	O
0	O
.	O
15	O
)	O
.	O

The	O
mean	O
SC	B-Chemical
-	I-Chemical
48334	I-Chemical
steady	O
-	O
state	O
trough	O
level	O
(	O
4	O
.	O
04	O
+	O
/	O
-	O
0	O
.	O
99	O
micrograms	O
/	O
ml	O
)	O
was	O
below	O
the	O
in	O
vitro	O
inhibitory	O
concentration	O
for	O
human	O
immunodeficiency	B-Disease
virus	O
(	O
HIV	O
)	O
.	O

The	O
mean	O
increase	O
in	O
CD4	O
cells	O
at	O
week	O
4	O
was	O
73	O
.	O
8	O
cells	O
/	O
mm3	O
and	O
52	O
.	O
4	O
cells	O
/	O
mm3	O
for	O
the	O
combination	O
and	O
zidovudine	B-Chemical
groups	O
,	O
respectively	O
(	O
p	O
>	O
0	O
.	O
36	O
)	O
.	O

For	O
patients	O
with	O
prior	O
zidovudine	B-Chemical
therapy	O
,	O
the	O
mean	O
change	O
in	O
CD4	O
cells	O
in	O
the	O
combination	O
and	O
zidovudine	B-Chemical
groups	O
was	O
63	O
.	O
7	O
cells	O
/	O
mm3	O
and	O
4	O
.	O
9	O
cells	O
/	O
mm3	O
at	O
week	O
8	O
and	O
6	O
.	O
8	O
cells	O
/	O
mm3	O
and	O
-	O
45	O
.	O
1	O
cells	O
/	O
mm3	O
at	O
week	O
16	O
,	O
respectively	O
.	O

The	O
number	O
of	O
patients	O
with	O
suppression	O
of	O
HIV	O
p24	O
antigenemia	O
in	O
the	O
combination	O
and	O
zidovudine	B-Chemical
groups	O
was	O
six	O
(	O
40	O
%	O
)	O
and	O
two	O
(	O
11	O
%	O
)	O
at	O
week	O
4	O
(	O
p	O
=	O
0	O
.	O
10	O
)	O
and	O
five	O
(	O
45	O
%	O
)	O
and	O
two	O
(	O
14	O
%	O
)	O
at	O
week	O
24	O
(	O
p	O
=	O
0	O
.	O
08	O
)	O
,	O
respectively	O
.	O

Diarrhea	B-Disease
,	O
flatulence	B-Disease
,	O
abdominal	B-Disease
pain	I-Disease
,	O
and	O
weight	B-Disease
loss	I-Disease
were	O
common	O
for	O
combination	O
recipients	O
.	O
(	O
ABSTRACT	O
TRUNCATED	O
AT	O
250	O
WORDS	O
)	O

Prolonged	O
paralysis	B-Disease
due	O
to	O
nondepolarizing	B-Chemical
neuromuscular	I-Chemical
blocking	I-Chemical
agents	I-Chemical
and	O
corticosteroids	B-Chemical
.	O

The	O
long	O
-	O
term	O
use	O
of	O
nondepolarizing	B-Chemical
neuromuscular	I-Chemical
blocking	I-Chemical
agents	I-Chemical
(	O
ND	B-Chemical
-	I-Chemical
NMBA	I-Chemical
)	O
has	O
recently	O
been	O
implicated	O
as	O
a	O
cause	O
of	O
prolonged	O
muscle	B-Disease
weakness	I-Disease
,	O
although	O
the	O
site	O
of	O
the	O
lesion	O
and	O
the	O
predisposing	O
factors	O
have	O
been	O
unclear	O
.	O

We	O
report	O
3	O
patients	O
(	O
age	O
37	O
-	O
52	O
years	O
)	O
with	O
acute	O
respiratory	B-Disease
insufficiency	I-Disease
who	O
developed	O
prolonged	O
weakness	B-Disease
following	O
the	O
discontinuation	O
of	O
ND	B-Chemical
-	I-Chemical
NMBAs	I-Chemical
.	O

Two	O
patients	O
also	O
received	O
intravenous	O
corticosteroids	B-Chemical
.	O

Renal	O
function	O
was	O
normal	O
but	O
hepatic	O
function	O
was	O
impaired	O
in	O
all	O
patients	O
,	O
and	O
all	O
had	O
acidosis	B-Disease
.	O

Electrophysiologic	O
studies	O
revealed	O
low	O
amplitude	O
compound	O
motor	O
action	O
potentials	O
,	O
normal	O
sensory	O
studies	O
,	O
and	O
fibrillations	O
.	O

Repetitive	O
stimulation	O
at	O
2	O
Hz	O
showed	O
a	O
decremental	O
response	O
in	O
2	O
patients	O
.	O

The	O
serum	O
vecuronium	B-Chemical
level	O
measured	O
in	O
1	O
patient	O
14	O
days	O
after	O
the	O
drug	O
had	O
been	O
discontinued	O
was	O
172	O
ng	O
/	O
mL	O
.	O

A	O
muscle	O
biopsy	O
in	O
this	O
patient	O
showed	O
loss	B-Disease
of	I-Disease
thick	I-Disease
,	I-Disease
myosin	I-Disease
filaments	I-Disease
.	O

The	O
weakness	B-Disease
in	O
these	O
patients	O
is	O
due	O
to	O
pathology	B-Disease
at	I-Disease
both	I-Disease
the	I-Disease
neuromuscular	I-Disease
junction	I-Disease
(	O
most	O
likely	O
due	O
to	O
ND	B-Chemical
-	I-Chemical
NMBA	I-Chemical
)	O
and	O
muscle	O
(	O
most	O
likely	O
due	O
to	O
corticosteroids	B-Chemical
)	O
.	O

Hepatic	B-Disease
dysfunction	I-Disease
and	O
acidosis	B-Disease
are	O
contributing	O
risk	O
factors	O
.	O

Failure	O
of	O
ancrod	O
in	O
the	O
treatment	O
of	O
heparin	B-Chemical
-	O
induced	O
arterial	O
thrombosis	B-Disease
.	O

The	O
morbidity	O
and	O
mortality	O
associated	O
with	O
heparin	B-Chemical
-	O
induced	O
thrombosis	B-Disease
remain	O
high	O
despite	O
numerous	O
empirical	O
therapies	O
.	O

Ancrod	O
has	O
been	O
used	O
successfully	O
for	O
prophylaxis	O
against	O
development	O
of	O
thrombosis	B-Disease
in	O
patients	O
with	O
heparin	B-Chemical
induced	O
platelet	B-Disease
aggregation	I-Disease
who	O
require	O
brief	O
reexposure	O
to	O
heparin	B-Chemical
,	O
but	O
its	O
success	O
in	O
patients	O
who	O
have	O
developed	O
the	O
thrombosis	B-Disease
syndrome	O
is	O
not	O
well	O
defined	O
.	O

The	O
authors	O
present	O
a	O
case	O
of	O
failure	O
of	O
ancrod	O
treatment	O
in	O
a	O
patient	O
with	O
heparin	B-Chemical
-	O
induced	O
thrombosis	B-Disease
.	O

Water	B-Disease
intoxication	I-Disease
associated	O
with	O
oxytocin	B-Chemical
administration	O
during	O
saline	O
-	O
induced	O
abortion	B-Disease
.	O

Four	O
cases	O
of	O
water	B-Disease
intoxication	I-Disease
in	O
connection	O
with	O
oxytocin	B-Chemical
administration	O
during	O
saline	O
-	O
induced	O
abortions	B-Disease
are	O
described	O
.	O

The	O
mechanism	O
of	O
water	B-Disease
intoxication	I-Disease
is	O
discussed	O
in	O
regard	O
to	O
these	O
cases	O
.	O

Oxytocin	B-Chemical
administration	O
during	O
midtrimester	O
-	O
induced	O
abortions	B-Disease
is	O
advocated	O
only	O
if	O
it	O
can	O
be	O
carried	O
out	O
under	O
careful	O
observations	O
of	O
an	O
alert	O
nursing	O
staff	O
,	O
aware	O
of	O
the	O
symptoms	O
of	O
water	B-Disease
intoxication	I-Disease
and	O
instructed	O
to	O
watch	O
the	O
diuresis	O
and	O
report	O
such	O
early	O
signs	O
of	O
the	O
syndrome	O
as	O
asthenia	B-Disease
,	O
muscular	O
irritability	B-Disease
,	O
or	O
headaches	B-Disease
.	O

The	O
oxytocin	B-Chemical
should	O
be	O
given	O
only	O
in	O
Ringers	O
lactate	B-Chemical
or	O
,	O
alternately	O
,	O
in	O
Ringers	O
lactate	B-Chemical
and	O
a	O
5	O
per	O
cent	O
dextrose	B-Chemical
and	O
water	O
solutions	O
.	O

The	O
urinary	O
output	O
should	O
be	O
monitored	O
and	O
the	O
oxytocin	B-Chemical
administration	O
discontinued	O
and	O
the	O
serum	O
electrolytes	O
checked	O
if	O
the	O
urinary	O
output	O
decreases	O
.	O

The	O
oxytocin	B-Chemical
should	O
not	O
be	O
administered	O
in	O
excess	O
of	O
36	O
hours	O
.	O

If	O
the	O
patient	O
has	O
not	O
aborted	O
by	O
then	O
the	O
oxytocin	B-Chemical
should	O
be	O
discontinued	O
for	O
10	O
to	O
12	O
hours	O
in	O
order	O
to	O
perform	O
electrolyte	O
determinations	O
and	O
correct	O
any	O
electrolyte	O
imbalance	O
.	O

Light	O
chain	O
proteinuria	B-Disease
and	O
cellular	O
mediated	O
immunity	O
in	O
rifampin	B-Chemical
treated	O
patients	O
with	O
tuberculosis	B-Disease
.	O

Light	O
chain	O
proteinuria	B-Disease
was	O
found	O
in	O
9	O
of	O
17	O
tuberculosis	B-Disease
patients	O
treated	O
with	O
rifampin	B-Chemical
.	O

Concomitant	O
assay	O
of	O
cellular	O
mediated	O
immunity	O
in	O
these	O
patients	O
using	O
skin	O
test	O
antigen	O
and	O
a	O
lymphokine	O
in	O
vitro	O
test	O
provided	O
results	O
that	O
were	O
different	O
.	O

Response	O
to	O
Varidase	O
skin	O
test	O
antigen	O
was	O
negative	O
for	O
all	O
eight	O
tuberculosis	B-Disease
patients	O
tested	O
,	O
but	O
there	O
occurred	O
a	O
hyper	O
-	O
responsiveness	O
of	O
the	O
lymphocytes	O
of	O
these	O
eight	O
patients	O
to	O
phytomitogen	O
(	O
PHA	O
-	O
P	O
)	O
.	O
as	O
well	O
as	O
of	O
those	O
of	O
seven	O
other	O
tuberculous	B-Disease
patients	O
.	O

This	O
last	O
finding	O
may	O
be	O
related	O
to	O
time	O
of	O
testing	O
and	O
/	O
or	O
endogenous	O
serum	O
binding	O
of	O
rifampin	B-Chemical
which	O
could	O
have	O
inhibited	O
mitogen	O
activity	O
for	O
the	O
lymphocyte	O
.	O

KF17837	B-Chemical
:	O
a	O
novel	O
selective	O
adenosine	B-Chemical
A2A	O
receptor	O
antagonist	O
with	O
anticataleptic	O
activity	O
.	O

KF17837	B-Chemical
is	O
a	O
novel	O
selective	O
adenosine	B-Chemical
A2A	O
receptor	O
antagonist	O
.	O

Oral	O
administration	O
of	O
KF17837	B-Chemical
(	O
2	O
.	O
5	O
,	O
10	O
.	O
0	O
and	O
30	O
.	O
0	O
mg	O
/	O
kg	O
)	O
significantly	O
ameliorated	O
the	O
cataleptic	B-Disease
responses	O
induced	O
by	O
intracerebroventricular	O
administration	O
of	O
an	O
adenosine	B-Chemical
A2A	O
receptor	O
agonist	O
,	O
CGS	B-Chemical
21680	I-Chemical
(	O
10	O
micrograms	O
)	O
,	O
in	O
a	O
dose	O
-	O
dependent	O
manner	O
.	O

KF17837	B-Chemical
also	O
reduced	O
the	O
catalepsy	B-Disease
induced	O
by	O
haloperidol	B-Chemical
(	O
1	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
and	O
by	O
reserpine	B-Chemical
(	O
5	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
.	O

These	O
anticataleptic	O
effects	O
were	O
exhibited	O
dose	O
dependently	O
at	O
doses	O
from	O
0	O
.	O
625	O
and	O
2	O
.	O
5	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
,	O
respectively	O
.	O

Moreover	O
,	O
KF17837	B-Chemical
(	O
0	O
.	O
625	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
)	O
potentiated	O
the	O
anticataleptic	O
effects	O
of	O
a	O
subthreshold	O
dose	O
of	O
L	B-Chemical
-	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dihydroxyphenylalanine	I-Chemical
(	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
;	O
25	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
plus	O
benserazide	B-Chemical
(	O
6	O
.	O
25	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
.	O

These	O
results	O
suggested	O
that	O
KF17837	B-Chemical
is	O
a	O
centrally	O
active	O
adenosine	B-Chemical
A2A	O
receptor	O
antagonist	O
and	O
that	O
the	O
dopaminergic	O
function	O
of	O
the	O
nigrostriatal	O
pathway	O
is	O
potentiated	O
by	O
adenosine	B-Chemical
A2A	O
receptor	O
antagonists	O
.	O

Furthermore	O
,	O
KF17837	B-Chemical
may	O
be	O
a	O
useful	O
drug	O
in	O
the	O
treatment	O
of	O
parkinsonism	B-Disease
.	O

Effect	O
of	O
nondopaminergic	O
drugs	O
on	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
-	O
induced	O
dyskinesias	B-Disease
in	O
MPTP	B-Chemical
-	O
treated	O
monkeys	O
.	O

A	O
group	O
of	O
four	O
monkeys	O
was	O
rendered	O
parkinsonian	B-Disease
with	O
the	O
toxin	O
MPTP	B-Chemical
.	O

They	O
were	O
then	O
treated	O
chronically	O
with	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
/	I-Chemical
benserazide	I-Chemical
50	O
/	O
12	O
.	O
5	O
mg	O
/	O
kg	O
given	O
orally	O
daily	O
for	O
2	O
months	O
.	O

This	O
dose	O
produced	O
a	O
striking	O
antiparkinsonian	O
effect	O
,	O
but	O
all	O
animals	O
manifested	O
dyskinesia	B-Disease
.	O

A	O
series	O
of	O
agents	O
acting	O
primarily	O
on	O
neurotransmitters	O
other	O
than	O
dopamine	B-Chemical
were	O
then	O
tested	O
in	O
combination	O
with	O
L	B-Chemical
-	I-Chemical
DOPA	I-Chemical
to	O
see	O
if	O
the	O
dyskinetic	B-Disease
movements	O
would	O
be	O
modified	O
.	O

Several	O
drugs	O
,	O
including	O
clonidine	B-Chemical
,	O
physostigmine	B-Chemical
,	O
methysergide	B-Chemical
,	O
5	B-Chemical
-	I-Chemical
MDOT	I-Chemical
,	O
propranolol	B-Chemical
,	O
and	O
MK	B-Chemical
-	I-Chemical
801	I-Chemical
,	O
markedly	O
reduced	O
the	O
dyskinetic	B-Disease
movements	O
but	O
at	O
the	O
cost	O
of	O
a	O
return	O
of	O
parkinsonian	B-Disease
symptomatology	O
.	O

However	O
,	O
yohimbine	B-Chemical
and	O
meperidine	B-Chemical
reduced	O
predominantly	O
the	O
dyskinetic	B-Disease
movements	O
.	O

Baclofen	B-Chemical
was	O
also	O
useful	O
in	O
one	O
monkey	O
against	O
a	O
more	O
dystonic	B-Disease
form	O
of	O
dyskinesia	B-Disease
.	O

Atropine	B-Chemical
converted	O
the	O
dystonic	B-Disease
movements	O
into	O
chorea	B-Disease
.	O

Hallucinations	B-Disease
and	O
ifosfamide	B-Chemical
-	O
induced	O
neurotoxicity	B-Disease
.	O

BACKGROUND	O
:	O
Hallucinations	B-Disease
as	O
a	O
symptom	O
of	O
central	O
neurotoxicity	B-Disease
are	O
a	O
known	O
but	O
poorly	O
described	O
side	O
effect	O
of	O
ifosfamide	B-Chemical
.	O

Most	O
cases	O
of	O
ifosfamide	B-Chemical
-	O
induced	O
hallucinations	B-Disease
have	O
been	O
reported	O
with	O
other	O
mental	O
status	O
changes	O
.	O

METHODS	O
:	O
The	O
authors	O
interviewed	O
six	O
persons	O
with	O
ifosfamide	B-Chemical
-	O
induced	O
hallucinations	B-Disease
in	O
the	O
presence	O
of	O
a	O
clear	O
sensorium	O
.	O

All	O
patients	O
were	O
receiving	O
high	O
-	O
dose	O
ifosfamide	B-Chemical
as	O
part	O
of	O
their	O
bone	O
marrow	O
transplant	O
procedure	O
.	O

RESULTS	O
:	O
Hallucinations	B-Disease
occurred	O
only	O
when	O
the	O
patient	O
'	O
s	O
eyes	O
were	O
closed	O
and	O
,	O
in	O
all	O
but	O
one	O
case	O
,	O
were	O
reported	O
as	O
disturbing	O
or	O
frightening	O
.	O

Underreporting	O
of	O
these	O
hallucinations	B-Disease
by	O
patients	O
is	O
likely	O
.	O

CONCLUSIONS	O
:	O
Hallucinations	B-Disease
may	O
be	O
the	O
sole	O
or	O
first	O
manifestation	O
of	O
neurotoxicity	B-Disease
.	O

The	O
incidence	O
may	O
be	O
dose	O
and	O
infusion	O
-	O
time	O
related	O
.	O

The	O
clinician	O
should	O
be	O
alerted	O
for	O
possible	O
ifosfamide	B-Chemical
-	O
induced	O
hallucinations	B-Disease
,	O
which	O
may	O
occur	O
without	O
other	O
signs	O
of	O
neurotoxicity	B-Disease
.	O

"	O
Eyes	O
-	O
closed	O
"	O
hallucinatory	B-Disease
experiences	O
appear	O
to	O
be	O
an	O
unusual	O
feature	O
of	O
this	O
presentation	O
.	O

Patients	O
anxious	O
about	O
this	O
experience	O
respond	O
well	O
to	O
support	O
and	O
education	O
about	O
this	O
occurrence	O
.	O

Optimal	O
pharmacologic	O
management	O
of	O
disturbed	O
patients	O
is	O
unclear	O
.	O

If	O
agitation	B-Disease
becomes	O
marked	O
,	O
high	O
-	O
potency	O
neuroleptics	O
(	O
i	O
.	O
e	O
.	O
,	O
haloperidol	B-Chemical
)	O
may	O
be	O
effective	O
.	O

Photodistributed	O
nifedipine	B-Chemical
-	O
induced	O
facial	O
telangiectasia	B-Disease
.	O

Five	O
months	O
after	O
starting	O
nifedipine	B-Chemical
(	O
Adalat	B-Chemical
)	O
,	O
two	O
patients	O
developed	O
photodistributed	O
facial	O
telangiectasia	B-Disease
,	O
which	O
became	O
more	O
noticeable	O
with	O
time	O
.	O

Neither	O
patient	O
complained	O
of	O
photosensitivity	O
or	O
flushing	B-Disease
.	O

Both	O
patients	O
reported	O
a	O
significant	O
cosmetic	O
improvement	O
after	O
discontinuing	O
the	O
drug	O
.	O

One	O
commenced	O
the	O
closely	O
related	O
drug	O
amlodipine	B-Chemical
3	O
years	O
later	O
,	O
with	O
recurrence	O
of	O
telangiectasia	B-Disease
.	O

The	O
photodistribution	O
of	O
the	O
telangiectasia	B-Disease
suggests	O
a	O
significant	O
drug	O
/	O
light	O
interaction	O
.	O

Penicillamine	B-Chemical
-	O
induced	O
rapidly	O
progressive	O
glomerulonephritis	B-Disease
in	O
a	O
patient	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
.	O

A	O
67	O
-	O
year	O
-	O
old	O
woman	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
presented	O
rapidly	O
progressive	O
glomerulonephritis	B-Disease
(	O
RPGN	B-Disease
)	O
after	O
5	O
months	O
of	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
(	O
250	O
mg	O
/	O
day	O
)	O
treatment	O
.	O

Light	O
microscopy	O
study	O
showed	O
severe	O
glomerulonephritis	B-Disease
with	O
crescent	O
formation	O
in	O
60	O
%	O
of	O
the	O
glomeruli	O
and	O
infiltration	O
of	O
inflammatory	O
cells	O
in	O
the	O
wall	O
of	O
an	O
arteriole	O
.	O

Immunofluorescence	O
revealed	O
scanty	O
granular	O
IgG	O
,	O
IgA	O
and	O
C3	O
deposits	O
along	O
the	O
capillary	O
walls	O
and	O
mesangium	O
.	O

The	O
patient	O
was	O
treated	O
with	O
steroid	B-Chemical
pulse	O
,	O
plasmapheresis	O
,	O
cyclophosphamide	B-Chemical
and	O
antiplatelet	B-Chemical
agents	I-Chemical
.	O

A	O
complete	O
recovery	O
of	O
renal	O
function	O
was	O
achieved	O
in	O
a	O
few	O
weeks	O
.	O

This	O
new	O
case	O
of	O
RPGN	B-Disease
in	O
the	O
course	O
of	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
treatment	O
emphasizes	O
the	O
need	O
for	O
frequent	O
monitoring	O
of	O
renal	O
function	O
and	O
evaluation	O
of	O
urinary	O
sediment	O
and	O
proteinuria	B-Disease
in	O
these	O
patients	O
.	O

The	O
prompt	O
discontinuation	O
of	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
and	O
vigorous	O
treatment	O
measures	O
could	O
allow	O
for	O
a	O
good	O
prognosis	O
as	O
in	O
this	O
case	O
.	O

A	O
case	O
of	O
polymyositis	B-Disease
in	O
a	O
patient	O
with	O
primary	B-Disease
biliary	I-Disease
cirrhosis	I-Disease
treated	O
with	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
.	O

Although	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
has	O
been	O
used	O
for	O
many	O
rheumatologic	B-Disease
diseases	I-Disease
,	O
toxicity	B-Disease
limits	O
its	O
usefulness	O
in	O
many	O
patients	O
.	O

Polymyositis	B-Disease
/	O
dermatomyositis	B-Disease
can	O
develop	O
as	O
one	O
of	O
the	O
autoimmune	O
complications	O
of	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
treatment	O
,	O
but	O
its	O
exact	O
pathogenesis	O
remains	O
unclear	O
.	O

We	O
report	O
a	O
patient	O
with	O
primary	B-Disease
biliary	I-Disease
cirrhosis	I-Disease
,	O
who	O
developed	O
polymyositis	B-Disease
while	O
receiving	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
therapy	O
.	O

We	O
described	O
the	O
special	O
clinical	O
course	O
of	O
the	O
patient	O
.	O

Patients	O
receiving	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
therapy	O
should	O
be	O
followed	O
carefully	O
for	O
the	O
development	O
of	O
autoimmune	O
complications	O
like	O
polymyositis	B-Disease
/	O
dermatomyositis	B-Disease
.	O

Hyperalgesia	B-Disease
and	O
myoclonus	B-Disease
in	O
terminal	O
cancer	B-Disease
patients	O
treated	O
with	O
continuous	O
intravenous	O
morphine	B-Chemical
.	O

Eight	O
cancer	B-Disease
patients	O
in	O
the	O
terminal	O
stages	O
of	O
the	O
disease	O
treated	O
with	O
high	O
doses	O
of	O
intravenous	O
morphine	B-Chemical
developed	O
hyperalgesia	B-Disease
.	O

All	O
cases	O
were	O
retrospectively	O
sampled	O
from	O
three	O
different	O
hospitals	O
in	O
Copenhagen	O
.	O

Five	O
patients	O
developed	O
universal	O
hyperalgesia	B-Disease
and	O
hyperesthesia	B-Disease
which	O
in	O
2	O
cases	O
were	O
accompanied	O
by	O
myoclonus	B-Disease
.	O

In	O
3	O
patients	O
a	O
pre	O
-	O
existing	O
neuralgia	B-Disease
increased	O
to	O
excruciating	O
intensity	O
and	O
in	O
2	O
of	O
these	O
cases	O
myoclonus	B-Disease
occurred	O
simultaneously	O
.	O

Although	O
only	O
few	O
clinical	O
descriptions	O
of	O
the	O
relationship	O
between	O
hyperalgesia	B-Disease
/	O
myoclonus	B-Disease
and	O
high	O
doses	O
of	O
morphine	B-Chemical
are	O
available	O
,	O
experimental	O
support	O
from	O
animal	O
studies	O
indicates	O
that	O
morphine	B-Chemical
,	O
or	O
its	O
metabolites	O
,	O
plays	O
a	O
causative	O
role	O
for	O
the	O
observed	O
behavioural	O
syndrome	O
.	O

The	O
possible	O
mechanisms	O
are	O
discussed	O
and	O
treatment	O
proposals	O
given	O
suggesting	O
the	O
use	O
of	O
more	O
efficacious	O
opioids	O
with	O
less	O
excitatory	O
potency	O
in	O
these	O
situations	O
.	O

Liposomal	O
daunorubicin	B-Chemical
in	O
advanced	O
Kaposi	B-Disease
'	I-Disease
s	I-Disease
sarcoma	I-Disease
:	O
a	O
phase	O
II	O
study	O
.	O

We	O
report	O
a	O
non	O
-	O
randomized	O
Phase	O
II	O
clinical	O
trial	O
to	O
assess	O
the	O
efficacy	O
and	O
safety	O
of	O
liposomal	O
daunorubicin	B-Chemical
(	O
DaunoXome	O
)	O
in	O
the	O
treatment	O
of	O
AIDS	B-Disease
related	O
Kaposi	B-Disease
'	I-Disease
s	I-Disease
sarcoma	I-Disease
.	O

Eleven	O
homosexual	O
men	O
with	O
advanced	O
Kaposi	B-Disease
'	I-Disease
s	I-Disease
sarcoma	I-Disease
were	O
entered	O
in	O
the	O
trial	O
.	O

Changes	O
in	O
size	O
,	O
colour	O
and	O
associated	O
oedema	B-Disease
of	O
selected	O
'	O
target	O
'	O
lesions	O
were	O
measured	O
.	O

Clinical	O
,	O
biochemical	O
and	O
haematological	O
toxicities	B-Disease
were	O
assessed	O
.	O

Ten	O
subjects	O
were	O
evaluated	O
.	O

A	O
partial	O
response	O
was	O
achieved	O
in	O
four	O
,	O
of	O
whom	O
two	O
subsequently	O
relapsed	O
.	O

Stabilization	O
of	O
Kaposi	B-Disease
'	I-Disease
s	I-Disease
sarcoma	I-Disease
occurred	O
in	O
the	O
remaining	O
six	O
,	O
maintained	O
until	O
the	O
end	O
of	O
the	O
trial	O
period	O
in	O
four	O
.	O

The	O
drug	O
was	O
generally	O
well	O
tolerated	O
,	O
with	O
few	O
mild	O
symptoms	O
of	O
toxicity	B-Disease
.	O

The	O
main	O
problem	O
encountered	O
was	O
haematological	O
toxicity	B-Disease
,	O
with	O
three	O
subjects	O
experiencing	O
severe	O
neutropenia	B-Disease
(	O
neutrophil	O
count	O
<	O
0	O
.	O
5	O
x	O
10	O
(	O
9	O
)	O
/	O
l	O
)	O
.	O

There	O
was	O
no	O
evidence	O
of	O
cardiotoxicity	B-Disease
.	O

In	O
this	O
small	O
patient	O
sample	O
,	O
liposomal	O
daunorubicin	B-Chemical
was	O
an	O
effective	O
and	O
well	O
tolerated	O
agent	O
in	O
the	O
treatment	O
of	O
Kaposi	B-Disease
'	I-Disease
s	I-Disease
sarcoma	I-Disease
.	O

Long	O
-	O
term	O
effects	O
of	O
vincristine	B-Chemical
on	O
the	O
peripheral	O
nervous	O
system	O
.	O

Forty	O
patients	O
with	O
Non	B-Disease
-	I-Disease
Hodgkin	I-Disease
'	I-Disease
s	I-Disease
Lymphoma	I-Disease
treated	O
with	O
vincristine	B-Chemical
between	O
1984	O
and	O
1990	O
(	O
cumulative	O
dose	O
12	O
mg	O
in	O
18	O
-	O
24	O
weeks	O
)	O
were	O
investigated	O
in	O
order	O
to	O
evaluate	O
the	O
long	O
term	O
effects	O
of	O
vincristine	B-Chemical
on	O
the	O
peripheral	O
nervous	O
system	O
.	O

The	O
patients	O
were	O
interviewed	O
with	O
emphasis	O
on	O
neuropathic	B-Disease
symptoms	I-Disease
.	O

Physical	O
and	O
quantitative	O
sensory	O
examination	O
with	O
determination	O
of	O
vibratory	O
perception	O
and	O
thermal	O
discrimination	O
thresholds	O
were	O
performed	O
,	O
four	O
to	O
77	O
months	O
(	O
median	O
34	O
months	O
)	O
after	O
vincristine	B-Chemical
treatment	O
.	O

Twenty	O
-	O
seven	O
patients	O
reported	O
neuropathic	B-Disease
symptoms	I-Disease
.	O

In	O
13	O
of	O
these	O
27	O
patients	O
symptoms	O
were	O
still	O
present	O
at	O
the	O
time	O
of	O
examination	O
.	O

In	O
these	O
patients	O
sensory	O
signs	O
and	O
symptoms	O
predominated	O
.	O

In	O
the	O
other	O
14	O
patients	O
symptoms	O
had	O
been	O
present	O
in	O
the	O
past	O
.	O

Symptoms	O
persisted	O
maximally	O
40	O
months	O
since	O
cessation	O
of	O
therapy	O
.	O

There	O
was	O
no	O
age	O
difference	O
between	O
patients	O
with	O
and	O
without	O
complaints	O
at	O
the	O
time	O
of	O
examination	O
.	O

Normal	O
reflexes	O
were	O
found	O
in	O
two	O
third	O
of	O
patients	O
.	O

Neuropathic	O
complaints	O
were	O
not	O
very	O
troublesome	O
on	O
the	O
long	O
term	O
.	O

It	O
is	O
concluded	O
that	O
with	O
the	O
above	O
mentioned	O
vincristine	B-Chemical
dose	O
schedule	O
signs	O
and	O
symptoms	O
of	O
vincristine	B-Chemical
neuropathy	B-Disease
are	O
reversible	O
for	O
a	O
great	O
deal	O
and	O
prognosis	O
is	O
fairly	O
good	O
.	O

Hepatic	O
adenomas	B-Disease
and	O
focal	B-Disease
nodular	I-Disease
hyperplasia	I-Disease
of	O
the	O
liver	O
in	O
young	O
women	O
on	O
oral	B-Chemical
contraceptives	I-Chemical
:	O
case	O
reports	O
.	O

Two	O
cases	O
of	O
hepatic	O
adenoma	B-Disease
and	O
one	O
of	O
focal	B-Disease
nodular	I-Disease
hyperplasia	I-Disease
presumably	O
associated	O
with	O
the	O
use	O
of	O
oral	B-Chemical
contraceptives	I-Chemical
,	O
are	O
reported	O
.	O

Special	O
reference	O
is	O
made	O
to	O
their	O
clinical	O
presentation	O
,	O
which	O
may	O
be	O
totally	O
asymptomatic	O
.	O

Liver	O
-	O
function	O
tests	O
are	O
of	O
little	O
diagnostic	O
value	O
,	O
but	O
valuable	O
information	O
may	O
be	O
obtained	O
from	O
both	O
liver	O
scanning	O
and	O
hepatic	O
angiography	O
.	O

Histologic	O
differences	O
and	O
clinical	O
similarities	O
between	O
hepatic	O
adenoma	B-Disease
and	O
focal	B-Disease
nodular	I-Disease
hyperplasia	I-Disease
of	O
the	O
liver	O
are	O
discussed	O
.	O

Loss	O
of	O
glutamate	B-Chemical
decarboxylase	O
mRNA	O
-	O
containing	O
neurons	O
in	O
the	O
rat	O
dentate	O
gyrus	O
following	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

In	O
situ	O
hybridization	O
methods	O
were	O
used	O
to	O
determine	O
if	O
glutamic	B-Chemical
acid	I-Chemical
decarboxylase	O
(	O
GAD	O
)	O
mRNA	O
-	O
containing	O
neurons	O
within	O
the	O
hilus	O
of	O
the	O
dentate	O
gyrus	O
are	O
vulnerable	O
to	O
seizure	B-Disease
-	O
induced	O
damage	O
in	O
a	O
model	O
of	O
chronic	O
seizures	B-Disease
.	O

Sprague	O
-	O
Dawley	O
rats	O
were	O
injected	O
intraperitoneally	O
with	O
pilocarpine	B-Chemical
,	O
and	O
the	O
hippocampal	O
formation	O
was	O
studied	O
histologically	O
at	O
1	O
,	O
2	O
,	O
4	O
,	O
and	O
8	O
week	O
intervals	O
after	O
pilocarpine	B-Chemical
-	O
induced	O
seizures	B-Disease
.	O

In	O
situ	O
hybridization	O
histochemistry	O
,	O
using	O
a	O
digoxigenin	B-Chemical
-	O
labeled	O
GAD	O
cRNA	O
probe	O
,	O
demonstrated	O
a	O
substantial	O
decrease	O
in	O
the	O
number	O
of	O
GAD	O
mRNA	O
-	O
containing	O
neurons	O
in	O
the	O
hilus	O
of	O
the	O
dentate	O
gyrus	O
in	O
the	O
pilocarpine	B-Chemical
-	O
treated	O
rats	O
as	O
compared	O
to	O
controls	O
at	O
all	O
time	O
intervals	O
.	O

Additional	O
neuronanatomical	O
studies	O
,	O
including	O
cresyl	B-Chemical
violet	I-Chemical
staining	O
,	O
neuronal	B-Disease
degeneration	I-Disease
methods	O
,	O
and	O
histochemical	O
localization	O
of	O
glial	O
fibrillary	O
acidic	O
protein	O
,	O
suggested	O
that	O
the	O
decrease	O
in	O
the	O
number	O
of	O
GAD	O
mRNA	O
-	O
containing	O
neurons	O
was	O
related	O
to	O
neuronal	B-Disease
loss	I-Disease
rather	O
than	O
to	O
a	O
decrease	O
in	O
GAD	O
mRNA	O
levels	O
.	O

The	O
loss	O
of	O
GAD	O
mRNA	O
-	O
containing	O
neurons	O
in	O
the	O
hilus	O
contrasted	O
with	O
the	O
relative	O
preservation	O
of	O
labeled	O
putative	O
basket	O
cells	O
along	O
the	O
inner	O
margin	O
of	O
the	O
granule	O
cell	O
layer	O
.	O

Quantitative	O
analyses	O
of	O
labeled	O
neurons	O
in	O
three	O
regions	O
of	O
the	O
dentate	O
gyrus	O
in	O
the	O
1	O
and	O
2	O
week	O
groups	O
showed	O
statistically	O
significant	O
decreases	O
in	O
the	O
mean	O
number	O
of	O
GAD	O
mRNA	O
-	O
containing	O
neurons	O
in	O
the	O
hilus	O
of	O
both	O
groups	O
of	O
experimental	O
animals	O
.	O

No	O
significant	O
differences	O
were	O
found	O
in	O
the	O
molecular	O
layer	O
or	O
the	O
granule	O
cell	O
layer	O
,	O
which	O
included	O
labeled	O
neurons	O
along	O
the	O
lower	O
margin	O
of	O
the	O
granule	O
cell	O
layer	O
.	O

The	O
results	O
indicate	O
that	O
,	O
in	O
this	O
model	O
,	O
a	O
subpopulation	O
of	O
GAD	O
mRNA	O
-	O
containing	O
neurons	O
within	O
the	O
dentate	O
gyrus	O
is	O
selectively	O
vulnerable	O
to	O
seizure	B-Disease
-	O
induced	O
damage	O
.	O

Such	O
differential	O
vulnerability	O
appears	O
to	O
be	O
another	O
indication	O
of	O
the	O
heterogeneity	O
of	O
GABA	B-Chemical
neurons	O
.	O

Effects	O
of	O
deliberate	O
hypotension	B-Disease
induced	O
by	O
labetalol	B-Chemical
with	O
isoflurane	B-Chemical
on	O
neuropsychological	O
function	O
.	O

The	O
effect	O
of	O
deliberate	O
hypotension	B-Disease
on	O
brain	O
function	O
measured	O
by	O
neuropsychological	O
tests	O
was	O
studied	O
in	O
41	O
adult	O
patients	O
.	O

Twenty	O
-	O
four	O
patients	O
were	O
anaesthetized	O
for	O
middle	O
-	O
ear	O
surgery	O
with	O
deliberate	O
hypotension	B-Disease
induced	O
by	O
labetalol	B-Chemical
with	O
isoflurane	B-Chemical
(	O
hypotensive	B-Disease
group	O
)	O
.	O

Seventeen	O
patients	O
without	O
hypotension	B-Disease
served	O
as	O
a	O
control	O
group	O
.	O

The	O
mean	O
arterial	O
pressure	O
was	O
77	O
+	O
/	O
-	O
2	O
mmHg	O
(	O
10	O
.	O
3	O
+	O
/	O
-	O
0	O
.	O
3	O
kPa	O
)	O
before	O
hypotension	B-Disease
and	O
50	O
+	O
/	O
-	O
0	O
mmHg	O
(	O
6	O
.	O
7	O
+	O
/	O
-	O
0	O
.	O
0	O
kPa	O
)	O
during	O
hypotension	B-Disease
in	O
the	O
hypotensive	B-Disease
group	O
,	O
and	O
86	O
+	O
/	O
-	O
2	O
mmHg	O
(	O
11	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
3	O
kPa	O
)	O
during	O
anaesthesia	O
in	O
the	O
control	O
group	O
.	O

The	O
following	O
psychological	O
tests	O
were	O
performed	O
:	O
four	O
subtests	O
of	O
the	O
Wechsler	O
Adult	O
Intelligence	O
Scale	O
(	O
similarities	O
,	O
digit	O
span	O
,	O
vocabulary	O
and	O
digit	O
symbol	O
)	O
,	O
Trail	O
-	O
Making	O
tests	O
A	O
and	O
B	O
,	O
Zung	O
tests	O
(	O
self	O
-	O
rating	O
anxiety	B-Disease
scale	O
and	O
self	O
-	O
rating	O
depression	B-Disease
scale	O
)	O
and	O
two	O
-	O
part	O
memory	O
test	O
battery	O
with	O
immediate	O
and	O
delayed	O
recall	O
.	O

The	O
tests	O
were	O
performed	O
preoperatively	O
and	O
2	O
days	O
postoperatively	O
.	O

There	O
were	O
no	O
statistically	O
significant	O
differences	O
between	O
the	O
groups	O
in	O
any	O
of	O
the	O
tests	O
in	O
the	O
changes	O
from	O
preoperative	O
value	O
to	O
postoperative	O
value	O
.	O

The	O
results	O
indicate	O
that	O
hypotension	B-Disease
induced	O
by	O
labetalol	B-Chemical
with	O
isoflurane	B-Chemical
has	O
no	O
significant	O
harmful	O
effects	O
on	O
mental	O
functions	O
compared	O
to	O
normotensive	O
anaesthesia	O
.	O

Apparent	O
cure	O
of	O
rheumatoid	B-Disease
arthritis	I-Disease
by	O
bone	O
marrow	O
transplantation	O
.	O

We	O
describe	O
the	O
induction	O
of	O
sustained	O
remissions	O
and	O
possible	O
cure	O
of	O
severe	O
erosive	O
rheumatoid	B-Disease
arthritis	I-Disease
(	O
RA	B-Disease
)	O
by	O
bone	O
marrow	O
transplantation	O
(	O
BMT	O
)	O
in	O
2	O
patients	O
.	O

BMT	O
was	O
used	O
to	O
treat	O
severe	O
aplastic	B-Disease
anemia	I-Disease
which	O
was	O
caused	O
by	O
gold	B-Chemical
in	O
one	O
case	O
and	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
in	O
the	O
other	O
.	O

In	O
the	O
8	O
and	O
6	O
years	O
since	O
the	O
transplants	O
(	O
representing	O
8	O
and	O
4	O
years	O
since	O
cessation	O
of	O
all	O
immunosuppressive	O
therapy	O
,	O
respectively	O
)	O
,	O
the	O
RA	B-Disease
in	O
each	O
case	O
has	O
been	O
completely	O
quiescent	O
.	O

Although	O
short	O
term	O
remission	O
of	O
severe	O
RA	B-Disease
following	O
BMT	O
has	O
been	O
reported	O
,	O
these	O
are	O
the	O
first	O
cases	O
for	O
which	O
prolonged	O
followup	O
has	O
been	O
available	O
.	O

This	O
experience	O
raises	O
the	O
question	O
of	O
the	O
role	O
of	O
BMT	O
itself	O
as	O
a	O
therapeutic	O
option	O
for	O
patients	O
with	O
uncontrolled	O
destructive	O
synovitis	B-Disease
.	O

Seizures	B-Disease
induced	O
by	O
combined	O
levomepromazine	B-Chemical
-	O
fluvoxamine	B-Chemical
treatment	O
.	O

We	O
report	O
a	O
case	O
of	O
combined	O
levomepromazine	B-Chemical
-	O
fluvoxamine	B-Chemical
treatment	O
-	O
induced	O
seizures	B-Disease
.	O

It	O
seems	O
that	O
combined	O
treatment	O
of	O
fluvoxamine	B-Chemical
with	O
phenothiazines	B-Chemical
may	O
possess	O
proconvulsive	O
activity	O
.	O

Case	O
report	O
:	O
pentamidine	B-Chemical
and	O
polymorphic	O
ventricular	B-Disease
tachycardia	I-Disease
revisited	O
.	O

Pentamidine	B-Chemical
isethionate	I-Chemical
has	O
been	O
associated	O
with	O
ventricular	B-Disease
tachyarrhythmias	I-Disease
,	O
including	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
.	O

This	O
article	O
reports	O
two	O
cases	O
of	O
this	O
complication	O
and	O
reviews	O
all	O
reported	O
cases	O
to	O
date	O
.	O

Pentamidine	B-Chemical
-	O
induced	O
torsade	B-Disease
de	I-Disease
pointes	I-Disease
may	O
be	O
related	O
to	O
serum	O
magnesium	B-Chemical
levels	O
and	O
hypomagnesemia	B-Disease
may	O
synergistically	O
induce	O
torsade	O
.	O

Torsade	B-Disease
de	I-Disease
pointes	I-Disease
occurred	O
after	O
an	O
average	O
of	O
10	O
days	O
of	O
treatment	O
with	O
pentamidine	B-Chemical
.	O

In	O
these	O
patients	O
,	O
no	O
other	O
acute	O
side	O
effects	O
of	O
pentamidine	B-Chemical
were	O
observed	O
.	O

Torsade	B-Disease
de	I-Disease
pointes	I-Disease
can	O
be	O
treated	O
when	O
recognized	O
early	O
,	O
possibly	O
without	O
discontinuation	O
of	O
pentamidine	B-Chemical
.	O

When	O
QTc	B-Disease
interval	I-Disease
prolongation	I-Disease
is	O
observed	O
,	O
early	O
magnesium	B-Chemical
supplementation	O
is	O
advocated	O
.	O

Efficacy	O
and	O
tolerability	O
of	O
lovastatin	B-Chemical
in	O
3390	O
women	O
with	O
moderate	O
hypercholesterolemia	B-Disease
.	O

OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
efficacy	O
and	O
safety	O
of	O
lovastatin	B-Chemical
in	O
women	O
with	O
moderate	O
hypercholesterolemia	B-Disease
.	O

DESIGN	O
:	O
The	O
Expanded	O
Clinical	O
Evaluation	O
of	O
Lovastatin	B-Chemical
(	O
EXCEL	O
)	O
Study	O
,	O
a	O
multicenter	O
,	O
double	O
-	O
blind	O
,	O
diet	O
-	O
and	O
placebo	O
-	O
controlled	O
trial	O
,	O
in	O
which	O
participants	O
were	O
randomly	O
assigned	O
to	O
receive	O
placebo	O
or	O
lovastatin	B-Chemical
at	O
doses	O
of	O
20	O
or	O
40	O
mg	O
once	O
daily	O
,	O
or	O
20	O
or	O
40	O
mg	O
twice	O
daily	O
for	O
48	O
weeks	O
.	O

SETTING	O
:	O
Ambulatory	O
patients	O
recruited	O
by	O
362	O
participating	O
centers	O
throughout	O
the	O
United	O
States	O
.	O

PATIENTS	O
:	O
Women	O
(	O
n	O
=	O
3390	O
)	O
from	O
the	O
total	O
cohort	O
of	O
8245	O
volunteers	O
.	O

MEASUREMENTS	O
:	O
Plasma	O
total	O
,	O
low	O
-	O
density	O
lipoprotein	O
(	O
LDL	O
)	O
,	O
and	O
high	O
-	O
density	O
lipoprotein	O
(	O
HDL	O
)	O
cholesterol	B-Chemical
,	O
and	O
triglycerides	B-Chemical
;	O
and	O
laboratory	O
and	O
clinical	O
evidence	O
of	O
adverse	O
events	O
monitored	O
periodically	O
throughout	O
the	O
study	O
.	O

RESULTS	O
:	O
Among	O
women	O
,	O
lovastatin	B-Chemical
(	O
20	O
to	O
80	O
mg	O
/	O
d	O
)	O
produced	O
sustained	O
(	O
12	O
-	O
to	O
48	O
-	O
week	O
)	O
,	O
dose	O
-	O
related	O
changes	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
:	O
decreases	O
in	O
LDL	O
cholesterol	B-Chemical
(	O
24	O
%	O
to	O
40	O
%	O
)	O
and	O
triglycerides	B-Chemical
(	O
9	O
%	O
to	O
18	O
%	O
)	O
,	O
and	O
increases	O
in	O
HDL	O
cholesterol	B-Chemical
(	O
6	O
.	O
7	O
%	O
to	O
8	O
.	O
6	O
%	O
)	O
.	O

Depending	O
on	O
the	O
dose	O
,	O
from	O
82	O
%	O
to	O
95	O
%	O
of	O
lovastatin	B-Chemical
-	O
treated	O
women	O
achieved	O
the	O
National	O
Cholesterol	B-Chemical
Education	O
Program	O
goal	O
of	O
LDL	O
cholesterol	B-Chemical
levels	O
less	O
than	O
4	O
.	O
14	O
mmol	O
/	O
L	O
(	O
160	O
mg	O
/	O
dL	O
)	O
,	O
and	O
40	O
%	O
to	O
87	O
%	O
achieved	O
the	O
goal	O
of	O
3	O
.	O
36	O
mmol	O
/	O
L	O
(	O
130	O
mg	O
/	O
dL	O
)	O
.	O

Successive	O
transaminase	O
elevations	O
greater	O
than	O
three	O
times	O
the	O
upper	O
limit	O
of	O
normal	O
occurred	O
in	O
0	O
.	O
1	O
%	O
of	O
women	O
and	O
were	O
dose	O
dependent	O
above	O
the	O
20	O
-	O
mg	O
dose	O
.	O

Myopathy	B-Disease
,	O
defined	O
as	O
muscle	O
symptoms	O
with	O
creatine	B-Chemical
kinase	O
elevations	O
greater	O
than	O
10	O
times	O
the	O
upper	O
limit	O
of	O
normal	O
,	O
was	O
rare	O
and	O
associated	O
with	O
the	O
highest	O
recommended	O
daily	O
dose	O
of	O
lovastatin	B-Chemical
(	O
80	O
mg	O
)	O
.	O

Estrogen	O
-	O
replacement	O
therapy	O
appeared	O
to	O
have	O
no	O
effect	O
on	O
either	O
the	O
efficacy	O
or	O
safety	O
profile	O
of	O
lovastatin	B-Chemical
.	O

CONCLUSION	O
:	O
Lovastatin	B-Chemical
is	O
highly	O
effective	O
and	O
generally	O
well	O
tolerated	O
as	O
therapy	O
for	O
primary	O
hypercholesterolemia	B-Disease
in	O
women	O
.	O

Tetany	B-Disease
and	O
rhabdomyolysis	B-Disease
due	O
to	O
surreptitious	O
furosemide	B-Chemical
-	O
-	O
importance	O
of	O
magnesium	B-Chemical
supplementation	O
.	O

Diuretics	O
may	O
induce	O
hypokalemia	B-Disease
,	O
hypocalcemia	B-Disease
and	O
hypomagnesemia	B-Disease
.	O

While	O
severe	O
hypokalemia	B-Disease
may	O
cause	O
muscle	B-Disease
weakness	I-Disease
,	O
severe	O
hypomagnesemia	B-Disease
is	O
associated	O
with	O
muscle	B-Disease
spasms	I-Disease
and	O
tetany	B-Disease
which	O
cannot	O
be	O
corrected	O
by	O
potassium	B-Chemical
and	O
calcium	B-Chemical
supplementation	O
alone	O
(	O
1	O
,	O
2	O
)	O
.	O

Surreptitious	O
diuretic	O
ingestion	O
has	O
been	O
described	O
,	O
mainly	O
in	O
women	O
who	O
are	O
concerned	O
that	O
they	O
are	O
obese	B-Disease
or	O
edematous	B-Disease
.	O

Symptomatic	O
hypokalemia	B-Disease
has	O
been	O
reported	O
in	O
such	O
patients	O
(	O
3	O
-	O
7	O
)	O
and	O
in	O
one	O
case	O
hypocalcemia	B-Disease
was	O
observed	O
(	O
8	O
)	O
,	O
but	O
the	O
effects	O
of	O
magnesium	B-Chemical
depletion	O
were	O
not	O
noted	O
in	O
these	O
patients	O
.	O

Ciprofloxacin	B-Chemical
-	O
induced	O
nephrotoxicity	B-Disease
in	O
patients	O
with	O
cancer	B-Disease
.	O

Nephrotoxicity	B-Disease
associated	O
with	O
ciprofloxacin	B-Chemical
is	O
uncommon	O
.	O

Five	O
patients	O
with	O
cancer	B-Disease
who	O
developed	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
that	O
followed	O
treatment	O
with	O
ciprofloxacin	B-Chemical
are	O
described	O
and	O
an	O
additional	O
15	O
cases	O
reported	O
in	O
the	O
literature	O
are	O
reviewed	O
.	O

Other	O
than	O
elevation	O
of	O
serum	O
creatinine	B-Chemical
levels	O
,	O
characteristic	O
clinical	O
manifestations	O
and	O
abnormal	O
laboratory	O
findings	O
are	O
not	O
frequently	O
present	O
.	O

Allergic	O
interstitial	B-Disease
nephritis	I-Disease
is	O
believed	O
to	O
be	O
the	O
underlying	O
pathological	O
-	O
process	O
.	O

Definitive	O
diagnosis	O
requires	O
performance	O
of	O
renal	O
biopsy	O
,	O
although	O
this	O
is	O
not	O
always	O
feasible	O
.	O

An	O
improvement	O
in	O
renal	O
function	O
that	O
followed	O
the	O
discontinuation	O
of	O
the	O
offending	O
antibiotic	O
supports	O
the	O
presumptive	O
diagnosis	O
of	O
ciprofloxacin	B-Chemical
-	O
induced	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
.	O

Venous	B-Disease
complications	I-Disease
of	O
midazolam	B-Chemical
versus	O
diazepam	B-Chemical
.	O

Although	O
some	O
studies	O
have	O
suggested	O
fewer	O
venous	B-Disease
complications	I-Disease
are	O
associated	O
with	O
midazolam	B-Chemical
than	O
with	O
diazepam	B-Chemical
for	O
endoscopic	O
procedures	O
,	O
this	O
variable	O
has	O
not	O
been	O
well	O
documented	O
.	O

We	O
prospectively	O
evaluated	O
the	O
incidence	O
of	O
venous	B-Disease
complications	I-Disease
after	O
intravenous	O
injection	O
of	O
diazepam	B-Chemical
or	O
midazolam	B-Chemical
in	O
122	O
consecutive	O
patients	O
undergoing	O
colonoscopy	O
and	O
esophagogastroduodenoscopy	O
.	O

Overall	O
,	O
venous	B-Disease
complications	I-Disease
were	O
more	O
frequent	O
with	O
diazepam	B-Chemical
(	O
22	O
of	O
62	O
patients	O
)	O
than	O
with	O
midazolam	B-Chemical
(	O
4	O
of	O
60	O
patients	O
)	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

A	O
palpable	O
venous	O
cord	O
was	O
present	O
in	O
23	O
%	O
(	O
14	O
of	O
62	O
)	O
of	O
patients	O
in	O
the	O
diazepam	B-Chemical
group	O
,	O
compared	O
with	O
2	O
%	O
(	O
1	O
of	O
60	O
patients	O
)	O
in	O
the	O
midazolam	B-Chemical
group	O
(	O
p	O
<	O
0	O
.	O
002	O
)	O
.	O

Pain	B-Disease
at	O
the	O
injection	O
site	O
occurred	O
in	O
35	O
%	O
(	O
22	O
of	O
62	O
)	O
of	O
patients	O
in	O
the	O
diazepam	B-Chemical
group	O
compared	O
with	O
7	O
%	O
(	O
4	O
of	O
60	O
patients	O
)	O
in	O
the	O
midazolam	B-Chemical
group	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
.	O

Swelling	B-Disease
and	O
warmth	O
at	O
the	O
injection	O
site	O
were	O
not	O
significantly	O
different	O
between	O
the	O
two	O
groups	O
.	O

Smoking	O
,	O
nonsteroidal	O
anti	O
-	O
inflammatory	O
drug	O
use	O
,	O
intravenous	O
catheter	O
site	O
,	O
dwell	O
time	O
of	O
the	O
needle	O
,	O
alcohol	B-Chemical
use	O
,	O
and	O
pain	B-Disease
during	O
the	O
injection	O
had	O
no	O
effect	O
on	O
the	O
incidence	O
of	O
venous	B-Disease
complications	I-Disease
.	O

Clarithromycin	B-Chemical
-	O
associated	O
visual	B-Disease
hallucinations	I-Disease
in	O
a	O
patient	O
with	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
on	O
continuous	O
ambulatory	O
peritoneal	O
dialysis	O
.	O

Visual	B-Disease
hallucinations	I-Disease
are	O
a	O
rare	O
event	O
in	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
and	O
not	O
related	O
to	O
uremia	B-Disease
per	O
se	O
.	O

Unreported	O
in	O
the	O
literature	O
is	O
visual	B-Disease
hallucinations	I-Disease
occurring	O
in	O
association	O
with	O
the	O
new	O
macrolide	B-Chemical
antibiotic	O
,	O
clarithromycin	B-Chemical
.	O

We	O
describe	O
such	O
a	O
case	O
in	O
a	O
patient	O
with	O
end	B-Disease
-	I-Disease
stage	I-Disease
renal	I-Disease
disease	I-Disease
(	O
ESRD	B-Disease
)	O
maintained	O
on	O
continuous	O
ambulatory	O
peritoneal	O
dialysis	O
(	O
CAPD	O
)	O
.	O

The	O
combination	O
of	O
a	O
relatively	O
high	O
dose	O
of	O
clarithromycin	B-Chemical
in	O
face	O
of	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
in	O
a	O
functionally	O
anephric	O
patient	O
,	O
with	O
underlying	O
aluminum	B-Chemical
intoxication	O
,	O
may	O
have	O
facilitated	O
the	O
appearance	O
of	O
this	O
neurotoxic	B-Disease
side	O
effect	O
.	O

It	O
is	O
important	O
to	O
understand	O
the	O
pharmacokinetics	O
of	O
medications	O
in	O
face	O
of	O
chronic	B-Disease
renal	I-Disease
failure	I-Disease
,	O
the	O
possibility	O
of	O
drug	O
interactions	O
,	O
and	O
how	O
these	O
factors	O
should	O
help	O
guide	O
medication	O
therapy	O
in	O
the	O
ESRD	B-Disease
patient	O
.	O

Changes	O
in	O
peroxisomes	O
in	O
preneoplastic	O
liver	O
and	O
hepatoma	B-Disease
of	O
mice	O
induced	O
by	O
alpha	B-Chemical
-	I-Chemical
benzene	I-Chemical
hexachloride	I-Chemical
.	O

Peroxisomes	O
in	O
hepatomas	B-Disease
and	O
hyperplastic	O
preneoplastic	O
liver	B-Disease
lesions	I-Disease
induced	O
in	O
mice	O
by	O
500	O
ppm	O
alpha	B-Chemical
-	I-Chemical
benzene	I-Chemical
hexachloride	I-Chemical
were	O
examined	O
histochemically	O
and	O
electron	O
microscopically	O
.	O

Although	O
most	O
of	O
the	O
hepatomas	B-Disease
were	O
well	O
-	O
differentiated	O
tumors	B-Disease
and	O
contained	O
a	O
considerable	O
number	O
of	O
peroxisomes	O
,	O
the	O
tumor	B-Disease
cells	O
did	O
not	O
respond	O
to	O
ethyl	B-Chemical
-	I-Chemical
alpha	I-Chemical
-	I-Chemical
p	I-Chemical
-	I-Chemical
chlorophenoxyisobutyrate	I-Chemical
with	O
proliferation	O
of	O
peroxisomes	O
.	O

At	O
the	O
16th	O
week	O
of	O
carcinogen	O
feeding	O
,	O
hyperplastic	O
nodules	O
appeared	O
and	O
advanced	O
to	O
further	O
stages	O
.	O

A	O
majority	O
of	O
the	O
nodules	O
showed	O
a	O
considerable	O
number	O
of	O
peroxisomes	O
and	O
the	O
inductive	O
proliferation	O
of	O
peroxisomes	O
.	O

Within	O
the	O
nodules	O
,	O
foci	O
of	O
proliferation	O
of	O
the	O
cells	O
that	O
showed	O
no	O
inducibility	O
of	O
proliferation	O
of	O
peroxisomes	O
appeared	O
.	O

These	O
cells	O
proliferated	O
further	O
,	O
replacing	O
the	O
most	O
part	O
of	O
the	O
nodules	O
,	O
and	O
with	O
this	O
process	O
hepatomas	B-Disease
appeared	O
to	O
have	O
been	O
formed	O
.	O

No	O
abnormal	O
matrical	O
inclusions	O
of	O
peroxisomes	O
were	O
formed	O
in	O
the	O
cells	O
of	O
hyperplastic	O
nodules	O
by	O
ethyl	B-Chemical
-	I-Chemical
alpha	I-Chemical
-	I-Chemical
p	I-Chemical
-	I-Chemical
chlorophenoxyisobutyrate	I-Chemical
unlike	O
in	O
the	O
case	O
of	O
rats	O
.	O

Contribution	O
of	O
the	O
sympathetic	O
nervous	O
system	O
to	O
salt	O
-	O
sensitivity	O
in	O
lifetime	O
captopril	B-Chemical
-	O
treated	O
spontaneously	O
hypertensive	B-Disease
rats	O
.	O

OBJECTIVE	O
:	O
To	O
test	O
the	O
hypothesis	O
that	O
,	O
in	O
lifetime	O
captopril	B-Chemical
-	O
treated	O
spontaneously	O
hypertensive	B-Disease
rats	O
(	O
SHR	O
)	O
,	O
the	O
sympathetic	O
nervous	O
system	O
contributes	O
importantly	O
to	O
the	O
hypertensive	B-Disease
effect	O
of	O
dietary	B-Chemical
sodium	I-Chemical
chloride	I-Chemical
supplementation	O
.	O

METHODS	O
:	O
Male	O
SHR	O
(	O
aged	O
6	O
weeks	O
)	O
that	O
had	O
been	O
treated	O
from	O
conception	O
onward	O
with	O
either	O
captopril	B-Chemical
or	O
vehicle	O
remained	O
on	O
a	O
basal	O
sodium	B-Chemical
chloride	I-Chemical
diet	O
or	O
were	O
fed	O
a	O
high	O
sodium	B-Chemical
chloride	I-Chemical
diet	O
.	O

After	O
2	O
weeks	O
,	O
the	O
rats	O
were	O
subjected	O
to	O
ganglionic	O
blockade	O
and	O
2	O
days	O
later	O
,	O
an	O
infusion	O
of	O
clonidine	B-Chemical
.	O

RESULTS	O
:	O
Lifetime	O
captopril	B-Chemical
treatment	O
significantly	O
lowered	O
mean	O
arterial	O
pressure	O
in	O
both	O
groups	O
.	O

Intravenous	O
infusion	O
of	O
the	O
ganglionic	O
blocker	O
hexamethonium	B-Chemical
resulted	O
in	O
a	O
rapid	O
decline	O
in	O
MAP	O
that	O
eliminated	O
the	O
dietary	B-Chemical
sodium	I-Chemical
chloride	I-Chemical
-	O
induced	O
increase	B-Disease
in	I-Disease
MAP	I-Disease
in	O
both	O
groups	O
.	O

Infusion	O
of	O
the	O
central	O
nervous	O
system	O
alpha2	B-Chemical
-	I-Chemical
adrenergic	I-Chemical
receptor	I-Chemical
agonist	I-Chemical
clonidine	B-Chemical
also	O
resulted	O
in	O
a	O
greater	O
reduction	O
in	O
MAP	O
in	O
both	O
groups	O
of	O
SHR	O
that	O
were	O
fed	O
the	O
high	O
(	O
compared	O
with	O
the	O
basal	O
)	O
sodium	B-Chemical
chloride	I-Chemical
diet	O
.	O

CONCLUSIONS	O
:	O
In	O
both	O
lifetime	O
captopril	B-Chemical
-	O
treated	O
and	O
control	O
SHR	O
,	O
the	O
sympathetic	O
nervous	O
system	O
contributes	O
to	O
the	O
pressor	O
effects	O
of	O
a	O
high	O
sodium	B-Chemical
chloride	I-Chemical
diet	O
.	O

Angioedema	B-Disease
associated	O
with	O
droperidol	B-Chemical
administration	O
.	O

Angioedema	B-Disease
,	O
also	O
known	O
as	O
angioneurotic	B-Disease
edema	I-Disease
or	O
Quincke	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
,	O
is	O
a	O
well	O
-	O
demarcated	O
,	O
localized	O
edema	B-Disease
involving	O
the	O
subcutaneous	O
tissues	O
that	O
may	O
cause	O
upper	B-Disease
-	I-Disease
airway	I-Disease
obstruction	I-Disease
.	O

We	O
report	O
the	O
case	O
of	O
a	O
previously	O
healthy	O
19	O
-	O
year	O
-	O
old	O
man	O
with	O
no	O
known	O
drug	B-Disease
allergies	I-Disease
in	O
whom	O
angioedema	B-Disease
with	O
significant	O
tongue	B-Disease
swelling	I-Disease
and	O
protrusion	O
developed	O
within	O
10	O
minutes	O
of	O
the	O
administration	O
of	O
a	O
single	O
IV	O
dose	O
of	O
droperidol	B-Chemical
.	O

Late	O
cardiotoxicity	B-Disease
after	O
treatment	O
for	O
a	O
malignant	O
bone	B-Disease
tumor	I-Disease
.	O

Cardiac	O
function	O
was	O
assessed	O
in	O
long	O
-	O
term	O
survivors	O
of	O
malignant	O
bone	B-Disease
tumors	I-Disease
who	O
were	O
treated	O
according	O
to	O
Rosen	B-Chemical
'	I-Chemical
s	I-Chemical
T5	I-Chemical
or	I-Chemical
T10	I-Chemical
protocol	I-Chemical
,	O
both	O
including	O
doxorubicin	B-Chemical
.	O

Thirty	O
-	O
one	O
patients	O
,	O
age	O
10	O
-	O
45	O
years	O
(	O
median	O
age	O
17	O
.	O
8	O
years	O
)	O
were	O
evaluated	O
2	O
.	O
3	O
-	O
14	O
.	O
1	O
years	O
(	O
median	O
8	O
.	O
9	O
years	O
)	O
following	O
completion	O
of	O
treatment	O
.	O

Cumulative	O
doses	O
of	O
doxorubicin	B-Chemical
were	O
225	O
-	O
550	O
mg	O
/	O
m2	O
(	O
median	O
dose	O
360	O
)	O
.	O

The	O
evaluation	O
consisted	O
of	O
a	O
history	O
,	O
physical	O
examination	O
,	O
electrocardiogram	O
(	O
ECG	O
)	O
,	O
signal	O
averaged	O
ECG	O
,	O
24	O
-	O
hour	O
ambulatory	O
ECG	O
,	O
echocardiography	O
and	O
radionuclide	O
angiography	O
.	O

Eighteen	O
of	O
31	O
(	O
58	O
%	O
)	O
patients	O
showed	O
cardiac	B-Disease
toxicity	I-Disease
,	O
defined	O
as	O
having	O
one	O
or	O
more	O
of	O
the	O
following	O
abnormalities	O
:	O
late	O
potentials	O
,	O
complex	O
ventricular	B-Disease
arrhythmias	I-Disease
,	O
left	O
ventricular	B-Disease
dilation	I-Disease
,	O
decreased	O
shortening	O
fraction	O
,	O
or	O
decreased	O
ejection	O
fraction	O
.	O

The	O
incidence	O
of	O
cardiac	B-Disease
abnormalities	I-Disease
increased	O
with	O
length	O
of	O
follow	O
-	O
up	O
(	O
P	O
<	O
or	O
=	O
.	O
05	O
)	O
.	O

No	O
correlation	O
could	O
be	O
demonstrated	O
between	O
cumulative	O
dose	O
of	O
doxorubicin	B-Chemical
and	O
cardiac	O
status	O
,	O
except	O
for	O
heart	O
rate	O
variability	O
.	O

When	O
adjusted	O
to	O
body	O
surface	O
area	O
,	O
the	O
left	O
ventricular	O
posterior	O
wall	O
thickness	O
(	O
LVPW	O
index	O
)	O
was	O
decreased	O
in	O
all	O
patients	O
.	O

The	O
incidence	O
of	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
is	O
high	O
and	O
increases	O
with	O
follow	O
-	O
up	O
,	O
irrespective	O
of	O
cumulative	O
dose	O
.	O

Life	O
-	O
long	O
cardiac	O
follow	O
-	O
up	O
in	O
these	O
patients	O
is	O
warranted	O
.	O

The	O
results	O
of	O
our	O
study	O
suggest	O
that	O
heart	O
rate	O
variability	O
and	O
LVPW	O
index	O
could	O
be	O
sensitive	O
indicators	O
for	O
cardiotoxicity	B-Disease
.	O

Acute	O
blood	O
pressure	O
elevations	O
with	O
caffeine	B-Chemical
in	O
men	O
with	O
borderline	O
systemic	O
hypertension	B-Disease
.	O

Whether	O
the	O
vasoconstrictive	O
actions	O
of	O
caffeine	B-Chemical
are	O
enhanced	O
in	O
hypertensive	B-Disease
persons	O
has	O
not	O
been	O
demonstrated	O
.	O

Thus	O
,	O
caffeine	B-Chemical
(	O
3	O
.	O
3	O
mg	O
/	O
kg	O
)	O
versus	O
placebo	O
was	O
tested	O
in	O
48	O
healthy	O
men	O
(	O
aged	O
20	O
to	O
35	O
years	O
)	O
selected	O
after	O
screening	O
on	O
2	O
separate	O
occasions	O
.	O

Borderline	O
hypertensive	B-Disease
men	O
(	O
n	O
=	O
24	O
)	O
were	O
selected	O
with	O
screening	O
systolic	O
blood	O
pressure	O
(	O
BP	O
)	O
of	O
140	O
to	O
160	O
mm	O
Hg	O
and	O
/	O
or	O
diastolic	O
BP	O
90	O
to	O
99	O
mm	O
Hg	O
.	O

Low	O
-	O
risk	O
controls	O
(	O
n	O
=	O
24	O
)	O
reported	O
no	O
parental	O
history	O
of	O
hypertension	B-Disease
and	O
had	O
screening	O
BP	O
<	O
130	O
/	O
85	O
mm	O
Hg	O
.	O

Participants	O
were	O
then	O
tested	O
on	O
2	O
occasions	O
after	O
12	O
-	O
hour	O
abstinence	O
from	O
caffeine	B-Chemical
in	O
each	O
of	O
2	O
protocols	O
;	O
this	O
required	O
a	O
total	O
of	O
4	O
laboratory	O
visits	O
.	O

Caffeine	B-Chemical
-	O
induced	O
changes	O
in	O
diastolic	O
BP	O
were	O
2	O
to	O
3	O
times	O
larger	O
in	O
borderline	O
subjects	O
than	O
in	O
controls	O
(	O
+	O
8	O
.	O
4	O
vs	O
+	O
3	O
.	O
8	O
mm	O
Hg	O
,	O
p	O
<	O
0	O
.	O
0001	O
)	O
,	O
and	O
were	O
attributable	O
to	O
larger	O
changes	O
in	O
impedance	O
-	O
derived	O
measures	O
of	O
systemic	O
vascular	O
resistance	O
(	O
+	O
135	O
vs	O
+	O
45	O
dynes	O
.	O
s	O
.	O
cm	O
-	O
5	O
,	O
p	O
<	O
0	O
.	O
004	O
)	O
.	O

These	O
findings	O
were	O
consistent	O
and	O
reached	O
significance	O
in	O
both	O
protocols	O
.	O

The	O
percentage	O
of	O
borderline	O
subjects	O
in	O
whom	O
diastolic	O
BP	O
changes	O
exceeded	O
the	O
median	O
control	O
response	O
was	O
96	O
%	O
.	O

Consequently	O
,	O
whereas	O
all	O
participants	O
exhibited	O
normotensive	O
levels	O
during	O
the	O
resting	O
predrug	O
baseline	O
,	O
33	O
%	O
of	O
borderline	O
subjects	O
achieved	O
hypertensive	B-Disease
BP	O
levels	O
after	O
caffeine	B-Chemical
ingestion	O
.	O

Thus	O
,	O
in	O
borderline	O
hypertensive	B-Disease
men	O
,	O
exaggerated	O
responses	O
to	O
caffeine	B-Chemical
were	O
:	O
selective	O
for	O
diastolic	O
BP	O
,	O
consistent	O
with	O
greater	O
vasoconstriction	O
,	O
replicated	O
in	O
2	O
protocols	O
,	O
and	O
representative	O
of	O
nearly	O
all	O
borderline	O
hypertensives	B-Disease
.	O

We	O
suspect	O
that	O
the	O
potential	O
for	O
caffeine	B-Chemical
to	O
stabilize	O
high	O
resistance	O
states	O
in	O
susceptible	O
persons	O
suggests	O
that	O
its	O
use	O
may	O
facilitate	O
their	O
disease	O
progression	O
,	O
as	O
well	O
as	O
hinder	O
accurate	O
diagnosis	O
and	O
treatment	O
.	O

Absence	O
of	O
effect	O
of	O
sertraline	B-Chemical
on	O
time	O
-	O
based	O
sensitization	O
of	O
cognitive	B-Disease
impairment	I-Disease
with	O
haloperidol	B-Chemical
.	O

This	O
double	O
-	O
blind	O
,	O
randomized	O
,	O
placebo	O
-	O
controlled	O
study	O
evaluated	O
the	O
effects	O
of	O
haloperidol	B-Chemical
alone	O
and	O
haloperidol	B-Chemical
plus	O
sertraline	B-Chemical
on	O
cognitive	O
and	O
psychomotor	O
function	O
in	O
24	O
healthy	O
male	O
subjects	O
.	O

METHOD	O
:	O
All	O
subjects	O
received	O
placebo	O
on	O
Day	O
1	O
and	O
haloperidol	B-Chemical
2	O
mg	O
on	O
Days	O
2	O
and	O
25	O
.	O

From	O
Days	O
9	O
to	O
25	O
,	O
subjects	O
were	O
randomly	O
assigned	O
to	O
either	O
sertraline	B-Chemical
(	O
12	O
subjects	O
)	O
or	O
placebo	O
(	O
12	O
subjects	O
)	O
;	O
the	O
sertraline	B-Chemical
dose	O
was	O
titrated	O
from	O
50	O
to	O
200	O
mg	O
/	O
day	O
from	O
Days	O
9	O
to	O
16	O
,	O
and	O
remained	O
at	O
200	O
mg	O
/	O
day	O
for	O
the	O
final	O
10	O
days	O
of	O
the	O
drug	O
administration	O
period	O
.	O

Cognitive	O
function	O
testing	O
was	O
performed	O
before	O
dosing	O
and	O
over	O
a	O
24	O
-	O
hour	O
period	O
after	O
dosing	O
on	O
Days	O
1	O
,	O
2	O
,	O
and	O
25	O
.	O

RESULTS	O
:	O
Impairment	B-Disease
of	I-Disease
cognitive	I-Disease
function	I-Disease
was	O
observed	O
6	O
to	O
8	O
hours	O
after	O
administration	O
of	O
haloperidol	B-Chemical
on	O
Day	O
2	O
but	O
was	O
not	O
evident	O
23	O
hours	O
after	O
dosing	O
.	O

When	O
single	O
-	O
dose	O
haloperidol	B-Chemical
was	O
given	O
again	O
25	O
days	O
later	O
,	O
greater	O
impairment	O
with	O
earlier	O
onset	O
was	O
noted	O
in	O
several	O
tests	O
in	O
both	O
treatment	O
groups	O
,	O
suggesting	O
enhancement	O
of	O
this	O
effect	O
.	O

There	O
was	O
no	O
indication	O
that	O
sertraline	B-Chemical
exacerbated	O
the	O
impairment	O
produced	O
by	O
haloperidol	B-Chemical
since	O
an	O
equivalent	O
effect	O
also	O
occurred	O
in	O
the	O
placebo	O
group	O
.	O

Three	O
subjects	O
(	O
2	O
on	O
sertraline	B-Chemical
and	O
1	O
on	O
placebo	O
)	O
withdrew	O
from	O
the	O
study	O
because	O
of	O
side	O
effects	O
.	O

Ten	O
subjects	O
in	O
each	O
group	O
reported	O
side	O
effects	O
related	O
to	O
treatment	O
.	O

The	O
side	O
effect	O
profiles	O
of	O
sertraline	B-Chemical
and	O
of	O
placebo	O
were	O
similar	O
.	O

CONCLUSION	O
:	O
Haloperidol	B-Chemical
produced	O
a	O
clear	O
profile	O
of	O
cognitive	B-Disease
impairment	I-Disease
that	O
was	O
not	O
worsened	O
by	O
concomitant	O
sertraline	B-Chemical
administration	O
.	O

Coexistence	O
of	O
cerebral	B-Disease
venous	I-Disease
sinus	I-Disease
and	I-Disease
internal	I-Disease
carotid	I-Disease
artery	I-Disease
thrombosis	I-Disease
associated	O
with	O
exogenous	O
sex	O
hormones	O
.	O

A	O
case	O
report	O
.	O

A	O
forty	O
-	O
six	O
year	O
-	O
old	O
premenopausal	O
woman	O
developed	O
headache	B-Disease
,	O
nausea	B-Disease
and	O
vomiting	B-Disease
,	O
left	O
hemiparesis	B-Disease
and	O
seizure	B-Disease
two	O
days	O
after	O
parenteral	O
use	O
of	O
progesterone	B-Chemical
and	O
estradiol	B-Chemical
.	O

Diabetes	B-Disease
mellitus	I-Disease
(	O
DM	B-Disease
)	O
was	O
found	O
during	O
admission	O
.	O

Computed	O
tomography	O
showed	O
a	O
hemorrhagic	B-Disease
infarct	I-Disease
in	O
the	O
right	O
frontal	O
lobe	O
and	O
increased	O
density	O
in	O
the	O
superior	O
sagittal	O
sinus	O
(	O
SSS	O
)	O
.	O

Left	O
carotid	O
angiography	O
found	O
occlusion	B-Disease
of	I-Disease
the	I-Disease
left	I-Disease
internal	I-Disease
carotid	I-Disease
artery	I-Disease
(	O
ICA	O
)	O
.	O

Right	O
carotid	O
angiograms	O
failed	O
to	O
show	O
the	O
SSS	O
and	O
inferior	O
sagittal	O
sinus	O
,	O
suggestive	O
of	O
venous	B-Disease
sinus	I-Disease
thrombosis	I-Disease
.	O

Coexistence	O
of	O
the	O
cerebral	B-Disease
artery	I-Disease
and	I-Disease
the	I-Disease
venous	I-Disease
sinus	I-Disease
occlusion	I-Disease
has	O
been	O
described	O
infrequently	O
.	O

In	O
this	O
case	O
,	O
the	O
authors	O
postulate	O
that	O
the	O
use	O
of	O
estradiol	B-Chemical
and	O
progesterone	B-Chemical
and	O
the	O
underlying	O
DM	B-Disease
increased	O
vascular	O
thrombogenicity	O
,	O
which	O
provided	O
a	O
common	O
denominator	O
for	O
thrombosis	B-Disease
of	I-Disease
both	I-Disease
the	I-Disease
ICA	I-Disease
and	I-Disease
the	I-Disease
venous	I-Disease
sinus	I-Disease
.	O

Chemotherapy	O
of	O
advanced	O
inoperable	O
non	B-Disease
-	I-Disease
small	I-Disease
cell	I-Disease
lung	I-Disease
cancer	I-Disease
with	O
paclitaxel	B-Chemical
:	O
a	O
phase	O
II	O
trial	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
has	O
demonstrated	O
significant	O
antineoplastic	O
activity	O
against	O
different	O
tumor	B-Disease
types	O
,	O
notably	O
ovarian	B-Disease
and	I-Disease
breast	I-Disease
carcinoma	I-Disease
.	O

Two	O
phase	O
II	O
trials	O
of	O
24	O
-	O
hour	O
paclitaxel	B-Chemical
infusions	O
in	O
chemotherapy	O
-	O
naive	O
patients	O
with	O
stage	O
IIIB	O
or	O
IV	O
non	B-Disease
-	I-Disease
small	I-Disease
cell	I-Disease
lung	I-Disease
cancer	I-Disease
(	O
NSCLC	B-Disease
)	O
reported	O
response	O
rates	O
of	O
21	O
%	O
and	O
24	O
%	O
.	O

Leukopenia	B-Disease
was	O
dose	O
limiting	O
:	O
as	O
many	O
as	O
62	O
.	O
5	O
%	O
of	O
patients	O
experienced	O
grade	O
4	O
leukopenia	B-Disease
.	O

We	O
investigated	O
the	O
efficacy	O
and	O
toxicity	B-Disease
of	O
a	O
3	O
-	O
hour	O
paclitaxel	B-Chemical
infusion	O
in	O
a	O
phase	O
II	O
trial	O
in	O
patients	O
with	O
inoperable	O
stage	O
IIIB	O
or	O
IV	O
NSCLC	B-Disease
.	O

The	O
58	O
patients	O
treated	O
(	O
41	O
men	O
and	O
17	O
women	O
)	O
had	O
a	O
median	O
age	O
of	O
59	O
years	O
(	O
age	O
range	O
,	O
25	O
to	O
75	O
)	O
and	O
a	O
performance	O
status	O
of	O
0	O
through	O
2	O
.	O

Most	O
patients	O
(	O
72	O
.	O
4	O
%	O
)	O
had	O
stage	O
IV	O
NSCLC	B-Disease
.	O

Paclitaxel	B-Chemical
225	O
mg	O
/	O
m2	O
was	O
infused	O
over	O
3	O
hours	O
every	O
3	O
weeks	O
with	O
standard	O
prophylactic	O
premedication	O
.	O

Of	O
50	O
patients	O
evaluable	O
for	O
response	O
,	O
12	O
(	O
24	O
%	O
)	O
had	O
partial	O
remission	O
,	O
26	O
(	O
52	O
%	O
)	O
had	O
no	O
change	O
,	O
and	O
12	O
had	O
disease	O
progression	O
(	O
24	O
%	O
)	O
.	O

Hematologic	O
toxicities	B-Disease
were	O
mild	O
:	O
only	O
one	O
patient	O
(	O
2	O
%	O
)	O
developed	O
grade	O
3	O
or	O
4	O
neutropenia	B-Disease
,	O
while	O
29	O
%	O
had	O
grade	O
1	O
or	O
2	O
.	O

Grade	O
1	O
or	O
2	O
polyneuropathy	B-Disease
affected	O
56	O
%	O
of	O
patients	O
while	O
only	O
one	O
(	O
2	O
%	O
)	O
experienced	O
severe	O
polyneuropathy	B-Disease
.	O

Similarly	O
,	O
grade	O
1	O
or	O
2	O
myalgia	B-Disease
/	O
arthralgia	B-Disease
was	O
observed	O
in	O
63	O
.	O
2	O
%	O
of	O
patients	O
,	O
but	O
only	O
14	O
.	O
3	O
%	O
experienced	O
grade	O
3	O
or	O
4	O
.	O

Nausea	B-Disease
and	O
vomiting	B-Disease
were	O
infrequent	O
,	O
with	O
14	O
%	O
of	O
patients	O
experiencing	O
grade	O
1	O
or	O
2	O
and	O
only	O
2	O
%	O
experiencing	O
grade	O
3	O
or	O
4	O
.	O

Paclitaxel	B-Chemical
is	O
thus	O
an	O
active	O
single	O
agent	O
in	O
this	O
patient	O
population	O
,	O
with	O
a	O
3	O
-	O
hour	O
infusion	O
proving	O
comparably	O
effective	O
to	O
a	O
24	O
-	O
hour	O
infusion	O
and	O
superior	O
in	O
terms	O
of	O
the	O
incidence	O
of	O
hematologic	O
and	O
nonhematologic	O
toxicity	B-Disease
.	O

Further	O
phase	O
II	O
studies	O
with	O
paclitaxel	B-Chemical
combined	O
with	O
other	O
drugs	O
active	O
against	O
NSCLC	B-Disease
are	O
indicated	O
,	O
and	O
phase	O
III	O
studies	O
comparing	O
paclitaxel	B-Chemical
with	O
standard	O
chemotherapy	O
remain	O
to	O
be	O
completed	O
.	O

Paclitaxel	B-Chemical
combined	O
with	O
carboplatin	B-Chemical
in	O
the	O
first	O
-	O
line	O
treatment	O
of	O
advanced	O
ovarian	B-Disease
cancer	I-Disease
.	O

In	O
a	O
phase	O
I	O
study	O
to	O
determine	O
the	O
maximum	O
tolerated	O
dose	O
of	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
given	O
as	O
a	O
3	O
-	O
hour	O
infusion	O
in	O
combination	O
with	O
carboplatin	B-Chemical
administered	O
every	O
21	O
days	O
to	O
women	O
with	O
advanced	O
ovarian	B-Disease
cancer	I-Disease
,	O
paclitaxel	B-Chemical
doses	O
were	O
escalated	O
as	O
follows	O
:	O
level	O
1	O
,	O
135	O
mg	O
/	O
m2	O
;	O
level	O
2	O
,	O
160	O
mg	O
/	O
m2	O
;	O
level	O
3	O
,	O
185	O
mg	O
/	O
m2	O
;	O
and	O
level	O
4	O
,	O
210	O
mg	O
/	O
m2	O
.	O

The	O
fixed	O
dose	O
of	O
carboplatin	B-Chemical
at	O
levels	O
1	O
through	O
4	O
was	O
given	O
to	O
achieve	O
an	O
area	O
under	O
the	O
concentration	O
-	O
time	O
curve	O
(	O
AUC	O
)	O
of	O
5	O
using	O
the	O
Calvert	O
formula	O
.	O

In	O
levels	O
5	O
and	O
6	O
the	O
carboplatin	B-Chemical
dose	O
was	O
targeted	O
at	O
AUCs	O
of	O
6	O
and	O
7	O
.	O
5	O
,	O
respectively	O
,	O
combined	O
with	O
a	O
fixed	O
paclitaxel	B-Chemical
dose	O
of	O
185	O
mg	O
/	O
m2	O
.	O

To	O
date	O
,	O
30	O
previously	O
untreated	O
patients	O
,	O
all	O
with	O
a	O
good	O
performance	O
status	O
(	O
Eastern	O
Cooperative	O
Oncology	O
Group	O
0	O
to	O
2	O
)	O
have	O
been	O
entered	O
into	O
this	O
ongoing	O
study	O
.	O

The	O
dose	O
-	O
limiting	O
toxicity	B-Disease
of	O
the	O
combination	O
was	O
myelosuppression	B-Disease
(	O
leukopenia	B-Disease
,	O
granulocytopenia	B-Disease
,	O
and	O
thrombocytopenia	B-Disease
)	O
.	O

Neurotoxicity	B-Disease
was	O
largely	O
moderate	O
.	O

So	O
far	O
,	O
14	O
patients	O
are	O
evaluable	O
for	O
response	O
;	O
of	O
these	O
,	O
eight	O
(	O
57	O
%	O
)	O
showed	O
objective	O
(	O
complete	O
or	O
partial	O
)	O
response	O
and	O
disease	O
stabilized	O
in	O
six	O
patients	O
.	O

No	O
patient	O
had	O
disease	O
progression	O
.	O

We	O
conclude	O
that	O
the	O
combination	O
of	O
paclitaxel	B-Chemical
185	O
mg	O
/	O
m2	O
administered	O
as	O
a	O
3	O
-	O
hour	O
infusion	O
followed	O
immediately	O
by	O
a	O
1	O
-	O
hour	O
infusion	O
of	O
carboplatin	B-Chemical
at	O
an	O
AUC	O
of	O
6	O
can	O
be	O
administered	O
safely	O
in	O
a	O
21	O
-	O
day	O
schedule	O
in	O
the	O
outpatient	O
setting	O
.	O

The	O
recommended	O
dose	O
for	O
phase	O
III	O
studies	O
is	O
paclitaxel	B-Chemical
185	O
mg	O
/	O
m2	O
and	O
carboplatin	B-Chemical
AUC	O
6	O
.	O

Effects	O
of	O
acute	O
steroid	B-Chemical
administration	O
on	O
ventilatory	O
and	O
peripheral	O
muscles	O
in	O
rats	O
.	O

Occasional	O
case	O
reports	O
have	O
shown	O
that	O
acute	O
myopathy	B-Disease
may	O
occur	O
in	O
patients	O
treated	O
with	O
massive	O
doses	O
of	O
corticosteroids	B-Chemical
.	O

The	O
mechanism	O
of	O
this	O
myopathy	B-Disease
is	O
poorly	O
understood	O
.	O

Therefore	O
,	O
60	O
male	O
rats	O
were	O
randomly	O
assigned	O
to	O
receive	O
daily	O
injection	O
of	O
saline	O
(	O
C	O
)	O
,	O
methylprednisolone	B-Chemical
(	O
M	B-Chemical
)	O
,	O
or	O
triamcinolone	B-Chemical
(	O
T	B-Chemical
)	O
80	O
mg	O
/	O
kg	O
/	O
d	O
for	O
5	O
d	O
.	O

Nutritional	O
intake	O
,	O
measured	O
daily	O
in	O
15	O
animals	O
,	O
showed	O
a	O
significant	O
reduction	B-Disease
of	I-Disease
food	I-Disease
intake	I-Disease
in	O
the	O
steroid	B-Chemical
-	O
treated	O
groups	O
(	O
-	O
50	O
and	O
-	O
79	O
%	O
in	O
M	B-Chemical
and	O
T	B-Chemical
,	O
respectively	O
)	O
.	O

This	O
was	O
associated	O
with	O
a	O
similar	O
loss	B-Disease
in	I-Disease
body	I-Disease
weight	I-Disease
.	O

In	O
the	O
45	O
remaining	O
animals	O
,	O
diaphragm	O
contractility	O
and	O
histopathologic	O
features	O
of	O
several	O
muscles	O
were	O
studied	O
.	O

Weights	O
of	O
respiratory	O
and	O
peripheral	O
muscles	O
were	O
similarly	O
decreased	O
after	O
steroid	B-Chemical
treatment	O
.	O

Maximal	O
twitches	O
of	O
the	O
diaphragm	O
were	O
lower	O
in	O
the	O
C	O
group	O
(	O
653	O
+	O
/	O
-	O
174	O
g	O
/	O
cm	O
(	O
2	O
)	O
)	O
than	O
in	O
the	O
M	B-Chemical
group	O
(	O
837	O
+	O
/	O
-	O
171	O
g	O
/	O
cm	O
(	O
2	O
)	O
;	O
p	O
<	O
0	O
.	O
05	O
)	O
and	O
the	O
T	B-Chemical
group	O
(	O
765	O
+	O
/	O
-	O
145	O
g	O
/	O
cm	O
(	O
2	O
)	O
,	O
NS	O
)	O
.	O

Half	O
-	O
relaxation	O
time	O
was	O
prolonged	O
in	O
both	O
steroid	B-Chemical
groups	O
,	O
and	O
time	O
to	O
peak	O
tension	O
was	O
longer	O
with	O
M	B-Chemical
,	O
whereas	O
tetanic	B-Disease
tensions	O
were	O
similar	O
.	O

Steroid	B-Chemical
treatment	O
also	O
induced	O
a	O
leftward	O
shift	O
of	O
the	O
force	O
-	O
frequency	O
curve	O
at	O
25	O
and	O
50	O
Hz	O
when	O
compared	O
with	O
saline	O
treatment	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
.	O

ATPase	O
staining	O
of	O
the	O
diaphragm	O
,	O
scalenus	O
medius	O
,	O
and	O
gastrocnemius	O
showed	O
type	O
IIb	O
fiber	O
atrophy	B-Disease
in	O
the	O
steroid	B-Chemical
groups	O
and	O
also	O
diaphragmatic	O
type	O
IIa	O
atrophy	B-Disease
with	O
T	B-Chemical
,	O
whereas	O
histologic	O
examinations	O
revealed	O
a	O
normal	O
muscular	O
pattern	O
with	O
absence	O
of	O
necrosis	B-Disease
.	O

Finally	O
,	O
a	O
pair	O
-	O
fed	O
(	O
PF	O
)	O
study	O
,	O
performed	O
in	O
18	O
rats	O
(	O
C	O
,	O
T	B-Chemical
,	O
and	O
PF	O
)	O
,	O
showed	O
that	O
muscle	B-Disease
atrophy	I-Disease
was	O
considerably	O
less	O
pronounced	O
in	O
PF	O
animals	O
than	O
in	O
T	B-Chemical
-	O
treated	O
animals	O
.	O

We	O
conclude	O
that	O
(	O
1	O
)	O
short	O
-	O
term	O
treatment	O
with	O
massive	O
doses	O
of	O
steroids	B-Chemical
induced	O
severe	O
respiratory	O
and	O
limb	O
muscle	O
wasting	O
;	O
(	O
2	O
)	O
both	O
types	O
of	O
steroids	B-Chemical
induced	O
predominantly	O
type	O
IIb	O
atrophy	B-Disease
,	O
resulting	O
in	O
the	O
expected	O
alterations	O
in	O
diaphragm	O
contractile	O
properties	O
;	O
(	O
3	O
)	O
neither	O
steroid	B-Chemical
caused	O
muscle	O
necrosis	B-Disease
;	O
(	O
4	O
)	O
type	O
IIb	O
atrophy	B-Disease
was	O
not	O
caused	O
by	O
acute	O
nutritional	O
deprivation	O
alone	O
.	O

Continuous	O
subcutaneous	O
administration	O
of	O
mesna	B-Chemical
to	O
prevent	O
ifosfamide	B-Chemical
-	O
induced	O
hemorrhagic	B-Disease
cystitis	I-Disease
.	O

Hemorrhagic	B-Disease
cystitis	I-Disease
is	O
a	O
major	O
potential	O
toxicity	B-Disease
of	O
ifosfamide	B-Chemical
that	O
can	O
be	O
prevented	O
by	O
administering	O
mesna	B-Chemical
along	O
with	O
the	O
cytotoxic	O
agent	O
.	O

Mesna	B-Chemical
is	O
generally	O
administered	O
by	O
the	O
intravenous	O
route	O
,	O
although	O
experience	O
with	O
oral	O
delivery	O
of	O
the	O
drug	O
has	O
increased	O
.	O

The	O
continuous	O
subcutaneous	O
administration	O
of	O
mesna	B-Chemical
has	O
the	O
advantage	O
of	O
not	O
requiring	O
intravenous	O
access	O
.	O

In	O
addition	O
,	O
subcutaneous	O
delivery	O
of	O
the	O
neutralizing	O
agent	O
will	O
not	O
be	O
associated	O
with	O
the	O
risk	O
of	O
inadequate	O
urinary	O
mesna	B-Chemical
concentrations	O
,	O
such	O
as	O
in	O
a	O
patient	O
taking	O
oral	O
mesna	B-Chemical
who	O
experiences	O
severe	O
ifosfamide	B-Chemical
-	O
induced	O
emesis	B-Disease
and	O
is	O
unable	O
to	O
absorb	O
the	O
drug	O
.	O

Limited	O
clinical	O
experience	O
with	O
continuous	O
subcutaneous	O
mesna	B-Chemical
administration	O
suggests	O
it	O
is	O
a	O
safe	O
,	O
practical	O
,	O
and	O
economic	O
method	O
of	O
drug	O
delivery	O
that	O
permits	O
ifosfamide	B-Chemical
to	O
be	O
administered	O
successfully	O
in	O
the	O
outpatient	O
setting	O
.	O

Leg	B-Disease
and	I-Disease
back	I-Disease
pain	I-Disease
after	O
spinal	O
anaesthesia	O
involving	O
hyperbaric	O
5	O
%	O
lignocaine	B-Chemical
.	O

Fifty	O
-	O
four	O
patients	O
,	O
aged	O
27	O
-	O
90	O
years	O
,	O
who	O
were	O
given	O
lignocaine	B-Chemical
5	O
%	O
in	O
6	O
.	O
8	O
%	O
glucose	B-Chemical
solution	O
for	O
spinal	O
anaesthesia	O
were	O
studied	O
.	O

Thirteen	O
of	O
these	O
patients	O
experienced	O
pain	B-Disease
in	I-Disease
the	I-Disease
legs	I-Disease
and	I-Disease
/	I-Disease
or	I-Disease
back	I-Disease
after	O
recovery	O
from	O
anaesthesia	O
.	O

The	O
patients	O
affected	O
were	O
younger	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
and	O
the	O
site	O
of	O
the	O
dural	O
puncture	O
was	O
higher	O
(	O
p	O
<	O
0	O
.	O
01	O
)	O
than	O
those	O
individuals	O
without	O
pain	B-Disease
.	O

Five	O
of	O
the	O
13	O
patients	O
(	O
38	O
%	O
)	O
with	O
pain	B-Disease
and	O
seven	O
of	O
the	O
41	O
patients	O
(	O
17	O
%	O
)	O
without	O
pain	B-Disease
admitted	O
to	O
a	O
high	O
alcohol	B-Chemical
intake	O
,	O
which	O
might	O
be	O
a	O
contributing	O
factor	O
.	O

Leg	B-Disease
and	I-Disease
/	I-Disease
or	I-Disease
back	I-Disease
pain	I-Disease
is	O
associated	O
with	O
the	O
intrathecal	O
use	O
of	O
hyperbaric	O
5	O
%	O
lignocaine	B-Chemical
.	O

The	O
use	O
of	O
serum	O
cholinesterase	O
in	O
succinylcholine	B-Chemical
apnoea	B-Disease
.	O

Fifteen	O
patients	O
demonstrating	O
unexpected	O
prolonged	O
apnoea	B-Disease
lasting	O
several	O
hours	O
after	O
succinylcholine	B-Chemical
have	O
been	O
treated	O
by	O
a	O
new	O
preparation	O
of	O
human	O
serum	O
cholinesterase	O
.	O

Adequate	O
spontaneous	O
respiration	O
was	O
re	O
-	O
established	O
in	O
an	O
average	O
period	O
of	O
ten	O
minutes	O
after	O
the	O
injection	O
.	O

In	O
12	O
patients	O
biochemical	O
genetic	O
examinations	O
confirmed	O
the	O
presence	O
of	O
an	O
atypical	O
serum	O
cholinesterase	O
.	O

In	O
three	O
patients	O
none	O
of	O
the	O
usual	O
variants	O
were	O
found	O
.	O

It	O
is	O
therefore	O
supposed	O
that	O
other	O
unknown	O
variants	O
of	O
serum	O
cholinesterase	O
exist	O
which	O
cannot	O
hydrolyze	O
succinylcholine	B-Chemical
.	O

The	O
use	O
of	O
serum	O
cholinesterase	O
in	O
succinylcholine	B-Chemical
apnoea	B-Disease
provided	O
considerable	O
relief	O
to	O
both	O
patient	O
and	O
anaesthetist	O
.	O

Increased	O
sulfation	O
and	O
decreased	O
7alpha	O
-	O
hydroxylation	O
of	O
deoxycholic	B-Chemical
acid	I-Chemical
in	O
ethinyl	B-Chemical
estradiol	I-Chemical
-	O
induced	O
cholestasis	B-Disease
in	O
rats	O
.	O

Deoxycholic	B-Chemical
acid	I-Chemical
conjugation	O
,	O
transport	O
capacity	O
,	O
and	O
metabolism	O
were	O
compared	O
in	O
control	O
and	O
ethinyl	B-Chemical
estradiol	I-Chemical
-	O
treated	O
rats	O
.	O

Control	O
rats	O
were	O
found	O
to	O
have	O
a	O
lower	O
capacity	O
to	O
transport	O
deoxycholic	B-Chemical
acid	I-Chemical
than	O
taurodeoxycholic	B-Chemical
acid	I-Chemical
,	O
and	O
both	O
were	O
decreased	O
by	O
ethinyl	B-Chemical
estradiol	I-Chemical
treatment	O
.	O

During	O
[	O
24	O
-	O
14C	O
]	O
sodium	B-Chemical
deoxycholate	I-Chemical
infusion	O
,	O
[	O
14C	O
]	O
biliary	O
bile	B-Chemical
acid	I-Chemical
secretion	O
increased	O
,	O
but	O
bile	O
flow	O
did	O
not	O
change	O
significantly	O
in	O
either	O
control	O
or	O
ethinyl	B-Chemical
estradiol	I-Chemical
-	O
treated	O
rats	O
.	O

Ethinyl	B-Chemical
estradiol	I-Chemical
-	O
treated	O
animals	O
excreted	O
significantly	O
less	O
14C	O
as	O
taurocholic	B-Chemical
acid	I-Chemical
than	O
did	O
control	O
animals	O
,	O
consistent	O
with	O
an	O
impairment	O
of	O
7alpha	O
-	O
hydroxylation	O
of	O
taurodeoxycholic	B-Chemical
acid	I-Chemical
.	O

Ethinyl	B-Chemical
estradiol	I-Chemical
treatment	O
did	O
not	O
impair	O
conjugation	O
of	O
deoxycholic	B-Chemical
acid	I-Chemical
,	O
but	O
did	O
result	O
in	O
an	O
increase	O
in	O
sulfation	O
of	O
taurodeoxycholic	B-Chemical
acid	I-Chemical
from	O
1	O
.	O
5	O
%	O
in	O
controls	O
to	O
nearly	O
4	O
.	O
0	O
%	O
(	O
P	O
less	O
than	O
0	O
.	O
01	O
)	O
.	O

These	O
results	O
are	O
consistent	O
with	O
the	O
hypothesis	O
that	O
the	O
rat	O
has	O
a	O
poorer	O
tolerance	O
for	O
deoxycholic	B-Chemical
acid	I-Chemical
than	O
do	O
certain	O
other	O
species	O
.	O

Furthermore	O
,	O
the	O
rat	O
converts	O
deoxycholic	B-Chemical
acid	I-Chemical
,	O
a	O
poor	O
choleretic	O
,	O
to	O
taurocholic	B-Chemical
acid	I-Chemical
,	O
a	O
good	O
choleretic	O
.	O

When	O
this	O
conversion	O
is	O
impaired	O
with	O
ethinyl	B-Chemical
estradiol	I-Chemical
treatment	O
,	O
sulfation	O
may	O
be	O
an	O
important	O
alternate	O
pathway	O
for	O
excretion	O
of	O
this	O
potentially	O
harmful	O
bile	B-Chemical
acid	I-Chemical
.	O

Influence	O
of	O
diet	O
free	O
of	O
NAD	B-Chemical
-	O
precursors	O
on	O
acetaminophen	B-Chemical
hepatotoxicity	B-Disease
in	O
mice	O
.	O

Recently	O
,	O
we	O
demonstrated	O
the	O
hepatoprotective	O
effects	O
of	O
nicotinic	B-Chemical
acid	I-Chemical
amide	I-Chemical
,	O
a	O
selective	O
inhibitor	O
of	O
poly	B-Chemical
(	I-Chemical
ADP	I-Chemical
-	I-Chemical
ribose	I-Chemical
)	I-Chemical
polymerase	O
(	O
PARP	O
;	O
EC	O
2	O
.	O
4	O
.	O
2	O
.	O
30	O
)	O
on	O
mice	O
suffering	O
from	O
acetaminophen	B-Chemical
(	O
AAP	B-Chemical
)	O
-	O
hepatitis	B-Disease
,	O
suggesting	O
that	O
the	O
AAP	B-Chemical
-	O
induced	O
liver	B-Disease
injury	I-Disease
involves	O
a	O
step	O
which	O
depends	O
on	O
adenoribosylation	O
.	O

The	O
present	O
study	O
investigates	O
the	O
effects	O
of	O
a	O
diet	O
free	O
of	O
precursors	O
of	O
NAD	B-Chemical
,	O
the	O
substrate	O
on	O
which	O
PARP	O
acts	O
,	O
in	O
female	O
NMRI	O
mice	O
with	O
AAP	B-Chemical
hepatitis	B-Disease
and	O
evaluates	O
the	O
influence	O
of	O
simultaneous	O
ethanol	B-Chemical
consumption	O
in	O
these	O
animals	O
.	O

Liver	B-Disease
injuries	I-Disease
were	O
quantified	O
as	O
serum	O
activities	O
of	O
glutamate	B-Chemical
-	O
oxaloacetate	B-Chemical
transaminase	O
(	O
GOT	O
)	O
and	O
glutamate	B-Chemical
-	O
pyruvate	B-Chemical
transaminase	O
(	O
GPT	O
)	O
.	O

While	O
AAP	B-Chemical
caused	O
a	O
117	O
-	O
fold	O
elevation	O
of	O
serum	O
transaminase	O
activities	O
in	O
mice	O
kept	O
on	O
a	O
standard	O
laboratory	O
diet	O
,	O
which	O
was	O
significantly	O
exacerbated	O
by	O
ethanol	B-Chemical
and	O
inhibited	O
by	O
nicotinic	B-Chemical
acid	I-Chemical
amide	I-Chemical
(	O
NAA	B-Chemical
)	O
,	O
adverse	O
effects	O
were	O
noted	O
in	O
animals	O
fed	O
a	O
diet	O
free	O
of	O
precursors	O
of	O
NAD	B-Chemical
.	O

In	O
these	O
animals	O
,	O
only	O
minor	O
increases	O
of	O
serum	O
transaminase	O
activities	O
were	O
measured	O
in	O
the	O
presence	O
of	O
AAP	B-Chemical
,	O
and	O
unlike	O
the	O
exacerbation	O
caused	O
by	O
ethanol	B-Chemical
in	O
mice	O
on	O
a	O
standard	O
diet	O
,	O
the	O
liver	B-Disease
damage	I-Disease
was	O
inhibited	O
by	O
50	O
%	O
by	O
ethanol	B-Chemical
.	O

A	O
further	O
64	O
%	O
reduction	O
of	O
hepatitis	B-Disease
was	O
observed	O
,	O
when	O
NAA	B-Chemical
was	O
given	O
to	O
ethanol	B-Chemical
/	O
AAP	B-Chemical
-	O
mice	O
.	O

Our	O
results	O
provide	O
evidence	O
that	O
the	O
AAP	B-Chemical
-	O
induced	O
hepatitis	B-Disease
and	O
its	O
exacerbation	O
by	O
ethanol	B-Chemical
can	O
either	O
be	O
reduced	O
by	O
end	O
-	O
product	O
inhibition	O
of	O
PARP	O
by	O
NAA	B-Chemical
or	O
by	O
dietary	O
depletion	O
of	O
the	O
enzyme	O
'	O
s	O
substrate	O
NAD	B-Chemical
.	O

We	O
see	O
the	O
main	O
application	O
of	O
NAA	B-Chemical
as	O
for	O
the	O
combinational	O
use	O
in	O
pharmaceutical	O
preparations	O
of	O
acetaminophen	B-Chemical
in	O
order	O
to	O
avoid	O
hepatic	B-Disease
damage	I-Disease
in	O
patients	O
treated	O
with	O
this	O
widely	O
used	O
analgesic	O
.	O

Nightmares	O
and	O
hallucinations	B-Disease
after	O
long	O
-	O
term	O
intake	O
of	O
tramadol	B-Chemical
combined	O
with	O
antidepressants	O
.	O

Tramadol	B-Chemical
is	O
a	O
weak	O
opioid	O
with	O
effects	O
on	O
adrenergic	O
and	O
serotonergic	O
neurotransmission	O
that	O
is	O
used	O
to	O
treat	O
cancer	B-Disease
pain	B-Disease
and	O
chronic	O
non	O
malignant	O
pain	B-Disease
.	O

This	O
drug	O
was	O
initiated	O
in	O
association	O
with	O
paroxetine	B-Chemical
and	O
dosulepine	B-Chemical
hydrochloride	I-Chemical
in	O
a	O
tetraparetic	B-Disease
patient	O
with	O
chronic	B-Disease
pain	I-Disease
.	O

Fifty	O
-	O
six	O
days	O
after	O
initiation	O
of	O
the	O
treatment	O
the	O
patient	O
presented	O
hallucinations	B-Disease
that	O
only	O
stopped	O
after	O
the	O
withdrawal	O
of	O
psycho	O
-	O
active	O
drugs	O
and	O
tramadol	B-Chemical
.	O

The	O
case	O
report	O
questions	O
the	O
long	O
term	O
use	O
of	O
pain	B-Disease
killers	O
combined	O
with	O
psycho	O
-	O
active	O
drugs	O
in	O
chronic	O
non	O
malignant	O
pain	B-Disease
,	O
especially	O
if	O
pain	B-Disease
is	O
under	O
control	O
.	O

Effect	O
of	O
calcium	B-Chemical
chloride	I-Chemical
and	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
therapy	O
on	O
desipramine	B-Chemical
toxicity	B-Disease
in	O
rats	O
.	O

BACKGROUND	O
:	O
Hypotension	B-Disease
is	O
a	O
major	O
contributor	O
to	O
mortality	O
in	O
tricyclic	O
antidepressant	O
overdose	B-Disease
.	O

Recent	O
data	O
suggest	O
that	O
tricyclic	O
antidepressants	O
inhibit	O
calcium	B-Chemical
influx	O
in	O
some	O
tissues	O
.	O

This	O
study	O
addressed	O
the	O
potential	O
role	O
of	O
calcium	B-Chemical
channel	O
blockade	O
in	O
tricyclic	O
antidepressant	O
-	O
induced	O
hypotension	B-Disease
.	O

METHODS	O
:	O
Two	O
interventions	O
were	O
studied	O
that	O
have	O
been	O
shown	O
previously	O
to	O
improve	O
blood	O
pressure	O
with	O
calcium	B-Chemical
channel	O
blocker	O
overdose	B-Disease
.	O

CaCl2	B-Chemical
and	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
.	O

Anesthetized	O
rats	O
received	O
the	O
tricyclic	O
antidepressant	O
desipramine	B-Chemical
IP	O
to	O
produce	O
hypotension	B-Disease
,	O
QRS	O
prolongation	O
,	O
and	O
bradycardia	B-Disease
.	O

Fifteen	O
min	O
later	O
,	O
animals	O
received	O
CaCl2	B-Chemical
,	O
NaHCO3	B-Chemical
,	O
or	O
saline	O
.	O

In	O
a	O
second	O
experiment	O
,	O
rats	O
received	O
tricyclic	O
antidepressant	O
desipramine	B-Chemical
IP	O
followed	O
in	O
15	O
min	O
by	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
or	O
saline	O
.	O

RESULTS	O
:	O
NaHCO3	B-Chemical
briefly	O
(	O
5	O
min	O
)	O
reversed	O
hypotension	B-Disease
and	O
QRS	O
prolongation	O
.	O

CaCl2	B-Chemical
and	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
failed	O
to	O
improve	O
blood	O
pressure	O
.	O

The	O
incidence	O
of	O
ventricular	B-Disease
arrhythmias	I-Disease
(	O
p	O
=	O
0	O
.	O
004	O
)	O
and	O
seizures	B-Disease
(	O
p	O
=	O
0	O
.	O
03	O
)	O
in	O
the	O
CaCl2	B-Chemical
group	O
was	O
higher	O
than	O
the	O
other	O
groups	O
.	O

CONCLUSION	O
:	O
The	O
administration	O
of	O
CaCl2	B-Chemical
or	O
4	B-Chemical
-	I-Chemical
aminopyridine	I-Chemical
did	O
not	O
reverse	O
tricyclic	O
antidepressant	O
-	O
induced	O
hypotension	B-Disease
in	O
rats	O
.	O

CaCl2	B-Chemical
therapy	O
may	O
possibly	O
worsen	O
both	O
cardiovascular	B-Disease
and	I-Disease
central	I-Disease
nervous	I-Disease
system	I-Disease
toxicity	I-Disease
.	O

These	O
findings	O
do	O
not	O
support	O
a	O
role	O
for	O
calcium	B-Chemical
channel	O
inhibition	O
in	O
the	O
pathogenesis	O
of	O
tricyclic	O
antidepressant	O
-	O
induced	O
hypotension	B-Disease
.	O

Valsartan	B-Chemical
,	O
a	O
new	O
angiotensin	B-Chemical
II	I-Chemical
antagonist	O
for	O
the	O
treatment	O
of	O
essential	O
hypertension	B-Disease
:	O
a	O
comparative	O
study	O
of	O
the	O
efficacy	O
and	O
safety	O
against	O
amlodipine	B-Chemical
.	O

OBJECTIVE	O
:	O
To	O
compare	O
the	O
antihypertensive	O
efficacy	O
of	O
a	O
new	O
angiotensin	B-Chemical
II	I-Chemical
antagonist	O
,	O
valsartan	B-Chemical
,	O
with	O
a	O
reference	O
therapy	O
,	O
amlodipine	B-Chemical
.	O

METHODS	O
:	O
One	O
hundred	O
sixty	O
-	O
eight	O
adult	O
outpatients	O
with	O
mild	O
to	O
moderate	O
hypertension	B-Disease
were	O
randomly	O
allocated	O
in	O
double	O
-	O
blind	O
fashion	O
and	O
equal	O
number	O
to	O
receive	O
80	O
mg	O
valsartan	B-Chemical
or	O
5	O
mg	O
amlodipine	B-Chemical
for	O
12	O
weeks	O
.	O

After	O
8	O
weeks	O
of	O
therapy	O
,	O
in	O
patients	O
whose	O
blood	O
pressure	O
remained	O
uncontrolled	O
,	O
5	O
mg	O
amlodipine	B-Chemical
was	O
added	O
to	O
the	O
initial	O
therapy	O
.	O

Patients	O
were	O
assessed	O
at	O
4	O
,	O
8	O
,	O
and	O
12	O
weeks	O
.	O

The	O
primary	O
efficacy	O
variable	O
was	O
change	O
from	O
baseline	O
in	O
mean	O
sitting	O
diastolic	O
blood	O
pressure	O
at	O
8	O
weeks	O
.	O

Secondary	O
variables	O
included	O
change	O
in	O
sitting	O
systolic	O
blood	O
pressure	O
and	O
responder	O
rates	O
.	O

RESULTS	O
:	O
Both	O
valsartan	B-Chemical
and	O
amlodipine	B-Chemical
were	O
effective	O
at	O
lowering	O
blood	O
pressure	O
at	O
4	O
,	O
8	O
,	O
and	O
12	O
weeks	O
.	O

Similar	O
decreases	O
were	O
observed	O
in	O
both	O
groups	O
,	O
with	O
no	O
statistically	O
significant	O
differences	O
between	O
the	O
groups	O
for	O
any	O
variable	O
analyzed	O
.	O

For	O
the	O
primary	O
variable	O
the	O
difference	O
was	O
0	O
.	O
5	O
mm	O
Hg	O
in	O
favor	O
of	O
valsartan	B-Chemical
(	O
p	O
=	O
0	O
.	O
68	O
;	O
95	O
%	O
confidence	O
interval	O
,	O
-	O
2	O
.	O
7	O
to	O
1	O
.	O
7	O
)	O
.	O

Responder	O
rates	O
at	O
8	O
weeks	O
were	O
66	O
.	O
7	O
%	O
for	O
valsartan	B-Chemical
and	O
60	O
.	O
2	O
%	O
for	O
amlodipine	B-Chemical
(	O
p	O
=	O
0	O
.	O
39	O
)	O
.	O

Both	O
treatments	O
were	O
well	O
tolerated	O
.	O

The	O
incidence	O
of	O
drug	O
-	O
related	O
dependent	O
edema	B-Disease
was	O
somewhat	O
higher	O
in	O
the	O
amlodipine	B-Chemical
group	O
,	O
particularly	O
at	O
a	O
dose	O
of	O
10	O
mg	O
per	O
day	O
(	O
2	O
.	O
4	O
%	O
for	O
80	O
mg	O
valsartan	B-Chemical
;	O
3	O
.	O
6	O
%	O
for	O
5	O
mg	O
amlodipine	B-Chemical
;	O
0	O
%	O
for	O
valsartan	B-Chemical
plus	O
5	O
mg	O
amlodipine	B-Chemical
;	O
14	O
.	O
3	O
%	O
for	O
10	O
mg	O
amlodipine	B-Chemical
)	O
.	O

CONCLUSIONS	O
:	O
The	O
data	O
show	O
that	O
valsartan	B-Chemical
is	O
at	O
least	O
as	O
effective	O
as	O
amlodipine	B-Chemical
in	O
the	O
treatment	O
of	O
mild	O
to	O
moderate	O
hypertension	B-Disease
.	O

The	O
results	O
also	O
show	O
valsartan	B-Chemical
to	O
be	O
well	O
tolerated	O
and	O
suggest	O
that	O
it	O
is	O
not	O
associated	O
with	O
side	O
effects	O
characteristic	O
of	O
this	O
comparator	O
class	O
,	O
dihydropyridine	B-Chemical
calcium	B-Chemical
antagonists	O
.	O

A	O
measure	O
of	O
pupillary	B-Disease
oscillation	I-Disease
as	O
a	O
marker	O
of	O
cocaine	B-Chemical
-	O
induced	O
paranoia	B-Disease
.	O

Cocaine	B-Chemical
-	O
induced	O
paranoia	B-Disease
(	O
CIP	B-Disease
)	O
remains	O
an	O
important	O
drug	O
-	O
induced	O
model	O
of	O
idiopathic	O
paranoia	B-Disease
for	O
which	O
no	O
psychophysiologic	O
marker	O
has	O
yet	O
emerged	O
.	O

Measures	O
of	O
pupillary	B-Disease
oscillation	I-Disease
were	O
able	O
to	O
significantly	O
distinguish	O
a	O
group	O
of	O
abstinent	O
crack	B-Chemical
cocaine	I-Chemical
abusers	O
endorsing	O
past	O
CIP	B-Disease
(	O
n	O
=	O
32	O
)	O
from	O
another	O
group	O
of	O
crack	B-Chemical
addicts	O
who	O
denied	O
past	O
CIP	B-Disease
(	O
n	O
=	O
29	O
)	O
.	O

Serotonin	B-Disease
syndrome	I-Disease
from	O
venlafaxine	B-Chemical
-	O
tranylcypromine	B-Chemical
interaction	O
.	O

Excessive	O
stimulation	O
of	O
serotonin	B-Chemical
5HT1A	O
receptors	O
causes	O
a	O
syndrome	O
of	O
serotonin	B-Chemical
excess	O
that	O
consists	O
of	O
shivering	O
,	O
muscle	B-Disease
rigidity	I-Disease
,	O
salivation	B-Disease
,	O
confusion	B-Disease
,	O
agitation	B-Disease
and	O
hyperthermia	B-Disease
.	O

The	O
most	O
common	O
cause	O
of	O
this	O
syndrome	O
is	O
an	O
interaction	O
between	O
a	O
monoamine	O
oxidase	O
inhibitor	O
(	O
MAOI	O
)	O
and	O
a	O
specific	O
serotonin	B-Chemical
reuptake	O
inhibitor	O
.	O

Venlafaxine	B-Chemical
is	O
a	O
new	O
antidepressant	O
agent	O
that	O
inhibits	O
the	O
reuptake	O
of	O
serotonin	B-Chemical
and	O
norepinephrine	B-Chemical
.	O

We	O
report	O
a	O
venlafaxine	B-Chemical
-	O
MAOI	O
interaction	O
that	O
resulted	O
in	O
the	O
serotonin	B-Disease
syndrome	I-Disease
in	O
a	O
23	O
-	O
y	O
-	O
old	O
male	O
who	O
was	O
taking	O
tranylcypromine	B-Chemical
for	O
depression	B-Disease
.	O

He	O
had	O
been	O
well	O
until	O
the	O
morning	O
of	O
presentation	O
when	O
he	O
took	O
1	O
/	O
2	O
tab	O
of	O
venlafaxine	B-Chemical
.	O

Within	O
2	O
h	O
he	O
became	O
confused	O
with	O
jerking	O
movements	O
of	O
his	O
extremities	O
,	O
tremors	B-Disease
and	O
rigidity	B-Disease
.	O

He	O
was	O
brought	O
directly	O
to	O
a	O
hospital	O
where	O
he	O
was	O
found	O
to	O
be	O
agitated	O
and	O
confused	O
with	O
shivering	O
,	O
myoclonic	B-Disease
jerks	I-Disease
,	O
rigidity	B-Disease
,	O
salivation	B-Disease
and	O
diaphoresis	O
.	O

His	O
pupils	O
were	O
7	O
mm	O
and	O
sluggishly	O
reactive	O
to	O
light	O
.	O

Vital	O
signs	O
were	O
:	O
blood	O
pressure	O
120	O
/	O
67	O
mm	O
Hg	O
,	O
heart	O
rate	O
127	O
/	O
min	O
,	O
respiratory	O
rate	O
28	O
/	O
min	O
,	O
and	O
temperature	O
97	O
F	O
.	O

After	O
180	O
mg	O
of	O
diazepam	B-Chemical
i	O
.	O
v	O
.	O
he	O
remained	O
tremulous	O
with	O
muscle	B-Disease
rigidity	I-Disease
and	O
clenched	O
jaws	O
.	O

He	O
was	O
intubated	O
for	O
airway	O
protection	O
and	O
because	O
of	O
hypoventilation	B-Disease
,	O
and	O
was	O
paralyzed	B-Disease
to	O
control	O
muscle	B-Disease
rigidity	I-Disease
.	O

His	O
subsequent	O
course	O
was	O
remarkable	O
for	O
non	O
-	O
immune	O
thrombocytopenia	B-Disease
which	O
resolved	O
.	O

The	O
patient	O
'	O
s	O
maximal	O
temperature	O
was	O
101	O
.	O
2	O
F	O
and	O
his	O
CPK	O
remained	O
<	O
500	O
units	O
/	O
L	O
with	O
no	O
other	O
evidence	O
of	O
rhabdomyolysis	B-Disease
.	O

His	O
mental	O
status	O
normalized	O
and	O
he	O
was	O
transferred	O
to	O
a	O
psychiatry	O
ward	O
.	O

This	O
patient	O
survived	O
without	O
sequelae	O
due	O
to	O
the	O
aggressive	O
sedation	O
and	O
neuromuscular	O
paralysis	B-Disease
.	O

Cyclophosphamide	B-Chemical
associated	O
bladder	B-Disease
cancer	I-Disease
-	O
-	O
a	O
highly	O
aggressive	O
disease	O
:	O
analysis	O
of	O
12	O
cases	O
.	O

PURPOSE	O
:	O
We	O
gained	O
knowledge	O
of	O
the	O
etiology	O
,	O
treatment	O
and	O
prevention	O
of	O
cyclophosphamide	B-Chemical
associated	O
urothelial	B-Disease
cancer	I-Disease
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
The	O
medical	O
records	O
of	O
6	O
men	O
and	O
6	O
women	O
(	O
mean	O
age	O
55	O
years	O
)	O
with	O
cyclophosphamide	B-Chemical
associated	O
bladder	B-Disease
cancer	I-Disease
were	O
reviewed	O
.	O

RESULTS	O
:	O
All	O
tumors	B-Disease
were	O
grade	O
3	O
or	O
4	O
transitional	O
cell	O
carcinoma	B-Disease
.	O

Of	O
the	O
5	O
patients	O
initially	O
treated	O
with	O
endoscopic	O
resection	O
alone	O
only	O
1	O
is	O
alive	O
without	O
disease	O
.	O

Of	O
the	O
6	O
patients	O
who	O
underwent	O
early	O
cystectomy	O
4	O
were	O
alive	O
at	O
24	O
to	O
111	O
months	O
.	O

The	O
remaining	O
patient	O
with	O
extensive	O
cancer	B-Disease
underwent	O
partial	O
cystectomy	O
for	O
palliation	O
and	O
died	O
3	O
months	O
later	O
.	O

CONCLUSIONS	O
:	O
Cyclophosphamide	B-Chemical
associated	O
bladder	B-Disease
tumor	I-Disease
is	O
an	O
aggressive	O
disease	O
.	O

However	O
,	O
long	O
-	O
term	O
survival	O
is	O
possible	O
when	O
radical	O
cystectomy	O
is	O
performed	O
for	O
bladder	B-Disease
tumors	I-Disease
with	O
any	O
sign	O
of	O
invasion	O
and	O
for	O
recurrent	O
high	O
grade	O
disease	O
,	O
even	O
when	O
noninvasive	O
.	O

A	O
phase	O
I	O
clinical	O
study	O
of	O
the	O
antipurine	B-Chemical
antifolate	O
lometrexol	B-Chemical
(	O
DDATHF	B-Chemical
)	O
given	O
with	O
oral	O
folic	B-Chemical
acid	I-Chemical
.	O

Lometrexol	B-Chemical
is	O
an	O
antifolate	O
which	O
inhibits	O
glycinamide	B-Chemical
ribonucleotide	I-Chemical
formyltransferase	O
(	O
GARFT	O
)	O
,	O
an	O
enzyme	O
essential	O
for	O
de	O
novo	O
purine	B-Chemical
synthesis	O
.	O

Extensive	O
experimental	O
and	O
limited	O
clinical	O
data	O
have	O
shown	O
that	O
lometrexol	B-Chemical
has	O
activity	O
against	O
tumours	B-Disease
which	O
are	O
refractory	O
to	O
other	O
drugs	O
,	O
notably	O
methotrexate	B-Chemical
.	O

However	O
,	O
the	O
initial	O
clinical	O
development	O
of	O
lometrexol	B-Chemical
was	O
curtailed	O
because	O
of	O
severe	O
and	O
cumulative	O
antiproliferative	O
toxicities	B-Disease
.	O

Preclinical	O
murine	O
studies	O
demonstrated	O
that	O
the	O
toxicity	B-Disease
of	O
lometrexol	B-Chemical
can	O
be	O
prevented	O
by	O
low	O
dose	O
folic	B-Chemical
acid	I-Chemical
administration	O
,	O
i	O
.	O
e	O
.	O
for	O
7	O
days	O
prior	O
to	O
and	O
7	O
days	O
following	O
a	O
single	O
bolus	O
dose	O
.	O

This	O
observation	O
prompted	O
a	O
Phase	O
I	O
clinical	O
study	O
of	O
lometrexol	B-Chemical
given	O
with	O
folic	B-Chemical
acid	I-Chemical
supplementation	O
which	O
has	O
confirmed	O
that	O
the	O
toxicity	B-Disease
of	O
lometrexol	B-Chemical
can	O
be	O
markedly	O
reduced	O
by	O
folic	B-Chemical
acid	I-Chemical
supplementation	O
.	O

Thrombocytopenia	B-Disease
and	O
mucositis	B-Disease
were	O
the	O
major	O
toxicities	B-Disease
.	O

There	O
was	O
no	O
clear	O
relationship	O
between	O
clinical	O
toxicity	B-Disease
and	O
the	O
extent	O
of	O
plasma	O
folate	B-Chemical
elevation	O
.	O

Associated	O
studies	O
demonstrated	O
that	O
lometrexol	B-Chemical
plasma	O
pharmacokinetics	O
were	O
not	O
altered	O
by	O
folic	B-Chemical
acid	I-Chemical
administration	O
indicating	O
that	O
supplementation	O
is	O
unlikely	O
to	O
reduce	O
toxicity	B-Disease
by	O
enhancing	O
lometrexol	B-Chemical
plasma	O
clearance	O
.	O

The	O
work	O
described	O
in	O
this	O
report	O
has	O
identified	O
for	O
the	O
first	O
time	O
a	O
clinically	O
acceptable	O
schedule	O
for	O
the	O
administration	O
of	O
a	O
GARFT	O
inhibitor	O
.	O

This	O
information	O
will	O
facilitate	O
the	O
future	O
evaluation	O
of	O
this	O
class	O
of	O
compounds	O
in	O
cancer	B-Disease
therapy	O
.	O

Fatal	O
excited	O
delirium	B-Disease
following	O
cocaine	B-Chemical
use	O
:	O
epidemiologic	O
findings	O
provide	O
new	O
evidence	O
for	O
mechanisms	O
of	O
cocaine	B-Chemical
toxicity	B-Disease
.	O

We	O
describe	O
an	O
outbreak	O
of	O
deaths	O
from	O
cocaine	B-Chemical
-	O
induced	O
excited	O
delirium	B-Disease
(	O
EDDs	B-Disease
)	O
in	O
Dade	O
County	O
,	O
Florida	O
between	O
1979	O
and	O
1990	O
.	O

From	O
a	O
registry	O
of	O
all	O
cocaine	B-Chemical
-	O
related	O
deaths	O
in	O
Dade	O
County	O
,	O
Florida	O
,	O
from	O
1969	O
-	O
1990	O
,	O
58	O
EDDs	B-Disease
were	O
compared	O
with	O
125	O
victims	O
of	O
accidental	O
cocaine	B-Chemical
overdose	B-Disease
without	O
excited	O
delirium	B-Disease
.	O

Compared	O
with	O
controls	O
,	O
EDDs	B-Disease
were	O
more	O
frequently	O
black	O
,	O
male	O
,	O
and	O
younger	O
.	O

They	O
were	O
less	O
likely	O
to	O
have	O
a	O
low	O
body	O
mass	O
index	O
,	O
and	O
more	O
likely	O
to	O
have	O
died	O
in	O
police	O
custody	O
,	O
to	O
have	O
received	O
medical	O
treatment	O
immediately	O
before	O
death	O
,	O
to	O
have	O
survived	O
for	O
a	O
longer	O
period	O
,	O
to	O
have	O
developed	O
hyperthermia	B-Disease
,	O
and	O
to	O
have	O
died	O
in	O
summer	O
months	O
.	O

EDDs	B-Disease
had	O
concentrations	O
of	O
cocaine	B-Chemical
and	O
benzoylecgonine	B-Chemical
in	O
autopsy	O
blood	O
that	O
were	O
similar	O
to	O
those	O
for	O
controls	O
.	O

The	O
epidemiologic	O
findings	O
are	O
most	O
consistent	O
with	O
the	O
hypothesis	O
that	O
chronic	O
cocaine	B-Chemical
use	O
disrupts	O
dopaminergic	O
function	O
and	O
,	O
when	O
coupled	O
with	O
recent	O
cocaine	B-Chemical
use	O
,	O
may	O
precipitate	O
agitation	B-Disease
,	O
delirium	B-Disease
,	O
aberrant	O
thermoregulation	O
,	O
rhabdomyolysis	B-Disease
,	O
and	O
sudden	B-Disease
death	I-Disease
.	O

Pemoline	B-Chemical
induced	O
acute	O
choreoathetosis	B-Disease
:	O
case	O
report	O
and	O
review	O
of	O
the	O
literature	O
.	O

BACKGROUND	O
:	O
Pemoline	B-Chemical
is	O
an	O
oxazolidine	B-Chemical
derivative	O
that	O
is	O
structurally	O
different	O
from	O
amphetamines	B-Chemical
and	O
used	O
in	O
the	O
treatment	O
of	O
attention	B-Disease
deficit	I-Disease
disorder	I-Disease
.	O

Pemoline	B-Chemical
has	O
not	O
been	O
commonly	O
associated	O
in	O
the	O
literature	O
as	O
a	O
cause	O
of	O
acute	O
movement	B-Disease
disorders	I-Disease
.	O

The	O
following	O
case	O
describes	O
two	O
children	O
acutely	O
poisoned	O
with	O
pemoline	B-Chemical
who	O
experienced	O
profound	O
choreoathetosis	B-Disease
.	O

CASE	O
REPORT	O
:	O
Two	O
,	O
3	O
-	O
year	O
-	O
old	O
male	O
,	O
identical	O
twin	O
siblings	O
presented	O
to	O
the	O
emergency	O
department	O
after	O
found	O
playing	O
with	O
a	O
an	O
empty	O
bottle	O
of	O
pemoline	B-Chemical
originally	O
containing	O
59	O
tablets	O
.	O

The	O
children	O
had	O
a	O
medical	O
history	O
significant	O
for	O
attention	B-Disease
deficit	I-Disease
disorder	I-Disease
previously	O
treated	O
with	O
methylphenidate	B-Chemical
without	O
success	O
.	O

This	O
was	O
their	O
first	O
day	O
of	O
pemoline	B-Chemical
therapy	O
.	O

The	O
choreoathetoid	B-Disease
movements	O
began	O
45	O
min	O
to	O
1	O
h	O
after	O
ingestion	O
.	O

The	O
children	O
gave	O
no	O
history	O
of	O
prior	O
movement	B-Disease
disorders	I-Disease
and	O
there	O
was	O
no	O
family	O
history	O
of	O
movement	B-Disease
disorders	I-Disease
.	O

The	O
children	O
received	O
gastrointestinal	O
decontamination	O
and	O
high	O
doses	O
of	O
intravenous	O
benzodiazepines	B-Chemical
in	O
an	O
attempt	O
to	O
control	O
the	O
choreoathetoid	B-Disease
movements	O
.	O

Despite	O
treatment	O
,	O
the	O
children	O
continued	O
to	O
have	O
choreoathetosis	B-Disease
for	O
approximately	O
24	O
hours	O
.	O

Forty	O
-	O
eight	O
hours	O
after	O
admission	O
,	O
the	O
children	O
appeared	O
to	O
be	O
at	O
their	O
baseline	O
and	O
were	O
discharged	O
home	O
.	O

CONCLUSION	O
:	O
Pemoline	B-Chemical
associated	O
movement	B-Disease
disorder	I-Disease
has	O
been	O
rarely	O
reported	O
in	O
the	O
acute	O
toxicology	O
literature	O
.	O

The	O
possibility	O
of	O
choreoathetoid	B-Disease
movements	O
should	O
be	O
considered	O
in	O
patients	O
presenting	O
after	O
pemoline	B-Chemical
overdose	B-Disease
.	O

Effect	O
of	O
myopic	O
excimer	O
laser	O
photorefractive	O
keratectomy	O
on	O
the	O
electrophysiologic	O
function	O
of	O
the	O
retina	O
and	O
optic	O
nerve	O
.	O

PURPOSE	O
:	O
To	O
assess	O
by	O
electrophysiologic	O
testing	O
the	O
effect	O
of	O
photorefractive	O
keratectomy	O
(	O
PRK	O
)	O
on	O
the	O
retina	O
and	O
optic	O
nerve	O
.	O

SETTING	O
:	O
Eye	O
Clinic	O
,	O
S	O
.	O

Salvatore	O
Hospital	O
,	O
L	O
'	O
Aquila	O
University	O
,	O
Italy	O
.	O

METHODS	O
:	O
Standard	O
pattern	O
electroretinograms	O
(	O
P	O
-	O
ERGs	O
)	O
and	O
standard	O
pattern	O
visual	O
evoked	O
potentials	O
(	O
P	O
-	O
VEPs	O
)	O
were	O
done	O
in	O
25	O
eyes	O
of	O
25	O
patients	O
who	O
had	O
myopic	O
PRK	O
for	O
an	O
attempted	O
correction	O
between	O
5	O
.	O
00	O
and	O
15	O
.	O
00	O
diopters	O
(	O
D	O
)	O
(	O
mean	O
8	O
.	O
00	O
D	O
)	O
.	O

Testing	O
was	O
done	O
preoperatively	O
and	O
3	O
,	O
6	O
,	O
12	O
,	O
and	O
18	O
months	O
postoperatively	O
.	O

The	O
contralateral	O
eyes	O
served	O
as	O
controls	O
.	O

During	O
the	O
follow	O
-	O
up	O
,	O
3	O
patients	O
(	O
12	O
%	O
)	O
developed	O
steroid	B-Chemical
-	O
induced	O
elevated	B-Disease
intraocular	I-Disease
pressure	I-Disease
(	O
IOP	O
)	O
that	O
resolved	O
after	O
corticosteroid	B-Chemical
therapy	O
was	O
discontinued	O
.	O

RESULTS	O
:	O
No	O
statistically	O
significant	O
differences	O
were	O
seen	O
between	O
treated	O
and	O
control	O
eyes	O
nor	O
between	O
treated	O
eyes	O
preoperatively	O
and	O
postoperatively	O
.	O

CONCLUSION	O
:	O
Myopic	O
excimer	O
laser	O
PRK	O
did	O
not	O
seem	O
to	O
affect	O
the	O
posterior	O
segment	O
.	O

The	O
transient	O
steroid	B-Chemical
-	O
induced	O
IOP	B-Disease
rise	I-Disease
did	O
not	O
seem	O
to	O
cause	O
functional	O
impairment	O
.	O

Neutrophil	O
superoxide	B-Chemical
and	O
hydrogen	B-Chemical
peroxide	I-Chemical
production	O
in	O
patients	O
with	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
.	O

Defects	O
in	O
superoxide	B-Chemical
and	O
hydrogen	B-Chemical
peroxide	I-Chemical
production	O
may	O
be	O
implicated	O
in	O
the	O
high	O
incidence	O
of	O
bacterial	B-Disease
infections	I-Disease
in	O
patients	O
with	O
acute	B-Disease
liver	I-Disease
failure	I-Disease
(	O
ALF	B-Disease
)	O
.	O

In	O
the	O
present	O
study	O
,	O
oxygen	B-Chemical
radical	O
production	O
in	O
patients	O
with	O
ALF	B-Disease
due	O
to	O
paracetamol	B-Chemical
overdose	B-Disease
was	O
compared	O
with	O
that	O
of	O
healthy	O
volunteers	O
.	O

Neutrophils	O
from	O
14	O
ALF	B-Disease
patients	O
were	O
stimulated	O
via	O
the	O
complement	O
receptors	O
using	O
zymosan	O
opsonized	O
with	O
ALF	B-Disease
or	O
control	O
serum	O
.	O

Superoxide	B-Chemical
and	O
hydrogen	B-Chemical
peroxide	I-Chemical
production	O
by	O
ALF	B-Disease
neutrophils	O
stimulated	O
with	O
zymosan	O
opsonized	O
with	O
ALF	B-Disease
serum	O
was	O
significantly	O
reduced	O
compared	O
with	O
the	O
control	O
subjects	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

This	O
defect	O
persisted	O
when	O
zymosan	O
opsonized	O
by	O
control	O
serum	O
was	O
used	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
.	O

Superoxide	B-Chemical
and	O
hydrogen	B-Chemical
peroxide	I-Chemical
production	O
in	O
neutrophils	O
stimulated	O
with	O
formyl	B-Chemical
-	I-Chemical
methionyl	I-Chemical
-	I-Chemical
leucyl	I-Chemical
-	I-Chemical
phenylalanine	I-Chemical
(	O
fMLP	B-Chemical
)	O
from	O
a	O
further	O
18	O
ALF	B-Disease
patients	O
was	O
unaffected	O
compared	O
with	O
control	O
neutrophils	O
.	O

Serum	O
C3	O
complement	O
levels	O
were	O
significantly	O
reduced	O
in	O
ALF	B-Disease
patients	O
compared	O
with	O
control	O
subjects	O
(	O
P	O
<	O
0	O
.	O
0005	O
)	O
.	O

These	O
results	O
demonstrate	O
a	O
neutrophil	O
defect	O
in	O
ALF	B-Disease
due	O
to	O
paracetamol	B-Chemical
overdose	B-Disease
,	O
that	O
is	O
complement	O
dependent	O
but	O
independent	O
of	O
serum	O
complement	O
,	O
possibly	O
connected	O
to	O
the	O
complement	O
receptor	O
.	O

Cholesteryl	B-Chemical
hemisuccinate	I-Chemical
treatment	O
protects	O
rodents	O
from	O
the	O
toxic	O
effects	O
of	O
acetaminophen	B-Chemical
,	O
adriamycin	B-Chemical
,	O
carbon	B-Chemical
tetrachloride	I-Chemical
,	O
chloroform	B-Chemical
and	O
galactosamine	B-Chemical
.	O

In	O
addition	O
to	O
its	O
use	O
as	O
a	O
stabilizer	O
/	O
rigidifier	O
of	O
membranes	O
,	O
cholesteryl	B-Chemical
hemisuccinate	I-Chemical
,	O
tris	B-Chemical
salt	I-Chemical
(	O
CS	B-Chemical
)	O
administration	O
has	O
also	O
been	O
shown	O
to	O
protect	O
rats	O
from	O
the	O
hepatotoxic	B-Disease
effects	O
of	O
carbon	B-Chemical
tetrachloride	I-Chemical
(	O
CCl4	B-Chemical
)	O
.	O

To	O
further	O
our	O
understanding	O
of	O
the	O
mechanism	O
of	O
CS	B-Chemical
cytoprotection	O
,	O
we	O
examined	O
in	O
rats	O
and	O
mice	O
the	O
protective	O
abilities	O
of	O
CS	B-Chemical
and	O
the	O
non	O
-	O
hydrolyzable	O
ether	O
form	O
of	O
CS	B-Chemical
,	O
gamma	B-Chemical
-	I-Chemical
cholesteryloxybutyric	I-Chemical
acid	I-Chemical
,	O
tris	B-Chemical
salt	I-Chemical
(	O
CSE	B-Chemical
)	O
against	O
acetaminophen	B-Chemical
-	O
,	O
adriamycin	B-Chemical
-	O
,	O
carbon	B-Chemical
tetrachloride	I-Chemical
-	O
,	O
chloroform	B-Chemical
-	O
and	O
galactosamine	B-Chemical
-	O
induced	O
toxicity	B-Disease
.	O

The	O
results	O
of	O
these	O
studies	O
demonstrated	O
that	O
CS	B-Chemical
-	O
mediated	O
protection	O
is	O
not	O
selective	O
for	O
a	O
particular	O
species	O
,	O
organ	O
system	O
or	O
toxic	O
chemical	O
.	O

A	O
24	O
-	O
h	O
pretreatment	O
of	O
both	O
rats	O
and	O
mice	O
with	O
a	O
single	O
dose	O
of	O
CS	B-Chemical
(	O
100mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
,	O
resulted	O
in	O
significant	O
protection	O
against	O
the	O
hepatotoxic	B-Disease
effects	O
of	O
CCl4	B-Chemical
,	O
CHCl3	B-Chemical
,	O
acetaminophen	B-Chemical
and	O
galactosamine	B-Chemical
and	O
against	O
the	O
lethal	O
(	O
and	O
presumably	O
cardiotoxic	B-Disease
)	O
effect	O
of	O
adriamycin	B-Chemical
administration	O
.	O

Maximal	O
CS	B-Chemical
-	O
mediated	O
protection	O
was	O
observed	O
in	O
experimental	O
animals	O
pretreated	O
24	O
h	O
prior	O
to	O
the	O
toxic	O
insult	O
.	O

These	O
data	O
suggest	O
that	O
CS	B-Chemical
intervenes	O
in	O
a	O
critical	O
cellular	O
event	O
that	O
is	O
an	O
important	O
common	O
pathway	O
to	O
toxic	O
cell	O
death	O
.	O

The	O
mechanism	O
of	O
CS	B-Chemical
protection	O
does	O
not	O
appear	O
to	O
be	O
dependent	O
on	O
the	O
inhibition	O
of	O
chemical	O
bioactivation	O
to	O
a	O
toxic	O
reactive	O
intermediate	O
(	O
in	O
light	O
of	O
the	O
protection	O
observed	O
against	O
galactosamine	B-Chemical
hepatotoxicity	B-Disease
)	O
.	O

However	O
,	O
based	O
on	O
the	O
data	O
presented	O
,	O
we	O
can	O
not	O
exclude	O
the	O
possibility	O
that	O
CS	B-Chemical
administration	O
inhibits	O
chemical	O
bioactivation	O
.	O

Our	O
findings	O
do	O
suggest	O
that	O
CS	B-Chemical
-	O
mediated	O
protection	O
is	O
dependent	O
on	O
the	O
action	O
of	O
the	O
intact	O
anionic	O
CS	B-Chemical
molecule	O
(	O
non	O
-	O
hydrolyzable	O
CSE	B-Chemical
was	O
as	O
protective	O
as	O
CS	B-Chemical
)	O
,	O
whose	O
mechanism	O
has	O
yet	O
to	O
be	O
defined	O
.	O

A	O
murine	O
model	O
of	O
adenomyosis	B-Disease
:	O
the	O
effects	O
of	O
hyperprolactinemia	B-Disease
induced	O
by	O
fluoxetine	B-Chemical
hydrochloride	I-Chemical
,	O
a	O
selective	O
serotonin	B-Chemical
reuptake	O
inhibitor	O
,	O
on	O
adenomyosis	B-Disease
induction	O
in	O
Wistar	O
albino	O
rats	O
.	O

OBJECTIVE	O
:	O
The	O
aim	O
of	O
this	O
study	O
was	O
to	O
investigate	O
whether	O
fluoxetine	B-Chemical
given	O
to	O
castrated	O
and	O
noncastrated	O
rats	O
caused	O
hyperprolactinemia	B-Disease
and	O
its	O
effects	O
with	O
respect	O
to	O
adenomyosis	B-Disease
.	O

DESIGN	O
:	O
Fluoxetine	B-Chemical
,	O
a	O
serotonin	B-Chemical
reuptake	O
inhibitor	O
,	O
was	O
given	O
to	O
Wistar	O
Albino	O
rats	O
for	O
98	O
days	O
to	O
produce	O
hyperprolactinemia	B-Disease
.	O

The	O
drug	O
was	O
given	O
to	O
two	O
groups	O
consisting	O
of	O
castrated	O
and	O
noncastrated	O
rats	O
and	O
compared	O
to	O
two	O
groups	O
of	O
castrated	O
and	O
noncastrated	O
controls	O
.	O

Prolactin	O
levels	O
were	O
measured	O
and	O
the	O
uteri	O
of	O
the	O
rats	O
were	O
removed	O
for	O
histopathological	O
analysis	O
at	O
the	O
end	O
of	O
98	O
days	O
.	O

SETTING	O
:	O
Marmara	O
University	O
School	O
of	O
Medicine	O
,	O
Department	O
of	O
Histology	O
and	O
Embryology	O
,	O
Zeynep	O
Kamil	O
Women	O
and	O
Children	O
'	O
s	O
Hospital	O
.	O

MAIN	O
OUTCOME	O
MEASURES	O
:	O
Serum	O
prolactin	O
levels	O
,	O
uterine	O
histopathology	O
.	O

RESULTS	O
:	O
The	O
prolactin	O
levels	O
of	O
castrated	O
and	O
noncastrated	O
groups	O
treated	O
with	O
fluoxetine	B-Chemical
were	O
statistically	O
significantly	O
higher	O
when	O
compared	O
to	O
their	O
respective	O
control	O
groups	O
.	O

Histological	O
studies	O
revealed	O
11	O
cases	O
of	O
adenomyosis	B-Disease
,	O
all	O
within	O
the	O
noncastrated	O
group	O
receiving	O
fluoxetine	B-Chemical
.	O

CONCLUSION	O
:	O
It	O
was	O
suggested	O
that	O
high	O
serum	O
prolactin	O
levels	O
cause	O
degeneration	O
of	O
myometrial	O
cells	O
in	O
the	O
presence	O
of	O
ovarian	O
steroids	B-Chemical
that	O
results	O
in	O
a	O
myometrial	O
invasion	O
by	O
endometrial	O
stroma	O
.	O

This	O
invasion	O
eventually	O
progresses	O
to	O
adenomyosis	B-Disease
.	O

Postinfarction	O
ventricular	B-Disease
septal	I-Disease
defect	I-Disease
associated	O
with	O
long	O
-	O
term	O
steroid	B-Chemical
therapy	O
.	O

Two	O
cases	O
of	O
postinfarction	O
ventricular	B-Disease
septal	I-Disease
rupture	I-Disease
in	O
patients	O
on	O
long	O
-	O
term	O
steroid	B-Chemical
therapy	O
are	O
presented	O
and	O
the	O
favourable	O
outcome	O
in	O
both	O
cases	O
described	O
.	O

A	O
possible	O
association	O
between	O
steroid	B-Chemical
therapy	O
and	O
subsequent	O
postinfarction	O
septal	B-Disease
rupture	I-Disease
is	O
discussed	O
.	O

Neuroactive	O
steroids	B-Chemical
protect	O
against	O
pilocarpine	B-Chemical
-	O
and	O
kainic	B-Chemical
acid	I-Chemical
-	O
induced	O
limbic	O
seizures	B-Disease
and	O
status	B-Disease
epilepticus	I-Disease
in	O
mice	O
.	O

Several	O
structurally	O
related	O
metabolites	O
of	O
progesterone	B-Chemical
(	O
3	B-Chemical
alpha	I-Chemical
-	I-Chemical
hydroxy	I-Chemical
pregnane	I-Chemical
-	I-Chemical
20	I-Chemical
-	I-Chemical
ones	I-Chemical
)	O
and	O
deoxycorticosterone	B-Chemical
(	O
3	B-Chemical
alpha	I-Chemical
-	I-Chemical
hydroxy	I-Chemical
pregnane	I-Chemical
-	I-Chemical
21	I-Chemical
-	I-Chemical
diol	I-Chemical
-	I-Chemical
20	I-Chemical
-	I-Chemical
ones	I-Chemical
)	O
and	O
their	O
3	O
beta	O
-	O
epimers	O
were	O
evaluated	O
for	O
protective	O
activity	O
against	O
pilocarpine	B-Chemical
-	O
,	O
kainic	B-Chemical
acid	I-Chemical
-	O
and	O
N	B-Chemical
-	I-Chemical
methyl	I-Chemical
-	I-Chemical
D	I-Chemical
-	I-Chemical
aspartate	I-Chemical
(	O
NMDA	B-Chemical
)	O
-	O
induced	O
seizures	B-Disease
in	O
mice	O
.	O

Steroids	B-Chemical
with	O
the	O
3	O
-	O
hydroxy	O
group	O
in	O
the	O
alpha	O
-	O
position	O
and	O
5	O
-	O
H	O
in	O
the	O
alpha	O
-	O
or	O
beta	O
-	O
configurations	O
were	O
highly	O
effective	O
in	O
protecting	O
against	O
pilocarpine	B-Chemical
(	O
416	O
mg	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
-	O
induced	O
limbic	O
motor	O
seizures	B-Disease
and	O
status	B-Disease
epilepticus	I-Disease
(	O
ED50	O
values	O
,	O
7	O
.	O
0	O
-	O
18	O
.	O
7	O
mg	O
/	O
kg	O
,	O
i	O
.	O
p	O
.	O
)	O
.	O

The	O
corresponding	O
epimers	O
with	O
the	O
3	O
-	O
hydroxy	O
group	O
in	O
the	O
beta	O
-	O
position	O
were	O
also	O
effective	O
but	O
less	O
potent	O
(	O
ED50	O
values	O
,	O
33	O
.	O
8	O
-	O
63	O
.	O
5	O
,	O
i	O
.	O
p	O
.	O
)	O
.	O

Although	O
the	O
neuroactive	O
steroids	B-Chemical
were	O
considerably	O
less	O
potent	O
than	O
the	O
benzodiazepine	B-Chemical
clonazepam	B-Chemical
in	O
protecting	O
against	O
pilocarpine	B-Chemical
seizures	B-Disease
,	O
steroids	B-Chemical
with	O
the	O
5	O
alpha	O
,	O
3	O
alpha	O
-	O
configuration	O
had	O
comparable	O
or	O
higher	O
protective	O
index	O
values	O
(	O
TD50	O
for	O
motor	O
impairment	O
divided	O
by	O
ED50	O
for	O
seizure	B-Disease
protection	O
)	O
than	O
clonazepam	B-Chemical
,	O
indicating	O
that	O
some	O
neuroactive	O
steroids	B-Chemical
may	O
have	O
lower	O
relative	O
toxicity	B-Disease
.	O

Steroids	B-Chemical
with	O
the	O
5	O
alpha	O
,	O
3	O
alpha	O
-	O
or	O
5	O
beta	O
,	O
3	O
alpha	O
-	O
configurations	O
also	O
produced	O
a	O
dose	O
-	O
dependent	O
delay	O
in	O
the	O
onset	O
of	O
limbic	O
seizures	B-Disease
induced	O
by	O
kainic	B-Chemical
acid	I-Chemical
(	O
32	O
mg	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
,	O
but	O
did	O
not	O
completely	O
protect	O
against	O
the	O
seizures	B-Disease
.	O

However	O
,	O
when	O
a	O
second	O
dose	O
of	O
the	O
steroid	B-Chemical
was	O
administered	O
1	O
hr	O
after	O
the	O
first	O
dose	O
,	O
complete	O
protection	O
from	O
the	O
kainic	B-Chemical
acid	I-Chemical
-	O
induced	O
limbic	O
seizures	B-Disease
and	O
status	B-Disease
epilepticus	I-Disease
was	O
obtained	O
.	O

The	O
steroids	B-Chemical
also	O
caused	O
a	O
dose	O
-	O
dependent	O
delay	O
in	O
NMDA	B-Chemical
(	O
257	O
mg	O
/	O
kg	O
,	O
s	O
.	O
c	O
.	O
)	O
-	O
induced	O
lethality	O
,	O
but	O
did	O
not	O
completely	O
protect	O
against	O
NMDA	B-Chemical
seizures	B-Disease
or	O
lethality	O
.	O

We	O
conclude	O
that	O
neuroactive	O
steroids	B-Chemical
are	O
highly	O
effective	O
in	O
protecting	O
against	O
pilocarpine	B-Chemical
-	O
and	O
kainic	B-Chemical
acid	I-Chemical
-	O
induced	O
seizures	B-Disease
and	O
status	B-Disease
epilepticus	I-Disease
in	O
mice	O
,	O
and	O
may	O
be	O
of	O
utility	O
in	O
the	O
treatment	O
of	O
some	O
forms	O
of	O
status	B-Disease
epilepticus	I-Disease
in	O
humans	O
.	O

Hepatic	O
and	O
extrahepatic	O
angiotensinogen	O
gene	O
expression	O
in	O
rats	O
with	O
acute	O
nephrotic	B-Disease
syndrome	I-Disease
.	O

Plasma	O
concentration	O
and	O
urine	O
excretion	O
of	O
the	O
renin	O
-	O
angiotensin	B-Chemical
system	O
proteins	O
are	O
altered	O
in	O
rats	O
with	O
nephrotic	B-Disease
syndrome	I-Disease
(	O
NS	B-Disease
)	O
.	O

In	O
this	O
work	O
the	O
messenger	O
ribonucleic	O
acid	O
(	O
mRNA	O
)	O
levels	O
of	O
angiotensinogen	O
(	O
Ao	O
)	O
were	O
analyzed	O
with	O
the	O
slot	O
-	O
blot	O
hybridization	O
technique	O
in	O
liver	O
and	O
other	O
extrahepatic	O
tissues	O
:	O
kidney	O
,	O
heart	O
,	O
brain	O
,	O
and	O
adrenal	O
gland	O
from	O
control	O
,	O
nephrotic	B-Disease
,	O
and	O
pair	O
-	O
fed	O
(	O
PF	O
)	O
rats	O
.	O

NS	B-Disease
was	O
induced	O
by	O
a	O
single	O
injection	O
of	O
puromycin	B-Chemical
amino	I-Chemical
-	I-Chemical
nucleoside	I-Chemical
(	O
PAN	B-Chemical
)	O
.	O

Although	O
a	O
great	O
urinary	O
excretion	O
and	O
half	O
-	O
normal	O
plasma	O
levels	O
of	O
Ao	O
were	O
observed	O
on	O
day	O
6	O
after	O
PAN	B-Chemical
injection	O
,	O
when	O
NS	B-Disease
was	O
clearly	O
established	O
,	O
hepatic	O
Ao	O
mRNA	O
levels	O
did	O
not	O
change	O
.	O

Furthermore	O
,	O
the	O
Ao	O
mRNA	O
levels	O
did	O
not	O
change	O
in	O
any	O
of	O
the	O
extrahepatic	O
tissues	O
studied	O
on	O
day	O
6	O
,	O
nor	O
did	O
its	O
hepatic	O
levels	O
at	O
days	O
1	O
,	O
3	O
,	O
5	O
,	O
or	O
7	O
after	O
PAN	B-Chemical
injection	O
.	O

These	O
data	O
suggest	O
that	O
the	O
hepatic	O
and	O
extrahepatic	O
Ao	O
mRNA	O
levels	O
are	O
unaltered	O
during	O
the	O
development	O
of	O
the	O
acute	O
NS	B-Disease
induced	O
by	O
PAN	B-Chemical
.	O

Neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
with	O
risperidone	B-Chemical
.	O

Neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
is	O
thought	O
to	O
be	O
a	O
result	O
of	O
dopamine	B-Chemical
D2	O
receptor	O
blockade	O
in	O
the	O
striatum	O
of	O
the	O
basal	O
ganglia	O
.	O

Risperidone	B-Chemical
,	O
a	O
benzisoxazole	B-Chemical
derivative	O
antipsychotic	O
,	O
has	O
high	O
serotonin	B-Chemical
5	O
-	O
HT2	O
receptor	O
blockade	O
and	O
dose	O
-	O
related	O
D2	O
receptor	O
blockade	O
.	O

The	O
high	O
ratio	O
is	O
believed	O
to	O
impart	O
the	O
low	O
frequency	O
of	O
extrapyramidal	B-Disease
symptoms	I-Disease
with	O
risperidone	B-Chemical
at	O
low	O
dosages	O
.	O

With	O
this	O
low	O
frequency	O
of	O
extrapyramidal	B-Disease
symptoms	I-Disease
,	O
it	O
was	O
thought	O
the	O
frequency	O
of	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
might	O
also	O
be	O
lowered	O
.	O

A	O
73	O
-	O
year	O
-	O
old	O
woman	O
developed	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
after	O
monotherapy	O
with	O
risperidone	B-Chemical
.	O

The	O
syndrome	O
reversed	O
after	O
discontinuing	O
risperidone	B-Chemical
and	O
starting	O
treatment	O
with	O
dantrolene	B-Chemical
and	O
bromocriptine	B-Chemical
.	O

It	O
appears	O
that	O
the	O
protection	O
from	O
extrapyramidal	O
side	O
effects	O
observed	O
with	O
risperidone	B-Chemical
does	O
not	O
ensure	O
protection	O
from	O
neuroleptic	B-Disease
malignant	I-Disease
syndrome	I-Disease
.	O

The	O
attenuating	O
effect	O
of	O
carteolol	B-Chemical
hydrochloride	I-Chemical
,	O
a	O
beta	O
-	O
adrenoceptor	O
antagonist	O
,	O
on	O
neuroleptic	O
-	O
induced	O
catalepsy	B-Disease
in	O
rats	O
.	O

It	O
is	O
known	O
that	O
beta	O
-	O
adrenoceptor	O
antagonists	O
are	O
effective	O
in	O
the	O
treatment	O
of	O
akathisia	B-Disease
,	O
one	O
of	O
the	O
extrapyramidal	O
side	O
effects	O
that	O
occur	O
during	O
neuroleptic	O
treatment	O
.	O

Neuroleptic	O
-	O
induced	O
catalepsy	B-Disease
,	O
a	O
model	O
of	O
neuroleptic	O
-	O
induced	O
extrapyramidal	O
side	O
effects	O
,	O
was	O
considered	O
suitable	O
as	O
a	O
model	O
for	O
predicting	O
neuroleptic	O
-	O
induced	O
akathisia	B-Disease
in	O
humans	O
,	O
although	O
neuroleptic	O
-	O
induced	O
catalepsy	B-Disease
was	O
not	O
considered	O
a	O
specific	O
test	O
for	O
neuroleptic	O
-	O
induced	O
akathisia	B-Disease
.	O

Therefore	O
,	O
the	O
effects	O
of	O
carteolol	B-Chemical
,	O
a	O
beta	O
-	O
adrenoceptor	O
antagonist	O
,	O
on	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
in	O
rats	O
were	O
behaviorally	O
studied	O
and	O
compared	O
with	O
those	O
of	O
propranolol	B-Chemical
and	O
biperiden	B-Chemical
,	O
a	O
muscarinic	O
receptor	O
antagonist	O
.	O

Carteolol	B-Chemical
,	O
as	O
well	O
as	O
propranolol	B-Chemical
and	O
biperiden	B-Chemical
,	O
inhibited	O
the	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
.	O

The	O
inhibitory	O
effect	O
of	O
carteolol	B-Chemical
was	O
almost	O
comparable	O
to	O
that	O
of	O
propranolol	B-Chemical
,	O
but	O
was	O
weaker	O
than	O
that	O
of	O
biperiden	B-Chemical
.	O

Carteolol	B-Chemical
did	O
not	O
evoke	O
postsynaptic	O
dopamine	B-Chemical
receptor	O
-	O
stimulating	O
behavioral	O
signs	O
such	O
as	O
stereotypy	O
and	O
hyperlocomotion	B-Disease
in	O
rats	O
.	O

Carteolol	B-Chemical
did	O
not	O
antagonize	O
the	O
inhibitory	O
effects	O
of	O
haloperidol	B-Chemical
on	O
apomorphine	B-Chemical
-	O
induced	O
stereotypy	O
and	O
locomotor	O
activity	O
in	O
rats	O
.	O

In	O
addition	O
,	O
carteolol	B-Chemical
did	O
not	O
evoke	O
5	O
-	O
HT1A	O
receptor	O
-	O
stimulating	O
behavioral	O
signs	O
such	O
as	O
flat	O
body	O
posture	O
and	O
forepaw	O
treading	O
and	O
did	O
not	O
inhibit	O
5	B-Chemical
-	I-Chemical
hydroxytryptophan	I-Chemical
-	O
induced	O
head	O
twitch	O
in	O
rats	O
.	O

Finally	O
,	O
carteolol	B-Chemical
did	O
not	O
inhibit	O
physostigmine	B-Chemical
-	O
induced	O
lethality	O
in	O
rats	O
.	O

These	O
results	O
strongly	O
suggest	O
that	O
carteolol	B-Chemical
improves	O
haloperidol	B-Chemical
-	O
induced	O
catalepsy	B-Disease
via	O
its	O
beta	O
-	O
adrenoceptor	O
antagonistic	O
activity	O
and	O
is	O
expected	O
to	O
be	O
effective	O
in	O
the	O
treatment	O
of	O
akathisia	B-Disease
without	O
attenuating	O
neuroleptic	O
-	O
induced	O
antipsychotic	O
effects	O
due	O
to	O
its	O
postsynaptic	O
dopamine	B-Chemical
receptor	O
antagonistic	O
activity	O
.	O

Granulosa	B-Disease
cell	I-Disease
tumor	I-Disease
of	I-Disease
the	I-Disease
ovary	I-Disease
associated	O
with	O
antecedent	O
tamoxifen	B-Chemical
use	O
.	O

BACKGROUND	O
:	O
Increased	O
attention	O
has	O
been	O
focused	O
recently	O
on	O
the	O
estrogenic	O
effects	O
of	O
tamoxifen	B-Chemical
.	O

Review	O
of	O
the	O
literature	O
reveals	O
an	O
association	O
between	O
tamoxifen	B-Chemical
use	O
and	O
gynecologic	O
tumors	B-Disease
.	O

CASE	O
:	O
A	O
52	O
-	O
year	O
-	O
old	O
postmenopausal	O
woman	O
was	O
treated	O
with	O
tamoxifen	B-Chemical
for	O
stage	O
II	O
estrogen	B-Chemical
receptor	O
-	O
positive	O
breast	B-Disease
carcinoma	I-Disease
.	O

Her	O
aspartate	B-Chemical
transaminase	O
and	O
alanine	B-Chemical
transaminase	O
levels	O
increase	O
markedly	O
after	O
6	O
months	O
of	O
tamoxifen	B-Chemical
use	O
.	O

After	O
an	O
additional	O
17	O
months	O
of	O
elevated	O
serum	O
transaminases	O
,	O
the	O
patient	O
was	O
found	O
to	O
have	O
a	O
stage	O
Ic	O
granulosa	B-Disease
cell	I-Disease
tumor	I-Disease
of	I-Disease
the	I-Disease
ovary	I-Disease
.	O

CONCLUSION	O
:	O
Patients	O
with	O
tamoxifen	B-Chemical
-	O
induced	O
liver	B-Disease
dysfunction	I-Disease
may	O
be	O
at	O
increased	O
risk	O
for	O
granulosa	B-Disease
cell	I-Disease
tumors	I-Disease
because	O
of	O
alterations	O
in	O
tamoxifen	B-Chemical
metabolism	O
.	O

Lifetime	O
treatment	O
of	O
mice	O
with	O
azidothymidine	B-Chemical
(	O
AZT	B-Chemical
)	O
produces	O
myelodysplasia	B-Disease
.	O

AZT	B-Chemical
has	O
induced	O
a	O
macrocytic	B-Disease
anemia	I-Disease
in	O
AIDS	B-Disease
patients	O
on	O
long	O
term	O
AZT	B-Chemical
therapy	O
.	O

It	O
is	O
generally	O
assumed	O
that	O
DNA	O
elongation	O
is	O
stopped	O
by	O
the	O
insertion	O
of	O
AZT	B-Chemical
into	O
the	O
chain	O
in	O
place	O
of	O
thymidine	B-Chemical
thus	O
preventing	O
the	O
phosphate	B-Chemical
hydroxyl	O
linkages	O
and	O
therefore	O
suppresses	O
hemopoietic	O
progenitor	O
cell	O
proliferation	O
in	O
an	O
early	O
stage	O
of	O
differentiation	O
.	O

CBA	O
/	O
Ca	O
male	O
mice	O
started	O
on	O
AZT	B-Chemical
0	O
.	O
75	O
mg	O
/	O
ml	O
H2O	O
at	O
84	O
days	O
of	O
age	O
and	O
kept	O
on	O
it	O
for	O
687	O
days	O
when	O
dosage	O
reduced	O
to	O
0	O
.	O
5	O
mg	O
/	O
ml	O
H2O	O
for	O
a	O
group	O
,	O
another	O
group	O
removed	O
from	O
AZT	B-Chemical
to	O
see	O
recovery	O
,	O
and	O
third	O
group	O
remained	O
on	O
0	O
.	O
75	O
mg	O
.	O

At	O
687	O
days	O
mice	O
that	O
had	O
been	O
on	O
0	O
.	O
75	O
mg	O
had	O
average	O
platelet	O
counts	O
of	O
2	O
.	O
5	O
x	O
10	O
(	O
6	O
)	O
.	O

Histological	O
examination	O
on	O
9	O
of	O
10	O
mice	O
with	O
such	O
thrombocytopenia	B-Disease
showed	O
changes	O
compatible	O
with	O
myelodysplastic	B-Disease
syndrome	I-Disease
(	O
MDS	B-Disease
)	O
.	O

A	O
variety	O
of	O
histological	O
patterns	O
was	O
observed	O
.	O

There	O
were	O
two	O
cases	O
of	O
hypocellular	O
myelodysplasia	B-Disease
,	O
two	O
cases	O
of	O
hypersegmented	O
myelodysplastic	B-Disease
granulocytosis	O
,	O
two	O
cases	O
of	O
hypercellular	O
marrow	O
with	O
abnormal	O
megakaryocytes	O
with	O
bizarre	O
nuclei	O
,	O
one	O
case	O
of	O
megakaryocytic	O
myelosis	O
associated	O
with	O
a	O
hyperplastic	B-Disease
marrow	I-Disease
,	O
dysmyelopoiesis	B-Disease
and	O
a	O
hypocellular	B-Disease
marrow	I-Disease
and	O
two	O
cases	O
of	O
myelodysplasia	B-Disease
with	O
dyserythropoiesis	B-Disease
,	O
hemosiderosis	B-Disease
and	O
a	O
hypocellular	B-Disease
marrow	I-Disease
.	O

Above	O
mentioned	O
AZT	B-Chemical
incorporation	O
may	O
have	O
induced	O
an	O
ineffective	O
hemopoiesis	O
in	O
the	O
primitive	O
hemopoietic	O
progenitor	O
cells	O
,	O
which	O
is	O
known	O
to	O
be	O
seen	O
commonly	O
in	O
the	O
myelodysplastic	B-Disease
syndrome	I-Disease
.	O

Biphasic	O
response	O
of	O
the	O
SA	O
node	O
of	O
the	O
dog	O
heart	O
in	O
vivo	O
to	O
selective	O
administration	O
of	O
ketamine	B-Chemical
.	O

Effect	O
of	O
ketamine	B-Chemical
on	O
the	O
SA	O
node	O
of	O
the	O
dog	O
heart	O
was	O
studied	O
in	O
vivo	O
using	O
a	O
selective	O
perfusion	O
technique	O
of	O
the	O
SA	O
node	O
artery	O
.	O

Injections	O
of	O
ketamine	B-Chemical
in	O
doses	O
from	O
100	O
microgram	O
to	O
3	O
mg	O
into	O
the	O
artery	O
produced	O
a	O
depression	B-Disease
of	O
the	O
SA	O
nodal	O
activity	O
by	O
a	O
direct	O
action	O
.	O

This	O
depression	B-Disease
was	O
followed	O
by	O
the	O
sudden	O
appearance	O
of	O
a	O
stimulatory	O
phase	O
.	O

Bilateral	O
vagotomy	O
and	O
sympathectomy	O
or	O
prior	O
administration	O
of	O
a	O
ganglion	O
blocker	O
failed	O
to	O
inhibit	O
the	O
occurrence	O
of	O
the	O
ketamine	B-Chemical
-	O
induced	O
tachycardia	B-Disease
,	O
while	O
it	O
was	O
completely	O
abolished	O
in	O
the	O
reserpinized	O
dogs	O
or	O
by	O
a	O
prior	O
injection	O
of	O
a	O
beta	O
-	O
blocking	O
agent	O
into	O
the	O
SA	O
node	O
artery	O
.	O

This	O
may	O
indicate	O
that	O
an	O
activation	O
of	O
the	O
peripheral	O
adrenergic	O
mechanism	O
plays	O
an	O
important	O
role	O
in	O
the	O
induction	O
of	O
the	O
excitatory	O
effect	O
of	O
ketamine	B-Chemical
injected	O
in	O
the	O
SA	O
node	O
artery	O
.	O

Over	O
expression	O
of	O
vascular	O
endothelial	O
growth	O
factor	O
and	O
its	O
receptor	O
during	O
the	O
development	O
of	O
estrogen	B-Chemical
-	O
induced	O
rat	O
pituitary	B-Disease
tumors	I-Disease
may	O
mediate	O
estrogen	B-Chemical
-	O
initiated	O
tumor	B-Disease
angiogenesis	O
.	O

Estrogens	B-Chemical
,	O
which	O
have	O
been	O
associated	O
with	O
several	O
types	O
of	O
human	O
and	O
animal	O
cancers	B-Disease
,	O
can	O
induce	O
tumor	B-Disease
angiogenesis	O
in	O
the	O
pituitary	O
of	O
Fischer	O
344	O
rats	O
.	O

The	O
mechanistic	O
details	O
of	O
tumor	B-Disease
angiogenesis	O
induction	O
,	O
during	O
estrogen	B-Chemical
carcinogenesis	B-Disease
,	O
are	O
still	O
unknown	O
.	O

To	O
elucidate	O
the	O
role	O
of	O
estrogen	B-Chemical
in	O
the	O
regulation	O
of	O
tumor	B-Disease
angiogenesis	O
in	O
the	O
pituitary	O
of	O
female	O
rats	O
,	O
the	O
density	O
of	O
blood	O
vessels	O
was	O
analysed	O
using	O
factor	O
VIII	O
related	O
antigen	O
(	O
FVIIIRAg	O
)	O
immunohistochemistry	O
and	O
the	O
expression	O
of	O
vascular	O
endothelial	O
growth	O
factor	O
/	O
vascular	O
permeability	O
factor	O
(	O
VEGF	O
/	O
VPF	O
)	O
was	O
examined	O
by	O
Western	O
blot	O
and	O
immunohistochemical	O
analysis	O
.	O

The	O
expression	O
of	O
VEGF	O
receptor	O
(	O
VEGFR	O
-	O
2	O
/	O
Flk	O
-	O
1	O
/	O
KDR	O
)	O
was	O
also	O
examined	O
by	O
immunohistochemistry	O
.	O

The	O
results	O
demonstrated	O
that	O
17beta	B-Chemical
-	I-Chemical
estradiol	I-Chemical
(	O
E2	B-Chemical
)	O
induces	O
neovascularization	O
,	O
as	O
well	O
as	O
the	O
growth	O
and	O
enlargement	O
of	O
blood	O
vessels	O
after	O
7	O
days	O
of	O
exposure	O
.	O

The	O
high	O
tumor	B-Disease
angiogenic	O
potential	O
was	O
associated	O
with	O
an	O
elevated	O
VEGF	O
/	O
VPF	O
protein	O
expression	O
in	O
the	O
E2	B-Chemical
exposed	O
pituitary	O
of	O
ovariectomized	O
(	O
OVEX	O
)	O
rats	O
.	O

VEGF	O
/	O
VPF	O
and	O
FVIIIRAg	O
immunohistochemistry	O
and	O
endothelial	O
specific	O
lectin	O
(	O
UEA1	O
)	O
binding	O
studies	O
,	O
indicate	O
that	O
the	O
elevation	O
of	O
VEGF	O
protein	O
expression	O
initially	O
occurred	O
in	O
both	O
blood	O
vessels	O
and	O
non	O
-	O
endothelial	O
cells	O
.	O

After	O
15	O
days	O
of	O
E2	B-Chemical
exposure	O
,	O
VEGF	O
/	O
VPF	O
protein	O
expression	O
,	O
in	O
the	O
non	O
-	O
endothelial	O
cell	O
population	O
,	O
sharply	O
declined	O
and	O
was	O
restricted	O
to	O
the	O
blood	O
vessels	O
.	O

The	O
function	O
of	O
non	O
-	O
endothelial	O
-	O
derived	O
VEGF	O
is	O
not	O
clear	O
.	O

Furthermore	O
,	O
immunohistochemical	O
studies	O
demonstrated	O
that	O
VEGFR	O
-	O
2	O
(	O
flk	O
-	O
1	O
/	O
KDR	O
)	O
,	O
expression	O
was	O
elevated	O
significantly	O
in	O
the	O
endothelial	O
cells	O
of	O
microblood	O
vessels	O
after	O
7	O
days	O
of	O
E2	B-Chemical
exposure	O
.	O

These	O
findings	O
suggest	O
that	O
over	O
expression	O
of	O
VEGF	O
and	O
its	O
receptor	O
(	O
VEGFR	O
-	O
2	O
)	O
may	O
play	O
an	O
important	O
role	O
in	O
the	O
initial	O
step	O
of	O
the	O
regulation	O
of	O
estrogen	B-Chemical
induced	O
tumor	B-Disease
angiogenesis	O
in	O
the	O
rat	O
pituitary	O
.	O

Persistent	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
following	O
lithium	B-Chemical
therapy	O
.	O

We	O
report	O
the	O
case	O
of	O
a	O
patient	O
who	O
developed	O
severe	O
hypernatraemic	O
dehydration	B-Disease
following	O
a	O
head	B-Disease
injury	I-Disease
.	O

Ten	O
years	O
previously	O
he	O
had	O
been	O
diagnosed	O
to	O
have	O
lithium	B-Chemical
-	O
induced	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
,	O
and	O
lithium	B-Chemical
therapy	O
had	O
been	O
discontinued	O
.	O

He	O
remained	O
thirsty	O
and	O
polyuric	B-Disease
despite	O
cessation	O
of	O
lithium	B-Chemical
and	O
investigations	O
on	O
admission	O
showed	O
him	O
to	O
have	O
normal	O
osmoregulated	O
thirst	O
and	O
vasopressin	B-Chemical
secretion	O
,	O
with	O
clear	O
evidence	O
of	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
.	O

Lithium	B-Chemical
induced	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
is	O
considered	O
to	O
be	O
reversible	O
on	O
cessation	O
of	O
therapy	O
but	O
polyuria	B-Disease
persisted	O
in	O
this	O
patient	O
for	O
ten	O
years	O
after	O
lithium	B-Chemical
was	O
stopped	O
.	O

We	O
discuss	O
the	O
possible	O
renal	O
mechanisms	O
and	O
the	O
implications	O
for	O
management	O
of	O
patients	O
with	O
lithium	B-Chemical
-	O
induced	O
nephrogenic	B-Disease
diabetes	I-Disease
insipidus	I-Disease
.	O

Effects	O
of	O
NIK	B-Chemical
-	I-Chemical
247	I-Chemical
on	O
cholinesterase	O
and	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
.	O

The	O
effects	O
of	O
NIK	B-Chemical
-	I-Chemical
247	I-Chemical
on	O
cholinesterase	O
,	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
and	O
spontaneous	O
movement	O
were	O
examined	O
and	O
compared	O
with	O
those	O
of	O
the	O
well	O
-	O
known	O
cholinesterase	O
inhibitors	O
tacrine	B-Chemical
and	O
E	B-Chemical
-	I-Chemical
2020	I-Chemical
.	O

NIK	B-Chemical
-	I-Chemical
247	I-Chemical
,	O
tacrine	B-Chemical
and	O
E	B-Chemical
-	I-Chemical
2020	I-Chemical
all	O
strongly	O
inhibited	O
acetylcholinesterase	O
(	O
AChE	O
)	O
in	O
human	O
red	O
blood	O
cells	O
(	O
IC50s	O
=	O
1	O
.	O
0	O
x	O
10	O
(	O
-	O
6	O
)	O
,	O
2	O
.	O
9	O
x	O
10	O
(	O
-	O
7	O
)	O
and	O
3	O
.	O
7	O
x	O
10	O
(	O
-	O
8	O
)	O
M	O
,	O
respectively	O
)	O
.	O

In	O
addition	O
,	O
NIK	B-Chemical
-	I-Chemical
247	I-Chemical
and	O
tacrine	B-Chemical
,	O
but	O
not	O
E	B-Chemical
-	I-Chemical
2020	I-Chemical
,	O
strongly	O
inhibited	O
butyrylcholinestrase	O
(	O
BuChE	O
)	O
in	O
human	O
serum	O
.	O

All	O
three	O
drugs	O
produced	O
mixed	O
inhibition	O
of	O
AChE	O
activity	O
.	O

Moreover	O
,	O
the	O
inhibitory	O
effect	O
of	O
NIK	B-Chemical
-	I-Chemical
247	I-Chemical
on	O
AChE	O
was	O
reversible	O
.	O

All	O
compounds	O
at	O
0	O
.	O
1	O
-	O
1	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
significantly	O
improved	O
the	O
amnesia	B-Disease
induced	O
by	O
scopolamine	B-Chemical
(	O
0	O
.	O
5	O
mg	O
/	O
kg	O
s	O
.	O
c	O
.	O
)	O
in	O
rats	O
performing	O
a	O
passive	O
avoidance	O
task	O
.	O

The	O
three	O
compounds	O
at	O
1	O
and	O
3	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
did	O
not	O
significantly	O
decrease	O
spontaneous	O
movement	O
by	O
rats	O
.	O

These	O
findings	O
suggest	O
that	O
NIK	B-Chemical
-	I-Chemical
247	I-Chemical
at	O
a	O
low	O
dose	O
(	O
0	O
.	O
1	O
-	O
1	O
mg	O
/	O
kg	O
p	O
.	O
o	O
.	O
)	O
improves	O
scopolamine	B-Chemical
-	O
induced	O
amnesia	B-Disease
but	O
does	O
not	O
affect	O
spontaneous	O
movement	O
.	O

The	O
findings	O
suggest	O
that	O
NIK	B-Chemical
-	I-Chemical
247	I-Chemical
may	O
be	O
a	O
useful	O
drug	O
for	O
the	O
treatment	O
of	O
Alzheimer	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

Potential	O
therapeutic	O
use	O
of	O
the	O
selective	O
dopamine	B-Chemical
D1	O
receptor	O
agonist	O
,	O
A	B-Chemical
-	I-Chemical
86929	I-Chemical
:	O
an	O
acute	O
study	O
in	O
parkinsonian	B-Disease
levodopa	B-Chemical
-	O
primed	O
monkeys	O
.	O

The	O
clinical	O
utility	O
of	O
dopamine	B-Chemical
(	O
DA	B-Chemical
)	O
D1	O
receptor	O
agonists	O
in	O
the	O
treatment	O
of	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
(	O
PD	B-Disease
)	O
is	O
still	O
unclear	O
.	O

The	O
therapeutic	O
use	O
of	O
selective	O
DA	B-Chemical
D1	O
receptor	O
agonists	O
such	O
as	O
SKF	B-Chemical
-	I-Chemical
82958	I-Chemical
(	O
6	B-Chemical
-	I-Chemical
chloro	I-Chemical
-	I-Chemical
7	I-Chemical
,	I-Chemical
8	I-Chemical
-	I-Chemical
dihydroxy	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
allyl	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
phenyl	I-Chemical
-	I-Chemical
2	I-Chemical
,	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
,	I-Chemical
5	I-Chemical
-	I-Chemical
tetrahydro	I-Chemical
-	I-Chemical
1H	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
benzaze	I-Chemical
pine	I-Chemical
hydrobromide	I-Chemical
)	O
and	O
A	B-Chemical
-	I-Chemical
77636	I-Chemical
(	O
[	B-Chemical
1R	I-Chemical
,	I-Chemical
3S	I-Chemical
]	I-Chemical
3	I-Chemical
-	I-Chemical
[	I-Chemical
1	I-Chemical
'	I-Chemical
-	I-Chemical
admantyl	I-Chemical
]	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
aminomethyl	I-Chemical
-	I-Chemical
3	I-Chemical
,	I-Chemical
4	I-Chemical
-	I-Chemical
dihydro	I-Chemical
-	I-Chemical
5	I-Chemical
,	I-Chemical
6	I-Chemical
-	I-Chemical
dihydroxy	I-Chemical
-	I-Chemical
1H	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
benzo	I-Chemical
pyran	I-Chemical
hydrochloride	I-Chemical
)	O
seems	O
limited	O
because	O
of	O
their	O
duration	O
of	O
action	O
,	O
which	O
is	O
too	O
short	O
for	O
SKF	B-Chemical
-	I-Chemical
82958	I-Chemical
(	O
<	O
1	O
hr	O
)	O
and	O
too	O
long	O
for	O
A	B-Chemical
-	I-Chemical
77636	I-Chemical
(	O
>	O
20	O
hr	O
,	O
leading	O
to	O
behavioral	O
tolerance	O
)	O
.	O

We	O
therefore	O
conducted	O
the	O
present	O
acute	O
dose	O
-	O
response	O
study	O
in	O
four	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
MPTP	B-Chemical
)	O
-	O
exposed	O
cynomolgus	O
monkeys	O
primed	O
to	O
exhibit	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
to	O
evaluate	O
the	O
locomotor	O
and	O
dyskinetic	B-Disease
effects	O
on	O
challenge	O
with	O
four	O
doses	O
(	O
from	O
0	O
.	O
03	O
to	O
1	O
.	O
0	O
mg	O
/	O
kg	O
)	O
of	O
A	B-Chemical
-	I-Chemical
86929	I-Chemical
(	O
[	B-Chemical
-	I-Chemical
]	I-Chemical
-	I-Chemical
[	I-Chemical
5aR	I-Chemical
,	I-Chemical
11bS	I-Chemical
]	I-Chemical
-	I-Chemical
4	I-Chemical
,	I-Chemical
5	I-Chemical
,	I-Chemical
5a	I-Chemical
,	I-Chemical
6	I-Chemical
,	I-Chemical
7	I-Chemical
,	I-Chemical
11b	I-Chemical
-	I-Chemical
hexahydro	I-Chemical
-	I-Chemical
2	I-Chemical
-	I-Chemical
propyl	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
thia	I-Chemical
-	I-Chemical
5	I-Chemical
-	I-Chemical
+	I-Chemical
+	I-Chemical
+	I-Chemical
azacyclopent	I-Chemical
-	I-Chemical
1	I-Chemical
-	I-Chemical
ena	I-Chemical
[	I-Chemical
c	I-Chemical
]	I-Chemical
phenathrene	I-Chemical
-	I-Chemical
9	I-Chemical
-	I-Chemical
10	I-Chemical
-	I-Chemical
diol	I-Chemical
)	O
,	O
a	O
selective	O
and	O
full	O
DA	B-Chemical
D1	O
-	O
like	O
receptor	O
agonist	O
with	O
an	O
intermediate	O
duration	O
of	O
action	O
.	O

Levodopa	B-Chemical
and	O
the	O
DA	B-Chemical
D2	O
-	O
like	O
receptor	O
agonist	O
,	O
LY	B-Chemical
-	I-Chemical
171555	I-Chemical
(	O
[	B-Chemical
4aR	I-Chemical
-	I-Chemical
trans	I-Chemical
]	I-Chemical
-	I-Chemical
4	I-Chemical
,	I-Chemical
4a	I-Chemical
,	I-Chemical
5	I-Chemical
,	I-Chemical
6	I-Chemical
,	I-Chemical
7	I-Chemical
,	I-Chemical
8	I-Chemical
,	I-Chemical
8a	I-Chemical
,	I-Chemical
9	I-Chemical
-	I-Chemical
o	I-Chemical
-	I-Chemical
dihydro	I-Chemical
-	I-Chemical
5n	I-Chemical
-	I-Chemical
propyl	I-Chemical
-	I-Chemical
2H	I-Chemical
-	I-Chemical
pyrazo	I-Chemical
lo	I-Chemical
-	I-Chemical
3	I-Chemical
-	I-Chemical
4	I-Chemical
-	I-Chemical
quinoline	I-Chemical
hydrochloride	I-Chemical
)	O
were	O
also	O
used	O
for	O
comparison	O
.	O

Acute	O
administration	O
of	O
A	B-Chemical
-	I-Chemical
86929	I-Chemical
was	O
as	O
efficacious	O
in	O
alleviating	O
MPTP	B-Chemical
-	O
induced	O
parkinsonism	B-Disease
as	O
levodopa	B-Chemical
and	O
LY	B-Chemical
-	I-Chemical
171555	I-Chemical
,	O
but	O
was	O
less	O
likely	O
to	O
reproduce	O
the	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
in	O
these	O
animals	O
than	O
with	O
either	O
LY	B-Chemical
-	I-Chemical
171555	I-Chemical
or	O
subsequent	O
challenge	O
of	O
levodopa	B-Chemical
.	O

Selective	O
stimulation	O
of	O
the	O
DA	B-Chemical
D1	O
receptor	O
may	O
provide	O
better	O
integration	O
of	O
neural	O
inputs	O
transmitted	O
to	O
the	O
internal	O
segment	O
of	O
the	O
globus	O
pallidus	O
(	O
referred	O
to	O
as	O
the	O
basal	O
ganglia	O
output	O
)	O
compared	O
with	O
levodopa	B-Chemical
and	O
selective	O
DA	B-Chemical
D2	O
receptor	O
agonist	O
.	O

Potent	O
DA	B-Chemical
D1	O
receptor	O
agents	O
with	O
an	O
intermediate	O
duration	O
of	O
efficacy	O
such	O
as	O
A	B-Chemical
-	I-Chemical
86929	I-Chemical
(	O
approximately	O
4	O
hr	O
at	O
higher	O
doses	O
tested	O
)	O
are	O
potential	O
therapeutic	O
tools	O
in	O
PD	B-Disease
and	O
merit	O
further	O
attention	O
.	O

Neuropeptide	O
-	O
Y	O
immunoreactivity	O
in	O
the	O
pilocarpine	B-Chemical
model	O
of	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
.	O

Neuropeptide	O
-	O
Y	O
(	O
NPY	O
)	O
is	O
expressed	O
by	O
granule	O
cells	O
and	O
mossy	O
fibres	O
of	O
the	O
hippocampal	O
dentate	O
gyrus	O
during	O
experimental	O
temporal	B-Disease
lobe	I-Disease
epilepsy	I-Disease
(	O
TLE	B-Disease
)	O
.	O

This	O
expression	O
may	O
represent	O
an	O
endogenous	O
damping	O
mechanism	O
since	O
NPY	O
has	O
been	O
shown	O
to	O
block	O
seizure	B-Disease
-	O
like	O
events	O
following	O
high	O
-	O
frequency	O
stimulation	O
in	O
hippocampal	O
slices	O
.	O

The	O
pilocarpine	B-Chemical
(	O
PILO	B-Chemical
)	O
model	O
of	O
epilepsy	B-Disease
is	O
characterized	O
by	O
an	O
acute	O
period	O
of	O
status	B-Disease
epilepticus	I-Disease
followed	O
by	O
spontaneous	O
recurrent	O
seizures	B-Disease
and	O
related	O
brain	B-Disease
damage	I-Disease
.	O

We	O
report	O
peroxidase	O
-	O
antiperoxidase	O
immunostaining	O
for	O
NPY	O
in	O
several	O
brain	O
regions	O
in	O
this	O
model	O
.	O

PILO	B-Chemical
-	O
injected	O
animals	O
exhibited	O
NPY	O
immunoreactivity	O
in	O
the	O
region	O
of	O
the	O
mossy	O
fibre	O
terminals	O
,	O
in	O
the	O
dentate	O
gyrus	O
inner	O
molecular	O
layer	O
and	O
,	O
in	O
a	O
few	O
cases	O
,	O
within	O
presumed	O
granule	O
cells	O
.	O

NPY	O
immunoreactivity	O
was	O
also	O
dramatically	O
changed	O
in	O
the	O
entorhinal	O
cortex	O
,	O
amygdala	O
and	O
sensorimotor	O
areas	O
.	O

In	O
addition	O
,	O
PILO	B-Chemical
injected	O
animals	O
exhibited	O
a	O
reduction	O
in	O
the	O
number	O
of	O
NPY	O
-	O
immunoreactive	O
interneurons	O
compared	O
with	O
controls	O
.	O

The	O
results	O
demonstrate	O
that	O
changes	O
in	O
NPY	O
expression	O
,	O
including	O
expression	O
in	O
the	O
granule	O
cells	O
and	O
mossy	O
fibres	O
and	O
the	O
loss	O
of	O
vulnerable	O
NPY	O
neurons	O
,	O
are	O
present	O
in	O
the	O
PILO	B-Chemical
model	O
of	O
TLE	B-Disease
.	O

However	O
,	O
the	O
significance	O
of	O
this	O
changed	O
synthesis	O
of	O
NPY	O
remains	O
to	O
be	O
determined	O
.	O

Posteroventral	O
medial	O
pallidotomy	O
in	O
advanced	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
.	O

BACKGROUND	O
:	O
Posteroventral	O
medial	O
pallidotomy	O
sometimes	O
produces	O
striking	O
improvement	O
in	O
patients	O
with	O
advanced	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
,	O
but	O
the	O
studies	O
to	O
date	O
have	O
involved	O
small	O
numbers	O
of	O
patients	O
and	O
short	O
-	O
term	O
follow	O
-	O
up	O
.	O

METHODS	O
:	O
Forty	O
patients	O
with	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
underwent	O
serial	O
,	O
detailed	O
assessments	O
both	O
after	O
drug	O
withdrawal	O
(	O
"	O
off	O
"	O
period	O
)	O
and	O
while	O
taking	O
their	O
optimal	O
medical	O
regimens	O
(	O
"	O
on	O
"	O
period	O
)	O
.	O

All	O
patients	O
were	O
examined	O
preoperatively	O
and	O
39	O
were	O
examined	O
at	O
six	O
months	O
;	O
27	O
of	O
the	O
patients	O
were	O
also	O
examined	O
at	O
one	O
year	O
,	O
and	O
11	O
at	O
two	O
years	O
.	O

RESULTS	O
:	O
The	O
percent	O
improvements	O
at	O
six	O
months	O
were	O
as	O
follows	O
:	O
off	O
-	O
period	O
score	O
for	O
overall	O
motor	O
function	O
,	O
28	O
percent	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
19	O
to	O
38	O
percent	O
)	O
,	O
with	O
most	O
of	O
the	O
improvement	O
in	O
the	O
contralateral	O
limbs	O
;	O
off	O
-	O
period	O
score	O
for	O
activities	O
of	O
daily	O
living	O
,	O
29	O
percent	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
19	O
to	O
39	O
percent	O
)	O
;	O
on	O
-	O
period	O
score	O
for	O
contralateral	O
dyskinesias	B-Disease
,	O
82	O
percent	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
72	O
to	O
91	O
percent	O
)	O
;	O
and	O
on	O
-	O
period	O
score	O
for	O
ipsilateral	O
dyskinesias	B-Disease
,	O
44	O
percent	O
(	O
95	O
percent	O
confidence	O
interval	O
,	O
29	O
to	O
59	O
percent	O
)	O
.	O

The	O
improvements	O
in	O
dyskinesias	B-Disease
and	O
the	O
total	O
scores	O
for	O
off	O
-	O
period	O
parkinsonism	B-Disease
,	O
contralateral	O
bradykinesia	B-Disease
,	O
and	O
rigidity	B-Disease
were	O
sustained	O
in	O
the	O
11	O
patients	O
examined	O
at	O
two	O
years	O
.	O

The	O
improvement	O
in	O
ipsilateral	O
dyskinesias	B-Disease
was	O
lost	O
after	O
one	O
year	O
,	O
and	O
the	O
improvements	O
in	O
postural	O
stability	O
and	O
gait	O
lasted	O
only	O
three	O
to	O
six	O
months	O
.	O

Approximately	O
half	O
the	O
patients	O
who	O
had	O
been	O
dependent	O
on	O
assistance	O
in	O
activities	O
of	O
daily	O
living	O
in	O
the	O
off	O
period	O
before	O
surgery	O
became	O
independent	O
after	O
surgery	O
.	O

The	O
complications	O
of	O
surgery	O
were	O
generally	O
well	O
tolerated	O
,	O
and	O
there	O
were	O
no	O
significant	O
changes	O
in	O
the	O
use	O
of	O
medication	O
.	O

CONCLUSIONS	O
:	O
In	O
late	O
-	O
stage	O
Parkinson	B-Disease
'	I-Disease
s	I-Disease
disease	I-Disease
,	O
pallidotomy	O
significantly	O
reduces	O
levodopa	B-Chemical
-	O
induced	O
dyskinesias	B-Disease
and	O
off	O
-	O
period	O
disability	O
.	O

Much	O
of	O
the	O
benefit	O
is	O
sustained	O
at	O
two	O
years	O
,	O
although	O
some	O
improvements	O
,	O
such	O
as	O
those	O
on	O
the	O
ipsilateral	O
side	O
and	O
in	O
axial	O
symptoms	O
,	O
wane	O
within	O
the	O
first	O
year	O
.	O

The	O
on	O
-	O
period	O
symptoms	O
that	O
are	O
resistant	O
to	O
dopaminergic	O
therapy	O
do	O
not	O
respond	O
to	O
pallidotomy	O
.	O

Clarithromycin	B-Chemical
-	O
induced	O
ventricular	B-Disease
tachycardia	I-Disease
.	O

Clarithromycin	B-Chemical
is	O
a	O
relatively	O
new	O
macrolide	B-Chemical
antibiotic	O
that	O
offers	O
twice	O
-	O
daily	O
dosing	O
.	O

It	O
differs	O
from	O
erythromycin	B-Chemical
only	O
in	O
the	O
methylation	O
of	O
the	O
hydroxyl	O
group	O
at	O
position	O
6	O
.	O

Although	O
the	O
side	O
-	O
effect	O
profile	O
of	O
erythromycin	B-Chemical
is	O
established	O
,	O
including	O
gastroenteritis	B-Disease
and	O
interactions	O
with	O
other	O
drugs	O
subject	O
to	O
hepatic	O
mixed	O
-	O
function	O
oxidase	O
metabolism	O
,	O
experience	O
with	O
the	O
newer	O
macrolides	B-Chemical
is	O
still	O
being	O
recorded	O
.	O

Cardiotoxicity	B-Disease
has	O
been	O
demonstrated	O
after	O
both	O
intravenous	O
and	O
oral	O
administration	O
of	O
erythromycin	B-Chemical
but	O
has	O
never	O
been	O
reported	O
with	O
the	O
newer	O
macrolides	B-Chemical
.	O

We	O
report	O
a	O
case	O
of	O
ventricular	B-Disease
dysrhythmias	I-Disease
that	O
occurred	O
after	O
six	O
therapeutic	O
doses	O
of	O
clarithromycin	B-Chemical
.	O

The	O
dysrhythmias	B-Disease
resolved	O
after	O
discontinuation	O
of	O
the	O
drug	O
.	O

Effect	O
of	O
glyceryl	B-Chemical
trinitrate	I-Chemical
on	O
the	O
sphincter	B-Disease
of	I-Disease
Oddi	I-Disease
spasm	I-Disease
evoked	O
by	O
prostigmine	B-Chemical
-	O
morphine	B-Chemical
administration	O
.	O

OBJECTIVE	O
:	O
In	O
this	O
study	O
the	O
effect	O
of	O
glyceryl	B-Chemical
trinitrate	I-Chemical
on	O
the	O
prostigmine	B-Chemical
-	O
morphine	B-Chemical
-	O
induced	O
sphincter	B-Disease
of	I-Disease
Oddi	I-Disease
spasm	I-Disease
was	O
evaluated	O
in	O
nine	O
female	O
patients	O
with	O
sphincter	B-Disease
of	I-Disease
Oddi	I-Disease
dyskinesia	I-Disease
.	O

METHOD	O
:	O
Sphincter	B-Disease
of	I-Disease
Oddi	I-Disease
spasm	I-Disease
was	O
induced	O
by	O
prostigmine	B-Chemical
-	O
morphine	B-Chemical
administration	O
(	O
0	O
.	O
5	O
mg	O
prostigmine	B-Chemical
intramuscularly	O
and	O
10	O
mg	O
morphine	B-Chemical
subcutaneously	O
)	O
and	O
visualized	O
by	O
quantitative	O
hepatobiliary	O
scintigraphy	O
.	O

The	O
entire	O
procedure	O
was	O
repeated	O
during	O
glyceryl	B-Chemical
trinitrate	I-Chemical
infusion	O
(	O
Nitrolingual	B-Chemical
1	O
microg	O
/	O
kg	O
/	O
min	O
for	O
120	O
min	O
)	O
.	O

RESULTS	O
:	O
Prostigmine	B-Chemical
-	O
morphine	B-Chemical
provocation	O
caused	O
significant	O
increases	O
in	O
the	O
time	O
to	O
peak	O
activity	O
(	O
Tmax	O
)	O
over	O
the	O
hepatic	O
hilum	O
(	O
HH	O
:	O
34	O
.	O
33	O
+	O
/	O
-	O
5	O
.	O
05	O
vs	O
.	O
22	O
.	O
77	O
+	O
/	O
-	O
3	O
.	O
26	O
)	O
and	O
the	O
common	O
bile	O
duct	O
(	O
CBD	O
:	O
60	O
.	O
44	O
+	O
/	O
-	O
5	O
.	O
99	O
vs	O
.	O
40	O
.	O
0	O
+	O
/	O
-	O
2	O
.	O
88	O
)	O
and	O
in	O
the	O
half	O
-	O
time	O
of	O
excretion	O
(	O
T1	O
/	O
2	O
)	O
over	O
the	O
liver	O
parenchyma	O
(	O
LP	O
:	O
120	O
.	O
04	O
+	O
/	O
-	O
16	O
.	O
01	O
vs	O
.	O
27	O
.	O
37	O
+	O
/	O
-	O
2	O
.	O
19	O
)	O
,	O
HH	O
(	O
117	O
.	O
61	O
+	O
/	O
-	O
14	O
.	O
71	O
vs	O
.	O
31	O
.	O
85	O
+	O
/	O
-	O
3	O
.	O
99	O
)	O
and	O
CBD	O
(	O
158	O
.	O
11	O
+	O
/	O
-	O
9	O
.	O
18	O
vs	O
.	O
40	O
.	O
1	O
+	O
/	O
-	O
6	O
.	O
24	O
)	O
,	O
indicating	O
a	O
complete	O
spasm	B-Disease
at	O
the	O
level	O
of	O
the	O
sphincter	O
of	O
Oddi	O
.	O

Glyceryl	B-Chemical
trinitrate	I-Chemical
infusion	O
completely	O
normalized	O
the	O
prostigmine	B-Chemical
-	O
morphine	B-Chemical
-	O
induced	O
alterations	O
in	O
these	O
quantitative	O
parameters	O
(	O
TmaX	O
over	O
the	O
LP	O
:	O
11	O
.	O
33	O
+	O
/	O
-	O
1	O
.	O
13	O
;	O
over	O
the	O
HH	O
:	O
18	O
.	O
88	O
+	O
/	O
-	O
1	O
.	O
48	O
;	O
and	O
over	O
the	O
CBD	O
:	O
36	O
.	O
22	O
+	O
/	O
-	O
1	O
.	O
92	O
;	O
and	O
T1	O
/	O
2	O
over	O
the	O
LP	O
:	O
28	O
.	O
21	O
+	O
/	O
-	O
1	O
.	O
83	O
;	O
over	O
the	O
HH	O
:	O
33	O
.	O
42	O
+	O
/	O
-	O
3	O
.	O
10	O
;	O
and	O
over	O
the	O
CBD	O
:	O
41	O
.	O
66	O
+	O
/	O
-	O
6	O
.	O
33	O
)	O
,	O
suggesting	O
an	O
effective	O
sphincter	O
-	O
relaxing	O
effect	O
of	O
glyceryl	B-Chemical
trinitrate	I-Chemical
.	O

CONCLUSION	O
:	O
These	O
results	O
provide	O
the	O
first	O
evidence	O
of	O
the	O
effectiveness	O
of	O
glyceryl	B-Chemical
trinitrate	I-Chemical
on	O
the	O
morphine	B-Chemical
-	O
induced	O
sphincter	B-Disease
of	I-Disease
Oddi	I-Disease
spasm	I-Disease
in	O
humans	O
.	O

Since	O
glyceryl	B-Chemical
trinitrate	I-Chemical
is	O
able	O
to	O
overcome	O
even	O
the	O
drastic	O
effect	O
of	O
morphine	B-Chemical
,	O
it	O
might	O
be	O
of	O
relevance	O
in	O
the	O
treatment	O
of	O
sphincter	B-Disease
of	I-Disease
Oddi	I-Disease
dyskinesia	I-Disease
.	O

Immunopathology	O
of	O
penicillamine	B-Chemical
-	O
induced	O
glomerular	B-Disease
disease	I-Disease
.	O

Four	O
patients	O
with	O
rheumatoid	B-Disease
arthritis	I-Disease
developed	O
heavy	O
proteinuria	B-Disease
after	O
five	O
to	O
12	O
months	O
of	O
treatment	O
with	O
D	B-Chemical
-	I-Chemical
penicillamine	I-Chemical
.	O

Light	O
microscopy	O
of	O
renal	O
biopsy	O
samples	O
showed	O
minimal	O
glomerular	O
capillary	O
wall	O
thickening	O
and	O
mesangial	O
matrix	O
increase	O
,	O
or	O
no	O
departure	O
from	O
normal	O
.	O

Electron	O
microscopy	O
,	O
however	O
,	O
revealed	O
subepithelial	O
electron	O
-	O
dense	O
deposits	O
,	O
fusion	O
of	O
epithelial	O
cell	O
foot	O
processes	O
,	O
and	O
evidence	O
of	O
mesangial	O
cell	O
hyperactivity	O
.	O

Immunofluorescence	O
microscopy	O
demonstrated	O
granular	O
capillary	O
wall	O
deposits	O
of	O
IgG	O
and	O
C3	O
.	O

The	O
findings	O
were	O
similar	O
to	O
those	O
in	O
early	O
membranous	B-Disease
glomerulonephritis	I-Disease
,	O
differences	O
being	O
observed	O
however	O
in	O
the	O
results	O
of	O
staining	O
for	O
the	O
early	O
-	O
acting	O
complement	O
components	O
C1q	O
and	O
C4	O
.	O

It	O
is	O
tentatively	O
concluded	O
that	O
complement	O
was	O
activated	O
by	O
the	O
classical	O
pathway	O
.	O

Experimental	O
cranial	O
pain	B-Disease
elicited	O
by	O
capsaicin	B-Chemical
:	O
a	O
PET	O
study	O
.	O

Using	O
a	O
positron	O
emission	O
tomography	O
(	O
PET	O
)	O
study	O
it	O
was	O
shown	O
recently	O
that	O
in	O
migraine	B-Disease
without	O
aura	O
certain	O
areas	O
in	O
the	O
brain	O
stem	O
were	O
activated	O
during	O
the	O
headache	B-Disease
state	O
,	O
but	O
not	O
in	O
the	O
headache	B-Disease
free	O
interval	O
.	O

It	O
was	O
suggested	O
that	O
this	O
brain	O
stem	O
activation	O
is	O
inherent	O
to	O
the	O
migraine	B-Disease
attack	O
itself	O
and	O
represents	O
the	O
so	O
called	O
'	O
migraine	B-Disease
generator	O
'	O
.	O

To	O
test	O
this	O
hypothesis	O
we	O
performed	O
an	O
experimental	O
pain	B-Disease
study	O
in	O
seven	O
healthy	O
volunteers	O
,	O
using	O
the	O
same	O
positioning	O
in	O
the	O
PET	O
scanner	O
as	O
in	O
the	O
migraine	B-Disease
patients	O
.	O

A	O
small	O
amount	O
of	O
capsaicin	B-Chemical
was	O
administered	O
subcutaneously	O
in	O
the	O
right	O
forehead	O
to	O
evoke	O
a	O
burning	O
painful	B-Disease
sensation	O
in	O
the	O
first	O
division	O
of	O
the	O
trigeminal	O
nerve	O
.	O

Increases	O
of	O
regional	O
cerebral	O
blood	O
flow	O
(	O
rCBF	O
)	O
were	O
found	O
bilaterally	O
in	O
the	O
insula	O
,	O
in	O
the	O
anterior	O
cingulate	O
cortex	O
,	O
the	O
cavernous	O
sinus	O
and	O
the	O
cerebellum	O
.	O

Using	O
the	O
same	O
stereotactic	O
space	O
limits	O
as	O
in	O
the	O
above	O
mentioned	O
migraine	B-Disease
study	O
no	O
brain	O
stem	O
activation	O
was	O
found	O
in	O
the	O
acute	O
pain	B-Disease
state	O
compared	O
to	O
the	O
pain	B-Disease
free	O
state	O
.	O

The	O
increase	O
of	O
activation	O
in	O
the	O
region	O
of	O
the	O
cavernous	O
sinus	O
however	O
,	O
suggests	O
that	O
this	O
structure	O
is	O
more	O
likely	O
to	O
be	O
involved	O
in	O
trigeminal	O
transmitted	O
pain	B-Disease
as	O
such	O
,	O
rather	O
than	O
in	O
a	O
specific	O
type	O
of	O
headache	B-Disease
as	O
was	O
suggested	O
for	O
cluster	B-Disease
headache	I-Disease
.	O

Value	O
of	O
methylprednisolone	B-Chemical
in	O
prevention	O
of	O
the	O
arthralgia	B-Disease
-	O
myalgia	B-Disease
syndrome	O
associated	O
with	O
the	O
total	O
dose	O
infusion	O
of	O
iron	B-Chemical
dextran	I-Chemical
:	O
a	O
double	O
blind	O
randomized	O
trial	O
.	O

The	O
safety	O
and	O
efficacy	O
of	O
total	O
dose	O
infusion	O
(	O
TDI	O
)	O
of	O
iron	B-Chemical
dextran	I-Chemical
has	O
been	O
well	O
documented	O
.	O

In	O
40	O
%	O
of	O
treated	O
patients	O
,	O
an	O
arthralgia	B-Disease
-	O
myalgia	B-Disease
syndrome	O
develops	O
.	O

The	O
purpose	O
of	O
this	O
randomized	O
,	O
double	O
-	O
blind	O
,	O
prospective	O
study	O
was	O
to	O
investigate	O
whether	O
intravenous	O
(	O
i	O
.	O
v	O
.	O
)	O
administration	O
of	O
methylprednisolone	B-Chemical
(	O
MP	B-Chemical
)	O
prevents	O
this	O
complication	O
.	O

Sixty	O
-	O
five	O
patients	O
,	O
34	O
women	O
and	O
31	O
men	O
,	O
ages	O
36	O
to	O
80	O
years	O
,	O
received	O
either	O
normal	O
saline	O
before	O
and	O
after	O
TDI	O
(	O
group	O
1	O
)	O
,	O
125	O
mg	O
i	O
.	O
v	O
.	O
MP	B-Chemical
before	O
and	O
saline	O
after	O
TDI	O
(	O
group	O
2	O
)	O
,	O
or	O
125	O
mg	O
i	O
.	O
v	O
.	O
MP	B-Chemical
before	O
and	O
after	O
TDI	O
(	O
group	O
3	O
)	O
.	O

Patients	O
were	O
observed	O
for	O
72	O
hours	O
and	O
reactions	O
were	O
recorded	O
and	O
graded	O
according	O
to	O
severity	O
.	O

Fifty	O
-	O
eight	O
percent	O
of	O
group	O
1	O
patients	O
,	O
33	O
%	O
of	O
group	O
2	O
,	O
and	O
26	O
%	O
of	O
group	O
3	O
had	O
reactions	O
to	O
TDI	O
.	O

The	O
severity	O
of	O
reactions	O
(	O
minimal	O
,	O
mild	O
,	O
and	O
moderate	O
,	O
respectively	O
)	O
was	O
as	O
follows	O
:	O
group	O
1	O
-	O
-	O
6	O
,	O
6	O
,	O
and	O
2	O
;	O
group	O
2	O
-	O
-	O
1	O
,	O
5	O
,	O
and	O
0	O
;	O
group	O
3	O
-	O
-	O
5	O
,	O
1	O
,	O
and	O
0	O
.	O

Data	O
were	O
analyzed	O
by	O
the	O
two	O
-	O
sided	O
Fisher	O
'	O
s	O
exact	O
test	O
using	O
95	O
%	O
confidence	O
intervals	O
with	O
the	O
approximation	O
of	O
Woolf	O
.	O

These	O
data	O
demonstrate	O
that	O
administration	O
of	O
MP	B-Chemical
before	O
and	O
after	O
TDI	O
reduces	O
the	O
frequency	O
and	O
severity	O
of	O
the	O
arthralgia	B-Disease
-	O
myalgia	B-Disease
syndrome	O
.	O

We	O
conclude	O
that	O
125	O
mg	O
i	O
.	O
v	O
.	O
MP	B-Chemical
should	O
be	O
given	O
routinely	O
before	O
and	O
after	O
TDI	O
of	O
iron	B-Chemical
dextran	I-Chemical
.	O

Prolongation	B-Disease
of	I-Disease
the	I-Disease
QT	I-Disease
interval	I-Disease
related	O
to	O
cisapride	B-Chemical
-	O
diltiazem	B-Chemical
interaction	O
.	O

Cisapride	B-Chemical
,	O
a	O
cytochrome	O
P450	O
3A4	O
(	O
CYP3A4	O
)	O
substrate	O
,	O
is	O
widely	O
prescribed	O
for	O
the	O
treatment	O
of	O
gastrointestinal	B-Disease
motility	I-Disease
disorders	I-Disease
.	O

Prolongation	B-Disease
of	I-Disease
QT	I-Disease
interval	I-Disease
,	O
torsades	B-Disease
de	I-Disease
pointes	I-Disease
,	O
and	O
sudden	B-Disease
cardiac	I-Disease
death	I-Disease
have	O
been	O
reported	O
after	O
concomitant	O
administration	O
with	O
erythromycin	B-Chemical
or	O
azole	B-Chemical
antifungal	O
agents	O
,	O
but	O
not	O
with	O
other	O
CYP3A4	O
inhibitors	O
.	O

A	O
possible	O
drug	O
interaction	O
occurred	O
in	O
a	O
45	O
-	O
year	O
-	O
old	O
woman	O
who	O
was	O
taking	O
cisapride	B-Chemical
for	O
gastroesophageal	B-Disease
reflux	I-Disease
disorder	I-Disease
and	O
diltiazem	B-Chemical
,	O
an	O
agent	O
that	O
has	O
inhibitory	O
effect	O
on	O
CYP3A4	O
,	O
for	O
hypertension	B-Disease
.	O

The	O
patient	O
was	O
in	O
near	O
syncope	B-Disease
and	O
had	O
QT	B-Disease
-	I-Disease
interval	I-Disease
prolongation	I-Disease
.	O

After	O
discontinuing	O
cisapride	B-Chemical
,	O
the	O
QT	O
interval	O
returned	O
to	O
normal	O
and	O
symptoms	O
did	O
not	O
recur	O
.	O

We	O
suggest	O
that	O
caution	O
be	O
taken	O
when	O
cisapride	B-Chemical
is	O
prescribed	O
with	O
any	O
potent	O
inhibitor	O
of	O
CYP3A4	O
,	O
including	O
diltiazem	B-Chemical
.	O

Cortical	O
motor	O
overactivation	O
in	O
parkinsonian	B-Disease
patients	O
with	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
-	O
induced	O
peak	O
-	O
dose	O
dyskinesia	B-Disease
.	O

We	O
have	O
studied	O
the	O
regional	O
cerebral	O
blood	O
flow	O
(	O
rCBF	O
)	O
changes	O
induced	O
by	O
the	O
execution	O
of	O
a	O
finger	O
-	O
to	O
-	O
thumb	O
opposition	O
motor	O
task	O
in	O
the	O
supplementary	O
and	O
primary	O
motor	O
cortex	O
of	O
two	O
groups	O
of	O
parkinsonian	B-Disease
patients	O
on	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
medication	O
,	O
the	O
first	O
one	O
without	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
induced	O
dyskinesia	B-Disease
(	O
n	O
=	O
23	O
)	O
and	O
the	O
other	O
with	O
moderate	O
peak	O
-	O
dose	O
dyskinesia	B-Disease
(	O
n	O
=	O
15	O
)	O
,	O
and	O
of	O
a	O
group	O
of	O
14	O
normal	O
subjects	O
.	O

Single	O
photon	O
emission	O
tomography	O
with	O
i	O
.	O
v	O
.	O
133Xe	O
was	O
used	O
to	O
measure	O
the	O
rCBF	O
changes	O
.	O

The	O
dyskinetic	B-Disease
parkinsonian	B-Disease
patients	O
exhibited	O
a	O
pattern	O
of	O
response	O
which	O
was	O
markedly	O
different	O
from	O
those	O
of	O
the	O
normal	O
subjects	O
and	O
non	O
-	O
dyskinetic	B-Disease
parkinsonian	B-Disease
patients	O
,	O
with	O
a	O
significant	O
overactivation	O
in	O
the	O
supplementary	O
motor	O
area	O
and	O
the	O
ipsi	O
-	O
and	O
contralateral	O
primary	O
motor	O
areas	O
.	O

These	O
results	O
are	O
compatible	O
with	O
the	O
hypothesis	O
that	O
an	O
hyperkinetic	B-Disease
abnormal	B-Disease
involuntary	I-Disease
movement	I-Disease
,	O
like	O
L	B-Chemical
-	I-Chemical
dopa	I-Chemical
-	O
induced	O
peak	O
dose	O
dyskinesia	B-Disease
,	O
is	O
due	O
to	O
a	O
disinhibition	O
of	O
the	O
primary	O
and	O
associated	O
motor	O
cortex	O
secondary	O
to	O
an	O
excessive	O
outflow	O
of	O
the	O
pallidothalamocortical	O
motor	O
loop	O
.	O

Open	O
-	O
label	O
assessment	O
of	O
levofloxacin	B-Chemical
for	O
the	O
treatment	O
of	O
acute	O
bacterial	O
sinusitis	B-Disease
in	O
adults	O
.	O

PURPOSE	O
:	O
To	O
evaluate	O
the	O
efficacy	O
and	O
safety	O
of	O
levofloxacin	B-Chemical
(	O
500	O
mg	O
orally	O
once	O
daily	O
for	O
10	O
to	O
14	O
days	O
)	O
in	O
treating	O
adult	O
outpatients	O
with	O
acute	O
bacterial	O
sinusitis	B-Disease
.	O

PATIENTS	O
AND	O
METHODS	O
:	O
A	O
total	O
of	O
329	O
patients	O
enrolled	O
in	O
the	O
study	O
at	O
24	O
centers	O
.	O

All	O
patients	O
had	O
a	O
pre	O
-	O
therapy	O
Gram	O
'	O
s	O
stain	O
and	O
culture	O
of	O
sinus	O
exudate	O
obtained	O
by	O
antral	O
puncture	O
or	O
nasal	O
endoscopy	O
.	O

Clinical	O
response	O
was	O
assessed	O
on	O
the	O
basis	O
of	O
signs	O
and	O
symptoms	O
and	O
sinus	O
radiograph	O
or	O
computed	O
tomography	O
results	O
.	O

Microbiologic	O
cure	O
rates	O
were	O
determined	O
on	O
the	O
basis	O
of	O
presumed	O
plus	O
documented	O
eradication	O
of	O
the	O
pre	O
-	O
therapy	O
pathogen	O
(	O
s	O
)	O
.	O

RESULTS	O
:	O
The	O
most	O
common	O
pathogens	O
were	O
Haemophilus	O
influenzae	O
,	O
Streptococcus	O
pneumoniae	O
,	O
Staphylococcus	O
aureus	O
,	O
and	O
Moraxella	O
catarrhalis	O
.	O

Of	O
300	O
clinically	O
evaluable	O
patients	O
,	O
175	O
(	O
58	O
%	O
)	O
were	O
cured	O
and	O
90	O
(	O
30	O
%	O
)	O
were	O
improved	O
at	O
the	O
post	O
-	O
therapy	O
evaluation	O
,	O
resulting	O
in	O
a	O
clinical	O
success	O
rate	O
of	O
88	O
%	O
.	O

Thirty	O
-	O
five	O
patients	O
(	O
12	O
%	O
)	O
clinically	O
failed	O
treatment	O
.	O

The	O
microbiologic	O
eradication	O
rate	O
(	O
presumed	O
plus	O
documented	O
)	O
among	O
138	O
microbiologically	O
evaluable	O
patients	O
was	O
92	O
%	O
.	O

Microbiologic	O
eradication	O
rates	O
(	O
presumed	O
plus	O
documented	O
)	O
of	O
the	O
most	O
common	O
pathogens	O
ranged	O
from	O
93	O
%	O
(	O
M	O
.	O
catarrhalis	O
)	O
to	O
100	O
%	O
(	O
S	O
.	O
pneumoniae	O
)	O
at	O
the	O
post	O
-	O
therapy	O
visit	O
.	O

All	O
but	O
one	O
of	O
the	O
265	O
patients	O
who	O
were	O
cured	O
or	O
improved	O
at	O
post	O
-	O
therapy	O
returned	O
for	O
a	O
long	O
-	O
term	O
follow	O
-	O
up	O
visit	O
;	O
243	O
(	O
92	O
%	O
)	O
remained	O
well	O
4	O
to	O
6	O
weeks	O
after	O
therapy	O
;	O
and	O
21	O
(	O
8	O
%	O
)	O
had	O
a	O
relapse	O
of	O
symptoms	O
.	O

Adverse	O
events	O
considered	O
to	O
be	O
related	O
to	O
levofloxacin	B-Chemical
administration	O
were	O
reported	O
by	O
29	O
patients	O
(	O
9	O
%	O
)	O
.	O

The	O
most	O
common	O
drug	O
-	O
related	O
adverse	O
events	O
were	O
diarrhea	B-Disease
,	O
flatulence	B-Disease
,	O
and	O
nausea	B-Disease
;	O
most	O
adverse	O
events	O
were	O
mild	O
to	O
moderate	O
in	O
severity	O
.	O

CONCLUSION	O
:	O
The	O
results	O
of	O
this	O
study	O
indicate	O
that	O
levofloxacin	B-Chemical
500	O
mg	O
once	O
daily	O
is	O
an	O
effective	O
and	O
safe	O
treatment	O
for	O
acute	O
bacterial	O
sinusitis	B-Disease
.	O

Iatrogenic	O
risks	O
of	O
endometrial	B-Disease
carcinoma	I-Disease
after	O
treatment	O
for	O
breast	B-Disease
cancer	I-Disease
in	O
a	O
large	O
French	O
case	O
-	O
control	O
study	O
.	O

F	O
d	O
ration	O
Nationale	O
des	O
Centres	O
de	O
Lutte	O
Contre	O
le	O
Cancer	O
(	O
FNCLCC	O
)	O
.	O

Since	O
tamoxifen	B-Chemical
is	O
widely	O
used	O
in	O
breast	B-Disease
cancer	I-Disease
treatment	O
and	O
has	O
been	O
proposed	O
for	O
the	O
prevention	O
of	O
breast	B-Disease
cancer	I-Disease
,	O
its	O
endometrial	O
iatrogenic	O
effects	O
must	O
be	O
carefully	O
examined	O
.	O

We	O
have	O
investigated	O
the	O
association	O
between	O
endometrial	B-Disease
cancer	I-Disease
and	O
tamoxifen	B-Chemical
use	O
or	O
other	O
treatments	O
in	O
women	O
treated	O
for	O
breast	B-Disease
cancer	I-Disease
in	O
a	O
case	O
-	O
control	O
study	O
.	O

Cases	O
of	O
endometrial	B-Disease
cancer	I-Disease
diagnosed	O
after	O
breast	B-Disease
cancer	I-Disease
(	O
n	O
=	O
135	O
)	O
and	O
467	O
controls	O
matched	O
for	O
age	O
,	O
year	O
of	O
diagnosis	O
of	O
breast	B-Disease
cancer	I-Disease
and	O
hospital	O
and	O
survival	O
time	O
with	O
an	O
intact	O
uterus	O
were	O
included	O
.	O

Women	O
who	O
had	O
received	O
tamoxifen	B-Chemical
were	O
significantly	O
more	O
likely	O
to	O
have	O
endometrial	B-Disease
cancer	I-Disease
diagnosed	O
than	O
those	O
who	O
had	O
not	O
(	O
crude	O
relative	O
risk	O
=	O
4	O
.	O
9	O
,	O
p	O
=	O
0	O
.	O
0001	O
)	O
.	O

Univariate	O
and	O
adjusted	O
analyses	O
showed	O
that	O
the	O
risk	O
increased	O
with	O
the	O
length	O
of	O
treatment	O
(	O
p	O
=	O
0	O
.	O
0001	O
)	O
or	O
the	O
cumulative	O
dose	O
of	O
tamoxifen	B-Chemical
received	O
(	O
p	O
=	O
0	O
.	O
0001	O
)	O
,	O
irrespective	O
of	O
the	O
daily	O
dose	O
.	O

Women	O
who	O
had	O
undergone	O
pelvic	O
radiotherapy	O
also	O
had	O
a	O
higher	O
risk	O
(	O
crude	O
relative	O
risk	O
=	O
7	O
.	O
8	O
,	O
p	O
=	O
0	O
.	O
0001	O
)	O
.	O

After	O
adjusting	O
for	O
confounding	O
factors	O
,	O
the	O
risk	O
was	O
higher	O
for	O
tamoxifen	B-Chemical
users	O
(	O
p	O
=	O
0	O
.	O
0012	O
)	O
,	O
treatment	O
for	O
more	O
than	O
3	O
years	O
(	O
all	O
p	O
<	O
0	O
.	O
03	O
)	O
and	O
pelvic	O
radiotherapy	O
(	O
p	O
=	O
0	O
.	O
012	O
)	O
.	O

Women	O
who	O
had	O
endometrial	B-Disease
cancer	I-Disease
and	O
had	O
received	O
tamoxifen	B-Chemical
had	O
more	O
advanced	B-Disease
disease	I-Disease
and	O
poorer	O
prognosis	O
than	O
those	O
with	O
endometrial	B-Disease
cancer	I-Disease
who	O
had	O
not	O
received	O
this	O
treatment	O
.	O

Our	O
results	O
suggest	O
a	O
causal	O
role	O
of	O
tamoxifen	B-Chemical
in	O
endometrial	B-Disease
cancer	I-Disease
,	O
particularly	O
when	O
used	O
as	O
currently	O
proposed	O
for	O
breast	B-Disease
cancer	I-Disease
prevention	O
.	O

Pelvic	O
radiotherapy	O
may	O
be	O
an	O
additional	O
iatrogenic	O
factor	O
for	O
women	O
with	O
breast	B-Disease
cancer	I-Disease
.	O

Endometrial	B-Disease
cancers	I-Disease
diagnosed	O
in	O
women	O
treated	O
with	O
tamoxifen	B-Chemical
have	O
poorer	O
prognosis	O
.	O

Women	O
who	O
receive	O
tamoxifen	B-Chemical
for	O
breast	B-Disease
cancer	I-Disease
should	O
be	O
offered	O
gynaecological	O
surveillance	O
during	O
and	O
after	O
treatment	O
.	O

A	O
long	O
-	O
term	O
evaluation	O
of	O
the	O
risk	O
-	O
benefit	O
ratio	O
of	O
tamoxifen	B-Chemical
as	O
a	O
preventive	O
treatment	O
for	O
breast	B-Disease
cancer	I-Disease
is	O
clearly	O
warranted	O
.	O

Contribution	O
of	O
the	O
glycine	B-Chemical
site	O
of	O
NMDA	B-Chemical
receptors	O
in	O
rostral	O
and	O
intermediate	O
-	O
caudal	O
parts	O
of	O
the	O
striatum	O
to	O
the	O
regulation	O
of	O
muscle	O
tone	O
in	O
rats	O
.	O

The	O
aim	O
of	O
the	O
present	O
study	O
was	O
to	O
assess	O
the	O
contribution	O
of	O
the	O
glycine	B-Chemical
site	O
of	O
NMDA	B-Chemical
receptors	O
in	O
the	O
striatum	O
to	O
the	O
regulation	O
of	O
muscle	O
tone	O
.	O

Muscle	O
tone	O
was	O
examined	O
using	O
a	O
combined	O
mechanoand	O
electromyographic	O
method	O
,	O
which	O
measured	O
simultaneously	O
the	O
muscle	O
resistance	O
(	O
MMG	O
)	O
of	O
the	O
rat	O
'	O
s	O
hind	O
foot	O
to	O
passive	O
extension	O
and	O
flexion	O
in	O
the	O
ankle	O
joint	O
and	O
the	O
electromyographic	O
activity	O
(	O
EMG	O
)	O
of	O
the	O
antagonistic	O
muscles	O
of	O
that	O
joint	O
:	O
gastrocnemius	O
and	O
tibialis	O
anterior	O
.	O

Muscle	B-Disease
rigidity	I-Disease
was	O
induced	O
by	O
haloperidol	B-Chemical
(	O
2	O
.	O
5	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
)	O
.	O

5	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
dichlorokynurenic	I-Chemical
acid	I-Chemical
(	O
5	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
DCKA	I-Chemical
)	O
,	O
a	O
selective	O
glycine	B-Chemical
site	O
antagonist	O
,	O
injected	O
in	O
doses	O
of	O
2	O
.	O
5	O
and	O
4	O
.	O
5	O
microg	O
/	O
0	O
.	O
5	O
microl	O
bilaterally	O
,	O
into	O
the	O
rostral	O
region	O
of	O
the	O
striatum	O
,	O
decreased	O
both	O
the	O
haloperidol	B-Chemical
-	O
induced	O
muscle	B-Disease
rigidity	I-Disease
(	O
MMG	O
)	O
and	O
the	O
enhanced	O
electromyographic	O
activity	O
(	O
EMG	O
)	O
.	O

5	B-Chemical
,	I-Chemical
7	I-Chemical
-	I-Chemical
DCKA	I-Chemical
injected	O
bilaterally	O
in	O
a	O
dose	O
of	O
4	O
.	O
5	O
microg	O
/	O
0	O
.	O
5	O
microl	O
into	O
the	O
intermediate	O
-	O
caudal	O
region	O
of	O
the	O
striatum	O
of	O
rats	O
not	O
pretreated	O
with	O
haloperidol	B-Chemical
had	O
no	O
effect	O
on	O
the	O
muscle	O
tone	O
.	O

The	O
present	O
results	O
suggest	O
that	O
blockade	O
of	O
the	O
glycine	B-Chemical
site	O
of	O
NMDA	B-Chemical
receptors	O
in	O
the	O
rostral	O
part	O
of	O
the	O
striatum	O
may	O
be	O
mainly	O
responsible	O
for	O
the	O
antiparkinsonian	O
action	O
of	O
this	O
drug	O
.	O

Carboplatin	B-Chemical
toxic	O
effects	O
on	O
the	O
peripheral	O
nervous	O
system	O
of	O
the	O
rat	O
.	O

BACKGROUND	O
:	O
The	O
most	O
striking	O
of	O
carboplatin	B-Chemical
'	O
s	O
advantages	O
(	O
CBDCA	B-Chemical
)	O
over	O
cisplatin	B-Chemical
(	O
CDDP	B-Chemical
)	O
is	O
its	O
markedly	O
reduced	O
rate	O
of	O
neurotoxic	B-Disease
effects	O
.	O

However	O
,	O
the	O
use	O
of	O
CBDCA	B-Chemical
higher	O
-	O
intensity	O
schedules	O
and	O
the	O
association	O
with	O
other	O
neurotoxic	B-Disease
drugs	O
in	O
polychemotherapy	O
may	O
cause	O
some	O
concern	O
about	O
its	O
safety	O
with	O
respect	O
to	O
peripheral	B-Disease
nervous	I-Disease
system	I-Disease
damage	I-Disease
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
Two	O
different	O
schedules	O
of	O
CBDCA	B-Chemical
administration	O
(	O
10	O
mg	O
/	O
kg	O
and	O
15	O
mg	O
/	O
kg	O
i	O
.	O
p	O
.	O
twice	O
a	O
week	O
for	O
nine	O
times	O
)	O
were	O
evaluated	O
in	O
Wistar	O
rats	O
.	O

Neurotoxicity	B-Disease
was	O
assessed	O
for	O
behavioral	O
(	O
tail	O
-	O
flick	O
test	O
)	O
,	O
neurophysiological	O
(	O
nerve	O
conduction	O
velocity	O
in	O
the	O
tail	O
nerve	O
)	O
,	O
morphological	O
,	O
morphometrical	O
and	O
analytical	O
effects	O
.	O

RESULTS	O
:	O
CBDCA	B-Chemical
administration	O
induced	O
dose	O
-	O
dependent	O
peripheral	B-Disease
neurotoxicity	I-Disease
.	O

Pain	B-Disease
perception	O
and	O
nerve	O
conduction	O
velocity	O
in	O
the	O
tail	O
were	O
significantly	O
impaired	O
,	O
particularly	O
after	O
the	O
high	O
-	O
dose	O
treatment	O
.	O

The	O
dorsal	O
root	O
ganglia	O
sensory	O
neurons	O
and	O
,	O
to	O
a	O
lesser	O
extent	O
,	O
satellite	O
cells	O
showed	O
the	O
same	O
changes	O
as	O
those	O
induced	O
by	O
CDDP	B-Chemical
,	O
mainly	O
affecting	O
the	O
nucleus	O
and	O
nucleolus	O
of	O
ganglionic	O
sensory	O
neurons	O
.	O

Moreover	O
,	O
significant	O
amounts	O
of	O
platinum	B-Chemical
were	O
detected	O
in	O
the	O
dorsal	O
root	O
ganglia	O
and	O
kidney	O
after	O
CBDCA	B-Chemical
treatment	O
.	O

CONCLUSIONS	O
:	O
CBDCA	B-Chemical
is	O
neurotoxic	B-Disease
in	O
our	O
model	O
,	O
and	O
the	O
type	O
of	O
pathological	O
changes	O
it	O
induces	O
are	O
so	O
closely	O
similar	O
to	O
those	O
caused	O
by	O
CDDP	B-Chemical
that	O
it	O
is	O
probable	O
that	O
neurotoxicity	B-Disease
is	O
induced	O
in	O
the	O
two	O
drugs	O
by	O
the	O
same	O
mechanism	O
.	O

This	O
model	O
can	O
be	O
used	O
alone	O
or	O
in	O
combination	O
with	O
other	O
drugs	O
to	O
explore	O
the	O
effect	O
of	O
CBDCA	B-Chemical
on	O
the	O
peripheral	O
nervous	O
system	O
.	O

Effects	O
of	O
cisapride	B-Chemical
on	O
symptoms	O
and	O
postcibal	O
small	O
-	O
bowel	O
motor	O
function	O
in	O
patients	O
with	O
irritable	B-Disease
bowel	I-Disease
syndrome	I-Disease
.	O

BACKGROUND	O
:	O
Irritable	B-Disease
bowel	I-Disease
syndrome	I-Disease
is	O
a	O
common	O
cause	O
of	O
abdominal	B-Disease
pain	I-Disease
and	O
discomfort	O
and	O
may	O
be	O
related	O
to	O
disordered	B-Disease
gastrointestinal	I-Disease
motility	I-Disease
.	O

Our	O
aim	O
was	O
to	O
assess	O
the	O
effects	O
of	O
long	O
-	O
term	O
treatment	O
with	O
a	O
prokinetic	O
agent	O
,	O
cisapride	B-Chemical
,	O
on	O
postprandial	O
jejunal	O
motility	O
and	O
symptoms	O
in	O
the	O
irritable	B-Disease
bowel	I-Disease
syndrome	I-Disease
(	O
IBS	B-Disease
)	O
.	O

METHODS	O
:	O
Thirty	O
-	O
eight	O
patients	O
with	O
IBS	B-Disease
(	O
constipation	B-Disease
-	O
predominant	O
,	O
n	O
=	O
17	O
;	O
diarrhoea	B-Disease
-	O
predominant	O
,	O
n	O
=	O
21	O
)	O
underwent	O
24	O
-	O
h	O
ambulatory	O
jejunal	O
manometry	O
before	O
and	O
after	O
12	O
week	O
'	O
s	O
treatment	O
[	O
cisapride	B-Chemical
,	O
5	O
mg	O
three	O
times	O
daily	O
(	O
n	O
=	O
19	O
)	O
or	O
placebo	O
(	O
n	O
=	O
19	O
)	O
]	O
.	O

RESULTS	O
:	O
In	O
diarrhoea	B-Disease
-	O
predominant	O
patients	O
significant	O
differences	O
in	O
contraction	O
characteristics	O
were	O
observed	O
between	O
the	O
cisapride	B-Chemical
and	O
placebo	O
groups	O
.	O

In	O
cisapride	B-Chemical
-	O
treated	O
diarrhoea	B-Disease
-	O
predominant	O
patients	O
the	O
mean	O
contraction	O
amplitude	O
was	O
higher	O
(	O
29	O
.	O
3	O
+	O
/	O
-	O
3	O
.	O
2	O
versus	O
24	O
.	O
9	O
+	O
/	O
-	O
2	O
.	O
6	O
mm	O
Hg	O
,	O
cisapride	B-Chemical
versus	O
placebo	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
;	O
pretreatment	O
,	O
25	O
.	O
7	O
+	O
/	O
-	O
6	O
.	O
0	O
mm	O
Hg	O
)	O
,	O
the	O
mean	O
contraction	O
duration	O
longer	O
(	O
3	O
.	O
4	O
+	O
/	O
-	O
0	O
.	O
2	O
versus	O
3	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
2	O
sec	O
,	O
cisapride	B-Chemical
versus	O
placebo	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
;	O
pretreatment	O
,	O
3	O
.	O
1	O
+	O
/	O
-	O
0	O
.	O
5	O
sec	O
)	O
,	O
and	O
the	O
mean	O
contraction	O
frequency	O
lower	O
(	O
2	O
.	O
0	O
+	O
/	O
-	O
0	O
.	O
2	O
versus	O
2	O
.	O
5	O
+	O
/	O
-	O
0	O
.	O
4	O
cont	O
.	O
/	O
min	O
,	O
cisapride	B-Chemical
versus	O
placebo	O
(	O
P	O
<	O
0	O
.	O
001	O
)	O
;	O
pretreatment	O
,	O
2	O
.	O
5	O
+	O
/	O
-	O
1	O
.	O
1	O
cont	O
.	O
/	O
min	O
]	O
than	O
patients	O
treated	O
with	O
placebo	O
.	O

No	O
significant	O
differences	O
in	O
jejunal	O
motility	O
were	O
found	O
in	O
the	O
constipation	B-Disease
-	O
predominant	O
IBS	B-Disease
group	O
.	O

Symptoms	O
were	O
assessed	O
by	O
using	O
a	O
visual	O
analogue	O
scale	O
before	O
and	O
after	O
treatment	O
.	O

Symptom	O
scores	O
relating	O
to	O
the	O
severity	O
of	O
constipation	B-Disease
were	O
lower	O
in	O
cisapride	B-Chemical
-	O
treated	O
constipation	B-Disease
-	O
predominant	O
IBS	B-Disease
patients	O
[	O
score	O
,	O
54	O
+	O
/	O
-	O
5	O
versus	O
67	O
+	O
/	O
-	O
14	O
mm	O
,	O
cisapride	B-Chemical
versus	O
placebo	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
;	O
pretreatment	O
,	O
62	O
+	O
/	O
-	O
19	O
mm	O
]	O
.	O

Diarrhoea	B-Disease
-	O
predominant	O
IBS	B-Disease
patients	O
had	O
a	O
higher	O
pain	B-Disease
score	O
after	O
cisapride	B-Chemical
therapy	O
[	O
score	O
,	O
55	O
+	O
/	O
-	O
15	O
versus	O
34	O
+	O
/	O
-	O
12	O
mm	O
,	O
cisapride	B-Chemical
versus	O
placebo	O
(	O
P	O
<	O
0	O
.	O
05	O
)	O
;	O
pretreatment	O
,	O
67	O
+	O
/	O
-	O
19	O
mm	O
]	O
.	O

CONCLUSION	O
:	O
Cisapride	B-Chemical
affects	O
jejunal	O
contraction	O
characteristics	O
and	O
some	O
symptoms	O
in	O
IBS	B-Disease
.	O

Prevention	O
of	O
breast	B-Disease
cancer	I-Disease
with	O
tamoxifen	B-Chemical
:	O
preliminary	O
findings	O
from	O
the	O
Italian	O
randomised	O
trial	O
among	O
hysterectomised	O
women	O
.	O

Italian	O
Tamoxifen	B-Chemical
Prevention	O
Study	O
.	O

BACKGROUND	O
:	O
Tamoxifen	B-Chemical
is	O
a	O
candidate	O
chemopreventive	O
agent	O
in	O
breast	B-Disease
cancer	I-Disease
,	O
although	O
the	O
drug	O
may	O
be	O
associated	O
with	O
the	O
development	O
of	O
endometrial	B-Disease
cancer	I-Disease
.	O

Therefore	O
we	O
did	O
a	O
trial	O
in	O
hysterectomised	O
women	O
of	O
tamoxifen	B-Chemical
as	O
a	O
chemopreventive	O
.	O

METHODS	O
:	O
In	O
October	O
,	O
1992	O
,	O
we	O
started	O
a	O
double	O
-	O
blind	O
placebo	O
-	O
controlled	O
,	O
randomised	O
trial	O
of	O
tamoxifen	B-Chemical
in	O
women	O
(	O
mainly	O
in	O
Italy	O
)	O
who	O
did	O
not	O
have	O
breast	B-Disease
cancer	I-Disease
and	O
who	O
had	O
had	O
a	O
hysterectomy	O
.	O

Women	O
were	O
randomised	O
to	O
receive	O
tamoxifen	B-Chemical
20	O
mg	O
per	O
day	O
or	O
placebo	O
,	O
both	O
orally	O
for	O
5	O
years	O
.	O

The	O
original	O
plan	O
was	O
to	O
follow	O
the	O
intervention	O
phase	O
by	O
5	O
years	O
'	O
follow	O
-	O
up	O
.	O

In	O
June	O
,	O
1997	O
,	O
the	O
trialists	O
and	O
the	O
data	O
-	O
monitoring	O
committee	O
decided	O
to	O
end	O
recruitment	O
primarily	O
because	O
of	O
the	O
number	O
of	O
women	O
dropping	O
out	O
of	O
the	O
study	O
.	O

Recruitment	O
ended	O
on	O
July	O
11	O
,	O
1997	O
,	O
and	O
the	O
study	O
will	O
continue	O
as	O
planned	O
.	O

The	O
primary	O
endpoints	O
are	O
the	O
occurrence	O
of	O
and	O
deaths	O
from	O
breast	B-Disease
cancer	I-Disease
.	O

This	O
preliminary	O
interim	O
analysis	O
is	O
based	O
on	O
intention	O
-	O
to	O
-	O
treat	O
.	O

FINDINGS	O
:	O
5408	O
women	O
were	O
randomised	O
;	O
participating	O
women	O
have	O
a	O
median	O
follow	O
-	O
up	O
of	O
46	O
months	O
for	O
major	O
endpoints	O
.	O

41	O
cases	O
of	O
breast	B-Disease
cancer	I-Disease
occurred	O
so	O
far	O
;	O
there	O
have	O
been	O
no	O
deaths	O
from	O
breast	B-Disease
cancer	I-Disease
.	O

There	O
is	O
no	O
difference	O
in	O
breast	B-Disease
-	I-Disease
cancer	I-Disease
frequency	O
between	O
the	O
placebo	O
(	O
22	O
cases	O
)	O
and	O
tamoxifen	B-Chemical
(	O
19	O
)	O
arms	O
.	O

There	O
is	O
a	O
statistically	O
significant	O
reduction	O
of	O
breast	B-Disease
cancer	I-Disease
among	O
women	O
receiving	O
tamoxifen	B-Chemical
who	O
also	O
used	O
hormone	O
-	O
replacement	O
therapy	O
during	O
the	O
trial	O
:	O
among	O
390	O
women	O
on	O
such	O
therapy	O
and	O
allocated	O
to	O
placebo	O
,	O
we	O
found	O
eight	O
cases	O
of	O
breast	B-Disease
cancer	I-Disease
compared	O
with	O
one	O
case	O
among	O
362	O
women	O
allocated	O
to	O
tamoxifen	B-Chemical
.	O

Compared	O
with	O
the	O
placebo	O
group	O
,	O
there	O
was	O
a	O
significantly	O
increased	O
risk	O
of	O
vascular	B-Disease
events	I-Disease
and	O
hypertriglyceridaemia	B-Disease
among	O
women	O
on	O
tamoxifen	B-Chemical
.	O

INTERPRETATION	O
:	O
Although	O
this	O
preliminary	O
analysis	O
has	O
low	O
power	O
,	O
in	O
this	O
cohort	O
of	O
women	O
at	O
low	O
-	O
to	O
-	O
normal	O
risk	O
of	O
breast	B-Disease
cancer	I-Disease
,	O
the	O
postulated	O
protective	O
effects	O
of	O
tamoxifen	B-Chemical
are	O
not	O
yet	O
apparent	O
.	O

Women	O
using	O
hormone	O
-	O
replacement	O
therapy	O
appear	O
to	O
have	O
benefited	O
from	O
use	O
of	O
tamoxifen	B-Chemical
.	O

There	O
were	O
no	O
deaths	O
from	O
breast	B-Disease
cancer	I-Disease
recorded	O
in	O
women	O
in	O
the	O
study	O
.	O

It	O
is	O
essential	O
to	O
continue	O
follow	O
-	O
up	O
to	O
quantify	O
the	O
long	O
-	O
term	O
risks	O
and	O
benefits	O
of	O
tamoxifen	B-Chemical
therapy	O
.	O

Epileptogenic	O
activity	O
of	O
folic	B-Chemical
acid	I-Chemical
after	O
drug	O
induces	O
SLE	B-Disease
(	O
folic	B-Chemical
acid	I-Chemical
and	O
epilepsy	B-Disease
)	O

OBJECTIVE	O
:	O
To	O
study	O
the	O
effect	O
of	O
folic	B-Chemical
acid	I-Chemical
-	O
containing	O
multivitamin	O
supplementation	O
in	O
epileptic	B-Disease
women	O
before	O
and	O
during	O
pregnancy	O
in	O
order	O
to	O
determine	O
the	O
rate	O
of	O
structural	O
birth	B-Disease
defects	I-Disease
and	O
epilepsy	B-Disease
-	O
related	O
side	O
effects	O
.	O

STUDY	O
DESIGN	O
:	O
First	O
a	O
randomised	O
trial	O
,	O
later	O
periconception	O
care	O
including	O
in	O
total	O
12225	O
females	O
.	O

RESULTS	O
:	O
Of	O
60	O
epileptic	B-Disease
women	O
with	O
periconceptional	O
folic	B-Chemical
acid	I-Chemical
(	O
0	O
.	O
8	O
mg	O
)	O
-	O
containing	O
multivitamin	O
supplementation	O
,	O
no	O
one	O
developed	O
epilepsy	B-Disease
-	O
related	O
side	O
effects	O
during	O
the	O
periconception	O
period	O
.	O

One	O
epileptic	B-Disease
woman	O
delivered	O
a	O
newborn	O
with	O
cleft	B-Disease
lip	I-Disease
and	I-Disease
palate	I-Disease
.	O

Another	O
patient	O
exhibited	O
with	O
a	O
cluster	O
of	O
seizures	B-Disease
after	O
the	O
periconception	O
period	O
using	O
another	O
multivitamin	O
.	O

This	O
22	O
-	O
year	O
-	O
old	O
epileptic	B-Disease
woman	O
was	O
treated	O
continuously	O
by	O
carbamazepine	B-Chemical
and	O
a	O
folic	B-Chemical
acid	I-Chemical
(	O
1	O
mg	O
)	O
-	O
containing	O
multivitamin	O
from	O
the	O
20th	O
week	O
of	O
gestation	O
.	O

She	O
developed	O
status	B-Disease
epilepticus	I-Disease
and	O
later	O
symptoms	O
of	O
systemic	B-Disease
lupus	I-Disease
erythematodes	I-Disease
.	O

Her	O
pregnancy	O
ended	O
with	O
stillbirth	B-Disease
.	O

CONCLUSIONS	O
:	O
The	O
epileptic	B-Disease
pregnant	O
patient	O
'	O
s	O
autoimmune	B-Disease
disease	I-Disease
(	O
probably	O
drug	O
-	O
induced	O
lupus	B-Disease
)	O
could	O
damage	O
the	O
blood	O
-	O
brain	O
barrier	O
,	O
therefore	O
the	O
therapeutic	O
dose	O
(	O
>	O
or	O
=	O
1	O
mg	O
)	O
of	O
folic	B-Chemical
acid	I-Chemical
triggered	O
a	O
cluster	O
of	O
seizures	B-Disease
.	O

Physiological	O
dose	O
(	O
<	O
1	O
mg	O
)	O
of	O
folic	B-Chemical
acid	I-Chemical
both	O
in	O
healthy	O
and	O
60	O
epileptic	B-Disease
women	O
,	O
all	O
without	O
any	O
autoimmune	B-Disease
disease	I-Disease
,	O
did	O
not	O
increase	O
the	O
risk	O
for	O
epileptic	B-Disease
seizures	I-Disease
.	O

Stroke	B-Disease
and	O
cocaine	B-Chemical
or	O
amphetamine	B-Chemical
use	O
.	O

The	O
association	O
of	O
cocaine	B-Chemical
and	O
amphetamine	B-Chemical
use	O
with	O
hemorrhagic	O
and	O
ischemic	B-Disease
stroke	B-Disease
is	O
based	O
almost	O
solely	O
on	O
data	O
from	O
case	O
series	O
.	O

The	O
limited	O
number	O
of	O
epidemiologic	O
studies	O
of	O
stroke	B-Disease
and	O
use	O
of	O
cocaine	B-Chemical
and	O
/	O
or	O
amphetamine	B-Chemical
have	O
been	O
done	O
in	O
settings	O
that	O
serve	O
mostly	O
the	O
poor	O
and	O
/	O
or	O
minorities	O
.	O

This	O
case	O
-	O
control	O
study	O
was	O
conducted	O
in	O
the	O
defined	O
population	O
comprising	O
members	O
of	O
Kaiser	O
Permanente	O
of	O
Northern	O
and	O
Southern	O
California	O
.	O

We	O
attempted	O
to	O
identify	O
all	O
incident	O
strokes	B-Disease
in	O
women	O
ages	O
15	O
-	O
44	O
years	O
during	O
a	O
3	O
-	O
year	O
period	O
using	O
hospital	O
admission	O
and	O
discharge	O
records	O
,	O
emergency	O
department	O
logs	O
,	O
and	O
payment	O
requests	O
for	O
out	O
-	O
of	O
-	O
plan	O
hospitalizations	O
.	O

We	O
selected	O
controls	O
,	O
matched	O
on	O
age	O
and	O
facility	O
of	O
usual	O
care	O
,	O
at	O
random	O
from	O
healthy	O
members	O
of	O
the	O
health	O
plan	O
.	O

We	O
obtained	O
information	O
in	O
face	O
-	O
to	O
-	O
face	O
interviews	O
.	O

There	O
were	O
347	O
confirmed	O
stroke	B-Disease
cases	O
and	O
1	O
,	O
021	O
controls	O
.	O

The	O
univariate	O
matched	O
odds	O
ratio	O
for	O
stroke	B-Disease
in	O
women	O
who	O
admitted	O
to	O
using	O
cocaine	B-Chemical
and	O
/	O
or	O
amphetamine	B-Chemical
was	O
8	O
.	O
5	O
(	O
95	O
%	O
confidence	O
interval	O
=	O
3	O
.	O
6	O
-	O
20	O
.	O
0	O
)	O
.	O

After	O
further	O
adjustment	O
for	O
potential	O
confounders	O
,	O
the	O
odds	O
ratio	O
in	O
women	O
who	O
reported	O
using	O
cocaine	B-Chemical
and	O
/	O
or	O
amphetamine	B-Chemical
was	O
7	O
.	O
0	O
(	O
95	O
%	O
confidence	O
interval	O
=	O
2	O
.	O
8	O
-	O
17	O
.	O
9	O
)	O
.	O

The	O
use	O
of	O
cocaine	B-Chemical
and	O
/	O
or	O
amphetamine	B-Chemical
is	O
a	O
strong	O
risk	O
factor	O
for	O
stroke	B-Disease
in	O
this	O
socioeconomically	O
heterogeneous	O
,	O
insured	O
urban	O
population	O
.	O

Acute	B-Disease
renal	I-Disease
failure	I-Disease
subsequent	O
to	O
the	O
administration	O
of	O
rifampicin	B-Chemical
.	O

A	O
follow	O
-	O
up	O
study	O
of	O
cases	O
reported	O
earlier	O
.	O

A	O
clinical	O
presentation	O
is	O
made	O
of	O
a	O
2	O
-	O
3	O
year	O
follow	O
-	O
up	O
of	O
six	O
cases	O
of	O
acute	B-Disease
renal	I-Disease
failure	I-Disease
that	O
have	O
been	O
reported	O
earlier	O
.	O

The	O
patients	O
had	O
developed	O
transient	O
renal	B-Disease
failure	I-Disease
after	O
the	O
intermittent	O
administration	O
of	O
rifampicin	B-Chemical
.	O

The	O
stage	O
of	O
olig	O
-	O
anuria	B-Disease
lasted	O
for	O
1	O
-	O
3	O
weeks	O
,	O
and	O
five	O
of	O
the	O
patients	O
were	O
treated	O
by	O
hemodialysis	O
.	O

Two	O
of	O
the	O
patients	O
died	O
due	O
to	O
unrelated	O
causes	O
during	O
the	O
follow	O
-	O
up	O
period	O
.	O

The	O
four	O
patients	O
re	O
-	O
examined	O
were	O
clinically	O
cured	O
.	O

Pathologic	O
findings	O
by	O
light	O
microscopy	O
and	O
immunofluorescence	O
at	O
biopsy	O
were	O
scarce	O
.	O

Nothing	O
abnormal	O
was	O
seen	O
by	O
electron	O
microscopy	O
in	O
two	O
of	O
the	O
cases	O
studied	O
.	O

Renal	O
function	O
was	O
normal	O
.	O

In	O
three	O
cases	O
the	O
excretion	O
at	O
131I	O
-	O
hippuran	O
renography	O
was	O
slightly	O
slowed	O
.	O

Although	O
in	O
the	O
acute	O
stage	O
the	O
renal	B-Disease
lesions	I-Disease
histologically	O
appeared	O
toxic	O
,	O
evidence	O
suggestive	O
of	O
an	O
immunological	O
mechanism	O
cannot	O
be	O
excluded	O
.	O

Chronic	O
effects	O
of	O
a	O
novel	O
synthetic	O
anthracycline	B-Chemical
derivative	O
(	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
)	O
on	O
normal	O
heart	O
and	O
doxorubicin	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
in	O
beagle	O
dogs	O
.	O

This	O
study	O
was	O
designed	O
to	O
investigate	O
the	O
chronic	O
cardiotoxic	B-Disease
potential	O
of	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
and	O
a	O
possible	O
deteriorating	O
effect	O
of	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
on	O
low	O
-	O
grade	O
cardiotoxicity	B-Disease
pre	O
-	O
induced	O
by	O
doxorubicin	B-Chemical
in	O
beagle	O
dogs	O
.	O

In	O
the	O
chronic	O
treatment	O
,	O
beagle	O
dogs	O
of	O
each	O
sex	O
were	O
given	O
intravenously	O
once	O
every	O
3	O
weeks	O
,	O
either	O
a	O
sublethal	O
dose	O
of	O
doxorubicin	B-Chemical
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
)	O
or	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
(	O
2	O
.	O
5	O
mg	O
/	O
kg	O
)	O
.	O

The	O
experiment	O
was	O
terminated	O
3	O
weeks	O
after	O
the	O
ninth	O
dosing	O
.	O

Animals	O
which	O
received	O
over	O
six	O
courses	O
of	O
doxorubicin	B-Chemical
demonstrated	O
the	O
electrocardiogram	O
(	O
ECG	O
)	O
changes	O
,	O
decrease	O
of	O
blood	O
pressure	O
and	O
high	O
-	O
grade	O
histopathological	O
cardiomyopathy	B-Disease
,	O
while	O
animals	O
which	O
were	O
terminally	O
sacrificed	O
after	O
the	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
administration	O
did	O
not	O
show	O
any	O
changes	O
in	O
ECG	O
,	O
blood	O
pressure	O
and	O
histopathological	O
examinations	O
.	O

To	O
examine	O
a	O
possibly	O
deteriorating	O
cardiotoxic	B-Disease
effect	O
of	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
,	O
low	O
-	O
grade	O
cardiomyopathy	B-Disease
was	O
induced	O
in	O
dogs	O
by	O
four	O
courses	O
of	O
doxorubicin	B-Chemical
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
)	O
.	O

Nine	O
weeks	O
after	O
pre	O
-	O
treatment	O
,	O
dogs	O
were	O
given	O
four	O
courses	O
of	O
either	O
doxorubicin	B-Chemical
(	O
1	O
.	O
5	O
mg	O
/	O
kg	O
)	O
or	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
(	O
2	O
.	O
5	O
mg	O
/	O
kg	O
)	O
once	O
every	O
3	O
weeks	O
.	O

The	O
low	O
-	O
grade	O
cardiotoxic	B-Disease
changes	O
were	O
enhanced	O
by	O
the	O
additional	O
doxorubicin	B-Chemical
treatment	O
.	O

On	O
the	O
contrary	O
,	O
the	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
treatment	O
did	O
not	O
progress	O
the	O
grade	O
of	O
cardiomyopathy	B-Disease
.	O

In	O
conclusion	O
,	O
SM	B-Chemical
-	I-Chemical
5887	I-Chemical
does	O
not	O
have	O
any	O
potential	O
of	O
chronic	O
cardiotoxicity	B-Disease
and	O
deteriorating	O
effect	O
on	O
doxorubicin	B-Chemical
-	O
induced	O
cardiotoxicity	B-Disease
in	O
dogs	O
.	O

Risk	O
for	O
valvular	B-Disease
heart	I-Disease
disease	I-Disease
among	O
users	O
of	O
fenfluramine	B-Chemical
and	O
dexfenfluramine	B-Chemical
who	O
underwent	O
echocardiography	O
before	O
use	O
of	O
medication	O
.	O

BACKGROUND	O
:	O
Because	O
uncontrolled	O
echocardiographic	O
surveys	O
suggested	O
that	O
up	O
to	O
30	O
%	O
to	O
38	O
%	O
of	O
users	O
of	O
fenfluramine	B-Chemical
and	O
dexfenfluramine	B-Chemical
had	O
valvular	B-Disease
disease	I-Disease
,	O
these	O
drugs	O
were	O
withdrawn	O
from	O
the	O
market	O
.	O

OBJECTIVE	O
:	O
To	O
determine	O
the	O
risk	O
for	O
new	O
or	O
worsening	O
valvular	B-Disease
abnormalities	I-Disease
among	O
users	O
of	O
fenfluramine	B-Chemical
or	O
dexfenfluramine	B-Chemical
who	O
underwent	O
echocardiography	O
before	O
they	O
began	O
to	O
take	O
these	O
medications	O
.	O

DESIGN	O
:	O
Cohort	O
study	O
.	O

SETTING	O
:	O
Academic	O
primary	O
care	O
practices	O
.	O

PATIENTS	O
:	O
46	O
patients	O
who	O
used	O
fenfluramine	B-Chemical
or	O
dexfenfluramine	B-Chemical
for	O
14	O
days	O
or	O
more	O
and	O
had	O
echocardiograms	O
obtained	O
before	O
therapy	O
.	O

MEASUREMENTS	O
:	O
Follow	O
-	O
up	O
echocardiography	O
.	O

The	O
primary	O
outcome	O
was	O
new	O
or	O
worsening	O
valvulopathy	B-Disease
,	O
defined	O
as	O
progression	O
of	O
either	O
aortic	B-Disease
or	I-Disease
mitral	I-Disease
regurgitation	I-Disease
by	O
at	O
least	O
one	O
degree	O
of	O
severity	O
and	O
disease	O
that	O
met	O
U	O
.	O
S	O
.	O

Food	O
and	O
Drug	O
Administration	O
criteria	O
(	O
at	O
least	O
mild	O
aortic	B-Disease
regurgitation	I-Disease
or	O
moderate	O
mitral	B-Disease
regurgitation	I-Disease
)	O
.	O

RESULTS	O
:	O
Two	O
patients	O
(	O
4	O
.	O
3	O
%	O
[	O
95	O
%	O
CI	O
,	O
0	O
.	O
6	O
%	O
to	O
14	O
.	O
8	O
%	O
]	O
)	O
receiving	O
fenfluramine	B-Chemical
-	O
phentermine	B-Chemical
developed	O
valvular	B-Disease
heart	I-Disease
disease	I-Disease
.	O

One	O
had	O
baseline	O
bicuspid	B-Disease
aortic	I-Disease
valve	I-Disease
and	O
mild	O
aortic	B-Disease
regurgitation	I-Disease
that	O
progressed	O
to	O
moderate	O
regurgitation	O
.	O

The	O
second	O
patient	O
developed	O
new	O
moderate	O
aortic	B-Disease
insufficiency	I-Disease
.	O

CONCLUSION	O
:	O
Users	O
of	O
diet	O
medications	O
are	O
at	O
risk	O
for	O
valvular	B-Disease
heart	I-Disease
disease	I-Disease
.	O

However	O
,	O
the	O
incidence	O
may	O
be	O
lower	O
than	O
that	O
reported	O
previously	O
.	O

Therapeutic	O
drug	O
monitoring	O
of	O
tobramycin	B-Chemical
:	O
once	O
-	O
daily	O
versus	O
twice	O
-	O
daily	O
dosage	O
schedules	O
.	O

OBJECTIVE	O
:	O
To	O
evaluate	O
the	O
effect	O
of	O
dosage	O
regimen	O
(	O
once	O
-	O
daily	O
vs	O
.	O
twice	O
-	O
daily	O
)	O
of	O
tobramicyn	B-Chemical
on	O
steady	O
-	O
state	O
serum	O
concentrations	O
and	O
toxicity	B-Disease
.	O

MATERIALS	O
AND	O
METHODS	O
:	O
Patients	O
undergoing	O
treatment	O
with	O
i	O
.	O
v	O
.	O
tobramycin	B-Chemical
(	O
4	O
mg	O
/	O
kg	O
/	O
day	O
)	O
were	O
randomised	O
to	O
two	O
groups	O
.	O

Group	O
OD	O
(	O
n	O
=	O
22	O
)	O
received	O
a	O
once	O
-	O
daily	O
dose	O
of	O
tobramycin	B-Chemical
and	O
group	O
TD	O
(	O
n	O
=	O
21	O
)	O
received	O
the	O
same	O
dose	O
divided	O
into	O
two	O
doses	O
daily	O
.	O

Tobramycin	B-Chemical
serum	O
concentrations	O
(	O
peak	O
and	O
trough	O
)	O
were	O
measured	O
by	O
enzyme	O
multiplied	O
immunoassay	O
.	O

The	O
renal	O
and	O
auditory	O
functions	O
of	O
the	O
patients	O
were	O
monitored	O
before	O
,	O
during	O
and	O
immediately	O
after	O
treatment	O
.	O

RESULTS	O
:	O
The	O
two	O
groups	O
were	O
comparable	O
with	O
respect	O
to	O
sex	O
,	O
age	O
,	O
body	O
weight	O
and	O
renal	O
function	O
.	O

No	O
statistically	O
significant	O
differences	O
were	O
found	O
in	O
mean	O
daily	O
dose	O
,	O
duration	O
of	O
treatment	O
,	O
or	O
cumulative	O
dose	O
.	O

Trough	O
concentrations	O
were	O
<	O
2	O
g	O
/	O
ml	O
in	O
the	O
two	O
groups	O
(	O
100	O
%	O
)	O
.	O

Peak	O
concentrations	O
were	O
>	O
6	O
microg	O
/	O
ml	O
in	O
100	O
%	O
of	O
the	O
OD	O
group	O
and	O
in	O
67	O
%	O
of	O
the	O
TD	O
group	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

Mean	O
peak	O
concentrations	O
were	O
markedly	O
different	O
:	O
11	O
.	O
00	O
+	O
/	O
-	O
2	O
.	O
89	O
microg	O
/	O
ml	O
in	O
OD	O
vs	O
.	O
6	O
.	O
53	O
+	O
/	O
-	O
1	O
.	O
45	O
microg	O
/	O
ml	O
in	O
TD	O
(	O
P	O
<	O
0	O
.	O
01	O
)	O
.	O

The	O
pharmacokinetics	O
parameters	O
were	O
:	O
Ke	O
,	O
(	O
0	O
.	O
15	O
+	O
/	O
-	O
0	O
.	O
03	O
/	O
h	O
in	O
OD	O
vs	O
.	O
0	O
.	O
24	O
+	O
/	O
-	O
0	O
.	O
06	O
/	O
h	O
in	O
TD	O
)	O
,	O
t1	O
/	O
2	O
,	O
(	O
4	O
.	O
95	O
+	O
/	O
-	O
1	O
.	O
41	O
h	O
in	O
OD	O
vs	O
.	O
3	O
.	O
07	O
+	O
/	O
-	O
0	O
.	O
71	O
h	O
in	O
TD	O
)	O
,	O
Vd	O
(	O
0	O
.	O
35	O
+	O
/	O
-	O
0	O
.	O
11	O
l	O
/	O
kg	O
in	O
OD	O
vs	O
.	O
0	O
.	O
33	O
+	O
/	O
-	O
0	O
.	O
09	O
l	O
/	O
kg	O
in	O
TD	O
)	O
,	O
Cl	O
(	O
0	O
.	O
86	O
+	O
/	O
-	O
0	O
.	O
29	O
ml	O
/	O
min	O
/	O
kg	O
in	O
OD	O
vs	O
.	O
1	O
.	O
28	O
+	O
/	O
-	O
0	O
.	O
33	O
ml	O
/	O
min	O
/	O
kg	O
in	O
TD	O
)	O
.	O

Increased	O
serum	O
creatinine	B-Chemical
was	O
observed	O
in	O
73	O
%	O
of	O
patients	O
in	O
OD	O
versus	O
57	O
%	O
of	O
patients	O
in	O
TD	O
,	O
without	O
evidence	O
of	O
nephrotoxicity	B-Disease
.	O

In	O
TD	O
group	O
,	O
three	O
patients	O
developed	O
decreased	B-Disease
auditory	I-Disease
function	I-Disease
,	O
of	O
which	O
one	O
presented	O
with	O
an	O
auditory	B-Disease
loss	I-Disease
of	O
-	O
30	O
dB	O
,	O
whereas	O
in	O
the	O
OD	O
group	O
only	O
one	O
patient	O
presented	O
decreased	B-Disease
auditory	I-Disease
function	I-Disease
.	O

CONCLUSION	O
:	O
This	O
small	O
study	O
suggests	O
that	O
a	O
once	O
-	O
daily	O
dosing	O
regimen	O
of	O
tobramycin	B-Chemical
is	O
at	O
least	O
as	O
effective	O
as	O
and	O
is	O
no	O
more	O
and	O
possibly	O
less	O
toxic	O
than	O
the	O
twice	O
-	O
daily	O
regimen	O
.	O

Using	O
a	O
single	O
-	O
dose	O
therapy	O
,	O
peak	O
concentration	O
determination	O
is	O
not	O
necessary	O
,	O
only	O
trough	O
samples	O
should	O
be	O
monitored	O
to	O
ensure	O
levels	O
below	O
2	O
microg	O
/	O
ml	O
.	O

Enhanced	O
bradycardia	B-Disease
induced	O
by	O
beta	O
-	O
adrenoceptor	O
antagonists	O
in	O
rats	O
pretreated	O
with	O
isoniazid	B-Chemical
.	O

High	O
doses	O
of	O
isoniazid	B-Chemical
increase	O
hypotension	B-Disease
induced	O
by	O
vasodilators	O
and	O
change	O
the	O
accompanying	O
reflex	O
tachycardia	B-Disease
to	O
bradycardia	B-Disease
,	O
an	O
interaction	O
attributed	O
to	O
decreased	O
synthesis	O
of	O
brain	O
gamma	B-Chemical
-	I-Chemical
aminobutyric	I-Chemical
acid	I-Chemical
(	O
GABA	B-Chemical
)	O
.	O

In	O
the	O
present	O
study	O
,	O
the	O
possible	O
enhancement	O
by	O
isoniazid	B-Chemical
of	O
bradycardia	B-Disease
induced	O
by	O
beta	O
-	O
adrenoceptor	O
antagonists	O
was	O
determined	O
in	O
rats	O
anaesthetised	O
with	O
chloralose	B-Chemical
-	O
urethane	B-Chemical
.	O

Isoniazid	B-Chemical
significantly	O
increased	O
bradycardia	B-Disease
after	O
propranolol	B-Chemical
,	O
pindolol	B-Chemical
,	O
labetalol	B-Chemical
and	O
atenolol	B-Chemical
,	O
as	O
well	O
as	O
after	O
clonidine	B-Chemical
,	O
but	O
not	O
after	O
hexamethonium	B-Chemical
or	O
carbachol	B-Chemical
.	O

Enhancement	O
was	O
not	O
observed	O
in	O
rats	O
pretreated	O
with	O
methylatropine	B-Chemical
or	O
previously	O
vagotomised	O
.	O

These	O
results	O
are	O
compatible	O
with	O
interference	O
by	O
isoniazid	B-Chemical
with	O
GABAergic	O
inhibition	O
of	O
cardiac	O
parasympathetic	O
tone	O
.	O

Such	O
interference	O
could	O
be	O
exerted	O
centrally	O
,	O
possibly	O
at	O
the	O
nucleus	O
ambiguus	O
,	O
or	O
peripherally	O
at	O
the	O
sinus	O
node	O
.	O

Structural	B-Disease
and	I-Disease
functional	I-Disease
impairment	I-Disease
of	I-Disease
mitochondria	I-Disease
in	O
adriamycin	B-Chemical
-	O
induced	O
cardiomyopathy	B-Disease
in	O
mice	O
:	O
suppression	O
of	O
cytochrome	O
c	O
oxidase	O
II	O
gene	O
expression	O
.	O

The	O
use	O
of	O
adriamycin	B-Chemical
(	O
ADR	B-Chemical
)	O
in	O
cancer	B-Disease
chemotherapy	O
has	O
been	O
limited	O
due	O
to	O
its	O
cumulative	O
cardiovascular	B-Disease
toxicity	I-Disease
.	O

Earlier	O
observations	O
that	O
ADR	B-Chemical
interacts	O
with	O
mitochondrial	O
cytochrome	O
c	O
oxidase	O
(	O
COX	O
)	O
and	O
suppresses	O
its	O
enzyme	O
activity	O
led	O
us	O
to	O
investigate	O
ADR	B-Chemical
'	O
s	O
action	O
on	O
the	O
cardiovascular	O
functions	O
and	O
heart	O
mitochondrial	O
morphology	O
in	O
Balb	O
-	O
c	O
mice	O
i	O
.	O
p	O
.	O
treated	O
with	O
ADR	B-Chemical
for	O
several	O
weeks	O
.	O

At	O
various	O
times	O
during	O
treatment	O
,	O
the	O
animals	O
were	O
assessed	O
for	O
cardiovascular	O
functions	O
by	O
electrocardiography	O
and	O
for	O
heart	O
tissue	O
damage	O
by	O
electron	O
microscopy	O
.	O

In	O
parallel	O
,	O
total	O
RNA	O
was	O
extracted	O
from	O
samples	O
of	O
dissected	O
heart	O
and	O
analyzed	O
by	O
Northern	O
blot	O
hybridization	O
to	O
determine	O
the	O
steady	O
-	O
state	O
level	O
of	O
three	O
RNA	O
transcripts	O
encoded	O
by	O
the	O
COXII	O
,	O
COXIII	O
,	O
and	O
COXIV	O
genes	O
.	O

Similarly	O
,	O
samples	O
obtained	O
from	O
the	O
liver	O
of	O
the	O
same	O
animals	O
were	O
analyzed	O
for	O
comparative	O
studies	O
.	O

Our	O
results	O
indicated	O
that	O
1	O
)	O
treatment	O
of	O
mice	O
with	O
ADR	B-Chemical
caused	O
cardiovascular	B-Disease
arrhythmias	I-Disease
characterized	O
by	O
bradycardia	B-Disease
,	O
extension	O
of	O
ventricular	O
depolarization	O
time	O
(	O
tQRS	O
)	O
,	O
and	O
failure	O
of	O
QRS	O
at	O
high	O
concentrations	O
(	O
10	O
-	O
14	O
mg	O
/	O
kg	O
body	O
weight	O
cumulative	O
dose	O
)	O
;	O
2	O
)	O
the	O
heart	O
mitochondria	O
underwent	O
swelling	B-Disease
,	O
fusion	O
,	O
dissolution	O
,	O
and	O
/	O
or	O
disruption	O
of	O
mitochondrial	O
cristae	O
after	O
several	O
weeks	O
of	O
treatment	O
.	O

Such	O
abnormalities	O
were	O
not	O
observed	O
in	O
the	O
mitochondria	O
of	O
liver	O
tissue	O
;	O
and	O
3	O
)	O
among	O
the	O
three	O
genes	O
of	O
COX	O
enzyme	O
examined	O
,	O
only	O
COXII	O
gene	O
expression	O
was	O
suppressed	O
by	O
ADR	B-Chemical
treatment	O
,	O
mainly	O
after	O
8	O
weeks	O
in	O
both	O
heart	O
and	O
liver	O
.	O

Knowing	O
that	O
heart	O
mitochondria	O
represent	O
almost	O
40	O
%	O
of	O
heart	O
muscle	O
by	O
weight	O
,	O
we	O
conclude	O
that	O
the	O
deteriorating	O
effects	O
of	O
ADR	B-Chemical
on	O
cardiovascular	O
function	O
involve	O
mitochondrial	B-Disease
structural	I-Disease
and	I-Disease
functional	I-Disease
impairment	I-Disease
.	O

Gene	O
expression	O
studies	O
in	O
isolated	O
mitochondria	O
:	O
Solanum	B
tuberosum	I
rps10	O
is	O
recognized	O
by	O
cognate	O
potato	B
but	O
not	O
by	O
the	O
transcription	O
,	O
splicing	O
and	O
editing	O
machinery	O
of	O
wheat	B
mitochondria	O

Abstract	O

The	O
complex	O
gene	O
expression	O
mechanisms	O
that	O
occur	O
in	O
plant	O
mitochondria	O
,	O
such	O
as	O
RNA	O
editing	O
and	O
splicing	O
,	O
are	O
not	O
yet	O
well	O
understood	O
.	O

RNA	O
editing	O
in	O
higher	O
plant	O
mitochondria	O
is	O
a	O
highly	O
specific	O
process	O
which	O
modifies	O
mRNA	O
sequences	O
by	O
C	O
-	O
to	O
-	O
U	O
conversions	O
.	O

It	O
has	O
been	O
suggested	O
that	O
in	O
some	O
cases	O
this	O
process	O
is	O
required	O
for	O
splicing	O
.	O

Here	O
,	O
we	O
use	O
an	O
experimental	O
model	O
based	O
on	O
the	O
introduction	O
of	O
DNA	O
into	O
isolated	O
mitochondria	O
by	O
electroporation	O
to	O
study	O
organellar	O
gene	O
expression	O
events	O
.	O

Our	O
aim	O
was	O
to	O
compare	O
processing	O
and	O
editing	O
of	O
potato	B
small	O
ribosomal	O
protein	O
10	O
gene	O
(	O
rps10	O
)	O
transcripts	O
in	O
heterologous	O
(	O
wheat	B
mitochondria	O
)	O
and	O
homologous	O
(	O
potato	B
mitochondria	O
)	O
contexts	O
.	O

rps10	O
is	O
a	O
suitable	O
model	O
because	O
it	O
contains	O
a	O
group	O
II	O
intron	O
,	O
is	O
absent	O
in	O
wheat	B
mitochondria	O
but	O
is	O
actively	O
expressed	O
in	O
potato	B
mitochondria	O
,	O
where	O
transcripts	O
are	O
spliced	O
and	O
undergo	O
five	O
C	O
-	O
to	O
-	O
U	O
editing	O
events	O
.	O

For	O
this	O
purpose	O
,	O
conditions	O
for	O
electroporating	O
isolated	O
potato	B
mitochondria	O
were	O
established	O
.	O

rps10	O
was	O
placed	O
under	O
the	O
control	O
of	O
either	O
potato	B
or	O
wheat	B
cox2	O
promoters	O
.	O

We	O
found	O
that	O
rps10	O
was	O
only	O
transcribed	O
under	O
the	O
control	O
of	O
a	O
cognate	O
promoter	O
.	O

In	O
wheat	B
mitochondria	O
,	O
rps10	O
transcripts	O
were	O
neither	O
spliced	O
nor	O
edited	O
while	O
they	O
are	O
correctly	O
processed	O
in	O
potato	B
mitochondria	O
.	O

Interestingly	O
,	O
a	O
wheat	B
editing	O
site	O
grafted	O
into	O
rps10	O
was	O
not	O
recognized	O
by	O
wheat	B
mitochondria	O
but	O
was	O
correctly	O
edited	O
in	O
potato	B
mitochondria	O
.	O

Taken	O
together	O
,	O
these	O
results	O
suggest	O
that	O
editing	O
might	O
occur	O
only	O
when	O
the	O
transcripts	O
are	O
engaged	O
in	O
processing	O
and	O
that	O
they	O
would	O
not	O
be	O
available	O
to	O
editing	O
factors	O
outside	O
of	O
a	O
putative	O
RNA	O
maturation	O
machinery	O
complex	O
.	O

INTRODUCTION	O

Gene	O
expression	O
in	O
plant	O
mitochondria	O
is	O
a	O
complex	O
process	O
involving	O
multiple	O
steps	O
such	O
as	O
transcription	O
,	O
cis	O
-	O
and	O
trans	O
-	O
splicing	O
,	O
RNA	O
trimming	O
and	O
RNA	O
editing	O
on	O
the	O
way	O
to	O
translation	O
(	O
1	O
)	O
.	O

RNA	O
editing	O
has	O
been	O
found	O
in	O
a	O
variety	O
of	O
organisms	O
and	O
occurs	O
through	O
different	O
mechanisms	O
such	O
as	O
insertion	O
or	O
deletion	O
of	O
nucleotides	O
,	O
or	O
base	O
conversions	O
[	O
for	O
details	O
see	O
reference	O
(	O
2	O
)	O
]	O
.	O

In	O
higher	O
plant	O
organelles	O
,	O
RNA	O
editing	O
is	O
an	O
important	O
post	O
-	O
transcriptional	O
event	O
characterized	O
by	O
C	O
-	O
to	O
-	O
U	O
changes	O
via	O
a	O
deamination	O
mechanism	O
(	O
3	O
-	O
5	O
)	O
.	O

In	O
Arabidopsis	B
thaliana	I
456	O
C	O
-	O
to	O
-	O
U	O
editing	O
events	O
have	O
been	O
described	O
(	O
6	O
)	O
.	O

RNA	O
editing	O
occurs	O
mostly	O
in	O
the	O
coding	O
regions	O
which	O
alter	O
the	O
identity	O
of	O
the	O
encoded	O
amino	O
acid	O
,	O
but	O
some	O
editing	O
events	O
occur	O
in	O
highly	O
structured	O
regions	O
of	O
introns	O
(	O
7	O
,	O
8	O
)	O
.	O

Like	O
other	O
maturation	O
processes	O
,	O
RNA	O
editing	O
is	O
an	O
essential	O
post	O
-	O
transcriptional	O
event	O
in	O
plant	O
mitochondrial	O
gene	O
expression	O
(	O
9	O
-	O
11	O
)	O
required	O
for	O
the	O
synthesis	O
of	O
functional	O
proteins	O
(	O
12	O
,	O
13	O
)	O
.	O

The	O
introduction	O
of	O
foreign	O
DNA	O
into	O
isolated	O
mitochondria	O
is	O
a	O
novel	O
experimental	O
model	O
which	O
has	O
provided	O
important	O
information	O
on	O
RNA	O
editing	O
and	O
RNA	O
splicing	O
enabling	O
the	O
use	O
of	O
a	O
site	O
-	O
directed	O
mutagenesis	O
approach	O
(	O
14	O
,	O
15	O
)	O
.	O

Using	O
a	O
cognate	O
cox2	O
chimeric	O
gene	O
construct	O
,	O
the	O
cis	O
-	O
recognition	O
elements	O
required	O
for	O
plant	O
mitochondria	O
RNA	O
editing	O
have	O
been	O
determined	O
(	O
16	O
,	O
17	O
)	O
.	O

Using	O
the	O
same	O
approach	O
,	O
Staudinger	O
and	O
Kempken	O
(	O
18	O
)	O
have	O
reported	O
that	O
transcripts	O
from	O
A	B
.	I
thaliana	I
cox2	O
,	O
but	O
not	O
Sorghum	B
bicolor	I
atp6	O
,	O
are	O
edited	O
when	O
the	O
genes	O
are	O
introduced	O
into	O
maize	B
mitochondria	O
.	O

Interestingly	O
,	O
higher	O
plant	O
mitochondrial	O
genomes	O
differ	O
in	O
their	O
gene	O
contents	O
due	O
to	O
an	O
evolutionary	O
information	O
transfer	O
from	O
the	O
organelle	O
to	O
the	O
nucleus	O
(	O
19	O
)	O
.	O

Of	O
particular	O
interest	O
is	O
the	O
situation	O
of	O
the	O
small	O
ribosomal	O
protein	O
10	O
gene	O
(	O
rps10	O
)	O
,	O
a	O
group	O
II	O
intron	O
-	O
bearing	O
gene	O
which	O
is	O
encoded	O
in	O
Solanum	B
tuberosum	I
mitochondrial	O
DNA	O
but	O
is	O
absent	O
from	O
the	O
wheat	B
mitochondrial	O
genome	O
(	O
20	O
)	O
.	O

Higher	O
plant	O
mitochondria	O
contain	O
group	O
II	O
introns	O
either	O
in	O
cis	O
-	O
or	O
trans	O
-	O
configuration	O
(	O
1	O
)	O
which	O
can	O
be	O
folded	O
in	O
a	O
characteristic	O
secondary	O
structure	O
(	O
21	O
)	O
.	O

Intron	O
removal	O
in	O
plant	O
mitochondrial	O
mRNAs	O
is	O
not	O
well	O
documented	O
because	O
such	O
introns	O
are	O
unable	O
to	O
self	O
-	O
splice	O
.	O

Previously	O
,	O
we	O
described	O
that	O
electroporated	O
cox2	O
constructs	O
were	O
a	O
good	O
model	O
for	O
the	O
study	O
of	O
the	O
splicing	O
process	O
.	O

Using	O
this	O
model	O
,	O
we	O
found	O
that	O
editing	O
and	O
splicing	O
of	O
cox2	O
transcripts	O
were	O
not	O
linked	O
in	O
wheat	B
mitochondria	O
(	O
15	O
)	O
.	O

To	O
challenge	O
the	O
ability	O
of	O
mitochondrial	O
gene	O
expression	O
machinery	O
to	O
recognize	O
genetic	O
information	O
which	O
has	O
been	O
lost	O
during	O
evolution	O
,	O
we	O
decided	O
to	O
introduce	O
the	O
S	B
.	I
tuberosum	I
non	O
-	O
cognate	O
rps10	O
gene	O
into	O
wheat	B
mitochondria	O
.	O

Five	O
C	O
residues	O
are	O
changed	O
to	O
U	O
in	O
potato	B
mitochondria	O
rps10	O
transcripts	O
by	O
editing	O
.	O

Two	O
of	O
them	O
have	O
been	O
postulated	O
as	O
being	O
necessary	O
for	O
acquisition	O
of	O
a	O
proper	O
secondary	O
and	O
/	O
or	O
tertiary	O
structure	O
for	O
splicing	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
it	O
was	O
necessary	O
to	O
set	O
up	O
the	O
conditions	O
for	O
electroporation	O
of	O
foreign	O
DNA	O
into	O
S	B
.	I
tuberosum	I
mitochondria	O
.	O

Here	O
,	O
we	O
show	O
that	O
a	O
potato	B
rps10	O
construct	O
is	O
transcribed	O
when	O
introduced	O
into	O
wheat	B
mitochondria	O
,	O
but	O
transcripts	O
are	O
not	O
recognized	O
by	O
the	O
post	O
-	O
transcriptional	O
processing	O
machinery	O
.	O

In	O
contrast	O
,	O
a	O
rps10	O
construct	O
is	O
correctly	O
expressed	O
and	O
processed	O
in	O
cognate	O
potato	B
mitochondria	O
.	O

Moreover	O
,	O
we	O
present	O
evidence	O
that	O
transcript	O
editing	O
might	O
be	O
linked	O
to	O
overall	O
RNA	O
processing	O
.	O

This	O
is	O
the	O
first	O
report	O
on	O
DNA	O
electroporation	O
into	O
potato	B
mitochondria	O
.	O

MATERIALS	O
AND	O
METHODS	O

Plasmids	O

All	O
plasmids	O
used	O
in	O
this	O
study	O
are	O
based	O
on	O
the	O
previously	O
described	O
pCOXII	O
vector	O
(	O
14	O
)	O
.	O

An	O
NsiI	O
restriction	O
site	O
was	O
introduced	O
at	O
the	O
initiation	O
codon	O
of	O
the	O
wheat	B
cox2	O
open	O
reading	O
frame	O
(	O
ORF	O
)	O
.	O

Then	O
,	O
NsiI	O
was	O
used	O
in	O
combination	O
with	O
a	O
SpeI	O
restriction	O
site	O
present	O
in	O
the	O
original	O
vector	O
after	O
the	O
stop	O
codon	O
,	O
to	O
produce	O
the	O
chimeric	O
vectors	O
.	O

S	B
.	I
tuberosum	I
cox2	O
gene	O
,	O
including	O
a	O
727	O
bp	O
non	O
-	O
coding	O
upstream	O
region	O
,	O
was	O
isolated	O
by	O
PCR	O
from	O
total	O
DNA	O
using	O
the	O
primer	O
A	O
designed	O
from	O
partial	O
sequences	O
reported	O
by	O
L	O
o	O
essl	O
et	O
al	O
.	O

(	O
22	O
)	O
,	O
accession	O
no	O
.	O

AF096321	O
,	O
containing	O
the	O
KpnI	O
restriction	O
sequence	O
,	O
and	O
primer	O
B	O
derived	O
from	O
Triticum	B
timopheevi	I
cox2	O
(	O
AF336134	O
)	O
.	O

A	O
fragment	O
of	O
2888	O
bp	O
was	O
obtained	O
and	O
cloned	O
on	O
pGEM	O
-	O
T	O
vector	O
.	O

The	O
complete	O
sequence	O
of	O
the	O
S	B
.	I
tuberosum	I
cox2	O
was	O
determined	O
(	O
accession	O
no	O
.	O
DQ18064	O
)	O
.	O

To	O
generate	O
the	O
plasmid	O
pCOXIISt	O
containing	O
the	O
S	B
.	I
tuberosum	I
cox2	O
gene	O
,	O
a	O
KpnI	O
/	O
SpeI	O
fragment	O
containing	O
the	O
727	O
bp	O
upstream	O
region	O
and	O
the	O
complete	O
coding	O
region	O
was	O
used	O
to	O
replace	O
the	O
wheat	B
gene	O
from	O
pCOXII	O
.	O

As	O
for	O
pCOXII	O
,	O
a	O
NsiI	O
site	O
was	O
inserted	O
at	O
the	O
ATG	O
start	O
codon	O
and	O
a	O
23	O
bp	O
fragment	O
was	O
inserted	O
at	O
position	O
-	O
20	O
.	O

This	O
23	O
bp	O
insertion	O
provides	O
a	O
specific	O
sequence	O
allowing	O
isolation	O
of	O
potato	B
cox2	O
transcripts	O
originating	O
from	O
the	O
introduced	O
DNA	O
by	O
RT	O
-	O
PCR	O
.	O

The	O
chimeric	O
wheat	B
/	O
potato	B
cox2	O
gene	O
was	O
constructed	O
by	O
replacing	O
727	O
bp	O
KpnI	O
/	O
NsiI	O
promoter	O
sequence	O
from	O
pCOXIISt	O
with	O
the	O
880	O
bp	O
wheat	B
upstream	O
region	O
from	O
pCOXII	O
.	O

The	O
vectors	O
pRPS10W	O
and	O
the	O
pRPS10St	O
derivative	O
,	O
containing	O
wheat	B
and	O
potato	B
cox2	O
promoters	O
,	O
respectively	O
,	O
were	O
constructed	O
by	O
inserting	O
the	O
1178	O
bp	O
rps10	O
sequence	O
containing	O
two	O
exons	O
separated	O
by	O
a	O
777	O
bp	O
intronic	O
sequence	O
[	O
(	O
23	O
)	O
,	O
accession	O
no	O
.	O
X74826	O
]	O
.	O

The	O
coding	O
region	O
was	O
isolated	O
from	O
total	O
S	B
.	I
tuberosum	I
DNA	O
by	O
PCR	O
using	O
primers	O
D1	O
and	O
D2	O
containing	O
the	O
restriction	O
sites	O
NsiI	O
and	O
SpeI	O
,	O
respectively	O
.	O

The	O
fragment	O
NsiI	O
/	O
SpeI	O
was	O
purified	O
and	O
cloned	O
into	O
pCOXII	O
and	O
pCOXIISt	O
,	O
replacing	O
the	O
respective	O
cox2	O
coding	O
regions	O
.	O

Since	O
all	O
vectors	O
used	O
here	O
were	O
based	O
on	O
pCOXII	O
,	O
they	O
contain	O
the	O
downstream	O
region	O
from	O
the	O
wheat	B
cob	O
gene	O
(	O
Ir	O
-	O
cob	O
)	O
(	O
accession	O
no	O
.	O
AF337547	O
)	O
(	O
14	O
)	O
.	O

This	O
sequence	O
,	O
combined	O
with	O
the	O
23	O
bp	O
upstream	O
insert	O
sequence	O
served	O
to	O
distinguish	O
,	O
using	O
primers	O
1a	O
and	O
1b	O
,	O
foreign	O
from	O
endogenous	O
transcripts	O
.	O

All	O
mutants	O
were	O
obtained	O
using	O
QuickChange	O
(	O
R	O
)	O
Site	O
-	O
Directed	O
Mutagenesis	O
kit	O
(	O
Stratagene	O
)	O
.	O

PCR	O
product	O
purifications	O
were	O
carried	O
out	O
with	O
the	O
Wizard	O
(	O
R	O
)	O
Clean	O
-	O
Up	O
System	O
(	O
Promega	O
)	O
.	O

PCR	O
primers	O
used	O

Oligonucleotides	O
sequences	O
are	O
in	O
5	O
'	O
to	O
3	O
'	O
orientation	O
.	O

(	O
1a	O
)	O
,	O
GCGGTGCAGTCATACAGATC	O
;	O
(	O
1b	O
)	O
,	O
TATCCAGATTTGGTACCAAA	O
;	O
(	O
2a	O
)	O
,	O
GCAGTCATACAGATCTGCCA	O
;	O
(	O
2b	O
)	O
,	O
AGATTTGGTACCAAACCCGG	O
;	O
(	O
A	O
)	O
,	O
TATAGGTACCTCTCAGGTGT	O
;	O
(	O
B	O
)	O
,	O
TATAACTAGTTTAAGCTTCC	O
;	O
(	O
D1	O
)	O
,	O
TATAATGCATAGACAAAGGA	O
;	O
(	O
D2	O
)	O
,	O
TATAACTAGTTCAGGAAAGG	O
.	O

Restriction	O
sites	O
are	O
underlined	O
.	O

Mutagenesis	O
primers	O
(	O
only	O
sense	O
primers	O
in	O
5	O
'	O
-	O
3	O
'	O
orientation	O
are	O
indicated	O
)	O

Single	O
C2	O
,	O
C3	O
and	O
C2	O
+	O
C3	O
double	O
mutant	O
plasmids	O
were	O
constructed	O
with	O
primers	O
(	O
C2	O
)	O
AAGAAGTTCTTTTGGTTAAA	O
and	O
(	O
C3	O
)	O
CGCCGTGCGACTTGGAGGAC	O
.	O

NsiI	O
-	O
pCOXII	O
:	O
GGAAATCCAATGCATCTTCG	O
and	O
NsiI	O
-	O
pCOXIISt	O
:	O
CCAAACCAAATGCATGTTCT	O
.	O

Construct	O
pCOXIISt	O
containing	O
a	O
23	O
nt	O
insertion	O
in	O
the	O
promoter	O
region	O
,	O
was	O
carried	O
out	O
into	O
two	O
consecutive	O
insertions	O
using	O
primers	O
:	O
TGGGGGGAGCAGAGCAGTGC	O
and	O
GCAGTGCGGTGCAGTCATAC	O
.	O

For	O
constructs	O
MA	O
and	O
MAB	O
containing	O
the	O
wheat	B
cox2	O
C259	O
editing	O
site	O
,	O
two	O
consecutive	O
insertions	O
were	O
carried	O
out	O
using	O
primers	O
:	O
GGAAGATTGGATTACTATCG	O
and	O
TACTATCGAAATTATTCGGA	O
.	O

For	O
ME6	O
and	O
ME6b	O
constructs	O
,	O
primers	O
CCGCGAGGAATCAACTACTA	O
and	O
CAACTACTATCGAAATTATT	O
were	O
used	O
.	O

Inserted	O
nucleotides	O
are	O
underlined	O
and	O
the	O
modified	O
residues	O
are	O
indicated	O
in	O
bold	O
.	O

Mitochondria	O
purification	O

S	B
.	I
tuberosum	I
cv	O
.	O

Rosevalt	O
tubers	O
and	O
T	B
.	I
aestivum	I
var	I
Fortal	I
seeds	O
were	O
used	O
.	O

Potato	B
mitochondria	O
were	O
prepared	O
from	O
2	O
kg	O
of	O
tubers	O
in	O
batches	O
of	O
200	O
g	O
with	O
200	O
ml	O
of	O
a	O
homogenization	O
buffer	O
containing	O
0	O
.	O
4	O
M	O
mannitol	O
,	O
25	O
mM	O
MOPS	O
(	O
pH	O
7	O
.	O
8	O
)	O
,	O
1	O
mM	O
EGTA	O
,	O
8	O
mM	O
cysteine	O
and	O
1	O
mg	O
/	O
ml	O
fatty	O
acid	O
-	O
free	O
BSA	O
.	O

Homogenization	O
was	O
carried	O
out	O
for	O
15	O
s	O
in	O
a	O
Waring	O
blendor	O
at	O
full	O
speed	O
.	O

Homogenate	O
was	O
centrifuged	O
in	O
a	O
Sorvall	O
GSA	O
rotor	O
at	O
1500	O
g	O
for	O
10	O
min	O
at	O
4	O
degrees	O
C	O
.	O

Supernatant	O
was	O
centrifuged	O
in	O
a	O
GSA	O
rotor	O
at	O
12	O
000	O
g	O
for	O
15	O
min	O
.	O

The	O
mitochondrial	O
pellet	O
was	O
resuspended	O
in	O
50	O
ml	O
of	O
homogenization	O
buffer	O
and	O
centrifuged	O
at	O
1500	O
g	O
.	O

The	O
supernatant	O
was	O
centrifuged	O
in	O
a	O
Sorvall	O
SS	O
-	O
34	O
rotor	O
at	O
15	O
000	O
g	O
for	O
10	O
min	O
,	O
the	O
pellet	O
was	O
resuspended	O
in	O
12	O
ml	O
of	O
homogenization	O
buffer	O
and	O
mitochondria	O
were	O
purified	O
by	O
centrifugation	O
on	O
a	O
sucrose	O
gradient	O
essentially	O
as	O
described	O
for	O
wheat	B
embryo	O
mitochondria	O
(	O
14	O
)	O
.	O

Electroporation	O

Electrotransfer	O
experiments	O
were	O
carried	O
out	O
with	O
1	O
mg	O
of	O
purified	O
wheat	B
embryo	O
or	O
potato	B
tuber	O
mitochondria	O
in	O
50	O
micro	O
l	O
of	O
0	O
.	O
33	O
M	O
sucrose	O
and	O
1	O
micro	O
g	O
of	O
recombinant	O
plasmid	O
as	O
described	O
(	O
14	O
)	O
.	O

The	O
electroporated	O
mitochondria	O
were	O
incubated	O
for	O
18	O
h	O
at	O
25	O
degrees	O
C	O
,	O
then	O
recovered	O
by	O
centrifugation	O
in	O
a	O
Sigma	O
N	O
degrees	O
12024	O
rotor	O
(	O
Sigma	O
1K15	O
refrigerated	O
centrifuge	O
)	O
at	O
15	O
000	O
g	O
for	O
15	O
min	O
at	O
4	O
degrees	O
C	O
.	O

In	O
the	O
case	O
of	O
potato	B
mitochondria	O
the	O
incubation	O
mixture	O
was	O
supplemented	O
with	O
1	O
mg	O
/	O
ml	O
of	O
fatty	O
acid	O
-	O
free	O
BSA	O
.	O

RNA	O
was	O
purified	O
with	O
200	O
micro	O
l	O
of	O
TRIzol	O
(	O
TM	O
)	O
reagent	O
(	O
Gibco	O
-	O
BRL	O
)	O
according	O
to	O
the	O
supplier	O
'	O
s	O
protocol	O
.	O

DNAse	O
I	O
protection	O
assay	O
and	O
DNA	O
purification	O

After	O
electroporation	O
and	O
centrifugation	O
,	O
the	O
mitochondrial	O
pellet	O
was	O
resuspended	O
in	O
100	O
micro	O
l	O
of	O
buffer	O
[	O
10	O
mM	O
Tris	O
-	O
HCl	O
(	O
pH	O
7	O
.	O
5	O
)	O
,	O
2	O
mM	O
magnesium	O
acetate	O
and	O
0	O
.	O
33	O
M	O
sucrose	O
]	O
containing	O
60	O
U	O
of	O
DNase	O
I	O
(	O
Gibco	O
-	O
BRL	O
)	O
and	O
incubated	O
for	O
1	O
h	O
at	O
room	O
temperature	O
.	O

The	O
DNase	O
reaction	O
was	O
stopped	O
by	O
adding	O
4	O
micro	O
l	O
of	O
0	O
.	O
5	O
M	O
EDTA	O
and	O
then	O
heating	O
for	O
10	O
min	O
at	O
65	O
degrees	O
C	O
.	O

Mitochondria	O
were	O
incubated	O
with	O
100	O
micro	O
g	O
of	O
Proteinase	O
K	O
(	O
Merck	O
)	O
for	O
4	O
h	O
at	O
37	O
degrees	O
C	O
.	O

One	O
microliter	O
of	O
20	O
%	O
SDS	O
was	O
added	O
to	O
achieve	O
mitochondrial	O
lysis	O
and	O
the	O
DNA	O
was	O
extracted	O
with	O
phenol	O
/	O
chloroform	O
,	O
precipitated	O
with	O
0	O
.	O
1	O
vol	O
of	O
3	O
M	O
Sodium	O
Acetate	O
(	O
pH	O
5	O
.	O
2	O
)	O
,	O
3	O
vol	O
of	O
100	O
%	O
ethanol	O
and	O
100	O
ng	O
of	O
carrier	O
yeast	B
tRNA	O
and	O
left	O
overnight	O
at	O
-	O
20	O
degrees	O
C	O
.	O

After	O
centrifugation	O
,	O
the	O
DNA	O
pellet	O
was	O
resuspended	O
in	O
TE	O
buffer	O
[	O
10	O
mM	O
Tris	O
-	O
HCl	O
(	O
pH	O
8	O
)	O
and	O
1	O
mM	O
EDTA	O
]	O
.	O

RT	O
-	O
PCR	O

RNA	O
(	O
1	O
micro	O
g	O
)	O
was	O
treated	O
with	O
2	O
U	O
of	O
Amplification	O
grade	O
DNase	O
I	O
(	O
Promega	O
)	O
.	O

cDNA	O
synthesis	O
was	O
performed	O
with	O
200	O
U	O
of	O
Superscript	O
II	O
RT	O
using	O
100	O
ng	O
of	O
random	O
hexamers	O
.	O

The	O
PCR	O
were	O
performed	O
with	O
primers	O
1a	O
and	O
1b	O
using	O
Advantage	O
(	O
R	O
)	O
2	O
Polymerase	O
Mix	O
(	O
Clontech	O
)	O
as	O
follows	O
:	O
95	O
degrees	O
C	O
,	O
1	O
min	O
;	O
5	O
cycles	O
at	O
95	O
degrees	O
C	O
for	O
30	O
s	O
and	O
68	O
degrees	O
C	O
for	O
1	O
min	O
;	O
30	O
cycles	O
at	O
95	O
degrees	O
C	O
for	O
30	O
s	O
,	O
58	O
degrees	O
C	O
for	O
30	O
s	O
and	O
68	O
degrees	O
C	O
for	O
30	O
s	O
,	O
and	O
finally	O
68	O
degrees	O
C	O
for	O
1	O
min	O
.	O

Primers	O
2a	O
and	O
2b	O
were	O
used	O
for	O
nested	O
PCR	O
from	O
1	O
micro	O
l	O
of	O
the	O
first	O
PCR	O
.	O

No	O
RT	O
-	O
PCR	O
amplification	O
products	O
were	O
obtained	O
with	O
RNA	O
from	O
non	O
-	O
electroporated	O
mitochondria	O
.	O

DNA	O
sequencing	O

Sequence	O
analyses	O
were	O
performed	O
directly	O
on	O
the	O
RT	O
-	O
PCR	O
product	O
using	O
an	O
automatic	O
DNA	O
sequencing	O
equipment	O
with	O
the	O
BigDye	O
(	O
R	O
)	O
Terminator	O
Cycle	O
Sequencing	O
Kit	O
(	O
Applied	O
Biosystem	O
)	O
.	O

RESULTS	O

S	B
.	I
tuberosum	I
rps10	O
transcripts	O
are	O
not	O
processed	O
in	O
wheat	B
mitochondria	O

The	O
S	B
.	I
tuberosum	I
rps10	O
construct	O
under	O
control	O
of	O
a	O
wheat	B
cox2	O
promoter	O
(	O
Figure	O
1A	O
)	O
was	O
incorporated	O
into	O
purified	O
wheat	B
mitochondria	O
by	O
electroporation	O
as	O
indicated	O
in	O
Materials	O
and	O
Methods	O
.	O

After	O
electroporation	O
and	O
incubation	O
in	O
expression	O
medium	O
,	O
mitochondrial	O
RNA	O
was	O
extracted	O
and	O
analysed	O
by	O
RT	O
-	O
PCR	O
.	O

The	O
primers	O
used	O
allowed	O
detection	O
of	O
the	O
transcripts	O
generated	O
by	O
the	O
constructs	O
introduced	O
and	O
excluded	O
any	O
product	O
from	O
endogenous	O
cox2	O
(	O
or	O
rps10	O
in	O
the	O
potato	B
system	O
)	O
.	O

Two	O
bands	O
of	O
1204	O
and	O
427	O
bp	O
were	O
expected	O
from	O
precursor	O
and	O
mature	O
rps10	O
mRNAs	O
,	O
respectively	O
.	O

Only	O
precursor	O
rps10	O
molecules	O
were	O
detected	O
(	O
Figure	O
1B	O
)	O
.	O

As	O
a	O
control	O
,	O
a	O
cognate	O
cox2	O
construct	O
(	O
16	O
)	O
was	O
used	O
.	O

In	O
this	O
case	O
,	O
the	O
2048	O
and	O
827	O
bp	O
RT	O
-	O
PCR	O
bands	O
representing	O
the	O
precursor	O
and	O
spliced	O
cox2	O
products	O
,	O
respectively	O
were	O
observed	O
(	O
Figure	O
1B	O
)	O
.	O

In	O
all	O
cases	O
,	O
the	O
PCR	O
bands	O
actually	O
represent	O
transcription	O
products	O
since	O
when	O
PCR	O
was	O
performed	O
without	O
the	O
RT	O
step	O
we	O
observed	O
no	O
amplification	O
products	O
.	O

Previously	O
,	O
five	O
C	O
residues	O
,	O
two	O
in	O
exon	O
1	O
,	O
one	O
in	O
the	O
intron	O
and	O
two	O
in	O
exon	O
2	O
have	O
been	O
reported	O
to	O
be	O
changed	O
to	O
U	O
by	O
editing	O
in	O
potato	B
mitochondria	O
(	O
23	O
)	O
.	O

To	O
determine	O
if	O
the	O
non	O
-	O
cognate	O
transcript	O
could	O
be	O
recognized	O
by	O
the	O
wheat	B
RNA	O
editing	O
machinery	O
,	O
the	O
1204	O
bp	O
RT	O
-	O
PCR	O
product	O
was	O
sequenced	O
.	O

While	O
wheat	B
cox2	O
editing	O
sites	O
were	O
correctly	O
edited	O
in	O
control	O
as	O
expected	O
(	O
Figure	O
1C	O
,	O
only	O
site	O
C77	O
is	O
shown	O
)	O
,	O
all	O
five	O
editable	O
residues	O
in	O
potato	B
rps10	O
transcript	O
remain	O
unchanged	O
.	O

cox2	O
C77	O
editing	O
sites	O
are	O
identical	O
in	O
potato	B
and	O
wheat	B
.	O

Failure	O
of	O
rps10	O
transcript	O
splicing	O
in	O
wheat	B
mitochondria	O
is	O
not	O
linked	O
to	O
the	O
absence	O
of	O
editing	O

It	O
has	O
been	O
suggested	O
that	O
residues	O
C2	O
and	O
C3	O
participate	O
in	O
the	O
secondary	O
structure	O
of	O
the	O
intron	O
necessary	O
for	O
splicing	O
(	O
23	O
)	O
.	O

A	O
possible	O
explanation	O
to	O
the	O
failure	O
observed	O
in	O
precursor	O
rps10	O
splicing	O
could	O
be	O
that	O
the	O
absence	O
of	O
edition	O
of	O
C2	O
and	O
C3	O
prevent	O
the	O
intron	O
from	O
organizing	O
itself	O
in	O
a	O
catalytically	O
competent	O
conformation	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
single	O
C2	O
and	O
C3	O
mutants	O
and	O
a	O
C2	O
+	O
C3	O
double	O
mutant	O
were	O
constructed	O
by	O
changing	O
the	O
C	O
residues	O
to	O
T	O
.	O

Neither	O
single	O
nor	O
double	O
mutants	O
were	O
able	O
to	O
undergo	O
splicing	O
(	O
Figure	O
2	O
)	O
.	O

Electroporation	O
of	O
S	B
.	I
tuberosum	I
mitochondria	O

Since	O
two	O
important	O
post	O
-	O
transcriptional	O
processes	O
,	O
RNA	O
editing	O
and	O
splicing	O
,	O
were	O
inoperative	O
when	O
S	B
.	I
tuberosum	I
rps10	O
was	O
expressed	O
in	O
wheat	B
mitochondria	O
,	O
we	O
decided	O
to	O
verify	O
whether	O
the	O
negative	O
results	O
were	O
inherent	O
to	O
the	O
rps10	O
chimeric	O
constructs	O
or	O
due	O
to	O
the	O
lack	O
of	O
trans	O
-	O
recognition	O
elements	O
in	O
wheat	B
mitochondria	O
.	O

For	O
this	O
purpose	O
,	O
it	O
was	O
necessary	O
to	O
set	O
up	O
an	O
electroporation	O
protocol	O
adapted	O
to	O
S	B
.	I
tuberosum	I
mitochondria	O
.	O

Purified	O
organelles	O
were	O
prepared	O
from	O
potato	B
tubers	O
as	O
indicated	O
in	O
Materials	O
and	O
Methods	O
.	O

Electric	O
pulses	O
in	O
the	O
range	O
between	O
8	O
and	O
20	O
kV	O
were	O
performed	O
.	O

Internalization	O
of	O
exogenous	O
DNA	O
was	O
measured	O
by	O
DNAse	O
protection	O
assays	O
(	O
14	O
)	O
.	O

Potato	B
mitochondria	O
show	O
a	O
broad	O
range	O
response	O
with	O
a	O
maximum	O
around	O
13	O
kV	O
(	O
Figure	O
3	O
)	O
.	O

This	O
voltage	O
setting	O
was	O
therefore	O
used	O
for	O
further	O
experiments	O
.	O

S	B
.	I
tuberosum	I
mitochondria	O
does	O
not	O
recognize	O
the	O
wheat	B
cox2	O
promoter	O

To	O
ascertain	O
the	O
ability	O
of	O
electroporated	O
mitochondria	O
to	O
perform	O
expression	O
of	O
the	O
exogenous	O
gene	O
construct	O
,	O
we	O
used	O
a	O
plasmid	O
containing	O
the	O
potato	B
cox2	O
gene	O
controlled	O
either	O
by	O
T	B
.	I
aestivum	I
or	O
S	B
.	I
tuberosum	I
promoters	O
.	O

As	O
shown	O
in	O
Figure	O
4	O
,	O
the	O
construct	O
containing	O
the	O
wheat	B
or	O
potato	B
promoters	O
was	O
transcribed	O
only	O
in	O
cognate	O
mitochondria	O
.	O

In	O
potato	B
,	O
the	O
mature	O
product	O
is	O
barely	O
detectable	O
.	O

In	O
contrast	O
to	O
wheat	B
mitochondria	O
,	O
the	O
821	O
nt	O
mature	O
transcript	O
was	O
only	O
detected	O
when	O
the	O
electroporated	O
potato	B
mitochondria	O
were	O
incubated	O
in	O
the	O
presence	O
of	O
fatty	O
acid	O
-	O
free	O
BSA	O
.	O

A	O
cognate	O
rps10	O
construct	O
is	O
correctly	O
expressed	O
,	O
edited	O
and	O
processed	O
in	O
potato	B
mitochondria	O

The	O
construct	O
expressing	O
potato	B
rps10	O
under	O
the	O
control	O
of	O
potato	B
cox2	O
promoter	O
was	O
introduced	O
into	O
S	B
.	I
tuberosum	I
isolated	O
mitochondria	O
.	O

After	O
incubation	O
,	O
the	O
precursor	O
and	O
mature	O
transcripts	O
were	O
amplified	O
by	O
RT	O
-	O
PCR	O
(	O
Figure	O
5A	O
)	O
and	O
sequenced	O
.	O

As	O
shown	O
in	O
Figure	O
5B	O
,	O
the	O
four	O
editing	O
sites	O
C1	O
,	O
C2	O
,	O
C4	O
and	O
C5	O
,	O
described	O
previously	O
in	O
endogenous	O
transcripts	O
,	O
were	O
found	O
edited	O
in	O
mature	O
mRNA	O
.	O

The	O
presence	O
of	O
spliced	O
molecules	O
containing	O
unedited	O
residues	O
(	O
Figure	O
5B	O
)	O
indicates	O
that	O
rps10	O
transcripts	O
could	O
be	O
spliced	O
before	O
editing	O
.	O

To	O
confirm	O
this	O
observation	O
,	O
the	O
PCR	O
product	O
was	O
cloned	O
and	O
sequenced	O
.	O

One	O
half	O
of	O
the	O
individual	O
clones	O
were	O
found	O
edited	O
at	O
sites	O
C1	O
and	O
C2	O
;	O
65	O
%	O
were	O
edited	O
at	O
site	O
C4	O
and	O
25	O
%	O
were	O
edited	O
at	O
site	O
C5	O
.	O

A	O
cognate	O
editing	O
site	O
in	O
a	O
non	O
-	O
native	O
context	O
is	O
not	O
recognized	O
by	O
wheat	B
mitochondria	O
but	O
is	O
recognized	O
in	O
heterologous	O
mitochondria	O

To	O
test	O
whether	O
wheat	B
mitochondria	O
are	O
able	O
to	O
edit	O
a	O
cognate	O
site	O
when	O
placed	O
in	O
the	O
context	O
of	O
a	O
potato	B
transcript	O
,	O
we	O
introduced	O
the	O
C259	O
-	O
16	O
/	O
+	O
6	O
region	O
from	O
wheat	B
cox2	O
into	O
potato	B
rps10	O
exon	O
1	O
or	O
intron	O
(	O
Figure	O
6A	O
,	O
construct	O
MA	O
and	O
ME6	O
,	O
respectively	O
)	O
.	O

As	O
reported	O
previously	O
,	O
the	O
23	O
nt	O
region	O
forming	O
the	O
C259	O
editing	O
site	O
from	O
wheat	B
cox2	O
was	O
efficiently	O
edited	O
when	O
grafted	O
into	O
a	O
different	O
context	O
in	O
a	O
wheat	B
transcript	O
(	O
17	O
)	O
.	O

Wild	O
-	O
type	O
rps10	O
(	O
pRPS10W	O
)	O
and	O
the	O
MA	O
and	O
ME6	O
mutants	O
were	O
expressed	O
in	O
wheat	B
mitochondria	O
but	O
no	O
splicing	O
was	O
observed	O
(	O
Figure	O
6B	O
)	O
.	O

Unexpectedly	O
,	O
wheat	B
mitochondria	O
appear	O
to	O
be	O
unable	O
to	O
edit	O
the	O
cognate	O
C259	O
site	O
when	O
the	O
-	O
16	O
/	O
+	O
6	O
region	O
is	O
located	O
on	O
a	O
potato	B
rps10	O
precursor	O
.	O

The	O
control	O
CM	O
construct	O
,	O
containing	O
the	O
C259	O
site	O
grafted	O
in	O
a	O
different	O
context	O
but	O
in	O
its	O
own	O
cox2	O
gene	O
,	O
was	O
expressed	O
,	O
spliced	O
and	O
edited	O
as	O
expected	O
[	O
(	O
17	O
)	O
,	O
Figure	O
6B	O
and	O
D	O
]	O
.	O

To	O
compare	O
the	O
editing	O
status	O
of	O
RNAs	O
at	O
the	O
same	O
stage	O
of	O
processing	O
,	O
the	O
editing	O
status	O
of	O
the	O
inserted	O
C259	O
site	O
in	O
precursor	O
cox2	O
transcripts	O
is	O
shown	O
(	O
Figure	O
6D	O
)	O
.	O

The	O
analogous	O
MAb	O
and	O
ME6b	O
constructs	O
,	O
containing	O
the	O
S	B
.	I
tuberosum	I
cox2	O
promoter	O
and	O
the	O
C259	O
region	O
inserted	O
into	O
rps10	O
exon	O
1	O
and	O
intron	O
were	O
used	O
to	O
electroporate	O
potato	B
mitochondria	O
.	O

As	O
shown	O
in	O
Figure	O
6C	O
,	O
MAb	O
and	O
ME6b	O
were	O
expressed	O
and	O
spliced	O
at	O
the	O
same	O
level	O
as	O
the	O
control	O
in	O
the	O
homologous	O
context	O
,	O
indicating	O
that	O
insertion	O
does	O
not	O
affect	O
the	O
splicing	O
process	O
.	O

Interestingly	O
,	O
while	O
C259	O
insertion	O
was	O
not	O
recognized	O
in	O
wheat	B
mitochondria	O
(	O
Figure	O
6D	O
)	O
,	O
the	O
potato	B
RNA	O
editing	O
machinery	O
edited	O
the	O
inserted	O
C259	O
region	O
(	O
Figure	O
6E	O
)	O
.	O

The	O
C259	O
region	O
inserted	O
in	O
the	O
rps10	O
intron	O
(	O
construct	O
ME6b	O
)	O
was	O
also	O
edited	O
,	O
although	O
at	O
a	O
very	O
low	O
level	O
,	O
showing	O
that	O
editing	O
may	O
precede	O
intron	O
removal	O
(	O
not	O
shown	O
)	O
.	O

DISCUSSION	O

Plant	O
mitochondria	O
undergo	O
complex	O
expression	O
mechanisms	O
which	O
are	O
poorly	O
understood	O
.	O

Most	O
studies	O
are	O
based	O
on	O
analysis	O
of	O
in	O
vivo	O
mature	O
or	O
intermediate	O
gene	O
products	O
giving	O
clues	O
on	O
possible	O
mechanisms	O
and	O
suggesting	O
pathways	O
operating	O
in	O
gene	O
expression	O
.	O

Direct	O
tests	O
using	O
in	O
vitro	O
approaches	O
have	O
been	O
fruitful	O
(	O
4	O
,	O
5	O
,	O
24	O
)	O
,	O
but	O
are	O
hampered	O
by	O
the	O
difficulty	O
of	O
obtaining	O
active	O
mitochondrial	O
extracts	O
.	O

Previously	O
,	O
we	O
devised	O
an	O
experimental	O
model	O
based	O
on	O
electroporation	O
of	O
isolated	O
mitochondria	O
that	O
allows	O
us	O
to	O
test	O
gene	O
expression	O
of	O
wild	O
-	O
type	O
and	O
mutant	O
genes	O
.	O

This	O
approach	O
has	O
been	O
very	O
useful	O
in	O
elucidating	O
the	O
process	O
of	O
RNA	O
maturation	O
in	O
plant	O
mitochondria	O
,	O
in	O
particular	O
splicing	O
and	O
editing	O
(	O
14	O
,	O
15	O
)	O
.	O

The	O
aim	O
of	O
this	O
work	O
was	O
to	O
analyse	O
different	O
gene	O
expression	O
events	O
when	O
a	O
foreign	O
gene	O
was	O
expressed	O
in	O
a	O
heterologous	O
context	O
.	O

rps10	O
was	O
chosen	O
precisely	O
because	O
this	O
genetic	O
information	O
is	O
lacking	O
in	O
wheat	B
mitochondria	O
but	O
is	O
active	O
in	O
potato	B
mitochondria	O
(	O
20	O
,	O
23	O
,	O
25	O
)	O
.	O

Moreover	O
,	O
rps10	O
transcripts	O
undergo	O
five	O
C	O
-	O
to	O
-	O
U	O
editing	O
events	O
in	O
potato	B
mitochondria	O
and	O
rps10	O
contains	O
an	O
intron	O
,	O
thus	O
facilitating	O
the	O
analysis	O
of	O
post	O
-	O
transcriptional	O
processing	O
.	O

To	O
best	O
evaluate	O
the	O
expression	O
of	O
rps10	O
in	O
the	O
non	O
-	O
cognate	O
mitochondria	O
,	O
it	O
was	O
necessary	O
to	O
set	O
up	O
electroporation	O
conditions	O
for	O
introducing	O
foreign	O
DNA	O
into	O
S	B
.	I
tuberosum	I
mitochondria	O
.	O

Potato	B
tuber	O
mitochondria	O
were	O
able	O
to	O
incorporate	O
DNA	O
essentially	O
under	O
the	O
same	O
conditions	O
described	O
for	O
wheat	B
embryo	O
organelles	O
(	O
14	O
)	O
,	O
except	O
that	O
the	O
optimal	O
voltage	O
range	O
was	O
larger	O
.	O

A	O
major	O
difference	O
to	O
wheat	B
was	O
that	O
isolated	O
potato	B
mitochondria	O
were	O
viable	O
for	O
3	O
-	O
4	O
h	O
as	O
measured	O
by	O
oxygen	O
consumption	O
(	O
data	O
not	O
shown	O
)	O
.	O

Thus	O
,	O
to	O
observe	O
transcript	O
maturation	O
after	O
electroporation	O
the	O
incubation	O
mixture	O
needed	O
to	O
be	O
supplemented	O
with	O
fatty	O
acid	O
-	O
free	O
BSA	O
(	O
see	O
Figure	O
4	O
)	O
.	O

This	O
behaviour	O
probably	O
reflects	O
the	O
uncoupling	O
of	O
oxidative	O
phosphorylation	O
by	O
fatty	O
acids	O
during	O
incubation	O
of	O
potato	B
mitochondria	O
(	O
26	O
)	O
.	O

In	O
fact	O
,	O
previously	O
we	O
found	O
that	O
proper	O
gene	O
expression	O
in	O
isolated	O
mitochondria	O
requires	O
a	O
functional	O
organelle	O
able	O
to	O
generate	O
ATP	O
from	O
ADP	O
and	O
succinate	O
(	O
14	O
)	O
.	O

An	O
interesting	O
observation	O
was	O
that	O
neither	O
the	O
wheat	B
nor	O
the	O
potato	B
cox2	O
promoters	O
were	O
recognized	O
in	O
a	O
heterologous	O
context	O
(	O
Figure	O
4A	O
and	O
B	O
)	O
.	O

This	O
situation	O
might	O
by	O
explained	O
by	O
the	O
fact	O
that	O
potato	B
and	O
wheat	B
promoter	O
sequences	O
have	O
no	O
recognizable	O
homologous	O
motifs	O
.	O

Plant	O
mitochondria	O
promoters	O
are	O
characterized	O
by	O
a	O
conserved	O
core	O
CRTA	O
sequence	O
with	O
differences	O
in	O
the	O
extent	O
and	O
the	O
composition	O
of	O
sequences	O
around	O
the	O
consensus	O
motif	O
(	O
27	O
,	O
28	O
)	O
.	O

While	O
the	O
transcription	O
initiation	O
site	O
in	O
wheat	B
mitochondria	O
is	O
located	O
at	O
position	O
-	O
170	O
(	O
29	O
)	O
,	O
the	O
potato	B
promoter	O
has	O
not	O
yet	O
been	O
described	O
.	O

Transcription	O
may	O
be	O
initiated	O
at	O
numerous	O
sites	O
suggesting	O
a	O
relaxed	O
promoter	O
recognition	O
by	O
the	O
transcription	O
machinery	O
(	O
28	O
)	O
.	O

However	O
,	O
the	O
lack	O
of	O
crossed	O
recognition	O
of	O
cox2	O
promoters	O
in	O
wheat	B
and	O
potato	B
is	O
not	O
a	O
general	O
situation	O
since	O
the	O
A	B
.	I
thaliana	I
cox2	O
gene	O
is	O
expressed	O
and	O
spliced	O
when	O
introduced	O
into	O
maize	B
mitochondria	O
,	O
indicating	O
that	O
the	O
Arabidopsis	B
gene	O
shares	O
some	O
signals	O
with	O
maize	B
cox2	O
promoter	O
that	O
are	O
sufficient	O
for	O
transcription	O
(	O
18	O
)	O
.	O

The	O
sites	O
required	O
for	O
transcript	O
initiation	O
have	O
been	O
recently	O
described	O
in	O
A	B
.	I
thaliana	I
mitochondrial	O
genes	O
(	O
28	O
)	O
.	O

Three	O
regions	O
were	O
described	O
as	O
important	O
for	O
transcription	O
initiation	O
.	O

We	O
found	O
no	O
such	O
homologous	O
sequences	O
in	O
the	O
potato	B
cox2	O
upstream	O
region	O
indicating	O
that	O
the	O
two	O
dicot	O
promoters	O
do	O
not	O
have	O
the	O
same	O
origin	O
.	O

This	O
in	O
turn	O
may	O
reflect	O
the	O
natural	O
history	O
of	O
this	O
particular	O
mitochondrial	O
gene	O
evolving	O
in	O
its	O
own	O
context	O
.	O

It	O
should	O
be	O
mentioned	O
that	O
the	O
presence	O
of	O
a	O
conserved	O
sequence	O
is	O
not	O
sufficient	O
for	O
expression	O
since	O
a	O
region	O
that	O
acts	O
as	O
promoter	O
in	O
Arabidopsis	B
,	O
potato	B
and	O
Oenothera	O
is	O
inactive	O
in	O
vivo	O
in	O
pea	B
(	O
30	O
)	O
.	O

Further	O
studies	O
will	O
be	O
required	O
to	O
understand	O
the	O
transcriptional	O
events	O
in	O
plant	O
mitochondria	O
.	O

Electroporation	O
of	O
foreign	O
DNA	O
into	O
isolated	O
mitochondria	O
provides	O
an	O
interesting	O
functional	O
model	O
,	O
complementary	O
to	O
in	O
vitro	O
transcription	O
assay	O
,	O
for	O
answering	O
these	O
questions	O
.	O

The	O
potato	B
rps10	O
gene	O
controlled	O
by	O
a	O
T	B
.	I
aestivum	I
promoter	O
(	O
Figure	O
1A	O
)	O
was	O
transcribed	O
as	O
a	O
1204	O
nt	O
precursor	O
in	O
wheat	B
mitochondria	O
,	O
but	O
no	O
traces	O
of	O
mature	O
RNA	O
were	O
observed	O
.	O

Moreover	O
,	O
the	O
five	O
C	O
residues	O
reported	O
as	O
RNA	O
editing	O
targets	O
in	O
vivo	O
(	O
23	O
)	O
remain	O
unchanged	O
,	O
indicating	O
that	O
rps10	O
transcript	O
was	O
not	O
recognized	O
by	O
the	O
wheat	B
splicing	O
and	O
editing	O
machinery	O
.	O

A	O
control	O
using	O
the	O
cognate	O
cox2	O
construct	O
demonstrates	O
that	O
electroporated	O
organelles	O
were	O
competent	O
for	O
splicing	O
and	O
editing	O
(	O
Figure	O
1B	O
and	O
C	O
)	O
.	O

Some	O
editing	O
events	O
occur	O
in	O
highly	O
structured	O
domains	O
of	O
introns	O
.	O

Because	O
in	O
some	O
cases	O
,	O
editing	O
corrects	O
A	O
-	O
C	O
mispairing	O
improving	O
conformation	O
of	O
the	O
intron	O
,	O
it	O
has	O
been	O
proposed	O
that	O
the	O
C	O
-	O
to	O
-	O
U	O
change	O
might	O
be	O
necessary	O
for	O
efficient	O
splicing	O
(	O
8	O
,	O
9	O
,	O
23	O
,	O
31	O
)	O
.	O

Based	O
on	O
the	O
canonical	O
structure	O
of	O
group	O
II	O
mitochondrial	O
introns	O
(	O
21	O
)	O
,	O
two	O
editing	O
sites	O
,	O
C2	O
located	O
at	O
the	O
Intron	O
Binding	O
Site	O
2	O
(	O
IBS2	O
)	O
and	O
C3	O
located	O
in	O
the	O
intron	O
,	O
nine	O
residues	O
downstream	O
from	O
the	O
end	O
of	O
exon	O
1	O
in	O
S	B
.	I
tuberosum	I
rps10	O
are	O
of	O
particular	O
interest	O
.	O

It	O
has	O
been	O
predicted	O
that	O
both	O
edited	O
residues	O
participate	O
in	O
base	O
-	O
pair	O
interactions	O
in	O
the	O
putative	O
secondary	O
structure	O
.	O

Of	O
particular	O
interest	O
is	O
the	O
site	O
C3	O
located	O
in	O
intron	O
domain	O
I	O
(	O
23	O
)	O
.	O

This	O
position	O
may	O
be	O
crucial	O
for	O
splicing	O
as	O
inferred	O
from	O
mutants	O
of	O
a	O
yeast	B
mitochondrial	O
intron	O
(	O
32	O
)	O
.	O

We	O
addressed	O
this	O
question	O
by	O
introducing	O
rps10	O
mutant	O
genes	O
presenting	O
C2	O
,	O
C3	O
or	O
both	O
positions	O
in	O
the	O
edited	O
form	O
into	O
mitochondria	O
.	O

As	O
shown	O
in	O
Figure	O
2	O
,	O
transcription	O
was	O
as	O
efficient	O
as	O
for	O
the	O
cognate	O
cox2	O
construct	O
but	O
neither	O
wild	O
-	O
type	O
rps10	O
nor	O
the	O
C	O
-	O
U	O
mutants	O
underwent	O
splicing	O
.	O

These	O
results	O
clearly	O
demonstrate	O
that	O
C2	O
and	O
C3	O
editing	O
is	O
not	O
sufficient	O
for	O
splicing	O
of	O
rps10	O
precursor	O
in	O
wheat	B
mitochondria	O
and	O
lead	O
us	O
to	O
conclude	O
that	O
splicing	O
failure	O
is	O
probably	O
linked	O
to	O
the	O
lack	O
of	O
trans	O
-	O
recognition	O
elements	O
.	O

One	O
may	O
speculate	O
that	O
these	O
trans	O
-	O
acting	O
factors	O
,	O
for	O
instance	O
nuclear	O
-	O
encoded	O
maturases	O
,	O
were	O
lost	O
after	O
rps10	O
was	O
transferred	O
to	O
the	O
nucleus	O
in	O
monocots	O
(	O
20	O
,	O
25	O
)	O
.	O

The	O
C	O
-	O
to	O
-	O
U	O
mutants	O
were	O
also	O
tested	O
in	O
potato	B
mitochondria	O
;	O
no	O
significant	O
differences	O
were	O
detected	O
in	O
splicing	O
efficiency	O
when	O
compared	O
to	O
the	O
unedited	O
construct	O
(	O
D	O
.	O
Choury	O
,	O
unpublished	O
data	O
)	O
.	O

It	O
should	O
be	O
noted	O
that	O
the	O
lack	O
of	O
splicing	O
in	O
wheat	B
mitochondria	O
is	O
not	O
a	O
general	O
feature	O
of	O
potato	B
introns	O
,	O
since	O
the	O
potato	B
cox2	O
intron	O
is	O
removed	O
efficiently	O
(	O
Figure	O
4B	O
)	O
.	O

This	O
is	O
consistent	O
with	O
the	O
hypothesis	O
that	O
potato	B
and	O
wheat	B
mitochondria	O
have	O
similar	O
trans	O
-	O
acting	O
factors	O
for	O
cox2	O
intron	O
removal	O
.	O

A	O
possible	O
link	O
between	O
intron	O
removal	O
and	O
editing	O
has	O
been	O
proposed	O
for	O
splicing	O
of	O
nad1e	O
and	O
nad5III	O
trans	O
-	O
introns	O
where	O
domain	O
six	O
may	O
require	O
editing	O
to	O
be	O
structured	O
in	O
a	O
catalytic	O
competent	O
secondary	O
conformation	O
(	O
8	O
)	O
.	O

In	O
rice	B
,	O
failure	O
of	O
RNA	O
maturation	O
and	O
editing	O
has	O
been	O
correlated	O
with	O
cytoplasmic	O
male	O
sterile	O
phenotype	O
.	O

In	O
this	O
model	O
,	O
the	O
absence	O
of	O
the	O
nuclear	O
gene	O
Rf	O
-	O
1	O
affects	O
B	O
-	O
atp6	O
RNA	O
cleavage	O
and	O
editing	O
(	O
33	O
)	O
.	O

In	O
organello	O
studies	O
have	O
shown	O
that	O
S	B
.	I
bicolor	I
atp6	O
-	O
1	O
gene	O
was	O
transcribed	O
but	O
not	O
edited	O
when	O
introduced	O
into	O
maize	B
mitochondria	O
(	O
18	O
)	O
.	O

However	O
,	O
partially	O
edited	O
molecules	O
were	O
detected	O
in	O
sorghum	B
-	O
maize	B
atp6	O
chimeric	O
transcripts	O
when	O
they	O
included	O
the	O
maize	B
atp6	O
5	O
'	O
-	O
untranslated	O
sequence	O
,	O
suggesting	O
that	O
the	O
5	O
'	O
non	O
-	O
coding	O
region	O
provides	O
a	O
structural	O
motif	O
or	O
binding	O
site	O
for	O
a	O
transcript	O
-	O
specific	O
editing	O
factor	O
(	O
34	O
)	O
.	O

Unfortunately	O
,	O
no	O
data	O
on	O
atp6	O
processing	O
was	O
reported	O
to	O
determine	O
whether	O
this	O
region	O
is	O
directly	O
involved	O
in	O
editing	O
or	O
some	O
other	O
maturation	O
event	O
.	O

Since	O
wheat	B
mitochondria	O
do	O
not	O
have	O
rps10	O
encoded	O
in	O
the	O
mitochondrial	O
genome	O
(	O
20	O
)	O
,	O
it	O
was	O
interesting	O
to	O
test	O
whether	O
wheat	B
mitochondria	O
were	O
able	O
to	O
recognize	O
editing	O
sites	O
which	O
had	O
been	O
lost	O
during	O
evolution	O
.	O

In	O
other	O
words	O
,	O
whether	O
the	O
mitochondrial	O
trans	O
-	O
recognition	O
elements	O
are	O
specific	O
for	O
each	O
site	O
or	O
whether	O
they	O
are	O
operating	O
on	O
a	O
subset	O
of	O
editing	O
sites	O
.	O

This	O
question	O
is	O
important	O
since	O
to	O
date	O
the	O
factors	O
responsible	O
for	O
RNA	O
editing	O
in	O
plant	O
mitochondria	O
remain	O
unknown	O
.	O

Solving	O
this	O
issue	O
may	O
provide	O
clues	O
to	O
uncover	O
such	O
factors	O
.	O

As	O
described	O
above	O
,	O
the	O
rps10	O
transcript	O
was	O
not	O
processed	O
in	O
wheat	B
but	O
it	O
was	O
correctly	O
spliced	O
in	O
cognate	O
mitochondria	O
(	O
Figure	O
5A	O
)	O
.	O

Indeed	O
,	O
the	O
mature	O
transcript	O
had	O
identical	O
exon1	O
and	O
exon2	O
junction	O
as	O
found	O
in	O
endogenous	O
rps10	O
mRNA	O
(	O
data	O
not	O
shown	O
)	O
.	O

More	O
importantly	O
,	O
all	O
editing	O
sites	O
,	O
C1	O
,	O
C2	O
,	O
C4	O
and	O
C5	O
were	O
significantly	O
converted	O
to	O
Us	O
(	O
Figure	O
5B	O
)	O
.	O

The	O
fact	O
that	O
the	O
four	O
editing	O
sites	O
were	O
found	O
either	O
edited	O
or	O
unedited	O
in	O
spliced	O
rps10	O
mRNA	O
is	O
an	O
indication	O
that	O
editing	O
does	O
not	O
precede	O
splicing	O
as	O
was	O
previously	O
found	O
for	O
cox2	O
in	O
wheat	B
(	O
15	O
)	O
.	O

It	O
may	O
be	O
argued	O
that	O
the	O
absence	O
of	O
splicing	O
precluded	O
editing	O
.	O

This	O
possibility	O
can	O
be	O
discarded	O
since	O
potato	B
rps10	O
precursor	O
mRNA	O
was	O
found	O
to	O
be	O
edited	O
in	O
vivo	O
(	O
23	O
)	O
.	O

These	O
data	O
clearly	O
show	O
that	O
splicing	O
is	O
not	O
required	O
for	O
rps10	O
editing	O
,	O
similar	O
to	O
previous	O
findings	O
for	O
cox2	O
mRNA	O
and	O
also	O
in	O
cox2	O
mutant	O
derivatives	O
unable	O
to	O
remove	O
the	O
intron	O
(	O
15	O
)	O
.	O

This	O
led	O
us	O
to	O
postulate	O
that	O
the	O
inability	O
of	O
wheat	B
mitochondria	O
to	O
recognize	O
rps10	O
editing	O
sites	O
is	O
likely	O
due	O
to	O
the	O
fact	O
that	O
wheat	B
mitochondria	O
have	O
lost	O
the	O
editing	O
trans	O
-	O
recognition	O
elements	O
which	O
become	O
dispensable	O
after	O
transfer	O
of	O
rps10	O
to	O
the	O
nucleus	O
.	O

To	O
test	O
this	O
possibility	O
,	O
rps10	O
chimeric	O
plasmids	O
containing	O
editing	O
site	O
C259	O
from	O
wheat	B
cox2	O
inserted	O
either	O
in	O
exon1	O
or	O
the	O
intron	O
were	O
constructed	O
.	O

Site	O
C259	O
is	O
formed	O
by	O
23	O
nt	O
corresponding	O
to	O
the	O
-	O
16	O
/	O
+	O
6	O
sequence	O
embedding	O
the	O
target	O
C	O
.	O

Previously	O
we	O
found	O
that	O
this	O
small	O
region	O
could	O
be	O
recognized	O
by	O
the	O
RNA	O
editing	O
machinery	O
when	O
placed	O
outside	O
of	O
its	O
natural	O
context	O
(	O
16	O
,	O
17	O
)	O
.	O

The	O
wheat	B
C259	O
editing	O
site	O
in	O
the	O
chimeric	O
construct	O
was	O
correctly	O
edited	O
by	O
potato	B
mitochondria	O
.	O

This	O
result	O
is	O
not	O
unexpected	O
since	O
the	O
corresponding	O
region	O
in	O
endogenous	O
potato	B
cox2	O
mRNA	O
,	O
which	O
presents	O
two	O
differences	O
at	O
positions	O
-	O
3	O
(	O
C	O
instead	O
of	O
A	O
)	O
and	O
-	O
7	O
(	O
G	O
instead	O
of	O
A	O
)	O
,	O
is	O
edited	O
.	O

Furthermore	O
,	O
these	O
positions	O
were	O
not	O
crucial	O
for	O
editing	O
of	O
C259	O
(	O
17	O
)	O
.	O

Surprisingly	O
,	O
the	O
C259	O
editing	O
site	O
grafted	O
in	O
rps10	O
was	O
not	O
recognized	O
by	O
the	O
wheat	B
editing	O
machinery	O
.	O

We	O
cannot	O
exclude	O
the	O
possibility	O
that	O
editing	O
efficiency	O
in	O
precursor	O
molecules	O
is	O
very	O
low	O
and	O
so	O
is	O
undetectable	O
when	O
sequencing	O
RT	O
-	O
PCR	O
products	O
representing	O
a	O
pool	O
of	O
transcripts	O
.	O

However	O
,	O
analysis	O
of	O
the	O
same	O
region	O
in	O
cox2	O
precursors	O
indicates	O
that	O
this	O
was	O
not	O
the	O
case	O
since	O
significant	O
C	O
-	O
to	O
-	O
U	O
conversion	O
was	O
observed	O
(	O
Figure	O
6D	O
)	O
.	O

These	O
observations	O
lead	O
us	O
to	O
postulate	O
that	O
editing	O
is	O
occurring	O
only	O
when	O
the	O
transcript	O
is	O
engaged	O
in	O
post	O
-	O
transcriptional	O
processing	O
,	O
suggesting	O
that	O
rps10	O
transcripts	O
are	O
not	O
available	O
to	O
editing	O
factors	O
independently	O
of	O
the	O
RNA	O
maturation	O
machinery	O
.	O

The	O
fact	O
that	O
the	O
wheat	B
editing	O
site	O
C259	O
inserted	O
in	O
chimeric	O
rps10	O
transcripts	O
was	O
not	O
recognized	O
by	O
wheat	B
mitochondria	O
is	O
a	O
strong	O
argument	O
for	O
this	O
hypothesis	O
.	O

One	O
might	O
speculate	O
that	O
in	O
plant	O
mitochondria	O
,	O
transcripts	O
have	O
to	O
be	O
engaged	O
in	O
a	O
kind	O
of	O
multiprotein	O
processing	O
complex	O
.	O

A	O
failure	O
to	O
be	O
recognized	O
at	O
some	O
early	O
stage	O
will	O
lead	O
to	O
their	O
accumulation	O
as	O
unmodified	O
precursors	O
.	O

Rap1p	O
and	O
other	O
transcriptional	O
regulators	O
can	O
function	O
in	O
defining	O
distinct	O
domains	O
of	O
gene	O
expression	O

Abstract	O

Barrier	O
elements	O
that	O
are	O
able	O
to	O
block	O
the	O
propagation	O
of	O
transcriptional	O
silencing	O
in	O
yeast	B
are	O
functionally	O
similar	O
to	O
chromatin	O
boundary	O
/	O
insulator	O
elements	O
in	O
metazoans	O
that	O
delimit	O
functional	O
chromosomal	O
domains	O
.	O

We	O
show	O
that	O
the	O
upstream	O
activating	O
sequences	O
of	O
many	O
highly	O
expressed	O
ribosome	O
protein	O
genes	O
and	O
glycolytic	O
genes	O
exhibit	O
barrier	O
activity	O
.	O

Analyses	O
of	O
these	O
barriers	O
indicate	O
that	O
binding	O
sites	O
for	O
transcriptional	O
regulators	O
Rap1p	O
,	O
Abf1p	O
,	O
Reb1p	O
,	O
Adr1p	O
and	O
Gcn4p	O
may	O
participate	O
in	O
barrier	O
function	O
.	O

We	O
also	O
present	O
evidence	O
suggesting	O
that	O
Rap1p	O
is	O
directly	O
involved	O
in	O
barrier	O
activity	O
,	O
and	O
its	O
barrier	O
function	O
correlates	O
with	O
local	O
changes	O
in	O
chromatin	O
structure	O
.	O

We	O
further	O
demonstrate	O
that	O
tethering	O
the	O
transcriptional	O
activation	O
domain	O
of	O
Rap1p	O
to	O
DNA	O
is	O
sufficient	O
to	O
recapitulate	O
barrier	O
activity	O
.	O

Moreover	O
,	O
targeting	O
the	O
activation	O
domain	O
of	O
Adr1p	O
or	O
Gcn4p	O
also	O
establishes	O
a	O
barrier	O
to	O
silencing	O
.	O

These	O
results	O
support	O
the	O
notion	O
that	O
transcriptional	O
regulators	O
could	O
also	O
participate	O
in	O
delimiting	O
functional	O
domains	O
in	O
the	O
genome	O
.	O

INTRODUCTION	O

The	O
eukaryotic	O
genome	O
is	O
organized	O
into	O
discrete	O
functional	O
domains	O
in	O
which	O
gene	O
expression	O
is	O
either	O
permitted	O
or	O
repressed	O
.	O

Domains	O
permissive	O
for	O
gene	O
expression	O
are	O
usually	O
defined	O
as	O
euchromatin	O
or	O
active	O
chromatin	O
,	O
and	O
domains	O
that	O
repress	O
gene	O
expression	O
heterochromatin	O
or	O
silent	O
chromatin	O
.	O

The	O
HML	O
and	O
HMR	O
loci	O
in	O
Saccharomyces	B
cerevisiae	I
are	O
silent	O
chromatin	O
domains	O
(	O
1	O
)	O
.	O

Compared	O
to	O
active	O
chromatin	O
,	O
silent	O
chromatin	O
is	O
more	O
compact	O
and	O
its	O
histone	O
components	O
are	O
hypoacetylated	O
(	O
2	O
)	O
.	O

The	O
SIR	O
complex	O
consisting	O
of	O
Sir2p	O
through	O
Sir4p	O
is	O
an	O
integral	O
part	O
of	O
yeast	B
silent	O
chromatin	O
.	O

Sir3p	O
and	O
Sir4p	O
interact	O
with	O
the	O
N	O
-	O
terminal	O
tails	O
of	O
histones	O
H3	O
and	O
H4	O
providing	O
the	O
structural	O
basis	O
of	O
silent	O
chromatin	O
(	O
1	O
)	O
.	O

Sir2p	O
was	O
recently	O
found	O
to	O
be	O
an	O
NAD	O
-	O
dependent	O
histone	O
deacetylase	O
and	O
was	O
suggested	O
to	O
be	O
responsible	O
for	O
histone	O
hypoacetylation	O
in	O
silent	O
chromatin	O
(	O
3	O
)	O
.	O

Silent	O
chromatin	O
is	O
initiated	O
at	O
small	O
cis	O
-	O
acting	O
DNA	O
elements	O
known	O
as	O
the	O
E	O
and	O
I	O
silencers	O
flanking	O
each	O
of	O
the	O
HM	O
loci	O
(	O
4	O
)	O
.	O

Increasing	O
evidence	O
indicates	O
that	O
histone	O
deacetylation	O
is	O
key	O
to	O
the	O
propagation	O
of	O
silent	O
chromatin	O
(	O
4	O
)	O
.	O

In	O
vertebrates	O
and	O
fission	O
yeast	B
,	O
spread	O
of	O
silent	O
chromatin	O
involves	O
a	O
chain	O
of	O
events	O
of	O
histone	O
H3	O
deacetylation	O
-	O
-	O
>	O
H3	O
methylation	O
-	O
-	O
>	O
binding	O
of	O
methylated	O
H3	O
by	O
HP1	O
(	O
heterochromatin	O
protein	O
1	O
)	O
or	O
swi6	O
(	O
4	O
)	O
.	O

In	O
S	B
.	I
cerevisiae	I
,	O
there	O
is	O
evidence	O
that	O
Sir3p	O
(	O
hence	O
the	O
SIR	O
complex	O
)	O
has	O
much	O
higher	O
affinity	O
to	O
unacetylated	O
histone	O
H4	O
than	O
acetylated	O
H4	O
(	O
5	O
)	O
.	O

Based	O
on	O
this	O
and	O
the	O
fact	O
that	O
Sir2p	O
is	O
a	O
histone	O
deacetylase	O
,	O
a	O
refined	O
model	O
for	O
the	O
propagation	O
of	O
silent	O
chromatin	O
can	O
be	O
proposed	O
.	O

In	O
this	O
model	O
,	O
Sir2p	O
recruited	O
to	O
the	O
silencer	O
deacetylates	O
histones	O
in	O
an	O
adjacent	O
nucleosome	O
enabling	O
it	O
to	O
bind	O
another	O
SIR	O
complex	O
with	O
high	O
affinity	O
.	O

The	O
nucleosome	O
-	O
bound	O
SIR	O
complex	O
in	O
turn	O
deacetylates	O
the	O
neighboring	O
nucleosome	O
allowing	O
it	O
to	O
recruit	O
a	O
new	O
SIR	O
complex	O
.	O

In	O
this	O
manner	O
,	O
the	O
SIR	O
complex	O
promotes	O
its	O
own	O
propagation	O
along	O
an	O
array	O
of	O
nucleosomes	O
(	O
4	O
)	O
.	O

The	O
fact	O
that	O
transcriptionally	O
silent	O
chromatin	O
can	O
encroach	O
upon	O
active	O
chromatin	O
poses	O
the	O
question	O
of	O
how	O
interspersed	O
domains	O
of	O
silent	O
and	O
active	O
chromatin	O
are	O
demarcated	O
.	O

Studies	O
of	O
the	O
Drosophila	O
and	O
vertebrate	O
genomes	O
demonstrated	O
that	O
some	O
domains	O
are	O
delimited	O
by	O
boundary	O
or	O
insulator	O
elements	O
(	O
6	O
)	O
.	O

These	O
elements	O
are	O
specialized	O
DNA	O
sequences	O
that	O
act	O
as	O
barriers	O
to	O
enhancers	O
and	O
/	O
or	O
silent	O
chromatin	O
.	O

One	O
of	O
the	O
best	O
characterized	O
insulators	O
is	O
the	O
chicken	B
HS4	O
insulator	O
at	O
the	O
beta	O
-	O
globin	O
locus	O
.	O

Histones	O
surrounding	O
this	O
insulator	O
are	O
hyperacetylated	O
indicating	O
the	O
presence	O
of	O
histone	O
acetyltransferase	O
(	O
HAT	O
)	O
activity	O
at	O
the	O
insulator	O
(	O
6	O
)	O
.	O

Recently	O
,	O
sequences	O
that	O
could	O
block	O
the	O
spread	O
of	O
silent	O
chromatin	O
have	O
been	O
discovered	O
in	O
S	B
.	I
cerevisiae	I
(	O
7	O
,	O
8	O
)	O
.	O

These	O
sequences	O
(	O
referred	O
to	O
as	O
silent	O
chromatin	O
barriers	O
)	O
include	O
sub	O
-	O
telomeric	O
anti	O
-	O
silencing	O
regions	O
(	O
STARs	O
)	O
,	O
the	O
right	O
boundary	O
of	O
HMR	O
,	O
and	O
the	O
upstream	O
activating	O
sequence	O
(	O
UAS	O
)	O
of	O
the	O
highly	O
expressed	O
TEF2	O
gene	O
(	O
9	O
-	O
11	O
)	O
.	O

The	O
mechanisms	O
underlying	O
barrier	O
functions	O
in	O
yeast	B
are	O
not	O
known	O
.	O

TEF2	O
-	O
UAS	O
contains	O
three	O
tandem	O
repressor	O
activator	O
protein	O
1	O
(	O
Rap1p	O
)	O
-	O
binding	O
sites	O
that	O
are	O
necessary	O
and	O
sufficient	O
for	O
its	O
barrier	O
function	O
(	O
11	O
)	O
.	O

Rap1p	O
is	O
an	O
abundant	O
sequence	O
-	O
specific	O
DNA	O
-	O
binding	O
protein	O
(	O
12	O
)	O
.	O

Variants	O
of	O
the	O
13	O
bp	O
consensus	O
sequence	O
for	O
Rap1p	O
binding	O
(	O
ACACC	O
CRYACAYM	O
)	O
(	O
13	O
)	O
lie	O
not	O
only	O
in	O
the	O
UASs	O
of	O
numerous	O
genes	O
but	O
also	O
in	O
the	O
silencers	O
of	O
the	O
HM	O
loci	O
and	O
in	O
telomeric	O
C1	O
-	O
3A	O
repeats	O
.	O

Accordingly	O
,	O
Rap1p	O
functions	O
as	O
a	O
global	O
regulator	O
of	O
transcriptional	O
activation	O
and	O
repression	O
,	O
silencing	O
,	O
as	O
well	O
as	O
telomere	O
length	O
(	O
12	O
)	O
.	O

Rap1p	O
performs	O
these	O
diverse	O
functions	O
by	O
interacting	O
with	O
different	O
factors	O
in	O
respective	O
contexts	O
.	O

As	O
an	O
activator	O
,	O
Rap1p	O
binds	O
to	O
the	O
promoters	O
of	O
362	O
ORFs	O
(	O
13	O
)	O
and	O
can	O
function	O
via	O
at	O
least	O
three	O
mechanisms	O
.	O

First	O
,	O
Rap1p	O
binding	O
can	O
'	O
open	O
up	O
'	O
local	O
chromatin	O
structure	O
at	O
a	O
promoter	O
to	O
help	O
another	O
activator	O
to	O
bind	O
(	O
14	O
)	O
.	O

Secondly	O
,	O
Rap1p	O
bound	O
to	O
DNA	O
can	O
help	O
Gcr1p	O
bind	O
to	O
an	O
adjacent	O
site	O
in	O
the	O
promoter	O
through	O
physical	O
interaction	O
(	O
15	O
)	O
.	O

Thirdly	O
,	O
Rap1p	O
is	O
involved	O
in	O
the	O
recruitment	O
of	O
the	O
NuA4	O
HAT	O
complex	O
and	O
TFIID	O
to	O
ribosome	O
protein	O
genes	O
(	O
RPGs	O
)	O
(	O
16	O
,	O
17	O
)	O
.	O

As	O
a	O
silencing	O
factor	O
,	O
Rap1p	O
binds	O
to	O
silencers	O
or	O
telomeric	O
repeats	O
and	O
recruits	O
Sir3p	O
/	O
Sir4p	O
through	O
direct	O
interactions	O
(	O
18	O
)	O
.	O

Rap1p	O
also	O
interacts	O
with	O
telomere	O
-	O
specific	O
proteins	O
in	O
executing	O
its	O
role	O
in	O
regulating	O
telomere	O
length	O
(	O
19	O
)	O
.	O

It	O
is	O
puzzling	O
that	O
a	O
protein	O
that	O
helps	O
establish	O
silent	O
chromatin	O
could	O
also	O
act	O
as	O
a	O
barrier	O
to	O
its	O
propagation	O
.	O

In	O
this	O
study	O
,	O
we	O
found	O
that	O
in	O
addition	O
to	O
TEF2	O
-	O
UAS	O
,	O
UASs	O
of	O
many	O
yeast	B
genes	O
exhibit	O
barrier	O
activity	O
.	O

Analyses	O
of	O
these	O
UASs	O
indicate	O
that	O
binding	O
sites	O
for	O
transcriptional	O
regulators	O
Abf1p	O
,	O
Reb1p	O
,	O
Adr1p	O
,	O
Gcn4p	O
,	O
as	O
well	O
as	O
Rap1p	O
,	O
may	O
participate	O
in	O
barrier	O
function	O
.	O

These	O
UASs	O
are	O
dispersed	O
across	O
the	O
genome	O
and	O
might	O
play	O
a	O
role	O
in	O
defining	O
functional	O
chromosomal	O
domains	O
.	O

Moreover	O
,	O
we	O
demonstrated	O
that	O
targeting	O
the	O
activation	O
domain	O
of	O
Rap1p	O
,	O
Adr1p	O
or	O
Gcn4p	O
alone	O
,	O
led	O
to	O
barrier	O
function	O
.	O

Since	O
the	O
activation	O
domain	O
of	O
an	O
activator	O
was	O
usually	O
involved	O
in	O
interacting	O
with	O
co	O
-	O
activators	O
and	O
/	O
or	O
components	O
of	O
the	O
transcriptional	O
machinery	O
,	O
these	O
data	O
indicated	O
that	O
other	O
factors	O
might	O
also	O
be	O
involved	O
in	O
barrier	O
function	O
.	O

MATERIALS	O
AND	O
METHODS	O

Plasmids	O
and	O
strains	O

Plasmids	O
1	O
-	O
53	O
were	O
used	O
to	O
make	O
strains	O
1	O
-	O
53	O
,	O
respectively	O
(	O
see	O
Figs	O
1	O
-	O
6	O
)	O
.	O

Plasmid	O
1	O
was	O
previously	O
named	O
pMB22	O
-	O
a	O
that	O
contained	O
a	O
HindIII	O
-	O
BamHI	O
fragment	O
of	O
chromosome	O
III	O
(	O
coordinates	O
14838	O
-	O
16263	O
)	O
with	O
a	O
URA3	O
gene	O
inserted	O
at	O
its	O
EcoRV	O
site	O
(	O
20	O
)	O
.	O

Plasmid	O
2	O
was	O
derived	O
from	O
1	O
by	O
inserting	O
TEF2	O
-	O
UAS	O
(	O
-	O
511	O
to	O
-	O
407	O
bp	O
relative	O
to	O
the	O
translation	O
start	O
codon	O
)	O
at	O
the	O
SnaBI	O
site	O
.	O

Plasmids	O
3	O
-	O
38	O
were	O
identical	O
to	O
2	O
except	O
that	O
different	O
fragments	O
from	O
various	O
promoters	O
(	O
see	O
Figs	O
1	O
and	O
2	O
)	O
were	O
inserted	O
at	O
the	O
SnaBI	O
site	O
.	O

Plasmid	O
29	O
had	O
a	O
sequence	O
of	O
chromosome	O
III	O
(	O
295327	O
-	O
295713	O
)	O
containing	O
the	O
HMR	O
-	O
tRNA	O
gene	O
(	O
21	O
)	O
inserted	O
at	O
the	O
SnaBI	O
site	O
of	O
plasmid	O
1	O
.	O

Plasmids	O
39	O
and	O
40	O
were	O
previously	O
named	O
pYXB26	O
and	O
pYXB59	O
,	O
respectively	O
(	O
11	O
)	O
.	O

Plasmid	O
41	O
was	O
identical	O
to	O
pYXB59	O
except	O
bearing	O
mutations	O
illustrated	O
in	O
Figure	O
3A	O
.	O

Plasmids	O
42	O
-	O
48	O
were	O
previously	O
described	O
as	O
pYXB29	O
,	O
48	O
,	O
28	O
,	O
27	O
,	O
59	O
,	O
31	O
and	O
37	O
,	O
respectively	O
(	O
11	O
)	O
.	O

Plasmid	O
50	O
was	O
derived	O
from	O
plasmid	O
1	O
by	O
inserting	O
two	O
copies	O
of	O
a	O
sequence	O
bearing	O
the	O
consensus	O
binding	O
sequence	O
of	O
LexA	O
(	O
bold	O
)	O
(	O
22	O
)	O
,	O
GGGGTACGTACTGTATGTAC	O
,	O
at	O
the	O
SnaBI	O
site	O
.	O

Plasmid	O
51	O
was	O
identical	O
to	O
50	O
except	O
having	O
only	O
one	O
copy	O
of	O
the	O
LexA	O
-	O
binding	O
sequence	O
.	O

Plasmid	O
52	O
was	O
derived	O
from	O
pYXB26	O
(	O
11	O
)	O
by	O
inserting	O
a	O
SpeI	O
-	O
ADE2	O
-	O
AvrII	O
sequence	O
at	O
the	O
SpeI	O
site	O
.	O

Plasmid	O
53	O
was	O
derived	O
from	O
plasmid	O
52	O
by	O
inserting	O
TEF2	O
-	O
UAS	O
(	O
-	O
511	O
to	O
-	O
407	O
bp	O
relative	O
to	O
the	O
translation	O
start	O
codon	O
)	O
at	O
the	O
SpeI	O
site	O
.	O

Plasmid	O
L1	O
(	O
see	O
Fig	O
.	O
5A	O
)	O
was	O
made	O
by	O
inserting	O
LEU2	O
into	O
pBTM116	O
(	O
23	O
)	O
carrying	O
the	O
LexA	O
gene	O
flanked	O
by	O
the	O
promoter	O
and	O
terminator	O
of	O
ADH1	O
.	O

L2	O
through	O
L8	O
were	O
derived	O
from	O
L1	O
by	O
fusing	O
various	O
sequences	O
to	O
LexA	O
(	O
see	O
Fig	O
.	O
5A	O
and	O
B	O
)	O
.	O

Plasmid	O
pRS425	O
(	O
24	O
)	O
carried	O
the	O
2	O
micro	O
m	O
origin	O
and	O
LEU2	O
.	O

Strain	O
YXB76	O
was	O
MATa	O
ura3	O
-	O
52	O
leu2	O
-	O
3	O
,	O
112	O
ade2	O
-	O
1	O
lys1	O
-	O
1	O
his5	O
-	O
2	O
can1	O
-	O
100	O
,	O
E	O
-	O
HML	O
alpha	O
-	O
Iinverted	O
(	O
20	O
)	O
.	O

Y2047b	O
was	O
MATa	O
HMRa	O
HML	O
alpha	O
E	O
Delta	O
79	O
-	O
113	O
:	O
:	O
SUP4	O
-	O
o	O
I	O
Delta	O
242	O
LEU2	O
-	O
GAL10	O
-	O
FLP1	O
ura3	O
-	O
52	O
ade2	O
-	O
1	O
lys1	O
-	O
1	O
his5	O
-	O
1	O
can1	O
-	O
100	O
[	O
cir0	O
]	O
(	O
25	O
)	O
.	O

Strain	O
1	O
was	O
made	O
by	O
transforming	O
YXB76	O
to	O
Ura	O
+	O
with	O
HindIII	O
+	O
BamHI	O
digested	O
plasmid	O
1	O
.	O

Strains	O
2	O
-	O
38	O
,	O
50	O
and	O
51	O
were	O
similarly	O
made	O
with	O
corresponding	O
plasmids	O
,	O
respectively	O
(	O
e	O
.	O
g	O
.	O
strain	O
2	O
was	O
made	O
with	O
plasmid	O
2	O
)	O
.	O

Strains	O
39	O
,	O
40	O
and	O
42	O
-	O
48	O
were	O
previously	O
described	O
as	O
YXB26	O
,	O
48	O
,	O
29	O
,	O
48	O
,	O
28	O
,	O
27	O
,	O
59	O
,	O
31	O
and	O
37	O
,	O
respectively	O
(	O
11	O
)	O
.	O

Strains	O
41	O
,	O
52	O
and	O
53	O
(	O
see	O
Figs	O
3C	O
and	O
6	O
)	O
were	O
made	O
by	O
transforming	O
Y2047b	O
to	O
canavanine	O
-	O
resistant	O
by	O
BamHI	O
-	O
digested	O
plasmids	O
41	O
,	O
52	O
and	O
53	O
,	O
respectively	O
.	O

Strains	O
40	O
'	O
-	O
48	O
'	O
were	O
sir3	O
:	O
:	O
URA3	O
derivatives	O
of	O
strains	O
40	O
-	O
48	O
,	O
respectively	O
.	O

The	O
relevant	O
genotypes	O
of	O
all	O
the	O
strains	O
were	O
confirmed	O
by	O
Southern	O
blotting	O
.	O

Quantitative	O
mating	O
assay	O

Quantitative	O
mating	O
was	O
performed	O
as	O
described	O
(	O
11	O
)	O
.	O

Electrophoresis	O
mobility	O
shift	O
assay	O
(	O
EMSA	O
)	O

Rap1p	O
was	O
expressed	O
in	O
Escherichia	B
coli	I
BL21	I
(	I
DE3	I
)	I
from	O
pL3S5	O
,	O
a	O
pET	O
vector	O
carrying	O
the	O
RAP1	O
gene	O
downstream	O
of	O
a	O
T7	O
promoter	O
(	O
26	O
)	O
.	O

Crude	O
protein	O
extracts	O
were	O
prepared	O
from	O
40	O
ml	O
cultures	O
harvested	O
after	O
3	O
h	O
of	O
IPTG	O
induction	O
and	O
resuspended	O
in	O
1	O
ml	O
of	O
lysis	O
buffer	O
(	O
50	O
mM	O
NaH2PO4	O
,	O
300	O
mM	O
NaCl	O
,	O
pH	O
8	O
.	O
0	O
)	O
.	O

A	O
control	O
extract	O
was	O
prepared	O
from	O
a	O
culture	O
without	O
IPTG	O
induction	O
.	O

Western	O
blotting	O
revealed	O
that	O
Rap1p	O
protein	O
was	O
present	O
in	O
the	O
induced	O
extract	O
but	O
not	O
the	O
uninduced	O
one	O
(	O
data	O
not	O
shown	O
)	O
.	O

DNA	O
fragments	O
of	O
26	O
bp	O
in	O
length	O
(	O
see	O
Fig	O
.	O
3A	O
)	O
were	O
end	O
-	O
labeled	O
with	O
32P	O
-	O
phosphate	O
.	O

Fifteen	O
microliter	O
binding	O
reactions	O
were	O
prepared	O
,	O
each	O
consisting	O
of	O
20	O
000	O
c	O
.	O
p	O
.	O
m	O
.	O
radiolabeled	O
DNA	O
probe	O
,	O
5	O
micro	O
g	O
of	O
crude	O
protein	O
extract	O
,	O
non	O
-	O
specific	O
competitor	O
DNAs	O
(	O
0	O
.	O
3	O
micro	O
g	O
of	O
yeast	B
tRNA	O
,	O
0	O
.	O
3	O
micro	O
g	O
of	O
salmon	B
sperm	O
DNA	O
and	O
0	O
.	O
5	O
micro	O
g	O
of	O
E	B
.	I
coli	I
DNA	O
)	O
,	O
10	O
micro	O
g	O
of	O
BSA	O
,	O
10	O
mM	O
Tris	O
-	O
HCl	O
(	O
pH	O
8	O
.	O
0	O
)	O
,	O
10	O
mM	O
MgCl2	O
and	O
8	O
%	O
glycerol	O
.	O

The	O
reactions	O
were	O
incubated	O
at	O
25	O
degrees	O
C	O
for	O
20	O
min	O
and	O
loaded	O
onto	O
non	O
-	O
denaturing	O
polyacrylamide	O
gels	O
(	O
4	O
-	O
5	O
%	O
)	O
.	O

Gels	O
were	O
run	O
at	O
40	O
mA	O
for	O
1	O
h	O
in	O
0	O
.	O
5	O
x	O
TBE	O
buffer	O
.	O

Analysis	O
of	O
the	O
supercoiling	O
of	O
DNA	O
circles	O

Cells	O
were	O
grown	O
in	O
YPR	O
(	O
yeast	B
extract	O
+	O
bacto	O
peptone	O
+	O
2	O
%	O
raffinose	O
)	O
to	O
early	O
log	O
phase	O
.	O

Galactose	O
(	O
2	O
%	O
)	O
was	O
then	O
added	O
to	O
the	O
culture	O
to	O
induce	O
the	O
expression	O
of	O
FLP1	O
.	O

After	O
2	O
.	O
5	O
h	O
of	O
incubation	O
,	O
nucleic	O
acid	O
was	O
isolated	O
using	O
the	O
glass	O
bead	O
method	O
and	O
fractionated	O
on	O
agarose	O
gels	O
with	O
30	O
micro	O
g	O
/	O
ml	O
chloroquine	O
.	O

DNA	O
circles	O
were	O
detected	O
by	O
Southern	O
blotting	O
.	O

RESULTS	O

UASs	O
of	O
many	O
highly	O
expressed	O
genes	O
can	O
function	O
as	O
barriers	O
to	O
the	O
spread	O
of	O
silencing	O

We	O
have	O
previously	O
shown	O
that	O
TEF2	O
-	O
UAS	O
was	O
able	O
to	O
block	O
the	O
spread	O
of	O
silencing	O
in	O
a	O
silencer	O
-	O
blocking	O
assay	O
(	O
11	O
)	O
.	O

Such	O
an	O
assay	O
tested	O
if	O
a	O
sequence	O
had	O
the	O
ability	O
to	O
prevent	O
a	O
silencer	O
from	O
silencing	O
a	O
reporter	O
gene	O
when	O
it	O
was	O
positioned	O
between	O
the	O
silencer	O
and	O
the	O
reporter	O
.	O

In	O
this	O
report	O
we	O
used	O
a	O
new	O
silencer	O
-	O
blocking	O
assay	O
to	O
identify	O
more	O
barrier	O
elements	O
.	O

This	O
assay	O
employed	O
the	O
URA3	O
gene	O
and	O
an	O
inverted	O
HML	O
-	O
I	O
that	O
could	O
silence	O
sequences	O
to	O
the	O
right	O
of	O
HML	O
(	O
20	O
)	O
(	O
Fig	O
.	O
1	O
,	O
strain	O
1	O
)	O
.	O

URA3	O
expression	O
makes	O
cells	O
sensitive	O
to	O
5	O
-	O
fluoroorotic	O
acid	O
(	O
FOA	O
)	O
thus	O
URA3	O
silencing	O
could	O
be	O
measured	O
by	O
cell	O
growth	O
on	O
FOA	O
medium	O
(	O
Fig	O
.	O
1	O
,	O
strain	O
1	O
)	O
.	O

As	O
expected	O
,	O
TEF2	O
-	O
UAS	O
and	O
another	O
known	O
barrier	O
element	O
,	O
HMR	O
-	O
tRNA	O
gene	O
(	O
21	O
)	O
exhibited	O
barrier	O
activity	O
in	O
this	O
assay	O
as	O
indicated	O
by	O
the	O
lack	O
of	O
silencing	O
of	O
URA3	O
in	O
strains	O
2	O
and	O
29	O
(	O
Fig	O
.	O
1	O
)	O
.	O

TEF2	O
encoding	O
translation	O
elongation	O
factor	O
1	O
alpha	O
is	O
one	O
of	O
the	O
most	O
highly	O
expressed	O
genes	O
in	O
yeast	B
(	O
27	O
)	O
.	O

Other	O
highly	O
expressed	O
genes	O
include	O
ribosome	O
protein	O
genes	O
(	O
RPGs	O
)	O
and	O
genes	O
coding	O
for	O
glycolytic	O
enzymes	O
(	O
27	O
)	O
.	O

The	O
coordinated	O
regulation	O
of	O
most	O
of	O
these	O
genes	O
requires	O
the	O
so	O
-	O
called	O
general	O
regulatory	O
factors	O
Rap1p	O
,	O
Abf1p	O
and	O
Reb1p	O
(	O
28	O
,	O
29	O
)	O
.	O

Using	O
the	O
above	O
silencer	O
-	O
blocking	O
assay	O
,	O
we	O
tested	O
if	O
the	O
UASs	O
of	O
other	O
highly	O
expressed	O
genes	O
could	O
also	O
block	O
URA3	O
silencing	O
(	O
Fig	O
.	O
1	O
)	O
.	O

Seventeen	O
new	O
barrier	O
elements	O
were	O
identified	O
from	O
a	O
total	O
of	O
26	O
UASs	O
tested	O
.	O

These	O
17	O
elements	O
were	O
UASs	O
of	O
eight	O
RPGs	O
(	O
see	O
Fig	O
.	O
1	O
,	O
strains	O
3	O
-	O
10	O
)	O
,	O
eight	O
glycolytic	O
genes	O
(	O
strains	O
18	O
-	O
25	O
)	O
and	O
the	O
HIS3	O
gene	O
(	O
strain	O
26	O
)	O
.	O

All	O
17	O
elements	O
except	O
ADH2	O
-	O
UAS	O
and	O
HIS3	O
-	O
UAS	O
exhibited	O
very	O
strong	O
barrier	O
activity	O
as	O
evidenced	O
by	O
the	O
absence	O
of	O
URA3	O
-	O
silencing	O
in	O
strains	O
3	O
-	O
10	O
and	O
18	O
-	O
24	O
(	O
Fig	O
.	O
1	O
)	O
.	O

Seven	O
of	O
the	O
eight	O
RPG	O
-	O
UASs	O
that	O
had	O
barrier	O
activity	O
,	O
contained	O
a	O
single	O
or	O
a	O
pair	O
of	O
tandem	O
Rap1p	O
-	O
binding	O
sites	O
(	O
Fig	O
.	O
1	O
,	O
strains	O
3	O
-	O
9	O
)	O
.	O

Three	O
of	O
them	O
also	O
contained	O
an	O
Abf1p	O
or	O
Reb1p	O
site	O
(	O
strains	O
6	O
,	O
8	O
and	O
9	O
)	O
.	O

One	O
barrier	O
RPG	O
-	O
UAS	O
(	O
strain	O
10	O
)	O
had	O
only	O
a	O
predicted	O
Abf1p	O
site	O
.	O

Of	O
the	O
seven	O
RPG	O
-	O
UASs	O
that	O
had	O
no	O
barrier	O
activity	O
(	O
Fig	O
.	O
1	O
,	O
11	O
-	O
17	O
)	O
,	O
only	O
two	O
bore	O
no	O
site	O
for	O
Rap1p	O
,	O
Abf1p	O
or	O
Reb1p	O
(	O
11	O
and	O
12	O
)	O
.	O

The	O
remaining	O
five	O
each	O
contained	O
one	O
to	O
three	O
Rap1p	O
sites	O
(	O
strains	O
13	O
-	O
17	O
)	O
.	O

RPL15A	O
-	O
UAS	O
(	O
17	O
)	O
also	O
contained	O
an	O
Abf1p	O
site	O
.	O

For	O
most	O
of	O
the	O
15	O
RPG	O
-	O
UASs	O
tested	O
(	O
3	O
-	O
17	O
)	O
,	O
the	O
presence	O
or	O
absence	O
of	O
predicted	O
Rap1p	O
sites	O
correlated	O
with	O
the	O
presence	O
or	O
absence	O
of	O
Rap1p	O
association	O
in	O
vivo	O
as	O
previously	O
examined	O
by	O
chromatin	O
immunoprecipitation	O
assays	O
(	O
13	O
)	O
.	O

Exceptions	O
were	O
the	O
UASs	O
of	O
RPS24B	O
,	O
RPS28A	O
and	O
RPL15A	O
(	O
13	O
)	O
.	O

Of	O
the	O
eight	O
UASs	O
of	O
glycolytic	O
genes	O
tested	O
(	O
Fig	O
.	O
1	O
,	O
strains	O
18	O
-	O
25	O
)	O
,	O
seven	O
exhibited	O
strong	O
barrier	O
activity	O
(	O
18	O
-	O
24	O
)	O
and	O
one	O
had	O
weaker	O
but	O
detectable	O
barrier	O
activity	O
(	O
strain	O
25	O
)	O
.	O

Glycolytic	O
genes	O
are	O
among	O
the	O
most	O
highly	O
expressed	O
genes	O
and	O
their	O
high	O
expression	O
depends	O
on	O
the	O
functions	O
of	O
Rap1p	O
,	O
Abf1p	O
or	O
Reb1p	O
as	O
well	O
as	O
Gcr1p	O
(	O
29	O
,	O
30	O
)	O
.	O

The	O
seven	O
strong	O
glycolytic	O
barriers	O
all	O
consist	O
of	O
one	O
or	O
two	O
Rap1p	O
sites	O
plus	O
one	O
or	O
two	O
Reb1p	O
or	O
Abf1p	O
sites	O
(	O
Fig	O
.	O
1	O
,	O
strains	O
18	O
-	O
24	O
)	O
.	O

In	O
addition	O
,	O
one	O
or	O
more	O
Gcr1p	O
-	O
binding	O
sites	O
are	O
found	O
adjacent	O
to	O
each	O
Rap1p	O
site	O
.	O

It	O
was	O
proposed	O
that	O
the	O
function	O
of	O
Rap1p	O
was	O
to	O
facilitate	O
the	O
binding	O
of	O
Gcr1p	O
to	O
the	O
UAS	O
(	O
15	O
)	O
.	O

Abf1p	O
or	O
Reb1p	O
was	O
shown	O
to	O
play	O
a	O
role	O
similar	O
to	O
that	O
of	O
Rap1p	O
in	O
activating	O
glycolytic	O
genes	O
(	O
31	O
-	O
33	O
)	O
.	O

Although	O
the	O
above	O
data	O
reinforced	O
the	O
notion	O
that	O
certain	O
Rap1p	O
-	O
binding	O
UASs	O
could	O
serve	O
as	O
barriers	O
to	O
silencing	O
,	O
they	O
raised	O
new	O
questions	O
about	O
the	O
essential	O
components	O
of	O
a	O
barrier	O
element	O
.	O

For	O
example	O
,	O
some	O
of	O
the	O
UASs	O
that	O
contained	O
only	O
a	O
single	O
Rap1p	O
site	O
had	O
barrier	O
activity	O
(	O
e	O
.	O
g	O
.	O
RPL19B	O
-	O
UAS	O
,	O
strain	O
3	O
)	O
whereas	O
others	O
that	O
contained	O
two	O
or	O
three	O
sites	O
had	O
no	O
activity	O
(	O
e	O
.	O
g	O
.	O
RPL39	O
,	O
strain	O
16	O
)	O
.	O

One	O
explanation	O
was	O
that	O
sequences	O
flanking	O
the	O
Rap1p	O
site	O
(	O
s	O
)	O
in	O
a	O
particular	O
UAS	O
could	O
positively	O
or	O
negatively	O
influence	O
barrier	O
function	O
.	O

Moreover	O
,	O
the	O
presence	O
of	O
Abf1p	O
or	O
Reb1p	O
sites	O
in	O
11	O
of	O
the	O
17	O
new	O
barriers	O
made	O
us	O
wonder	O
if	O
they	O
also	O
participated	O
in	O
barrier	O
function	O
.	O

We	O
began	O
to	O
address	O
these	O
issues	O
by	O
analyzing	O
three	O
new	O
barrier	O
elements	O
(	O
Fig	O
.	O
2	O
)	O
.	O

RPS10A	O
-	O
UAS	O
containing	O
an	O
Abf1p	O
-	O
binding	O
site	O
and	O
a	O
pair	O
of	O
Rap1p	O
sites	O
was	O
divided	O
into	O
three	O
fragments	O
that	O
were	O
tested	O
in	O
a	O
silencer	O
-	O
blocking	O
assay	O
(	O
Fig	O
.	O
2	O
,	O
strains	O
30	O
-	O
32	O
)	O
.	O

It	O
was	O
clear	O
that	O
only	O
the	O
fragment	O
containing	O
Rap1p	O
sites	O
functioned	O
as	O
a	O
barrier	O
(	O
strain	O
31	O
)	O
.	O

TPI1	O
-	O
UAS	O
bearing	O
a	O
Reb1p	O
site	O
and	O
a	O
Rap1p	O
site	O
was	O
divided	O
into	O
two	O
parts	O
with	O
one	O
containing	O
the	O
Rap1p	O
site	O
(	O
Fig	O
.	O
2	O
,	O
strain	O
34	O
)	O
and	O
the	O
other	O
Reb1p	O
site	O
(	O
strain	O
33	O
)	O
.	O

Neither	O
of	O
these	O
fragments	O
alone	O
retained	O
barrier	O
activity	O
indicating	O
that	O
concerted	O
action	O
of	O
Reb1p	O
and	O
Rap1p	O
was	O
required	O
for	O
barrier	O
activity	O
.	O

Duplicating	O
the	O
Reb1p	O
-	O
bearing	O
part	O
of	O
TPI1	O
-	O
UAS	O
didn	O
'	O
t	O
restore	O
barrier	O
activity	O
(	O
strain	O
35	O
)	O
.	O

However	O
,	O
triplicating	O
the	O
Rap1p	O
-	O
containing	O
part	O
did	O
re	O
-	O
create	O
barrier	O
function	O
(	O
strain	O
36	O
)	O
.	O

RPS28A	O
-	O
UAS	O
bore	O
,	O
in	O
addition	O
to	O
a	O
Rap1p	O
site	O
,	O
an	O
Abf1p	O
site	O
and	O
an	O
adjacent	O
T	O
-	O
rich	O
region	O
that	O
are	O
required	O
for	O
efficient	O
transcription	O
of	O
RPS28A	O
(	O
34	O
)	O
.	O

A	O
sequence	O
of	O
RPS28A	O
-	O
UAS	O
deleted	O
for	O
a	O
fragment	O
bearing	O
the	O
Rap1p	O
site	O
lost	O
the	O
barrier	O
activity	O
(	O
Fig	O
.	O
2	O
,	O
strain	O
37	O
)	O
.	O

However	O
,	O
duplicating	O
this	O
sequence	O
restored	O
barrier	O
activity	O
(	O
strain	O
38	O
)	O
.	O

The	O
above	O
results	O
indicated	O
again	O
that	O
Rap1p	O
sites	O
could	O
form	O
barriers	O
(	O
strains	O
31	O
and	O
36	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
they	O
also	O
suggested	O
that	O
synergistic	O
actions	O
of	O
Abf1p	O
sites	O
(	O
strain	O
38	O
)	O
,	O
Reb1p	O
site	O
+	O
Rap1p	O
site	O
(	O
strain	O
18	O
)	O
,	O
or	O
Abf1p	O
site	O
+	O
Rap1p	O
site	O
(	O
strain	O
16	O
)	O
could	O
all	O
lead	O
to	O
barrier	O
function	O
.	O

This	O
was	O
not	O
very	O
surprising	O
since	O
Rap1p	O
,	O
Abf1p	O
and	O
Reb1p	O
could	O
perform	O
similar	O
and	O
sometimes	O
interchangeable	O
functions	O
in	O
gene	O
regulation	O
(	O
16	O
,	O
35	O
,	O
36	O
)	O
.	O

Note	O
,	O
however	O
,	O
we	O
haven	O
'	O
t	O
ruled	O
out	O
the	O
possibility	O
that	O
other	O
factors	O
(	O
e	O
.	O
g	O
.	O
Gcr1p	O
)	O
or	O
structure	O
features	O
of	O
DNA	O
(	O
e	O
.	O
g	O
.	O
T	O
-	O
tracks	O
)	O
were	O
also	O
involved	O
in	O
barrier	O
function	O
.	O

It	O
was	O
interesting	O
that	O
ADH2	O
-	O
UAS	O
and	O
HIS3	O
-	O
UAS	O
bearing	O
no	O
site	O
for	O
Rap1p	O
,	O
Abf1p	O
or	O
Reb1p	O
exhibited	O
detectable	O
barrier	O
activity	O
(	O
Fig	O
.	O
1	O
,	O
strains	O
25	O
and	O
26	O
)	O
.	O

However	O
,	O
binding	O
sites	O
for	O
other	O
transcriptional	O
activators	O
existed	O
in	O
these	O
UASs	O
.	O

The	O
major	O
regulator	O
that	O
binds	O
to	O
ADH2	O
-	O
UAS	O
is	O
Adr1p	O
(	O
37	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
Gcn4p	O
binds	O
to	O
multiple	O
sites	O
in	O
HIS3	O
-	O
UAS	O
and	O
activates	O
HIS3	O
transcription	O
(	O
38	O
)	O
.	O

The	O
possible	O
involvement	O
of	O
Adr1p	O
or	O
Gcn4p	O
in	O
barrier	O
function	O
was	O
examined	O
below	O
.	O

Note	O
Adr1p	O
function	O
was	O
subject	O
to	O
glucose	O
repression	O
(	O
37	O
)	O
,	O
which	O
might	O
explain	O
why	O
ADH2	O
-	O
UAS	O
only	O
exhibited	O
limited	O
barrier	O
activity	O
since	O
glucose	O
was	O
used	O
in	O
the	O
media	O
used	O
in	O
our	O
assay	O
.	O

Effect	O
of	O
mutating	O
Rap1p	O
-	O
binding	O
sites	O
in	O
TEF2	O
-	O
UAS	O
on	O
barrier	O
function	O

Although	O
we	O
had	O
shown	O
that	O
the	O
three	O
Rap1p	O
-	O
binding	O
sites	O
in	O
TEF2	O
-	O
UAS	O
were	O
necessary	O
and	O
sufficient	O
for	O
its	O
barrier	O
activity	O
(	O
11	O
)	O
,	O
we	O
had	O
not	O
shown	O
if	O
binding	O
of	O
Rap1p	O
to	O
these	O
sites	O
was	O
required	O
.	O

To	O
address	O
this	O
we	O
performed	O
mutational	O
analysis	O
of	O
TEF2	O
-	O
UAS	O
.	O

As	O
shown	O
in	O
Figure	O
3A	O
and	O
B	O
,	O
the	O
three	O
Rap1p	O
-	O
binding	O
sites	O
in	O
TEF2	O
-	O
UAS	O
(	O
designated	O
as	O
R1	O
,	O
R2	O
and	O
R3	O
)	O
were	O
all	O
able	O
to	O
bind	O
Rap1p	O
in	O
an	O
EMSA	O
(	O
Fig	O
.	O
3B	O
)	O
.	O

Single	O
or	O
double	O
C	O
-	O
-	O
>	O
A	O
mutations	O
were	O
introduced	O
into	O
R1	O
,	O
R2	O
and	O
R3	O
resulting	O
in	O
m1	O
,	O
m2	O
and	O
m3	O
,	O
respectively	O
(	O
Fig	O
.	O
3A	O
)	O
.	O

The	O
m2	O
and	O
m3	O
sites	O
had	O
both	O
lost	O
the	O
ability	O
to	O
bind	O
Rap1p	O
,	O
whereas	O
m1	O
still	O
bound	O
Rap1p	O
(	O
Fig	O
.	O
3B	O
)	O
,	O
which	O
could	O
be	O
predicted	O
from	O
the	O
specific	O
mutations	O
in	O
each	O
site	O
(	O
Fig	O
.	O
3A	O
,	O
compare	O
m1	O
,	O
m2	O
and	O
m3	O
to	O
the	O
consensus	O
sequence	O
)	O
.	O

We	O
then	O
tested	O
a	O
mutated	O
TEF2	O
-	O
UAS	O
containing	O
m1	O
,	O
m2	O
and	O
m3	O
in	O
a	O
silencer	O
-	O
blocking	O
assay	O
using	O
the	O
HML	O
-	O
E	O
silencer	O
and	O
the	O
HML	O
alpha	O
genes	O
(	O
Fig	O
.	O
3C	O
)	O
.	O

In	O
this	O
assay	O
,	O
the	O
HML	O
-	O
I	O
silencer	O
was	O
deleted	O
but	O
the	O
HML	O
-	O
E	O
silencer	O
was	O
sufficient	O
to	O
silence	O
the	O
HML	O
alpha	O
genes	O
(	O
Fig	O
.	O
3C	O
,	O
strain	O
39	O
)	O
(	O
11	O
)	O
.	O

Silencing	O
in	O
strain	O
39	O
(	O
a	O
-	O
type	O
)	O
was	O
measured	O
by	O
its	O
ability	O
to	O
mate	O
with	O
an	O
alpha	O
-	O
type	O
strain	O
(	O
Fig	O
.	O
3C	O
)	O
.	O

As	O
predicted	O
,	O
the	O
wild	O
-	O
type	O
TEF2	O
-	O
UAS	O
blocked	O
HML	O
alpha	O
silencing	O
(	O
11	O
)	O
(	O
Fig	O
.	O
3C	O
,	O
strain	O
40	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
mutated	O
TEF2	O
-	O
UAS	O
containing	O
m1	O
,	O
m2	O
and	O
m3	O
had	O
lost	O
barrier	O
activity	O
(	O
Fig	O
.	O
3C	O
,	O
compare	O
the	O
mating	O
efficiencies	O
of	O
strains	O
41	O
and	O
40	O
)	O
.	O

Therefore	O
,	O
mutations	O
that	O
prevented	O
Rap1p	O
from	O
binding	O
two	O
of	O
the	O
three	O
sites	O
in	O
TEF2	O
-	O
UAS	O
abolished	O
its	O
barrier	O
activity	O
,	O
indicating	O
that	O
association	O
of	O
Rap1p	O
with	O
TEF2	O
-	O
UAS	O
at	O
more	O
than	O
one	O
site	O
was	O
required	O
for	O
barrier	O
function	O
.	O

The	O
barrier	O
TEF2	O
-	O
UAS	O
alters	O
local	O
chromatin	O
structure	O

In	O
eukaryotic	O
cells	O
,	O
the	O
topology	O
of	O
local	O
DNA	O
reflects	O
the	O
chromatin	O
structure	O
in	O
which	O
it	O
resides	O
.	O

We	O
had	O
previously	O
developed	O
a	O
DNA	O
topology	O
-	O
based	O
assay	O
to	O
examine	O
chromatin	O
structure	O
in	O
vivo	O
,	O
which	O
involved	O
excising	O
a	O
chromosomal	O
region	O
of	O
interest	O
from	O
its	O
genomic	O
location	O
as	O
a	O
circle	O
using	O
site	O
-	O
specific	O
recombination	O
(	O
39	O
)	O
.	O

Using	O
this	O
strategy	O
,	O
we	O
demonstrated	O
that	O
DNA	O
in	O
silenced	O
chromatin	O
was	O
more	O
negatively	O
supercoiled	O
than	O
that	O
in	O
active	O
chromatin	O
(	O
39	O
)	O
.	O

In	O
this	O
report	O
we	O
used	O
the	O
topology	O
assay	O
to	O
address	O
if	O
barrier	O
elements	O
altered	O
local	O
chromatin	O
structure	O
as	O
Drosophila	B
or	O
chicken	B
insulators	O
did	O
(	O
40	O
,	O
41	O
)	O
.	O

Various	O
sequences	O
(	O
designated	O
X	O
)	O
from	O
UASs	O
of	O
TEF2	O
,	O
AgTEF	O
(	O
TEF	O
gene	O
from	O
Ashbya	B
gossypii	I
)	O
and	O
ADE2	O
were	O
inserted	O
between	O
HML	O
-	O
E	O
and	O
HML	O
alpha	O
at	O
HML	O
Delta	O
I	O
(	O
HML	O
locus	O
deleted	O
for	O
the	O
I	O
silencer	O
)	O
flanked	O
by	O
the	O
FRT	O
sites	O
for	O
the	O
Flp1p	O
site	O
-	O
specific	O
recombinase	O
(	O
Fig	O
.	O
4A	O
and	O
B	O
)	O
.	O

The	O
FLP1	O
gene	O
was	O
under	O
the	O
control	O
of	O
the	O
inducible	O
GAL10	O
promoter	O
(	O
39	O
)	O
.	O

The	O
mating	O
efficiency	O
of	O
each	O
strain	O
measured	O
silencing	O
of	O
HML	O
alpha	O
(	O
Fig	O
.	O
4C	O
)	O
.	O

In	O
strains	O
40	O
,	O
42	O
,	O
44	O
and	O
47	O
,	O
silencing	O
was	O
restricted	O
to	O
the	O
left	O
of	O
the	O
X	O
insertions	O
and	O
HML	O
alpha	O
was	O
derepressed	O
(	O
Fig	O
.	O
4C	O
)	O
.	O

Consistently	O
,	O
the	O
proportion	O
of	O
silent	O
chromatin	O
in	O
the	O
region	O
flanked	O
by	O
the	O
FRT	O
sites	O
in	O
each	O
of	O
these	O
strains	O
was	O
decreased	O
,	O
as	O
indicated	O
by	O
the	O
reduced	O
negative	O
supercoiling	O
of	O
the	O
excised	O
circle	O
(	O
11	O
)	O
(	O
data	O
not	O
shown	O
)	O
.	O

Note	O
that	O
the	O
above	O
effect	O
of	O
a	O
barrier	O
on	O
HML	O
chromatin	O
reflected	O
both	O
change	O
in	O
the	O
scope	O
of	O
silencing	O
caused	O
by	O
the	O
barrier	O
activity	O
and	O
alteration	O
(	O
if	O
any	O
)	O
in	O
chromatin	O
structure	O
at	O
the	O
barrier	O
independent	O
of	O
the	O
silencing	O
state	O
of	O
the	O
locus	O
.	O

To	O
exclusively	O
examine	O
the	O
latter	O
,	O
we	O
analyzed	O
the	O
topology	O
of	O
HML	O
DNA	O
in	O
a	O
silencing	O
-	O
deficient	O
background	O
.	O

The	O
SIR3	O
gene	O
in	O
strains	O
described	O
in	O
Figure	O
4B	O
was	O
disrupted	O
rendering	O
them	O
defective	O
in	O
silencing	O
(	O
strains	O
40	O
'	O
-	O
48	O
'	O
in	O
Fig	O
.	O
4D	O
)	O
.	O

Recombination	O
mediated	O
by	O
Flp1p	O
in	O
these	O
strains	O
led	O
to	O
the	O
excision	O
of	O
a	O
group	O
of	O
chromosomal	O
circles	O
that	O
differed	O
only	O
in	O
the	O
X	O
insertion	O
.	O

The	O
supercoiling	O
of	O
these	O
circles	O
was	O
analyzed	O
as	O
a	O
function	O
of	O
the	O
length	O
of	O
the	O
insertion	O
(	O
Fig	O
.	O
4D	O
)	O
.	O

If	O
an	O
insertion	O
simply	O
lengthened	O
a	O
circle	O
without	O
causing	O
abnormal	O
changes	O
in	O
nucleosomal	O
structure	O
and	O
/	O
or	O
density	O
,	O
the	O
topoisomers	O
of	O
this	O
circle	O
would	O
migrate	O
slower	O
relative	O
to	O
those	O
of	O
a	O
similar	O
circle	O
with	O
a	O
smaller	O
size	O
.	O

Otherwise	O
,	O
migration	O
of	O
the	O
topoisomers	O
would	O
deviate	O
from	O
that	O
predicted	O
based	O
on	O
the	O
size	O
of	O
the	O
circle	O
.	O

As	O
shown	O
in	O
Figure	O
4D	O
,	O
the	O
circle	O
from	O
strain	O
40	O
'	O
bearing	O
a	O
104	O
bp	O
barrier	O
element	O
migrated	O
faster	O
rather	O
than	O
slower	O
than	O
the	O
circle	O
from	O
strain	O
46	O
'	O
bearing	O
a	O
91	O
bp	O
non	O
-	O
barrier	O
element	O
.	O

Circles	O
bearing	O
other	O
barrier	O
elements	O
also	O
exhibited	O
unexpected	O
faster	O
migration	O
(	O
compare	O
strains	O
44	O
'	O
to	O
45	O
'	O
,	O
47	O
'	O
to	O
43	O
'	O
,	O
42	O
'	O
to	O
48	O
'	O
,	O
respectively	O
)	O
.	O

Therefore	O
,	O
these	O
data	O
indicated	O
that	O
barrier	O
function	O
correlated	O
with	O
altered	O
topology	O
of	O
local	O
DNA	O
.	O

This	O
was	O
further	O
demonstrated	O
by	O
that	O
mutations	O
in	O
TEF2	O
-	O
UAS	O
that	O
abolished	O
its	O
barrier	O
activity	O
also	O
abolished	O
its	O
effect	O
on	O
DNA	O
topology	O
(	O
Fig	O
.	O
4D	O
,	O
compare	O
41	O
'	O
to	O
40	O
'	O
;	O
note	O
that	O
circles	O
from	O
both	O
strains	O
had	O
the	O
same	O
size	O
)	O
.	O

Since	O
in	O
our	O
gel	O
assay	O
more	O
negatively	O
supercoiled	O
DNA	O
migrate	O
slower	O
,	O
we	O
concluded	O
that	O
every	O
fragment	O
with	O
barrier	O
activity	O
caused	O
a	O
reduction	O
in	O
negative	O
supercoiling	O
of	O
approximately	O
one	O
to	O
two	O
turns	O
in	O
HML	O
Delta	O
I	O
DNA	O
(	O
Fig	O
.	O
4D	O
,	O
compare	O
the	O
centers	O
of	O
distributions	O
of	O
topoisomers	O
in	O
pairs	O
of	O
lanes	O
,	O
e	O
.	O
g	O
.	O
40	O
'	O
and	O
41	O
'	O
)	O
.	O

The	O
topology	O
of	O
eukaryotic	O
DNA	O
reflects	O
mainly	O
the	O
wrapping	O
of	O
DNA	O
into	O
nucleosomes	O
(	O
approximately	O
one	O
negative	O
superhelical	O
turn	O
is	O
associated	O
with	O
each	O
nucleosome	O
)	O
(	O
42	O
)	O
.	O

Therefore	O
,	O
removal	O
of	O
one	O
nucleosome	O
would	O
eliminate	O
approximately	O
one	O
turn	O
.	O

On	O
the	O
other	O
hand	O
,	O
histone	O
acetylation	O
can	O
reduce	O
negative	O
supercoiling	O
associated	O
with	O
a	O
nucleosome	O
by	O
approximately	O
0	O
.	O
2	O
turns	O
(	O
43	O
)	O
.	O

Therefore	O
,	O
acetylating	O
five	O
nucleosomes	O
would	O
reduce	O
negative	O
supercoiling	O
by	O
approximately	O
one	O
turn	O
.	O

Consequently	O
,	O
the	O
linking	O
number	O
change	O
of	O
one	O
to	O
two	O
brought	O
about	O
by	O
TEF2	O
-	O
UAS	O
can	O
be	O
accounted	O
for	O
by	O
either	O
the	O
loss	O
of	O
one	O
to	O
two	O
nucleosomes	O
or	O
acetylation	O
of	O
five	O
to	O
10	O
nucleosomes	O
.	O

Further	O
experiments	O
are	O
under	O
way	O
to	O
clarify	O
the	O
nature	O
of	O
change	O
in	O
chromatin	O
induced	O
by	O
a	O
barrier	O
.	O

Targeting	O
the	O
transcription	O
activation	O
domain	O
of	O
Rap1p	O
recapitulates	O
its	O
barrier	O
activity	O

The	O
multifunctional	O
Rap1p	O
can	O
be	O
divided	O
into	O
at	O
least	O
four	O
functional	O
domains	O
(	O
Fig	O
.	O
5A	O
)	O
(	O
12	O
)	O
.	O

We	O
were	O
interested	O
in	O
defining	O
which	O
of	O
these	O
domains	O
might	O
be	O
involved	O
in	O
the	O
barrier	O
activity	O
of	O
Rap1p	O
.	O

To	O
this	O
end	O
,	O
we	O
fused	O
various	O
parts	O
of	O
Rap1p	O
to	O
the	O
bacterial	O
LexA	O
protein	O
and	O
tested	O
if	O
targeting	O
any	O
of	O
the	O
fusion	O
proteins	O
to	O
LexA	O
-	O
binding	O
sites	O
could	O
re	O
-	O
create	O
a	O
barrier	O
to	O
silencing	O
(	O
Fig	O
.	O
5A	O
)	O
.	O

The	O
LexA	O
-	O
RAP1	O
fusion	O
genes	O
were	O
carried	O
on	O
2	O
micro	O
m	O
based	O
plasmids	O
marked	O
by	O
LEU2	O
(	O
designated	O
L1	O
-	O
L6	O
,	O
Fig	O
.	O
5A	O
)	O
.	O

When	O
introduced	O
into	O
strain	O
50	O
in	O
which	O
two	O
LexA	O
-	O
binding	O
sites	O
had	O
been	O
inserted	O
between	O
the	O
inverted	O
HML	O
-	O
I	O
and	O
URA3	O
,	O
LexA	O
alone	O
had	O
no	O
effect	O
on	O
URA3	O
silencing	O
(	O
Fig	O
.	O
5A	O
,	O
plasmid	O
L1	O
)	O
.	O

Targeting	O
the	O
DNA	O
binding	O
domain	O
,	O
DNA	O
bending	O
domain	O
,	O
silencing	O
domain	O
,	O
or	O
the	O
activating	O
+	O
silencing	O
domain	O
of	O
Rap1p	O
also	O
did	O
not	O
affect	O
URA3	O
silencing	O
(	O
L2	O
-	O
L5	O
)	O
.	O

On	O
the	O
other	O
hand	O
,	O
targeting	O
the	O
activation	O
domain	O
alone	O
recapitulated	O
the	O
barrier	O
activity	O
of	O
Rap1p	O
(	O
L6	O
)	O
.	O

These	O
results	O
indicated	O
that	O
the	O
activation	O
domain	O
of	O
Rap1p	O
was	O
involved	O
in	O
barrier	O
activity	O
.	O

The	O
inability	O
of	O
the	O
Rap1p	O
-	O
silencing	O
domain	O
to	O
block	O
URA3	O
silencing	O
in	O
our	O
assay	O
did	O
not	O
necessarily	O
mean	O
that	O
this	O
domain	O
had	O
no	O
barrier	O
function	O
,	O
since	O
such	O
a	O
function	O
might	O
be	O
suppressed	O
by	O
much	O
stronger	O
silencing	O
activity	O
associated	O
with	O
the	O
silencing	O
domain	O
.	O

Was	O
the	O
lack	O
of	O
barrier	O
function	O
of	O
fusion	O
constructs	O
L2	O
-	O
L5	O
due	O
to	O
a	O
lack	O
of	O
expression	O
of	O
these	O
proteins	O
?	O

To	O
address	O
this	O
possibility	O
,	O
we	O
examined	O
the	O
levels	O
of	O
L1	O
-	O
L6	O
proteins	O
as	O
well	O
as	O
L7	O
and	O
L8	O
proteins	O
described	O
in	O
Figure	O
5B	O
by	O
western	O
blotting	O
using	O
an	O
antibody	O
against	O
LexA	O
.	O

As	O
shown	O
in	O
Figure	O
5C	O
,	O
L5	O
was	O
expressed	O
at	O
a	O
level	O
comparable	O
to	O
L6	O
,	O
and	O
L4	O
was	O
expressed	O
at	O
a	O
higher	O
level	O
than	O
L6	O
.	O

Therefore	O
,	O
the	O
lack	O
of	O
barrier	O
function	O
of	O
L4	O
and	O
L6	O
was	O
not	O
the	O
result	O
of	O
their	O
lack	O
of	O
expression	O
.	O

On	O
the	O
other	O
hand	O
,	O
the	O
level	O
of	O
L2	O
or	O
L3	O
was	O
significantly	O
lower	O
than	O
that	O
of	O
L6	O
,	O
hence	O
the	O
lack	O
of	O
barrier	O
function	O
of	O
L2	O
and	O
L3	O
might	O
be	O
due	O
to	O
their	O
insufficient	O
expression	O
.	O

As	O
an	O
important	O
control	O
for	O
the	O
above	O
targeting	O
experiments	O
,	O
we	O
showed	O
that	O
plasmids	O
L1	O
-	O
L6	O
(	O
Fig	O
.	O
5A	O
)	O
as	O
well	O
as	O
L7	O
and	O
L8	O
(	O
Fig	O
.	O
5B	O
)	O
bearing	O
LexA	O
-	O
fusion	O
genes	O
had	O
no	O
effect	O
on	O
URA3	O
silencing	O
in	O
strain	O
1	O
(	O
Fig	O
.	O
1	O
)	O
in	O
which	O
there	O
was	O
no	O
binding	O
site	O
for	O
LexA	O
present	O
between	O
HML	O
-	O
I	O
and	O
URA3	O
(	O
data	O
not	O
shown	O
)	O
.	O

Hence	O
,	O
the	O
effect	O
of	O
the	O
fusion	O
proteins	O
on	O
URA3	O
silencing	O
was	O
the	O
result	O
of	O
their	O
targeting	O
to	O
specific	O
loci	O
,	O
not	O
the	O
consequence	O
of	O
non	O
-	O
specific	O
,	O
indirect	O
functions	O
(	O
if	O
any	O
)	O
of	O
these	O
proteins	O
.	O

Targeted	O
activation	O
domain	O
of	O
Adr1p	O
or	O
Gcn4p	O
can	O
also	O
act	O
as	O
a	O
barrier	O
factor	O

We	O
have	O
shown	O
above	O
that	O
ADH2	O
-	O
UAS	O
bearing	O
Adr1p	O
-	O
binding	O
sites	O
and	O
HIS3	O
-	O
UAS	O
bearing	O
Gcn4p	O
sites	O
both	O
had	O
detectable	O
barrier	O
activity	O
(	O
Fig	O
.	O
1	O
,	O
strains	O
25	O
and	O
26	O
)	O
.	O

Given	O
that	O
tethering	O
the	O
activation	O
domain	O
of	O
Rap1p	O
is	O
sufficient	O
for	O
barrier	O
function	O
,	O
we	O
tested	O
if	O
targeting	O
the	O
activation	O
domain	O
of	O
Adr1p	O
or	O
Gcn4p	O
could	O
also	O
establish	O
a	O
barrier	O
.	O

Adr1p	O
contains	O
four	O
separate	O
activation	O
domains	O
(	O
TADI	O
-	O
TADIV	O
)	O
that	O
can	O
contact	O
Ada2p	O
,	O
Gcn5p	O
and	O
/	O
or	O
TFIIB	O
(	O
45	O
)	O
.	O

TAD	O
III	O
(	O
415	O
-	O
467	O
)	O
interacts	O
with	O
only	O
Gcn5p	O
but	O
not	O
Ada2p	O
or	O
TFIIB	O
.	O

We	O
fused	O
this	O
domain	O
of	O
Adr1p	O
and	O
the	O
activation	O
domain	O
of	O
Gcn4p	O
(	O
102	O
-	O
149	O
)	O
to	O
LexA	O
,	O
respectively	O
(	O
Fig	O
.	O
5B	O
,	O
L7	O
and	O
L8	O
)	O
.	O

Targeting	O
these	O
fusion	O
proteins	O
to	O
two	O
LexA	O
-	O
binding	O
sites	O
between	O
HML	O
-	O
I	O
and	O
URA3	O
in	O
strain	O
50	O
dramatically	O
reduced	O
URA3	O
silencing	O
(	O
Fig	O
.	O
5B	O
,	O
compare	O
L7	O
and	O
L8	O
to	O
L1	O
)	O
.	O

Therefore	O
,	O
like	O
LexA	O
-	O
Rap1p	O
(	O
627	O
-	O
695	O
)	O
,	O
both	O
LexA	O
-	O
Adr1p	O
(	O
415	O
-	O
467	O
)	O
and	O
LexA	O
-	O
Gcn4p	O
(	O
102	O
-	O
149	O
)	O
also	O
had	O
barrier	O
activity	O
.	O

Barrier	O
function	O
of	O
these	O
fusion	O
proteins	O
was	O
significantly	O
decreased	O
in	O
strain	O
51	O
in	O
which	O
only	O
one	O
LexA	O
site	O
was	O
inserted	O
between	O
HML	O
-	O
I	O
and	O
URA3	O
(	O
compare	O
strains	O
50	O
and	O
51	O
carrying	O
plasmid	O
L7	O
)	O
,	O
indicating	O
that	O
the	O
potency	O
of	O
such	O
barriers	O
was	O
dependent	O
on	O
the	O
amount	O
of	O
tethered	O
fusion	O
proteins	O
.	O

DISCUSSION	O

We	O
have	O
shown	O
in	O
this	O
report	O
that	O
UASs	O
of	O
many	O
highly	O
expressed	O
genes	O
could	O
function	O
as	O
barriers	O
to	O
the	O
spread	O
of	O
transcriptional	O
silencing	O
.	O

These	O
newly	O
identified	O
barrier	O
elements	O
together	O
with	O
previously	O
described	O
barrier	O
elements	O
(	O
STARs	O
,	O
HMR	O
-	O
tRNA	O
gene	O
,	O
TEF2	O
-	O
UAS	O
and	O
CHA1	O
-	O
UAS	O
)	O
(	O
9	O
-	O
11	O
,	O
21	O
)	O
are	O
scattered	O
across	O
the	O
yeast	B
genome	O
and	O
may	O
play	O
a	O
role	O
in	O
dividing	O
the	O
genome	O
into	O
functional	O
domains	O
.	O

Analyses	O
of	O
the	O
barrier	O
UASs	O
suggest	O
that	O
binding	O
sites	O
for	O
transcriptional	O
regulators	O
Rap1p	O
,	O
Abf1p	O
,	O
Reb1p	O
,	O
Adr1p	O
and	O
Gcn4p	O
can	O
participate	O
in	O
barrier	O
function	O
.	O

Barrier	O
activity	O
often	O
requires	O
concerted	O
actions	O
of	O
more	O
than	O
one	O
factor	O
-	O
binding	O
site	O
.	O

Our	O
mutational	O
analysis	O
of	O
TEF2	O
-	O
UAS	O
suggests	O
a	O
direct	O
involvement	O
of	O
Rap1p	O
in	O
its	O
barrier	O
function	O
.	O

It	O
is	O
noteworthy	O
that	O
not	O
all	O
UASs	O
of	O
highly	O
expressed	O
genes	O
have	O
barrier	O
activity	O
.	O

Many	O
non	O
-	O
barrier	O
UASs	O
also	O
consist	O
of	O
multiple	O
regulator	O
binding	O
sites	O
,	O
therefore	O
other	O
unknown	O
factors	O
might	O
determine	O
whether	O
a	O
UAS	O
could	O
act	O
as	O
a	O
barrier	O
.	O

How	O
Rap1p	O
and	O
the	O
other	O
transcriptional	O
regulators	O
act	O
to	O
block	O
silencing	O
is	O
not	O
clear	O
.	O

Since	O
they	O
can	O
all	O
act	O
as	O
transcriptional	O
activators	O
,	O
one	O
natural	O
explanation	O
is	O
that	O
they	O
may	O
overcome	O
the	O
silencing	O
effect	O
of	O
a	O
silencer	O
and	O
directly	O
activate	O
the	O
reporter	O
gene	O
.	O

However	O
,	O
it	O
has	O
been	O
well	O
documented	O
that	O
Rap1p	O
and	O
the	O
other	O
transcriptional	O
regulators	O
usually	O
act	O
at	O
relatively	O
short	O
distances	O
(	O
less	O
than	O
~	O
600	O
bp	O
upstream	O
of	O
the	O
translation	O
start	O
codon	O
)	O
(	O
28	O
,	O
29	O
,	O
46	O
)	O
,	O
but	O
the	O
binding	O
sites	O
for	O
these	O
regulators	O
were	O
>	O
800	O
bp	O
from	O
the	O
translation	O
start	O
codon	O
in	O
most	O
of	O
the	O
silencing	O
-	O
blocking	O
tests	O
in	O
this	O
report	O
(	O
Figs	O
1	O
and	O
2	O
)	O
.	O

In	O
the	O
test	O
shown	O
in	O
Figure	O
6	O
,	O
TEF2	O
-	O
UAS	O
blocked	O
ADE2	O
silencing	O
when	O
it	O
was	O
~	O
2	O
kb	O
downstream	O
from	O
the	O
translation	O
start	O
codon	O
of	O
the	O
gene	O
.	O

Moreover	O
,	O
Fourel	O
et	O
al	O
.	O

(	O
44	O
)	O
demonstrated	O
that	O
the	O
barrier	O
function	O
(	O
or	O
anti	O
-	O
silencing	O
function	O
)	O
of	O
an	O
activator	O
was	O
independent	O
of	O
its	O
role	O
in	O
activating	O
transcription	O
.	O

Therefore	O
,	O
it	O
is	O
unlikely	O
that	O
the	O
ability	O
of	O
a	O
UAS	O
to	O
prevent	O
gene	O
silencing	O
is	O
due	O
to	O
its	O
direct	O
activation	O
of	O
the	O
gene	O
.	O

In	O
light	O
of	O
this	O
,	O
our	O
results	O
are	O
in	O
agreement	O
with	O
the	O
notion	O
that	O
transcriptional	O
regulators	O
can	O
also	O
participate	O
in	O
defining	O
the	O
boundaries	O
of	O
functional	O
chromosomal	O
domains	O
.	O

A	O
few	O
models	O
have	O
been	O
proposed	O
for	O
the	O
barrier	O
functions	O
of	O
transcriptional	O
regulators	O
.	O

One	O
model	O
proposed	O
that	O
binding	O
of	O
a	O
regulator	O
to	O
a	O
barrier	O
led	O
to	O
the	O
formation	O
of	O
a	O
nucleosome	O
-	O
free	O
region	O
thereby	O
disrupting	O
a	O
continuous	O
nucleosome	O
array	O
(	O
11	O
)	O
.	O

Since	O
the	O
SIR	O
complexes	O
spread	O
by	O
self	O
-	O
interaction	O
and	O
interacting	O
with	O
adjacent	O
nucleosmes	O
in	O
a	O
stepwise	O
fashion	O
(	O
4	O
)	O
,	O
a	O
nucleosome	O
-	O
free	O
gap	O
could	O
present	O
a	O
barrier	O
to	O
the	O
spreading	O
SIR	O
complex	O
.	O

This	O
'	O
nucleosome	O
gap	O
'	O
hypothesis	O
is	O
consistent	O
with	O
that	O
certain	O
barrier	O
factors	O
such	O
as	O
Rap1p	O
and	O
Reb1p	O
could	O
indeed	O
prevent	O
nucleosome	O
formation	O
around	O
their	O
binding	O
sites	O
(	O
14	O
)	O
and	O
the	O
barrier	O
function	O
of	O
TEF2	O
-	O
UAS	O
correlated	O
with	O
its	O
ability	O
to	O
alter	O
local	O
chromatin	O
structure	O
(	O
this	O
report	O
)	O
.	O

In	O
fact	O
,	O
many	O
insulator	O
/	O
boundary	O
elements	O
in	O
higher	O
organisms	O
have	O
also	O
been	O
shown	O
to	O
alter	O
local	O
chromatin	O
structure	O
.	O

For	O
instance	O
,	O
the	O
chicken	B
beta	O
-	O
globin	O
insulator	O
was	O
linked	O
to	O
changes	O
in	O
nucleosome	O
positioning	O
,	O
and	O
the	O
Drosophila	B
scs	O
and	O
scs	O
'	O
boundary	O
elements	O
are	O
associated	O
with	O
unusual	O
chromatin	O
structures	O
that	O
are	O
hypersensitive	O
to	O
nucleases	O
(	O
40	O
,	O
41	O
)	O
.	O

However	O
,	O
it	O
is	O
not	O
clear	O
whether	O
any	O
chromatin	O
change	O
associated	O
with	O
barrier	O
function	O
in	O
yeast	B
or	O
insulator	O
function	O
in	O
higher	O
cells	O
is	O
the	O
cause	O
or	O
effect	O
of	O
the	O
function	O
.	O

Another	O
model	O
for	O
barrier	O
action	O
proposed	O
by	O
R	O
.	O

Kamakaka	O
and	O
colleagues	O
(	O
21	O
)	O
proposed	O
that	O
barrier	O
factors	O
recruit	O
chromatin	O
modifying	O
and	O
/	O
or	O
remodeling	O
complexes	O
to	O
counteract	O
the	O
more	O
compact	O
,	O
hypoacetylated	O
silent	O
chromatin	O
.	O

In	O
agreement	O
with	O
this	O
hypothesis	O
,	O
targeted	O
HATs	O
SAS2	O
,	O
GCN5	O
and	O
ESA1	O
all	O
had	O
barrier	O
activity	O
(	O
21	O
;	O
Y	O
.	O
-	O
H	O
.	O
Chiu	O
,	O
Q	O
.	O
Yu	O
and	O
X	O
.	O
Bi	O
,	O
unpublished	O
results	O
)	O
.	O

Interestingly	O
,	O
Rap1p	O
,	O
Adr1p	O
,	O
Gcn4p	O
and	O
Abf1p	O
share	O
the	O
ability	O
to	O
recruit	O
HAT	O
complexes	O
NuA4	O
and	O
/	O
or	O
SAGA	O
to	O
target	O
genes	O
(	O
16	O
,	O
45	O
,	O
47	O
-	O
49	O
)	O
.	O

Therefore	O
,	O
these	O
factors	O
that	O
are	O
capable	O
of	O
binding	O
to	O
the	O
newly	O
identified	O
barriers	O
may	O
function	O
as	O
barrier	O
factors	O
by	O
recruiting	O
HAT	O
complexes	O
.	O

In	O
fact	O
,	O
recruitment	O
of	O
HAT	O
activity	O
has	O
also	O
been	O
suggested	O
to	O
be	O
the	O
mechanism	O
underlying	O
the	O
function	O
of	O
the	O
chicken	B
beta	O
-	O
globin	O
insulator	O
(	O
6	O
)	O
,	O
although	O
it	O
was	O
not	O
known	O
what	O
HAT	O
might	O
be	O
involved	O
.	O

Our	O
demonstration	O
that	O
tethering	O
the	O
activation	O
domain	O
of	O
Rap1p	O
,	O
Adr1p	O
or	O
Gcn4p	O
alone	O
recapitulates	O
barrier	O
activity	O
is	O
consistent	O
with	O
the	O
above	O
HAT	O
model	O
for	O
barrier	O
function	O
,	O
since	O
at	O
least	O
the	O
activation	O
domain	O
of	O
Adr1p	O
has	O
been	O
shown	O
to	O
directly	O
interact	O
with	O
HAT	O
complexes	O
(	O
45	O
)	O
.	O

However	O
,	O
we	O
haven	O
'	O
t	O
ruled	O
out	O
the	O
possibility	O
that	O
the	O
barrier	O
function	O
of	O
the	O
targeted	O
activation	O
domain	O
of	O
Rap1p	O
,	O
Adr1p	O
or	O
Gcn4p	O
is	O
not	O
related	O
to	O
the	O
barrier	O
function	O
of	O
the	O
native	O
protein	O
.	O

Note	O
that	O
the	O
'	O
nucleosome	O
gap	O
'	O
model	O
and	O
the	O
HAT	O
model	O
are	O
not	O
mutually	O
exclusive	O
since	O
the	O
nucleosome	O
gap	O
could	O
result	O
from	O
destabilization	O
of	O
nucelosomes	O
caused	O
by	O
HAT	O
function	O
.	O

A	O
recent	O
intriguing	O
study	O
showed	O
that	O
targeting	O
proteins	O
of	O
the	O
nuclear	O
pore	O
complex	O
(	O
NPC	O
)	O
could	O
also	O
establish	O
a	O
boundary	O
for	O
silent	O
chromatin	O
,	O
and	O
that	O
tethering	O
to	O
NPC	O
was	O
required	O
for	O
boundary	O
activity	O
(	O
50	O
)	O
.	O

This	O
led	O
to	O
a	O
revisit	O
to	O
the	O
looping	O
model	O
for	O
the	O
function	O
of	O
boundary	O
/	O
insulator	O
elements	O
(	O
51	O
)	O
.	O

However	O
,	O
an	O
alternative	O
explanation	O
was	O
that	O
the	O
NPC	O
compartment	O
could	O
simply	O
be	O
rich	O
in	O
transcriptional	O
activating	O
factors	O
or	O
poor	O
in	O
silencing	O
factors	O
like	O
the	O
SIR	O
proteins	O
(	O
50	O
)	O
.	O

In	O
summary	O
,	O
results	O
from	O
this	O
and	O
other	O
studies	O
indicate	O
that	O
factors	O
previously	O
identified	O
as	O
positive	O
and	O
/	O
or	O
negative	O
regulators	O
of	O
gene	O
activation	O
could	O
also	O
function	O
in	O
demarcating	O
distinct	O
domains	O
of	O
gene	O
activity	O
.	O

How	O
these	O
factors	O
carry	O
out	O
their	O
boundary	O
function	O
is	O
not	O
resolved	O
but	O
recruitment	O
of	O
other	O
factors	O
(	O
e	O
.	O
g	O
.	O
chromatin	O
modifying	O
complexes	O
)	O
is	O
likely	O
to	O
be	O
involved	O
.	O

NOTE	O
ADDED	O
IN	O
PROOF	O

After	O
this	O
work	O
was	O
completed	O
and	O
submitted	O
for	O
publication	O
the	O
first	O
time	O
,	O
Fourel	O
et	O
al	O
.	O

(	O
52	O
)	O
reported	O
that	O
targeted	O
activation	O
domains	O
of	O
Rap1p	O
and	O
Abf1p	O
had	O
insulating	O
capacity	O
.	O

Comparison	O
of	O
age	O
-	O
specific	O
cataract	O
prevalence	O
in	O
two	O
population	O
-	O
based	O
surveys	O
6	O
years	O
apart	O

Abstract	O

Background	O

In	O
this	O
study	O
,	O
we	O
aimed	O
to	O
compare	O
age	O
-	O
specific	O
cortical	O
,	O
nuclear	O
and	O
posterior	O
subcapsular	O
(	O
PSC	O
)	O
cataract	O
prevalence	O
in	O
two	O
surveys	O
6	O
years	O
apart	O
.	O

Methods	O

The	O
Blue	O
Mountains	O
Eye	O
Study	O
examined	O
3654	O
participants	B
(	O
82	O
.	O
4	O
%	O
of	O
those	O
eligible	O
)	O
in	O
cross	O
-	O
section	O
I	O
(	O
1992	O
-	O
4	O
)	O
and	O
3509	O
participants	B
(	O
75	O
.	O
1	O
%	O
of	O
survivors	O
and	O
85	O
.	O
2	O
%	O
of	O
newly	O
eligible	O
)	O
in	O
cross	O
-	O
section	O
II	O
(	O
1997	O
-	O
2000	O
,	O
66	O
.	O
5	O
%	O
overlap	O
with	O
cross	O
-	O
section	O
I	O
)	O
.	O

Cataract	O
was	O
assessed	O
from	O
lens	O
photographs	O
following	O
the	O
Wisconsin	O
Cataract	O
Grading	O
System	O
.	O

Cortical	O
cataract	O
was	O
defined	O
if	O
cortical	O
opacity	O
comprised	O
>	O
=	O
5	O
%	O
of	O
lens	O
area	O
.	O

Nuclear	O
cataract	O
was	O
defined	O
if	O
nuclear	O
opacity	O
>	O
=	O
Wisconsin	O
standard	O
4	O
.	O

PSC	O
was	O
defined	O
if	O
any	O
present	O
.	O

Any	O
cataract	O
was	O
defined	O
to	O
include	O
persons	B
who	O
had	O
previous	O
cataract	O
surgery	O
.	O

Weighted	O
kappa	O
for	O
inter	O
-	O
grader	O
reliability	O
was	O
0	O
.	O
82	O
,	O
0	O
.	O
55	O
and	O
0	O
.	O
82	O
for	O
cortical	O
,	O
nuclear	O
and	O
PSC	O
cataract	O
,	O
respectively	O
.	O

We	O
assessed	O
age	O
-	O
specific	O
prevalence	O
using	O
an	O
interval	O
of	O
5	O
years	O
,	O
so	O
that	O
participants	B
within	O
each	O
age	O
group	O
were	O
independent	O
between	O
the	O
two	O
surveys	O
.	O

Results	O

Age	O
and	O
gender	O
distributions	O
were	O
similar	O
between	O
the	O
two	O
populations	O
.	O

The	O
age	O
-	O
specific	O
prevalence	O
of	O
cortical	O
(	O
23	O
.	O
8	O
%	O
in	O
1st	O
,	O
23	O
.	O
7	O
%	O
in	O
2nd	O
)	O
and	O
PSC	O
cataract	O
(	O
6	O
.	O
3	O
%	O
,	O
6	O
.	O
0	O
%	O
)	O
was	O
similar	O
.	O

The	O
prevalence	O
of	O
nuclear	O
cataract	O
increased	O
slightly	O
from	O
18	O
.	O
7	O
%	O
to	O
23	O
.	O
9	O
%	O
.	O

After	O
age	O
standardization	O
,	O
the	O
similar	O
prevalence	O
of	O
cortical	O
(	O
23	O
.	O
8	O
%	O
,	O
23	O
.	O
5	O
%	O
)	O
and	O
PSC	O
cataract	O
(	O
6	O
.	O
3	O
%	O
,	O
5	O
.	O
9	O
%	O
)	O
,	O
and	O
the	O
increased	O
prevalence	O
of	O
nuclear	O
cataract	O
(	O
18	O
.	O
7	O
%	O
,	O
24	O
.	O
2	O
%	O
)	O
remained	O
.	O

Conclusion	O

In	O
two	O
surveys	O
of	O
two	O
population	O
-	O
based	O
samples	O
with	O
similar	O
age	O
and	O
gender	O
distributions	O
,	O
we	O
found	O
a	O
relatively	O
stable	O
cortical	O
and	O
PSC	O
cataract	O
prevalence	O
over	O
a	O
6	O
-	O
year	O
period	O
.	O

The	O
increased	O
prevalence	O
of	O
nuclear	O
cataract	O
deserves	O
further	O
study	O
.	O

Background	O

Age	O
-	O
related	O
cataract	O
is	O
the	O
leading	O
cause	O
of	O
reversible	O
visual	O
impairment	O
in	O
older	O
persons	B
[	O
1	O
-	O
6	O
]	O
.	O

In	O
Australia	O
,	O
it	O
is	O
estimated	O
that	O
by	O
the	O
year	O
2021	O
,	O
the	O
number	O
of	O
people	B
affected	O
by	O
cataract	O
will	O
increase	O
by	O
63	O
%	O
,	O
due	O
to	O
population	O
aging	O
[	O
7	O
]	O
.	O

Surgical	O
intervention	O
is	O
an	O
effective	O
treatment	O
for	O
cataract	O
and	O
normal	O
vision	O
(	O
>	O
20	O
/	O
40	O
)	O
can	O
usually	O
be	O
restored	O
with	O
intraocular	O
lens	O
(	O
IOL	O
)	O
implantation	O
.	O

Cataract	O
surgery	O
with	O
IOL	O
implantation	O
is	O
currently	O
the	O
most	O
commonly	O
performed	O
,	O
and	O
is	O
,	O
arguably	O
,	O
the	O
most	O
cost	O
effective	O
surgical	O
procedure	O
worldwide	O
.	O

Performance	O
of	O
this	O
surgical	O
procedure	O
has	O
been	O
continuously	O
increasing	O
in	O
the	O
last	O
two	O
decades	O
.	O

Data	O
from	O
the	O
Australian	O
Health	O
Insurance	O
Commission	O
has	O
shown	O
a	O
steady	O
increase	O
in	O
Medicare	O
claims	O
for	O
cataract	O
surgery	O
[	O
8	O
]	O
.	O

A	O
2	O
.	O
6	O
-	O
fold	O
increase	O
in	O
the	O
total	O
number	O
of	O
cataract	O
procedures	O
from	O
1985	O
to	O
1994	O
has	O
been	O
documented	O
in	O
Australia	O
[	O
9	O
]	O
.	O

The	O
rate	O
of	O
cataract	O
surgery	O
per	O
thousand	O
persons	B
aged	O
65	O
years	O
or	O
older	O
has	O
doubled	O
in	O
the	O
last	O
20	O
years	O
[	O
8	O
,	O
9	O
]	O
.	O

In	O
the	O
Blue	O
Mountains	O
Eye	O
Study	O
population	O
,	O
we	O
observed	O
a	O
one	O
-	O
third	O
increase	O
in	O
cataract	O
surgery	O
prevalence	O
over	O
a	O
mean	O
6	O
-	O
year	O
interval	O
,	O
from	O
6	O
%	O
to	O
nearly	O
8	O
%	O
in	O
two	O
cross	O
-	O
sectional	O
population	O
-	O
based	O
samples	O
with	O
a	O
similar	O
age	O
range	O
[	O
10	O
]	O
.	O

Further	O
increases	O
in	O
cataract	O
surgery	O
performance	O
would	O
be	O
expected	O
as	O
a	O
result	O
of	O
improved	O
surgical	O
skills	O
and	O
technique	O
,	O
together	O
with	O
extending	O
cataract	O
surgical	O
benefits	O
to	O
a	O
greater	O
number	O
of	O
older	O
people	B
and	O
an	O
increased	O
number	O
of	O
persons	B
with	O
surgery	O
performed	O
on	O
both	O
eyes	O
.	O

Both	O
the	O
prevalence	O
and	O
incidence	O
of	O
age	O
-	O
related	O
cataract	O
link	O
directly	O
to	O
the	O
demand	O
for	O
,	O
and	O
the	O
outcome	O
of	O
,	O
cataract	O
surgery	O
and	O
eye	O
health	O
care	O
provision	O
.	O

This	O
report	O
aimed	O
to	O
assess	O
temporal	O
changes	O
in	O
the	O
prevalence	O
of	O
cortical	O
and	O
nuclear	O
cataract	O
and	O
posterior	O
subcapsular	O
cataract	O
(	O
PSC	O
)	O
in	O
two	O
cross	O
-	O
sectional	O
population	O
-	O
based	O
surveys	O
6	O
years	O
apart	O
.	O

Methods	O

The	O
Blue	O
Mountains	O
Eye	O
Study	O
(	O
BMES	O
)	O
is	O
a	O
population	O
-	O
based	O
cohort	O
study	O
of	O
common	O
eye	O
diseases	O
and	O
other	O
health	O
outcomes	O
.	O

The	O
study	O
involved	O
eligible	O
permanent	O
residents	O
aged	O
49	O
years	O
and	O
older	O
,	O
living	O
in	O
two	O
postcode	O
areas	O
in	O
the	O
Blue	O
Mountains	O
,	O
west	O
of	O
Sydney	O
,	O
Australia	O
.	O

Participants	B
were	O
identified	O
through	O
a	O
census	O
and	O
were	O
invited	O
to	O
participate	O
.	O

The	O
study	O
was	O
approved	O
at	O
each	O
stage	O
of	O
the	O
data	O
collection	O
by	O
the	O
Human	B
Ethics	O
Committees	O
of	O
the	O
University	O
of	O
Sydney	O
and	O
the	O
Western	O
Sydney	O
Area	O
Health	O
Service	O
and	O
adhered	O
to	O
the	O
recommendations	O
of	O
the	O
Declaration	O
of	O
Helsinki	O
.	O

Written	O
informed	O
consent	O
was	O
obtained	O
from	O
each	O
participant	B
.	O

Details	O
of	O
the	O
methods	O
used	O
in	O
this	O
study	O
have	O
been	O
described	O
previously	O
[	O
11	O
]	O
.	O

The	O
baseline	O
examinations	O
(	O
BMES	O
cross	O
-	O
section	O
I	O
)	O
were	O
conducted	O
during	O
1992	O
-	O
1994	O
and	O
included	O
3654	O
(	O
82	O
.	O
4	O
%	O
)	O
of	O
4433	O
eligible	O
residents	O
.	O

Follow	O
-	O
up	O
examinations	O
(	O
BMES	O
IIA	O
)	O
were	O
conducted	O
during	O
1997	O
-	O
1999	O
,	O
with	O
2335	O
(	O
75	O
.	O
0	O
%	O
of	O
BMES	O
cross	O
section	O
I	O
survivors	O
)	O
participating	O
.	O

A	O
repeat	O
census	O
of	O
the	O
same	O
area	O
was	O
performed	O
in	O
1999	O
and	O
identified	O
1378	O
newly	O
eligible	O
residents	O
who	O
moved	O
into	O
the	O
area	O
or	O
the	O
eligible	O
age	O
group	O
.	O

During	O
1999	O
-	O
2000	O
,	O
1174	O
(	O
85	O
.	O
2	O
%	O
)	O
of	O
this	O
group	O
participated	O
in	O
an	O
extension	O
study	O
(	O
BMES	O
IIB	O
)	O
.	O

BMES	O
cross	O
-	O
section	O
II	O
thus	O
includes	O
BMES	O
IIA	O
(	O
66	O
.	O
5	O
%	O
)	O
and	O
BMES	O
IIB	O
(	O
33	O
.	O
5	O
%	O
)	O
participants	B
(	O
n	O
=	O
3509	O
)	O
.	O

Similar	O
procedures	O
were	O
used	O
for	O
all	O
stages	O
of	O
data	O
collection	O
at	O
both	O
surveys	O
.	O

A	O
questionnaire	O
was	O
administered	O
including	O
demographic	O
,	O
family	O
and	O
medical	O
history	O
.	O

A	O
detailed	O
eye	O
examination	O
included	O
subjective	O
refraction	O
,	O
slit	O
-	O
lamp	O
(	O
Topcon	O
SL	O
-	O
7e	O
camera	O
,	O
Topcon	O
Optical	O
Co	O
,	O
Tokyo	O
,	O
Japan	O
)	O
and	O
retroillumination	O
(	O
Neitz	O
CT	O
-	O
R	O
camera	O
,	O
Neitz	O
Instrument	O
Co	O
,	O
Tokyo	O
,	O
Japan	O
)	O
photography	O
of	O
the	O
lens	O
.	O

Grading	O
of	O
lens	O
photographs	O
in	O
the	O
BMES	O
has	O
been	O
previously	O
described	O
[	O
12	O
]	O
.	O

Briefly	O
,	O
masked	O
grading	O
was	O
performed	O
on	O
the	O
lens	O
photographs	O
using	O
the	O
Wisconsin	O
Cataract	O
Grading	O
System	O
[	O
13	O
]	O
.	O

Cortical	O
cataract	O
and	O
PSC	O
were	O
assessed	O
from	O
the	O
retroillumination	O
photographs	O
by	O
estimating	O
the	O
percentage	O
of	O
the	O
circular	O
grid	O
involved	O
.	O

Cortical	O
cataract	O
was	O
defined	O
when	O
cortical	O
opacity	O
involved	O
at	O
least	O
5	O
%	O
of	O
the	O
total	O
lens	O
area	O
.	O

PSC	O
was	O
defined	O
when	O
opacity	O
comprised	O
at	O
least	O
1	O
%	O
of	O
the	O
total	O
lens	O
area	O
.	O

Slit	O
-	O
lamp	O
photographs	O
were	O
used	O
to	O
assess	O
nuclear	O
cataract	O
using	O
the	O
Wisconsin	O
standard	O
set	O
of	O
four	O
lens	O
photographs	O
[	O
13	O
]	O
.	O

Nuclear	O
cataract	O
was	O
defined	O
when	O
nuclear	O
opacity	O
was	O
at	O
least	O
as	O
great	O
as	O
the	O
standard	O
4	O
photograph	O
.	O

Any	O
cataract	O
was	O
defined	O
to	O
include	O
persons	B
who	O
had	O
previous	O
cataract	O
surgery	O
as	O
well	O
as	O
those	O
with	O
any	O
of	O
three	O
cataract	O
types	O
.	O

Inter	O
-	O
grader	O
reliability	O
was	O
high	O
,	O
with	O
weighted	O
kappa	O
0	O
.	O
82	O
for	O
cortical	O
cataract	O
,	O
0	O
.	O
55	O
(	O
simple	O
kappa	O
0	O
.	O
75	O
)	O
for	O
nuclear	O
cataract	O
and	O
0	O
.	O
82	O
for	O
PSC	O
grading	O
.	O

The	O
intra	O
-	O
grader	O
reliability	O
for	O
nuclear	O
cataract	O
was	O
assessed	O
with	O
simple	O
kappa	O
0	O
.	O
83	O
for	O
the	O
senior	O
grader	O
who	O
graded	O
nuclear	O
cataract	O
at	O
both	O
surveys	O
.	O

All	O
PSC	O
cases	O
were	O
confirmed	O
by	O
an	O
ophthalmologist	O
(	O
PM	O
)	O
.	O

In	O
cross	O
-	O
section	O
I	O
,	O
219	O
persons	B
(	O
6	O
.	O
0	O
%	O
)	O
had	O
missing	O
or	O
ungradable	O
Neitz	O
photographs	O
,	O
leaving	O
3435	O
with	O
photographs	O
available	O
for	O
cortical	O
cataract	O
and	O
PSC	O
assessment	O
,	O
while	O
1153	O
(	O
31	O
.	O
6	O
%	O
)	O
had	O
randomly	O
missing	O
or	O
ungradable	O
Topcon	O
photographs	O
due	O
to	O
a	O
camera	O
malfunction	O
,	O
leaving	O
2501	O
with	O
photographs	O
available	O
for	O
nuclear	O
cataract	O
assessment	O
.	O

Comparison	O
of	O
characteristics	O
between	O
participants	B
with	O
and	O
without	O
Neitz	O
or	O
Topcon	O
photographs	O
in	O
cross	O
-	O
section	O
I	O
showed	O
no	O
statistically	O
significant	O
differences	O
between	O
the	O
two	O
groups	O
,	O
as	O
reported	O
previously	O
[	O
12	O
]	O
.	O

In	O
cross	O
-	O
section	O
II	O
,	O
441	O
persons	B
(	O
12	O
.	O
5	O
%	O
)	O
had	O
missing	O
or	O
ungradable	O
Neitz	O
photographs	O
,	O
leaving	O
3068	O
for	O
cortical	O
cataract	O
and	O
PSC	O
assessment	O
,	O
and	O
648	O
(	O
18	O
.	O
5	O
%	O
)	O
had	O
missing	O
or	O
ungradable	O
Topcon	O
photographs	O
,	O
leaving	O
2860	O
for	O
nuclear	O
cataract	O
assessment	O
.	O

Data	O
analysis	O
was	O
performed	O
using	O
the	O
Statistical	O
Analysis	O
System	O
(	O
SAS	O
,	O
SAS	O
Institute	O
,	O
Cary	O
,	O
NC	O
,	O
USA	O
)	O
.	O

Age	O
-	O
adjusted	O
prevalence	O
was	O
calculated	O
using	O
direct	O
standardization	O
of	O
the	O
cross	O
-	O
section	O
II	O
population	O
to	O
the	O
cross	O
-	O
section	O
I	O
population	O
.	O

We	O
assessed	O
age	O
-	O
specific	O
prevalence	O
using	O
an	O
interval	O
of	O
5	O
years	O
,	O
so	O
that	O
participants	B
within	O
each	O
age	O
group	O
were	O
independent	O
between	O
the	O
two	O
cross	O
-	O
sectional	O
surveys	O
.	O

Results	O

Characteristics	O
of	O
the	O
two	O
survey	O
populations	O
have	O
been	O
previously	O
compared	O
[	O
14	O
]	O
and	O
showed	O
that	O
age	O
and	O
sex	O
distributions	O
were	O
similar	O
.	O

Table	O
1	O
compares	O
participant	B
characteristics	O
between	O
the	O
two	O
cross	O
-	O
sections	O
.	O

Cross	O
-	O
section	O
II	O
participants	B
generally	O
had	O
higher	O
rates	O
of	O
diabetes	O
,	O
hypertension	O
,	O
myopia	O
and	O
more	O
users	O
of	O
inhaled	O
steroids	O
.	O

Cataract	O
prevalence	O
rates	O
in	O
cross	O
-	O
sections	O
I	O
and	O
II	O
are	O
shown	O
in	O
Figure	O
1	O
.	O

The	O
overall	O
prevalence	O
of	O
cortical	O
cataract	O
was	O
23	O
.	O
8	O
%	O
and	O
23	O
.	O
7	O
%	O
in	O
cross	O
-	O
sections	O
I	O
and	O
II	O
,	O
respectively	O
(	O
age	O
-	O
sex	O
adjusted	O
P	O
=	O
0	O
.	O
81	O
)	O
.	O

Corresponding	O
prevalence	O
of	O
PSC	O
was	O
6	O
.	O
3	O
%	O
and	O
6	O
.	O
0	O
%	O
for	O
the	O
two	O
cross	O
-	O
sections	O
(	O
age	O
-	O
sex	O
adjusted	O
P	O
=	O
0	O
.	O
60	O
)	O
.	O

There	O
was	O
an	O
increased	O
prevalence	O
of	O
nuclear	O
cataract	O
,	O
from	O
18	O
.	O
7	O
%	O
in	O
cross	O
-	O
section	O
I	O
to	O
23	O
.	O
9	O
%	O
in	O
cross	O
-	O
section	O
II	O
over	O
the	O
6	O
-	O
year	O
period	O
(	O
age	O
-	O
sex	O
adjusted	O
P	O
<	O
0	O
.	O
001	O
)	O
.	O

Prevalence	O
of	O
any	O
cataract	O
(	O
including	O
persons	B
who	O
had	O
cataract	O
surgery	O
)	O
,	O
however	O
,	O
was	O
relatively	O
stable	O
(	O
46	O
.	O
9	O
%	O
and	O
46	O
.	O
8	O
%	O
in	O
cross	O
-	O
sections	O
I	O
and	O
II	O
,	O
respectively	O
)	O
.	O

After	O
age	O
-	O
standardization	O
,	O
these	O
prevalence	O
rates	O
remained	O
stable	O
for	O
cortical	O
cataract	O
(	O
23	O
.	O
8	O
%	O
and	O
23	O
.	O
5	O
%	O
in	O
the	O
two	O
surveys	O
)	O
and	O
PSC	O
(	O
6	O
.	O
3	O
%	O
and	O
5	O
.	O
9	O
%	O
)	O
.	O

The	O
slightly	O
increased	O
prevalence	O
of	O
nuclear	O
cataract	O
(	O
from	O
18	O
.	O
7	O
%	O
to	O
24	O
.	O
2	O
%	O
)	O
was	O
not	O
altered	O
.	O

Table	O
2	O
shows	O
the	O
age	O
-	O
specific	O
prevalence	O
rates	O
for	O
cortical	O
cataract	O
,	O
PSC	O
and	O
nuclear	O
cataract	O
in	O
cross	O
-	O
sections	O
I	O
and	O
II	O
.	O

A	O
similar	O
trend	O
of	O
increasing	O
cataract	O
prevalence	O
with	O
increasing	O
age	O
was	O
evident	O
for	O
all	O
three	O
types	O
of	O
cataract	O
in	O
both	O
surveys	O
.	O

Comparing	O
the	O
age	O
-	O
specific	O
prevalence	O
between	O
the	O
two	O
surveys	O
,	O
a	O
reduction	O
in	O
PSC	O
prevalence	O
in	O
cross	O
-	O
section	O
II	O
was	O
observed	O
in	O
the	O
older	O
age	O
groups	O
(	O
>	O
=	O
75	O
years	O
)	O
.	O

In	O
contrast	O
,	O
increased	O
nuclear	O
cataract	O
prevalence	O
in	O
cross	O
-	O
section	O
II	O
was	O
observed	O
in	O
the	O
older	O
age	O
groups	O
(	O
>	O
=	O
70	O
years	O
)	O
.	O

Age	O
-	O
specific	O
cortical	O
cataract	O
prevalence	O
was	O
relatively	O
consistent	O
between	O
the	O
two	O
surveys	O
,	O
except	O
for	O
a	O
reduction	O
in	O
prevalence	O
observed	O
in	O
the	O
80	O
-	O
84	O
age	O
group	O
and	O
an	O
increasing	O
prevalence	O
in	O
the	O
older	O
age	O
groups	O
(	O
>	O
=	O
85	O
years	O
)	O
.	O

Similar	O
gender	O
differences	O
in	O
cataract	O
prevalence	O
were	O
observed	O
in	O
both	O
surveys	O
(	O
Table	O
3	O
)	O
.	O

Higher	O
prevalence	O
of	O
cortical	O
and	O
nuclear	O
cataract	O
in	O
women	B
than	O
men	B
was	O
evident	O
but	O
the	O
difference	O
was	O
only	O
significant	O
for	O
cortical	O
cataract	O
(	O
age	O
-	O
adjusted	O
odds	O
ratio	O
,	O
OR	O
,	O
for	O
women	B
1	O
.	O
3	O
,	O
95	O
%	O
confidence	O
intervals	O
,	O
CI	O
,	O
1	O
.	O
1	O
-	O
1	O
.	O
5	O
in	O
cross	O
-	O
section	O
I	O
and	O
OR	O
1	O
.	O
4	O
,	O
95	O
%	O
CI	O
1	O
.	O
1	O
-	O
1	O
.	O
6	O
in	O
cross	O
-	O
section	O
II	O
)	O
.	O

In	O
contrast	O
,	O
men	B
had	O
slightly	O
higher	O
PSC	O
prevalence	O
than	O
women	B
in	O
both	O
cross	O
-	O
sections	O
but	O
the	O
difference	O
was	O
not	O
significant	O
(	O
OR	O
1	O
.	O
1	O
,	O
95	O
%	O
CI	O
0	O
.	O
8	O
-	O
1	O
.	O
4	O
for	O
men	B
in	O
cross	O
-	O
section	O
I	O
and	O
OR	O
1	O
.	O
2	O
,	O
95	O
%	O
0	O
.	O
9	O
-	O
1	O
.	O
6	O
in	O
cross	O
-	O
section	O
II	O
)	O
.	O

Discussion	O

Findings	O
from	O
two	O
surveys	O
of	O
BMES	O
cross	O
-	O
sectional	O
populations	O
with	O
similar	O
age	O
and	O
gender	O
distribution	O
showed	O
that	O
the	O
prevalence	O
of	O
cortical	O
cataract	O
and	O
PSC	O
remained	O
stable	O
,	O
while	O
the	O
prevalence	O
of	O
nuclear	O
cataract	O
appeared	O
to	O
have	O
increased	O
.	O

Comparison	O
of	O
age	O
-	O
specific	O
prevalence	O
,	O
with	O
totally	O
independent	O
samples	O
within	O
each	O
age	O
group	O
,	O
confirmed	O
the	O
robustness	O
of	O
our	O
findings	O
from	O
the	O
two	O
survey	O
samples	O
.	O

Although	O
lens	O
photographs	O
taken	O
from	O
the	O
two	O
surveys	O
were	O
graded	O
for	O
nuclear	O
cataract	O
by	O
the	O
same	O
graders	O
,	O
who	O
documented	O
a	O
high	O
inter	O
-	O
and	O
intra	O
-	O
grader	O
reliability	O
,	O
we	O
cannot	O
exclude	O
the	O
possibility	O
that	O
variations	O
in	O
photography	O
,	O
performed	O
by	O
different	O
photographers	O
,	O
may	O
have	O
contributed	O
to	O
the	O
observed	O
difference	O
in	O
nuclear	O
cataract	O
prevalence	O
.	O

However	O
,	O
the	O
overall	O
prevalence	O
of	O
any	O
cataract	O
(	O
including	O
cataract	O
surgery	O
)	O
was	O
relatively	O
stable	O
over	O
the	O
6	O
-	O
year	O
period	O
.	O

Although	O
different	O
population	O
-	O
based	O
studies	O
used	O
different	O
grading	O
systems	O
to	O
assess	O
cataract	O
[	O
15	O
]	O
,	O
the	O
overall	O
prevalence	O
of	O
the	O
three	O
cataract	O
types	O
were	O
similar	O
across	O
different	O
study	O
populations	O
[	O
12	O
,	O
16	O
-	O
23	O
]	O
.	O

Most	O
studies	O
have	O
suggested	O
that	O
nuclear	O
cataract	O
is	O
the	O
most	O
prevalent	O
type	O
of	O
cataract	O
,	O
followed	O
by	O
cortical	O
cataract	O
[	O
16	O
-	O
20	O
]	O
.	O

Ours	O
and	O
other	O
studies	O
reported	O
that	O
cortical	O
cataract	O
was	O
the	O
most	O
prevalent	O
type	O
[	O
12	O
,	O
21	O
-	O
23	O
]	O
.	O

Our	O
age	O
-	O
specific	O
prevalence	O
data	O
show	O
a	O
reduction	O
of	O
15	O
.	O
9	O
%	O
in	O
cortical	O
cataract	O
prevalence	O
for	O
the	O
80	O
-	O
84	O
year	O
age	O
group	O
,	O
concordant	O
with	O
an	O
increase	O
in	O
cataract	O
surgery	O
prevalence	O
by	O
9	O
%	O
in	O
those	O
aged	O
80	O
+	O
years	O
observed	O
in	O
the	O
same	O
study	O
population	O
[	O
10	O
]	O
.	O

Although	O
cortical	O
cataract	O
is	O
thought	O
to	O
be	O
the	O
least	O
likely	O
cataract	O
type	O
leading	O
to	O
a	O
cataract	O
surgery	O
,	O
this	O
may	O
not	O
be	O
the	O
case	O
in	O
all	O
older	O
persons	B
.	O

A	O
relatively	O
stable	O
cortical	O
cataract	O
and	O
PSC	O
prevalence	O
over	O
the	O
6	O
-	O
year	O
period	O
is	O
expected	O
.	O

We	O
cannot	O
offer	O
a	O
definitive	O
explanation	O
for	O
the	O
increase	O
in	O
nuclear	O
cataract	O
prevalence	O
.	O

A	O
possible	O
explanation	O
could	O
be	O
that	O
a	O
moderate	O
level	O
of	O
nuclear	O
cataract	O
causes	O
less	O
visual	O
disturbance	O
than	O
the	O
other	O
two	O
types	O
of	O
cataract	O
,	O
thus	O
for	O
the	O
oldest	O
age	O
groups	O
,	O
persons	B
with	O
nuclear	O
cataract	O
could	O
have	O
been	O
less	O
likely	O
to	O
have	O
surgery	O
unless	O
it	O
is	O
very	O
dense	O
or	O
co	O
-	O
existing	O
with	O
cortical	O
cataract	O
or	O
PSC	O
.	O

Previous	O
studies	O
have	O
shown	O
that	O
functional	O
vision	O
and	O
reading	O
performance	O
were	O
high	O
in	O
patients	B
undergoing	O
cataract	O
surgery	O
who	O
had	O
nuclear	O
cataract	O
only	O
compared	O
to	O
those	O
with	O
mixed	O
type	O
of	O
cataract	O
(	O
nuclear	O
and	O
cortical	O
)	O
or	O
PSC	O
[	O
24	O
,	O
25	O
]	O
.	O

In	O
addition	O
,	O
the	O
overall	O
prevalence	O
of	O
any	O
cataract	O
(	O
including	O
cataract	O
surgery	O
)	O
was	O
similar	O
in	O
the	O
two	O
cross	O
-	O
sections	O
,	O
which	O
appears	O
to	O
support	O
our	O
speculation	O
that	O
in	O
the	O
oldest	O
age	O
group	O
,	O
nuclear	O
cataract	O
may	O
have	O
been	O
less	O
likely	O
to	O
be	O
operated	O
than	O
the	O
other	O
two	O
types	O
of	O
cataract	O
.	O

This	O
could	O
have	O
resulted	O
in	O
an	O
increased	O
nuclear	O
cataract	O
prevalence	O
(	O
due	O
to	O
less	O
being	O
operated	O
)	O
,	O
compensated	O
by	O
the	O
decreased	O
prevalence	O
of	O
cortical	O
cataract	O
and	O
PSC	O
(	O
due	O
to	O
these	O
being	O
more	O
likely	O
to	O
be	O
operated	O
)	O
,	O
leading	O
to	O
stable	O
overall	O
prevalence	O
of	O
any	O
cataract	O
.	O

Possible	O
selection	O
bias	O
arising	O
from	O
selective	O
survival	O
among	O
persons	B
without	O
cataract	O
could	O
have	O
led	O
to	O
underestimation	O
of	O
cataract	O
prevalence	O
in	O
both	O
surveys	O
.	O

We	O
assume	O
that	O
such	O
an	O
underestimation	O
occurred	O
equally	O
in	O
both	O
surveys	O
,	O
and	O
thus	O
should	O
not	O
have	O
influenced	O
our	O
assessment	O
of	O
temporal	O
changes	O
.	O

Measurement	O
error	O
could	O
also	O
have	O
partially	O
contributed	O
to	O
the	O
observed	O
difference	O
in	O
nuclear	O
cataract	O
prevalence	O
.	O

Assessment	O
of	O
nuclear	O
cataract	O
from	O
photographs	O
is	O
a	O
potentially	O
subjective	O
process	O
that	O
can	O
be	O
influenced	O
by	O
variations	O
in	O
photography	O
(	O
light	O
exposure	O
,	O
focus	O
and	O
the	O
slit	O
-	O
lamp	O
angle	O
when	O
the	O
photograph	O
was	O
taken	O
)	O
and	O
grading	O
.	O

Although	O
we	O
used	O
the	O
same	O
Topcon	O
slit	O
-	O
lamp	O
camera	O
and	O
the	O
same	O
two	O
graders	O
who	O
graded	O
photos	O
from	O
both	O
surveys	O
,	O
we	O
are	O
still	O
not	O
able	O
to	O
exclude	O
the	O
possibility	O
of	O
a	O
partial	O
influence	O
from	O
photographic	O
variation	O
on	O
this	O
result	O
.	O

A	O
similar	O
gender	O
difference	O
(	O
women	B
having	O
a	O
higher	O
rate	O
than	O
men	B
)	O
in	O
cortical	O
cataract	O
prevalence	O
was	O
observed	O
in	O
both	O
surveys	O
.	O

Our	O
findings	O
are	O
in	O
keeping	O
with	O
observations	O
from	O
the	O
Beaver	O
Dam	O
Eye	O
Study	O
[	O
18	O
]	O
,	O
the	O
Barbados	O
Eye	O
Study	O
[	O
22	O
]	O
and	O
the	O
Lens	O
Opacities	O
Case	O
-	O
Control	O
Group	O
[	O
26	O
]	O
.	O

It	O
has	O
been	O
suggested	O
that	O
the	O
difference	O
could	O
be	O
related	O
to	O
hormonal	O
factors	O
[	O
18	O
,	O
22	O
]	O
.	O

A	O
previous	O
study	O
on	O
biochemical	O
factors	O
and	O
cataract	O
showed	O
that	O
a	O
lower	O
level	O
of	O
iron	O
was	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
cortical	O
cataract	O
[	O
27	O
]	O
.	O

No	O
interaction	O
between	O
sex	O
and	O
biochemical	O
factors	O
were	O
detected	O
and	O
no	O
gender	O
difference	O
was	O
assessed	O
in	O
this	O
study	O
[	O
27	O
]	O
.	O

The	O
gender	O
difference	O
seen	O
in	O
cortical	O
cataract	O
could	O
be	O
related	O
to	O
relatively	O
low	O
iron	O
levels	O
and	O
low	O
hemoglobin	O
concentration	O
usually	O
seen	O
in	O
women	B
[	O
28	O
]	O
.	O

Diabetes	O
is	O
a	O
known	O
risk	O
factor	O
for	O
cortical	O
cataract	O
but	O
in	O
this	O
particular	O
population	O
diabetes	O
is	O
more	O
prevalent	O
in	O
men	B
than	O
women	B
in	O
all	O
age	O
groups	O
[	O
29	O
]	O
.	O

Differential	O
exposures	O
to	O
cataract	O
risk	O
factors	O
or	O
different	O
dietary	O
or	O
lifestyle	O
patterns	O
between	O
men	B
and	O
women	B
may	O
also	O
be	O
related	O
to	O
these	O
observations	O
and	O
warrant	O
further	O
study	O
.	O

Conclusion	O

In	O
summary	O
,	O
in	O
two	O
population	O
-	O
based	O
surveys	O
6	O
years	O
apart	O
,	O
we	O
have	O
documented	O
a	O
relatively	O
stable	O
prevalence	O
of	O
cortical	O
cataract	O
and	O
PSC	O
over	O
the	O
period	O
.	O

The	O
observed	O
overall	O
increased	O
nuclear	O
cataract	O
prevalence	O
by	O
5	O
%	O
over	O
a	O
6	O
-	O
year	O
period	O
needs	O
confirmation	O
by	O
future	O
studies	O
,	O
and	O
reasons	O
for	O
such	O
an	O
increase	O
deserve	O
further	O
study	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

AGT	O
graded	O
the	O
photographs	O
,	O
performed	O
literature	O
search	O
and	O
wrote	O
the	O
first	O
draft	O
of	O
the	O
manuscript	O
.	O

JJW	O
graded	O
the	O
photographs	O
,	O
critically	O
reviewed	O
and	O
modified	O
the	O
manuscript	O
.	O

ER	O
performed	O
the	O
statistical	O
analysis	O
and	O
critically	O
reviewed	O
the	O
manuscript	O
.	O

PM	O
designed	O
and	O
directed	O
the	O
study	O
,	O
adjudicated	O
cataract	O
cases	O
and	O
critically	O
reviewed	O
and	O
modified	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

QGRS	O
Mapper	O
:	O
a	O
web	O
-	O
based	O
server	O
for	O
predicting	O
G	O
-	O
quadruplexes	O
in	O
nucleotide	O
sequences	O

Abstract	O

The	O
quadruplex	O
structures	O
formed	O
by	O
guanine	O
-	O
rich	O
nucleic	O
acid	O
sequences	O
have	O
received	O
significant	O
attention	O
recently	O
because	O
of	O
growing	O
evidence	O
for	O
their	O
role	O
in	O
important	O
biological	O
processes	O
and	O
as	O
therapeutic	O
targets	O
.	O

G	O
-	O
quadruplex	O
DNA	O
has	O
been	O
suggested	O
to	O
regulate	O
DNA	O
replication	O
and	O
may	O
control	O
cellular	O
proliferation	O
.	O

Sequences	O
capable	O
of	O
forming	O
G	O
-	O
quadruplexes	O
in	O
the	O
RNA	O
have	O
been	O
shown	O
to	O
play	O
significant	O
roles	O
in	O
regulation	O
of	O
polyadenylation	O
and	O
splicing	O
events	O
in	O
mammalian	O
transcripts	O
.	O

Whether	O
quadruplex	O
structure	O
directly	O
plays	O
a	O
role	O
in	O
regulating	O
RNA	O
processing	O
requires	O
investigation	O
.	O

Computational	O
approaches	O
to	O
study	O
G	O
-	O
quadruplexes	O
allow	O
detailed	O
analysis	O
of	O
mammalian	O
genomes	O
.	O

There	O
are	O
no	O
known	O
easily	O
accessible	O
user	O
-	O
friendly	O
tools	O
that	O
can	O
compute	O
G	O
-	O
quadruplexes	O
in	O
the	O
nucleotide	O
sequences	O
.	O

We	O
have	O
developed	O
a	O
web	O
-	O
based	O
server	O
,	O
QGRS	O
Mapper	O
,	O
that	O
predicts	O
quadruplex	O
forming	O
G	O
-	O
rich	O
sequences	O
(	O
QGRS	O
)	O
in	O
nucleotide	O
sequences	O
.	O

It	O
is	O
a	O
user	O
-	O
friendly	O
application	O
that	O
provides	O
many	O
options	O
for	O
defining	O
and	O
studying	O
G	O
-	O
quadruplexes	O
.	O

It	O
performs	O
analysis	O
of	O
the	O
user	O
provided	O
genomic	O
sequences	O
,	O
e	O
.	O
g	O
.	O
promoter	O
and	O
telomeric	O
regions	O
,	O
as	O
well	O
as	O
RNA	O
sequences	O
.	O

It	O
is	O
also	O
useful	O
for	O
predicting	O
G	O
-	O
quadruplex	O
structures	O
in	O
oligonucleotides	O
.	O

The	O
program	O
provides	O
options	O
to	O
search	O
and	O
retrieve	O
desired	O
gene	O
/	O
nucleotide	O
sequence	O
entries	O
from	O
NCBI	O
databases	O
for	O
mapping	O
G	O
-	O
quadruplexes	O
in	O
the	O
context	O
of	O
RNA	O
processing	O
sites	O
.	O

This	O
feature	O
is	O
very	O
useful	O
for	O
investigating	O
the	O
functional	O
relevance	O
of	O
G	O
-	O
quadruplex	O
structure	O
,	O
in	O
particular	O
its	O
role	O
in	O
regulating	O
the	O
gene	O
expression	O
by	O
alternative	O
processing	O
.	O

In	O
addition	O
to	O
providing	O
data	O
on	O
composition	O
and	O
locations	O
of	O
QGRS	O
relative	O
to	O
the	O
processing	O
sites	O
in	O
the	O
pre	O
-	O
mRNA	O
sequence	O
,	O
QGRS	O
Mapper	O
features	O
interactive	O
graphic	O
representation	O
of	O
the	O
data	O
.	O

The	O
user	O
can	O
also	O
use	O
the	O
graphics	O
module	O
to	O
visualize	O
QGRS	O
distribution	O
patterns	O
among	O
all	O
the	O
alternative	O
RNA	O
products	O
of	O
a	O
gene	O
simultaneously	O
on	O
a	O
single	O
screen	O
.	O

QGRS	O
Mapper	O
can	O
be	O
accessed	O
at	O
.	O

INTRODUCTION	O

The	O
quadruplex	O
structures	O
formed	O
by	O
guanine	O
-	O
rich	O
nucleic	O
acid	O
sequences	O
have	O
received	O
significant	O
attention	O
recently	O
because	O
of	O
increasing	O
evidence	O
for	O
their	O
role	O
in	O
important	O
biological	O
processes	O
and	O
as	O
therapeutic	O
targets	O
(	O
1	O
-	O
5	O
)	O
.	O

The	O
G	O
-	O
quadruplex	O
structure	O
,	O
also	O
known	O
as	O
a	O
G	O
-	O
quartet	O
,	O
is	O
formed	O
by	O
repeated	O
folding	O
of	O
either	O
the	O
single	O
polynucleotide	O
molecule	O
or	O
by	O
association	O
of	O
two	O
or	O
four	O
molecules	O
.	O

The	O
structure	O
consists	O
of	O
stacked	O
G	O
-	O
tetrads	O
,	O
which	O
are	O
square	O
co	O
-	O
planar	O
arrays	O
of	O
four	O
guanine	O
bases	O
each	O
(	O
6	O
)	O
.	O

G	O
-	O
quadruplex	O
is	O
stabilized	O
with	O
cyclic	O
Hoogsteen	O
hydrogen	O
bonding	O
between	O
the	O
four	O
guanines	O
within	O
each	O
tetrad	O
.	O

The	O
present	O
work	O
focuses	O
only	O
on	O
the	O
unimolecular	O
quadruplexes	O
,	O
since	O
it	O
is	O
more	O
likely	O
to	O
be	O
encountered	O
in	O
physiological	O
conditions	O
(	O
7	O
,	O
8	O
)	O
.	O

Guanine	O
-	O
rich	O
sequences	O
capable	O
of	O
forming	O
G	O
-	O
quadruplexes	O
are	O
found	O
in	O
telomeres	O
,	O
promoter	O
regions	O
,	O
transcribed	O
and	O
other	O
biologically	O
important	O
regions	O
of	O
the	O
mammalian	O
genomes	O
.	O

G	O
-	O
quadruplex	O
DNA	O
has	O
been	O
suggested	O
to	O
regulate	O
DNA	O
replication	O
in	O
retinoblastoma	O
susceptibility	O
gene	O
(	O
Rb	O
)	O
region	O
(	O
9	O
)	O
.	O

This	O
structure	O
may	O
control	O
cellular	O
proliferation	O
at	O
telomeric	O
level	O
and	O
by	O
transcriptional	O
regulation	O
of	O
oncogenes	O
like	O
c	O
-	O
myc	O
(	O
2	O
,	O
10	O
,	O
11	O
)	O
and	O
c	O
-	O
kit	O
(	O
12	O
)	O
.	O

Formation	O
of	O
G	O
-	O
quadruplex	O
seems	O
to	O
be	O
regulated	O
through	O
interactions	O
with	O
cellular	O
proteins	O
.	O

While	O
some	O
proteins	O
help	O
stabilize	O
the	O
structure	O
(	O
13	O
)	O
,	O
others	O
are	O
known	O
to	O
resolve	O
it	O
(	O
1	O
,	O
4	O
,	O
14	O
,	O
15	O
)	O
.	O

Proteins	O
and	O
chemicals	O
that	O
stabilize	O
the	O
G	O
-	O
quadruplex	O
structure	O
can	O
inhibit	O
telomerase	O
action	O
and	O
,	O
therefore	O
,	O
are	O
being	O
evaluated	O
as	O
anticancer	O
therapeutic	O
agents	O
(	O
16	O
-	O
20	O
)	O
.	O

Chemical	O
compounds	O
that	O
inhibit	O
G	O
-	O
quadruplex	O
helicase	O
activity	O
may	O
also	O
be	O
capable	O
of	O
regulating	O
cellular	O
proliferation	O
(	O
4	O
)	O
.	O

G	O
-	O
quadruplexes	O
are	O
also	O
being	O
eyed	O
as	O
potential	O
antimicrobial	O
agents	O
due	O
to	O
their	O
ability	O
to	O
transport	O
monovalent	O
anions	O
(	O
21	O
)	O
.	O

G	O
-	O
quadruplex	O
motifs	O
in	O
the	O
RNA	O
have	O
been	O
shown	O
to	O
play	O
significant	O
roles	O
in	O
mRNA	O
turnover	O
(	O
1	O
)	O
,	O
FMRP	O
binding	O
(	O
22	O
)	O
,	O
translation	O
initiation	O
(	O
23	O
)	O
as	O
well	O
as	O
repression	O
(	O
24	O
)	O
.	O

We	O
have	O
shown	O
previously	O
that	O
a	O
G	O
-	O
rich	O
sequence	O
(	O
GRS	O
)	O
can	O
mediate	O
3	O
'	O
end	O
processing	O
of	O
mammalian	O
pre	O
-	O
mRNAs	O
by	O
interacting	O
with	O
DSEF	O
-	O
1	O
/	O
hnRNPH	O
/	O
H	O
'	O
protein	O
(	O
25	O
-	O
27	O
)	O
.	O

Members	O
of	O
the	O
hnRNP	O
H	O
protein	O
family	O
recognize	O
G	O
-	O
rich	O
motifs	O
capable	O
of	O
forming	O
G	O
-	O
quadruplexes	O
and	O
are	O
known	O
to	O
regulate	O
polyadenylation	O
and	O
splicing	O
events	O
in	O
mammalian	O
transcripts	O
(	O
28	O
-	O
30	O
)	O
.	O

Regulated	O
RNA	O
processing	O
is	O
an	O
essential	O
component	O
of	O
differential	O
gene	O
expression	O
which	O
is	O
central	O
to	O
many	O
important	O
biologically	O
processes	O
.	O

More	O
than	O
half	O
of	O
human	B
genes	O
are	O
known	O
to	O
have	O
alternative	O
polyadenylation	O
(	O
31	O
)	O
.	O

Over	O
two	O
-	O
thirds	O
of	O
human	B
genes	O
are	O
thought	O
to	O
undergo	O
alternative	O
splicing	O
(	O
32	O
)	O
.	O

Sequences	O
capable	O
of	O
forming	O
G	O
-	O
quadruplexes	O
found	O
in	O
the	O
vicinity	O
of	O
polyadenylation	O
and	O
splice	O
sites	O
act	O
as	O
regulators	O
by	O
interacting	O
with	O
hnRNP	O
F	O
and	O
H	O
proteins	O
(	O
25	O
-	O
27	O
,	O
30	O
,	O
33	O
)	O
.	O

Whether	O
quadruplex	O
structure	O
directly	O
plays	O
a	O
role	O
in	O
regulating	O
RNA	O
processing	O
events	O
requires	O
investigation	O
.	O

Computational	O
approaches	O
to	O
study	O
G	O
-	O
quadruplexes	O
in	O
the	O
mammalian	O
genomes	O
allow	O
large	O
-	O
scale	O
and	O
detailed	O
analysis	O
of	O
mammalian	O
genes	O
.	O

Although	O
,	O
G	O
-	O
quadruplexes	O
have	O
been	O
surveyed	O
in	O
the	O
human	B
genome	O
with	O
such	O
techniques	O
(	O
34	O
,	O
35	O
)	O
,	O
there	O
are	O
no	O
known	O
user	O
-	O
friendly	O
computational	O
tools	O
easily	O
accessible	O
to	O
the	O
public	O
.	O

We	O
had	O
previously	O
built	O
a	O
database	O
of	O
mapped	O
G	O
-	O
quadruplex	O
sequences	O
in	O
selected	O
alternatively	O
processed	O
human	B
and	O
mouse	B
genes	O
(	O
36	O
)	O
.	O

Our	O
preliminary	O
analysis	O
of	O
the	O
database	O
suggests	O
prevalence	O
of	O
such	O
motifs	O
near	O
alternative	O
splice	O
and	O
poly	O
(	O
A	O
)	O
sites	O
.	O

We	O
have	O
now	O
developed	O
a	O
web	O
-	O
based	O
server	O
,	O
QGRS	O
Mapper	O
,	O
that	O
generates	O
detailed	O
information	O
on	O
composition	O
and	O
distribution	O
of	O
putative	O
quadruplex	O
forming	O
G	O
-	O
rich	O
sequences	O
(	O
QGRS	O
)	O
in	O
any	O
NCBI	O
nucleotide	O
sequence	O
identified	O
or	O
provided	O
by	O
the	O
user	O
.	O

The	O
program	O
is	O
also	O
designed	O
to	O
handle	O
the	O
analysis	O
of	O
mammalian	O
pre	O
-	O
mRNA	O
sequences	O
,	O
including	O
those	O
that	O
are	O
alternatively	O
processed	O
(	O
alternatively	O
spliced	O
or	O
alternatively	O
polyadenylated	O
)	O
.	O

Researchers	O
interested	O
in	O
predicting	O
the	O
ability	O
of	O
a	O
nucleotide	O
sequence	O
to	O
form	O
G	O
-	O
quadruplex	O
structure	O
will	O
find	O
QGRS	O
Mapper	O
to	O
be	O
a	O
user	O
-	O
friendly	O
application	O
that	O
provides	O
many	O
options	O
for	O
analysis	O
.	O

The	O
user	O
can	O
define	O
the	O
minimum	O
number	O
of	O
tetrads	O
,	O
maximum	O
length	O
of	O
the	O
G	O
-	O
quadruplex	O
motif	O
,	O
and	O
size	O
as	O
well	O
as	O
composition	O
of	O
the	O
loops	O
.	O

The	O
program	O
can	O
map	O
unimolecular	O
QGRS	O
in	O
the	O
entire	O
nucleotide	O
sequence	O
provided	O
in	O
the	O
raw	O
or	O
FASTA	O
format	O
by	O
the	O
user	O
.	O

This	O
method	O
can	O
be	O
used	O
for	O
the	O
analysis	O
of	O
genomic	O
sequences	O
,	O
e	O
.	O
g	O
.	O
promoter	O
and	O
telomeric	O
regions	O
,	O
as	O
well	O
as	O
RNA	O
sequences	O
.	O

It	O
is	O
also	O
useful	O
for	O
predicting	O
G	O
-	O
quadruplex	O
structures	O
in	O
oligonucleotides	O
.	O

Alternatively	O
,	O
the	O
program	O
provides	O
options	O
to	O
search	O
the	O
entire	O
NCBI	O
Gene	O
Entrez	O
,	O
RefSeq	O
and	O
GenBank	O
databases	O
in	O
order	O
to	O
retrieve	O
the	O
desired	O
gene	O
/	O
nucleotide	O
sequence	O
entries	O
for	O
analysis	O
of	O
their	O
transcribed	O
regions	O
.	O

Furthermore	O
,	O
QGRS	O
Mapper	O
is	O
a	O
unique	O
tool	O
for	O
mapping	O
G	O
-	O
quadruplex	O
forming	O
sequences	O
in	O
the	O
context	O
of	O
RNA	O
processing	O
sites	O
.	O

This	O
feature	O
is	O
very	O
useful	O
for	O
investigating	O
the	O
functional	O
relevance	O
of	O
G	O
-	O
quadruplex	O
structure	O
,	O
in	O
particular	O
its	O
role	O
in	O
regulating	O
the	O
gene	O
expression	O
by	O
alternative	O
processing	O
.	O

In	O
addition	O
to	O
providing	O
data	O
on	O
composition	O
and	O
locations	O
of	O
QGRS	O
relative	O
to	O
the	O
processing	O
sites	O
in	O
the	O
pre	O
-	O
mRNA	O
sequence	O
,	O
QGRS	O
Mapper	O
offers	O
interactive	O
graphic	O
representation	O
of	O
the	O
data	O
.	O

The	O
user	O
can	O
also	O
use	O
a	O
graphics	O
module	O
to	O
visualize	O
QGRS	O
distribution	O
patterns	O
among	O
all	O
the	O
alternative	O
RNA	O
products	O
of	O
a	O
gene	O
simultaneously	O
on	O
a	O
single	O
screen	O
.	O

METHODS	O

QGRS	O
definition	O

The	O
main	O
goal	O
of	O
the	O
QGRS	O
Mapper	O
program	O
is	O
to	O
predict	O
the	O
presence	O
of	O
QGRS	O
in	O
nucleotide	O
entries	O
.	O

These	O
putative	O
G	O
-	O
quadruplexes	O
are	O
identified	O
using	O
the	O
following	O
motif	O
.	O

GxNy1GxNy2GxNy3Gx	O

Here	O
x	O
=	O
number	O
of	O
guanine	O
tetrads	O
in	O
the	O
G	O
-	O
quadruplex	O
and	O
y1	O
,	O
y2	O
,	O
y3	O
=	O
length	O
of	O
gaps	O
(	O
i	O
.	O
e	O
.	O
the	O
length	O
of	O
the	O
loops	O
connecting	O
the	O
guanine	O
tetrads	O
)	O
.	O

The	O
motif	O
consists	O
of	O
four	O
equal	O
length	O
sets	O
of	O
guanines	O
(	O
which	O
we	O
call	O
G	O
-	O
groups	O
)	O
,	O
separated	O
by	O
arbitrary	O
nucleotide	O
sequences	O
,	O
with	O
the	O
following	O
restrictions	O
.	O

The	O
sequence	O
must	O
contain	O
at	O
least	O
two	O
tetrads	O
(	O
i	O
.	O
e	O
.	O
x	O
>	O
=	O
2	O
)	O
.	O

Although	O
structures	O
with	O
three	O
or	O
more	O
G	O
-	O
tetrads	O
are	O
considered	O
to	O
be	O
more	O
stable	O
,	O
many	O
nucleotide	O
sequences	O
are	O
known	O
to	O
form	O
quadruplexes	O
with	O
two	O
G	O
-	O
tetrads	O
(	O
37	O
,	O
38	O
)	O
.	O

QGRS	O
Mapper	O
is	O
meant	O
to	O
be	O
a	O
flexible	O
and	O
comprehensive	O
tool	O
for	O
investigating	O
G	O
-	O
quadruplexes	O
;	O
hence	O
it	O
considers	O
sequences	O
with	O
two	O
tetrads	O
.	O
By	O
default	O
,	O
only	O
QGRS	O
of	O
maximum	O
length	O
of	O
30	O
bases	O
are	O
considered	O
.	O

However	O
,	O
the	O
program	O
gives	O
the	O
user	O
the	O
option	O
to	O
search	O
for	O
sequences	O
up	O
to	O
45	O
bases	O
.	O

This	O
restriction	O
on	O
the	O
length	O
of	O
the	O
sequences	O
being	O
considered	O
is	O
in	O
agreement	O
with	O
recent	O
literature	O
(	O
34	O
,	O
35	O
)	O
.	O

The	O
maximum	O
length	O
of	O
30	O
bases	O
restricts	O
G	O
-	O
groups	O
to	O
a	O
maximum	O
size	O
of	O
6	O
.	O
The	O
gaps	O
or	O
loops	O
between	O
the	O
G	O
-	O
groups	O
may	O
be	O
arbitrary	O
in	O
composition	O
or	O
length	O
(	O
within	O
the	O
overall	O
restrictions	O
on	O
the	O
length	O
of	O
QGRS	O
)	O
.	O

The	O
program	O
gives	O
the	O
user	O
the	O
option	O
to	O
search	O
for	O
QGRS	O
having	O
loops	O
with	O
a	O
specified	O
length	O
range	O
(	O
e	O
.	O
g	O
.	O
the	O
user	O
can	O
search	O
for	O
QGRS	O
with	O
loops	O
of	O
lengths	O
between	O
1	O
and	O
4	O
)	O
.	O

The	O
user	O
can	O
also	O
specify	O
a	O
string	O
that	O
one	O
or	O
more	O
loops	O
of	O
each	O
QGRS	O
must	O
contain	O
.	O

This	O
string	O
can	O
be	O
given	O
as	O
a	O
regular	O
expression	O
.	O

For	O
example	O
,	O
entering	O
the	O
regular	O
expression	O
'	O
T	O
{	O
3	O
,	O
5	O
}	O
'	O
will	O
search	O
for	O
QGRS	O
having	O
one	O
or	O
more	O
loops	O
that	O
contain	O
three	O
to	O
five	O
consecutive	O
T	O
'	O
s	O
.	O
Also	O
,	O
at	O
most	O
one	O
of	O
the	O
gaps	O
is	O
allowed	O
to	O
be	O
of	O
zero	O
length	O

Table	O
1	O
shows	O
some	O
examples	O
of	O
valid	O
QGRS	O
.	O

The	O
guanine	O
groups	O
which	O
form	O
the	O
tetrads	O
are	O
underlined	O
.	O

The	O
first	O
sequence	O
has	O
four	O
tetrads	O
and	O
equal	O
length	O
gaps	O
.	O

This	O
would	O
seem	O
to	O
provide	O
a	O
G	O
-	O
quadruplex	O
that	O
is	O
the	O
most	O
stable	O
of	O
the	O
three	O
sequences	O
.	O

The	O
second	O
sequence	O
is	O
notable	O
for	O
the	O
significant	O
differences	O
in	O
the	O
size	O
of	O
its	O
loops	O
.	O

The	O
third	O
sequence	O
has	O
two	O
tetrads	O
,	O
even	O
though	O
three	O
of	O
the	O
G	O
-	O
groups	O
could	O
have	O
included	O
another	O
G	O
(	O
since	O
all	O
G	O
-	O
groups	O
must	O
be	O
equal	O
in	O
size	O
)	O
.	O

G	O
-	O
scores	O

We	O
have	O
devised	O
a	O
scoring	O
system	O
that	O
evaluates	O
a	O
QGRS	O
for	O
its	O
likelihood	O
to	O
form	O
a	O
stable	O
G	O
-	O
quadruplex	O
.	O

Higher	O
scoring	O
sequences	O
will	O
make	O
better	O
candidates	O
for	O
G	O
-	O
quadruplexes	O
.	O

The	O
scoring	O
method	O
uses	O
the	O
following	O
principles	O
which	O
are	O
based	O
on	O
previous	O
studies	O
(	O
34	O
,	O
35	O
,	O
39	O
-	O
42	O
)	O
.	O

Shorter	O
loops	O
are	O
more	O
common	O
than	O
longer	O
loops	O
.	O
G	O
-	O
quadruplexes	O
tend	O
to	O
have	O
loops	O
roughly	O
equal	O
in	O
size	O
.	O
The	O
greater	O
the	O
number	O
of	O
guanine	O
tetrads	O
,	O
the	O
more	O
stable	O
the	O
quadruplex	O
.	O

The	O
computed	O
G	O
-	O
scores	O
are	O
dependent	O
on	O
the	O
user	O
selected	O
maximum	O
QGRS	O
length	O
.	O

The	O
highest	O
possible	O
G	O
-	O
score	O
,	O
using	O
the	O
default	O
maximum	O
QGRS	O
length	O
of	O
30	O
,	O
is	O
105	O
.	O

Here	O
is	O
a	O
sequence	O
attaining	O
that	O
score	O
:	O

GGGGGGTGGGGGGTGGGGGG	O
.	O

Eliminating	O
QGRS	O
overlaps	O

Two	O
QGRS	O
are	O
said	O
to	O
overlap	O
if	O
their	O
positions	O
in	O
the	O
nucleotide	O
sequence	O
overlap	O
.	O

QGRS	O
Mapper	O
will	O
start	O
with	O
a	O
nucleotide	O
sequence	O
,	O
find	O
all	O
QGRS	O
occurring	O
in	O
the	O
sequence	O
and	O
then	O
produce	O
a	O
non	O
-	O
overlapping	O
set	O
of	O
QGRS	O
.	O

Overlaps	O
are	O
eliminated	O
by	O
selecting	O
the	O
higher	O
scoring	O
QGRS	O
.	O

In	O
the	O
non	O
-	O
overlapping	O
view	O
,	O
only	O
this	O
sequence	O
will	O
be	O
displayed	O
,	O
although	O
the	O
user	O
can	O
request	O
that	O
all	O
overlapping	O
sequences	O
be	O
displayed	O
.	O

Please	O
see	O
supplementary	O
materials	O
at	O
NAR	O
online	O
for	O
more	O
details	O
on	O
the	O
elimination	O
of	O
overlapping	O
QGRS	O
.	O

FEATURES	O

Design	O
and	O
implementation	O

QGRS	O
Mapper	O
is	O
a	O
web	O
-	O
based	O
program	O
,	O
written	O
in	O
PHP	O
,	O
with	O
Java	O
being	O
used	O
for	O
some	O
of	O
its	O
graphics	O
.	O

The	O
program	O
takes	O
a	O
nucleotide	O
sequence	O
from	O
NCBI	O
(	O
or	O
as	O
provided	O
by	O
the	O
user	O
)	O
and	O
analyzes	O
it	O
for	O
the	O
presence	O
of	O
putative	O
G	O
-	O
quadruplexes	O
.	O

The	O
structure	O
of	O
QGRS	O
Mapper	O
is	O
summarized	O
in	O
Table	O
2	O
.	O

Search	O
and	O
analysis	O

QGRS	O
Mapper	O
allows	O
the	O
user	O
to	O
search	O
for	O
putative	O
G	O
-	O
quadruplexes	O
in	O
a	O
variety	O
of	O
ways	O
.	O

It	O
is	O
possible	O
to	O
enter	O
a	O
nucleotide	O
sequence	O
in	O
raw	O
or	O
FASTA	O
format	O
for	O
analysis	O
.	O

One	O
can	O
search	O
and	O
analyze	O
gene	O
sequences	O
by	O
Gene	O
ID	O
,	O
Gene	O
name	O
or	O
symbol	O
,	O
accession	O
number	O
or	O
GI	O
number	O
for	O
an	O
NCBI	O
nucleotide	O
sequence	O
entry	O
.	O

The	O
user	O
can	O
opt	O
to	O
change	O
the	O
maximum	O
length	O
of	O
QGRS	O
that	O
will	O
be	O
searched	O
for	O
(	O
the	O
default	O
maximum	O
length	O
being	O
30	O
)	O
and	O
change	O
the	O
minimum	O
sized	O
G	O
-	O
group	O
(	O
which	O
is	O
two	O
by	O
default	O
)	O
.	O

Also	O
,	O
the	O
user	O
can	O
specify	O
that	O
the	O
loops	O
in	O
the	O
QGRS	O
fall	O
within	O
a	O
given	O
size	O
range	O
and	O
that	O
one	O
or	O
more	O
loops	O
of	O
the	O
QGRS	O
contain	O
a	O
given	O
string	O
(	O
for	O
which	O
the	O
user	O
may	O
enter	O
a	O
regular	O
expression	O
)	O
.	O

The	O
web	O
page	O
for	O
QGRS	O
analysis	O
can	O
be	O
seen	O
in	O
Figure	O
1	O
.	O

After	O
entering	O
a	O
sequence	O
in	O
raw	O
or	O
FASTA	O
format	O
,	O
QGRS	O
Mapper	O
will	O
search	O
the	O
sequence	O
for	O
occurrences	O
of	O
QGRS	O
.	O

The	O
user	O
may	O
enter	O
any	O
combination	O
of	O
the	O
letters	O
A	O
,	O
C	O
,	O
T	O
,	O
G	O
,	O
U	O
,	O
N	O
.	O

The	O
Gene	O
ID	O
field	O
allows	O
the	O
user	O
to	O
search	O
the	O
NCBI	O
Entrez	O
Gene	O
database	O
.	O

QGRS	O
Mapper	O
will	O
connect	O
to	O
NCBI	O
,	O
download	O
and	O
parse	O
the	O
gene	O
entry	O
,	O
and	O
then	O
analyze	O
the	O
transcribed	O
region	O
of	O
its	O
nucleotide	O
sequence	O
for	O
the	O
presence	O
of	O
QGRS	O
.	O

For	O
example	O
,	O
entering	O
the	O
gene	O
ID	O
403437	O
results	O
in	O
downloading	O
the	O
Brca1	O
gene	O
sequence	O
for	O
Canis	B
familiaris	I
.	O

Using	O
the	O
default	O
QGRS	O
search	O
parameters	O
,	O
QGRS	O
Mapper	O
finds	O
156	O
non	O
-	O
overlapping	O
QGRS	O
and	O
3394	O
overlapping	O
QGRS	O
in	O
the	O
transcribed	O
region	O
of	O
this	O
gene	O
.	O

The	O
Gene	O
Name	O
or	O
Gene	O
Symbol	O
field	O
also	O
allows	O
the	O
user	O
to	O
search	O
the	O
NCBI	O
databases	O
for	O
all	O
such	O
genes	O
.	O

Entering	O
the	O
gene	O
name	O
Bcl2	O
results	O
in	O
nine	O
different	O
hits	O
which	O
are	O
displayed	O
in	O
Table	O
3	O
.	O

All	O
nine	O
of	O
these	O
entries	O
can	O
be	O
analyzed	O
for	O
the	O
occurrence	O
of	O
QGRS	O
.	O

Clicking	O
on	O
the	O
Gene	O
ID	O
takes	O
the	O
user	O
to	O
the	O
respective	O
Entrez	O
Gene	O
entry	O
.	O

Clicking	O
on	O
the	O
last	O
column	O
initiates	O
analysis	O
of	O
the	O
selection	O
by	O
QGRS	O
Mapper	O
.	O

Similarly	O
,	O
the	O
user	O
can	O
also	O
enter	O
an	O
NCBI	O
accession	O
number	O
to	O
search	O
for	O
gene	O
sequences	O
.	O

For	O
example	O
,	O
searching	O
the	O
accession	O
number	O
AF312033	O
results	O
in	O
12	O
hits	O
being	O
displayed	O
for	O
this	O
GenBank	O
nucleotide	O
sequence	O
entry	O
.	O

The	O
search	O
phase	O
of	O
the	O
program	O
is	O
followed	O
by	O
an	O
analysis	O
of	O
the	O
QGRS	O
contained	O
in	O
the	O
query	O
sequence	O
.	O

In	O
this	O
phase	O
of	O
QGRS	O
Mapper	O
,	O
the	O
sequence	O
data	O
downloaded	O
previously	O
is	O
analyzed	O
to	O
identify	O
and	O
map	O
all	O
QGRS	O
relative	O
to	O
locations	O
such	O
as	O
splice	O
sites	O
in	O
exons	O
/	O
introns	O
,	O
and	O
poly	O
(	O
A	O
)	O
site	O
(	O
if	O
these	O
locations	O
are	O
known	O
)	O
.	O

Furthermore	O
the	O
QGRS	O
are	O
scored	O
by	O
the	O
method	O
described	O
above	O
.	O

The	O
computed	O
G	O
-	O
score	O
is	O
used	O
to	O
eliminate	O
overlapping	O
QGRS	O
.	O

At	O
times	O
,	O
QGRS	O
Mapper	O
must	O
analyze	O
a	O
considerable	O
amount	O
of	O
data	O
.	O

For	O
example	O
,	O
the	O
mouse	B
version	O
of	O
the	O
gene	O
PTPRU	O
,	O
which	O
is	O
69822	O
bases	O
long	O
,	O
contains	O
94681	O
QGRS	O
of	O
length	O
up	O
to	O
45	O
bases	O
.	O

QGRS	O
Mapper	O
will	O
find	O
,	O
analyze	O
and	O
map	O
all	O
of	O
these	O
sequences	O
.	O

During	O
this	O
analysis	O
a	O
message	O
is	O
displayed	O
indicating	O
the	O
estimated	O
time	O
left	O
to	O
completion	O
.	O

QGRS	O
Mapper	O
output	O

After	O
the	O
analysis	O
of	O
overlaps	O
is	O
completed	O
,	O
QGRS	O
Mapper	O
displays	O
a	O
summary	O
of	O
its	O
findings	O
,	O
in	O
the	O
Gene	O
View	O
.	O

This	O
summary	O
includes	O
basic	O
gene	O
information	O
such	O
as	O
the	O
gene	O
ID	O
,	O
gene	O
symbol	O
,	O
gene	O
name	O
,	O
a	O
link	O
to	O
the	O
NCBI	O
entry	O
,	O
organism	O
name	O
,	O
chromosome	O
number	O
and	O
number	O
of	O
products	O
and	O
poly	O
(	O
A	O
)	O
signals	O
.	O

Information	O
is	O
also	O
given	O
for	O
each	O
product	O
,	O
such	O
as	O
the	O
number	O
of	O
exons	O
and	O
introns	O
,	O
number	O
of	O
QGRS	O
(	O
non	O
-	O
overlapping	O
and	O
overlapping	O
)	O
,	O
number	O
of	O
QGRS	O
found	O
near	O
RNA	O
processing	O
sites	O
,	O
and	O
a	O
visual	O
map	O
of	O
the	O
product	O
.	O

As	O
an	O
example	O
,	O
the	O
Gene	O
View	O
for	O
the	O
human	B
GREB1	O
is	O
displayed	O
in	O
Figure	O
2	O
,	O
showing	O
the	O
table	O
of	O
gene	O
information	O
and	O
product	O
information	O
for	O
the	O
first	O
product	O
(	O
the	O
output	O
for	O
all	O
products	O
may	O
be	O
seen	O
in	O
the	O
supplementary	O
material	O
)	O
.	O

At	O
this	O
stage	O
in	O
the	O
analysis	O
the	O
user	O
can	O
choose	O
among	O
three	O
further	O
displays	O
:	O
'	O
Data	O
View	O
'	O
,	O
'	O
Data	O
View	O
(	O
with	O
overlaps	O
)	O
'	O
and	O
'	O
Graphics	O
View	O
'	O
.	O

This	O
can	O
be	O
done	O
for	O
the	O
entire	O
gene	O
or	O
for	O
any	O
particular	O
product	O
.	O

In	O
the	O
Data	O
View	O
,	O
a	O
table	O
is	O
displayed	O
showing	O
information	O
for	O
each	O
of	O
the	O
set	O
of	O
non	O
-	O
overlapping	O
QGRS	O
.	O

This	O
table	O
displays	O
the	O
position	O
of	O
the	O
QGRS	O
,	O
which	O
exon	O
/	O
intron	O
it	O
appears	O
in	O
,	O
its	O
distance	O
from	O
3	O
'	O
and	O
5	O
'	O
splice	O
sites	O
,	O
the	O
QGRS	O
sequence	O
(	O
with	O
each	O
G	O
-	O
group	O
underlined	O
)	O
and	O
the	O
corresponding	O
G	O
-	O
score	O
.	O

Similar	O
display	O
is	O
also	O
shown	O
for	O
each	O
QGRS	O
mapped	O
to	O
poly	O
(	O
A	O
)	O
region	O
in	O
the	O
product	O
.	O

If	O
the	O
user	O
requests	O
the	O
Data	O
View	O
for	O
the	O
entire	O
gene	O
,	O
then	O
the	O
QGRS	O
information	O
is	O
shown	O
for	O
each	O
product	O
.	O

The	O
'	O
Data	O
View	O
(	O
with	O
overlaps	O
)	O
'	O
gives	O
the	O
same	O
information	O
but	O
shows	O
the	O
locations	O
of	O
all	O
QGRS	O
.	O

Figure	O
3	O
shows	O
the	O
Data	O
View	O
for	O
product	O
1	O
of	O
the	O
GREB1	O
gene	O
.	O

The	O
user	O
can	O
also	O
choose	O
the	O
Graphics	O
View	O
to	O
give	O
a	O
visual	O
display	O
of	O
the	O
location	O
of	O
QGRS	O
.	O

This	O
allows	O
the	O
user	O
to	O
see	O
the	O
location	O
of	O
QGRS	O
relative	O
to	O
exons	O
and	O
introns	O
(	O
if	O
that	O
information	O
is	O
available	O
)	O
.	O

The	O
Graphics	O
View	O
has	O
the	O
following	O
components	O
.	O

A	O
graphic	O
display	O
of	O
the	O
entire	O
gene	O
(	O
showing	O
the	O
location	O
of	O
the	O
exons	O
)	O
.	O

This	O
display	O
includes	O
a	O
sliding	O
window	O
that	O
can	O
be	O
used	O
to	O
focus	O
on	O
any	O
particular	O
segment	O
of	O
the	O
gene	O
.	O

This	O
window	O
may	O
be	O
dragged	O
to	O
the	O
left	O
or	O
right	O
to	O
change	O
position	O
within	O
the	O
gene	O
.	O
A	O
magnified	O
view	O
of	O
the	O
fragment	O
of	O
the	O
gene	O
within	O
the	O
sliding	O
window	O
.	O
A	O
graph	O
showing	O
the	O
location	O
of	O
QGRS	O
within	O
the	O
fragment	O
,	O
with	O
each	O
QGRS	O
being	O
displayed	O
by	O
a	O
bar	O
whose	O
height	O
represents	O
its	O
G	O
-	O
score	O
.	O
A	O
vertical	O
slider	O
that	O
allows	O
the	O
user	O
to	O
change	O
the	O
size	O
of	O
the	O
window	O
.	O

This	O
allows	O
the	O
user	O
to	O
zoom	O
in	O
or	O
out	O
on	O
any	O
part	O
of	O
the	O
gene	O
.	O

The	O
sliding	O
window	O
on	O
the	O
gene	O
expands	O
or	O
contracts	O
as	O
one	O
zooms	O
in	O
or	O
out	O
.	O

It	O
is	O
possible	O
to	O
see	O
the	O
nucleotide	O
sequence	O
of	O
the	O
product	O
at	O
maximum	O
zoom	O
levels	O
.	O

The	O
Graphics	O
View	O
for	O
the	O
entire	O
gene	O
shows	O
the	O
G	O
-	O
score	O
graph	O
together	O
with	O
an	O
exon	O
/	O
intron	O
map	O
for	O
each	O
product	O
.	O

This	O
allows	O
the	O
user	O
to	O
visually	O
compare	O
the	O
location	O
of	O
QGRS	O
for	O
each	O
product	O
relative	O
to	O
that	O
of	O
splice	O
sites	O
.	O

The	O
Graphics	O
View	O
for	O
the	O
first	O
product	O
of	O
the	O
GREB1	O
gene	O
is	O
represented	O
in	O
Figure	O
4	O
.	O

The	O
Graphics	O
View	O
for	O
the	O
entire	O
GREB1	O
gene	O
may	O
be	O
seen	O
in	O
the	O
Supplementary	O
Data	O
.	O

CONCLUSIONS	O

QGRS	O
Mapper	O
is	O
a	O
user	O
-	O
friendly	O
web	O
-	O
based	O
server	O
that	O
provides	O
computational	O
tools	O
for	O
prediction	O
of	O
Quadruplex	O
forming	O
G	O
-	O
rich	O
sequences	O
in	O
the	O
nucleotide	O
sequences	O
identified	O
or	O
provided	O
by	O
the	O
user	O
.	O

The	O
program	O
offers	O
many	O
options	O
,	O
including	O
user	O
-	O
defined	O
composition	O
of	O
the	O
quadruplex	O
.	O

It	O
can	O
analyze	O
DNA	O
or	O
RNA	O
sequence	O
provided	O
by	O
the	O
user	O
in	O
the	O
raw	O
or	O
FASTA	O
format	O
.	O

The	O
application	O
also	O
provides	O
tools	O
for	O
searching	O
and	O
retrieving	O
gene	O
/	O
nucleotide	O
entries	O
from	O
a	O
variety	O
of	O
NCBI	O
databases	O
.	O

There	O
are	O
several	O
options	O
for	O
data	O
output	O
format	O
,	O
including	O
an	O
interactive	O
graphic	O
module	O
.	O

Researchers	O
interested	O
in	O
evaluating	O
the	O
ability	O
of	O
nucleotide	O
sequences	O
to	O
form	O
unimolecular	O
G	O
-	O
quadruplexes	O
will	O
find	O
QGRS	O
Mapper	O
to	O
be	O
very	O
useful	O
.	O

Owing	O
to	O
the	O
flexible	O
and	O
comprehensive	O
nature	O
of	O
the	O
design	O
,	O
it	O
is	O
expected	O
to	O
serve	O
a	O
variety	O
of	O
scientists	O
.	O

The	O
application	O
will	O
be	O
especially	O
attractive	O
to	O
individuals	O
interested	O
in	O
exploring	O
the	O
role	O
of	O
G	O
-	O
quadruplexes	O
in	O
regulated	O
RNA	O
processing	O
.	O

We	O
are	O
using	O
the	O
server	O
to	O
perform	O
a	O
large	O
-	O
scale	O
analysis	O
of	O
alternatively	O
processed	O
mammalian	O
transcripts	O
.	O

We	O
are	O
particularly	O
interested	O
in	O
studying	O
the	O
composition	O
and	O
distribution	O
patterns	O
of	O
G	O
-	O
quadruplexes	O
in	O
the	O
transcribed	O
regions	O
of	O
mammalian	O
genes	O
.	O

SUPPLEMENTARY	O
DATA	O

Supplementary	O
Data	O
are	O
available	O
at	O
NAR	O
online	O
.	O

Drug	O
information	O
resources	O
used	O
by	O
nurse	O
practitioners	O
and	O
collaborating	O
physicians	O
at	O
the	O
point	O
of	O
care	O
in	O
Nova	O
Scotia	O
,	O
Canada	O
:	O
a	O
survey	O
and	O
review	O
of	O
the	O
literature	O

Abstract	O

Background	O

Keeping	O
current	O
with	O
drug	O
therapy	O
information	O
is	O
challenging	O
for	O
health	O
care	O
practitioners	O
.	O

Technologies	O
are	O
often	O
implemented	O
to	O
facilitate	O
access	O
to	O
current	O
and	O
credible	O
drug	O
information	O
sources	O
.	O

In	O
the	O
Canadian	O
province	O
of	O
Nova	O
Scotia	O
,	O
legislation	O
was	O
passed	O
in	O
2002	O
to	O
allow	O
nurse	O
practitioners	O
(	O
NPs	O
)	O
to	O
practice	O
collaboratively	O
with	O
physician	O
partners	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
determine	O
the	O
current	O
utilization	O
patterns	O
of	O
information	O
technologies	O
by	O
these	O
groups	O
of	O
practitioners	O
.	O

Methods	O

Nurse	O
practitioners	O
and	O
their	O
collaborating	O
physician	O
partners	O
in	O
Nova	O
Scotia	O
were	O
sent	O
a	O
survey	O
in	O
February	O
2005	O
to	O
determine	O
the	O
frequency	O
of	O
use	O
,	O
usefulness	O
,	O
accessibility	O
,	O
credibility	O
,	O
and	O
current	O
/	O
timeliness	O
of	O
personal	O
digital	O
assistant	O
(	O
PDA	O
)	O
,	O
computer	O
,	O
and	O
print	O
drug	O
information	O
resources	O
.	O

Two	O
surveys	O
were	O
developed	O
(	O
one	O
for	O
PDA	O
users	O
and	O
one	O
for	O
computer	O
users	O
)	O
and	O
revised	O
based	O
on	O
a	O
literature	O
search	O
,	O
stakeholder	O
consultation	O
,	O
and	O
pilot	O
-	O
testing	O
results	O
.	O

A	O
second	O
distribution	O
to	O
nonresponders	O
occurred	O
two	O
weeks	O
following	O
the	O
first	O
.	O

Data	O
were	O
entered	O
and	O
analysed	O
with	O
SPSS	O
.	O

Results	O

Twenty	O
-	O
seven	O
(	O
14	O
NPs	O
and	O
13	O
physicians	O
)	O
of	O
36	O
(	O
75	O
%	O
)	O
recipients	O
responded	O
.	O

22	O
%	O
(	O
6	O
)	O
returned	O
personal	O
digital	O
assistant	O
(	O
PDA	O
)	O
surveys	O
.	O

Respondents	O
reported	O
print	O
,	O
health	O
professionals	O
,	O
and	O
online	O
/	O
electronic	O
resources	O
as	O
the	O
most	O
to	O
least	O
preferred	O
means	O
to	O
access	O
drug	O
information	O
,	O
respectively	O
.	O

37	O
%	O
and	O
35	O
%	O
of	O
respondents	O
reported	O
using	O
"	O
both	O
print	O
and	O
electronic	O
but	O
print	O
more	O
than	O
electronic	O
"	O
and	O
"	O
print	O
only	O
"	O
,	O
respectively	O
,	O
to	O
search	O
monograph	O
-	O
related	O
drug	O
information	O
queries	O
whereas	O
4	O
%	O
reported	O
using	O
"	O
PDA	O
only	O
"	O
.	O

Analysis	O
of	O
respondent	O
ratings	O
for	O
all	O
resources	O
in	O
the	O
categories	O
print	O
,	O
health	O
professionals	O
and	O
other	O
,	O
and	O
online	O
/	O
electronic	O
resources	O
,	O
indicated	O
that	O
the	O
Compendium	O
of	O
Pharmaceuticals	O
and	O
Specialties	O
and	O
pharmacists	O
ranked	O
highly	O
for	O
frequency	O
of	O
use	O
,	O
usefulness	O
,	O
accessibility	O
,	O
credibility	O
,	O
and	O
current	O
/	O
timeliness	O
by	O
both	O
groups	O
of	O
practitioners	O
.	O

Respondents	O
'	O
preferences	O
and	O
resource	O
ratings	O
were	O
consistent	O
with	O
self	O
-	O
reported	O
methods	O
for	O
conducting	O
drug	O
information	O
queries	O
.	O

Few	O
differences	O
existed	O
between	O
NP	O
and	O
physician	O
rankings	O
of	O
resources	O
.	O

Conclusion	O

The	O
use	O
of	O
computers	O
and	O
PDAs	O
remains	O
limited	O
,	O
which	O
is	O
also	O
consistent	O
with	O
preferred	O
and	O
frequent	O
use	O
of	O
print	O
resources	O
.	O

Education	O
for	O
these	O
practitioners	O
regarding	O
available	O
electronic	O
drug	O
information	O
resources	O
may	O
facilitate	O
future	O
computer	O
and	O
PDA	O
use	O
.	O

Further	O
research	O
is	O
needed	O
to	O
determine	O
methods	O
to	O
increase	O
computer	O
and	O
PDA	O
use	O
and	O
whether	O
these	O
technologies	O
affect	O
prescribing	O
and	O
patient	B
outcomes	O
.	O

Background	O

Challenges	O
with	O
knowledge	O
management	O
for	O
health	O
care	O
professionals	O

In	O
1986	O
,	O
Haynes	O
et	O
al	O
.	O
published	O
a	O
series	O
of	O
6	O
articles	O
entitled	O
"	O
how	O
to	O
keep	O
up	O
with	O
the	O
medical	O
literature	O
"	O
in	O
an	O
effort	O
to	O
help	O
clinicians	O
with	O
information	O
management	O
,	O
but	O
this	O
challenge	O
has	O
not	O
decreased	O
in	O
last	O
two	O
decades	O
[	O
1	O
-	O
6	O
]	O
.	O

Alper	O
et	O
al	O
.	O
suggest	O
that	O
maintaining	O
currency	O
with	O
relevant	O
literature	O
in	O
primary	O
care	O
would	O
"	O
require	O
627	O
.	O
5	O
hours	O
per	O
month	O
,	O
or	O
about	O
29	O
hours	O
per	O
weekday	O
,	O
or	O
3	O
.	O
6	O
full	O
-	O
time	O
equivalents	O
of	O
physician	O
effort	O
"	O
[	O
7	O
]	O
.	O

The	O
volume	O
of	O
information	O
associated	O
with	O
keeping	O
up	O
to	O
date	O
is	O
frequently	O
cited	O
as	O
a	O
barrier	O
[	O
8	O
]	O
.	O

It	O
is	O
estimated	O
that	O
annually	O
there	O
are	O
approximately	O
10	O
,	O
000	O
new	O
randomized	O
trials	O
in	O
MEDLINE	O
and	O
over	O
450	O
,	O
000	O
clinical	O
trials	O
identified	O
by	O
the	O
Cochrane	O
Collaboration	O
[	O
9	O
,	O
10	O
]	O
.	O

Keeping	O
up	O
to	O
date	O
has	O
been	O
described	O
with	O
several	O
analogies	O
including	O
clinicians	O
attempting	O
to	O
drink	O
water	O
from	O
a	O
fire	O
hose	O
and	O
swimming	O
in	O
rivers	O
of	O
clinical	O
research	O
with	O
unprecedented	O
depth	O
,	O
velocity	O
,	O
and	O
turbulence	O
[	O
11	O
,	O
12	O
]	O
.	O

Difficulties	O
with	O
dissemination	O
of	O
research	O
evidence	O
and	O
keeping	O
up	O
to	O
date	O
on	O
pharmacotherapeutic	O
interventions	O
are	O
reported	O
despite	O
the	O
development	O
of	O
tools	O
such	O
as	O
clinical	O
practice	O
guidelines	O
and	O
systematic	O
reviews	O
that	O
are	O
intended	O
to	O
reduce	O
the	O
need	O
for	O
practitioners	O
to	O
evaluate	O
original	O
research	O
[	O
13	O
]	O
.	O

To	O
complicate	O
matters	O
further	O
,	O
there	O
are	O
often	O
issues	O
of	O
credibility	O
,	O
timeliness	O
,	O
and	O
volume	O
of	O
clinical	O
practice	O
guidelines	O
and	O
reviews	O
.	O

Many	O
guidelines	O
are	O
criticized	O
for	O
their	O
methodological	O
development	O
.	O

Shaneyfelt	O
et	O
al	O
.	O
reviewed	O
279	O
guidelines	O
for	O
methodological	O
standards	O
from	O
peer	O
reviewed	O
medical	O
literature	O
[	O
14	O
]	O
.	O

These	O
authors	O
found	O
that	O
only	O
51	O
%	O
,	O
33	O
.	O
6	O
%	O
,	O
and	O
46	O
%	O
adhered	O
to	O
standards	O
on	O
guideline	O
development	O
and	O
format	O
,	O
evidence	O
identification	O
and	O
summary	O
,	O
and	O
formulation	O
of	O
recommendations	O
,	O
respectively	O
[	O
14	O
]	O
.	O

A	O
Canadian	O
review	O
on	O
drug	O
therapy	O
guidelines	O
found	O
significant	O
variation	O
in	O
quality	O
depending	O
on	O
the	O
developer	O
[	O
13	O
]	O
.	O

Approximately	O
25	O
%	O
of	O
guidelines	O
were	O
not	O
recommended	O
for	O
use	O
in	O
practice	O
by	O
the	O
appraisers	O
'	O
criteria	O
[	O
13	O
]	O
.	O

As	O
an	O
example	O
of	O
the	O
volume	O
of	O
clinical	O
practice	O
guidelines	O
available	O
,	O
eleven	O
recent	O
guidelines	O
on	O
community	O
acquired	O
pneumonia	O
exist	O
[	O
15	O
]	O
.	O

To	O
add	O
to	O
the	O
complexities	O
involved	O
with	O
keeping	O
current	O
with	O
pharmacotherapeutic	O
management	O
strategies	O
,	O
as	O
of	O
2000	O
,	O
there	O
were	O
over	O
22	O
,	O
000	O
drug	O
products	O
approved	O
for	O
sale	O
in	O
Canada	O
for	O
human	B
use	O
[	O
16	O
]	O
.	O

There	O
is	O
also	O
considerable	O
debate	O
regarding	O
what	O
constitutes	O
"	O
evidence	O
"	O
in	O
practice	O
,	O
which	O
contributes	O
to	O
confusion	O
for	O
clinicians	O
[	O
17	O
,	O
18	O
]	O
.	O

Sim	O
et	O
al	O
.	O
succinctly	O
describe	O
the	O
gap	O
between	O
evidence	O
and	O
action	O
as	O
difficulties	O
with	O
obtaining	O
,	O
systematically	O
reviewing	O
,	O
applying	O
in	O
context	O
,	O
and	O
measuring	O
the	O
outcome	O
following	O
application	O
of	O
evidence	O
[	O
19	O
]	O
.	O

Maintaining	O
competence	O
-	O
nurse	O
practitioners	O
as	O
a	O
new	O
group	O
of	O
prescribers	O

Competencies	O
for	O
nurse	O
practitioners	O
(	O
NPs	O
)	O
on	O
a	O
local	O
and	O
international	O
level	O
include	O
critically	O
appraising	O
and	O
applying	O
literature	O
and	O
research	O
findings	O
in	O
practice	O
[	O
20	O
-	O
23	O
]	O
.	O

The	O
Canadian	O
Nurses	O
Association	O
(	O
CNA	O
)	O
has	O
developed	O
the	O
Canadian	O
Nurse	O
Practitioner	O
Core	O
Competency	O
Framework	O
that	O
describes	O
the	O
knowledge	O
,	O
skills	O
,	O
judgment	O
,	O
and	O
attributes	O
required	O
for	O
practice	O
.	O

Evidence	O
based	O
practice	O
is	O
integral	O
to	O
pharmacotherapeutic	O
interventions	O
and	O
prescribing	O
competencies	O
[	O
23	O
]	O
.	O

The	O
National	O
Prescribing	O
Centre	O
,	O
an	O
organization	O
of	O
the	O
National	O
Health	O
Service	O
in	O
the	O
UK	O
,	O
describes	O
several	O
competencies	O
around	O
information	O
needs	O
relevant	O
to	O
prescribing	O
and	O
emphasis	O
is	O
placed	O
on	O
using	O
relevant	O
and	O
up	O
to	O
date	O
information	O
in	O
various	O
formats	O
(	O
e	O
.	O
g	O
.	O
print	O
,	O
electronic	O
,	O
verbal	O
)	O
.	O

Several	O
related	O
competencies	O
include	O
understanding	O
advantages	O
and	O
disadvantages	O
of	O
information	O
sources	O
and	O
the	O
currency	O
of	O
resources	O
[	O
21	O
]	O
.	O

Researchers	O
in	O
the	O
US	O
developed	O
NP	O
informatics	O
competencies	O
for	O
integration	O
into	O
advanced	O
nursing	O
practice	O
curricula	O
[	O
24	O
]	O
.	O

Competencies	O
related	O
to	O
informatics	O
knowledge	O
include	O
critical	O
analysis	O
of	O
data	O
and	O
information	O
for	O
use	O
in	O
evidence	O
based	O
practice	O
,	O
evaluating	O
and	O
applying	O
relevant	O
information	O
,	O
synthesizing	O
best	O
evidence	O
,	O
and	O
using	O
optimal	O
search	O
strategies	O
to	O
locate	O
clinically	O
sound	O
and	O
useful	O
studies	O
from	O
information	O
resources	O
[	O
24	O
]	O
.	O

Achieving	O
and	O
maintaining	O
competence	O
in	O
these	O
domains	O
as	O
well	O
as	O
a	O
solid	O
foundation	O
in	O
pharmacology	O
is	O
necessary	O
to	O
support	O
NPs	O
in	O
their	O
relatively	O
new	O
role	O
as	O
a	O
prescriber	O
[	O
25	O
-	O
27	O
]	O
.	O

Knowledge	O
management	O
and	O
information	O
seeking	O
behaviours	O
among	O
nurse	O
practitioners	O
and	O
physicians	O

Information	O
seeking	O
behaviours	O
of	O
physicians	O
are	O
better	O
documented	O
than	O
NPs	O
[	O
11	O
]	O
.	O

Information	O
related	O
to	O
diagnosis	O
is	O
important	O
to	O
both	O
groups	O
but	O
drug	O
therapy	O
queries	O
may	O
occur	O
more	O
frequently	O
with	O
NPs	O
[	O
28	O
-	O
33	O
]	O
.	O

Research	O
on	O
nurses	O
'	O
behaviours	O
related	O
to	O
information	O
seeking	O
is	O
available	O
from	O
the	O
hospital	O
setting	O
[	O
33	O
-	O
35	O
]	O
but	O
the	O
generalizability	O
of	O
these	O
behaviours	O
to	O
NPs	O
with	O
a	O
prescribing	O
role	O
is	O
unclear	O
.	O

Differences	O
in	O
nursing	O
roles	O
,	O
responsibilities	O
,	O
and	O
legislation	O
,	O
including	O
prescriptive	O
authority	O
,	O
exist	O
depending	O
on	O
the	O
country	O
of	O
practice	O
.	O

Nurse	O
practitioners	O
and	O
their	O
collaborating	O
physician	O
partners	O
in	O
Nova	O
Scotia	O

Nova	O
Scotia	O
is	O
a	O
Canadian	O
province	O
with	O
a	O
population	O
of	O
approximately	O
942	O
,	O
000	O
[	O
36	O
]	O
.	O

The	O
province	O
is	O
divided	O
into	O
six	O
health	O
zones	O
that	O
include	O
nine	O
district	O
health	O
authorities	O
,	O
one	O
of	O
which	O
includes	O
the	O
provincial	O
capital	O
and	O
is	O
considered	O
to	O
be	O
urban	O
[	O
37	O
,	O
38	O
]	O
.	O

Health	O
care	O
service	O
delivery	O
is	O
challenging	O
due	O
to	O
many	O
factors	O
including	O
the	O
rural	O
nature	O
of	O
the	O
province	O
,	O
which	O
is	O
estimated	O
to	O
be	O
60	O
%	O
of	O
population	O
[	O
37	O
,	O
39	O
]	O
.	O

Starting	O
in	O
1998	O
,	O
the	O
Nova	O
Scotia	O
Department	O
of	O
Health	O
led	O
an	O
initiative	O
to	O
explore	O
different	O
methods	O
of	O
delivering	O
,	O
managing	O
,	O
and	O
funding	O
primary	O
care	O
services	O
.	O

The	O
Strengthening	O
Primary	O
Care	O
in	O
Nova	O
Scotia	O
Communities	O
Initiative	O
(	O
SPCI	O
)	O
was	O
established	O
with	O
the	O
selection	O
of	O
four	O
primary	O
care	O
demonstration	O
sites	O
where	O
a	O
primary	O
health	O
care	O
NP	O
was	O
hired	O
to	O
practice	O
collaboratively	O
with	O
one	O
or	O
more	O
family	O
/	O
general	O
physicians	O
and	O
other	O
members	O
of	O
an	O
interdisciplinary	O
team	O
.	O

Each	O
demonstration	O
site	O
adopted	O
alternative	O
(	O
non	O
fee	O
-	O
for	O
-	O
service	O
)	O
physician	O
payment	O
mechanisms	O
and	O
used	O
electronic	O
patient	B
records	O
(	O
EPRs	O
)	O
to	O
support	O
service	O
delivery	O
[	O
41	O
]	O
.	O

Demonstration	O
sites	O
participated	O
in	O
project	O
evaluation	O
components	O
that	O
included	O
,	O
but	O
were	O
not	O
limited	O
to	O
,	O
NP	O
roles	O
,	O
alternative	O
fee	O
structures	O
,	O
consumer	O
satisfaction	O
,	O
and	O
implementation	O
and	O
integration	O
of	O
EPRs	O
[	O
41	O
,	O
42	O
]	O
.	O

Legislation	O
to	O
allow	O
NPs	O
to	O
practice	O
collaboratively	O
with	O
physicians	O
in	O
Nova	O
Scotia	O
was	O
passed	O
in	O
2002	O
,	O
part	O
way	O
through	O
the	O
SPCI	O
project	O
[	O
39	O
]	O
.	O

Prescriptive	O
authority	O
granted	O
through	O
legislation	O
authorizes	O
NPs	O
to	O
prescribe	O
from	O
a	O
schedule	O
of	O
drugs	O
[	O
43	O
,	O
44	O
]	O
.	O

At	O
the	O
time	O
of	O
conducting	O
this	O
research	O
project	O
,	O
16	O
primary	O
health	O
care	O
NPs	O
were	O
in	O
active	O
practice	O
[	O
43	O
]	O
.	O

The	O
EPR	O
component	O
of	O
the	O
SPCI	O
project	O
evaluation	O
provided	O
information	O
on	O
the	O
use	O
of	O
technologies	O
in	O
the	O
community	O
context	O
.	O

Results	O
from	O
the	O
implementation	O
process	O
indicated	O
that	O
considerable	O
attention	O
is	O
required	O
for	O
technology	O
literacy	O
,	O
time	O
for	O
training	O
,	O
and	O
selection	O
of	O
software	O
for	O
EPRs	O
[	O
41	O
]	O
.	O

Although	O
the	O
majority	O
of	O
community	O
-	O
based	O
,	O
non	O
-	O
institutional	O
clinical	O
practice	O
settings	O
in	O
Nova	O
Scotia	O
primarily	O
operate	O
with	O
paper	O
-	O
based	O
charting	O
systems	O
,	O
there	O
is	O
a	O
movement	O
toward	O
integrating	O
electronic	O
technologies	O
,	O
including	O
the	O
EPR	O
,	O
in	O
practice	O
among	O
health	O
care	O
providers	O
,	O
administrators	O
,	O
and	O
the	O
provincial	O
government	O
.	O

In	O
addition	O
to	O
recording	O
patient	B
visit	O
information	O
,	O
a	O
component	O
of	O
the	O
EPR	O
package	O
serves	O
to	O
provide	O
drug	O
information	O
resources	O
.	O

Drug	O
therapy	O
information	O
resources	O
for	O
NPs	O
and	O
nurse	O
prescribers	O
have	O
frequently	O
been	O
described	O
as	O
essential	O
in	O
supporting	O
practice	O
[	O
25	O
,	O
28	O
,	O
29	O
]	O
.	O

The	O
role	O
of	O
NPs	O
is	O
relatively	O
new	O
in	O
Canada	O
[	O
39	O
]	O
and	O
there	O
is	O
limited	O
information	O
available	O
to	O
indicate	O
the	O
type	O
of	O
resources	O
(	O
e	O
.	O
g	O
.	O
print	O
,	O
electronic	O
,	O
EPR	O
based	O
)	O
these	O
prescribers	O
use	O
for	O
drug	O
and	O
therapeutic	O
information	O
queries	O
at	O
the	O
point	O
of	O
care	O
.	O

It	O
is	O
unknown	O
as	O
to	O
whether	O
differences	O
exist	O
regarding	O
types	O
of	O
resources	O
used	O
,	O
drug	O
information	O
needs	O
,	O
and	O
utilization	O
patterns	O
among	O
NPs	O
and	O
collaborating	O
physician	O
partners	O
.	O

Some	O
research	O
has	O
suggested	O
that	O
the	O
degree	O
of	O
multidisciplinary	O
team	O
functioning	O
relates	O
to	O
the	O
adoption	O
of	O
technology	O
or	O
innovations	O
in	O
practice	O
but	O
more	O
research	O
is	O
required	O
to	O
determine	O
the	O
extent	O
of	O
these	O
relationships	O
[	O
45	O
,	O
46	O
]	O
.	O

The	O
use	O
of	O
EPR	O
technology	O
is	O
increasing	O
in	O
Nova	O
Scotia	O
but	O
little	O
information	O
is	O
available	O
regarding	O
the	O
readiness	O
of	O
practitioners	O
for	O
use	O
of	O
specific	O
features	O
such	O
as	O
drug	O
information	O
resources	O
.	O

Based	O
on	O
the	O
EPR	O
related	O
results	O
of	O
the	O
SPCI	O
evaluation	O
,	O
use	O
of	O
these	O
functions	O
could	O
be	O
challenging	O
without	O
proper	O
facilitation	O
.	O

The	O
purpose	O
of	O
the	O
survey	O
for	O
this	O
research	O
was	O
to	O
describe	O
drug	O
information	O
resources	O
used	O
by	O
NPs	O
and	O
their	O
collaborating	O
physician	O
partners	O
at	O
the	O
point	O
of	O
care	O
.	O

The	O
results	O
of	O
the	O
survey	O
will	O
be	O
used	O
to	O
guide	O
further	O
technology	O
implementation	O
strategies	O
and	O
stimulate	O
further	O
discussion	O
around	O
drug	O
information	O
resource	O
usage	O
at	O
the	O
point	O
of	O
care	O
.	O

Methods	O

Survey	O
development	O

Survey	O
development	O
involved	O
three	O
stages	O
including	O
identification	O
of	O
important	O
content	O
areas	O
,	O
development	O
of	O
draft	O
questions	O
,	O
and	O
survey	O
refinement	O
.	O

Identifying	O
important	O
content	O
areas	O
for	O
inclusion	O
in	O
the	O
survey	O
involved	O
conducting	O
a	O
comprehensive	O
English	O
language	O
literature	O
search	O
,	O
consultation	O
with	O
relevant	O
stakeholders	O
(	O
e	O
.	O
g	O
.	O
members	O
of	O
the	O
Nova	O
Scotia	O
Department	O
of	O
Health	O
)	O
,	O
and	O
input	O
from	O
subject	O
matter	O
experts	O
at	O
Dalhousie	O
University	O
.	O

The	O
literature	O
review	O
was	O
conducted	O
using	O
the	O
following	O
bibliographic	O
databases	O
:	O
PubMed	O
,	O
Cumulative	O
Index	O
to	O
Nursing	O
and	O
Allied	O
Health	O
Literature	O
(	O
CINAHL	O
)	O
,	O
International	O
Pharmaceutical	O
Abstracts	O
(	O
IPA	O
)	O
,	O
and	O
Web	O
of	O
Science	O
Citation	O
Databases	O
.	O

Hand	O
and	O
electronic	O
searching	O
of	O
relevant	O
journals	O
was	O
also	O
conducted	O
.	O

Broad	O
search	O
terms	O
were	O
used	O
without	O
limits	O
on	O
publication	O
date	O
or	O
place	O
as	O
nurse	O
practitioner	O
titles	O
,	O
roles	O
and	O
scopes	O
of	O
practice	O
,	O
and	O
terminology	O
regarding	O
technology	O
vary	O
nationally	O
and	O
internationally	O
.	O

Some	O
examples	O
of	O
terms	O
used	O
included	O
nurse	O
practitioner	O
,	O
nurse	O
prescriber	O
,	O
nurse	O
clinicians	O
,	O
district	O
nurse	O
,	O
health	O
visitor	O
,	O
drug	O
information	O
resources	O
,	O
drug	O
information	O
services	O
,	O
information	O
needs	O
,	O
and	O
information	O
technology	O
.	O

The	O
draft	O
survey	O
was	O
reviewed	O
by	O
the	O
research	O
team	O
to	O
reduce	O
the	O
number	O
of	O
items	O
and	O
improve	O
clarity	O
.	O

The	O
layout	O
of	O
the	O
questionnaire	O
was	O
carefully	O
examined	O
to	O
ensure	O
that	O
it	O
was	O
easy	O
to	O
follow	O
and	O
complete	O
.	O

Research	O
results	O
from	O
a	O
previous	O
investigation	O
of	O
Nova	O
Scotian	O
physicians	O
'	O
behaviours	O
regarding	O
drug	O
information	O
were	O
also	O
used	O
to	O
further	O
revise	O
the	O
survey	O
[	O
47	O
]	O
.	O

This	O
draft	O
questionnaire	O
was	O
pilot	O
tested	O
by	O
two	O
out	O
of	O
province	O
NPs	O
and	O
one	O
physician	O
.	O

The	O
results	O
of	O
the	O
pilot	O
were	O
used	O
to	O
make	O
final	O
revisions	O
to	O
the	O
survey	O
.	O

Based	O
on	O
pilot	O
-	O
testing	O
feedback	O
and	O
investigator	O
consensus	O
,	O
the	O
final	O
survey	O
was	O
divided	O
into	O
2	O
versions	O
,	O
one	O
for	O
personal	O
digital	O
assistant	O
(	O
PDA	O
)	O
users	O
and	O
one	O
for	O
computer	O
users	O
.	O

The	O
10	O
page	O
surveys	O
for	O
PDA	O
and	O
computer	O
users	O
had	O
5	O
or	O
6	O
sections	O
,	O
respectively	O
,	O
and	O
37	O
questions	O
,	O
many	O
with	O
multiple	O
parts	O
.	O

The	O
survey	O
content	O
included	O
demographics	O
,	O
computer	O
or	O
PDA	O
use	O
and	O
experience	O
,	O
drug	O
and	O
therapeutic	O
resource	O
use	O
and	O
preferences	O
,	O
PDA	O
future	O
use	O
,	O
perceived	O
barriers	O
and	O
facilitators	O
to	O
PDA	O
use	O
,	O
and	O
technology	O
training	O
preferences	O
.	O

Section	O
one	O
contained	O
demographic	O
questions	O
such	O
as	O
gender	O
,	O
age	O
,	O
job	O
title	O
,	O
volume	O
of	O
patients	B
,	O
and	O
EPR	O
availability	O
in	O
the	O
practice	O
setting	O
.	O

Section	O
two	O
was	O
designed	O
to	O
determine	O
PDA	O
or	O
computer	O
use	O
and	O
experience	O
in	O
the	O
practice	O
setting	O
with	O
questions	O
regarding	O
length	O
of	O
use	O
,	O
costs	O
,	O
and	O
work	O
versus	O
home	O
usage	O
.	O

This	O
section	O
also	O
addressed	O
usage	O
and	O
rating	O
of	O
different	O
drug	O
information	O
resources	O
.	O

Resource	O
ratings	O
were	O
based	O
on	O
the	O
frequency	O
of	O
usage	O
,	O
usefulness	O
,	O
accessibility	O
,	O
credibility	O
,	O
and	O
current	O
/	O
timeliness	O
.	O

Resources	O
were	O
grouped	O
as	O
print	O
(	O
i	O
.	O
e	O
.	O
books	O
,	O
journals	O
,	O
and	O
clinical	O
practice	O
guidelines	O
)	O
,	O
online	O
/	O
electronic	O
resources	O
,	O
and	O
health	O
professionals	O
and	O
other	O
.	O

Respondents	O
used	O
5	O
-	O
point	O
Likert	O
scales	O
(	O
strongly	O
agree	O
to	O
strongly	O
disagree	O
)	O
for	O
rating	O
opinions	O
related	O
to	O
resources	O
.	O

A	O
rating	O
of	O
6	O
(	O
not	O
applicable	O
,	O
I	O
do	O
not	O
use	O
this	O
resource	O
)	O
was	O
also	O
included	O
for	O
respondents	O
who	O
did	O
not	O
use	O
a	O
particular	O
resource	O
.	O

Frequency	O
of	O
searching	O
for	O
specific	O
information	O
was	O
rated	O
on	O
a	O
3	O
-	O
point	O
Likert	O
scale	O
(	O
frequently	O
to	O
never	O
)	O
.	O

The	O
final	O
sections	O
of	O
the	O
survey	O
included	O
categorical	O
,	O
open	O
-	O
ended	O
,	O
and	O
Likert	O
scale	O
questions	O
regarding	O
preferred	O
resources	O
,	O
technology	O
barriers	O
,	O
PDA	O
future	O
use	O
,	O
and	O
technology	O
training	O
preferences	O
.	O

Copies	O
of	O
the	O
surveys	O
are	O
attached	O
as	O
an	O
appendix	O
in	O
PDF	O
format	O
[	O
see	O
additional	O
file	O
1	O
and	O
2	O
]	O
or	O
can	O
also	O
be	O
accessed	O
from	O
the	O
Initiative	O
for	O
Medication	O
Management	O
,	O
Policy	O
Analysis	O
,	O
Research	O
&	O
Training	O
(	O
IMPART	O
)	O
website	O
[	O
48	O
]	O
.	O

Ethics	O
approval	O
for	O
the	O
survey	O
was	O
granted	O
through	O
Dalhousie	O
University	O
Research	O
Ethics	O
Board	O
on	O
February	O
3	O
,	O
2005	O
.	O

Survey	O
population	O

Licensed	O
,	O
actively	O
practicing	O
,	O
primary	O
health	O
care	O
NPs	O
(	O
n	O
=	O
16	O
)	O
and	O
their	O
collaborating	O
physician	O
partners	O
(	O
n	O
=	O
21	O
)	O
were	O
eligible	O
to	O
participate	O
.	O

Survey	O
procedures	O

The	O
survey	O
recruitment	O
procedures	O
were	O
based	O
on	O
the	O
methods	O
of	O
Dillman	O
[	O
49	O
]	O
and	O
Salant	O
and	O
Dillman	O
[	O
50	O
]	O
.	O

Survey	O
packages	O
contained	O
a	O
cover	O
letter	O
,	O
separate	O
surveys	O
for	O
PDA	O
and	O
computer	O
users	O
,	O
and	O
a	O
return	O
self	O
-	O
addressed	O
stamped	O
envelope	O
.	O

The	O
covering	O
letter	O
instructed	O
respondents	O
to	O
self	O
-	O
select	O
the	O
appropriate	O
survey	O
(	O
either	O
PDA	O
or	O
computer	O
)	O
based	O
on	O
their	O
drug	O
information	O
seeking	O
behaviours	O
.	O

Participants	B
who	O
had	O
used	O
a	O
PDA	O
at	O
any	O
time	O
were	O
instructed	O
to	O
complete	O
the	O
PDA	O
version	O
of	O
the	O
survey	O
.	O

Those	O
who	O
had	O
never	O
used	O
a	O
PDA	O
for	O
drug	O
information	O
were	O
instructed	O
to	O
complete	O
the	O
computer	O
version	O
of	O
the	O
survey	O
.	O

Several	O
strategies	O
were	O
used	O
to	O
optimize	O
response	O
rate	O
and	O
included	O
:	O
personalized	O
cover	O
letters	O
,	O
coloured	O
paper	O
for	O
surveys	O
,	O
stamped	O
return	O
envelopes	O
,	O
follow	O
-	O
up	O
mailing	O
,	O
and	O
a	O
priority	O
post	O
mailing	O
[	O
51	O
]	O
.	O

The	O
covering	O
letter	O
included	O
coloured	O
logos	O
of	O
Dalhousie	O
University	O
and	O
the	O
Nova	O
Scotia	O
Department	O
of	O
Health	O
representing	O
the	O
investigator	O
affiliations	O
and	O
endorsement	O
of	O
the	O
project	O
.	O

A	O
master	O
mailing	O
list	O
with	O
names	O
and	O
addresses	O
of	O
NPs	O
and	O
their	O
collaborating	O
physician	O
partners	O
was	O
created	O
.	O

To	O
maintain	O
confidentiality	O
of	O
respondents	O
,	O
a	O
number	O
placed	O
on	O
the	O
bottom	O
right	O
corner	O
of	O
each	O
survey	O
corresponded	O
to	O
a	O
name	O
on	O
the	O
confidential	O
master	O
mailing	O
sheet	O
.	O

The	O
postage	O
paid	O
return	O
envelopes	O
were	O
addressed	O
to	O
the	O
research	O
coordinator	O
at	O
the	O
School	O
of	O
Nursing	O
,	O
Dalhousie	O
University	O
,	O
who	O
matched	O
respondents	O
to	O
the	O
mailing	O
list	O
from	O
the	O
first	O
distribution	O
.	O

The	O
cross	O
-	O
referenced	O
mailing	O
list	O
was	O
not	O
accessible	O
to	O
those	O
entering	O
or	O
analysing	O
data	O
.	O

The	O
research	O
coordinator	O
sent	O
the	O
second	O
distribution	O
to	O
those	O
who	O
had	O
not	O
initially	O
responded	O
.	O

A	O
fluorescent	O
coloured	O
page	O
was	O
included	O
in	O
the	O
second	O
mailing	O
to	O
notify	O
recipients	O
of	O
the	O
second	O
and	O
final	O
mailing	O
status	O
.	O

The	O
second	O
mailing	O
followed	O
2	O
weeks	O
after	O
the	O
initial	O
mailing	O
(	O
February	O
2005	O
)	O
.	O

The	O
surveys	O
were	O
sent	O
via	O
Xpresspost	O
(	O
TM	O
)	O
through	O
Canada	O
Post	O
.	O

Data	O
analyses	O

Quantitative	O

Data	O
were	O
entered	O
and	O
analysed	O
in	O
Statistical	O
Package	O
for	O
Social	O
Sciences	O
(	O
SPSS	O
)	O
(	O
version	O
11	O
.	O
5	O
for	O
Windows	O
)	O
.	O

Five	O
surveys	O
were	O
randomly	O
selected	O
as	O
a	O
check	O
for	O
accuracy	O
of	O
data	O
entry	O
.	O

Descriptive	O
statistics	O
were	O
used	O
to	O
describe	O
resource	O
usage	O
by	O
practitioners	O
.	O

Chi	O
Square	O
(	O
Fisher	O
'	O
s	O
Exact	O
when	O
cell	O
count	O
less	O
than	O
5	O
)	O
analyses	O
were	O
used	O
to	O
determine	O
differences	O
in	O
computer	O
or	O
PDA	O
use	O
based	O
on	O
predetermined	O
variables	O
(	O
e	O
.	O
g	O
.	O
high	O
speed	O
Internet	O
connection	O
,	O
number	O
of	O
patients	B
per	O
day	O
)	O
.	O

Mann	O
Whitney	O
U	O
tests	O
were	O
used	O
to	O
compare	O
physician	O
and	O
NPs	O
Likert	O
scale	O
ratings	O
(	O
1	O
=	O
strongly	O
agree	O
to	O
5	O
=	O
strongly	O
disagree	O
)	O
of	O
resource	O
use	O
.	O

Physician	O
and	O
NP	O
rankings	O
of	O
all	O
resources	O
(	O
print	O
,	O
online	O
/	O
electronic	O
,	O
and	O
health	O
professionals	O
and	O
other	O
)	O
were	O
determined	O
from	O
means	O
of	O
Likert	O
scale	O
ratings	O
(	O
1	O
=	O
strongly	O
agree	O
,	O
5	O
=	O
strongly	O
disagree	O
)	O
for	O
each	O
of	O
the	O
pre	O
-	O
specified	O
characteristics	O
(	O
e	O
.	O
g	O
.	O
frequency	O
of	O
use	O
,	O
accessibility	O
,	O
etc	O
.	O
)	O
and	O
the	O
frequency	O
of	O
use	O
of	O
the	O
resources	O
.	O

The	O
best	O
rankings	O
were	O
assigned	O
for	O
the	O
lowest	O
mean	O
scores	O
and	O
the	O
largest	O
number	O
of	O
the	O
sample	O
using	O
a	O
resource	O
.	O

These	O
rankings	O
(	O
ranks	O
based	O
on	O
mean	O
and	O
ranks	O
based	O
on	O
sample	O
)	O
were	O
then	O
entered	O
into	O
a	O
formula	O
to	O
calculate	O
an	O
overall	O
rank	O
.	O

The	O
formula	O
includes	O
:	O
rank	O
=	O
[	O
(	O
rank	O
according	O
to	O
%	O
of	O
sample	O
using	O
the	O
resource	O
+	O
rank	O
based	O
on	O
mean	O
score	O
)	O
/	O
2	O
]	O
.	O

This	O
formula	O
was	O
used	O
to	O
account	O
for	O
mean	O
scores	O
based	O
on	O
small	O
samples	O
as	O
these	O
numbers	O
could	O
potentially	O
over	O
or	O
underestimate	O
the	O
value	O
of	O
a	O
resource	O
.	O

Ratings	O
of	O
6	O
(	O
i	O
.	O
e	O
.	O
not	O
applicable	O
,	O
I	O
do	O
not	O
use	O
this	O
resource	O
)	O
were	O
excluded	O
from	O
the	O
analyses	O
.	O

Qualitative	O

Comments	O
were	O
entered	O
in	O
a	O
word	O
-	O
processing	O
program	O
and	O
organized	O
by	O
type	O
of	O
respondent	O
(	O
PDA	O
versus	O
computer	O
)	O
and	O
question	O
number	O
.	O

The	O
coded	O
survey	O
number	O
and	O
respondent	O
type	O
(	O
NP	O
or	O
physician	O
)	O
were	O
also	O
included	O
next	O
to	O
comments	O
.	O

Investigators	O
determined	O
themes	O
and	O
categorized	O
comments	O
based	O
on	O
previous	O
experience	O
,	O
knowledge	O
,	O
and	O
familiarity	O
with	O
the	O
topic	O
.	O

Results	O

Surveys	O
were	O
completed	O
and	O
returned	O
by	O
75	O
%	O
of	O
eligible	O
participants	B
(	O
27	O
of	O
36	O
)	O
.	O

One	O
physician	O
survey	O
was	O
undeliverable	O
.	O

The	O
response	O
rates	O
from	O
within	O
the	O
NP	O
and	O
physician	O
samples	O
were	O
88	O
%	O
and	O
65	O
%	O
,	O
respectively	O
.	O

Complete	O
demographic	O
information	O
is	O
available	O
in	O
Table	O
1	O
.	O

Methods	O
for	O
accessing	O
resources	O
and	O
self	O
-	O
reported	O
resource	O
use	O

Resource	O
use	O
was	O
similar	O
amongst	O
practitioners	O
.	O

Respondents	O
indicated	O
that	O
print	O
resources	O
(	O
mean	O
4	O
.	O
56	O
,	O
SD	O
0	O
.	O
80	O
)	O
,	O
health	O
professionals	O
(	O
mean	O
3	O
.	O
26	O
,	O
SD	O
0	O
.	O
90	O
)	O
,	O
and	O
online	O
/	O
electronic	O
resources	O
(	O
mean	O
2	O
.	O
70	O
,	O
SD	O
1	O
.	O
20	O
)	O
were	O
the	O
preferred	O
method	O
(	O
1	O
=	O
least	O
preferred	O
to	O
5	O
=	O
most	O
preferred	O
)	O
for	O
accessing	O
drug	O
information	O
.	O

Thirty	O
-	O
seven	O
percent	O
of	O
respondents	O
reported	O
that	O
searching	O
for	O
specific	O
questions	O
related	O
to	O
drug	O
information	O
(	O
e	O
.	O
g	O
.	O
usual	O
dosage	O
,	O
duration	O
of	O
therapy	O
)	O
was	O
conducted	O
using	O
both	O
print	O
and	O
electronic	O
resources	O
(	O
but	O
print	O
use	O
greater	O
than	O
electronic	O
)	O
(	O
Table	O
2	O
)	O
.	O

The	O
preferred	O
means	O
(	O
i	O
.	O
e	O
.	O
print	O
)	O
to	O
access	O
resources	O
was	O
consistent	O
with	O
the	O
most	O
common	O
means	O
of	O
conducting	O
searches	O
for	O
specific	O
drug	O
information	O
queries	O
.	O

Respondents	O
'	O
ratings	O
for	O
pre	O
-	O
specified	O
print	O
,	O
online	O
/	O
electronic	O
,	O
and	O
professional	O
resources	O
and	O
other	O
,	O
based	O
on	O
means	O
from	O
Likert	O
scales	O
and	O
number	O
of	O
respondents	O
using	O
the	O
resources	O
,	O
are	O
presented	O
in	O
Tables	O
3	O
,	O
4	O
,	O
and	O
5	O
.	O

Of	O
all	O
resources	O
within	O
the	O
print	O
,	O
online	O
/	O
electronic	O
,	O
and	O
health	O
professionals	O
or	O
other	O
categories	O
,	O
NPs	O
and	O
physicians	O
rated	O
the	O
Compendium	O
of	O
Pharmaceuticals	O
and	O
Specialties	O
(	O
CPS	O
)	O
[	O
52	O
]	O
and	O
pharmacists	O
as	O
the	O
top	O
two	O
most	O
frequently	O
used	O
resources	O
for	O
providing	O
drug	O
and	O
therapeutic	O
information	O
.	O

Physicians	O
rated	O
other	O
physicians	O
as	O
the	O
third	O
most	O
frequently	O
used	O
resource	O
.	O

The	O
book	O
Therapeutic	O
Choices	O
[	O
53	O
]	O
ranked	O
third	O
for	O
NPs	O
.	O

Based	O
on	O
written	O
feedback	O
,	O
physicians	O
and	O
NPs	O
consulted	O
pharmacists	O
and	O
other	O
physicians	O
most	O
frequently	O
.	O

The	O
CPS	O
and	O
pharmacists	O
were	O
also	O
ranked	O
as	O
the	O
top	O
two	O
resources	O
overall	O
in	O
terms	O
of	O
usefulness	O
,	O
accessibility	O
,	O
credibility	O
,	O
and	O
current	O
/	O
timeliness	O
for	O
physicians	O
.	O

Rankings	O
by	O
NPs	O
were	O
similar	O
for	O
usefulness	O
,	O
accessibility	O
,	O
and	O
credibility	O
.	O

NPs	O
ranked	O
pharmacists	O
,	O
Therapeutic	O
Choices	O
,	O
and	O
academic	O
detailing	O
first	O
and	O
the	O
CPS	O
as	O
second	O
for	O
current	O
/	O
timeliness	O
.	O

Within	O
the	O
online	O
/	O
electronic	O
category	O
,	O
electronic	O
clinical	O
practice	O
guidelines	O
(	O
eCPGs	O
)	O
were	O
rated	O
the	O
highest	O
for	O
all	O
characteristics	O
(	O
e	O
.	O
g	O
.	O
usefulness	O
,	O
credibility	O
)	O
.	O

Although	O
eCPGs	O
were	O
highly	O
ranked	O
,	O
approximately	O
30	O
%	O
of	O
the	O
sample	O
reported	O
not	O
using	O
this	O
resource	O
.	O

Other	O
resources	O
in	O
this	O
category	O
were	O
infrequently	O
used	O
based	O
on	O
respondents	O
'	O
self	O
-	O
reports	O
.	O

Pharmaceutical	O
industry	O
representatives	O
were	O
used	O
as	O
a	O
source	O
of	O
drug	O
information	O
by	O
85	O
%	O
and	O
86	O
%	O
of	O
physicians	O
and	O
NPs	O
,	O
respectively	O
(	O
Table	O
5	O
)	O
.	O

This	O
was	O
higher	O
than	O
regional	O
drug	O
information	O
services	O
(	O
used	O
by	O
23	O
%	O
of	O
physicians	O
and	O
50	O
%	O
of	O
NPs	O
)	O
.	O

After	O
exclusion	O
of	O
traditional	O
health	O
professionals	O
(	O
i	O
.	O
e	O
.	O
physicians	O
,	O
nurses	O
,	O
pharmacists	O
,	O
allied	O
health	O
)	O
in	O
the	O
health	O
professionals	O
and	O
other	O
category	O
,	O
pharmaceutical	O
industry	O
representatives	O
received	O
rankings	O
for	O
second	O
or	O
third	O
for	O
frequency	O
of	O
use	O
,	O
usefulness	O
,	O
accessibility	O
,	O
credibility	O
,	O
and	O
current	O
/	O
timeliness	O
,	O
based	O
on	O
means	O
and	O
number	O
of	O
respondents	O
using	O
this	O
resource	O
(	O
data	O
not	O
shown	O
)	O
.	O

Differences	O
between	O
nurse	O
practitioners	O
and	O
physicians	O

A	O
series	O
of	O
Mann	O
Whitney	O
U	O
tests	O
were	O
used	O
to	O
compare	O
the	O
responses	O
of	O
NPs	O
and	O
physicians	O
on	O
their	O
use	O
of	O
print	O
,	O
online	O
/	O
electronic	O
,	O
and	O
health	O
professional	O
resources	O
.	O

In	O
total	O
95	O
statistical	O
tests	O
were	O
conducted	O
.	O

The	O
large	O
number	O
of	O
tests	O
increases	O
the	O
likelihood	O
of	O
a	O
type	O
I	O
error	O
as	O
five	O
significant	O
differences	O
would	O
be	O
expected	O
by	O
chance	O
alone	O
at	O
an	O
alpha	O
threshold	O
of	O
0	O
.	O
05	O
.	O

It	O
is	O
therefore	O
important	O
to	O
treat	O
these	O
results	O
with	O
caution	O
.	O

A	O
limited	O
number	O
of	O
statistically	O
significant	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
differences	O
were	O
identified	O
between	O
physicians	O
and	O
NPs	O
and	O
are	O
reported	O
in	O
Table	O
6	O
.	O

Therapeutic	O
Choices	O
differed	O
significantly	O
for	O
frequency	O
of	O
use	O
with	O
more	O
NPs	O
making	O
use	O
of	O
this	O
resource	O
.	O

Allied	O
health	O
professionals	O
significantly	O
differed	O
between	O
NPs	O
and	O
physicians	O
for	O
accessibility	O
and	O
current	O
/	O
timeliness	O
while	O
NPs	O
were	O
more	O
in	O
agreement	O
with	O
these	O
characteristics	O
of	O
the	O
resource	O
.	O

Nurse	O
colleague	O
credibility	O
and	O
current	O
/	O
timeliness	O
was	O
rated	O
significantly	O
higher	O
by	O
NPs	O
versus	O
physicians	O
.	O

Factors	O
influencing	O
electronic	O
technology	O
use	O
at	O
the	O
point	O
of	O
care	O

Factors	O
such	O
as	O
gender	O
,	O
age	O
,	O
practitioner	O
type	O
(	O
NP	O
vs	O
physician	O
)	O
,	O
accessibility	O
,	O
technical	O
support	O
,	O
Internet	O
connection	O
speed	O
,	O
patient	B
volume	O
,	O
presence	O
of	O
an	O
EPR	O
,	O
and	O
home	O
computer	O
use	O
were	O
examined	O
to	O
determine	O
if	O
they	O
were	O
associated	O
with	O
the	O
use	O
of	O
a	O
work	O
computer	O
to	O
search	O
for	O
drug	O
information	O
at	O
the	O
point	O
of	O
care	O
.	O

No	O
statistically	O
significant	O
associations	O
were	O
found	O
(	O
Fisher	O
'	O
s	O
Exact	O
)	O
.	O

Additional	O
resources	O
from	O
respondent	O
comments	O

Respondents	O
indicated	O
other	O
resources	O
and	O
programs	O
,	O
such	O
as	O
clinical	O
calculators	O
,	O
that	O
they	O
would	O
like	O
to	O
access	O
from	O
their	O
computer	O
or	O
PDA	O
.	O

The	O
top	O
three	O
resources	O
that	O
were	O
desired	O
included	O
Canadian	O
clinical	O
practice	O
guidelines	O
,	O
patient	B
education	O
information	O
,	O
and	O
ability	O
to	O
track	O
clinical	O
activities	O
/	O
statistics	O
.	O

Further	O
comments	O
from	O
two	O
NP	O
computer	O
survey	O
respondents	O
revealed	O
that	O
a	O
resource	O
on	O
drug	O
interactions	O
and	O
dosages	O
would	O
be	O
desired	O
.	O

One	O
other	O
NP	O
also	O
indicated	O
"	O
up	O
to	O
date	O
info	O
[	O
sic	O
]	O
on	O
drugs	O
to	O
treat	O
various	O
illnesses	O
ie	O
doseage	O
[	O
sic	O
]	O
,	O
length	O
of	O
use	O
etc	O
.	O
"	O

Computer	O
or	O
personal	O
digital	O
assistant	O
use	O
in	O
practice	O

Approximately	O
50	O
%	O
of	O
computer	O
survey	O
respondents	O
reported	O
using	O
their	O
work	O
computers	O
for	O
searching	O
drug	O
or	O
therapeutic	O
information	O
related	O
to	O
patient	B
care	O
.	O

Of	O
those	O
respondents	O
,	O
just	O
over	O
half	O
(	O
54	O
%	O
)	O
also	O
reported	O
using	O
their	O
home	O
computer	O
for	O
this	O
purpose	O
.	O

Sixty	O
-	O
seven	O
and	O
17	O
%	O
of	O
PDA	O
survey	O
respondents	O
reported	O
using	O
their	O
PDA	O
for	O
searching	O
drug	O
or	O
therapeutic	O
information	O
related	O
to	O
patient	B
care	O
at	O
work	O
and	O
home	O
,	O
respectively	O
.	O

Searching	O
on	O
a	O
weekly	O
basis	O
for	O
specific	O
information	O
related	O
to	O
drugs	O

Of	O
the	O
24	O
specified	O
categories	O
of	O
drug	O
information	O
included	O
in	O
the	O
survey	O
,	O
the	O
majority	O
were	O
reported	O
as	O
infrequently	O
searched	O
and	O
a	O
smaller	O
percentage	O
as	O
never	O
searched	O
by	O
respondents	O
(	O
data	O
not	O
shown	O
)	O
.	O

The	O
top	O
three	O
categories	O
rated	O
as	O
frequently	O
searched	O
were	O
side	O
effects	O
,	O
adult	O
or	O
usual	O
drug	O
dosage	O
,	O
and	O
most	O
appropriate	O
drug	O
for	O
an	O
indication	O
.	O

(	O
Table	O
7	O
)	O

Issues	O
related	O
to	O
personal	O
digital	O
assistants	O

Respondents	O
reported	O
their	O
level	O
of	O
agreement	O
with	O
statements	O
related	O
to	O
how	O
PDAs	O
may	O
influence	O
their	O
practice	O
.	O

The	O
statements	O
included	O
aspects	O
of	O
workload	O
(	O
organization	O
and	O
paper	O
work	O
)	O
,	O
convenience	O
,	O
and	O
improving	O
quality	O
of	O
care	O
and	O
patient	B
outcomes	O
.	O

(	O
Table	O
8	O
)	O
Respondents	O
agreed	O
that	O
PDAs	O
are	O
a	O
convenient	O
resource	O
but	O
indicated	O
that	O
PDAs	O
would	O
not	O
decrease	O
paperwork	O
or	O
improve	O
patient	B
health	O
outcomes	O
.	O

Barriers	O
and	O
facilitators	O
to	O
personal	O
digital	O
assistants	O
:	O
themes	O
from	O
written	O
comments	O

Peer	O
support	O
from	O
colleagues	O
,	O
convenience	O
,	O
standardized	O
usage	O
,	O
and	O
financial	O
and	O
technical	O
support	O
were	O
the	O
main	O
perceived	O
facilitators	O
to	O
PDA	O
use	O
reported	O
by	O
respondents	O
.	O

The	O
main	O
perceived	O
barrier	O
to	O
PDA	O
use	O
reported	O
by	O
respondents	O
(	O
n	O
=	O
10	O
)	O
included	O
cost	O
.	O

Other	O
factors	O
such	O
as	O
technology	O
literacy	O
,	O
time	O
,	O
lack	O
of	O
peer	O
support	O
,	O
no	O
high	O
speed	O
internet	O
for	O
downloads	O
,	O
lack	O
of	O
needed	O
resources	O
,	O
keeping	O
up	O
to	O
date	O
on	O
resources	O
,	O
and	O
searching	O
speed	O
were	O
also	O
reported	O
.	O

Future	O
use	O
of	O
personal	O
digital	O
assistants	O

Fifty	O
-	O
two	O
percent	O
,	O
including	O
current	O
PDA	O
users	O
,	O
reported	O
that	O
they	O
would	O
use	O
a	O
PDA	O
in	O
the	O
future	O
.	O

Twenty	O
two	O
percent	O
were	O
uncertain	O
and	O
19	O
%	O
reported	O
that	O
they	O
would	O
not	O
use	O
a	O
PDA	O
in	O
the	O
future	O
.	O

Two	O
people	B
did	O
not	O
respond	O
.	O

Confidentiality	O

Fifty	O
two	O
percent	O
of	O
respondents	O
indicated	O
that	O
patient	B
confidentiality	O
with	O
PDAs	O
was	O
no	O
more	O
concerning	O
compared	O
to	O
use	O
of	O
other	O
technologies	O
.	O

Forty	O
-	O
four	O
percent	O
did	O
not	O
know	O
if	O
they	O
had	O
a	O
policy	O
on	O
patient	B
confidentiality	O
with	O
regard	O
to	O
technologies	O
.	O

Technology	O
training	O
and	O
reimbursement	O

Respondents	O
rated	O
(	O
1	O
=	O
least	O
preferred	O
to	O
5	O
=	O
most	O
preferred	O
)	O
one	O
on	O
one	O
instruction	O
and	O
group	O
learning	O
led	O
by	O
an	O
expert	O
facilitator	O
as	O
the	O
most	O
preferred	O
(	O
mean	O
4	O
.	O
32	O
,	O
SD	O
0	O
.	O
99	O
)	O
means	O
by	O
which	O
to	O
receive	O
instruction	O
on	O
a	O
new	O
technology	O
.	O

Least	O
preferred	O
methods	O
included	O
online	O
discussions	O
/	O
chatrooms	O
(	O
mean	O
1	O
.	O
52	O
,	O
SD	O
1	O
.	O
04	O
)	O
,	O
internet	O
videos	O
(	O
live	O
:	O
mean	O
1	O
.	O
70	O
,	O
SD	O
1	O
.	O
10	O
,	O
or	O
static	O
:	O
mean	O
1	O
.	O
87	O
,	O
SD	O
1	O
.	O
14	O
)	O
,	O
video	O
cassettes	O
(	O
mean	O
2	O
.	O
30	O
,	O
SD	O
1	O
.	O
55	O
)	O
,	O
trial	O
and	O
error	O
learning	O
(	O
mean	O
2	O
.	O
32	O
,	O
SD	O
1	O
.	O
28	O
)	O
,	O
and	O
written	O
manuals	O
(	O
mean	O
2	O
.	O
92	O
,	O
SD	O
1	O
.	O
44	O
)	O
.	O

Paid	O
leave	O
for	O
attendance	O
at	O
technology	O
training	O
sessions	O
was	O
the	O
preferred	O
means	O
(	O
mean	O
1	O
.	O
77	O
,	O
SD	O
0	O
.	O
86	O
;	O
1	O
=	O
strongly	O
agree	O
to	O
5	O
=	O
strongly	O
disagree	O
)	O
of	O
remuneration	O
for	O
respondents	O
.	O

Respondents	O
also	O
indicated	O
that	O
if	O
financial	O
remuneration	O
was	O
to	O
occur	O
,	O
it	O
should	O
correspond	O
to	O
the	O
amount	O
of	O
time	O
for	O
training	O
that	O
is	O
required	O
(	O
versus	O
a	O
flat	O
rate	O
)	O
(	O
mean	O
1	O
.	O
96	O
,	O
SD	O
1	O
.	O
08	O
)	O
.	O

Continuing	O
education	O
credits	O
were	O
not	O
viewed	O
as	O
an	O
incentive	O
(	O
mean	O
2	O
.	O
69	O
,	O
SD	O
1	O
.	O
44	O
)	O
.	O

Discussion	O

Preferred	O
resources	O

In	O
our	O
study	O
,	O
printed	O
materials	O
(	O
e	O
.	O
g	O
.	O
compendia	O
,	O
journals	O
,	O
textbook	O
resources	O
)	O
and	O
professionals	O
(	O
e	O
.	O
g	O
.	O
pharmacists	O
)	O
were	O
the	O
most	O
preferred	O
and	O
frequently	O
used	O
means	O
to	O
access	O
information	O
.	O

Physician	O
reliance	O
on	O
text	O
and	O
compendia	O
relative	O
to	O
online	O
/	O
electronic	O
resources	O
has	O
been	O
frequently	O
reported	O
[	O
11	O
]	O
.	O

In	O
a	O
study	O
examining	O
family	O
doctors	O
'	O
use	O
of	O
information	O
sources	O
to	O
answer	O
clinical	O
questions	O
,	O
human	B
resources	O
(	O
e	O
.	O
g	O
.	O
doctor	O
,	O
pharmacist	O
)	O
,	O
non	O
-	O
prescribing	O
print	O
information	O
(	O
e	O
.	O
g	O
.	O
textbooks	O
and	O
journal	O
articles	O
)	O
,	O
and	O
prescribing	O
texts	O
were	O
used	O
36	O
%	O
,	O
32	O
%	O
,	O
and	O
25	O
%	O
of	O
the	O
time	O
,	O
respectively	O
[	O
54	O
]	O
.	O

Books	O
from	O
the	O
workplace	O
were	O
reported	O
by	O
approximately	O
79	O
%	O
of	O
UK	O
primary	O
care	O
nurses	O
as	O
a	O
commonly	O
used	O
source	O
of	O
knowledge	O
and	O
information	O
used	O
to	O
support	O
practice	O
[	O
55	O
]	O
.	O

Fewer	O
than	O
one	O
-	O
third	O
(	O
31	O
%	O
)	O
reported	O
using	O
electronic	O
resources	O
(	O
e	O
.	O
g	O
.	O
Internet	O
,	O
electronic	O
journals	O
)	O
for	O
this	O
purpose	O
[	O
55	O
]	O
.	O

Results	O
of	O
a	O
postal	O
questionnaire	O
to	O
NPs	O
demonstrated	O
that	O
61	O
%	O
and	O
51	O
%	O
of	O
respondents	O
reported	O
using	O
drug	O
reference	O
manuals	O
and	O
textbooks	O
,	O
respectively	O
,	O
a	O
few	O
times	O
a	O
week	O
or	O
more	O
[	O
29	O
]	O
.	O

These	O
frequencies	O
were	O
second	O
and	O
third	O
only	O
to	O
consulting	O
with	O
their	O
physician	O
supervisor	O
(	O
63	O
%	O
)	O
.	O

Data	O
from	O
structured	O
interviews	O
of	O
a	O
sample	O
of	O
22	O
community	O
nurse	O
prescribers	O
reported	O
by	O
Hall	O
et	O
al	O
.	O
revealed	O
that	O
the	O
majority	O
relied	O
on	O
print	O
materials	O
to	O
access	O
information	O
,	O
namely	O
the	O
British	O
National	O
Formulary	O
[	O
32	O
]	O
.	O

A	O
survey	O
of	O
a	O
primary	O
care	O
practice	O
-	O
based	O
research	O
network	O
in	O
the	O
US	O
that	O
included	O
physicians	O
,	O
physician	O
assistants	O
,	O
and	O
nurse	O
practitioners	O
,	O
revealed	O
that	O
interpersonal	O
and	O
rapidly	O
accessed	O
print	O
resources	O
were	O
preferred	O
.	O

Sixty	O
-	O
one	O
and	O
58	O
%	O
of	O
respondents	O
reported	O
using	O
drug	O
reference	O
sources	O
such	O
as	O
the	O
Physician	O
'	O
s	O
Desk	O
Reference	O
(	O
PDR	O
)	O
and	O
medical	O
textbooks	O
,	O
respectively	O
,	O
a	O
few	O
times	O
a	O
day	O
or	O
daily	O
[	O
56	O
]	O
.	O

The	O
clinicians	O
in	O
our	O
sample	O
perceived	O
the	O
Canadian	O
compendium	O
,	O
the	O
CPS	O
,	O
to	O
be	O
useful	O
,	O
accessible	O
,	O
credible	O
,	O
and	O
current	O
/	O
timely	O
.	O

The	O
CPS	O
,	O
is	O
described	O
as	O
"	O
the	O
Canadian	O
drug	O
reference	O
for	O
health	O
professionals	O
"	O
and	O
is	O
intended	O
to	O
provide	O
a	O
central	O
source	O
of	O
drug	O
information	O
on	O
drug	O
products	O
available	O
in	O
Canada	O
[	O
52	O
]	O
.	O

It	O
is	O
available	O
in	O
print	O
(	O
English	O
and	O
French	O
)	O
and	O
became	O
available	O
online	O
in	O
June	O
2004	O
.	O

The	O
CPS	O
includes	O
drug	O
monographs	O
for	O
commonly	O
used	O
products	O
approved	O
for	O
use	O
in	O
Canada	O
,	O
but	O
it	O
does	O
not	O
include	O
all	O
drugs	O
available	O
on	O
the	O
Canadian	O
market	O
[	O
57	O
]	O
.	O

The	O
majority	O
of	O
these	O
product	O
monographs	O
are	O
based	O
on	O
monographs	O
submitted	O
by	O
pharmaceutical	O
manufacturers	O
and	O
approved	O
by	O
Health	O
Canada	O
.	O

Some	O
of	O
the	O
monographs	O
are	O
written	O
by	O
the	O
Canadian	O
Pharmacists	O
Association	O
and	O
are	O
described	O
as	O
being	O
evidence	O
-	O
based	O
[	O
52	O
]	O
.	O

The	O
CPS	O
also	O
includes	O
more	O
than	O
100	O
pages	O
of	O
clinical	O
tools	O
[	O
52	O
]	O
.	O

The	O
CPS	O
has	O
been	O
criticized	O
for	O
including	O
pharmaceutical	O
company	O
advertising	O
and	O
requiring	O
manufacturer	O
payment	O
for	O
inclusion	O
of	O
product	O
monographs	O
[	O
58	O
]	O
.	O

The	O
accuracy	O
of	O
particular	O
components	O
of	O
CPS	O
monographs	O
has	O
also	O
been	O
investigated	O
.	O

A	O
review	O
of	O
overdose	O
management	O
in	O
119	O
monographs	O
from	O
the	O
2001	O
CPS	O
revealed	O
considerable	O
variability	O
in	O
the	O
utility	O
of	O
information	O
with	O
50	O
%	O
of	O
the	O
monographs	O
containing	O
misleading	O
or	O
dangerous	O
advice	O
[	O
59	O
]	O
.	O

Since	O
2004	O
,	O
the	O
CPS	O
has	O
included	O
an	O
alert	O
box	O
in	O
the	O
overdose	O
section	O
of	O
monographs	O
notifying	O
users	O
to	O
contact	O
Poison	O
Control	O
Centres	O
for	O
overdose	O
management	O
information	O
.	O

Some	O
authors	O
have	O
criticized	O
references	O
that	O
are	O
similar	O
to	O
the	O
CPS	O
as	O
being	O
inadequate	O
with	O
regard	O
to	O
inclusion	O
of	O
evidence	O
based	O
information	O
[	O
60	O
]	O
.	O

The	O
NPs	O
in	O
our	O
sample	O
also	O
rated	O
Therapeutic	O
Choices	O
highly	O
for	O
all	O
characteristics	O
.	O

This	O
finding	O
is	O
most	O
likely	O
attributable	O
to	O
the	O
fact	O
that	O
it	O
is	O
a	O
recommended	O
resource	O
for	O
coursework	O
associated	O
with	O
the	O
Dalhousie	O
NP	O
university	O
program	O
curriculum	O
.	O

Therapeutic	O
Choices	O
is	O
a	O
concise	O
therapeutics	O
reference	O
text	O
published	O
by	O
the	O
Canadian	O
Pharmacists	O
Association	O
.	O

The	O
text	O
contains	O
approximately	O
120	O
extensively	O
referenced	O
chapters	O
with	O
a	O
disease	O
management	O
approach	O
including	O
easy	O
to	O
use	O
algorithms	O
and	O
tables	O
.	O

An	O
editorial	O
board	O
is	O
responsible	O
for	O
extensively	O
reviewing	O
the	O
content	O
to	O
ensure	O
unbiased	O
and	O
objective	O
information	O
is	O
presented	O
[	O
53	O
]	O
.	O

Health	O
professionals	O

Reliance	O
on	O
other	O
health	O
professionals	O
,	O
especially	O
pharmacists	O
and	O
physicians	O
,	O
as	O
a	O
resource	O
for	O
information	O
was	O
evident	O
from	O
our	O
study	O
and	O
concurs	O
with	O
the	O
findings	O
of	O
others	O
[	O
28	O
,	O
32	O
,	O
55	O
,	O
61	O
]	O
.	O

Nurse	O
practitioners	O
have	O
reported	O
that	O
collaborative	O
relationships	O
with	O
pharmacists	O
increase	O
NP	O
role	O
satisfaction	O
[	O
61	O
]	O
.	O

NPs	O
frequently	O
consult	O
with	O
allied	O
health	O
care	O
professionals	O
in	O
their	O
primary	O
health	O
care	O
provider	O
role	O
and	O
this	O
is	O
supported	O
by	O
written	O
feedback	O
from	O
our	O
sample	O
regarding	O
frequently	O
consulted	O
health	O
professionals	O
.	O

Nursing	O
colleagues	O
are	O
also	O
likely	O
to	O
be	O
rated	O
highly	O
by	O
NPs	O
due	O
to	O
their	O
affiliation	O
with	O
peers	O
from	O
the	O
same	O
profession	O
.	O

Some	O
investigators	O
have	O
shown	O
that	O
non	O
-	O
human	B
references	O
(	O
e	O
.	O
g	O
.	O
textbook	O
)	O
are	O
sought	O
for	O
more	O
technical	O
aspects	O
of	O
prescribing	O
(	O
e	O
.	O
g	O
.	O
dose	O
)	O
,	O
whereas	O
guidance	O
regarding	O
selection	O
of	O
agents	O
(	O
i	O
.	O
e	O
.	O
right	O
drug	O
for	O
an	O
indication	O
)	O
is	O
sought	O
from	O
human	B
resources	O
(	O
e	O
.	O
g	O
.	O
pharmacists	O
or	O
physicians	O
)	O
[	O
62	O
]	O
.	O

We	O
were	O
unable	O
to	O
determine	O
what	O
kinds	O
of	O
resources	O
were	O
used	O
for	O
specific	O
purposes	O
from	O
our	O
study	O
.	O

Online	O
and	O
electronic	O
resources	O
,	O
computers	O
,	O
and	O
personal	O
digital	O
assistants	O

From	O
our	O
study	O
,	O
computer	O
survey	O
respondents	O
ranked	O
online	O
/	O
electronic	O
resources	O
third	O
in	O
preference	O
following	O
print	O
and	O
health	O
professionals	O
.	O

Various	O
barriers	O
and	O
facilitators	O
to	O
accessing	O
information	O
online	O
/	O
electronically	O
or	O
via	O
the	O
Internet	O
have	O
been	O
described	O
in	O
the	O
literature	O
[	O
55	O
,	O
63	O
-	O
66	O
]	O
.	O

Variables	O
that	O
have	O
been	O
described	O
by	O
others	O
as	O
barriers	O
such	O
as	O
accessibility	O
,	O
high	O
speed	O
internet	O
access	O
,	O
patient	B
volume	O
,	O
age	O
,	O
practitioner	O
type	O
,	O
and	O
technology	O
support	O
did	O
not	O
appear	O
to	O
influence	O
computer	O
searching	O
for	O
information	O
on	O
drugs	O
or	O
therapeutics	O
related	O
to	O
patient	B
care	O
in	O
our	O
results	O
.	O

Some	O
qualitative	O
feedback	O
does	O
however	O
support	O
this	O
notion	O
.	O

As	O
an	O
example	O
,	O
in	O
response	O
to	O
a	O
request	O
for	O
a	O
rationale	O
for	O
not	O
using	O
computers	O
one	O
physician	O
commented	O
:	O
"	O
Retro	O
tech	O
[	O
sic	O
]	O
/	O
old	O
fashion	O
.	O

I	O
still	O
like	O
to	O
use	O
my	O
mind	O
and	O
have	O
always	O
been	O
a	O
fan	O
of	O
pen	O
and	O
paper	O
"	O
.	O

Barriers	O
that	O
were	O
identified	O
with	O
our	O
sample	O
regarding	O
the	O
use	O
of	O
handheld	O
technologies	O
such	O
as	O
PDAs	O
included	O
cost	O
,	O
time	O
,	O
and	O
issues	O
related	O
to	O
technology	O
literacy	O
.	O

Several	O
people	B
questioned	O
the	O
value	O
of	O
PDAs	O
.	O

One	O
GP	O
stated	O
when	O
referring	O
to	O
a	O
PDA	O
:	O
"	O
So	O
far	O
I	O
have	O
not	O
discovered	O
a	O
use	O
for	O
one	O
"	O
.	O

Other	O
respondents	O
reinforced	O
their	O
preferences	O
for	O
other	O
resources	O
(	O
e	O
.	O
g	O
.	O
books	O
)	O
and	O
resistance	O
to	O
technology	O
.	O

When	O
responding	O
to	O
barriers	O
for	O
the	O
use	O
of	O
PDAs	O
,	O
one	O
NP	O
commented	O
,	O
"	O
My	O
huge	O
dislike	O
for	O
machinery	O
that	O
frequently	O
requires	O
updating	O
and	O
patience	O
"	O
.	O

A	O
physician	O
responded	O
,	O
"	O
as	O
stated	O
,	O
I	O
like	O
to	O
use	O
my	O
own	O
mind	O
,	O
and	O
can	O
get	O
all	O
the	O
info	O
I	O
need	O
from	O
books	O
relatively	O
quickly	O
"	O
.	O

Facilitators	O
to	O
the	O
use	O
of	O
PDAs	O
mainly	O
included	O
convenience	O
factors	O
such	O
as	O
having	O
resources	O
all	O
in	O
one	O
place	O
,	O
faster	O
means	O
to	O
get	O
information	O
,	O
and	O
portability	O
.	O

Our	O
sample	O
was	O
not	O
in	O
agreement	O
with	O
some	O
convenience	O
factors	O
in	O
that	O
they	O
did	O
not	O
feel	O
that	O
PDAs	O
would	O
decrease	O
paperwork	O
.	O

Practitioners	O
from	O
our	O
sample	O
felt	O
relatively	O
neutral	O
about	O
PDAs	O
improving	O
patient	B
'	O
s	O
health	O
outcomes	O
with	O
41	O
%	O
responding	O
in	O
this	O
manner	O
.	O

Results	O
from	O
a	O
sample	O
of	O
primary	O
care	O
practitioners	O
in	O
the	O
US	O
revealed	O
that	O
76	O
%	O
agreed	O
that	O
the	O
use	O
of	O
handheld	O
devices	O
for	O
electronic	O
prescribing	O
would	O
substantially	O
reduce	O
medical	O
errors	O
and	O
improve	O
the	O
quality	O
of	O
health	O
care	O
[	O
67	O
]	O
.	O

Our	O
study	O
also	O
suggests	O
that	O
resources	O
such	O
as	O
the	O
Cochrane	O
Library	O
and	O
its	O
Database	O
of	O
Systematic	O
Reviews	O
were	O
not	O
frequently	O
used	O
.	O

This	O
finding	O
is	O
similar	O
to	O
that	O
of	O
other	O
investigators	O
[	O
30	O
,	O
35	O
,	O
64	O
]	O
.	O

Despite	O
the	O
desire	O
of	O
some	O
clinicians	O
to	O
use	O
these	O
resources	O
,	O
lack	O
of	O
confidence	O
and	O
ability	O
to	O
use	O
them	O
appropriately	O
has	O
been	O
found	O
[	O
30	O
,	O
64	O
,	O
68	O
,	O
69	O
]	O
.	O

Our	O
study	O
suggests	O
that	O
although	O
this	O
resource	O
is	O
perceived	O
as	O
credible	O
,	O
current	O
/	O
timely	O
,	O
and	O
useful	O
,	O
it	O
is	O
also	O
perceived	O
to	O
be	O
somewhat	O
inaccessible	O
.	O

The	O
Cochrane	O
Library	O
is	O
available	O
to	O
the	O
health	O
professionals	O
(	O
e	O
.	O
g	O
.	O
nurses	O
,	O
physicians	O
,	O
pharmacists	O
,	O
occupational	O
therapists	O
,	O
physiotherapists	O
,	O
etc	O
.	O
)	O
in	O
our	O
sample	O
through	O
professional	O
bodies	O
via	O
the	O
Atlantic	O
Health	O
Knowledge	O
Partnership	O
[	O
70	O
]	O
.	O

Technology	O
training	O
:	O
preferences	O
and	O
incentives	O

With	O
regard	O
to	O
receiving	O
training	O
for	O
a	O
new	O
technology	O
,	O
our	O
study	O
demonstrates	O
that	O
in	O
person	B
conferences	O
or	O
one	O
on	O
one	O
training	O
sessions	O
are	O
the	O
preferred	O
means	O
to	O
receive	O
continuing	O
education	O
.	O

Person	B
to	O
person	B
interaction	O
has	O
been	O
reported	O
as	O
the	O
preferred	O
and	O
most	O
frequently	O
used	O
means	O
to	O
access	O
continuing	O
education	O
or	O
training	O
by	O
other	O
investigators	O
[	O
55	O
,	O
71	O
]	O
.	O

Our	O
study	O
also	O
indicates	O
that	O
this	O
group	O
of	O
practitioners	O
may	O
benefit	O
from	O
accessing	O
resources	O
[	O
72	O
-	O
80	O
]	O
that	O
provide	O
guidance	O
on	O
useful	O
drug	O
information	O
resources	O
available	O
for	O
devices	O
such	O
as	O
PDAs	O
.	O

This	O
is	O
exemplified	O
by	O
one	O
respondent	O
'	O
s	O
statement	O
"	O
knowledge	O
regarding	O
good	O
software	O
programs	O
"	O
as	O
a	O
barrier	O
to	O
the	O
use	O
of	O
PDAs	O
.	O

Pharmaceutical	O
industry	O

The	O
influence	O
of	O
the	O
pharmaceutical	O
industry	O
on	O
physician	O
prescribing	O
and	O
research	O
outcomes	O
has	O
been	O
documented	O
[	O
81	O
,	O
82	O
]	O
.	O

Although	O
NP	O
use	O
of	O
industry	O
representatives	O
as	O
a	O
source	O
of	O
pharmacological	O
information	O
has	O
been	O
documented	O
,	O
the	O
influence	O
on	O
prescribing	O
is	O
largely	O
uninvestigated	O
[	O
32	O
,	O
61	O
,	O
83	O
-	O
85	O
]	O
.	O

The	O
CNA	O
competency	O
framework	O
includes	O
a	O
statement	O
regarding	O
prescribing	O
and	O
industry	O
relations	O
[	O
23	O
]	O
.	O

In	O
our	O
study	O
,	O
the	O
physician	O
and	O
NP	O
rankings	O
of	O
industry	O
representatives	O
were	O
similar	O
.	O

Within	O
the	O
health	O
professionals	O
and	O
other	O
category	O
,	O
pharmaceutical	O
representatives	O
were	O
used	O
as	O
a	O
resource	O
by	O
more	O
of	O
the	O
sample	O
than	O
regional	O
drug	O
information	O
services	O
and	O
comparably	O
to	O
academic	O
detailing	O
services	O
.	O

Academic	O
detailing	O
is	O
a	O
form	O
of	O
continuing	O
medical	O
education	O
where	O
a	O
trained	O
health	O
professional	O
visits	O
prescribers	O
for	O
a	O
fifteen	O
to	O
twenty	O
minute	O
session	O
to	O
provide	O
objective	O
information	O
regarding	O
a	O
therapeutic	O
topic	O
based	O
on	O
best	O
available	O
evidence	O
[	O
86	O
,	O
87	O
]	O
.	O

Following	O
academic	O
detailing	O
,	O
physician	O
and	O
NP	O
rankings	O
of	O
pharmaceutical	O
industry	O
representatives	O
were	O
second	O
or	O
third	O
for	O
frequency	O
of	O
use	O
,	O
usefulness	O
,	O
accessibility	O
,	O
credibility	O
,	O
and	O
current	O
/	O
timeliness	O
.	O

Limitations	O

We	O
do	O
not	O
have	O
demographics	O
or	O
information	O
regarding	O
the	O
reasons	O
why	O
survey	O
recipients	O
did	O
not	O
respond	O
.	O

As	O
per	O
ethical	O
requirements	O
to	O
maintain	O
confidentiality	O
of	O
respondents	O
,	O
we	O
were	O
not	O
able	O
to	O
match	O
respondents	O
from	O
their	O
respective	O
place	O
of	O
practice	O
and	O
therefore	O
cannot	O
conclude	O
whether	O
the	O
practitioners	O
within	O
a	O
practice	O
setting	O
influenced	O
the	O
others	O
'	O
responses	O
.	O

The	O
sample	O
size	O
of	O
the	O
survey	O
is	O
small	O
although	O
it	O
includes	O
88	O
%	O
response	O
from	O
community	O
based	O
NPs	O
in	O
Nova	O
Scotia	O
.	O

The	O
generalizability	O
of	O
the	O
results	O
is	O
limited	O
due	O
to	O
the	O
variations	O
in	O
NP	O
scopes	O
of	O
practice	O
nationally	O
and	O
internationally	O
.	O

It	O
is	O
unknown	O
whether	O
the	O
findings	O
are	O
generalizable	O
to	O
nonresponding	O
physicians	O
within	O
Nova	O
Scotia	O
collaborating	O
with	O
NPs	O
or	O
to	O
physicians	O
not	O
in	O
collaborative	O
practices	O
with	O
NPs	O
as	O
they	O
were	O
not	O
included	O
as	O
a	O
part	O
of	O
the	O
sample	O
.	O

Due	O
to	O
multiple	O
statistical	O
comparisons	O
(	O
Mann	O
Whitney	O
U	O
)	O
,	O
the	O
results	O
comparing	O
NP	O
and	O
physician	O
ratings	O
of	O
results	O
should	O
be	O
interpreted	O
with	O
caution	O
.	O

Conclusion	O

Respondent	O
ratings	O
of	O
resources	O
and	O
preferences	O
for	O
resource	O
use	O
were	O
consistent	O
with	O
self	O
-	O
reported	O
means	O
of	O
conducting	O
searches	O
for	O
specific	O
drug	O
information	O
queries	O
.	O

The	O
use	O
of	O
computers	O
and	O
PDAs	O
remains	O
limited	O
and	O
also	O
matches	O
preferences	O
and	O
resource	O
ratings	O
.	O

Education	O
to	O
this	O
group	O
of	O
practitioners	O
regarding	O
available	O
drug	O
information	O
resources	O
may	O
facilitate	O
use	O
of	O
computer	O
and	O
PDA	O
resources	O
.	O

Further	O
research	O
is	O
needed	O
to	O
determine	O
methods	O
to	O
increase	O
the	O
use	O
of	O
computers	O
and	O
PDAs	O
and	O
if	O
use	O
of	O
these	O
technologies	O
affects	O
prescribing	O
and	O
patient	B
outcomes	O
.	O

Competing	O
interests	O

Ingrid	O
Sketris	O
holds	O
a	O
Chair	O
from	O
Canadian	O
Institutes	O
of	O
Health	O
Research	O
(	O
CIHR	O
)	O
,	O
Canadian	O
Health	O
Services	O
Research	O
Foundation	O
(	O
CHSRF	O
)	O
co	O
-	O
sponsored	O
by	O
the	O
Nova	O
Scotia	O
Health	O
Research	O
Foundation	O
(	O
NSHRF	O
)	O
.	O

Andrea	O
Murphy	O
received	O
salary	O
support	O
through	O
this	O
Chair	O
as	O
a	O
research	O
fellow	O
at	O
the	O
time	O
of	O
conducting	O
this	O
research	O
.	O

The	O
survey	O
was	O
performed	O
in	O
fulfillment	O
of	O
the	O
requirements	O
for	O
the	O
Drug	O
Use	O
Management	O
and	O
Policy	O
Residency	O
that	O
Murphy	O
participated	O
in	O
as	O
a	O
part	O
of	O
her	O
fellowship	O
.	O

The	O
residency	O
was	O
conducted	O
with	O
a	O
decision	O
making	O
partner	O
from	O
the	O
Nova	O
Scotia	O
Department	O
of	O
Health	O
.	O

The	O
opinions	O
expressed	O
in	O
this	O
paper	O
are	O
those	O
of	O
the	O
authors	O
and	O
do	O
not	O
represent	O
the	O
opinions	O
of	O
the	O
Nova	O
Scotia	O
Department	O
of	O
Health	O
,	O
CIHR	O
/	O
CHSRF	O
or	O
NSHRF	O
.	O

MF	O
,	O
MM	O
,	O
RMM	O
,	O
and	O
DG	O
have	O
no	O
competing	O
interests	O
to	O
declare	O
.	O

Authors	O
'	O
contributions	O

AM	O
conceptualized	O
the	O
design	O
and	O
composed	O
the	O
survey	O
instruments	O
,	O
carried	O
out	O
the	O
study	O
,	O
entered	O
and	O
analyzed	O
the	O
data	O
,	O
drafted	O
the	O
original	O
manuscript	O
,	O
and	O
modified	O
subsequent	O
drafts	O
based	O
on	O
authors	O
'	O
and	O
reviewers	O
'	O
feedback	O
.	O

MF	O
,	O
RMM	O
,	O
IS	O
,	O
MM	O
,	O
and	O
DG	O
reviewed	O
and	O
suggested	O
revisions	O
to	O
the	O
survey	O
tools	O
,	O
covering	O
letters	O
,	O
overall	O
study	O
design	O
,	O
and	O
contributed	O
to	O
feedback	O
on	O
the	O
analysis	O
and	O
manuscript	O
revisions	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

Expression	O
of	O
C	O
-	O
terminal	O
deleted	O
p53	O
isoforms	O
in	O
neuroblastoma	O

Abstract	O

The	O
tumor	O
suppressor	O
gene	O
,	O
p53	O
,	O
is	O
rarely	O
mutated	O
in	O
neuroblastomas	O
(	O
NB	O
)	O
at	O
the	O
time	O
of	O
diagnosis	O
,	O
but	O
its	O
dysfunction	O
could	O
result	O
from	O
a	O
nonfunctional	O
conformation	O
or	O
cytoplasmic	O
sequestration	O
of	O
the	O
wild	O
-	O
type	O
p53	O
protein	O
.	O

However	O
,	O
p53	O
mutation	O
,	O
when	O
it	O
occurs	O
,	O
is	O
found	O
in	O
NB	O
tumors	O
with	O
drug	O
resistance	O
acquired	O
over	O
the	O
course	O
of	O
chemotherapy	O
.	O

As	O
yet	O
,	O
no	O
study	O
has	O
been	O
devoted	O
to	O
the	O
function	O
of	O
the	O
specific	O
p53	O
mutants	O
identified	O
in	O
NB	O
cells	O
.	O

This	O
study	O
includes	O
characterization	O
and	O
functional	O
analysis	O
of	O
p53	O
expressed	O
in	O
eight	O
cell	O
lines	O
:	O
three	O
wild	O
-	O
type	O
cell	O
lines	O
and	O
five	O
cell	O
lines	O
harboring	O
mutations	O
.	O

We	O
identified	O
two	O
transcription	O
-	O
inactive	O
p53	O
variants	O
truncated	O
in	O
the	O
C	O
-	O
terminus	O
,	O
one	O
of	O
which	O
corresponded	O
to	O
the	O
p53	O
beta	O
isoform	O
recently	O
identified	O
in	O
normal	O
tissue	O
by	O
Bourdon	O
et	O
al	O
.	O

[	O
J	O
.	O
C	O
.	O
Bourdon	O
,	O
K	O
.	O
Fernandes	O
,	O
F	O
.	O
Murray	O
-	O
Zmijewski	O
,	O
G	O
.	O
Liu	O
,	O
A	O
.	O
Diot	O
,	O
D	O
.	O
P	O
.	O
Xirodimas	O
,	O
M	O
.	O
K	O
.	O
Saville	O
and	O
D	O
.	O
P	O
.	O
Lane	O
(	O
2005	O
)	O
Genes	O
Dev	O
.	O
,	O
19	O
,	O
2122	O
-	O
2137	O
]	O
.	O

Our	O
results	O
show	O
,	O
for	O
the	O
first	O
time	O
,	O
that	O
the	O
p53	O
beta	O
isoform	O
is	O
the	O
only	O
p53	O
species	O
to	O
be	O
endogenously	O
expressed	O
in	O
the	O
human	B
NB	O
cell	O
line	O
SK	O
-	O
N	O
-	O
AS	O
,	O
suggesting	O
that	O
the	O
C	O
-	O
terminus	O
truncated	O
p53	O
isoforms	O
may	O
play	O
an	O
important	O
role	O
in	O
NB	O
tumor	O
development	O
.	O

INTRODUCTION	O

The	O
p53	O
tumor	O
suppressor	O
gene	O
remains	O
the	O
most	O
frequently	O
altered	O
gene	O
in	O
human	B
tumors	O
.	O

Several	O
p53	O
mutation	O
databases	O
have	O
been	O
reported	O
previously	O
(	O
1	O
-	O
3	O
)	O
,	O
and	O
to	O
date	O
,	O
more	O
than	O
1500	O
different	O
p53	O
mutants	O
have	O
been	O
described	O
(	O
4	O
)	O
.	O

Functional	O
inactivation	O
of	O
p53	O
is	O
usually	O
due	O
to	O
gene	O
mutation	O
,	O
deletion	O
or	O
protein	O
degradation	O
.	O

In	O
general	O
,	O
the	O
majority	O
of	O
p53	O
mutations	O
in	O
human	B
neoplasia	O
are	O
missense	O
mutations	O
affecting	O
the	O
DNA	O
-	O
binding	O
domain	O
(	O
DBD	O
)	O
.	O

Unlike	O
other	O
human	B
cancers	O
,	O
p53	O
in	O
neuroblastoma	O
(	O
NB	O
)	O
is	O
rarely	O
mutated	O
in	O
the	O
primary	O
tumor	O
at	O
diagnosis	O
but	O
high	O
levels	O
of	O
wild	O
-	O
type	O
p53	O
(	O
wt	O
p53	O
)	O
protein	O
expression	O
have	O
been	O
found	O
in	O
the	O
cytoplasm	O
of	O
undifferentiated	O
tumors	O
(	O
5	O
,	O
6	O
)	O
.	O

More	O
recently	O
,	O
in	O
normal	O
unstressed	O
cells	O
,	O
wt	O
p53	O
protein	O
was	O
found	O
to	O
be	O
retained	O
in	O
the	O
cytoplasm	O
as	O
a	O
latent	O
form	O
,	O
in	O
huge	O
,	O
p53	O
-	O
associated	O
protein	O
complexes	O
known	O
as	O
'	O
Parc	O
'	O
(	O
7	O
)	O
.	O

The	O
steady	O
-	O
state	O
concentration	O
of	O
p53	O
in	O
normal	O
unstressed	O
cells	O
is	O
usually	O
very	O
low	O
because	O
of	O
the	O
short	O
half	O
-	O
life	O
of	O
the	O
wild	O
-	O
type	O
(	O
wt	O
)	O
protein	O
.	O

Overexpression	O
of	O
p53	O
in	O
most	O
of	O
the	O
transformed	O
cells	O
containing	O
a	O
missense	O
mutation	O
within	O
the	O
p53	O
gene	O
appears	O
to	O
be	O
due	O
to	O
the	O
increased	O
stability	O
of	O
mutated	O
p53	O
(	O
8	O
)	O
.	O

In	O
unstressed	O
NB	O
cells	O
,	O
high	O
wt	O
p53	O
expression	O
may	O
reflect	O
the	O
embryonic	O
origin	O
of	O
NBs	O
,	O
in	O
which	O
precursor	O
cells	O
fail	O
to	O
mature	O
(	O
9	O
)	O
.	O

p53	O
mutations	O
are	O
unusual	O
in	O
human	B
NB	O
but	O
,	O
when	O
they	O
do	O
occur	O
,	O
are	O
found	O
in	O
post	O
-	O
chemotherapy	O
tumors	O
.	O

In	O
this	O
respect	O
,	O
Tweddle	O
et	O
al	O
.	O

(	O
10	O
)	O
described	O
how	O
two	O
NB	O
cell	O
lines	O
derived	O
from	O
the	O
same	O
patient	B
can	O
elicit	O
a	O
different	O
p53	O
status	O
:	O
wt	O
p53	O
for	O
SK	O
-	O
N	O
-	O
BE	O
(	O
1a	O
)	O
established	O
before	O
treatment	O
,	O
and	O
mutated	O
p53	O
for	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2c	O
)	O
established	O
after	O
relapse	O
of	O
the	O
patient	B
under	O
treatment	O
with	O
cytotoxic	O
agents	O
such	O
as	O
cyclophosphamide	O
,	O
doxorubicin	O
,	O
vincristine	O
and	O
radiotherapy	O
.	O

In	O
NB	O
cell	O
lines	O
,	O
p53	O
mutation	O
has	O
been	O
found	O
in	O
multidrug	O
-	O
resistant	O
cells	O
(	O
11	O
)	O
.	O

Various	O
types	O
of	O
p53	O
mutation	O
have	O
been	O
detected	O
in	O
NB	O
cells	O
and	O
can	O
lead	O
to	O
inactivation	O
either	O
by	O
shut	O
-	O
down	O
of	O
protein	O
expression	O
or	O
production	O
of	O
aberrant	O
p53	O
products	O
.	O

Indeed	O
,	O
in	O
LAN	O
-	O
1	O
cells	O
,	O
p53	O
nonsense	O
mutation	O
at	O
cysteine	O
182	O
in	O
exon	O
5	O
leads	O
to	O
the	O
absence	O
of	O
protein	O
(	O
9	O
)	O
,	O
whereas	O
in	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
cells	O
,	O
missense	O
mutation	O
at	O
codon	O
135	O
(	O
C135F	O
)	O
leads	O
to	O
stable	O
overexpressed	O
protein	O
(	O
11	O
)	O
.	O

By	O
analyzing	O
IGR	O
-	O
N	O
-	O
91	O
,	O
a	O
cell	O
line	O
established	O
in	O
our	O
laboratory	O
from	O
the	O
bone	O
marrow	O
of	O
a	O
patient	B
with	O
metastatic	O
NB	O
after	O
unsuccessful	O
Adriamycin	O
-	O
vincristine	O
chemotherapy	O
(	O
12	O
)	O
,	O
we	O
identified	O
another	O
type	O
of	O
aberrant	O
protein	O
that	O
arises	O
from	O
the	O
duplication	O
of	O
exons	O
7	O
-	O
8	O
-	O
9	O
.	O

This	O
duplication	O
spans	O
from	O
amino	O
acids	O
225	O
to	O
331	O
,	O
which	O
represent	O
part	O
of	O
the	O
DBD	O
and	O
part	O
of	O
the	O
oligomerization	O
domain	O
(	O
13	O
)	O
.	O

However	O
,	O
each	O
p53	O
mutant	O
has	O
been	O
described	O
in	O
the	O
literature	O
as	O
a	O
case	O
report	O
,	O
and	O
so	O
far	O
,	O
no	O
comparative	O
study	O
has	O
been	O
undertaken	O
to	O
link	O
their	O
biochemical	O
features	O
with	O
functional	O
properties	O
.	O

In	O
the	O
present	O
study	O
we	O
report	O
two	O
novel	O
p53	O
C	O
-	O
terminus	O
mutants	O
identified	O
in	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
human	B
NB	O
cell	O
lines	O
.	O

The	O
biological	O
properties	O
of	O
these	O
two	O
new	O
variants	O
were	O
analyzed	O
in	O
comparison	O
with	O
p53	O
isolated	O
from	O
six	O
other	O
human	B
NB	O
lines	O
:	O
three	O
[	O
LAN	O
-	O
1	O
,	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
and	O
IGR	O
-	O
N	O
-	O
91	O
]	O
expressing	O
mutant	O
p53	O
and	O
three	O
(	O
SH	O
-	O
SY5Y	O
,	O
LAN	O
-	O
5	O
and	O
IMR	O
-	O
32	O
)	O
expressing	O
the	O
wt	O
protein	O
.	O

This	O
characterization	O
was	O
done	O
by	O
using	O
a	O
range	O
of	O
functional	O
assays	O
:	O
(	O
i	O
)	O
the	O
ability	O
of	O
the	O
protein	O
to	O
bind	O
with	O
p53	O
consensus	O
sequence	O
using	O
the	O
functional	O
analysis	O
of	O
separated	O
allele	O
in	O
yeast	B
(	O
FASAY	O
)	O
;	O
(	O
ii	O
)	O
the	O
ability	O
of	O
the	O
protein	O
to	O
transactivate	O
the	O
p53	O
-	O
responsive	O
element	O
(	O
RE	O
)	O
identified	O
either	O
in	O
the	O
promoter	O
of	O
p21	O
/	O
WAF1	O
or	O
in	O
the	O
first	O
intron	O
of	O
BAX	O
,	O
using	O
luciferase	O
reporter	O
assay	O
;	O
(	O
iii	O
)	O
the	O
induction	O
of	O
endogenous	O
p21	O
/	O
WAF1	O
gene	O
expression	O
under	O
stress	O
conditions	O
.	O

MATERIALS	O
AND	O
METHODS	O

Neuroblastoma	O
cell	O
lines	O
,	O
culture	O
and	O
drug	O
treatments	O

The	O
parental	O
human	B
NB	O
SH	O
-	O
SY5Y	O
,	O
SK	O
-	O
N	O
-	O
AS	O
,	O
IMR	O
-	O
32	O
and	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
cell	O
lines	O
were	O
purchased	O
from	O
the	O
European	O
Collection	O
of	O
Cell	O
Cultures	O
(	O
ECACC	O
,	O
Wiltshire	O
,	O
UK	O
)	O
.	O

The	O
human	B
IGR	O
-	O
NB8	O
cells	O
(	O
a	O
gift	O
of	O
Prof	O
.	O
Gilles	O
Vassal	O
,	O
UPRES	O
EA	O
3535	O
,	O
Institut	O
Gustave	O
Roussy	O
,	O
Villejuif	O
)	O
were	O
derived	O
from	O
a	O
previously	O
untreated	O
localized	O
NB	O
(	O
14	O
)	O
.	O

The	O
LAN	O
-	O
1	O
and	O
LAN	O
-	O
5	O
cell	O
lines	O
were	O
provided	O
by	O
Dr	O
Nicole	O
Gross	O
(	O
Pediatric	O
Oncology	O
Research	O
,	O
Lausanne	O
,	O
Switzerland	O
)	O
.	O

The	O
human	B
IGR	O
-	O
N	O
-	O
91	O
cell	O
line	O
was	O
established	O
in	O
our	O
laboratory	O
from	O
the	O
bone	O
marrow	O
of	O
a	O
patient	B
with	O
metastatic	O
NB	O
after	O
unsuccessful	O
adriamycin	O
-	O
vincristin	O
chemotherapy	O
(	O
12	O
)	O
.	O

LAN	O
-	O
1	O
,	O
LAN	O
-	O
5	O
and	O
IMR	O
-	O
32	O
were	O
grown	O
in	O
RPMI	O
medium	O
supplemented	O
with	O
2	O
mM	O
l	O
-	O
glutamine	O
and	O
10	O
%	O
fetal	O
calf	O
serum	O
and	O
gentamicine	O
10	O
mu	O
g	O
/	O
ml	O
.	O

Others	O
cell	O
lines	O
were	O
cultured	O
in	O
DMEM	O
.	O

For	O
activation	O
of	O
endogenous	O
p53	O
,	O
cells	O
were	O
treated	O
with	O
cis	O
-	O
platinum	O
(	O
Sigma	O
)	O
(	O
10	O
mu	O
g	O
/	O
ml	O
)	O
for	O
24	O
h	O
then	O
lysed	O
for	O
western	O
blot	O
analysis	O
.	O

Western	O
blot	O
analysis	O

This	O
procedure	O
was	O
carried	O
out	O
as	O
described	O
previously	O
(	O
13	O
)	O
.	O

Protein	O
lysates	O
(	O
50	O
mu	O
g	O
)	O
were	O
submitted	O
to	O
10	O
%	O
SDS	O
-	O
PAGE	O
,	O
and	O
then	O
transferred	O
onto	O
nitrocellulose	O
filters	O
.	O

After	O
saturation	O
,	O
the	O
membranes	O
were	O
incubated	O
with	O
primary	O
antibody	O
diluted	O
in	O
0	O
.	O
1	O
%	O
phosphate	O
-	O
buffered	O
saline	O
,	O
Tween	O
-	O
20	O
and	O
3	O
%	O
skim	O
milk	O
.	O

The	O
primary	O
antibodies	O
used	O
were	O
anti	O
-	O
p53	O
monoclonal	O
antibody	O
(	O
clone	O
DO	O
-	O
7	O
,	O
1	O
/	O
1000	O
,	O
DAKO	O
)	O
,	O
anti	O
-	O
p21	O
/	O
WAF1	O
monoclonal	O
antibody	O
(	O
Ab	O
-	O
1	O
,	O
1	O
/	O
200	O
,	O
Oncogene	O
Research	O
)	O
and	O
anti	O
-	O
beta	O
-	O
actin	O
monoclonal	O
antibody	O
(	O
1	O
/	O
1000	O
;	O
Chemicon	O
)	O
as	O
internal	O
control	O
.	O

Protein	O
bands	O
were	O
detected	O
by	O
ECL	O
system	O
(	O
Amersham	O
)	O
.	O

PCR	O
,	O
plasmids	O
cloning	O

Genomic	O
DNA	O
was	O
extracted	O
using	O
lysis	O
buffer	O
containing	O
20	O
mM	O
Tris	O
-	O
HCl	O
,	O
pH	O
7	O
.	O
5	O
;	O
0	O
.	O
4	O
M	O
NaCl	O
;	O
0	O
.	O
5	O
%	O
SDS	O
;	O
10	O
mM	O
EDTA	O
,	O
treated	O
with	O
proteinase	O
K	O
(	O
200	O
mu	O
g	O
/	O
mu	O
l	O
)	O
,	O
purified	O
with	O
phenol	O
/	O
chloroform	O
,	O
precipitated	O
with	O
ethanol	O
and	O
dissolved	O
in	O
DNase	O
free	O
water	O
.	O

Total	O
RNA	O
were	O
purified	O
using	O
RNAble	O
reagent	O
(	O
Eurobio	O
)	O
,	O
precipitated	O
with	O
isopropanol	O
and	O
dissolved	O
in	O
RNase	O
free	O
water	O
.	O

cDNA	O
was	O
obtained	O
by	O
reverse	O
transcription	O
of	O
1	O
mu	O
g	O
of	O
total	O
RNA	O
using	O
Superscript	O
II	O
(	O
TM	O
)	O
RNase	O
H	O
-	O
Reverse	O
transcriptase	O
(	O
Invitrogen	O
)	O
and	O
Oligo	O
-	O
d	O
(	O
T	O
)	O
16	O
in	O
conditions	O
specified	O
by	O
the	O
manufacturer	O
.	O

Amplification	O
of	O
full	O
-	O
length	O
p53	O
coding	O
region	O
from	O
SH	O
-	O
SY5Y	O
,	O
IGR	O
-	O
N	O
-	O
91	O
,	O
IGR	O
-	O
NB8	O
and	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
cell	O
lines	O
was	O
performed	O
using	O
forward	O
primer	O
at	O
position	O
152	O
and	O
reverse	O
primer	O
at	O
position	O
1583	O
(	O
F1	O
and	O
R7	O
,	O
respectively	O
,	O
Table	O
1	O
;	O
GenBank	O
accession	O
no	O
.	O
K03199	O
)	O
.	O

p53	O
cDNA	O
from	O
SK	O
-	O
N	O
-	O
AS	O
cells	O
for	O
cloning	O
was	O
obtained	O
from	O
RT	O
-	O
PCR	O
using	O
F1	O
and	O
reverse	O
primer	O
i9	O
+	O
:	O
5	O
'	O
-	O
GCAAAGTCATAGAACCATTT	O
-	O
3	O
'	O
(	O
nucleotide	O
position	O
14989	O
,	O
GenBank	O
accession	O
no	O
.	O
X54156	O
)	O
primers	O
which	O
encompass	O
from	O
exon	O
1	O
to	O
exon	O
i9	O
+	O
first	O
identified	O
by	O
Flaman	O
et	O
al	O
.	O

(	O
15	O
)	O
included	O
.	O

The	O
PCR	O
was	O
done	O
in	O
the	O
presence	O
of	O
pfu	O
Hotstart	O
DNA	O
polymerase	O
(	O
Stratagene	O
)	O
for	O
30	O
cycles	O
of	O
1	O
min	O
at	O
90	O
degrees	O
C	O
,	O
1	O
min	O
at	O
65	O
degrees	O
C	O
and	O
2	O
min	O
30	O
s	O
at	O
72	O
degrees	O
C	O
using	O
PTC	O
-	O
100	O
thermocycler	O
(	O
MJ	O
-	O
Research	O
)	O
.	O

The	O
p53	O
cDNA	O
from	O
SH	O
-	O
SY5Y	O
,	O
SK	O
-	O
N	O
-	O
AS	O
,	O
IGR	O
-	O
N	O
-	O
91	O
,	O
IGR	O
-	O
NB8	O
and	O
SK	O
-	O
N	O
-	O
AS	O
cells	O
were	O
then	O
cloned	O
into	O
pcDNA3	O
.	O
1	O
/	O
V5	O
-	O
His	O
-	O
Topo	O
vector	O
(	O
Invitrogen	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instruction	O
.	O

The	O
p53	O
sequence	O
of	O
each	O
cell	O
line	O
was	O
investigated	O
by	O
sequencing	O
of	O
plasmids	O
after	O
cloning	O
.	O

Sequencing	O
was	O
performed	O
by	O
Genome	O
Express	O
(	O
Meylan	O
,	O
France	O
)	O
.	O

The	O
pDDm	O
-	O
TO	O
harboring	O
p53	O
dominant	O
negative	O
form	O
(	O
p53DD	O
)	O
pGL3	O
-	O
E1bTATA	O
and	O
the	O
pE1B	O
-	O
hWAF1	O
firefly	O
luciferase	O
reporter	O
containing	O
the	O
p53	O
-	O
responsive	O
element	O
of	O
the	O
p21	O
/	O
WAF1	O
promoter	O
were	O
described	O
previously	O
(	O
16	O
,	O
17	O
)	O
pE1B	O
-	O
BAXi	O
contains	O
the	O
p53RE	O
identified	O
in	O
the	O
intron	O
1	O
of	O
the	O
BAX	O
gene	O
[	O
(	O
18	O
)	O
and	O
D	O
.	O
Munsch	O
,	O
personal	O
communication	O
]	O
.	O

Oligonucleotides	O
TCGAGGGCAGGCCCGGGCTT	O
and	O
CTAGCGACAAGCCCGGGCCT	O
were	O
annealed	O
and	O
cloned	O
into	O
pGL3	O
-	O
E1bTATA	O
digested	O
with	O
NheI	O
and	O
XhoI	O
to	O
obtain	O
pE1B	O
-	O
BAXi	O
.	O

The	O
pcDNA3	O
-	O
Delta	O
Np73	O
alpha	O
expression	O
plasmid	O
was	O
a	O
gift	O
of	O
Dr	O
Daniel	O
Caput	O
(	O
SANOFI	O
,	O
Lab	O
e	O
ges	O
,	O
France	O
)	O
.	O

Fluorescent	O
in	O
situ	O
hybridization	O
(	O
FISH	O
)	O

Cytogenetic	O
preparations	O

Metaphase	O
spreads	O
from	O
healthy	O
human	B
male	O
lymphocytes	O
and	O
tumor	O
cell	O
lines	O
were	O
prepared	O
as	O
described	O
previously	O
(	O
19	O
)	O
.	O

BAC	O
probe	O
RP11	O
-	O
199F11	O
,	O
containing	O
a	O
167	O
kb	O
region	O
spanning	O
TP53	O
gene	O
,	O
was	O
labeled	O
by	O
random	O
priming	O
in	O
the	O
presence	O
of	O
Alexa	O
594	O
-	O
dUTP	O
(	O
Molecular	O
Probes	O
)	O
.	O

A	O
commercial	O
probe	O
specific	O
for	O
chromosome	O
17	O
centromere	O
,	O
and	O
labeled	O
with	O
spectrum	O
green	O
,	O
was	O
obtained	O
from	O
Vysis	O
.	O

After	O
over	O
-	O
night	O
cohybridization	O
of	O
the	O
probes	O
in	O
the	O
presence	O
of	O
Cot	O
-	O
1	O
DNA	O
,	O
the	O
slides	O
were	O
washed	O
and	O
DNA	O
counterstained	O
with	O
DAPI	O
.	O

The	O
preparations	O
were	O
observed	O
with	O
an	O
epifluorescence	O
microscope	O
and	O
images	O
captured	O
with	O
a	O
Vysis	O
imaging	O
station	O
.	O

Between	O
3	O
and	O
14	O
metaphases	O
spreads	O
and	O
30	O
-	O
200	O
nuclei	O
were	O
examined	O
for	O
each	O
cell	O
line	O
.	O

Luciferase	O
reporter	O
assays	O

LAN	O
-	O
1	O
or	O
SH	O
-	O
SY5Y	O
cells	O
were	O
seeded	O
in	O
duplicates	O
onto	O
6	O
-	O
well	O
plates	O
at	O
a	O
density	O
of	O
2	O
x	O
104	O
cells	O
per	O
cm2	O
and	O
cotransfected	O
24	O
h	O
later	O
with	O
0	O
.	O
5	O
mu	O
g	O
(	O
2	O
.	O
5	O
mu	O
g	O
/	O
ml	O
)	O
of	O
pGL3	O
firefly	O
luciferase	O
reporter	O
gene	O
plasmid	O
under	O
the	O
control	O
of	O
either	O
pE1B	O
-	O
hWAF1	O
or	O
pE1B	O
-	O
BAX	O
using	O
lipofectamine	O
2000	O
and	O
1	O
mu	O
g	O
of	O
either	O
a	O
p53	O
expressing	O
plasmid	O
or	O
an	O
empty	O
vector	O
.	O

At	O
24	O
h	O
after	O
transfection	O
,	O
cells	O
were	O
lysed	O
with	O
200	O
mu	O
l	O
/	O
well	O
of	O
passive	O
lysis	O
buffer	O
provided	O
with	O
the	O
'	O
Luciferase	O
assay	O
kit	O
'	O
(	O
Promega	O
)	O
.	O

Luciferase	O
activity	O
was	O
measured	O
using	O
Microlumat	O
LB96P	O
luminometer	O
(	O
EG	O
&	O
G	O
Berthold	O
Instrument	O
)	O
.	O

Functional	O
assay	O
in	O
yeast	B

cDNA	O
was	O
obtained	O
by	O
RT	O
of	O
1	O
mu	O
g	O
of	O
total	O
RNA	O
using	O
Superscript	O
II	O
(	O
TM	O
)	O
RNase	O
H	O
-	O
Reverse	O
transcriptase	O
(	O
Invitrogen	O
)	O
and	O
random	O
hexamers	O
to	O
prime	O
the	O
synthesis	O
in	O
conditions	O
specified	O
by	O
the	O
manufacturer	O
.	O

p53	O
cDNA	O
was	O
amplified	O
by	O
PCR	O
and	O
cotransformed	O
into	O
yeast	B
,	O
IG397	O
Ade2	O
strain	O
,	O
together	O
with	O
either	O
pRDI	O
-	O
22	O
vector	O
for	O
p53	O
-	O
standard	O
assay	O
or	O
pFW35	O
and	O
pFW34	O
plasmid	O
for	O
5	O
'	O
or	O
3	O
'	O
split	O
assay	O
,	O
respectively	O
,	O
carrying	O
the	O
ADE2	O
open	O
reading	O
frame	O
under	O
the	O
control	O
of	O
a	O
p53	O
-	O
responsive	O
promoter	O
(	O
20	O
)	O
.	O

In	O
a	O
selective	O
medium	O
lacking	O
leucine	O
,	O
wt	O
-	O
p53	O
activates	O
transcription	O
of	O
ADE2	O
gene	O
that	O
encodes	O
enzyme	O
-	O
-	O
phosphoribosylimidaz	O
carboxylase	O
-	O
-	O
implicated	O
in	O
adenine	O
biosynthesis	O
.	O

Therefore	O
,	O
a	O
colony	O
of	O
cells	O
that	O
expresses	O
ADE2	O
gene	O
is	O
white	O
whereas	O
the	O
one	O
composed	O
of	O
cells	O
where	O
ADE2	O
gene	O
is	O
not	O
expressed	O
owing	O
p53	O
mutation	O
is	O
red	O
.	O

RESULTS	O

P53	O
status	O
in	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
cells	O

We	O
first	O
compared	O
the	O
migration	O
profiles	O
of	O
p53	O
expressed	O
in	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
with	O
those	O
expressed	O
in	O
the	O
other	O
six	O
NB	O
cells	O
,	O
SH	O
-	O
SY5Y	O
,	O
LAN	O
-	O
5	O
,	O
LAN	O
-	O
1	O
,	O
IMR	O
-	O
32	O
,	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
and	O
IGR	O
-	O
N	O
-	O
91	O
.	O

Western	O
blots	O
from	O
50	O
mu	O
g	O
of	O
total	O
protein	O
extracts	O
were	O
revealed	O
with	O
p53	O
monoclonal	O
antibody	O
(	O
DO	O
-	O
7	O
)	O
.	O

A	O
range	O
of	O
profiles	O
was	O
identified	O
as	O
shown	O
in	O
Figure	O
1A	O
.	O

As	O
expected	O
,	O
p53	O
extracted	O
from	O
the	O
three	O
cell	O
lines	O
,	O
SH	O
-	O
SY5Y	O
,	O
LAN	O
-	O
5	O
and	O
IMR	O
-	O
32	O
,	O
expressing	O
wt	O
protein	O
(	O
13	O
,	O
21	O
)	O
migrated	O
at	O
the	O
wt	O
position	O
.	O

Of	O
particular	O
note	O
in	O
these	O
three	O
wt	O
p53	O
cell	O
lines	O
was	O
an	O
additional	O
faint	O
band	O
that	O
migrated	O
faster	O
than	O
the	O
full	O
-	O
length	O
protein	O
.	O

The	O
LAN	O
-	O
1	O
cells	O
were	O
found	O
to	O
be	O
p53	O
deficient	O
(	O
9	O
)	O
.	O

The	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
cell	O
line	O
showed	O
an	O
intense	O
band	O
reflecting	O
p53	O
stability	O
due	O
to	O
a	O
missense	O
mutation	O
at	O
codon	O
135	O
(	O
11	O
)	O
.	O

As	O
expected	O
,	O
due	O
to	O
the	O
previously	O
identified	O
duplication	O
of	O
exons	O
7	O
-	O
8	O
-	O
9	O
(	O
13	O
)	O
,	O
p53	O
protein	O
migration	O
was	O
delayed	O
in	O
the	O
IGR	O
-	O
N	O
-	O
91	O
cells	O
.	O

In	O
contrast	O
,	O
the	O
p53	O
protein	O
in	O
the	O
SK	O
-	O
N	O
-	O
AS	O
cell	O
line	O
migrated	O
noticeably	O
faster	O
than	O
the	O
wt	O
protein	O
,	O
indicating	O
that	O
it	O
was	O
smaller	O
in	O
size	O
.	O

The	O
p53	O
protein	O
in	O
the	O
IGR	O
-	O
NB8	O
cell	O
line	O
was	O
even	O
smaller	O
than	O
that	O
in	O
SK	O
-	O
N	O
-	O
AS	O
.	O

To	O
analyze	O
the	O
coding	O
region	O
of	O
each	O
of	O
the	O
p53	O
variants	O
,	O
RT	O
-	O
PCR	O
was	O
performed	O
using	O
p53	O
-	O
specific	O
F1	O
-	O
R7	O
primers	O
(	O
Table	O
1	O
and	O
Figure	O
1B	O
)	O
.	O

The	O
expected	O
1430	O
bp	O
for	O
full	O
-	O
length	O
p53	O
was	O
amplified	O
from	O
wt	O
p53	O
-	O
expressing	O
SH	O
-	O
SY5Y	O
,	O
LAN	O
-	O
5	O
and	O
IMR	O
-	O
32	O
cell	O
lines	O
.	O

As	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
harbors	O
a	O
single	O
point	O
mutation	O
at	O
codon	O
135	O
(	O
C135F	O
)	O
,	O
the	O
amplified	O
fragment	O
analyzed	O
by	O
electrophoresis	O
migrated	O
as	O
wt	O
p53	O
(	O
Figure	O
1B	O
)	O
.	O

The	O
longer	O
RT	O
-	O
PCR	O
fragment	O
from	O
the	O
mutated	O
IGR	O
-	O
N	O
-	O
91	O
cell	O
line	O
resulted	O
from	O
the	O
duplication	O
of	O
exons	O
7	O
-	O
8	O
-	O
9	O
,	O
as	O
shown	O
in	O
our	O
previous	O
data	O
(	O
13	O
)	O
,	O
which	O
corresponds	O
to	O
extra	O
nucleic	O
material	O
of	O
321	O
nt	O
.	O

For	O
the	O
LAN	O
-	O
1	O
cells	O
,	O
no	O
amplified	O
fragment	O
was	O
observed	O
in	O
accordance	O
with	O
published	O
data	O
,	O
which	O
demonstrates	O
the	O
extremely	O
low	O
levels	O
of	O
p53	O
mRNA	O
and	O
the	O
undetectable	O
level	O
of	O
protein	O
(	O
9	O
)	O
.	O

An	O
amplified	O
fragment	O
of	O
the	O
same	O
length	O
as	O
the	O
wt	O
protein	O
was	O
observed	O
in	O
the	O
IGR	O
-	O
NB8	O
cell	O
line	O
(	O
Figure	O
1B	O
)	O
.	O

Indeed	O
,	O
complete	O
gene	O
sequencing	O
revealed	O
a	O
point	O
mutation	O
E326STOP	O
leading	O
to	O
a	O
truncated	O
protein	O
at	O
C	O
-	O
terminus	O
.	O

No	O
fragment	O
,	O
however	O
,	O
was	O
amplified	O
from	O
SK	O
-	O
N	O
-	O
AS	O
with	O
F1	O
-	O
R7	O
primers	O
.	O

To	O
further	O
map	O
the	O
p53	O
mRNA	O
transcribed	O
in	O
these	O
cells	O
,	O
series	O
of	O
RT	O
-	O
PCR	O
tests	O
were	O
performed	O
using	O
the	O
forward	O
primer	O
,	O
F2	O
(	O
exon	O
8	O
position	O
1008th	O
according	O
to	O
GenBank	O
accession	O
no	O
.	O
K03199	O
)	O
,	O
matched	O
with	O
different	O
reverse	O
primers	O
,	O
R3	O
(	O
at	O
the	O
junction	O
of	O
exon	O
8	O
/	O
9	O
,	O
nt	O
position	O
1124	O
)	O
,	O
R4	O
,	O
R5	O
(	O
in	O
exon	O
9	O
at	O
positions	O
1154	O
and	O
1184	O
,	O
respectively	O
)	O
,	O
and	O
R6	O
(	O
in	O
exon	O
10	O
,	O
at	O
position	O
1230	O
)	O
.	O

The	O
sequences	O
of	O
these	O
primers	O
are	O
given	O
in	O
Table	O
1	O
and	O
the	O
results	O
are	O
presented	O
in	O
Figure	O
2A	O
.	O

SK	O
-	O
N	O
-	O
AS	O
cDNA	O
gave	O
an	O
amplified	O
fragment	O
of	O
the	O
same	O
size	O
as	O
SH	O
-	O
SY5Y	O
cDNA	O
with	O
the	O
three	O
primer	O
pairs	O
,	O
F2	O
/	O
R3	O
,	O
F2	O
/	O
R4	O
and	O
F3	O
/	O
R5	O
.	O

However	O
,	O
in	O
contrast	O
to	O
SH	O
-	O
SY5Y	O
,	O
no	O
fragment	O
was	O
obtained	O
with	O
SK	O
-	O
N	O
-	O
AS	O
cDNA	O
using	O
the	O
F2	O
/	O
R6	O
primer	O
pair	O
,	O
which	O
suggests	O
the	O
absence	O
of	O
exon	O
10	O
in	O
SK	O
-	O
N	O
-	O
AS	O
mRNA	O
.	O

The	O
p53	O
protein	O
expressed	O
in	O
SK	O
-	O
N	O
-	O
AS	O
is	O
the	O
p53	O
beta	O
isoform	O

An	O
alternatively	O
spliced	O
form	O
of	O
human	B
p53	O
mRNA	O
with	O
an	O
additional	O
133	O
bp	O
exon	O
derived	O
from	O
intron	O
9	O
has	O
been	O
detected	O
in	O
normal	O
human	B
lymphocytes	O
(	O
15	O
)	O
.	O

This	O
spliced	O
variant	O
named	O
'	O
i9	O
+	O
'	O
encodes	O
a	O
truncated	O
protein	O
of	O
341	O
amino	O
acids	O
including	O
10	O
new	O
amino	O
acids	O
derived	O
from	O
the	O
novel	O
exon	O
,	O
the	O
p53	O
beta	O
isoform	O
according	O
to	O
Bourdon	O
et	O
al	O
.	O
nomenclature	O
(	O
22	O
)	O
.	O

This	O
led	O
us	O
to	O
hypothesize	O
that	O
the	O
shorter	O
protein	O
expressed	O
by	O
the	O
SK	O
-	O
N	O
-	O
AS	O
cell	O
line	O
could	O
be	O
the	O
p53	O
beta	O
isoform	O
.	O

To	O
test	O
this	O
hypothesis	O
,	O
RT	O
-	O
PCRs	O
were	O
performed	O
using	O
primer	O
sets	O
designed	O
to	O
amplify	O
the	O
3	O
'	O
region	O
of	O
p53	O
mRNA	O
encoding	O
either	O
the	O
specific	O
C	O
-	O
terminal	O
part	O
of	O
the	O
wt	O
protein	O
(	O
wt	O
C	O
-	O
ter	O
)	O
or	O
the	O
specific	O
C	O
-	O
terminal	O
part	O
of	O
the	O
beta	O
isoform	O
(	O
beta	O
C	O
-	O
ter	O
)	O
.	O

In	O
parallel	O
amplification	O
with	O
a	O
primer	O
pair	O
amplifying	O
the	O
DBD	O
was	O
used	O
as	O
control	O
.	O

The	O
sequences	O
of	O
these	O
oligonucleotides	O
are	O
given	O
in	O
Table	O
1	O
.	O

The	O
results	O
presented	O
in	O
Figure	O
2B	O
are	O
consistent	O
with	O
the	O
only	O
expression	O
of	O
the	O
p53	O
beta	O
isoform	O
in	O
SK	O
-	O
N	O
-	O
AS	O
as	O
no	O
band	O
was	O
observed	O
in	O
lane	O
using	O
specific	O
C	O
-	O
ter	O
primer	O
located	O
in	O
exon	O
10	O
.	O

Interestingly	O
,	O
RT	O
-	O
PCR	O
using	O
SH	O
-	O
SY5Y	O
(	O
SH	O
)	O
gave	O
an	O
amplified	O
fragment	O
not	O
only	O
with	O
the	O
primer	O
pair	O
specific	O
to	O
the	O
C	O
-	O
ter	O
domain	O
of	O
wt	O
p53	O
but	O
also	O
with	O
the	O
primer	O
pair	O
specific	O
to	O
the	O
p53	O
beta	O
isoform	O
.	O

This	O
result	O
,	O
combined	O
with	O
the	O
presence	O
of	O
an	O
additional	O
faint	O
band	O
migrating	O
faster	O
than	O
wt	O
p53	O
in	O
denaturing	O
polyacrylamide	O
gel	O
(	O
Figure	O
1A	O
)	O
,	O
strongly	O
suggests	O
that	O
both	O
the	O
p53	O
full	O
-	O
length	O
protein	O
and	O
the	O
beta	O
isoform	O
were	O
expressed	O
in	O
the	O
SH	O
-	O
SY5Y	O
cells	O
.	O

The	O
full	O
-	O
length	O
SK	O
-	O
N	O
-	O
AS	O
p53	O
cDNA	O
was	O
then	O
amplified	O
with	O
the	O
forward	O
primer	O
F1	O
and	O
a	O
reverse	O
primer	O
located	O
within	O
the	O
novel	O
exon	O
i9	O
+	O
(	O
Table	O
1	O
)	O
.	O

This	O
amplified	O
fragment	O
was	O
cloned	O
in	O
pcDNA3	O
/	O
V5	O
-	O
His	O
-	O
Topo	O
,	O
as	O
described	O
in	O
Materials	O
and	O
Methods	O
.	O

Its	O
sequence	O
analysis	O
confirmed	O
that	O
the	O
truncated	O
p53	O
expressed	O
in	O
SK	O
-	O
N	O
-	O
AS	O
was	O
encoded	O
by	O
the	O
i9	O
+	O
splice	O
variant	O
described	O
previously	O
by	O
Flaman	O
et	O
al	O
.	O

(	O
15	O
)	O
that	O
encodes	O
the	O
p53	O
beta	O
isoform	O
characterized	O
by	O
Bourdon	O
et	O
al	O
.	O

(	O
22	O
)	O
.	O

A	O
series	O
of	O
genomic	O
amplifications	O
were	O
performed	O
to	O
identify	O
a	O
possible	O
deletion	O
within	O
the	O
intron	O
9	O
that	O
could	O
account	O
for	O
the	O
absence	O
of	O
normal	O
size	O
p53	O
in	O
SK	O
-	O
N	O
-	O
AS	O
cells	O
.	O

The	O
primer	O
sequences	O
are	O
given	O
in	O
Table	O
1	O
.	O

Amplifications	O
were	O
performed	O
in	O
parallel	O
with	O
total	O
DNA	O
extracted	O
from	O
SH	O
-	O
SY5Y	O
and	O
SK	O
-	O
N	O
-	O
AS	O
cells	O
.	O

Results	O
are	O
presented	O
in	O
Figure	O
3	O
.	O

Normal	O
size	O
fragments	O
that	O
encompass	O
the	O
acceptor	O
site	O
of	O
intron	O
9	O
were	O
amplified	O
with	O
SH	O
-	O
SY5Y	O
as	O
well	O
as	O
with	O
SK	O
-	O
N	O
-	O
AS	O
DNA	O
.	O

On	O
the	O
contrary	O
amplification	O
fragments	O
that	O
encompass	O
the	O
intron	O
9	O
donor	O
site	O
were	O
obtained	O
only	O
with	O
SH	O
-	O
SY5Y	O
but	O
not	O
with	O
SK	O
-	O
N	O
-	O
AS	O
DNA	O
.	O

These	O
results	O
identify	O
a	O
deletion	O
of	O
the	O
intron	O
9	O
/	O
exon	O
10	O
junction	O
within	O
the	O
SK	O
-	O
N	O
-	O
AS	O
p53	O
gene	O
.	O

A	O
yeast	B
functional	O
assay	O
confirmed	O
the	O
absence	O
of	O
p53	O
full	O
-	O
length	O
expression	O
in	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O

It	O
is	O
possible	O
to	O
detect	O
p53	O
mutation	O
using	O
a	O
simple	O
yeast	B
colony	O
color	O
assay	O
as	O
described	O
by	O
Flaman	O
et	O
al	O
.	O

(	O
23	O
)	O
.	O

When	O
the	O
strain	O
is	O
transformed	O
with	O
a	O
plasmid	O
-	O
encoding	O
wt	O
p53	O
,	O
the	O
cells	O
express	O
the	O
ADE2	O
gene	O
and	O
produce	O
white	O
colonies	O
(	O
Figure	O
4A	O
,	O
a	O
,	O
b2	O
and	O
c1	O
,	O
and	O
Figure	O
4B	O
,	O
dish	O
a	O
)	O
.	O

Cells	O
containing	O
mutant	O
p53	O
fail	O
to	O
express	O
ADE2	O
and	O
form	O
small	O
red	O
colonies	O
(	O
Figure	O
4A	O
,	O
b	O
and	O
b1	O
,	O
and	O
Figure	O
4B	O
,	O
dish	O
c	O
)	O
.	O

When	O
the	O
p53	O
cDNA	O
fragment	O
is	O
deleted	O
,	O
cells	O
are	O
unable	O
to	O
form	O
a	O
colony	O
(	O
Figure	O
4A	O
,	O
c	O
and	O
c2	O
)	O
.	O

As	O
shown	O
in	O
Table	O
2	O
,	O
FASAY	O
was	O
performed	O
as	O
a	O
p53	O
-	O
standard	O
test	O
with	O
full	O
-	O
length	O
cDNA	O
or	O
with	O
the	O
split	O
version	O
at	O
the	O
5	O
'	O
and	O
3	O
'	O
end	O
(	O
15	O
)	O
.	O

The	O
background	O
of	O
FASAY	O
experiments	O
is	O
around	O
10	O
%	O
.	O

p53	O
wt	O
expressing	O
SH	O
-	O
SY5Y	O
and	O
LAN	O
-	O
5	O
,	O
2	O
wt	O
cell	O
lines	O
,	O
yielded	O
~	O
92	O
-	O
97	O
%	O
of	O
white	O
colonies	O
(	O
Table	O
2	O
)	O
.	O

One	O
hundred	O
percent	O
of	O
the	O
colonies	O
carrying	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
p53	O
,	O
which	O
is	O
homozygous	O
for	O
the	O
C135F	O
mutation	O
,	O
turned	O
red	O
with	O
the	O
standard	O
or	O
5	O
'	O
split	O
assay	O
,	O
whereas	O
94	O
%	O
of	O
the	O
colonies	O
turned	O
white	O
with	O
the	O
3	O
'	O
split	O
assay	O
since	O
the	O
missense	O
mutation	O
does	O
not	O
extend	O
to	O
the	O
C	O
'	O
-	O
terminus	O
of	O
the	O
gene	O
(	O
Table	O
2	O
and	O
Figure	O
4B	O
,	O
dish	O
c	O
)	O
.	O

No	O
colonies	O
were	O
observed	O
with	O
p53	O
-	O
deficient	O
LAN	O
-	O
1	O
cells	O
,	O
(	O
see	O
also	O
Figure	O
4A	O
,	O
c	O
and	O
c2	O
)	O
.	O

With	O
SK	O
-	O
N	O
-	O
AS	O
cells	O
,	O
the	O
split	O
5	O
'	O
assay	O
gave	O
96	O
%	O
white	O
colonies	O
,	O
while	O
the	O
p53	O
-	O
standard	O
and	O
split	O
3	O
'	O
assay	O
did	O
not	O
produce	O
any	O
colonies	O
(	O
Table	O
2	O
)	O
.	O

This	O
means	O
that	O
the	O
5	O
'	O
terminus	O
was	O
intact	O
whereas	O
the	O
3	O
'	O
terminus	O
had	O
been	O
deleted	O
,	O
as	O
was	O
confirmed	O
by	O
nucleotide	O
sequence	O
analysis	O
.	O

The	O
IGR	O
-	O
NB8	O
colonies	O
,	O
however	O
,	O
were	O
red	O
both	O
with	O
the	O
p53	O
-	O
standard	O
assay	O
and	O
the	O
split	O
3	O
'	O
assay	O
.	O

In	O
the	O
IGR	O
-	O
N	O
-	O
91	O
cell	O
line	O
,	O
where	O
p53	O
harbors	O
two	O
contiguous	O
sets	O
of	O
exons	O
7	O
-	O
9	O
,	O
spanning	O
the	O
DBD	O
and	O
oligomerization	O
domain	O
,	O
it	O
is	O
interesting	O
to	O
note	O
that	O
the	O
yeast	B
colonies	O
were	O
predominantly	O
white	O
(	O
Figure	O
4B	O
,	O
dish	O
b	O
)	O
with	O
the	O
split	O
5	O
'	O
and	O
the	O
split	O
3	O
'	O
assay	O
(	O
96	O
and	O
87	O
%	O
of	O
white	O
colonies	O
,	O
respectively	O
)	O
This	O
suggests	O
that	O
the	O
cells	O
express	O
a	O
binding	O
ability	O
that	O
is	O
specific	O
to	O
wild	O
-	O
type	O
p53	O
rather	O
than	O
mutated	O
p53	O
(	O
Table	O
2	O
)	O
.	O

Transcription	O
activity	O
of	O
SH	O
-	O
SY5Y	O
,	O
IGR	O
-	O
N	O
-	O
91	O
,	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
,	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
p53	O
variants	O
in	O
mammalian	O
cells	O

To	O
determine	O
the	O
transactivation	O
ability	O
of	O
p53	O
variants	O
in	O
mammalian	O
cells	O
,	O
we	O
used	O
a	O
reporter	O
gene	O
strategy	O
.	O

The	O
p53RE	O
located	O
within	O
either	O
the	O
human	B
p21	O
/	O
WAF1	O
promoter	O
or	O
the	O
intron	O
1	O
of	O
the	O
mouse	B
and	O
human	B
BAX	O
gene	O
[	O
(	O
18	O
)	O
and	O
D	O
.	O

Munsch	O
,	O
personnal	O
communication	O
)	O
were	O
cloned	O
in	O
a	O
luciferase	O
reporter	O
gene	O
plasmid	O
upstream	O
of	O
the	O
E1B	O
minimal	O
promoter	O
as	O
described	O
in	O
Materials	O
and	O
Methods	O
.	O

The	O
p53	O
-	O
negative	O
LAN	O
-	O
1	O
cells	O
were	O
cotransfected	O
with	O
the	O
p53	O
vectors	O
expressing	O
the	O
p53	O
cloned	O
from	O
either	O
SH	O
-	O
SY5Y	O
,	O
IGR	O
-	O
N	O
-	O
91	O
,	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
,	O
SK	O
-	O
N	O
-	O
AS	O
or	O
IGR	O
-	O
NB8	O
and	O
the	O
luciferase	O
reporter	O
plasmids	O
.	O

Both	O
p53RE	O
were	O
strongly	O
stimulated	O
in	O
cells	O
cotransfected	O
with	O
wt	O
p53	O
cloned	O
from	O
SH	O
-	O
SY5Y	O
,	O
as	O
compared	O
to	O
cells	O
cotransfected	O
with	O
an	O
empty	O
plasmid	O
.	O

In	O
contrast	O
,	O
none	O
of	O
the	O
p53	O
variants	O
was	O
able	O
to	O
transactivate	O
the	O
expression	O
of	O
luciferase	O
driven	O
by	O
either	O
p21	O
/	O
WAF1	O
or	O
BAX	O
p53RE	O
(	O
Figure	O
5	O
)	O
.	O

To	O
test	O
transactivation	O
capability	O
at	O
the	O
protein	O
level	O
,	O
each	O
variant	O
was	O
transfected	O
into	O
p53	O
-	O
negative	O
LAN	O
-	O
1	O
cells	O
and	O
the	O
stimulation	O
of	O
endogenous	O
p21	O
/	O
Waf1	O
gene	O
expression	O
was	O
analyzed	O
by	O
western	O
blotting	O
.	O

As	O
shown	O
in	O
Figure	O
6	O
,	O
in	O
contrast	O
to	O
wt	O
p53	O
,	O
none	O
of	O
the	O
p53	O
variants	O
was	O
able	O
to	O
induce	O
p21	O
protein	O
accumulation	O
.	O

We	O
then	O
tested	O
for	O
a	O
possible	O
dominant	O
negative	O
effect	O
of	O
these	O
various	O
mutants	O
on	O
wt	O
p53	O
-	O
dependent	O
transcriptional	O
activity	O
.	O

To	O
this	O
end	O
,	O
SH	O
-	O
SY5Y	O
cells	O
were	O
cotransfected	O
with	O
constructs	O
encoding	O
the	O
luciferase	O
gene	O
driven	O
by	O
either	O
the	O
p21	O
/	O
Waf1	O
or	O
BAX	O
p53RE	O
and	O
the	O
constructs	O
expressing	O
the	O
various	O
p53s	O
cloned	O
from	O
IGR	O
-	O
NB8	O
,	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
,	O
IGR	O
-	O
N	O
-	O
91	O
,	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
NB	O
cells	O
or	O
p53DD	O
,	O
a	O
dominant	O
negative	O
mutant	O
of	O
wt	O
p53	O
(	O
24	O
)	O
.	O

The	O
stress	O
induced	O
by	O
transfection	O
activated	O
the	O
transcriptional	O
activity	O
of	O
the	O
wt	O
p53	O
expressed	O
in	O
SH	O
-	O
SY5Y	O
,	O
leading	O
to	O
a	O
p53	O
-	O
dependent	O
expression	O
of	O
luciferase	O
as	O
illustrated	O
by	O
the	O
fact	O
that	O
coexpression	O
of	O
p53DD	O
led	O
to	O
a	O
substantial	O
decrease	O
in	O
luciferase	O
activity	O
when	O
compared	O
to	O
the	O
luciferase	O
activity	O
of	O
cells	O
cotransfected	O
with	O
an	O
empty	O
plasmid	O
(	O
Figure	O
5	O
)	O
.	O

Compared	O
to	O
p53DD	O
,	O
mutants	O
within	O
the	O
DBD	O
isolated	O
from	O
IGR	O
-	O
N	O
-	O
91	O
or	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
had	O
only	O
a	O
moderate	O
dominant	O
negative	O
effect	O
on	O
endogenous	O
wt	O
p53	O
transcriptional	O
activity	O
.	O

More	O
surprisingly	O
,	O
the	O
transfection	O
of	O
the	O
C	O
-	O
terminal	O
truncated	O
variant	O
IGR	O
-	O
NB8	O
enhanced	O
both	O
BAX	O
and	O
p21	O
/	O
WAF1	O
p53RE	O
activity	O
.	O

The	O
coexpression	O
of	O
p53	O
beta	O
cloned	O
from	O
SK	O
-	O
N	O
-	O
AS	O
also	O
enhanced	O
BAX	O
p53RE	O
activity	O
.	O

A	O
similar	O
effect	O
has	O
been	O
reported	O
already	O
for	O
p53	O
beta	O
by	O
Bourdon	O
et	O
al	O
.	O

(	O
22	O
)	O
.	O

When	O
combined	O
,	O
these	O
results	O
show	O
that	O
all	O
the	O
p53	O
variants	O
isolated	O
from	O
the	O
NB	O
cells	O
had	O
lost	O
the	O
ability	O
to	O
specifically	O
transactivate	O
the	O
p53	O
target	O
genes	O
.	O

Their	O
effect	O
on	O
the	O
transcriptional	O
activity	O
of	O
endogenous	O
wt	O
p53	O
expressed	O
in	O
SH	O
-	O
SY5Y	O
cells	O
,	O
however	O
,	O
largely	O
depended	O
on	O
the	O
p53	O
domain	O
affected	O
by	O
the	O
modification	O
.	O

All	O
the	O
identified	O
p53	O
variants	O
inhibited	O
the	O
induction	O
of	O
endogenous	O
p21	O
/	O
WAF1	O
gene	O
expression	O
under	O
stress	O
conditions	O

We	O
further	O
examined	O
whether	O
the	O
four	O
p53	O
variants	O
,	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
,	O
IGR	O
-	O
N	O
-	O
91	O
,	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
,	O
had	O
loss	O
their	O
ability	O
to	O
stimulate	O
the	O
endogenous	O
expression	O
of	O
the	O
p21	O
/	O
WAF1	O
gene	O
,	O
the	O
archetypical	O
cell	O
cycle	O
inhibitor	O
and	O
the	O
true	O
target	O
of	O
p53	O
.	O

To	O
this	O
end	O
,	O
cellular	O
response	O
to	O
genotoxic	O
stress	O
was	O
analyzed	O
by	O
western	O
blot	O
following	O
treatment	O
of	O
the	O
various	O
cell	O
lines	O
with	O
cisplatin	O
,	O
one	O
of	O
the	O
most	O
potent	O
antitumor	O
agents	O
used	O
in	O
neuroblastoma	O
.	O

Results	O
are	O
presented	O
in	O
Figure	O
7	O
.	O

None	O
of	O
the	O
mutant	O
cells	O
,	O
regardless	O
of	O
the	O
type	O
of	O
mutation	O
,	O
was	O
able	O
to	O
induce	O
p21	O
/	O
WAF1	O
protein	O
accumulation	O
,	O
unlike	O
the	O
3	O
p53	O
wild	O
-	O
type	O
cells	O
(	O
SH	O
-	O
SY5Y	O
,	O
IMR	O
-	O
32	O
and	O
LAN	O
-	O
5	O
)	O
.	O

Genomic	O
status	O
of	O
TP53	O
region	O
in	O
the	O
various	O
cell	O
lines	O

According	O
to	O
Knudson	O
'	O
s	O
'	O
two	O
hit	O
'	O
model	O
of	O
tumor	O
suppressor	O
gene	O
functional	O
inactivation	O
,	O
the	O
mutation	O
of	O
one	O
allele	O
is	O
supposed	O
to	O
be	O
associated	O
with	O
a	O
deletion	O
of	O
the	O
second	O
allele	O
.	O

To	O
assess	O
this	O
genetic	O
mechanism	O
,	O
we	O
performed	O
FISH	O
experiments	O
to	O
search	O
for	O
deletions	O
of	O
one	O
copy	O
of	O
the	O
TP53	O
region	O
,	O
especially	O
in	O
cell	O
lines	O
with	O
a	O
mutated	O
TP53	O
gene	O
.	O

For	O
this	O
purpose	O
,	O
metaphase	O
preparations	O
of	O
the	O
studied	O
cell	O
lines	O
were	O
cohybridized	O
with	O
a	O
p53	O
DNA	O
probe	O
labeled	O
in	O
red	O
(	O
BAC	O
clone	O
RP11	O
-	O
199F11	O
)	O
as	O
described	O
previously	O
(	O
25	O
)	O
and	O
a	O
chromosome	O
17	O
-	O
specific	O
centromeric	O
probe	O
labeled	O
in	O
green	O
.	O

The	O
three	O
cell	O
lines	O
shown	O
previously	O
to	O
express	O
a	O
wt	O
p53	O
protein	O
(	O
LAN5	O
,	O
IMR32	O
and	O
SH	O
-	O
SY5Y	O
)	O
,	O
displayed	O
as	O
expected	O
two	O
signals	O
with	O
each	O
probe	O
,	O
confirming	O
the	O
presence	O
of	O
both	O
TP53	O
alleles	O
in	O
these	O
cells	O
(	O
Figure	O
8	O
and	O
Table	O
3	O
)	O
.	O

Conversely	O
,	O
IGR	O
-	O
N	O
-	O
91	O
and	O
SK	O
-	O
N	O
-	O
AS	O
cell	O
lines	O
displayed	O
only	O
one	O
fluorescent	O
signal	O
for	O
each	O
probe	O
,	O
suggesting	O
a	O
whole	O
chromosome	O
17	O
lost	O
,	O
or	O
at	O
least	O
losses	O
of	O
the	O
17p	O
arm	O
and	O
the	O
centromeric	O
region	O
.	O

The	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
cell	O
line	O
has	O
been	O
described	O
as	O
containing	O
only	O
one	O
chromosome	O
17	O
and	O
one	O
TP53	O
signal	O
(	O
10	O
)	O
.	O

In	O
our	O
analysis	O
,	O
only	O
10	O
%	O
of	O
the	O
cells	O
displayed	O
this	O
characteristic	O
,	O
whilst	O
most	O
of	O
the	O
cells	O
had	O
two	O
copies	O
of	O
both	O
(	O
Figure	O
8	O
and	O
Table	O
3	O
)	O
.	O

p53	O
sequencing	O
,	O
however	O
,	O
confirmed	O
the	O
previously	O
described	O
mutation	O
,	O
and	O
the	O
absence	O
of	O
a	O
normal	O
allele	O
,	O
suggesting	O
that	O
the	O
cells	O
used	O
in	O
our	O
study	O
had	O
acquired	O
,	O
during	O
culture	O
,	O
an	O
uniparental	O
disomy	O
for	O
the	O
TP53	O
-	O
mutated	O
chromosome	O
17	O
.	O

Finally	O
,	O
the	O
other	O
two	O
cell	O
lines	O
(	O
LAN	O
-	O
1	O
and	O
IGR	O
-	O
NB8	O
)	O
displayed	O
highly	O
variable	O
genetic	O
heterogeneity	O
from	O
one	O
cell	O
to	O
the	O
next	O
(	O
Table	O
3	O
)	O
.	O

Surprisingly	O
,	O
although	O
p53	O
transcripts	O
are	O
extremely	O
faintly	O
expressed	O
in	O
LAN	O
-	O
1	O
cell	O
line	O
,	O
all	O
cells	O
showed	O
several	O
FISH	O
signals	O
with	O
the	O
167	O
kb	O
BAC	O
probe	O
used	O
here	O
.	O

To	O
understand	O
this	O
apparent	O
contradiction	O
,	O
an	O
array	O
-	O
CGH	O
experiment	O
was	O
performed	O
on	O
an	O
oligo	O
-	O
array	O
Agilent	O
,	O
which	O
indicated	O
a	O
133	O
kb	O
interstitial	O
deletion	O
corresponding	O
to	O
the	O
p53	O
coding	O
region	O
and	O
the	O
97	O
kb	O
upstream	O
region	O
.	O

Accordingly	O
,	O
the	O
fluorescent	O
spots	O
observed	O
in	O
FISH	O
experiments	O
on	O
LAN	O
-	O
1	O
cells	O
should	O
be	O
related	O
to	O
the	O
hybridization	O
of	O
the	O
57	O
kb	O
region	O
downstream	O
of	O
p53	O
gene	O
present	O
in	O
the	O
BAC	O
probe	O
.	O

IGRN	O
-	O
B8	O
cell	O
line	O
displayed	O
a	O
number	O
of	O
signals	O
of	O
both	O
colors	O
ranging	O
from	O
0	O
to	O
4	O
,	O
with	O
87	O
%	O
of	O
cells	O
displaying	O
a	O
loss	O
for	O
one	O
TP53	O
allele	O
.	O

Despite	O
this	O
genomic	O
variability	O
,	O
analysis	O
of	O
the	O
p53	O
protein	O
showed	O
a	O
single	O
shortened	O
form	O
in	O
IGR	O
-	O
N	O
-	O
B8	O
cell	O
line	O
(	O
Figure	O
1	O
)	O
.	O

Consequently	O
,	O
and	O
as	O
suggested	O
for	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
cell	O
line	O
,	O
IGR	O
-	O
N	O
-	O
B8	O
cell	O
line	O
should	O
contain	O
a	O
variable	O
number	O
of	O
copies	O
of	O
chromosome	O
17	O
with	O
mutated	O
p53	O
.	O

DISCUSSION	O

The	O
p53	O
gene	O
,	O
the	O
'	O
genome	O
guardian	O
'	O
,	O
is	O
mutated	O
in	O
over	O
50	O
%	O
of	O
human	B
cancers	O
,	O
with	O
the	O
most	O
common	O
mutations	O
being	O
missense	O
mutations	O
(	O
>	O
2	O
/	O
3	O
of	O
mutations	O
)	O
(	O
26	O
)	O
.	O

In	O
human	B
neuroblastoma	O
tumors	O
,	O
p53	O
mutations	O
are	O
rarely	O
present	O
at	O
the	O
time	O
of	O
diagnosis	O
(	O
5	O
,	O
27	O
)	O
;	O
however	O
,	O
oncogenic	O
p53	O
mutations	O
can	O
be	O
found	O
in	O
advanced	O
neuroblastomas	O
that	O
often	O
relapse	O
following	O
high	O
-	O
dose	O
chemotherapy	O
(	O
10	O
)	O
.	O

In	O
contrast	O
,	O
in	O
breast	O
cancers	O
,	O
it	O
has	O
been	O
reported	O
that	O
p53	O
mutations	O
might	O
improve	O
response	O
to	O
high	O
-	O
dose	O
chemotherapy	O
including	O
therapy	O
with	O
epirubicin	O
and	O
cyclophosphamide	O
(	O
28	O
)	O
.	O

An	O
investigation	O
into	O
the	O
p53	O
genomic	O
status	O
and	O
functions	O
of	O
eight	O
human	B
NB	O
lines	O
revealed	O
that	O
all	O
five	O
of	O
the	O
mutated	O
cell	O
lines	O
had	O
distinct	O
genetic	O
characteristics	O
as	O
is	O
schematically	O
represented	O
in	O
Figure	O
9	O
:	O
SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
with	O
a	O
single	O
missense	O
mutation	O
in	O
the	O
p53	O
gene	O
,	O
encoding	O
a	O
highly	O
stable	O
full	O
-	O
length	O
protein	O
.	O

SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
proteins	O
,	O
although	O
they	O
have	O
intact	O
transactivation	O
and	O
DBDs	O
,	O
were	O
truncated	O
at	O
the	O
C	O
-	O
terminus	O
generating	O
341	O
and	O
326	O
amino	O
acids	O
respectively	O
;	O
they	O
therefore	O
lack	O
the	O
tetramerization	O
domain	O
that	O
is	O
essential	O
for	O
an	O
active	O
conformation	O
.	O

Very	O
recently	O
,	O
Bourdon	O
et	O
al	O
.	O

(	O
22	O
)	O
reported	O
the	O
putative	O
occurrence	O
of	O
beta	O
and	O
gamma	O
isoforms	O
from	O
different	O
tissues	O
due	O
to	O
alternate	O
splicing	O
that	O
indicates	O
the	O
similarity	O
to	O
those	O
of	O
p73	O
and	O
p63	O
as	O
identified	O
previously	O
by	O
Daniel	O
Caput	O
and	O
co	O
-	O
workers	O
(	O
29	O
)	O
.	O

In	O
the	O
p53	O
isoforms	O
scheme	O
proposed	O
by	O
Bourdon	O
et	O
al	O
.	O

(	O
22	O
)	O
,	O
the	O
SK	O
-	O
N	O
-	O
AS	O
cell	O
line	O
that	O
elicits	O
p53i9	O
protein	O
expression	O
is	O
consistent	O
with	O
the	O
p53	O
beta	O
isoform	O
.	O

Genomic	O
analysis	O
reveals	O
that	O
the	O
only	O
occurrence	O
of	O
the	O
p53	O
beta	O
isoform	O
in	O
SK	O
-	O
N	O
-	O
AS	O
results	O
from	O
a	O
deletion	O
spanning	O
the	O
intron	O
9	O
/	O
exon	O
10	O
junction	O
.	O

Similar	O
to	O
the	O
p53	O
beta	O
isoform	O
in	O
SK	O
-	O
N	O
-	O
AS	O
,	O
the	O
p53	O
in	O
IGR	O
-	O
NB8	O
that	O
lacks	O
67	O
amino	O
acids	O
at	O
C	O
-	O
terminus	O
was	O
,	O
alone	O
,	O
unable	O
to	O
induce	O
p21	O
/	O
WAF1	O
promoter	O
activation	O
except	O
with	O
endogenous	O
wt	O
-	O
p53	O
on	O
SH	O
-	O
SY5Y	O
cells	O
where	O
transfection	O
with	O
IGR	O
-	O
NB8	O
significantly	O
augmented	O
the	O
transcriptional	O
activation	O
of	O
the	O
p21	O
/	O
Waf	O
-	O
1	O
promoter	O
(	O
Figure	O
5A	O
)	O
.	O

Studies	O
by	O
other	O
authors	O
have	O
reported	O
the	O
interaction	O
between	O
the	O
C	O
-	O
terminal	O
domain	O
and	O
another	O
region	O
that	O
impedes	O
the	O
active	O
conformation	O
of	O
p53	O
,	O
suggesting	O
an	O
allosteric	O
model	O
for	O
p53	O
activity	O
regulation	O
(	O
30	O
)	O
.	O

Such	O
events	O
have	O
been	O
demonstrated	O
for	O
the	O
342	O
-	O
stop	O
mutant	O
,	O
generated	O
by	O
mutagenesis	O
,	O
which	O
can	O
modulate	O
transactivation	O
,	O
growth	O
and	O
apoptosis	O
(	O
31	O
)	O
.	O

Moreover	O
,	O
Harms	O
and	O
Chen	O
(	O
32	O
)	O
reported	O
that	O
the	O
C	O
-	O
terminal	O
basic	O
domain	O
inhibits	O
induction	O
of	O
the	O
proapoptotic	O
target	O
gene	O
insulin	O
-	O
like	O
growth	O
factor	O
binding	O
protein	O
3	O
,	O
suggesting	O
that	O
IGR	O
-	O
NB8	O
might	O
induce	O
this	O
gene	O
.	O

IGR	O
-	O
N	O
-	O
91	O
had	O
an	O
abnormally	O
high	O
molecular	O
weight	O
protein	O
due	O
to	O
the	O
duplication	O
of	O
wild	O
-	O
type	O
exons	O
7	O
-	O
8	O
-	O
9	O
,	O
thus	O
affecting	O
the	O
DBD	O
and	O
OD	O
;	O
and	O
LAN	O
-	O
1	O
,	O
with	O
a	O
mutation	O
at	O
codon	O
182	O
(	O
Cys	O
-	O
-	O
>	O
stop	O
)	O
concurred	O
with	O
an	O
earlier	O
report	O
showing	O
extremely	O
low	O
levels	O
of	O
mRNA	O
and	O
undetectable	O
protein	O
expression	O
(	O
9	O
)	O
.	O

Notably	O
,	O
all	O
the	O
p53	O
variants	O
,	O
including	O
SK	O
-	O
N	O
-	O
AS	O
(	O
beta	O
isoform	O
)	O
and	O
IGR	O
-	O
NB8	O
(	O
C	O
-	O
terminal	O
truncated	O
p53	O
)	O
,	O
elicited	O
a	O
total	O
lack	O
of	O
p21	O
promoter	O
activation	O
.	O

In	O
particular	O
,	O
the	O
p53	O
beta	O
isoform	O
was	O
unable	O
to	O
induce	O
endogenous	O
p21	O
expression	O
in	O
SK	O
-	O
N	O
-	O
AS	O
(	O
Figure	O
6	O
)	O
,	O
concurring	O
with	O
data	O
obtained	O
from	O
in	O
vitro	O
transfection	O
experiments	O
in	O
H1299	O
cells	O
by	O
Bourdon	O
et	O
al	O
.	O

(	O
22	O
)	O
.	O

For	O
the	O
IGR	O
-	O
N	O
-	O
91	O
cells	O
,	O
although	O
p53	O
was	O
mutated	O
and	O
unable	O
to	O
transactivate	O
the	O
p21	O
/	O
WAF1	O
promoter	O
,	O
the	O
FASAY	O
global	O
test	O
was	O
not	O
conclusive	O
since	O
~	O
80	O
%	O
of	O
colonies	O
were	O
white	O
and	O
nearly	O
20	O
%	O
(	O
see	O
also	O
Table	O
2	O
)	O
,	O
though	O
not	O
enough	O
,	O
were	O
red	O
.	O

Moreover	O
,	O
in	O
this	O
particular	O
line	O
,	O
standard	O
sequencing	O
on	O
cDNA	O
using	O
primers	O
located	O
within	O
each	O
exon	O
as	O
used	O
for	O
routine	O
tumor	O
analysis	O
was	O
unable	O
to	O
detect	O
any	O
anomalies	O
in	O
p53	O
genetic	O
status	O
(	O
data	O
not	O
shown	O
)	O
.	O

These	O
results	O
enlighten	O
the	O
limit	O
of	O
the	O
conventional	O
tests	O
to	O
detect	O
a	O
transcription	O
inactivation	O
of	O
p53	O
brought	O
by	O
duplication	O
within	O
the	O
DBD	O
.	O

Analysis	O
of	O
p53	O
genomic	O
status	O
was	O
explored	O
by	O
FISH	O
experiments	O
,	O
in	O
search	O
for	O
a	O
potential	O
biallelic	O
inactivation	O
of	O
p53	O
,	O
with	O
a	O
mutation	O
of	O
one	O
allele	O
and	O
a	O
deletion	O
of	O
the	O
second	O
one	O
.	O

This	O
situation	O
was	O
indeed	O
clearly	O
observed	O
in	O
IGR	O
-	O
N	O
-	O
91	O
and	O
SK	O
-	O
N	O
-	O
AS	O
cell	O
lines	O
,	O
with	O
an	O
unambiguous	O
loss	O
of	O
one	O
chromosome	O
17p	O
arm	O
in	O
all	O
cells	O
of	O
both	O
.	O

SK	O
-	O
N	O
-	O
BE	O
(	O
2	O
)	O
,	O
LAN	O
-	O
1	O
and	O
IGR	O
-	O
NB	O
-	O
8	O
cell	O
lines	O
showed	O
a	O
more	O
complex	O
genomic	O
situation	O
which	O
should	O
be	O
relevant	O
of	O
variable	O
copy	O
numbers	O
of	O
chromosome	O
17	O
bearing	O
in	O
most	O
cases	O
(	O
LAN	O
-	O
1	O
)	O
or	O
in	O
all	O
cases	O
[	O
SKN	O
-	O
BE	O
(	O
2	O
)	O
,	O
IGR	O
-	O
NB8	O
]	O
the	O
mutated	O
characteristic	O
p53	O
allele	O
.	O

Our	O
data	O
therefore	O
clearly	O
demonstrate	O
that	O
each	O
technique	O
has	O
a	O
role	O
and	O
a	O
combination	O
of	O
techniques	O
is	O
required	O
in	O
order	O
to	O
correctly	O
define	O
the	O
p53	O
phenotype	O
and	O
genotype	O
in	O
tumor	O
and	O
particularly	O
in	O
NB	O
cells	O
.	O

Our	O
data	O
enlighten	O
a	O
high	O
frequency	O
of	O
the	O
C	O
-	O
terminal	O
abnormalities	O
(	O
3	O
/	O
5	O
mutated	O
)	O
in	O
NB	O
cell	O
lines	O
.	O

For	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
,	O
a	O
part	O
of	O
the	O
oligomerization	O
domain	O
was	O
lost	O
and	O
IGR	O
-	O
N	O
-	O
91	O
gained	O
an	O
extra	O
oligomerization	O
domain	O
.	O

According	O
to	O
FASAY	O
assay	O
the	O
p53	O
expressed	O
in	O
IGR	O
-	O
N	O
-	O
91	O
still	O
specifically	O
bind	O
DNA	O
but	O
not	O
the	O
p53	O
expressed	O
in	O
SK	O
-	O
N	O
-	O
AS	O
and	O
IGR	O
-	O
NB8	O
in	O
agreement	O
with	O
previous	O
published	O
data	O
obtained	O
by	O
electrophoretic	O
mobility	O
shift	O
assay	O
(	O
33	O
)	O
.	O

With	O
regards	O
to	O
biological	O
relevance	O
,	O
different	O
mutants	O
within	O
the	O
DBD	O
vary	O
in	O
their	O
oncogenicity	O
.	O

They	O
are	O
classified	O
into	O
two	O
types	O
depending	O
of	O
the	O
location	O
of	O
the	O
mutation	O
,	O
mutations	O
of	O
class	O
I	O
occur	O
in	O
the	O
DNA	O
contact	O
areas	O
,	O
while	O
class	O
II	O
mutations	O
occur	O
in	O
areas	O
important	O
for	O
the	O
conformational	O
stability	O
of	O
p53	O
protein	O
(	O
30	O
)	O
.	O

Although	O
both	O
class	O
I	O
and	O
class	O
II	O
mutants	O
have	O
loss	O
its	O
ability	O
to	O
specifically	O
bind	O
DNA	O
,	O
class	O
II	O
mutations	O
have	O
been	O
shown	O
to	O
be	O
more	O
oncogenic	O
than	O
class	O
I	O
.	O

However	O
,	O
to	O
our	O
knowledge	O
the	O
oncogenicity	O
of	O
mutant	O
affecting	O
the	O
C	O
-	O
terminal	O
domain	O
have	O
not	O
been	O
studied	O
.	O

The	O
biological	O
role	O
of	O
the	O
C	O
-	O
terminal	O
mutants	O
needs	O
now	O
to	O
be	O
thoroughly	O
investigated	O
in	O
NB	O
tumors	O
.	O

MUC1	O
alters	O
oncogenic	O
events	O
and	O
transcription	O
in	O
human	B
breast	O
cancer	O
cells	O

Abstract	O

Introduction	O

MUC1	O
is	O
an	O
oncoprotein	O
whose	O
overexpression	O
correlates	O
with	O
aggressiveness	O
of	O
tumors	O
and	O
poor	O
survival	O
of	O
cancer	O
patients	B
.	O

Many	O
of	O
the	O
oncogenic	O
effects	O
of	O
MUC1	O
are	O
believed	O
to	O
occur	O
through	O
interaction	O
of	O
its	O
cytoplasmic	O
tail	O
with	O
signaling	O
molecules	O
.	O

As	O
expected	O
for	O
a	O
protein	O
with	O
oncogenic	O
functions	O
,	O
MUC1	O
is	O
linked	O
to	O
regulation	O
of	O
proliferation	O
,	O
apoptosis	O
,	O
invasion	O
,	O
and	O
transcription	O
.	O

Methods	O

To	O
clarify	O
the	O
role	O
of	O
MUC1	O
in	O
cancer	O
,	O
we	O
transfected	O
two	O
breast	O
cancer	O
cell	O
lines	O
(	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
)	O
with	O
small	O
interfering	O
(	O
si	O
)	O
RNA	O
directed	O
against	O
MUC1	O
and	O
analyzed	O
transcriptional	O
responses	O
and	O
oncogenic	O
events	O
(	O
proliferation	O
,	O
apoptosis	O
and	O
invasion	O
)	O
.	O

Results	O

Transcription	O
of	O
several	O
genes	O
was	O
altered	O
after	O
transfection	O
of	O
MUC1	O
siRNA	O
,	O
including	O
decreased	O
MAP2K1	O
(	O
MEK1	O
)	O
,	O
JUN	O
,	O
PDGFA	O
,	O
CDC25A	O
,	O
VEGF	O
and	O
ITGAV	O
(	O
integrin	O
alpha	O
v	O
)	O
,	O
and	O
increased	O
TNF	O
,	O
RAF1	O
,	O
and	O
MMP2	O
.	O

Additional	O
changes	O
were	O
seen	O
at	O
the	O
protein	O
level	O
,	O
such	O
as	O
increased	O
expression	O
of	O
c	O
-	O
Myc	O
,	O
heightened	O
phosphorylation	O
of	O
AKT	O
,	O
and	O
decreased	O
activation	O
of	O
MEK1	O
/	O
2	O
and	O
ERK1	O
/	O
2	O
.	O

These	O
were	O
correlated	O
with	O
cellular	O
events	O
,	O
as	O
MUC1	O
siRNA	O
in	O
the	O
MDA	O
-	O
MB	O
-	O
468	O
line	O
decreased	O
proliferation	O
and	O
invasion	O
,	O
and	O
increased	O
stress	O
-	O
induced	O
apoptosis	O
.	O

Intriguingly	O
,	O
BT	O
-	O
20	O
cells	O
displayed	O
similar	O
levels	O
of	O
apoptosis	O
regardless	O
of	O
siRNA	O
,	O
and	O
actually	O
increased	O
proliferation	O
after	O
MUC1	O
siRNA	O
.	O

Conclusion	O

These	O
results	O
further	O
the	O
growing	O
knowledge	O
of	O
the	O
role	O
of	O
MUC1	O
in	O
transcription	O
,	O
and	O
suggest	O
that	O
the	O
regulation	O
of	O
MUC1	O
in	O
breast	O
cancer	O
may	O
be	O
more	O
complex	O
than	O
previously	O
appreciated	O
.	O

The	O
differences	O
between	O
these	O
two	O
cell	O
lines	O
emphasize	O
the	O
importance	O
of	O
understanding	O
the	O
context	O
of	O
cell	O
-	O
specific	O
signaling	O
events	O
when	O
analyzing	O
the	O
oncogenic	O
functions	O
of	O
MUC1	O
,	O
and	O
caution	O
against	O
generalizing	O
the	O
results	O
of	O
individual	O
cell	O
lines	O
without	O
adequate	O
confirmation	O
in	O
intact	O
biological	O
systems	O
.	O

Introduction	O

MUC1	O
is	O
the	O
founding	O
member	O
of	O
the	O
mucin	O
family	O
:	O
proteins	O
characterized	O
by	O
heavy	O
O	O
-	O
glycosylation	O
centering	O
around	O
a	O
variable	O
number	O
of	O
tandem	O
repeats	O
that	O
are	O
rich	O
in	O
serine	O
and	O
threonine	O
residues	O
[	O
1	O
,	O
2	O
]	O
.	O

MUC1	O
is	O
a	O
transmembrane	O
heterodimer	O
with	O
one	O
subunit	O
solely	O
extracellular	O
(	O
MUC1	O
-	O
EX	O
)	O
,	O
and	O
the	O
other	O
subunit	O
composed	O
of	O
a	O
short	O
extracellular	O
stem	O
,	O
a	O
single	O
transmembrane	O
domain	O
,	O
and	O
the	O
cytoplasmic	O
tail	O
(	O
together	O
called	O
the	O
MUC1	O
-	O
CT	O
)	O
.	O

MUC1	O
possesses	O
both	O
pro	O
-	O
and	O
anti	O
-	O
adhesive	O
capacities	O
,	O
as	O
the	O
MUC1	O
-	O
EX	O
provides	O
binding	O
sites	O
for	O
a	O
variety	O
of	O
adhesion	O
proteins	O
,	O
while	O
its	O
large	O
size	O
and	O
extended	O
structure	O
prevents	O
cell	O
-	O
cell	O
contact	O
[	O
3	O
-	O
5	O
]	O
.	O

Initially	O
described	O
as	O
a	O
tumor	O
antigen	O
overexpressed	O
in	O
>	O
90	O
%	O
of	O
breast	O
cancers	O
,	O
MUC1	O
is	O
now	O
known	O
to	O
be	O
an	O
oncogene	O
with	O
roles	O
in	O
both	O
tumor	O
formation	O
and	O
progression	O
[	O
1	O
,	O
6	O
]	O
.	O

Mouse	B
studies	O
have	O
been	O
integral	O
to	O
the	O
current	O
understanding	O
of	O
MUC1	O
in	O
cancer	O
.	O

Muc1	O
knockout	O
mice	B
(	O
Muc1	O
-	O
/	O
-	O
;	O
MUC1	O
is	O
human	B
;	O
Muc1	O
is	O
mouse	B
)	O
show	O
a	O
reduction	O
in	O
tumorigenic	O
phenotype	O
when	O
crossed	O
onto	O
mice	B
overexpressing	O
the	O
Wnt	O
-	O
1	O
[	O
7	O
]	O
or	O
polyomavirus	O
middle	O
T	O
antigen	O
[	O
8	O
]	O
oncogenes	O
in	O
the	O
mammary	O
gland	O
.	O

In	O
contrast	O
,	O
MUC1	O
overexpression	O
in	O
the	O
mammary	O
gland	O
drives	O
tumor	O
formation	O
[	O
9	O
]	O
,	O
indicating	O
that	O
MUC1	O
is	O
a	O
true	O
oncogene	O
.	O

Many	O
of	O
the	O
oncogenic	O
effects	O
of	O
MUC1	O
stem	O
from	O
its	O
cytoplasmic	O
tail	O
,	O
which	O
binds	O
to	O
several	O
proteins	O
implicated	O
in	O
cancer	O
,	O
including	O
c	O
-	O
Src	O
[	O
10	O
,	O
11	O
]	O
and	O
the	O
epidermal	O
growth	O
factor	O
receptor	O
(	O
EGFR	O
)	O
family	O
[	O
12	O
,	O
13	O
]	O
.	O

MUC1	O
stimulates	O
mitogen	O
activated	O
protein	O
kinase	O
(	O
MAPK	O
)	O
signaling	O
through	O
the	O
extracellular	O
signal	O
regulated	O
kinases	O
(	O
ERK1	O
/	O
2	O
)	O
[	O
12	O
,	O
14	O
]	O
;	O
this	O
can	O
occur	O
through	O
MUC1	O
association	O
with	O
Grb2	O
and	O
son	O
of	O
sevenless	O
to	O
activate	O
Ras	O
[	O
15	O
]	O
.	O

ERK1	O
/	O
2	O
signaling	O
is	O
commonly	O
stimulated	O
by	O
the	O
Ras	O
-	O
Raf	O
-	O
MEK	O
(	O
MAPK	O
and	O
ERK	O
kinase	O
)	O
cascade	O
downstream	O
of	O
mitogens	O
such	O
as	O
EGFR	O
[	O
16	O
]	O
,	O
and	O
regulates	O
transcription	O
via	O
factors	O
like	O
the	O
activator	O
protein	O
-	O
1	O
complex	O
.	O

Loss	O
of	O
MUC1	O
can	O
reduce	O
EGFR	O
expression	O
[	O
17	O
]	O
,	O
providing	O
another	O
means	O
of	O
affecting	O
MAPK	O
signaling	O
.	O

Our	O
results	O
describe	O
a	O
novel	O
mechanism	O
by	O
which	O
MUC1	O
regulates	O
the	O
ERK1	O
/	O
2	O
pathway	O
,	O
through	O
modulating	O
transcription	O
of	O
the	O
genes	O
encoding	O
MEK1	O
,	O
Raf	O
-	O
1	O
,	O
and	O
c	O
-	O
Jun	O
.	O

MUC1	O
expression	O
correlates	O
with	O
increased	O
survival	O
in	O
response	O
to	O
cytotoxic	O
or	O
oxidative	O
agents	O
[	O
18	O
-	O
21	O
]	O
,	O
and	O
can	O
activate	O
the	O
phosphoinositol	O
-	O
3	O
kinase	O
-	O
AKT	O
pathway	O
as	O
part	O
of	O
an	O
anti	O
-	O
apoptotic	O
response	O
[	O
18	O
]	O
.	O

MUC1	O
has	O
also	O
recently	O
been	O
linked	O
to	O
transcription	O
,	O
as	O
the	O
MUC1	O
-	O
CT	O
localizes	O
to	O
the	O
nucleus	O
[	O
22	O
]	O
and	O
affects	O
transcription	O
by	O
beta	O
-	O
catenin	O
[	O
22	O
,	O
23	O
]	O
,	O
FOXO3a	O
[	O
21	O
]	O
,	O
p53	O
[	O
24	O
]	O
,	O
and	O
estrogen	O
receptor	O
alpha	O
[	O
25	O
]	O
.	O

However	O
,	O
there	O
are	O
indications	O
that	O
the	O
role	O
of	O
MUC1	O
in	O
oncogenesis	O
is	O
regulated	O
by	O
cell	O
type	O
and	O
signaling	O
context	O
.	O

For	O
example	O
,	O
MUC1	O
can	O
stimulate	O
Fas	O
-	O
mediated	O
apoptosis	O
[	O
26	O
]	O
,	O
while	O
Muc1	O
is	O
specifically	O
down	O
-	O
regulated	O
in	O
c	O
-	O
neu	O
-	O
induced	O
mammary	O
tumors	O
[	O
27	O
]	O
.	O

This	O
report	O
emphasizes	O
the	O
complexity	O
of	O
MUC1	O
signaling	O
in	O
breast	O
cancer	O
by	O
contrasting	O
results	O
from	O
two	O
established	O
breast	O
cancer	O
cell	O
lines	O
.	O

To	O
understand	O
MUC1	O
function	O
in	O
cells	O
with	O
high	O
endogenous	O
expression	O
,	O
that	O
is	O
,	O
cells	O
likely	O
to	O
have	O
evolved	O
with	O
active	O
MUC1	O
signaling	O
,	O
we	O
used	O
small	O
interfering	O
RNA	O
(	O
siRNA	O
)	O
to	O
knock	O
down	O
MUC1	O
in	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
cells	O
.	O

We	O
then	O
analyzed	O
transcription	O
of	O
84	O
genes	O
involved	O
in	O
cancer	O
,	O
as	O
well	O
as	O
the	O
effects	O
upon	O
cellular	O
events	O
linked	O
to	O
oncogenesis	O
,	O
such	O
as	O
apoptosis	O
and	O
proliferation	O
.	O

Though	O
the	O
cell	O
lines	O
show	O
some	O
similarity	O
in	O
transcriptional	O
alterations	O
after	O
transfection	O
with	O
MUC1	O
siRNA	O
,	O
their	O
phenotypes	O
are	O
quite	O
dissimilar	O
:	O
MDA	O
-	O
MB	O
-	O
468	O
increases	O
apoptosis	O
and	O
reduces	O
proliferation	O
and	O
invasion	O
,	O
while	O
BT	O
-	O
20	O
proliferates	O
more	O
rapidly	O
after	O
loss	O
of	O
MUC1	O
.	O

This	O
last	O
may	O
reflect	O
the	O
striking	O
amount	O
of	O
active	O
AKT	O
in	O
BT	O
-	O
20	O
;	O
AKT	O
activity	O
is	O
increased	O
in	O
both	O
cell	O
lines	O
after	O
MUC1	O
siRNA	O
,	O
which	O
agrees	O
with	O
a	O
previous	O
study	O
of	O
MUC1	O
siRNA	O
[	O
21	O
]	O
,	O
but	O
disagrees	O
with	O
results	O
from	O
3Y1	O
fibroblasts	O
[	O
18	O
]	O
.	O

Recent	O
studies	O
have	O
emphasized	O
the	O
complex	O
and	O
context	O
-	O
specific	O
regulation	O
of	O
even	O
such	O
classic	O
oncogenes	O
as	O
AKT	O
[	O
28	O
]	O
.	O

The	O
differences	O
between	O
the	O
two	O
breast	O
cancer	O
cell	O
lines	O
in	O
this	O
study	O
suggest	O
that	O
MUC1	O
oncogenic	O
functions	O
are	O
also	O
subject	O
to	O
cell	O
-	O
specific	O
regulation	O
,	O
and	O
stress	O
the	O
need	O
for	O
understanding	O
the	O
cellular	O
signaling	O
context	O
when	O
interpreting	O
results	O
.	O

Materials	O
and	O
methods	O

Cell	O
culture	O
and	O
siRNA	O
transfection	O

MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
cells	O
(	O
American	O
Type	O
Culture	O
Collection	O
)	O
were	O
cultured	O
in	O
Dulbecco	O
'	O
s	O
modified	O
Eagle	O
'	O
s	O
medium	O
(	O
Invitrogen	O
,	O
Carlsbad	O
,	O
CA	O
,	O
USA	O
)	O
plus	O
10	O
%	O
fetal	O
calf	B
serum	O
,	O
1	O
%	O
Glutamax	O
(	O
Invitrogen	O
)	O
and	O
1	O
%	O
penicillin	O
/	O
streptomycin	O
.	O

Stable	O
cell	O
lines	O
(	O
468	O
.	O
Neo	O
and	O
468	O
.	O
MUC1	O
Delta	O
8	O
)	O
were	O
selected	O
with	O
0	O
.	O
5	O
mg	O
/	O
ml	O
G418	O
.	O

For	O
epidermal	O
growth	O
factor	O
(	O
EGF	O
)	O
stimulation	O
,	O
MDA	O
-	O
MB	O
-	O
468	O
cells	O
were	O
serum	O
-	O
starved	O
overnight	O
and	O
treated	O
for	O
10	O
minutes	O
at	O
37	O
degrees	O
C	O
with	O
100	O
ng	O
/	O
ml	O
EGF	O
.	O

Transient	O
siRNA	O
transfection	O
was	O
performed	O
with	O
Lipofectamine2000	O
(	O
Invitrogen	O
)	O
and	O
100	O
nM	O
siRNA	O
oligonucleotides	O
.	O

The	O
commercially	O
available	O
siRNA	O
constructs	O
(	O
all	O
from	O
Dharmacon	O
,	O
Lafayette	O
,	O
CO	O
,	O
USA	O
)	O
were	O
scrambled	O
(	O
siCONTROL	O
non	O
-	O
targeting	O
siRNA	O
#	O
1	O
)	O
,	O
or	O
directed	O
against	O
firefly	O
luciferase	O
(	O
siCONTROL	O
non	O
-	O
targeting	O
siRNA	O
#	O
2	O
)	O
or	O
MUC1	O
(	O
siGENOME	O
smartpool	O
)	O
.	O

The	O
independent	O
oligonucleotides	O
designed	O
in	O
our	O
laboratory	O
target	O
sequences	O
beginning	O
at	O
MUC1	O
codons	O
882	O
and	O
956	O
,	O
and	O
have	O
been	O
described	O
previously	O
[	O
29	O
]	O
.	O

The	O
scrambled	O
siRNA	O
construct	O
was	O
used	O
only	O
in	O
BT	O
-	O
20	O
cells	O
as	O
it	O
causes	O
a	O
non	O
-	O
specific	O
knockdown	O
of	O
MUC1	O
in	O
the	O
MDA	O
-	O
MB	O
-	O
468	O
line	O
.	O

Cloning	O
of	O
MUC1	O
WT	O
vector	O
and	O
stable	O
transfection	O

Two	O
silent	O
mutations	O
(	O
G891A	O
and	O
T894C	O
)	O
were	O
introduced	O
into	O
the	O
MUC1	O
cDNA	O
(	O
called	O
MUC1	O
Delta	O
8	O
)	O
to	O
make	O
it	O
resistant	O
to	O
the	O
882	O
siRNA	O
that	O
targets	O
that	O
region	O
of	O
the	O
mRNA	O
.	O

The	O
mutant	O
cDNA	O
was	O
cloned	O
into	O
the	O
pLNCX	O
.	O
1	O
vector	O
with	O
neomycin	O
resistance	O
(	O
gift	O
of	O
Joseph	O
Loftus	O
,	O
Mayo	O
Clinic	O
,	O
Arizona	O
,	O
USA	O
)	O
.	O

Stable	O
transfection	O
was	O
performed	O
with	O
Lipofectamine2000	O
;	O
cells	O
were	O
selected	O
beginning	O
24	O
hours	O
post	O
-	O
transfection	O
and	O
maintained	O
as	O
a	O
polyclonal	O
population	O
.	O

Western	O
blots	O
and	O
antibodies	O

Cells	O
were	O
lysed	O
in	O
buffer	O
(	O
20	O
mM	O
HEPES	O
pH	O
8	O
.	O
0	O
,	O
150	O
mM	O
sodium	O
chloride	O
,	O
1	O
%	O
Triton	O
X	O
-	O
100	O
,	O
2	O
mM	O
EDTA	O
)	O
with	O
commercial	O
protease	O
(	O
Complete	O
inhibitor	O
cocktail	O
,	O
Roche	O
,	O
Pleasanton	O
,	O
CA	O
,	O
USA	O
)	O
and	O
phosphatase	O
inhibitors	O
(	O
10	O
mM	O
sodium	O
fluoride	O
,	O
2	O
mM	O
sodium	O
vanadate	O
,	O
50	O
mu	O
M	O
ammonium	O
molybdate	O
)	O
.	O

Protein	O
concentration	O
was	O
determined	O
by	O
BCA	O
(	O
Pierce	O
,	O
Rockford	O
,	O
IL	O
,	O
USA	O
)	O
;	O
50	O
mu	O
g	O
of	O
lysate	O
were	O
loaded	O
on	O
SDS	O
-	O
PAGE	O
gels	O
for	O
each	O
experiment	O
,	O
except	O
for	O
the	O
pMEK1	O
/	O
2	O
blot	O
in	O
MDA	O
-	O
MB	O
-	O
468	O
,	O
where	O
150	O
mu	O
g	O
were	O
used	O
.	O

Non	O
-	O
commercial	O
antibodies	O
used	O
were	O
:	O
BC2	O
,	O
a	O
mouse	B
monoclonal	O
to	O
the	O
MUC1	O
-	O
EX	O
(	O
gift	O
of	O
Dr	O
McGuckin	O
,	O
Queensland	O
University	O
,	O
Queensland	O
,	O
Australia	O
)	O
,	O
and	O
CT2	O
,	O
an	O
Armenian	B
hamster	I
monoclonal	O
to	O
the	O
MUC1	O
-	O
CT	O
developed	O
in	O
our	O
lab	O
[	O
12	O
]	O
.	O

Antibodies	O
to	O
pMEK1	O
/	O
2	O
,	O
MEK1	O
/	O
2	O
,	O
ERK1	O
/	O
2	O
,	O
Myc	O
,	O
pAKT	O
,	O
AKT	O
,	O
beta	O
-	O
tubulin	O
(	O
all	O
Cell	O
Signaling	O
,	O
Danvers	O
,	O
MA	O
,	O
USA	O
)	O
,	O
beta	O
-	O
actin	O
and	O
dpERK1	O
/	O
2	O
(	O
both	O
Sigma	O
,	O
St	O
.	O
Louis	O
,	O
MO	O
,	O
USA	O
)	O
were	O
used	O
according	O
to	O
manufacturers	O
'	O
recommendations	O
.	O

All	O
antibodies	O
except	O
beta	O
-	O
actin	O
(	O
1	O
:	O
2	O
,	O
500	O
)	O
and	O
dpERK1	O
/	O
2	O
(	O
1	O
:	O
10	O
,	O
000	O
)	O
were	O
used	O
at	O
1	O
:	O
1	O
,	O
000	O
dilution	O
for	O
western	O
blots	O
.	O

Flow	O
cytometric	O
analysis	O
of	O
MUC1	O
was	O
done	O
with	O
HMPV	O
-	O
FITC	O
,	O
which	O
recognizes	O
the	O
core	O
peptide	O
of	O
the	O
MUC1	O
-	O
EX	O
tandem	O
repeats	O
(	O
Pharmingen	O
,	O
San	O
Diego	O
,	O
CA	O
,	O
USA	O
)	O
.	O

Bromodeoxyuridine	O
(	O
BrdU	O
)	O
staining	O
was	O
performed	O
with	O
a	O
fluorescently	O
conjugated	O
antibody	O
to	O
BrdU	O
(	O
BrdU	O
-	O
PE	O
,	O
BD	O
Biosciences	O
,	O
San	O
Diego	O
,	O
CA	O
,	O
USA	O
)	O
as	O
described	O
below	O
.	O

Densitometry	O
was	O
performed	O
using	O
the	O
public	O
domain	O
ImageJ	O
program	O
(	O
developed	O
at	O
the	O
NIH	O
and	O
available	O
at	O
[	O
30	O
]	O
.	O

Each	O
band	O
was	O
measured	O
in	O
three	O
places	O
;	O
the	O
results	O
were	O
averaged	O
and	O
normalized	O
to	O
tubulin	O
to	O
control	O
for	O
loading	O
.	O

Transwell	O
invasion	O
assays	O

Cells	O
were	O
serum	O
-	O
starved	O
beginning	O
24	O
hours	O
post	O
-	O
siRNA	O
transfection	O
.	O

Cells	O
were	O
re	O
-	O
plated	O
in	O
serum	O
-	O
free	O
medium	O
48	O
hours	O
post	O
-	O
transfection	O
at	O
50	O
,	O
000	O
cells	O
per	O
insert	O
(	O
sized	O
for	O
24	O
-	O
well	O
plates	O
)	O
,	O
with	O
serum	O
-	O
containing	O
medium	O
in	O
the	O
bottom	O
of	O
the	O
growth	O
well	O
as	O
an	O
attractant	O
.	O

Transwell	O
inserts	O
(	O
BD	O
Biosciences	O
)	O
pre	O
-	O
coated	O
with	O
laminin	O
,	O
fibronectin	O
,	O
collagen	O
IV	O
,	O
or	O
control	O
(	O
no	O
matrix	O
)	O
were	O
used	O
,	O
and	O
cells	O
were	O
permitted	O
to	O
invade	O
for	O
48	O
hours	O
.	O

At	O
this	O
point	O
(	O
96	O
hours	O
post	O
-	O
transfection	O
)	O
,	O
visual	O
inspection	O
of	O
the	O
growth	O
wells	O
confirmed	O
that	O
negligible	O
numbers	O
of	O
cells	O
went	O
through	O
to	O
the	O
bottom	O
of	O
the	O
plate	O
.	O

Non	O
-	O
invaded	O
cells	O
were	O
swabbed	O
from	O
the	O
tops	O
of	O
half	O
of	O
the	O
inserts	O
(	O
'	O
samples	O
'	O
,	O
containing	O
only	O
invaded	O
cells	O
)	O
,	O
and	O
retained	O
in	O
the	O
others	O
(	O
'	O
controls	O
'	O
,	O
all	O
cells	O
)	O
.	O

Inserts	O
were	O
stained	O
for	O
10	O
minutes	O
with	O
crystal	O
violet	O
(	O
0	O
.	O
5	O
%	O
in	O
20	O
%	O
methanol	O
)	O
and	O
washed	O
with	O
water	O
.	O

Membranes	O
were	O
cut	O
out	O
and	O
destained	O
for	O
10	O
minutes	O
in	O
10	O
%	O
acetic	O
acid	O
in	O
a	O
96	O
-	O
well	O
plate	O
;	O
membranes	O
were	O
removed	O
and	O
absorbance	O
was	O
read	O
at	O
570	O
nm	O
.	O

Percent	O
invasion	O
is	O
defined	O
as	O
(	O
absorbance	O
of	O
samples	O
/	O
absorbance	O
of	O
controls	O
)	O
x	O
100	O
.	O

[	O
3H	O
]	O
Thymidine	O
incorporation	O
assays	O

Cells	O
were	O
re	O
-	O
plated	O
in	O
quadruplicate	O
24	O
hours	O
post	O
-	O
siRNA	O
transfection	O
at	O
15	O
,	O
000	O
cells	O
/	O
well	O
(	O
96	O
-	O
well	O
plate	O
)	O
with	O
[	O
3H	O
]	O
thymidine	O
(	O
1	O
mu	O
Ci	O
/	O
well	O
)	O
,	O
then	O
incubated	O
in	O
normal	O
conditions	O
for	O
24	O
hours	O
.	O

At	O
this	O
time	O
(	O
48	O
hours	O
post	O
-	O
siRNA	O
transfection	O
)	O
excess	O
radioactivity	O
was	O
washed	O
off	O
and	O
the	O
cells	O
were	O
harvested	O
and	O
read	O
on	O
a	O
TopCount	O
plate	O
reader	O
.	O

Statistical	O
analysis	O
was	O
performed	O
using	O
JMP	O
5	O
.	O
1	O
.	O
2	O
software	O
(	O
SAS	O
Institute	O
,	O
Inc	O
.	O
,	O
Cary	O
,	O
NC	O
,	O
USA	O
)	O
;	O
the	O
student	O
'	O
s	O
t	O
test	O
was	O
used	O
to	O
determine	O
p	O
values	O
and	O
significance	O
was	O
confirmed	O
with	O
Wilcoxon	O
rank	O
sum	O
and	O
Pearson	O
chi	O
squared	O
analyses	O
.	O

BrdU	O
incorporation	O

BrdU	O
(	O
50	O
mu	O
M	O
)	O
was	O
given	O
to	O
cells	O
48	O
hours	O
post	O
-	O
siRNA	O
transfection	O
and	O
permitted	O
to	O
incorporate	O
for	O
1	O
.	O
5	O
hours	O
.	O

Cells	O
were	O
then	O
washed	O
with	O
PBS	O
,	O
trypsinized	O
,	O
and	O
washed	O
again	O
.	O

BrdU	O
staining	O
was	O
performed	O
according	O
to	O
an	O
adaptation	O
of	O
the	O
manufacturer	O
'	O
s	O
protocol	O
:	O
cells	O
were	O
re	O
-	O
suspended	O
in	O
PBS	O
,	O
mixed	O
1	O
:	O
1	O
with	O
-	O
20	O
degrees	O
C	O
neat	O
ethanol	O
,	O
and	O
incubated	O
1	O
hour	O
at	O
-	O
20	O
degrees	O
C	O
to	O
fix	O
.	O

Fixed	O
cells	O
were	O
then	O
washed	O
gently	O
and	O
denatured	O
in	O
2	O
M	O
HCl	O
for	O
20	O
minutes	O
at	O
room	O
temperature	O
.	O

Following	O
washing	O
and	O
2	O
minute	O
'	O
s	O
incubation	O
with	O
0	O
.	O
1	O
M	O
Tris	O
to	O
neutralize	O
the	O
acid	O
,	O
cells	O
were	O
re	O
-	O
suspended	O
in	O
FACS	O
buffer	O
(	O
0	O
.	O
5	O
%	O
fetal	O
calf	B
serum	O
in	O
PBS	O
)	O
and	O
stained	O
with	O
Phycoerythrin	O
(	O
PE	O
)	O
-	O
conjugated	O
anti	O
-	O
BrdU	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
for	O
flow	O
cytometry	O
analysis	O
on	O
a	O
FACScan	O
instrument	O
.	O

Apoptosis	O
and	O
trypan	O
blue	O
staining	O

Apoptosis	O
was	O
measured	O
using	O
a	O
kit	O
(	O
BD	O
Biosciences	O
)	O
containing	O
propidium	O
iodide	O
(	O
PI	O
)	O
and	O
FITC	O
-	O
conjugated	O
annexin	O
V	O
.	O

Cells	O
were	O
stained	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
and	O
the	O
level	O
of	O
apoptosis	O
determined	O
by	O
flow	O
cytometry	O
.	O

Quadrants	O
are	O
:	O
early	O
apoptosis	O
(	O
annexin	O
V	O
+	O
/	O
PI	O
-	O
,	O
lower	O
right	O
)	O
late	O
apoptosis	O
(	O
annexin	O
V	O
+	O
/	O
PI	O
+	O
,	O
upper	O
right	O
)	O
and	O
non	O
-	O
apoptotic	O
cell	O
death	O
(	O
annexin	O
V	O
-	O
/	O
PI	O
+	O
,	O
upper	O
left	O
)	O
.	O

Treatments	O
for	O
the	O
stress	O
panel	O
were	O
:	O
no	O
treatment	O
(	O
control	O
)	O
;	O
DMSO	O
as	O
a	O
control	O
for	O
celecoxib	O
;	O
20	O
mM	O
celecoxib	O
,	O
brand	O
name	O
Celebrex	O
(	O
TM	O
)	O
(	O
dissolved	O
in	O
DMSO	O
)	O
[	O
31	O
]	O
;	O
0	O
.	O
2	O
mM	O
H2O2	O
[	O
32	O
]	O
;	O
or	O
1	O
mg	O
/	O
mL	O
G418	O
(	O
Pfizer	O
,	O
New	O
York	O
,	O
NY	O
,	O
USA	O
)	O
.	O

Real	O
-	O
time	O
PCR	O
arrays	O

Transcriptional	O
analysis	O
using	O
Cancer	O
PathwayFinder	O
RT2	O
profiler	O
arrays	O
(	O
SuperArray	O
,	O
Frederick	O
,	O
MD	O
,	O
USA	O
)	O
was	O
performed	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

Briefly	O
,	O
total	O
RNA	O
was	O
isolated	O
using	O
an	O
RNeasy	O
extraction	O
kit	O
(	O
Qiagen	O
,	O
Valencia	O
,	O
CA	O
,	O
USA	O
)	O
;	O
1	O
mu	O
g	O
of	O
RNA	O
was	O
reverse	O
transcribed	O
with	O
the	O
cDNA	O
synthesis	O
kit	O
(	O
SuperArray	O
)	O
and	O
cDNA	O
was	O
subjected	O
to	O
real	O
-	O
time	O
PCR	O
using	O
SYBR	O
green	O
to	O
detect	O
product	O
.	O

Arrays	O
were	O
performed	O
independently	O
at	O
least	O
twice	O
for	O
each	O
cell	O
line	O
;	O
all	O
PCR	O
products	O
were	O
checked	O
on	O
agarose	O
gels	O
.	O

Values	O
were	O
obtained	O
for	O
the	O
threshold	O
cycle	O
(	O
Ct	O
)	O
for	O
each	O
gene	O
and	O
normalized	O
using	O
the	O
average	O
of	O
four	O
housekeeping	O
genes	O
on	O
the	O
same	O
array	O
(	O
HPRT1	O
,	O
RPL13A	O
,	O
GAPD	O
,	O
ACTB	O
)	O
.	O

Ct	O
values	O
for	O
housekeeping	O
genes	O
and	O
a	O
dilution	O
series	O
of	O
ACTB	O
were	O
monitored	O
for	O
consistency	O
between	O
arrays	O
.	O

Change	O
(	O
Delta	O
Ct	O
)	O
between	O
MUC1	O
siRNA	O
and	O
control	O
siRNA	O
was	O
found	O
by	O
:	O

Delta	O
Ct	O
=	O
Ct	O
(	O
MUC1	O
siRNA	O
)	O
-	O
Ct	O
(	O
control	O
siRNA	O
)	O

and	O
fold	O
change	O
by	O
:	O

Fold	O
change	O
=	O
2	O
(	O
-	O
Delta	O
Ct	O
)	O

Values	O
are	O
given	O
as	O
fold	O
change	O
;	O
only	O
genes	O
showing	O
two	O
-	O
fold	O
or	O
greater	O
change	O
were	O
considered	O
.	O

Both	O
luciferase	O
and	O
scrambled	O
siRNA	O
controls	O
were	O
used	O
in	O
BT	O
-	O
20	O
;	O
only	O
genes	O
showing	O
consistent	O
alteration	O
with	O
both	O
controls	O
were	O
included	O
in	O
the	O
results	O
reported	O
here	O
.	O

The	O
scrambled	O
siRNA	O
could	O
be	O
not	O
used	O
in	O
MDA	O
-	O
MB	O
-	O
468	O
as	O
these	O
cells	O
decrease	O
MUC1	O
expression	O
in	O
response	O
to	O
this	O
construct	O
.	O

Results	O

siRNA	O
transfection	O
decreases	O
MUC1	O
expression	O
in	O
breast	O
cancer	O
cell	O
lines	O

Two	O
human	B
breast	O
cancer	O
cell	O
lines	O
,	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
,	O
were	O
transiently	O
transfected	O
with	O
a	O
pool	O
of	O
four	O
siRNA	O
oligonucleotides	O
directed	O
against	O
the	O
MUC1	O
mRNA	O
(	O
468	O
.	O
siMUC1	O
and	O
BT	O
.	O
siMUC1	O
)	O
,	O
or	O
a	O
control	O
oligonucleotide	O
directed	O
against	O
luciferase	O
(	O
468	O
.	O
siLuc	O
and	O
BT	O
.	O
siLuc	O
)	O
.	O

Both	O
cell	O
lines	O
express	O
high	O
levels	O
of	O
MUC1	O
,	O
making	O
them	O
promising	O
targets	O
for	O
this	O
analysis	O
.	O

Western	O
blots	O
(	O
Figure	O
1a	O
)	O
show	O
successful	O
knockdown	O
of	O
both	O
the	O
extracellular	O
domain	O
and	O
cytoplasmic	O
tail	O
fragments	O
of	O
MUC1	O
;	O
luciferase	O
siRNA	O
does	O
not	O
substantially	O
change	O
the	O
level	O
of	O
MUC1	O
compared	O
to	O
parental	O
cells	O
.	O

468	O
.	O
siMUC1	O
show	O
a	O
substantial	O
decrease	O
in	O
the	O
amount	O
of	O
MUC1	O
-	O
CT	O
,	O
while	O
BT	O
.	O
siMUC1	O
show	O
slightly	O
less	O
knockdown	O
of	O
MUC1	O
-	O
CT	O
.	O

Both	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
display	O
a	O
less	O
dramatic	O
decrease	O
of	O
MUC1	O
extracellular	O
domain	O
compared	O
to	O
MUC1	O
-	O
CT	O
(	O
Figure	O
1a	O
)	O
;	O
this	O
likely	O
represents	O
protein	O
synthesized	O
prior	O
to	O
transfection	O
,	O
and	O
may	O
reflect	O
differences	O
in	O
the	O
turnover	O
rates	O
of	O
the	O
two	O
subunits	O
.	O

Analysis	O
of	O
the	O
MUC1	O
extracellular	O
domain	O
by	O
flow	O
cytometry	O
confirms	O
that	O
both	O
cell	O
lines	O
substantially	O
decrease	O
MUC1	O
expression	O
after	O
siRNA	O
(	O
Figure	O
1b	O
)	O
.	O

By	O
flow	O
cytometry	O
,	O
468	O
.	O
siMUC1	O
averaged	O
75	O
%	O
knockdown	O
of	O
MUC1	O
compared	O
to	O
468	O
.	O
siLuc	O
;	O
and	O
BT	O
.	O
siMUC1	O
averaged	O
50	O
%	O
knockdown	O
relative	O
to	O
BT	O
.	O
siLuc	O
.	O

These	O
effects	O
could	O
be	O
titrated	O
with	O
the	O
concentration	O
of	O
siRNA	O
,	O
were	O
seen	O
as	O
early	O
as	O
24	O
hours	O
post	O
-	O
transfection	O
(	O
data	O
not	O
shown	O
)	O
and	O
lasted	O
to	O
at	O
least	O
96	O
h	O
post	O
-	O
transfection	O
(	O
Figure	O
1b	O
)	O
.	O

All	O
experiments	O
were	O
conducted	O
within	O
48	O
to	O
96	O
hours	O
after	O
siRNA	O
transfection	O
.	O

Similar	O
results	O
were	O
obtained	O
using	O
two	O
independent	O
oligonucleotides	O
designed	O
in	O
our	O
lab	O
(	O
data	O
not	O
shown	O
)	O
,	O
designated	O
'	O
882	O
'	O
and	O
'	O
956	O
'	O
for	O
the	O
initial	O
codon	O
recognized	O
by	O
each	O
.	O

Transcriptional	O
changes	O
are	O
seen	O
after	O
MUC1	O
siRNA	O

Recent	O
work	O
indicates	O
that	O
MUC1	O
may	O
affect	O
transcription	O
both	O
directly	O
via	O
interaction	O
with	O
transcription	O
factors	O
and	O
indirectly	O
(	O
for	O
example	O
,	O
through	O
modulating	O
signaling	O
)	O
.	O

To	O
study	O
the	O
effects	O
of	O
MUC1	O
knockdown	O
in	O
breast	O
cancer	O
cell	O
lines	O
,	O
real	O
-	O
time	O
PCR	O
arrays	O
were	O
used	O
to	O
analyze	O
transcription	O
of	O
84	O
genes	O
implicated	O
in	O
cancer	O
.	O

Only	O
genes	O
with	O
greater	O
than	O
two	O
-	O
fold	O
change	O
were	O
considered	O
.	O

Three	O
genes	O
(	O
MAP2K1	O
,	O
VEGF	O
,	O
PDGFA	O
)	O
were	O
altered	O
two	O
-	O
fold	O
or	O
more	O
after	O
MUC1	O
siRNA	O
in	O
both	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
cells	O
(	O
Figure	O
2	O
)	O
;	O
two	O
genes	O
(	O
ITGAV	O
,	O
MMP2	O
)	O
changed	O
only	O
in	O
468	O
.	O
siMUC1	O
;	O
and	O
five	O
genes	O
(	O
TIMP3	O
,	O
RAF1	O
,	O
JUN	O
,	O
TNF	O
,	O
CDC25A	O
)	O
only	O
in	O
BT	O
.	O
siMUC1	O
.	O

This	O
list	O
represents	O
all	O
genes	O
affected	O
greater	O
than	O
two	O
-	O
fold	O
after	O
MUC1	O
siRNA	O
,	O
rather	O
than	O
a	O
select	O
group	O
.	O

Three	O
genes	O
whose	O
transcription	O
was	O
changed	O
by	O
less	O
than	O
two	O
-	O
fold	O
are	O
shown	O
,	O
two	O
of	O
which	O
(	O
PDGFB	O
and	O
ITGB1	O
)	O
are	O
listed	O
because	O
they	O
relate	O
closely	O
to	O
genes	O
altered	O
by	O
two	O
-	O
fold	O
(	O
PDGFA	O
and	O
ITGAV	O
)	O
.	O

The	O
third	O
,	O
MYC	O
,	O
is	O
included	O
because	O
western	O
blots	O
confirmed	O
a	O
substantial	O
change	O
at	O
the	O
protein	O
level	O
(	O
Figure	O
3a	O
)	O
that	O
may	O
reflect	O
both	O
transcriptional	O
and	O
post	O
-	O
transcriptional	O
regulation	O
.	O

Interestingly	O
,	O
transcription	O
of	O
MAP2K1	O
was	O
decreased	O
in	O
both	O
cell	O
lines	O
after	O
MUC1	O
siRNA	O
.	O

This	O
gene	O
encodes	O
MEK1	O
,	O
one	O
of	O
the	O
primary	O
regulators	O
of	O
the	O
ERK1	O
/	O
2	O
MAPK	O
pathway	O
[	O
33	O
]	O
,	O
a	O
network	O
that	O
has	O
been	O
linked	O
several	O
times	O
to	O
MUC1	O
[	O
12	O
,	O
34	O
-	O
36	O
]	O
.	O

We	O
examined	O
MEK1	O
and	O
MEK2	O
levels	O
by	O
western	O
blot	O
to	O
confirm	O
decreased	O
protein	O
in	O
MUC1	O
siRNA	O
-	O
treated	O
cells	O
(	O
Figure	O
3a	O
)	O
,	O
and	O
found	O
that	O
not	O
only	O
were	O
total	O
MEK1	O
/	O
2	O
levels	O
lower	O
in	O
468	O
.	O
siMUC1	O
and	O
BT	O
.	O
siMUC1	O
compared	O
to	O
controls	O
(	O
0	O
.	O
48	O
and	O
0	O
.	O
68	O
relative	O
to	O
siLuc	O
,	O
respectively	O
)	O
,	O
but	O
so	O
were	O
the	O
basal	O
amounts	O
of	O
active	O
(	O
phosphorylated	O
)	O
MEK1	O
/	O
2	O
(	O
pMEK1	O
/	O
2	O
;	O
0	O
.	O
12	O
and	O
0	O
.	O
42	O
relative	O
to	O
siLuc	O
,	O
respectively	O
)	O
.	O

Both	O
468	O
.	O
siMUC1	O
and	O
BT	O
.	O
siMUC1	O
also	O
showed	O
reduced	O
activation	O
of	O
ERK1	O
/	O
2	O
(	O
dpERK1	O
/	O
2	O
;	O
0	O
.	O
21	O
and	O
0	O
.	O
27	O
relative	O
to	O
siLuc	O
,	O
respectively	O
)	O
,	O
as	O
would	O
be	O
expected	O
with	O
diminished	O
signaling	O
through	O
MEK1	O
/	O
2	O
;	O
total	O
ERK1	O
/	O
2	O
levels	O
remain	O
unchanged	O
.	O

As	O
both	O
lines	O
have	O
high	O
levels	O
of	O
EGFR	O
and	O
thus	O
activate	O
the	O
MEK	O
-	O
ERK	O
cascade	O
intensely	O
when	O
stimulated	O
with	O
EGF	O
[	O
37	O
]	O
,	O
siRNA	O
-	O
transfected	O
cells	O
were	O
treated	O
with	O
EGF	O
.	O

Notably	O
,	O
MUC1	O
siRNA	O
impairs	O
this	O
important	O
oncogenic	O
pathway	O
in	O
MDA	O
-	O
MB	O
-	O
468	O
cells	O
,	O
as	O
468	O
.	O
siMUC1	O
display	O
less	O
pMEK1	O
/	O
2	O
in	O
response	O
to	O
EGF	O
than	O
do	O
468	O
.	O
siLuc	O
(	O
Figure	O
3b	O
)	O
.	O

Interestingly	O
,	O
EGF	O
treatment	O
of	O
BT	O
-	O
20	O
cells	O
results	O
in	O
slightly	O
higher	O
pMEK1	O
/	O
2	O
levels	O
in	O
BT	O
.	O
siMUC1	O
compared	O
to	O
BT	O
.	O
siLuc	O
.	O

Though	O
this	O
result	O
seems	O
paradoxical	O
in	O
light	O
of	O
decreased	O
MAP2K1	O
transcription	O
in	O
BT	O
.	O
siMUC1	O
,	O
it	O
likely	O
results	O
from	O
differential	O
functions	O
of	O
Raf	O
isoforms	O
in	O
combination	O
with	O
the	O
increased	O
RAF1	O
transcription	O
(	O
Figure	O
2	O
)	O
and	O
protein	O
level	O
(	O
Figure	O
3a	O
)	O
in	O
these	O
cells	O
.	O

Specifically	O
,	O
B	O
-	O
Raf	O
is	O
thought	O
to	O
be	O
the	O
main	O
activator	O
of	O
MEK	O
under	O
normal	O
conditions	O
;	O
Raf	O
-	O
1	O
activates	O
MEK	O
in	O
response	O
to	O
stimulus	O
[	O
38	O
]	O
.	O

Thus	O
,	O
it	O
appears	O
that	O
basal	O
pMEK1	O
/	O
2	O
levels	O
are	O
not	O
greatly	O
affected	O
by	O
Raf	O
-	O
1	O
overexpression	O
in	O
BT	O
.	O
siMUC1	O
cells	O
,	O
likely	O
because	O
MEK	O
is	O
regulated	O
primarily	O
by	O
B	O
-	O
Raf	O
under	O
normal	O
growth	O
conditions	O
.	O

In	O
contrast	O
,	O
when	O
the	O
cells	O
are	O
stimulated	O
(	O
EGF	O
)	O
,	O
increased	O
Raf	O
-	O
1	O
levels	O
in	O
BT	O
.	O
siMUC1	O
leads	O
to	O
heightened	O
pMEK1	O
/	O
2	O
(	O
Figure	O
3b	O
)	O
.	O

MUC1	O
siRNA	O
increases	O
apoptosis	O
in	O
MDA	O
-	O
MB	O
-	O
468	O
but	O
not	O
BT	O
-	O
20	O

We	O
next	O
examined	O
whether	O
MUC1	O
knockdown	O
and	O
its	O
associated	O
transcriptional	O
alterations	O
would	O
affect	O
overall	O
cellular	O
events	O
.	O

As	O
several	O
of	O
the	O
genes	O
shown	O
in	O
Figure	O
2	O
are	O
important	O
in	O
regulating	O
proliferation	O
and	O
survival	O
,	O
and	O
because	O
of	O
the	O
recently	O
described	O
role	O
of	O
MUC1	O
in	O
modulating	O
apoptosis	O
in	O
response	O
to	O
cellular	O
stresses	O
[	O
20	O
,	O
21	O
,	O
24	O
]	O
,	O
we	O
first	O
analyzed	O
whether	O
MUC1	O
siRNA	O
would	O
alter	O
apoptosis	O
in	O
these	O
lines	O
.	O

Although	O
there	O
was	O
no	O
change	O
in	O
basal	O
apoptosis	O
in	O
either	O
line	O
(	O
Figure	O
4a	O
)	O
,	O
we	O
observed	O
that	O
the	O
cell	O
lines	O
responded	O
differently	O
when	O
trypsinized	O
for	O
re	O
-	O
plating	O
24	O
hours	O
after	O
transfection	O
(	O
Figure	O
4b	O
)	O
.	O

Interestingly	O
,	O
468	O
.	O
siMUC1	O
cells	O
show	O
greater	O
apoptosis	O
after	O
trypsinization	O
than	O
do	O
468	O
.	O
siLuc	O
(	O
49	O
.	O
8	O
%	O
versus	O
34	O
.	O
0	O
%	O
,	O
respectively	O
)	O
,	O
while	O
BT	O
-	O
20	O
cells	O
from	O
both	O
siRNA	O
treatments	O
display	O
similar	O
levels	O
of	O
apoptosis	O
(	O
around	O
22	O
%	O
)	O
.	O

To	O
examine	O
whether	O
this	O
phenomenon	O
is	O
specific	O
to	O
trypsin	O
treatment	O
or	O
part	O
of	O
a	O
general	O
stress	O
response	O
involving	O
MUC1	O
,	O
we	O
subjected	O
cells	O
to	O
a	O
panel	O
of	O
stresses	O
and	O
measured	O
cell	O
death	O
.	O

In	O
agreement	O
with	O
the	O
patterns	O
seen	O
with	O
trypsinization	O
,	O
BT	O
.	O
siLuc	O
and	O
BT	O
.	O
siMUC1	O
respond	O
similarly	O
to	O
all	O
treatments	O
(	O
data	O
not	O
shown	O
)	O
,	O
while	O
468	O
.	O
siMUC1	O
die	O
more	O
readily	O
than	O
468	O
.	O
siLuc	O
in	O
response	O
to	O
trypsin	O
,	O
G418	O
,	O
hydrogen	O
peroxide	O
,	O
or	O
celecoxib	O
,	O
a	O
chemotherapeutic	O
that	O
targets	O
the	O
cyclooxygenase	O
-	O
2	O
(	O
COX	O
-	O
2	O
)	O
pathway	O
(	O
Figure	O
4c	O
)	O
;	O
these	O
data	O
were	O
confirmed	O
with	O
two	O
independent	O
siRNA	O
constructs	O
(	O
data	O
not	O
shown	O
)	O
.	O

Like	O
the	O
MAPK	O
pathway	O
,	O
AKT	O
signaling	O
has	O
been	O
linked	O
to	O
MUC1	O
in	O
cancer	O
.	O

Although	O
transcription	O
of	O
AKT	O
was	O
not	O
altered	O
in	O
MUC1	O
siRNA	O
-	O
treated	O
cells	O
,	O
the	O
results	O
of	O
our	O
apoptosis	O
studies	O
prompted	O
us	O
to	O
investigate	O
levels	O
of	O
AKT	O
further	O
.	O

As	O
expected	O
,	O
the	O
total	O
AKT	O
protein	O
level	O
is	O
not	O
greatly	O
changed	O
after	O
MUC1	O
siRNA	O
in	O
either	O
cell	O
line	O
,	O
though	O
the	O
active	O
form	O
(	O
pAKT	O
)	O
is	O
increased	O
in	O
both	O
468	O
.	O
siMUC1	O
and	O
BT	O
.	O
siMUC1	O
compared	O
to	O
controls	O
(	O
Figure	O
3a	O
)	O
.	O

This	O
result	O
disagrees	O
with	O
MUC1	O
activation	O
of	O
the	O
AKT	O
pathway	O
in	O
rat	B
3Y1	O
cells	O
[	O
18	O
]	O
,	O
and	O
may	O
reflect	O
regulation	O
more	O
appropriate	O
to	O
breast	O
cancer	O
cells	O
;	O
this	O
is	O
supported	O
by	O
activation	O
of	O
AKT	O
in	O
response	O
to	O
MUC1	O
siRNA	O
in	O
other	O
lines	O
[	O
21	O
]	O
.	O

In	O
addition	O
,	O
there	O
is	O
a	O
striking	O
difference	O
in	O
the	O
relative	O
amounts	O
of	O
AKT	O
and	O
pAKT	O
in	O
the	O
two	O
cell	O
lines	O
(	O
Figure	O
4d	O
)	O
.	O

When	O
lysates	O
from	O
both	O
lines	O
are	O
exposed	O
to	O
film	O
for	O
the	O
same	O
length	O
of	O
time	O
(	O
overexposure	O
masks	O
the	O
differences	O
between	O
BT	O
.	O
siLuc	O
and	O
BT	O
.	O
siMUC1	O
that	O
are	O
apparent	O
in	O
Figure	O
3a	O
)	O
,	O
it	O
is	O
clear	O
that	O
pAKT	O
levels	O
are	O
much	O
higher	O
in	O
BT	O
-	O
20	O
than	O
in	O
MDA	O
-	O
MB	O
-	O
468	O
,	O
despite	O
lower	O
total	O
AKT	O
expression	O
.	O

This	O
difference	O
in	O
AKT	O
activation	O
between	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
likely	O
contributes	O
to	O
the	O
disparity	O
in	O
their	O
sensitivity	O
to	O
the	O
increased	O
apoptosis	O
expected	O
with	O
loss	O
of	O
MUC1	O
.	O

MUC1	O
siRNA	O
alters	O
proliferation	O
and	O
invasion	O

As	O
MUC1	O
is	O
involved	O
in	O
apoptosis	O
,	O
we	O
next	O
analyzed	O
its	O
effects	O
on	O
proliferation	O
.	O

BrdU	O
and	O
[	O
3H	O
]	O
thymidine	O
incorporation	O
were	O
used	O
to	O
analyze	O
proliferation	O
after	O
MUC1	O
siRNA	O
.	O

468	O
.	O
siMUC1	O
cells	O
show	O
a	O
significant	O
decrease	O
in	O
[	O
3H	O
]	O
thymidine	O
incorporation	O
compared	O
to	O
468	O
.	O
siLuc	O
,	O
while	O
intriguingly	O
,	O
BT	O
.	O
siMUC1	O
cells	O
show	O
a	O
significant	O
increase	O
in	O
proliferation	O
(	O
Figure	O
5a	O
)	O
.	O

Growth	O
curves	O
mirror	O
these	O
results	O
,	O
as	O
do	O
experiments	O
with	O
the	O
two	O
independent	O
MUC1	O
siRNA	O
oligonucleotides	O
(	O
data	O
not	O
shown	O
)	O
.	O

Note	O
that	O
these	O
assays	O
require	O
trypsinizing	O
cells	O
24	O
hours	O
post	O
-	O
transfection	O
;	O
therefore	O
,	O
the	O
results	O
in	O
the	O
MDA	O
-	O
MB	O
-	O
468	O
line	O
could	O
stem	O
from	O
the	O
changes	O
in	O
apoptosis	O
described	O
in	O
the	O
previous	O
section	O
,	O
rather	O
than	O
a	O
true	O
effect	O
on	O
proliferation	O
.	O

To	O
control	O
for	O
this	O
,	O
we	O
incubated	O
non	O
-	O
trypsinized	O
,	O
siRNA	O
-	O
transfected	O
cells	O
at	O
similar	O
confluence	O
with	O
BrdU	O
to	O
measure	O
incorporation	O
.	O

The	O
'	O
clumped	O
'	O
profile	O
of	O
cells	O
(	O
contrast	O
to	O
Figure	O
4b	O
)	O
is	O
likely	O
a	O
result	O
of	O
the	O
acid	O
denaturation	O
(	O
recommended	O
by	O
the	O
antibody	O
manufacturer	O
)	O
,	O
as	O
it	O
occurs	O
uniformly	O
in	O
these	O
experiments	O
.	O

BrdU	O
incorporation	O
(	O
Figure	O
5b	O
)	O
confirms	O
that	O
the	O
[	O
3H	O
]	O
thymidine	O
results	O
are	O
not	O
solely	O
due	O
to	O
alterations	O
in	O
apoptosis	O
,	O
as	O
468	O
.	O
siMUC1	O
cells	O
incorporate	O
less	O
BrdU	O
than	O
468	O
.	O
siLuc	O
;	O
once	O
again	O
,	O
BT	O
.	O
siMUC1	O
cells	O
show	O
increased	O
proliferation	O
over	O
BT	O
.	O
siLuc	O
.	O

Given	O
the	O
role	O
of	O
MUC1	O
in	O
adhesion	O
,	O
we	O
examined	O
whether	O
MUC1	O
siRNA	O
affects	O
cellular	O
invasion	O
.	O

In	O
transwell	O
assays	O
,	O
BT	O
-	O
20	O
cells	O
invaded	O
poorly	O
,	O
regardless	O
of	O
the	O
siRNA	O
used	O
(	O
data	O
not	O
shown	O
)	O
.	O

However	O
,	O
MDA	O
-	O
MB	O
-	O
468	O
cells	O
invade	O
more	O
readily	O
,	O
and	O
were	O
analyzed	O
on	O
a	O
panel	O
of	O
three	O
different	O
extracellular	O
matrix	O
proteins	O
.	O

Interestingly	O
,	O
468	O
.	O
siMUC1	O
cells	O
display	O
somewhat	O
decreased	O
invasion	O
on	O
collagen	O
IV	O
,	O
laminin	O
,	O
and	O
fibronectin	O
matrices	O
,	O
and	O
on	O
a	O
no	O
-	O
matrix	O
control	O
(	O
Figure	O
5c	O
)	O
,	O
which	O
is	O
in	O
agreement	O
with	O
the	O
trend	O
towards	O
decreased	O
metastasis	O
observed	O
in	O
Muc1	O
-	O
/	O
-	O
x	O
MMTV	B
-	O
PyV	O
MT	O
mice	B
[	O
8	O
]	O
.	O

Transfection	O
of	O
MUC1	O
rescues	O
the	O
468	O
.	O
siMUC1	O
phenotype	O

To	O
determine	O
if	O
the	O
above	O
effects	O
are	O
specific	O
to	O
MUC1	O
,	O
we	O
created	O
stable	O
transfectants	O
of	O
the	O
MDA	O
-	O
MB	O
-	O
468	O
line	O
using	O
empty	O
vector	O
(	O
468	O
.	O
Neo	O
)	O
or	O
a	O
full	O
-	O
length	O
MUC1	O
construct	O
(	O
468	O
.	O
MUC1	O
Delta	O
8	O
)	O
that	O
is	O
resistant	O
to	O
one	O
of	O
the	O
independent	O
MUC1	O
-	O
directed	O
oligonucleotides	O
(	O
'	O
882	O
'	O
)	O
.	O

These	O
cells	O
were	O
maintained	O
in	O
G418	O
-	O
containing	O
medium	O
to	O
retain	O
transgene	O
selection	O
.	O

As	O
expected	O
,	O
468	O
.	O
MUC1	O
Delta	O
8	O
cells	O
show	O
higher	O
levels	O
of	O
both	O
the	O
MUC1	O
extracellular	O
domain	O
and	O
the	O
MUC1	O
-	O
CT	O
than	O
do	O
468	O
.	O
Neo	O
(	O
Figure	O
6a	O
)	O
.	O

Note	O
that	O
468	O
.	O
Neo	O
have	O
MUC1	O
expression	O
comparable	O
to	O
parental	O
MDA	O
-	O
MB	O
-	O
468	O
;	O
the	O
exposures	O
in	O
Figure	O
6a	O
are	O
lighter	O
than	O
those	O
in	O
Figure	O
1a	O
,	O
in	O
order	O
to	O
clearly	O
show	O
the	O
relative	O
levels	O
of	O
MUC1	O
in	O
the	O
stable	O
transfectants	O
.	O

After	O
MUC1	O
siRNA	O
,	O
468	O
.	O
MUC1	O
Delta	O
8	O
lose	O
some	O
MUC1	O
(	O
likely	O
endogenous	O
protein	O
,	O
which	O
is	O
not	O
siRNA	O
-	O
resistant	O
)	O
but	O
retain	O
high	O
-	O
level	O
expression	O
,	O
while	O
468	O
.	O
Neo	O
show	O
a	O
decrease	O
in	O
MUC1	O
levels	O
similar	O
to	O
parental	O
468	O
.	O
siMUC1	O
cells	O
(	O
Figures	O
6a	O
,	O
b	O
)	O
.	O

The	O
difference	O
in	O
the	O
amount	O
of	O
MUC1	O
knockdown	O
between	O
468	O
.	O
Neo	O
and	O
468	O
.	O
MUC1	O
Delta	O
8	O
is	O
highlighted	O
by	O
the	O
purple	O
shading	O
in	O
Figure	O
6b	O
.	O

BrdU	O
incorporation	O
(	O
Figure	O
6c	O
)	O
indicates	O
that	O
468	O
.	O
Neo	O
show	O
decreased	O
nucleotide	O
incorporation	O
after	O
MUC1	O
siRNA	O
compared	O
to	O
control	O
(	O
3	O
.	O
3	O
%	O
versus	O
25	O
.	O
0	O
%	O
,	O
respectively	O
)	O
;	O
this	O
is	O
not	O
seen	O
in	O
468	O
.	O
MUC1	O
Delta	O
8	O
cells	O
,	O
which	O
show	O
similar	O
levels	O
of	O
BrdU	O
incorporation	O
regardless	O
of	O
the	O
siRNA	O
used	O
(	O
21	O
.	O
5	O
%	O
for	O
luciferase	O
,	O
23	O
.	O
9	O
%	O
for	O
MUC1	O
)	O
.	O

468	O
.	O
Neo	O
cells	O
display	O
a	O
more	O
dramatic	O
decrease	O
in	O
BrdU	O
incorporation	O
after	O
MUC1	O
siRNA	O
than	O
what	O
is	O
seen	O
in	O
parental	O
468	O
.	O
siMUC1	O
cells	O
,	O
which	O
may	O
reflect	O
the	O
additional	O
stress	O
of	O
being	O
maintained	O
in	O
G418	O
-	O
containing	O
medium	O
.	O

Similarly	O
,	O
analysis	O
of	O
apoptosis	O
in	O
trypsinized	O
cells	O
indicates	O
that	O
the	O
increased	O
apoptosis	O
seen	O
in	O
parental	O
468	O
.	O
siMUC1	O
cells	O
is	O
also	O
present	O
in	O
the	O
468	O
.	O
Neo	O
line	O
after	O
MUC1	O
siRNA	O
(	O
Figure	O
6d	O
;	O
43	O
.	O
6	O
%	O
in	O
control	O
versus	O
59	O
.	O
6	O
%	O
in	O
MUC1	O
siRNA	O
)	O
.	O

However	O
,	O
in	O
468	O
.	O
MUC1	O
Delta	O
8	O
cells	O
,	O
the	O
level	O
of	O
apoptosis	O
after	O
luciferase	O
siRNA	O
(	O
34	O
.	O
1	O
%	O
)	O
is	O
lower	O
than	O
that	O
in	O
468	O
.	O
Neo	O
cells	O
;	O
MUC1	O
siRNA	O
increases	O
the	O
amount	O
of	O
apoptosis	O
slightly	O
(	O
42	O
.	O
8	O
%	O
)	O
,	O
restoring	O
it	O
to	O
a	O
level	O
similar	O
to	O
that	O
seen	O
in	O
luciferase	O
siRNA	O
-	O
treated	O
468	O
.	O
Neo	O
cells	O
.	O

Together	O
,	O
these	O
studies	O
suggest	O
that	O
the	O
above	O
-	O
described	O
results	O
are	O
specific	O
to	O
MUC1	O
,	O
as	O
stable	O
transfection	O
of	O
an	O
siRNA	O
-	O
resistant	O
MUC1	O
rescues	O
the	O
phenotype	O
seen	O
in	O
468	O
.	O
siMUC1	O
cells	O
.	O

Discussion	O

This	O
report	O
describes	O
both	O
the	O
transcriptional	O
alterations	O
seen	O
after	O
transfection	O
with	O
MUC1	O
siRNA	O
in	O
human	B
breast	O
cancer	O
cells	O
and	O
the	O
effects	O
on	O
events	O
such	O
as	O
apoptosis	O
and	O
proliferation	O
.	O

The	O
two	O
cell	O
lines	O
used	O
(	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
)	O
were	O
chosen	O
for	O
high	O
expression	O
of	O
MUC1	O
and	O
a	O
substantial	O
(	O
50	O
%	O
to	O
75	O
%	O
)	O
,	O
consistent	O
decrease	O
in	O
MUC1	O
expression	O
after	O
siRNA	O
.	O

Both	O
lines	O
have	O
epithelial	O
morphology	O
,	O
form	O
tumors	O
slowly	O
in	O
nude	B
mice	I
[	O
37	O
]	O
,	O
have	O
mutant	O
p53	O
[	O
39	O
,	O
40	O
]	O
,	O
express	O
EGFR	O
[	O
37	O
]	O
,	O
and	O
lack	O
estrogen	O
receptor	O
alpha	O
[	O
41	O
]	O
.	O

One	O
striking	O
difference	O
between	O
these	O
lines	O
,	O
however	O
,	O
is	O
their	O
response	O
to	O
MUC1	O
siRNA	O
.	O

MDA	O
-	O
MB	O
-	O
468	O
cells	O
behave	O
as	O
expected	O
for	O
loss	O
of	O
an	O
oncogene	O
:	O
MUC1	O
siRNA	O
correlates	O
with	O
increased	O
apoptosis	O
in	O
response	O
to	O
stress	O
,	O
decreased	O
proliferation	O
,	O
and	O
reduced	O
invasion	O
.	O

In	O
contrast	O
,	O
BT	O
.	O
siMUC1	O
cells	O
proliferate	O
more	O
rapidly	O
than	O
BT	O
.	O
siLuc	O
cells	O
with	O
little	O
effect	O
on	O
apoptosis	O
.	O

Much	O
of	O
the	O
phenotype	O
of	O
these	O
cells	O
can	O
be	O
understood	O
in	O
light	O
of	O
protein	O
levels	O
and	O
transcriptional	O
activity	O
after	O
MUC1	O
siRNA	O
.	O

As	O
mentioned	O
,	O
both	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
display	O
increased	O
pAKT	O
after	O
MUC1	O
siRNA	O
,	O
but	O
the	O
ratio	O
of	O
active	O
to	O
total	O
AKT	O
is	O
considerably	O
higher	O
in	O
the	O
BT	O
-	O
20	O
line	O
,	O
which	O
may	O
help	O
these	O
cells	O
resist	O
the	O
increased	O
apoptosis	O
expected	O
with	O
loss	O
of	O
MUC1	O
.	O

Myc	O
levels	O
are	O
also	O
higher	O
in	O
both	O
cell	O
lines	O
after	O
MUC1	O
siRNA	O
,	O
although	O
the	O
ability	O
of	O
Myc	O
to	O
promote	O
proliferation	O
and	O
apoptosis	O
in	O
different	O
cellular	O
contexts	O
[	O
42	O
]	O
complicates	O
the	O
interpretation	O
of	O
this	O
finding	O
.	O

Both	O
cell	O
lines	O
show	O
reduced	O
transcription	O
of	O
VEGF	O
,	O
PDGFA	O
,	O
PDGFB	O
,	O
and	O
MAP2K1	O
(	O
MEK1	O
)	O
after	O
MUC1	O
siRNA	O
.	O

The	O
genes	O
encoding	O
vascular	O
endothelial	O
growth	O
factor	O
(	O
VEGF	O
)	O
and	O
the	O
A	O
and	O
B	O
chains	O
of	O
platelet	O
-	O
derived	O
growth	O
factor	O
(	O
PDGF	O
-	O
A	O
and	O
PDGF	O
-	O
B	O
)	O
are	O
interesting	O
as	O
these	O
proteins	O
have	O
been	O
heavily	O
implicated	O
in	O
angiogenesis	O
,	O
suggesting	O
a	O
novel	O
function	O
for	O
MUC1	O
in	O
regulating	O
this	O
process	O
.	O

Vascular	O
endothelial	O
growth	O
factor	O
expression	O
in	O
cancer	O
is	O
linked	O
to	O
tumor	O
growth	O
and	O
metastasis	O
[	O
43	O
,	O
44	O
]	O
;	O
platelet	O
-	O
derived	O
growth	O
factor	O
is	O
also	O
angiogenic	O
,	O
but	O
has	O
an	O
additional	O
role	O
in	O
stimulating	O
desmoplasia	O
[	O
45	O
]	O
.	O

Reduced	O
transcription	O
of	O
these	O
genes	O
after	O
MUC1	O
siRNA	O
suggests	O
that	O
MUC1	O
may	O
foster	O
angiogenesis	O
and	O
stromal	O
proliferation	O
,	O
although	O
this	O
must	O
be	O
confirmed	O
in	O
a	O
more	O
appropriate	O
model	O
system	O
.	O

Decreased	O
MAP2K1	O
(	O
MEK1	O
)	O
transcription	O
after	O
MUC1	O
siRNA	O
provides	O
a	O
novel	O
mechanism	O
by	O
which	O
MUC1	O
can	O
affect	O
the	O
ERK1	O
/	O
2	O
MAPK	O
pathway	O
.	O

MUC1	O
has	O
often	O
been	O
linked	O
to	O
the	O
Ras	O
-	O
Raf	O
-	O
MEK	O
-	O
ERK	O
cascade	O
[	O
12	O
,	O
34	O
-	O
36	O
,	O
46	O
]	O
,	O
and	O
at	O
least	O
two	O
mechanisms	O
by	O
which	O
MUC1	O
can	O
alter	O
MAPK	O
signaling	O
have	O
been	O
described	O
:	O
MUC1	O
interaction	O
with	O
and	O
phosphorylation	O
by	O
the	O
EGFR	O
family	O
[	O
12	O
,	O
13	O
]	O
,	O
and	O
MUC1	O
binding	O
to	O
the	O
Grb2	O
/	O
Sos	O
complex	O
that	O
activates	O
Ras	O
[	O
46	O
]	O
.	O

Reduction	O
of	O
MEK1	O
levels	O
after	O
MUC1	O
siRNA	O
agrees	O
with	O
the	O
role	O
of	O
MUC1	O
in	O
strengthening	O
MAPK	O
signaling	O
,	O
and	O
indicates	O
that	O
MUC1	O
can	O
regulate	O
both	O
the	O
transcription	O
and	O
activity	O
of	O
members	O
of	O
this	O
pathway	O
.	O

Two	O
additional	O
MAPK	O
pathway	O
members	O
are	O
altered	O
specifically	O
in	O
BT	O
.	O
siMUC1	O
,	O
with	O
no	O
corresponding	O
change	O
in	O
468	O
.	O
siMUC1	O
cells	O
.	O

These	O
genes	O
are	O
RAF1	O
and	O
JUN	O
which	O
are	O
increased	O
and	O
decreased	O
,	O
respectively	O
,	O
after	O
MUC1	O
siRNA	O
.	O

Raf	O
-	O
1	O
and	O
c	O
-	O
Jun	O
both	O
function	O
outside	O
of	O
the	O
ERK1	O
/	O
2	O
MAPK	O
pathway	O
,	O
which	O
may	O
explain	O
the	O
seeming	O
paradox	O
of	O
increased	O
RAF1	O
transcription	O
with	O
simultaneous	O
decreases	O
in	O
MAP2K1	O
and	O
JUN	O
.	O

Specifically	O
,	O
Raf	O
-	O
1	O
can	O
inhibit	O
ASK1	O
(	O
apoptosis	O
signal	O
-	O
regulated	O
kinase	O
1	O
)	O
upstream	O
of	O
p38	O
and	O
JNK	O
(	O
Jun	O
N	O
-	O
terminal	O
kinase	O
)	O
[	O
38	O
]	O
.	O

ASK1	O
phosphorylates	O
JNK	O
in	O
response	O
to	O
stress	O
,	O
resulting	O
in	O
activation	O
of	O
c	O
-	O
Jun	O
and	O
stimulation	O
of	O
apoptosis	O
[	O
47	O
]	O
,	O
indicating	O
that	O
the	O
coordinate	O
up	O
-	O
regulation	O
of	O
RAF1	O
and	O
down	O
-	O
regulation	O
of	O
JUN	O
may	O
provide	O
a	O
potent	O
anti	O
-	O
apoptotic	O
effect	O
in	O
BT	O
.	O
siMUC1	O
.	O

Regulation	O
of	O
life	O
and	O
death	O
is	O
also	O
a	O
hallmark	O
of	O
the	O
CDC25A	O
and	O
TNF	O
gene	O
products	O
.	O

CDC25A	O
is	O
a	O
phosphatase	O
that	O
stimulates	O
cell	O
cycle	O
progression	O
[	O
48	O
]	O
,	O
thus	O
the	O
effects	O
of	O
its	O
decrease	O
in	O
BT	O
.	O
siMUC1	O
are	O
unclear	O
in	O
light	O
of	O
the	O
increased	O
proliferation	O
of	O
these	O
cells	O
.	O

However	O
,	O
the	O
CDC25	O
proteins	O
(	O
A	O
,	O
B	O
,	O
and	O
C	O
)	O
were	O
recently	O
shown	O
to	O
have	O
greater	O
functional	O
overlap	O
than	O
was	O
previously	O
thought	O
[	O
49	O
]	O
,	O
suggesting	O
that	O
the	O
other	O
two	O
isoforms	O
may	O
compensate	O
for	O
reduced	O
CDC25A	O
levels	O
.	O

TNF	O
encodes	O
tumor	O
necrosis	O
factor	O
(	O
TNF	O
)	O
alpha	O
,	O
known	O
for	O
its	O
potent	O
,	O
cell	O
type	O
-	O
specific	O
control	O
of	O
life	O
and	O
death	O
.	O

In	O
tumor	O
cells	O
,	O
TNF	O
alpha	O
expression	O
can	O
promote	O
proliferation	O
and	O
inhibit	O
apoptosis	O
[	O
50	O
]	O
,	O
suggesting	O
that	O
increased	O
TNF	O
transcription	O
in	O
BT	O
.	O
siMUC1	O
could	O
contribute	O
to	O
the	O
increased	O
proliferation	O
seen	O
in	O
these	O
cells	O
.	O

Interestingly	O
,	O
the	O
increase	O
in	O
TNF	O
is	O
accompanied	O
by	O
decreased	O
transcription	O
of	O
TIMP3	O
,	O
encoding	O
tissue	O
inhibitor	O
of	O
metalloproteinases	O
(	O
TIMP	O
)	O
3	O
.	O

The	O
TIMP	O
family	O
disrupts	O
the	O
function	O
of	O
matrix	O
metalloproteinases	O
(	O
MMPs	O
)	O
,	O
generally	O
resulting	O
in	O
decreased	O
invasion	O
[	O
51	O
]	O
.	O

TIMP3	O
is	O
unique	O
in	O
that	O
it	O
can	O
also	O
inhibit	O
TNF	O
alpha	O
converting	O
enzyme	O
(	O
TACE	O
)	O
,	O
which	O
activates	O
TNF	O
alpha	O
by	O
cleaving	O
it	O
from	O
the	O
cell	O
surface	O
[	O
50	O
]	O
.	O

Reduced	O
expression	O
of	O
TIMP3	O
would	O
,	O
therefore	O
,	O
foster	O
signaling	O
through	O
TNF	O
alpha	O
by	O
releasing	O
inhibition	O
of	O
TNF	O
alpha	O
converting	O
enzyme	O
.	O

In	O
agreement	O
with	O
this	O
,	O
TIMP3	O
can	O
promote	O
apoptosis	O
[	O
52	O
]	O
;	O
thus	O
,	O
its	O
down	O
-	O
regulation	O
in	O
BT	O
.	O
siMUC1	O
provides	O
another	O
mechanism	O
by	O
which	O
these	O
cells	O
are	O
able	O
to	O
resist	O
the	O
increased	O
apoptosis	O
expected	O
with	O
loss	O
of	O
MUC1	O
.	O

Another	O
TIMP	O
target	O
responds	O
to	O
MUC1	O
siRNA	O
,	O
as	O
468	O
.	O
siMUC1	O
cells	O
show	O
significantly	O
increased	O
expression	O
of	O
MMP2	O
(	O
encoding	O
MMP	O
-	O
2	O
/	O
gelatinase	O
A	O
)	O
,	O
the	O
product	O
of	O
which	O
degrades	O
type	O
IV	O
collagen	O
[	O
52	O
]	O
.	O

In	O
breast	O
cancer	O
,	O
the	O
ratio	O
of	O
active	O
to	O
latent	O
MMP	O
-	O
2	O
increases	O
with	O
tumor	O
progression	O
;	O
MMP	O
-	O
2	O
may	O
facilitate	O
both	O
angiogenesis	O
and	O
metastasis	O
[	O
52	O
]	O
.	O

Its	O
increase	O
after	O
loss	O
of	O
MUC1	O
is	O
,	O
therefore	O
,	O
unexpected	O
,	O
but	O
at	O
least	O
two	O
factors	O
may	O
clarify	O
this	O
result	O
.	O

First	O
,	O
though	O
MMP	O
-	O
2	O
levels	O
are	O
increased	O
in	O
mouse	B
mammary	O
tumors	O
,	O
its	O
expression	O
is	O
confined	O
to	O
the	O
stroma	O
[	O
53	O
]	O
,	O
suggesting	O
that	O
increased	O
MMP2	O
transcription	O
after	O
loss	O
of	O
the	O
epithelium	O
-	O
specific	O
MUC1	O
might	O
reflect	O
a	O
shift	O
towards	O
a	O
more	O
mesenchymal	O
phenotype	O
.	O

Second	O
,	O
MMP	O
-	O
2	O
levels	O
are	O
increased	O
by	O
overexpression	O
of	O
erbB2	O
[	O
52	O
]	O
;	O
previous	O
studies	O
have	O
shown	O
that	O
erbB2	O
and	O
Muc1	O
expression	O
are	O
mutually	O
exclusive	O
in	O
mammary	O
tumors	O
[	O
27	O
]	O
,	O
implying	O
that	O
MMP2	O
might	O
be	O
part	O
of	O
a	O
transcriptional	O
profile	O
linked	O
to	O
low	O
MUC1	O
levels	O
.	O

It	O
is	O
intriguing	O
that	O
,	O
despite	O
increased	O
MMP2	O
transcription	O
,	O
invasion	O
is	O
decreased	O
in	O
468	O
.	O
siMUC1	O
cells	O
,	O
even	O
on	O
collagen	O
IV	O
.	O

This	O
may	O
reflect	O
insufficient	O
activation	O
of	O
MMP	O
-	O
2	O
,	O
as	O
the	O
precursor	O
protein	O
must	O
be	O
cleaved	O
for	O
enzymatic	O
function	O
[	O
52	O
]	O
.	O

Alternatively	O
,	O
the	O
slowed	O
invasion	O
of	O
these	O
cells	O
may	O
relate	O
to	O
impaired	O
adhesion	O
resulting	O
from	O
decreased	O
transcription	O
of	O
ITGAV	O
and	O
ITGB1	O
(	O
alpha	O
v	O
and	O
beta	O
1	O
integrins	O
,	O
respectively	O
)	O
.	O

Integrin	O
signaling	O
is	O
tied	O
to	O
life	O
-	O
or	O
-	O
death	O
decisions	O
in	O
epithelial	O
cells	O
,	O
and	O
integrin	O
expression	O
is	O
vital	O
for	O
processes	O
from	O
wound	O
healing	O
to	O
metastasis	O
[	O
54	O
]	O
.	O

Integrin	O
alpha	O
v	O
beta	O
3	O
is	O
implicated	O
in	O
facilitating	O
metastasis	O
of	O
breast	O
cancer	O
cells	O
to	O
bone	O
[	O
55	O
]	O
;	O
decreased	O
transcription	O
of	O
ITGAV	O
after	O
MUC1	O
siRNA	O
may	O
,	O
therefore	O
,	O
suggest	O
that	O
MUC1	O
is	O
involved	O
in	O
this	O
lethal	O
process	O
as	O
well	O
.	O

The	O
MUC1	O
oncogene	O
has	O
been	O
linked	O
to	O
apoptosis	O
[	O
18	O
,	O
20	O
,	O
26	O
]	O
,	O
proliferation	O
[	O
17	O
]	O
,	O
and	O
transcription	O
[	O
21	O
,	O
23	O
-	O
25	O
]	O
in	O
cancer	O
.	O

However	O
,	O
the	O
two	O
cell	O
lines	O
chosen	O
for	O
our	O
study	O
display	O
very	O
different	O
responses	O
to	O
MUC1	O
siRNA	O
,	O
indicating	O
that	O
regulation	O
of	O
MUC1	O
in	O
breast	O
cancer	O
is	O
likely	O
quite	O
complex	O
and	O
cautioning	O
against	O
over	O
-	O
generalization	O
of	O
results	O
from	O
individual	O
cell	O
lines	O
.	O

Previous	O
reports	O
suggest	O
that	O
,	O
though	O
most	O
studies	O
outline	O
a	O
clearly	O
oncogenic	O
role	O
for	O
MUC1	O
in	O
breast	O
cancer	O
,	O
the	O
exact	O
details	O
may	O
vary	O
depending	O
on	O
factors	O
such	O
as	O
cell	O
type	O
and	O
signaling	O
context	O
.	O

For	O
example	O
,	O
MUC1	O
stimulates	O
Fas	O
-	O
mediated	O
apoptosis	O
in	O
CHO	O
cells	O
[	O
26	O
]	O
,	O
quite	O
unlike	O
the	O
inhibition	O
of	O
apoptosis	O
seen	O
in	O
other	O
cell	O
lines	O
.	O

Similarly	O
,	O
though	O
MUC1	O
drives	O
mammary	O
oncogenesis	O
in	O
its	O
own	O
right	O
[	O
9	O
]	O
and	O
facilitates	O
tumorigenesis	O
driven	O
by	O
other	O
oncogenes	O
[	O
7	O
,	O
8	O
]	O
,	O
Muc1	O
is	O
selectively	O
down	O
-	O
regulated	O
in	O
c	O
-	O
neu	O
-	O
induced	O
mouse	B
mammary	O
tumors	O
[	O
27	O
]	O
,	O
indicating	O
that	O
the	O
context	O
of	O
oncogenic	O
signaling	O
is	O
vital	O
to	O
understanding	O
the	O
function	O
of	O
MUC1	O
.	O

Thus	O
,	O
it	O
is	O
important	O
to	O
consider	O
the	O
relative	O
levels	O
of	O
knockdown	O
of	O
MUC1	O
in	O
the	O
two	O
cell	O
lines	O
:	O
BT	O
-	O
20	O
cells	O
reduce	O
MUC1	O
expression	O
after	O
siRNA	O
less	O
strongly	O
than	O
do	O
MDA	O
-	O
MB	O
-	O
468	O
(	O
50	O
%	O
versus	O
75	O
%	O
knockdown	O
,	O
respectively	O
)	O
.	O

As	O
MUC1	O
serves	O
as	O
a	O
scaffold	O
[	O
11	O
]	O
,	O
overexpression	O
of	O
MUC1	O
relative	O
to	O
its	O
associated	O
signaling	O
proteins	O
might	O
create	O
a	O
dilution	O
effect	O
,	O
sequestering	O
signal	O
transducers	O
away	O
from	O
each	O
other	O
;	O
this	O
would	O
be	O
relieved	O
by	O
MUC1	O
siRNA	O
.	O

Thus	O
,	O
enough	O
MUC1	O
may	O
be	O
retained	O
in	O
BT	O
.	O
siMUC1	O
cells	O
for	O
its	O
oncogenic	O
effects	O
,	O
while	O
signaling	O
complex	O
formation	O
would	O
be	O
enhanced	O
by	O
lowering	O
the	O
amount	O
of	O
MUC1	O
relative	O
to	O
other	O
signaling	O
proteins	O
.	O

Conclusion	O

The	O
contrast	O
between	O
the	O
MDA	O
-	O
MB	O
-	O
468	O
and	O
BT	O
-	O
20	O
lines	O
in	O
response	O
to	O
MUC1	O
siRNA	O
serves	O
as	O
a	O
reminder	O
that	O
simplified	O
models	O
such	O
as	O
cell	O
lines	O
fail	O
to	O
encompass	O
the	O
complexity	O
of	O
intact	O
biological	O
systems	O
.	O

This	O
report	O
describes	O
transcriptional	O
alterations	O
seen	O
after	O
MUC1	O
knockdown	O
:	O
decreased	O
transcription	O
of	O
MAP2K1	O
,	O
VEGF	O
,	O
PDGFA	O
,	O
ITGAV	O
,	O
TIMP3	O
,	O
CDC25A	O
,	O
and	O
JUN	O
,	O
and	O
increased	O
transcription	O
of	O
MMP2	O
,	O
TNF	O
,	O
and	O
RAF1	O
.	O

The	O
alterations	O
in	O
MAP2K1	O
,	O
RAF1	O
,	O
and	O
JUN	O
represent	O
a	O
novel	O
means	O
by	O
which	O
MUC1	O
can	O
affect	O
ERK1	O
/	O
2	O
signaling	O
:	O
transcriptional	O
regulation	O
of	O
MAPK	O
pathway	O
members	O
.	O

Oncogenic	O
events	O
are	O
also	O
altered	O
in	O
both	O
cell	O
lines	O
after	O
MUC1	O
siRNA	O
.	O

These	O
results	O
strengthen	O
the	O
growing	O
ties	O
linking	O
MUC1	O
and	O
transcriptional	O
regulation	O
,	O
and	O
suggest	O
that	O
the	O
role	O
of	O
MUC1	O
in	O
breast	O
cancer	O
may	O
be	O
more	O
complex	O
than	O
a	O
direct	O
correlation	O
between	O
MUC1	O
level	O
and	O
oncogenic	O
function	O
.	O

Abbreviations	O

BrdU	O
=	O
bromodeoxyuridine	O
;	O
EGF	O
=	O
epidermal	O
growth	O
factor	O
;	O
EGFR	O
=	O
epidermal	O
growth	O
factor	O
receptor	O
;	O
ERK	O
=	O
extracellular	O
signal	O
regulated	O
kinase	O
;	O
MAPK	O
=	O
mitogen	O
activated	O
protein	O
kinase	O
;	O
MEK	O
=	O
MAPK	O
and	O
ERK	O
kinase	O
;	O
MMP	O
=	O
matrix	O
metalloproteinases	O
;	O
MUC1	O
-	O
CT	O
=	O
MUC1	O
cytoplasmic	O
tail	O
;	O
MUC1	O
-	O
EX	O
=	O
MUC1	O
extracellular	O
subunit	O
;	O
PBS	O
=	O
phosphate	O
-	O
buffered	O
saline	O
;	O
PI	O
=	O
propidium	O
iodide	O
;	O
siRNA	O
=	O
small	O
interfering	O
RNA	O
;	O
TIMP	O
=	O
tissue	O
inhibitor	O
of	O
metalloproteinases	O
;	O
TNF	O
=	O
tumor	O
necrosis	O
factor	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

CLH	O
performed	O
all	O
studies	O
and	O
composed	O
the	O
manuscript	O
.	O

SJG	O
participated	O
in	O
the	O
design	O
and	O
coordination	O
of	O
the	O
studies	O
and	O
contributed	O
strongly	O
to	O
the	O
revision	O
of	O
the	O
manuscript	O
.	O

Both	O
authors	O
have	O
read	O
and	O
approved	O
the	O
manuscript	O
.	O

The	O
recombination	O
-	O
associated	O
protein	O
RdgC	O
adopts	O
a	O
novel	O
toroidal	O
architecture	O
for	O
DNA	O
binding	O

Abstract	O

RecA	O
plays	O
a	O
central	O
role	O
in	O
the	O
nonmutagenic	O
repair	O
of	O
stalled	O
replication	O
forks	O
in	O
bacteria	O
.	O

RdgC	O
,	O
a	O
recombination	O
-	O
associated	O
DNA	O
-	O
binding	O
protein	O
,	O
is	O
a	O
potential	O
negative	O
regulator	O
of	O
RecA	O
function	O
.	O

Here	O
,	O
we	O
have	O
determined	O
the	O
crystal	O
structure	O
of	O
RdgC	O
from	O
Pseudomonas	B
aeruginosa	I
.	O

The	O
J	O
-	O
shaped	O
monomer	O
has	O
a	O
unique	O
fold	O
and	O
can	O
be	O
divided	O
into	O
three	O
structural	O
domains	O
:	O
tip	O
domain	O
,	O
center	O
domain	O
and	O
base	O
domain	O
.	O

Two	O
such	O
monomers	O
dimerize	O
to	O
form	O
a	O
ring	O
-	O
shaped	O
molecule	O
of	O
approximate	O
2	O
-	O
fold	O
symmetry	O
.	O

Of	O
the	O
two	O
inter	O
-	O
subunit	O
interfaces	O
within	O
the	O
dimer	O
,	O
one	O
interface	O
(	O
'	O
interface	O
A	O
'	O
)	O
between	O
tip	O
/	O
center	O
domains	O
is	O
more	O
nonpolar	O
than	O
the	O
other	O
(	O
'	O
interface	O
B	O
'	O
)	O
between	O
base	O
domains	O
.	O

The	O
structure	O
allows	O
us	O
to	O
propose	O
that	O
the	O
RdgC	O
dimer	O
binds	O
dsDNA	O
through	O
the	O
central	O
hole	O
of	O
~	O
30	O
A	O
diameter	O
.	O

The	O
proposed	O
model	O
is	O
supported	O
by	O
our	O
DNA	O
-	O
binding	O
assays	O
coupled	O
with	O
mutagenesis	O
,	O
which	O
indicate	O
that	O
the	O
conserved	O
positively	O
charged	O
residues	O
on	O
the	O
protein	O
surface	O
around	O
the	O
central	O
hole	O
play	O
important	O
roles	O
in	O
DNA	O
binding	O
.	O

The	O
novel	O
ring	O
-	O
shaped	O
architecture	O
of	O
the	O
RdgC	O
dimer	O
has	O
significant	O
implications	O
for	O
its	O
role	O
in	O
homologous	O
recombination	O
.	O

INTRODUCTION	O

Homologous	O
recombination	O
systems	O
contribute	O
to	O
the	O
maintenance	O
of	O
genome	O
integrity	O
and	O
are	O
essential	O
for	O
the	O
repair	O
of	O
stalled	O
replication	O
forks	O
(	O
1	O
)	O
.	O

Genetic	O
studies	O
of	O
the	O
recombination	O
-	O
dependent	O
growth	O
C	O
(	O
rdgC	O
)	O
gene	O
in	O
bacterial	O
systems	O
have	O
suggested	O
that	O
it	O
is	O
involved	O
in	O
DNA	O
replication	O
and	O
recombination	O
(	O
2	O
,	O
3	O
)	O
.	O

In	O
Neisseria	B
gonorrhoeae	I
(	O
the	O
gonococcus	O
)	O
,	O
RdgC	O
is	O
required	O
for	O
efficient	O
pilin	O
antigenic	O
variation	O
and	O
plays	O
some	O
role	O
in	O
cell	O
growth	O
(	O
4	O
,	O
5	O
)	O
.	O

The	O
Escherichia	B
coli	I
rdgC	O
gene	O
encodes	O
a	O
DNA	O
-	O
binding	O
protein	O
of	O
34	O
kDa	O
,	O
whose	O
expression	O
level	O
was	O
at	O
its	O
highest	O
during	O
exponential	O
phase	O
,	O
reaching	O
its	O
maximum	O
at	O
~	O
1000	O
dimers	O
per	O
cell	O
(	O
2	O
)	O
.	O

Its	O
level	O
decreased	O
sharply	O
to	O
~	O
50	O
dimers	O
per	O
cell	O
in	O
stationary	O
phase	O
.	O

This	O
profile	O
suggests	O
that	O
RdgC	O
might	O
function	O
during	O
the	O
period	O
of	O
DNA	O
replication	O
(	O
2	O
)	O
.	O

The	O
RecA	O
proteins	O
and	O
their	O
homologs	O
play	O
a	O
key	O
role	O
in	O
recombinational	O
DNA	O
repair	O
in	O
bacteria	O
and	O
eukaryotes	O
.	O

Their	O
aberrant	O
reactions	O
could	O
result	O
in	O
gross	O
chromosomal	O
rearrangements	O
that	O
lead	O
to	O
human	B
diseases	O
,	O
including	O
cancer	O
.	O

Therefore	O
,	O
their	O
functions	O
must	O
be	O
tightly	O
regulated	O
,	O
and	O
understanding	O
how	O
the	O
RecA	O
family	O
of	O
recombinases	O
is	O
regulated	O
is	O
of	O
utmost	O
importance	O
(	O
1	O
)	O
.	O

The	O
E	B
.	I
coli	I
RdgC	O
protein	O
is	O
a	O
potential	O
negative	O
regulator	O
of	O
the	O
function	O
of	O
RecA	O
(	O
1	O
)	O
.	O

It	O
inhibits	O
RecA	O
-	O
promoted	O
DNA	O
strand	O
exchange	O
,	O
RecA	O
-	O
mediated	O
ATPase	O
activity	O
and	O
RecA	O
-	O
dependent	O
LexA	O
cleavage	O
(	O
1	O
)	O
.	O

Sedimentation	O
equilibrium	O
data	O
indicated	O
that	O
E	B
.	I
coli	I
RdgC	O
exists	O
in	O
solution	O
as	O
a	O
mixture	O
of	O
oligomeric	O
states	O
in	O
equilibrium	O
,	O
most	O
likely	O
monomers	O
,	O
dimers	O
and	O
tetramers	O
(	O
1	O
)	O
.	O

This	O
concentration	O
-	O
dependent	O
change	O
in	O
the	O
oligomeric	O
state	O
appears	O
to	O
affect	O
its	O
mode	O
of	O
binding	O
to	O
DNA	O
and	O
its	O
capacity	O
to	O
inhibit	O
RecA	O
(	O
1	O
)	O
.	O

The	O
primary	O
mechanism	O
of	O
RdgC	O
inhibition	O
appears	O
to	O
involve	O
a	O
simple	O
competition	O
for	O
DNA	O
-	O
binding	O
sites	O
,	O
especially	O
on	O
double	O
-	O
stranded	O
DNA	O
(	O
dsDNA	O
)	O
(	O
1	O
)	O
.	O

Deletion	O
of	O
the	O
E	B
.	I
coli	I
rdgC	O
gene	O
alone	O
causes	O
no	O
obvious	O
phenotype	O
but	O
is	O
highly	O
deleterious	O
in	O
strains	O
lacking	O
certain	O
enzymes	O
involved	O
in	O
recombination	O
and	O
replication	O
restart	O
(	O
2	O
,	O
3	O
)	O
.	O

RdgC	O
is	O
essential	O
for	O
the	O
growth	O
of	O
an	O
E	B
.	I
coli	I
strain	O
lacking	O
PriA	O
,	O
indicating	O
that	O
it	O
might	O
affect	O
replication	O
fork	O
progression	O
or	O
fork	O
rescue	O
(	O
2	O
)	O
.	O

PriA	O
provides	O
a	O
means	O
to	O
load	O
the	O
DnaB	O
replicative	O
helicase	O
at	O
DNA	O
replication	O
fork	O
and	O
D	O
loop	O
structures	O
(	O
2	O
)	O
.	O

RdgC	O
is	O
,	O
therefore	O
,	O
a	O
key	O
factor	O
in	O
the	O
rescue	O
of	O
stalled	O
or	O
broken	O
forks	O
and	O
subsequent	O
replication	O
restart	O
.	O

dnaC	O
suppressors	O
of	O
PriA	O
can	O
overcome	O
this	O
inviability	O
,	O
especially	O
when	O
RecF	O
,	O
RecO	O
or	O
RecR	O
is	O
inactivated	O
,	O
which	O
indicates	O
that	O
RdgC	O
avoids	O
or	O
counters	O
the	O
toxic	O
effect	O
of	O
these	O
proteins	O
by	O
limiting	O
inappropriate	O
RecA	O
loading	O
on	O
SSB	O
-	O
coated	O
ssDNA	O
(	O
2	O
)	O
.	O

The	O
DNA	O
-	O
binding	O
ability	O
of	O
the	O
RdgC	O
protein	O
has	O
been	O
demonstrated	O
clearly	O
using	O
electrophoretic	O
mobility	O
shift	O
assays	O
(	O
2	O
)	O
.	O

Escherichia	B
coli	I
RdgC	O
binds	O
non	O
-	O
specifically	O
to	O
dsDNA	O
and	O
with	O
higher	O
affinity	O
than	O
ssDNA	O
(	O
2	O
)	O
.	O

RdgC	O
from	O
N	B
.	I
meningitidis	I
also	O
binds	O
DNA	O
with	O
little	O
specificity	O
for	O
sequence	O
or	O
structure	O
,	O
like	O
the	O
E	B
.	I
coli	I
protein	O
(	O
4	O
)	O
.	O

RdgC	O
exhibits	O
no	O
preference	O
for	O
DNA	O
replication	O
or	O
recombination	O
intermediates	O
(	O
2	O
)	O
.	O

However	O
,	O
no	O
detectable	O
domains	O
or	O
nuclease	O
activity	O
could	O
be	O
identified	O
for	O
the	O
E	B
.	I
coli	I
RdgC	O
protein	O
(	O
2	O
,	O
6	O
)	O
.	O

The	O
complexes	O
of	O
E	B
.	I
coli	I
RdgC	O
with	O
both	O
linear	O
and	O
supercoiled	O
circular	O
plasmid	O
DNA	O
were	O
imaged	O
using	O
atomic	O
force	O
microscopy	O
(	O
7	O
)	O
.	O

RdgC	O
was	O
found	O
to	O
have	O
an	O
increased	O
affinity	O
to	O
DNA	O
ends	O
and	O
to	O
promote	O
bending	O
of	O
DNA	O
(	O
7	O
)	O
.	O

RdgC	O
has	O
the	O
effect	O
on	O
DNA	O
superstructure	O
;	O
the	O
promotion	O
of	O
DNA	O
condensation	O
was	O
observed	O
at	O
high	O
protein	O
concentrations	O
(	O
7	O
)	O
.	O

Recombination	O
is	O
largely	O
enhanced	O
by	O
close	O
contacts	O
of	O
distant	O
regions	O
along	O
the	O
DNA	O
strands	O
through	O
condensation	O
(	O
7	O
)	O
.	O

Pseudomonas	B
aeruginosa	I
is	O
a	O
ubiquitous	O
environmental	O
Gram	O
-	O
negative	O
bacterium	O
that	O
belongs	O
to	O
the	O
gamma	O
subdivision	O
of	O
the	O
Proteobacteria	O
.	O

Orthologs	O
of	O
the	O
rdgC	O
gene	O
are	O
found	O
only	O
in	O
beta	O
and	O
gamma	O
subdivisions	O
of	O
the	O
Proteobacteria	O
(	O
2	O
)	O
.	O

The	O
amino	O
acid	O
sequence	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
,	O
a	O
306	O
-	O
residue	O
protein	O
,	O
shows	O
46	O
and	O
36	O
%	O
identities	O
against	O
those	O
of	O
E	B
.	I
coli	I
and	O
N	B
.	I
meningitidis	I
,	O
respectively	O
.	O

Despite	O
the	O
importance	O
of	O
DNA	O
-	O
binding	O
ability	O
of	O
RdgC	O
in	O
its	O
biological	O
roles	O
,	O
the	O
structural	O
details	O
of	O
RdgC	O
and	O
the	O
mechanism	O
of	O
its	O
action	O
remain	O
unclear	O
.	O

Here	O
,	O
we	O
report	O
the	O
crystal	O
structure	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
as	O
determined	O
by	O
the	O
multiwavelength	O
anomalous	O
diffraction	O
(	O
MAD	O
)	O
method	O
of	O
X	O
-	O
ray	O
crystallography	O
.	O

It	O
reveals	O
that	O
RdgC	O
dimer	O
is	O
ring	O
-	O
shaped	O
,	O
with	O
a	O
central	O
hole	O
of	O
~	O
30	O
A	O
diameter	O
.	O

The	O
inside	O
surface	O
around	O
the	O
central	O
hole	O
is	O
rich	O
in	O
conserved	O
,	O
positively	O
charged	O
residues	O
,	O
which	O
are	O
implicated	O
in	O
DNA	O
-	O
binding	O
by	O
mutagenesis	O
.	O

We	O
propose	O
that	O
dsDNA	O
binds	O
to	O
RdgC	O
through	O
this	O
central	O
hole	O
.	O

Our	O
structure	O
provides	O
a	O
solid	O
structural	O
framework	O
for	O
a	O
better	O
understanding	O
of	O
the	O
role	O
of	O
RdgC	O
in	O
homologous	O
recombination	O
.	O

MATERIALS	O
AND	O
METHODS	O

Protein	O
expression	O
and	O
purification	O

The	O
rdgC	O
gene	O
(	O
PA3263	O
)	O
was	O
amplified	O
by	O
the	O
polymerase	O
chain	O
reaction	O
(	O
PCR	O
)	O
using	O
the	O
genomic	O
DNA	O
of	O
P	B
.	I
aeruginosa	I
strain	O
PAO1	O
as	O
a	O
template	O
.	O

The	O
oligonucleotide	O
primers	O
designed	O
using	O
the	O
published	O
genome	O
sequence	O
(	O
8	O
)	O
were	O
5	O
'	O
-	O
G	O
GAA	O
TTC	O
CAT	O
ATG	O
TGG	O
TTC	O
CGC	O
AAT	O
CTG	O
CTC	O
G	O
-	O
3	O
'	O
(	O
forward	O
)	O
and	O
5	O
'	O
-	O
CCG	O
CCG	O
CTC	O
GAG	O
GAC	O
GCC	O
CTG	O
GGG	O
GAT	O
TTC	O
TTC	O
-	O
3	O
'	O
(	O
reverse	O
)	O
.	O

The	O
bases	O
in	O
bold	O
denote	O
the	O
NdeI	O
and	O
XhoI	O
cleavage	O
sites	O
,	O
respectively	O
.	O

The	O
PCR	O
product	O
was	O
digested	O
with	O
NdeI	O
and	O
XhoI	O
,	O
and	O
was	O
then	O
inserted	O
into	O
the	O
NdeI	O
/	O
XhoI	O
-	O
digested	O
expression	O
vector	O
pET	O
-	O
21a	O
(	O
+	O
)	O
(	O
Novagen	O
)	O
.	O

This	O
vector	O
construction	O
adds	O
an	O
eight	O
-	O
residue	O
tag	O
(	O
LEHHHHHH	O
)	O
to	O
the	O
carboxyl	O
terminus	O
of	O
the	O
gene	O
product	O
to	O
facilitate	O
protein	O
purification	O
.	O

The	O
protein	O
was	O
expressed	O
in	O
E	B
.	I
coli	I
C41	O
(	O
DE3	O
)	O
cells	O
(	O
9	O
)	O
.	O

The	O
cells	O
were	O
grown	O
at	O
37	O
degrees	O
C	O
up	O
to	O
OD600	O
of	O
0	O
.	O
6	O
in	O
Luria	O
-	O
Bertani	O
medium	O
that	O
contained	O
50	O
mu	O
g	O
ml	O
-	O
1	O
ampicillin	O
,	O
and	O
the	O
protein	O
expression	O
was	O
induced	O
by	O
0	O
.	O
5	O
mM	O
isopropyl	O
-	O
beta	O
-	O
d	O
-	O
thiogalactopyranosid	O
(	O
IPTG	O
)	O
.	O

The	O
cells	O
were	O
allowed	O
to	O
grow	O
at	O
20	O
degrees	O
C	O
for	O
22	O
h	O
after	O
IPTG	O
induction	O
and	O
were	O
harvested	O
by	O
centrifugation	O
at	O
4200	O
g	O
(	O
6000	O
rev	O
min	O
-	O
1	O
;	O
Sorvall	O
GSA	O
rotor	O
)	O
for	O
10	O
min	O
at	O
4	O
degrees	O
C	O
.	O

The	O
cell	O
pellet	O
was	O
resuspended	O
in	O
an	O
ice	O
-	O
cold	O
lysis	O
buffer	O
[	O
20	O
mM	O
Tris	O
-	O
HCl	O
(	O
pH	O
7	O
.	O
9	O
)	O
,	O
500	O
mM	O
sodium	O
chloride	O
,	O
5	O
mM	O
imidazole	O
]	O
and	O
was	O
then	O
homogenized	O
with	O
an	O
ultrasonic	O
processor	O
.	O

The	O
crude	O
cell	O
extract	O
was	O
centrifuged	O
at	O
36	O
000	O
g	O
(	O
18	O
000	O
rev	O
min	O
-	O
1	O
;	O
Hanil	O
Supra	O
21	O
K	O
rotor	O
)	O
for	O
60	O
min	O
at	O
4	O
degrees	O
C	O
,	O
and	O
the	O
recombinant	O
protein	O
in	O
the	O
supernatant	O
fraction	O
was	O
purified	O
in	O
three	O
chromatographic	O
steps	O
.	O

The	O
first	O
purification	O
step	O
utilized	O
the	O
C	O
-	O
terminal	O
hexahistidine	O
-	O
tag	O
by	O
Ni2	O
+	O
-	O
chelated	O
HiTrap	O
chelating	O
column	O
(	O
GE	O
Healthcare	O
)	O
.	O

The	O
eluent	O
was	O
diluted	O
3	O
-	O
fold	O
with	O
50	O
mM	O
Tris	O
-	O
HCl	O
at	O
pH	O
7	O
.	O
4	O
.	O

The	O
diluted	O
solution	O
was	O
applied	O
to	O
a	O
20	O
-	O
ml	O
heparin	O
-	O
Sepharose	O
column	O
(	O
GE	O
Healthcare	O
)	O
,	O
which	O
was	O
previously	O
equilibrated	O
with	O
a	O
buffer	O
of	O
50	O
mM	O
Tris	O
-	O
HCl	O
(	O
pH	O
7	O
.	O
4	O
)	O
,	O
1	O
mM	O
dithiothreitol	O
and	O
1	O
mM	O
EDTA	O
.	O

The	O
protein	O
was	O
eluted	O
with	O
a	O
linear	O
gradient	O
of	O
0	O
-	O
2	O
.	O
0	O
M	O
sodium	O
chloride	O
in	O
the	O
same	O
buffer	O
.	O

The	O
first	O
peak	O
corresponded	O
to	O
high	O
molecular	O
aggregates	O
of	O
RdgC	O
and	O
the	O
second	O
peak	O
to	O
RdgC	O
dimers	O
,	O
which	O
was	O
also	O
consistent	O
with	O
our	O
dynamic	O
light	O
scattering	O
measurements	O
.	O

When	O
the	O
aggregates	O
were	O
not	O
separated	O
from	O
the	O
dimers	O
,	O
the	O
protein	O
readily	O
aggregated	O
within	O
a	O
day	O
.	O

The	O
dimer	O
fractions	O
were	O
concentrated	O
to	O
~	O
6	O
mg	O
ml	O
-	O
1	O
concentration	O
using	O
an	O
YM10	O
ultrafiltration	O
membrane	O
(	O
Millipore	O
-	O
Amicon	O
)	O
and	O
further	O
purified	O
by	O
gel	O
filtration	O
on	O
a	O
HiLoad	O
XK	O
16	O
Superdex	O
200	O
prep	O
-	O
grade	O
column	O
(	O
GE	O
Healthcare	O
)	O
,	O
which	O
was	O
previously	O
equilibrated	O
with	O
a	O
buffer	O
of	O
50	O
mM	O
Tris	O
-	O
HCl	O
(	O
pH	O
7	O
.	O
4	O
)	O
,	O
200	O
mM	O
sodium	O
chloride	O
,	O
1	O
mM	O
dithiothreitol	O
and	O
1	O
mM	O
EDTA	O
.	O

The	O
first	O
peak	O
corresponding	O
to	O
the	O
high	O
molecular	O
aggregates	O
of	O
RdgC	O
was	O
only	O
a	O
minor	O
component	O
,	O
and	O
the	O
second	O
peak	O
corresponding	O
to	O
RdgC	O
dimers	O
was	O
stable	O
for	O
several	O
weeks	O
when	O
frozen	O
at	O
-	O
70	O
degrees	O
C	O
.	O

The	O
procedure	O
for	O
purifying	O
the	O
SeMet	O
-	O
substituted	O
protein	O
was	O
the	O
same	O
,	O
except	O
for	O
the	O
presence	O
of	O
10	O
mM	O
dithiothreitol	O
in	O
all	O
buffers	O
used	O
during	O
purification	O
steps	O
.	O

Dynamic	O
light	O
scattering	O
experiments	O
were	O
performed	O
at	O
24	O
degrees	O
C	O
,	O
with	O
the	O
protein	O
(	O
at	O
2	O
mg	O
ml	O
-	O
1	O
concentration	O
)	O
dissolved	O
in	O
a	O
buffer	O
consisting	O
of	O
50	O
mM	O
Tris	O
-	O
HCl	O
(	O
pH	O
7	O
.	O
4	O
)	O
,	O
1	O
mM	O
dithiothreitol	O
,	O
1	O
mM	O
EDTA	O
and	O
200	O
mM	O
sodium	O
chloride	O
on	O
a	O
Model	O
DynaPro	O
-	O
801	O
instrument	O
(	O
Wyatt	O
,	O
Santa	O
Barbara	O
,	O
CA	O
,	O
USA	O
)	O
.	O

The	O
protein	O
concentration	O
was	O
estimated	O
by	O
measuring	O
the	O
absorbance	O
at	O
280	O
nm	O
,	O
employing	O
the	O
calculated	O
extinction	O
coefficient	O
of	O
20	O
910	O
M	O
-	O
1	O
cm	O
-	O
1	O
(	O
SWISS	O
-	O
PROT	O
;	O
http	O
:	O
/	O
/	O
www	O
.	O
expasy	O
.	O
ch	O
/	O
)	O
.	O

Mutagenesis	O
and	O
electrophoretic	O
mobility	O
shift	O
assay	O

Point	O
mutants	O
were	O
prepared	O
using	O
the	O
QuikChange	O
Site	O
-	O
Directed	O
Mutagenesis	O
kit	O
(	O
Stratagene	O
)	O
,	O
and	O
the	O
mutations	O
were	O
confirmed	O
by	O
DNA	O
sequencing	O
.	O

The	O
seven	O
mutants	O
R4A	O
,	O
F120A	O
,	O
K146A	O
,	O
R198A	O
,	O
R208A	O
,	O
Q212A	O
and	O
R252A	O
were	O
well	O
expressed	O
and	O
soluble	O
.	O

The	O
three	O
mutants	O
K70A	O
,	O
R81A	O
and	O
R211A	O
were	O
not	O
expressed	O
,	O
while	O
R122A	O
mutant	O
was	O
expressed	O
but	O
was	O
not	O
soluble	O
.	O

Therefore	O
,	O
we	O
mutated	O
Lys70	O
,	O
Arg81	O
,	O
Arg122	O
and	O
Arg211	O
into	O
aspartate	O
.	O

The	O
K70D	O
,	O
R81D	O
,	O
R122D	O
and	O
R211D	O
mutants	O
were	O
well	O
expressed	O
and	O
soluble	O
.	O

The	O
soluble	O
mutants	O
were	O
expressed	O
and	O
purified	O
under	O
the	O
conditions	O
identical	O
to	O
those	O
for	O
the	O
wild	O
type	O
,	O
except	O
that	O
the	O
heparin	O
-	O
Sepharose	O
column	O
step	O
was	O
omitted	O
.	O

All	O
of	O
the	O
soluble	O
mutants	O
had	O
similar	O
elution	O
profiles	O
as	O
the	O
wild	O
type	O
upon	O
gel	O
filtration	O
,	O
and	O
the	O
dimer	O
fractions	O
were	O
used	O
for	O
DNA	O
-	O
binding	O
assays	O
.	O

We	O
mixed	O
5	O
mu	O
l	O
of	O
RdgC	O
(	O
1	O
.	O
1	O
mu	O
g	O
mu	O
l	O
-	O
1	O
)	O
and	O
5	O
mu	O
l	O
of	O
a	O
linear	O
dsDNA	O
with	O
414	O
bp	O
(	O
63	O
ng	O
mu	O
l	O
-	O
1	O
)	O
,	O
corresponding	O
to	O
the	O
molar	O
ratio	O
of	O
64	O
:	O
1	O
for	O
RdgC	O
dimer	O
to	O
dsDNA	O
.	O

The	O
reaction	O
mixtures	O
were	O
incubated	O
for	O
10	O
min	O
at	O
room	O
temperature	O
.	O

RdgC	O
-	O
DNA	O
complexes	O
were	O
analyzed	O
by	O
1	O
.	O
5	O
%	O
(	O
w	O
/	O
v	O
)	O
agarose	O
gel	O
electrophoresis	O
in	O
1	O
x	O
TAE	O
buffer	O
(	O
45	O
mM	O
Tris	O
-	O
acetate	O
at	O
pH	O
8	O
.	O
3	O
,	O
1	O
mM	O
EDTA	O
)	O
.	O

DNA	O
bands	O
were	O
visualized	O
by	O
ethidium	O
bromide	O
staining	O
.	O

For	O
DNA	O
-	O
binding	O
assays	O
,	O
the	O
protein	O
concentration	O
was	O
measured	O
with	O
a	O
Bio	O
-	O
Rad	O
protein	O
assay	O
kit	O
.	O

Crystallization	O
and	O
X	O
-	O
ray	O
data	O
collection	O

Crystals	O
were	O
grown	O
by	O
the	O
hanging	O
-	O
drop	O
vapor	O
diffusion	O
method	O
at	O
24	O
degrees	O
C	O
by	O
mixing	O
equal	O
volumes	O
(	O
2	O
mu	O
l	O
each	O
)	O
of	O
the	O
protein	O
solution	O
(	O
at	O
19	O
mg	O
ml	O
-	O
1	O
concentration	O
in	O
a	O
buffer	O
consisting	O
of	O
50	O
mM	O
Tris	O
-	O
HCl	O
(	O
pH	O
7	O
.	O
4	O
)	O
,	O
1	O
mM	O
dithiothreitol	O
,	O
1	O
mM	O
EDTA	O
and	O
200	O
mM	O
sodium	O
chloride	O
)	O
and	O
the	O
reservoir	O
solution	O
.	O

To	O
grow	O
the	O
native	O
crystals	O
,	O
we	O
used	O
a	O
reservoir	O
solution	O
consisting	O
of	O
0	O
.	O
1	O
M	O
sodium	O
HEPES	O
(	O
pH	O
7	O
.	O
5	O
)	O
,	O
1	O
.	O
0	O
M	O
tri	O
-	O
sodium	O
citrate	O
and	O
1	O
%	O
(	O
w	O
/	O
v	O
)	O
Anapoe	O
(	O
R	O
)	O
35	O
as	O
the	O
detergent	O
.	O

Native	O
crystals	O
grew	O
to	O
approximate	O
dimensions	O
of	O
0	O
.	O
2	O
mm	O
x	O
0	O
.	O
1	O
mm	O
x	O
0	O
.	O
1	O
mm	O
within	O
a	O
few	O
days	O
.	O

The	O
SeMet	O
-	O
substituted	O
protein	O
was	O
crystallized	O
under	O
conditions	O
identical	O
to	O
those	O
for	O
the	O
native	O
crystals	O
except	O
for	O
the	O
presence	O
of	O
10	O
mM	O
dithiothreitol	O
in	O
the	O
protein	O
solution	O
.	O

A	O
crystal	O
of	O
the	O
SeMet	O
-	O
substituted	O
protein	O
was	O
dipped	O
into	O
a	O
cryoprotectant	O
solution	O
for	O
a	O
few	O
seconds	O
and	O
was	O
flash	O
-	O
cooled	O
in	O
the	O
cold	O
nitrogen	O
gas	O
stream	O
at	O
100	O
K	O
.	O

The	O
cryoprotectant	O
solution	O
consisted	O
of	O
0	O
.	O
1	O
M	O
sodium	O
HEPES	O
(	O
pH	O
7	O
.	O
5	O
)	O
,	O
1	O
.	O
0	O
M	O
tri	O
-	O
sodium	O
citrate	O
,	O
1	O
%	O
(	O
w	O
/	O
v	O
)	O
Anapoe	O
(	O
R	O
)	O
35	O
as	O
the	O
detergent	O
and	O
10	O
%	O
(	O
v	O
/	O
v	O
)	O
glycerol	O
.	O

A	O
set	O
of	O
Se	O
MAD	O
data	O
was	O
collected	O
at	O
100	O
K	O
at	O
three	O
different	O
wavelengths	O
using	O
an	O
Area	O
Detector	O
System	O
Corporation	O
Quantum	O
210	O
charge	O
-	O
coupled	O
device	O
detector	O
at	O
the	O
beamline	O
NW12A	O
of	O
Photon	O
Factory	O
,	O
Tsukuba	O
,	O
Japan	O
.	O

The	O
crystal	O
was	O
rotated	O
through	O
a	O
total	O
of	O
180	O
degrees	O
with	O
a	O
1	O
degrees	O
oscillation	O
range	O
per	O
frame	O
.	O

The	O
raw	O
data	O
were	O
processed	O
and	O
scaled	O
using	O
the	O
program	O
suit	O
HKL2000	O
(	O
10	O
)	O
.	O

The	O
SeMet	O
-	O
substituted	O
crystal	O
belongs	O
to	O
the	O
space	O
group	O
P21212	O
,	O
with	O
unit	O
cell	O
parameters	O
of	O
a	O
=	O
87	O
.	O
04	O
A	O
,	O
b	O
=	O
115	O
.	O
60	O
A	O
and	O
c	O
=	O
76	O
.	O
07	O
A	O
.	O

The	O
native	O
crystals	O
were	O
soaked	O
for	O
10	O
min	O
in	O
10	O
mM	O
ethyl	O
mercury	O
thiosalicylate	O
(	O
EMTS	O
)	O
to	O
collect	O
a	O
set	O
of	O
Hg	O
MAD	O
data	O
at	O
four	O
different	O
wavelengths	O
.	O

X	O
-	O
ray	O
diffraction	O
data	O
from	O
the	O
EMTS	O
-	O
derivatized	O
crystal	O
,	O
as	O
well	O
as	O
a	O
native	O
crystal	O
,	O
were	O
collected	O
on	O
a	O
Bruker	O
charge	O
-	O
coupled	O
device	O
detector	O
at	O
the	O
beamline	O
BL	O
-	O
6B	O
of	O
Pohang	O
Light	O
Source	O
,	O
Pohang	O
,	O
Korea	O
.	O

The	O
EMTS	O
-	O
soaked	O
crystal	O
belongs	O
to	O
the	O
space	O
group	O
P21212	O
,	O
with	O
unit	O
cell	O
parameters	O
of	O
a	O
=	O
87	O
.	O
16	O
A	O
,	O
b	O
=	O
116	O
.	O
02	O
A	O
and	O
c	O
=	O
74	O
.	O
97	O
A	O
.	O

The	O
native	O
crystal	O
belongs	O
to	O
the	O
space	O
group	O
P21212	O
,	O
with	O
unit	O
cell	O
parameters	O
of	O
a	O
=	O
87	O
.	O
49	O
A	O
,	O
b	O
=	O
116	O
.	O
04	O
A	O
and	O
c	O
=	O
76	O
.	O
03	O
A	O
.	O

If	O
the	O
presence	O
of	O
a	O
dimeric	O
molecule	O
in	O
the	O
asymmetric	O
unit	O
is	O
assumed	O
,	O
the	O
calculated	O
crystal	O
volume	O
per	O
protein	O
mass	O
(	O
VM	O
)	O
is	O
2	O
.	O
75	O
A	O
3	O
Da	O
-	O
1	O
and	O
the	O
solvent	O
content	O
is	O
55	O
.	O
3	O
%	O
.	O

Supplementary	O
Table	O
1	O
summarizes	O
the	O
statistics	O
of	O
X	O
-	O
ray	O
diffraction	O
data	O
collection	O
.	O

Structure	O
solution	O
and	O
refinement	O

Heavy	O
atom	O
sites	O
were	O
located	O
with	O
the	O
program	O
SOLVE	O
(	O
11	O
)	O
.	O

Four	O
Se	O
sites	O
from	O
the	O
SeMet	O
-	O
substituted	O
crystal	O
and	O
two	O
Hg	O
sites	O
from	O
the	O
EMTS	O
-	O
soaked	O
crystal	O
were	O
located	O
.	O

Two	O
sets	O
of	O
the	O
initial	O
Se	O
and	O
Hg	O
MAD	O
phases	O
were	O
separately	O
improved	O
using	O
the	O
program	O
RESOLVE	O
(	O
12	O
)	O
.	O

Two	O
electron	O
density	O
maps	O
were	O
independently	O
interpreted	O
,	O
and	O
the	O
fragments	O
of	O
the	O
two	O
models	O
were	O
combined	O
into	O
a	O
single	O
model	O
,	O
since	O
the	O
two	O
maps	O
were	O
complementary	O
to	O
each	O
other	O
.	O

Non	O
-	O
crystallographic	O
symmetry	O
(	O
NCS	O
)	O
matrices	O
were	O
found	O
from	O
a	O
partial	O
model	O
built	O
from	O
the	O
initial	O
electron	O
density	O
map	O
,	O
and	O
phases	O
were	O
further	O
improved	O
by	O
the	O
2	O
-	O
fold	O
NCS	O
averaging	O
,	O
solvent	O
flattening	O
and	O
histogram	O
matching	O
with	O
the	O
program	O
DM	O
(	O
13	O
)	O
.	O

The	O
model	O
was	O
built	O
with	O
O	O
(	O
14	O
)	O
.	O

The	O
model	O
was	O
refined	O
with	O
the	O
program	O
CNS	O
(	O
15	O
)	O
,	O
including	O
the	O
bulk	O
solvent	O
correction	O
.	O

10	O
%	O
of	O
the	O
data	O
were	O
randomly	O
set	O
aside	O
as	O
the	O
test	O
data	O
for	O
the	O
calculation	O
of	O
Rfree	O
(	O
16	O
)	O
.	O

Several	O
rounds	O
of	O
model	O
building	O
,	O
simulated	O
annealing	O
,	O
positional	O
refinement	O
and	O
individual	O
B	O
-	O
factor	O
refinement	O
were	O
performed	O
.	O

Subsequently	O
,	O
this	O
model	O
was	O
used	O
to	O
refine	O
the	O
structure	O
of	O
the	O
native	O
protein	O
.	O

The	O
model	O
has	O
excellent	O
stereochemistry	O
,	O
as	O
evaluated	O
by	O
the	O
program	O
PROCHECK	O
(	O
17	O
)	O
.	O

Refinement	O
statistics	O
are	O
summarized	O
in	O
Supplementary	O
Table	O
1	O
.	O

RESULTS	O
AND	O
DISCUSSION	O

Model	O
quality	O
and	O
monomer	O
structure	O

The	O
structure	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
was	O
solved	O
using	O
two	O
sets	O
of	O
MAD	O
data	O
collected	O
from	O
a	O
crystal	O
of	O
the	O
selenomethionine	O
(	O
SeMet	O
)	O
-	O
substituted	O
protein	O
and	O
from	O
a	O
mercury	O
derivative	O
crystal	O
of	O
the	O
native	O
protein	O
(	O
Supplementary	O
Table	O
1	O
)	O
.	O

The	O
model	O
has	O
subsequently	O
been	O
refined	O
using	O
the	O
20	O
.	O
0	O
-	O
2	O
.	O
50	O
A	O
data	O
from	O
a	O
native	O
crystal	O
to	O
crystallographic	O
Rwork	O
and	O
Rfree	O
values	O
of	O
23	O
.	O
4	O
and	O
27	O
.	O
9	O
%	O
,	O
respectively	O
,	O
with	O
no	O
sigma	O
cut	O
-	O
off	O
.	O

The	O
refined	O
model	O
contains	O
612	O
residues	O
of	O
the	O
two	O
monomers	O
in	O
the	O
asymmetric	O
unit	O
of	O
the	O
crystal	O
(	O
residues	O
1	O
-	O
306	O
for	O
both	O
chains	O
A	O
and	O
B	O
)	O
and	O
87	O
water	O
molecules	O
.	O

The	O
C	O
-	O
terminal	O
eight	O
-	O
residue	O
fusion	O
tag	O
has	O
no	O
electron	O
density	O
in	O
both	O
subunits	O
and	O
has	O
not	O
been	O
modeled	O
.	O

Conformations	O
of	O
the	O
two	O
monomers	O
in	O
the	O
asymmetric	O
unit	O
are	O
similar	O
.	O

The	O
root	O
-	O
mean	O
-	O
square	O
(	O
r	O
.	O
m	O
.	O
s	O
.	O
)	O
difference	O
between	O
the	O
two	O
monomers	O
is	O
0	O
.	O
69	O
A	O
for	O
306	O
C	O
alpha	O
atom	O
pairs	O
,	O
with	O
a	O
maximum	O
deviation	O
of	O
8	O
.	O
8	O
A	O
for	O
the	O
C	O
alpha	O
atom	O
of	O
Gly305	O
.	O

The	O
residues	O
giving	O
r	O
.	O
m	O
.	O
s	O
.	O
differences	O
larger	O
than	O
2	O
.	O
0	O
A	O
are	O
14	O
-	O
16	O
,	O
94	O
-	O
96	O
,	O
201	O
-	O
202	O
and	O
303	O
-	O
306	O
,	O
which	O
correspond	O
to	O
loops	O
connecting	O
secondary	O
structure	O
elements	O
or	O
the	O
C	O
-	O
terminus	O
.	O

They	O
are	O
located	O
on	O
the	O
surface	O
of	O
the	O
dimer	O
.	O

Subunit	O
A	O
has	O
a	O
better	O
map	O
quality	O
than	O
subunit	O
B	O
,	O
and	O
thus	O
has	O
a	O
lower	O
mean	O
B	O
-	O
factor	O
than	O
subunit	O
B	O
(	O
40	O
.	O
3	O
A	O
2	O
versus	O
.	O
56	O
.	O
1	O
A	O
2	O
for	O
all	O
4788	O
atoms	O
)	O
(	O
Supplementary	O
Figure	O
1	O
)	O
.	O

Therefore	O
,	O
subunit	O
A	O
is	O
chosen	O
for	O
discussions	O
,	O
unless	O
otherwise	O
stated	O
.	O

The	O
P	B
.	I
aeruginosa	I
RdgC	O
monomer	O
is	O
J	O
-	O
shaped	O
and	O
has	O
approximate	O
dimensions	O
of	O
72	O
A	O
x	O
60	O
A	O
x	O
40	O
A	O
(	O
Figure	O
1	O
)	O
.	O

It	O
can	O
be	O
divided	O
into	O
three	O
structural	O
domains	O
:	O
center	O
domain	O
,	O
tip	O
domain	O
and	O
base	O
domain	O
.	O

Center	O
domain	O
(	O
residues	O
1	O
-	O
73	O
and	O
121	O
-	O
167	O
)	O
includes	O
a	O
six	O
-	O
stranded	O
anti	O
-	O
parallel	O
beta	O
-	O
sheet	O
with	O
two	O
flanking	O
alpha	O
helices	O
(	O
alpha	O
1	O
and	O
alpha	O
4	O
)	O
.	O

The	O
helix	O
alpha	O
1	O
runs	O
nearly	O
parallel	O
to	O
the	O
two	O
outermost	O
strands	O
beta	O
2	O
and	O
beta	O
3	O
,	O
which	O
in	O
turn	O
lie	O
adjacent	O
to	O
beta	O
4	O
.	O

Strands	O
beta	O
2	O
and	O
beta	O
3	O
are	O
separated	O
by	O
a	O
loop	O
.	O

The	O
helix	O
alpha	O
4	O
is	O
nearly	O
orthogonal	O
to	O
the	O
beta	O
-	O
strands	O
.	O

Tip	O
domain	O
(	O
residues	O
74	O
-	O
120	O
)	O
contains	O
two	O
alpha	O
helices	O
(	O
alpha	O
2	O
and	O
alpha	O
3	O
)	O
and	O
is	O
inserted	O
between	O
strands	O
beta	O
4	O
and	O
beta	O
5	O
of	O
the	O
center	O
domain	O
.	O

It	O
sticks	O
out	O
from	O
the	O
center	O
domain	O
.	O

The	O
two	O
connections	O
between	O
the	O
center	O
domain	O
and	O
the	O
tip	O
domain	O
are	O
rich	O
in	O
conserved	O
residues	O
,	O
hinting	O
at	O
an	O
important	O
functional	O
role	O
of	O
these	O
joints	O
.	O

They	O
could	O
act	O
as	O
a	O
hinge	O
for	O
a	O
possible	O
conformational	O
change	O
.	O

The	O
C	O
-	O
terminal	O
region	O
of	O
the	O
polypeptide	O
chain	O
is	O
folded	O
into	O
the	O
base	O
domain	O
(	O
residues	O
168	O
-	O
306	O
)	O
,	O
which	O
consists	O
of	O
a	O
five	O
-	O
stranded	O
anti	O
-	O
parallel	O
beta	O
-	O
sheet	O
with	O
four	O
alpha	O
-	O
helices	O
,	O
three	O
of	O
which	O
(	O
alpha	O
5	O
,	O
alpha	O
6	O
and	O
alpha	O
8	O
)	O
cover	O
one	O
side	O
of	O
the	O
beta	O
-	O
sheet	O
.	O

The	O
long	O
helix	O
alpha	O
8	O
is	O
slightly	O
bent	O
.	O

Structural	O
similarity	O
searches	O

When	O
we	O
searched	O
for	O
structural	O
similarity	O
against	O
the	O
Protein	O
Data	O
Bank	O
database	O
using	O
the	O
program	O
DALI	O
(	O
18	O
)	O
,	O
the	O
P	B
.	I
aeruginosa	I
RdgC	O
monomer	O
showed	O
no	O
significant	O
similarity	O
with	O
a	O
Z	O
score	O
above	O
5	O
.	O

Therefore	O
,	O
we	O
conclude	O
that	O
the	O
overall	O
fold	O
of	O
the	O
RdgC	O
polypeptide	O
chain	O
is	O
unique	O
.	O

When	O
we	O
elaborated	O
the	O
structural	O
comparisons	O
with	O
individual	O
domains	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
,	O
only	O
the	O
center	O
domain	O
gave	O
a	O
Z	O
score	O
above	O
5	O
.	O

Using	O
the	O
center	O
domain	O
(	O
residues	O
1	O
-	O
73	O
and	O
121	O
-	O
167	O
)	O
alone	O
,	O
the	O
highest	O
structural	O
similarity	O
is	O
found	O
with	O
the	O
human	B
beta	O
2	O
-	O
adaptin	O
appendage	O
domain	O
(	O
PDB	O
code	O
1E42	O
,	O
Z	O
score	O
=	O
7	O
.	O
1	O
,	O
r	O
.	O
m	O
.	O
s	O
.	O
deviation	O
=	O
2	O
.	O
5	O
A	O
for	O
85	O
structurally	O
aligned	O
residues	O
,	O
residues	O
1	O
-	O
12	O
,	O
14	O
-	O
30	O
,	O
44	O
-	O
47	O
,	O
58	O
-	O
72	O
,	O
122	O
-	O
133	O
and	O
135	O
-	O
160	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
chain	O
A	O
and	O
residues	O
838	O
-	O
841	O
,	O
848	O
-	O
880	O
,	O
885	O
-	O
906	O
and	O
912	O
-	O
967	O
of	O
the	O
human	B
beta	O
2	O
-	O
adaptin	O
appendage	O
domain	O
chain	O
A	O
)	O
(	O
19	O
)	O
.	O

There	O
does	O
not	O
appear	O
to	O
be	O
any	O
functional	O
relatedness	O
between	O
these	O
two	O
proteins	O
.	O

The	O
next	O
highest	O
similarity	O
is	O
found	O
with	O
the	O
yeast	B
TATA	O
-	O
box	O
-	O
binding	O
protein	O
(	O
PDB	O
code	O
1YTB	O
,	O
Z	O
score	O
=	O
5	O
.	O
7	O
,	O
r	O
.	O
m	O
.	O
s	O
.	O
deviation	O
=	O
2	O
.	O
6	O
A	O
for	O
79	O
structurally	O
aligned	O
residues	O
,	O
residues	O
4	O
-	O
12	O
,	O
14	O
-	O
19	O
,	O
21	O
-	O
27	O
,	O
56	O
-	O
70	O
,	O
124	O
-	O
132	O
and	O
134	O
-	O
166	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
chain	O
A	O
and	O
residues	O
69	O
-	O
96	O
,	O
100	O
-	O
126	O
and	O
132	O
-	O
155	O
of	O
TATA	O
-	O
box	O
-	O
binding	O
protein	O
,	O
N	O
-	O
terminal	O
half	O
of	O
chain	O
A	O
)	O
(	O
20	O
)	O
.	O

The	O
TATA	O
-	O
box	O
-	O
binding	O
protein	O
is	O
composed	O
of	O
a	O
ten	O
-	O
stranded	O
antiparallel	O
beta	O
-	O
sheet	O
with	O
four	O
flanking	O
alpha	O
-	O
helices	O
on	O
the	O
convex	O
side	O
of	O
the	O
beta	O
-	O
sheet	O
(	O
20	O
)	O
.	O

It	O
has	O
an	O
internal	O
quasi	O
2	O
-	O
fold	O
symmetry	O
,	O
and	O
its	O
beta	O
-	O
strands	O
are	O
involved	O
in	O
DNA	O
binding	O
.	O

There	O
is	O
,	O
however	O
,	O
no	O
structural	O
similarity	O
of	O
functional	O
significance	O
,	O
because	O
the	O
two	O
center	O
domains	O
of	O
the	O
RdgC	O
dimer	O
are	O
well	O
separated	O
and	O
do	O
not	O
associate	O
into	O
a	O
single	O
unit	O
(	O
Figure	O
1C	O
and	O
D	O
)	O
.	O

Using	O
the	O
tip	O
domain	O
(	O
residues	O
74	O
-	O
120	O
)	O
alone	O
,	O
the	O
ATPase	O
domain	O
of	O
bovine	B
Hsc70	O
chaperone	O
shows	O
highest	O
structural	O
similarity	O
(	O
PDB	O
code	O
1BA1	O
,	O
Z	O
score	O
=	O
4	O
.	O
8	O
,	O
r	O
.	O
m	O
.	O
s	O
.	O
deviation	O
=	O
1	O
.	O
7	O
A	O
for	O
45	O
structurally	O
aligned	O
residues	O
,	O
residues	O
76	O
-	O
120	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
chain	O
A	O
and	O
residues	O
230	O
-	O
253	O
and	O
256	O
-	O
276	O
of	O
the	O
Hsc70	O
ATPase	O
domain	O
)	O
(	O
21	O
)	O
.	O

There	O
does	O
not	O
seem	O
to	O
be	O
any	O
significant	O
functional	O
relationship	O
between	O
these	O
two	O
proteins	O
.	O

The	O
alpha	O
-	O
helix	O
-	O
loop	O
-	O
alpha	O
-	O
helix	O
structure	O
of	O
the	O
tip	O
domain	O
is	O
reminiscent	O
of	O
the	O
helix	O
-	O
hairpin	O
-	O
helix	O
(	O
HhH	O
)	O
DNA	O
-	O
binding	O
motif	O
that	O
is	O
present	O
in	O
a	O
number	O
of	O
DNA	O
repair	O
enzymes	O
(	O
22	O
-	O
25	O
)	O
.	O

The	O
HhH	O
motifs	O
are	O
characterized	O
by	O
the	O
conserved	O
sequence	O
motif	O
hxxhxGhGxxxAxxxhh	O
,	O
where	O
h	O
is	O
any	O
hydrophobic	O
residue	O
(	O
VILMWFYA	O
)	O
and	O
x	O
any	O
residue	O
(	O
23	O
)	O
.	O

Two	O
conserved	O
glycines	O
allow	O
a	O
tight	O
turn	O
between	O
two	O
alpha	O
-	O
helices	O
.	O

However	O
,	O
the	O
tip	O
domain	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
protein	O
does	O
not	O
have	O
such	O
a	O
sequence	O
motif	O
,	O
and	O
the	O
loop	O
in	O
the	O
RdgC	O
tip	O
domain	O
is	O
much	O
more	O
extended	O
than	O
that	O
of	O
the	O
HhH	O
motifs	O
.	O

Therefore	O
,	O
the	O
RdgC	O
tip	O
domain	O
is	O
uniquely	O
folded	O
.	O

With	O
the	O
base	O
domain	O
(	O
residues	O
168	O
-	O
306	O
)	O
alone	O
,	O
the	O
highest	O
similarity	O
is	O
found	O
with	O
P	B
.	I
aeruginosa	I
isochorismate	O
-	O
pyruvate	O
lyase	O
(	O
unpublished	O
deposition	O
;	O
PDB	O
code	O
2H9C	O
,	O
Z	O
score	O
=	O
4	O
.	O
0	O
,	O
r	O
.	O
m	O
.	O
s	O
.	O
deviation	O
=	O
4	O
.	O
8	O
A	O
for	O
51	O
structurally	O
aligned	O
residues	O
,	O
residues	O
186	O
-	O
191	O
,	O
237	O
-	O
240	O
,	O
257	O
-	O
272	O
and	O
274	O
-	O
298	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
chain	O
A	O
and	O
residues	O
36	O
-	O
41	O
,	O
50	O
-	O
53	O
,	O
55	O
-	O
66	O
and	O
68	O
-	O
96	O
of	O
P	B
.	I
aeruginosa	I
isochorismate	O
-	O
pyruvate	O
lyase	O
chain	O
A	O
)	O
.	O

There	O
does	O
not	O
appear	O
to	O
be	O
any	O
functional	O
relationship	O
between	O
the	O
two	O
proteins	O
,	O
and	O
the	O
base	O
domain	O
of	O
RdgC	O
is	O
uniquely	O
folded	O
.	O

The	O
101	O
-	O
residue	O
chain	O
of	O
P	B
.	I
aeruginosa	I
isochorismate	O
-	O
pyruvate	O
lyase	O
is	O
folded	O
into	O
three	O
alpha	O
-	O
helices	O
,	O
two	O
of	O
which	O
overlap	O
with	O
two	O
alpha	O
-	O
helices	O
(	O
alpha	O
2	O
and	O
alpha	O
3	O
)	O
of	O
the	O
base	O
domain	O
of	O
RdgC	O
.	O

Ring	O
-	O
shaped	O
dimer	O
structure	O
and	O
inter	O
-	O
subunit	O
interface	O

Our	O
structure	O
reveals	O
that	O
P	B
.	I
aeruginosa	I
RdgC	O
forms	O
a	O
ring	O
-	O
shaped	O
dimer	O
of	O
approximate	O
2	O
-	O
fold	O
symmetry	O
in	O
the	O
crystal	O
(	O
Figure	O
1	O
)	O
.	O

This	O
observation	O
is	O
consistent	O
with	O
the	O
results	O
of	O
previous	O
gel	O
filtration	O
and	O
sedimentation	O
equilibrium	O
experiments	O
,	O
which	O
suggested	O
the	O
presence	O
of	O
dimeric	O
species	O
of	O
E	B
.	I
coli	I
RdgC	O
in	O
solution	O
(	O
1	O
,	O
2	O
)	O
.	O

Depending	O
on	O
the	O
concentration	O
,	O
RdgC	O
could	O
also	O
exist	O
in	O
solution	O
as	O
monomers	O
,	O
tetramers	O
and	O
higher	O
oligomers	O
(	O
1	O
)	O
.	O

In	O
the	O
crystal	O
lattice	O
,	O
no	O
monomeric	O
,	O
trimeric	O
or	O
tetrameric	O
species	O
exist	O
.	O

Our	O
structure	O
unequivocally	O
rules	O
out	O
the	O
monomer	O
-	O
trimer	O
model	O
,	O
which	O
fits	O
the	O
sedimentation	O
equilibrium	O
data	O
approximately	O
,	O
as	O
well	O
as	O
the	O
monomer	O
-	O
dimer	O
-	O
tetramer	O
model	O
(	O
1	O
)	O
.	O

The	O
RdgC	O
dimer	O
has	O
approximate	O
dimensions	O
of	O
80	O
A	O
x	O
60	O
A	O
x	O
40	O
A	O
,	O
with	O
a	O
central	O
hole	O
of	O
~	O
30	O
A	O
diameter	O
.	O

Only	O
a	O
moderate	O
amount	O
of	O
surface	O
area	O
is	O
buried	O
upon	O
the	O
formation	O
of	O
the	O
RdgC	O
dimer	O
.	O

The	O
monomer	O
-	O
monomer	O
interface	O
buries	O
a	O
solvent	O
-	O
accessible	O
surface	O
area	O
of	O
~	O
1360	O
A	O
2	O
per	O
monomer	O
,	O
corresponding	O
to	O
~	O
8	O
%	O
of	O
the	O
total	O
surface	O
area	O
of	O
the	O
monomer	O
(	O
Protein	O
-	O
Protein	O
Interaction	O
Server	O
at	O
http	O
:	O
/	O
/	O
www	O
.	O
biochem	O
.	O
ucl	O
.	O
ac	O
.	O
uk	O
/	O
bsm	O
/	O
PP	O
/	O
server	O
/	O
)	O
.	O

Polar	O
and	O
nonpolar	O
atoms	O
in	O
interface	O
are	O
44	O
and	O
56	O
%	O
,	O
respectively	O
.	O

The	O
interface	O
can	O
be	O
divided	O
into	O
two	O
kinds	O
:	O
'	O
interface	O
A	O
'	O
involving	O
both	O
the	O
tip	O
domains	O
and	O
center	O
domains	O
,	O
and	O
'	O
interface	O
B	O
'	O
involving	O
the	O
base	O
domains	O
(	O
Figure	O
2A	O
)	O
.	O

These	O
two	O
interfaces	O
have	O
significantly	O
different	O
characters	O
.	O

The	O
interface	O
A	O
is	O
formed	O
largely	O
by	O
the	O
crossing	O
over	O
of	O
the	O
two	O
tip	O
domains	O
in	O
the	O
dimer	O
(	O
Figure	O
1	O
)	O
.	O

This	O
interface	O
covers	O
a	O
surface	O
area	O
of	O
~	O
565	O
A	O
2	O
and	O
is	O
largely	O
nonpolar	O
,	O
with	O
the	O
polar	O
and	O
nonpolar	O
atoms	O
in	O
the	O
interface	O
being	O
37	O
.	O
5	O
and	O
2	O
.	O
5	O
%	O
,	O
respectively	O
.	O

Phe120	O
contributes	O
considerably	O
to	O
the	O
nonpolar	O
character	O
of	O
the	O
interface	O
between	O
the	O
tip	O
domains	O
,	O
accounting	O
for	O
~	O
150	O
A	O
2	O
of	O
the	O
interface	O
area	O
.	O

Phe120	O
is	O
part	O
of	O
a	O
highly	O
conserved	O
sequence	O
segment	O
and	O
lies	O
at	O
the	O
boundary	O
between	O
the	O
tip	O
domain	O
and	O
the	O
center	O
domain	O
.	O

The	O
aromatic	O
ring	O
of	O
Phe120	O
'	O
inserts	O
into	O
a	O
hydrophobic	O
pocket	O
,	O
which	O
is	O
formed	O
by	O
the	O
hydrophobic	O
residues	O
Ile74	O
,	O
Leu75	O
,	O
Pro76	O
,	O
Val79	O
,	O
Leu115	O
,	O
Ala119	O
and	O
Phe120	O
of	O
the	O
neighboring	O
monomer	O
(	O
Figure	O
2B	O
)	O
.	O

The	O
primed	O
residue	O
belongs	O
to	O
the	O
adjacent	O
subunit	O
.	O

These	O
residues	O
are	O
well	O
conserved	O
in	O
the	O
RdgC	O
family	O
(	O
indicated	O
by	O
green	O
triangles	O
below	O
the	O
aligned	O
sequences	O
in	O
Figure	O
3	O
)	O
.	O

As	O
these	O
hydrophobic	O
residues	O
are	O
located	O
near	O
the	O
molecular	O
2	O
-	O
fold	O
axis	O
,	O
the	O
two	O
clusters	O
of	O
hydrophobic	O
side	O
chains	O
are	O
merged	O
into	O
a	O
single	O
,	O
large	O
cluster	O
in	O
the	O
dimer	O
(	O
Figure	O
2B	O
)	O
.	O

Of	O
the	O
16	O
hydrogen	O
bonds	O
that	O
exist	O
between	O
the	O
two	O
subunits	O
,	O
only	O
one	O
is	O
made	O
in	O
this	O
interface	O
between	O
Arg118	O
and	O
Arg118	O
'	O
.	O

The	O
interface	O
B	O
is	O
contributed	O
to	O
exclusively	O
by	O
the	O
two	O
base	O
domains	O
.	O

This	O
interface	O
covers	O
a	O
surface	O
area	O
of	O
~	O
795	O
A	O
2	O
.	O

The	O
polar	O
and	O
nonpolar	O
atoms	O
in	O
this	O
interface	O
are	O
50	O
%	O
each	O
.	O

The	O
two	O
beta	O
-	O
sheets	O
of	O
the	O
two	O
base	O
domains	O
merge	O
into	O
a	O
single	O
ten	O
-	O
stranded	O
antiparallel	O
beta	O
-	O
sheet	O
in	O
this	O
interface	O
(	O
Figure	O
2A	O
)	O
.	O

Thus	O
,	O
15	O
of	O
16	O
inter	O
-	O
subunit	O
hydrogen	O
bonds	O
are	O
clustered	O
in	O
this	O
interface	O
.	O

The	O
hydrogen	O
bond	O
networks	O
can	O
be	O
divided	O
into	O
two	O
types	O
.	O

The	O
first	O
type	O
involves	O
the	O
main	O
chain	O
atoms	O
of	O
Val206	O
,	O
Arg208	O
and	O
Lys210	O
in	O
strand	O
beta	O
9	O
;	O
this	O
strand	O
associates	O
with	O
the	O
equivalent	O
strand	O
from	O
the	O
other	O
subunit	O
in	O
an	O
antiparallel	O
manner	O
(	O
Figure	O
2C	O
)	O
.	O

The	O
other	O
type	O
involves	O
both	O
the	O
side	O
chain	O
and	O
main	O
chain	O
atoms	O
.	O

The	O
side	O
chain	O
of	O
Arg211	O
'	O
interacts	O
with	O
the	O
backbone	O
of	O
Gly204	O
,	O
while	O
the	O
side	O
chain	O
of	O
Lys227	O
hydrogen	O
bonds	O
to	O
those	O
of	O
both	O
Gln212	O
'	O
and	O
Glu218	O
(	O
Figure	O
2D	O
)	O
.	O

In	O
addition	O
,	O
the	O
side	O
chain	O
of	O
Gln212	O
'	O
interacts	O
with	O
that	O
of	O
Asp199	O
and	O
the	O
backbone	O
of	O
Arg211	O
'	O
(	O
Figure	O
2D	O
)	O
.	O

Arg211	O
,	O
Gln212	O
,	O
Glu218	O
and	O
Lys227	O
are	O
highly	O
conserved	O
among	O
the	O
RdgC	O
family	O
members	O
.	O

The	O
residues	O
participating	O
in	O
the	O
hydrogen	O
bond	O
networks	O
are	O
indicated	O
by	O
red	O
circles	O
below	O
the	O
aligned	O
sequences	O
in	O
Figure	O
3	O
.	O

The	O
observation	O
that	O
conserved	O
residues	O
play	O
important	O
roles	O
in	O
forming	O
the	O
dimer	O
implies	O
that	O
dimerization	O
of	O
RdgC	O
is	O
critical	O
for	O
its	O
function	O
.	O

If	O
one	O
or	O
both	O
of	O
interfaces	O
A	O
and	O
B	O
are	O
to	O
be	O
broken	O
for	O
functional	O
reasons	O
such	O
as	O
for	O
allowing	O
dsDNA	O
to	O
enter	O
into	O
the	O
central	O
hole	O
of	O
the	O
RdgC	O
dimer	O
,	O
we	O
can	O
conceive	O
of	O
three	O
scenarios	O
.	O

The	O
first	O
possibility	O
would	O
be	O
a	O
simultaneous	O
breakage	O
of	O
the	O
two	O
interfaces	O
A	O
and	O
B	O
.	O

The	O
second	O
would	O
be	O
the	O
sequential	O
disruption	O
of	O
the	O
interfaces	O
A	O
and	O
B	O
.	O

The	O
third	O
would	O
be	O
the	O
disruption	O
of	O
only	O
one	O
of	O
the	O
two	O
interfaces	O
A	O
and	O
B	O
.	O

Sedimentation	O
equilibrium	O
indicated	O
the	O
presence	O
of	O
monomers	O
in	O
solution	O
(	O
1	O
)	O
,	O
which	O
is	O
consistent	O
with	O
the	O
first	O
two	O
scenarios	O
.	O

If	O
the	O
third	O
scenario	O
holds	O
,	O
RdgC	O
dimers	O
could	O
possibly	O
exist	O
in	O
two	O
conformations	O
in	O
solution	O
,	O
i	O
.	O
e	O
.	O
a	O
closed	O
form	O
as	O
observed	O
in	O
the	O
present	O
crystal	O
structure	O
,	O
and	O
an	O
open	O
form	O
,	O
in	O
which	O
one	O
of	O
the	O
two	O
interfaces	O
A	O
and	O
B	O
is	O
broken	O
.	O

A	O
model	O
for	O
DNA	O
binding	O
by	O
RdgC	O
and	O
DNA	O
-	O
binding	O
assay	O

The	O
net	O
charge	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
is	O
highly	O
negative	O
,	O
since	O
each	O
monomer	O
contains	O
12	O
aspartate	O
,	O
13	O
glutamate	O
,	O
10	O
lysine	O
,	O
9	O
arginine	O
and	O
2	O
histidine	O
residues	O
.	O

The	O
net	O
charge	O
of	O
a	O
dimer	O
would	O
be	O
-	O
12	O
(	O
or	O
-	O
8	O
)	O
,	O
if	O
we	O
assume	O
none	O
(	O
or	O
all	O
)	O
of	O
histidines	O
to	O
be	O
positively	O
charged	O
.	O

The	O
electrostatic	O
potential	O
at	O
the	O
molecular	O
surface	O
of	O
RdgC	O
dimer	O
shows	O
that	O
the	O
charge	O
distribution	O
on	O
the	O
protein	O
surface	O
is	O
highly	O
nonuniform	O
(	O
Figure	O
4A	O
)	O
.	O

Since	O
the	O
inner	O
surface	O
of	O
the	O
RdgC	O
dimer	O
is	O
rich	O
in	O
conserved	O
,	O
positively	O
charged	O
residues	O
and	O
the	O
diameter	O
of	O
the	O
central	O
hole	O
(	O
~	O
30	O
A	O
)	O
is	O
approximately	O
similar	O
to	O
that	O
of	O
other	O
toroidal	O
DNA	O
-	O
binding	O
proteins	O
(	O
26	O
)	O
,	O
it	O
appears	O
likely	O
that	O
RdgC	O
dimers	O
bind	O
dsDNA	O
through	O
the	O
central	O
hole	O
.	O

Despite	O
extensive	O
co	O
-	O
crystallization	O
and	O
soaking	O
trials	O
with	O
linear	O
dsDNAs	O
of	O
different	O
lengths	O
(	O
14	O
-	O
mer	O
,	O
16	O
-	O
mer	O
and	O
18	O
-	O
mer	O
)	O
,	O
we	O
could	O
not	O
locate	O
the	O
bound	O
DNA	O
experimentally	O
.	O

We	O
attribute	O
this	O
difficulty	O
to	O
the	O
nature	O
of	O
sequence	O
-	O
nonspecific	O
DNA	O
binding	O
by	O
RdgC	O
.	O

Therefore	O
,	O
we	O
built	O
a	O
crude	O
model	O
of	O
a	O
DNA	O
complex	O
of	O
the	O
RdgC	O
dimer	O
by	O
fitting	O
dsDNA	O
into	O
the	O
central	O
hole	O
(	O
Figure	O
4B	O
)	O
.	O

This	O
model	O
is	O
supported	O
by	O
the	O
DNA	O
-	O
binding	O
assays	O
coupled	O
with	O
mutagenesis	O
,	O
as	O
described	O
below	O
.	O

It	O
is	O
also	O
consistent	O
with	O
the	O
suggested	O
binding	O
site	O
size	O
of	O
~	O
16	O
nt	O
for	O
the	O
E	B
.	I
coli	I
RdgC	O
dimer	O
(	O
1	O
)	O
and	O
the	O
approximate	O
thickness	O
(	O
~	O
40	O
A	O
)	O
of	O
the	O
P	B
.	I
aeruginosa	I
RdgC	O
dimer	O
.	O

When	O
we	O
performed	O
electrophoretic	O
mobility	O
shift	O
assay	O
for	O
dsDNA	O
binding	O
,	O
P	B
.	I
aeruginosa	I
RdgC	O
did	O
not	O
require	O
Mg2	O
+	O
ions	O
(	O
Supplementary	O
Figure	O
2	O
)	O
,	O
unlike	O
Deinococcus	B
radiodurans	I
RecR	O
,	O
which	O
required	O
high	O
concentrations	O
of	O
Mg2	O
+	O
ions	O
(	O
27	O
)	O
.	O

ATP	O
was	O
not	O
required	O
for	O
dsDNA	O
binding	O
by	O
P	B
.	I
aeruginosa	I
RdgC	O
,	O
either	O
(	O
Supplementary	O
Figure	O
2	O
)	O
.	O

This	O
is	O
consistent	O
with	O
an	O
apparent	O
lack	O
of	O
an	O
ATP	O
-	O
binding	O
pocket	O
in	O
the	O
RdgC	O
dimer	O
structure	O
.	O

In	O
order	O
to	O
identify	O
the	O
residues	O
that	O
are	O
important	O
for	O
dsDNA	O
binding	O
,	O
we	O
carried	O
out	O
mutational	O
analyses	O
.	O

The	O
residues	O
for	O
mutagenesis	O
were	O
selected	O
on	O
the	O
basis	O
of	O
the	O
modeled	O
complex	O
between	O
RdgC	O
dimer	O
and	O
dsDNA	O
,	O
together	O
with	O
sequence	O
conservation	O
(	O
Figure	O
4C	O
)	O
.	O

We	O
prepared	O
eleven	O
point	O
mutants	O
(	O
R4A	O
,	O
K70D	O
,	O
R81D	O
,	O
F120A	O
,	O
R122D	O
,	O
K146A	O
,	O
R198A	O
,	O
R208A	O
,	O
R211D	O
,	O
Q212A	O
and	O
R252A	O
)	O
.	O

These	O
eleven	O
mutated	O
residues	O
are	O
well	O
conserved	O
among	O
RdgC	O
proteins	O
.	O

Eight	O
mutants	O
(	O
R4A	O
,	O
K70D	O
,	O
R81D	O
,	O
R122D	O
,	O
K146A	O
,	O
R198A	O
,	O
R208A	O
and	O
R252A	O
)	O
had	O
a	O
lower	O
affinity	O
for	O
dsDNA	O
than	O
the	O
wild	O
-	O
type	O
RdgC	O
(	O
Figure	O
4D	O
)	O
.	O

These	O
eight	O
mutated	O
residues	O
are	O
indicated	O
by	O
blue	O
squares	O
below	O
the	O
aligned	O
sequences	O
in	O
Figure	O
3	O
.	O

This	O
result	O
indicates	O
that	O
dsDNA	O
binds	O
to	O
the	O
inside	O
surface	O
around	O
the	O
central	O
hole	O
of	O
the	O
RdgC	O
dimer	O
,	O
since	O
the	O
mutated	O
residues	O
are	O
located	O
on	O
the	O
inner	O
surface	O
of	O
the	O
RdgC	O
dimer	O
.	O

It	O
is	O
worth	O
mentioning	O
that	O
a	O
single	O
mutation	O
introduces	O
two	O
alterations	O
per	O
RdgC	O
dimer	O
.	O

The	O
three	O
mutants	O
(	O
F120A	O
,	O
R211D	O
and	O
Q212A	O
)	O
were	O
prepared	O
to	O
investigate	O
whether	O
dimerization	O
of	O
RdgC	O
is	O
crucial	O
for	O
dsDNA	O
binding	O
.	O

Phe120	O
is	O
a	O
key	O
residue	O
located	O
in	O
the	O
inter	O
-	O
subunit	O
interface	O
A	O
(	O
Figure	O
2B	O
)	O
,	O
while	O
Arg211	O
makes	O
hydrogen	O
bonds	O
in	O
the	O
interface	O
B	O
(	O
Figure	O
2D	O
)	O
and	O
Gln212	O
is	O
involved	O
in	O
both	O
intra	O
-	O
and	O
inter	O
-	O
subunit	O
interactions	O
(	O
Figure	O
2D	O
)	O
.	O

dsDNA	O
binding	O
by	O
the	O
F120A	O
mutant	O
is	O
considerably	O
weakened	O
,	O
compared	O
to	O
either	O
the	O
R211D	O
or	O
Q212A	O
mutant	O
(	O
Figure	O
4D	O
)	O
.	O

This	O
result	O
suggests	O
that	O
destabilization	O
of	O
the	O
ring	O
-	O
shaped	O
architecture	O
of	O
the	O
RdgC	O
dimer	O
is	O
deleterious	O
for	O
tight	O
dsDNA	O
binding	O
and	O
that	O
interface	O
A	O
is	O
probably	O
more	O
important	O
than	O
interface	O
B	O
for	O
dsDNA	O
binding	O
.	O

dsDNA	O
-	O
binding	O
affinity	O
of	O
the	O
Q212A	O
mutant	O
was	O
lower	O
than	O
the	O
wild	O
type	O
(	O
Figure	O
4D	O
)	O
,	O
whereas	O
that	O
of	O
the	O
R211D	O
mutant	O
was	O
comparable	O
to	O
the	O
wild	O
type	O
(	O
Figure	O
4D	O
)	O
.	O

This	O
result	O
suggests	O
that	O
disruption	O
of	O
the	O
inter	O
-	O
subunit	O
interface	O
B	O
is	O
also	O
detrimental	O
for	O
dsDNA	O
binding	O
but	O
to	O
a	O
smaller	O
extent	O
than	O
disruption	O
of	O
the	O
interface	O
A	O
.	O

It	O
further	O
suggests	O
that	O
the	O
side	O
chain	O
of	O
Arg211	O
is	O
not	O
involved	O
in	O
recognizing	O
dsDNA	O
.	O

It	O
is	O
interesting	O
that	O
the	O
DNA	O
complex	O
for	O
wild	O
type	O
forms	O
a	O
distinct	O
band	O
(	O
lane	O
3	O
in	O
Figure	O
4D	O
)	O
,	O
as	O
opposed	O
to	O
a	O
more	O
diffuse	O
band	O
as	O
one	O
would	O
expect	O
if	O
the	O
complexes	O
contained	O
different	O
numbers	O
of	O
RdgC	O
dimers	O
.	O

Assuming	O
a	O
binding	O
site	O
size	O
of	O
~	O
16	O
nt	O
(	O
1	O
)	O
,	O
the	O
414	O
-	O
bp	O
duplex	O
DNA	O
would	O
bind	O
~	O
25	O
RdgC	O
dimers	O
if	O
it	O
is	O
fully	O
saturated	O
.	O

RdgC	O
is	O
unique	O
among	O
ring	O
-	O
shaped	O
DNA	O
-	O
binding	O
proteins	O

Pseudomonas	B
aeruginosa	I
RdgC	O
adds	O
a	O
unique	O
member	O
to	O
the	O
repertoire	O
of	O
toroidal	O
DNA	O
-	O
binding	O
proteins	O
(	O
26	O
)	O
such	O
as	O
D	B
.	I
radiodurans	I
RecR	O
(	O
27	O
)	O
and	O
DNA	O
polymerase	O
processivity	O
factors	O
,	O
including	O
the	O
beta	O
subunit	O
of	O
E	B
.	I
coli	I
DNA	O
polymerase	O
III	O
(	O
28	O
)	O
,	O
gp45	O
of	O
T4	O
DNA	O
polymerase	O
(	O
29	O
)	O
and	O
PCNA	O
of	O
eukaryotic	O
DNA	O
polymerase	O
delta	O
(	O
30	O
,	O
31	O
)	O
(	O
Figure	O
5	O
)	O
.	O

These	O
proteins	O
do	O
not	O
have	O
an	O
overall	O
sequence	O
similarity	O
among	O
themselves	O
,	O
and	O
their	O
quaternary	O
structures	O
also	O
vary	O
.	O

P	B
.	I
aeruginosa	I
RdgC	O
and	O
E	B
.	I
coli	I
beta	O
clamp	O
are	O
homodimers	O
,	O
T4	O
gp45	O
and	O
eukaryotic	O
PCNAs	O
are	O
homotrimers	O
and	O
D	B
.	I
radiodurans	I
RecR	O
is	O
a	O
homotetramer	O
.	O

In	O
P	B
.	I
aeruginosa	I
RdgC	O
,	O
the	O
inner	O
surface	O
of	O
the	O
ring	O
-	O
shaped	O
dimer	O
is	O
largely	O
formed	O
by	O
beta	O
-	O
strands	O
,	O
while	O
the	O
outer	O
surface	O
of	O
the	O
ring	O
is	O
mostly	O
formed	O
by	O
alpha	O
-	O
helices	O
(	O
Figure	O
5	O
)	O
.	O

The	O
predicted	O
DNA	O
-	O
binding	O
site	O
of	O
P	B
.	I
aeruginosa	I
RdgC	O
dimer	O
is	O
primarily	O
formed	O
by	O
beta	O
-	O
strands	O
and	O
loops	O
.	O

In	O
contrast	O
,	O
in	O
other	O
ring	O
-	O
shaped	O
DNA	O
-	O
binding	O
proteins	O
such	O
as	O
the	O
beta	O
subunit	O
of	O
E	B
.	I
coli	I
DNA	O
polymerase	O
III	O
(	O
28	O
)	O
,	O
gp45	O
of	O
T4	O
DNA	O
polymerase	O
(	O
29	O
)	O
,	O
PCNA	O
of	O
eukaryotic	O
DNA	O
polymerases	O
delta	O
(	O
30	O
,	O
31	O
)	O
and	O
D	B
.	I
radiodurans	I
RecR	O
(	O
27	O
)	O
,	O
alpha	O
-	O
helices	O
are	O
located	O
toward	O
the	O
center	O
of	O
the	O
ring	O
and	O
are	O
surrounded	O
by	O
beta	O
-	O
strands	O
in	O
the	O
outermost	O
side	O
of	O
the	O
ring	O
(	O
Figure	O
5	O
)	O
.	O

Despite	O
a	O
superficial	O
resemblance	O
of	O
the	O
overall	O
ring	O
-	O
shaped	O
architecture	O
of	O
the	O
RdgC	O
dimer	O
with	O
those	O
of	O
other	O
toroidal	O
DNA	O
-	O
binding	O
proteins	O
,	O
the	O
internal	O
arrangement	O
of	O
the	O
secondary	O
structure	O
elements	O
in	O
the	O
RdgC	O
dimer	O
is	O
strikingly	O
different	O
from	O
those	O
of	O
other	O
toroidal	O
DNA	O
-	O
binding	O
proteins	O
.	O

Thus	O
,	O
RdgC	O
is	O
unique	O
among	O
ring	O
-	O
shaped	O
DNA	O
-	O
binding	O
proteins	O
.	O

A	O
number	O
of	O
other	O
proteins	O
involved	O
in	O
DNA	O
metabolism	O
also	O
adopt	O
a	O
ring	O
-	O
shaped	O
structure	O
despite	O
diversity	O
in	O
the	O
molecular	O
functions	O
(	O
26	O
)	O
.	O

They	O
include	O
NAD	O
+	O
-	O
dependent	O
DNA	O
ligase	O
(	O
25	O
)	O
,	O
lambda	O
exonuclease	O
(	O
32	O
)	O
,	O
hexameric	O
helicases	O
,	O
topoisomerases	O
,	O
the	O
trp	O
RNA	O
-	O
binding	O
attenuation	O
protein	O
,	O
the	O
bacteriophage	O
head	O
-	O
to	O
-	O
tail	O
connector	O
and	O
translin	O
(	O
26	O
)	O
.	O

There	O
are	O
also	O
many	O
examples	O
of	O
the	O
proteins	O
in	O
DNA	O
recombination	O
pathways	O
that	O
assemble	O
into	O
multi	O
-	O
subunit	O
toroids	O
containing	O
a	O
central	O
channel	O
(	O
26	O
)	O
.	O

Electron	O
microscopy	O
showed	O
that	O
the	O
E	B
.	I
coli	I
RuvB	O
protein	O
,	O
in	O
the	O
presence	O
of	O
ATP	O
,	O
forms	O
a	O
dodecamer	O
on	O
double	O
-	O
stranded	O
DNA	O
in	O
which	O
two	O
stacked	O
hexameric	O
rings	O
encircle	O
the	O
DNA	O
and	O
are	O
oriented	O
in	O
opposite	O
directions	O
with	O
D6	O
symmetry	O
(	O
33	O
)	O
.	O

The	O
human	B
RAD52	O
protein	O
was	O
found	O
to	O
assemble	O
into	O
heptameric	O
rings	O
with	O
a	O
large	O
funnel	O
-	O
shaped	O
channel	O
,	O
40	O
-	O
60	O
A	O
in	O
diameter	O
(	O
34	O
)	O
.	O

The	O
human	B
DMC1	O
protein	O
has	O
so	O
far	O
been	O
detected	O
only	O
as	O
an	O
octameric	O
ring	O
(	O
35	O
)	O
.	O

Inhibition	O
mechanism	O
of	O
RecA	O
function	O
by	O
RdgC	O

RdgC	O
inhibits	O
RecA	O
-	O
promoted	O
DNA	O
strand	O
exchange	O
,	O
RecA	O
-	O
mediated	O
ATPase	O
activity	O
and	O
RecA	O
-	O
dependent	O
LexA	O
cleavage	O
(	O
1	O
)	O
.	O

It	O
was	O
observed	O
that	O
the	O
effects	O
of	O
RdgC	O
on	O
RecA	O
-	O
promoted	O
DNA	O
strand	O
exchange	O
were	O
much	O
more	O
pronounced	O
than	O
the	O
effects	O
of	O
RdgC	O
on	O
other	O
RecA	O
functions	O
,	O
when	O
RdgC	O
was	O
added	O
to	O
the	O
reaction	O
late	O
(	O
1	O
)	O
.	O

By	O
examining	O
the	O
effects	O
of	O
the	O
DinI	O
protein	O
on	O
RdgC	O
-	O
mediated	O
inhibition	O
of	O
RecA	O
activities	O
,	O
it	O
was	O
concluded	O
that	O
the	O
potent	O
effect	O
of	O
RdgC	O
in	O
the	O
inhibition	O
of	O
strand	O
exchange	O
did	O
not	O
primarily	O
reflect	O
a	O
displacement	O
of	O
RecA	O
in	O
the	O
nucleoprotein	O
filament	O
by	O
RdgC	O
,	O
but	O
instead	O
a	O
binding	O
of	O
RdgC	O
to	O
the	O
dsDNA	O
substrate	O
so	O
as	O
to	O
make	O
it	O
unavailable	O
to	O
the	O
filaments	O
for	O
strand	O
exchange	O
(	O
1	O
)	O
.	O

Our	O
work	O
contributes	O
to	O
a	O
better	O
understanding	O
of	O
the	O
inhibition	O
mechanism	O
of	O
RecA	O
function	O
by	O
RdgC	O
.	O

The	O
ring	O
-	O
shaped	O
architecture	O
with	O
a	O
central	O
hole	O
that	O
is	O
suitable	O
for	O
the	O
binding	O
of	O
dsDNA	O
lends	O
RdgC	O
with	O
a	O
capacity	O
to	O
hold	O
dsDNA	O
very	O
tightly	O
.	O

Therefore	O
,	O
we	O
suggest	O
that	O
RdgC	O
dimers	O
probably	O
function	O
as	O
a	O
tight	O
dsDNA	O
gripper	O
and	O
physically	O
block	O
access	O
to	O
the	O
target	O
dsDNA	O
by	O
RecA	O
filaments	O
,	O
because	O
tight	O
encircling	O
of	O
dsDNA	O
by	O
RdgC	O
dimers	O
,	O
possibly	O
as	O
a	O
linear	O
aggregate	O
,	O
would	O
prevent	O
the	O
two	O
strands	O
from	O
dissociating	O
.	O

However	O
,	O
it	O
remains	O
unclear	O
how	O
the	O
closed	O
-	O
ring	O
structure	O
of	O
the	O
RdgC	O
dimer	O
might	O
allow	O
binding	O
of	O
a	O
large	O
number	O
of	O
RdgC	O
dimers	O
on	O
the	O
duplex	O
DNA	O
.	O

It	O
may	O
be	O
conceivable	O
that	O
each	O
RdgC	O
dimer	O
can	O
open	O
temporarily	O
at	O
one	O
or	O
both	O
of	O
its	O
two	O
inter	O
-	O
subunit	O
interfaces	O
so	O
that	O
dsDNA	O
can	O
enter	O
the	O
central	O
hole	O
.	O

RdgC	O
was	O
at	O
its	O
highest	O
level	O
during	O
exponential	O
phase	O
,	O
reaching	O
its	O
maximum	O
of	O
~	O
1000	O
dimers	O
per	O
E	B
.	I
coli	I
cell	O
.	O

Its	O
level	O
decreased	O
sharply	O
to	O
~	O
50	O
dimers	O
per	O
cell	O
in	O
stationary	O
phase	O
(	O
2	O
)	O
.	O

Under	O
normal	O
cellular	O
conditions	O
,	O
RecA	O
is	O
maintained	O
at	O
~	O
1000	O
molecules	O
per	O
cell	O
(	O
http	O
:	O
/	O
/	O
www	O
.	O
els	O
.	O
net	O
/	O
)	O
.	O

Following	O
LexA	O
repressor	O
cleavage	O
,	O
the	O
level	O
of	O
RecA	O
protein	O
in	O
the	O
cell	O
increases	O
by	O
as	O
much	O
as	O
20	O
-	O
fold	O
.	O

RdgC	O
inhibition	O
of	O
the	O
RecA	O
function	O
by	O
a	O
simple	O
competition	O
mechanism	O
at	O
the	O
cellular	O
concentration	O
of	O
RdgC	O
clearly	O
requires	O
a	O
much	O
higher	O
affinity	O
for	O
DNA	O
by	O
RdgC	O
than	O
RecA	O
.	O

Possible	O
protein	O
-	O
protein	O
interactions	O
between	O
RdgC	O
dimers	O
might	O
have	O
a	O
profound	O
effect	O
on	O
the	O
affinity	O
for	O
DNA	O
,	O
when	O
a	O
large	O
number	O
of	O
RdgC	O
dimers	O
are	O
bound	O
on	O
a	O
duplex	O
DNA	O
.	O

If	O
only	O
one	O
of	O
the	O
two	O
inter	O
-	O
subunit	O
interfaces	O
can	O
open	O
up	O
and	O
the	O
2	O
-	O
fold	O
symmetry	O
axes	O
of	O
the	O
RdgC	O
dimers	O
are	O
misaligned	O
sufficiently	O
,	O
the	O
escape	O
of	O
DNA	O
from	O
a	O
linear	O
array	O
of	O
interacting	O
RdgC	O
dimers	O
would	O
be	O
extremely	O
difficult	O
.	O

Alternatively	O
,	O
both	O
inter	O
-	O
subunit	O
interfaces	O
of	O
each	O
dimer	O
may	O
open	O
up	O
simultaneously	O
.	O

A	O
line	O
of	O
indirect	O
evidence	O
for	O
the	O
possible	O
protein	O
-	O
protein	O
interactions	O
between	O
RdgC	O
dimers	O
is	O
provided	O
by	O
the	O
cooperative	O
binding	O
of	O
RdgC	O
to	O
DNA	O
(	O
7	O
)	O
.	O

Cooperativity	O
of	O
RdgC	O
binding	O
may	O
be	O
caused	O
by	O
local	O
and	O
distant	O
protein	O
-	O
protein	O
interactions	O
(	O
7	O
)	O
.	O

A	O
kind	O
of	O
side	O
-	O
by	O
-	O
side	O
interaction	O
between	O
two	O
adjacent	O
molecules	O
of	O
RdgC	O
dimer	O
is	O
present	O
in	O
the	O
crystal	O
,	O
burying	O
an	O
accessible	O
surface	O
area	O
of	O
~	O
750	O
A	O
2	O
at	O
the	O
interface	O
.	O

The	O
interaction	O
involves	O
mostly	O
the	O
less	O
polar	O
side	O
surface	O
of	O
the	O
dimer	O
(	O
left	O
side	O
of	O
Figure	O
4A	O
)	O
,	O
with	O
2	O
-	O
fold	O
symmetry	O
axes	O
of	O
the	O
two	O
interacting	O
RdgC	O
molecules	O
making	O
an	O
angle	O
of	O
~	O
90	O
degrees	O
when	O
viewed	O
down	O
the	O
central	O
holes	O
and	O
~	O
15	O
degrees	O
when	O
viewed	O
perpendicular	O
to	O
the	O
holes	O
.	O

This	O
may	O
explain	O
the	O
observed	O
DNA	O
bending	O
by	O
RdgC	O
,	O
which	O
was	O
speculated	O
to	O
be	O
a	O
necessary	O
step	O
in	O
the	O
working	O
mechanism	O
of	O
RdgC	O
,	O
if	O
one	O
can	O
assume	O
that	O
the	O
strong	O
protein	O
-	O
protein	O
interactions	O
in	O
the	O
crystal	O
were	O
relevant	O
for	O
protein	O
-	O
protein	O
interactions	O
in	O
solution	O
(	O
7	O
)	O
.	O

RdgC	O
protein	O
was	O
shown	O
to	O
have	O
a	O
potent	O
effect	O
on	O
RecA	O
protein	O
-	O
promoted	O
DNA	O
strand	O
exchange	O
in	O
E	B
.	I
coli	I
(	O
1	O
)	O
.	O

In	O
a	O
series	O
of	O
experiments	O
,	O
RdgC	O
was	O
added	O
after	O
RecA	O
filaments	O
had	O
formed	O
on	O
the	O
ssDNA	O
and	O
5	O
min	O
after	O
the	O
linear	O
dsDNA	O
was	O
added	O
.	O

With	O
3	O
mu	O
M	O
RecA	O
,	O
a	O
sharp	O
reduction	O
in	O
DNA	O
strand	O
exchange	O
products	O
was	O
seen	O
with	O
0	O
.	O
4	O
mu	O
M	O
RdgC	O
,	O
and	O
the	O
generation	O
of	O
products	O
was	O
abolished	O
at	O
0	O
.	O
8	O
mu	O
M	O
RdgC	O
(	O
1	O
)	O
.	O

This	O
suggests	O
that	O
the	O
binding	O
affinity	O
of	O
RdgC	O
to	O
dsDNA	O
is	O
considerably	O
higher	O
than	O
that	O
of	O
RecA	O
.	O

The	O
high	O
affinity	O
of	O
RdgC	O
could	O
be	O
explained	O
by	O
its	O
ring	O
shape	O
and	O
the	O
suggested	O
mode	O
of	O
DNA	O
binding	O
.	O

Tetrameric	O
species	O
of	O
E	B
.	I
coli	I
RdgC	O
,	O
which	O
started	O
to	O
form	O
at	O
around	O
2	O
micro	O
M	O
concentrations	O
,	O
were	O
speculated	O
to	O
be	O
the	O
species	O
with	O
the	O
most	O
potent	O
inhibitory	O
effect	O
,	O
possibly	O
by	O
having	O
a	O
higher	O
affinity	O
for	O
DNA	O
(	O
1	O
)	O
.	O

Higher	O
affinity	O
for	O
DNA	O
of	O
the	O
tetrameric	O
species	O
could	O
be	O
understood	O
,	O
if	O
the	O
formation	O
of	O
a	O
tetramer	O
in	O
solution	O
involves	O
a	O
protein	O
-	O
protein	O
interaction	O
similar	O
to	O
the	O
side	O
-	O
by	O
-	O
side	O
interaction	O
between	O
two	O
adjacent	O
RdgC	O
dimers	O
in	O
the	O
crystal	O
,	O
although	O
there	O
is	O
no	O
experimental	O
evidence	O
.	O

Obviously	O
,	O
there	O
are	O
still	O
many	O
open	O
questions	O
that	O
need	O
to	O
be	O
addressed	O
in	O
future	O
biochemical	O
experiments	O
.	O

SUMMARY	O

The	O
crystal	O
structure	O
of	O
RdgC	O
,	O
a	O
recombination	O
-	O
associated	O
DNA	O
-	O
binding	O
protein	O
,	O
determined	O
in	O
this	O
study	O
reveals	O
that	O
the	O
polypeptide	O
chain	O
is	O
uniquely	O
folded	O
and	O
two	O
monomers	O
associate	O
to	O
form	O
a	O
ring	O
-	O
shaped	O
dimer	O
with	O
a	O
central	O
hole	O
of	O
~	O
30	O
A	O
diameter	O
.	O

The	O
inner	O
surface	O
around	O
the	O
central	O
hole	O
is	O
rich	O
in	O
positively	O
charged	O
residues	O
.	O

These	O
structural	O
features	O
suggest	O
that	O
dsDNA	O
runs	O
through	O
the	O
central	O
hole	O
when	O
it	O
binds	O
to	O
RdgC	O
dimers	O
.	O

This	O
idea	O
is	O
supported	O
by	O
our	O
mutational	O
studies	O
,	O
which	O
indicate	O
that	O
the	O
conserved	O
,	O
positively	O
charged	O
residues	O
around	O
the	O
central	O
hole	O
are	O
important	O
for	O
dsDNA	O
binding	O
.	O

The	O
toroidal	O
architecture	O
of	O
the	O
RdgC	O
dimer	O
provides	O
a	O
sound	O
framework	O
for	O
a	O
better	O
understanding	O
of	O
its	O
role	O
in	O
homologous	O
recombination	O
.	O

Coordinates	O

Atomic	O
coordinates	O
and	O
the	O
structure	O
factor	O
data	O
have	O
been	O
deposited	O
in	O
the	O
Protein	O
Data	O
Bank	O
(	O
accession	O
code	O
2OWY	O
)	O
.	O

SUPPLEMENTARY	O
DATA	O

Supplementary	O
Data	O
are	O
available	O
at	O
NAR	O
Online	O
.	O

Supplementary	O
Material	O

Port	O
site	O
herniation	O
of	O
the	O
small	O
bowel	O
following	O
laparoscopy	O
-	O
assisted	O
distal	O
gastrectomy	O
:	O
a	O
case	O
report	O

Abstract	O

Introduction	O

Port	O
-	O
site	O
herniation	O
is	O
a	O
rare	O
but	O
potentially	O
dangerous	O
complication	O
after	O
laparoscopic	O
surgery	O
.	O

Closure	O
of	O
port	O
sites	O
,	O
especially	O
those	O
measuring	O
10	O
mm	O
or	O
more	O
,	O
has	O
been	O
recommended	O
to	O
avoid	O
such	O
an	O
event	O
.	O

Case	O
presentation	O

We	O
herein	O
report	O
the	O
only	O
case	O
of	O
a	O
port	O
site	O
hernia	O
among	O
a	O
series	O
52	O
consecutive	O
cases	O
of	O
laparoscopy	O
-	O
assisted	O
distal	O
gastrectomy	O
(	O
LADG	O
)	O
carried	O
out	O
by	O
our	O
unit	O
between	O
July	O
2002	O
and	O
March	O
2007	O
.	O

In	O
this	O
case	O
the	O
small	O
bowel	O
herniated	O
and	O
incarcerated	O
through	O
the	O
port	O
site	O
on	O
day	O
4	O
after	O
LADG	O
despite	O
closure	O
of	O
the	O
fascia	O
.	O

Initial	O
manifestations	O
experienced	O
by	O
the	O
patient	B
,	O
possibly	O
due	O
to	O
obstruction	O
,	O
and	O
including	O
mild	O
abdominal	O
pain	O
and	O
nausea	O
,	O
occurred	O
on	O
the	O
third	O
day	O
postoperatively	O
.	O

The	O
definitive	O
diagnosis	O
was	O
made	O
on	O
day	O
4	O
based	O
on	O
symptoms	O
related	O
to	O
leakage	O
from	O
the	O
duodenal	O
stump	O
,	O
which	O
was	O
considered	O
to	O
have	O
developed	O
after	O
severe	O
obstruction	O
of	O
the	O
bowel	O
.	O

Re	O
-	O
operation	O
for	O
reduction	O
of	O
the	O
incarcerated	O
bowel	O
and	O
tube	O
duodenostomy	O
with	O
peritoneal	O
drainage	O
were	O
required	O
to	O
manage	O
this	O
complication	O
.	O

Conclusion	O

We	O
present	O
this	O
case	O
report	O
and	O
review	O
of	O
literature	O
to	O
discuss	O
further	O
regarding	O
methods	O
of	O
fascial	O
closure	O
after	O
laparoscopic	O
surgery	O
.	O

Introduction	O

Bowel	O
herniation	O
through	O
the	O
fascial	O
defect	O
created	O
by	O
the	O
entry	O
of	O
trocars	O
is	O
now	O
recognized	O
as	O
a	O
rare	O
but	O
potentially	O
serious	O
complication	O
of	O
laparoscopic	O
surgery	O
[	O
1	O
]	O
.	O

Although	O
port	O
site	O
herniation	O
is	O
an	O
infrequent	O
complication	O
,	O
there	O
are	O
still	O
some	O
reports	O
of	O
port	O
site	O
herniation	O
after	O
these	O
procedures	O
,	O
even	O
with	O
closure	O
of	O
trocar	O
sites	O
[	O
1	O
,	O
2	O
]	O
.	O

The	O
following	O
report	O
describes	O
a	O
case	O
of	O
a	O
trocar	O
site	O
hernia	O
that	O
evolved	O
into	O
leakage	O
from	O
the	O
duodenal	O
stump	O
after	O
laparoscopy	O
-	O
assisted	O
distal	O
gastrectomy	O
(	O
LADG	O
)	O
.	O

Progression	O
occurred	O
because	O
of	O
complete	O
obstruction	O
of	O
the	O
incarcerated	O
bowel	O
after	O
a	O
Roux	O
-	O
en	O
-	O
Y	O
reconstruction	O
.	O

We	O
describe	O
the	O
significance	O
of	O
complete	O
closure	O
of	O
the	O
fascial	O
defect	O
at	O
the	O
trocar	O
site	O
including	O
the	O
peritoneum	O
in	O
the	O
prevention	O
of	O
this	O
condition	O
,	O
as	O
well	O
as	O
the	O
importance	O
of	O
early	O
diagnosis	O
to	O
avoid	O
serious	O
subsequent	O
events	O
.	O

Case	O
presentation	O

An	O
80	O
-	O
year	O
-	O
old	O
man	B
was	O
found	O
to	O
have	O
early	O
gastric	O
cancer	O
during	O
his	O
yearly	O
check	O
-	O
up	O
by	O
gastrointestinal	O
endoscopy	O
.	O

He	O
was	O
158	O
cm	O
in	O
height	O
and	O
weighed	O
62	O
kg	O
.	O

Gastrointestinal	O
endoscopy	O
showed	O
a	O
depressed	O
lesion	O
that	O
was	O
diagnosed	O
as	O
early	O
gastric	O
cancer	O
by	O
pathological	O
examination	O
of	O
biopsy	O
specimens	O
.	O

He	O
underwent	O
LADG	O
with	O
regional	O
lymph	O
node	O
dissection	O
(	O
D1	O
including	O
the	O
nodes	O
surrounding	O
the	O
origin	O
of	O
left	O
gastric	O
artery	O
)	O
.	O

A	O
12	O
-	O
mm	O
trocar	O
for	O
the	O
laparoscope	O
was	O
placed	O
in	O
the	O
umbilicus	O
.	O

Pneumoperitoneum	O
was	O
then	O
established	O
with	O
carbon	O
dioxide	O
and	O
the	O
intraperitoneal	O
pressure	O
was	O
maintained	O
at	O
10	O
mm	O
Hg	O
.	O

Two	O
more	O
12	O
-	O
mm	O
trocars	O
were	O
inserted	O
in	O
the	O
midclavicular	O
line	O
below	O
the	O
costal	O
margin	O
and	O
2	O
cm	O
above	O
the	O
umbilicus	O
on	O
each	O
of	O
both	O
flanks	O
and	O
were	O
used	O
for	O
active	O
surgical	O
instruments	O
.	O

All	O
trocars	O
used	O
were	O
the	O
non	O
-	O
bladed	O
type	O
.	O

The	O
specimen	O
was	O
removed	O
through	O
a	O
small	O
medial	O
incision	O
which	O
was	O
55	O
mm	O
in	O
length	O
placed	O
after	O
resection	O
of	O
the	O
stomach	O
,	O
and	O
then	O
Roux	O
-	O
en	O
-	O
Y	O
reconstruction	O
(	O
RY	O
)	O
was	O
carried	O
out	O
(	O
Fig	O
.	O
1	O
)	O
.	O

A	O
tubular	O
shaped	O
drainage	O
tube	O
10	O
mm	O
in	O
diameter	O
was	O
inserted	O
and	O
placed	O
through	O
the	O
upper	O
trocar	O
site	O
made	O
on	O
the	O
right	O
flank	O
.	O

Wound	O
defect	O
at	O
the	O
umbilical	O
port	O
site	O
was	O
sutured	O
completely	O
including	O
the	O
peritoneum	O
with	O
0	O
absorbable	O
suture	O
and	O
fascial	O
incisions	O
at	O
all	O
other	O
trocar	O
insertion	O
sites	O
were	O
closed	O
with	O
2	O
-	O
0	O
absorbable	O
sutures	O
.	O

Surgical	O
duration	O
was	O
263	O
min	O
,	O
and	O
the	O
volume	O
of	O
blood	O
loss	O
was	O
less	O
than	O
50	O
mL	O
with	O
no	O
blood	O
transfusion	O
.	O

Postoperatively	O
,	O
the	O
patient	B
complained	O
of	O
an	O
acidic	O
feeling	O
in	O
his	O
stomach	O
;	O
however	O
,	O
there	O
were	O
no	O
remarkable	O
abnormalities	O
on	O
biochemical	O
examination	O
of	O
serum	O
.	O

Radiological	O
findings	O
did	O
not	O
suggest	O
bowel	O
obstruction	O
until	O
3	O
days	O
postoperatively	O
,	O
although	O
mild	O
symptoms	O
such	O
as	O
general	O
malaise	O
and	O
vague	O
abdominal	O
pain	O
were	O
reported	O
on	O
day	O
three	O
.	O

However	O
,	O
on	O
day	O
4	O
,	O
the	O
patient	B
started	O
to	O
complain	O
of	O
upper	O
abdominal	O
pain	O
and	O
developed	O
a	O
high	O
grade	O
fever	O
(	O
38	O
degrees	O
C	O
)	O
.	O

Complete	O
obstruction	O
of	O
the	O
small	O
bowel	O
and	O
leakage	O
of	O
contrast	O
media	O
were	O
demonstrated	O
by	O
Gastrografin	O
swallow	O
and	O
subsequent	O
abdominal	O
computed	O
tomography	O
(	O
CT	O
)	O
.	O

CT	O
also	O
showed	O
a	O
mass	O
lesion	O
at	O
the	O
trocar	O
insertion	O
site	O
on	O
the	O
upper	O
left	O
flank	O
,	O
suggesting	O
herniation	O
through	O
the	O
port	O
site	O
(	O
Fig	O
.	O
2	O
)	O
.	O

Marked	O
dilatation	O
of	O
the	O
duodenum	O
including	O
the	O
horizontal	O
part	O
and	O
second	O
portion	O
was	O
observed	O
.	O

A	O
diagnosis	O
of	O
staple	O
failure	O
of	O
the	O
stump	O
of	O
the	O
duodenum	O
and	O
port	O
-	O
site	O
herniation	O
of	O
the	O
small	O
bowel	O
was	O
made	O
,	O
and	O
exploratory	O
laparotomy	O
was	O
carried	O
out	O
.	O

A	O
small	O
medial	O
incision	O
that	O
had	O
been	O
made	O
at	O
the	O
initial	O
surgery	O
was	O
extended	O
downward	O
to	O
the	O
umbilicus	O
to	O
open	O
the	O
peritoneal	O
cavity	O
.	O

As	O
we	O
expected	O
,	O
the	O
small	O
bowel	O
was	O
incarcerated	O
into	O
the	O
peritoneal	O
defect	O
in	O
the	O
abdominal	O
wall	O
created	O
by	O
the	O
trocar	O
placed	O
in	O
the	O
left	O
upper	O
flank	O
leading	O
to	O
complete	O
obstruction	O
of	O
the	O
bowel	O
(	O
Fig	O
.	O
3	O
)	O
.	O

Part	O
of	O
the	O
jejunum	O
30	O
cm	O
distal	O
from	O
the	O
ligament	O
of	O
Treitz	O
herniated	O
around	O
the	O
fascial	O
stitch	O
,	O
which	O
still	O
existed	O
at	O
the	O
time	O
of	O
the	O
re	O
-	O
exploration	O
.	O

The	O
peritoneal	O
cavity	O
was	O
contaminated	O
with	O
intestinal	O
juice	O
.	O

Close	O
examination	O
after	O
reduction	O
of	O
the	O
incarcerated	O
bowel	O
did	O
not	O
demonstrate	O
necrosis	O
of	O
the	O
intestine	O
,	O
and	O
thus	O
,	O
we	O
decided	O
not	O
to	O
resect	O
this	O
lesion	O
.	O

Leakage	O
of	O
intestinal	O
juice	O
through	O
a	O
pinhole	O
fistula	O
at	O
the	O
duodenal	O
stump	O
was	O
also	O
observed	O
.	O

Tube	O
duodenostomy	O
was	O
performed	O
with	O
an	O
omental	O
patch	O
used	O
for	O
closure	O
of	O
the	O
fistula	O
.	O

The	O
peritoneal	O
defect	O
was	O
also	O
closed	O
.	O

The	O
postoperative	O
course	O
was	O
fairly	O
good	O
without	O
high	O
output	O
of	O
the	O
intestinal	O
juice	O
leakage	O
or	O
sepsis	O
.	O

The	O
patient	B
remained	O
in	O
the	O
intensive	O
care	O
unit	O
for	O
5	O
days	O
after	O
re	O
-	O
operation	O
,	O
and	O
was	O
then	O
transferred	O
to	O
the	O
general	O
ward	O
.	O

Discussion	O

Port	O
-	O
site	O
herniation	O
,	O
which	O
is	O
one	O
of	O
the	O
major	O
complications	O
after	O
laparoscopic	O
procedures	O
[	O
1	O
]	O
,	O
sometimes	O
develops	O
into	O
serious	O
complications	O
,	O
such	O
as	O
bowel	O
obstruction	O
due	O
to	O
incarceration	O
into	O
the	O
fascial	O
defect	O
at	O
the	O
port	O
site	O
.	O

Boughey	O
et	O
al	O
.	O
have	O
reported	O
four	O
cases	O
of	O
Richter	O
'	O
s	O
hernia	O
that	O
occurred	O
at	O
a	O
port	O
site	O
after	O
laparoscopic	O
surgery	O
[	O
1	O
]	O
.	O

They	O
reviewed	O
previous	O
reports	O
and	O
found	O
the	O
incidence	O
to	O
be	O
0	O
.	O
2	O
to	O
3	O
%	O
.	O

A	O
report	O
describes	O
the	O
incidence	O
of	O
hernia	O
as	O
0	O
.	O
23	O
%	O
for	O
10	O
-	O
mm	O
trocar	O
use	O
,	O
rising	O
to	O
3	O
.	O
1	O
%	O
for	O
the	O
12	O
-	O
mm	O
trocar	O
[	O
2	O
]	O
suggesting	O
that	O
the	O
wound	O
created	O
by	O
a	O
larger	O
port	O
carries	O
a	O
greater	O
risk	O
of	O
herniation	O
.	O

Most	O
surgeons	O
now	O
routinely	O
close	O
the	O
fascia	O
of	O
port	O
sites	O
to	O
prevent	O
this	O
complication	O
[	O
2	O
]	O
.	O

According	O
to	O
previous	O
reports	O
,	O
port	O
site	O
herniation	O
apparently	O
happens	O
more	O
often	O
with	O
the	O
use	O
of	O
bladed	O
type	O
trocars	O
than	O
non	O
-	O
bladed	O
type	O
trocars	O
[	O
3	O
]	O
.	O

Indeed	O
,	O
Kolata	O
demonstrated	O
that	O
the	O
wounds	O
made	O
by	O
the	O
non	O
-	O
bladed	O
trocar	O
were	O
narrower	O
than	O
those	O
created	O
by	O
cutting	O
tip	O
trocars	O
in	O
a	O
pig	B
experimental	O
model	O
[	O
4	O
]	O
.	O

Several	O
reports	O
even	O
concluded	O
that	O
port	O
sites	O
created	O
by	O
non	O
-	O
bladed	O
trocars	O
do	O
not	O
require	O
fascial	O
closure	O
[	O
3	O
]	O
.	O

However	O
,	O
the	O
current	O
case	O
suggests	O
that	O
thick	O
preperitoneum	O
is	O
a	O
potential	O
space	O
that	O
allows	O
for	O
the	O
development	O
of	O
bowel	O
herniation	O
even	O
with	O
the	O
use	O
of	O
non	O
-	O
bladed	O
type	O
trocars	O
.	O

A	O
previous	O
report	O
also	O
described	O
port	O
-	O
site	O
herniation	O
,	O
despite	O
the	O
closure	O
of	O
the	O
superficial	O
layer	O
of	O
the	O
fascial	O
defect	O
[	O
5	O
]	O
.	O

The	O
current	O
case	O
did	O
not	O
demonstrate	O
any	O
of	O
the	O
risk	O
factors	O
suggested	O
previously	O
[	O
6	O
]	O
;	O
1	O
)	O
enlargement	O
of	O
a	O
port	O
site	O
to	O
remove	O
specimen	O
;	O
2	O
)	O
glucose	O
intolerance	O
;	O
3	O
)	O
obesity	O
;	O
or	O
4	O
)	O
extensive	O
manipulation	O
of	O
the	O
trocar	O
during	O
relatively	O
prolonged	O
surgical	O
duration	O
,	O
which	O
might	O
have	O
enlarged	O
the	O
trocar	O
site	O
and	O
thus	O
induced	O
bowel	O
herniation	O
.	O

Therefore	O
,	O
we	O
recommend	O
closing	O
the	O
fascial	O
defect	O
,	O
including	O
the	O
peritoneum	O
,	O
especially	O
if	O
the	O
trocar	O
size	O
is	O
more	O
than	O
10	O
-	O
mm	O
and	O
in	O
the	O
presence	O
of	O
any	O
of	O
the	O
risk	O
factors	O
described	O
above	O
.	O

However	O
,	O
it	O
is	O
sometimes	O
difficult	O
to	O
completely	O
close	O
the	O
defect	O
,	O
including	O
the	O
peritoneum	O
,	O
especially	O
in	O
obese	O
patients	B
.	O

Shaher	O
reviewed	O
different	O
wound	O
closure	O
techniques	O
by	O
a	O
literature	O
search	O
[	O
7	O
]	O
.	O

In	O
this	O
review	O
,	O
old	O
methods	O
using	O
classical	O
instruments	O
including	O
Deschamps	O
needle	O
are	O
also	O
useful	O
as	O
well	O
as	O
special	O
wound	O
devices	O
designed	O
for	O
port	O
site	O
closure	O
.	O

Elashry	O
et	O
al	O
.	O
described	O
a	O
prospective	O
randomized	O
study	O
demonstrating	O
that	O
the	O
Carter	O
-	O
Thomason	O
device	O
was	O
faster	O
and	O
resulted	O
in	O
fewer	O
port	O
-	O
closure	O
-	O
related	O
complications	O
among	O
eight	O
different	O
techniques	O
tested	O
[	O
8	O
]	O
.	O

Insertion	O
of	O
a	O
SURGICEL	O
plug	O
into	O
the	O
muscular	O
layer	O
of	O
trocar	O
wounds	O
has	O
also	O
been	O
proposed	O
by	O
Chiu	O
et	O
al	O
[	O
9	O
]	O
.	O

Alternatively	O
,	O
tangential	O
insertion	O
of	O
a	O
trocar	O
through	O
the	O
abdominal	O
wall	O
might	O
be	O
effective	O
in	O
reducing	O
the	O
size	O
of	O
fascial	O
defects	O
.	O

Moreover	O
,	O
recent	O
publications	O
have	O
demonstrated	O
that	O
radially	O
expanding	O
type	O
trocars	O
could	O
be	O
useful	O
to	O
avoid	O
the	O
necessity	O
of	O
closing	O
the	O
fascial	O
defect	O
[	O
10	O
]	O
.	O

Symptoms	O
of	O
trocar	O
-	O
site	O
herniation	O
vary	O
depending	O
on	O
the	O
severity	O
of	O
bowel	O
obstruction	O
.	O

Mild	O
symptoms	O
such	O
as	O
slight	O
nausea	O
and	O
vague	O
abdominal	O
pain	O
,	O
both	O
of	O
which	O
are	O
most	O
frequently	O
seen	O
in	O
the	O
early	O
normal	O
postoperative	O
course	O
after	O
abdominal	O
surgery	O
,	O
could	O
be	O
the	O
first	O
and	O
only	O
complaints	O
at	O
the	O
early	O
stage	O
of	O
this	O
complication	O
.	O

Thus	O
,	O
the	O
diagnosis	O
may	O
be	O
delayed	O
.	O

In	O
our	O
case	O
,	O
mild	O
abdominal	O
pain	O
with	O
general	O
malaise	O
might	O
have	O
been	O
symptoms	O
related	O
to	O
the	O
early	O
stage	O
of	O
the	O
onset	O
.	O

Abdominal	O
CT	O
showing	O
the	O
enlarged	O
duodenum	O
also	O
suggested	O
that	O
leakage	O
from	O
the	O
duodenal	O
stump	O
occurred	O
due	O
to	O
the	O
obstruction	O
of	O
the	O
distal	O
bowel	O
.	O

Thus	O
,	O
severe	O
complication	O
might	O
have	O
been	O
avoided	O
,	O
if	O
early	O
diagnosis	O
had	O
been	O
made	O
.	O

Although	O
the	O
benefit	O
of	O
Roux	O
-	O
en	O
-	O
Y	O
is	O
apparent	O
[	O
11	O
]	O
,	O
the	O
duodenal	O
stump	O
could	O
be	O
vulnerable	O
to	O
leakage	O
due	O
to	O
increased	O
intrabowel	O
pressure	O
.	O

Therefore	O
,	O
careful	O
management	O
of	O
the	O
postoperative	O
course	O
is	O
warranted	O
,	O
especially	O
after	O
procedures	O
involving	O
division	O
of	O
the	O
bowel	O
such	O
as	O
LADG	O
.	O

Moreover	O
,	O
special	O
attention	O
should	O
be	O
paid	O
in	O
patients	B
with	O
risk	O
factors	O
for	O
port	O
site	O
hernia	O
such	O
as	O
obesity	O
,	O
aggressive	O
manipulation	O
through	O
the	O
port	O
sites	O
,	O
and	O
prolonged	O
surgery	O
.	O

Conclusion	O

Port	O
-	O
site	O
herniation	O
is	O
a	O
potentially	O
dangerous	O
complication	O
after	O
laparoscopic	O
procedures	O
.	O

Careful	O
management	O
of	O
the	O
postoperative	O
course	O
is	O
recommended	O
especially	O
for	O
patients	B
with	O
risk	O
factors	O
such	O
as	O
obesity	O
and	O
extensive	O
manipulation	O
of	O
the	O
trocar	O
during	O
prolonged	O
surgical	O
duration	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

TI	O
,	O
NF	O
,	O
HT	O
and	O
TK	O
performed	O
the	O
first	O
and	O
second	O
operation	O
.	O

TI	O
and	O
KK	O
were	O
responsible	O
for	O
the	O
postoperative	O
management	O
.	O

TI	O
,	O
HT	O
,	O
TW	O
,	O
and	O
KN	O
were	O
involved	O
in	O
editing	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

Consent	O

Written	O
informed	O
consent	O
was	O
obtained	O
from	O
the	O
patient	B
for	O
publication	O
of	O
this	O
case	O
report	O
and	O
any	O
accompanying	O
images	O
.	O

A	O
copy	O
of	O
the	O
written	O
consent	O
is	O
available	O
for	O
review	O
by	O
the	O
Editor	O
-	O
in	O
-	O
Chief	O
of	O
this	O
journal	O
.	O

Comparison	O
of	O
strategies	O
for	O
identification	O
of	O
regulatory	O
quantitative	O
trait	O
loci	O
of	O
transcript	O
expression	O
traits	O

Abstract	O

In	O
order	O
to	O
identify	O
regulatory	O
genes	O
,	O
we	O
determined	O
the	O
heritability	O
of	O
gene	O
transcripts	O
,	O
performed	O
linkage	O
analysis	O
to	O
identify	O
quantitative	O
trait	O
loci	O
(	O
QTLs	O
)	O
,	O
and	O
evaluated	O
the	O
evidence	O
for	O
shared	O
genetic	O
effects	O
among	O
transcripts	O
with	O
co	O
-	O
localized	O
QTLs	O
in	O
non	O
-	O
diseased	O
participants	B
from	O
14	O
CEPH	O
(	O
Centre	O
d	O
'	O
Etude	O
du	O
Polymorphisme	O
Humain	O
)	O
Utah	O
families	O
.	O

Seventy	O
-	O
six	O
percent	O
of	O
transcripts	O
had	O
a	O
significant	O
heritability	O
and	O
54	O
%	O
of	O
them	O
had	O
LOD	O
score	O
>	O
=	O
1	O
.	O
8	O
.	O

Bivariate	O
genetic	O
analysis	O
of	O
15	O
transcripts	O
that	O
had	O
co	O
-	O
localized	O
QTLs	O
on	O
4q28	O
.	O
2	O
-	O
q31	O
.	O
1	O
identified	O
significant	O
genetic	O
correlation	O
among	O
some	O
transcripts	O
although	O
no	O
improvement	O
in	O
the	O
magnitude	O
of	O
LOD	O
scores	O
in	O
this	O
region	O
was	O
noted	O
.	O

Similar	O
results	O
were	O
found	O
in	O
analysis	O
of	O
12	O
transcripts	O
,	O
that	O
had	O
co	O
-	O
localized	O
QTLs	O
in	O
the	O
13q34	O
region	O
.	O

Principal	O
-	O
component	O
analyses	O
did	O
not	O
improve	O
the	O
ability	O
to	O
identify	O
chromosomal	O
regions	O
of	O
co	O
-	O
localized	O
gene	O
expressions	O
.	O

Background	O

There	O
is	O
a	O
breadth	O
of	O
information	O
being	O
generated	O
by	O
the	O
Human	B
Genome	O
Project	O
and	O
the	O
interpretation	O
of	O
these	O
data	O
has	O
been	O
a	O
major	O
area	O
of	O
research	O
.	O

For	O
simple	O
Mendelian	O
disorders	O
,	O
the	O
identification	O
of	O
genetic	O
effects	O
is	O
fairly	O
straightforward	O
due	O
to	O
understanding	O
the	O
biology	O
that	O
drives	O
these	O
disorders	O
.	O

However	O
,	O
for	O
complex	O
oligogenic	O
or	O
polygenic	O
disorders	O
,	O
understanding	O
all	O
the	O
interconnections	O
between	O
genes	O
influencing	O
a	O
trait	O
is	O
a	O
difficult	O
task	O
because	O
the	O
understanding	O
of	O
the	O
biology	O
of	O
many	O
of	O
these	O
disorders	O
is	O
still	O
evolving	O
.	O

Multiple	O
gene	O
x	O
gene	O
and	O
gene	O
x	O
environment	O
interactions	O
can	O
influence	O
the	O
expression	O
of	O
phenotypes	O
.	O

Genes	O
can	O
interact	O
by	O
modifying	O
the	O
expression	O
of	O
other	O
genes	O
and	O
therefore	O
function	O
as	O
regulatory	O
genes	O
[	O
1	O
]	O
.	O

In	O
an	O
effort	O
to	O
dissect	O
some	O
of	O
these	O
complexities	O
,	O
we	O
performed	O
linkage	O
analysis	O
of	O
gene	O
expression	O
transcripts	O
of	O
members	O
of	O
Centre	O
d	O
'	O
Etude	O
du	O
Polymorphisme	O
Humain	O
(	O
CEPH	O
)	O
Utah	O
families	O
to	O
determine	O
the	O
heritability	O
of	O
transcripts	O
and	O
the	O
evidence	O
for	O
regulatory	O
quantitative	O
trait	O
loci	O
(	O
QTLs	O
)	O
and	O
we	O
performed	O
pairwise	O
bivariate	O
linkage	O
analysis	O
and	O
principal	O
-	O
component	O
analysis	O
(	O
PCA	O
)	O
for	O
data	O
-	O
reduction	O
to	O
evaluate	O
the	O
evidence	O
for	O
shared	O
genetic	O
effects	O
.	O

The	O
ability	O
to	O
assess	O
gene	O
expression	O
traits	O
simultaneously	O
and	O
to	O
link	O
them	O
to	O
QTLs	O
offers	O
the	O
possibility	O
of	O
identifying	O
previously	O
unknown	O
underlying	O
molecular	O
processes	O
for	O
future	O
investigation	O
.	O

Methods	O

Population	O
and	O
phenotypes	O

We	O
used	O
the	O
Genetic	O
Analysis	O
Workshop	O
15	O
(	O
GAW	O
15	O
)	O
Problem	O
1	O
microarray	O
gene	O
expression	O
profiles	O
for	O
the	O
analyses	O
.	O

Data	O
were	O
available	O
for	O
14	O
three	O
-	O
generation	O
CEPH	O
Utah	O
families	O
.	O

Expression	O
levels	O
of	O
genes	O
were	O
obtained	O
from	O
lymphoblastoid	O
cells	O
using	O
the	O
Affymetrix	O
Human	B
Focus	O
Arrays	O
[	O
2	O
]	O
.	O

We	O
were	O
provided	O
with	O
data	O
on	O
3554	O
transcripts	O
that	O
showed	O
greater	O
variation	O
between	O
individuals	O
than	O
within	O
the	O
same	O
individual	O
.	O

Family	O
members	O
were	O
genotyped	O
for	O
2882	O
autosomal	O
and	O
X	O
-	O
linked	O
single	O
-	O
nucleotide	O
polymorphisms	O
(	O
SNP	O
)	O
generated	O
by	O
the	O
SNP	O
Consortium	O
.	O

Genetic	O
map	O
positions	O
were	O
obtained	O
using	O
the	O
SNP	O
Mapping	O
web	O
application	O
developed	O
by	O
the	O
University	O
College	O
Dublin	O
Conway	O
Institute	O
of	O
Biomolecular	O
and	O
Biomedical	O
Research	O
,	O
which	O
uses	O
the	O
Rutgers	O
Combined	O
Linkage	O
-	O
Physical	O
Map	O
of	O
the	O
Human	B
Genome	O
and	O
data	O
taken	O
from	O
the	O
NCBI	O
dbSNP	O
Build	O
123	O
(	O
in	O
Kosambi	O
centimorgans	O
)	O
.	O

This	O
information	O
was	O
used	O
to	O
calculate	O
multipoint	O
identity	O
by	O
descent	O
matrices	O
(	O
MIBDs	O
)	O
with	O
Merlin	O
and	O
Minx	O
[	O
3	O
]	O
,	O
after	O
removal	O
of	O
Mendelian	O
inconsistencies	O
and	O
double	O
recombinants	O
with	O
Preswalk	O
(	O
based	O
on	O
Simwalk	O
mistyping	O
probabilities	O
)	O
[	O
4	O
]	O
.	O

MIBDs	O
were	O
used	O
for	O
linkage	O
analyses	O
.	O

Transcript	O
distributions	O
were	O
normalized	O
using	O
an	O
inverse	O
normalization	O
transformation	O
of	O
z	O
-	O
scores	O
of	O
individual	O
transcripts	O
regressed	O
on	O
the	O
mean	O
individual	O
transcript	O
level	O
.	O

We	O
further	O
adjusted	O
for	O
the	O
effects	O
of	O
age	O
,	O
age2	O
,	O
sex	O
,	O
age	O
x	O
sex	O
and	O
age2	O
x	O
sex	O
interaction	O
using	O
predictive	O
linear	O
regression	O
models	O
in	O
SAS	O
9	O
.	O
1	O
(	O
Cary	O
,	O
NC	O
)	O
.	O

We	O
generated	O
these	O
residuals	O
as	O
part	O
of	O
our	O
processing	O
of	O
the	O
transcripts	O
for	O
linkage	O
analyses	O
.	O

Heritability	O
estimation	O
and	O
linkage	O
analysis	O

Heritability	O
was	O
estimated	O
using	O
maximum	O
likelihood	O
variance	O
decomposition	O
methods	O
in	O
SOLAR	O
[	O
5	O
,	O
6	O
]	O
.	O

Genome	O
scans	O
were	O
performed	O
using	O
multipoint	O
variance	O
-	O
components	O
models	O
that	O
test	O
for	O
linkage	O
between	O
traits	O
and	O
genetic	O
variants	O
by	O
partitioning	O
the	O
variance	O
of	O
the	O
expression	O
level	O
into	O
its	O
additive	O
genetic	O
and	O
environmental	O
variance	O
components	O
[	O
7	O
]	O
.	O

For	O
transcripts	O
with	O
co	O
-	O
localized	O
QTLs	O
,	O
we	O
performed	O
bivariate	O
linkage	O
analysis	O
to	O
identify	O
shared	O
genetic	O
effects	O
.	O

The	O
bivariate	O
polygenic	O
model	O
estimates	O
correlations	O
caused	O
by	O
residual	O
additive	O
genetic	O
effects	O
(	O
rho	O
G	O
)	O
and	O
correlations	O
caused	O
by	O
random	O
environmental	O
effects	O
(	O
rho	O
E	O
)	O
[	O
8	O
]	O
.	O

To	O
test	O
for	O
additive	O
genetic	O
correlation	O
among	O
pairs	O
of	O
traits	O
,	O
the	O
log	O
likelihood	O
of	O
a	O
model	O
in	O
which	O
rho	O
G	O
is	O
constrained	O
to	O
0	O
(	O
null	O
hypothesis	O
,	O
no	O
correlation	O
)	O
or	O
rho	O
G	O
=	O
1	O
(	O
null	O
hypothesis	O
,	O
complete	O
shared	O
genetic	O
effect	O
)	O
is	O
compared	O
to	O
that	O
of	O
a	O
model	O
in	O
which	O
rho	O
G	O
is	O
estimated	O
for	O
the	O
traits	O
.	O

Significant	O
differences	O
among	O
the	O
models	O
(	O
rho	O
G	O
!	O
=	O
0	O
)	O
suggest	O
that	O
some	O
of	O
the	O
same	O
genes	O
influence	O
both	O
traits	O
.	O

We	O
also	O
performed	O
linkage	O
analysis	O
using	O
the	O
factors	O
obtained	O
from	O
the	O
PCA	O
in	O
a	O
sample	O
of	O
transcripts	O
with	O
co	O
-	O
localized	O
QTLs	O
.	O

Principal	O
-	O
component	O
analysis	O

PCA	O
was	O
used	O
to	O
reduce	O
the	O
number	O
of	O
expression	O
profiles	O
into	O
statistically	O
meaningful	O
groups	O
while	O
retaining	O
the	O
original	O
total	O
variance	O
using	O
all	O
the	O
expression	O
profiles	O
[	O
9	O
,	O
10	O
]	O
.	O

We	O
selected	O
two	O
different	O
chromosomal	O
regions	O
of	O
a	O
length	O
of	O
10	O
to	O
12	O
MB	O
in	O
which	O
the	O
QTLs	O
of	O
at	O
least	O
10	O
transcripts	O
were	O
co	O
-	O
localized	O
.	O

Only	O
transcripts	O
of	O
genes	O
that	O
were	O
not	O
located	O
in	O
these	O
selected	O
chromosomal	O
regions	O
were	O
included	O
in	O
the	O
analyses	O
(	O
trans	O
-	O
regulatory	O
genes	O
)	O
.	O

Because	O
of	O
the	O
small	O
number	O
of	O
individuals	O
in	O
the	O
study	O
and	O
concerns	O
of	O
overfitting	O
the	O
model	O
,	O
a	O
maximum	O
sample	O
of	O
50	O
transcript	O
values	O
were	O
considered	O
at	O
one	O
time	O
[	O
11	O
]	O
.	O

The	O
number	O
of	O
factors	O
was	O
determined	O
using	O
the	O
eigenvalue	O
-	O
one	O
requirement	O
[	O
11	O
]	O
.	O

Factors	O
are	O
interpreted	O
by	O
examining	O
the	O
varimax	O
-	O
rotated	O
factor	O
loadings	O
,	O
which	O
are	O
the	O
correlations	O
between	O
each	O
phenotype	O
and	O
the	O
factor	O
in	O
question	O
.	O

Factor	O
loadings	O
greater	O
than	O
or	O
equal	O
to	O
0	O
.	O
40	O
in	O
absolute	O
value	O
were	O
used	O
to	O
interpret	O
factors	O
and	O
to	O
characterize	O
the	O
factor	O
structures	O
;	O
this	O
criterion	O
ensures	O
that	O
the	O
individual	O
factor	O
variables	O
share	O
at	O
least	O
15	O
%	O
of	O
their	O
variance	O
with	O
the	O
given	O
factor	O
[	O
9	O
]	O
.	O

The	O
principle	O
components	O
were	O
obtained	O
by	O
calculating	O
the	O
eigenvalues	O
of	O
the	O
sample	O
covariance	O
matrix	O
,	O
which	O
represent	O
the	O
amount	O
of	O
variance	O
contributed	O
by	O
each	O
factor	O
.	O

Only	O
factors	O
with	O
eigenvalues	O
higher	O
than	O
1	O
were	O
considered	O
for	O
linkage	O
analysis	O
.	O

Integrating	O
data	O
from	O
linkage	O
analysis	O
for	O
gene	O
co	O
-	O
expression	O

Linkage	O
signals	O
of	O
individual	O
transcript	O
expressions	O
were	O
recorded	O
and	O
the	O
location	O
of	O
QTLs	O
was	O
compared	O
to	O
the	O
location	O
of	O
the	O
transcript	O
gene	O
in	O
order	O
to	O
identify	O
trans	O
-	O
regulatory	O
sites	O
.	O

In	O
addition	O
,	O
the	O
location	O
and	O
LOD	O
scores	O
of	O
QTLs	O
identified	O
in	O
single	O
individual	O
transcript	O
analysis	O
(	O
univariate	O
analysis	O
)	O
were	O
compared	O
with	O
the	O
location	O
of	O
the	O
QTLs	O
identified	O
using	O
bivariate	O
analysis	O
or	O
factors	O
of	O
the	O
PCA	O
.	O

This	O
allowed	O
a	O
determination	O
of	O
whether	O
the	O
bivariate	O
analysis	O
or	O
PCA	O
data	O
reduction	O
analysis	O
improved	O
our	O
evidence	O
for	O
linkage	O
,	O
and	O
if	O
so	O
,	O
a	O
more	O
in	O
-	O
depth	O
examination	O
of	O
the	O
transcripts	O
included	O
in	O
the	O
principal	O
components	O
needs	O
to	O
be	O
examined	O
for	O
biologic	O
interactions	O
on	O
complex	O
disorders	O
.	O

Results	O

Among	O
194	O
individuals	O
from	O
14	O
families	O
,	O
17	O
individuals	O
with	O
missing	O
information	O
on	O
age	O
were	O
excluded	O
.	O

Seventy	O
-	O
six	O
percent	O
(	O
n	O
=	O
2688	O
)	O
of	O
the	O
transcripts	O
had	O
significant	O
heritability	O
(	O
p	O
<	O
0	O
.	O
05	O
)	O
and	O
were	O
considered	O
for	O
the	O
linkage	O
analysis	O
.	O

Of	O
this	O
,	O
1448	O
(	O
54	O
%	O
)	O
transcripts	O
displayed	O
suggestive	O
evidence	O
of	O
linkage	O
(	O
had	O
a	O
maximum	O
LOD	O
score	O
>	O
=	O
1	O
.	O
8	O
[	O
12	O
]	O
)	O
.	O

The	O
QTLs	O
of	O
1661	O
transcripts	O
(	O
759	O
of	O
which	O
with	O
LOD	O
>	O
=	O
1	O
.	O
8	O
)	O
were	O
localized	O
in	O
a	O
different	O
region	O
than	O
the	O
gene	O
transcript	O
(	O
trans	O
-	O
regulatory	O
sites	O
)	O
.	O

We	O
used	O
two	O
different	O
chromosomal	O
regions	O
with	O
co	O
-	O
localized	O
transcript	O
QTLs	O
,	O
chromosomes	O
4q28	O
.	O
2	O
-	O
q31	O
.	O
1	O
and	O
13q34	O
,	O
for	O
more	O
in	O
-	O
depth	O
analyses	O
.	O

Chromosome	O
4q28	O
.	O
2	O
-	O
q31	O
.	O
1	O
region	O

Table	O
1	O
reports	O
the	O
results	O
for	O
the	O
chromosome	O
4q28	O
.	O
2	O
-	O
q31	O
.	O
1	O
region	O
.	O

Fifteen	O
transcripts	O
co	O
-	O
localized	O
in	O
this	O
region	O
in	O
the	O
univariate	O
linkage	O
analysis	O
,	O
and	O
the	O
LOD	O
scores	O
ranged	O
from	O
1	O
.	O
17	O
to	O
3	O
.	O
72	O
.	O

The	O
strongest	O
linkage	O
signals	O
were	O
observed	O
for	O
the	O
transcripts	O
of	O
the	O
MX2	O
,	O
NUCB2	O
,	O
and	O
SNX4	O
genes	O
.	O

Using	O
PCA	O
,	O
we	O
obtained	O
five	O
factors	O
from	O
the	O
15	O
transcripts	O
with	O
eigenvalues	O
greater	O
than	O
1	O
.	O

Only	O
one	O
factor	O
,	O
with	O
a	O
high	O
positive	O
loading	O
for	O
the	O
MX2	O
gene	O
transcript	O
,	O
had	O
a	O
significant	O
heritability	O
and	O
a	O
LOD	O
score	O
>	O
=	O
1	O
.	O
8	O
.	O

The	O
linkage	O
analysis	O
using	O
this	O
factor	O
identified	O
the	O
chromosome	O
region	O
for	O
the	O
MX2	O
gene	O
,	O
but	O
the	O
LOD	O
score	O
was	O
lower	O
than	O
the	O
one	O
obtained	O
by	O
single	O
linkage	O
analysis	O
of	O
the	O
MX2	O
transcript	O
.	O

We	O
then	O
performed	O
bivariate	O
analysis	O
of	O
all	O
pairwise	O
co	O
-	O
localized	O
transcripts	O
on	O
4q28	O
.	O
2	O
-	O
q31	O
.	O
1	O
and	O
found	O
evidence	O
for	O
genetic	O
correlation	O
of	O
co	O
-	O
localized	O
genes	O
,	O
although	O
without	O
much	O
increase	O
in	O
the	O
magnitude	O
of	O
the	O
LOD	O
score	O
(	O
Figure	O
1	O
)	O
.	O

This	O
analysis	O
identified	O
two	O
networks	O
of	O
gene	O
expressions	O
(	O
Figure	O
1	O
)	O
.	O

We	O
obtained	O
two	O
factors	O
using	O
PCA	O
of	O
the	O
first	O
network	O
(	O
Group	O
1	O
,	O
SNX4	O
,	O
YWHAQ	O
,	O
ASS	O
,	O
MX2	O
,	O
and	O
ISGF3G	O
gene	O
transcripts	O
)	O
.	O

Both	O
factors	O
had	O
significant	O
heritability	O
;	O
however	O
,	O
only	O
Factor	O
1	O
,	O
loading	O
heavily	O
on	O
the	O
MX2	O
gene	O
,	O
localized	O
to	O
the	O
4q28	O
.	O
2	O
-	O
q31	O
.	O
1	O
region	O
(	O
Table	O
1	O
)	O
,	O
and	O
the	O
magnitude	O
of	O
the	O
LOD	O
score	O
was	O
lower	O
than	O
that	O
of	O
the	O
univariate	O
MX2	O
gene	O
transcript	O
analysis	O
(	O
LOD	O
=	O
2	O
.	O
28	O
)	O
.	O

The	O
heritability	O
of	O
one	O
factor	O
obtained	O
using	O
PCA	O
for	O
Group	O
2	O
transcripts	O
was	O
not	O
significant	O
and	O
further	O
analysis	O
was	O
not	O
performed	O
.	O

Chromosome	O
13q34	O
region	O

We	O
performed	O
analysis	O
in	O
an	O
additional	O
chromosome	O
region	O
of	O
co	O
-	O
localized	O
transcripts	O
,	O
13q34	O
region	O
,	O
and	O
noted	O
similar	O
results	O
.	O

Using	O
univariate	O
analysis	O
,	O
12	O
transcripts	O
co	O
-	O
localized	O
in	O
this	O
region	O
;	O
and	O
bivariate	O
analysis	O
revealed	O
an	O
intricate	O
network	O
of	O
correlated	O
traits	O
(	O
Table	O
2	O
and	O
Figure	O
2	O
)	O
.	O

Using	O
PCA	O
,	O
we	O
obtained	O
five	O
factors	O
,	O
three	O
of	O
them	O
with	O
significant	O
heritability	O
.	O

Similar	O
to	O
our	O
previous	O
findings	O
on	O
chomosome	O
4	O
,	O
PCA	O
factors	O
did	O
not	O
improve	O
the	O
magnitude	O
of	O
the	O
LOD	O
scores	O
when	O
compared	O
to	O
univariate	O
analysis	O
.	O

Discussion	O

In	O
this	O
study	O
,	O
we	O
identified	O
co	O
-	O
localized	O
QTLs	O
of	O
individual	O
transcripts	O
and	O
compared	O
the	O
univariate	O
and	O
bivariate	O
linkage	O
results	O
using	O
single	O
transcripts	O
to	O
those	O
using	O
factors	O
obtained	O
from	O
PCA	O
.	O

By	O
using	O
factors	O
that	O
accounted	O
for	O
the	O
variance	O
of	O
multiple	O
transcripts	O
with	O
co	O
-	O
localized	O
QTLs	O
,	O
we	O
attempted	O
to	O
reduce	O
the	O
number	O
of	O
linkage	O
analyses	O
performed	O
as	O
well	O
as	O
possibly	O
identifying	O
previously	O
unknown	O
patterns	O
of	O
associated	O
gene	O
expression	O
profiles	O
.	O

The	O
PCA	O
did	O
in	O
fact	O
reduce	O
the	O
number	O
of	O
linkage	O
analyses	O
performed	O
,	O
but	O
it	O
did	O
not	O
improve	O
the	O
magnitude	O
of	O
signals	O
in	O
the	O
target	O
QTLs	O
as	O
compared	O
with	O
univariate	O
or	O
bivariate	O
analyses	O
.	O

In	O
fact	O
,	O
in	O
at	O
least	O
one	O
case	O
,	O
PCA	O
was	O
unable	O
to	O
detect	O
a	O
linkage	O
signal	O
for	O
the	O
main	O
gene	O
transcript	O
loading	O
in	O
the	O
factor	O
(	O
Table	O
1	O
,	O
Group	O
1	O
,	O
Factor	O
2	O
)	O
.	O

We	O
also	O
performed	O
pairwise	O
bivariate	O
genetic	O
analysis	O
on	O
those	O
transcripts	O
that	O
co	O
-	O
localized	O
to	O
the	O
same	O
genomic	O
region	O
,	O
presumably	O
because	O
this	O
area	O
of	O
the	O
genome	O
harbored	O
genes	O
involved	O
in	O
the	O
regulation	O
of	O
these	O
transcripts	O
[	O
2	O
]	O
.	O

We	O
detected	O
significant	O
genetic	O
correlation	O
of	O
these	O
co	O
-	O
localized	O
transcripts	O
,	O
indicating	O
potential	O
gene	O
networks	O
operating	O
in	O
these	O
regions	O
.	O

However	O
,	O
in	O
most	O
cases	O
,	O
bivariate	O
linkage	O
analysis	O
did	O
not	O
improve	O
the	O
magnitude	O
of	O
the	O
LOD	O
score	O
compared	O
to	O
univariate	O
analysis	O
.	O

Most	O
traits	O
were	O
highly	O
correlated	O
(	O
rho	O
G	O
>	O
0	O
.	O
60	O
)	O
,	O
and	O
therefore	O
they	O
may	O
provide	O
redundant	O
information	O
that	O
may	O
reduce	O
the	O
power	O
for	O
detection	O
of	O
the	O
bivariate	O
signal	O
[	O
8	O
]	O
.	O

In	O
addition	O
,	O
because	O
rho	O
G	O
is	O
a	O
test	O
of	O
the	O
overall	O
additive	O
genetic	O
correlation	O
among	O
two	O
traits	O
and	O
not	O
the	O
QTL	O
-	O
specific	O
pleiotropy	O
,	O
it	O
is	O
possible	O
that	O
the	O
co	O
-	O
localized	O
linkage	O
signals	O
are	O
not	O
in	O
fact	O
genetically	O
correlated	O
.	O

Further	O
analysis	O
is	O
required	O
to	O
address	O
these	O
issues	O
.	O

The	O
chromosome	O
regions	O
selected	O
for	O
detailed	O
analyses	O
were	O
arbitrarily	O
chosen	O
as	O
we	O
identified	O
multiple	O
other	O
regions	O
with	O
co	O
-	O
localized	O
linkage	O
of	O
gene	O
expressions	O
.	O

The	O
results	O
from	O
our	O
univariate	O
genome	O
scan	O
differ	O
markedly	O
from	O
those	O
reported	O
by	O
Morley	O
et	O
al	O
.	O

[	O
2	O
]	O
because	O
we	O
included	O
a	O
smaller	O
sample	O
of	O
individuals	O
so	O
that	O
adjustment	O
for	O
covariate	O
effects	O
of	O
age	O
could	O
be	O
made	O
.	O

Our	O
analysis	O
strategy	O
also	O
adjusted	O
for	O
the	O
effects	O
of	O
age	O
and	O
sex	O
,	O
which	O
could	O
also	O
add	O
to	O
the	O
observed	O
differences	O
[	O
13	O
]	O
.	O

Finally	O
,	O
our	O
definition	O
of	O
genome	O
window	O
size	O
for	O
co	O
-	O
localized	O
gene	O
expressions	O
was	O
twice	O
larger	O
than	O
the	O
one	O
described	O
in	O
the	O
study	O
of	O
Morley	O
et	O
al	O
.	O

Conclusion	O

We	O
identified	O
several	O
chromosomal	O
regions	O
of	O
co	O
-	O
localized	O
trans	O
-	O
regulatory	O
genes	O
with	O
significant	O
heritability	O
.	O

Some	O
of	O
these	O
regulatory	O
genes	O
displayed	O
strong	O
additive	O
genetic	O
correlations	O
,	O
and	O
may	O
be	O
part	O
of	O
genetic	O
networks	O
.	O

However	O
,	O
when	O
compared	O
to	O
univariate	O
analysis	O
,	O
linkage	O
analysis	O
of	O
bivariate	O
phenotypes	O
and	O
factor	O
scores	O
obtained	O
from	O
PCA	O
did	O
not	O
improve	O
the	O
ability	O
to	O
identify	O
chromosomal	O
regions	O
of	O
co	O
-	O
localized	O
gene	O
expressions	O
.	O

List	O
of	O
Abbreviations	O

CEPH	O
:	O
Centre	O
d	O
'	O
Etude	O
du	O
Polymorphisme	O
Humain	O

GAW	O
:	O
Genetic	O
Analysis	O
Workshop	O

H2	O
:	O
heritability	O

LOD	O
:	O
logarithm	O
of	O
the	O
odds	O

MIBD	O
:	O
multipoint	O
identity	O
-	O
by	O
-	O
descent	O
matrices	O

N	O
/	O
A	O
:	O
not	O
apply	O

NCBI	O
:	O
National	O
Center	O
for	O
Biotechnology	O
Information	O

PCA	O
:	O
principal	O
-	O
component	O
analysis	O

QTL	O
:	O
quantitative	O
trait	O
loci	O

SE	O
:	O
standard	O
error	O
of	O
the	O
mean	O

SNP	O
:	O
single	O
-	O
nucleotide	O
polymorphism	O

SOLAR	O
:	O
Sequential	O
Oligogenic	O
Linkage	O
Analysis	O
Routines	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

Potentiation	O
of	O
Nerve	O
Growth	O
Factor	O
-	O
Induced	O
Neurite	O
Outgrowth	O
by	O
Fluvoxamine	O
:	O
Role	O
of	O
Sigma	O
-	O
1	O
Receptors	O
,	O
IP3	O
Receptors	O
and	O
Cellular	O
Signaling	O
Pathways	O

Abstract	O

Background	O

Selective	O
serotonin	O
reuptake	O
inhibitors	O
(	O
SSRIs	O
)	O
have	O
been	O
widely	O
used	O
and	O
are	O
a	O
major	O
therapeutic	O
advance	O
in	O
psychopharmacology	O
.	O

However	O
,	O
their	O
pharmacology	O
is	O
quite	O
heterogeneous	O
.	O

The	O
SSRI	O
fluvoxamine	O
,	O
with	O
sigma	O
-	O
1	O
receptor	O
agonism	O
,	O
is	O
shown	O
to	O
potentiate	O
nerve	O
-	O
growth	O
factor	O
(	O
NGF	O
)	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC	O
12	O
cells	O
.	O

However	O
,	O
the	O
precise	O
cellular	O
and	O
molecular	O
mechanisms	O
underlying	O
potentiation	O
by	O
fluvoxamine	O
are	O
not	O
fully	O
understood	O
.	O

In	O
this	O
study	O
,	O
we	O
examined	O
the	O
roles	O
of	O
cellular	O
signaling	O
pathways	O
in	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
fluvoxamine	O
and	O
sigma	O
-	O
1	O
receptor	O
agonists	O
.	O

Methods	O
and	O
Findings	O

The	O
effects	O
of	O
three	O
SSRIs	O
(	O
fluvoxamine	O
,	O
sertraline	O
,	O
paroxetine	O
)	O
and	O
three	O
sigma	O
-	O
1	O
receptor	O
agonists	O
(	O
SA4503	O
,	O
4	O
-	O
phenyl	O
-	O
1	O
-	O
(	O
4	O
-	O
phenylbutyl	O
)	O
piperidine	O
(	O
PPBP	O
)	O
,	O
and	O
dehydroepiandrostero	O
(	O
DHEA	O
)	O
-	O
sulfate	O
)	O
on	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
were	O
examined	O
.	O

Also	O
examined	O
were	O
the	O
effects	O
of	O
the	O
sigma	O
-	O
1	O
receptor	O
antagonist	O
NE	O
-	O
100	O
,	O
inositol	O
1	O
,	O
4	O
,	O
5	O
-	O
triphosphate	O
(	O
IP3	O
)	O
receptor	O
antagonist	O
,	O
and	O
specific	O
inhibitors	O
of	O
signaling	O
pathways	O
in	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
selective	O
sigma	O
-	O
1	O
receptor	O
agonist	O
SA4503	O
.	O

Fluvoxamine	O
(	O
but	O
not	O
sertraline	O
or	O
paroxetine	O
)	O
and	O
the	O
sigma	O
-	O
1	O
receptor	O
agonists	O
SA4503	O
,	O
PPBP	O
,	O
and	O
DHEA	O
-	O
sulfate	O
significantly	O
potentiated	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
in	O
a	O
concentration	O
-	O
dependent	O
manner	O
.	O

The	O
potentiation	O
by	O
fluvoxamine	O
and	O
the	O
three	O
sigma	O
-	O
1	O
receptor	O
agonists	O
was	O
blocked	O
by	O
co	O
-	O
administration	O
of	O
the	O
selective	O
sigma	O
-	O
1	O
receptor	O
antagonist	O
NE	O
-	O
100	O
,	O
suggesting	O
that	O
sigma	O
-	O
1	O
receptors	O
play	O
a	O
role	O
in	O
blocking	O
the	O
enhancement	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
.	O

Moreover	O
,	O
the	O
potentiation	O
by	O
SA4503	O
was	O
blocked	O
by	O
co	O
-	O
administration	O
of	O
the	O
IP3	O
receptor	O
antagonist	O
xestospongin	O
C	O
.	O

In	O
addition	O
,	O
the	O
specific	O
inhibitors	O
of	O
phospholipase	O
C	O
(	O
PLC	O
-	O
gamma	O
)	O
,	O
phosphatidylinositol	O
3	O
-	O
kinase	O
(	O
PI3K	O
)	O
,	O
p38MAPK	O
,	O
c	O
-	O
Jun	O
N	O
-	O
terminal	O
kinase	O
(	O
JNK	O
)	O
,	O
and	O
the	O
Ras	O
/	O
Raf	O
/	O
mitogen	O
-	O
activated	O
protein	O
kinase	O
(	O
MAPK	O
)	O
signaling	O
pathways	O
blocked	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
.	O

Conclusion	O

These	O
findings	O
suggest	O
that	O
stimulation	O
of	O
sigma	O
-	O
1	O
receptors	O
and	O
subsequent	O
interaction	O
with	O
IP3	O
receptors	O
,	O
PLC	O
-	O
gamma	O
,	O
PI3K	O
,	O
p38MAPK	O
,	O
JNK	O
,	O
and	O
the	O
Ras	O
/	O
Raf	O
/	O
MAPK	O
signaling	O
pathways	O
are	O
involved	O
in	O
the	O
mechanisms	O
of	O
action	O
of	O
sigma	O
-	O
1	O
receptor	O
agonists	O
such	O
as	O
fluvoxamine	O
and	O
SA4503	O
.	O

Introduction	O

Selective	O
serotonin	O
(	O
5	O
-	O
HT	O
;	O
5	O
-	O
hydroxytryptamine	O
)	O
reuptake	O
inhibitors	O
(	O
SSRIs	O
)	O
have	O
emerged	O
as	O
a	O
major	O
therapeutic	O
advance	O
in	O
psychopharmacology	O
.	O

SSRIs	O
are	O
the	O
treatment	O
of	O
choice	O
for	O
many	O
indications	O
,	O
including	O
major	O
depressive	O
disorder	O
,	O
dysthymia	O
,	O
panic	O
disorder	O
,	O
obsessive	O
-	O
compulsive	O
disorder	O
,	O
eating	O
disorders	O
,	O
and	O
premenstrual	O
dysphoric	O
disorder	O
.	O

In	O
contrast	O
,	O
it	O
is	O
well	O
known	O
that	O
their	O
pharmacology	O
is	O
quite	O
heterogeneous	O
,	O
although	O
all	O
of	O
them	O
block	O
5	O
-	O
HT	O
transporters	O
,	O
thus	O
increasing	O
5	O
-	O
HT	O
levels	O
throughout	O
the	O
central	O
nervous	O
system	O
(	O
CNS	O
)	O
[	O
1	O
]	O
-	O
[	O
9	O
]	O
.	O

Accumulating	O
evidence	O
suggests	O
that	O
sigma	O
-	O
1	O
receptors	O
,	O
which	O
are	O
intracellular	O
endoplasmic	O
reticulum	O
(	O
ER	O
)	O
proteins	O
,	O
are	O
involved	O
in	O
both	O
the	O
neuroplasticity	O
and	O
pathophysiology	O
of	O
neuropsychiatric	O
diseases	O
such	O
as	O
major	O
depressive	O
disorder	O
,	O
anxiety	O
,	O
schizophrenia	O
,	O
and	O
Alzheimer	O
'	O
s	O
disease	O
[	O
10	O
]	O
-	O
[	O
18	O
]	O
.	O

Previously	O
,	O
we	O
reported	O
that	O
some	O
SSRIs	O
possess	O
high	O
to	O
moderate	O
affinities	O
for	O
sigma	O
-	O
1	O
receptors	O
in	O
the	O
rat	B
brain	O
.	O

The	O
rank	O
order	O
of	O
SSRIs	O
affinities	O
for	O
sigma	O
-	O
1	O
receptors	O
is	O
fluvoxamine	O
(	O
Ki	O
=	O
36	O
nM	O
)	O
>	O
sertraline	O
(	O
Ki	O
=	O
57	O
nM	O
)	O
>	O
>	O
paroxetine	O
(	O
Ki	O
=	O
1893	O
nM	O
)	O
[	O
19	O
]	O
.	O

Recently	O
,	O
we	O
reported	O
that	O
fluvoxamine	O
,	O
but	O
not	O
paroxetine	O
,	O
significantly	O
ameliorated	O
cognitive	O
deficits	O
in	O
mice	B
after	O
repeated	O
phencyclidine	O
administration	O
,	O
and	O
that	O
the	O
effects	O
of	O
fluvoxamine	O
were	O
antagonized	O
by	O
co	O
-	O
administration	O
of	O
the	O
selective	O
sigma	O
-	O
1	O
receptor	O
antagonist	O
NE	O
-	O
100	O
[	O
20	O
]	O
,	O
suggesting	O
that	O
sigma	O
-	O
1	O
receptors	O
are	O
involved	O
in	O
the	O
mechanism	O
of	O
action	O
of	O
fluvoxamine	O
[	O
9	O
]	O
.	O

Interestingly	O
,	O
it	O
has	O
been	O
demonstrated	O
that	O
sigma	O
-	O
1	O
receptor	O
agonists	O
including	O
fluvoxamine	O
could	O
potentiate	O
nerve	O
growth	O
factor	O
(	O
NGF	O
)	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
,	O
and	O
that	O
NE	O
-	O
100	O
blocked	O
the	O
potentiation	O
by	O
sigma	O
-	O
1	O
receptor	O
agonists	O
,	O
suggesting	O
sigma	O
-	O
1	O
receptors	O
are	O
involved	O
in	O
neuroplasticity	O
[	O
21	O
]	O
.	O

However	O
,	O
the	O
precise	O
cellular	O
mechanisms	O
underlying	O
the	O
potentiation	O
by	O
sigma	O
-	O
1	O
receptor	O
agonists	O
are	O
not	O
fully	O
understood	O
[	O
13	O
]	O
,	O
[	O
21	O
]	O
.	O

It	O
is	O
therefore	O
of	O
great	O
interest	O
to	O
study	O
the	O
precise	O
cellular	O
mechanisms	O
underlying	O
the	O
enhancement	O
by	O
fluvoxamine	O
on	O
NGF	O
-	O
induced	O
neurite	O
sprouting	O
in	O
PC12	O
cells	O
.	O

In	O
the	O
present	O
study	O
,	O
we	O
examined	O
the	O
effects	O
of	O
three	O
SSRIs	O
(	O
fluvoxamine	O
,	O
sertraline	O
,	O
paroxetine	O
)	O
,	O
as	O
well	O
as	O
the	O
effects	O
of	O
a	O
sigma	O
-	O
1	O
receptor	O
agonist	O
(	O
4	O
-	O
phenyl	O
-	O
1	O
-	O
(	O
4	O
-	O
phenylbutyl	O
)	O
piperidine	O
(	O
PPBP	O
)	O
,	O
dehydroepiandrostero	O
-	O
sulphate	O
(	O
DHEA	O
)	O
-	O
sulfate	O
)	O
[	O
9	O
]	O
,	O
[	O
22	O
]	O
-	O
[	O
28	O
]	O
and	O
the	O
selective	O
sigma	O
-	O
1	O
receptor	O
agonist	O
SA4503	O
[	O
29	O
]	O
,	O
[	O
30	O
]	O
,	O
on	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
.	O

Furthermore	O
,	O
it	O
is	O
also	O
known	O
that	O
sigma	O
-	O
1	O
receptors	O
have	O
been	O
shown	O
to	O
interact	O
with	O
IP3	O
receptors	O
(	O
17	O
,	O
18	O
)	O
.	O

Therefore	O
,	O
we	O
examined	O
the	O
effects	O
of	O
NE	O
-	O
100	O
and	O
xestospongin	O
C	O
(	O
a	O
selective	O
inositol	O
1	O
,	O
4	O
,	O
5	O
-	O
triphosphate	O
(	O
IP3	O
)	O
receptor	O
antagonist	O
)	O
[	O
31	O
]	O
in	O
order	O
to	O
investigate	O
the	O
roles	O
of	O
sigma	O
-	O
1	O
receptors	O
and	O
IP3	O
receptors	O
in	O
the	O
mechanisms	O
underlying	O
the	O
enhancement	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
.	O

Moreover	O
,	O
we	O
examined	O
the	O
effects	O
of	O
specific	O
inhibitors	O
of	O
several	O
cellular	O
signaling	O
targets	O
on	O
the	O
enhancement	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
,	O
since	O
several	O
signal	O
transduction	O
molecules	O
have	O
been	O
implicated	O
in	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
[	O
32	O
]	O
.	O

Materials	O
and	O
Methods	O

Drugs	O

The	O
drugs	O
were	O
obtained	O
from	O
the	O
following	O
sources	O
:	O
fluvoxamine	O
maleate	O
(	O
Solvay	O
Seiyaku	O
K	O
.	O
K	O
.	O
,	O
Tokyo	O
,	O
Japan	O
)	O
;	O
paroxetine	O
hydrochloride	O
,	O
dehydroepiandosteron	O
-	O
sulfate	O
(	O
DHEA	O
-	O
sulfate	O
)	O
,	O
LY294002	O
(	O
Sigma	O
-	O
Aldrich	O
,	O
St	O
Louis	O
,	O
MO	O
,	O
USA	O
)	O
;	O
sertraline	O
(	O
Toronto	O
Research	O
Chemicals	O
Inc	O
.	O
,	O
North	O
York	O
,	O
ON	O
,	O
Canada	O
)	O
;	O
SA4503	O
(	O
M	O
'	O
s	O
Science	O
Corporation	O
,	O
Kobe	O
,	O
Japan	O
)	O
;	O
NGF	O
(	O
Promega	O
,	O
Madison	O
,	O
WI	O
)	O
;	O
xestospongin	O
C	O
,	O
lovastatin	O
,	O
PD98059	O
,	O
GW5074	O
,	O
SB203580	O
,	O
MEK	O
1	O
/	O
2	O
inhibitor	O
(	O
SL327	O
)	O
,	O
and	O
SP600125	O
(	O
Calbiochem	O
-	O
Novabiochem	O
,	O
San	O
Diego	O
,	O
CA	O
)	O
.	O

The	O
selective	O
sigma	O
-	O
1	O
receptor	O
antagonists	O
NE	O
-	O
100	O
and	O
4	O
-	O
phenyl	O
-	O
1	O
-	O
(	O
4	O
-	O
phenylbutyl	O
)	O
piperidine	O
(	O
PPBP	O
)	O
were	O
synthesized	O
in	O
our	O
laboratory	O
.	O

Other	O
drugs	O
were	O
purchased	O
from	O
commercial	O
sources	O
.	O

Cell	O
culture	O

PC12	O
sells	O
(	O
RIKEN	O
Cell	O
Bank	O
,	O
Tsukuba	O
,	O
Japan	O
)	O
were	O
cultured	O
at	O
37	O
degrees	O
C	O
,	O
5	O
%	O
CO2	O
with	O
Dulbecco	O
'	O
s	O
modified	O
Eagle	O
'	O
s	O
medium	O
(	O
DMEM	O
)	O
supplemented	O
with	O
5	O
%	O
heat	O
-	O
inactivated	O
fetal	O
bovine	B
serum	O
(	O
FBS	O
)	O
,	O
10	O
%	O
heat	O
-	O
inactivated	O
horse	B
serum	O
,	O
and	O
1	O
%	O
penicillin	O
.	O

The	O
medium	O
was	O
changed	O
two	O
or	O
three	O
times	O
a	O
week	O
.	O

PC12	O
cells	O
were	O
plated	O
onto	O
24	O
-	O
well	O
tissue	O
culture	O
plates	O
coated	O
with	O
poly	O
-	O
D	O
-	O
lysine	O
/	O
laminin	O
.	O

Cells	O
were	O
plated	O
at	O
relatively	O
low	O
density	O
(	O
0	O
.	O
25	O
x	O
104	O
cells	O
/	O
cm2	O
)	O
in	O
DMEM	O
medium	O
containing	O
0	O
.	O
5	O
%	O
FBS	O
,	O
1	O
%	O
penicillin	O
streptomycin	O
.	O

Medium	O
containing	O
a	O
minimal	O
level	O
of	O
serum	O
(	O
0	O
.	O
5	O
%	O
FBS	O
)	O
was	O
used	O
,	O
since	O
serum	O
is	O
known	O
to	O
contain	O
steroid	O
hormones	O
that	O
bind	O
to	O
sigma	O
-	O
1	O
receptors	O
[	O
21	O
]	O
.	O

First	O
,	O
we	O
examined	O
the	O
optimal	O
concentration	O
of	O
NGF	O
for	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
.	O

NGF	O
(	O
2	O
.	O
5	O
,	O
5	O
,	O
10	O
,	O
20	O
,	O
40	O
ng	O
/	O
ml	O
)	O
increased	O
the	O
number	O
of	O
cells	O
with	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
in	O
a	O
concentration	O
-	O
dependent	O
manner	O
(	O
Figure	O
1	O
)	O
.	O

In	O
the	O
subsequent	O
studies	O
,	O
2	O
.	O
5	O
ng	O
/	O
ml	O
of	O
NGF	O
was	O
used	O
to	O
study	O
the	O
potentiating	O
effects	O
of	O
sigma	O
-	O
1	O
receptor	O
agonists	O
on	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
.	O

Twenty	O
-	O
four	O
hours	O
after	O
plating	O
,	O
the	O
medium	O
was	O
replaced	O
with	O
DMEM	O
medium	O
containing	O
0	O
.	O
5	O
%	O
FBS	O
and	O
1	O
%	O
penicillin	O
streptomycin	O
with	O
NGF	O
(	O
2	O
.	O
5	O
ng	O
/	O
ml	O
)	O
with	O
or	O
without	O
several	O
drugs	O
.	O

Quantification	O
of	O
neurite	O
sprouting	O

Five	O
days	O
after	O
incubation	O
with	O
NGF	O
(	O
2	O
.	O
5	O
ng	O
/	O
ml	O
)	O
with	O
or	O
without	O
the	O
several	O
drugs	O
,	O
morphometric	O
analysis	O
was	O
performed	O
on	O
digitized	O
images	O
of	O
live	O
cells	O
taken	O
under	O
phase	O
-	O
contrast	O
illumination	O
with	O
an	O
inverted	O
microscope	O
linked	O
to	O
a	O
camera	O
.	O

Images	O
of	O
three	O
fields	O
per	O
well	O
were	O
taken	O
,	O
with	O
an	O
average	O
of	O
100	O
cells	O
per	O
field	O
.	O

Differentiated	O
cells	O
were	O
counted	O
by	O
visual	O
examination	O
of	O
the	O
field	O
;	O
only	O
cells	O
that	O
had	O
at	O
least	O
one	O
neurite	O
with	O
a	O
length	O
equal	O
to	O
the	O
cell	O
body	O
diameter	O
were	O
counted	O
,	O
and	O
were	O
then	O
expressed	O
as	O
a	O
percentage	O
of	O
the	O
total	O
cells	O
in	O
the	O
field	O
.	O

The	O
counting	O
was	O
performed	O
in	O
a	O
blinded	O
manner	O
.	O

Immunocytochemistry	O

Cells	O
were	O
fixed	O
for	O
30	O
min	O
at	O
room	O
temperature	O
with	O
4	O
%	O
paraformaldehyde	O
then	O
permeabilized	O
with	O
0	O
.	O
2	O
%	O
Triton	O
and	O
blocked	O
with	O
1	O
.	O
5	O
%	O
normal	O
goat	B
serum	O
,	O
0	O
.	O
1	O
%	O
bovine	B
serum	O
albumin	O
(	O
BSA	O
)	O
in	O
0	O
.	O
1	O
M	O
phosphate	O
-	O
buffer	O
saline	O
for	O
1	O
h	O
to	O
reduce	O
nonspecific	O
binding	O
.	O

Cells	O
were	O
incubated	O
overnight	O
at	O
4	O
degrees	O
C	O
with	O
anti	O
-	O
microtubule	O
-	O
associated	O
protein	O
2	O
(	O
MAP	O
-	O
2	O
)	O
antibodies	O
(	O
1	O
:	O
1000	O
dilution	O
in	O
blocking	O
solution	O
,	O
Chemicon	O
International	O
,	O
Temecula	O
,	O
CA	O
,	O
USA	O
)	O
.	O

The	O
immunolabeling	O
was	O
visualized	O
with	O
secondary	O
antibodies	O
conjugated	O
to	O
Alexa	O
-	O
488	O
(	O
1	O
:	O
1000	O
;	O
Invitrogen	O
,	O
Carlsbad	O
,	O
CA	O
,	O
USA	O
)	O
.	O

MAP	O
-	O
2	O
immuncytochemistry	O
was	O
visualized	O
with	O
a	O
fluorescence	O
microscope	O
(	O
Axiovert	O
200	O
,	O
Carl	O
Zeiss	O
,	O
Oberkocken	O
,	O
Germany	O
)	O
.	O

Statistical	O
analysis	O

Data	O
are	O
expressed	O
as	O
means	O
+	O
/	O
-	O
S	O
.	O
E	O
.	O
M	O
.	O

Statistical	O
analysis	O
was	O
performed	O
by	O
using	O
one	O
-	O
way	O
analysis	O
of	O
variance	O
(	O
ANOVA	O
)	O
and	O
the	O
post	O
hoc	O
Bonferroni	O
/	O
Dunn	O
test	O
.	O

P	O
values	O
less	O
than	O
0	O
.	O
05	O
were	O
considered	O
statistically	O
significant	O
.	O

Results	O

Effects	O
of	O
SSRIs	O
on	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O

Fluvoxamine	O
(	O
0	O
.	O
1	O
,	O
1	O
.	O
0	O
,	O
or	O
10	O
micro	O
M	O
)	O
significantly	O
increased	O
the	O
number	O
of	O
cells	O
with	O
neurite	O
outgrowth	O
by	O
NGF	O
(	O
2	O
.	O
5	O
ng	O
/	O
ml	O
)	O
in	O
PC12	O
cells	O
,	O
in	O
a	O
concentration	O
-	O
dependent	O
manner	O
(	O
Figure	O
2	O
and	O
4	O
)	O
.	O

In	O
contrast	O
,	O
sertraline	O
(	O
0	O
.	O
1	O
,	O
1	O
.	O
0	O
,	O
or	O
10	O
micro	O
M	O
)	O
and	O
paroxetine	O
(	O
0	O
.	O
1	O
,	O
1	O
.	O
0	O
,	O
or	O
10	O
micro	O
M	O
)	O
did	O
not	O
increase	O
the	O
number	O
of	O
cells	O
with	O
neurite	O
outgrowth	O
by	O
NGF	O
(	O
2	O
.	O
5	O
ng	O
/	O
ml	O
)	O
.	O

A	O
higher	O
concentration	O
(	O
10	O
micro	O
M	O
)	O
of	O
paroxetine	O
and	O
sertraline	O
significantly	O
decreased	O
the	O
number	O
of	O
cells	O
with	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
,	O
suggesting	O
the	O
cellular	O
toxicity	O
of	O
these	O
drugs	O
in	O
PC12	O
cells	O
(	O
Figure	O
2	O
)	O
.	O

Role	O
of	O
sigma	O
-	O
1	O
receptors	O
in	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
fluvoxamine	O
and	O
SA4503	O

The	O
selective	O
and	O
potent	O
sigma	O
-	O
1	O
receptor	O
agonist	O
SA4503	O
(	O
0	O
.	O
01	O
,	O
0	O
.	O
1	O
,	O
or	O
1	O
.	O
0	O
micro	O
M	O
)	O
significantly	O
increased	O
the	O
number	O
of	O
cells	O
with	O
neurite	O
outgrowth	O
by	O
NGF	O
(	O
2	O
.	O
5	O
ng	O
/	O
ml	O
)	O
in	O
PC12	O
cells	O
,	O
in	O
a	O
concentration	O
-	O
dependent	O
manner	O
(	O
Figure	O
3	O
and	O
4	O
)	O
.	O

In	O
addition	O
,	O
other	O
sigma	O
-	O
1	O
receptor	O
agonists	O
-	O
PPBP	O
(	O
0	O
.	O
1	O
,	O
1	O
.	O
0	O
,	O
or	O
10	O
micro	O
M	O
)	O
[	O
22	O
]	O
-	O
[	O
26	O
]	O
and	O
DHEA	O
-	O
sulphate	O
(	O
0	O
.	O
1	O
,	O
1	O
.	O
0	O
,	O
or	O
10	O
micro	O
M	O
)	O
[	O
9	O
]	O
,	O
[	O
27	O
]	O
,	O
[	O
28	O
]	O
-	O
significantly	O
increased	O
the	O
number	O
of	O
such	O
cells	O
,	O
also	O
in	O
a	O
concentration	O
-	O
dependent	O
manner	O
(	O
Figure	O
3	O
)	O
.	O

In	O
the	O
absence	O
of	O
NGF	O
,	O
sigma	O
-	O
1	O
receptor	O
agonists	O
did	O
not	O
produce	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
(	O
data	O
not	O
shown	O
)	O
.	O

To	O
investigate	O
the	O
role	O
of	O
sigma	O
-	O
1	O
receptors	O
,	O
we	O
examined	O
the	O
effects	O
of	O
NE	O
-	O
100	O
(	O
a	O
selective	O
sigma	O
-	O
1	O
receptor	O
antagonist	O
)	O
on	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
fluvoxamine	O
,	O
SA4503	O
,	O
PPBP	O
,	O
and	O
DHEA	O
-	O
sulphate	O
.	O

Co	O
-	O
administration	O
of	O
NE	O
-	O
100	O
(	O
1	O
.	O
0	O
micro	O
M	O
)	O
significantly	O
blocked	O
such	O
potentiation	O
by	O
fluvoxamine	O
(	O
10	O
micro	O
M	O
)	O
,	O
SA4503	O
(	O
1	O
.	O
0	O
micro	O
M	O
)	O
,	O
PPBP	O
(	O
10	O
micro	O
M	O
)	O
,	O
or	O
DHEA	O
-	O
sulphate	O
(	O
10	O
micro	O
M	O
)	O
(	O
Figure	O
2	O
and	O
3	O
)	O
.	O

Furthermore	O
,	O
administration	O
of	O
NE	O
-	O
100	O
(	O
1	O
.	O
0	O
micro	O
M	O
)	O
alone	O
did	O
not	O
alter	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
(	O
Figure	O
2	O
)	O
.	O

Role	O
of	O
IP3	O
receptors	O
in	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O

Sigma	O
-	O
1	O
receptors	O
have	O
been	O
shown	O
to	O
interact	O
with	O
IP3	O
receptors	O
(	O
17	O
,	O
18	O
,	O
33	O
-	O
35	O
)	O
.	O

To	O
investigate	O
the	O
role	O
of	O
IP3	O
receptors	O
in	O
the	O
effects	O
of	O
SA4503	O
on	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
,	O
we	O
examined	O
the	O
effects	O
of	O
xestospongin	O
C	O
(	O
a	O
selective	O
,	O
reversible	O
,	O
and	O
membrane	O
-	O
permeable	O
inhibitor	O
of	O
IP3	O
receptors	O
)	O
[	O
31	O
]	O
on	O
the	O
effects	O
of	O
SA4503	O
on	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
.	O

Co	O
-	O
administration	O
of	O
xestospongin	O
C	O
(	O
1	O
.	O
0	O
micro	O
M	O
)	O
significantly	O
blocked	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
(	O
1	O
.	O
0	O
micro	O
M	O
)	O
(	O
Figure	O
5	O
)	O
.	O

Furthermore	O
,	O
administration	O
of	O
xestospongin	O
C	O
(	O
1	O
.	O
0	O
micro	O
M	O
)	O
alone	O
did	O
not	O
alter	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
(	O
Figure	O
5	O
)	O
.	O

Role	O
of	O
signaling	O
molecules	O
proximal	O
to	O
TrkA	O
in	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O

Next	O
,	O
we	O
examined	O
the	O
effects	O
of	O
the	O
specific	O
inhibitors	O
of	O
PLC	O
-	O
gamma	O
,	O
PI3K	O
,	O
p38	O
MAPK	O
,	O
and	O
c	O
-	O
Jun	O
N	O
-	O
terminal	O
kinase	O
(	O
JNK	O
)	O
,	O
since	O
these	O
signaling	O
molecules	O
are	O
activated	O
upon	O
the	O
addition	O
of	O
NGF	O
[	O
36	O
]	O
.	O

The	O
PLC	O
-	O
gamma	O
inhibitor	O
(	O
U73122	O
;	O
1	O
.	O
0	O
micro	O
M	O
)	O
,	O
PI3K	O
inhibitor	O
(	O
LY294002	O
;	O
1	O
.	O
0	O
micro	O
M	O
)	O
,	O
p38	O
MAPK	O
inhibitor	O
(	O
SB203580	O
;	O
1	O
.	O
0	O
micro	O
M	O
)	O
,	O
and	O
JNK	O
inhibitor	O
(	O
SP600125	O
;	O
1	O
.	O
0	O
micro	O
M	O
)	O
significantly	O
blocked	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
(	O
1	O
.	O
0	O
micro	O
M	O
)	O
(	O
Figure	O
6	O
)	O
.	O

In	O
contrast	O
,	O
these	O
inhibitors	O
alone	O
did	O
not	O
alter	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
(	O
Figure	O
6	O
)	O
.	O

Role	O
of	O
Raf	O
/	O
Ras	O
/	O
ERK	O
/	O
MAPK	O
pathway	O
in	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O

The	O
Raf	O
/	O
Ras	O
/	O
ERK	O
/	O
MAPK	O
pathway	O
is	O
known	O
to	O
be	O
involved	O
in	O
NGF	O
-	O
induced	O
outgrowth	O
[	O
32	O
]	O
.	O

Therefore	O
,	O
we	O
examined	O
the	O
effects	O
of	O
this	O
pathway	O
'	O
s	O
specific	O
inhibitors	O
.	O

The	O
Ras	O
inhibitor	O
(	O
GW5074	O
;	O
1	O
.	O
0	O
micro	O
M	O
)	O
,	O
Raf	O
inhibitor	O
(	O
lovastatin	O
;	O
1	O
.	O
0	O
micro	O
M	O
)	O
,	O
MEK1	O
/	O
2	O
inhibitor	O
(	O
SL327	O
;	O
1	O
.	O
0	O
micro	O
M	O
)	O
,	O
and	O
MAPK	O
inhibitor	O
(	O
PD98059	O
;	O
1	O
.	O
0	O
micro	O
M	O
)	O
significantly	O
blocked	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
(	O
1	O
.	O
0	O
micro	O
M	O
)	O
(	O
Figure	O
7	O
)	O
.	O

In	O
contrast	O
,	O
these	O
inhibitors	O
alone	O
did	O
not	O
alter	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
(	O
Figure	O
7	O
)	O
.	O

Discussion	O

In	O
the	O
present	O
study	O
,	O
we	O
found	O
that	O
fluvoxamine	O
(	O
but	O
not	O
sertraline	O
or	O
paroxetine	O
)	O
and	O
the	O
sigma	O
-	O
1	O
receptor	O
agonists	O
(	O
SA4503	O
,	O
PPBP	O
,	O
DHEA	O
-	O
sulfate	O
)	O
could	O
potentiate	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
,	O
and	O
that	O
the	O
effects	O
of	O
these	O
drugs	O
were	O
blocked	O
by	O
co	O
-	O
incubation	O
with	O
the	O
selective	O
sigma	O
-	O
1	O
receptor	O
antagonist	O
NE	O
-	O
100	O
.	O

These	O
findings	O
suggest	O
that	O
agonism	O
at	O
sigma	O
-	O
1	O
receptors	O
for	O
these	O
drugs	O
is	O
involved	O
in	O
the	O
mechanisms	O
underlying	O
the	O
drugs	O
'	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
.	O

As	O
shown	O
in	O
Figure	O
1	O
,	O
NGF	O
increased	O
the	O
number	O
of	O
cells	O
with	O
neurite	O
outgrowth	O
in	O
PC12	O
,	O
in	O
a	O
concentration	O
dependent	O
manner	O
.	O

To	O
examine	O
whether	O
or	O
not	O
the	O
NGF	O
levels	O
are	O
altered	O
by	O
incubation	O
with	O
sigma	O
-	O
1	O
receptor	O
agonists	O
,	O
we	O
measured	O
the	O
levels	O
of	O
NGF	O
in	O
PC12	O
cells	O
with	O
or	O
without	O
sigma	O
-	O
1	O
receptor	O
agonist	O
SA4503	O
.	O

No	O
differences	O
of	O
NGF	O
levels	O
were	O
shown	O
in	O
the	O
between	O
control	O
group	O
and	O
SA4503	O
-	O
treated	O
group	O
(	O
data	O
not	O
shown	O
)	O
.	O

It	O
is	O
,	O
therefore	O
,	O
unlikely	O
that	O
the	O
potentaition	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
sigma	O
-	O
1	O
receptor	O
agonists	O
might	O
be	O
due	O
to	O
increased	O
levels	O
of	O
NGF	O
.	O

Unlike	O
fluvoxamine	O
,	O
sertraline	O
,	O
which	O
has	O
a	O
moderate	O
affinity	O
for	O
sigma	O
-	O
1	O
receptors	O
,	O
did	O
not	O
alter	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
.	O

The	O
reasons	O
underlying	O
this	O
discrepancy	O
between	O
these	O
two	O
SSRIs	O
are	O
currently	O
unclear	O
.	O

One	O
possibility	O
may	O
involve	O
the	O
difference	O
in	O
pharmacological	O
actions	O
(	O
agonist	O
vs	O
.	O
antagonist	O
)	O
between	O
these	O
SSRIs	O
at	O
sigma	O
-	O
1	O
receptors	O
.	O

Interestingly	O
,	O
we	O
recently	O
found	O
that	O
,	O
in	O
a	O
novel	O
object	O
recognition	O
test	O
,	O
phencyclidine	O
-	O
induced	O
cognitive	O
deficits	O
could	O
be	O
significantly	O
improved	O
by	O
subsequent	O
subchronic	O
(	O
14	O
days	O
)	O
administration	O
of	O
fluvoxamine	O
,	O
but	O
not	O
of	O
sertraline	O
,	O
suggesting	O
that	O
sigma	O
-	O
1	O
receptor	O
agonism	O
is	O
involved	O
in	O
fluvoxamine	O
'	O
s	O
mechanism	O
of	O
action	O
[	O
9	O
]	O
,	O
Ishima	O
et	O
al	O
.	O
,	O
submitted	O
.	O

Taken	O
together	O
,	O
these	O
findings	O
suggest	O
that	O
fluvoxamine	O
and	O
sertraline	O
may	O
function	O
as	O
an	O
agonist	O
and	O
an	O
antagonist	O
at	O
sigma	O
-	O
1	O
receptors	O
,	O
respectively	O
,	O
although	O
further	O
study	O
is	O
necessary	O
.	O

Another	O
possibility	O
may	O
be	O
that	O
other	O
pharmacological	O
activities	O
of	O
sertraline	O
mask	O
the	O
effects	O
of	O
sigma	O
-	O
1	O
receptor	O
agonism	O
.	O

In	O
this	O
study	O
,	O
we	O
also	O
found	O
that	O
high	O
concentration	O
(	O
10	O
micro	O
M	O
)	O
of	O
paroxetine	O
and	O
sertraline	O
,	O
but	O
not	O
fluvoxamine	O
,	O
showed	O
cytotoxicity	O
in	O
PC12	O
cells	O
,	O
suggesting	O
that	O
fluvoxamine	O
may	O
be	O
a	O
safe	O
drug	O
than	O
paroxetine	O
and	O
sertraline	O
.	O

Sigma	O
-	O
1	O
receptors	O
have	O
been	O
shown	O
to	O
affect	O
intracellular	O
Ca2	O
+	O
signaling	O
,	O
although	O
the	O
precise	O
molecular	O
and	O
cellular	O
mechanisms	O
underlying	O
this	O
effect	O
are	O
unknown	O
.	O

Sigma	O
-	O
1	O
receptors	O
bind	O
to	O
IP3	O
receptors	O
in	O
ER	O
,	O
and	O
sigma	O
-	O
1	O
receptors	O
regulate	O
Ca2	O
+	O
release	O
from	O
intracellular	O
Ca2	O
+	O
storage	O
sites	O
[	O
12	O
]	O
.	O

Very	O
recently	O
,	O
Hayashi	O
and	O
Su	O
[	O
17	O
]	O
reported	O
that	O
sigma	O
-	O
1	O
receptors	O
function	O
as	O
novel	O
ligand	O
-	O
operated	O
chaperones	O
that	O
specifically	O
target	O
mitochondrion	O
-	O
associated	O
ER	O
membrane	O
.	O

Furthermore	O
,	O
sigma	O
-	O
1	O
receptors	O
form	O
Ca2	O
+	O
-	O
sensitive	O
chaperone	O
machinery	O
with	O
another	O
chaperone	O
,	O
BiP	O
,	O
and	O
prolong	O
Ca2	O
+	O
signaling	O
from	O
ER	O
into	O
mitochondria	O
by	O
stabilizing	O
IP3	O
receptors	O
at	O
mitochondrion	O
-	O
associated	O
ER	O
membrane	O
[	O
17	O
]	O
.	O

In	O
this	O
study	O
,	O
we	O
found	O
that	O
the	O
IP3	O
receptor	O
antagonist	O
xestospongin	O
C	O
significantly	O
blocked	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
,	O
suggesting	O
the	O
role	O
of	O
IP3	O
receptors	O
on	O
sigma	O
-	O
1	O
receptor	O
-	O
mediated	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
.	O

Therefore	O
,	O
it	O
is	O
likely	O
that	O
stimulation	O
at	O
sigma	O
-	O
1	O
receptors	O
by	O
sigma	O
-	O
1	O
receptor	O
agonists	O
and	O
subsequent	O
interaction	O
with	O
IP3	O
receptors	O
are	O
involved	O
in	O
the	O
mechanism	O
underlying	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
sigma	O
-	O
1	O
receptor	O
agonists	O
.	O

NGF	O
binds	O
to	O
the	O
high	O
-	O
affinity	O
tyrosine	O
receptor	O
TrkA	O
,	O
initiating	O
several	O
signaling	O
pathways	O
affecting	O
both	O
morphological	O
and	O
transcriptional	O
targets	O
[	O
32	O
]	O
,	O
[	O
36	O
]	O
,	O
[	O
37	O
]	O
.	O

The	O
signaling	O
molecules	O
,	O
including	O
PLC	O
-	O
gamma	O
,	O
PI3K	O
,	O
p38	O
MAPK	O
,	O
and	O
JNK	O
,	O
are	O
activated	O
upon	O
the	O
addition	O
of	O
NGF	O
[	O
38	O
]	O
.	O

PLC	O
-	O
gamma	O
catalyzes	O
the	O
hydrolysis	O
of	O
phosphatidylinositol	O
-	O
4	O
,	O
5	O
-	O
bisphosphate	O
(	O
PIP2	O
)	O
to	O
diacylglycerol	O
(	O
DAG	O
)	O
and	O
inositol	O
triphosphate	O
(	O
IP3	O
)	O
.	O

DAG	O
activates	O
protein	O
kinase	O
C	O
,	O
and	O
IP3	O
promotes	O
transient	O
release	O
of	O
Ca2	O
+	O
from	O
the	O
ER	O
[	O
39	O
]	O
.	O

The	O
pathway	O
via	O
PLC	O
-	O
gamma	O
is	O
responsible	O
for	O
NGF	O
-	O
induced	O
cell	O
differentiation	O
[	O
40	O
]	O
and	O
neurite	O
outgrowth	O
[	O
41	O
]	O
.	O

Furthermore	O
,	O
stimulation	O
of	O
PI3K	O
is	O
reported	O
to	O
be	O
involved	O
in	O
the	O
promotion	O
of	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
[	O
42	O
]	O
.	O

In	O
this	O
study	O
,	O
we	O
found	O
that	O
the	O
PLC	O
-	O
gamma	O
inhibitor	O
U73122	O
and	O
the	O
PI3K	O
inhibitor	O
LY294002	O
significantly	O
blocked	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
.	O

Moreover	O
,	O
we	O
found	O
that	O
both	O
the	O
p38MAPK	O
inhibitor	O
SB203580	O
and	O
the	O
JNK	O
inhibitor	O
SP600125	O
significantly	O
blocked	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
.	O

In	O
addition	O
,	O
it	O
is	O
also	O
interesting	O
that	O
neurite	O
outgrowth	O
induced	O
by	O
low	O
concentration	O
(	O
2	O
.	O
5	O
ng	O
/	O
ml	O
)	O
of	O
NGF	O
was	O
not	O
blocked	O
by	O
these	O
inihibitors	O
,	O
consistent	O
with	O
a	O
previous	O
report	O
[	O
43	O
]	O
,	O
[	O
44	O
]	O
,	O
suggesting	O
the	O
existence	O
of	O
novel	O
pathway	O
(	O
s	O
)	O
for	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
.	O

These	O
findings	O
suggest	O
that	O
the	O
PLC	O
-	O
gamma	O
,	O
PI3K	O
,	O
p38MAPK	O
,	O
and	O
JNK	O
signaling	O
pathways	O
are	O
involved	O
in	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
sigma	O
-	O
1	O
receptor	O
agonists	O
(	O
Figure	O
8	O
)	O
.	O

In	O
addition	O
,	O
we	O
found	O
that	O
the	O
specific	O
inhibitors	O
for	O
the	O
Raf	O
/	O
Ras	O
/	O
MEK	O
/	O
MAPK	O
pathways	O
significantly	O
blocked	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
SA4503	O
,	O
suggesting	O
that	O
these	O
pathways	O
are	O
involved	O
in	O
the	O
potentiation	O
of	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
by	O
sigma	O
-	O
1	O
receptor	O
agonists	O
(	O
Figure	O
8	O
)	O
.	O

Our	O
recent	O
positron	O
emission	O
tomography	O
(	O
PET	O
)	O
study	O
demonstrated	O
that	O
,	O
after	O
a	O
single	O
oral	O
administration	O
,	O
fluvoxamine	O
bound	O
to	O
sigma	O
-	O
1	O
receptors	O
in	O
the	O
living	O
human	B
brain	O
[	O
45	O
]	O
.	O

This	O
finding	O
suggests	O
that	O
sigma	O
-	O
1	O
receptors	O
are	O
involved	O
in	O
the	O
mechanism	O
of	O
action	O
of	O
fluvoxamine	O
in	O
the	O
human	B
brain	O
[	O
45	O
]	O
.	O

Taken	O
together	O
,	O
the	O
past	O
and	O
present	O
findings	O
suggest	O
that	O
,	O
unlike	O
paroxetine	O
and	O
sertraline	O
,	O
the	O
SSRI	O
fluvoxamine	O
,	O
with	O
its	O
sigma	O
-	O
1	O
receptor	O
agonistic	O
activity	O
,	O
might	O
be	O
a	O
unique	O
therapeutic	O
drug	O
for	O
neuropsychiatric	O
diseases	O
.	O

In	O
conclusion	O
,	O
the	O
present	O
results	O
suggest	O
that	O
,	O
as	O
a	O
sigma	O
-	O
1	O
receptor	O
agonist	O
,	O
fluvoxamine	O
could	O
potentiate	O
the	O
NGF	O
-	O
induced	O
neurite	O
outgrowth	O
in	O
PC12	O
cells	O
.	O

Furthermore	O
,	O
it	O
is	O
likely	O
that	O
interaction	O
with	O
IP3	O
receptors	O
and	O
several	O
subsequent	O
signaling	O
molecules	O
are	O
involved	O
in	O
the	O
mechanism	O
underlying	O
the	O
pharmacological	O
action	O
of	O
sigma	O
-	O
1	O
receptor	O
agonists	O
.	O

Therefore	O
,	O
it	O
is	O
likely	O
that	O
sigma	O
-	O
1	O
receptor	O
agonists	O
such	O
as	O
fluvoxamine	O
and	O
DHEA	O
-	O
sulfate	O
,	O
which	O
are	O
available	O
around	O
the	O
world	O
,	O
would	O
be	O
unique	O
therapeutic	O
drugs	O
for	O
neuropsychiatric	O
diseases	O
.	O

A	O
novel	O
,	O
non	O
-	O
invasive	O
,	O
online	O
-	O
monitoring	O
,	O
versatile	O
and	O
easy	O
plant	O
-	O
based	O
probe	O
for	O
measuring	O
leaf	O
water	O
status	O

Abstract	O

A	O
high	O
-	O
precision	O
pressure	O
probe	O
is	O
described	O
which	O
allows	O
non	O
-	O
invasive	O
online	O
-	O
monitoring	O
of	O
the	O
water	O
relations	O
of	O
intact	O
leaves	O
.	O

Real	O
-	O
time	O
recording	O
of	O
the	O
leaf	O
water	O
status	O
occurred	O
by	O
data	O
transfer	O
to	O
an	O
Internet	O
server	O
.	O

The	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
measures	O
the	O
attenuated	O
pressure	O
,	O
Pp	O
,	O
of	O
a	O
leaf	O
patch	O
in	O
response	O
to	O
a	O
constant	O
clamp	O
pressure	O
,	O
Pclamp	O
.	O

Pp	O
is	O
sensed	O
by	O
a	O
miniaturized	O
silicone	O
pressure	O
sensor	O
integrated	O
into	O
the	O
device	O
.	O

The	O
magnitude	O
of	O
Pp	O
is	O
dictated	O
by	O
the	O
transfer	O
function	O
of	O
the	O
leaf	O
,	O
Tf	O
,	O
which	O
is	O
a	O
function	O
of	O
leaf	O
patch	O
volume	O
and	O
ultimately	O
of	O
cell	O
turgor	O
pressure	O
,	O
Pc	O
,	O
as	O
shown	O
theoretically	O
.	O

The	O
power	O
function	O
Tf	O
=	O
f	O
(	O
Pc	O
)	O
theoretically	O
derived	O
was	O
experimentally	O
confirmed	O
by	O
concomitant	O
Pp	O
and	O
Pc	O
measurements	O
on	O
intact	O
leaflets	O
of	O
the	O
liana	O
Tetrastigma	B
voinierianum	I
under	O
greenhouse	O
conditions	O
.	O

Simultaneous	O
Pp	O
recordings	O
on	O
leaflets	O
up	O
to	O
10	O
m	O
height	O
above	O
ground	O
demonstrated	O
that	O
changes	O
in	O
Tf	O
induced	O
by	O
Pc	O
changes	O
due	O
to	O
changes	O
of	O
microclimate	O
and	O
/	O
or	O
of	O
the	O
irrigation	O
regime	O
were	O
sensitively	O
reflected	O
in	O
corresponding	O
changes	O
of	O
Pp	O
.	O

Analysis	O
of	O
the	O
data	O
show	O
that	O
transpirational	O
water	O
loss	O
during	O
the	O
morning	O
hours	O
was	O
associated	O
with	O
a	O
transient	O
rise	O
in	O
turgor	O
pressure	O
gradients	O
within	O
the	O
leaflets	O
.	O

Subsequent	O
recovery	O
of	O
turgescence	O
during	O
the	O
afternoon	O
was	O
much	O
faster	O
than	O
the	O
preceding	O
transpiration	O
-	O
induced	O
water	O
loss	O
if	O
the	O
plants	O
were	O
well	O
irrigated	O
.	O

Our	O
data	O
show	O
the	O
enormous	O
potential	O
of	O
the	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
for	O
leaf	O
water	O
studies	O
including	O
unravelling	O
of	O
the	O
hydraulic	O
communication	O
between	O
neighbouring	O
leaves	O
and	O
over	O
long	O
distances	O
within	O
tall	O
plants	O
(	O
trees	O
)	O
.	O

Introduction	O

Optimum	O
water	O
supply	O
,	O
particularly	O
at	O
peak	O
needs	O
of	O
the	O
plants	O
,	O
is	O
an	O
important	O
issue	O
for	O
greenhouse	O
and	O
field	O
vegetable	O
production	O
.	O

In	O
a	O
greenhouse	O
on	O
a	O
sunny	O
day	O
,	O
evaporation	O
and	O
transpiration	O
(	O
so	O
-	O
called	O
evapotranspiration	O
)	O
can	O
occur	O
so	O
rapidly	O
that	O
water	O
loss	O
can	O
cause	O
plant	O
damage	O
before	O
wilting	O
symptoms	O
are	O
visible	O
.	O

Even	O
at	O
lower	O
temperatures	O
the	O
restricted	O
rooting	O
in	O
greenhouses	O
leads	O
frequently	O
to	O
plant	O
water	O
deficiency	O
.	O

Thus	O
,	O
no	O
matter	O
how	O
slight	O
,	O
drought	O
stress	O
will	O
result	O
in	O
a	O
significant	O
reduction	O
in	O
growth	O
and	O
,	O
in	O
turn	O
,	O
of	O
harvest	O
yield	O
.	O

On	O
the	O
other	O
hand	O
,	O
over	O
-	O
irrigation	O
must	O
be	O
avoided	O
and	O
the	O
appropriate	O
method	O
of	O
watering	O
must	O
be	O
selected	O
because	O
wet	O
soils	O
and	O
permanent	O
moisture	O
on	O
plant	O
organs	O
promote	O
the	O
incidence	O
of	O
root	O
mould	O
,	O
grey	O
mould	O
(	O
Botrytis	O
blight	O
)	O
,	O
formation	O
of	O
leaf	O
oedema	O
,	O
and	O
other	O
plant	O
diseases	O
(	O
Sherf	O
and	O
MacNab	O
,	O
1986	O
)	O
.	O

Conservation	O
of	O
water	O
is	O
another	O
important	O
issue	O
in	O
semi	O
-	O
arid	O
and	O
arid	O
regions	O
where	O
water	O
is	O
scarce	O
.	O

The	O
advent	O
of	O
(	O
subsurface	O
)	O
drip	O
irrigation	O
has	O
considerably	O
reduced	O
water	O
consumption	O
of	O
agricultural	O
,	O
horticultural	O
,	O
and	O
greenhouse	O
crops	O
,	O
but	O
has	O
also	O
highlighted	O
the	O
need	O
for	O
sensors	O
monitoring	O
water	O
deficiency	O
of	O
plants	O
directly	O
and	O
online	O
(	O
Jones	O
,	O
2004	O
)	O
.	O

In	O
plant	O
physiology	O
and	O
agriculture	O
the	O
pressure	O
bomb	O
technique	O
pioneered	O
by	O
Scholander	O
et	O
al	O
.	O

(	O
1965	O
)	O
is	O
a	O
widely	O
accepted	O
reference	O
technique	O
for	O
measuring	O
leaf	O
water	O
status	O
.	O

However	O
,	O
the	O
method	O
is	O
massively	O
invasive	O
,	O
slow	O
,	O
labour	O
-	O
intensive	O
(	O
and	O
therefore	O
expensive	O
)	O
,	O
unsuitable	O
for	O
automation	O
,	O
and	O
gives	O
only	O
spot	O
measurements	O
.	O

Furthermore	O
,	O
interpretation	O
of	O
the	O
data	O
is	O
still	O
a	O
matter	O
of	O
debate	O
(	O
Zimmermann	O
U	O
et	O
al	O
.	O
,	O
2004	O
;	O
Zimmermann	O
D	O
et	O
al	O
.	O
,	O
2007	O
)	O
.	O

Leaf	O
thickness	O
is	O
also	O
sometimes	O
used	O
as	O
an	O
indicator	O
for	O
water	O
stress	O
(	O
Burquez	O
,	O
1987	O
;	O
McBurney	O
,	O
1992	O
;	O
Malone	O
,	O
1993	O
)	O
.	O

Leaf	O
thickness	O
monitoring	O
devices	O
are	O
commercially	O
available	O
.	O

They	O
are	O
non	O
-	O
invasive	O
and	O
suitable	O
for	O
online	O
measurements	O
,	O
but	O
have	O
the	O
disadvantage	O
that	O
changes	O
in	O
water	O
status	O
are	O
frequently	O
not	O
reflected	O
sensitively	O
in	O
changes	O
of	O
leaf	O
thickness	O
.	O

The	O
pressure	O
probe	O
technique	O
pioneered	O
by	O
Zimmermann	O
,	O
Tomos	O
,	O
and	O
others	O
(	O
Zimmermann	O
et	O
al	O
.	O
,	O
1969	O
,	O
2004	O
;	O
Tomos	O
,	O
1988	O
;	O
Balling	O
and	O
Zimmermann	O
,	O
1990	O
)	O
,	O
on	O
the	O
other	O
hand	O
,	O
is	O
a	O
well	O
established	O
technology	O
for	O
measuring	O
turgor	O
and	O
xylem	O
pressure	O
on	O
the	O
levels	O
of	O
individual	O
cells	O
and	O
xylem	O
vessels	O
,	O
respectively	O
.	O

This	O
technique	O
is	O
not	O
suitable	O
for	O
automation	O
.	O

Moreover	O
,	O
the	O
probe	O
technique	O
requires	O
rather	O
sophisticated	O
equipment	O
and	O
a	O
high	O
level	O
of	O
technical	O
skill	O
.	O

These	O
disadvantages	O
are	O
also	O
shared	O
by	O
the	O
ball	O
tonometry	O
,	O
a	O
method	O
which	O
allows	O
non	O
-	O
invasive	O
monitoring	O
of	O
cell	O
turgor	O
pressure	O
by	O
application	O
of	O
an	O
external	O
pressure	O
(	O
Lintilhac	O
et	O
al	O
.	O
,	O
2000	O
;	O
Geitmann	O
,	O
2006	O
)	O
.	O

Other	O
water	O
stress	O
monitoring	O
devices	O
are	O
described	O
in	O
the	O
literature	O
,	O
but	O
all	O
of	O
them	O
have	O
various	O
disadvantages	O
which	O
prevented	O
their	O
implementation	O
for	O
leaf	O
water	O
status	O
measurements	O
in	O
greenhouses	O
or	O
in	O
the	O
field	O
(	O
see	O
,	O
for	O
example	O
,	O
the	O
review	O
article	O
of	O
Jones	O
,	O
2004	O
,	O
and	O
also	O
Grant	O
et	O
al	O
.	O
,	O
2007	O
)	O
.	O

In	O
this	O
communication	O
a	O
novel	O
,	O
non	O
-	O
invasive	O
,	O
online	O
-	O
monitoring	O
plant	O
-	O
based	O
probe	O
is	O
described	O
that	O
meets	O
the	O
demands	O
of	O
controlling	O
horticultural	O
and	O
agricultural	O
water	O
applications	O
.	O

The	O
probe	O
is	O
characterized	O
by	O
high	O
precision	O
,	O
operating	O
convenience	O
,	O
minimum	O
costs	O
,	O
and	O
by	O
automation	O
suitability	O
.	O

Data	O
can	O
be	O
transferred	O
wireless	O
to	O
a	O
personal	O
computer	O
or	O
to	O
an	O
Internet	O
server	O
via	O
a	O
mobile	O
phone	O
network	O
for	O
real	O
-	O
time	O
evaluation	O
and	O
for	O
the	O
automatic	O
regulation	O
of	O
irrigation	O
.	O

The	O
technology	O
includes	O
a	O
miniaturized	O
silicone	O
pressure	O
sensor	O
integrated	O
into	O
a	O
spring	O
clamp	O
that	O
is	O
clamped	O
to	O
a	O
patch	O
of	O
an	O
intact	O
plant	O
leaf	O
.	O

The	O
patch	O
clamp	O
pressure	O
probe	O
measures	O
the	O
attenuated	O
pressure	O
response	O
of	O
the	O
leaf	O
patch	O
upon	O
the	O
application	O
of	O
a	O
constant	O
,	O
clamped	O
pressure	O
.	O

The	O
attenuation	O
of	O
the	O
applied	O
pressure	O
depends	O
on	O
the	O
transfer	O
function	O
of	O
the	O
leaf	O
.	O

The	O
magnitude	O
of	O
the	O
transfer	O
function	O
depends	O
on	O
two	O
terms	O
,	O
a	O
turgor	O
pressure	O
-	O
independent	O
term	O
(	O
related	O
to	O
the	O
compression	O
of	O
the	O
cuticle	O
,	O
cell	O
walls	O
,	O
and	O
other	O
structural	O
elements	O
)	O
and	O
a	O
turgor	O
pressure	O
-	O
dependent	O
term	O
.	O

Theory	O
shows	O
that	O
the	O
turgor	O
pressure	O
-	O
dependent	O
part	O
of	O
the	O
transfer	O
function	O
Tf	O
is	O
a	O
power	O
function	O
of	O
the	O
cell	O
turgor	O
pressure	O
,	O
Pc	O
,	O
and	O
predicts	O
that	O
Tf	O
assumes	O
values	O
close	O
to	O
zero	O
if	O
Pc	O
is	O
high	O
and	O
,	O
vice	O
versa	O
,	O
values	O
close	O
to	O
unity	O
if	O
Pc	O
is	O
low	O
.	O

This	O
could	O
be	O
verified	O
by	O
combined	O
turgor	O
pressure	O
probe	O
and	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
measurements	O
on	O
leaflets	O
of	O
the	O
liana	O
Tetrastigma	B
voinierianum	I
.	O

The	O
10	O
-	O
m	O
tall	O
liana	O
growing	O
in	O
a	O
tropical	O
greenhouse	O
was	O
selected	O
for	O
the	O
first	O
studies	O
because	O
a	O
comprehensive	O
data	O
set	O
about	O
diurnal	O
changes	O
in	O
xylem	O
and	O
turgor	O
pressure	O
gradients	O
under	O
various	O
environmental	O
conditions	O
existed	O
for	O
this	O
greenhouse	O
plant	O
(	O
Benkert	O
et	O
al	O
.	O
,	O
1995	O
;	O
Th	O
u	O
rmer	O
et	O
al	O
.	O
,	O
1999	O
;	O
see	O
also	O
Zimmermann	O
et	O
al	O
.	O
,	O
2004	O
)	O
.	O

Measurements	O
of	O
diurnal	O
changes	O
of	O
the	O
patch	O
clamp	O
pressure	O
performed	O
here	O
yielded	O
results	O
which	O
were	O
consistent	O
with	O
the	O
previous	O
pressure	O
probe	O
work	O
on	O
the	O
liana	O
.	O

The	O
data	O
also	O
demonstrated	O
that	O
changes	O
in	O
the	O
irrigation	O
regime	O
and	O
in	O
microclimate	O
can	O
be	O
sensed	O
by	O
this	O
novel	O
probe	O
very	O
sensitively	O
and	O
that	O
use	O
of	O
several	O
probes	O
allowed	O
the	O
study	O
of	O
the	O
diurnal	O
water	O
transport	O
at	O
multiple	O
scales	O
from	O
single	O
leaves	O
to	O
the	O
whole	O
organism	O
(	O
Meinzer	O
et	O
al	O
.	O
,	O
2001	O
)	O
.	O

This	O
can	O
be	O
done	O
without	O
knowledge	O
of	O
the	O
turgor	O
pressure	O
because	O
the	O
transfer	O
function	O
is	O
a	O
direct	O
measure	O
of	O
leaf	O
water	O
status	O
.	O

Materials	O
and	O
methods	O

Plant	O
material	O

Experiments	O
were	O
performed	O
on	O
two	O
specimens	O
of	O
the	O
liana	O
Tetrastigma	B
voinierianum	I
,	O
growing	O
in	O
the	O
c	O
.	O

12	O
m	O
tall	O
tropical	O
greenhouse	O
of	O
the	O
University	O
of	O
Salzburg	O
,	O
Austria	O
.	O

The	O
ground	O
ascended	O
by	O
about	O
5	O
m	O
towards	O
the	O
backstage	O
of	O
the	O
greenhouse	O
.	O

The	O
height	O
of	O
the	O
plant	O
in	O
this	O
area	O
was	O
about	O
4	O
.	O
5	O
m	O
,	O
whereas	O
the	O
height	O
of	O
the	O
plant	O
in	O
the	O
front	O
area	O
reached	O
10	O
m	O
.	O

However	O
,	O
the	O
stem	O
and	O
the	O
branches	O
of	O
the	O
two	O
plants	O
were	O
considerably	O
longer	O
,	O
because	O
the	O
plants	O
had	O
grown	O
vertically	O
upwards	O
and	O
then	O
part	O
of	O
the	O
way	O
downwards	O
.	O

First	O
measurements	O
were	O
performed	O
during	O
the	O
last	O
week	O
of	O
May	O
,	O
2007	O
.	O

This	O
week	O
was	O
very	O
sunny	O
and	O
warm	O
.	O

Experiments	O
were	O
repeated	O
during	O
the	O
last	O
week	O
of	O
August	O
and	O
the	O
first	O
week	O
of	O
September	O
,	O
2007	O
.	O

At	O
this	O
time	O
of	O
the	O
year	O
the	O
weather	O
conditions	O
were	O
quite	O
poor	O
.	O

The	O
weeks	O
were	O
rainy	O
,	O
sunshine	O
occurred	O
only	O
occasionally	O
.	O

On	O
average	O
,	O
the	O
sky	O
was	O
very	O
cloudy	O
.	O

Due	O
to	O
the	O
variable	O
weather	O
conditions	O
the	O
ambient	O
temperature	O
,	O
T	O
,	O
in	O
the	O
greenhouse	O
usually	O
varied	O
between	O
19	O
degrees	O
C	O
and	O
27	O
degrees	O
C	O
.	O

By	O
contrast	O
,	O
during	O
the	O
hot	O
week	O
in	O
May	O
temperatures	O
at	O
the	O
top	O
of	O
the	O
plants	O
could	O
reach	O
up	O
to	O
44	O
degrees	O
C	O
.	O

The	O
greenhouse	O
was	O
illuminated	O
between	O
07	O
.	O
30	O
h	O
and	O
19	O
.	O
00	O
h	O
(	O
CET	O
=	O
Central	O
European	O
Time	O
)	O
.	O

During	O
the	O
day	O
-	O
time	O
,	O
the	O
artificial	O
illumination	O
was	O
switched	O
off	O
automatically	O
once	O
the	O
natural	O
irradiance	O
exceeded	O
about	O
45	O
mu	O
mol	O
photons	O
m	O
-	O
2	O
s	O
-	O
1	O
at	O
ground	O
level	O
.	O

At	O
full	O
sunshine	O
,	O
the	O
light	O
intensity	O
was	O
limited	O
by	O
automatically	O
operating	O
blinds	O
.	O

The	O
relative	O
humidity	O
(	O
r	O
.	O
h	O
.	O
)	O
of	O
the	O
air	O
was	O
regulated	O
by	O
overhead	O
misters	O
.	O

Despite	O
attempts	O
to	O
keep	O
the	O
r	O
.	O
h	O
.	O
above	O
60	O
-	O
70	O
%	O
large	O
axial	O
r	O
.	O
h	O
.	O
gradients	O
along	O
the	O
stem	O
of	O
the	O
liana	O
were	O
observed	O
during	O
sunny	O
days	O
(	O
see	O
below	O
)	O
.	O

The	O
ambient	O
temperature	O
and	O
relative	O
humidity	O
at	O
the	O
measuring	O
sites	O
were	O
determined	O
by	O
using	O
thermistors	O
(	O
Tinytag	O
;	O
RS	O
Components	O
GmbH	O
,	O
M	O
o	O
rfelden	O
-	O
Walldorf	O
,	O
Germany	O
)	O
.	O

Leaf	O
patch	O
clamp	O
pressure	O
probe	O
and	O
data	O
acquisition	O

The	O
pressure	O
sensor	O
chip	O
allows	O
pressure	O
measurements	O
up	O
to	O
100	O
kPa	O
.	O

The	O
sensor	O
consists	O
of	O
a	O
miniature	O
piezoresistive	O
Wheatstone	O
bridge	O
.	O

The	O
sensors	O
used	O
in	O
this	O
work	O
were	O
purchased	O
from	O
the	O
company	O
'	O
Raumedic	O
'	O
(	O
Helmbrechts	O
,	O
Germany	O
)	O
and	O
from	O
the	O
company	O
'	O
Keller	O
'	O
(	O
AG	O
,	O
Druckmesstechnik	O
;	O
Winterthur	O
,	O
Switzerland	O
)	O
.	O

However	O
,	O
it	O
has	O
to	O
be	O
pointed	O
out	O
that	O
any	O
other	O
miniaturized	O
pressure	O
or	O
force	O
sensor	O
could	O
be	O
used	O
.	O

The	O
sensor	O
chip	O
was	O
integrated	O
into	O
one	O
of	O
the	O
planar	O
circular	O
pads	O
of	O
a	O
spring	O
clamp	O
shown	O
schematically	O
in	O
Fig	O
.	O

1	O
.	O

The	O
spring	O
clamp	O
consisted	O
of	O
two	O
curved	O
arms	O
bridged	O
by	O
a	O
spring	O
in	O
the	O
middle	O
(	O
Wolfcraft	O
GmbH	O
;	O
microfix	O
S	O
(	O
B3630Fz60	O
)	O
,	O
Kempenich	O
,	O
Germany	O
)	O
.	O

The	O
clamp	O
pressure	O
exerted	O
by	O
the	O
spring	O
on	O
the	O
leaf	O
,	O
Pclamp	O
,	O
could	O
be	O
varied	O
by	O
a	O
stiff	O
strap	O
(	O
made	O
of	O
synthetic	O
material	O
)	O
spanned	O
between	O
the	O
arms	O
of	O
the	O
spring	O
clip	O
at	O
the	O
handhold	O
site	O
(	O
Fig	O
.	O
1	O
)	O
.	O

The	O
length	O
of	O
the	O
strap	O
and	O
thus	O
the	O
spring	O
load	O
acting	O
on	O
the	O
leaflet	O
between	O
the	O
two	O
pads	O
could	O
be	O
varied	O
by	O
regularly	O
punched	O
holes	O
(	O
as	O
in	O
a	O
belt	O
)	O
.	O

Calibration	O
of	O
the	O
sensor	O
chips	O
was	O
performed	O
by	O
pressurization	O
in	O
a	O
pressure	O
chamber	O
equipped	O
with	O
an	O
integrated	O
manometer	O
(	O
LEO	O
1	O
,	O
Keller	O
AG	O
,	O
Winterthur	O
,	O
Switzerland	O
)	O
.	O

The	O
readings	O
of	O
all	O
sensors	O
used	O
in	O
this	O
study	O
increased	O
linearly	O
with	O
pressure	O
in	O
the	O
range	O
between	O
0	O
kPa	O
and	O
100	O
kPa	O
.	O

The	O
pressure	O
sensitivity	O
of	O
the	O
various	O
sensors	O
was	O
found	O
to	O
be	O
almost	O
identical	O
for	O
all	O
probes	O
.	O

Before	O
use	O
the	O
probes	O
were	O
also	O
tested	O
for	O
temperature	O
-	O
sensitivity	O
in	O
an	O
accessible	O
climate	O
chamber	O
because	O
it	O
is	O
well	O
-	O
known	O
that	O
silicone	O
-	O
embedded	O
sensors	O
tend	O
to	O
become	O
temperature	O
-	O
sensitive	O
during	O
storage	O
.	O

Probes	O
were	O
subject	O
to	O
temperature	O
regimes	O
ranging	O
from	O
10	O
degrees	O
C	O
to	O
35	O
degrees	O
C	O
.	O

Probes	O
were	O
not	O
used	O
if	O
the	O
temperature	O
treatment	O
induced	O
a	O
pressure	O
change	O
larger	O
than	O
0	O
.	O
5	O
kPa	O
.	O

The	O
signals	O
of	O
the	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
were	O
transmitted	O
by	O
a	O
telemetry	O
system	O
(	O
teleBITcom	O
gmbh	O
,	O
Teltow	O
,	O
Germany	O
)	O
.	O

The	O
operating	O
distance	O
between	O
the	O
battery	O
-	O
powered	O
wireless	O
telemetric	O
transmitter	O
and	O
the	O
receiver	O
base	O
station	O
was	O
up	O
to	O
400	O
m	O
.	O

Each	O
transmitter	O
read	O
,	O
amplified	O
,	O
and	O
converted	O
the	O
analogue	O
signals	O
of	O
the	O
pressure	O
sensor	O
into	O
digitalized	O
signals	O
.	O

The	O
data	O
were	O
sent	O
together	O
with	O
the	O
transmitter	O
ID	O
-	O
code	O
every	O
90	O
s	O
via	O
the	O
ISM	O
band	O
of	O
433	O
MHz	O
to	O
the	O
receiver	O
base	O
station	O
which	O
logged	O
and	O
transferred	O
the	O
data	O
to	O
a	O
personal	O
computer	O
or	O
to	O
a	O
GPRS	O
modem	O
linked	O
to	O
an	O
Internet	O
server	O
(	O
NTBB	O
Systemtechnik	O
GmbH	O
,	O
Zeuthen	O
,	O
Germany	O
)	O
for	O
analysis	O
and	O
archival	O
storage	O
.	O

For	O
sensor	O
calibration	O
and	O
data	O
recording	O
the	O
SENBIT	O
software	O
(	O
teleBITcom	O
gmbh	O
,	O
Teltow	O
,	O
Germany	O
)	O
was	O
used	O
.	O

The	O
software	O
allowed	O
communication	O
with	O
up	O
to	O
32	O
sensors	O
at	O
regular	O
short	O
intervals	O
(	O
90	O
s	O
to	O
5	O
min	O
)	O
.	O

In	O
this	O
study	O
,	O
up	O
to	O
10	O
sensor	O
/	O
transmitter	O
units	O
were	O
installed	O
at	O
different	O
heights	O
on	O
the	O
two	O
lianas	O
.	O

Data	O
transfer	O
to	O
the	O
Internet	O
server	O
operated	O
without	O
any	O
problem	O
during	O
the	O
entire	O
experimental	O
period	O
.	O

However	O
,	O
for	O
safety	O
reasons	O
hard	O
-	O
wired	O
conventional	O
data	O
acquisition	O
was	O
also	O
performed	O
using	O
dataloggers	O
(	O
Raumedic	O
,	O
Helmbrechts	O
,	O
Germany	O
)	O
.	O

The	O
dataloggers	O
were	O
controlled	O
by	O
a	O
computer	O
program	O
that	O
provided	O
functions	O
for	O
data	O
storage	O
and	O
sensor	O
calibration	O
.	O

Data	O
were	O
transferred	O
regularly	O
from	O
the	O
dataloggers	O
to	O
a	O
personal	O
computer	O
.	O

Cell	O
turgor	O
pressure	O
probe	O

Turgor	O
pressure	O
measurements	O
were	O
performed	O
on	O
leaflets	O
of	O
the	O
10	O
-	O
m	O
tall	O
liana	O
at	O
c	O
.	O

0	O
.	O
2	O
m	O
height	O
above	O
the	O
roots	O
.	O

The	O
construction	O
and	O
function	O
of	O
the	O
cell	O
turgor	O
pressure	O
probe	O
has	O
been	O
described	O
elsewhere	O
(	O
Zimmermann	O
et	O
al	O
.	O
,	O
1969	O
,	O
2004	O
)	O
.	O

Briefly	O
,	O
the	O
microcapillary	O
was	O
filled	O
with	O
oil	O
up	O
to	O
the	O
very	O
tip	O
and	O
was	O
then	O
inserted	O
into	O
the	O
upper	O
leaflet	O
surface	O
between	O
the	O
main	O
vein	O
and	O
the	O
leaflet	O
edge	O
.	O

Insertion	O
was	O
made	O
under	O
a	O
small	O
overpressure	O
(	O
about	O
20	O
kPa	O
)	O
achieved	O
by	O
appropriate	O
displacement	O
of	O
the	O
metal	O
rod	O
in	O
the	O
probe	O
in	O
order	O
to	O
avoid	O
tip	O
clogging	O
.	O

Penetration	O
was	O
stopped	O
upon	O
reaching	O
the	O
mesophyll	O
cell	O
layer	O
and	O
formation	O
of	O
a	O
stable	O
oil	O
/	O
sap	O
meniscus	O
within	O
the	O
tip	O
region	O
of	O
the	O
microcapillary	O
of	O
the	O
probe	O
.	O

During	O
the	O
measurements	O
it	O
was	O
regularly	O
proved	O
whether	O
the	O
tip	O
was	O
clogged	O
or	O
not	O
by	O
appropriate	O
displacement	O
of	O
the	O
metal	O
rod	O
.	O

Theoretical	O
background	O

The	O
input	O
pressure	O
,	O
Pin	O
,	O
experienced	O
by	O
the	O
cells	O
in	O
a	O
leaf	O
patch	O
is	O
equal	O
to	O
the	O
clamp	O
pressure	O
,	O
Pclamp	O
,	O
only	O
if	O
the	O
pressure	O
signal	O
is	O
transferred	O
lossless	O
to	O
the	O
cells	O
in	O
the	O
leaves	O
.	O

However	O
,	O
losses	O
usually	O
occur	O
due	O
to	O
the	O
compressibility	O
and	O
the	O
deformability	O
of	O
the	O
silicone	O
of	O
the	O
pressure	O
sensor	O
as	O
well	O
as	O
of	O
the	O
compressibility	O
of	O
the	O
cuticle	O
and	O
other	O
structural	O
elements	O
of	O
the	O
leaf	O
.	O

Therefore	O
,	O
theory	O
shows	O
that	O
only	O
a	O
fraction	O
of	O
Pclamp	O
may	O
arrive	O
at	O
the	O
cells	O
,	O
i	O
.	O
e	O
.	O
that	O
the	O
attenuation	O
factor	O
,	O
Fa	O
=	O
Pin	O
/	O
Pclamp	O
,	O
is	O
smaller	O
than	O
unity	O
.	O

Fa	O
depends	O
on	O
the	O
individual	O
leaf	O
properties	O
.	O

Fa	O
can	O
be	O
assumed	O
to	O
be	O
constant	O
(	O
and	O
leaf	O
thickness	O
changes	O
are	O
negligible	O
)	O
if	O
the	O
structural	O
elements	O
are	O
completely	O
pre	O
-	O
compressed	O
by	O
application	O
of	O
an	O
appropriate	O
Pclamp	O
.	O

If	O
Pclamp	O
is	O
kept	O
constant	O
during	O
the	O
following	O
experimental	O
period	O
,	O
Pin	O
is	O
constant	O
and	O
the	O
output	O
pressure	O
,	O
Pp	O
,	O
is	O
only	O
determined	O
by	O
the	O
cell	O
transfer	O
function	O
,	O
Tf	O
(	O
V	O
)	O
,	O
where	O
V	O
is	O
the	O
leaf	O
patch	O
volume	O
.	O

In	O
other	O
words	O
,	O
Tf	O
(	O
V	O
)	O
determines	O
the	O
fraction	O
of	O
Pin	O
sensed	O
by	O
the	O
probe	O
.	O

It	O
is	O
dimensionless	O
and	O
assumes	O
values	O
between	O
zero	O
and	O
unity	O
:	O
(	O
1	O
)	O
Tf	O
depends	O
on	O
the	O
volume	O
of	O
the	O
leaf	O
patch	O
,	O
V	O
,	O
at	O
constant	O
ambient	O
temperature	O
,	O
T	O
:	O
(	O
2	O
)	O
delta	O
V	O
depends	O
on	O
changes	O
in	O
cell	O
turgor	O
pressure	O
,	O
delta	O
Pc	O
,	O
as	O
follows	O
:	O
(	O
3	O
)	O
where	O
op	O
is	O
the	O
average	O
volumetric	O
elastic	O
modulus	O
of	O
the	O
clamped	O
tissue	O
(	O
Philip	O
,	O
1958	O
)	O
.	O

op	O
is	O
a	O
very	O
complex	O
parameter	O
and	O
will	O
be	O
dictated	O
by	O
the	O
turgor	O
pressure	O
in	O
the	O
turgescent	O
state	O
.	O

For	O
a	O
first	O
approximation	O
it	O
is	O
assumed	O
that	O
op	O
increases	O
linearly	O
with	O
Pc	O
(	O
support	O
for	O
this	O
assumption	O
is	O
given	O
by	O
Zimmermann	O
and	O
Steudle	O
,	O
1978	O
;	O
Zimmermann	O
and	O
H	O
u	O
sken	O
,	O
1980	O
;	O
Wendler	O
et	O
al	O
.	O
,	O
1983	O
)	O
:	O
(	O
4	O
)	O
where	O
a	O
and	O
b	O
are	O
constants	O
for	O
individual	O
leaf	O
properties	O
.	O

Because	O
of	O
the	O
viscoelastic	O
properties	O
of	O
the	O
cell	O
wall	O
,	O
the	O
magnitude	O
of	O
the	O
constants	O
depends	O
on	O
the	O
duration	O
of	O
the	O
external	O
pressure	O
application	O
(	O
Zimmermann	O
and	O
H	O
u	O
sken	O
,	O
1980	O
)	O
.	O

The	O
constants	O
are	O
relatively	O
large	O
if	O
rapid	O
turgor	O
pressure	O
changes	O
are	O
induced	O
(	O
e	O
.	O
g	O
.	O
by	O
using	O
the	O
cell	O
turgor	O
pressure	O
probe	O
)	O
,	O
whereas	O
slow	O
turgor	O
pressure	O
changes	O
(	O
e	O
.	O
g	O
.	O
under	O
transpirational	O
conditions	O
)	O
result	O
in	O
small	O
values	O
.	O

Combining	O
equations	O
2	O
-	O
4	O
leads	O
to	O
equation	O
5	O
.	O
(	O
5	O
)	O

Equation	O
5	O
can	O
be	O
integrated	O
by	O
assuming	O
for	O
a	O
first	O
approximation	O
that	O
at	O
Pc	O
=	O
0	O
Tf	O
=	O
1	O
and	O
that	O
the	O
internal	O
osmotic	O
pressure	O
of	O
the	O
cells	O
remained	O
constant	O
.	O

After	O
appropriate	O
re	O
-	O
arrangements	O
equation	O
6	O
is	O
obtained	O
:	O
(	O
6	O
)	O
and	O
,	O
respectively	O
,	O
if	O
the	O
denominator	O
is	O
replaced	O
by	O
equation	O
4	O
:	O
(	O
7	O
)	O

Introducing	O
equation	O
6	O
into	O
equation	O
1	O
yields	O
the	O
wanted	O
relationship	O
between	O
the	O
parameters	O
Pp	O
and	O
Pin	O
:	O
(	O
8	O
)	O

Equation	O
8	O
can	O
be	O
verified	O
experimentally	O
.	O

Inspection	O
of	O
the	O
equation	O
shows	O
that	O
the	O
patch	O
clamp	O
pressure	O
,	O
Pp	O
,	O
is	O
a	O
power	O
function	O
of	O
the	O
turgor	O
pressure	O
,	O
Pc	O
.	O

The	O
exponent	O
of	O
the	O
function	O
is	O
equal	O
to	O
or	O
smaller	O
than	O
unity	O
.	O

If	O
a	O
=	O
1	O
and	O
b	O
<	O
<	O
Pc	O
,	O
equation	O
8	O
turns	O
into	O
Pp	O
=	O
b	O
/	O
Pc	O
,	O
i	O
.	O
e	O
.	O
both	O
parameters	O
are	O
directly	O
reciprocally	O
coupled	O
with	O
each	O
other	O
.	O

Thus	O
Tf	O
assumes	O
low	O
values	O
if	O
Pc	O
is	O
high	O
and	O
,	O
vice	O
versa	O
,	O
a	O
value	O
close	O
to	O
unity	O
if	O
Pc	O
is	O
close	O
to	O
zero	O
.	O

Using	O
appropriate	O
values	O
for	O
a	O
and	O
b	O
for	O
a	O
given	O
leaf	O
(	O
see	O
below	O
)	O
it	O
can	O
be	O
shown	O
that	O
below	O
Pc	O
=	O
100	O
kPa	O
,	O
Pp	O
increases	O
dramatically	O
.	O

This	O
means	O
that	O
the	O
transfer	O
function	O
responds	O
very	O
sensitively	O
upon	O
loss	O
of	O
complete	O
turgor	O
pressure	O
.	O

In	O
the	O
derivation	O
of	O
equation	O
8	O
it	O
was	O
assumed	O
that	O
op	O
is	O
temperature	O
-	O
independent	O
.	O

However	O
,	O
temperature	O
effects	O
on	O
cell	O
elasticity	O
are	O
well	O
-	O
known	O
,	O
although	O
they	O
are	O
not	O
very	O
large	O
in	O
the	O
temperature	O
range	O
investigated	O
here	O
(	O
see	O
,	O
for	O
example	O
,	O
Petersen	O
et	O
al	O
.	O
,	O
1982	O
;	O
Niklas	O
,	O
1992	O
;	O
Hogan	O
and	O
Niklas	O
,	O
2004	O
;	O
Edelmann	O
et	O
al	O
.	O
,	O
2005	O
)	O
.	O

Temperature	O
effects	O
on	O
op	O
cannot	O
be	O
excluded	O
if	O
different	O
values	O
for	O
the	O
Pclamp	O
,	O
and	O
,	O
in	O
turn	O
,	O
for	O
the	O
input	O
pressure	O
,	O
Pin	O
,	O
are	O
selected	O
,	O
as	O
well	O
as	O
if	O
significantly	O
different	O
values	O
for	O
the	O
constants	O
a	O
and	O
b	O
are	O
assumed	O
for	O
optimum	O
fitting	O
of	O
the	O
Pp	O
=	O
f	O
(	O
Pc	O
)	O
curves	O
.	O

Therefore	O
,	O
in	O
the	O
case	O
of	O
large	O
temperature	O
gradients	O
as	O
observed	O
here	O
(	O
see	O
Figs	O
2	O
and	O
3	O
)	O
only	O
the	O
relative	O
,	O
but	O
not	O
the	O
absolute	O
changes	O
in	O
Pp	O
measured	O
at	O
the	O
different	O
heights	O
can	O
be	O
compared	O
with	O
each	O
other	O
.	O

However	O
,	O
Pp	O
values	O
measured	O
at	O
the	O
same	O
height	O
are	O
still	O
comparable	O
and	O
give	O
information	O
about	O
the	O
turgescence	O
,	O
i	O
.	O
e	O
.	O
about	O
the	O
water	O
status	O
of	O
the	O
leaf	O
cells	O
.	O

Results	O

The	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
was	O
clamped	O
about	O
2	O
cm	O
away	O
from	O
the	O
edge	O
of	O
a	O
leaflet	O
of	O
the	O
compound	O
leaves	O
.	O

Leaflets	O
of	O
similar	O
size	O
(	O
176	O
+	O
/	O
-	O
58	O
cm2	O
,	O
n	O
=	O
12	O
)	O
were	O
used	O
.	O

Inspection	O
of	O
the	O
leaf	O
patches	O
after	O
removal	O
of	O
the	O
probes	O
under	O
the	O
microscope	O
revealed	O
no	O
changes	O
in	O
leaflet	O
appearance	O
beneath	O
the	O
pads	O
,	O
even	O
after	O
several	O
weeks	O
.	O

Lesions	O
on	O
the	O
leaves	O
were	O
never	O
found	O
.	O

Only	O
occasionally	O
were	O
very	O
slight	O
impressions	O
of	O
the	O
pads	O
on	O
the	O
leaflet	O
surface	O
observed	O
.	O

Clamping	O
of	O
the	O
leaves	O
could	O
be	O
performed	O
at	O
any	O
time	O
of	O
the	O
day	O
.	O

Clamp	O
pressures	O
,	O
Pclamp	O
,	O
applied	O
to	O
the	O
leaves	O
were	O
of	O
the	O
order	O
of	O
80	O
-	O
200	O
kPa	O
.	O

The	O
optimum	O
value	O
for	O
Pclamp	O
of	O
a	O
given	O
leaf	O
has	O
to	O
be	O
found	O
empirically	O
.	O

Experience	O
shows	O
that	O
Pclamp	O
values	O
could	O
be	O
considered	O
as	O
optimal	O
if	O
the	O
output	O
pressure	O
Pp	O
assumed	O
values	O
between	O
10	O
kPa	O
and	O
25	O
kPa	O
upon	O
clamping	O
in	O
the	O
early	O
morning	O
(	O
when	O
turgor	O
pressure	O
was	O
high	O
)	O
or	O
between	O
50	O
kPa	O
and	O
70	O
kPa	O
upon	O
clamping	O
around	O
noon	O
or	O
towards	O
early	O
afternoon	O
(	O
when	O
turgor	O
pressure	O
was	O
usually	O
low	O
)	O
.	O

The	O
magnitude	O
of	O
Pp	O
depended	O
on	O
the	O
compressibility	O
and	O
deformability	O
properties	O
of	O
the	O
individual	O
leaves	O
which	O
may	O
vary	O
considerably	O
due	O
to	O
age	O
,	O
morphology	O
,	O
leaf	O
thickness	O
,	O
abiotic	O
factors	O
etc	O
.	O

The	O
magnitude	O
of	O
Pclamp	O
had	O
no	O
effect	O
on	O
the	O
diurnal	O
profiles	O
of	O
Pp	O
,	O
in	O
response	O
to	O
changes	O
in	O
microclimate	O
and	O
/	O
or	O
changes	O
in	O
the	O
irrigation	O
regime	O
.	O

Probes	O
clamped	O
on	O
the	O
same	O
leaflet	O
or	O
nearby	O
leaflets	O
of	O
leaves	O
responded	O
almost	O
identically	O
upon	O
temporary	O
changes	O
in	O
transpiration	O
and	O
/	O
or	O
water	O
supply	O
even	O
if	O
the	O
Pclamp	O
values	O
were	O
different	O
due	O
to	O
different	O
leaf	O
thickness	O
as	O
well	O
as	O
local	O
compressibility	O
and	O
deformability	O
properties	O
(	O
data	O
not	O
shown	O
)	O
.	O

This	O
was	O
found	O
over	O
the	O
entire	O
height	O
of	O
the	O
plants	O
.	O

Screening	O
experiments	O
proved	O
further	O
that	O
a	O
high	O
surface	O
roughness	O
prevented	O
a	O
uniform	O
contact	O
between	O
the	O
pads	O
of	O
the	O
probe	O
and	O
the	O
leaf	O
.	O

Non	O
-	O
uniform	O
contact	O
resulted	O
in	O
a	O
reduced	O
pressure	O
response	O
of	O
the	O
probe	O
(	O
data	O
not	O
shown	O
)	O
.	O

Thus	O
,	O
in	O
order	O
to	O
obtain	O
maximum	O
resolution	O
of	O
microclimate	O
-	O
induced	O
and	O
/	O
or	O
plant	O
-	O
based	O
effects	O
on	O
the	O
Pp	O
values	O
,	O
it	O
was	O
crucial	O
that	O
the	O
probe	O
was	O
placed	O
on	O
relatively	O
smooth	O
areas	O
,	O
i	O
.	O
e	O
.	O
preferentially	O
between	O
the	O
veins	O
rather	O
than	O
on	O
the	O
veins	O
in	O
order	O
to	O
guarantee	O
a	O
uniform	O
pressure	O
transmission	O
.	O

It	O
also	O
turned	O
out	O
that	O
areas	O
with	O
lesions	O
or	O
covered	O
with	O
dust	O
should	O
be	O
avoided	O
.	O

Probably	O
due	O
to	O
the	O
absence	O
of	O
dust	O
,	O
high	O
resolution	O
results	O
were	O
obtained	O
when	O
the	O
sensor	O
-	O
containing	O
pad	O
faced	O
the	O
abaxial	O
side	O
,	O
but	O
not	O
the	O
adaxial	O
side	O
of	O
the	O
leaf	O
.	O

Diurnal	O
changes	O
in	O
the	O
patch	O
clamp	O
pressure	O

Figure	O
2A	O
represents	O
Pp	O
recordings	O
conducted	O
on	O
the	O
10	O
m	O
tall	O
liana	O
on	O
24	O
May	O
and	O
25	O
May	O
,	O
2007	O
.	O

The	O
plant	O
was	O
well	O
-	O
watered	O
before	O
the	O
beginning	O
of	O
the	O
measurements	O
(	O
22	O
May	O
)	O
and	O
was	O
also	O
watered	O
regularly	O
during	O
the	O
experimental	O
period	O
.	O

The	O
sufficient	O
supply	O
of	O
the	O
leaves	O
with	O
water	O
was	O
indicated	O
by	O
high	O
turgor	O
pressure	O
values	O
of	O
c	O
.	O

500	O
kPa	O
at	O
predawn	O
and	O
guttation	O
up	O
to	O
a	O
height	O
of	O
6	O
m	O
around	O
sunrise	O
(	O
see	O
also	O
Th	O
u	O
rmer	O
et	O
al	O
.	O
,	O
1999	O
)	O
.	O

Diurnal	O
changes	O
of	O
the	O
Pp	O
values	O
were	O
recorded	O
simultaneously	O
at	O
0	O
.	O
2	O
m	O
,	O
6	O
m	O
,	O
and	O
10	O
m	O
height	O
.	O

The	O
corresponding	O
diurnal	O
changes	O
in	O
the	O
ambient	O
temperature	O
,	O
T	O
,	O
and	O
relative	O
humidity	O
,	O
r	O
.	O
h	O
.	O
,	O
measured	O
close	O
to	O
the	O
sites	O
of	O
the	O
patch	O
clamp	O
pressure	O
probes	O
,	O
are	O
given	O
in	O
Fig	O
.	O

2B	O
and	O
C	O
.	O

It	O
was	O
very	O
sunny	O
on	O
24	O
May	O
resulting	O
in	O
a	O
rapid	O
heating	O
-	O
up	O
of	O
the	O
greenhouse	O
,	O
particularly	O
in	O
the	O
upper	O
part	O
.	O

This	O
led	O
to	O
the	O
development	O
of	O
large	O
vertical	O
gradients	O
in	O
T	O
and	O
r	O
.	O
h	O
.	O
along	O
the	O
stem	O
of	O
the	O
liana	O
(	O
Fig	O
.	O
2B	O
,	O
C	O
)	O
.	O

Because	O
sunlight	O
was	O
dimmed	O
by	O
operation	O
of	O
the	O
automatic	O
blinds	O
at	O
noon	O
(	O
see	O
Materials	O
and	O
methods	O
)	O
the	O
gradients	O
did	O
not	O
reach	O
maximum	O
values	O
before	O
the	O
afternoon	O
.	O

Between	O
15	O
.	O
30	O
h	O
and	O
16	O
.	O
30	O
h	O
an	O
ambient	O
temperature	O
of	O
44	O
degrees	O
C	O
and	O
a	O
relative	O
humidity	O
of	O
20	O
%	O
were	O
recorded	O
at	O
the	O
top	O
of	O
the	O
liana	O
,	O
whereas	O
at	O
0	O
.	O
2	O
m	O
height	O
T	O
and	O
r	O
.	O
h	O
.	O
were	O
27	O
degrees	O
C	O
and	O
70	O
%	O
,	O
respectively	O
.	O

The	O
gradients	O
in	O
T	O
and	O
r	O
.	O
h	O
.	O
disappeared	O
at	O
c	O
.	O

22	O
.	O
00	O
h	O
.	O

Due	O
to	O
the	O
dense	O
foliage	O
of	O
the	O
plant	O
above	O
c	O
.	O

7	O
m	O
and	O
due	O
to	O
light	O
dimming	O
by	O
the	O
blinds	O
,	O
leaves	O
closer	O
to	O
the	O
ground	O
only	O
became	O
exposed	O
to	O
direct	O
sunshine	O
towards	O
the	O
early	O
afternoon	O
.	O

In	O
contrast	O
to	O
24	O
May	O
,	O
the	O
following	O
day	O
was	O
cloudy	O
until	O
noon	O
.	O

Thus	O
,	O
leaves	O
in	O
the	O
upper	O
part	O
of	O
the	O
liana	O
became	O
fully	O
exposed	O
to	O
bright	O
sunshine	O
first	O
around	O
14	O
.	O
00	O
h	O
as	O
indicated	O
by	O
the	O
rapid	O
increase	O
in	O
T	O
and	O
the	O
corresponding	O
decrease	O
of	O
r	O
.	O
h	O
.	O
above	O
a	O
height	O
of	O
6	O
m	O
(	O
Fig	O
.	O
2B	O
,	O
C	O
)	O
.	O

Despite	O
the	O
strongly	O
delayed	O
exposure	O
of	O
the	O
leaves	O
to	O
sunshine	O
,	O
comparable	O
maximum	O
values	O
for	O
T	O
and	O
r	O
.	O
h	O
.	O
at	O
the	O
three	O
measuring	O
sites	O
,	O
as	O
well	O
as	O
vertical	O
gradients	O
in	O
T	O
and	O
r	O
.	O
h	O
.	O
of	O
comparable	O
size	O
,	O
were	O
measured	O
between	O
15	O
.	O
30	O
h	O
and	O
16	O
.	O
30	O
h	O
as	O
on	O
the	O
day	O
before	O
.	O

Inspection	O
of	O
Fig	O
.	O

2	O
shows	O
that	O
the	O
diurnal	O
changes	O
of	O
T	O
and	O
r	O
.	O
h	O
.	O
at	O
the	O
three	O
measuring	O
sites	O
are	O
reflected	O
in	O
corresponding	O
changes	O
of	O
Pp	O
.	O

During	O
the	O
nights	O
the	O
Pp	O
values	O
were	O
low	O
.	O

After	O
sunrise	O
at	O
04	O
.	O
24	O
h	O
the	O
Pp	O
values	O
remained	O
low	O
for	O
further	O
4	O
-	O
5	O
h	O
,	O
except	O
at	O
6	O
m	O
height	O
where	O
a	O
slight	O
and	O
continuous	O
increase	O
in	O
the	O
Pp	O
values	O
was	O
very	O
often	O
recorded	O
.	O

After	O
about	O
09	O
.	O
00	O
h	O
the	O
Pp	O
values	O
increased	O
over	O
the	O
entire	O
height	O
of	O
the	O
liana	O
.	O

Peaking	O
of	O
the	O
Pp	O
values	O
occurred	O
between	O
15	O
.	O
30	O
h	O
and	O
16	O
.	O
30	O
h	O
at	O
all	O
heights	O
when	O
the	O
T	O
and	O
r	O
.	O
h	O
.	O
gradients	O
reached	O
maximum	O
values	O
.	O

Towards	O
the	O
evening	O
the	O
Pp	O
values	O
decreased	O
again	O
in	O
order	O
to	O
reach	O
the	O
original	O
low	O
values	O
at	O
c	O
.	O

22	O
.	O
00	O
h	O
.	O

Until	O
peaking	O
in	O
the	O
afternoon	O
,	O
more	O
or	O
less	O
pronounced	O
fluctuations	O
of	O
the	O
Pp	O
values	O
were	O
seen	O
.	O

A	O
part	O
of	O
these	O
fluctuations	O
seemed	O
to	O
be	O
correlated	O
with	O
changes	O
in	O
the	O
local	O
ambient	O
temperature	O
,	O
relative	O
humidity	O
and	O
/	O
or	O
with	O
a	O
temporary	O
exposure	O
of	O
the	O
clamped	O
leaflet	O
to	O
sunshine	O
(	O
compare	O
Fig	O
.	O
2A	O
with	O
Fig	O
.	O
2B	O
,	O
C	O
)	O
.	O

However	O
,	O
there	O
was	O
also	O
a	O
considerable	O
number	O
of	O
fluctuations	O
which	O
could	O
not	O
be	O
traced	O
back	O
to	O
changes	O
in	O
the	O
microclimate	O
.	O

An	O
example	O
can	O
be	O
found	O
in	O
Fig	O
.	O

2A	O
(	O
arrow	O
)	O
.	O

The	O
peaking	O
of	O
the	O
Pp	O
value	O
measured	O
at	O
a	O
height	O
of	O
0	O
.	O
2	O
m	O
around	O
14	O
.	O
00	O
h	O
is	O
obviously	O
not	O
induced	O
by	O
changes	O
in	O
the	O
local	O
temperature	O
and	O
relative	O
humidity	O
or	O
by	O
exposure	O
to	O
sunshine	O
.	O

Similar	O
diurnal	O
changes	O
in	O
Pp	O
,	O
T	O
,	O
and	O
r	O
.	O
h	O
.	O
were	O
also	O
found	O
for	O
the	O
4	O
.	O
5	O
m	O
tall	O
liana	O
in	O
the	O
backstage	O
of	O
the	O
greenhouse	O
(	O
data	O
not	O
shown	O
)	O
.	O

Figure	O
3	O
shows	O
long	O
-	O
term	O
Pp	O
,	O
T	O
,	O
and	O
r	O
.	O
h	O
.	O
measurements	O
performed	O
at	O
0	O
.	O
2	O
m	O
,	O
6	O
m	O
,	O
and	O
10	O
m	O
height	O
in	O
late	O
summer	O
2007	O
.	O

In	O
contrast	O
to	O
the	O
experimental	O
conditions	O
in	O
late	O
spring	O
(	O
Fig	O
.	O
2	O
)	O
the	O
liana	O
had	O
been	O
watered	O
only	O
sporadically	O
during	O
the	O
weeks	O
before	O
the	O
measurements	O
.	O

The	O
soil	O
was	O
extremely	O
dry	O
and	O
no	O
guttation	O
was	O
observed	O
at	O
predawn	O
,	O
even	O
at	O
0	O
.	O
2	O
m	O
height	O
.	O

Turgor	O
pressure	O
measurements	O
performed	O
at	O
0	O
.	O
2	O
m	O
height	O
yielded	O
values	O
below	O
250	O
kPa	O
at	O
predawn	O
.	O

Continuous	O
irrigation	O
was	O
started	O
at	O
10	O
.	O
00	O
h	O
on	O
28	O
August	O
(	O
c	O
.	O
400	O
l	O
d	O
-	O
1	O
)	O
.	O

Guttation	O
occurred	O
at	O
0	O
.	O
2	O
m	O
height	O
,	O
but	O
not	O
at	O
6	O
m	O
height	O
on	O
1	O
September	O
.	O

At	O
sunrise	O
(	O
05	O
.	O
25	O
h	O
)	O
,	O
turgor	O
pressures	O
of	O
c	O
.	O

500	O
kPa	O
were	O
recorded	O
at	O
the	O
base	O
of	O
the	O
liana	O
.	O

Guttation	O
at	O
6	O
m	O
height	O
was	O
still	O
not	O
observed	O
on	O
3	O
September	O
indicating	O
that	O
the	O
hydration	O
state	O
of	O
the	O
plant	O
was	O
still	O
less	O
than	O
in	O
the	O
last	O
week	O
of	O
May	O
.	O

The	O
T	O
and	O
r	O
.	O
h	O
.	O
profiles	O
during	O
the	O
end	O
of	O
summer	O
were	O
also	O
different	O
to	O
those	O
in	O
late	O
spring	O
(	O
compare	O
Fig	O
.	O
2B	O
,	O
C	O
with	O
Fig	O
.	O
3B	O
,	O
C	O
)	O
.	O

On	O
28	O
August	O
when	O
irrigation	O
started	O
it	O
was	O
sunny	O
.	O

Similarly	O
to	O
May	O
,	O
peak	O
values	O
of	O
T	O
and	O
r	O
.	O
h	O
.	O
were	O
reached	O
at	O
c	O
.	O

15	O
.	O
30	O
h	O
.	O

However	O
,	O
temperatures	O
at	O
the	O
top	O
of	O
the	O
plant	O
did	O
not	O
exceed	O
35	O
degrees	O
C	O
and	O
r	O
.	O
h	O
.	O
did	O
not	O
drop	O
below	O
40	O
%	O
.	O

Accordingly	O
,	O
the	O
vertical	O
T	O
and	O
r	O
.	O
h	O
.	O
gradients	O
were	O
smaller	O
than	O
those	O
measured	O
at	O
the	O
end	O
of	O
May	O
.	O

On	O
29	O
August	O
,	O
when	O
it	O
became	O
very	O
rainy	O
and	O
light	O
irradiance	O
dropped	O
dramatically	O
,	O
gradients	O
in	O
T	O
and	O
r	O
.	O
h	O
.	O
of	O
slightly	O
decreased	O
size	O
were	O
still	O
recorded	O
.	O

Peaking	O
of	O
T	O
and	O
r	O
.	O
h	O
.	O
occurred	O
at	O
c	O
.	O

14	O
.	O
30	O
h	O
.	O

T	O
and	O
r	O
.	O
h	O
.	O
gradients	O
did	O
not	O
develop	O
in	O
the	O
following	O
three	O
days	O
which	O
were	O
very	O
cloudy	O
and	O
rainy	O
.	O

An	O
almost	O
constant	O
temperature	O
of	O
c	O
.	O

25	O
degrees	O
C	O
and	O
a	O
relative	O
humidity	O
of	O
80	O
%	O
were	O
measured	O
on	O
the	O
ground	O
and	O
at	O
the	O
top	O
of	O
the	O
greenhouse	O
throughout	O
the	O
day	O
;	O
light	O
irradiance	O
did	O
not	O
exceed	O
40	O
mu	O
mol	O
photons	O
m	O
-	O
2	O
s	O
-	O
1	O
.	O

Only	O
on	O
31	O
August	O
,	O
did	O
the	O
rain	O
stop	O
and	O
the	O
upper	O
part	O
of	O
the	O
liana	O
was	O
exposed	O
to	O
sunshine	O
for	O
1	O
-	O
2	O
h	O
and	O
thus	O
small	O
T	O
and	O
r	O
.	O
h	O
.	O
gradients	O
developed	O
.	O

The	O
following	O
days	O
of	O
2	O
and	O
3	O
September	O
were	O
partly	O
cloudy	O
and	O
sunny	O
and	O
the	O
peaking	O
of	O
T	O
and	O
r	O
.	O
h	O
.	O
occurred	O
at	O
c	O
.	O

13	O
.	O
00	O
h	O
.	O

The	O
upper	O
,	O
but	O
not	O
the	O
lower	O
part	O
of	O
the	O
liana	O
was	O
exposed	O
to	O
sunshine	O
for	O
several	O
hours	O
.	O

This	O
resulted	O
in	O
the	O
formation	O
of	O
T	O
and	O
r	O
.	O
h	O
.	O
gradients	O
.	O

The	O
size	O
of	O
the	O
gradients	O
was	O
similar	O
to	O
that	O
measured	O
on	O
29	O
August	O
.	O

Inspection	O
of	O
Fig	O
.	O

3A	O
indicates	O
that	O
peaking	O
of	O
the	O
Pp	O
values	O
coincided	O
with	O
peaking	O
of	O
r	O
.	O
h	O
.	O
and	O
T	O
in	O
Fig	O
.	O

3B	O
and	O
C	O
.	O

Figure	O
3A	O
shows	O
further	O
that	O
the	O
peak	O
amplitude	O
of	O
the	O
Pp	O
values	O
recorded	O
at	O
the	O
three	O
measuring	O
sites	O
decreased	O
continuously	O
from	O
28	O
August	O
whereas	O
the	O
low	O
Pp	O
values	O
at	O
the	O
nights	O
remained	O
unaltered	O
.	O

The	O
peak	O
amplitude	O
measured	O
on	O
29	O
August	O
was	O
only	O
slightly	O
lower	O
than	O
that	O
measured	O
on	O
the	O
day	O
before	O
,	O
the	O
peak	O
amplitude	O
was	O
rather	O
low	O
on	O
30	O
August	O
.	O

It	O
remained	O
at	O
this	O
low	O
level	O
until	O
2	O
September	O
,	O
except	O
that	O
on	O
31	O
August	O
the	O
peak	O
amplitude	O
at	O
the	O
three	O
measuring	O
sites	O
increased	O
slightly	O
,	O
presumably	O
because	O
of	O
the	O
short	O
-	O
time	O
exposure	O
of	O
the	O
upper	O
leaves	O
to	O
sun	O
(	O
see	O
above	O
)	O
.	O

Comparison	O
of	O
the	O
diurnal	O
changes	O
in	O
the	O
Pp	O
values	O
with	O
the	O
corresponding	O
T	O
and	O
r	O
.	O
h	O
.	O
changes	O
in	O
Fig	O
.	O

3B	O
and	O
C	O
indicates	O
that	O
part	O
of	O
the	O
changes	O
in	O
the	O
peak	O
amplitude	O
of	O
the	O
Pp	O
values	O
were	O
induced	O
by	O
changes	O
in	O
the	O
environmental	O
parameters	O
.	O

However	O
,	O
part	O
of	O
the	O
changes	O
must	O
obviously	O
be	O
attributed	O
to	O
irrigation	O
.	O

This	O
conclusion	O
can	O
be	O
drawn	O
if	O
,	O
for	O
example	O
,	O
the	O
peaking	O
of	O
Pp	O
on	O
2	O
and	O
3	O
September	O
is	O
compared	O
with	O
the	O
peaking	O
of	O
Pp	O
on	O
29	O
August	O
.	O

Despite	O
the	O
comparable	O
size	O
of	O
the	O
T	O
and	O
r	O
.	O
h	O
.	O
gradients	O
,	O
the	O
peak	O
Pp	O
values	O
were	O
much	O
smaller	O
,	O
particularly	O
at	O
0	O
.	O
2	O
m	O
height	O
,	O
on	O
2	O
and	O
3	O
September	O
compared	O
with	O
29	O
August	O
.	O

Plots	O
of	O
the	O
Pp	O
values	O
measured	O
at	O
6	O
m	O
and	O
10	O
m	O
height	O
on	O
24	O
May	O
,	O
28	O
August	O
,	O
and	O
2	O
September	O
against	O
r	O
.	O
h	O
.	O

(	O
or	O
against	O
T	O
since	O
both	O
parameters	O
were	O
usually	O
closely	O
related	O
)	O
also	O
support	O
the	O
view	O
that	O
the	O
local	O
microclimate	O
is	O
not	O
the	O
only	O
factor	O
which	O
determined	O
the	O
magnitude	O
of	O
the	O
Pp	O
values	O
at	O
the	O
three	O
measuring	O
sites	O
.	O

Figure	O
4	O
shows	O
that	O
the	O
Pp	O
values	O
recorded	O
at	O
6	O
m	O
and	O
10	O
m	O
height	O
increased	O
with	O
decreasing	O
r	O
.	O
h	O
.	O
from	O
c	O
.	O

09	O
.	O
00	O
h	O
until	O
r	O
.	O
h	O
.	O
reached	O
the	O
minimum	O
value	O
(	O
and	O
T	O
the	O
maximum	O
value	O
,	O
respectively	O
)	O
,	O
when	O
with	O
the	O
progression	O
of	O
the	O
day	O
r	O
.	O
h	O
.	O
increased	O
and	O
T	O
decreased	O
,	O
Pp	O
decreased	O
again	O
.	O

This	O
decrease	O
was	O
much	O
faster	O
than	O
expected	O
in	O
the	O
light	O
of	O
the	O
preceding	O
r	O
.	O
h	O
.	O
-	O
induced	O
increase	O
of	O
Pp	O
if	O
the	O
plant	O
was	O
well	O
-	O
watered	O
(	O
24	O
May	O
;	O
Fig	O
.	O
4A	O
,	O
B	O
)	O
.	O

Refilling	O
of	O
the	O
leaf	O
cells	O
was	O
apparently	O
enhanced	O
by	O
the	O
high	O
hydration	O
state	O
of	O
the	O
plant	O
.	O

By	O
contrast	O
,	O
when	O
the	O
liana	O
had	O
not	O
been	O
irrigated	O
well	O
(	O
28	O
August	O
,	O
Fig	O
.	O
4C	O
,	O
D	O
)	O
both	O
kinetics	O
of	O
the	O
changes	O
of	O
Pp	O
with	O
r	O
.	O
h	O
.	O
were	O
comparable	O
.	O

The	O
low	O
hydration	O
state	O
of	O
the	O
plant	O
apparently	O
delayed	O
cell	O
refilling	O
.	O

After	O
4	O
d	O
irrigation	O
(	O
2	O
September	O
)	O
,	O
the	O
low	O
value	O
of	O
Pp	O
recovered	O
at	O
relatively	O
low	O
r	O
.	O
h	O
.	O
as	O
in	O
May	O
at	O
10	O
m	O
height	O
(	O
Fig	O
.	O
4F	O
)	O
,	O
but	O
not	O
at	O
6	O
m	O
height	O
(	O
Fig	O
.	O
4E	O
)	O
.	O

Recovery	O
of	O
the	O
low	O
Pp	O
values	O
at	O
this	O
height	O
occurred	O
,	O
however	O
,	O
at	O
significantly	O
lower	O
r	O
.	O
h	O
.	O
than	O
on	O
28	O
August	O
,	O
indicating	O
that	O
rehydration	O
of	O
the	O
leaves	O
at	O
this	O
height	O
had	O
not	O
been	O
completed	O
.	O

Evaluation	O
of	O
other	O
data	O
sets	O
yielded	O
similar	O
results	O
(	O
not	O
shown	O
)	O
.	O

Patch	O
clamp	O
pressure	O
versus	O
cell	O
turgor	O
pressure	O
measurements	O

The	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
measures	O
the	O
pressure	O
transfer	O
function	O
of	O
a	O
defined	O
leaflet	O
area	O
.	O

The	O
above	O
theoretical	O
considerations	O
have	O
shown	O
that	O
the	O
transfer	O
function	O
is	O
mainly	O
determined	O
by	O
turgor	O
pressure	O
provided	O
that	O
the	O
structural	O
elements	O
do	O
not	O
contribute	O
or	O
constantly	O
contribute	O
to	O
the	O
pressure	O
signal	O
transfer	O
.	O

In	O
order	O
to	O
prove	O
the	O
theory	O
parallel	O
measurements	O
of	O
leaf	O
patch	O
clamp	O
pressure	O
(	O
Pp	O
)	O
and	O
cell	O
turgor	O
pressure	O
(	O
Pc	O
)	O
were	O
performed	O
on	O
a	O
leaflet	O
at	O
0	O
.	O
2	O
m	O
height	O
(	O
Fig	O
.	O
5A	O
)	O
.	O

Simultaneously	O
,	O
the	O
Pp	O
values	O
were	O
recorded	O
at	O
6	O
m	O
and	O
10	O
m	O
height	O
(	O
Fig	O
.	O
5B	O
,	O
C	O
)	O
.	O

Measurements	O
were	O
performed	O
after	O
several	O
days	O
of	O
irrigation	O
.	O

In	O
these	O
experiments	O
,	O
the	O
microcapillary	O
of	O
the	O
turgor	O
pressure	O
probe	O
was	O
inserted	O
into	O
parenchymal	O
cells	O
located	O
close	O
to	O
the	O
main	O
vein	O
on	O
the	O
abaxial	O
side	O
of	O
a	O
leaflet	O
,	O
i	O
.	O
e	O
.	O
c	O
.	O

10	O
cm	O
away	O
from	O
the	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
near	O
the	O
leaflet	O
periphery	O
.	O

Turgor	O
pressure	O
measurements	O
on	O
leaf	O
cells	O
of	O
T	B
.	I
voinierianum	I
were	O
difficult	O
to	O
perform	O
because	O
of	O
the	O
presence	O
of	O
mucilage	O
.	O

Mucilage	O
resulted	O
in	O
clogging	O
of	O
the	O
tip	O
of	O
the	O
microcapillary	O
of	O
the	O
cell	O
turgor	O
pressure	O
probe	O
.	O

For	O
this	O
reason	O
,	O
measurements	O
with	O
the	O
Scholander	O
pressure	O
chamber	O
were	O
not	O
very	O
reliable	O
.	O

It	O
was	O
extremely	O
difficult	O
to	O
determine	O
exactly	O
the	O
balancing	O
pressure	O
at	O
which	O
water	O
appears	O
at	O
the	O
cut	O
end	O
of	O
the	O
petiole	O
of	O
the	O
leaf	O
.	O

In	O
Fig	O
.	O

5A	O
the	O
average	O
turgor	O
pressure	O
values	O
are	O
plotted	O
which	O
were	O
calculated	O
from	O
3	O
-	O
8	O
min	O
long	O
measurements	O
.	O

Inspection	O
of	O
Fig	O
.	O

5A	O
-	O
C	O
shows	O
that	O
Pc	O
exhibited	O
similar	O
diurnal	O
changes	O
as	O
the	O
Pp	O
values	O
at	O
0	O
.	O
2	O
m	O
,	O
6	O
m	O
,	O
and	O
10	O
m	O
height	O
.	O

Changes	O
in	O
Pc	O
after	O
sunrise	O
preceded	O
changes	O
in	O
Pp	O
,	O
most	O
likely	O
due	O
to	O
the	O
different	O
measuring	O
sites	O
on	O
the	O
leaflets	O
.	O

After	O
the	O
onset	O
of	O
transpiration	O
the	O
loss	O
of	O
turgor	O
pressure	O
of	O
cells	O
located	O
at	O
the	O
periphery	O
of	O
the	O
leaflets	O
(	O
where	O
Pp	O
is	O
recorded	O
)	O
is	O
apparently	O
immediately	O
compensated	O
by	O
water	O
shifting	O
from	O
the	O
xylem	O
and	O
the	O
cells	O
located	O
close	O
to	O
the	O
main	O
vein	O
(	O
where	O
Pc	O
is	O
measured	O
)	O
.	O

Consistent	O
with	O
this	O
explanation	O
,	O
towards	O
the	O
afternoon	O
when	O
all	O
cells	O
throughout	O
the	O
leaflets	O
exhibit	O
low	O
turgor	O
pressure	O
,	O
the	O
increase	O
in	O
Pc	O
and	O
the	O
decrease	O
in	O
Pp	O
occurred	O
nearly	O
concomitantly	O
.	O

Interestingly	O
,	O
the	O
delay	O
between	O
the	O
response	O
of	O
Pc	O
and	O
Pp	O
upon	O
changes	O
in	O
T	O
and	O
r	O
.	O
h	O
.	O
in	O
the	O
early	O
morning	O
hours	O
decreased	O
from	O
about	O
2	O
.	O
5	O
h	O
at	O
0	O
.	O
2	O
m	O
height	O
to	O
1	O
.	O
5	O
h	O
at	O
6	O
m	O
height	O
,	O
and	O
to	O
1	O
h	O
at	O
10	O
m	O
height	O
.	O

In	O
Fig	O
.	O

5D	O
the	O
Pp	O
values	O
measured	O
at	O
the	O
three	O
heights	O
are	O
plotted	O
against	O
the	O
corresponding	O
Pc	O
values	O
(	O
i	O
.	O
e	O
.	O
neglecting	O
the	O
delayed	O
response	O
of	O
Pp	O
)	O
.	O

The	O
curves	O
could	O
be	O
fitted	O
quite	O
well	O
by	O
equation	O
8	O
.	O

Fitting	O
of	O
the	O
curves	O
required	O
the	O
assumption	O
of	O
different	O
values	O
for	O
the	O
constants	O
a	O
and	O
b	O
in	O
equation	O
4	O
(	O
see	O
legend	O
to	O
Fig	O
.	O
5	O
)	O
indicating	O
that	O
the	O
elastic	O
properties	O
of	O
the	O
leaves	O
were	O
different	O
,	O
presumably	O
due	O
to	O
changes	O
of	O
the	O
ambient	O
temperature	O
with	O
height	O
(	O
see	O
above	O
)	O
.	O

Turgor	O
pressure	O
measurements	O
at	O
5	O
m	O
height	O
failed	O
because	O
of	O
abundant	O
mucilage	O
in	O
the	O
leaflet	O
tissue	O
at	O
this	O
time	O
of	O
the	O
year	O
.	O

Mucilage	O
in	O
the	O
cells	O
and	O
xylem	O
vessels	O
was	O
less	O
abundant	O
when	O
turgor	O
pressure	O
measurements	O
were	O
performed	O
during	O
the	O
summer	O
of	O
1999	O
.	O

Plot	O
of	O
the	O
Pc	O
data	O
measured	O
by	O
Th	O
u	O
rmer	O
et	O
al	O
.	O

(	O
1999	O
)	O
at	O
5	O
m	O
height	O
against	O
online	O
recordings	O
of	O
Pp	O
in	O
May	O
2007	O
revealed	O
very	O
good	O
agreement	O
between	O
both	O
parameters	O
,	O
even	O
though	O
the	O
microcapillary	O
was	O
inserted	O
into	O
cells	O
located	O
on	O
the	O
upper	O
leaflet	O
surface	O
between	O
the	O
main	O
vein	O
and	O
the	O
leaflet	O
edge	O
(	O
Fig	O
.	O
6	O
)	O
.	O

On	O
both	O
measuring	O
days	O
in	O
1999	O
and	O
2007	O
,	O
similar	O
environmental	O
conditions	O
existed	O
.	O

Inspection	O
of	O
Fig	O
.	O

6	O
shows	O
that	O
Pp	O
measured	O
at	O
6	O
m	O
height	O
was	O
delayed	O
by	O
c	O
.	O

1	O
.	O
5	O
h	O
.	O

A	O
plot	O
of	O
the	O
Pp	O
values	O
against	O
the	O
Pc	O
values	O
according	O
to	O
Fig	O
.	O

5D	O
could	O
also	O
be	O
fitted	O
very	O
well	O
by	O
equation	O
8	O
(	O
see	O
inset	O
of	O
Fig	O
.	O
6	O
)	O
indicating	O
the	O
validity	O
of	O
equation	O
8	O
to	O
describe	O
properly	O
the	O
relationship	O
between	O
Pp	O
and	O
Pc	O
.	O

Discussion	O

The	O
results	O
presented	O
here	O
demonstrate	O
that	O
the	O
novel	O
patch	O
clamp	O
pressure	O
probe	O
is	O
a	O
very	O
sensitive	O
,	O
versatile	O
,	O
and	O
easy	O
-	O
to	O
-	O
handle	O
plant	O
-	O
based	O
tool	O
for	O
online	O
monitoring	O
of	O
the	O
effects	O
of	O
evapotranspiration	O
and	O
/	O
or	O
of	O
irrigation	O
regimes	O
on	O
the	O
water	O
relations	O
of	O
leaves	O
(	O
Figs	O
2	O
,	O
3	O
)	O
.	O

The	O
probe	O
measures	O
the	O
output	O
signal	O
upon	O
application	O
of	O
a	O
constantly	O
clamped	O
pressure	O
,	O
i	O
.	O
e	O
.	O
the	O
pressure	O
transfer	O
function	O
of	O
leaf	O
patches	O
.	O

Since	O
the	O
application	O
of	O
the	O
probe	O
is	O
not	O
restricted	O
to	O
special	O
leaves	O
,	O
patch	O
clamp	O
pressure	O
measurements	O
will	O
readily	O
show	O
which	O
crop	O
varieties	O
can	O
be	O
grown	O
with	O
the	O
least	O
water	O
for	O
the	O
most	O
yield	O
.	O

It	O
has	O
also	O
been	O
demonstated	O
here	O
that	O
the	O
plant	O
-	O
based	O
data	O
can	O
be	O
sent	O
by	O
small	O
telemetric	O
units	O
connected	O
to	O
the	O
patch	O
clamp	O
pressure	O
probes	O
to	O
a	O
receiver	O
base	O
station	O
which	O
logs	O
and	O
stores	O
the	O
data	O
pending	O
transfer	O
to	O
a	O
GPRS	O
modem	O
linked	O
to	O
an	O
Internet	O
server	O
.	O

The	O
telemetric	O
systems	O
operated	O
faultlessly	O
.	O

This	O
is	O
a	O
very	O
important	O
result	O
because	O
there	O
is	O
agreement	O
between	O
scientists	O
and	O
growers	O
(	O
Jones	O
,	O
2004	O
)	O
that	O
control	O
of	O
irrigation	O
must	O
be	O
tied	O
to	O
remote	O
sensing	O
devices	O
in	O
order	O
to	O
reduce	O
manpower	O
and	O
to	O
conserve	O
water	O
.	O

The	O
patch	O
clamp	O
pressure	O
probe	O
technique	O
introduced	O
here	O
meets	O
these	O
demands	O
.	O

A	O
further	O
advantage	O
is	O
that	O
the	O
probe	O
is	O
cheap	O
and	O
easy	O
to	O
handle	O
.	O

Some	O
care	O
is	O
required	O
only	O
when	O
clamping	O
the	O
leaf	O
.	O

Leaves	O
must	O
be	O
clean	O
and	O
any	O
rough	O
surface	O
topography	O
must	O
be	O
avoided	O
.	O

This	O
implies	O
that	O
the	O
dimensions	O
of	O
the	O
pads	O
of	O
the	O
spring	O
clamp	O
must	O
be	O
adjusted	O
to	O
the	O
size	O
of	O
the	O
intercostal	O
area	O
since	O
non	O
-	O
uniform	O
contact	O
between	O
leaf	O
surface	O
and	O
pads	O
lowered	O
the	O
output	O
pressure	O
signal	O
.	O

Experience	O
collected	O
with	O
patch	O
clamp	O
pressure	O
measurements	O
on	O
T	B
.	I
voinierianum	I
and	O
on	O
preliminary	O
results	O
of	O
other	O
plants	O
(	O
e	O
.	O
g	O
.	O
grapevines	O
,	O
bananas	B
,	O
Eucalyptus	O
,	O
and	O
Arabidopsis	O
)	O
showed	O
that	O
a	O
smooth	O
intercostal	O
leaf	O
area	O
for	O
clamping	O
can	O
readily	O
be	O
found	O
.	O

Equally	O
,	O
optimum	O
values	O
for	O
the	O
clamp	O
pressure	O
can	O
also	O
be	O
relatively	O
quickly	O
selected	O
empirically	O
if	O
the	O
guidelines	O
mentioned	O
above	O
are	O
followed	O
.	O

For	O
many	O
purposes	O
calibration	O
of	O
the	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
against	O
the	O
cell	O
turgor	O
pressure	O
probe	O
is	O
not	O
stringent	O
.	O

It	O
may	O
be	O
sufficient	O
to	O
know	O
that	O
the	O
transfer	O
function	O
assumes	O
small	O
values	O
at	O
full	O
turgescence	O
and	O
is	O
nearly	O
unity	O
at	O
low	O
turgescence	O
.	O

However	O
,	O
for	O
scientific	O
reasons	O
and	O
for	O
the	O
application	O
of	O
the	O
probe	O
in	O
basic	O
research	O
,	O
the	O
dependency	O
of	O
the	O
transfer	O
function	O
on	O
cell	O
turgor	O
pressure	O
might	O
be	O
of	O
great	O
interest	O
.	O

The	O
theoretical	O
considerations	O
have	O
demonstrated	O
that	O
the	O
relationship	O
between	O
the	O
transfer	O
function	O
and	O
the	O
turgor	O
pressure	O
can	O
obviously	O
be	O
described	O
by	O
equation	O
8	O
,	O
i	O
.	O
e	O
.	O
by	O
a	O
power	O
function	O
.	O

Concomitant	O
measurements	O
of	O
turgor	O
pressure	O
and	O
patch	O
clamp	O
pressure	O
have	O
confirmed	O
the	O
theoretical	O
considerations	O
(	O
Fig	O
.	O
5	O
)	O
.	O

Analogous	O
recordings	O
of	O
turgor	O
pressure	O
and	O
patch	O
clamp	O
pressure	O
on	O
grapevines	O
,	O
bananas	B
,	O
and	O
Eucalyptus	B
trees	O
also	O
yielded	O
results	O
(	O
D	O
Zimmermann	O
,	O
unpublished	O
results	O
)	O
which	O
were	O
consistent	O
with	O
the	O
predictions	O
of	O
equation	O
8	O
.	O

Patch	O
clamp	O
pressure	O
measurements	O
allow	O
,	O
therefore	O
,	O
calculation	O
of	O
turgor	O
pressures	O
if	O
the	O
constants	O
a	O
and	O
b	O
defined	O
by	O
equation	O
4	O
are	O
known	O
.	O

These	O
parameters	O
can	O
be	O
obtained	O
by	O
numerical	O
fitting	O
of	O
Pp	O
versus	O
Pc	O
curves	O
.	O

Online	O
patch	O
clamp	O
pressure	O
measurements	O
open	O
up	O
new	O
possibilities	O
to	O
unravel	O
the	O
hydraulic	O
communication	O
among	O
leaves	O
,	O
including	O
tall	O
trees	O
.	O

It	O
is	O
shown	O
here	O
that	O
the	O
patch	O
clamp	O
pressure	O
can	O
simultaneously	O
be	O
monitored	O
in	O
shaded	O
or	O
sun	O
-	O
exposed	O
leaflets	O
at	O
different	O
heights	O
under	O
greenhouse	O
conditions	O
by	O
using	O
several	O
probes	O
.	O

It	O
was	O
even	O
possible	O
to	O
measure	O
the	O
turgor	O
pressure	O
at	O
different	O
sites	O
on	O
the	O
leaf	O
.	O

Therefore	O
,	O
water	O
shifting	O
between	O
leaf	O
cells	O
via	O
the	O
apoplastic	O
and	O
symplastic	O
pathways	O
can	O
be	O
studied	O
.	O

Physically	O
sound	O
theories	O
are	O
available	O
(	O
Molz	O
and	O
Ikenberry	O
,	O
1974	O
;	O
Molz	O
et	O
al	O
.	O
,	O
1979	O
)	O
,	O
but	O
experimental	O
facts	O
are	O
not	O
available	O
or	O
are	O
mainly	O
based	O
on	O
speculations	O
(	O
Steudle	O
and	O
French	O
,	O
1996	O
)	O
.	O

The	O
first	O
evidence	O
for	O
the	O
dynamics	O
of	O
the	O
hydraulic	O
communication	O
between	O
leaflets	O
at	O
different	O
height	O
and	O
within	O
leaflets	O
is	O
given	O
here	O
.	O

Th	O
u	O
rmer	O
et	O
al	O
.	O

(	O
1999	O
)	O
have	O
shown	O
by	O
using	O
the	O
xylem	O
and	O
turgor	O
pressure	O
probe	O
that	O
the	O
decrease	O
in	O
local	O
xylem	O
pressure	O
after	O
daybreak	O
from	O
positive	O
,	O
sub	O
-	O
atmospheric	O
or	O
slightly	O
above	O
-	O
atmospheric	O
values	O
to	O
negative	O
values	O
was	O
associated	O
with	O
an	O
almost	O
1	O
:	O
1	O
decrease	O
in	O
turgor	O
pressure	O
of	O
the	O
cells	O
located	O
close	O
to	O
the	O
main	O
vein	O
of	O
the	O
leaflets	O
(	O
see	O
also	O
Zimmermann	O
et	O
al	O
.	O
,	O
2004	O
)	O
.	O

Similarly	O
,	O
in	O
the	O
afternoon	O
,	O
the	O
increase	O
of	O
xylem	O
pressure	O
in	O
non	O
-	O
cavitated	O
vessels	O
towards	O
more	O
positive	O
values	O
correlated	O
with	O
a	O
1	O
:	O
1	O
increase	O
in	O
cell	O
turgor	O
pressure	O
.	O

Obviously	O
,	O
changes	O
in	O
transpiration	O
resulted	O
in	O
a	O
very	O
rapid	O
establishment	O
of	O
a	O
new	O
local	O
water	O
equilibrium	O
state	O
between	O
the	O
xylem	O
and	O
the	O
turgor	O
pressure	O
of	O
the	O
adjacent	O
cells	O
.	O

The	O
turgor	O
pressure	O
measurements	O
of	O
Th	O
u	O
rmer	O
et	O
al	O
.	O

(	O
1999	O
)	O
were	O
performed	O
at	O
1	O
m	O
and	O
5	O
m	O
height	O
.	O

No	O
significant	O
differences	O
in	O
the	O
turgor	O
pressure	O
values	O
were	O
found	O
over	O
the	O
day	O
.	O

The	O
turgor	O
pressure	O
measurements	O
at	O
0	O
.	O
2	O
m	O
height	O
reported	O
here	O
confirmed	O
the	O
finding	O
of	O
Th	O
u	O
rmer	O
et	O
al	O
.	O

(	O
1999	O
)	O
that	O
the	O
turgor	O
pressure	O
in	O
the	O
cells	O
located	O
near	O
the	O
main	O
vein	O
dropped	O
immediately	O
upon	O
daybreak	O
.	O

However	O
,	O
our	O
patch	O
clamp	O
pressure	O
measurements	O
at	O
the	O
periphery	O
of	O
the	O
leaflets	O
imply	O
that	O
the	O
turgor	O
pressure	O
of	O
these	O
cells	O
apparently	O
had	O
a	O
significantly	O
delayed	O
response	O
upon	O
the	O
onset	O
of	O
transpiration	O
.	O

This	O
finding	O
can	O
be	O
taken	O
as	O
evidence	O
that	O
turgor	O
pressure	O
gradients	O
are	O
temporarily	O
generated	O
within	O
the	O
leaf	O
during	O
the	O
early	O
morning	O
hours	O
.	O

This	O
delay	O
in	O
the	O
response	O
of	O
patch	O
clamp	O
pressure	O
after	O
daybreak	O
was	O
c	O
.	O

1	O
h	O
for	O
leaves	O
at	O
the	O
top	O
,	O
but	O
c	O
.	O

2	O
.	O
5	O
h	O
for	O
leaves	O
at	O
the	O
base	O
.	O

The	O
data	O
suggest	O
that	O
with	O
progression	O
of	O
the	O
day	O
the	O
gradients	O
collapsed	O
first	O
at	O
the	O
top	O
of	O
the	O
liana	O
,	O
where	O
transpiration	O
was	O
high	O
,	O
before	O
it	O
occurred	O
in	O
leaves	O
further	O
down	O
.	O

During	O
the	O
afternoon	O
hours	O
the	O
increase	O
in	O
the	O
turgor	O
pressure	O
values	O
measured	O
close	O
to	O
the	O
main	O
vein	O
coincided	O
with	O
the	O
values	O
measured	O
by	O
the	O
patch	O
clamp	O
pressure	O
probe	O
(	O
Fig	O
.	O
5	O
)	O
.	O

The	O
unbalanced	O
osmotic	O
pressure	O
throughout	O
the	O
leaflets	O
obviously	O
favoured	O
simultaneous	O
turgor	O
pressure	O
regeneration	O
in	O
all	O
leaflet	O
cells	O
.	O

The	O
process	O
seemed	O
to	O
be	O
very	O
similar	O
to	O
the	O
refilling	O
of	O
the	O
cells	O
of	O
the	O
resurrection	O
plant	O
Myrothamnus	B
flabellifolia	I
with	O
water	O
after	O
desiccation	O
(	O
Wagner	O
et	O
al	O
.	O
,	O
2000	O
)	O
.	O

Uniform	O
radial	O
refilling	O
of	O
cells	O
with	O
water	O
in	O
this	O
species	O
is	O
also	O
driven	O
by	O
the	O
unbalanced	O
osmotic	O
pressure	O
throughout	O
the	O
tissue	O
.	O

As	O
indicated	O
by	O
Fig	O
.	O

4A	O
and	O
B	O
,	O
restoration	O
of	O
full	O
turgescence	O
in	O
T	B
.	I
voinierianum	I
was	O
faster	O
than	O
the	O
preceding	O
turgor	O
pressure	O
loss	O
if	O
the	O
lianas	O
were	O
well	O
-	O
watered	O
.	O

By	O
contrast	O
,	O
limitations	O
in	O
water	O
supply	O
resulted	O
in	O
the	O
coincidence	O
of	O
the	O
phases	O
of	O
turgor	O
pressure	O
loss	O
and	O
regeneration	O
.	O

Interestingly	O
,	O
watering	O
of	O
the	O
lianas	O
after	O
non	O
-	O
irrigation	O
seemed	O
to	O
lead	O
preferentially	O
to	O
water	O
shifting	O
to	O
the	O
top	O
of	O
the	O
plant	O
,	O
because	O
,	O
after	O
3	O
d	O
of	O
irrigation	O
,	O
turgor	O
pressure	O
regeneration	O
during	O
the	O
afternoon	O
was	O
very	O
fast	O
again	O
at	O
10	O
m	O
height	O
(	O
Fig	O
.	O
4F	O
)	O
,	O
but	O
not	O
at	O
5	O
m	O
height	O
(	O
Fig	O
.	O
4E	O
)	O
.	O

Rapid	O
water	O
movement	O
to	O
the	O
top	O
is	O
expected	O
if	O
hydrostatic	O
pressure	O
,	O
osmotic	O
pressure	O
,	O
and	O
/	O
or	O
gel	O
-	O
based	O
gradients	O
throughout	O
the	O
vessels	O
exist	O
or	O
are	O
generated	O
rapidly	O
in	O
the	O
afternoon	O
when	O
cavitation	O
has	O
occurred	O
.	O

This	O
was	O
demonstrated	O
by	O
Benkert	O
et	O
al	O
.	O

(	O
1995	O
)	O
and	O
Th	O
u	O
rmer	O
et	O
al	O
.	O

(	O
1999	O
)	O
by	O
using	O
the	O
xylem	O
pressure	O
probe	O
.	O

Continuous	O
xylem	O
pressure	O
gradients	O
during	O
the	O
morning	O
hours	O
can	O
also	O
explain	O
why	O
changes	O
in	O
Pp	O
at	O
lower	O
heights	O
were	O
frequently	O
found	O
which	O
could	O
not	O
be	O
correlated	O
with	O
changes	O
in	O
local	O
temperature	O
or	O
relative	O
humidity	O
.	O

Water	O
loss	O
at	O
the	O
top	O
of	O
the	O
plant	O
induces	O
a	O
drop	O
in	O
xylem	O
pressure	O
which	O
is	O
transferred	O
rapidly	O
to	O
the	O
basal	O
leaves	O
where	O
it	O
induces	O
a	O
temporary	O
turgor	O
pressure	O
loss	O
that	O
is	O
soon	O
compensated	O
by	O
water	O
uptake	O
from	O
the	O
roots	O
(	O
arrow	O
in	O
Fig	O
.	O
2	O
)	O
.	O

Even	O
though	O
more	O
work	O
is	O
required	O
,	O
the	O
present	O
study	O
shows	O
that	O
the	O
leaf	O
patch	O
clamp	O
pressure	O
probe	O
is	O
a	O
promising	O
tool	O
to	O
elucidate	O
short	O
-	O
and	O
long	O
-	O
distance	O
water	O
transport	O
in	O
T	B
.	I
voinierianum	I
and	O
other	O
plants	O
.	O

CHEK2	O
Mutations	O
Affecting	O
Kinase	O
Activity	O
Together	O
With	O
Mutations	O
in	O
TP53	O
Indicate	O
a	O
Functional	O
Pathway	O
Associated	O
with	O
Resistance	O
to	O
Epirubicin	O
in	O
Primary	O
Breast	O
Cancer	O

Abstract	O

Background	O

Chemoresistance	O
is	O
the	O
main	O
obstacle	O
to	O
cure	O
in	O
most	O
malignant	O
diseases	O
.	O

Anthracyclines	O
are	O
among	O
the	O
main	O
drugs	O
used	O
for	O
breast	O
cancer	O
therapy	O
and	O
in	O
many	O
other	O
malignant	O
conditions	O
.	O

Single	O
parameter	O
analysis	O
or	O
global	O
gene	O
expression	O
profiles	O
have	O
failed	O
to	O
identify	O
mechanisms	O
causing	O
in	O
vivo	O
resistance	O
to	O
anthracyclines	O
.	O

While	O
we	O
previously	O
found	O
TP53	O
mutations	O
in	O
the	O
L2	O
/	O
L3	O
domains	O
to	O
be	O
associated	O
with	O
drug	O
resistance	O
,	O
some	O
tumors	O
harboring	O
wild	O
-	O
type	O
TP53	O
were	O
also	O
therapy	O
resistant	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
;	O
1	O
)	O
To	O
explore	O
alterations	O
in	O
the	O
TP53	O
gene	O
with	O
respect	O
to	O
resistance	O
to	O
a	O
regular	O
dose	O
epirubicin	O
regimen	O
(	O
90	O
mg	O
/	O
m2	O
every	O
3	O
week	O
)	O
in	O
patients	B
with	O
primary	O
,	O
locally	O
advanced	O
breast	O
cancer	O
;	O
2	O
)	O
Identify	O
critical	O
mechanisms	O
activating	O
p53	O
in	O
response	O
to	O
DNA	O
damage	O
in	O
breast	O
cancer	O
;	O
3	O
)	O
Evaluate	O
in	O
vitro	O
function	O
of	O
Chk2	O
and	O
p14	O
proteins	O
corresponding	O
to	O
identified	O
mutations	O
in	O
the	O
CHEK2	O
and	O
p14	O
(	O
ARF	O
)	O
genes	O
;	O
and	O
4	O
)	O
Explore	O
potential	O
CHEK2	O
or	O
p14	O
(	O
ARF	O
)	O
germline	O
mutations	O
with	O
respect	O
to	O
family	O
cancer	O
incidence	O
.	O

Methods	O
and	O
Findings	O

Snap	O
-	O
frozen	O
biopsies	O
from	O
109	O
patients	B
collected	O
prior	O
to	O
epirubicin	O
(	O
as	O
preoperative	O
therapy	O
were	O
investigated	O
for	O
TP53	O
,	O
CHEK2	O
and	O
p14	O
(	O
ARF	O
)	O
mutations	O
by	O
sequencing	O
the	O
coding	O
region	O
and	O
p14	O
(	O
ARF	O
)	O
promoter	O
methylations	O
.	O

TP53	O
mutastions	O
were	O
associated	O
with	O
chemoresistance	O
,	O
defined	O
as	O
progressive	O
disease	O
on	O
therapy	O
(	O
p	O
=	O
0	O
.	O
0358	O
;	O
p	O
=	O
0	O
.	O
0136	O
for	O
mutations	O
affecting	O
p53	O
loop	O
domains	O
L2	O
/	O
L3	O
)	O
.	O

Germline	O
CHEK2	O
mutations	O
(	O
n	O
=	O
3	O
)	O
were	O
associated	O
with	O
therapy	O
resistance	O
(	O
p	O
=	O
0	O
.	O
0226	O
)	O
.	O

Combined	O
,	O
mutations	O
affecting	O
either	O
CHEK2	O
or	O
TP53	O
strongly	O
predicted	O
therapy	O
resistance	O
(	O
p	O
=	O
0	O
.	O
0101	O
;	O
TP53	O
mutations	O
restricted	O
to	O
the	O
L2	O
/	O
L3	O
domains	O
:	O
p	O
=	O
0	O
.	O
0032	O
)	O
.	O

Two	O
patients	B
progressing	O
on	O
therapy	O
harbored	O
the	O
CHEK2	O
mutation	O
,	O
Arg95Ter	O
,	O
completely	O
abrogating	O
Chk2	O
protein	O
dimerization	O
and	O
kinase	O
activity	O
.	O

One	O
patient	B
(	O
Epi132	O
)	O
revealed	O
family	O
cancer	O
occurrence	O
resembling	O
families	O
harboring	O
CHEK2	O
mutations	O
in	O
general	O
,	O
the	O
other	O
patient	B
(	O
epi203	O
)	O
was	O
non	O
-	O
conclusive	O
.	O

No	O
mutation	O
or	O
promoter	O
hypermethylation	O
in	O
p14	O
(	O
ARF	O
)	O
were	O
detected	O
.	O

Conclusion	O

This	O
study	O
is	O
the	O
first	O
reporting	O
an	O
association	O
between	O
CHEK2	O
mutations	O
and	O
therapy	O
resistance	O
in	O
human	B
cancers	O
and	O
to	O
document	O
mutations	O
in	O
two	O
genes	O
acting	O
direct	O
up	O
/	O
down	O
-	O
stream	O
to	O
each	O
other	O
to	O
cause	O
therapy	O
failure	O
,	O
emphasizing	O
the	O
need	O
to	O
investigate	O
functional	O
cascades	O
in	O
future	O
studies	O
.	O

Introduction	O

Chemoresistance	O
is	O
the	O
main	O
obstacle	O
to	O
cure	O
in	O
most	O
malignancies	O
,	O
including	O
breast	O
cancer	O
.	O

While	O
adjuvant	O
chemotherapy	O
may	O
reduce	O
the	O
hazard	O
rate	O
of	O
relapse	O
by	O
about	O
one	O
third	O
in	O
breast	O
cancer	O
patients	B
[	O
1	O
]	O
,	O
the	O
majority	O
among	O
patients	B
harboring	O
micro	O
-	O
metastases	O
are	O
not	O
cured	O
by	O
today	O
'	O
s	O
standards	O
.	O

Considering	O
patients	B
harboring	O
distant	O
metastases	O
,	O
resistance	O
and	O
therapy	O
failure	O
inevitably	O
occurs	O
,	O
in	O
general	O
over	O
a	O
time	O
period	O
of	O
less	O
than	O
one	O
year	O
for	O
each	O
individual	O
regimen	O
[	O
2	O
]	O
.	O

Despite	O
extensive	O
experimental	O
research	O
[	O
3	O
]	O
,	O
little	O
data	O
are	O
available	O
considering	O
chemoresistance	O
in	O
vivo	O
.	O

For	O
anthracycline	O
therapy	O
in	O
breast	O
cancer	O
,	O
topoisomerase	O
-	O
II	O
amplifications	O
have	O
been	O
associated	O
with	O
a	O
dose	O
-	O
responsiveness	O
different	O
from	O
what	O
is	O
observed	O
in	O
non	O
-	O
amplified	O
tumors	O
4	O
,	O
5	O
.	O

Several	O
studies	O
have	O
tried	O
to	O
generate	O
"	O
prediction	O
profiles	O
"	O
based	O
on	O
gene	O
expression	O
microarrays	O
[	O
6	O
]	O
,	O
[	O
7	O
]	O
,	O
[	O
8	O
]	O
,	O
however	O
,	O
none	O
of	O
the	O
different	O
profiles	O
generated	O
expressed	O
a	O
sensitivity	O
suitable	O
for	O
clinical	O
applications	O
,	O
or	O
have	O
been	O
successfully	O
reproduced	O
by	O
others	O
(	O
see	O
references	O
to	O
original	O
works	O
in	O
[	O
9	O
]	O
and	O
[	O
10	O
]	O
)	O
.	O

p53	O
(	O
the	O
protein	O
encoded	O
by	O
the	O
TP53	O
gene	O
)	O
plays	O
a	O
key	O
role	O
in	O
executing	O
DNA	O
-	O
damage	O
induced	O
apoptosis	O
and	O
growth	O
arrest	O
[	O
11	O
]	O
.	O

Previously	O
,	O
our	O
group	O
reported	O
mutations	O
in	O
the	O
zink	O
-	O
binding	O
domains	O
L2	O
(	O
codons	O
163	O
-	O
195	O
)	O
and	O
L3	O
(	O
codons	O
236	O
-	O
251	O
)	O
of	O
p53	O
critical	O
to	O
DNA	O
binding	O
[	O
12	O
]	O
to	O
be	O
associated	O
with	O
but	O
not	O
fully	O
predictive	O
for	O
resistance	O
to	O
chemotherapy	O
with	O
a	O
low	O
-	O
dose	O
weekly	O
anthracycline	O
[	O
13	O
]	O
or	O
a	O
mitomycin	O
plus	O
5	O
-	O
fluoro	O
-	O
uracil	O
containing	O
[	O
14	O
]	O
regimen	O
.	O

Similar	O
findings	O
were	O
reported	O
by	O
another	O
group	O
[	O
15	O
]	O
.	O

In	O
contrast	O
,	O
others	O
reported	O
TP53	O
mutations	O
to	O
predict	O
sensitivity	O
to	O
a	O
dose	O
-	O
dense	O
epirubicin	O
-	O
cyclophosphamide	O
regimen	O
[	O
16	O
]	O
.	O

The	O
finding	O
that	O
some	O
tumors	O
harboring	O
wild	O
-	O
type	O
TP53	O
may	O
be	O
resistant	O
to	O
anthracycline	O
therapy	O
lead	O
us	O
to	O
postulate	O
that	O
other	O
genes	O
involved	O
in	O
the	O
p53	O
pathway	O
could	O
be	O
mutated	O
in	O
these	O
tumors	O
[	O
3	O
]	O
.	O

p53	O
is	O
activated	O
by	O
post	O
-	O
translational	O
modifications	O
,	O
and	O
the	O
protein	O
is	O
phosphorylated	O
at	O
multiple	O
amino	O
acids	O
[	O
17	O
]	O
.	O

Phosphorylation	O
at	O
Ser	O
20	O
(	O
Ser	O
23	O
in	O
mice	B
)	O
by	O
the	O
Chk2	O
protein	O
(	O
coded	O
by	O
the	O
CHEK2	O
gene	O
)	O
in	O
response	O
to	O
DNA	O
damage	O
activates	O
p53	O
by	O
inhibiting	O
binding	O
to	O
,	O
and	O
deactivation	O
by	O
,	O
the	O
MDM2	O
(	O
Mouse	B
Minute	O
2	O
homolog	O
;	O
HDM2	O
)	O
protein	O
[	O
18	O
]	O
,	O
[	O
19	O
]	O
,	O
[	O
20	O
]	O
.	O

While	O
experimental	O
studies	O
have	O
suggested	O
a	O
critical	O
role	O
of	O
Chk2	O
in	O
activating	O
p53	O
apoptotic	O
response	O
to	O
genotoxic	O
stress	O
[	O
21	O
]	O
,	O
[	O
22	O
]	O
,	O
others	O
claim	O
Chk2	O
to	O
be	O
dispensable	O
for	O
p53	O
activation	O
with	O
respect	O
to	O
apoptosis	O
as	O
well	O
as	O
growth	O
arrest	O
[	O
23	O
]	O
.	O

Following	O
an	O
initial	O
report	O
of	O
a	O
CHEK2	O
germline	O
mutation	O
in	O
a	O
family	O
filling	O
the	O
characteristics	O
of	O
a	O
Li	O
-	O
Fraumeni	O
syndrome	O
(	O
LFS	O
)	O
[	O
24	O
]	O
,	O
recent	O
papers	O
have	O
suggested	O
germline	O
mutations	O
in	O
CHEK2	O
to	O
be	O
associated	O
with	O
a	O
moderately	O
increased	O
risk	O
of	O
breast	O
and	O
colon	O
cancers	O
(	O
see	O
references	O
in	O
[	O
25	O
]	O
)	O
.	O

Recently	O
,	O
we	O
discovered	O
a	O
somatic	O
,	O
nonsense	O
CHEK2	O
mutation	O
in	O
a	O
single	O
patient	B
expressing	O
resistance	O
to	O
doxorubicin	O
low	O
dose	O
therapy	O
[	O
26	O
]	O
.	O

A	O
second	O
mechanism	O
of	O
p53	O
activation	O
is	O
through	O
p14	O
(	O
ARF	O
)	O
(	O
p19	O
in	O
mice	B
)	O
function	O
.	O

p14	O
(	O
ARF	O
)	O
does	O
not	O
phosphorylate	O
p53	O
,	O
but	O
inhibits	O
MDM2	O
dependent	O
p53	O
degradation	O
through	O
direct	O
MDM2	O
binding	O
.	O

While	O
p14	O
(	O
ARF	O
)	O
-	O
mediated	O
p53	O
activation	O
has	O
been	O
linked	O
to	O
oncogene	O
-	O
induced	O
p53	O
activation	O
and	O
,	O
in	O
general	O
,	O
considered	O
not	O
involved	O
in	O
response	O
to	O
DNA	O
damage	O
(	O
see	O
references	O
in	O
[	O
27	O
]	O
)	O
,	O
p14	O
(	O
ARF	O
)	O
may	O
be	O
activated	O
through	O
the	O
E2F1	O
/	O
retinoblastoma	O
pathway	O
[	O
28	O
]	O
.	O

Importantly	O
,	O
two	O
recent	O
studies	O
revealed	O
lack	O
of	O
p19	O
(	O
mouse	B
homologue	O
of	O
human	B
p14	O
(	O
ARF	O
)	O
)	O
function	O
in	O
mice	B
to	O
inhibit	O
p53	O
tumor	O
suppressor	O
function	O
in	O
response	O
to	O
ionizing	O
radiation	O
as	O
well	O
as	O
DNA	O
damaging	O
agents	O
[	O
29	O
]	O
,	O
[	O
30	O
]	O
.	O

The	O
aim	O
of	O
this	O
study	O
was	O
1	O
)	O
to	O
explore	O
alterations	O
in	O
the	O
TP53	O
gene	O
with	O
respect	O
to	O
resistance	O
to	O
a	O
regular	O
dose	O
epirubicin	O
regimen	O
(	O
90	O
mg	O
/	O
m2	O
body	O
surface	O
every	O
3	O
week	O
)	O
in	O
patient	B
with	O
primary	O
,	O
locally	O
advanced	O
,	O
breast	O
cancer	O
;	O
2	O
)	O
To	O
explore	O
defects	O
in	O
potential	O
mechanisms	O
activating	O
p53	O
in	O
response	O
to	O
DNA	O
damage	O
in	O
breast	O
cancer	O
as	O
a	O
cause	O
of	O
drug	O
resistance	O
in	O
wild	O
-	O
type	O
tumors	O
.	O

To	O
do	O
so	O
,	O
we	O
sequenced	O
the	O
complete	O
coding	O
regions	O
for	O
the	O
CHEK2	O
and	O
p14	O
(	O
ARF	O
)	O
genes	O
and	O
analyzed	O
for	O
p14	O
(	O
ARF	O
)	O
promoter	O
hypermetylations	O
;	O
3	O
)	O
Evaluate	O
in	O
vitro	O
function	O
of	O
potential	O
Chk2	O
and	O
p14	O
(	O
ARF	O
)	O
protein	O
translates	O
corresponding	O
to	O
identified	O
mutations	O
in	O
the	O
CHEK2	O
and	O
p14	O
(	O
ARF	O
)	O
genes	O
;	O
4	O
)	O
Identify	O
potential	O
TP53	O
,	O
CHEK2	O
and	O
p14	O
(	O
ARF	O
)	O
mutations	O
to	O
be	O
germline	O
,	O
explore	O
the	O
incidence	O
of	O
different	O
cancers	O
among	O
affected	O
relatives	O
with	O
respect	O
to	O
specific	O
mutations	O
.	O

By	O
comparing	O
in	O
vitro	O
characteristics	O
of	O
specific	O
mutations	O
to	O
drug	O
sensitivity	O
and	O
family	O
cancer	O
risk	O
syndromes	O
,	O
this	O
may	O
add	O
to	O
our	O
understanding	O
of	O
the	O
importance	O
of	O
these	O
gene	O
cascades	O
executing	O
response	O
to	O
DNA	O
damage	O
versus	O
tumor	O
suppression	O
activity	O
.	O

Analyzing	O
tumor	O
samples	O
from	O
a	O
total	O
of	O
109	O
primary	O
locally	O
advanced	O
breast	O
cancer	O
patients	B
treated	O
with	O
epirubicin	O
90mg	O
/	O
3	O
weekly	O
,	O
we	O
found	O
TP53	O
mutations	O
affecting	O
the	O
L2	O
/	O
L3	O
domains	O
or	O
protein	O
dimerization	O
,	O
as	O
well	O
as	O
non	O
-	O
functional	O
CHEK2	O
mutations	O
abrogating	O
dimerization	O
and	O
phosphorylation	O
,	O
to	O
be	O
associated	O
with	O
therapy	O
resistance	O
;	O
no	O
mutation	O
or	O
promoter	O
hypermethylations	O
of	O
the	O
p14	O
(	O
ARF	O
)	O
gene	O
was	O
discovered	O
.	O

Our	O
findings	O
suggest	O
a	O
critical	O
role	O
for	O
Chk2	O
with	O
respect	O
to	O
DNA	O
-	O
damage	O
-	O
dependent	O
p53	O
activation	O
and	O
resistance	O
to	O
anthracycline	O
therapy	O
in	O
human	B
breast	O
cancer	O
.	O

Materials	O
and	O
Methods	O

Patients	B

A	O
total	O
of	O
223	O
patients	B
with	O
locally	O
advanced	O
non	O
-	O
inflammatory	O
breast	O
cancer	O
(	O
T3	O
-	O
4	O
and	O
/	O
or	O
N2	O
)	O
were	O
randomly	O
allocated	O
to	O
primary	O
treatment	O
either	O
with	O
epirubicin	O
90	O
mg	O
/	O
m2	O
or	O
paclitaxel	O
200	O
mg	O
/	O
m2	O
.	O

The	O
primary	O
aim	O
of	O
the	O
study	O
was	O
identification	O
of	O
markers	O
predicting	O
drug	O
resistance	O
to	O
the	O
regimens	O
.	O

Thus	O
,	O
the	O
reason	O
for	O
randomizing	O
patients	B
was	O
not	O
for	O
effect	O
comparison	O
,	O
but	O
to	O
achieve	O
similar	O
patient	B
cohorts	O
in	O
the	O
two	O
arms	O
.	O

Based	O
on	O
the	O
findings	O
of	O
a	O
clinical	O
lack	O
of	O
cross	O
-	O
resistance	O
between	O
anthracyclines	O
and	O
taxane	O
therapies	O
in	O
breast	O
cancer	O
[	O
31	O
]	O
,	O
we	O
hypothesized	O
the	O
mechanisms	O
of	O
resistance	O
to	O
be	O
different	O
between	O
the	O
two	O
compounds	O
.	O

While	O
the	O
analysis	O
of	O
tumor	O
samples	O
from	O
the	O
paclitaxel	O
is	O
ongoing	O
,	O
we	O
here	O
report	O
our	O
findings	O
from	O
the	O
patients	B
allocated	O
to	O
the	O
epirubicin	O
arm	O
.	O

The	O
epirubicin	O
arm	O
included	O
a	O
total	O
of	O
109	O
patients	B
(	O
age	O
28	O
to	O
70	O
years	O
,	O
median	O
51	O
years	O
)	O
.	O

Two	O
patients	B
were	O
analyzed	O
for	O
gene	O
mutations	O
but	O
omitted	O
from	O
statistical	O
analysis	O
as	O
protocol	O
violators	O
;	O
histopathological	O
examination	O
revealed	O
one	O
patient	B
(	O
Epi089	O
)	O
to	O
harbor	O
a	O
sarcomatoid	O
tumor	O
,	O
while	O
one	O
patient	B
Epi232	O
was	O
erroneously	O
enrolled	O
with	O
stage	O
II	O
disease	O
.	O

The	O
study	O
protocol	O
was	O
approved	O
by	O
the	O
Regional	O
Ethical	O
Committee	O
(	O
Norwegian	O
Health	O
Region	O
III	O
)	O
,	O
including	O
formal	O
Biobank	O
registration	O
in	O
accordance	O
to	O
Norwegian	O
law	O
.	O

The	O
study	O
and	O
protocol	O
is	O
registered	O
under	O
the	O
Norwegian	O
Social	O
Science	O
Data	O
services	O
(	O
(	O
www	O
.	O
nsd	O
/	O
uib	O
/	O
personvern	O
/	O
database	O
/	O
)	O
,	O
University	O
of	O
Bergen	O
project	O
no	O
16297	O
and	O
Helse	O
Bergen	O
project	O
no	O
13025	O
)	O
.	O

Each	O
patient	B
gave	O
written	O
informed	O
consent	O
.	O

Tissue	O
Sampling	O

Before	O
commencing	O
chemotherapy	O
,	O
each	O
patient	B
had	O
an	O
incisional	O
tumor	O
biopsy	O
as	O
described	O
previously	O
[	O
14	O
]	O
.	O

All	O
tissue	O
samples	O
were	O
snap	O
-	O
frozen	O
immediately	O
on	O
removal	O
in	O
the	O
theatre	O
.	O

Treatment	O
Regime	O
and	O
Staging	O

Primary	O
treatment	O
consisted	O
of	O
epirubicin	O
(	O
90	O
mg	O
/	O
m2	O
)	O
administered	O
as	O
a	O
3	O
-	O
weekly	O
schedule	O
.	O

Treatment	O
was	O
scheduled	O
for	O
four	O
cycles	O
unless	O
progression	O
occurred	O
at	O
an	O
earlier	O
stage	O
.	O

Clinical	O
response	O
was	O
assessed	O
before	O
each	O
treatment	O
cycle	O
,	O
and	O
the	O
final	O
response	O
evaluated	O
3	O
weeks	O
after	O
the	O
4th	O
cycle	O
for	O
overall	O
response	O
classification	O
.	O

Because	O
the	O
protocol	O
was	O
implemented	O
by	O
October	O
1997	O
with	O
patients	B
enrolled	O
between	O
November	O
1997	O
and	O
December	O
2003	O
,	O
responses	O
were	O
consistently	O
graded	O
by	O
the	O
UICC	O
system	O
[	O
32	O
]	O
and	O
not	O
the	O
more	O
recently	O
implemented	O
"	O
RECIST	O
"	O
criteria	O
[	O
33	O
]	O
.	O

Thus	O
,	O
responses	O
were	O
classified	O
as	O
CR	O
(	O
Complete	O
Response	O
,	O
complete	O
disappearance	O
of	O
all	O
tumor	O
lesions	O
)	O
,	O
PR	O
(	O
Partial	O
Response	O
,	O
reduction	O
>	O
=	O
50	O
%	O
in	O
the	O
sum	O
of	O
all	O
tumor	O
lesions	O
,	O
calculated	O
for	O
each	O
as	O
the	O
product	O
of	O
the	O
largest	O
diameter	O
and	O
the	O
one	O
perpendicular	O
to	O
it	O
)	O
,	O
PD	O
(	O
Progressive	O
Disease	O
,	O
increase	O
in	O
the	O
diameter	O
product	O
of	O
any	O
individual	O
tumor	O
lesion	O
by	O
>	O
=	O
25	O
%	O
)	O
,	O
and	O
SD	O
(	O
Stable	O
Disease	O
,	O
anything	O
between	O
PR	O
and	O
PD	O
)	O
.	O

To	O
analyze	O
for	O
the	O
predictive	O
value	O
of	O
the	O
different	O
parameters	O
,	O
similar	O
to	O
our	O
previous	O
studies	O
[	O
13	O
]	O
,	O
[	O
14	O
]	O
we	O
compared	O
PD	O
tumors	O
(	O
non	O
responders	O
)	O
with	O
the	O
combined	O
group	O
of	O
tumors	O
classified	O
as	O
SD	O
/	O
PR	O
/	O
CR	O
(	O
responders	O
)	O
;	O
the	O
reason	O
for	O
this	O
approach	O
is	O
discussed	O
in	O
detail	O
elsewhere	O
[	O
34	O
]	O
.	O

Median	O
follow	O
-	O
up	O
time	O
was	O
defined	O
from	O
patient	B
inclusion	O
in	O
the	O
study	O
up	O
to	O
October	O
31	O
,	O
2006	O
.	O

Deaths	O
attributable	O
to	O
causes	O
other	O
than	O
breast	O
cancer	O
were	O
treated	O
as	O
censored	O
observations	O
.	O

All	O
patient	B
records	O
were	O
subject	O
to	O
central	O
audit	O
for	O
response	O
classification	O
(	O
by	O
E	O
.	O
L	O
.	O
,	O
B	O
.	O
O	O
.	O
and	O
P	O
.	O
E	O
.	O
L	O
.	O
)	O
.	O

Response	O
classifications	O
were	O
completed	O
and	O
approved	O
without	O
any	O
knowledge	O
about	O
result	O
from	O
laboratory	O
analysis	O
.	O

RNA	O
Purification	O

Total	O
RNA	O
was	O
purified	O
by	O
Trizol	O
(	O
Life	O
Technologies	O
,	O
Inc	O
.	O
)	O
extraction	O
from	O
snap	O
-	O
frozen	O
tissue	O
samples	O
according	O
to	O
manufacturer	O
'	O
s	O
instructions	O
.	O

After	O
extraction	O
,	O
the	O
RNA	O
was	O
dissolved	O
in	O
100	O
micro	O
l	O
of	O
DEPC	O
treated	O
ddH2O	O
.	O

cDNA	O
was	O
synthesized	O
by	O
reverse	O
transcription	O
using	O
Transcriptor	O
reverse	O
transcriptase	O
(	O
Roche	O
)	O
,	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

DNA	O
Purification	O

Genomic	O
DNA	O
from	O
tumor	O
biopsies	O
and	O
blood	O
lymphocytes	O
was	O
isolated	O
using	O
QIAamp	O
DNA	O
Mini	O
kit	O
(	O
Qiagen	O
,	O
Chatsworth	O
,	O
CA	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

Mutation	O
Analysis	O

All	O
mutational	O
analysis	O
was	O
performed	O
blinded	O
to	O
clinical	O
data	O
.	O

Mutations	O
in	O
TP53	O
,	O
CHEK2	O
and	O
p14	O
(	O
ARF	O
)	O
genes	O
were	O
analyzed	O
by	O
PCR	O
(	O
or	O
nested	O
PCR	O
)	O
amplification	O
and	O
sequencing	O
of	O
PCR	O
product	O
,	O
or	O
by	O
cloning	O
of	O
PCR	O
products	O
and	O
sequencing	O
of	O
the	O
resulting	O
plasmids	O
(	O
all	O
primers	O
described	O
in	O
Table	O
1	O
)	O
.	O

Cloning	O
was	O
performed	O
using	O
the	O
TOPO	O
TA	O
Cloning	O
kit	O
(	O
Invitrogen	O
)	O
.	O

Sequencing	O
of	O
clones	O
was	O
performed	O
until	O
at	O
least	O
10	O
different	O
sequences	O
covered	O
all	O
parts	O
of	O
the	O
CHEK2	O
coding	O
sequence	O
.	O

DNA	O
sequencing	O
was	O
carried	O
out	O
directly	O
on	O
1	O
micro	O
l	O
PCR	O
product	O
or	O
plasmid	O
using	O
Big	O
Dye	O
terminator	O
mix	O
(	O
Applied	O
Biosystems	O
)	O
.	O

Capillary	O
gel	O
electrophoresis	O
,	O
data	O
collection	O
,	O
and	O
sequence	O
analysis	O
were	O
done	O
on	O
an	O
automated	O
DNA	O
sequencer	O
(	O
ABI	O
3700	O
)	O
.	O

When	O
a	O
mutation	O
was	O
detected	O
,	O
the	O
relevant	O
exon	O
was	O
amplified	O
by	O
PCR	O
from	O
genomic	O
tumor	O
DNA	O
and	O
DNA	O
from	O
blood	O
lymphocytes	O
and	O
sequenced	O
for	O
verification	O
and	O
germline	O
detection	O
.	O

(	O
Primers	O
described	O
in	O
Table	O
1	O
)	O
.	O

Loss	O
of	O
Heterozygosity	O
(	O
LOH	O
)	O

Loss	O
of	O
heterozygosity	O
(	O
LOH	O
)	O
in	O
tumors	O
with	O
mutations	O
in	O
CHEK2	O
was	O
assessed	O
using	O
the	O
microsatellite	O
marker	O
,	O
D22S275	O
,	O
which	O
maps	O
to	O
intron	O
4	O
of	O
CHEK2	O
.	O

LOH	O
in	O
tumors	O
with	O
mutation	O
in	O
TP53	O
was	O
assessed	O
using	O
two	O
markers	O
,	O
one	O
variable	O
number	O
tandem	O
repeat	O
in	O
intron	O
1	O
[	O
35	O
]	O
and	O
a	O
CA	O
repeat	O
close	O
to	O
the	O
TP53	O
gene	O
[	O
36	O
]	O
.	O

Fluorescently	O
end	O
-	O
labeled	O
primers	O
were	O
used	O
in	O
the	O
PCR	O
,	O
and	O
the	O
PCR	O
products	O
were	O
analyzed	O
on	O
an	O
ABI	O
3700	O
.	O

LOH	O
was	O
evaluated	O
by	O
comparing	O
the	O
allele	O
peak	O
-	O
height	O
ratios	O
from	O
blood	O
DNA	O
and	O
tumor	O
DNA	O
.	O

A	O
sample	O
was	O
scored	O
as	O
having	O
AI	O
(	O
Allelic	O
Imbalance	O
)	O
when	O
a	O
reduction	O
in	O
peak	O
height	O
of	O
one	O
allele	O
in	O
tumor	O
sample	O
was	O
at	O
least	O
18	O
%	O
compared	O
with	O
that	O
of	O
blood	O
DNA	O
from	O
the	O
same	O
patient	B
[	O
37	O
]	O
.	O

Analysis	O
of	O
p14	O
(	O
ARF	O
)	O
promoter	O
methylation	O

Genomic	O
DNA	O
was	O
subjected	O
to	O
bisulphate	O
conversion	O
using	O
the	O
CpGenome	O
DNA	O
Modification	O
Kit	O
(	O
Intergen	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
protocol	O
.	O

Both	O
the	O
unmethylated	O
-	O
and	O
methylated	O
-	O
specific	O
PCRs	O
were	O
performed	O
in	O
50	O
micro	O
l	O
reaction	O
mixes	O
containing	O
2	O
.	O
5	O
U	O
AmpliTaq	O
Gold	O
DNA	O
Polymerase	O
(	O
Applied	O
Biosystems	O
)	O
,	O
1	O
x	O
PCR	O
buffer	O
,	O
1	O
.	O
5	O
mM	O
MgCl2	O
,	O
0	O
.	O
1	O
mM	O
of	O
each	O
deoxynucleotide	O
triphosphate	O
,	O
0	O
.	O
2	O
micro	O
M	O
of	O
each	O
primer	O
(	O
Table	O
1	O
)	O
and	O
2	O
micro	O
l	O
of	O
modified	O
genomic	O
DNA	O
.	O

Thermocycling	O
conditions	O
for	O
both	O
the	O
unmethylated	O
-	O
and	O
methylated	O
-	O
specific	O
PCRs	O
were	O
an	O
initial	O
step	O
of	O
5	O
minutes	O
at	O
95	O
degrees	O
C	O
followed	O
by	O
35	O
cycles	O
of	O
30	O
sec	O
.	O
at	O
94	O
degrees	O
C	O
,	O
30	O
sec	O
.	O
at	O
60	O
.	O
5	O
degrees	O
C	O
and	O
60	O
sec	O
.	O
at	O
72	O
degrees	O
C	O
before	O
a	O
final	O
elongation	O
step	O
at	O
72	O
degrees	O
C	O
for	O
7	O
min	O
.	O

Chk2	O
Dimerisation	O

Chk2	O
mutant	O
'	O
s	O
ability	O
to	O
form	O
dimers	O
with	O
the	O
wild	O
-	O
type	O
protein	O
was	O
investigated	O
by	O
immunoprecipitation	O
.	O

U	O
-	O
2	O
-	O
OS	O
cells	O
were	O
co	O
-	O
transfected	O
with	O
expression	O
vectors	O
expressing	O
wild	O
-	O
type	O
Chk2	O
with	O
N	O
-	O
terminal	O
Xpr	O
-	O
tag	O
(	O
pcDNA4	O
/	O
HisMax	O
,	O
Invitrogen	O
)	O
and	O
mutated	O
Chk2	O
forms	O
with	O
C	O
-	O
terminal	O
V5	O
-	O
tag	O
(	O
pcDNA3	O
.	O
1	O
/	O
V5	O
-	O
His	O
,	O
Invitrogen	O
)	O
.	O

Transfection	O
was	O
performed	O
using	O
FuGene	O
6	O
.	O
0	O
transfection	O
reagent	O
(	O
Roche	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
.	O

Cells	O
were	O
harvested	O
in	O
lysisbuffer	O
(	O
50	O
mM	O
TrisHCl	O
pH	O
8	O
.	O
0	O
,	O
150	O
mM	O
NaCl	O
,	O
0	O
.	O
5	O
%	O
NP40	O
,	O
5	O
mM	O
EDTA	O
pH	O
8	O
.	O
0	O
)	O
48	O
hours	O
after	O
transfection	O
.	O

An	O
aliquote	O
of	O
the	O
cell	O
lysate	O
was	O
harvested	O
for	O
subsequent	O
Chk2	O
-	O
mutant	O
-	O
V5	O
transfection	O
verification	O
.	O

Samples	O
were	O
further	O
incubated	O
with	O
A	O
/	O
G	O
Pluss	O
Agarose	O
beads	O
(	O
Santa	O
Cruz	O
Biotechnology	O
)	O
at	O
4	O
degrees	O
C	O
for	O
25	O
minutes	O
before	O
the	O
beads	O
were	O
removed	O
by	O
centrifugation	O
at	O
5000g	O
for	O
4	O
minutes	O
and	O
the	O
samples	O
were	O
incubated	O
with	O
1	O
.	O
5	O
micro	O
g	O
anti	O
-	O
V5	O
(	O
Invitrogen	O
)	O
at	O
4	O
degrees	O
C	O
for	O
90	O
minutes	O
.	O

Fresh	O
A	O
/	O
G	O
Pluss	O
Agarose	O
beads	O
were	O
added	O
and	O
the	O
samples	O
were	O
incubated	O
for	O
another	O
90	O
minutes	O
at	O
4	O
degrees	O
C	O
.	O

The	O
beads	O
were	O
washed	O
three	O
times	O
with	O
1	O
x	O
PBS	O
,	O
before	O
being	O
separated	O
on	O
a	O
10	O
%	O
polyacrylamide	O
gel	O
and	O
blotted	O
on	O
to	O
a	O
nitrocellulose	O
membrane	O
.	O

Chk2	O
-	O
wild	O
-	O
type	O
-	O
Xpr	O
co	O
-	O
precipitated	O
with	O
Chk2	O
-	O
mutant	O
-	O
V5	O
was	O
detected	O
through	O
incubations	O
with	O
anti	O
-	O
Xpr	O
antibody	O
(	O
Invitrogen	O
)	O
,	O
HRP	O
-	O
conjugated	O
secondary	O
antibody	O
and	O
ECL	O
detection	O
reagent	O
(	O
GE	O
Healthcare	O
)	O
.	O

Kinase	O
Activity	O

Chk2	O
mutant	O
'	O
s	O
ability	O
to	O
function	O
as	O
kinases	O
was	O
investigated	O
through	O
an	O
in	O
vitro	O
kinase	O
assay	O
.	O

The	O
V5	O
expression	O
vectors	O
used	O
for	O
the	O
dimerisation	O
study	O
were	O
also	O
used	O
to	O
express	O
Chk2	O
mutants	O
in	O
the	O
kinase	O
assay	O
.	O

U	O
-	O
2	O
-	O
OS	O
cells	O
were	O
transfected	O
using	O
the	O
FuGene	O
6	O
.	O
0	O
transfection	O
reagent	O
(	O
Roche	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instructions	O
.	O

Cells	O
were	O
then	O
incubated	O
at	O
37	O
degrees	O
C	O
in	O
5	O
%	O
CO2	O
and	O
humidified	O
atmosphere	O
.	O

After	O
24	O
hours	O
doxorubicin	O
(	O
Nycomed	O
Pharma	O
)	O
was	O
added	O
to	O
the	O
media	O
to	O
a	O
final	O
concentration	O
of	O
50ng	O
/	O
ml	O
and	O
the	O
cells	O
were	O
further	O
incubated	O
for	O
24	O
hours	O
before	O
harvest	O
.	O

75	O
cm2	O
of	O
90	O
%	O
confluent	O
cells	O
were	O
harvested	O
in	O
500	O
micro	O
l	O
lysis	O
buffer	O
(	O
50	O
mM	O
HEPES	O
,	O
150	O
mM	O
NaCl	O
,	O
10	O
%	O
glycerol	O
,	O
0	O
.	O
5	O
%	O
Triton	O
X	O
-	O
100	O
,	O
2	O
mM	O
MgCl2	O
,	O
5	O
mM	O
EDTA	O
)	O
,	O
and	O
the	O
cytosol	O
was	O
incubated	O
for	O
90	O
minutes	O
at	O
4	O
degrees	O
C	O
with	O
50	O
micro	O
l	O
50	O
%	O
Glutathione	O
Sepharose	O
beads	O
(	O
Amersham	O
Biosciences	O
)	O
linked	O
to	O
anti	O
-	O
V5	O
antibody	O
(	O
Invitrogen	O
)	O
.	O

The	O
beads	O
were	O
then	O
washed	O
twice	O
with	O
lysisbuffer	O
containing	O
500	O
mM	O
NaCl	O
and	O
twice	O
with	O
kinase	O
assay	O
buffer	O
(	O
50	O
mM	O
HEPES	O
,	O
10	O
mM	O
MgCl2	O
,	O
5	O
mM	O
MnCl2	O
,	O
2	O
.	O
5	O
mM	O
EGTA	O
)	O
.	O

The	O
beads	O
received	O
30	O
micro	O
l	O
kinase	O
assay	O
buffer	O
with	O
7	O
.	O
5	O
micro	O
M	O
cold	O
ATP	O
,	O
10	O
micro	O
Ci	O
32P	O
-	O
gamma	O
-	O
ATP	O
(	O
GE	O
Healthcare	O
)	O
and	O
2	O
micro	O
g	O
isolated	O
Cdc25C	O
peptide	O
,	O
and	O
was	O
incubated	O
at	O
30	O
degrees	O
C	O
for	O
30	O
minutes	O
.	O

Samples	O
were	O
separated	O
on	O
a	O
12	O
.	O
5	O
%	O
polyacrylamide	O
gel	O
and	O
blotted	O
on	O
to	O
a	O
nitrocellulose	O
membrane	O
.	O

A	O
radiosensitive	O
imaging	O
plate	O
was	O
exposed	O
to	O
the	O
membrane	O
and	O
the	O
plate	O
was	O
read	O
in	O
a	O
FLA200	O
imager	O
(	O
Fuji	O
)	O
.	O

The	O
kinase	O
assay	O
described	O
above	O
was	O
also	O
used	O
to	O
determine	O
the	O
Chk2	O
mutants	O
'	O
kinase	O
activity	O
after	O
co	O
-	O
transfection	O
of	O
each	O
Chk2	O
mutant	O
and	O
wild	O
-	O
type	O
Chk2	O
in	O
equal	O
amounts	O
.	O

Statistical	O
Analysis	O

Statistical	O
analysis	O
was	O
performed	O
using	O
the	O
Primer	O
of	O
Biostatistics	O
system	O
,	O
version	O
5	O
.	O
0	O
[	O
38	O
]	O
.	O

The	O
differences	O
in	O
the	O
distribution	O
of	O
TP53	O
and	O
CHEK2	O
mutations	O
among	O
patients	B
revealing	O
a	O
PD	O
and	O
the	O
responders	O
were	O
analyzed	O
with	O
use	O
of	O
Fisher	O
'	O
s	O
exact	O
test	O
.	O

P	O
-	O
values	O
are	O
reported	O
as	O
accumulated	O
two	O
-	O
sided	O
.	O

Because	O
of	O
the	O
limited	O
time	O
of	O
the	O
follow	O
-	O
up	O
,	O
no	O
formal	O
statistical	O
assessment	O
of	O
overall	O
survival	O
was	O
performed	O
.	O

Relapse	O
-	O
free	O
survival	O
was	O
analyzed	O
by	O
the	O
log	O
-	O
rank	O
test	O
.	O

Details	O
regarding	O
outcome	O
in	O
individual	O
patients	B
with	O
mutations	O
are	O
shown	O
in	O
Table	O
2	O
and	O
3	O
to	O
make	O
them	O
available	O
to	O
the	O
reader	O
.	O

Results	O

TP53	O
Mutations	O
and	O
Response	O
to	O
Therapy	O

The	O
TP53	O
mutations	O
identified	O
in	O
the	O
tumors	O
of	O
the	O
patients	B
treated	O
with	O
epirubicin	O
together	O
with	O
the	O
clinical	O
response	O
to	O
therapy	O
and	O
follow	O
-	O
up	O
data	O
are	O
presented	O
in	O
Table	O
2	O
.	O

Somatic	O
TP53	O
mutations	O
were	O
identified	O
in	O
23	O
(	O
21	O
.	O
5	O
%	O
)	O
of	O
the	O
patients	B
.	O

Normal	O
tissue	O
(	O
WBC	O
)	O
was	O
available	O
from	O
18	O
of	O
these	O
for	O
germline	O
characterization	O
,	O
revealing	O
none	O
of	O
the	O
mutations	O
identified	O
to	O
be	O
germline	O
alterations	O
.	O

Of	O
the	O
23	O
mutations	O
detected	O
,	O
20	O
were	O
missense	O
and	O
3	O
were	O
nonsense	O
.	O

One	O
mutation	O
(	O
del483CAT	O
)	O
has	O
not	O
been	O
reported	O
previously	O
either	O
in	O
breast	O
cancer	O
or	O
in	O
any	O
other	O
tumor	O
type	O
(	O
IARC	O
database	O
:	O
http	O
:	O
/	O
/	O
www	O
.	O
iarc	O
.	O
fr	O
/	O
p53	O
/	O
)	O
.	O

Twelve	O
of	O
the	O
mutations	O
directly	O
or	O
indirectly	O
affected	O
the	O
L2	O
/	O
L3	O
domains	O
of	O
the	O
p53	O
protein	O
(	O
Table	O
2	O
)	O
previous	O
found	O
to	O
predict	O
a	O
poor	O
prognosis	O
[	O
39	O
]	O
and	O
drug	O
resistance	O
[	O
14	O
]	O
,	O
[	O
40	O
]	O
.	O

For	O
statistical	O
comparison	O
,	O
mutation	O
Gly325Ter	O
(	O
patient	B
Epi215	O
)	O
located	O
to	O
the	O
tetramerization	O
domain	O
is	O
grouped	O
together	O
with	O
the	O
mutations	O
affecting	O
the	O
L2	O
/	O
L3	O
domain	O
,	O
since	O
this	O
mutation	O
leads	O
to	O
truncation	O
of	O
the	O
protein	O
and	O
with	O
loss	O
of	O
tetramerization	O
and	O
functional	O
defects	O
similar	O
to	O
L2	O
/	O
L3	O
mutations	O
[	O
41	O
]	O
.	O

There	O
was	O
a	O
statistical	O
significant	O
correlation	O
between	O
TP53	O
mutation	O
status	O
and	O
lack	O
of	O
treatment	O
response	O
(	O
PD	O
)	O
(	O
Table	O
4	O
;	O
p	O
=	O
0	O
.	O
0358	O
;	O
Fisher	O
exact	O
test	O
)	O
.	O

When	O
tumors	O
harboring	O
TP53	O
mutations	O
affecting	O
the	O
p53	O
L2	O
/	O
L3	O
DNA	O
-	O
binding	O
domains	O
were	O
compared	O
to	O
those	O
with	O
wild	O
-	O
type	O
TP53	O
or	O
TP53	O
mutations	O
outside	O
the	O
L2	O
/	O
L3	O
domains	O
,	O
this	O
correlation	O
was	O
further	O
strengthened	O
(	O
p	O
=	O
0	O
.	O
0136	O
)	O
.	O

The	O
previously	O
described	O
TP53	O
polymorphism	O
,	O
Arg72Pro	O
[	O
42	O
]	O
was	O
detected	O
in	O
31	O
(	O
29	O
%	O
)	O
of	O
our	O
patients	B
.	O

No	O
correlation	O
was	O
found	O
between	O
this	O
polymorphism	O
and	O
lack	O
of	O
treatment	O
response	O
(	O
p	O
=	O
0	O
.	O
2750	O
;	O
Fisher	O
exact	O
test	O
)	O
or	O
TP53	O
mutational	O
status	O
(	O
p	O
=	O
0	O
.	O
2024	O
)	O
.	O

CHEK2	O
Mutations	O
and	O
Response	O
to	O
Therapy	O

Table	O
3	O
presents	O
the	O
patients	B
with	O
detected	O
CHEK2	O
mutations	O
together	O
with	O
a	O
description	O
of	O
the	O
clinical	O
response	O
and	O
follow	O
up	O
-	O
data	O
.	O

CHEK2	O
mutations	O
were	O
identified	O
in	O
three	O
out	O
of	O
the	O
109	O
patients	B
(	O
2	O
.	O
8	O
%	O
)	O
.	O

Notably	O
,	O
each	O
of	O
the	O
CHEK2	O
mutations	O
identified	O
was	O
also	O
present	O
in	O
patient	B
lymphocyte	O
DNA	O
,	O
confirming	O
a	O
germline	O
origin	O
.	O

The	O
Arg95Ter	O
(	O
C283T	O
)	O
mutation	O
is	O
novel	O
.	O

This	O
mutation	O
was	O
present	O
in	O
two	O
patients	B
(	O
Epi132	O
and	O
Epi203	O
)	O
living	O
in	O
different	O
parts	O
of	O
Norway	O
with	O
no	O
known	O
family	O
relationship	O
.	O

However	O
,	O
linkage	O
analysis	O
using	O
microsatellite	O
markers	O
(	O
D22S275	O
,	O
D22S272	O
,	O
D22S1172	O
and	O
D22S423	O
)	O
suggested	O
a	O
common	O
founder	O
mutation	O
(	O
data	O
not	O
shown	O
)	O
.	O

The	O
C283T	O
transition	O
generates	O
a	O
novel	O
stop	O
codon	O
in	O
exon	O
1	O
of	O
CHEK2	O
,	O
leading	O
to	O
truncation	O
of	O
the	O
Chk2	O
protein	O
.	O

LOH	O
analysis	O
indicated	O
loss	O
of	O
the	O
wild	O
-	O
type	O
CHEK2	O
allele	O
in	O
the	O
both	O
tumors	O
from	O
the	O
two	O
patients	B
harboring	O
this	O
mutation	O
(	O
Epi132	O
and	O
Epi203	O
)	O
.	O

Both	O
these	O
tumors	O
were	O
non	O
-	O
responsive	O
to	O
epirubicin	O
therapy	O
(	O
PD	O
)	O
.	O

In	O
contrast	O
,	O
the	O
third	O
patient	B
with	O
a	O
germline	O
CHEK2	O
mutation	O
(	O
patient	B
Epi151	O
;	O
point	O
mutation	O
at	O
T1091C	O
,	O
Ile364Thr	O
)	O
had	O
a	O
partial	O
response	O
to	O
epirubicin	O
therapy	O
.	O

This	O
tumor	O
was	O
non	O
-	O
informative	O
with	O
respect	O
to	O
LOH	O
.	O

Taking	O
all	O
CHEK2	O
mutations	O
together	O
,	O
they	O
predicted	O
resistance	O
to	O
epirubicin	O
(	O
p	O
=	O
0	O
.	O
0226	O
)	O
.	O

The	O
previously	O
described	O
silent	O
Glu84Glu	O
(	O
A252G	O
)	O
polymorphism	O
[	O
24	O
]	O
,	O
[	O
43	O
]	O
in	O
exon	O
1	O
was	O
detected	O
in	O
two	O
(	O
1	O
.	O
9	O
%	O
)	O
patients	B
.	O

No	O
association	O
between	O
this	O
polymorphism	O
and	O
treatment	O
response	O
was	O
recorded	O
.	O

One	O
of	O
the	O
tumors	O
(	O
Epi203	O
)	O
harboring	O
the	O
C283T	O
substitution	O
(	O
Arg95Ter	O
)	O
also	O
harbored	O
a	O
somatic	O
TP53	O
mutation	O
in	O
codon	O
175	O
,	O
Arg175His	O
,	O
located	O
in	O
the	O
L2	O
domain	O
of	O
p53	O
(	O
Table	O
2	O
)	O
.	O

This	O
mutation	O
was	O
detected	O
in	O
another	O
four	O
of	O
our	O
patients	B
treated	O
with	O
epirubicin	O
(	O
Table	O
2	O
)	O
.	O

In	O
addition	O
,	O
TP53	O
Arg175His	O
mutation	O
was	O
recorded	O
in	O
one	O
patient	B
of	O
our	O
previous	O
study	O
evaluating	O
response	O
to	O
doxorubicin	O
[	O
13	O
]	O
.	O

The	O
fact	O
that	O
none	O
of	O
the	O
Arg175His	O
patients	B
presented	O
here	O
or	O
in	O
our	O
previous	O
study	O
revealed	O
resistance	O
to	O
therapy	O
(	O
PD	O
)	O
suggests	O
this	O
mutation	O
may	O
not	O
cause	O
resistance	O
to	O
anthracyclines	O
in	O
breast	O
cancers	O
in	O
vivo	O
.	O

Omitting	O
the	O
tumor	O
harboring	O
both	O
a	O
CHEK2	O
and	O
a	O
TP53	O
mutation	O
(	O
patient	B
Epi203	O
)	O
from	O
statistical	O
analysis	O
,	O
Chk2	O
mutations	O
(	O
n	O
=	O
2	O
)	O
were	O
non	O
-	O
significantly	O
associated	O
with	O
therapy	O
resistance	O
(	O
p	O
=	O
0	O
.	O
1633	O
)	O
.	O

In	O
a	O
previous	O
study	O
[	O
26	O
]	O
,	O
however	O
,	O
we	O
analyzed	O
for	O
CHEK2	O
mutation	O
status	O
in	O
relation	O
to	O
therapy	O
outcome	O
in	O
a	O
cohort	O
of	O
patients	B
from	O
doxorubicin	O
study	O
[	O
13	O
]	O
.	O

In	O
that	O
study	O
[	O
26	O
]	O
,	O
we	O
detected	O
the	O
previously	O
identified	O
mutation	O
Ile157Thr	O
.	O

In	O
addition	O
,	O
we	O
detected	O
a	O
novel	O
nonsense	O
somatic	O
mutation	O
(	O
1368InsA	O
)	O
.	O

This	O
mutation	O
was	O
associated	O
with	O
lack	O
of	O
function	O
in	O
vitro	O
;	O
moreover	O
,	O
it	O
was	O
associated	O
with	O
drug	O
resistance	O
in	O
vivo	O
.	O

Analyzing	O
our	O
material	O
and	O
this	O
cohort	O
[	O
26	O
]	O
together	O
,	O
(	O
n	O
=	O
160	O
)	O
,	O
CHEK2	O
mutations	O
(	O
n	O
=	O
5	O
in	O
total	O
)	O
predicted	O
for	O
resistance	O
to	O
doxorubicin	O
and	O
epirubicin	O
therapy	O
(	O
p	O
=	O
0	O
.	O
0123	O
)	O
.	O

Even	O
though	O
,	O
excluding	O
patient	B
Epi203	O
(	O
harboring	O
TP53	O
Arg175His	O
and	O
Arg95Ter	O
CHEK2	O
mutation	O
)	O
as	O
well	O
as	O
other	O
patients	B
harboring	O
TP53	O
L2	O
/	O
L3	O
mutations	O
(	O
n	O
=	O
129	O
)	O
,	O
CHEK2	O
mutations	O
(	O
n	O
=	O
4	O
in	O
total	O
)	O
predicted	O
for	O
resistance	O
to	O
doxorubicin	O
and	O
epirubicin	O
therapy	O
(	O
p	O
=	O
0	O
.	O
030	O
)	O
.	O

TP53	O
and	O
CHEK2	O
Mutations	O
Combined	O
and	O
Response	O
to	O
Therapy	O

Assuming	O
that	O
TP53	O
and	O
CHEK2	O
mutations	O
may	O
substitute	O
for	O
each	O
other	O
,	O
we	O
analyzed	O
for	O
the	O
predictive	O
effect	O
of	O
mutations	O
in	O
both	O
genes	O
.	O

The	O
occurrence	O
of	O
a	O
mutation	O
affecting	O
either	O
CHEK2	O
or	O
TP53	O
strongly	O
predicted	O
therapy	O
resistance	O
(	O
p	O
=	O
0	O
.	O
0101	O
;	O
Fisher	O
exact	O
test	O
)	O
.	O

When	O
tumors	O
harboring	O
TP53	O
-	O
L2	O
/	O
L3	O
mutations	O
and	O
CHEK2	O
mutations	O
were	O
compared	O
with	O
those	O
wild	O
-	O
type	O
or	O
TP53	O
mutations	O
outside	O
the	O
L2	O
/	O
L3	O
domain	O
,	O
the	O
correlation	O
was	O
further	O
strengthened	O
(	O
p	O
=	O
0	O
.	O
0032	O
;	O
Fisher	O
exact	O
test	O
)	O
.	O

The	O
significance	O
was	O
preserved	O
when	O
comparing	O
patients	B
with	O
a	O
PD	O
to	O
objective	O
responders	O
(	O
CR	O
and	O
PR	O
)	O
excluding	O
patients	B
with	O
stable	O
disease	O
(	O
SD	O
)	O
from	O
the	O
statistical	O
analysis	O
(	O
Table	O
4	O
)	O
.	O

p14	O
(	O
ARF	O
)	O
Mutations	O
and	O
Promoter	O
Methylations	O

Neither	O
mutations	O
nor	O
polymorphisms	O
in	O
the	O
coding	O
region	O
of	O
p14	O
(	O
ARF	O
)	O
were	O
observed	O
among	O
the	O
107	O
patients	B
analyzed	O
.	O

Likewise	O
,	O
no	O
promoter	O
methylations	O
were	O
detected	O
.	O

Influence	O
of	O
CHEK2	O
and	O
TP53	O
Mutation	O
Status	O
on	O
Relapse	O
-	O
Free	O
Survival	O

Because	O
of	O
the	O
limited	O
time	O
of	O
the	O
follow	O
-	O
up	O
,	O
no	O
formal	O
statistical	O
assessment	O
of	O
overall	O
survival	O
was	O
performed	O
.	O

Details	O
regarding	O
outcome	O
for	O
individual	O
patients	B
with	O
mutations	O
are	O
described	O
in	O
Table	O
2	O
and	O
3	O
to	O
make	O
these	O
data	O
available	O
to	O
the	O
reader	O
.	O

Relapse	O
-	O
free	O
survival	O
is	O
depicted	O
in	O
(	O
Figure	O
1	O
)	O
.	O

Figure	O
1A	O
shows	O
relapse	O
-	O
free	O
survival	O
for	O
the	O
patients	B
with	O
TP53	O
and	O
CHEK2	O
mutations	O
(	O
all	O
mutations	O
found	O
)	O
compared	O
to	O
patients	B
without	O
any	O
TP53	O
or	O
CHEK2	O
mutations	O
,	O
no	O
difference	O
in	O
relapse	O
-	O
free	O
survival	O
was	O
observed	O
.	O

Similar	O
,	O
no	O
difference	O
was	O
seen	O
when	O
grouping	O
TP53	O
mutations	O
outside	O
L2	O
/	O
L3	O
and	O
CHEK2	O
mutation	O
not	O
affecting	O
kinase	O
function	O
(	O
Ile364Thr	O
)	O
as	O
wild	O
-	O
type	O
(	O
Figure	O
1B	O
)	O
.	O

Grouping	O
tumors	O
harboring	O
a	O
mutation	O
in	O
L2	O
/	O
L3	O
together	O
with	O
CHEK2	O
mutations	O
affecting	O
kinase	O
domain	O
(	O
Arg95Ter	O
)	O
in	O
one	O
group	O
,	O
mutations	O
outside	O
TP53	O
L2	O
/	O
L3	O
and	O
Ile364Thr	O
as	O
one	O
group	O
and	O
tumors	O
without	O
any	O
found	O
mutations	O
in	O
TP53	O
and	O
CHEK2	O
separately	O
,	O
again	O
no	O
noticeably	O
difference	O
in	O
relapse	O
-	O
free	O
survival	O
were	O
seen	O
(	O
Figure	O
1C	O
)	O
.	O

Notably	O
,	O
in	O
addition	O
to	O
a	O
short	O
median	O
follow	O
-	O
up	O
time	O
,	O
a	O
total	O
of	O
35	O
patients	B
with	O
a	O
sub	O
-	O
optimal	O
response	O
to	O
epirubicin	O
received	O
subsequent	O
treatment	O
with	O
paclitaxel	O
,	O
which	O
may	O
have	O
influenced	O
the	O
outcome	O
.	O

CHEK2	O
Mutant	O
'	O
s	O
Capability	O
to	O
Form	O
Dimers	O

To	O
investigate	O
whether	O
the	O
identified	O
CHEK2	O
mutations	O
affect	O
the	O
ability	O
of	O
the	O
Chk2	O
protein	O
to	O
form	O
dimers	O
,	O
co	O
-	O
transfection	O
and	O
immunopresipitation	O
of	O
V5	O
-	O
tagged	O
mutants	O
and	O
Xpress	O
-	O
tagged	O
wild	O
-	O
type	O
Chk2	O
were	O
performed	O
using	O
CHEK2	O
low	O
-	O
expressing	O
U	O
-	O
2	O
-	O
OS	O
cells	O
.	O

As	O
we	O
identified	O
the	O
previously	O
characterized	O
CHEK2	O
germline	O
mutants	O
variants	O
Arg117His	O
(	O
n	O
=	O
2	O
and	O
Ile157Thr	O
(	O
n	O
=	O
1	O
)	O
among	O
patients	B
allocated	O
to	O
primary	O
treatment	O
with	O
paclitaxel	O
in	O
our	O
ongoing	O
study	O
,	O
these	O
mutants	O
were	O
evaluated	O
together	O
with	O
Arg95Ter	O
and	O
Ile364Thr	O
.	O

The	O
results	O
presented	O
in	O
Figure	O
2	O
show	O
that	O
all	O
Chk2	O
variants	O
carrying	O
a	O
point	O
mutation	O
were	O
able	O
to	O
form	O
dimers	O
with	O
wild	O
-	O
type	O
Chk2	O
,	O
whereas	O
the	O
Arg95Ter	O
variant	O
was	O
not	O
.	O

Kinase	O
Activity	O
of	O
CHEK2	O
Mutants	O

To	O
investigate	O
whether	O
the	O
identified	O
CHEK2	O
mutants	O
retained	O
the	O
wild	O
-	O
type	O
kinase	O
activity	O
,	O
an	O
in	O
vitro	O
Chk2	O
kinase	O
assay	O
with	O
respect	O
to	O
Chk2	O
autophosphorylation	O
and	O
Cdc25	O
substrate	O
phosphorylation	O
was	O
performed	O
.	O

The	O
U	O
-	O
2	O
-	O
OS	O
cells	O
were	O
preferred	O
for	O
this	O
assay	O
because	O
they	O
were	O
previously	O
found	O
to	O
express	O
only	O
low	O
levels	O
of	O
endogenous	O
Chk2	O
[	O
44	O
]	O
.	O

This	O
was	O
confirmed	O
by	O
us	O
using	O
an	O
antibody	O
recognizing	O
endogenous	O
protein	O
(	O
data	O
not	O
shown	O
)	O
.	O

These	O
cells	O
have	O
previously	O
been	O
used	O
by	O
other	O
investigators	O
to	O
study	O
Chk2	O
kinase	O
activity	O
[	O
44	O
]	O
,	O
[	O
45	O
]	O
,	O
[	O
46	O
]	O
.	O

The	O
two	O
mutants	O
Arg117Gly	O
and	O
Ile157Thr	O
were	O
previously	O
tested	O
for	O
in	O
vitro	O
kinase	O
activity	O
[	O
47	O
]	O
,	O
but	O
were	O
both	O
included	O
here	O
,	O
together	O
with	O
wild	O
-	O
type	O
CHEK2	O
as	O
controls	O
.	O

Compared	O
to	O
wild	O
-	O
type	O
Chk2	O
,	O
the	O
Ile157Thr	O
mutant	O
retained	O
wild	O
-	O
type	O
kinase	O
activity	O
.	O

The	O
mutant	O
Ile364Thr	O
showed	O
partially	O
reduced	O
kinase	O
activity	O
both	O
in	O
term	O
of	O
Cdc25	O
-	O
phosphorylation	O
and	O
autophosphorylation	O
(	O
Figure	O
3	O
)	O
.	O

In	O
contrast	O
,	O
the	O
mutant	O
Arg117Gly	O
showed	O
strongly	O
reduced	O
kinase	O
activity	O
while	O
the	O
Arg95Ter	O
mutant	O
was	O
totally	O
devoid	O
of	O
any	O
Chk2	O
kinase	O
activity	O
.	O

The	O
activity	O
recorded	O
for	O
Ile157Thr	O
and	O
Arg117Gly	O
was	O
consistent	O
with	O
previously	O
reported	O
results	O
for	O
these	O
two	O
mutants	O
[	O
47	O
]	O
.	O

Notably	O
,	O
there	O
was	O
an	O
internal	O
consistency	O
with	O
respect	O
to	O
percentage	O
activity	O
reduction	O
comparing	O
individual	O
mutants	O
with	O
respect	O
to	O
autophosphorylation	O
and	O
phosphorylation	O
of	O
Cdc25	O
(	O
Figure	O
3	O
)	O
.	O

Since	O
enzymatically	O
active	O
Chk2	O
exists	O
as	O
dimers	O
,	O
it	O
was	O
important	O
to	O
determine	O
the	O
effect	O
of	O
Chk2	O
mutants	O
on	O
wild	O
-	O
type	O
/	O
mutant	O
heterodimer	O
kinase	O
activity	O
.	O

The	O
effect	O
on	O
Chk2	O
kinase	O
activities	O
(	O
Chk2	O
autophosphorylation	O
and	O
Cdc25	O
substrate	O
phosphorylation	O
)	O
of	O
the	O
individual	O
mutants	O
were	O
therefore	O
determined	O
after	O
co	O
-	O
transfection	O
with	O
wild	O
-	O
type	O
Chk2	O
as	O
described	O
in	O
Materials	O
and	O
Methods	O
.	O

The	O
results	O
from	O
this	O
co	O
-	O
transfection	O
-	O
kinase	O
assay	O
(	O
Figure	O
4	O
)	O
were	O
similar	O
to	O
those	O
of	O
the	O
single	O
-	O
transfection	O
assay	O
(	O
Figure	O
3	O
)	O
except	O
in	O
the	O
case	O
of	O
the	O
Arg117Gly	O
mutant	O
,	O
which	O
expressed	O
a	O
substantial	O
kinase	O
activity	O
when	O
complexed	O
with	O
wild	O
-	O
type	O
Chk2	O
.	O

This	O
is	O
consistent	O
with	O
previous	O
data	O
indicating	O
that	O
the	O
Arg117Gly	O
mutant	O
has	O
neglectable	O
kinase	O
activity	O
itself	O
but	O
dimerizes	O
efficiently	O
to	O
Chk2	O
wild	O
-	O
type	O
without	O
strongly	O
affecting	O
the	O
wild	O
-	O
type	O
Chk2	O
activity	O
.	O

Hence	O
,	O
the	O
activity	O
detected	O
is	O
probably	O
caused	O
by	O
the	O
co	O
-	O
transfected	O
and	O
co	O
-	O
precipitated	O
wild	O
-	O
type	O
protein	O
.	O

To	O
rule	O
out	O
the	O
possibility	O
that	O
endogenously	O
expressed	O
wild	O
-	O
type	O
Chk2	O
contributed	O
to	O
observed	O
Arg117Gly	O
kinase	O
activity	O
shown	O
in	O
Figure	O
4	O
,	O
we	O
compared	O
the	O
Arg117Gly	O
variant	O
activity	O
in	O
the	O
presence	O
or	O
absence	O
of	O
co	O
-	O
transfected	O
wild	O
-	O
type	O
Chk2	O
to	O
the	O
activities	O
of	O
Arg95Ter	O
under	O
the	O
same	O
conditions	O
.	O

The	O
Arg95Ter	O
variant	O
does	O
not	O
form	O
dimers	O
with	O
wild	O
-	O
type	O
Chk2	O
.	O

As	O
seen	O
in	O
Figure	O
5	O
,	O
Arg117Gly	O
,	O
which	O
forms	O
dimers	O
with	O
Chk2	O
wild	O
-	O
type	O
,	O
allows	O
increased	O
activity	O
when	O
co	O
-	O
transfected	O
with	O
wild	O
-	O
type	O
as	O
compared	O
to	O
the	O
corresponding	O
activity	O
for	O
the	O
Arg95Ter	O
mutant	O
.	O

The	O
fact	O
that	O
Arg117Gly	O
,	O
when	O
transfected	O
alone	O
,	O
displays	O
very	O
similar	O
activity	O
as	O
Arg95Ter	O
or	O
negative	O
control	O
(	O
background	O
levels	O
)	O
,	O
strongly	O
indicates	O
that	O
the	O
contribution	O
of	O
endogenous	O
Chk2	O
,	O
which	O
,	O
similarly	O
to	O
exogenously	O
expressed	O
wild	O
-	O
type	O
Chk2	O
co	O
-	O
precipitate	O
with	O
Arg117Gly	O
is	O
non	O
-	O
significant	O
.	O

Family	O
Cancer	O
Incidence	O
in	O
Relation	O
to	O
CHEK2	O
Germline	O
Mutations	O

Following	O
an	O
initial	O
report	O
of	O
a	O
family	O
with	O
a	O
CHEK2	O
germline	O
mutation	O
expressing	O
an	O
increased	O
cancer	O
incidence	O
resembling	O
the	O
Li	O
-	O
Fraumeni	O
syndrome	O
[	O
24	O
]	O
,	O
recent	O
studies	O
have	O
revealed	O
the	O
more	O
common	O
CHEK2	O
mutations	O
to	O
be	O
associated	O
with	O
a	O
moderately	O
increased	O
risk	O
of	O
breast	O
and	O
colorectal	O
cancers	O
.	O

We	O
hypothesized	O
that	O
CHEK2	O
mutations	O
having	O
a	O
detrimental	O
effect	O
on	O
drug	O
sensitivity	O
could	O
be	O
associated	O
with	O
a	O
more	O
aggressive	O
,	O
Li	O
-	O
Fraumeni	O
or	O
a	O
Li	O
-	O
Fraumeni	O
-	O
like	O
(	O
LFL	O
)	O
cancer	O
syndrome	O
[	O
48	O
]	O
.	O

Except	O
from	O
the	O
patient	B
harboring	O
the	O
Ile364Thr	O
mutation	O
who	O
did	O
not	O
have	O
any	O
known	O
congestion	O
of	O
cancer	O
disease	O
in	O
the	O
family	O
,	O
a	O
detailed	O
assessment	O
of	O
family	O
cancer	O
history	O
was	O
performed	O
for	O
each	O
patient	B
harboring	O
a	O
germline	O
CHEK2	O
mutation	O
.	O

The	O
family	O
cancer	O
pedigrees	O
are	O
depicted	O
in	O
Figure	O
6	O
.	O

While	O
patients	B
harboring	O
CHEK2	O
germline	O
mutations	O
revealed	O
different	O
types	O
of	O
cancers	O
(	O
mainly	O
breast	O
and	O
tumors	O
of	O
the	O
gastrointestinal	O
area	O
)	O
in	O
their	O
family	O
,	O
surprisingly	O
,	O
no	O
distinct	O
pattern	O
discriminating	O
families	O
harboring	O
the	O
Arg95Ter	O
mutation	O
from	O
the	O
other	O
CHEK2	O
mutated	O
families	O
could	O
be	O
identified	O
.	O

One	O
of	O
them	O
(	O
Epi203	O
)	O
,	O
who	O
inherited	O
the	O
mutation	O
from	O
her	O
father	O
'	O
s	O
side	O
of	O
the	O
family	O
,	O
had	O
no	O
accumulation	O
of	O
either	O
breast	O
or	O
colorectal	O
cancer	O
on	O
that	O
side	O
.	O

It	O
should	O
be	O
noted	O
,	O
however	O
,	O
that	O
two	O
brothers	O
of	O
her	O
fathers	O
mother	O
had	O
prostate	O
cancer	O
,	O
and	O
two	O
siblings	O
of	O
his	O
father	O
having	O
hepatocellular	O
carcinoma	O
and	O
bladder	O
cancer	O
,	O
respectively	O
)	O
,	O
while	O
the	O
other	O
expressed	O
a	O
disease	O
pattern	O
resembling	O
what	O
has	O
been	O
seen	O
with	O
the	O
more	O
common	O
CHEK2	O
mutations	O
,	O
like	O
del1100C	O
[	O
25	O
]	O
.	O

Discussion	O

TP53	O
plays	O
a	O
key	O
role	O
as	O
a	O
tumor	O
suppressor	O
gene	O
.	O

Its	O
protein	O
product	O
activates	O
processes	O
such	O
as	O
growth	O
arrest	O
,	O
DNA	O
repair	O
,	O
apoptosis	O
and	O
/	O
or	O
senescence	O
in	O
response	O
to	O
genotoxic	O
damage	O
as	O
well	O
as	O
oncogene	O
activity	O
[	O
49	O
]	O
,	O
[	O
50	O
]	O
.	O

Despite	O
being	O
extensively	O
studied	O
,	O
critical	O
issues	O
regarding	O
regulation	O
of	O
the	O
p53	O
protein	O
remain	O
poorly	O
understood	O
,	O
and	O
conflicting	O
evidence	O
obtained	O
in	O
different	O
experimental	O
systems	O
make	O
the	O
clinical	O
relevance	O
of	O
experimental	O
data	O
questionable	O
.	O

Chemoresistance	O
is	O
the	O
main	O
obstacle	O
to	O
cancer	O
cure	O
in	O
most	O
malignancies	O
,	O
including	O
breast	O
cancer	O
.	O

Previously	O
,	O
we	O
found	O
TP53	O
mutations	O
affecting	O
the	O
L2	O
/	O
L3	O
DNA	O
binding	O
domain	O
to	O
be	O
associated	O
with	O
lack	O
of	O
responsiveness	O
to	O
doxorubicin	O
monotherapy	O
[	O
13	O
]	O
as	O
well	O
as	O
mitomycin	O
and	O
5	O
-	O
fluoro	O
-	O
uracil	O
in	O
concert	O
[	O
14	O
]	O
.	O

However	O
,	O
some	O
tumors	O
revealed	O
therapy	O
resistance	O
despite	O
harboring	O
wild	O
-	O
type	O
TP53	O
.	O

Postulating	O
that	O
these	O
tumors	O
may	O
harbor	O
genetic	O
disturbances	O
in	O
genes	O
playing	O
a	O
key	O
role	O
in	O
the	O
p53	O
pathway	O
,	O
we	O
here	O
sequenced	O
TP53	O
along	O
with	O
CHEK2	O
and	O
p14	O
(	O
ARF	O
)	O
,	O
the	O
latter	O
two	O
known	O
to	O
play	O
a	O
critical	O
role	O
as	O
p53	O
activators	O
,	O
in	O
tumors	O
from	O
109	O
patients	B
treated	O
with	O
epirubicin	O
monotherapy	O
.	O

Our	O
results	O
confirm	O
TP53	O
mutations	O
,	O
in	O
particular	O
those	O
affecting	O
the	O
L2	O
/	O
L3	O
domains	O
,	O
to	O
be	O
associated	O
with	O
drug	O
resistance	O
.	O

Most	O
importantly	O
,	O
we	O
also	O
found	O
CHEK2	O
mutations	O
generating	O
a	O
non	O
-	O
functional	O
protein	O
in	O
our	O
in	O
vitro	O
assays	O
to	O
be	O
associated	O
with	O
drug	O
resistance	O
.	O

In	O
contrast	O
,	O
none	O
of	O
our	O
tumors	O
harbored	O
either	O
mutations	O
or	O
expressed	O
promoter	O
hypermethylations	O
affecting	O
the	O
p14	O
.	O

Based	O
on	O
in	O
vitro	O
assays	O
,	O
we	O
were	O
able	O
to	O
classify	O
the	O
different	O
Chk2	O
mutants	O
with	O
respect	O
to	O
dimerization	O
capability	O
as	O
well	O
as	O
kinase	O
activity	O
(	O
Chk2	O
autophosphorylation	O
and	O
Cdc25	O
substrate	O
phosphorylation	O
)	O
.	O

In	O
addition	O
,	O
the	O
kinase	O
activities	O
of	O
the	O
Chk2	O
wild	O
-	O
type	O
/	O
mutant	O
complexes	O
were	O
monitored	O
in	O
co	O
-	O
transfection	O
experiments	O
.	O

Notably	O
,	O
each	O
point	O
mutation	O
(	O
except	O
for	O
Arg117Gly	O
)	O
revealed	O
similar	O
relative	O
kinase	O
efficacy	O
whether	O
co	O
-	O
transfected	O
with	O
wild	O
-	O
type	O
Chk2	O
or	O
not	O
(	O
Figure	O
3	O
and	O
4	O
)	O
.	O

Cells	O
co	O
-	O
transfected	O
with	O
Arg117Gly	O
and	O
wild	O
-	O
type	O
Chk2	O
revealed	O
kinase	O
activity	O
,	O
probably	O
due	O
to	O
the	O
contribution	O
of	O
the	O
wild	O
type	O
protein	O
in	O
Chk2	O
mutant	O
-	O
wild	O
-	O
type	O
heterodimers	O
.	O

In	O
contrast	O
,	O
cells	O
transfected	O
with	O
Arg95Ter	O
revealed	O
no	O
kinase	O
activity	O
whether	O
co	O
-	O
transfected	O
with	O
wild	O
-	O
type	O
Chk2	O
or	O
not	O
,	O
clearly	O
distinguishing	O
this	O
mutation	O
from	O
the	O
others	O
(	O
Figure	O
3	O
and	O
5	O
)	O
.	O

All	O
in	O
vitro	O
assays	O
were	O
based	O
on	O
transfection	O
of	O
the	O
U	O
-	O
2	O
-	O
OS	O
cell	O
line	O
,	O
a	O
cell	O
line	O
known	O
to	O
express	O
wild	O
-	O
type	O
Chk2	O
at	O
low	O
levels	O
,	O
and	O
previously	O
used	O
by	O
other	O
investigators	O
to	O
study	O
Chk2	O
activity	O
[	O
44	O
]	O
,	O
[	O
45	O
]	O
,	O
[	O
46	O
]	O
.	O

Since	O
we	O
were	O
not	O
able	O
to	O
obtain	O
satisfactory	O
technical	O
quality	O
of	O
the	O
kinase	O
assay	O
in	O
cell	O
lines	O
negative	O
for	O
Chk2	O
(	O
HCT	O
15	O
and	O
HCT	O
116	O
)	O
,	O
we	O
assessed	O
potential	O
background	O
kinase	O
activity	O
due	O
to	O
endogenous	O
Chk2	O
by	O
performing	O
western	O
blot	O
analysis	O
revealing	O
the	O
endogenous	O
levels	O
of	O
Chk2	O
in	O
U	O
-	O
2	O
-	O
OS	O
cells	O
to	O
be	O
non	O
-	O
significant	O
compared	O
to	O
the	O
exogenously	O
expressed	O
Chk2	O
levels	O
(	O
data	O
not	O
shown	O
)	O
.	O

We	O
also	O
performed	O
a	O
separate	O
kinase	O
assay	O
,	O
directly	O
comparing	O
the	O
effect	O
of	O
binding	O
partners	O
for	O
the	O
dimerizing	O
Arg117Gly	O
and	O
the	O
non	O
-	O
dimerizing	O
Arg95Ter	O
.	O

This	O
assay	O
also	O
revealed	O
the	O
contribution	O
of	O
endogenous	O
Chk2	O
to	O
be	O
non	O
-	O
significant	O
(	O
Figure	O
5	O
)	O
.	O

Taking	O
our	O
in	O
vitro	O
findings	O
together	O
with	O
in	O
vivo	O
observations	O
,	O
our	O
present	O
data	O
confirm	O
that	O
the	O
functionally	O
defective	O
CHEK2	O
Arg95Ter	O
mutation	O
,	O
together	O
with	O
LOH	O
,	O
is	O
associated	O
with	O
resistance	O
to	O
anthracycline	O
therapy	O
.	O

In	O
contrast	O
,	O
the	O
patient	B
harboring	O
the	O
Ile364Thr	O
mutation	O
,	O
moderately	O
reducing	O
phosphorylation	O
activity	O
,	O
responded	O
well	O
to	O
therapy	O
.	O

The	O
other	O
missense	O
mutations	O
;	O
Arg117Gly	O
and	O
Ile157Thr	O
were	O
observed	O
among	O
patients	B
receiving	O
paclitaxel	O
therapy	O
only	O
;	O
thus	O
,	O
their	O
influence	O
on	O
anthracycline	O
sensitivity	O
in	O
vivo	O
could	O
not	O
be	O
addressed	O
.	O

Yet	O
,	O
based	O
on	O
the	O
finding	O
that	O
the	O
Arg117Gly	O
mutant	O
expressed	O
no	O
intrinsic	O
activity	O
,	O
but	O
readily	O
dimerized	O
to	O
the	O
wild	O
-	O
type	O
protein	O
without	O
abolishing	O
its	O
activity	O
,	O
we	O
hypothesize	O
that	O
this	O
mutation	O
and	O
,	O
probably	O
,	O
other	O
yet	O
unidentified	O
CHEK2	O
mutations	O
with	O
a	O
similar	O
lack	O
of	O
intrinsic	O
kinase	O
activity	O
,	O
may	O
cause	O
resistance	O
to	O
anthracycline	O
therapy	O
if	O
combined	O
with	O
LOH	O
in	O
breast	O
cancer	O
.	O

Our	O
present	O
findings	O
have	O
two	O
major	O
implications	O
.	O

First	O
,	O
we	O
confirm	O
that	O
mutations	O
in	O
genes	O
encoding	O
proteins	O
located	O
within	O
the	O
same	O
functional	O
pathway	O
may	O
substitute	O
for	O
each	O
other	O
with	O
respect	O
to	O
drug	O
sensitivity	O
,	O
revealing	O
for	O
the	O
first	O
time	O
a	O
functional	O
pathway	O
critical	O
to	O
chemotherapy	O
response	O
in	O
vivo	O
.	O

Second	O
,	O
the	O
identification	O
of	O
mutations	O
in	O
the	O
CHEK2	O
but	O
not	O
in	O
the	O
p14	O
(	O
ARF	O
)	O
gene	O
in	O
resistant	O
tumors	O
suggests	O
that	O
Chk2	O
mediated	O
phosphorylation	O
of	O
p53	O
is	O
a	O
critical	O
event	O
in	O
executing	O
anti	O
-	O
tumor	O
effect	O
as	O
a	O
response	O
to	O
DNA	O
damaging	O
agents	O
in	O
breast	O
cancer	O
.	O

This	O
adds	O
to	O
our	O
understanding	O
not	O
only	O
of	O
the	O
function	O
of	O
p53	O
but	O
Chk2	O
as	O
well	O
.	O

p53	O
undergoes	O
phosphorylation	O
at	O
multiple	O
sites	O
by	O
different	O
kinases	O
,	O
including	O
Chk2	O
[	O
51	O
]	O
.	O

While	O
activation	O
of	O
the	O
ATM	O
leading	O
to	O
direct	O
(	O
Ser	O
15	O
)	O
and	O
Chk2	O
-	O
mediated	O
(	O
Ser	O
20	O
)	O
phosphorylation	O
of	O
p53	O
is	O
considered	O
an	O
important	O
mechanism	O
for	O
triggering	O
p53	O
activation	O
in	O
response	O
to	O
DNA	O
damage	O
[	O
52	O
]	O
,	O
some	O
reports	O
suggest	O
ATM	O
[	O
53	O
]	O
and	O
even	O
Chk2	O
[	O
23	O
]	O
to	O
be	O
redundant	O
to	O
this	O
function	O
.	O

Importantly	O
,	O
Chk2	O
has	O
been	O
shown	O
capable	O
of	O
inducing	O
ATM	O
-	O
independent	O
apoptosis	O
in	O
vitro	O
[	O
21	O
]	O
.	O

While	O
Chk2	O
phosphorylates	O
p53	O
at	O
Ser	O
20	O
,	O
thereby	O
stabilizing	O
p53	O
by	O
preventing	O
MDM2	O
binding	O
[	O
19	O
]	O
,	O
Chk2	O
also	O
phosphorylates	O
p53	O
at	O
six	O
additional	O
sites	O
,	O
including	O
Ser	O
313	O
and	O
Ser	O
314	O
located	O
in	O
the	O
nuclear	O
localization	O
signal	O
domain	O
of	O
p53	O
[	O
51	O
]	O
.	O

In	O
addition	O
,	O
Chk2	O
phosphorylates	O
other	O
important	O
targets	O
like	O
BRCA1	O
,	O
Cdc25A	O
and	O
Cdc25C	O
involved	O
in	O
DNA	O
repair	O
,	O
G1	O
and	O
G2	O
arrest	O
,	O
respectively	O
[	O
54	O
]	O
.	O

Despite	O
the	O
wide	O
range	O
of	O
known	O
Chk2	O
substrates	O
relevant	O
for	O
DNA	O
repair	O
and	O
cell	O
cycle	O
control	O
,	O
our	O
present	O
findings	O
that	O
CHEK2	O
mutations	O
leading	O
to	O
non	O
-	O
functional	O
Chk2	O
protein	O
may	O
substitute	O
for	O
p53	O
mutations	O
strongly	O
advocate	O
a	O
role	O
for	O
Chk2	O
with	O
respect	O
to	O
drug	O
sensitivity	O
executed	O
through	O
p53	O
activation	O
.	O

Notably	O
,	O
one	O
of	O
the	O
tumors	O
(	O
Epi203	O
)	O
with	O
the	O
Arg95Ter	O
CHEK2	O
mutation	O
in	O
addition	O
harbored	O
a	O
somatic	O
TP53	O
mutation	O
,	O
Arg175His	O
,	O
with	O
allelic	O
imbalance	O
for	O
the	O
TP53	O
gene	O
(	O
Table	O
2	O
)	O
.	O

Importantly	O
,	O
among	O
another	O
four	O
patients	B
in	O
this	O
study	O
(	O
Epi063	O
,	O
Epi071	O
,	O
Epi087	O
,	O
Epi153	O
)	O
and	O
one	O
patient	B
from	O
our	O
previous	O
doxorubicin	O
protocol	O
[	O
13	O
]	O
harboring	O
the	O
Arg175His	O
mutation	O
together	O
with	O
allelic	O
imbalance	O
for	O
TP53	O
,	O
all	O
five	O
of	O
these	O
patients	B
responded	O
to	O
anthracycline	O
therapy	O
either	O
with	O
a	O
partial	O
response	O
or	O
stable	O
disease	O
.	O

In	O
contrast	O
,	O
Epi132	O
and	O
the	O
only	O
patient	B
for	O
whom	O
we	O
previously	O
identified	O
a	O
non	O
-	O
functional	O
CHEK2	O
mutation	O
(	O
1368InsA	O
;	O
coding	O
for	O
a	O
non	O
-	O
functional	O
protein	O
translate	O
with	O
cytoplasmic	O
location	O
[	O
26	O
]	O
)	O
expressed	O
resistance	O
to	O
epirubicin	O
and	O
doxorubicin	O
,	O
respectively	O
.	O

Arg175His	O
is	O
a	O
p53	O
"	O
hot	O
-	O
spot	O
"	O
structural	O
mutation	O
reported	O
to	O
have	O
defects	O
with	O
respect	O
to	O
transcriptional	O
activation	O
and	O
also	O
to	O
negatively	O
interact	O
with	O
wild	O
-	O
type	O
p53	O
[	O
55	O
]	O
.	O

While	O
this	O
mutation	O
has	O
been	O
shown	O
to	O
enhance	O
chemoresistance	O
upon	O
transfection	O
into	O
p53	O
null	O
Saos	O
-	O
2	O
cells	O
[	O
56	O
]	O
,	O
these	O
osteosarcoma	O
-	O
derived	O
cells	O
may	O
not	O
necessarily	O
be	O
representative	O
for	O
breast	O
cancers	O
in	O
vivo	O
.	O

Recent	O
evidence	O
strongly	O
support	O
p53	O
to	O
be	O
involved	O
also	O
in	O
non	O
-	O
transcriptional	O
mediated	O
apoptosis	O
by	O
interacting	O
with	O
the	O
Bcl	O
-	O
2	O
/	O
Bax	O
system	O
[	O
57	O
]	O
,	O
and	O
transcription	O
-	O
defect	O
structural	O
p53	O
mutants	O
have	O
been	O
shown	O
to	O
execute	O
non	O
-	O
transcriptional	O
apoptosis	O
in	O
experimental	O
systems	O
[	O
58	O
]	O
.	O

Concomitant	O
inactivation	O
of	O
Chk2	O
and	O
p53	O
in	O
breast	O
cancer	O
has	O
been	O
recorded	O
by	O
others	O
[	O
59	O
]	O
,	O
and	O
the	O
finding	O
that	O
a	O
somatic	O
mutation	O
may	O
generate	O
a	O
"	O
growth	O
advantage	O
"	O
in	O
tumor	O
cells	O
already	O
harboring	O
a	O
germline	O
CHEK2	O
mutation	O
may	O
not	O
implicate	O
an	O
effect	O
on	O
drug	O
sensitivity	O
in	O
tumors	O
not	O
yet	O
exposed	O
to	O
cytotoxic	O
compounds	O
.	O

Rather	O
,	O
it	O
may	O
indicate	O
a	O
growth	O
advantage	O
,	O
probably	O
related	O
to	O
loss	O
of	O
p21	O
function	O
.	O

Notably	O
,	O
in	O
a	O
previous	O
study	O
we	O
found	O
the	O
p21	O
polymorphism	O
G251A	O
to	O
be	O
associated	O
with	O
an	O
increased	O
risk	O
of	O
developing	O
large	O
breast	O
cancers	O
but	O
to	O
have	O
no	O
effect	O
on	O
drug	O
sensitivity	O
[	O
60	O
]	O
,	O
indicating	O
that	O
growth	O
rate	O
and	O
drug	O
resistance	O
may	O
be	O
regulated	O
independently	O
.	O

Taken	O
together	O
,	O
we	O
believe	O
our	O
findings	O
advocate	O
a	O
role	O
for	O
Chk2	O
in	O
executing	O
cellular	O
response	O
to	O
anthracycline	O
-	O
induced	O
DNA	O
damage	O
.	O

As	O
mentioned	O
above	O
,	O
removing	O
TP53	O
mutated	O
tumors	O
including	O
the	O
double	O
-	O
mutated	O
Epi203	O
from	O
statistical	O
analysis	O
,	O
CHEK2	O
mutation	O
status	O
still	O
predicted	O
for	O
resistance	O
to	O
anthracycline	O
therapy	O
.	O

In	O
addition	O
,	O
removing	O
the	O
tumors	O
harboring	O
the	O
Arg175His	O
mutation	O
from	O
the	O
p53	O
"	O
L2	O
/	O
L3	O
"	O
group	O
strengthened	O
the	O
correlation	O
to	O
lack	O
of	O
treatment	O
response	O
to	O
epirubicin	O
(	O
p	O
=	O
0	O
.	O
0005	O
)	O
.	O

Comparing	O
the	O
effects	O
of	O
mutations	O
in	O
the	O
CHEK2	O
gene	O
to	O
TP53	O
mutations	O
indirectly	O
underlines	O
the	O
importance	O
of	O
the	O
role	O
of	O
Chk2	O
to	O
chemoresistance	O
.	O

Our	O
present	O
findings	O
as	O
well	O
as	O
results	O
from	O
our	O
previous	O
studies	O
[	O
13	O
]	O
,	O
[	O
14	O
]	O
revealed	O
that	O
about	O
50	O
%	O
of	O
the	O
patients	B
with	O
tumors	O
harboring	O
TP53	O
L2	O
/	O
L3	O
mutations	O
to	O
be	O
non	O
-	O
responders	O
to	O
primary	O
therapy	O
.	O

In	O
contrast	O
,	O
all	O
our	O
three	O
patients	B
harboring	O
a	O
non	O
-	O
functional	O
CHEK2	O
mutation	O
(	O
the	O
two	O
Arg95Ter	O
mutated	O
patients	B
here	O
and	O
our	O
previous	O
patient	B
harboring	O
the	O
1368InsA	O
)	O
expressed	O
primary	O
resistance	O
to	O
therapy	O
.	O

We	O
previously	O
hypothesized	O
that	O
therapy	O
response	O
in	O
tumors	O
harboring	O
TP53	O
L2	O
/	O
L3	O
mutations	O
could	O
be	O
due	O
to	O
redundant	O
pathways	O
acting	O
in	O
concert	O
[	O
3	O
]	O
.	O

Although	O
no	O
definite	O
conclusion	O
should	O
be	O
drawn	O
from	O
a	O
limited	O
number	O
of	O
observation	O
,	O
the	O
fact	O
that	O
Chk2	O
not	O
only	O
phosphorylates	O
p53	O
but	O
also	O
phosphorylates	O
other	O
substrates	O
such	O
as	O
Cdc25A	O
and	O
Cdc25C	O
[	O
54	O
]	O
and	O
E2F1	O
in	O
response	O
to	O
etoposide	O
-	O
induced	O
DNA	O
damage	O
[	O
61	O
]	O
may	O
indicate	O
that	O
inactivation	O
of	O
redundant	O
pathways	O
could	O
take	O
place	O
in	O
parallel	O
.	O

The	O
literature	O
remains	O
inconsistent	O
with	O
respect	O
to	O
whether	O
the	O
border	O
amino	O
acids	O
163	O
,	O
195	O
,	O
236	O
and	O
251	O
should	O
be	O
included	O
in	O
the	O
p53	O
L2	O
and	O
L3	O
domains	O
[	O
12	O
]	O
.	O

Taking	O
a	O
conservative	O
approach	O
,	O
we	O
classified	O
patient	B
Epi56	O
,	O
harboring	O
a	O
mutation	O
in	O
codon	O
163	O
,	O
as	O
a	O
L2	O
/	O
L3	O
mutant	O
.	O

The	O
patient	B
harboring	O
this	O
mutation	O
responded	O
to	O
therapy	O
(	O
PR	O
)	O
.	O

If	O
this	O
mutation	O
was	O
classified	O
as	O
outside	O
the	O
L2	O
domain	O
,	O
our	O
p	O
-	O
value	O
had	O
been	O
strengthened	O
from	O
p	O
=	O
0	O
.	O
0136	O
to	O
p	O
=	O
0	O
.	O
0096	O
.	O

Germline	O
mutations	O
in	O
TP53	O
cause	O
the	O
Li	O
-	O
Fraumeni	O
and	O
Li	O
-	O
Fraumeni	O
-	O
like	O
cancer	O
disposition	O
syndromes	O
.	O

However	O
,	O
while	O
the	O
germline	O
and	O
somatic	O
mutations	O
associated	O
with	O
these	O
syndromes	O
reveal	O
a	O
preference	O
for	O
the	O
same	O
codons	O
[	O
48	O
]	O
,	O
TP53	O
mutations	O
affecting	O
the	O
DNA	O
-	O
binding	O
domains	O
seem	O
associated	O
with	O
a	O
poor	O
prognosis	O
[	O
62	O
]	O
,	O
[	O
63	O
]	O
,	O
[	O
64	O
]	O
and	O
,	O
in	O
particular	O
,	O
drug	O
resistance	O
[	O
14	O
]	O
,	O
[	O
40	O
]	O
in	O
breast	O
cancer	O
.	O

Thus	O
,	O
tumor	O
suppression	O
and	O
tumor	O
cell	O
response	O
to	O
chemotherapeutics	O
may	O
involve	O
different	O
parts	O
of	O
p53	O
protein	O
function	O
.	O

Following	O
an	O
initial	O
report	O
identifying	O
a	O
CHEK2	O
mutation	O
in	O
a	O
family	O
expressing	O
characteristics	O
of	O
the	O
Li	O
-	O
Fraumeni	O
syndrome	O
[	O
65	O
]	O
,	O
recent	O
evidence	O
has	O
linked	O
CHEK2	O
founder	O
mutations	O
to	O
a	O
moderately	O
increased	O
risk	O
of	O
breast	O
-	O
and	O
colorectal	O
cancers	O
with	O
some	O
additional	O
disposition	O
for	O
other	O
malignancies	O
as	O
well	O
[	O
66	O
]	O
.	O

However	O
,	O
cancer	O
incidence	O
and	O
phenotypes	O
did	O
not	O
reveal	O
an	O
aggressive	O
Li	O
-	O
Fraumeni	O
or	O
Li	O
-	O
Fraumeni	O
-	O
like	O
tumor	O
pattern	O
.	O

Similar	O
to	O
the	O
two	O
patients	B
in	O
our	O
paclitaxel	O
treatment	O
arm	O
harboring	O
the	O
rare	O
but	O
previously	O
characterized	O
mutation	O
Arg117Gly	O
and	O
the	O
patient	B
with	O
the	O
Ile157Thr	O
mutation	O
,	O
they	O
expressed	O
a	O
moderately	O
increased	O
risk	O
of	O
breast	O
and	O
gastrointestinal	O
cancers	O
(	O
Fig	O
.	O
6	O
)	O
.	O

Thus	O
,	O
CHEK2	O
resembles	O
TP53	O
in	O
as	O
much	O
as	O
there	O
seems	O
to	O
be	O
no	O
direct	O
correlation	O
between	O
effects	O
of	O
individual	O
mutations	O
with	O
respect	O
to	O
tumor	O
suppression	O
and	O
drug	O
resistance	O
.	O

Our	O
finding	O
that	O
TP53	O
mutations	O
located	O
to	O
the	O
DNA	O
-	O
binding	O
domains	O
predicts	O
drug	O
resistance	O
may	O
indicate	O
transcriptional	O
mechanisms	O
to	O
be	O
involved	O
in	O
drug	O
-	O
induced	O
cell	O
death	O
.	O

p53	O
induced	O
apoptosis	O
has	O
been	O
associated	O
with	O
transcriptional	O
induction	O
of	O
genes	O
including	O
Puma	O
and	O
Noxa	O
as	O
well	O
as	O
Bax	O
in	O
experimental	O
systems	O
[	O
55	O
]	O
,	O
[	O
67	O
]	O
,	O
[	O
68	O
]	O
.	O

Yet	O
,	O
recent	O
evidence	O
has	O
revealed	O
p53	O
to	O
induce	O
apoptosis	O
through	O
non	O
-	O
transcriptional	O
mechanisms	O
by	O
direct	O
protein	O
interactions	O
with	O
members	O
of	O
the	O
Bcl	O
-	O
2	O
/	O
Bax	O
system	O
and	O
mitochondrial	O
release	O
of	O
cytochrom	O
c	O
[	O
57	O
]	O
,	O
[	O
69	O
]	O
.	O

In	O
deed	O
,	O
there	O
is	O
evidence	O
that	O
the	O
DNA	O
-	O
binding	O
domains	O
,	O
in	O
particular	O
the	O
L3	O
part	O
of	O
the	O
protein	O
,	O
may	O
be	O
critical	O
also	O
to	O
transcriptional	O
-	O
independent	O
apoptosis	O
[	O
70	O
]	O
.	O

Of	O
particular	O
note	O
is	O
the	O
finding	O
that	O
Chk2	O
may	O
regulate	O
transcriptional	O
-	O
independent	O
p53	O
-	O
mediated	O
apoptosis	O
in	O
response	O
to	O
DNA	O
-	O
damage	O
created	O
through	O
ionizing	O
irradiation	O
[	O
71	O
]	O
.	O

Interestingly	O
,	O
Krajewski	O
et	O
al	O
[	O
72	O
]	O
reported	O
low	O
expression	O
of	O
Bax	O
assessed	O
by	O
immunostaining	O
to	O
be	O
associated	O
with	O
a	O
low	O
response	O
to	O
chemotherapy	O
in	O
metastatic	O
breast	O
cancer	O
.	O

Although	O
no	O
conclusion	O
should	O
be	O
drawn	O
at	O
this	O
stage	O
,	O
together	O
these	O
findings	O
are	O
consistent	O
with	O
the	O
challenging	O
hypothesis	O
that	O
transcription	O
-	O
independent	O
activation	O
of	O
Bax	O
following	O
Chk2	O
-	O
phosphorylation	O
may	O
represent	O
a	O
key	O
pathway	O
in	O
p53	O
dependent	O
cell	O
death	O
in	O
breast	O
cancer	O
in	O
vivo	O
.	O

p14	O
acts	O
by	O
releasing	O
p53	O
from	O
MDM2	O
binding	O
,	O
and	O
has	O
been	O
related	O
to	O
oncogene	O
-	O
induced	O
p53	O
activation	O
[	O
73	O
]	O
.	O

Recently	O
,	O
p14	O
was	O
shown	O
to	O
affect	O
p53	O
by	O
additional	O
mechanisms	O
,	O
including	O
acetylations	O
[	O
74	O
]	O
,	O
response	O
to	O
ionizing	O
radiation	O
in	O
human	B
fibroblasts	O
[	O
75	O
]	O
,	O
and	O
tumor	O
-	O
suppression	O
following	O
ionizing	O
radiation	O
in	O
mice	B
[	O
76	O
]	O
,	O
[	O
77	O
]	O
.	O

These	O
findings	O
further	O
links	O
the	O
retinoblastoma	O
and	O
p53	O
pathways	O
[	O
28	O
]	O
.	O

As	O
such	O
,	O
we	O
believe	O
the	O
negative	O
finding	O
with	O
respect	O
to	O
its	O
role	O
in	O
chemoresistance	O
adds	O
important	O
information	O
.	O

Contrasting	O
earlier	O
findings	O
by	O
us	O
and	O
others	O
[	O
15	O
]	O
,	O
a	O
recent	O
study	O
revealed	O
TP53	O
mutations	O
to	O
be	O
associated	O
with	O
increased	O
likelihood	O
of	O
having	O
a	O
complete	O
response	O
to	O
chemotherapy	O
[	O
16	O
]	O
.	O

These	O
results	O
may	O
not	O
necessarily	O
be	O
at	O
conflict	O
.	O

In	O
the	O
latter	O
study	O
,	O
patients	B
received	O
treatment	O
with	O
a	O
"	O
dose	O
-	O
dense	O
"	O
chemotherapy	O
regimen	O
;	O
if	O
confirmed	O
,	O
the	O
combined	O
data	O
may	O
outline	O
a	O
therapeutic	O
indication	O
for	O
aggressive	O
dose	O
-	O
dense	O
therapy	O
based	O
on	O
tumor	O
TP53	O
/	O
CHEK2	O
status	O
.	O

So	O
far	O
attempts	O
to	O
identify	O
single	O
markers	O
and	O
,	O
more	O
recently	O
,	O
gene	O
expression	O
arrays	O
predicting	O
chemoresistance	O
have	O
not	O
proved	O
successful	O
(	O
see	O
refs	O
in	O
[	O
9	O
]	O
,	O
[	O
10	O
]	O
)	O
.	O

The	O
findings	O
presented	O
here	O
reveal	O
for	O
the	O
first	O
time	O
defects	O
in	O
a	O
functional	O
gene	O
cascade	O
to	O
be	O
associated	O
with	O
drug	O
resistance	O
in	O
a	O
human	B
cancer	O
in	O
vivo	O
.	O

Moreover	O
,	O
the	O
findings	O
are	O
made	O
in	O
breast	O
cancer	O
,	O
the	O
most	O
frequent	O
malignant	O
disease	O
among	O
women	O
in	O
the	O
industrialized	O
world	O
,	O
and	O
relate	O
to	O
resistance	O
to	O
anthracyclines	O
,	O
the	O
type	O
of	O
cytotoxic	O
compounds	O
most	O
frequently	O
employed	O
for	O
this	O
malignancy	O
.	O

While	O
the	O
only	O
study	O
we	O
are	O
aware	O
of	O
comparing	O
TP53	O
mutation	O
status	O
in	O
primaries	O
and	O
their	O
distant	O
metastases	O
suggested	O
an	O
increasing	O
fraction	O
of	O
tumors	O
to	O
express	O
mutated	O
TP53	O
during	O
progression	O
[	O
78	O
]	O
,	O
we	O
do	O
not	O
know	O
the	O
potential	O
contribution	O
of	O
either	O
TP53	O
or	O
CHEK2	O
mutations	O
to	O
drug	O
resistance	O
in	O
micrometastases	O
or	O
in	O
metastatic	O
disease	O
.	O

Yet	O
the	O
finding	O
that	O
one	O
of	O
our	O
non	O
-	O
functional	O
CHEK2	O
mutations	O
associated	O
with	O
chemoresistance	O
(	O
1368InsA	O
)	O
occurred	O
as	O
a	O
somatic	O
,	O
not	O
germline	O
mutation	O
,	O
suggest	O
such	O
mutations	O
may	O
be	O
selected	O
for	O
during	O
tumor	O
progression	O
.	O

We	O
propose	O
the	O
findings	O
presented	O
here	O
provide	O
important	O
beacons	O
identifying	O
a	O
functional	O
pathway	O
[	O
3	O
]	O
likely	O
to	O
be	O
disturbed	O
through	O
different	O
mechanisms	O
in	O
relation	O
to	O
therapy	O
resistance	O
in	O
advanced	O
disease	O
.	O

In	O
conclusion	O
,	O
we	O
believe	O
our	O
findings	O
here	O
that	O
mutations	O
in	O
the	O
TP53	O
and	O
CHEK2	O
genes	O
each	O
may	O
cause	O
resistance	O
to	O
anthracycline	O
therapy	O
in	O
primary	O
tumors	O
to	O
have	O
wide	O
implications	O
to	O
future	O
research	O
in	O
this	O
area	O
.	O

While	O
results	O
from	O
experimental	O
systems	O
are	O
mandatory	O
generating	O
hypotheses	O
,	O
conflicting	O
data	O
from	O
in	O
vitro	O
studies	O
underlines	O
the	O
pivotal	O
role	O
of	O
identifying	O
defects	O
associated	O
with	O
therapy	O
resistance	O
in	O
vivo	O
.	O

Either	O
through	O
mutations	O
of	O
the	O
genes	O
themselves	O
,	O
or	O
inactivation	O
of	O
this	O
functional	O
cascade	O
through	O
co	O
-	O
factors	O
,	O
we	O
believe	O
identification	O
of	O
the	O
Chk2	O
-	O
p53	O
axis	O
as	O
critical	O
to	O
anthracycline	O
therapy	O
response	O
provides	O
a	O
functional	O
clue	O
for	O
further	O
investigations	O
in	O
this	O
area	O
.	O

Host	O
immunity	O
in	O
the	O
protective	O
response	O
to	O
vaccination	O
with	O
heat	O
-	O
killed	O
Burkholderia	B
mallei	I

Abstract	O

Background	O

We	O
performed	O
initial	O
cell	O
,	O
cytokine	O
and	O
complement	O
depletion	O
studies	O
to	O
investigate	O
the	O
possible	O
role	O
of	O
these	O
effectors	O
in	O
response	O
to	O
vaccination	O
with	O
heat	O
-	O
killed	O
Burkholderia	B
mallei	I
in	O
a	O
susceptible	O
BALB	O
/	O
c	O
mouse	B
model	O
of	O
infection	O
.	O

Results	O

While	O
protection	O
with	O
heat	O
-	O
killed	O
bacilli	O
did	O
not	O
result	O
in	O
sterilizing	O
immunity	O
,	O
limited	O
protection	O
was	O
afforded	O
against	O
an	O
otherwise	O
lethal	O
infection	O
and	O
provided	O
insight	O
into	O
potential	O
host	O
protective	O
mechanisms	O
.	O

Our	O
results	O
demonstrated	O
that	O
mice	B
depleted	O
of	O
either	O
B	O
cells	O
,	O
TNF	O
-	O
alpha	O
or	O
IFN	O
-	O
gamma	O
exhibited	O
decreased	O
survival	O
rates	O
,	O
indicating	O
a	O
role	O
for	O
these	O
effectors	O
in	O
obtaining	O
partial	O
protection	O
from	O
a	O
lethal	O
challenge	O
by	O
the	O
intraperitoneal	O
route	O
.	O

Additionally	O
,	O
complement	O
depletion	O
had	O
no	O
effect	O
on	O
immunoglobulin	O
production	O
when	O
compared	O
to	O
non	O
-	O
complement	O
depleted	O
controls	O
infected	O
intranasally	O
.	O

Conclusion	O

The	O
data	O
provide	O
a	O
basis	O
for	O
future	O
studies	O
of	O
protection	O
via	O
vaccination	O
using	O
either	O
subunit	O
or	O
whole	O
-	O
organism	O
vaccine	O
preparations	O
from	O
lethal	O
infection	O
in	O
the	O
experimental	O
BALB	O
/	O
c	O
mouse	B
model	O
.	O

The	O
results	O
of	O
this	O
study	O
demonstrate	O
participation	O
of	O
B220	O
+	O
cells	O
and	O
pro	O
-	O
inflammatory	O
cytokines	O
IFN	O
-	O
gamma	O
and	O
TNF	O
-	O
alpha	O
in	O
protection	O
following	O
HK	O
vaccination	O
.	O

Background	O

Burkholderia	B
mallei	I
,	O
the	O
etiologic	O
agent	O
of	O
glanders	O
,	O
is	O
a	O
gram	O
-	O
negative	O
,	O
capsulated	O
,	O
non	O
-	O
motile	O
,	O
facultative	O
intracelluar	O
bacterium	O
.	O

Most	O
known	O
members	O
of	O
the	O
Burkholderiaceae	O
are	O
resident	O
in	O
the	O
soil	O
;	O
however	O
,	O
B	B
.	I
mallei	I
is	O
thought	O
to	O
be	O
an	O
obligate	O
mammalian	O
pathogen	O
.	O

Horses	B
are	O
highly	O
susceptible	O
to	O
infection	O
and	O
considered	O
the	O
natural	O
reservoir	O
for	O
infection	O
,	O
although	O
mules	B
and	O
donkeys	B
are	O
also	O
susceptible	O
[	O
1	O
]	O
.	O

Clinically	O
,	O
glanders	O
in	O
solipeds	O
can	O
present	O
as	O
either	O
a	O
chronic	O
(	O
horses	B
)	O
or	O
acute	O
(	O
mules	B
and	O
donkeys	B
)	O
form	O
.	O

Naturally	O
acquired	O
human	B
infection	O
with	O
B	B
.	I
mallei	I
,	O
although	O
not	O
seen	O
in	O
the	O
United	O
States	O
since	O
1945	O
,	O
has	O
occurred	O
rarely	O
and	O
sporadically	O
among	O
laboratory	O
workers	O
and	O
those	O
in	O
direct	O
contact	O
with	O
infected	O
animals	O
[	O
2	O
]	O
.	O

However	O
,	O
glanders	O
is	O
endemic	O
among	O
domestic	O
animals	O
in	O
Africa	O
,	O
Asia	O
,	O
the	O
Middle	O
East	O
,	O
and	O
Central	O
and	O
South	O
America	O
.	O

The	O
course	O
of	O
infection	O
is	O
dependent	O
on	O
the	O
route	O
of	O
exposure	O
.	O

Direct	O
contact	O
with	O
the	O
skin	O
can	O
lead	O
to	O
a	O
systemic	O
infection	O
.	O

Inhalation	O
of	O
aerosol	O
or	O
dust	O
containing	O
B	B
.	I
mallei	I
can	O
lead	O
to	O
septicemic	O
,	O
pulmonary	O
,	O
or	O
chronic	O
infections	O
of	O
the	O
muscle	O
,	O
liver	O
and	O
spleen	O
.	O

The	O
disease	O
has	O
a	O
95	O
%	O
case	O
fatality	O
rate	O
for	O
untreated	O
septicemic	O
infections	O
and	O
a	O
50	O
%	O
case	O
fatality	O
rate	O
in	O
antibiotic	O
-	O
treated	O
individuals	O
[	O
3	O
]	O
.	O

There	O
is	O
no	O
human	B
or	O
animal	O
vaccine	O
available	O
for	O
glanders	O
,	O
and	O
development	O
of	O
a	O
partial	O
or	O
fully	O
protective	O
adaptive	O
host	O
response	O
to	O
the	O
organism	O
has	O
not	O
been	O
well	O
-	O
defined	O
.	O

Previous	O
studies	O
with	O
B	B
.	I
mallei	I
and	O
the	O
host	O
response	O
have	O
shown	O
that	O
a	O
mixed	O
immune	O
response	O
consisting	O
of	O
both	O
Th1	O
and	O
Th2	O
-	O
associated	O
cytokines	O
with	O
a	O
predominant	O
IgG1	O
subclass	O
does	O
not	O
correlate	O
with	O
protection	O
[	O
4	O
]	O
.	O

Additional	O
studies	O
with	O
passive	O
transfer	O
of	O
monoclonal	O
antibodies	O
specific	O
for	O
B	B
.	I
mallei	I
have	O
correlated	O
with	O
early	O
protection	O
from	O
infection	O
[	O
5	O
]	O
.	O

Recent	O
studies	O
have	O
also	O
shown	O
the	O
Th1	O
cytokine	O
IL	O
-	O
12	O
to	O
mediate	O
partial	O
protection	O
to	O
non	O
-	O
viable	O
B	B
.	I
mallei	I
-	O
vaccinated	O
mice	B
[	O
6	O
]	O
.	O

Thus	O
,	O
full	O
correlates	O
of	O
protection	O
mediated	O
by	O
the	O
adaptive	O
immune	O
system	O
against	O
B	B
.	I
mallei	I
remain	O
to	O
be	O
fully	O
elucidated	O
.	O

In	O
this	O
series	O
of	O
studies	O
,	O
we	O
sought	O
to	O
address	O
the	O
impact	O
of	O
depletion	O
of	O
the	O
major	O
effector	O
lymphoid	O
cell	O
populations	O
(	O
B220	O
+	O
B	O
cells	O
,	O
CD4	O
+	O
or	O
CD8	O
+	O
T	O
cells	O
)	O
and	O
key	O
pro	O
-	O
inflammatory	O
/	O
Type	O
1	O
cytokines	O
(	O
IFN	O
-	O
gamma	O
or	O
TNF	O
-	O
alpha	O
)	O
on	O
survival	O
in	O
BALB	O
/	O
c	O
mice	B
vaccinated	O
with	O
heat	O
killed	O
(	O
HK	O
)	O
bacilli	O
followed	O
by	O
an	O
intraperitoneal	O
(	O
i	O
.	O
p	O
.	O
)	O
challenge	O
with	O
live	O
organism	O
.	O

In	O
addition	O
,	O
studies	O
investigating	O
the	O
effect	O
of	O
complement	O
on	O
opsonization	O
of	O
organism	O
and	O
antibody	O
production	O
were	O
assessed	O
.	O

Heat	O
killed	O
bacteria	O
were	O
used	O
as	O
a	O
model	O
of	O
vaccination	O
to	O
allow	O
evaluation	O
of	O
B	B
.	I
mallei	I
specific	O
immune	O
responses	O
.	O

The	O
results	O
of	O
this	O
study	O
demonstrate	O
participation	O
of	O
B220	O
+	O
cells	O
and	O
pro	O
-	O
inflammatory	O
cytokines	O
IFN	O
-	O
gamma	O
and	O
TNF	O
-	O
alpha	O
in	O
protection	O
following	O
HK	O
vaccination	O
.	O

Results	O

Heat	O
-	O
killed	O
B	B
.	I
mallei	I
vaccination	O
mediates	O
partial	O
protection	O
from	O
lethal	O
challenge	O

To	O
begin	O
to	O
address	O
this	O
issue	O
in	O
an	O
animal	O
model	O
of	O
acute	O
infection	O
,	O
we	O
established	O
that	O
immunologically	O
naive	O
BALB	O
/	O
c	O
mice	B
challenged	O
i	O
.	O
p	O
.	O
with	O
2	O
x	O
107	O
CFU	O
resulted	O
in	O
death	O
by	O
day	O
4	O
-	O
6	O
,	O
while	O
i	O
.	O
p	O
.	O
immunization	O
with	O
1	O
x	O
105	O
heat	O
killed	O
(	O
HK	O
)	O
bacteria	O
provided	O
partial	O
protection	O
against	O
a	O
subsequent	O
challenge	O
.	O

Two	O
independent	O
experiments	O
resulted	O
in	O
similar	O
findings	O
of	O
40	O
%	O
survival	O
for	O
HK	O
-	O
vaccinated	O
mice	B
with	O
a	O
mean	O
survival	O
time	O
(	O
MST	O
)	O
of	O
8	O
days	O
versus	O
4	O
days	O
in	O
na	O
i	O
ve	O
mice	B
(	O
Fig	O
.	O
1	O
)	O
.	O

The	O
administration	O
of	O
vaccines	O
for	O
B	B
.	I
mallei	I
during	O
an	O
outbreak	O
would	O
mandate	O
relatively	O
rapid	O
onset	O
of	O
protection	O
for	O
human	B
or	O
veterinary	O
use	O
.	O

Based	O
on	O
non	O
-	O
routine	O
use	O
and	O
vaccine	O
implementation	O
in	O
the	O
course	O
of	O
an	O
outbreak	O
,	O
a	O
14	O
day	O
window	O
was	O
chosen	O
for	O
assessment	O
of	O
protection	O
.	O

Our	O
results	O
indicate	O
that	O
HK	O
vaccination	O
can	O
afford	O
partial	O
protection	O
to	O
an	O
otherwise	O
lethal	O
challenge	O
of	O
B	B
.	I
mallei	I
by	O
the	O
i	O
.	O
p	O
.	O
route	O
.	O

Effects	O
of	O
cell	O
depletion	O
on	O
HK	O
-	O
vaccinated	O
survival	O

To	O
dissect	O
the	O
cellular	O
basis	O
for	O
protection	O
mediated	O
by	O
HK	O
vaccination	O
,	O
13	O
days	O
after	O
immunization	O
with	O
HK	O
bacteria	O
(	O
day	O
-	O
1	O
)	O
,	O
and	O
at	O
day	O
of	O
challenge	O
,	O
mice	B
were	O
dosed	O
with	O
antibodies	O
to	O
deplete	O
CD4	O
+	O
,	O
CD8	O
+	O
or	O
B220	O
+	O
cells	O
.	O

Antibody	O
depletion	O
of	O
CD4	O
+	O
,	O
CD8	O
+	O
,	O
or	O
B220	O
+	O
cells	O
in	O
these	O
mice	B
was	O
confirmed	O
by	O
flow	O
cytometric	O
analysis	O
with	O
depletion	O
efficiencies	O
for	O
CD4	O
,	O
CD8	O
,	O
and	O
B220	O
populations	O
at	O
99	O
.	O
7	O
%	O
,	O
96	O
%	O
,	O
and	O
95	O
%	O
,	O
respectively	O
,	O
relative	O
to	O
mice	B
treated	O
with	O
isotype	O
control	O
monoclonal	O
antibodies	O
(	O
data	O
not	O
shown	O
)	O
.	O

Our	O
results	O
demonstrated	O
decreased	O
survival	O
rates	O
in	O
B220	O
(	O
p	O
=	O
0	O
.	O
3418	O
)	O
,	O
CD4	O
+	O
(	O
p	O
=	O
0	O
.	O
5417	O
)	O
and	O
CD8	O
+	O
(	O
p	O
=	O
0	O
.	O
4684	O
)	O
antibody	O
depleted	O
mice	B
,	O
compared	O
to	O
isotype	O
control	O
antibody	O
,	O
a	O
finding	O
that	O
indicated	O
a	O
possible	O
role	O
for	O
vaccine	O
induced	O
antibody	O
production	O
.	O

When	O
challenged	O
with	O
2	O
x	O
107	O
CFU	O
/	O
mouse	B
by	O
the	O
i	O
.	O
p	O
.	O
route	O
,	O
loss	O
of	O
T	O
cells	O
resulted	O
in	O
reduced	O
survival	O
(	O
50	O
%	O
)	O
relative	O
to	O
the	O
non	O
-	O
specific	O
isotype	O
control	O
(	O
Fig	O
.	O
2	O
)	O
.	O

In	O
contrast	O
to	O
the	O
loss	O
of	O
T	O
cells	O
,	O
depletion	O
of	O
B220	O
+	O
cells	O
resulted	O
in	O
100	O
%	O
mortality	O
relative	O
to	O
the	O
non	O
-	O
specific	O
isotype	O
control	O
(	O
Fig	O
.	O
2	O
)	O
.	O

To	O
further	O
evaluate	O
the	O
necessity	O
of	O
these	O
effector	O
cells	O
in	O
providing	O
protection	O
following	O
HK	O
vaccination	O
,	O
relatively	O
resistant	O
C57BL	O
/	O
6	O
mice	B
,	O
deficient	O
in	O
mature	O
B	O
-	O
cells	O
(	O
mu	O
MT	O
)	O
,	O
CD4	O
T	O
-	O
cells	O
(	O
CD4	O
-	O
/	O
-	O
)	O
or	O
CD8	O
T	O
-	O
cells	O
(	O
CD8	O
-	O
/	O
-	O
)	O
were	O
subjected	O
to	O
an	O
identical	O
HK	O
vaccination	O
and	O
challenge	O
regimen	O
.	O

Mature	O
,	O
B	O
-	O
cell	O
-	O
deficient	O
mice	B
demonstrated	O
a	O
50	O
%	O
decreased	O
survival	O
(	O
p	O
=	O
0	O
.	O
0888	O
)	O
compared	O
to	O
the	O
wild	O
-	O
type	O
mice	B
with	O
an	O
MST	O
of	O
35	O
.	O
5	O
days	O
(	O
Fig	O
.	O
3	O
)	O
.	O

CD4	O
-	O
/	O
-	O
and	O
CD8	O
-	O
/	O
-	O
mice	B
exhibited	O
a	O
60	O
%	O
(	O
p	O
=	O
0	O
.	O
1343	O
)	O
and	O
0	O
%	O
reduced	O
survival	O
,	O
respectively	O
(	O
Fig	O
.	O
3	O
)	O
.	O

Effects	O
of	O
cytokine	O
depletion	O
on	O
HK	O
vaccination	O

Similar	O
studies	O
were	O
performed	O
to	O
determine	O
the	O
role	O
of	O
IFN	O
-	O
gamma	O
or	O
TNF	O
-	O
alpha	O
in	O
acute	O
infection	O
in	O
BALB	O
/	O
c	O
mice	B
immunized	O
with	O
HK	O
bacteria	O
.	O

Six	O
hours	O
before	O
challenge	O
,	O
mice	B
were	O
dosed	O
with	O
antibodies	O
that	O
neutralize	O
IFN	O
-	O
gamma	O
or	O
TNF	O
-	O
alpha	O
.	O

Individual	O
depletion	O
of	O
either	O
TNF	O
-	O
alpha	O
(	O
p	O
=	O
0	O
.	O
0145	O
)	O
or	O
IFN	O
-	O
gamma	O
(	O
p	O
=	O
0	O
.	O
0446	O
)	O
resulted	O
in	O
100	O
%	O
mortality	O
with	O
an	O
MST	O
of	O
3	O
and	O
2	O
days	O
,	O
respectively	O
,	O
compared	O
to	O
the	O
HK	O
-	O
vaccinated	O
isotype	O
control	O
mice	B
(	O
Fig	O
.	O
4	O
)	O
.	O

In	O
contrast	O
,	O
40	O
%	O
of	O
HK	O
-	O
vaccinated	O
,	O
isotype	O
control	O
mice	B
survived	O
to	O
at	O
least	O
12	O
days	O
post	O
-	O
challenge	O
(	O
Fig	O
4	O
)	O
.	O

To	O
further	O
evaluate	O
the	O
host	O
TNF	O
-	O
alpha	O
response	O
during	O
an	O
established	O
B	B
.	I
mallei	I
chronic	O
infection	O
,	O
we	O
infected	O
12	O
BALB	O
/	O
c	O
mice	B
by	O
the	O
i	O
.	O
p	O
.	O
route	O
with	O
1	O
x	O
106	O
CFU	O
B	B
.	I
mallei	I
.	O

One	O
animal	O
was	O
terminally	O
ill	O
on	O
day	O
37	O
post	O
-	O
infection	O
.	O

On	O
day	O
42	O
post	O
-	O
infection	O
,	O
the	O
remaining	O
11	O
mice	B
were	O
dosed	O
with	O
either	O
anti	O
-	O
TNF	O
-	O
alpha	O
(	O
n	O
=	O
6	O
)	O
,	O
or	O
control	O
mAb	O
(	O
AFRC	O
Mac	O
49	O
)	O
(	O
n	O
=	O
5	O
)	O
.	O

No	O
further	O
deaths	O
were	O
observed	O
in	O
the	O
control	O
mAb	O
-	O
treated	O
mice	B
.	O

Rapid	O
mortality	O
was	O
observed	O
in	O
the	O
anti	O
-	O
TNF	O
-	O
alpha	O
-	O
treated	O
group	O
,	O
with	O
all	O
mice	B
dying	O
within	O
7	O
days	O
of	O
treatment	O
(	O
p	O
=	O
0	O
.	O
0023	O
)	O
relative	O
to	O
the	O
isotype	O
-	O
treated	O
controls	O
(	O
Fig	O
.	O
5	O
)	O
.	O

J774A	O
.	O
1	O
uptake	O
of	O
serum	O
treated	O
B	B
.	I
mallei	I

Complement	O
mediated	O
uptake	O
assays	O
were	O
performed	O
to	O
evaluate	O
opsonization	O
.	O

Results	O
indicated	O
enhanced	O
bacterial	O
uptake	O
in	O
J774A	O
.	O
1	O
phagocytes	O
inoculated	O
with	O
serum	O
treated	O
B	B
.	I
mallei	I
(	O
p	O
=	O
.	O
0082	O
)	O
,	O
compared	O
to	O
B	B
.	I
mallei	I
alone	O
,	O
while	O
heat	O
-	O
inactivated	O
serum	O
produced	O
uptake	O
percentages	O
similar	O
to	O
those	O
prior	O
to	O
serum	O
addition	O
(	O
Fig	O
.	O
6	O
)	O
.	O

Taken	O
together	O
,	O
these	O
results	O
imply	O
an	O
active	O
role	O
for	O
complement	O
components	O
in	O
the	O
uptake	O
of	O
organism	O
by	O
macrophages	O
.	O

Immunoglobulin	O
production	O
in	O
HK	O
vaccinated	O
BALB	O
/	O
c	O
mice	B

We	O
further	O
characterized	O
the	O
ability	O
of	O
HK	O
vaccination	O
to	O
induce	O
a	O
predominant	O
IgG	O
isotype	O
by	O
determining	O
IgG2a	O
/	O
IgG1	O
ratios	O
in	O
i	O
.	O
p	O
.	O
and	O
i	O
.	O
n	O
.	O
vaccinated	O
BALB	O
/	O
c	O
mice	B
.	O

Pre	O
(	O
day	O
14	O
post	O
vaccination	O
)	O
and	O
post	O
(	O
day	O
2	O
post	O
infection	O
)	O
exposure	O
serum	O
samples	O
were	O
obtained	O
and	O
evaluated	O
for	O
IgG	O
isotype	O
concentrations	O
(	O
Table	O
1	O
)	O
.	O

No	O
appreciable	O
differences	O
in	O
IgG	O
pre	O
-	O
exposure	O
levels	O
were	O
seen	O
when	O
comparing	O
i	O
.	O
n	O
.	O
to	O
i	O
.	O
p	O
.	O
vaccination	O
.	O

In	O
addition	O
,	O
cobra	O
venom	O
factor	O
-	O
treated	O
animals	O
showed	O
no	O
significant	O
differences	O
to	O
non	O
-	O
cobra	O
venom	O
factor	O
-	O
treated	O
animals	O
in	O
IgG	O
pre	O
-	O
exposure	O
(	O
challenge	O
)	O
levels	O
.	O

Conversely	O
,	O
isotype	O
switching	O
in	O
the	O
cobra	O
venom	O
factor	O
treated	O
animals	O
was	O
enhanced	O
in	O
post	O
-	O
exposure	O
serum	O
IgG2a	O
(	O
Table	O
1	O
)	O
.	O

Discussion	O

Recent	O
studies	O
have	O
shown	O
a	O
key	O
role	O
in	O
protection	O
from	O
lethal	O
challenge	O
for	O
IFN	O
-	O
gamma	O
in	O
non	O
-	O
vaccinated	O
mice	B
from	O
either	O
NK	O
and	O
/	O
or	O
NKT	O
cells	O
following	O
experimental	O
exposure	O
to	O
B	B
.	I
mallei	I
and	O
B	B
.	I
pseudomallei	I
[	O
7	O
,	O
8	O
]	O
.	O

A	O
similar	O
protective	O
role	O
in	O
the	O
innate	O
response	O
to	O
infection	O
has	O
been	O
demonstrated	O
for	O
TNF	O
-	O
alpha	O
in	O
B	B
.	I
pseudomallei	I
infection	O
[	O
8	O
]	O
.	O

The	O
studies	O
presented	O
here	O
are	O
consistent	O
with	O
the	O
essential	O
role	O
of	O
these	O
factors	O
in	O
the	O
relative	O
levels	O
of	O
protection	O
conferred	O
by	O
vaccination	O
with	O
heat	O
-	O
killed	O
B	B
.	I
pseudomallei	I
and	O
would	O
appear	O
to	O
be	O
viable	O
early	O
markers	O
for	O
protection	O
from	O
lethal	O
acute	O
infection	O
[	O
9	O
]	O
.	O

Currently	O
,	O
there	O
are	O
no	O
fully	O
protective	O
vaccines	O
against	O
B	B
.	I
mallei	I
or	O
B	B
.	I
pseudomallei	I
in	O
a	O
murine	B
model	O
,	O
particularly	O
for	O
the	O
sensitive	O
BALB	O
/	O
c	O
versus	O
C57BL6	O
models	O
.	O

Previous	O
studies	O
have	O
also	O
demonstrated	O
that	O
both	O
the	O
humoral	O
and	O
cell	O
-	O
mediated	O
arms	O
are	O
essential	O
for	O
protection	O
from	O
B	B
.	I
pseudomallei	I
infection	O
[	O
10	O
]	O
.	O

Thus	O
,	O
loss	O
or	O
reduction	O
of	O
TNF	O
-	O
alpha	O
and	O
IFN	O
-	O
gamma	O
levels	O
result	O
in	O
significantly	O
reduced	O
survival	O
rates	O
,	O
substantiating	O
previous	O
reports	O
of	O
the	O
role	O
of	O
these	O
factors	O
in	O
protection	O
against	O
B	B
.	I
mallei	I
[	O
7	O
]	O
.	O

Moreover	O
,	O
we	O
demonstrate	O
a	O
role	O
for	O
sustained	O
TNF	O
-	O
alpha	O
production	O
in	O
the	O
maintenance	O
of	O
host	O
survival	O
throughout	O
the	O
course	O
of	O
B	B
.	I
mallei	I
infection	O
.	O

Mice	B
with	O
an	O
established	O
B	B
.	I
mallei	I
chronic	O
infection	O
rapidly	O
lost	O
the	O
ability	O
to	O
control	O
the	O
growth	O
of	O
the	O
bacillus	O
upon	O
neutralization	O
of	O
TNF	O
-	O
alpha	O
.	O

This	O
would	O
suggest	O
a	O
potential	O
role	O
for	O
TNF	O
-	O
alpha	O
in	O
the	O
maintenance	O
of	O
productive	O
granulomas	O
which	O
may	O
limit	O
the	O
spread	O
of	O
bacteria	O
in	O
chronically	O
infected	O
hosts	O
,	O
or	O
,	O
alternatively	O
,	O
in	O
direct	O
or	O
indirect	O
microbicidal	O
or	O
bacteriostatic	O
activities	O
at	O
the	O
sites	O
of	O
infection	O
.	O

Additional	O
studies	O
are	O
underway	O
to	O
determine	O
more	O
precisely	O
the	O
role	O
of	O
TNF	O
-	O
alpha	O
in	O
host	O
protection	O
to	O
B	B
.	I
mallei	I
.	O

Multiple	O
innate	O
and	O
adaptive	O
cell	O
types	O
may	O
contribute	O
to	O
the	O
production	O
of	O
IFN	O
-	O
gamma	O
in	O
response	O
to	O
infection	O
with	O
B	B
.	I
mallei	I
following	O
vaccination	O
.	O

Our	O
results	O
with	O
individual	O
depletion	O
of	O
CD4	O
+	O
and	O
CD8	O
+	O
T	O
cells	O
suggests	O
that	O
both	O
cell	O
types	O
may	O
compensate	O
for	O
the	O
functional	O
loss	O
of	O
the	O
other	O
effector	O
cell	O
type	O
in	O
the	O
production	O
of	O
this	O
key	O
cytokine	O
.	O

The	O
effector	O
role	O
for	O
IFN	O
-	O
gamma	O
in	O
mediating	O
protection	O
against	O
B	B
.	I
mallei	I
may	O
include	O
both	O
immunoregulatory	O
and	O
non	O
-	O
regulatory	O
functions	O
.	O

Regardless	O
,	O
the	O
requirement	O
of	O
IFN	O
-	O
gamma	O
,	O
as	O
demonstrated	O
by	O
administration	O
of	O
neutralizing	O
antibody	O
prior	O
to	O
infection	O
,	O
indicates	O
that	O
stimulation	O
of	O
IFN	O
-	O
gamma	O
response	O
is	O
a	O
desirable	O
goal	O
for	O
a	O
B	B
.	I
mallei	I
vaccine	O
.	O

Similarly	O
,	O
B220	O
-	O
positive	O
cells	O
appear	O
to	O
play	O
a	O
role	O
in	O
protection	O
following	O
vaccination	O
with	O
heat	O
-	O
killed	O
B	B
.	I
mallei	I
.	O

Interestingly	O
,	O
this	O
protective	O
immunity	O
,	O
occurring	O
in	O
other	O
intracellular	O
pathogens	O
,	O
is	O
not	O
exclusively	O
dependent	O
on	O
B	O
cells	O
[	O
11	O
]	O
.	O

Passive	O
protection	O
has	O
been	O
demonstrated	O
against	O
acute	O
Burkholderia	O
infection	O
by	O
monoclonal	O
antibodies	O
[	O
5	O
,	O
12	O
]	O
.	O

Protection	O
against	O
B	B
.	I
pseudomallei	I
infection	O
by	O
anti	O
-	O
LPS	O
,	O
capsular	O
polysaccharide	O
and	O
proteins	O
has	O
been	O
short	O
-	O
lived	O
,	O
suggesting	O
that	O
antibody	O
production	O
offers	O
limited	O
protection	O
in	O
the	O
initial	O
stages	O
of	O
infection	O
by	O
an	O
as	O
-	O
yet	O
-	O
undefined	O
mechanism	O
[	O
12	O
]	O
.	O

We	O
have	O
shown	O
that	O
following	O
depletion	O
of	O
B220	O
+	O
cells	O
,	O
survival	O
rates	O
decreased	O
as	O
much	O
as	O
100	O
%	O
relative	O
to	O
non	O
-	O
depleted	O
controls	O
and	O
individual	O
CD4	O
/	O
CD8	O
-	O
depleted	O
mice	B
via	O
the	O
intraperitoneal	O
route	O
.	O

Results	O
from	O
C57BL	O
/	O
6	O
mice	B
deficient	O
in	O
mature	O
B	O
-	O
cells	O
(	O
mu	O
MT	O
)	O
,	O
CD4	O
T	O
-	O
cells	O
(	O
CD4	O
-	O
/	O
-	O
)	O
or	O
CD8	O
T	O
-	O
cells	O
(	O
CD8	O
-	O
/	O
-	O
)	O
substantiate	O
the	O
requirement	O
for	O
B	O
-	O
cell	O
involvement	O
by	O
evidence	O
of	O
mu	O
MT	O
and	O
CD4	O
-	O
/	O
-	O
decreased	O
survival	O
.	O

The	O
lack	O
of	O
an	O
effective	O
CTL	O
response	O
to	O
vaccination	O
did	O
not	O
appear	O
to	O
alter	O
survival	O
in	O
what	O
would	O
appear	O
to	O
be	O
a	O
CD4	O
/	O
B	O
-	O
cell	O
(	O
humoral	O
)	O
-	O
driven	O
response	O
.	O

In	O
CD4	O
-	O
deficient	O
mice	B
,	O
we	O
have	O
the	O
additional	O
potential	O
variable	O
that	O
a	O
CD4	O
-	O
dependent	O
antibody	O
response	O
might	O
also	O
be	O
inhibited	O
during	O
the	O
vaccination	O
phase	O
relative	O
to	O
mice	B
treated	O
with	O
antibody	O
immediately	O
prior	O
to	O
and	O
during	O
the	O
early	O
phases	O
of	O
infection	O
.	O

Although	O
not	O
statistically	O
significant	O
,	O
we	O
did	O
observe	O
a	O
decrease	O
in	O
survival	O
in	O
mu	O
MT	O
(	O
mature	O
B	O
cell	O
)	O
deficient	O
mice	B
as	O
early	O
as	O
day	O
9	O
post	O
challenge	O
,	O
whereas	O
CD4	O
-	O
deficient	O
mice	B
produced	O
similar	O
results	O
at	O
day	O
32	O
post	O
challenge	O
,	O
indicating	O
a	O
role	O
for	O
B	O
cells	O
independent	O
of	O
CD4	O
T	O
cell	O
help	O
,	O
perhaps	O
through	O
a	O
T	O
-	O
independent	O
mechanism	O
of	O
antibody	O
production	O
.	O

Although	O
CD8	O
-	O
/	O
-	O
C57BL	O
/	O
6	O
demonstrated	O
no	O
decreased	O
survival	O
in	O
our	O
HK	O
-	O
vaccinated	O
model	O
,	O
a	O
lack	O
of	O
potential	O
endogenous	O
protein	O
production	O
by	O
HK	O
B	B
.	I
mallei	I
may	O
have	O
contributed	O
to	O
limited	O
MHC	O
-	O
I	O
presentation	O
.	O

Complement	O
associated	O
studies	O
revealed	O
increased	O
J774A	O
.	O
1	O
uptake	O
of	O
serum	O
-	O
treated	O
B	B
.	I
mallei	I
.	O

Complement	O
-	O
mediated	O
uptake	O
studies	O
of	O
B	B
.	I
pseudomallei	I
by	O
polymorphonuclear	O
leukocytes	O
(	O
PMNs	O
)	O
suggest	O
that	O
capsule	O
production	O
contributes	O
to	O
resistance	O
of	O
phagocytosis	O
by	O
reducing	O
C3b	O
bacterial	O
deposition	O
[	O
13	O
]	O
.	O

Previous	O
studies	O
have	O
demonstrated	O
that	O
a	O
polysaccharide	O
capsule	O
is	O
present	O
in	O
B	B
.	I
mallei	I
,	O
[	O
14	O
,	O
15	O
]	O
although	O
in	O
the	O
present	O
study	O
enhanced	O
uptake	O
with	O
serum	O
-	O
treated	O
B	B
.	I
mallei	I
was	O
observed	O
.	O

Intracellular	O
survival	O
assays	O
of	O
complement	O
mediated	O
uptake	O
of	O
organisms	O
were	O
not	O
performed	O
in	O
the	O
present	O
study	O
,	O
thus	O
,	O
the	O
role	O
of	O
complement	O
opsonization	O
on	O
intracellular	O
survival	O
is	O
not	O
fully	O
resolved	O
.	O

Previous	O
reports	O
have	O
demonstrated	O
the	O
ability	O
of	O
B	B
.	I
mallei	I
to	O
survive	O
within	O
macrophage	O
without	O
the	O
aid	O
of	O
serum	O
coating	O
organisms	O
[	O
16	O
]	O
.	O

Conversely	O
,	O
the	O
idea	O
of	O
antibody	O
mediated	O
opsonization	O
to	O
facilitate	O
macrophage	O
activation	O
and	O
clearance	O
of	O
intracellular	O
organisms	O
may	O
offer	O
support	O
to	O
the	O
role	O
of	O
B	O
cells	O
in	O
an	O
effective	O
immune	O
response	O
.	O

A	O
possible	O
protective	O
mechanism	O
may	O
include	O
HK	O
vaccination	O
induced	O
production	O
of	O
opsonizing	O
antibodies	O
which	O
may	O
aid	O
in	O
complement	O
mediated	O
uptake	O
,	O
thereby	O
limiting	O
the	O
initial	O
bacterial	O
threshold	O
below	O
a	O
lethal	O
level	O
.	O

Immunoglobulin	O
responses	O
to	O
HK	O
vaccination	O
resulted	O
in	O
modest	O
levels	O
of	O
IgG1	O
following	O
2	O
weeks	O
post	O
vaccination	O
,	O
while	O
post	O
-	O
exposure	O
levels	O
were	O
indicative	O
of	O
efficient	O
class	O
switching	O
to	O
a	O
favorable	O
IgG2a	O
isotype	O
.	O

Importantly	O
,	O
cobra	O
venom	O
factor	O
treatment	O
of	O
animals	O
at	O
time	O
of	O
vaccination	O
did	O
not	O
alter	O
their	O
ability	O
to	O
produce	O
immunoglobulin	O
.	O

In	O
fact	O
,	O
cobra	O
venom	O
factor	O
treated	O
animals	O
resulted	O
in	O
higher	O
IgG2a	O
levels	O
when	O
compared	O
to	O
non	O
-	O
treated	O
.	O

Complement	O
activation	O
can	O
modulate	O
both	O
the	O
primary	O
and	O
secondary	O
immune	O
responses	O
and	O
has	O
been	O
shown	O
to	O
enhance	O
secondary	O
immune	O
responses	O
to	O
vaccination	O
[	O
17	O
]	O
.	O

The	O
current	O
results	O
suggest	O
that	O
cobra	O
venom	O
factor	O
treatment	O
may	O
affect	O
the	O
modulation	O
of	O
the	O
immune	O
response	O
to	O
B	B
.	I
mallei	I
infection	O
through	O
B	O
cell	O
activation	O
and	O
/	O
or	O
memory	O
B	O
cell	O
generation	O
.	O

Conclusion	O

In	O
summary	O
,	O
our	O
results	O
provide	O
a	O
basis	O
for	O
future	O
studies	O
of	O
protection	O
via	O
vaccination	O
using	O
either	O
subunit	O
or	O
whole	O
-	O
organism	O
vaccine	O
preparations	O
from	O
lethal	O
infection	O
in	O
the	O
experimental	O
BALB	O
/	O
c	O
mouse	B
model	O
.	O

Understanding	O
and	O
defining	O
the	O
role	O
of	O
B	O
cells	O
in	O
adaptive	O
B	B
.	I
mallei	I
immunity	O
will	O
likely	O
be	O
fundamental	O
to	O
the	O
design	O
of	O
an	O
efficacious	O
vaccine	O
and	O
important	O
goals	O
of	O
future	O
research	O
.	O

Methods	O

Bacterial	O
strain	O
and	O
mice	B

B	B
.	I
mallei	I
strain	O
ATCC	O
23344	O
(	O
China	O
7	O
)	O
was	O
cultured	O
on	O
Luria	O
-	O
Bertani	O
agar	O
supplemented	O
with	O
4	O
%	O
glycerol	O
(	O
LB	O
+	O
4	O
%	O
G	O
)	O
agar	O
plates	O
for	O
48	O
h	O
at	O
37	O
degrees	O
C	O
.	O

Isolated	O
colonies	O
were	O
sub	O
-	O
cultured	O
to	O
LB	O
+	O
4	O
%	O
G	O
broth	O
,	O
and	O
cultures	O
were	O
incubated	O
at	O
37	O
degrees	O
C	O
until	O
optical	O
density	O
readings	O
at	O
600	O
nm	O
(	O
OD600	O
)	O
reached	O
an	O
exponential	O
phase	O
of	O
growth	O
.	O

Bacteria	O
were	O
pelleted	O
by	O
centrifugation	O
,	O
washed	O
and	O
re	O
-	O
suspended	O
in	O
sterile	O
1	O
x	O
phosphate	O
-	O
buffered	O
saline	O
(	O
PBS	O
,	O
pH	O
7	O
.	O
4	O
)	O
to	O
obtain	O
the	O
desired	O
CFU	O
/	O
ml	O
.	O

To	O
obtain	O
HK	O
inoculums	O
,	O
bacterial	O
suspensions	O
were	O
incubated	O
at	O
85	O
degrees	O
C	O
for	O
3	O
h	O
and	O
stored	O
at	O
4	O
degrees	O
C	O
until	O
use	O
.	O

The	O
absence	O
of	O
live	O
B	B
.	I
mallei	I
organisms	O
in	O
the	O
HK	O
preparations	O
was	O
confirmed	O
after	O
plating	O
10	O
%	O
of	O
the	O
total	O
inoculums	O
(	O
v	O
/	O
v	O
)	O
and	O
incubating	O
these	O
at	O
37	O
degrees	O
C	O
for	O
48	O
h	O
.	O

All	O
procedures	O
were	O
performed	O
under	O
a	O
class	O
II	O
biosafety	O
cabinet	O
in	O
a	O
biosafety	O
level	O
3	O
laboratory	O
.	O

Female	O
,	O
6	O
-	O
to	O
8	O
-	O
week	O
-	O
old	O
,	O
BALB	O
/	O
c	O
mice	B
(	O
n	O
=	O
5	O
-	O
7	O
)	O
were	O
obtained	O
from	O
Harlan	O
Sprague	O
Dawley	O
,	O
Inc	O
.	O

(	O
Indianapolis	O
,	O
Indiana	O
)	O
.	O

Female	O
,	O
6	O
-	O
to	O
8	O
-	O
week	O
-	O
old	O
,	O
C57BL	O
/	O
6	O
mice	B
deficient	O
in	O
mature	O
B	O
-	O
cells	O
(	O
mu	O
MT	O
)	O
,	O
CD4	O
T	O
-	O
cells	O
(	O
CD4	O
-	O
/	O
-	O
)	O
and	O
CD8	O
T	O
-	O
cells	O
(	O
CD8	O
-	O
/	O
-	O
)	O
and	O
wild	O
-	O
type	O
mice	B
were	O
obtained	O
from	O
The	O
Jackson	O
Laboratory	O
(	O
Bar	O
Harbor	O
,	O
Maine	O
)	O
.	O

Vaccination	O
and	O
challenge	O

BALB	O
/	O
c	O
and	O
C57BL	O
/	O
6	O
mice	B
were	O
grouped	O
and	O
vaccinated	O
with	O
0	O
.	O
5	O
mu	O
g	O
of	O
HK	O
B	B
.	I
mallei	I
(	O
without	O
adjuvant	O
)	O
by	O
i	O
.	O
p	O
.	O
injection	O
using	O
a	O
25	O
-	O
gauge	O
syringe	O
.	O

Two	O
weeks	O
post	O
HK	O
vaccination	O
mice	B
were	O
injected	O
i	O
.	O
p	O
.	O
with	O
2	O
x	O
107	O
CFU	O
/	O
100	O
mu	O
l	O
of	O
live	O
B	B
.	I
mallei	I
(	O
~	O
20	O
LD50	O
)	O
[	O
18	O
]	O
.	O

Complement	O
depleted	O
animals	O
were	O
challenged	O
with	O
2	O
.	O
5	O
x	O
104	O
CFU	O
/	O
50	O
mu	O
l	O
(	O
~	O
0	O
.	O
25	O
LD50	O
)	O
by	O
intranasal	O
(	O
i	O
.	O
n	O
.	O
)	O
route	O
.	O

Aliquots	O
from	O
the	O
inoculums	O
were	O
plated	O
to	O
confirm	O
the	O
infecting	O
dose	O
.	O

All	O
procedures	O
and	O
animal	O
protocols	O
used	O
in	O
this	O
study	O
were	O
approved	O
by	O
the	O
Biosafety	O
and	O
IACUC	O
committees	O
at	O
UTMB	O
and	O
conducted	O
in	O
either	O
BSL	O
-	O
3	O
or	O
ABSL	O
-	O
3	O
laboratories	O
.	O

Cell	O
and	O
cytokine	O
depletions	O

Acute	O
in	O
vivo	O
cell	O
/	O
cytokine	O
depletion	O
was	O
performed	O
with	O
monoclonal	O
rat	B
anti	O
-	O
mouse	B
CD4	O
(	O
GK1	O
.	O
5	O
)	O
,	O
CD8	O
alpha	O
(	O
53	O
-	O
6	O
.	O
7	O
)	O
or	O
B220	O
(	O
RA3	O
-	O
6B2	O
)	O
obtained	O
from	O
R	O
&	O
D	O
Systems	O
,	O
Inc	O
.	O

(	O
Minneapolis	O
,	O
MN	O
)	O
by	O
methods	O
similar	O
to	O
those	O
we	O
have	O
previously	O
described	O
[	O
19	O
]	O
.	O

Functional	O
grade	O
purified	O
rat	B
anti	O
-	O
mouse	B
interferon	O
-	O
gamma	O
(	O
IFN	O
-	O
gamma	O
,	O
AN	O
-	O
18	O
)	O
was	O
obtained	O
from	O
eBioscience	O
(	O
San	O
Diego	O
,	O
CA	O
)	O
and	O
purified	O
anti	O
-	O
mouse	B
tumor	O
necrosis	O
factor	O
(	O
TNF	O
-	O
alpha	O
,	O
MP6	O
-	O
XT3	O
)	O
from	O
BD	O
Pharmingen	O
(	O
San	O
Diego	O
,	O
CA	O
)	O
.	O

IFN	O
-	O
gamma	O
and	O
TNF	O
-	O
alpha	O
antibodies	O
were	O
injected	O
i	O
.	O
p	O
.	O

6	O
h	O
prior	O
to	O
challenge	O
,	O
200	O
mu	O
g	O
per	O
mouse	B
in	O
200	O
mu	O
l	O
PBS	O
or	O
at	O
later	O
time	O
points	O
as	O
indicated	O
.	O

Rat	B
IgG	O
isotype	O
control	O
was	O
obtained	O
from	O
Southern	O
Biotech	O
(	O
Birmingham	O
,	O
AL	O
)	O
and	O
administered	O
i	O
.	O
p	O
.	O
on	O
day	O
of	O
challenge	O
,	O
200	O
mu	O
g	O
/	O
mouse	B
.	O

Rat	B
anti	O
-	O
mouse	B
CD4	O
,	O
CD8	O
alpha	O
and	O
B220	O
were	O
injected	O
i	O
.	O
p	O
.	O
twice	O
,	O
1	O
day	O
prior	O
to	O
challenge	O
and	O
on	O
day	O
of	O
challenge	O
,	O
with	O
an	O
equivalent	O
dosage	O
sufficient	O
to	O
deplete	O
T	O
or	O
B	O
cells	O
from	O
6	O
x	O
108	O
bone	O
marrow	O
cells	O
per	O
injection	O
.	O

The	O
efficiency	O
of	O
depletion	O
at	O
time	O
of	O
infection	O
for	O
CD4	O
+	O
,	O
CD8	O
+	O
,	O
and	O
B220	O
+	O
cells	O
was	O
confirmed	O
by	O
flow	O
cytometry	O
analysis	O
immediately	O
prior	O
to	O
infection	O
.	O

Complement	O
depletion	O
with	O
cobra	O
venom	O
factor	O

Mice	B
,	O
six	O
to	O
seven	O
per	O
group	O
,	O
were	O
vaccinated	O
i	O
.	O
p	O
.	O
with	O
1	O
x	O
105	O
CFU	O
of	O
nonviable	O
B	B
.	I
mallei	I
cell	O
preparation	O
in	O
a	O
total	O
volume	O
of	O
0	O
.	O
1	O
ml	O
.	O

Two	O
weeks	O
later	O
,	O
24	O
h	O
and	O
1	O
h	O
before	O
challenge	O
,	O
complement	O
depleted	O
mice	B
were	O
treated	O
i	O
.	O
p	O
.	O
with	O
12	O
.	O
5	O
units	O
total	O
cobra	O
venom	O
factor	O
(	O
Quidel	O
Corporation	O
Speciality	O
Products	O
,	O
San	O
Diego	O
,	O
CA	O
)	O
in	O
0	O
.	O
1	O
ml	O
of	O
PBS	O
.	O

Complement	O
depletion	O
was	O
confirmed	O
prior	O
to	O
challenge	O
by	O
micro	O
-	O
titer	O
hemolytic	O
complement	O
activity	O
(	O
CH50	O
)	O
assay	O
as	O
previously	O
described	O
[	O
20	O
]	O
.	O

B	B
.	I
mallei	I
J774A	O
.	O
1	O
uptake	O
assays	O

J774A	O
.	O
1	O
cells	O
were	O
seeded	O
(	O
5	O
x	O
105	O
)	O
onto	O
Corning	O
costar	O
24	O
well	O
plates	O
(	O
Corning	O
,	O
NY	O
)	O
with	O
DMEM	O
and	O
incubated	O
overnight	O
at	O
37	O
degrees	O
C	O
with	O
5	O
%	O
CO2	O
.	O

Bacterial	O
suspensions	O
were	O
incubated	O
at	O
37	O
degrees	O
C	O
for	O
45	O
minutes	O
supplemented	O
with	O
2	O
%	O
mouse	B
serum	O
from	O
Sigma	O
-	O
Aldrich	O
(	O
St	O
.	O
Louis	O
,	O
MO	O
.	O
)	O
,	O
heat	O
inactivated	O
mouse	B
serum	O
(	O
56	O
degrees	O
C	O
30	O
minutes	O
)	O
,	O
or	O
bacteria	O
alone	O
and	O
then	O
added	O
at	O
an	O
MOI	O
of	O
10	O
:	O
1	O
to	O
J774A	O
.	O
1	O
cells	O
in	O
triplicate	O
.	O

Inoculated	O
wells	O
were	O
centrifuged	O
at	O
800	O
g	O
for	O
2	O
minutes	O
and	O
incubated	O
for	O
2	O
hours	O
at	O
37	O
degrees	O
C	O
with	O
5	O
%	O
CO2	O
followed	O
by	O
a	O
PBS	O
wash	O
(	O
x	O
2	O
)	O
and	O
2	O
hour	O
incubation	O
with	O
250	O
mu	O
g	O
/	O
ml	O
kanamycin	O
.	O

Wells	O
were	O
washed	O
twice	O
with	O
PBS	O
and	O
lysed	O
with	O
0	O
.	O
1	O
%	O
Triton	O
X	O
-	O
100	O
,	O
followed	O
by	O
serial	O
10	O
-	O
fold	O
dilutions	O
plated	O
on	O
LBG	O
plates	O
and	O
incubated	O
at	O
37	O
degrees	O
C	O
for	O
2	O
days	O
.	O

Colony	O
forming	O
units	O
were	O
enumerated	O
and	O
uptake	O
expressed	O
as	O
a	O
percentage	O
of	O
initial	O
inoculating	O
dose	O
+	O
/	O
-	O
SEM	O
.	O

Antibodies	O
and	O
flow	O
cytometry	O

Flow	O
cytometric	O
analysis	O
was	O
performed	O
on	O
0	O
.	O
1	O
-	O
ml	O
blood	O
samples	O
transferred	O
to	O
micro	O
centrifuge	O
tubes	O
containing	O
90	O
mu	O
l	O
of	O
acid	O
citrate	O
dextrose	O
(	O
ACD	O
)	O
solution	O
.	O

Red	O
blood	O
cells	O
were	O
lysed	O
using	O
ACK	O
-	O
lysing	O
buffer	O
(	O
Biosource	O
International	O
,	O
Inc	O
.	O
,	O
Camarillo	O
,	O
CA	O
)	O
according	O
to	O
the	O
manufacturer	O
'	O
s	O
instruction	O
.	O

Antibodies	O
used	O
for	O
analysis	O
of	O
surface	O
markers	O
included	O
:	O
FITC	O
-	O
conjugated	O
rat	B
anti	O
-	O
mouse	B
CD45R	O
/	O
B220	O
(	O
RA3	O
-	O
6B2	O
,	O
BD	O
Pharmingen	O
San	O
Diego	O
,	O
CA	O
)	O
for	O
B	O
cells	O
;	O
FITC	O
-	O
conjugated	O
rat	B
anti	O
-	O
mouse	B
CD8	O
alpha	O
(	O
53	O
-	O
6	O
.	O
7	O
)	O
and	O
CD4	O
(	O
GK1	O
.	O
5	O
,	O
BD	O
Pharmingen	O
,	O
San	O
Diego	O
,	O
CA	O
)	O
for	O
CD8	O
+	O
or	O
CD4	O
+	O
cells	O
,	O
respectively	O
.	O

Samples	O
evaluated	O
for	O
CD4	O
+	O
and	O
CD8	O
alpha	O
+	O
cells	O
were	O
also	O
incubated	O
with	O
biotin	O
-	O
conjugated	O
hamster	O
anti	O
-	O
mouse	B
CD3e	O
(	O
145	O
-	O
2C11	O
)	O
monoclonal	O
antibody	O
(	O
BD	O
Pharmingen	O
,	O
San	O
Diego	O
,	O
CA	O
)	O
and	O
subsequently	O
with	O
streptavidin	O
APC	O
Cy7	O
.	O

Isotype	O
-	O
matched	O
,	O
non	O
-	O
specific	O
controls	O
were	O
assayed	O
in	O
parallel	O
(	O
BD	O
Pharmingen	O
,	O
San	O
Diego	O
,	O
CA	O
)	O
.	O

Surface	O
staining	O
was	O
performed	O
according	O
to	O
previously	O
published	O
protocols	O
[	O
21	O
]	O
.	O

Following	O
cell	O
staining	O
,	O
the	O
samples	O
were	O
fixed	O
with	O
2	O
%	O
buffered	O
paraformaldehyde	O
overnight	O
prior	O
to	O
analysis	O
by	O
flow	O
cytometry	O
.	O

Samples	O
were	O
analyzed	O
using	O
a	O
FACSCalibur	O
flow	O
cytometer	O
with	O
BD	O
CellQuest	O
Pro	O
software	O
.	O

Antibody	O
assays	O

Immunoglobulin	O
subclass	O
IgG1	O
and	O
IgG2a	O
titers	O
in	O
mice	B
were	O
determined	O
by	O
a	O
whole	O
bacterial	O
cell	O
ELISA	O
performed	O
in	O
96	O
-	O
well	O
,	O
Immulon	O
2	O
HB	O
,	O
round	O
-	O
bottom	O
plates	O
(	O
Dynex	O
Technologies	O
)	O
.	O

B	B
.	I
mallei	I
antigen	O
was	O
diluted	O
in	O
0	O
.	O
1	O
M	O
carbonate	O
buffer	O
(	O
pH	O
9	O
.	O
5	O
)	O
and	O
50	O
mu	O
l	O
of	O
diluted	O
cells	O
placed	O
into	O
wells	O
.	O

Plates	O
were	O
stored	O
overnight	O
at	O
4	O
degrees	O
C	O
.	O

The	O
plates	O
were	O
washed	O
with	O
washing	O
solution	O
(	O
1	O
x	O
PBS	O
,	O
0	O
.	O
05	O
%	O
Tween	O
20	O
)	O
,	O
and	O
incubated	O
with	O
100	O
mu	O
l	O
of	O
blocking	O
solution	O
(	O
1	O
x	O
PBS	O
,	O
1	O
%	O
bovine	B
serum	O
albumin	O
,	O
0	O
.	O
05	O
%	O
Tween	O
20	O
)	O
for	O
1	O
h	O
at	O
37	O
degrees	O
C	O
.	O

Dilutions	O
of	O
mouse	B
sera	O
were	O
made	O
with	O
blocking	O
solution	O
in	O
duplicate	O
and	O
plates	O
were	O
incubated	O
for	O
1	O
h	O
at	O
37	O
degrees	O
C	O
.	O

Following	O
incubation	O
,	O
plates	O
were	O
washed	O
and	O
50	O
mu	O
l	O
of	O
anti	O
-	O
Ig	O
-	O
horseradish	B
peroxidase	O
subclass	O
conjugate	O
,	O
diluted	O
accordingly	O
to	O
manufacturer	O
'	O
s	O
instructions	O
(	O
Southern	O
Biotechnology	O
Associates	O
,	O
Inc	O
.	O
Birmingham	O
,	O
Ala	O
.	O
)	O
,	O
was	O
added	O
to	O
each	O
well	O
and	O
incubated	O
for	O
1	O
h	O
at	O
37	O
degrees	O
C	O
.	O

After	O
washing	O
,	O
50	O
mu	O
l	O
of	O
2	O
,	O
2	O
'	O
-	O
azino	O
-	O
di	O
-	O
(	O
3	O
-	O
ethylbenzthizoline	O
)	O
-	O
6	O
-	O
sulfonate	O
(	O
ABTS	O
)	O
peroxidase	O
substrate	O
(	O
KPL	O
,	O
Inc	O
.	O
,	O
Gaithersburg	O
,	O
Maryland	O
)	O
was	O
added	O
to	O
each	O
well	O
and	O
plates	O
incubated	O
for	O
25	O
min	O
at	O
room	O
temperature	O
.	O

The	O
amount	O
of	O
bound	O
antibody	O
was	O
determined	O
colorimetrically	O
by	O
absorbance	O
at	O
405	O
nm	O
.	O

Statistical	O
analysis	O

Survival	O
curves	O
were	O
calculated	O
by	O
Kaplan	O
Meier	O
survival	O
analysis	O
with	O
log	O
-	O
rank	O
tests	O
between	O
groups	O
using	O
GraphPad	O
Prism	O
(	O
V	O
.	O
4	O
.	O
03	O
for	O
windows	O
)	O
.	O

Statistical	O
analysis	O
was	O
generally	O
performed	O
with	O
the	O
paired	O
Student	O
'	O
s	O
t	O
-	O
test	O
.	O

P	O
value	O
<	O
=	O
0	O
.	O
05	O
was	O
considered	O
significant	O
.	O

Abbreviations	O

HK	O
:	O
Heat	O
-	O
killed	O
;	O
i	O
.	O
p	O
.	O
:	O
intraperitoneal	O
;	O
i	O
.	O
n	O
.	O
:	O
intranasal	O
.	O

Authors	O
'	O
contributions	O

GCW	O
designed	O
and	O
conducted	O
experiments	O
and	O
drafted	O
the	O
manuscript	O
.	O

BMJ	O
carried	O
out	O
the	O
immunoassays	O
and	O
animal	O
work	O
.	O

SP	O
provided	O
analysis	O
of	O
data	O
and	O
contributed	O
to	O
design	O
and	O
animal	O
work	O
.	O

RAL	O
participated	O
in	O
the	O
generation	O
and	O
analysis	O
of	O
chronic	O
TNF	O
-	O
alpha	O
data	O
.	O

DME	O
conceived	O
the	O
study	O
,	O
and	O
participated	O
in	O
its	O
design	O
and	O
coordination	O
and	O
helped	O
to	O
draft	O
the	O
manuscript	O
.	O

AGT	O
participated	O
in	O
the	O
bacterial	O
work	O
and	O
drafting	O
of	O
the	O
manuscript	O
.	O

All	O
authors	O
read	O
and	O
approved	O
the	O
final	O
manuscript	O
.	O

The	O
ineffectiveness	O
of	O
tobramycin	O
combination	O
therapy	O
in	O
Streptococcus	B
faecium	I
endocarditis	O
.	O

Abstract	O

A	O
patient	B
required	O
mitral	O
valve	O
replacement	O
following	O
ineffective	O
antibiotic	O
treatment	O
of	O
enterococcal	O
endocarditis	O
caused	O
by	O
Streptococcus	B
faecium	I
.	O

Endocarditis	O
had	O
relapsed	O
despite	O
therapy	O
with	O
ampicillin	O
and	O
tobramycin	O
for	O
six	O
weeks	O
.	O

A	O
second	O
relapse	O
had	O
occurred	O
following	O
treatment	O
with	O
penicillin	O
and	O
gentamicin	O
.	O

Initial	O
failure	O
of	O
antibiotic	O
therapy	O
may	O
be	O
related	O
to	O
the	O
known	O
lack	O
of	O
in	O
vitro	O
and	O
in	O
vivo	O
synergy	O
between	O
penicillin	O
and	O
tobramycin	O
against	O
S	B
.	I
faecium	I
.	O

Effective	O
therapy	O
of	O
enterococcal	O
endocarditis	O
requires	O
considerations	O
of	O
bacterial	O
speciation	O
,	O
determination	O
of	O
high	O
-	O
level	O
aminoglycoside	O
resistance	O
,	O
and	O
preferably	O
adequate	O
antibiotic	O
synergy	O
studies	O
to	O
assure	O
effective	O
therapy	O
.	O

THE	O
YALE	O
JOURNAL	O
OF	O
BIOLOGY	O
AND	O
MEDICINE	O
56	O
(	O
1983	O
)	O
,	O
243	O
-	O
249	O

The	O
Ineffectiveness	O
of	O
Tobramycin	O
Combination	O
Therapy	O

in	O
Streptococcus	B
Faecium	I
Endocarditis	O

JUDITH	O
A	O
.	O

GOLDSTEIN	O
,	O
M	O
.	O
D	O
.	O
,	O
a	O
HOWARD	O
COHEN	O
,	O
M	O
.	O
D	O
.	O
,	O
a	O
AND	O

FRANK	O
J	O
.	O

BIA	O
,	O
M	O
.	O
D	O
.	O
,	O
M	O
.	O
P	O
.	O
H	O
.	O
a	O
,	O
b	O

aInfectious	O
Disease	O
Section	O
of	O
the	O
Department	O
of	O
Medicine	O
,	O
and	O
bThe	O
Department	O
of	O

Laboratory	O
Medicine	O
,	O
Veterans	O
Administration	O
Medical	O
Center	O
,	O

West	O
Haven	O
,	O
and	O
Yale	O
University	O
School	O
of	O
Medicine	O
,	O

New	O
Haven	O
,	O
Connecticut	O

Received	O
July	O
11	O
,	O
1983	O

A	O
patient	B
required	O
mitral	O
valve	O
replacement	O
following	O
ineffective	O
antibiotic	O
treatment	O
of	O
enterococcal	O
endocarditis	O
caused	O
by	O
Streptococcusfaecium	B
.	O

Endocarditis	O
had	O
relapsed	O
despite	O
therapy	O
with	O
ampicillin	O
and	O
tobramycin	O
for	O
six	O
weeks	O
.	O

A	O
second	O
relapse	O
had	O
occurred	O
following	O
treatment	O
with	O
penicillin	O
and	O
gentamicin	O
.	O

Initial	O
failure	O
of	O
antibiotic	O
therapy	O
may	O
be	O
related	O
to	O
the	O
known	O
lack	O
of	O
in	O
vitro	O
and	O
in	O
vivo	O
synergy	O
between	O
penicillin	O
and	O
tobramycin	O
against	O
S	B
.	I
faecium	I
.	O

Effective	O
therapy	O
of	O
enterococcal	O
endocarditis	O
requires	O
considerations	O
of	O
bacterial	O
speciation	O
,	O
determination	O
of	O
high	O
-	O
level	O
aminoglycoside	O
resistance	O
,	O
and	O
preferably	O
adequate	O
antibiotic	O
synergy	O
studies	O
to	O
assure	O
effective	O
therapy	O
.	O

INTRODUCTION	O

Enterococcal	O
endocarditis	O
requires	O
special	O
therapeutic	O
considerations	O
because	O
the	O
responsible	O
organisms	O
are	O
relatively	O
penicillin	O
-	O
resistant	O
streptococci	O
which	O
require	O
synergistic	O
combinations	O
of	O
antibiotics	O
to	O
achieve	O
acceptable	O
cure	O
rates	O
[	O
1	O
,	O
2	O
]	O
.	O

The	O
group	O
D	O
enterococci	O
include	O
three	O
main	O
species	O
S	B
.	I
faecalis	I
,	O
S	B
.	I
faecium	I
,	O
and	O
S	B
.	I
durans	I
.	O

S	B
.	I
faecium	I
cause	O
a	O
minority	O
of	O
all	O
cases	O
of	O
enterococcal	O
endocarditis	O
,	O
in	O
those	O
instances	O
in	O
which	O
enterococci	O
have	O
been	O
speciated	O
[	O
3	O
]	O
,	O
but	O
they	O
have	O
been	O
more	O
resistant	O
both	O
to	O
penicillin	O
and	O
penicillin	O
-	O
aminoglycoside	O
combinations	O
than	O
S	B
.	I
faecalis	I
[	O
4	O
,	O
5	O
,	O
6	O
]	O
.	O

We	O
describe	O
a	O
64	O
-	O
year	O
-	O
old	O
man	B
with	O
S	B
.	I
faecium	I
endocarditis	O
in	O
whom	O
a	O
six	O
-	O
week	O
course	O
of	O
ampicillin	O
and	O
tobramycin	O
,	O
followed	O
by	O
additional	O
courses	O
of	O
penicillin	O
and	O
other	O
aminoglycosides	O
,	O
failed	O
to	O
eradicate	O
the	O
organism	O
from	O
the	O
patient	B
'	O
s	O
mitral	O
valve	O
.	O

This	O
case	O
is	O
of	O
interest	O
because	O
therapeutic	O
failure	O
of	O
ampicillin	O
and	O
tobramycin	O
in	O
S	B
.	I
faecium	I
endocarditis	O
has	O
not	O
been	O
reported	O
previously	O
,	O
but	O
might	O
have	O
been	O
predicted	O
on	O
the	O
basis	O
of	O
previous	O
in	O
vitro	O
and	O
in	O
vivo	O
studies	O
[	O
6	O
]	O
.	O

Although	O
the	O
need	O
for	O
both	O
a	O
penicillin	O
derivative	O
and	O
an	O
aminoglycoside	O
in	O
the	O
therapy	O
of	O
enterococcal	O
endocarditis	O
is	O
widely	O
known	O
,	O
it	O
is	O
important	O
to	O
distinguish	O
between	O
the	O
differing	O
efficacies	O
of	O
penicillin	O
-	O
aminoglycoside	O
combinations	O
for	O
treating	O
various	O
species	O
of	O
enterococci	O
such	O
as	O
S	B
.	I
faecium	I
.	O

243	O

Address	O
reprint	O
requests	O
to	O
:	O
Judith	O
A	O
.	O
Goldstein	O
,	O
M	O
.	O
D	O
.	O
,	O
Section	O
of	O
Infectious	O
Diseases	O
,	O
Department	O
of	O
Medicine	O
,	O
Long	O
Island	O
Jewish	O
-	O
Hillside	O
Medical	O
Center	O
,	O
Queen	O
'	O
s	O
Hosp	O
.	O

Center	O
Affiliate	O
,	O
82	O
-	O
68	O
164th	O
Street	O
,	O
Jamaica	O
,	O
NY	O
11432	O

Copyright	O
c	O
1983	O
by	O
The	O
Yale	O
Journal	O
of	O
Biology	O
and	O
Medicine	O
,	O
Inc	O
.	O

All	O
rights	O
of	O
reproduction	O
in	O
any	O
form	O
reserved	O
.	O

GOLDSTEIN	O
ET	O
AL	O
.	O

CASE	O
REPORT	O

A	O
64	O
-	O
year	O
-	O
old	O
male	O
was	O
in	O
good	O
health	O
until	O
December	O
1980	O
,	O
when	O
he	O
noted	O
intermittent	O
night	O
sweats	O
,	O
malaise	O
,	O
fever	O
,	O
and	O
fatigue	O
.	O

He	O
received	O
oral	O
erythromycin	O
for	O
14	O
days	O
with	O
transient	O
improvement	O
of	O
symptoms	O
.	O

However	O
,	O
after	O
completing	O
therapy	O
,	O
symptoms	O
reappeared	O
and	O
he	O
noted	O
a	O
15	O
-	O
pound	O
weight	O
loss	O
with	O
low	O
-	O
grade	O
fever	O
(	O
99	O
-	O
100	O
.	O
5	O
?	O
F	O
)	O
during	O
the	O
two	O
months	O
preceding	O
admission	O
.	O

There	O
was	O
no	O
previous	O
history	O
of	O
rheumatic	O
or	O
congenital	O
heart	O
disease	O
.	O

In	O
March	O
1981	O
,	O
the	O
patient	B
was	O
admitted	O
to	O
his	O
community	O
hospital	O
where	O
evaluation	O
revealed	O
a	O
new	O
apical	O
systolic	O
murmur	O
radiating	O
to	O
the	O
axilla	O
.	O

There	O
were	O
no	O
petechiae	O
,	O
Janeway	O
lesions	O
,	O
Osler	O
'	O
s	O
nodes	O
,	O
Roth	O
spots	O
,	O
or	O
splenomegaly	O
.	O

The	O
hematocrit	O
was	O
34	O
.	O
8	O
percent	O
,	O
WBC	O
count	O
9	O
,	O
300	O
cells	O
per	O
cu	O
mm	O
with	O
a	O
differential	O
count	O
of	O
67	O
segmented	O
forms	O
,	O
9	O
bands	O
,	O
15	O
lymphocytes	O
,	O
7	O
monocytes	O
,	O
1	O
eosinophil	O
,	O
and	O
1	O
basophil	O
.	O

The	O
erythrocyte	O
sedimentation	O
rate	O
(	O
ESR	O
)	O
was	O
62	O
mm	O
per	O
hour	O
(	O
nl	O
<	O
10	O
mm	O
per	O
hour	O
)	O
and	O
the	O
serum	O
rheumatoid	O
factor	O
titer	O
was	O
1	O
:	O
320	O
.	O

Chest	O
films	O
and	O
electrocardiogram	O
were	O
reportedly	O
normal	O
.	O

Group	O
D	O
streptococci	O
grew	O
from	O
three	O
sets	O
of	O
blood	O
cultures	O
.	O

Enterococcal	O
endocarditis	O
was	O
diagnosed	O
and	O
he	O
was	O
treated	O
with	O
six	O
weeks	O
of	O
parenteral	O
ampicillin	O
(	O
12	O
grams	O
per	O
day	O
)	O
and	O
tobramycin	O
(	O
3	O
mg	O
per	O
kg	O
per	O
day	O
)	O
.	O

Resolution	O
of	O
symptoms	O
occurred	O
within	O
several	O
days	O
after	O
antibiotics	O
were	O
begun	O
.	O

Serum	O
bactericidal	O
titers	O
against	O
the	O
organism	O
,	O
obtained	O
during	O
peak	O
antibiotic	O
levels	O
,	O
were	O
1	O
:	O
8	O
or	O
greater	O
on	O
several	O
occasions	O
,	O
and	O
blood	O
cultures	O
were	O
negative	O
while	O
the	O
patient	B
was	O
receiving	O
antibiotics	O
.	O

M	O
-	O
mode	O
echocardiography	O
demonstrated	O
left	O
atrial	O
enlargement	O
but	O
no	O
definable	O
abnormalities	O
of	O
the	O
mitral	O
or	O
aortic	O
valves	O
.	O

Intravenous	O
pyelogram	O
,	O
oral	O
cholecystogram	O
,	O
cystoscopy	O
,	O
liver	O
-	O
spleen	O
scan	O
,	O
and	O
upper	O
and	O
lower	O
gastrointestinal	O
series	O
were	O
normal	O
except	O
for	O
a	O
few	O
sigmoid	O
diverticuli	O
.	O

Flexible	O
signoidoscopy	O
demonstrated	O
both	O
a	O
small	O
perianal	O
fissure	O
and	O
hemorrhoids	O
.	O

Blood	O
cultures	O
two	O
weeks	O
after	O
therapy	O
were	O
negative	O
.	O

Second	O
Admission	O
(	O
June	O
19	O
-	O
August	O
4	O
,	O
1981	O
)	O

In	O
June	O
1981	O
,	O
he	O
again	O
noted	O
intermittent	O
fever	O
,	O
night	O
sweats	O
,	O
and	O
fatigue	O
.	O

Group	O
D	O
streptococci	O
grew	O
from	O
three	O
sets	O
of	O
blood	O
cultures	O
and	O
he	O
was	O
admitted	O
to	O
the	O
West	O
Haven	O
VA	O
Medical	O
Center	O
for	O
recurrent	O
endocarditis	O
.	O

On	O
examination	O
a	O
somewhat	O
louder	O
apical	O
systolic	O
murmur	O
was	O
noted	O
.	O

The	O
ESR	O
was	O
50	O
mm	O
/	O
hour	O
and	O
rheumatoid	O
factor	O
titer	O
was	O
1	O
:	O
320	O
.	O

Serum	O
complement	O
levels	O
were	O
normal	O
and	O
cryoglobulins	O
were	O
not	O
detectable	O
.	O

Chest	O
films	O
,	O
EKG	O
,	O
and	O
urinalysis	O
were	O
normal	O
.	O

Cardiac	O
M	O
-	O
mode	O
echocardiogram	O
revealed	O
a	O
globular	O
mass	O
attached	O
to	O
the	O
posterior	O
mitral	O
valve	O
leaflet	O
with	O
prolapse	O
into	O
a	O
slightly	O
enlarged	O
left	O
atrium	O
.	O

A	O
twodimensional	O
echocardiogram	O
confirmed	O
mitral	O
valve	O
prolapse	O
and	O
suggested	O
a	O
posterior	O
leaflet	O
vegetation	O
.	O

Gallium	O
citrate	O
scan	O
was	O
negative	O
.	O

Three	O
separate	O
morphologic	O
colony	O
variants	O
were	O
isolated	O
from	O
blood	O
,	O
each	O
identified	O
as	O
S	B
.	I
faecium	I
by	O
Dr	O
.	O
R	O
.	O
R	O
.	O

Facklam	O
(	O
Center	O
for	O
Disease	O
Control	O
,	O
Atlanta	O
,	O
Georgia	O
)	O
.	O

The	O
patient	B
received	O
intravenous	O
penicillin	O
(	O
20	O
million	O
units	O
per	O
day	O
)	O
and	O
gentamicin	O
(	O
3	O
mg	O
per	O
kg	O
per	O
day	O
)	O
for	O
six	O
weeks	O
with	O
improvement	O
.	O

Peak	O
serum	O
bactericidal	O
titers	O
of	O
1	O
:	O
8	O
or	O
greater	O
were	O
achieved	O
against	O
two	O
of	O
the	O
colony	O
variants	O
;	O
however	O
,	O
against	O
the	O
large	O
colony	O
morphotype	O
,	O
a	O
titer	O
of	O
only	O
1	O
:	O
2	O
was	O
obtained	O
.	O

An	O
enlarged	O
left	O
atrium	O
with	O
intermittent	O
fluttering	O
and	O
prolapse	O
of	O
the	O
mitral	O
valve	O
was	O
noted	O
on	O
echocardiography	O
three	O
weeks	O
into	O
therapy	O
.	O

Multiple	O
blood	O
cultures	O
taken	O
while	O
the	O
patient	B
was	O
receiving	O
antibiotics	O
were	O
negative	O
,	O
as	O
were	O
those	O
obtained	O
48	O
and	O
72	O
hours	O
after	O
discontinuation	O
of	O
antibiotics	O
.	O

244	O

S	B
.	I

FAECIUM	B
ENDOCARDITIS	O

Third	O
Admission	O
(	O
August	O
12	O
-	O
October	O
4	O
,	O
1981	O
)	O

Withing	O
a	O
week	O
following	O
discharge	O
,	O
the	O
patient	B
again	O
developed	O
fever	O
,	O
nocturnal	O
sweats	O
,	O
and	O
malaise	O
.	O

S	B
.	I
faecium	I
(	O
large	O
colony	O
morphotype	O
,	O
and	O
poorly	O
growing	O
small	O
colony	O
morphotype	O
)	O
grew	O
from	O
six	O
sets	O
of	O
blood	O
cultures	O
obtained	O
on	O
admission	O
.	O

Penicillin	O
(	O
30	O
million	O
units	O
/	O
day	O
)	O
and	O
gentamicin	O
(	O
3	O
mg	O
/	O
kg	O
/	O
day	O
)	O
were	O
again	O
administered	O
,	O
initially	O
achieving	O
peak	O
serum	O
inhibitory	O
and	O
bactericidal	O
dilutions	O
of	O
1	O
:	O
16	O
and	O
1	O
:	O
8	O
against	O
the	O
organism	O
,	O
respectively	O
.	O

However	O
,	O
the	O
organism	O
had	O
a	O
lowlevel	O
resistance	O
to	O
streptomycin	O
(	O
MIC	O
<	O
125	O
/	O
Ag	O
/	O
ml	O
)	O
,	O
and	O
streptomycin	O
(	O
2	O
grams	O
per	O
day	O
)	O
was	O
substituted	O
for	O
gentamicin	O
two	O
weeks	O
into	O
antibiotic	O
therapy	O
.	O

Repeat	O
echocardiograms	O
showed	O
irregular	O
and	O
shaggy	O
densities	O
of	O
both	O
mitral	O
valve	O
leaflets	O
with	O
partial	O
prolapse	O
.	O

Cardiac	O
catheterization	O
demonstrated	O
marked	O
mitral	O
valve	O
prolapse	O
with	O
mitral	O
regurgitation	O
.	O

A	O
radiolucent	O
filling	O
defect	O
was	O
noted	O
,	O
suggesting	O
a	O
coronary	O
artery	O
embolus	O
at	O
the	O
origin	O
of	O
the	O
left	O
anterior	O
descending	O
(	O
LAD	O
)	O
artery	O
,	O
causing	O
75	O
percent	O
occlusion	O
of	O
the	O
lumen	O
.	O

The	O
patient	B
underwent	O
mitral	O
valve	O
replacement	O
,	O
receiving	O
a	O
number	O
31	O
porcine	O
Hancock	O
bioprosthesis	O
and	O
bypass	O
graft	O
to	O
the	O
midportion	O
of	O
the	O
LAD	O
.	O

The	O
mitral	O
valve	O
was	O
thickened	O
with	O
several	O
ruptured	O
chordae	O
of	O
the	O
posterior	O
leaflet	O
noted	O
,	O
but	O
no	O
vegetations	O
.	O

The	O
aortic	O
valve	O
appeared	O
normal	O
,	O
with	O
no	O
visible	O
septal	O
or	O
ring	O
abscesses	O
.	O

The	O
occlusion	O
in	O
the	O
LAD	O
was	O
not	O
approached	O
to	O
avoid	O
embolizing	O
distal	O
fragments	O
.	O

Histopathologically	O
the	O
mitral	O
valve	O
showed	O
mild	O
fibrosis	O
and	O
myxoid	O
degeneration	O
without	O
inflammatory	O
changes	O
.	O

Bacterial	O
and	O
fungal	O
stains	O
were	O
negative	O
but	O
S	B
.	I
faecium	I
grew	O
from	O
fragments	O
of	O
the	O
resected	O
valve	O
.	O

Following	O
surgery	O
the	O
patient	B
received	O
six	O
additional	O
weeks	O
parenteral	O
penicillin	O
and	O
streptomycin	O
.	O

Repeat	O
blood	O
cultures	O
on	O
this	O
regimen	O
and	O
following	O
therapy	O
were	O
negative	O
.	O

Evaluation	O
six	O
months	O
following	O
discontinuation	O
of	O
antibiotics	O
showed	O
no	O
evidence	O
of	O
recurrent	O
endocarditis	O
.	O

LABORATORY	O
EVALUATION	O

The	O
minimum	O
inhibitory	O
and	O
bactericidal	O
concentrations	O
of	O
penicillin	O
,	O
ampicillin	O
,	O
and	O
tobramycin	O
against	O
the	O
S	B
.	I
faecium	I
isolated	O
from	O
the	O
patient	B
'	O
s	O
blood	O
cultures	O

TABLE	O
1	O

Minimum	O
Inhibitory	O
and	O
Bactericidal	O
Concentrations	O
of	O
Antibiotics	O
,	O

Against	O
Streptococcus	B
faecium	I
Isolates	O
from	O
Blood	O
Cultures	O

Date	O
Penicillin	O
Ampicillin	O
Tobramycin	O

Organism	O
Isolated	O
MIC	O
MIC	O
MBC	O
MIC	O
MBC	O
S	B
.	I
faecium	I
,	O
prior	O
to	O
ampicillin	O
/	O

tobramycin	O
therapy	O
3	O
/	O
17	O
/	O
81	O
2	O
1	O
2	O
>	O
32	O
>	O
32	O
S	B
.	I
faecium	I
,	O
after	O
ampicillin	O
/	O

tobramycin	O
therapy	O

a	O
.	O

Large	O
colony	O

variant	O
6	O
/	O
16	O
/	O
81	O
2	O
1	O
1	O
>	O
32	O
>	O
32	O
b	O
.	O

Medium	O
colony	O

variant	O
6	O
/	O
16	O
/	O
81	O
2	O
1	O
2	O
32	O
32	O
c	O
.	O

Small	O
colony	O

variant	O
6	O
/	O
16	O
/	O
81	O
4	O
2	O
4	O
>	O
32	O
>	O
32	O
aMIC	O
and	O
MBC	O
are	O
minimum	O
inhibitory	O
and	O
bactericidal	O
concentrations	O
of	O
antibiotics	O
,	O
respectively	O
,	O
in	O
tig	O
/	O
ml	O
.	O

245	O

GOLDSTEIN	O
ET	O
AL	O
.	O

FIG	O
.	O

1	O
.	O

Time	O
-	O
kill	O
curve	O
demonstrat8	O
3	O
-	O
\	O
"	O
'	O
'	O
ing	O
the	O
effects	O
of	O
various	O
penicillinO	O
aminoglycoside	O
combinations	O
on	O
S	O
.	O

{	O
73	O
2	O
-	O
\	O
>	O
,	O
faecium	O
obtained	O
from	O
the	O
patient	B
'	O
s	O

blood	O
cultures	O
immediately	O
prior	O
to	O
mitral	O
valve	O
excision	O
.	O

Note	O
the	O
lack	O
of	O
4u	O
,	O
synergy	O
between	O
penicillin	O
and	O
tobra25kg	O
/	O
rm	O
Streporrrychn	O
t	O
mycin	O
against	O
this	O
organism	O
when	O

/	O
0	O
units	O
/	O
mI	O
Penicillin	O
_	O
compared	O
to	O
synergistic	O
combinations	O
0	O
4	O
8	O
12	O
6	O
20	O
24	O
of	O
penicillin	O
-	O
gentamicin	O
and	O
penicillin	O

HOURS	O
streptomycin	O
.	O

after	O
initial	O
oral	O
erythromycin	O
therapy	O
,	O
and	O
prior	O
to	O
therapy	O
for	O
endocarditis	O
,	O
are	O
shown	O
in	O
Table	O
1	O
.	O

Following	O
combined	O
therapy	O
with	O
ampicillin	O
and	O
tobramycin	O
and	O
relapse	O
of	O
endocarditis	O
,	O
three	O
morphological	O
variants	O
were	O
isolated	O
from	O
blood	O
cultures	O
and	O
also	O
evaluated	O
.	O

Twenty	O
-	O
four	O
hour	O
time	O
-	O
kill	O
curves	O
for	O
penicillin	O
in	O
combination	O
with	O
various	O
aminoglycosides	O
were	O
performed	O
by	O
Dr	O
.	O
Robert	O
Moellering	O
on	O
the	O
S	B
.	I
faecium	I
isolated	O
from	O
the	O
patient	B
'	O
s	O
blood	O
immediately	O
prior	O
to	O
mitral	O
valve	O
excision	O
and	O
replacement	O
(	O
Fig	O
.	O
1	O
)	O
.	O

Synergy	O
was	O
readily	O
demonstrable	O
against	O
this	O
organism	O
by	O
penicillin	O
-	O
streptomycin	O
and	O
penicillin	O
-	O
gentamicin	O
combinations	O
in	O
vitro	O
,	O
but	O
not	O
by	O
penicillin	O
-	O
tobramycin	O
.	O

DISCUSSION	O

Among	O
streptococci	O
,	O
the	O
enterococci	O
are	O
unusual	O
in	O
their	O
relative	O
resistance	O
to	O
a	O
broad	O
spectrum	O
of	O
antimicrobial	O
agents	O
,	O
and	O
single	O
-	O
agent	O
therapy	O
is	O
rarely	O
bactericidal	O
against	O
them	O
[	O
2	O
]	O
.	O

Since	O
Hunter	O
'	O
s	O
original	O
observations	O
in	O
1947	O
,	O
it	O
has	O
become	O
increasingly	O
clear	O
that	O
effective	O
synergistic	O
combinations	O
of	O
antibiotics	O
are	O
necessary	O
to	O
successfully	O
treat	O
enterococcal	O
endocarditis	O
[	O
1	O
]	O
.	O

Although	O
S	B
.	I
faecalis	I
represents	O
the	O
majority	O
of	O
clinical	O
enterococcal	O
isolates	O
,	O
S	B
.	I
faecium	I
nonetheless	O
comprises	O
5	O
-	O
10	O
percent	O
of	O
these	O
isolates	O
in	O
some	O
series	O
[	O
3	O
,	O
4	O
]	O
.	O

Moreover	O
,	O
major	O
differences	O
exist	O
in	O
antimicrobial	O
susceptibility	O
and	O
resistance	O
to	O
penicillin	O
-	O
aminoglycoside	O
synergism	O
between	O
these	O
two	O
enterococcal	O
species	O
.	O

The	O
MIC	O
of	O
penicillin	O
against	O
S	B
.	I
faecium	I
is	O
higher	O
and	O
this	O
organism	O
is	O
more	O
resistant	O
to	O
a	O
number	O
of	O
different	O
combinations	O
of	O
penicillin	O
and	O
various	O
aminoglycosides	O
than	O
is	O
S	B
.	I
faecalis	I
[	O
6	O
]	O
.	O

The	O
mechanisms	O
of	O
resistance	O
exhibited	O
by	O
enterococci	O
to	O
penicillin	O
-	O
aminoglycoside	O
synergy	O
have	O
been	O
investigated	O
.	O

Clinically	O
achievable	O
levels	O
of	O
amino	O

246	O

S	B
.	I

FAECIUM	B
ENDOCARDITIS	O

glycosides	O
are	O
generally	O
ineffective	O
against	O
enterococci	O
.	O

This	O
intrinsic	O
low	O
-	O
level	O
resistance	O
(	O
MIC	O
c	O
250	O
isg	O
/	O
ml	O
)	O
is	O
thought	O
to	O
be	O
the	O
result	O
of	O
poor	O
antibiotic	O
penetration	O
of	O
the	O
bacterial	O
cell	O
wall	O
.	O

However	O
,	O
in	O
the	O
presence	O
of	O
antibiotics	O
that	O
interfere	O
with	O
cell	O
wall	O
synthesis	O
,	O
there	O
is	O
enhanced	O
aminoglycoside	O
uptake	O
[	O
7	O
]	O
.	O

In	O
concert	O
,	O
these	O
events	O
are	O
the	O
basis	O
for	O
penicillin	O
-	O
aminoglycoside	O
synergism	O
.	O

Ribosomal	O
resistance	O
of	O
the	O
30S	O
subunit	O
to	O
streptomycin	O
and	O
defective	O
uptake	O
of	O
gentamicin	O
in	O
the	O
presence	O
of	O
penicillin	O
have	O
been	O
reported	O
mechanisms	O
of	O
resistance	O
among	O
enterococcal	O
isolates	O
[	O
8	O
,	O
9	O
]	O
.	O

However	O
,	O
in	O
the	O
majority	O
of	O
instances	O
,	O
failure	O
of	O
synergy	O
involves	O
plasmid	O
-	O
mediated	O
production	O
of	O
aminoglycoside	O
-	O
modifying	O
enzymes	O
.	O

For	O
streptomycin	O
and	O
kanamycin	O
,	O
plasmid	O
-	O
mediated	O
enzymatic	O
inactivation	O
confers	O
high	O
-	O
level	O
resistance	O
(	O
MIC	O
>	O
2	O
,	O
000	O
Ag	O
/	O
ml	O
)	O
and	O
correlates	O
with	O
failure	O
of	O
these	O
aminoglycosides	O
to	O
exert	O
a	O
synergistic	O
effect	O
when	O
combined	O
with	O
penicillin	O
[	O
10	O
,	O
11	O
]	O
.	O

Plasmid	O
-	O
mediated	O
modifying	O
enzymes	O
have	O
been	O
found	O
in	O
both	O
S	B
.	I
faecalis	I
and	O
S	B
.	I
faecium	I
'	O
[	O
12	O
]	O
.	O

Currently	O
,	O
approximately	O
one	O
-	O
half	O
of	O
clinical	O
enterococcal	O
isolates	O
demonstrate	O
high	O
-	O
level	O
resistance	O
to	O
streptomycin	O
and	O
kanamycin	O
[	O
13	O
]	O
.	O

Combinations	O
of	O
penicillin	O
with	O
kanamycin	O
,	O
tobramycin	O
,	O
sisomicin	O
,	O
and	O
netilmicin	O
have	O
consistently	O
failed	O
to	O
demonstrate	O
synergistic	O
killing	O
of	O
S	B
.	I
faecium	I
in	O
vitro	O
[	O
6	O
]	O
.	O

This	O
failure	O
of	O
synergy	O
occurs	O
even	O
when	O
high	O
-	O
level	O
resistance	O
to	O
these	O
aminoglycosides	O
is	O
not	O
present	O
.	O

The	O
mechanism	O
of	O
resistance	O
appears	O
to	O
be	O
related	O
to	O
the	O
production	O
of	O
an	O
inactivating	O
enzyme	O
that	O
acetylates	O
the	O
aminoglycoside	O
substrate	O
at	O
the	O
6	O
'	O
position1	O
[	O
14	O
]	O
.	O

The	O
genetic	O
basis	O
for	O
production	O
of	O
this	O
enzyme	O
has	O
not	O
been	O
well	O
-	O
defined	O
and	O
plasmid	O
transfer	O
experiments	O
have	O
thus	O
far	O
been	O
unsucessful	O
in	O
demonstrating	O
the	O
encodement	O
of	O
this	O
enzyme	O
by	O
extrachromosomal	O
DNA	O
[	O
14	O
]	O
.	O

Moellering	O
et	O
al	O
.	O
demonstrated	O
in	O
vivo	O
,	O
utilizing	O
the	O
rabbit	B
model	O
of	O
endocarditis	O
,	O
that	O
penicillin	O
and	O
netilmicin	O
were	O
not	O
efficacious	O
in	O
the	O
treatment	O
of	O
endocarditis	O
caused	O
by	O
a	O
low	O
-	O
level	O
aminoglycoside	O
-	O
resistant	O
strain	O
of	O
S	B
.	I
faecium	I
[	O
6	O
]	O
.	O

Although	O
combinations	O
of	O
penicillin	O
with	O
tobramycin	O
,	O
kanamycin	O
,	O
or	O
sisomicin	O
were	O
not	O
evaluated	O
,	O
the	O
authors	O
postulated	O
that	O
the	O
same	O
ineffectual	O
result	O
would	O
have	O
occurred	O
.	O

In	O
the	O
present	O
case	O
,	O
the	O
recurrence	O
of	O
S	B
.	I
faecium	I
endocarditis	O
after	O
six	O
weeks	O
of	O
therapy	O
with	O
ampicillin	O
and	O
tobramycin	O
confirms	O
the	O
therapeutic	O
and	O
clinical	O
significance	O
of	O
their	O
data	O
,	O
and	O
emphasizes	O
that	O
tobramycin	O
is	O
not	O
an	O
aminoglycoside	O
to	O
be	O
used	O
for	O
treatment	O
of	O
serious	O
S	B
.	I
faecium	I
infections	O
.	O

Bacterial	O
tolerance	O
has	O
been	O
suggested	O
as	O
a	O
possible	O
basis	O
for	O
therapeutic	O
failures	O
,	O
particularly	O
in	O
the	O
treatment	O
of	O
infections	O
caused	O
by	O
Staphylococcus	B
aureus	I
with	O
defects	O
in	O
the	O
production	O
of	O
autolysins	O
.	O

MBCs	O
are	O
generally	O
several	O
-	O
fold	O
higher	O
than	O
MICs	O
and	O
this	O
phenomenon	O
appears	O
to	O
be	O
associated	O
with	O
the	O
autolysin	O
defect	O
[	O
5	O
]	O
.	O

Lorian	O
has	O
also	O
described	O
the	O
formation	O
of	O
numerous	O
aberrant	O
cross	O
-	O
walls	O
by	O
S	B
.	I
faecalis	I
grown	O
in	O
the	O
presence	O
of	O
subinhibitory	O
concentrations	O
of	O
penicillin	O
[	O
15	O
]	O
.	O

MBCs	O
were	O
only	O
slightly	O
higher	O
than	O
MICs	O
for	O
the	O
three	O
S	B
.	I
faecium	I
variants	O
obtained	O
from	O
our	O
patient	B
,	O
and	O
they	O
did	O
not	O
appear	O
to	O
be	O
tolerant	O
strains	O
of	O
S	B
.	I
faecium	I
.	O

There	O
was	O
no	O
evidence	O
that	O
any	O
of	O
the	O
morphological	O
variants	O
isolated	O
were	O
unusually	O
resistant	O
to	O
antibiotics	O
.	O

Therefore	O
,	O
subsequent	O
failure	O
of	O
therapy	O
could	O
not	O
be	O
explained	O
on	O
the	O
basis	O
of	O
antibiotic	O
resistance	O
patterns	O
.	O

The	O
initial	O
failure	O
of	O
ampicillin	O
and	O
tobramycin	O
therapy	O
may	O
have	O
allowed	O
the	O
infecting	O
organism	O
to	O
become	O
better	O
established	O
and	O
more	O
difficult	O
to	O
eradicate	O
from	O
the	O
valve	O
.	O

Alternatively	O
,	O
a	O

'	O
Wennersten	O
C	O
,	O
Moellering	O
RC	O
Jr	O
:	O
Mechanism	O
of	O
resistance	O
to	O
penicillin	O
-	O
aminoglycoside	O
synergism	O
in	O
Streptococcus	B
faecium	I
.	O

Proceedings	O
of	O
the	O
1th	O
International	O
Congress	O
of	O
Chemotherapy	O
and	O
19th	O
Interscience	O
Conference	O
on	O
Antimicrobial	O
Agents	O
and	O
Chemotherapy	O
1	O
:	O
710	O
-	O
711	O
,	O
1979	O

247	O

248	O
GOLDSTEIN	O
ET	O
AL	O
.	O

persistent	O
focus	O
of	O
infection	O
causing	O
the	O
LAD	O
lesion	O
seen	O
by	O
arteriography	O
may	O
have	O
slowly	O
resolved	O
and	O
accounted	O
for	O
the	O
apparent	O
failure	O
to	O
respond	O
to	O
synergistic	O
combinations	O
of	O
antibiotics	O
.	O

In	O
summary	O
,	O
our	O
patient	B
was	O
treated	O
for	O
Streptococcusfaecium	B
endocarditis	O
with	O
both	O
ampicillin	O
and	O
the	O
aminoglycoside	O
antibiotic	O
,	O
tobramycin	O
.	O

Relapse	O
of	O
endocarditis	O
might	O
have	O
been	O
anticipated	O
on	O
the	O
basis	O
of	O
previous	O
experimental	O
data	O
showing	O
lack	O
of	O
synergy	O
when	O
tobramycin	O
is	O
used	O
against	O
this	O
organism	O
.	O

This	O
case	O
graphically	O
illustrates	O
the	O
relevance	O
of	O
synergy	O
studies	O
to	O
therapeutic	O
considerations	O
in	O
the	O
treatment	O
of	O
endocarditis	O
.	O

However	O
,	O
subsequent	O
therapy	O
with	O
synergistic	O
combinations	O
of	O
antibiotics	O
did	O
not	O
result	O
in	O
cure	O
.	O

The	O
data	O
do	O
not	O
implicate	O
tolerant	O
organisms	O
as	O
a	O
cause	O
for	O
relapses	O
.	O

Failure	O
of	O
therapy	O
may	O
have	O
been	O
related	O
to	O
the	O
presence	O
of	O
protected	O
organisms	O
in	O
vegetations	O
which	O
were	O
seen	O
on	O
echocardiograms	O
,	O
and	O
also	O
suggested	O
by	O
the	O
presence	O
of	O
a	O
possible	O
coronary	O
artery	O
embolus	O
seen	O
on	O
coronary	O
arteriograms	O
.	O

In	O
conclusion	O
,	O
speciation	O
of	O
isolates	O
suspected	O
of	O
causing	O
endocarditis	O
and	O
adequate	O
synergy	O
studies	O
of	O
antibiotic	O
combinations	O
are	O
indicated	O
before	O
a	O
long	O
and	O
expensive	O
course	O
of	O
therapy	O
with	O
antimicrobial	O
agents	O
is	O
undertaken	O
for	O
this	O
disease	O
.	O

However	O
,	O
as	O
this	O
case	O
also	O
illustrates	O
,	O
demonstration	O
of	O
synergism	O
in	O
vitro	O
does	O
not	O
assure	O
clinical	O
cure	O
.	O

ACKNOWLEDGEMENTS	O

Dr	O
.	O
Goldstein	O
was	O
supported	O
by	O
training	O
grant	O
Al	O
07033	O
-	O
05	O
from	O
the	O
National	O
Institute	O
of	O
Allergy	O
and	O
Infectious	O
Diseases	O
.	O

The	O
authors	O
gratefully	O
acknowledge	O
the	O
advice	O
,	O
laboratory	O
assistance	O
,	O
and	O
careful	O
review	O
of	O
this	O
manuscript	O
by	O
Dr	O
.	O
Robert	O
C	O
.	O
Moellering	O
,	O
Jr	O
.	O

The	O
authors	O
also	O
wish	O
to	O
thank	O
Dr	O
.	O
Howard	O
S	O
.	O
Forster	O
for	O
referring	O
this	O
patient	B
to	O
us	O
,	O
Ms	O
.	O
Mary	O
Murray	O
and	O
Deborah	O
Beauvais	O
for	O
manuscript	O
preparation	O
,	O
and	O
Ms	O
.	O
Gertrude	O
Barden	O
,	O
MT	O
(	O
ASCP	O
)	O
,	O
MHS	O
,	O
for	O
technical	O
assistance	O
and	O
advice	O
in	O
evaluation	O
of	O
this	O
patient	B
.	O

REFERENCES	O

1	O
.	O

Hunter	O
TH	O
:	O
Use	O
of	O
streptomycin	O
in	O
the	O
treatment	O
of	O
bacterial	O
endocarditis	O
.	O

Am	O
J	O
Med	O
2	O
:	O
436	O
-	O
442	O
,	O

1947	O

2	O
.	O

Moellering	O
RC	O
Jr	O
,	O
Krogstad	O
DJ	O
:	O
Antibiotic	O
resistance	O
in	O
enterococci	O
.	O

Microbiology	O
293	O
-	O
298	O
,	O
1979	O
3	O
.	O

Facklam	O
RR	O
:	O
Recognition	O
of	O
group	O
D	O
streptococcal	O
species	O
of	O
human	B
origin	O
by	O
biochemical	O
and	O

physiological	O
tests	O
.	O

Appl	O
Microbiol	O
23	O
:	O
1131	O
-	O
1139	O
,	O
1972	O

4	O
.	O

Toala	O
P	O
,	O
McDonald	O
A	O
,	O
Wilcox	O
C	O
,	O
et	O
al	O
:	O
Susceptibility	O
of	O
group	O
D	O
streptococcus	O
(	O
enterococcus	O
)	O
to	O
21	O

antibiotics	O
in	O
vitro	O
,	O
with	O
special	O
reference	O
to	O
species	O
differences	O
.	O

Am	O
J	O
Med	O
Sci	O
258	O
:	O
416	O
-	O
430	O
,	O
1969	O
5	O
.	O

Shungu	O
DL	O
,	O
Cornett	O
JB	O
,	O
Shockman	O
GD	O
:	O
Morphological	O
and	O
physiological	O
study	O
of	O
autolytic	O

defective	O
Streptococcus	B
faecium	I
strains	O
.	O

J	O
Bacteriol	O
138	O
:	O
598	O
-	O
608	O
,	O
1979	O

6	O
.	O

Moellering	O
RC	O
Jr	O
,	O
Korzeniowski	O
OM	O
,	O
Sande	O
MA	O
,	O
et	O
al	O
:	O
Species	O
-	O
specific	O
resistance	O
to	O
antimicrobial	O

synergism	O
in	O
Streptococcusfaecium	B
and	O
Streptococcusfaecali	B
.	O

J	O
Infect	O
Dis	O
140	O
:	O
203	O
-	O
208	O
,	O
1979	O

7	O
.	O

Moellering	O
RC	O
Jr	O
,	O
Weinberg	O
AN	O
:	O
Studies	O
on	O
antibiotic	O
synergism	O
against	O
enterococci	O
.	O

11	O
.	O

Effect	O
of	O

various	O
antibiotics	O
on	O
the	O
uptake	O
of	O
'	O
4C	O
-	O
labelled	O
streptomycin	O
by	O
enterococci	O
.	O

J	O
Clin	O
Invest	O
50	O
:	O
2580	O
-	O
2584	O
,	O
1971	O

8	O
.	O

Zimmermann	O
RA	O
,	O
Moellering	O
RC	O
Jr	O
,	O
Weinberg	O
AN	O
:	O
Mechanisms	O
of	O
resistance	O
to	O
antibiotic	O

synergism	O
in	O
enterococci	O
.	O

J	O
Bacteriol	O
105	O
:	O
873	O
-	O
879	O
,	O
1971	O

9	O
.	O

Moellering	O
RC	O
Jr	O
,	O
Murray	O
BE	O
,	O
Schoenbaum	O
SC	O
,	O
et	O
al	O
:	O
A	O
novel	O
mechanism	O
of	O
resistance	O
to	O
penicillin	O

gentamicin	O
synergism	O
in	O
S	B
.	I
faecalis	I
.	O

J	O
Infect	O
Dis	O
141	O
:	O
81	O
-	O
86	O
,	O
1980	O

10	O
.	O

Krogstad	O
DJ	O
,	O
Korfhagen	O
TR	O
,	O
Moellering	O
RC	O
Jr	O
,	O
et	O
al	O
:	O
Plasmid	O
-	O
mediated	O
resistance	O
to	O
antibiotic	O

synergism	O
in	O
enterococci	O
.	O

J	O
Clin	O
Invest	O
61	O
:	O
1645	O
-	O
1653	O
,	O
1978	O

11	O
.	O

Krogstad	O
DJ	O
,	O
Korfhagen	O
TR	O
,	O
Moellering	O
RC	O
Jr	O
,	O
et	O
al	O
:	O
Aminoglycoside	O
-	O
inactivating	O
enzymes	O
in	O

clinical	O
isolates	O
of	O
Streptococcusfaecali	B
:	O
An	O
explanation	O
for	O
resistance	O
to	O
antibiotic	O
synergism	O
.	O

J	O
Clin	O
Invest	O
62	O
:	O
480	O
-	O
486	O
,	O
1978	O

S	B
.	I

FAECIUM	B
ENDOCARDITIS	O
249	O

12	O
.	O

Courvalin	O
PM	O
,	O
Shaw	O
WV	O
,	O
Jacob	O
AE	O
:	O
Plasmid	O
-	O
mediated	O
mechanisms	O
of	O
resistance	O
to	O

aminoglycoside	O
-	O
aminocyclitol	O
antibiotics	O
and	O
to	O
chloramphenicol	O
in	O
group	O
D	O
streptococci	O
.	O

Antimicrob	O
Agents	O
Chemother	O
13	O
:	O
716	O
-	O
725	O
,	O
1978	O

13	O
.	O

Calderwood	O
SA	O
,	O
Wennersten	O
C	O
,	O
Moellering	O
RC	O
Jr	O
,	O
et	O
al	O
:	O
Resistance	O
to	O
six	O
aminoglycosidic	O

aminocyclitol	O
antibiotics	O
among	O
enterococci	O
:	O
Prevalence	O
,	O
evolution	O
,	O
and	O
relationship	O
to	O
synergism	O
with	O
penicillin	O
.	O

Antimicrob	O
Agents	O
Chemother	O
12	O
:	O
401	O
-	O
405	O
,	O
1977	O

14	O
.	O

Bisno	O
AL	O
:	O
Treatment	O
of	O
infective	O
endocarditis	O
.	O

New	O
York	O
,	O
Grune	O
and	O
Stratton	O
,	O
1981	O
,	O
p	O
90	O

15	O
.	O

Lorian	O
V	O
:	O
Effects	O
of	O
subminimum	O
inhibitory	O
concentrations	O
of	O
antibiotics	O
on	O
bacteria	O
.	O

In	O
Antibiotics	O

in	O
Laboratory	O
Medicine	O
.	O

Edited	O
by	O
V	O
Lorian	O
.	O

Baltimore	O
,	O
Williams	O
and	O
Wilkins	O
,	O
1980	O
,	O
p	O
342	O

Structural	O
organization	O
of	O
a	O
17	O
KB	O
segment	O
of	O
the	O
alpha	O
2	O
collagen	O
gene	O
:	O
evaluation	O
by	O
R	O
loop	O
mapping	O
.	O

Abstract	O

A	O
recombinant	O
phage	O
,	O
SpC3	O
,	O
containing	O
a	O
17	O
kb	O
genomic	O
DNA	O
insert	O
representing	O
approximately	O
60	O
%	O
of	O
the	O
3	O
'	O
portion	O
of	O
the	O
sheep	B
collagen	O
alpha	O
2	O
gene	O
,	O
was	O
evaluated	O
by	O
electron	O
microscopic	O
R	O
loop	O
analysis	O
.	O

A	O
minimum	O
of	O
17	O
intervening	O
sequences	O
(	O
introns	O
)	O
and	O
18	O
alpha	O
2	O
coding	O
sequences	O
(	O
exons	O
)	O
were	O
mapped	O
.	O

With	O
the	O
exception	O
of	O
the	O
850	O
base	O
pair	O
exon	O
located	O
at	O
the	O
extreme	O
3	O
'	O
end	O
of	O
the	O
insert	O
,	O
all	O
exons	O
contained	O
250	O
base	O
pairs	O
or	O
less	O
.	O

The	O
total	O
length	O
of	O
all	O
the	O
exons	O
in	O
SpC3	O
was	O
3	O
,	O
014	O
base	O
pairs	O
.	O

The	O
length	O
distribution	O
of	O
the	O
17	O
introns	O
ranged	O
from	O
300	O
to	O
1600	O
base	O
pairs	O
;	O
together	O
,	O
all	O
of	O
the	O
introns	O
comprised	O
14	O
,	O
070	O
base	O
pairs	O
of	O
SpC3	O
DNA	O
.	O

Thus	O
,	O
the	O
DNA	O
region	O
required	O
for	O
coding	O
the	O
interspersed	O
3	O
kb	O
of	O
alpha	O
2	O
collagen	O
genetic	O
information	O
was	O
5	O
.	O
6	O
fold	O
longer	O
than	O
the	O
corresponding	O
alpha	O
2	O
mRNA	O
coding	O
sequences	O
.	O
Images	O

Nucleic	O
Acids	O
Research	O

Structural	O
organization	O
of	O
a	O
17	O
KB	O
segment	O
of	O
the	O
a2	O
collagen	O
gene	O
:	O
evaluation	O
by	O
R	O
loop	O
mapping	O
Millie	O
P	O
.	O
Schafer	O
,	O
Charles	O
D	O
.	O
Boyd	O
,	O
Paul	O
Tolstoshev	O
and	O
Ronald	O
G	O
.	O
Crystal	O

Pulmonary	O
Branch	O
,	O
National	O
Heart	O
,	O
Lung	O
and	O
Blood	O
Institute	O
,	O
National	O
Institutes	O
of	O
Health	O
,	O
Bethesda	O
,	O
MD	O
20205	O
,	O
USA	O

Received	O
13	O
February	O
1980	O

ABSTRACT	O

A	O
recombinant	O
phage	O
,	O
SpC3	O
,	O
containing	O
a	O
17	O
kb	O
genomic	O
DNA	O
insert	O
rep	O

resenting	O
approximately	O
60	O
%	O
of	O
the	O
3	O
'	O
portion	O
of	O
the	O
sheep	B
collagen	O
a2	O
gene	O
,	O
was	O
evaluated	O
by	O
electron	O
microscopic	O
R	O
loop	O
analysis	O
.	O

A	O
minimum	O
of	O
17	O
intervening	O
sequences	O
(	O
introns	O
)	O
and	O
18	O
a2	O
coding	O
sequences	O
(	O
exons	O
)	O
were	O

mapped	O
.	O

With	O
the	O
exception	O
of	O
the	O
850	O
base	O
pair	O
exon	O
located	O
at	O
the	O
extreme	O
3	O
'	O
end	O
of	O
the	O
insert	O
,	O
all	O
exons	O
contained	O
250	O
base	O
pairs	O
or	O
less	O
.	O

The	O
total	O
length	O
of	O
all	O
the	O
exons	O
in	O
SpC3	O
was	O
3	O
,	O
014	O
base	O
pairs	O
.	O

The	O
length	O
distribution	O
of	O
the	O
17	O
introns	O
ranged	O
from	O
300	O
to	O
1600	O
base	O
pairs	O
;	O
together	O
,	O
all	O
of	O
the	O
introns	O
comprised	O
14	O
,	O
070	O
base	O
pairs	O
of	O
SpC3	O
DNA	O
.	O

Thus	O
,	O
the	O
DNA	O
region	O

required	O
for	O
coding	O
the	O
interspersed	O
3	O
kb	O
of	O
a2	O
collagen	O
genetic	O
information	O
was	O
5	O
.	O
6	O
fold	O
longer	O
than	O
the	O
corresponding	O
a2	O
mRNA	O
coding	O
sequences	O
.	O

INTRODUCTION	O

Type	O
I	O
collagen	O
,	O
composed	O
of	O
two	O
al	O
(	O
I	O
)	O
and	O
one	O
a2	O
polypeptide	O
chains	O
,	O
is	O
the	O
most	O
abundant	O
of	O
the	O
five	O
known	O
mammalian	O
collagen	O
types	O
.	O

It	O
is	O
a	O
major	O
extracellular	O
constituent	O
of	O
tissues	O
such	O
as	O
bone	O
,	O
tendon	O
,	O
skin	O
and	O
lung	O
where	O
,	O
because	O
of	O
its	O
great	O
tensile	O
strength	O
,	O
it	O
plays	O
an	O
important	O

role	O
in	O
tissue	O
structure	O
and	O
function	O
.	O

The	O
polypeptides	O
comprising	O
type	O
I	O

collagen	O
are	O
synthesized	O
in	O
long	O
,	O
precursor	O
forms	O
,	O
referred	O
to	O
as	O
pro	O
al	O
(	O
I	O
)	O
and	O
pro	O
a2	O
chains	O
,	O
1	O
each	O
containing	O
approximately	O
1500	O
amino	O
acid	O
residues	O
(	O
1	O
)	O
.	O

1	O
The	O
terminology	O
for	O
the	O
primary	O
translation	O
products	O
of	O
the	O
various	O

collagen	O
messenger	O
RNAs	O
is	O
still	O
in	O
a	O
state	O
of	O
flux	O
.	O

It	O
is	O
known	O
that	O
al	O
(	O
I	O
)	O
and	O
a2	O
chains	O
are	O
synthesized	O
in	O
precursor	O
forms	O
;	O
these	O
are	O
currently	O
termed	O
pro	O
al	O
(	O
I	O
)	O
and	O
pro	O
a2	O
chains	O
(	O
1	O
)	O
.	O

However	O
,	O
recent	O
studies	O
(	O
43	O
,	O
44	O
)	O
have	O
shown	O
that	O
the	O
actual	O
primary	O
translation	O
product	O
of	O
al	O
(	O
I	O
)	O
mRNA	O
is	O
somewhat	O
larger	O

than	O
the	O
pro	O
al	O
(	O
I	O
)	O
chain	O
;	O
this	O
translation	O
product	O
has	O
been	O
termed	O
a	O
"	O
pre	O
-	O
pro	O
al	O
(	O
I	O
)	O
chain	O
.	O
"	O
Although	O
the	O
corresponding	O
"	O
pre	O
-	O
pro	O
a2	O
chain	O
"	O
likely	O
exists	O
,	O
it	O
has	O
not	O
yet	O
been	O
characterized	O
.	O

For	O
simplicity	O
,	O
therefore	O
,	O
until	O
the	O

proper	O
terminology	O
for	O
the	O
primary	O
translation	O
product	O
is	O
clarified	O
,	O
we	O
have	O

chosen	O
to	O
use	O
the	O
terms	O
"	O
al	O
(	O
I	O
)	O
"	O
and	O
"	O
a2	O
"	O
to	O
refer	O
to	O
the	O
type	O
I	O
collagen	O
mRNAs	O
and	O
collagen	O
structural	O
gene	O
sequences	O
.	O

?	O
)	O
IRL	O
Press	O
Umited	O
,	O
1	O
Falconberg	O
Court	O
,	O
London	O
W1V	O
5FG	O
,	O
U	O
.	O
K	O
.	O

Volurne	O
8	O
Number	O
10	O
1980	O

2241	O

Nucleic	O
Acids	O
Research	O

There	O
is	O
increasing	O
evidence	O
that	O
the	O
quantities	O
of	O
al	O
(	O
I	O
)	O
and	O
a2	O

chains	O
produced	O
by	O
cells	O
may	O
be	O
regulated	O
,	O
in	O
part	O
,	O
at	O
the	O
genomic	O
level	O

(	O
1	O
)	O
.	O

However	O
,	O
to	O
understand	O
the	O
processes	O
which	O
mediate	O
their	O
expression	O
,	O

it	O
is	O
necessary	O
to	O
understand	O
the	O
structural	O
organization	O
of	O
these	O
collagen	O
genes	O
and	O
the	O
various	O
enzymes	O
that	O
modify	O
the	O
collagen	O
chains	O
after	O
its	O

synthesis	O
(	O
1	O
)	O
.	O

As	O
an	O
initial	O
approach	O
to	O
this	O
problem	O
,	O
we	O
have	O
recently	O

isolated	O
a	O
recombinant	O
bacteriophage	O
,	O
termed	O
SpC3	O
,	O
containing	O
approximately	O
60	O
%	O
of	O
the	O
a2	O
gene	O
for	O
type	O
I	O
collagen	O
.	O

Partial	O
characterization	O
of	O
this	O

a2	O
gene	O
demonstrated	O
that	O
,	O
like	O
most	O
other	O
structurally	O
evaluated	O
eukaryotic	O
genes	O
,	O
the	O
coding	O
sequences	O
are	O
interspersed	O
with	O
intervening	O
sequences	O
(	O
2	O
)	O
.	O

The	O
present	O
study	O
further	O
characterizes	O
this	O
portion	O
of	O
the	O
a2	O

gene	O
by	O
utilizing	O
electron	O
microscopic	O
R	O
loop	O
analysis	O
to	O
map	O
the	O
coding	O
regions	O
(	O
exons	O
)	O
and	O
intervening	O
sequences	O
(	O
introns	O
)	O
contained	O
within	O
the	O
sheep	B
genomic	O
insert	O
of	O
SpC3	O
.	O

The	O
data	O
suggests	O
that	O
the	O
structural	O

organization	O
of	O
this	O
portion	O
of	O
the	O
a2	O
collagen	O
gene	O
represents	O
3	O
kb	O
of	O
coding	O
information	O
that	O
is	O
interspersed	O
in	O
a	O
complex	O
fashion	O
with	O
17	O
introns	O
over	O
17	O
kb	O
of	O
genome	O
.	O

MATERIALS	O
AND	O
METHODS	O

Isolation	O
and	O
characterization	O
of	O
a2	O
collagen	O
recombinant	O
clone	O
,	O
SpC3	O
.	O

The	O
sheep	B
a2	O
collagen	O
recombinant	O
clone	O
,	O
SpC3	O
,	O
containing	O
a	O
portion	O
of	O
the	O
sheep	B
a2	O
gene	O
,	O
was	O
isolated	O
as	O
previously	O
described	O
(	O
2	O
)	O
.	O

Briefly	O
,	O

high	O
molecular	O
weight	O
fetal	O
sheep	B
liver	O
DNA	O
was	O
extracted	O
by	O
the	O
method	O
of	O
Blin	O
and	O
Stafford	O
(	O
3	O
)	O
,	O
and	O
15	O
-	O
20	O
kb	O
DNA	O
fragments	O
,	O
resulting	O
from	O
partial	O
Eco	O
RI	O
digestion	O
,	O
were	O
isolated	O
and	O
ligated	O
to	O
the	O
left	O
and	O
right	O
arms	O
of	O
Charon	O
4A	O
.	O

The	O
recombinant	O
DNA	O
was	O
then	O
packaged	O
in	O
vitro	O
and	O
the	O
sheep	B

genomic	O
library	O
amplified	O
(	O
4	O
-	O
6	O
)	O
.	O

Screening	O
of	O
the	O
sheep	B
genomic	O
library	O
was	O

conducted	O
utilizing	O
[	O
32	O
P	O
]	O
-	O
labeled	O
fetal	O
sheep	B
tendon	O
type	O
I	O
collagen	O
cDNA	O
and	O

several	O
positive	O
recombinant	O
phages	O
were	O
isolated	O
.	O

One	O
recombinant	O
,	O
containing	O
a	O
17	O
kb	O
sheep	B
genomic	O
insert	O
,	O
was	O
demonstrated	O
to	O
have	O
coding	O
sequences	O
corresponding	O
to	O
60	O
%	O
of	O
the	O
3	O
'	O
end	O
of	O
a2	O
mRNA	O
.	O

Prior	O
studies	O
showed	O
that	O
the	O
insert	O
in	O
SpC3	O
was	O
not	O
due	O
to	O
ligation	O
of	O
noncontiguous	O
restriction	O
fragments	O
and	O
/	O
or	O
genetic	O
rearrangement	O
during	O
the	O
cloning	O
process	O
(	O
2	O
)	O
.	O

Electron	O
mi	O
croscopy	O
.	O

To	O
visualize	O
the	O
recombinant	O
bacteriophage	O
DNA	O
structure	O
complementary	O
to	O
a2	O
collagen	O
mRNA	O
,	O
1	O
iig	O
of	O
SpC3	O
DNA	O
was	O
lyophilized	O
with	O
1	O
ig	O
or	O
100	O
ng	O
of	O
mRNA	O

to	O
give	O
DNA	O
:	O
mRNA	O
ratios	O
of	O
1	O
:	O
1	O
and	O
10	O
:	O
1	O
,	O
respectively	O
.	O

These	O
were	O
then	O
dissolved	O
in	O
10	O
i1	O
of	O
R	O
loop	O
buffer	O
[	O
70	O
%	O
(	O
v	O
/	O
v	O
)	O
deionized	O
formamide	O
,	O
0	O
.	O
1	O
N	O
-	O
[	O
tris	O
(	O
hydroxy	O

2242	O

Nucleic	O
Acids	O
Research	O

methyl	O
)	O
methyl	O
]	O
glycine	O
(	O
tricine	O
)	O
-	O
NaOH	O
,	O
pH	O
8	O
.	O
0	O
,	O
0	O
.	O
5	O
M	O
NaCl	O
,	O
and	O
0	O
.	O
01	O
M	O
ethyl	O

enediaminetetraaceta	O
(	O
EDTA	O
)	O
]	O
,	O
incubated	O
in	O
sealed	O
capillary	O
tubes	O
at	O
520	O
for	O
14	O
hr	O
(	O
7	O
)	O
,	O
and	O
then	O
diluted	O
1	O
:	O
10	O
with	O
R	O
loop	O
buffer	O
.	O

Two	O
spreading	O
methods	O
were	O
used	O
to	O
subsequently	O
prepare	O
the	O
hybrids	O
for	O
visualization	O
in	O
the	O
electron	O
microscope	O
.	O

70	O
%	O
formamide	O
method	O
.	O

Immediately	O
before	O
spreading	O
onto	O
a	O
deionized	O

water	O
hypophase	O
,	O
the	O
nucleic	O
acid	O
mixtures	O
were	O
diluted	O
an	O
additional	O
10	O
-	O
fold	O
in	O
R	O
loop	O
buffer	O
and	O
cytochrome	O
c	O
,	O
100	O
vg	O
/	O
ml	O
,	O
was	O
added	O
.	O

Urea	O
-	O
formamide	O
method	O
.	O

The	O
nucleic	O
acid	O
solutions	O
were	O
spread	O
using	O
a	O
modification	O
of	O
the	O
method	O
of	O
Westphal	O
and	O
Lai	O
(	O
8	O
,	O
9	O
)	O
.	O

The	O
hyperphase	O
contained	O
55	O
%	O
formamide	O
,	O
2	O
.	O
6	O
M	O
urea	O
,	O
0	O
.	O
009	O
M	O
EDTA	O
,	O
0	O
.	O
09	O
M	O
tricine	O
-	O
NaOH	O
,	O
pH	O
8	O
.	O
0	O
,	O
and	O
the	O
nucleic	O
acid	O
mixture	O
(	O
approximately	O
0	O
.	O
1	O
to	O
1	O
.	O
0	O
ig	O
/	O
ml	O
)	O
.	O

The	O
mixture	O
was	O
heated	O
at	O
40	O
?	O
for	O
30	O
sec	O
,	O
placed	O
in	O
ice	O
water	O
,	O
and	O
then	O
allowed	O
to	O
reach	O
room	O
temperature	O
.	O

Cytochrome	O
c	O
,	O
100	O
pg	O
/	O
ml	O
,	O
was	O
added	O
immediately	O
before	O
spreading	O
onto	O
a	O
deionized	O
water	O
hypophase	O
.	O

The	O
nucleic	O
acid	O
-	O
protein	O
films	O
from	O
both	O
methods	O
were	O
absorbed	O
onto	O

parlodion	O
-	O
coated	O
grids	O
,	O
stained	O
with	O
uranyl	O
acetate	O
(	O
10	O
)	O
,	O
dehydrated	O
in	O
90	O
%	O
ethanol	O
and	O
rotary	O
-	O
shadowed	O
with	O
platinum	O
-	O
palladium	O
(	O
80	O
:	O
20	O
)	O
at	O
an	O
angle	O
of	O
50	O
.	O

Micrographs	O
were	O
taken	O
with	O
a	O
Siemens	O
Elmiskop	O
101	O
electron	O
microscope	O
at	O
an	O
original	O
magnification	O
of	O
10	O
,	O
000	O
and	O
an	O
accelerating	O
voltage	O
of	O
60	O
kv	O
.	O

Nucleic	O
acid	O
lengths	O
were	O
measured	O
at	O
a	O
final	O
magnification	O
of	O
43	O
,	O
000	O
with	O
a	O

Hewlett	O
-	O
Packard	O
9810A	O
calculator	O
equipped	O
with	O
a	O
9864A	O
digitizer	O
using	O
pBR322	O
and	O
fX	O
-	O
174	O
double	O
and	O
single	O
stranded	O
DNA	O
,	O
respectively	O
,	O
as	O
internal	O
length	O
standards	O
.	O

Approximately	O
10	O
,	O
000	O
hybrid	O
molecules	O
were	O
screened	O
for	O
these	O
studies	O
;	O
approximately	O
200	O
represented	O
molecules	O
containing	O
unambiguous	O
regions	O

appropriate	O
for	O
quantitative	O
analysis	O
.	O

The	O
mean	O
lengths	O
of	O
each	O
intron	O
and	O
exon	O
were	O
determined	O
for	O
each	O
method	O
and	O
the	O
data	O
expressed	O
as	O
mean	O
?	O

standard	O
deviation	O
.	O

Nucleic	O
acid	O
lengths	O
of	O
<	O
50	O
base	O
pairs	O
could	O
not	O
be	O

accurately	O
determined	O
using	O
the	O
methods	O
outlined	O
above	O
.	O

Thus	O
,	O
in	O
the	O
cases	O

where	O
introns	O
or	O
exons	O
were	O
of	O
this	O
length	O
or	O
less	O
,	O
accurate	O
error	O
estimates	O
could	O
not	O
be	O
made	O
.	O

Bi	O
ohazard	O
precauti	O
ons	O
.	O

The	O
construction	O
and	O
screening	O
of	O
the	O
sheep	B
genomic	O
library	O
together	O
with	O
amplification	O
of	O
pCg45	O
and	O
preparation	O
of	O
high	O
titre	O
lysates	O
of	O
chimaeric	O

Charon	O
4A	O
were	O
performed	O
under	O
the	O
physical	O
and	O
biological	O
containment	O
levels	O
specified	O
by	O
the	O
NIH	O
guidelines	O
for	O
recombinant	O
DNA	O
research	O
(	O
11	O
)	O
.	O

2243	O

Nucleic	O
Acids	O
Research	O

RESULTS	O

Location	O
and	O
orientation	O
of	O
the	O
intervening	O
and	O
a2	O
mRNA	O
coding	O
sequences	O
in	O
the	O
SpC3	O
recombinant	O
DNA	O
.	O

Hybridization	O
of	O
fetal	O
sheep	B
tendon	O
type	O
I	O
collagen	O
mRNA	O
to	O
SpC3	O
DNA	O

yielded	O
a	O
complex	O
R	O
loop	O
pattern	O
in	O
the	O
region	O
where	O
the	O
sheep	B
genomic	O
insert	O
was	O
expected	O
to	O
be	O
ligated	O
to	O
the	O
arms	O
of	O
the	O
lambda	O
vector	O
,	O
Charon	O
4A	O
.	O

To	O

confirm	O
that	O
these	O
hybridization	O
events	O
were	O
restricted	O
to	O
the	O
inserted	O
sheep	B
DNA	O
fragment	O
,	O
duplex	O
DNA	O
strands	O
on	O
both	O
sides	O
of	O
this	O
hybridization	O
area	O
were	O
measured	O
.	O

Using	O
pBR322	O
as	O
an	O
internal	O
length	O
standard	O
,	O
the	O
left	O
arm	O
of	O
the	O
phage	O
was	O
found	O
to	O
contain	O
21	O
,	O
780	O
?	O

1500	O
bp	O
,	O
and	O
the	O
right	O
arm	O
,	O
11	O
,	O
950	O
?	O

1030	O
bp	O
,	O
corresponding	O
to	O
the	O
report	O
values	O
for	O
the	O
left	O
and	O
right	O
arms	O
,	O
respectively	O
,	O
of	O
Charon	O
4A	O
DNA	O
(	O
5	O
,	O
6	O
)	O
.	O

The	O
hybridization	O
of	O
SpC3	O
to	O
a2	O
mRNA	O
resulted	O
in	O
the	O
destabilization	O
of	O

the	O
inserted	O
helical	O
duplex	O
DNA	O
fragment	O
such	O
that	O
one	O
DNA	O
strand	O
was	O
displaced	O
(	O
Figure	O
1	O
)	O
.	O

Occasionally	O
,	O
the	O
displaced	O
DNA	O
strand	O
was	O
mostly	O
absent	O
,	O
probably	O
due	O
to	O
fragmentation	O
induced	O
by	O
accidental	O
mechanical	O
shearing	O
.	O

This	O
event	O
considerably	O
enhanced	O
the	O
visualization	O
and	O
ordering	O
of	O
the	O
introns	O
.	O

As	O
the	O
a2	O
mRNA	O
annealed	O
to	O
complementary	O
DNA	O
regions	O
present	O
in	O
one	O

DNA	O
strand	O
,	O
numerous	O
single	O
-	O
stranded	O
loops	O
resulted	O
.	O

These	O
loops	O
,	O
referred	O
to	O
as	O
introns	O
,	O
represented	O
DNA	O
sequences	O
not	O
complementary	O
to	O
the	O
mRNA	O
.	O

Although	O
,	O
by	O
convention	O
,	O
introns	O
are	O
usually	O
sequentially	O
labeled	O
5	O
'	O
to	O
3	O
'	O
,	O
an	O
opposite	O
order	O
had	O
to	O
be	O
employed	O
in	O
this	O
case	O
as	O
SpC3	O
does	O
not	O
contain	O
the	O
sequences	O
coding	O
for	O
the	O
5	O
'	O
end	O
of	O
sheep	B
a2	O
mRNA	O
.	O

Infrequently	O
,	O
all	O
introns	O

were	O
clearly	O
observed	O
within	O
the	O
same	O
hybrid	O
molecule	O
(	O
Figure	O
1	O
)	O
.	O

The	O
largest	O
introns	O
were	O
towards	O
the	O
left	O
arm	O
of	O
Charon	O
4A	O
and	O
were	O
more	O
clustered	O
than	O
the	O
introns	O
at	O
the	O
opposite	O
end	O
of	O
the	O
hybrid	O
.	O

Thus	O
,	O
much	O
of	O
the	O
genetic	O

information	O
coding	O
for	O
the	O
a2	O
mRNA	O
was	O
contained	O
in	O
that	O
half	O
of	O
the	O
hybrid	O
attached	O
to	O
the	O
right	O
arm	O
.	O

A	O
small	O
non	O
-	O
hybridized	O
tail	O
was	O
consistently	O
found	O
in	O
the	O
region	O
where	O

the	O
right	O
arm	O
of	O
the	O
phage	O
was	O
ligated	O
to	O
the	O
sheep	B
genomic	O
insert	O
(	O
Figure	O
1	O
)	O
.	O

This	O
tail	O
likely	O
corresponded	O
to	O
the	O
3	O
'	O
poly	O
A	O
sequence	O
of	O
the	O
a2	O
mRNA	O
.	O

At	O

the	O
extreme	O
5	O
'	O
end	O
of	O
the	O
insert	O
,	O
a	O
variable	O
length	O
was	O
often	O
observed	O
for	O
the	O
remaining	O
unhybridized	O
mRNA	O
strand	O
.	O

This	O
was	O
most	O
likely	O
due	O
to	O
the	O
size	O
heterogeneity	O
of	O
the	O
a2	O
mRNA	O
used	O
in	O
these	O
studies	O
.	O

Size	O
determination	O
and	O
comparative	O
analysis	O
of	O
SpC3	O
introns	O
.	O

Although	O
localization	O
of	O
exon	O
and	O
intron	O
sequences	O
was	O
possible	O
with	O
both	O
the	O
70	O
%	O
formamide	O
and	O
urea	O
-	O
formamide	O
spreading	O
methods	O
,	O
the	O
probability	O
of	O

detecting	O
unambiguous	O
regions	O
in	O
a	O
hybrid	O
molecule	O
was	O
far	O
greater	O
with	O
the	O

2244	O

Nucleic	O
Acids	O
Research	O

A	O
B	O
'	O
,	O
:	O
'	O
14	O
.	O
0	O
.	O

13	O

7	O
1	O

-	O
5	O
13	O

.	O
.	O

.	O
.	O

,	O
4	O
x2	O
%	O
.	O

N1	O

9	O

>	O
10	O
R	O
4	O

Figure	O
1	O
.	O

Electron	O
microscopic	O
visualization	O
of	O
all	O
17	O
introns	O
and	O
18	O
exons	O

from	O
hybrid	O
molecules	O
formed	O
between	O
recombinant	O
clone	O
SpC3	O
DNA	O
and	O
fetal	O
sheep	B

tendon	O
a2	O
mRNA	O
.	O

(	O
A	O
,	O
B	O
)	O
Shown	O
are	O
the	O
double	O
-	O
stranded	O
segment	O
of	O
the	O
right	O
arm	O
CR	O
)	O
of	O
Charon	O
4A	O
;	O
double	O
-	O
stranded	O
segment	O
of	O
the	O
left	O
arm	O
CL	O
)	O
of	O
Charon	O
4A	O
;	O
the	O

displaced	O
single	O
-	O
stranded	O
DNA	O
segment	O
of	O
the	O
insert	O
(	O
5	O
)	O
;	O
single	O
-	O
stranded	O
DNA	O
loops	O
representing	O
introns	O
sequentially	O
labeled	O
1	O
through	O
17	O
in	O
the	O
3	O
'	O
to	O
5	O
'	O
direction	O
;	O
and	O
18	O
regions	O
of	O
insert	O
DNA	O
sequences	O
hybridized	O
to	O
ct2	O
mRNA	O

-	O
-	O
-	O
-	O
)	O
.	O

(	O
C	O
,	O
D	O
)	O
Similar	O
to	O
(	O
A	O
,	O
B	O
)	O
but	O
the	O
single	O
-	O
stranded	O
DNA	O
segment	O
(	O
5	O
)	O
of	O
the	O
insert	O
is	O
mostly	O
absent	O
.	O

The	O
urea	O
-	O
formamide	O
spreading	O
method	O
,	O
as	O
described	O
in	O
Materials	O
and	O
Methods	O
,	O
was	O
employed	O
.	O

2245	O

Nucleic	O
Acids	O
Research	O

urea	O
-	O
formamide	O
method	O
than	O
with	O
the	O
70	O
%	O
formamide	O
procedure	O
.	O

For	O
this	O
reason	O
,	O
most	O
measurements	O
were	O
made	O
with	O
the	O
urea	O
-	O
formamide	O
method	O
(	O
Tables	O
1	O
,	O
2	O
)	O
.	O

For	O

example	O
,	O
the	O
lowest	O
probability	O
event	O
,	O
the	O
detection	O
of	O
intron	O
17	O
and	O
the	O
surrounding	O
small	O
exons	O
,	O
"	O
q	O
"	O
and	O
"	O
r	O
"	O
,	O
was	O
only	O
observed	O
by	O
way	O
of	O
the	O
ureaformamide	O
spreading	O
procedure	O
.	O

The	O
smallest	O
introns	O
,	O
7	O
and	O
12	O
,	O
were	O
found	O
to	O
contain	O
approximately	O

the	O
same	O
number	O
of	O
bases	O
.	O

Introns	O
1	O
through	O
8	O
,	O
representing	O
the	O
DNA	O
sequences	O
which	O
split	O
the	O
a2	O
coding	O
sequence	O
corresponding	O
to	O
the	O
3	O
'	O
end	O
of	O
the	O
a2	O
mRNA	O
,	O
varied	O
in	O
length	O
over	O
approximately	O
a	O
2	O
.	O
4	O
-	O
fold	O
range	O
.	O

With	O
the	O
exception	O
of	O

Table	O
1	O
.	O

Electron	O
microscopic	O
R	O
loop	O
analysis	O

present	O
in	O
SpC3	O
DNA1	O
.	O

of	O
the	O
sheep	B
a2	O
introns	O

SpC3	O
was	O
hybridized	O
to	O
sheep	B
a2	O
mRNA	O
as	O
described	O
in	O
Materials	O
and	O
Methods	O
;	O
intron	O
lengths	O
were	O
determined	O
by	O
comparison	O
with	O
*	O
X	O
-	O
174	O
DNA	O
lengths	O
.	O

2	O
Introns	O
are	O
designated	O
sequentially	O
3	O
'	O
to	O
5	O
'	O
.	O

3	O
All	O
data	O
is	O
presented	O
as	O
mean	O
?	O

standard	O
deviation	O
.	O

4	O
Intron	O
17	O
was	O
visualized	O
only	O
by	O
the	O
urea	O
-	O
formamide	O
method	O
.	O

2246	O

70	O
%	O
Formamide	O
Method	O
Urea	O
-	O
Formamide	O
Method	O

Intron2	O
Number	O
of	O
Intron	O
length	O
Number	O
of	O
Intron	O
length	O

introns	O
analyzed	O
(	O
bases	O
)	O
introns	O
analyzed	O
(	O
bases	O
)	O

1	O
10	O
819	O
t	O
063	O
35	O
806	O
t	O
76	O
2	O
12	O
771	O
?	O

89	O
46	O
757	O
t	O
78	O
3	O
11	O
458	O
?	O

58	O
47	O
464	O
?	O

66	O
4	O
6	O
627	O
?	O

53	O
41	O
611	O
?	O

73	O
5	O
5	O
554	O
?	O

51	O
34	O
562	O
?	O

76	O
6	O
6	O
675	O
?	O

19	O
40	O
684	O
?	O

76	O
7	O
5	O
386	O
?	O

48	O
50	O
342	O
?	O

54	O
8	O
7	O
771	O
?	O

84	O
49	O
757	O
?	O

82	O
9	O
8	O
1	O
,	O
181	O
?	O

94	O
52	O
1	O
,	O
124	O
?	O
122	O
10	O
8	O
1	O
,	O
133	O
?	O
106	O
53	O
1	O
,	O
124	O
?	O
137	O
11	O
10	O
964	O
t	O
?	O
79	O
61	O
952	O
?	O
105	O
12	O
9	O
362	O
?	O

77	O
62	O
342	O
?	O

71	O
13	O
4	O
723	O
?	O
222	O
53	O
806	O
?	O
105	O
14	O
4	O
1	O
,	O
085	O
?	O
142	O
53	O
1	O
,	O
075	O
?	O
105	O
15	O
3	O
795	O
?	O

60	O
47	O
806	O
?	O
100	O
16	O
2	O
1	O
,	O
229	O
?	O

48	O
43	O
1	O
,	O
319	O
?	O
146	O
174	O
-	O
-	O
12	O
1	O
,	O
539	O
?	O
166	O

1	O

Nucleic	O
Acids	O
Research	O

Table	O
2	O
.	O

Electron	O
microscopic	O
R	O
loop	O
analysis	O
of	O
the	O
sheep	B
a2	O
exons	O

present	O
in	O
SpC3	O
DNA1	O
.	O

70	O
%	O
Formamide	O
Method	O
Urea	O
-	O
Formamide	O
Method	O

Exon2	O
Number	O
of	O
Exon	O
length	O
Number	O
of	O
Exon	O
length	O

exons	O
analyzed	O
(	O
base	O
pairs	O
)	O
exons	O
analyzed	O
(	O
base	O
pairs	O
)	O

a	O
7	O
807	O
?	O

883	O
26	O
883	O
?	O
132	O
b	O
10	O
252	O
?	O

35	O
41	O
234	O
?	O

49	O
c	O
11	O
151	O
?	O

25	O
48	O
182	O
?	O

42	O
d	O
6	O
252	O
?	O

60	O
44	O
234	O
?	O

62	O
e	O
5	O
126	O
?	O

45	O
37	O
129	O
?	O

47	O
f	O
5	O
126	O
?	O

38	O
35	O
104	O
?	O

41	O
9	O
5	O
176	O
?	O

48	O
40	O
182	O
?	O

54	O
h	O
5	O
100	O
?	O

43	O
47	O
104	O
?	O

31	O

7	O
100	O
?	O

35	O
50	O
104	O
?	O

28	O
j	O
7	O
126	O
?	O

48	O
45	O
130	O
?	O

47	O
k	O
8	O
50	O
?	O

48	O
51	O
52	O
?	O

39	O
1	O
9	O
75	O
?	O

10	O
60	O
52	O
?	O

44	O
m	O
6	O
126	O
?	O

43	O
51	O
182	O
?	O

54	O
n	O
4	O
100	O
?	O

45	O
53	O
52	O
?	O

42	O
o	O
3	O
<	O
504	O
50	O
78	O
?	O

36	O
p	O
2	O
126	O
?	O

71	O
47	O
104	O
?	O

36	O
q5	O
-	O
_	O
33	O
130	O
?	O
47	O
r5	O
r	O
6	O
78	O
?	O
36	O

SpC3	O
was	O
hybridized	O
to	O
sheep	B
a2	O
mRNA	O
as	O
described	O
in	O
M4aterials	O
and	O

Methods	O
;	O
exon	O
lengths	O
were	O
determined	O
by	O
comparison	O
with	O
pBR322	O
DNA	O
lengths	O
.	O

2	O
Exons	O
are	O
designated	O
sequentially	O
3	O
'	O
to	O
5	O
'	O
.	O

3	O
All	O
data	O
is	O
presented	O
as	O
mean	O
?	O

standard	O
deviation	O
.	O

4	O
5	O

No	O
statistical	O
evaluation	O
was	O
possible	O
because	O
of	O
the	O
size	O
of	O
the	O
exon	O
(	O
see	O
(	O
Materials	O
and	O
Methods	O
)	O
.	O

Exons	O
q	O
and	O
r	O
were	O
only	O
analyzed	O
by	O
the	O
urea	O
-	O
formamide	O
method	O
.	O

intron	O
1	O
,	O
the	O
nucleotide	O
size	O
of	O
these	O
introns	O
was	O
less	O
than	O
800	O
bases	O
.	O

In	O
contrast	O
,	O
introns	O
9	O
through	O
17	O
varied	O
over	O
a	O
4	O
.	O
5	O
-	O
fold	O
range	O
.	O

Except	O
for	O
intron	O
12	O
,	O
all	O
of	O
the	O
introns	O
9	O
through	O
17	O
contained	O
800	O
bases	O
or	O
more	O
.	O

Summation	O
of	O
introns	O
1	O
through	O
16	O
for	O
the	O
70	O
%	O
formamide	O
and	O
urea	O

formamide	O
spreading	O
methods	O
yielded	O
12	O
,	O
533	O
and	O
12	O
,	O
531	O
bases	O
,	O
respectively	O
.	O

However	O
,	O
detection	O
of	O
intron	O
17	O
by	O
the	O
urea	O
-	O
formamide	O
method	O
indicates	O
that	O

the	O
actual	O
summed	O
value	O
for	O
the	O
intervening	O
sequences	O
of	O
SpC3	O
is	O
14	O
,	O
070	O
bases	O
.	O

2247	O

1	O

Nucleic	O
Acids	O
Research	O

Size	O
determination	O
and	O
the	O
comparative	O
analysis	O
of	O
SpC3	O
exons	O
.	O

Eighteen	O
exons	O
,	O
"	O
a	O
"	O
through	O
"	O
r	O
"	O
,	O
were	O
mapped	O
(	O
Table	O
2	O
)	O
.	O

The	O
largest	O
exon	O
,	O
"	O
a	O
"	O
,	O
located	O
on	O
the	O
extreme	O
3	O
'	O
end	O
of	O
the	O
sheep	B
genomic	O
insert	O
,	O
contained	O

approximately	O
800	O
bp	O
.	O

With	O
the	O
exception	O
of	O
exon	O
"	O
m	O
"	O
,	O
exons	O
larger	O
than	O
150	O

base	O
pairs	O
were	O
confined	O
to	O
the	O
genetic	O
region	O
corresponding	O
to	O
the	O
far	O
3	O
'	O
end	O
of	O
the	O
a2	O
mRNA	O
.	O

Exon	O
"	O
a	O
"	O
and	O
exon	O
"	O
b	O
"	O
,	O
the	O
two	O
exons	O
situated	O
on	O
either	O
side	O
of	O
intron	O
1	O
,	O
coded	O
for	O
around	O
1000	O
bases	O
of	O
a2	O
collagen	O
information	O
;	O
these	O
two	O

exons	O
contained	O
one	O
-	O
third	O
of	O
the	O
mapped	O
3	O
,	O
014	O
DNA	O
bases	O
complementary	O
to	O
a2	O
mRNA	O
Length	O
distribution	O
and	O
organization	O
of	O
the	O
introns	O
and	O
exons	O
in	O
the	O
sheep	B
genomi	O
c	O
i	O
nsert	O
.	O

There	O
was	O
a	O
sharp	O
contrast	O
in	O
the	O
size	O
distribution	O
of	O
the	O
exons	O
and	O
introns	O
contained	O
within	O
SpC3	O
(	O
Figure	O
2	O
)	O
.	O

While	O
the	O
intron	O
sizes	O
varied	O

considerably	O
,	O
the	O
exons	O
,	O
in	O
general	O
,	O
showed	O
a	O
very	O
narrow	O
distribution	O
of	O

lengths	O
,	O
and	O
thus	O
tended	O
to	O
cluster	O
at	O
the	O
lowest	O
end	O
of	O
the	O
length	O
distri	O

A	O
.	O

(	O
I	O
)	O

z	O
6	O
0	O

z	O

ZL4	O
0	O

021	O

z	O

10	O

B	O
.	O

8	O

z	O
0	O

16	O
0	O
z	O

2	O

20	O
400	O
600	O
800	O
1000	O
1200	O
1400	O
1600	O

LENGTH	O
IN	O
NUCLEOTIDES	O

Figure	O
2	O
.	O

Length	O
distribution	O
of	O
the	O
intron	O
and	O
exon	O
mean	O
lengths	O
measured	O
from	O
micrographs	O
prepared	O
by	O
the	O
urea	O
-	O
formamide	O
method	O
.	O

(	O
A	O
)	O
Introns	O
;	O
(	O
b	O
)	O
Exons	O
.	O

See	O
Tables	O
1	O
and	O
2	O
for	O
details	O
.	O

2248	O

Nucleic	O
Acids	O
Research	O
bution	O
graph	O
.	O

The	O
exon	O
in	O
the	O
800	O
-	O
900	O
bp	O
region	O
was	O
unique	O
and	O
was	O
the	O
only	O
exon	O
which	O
exhibited	O
length	O
overlap	O
with	O
introns	O
.	O

The	O
maps	O
of	O
the	O
a2	O
collagen	O
gene	O
obtained	O
with	O
both	O
electron	O
micro	O

scopic	O
spreading	O
methods	O
were	O
almost	O
identical	O
(	O
Figure	O
3	O
)	O
,	O
except	O
that	O
the	O

region	O
at	O
the	O
extreme	O
5	O
'	O
end	O
of	O
the	O
insert	O
could	O
only	O
be	O
mapped	O
with	O
the	O
ureaformamide	O
method	O
.	O

From	O
these	O
measurements	O
we	O
concluded	O
that	O
the	O
length	O
of	O
the	O
a2	O
collagen	O
genetic	O
regi	O
?	O
on	O
in	O
SpC3	O
was	O
17	O
,	O
084	O
bases	O
long	O
with	O
only	O
3	O
,	O
014	O
bases	O
actually	O
coding	O
for	O
a2	O
mRNA	O
.	O

Therefore	O
,	O
only	O
18	O
%	O
of	O
the	O
mapped	O
17	O
kb	O
sheep	B
genetic	O
insert	O
actually	O
contained	O
a2	O
structural	O
information	O
.	O

DISCUSSION	O

The	O
organizational	O
structure	O
of	O
the	O
a2	O
collagen	O
gene	O
is	O
complex	O
.	O

A	O
minimum	O
of	O
17	O
introns	O
interrupt	O
the	O
3	O
kb	O
of	O
ca2	O
genetic	O
information	O
interspersed	O
as	O
18	O
exons	O
over	O
17	O
kb	O
of	O
sheep	B
DNA	O
.	O

With	O
the	O
exception	O
of	O
exon	O
"	O
a	O
"	O
located	O
at	O
the	O
extreme	O
3	O
'	O
end	O
of	O
the	O
inserted	O
a2	O
gene	O
,	O
all	O
other	O
mapped	O
exons	O
are	O
rather	O
small	O
,	O
exhibiting	O
a	O
size	O
distribution	O
range	O
of	O
50	O
to	O
250	O
bp	O
.	O

In	O

contrast	O
,	O
the	O
intron	O
sizes	O
range	O
from	O
340	O
to	O
1540	O
bases	O
occupying	O
a	O
total	O

of	O
14	O
kb	O
.	O

Thus	O
,	O
the	O
DNA	O
region	O
containing	O
the	O
3	O
kb	O
of	O
a2	O
collagen	O
genetic	O
information	O
is	O
5	O
.	O
6	O
fold	O
longer	O
than	O
the	O
corresponding	O
co2	O
mRNA	O
sequences	O
.	O

Although	O
the	O
total	O
number	O
of	O
introns	O
present	O
within	O
the	O
60	O
%	O
3	O
'	O
portion	O

of	O
the	O
a2	O
sheep	B
gene	O
was	O
determined	O
to	O
be	O
17	O
,	O
variation	O
in	O
the	O
precise	O
number	O

TRANSRIPTlO	O

A	O
5w	O
r	O

1	O
"	O
2a4	O
133	O
112s	O
11	O
.	O
17	O
0	O
.	O

3O	O
2	O
715	O
6	O
.	O
2	O
313	O
04	O
4	O
.	O
2B	O
3	O
.	O
51	O
2	O
.	O
2	O
12	O

EXON0	O
p	O
o	O
n	O
5	O
Ik	O
h	O
f	O
d	O
4	O
.	O

b	O

WPM300	O
16	O
16	O
14	O
13	O
12	O
11	O
10	O
9	O
6	O
7	O
6	O
5	O
4	O
3	O
2	O
1	O

B	O

110	O
16	O
4	O
.	O
2	O
13111	O
112n	O
1113104	O
3	O
.	O
6	O
gm74	O
2	O
6	O
.	O

4	O
4	O
2	O
3	O
.	O
2	O
22	O
in	O

1	O
a1m03	O
133	O
1	O
.	O
2	O
11	O
10	O
01	O
341	O
6	O
.	O

1	O
117	O
6	O
.	O
2	O
4	O
12	O
417	O
3I5	O
'	O
m	O
2	O

DM00	O
1	O
q5	O
p	O
0	O
n	O
m	O
I	O
k	O
.	O

j	O
i	O
h	O
g	O
f	O
d	O
c	O
b	O
a	O
147306	O
17	O
16	O
15	O
14	O
13	O
12	O
11	O
10	O
9	O
a	O
7	O
6	O
5	O
4	O
3	O
2	O
1	O

175	O
17	O
.	O
0	O
16	O
.	O
6	O
&	O
16	O
'	O
5	O
.	O
5	O
15	O
.	O
0	O
14	O
.	O
5	O
14	O
.	O

13	O
.	O
5	O
13	O
.	O
0	O
12	O
.	O
5	O
12	O
.	O
0	O
11	O
.	O
5	O
11	O
10	O
.	O
5M	O
10	O
.	O
0	O
9	O
.	O
5	O
9	O
.	O
0	O
8	O
.	O

5	O
.	O
0	O
71	O
7	O
.	O
0	O
6	O
.	O
5	O
6	O
.	O

5	O
.	O
5	O
50	O
4	O
.	O
5	O
4	O
.	O
0	O
3	O
.	O
5	O
3	O
.	O
0	O
2	O
.	O
5	O
2	O
.	O
0	O
1	O
.	O
5	O
1	O
.	O
0	O

KILOBASE	O

Fiue3	O
Organization	O
of	O
60	O
%	O
of	O
the	O
3	O
'	O
end	O
of	O
the	O
sheep	B
a2	O
collagen	O
gene	O
.	O

(	O
A	O
)	O
}	O
The	O
exon	O
(	O
)	O
and	O
intron	O
(	O
CDJ	O
)	O
order	O
within	O
the	O
a2	O
gene	O
as	O
determined	O
by	O
R	O
loop	O
analysis	O
of	O
SpC3	O
DNA	O
-	O
a2	O
mRNA	O
hybrid	O
molecules	O
visualized	O
by	O
the	O
electron	O
microscopic	O
70	O
%	O
formamide	O
spreading	O
method	O
.	O

(	O
B	O
)	O
The	O
exon	O
Um	O
)	O

and	O
intron	O
(	O
Efl	O
)	O
order	O
within	O
the	O
a2	O
gene	O
as	O
determined	O
by	O
R	O
loop	O
analysis	O
of	O
SpC3	O
DNA	O
-	O
a2	O
mRNA	O
hybrid	O
molecules	O
evaluated	O
by	O
the	O
electron	O
microscopic	O

urea	O
-	O
formamide	O
spreading	O
method	O
.	O

Arrows	O
represent	O
the	O
approximate	O
location	O
of	O
intron	O
-	O
exon	O
junctions	O
.	O

All	O
values	O
are	O
presented	O
as	O
kilobase	O
pairs	O
.	O

2249	O

Nucleic	O
Acids	O
Research	O

of	O
introns	O
present	O
in	O
individual	O
hybrid	O
molecules	O
was	O
observed	O
.	O

The	O
reason	O

for	O
this	O
may	O
be	O
due	O
to	O
size	O
heterogeneity	O
of	O
the	O
a2	O
mRNA	O
used	O
as	O
a	O
complementary	O
probe	O
.	O

Although	O
the	O
a2	O
mRNA	O
was	O
extensively	O
purified	O
(	O
2	O
)	O
,	O
some	O
degradation	O
was	O
likely	O
present	O
.	O

It	O
is	O
also	O
possible	O
that	O
additional	O
introns	O
exist	O
that	O
are	O
too	O
small	O
to	O
be	O
detected	O
by	O
electron	O
microscopic	O
R	O
loop	O
analysis	O
.	O

The	O
most	O
likely	O
a2	O
genetic	O
regions	O
containing	O
such	O
introns	O
are	O
exons	O
"	O
g	O
"	O
and	O
"	O
m	O
"	O
.	O

Small	O

"	O
protrusions	O
"	O
were	O
sometimes	O
observed	O
within	O
these	O
exons	O
that	O
could	O
represent	O
small	O
introns	O
.	O

Very	O
small	O
introns	O
have	O
been	O
reported	O
for	O
tRNA	O
genes	O
(	O
12	O
,	O
13	O
)	O
,	O

and	O
it	O
will	O
be	O
necessary	O
to	O
sequence	O
these	O
regions	O
of	O
SpC3	O
to	O
determine	O
if	O
such	O
introns	O
are	O
present	O
within	O
the	O
a2	O
sheep	B
genome	O
.	O

The	O
existence	O
of	O
mRNAs	O
comprised	O
of	O
sequences	O
complementary	O
to	O
noncontiguous	O
regions	O
in	O
a	O
DNA	O
genome	O
was	O
first	O
described	O
for	O
adenovirus	B
(	O
14	O
,	O
15	O
)	O
and	O

simian	O
virus	O
(	O
16	O
,	O
17	O
)	O
genes	O
.	O

Similar	O
observations	O
were	O
soon	O
reported	O
for	O
eukaryotic	O
genes	O
,	O
including	O
serum	O
albumin	O
(	O
18	O
)	O
,	O
conalbumin	O
(	O
19	O
)	O
,	O
fibroin	O
(	O
20	O
)	O
,	O
s	O

globin	O
(	O
21	O
,	O
22	O
)	O
,	O
growth	O
hormones	O
(	O
23	O
,	O
24	O
)	O
,	O
immunoglobulin	O
(	O
25	O
)	O
,	O
lysozyme	O
(	O
26	O
)	O
,	O

ovalbumin	O
(	O
27	O
-	O
29	O
)	O
,	O
ovomucoid	O
(	O
30	O
)	O
,	O
rRNA	O
(	O
31	O
-	O
34	O
)	O
,	O
tRNA	O
(	O
12	O
,	O
13	O
)	O
,	O
and	O
vitellogenin	O
(	O
35	O
)	O
.	O

The	O
precise	O
number	O
or	O
occurrence	O
of	O
introns	O
within	O
these	O
genes	O
does	O
not	O
seem	O
to	O
follow	O
any	O
clear	O
pattern	O
.	O

However	O
,	O
the	O
genes	O
for	O
albumin	O
,	O
conalbumin	O
,	O

lysozyme	O
,	O
ovalbumin	O
,	O
and	O
ovomucoid	O
exhibit	O
a	O
structural	O
organization	O
comparable	O
to	O
the	O
a2	O
collagen	O
gene	O
.	O

All	O
of	O
these	O
genes	O
are	O
composed	O
of	O
numerous	O
small	O

exons	O
,	O
usually	O
less	O
than	O
250	O
base	O
pairs	O
,	O
and	O
introns	O
which	O
show	O
a	O
large	O
size	O
variation	O
within	O
an	O
individual	O
gene	O
.	O

Within	O
all	O
of	O
these	O
genomes	O
,	O
the	O
DNA	O

regions	O
required	O
for	O
coding	O
structural	O
formation	O
are	O
4	O
to	O
7	O
times	O
longer	O
than	O
the	O
corresponding	O
mRNA	O
coding	O
sequences	O
.	O

As	O
with	O
the	O
a2	O
collagen	O
gene	O
,	O
a	O
large	O
unique	O
exon	O
at	O
the	O
extreme	O
3	O
'	O
end	O

is	O
also	O
present	O
in	O
the	O
ovalbumin	O
gene	O
(	O
36	O
,	O
37	O
)	O
.	O

In	O
the	O
a2	O
gene	O
,	O
this	O
exon	O
was	O
800	O
to	O
900	O
nucleotides	O
in	O
length	O
,	O
while	O
in	O
the	O
ovalbumin	O
gene	O
the	O
exon	O
contained	O
1	O
,	O
030	O
base	O
pairs	O
.	O

Interestingly	O
,	O
this	O
ovalbumin	O
exon	O
contained	O
634	O
-	O
650	O
base	O
pairs	O
ot	O
DNA	O
sequence	O
to	O
the	O
3	O
'	O
side	O
of	O
the	O
terminator	O

triplet	O
,	O
suggesting	O
the	O
ovalbumin	O
mRNA	O
has	O
a	O
large	O
untranslated	O
region	O
at	O
the	O
3	O
'	O
end	O
.	O

The	O
consistent	O
appearance	O
of	O
a	O
small	O
non	O
-	O
hybridized	O
tail	O
,	O
approximately	O
100	O
nucleotides	O
in	O
length	O
,	O
in	O
the	O
region	O
where	O
the	O
right	O
arm	O
of	O
the	O
phage	O
was	O
ligated	O
to	O
the	O
sheep	B
genomic	O
insert	O
of	O
SpC3	O
very	O
likely	O
corresponded	O
to	O
the	O

3	O
'	O
poly	O
A	O
sequence	O
of	O
the	O
a2	O
mRNA	O
.	O

This	O
would	O
suggest	O
that	O
the	O
a2	O
mRNA	O
coding	O
sequence	O
terminates	O
very	O
near	O
or	O
at	O
this	O
point	O
in	O
the	O
genome	O
.	O

Previously	O
published	O
biochemical	O
evidence	O
(	O
2	O
)	O
obtained	O
from	O
restriction	O
mapping	O
and	O
Southern	O
blot	O
analysis	O
using	O
[	O
32P	O
]	O
-	O
labeled	O
chick	O
a2	O
cDNA	O
probe	O
supports	O

2250	O

Nucleic	O
Acids	O
Research	O

this	O
observation	O
.	O

It	O
is	O
unclear	O
what	O
role	O
introns	O
play	O
in	O
genetic	O
expression	O
.	O

However	O
,	O

it	O
is	O
known	O
that	O
these	O
sequences	O
are	O
tranncribed	O
as	O
part	O
of	O
larger	O
precursor	O
mRNAs	O
and	O
the	O
introns	O
are	O
then	O
excised	O
and	O
the	O
fragmented	O
mRNA	O
chains	O

covalently	O
rejoined	O
(	O
38	O
)	O
.	O

Some	O
evidence	O
has	O
recently	O
accumulated	O
demonstrating	O
the	O
existence	O
of	O
precursor	O
a2	O
mRNAs	O
(	O
39	O
,	O
40	O
)	O
.	O

However	O
,	O
if	O
the	O
introns	O
in	O
the	O
a2	O
gene	O
are	O
transcribed	O
in	O
their	O
entirety	O
,	O
as	O
has	O
been	O

demonstrated	O
for	O
the	O
introns	O
in	O
ovalbumin	O
and	O
globin	O
(	O
41	O
,	O
42	O
)	O
,	O
much	O
larger	O
precursor	O
a2	O
mRNAs	O
may	O
exist	O
than	O
those	O
reported	O
to	O
date	O
.	O

For	O
if	O
the	O
re	O

mainder	O
of	O
the	O
a2	O
collagen	O
gene	O
has	O
a	O
structural	O
organization	O
comparable	O
to	O
the	O
60	O
%	O
3	O
'	O
portion	O
that	O
has	O
been	O
analyzed	O
,	O
it	O
is	O
probable	O
that	O
the	O
a2	O

collagen	O
gene	O
in	O
its	O
entirety	O
is	O
dispersed	O
throughout	O
a	O
30	O
kb	O
DNA	O
segment	O
.	O

ACKNOWLEDGMENTS	O

We	O
thank	O
Dr	O
.	O
John	O
Dahlberg	O
and	O
Frances	O
Loebenstein	O
,	O
Laboratory	O
of	O
Cellular	O
and	O
Molecular	O
Biology	O
,	O
National	O
Cancer	O
Institute	O
,	O
for	O
the	O
generous	O
use	O
of	O
a	O

Siemens	O
Elmiskop	O
101	O
electron	O
microscope	O
;	O
Dr	O
.	O
Ursula	O
Heine	O
and	O
Benjamin	O
Elliott	O
,	O
Laboratory	O
of	O
Viral	O
Carcinogenesis	O
,	O
National	O
Cancer	O
Institute	O
,	O
for	O
the	O
use	O
of	O
a	O
Hewlett	O
-	O
Packard	O
calculator	O
equipped	O
with	O
a	O
digitizer	O
and	O
a	O
Denton	O
vacuum	O

evaporator	O
,	O
and	O
Drs	O
.	O

Victor	O
Ferrans	O
and	O
Oichi	O
Kawanami	O
,	O
Laboratory	O
of	O
Pathology	O
,	O

National	O
Heart	O
,	O
Lung	O
,	O
and	O
Blood	O
Institute	O
,	O
for	O
expert	O
assistance	O
with	O
photography	O
.	O

We	O
are	O
also	O
grateful	O
to	O
Margery	O
Sullivan	O
,	O
Laboratory	O
of	O
Molecular	O
Genetics	O
,	O

National	O
Institute	O
of	O
Child	B
Health	O
and	O
Human	B
Development	O
,	O
for	O
helpful	O
discussions	O
and	O
to	O
Dr	O
.	O
Helga	O
Boedtker	O
,	O
Department	O
of	O
Chemistry	O
,	O
Harvard	O
University	O
,	O
for	O
making	O
available	O
the	O
recombinant	O
plasmid	O
pCg45	O
.	O

References	O

1	O
.	O

Prockop	O
,	O
D	O
.	O

J	O
.	O
,	O
Kivirikko	O
,	O
k	O
.	O

I	O
.	O
,	O
Tuderman	O
,	O
L	O
.	O
,	O
and	O
Guzman	O
,	O
N	O
.	O

A	O
.	O

(	O
1979	O
)	O
New	O
Engl	O
.	O

J	O
.	O

Med	O
.	O

301	O
,	O
13	O
-	O
23	O
and	O
77	O
-	O
85	O
.	O

2	O
.	O

Boyd	O
,	O
C	O
.	O

D	O
.	O
,	O
Tolstoshev	O
,	O
P	O
.	O
,	O
Schafer	O
,	O
M	O
.	O

P	O
.	O
,	O
Trapnell	O
,	O
B	O
.	O

C	O
.	O
,	O
Coon	O
,	O

H	O
.	O

C	O
.	O
,	O
Kretschmer	O
,	O
P	O
.	O

J	O
.	O
,	O
Nienhuis	O
,	O
A	O
.	O

W	O
.	O
,	O
and	O
Crystal	O
,	O
R	O
.	O

G	O
.	O

(	O
1980	O
)	O
J	O
.	O

Biol	O
.	O

Chem	O
.	O
,	O
in	O
press	O
.	O

3	O
.	O

Blin	O
,	O
N	O
.	O
,	O
and	O
Stafford	O
,	O
D	O
.	O

W	O
.	O

(	O
1976	O
)	O
Nucl	O
.	O

Acids	O
Res	O
.	O

3	O
,	O
2303	O
-	O
2308	O
.	O

4	O
.	O

Kretschmer	O
,	O
P	O
.	O

J	O
.	O
,	O
Kaufman	O
,	O
R	O
.	O

E	O
.	O
,	O
Coon	O
,	O
H	O
.	O

C	O
.	O
,	O
Chen	O
,	O
M	O
.	O

JY	O
.	O
,	O
Geist	O

C	O
.	O

E	O
.	O
,	O
and	O
Nienhuis	O
,	O
A	O
.	O

W	O
.	O

(	O
1980	O
)	O
J	O
.	O

Biol	O
.	O

Chem	O
.	O
,	O
in	O
press	O
.	O

5	O
.	O

Maniatis	O
,	O
T	O
.	O
,	O
Hardison	O
,	O
R	O
.	O

C	O
.	O
,	O
Lacey	O
,	O
E	O
.	O
,	O
Laver	O
,	O
H	O
.	O
,	O
O	O
'	O
Connell	O
,	O
C	O
.	O
,	O

Quon	O
,	O
D	O
.	O
,	O
Sim	O
,	O
G	O
.	O

K	O
.	O
,	O
and	O
Efstratiadis	O
,	O
A	O
.	O

(	O
1975	O
)	O
Cell	O
15	O
,	O
687	O
-	O
701	O
.	O

6	O
.	O

Blattner	O
,	O
F	O
.	O

R	O
.	O
,	O
Blechl	O
,	O
A	O
.	O

E	O
.	O
,	O
Denniston	O
-	O
Thompson	O
,	O
K	O
.	O
,	O
Faber	O
,	O
H	O
.	O

E	O
.	O
,	O

Richards	O
,	O
J	O
.	O

E	O
.	O
,	O
Slightom	O
,	O
H	O
.	O

L	O
.	O
,	O
Tucker	O
,	O
P	O
.	O

W	O
.	O
,	O
and	O
Smithies	O
,	O
0	O
.	O

(	O
1978	O
)	O
Science	O
202	O
,	O
1279	O
-	O
1284	O
.	O

7	O
.	O

Meyer	O
,	O
J	O
.	O
,	O
Neuwald	O
,	O
P	O
.	O

D	O
.	O
,	O
Lai	O
,	O
S	O
.	O
,	O
Maizel	O
,	O
J	O
.	O

V	O
.	O
,	O
Jr	O
.	O
,	O
and	O
Westphal	O
,	O

H	O
.	O

(	O
1977	O
)	O
J	O
.	O

Virol	O
.	O

21	O
,	O
1010	O
-	O
1014	O
.	O

2251	O

Nucleic	O
Acids	O
Research	O

8	O
.	O

Westphal	O
,	O
H	O
.	O
,	O
and	O
Lai	O
,	O
S	O
.	O

P	O
.	O

(	O
1977	O
)	O
J	O
.	O

Mol	O
.	O

Biol	O
.	O

116	O
,	O
525	O
-	O
548	O
.	O

9	O
.	O

Schafer	O
,	O
M	O
.	O

P	O
.	O
,	O
Rohrmann	O
,	O
G	O
.	O
,	O
Heine	O
,	O
U	O
.	O
,	O
and	O
Beaudreau	O
,	O
G	O
.	O

S	O
.	O

(	O
1979	O
)	O
Virol	O
.	O

95	O
,	O
176	O
-	O
184	O
.	O

10	O
.	O

Davis	O
,	O
R	O
.	O

W	O
.	O
,	O
Simon	O
,	O
M	O
.	O

M	O
.	O
,	O
and	O
Davison	O
,	O
N	O
.	O

(	O
1971	O
)	O
in	O
Methods	O
in	O

Enzymology	O
(	O
Grossman	O
,	O
L	O
.	O
and	O
Moldave	O
,	O
K	O
.	O
,	O
eds	O
)	O
Vol	O
.	O

21	O
,	O
pp	O
.	O

413428	O
,	O
Academic	O
Press	O
,	O
New	O
York	O
.	O

11	O
.	O

Federal	O
Register	O
(	O
1978	O
)	O
43	O
,	O
60108	O
-	O
60131	O
.	O

12	O
.	O

Goodman	O
,	O
H	O
.	O

M	O
.	O
,	O
Olson	O
,	O
M	O
.	O

V	O
.	O
,	O
Hall	O
,	O
B	O
.	O

D	O
.	O

(	O
1977	O
)	O
Pro	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

74	O
,	O
5453	O
-	O
5457	O
.	O

13	O
.	O

Valenzuela	O
,	O
P	O
.	O
,	O
Venegas	O
,	O
A	O
.	O
,	O
Weinberg	O
,	O
F	O
.	O
,	O
Bishop	O
,	O
R	O
.	O
,	O
Rutter	O
,	O

W	O
.	O

J	O
.	O

(	O
1978	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

75	O
,	O
190	O
-	O
194	O
.	O

14	O
.	O

Berget	O
,	O
S	O
.	O

M	O
.	O
,	O
Moore	O
,	O
C	O
.	O
,	O
and	O
Sharp	O
,	O
P	O
.	O

A	O
.	O

(	O
1977	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

74	O
,	O
3171	O
-	O
3175	O
.	O

15	O
.	O

Chow	O
,	O
L	O
.	O

T	O
.	O
,	O
Gelinas	O
,	O
R	O
.	O

E	O
.	O
,	O
Broker	O
,	O
T	O
.	O
,	O
and	O
Roberts	O
,	O
R	O
.	O

J	O
.	O

(	O
1977	O
)	O

Cell	O
12	O
,	O
1	O
-	O
8	O
.	O

16	O
.	O

Berk	O
,	O
A	O
.	O

J	O
.	O
,	O
and	O
Sharp	O
,	O
P	O
.	O

A	O
.	O

(	O
1978	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

75	O
,	O
1274	O
-	O
1278	O
.	O

17	O
.	O

Bratosin	O
,	O
S	O
.	O
,	O
Horowitz	O
,	O
M	O
.	O
,	O
Laub	O
,	O
0	O
.	O
,	O
and	O
Aloni	O
,	O
Y	O
.	O

(	O
1978	O
)	O

Cell	O
13	O
,	O
783	O
-	O
790	O
.	O

18	O
.	O

Sargent	O
,	O
T	O
.	O

D	O
.	O
,	O
Wu	O
,	O
J	O
.	O

R	O
.	O
,	O
Sala	O
-	O
Trepat	O
,	O
J	O
.	O

M	O
.	O
,	O
Wallace	O
,	O
R	O
.	O

B	O
.	O
,	O

Reyes	O
,	O
A	O
.	O

A	O
.	O
,	O
and	O
Bonner	O
,	O
J	O
.	O

(	O
1979	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

76	O
,	O
3256	O
-	O
3260	O
.	O

19	O
.	O

Perrin	O
,	O
F	O
.	O
,	O
Cochet	O
,	O
M	O
.	O
,	O
Gerlinger	O
,	O
P	O
.	O
,	O
Cami	O
,	O
B	O
.	O
,	O
LePennec	O
,	O
J	O
.	O

P	O
.	O
,	O

and	O
Chambon	O
,	O
P	O
.	O

(	O
1979	O
)	O
Nucl	O
.	O

Acids	O
Res	O
.	O

6	O
2731	O
-	O
2748	O
.	O

20	O
.	O

Tsujimoto	O
,	O
Y	O
.	O
,	O
and	O
Suzuki	O
,	O
Y	O
.	O

(	O
1979	O
)	O
Cell	O
16	O
425	O
-	O
436	O
.	O

21	O
.	O

Jeffreys	O
,	O
A	O
.	O

J	O
.	O
,	O
and	O
Flavell	O
,	O
R	O
.	O

A	O
.	O

(	O
1977	O
)	O
Cell	O
12	O
,	O
1097	O
-	O
1108	O
.	O

22	O
.	O

Tilghman	O
,	O
S	O
.	O

M	O
.	O
,	O
Tiemeier	O
,	O
D	O
.	O

C	O
.	O
,	O
Seidman	O
,	O
J	O
.	O

C	O
.	O
,	O
Matija	O
Peterlin	O
,	O
B	O
.	O
,	O

Sullivan	O
,	O
M	O
.	O
,	O
Maizel	O
,	O
J	O
.	O

V	O
.	O
,	O
and	O
Leder	O
,	O
P	O
.	O

(	O
1978	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

75	O
,	O
725	O
-	O
729	O
.	O

23	O
.	O

Fiddes	O
,	O
J	O
.	O

C	O
.	O
,	O
Seeburg	O
,	O
P	O
.	O

H	O
.	O
,	O
DeNoto	O
,	O
F	O
.	O

M	O
.	O
,	O
Hallewell	O
,	O
R	O
.	O

A	O
.	O
,	O

Baxter	O
,	O
J	O
.	O

D	O
.	O
,	O
and	O
Goodman	O
,	O
H	O
.	O

M	O
.	O

(	O
1979	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

76	O
,	O
4294	O
-	O
4298	O
.	O

24	O
.	O

Soreq	O
,	O
H	O
.	O
,	O
Harpold	O
,	O
M	O
.	O
,	O
Evans	O
,	O
R	O
.	O
,	O
Darnell	O
,	O
Jr	O
.	O
,	O
J	O
.	O

E	O
.	O
,	O
and	O

Bancroft	O
,	O
F	O
.	O

C	O
.	O

(	O
1979	O
)	O
Nucl	O
.	O

Acids	O
Res	O
.	O

6	O
,	O
2471	O
-	O
2482	O
.	O

25	O
.	O

Tonegawa	O
,	O
S	O
.	O
,	O
Maxam	O
,	O
A	O
.	O

M	O
.	O
,	O
Tizard	O
,	O
R	O
.	O
,	O
Bernard	O
,	O
0	O
.	O
,	O
and	O
Gilbert	O
,	O
W	O
.	O

(	O
1978	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

75	O
,	O
1485	O
-	O
1489	O
.	O

26	O
.	O

Nguyen	O
-	O
Huu	O
,	O
M	O
.	O

C	O
.	O
,	O
Stratmann	O
,	O
M	O
.	O
,	O
Groner	O
,	O
B	O
.	O
,	O
Wurtz	O
,	O
T	O
.	O
,	O
Land	O
,	O
M	O
.	O
,	O

Glesecke	O
,	O
K	O
.	O
,	O
Sippel	O
,	O
A	O
.	O

F	O
.	O
,	O
and	O
Schutz	O
,	O
G	O
.	O

(	O
1979	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

76	O
,	O
76	O
-	O
80	O
.	O

27	O
.	O

Breathnach	O
,	O
R	O
.	O
,	O
Mandel	O
,	O
J	O
.	O

L	O
.	O
,	O
and	O
Chambon	O
,	O
P	O
.	O

(	O
1977	O
)	O
Nature	O
270	O
,	O

314	O
-	O
319	O
.	O

28	O
.	O

Dugaiczyk	O
,	O
A	O
.	O
,	O
Woo	O
,	O
S	O
.	O

L	O
.	O

C	O
.	O
,	O
Lai	O
,	O
E	O
.	O

C	O
.	O
,	O
Mace	O
,	O
M	O
.	O

L	O
.	O
,	O
Jr	O
.	O
,	O

McReynolds	O
,	O
L	O
.	O
,	O
and	O
O	O
'	O
Malley	O
,	O
B	O
.	O

W	O
.	O

(	O
1978	O
)	O
Nature	O
274	O
,	O
328	O
-	O
333	O
.	O

29	O
.	O

Weinstock	O
,	O
R	O
.	O
,	O
Sweet	O
,	O
R	O
.	O
,	O
Weiss	O
,	O
M	O
.	O
,	O
Cedar	O
,	O
M	O
.	O
,	O
and	O
Axel	O
,	O
R	O
.	O

(	O
1978	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

75	O
,	O
1299	O
-	O
1303	O
.	O

30	O
.	O

Catterall	O
,	O
J	O
.	O

F	O
.	O
,	O
Stein	O
,	O
J	O
.	O

P	O
.	O
,	O
Lai	O
,	O
E	O
.	O

C	O
.	O
,	O
Woo	O
,	O
S	O
.	O

L	O
.	O

C	O
.	O
,	O

Dugaiczyk	O
,	O
Mace	O
,	O
M	O
.	O

L	O
.	O
,	O
Means	O
,	O
A	O
.	O

R	O
.	O
,	O
and	O
O	O
'	O
Malley	O
,	O
B	O
.	O

W	O
.	O

(	O
1979	O
)	O
Nature	O
278	O
,	O
323	O
-	O
327	O
.	O

31	O
.	O

White	O
,	O
R	O
.	O

L	O
.	O
,	O
and	O
Hogness	O
,	O
D	O
.	O

S	O
.	O

(	O
1977	O
)	O
Cell	O
10	O
,	O
177	O
-	O
192	O
.	O

32	O
.	O

Glover	O
,	O
D	O
.	O

M	O
.	O
,	O
and	O
Hogness	O
,	O
D	O
.	O

S	O
.	O

(	O
1977	O
)	O
Cell	O
16	O
,	O
167	O
-	O
176	O
.	O

33	O
.	O

Wellauer	O
,	O
P	O
.	O

K	O
.	O
,	O
and	O
David	O
,	O
I	O
.	O

B	O
.	O

(	O
1977	O
)	O
Cell	O
10	O
,	O
193	O
-	O
212	O
.	O

34	O
.	O

Pellegrini	O
,	O
M	O
.	O
,	O
Manning	O
,	O
J	O
.	O
,	O
and	O
Davidson	O
,	O
N	O
.	O

(	O
1977	O
)	O
Cell	O
10	O
,	O

213	O
-	O
214	O
.	O

35	O
.	O

Wahli	O
,	O
W	O
.	O
,	O
David	O
,	O
I	O
.	O

B	O
.	O
,	O
Wyler	O
,	O
T	O
.	O
,	O
Jaggi	O
,	O
R	O
.	O

B	O
.	O
,	O
Weber	O
,	O
R	O
.	O
,	O
and	O

Ryffel	O
,	O
G	O
.	O

V	O
.	O

(	O
1979	O
)	O
Cell	O
16	O
,	O
535	O
-	O
549	O
.	O

36	O
.	O

McReynolds	O
,	O
L	O
.	O
,	O
O	O
'	O
Malley	O
,	O
B	O
.	O

W	O
.	O
,	O
Nisbet	O
,	O
A	O
.	O

D	O
.	O
,	O
Fothergill	O
,	O
J	O
.	O

E	O
.	O
,	O

2252	O

Nucleic	O
Acids	O
Research	O

Givol	O
,	O
D	O
.	O
,	O
Fields	O
,	O
S	O
.	O
,	O
Robertson	O
,	O
M	O
.	O
,	O
Brownlee	O
,	O
G	O
.	O

G	O
.	O

(	O
1978	O
)	O
Nature	O
273	O
,	O
723	O
-	O
728	O
.	O

37	O
.	O

O	O
'	O
Hare	O
,	O
K	O
.	O
,	O
Breathnach	O
,	O
R	O
.	O
,	O
Benoist	O
,	O
C	O
.	O
,	O
Chambon	O
,	O
P	O
.	O

(	O
1979	O
)	O

Nucl	O
.	O

Acids	O
Res	O
.	O

7	O
,	O
321	O
-	O
334	O
.	O

38	O
.	O

Abelson	O
,	O
J	O
.	O

(	O
1979	O
)	O
Ann	O
.	O

Rev	O
.	O

Biochem	O
.	O

48	O
,	O
1035	O
-	O
1069	O
.	O

39	O
.	O

Adams	O
,	O
S	O
.	O

L	O
.	O
,	O
Alwine	O
,	O
J	O
.	O

C	O
.	O
,	O
de	O
Chrombrugghe	O
,	O
B	O
.	O
,	O
and	O
Pastan	O
,	O
I	O
.	O

(	O
1979	O
)	O
J	O
.	O

Biol	O
.	O

Chem	O
.	O

254	O
,	O
4935	O
-	O
4938	O
,	O

40	O
.	O

Rave	O
,	O
N	O
.	O
,	O
Crkvenjakow	O
,	O
R	O
.	O
,	O
and	O
Boedtker	O
,	O
H	O
.	O

(	O
1979	O
)	O
Nucl	O
.	O

Acids	O
Res	O
.	O

6	O
,	O
3559	O
-	O
3567	O
.	O

41	O
.	O

Roop	O
,	O
D	O
.	O

R	O
.	O
,	O
Nordstrom	O
,	O
J	O
.	O

L	O
.	O
,	O
Tsai	O
,	O
S	O
.	O

Y	O
.	O
,	O
Tsai	O
,	O
M	O
.	O

J	O
.	O
,	O
and	O

O	O
'	O
Malley	O
,	O
B	O
.	O

W	O
.	O

(	O
1978	O
)	O
Cell	O
15	O
,	O
671	O
-	O
685	O
.	O

42	O
.	O

Tilghman	O
,	O
S	O
.	O

M	O
.	O
,	O
Curtis	O
,	O
P	O
.	O

J	O
.	O
,	O
Tiemeier	O
,	O
D	O
.	O

C	O
.	O
,	O
Leder	O
,	O
P	O
.	O
,	O
and	O

Weissmann	O
,	O
C	O
.	O

(	O
1978	O
)	O
Proc	O
.	O

Natl	O
.	O

Acad	O
.	O

Sci	O
.	O

U	O
.	O
S	O
.	O
A	O
.	O

75	O
,	O
1309	O
-	O
1313	O
.	O

43	O
.	O

Palmiter	O
,	O
R	O
.	O

D	O
.	O
,	O
Davidson	O
,	O
J	O
.	O

M	O
.	O
,	O
Gagnon	O
,	O
H	O
.	O
,	O
Rowe	O
,	O
D	O
.	O

W	O
.	O
,	O
and	O

Bornstein	O
,	O
P	O
.	O

(	O
1979	O
)	O
J	O
.	O

Biol	O
.	O

Chem	O
.	O

254	O
,	O
1433	O
-	O
1436	O
.	O

44	O
.	O

Graves	O
,	O
P	O
.	O

N	O
.	O
,	O
Olsen	O
,	O
B	O
.	O

R	O
.	O
,	O
Feitzig	O
,	O
P	O
.	O

P	O
.	O
,	O
Monson	O
,	O
J	O
.	O

M	O
.	O
and	O

Prockop	O
,	O
D	O
.	O

J	O
.	O

(	O
1979	O
)	O
Fed	O
.	O

Proc	O
.	O

38	O
,	O
620	O
.	O

2253	O

Thumb	O
force	O
deficit	O
after	O
lower	O
median	O
nerve	O
block	O

Abstract	O

Purpose	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
characterize	O
thumb	O
motor	O
dysfunction	O
resulting	O
from	O
simulated	O
lower	O
median	O
nerve	O
lesions	O
at	O
the	O
wrist	O
.	O

Methods	O

Bupivacaine	O
hydrochloride	O
was	O
injected	O
into	O
the	O
carpal	O
tunnel	O
of	O
six	O
healthy	O
subjects	O
to	O
locally	O
anesthetize	O
the	O
median	O
nerve	O
.	O

Motor	O
function	O
was	O
subsequently	O
evaluated	O
by	O
measuring	O
maximal	O
force	O
production	O
in	O
all	O
directions	O
within	O
the	O
transverse	O
plane	O
perpendicular	O
to	O
the	O
longitudinal	O
axis	O
of	O
the	O
thumb	O
.	O

Force	O
envelopes	O
were	O
constructed	O
using	O
these	O
measured	O
multidirectional	O
forces	O
.	O

Results	O

Blockage	O
of	O
the	O
median	O
nerve	O
resulted	O
in	O
decreased	O
force	O
magnitudes	O
and	O
thus	O
smaller	O
force	O
envelopes	O
.	O

The	O
average	O
force	O
decrease	O
around	O
the	O
force	O
envelope	O
was	O
27	O
.	O
9	O
%	O
.	O

A	O
maximum	O
decrease	O
of	O
42	O
.	O
4	O
%	O
occurred	O
in	O
a	O
direction	O
combining	O
abduction	O
and	O
slight	O
flexion	O
,	O
while	O
a	O
minimum	O
decrease	O
of	O
10	O
.	O
5	O
%	O
occurred	O
in	O
a	O
direction	O
combining	O
adduction	O
and	O
slight	O
flexion	O
.	O

Relative	O
decreases	O
in	O
adduction	O
,	O
extension	O
,	O
abduction	O
,	O
and	O
flexion	O
were	O
17	O
.	O
3	O
%	O
,	O
21	O
.	O
2	O
%	O
,	O
41	O
.	O
2	O
%	O
and	O
33	O
.	O
5	O
%	O
,	O
respectively	O
.	O

Areas	O
enclosed	O
by	O
pre	O
-	O
and	O
post	O
-	O
block	O
force	O
envelopes	O
were	O
20628	O
+	O
/	O
-	O
7747	O
N	O
.	O
N	O
,	O
and	O
10700	O
+	O
/	O
-	O
4474	O
N	O
.	O
N	O
,	O
respectively	O
,	O
representing	O
an	O
average	O
decrease	O
of	O
48	O
.	O
1	O
%	O
.	O

Relative	O
decreases	O
in	O
the	O
adduction	O
,	O
extension	O
,	O
abduction	O
,	O
and	O
flexion	O
quadrant	O
areas	O
were	O
31	O
.	O
5	O
%	O
,	O
42	O
.	O
3	O
%	O
,	O
60	O
.	O
9	O
%	O
,	O
and	O
52	O
.	O
3	O
%	O
,	O
respectively	O
.	O

Conclusion	O

Lower	O
median	O
nerve	O
lesion	O
,	O
simulated	O
by	O
a	O
nerve	O
block	O
at	O
the	O
wrist	O
,	O
compromise	O
normal	O
motor	O
function	O
of	O
the	O
thumb	O
.	O

A	O
median	O
nerve	O
block	O
results	O
in	O
force	O
deficits	O
in	O
all	O
directions	O
,	O
with	O
the	O
most	O
severe	O
impairment	O
in	O
abduction	O
and	O
flexion	O
.	O

From	O
our	O
results	O
,	O
such	O
a	O
means	O
of	O
motor	O
function	O
assessment	O
can	O
potentially	O
be	O
applied	O
to	O
functionally	O
evaluate	O
peripheral	O
neuropathies	O
.	O

Introduction	O

The	O
thumb	O
has	O
unique	O
anatomical	O
and	O
biomechanical	O
characteristics	O
that	O
are	O
required	O
to	O
perform	O
many	O
manipulative	O
tasks	O
.	O

Thumb	O
motor	O
dysfunction	O
resulting	O
from	O
neuromuscular	O
and	O
musculoskeletal	O
pathologies	O
severely	O
hinders	O
the	O
performance	O
of	O
these	O
daily	O
tasks	O
.	O

Clinical	O
treatment	O
,	O
prevention	O
protocols	O
,	O
and	O
rehabilitation	O
efficacy	O
requires	O
a	O
thorough	O
understanding	O
of	O
thumb	O
motor	O
capabilities	O
,	O
as	O
well	O
as	O
its	O
associated	O
functional	O
deficit	O
.	O

Investigations	O
of	O
underlying	O
pathological	O
mechanism	O
of	O
the	O
thumb	O
help	O
advance	O
clinical	O
treatments	O
such	O
as	O
tendon	O
transfers	O
[	O
1	O
]	O
,	O
functional	O
electrical	O
stimulation	O
[	O
2	O
]	O
and	O
plasticity	O
suppression	O
[	O
3	O
]	O
.	O

Measurement	O
of	O
strength	O
during	O
maximum	O
voluntary	O
contraction	O
is	O
a	O
simple	O
and	O
direct	O
means	O
of	O
assessing	O
neuromuscular	O
function	O
.	O

Popular	O
instruments	O
used	O
for	O
quantitative	O
assessment	O
of	O
thumb	O
strength	O
are	O
pinch	O
dynamometers	O
.	O

The	O
pinch	O
output	O
,	O
however	O
,	O
provides	O
limited	O
information	O
about	O
thumb	O
motor	O
function	O
in	O
that	O
it	O
offers	O
a	O
single	O
generic	O
force	O
in	O
one	O
specific	O
direction	O
.	O

Each	O
muscle	O
/	O
tendon	O
within	O
the	O
thumb	O
has	O
a	O
distinct	O
anatomical	O
origin	O
and	O
insertion	O
,	O
suggesting	O
its	O
external	O
force	O
potential	O
in	O
a	O
particular	O
direction	O
[	O
4	O
-	O
6	O
]	O
.	O

Hence	O
,	O
evaluation	O
of	O
strengths	O
in	O
multiple	O
directions	O
offers	O
insight	O
concerning	O
the	O
motor	O
capacity	O
of	O
individual	O
muscles	O
.	O

Force	O
production	O
of	O
a	O
digit	O
has	O
been	O
measured	O
in	O
various	O
directions	O
such	O
as	O
flexion	O
/	O
extension	O
[	O
7	O
,	O
8	O
]	O
,	O
abduction	O
/	O
adduction	O
[	O
9	O
-	O
14	O
]	O
,	O
or	O
in	O
combined	O
directions	O
[	O
15	O
,	O
16	O
]	O
.	O

Bourbonnais	O
et	O
al	O
.	O
developed	O
an	O
apparatus	O
to	O
measure	O
thumb	O
force	O
production	O
in	O
eight	O
directions	O
in	O
the	O
transverse	O
plane	O
of	O
the	O
thumb	O
and	O
investigated	O
force	O
dependence	O
on	O
the	O
direction	O
of	O
effort	O
[	O
15	O
]	O
.	O

Yokogawa	O
and	O
Hara	O
measured	O
index	O
fingertip	O
forces	O
in	O
various	O
directions	O
within	O
the	O
flexion	O
/	O
extension	O
plane	O
[	O
8	O
]	O
.	O

Recently	O
,	O
we	O
developed	O
experimental	O
apparatuses	O
to	O
measure	O
multi	O
-	O
directional	O
forces	O
of	O
a	O
digit	O
in	O
its	O
transverse	O
plane	O
[	O
17	O
-	O
19	O
]	O
.	O

From	O
these	O
multi	O
-	O
directional	O
forces	O
we	O
constructed	O
force	O
envelopes	O
representative	O
of	O
the	O
characteristic	O
force	O
output	O
pattern	O
of	O
a	O
digit	O
[	O
17	O
-	O
19	O
]	O
.	O

Disorders	O
resulting	O
from	O
traumatic	O
injuries	O
to	O
and	O
various	O
diseases	O
of	O
these	O
nerves	O
are	O
common	O
in	O
clinical	O
practice	O
.	O

Clinical	O
manifestations	O
of	O
hand	O
dysfunction	O
are	O
distinctive	O
depending	O
on	O
the	O
nerve	O
involved	O
.	O

For	O
example	O
,	O
thenar	O
atrophy	O
is	O
a	O
major	O
clinical	O
observation	O
affecting	O
thumb	O
function	O
at	O
the	O
later	O
stages	O
of	O
compression	O
neuropathy	O
of	O
the	O
median	O
nerve	O
.	O

Several	O
studies	O
have	O
been	O
conducted	O
to	O
investigate	O
the	O
effects	O
of	O
simulated	O
peripheral	O
neuropathies	O
using	O
local	O
anesthetization	O
[	O
5	O
,	O
16	O
,	O
20	O
,	O
21	O
]	O
.	O

Kozin	O
et	O
al	O
.	O

[	O
21	O
]	O
studied	O
the	O
effects	O
of	O
median	O
and	O
ulnar	O
nerve	O
blocks	O
on	O
grip	O
and	O
pinch	O
strength	O
and	O
showed	O
significant	O
decreases	O
following	O
nerve	O
blockage	O
[	O
21	O
]	O
.	O

Boatright	O
and	O
Kiebzak	O
[	O
20	O
]	O
investigated	O
the	O
effects	O
of	O
median	O
nerve	O
block	O
on	O
thumb	O
abduction	O
strength	O
.	O

Kaufman	O
et	O
al	O
.	O

[	O
5	O
]	O
measured	O
isometric	O
thumb	O
forces	O
in	O
eight	O
directions	O
together	O
with	O
electromyographic	O
signals	O
of	O
thumb	O
muscles	O
after	O
block	O
of	O
the	O
median	O
nerve	O
.	O

Labosky	O
and	O
Waggy	O
[	O
22	O
]	O
studied	O
the	O
strength	O
related	O
to	O
grip	O
,	O
pinch	O
,	O
thumb	O
adduction	O
,	O
thumb	O
abduction	O
,	O
and	O
finger	O
flexion	O
after	O
radial	O
nerve	O
block	O
[	O
22	O
]	O
.	O

Kuxhaus	O
studied	O
the	O
three	O
dimensional	O
feasible	O
force	O
set	O
at	O
the	O
thumb	O
-	O
tip	O
before	O
and	O
after	O
ulnar	O
nerve	O
block	O
and	O
reported	O
this	O
to	O
be	O
a	O
reproducible	O
and	O
sensitive	O
means	O
to	O
detect	O
impairment	O
.	O

The	O
purpose	O
of	O
this	O
study	O
was	O
to	O
utilize	O
our	O
developed	O
apparatus	O
and	O
protocols	O
to	O
investigate	O
the	O
effects	O
of	O
lower	O
median	O
nerve	O
lesion	O
on	O
thumb	O
motor	O
function	O
.	O

The	O
lesion	O
was	O
simulated	O
by	O
blocking	O
the	O
median	O
nerve	O
at	O
the	O
wrist	O
using	O
an	O
anesthetic	O
.	O

We	O
hypothesized	O
that	O
a	O
median	O
nerve	O
block	O
would	O
cause	O
(	O
1	O
)	O
a	O
decrease	O
in	O
force	O
production	O
,	O
which	O
would	O
be	O
direction	O
-	O
dependent	O
with	O
the	O
most	O
severe	O
reduction	O
in	O
the	O
abduction	O
direction	O
,	O
and	O
(	O
2	O
)	O
a	O
decrease	O
in	O
the	O
force	O
envelope	O
area	O
and	O
force	O
quadrant	O
area	O
,	O
with	O
the	O
greatest	O
decrease	O
in	O
the	O
abduction	O
quadrant	O
.	O

Methods	O

Subjects	O

Six	O
healthy	O
male	O
subjects	O
(	O
mean	O
age	O
:	O
26	O
.	O
9	O
+	O
/	O
-	O
5	O
.	O
1	O
years	O
)	O
participated	O
in	O
this	O
study	O
.	O

The	O
subjects	O
had	O
no	O
previous	O
history	O
of	O
neuromuscular	O
or	O
musculoskeletal	O
disorders	O
of	O
the	O
upper	O
extremities	O
.	O

Each	O
subject	O
signed	O
an	O
informed	O
consent	O
form	O
approved	O
by	O
the	O
Institutional	O
Review	O
Board	O
prior	O
to	O
participating	O
in	O
the	O
experiment	O
.	O

Median	O
nerve	O
block	O

Injections	O
were	O
performed	O
under	O
aseptic	O
conditions	O
while	O
the	O
subjects	O
sat	O
with	O
the	O
forearm	O
supinated	O
and	O
the	O
wrist	O
slightly	O
extended	O
.	O

After	O
the	O
skin	O
at	O
the	O
palmer	O
area	O
of	O
the	O
wrist	O
was	O
cleaned	O
with	O
alcohol	O
,	O
4	O
mL	O
of	O
0	O
.	O
5	O
%	O
bupivacaine	O
hydrochloride	O
(	O
Astra	O
Pharmaceuticals	O
,	O
Westborough	O
,	O
MA	O
,	O
USA	O
)	O
was	O
injected	O
into	O
the	O
carpal	O
tunnel	O
with	O
a	O
sterile	O
25	O
-	O
gauge	O
short	O
-	O
bevel	O
needle	O
.	O

The	O
needle	O
was	O
inserted	O
through	O
the	O
transverse	O
carpal	O
ligament	O
in	O
line	O
with	O
the	O
radial	O
border	O
of	O
the	O
fourth	O
digit	O
slightly	O
ulnar	O
to	O
the	O
palmaris	O
longus	O
tendon	O
at	O
the	O
level	O
of	O
the	O
distal	O
wrist	O
crease	O
.	O

Forty	O
minutes	O
was	O
allowed	O
for	O
the	O
median	O
nerve	O
block	O
to	O
reach	O
complete	O
effectiveness	O
[	O
23	O
]	O
and	O
was	O
verified	O
using	O
the	O
Semmes	O
-	O
Weinstein	O
monofilament	O
test	O
.	O

The	O
average	O
monofilament	O
score	O
was	O
2	O
.	O
85	O
across	O
the	O
five	O
digits	O
before	O
nerve	O
block	O
.	O

About	O
40	O
minutes	O
after	O
nerve	O
injection	O
,	O
little	O
sensory	O
impairment	O
occurred	O
in	O
the	O
ulnar	O
distribution	O
(	O
score	O
=	O
3	O
.	O
22	O
)	O
,	O
while	O
the	O
sensory	O
score	O
in	O
the	O
median	O
distribution	O
was	O
greater	O
than	O
6	O
.	O
15	O
.	O

The	O
effects	O
of	O
nerve	O
block	O
lasted	O
more	O
than	O
6	O
hours	O
with	O
all	O
subjects	O
regaining	O
normal	O
hand	O
function	O
within	O
12	O
hours	O
.	O

Testing	O
apparatus	O

The	O
experimental	O
apparatus	O
was	O
designed	O
and	O
constructed	O
to	O
measure	O
maximum	O
voluntary	O
contraction	O
forces	O
of	O
any	O
digit	O
at	O
any	O
point	O
along	O
the	O
digit	O
.	O

Force	O
application	O
was	O
possible	O
in	O
any	O
direction	O
within	O
the	O
transverse	O
plane	O
of	O
the	O
longitudinal	O
axis	O
of	O
the	O
digit	O
.	O

The	O
apparatus	O
consisted	O
of	O
position	O
control	O
accessories	O
,	O
a	O
force	O
transducer	O
,	O
and	O
a	O
custom	O
fitted	O
aluminum	O
ring	O
attached	O
to	O
the	O
transducer	O
(	O
Figure	O
1A	O
,	O
1B	O
)	O
.	O

The	O
transducer	O
(	O
Mini40	O
,	O
ATI	O
Industrial	O
Automation	O
,	O
NC	O
,	O
USA	O
)	O
,	O
capable	O
of	O
measuring	O
6	O
degrees	O
of	O
freedom	O
forces	O
and	O
moments	O
,	O
was	O
attached	O
to	O
a	O
mounting	O
clamp	O
via	O
an	O
aluminum	O
adapter	O
plate	O
while	O
the	O
aluminum	O
ring	O
was	O
secured	O
to	O
the	O
tool	O
side	O
of	O
the	O
transducer	O
using	O
a	O
custom	O
adapter	O
.	O

The	O
ring	O
served	O
as	O
a	O
connection	O
anchor	O
for	O
the	O
transducer	O
and	O
the	O
digit	O
.	O

The	O
force	O
transducer	O
and	O
ring	O
attachment	O
were	O
positioned	O
in	O
a	O
desired	O
orientation	O
using	O
an	O
aluminum	O
slide	O
rail	O
,	O
tubing	O
,	O
and	O
lockable	O
mounting	O
clamps	O
(	O
80	O
/	O
20	O
Inc	O
.	O
,	O
Columbia	O
City	O
,	O
IN	O
,	O
USA	O
)	O
.	O

The	O
slide	O
rail	O
was	O
secured	O
to	O
an	O
aluminum	O
base	O
plate	O
.	O

Foam	O
padded	O
wooden	O
blocks	O
with	O
two	O
locking	O
straps	O
secured	O
the	O
arm	O
to	O
the	O
base	O
plate	O
.	O

The	O
analog	O
outputs	O
from	O
the	O
transducer	O
were	O
digitized	O
using	O
a	O
16	O
-	O
bit	O
analog	O
-	O
to	O
-	O
digital	O
converter	O
(	O
PCI	O
-	O
6031	O
,	O
National	O
Instruments	O
,	O
TX	O
,	O
USA	O
)	O
.	O

The	O
X	O
(	O
abduction	O
/	O
adduction	O
)	O
and	O
Y	O
(	O
flexion	O
/	O
extension	O
)	O
force	O
components	O
in	O
the	O
transverse	O
plane	O
were	O
displayed	O
on	O
the	O
screen	O
while	O
the	O
subject	O
performed	O
a	O
force	O
production	O
task	O
.	O

The	O
resolutions	O
of	O
the	O
force	O
transducer	O
in	O
its	O
axial	O
(	O
flexion	O
/	O
extension	O
)	O
and	O
horizontal	O
(	O
abduction	O
/	O
adduction	O
)	O
directions	O
were	O
0	O
.	O
16	O
N	O
and	O
0	O
.	O
08	O
N	O
,	O
respectively	O
.	O

A	O
personal	O
computer	O
equipped	O
with	O
LabVIEW	O
(	O
National	O
Instrument	O
,	O
TX	O
,	O
USA	O
)	O
was	O
used	O
for	O
force	O
data	O
acquisition	O
,	O
display	O
,	O
and	O
processing	O
.	O

Experimental	O
procedures	O

Each	O
subject	O
was	O
tested	O
before	O
and	O
after	O
median	O
nerve	O
block	O
.	O

The	O
nerve	O
block	O
procedures	O
were	O
performed	O
immediately	O
after	O
the	O
completion	O
of	O
the	O
first	O
testing	O
session	O
.	O

Post	O
-	O
block	O
testing	O
started	O
after	O
the	O
verification	O
of	O
complete	O
median	O
nerve	O
block	O
,	O
approximately	O
40	O
minutes	O
after	O
the	O
injection	O
.	O

During	O
each	O
test	O
,	O
the	O
subject	O
was	O
seated	O
in	O
a	O
chair	O
adjacent	O
to	O
the	O
testing	O
station	O
modified	O
with	O
a	O
wooden	O
board	O
to	O
align	O
their	O
back	O
vertically	O
throughout	O
the	O
trials	O
.	O

The	O
subjects	O
rested	O
their	O
forearm	O
on	O
padded	O
wooden	O
blocks	O
positioning	O
their	O
shoulder	O
in	O
approximately	O
60	O
degrees	O
of	O
frontal	O
plane	O
abduction	O
.	O

Nylon	O
straps	O
fitted	O
with	O
plastic	O
snap	O
locking	O
mechanisms	O
secured	O
the	O
forearm	O
and	O
minimized	O
the	O
intervention	O
of	O
the	O
elbow	O
and	O
shoulder	O
during	O
thumb	O
force	O
application	O
.	O

Subjects	O
grasped	O
a	O
vertical	O
dowel	O
secured	O
to	O
the	O
distal	O
end	O
of	O
the	O
wooden	O
blocks	O
in	O
a	O
midprone	O
position	O
.	O

Formable	O
thermoplastic	O
braces	O
were	O
used	O
to	O
fix	O
the	O
elbow	O
in	O
90	O
degrees	O
of	O
flexion	O
,	O
and	O
the	O
wrist	O
in	O
20	O
degrees	O
of	O
extension	O
and	O
0	O
degrees	O
of	O
ulnar	O
deviation	O
.	O

A	O
metallic	O
brace	O
was	O
used	O
to	O
fix	O
the	O
interphalangeal	O
joint	O
of	O
the	O
thumb	O
in	O
full	O
extension	O
.	O

The	O
aluminum	O
ring	O
was	O
placed	O
around	O
the	O
middle	O
of	O
the	O
proximal	O
phalanx	O
and	O
oriented	O
to	O
accommodate	O
comfortable	O
thumb	O
position	O
with	O
the	O
metacarpophalangeal	O
joint	O
flexed	O
approximately	O
15	O
degrees	O
.	O

Prior	O
to	O
testing	O
,	O
a	O
line	O
was	O
drawn	O
on	O
the	O
proximal	O
phalange	O
at	O
the	O
midpoint	O
between	O
the	O
interphalangeal	O
and	O
metacarpophalangeal	O
joints	O
.	O

The	O
alignment	O
of	O
the	O
ring	O
with	O
the	O
circumferential	O
line	O
standardized	O
the	O
location	O
of	O
force	O
application	O
within	O
and	O
between	O
subjects	O
.	O

As	O
force	O
application	O
was	O
at	O
the	O
middle	O
of	O
the	O
proximal	O
phalanx	O
,	O
mechanical	O
action	O
pertains	O
to	O
both	O
the	O
metacarpophalangeal	O
and	O
carpometacarpal	O
joints	O
.	O

We	O
chose	O
the	O
terminology	O
of	O
flexion	O
/	O
extension	O
and	O
adduction	O
/	O
adduction	O
based	O
on	O
the	O
mechanical	O
action	O
with	O
respect	O
to	O
the	O
metacarpophalangeal	O
joint	O
.	O

With	O
the	O
thumb	O
in	O
the	O
ring	O
(	O
Figure	O
1B	O
)	O
,	O
extension	O
and	O
flexion	O
occurred	O
in	O
parallel	O
with	O
the	O
palm	O
,	O
and	O
abduction	O
and	O
adduction	O
occurred	O
in	O
a	O
plane	O
perpendicular	O
to	O
the	O
palm	O
.	O

Each	O
subject	O
performed	O
15	O
circumferential	O
MVC	O
trials	O
with	O
randomized	O
starting	O
directions	O
(	O
Figure	O
1C	O
)	O
.	O

The	O
subject	O
was	O
allotted	O
15	O
seconds	O
to	O
complete	O
each	O
circumferential	O
trial	O
,	O
and	O
was	O
instructed	O
to	O
use	O
the	O
entire	O
time	O
allotted	O
to	O
traverse	O
the	O
perimeter	O
of	O
the	O
ring	O
once	O
.	O

A	O
dot	O
generated	O
on	O
the	O
computer	O
screen	O
was	O
programmed	O
to	O
traverse	O
a	O
circle	O
within	O
15	O
seconds	O
to	O
provide	O
the	O
subject	O
with	O
directional	O
feedback	O
of	O
their	O
force	O
application	O
.	O

Subjects	O
were	O
given	O
60	O
seconds	O
of	O
rest	O
between	O
each	O
circumferential	O
trial	O
.	O

Each	O
subject	O
was	O
familiarized	O
with	O
the	O
task	O
with	O
a	O
few	O
practice	O
trials	O
.	O

Data	O
were	O
collected	O
from	O
each	O
subject	O
at	O
100	O
samples	O
per	O
second	O
producing	O
a	O
total	O
of	O
22	O
,	O
500	O
pairs	O
of	O
force	O
components	O
from	O
the	O
15	O
circumferential	O
trials	O
.	O

Our	O
previous	O
study	O
[	O
19	O
]	O
indicated	O
that	O
the	O
testing	O
protocol	O
did	O
not	O
cause	O
noticeable	O
fatigue	O
.	O

Force	O
envelope	O
and	O
quadrants	O

Data	O
from	O
multiple	O
circumferential	O
trials	O
were	O
accumulated	O
to	O
construct	O
a	O
force	O
envelope	O
.	O

The	O
procedures	O
to	O
generate	O
a	O
force	O
envelope	O
were	O
as	O
follows	O
:	O

Cartesian	O
force	O
coordinates	O
(	O
Xi	O
,	O
Yi	O
)	O
were	O
transformed	O
into	O
polar	O
coordinates	O
(	O
R	O
alpha	O
,	O
alpha	O
)	O
,	O
where	O
R	O
alpha	O
was	O
the	O
force	O
magnitude	O
at	O
an	O
angular	O
position	O
alpha	O
.	O

Each	O
alpha	O
was	O
rounded	O
to	O
the	O
nearest	O
integer	O
ranging	O
from	O
0	O
to	O
359	O
degrees	O
.	O

The	O
maximum	O
,	O
F	O
alpha	O
,	O
was	O
determined	O
from	O
a	O
string	O
of	O
N	O
data	O
points	O
along	O
each	O
radial	O
line	O
defined	O
by	O
alpha	O
.	O

At	O
the	O
completion	O
of	O
the	O
15	O
trials	O
,	O
there	O
were	O
,	O
on	O
average	O
,	O
N	O
=	O
63	O
data	O
points	O
on	O
each	O
radial	O
line	O
of	O
alpha	O
based	O
on	O
the	O
distribution	O
off	O
the	O
22	O
,	O
500	O
data	O
points	O
around	O
360	O
degrees	O
.	O

A	O
moving	O
average	O
with	O
an	O
interval	O
of	O
10	O
degrees	O
was	O
applied	O
to	O
the	O
maximal	O
series	O
data	O
F	O
alpha	O
(	O
alpha	O
=	O
0	O
,	O
1	O
,	O
2	O
,	O
.	O
.	O
.	O
,	O
359	O
)	O
to	O
obtain	O
filtered	O
maximal	O
forces	O
.	O

These	O
forces	O
formed	O
a	O
force	O
envelope	O
.	O

The	O
area	O
formed	O
by	O
a	O
force	O
envelope	O
was	O
divided	O
into	O
adduction	O
-	O
extension	O
,	O
extension	O
-	O
abduction	O
,	O
abduction	O
-	O
flexion	O
,	O
and	O
flexion	O
-	O
adduction	O
quadrants	O
by	O
radial	O
lines	O
oriented	O
at	O
0	O
degrees	O
,	O
90	O
degrees	O
,	O
180	O
degrees	O
,	O
and	O
270	O
degrees	O
A	O
quadrant	O
force	O
was	O
represented	O
using	O
the	O
mean	O
magnitude	O
of	O
the	O
forces	O
in	O
that	O
quadrant	O
.	O

The	O
areas	O
of	O
the	O
entire	O
envelope	O
and	O
each	O
quadrant	O
were	O
calculated	O
by	O
summing	O
the	O
areas	O
of	O
individual	O
arc	O
sections	O
formed	O
by	O
the	O
polar	O
coordinates	O
of	O
the	O
force	O
envelope	O
.	O

(	O
Figure	O
2	O
)	O
.	O

Statistical	O
Analyses	O

One	O
-	O
and	O
two	O
-	O
factor	O
repeated	O
measures	O
analyses	O
of	O
variance	O
(	O
ANOVA	O
)	O
were	O
used	O
to	O
analyze	O
outcome	O
measures	O
.	O

The	O
independent	O
variables	O
were	O
testing	O
SESSION	O
(	O
n	O
=	O
2	O
,	O
i	O
.	O
e	O
.	O
,	O
pre	O
-	O
and	O
post	O
-	O
block	O
)	O
,	O
force	O
DIRECTION	O
(	O
n	O
=	O
16	O
)	O
,	O
and	O
force	O
QUADRANT	O
(	O
n	O
=	O
4	O
)	O
,	O
with	O
SESSION	O
as	O
a	O
repeated	O
variable	O
.	O

Dependent	O
variables	O
were	O
directional	O
force	O
,	O
individual	O
quadrant	O
area	O
and	O
force	O
envelope	O
area	O
.	O

Statistical	O
analyses	O
were	O
performed	O
using	O
SPSS	O
11	O
(	O
SPSS	O
Inc	O
.	O
,	O
Illinois	O
)	O
with	O
statistical	O
significance	O
set	O
at	O
alpha	O
=	O
0	O
.	O
05	O
.	O

Results	O

Force	O
envelope	O
and	O
directional	O
forces	O

Figure	O
3	O
shows	O
the	O
force	O
envelopes	O
produced	O
by	O
each	O
subject	O
(	O
A	O
to	O
F	O
)	O
before	O
and	O
after	O
median	O
nerve	O
block	O
.	O

The	O
post	O
-	O
block	O
force	O
envelope	O
was	O
inside	O
the	O
pre	O
-	O
block	O
envelope	O
for	O
each	O
subject	O
,	O
indicating	O
a	O
decrease	O
in	O
force	O
magnitude	O
in	O
all	O
directions	O
after	O
nerve	O
block	O
.	O

Figure	O
4	O
shows	O
the	O
average	O
pre	O
-	O
and	O
post	O
-	O
block	O
force	O
envelope	O
across	O
all	O
subjects	O
.	O

Force	O
magnitudes	O
were	O
significantly	O
reduced	O
after	O
nerve	O
block	O
(	O
p	O
<	O
0	O
.	O
001	O
)	O
resulting	O
in	O
significantly	O
smaller	O
force	O
envelopes	O
.	O

The	O
average	O
decrease	O
across	O
all	O
directions	O
was	O
27	O
.	O
9	O
%	O
.	O

A	O
maximum	O
decrease	O
of	O
42	O
.	O
4	O
%	O
occurred	O
at	O
199	O
degrees	O
,	O
corresponding	O
to	O
a	O
combined	O
direction	O
of	O
abduction	O
and	O
slight	O
flexion	O
,	O
while	O
a	O
minimum	O
decrease	O
of	O
10	O
.	O
5	O
%	O
occurred	O
at	O
328	O
degrees	O
corresponding	O
to	O
a	O
combined	O
direction	O
of	O
adduction	O
and	O
slight	O
flexion	O
.	O

Relative	O
decreases	O
at	O
0	O
degrees	O
(	O
adduction	O
)	O
,	O
90	O
degrees	O
(	O
extension	O
)	O
,	O
180	O
degrees	O
(	O
abduction	O
)	O
,	O
and	O
270	O
degrees	O
(	O
flexion	O
)	O
directions	O
were	O
17	O
.	O
3	O
%	O
,	O
21	O
.	O
2	O
%	O
,	O
41	O
.	O
2	O
%	O
and	O
33	O
.	O
5	O
%	O
,	O
respectively	O
.	O

A	O
single	O
force	O
in	O
each	O
quadrant	O
was	O
represented	O
using	O
the	O
mean	O
magnitude	O
of	O
the	O
forces	O
in	O
that	O
quadrant	O
(	O
see	O
description	O
in	O
the	O
Methods	O
)	O
.	O

The	O
average	O
quadrant	O
forces	O
were	O
significantly	O
decreased	O
after	O
nerve	O
block	O
(	O
p	O
<	O
0	O
.	O
001	O
;	O
Figure	O
5	O
)	O
.	O

The	O
amount	O
of	O
decrease	O
was	O
also	O
different	O
between	O
quadrants	O
(	O
p	O
<	O
0	O
.	O
005	O
)	O
.	O

Relative	O
decreases	O
in	O
mean	O
quadrant	O
forces	O
were	O
24	O
.	O
5	O
%	O
,	O
38	O
.	O
7	O
%	O
,	O
32	O
.	O
1	O
%	O
,	O
and	O
18	O
.	O
1	O
%	O
for	O
extension	O
,	O
abduction	O
,	O
flexion	O
,	O
and	O
adduction	O
,	O
respectively	O
.	O

The	O
maximal	O
decreases	O
in	O
mean	O
quadrant	O
force	O
,	O
38	O
.	O
7	O
%	O
,	O
occurred	O
in	O
the	O
abduction	O
quadrant	O
.	O

Force	O
envelope	O
areas	O
and	O
quadrant	O
areas	O

Areas	O
enclosed	O
by	O
the	O
post	O
-	O
block	O
envelopes	O
were	O
significantly	O
smaller	O
than	O
the	O
pre	O
-	O
block	O
envelopes	O
(	O
p	O
<	O
0	O
.	O
001	O
;	O
Figure	O
4	O
)	O
.	O

Post	O
-	O
block	O
force	O
envelope	O
area	O
,	O
10700	O
+	O
/	O
-	O
4474	O
N	O
.	O
N	O
,	O
was	O
51	O
.	O
9	O
%	O
of	O
pre	O
-	O
block	O
force	O
envelope	O
area	O
,	O
20628	O
+	O
/	O
-	O
7747	O
N	O
.	O
N	O
.	O

Quadrant	O
area	O
decreased	O
significantly	O
(	O
p	O
<	O
0	O
.	O
001	O
;	O
Figure	O
6	O
)	O
.	O

The	O
maximal	O
percentage	O
decrease	O
in	O
area	O
after	O
nerve	O
block	O
was	O
60	O
.	O
9	O
%	O
in	O
the	O
abduction	O
quadrant	O
,	O
followed	O
by	O
a	O
52	O
.	O
3	O
%	O
area	O
decrease	O
in	O
the	O
flexion	O
quadrant	O
.	O

Discussion	O

In	O
this	O
study	O
we	O
simulated	O
a	O
lower	O
median	O
nerve	O
lesion	O
and	O
evaluated	O
the	O
resultant	O
thumb	O
motor	O
function	O
deficit	O
.	O

Our	O
internal	O
control	O
via	O
pre	O
-	O
and	O
post	O
-	O
block	O
design	O
offered	O
a	O
particular	O
advantage	O
of	O
investigating	O
the	O
mechanical	O
role	O
of	O
muscles	O
innervated	O
by	O
a	O
targeted	O
nerve	O
.	O

The	O
testing	O
and	O
analytical	O
methods	O
employed	O
have	O
provided	O
advanced	O
quantification	O
of	O
thumb	O
motor	O
function	O
.	O

The	O
results	O
have	O
confirmed	O
our	O
initial	O
hypotheses	O
that	O
greatest	O
force	O
decreases	O
occurred	O
in	O
directions	O
related	O
to	O
abduction	O
,	O
and	O
that	O
the	O
post	O
-	O
block	O
thumb	O
force	O
envelope	O
area	O
was	O
smaller	O
than	O
the	O
pre	O
-	O
block	O
force	O
envelope	O
area	O
.	O

Preferential	O
force	O
attenuation	O
in	O
the	O
quadrants	O
of	O
abduction	O
and	O
flexion	O
after	O
median	O
nerve	O
block	O
are	O
in	O
agreement	O
with	O
anatomical	O
and	O
neuromuscular	O
features	O
of	O
the	O
thumb	O
.	O

The	O
median	O
nerve	O
innervates	O
the	O
abductor	O
pollicis	O
brevis	O
,	O
the	O
opponens	O
pollicis	O
and	O
superficial	O
head	O
of	O
the	O
flexor	O
pollicis	O
brevis	O
,	O
all	O
of	O
which	O
contribute	O
to	O
the	O
abduction	O
and	O
flexion	O
of	O
the	O
thumb	O
[	O
4	O
]	O
;	O
therefore	O
,	O
denervation	O
of	O
these	O
muscles	O
after	O
median	O
nerve	O
block	O
would	O
cause	O
the	O
greatest	O
force	O
deficit	O
related	O
to	O
median	O
nerve	O
function	O
[	O
5	O
]	O
.	O

Additionally	O
,	O
as	O
force	O
application	O
moved	O
towards	O
adduction	O
,	O
the	O
force	O
deficit	O
decreased	O
as	O
neuromuscular	O
control	O
shifted	O
from	O
the	O
median	O
nerve	O
to	O
the	O
ulnar	O
nerve	O
via	O
the	O
first	O
dorsal	O
interosseous	O
and	O
adductor	O
pollicis	O
brevis	O
.	O

Force	O
deficit	O
in	O
extension	O
was	O
also	O
comparably	O
small	O
as	O
extension	O
forces	O
are	O
mainly	O
produced	O
by	O
the	O
extensors	O
pollicis	O
brevis	O
and	O
longus	O
originating	O
in	O
the	O
forearm	O
.	O

Our	O
reported	O
force	O
decreases	O
following	O
a	O
median	O
nerve	O
block	O
(	O
40	O
.	O
9	O
%	O
in	O
abduction	O
,	O
34	O
.	O
1	O
%	O
in	O
flexion	O
)	O
were	O
smaller	O
than	O
those	O
reported	O
in	O
the	O
literature	O
.	O

Kozin	O
et	O
al	O
.	O

[	O
21	O
]	O
reported	O
a	O
60	O
%	O
decrease	O
in	O
pinch	O
strength	O
after	O
a	O
median	O
nerve	O
block	O
using	O
mepivicaine	O
hydrochloride	O
[	O
21	O
]	O
.	O

Boatright	O
and	O
Kiebzak	O
[	O
20	O
]	O
reported	O
an	O
approximate	O
70	O
%	O
decrease	O
in	O
thumb	O
abduction	O
strength	O
after	O
median	O
nerve	O
block	O
using	O
Lidocaine	O
[	O
20	O
]	O
.	O

Kaufman	O
et	O
al	O
.	O

[	O
5	O
]	O
stated	O
that	O
a	O
median	O
nerve	O
block	O
with	O
Lidocaine	O
almost	O
completely	O
diminished	O
force	O
production	O
in	O
the	O
abduction	O
direction	O
[	O
5	O
]	O
.	O

The	O
discrepancy	O
may	O
be	O
due	O
to	O
the	O
anesthetic	O
used	O
and	O
strength	O
testing	O
method	O
.	O

Although	O
the	O
sensory	O
block	O
appeared	O
to	O
be	O
complete	O
for	O
each	O
method	O
,	O
the	O
motor	O
capabilities	O
of	O
the	O
muscles	O
associated	O
with	O
the	O
median	O
nerve	O
might	O
or	O
might	O
not	O
be	O
completely	O
eliminated	O
.	O

Such	O
a	O
result	O
is	O
largely	O
dependent	O
on	O
a	O
particular	O
anesthetic	O
,	O
its	O
concentration	O
and	O
dosage	O
,	O
as	O
well	O
as	O
the	O
efficacy	O
of	O
the	O
injection	O
technique	O
at	O
immersing	O
the	O
nerve	O
.	O

The	O
methods	O
of	O
strength	O
testing	O
may	O
also	O
help	O
explain	O
the	O
different	O
magnitudes	O
of	O
strength	O
deficit	O
after	O
the	O
nerve	O
block	O
.	O

All	O
previous	O
results	O
were	O
based	O
on	O
forces	O
obtained	O
in	O
discrete	O
direction	O
(	O
s	O
)	O
,	O
and	O
focused	O
exertions	O
,	O
while	O
the	O
current	O
study	O
utilized	O
a	O
method	O
of	O
force	O
production	O
in	O
a	O
continuous	O
,	O
circumferential	O
and	O
dynamic	O
manner	O
.	O

Furthermore	O
,	O
thumb	O
motor	O
performance	O
can	O
be	O
maintained	O
despite	O
the	O
absence	O
of	O
certain	O
individual	O
muscles	O
.	O

For	O
example	O
,	O
Britto	O
and	O
Elliot	O
reported	O
that	O
the	O
loss	O
of	O
abductor	O
pollicis	O
longus	O
and	O
extensor	O
pollicis	O
brevis	O
in	O
their	O
two	O
patients	B
did	O
not	O
show	O
functional	O
compromise	O
of	O
strength	O
and	O
grip	O
strength	O
[	O
24	O
]	O
.	O

In	O
a	O
broader	O
sense	O
,	O
the	O
neuromuscular	O
system	O
has	O
remarkable	O
capabilities	O
to	O
accomplish	O
the	O
same	O
motor	O
function	O
goal	O
using	O
different	O
effectors	O
and	O
different	O
goals	O
using	O
the	O
same	O
effectors	O
,	O
a	O
phenomenon	O
so	O
called	O
"	O
motor	O
equivalence	O
"	O
[	O
25	O
]	O
.	O

An	O
unexpected	O
finding	O
from	O
this	O
study	O
was	O
that	O
the	O
force	O
deficit	O
occurred	O
in	O
all	O
directions	O
(	O
Figure	O
4	O
)	O
.	O

In	O
other	O
words	O
,	O
the	O
median	O
nerve	O
block	O
caused	O
reduced	O
force	O
production	O
by	O
those	O
muscles	O
not	O
associated	O
with	O
the	O
median	O
nerve	O
.	O

Several	O
potential	O
explanations	O
exist	O
to	O
describe	O
such	O
a	O
phenomenon	O
.	O

First	O
,	O
the	O
injection	O
into	O
the	O
carpal	O
tunnel	O
at	O
the	O
wrist	O
,	O
although	O
localized	O
,	O
potentially	O
diffused	O
into	O
the	O
intrinsic	O
fascia	O
of	O
the	O
hand	O
partially	O
compromising	O
function	O
of	O
the	O
ulnar	O
nerve	O
,	O
which	O
innervates	O
the	O
adductor	O
pollicis	O
.	O

Although	O
Semmes	O
-	O
Weinstein	O
monofilament	O
testing	O
confirmed	O
the	O
continued	O
sensation	O
of	O
the	O
digits	O
within	O
the	O
ulnar	O
nerve	O
distribution	O
,	O
it	O
is	O
not	O
inconceivable	O
that	O
the	O
injection	O
could	O
have	O
contaminated	O
the	O
ulnar	O
innervated	O
muscles	O
,	O
the	O
first	O
dorsal	O
interosseous	O
and	O
deep	O
head	O
of	O
the	O
flexor	O
pollicis	O
brevis	O
[	O
20	O
]	O
.	O

Secondly	O
,	O
thumb	O
force	O
in	O
any	O
direction	O
is	O
produced	O
by	O
synergistic	O
activation	O
of	O
the	O
many	O
intrinsic	O
muscles	O
,	O
and	O
as	O
a	O
result	O
,	O
the	O
muscular	O
deficiency	O
associated	O
with	O
one	O
direction	O
may	O
hinder	O
the	O
force	O
production	O
in	O
other	O
directions	O
by	O
other	O
muscles	O
[	O
5	O
,	O
22	O
]	O
.	O

For	O
example	O
,	O
Kaufman	O
et	O
al	O
.	O
demonstrated	O
that	O
thumb	O
muscles	O
not	O
innervated	O
by	O
the	O
median	O
nerve	O
displayed	O
lower	O
electromyographical	O
activation	O
and	O
shifted	O
the	O
direction	O
of	O
maximum	O
activation	O
after	O
a	O
median	O
nerve	O
block	O
[	O
5	O
]	O
.	O

Labosky	O
and	O
Waggy	O
showed	O
that	O
a	O
radial	O
nerve	O
block	O
caused	O
a	O
53	O
%	O
decrease	O
in	O
thumb	O
abduction	O
strength	O
because	O
of	O
the	O
lack	O
of	O
stabilization	O
of	O
the	O
radial	O
innervated	O
extensor	O
muscles	O
[	O
22	O
]	O
.	O

Consequently	O
,	O
deficiency	O
of	O
median	O
innervated	O
muscles	O
inherently	O
limits	O
force	O
production	O
in	O
other	O
directions	O
as	O
neuromuscular	O
switching	O
is	O
necessary	O
to	O
produce	O
force	O
in	O
changing	O
directions	O
.	O

The	O
median	O
innervated	O
muscles	O
are	O
the	O
dominant	O
abductors	O
of	O
the	O
thumb	O
metacarpophalangeal	O
and	O
carpometacarpal	O
joint	O
.	O

The	O
more	O
than	O
50	O
%	O
residual	O
abduction	O
force	O
found	O
in	O
this	O
study	O
suggests	O
that	O
the	O
injection	O
did	O
not	O
totally	O
block	O
the	O
motor	O
function	O
of	O
these	O
muscles	O
,	O
even	O
though	O
a	O
complete	O
sensory	O
loss	O
was	O
verified	O
.	O

This	O
concurs	O
with	O
clinical	O
observations	O
of	O
median	O
compression	O
neuropathy	O
.	O

Individuals	O
with	O
carpal	O
tunnel	O
syndrome	O
complain	O
of	O
sensory	O
dysfunction	O
early	O
in	O
the	O
disease	O
process	O
(	O
at	O
the	O
beginning	O
)	O
,	O
while	O
motor	O
signs	O
of	O
thenar	O
wasting	O
and	O
thumb	O
weakness	O
occur	O
as	O
the	O
disease	O
advances	O
.	O

The	O
concept	O
that	O
the	O
motor	O
deficit	O
is	O
more	O
resistant	O
to	O
peripheral	O
median	O
neuropathy	O
than	O
sensory	O
loss	O
has	O
been	O
well	O
documented	O
[	O
23	O
,	O
26	O
,	O
27	O
]	O
.	O

Butterworth	O
et	O
al	O
.	O
studied	O
the	O
temporal	O
effects	O
on	O
sensory	O
and	O
motor	O
blockade	O
after	O
injection	O
of	O
bupivacaine	O
or	O
mepivacaine	O
,	O
and	O
found	O
that	O
sensory	O
loss	O
was	O
complete	O
but	O
about	O
a	O
20	O
%	O
compound	O
motor	O
action	O
potential	O
remained	O
after	O
40	O
minutes	O
[	O
23	O
]	O
.	O

In	O
conclusion	O
,	O
we	O
have	O
incorporated	O
a	O
method	O
for	O
assessing	O
thumb	O
motor	O
deficit	O
based	O
on	O
strength	O
measurement	O
with	O
a	O
standard	O
local	O
anesthetic	O
to	O
investigate	O
the	O
effects	O
of	O
a	O
simulated	O
median	O
neuropathy	O
on	O
thumb	O
motor	O
function	O
.	O

Median	O
nerve	O
block	O
results	O
in	O
force	O
deficits	O
in	O
all	O
directions	O
,	O
with	O
the	O
most	O
severe	O
impairment	O
in	O
abduction	O
and	O
flexion	O
.	O

Future	O
endeavors	O
using	O
this	O
methodology	O
can	O
potentially	O
further	O
elucidate	O
underlying	O
pathomechanisms	O
of	O
peripheral	O
neuropathies	O
in	O
all	O
digits	O
of	O
the	O
hand	O
.	O