bluuebunny/crossref_metadata_2025 huggingface dataset:
When does almost free imply free? (For groups, transversals, etc.)
Authors: Magidor Menachem , Shelah Saharon
Published: June 2010

We show that the construction of an almost free nonfree Abelian group can be pushed from a regular cardinal

κ
\kappa

to

ℵ

κ
+
1

{\aleph _{\kappa + 1}}

. Hence there are unboundedly many almost free nonfree Abelian groups below the first cardinal fixed point. We give a sufficient condition for “

κ
\kappa

free implies free”, and then we show, assuming the consistency of infinitely many supercompacts, that one can have a model of ZFC+G.C.H. in which

ℵ

ω
2

+
1

{\aleph _{{\omega ^2} + 1}}

free implies

ℵ

ω
2

+
2

{\aleph _{{\omega ^2} + 2}}

free. Similar construction yields a model in which

ℵ
κ

{\aleph _\kappa }

free implies free for

κ
\kappa

the first cardinal fixed point (namely, the first cardinal

α
\alpha

satisfying

α
=

ℵ
α

\alpha = {\aleph _\alpha }

). The absolute results about the existence of almost free nonfree groups require only minimal knowledge of set theory. Also, no knowledge of metamathematics is required for reading the section on the combinatorial principle used to show that almost free implies free. The consistency of the combinatorial principle requires acquaintance with forcing techniques.
On rigidity, limit sets, and end invariants of hyperbolic 3-manifolds
Authors: Minsky Yair N.
Published: June 2010

Thurston’s ending lamination conjecture states that a hyperbolic manifold is uniquely determined by a collection of Riemann surfaces and geodesic laminations that describe the asymptotic geometry of its ends. We prove this conjecture for the case of manifolds whose fundamental group is freely indecomposable, and which admit a positive lower bound on injectivity radii. The techniques of the proof apply to show that a Kleinian surface group admitting a positive lower bound on injectivity radii is continuously semiconjugate to a Fuchsian group. This extends results of Cannon and Thurston. A further consequence is a rigidity theorem for surface groups satisfying the injectivity radius condition, namely that two such groups whose actions on the sphere are conjugate by a homeomorphism that is conformal on the domains of discontinuity must be conjugate by a Möbius transformation.
Harmonic analysis and pointwise ergodic theorems for noncommuting transformations
Authors: Nevo Amos
Published: June 2010

Let

F
k

{F_k}

denote the free group on

k
k

generators,

1
>
k
>
∞

1 > k > \infty

, and let

S
S

denote a set of free generators and their inverses. Define

σ
n

=

d

1

#

S
n

Σ

w
∈

S
n

w

{\sigma _n} \stackrel {d}{=} \frac {1}{{\# {S_n}}}{\Sigma _{w \in {S_n}}}w

, where

S
n

=
{
w
:

|

w

|

=
n
}

{S_n} = \{ w:|w| = n\}

, and

|

⋅

|

| \cdot |

denotes the word length on

F
k

{F_k}

induced by

S
S

. Let

(
X
,

B

,
m
)

(X, \mathcal {B}, m)

be a probability space on which

F
k

{F_k}

acts ergodically by measure preserving transformations. We prove a pointwise ergodic theorem for the sequence of operators

σ
n
′

=

1
2

(

σ
n

+

σ

n
+
1

)

\sigma _n^\prime = \frac {1}{2}({\sigma _n} + {\sigma _{n + 1}})

acting on

L
2

(
X
)

{L^2}(X)

, namely:

σ
n
′

f
(
x
)
→

∫
X

f

d
m

\sigma _n^\prime f(x) \to \int _X {f\,dm}

almost everywhere, for each

f
f

in

L
2

(
X
)

{L^2}(X)

. We also show that the sequence

σ

2
n

{\sigma _{2n}}

converges to a conditional expectation operator with respect to a

σ
\sigma

-algebra which is invariant under

F
k

{F_k}

. The proof is based on the spectral theory of the (commutative) convolution subalgebra of

ℓ
1

(

F
k

)

{\ell ^1}({F_k})

generated by the elements

σ
n

,

n
≥
0

{\sigma _n},\,\;n \geq 0

. We then generalize the discussion to algebras arising as a Gelfand pair associated with the group of automorphisms

G
(

r
1

,

r
2

)

G({r_1},\;{r_2})

of a semi-homogeneous tree

T
(

r
1

,

r
2

)

T({r_1},\;{r_2})

, where

r
1

≥
2
,

r
2

≥
2
,

r
1

+

r
2

>
4

{r_1} \geq 2,\;{r_2} \geq 2,\;{r_1} + {r_2} > 4

. (The case of

F
k

{F_k}

corresponds to that of a homogeneous tree of valency

2
k

2k

.) We prove similar pointwise ergodic theorems for two classes of subgroups of

G
(

r
1

,

r
2

)

G({r_1},\;{r_2})

. One is the class of closed noncompact boundary-transitive subgroups, including any simple algebraic group of split rank one over a local field, for example,

P
S

L
2

(

Q

p

)

PS{L_2}({\mathbb {Q}_p})

. The second class is that of lattices complementing a maximal compact subgroup. We also prove a strong maximal inequality in

L
2

(
X
)

{L^2}(X)

for the groups listed above, as well as a mean ergodic theorem for unitary representations of the groups (due to

Y

{\text {Y}}

. Guivarc’h for

F
k

{F_k}

). Finally, we describe the structure and spectral theory of a noncommutative algebra which arises naturally in the present context, namely the double coset algebra associated with the subgroup of

G
(

r
1

,

r
2

)

G({r_1},\;{r_2})

stabilizing a geometric edge. The results are applied to prove mean ergodic theorems for a family of lattices in

G
(

r
1

,

r
2

)

G({r_1},\;{r_2})

, which includes, for example,

P
S

L
2

(

Z

)

PS{L_2}(\mathbb {Z})

.
Threshold functions for Ramsey properties
Authors: Rödl Vojtěch , Ruciński Andrzej
Published: June 2010

Probabilistic methods have been used to approach many problems of Ramsey theory. In this paper we study Ramsey type questions from the point of view of random structures. Let

K
(
n
,
N
)

K(n,N)

be the random graph chosen uniformly from among all graphs with

n
n

vertices and

N
N

edges. For a fixed graph

G
G

and an integer

r
r

we address the question what is the minimum

N
=
N
(
G
,
r
,
n
)

N = N(G,r,n)

such that the random graph

K
(
n
,
N
)

K(n,N)

contains, almost surely, a monochromatic copy of

G
G

in every

r
r

-coloring of its edges (

K
(
n
,
N
)
→

(
G

)
r

K(n,N) \to {(G)_r}

, in short). We find a graph parameter

γ
=
γ
(
G
)

\gamma = \gamma (G)

yielding
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="limit Underscript n right-arrow normal infinity Endscripts upper P r o b left-parenthesis upper K left-parenthesis n comma upper N right-parenthesis right-arrow left-parenthesis upper G right-parenthesis Subscript r Baseline right-parenthesis equals StartLayout Enlarged left-brace 1st Row 0 if upper N greater-than c n Superscript y Baseline comma 2nd Row 1 if upper N greater-than upper C n Superscript y Baseline comma EndLayout">

lim

n
→
∞

Prob
⁡
(
K
(
n
,
N
)
→

(
G

)
r

)
=

{

0

if 

N
>
c

n
y

,

1

if

N
>
C

n
y

,

\lim \limits _{n \to \infty } \operatorname {Prob}(K(n,N) \to {(G)_r}) = \left \{ {\begin {array}{*{20}{c}} {0\quad {\text {if }}\;N > c{n^y},} \\ {1\quad {\text {if}}\;N > C{n^y},} \\ \end {array} } \right .\quad

\]
for some

c
c

,

C
>
0

C > 0

. We use this to derive a number of consequences that deal with the existence of sparse Ramsey graphs. For example we show that for all

r
≥
2

r \geq 2

and

k
≥
3

k \geq 3

there exists

C
>
0

C > 0

such that almost all graphs

H
H

with

n
n

vertices and

C

n

2
k

k
+
1

C{n^{\frac {{2k}}{{k + 1}}}}

edges which are

K

k
+
1

{K_{k + 1}}

-free, satisfy

H
→

(

K
k

)
r

H \to {({K_k})_r}

. We also apply our method to the problem of finding the smallest

N
=
N
(
k
,
r
,
n
)

N = N(k,r,n)

guaranteeing that almost all sequences

1
≤

a
1

>

a
2

>
⋯
>

a
N

≤
n

1 \leq {a_1} > {a_2} > \cdots > {a_N} \leq n

contain an arithmetic progression of length

k
k

in every

r
r

-coloring, and show that

N
=
Θ
(

n

k
−
2

k
−
1

)

N = \Theta ({n^{\frac {{k - 2}}{{k - 1}}}})

is the threshold.
Phosphatidic Acid Plays a Regulatory Role in Clathrin-mediated Endocytosis
Authors: Antonescu Costin N. , Danuser Gaudenz , Schmid Sandra L.
Published: June 2010

Clathrin-mediated endocytosis (CME) is the main route of internalization of receptor-ligand complexes. Relatively little is known about the role of specific lipids in CME, in particular that of phosphatidic acid (PA). We examined the effect of altering cellular PA levels on CME by manipulating the activities and/or levels of either phospholipase D (PLD1 and PLD2) or diacylglycerol kinase (DGK), two enzyme classes involved in PA production. DGK inhibition resulted in a dramatic reduction of cellular PA, measured directly using an enzyme-coupled reaction, which resulted in a decreased rate of EGFR internalization measured biochemically. This corresponded to a decreased rate of clathrin-coated pit (CCP) initiation and increased lifetimes of productive CCPs, as determined by quantitative live-cell total internal reflection fluorescence microscopy. Unexpectedly, PLD inhibition caused an increase in cellular PA, suggesting that PLD activity negatively regulates PA synthesis by other more productive pathways. Consistent with opposite effects on cellular PA levels, PLD inhibition had opposite effects on EGFR internalization and CCP dynamics, compared with DGK inhibition. Importantly, the constitutive internalization of transferrin receptors was unaffected by either treatment. These findings demonstrate that PA plays a regulatory rather than obligatory role in CME and differentially regulates ligand-stimulated CME of EGFR.
Mathematical Modeling of Endocytic Actin Patch Kinetics in Fission Yeast: Disassembly Requires Release of Actin Filament Fragments
Authors: Berro Julien , Sirotkin Vladimir , Pollard Thomas D.
Published: June 2010

We used the dendritic nucleation hypothesis to formulate a mathematical model of the assembly and disassembly of actin filaments at sites of clathrin-mediated endocytosis in fission yeast. We used the wave of active WASp recruitment at the site of the patch formation to drive assembly reactions after activation of Arp2/3 complex. Capping terminated actin filament elongation. Aging of the filaments by ATP hydrolysis and γ-phosphate dissociation allowed actin filament severing by cofilin. The model could simulate the assembly and disassembly of actin and other actin patch proteins using measured cytoplasmic concentrations of the proteins. However, to account quantitatively for the numbers of proteins measured over time in the accompanying article ( Sirotkin et al., 2010 , MBoC 21: 2894–2904), two reactions must be faster in cells than in vitro. Conditions inside the cell allow capping protein to bind to the barbed ends of actin filaments and Arp2/3 complex to bind to the sides of filaments faster than the purified proteins in vitro. Simulations also show that depolymerization from pointed ends cannot account for rapid loss of actin filaments from patches in 10 s. An alternative mechanism consistent with the data is that severing produces short fragments that diffuse away from the patch.
AnOrange RipeningMutant Links Plastid NAD(P)H Dehydrogenase Complex Activity to Central and Specialized Metabolism during Tomato Fruit Maturation
Authors: Nashilevitz Shai , Melamed-Bessudo Cathy , Izkovich Yinon , Rogachev Ilana , Osorio Sonia , Itkin Maxim , Adato Avital , Pankratov Ilya , Hirschberg Joseph , Fernie Alisdair R. , Wolf Shmuel , Usadel Björn , Levy Avraham A. , Rumeau Dominique , Aharoni Asaph
Published: June 2010

In higher plants, the plastidial NADH dehydrogenase (Ndh) complex supports nonphotochemical electron fluxes from stromal electron donors to plastoquinones. Ndh functions in chloroplasts are not clearly established; however, its activity was linked to the prevention of the overreduction of stroma, especially under stress conditions. Here, we show by the characterization of OrrDs, a dominant transposon-tagged tomato (Solanum lycopersicum) mutant deficient in the NDH-M subunit, that this complex is also essential for the fruit ripening process. Alteration to the NDH complex in fruit changed the climacteric, ripening-associated metabolites and transcripts as well as fruit shelf life. Metabolic processes in chromoplasts of ripening tomato fruit were affected in OrrDs, as mutant fruit were yellow-orange and accumulated substantially less total carotenoids, mainly β-carotene and lutein. The changes in carotenoids were largely influenced by environmental conditions and accompanied by modifications in levels of other fruit antioxidants, namely, flavonoids and tocopherols. In contrast with the pigmentation phenotype in mature mutant fruit, OrrDs leaves and green fruits did not display a visible phenotype but exhibited reduced Ndh complex quantity and activity. This study therefore paves the way for further studies on the role of electron transport and redox reactions in the regulation of fruit ripening and its associated metabolism.
A Pseudomonas syringae ADP-Ribosyltransferase Inhibits Arabidopsis Mitogen-Activated Protein Kinase Kinases
Authors: Wang Yujing , Li Jifeng , Hou Shuguo , Wang Xingwei , Li Yuan , Ren Dongtao , Chen She , Tang Xiaoyan , Zhou Jian-Min
Published: June 2010

The successful recognition of pathogen-associated molecular patterns (PAMPs) as a danger signal is crucial for plants to fend off numerous potential pathogenic microbes. The signal is relayed through mitogen-activated protein kinase (MPK) cascades to activate defenses. Here, we show that the Pseudomonas syringae type III effector HopF2 can interact with Arabidopsis thaliana MAP KINASE KINASE5 (MKK5) and likely other MKKs to inhibit MPKs and PAMP-triggered immunity. Inhibition of PAMP-induced MPK phosphorylation was observed when HopF2 was delivered naturally by the bacterial type III secretion system. In addition, HopF2 Arg-71 and Asp-175 residues that are required for the interaction with MKK5 are also necessary for blocking MAP kinase activation, PAMP-triggered defenses, and virulence function in plants. HopF2 can inactivate MKK5 and ADP-ribosylate the C terminus of MKK5 in vitro. Arg-313 of MKK5 is required for ADP-ribosylation by HopF2 and MKK5 function in the plant cell. Together, these results indicate that MKKs are important targets of HopF2.
Sequential Probability Ratio Test Using Scaled Time-Intervals for Environmental Radiation Monitoring
Authors: Luo Peng , DeVol Timothy A. , Sharp Julia L.
Published: June 2010

Sequential probability ratio test (SPRT) of scaled time-interval data (time to record N radiation pulses),SPRT_scaled, was evaluated against commonly used single-interval test (SIT) and SPRT with a fixed counting interval,SPRT_fixed, on experimental and simulated data. Experimental data were acquired with a DGF-4C (XIA, Inc) system in list mode. Simulated time-interval data were obtained using Monte Carlo techniques to perform a random radiation sampling of the Poisson distribution. The three methods (SIT, SPRT_fixed and SPRT_scaled) were compared in terms of detection probability and average time to make a decision regarding the source of radiation. For both experimental and simulated data, SPRT_scaled provided similar detection probabilities as other tests, but was able to make a quicker decision with fewer pulses at relatively higher radiation levels. SPRT_scaled has a provision for varying the sampling time depending on the radiation level, which may further shorten the time needed for radiation monitoring. Parameter adjustments to the SPRT_scaled method for increased detection probability are discussed.
Habitat use and movement patterns of bull sharks Carcharhinus leucas determined using pop‐up satellite archival tags
Authors: Carlson J. K. , Ribera M. M. , Conrath C. L. , Heupel M. R. , Burgess G. H.
Published: June 2010

Habitat use, movement and residency of bull sharks Carcharhinus leucas were determined using satellite pop‐up archival transmitting (PAT) tags throughout coastal areas in the U.S., Gulf of Mexico and waters off the south‐east U.S. From 2005 to 2007, 18 fish (mean size = 164 cm fork length, LF) were tagged over all seasons. Fish retained tags for up to 85 days (median = 30 days). Based on geolocation data from initial tagging location to pop‐off location, C. leucas generally travelled c. 5–6 km day−1 and travelled an average of 143·6 km. Overall, mean proportions of time at depth revealed C. leucas spent the majority of their time in waters <20 m. They exhibited significant differences among depths but were not found at a particular depth regardless of diurnal period. Most fish occupied temperatures c. 32° C with individuals found mostly between 26 and 33° C. Geolocation data for C. leucas were generally poor and varied considerably but tracks for two individuals revealed long distance movements. One fish travelled from the south‐east coast of the U.S. to coastal Texas near Galveston while another moved up the east coast of the U.S. to South Carolina. Data on C. leucas movements indicated that they are found primarily in shallower waters and tend to remain in the same location over long periods. While some individuals made large‐scale movements over open ocean areas, the results emphasize the importance of the coastal zone for this species as potential essential habitat, particularly in areas of high freshwater inflow.
Meta‐analysis of drug‐related deaths soon after release from prison
Authors: Merrall Elizabeth L. C. , Kariminia Azar , Binswanger Ingrid A. , Hobbs Michael S. , Farrell Michael , Marsden John , Hutchinson Sharon J. , Bird Sheila M.
Published: June 2010

Aims  The transition from prison back into the community is particularly hazardous for drug‐using offenders whose tolerance for heroin has been reduced by imprisonment. Studies have indicated an increased risk of drug‐related death soon after release from prison, particularly in the first 2 weeks. For precise, up‐to‐date understanding of these risks, a meta‐analysis was conducted on the risk of drug‐related death in weeks 1 + 2 and 3 + 4 compared with later 2‐week periods in the first 12 weeks after release from prison.

Methods  English‐language studies were identified that followed up adult prisoners for mortality from time of index release for at least 12 weeks. Six studies from six prison systems met the inclusion criteria and relevant data were extracted independently.

Results  These studies contributed a total of 69 093 person‐years and 1033 deaths in the first 12 weeks after release, of which 612 were drug‐related. A three‐ to eightfold increased risk of drug‐related death was found when comparing weeks 1 + 2 with weeks 3–12, with notable heterogeneity between countries: United Kingdom, 7.5 (95% CI: 5.7–9.9); Australia, 4.0 (95% CI: 3.4–4.8); Washington State, USA, 8.4 (95% CI: 5.0–14.2) and New Mexico State, USA, 3.1 (95% CI: 1.3–7.1). Comparing weeks 3 + 4 with weeks 5–12, the pooled relative risk was: 1.7 (95% CI: 1.3–2.2).

Conclusions  These findings confirm that there is an increased risk of drug‐related death during the first 2 weeks after release from prison and that the risk remains elevated up to at least the fourth week.
Homodimerization of pokeweed antiviral protein as a mechanism to limit depurination of pokeweed ribosomes
Authors: TOURLAKIS MARINA E. , KARRAN RAJITA A. , DESOUZA LEROI , SIU K. W. MICHAEL , HUDAK KATALIN A.
Published: June 2010

Ribosome inactivating proteins are glycosidases synthesized by many plants and have been hypothesized to serve in defence against pathogens. These enzymes catalytically remove a conserved purine from the sarcin/ricin loop of the large ribosomal RNA, which has been shown in vitro to limit protein synthesis. The resulting toxicity suggests that plants may possess a mechanism to protect their ribosomes from depurination during the synthesis of these enzymes. For example, pokeweed antiviral protein (PAP) is cotranslationally inserted into the lumen of the endoplasmic reticulum and travels via the endomembrane system to be stored in the cell wall. However, some PAP may retrotranslocate across the endoplasmic reticulum membrane to be released back into the cytosol, thereby exposing ribosomes to depurination. In this work, we isolated and characterized a complexed form of the enzyme that exhibits substantially reduced activity. We showed that this complex is a homodimer of PAP and that dimerization involves a peptide that contains a conserved aromatic amino acid, tyrosine 123, located in the active site of the enzyme. Bimolecular fluorescence complementation demonstrated that the homodimer may form in vivo and that dimerization is prevented by the substitution of tyrosine 123 for alanine. The homodimer is a minor form of PAP, observed only in the cytosol of cells and not in the apoplast. Taken together, these data support a novel mechanism for the limitation of depurination of autologous ribosomes by molecules of the protein that escape transport to the cell wall by the endomembrane system.
Microarray‐based comparison of genetic differences between strains ofStreptomyces turgidiscabieswith focus on the pathogenicity island
Authors: AITTAMAA MARJA , SOMERVUO PANU , LAAKSO INTO , AUVINEN PETRI , VALKONEN JARI P. T.
Published: June 2010

The areas of the pathogenicity island (PAI) designated as ‘colonization region’ (CR) and ‘toxicogenic region’ (TR) [Leratet al. (2009)Mol. Plant Pathol.10, 579–585] contain genes required for virulence and phytoxin production, respectively, inStreptomycesspp. causing common scab on potatoes. The PAI was tested for genetic variability by microarray analysis in strains ofS. turgidiscabiesisolated from potatoes in Finland. The data revealed four types of PAI based on divergent CR and TR which occurred in different combinations. Only one PAI type was highly similar toS. scabies(strains 87.22 and ATTC49173). Using probes designed for the predicted genes ofS. scabies, two gene clusters inS. scabiesappeared to be similar to most strains ofS. turgidiscabiesand contained PAI genes corresponding to CR and TR. They were located approximately 5 Mb apart in theS. scabiesgenome, as compared with only 0.3 Mb inS. turgidiscabiesCar8. Data from comparative genomic hybridization with probes designed forS. scabiesgenes and for the PAI ofS. turgidiscabieswere compared by multilocus cluster analysis, which revealed two strains ofS. turgidiscabiesthat were very closely related at the whole‐genome level, but contained distinctly different PAIs. The type strain ofS. reticuliscabiei(DSM41804; synonymous toS. turgidiscabies) was clustered withS. turgidiscabies. Taken together, the data indicate wide genetic variability of PAIs among strains ofS. turgidiscabies, and demonstrate that PAI is made up of a mosaic of regions which may undergo independent evolution.
Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug–drug interaction trials
Authors: Gueorguieva Ivelina , Jackson Kimberley , Wrighton Steven A. , Sinha Vikram P. , Chien Jenny Y.
Published: June 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Desipramine is extensively metabolized by CYP2D6 to its main metabolite 2‐OH‐desipramine.

• Alternative metabolic pathways are 10‐hydroxylation and further demethylation to didesipramine, but the concentration of these metabolites in plasma upon therapeutic oral doses are very low both in extensive and poor metabolizers of substrates of CYP2D6.

• Desipramine has been used widely as a probe drug for CYP2D6 activity.

WHAT THIS STUDY ADDS

• The population pharmacokinetics of desipramine in healthy subjects were characterized.

• The model allows performing simulations of trials which assess CYP2D6 interaction potential of novel compounds.

• Study design elements, such as required sample size based on desipramine within and between‐subject variance and optimal sampling schedules for the three subgroups, intermediate, extensive and ultrarapid metabolizers of CYP2D6 are suggested.

AIMS

To develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50 mg dose. Additional objectives were to develop a semi‐mechanistic population pharmacokinetic model for desipramine, which allowed simulation of CYP2D6‐mediated inhibition, when using desipramine as a probe substrate, and to evaluate certain study design elements, such as duration of desipramine pharmacokinetic sampling, required sample size and optimal pharmacokinetic sampling schedule for intermediate, extensive and ultrarapid metabolizers of CYP2D6 substrates.

RESULTS

The mean population estimates of the first order absorption rate constant (ka), apparent clearance (CL/F) and apparent volume of distribution at steady state (Vss/F) were 0.15 h−1, 111 l h−1and 2950 l, respectively. Further, using the proposed semi‐mechanistic hepatic intrinsic clearance model with Bayesian inference, mean population desipramine hepatic intrinsic clearance was estimated to be 262 l h−1with between‐subject variability of 84%.d‐optimal PK sampling times for intermediate metabolizers were calculated to be approximately 0.25, 24, 75 and 200 h. Similar sampling times were found for ultrarapid and extensive metabolizers except that the secondd‐optimal sample was earlier at 14 and 19 h, respectively, compared with 24 h for intermediate metabolizers. This difference in sampling times between the three genotypes can be attributed to the different intrinsic clearances and elimination rates.

CONCLUSIONS

A two compartment population pharmacokinetic model best described desipramine disposition. The semi‐mechanistic population model developed is suitable to describe the pharmacokinetic behaviour of desipramine for the dose routinely used in drug–drug interaction (DDI) studies. Based on this meta‐analysis of seven trials, a sample size of 21 subjects in cross‐over design is appropriate for assessing CYP2D6 interaction with novel compounds.
Potential use of rapamycin in HIV infection
Authors: Donia Marco , McCubrey James A. , Bendtzen Klaus , Nicoletti Ferdinando
Published: June 2010

The strong need for the development of alternative anti‐HIV agents is primarily due to the emergence of strain‐resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies indicating that the immunomodulatory drug rapamycin (RAPA) possesses anti‐HIV properties both in vitro and in vivo that qualifies it as a potential new anti‐HIV drug. It represents a literature review of published studies that evaluated the in vitro and in vivo activity of RAPA in HIV. RAPA represses HIV‐1 replication in vitro through different mechanisms including, but not limited, to down regulation of CCR5. In addition RAPA synergistically enhances the anti‐HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide in vitro. RAPA also inhibits HIV‐1 infection in human peripheral blood leucocytes‐SCID reconstituted mice. In addition, a prospective nonrandomized trial of HIV patient series receiving RAPA monotherapy after liver transplantation indicated significantly better control of HIV and hepatitis C virus (HCV) replication among patients taking RAPA monotherapy. Taken together, the evidence presented in this review suggests that RAPA may be a useful drug that should be evaluated for the prevention and treatment of HIV‐1 infection.
Prognostic factors in adult acute lymphoblastic leukaemia
Authors: Rowe Jacob M.
Published: June 2010

Treatment of acute lymphoblastic leukaemia (ALL) in adults presents a formidable challenge. While overall results have improved over the past 3 decades, the long‐term survival for patients aged less than 60 years is only in the range of 30–40% and is 10–15% if between 60 and 70 years and <5% for those over 70 years. The historic lack of clear‐cut biological prognostic factors has led to over‐ or under‐treatment of some patients. Response to initial therapy is an important prognosticator of outcome based on disease biology, as well as pharmacogenetics, which include the patient’s response to drugs given. The more widespread availability of allogeneic transplantation and reduced‐intensity regimens for older patients have opened up this curative modality to a greater number of patients. Hopefully, those options, as well as novel cytogenetic and molecular markers, will enable a better selection of patients who undergo intensive therapies and finally break the 30–40% cure barrier for adults with ALL.
Confronting the psychological burden of haemophilia
Authors: COPPOLA A. , CERBONE A. M. , MANCUSO G. , MANSUETO M. F. , MAZZINI C. , ZANON E.
Published: June 2010

Summary.  Providing comprehensive care, counselling and support to haemophilic patients, and their parents have always been quite complex for haemophilia treatment centres. Nowadays, starting with recent developments in genetic counselling, prenatal diagnosis and carrier testing, the psychological burden on patients and parents might possibly have increased, compared with even the recent past. The emotional strains and worries associated with a possibly affected newborn and his care through childhood and adolescence may also have a grievous impact on couple dynamics and marital relationship. The impact may be even higher in families in which haemophilia is newly diagnosed. The main psychological problems faced by parents and then by affected individuals are herein chronologically reviewed, starting from genetic counselling before conception through childhood, adolescence and adulthood. Aware of the psychosocial burden on patients and their families associated with haemophilia, from prenatal diagnosis and carrier testing until later stages of life of the affected individual, a board of Italian haemophilia specialists and psychologists is designing and organizing an innovative network of psychological support services in some Italian haemophilia centres and promoting specific educational programmes in this setting.
Two Tor genes in the silkworm Bombyx mori
Authors: Zhou S. , Zhou Q. , Liu Y. , Wang S. , Wen D. , He Q. , Wang W. , Bendena W. G. , Li S.
Published: June 2010

Target of rapamycin (TOR), a member of the phosphatidylinositol kinase‐related kinase family, plays a critical role in the regulation of growth, metabolism, development and survival, at both the cellular and the organismal levels. Two paralogous Tor genes, BmTor1 and BmTor2, were identified as a pair of inverted repeats in the genome of the silkworm Bombyx mori. The synteny of BmTor1 and CG8360 indicates that BmTor1 is the orthologue while BmTor2 is a duplicate. Analyses of the two BmTor genes at both the nucleotide and amino acid levels reveal that they are evolutionally and structurally conserved. The two BmTor genes had similar expression patterns of tissue distribution with highest levels in the nervous system, and nearly identical developmental change profiles with maximal levels during the 4th‐larval‐moulting and the larval–pupal transition stages. Furthermore, both BmTor genes were up‐regulated by either starvation or the moulting hormone 20‐hydroxyecdysone (20E), while BmTor2 was more sensitive to both treatments than BmTor1. For the first time, we have identified two copies of the Tor gene in a higher eukaryote, which are induced by starvation and 20E during the larval moulting and the larval–pupal transition stage.
Ytterbium trifluoride as a radiopaque agent for dental cements
Authors: Collares F. M. , Ogliari F. A. , Lima G. S. , Fontanella V. R. C. , Piva E. , Samuel S. M. W.
Published: June 2010

Collares FM, Ogliari FA, Lima GS, Fontanella VRC, Piva E, Samuel SMW. Ytterbium trifluoride as a radiopaque agent for dental cements. International Endodontic Journal, 43, 792–797, 2010.

Aim  To evaluate the radiopacity, degree of conversion (DC) and flexural strength of an experimental dental cement, with several added radiopaque substances.

Methodology  Titanium dioxide, quartz, zirconia, bismuth oxide, barium sulphate and ytterbium trifluoride were added to the experimental cement in five different concentrations. Radiopacity was evaluated with a phosphor plate system, and the radiodensity of specimens was compared with an aluminium step‐wedge. DC was evaluated with FT‐infrared spectroscopy following 20 s of photo‐activation. Specimens with dimensions of 12 × 2 × 2 mm were used for the flexural strength test. Data were analysed with two‐way anova and Tukey’s post hoc test.

Results  Radiopacity of the experimental dental cements with barium sulphate and bismuth oxide at 40% and ytterbium fluoride at 30% and 40% showed no significant differences in comparison with 3 mm of Al (181, 96).

Conclusions  The experimental dental cements with at least 30% added ytterbium trifluoride had satisfactory radiopacity without influencing other properties.
Critical care nurses’ experiences of follow‐up visits to an ICU
Authors: Engström Åsa , Söderberg Siv
Published: June 2010

Aim.  The aim of this study was to describe critical care nurses’ experiences of follow‐up visits for formerly critically ill people discharged from an intensive care unit and their close relatives.

Background.  The critical illness experience affects the ill person and their close relatives not only during the stay in an intensive care unit, but also for a long time afterwards. Follow‐up visits were introduced to offer people the opportunity to talk about their experiences. This activity has not been studied earlier from the perspective of critical care nurses.

Design.  The design of this study was qualitative.

Method.  Eight critical care nurses narrated their experiences of follow‐up visits by formerly critically ill people and their close relatives to an intensive care unit. Data were collected during 2007–2008. Qualitative thematic content analysis was applied to the interview texts.

Results.  The findings show that to feel they were doing a good job it was vital for the critical care nurses to be well prepared for the follow‐up visits. It was difficult, in a positive way, to recognise formerly critically ill people when they returned looking healthy. The critical care nurses were disappointed that their former patients remembered so few real events. The follow‐up visits gave the critical care nurses a new picture of how the critically illness experience influenced the former patient’s everyday life during and after their stay in the intensive care unit and how it affected the lives of their close relatives.

Conclusions.  Through sharing the experiences of formerly critically ill peoples’ and their close relatives’ critical care nurses receive valuable feedback about their work.

Relevance to clinical practice.  Receiving feedback about one’s work from follow‐up visits gives critical care nurses the possibility for to evaluate given care. Follow‐up visits to intensive care units can provide them with valuable knowledge that might lead to improved nursing care.
Stress and stress‐related factors of patients after renal transplantation in Taiwan: a cross‐sectional study
Authors: Chen Kang‐Hua , Weng Li‐Chueh , Lee Sheuan
Published: June 2010

Aims.  The aim of this study is to quantify the amount and causes of stress in renal transplant recipients.

Background.  After renal transplantation, patients may encounter physical and psychosocial problems. Through patient collaboration with healthcare professionals, treatment after transplantation is aimed at restoring and maintaining a ‘normal’ life. To achieve quality of life, research needs to quantify the amount and causes of stress of renal transplant recipients, from a patient‐centred perspective.

Design.  A cross‐sectional, descriptive study.

Methods.  The study was conducted in the outpatient department of a medical centre in northern Taiwan from September 2005–February 2006. The recipients were a convenience sample of 153 participants who had undergone renal transplantation.

Results.  The results showed that renal transplant recipients had low to moderate stress in four areas. Gender (male), self‐efficacy and hospitalisation for infection explained 17% of the variance found for the stress of uncertainty; hospitalisation for rejection and infection explained 22% of the variance for complications; and gender (male) and self‐efficacy explained 8% of the variance for the interactions with others. Post‐transplant time was not found to be a predictor of stress.

Conclusion.  After renal transplantation, patients experience multi‐dimensional stresses that previous research has not explored. Self‐efficacy was shown to be a significant predictor of the stress of uncertainty and interactions with others. Enhancing recipients’ self‐efficacy of self‐care behaviour can lower the stress that found in three areas.

Relevance to clinical practice.  Healthcare professionals should develop an evidence‐based programme for stress management for renal transplantation patients that incorporates strategies to enhance patient’s self‐efficacy of self‐care behaviour. Recipients’ beliefs in their ability to successfully perform self‐care behaviour can be promoted by a mastery experience, vicarious experience with other patients, social persuasion and re‐explanation of somatic and emotional states by discussing coping methods with healthcare professionals.
Altered neural response of the appetitive emotional system in cocaine addiction: an fMRI Study
Authors: Asensio Samuel , Romero Maria J. , Palau Carmina , Sanchez Amparo , Senabre Isabel , Morales Julia L. , Carcelen Raquel , Romero Francisco J.
Published: June 2010

Research on addiction suggests that emotional alterations play an essential role in the development, maintenance, relapse and treatment outcome of substance abuse disorders. Although many neuroimaging studies focussed on the neural response to conditioned stimuli, much less is known about the neural response to natural affective stimuli in this pathological population. Previous research has demonstrated an altered emotional experience and autonomic response to emotional stimuli using the International Affective Picture System (IAPS) in drug abusers. Here we aimed, using functional magnetic resonance imaging (fMRI), to study the alterations in the neural responsitivity to pleasant (erotic), unpleasant and neutral IAPS stimuli in cocaine addiction. Thirty‐two cocaine‐dependent subjects and 26 matched controls completed an fMRI session during the presentation of a set of IAPS pictures as background, while performing a letter discrimination task. Consistent with previous studies, emotional pictures activated an emotional network including amygdala, medial prefrontal cortex, orbitofrontal cortex and occipito‐temporal areas in both groups. However, compared with controls, the cocaine group showed a significant hypoactivation of the dorsal and ventral striatum (including the nucleus accumbens), thalamus, parietal cortex and dorso‐medial prefrontal cortex (dmPFC) when processing pleasant pictures. The analysis of pleasant versus unpleasant stimuli suggested that between‐group differences in the dmPFC and striatal activation may be attributed to arousal processing rather than valence. These results could reflect the neural basis for the reduced ability of cocaine‐dependent subjects to experience pleasure by daily natural reinforcers, suggesting that these alterations in the emotion processing may play an important role in drug dependence, treatment and relapse.
Patient organizations in Finland: increasing numbers and great variation
Authors: Toiviainen Hanna K. , Vuorenkoski Lauri H. , Hemminki Elina K.
Published: June 2010

Objective  There is very little research on patient organizations (POs), even though their numbers and influence seem to be increasing. The purpose of this study was to describe the establishment, membership, size, organization, decision making and basic funding of national POs in Finland.

Setting and participants  National POs (n = 130) were identified from their umbrella organizations and by Internet searches. Data were collected from POs’ web pages (87% of POs had one), Finland’s Slot Machine Association (RAY, an important public financier of POs), a relevant survey done by a local TV‐company, and interviews and written materials of POs.

Results and conclusions  Some current national POs were established around the turn of the 19th century. The rate of establishment of new POs increased from the 1970s and particularly in the 1990s when POs were characterized by increasing specialization. POs focused on different patient groups and diseases and were founded by philanthropists, physicians, patients, parents and the drug industry. Members could be patients, patient relatives, health‐care professionals and organizations. POs widely varied in memberships (20–145 000, in 2002) and in number of paid personnel (0–1395, in 2002), organizational structure and decision making. Interest groups and financiers were often represented in decision‐making organs. Activities included mutual support and service production, and, increasingly, informing and lobbying. POs had wide domestic and international co‐operation and networking. Drug industry marketing was visible on PO web pages. Budget sizes varied (4000–15 million euros, in 2001). The main public financier was RAY. The old national POs were large and part of national social and health care, but newer ones were often established for mutual support and lobbying. National POs are not uniform but characterized by great variation. The number of national POs is increasing suggesting tighter competition for financing and visibility in the future.
Shared decision making in oncology: assessing oncologist behaviour in consultations in which adjuvant therapy is considered after primary surgical treatment
Authors: Singh Simron , Butow Phyllis , Charles Margaret , Tattersall Martin H.N.
Published: June 2010

Introduction  Shared decision making (SDM) is now considered a desirable goal in health care, yet little is known about current practice in cancer care, and its impact on patient outcomes. This study aimed to develop an oncology‐specific coding system for SDM, explore variations in SDM according to patient and disease characteristics, determine the relationship between SDM and patient satisfaction with the consultation, and explore the impact of SDM on patient anxiety.

Methods  Sixty‐three medical and radiation oncology consultations with patients with primary cancer involving consideration of adjuvant therapy after surgery were audio‐taped, transcribed and coded. Intra and inter‐rater reliability of the coding system was 95 and 90% respectively. Patients completed questionnaires before and after the consultation.

Results  Construct validity of the SDM coding system was successfully conducted. Oncologists demonstrated on average under 11 of 18 SDM behaviours. Behaviours seeking patient preferences were particularly rare. SDM behaviours were more apparent in consultations involving female breast cancer patients. SDM behaviour scores in combination with patient involvement preference could predict achievement of patient involvement preference but not overall patient satisfaction. Although there was no overall relationship between patient anxiety and SDM scores, it did appear that physicians may change SDM behaviour according to patient factors including anxiety.

Conclusion  Our findings reinforce the importance of the doctor in facilitating shared decision making in oncology consultations.
Is patient involvement during hospitalization for acute myocardial infarction associated with post‐discharge treatment outcome? An exploratory study
Authors: Arnetz Judith E. , Winblad Ulrika , Höglund Anna T. , Lindahl Bertil , Spångberg Kalle , Wallentin Lars , Wang Yun , Ager Joel , Arnetz Bengt B.
Published: June 2010

Objective  To investigate whether patient involvement during hospitalization for acute myocardial infarction (MI) was associated with health and behavioural outcomes 6–10 weeks after hospital discharge.

Background  Patient involvement has been associated with improved health outcomes in chronic disease, but less research has focused on the effects of patient involvement in acute conditions, such as MI.

Design  Self‐administered questionnaire study. Questionnaire results were run against medical outcome data in a national database of cardiac patients.

Setting and participants  Cardiac patients (n = 591) on their first follow‐up visit after hospitalization for MI at 11 Swedish hospitals.

Main outcome measures  Patient ratings of three questionnaire scales related to involvement; cardiovascular symptoms, medication compliance, participation in cardiac rehabilitation, and achievement of secondary preventive goals.

Results  More positive patient ratings of involvement were significantly associated with fewer cardiovascular symptoms 6–10 weeks after hospital discharge. In contrast, patients who attended cardiac rehabilitation and achieved the goals for smoking cessation and systolic blood pressure were significantly less satisfied with their involvement. No association was found between involvement ratings and medication compliance.

Conclusion  This study represents a first attempt to examine associations between patient involvement in the acute phase of illness and short‐term health outcomes. Some significant associations between involvement and health and behavioural outcomes after acute MI were found. However, higher involvement ratings were not consistently associated with more desirable outcomes, and involvement during hospitalization was not associated with MI patient health and behaviour 6–10 weeks after hospital discharge to the extent hypothesized.
YSPSL (rPSGL‐Ig) for improvement of early renal allograft function: a double‐blind, placebo‐controlled, multi‐center Phase IIa study1,2,3
Authors: Osama Gaber A. , Mulgaonkar Shamkant , Kahan Barry D. , Steve Woodle E. , Alloway Rita , Bajjoka Iman , Jensik Stephen , Klintmalm Goran B. , Patton Pamela R. , Wiseman Alexander , Lipshutz Gerald , Kupiec‐Weglinski Jerzy , Gaber Lilian W. , Katz Eliezer , Irish William , Squiers Elizabeth C. , Hemmerich Stefan
Published: June 2010

Gaber AO, Mulgaonkar S, Kahan BD, Woodle ES, Alloway R, Bajjoka I, Jensik S, Klintmalm GB, Patton PR, Wiseman A, Lipshutz G, Kupiec‐Weglinski J, Gaber LW, Katz E, Irish W, Squiers EC, Hemmerich S. YSPSL (rPSGL‐Ig) for improvement of early renal allograft function: A double‐blind, placebo‐controlled, multi‐center Phase IIa study.  Clin Transplant 2011: 25: 523–533. © 2010 John Wiley & Sons A/S.

Abstract: Introduction: Recombinant P‐selectin glycoprotein ligand IgG fusion protein, rPSGL‐Ig (YSPSL), a fusion protein of human P‐selectin ligand and IgG1‐Fc, blocks leukocyte adhesion and protects against ischemia reperfusion injury (IRI) in animal models.

Patients and Methods: This randomized 15‐center, double‐blind, 59‐patient Ph2a study assessed YSPSL’s safety in recipients of deceased‐donor kidney allografts and its potential efficacy in improving early graft function. Two doses and two dosing modalities were evaluated.

Results: No drug‐specific toxicities or increased adverse event rates were noted. Two YSPSL‐treated patients died of causes determined as unrelated to study drug. YSPSL did not reduce the incidence of dialysis within the first week post‐transplant (41% in treated vs. 20% in placebo patients). Renal function endpoints scored at post‐operative days 1 & 2 were also not impacted by YSPSL. However, at day 5, the fraction of patients with serum creatinine above 6 mg/dL was lower in the YSPSL vs. placebo group (26% vs. 55%, p = 0.043). Large variations in the dialysis‐delayed graft function (DGF) rates were observed between centers, independently of treatment assignment, indicating subjectivity of this endpoint.

Conclusion: In this first Ph2a study in kidney transplantation, YSPSL was safe but did not impact the dialysis‐DGF rate. Further studies with more objective efficacy endpoints are required to define the impact of YSPSL on early renal allograft function.