bluuebunny/crossref_metadata_2025 huggingface dataset:
Lamivudine Plus Interleukin-12 Combination Therapy in Chronic Hepatitis B: Antiviral and Immunological Activity *
Authors: Rigopoulou Eirini I. , Suri Deepak , Chokshi Shilpa , Mullerova Ivana , Rice Steven , Tedder Richard S. , Williams Roger , Naoumov Nikolai V.
Published: October 2005

Abstract

Interleukin-12 (IL-12) is an immunomodulatory cytokine that promotes cellular immunity. Pre-clinical data suggest that IL-12 inhibits hepatitis B virus (HBV) replication by stimulating interferon-gamma (IFN-γ) production. We investigated whether a combination treatment with lamivudine plus recombinant human interleukin-12 (rhIL-12) will result in a greater and prolonged suppression of HBV replication in comparison with lamivudine monotherapy. Fifteen patients with HBeAg-positive chronic hepatitis B were randomized to receive either lamivudine alone for 24 weeks (group 1); combination of lamivudine for 16 weeks and rhIL-12 (200 ng/kg twice weekly), starting 4 weeks after initiation of lamivudine, for 20 weeks (group 2), or the same schedule as for group 2, with lamivudine and a higher dose of rhIL-12 (500 ng/kg, group 3). Serum HBV DNA levels, T-cell proliferation, frequency of virus-specific T-cells, and IFN-γ production were evaluated serially during and 24 weeks posttreatment. Lamivudine plus rhIL-12/500 showed greater antiviral activity than lamivudine monotherapy. However, after stopping lamivudine in groups 2 and 3, serum HBV DNA increased significantly despite continuing rhIL-12 administration. Lamivudine plus rhIL-12 treatment was associated with a greater increase in virus-specific T-cell reactivity, IFN-γ production, and an inverse correlation between the frequency of IFN-γ–producing CD4+ T-cells and viremia. The T-cell proliferative response to HBcAg did not differ between the three groups.
In conclusion
, the addition of IL-12 to lamivudine enhances T-cell reactivity to HBV and IFN-γ production. However, IL-12 does not abolish HBV replication in HBeAg-positive patients and does not maintain inhibition of HBV replication after lamivudine withdrawal. (Hepatology 2005.)
Hepatocyte Transplantation Activates Hepatic Stellate Cells With Beneficial Modulation of Cell Engraftment in the Rat *
Authors: Benten Daniel , Kumaran Vinay , Joseph Brigid , Schattenberg Jörn , Popov Yury , Schuppan Detlef , Gupta Sanjeev
Published: October 2005

Abstract

We investigated whether transplanted hepatocytes interact with hepatic stellate cells, as cell–cell interactions could modulate their engraftment in the liver. We transplanted Fischer 344 rat hepatocytes into syngeneic dipeptidyl peptidase IV–deficient rats. Activation of hepatic stellate cells was analyzed by changes in gene expression, including desmin and α-smooth muscle actin, matrix proteases and their inhibitors, growth factors, and other stellate cell-associated genes with histological methods or polymerase chain reaction. Furthermore, the potential role of hepatic ischemia, Kupffer cells, and cytokine release in hepatic stellate cell activation was investigated. Hepatocyte transplantation activated desmin-positive hepatic stellate cells, as well as Kupffer cells, including in proximity with transplanted cells. Inhibition of Kupffer cells by gadolinium chloride, blockade of tumor necrosis factor alpha (TNF-α) activity with etanercept or attenuation of liver ischemia with nitroglycerin did not decrease this hepatic stellate cell perturbation. After cell transplantation, soluble signals capable of activating hepatic stellate cells were rapidly induced, along with early upregulated expression of matrix metalloproteinases-2, -3, -9, -13, -14, and their inhibitors. Moreover, prior depletion of activated hepatic stellate cells with gliotoxin decreased transplanted cell engraftment.
In conclusion
, cell transplantation activated hepatic stellate cells, which, in turn, contributed to transplanted cell engraftment in the liver. Manipulation of hepatic stellate cells might provide new strategies to improve liver repopulation after enhanced transplanted cell engraftment.

Supplementary material for this article can be found on the H

epatology

website

(
http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html
). (Hepatology 2005;42:1072–1081.)
Methotrexate (MTX) Plus Ursodeoxycholic Acid (UDCA) in the Treatment of Primary Biliary Cirrhosis * #
Authors: Combes Burton , Emerson Scott S. , Flye Nancy L. , Munoz Santiago J. , Luketic Velimir A. , Mayo Marlyn J. , McCashland Timothy M. , Zetterman Rowen K. , Peters Marion G. , Di Bisceglie Adrian M. , Benner Kent G. , Kowdley Kris V. , Carithers Robert L. , Rosoff Leonard , Garcia-Tsao Guadalupe , Boyer James L. , Boyer Thomas D. , Martinez Enrique J. , Bass Nathan M. , Lake John R. , Barnes David S. , Bonacini Maurizio , Lindsay Karen L. , Mills Scott A. , Markin Rodney S. , Rubin Raphael , West Brian A. , Wheeler Donald E. , Contos Melissa J. , Hofmann Alan F.
Published: October 2005

Abstract

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility.
In conclusion
, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.

Supplementary material for this article can be found on the Hepatology website

(
http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html
). (Hepatology 2005;42:1184–1193.)
Altered Disposition of Acetaminophen in Mice With a Disruption of the Mrp3 Gene * #
Authors: Manautou José E. , de Waart Dirk R. , Kunne Cindy , Zelcer Noam , Goedken Michael , Borst Piet , Elferink Ronald Oude
Published: October 2005

Abstract

MRP3 is an ABC transporter localized in the basolateral membrane of epithelial cells such as hepatocytes and enterocytes. In this study, the role of Mrp3 in drug disposition was investigated. Because Mrp3 preferentially transports glucuronide conjugates, we investigated the

in vivo

disposition of acetaminophen (APAP) and its metabolites.

Mrp3

+/+

and

Mrp3

−/−

knockout mice received APAP (150 mg/kg), and bile was collected. Basolateral and canalicular excretion of APAP was also assessed in the isolated perfused liver. In separate studies, mice received 400 mg APAP/kg for assessment of hepatotoxicity. No differences were found in the biliary excretion of APAP, APAP-sulfate, and APAP-glutathione between

Mrp3

+/+

and

Mrp3

−/−

mice. However, 20-fold higher accumulation of APAP-glucuronide (APAP-GLUC) was found in the liver of

Mrp3

−/−

mice. Concomitantly, plasma APAP-GLUC content in

Mrp3

−/−

mice was less than 10% of that in

Mrp3

+/+

mice

. In addition, APAP-GLUC excretion in bile of

Mrp3

−/−

mice was tenfold higher than in

Mrp3

+/+ mice. In the isolated perfused liver, we also found a strong decrease of APAP-GLUC secretion into the perfusate of

Mrp3

−/−

livers. Plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histopathology showed that

Mrp3

−/−

mice are more resistant to APAP hepatotoxicity than

Mrp3

+/+ mice, which is most likely a result of the faster repletion of hepatic GSH.
In conclusion
, basolateral excretion of APAP-GLUC in mice is nearly completely dependent on the function of Mrp3. In its absence, sufficient hepatic accumulation occurs to redirect some of the APAP-GLUC to bile. This altered disposition in

Mrp3

−/−

mice is associated with reduced hepatotoxicity. (Hepatology 2005;42:1091–1098.)
Temporal Correlation of Pathology and DNA Damage With Gene Expression in a Choline-Deficient Model of Rat Liver Injury *
Authors: Powell Christine L. , Kosyk Oksana , Bradford Blair U. , Parker Joel S. , Lobenhofer Edward K. , Denda Ayumi , Uematsu Fumiyuki , Nakae Dai , Rusyn Ivan
Published: October 2005

Abstract

Hepatocellular carcinoma (HCC) is the terminal event in chronic liver diseases with repeated cycles of cellular injury and regeneration. Although much is known about the cellular pathogenesis and etiological agents leading to HCC, the molecular events are not well understood. The choline-deficient (CD) model of rodent HCC involves the consecutive emergence of a fatty liver, apoptosis, compensatory proliferation, fibrosis, and cirrhosis that is markedly similar to the sequence of events typified by human HCC. Moreover, oxidative stress is thought to play a pivotal role in the progression of the disease. Here, we hypothesize that gene expression profiling can temporally mirror the histopathology and oxidative DNA damage observed with this model. We show that clusters of highly co-regulated genes representing distinct cellular pathways for lipid biosynthesis and metabolism, apoptosis, cell proliferation, and tissue remodeling temporally correlate with the well-defined sequential emergence of pathological alterations in the progression of liver disease. Additionally, an oxidative stress signature was observed that was corroborated in a time-dependent manner with increases in oxidized purines and abasic sites in DNA. Collectively, expression patterns were strongly driven by pathology, demonstrating that patterns of gene expression in advanced stages of liver disease are primarily driven by histopathological changes and to a much lesser degree by the original etiological agent.
In conclusion
, gene expression profiling coupled with the CD model of HCC provides a unique opportunity to unveil the molecular events associated with various stages of liver injury and carcinogenesis and to distinguish between causal and consecutive changes.

Supplementary material for this article can be found on the Hepatologywebsite

(
http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html
). (Hepatology 2005;42:1137–1147.)
Lack of gp130 Expression Results in More Bacterial Infection and Higher Mortality During Chronic Cholestasis in Mice *
Authors: Wuestefeld Torsten , Klein Christian , Streetz Konrad L. , Beraza Naiara , Schölmerich Jürgen , Burgart Lawrence J. , Zender Lars , Kubicka Stefan , Gores Gregory J. , Manns Michael P. , Trautwein Christian
Published: October 2005

Abstract

Chronic cholestasis is associated with increased bacterial infections and sepsis resulting in higher mortality in humans. In the current study, we investigated the relevance of gp130-dependent pathways after bile duct ligation (BDL). BDL was performed in conditional gp130 knockout (loxP/Cre system) mice and respective controls. Liver injury, regulation of the acute phase response, and the impact on survival and bacterial infections were determined. Acute BDL resulted in increased IL-6 levels, Stat3 activation, and an increase in acute-phase proteins (serum-amyloid-A [SAA]), which was blocked in gp130-deleted animals. In addition, the antimicrobial gene hepcidin was regulated in a gp130-dependent manner after BDL. During chronic cholestasis Stat3 activation was dramatically reduced, while high SAA levels were maintained via gp130-dependent signaling. Inhibition of gp130-dependent pathways resulted in higher mortality and liver damage, which was associated with higher infiltration of immune-activated cells and increased germ number in the liver.
In conclusion
, during acute and chronic cholestasis, the gp130 system is essential for controlling the acute-phase response. Lack of gp130 expression results in pronounced bacterial growth in bile and liver after BDL, which is associated with higher mortality. Activation of gp130-dependent pathways after BDL is essential and appears to be a therapeutic target during cholestasis. (Hepatology 2005;42:1082–1090.)
Insulin Resistance: A Metabolic Pathway to Chronic Liver Disease *
Authors: Bugianesi Elisabetta , McCullough Arthur J. , Marchesini Giulio
Published: October 2005

Abstract

Insulin resistance (IR) is the pathophysiological hallmark of nonalcoholic fatty liver disease (NAFLD), one of the most common causes of chronic liver disease in Western countries. We review the definition of IR, the methods for the quantitative assessment of insulin action, the pathophysiology of IR, and the role of IR in the pathogenesis of chronic liver disease. Increased free fatty acid flux from adipose tissue to nonadipose organs, a result of abnormal fat metabolism, leads to hepatic triglyceride accumulation and contributes to impaired glucose metabolism and insulin sensitivity in muscle and in the liver. Several factors secreted or expressed in the adipocyte contribute to the onset of a proinflammatory state, which may be limited to the liver or more extensively expressed throughout the body. IR is the common characteristic of the metabolic syndrome and its related features. It is a systemic disease affecting the nervous system, muscles, pancreas, kidney, heart, and immune system, in addition to the liver. A complex interaction between genes and the environment favors or enhances IR and the phenotypic expression of NAFLD in individual patients. Advanced fibrotic liver disease is associated with multiple features of the metabolic syndrome, and the risk of progressive liver disease should not be underestimated in individuals with metabolic disorders. Finally, the ability of insulin-sensitizing, pharmacological agents to treat NAFLD by reducing IR in the liver (metformin) and in the periphery (thiazolidinediones) are discussed. (Hepatology 2005;42:987–1000.)
Placebo Controlled Treatment Trials in Hepatic Encephalopathy Are Feasible and Ethical *
Authors: Ghanta Ravi K. , Mullen Kevin D. , Jaeschke Hartmut , Mullen Kevin , Moradpour Darius
Published: October 2005

Abstract

Gentile S, Guarino G, Romano M, Alagia IA, Fierro M, Annunziata S, Magliano PL, Gravina AG, Torella R. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005;3:184–191. (Reprinted with permission from Elsevier.)

Background & aims

Hepatic encephalopathy in cirrhosis is contributed to by toxic products deriving from the proteolytic bacterial flora–related degradation of dietary nitrogen substances. Acarbose is a novel hypoglycemic agent acting through the inhibition of glucose absorption in the gut and the promotion of intestinal saccharolytic bacterial flora at the expense of proteolytic flora. We assessed whether acarbose exerts a beneficial effect on hepatic encephalopathy and on postprandial hyperglycemia in cirrhotic patients with low-grade hepatic encephalopathy and type 2 diabetes mellitus.

Methods

One hundred seven cirrhotic patients with grade 1–2 hepatic encephalopathy and type 2 diabetes mellitus were randomized to acarbose 100 mg 3 times daily or placebo for 8 weeks; after a 2-week washout period, treatments were switched, and patients were followed for 8 more weeks. Ammonia blood levels, Reitan's number connection test, intellectual function, fasting and postprandial glucose levels, glycated hemoglobin values, and C peptide values were determined 2 weeks before and 4, 8, 11, 14, and 18 weeks after treatment.

Results

(1) Acarbose significantly decreased ammonia blood levels and improved Reitan's test score and intellectual function score compared with placebo (P< .01). (2) Acarbose caused a 33% decrease in fasting glucose level and an approximately 50% decrease in postprandial glucose level compared with placebo (P< .01). (3) Acarbose significantly lowered glycated hemoglobin values and postprandial C peptide compared with baseline values, whereas placebo did not. (4) No change in biochemical parameters of liver function was observed after acarbose treatment.

Conclusions

Acarbose is a safe and effective drug in cirrhotic patients with low-grade hepatic encephalopathy and type 2 diabetes mellitus.
Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: Immunotherapeutic implications
Authors: Coral Sandra , Sigalotti Luca , Colizzi Francesca , Spessotto Alberto , Nardi Gianpaolo , Cortini Enzo , Pezzani Laura , Fratta Elisabetta , Fonsatti Ester , Di Giacomo Anna Maria , Nicotra Maria Rita , Natali Pier Giorgio , Altomonte Maresa , Maio Michele
Published: October 2005

Emerging in vitro evidence points to an immunomodulatory activity of DNA hypomethylating drugs in human malignancies. We investigated the potential of 5‐aza‐2′‐deoxycytidine (5‐AZA‐CdR) to modulate the expression of cancer testis antigens (CTA) and of HLA class I antigens by melanoma xenografts, and the resulting modifications in immunogenicity of neoplastic cells. Three primary cultures of melanoma cells, selected for immune phenotype and growth rate, were grafted into BALB/c nu/nu mice that were injected intraperitoneally with different dose‐ and time‐schedules of 5‐AZA‐CdR. Molecular analyses demonstrated a de novo long‐lasting expression of the CTA MAGE‐1, ‐2, ‐3, ‐4, ‐10, GAGE 1–6, NY‐ESO‐1, and the upregulation of MAGE‐1, MAGE‐3, and NY‐ESO‐1 levels in melanoma xenografts from 5‐AZA‐CdR‐treated mice. Serological and biochemical analyses identified a de novo expression of NY‐ESO‐1 protein and a concomitant and persistent upregulation of HLA class I antigens and of HLA‐A1 and ‐A2 alleles. Immunization of BALB/c mice with 5‐AZA‐CdR‐treated melanoma cells generated high titer circulating anti‐NY‐ESO‐1 antibodies. Altogether, the data obtained identify an immunomodulatory activity of 5‐AZA‐CdR in vivo and strongly suggest for its clinical use to design novel strategies of CTA‐based chemo‐immunotherapy for melanoma patients. J. Cell. Physiol. 207: 58–66, 2006. © 2005 Wiley‐Liss, Inc.
Molecular evolution of evolutionary novelties: the vagina and uterus of therian mammals
Authors: Wagner Günter P. , Lynch Vincent J.
Published: October 2005

Innovations are an integral part of the evolutionary process if we accept the fact that more complex organisms derived from anatomically simple ones. All major taxa are distinguished not only by their closer genealogical relatedness relative to other species but also by the possession of novel anatomical and physiological features. The question is whether the origin of these novel characters can be simply understood as adaptations, like all other phenotypic differences that arise by natural selection, or whether the origin of these characters requires more profound genetic changes. In this paper, we argue that innovations constitute a distinct class of evolutionary processes that require a research program complementary to the study of adaptation. The distinguishing feature of innovations is the origin of novel organ identity gene functions specific to the novel character. By implication, research into the origin of novel characters has to identify the developmental regulatory links that were involved in the evolution of these characters. We suggest that novel regulatory links will include the evolution of cis‐regulatory elements as well as novel protein–protein interactions among transcription factor proteins. The latter hypothesis suggests that innovations should leave a trace in the evolution of the protein coding regions of transcription factor genes. We illustrate this idea with results on the evolution of HoxA‐11 and HoxA‐13 in the stem lineage of placental mammals. These genes are essential for female reproductive tract development and function. We show that, as predicted, these genes experience strong directional selection in the stem lineage of placental mammals and that these amino acid substitutions affect residues at the surface of the protein, consistent with their expected role in protein–protein interactions. We conclude that a careful analysis of sequence variation in developmental genes can aid in testing which developmental changes were instrumental in the origin of novel morphological characters. J. Exp. Zool. (Mol. Dev. Evol.) 304B, 2005. © 2005 Wiley‐Liss, Inc.
Survey of the year 2004 commercial optical biosensor literature
Authors: Rich Rebecca L. , Myszka David G.
Published: October 2005

The year 2004 represents a milestone for the biosensor research community: in this year, over 1000 articles were published describing experiments performed using commercially available systems. The 1038 papers we found represent a ∼10% increase over the past year and demonstrate that the implementation of biosensors continues to expand at a healthy pace. We evaluated the data presented in each paper and compiled a ‘top 10’ list. These 10 articles, which we recommend every biosensor user reads, describe well‐performed kinetic, equilibrium and qualitative/screening studies, provide comparisons between binding parameters obtained from different biosensor users, as well as from biosensor‐ and solution‐based interaction analyses, and summarize the cutting‐edge applications of the technology. We also re‐iterate some of the experimental pitfalls that lead to sub‐optimal data and over‐interpreted results. We are hopeful that the biosensor community, by applying the hints we outline, will obtain data on a par with that presented in the 10 spotlighted articles. This will ensure that the scientific community at large can be confident in the data we report from optical biosensors. Copyright © 2005 John Wiley & Sons, Ltd.
Enantiomeric composition studies in Lavandula species using supercritical fluids
Authors: Flores Gema , Blanch Gracia Patricia , Ruiz del Castillo Maria Luisa , Herraiz Marta
Published: October 2005

Characteristic aroma compounds in plants and essential oils of Lavandula from different varieties were examined. The study of the qualitative and quantitative composition of the major volatile components was faced by developing a method based on the use of supercritical fluid extraction‐GC‐MS (SFE‐GC‐MS). The optimization of a variety of parameters affecting SFE extraction enabled RSDs from three replicates lower than 2% to be achieved. Equally, recoveries of up to 59% were obtained by applying the proposed method. The use of multidimensional GC was necessary to enantiomerically resolve the target compounds. The obtained results showed enantiomeric purities >90% for all studied compounds in all varieties considered, proving the natural invariability of the enantiomeric composition of the compounds of interest. This information can be useful in authenticity studies as well as in selecting natural sources of enantiomerically pure compounds.
Chiral separation of 1,1′‐bi‐2‐naphthol and its analogue on molecular imprinting monolithic columns by HPLC
Authors: Ou Junjie , Tang Shouwan , Zou Hanfa
Published: October 2005

Two molecular imprinting polymer (MIP) monolithic columns with (S)‐(–)‐1,1′‐bi‐2‐naphthol and (R)‐(+)‐5,5′,6,6′,7,7′,8,8′‐octahydro‐1,1′‐bi‐2‐naphthol as the templating molecules, respectively, have been prepared by in situ polymerization using 4‐vinylpyridine and ethylene dimethacrylate as functional monomer and cross‐linker, respectively. The columns with good flow‐through properties were obtained by changing the molar ratio of the functional monomer and the template molecule. The effects of mobile‐phase composition on separation of enantiomers were systematically investigated. The results indicate that hydrophobic interaction in aqueous solution and hydrogen‐bonding interaction in ACN between the enantiomers and polymers could play important roles in the retention and resolution. The effects of chromatographic conditions, such as flow rate, column temperature, sample loading, on the enantioseparation were also studied. Further, these two MIP columns show a cross‐reactivity.
High performance liquid chromatographic separation of dipeptide and tripeptide enantiomers using a chiral crown ether stationary phase
Authors: Conrad Uwe , Chankvetadze Bezhan , Scriba Gerhard K. E.
Published: October 2005

A chiral stationary phase (CSP) based on (–)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid was evaluated for the direct resolution of the enantiomers of dipeptides and tripeptides. The type and concentration of the acid and the methanol content were optimized with regard to retention time and resolution using Ala‐Phe as model peptide. A mobile phase consisting of 10 mM sulfuric acid in 70% aqueous methanol was applied to the separation of a set of 16 structurally diverse dipeptides and tripeptides. Generally, the configuration of the amino acid at the N‐terminus determined the enantiomer elution order. With a few exceptions the LL‐ and LD‐enantiomers interacted stronger with the CSP compared to the corresponding DD‐ or DL‐enantiomers. The experimental conditions also allowed the simultaneous separation of all four stereoisomers of Ala‐Phe. Addition of ammonium sulfate generally reduced retention times and enantiomer resolution. Addition of triethylamine as modifier led to an overall increase of the retention times while the resolution did not show a general trend, increasing in the case of Ala‐Ala but decreasing in the case of Ala‐Phe.
Boundary elements for cracks and notches in three dimensions
Authors: Watson J. O.
Published: October 2005

Plane and curved cracks are modelled by boundary elements, of geometry defined by conforming quadratic and hybrid quadratic‐Hermitian cubic shape functions. Displacement and traction are interpolated by the quadratic functions, supplemented by singular functions by which are multiplied stress intensity factors corresponding to each of the three modes of crack opening displacement, for the first three eigenvalues of the Williams eigenfunction expansion and its equivalent for antiplane strain. Singular and hypersingular boundary integral equations are taken at nodes of elements and auxiliary collocation points. Singular and hypersingular components of integrals are evaluated by consideration of trial displacement fields (simple solutions) for subdomains lying to either side of the crack.

Examples are shown of buried and surface cracks, and computed results compared with those obtained by other methods. For surface cracks, the computed results reveal the cause of significant discrepancies between values given by well established empirical and other formulae. The modelling of notches is demonstrated by an analysis of stress in rock near a tunnel intersection. Computational efficiency is discussed, and improvements and extensions of the analysis are proposed. Copyright © 2005 John Wiley & Sons, Ltd.
Performance of time‐stepping schemes for discrete models in fracture dynamic analysis
Authors: Delaplace Arnaud , Ibrahimbegovic Adnan
Published: October 2005

In this work we present a critical evaluation of different time integration schemes within the setting of non‐linear dynamic analysis of brittle fracture problem represented by a discrete model. The discrete model of this kind consists of Voronoi cells representing the grains of a heterogeneous structure, which are interconnected by cohesive forces modelled by beam‐like links capable of taking properly into account both brittle dynamic fracture and large displacement of a still connected pack of grains that might split from the structure. The brittle behaviour of cohesive links requires that the dynamic analysis of such a model be treated with care, and the best possible integration scheme be selected. Four different schemes are explored and compared in application to a dynamic traction test, including Newmark explicit and implicit schemes, HHT‐α scheme and energy‐decaying scheme. Copyright © 2005 John Wiley & Sons, Ltd.
Localized Jacobian ILU preconditioners for hydraulic fractures
Authors: Peirce A. P.
Published: October 2005

We discuss the properties of a class of sparse localized approximations to the Jacobian operator that arises in modelling the evolution of a hydraulically driven fracture in a multi‐layered elastic medium. The governing equations involve a highly non‐linear coupled system of integro‐partial differential equations along with the fracture front free boundary problem. We demonstrate that an incomplete LU factorization of these localized Jacobians yields an efficient preconditioner for the fully populated, stiff, non‐symmetric system of algebraic equations that need to be solved multiple times for every growth increment of the fracture. The performance characteristics of this class of preconditioners is explored via spectral analysis and numerical experiment. Copyright © 2005 John Wiley & Sons, Ltd.
A meshless method with enriched weight functions for three‐dimensional crack propagation
Authors: Duflot Marc
Published: October 2005

The propagation of cracks in three dimensions is analysed by a meshless method. The cracks are modelled by a set of triangles that are added when the propagation occurs. Since the method is meshless, no remeshing of the domain is necessary during the propagation. To avoid using a large number of degrees of freedom, the stress singularity along the front of the cracks is taken into account by an enrichment of the shape functions of the meshless method by means of appropriate weight functions. This enrichment technique is an extension of the technique that proved to be successful in two dimensions in a previous paper. Several algorithms for efficiently implementing the meshless method in three dimensions are detailed. The accuracy of the enrichment is first assessed on simple examples and some results of non‐planar propagation of multiple cracks are then presented. Copyright © 2005 John Wiley & Sons, Ltd.
Crush dynamics of square honeycomb sandwich cores
Authors: Xue Zhenyu , Hutchinson John W.
Published: October 2005

Square honeycombs are effective as cores for all‐metal sandwich plates in that they combine excellent crushing strength and energy absorption with good stiffness and strength in out‐of‐plane shear and in‐plane stretch. In applications where sandwich plates must absorb significant energy in crushing under intense impulsive loads, dynamic effects play a significant role in the behaviour of the core. Three distinct dynamic effects can be identified: (i) inertial resistance, (ii) inertial stabilization of webs against buckling, and (iii) material strain‐rate dependence. Each contributes to dynamic strengthening of the core. These effects are illustrated and quantified with the aid of detailed numerical calculations for rates of deformation characteristic of shock loads in air and water. A continuum model for high rate deformation of square honeycomb cores is introduced that can be used to simulate core behaviour in large structural calculations when it is not feasible to mesh the detailed core geometry. The performance of the continuum model is demonstrated for crushing deformations. Copyright © 2005 John Wiley & Sons, Ltd.
Effect of temperature and solvent on the structure and transport of a tethered membrane: Monte Carlo simulation
Authors: Pandey R. B. , Anderson Kelly L. , Farmer B. L.
Published: October 2005

An extended bond‐fluctuation model, introduced previously to study the conformation and dynamics of a self‐avoiding sheet (SAS), is further used to understand the temperature dependence on the conformation and dynamics of a tethered membrane (i.e., nodes tethered by fluctuating bonds with excluded volume constraints) in an effective solvent media on a cubic lattice by Monte Carlo simulations. The node–node (nn) and node–solvent (ns) interactions and temperature orchestrate the stochastic motion of each membrane node, and therefore describe the morphology of the membrane. With increasing temperature, the radius of gyration (Rg) of the membrane decreases with repulsive node–node interactions in an attractive solvent medium (ns < 0). The inverse effect is seen in a repulsive medium. Changes in the membrane'sRgshow that the membrane contracts (stretches) with the range of attractive (repulsive) node–node interaction with more pronounced effects on lowering the temperature. The variations ofRgwithT, which are affected by wrinkles and crumpling, are complex (with the possibility of stretched exponential functions) depending on the type of membrane, quality of the solvent, and the temperature. Likewise, the segmental dynamics exhibits a range of power‐laws, different from that of a SAS, while the global membrane reaches its asymptotic diffusive behavior. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 3478–3486, 2005
Charged polypeptide diffusion at a very high ionic strength
Authors: Hong Liang , Granick Steve
Published: October 2005

Two charged polypeptides of opposite charge, poly(glutamic acid) (negative charge) and polylysine (positive charge), were end‐labeled with Alexa fluorescent dyes, and their translational diffusion coefficient (D) values in dilute solutions (∼10−4 mg mL−1) were studied at the biological pH with fluorescence correlation spectroscopy as a function of the ionic strength (Cs) mediated by the addition of NaCl. At a moderate ionic strength, D increased consistently with expected chain contraction because of electrostatic screening. At a very high ionic strength, D of poly(glutamic acid) increased more rapidly, following the empirical power law RH ∼ Cs−1/2 over a limited range of Cs, where the changes in D were interpreted as changes in the hydrodynamic radius, RH. However, D of polylysine at first decreased but eventually passed through a maximum followed by a decrease. These large increases implied that RH decreased considerably, in turn implying a strong contraction of the chain conformations even though the polymer remained soluble and showed no evidence of aggregation. For polylysine, the unexpected minimum RH value may be related to the salting‐in phenomenon. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 3497–3502, 2005
Knowledge‐based voting algorithm for automated protein functional annotation†
Authors: Yu G.X. , Glass E.M. , Karonis N.T. , Maltsev N.
Published: October 2005

Automated annotation of high‐throughput genome sequences is one of the earliest steps toward a comprehensive understanding of the dynamic behavior of living organisms. However, the step is often error‐prone because of its underlying algorithms, which rely mainly on a simple similarity analysis, and lack of guidance from biological rules. We present herein a knowledge‐based protein annotation algorithm. Our objectives are to reduce errors and to improve annotation confidences. This algorithm consists of two major components: a knowledge system, called “RuleMiner,” and a voting procedure. The knowledge system, which includes biological rules and functional profiles for each function, provides a platform for seamless integration of multiple sequence analysis tools and guidance for function annotation. The voting procedure, which relies on the knowledge system, is designed to make (possibly) unbiased judgments in functional assignments among complicated, sometimes conflicting, information. We have applied this algorithm to 10 prokaryotic bacterial genomes and observed a significant improvement in annotation confidences. We also discuss the current limitations of the algorithm and the potential for future improvement. Proteins 2005. © 2005 Wiley‐Liss, Inc.
Modelling age‐dependent force of infection from prevalence data using fractional polynomials
Authors: Shkedy Z. , Aerts M. , Molenberghs G. , Beutels Ph. , Van Damme P.
Published: October 2005

The force of infection is one of the primary epidemiological parameters of infectious diseases. For many infectious diseases it is assumed that the force of infection is age‐dependent. Although the force of infection can be estimated directly from a follow up study, it is much more common to have cross‐sectional seroprevalence data from which the prevalence and the force of infection can be estimated. In this paper, we propose to model the force of infection within the framework of fractional polynomials. We discuss several parametric examples from the literature and show that all of these examples can be expressed as special cases of fractional polynomial models. We illustrate the method on five seroprevalence samples, two of Hepatitis A, and one of Rubella, Mumps and Varicella. Copyright © 2005 John Wiley & Sons, Ltd.
Correcting for selection using frailty models
Authors: Olesen Anne Vingaard , Parner Erik Thorlund
Published: October 2005

Chronic diseases are roughly speaking lifelong transitions between the states: relapse and recovery. The long‐term pattern of recurrent times‐to‐relapse can be investigated with routine register data on hospital admissions. The relapses become readmissions to hospital, and the time spent in hospital are gaps between subsequent times‐at‐risk. However, problems of selection and dependent censoring arise because the calendar period of observation is limited and the study population likely to be heterogeneous. We will theoretically verify that an assumption of conditional independence of all times‐at‐risk and gaps, given the latent individual frailty level, allows for consistent inference in the shared frailty model. Using simulation studies, we also investigate cases where gaps (and/or staggered entry) are informative for the individual frailty. We found that the use of the shared frailty model can be extended to situations, where gaps are dependent on the frailty, but short compared to the distribution of the times‐to‐relapse. Our motivating example deals with the course of schizophrenia. We analysed routine register data on readmissions in almost 9000 persons with the disorder. Marginal survival curves of time‐to‐first‐readmission, time‐to‐second‐readmission, etc. were estimated in the shared frailty model. Based on the schizophrenia literature, the conclusion of our analysis was rather surprising: one of a stable course of disorder. Copyright © 2005 John Wiley & Sons, Ltd.
Confidence intervals for an effect size measure based on the Mann–Whitney statistic. Part 1: general issues and tail‐area‐based methods
Authors: Newcombe Robert G.
Published: October 2005

For two random variables X and Y, θ=Pr[Y>X] + ½Pr[Y=X] is advocated as a general measure of effect size to characterize the degree of separation of their distributions. It is estimated by U/mn, a generalization of the Mann–Whitney U statistic, derived by dividing U by the product of the two sample sizes. It is equivalent to the area under the receiver operating characteristic curve. It is readily visualized in terms of two Gaussian distributions with appropriately separated peaks. The effect of discretization of a continuous variable is explored. Tail‐area‐based confidence interval methods are developed which can be applied to very small samples or extreme outcomes. Copyright © 2005 John Wiley & Sons, Ltd.
Reduced models of doubly fed induction generator system for wind turbine simulations
Authors: Sørensen P. , Hansen A. D. , Lund T. , Bindner H.
Published: October 2005

This article compares three reduced models with a detailed model of a doubly fed induction generator system for wind turbine applications. The comparisons are based on simulations only. The main idea is to provide reduced generator models which are appropriate to simulate normal wind turbine operation in aeroelastic wind turbine models, e.g. for control system design or structural design of the wind turbine. The electrical behaviour such as grid influence will therefore not be considered. The work presented in this article shows that with an ideal, undisturbed grid the dynamics of the doubly fed induction generator system is very well represented by the dynamics due to the generator inertia and the generator control system, whereas the electromagnetic characteristics of the generator can be represented by the steady state relations. The parameters for the proposed models are derived from parameters typically available from the generator data sheet and from the controller settings. Thus the models are simple to apply in any case where the generator data sheet is available. Copyright © 2005 John Wiley & Sons, Ltd.
The Hospital for the Ruptured and Crippled: Knight to Gibney, 1870–1887
Authors: Levine David B.
Published: October 2005

In 1870, R&C moved to its second site on the corner of Lexington Avenue and 42nd Street. A newly constructed building designed by a specialist in ecclesiastical architecture became the home of a 200-bed children's hospital planned entirely by Dr. James Knight, founder of the hospital and its first Surgeon-in-Chief. Expansion of the facilities and of the professional staff, although needed and welcomed, brought new challenges, changes, and conflicts. The root of these was to lie in the complex character of James Knight with his dogmatic approach to patient care vs the open nature of his newly appointed assistant, Virgil Gibney, who was to become his successor and eventually the second Surgeon-in-Chief. How these two personalities worked together for 13 years, abruptly parted, and then after Knight's death, the reappearance of Gibney, is a fascinating story of the early development of the first orthopedic hospital in this country. It was a period after the Civil War described as the “Gilded Age,” where not only the country, but the city, was going through its own challenges, changes and conflicts. Emerging was a new era for R&C introducing surgery, postgraduate medical education, and eventually, clinical and basic research.
The combined effect of transport and temperature on distribution and growth of larvae and pelagic juveniles of Arcto-Norwegian cod
Authors: Vikebø Frode , Sundby Svein , Ådlandsvik Bjørn , Fiksen Øyvind
Published: October 2005

Temperature has been identified in field studies as the physical parameter most influential on growth and recruitment of Arcto-Norwegian cod. However, it has been pointed out by many authors that temperature in this context has not only direct effects on the cod, but also indirect effects through lower trophic levels. Moreover, it has been said that temperature might also be a proxy for other climatic parameters. The present paper analyses the direct quantitative effects of temperature on larval and pelagic juvenile growth from spawning in Lofoten until the 0-group fish settle in the Barents Sea. The approach taken is that of a modelling study, supported by analysis of existing data on fish stocks and climate. It is shown that transport and temperature alone can reproduce key features of the 0-group weight distribution and concentration in the Barents Sea for two consecutive years. The extent of the dispersion of the larvae and pelagic juveniles, as well as the ambient temperature they experience on their route, are shown to depend upon their depth in the water column and, to a lesser degree, the time of spawning.
Extensor Tendon Impingement in a Gymnast
Authors: WILSON S. M. , DUBERT T. , ROZENBLAT M.
Published: October 2005

Wrist injuries in the gymnast are due to the transformation of the upper extremity into a weight bearing entity. Gymnast wrist pain presents a difficult diagnostic and therapeutic challenge. Here, we present a new case of extensor tendon impingement in an elite gymnast. To our knowledge, there is no similar report in the literature.
The politicization of education: Identity formation in Moldova and Transnistria
Authors: Roper Steven D.
Published: October 2005

This article examines how education, linguistic and citizenship policies have influenced the development of Moldovan identity and relations with the breakaway region of Transnistria. The article explores the influence of three specific education policies (Russian language instruction, an integrated history course and Romanian language school closures in Transnistria) on the debate concerning Moldovan identity and ultimately Moldovan statehood. The Romanian language school closures in Transnistria demonstrate that education is not only an important agent of identity formation, but also that such crude political tactics as school closures ultimately affect other education policies, reinforce negative stereotypes and make meaningful dialogue impossible. The larger issue than the school closures in Transnistria is whether devolution of authority on issues such as education policy is possible no matter how autonomy is granted.
Faith and War Eyewitnesses to the Japanese invasion of China: Quebec's Jesuit priests
Authors: LARY DIANA
Published: October 2005

My thanks for help in writing this paper go to the Jesuit priests whose letters and diaries I have used; to Fathers Rosario Renaud and Jacques Langlais, the historians of the Quebec Mission in China; to Madame Isabelle Content, archivist of the Jesuit Order in St. Jerome, Quebec; and to my mother, M.M.E. Lainson, who helped me to understand the religious life of Roman Catholics in the 1930s.
Transcending Boundaries: Nishida Kitarō K'ang Yu-Wei, and the Politics of Unity
Authors: GOTO-JONES C. S.
Published: October 2005

Boundaries were smashed and broken as modernity struck its first blows in Asia in the nineteenth century. The British and the French chipped away at the borders of China, and the USA ripped open the seal that enveloped Japan in sakoku. Imperialism, or neo-imperialism, represented a way of overcoming boundaries, of decreasing the salience of other territorial units. However, it was also a way of expanding boundaries, of projecting one's own territory and sustaining the priority of these new (modern) borders over the claims of (allegedly pre-modern) indigenous peoples. Boundaries themselves began to take on a distinctly modern persona–and they were the property of the modern, Western powers.
Urban Riots and Cricket in South Asia: A Postscript to ‘Leveling Crowds’
Authors: TAMBIAH STANLEY J.
Published: October 2005

My book Leveling Crowds was published in 1996, and around the same time and in succeeding years there was a spate of books on much the same topic, but primarily focused on India. This essay discusses the implications of some of these studies for my chief submissions, and also responds to the comments of some reviews of my book. It is hoped that this postscript will amplify and enrich our investigation of the dynamics of ethnonationalist conflicts in South Asia.
Mullahs, Migrants and Murids: New Developments in the Study of Pakistan A Review Article
Authors: MARSDEN MAGNUS
Published: October 2005

The Ulama in Contemporary Islam: Custodians of Change. By MUHAMMAD QASIM ZAMAN. Princeton, N.J. and Oxford: Princeton University Press.

Migrants and Militants: Fun and Urban Violence in Pakistan. By OSKAR VERKAAIK. Princeton, N.J.: Princeton University Press.

Pilgrims of Love: The Anthropology of a Global Sufi Cult. By PNINA WERBNER. London: Hurst and Company.