Intrahepatic lymphocyte phenotypes in hepatitis C virus infection: a comparison between cirrhotic and non-cirrhotic livers.

Aim: The pathogenesis of viral hepatitis involves the activation of cellular immunity, including intrahepatic lymphocytes (IHL). Lym-phocyte phenotypes play a fundamental role in the pathogenesis of chronic hepatitis C virus (HCV) infection, the progression of liver fibrosis and subsequent hepatocellular carcinoma. The aim of this study was to evaluate the frequency of intrahepatic mononuclear cell phenotypes in patients with chronic HCV.

Hepatic steatosis in hepatitis C: comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial.

Background & Aims: Hepatic steatosis often is observed in patients with chronic hepatitis C and has been reported to be associated with hepatic fibrosis and impaired treatment response in some studies. Our aim was to determine the prevalence of and risk factors for hepatic steatosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, and to determine the relationship between steatosis, fibrosis, and sustained virologic response (SVR) to re-treatment with pegylated interferon and ribavirin.

Methods: Baseline data from 1143 Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, with a mean body mass index of 30, 5% with genotype 3, 38% with cirrhosis, and 24% with diabetes were analyzed.

Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C.

Background & Aims: Reducing the dose of peginterferon and/or ribavirin to <80% when treating chronic hepatitis C virus has been associated with a reduction in sustained virologic response (SVR). However, prior studies did not assess the impact of reducing the dose of peginterferon independent of ribavirin or differentiate between dose reduction or interrupting or prematurely discontinuing treatment.

Methods: Nine hundred thirty-six patients with chronic hepatitis C genotype 1, advanced fibrosis, or cirrhosis (Ishak 3-6) and prior nonresponse to standard interferon +/- ribavirin were retreated with peginterferon alfa-2a (180 microg/wk) and ribavirin (1000-1200 mg/day) during the lead-in phase of the HALT-C trial.

Clinical relevance of cognitive scores in hepatitis C patients with advanced fibrosis.

Mild neuropsychological impairment has previously been reported in chronic hepatitis C (CHC) patients. The aim of this study was to assess the presence and severity of cognitive impairment among a cohort of CHC patients with advanced fibrosis using clinician ratings compared to classification based upon statistical methods. In addition, we set out to determine the relationship between cognitive scores and functional status.

Expanding the scope of the acyl-type radical addition reactions promoted by SmI2.

N-acyl oxazolidinones of simple carboxylic acids and amino acids were observed to undergo successful SmI2-promoted couplings with substituted acrylamides and acrylates, affording a variety of functionalized gamma-ketoamides and -esters with yields attaining 85%. As many of these reductive couplings were previously found to be ineffective employing the corresponding 4-pyridylthio esters, the applicability of this methodology has been substantially improved. The methodology has been adapted to prepare structures related to two potent aspartate protease inhibitors, the renin inhibitor aliskiren, and the gamma-secretase inhibitor L-685,458.

A new approach to reconstruction models of dendritic branching patterns.

Quantitative models for characterising the detailed branching patterns of dendritic trees aim to explain these patterns either in terms of growth models based on principles of dendritic development or reconstruction models that describe an existing structure by means of a canonical set of elementary properties of dendritic morphology, which when incorporated into an algorithmic procedure will generate samples of dendrites that are statistically indistinguishable in both canonical and emergent features from those of the original sample of real neurons. This article introduces a conceptually new approach to reconstruction modelling based on the single assumption that dendritic segments are built from sequences of units of constant diameter, and that the distribution of the lengths of units of similar diameter is independent of location within a dendritic tree. This assumption in combination with non-parametric methods for estimating univariate and multivariate probability densities leads to an algorithm that significantly reduces the number of basic parameters required to simulate dendritic morphology.

Creating carbon-carbon bonds with samarium diiodide for the synthesis of modified amino acids and peptides.

In this perspective, an overview of our experiences on the application of samarium diiodide in organic synthesis for the preparation of amino acid and peptide analogues is presented. Three different carbon-carbon bond forming reactions are discussed, including side chain introductions, gamma-amino acid synthesis and acyl-like radical additions for the construction of C-C mimics of the peptidic bonds.

HCV RNA detection by TMA during the hepatitis C antiviral long-term treatment against cirrhosis (Halt-C) trial.

For making treatment decisions related to chronic hepatitis C, the utility of HCV RNA tests with increased sensitivity has not been defined. Prior interferon nonresponders with advanced fibrosis (n = 1,145) were retreated with peginterferon alpha-2a and ribavirin. Patients who were HCV RNA-negative by a polymerase chain reaction (PCR)-based assay (Roche COBAS Amplicor HCV Test, v.

Mechanistic evidence for intermolecular radical carbonyl additions promoted by samarium diiodide.

In this work, mechanistic studies were performed to understand the SmI2/H2O-mediated coupling of N-acyl oxazolidinones with acrylates and acrylamides, providing gamma-keto esters and amides, respectively. Our results provide experimental evidence that C-C bond formation via intermolecular radical addition reactions to carbonyl substrates can be promoted by samarium diiodide. Coupling reactions with N-cyclopropylcarbonyl-2-oxazolidinone suggest the alpha,beta-unsaturated esters/amides are reduced by the low-valent lanthanide reagent and not the N-acyl oxazolidinones, as originially proposed (J.

More advanced hepatic fibrosis in hispanics with chronic hepatitis C infection: role of patient demographics, hepatic necroinflammation, and steatosis.

Background And Aims: We sought to assess whether Hispanics have more advanced hepatitis C virus (HCV)-related liver disease than non-Hispanic whites (NHW) and to identify contributory factors.

Patients And Methods: Patients were recruited from the Los Angeles county hepatitis clinic. Liver fibrosis and necroinflammation (NI) were assessed by the Ishak scoring system.

Formal total synthesis of the potent renin inhibitor aliskiren: application of a SmI2-promoted acyl-like radical coupling.

A formal total synthesis of the potent renin inhibitor aliskiren is disclosed exploiting an alternative coupling strategy recently developed by this laboratory for the preparation of the hydroxyethylene isostere-based class of protease inhibitors. The thioester derivative of the amino acid representing the C5-C9 fragment of the aliskiren carbon skeleton underwent a carbon chain extension via a SmI2-promoted radical addition to n-butyl acrylate. Introduction of the C3-isopropyl group with the correct relative configuration was accomplished via stereoselective reduction of the obtained ketone with concomitant lactonization, followed by an aldol reaction with acetone.

Hepatitis C virus-specific immune responses and quasi-species variability at baseline are associated with nonresponse to antiviral therapy during advanced hepatitis C.

Pretreatment hepatitis C virus (HCV)-specific lymphoproliferative (LP) responses, neutralizing antibody (NA) responses, intrahepatic cytotoxic T lymphocyte (CTL) responses, and HCV quasi-species (QS) diversity and complexity were examined in patients with advanced hepatic fibrosis (Ishak fibrosis score of > or = 3) and prior nonresponse to interferon (IFN)- alpha therapy who were enrolled in the initial phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial. Positive baseline HCV E1- and/or E2-specific NA responses (P = .01) and higher baseline HCV QS diversity (P = .

Effect of time of day on the accuracy and consistency of the badminton serve.

In badminton, the short doubles serve requires accuracy, whereas the long singles serve also requires power. The present study investigated if there are time-of-day effects for these two types of serve. Eight male badminton players completed two familiarization sessions before being tested at 08:00, 14:00 and 20:00 hours, the session times being counterbalanced.

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

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.

Cognitive function in hepatitis C patients with advanced fibrosis enrolled in the HALT-C trial.

Background/aims: Prior studies have demonstrated neuropsychological abnormalities in chronic hepatitis C (CHC) patients even with mild fibrosis. The aim of this study was to determine the frequency, type, and severity of cognitive impairment in a large group of CHC patients with advanced fibrosis.

Methods: Ten validated neuropsychological tests were administered to 201 CHC patients.

Synthesis of a hydroxyethylene isostere of the tripeptide Arg-Gly-Leu via a convergent acyl-like radical addition strategy.

[reaction: see text] A hydroxyethylene isostere of the tripeptide Arg-Gly-Leu, representing an important fragment of a novel cyclic-peptide-based uPA inhibitor, was synthesized in few steps employing as the key step a samarium diiodide promoted coupling of either the 4-thiopyridyl ester of N(alpha)-Fmoc- or N(alpha)-Cbz-protected L-ornithine with the N-acryloyl derivative of L-leucine methyl ester. Epimerization under the coupling conditions at the chiral center in the alpha-position to the ketone was demonstrated not to take place. A stereoselective reduction of the Cbz-protected aminoketone obtained from this radical reaction was promoted by the same single-electron reducing agent in the presence of methanol providing the syn-amino alcohol with a diastereoselectivity of 85:15.

Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial.

Background/aims: Alpha-fetoprotein (AFP) has been useful in the diagnosis of hepatocellular carcinoma (HCC) but lacks specificity. We assessed serum AFP among patients with chronic hepatitis C and advanced fibrosis to establish predictors of AFP elevations and changes with antiviral therapy.

Methods: Serum AFP was measured at baseline and on therapy in patients in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C).

Increased computational accuracy in multi-compartmental cable models by a novel approach for precise point process localization.

Compartmental models of dendrites are the most widely used tool for investigating their electrical behaviour. Traditional models assign a single potential to a compartment. This potential is associated with the membrane potential at the centre of the segment represented by the compartment.

Metabolic gas kinetics depend upon the level of exercise performed.

Background: The kinetics of oxygen and carbon dioxide at the onset of and recovery from exercise are slowed in patients with chronic heart failure (CHF). The aim of the present study was to establish whether the kinetics of O2 are influenced by the work rate.

Methods: Thirteen CHF patients and 12 control subjects underwent bicycle-based peak exercise testing with metabolic gas exchange analysis.