Biochemical characterization of rhinovirus RNA-dependent RNA polymerase.

Human rhinoviruses (HRV) represent the single most important causative agent of the common cold. The HRV genome encodes an RNA-dependent RNA polymerase (RdRp) designated 3D polymerase that is required for replication of the HRV RNA genome. We have expressed and purified recombinant HRV-16 3D polymerase to near homogeneity from Escherichia coli transformed with an expression plasmid containing the full-length 460 amino acid HRV-16 3D sequence with a methionine at the N-terminus and a glycine-serine linker followed by a 6-histidine affinity tag at the C-terminus.

Characterization of a novel antibacterial agent that inhibits bacterial translation.

Bacterial protein synthesis is the target for several classes of established antibiotics. This report describes the characterization of a novel translation inhibitor produced by the soil bacterium Flexibacter. The dipeptide antibiotic TAN1057 A/B was synthesized and designated GS7128.

Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks.

Current therapies for chronic hepatitis B virus (HBV) infection do not provide adequate long-term control of viral replication in the majority of patients. Monotherapy with nucleoside analogs, such as lamivudine and famciclovir, is effective for short periods but results in the emergence of drug-resistant HBV in a substantial number of patients within 1 year of therapy. Adefovir dipivoxil (ADV) has demonstrated clinical activity against wild-type and lamivudine-resistant HBV, but it is unclear whether resistance mutations will emerge after long-term therapy with this drug.

Pulmonary sarcoidosis and the acute respiratory distress syndrome (ARDS).

A 50 year old man presented with 3 weeks of exertional dyspnoea. His chest radiograph on admission revealed diffuse bilateral interstitial infiltrates. He did not respond to antibiotics but subsequently improved on high dose corticosteroids.

Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review.

Background: Heart failure predisposes to stroke and thromboembolism, which in turn contribute to the high mortality and morbidity in heart failure.

Objectives: To determine the effect of antiplatelet agents, compared to placebo or anticoagulant therapy, on death and/or major thromboembolic events in adults with heart failure who are in sinus rhythm.

Design: Systematic review of randomized parallel group placebo or controlled trials comparing oral antiplatelet therapy with control or anticoagulation therapy in adults with chronic heart failure in sinus rhythm.

Anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review.

Background: Patients with chronic heart failure (heart failure) are at risk of thromboembolic events, and coronary ischaemic events also contribute to the progression of heart failure. Long-term oral anticoagulation is established in certain groups, including patients with heart failure and atrial fibrillation, but there is wide variation in the use of oral anticoagulation in the broader heart failure population.

Objective: To determine whether long-term oral anticoagulation reduces total deaths and/or major thromboembolic events in patients with heart failure.

Tropical spastic paraparesis.

Human T-cell lymphotropic virus type I (HTLV-I) is the cause of endemic tropical spastic paraparesis (TSP) or HTLV-I-associated myelopathy (HAM). Because TSP/HAM is not a fatal disease, the neuropathology of this disease, albeit relatively well understood, is based on the examination of just a few incidental cases. We summarise our experience with the neuropathology of tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM).

Inhibitory effect of adefovir on viral DNA synthesis and covalently closed circular DNA formation in duck hepatitis B virus-infected hepatocytes in vivo and in vitro.

The elimination of viral covalently closed circular DNA (CCC DNA) from the nucleus of infected hepatocytes is an obstacle to achieving sustained viral clearance during antiviral therapy of chronic hepatitis B virus (HBV) infection. The aim of our study was to determine whether treatment with adefovir, a new acyclic nucleoside phosphonate, the prodrug of which, adefovir dipivoxil, is in clinical evaluation, is able to suppress viral CCC DNA both in vitro and in vivo using the duck HBV (DHBV) model. First, the effect of adefovir on viral CCC DNA synthesis was examined with primary cultures of DHBV-infected fetal hepatocytes.

Identification of critical residues on thrombin mediating its interaction with fibrin.

Thrombin binding to fibrin may be important in localizing thrombin to the site of vascular injury. However, fibrin-bound thrombin retains its catalytic activity toward fibrinogen, and may be prothrombotic under certain conditions. A collection of 52 purified thrombin mutants was used to identify those residues mediating the thrombin-fibrin interaction.

Effects of acute exercise on hemorheological, endothelial, and platelet markers in patients with chronic heart failure in sinus rhythm.

Background: Chronic heart failure (CHF) is associated with an increased risk of thrombosis and thromboembolic events, including stroke and venous thromboembolism. which may be related to a prothrombotic or hypercoagulable state. Acute vigorous exercise has been associated with activation of hemostasis, and this risk may well be particularly increased in patients with CHF.

Anticoagulation for heart failure in sinus rhythm.

Background: Patients with chronic heart failure (heart failure) are at risk of thromboembolic events, including stroke, pulmonary embolism and peripheral arterial embolism, whilst coronary ischaemic events also contribute to the progression of heart failure. Long-term oral anticoagulation is established in certain groups, including patients with heart failure and atrial fibrillation but there is wide variation in the indications and use of oral anticoagulation in the broader heart failure population.

Objectives: To determine whether long-term oral anticoagulation reduces total deaths and/or major thromboembolic events in patients with heart failure, when compared to placebo.

Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm.

Background: Morbidity and mortality in patients with symptomatic chronic heart failure is high, it predisposes to stroke and thromboembolism which in turn contribute to high mortality in heart failure.

Objectives: To determine effect of antiplatelet agents when compared to placebo or anticoagulant therapy on death and/or major thromboembolic events in adults with heart failure who are in sinus rhythm.

Search Strategy: Systematic search of electronic databases (MEDLINE, EMBASE, DARE).

Cardiac basal metabolism.

We endeavor to show that the metabolism of the nonbeating heart can vary over an extreme range: from values approximating those measured in the beating heart to values of only a small fraction of normal--perhaps mimicking the situation of nonflow arrest during cardiac bypass surgery. We discuss some of the technical issues that make it difficult to establish the magnitude of basal metabolism in vivo. We consider some of the likely contributors to its magnitude and point out that the biochemical reasons for a sizable fraction of the heart's basal ATP usage remain unresolved.

Antiviral efficacy and pharmacokinetics of oral adefovir dipivoxil in chronically woodchuck hepatitis virus-infected woodchucks.

The antiviral efficacy of orally administered adefovir dipivoxil was evaluated in an 18-week study (12 weeks of treatment and 6 weeks of recovery) conducted with woodchucks chronically infected with woodchuck hepatitis virus (WHV). Adefovir dipivoxil is a prodrug of adefovir designed to enhance its oral bioavailability. Following administration of 15 mg of adefovir dipivoxil per kg of body weight in four WHV-infected animals, the mean maximum concentration of adefovir in serum was 0.

Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study.

Background: Lamivudine-resistant hepatitis B virus (HBV) is found in about 15-32% of infected patients with or without co-infection with HIV-1 after 1 year of lamivudine therapy. Adefovir dipivoxil is active in vivo and in vitro against wild-type and lamivudine-resistant HBV. We assessed the safety and efficacy of a once daily dose of adefovir dipivoxil in an open-label trial for the treatment of lamivudine-resistant HBV infection in HIV-1-infected patients.

Effect of acute exercise on the raised plasma fibrinogen, soluble P-selectin and von Willebrand factor levels in chronic atrial fibrillation.

Background: There is increasing evidence that chronic atrial fibrillation (AF) is associated with a prothrombotic or hypercoagulable state.

Hypothesis: This study was undertaken to determine whether short-term exercise in patients with chronic AF would shift the overall hemostatic balance toward a more prothrombotic state with a reduction in fibrinolytic potential.

Methods: We recruited 20 patients (13 men; mean age 65 years +/- 11 standard deviation [SD]) with chronic AF who were not treated with antithrombotic therapy and exercised them to exhaustion using a multistage treadmill exercise (standard Bruce) protocol.

Comparison of the efficiency of rat papillary muscles during afterloaded isotonic contractions and contractions with sinusoidal length changes.

The results of previous studies suggest that the maximum mechanical efficiency of rat papillary muscles is lower during a contraction protocol involving sinusoidal length changes than during one involving afterloaded isotonic contractions. The aim of this study was to compare directly the efficiency of isolated rat papillary muscle preparations in isotonic and sinusoidal contraction protocols. Experiments were performed in vitro (27 degrees C) using left ventricular papillary muscles from adult rats.

Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC).

Success in treating hepatitis B virus (HBV) infection with nucleoside analog drugs like lamivudine is limited by the emergence of drug-resistant viral strains upon prolonged therapy. The predominant lamivudine resistance mutations in HBV-infected patients are Met552IIe and Met552Val (Met552Ile/Val), frequently in association with a second mutation, Leu528Met. The effects of Leu528Met, Met552Ile, and Met552Val mutations on the binding of HBV polymerase inhibitors and the natural substrate dCTP were evaluated using an in vitro HBV polymerase assay.

Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy.

Background: To investigate the hypothesis that abnormalities of hemorheological (fibrinogen, plasma viscosity), endothelial (von Willebrand factor [vWF]), and platelet (soluble P-selectin) function would exist in patients with chronic heart failure (CHF) who are in sinus rhythm, we conducted a cross-sectional study of 120 patients with stable CHF (median ejection fraction 30%). We also hypothesized that ACE inhibitors and beta-blockers would beneficially affect the measured indices.

Methods And Results: In the cross-sectional analysis, plasma viscosity (P=0.

Increased dietary salt accelerates chronic allograft nephropathy in rats.

Background: Chronic allograft nephropathy (CAN), a major problem in renal transplantation, is related to both alloantigen-dependent and -independent processes. Because dietary salt intake modulated glomerular production of transforming growth factor-beta, which has been shown to play an important role in CAN, we hypothesized that dietary salt would directly enhance renal injury in a rodent model of CAN.

Methods: Dietary NaCl was increased from 1.

Effects of ageing on the activation metabolism of rat papillary muscles.

1. A myothermic technique has been used to investigate the mechanics and energetics of left ventricular papillary muscles from 6-, 15-, 22- and 27-32-month-old Sprague-Dawley rats. 2.

The tethered agonist approach to mapping ion channel proteins--toward a structural model for the agonist binding site of the nicotinic acetylcholine receptor.

Background: The integral membrane proteins of neurons and other excitable cells are generally resistant to high resolution structural tools. Structure-function studies, especially those enhanced by the nonsense suppression methodology for unnatural amino acid incorporation, constitute one of the most powerful probes of ion channels and related structures. The nonsense suppression methodology can also be used to incorporate functional side chains designed to deliver novel structural probes to membrane proteins.