Explicit formulas for charge conservation and steady-state volumes of the cytosol and endoplasmic
reticulum (ER) are derived in terms of membrane potential, amount of ions, Ca2+-bound buffer molecules, and initial cellular conditions. The formulations were applied to a ventricular myocyte RAD001 nmr model which has plasma-membrane Ca2+ currents with dynamic gating mechanisms, Ca2+-buffering reactions with diffusive and non-diffusive buffer proteins, and Ca2+ uptake into or release from the sarcoplasmic reticulum (SR) accompanied by compensatory cationic or anionic currents through the SR membrane. Time-dependent volume changes in cardiac myocytes induced by varying extracellular osmolarity or by action potential generation were successfully simulated by the novel formulations. Through application of bifurcation analysis, the existence and uniqueness of steady-state solutions of the cell volume were validated, and contributions of individual ion channels and transporters to the steady-state volume were systematically analyzed.
The new formulas are consistent with previous fundamental theory derived from simple models of minimum compositions. The new formulations may be useful for examination of the relationship between cell function and volume change PF299804 in other cell types. (C) 2012 Elsevier Ltd. All rights reserved.”
“BACKGROUND
In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously
untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection.
METHODS
We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned Ruboxistaurin cell line to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy.
RESULTS
In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon.