Effectiveness of Extending Treatment Duration in Therapy with Pegylated Interferon and Ribavirin for Genotype 2 Hepatitis C Virus Infection

The effectiveness of extending treatment duration as response guided therapy was previously reported for chronic hepatitis C (CHC) genotype 1, but is still controversial for genotype 2. The present study is a retrospective cohort study to investigate the effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for patients with CHC genotype 2 by focusing on the timing at which patients obtained undetectable HCV RNA. A total of 306 patients who obtained undetectable HCV RNA by week 24 of treatment and completed 24 weeks of treatment were enrolled. Rapid virological response (RVR) to standard therapy was achieved by 122 patients (51ｵ), and 89ｵ of them obtained sustained virological response (SVR), while 69ｵ of non-RVR patients achieved SVR. Non-RVR patients with undetectable HCV RNA at week 8, and insufficient adherence＜80ｵ pegylated interferon and ribavirin during the first 24 weeks, significantly improved their SVR rate by extended therapy. Among patients receiving extended therapy, drug adherences did not differ between SVR and non-SVR patients, indicating that extending treatment duration might compensate for insufficient antiviral effects due to insufficient drug adherences. This finding might be useful in creating a guideline for extending treatment duration for patients with CHC genotype 2

Magnesium Excretion in C. elegans Requires the Activity of the GTL-2 TRPM Channel

Systemic magnesium homeostasis in mammals is primarily governed by the activities of the TRPM6 and TRPM7 cation channels, which mediate both uptake by the intestinal epithelial cells and reabsorption by the distal convoluted tubule cells in the kidney. In the nematode, C. elegans, intestinal magnesium uptake is dependent on the activities of the TRPM channel proteins, GON-2 and GTL-1. In this paper we provide evidence that another member of the TRPM protein family, GTL-2, acts within the C. elegans excretory cell to mediate the excretion of excess magnesium. Thus, the activity of GTL-2 balances the activities of the paralogous TRPM channel proteins, GON-2 and GTL-1

Impact of Comorbid Hepatic Steatosis on Treatment of Chronic Hepatitis C in Japanese Patients and the Relationship with Genetic Polymorphism of IL28B, PNPLA3 and LDL Receptor

The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p＝0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association (p＝0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p＝0.049, and ＜0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy

Effect of Peripheral 5-HT on Glucose and Lipid Metabolism in Wether Sheep

In mice, peripheral 5-HT induces an increase in the plasma concentrations of glucose, insulin and bile acids, and a decrease in plasma triglyceride, NEFA and cholesterol concentrations. However, given the unique characteristics of the metabolism of ruminants relative to monogastric animals, the physiological role of peripheral 5-HT on glucose and lipid metabolism in sheep remains to be established. Therefore, in this study, we investigated the effect of 5-HT on the circulating concentrations of metabolites and insulin using five 5-HT receptor (5HTR) antagonists in sheep. After fasting for 24 h, sheep were intravenously injected with 5-HT, following which-, plasma glucose, insulin, triglyceride and NEFA concentrations were significantly elevated. In contrast, 5-HT did not affect the plasma cholesterol concentration, and it induced a decrease in bile acid concentrations. Increases in plasma glucose and insulin concentrations induced by 5-HT were attenuated by pre-treatment with Methysergide, a 5HTR 1, 2 and 7 antagonist. Additionally, decreased plasma bile acid concentrations induced by 5-HT were blocked by pre-treatment with Ketanserin, a 5HTR 2A antagonist. However, none of the 5HTR antagonists inhibited the increase in plasma triglyceride and NEFA levels induced by 5-HT. On the other hand, mRNA expressions of 5HTR1D and 1E were observed in the liver, pancreas and skeletal muscle. These results suggest that there are a number of differences in the physiological functions of peripheral 5-HT with respect to lipid metabolism between mice and sheep, though its effect on glucose metabolism appears to be similar between these species

The Rab3 GDP/GTP exchange factor homolog AEX-3 has a dual function in synaptic transmission

Guanine nucleotide exchange is essential for Rab GTPase activities in regulating intracellular vesicle trafficking. This exchange process is facilitated by guanine nucleotide exchange factor (GEF). Previously, we identified Caenorhabditis elegans AEX-3 as a GEF for Rab3 GTPase. Here we demonstrate that AEX-3 regulates neural activities through a second, previously unrecognized pathway via interactions with the novel protein CAB-1. CAB-1 is 425 amino acids long and has an 80 amino acid motif in common with the mouse neural protein NPDC-1. cab-1 and rab-3 mutants have different behavioral defects, and RAB-3 localization and function are apparently normal in cab-1 mutants, indicating that the CAB-1 pathway is distinct from the RAB-3 pathway. The aex-3 mutant phenotype resembles the sum of the rab-3 and cab-1 mutant phenotypes, indicating that AEX-3 regulates two different pathways for neural activities. We propose that connection of multiple pathways may be an important feature of Rab GEFs to coordinate various cellular events

CADLIVE dynamic simulator: Direct link of biochemical networks to dynamic models

We have developed the CADLIVE (Computer-Aided Design of LIVing systEms) Simulator that provided a rule-based automatic way to convert biochemical network maps into dynamic models, which enables simulating their dynamics without going through all of the reactions down to the details of exact kinetic parameters. The simulator supports the biochemical reaction maps that are generated by the previously developed GUI editor. Notice that the part of the GUI editor had been previously published, but, as yet, not the simulator. To directly link biochemical network maps to dynamic simulation, we have created the strategy of three layers and two stages with the efficient conversion rules in an XML representation. This strategy divides a molecular network into three layers, i.e., gene, protein, and metabolic layers, and partitions the conversion process into two stages. Once a biochemical map is provided, CADLIVE automatically builds a mathematical model, thereby facilitating one to simulate and analyze it. In order to demonstrate the feasibility of CADLIVE, we analyzed the Escherichia coli nitrogen-assimilation system (64 equations with 64 variables) that consists of multiple and complicated negative and positive feedback loops. CADLIVE predicted that the glnK gene is responsible for hysteresis or reversibility of nitrogen-related (Ntr) gene expression with respect to the ammonia concentration, supporting the experimental observation of the runaway expression of the Ntr genes

aex-3 encodes a novel regulator of presynaptic activity in C. elegans

mains unclear