AST/ALT ratio is not an index of liver fibrosis in chronic hepatitis C when aminotransferase activities are determinate according to the international recommendations.

OBJECTIVE: The aspartate aminotransferase activity (AST)/alanine aminotransferase activity (ALT) ratio is used as liver fibrosis index whereas the reported data are conflicting. In chronic hepatitis C (CHC), reported diagnostic accuracies range from none to good for significant fibrosis and to excellent for cirrhosis. Assuming that AST/ALT increases are mainly due to vitamin B6 defects since pyridoxal phosphate (PLP), active form of B6, acts as coenzyme in transamination reactions, we evaluated the diagnostic accuracy of the AST/ALT ratio using standardized methods for AST and ALT activities, with PLP addition as recommended, in a prospective multicenter cohort of CHC patients. METHODS: ALT and AST activities were measured using the recommended IFCC methods with addition of pyridoxal 5\u27-phosphate. We evaluated the AST/ALT ratio for the diagnosis of liver fibrosis or cirrhosis in a cohort of CHC patients included in a multicenter prospective study. A liver biopsy was performed in each patient and reviewed by two independent pathologists in order to determine the fibrosis stage according to Metavir classification which was the reference standard. RESULTS: AST/ALT ratio significantly increased with histological stage of liver fibrosis and there was a significant correlation between Metavir fibrosis stage and AST/ALT ratio (r=0.129, P<0.0035). The ROC curve analyses showed that the AST/ALT ratio does not discriminate significant fibrosis (F≥2) (AUROC=0.531) and had only very poor diagnostic accuracies for severe fibrosis (F≥3) (AUROC=0.584) or cirrhosis (F4) (AUROC=0.626). CONCLUSION: AST/ALT ratio is not a good and discriminative index of liver fibrosis in CHC when aminotransferase activities are determinate according to the international recommendations

Caveolin-1 expression and cavin stability regulate caveolae dynamics in adipocyte lipid store fluctuation

Adipocytes specialized in the storage of energy as fat are among the most caveolae-enriched cell types. Loss of caveolae produces lipodystrophic diabetes in humans, which cannot be reversed by endothelial rescue of caveolin expression in mice, indicating major importance of adipocyte caveolae. However, how caveolae participate in fat cell functions is poorly understood. We investigated dynamic conditions of lipid store fluctuations and demonstrate reciprocal regulation of caveolae density and fat cell lipid droplet storage. We identified caveolin-1 expression as a crucial step in adipose cell lines and in mice to raise the density of caveolae, to increase adipocyte ability to accommodate larger lipid droplets, and to promote cell expansion by increased glucose utilization. In human subjects enrolled in a trial of 8 weeks of overfeeding to promote fattening, adipocyte expansion response correlated with initial caveolin-1 expression. Conversely, lipid mobilization in cultured adipocytes to induce lipid droplet shrinkage led to biphasic response of cavin-1 with ultimate loss of expression of cavin-1 and -3 and EHD2 by protein degradation, coincident with caveolae disassembly. We have identified the key steps in cavin/caveolin interplay regulating adipocyte caveolae dynamics. Our data establish that caveolae participate in a unique cell response connected to lipid store fluctuation, suggesting lipid-induced mechanotension in adipocytes

The lipoatrophic caveolin-1 deficient mouse model reveals autophagy in mature adipocytes

Adipose tissue lipoatrophy caused by caveolin gene deletion in mice is not linked to defective adipocyte differentiation. We show that adipose tissue development cannot be rescued by endothelial specific caveolin-1 re-expression, indicating primordial role of caveolin in mature adipocytes. Partial or total caveolin deficiency in adipocytes induced broad protein expression defects, including but not limited to previously described downregulation of insulin receptor. Global alterations in protein turnover, and accelerated degradation of long-lived proteins were found in caveolin-deficient adipocytes. Lipidation of endogenous LC3 autophagy marker and distribution of GFP-LC3 into aggregates demonstrated activated autophagy in the absence of caveolin-1 in adipocytes. Furthermore, electron microscopy revealed autophagic vacuoles in caveolin-1 deficient but not control adipocytes. Surprisingly, significant levels of lipidated LC3-II were found around lipid droplets of normal adipocytes, maintained in nutrient-rich conditions or isolated from fed mice, which do not display autophagy. Altogether, these data indicate that caveolin deficiency induce autophagy in adipocytes, a feature that is not a physiological response to fasting in normal fat cells. This likely resulted from defective insulin and lipolytic responses that converge in chronic nutrient shortage in adipocytes lacking caveolin-1. This is the first report of a pathological situation with autophagy as an adaptative response to adipocyte failure

Regulated association of caveolins to lipid droplets during differentiation of 3T3-L1 adipocytes.

Caveolins, structural protein coats of caveolae primarily involved in membrane-related functions, have also been found associated to lipid droplets (LD), specialized organelles for fat storage. In the present study, we wanted to delineate the main features that govern the presence of caveolin-1 on adipocyte lipid droplets. Using either morphological or biochemical approaches, we found caveolins to associate to LD in 3T3-L1 adipocytes during their late maturation phase. The time course of this association could be modulated by constitutive activation of src-kinase, suggesting that the specific enrichment of caveolins in enlarged LD results from an active pathway rather than trapping of caveolins to lipid storage organelle acting as a passive sink. The fat cell size dependence of the association of organized caveolins on adipocytes LD suggests a role for these proteins in the long-term handling of lipid stores

Including osteoprotegerin and collagen IV in a score-based blood test for liver fibrosis increases diagnostic accuracy

BACKGROUND: Noninvasive methods for liver fibrosis evaluation in chronic liver diseases have been recently developed, i.e. transient elastography (Fibroscan™) and blood tests (Fibrometer®, Fibrotest®, and Hepascore®). In this study, we aimed to design a new score in chronic hepatitis C (CHC) by selecting blood markers in a large panel and we compared its diagnostic performance with those of other noninvasive methods. METHODS: Sixteen blood tests were performed in 306 untreated CHC patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using METAVIR histological fibrosis stage as reference. The new score was constructed by non linear regression using the most accurate biomarkers. RESULTS: Five markers (alpha-2-macroglobulin, apolipoprotein-A1, AST, collagen IV and osteoprotegerin) were included in the new function called Coopscore©. Using the Obuchowski Index, Coopscore© shows higher diagnostic performances than for Fibrometer®, Fibrotest®, Hepascore® and Fibroscan™ in CHC. Association between Fibroscan™ and Coopscore© might avoid 68% of liver biopsies for the diagnosis of significant fibrosis. CONCLUSION: Coopscore© provides higher accuracy than other noninvasive methods for the diagnosis of liver fibrosis in CHC. The association of Coopscore© with Fibroscan™ increases its predictive value

Toroidally Asymmetric Distributions of Hydrocarbon (CD) Emission and Chemical Sputtering Sources in DIII-D

Measurements in DIII-D show that the carbon chemical sputtering sources along the inner divertor and center post are toroidally periodic and highest at the upstream tile edge. Imaging with a tangentially viewing camera and visible spectroscopy were used to monitor the emission from molecular hydrocarbons (CH/CD) at 430.8 nm and deuterium neutrals in attached and partially detached divertors of low-confinement mode plasmas. In contrast to the toroidally periodic CD distribution, emission from deuterium neutrals was observed to be toroidally symmetric along the inner strike zone. The toroidal distribution of the measured tile surface temperature in the inner divertor correlates with that of the CD emission, suggesting larger parallel particle and heat fluxes to the upstream tile edge, either due to toroidal tile gaps or height steps between adjacent tiles

Visible and Infrared Optical Design for the ITER Upper Ports

This document contains the results of an optical design scoping study of visible-light and infrared optics for the ITER upper ports, performed by LLNL under contract for the US ITER Project Office. ITER is an international collaboration to build a large fusion energy tokamak with a goal of demonstrating net fusion power for pulses much longer than the energy confinement time. At the time of this report, six of the ITER upper ports are planned to each to contain a camera system for recording visible and infrared light, as well as other diagnostics. the performance specifications for the temporal and spatial resolution of this system are shown in the Section II, Functional Specifications. They acknowledge a debt to Y. Corre and co-authors of the CEA Cadarache report ''ITER wide-angle viewing and thermographic and visible system''. Several of the concepts used in this design are derived from that CEA report. The infrared spatial resolution for optics of this design is diffraction-limited by the size of the entrance aperture, at lower resolution than listed in the ITER diagnostic specifications. The size of the entrance aperture is a trade-off between spatial resolution, optics size in the port, and the location of relay optics. The signal-to-noise ratio allows operation at the specified time resolutions

Automation of the Hepascore and validation as a biochemical index of liver fibrosis in patients with chronic hepatitis C from the ANRS HC EP 23 Fibrostar cohort

Background Hepascore combining serum bilirubin, gamma glutamyl transpeptidase, hyaluronic acid (HA) and α2-macroglobulin with age and sex, was reported as relevant in predicting liver fibrosis in patients with chronic HCV infection and was proposed as an alternative to liver biopsy. Methods Since an automated HA assay (Latex method, Wako, Japan) became available, we investigated to automate Hepascore by simultaneous measurements of components using an OLYMPUS AU640 analyzer (Tokyo, Japan). For its clinical evaluation, we considered a cohort of chronic HCV patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar). Results Automated Hepascore was not significantly different than assayed as previously described. An improvement in HA variability was evidenced. In 512 chronic HCV patients, automated Hepascore, using ROC curves analysis, showed good predictive performances for significant fibrosis (AUROC = 0.81), severe fibrosis (AUROC = 0.82), and cirrhosis (AUROC = 0.88). For significant fibrosis, Hepascore (cut-off = 0.5) had a sensitivity of 0.77, a specificity of 0.70, a positive predictive value of 0.71 and a negative predictive value (NPV) of 0.77. Hepascore < 0.25 could exclude significant fibrosis with a sensitivity of 0.95 and a NPV of 0.90 and Hepascore < 0.75 could exclude cirrhosis with a sensitivity of 0.86 and a NPV of 0.97. Conclusions This study shows that Hepascore, a non-invasive index of liver fibrosis, necessitating only one serum sample, can be totally automated using a single analyzer and confirms that Hepascore accurately predicts liver fibrosis in chronic HCV. Hepascore might be largely used in assessing liver fibrosis as surrogate to the liver biopsy

Plasma Membrane Subdomain Compartmentalization Contributes to Distinct Mechanisms of Ceramide Action on Insulin Signaling

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