Similarly, there is a possibility that

Similarly, there is a possibility that Selleck PKC412 patients who recover from MHE may withdraw from treatment, or that treatment may positively affect driving skills in less than 78% of cases, as postulated

in the study. Indeed, even if MHE and reduced driving skills are related, they cannot be considered one and the same thing, since the assumption that ammonia-lowering strategies may affect driving to the same extent that they affect psychometric performance is not sufficiently proven. The combined effect of variations in some of these base-case parameters, or in the structure of the decision tree, might lead to partially different conclusions to the study.22 These limitations aside, check details which pertain to most of the pharmacoeconomic literature, the information provided by Bajaj et al. is welcome, as it might: (1) stimulate further, formal studies on the real-life effect of MHE screening/treatment on accident rates, and (2) attract the attention of the pertinent regulatory bodies on the relationship between MHE and driving, which has such profound implications for single patients, and for society at large. “
“Bile salt secretion is mediated primarily by the bile salt export pump (Bsep), a transporter on the canalicular membrane of the hepatocyte. However, little is known about the short-term regulation of Bsep activity. Ca2+ regulates

targeting and insertion of transporters in many cell systems, and Ca2+ release near the canalicular membrane is mediated by the type II inositol 1,4,5-trisphosphate ASK1 receptor (InsP3R2), so we investigated the possible role of InsP3R2 in modulating Bsep activity. The kinetics of Bsep activity were monitored by following secretion of the fluorescent Bsep substrate cholylglycylamido-fluorescein (CGamF) in rat hepatocytes in collagen sandwich culture, an isolated cell system in which structural and functional polarity

is preserved. CGamF secretion was nearly eliminated in cells treated with Bsep small interfering RNA (siRNA), demonstrating specificity of this substrate for Bsep. Secretion was also reduced after chelating intracellular calcium, inducing redistribution of InsP3R2 by depleting the cell membrane of cholesterol, or reducing InsP3R function by either knocking down InsP3R2 expression using siRNA or pharmacologic inhibition using xestospongin C. Confocal immunofluorescence showed that InsP3R2 and Bsep are in close proximity in the canalicular region, both in rat liver and in hepatocytes in sandwich culture. However, after knocking down InsP3R2 or inducing its dysfunction with cholesterol depletion, Bsep redistributed intracellularly. Finally, InsP3R2 was lost from the pericanalicular region in animal models of estrogen- and endotoxin-induced cholestasis.

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