7 Further challenging the activation-induced apoptosis hypothesis are data from Sugalski et al. and Mizuochi et al., which demonstrate that HCV-infected patient B cells manifest increased survival in vitro, relative to HD B-cells.8, 9 Our in vitro data do suggest that soluble factors in plasma from cirrhotic patients promote B-cell survival. A third explanation for peripheral memory B-cell loss could be compartmentalization of activated CD27+ memory B cells to the intrahepatic or lymphoid compartments resulting from up-regulation of homing markers, such as CXCR3,8, 10, 42 a possible mechanism that was

not explored in this study. In the intrahepatic compartment, a profibrotic role of B-cells has been suggested by work in the B-cell-deficient mice treated with carbon tetrachloride,43 by association of plasma cells and activated

stellate cells in autoimmune liver disease,44 and by anecdotal regression of cirrhosis Palbociclib chemical structure associated with rituximab in case reports.45 The intrahepatic compartment in cirrhotics does appear to be enriched for CD27+ memory B-cells (Supporting Fig. 3), but study of animal models will be critical to precisely define the fate of CD27+ memory B cells in cirrhosis and will be helpful in determining whether or not intrahepatic B-cells may play a pathological role in chronic liver injury/fibrosis. Independent of chronic HCV infection, memory buy Decitabine CD27+ and, more specifically, CD27+IgM+ B-cells are profoundly reduced in the peripheral blood of patients with cirrhosis with or without HCC in direct relationship with parameters associated with hepatic medchemexpress metabolic dysfunction and portal

hypertension. The remaining B-cells are hyporesponsive to activation via CD40 and TLR9, with impaired up-regulation of costimulation markers, production of TNF-β, and production of IgG. The remaining B cells, upon activation, are also less effective at stimulating CD4+ T-cell responses. The presence of elevated levels of sCD14 and attenuation of B-cell activation by TLR4 and TLR9 blockade in vitro suggest that the loss of peripheral memory B-cells may be a consequence of chronic B-cell activation as a result of increased gut permeability caused by portal hypertension. These findings shed light on vaccine hyporesponsiveness and increased susceptibility to bacterial infection in cirrhotic patients, which might be ameliorated by therapies designed to reduce microbial translocation or block chronic pathogen-induced B-cell activation. The authors thank Mary E. Valiga, R.N., for her support of the study. The authors also thank the patients and volunteers who contributed samples. Additional Supporting Information may be found in the online version of this article. “
“Nonalcoholic fatty liver disease (NAFLD) may increase the risk for cardiac dysfunction. The present study aimed to determine whether, in children, NAFLD is associated with subclinical left ventricular (LV) structural and functional abnormalities independently of metabolic risk factors.