To determine the roles of FGF15 in liver regeneration, liver regrowth in FGF15 knockout (KO)mice after 2/3 partial hepatectomy (PHx) was studied. Data demonstrated that mouse genetic background greatly impacted the outcome of liver regeneration in FGF15 KO mice after PHx. FGF15 KOmice on a pure C57BL/6J

genetic background were embryonic lethal. Under 75% C57BL/6J and 25% 129SvJ genetic background, KO mice exhibited higher rates of liver Erismodegib necrosis and death within 48 hrs following PHx compared to WT or KO mice with 25% C57BL/6J and 75% 129SvJ genetic background. Furthermore, FGF15 KO mice with 75% C57BL/6J and 25% 129SvJ genetic background showed increased bile acid and bilirubin levels and impaired expression of markers of DNA synthesis and cell cycle progression. Specifically, the cell signaling pathways critical for liver regeneration priming andmouse survival, including signal transducer and activator of transcription 3 (STAT3), nuclear factor kB (NFkB), mitogen-activated protein kinase (MAPK), protein kinase B (PKB/AKT) and mammalian

target of rapamycin (mTOR), were either interrupted or deactivated at 30 mins and/or 3 hrs following PHx. Additionally, 10 and 30 mins after PHx, there was a delayed and reduced induction of immediate-early Gefitinib chemical structure genes, including growth-control transcription factors that are critical for regenerative response in the post-hepatectomized 上海皓元 liver. In summary, the results suggest that FGF15 is critical for liver regeneration after PHx, likely by maintaining bile acid homeostasis and/or being involved in the initiation of liver regeneration, and its effects are modified by genetic background. Disclosures:

The following people have nothing to disclose: Bo Kong, Jiansheng Huang, Yan Zhu, Guodong Li, Jessica A. Williams, Steven H. Shen, Lauren M. Aleksunes, Jason R. Richardson, Udayan Apte, David A. Rudnick, Grace L. Guo Purpose: The pathogenic link between gut microbiota and chronic liver disease requires elucidation. In the present study, we hypothesized that small bowel bacterial overgrowth and translocation induces changes in bile composition through reduction in hepatobiliary transporter expression, which eventually lead to liver injury. Methods: In order to study this hypothesis, a 3 cm jejunal self-filling blind loop (SFBL) was surgically created in C57BL/6 mice, 5 cm distal to the ligament of Treitz. Control mice underwent laparotomy (sham). Mice were sacrificed three weeks after surgery. Aerobic and anaerobic bacterial cultures of SFBL luminal content, peritoneal cavity, mesenteric lymph node, liver and blood were performed to evaluate bacterial overgrowth and translocation. Histology scoring was performed on H&E-stained slides by a pathologist blinded to experimental design to evaluate intestinal and liver inflammation and injury.

34 Bile salt reabsorption was reduced by 30% in both models. Although bile salt reabsorption was not fully impaired, Fgf15 expression levels were not detectable in the ilea of sequestrant-treated wild-type mice. It is possible that bile salt sequestration decreases the cellular content of bile salts below a certain threshold value necessary to activate FXR in enterocytes, as observed in an in vivo study in rabbits.35 Interestingly, hepatic TG contents of colesevelam-treated lean and db/db mice were enhanced, this website which appeared to be mediated by an increased de novo synthesis of hepatic fatty acids and chain elongation. In contrast to our data, other studies addressing the effects of bile salt sequestration

on lipid metabolism showed that bile salt sequestration prevented TG accumulation in the liver.36, 37 It should be realized that those studies were performed in Z VAD FMK high-fat diet–fed mice in which the beneficial effects of bile salt sequestration are likely partly attributable to sequestrant-induced malabsorption of lipids. In addition, strain-specific responses to sequestrant treatment cannot be ruled out. At a molecular level, the interrelationship between bile salt and lipid metabolism is generally accepted to be mediated

by FXR. Nevertheless, data to explain the exact mechanisms of this relationship are still very inconsistent. Pharmacological activation of FXR has been shown to reduce free fatty acid levels in insulin-resistant rodents.15, 38 Absence of FXR signaling in Fxr−/− mice leads to increased very low-density lipoprotein–TG levels in plasma of these mice,39 suggestive of a role for FXR in control of very low-density lipoprotein

assembly. Colesevelam treatment induced hepatic expression levels of the lipogenic gene Srebp1c in lean and db/db mice. Hepatic expression levels of the lipogenic gene Srebp1c were reduced in Fxr−/− mice compared with controls.39, 40 Conversely, FXR 上海皓元医药股份有限公司 activation was also shown to repress the expression of Srebp1c in a pathway involving SHP.17, 40 Expression levels of the FXR target gene Shp were unaffected and decreased in colesevelam-treated lean and db/db mice, respectively. These results are suggestive of SHP-independent regulation of Srebp1c upon sequestrant treatment. Supportive of SHP-independent regulation of lipogenic gene expression by FXR was the observation that FXR regulates the transcription of the lipogenic gene Fas through direct binding to the Fas promoter.41 Because expression levels of well-known FXR target genes were differentially affected in lean and db/db mice, we studied the role of FXR in the lipogenic response of sequestrant treatment in Fxr−/− mice and found that in contrast to wild-type mice littermates, lipogenic gene expression levels were barely affected. Srebp1c, is strongly regulated by the oxysterol receptor LXRα.

45 Our study establishes the utility of two different AAV serotypes (AAV8 and AAV2) for hepatic gene targeting of both adult and neonatal mice in vivo. Interestingly, the biology of these two serotypes differed considerably in terms of gene targeting. Different kinetics for the two serotypes have been described previously with gene addition approaches wherein higher doses of AAV correlated Stem Cell Compound Library cell assay with higher levels of gene expression.36 Here, we observed a similar phenomenon where the highest doses administered produced the greatest gene repair frequencies

in vivo. Targeting was confirmed by immunohistochemistry, RT-PCR, and functional measures of liver correction using serum liver function tests. We also evaluated the frequency of random integration in cells with proper gene repair

using coinjection with a second, nonselectable AAV vector. The average copy number of the irrelevant vector corrected for repopulation efficiency indicated that 0.5%-1% of targeted cells also had a random integration. This number is similar to multiple estimates of random integration of AAV8 from the literature.35 Therefore, it can be concluded that gene repair does not result in a higher random integration frequency. In summary, our experiments demonstrated stable hepatic gene repair in both adult and neonatal mice with AAV-Fah serotypes 2 selleck chemicals and 8. Serial transplantation was possible without difficulty and serially reconstituted animals had normal hepatic function. Most importantly, this work was the first to show functional

metabolic correction of a disease model using AAV-mediated gene repair and can be envisioned as a therapeutic strategy for disorders with a selective advantage in corrected cells. Although these experiments focused on correcting the metabolic disease HTI, the novel approach described herein can serve as a model for gene repair in any monogenic disease caused by point mutations. We thank Angela Major for histology support and Terry Storm for AAV preparations. “
“Background and Aims:  Non-invasive diagnosis of compensated cirrhosis is important. We therefore compared liver stiffness by transient elastography, APRI score, AST/ALT ratio, hyaluronic acid and clinical signs to determine which modality 上海皓元医药股份有限公司 performed best at identifying compensated cirrhosis. Methods:  Patients undergoing evaluation at a single center were recruited and had clinical, serological, endoscopy, radiological imaging, liver stiffness measurement and liver biopsy. Patients were stratified into cirrhotic and non-cirrhotic. Results:  In 404 patients (124 cirrhosis), transient elastography was diagnostically superior to the other modalities yielding an AUC 0.9 ± 0.04 compared with hyaluronic acid (AUC 0.81 ± 0.04: P < 0.05), clinical signs (AUC 0.74 ± 0.04: P < 0.05), APRI score (AUC 0.71 ± 0.03: P < 0.05) and AST/ALT ratio (AUC 0.66 ± 0.03: P < 0.05).

Serum N- (NTX-I), C-terminal telopeptide of type I collagen (CTX-I) and tartrate-resistant acid phosphatase band-5b (TRAP-5b), as bone resorption markers, and osteocalcin (OC) and bone-specific

alkaline phosphatase (b-ALP), as bone formation markers, were assessed. Seventy men with haemophilia A (n = 59) or B (n = 11) were studied. Patients with low BMD had significantly higher b-ALP concentrations compared with those with normal BMD (12.8 ± 1.60 vs. 9.72 ± 0.58 μg/L, P = 0.009), without any differences in the other BTM. NTX-I PD-1 antibody inhibitor and CTX-I concentrations were negatively associated with oestradiol levels and hip BMD and positively with human immunodeficiency virus infection, number of affected joints and arthropathy scores. B-ALP and OC concentrations were negatively associated with hip BMD, severity of haemophilia and fracture history, and positively with the number of affected joints and testosterone concentrations. After multivariate analysis, NTX-I levels remained negatively associated with oestradiol levels, whereas b-ALP concentrations negatively correlated with the level of physical activity and positively with the number of affected joints. Increased bone metabolism exists in men with haemophilia and low BMD. Increased b-ALP levels may identify patients at high risk for fracture.

Increased number of target joints, low physical activity and low oestradiol Buparlisib in vitro concentrations are independently associated with increased bone metabolism. “
“Nordic Cochrane Centre at Rigshospitalet, Copenhagen, Denmark Amgen Canada at

Mississauga, Ontario, Canada Haemophilia A is a rare inherited bleeding disorder characterized by an inability MCE公司 of the blood to clot normally. Patients can experience spontaneous or trauma-induced joint and soft tissue bleeding and must keep coagulation factor VIII (FVIII) accessible at all times; thus, FVIII product storage and stability are critical. Our primary objective was to assess haemophilia A patients’ and caregivers’ experiences and preferences with FVIII product storage and stability. A secondary objective was to evaluate the use of the social media site Facebook in recruitment. In this cross-sectional study, 145 English-speaking adult patients and caregivers of children with haemophilia A were recruited through two state-based haemophilia organizations in the United States (US) and one national organization in Canada for a web-based survey assessing demographics and FVIII product ordering, usage, and storage practices. Of the 101 individuals who completed the survey, 60% resided in Canada; 57% were recruited through Facebook. Caregivers and patients responded similarly to questions about ordering practices and product usage, with some distinction between groups in storage practices. Two-thirds of participants noted challenges with storing FVIII products, especially storage away from home. More than half preferred storing FVIII products at room temperature vs.

Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council (RES-590-28-0005), Medical Research Council, the Welsh Assembly Government and the Wellcome Trust (WT087640MA), under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged.

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“The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify Ferroptosis inhibitor determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly

(18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning Tamoxifen datasheet degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets medchemexpress (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high-density lipoprotein (OR = 8.35,

P = 0.02). Conclusion: Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. (HEPATOLOGY 2013;58:1644–1654) Nonalcoholic fatty liver disease (NAFLD) afflicts one in every three adult Americans and it is the most common cause of elevated serum aminotransferases in the United States.[1-4] NAFLD is seen in individuals who consume little or no alcohol. It can range from the presence of steatosis alone, which is expected to have a nonprogressive course, to nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD that can lead to advanced fibrosis, cirrhosis, and hepatocellular carcinoma in a subset of patients.