A vaccine for Beethoven's vulnerable liver

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Tolvaptan treatment improves survival of cirrhotic patients with ascites and hyponatremia

Background: Although tolvaptan treatment improves hyponatremia, only few studies have investigated whether tolvaptan actually benefits the survival of cirrhotic patients. This study evaluated the impact of tolvaptan on six-month survival of decompensated cirrhotic patients with and without hyponatremia. Methods: Two hundred forty-nine decompensated cirrhotic patients with or without hyponatremia were enrolled in a multicenter cohort study. Patients were divided into two groups according to receiving either tolvaptan or placebo treatment for 7-day. Subsequently, the patients were followed up for 6 months. Results: Two hundred thirty patients, including 98 with hyponatremia (tolvaptan vs. placebo: 69 vs. 29) finished the study. Tolvaptan did not alter serum sodium levels and survival outcome of decompensated cirrhotic patients without hyponatremia. However, tolvaptan treatment remarkably improved serum sodium levels and six-month survival in patients with hyponatremia. Following tolvaptan treatment, serum sodium levels were restored to normal in 63.8% of patients, whereas in patients receiving placebo, only 36.2% showed the same effect (P < 0.05). Compared to a six-month survival rate of 68.97% in patients receiving placebo, the survival rate in tolvapatan-treated patients was 89.94% (P < 0.05). Furthermore, six-month survival rate in the tolvaptan-treated hyponatremia patients with resolved serum sodium was 81.32%, whereas the survival in those with unresolved serum sodium was only 24% (P < 0.05). Conclusions: Tolvaptan improves short term survival in most decompensated cirrhotic hyponatremia patients with resolved serum sodium. Trials registration: Clinical trial one: ClinicalTrials.gov ID: NCT00664014 , Registered on April 14, 2008. Clinical trial two: ClinicalTrials.gov ID: NCT01349335 , Registered on March 5, 2010. Clinical trial three: ClinicalTrials.gov ID: NCT01349348 , Registered on May 4, 2011

The Nuclear Spectroscopic Telescope Array (NuSTAR) High-Energy X-Ray Mission

The Nuclear Spectroscopic Telescope Array (NuSTAR) mission, launched on 2012 June 13, is the first focusing high-energy X-ray telescope in orbit. NuSTAR operates in the band from 3 to 79 keV, extending the sensitivity of focusing far beyond the ~10 keV high-energy cutoff achieved by all previous X-ray satellites. The inherently low background associated with concentrating the X-ray light enables NuSTAR to probe the hard X-ray sky with a more than 100-fold improvement in sensitivity over the collimated or coded mask instruments that have operated in this bandpass. Using its unprecedented combination of sensitivity and spatial and spectral resolution, NuSTAR will pursue five primary scientific objectives: (1) probe obscured active galactic nucleus (AGN) activity out to the peak epoch of galaxy assembly in the universe (at z lsim 2) by surveying selected regions of the sky; (2) study the population of hard X-ray-emitting compact objects in the Galaxy by mapping the central regions of the Milky Way; (3) study the non-thermal radiation in young supernova remnants, both the hard X-ray continuum and the emission from the radioactive element 44Ti; (4) observe blazars contemporaneously with ground-based radio, optical, and TeV telescopes, as well as with Fermi and Swift, to constrain the structure of AGN jets; and (5) observe line and continuum emission from core-collapse supernovae in the Local Group, and from nearby Type Ia events, to constrain explosion models. During its baseline two-year mission, NuSTAR will also undertake a broad program of targeted observations. The observatory consists of two co-aligned grazing-incidence X-ray telescopes pointed at celestial targets by a three-axis stabilized spacecraft. Deployed into a 600 km, near-circular, 6° inclination orbit, the observatory has now completed commissioning, and is performing consistent with pre-launch expectations. NuSTAR is now executing its primary science mission, and with an expected orbit lifetime of 10 yr, we anticipate proposing a guest investigator program, to begin in late 2014.Astronom

Transcription networks in liver development and acute liver failure

Acute liver failure (ALF) is a medical emergency due to massive hepatocyte loss. In such a harsh condition, maintaining transcriptional regulation in the remaining hepatocytes while activating similar transcription factor networks in liver progenitor cells (LPCs) to ensure essential liver functions are two critical processes to rescue patients from liver failure and death. In this review, we discuss the formation and functions of transcription networks in ALF and liver development. We focus on a hierarchical network of transcription factors that responds to different pathophysiological circumstances: (1) Under normal circumstances, pioneer factor forkhead box protein A2 (FOXA2) coordinates several constitutive hepatic transcription factors, such as hepatic nuclear factor 4 alpha (HNF4α) and CCAAT-enhancer binding protein α (C/EBPα), which ensure normal liver function; (2) When the expression of both HNF4α and C/EBPα in hepatocytes are disrupted by severe inflammation, retinoic acid receptor (RAR) is the alternative transcription factor that compensates for their absence; (3) When massive hepatic necrosis occurs, a similar transcription network including FOXA2 and HNF4α, is activated as a “rescue network” in LPCs to maintain vital liver functions when hepatocytes fail, and thus ensures survival. Expression of these master transcription factors in hepatocytes and LPCs is tightly regulated by hormone signals and inflammation. The performance of this hierarchical transcription network, in particularly the “rescue network” described above, significantly affects the clinical outcome of ALF

Modifiable Factors and Genetic Predisposition Associated with Gallbladder Cancer. A Concise Review

Gallbladder cancer (GbCa) is the most frequent malignancy of the biliary tract. It is also the 6th most common gastrointestinal tumor. It is associated with very high lethality, mainly due to the lack of symptoms up to a very late and thus incurable state. As many as 80% of patients are diagnosed at very late stages of disease, which allow only palliative therapy. As a result, most of the patients with GbCa will die within 6 months of the diagnosis, hence the average 5-year survival does not exceed 5%. Currently, surgical resection represents the only curative option in GbCa, but this approach is feasible only at an early stage of the disease. Other oncologic therapies are of limited use. The incidence of GbCa is remarkably increased in certain populations such as Native North Americans, South Indian females and, in Europe, in the Polish population. It is not clear to date if these enhanced risk populations are the result of common environmental exposure or of shared genetic risk factors. In this review we provide an overview of the state-of-art in GbCa research with the focus on the current knowledge concerning genetic and environmental triggers of this tumor

Can a fibrotic liver afford epithelial-mesenchymal transition?

The question whether epithelial-mesenchymal transition (EMT) occurs during liver fibrogenesis is a controversial issue. In vitro studies confirm that hepatocytes or cholangiocytes undergo EMT upon transforming growth factor beta (TGF-beta) stimulation, whereas in vivo experiments based on genetic fate mapping of specific cell populations suggest that EMT does not occur in fibrotic animal models. In this review we present current data supporting or opposing EMT in chronic liver disease and discuss conditions for the occurrence of EMT in patients. Based on the available data and our clinical observations we hypothesize that EMT-like alterations in liver cirrhosis are a side effect of high levels of TGF-beta and other pro-fibrotic mediators rather than a biological process converting functional parenchyma, i.e., hepatocytes, into myofibroblasts at a time when essential liver functions are deteriorating

The Frequent Adiponutrin (PNPLA3) Variant p.Ile148Met Is Associated with Early Liver Injury: Analysis of a German Pediatric Cohort

Introduction. The common adiponutrin (PNPLA3) variant p.Ile148Met is associated with liver injury. Here, we investigate the association of this polymorphism with hepatic and metabolic traits in a pediatric cohort. Patients and Methods. The study cohort comprised 142 German children (age 5–9 years, 98 overweight, 19 children with NAFLD). Results. Overweight children presented with increased serum ALT (P=0.001) and GGT (P<0.001) activities. ALT activities differed significantly (P=0.02) between carriers of different PNPLA3 genotypes in the entire study cohort, in normal weight children (P=0.02) and in children younger than 7 years (P=0.02). Carriers of the prosteatotic PNPLA3 genotype p.148Met/Met displayed higher ALT activities as compared to children with the frequent genotype p.148Ile/Ile (P=0.01). The BMI was however a stronger predictor of ALT activities compared to the PNPLA3 genotype (P<0.001 and P=0.06, resp.). The variant was associated with increased serum glucose levels (P=0.01) and HOMA index (P=0.02) in carriers of the p.148Ile/Met genotype but did not affect other metabolic traits or the presence of NAFLD. Discussion. The frequent PNPLA3 variant p.Ile148Met is associated with serum ALT activities already at a young age

PNPLA3 p.I148M and TM6SF2 p.E167K variants do not predispose to liver injury in cholestatic liver diseases: A prospective analysis of 178 patients with PSC.

BACKGROUND:The adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent major genetic risk factors for progressive liver injury in nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) and chronic viral hepatitis. The aim of this study was to find out whether these variants have a detrimental impact on the progression of chronic liver disease in patients with prolonged cholestasis induced by primary sclerosing cholangitis (PSC). METHODS:We prospectively recruited 178 PSC patients (112 male, age range 17-75 years, 55 with liver cirrhosis, 94 with ulcerative colitis, 48 transplanted during follow-up). PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms were genotyped using dedicated TaqMan assays. Associations between genotypes, biochemical and clinical phenotypes were analyzed using contingency tables. RESULTS:Allele and genotype distribution of both variants were consistent with Hardy-Weinberg equilibrium. No significant differences in the genotype distribution of PNPLA3 (P = 0.90) or TM6SF2 (P = 0.72) were observed between patients with cirrhosis and patients without cirrhosis. Serum liver enzyme activities were not modified by the presence of PNPLA3 (ALT P = 0.88, AST P = 0.77) or TM6SF2 (ALT P = 0.92, AST P = 0.49) risk variants. Increasing number of risk alleles had no impact on serum liver enzyme activities, as demonstrated by a separate analysis of patients carrying 0 (n = 99), 1 (n = 64), 2 (n = 12) or 3 (n = 3) risk alleles (P>0.05). No impact of PNPLA3 or TM6SF2 risk variants was detectable in patients with PSC and ulcerative colitis, and none of the variants increased the odds of transplantation. CONCLUSIONS:Neither PNPLA3 nor TM6SF2 polymorphisms seem to contribute significantly towards an increased risk for deterioration of liver function in patients with PSC. These results underscore the divergent mechanisms of liver damage in cholestatic conditions as compared to metabolic and viral liver diseases