SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Cirrhosis

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In cardiometabolic disorders, non-alcoholic fatty liver disease is frequent and presumably associated with increased mortality and cardiovascular risk.

Concepts: Obesity, Cirrhosis, Metabolic syndrome, Hepatology, Non-alcoholic fatty liver disease, Fatty liver, Steatosis, Medical conditions related to obesity

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(90)Y-microspheres are widely used for the radioembolization of metastatic liver cancer or hepatocellular carcinoma and there is a growing interest for imaging (90)Y-microspheres with PET. The aim of this study is to evaluate the performance of a current generation PET/CT scanner for (90)Y imaging and to optimize the PET protocol to improve the assessment and the quantification of (90)Y-microsphere biodistribution after radioembolization.

Concepts: Cancer, Oncology, Improve, Lung cancer, Cirrhosis, Hepatocellular carcinoma, Hepatitis C, Liver transplantation

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Liver fibrosis is a pathological condition originating from liver damage that leads to excess accumulation of extracellular matrix (ECM) proteins in the liver. Viral infection, chronic injury, local inflammatory responses and oxidative stress are the major factors contributing to the onset and progression of liver fibrosis. Multiple cell types and various growth factors and inflammatory cytokines are involved in the induction and progression of this disease. Various strategies currently being tried to attenuate liver fibrosis include the inhibition of HSC activation or induction of their apoptosis, reduction of collagen production and deposition, decrease in inflammation, and liver transplantation. Liver fibrosis treatment approaches are mainly based on small drug molecules, antibodies, oligonucleotides (ODNs), siRNA and miRNAs. MicroRNAs (miRNA or miR) are endogenous noncoding RNA of ~22 nucleotides that regulate gene expression at post transcription level. There are several miRNAs having aberrant expressions and play a key role in the pathogenesis of liver fibrosis. Single miRNA can target multiple mRNAs, and we can predict its targets based on seed region pairing, thermodynamic stability of pairing and species conservation. For in vivo delivery, we need some additional chemical modification in their structure, and suitable delivery systems like micelles, liposomes and conjugation with targeting or stabilizing the moiety. Here, we discuss the role of miRNAs in fibrogenesis and current approaches of utilizing these miRNAs for treating liver fibrosis.

Concepts: Immune system, Inflammation, DNA, Gene, Gene expression, RNA, Messenger RNA, Cirrhosis

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The best type of biliary anastomosis to use in lower weight pediatric liver transplant recipients is debatable. In this study, we share a single center’s experience comparing the rate of anastomotic biliary complications based on the type of biliary anastomosis performed in this population of patients. A retrospective review of pediatric liver transplants for recipients weighing <15 kg from 11/2003 till 12/2011 was performed. Patients were grouped based on the type of biliary anastomosis into two groups: duct-to-duct (d-d) and Roux-en-Y hepaticojejunostomy (h-j) anastomoses. A total of 24 patients (12 males, 12 females) with a mean age of 26 ± 20 months and a mean weight of 9.27 ± 2.63 kg (range = 5.3-13.9 kg) were studied. All anastomotic complications occurred in patients who received left lateral segments. No statistical differences were found in the post-operative biliary (p = 0.86) or vascular (p = 0.99) complications between the two groups. Acknowledging the limited sample size, our data suggest that duct-to-duct anastomosis can be performed safely in pediatric liver transplantation recipients weighing below 15 kg.

Concepts: Surgery, Cirrhosis, Liver, Organ transplant, Anastomosis, Weight, Surgical anastomosis, Roux-en-Y anastomosis

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The recent epidemic history of hepatitis B virus (HBV) infections in the United States is complex, as indicated by current disparity in HBV genotype distribution between acute and chronic hepatitis B cases and rapid decline in hepatitis B incidence since the 1990s. We report temporal changes in genetic composition of the HBV population using whole-genome sequences (n=179) from acute hepatitis B cases (n=1206) identified through the Sentinel County Surveillance for Acute Hepatitis (1998-2006). HBV belonged mainly to subtypes A2 (75%) and D3 (18%), with times of their most recent common ancestors being, respectively, 1979 and 1987, respectively. A2 underwent rapid population expansions in ca. 1995 and ca. 2002, coinciding with transient rises in acute hepatitis B notification rates among adults; D3 underwent expansion in ca. 1998. A2 strains from cases identified after 2002, compared to those before 2002, tended to cluster phylogenetically, indicating selective expansion of specific strains, and were significantly reduced in genetic diversity (p = 0.001) and frequency of drug-resistance mutations (p = 0.001). The expansion of genetically close HBV A2 strains was associated with risk of infection among male homosexuals (p = 0.03). Incident HBV strains circulating in the US were recent in origin, and restricted in genetic diversity. Disparate transmission dynamics among phylogenetic lineages affected the genetic composition of HBV populations and their capacity to maintain drug-resistance mutations. The tendency of selectively expanding HBV strains to be transmitted among male homosexuals highlights the need to improve hepatitis B vaccination coverage among at-risk adults.

Concepts: Genetics, Cirrhosis, Hepatitis, Hepatitis B, Hepatitis A, Hepatitis B virus, Hepadnaviridae, Hepatitis B vaccine

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Thirty-nine caudatin analogs were designed and synthesized. Their anti-hepatitis B virus (HBV) activities were evaluated in vitro. Among them, twenty-three compounds showed much better anti-HBV activity than caudatin, and eleven compounds significantly inhibited the HBV DNA replication with IC50 values < 10 μΜ. Interestingly, three compounds (22, 28, 29) exhibited excellent activity against the secretion of HBsAg (IC50 = 63.02 μΜ, 52.81 μΜ, 56.08 μΜ), HBeAg (IC50 = 204.80 μΜ, 173.51 μΜ, 70.39 μΜ), along with HBV DNA replication (IC50 = 24.55 μΜ, 5.69 μΜ, 8.23 μΜ) with lower cytotoxicity. The structure-activity relationships (SARs) of these caudatin analogs were also discussed.

Concepts: DNA, Cell, Cirrhosis, Hepatitis, DNA replication, Hepatitis B, Viruses, Hepatitis B virus

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Hepatocellular carcinoma (HCC) is a heterogeneous tumor with many factors implicated in its development, with chronic infection and cirrhosis by hepatitis B virus (HBV) being the most prevalent. Cirrhosis due to metabolic syndrome, alcohol consumption, viral infection with hepatitis C virus (HCV) is also involved in its development. Treatment of HCC remains unsatisfactory. Therapeutic management for HCC includes liver transplantation, liver resection, ablation, chemoembolization, which depend on the tumor stage, liver function, and patient performance status. The involvement of different signaling pathways in the initiation and modulation of HCC development based on clinical and research data provided a strong rationale for the development of anti-cancer agents targeting key components of the pathways. The complexity of the tumor prevents the major goal of this therapeutic approach, since sorafenib, a multi-kinase inhibitor, is the only successful drug so far that belongs to the target directed therapy in advanced stage HCC.

Concepts: Cancer, Cirrhosis, Hepatitis, Liver, Hepatocellular carcinoma, Hepatology, Hepatitis C, Hepatitis B

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Long-term exposure to carcinogens combined with chronic hepatitis contributes greatly to the worldwide high incidence of hepatocellular carcinoma (HCC). It is still unclear to which extent the release of pro-inflammatory reactive oxygen or nitrogen species contributes to the development of this malignancy. Here, we aim to elucidate the role of superoxide in a model of chemical hepatocarcinogenesis. p47(phox) knockout mice (KO), lacking superoxide formation by phagocytic NADPH oxidase (phox), and wild-type animals (WT) were subjected to two different initiation-promotion protocols: (1) single dose of diethylnitrosamine (DEN) at 6 weeks of age followed by phenobarbital (PB) via diet, or ethanol (EtOH) in drinking water; (2) DEN at neonatal age followed by three cytotoxic doses of DEN at intervals of 6-7 weeks. The appearance of tumors and prestages was quantified. There was no obvious difference in the capacity of DEN to initiate hepatocarcinogenesis in KO and WT mice. PB promoted tumor development in both genotypes without significant difference. EtOH induced steatosis significantly less in KO than in WT liver, but had no effect on tumor formation in either genotype. However, hepatocarcinogenesis by three cytotoxic DEN doses after neonatal initiation was attenuated significantly in KO. Macrophages/monocytes identified by the specific antigen F4/80 were more abundant in KO than in WT liver, possibly reflecting a compensatory response. We conclude that phox-derived superoxide is not essential but is supportive for the promotion of hepatocarcinogenesis by cytotoxic doses of DEN. The production of superoxide may therefore contribute to the promotion of hepatocarcinogenesis by cytotoxic/pro-inflammatory stimuli.

Concepts: Gene, Cancer, Oncology, Allele, Cirrhosis, Tumor, NADPH oxidase, Superoxide

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Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/L) on voriconazole pharmacokinetics, both in adult ICU patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples of ICU patients, spiked with voriconazole at a concentration of 1.5 mg/L, 2.9 mg/L and 9.0 mg/L (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/L. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/L. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by LC-MSMS. Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (p<0.001), implicating a higher unbound voriconazole concentration with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (p=0.05). We therefore propose to adjust measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin concentrations, who are showing adverse events potentially related to voriconazole, via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/L for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/L. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the saturated adult hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.

Concepts: Hemoglobin, Metabolism, Cirrhosis, Liver, Chemistry, Albumin, Bilirubin, Jaundice

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Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in Western countries, ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular cancer. Although the mechanisms underlying disease progression are incompletely understood, lipotoxic events in the liver resulting in inflammation and fibrosis appear to be central. Free fatty acids and their metabolites are potentially lipotoxic mediators triggering liver injury, suggesting a central role for metabolic lipases. These enzymes are major players in lipid partitioning between tissues and within cells, and provide ligands for nuclear receptors (NRs). We discuss the potential role of intracellular lipases and their lipolytic products in NAFLD. Because tissue-specific modulation of lipases is currently impossible, targeting NRs with ligands may open novel therapeutic perspectives.

Concepts: Protein, Fatty acid, Obesity, Cirrhosis, Fat, Non-alcoholic fatty liver disease, Fatty liver, Steatosis