Genotype-phenotype associations of polymorphisms within the gene locus of NOD-like receptor pyrin domain containing 3 in Swiss inflammatory bowel disease patients.

BACKGROUND Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn's Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1β and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS). METHODS We included 981 Crohn's disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients. RESULTS In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays. CONCLUSIONS In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity

The rs429358 locus in apolipoprotein E is associated with hepatocellular carcinoma in patients with cirrhosis

The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E (APOE), rs2642438 in mitochondrial amidoxime reducing component 1 (MARC1), rs2792751 in glycerol-3-phosphate acyltransferase (GPAM), and rs187429064 in transmembrane 6 superfamily member 2 (TM6SF2), previously associated with progressive alcohol-related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case-control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP-HCV), and one alcohol-related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed-effect meta-analysis was used to determine the pooled effect size across all data sets. Across four case-control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele (APOE) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61-0.84; P=2.9×10−5). Rs187429064:G (TM6SF2) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45-2.86; P=3.1×10−6). In contrast, rs2792751:T (GPAM) was not associated with HCC (OR, 1.01; 95% CI, 0.90-1.13; P=0.89), whereas rs2642438:A (MARC1) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84-1.00; P=0.043). Conclusion: This study associates carriage of rs429358:C (APOE) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis

Strengthening insights into host responses to mastitis infection in ruminants by combining heterogeneous microarray data sources

<p>Abstract</p> <p>Background</p> <p>Gene expression profiling studies of mastitis in ruminants have provided key but fragmented knowledge for the understanding of the disease. A systematic combination of different expression profiling studies via meta-analysis techniques has the potential to test the extensibility of conclusions based on single studies. Using the program Pointillist, we performed meta-analysis of transcription-profiling data from six independent studies of infections with mammary gland pathogens, including samples from cattle challenged <it>in vivo </it>with <it>S. aureus</it>, <it>E. coli</it>, and <it>S. uberis</it>, samples from goats challenged <it>in vivo </it>with <it>S. aureus</it>, as well as cattle macrophages and ovine dendritic cells infected <it>in vitro </it>with <it>S. aureus</it>. We combined different time points from those studies, testing different responses to mastitis infection: overall (common signature), early stage, late stage, and cattle-specific.</p> <p>Results</p> <p>Ingenuity Pathway Analysis of affected genes showed that the four meta-analysis combinations share biological functions and pathways (e.g. protein ubiquitination and polyamine regulation) which are intrinsic to the general disease response. In the overall response, pathways related to immune response and inflammation, as well as biological functions related to lipid metabolism were altered. This latter observation is consistent with the milk fat content depression commonly observed during mastitis infection. Complementarities between early and late stage responses were found, with a prominence of metabolic and stress signals in the early stage and of the immune response related to the lipid metabolism in the late stage; both mechanisms apparently modulated by few genes, including <it>XBP1 </it>and <it>SREBF1</it>.</p> <p>The cattle-specific response was characterized by alteration of the immune response and by modification of lipid metabolism. Comparison of <it>E. coli </it>and <it>S. aureus </it>infections in cattle <it>in vivo </it>revealed that affected genes showing opposite regulation had the same altered biological functions and provided evidence that <it>E. coli </it>caused a stronger host response.</p> <p>Conclusions</p> <p>This meta-analysis approach reinforces previous findings but also reveals several novel themes, including the involvement of genes, biological functions, and pathways that were not identified in individual studies. As such, it provides an interesting proof of principle for future studies combining information from diverse heterogeneous sources.</p

Evaluation du pronostic et avancées thérapeutiques des formes sévères de la maladie du foie liée à l'alcool

La maladie du foie liée à l’alcool correspond à un large éventail de lésions hépatiques induites par la consommation chronique et excessive d’alcool s’étendant de la simple stéatose, à la stéatohépatite et la fibrose ainsi qu’à des formes plus graves comprenant l’hépatite alcoolique, la cirrhose et le carcinome hépatocellulaire. La consommation excessive d’alcool est un problème majeur de santé publique et la cirrhose alcoolique est actuellement la deuxième indication la plus fréquente de transplantation hépatique dans le monde. Evaluer le pronostic des malades porteurs de formes sévères de maladie du foie liée à l’alcool est une étape capitale afin d’optimaliser leur prise en charge. L’abstinence a un impact majeur sur l’évolution des malades quel que soit le stade de la maladie hépatique. Les malades hautement sélectionnés et présentant une forme sévère d’hépatite alcoolique ne répondant pas au traitement médical peuvent bénéficier d’une transplantation hépatique précoce. Les travaux réalisés dans le cadre de cette thèse ont permis de montrer que :- Les malades porteurs d’une cirrhose alcoolique ont un moins bon pronostic et développent moins fréquemment un carcinome hépatocellulaire que les malades porteurs d’une cirrhose d’origine virale C ou secondaire à une NAFLD. - Un modèle pronostique combinant l’abstinence, le score de Child-Pugh et l’âge prédit mieux la mortalité hépatique à 5 ans chez des malades porteurs d’une cirrhose alcoolique que le score de Child-Pugh ou de MELD qui sont les scores de référence actuellement utilisés en pratique clinique. - Il est possible d’utiliser des modèles de prédiction du risque de développement d’un carcinome hépatocellulaire en tenant compte de l’impact de la cirrhose alcoolique et en stratifiant les malades en différents niveaux de risque. - L’abstinence est un facteur pronostique majeur dans la cirrhose alcoolique impactant le devenir des malades à différents stades de leur maladie y compris lors de la survenue d’un carcinome hépatocellulaire.- Deux possibilités thérapeutiques dans l’hépatite alcoolique ont été synthétisées sous la forme de méta-analyse :le G-CSF et la transplantation hépatique.Doctorat en Sciences médicales (Médecine)info:eu-repo/semantics/nonPublishe

Prognostic value of histologic parameters in alcoholic hepatitis: a word of caution.

SCOPUS: le.jinfo:eu-repo/semantics/publishe

[Factors influencing development and progression of alcoholic liver disease].

Only a minority ot excessive drinkers develop cirrhosis. The main cofactors implicated in the pathophysiology of alcoholic liver disease are obesity, diabetes or the metabolic syndrome. Several genetic polymorphisms have been associated with a higher risk of alcoholic cirrhosis. Recent data indicate that gut microbiota could play a role in the pathogenesis of alcoholic liver disease. The aim of this review is to summarize the factors that influence development and progression of alcoholic liver disease

Liver transplant for alcoholic hepatitis: a current clinical overview

Introduction: Current management of severe alcoholic hepatitis is based on corticosteroid therapy and abstinence from alcohol. As liver transplantation is lifesaving in alcoholic hepatitis patients at high risk of early death, refractory alcoholic hepatitis has become a new indication for liver transplantation in highly selected non-responders to corticosteroids. Areas covered: This review summarizes the conditions under which liver transplantation may be considered, the available data on liver transplantation for refractory alcoholic hepatitis and explores the ethical considerations surrounding the use of liver transplantation in these patients. Expert opinion: Selection of candidates should be made according to available scientific results on post-liver transplantation outcomes and the risk of alcohol relapse. Currently, a strict selection process based on a good psychosocial profile, including social stability, no previous treatments for alcohol dependence, no current drug use, and no co-existing severe mental disorder, seems to be the best way to manage these issues. Well-defined selection criteria for candidate selection and accurate tools to predict alcohol relapse after liver transplantation are still needed.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Outcomes after early liver transplantation for patients with severe alcoholic hepatitis: Additional evidence from a meta-analysis.

Dear Editors: We read with interest the article from Lee et al1 about early liver transplantation for severe alcoholic hepatitis. We compliment them for their exhaustive collection of data on patients transplanted for alcoholic hepatitis across the United States in the retrospective ACCELARATE-AH study. We would like to add some comments that may contribute to the debate on this hot topic. [...

Probing the photoreactivity of aryl chlorides with oxygen

Molecular oxygen was used to probe the mechanism of the phototransformation of chlorobenzene and 4-chloroanisole in organic solvents. Laser flash photolysis, electron paramagnetic resonance and product distribution studies clarified the reaction mechanisms of these compounds under a wide range of conditions. The main primary photochemical reaction step is the homolytic cleavage of the C-Cl bond to produce a triplet radical pair in the solvent cage. In non-polar solvents hydrogen abstraction, after radical diffusion, leads to reduction. In polar solvents, in addition to H-abstraction, electron transfer within the caged radical pair occurs and leads to an ion pair (phenyl cation and Cl-). In the presence of oxygen, phenyl radicals can form phenylperoxyl radicals which have a bathochromically shifted absorption, thus making the homolytic cleavage visible by flash photolysis. The peroxyl radicals can couple, leading to more polar compounds, or undergo back reaction to the phenyl radical. For concentrations of the aryl chlorides of higher than 10-3 M, dimerization becomes an important transformation process and occurs after reaction of the transients with ground state molecules. In addition, excimer formation is postulated to be involved in the dimerization process

Un foie qui fait mal aux reins

Ce vigneron de 50 ans est admis aux urgences pour des douleurs abdominales crampiformes en augmentation depuis 3 jours, diffuses, sans autre symptôme digestif. Il est porteur d’une cirrhose éthylique CHILD-PUGH C (13 points), compliquée de varices oesopha giennes de stade II traitées par ligatures et d’un carcinome hépa tocellulaire (CHC) multifocal traité par chimio- et radioembo li sation. Son traitement est le suivant: torasémide, spiro nolactone, propranolol, ésomeprazole, vitamines B, vita mine K et des laxatifs. L’examen clinique révèle une somnolence, un asterixis et divers signes d’hépatopathie (ascite, ictère, angiomes stellaires, peau fine, leuconychie, hépato-splénomégalie et plusieurs hématomes). L’abdomen est sensible,sans défense ni détente. Il n’y a pas de globe urinaire, ni de fécalome. Les examens de laboratoire mettent en évidence une insuffisance rénale aiguë (créatinine 319 mmol/l, clairance selon GFR à 18 ml/min/1,72 m2), une augmentation des transaminases à cinq fois la norme et une bilirubine totale à 300 mmol/l (norme <21 mmol/l). Les autres données anormales sont: ammonium 100 m mol/l (norme 10–50 mmol/l), thrombocytes 80 G/l (norme 150–350 G/l), albumine 22 g/l (norme 32–52 g/l), INR 1,5. Il n’y a pas de trouble électrolytique. Un CT cérébral exclut un processus expansif ou hémorragique. Il n’y a pas de trouble métabolique, de prise d’un médicament psychotrope ou d’anomalie centrale. Le diagnostic d’encéphalopathie hépatique (EH) est retenu