Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis

BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association between polymorphisms at the −308 and −627 positions in the TNF-α and IL-10 promoter genes, respectively, and susceptibility to PSC. METHODS TNF-α −308 genotypes were studied by polymerase chain reaction (PCR) in 160 PSC patients from Norway and the UK compared with 145 ethnically matched controls. IL-10 −627 genotypes were studied by PCR in 90 PSC patients compared with 84 ethnically matched controls. RESULTS A total of 16% of Norwegian PSC patients and 12% of British PSC patients were homozygous for the TNF2 allele compared with 3% and 6% of respective controls. The TNF2 allele was present in 60% of PSC patients versus 30% of controls (ORcombined data=3.2 (95% confidence intervals (CI) 1.8–4.5); pcorr=10−5). The association between the TNF2 allele and susceptibility to PSC was independent of the presence of concurrent inflammatory bowel disease (IBD) in the PSC patients; 61% of PSC patients without IBD had TNF2 compared with 30% of controls (ORcombined data=3.2 (95% CI 1.2–9.0); pcorr=0.006 ). There was no difference in the −627 IL-10 polymorphism distributions between patients and controls in either population. The increase in TNF2 allele in PSC patients only occurs in the presence of DRB1*0301 (DR3) and B8. In the combined population data, DRB1*0301 showed a stronger association with susceptibility to PSC than both the TNF2 and B8 alleles (ORcombined data=3.8, pcorr=10−6 v ORcombined data=3.2, pcorr=10−5 vORcombined data =3.41, pcorr=10−4, respectively). CONCLUSIONS This study identified a significant association between possession of the TNF2 allele, a G→A substitution at position −308 in the TNF-α promoter, and susceptibility to PSC. This association was secondary to the association of PSC with the A1-B8-DRB1*0301-DQA1*0501-DQB1*0201 haplotype. No association was found between the IL-10 −627 promoter polymorphism and PSC

Implicit and semi-implicit well-balanced finite-volume methods for systems of balance laws

The aim of this work is to design implicit and semi-implicit high-order well-balanced finite-volume numerical methods for 1D systems of balance laws. The strategy introduced by two of the authors in some previous papers for explicit schemes based on the application of a well-balanced reconstruction operator is applied. The well-balanced property is preserved when quadrature formulas are used to approximate the averages and the integral of the source term in the cells. Concerning the time evolution, this technique is combined with a time discretization method of type RK-IMEX or RK-implicit. The methodology will be applied to several systems of balance laws.This work is partially supported by projects RTI2018-096064-B-C21 funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe”, projects P18-RT-3163 of Junta de Andalucía and UMA18-FEDERJA-161 of Junta de Andalucía-FEDER-University of Málaga. G.Russo and S.Boscarino acknowledge partial support from the Italian Ministry of University and Research (MIUR), PRIN Project 2017 (No. 2017KKJP4X) entitled “Innovative numerical methods for evolu-tionary partial differential equations and applications”. I. Gómez-Bueno is also supported by a Grant from “El Ministerio de Ciencia, Innovación y Universidades”, Spain (FPU2019/01541) funded by MCIN/AEI/10.13039/501100011033 and “ESF Invest-ing in your future”. // Funding for open access charge: Universidad de Málaga/CBUA

Multi-scale effects of nestling diet on breeding performance in a terrestrial top predator inferred from stable isotope analysis

This is the final version of the article. Available from the publisher via the DOI in this record.Inter-individual diet variation within populations is likely to have important ecological and evolutionary implications. The diet-fitness relationships at the individual level and the emerging population processes are, however, poorly understood for most avian predators inhabiting complex terrestrial ecosystems. In this study, we use an isotopic approach to assess the trophic ecology of nestlings in a long-lived raptor, the Bonelli's eagle Aquila fasciata, and investigate whether nestling dietary breath and main prey consumption can affect the species' reproductive performance at two spatial scales: territories within populations and populations over a large geographic area. At the territory level, those breeding pairs whose nestlings consumed similar diets to the overall population (i.e. moderate consumption of preferred prey, but complemented by alternative prey categories) or those disproportionally consuming preferred prey were more likely to fledge two chicks. An increase in the diet diversity, however, related negatively with productivity. The age and replacements of breeding pair members had also an influence on productivity, with more fledglings associated to adult pairs with few replacements, as expected in long-lived species. At the population level, mean productivity was higher in those population-years with lower dietary breadth and higher diet similarity among territories, which was related to an overall higher consumption of preferred prey. Thus, we revealed a correspondence in diet-fitness relationships at two spatial scales: territories and populations. We suggest that stable isotope analyses may be a powerful tool to monitor the diet of terrestrial avian predators on large spatio-temporal scales, which could serve to detect potential changes in the availability of those prey on which predators depend for breeding. We encourage ecologists and evolutionary and conservation biologists concerned with the multi-scale fitness consequences of inter-individual variation in resource use to employ similar stable isotope-based approaches, which can be successfully applied to complex ecosystems such as the Mediterranean.Funding for this work was provided by projects CGL2007-64805 and CGL2010-17056 from the ‘‘Ministerio de Ciencia e Innovacio´n, Gobierno de Espan˜ a’’, the ‘‘A`rea d’Espais Naturals de la Diputacio´ de Barcelona’’, and Miquel Torres S.A. Fieldwork in France was carried out within the framework of the second National Action Plan for Bonelli’s eagle from the ‘‘Ministe`re franc¸ais de l’E´cologie, de L’E´nergie, du De´veloppement Durable et de la Mer’’ and coordinated by the DREAL LR ‘‘Direction Re´gionale de l’Environnement, de l’Ame´nagement et du Logement-Languedoc-Roussillon’’. J. Resano-Mayor was supported by a predoctoral grant from the ‘‘Departamento de Educacio´n, Gobierno de Navarra; Plan de Formacio´n y de I+D 2008–2009’’, and M. Moleo´n by a postdoctoral grant from the ‘‘Ministerio de Educacio´n, Gobierno de Espan˜ a; Plan Nacional de I+D+i 2008–2011’’. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Reduction and stabilization of bilirubin with obeticholic acid treatment in patients with primary biliary cholangitis

Total bilirubin is a predictor of survival in primary biliary cholangitis, with the main elevated component being direct bilirubin. The purpose of this post hoc analysis was to assess the efficacy and safety of obeticholic acid across quartiles of varying baseline levels of direct bilirubin in the phase 3, randomized, placebo-controlled Primary Biliary Cholangitis Obeticholic Acid International Study of Efficacy. This analysis assessed patients on the basis of their baseline direct bilirubin level (divided by quartile). Biochemistry and safety outcomes were evaluated within each quartile over time. In the quartile with the highest baseline direct bilirubin (>5.47 µmol/L), there was a significant reduction in both direct and total bilirubin at Month 12 compared with placebo. Least squares mean (standard error) change from baseline in direct bilirubin at Month 12 was 4.17 (1.42) µmol/L for placebo, −3.48 (1.63) µmol/L for obeticholic acid 5-10 mg and −3.66 (1.51) µmol/L for obeticholic acid 10 mg (P < .0001, obeticholic acid vs placebo); the corresponding values for total bilirubin at Month 12 were 4.38 (1.55) µmol/L for placebo, −4.53 (1.83) µmol/L for obeticholic acid 5-10 mg and −5.06 (1.64) µmol/L for obeticholic acid 10 mg (P < .0001, obeticholic acid vs placebo). Obeticholic acid treatment was associated with significant reductions in total and direct bilirubin, particularly in patients with high baseline direct bilirubin. Because raised direct bilirubin levels, even within the normal range, are predictive of survival in primary biliary cholangitis, these results suggest substantial benefits of obeticholic acid in at-risk patients