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Sökning: WFRF:(Kucharzik Torsten)

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  • Schafmayer, Clemens, et al. (författare)
  • Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
  • 2019
  • Ingår i: Gut. - 0017-5749 .- 1468-3288. ; 68:5, s. 854-865
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p< 0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10-10 and 0.002 (OR allelic = 1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). Conclusion I n silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
  • Adamina, Michel, et al. (författare)
  • ECCO Guidelines on Therapeutics in Crohns Disease: Surgical Treatment
  • 2020
  • Ingår i: Journal of Crohn's & Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 14:2, s. 155-168
  • Tidskriftsartikel (refereegranskat)abstract
    • This article is the second in a series of two publications relating to the European Crohns and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohns disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohns disease and an update of previous guidelines.
  • Heidemann, Jan, et al. (författare)
  • Expression of IL-12-related molecules in human intestinal microvascular endothelial cells is regulated by TLR3
  • 2007
  • Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - Bethesda, United States : American Physiological Society. - 0193-1857 .- 1522-1547. - 0193-1857 (Print) 0193-1857 (Linking) ; 293:6, s. G1315-G1324
  • Tidskriftsartikel (refereegranskat)abstract
    • Members of the interleukin (IL)-12 family constitute subunits of IL-12, -23, and -27. These ILs represent pivotal mediators in the regulation of cell-mediated immune responses and in animal models of human inflammatory bowel disease. Recent work has suggested that intestinal endothelial cells might serve as a second line of defense in bacterial sensing of invading pathogens. The purpose of this study was to examine the production of IL-12 family members in intestinal endothelial cells (HIMEC). HIMEC were stimulated with proinflammatory agents (TNF-alpha, IFN-gamma, IL-1beta) and microbial antigens [LPS, lipoteichoic acid, peptidoglycan, CpG-DNA, flagellin, poly(I:C)]. Expression of IL-12 family members and of Toll-like receptor (TLR)3 in HIMEC was assessed by real-time RT-PCR, immunostaining, flow cytometry, and immunoblot analysis. HIMEC display an induction of Epstein-Barr virus-induced gene 3 (EBI3), IL-12p35, and IL-23p19, whereas no expression of IL-12p40 and IL-27p28 was detectable. The strongest induction was induced by proinflammatory factors known to utilize the NF-kappaB pathway, and expression of EBI3 and IL-23p19 was diminished by an NF-kappaB inhibitor. HIMEC display regulated expression of TLR3. Adhesion and transmigration assays showed proinflammatory responses after HIMEC stimulation. HIMEC are capable of producing IL-12 family members as a response to microbial stimuli. The TLR3 agonist, poly(I:C), was shown to enhance leukocyte adhesion in vitro in HIMEC. Our data suggest that the intestinal microvasculature is responsive to ligands of TLR3 expressed on intestinal endothelial cells, thereby adding to the regulation of adaptive immunity and leukocyte recruitment.
  • Lugering, Andreas, et al. (författare)
  • Apoptosis as a therapeutic tool in IBD?
  • 2006
  • Ingår i: Annals of the New York Academy of Sciences. - : Wiley-Blackwell Publishing Inc.. - 0077-8923 .- 1749-6632. - 0077-8923 (Print) 0077-8923 (Linking) ; 1072, s. 62-77
  • Tidskriftsartikel (refereegranskat)abstract
    • Defective apoptosis of mucosal cell populations seems to be a relevant pathogenetic mechanism in inflammatory bowel disease (IBD). It has been suggested that the induction of apoptosis in various effector cells may be a relevant therapeutic mechanism in IBD. Indeed, it was shown that different drugs used for treatment of IBD have the capacity to induce apoptosis in T cells or monocytes in vitro and in vivo. However, it remains unclear whether these observations are related to clinical efficacy of these agents. TNF-alpha is one of the most relevant proinflammatory mediators in IBD and anti-TNF treatment has been shown to be of particular benefit for patients with IBD. It could subsequently be shown that various anti-TNF-alpha agents, such as infliximab and adalimumab, can induce apoptosis in activated monocytes and lymphocytes in vitro and in vivo. This mechanism requires reverse signaling via transmembranous TNF, thereby eliciting a signal transduction cascade that results in programmed cell death. Although other mechanisms might also contribute to the clinical effect of anti-TNF-alpha, current data suggest that apoptosis is a relevant mechanism that is associated with clinical efficacy of anti-TNF agents. Induction of apoptosis in activated monocytes or T cells may be regarded as therapeutic tool not only for anti-TNF agents, but also for other drugs used in IBD. Future strategies should focus on identification of mechanisms that prevent apoptosis in the mucosa of patients with IBD and in targeting apoptotic pathways as a therapeutic strategy in IBD.
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