Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a protease-activated receptor 1- and protease-activated receptor 4-dependent mechanism

International audienceExperimental Approach: Crypts were isolated from human colonic resections and cultured for 6 days, forming human colon organoids. Cultured organoids were exposed to 10 and 50 mU·mL−1 of thrombin, in the presence or not of protease‐activated receptor (PAR) antagonists. Organoid morphology, metabolism, proliferation and apoptosis were followed.Key Results: Thrombin favoured organoid maturation leading to a decreased number of immature cystic structures and a concomitant increased number of larger structures releasing cell debris and apoptotic cells. The size of budding structures, metabolic activity and proliferation were significantly reduced in organoid cultures exposed to thrombin, while apoptosis was dramatically increased. Both PAR1 and PAR4 antagonists inhibited apoptosis regardless of thrombin doses. Thrombin‐induced inhibition of proliferation and metabolic activity were reversed by PAR4 antagonist for thrombin's lowest dose and by PAR1 antagonist for thrombin's highest dose.Conclusions and Implications: Overall, our data suggest that the presence of thrombin in the vicinity of human colon epithelial cells favours their maturation at the expense of their regenerative capacities. Our data point to thrombin and its two receptors PAR1 and PAR4 as potential molecular targets for epithelial repair therapies

PLoS One

Compared to the general population, HIV-infected patients are at higher risk of developing non-AIDS-defining cancers. Chronic HCV infection has also been associated with a higher risk than that of the general population of developing cancers other than hepatocarcinoma. Evaluation of the impact of HCV-related factors on non-AIDS-defining and non HCV-liver (NANL) related cancers among HIV/HCV co-infected patients are scarce. The aim of this study was to identify the impact of HIV/HCV clinical characteristics on NANL related cancers in a large cohort of HIV/HCV-coinfected patients followed from 2005 to 2017. Cox proportional hazards models with delayed entry were used to estimate factors associated with NANL related cancer. Among 1391 patients followed for a median of 5 years, 60 patients developed NANL related cancers, yielding an incidence rate of 8.9 per 1000 person-years (95% CI, [6.6-11.1]). By final multivariable analysis, after adjustment for sex, tobacco or alcohol consumption, baseline CD4 cell count and HCV sustained viral response (SVR), age and a longer duration since HIV diagnosis were independently associated with a higher risk of NANL related cancer (aHR for each additional year 1.10, 95% CI 1.06-1.14, p<0.0001 and 1.06, 95% CI 1.01-1.11, p = 0.02, respectively). Duration of HCV infection, cirrhosis, HCV viral load, genotype and SVR were not associated with the occurrence of NANL related cancer. Among HIV/HCV-coinfected patients, age and the duration of HIV infection were the only characteristics found to be associated with the occurrence of NANL related cancer. In contrast, no association was observed with any HCV-related variables

A standardised model for stool banking for faecal microbiota transplantation : a consensus report from a multidisciplinary UEG working group

Background Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council. Objective Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document. Methods Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation. Results A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening. Conclusion The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients.Peer reviewe

Gaining Greater Insight into HCV Emergence in HIV-Infected Men Who Have Sex with Men: The HEPAIG Study

OBJECTIVES: The HEPAIG study was conducted to better understand Hepatitis C virus (HCV) transmission among human immuno-deficiency (HIV)-infected men who have sex with men (MSM) and assess incidence of HCV infection among this population in France. METHODS AND RESULTS: Acute HCV infection defined by anti-HCV or HCV ribonucleic acid (RNA) positivity within one year of documented anti-HCV negativity was notified among HIV-infected MSM followed up in HIV/AIDS clinics from a nationwide sampling frame. HIV and HCV infection characteristics, HCV potential exposures and sexual behaviour were collected by the physicians and via self-administered questionnaires. Phylogenetic analysis of the HCV-NS5B region was conducted. HCV incidence was 48/10 000 [95% Confidence Interval (CI):43-54] and 36/10 000 [95% CI: 30-42] in 2006 and 2007, respectively. Among the 80 men enrolled (median age: 40 years), 55% were HIV-diagnosed before 2000, 56% had at least one sexually transmitted infection in the year before HCV diagnosis; 55% were HCV-infected with genotype 4 (15 men in one 4d-cluster), 32.5% with genotype 1 (three 1a-clusters); five men were HCV re-infected; in the six-month preceding HCV diagnosis, 92% reported having casual sexual partners sought online (75.5%) and at sex venues (79%), unprotected anal sex (90%) and fisting (65%); using recreational drugs (62%) and bleeding during sex (55%). CONCLUSIONS: This study emphasizes the role of multiple unprotected sexual practices and recreational drugs use during sex in the HCV emergence in HIV-infected MSM. It becomes essential to adapt prevention strategies and inform HIV-infected MSM with recent acute HCV infection on risk of re-infection and on risk-reduction strategies

Manifestations extra-hépatiques de l'hépatite virale C

International audienc

Infection par le VHC et atteinte rénale

International audienc

Ascite non cirrhotique

International audienceObjectifs pédagogiques Connaître les étiologies de l’ascite non cirrhotique Stratégie diagnostique Connaître les stratégies thérapeutique

Grazoprevir + elbasvir for the treatment of hepatitis C virus infection

International audienceIntroduction: Hepatitis C virus (HCV)-related liver disease is a cause of significant morbidity and mortality worldwide. Currently, direct-acting antiviral drugs (DAAs) are associated with an increased sustained virologic response (SVR) and are the gold standard for treating HCV infection.Areas covered: The new combination of grazoprevir, an inhibitor of HCV NS3/4A, and elbasvir, an inhibitor of HCV NS5A, once daily will be available for the treatment of HCV infection. This combination therapy has a high efficacy in HCV genotype 1 and 4 infections, inducing a SVR up to 95%, even in difficult to treat patients such as cirrhotic, HIV co-infected, or dialysis-dependent patients, and patients with stage 4-5 chronic kidney disease or those who failed previous therapy. The safety of grazoprevir combined with elbasvir is very good and without significant adverse effects in phase 2 or 3 studies. For patients who failed prior DAA therapy, in vitro and in vivo studies showed that the grazoprevir and elbasvir combination is fully active against resistance to NS3/4A protease inhibitors. Resistance to NS5B inhibitors is least susceptible to grazoprevir or elbasvir.Expert opinion: This new combination of gazoprevir with elbasvir offers an opportunity to cure HCV infection with short interferon-free therapy, even in difficult to treat patients

Hépatite C chronique et polymyosite (à propos de 4 cas)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF