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Les derniers abstracts de la revue Gut current issue :


    Date de mise en ligne : Vendredi 06 janvier 2017
    Olivera, P., Danese, S., Peyrin-Biroulet, L.
    Next generation of small molecules in inflammatory bowel disease
    Introduction

    Inflammatory bowel disease (IBD) encompasses two major entities: ulcerative colitis (UC) and Crohn's disease (CD).1 Both are chronic, progressive, disabling conditions that require lifelong medical treatment in most cases. IBD has a major impact on the patient's health-related quality of life,2 and the treatment-related costs place a significant burden on healthcare systems.3

    Historically, the medical management of IBD has been based on the use of several small-molecule drugs (SMDs), including corticosteroids, immunomodulators (such as azathioprine, 6-mercaptopurine and methotrexate) and aminosalicylates.4 The introduction of biologic anti-tumour necrosis factor-α (TNF-α) agents in the first few years of this century has revolutionised the clinical management of IBD. In parallel, treatment goals have shifted from symptomatic control towards more objective endpoints (such as mucosal healing and deep remission) associated with better long-term outcomes.5 6 Over the past 20 years, drug...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Tan, P., Petty, R.
    Prognostic RNAs in oesophageal squamous cell carcinoma: small is beautiful

    Oesophageal cancer is a deadly malignancy and is highly heterogeneous at the histological, geographical and molecular levels. It is broadly divided into adenocarcinomas and oesophageal squamous cell carcinomas (OSCCs). OSCCs are particularly prevalent in Asia and Africa where the disease has been linked to tobacco smoking, alcohol consumption and population-specific genetic risk variants.1 Clinically, oesophagectomy is the standard of care for curative therapy, usually proceeded by neoadjuvant chemotherapy/concurrent chemoradiotherapy, or in some cases definitive chemoradiotherapy without surgery. Unfortunately, the majority of patients with OSCC will relapse, and many either present too late or are too frail for curative treatment, resulting in an overall 5-year survival rate of 20%. Recent genomic studies have revealed a plethora of genetic alterations in OSCC, including mutations in TP53, PIK3CA and chromatin modifier genes.2–4 Robust approaches are thus needed for accurately subtyping patients with OSCC, to...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Neesse, A., Ellenrieder, V.
    NEMO--CXCL12/CXCR4 axis: a novel vantage point for antifibrotic therapies in chronic pancreatitis?

    Chronic pancreatitis (CP) is a common GI disorder with an incidence of 4/100 000 and a prevalence of 41/100 000.1 Owing to the chronic nature of the disease, patients with CP are often admitted to hospital and represent a serious socioeconomic burden across continents. Patients with CP have an increased mortality by more than threefold compared with the normal population, and the 20-year survival rate is reduced to 45% compared with 65% of the normal population.1 The disease mostly occurs in repeated episodes of acute inflammatory bouts of the pancreas parenchyma that progressively leads to exocrine and endocrine insufficiency, chronic pain and cachexia. Besides known lifestyle risk factors such as alcohol and nicotine, predisposing genetic mutations have been identified with cystic fibrosis transmembrane conductance regulator (CFTR), carboxypeptidase-A, cationic trypsinogen and serine protease inhibitor Kazal-type 1 being the most prominent candidates. Histologically, CP is characterised by a progressive...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Targher, G.
    Non-alcoholic fatty liver disease as driving force in coronary heart disease?

    Non-alcoholic fatty liver disease (NAFLD) has emerged as an imperative public health problem worldwide. NAFLD is now the most common chronic liver disease in high-income countries, and is estimated to affect at least 25%–30% of the general population.1

    NAFLD typically exists in a ‘milieu’ of altered metabolism, including abdominal obesity, insulin resistance, dysglycaemia and atherogenic dyslipidaemia.1 Cumulatively, these aetiological factors increase the risk for cardiovascular disease (CVD), and so it is, perhaps, not surprising that CVD is the leading cause of mortality in patients with NAFLD.

    The challenge over the past decade has been to tease apart the complex inter-relationships between NAFLD and these aetiological factors, to establish whether NAFLD per se increases the risk of developing CVD. The validation of NAFLD as an independent risk factor would have direct relevance for primary preventative strategies against CVD.

    A prior narrative review published in 2010 by...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Jang, H.-J., Lee, H.-S., Burt, B. M., Lee, G. K., Yoon, K.-A., Park, Y.-Y., Sohn, B. H., Kim, S. B., Kim, M. S., Lee, J. M., Joo, J., Kim, S. C., Yun, J. S., Na, K. J., Choi, Y.-L., Park, J.-L., Kim, S.-Y., Lee, Y. S., Han, L., Liang, H., Mak, D., Burks, J. K., Zo, J. I., Sugarbaker, D. J., Shim, Y. M., Lee, J.-S.
    Integrated genomic analysis of recurrence-associated small non-coding RNAs in oesophageal cancer
    Objective

    Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict. A better understanding of the biology of ESCC recurrence is needed to improve patient care. Our goal was to identify small non-coding RNAs (sncRNAs) that could predict the likelihood of recurrence after surgical resection and to uncover potential molecular mechanisms that dictate clinical heterogeneity.

    Design

    We developed a robust prediction model for recurrence based on the analysis of the expression profile data of sncRNAs from 108 fresh frozen ESCC specimens as a discovery set and assessment of the associations between sncRNAs and recurrence-free survival (RFS). We also evaluated the mechanistic and therapeutic implications of sncRNA obtained through integrated analysis from multiple datasets.

    Results

    We developed a risk assessment score (RAS) for recurrence with three sncRNAs (microRNA (miR)-223, miR-1269a and nc886) whose expression was significantly associated with RFS in the discovery cohort (n=108). RAS was validated in an independent cohort of 512 patients. In multivariable analysis, RAS was an independent predictor of recurrence (HR, 2.27; 95% CI, 1.26 to 4.09; p=0.007). This signature implies the expression of Np63 and multiple alterations of driver genes like PIK3CA. We suggested therapeutic potentials of immune checkpoint inhibitors in low-risk patients, and Polo-like kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase inhibitors in high-risk patients.

    Conclusion

    We developed an easy-to-use prognostic model with three sncRNAs as robust prognostic markers for postoperative recurrence of ESCC. We anticipate that such a stratified and systematic, tumour-specific biological approach will potentially contribute to significant improvement in ESCC treatment.


    Date de mise en ligne : Vendredi 06 janvier 2017
    McGavigan, A. K., Garibay, D., Henseler, Z. M., Chen, J., Bettaieb, A., Haj, F. G., Ley, R. E., Chouinard, M. L., Cummings, B. P.
    TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice
    Objective

    Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible remain incompletely defined. VSG increases circulating bile acid concentrations and bile acid signalling through TGR5 improves glucose homeostasis. Therefore, we investigated the role of TGR5 signalling in mediating the glucoregulatory benefits of VSG.

    Design

    VSG or sham surgery was performed in high-fat-fed male Tgr5+/+ (wild type) and Tgr5–/– (knockout) littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Body weight, food intake, energy expenditure, insulin signalling and circulating bile acid profiles were measured and oral glucose tolerance testing, islet immunohistochemistry and gut microbial profiling were performed.

    Results

    VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes. However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic inflammation and islet morphology after VSG were attenuated in Tgr5–/– relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5–/– relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG.

    Conclusions

    These results suggest that TGR5 contributes to the glucoregulatory benefits of VSG surgery by promoting metabolically favourable shifts in the circulating bile acid pool.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Castano-Rodriguez, N., Kaakoush, N. O., Lee, W. S., Mitchell, H. M.
    Dual role of Helicobacter and Campylobacter species in IBD: a systematic review and meta-analysis
    Objective

    To conduct a comprehensive global systematic review and meta-analysis on the association between Helicobacter pylori infection and IBD. As bacterial antigen cross-reactivity has been postulated to be involved in this association, published data on enterohepatic Helicobacter spp (EHS) and Campylobacter spp and IBD was also analysed.

    Design

    Electronic databases were searched up to July 2015 for all case-control studies on H. pylori infection/EHS/Campylobacter spp and IBD. Pooled ORs (P-OR) and 95% CIs were obtained using the random effects model. Heterogeneity, sensitivity and stratified analyses were performed.

    Results

    Analyses comprising patients with Crohn's disease (CD), UC and IBD unclassified (IBDU), showed a consistent negative association between gastric H. pylori infection and IBD (P-OR: 0.43, p value <1e-10). This association appears to be stronger in patients with CD (P-OR: 0.38, p value <1e-10) and IBDU (P-OR: 0.43, p value=0.008) than UC (P-OR: 0.53, p value <1e-10). Stratification by age, ethnicity and medications showed significant results. In contrast to gastric H. pylori, non H. pylori-EHS (P-OR: 2.62, p value=0.001) and Campylobacter spp, in particular C. concisus (P-OR: 3.76, p value=0.006) and C. showae (P-OR: 2.39, p value=0.027), increase IBD risk.

    Conclusions

    H. pylori infection is negatively associated with IBD regardless of ethnicity, age, H. pylori detection methods and previous use of aminosalicylates and corticosteroids. Antibiotics influenced the magnitude of this association. Closely related bacteria including EHS and Campylobacter spp increase the risk of IBD. These results infer that H. pylori might exert an immunomodulatory effect in IBD.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Moreno, M. d. L., Cebolla, A., Munoz-Suano, A., Carrillo-Carrion, C., Comino, I., Pizarro, A., Leon, F., Rodriguez-Herrera, A., Sousa, C.
    Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing
    Objective

    Gluten-free diet (GFD) is the only management for coeliac disease (CD). Available methods to assess GFD compliance are insufficiently sensitive to detect occasional dietary transgressions that may cause gut mucosal damage. We aimed to develop a method to determine gluten intake and monitor GFD compliance in patients with CD and to evaluate its correlation with mucosal damage.

    Design

    Urine samples of 76 healthy subjects and 58 patients with CD subjected to different gluten dietary conditions were collected. A lateral flow test (LFT) with the highly sensitive and specific G12 monoclonal antibody for the most dominant gluten immunogenic peptides (GIP) and a LFT reader were used to quantify GIP in solid-phase extracted urines.

    Results

    GIP were detectable in concentrated urines from healthy individuals previously subjected to GFD as early as 4–6 h after single gluten intake, and remained detectable for 1–2 days. The urine assay revealed infringement of the GFD in about 50% of the patients. Analysis of duodenal biopsies revealed that most of patients with CD (89%) with no villous atrophy had no detectable GIP in urine, while all patients with quantifiable GIP in urine showed incomplete intestinal mucosa recovery.

    Conclusion

    GIP are detected in urine after gluten consumption, enabling a new and non-invasive method to monitor GFD compliance and transgressions. The method was sensitive, specific and simple enough to be convenient for clinical monitoring of patients with CD as well as for basic and clinical research applications including drug development.

    Trial registration number

    NCT02344758.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Fournel, A., Drougard, A., Duparc, T., Marlin, A., Brierley, S. M., Castro, J., Le-Gonidec, S., Masri, B., Colom, A., Lucas, A., Rousset, P., Cenac, N., Vergnolle, N., Valet, P., Cani, P. D., Knauf, C.
    Apelin targets gut contraction to control glucose metabolism via the brain
    Objective

    The gut–brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus.

    Design

    We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose.

    Results

    In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle.

    Conclusions

    Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Radaelli, F., Paggi, S., Hassan, C., Senore, C., Fasoli, R., Anderloni, A., Buffoli, F., Savarese, M. F., Spinzi, G., Rex, D. K., Repici, A.
    Split-dose preparation for colonoscopy increases adenoma detection rate: a randomised controlled trial in an organised screening programme
    Objective

    Although a split regimen of bowel preparation has been associated with higher levels of bowel cleansing, it is still uncertain whether it has a favourable effect on the adenoma detection rate (ADR). The present study was aimed at evaluating whether a split regimen was superior to the traditional ‘full-dose, day-before’ regimen in terms of ADR.

    Design

    In a multicentre, randomised, endoscopist-blinded study, 50–69-year-old subjects undergoing first colonoscopy after positive-faecal immunochemical test within an organised colorectal cancer organised screening programmes were 1:1 randomised to receive low-volume 2-L polyethylene glycol (PEG)-ascorbate solution in a ‘split-dose’ (Split-Dose Group, SDG) or ‘day-before’ regimen (Day-Before Group, DBG). The primary endpoint was the proportion of subjects with at least one adenoma. Secondary endpoints were the detection rates of advanced adenomas and serrated lesions at per-patient analysis and the total number of lesions.

    Results

    690 subjects were included in the study. At per-patient analysis, the proportion of subjects with at least one adenoma was significantly higher in the SDG than in the DBG (183/345, 53.0% vs 141/345, 40.9%, relative risk (RR) 1.22, 95% CI 1.03 to 1.46); corresponding figures for advanced adenomas were 26.4% (91/345) versus 20.0% (69/345, RR 1.35, 95% CI 1.06 to 1.73). At per-polyp analysis, the total numbers of both adenomas and advanced adenomas per subject were significantly higher in the SDG (1.15 vs 0.8, p <0.001; 0.36 vs 0.22, p<0.001).

    Conclusions

    In an organised screening setting, the adoption of a split regimen resulted into a higher detection rate of clinically relevant neoplastic lesions, thus improving the effectiveness of colonoscopy. Based on such evidence, the adoption of a split regimen for colonoscopy should be strongly recommended.

    Clinical trial registration number

    NCT02178033.


    Date de mise en ligne : Vendredi 06 janvier 2017
    IJspeert, J. E. G., Rana, S. A. Q., Atkinson, N. S. S., van Herwaarden, Y. J., Bastiaansen, B. A. J., van Leerdam, M. E., Sanduleanu, S., Bisseling, T. M., Spaander, M. C. W., Clark, S. K., Meijer, G. A., van Lelyveld, N., Koornstra, J. J., Nagtegaal, I. D., East, J. E., Latchford, A., Dekker, E., on behalf of the Dutch workgroup serrated polyps & polyposis (WASP)
    Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis
    Objective

    Serrated polyposis syndrome (SPS) is accompanied by an increased risk of colorectal cancer (CRC). Patients fulfilling the clinical criteria, as defined by the WHO, have a wide variation in CRC risk. We aimed to assess risk factors for CRC in a large cohort of patients with SPS and to evaluate the risk of CRC during surveillance.

    Design

    In this retrospective cohort analysis, all patients with SPS from seven centres in the Netherlands and two in the UK were enrolled. WHO criteria were used to diagnose SPS. Patients who only fulfilled WHO criterion-2, with IBD and/or a known hereditary CRC syndrome were excluded.

    Results

    In total, 434 patients with SPS were included for analysis; 127 (29.3%) were diagnosed with CRC. In a per-patient analysis ≥1 serrated polyp (SP) with dysplasia (OR 2.07; 95% CI 1.28 to 3.33), ≥1 advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) and the fulfilment of both WHO criteria 1 and 3 (OR 1.60; 95% CI 1.04 to 2.51) were associated with CRC, while a history of smoking was inversely associated with CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 patients underwent surveillance after clearing of all relevant lesions, during which two patients were diagnosed with CRC, corresponding to 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4).

    Conclusion

    The presence of SPs containing dysplasia, advanced adenomas and/or combined WHO criteria 1 and 3 phenotype is associated with CRC in patients with SPS. Patients with a history of smoking show a lower risk of CRC, possibly due to a different pathogenesis of disease. The risk of developing CRC during surveillance is lower than previously reported in literature, which may reflect a more mature multicentre cohort with less selection bias.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Roy, H. K., Turzhitsky, V., Wali, R., Radosevich, A. J., Jovanovic, B., Della'Zanna, G., Umar, A., Rubin, D. T., Goldberg, M. J., Bianchi, L., De La Cruz, M., Bogojevic, A., Helenowski, I. B., Rodriguez, L., Chatterton, R., Skripkauskas, S., Page, K., Weber, C. R., Huang, X., Richmond, E., Bergan, R. C., Backman, V.
    Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo-controlled double-blinded trial with aspirin
    Objective

    A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy.

    Design

    We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints.

    Results

    At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=–0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention.

    Conclusions

    We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice.

    Trial Number

    NCT00468910


    Date de mise en ligne : Vendredi 06 janvier 2017
    Chiu, S. Y.-H., Chuang, S.-L., Chen, S. L.-S., Yen, A. M.-F., Fann, J. C.-Y., Chang, D.-C., Lee, Y.-C., Wu, M.-S., Chou, C.-K., Hsu, W.-F., Chiou, S.-T., Chiu, H.-M.
    Faecal haemoglobin concentration influences risk prediction of interval cancers resulting from inadequate colonoscopy quality: analysis of the Taiwanese Nationwide Colorectal Cancer Screening Program
    Objectives

    Interval colorectal cancer (CRC) after colonoscopy may affect effectiveness and cost-effectiveness of screening programmes. We aimed to investigate whether and how faecal haemoglobin concentration (FHbC) of faecal immunochemical testing (FIT) affected the risk prediction of interval cancer (IC) caused by inadequate colonoscopy quality in a FIT-based population screening programme.

    Design

    From 2004 to 2009, 29 969 subjects underwent complete colonoscopy after positive FIT in the Taiwanese Nationwide CRC Screening Program. The IC rate was traced until the end of 2012. The incidence of IC was calculated in relation to patient characteristics, endoscopy-related factors (such adenoma detection rate (ADR)) and FHbC. Poisson regression analysis was performed to assess the potential risk factors for colonoscopy IC.

    Results

    One hundred and sixty-two ICs developed after an index colonoscopy and the estimated incidence was 1.14 per 1000 person-years of observation for the entire cohort. Increased risk of IC was most remarkable in the uptake of colonoscopy in settings with ADR lower than 15% (adjusted relative risk (aRR)=3.09, 95% CI 1.55 to 6.18) and then higher FHbC (μg Hb/g faeces) (100–149: aRR=2.55, 95% CI 1.52 to 4.29, ≥150: aRR=2.74, 95% CI 1.84 to 4.09) with adjustment for older age and colorectal neoplasm detected at baseline colonoscopy. Similar findings were observed for subjects with negative index colonoscopy.

    Conclusions

    Colonoscopy ICs arising from FIT-based population screening programmes were mainly influenced by inadequate colonoscopy quality and independently predicted by FHbC that is associated with a priori chance of advanced neoplasm. This finding is helpful for future modification of screening logistics based on FHbC.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Huang, W., Cane, M. C., Mukherjee, R., Szatmary, P., Zhang, X., Elliott, V., Ouyang, Y., Chvanov, M., Latawiec, D., Wen, L., Booth, D. M., Haynes, A. C., Petersen, O. H., Tepikin, A. V., Criddle, D. N., Sutton, R.
    Caffeine protects against experimental acute pancreatitis by inhibition of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ release
    Objective

    Caffeine reduces toxic Ca2+ signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated signalling, but effects of other xanthines have not been evaluated, nor effects of xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its xanthine metabolites on pancreatic acinar IP3R-mediated Ca2+ signalling and experimental AP.

    Design

    Isolated pancreatic acinar cells were exposed to secretagogues, uncaged IP3 or toxins that induce AP and effects of xanthines, non-xanthine phosphodiesterase (PDE) inhibitors and cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP/cGMP) determined. The intracellular cytosolic calcium concentration ([Ca2+]C), mitochondrial depolarisation and necrosis were assessed by confocal microscopy. Effects of xanthines were evaluated in caerulein-induced AP (CER-AP), taurolithocholic acid 3-sulfate-induced AP (TLCS-AP) or palmitoleic acid plus ethanol-induced AP (fatty acid ethyl ester AP (FAEE-AP)). Serum xanthines were measured by liquid chromatography-mass spectrometry.

    Results

    Caffeine, dimethylxanthines and non-xanthine PDE inhibitors blocked IP3-mediated Ca2+ oscillations, while monomethylxanthines had little effect. Caffeine and dimethylxanthines inhibited uncaged IP3-induced Ca2+ rises, toxin-induced Ca2+ release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca2+ rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraxanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylxanthines and trimethylxanthines peaked at >2 mM with 25 mg/kg caffeine but at <100 µM with 25 mg/kg paraxanthine or theophylline.

    Conclusions

    Caffeine and its dimethylxanthine metabolites reduced pathological IP3R-mediated pancreatic acinar Ca2+ signals but only caffeine ameliorated experimental AP. Caffeine is a suitable starting point for medicinal chemistry.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Gomez-Rubio, P., Zock, J.-P., Rava, M., Marquez, M., Sharp, L., Hidalgo, M., Carrato, A., Ilzarbe, L., Michalski, C., Molero, X., Farre, A., Perea, J., Greenhalf, W., O'Rorke, M., Tardon, A., Gress, T., Barbera, V., Crnogorac-Jurcevic, T., Dominguez-Munoz, E., Munoz-Bellvis, L., Alvarez-Urturi, C., Balcells, J., Barneo, L., Costello, E., Guillen-Ponce, C., Kleeff, J., Kong, B., Lawlor, R., Löhr, M., Mora, J., Murray, L., O'Driscoll, D., Pelaez, P., Poves, I., Scarpa, A., Real, F. X., Malats, N., PanGenEU Study Investigators
    Reduced risk of pancreatic cancer associated with asthma and nasal allergies
    Objective

    Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk.

    Design

    Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case–control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model.

    Results

    Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case–control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk.

    Conclusions

    This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Arnold, F., Patch, D., Yu, D., Westbrook, R. H.
    When banding fails; investigation hails
    Clinical presentation

    A 67-year-old man presented to our centre 5 years ago with a short history of jaundice and weight loss. A diagnosis of autoimmune hepatitis was made following laboratory investigations, imaging and a trans-jugular liver (TJ) biopsy. He was treated with prednisolone and azathioprine, which resulted in normalisation of his transaminases and bilirubin. Four years later, he was diagnosed with cirrhosis (Childs class A) based on clinical, biochemical and radiological parameters. He underwent a screening endoscopy, which revealed grade III oesophageal varices with multiple red signs and was started on propranolol as primary prophylaxis. He was unable to tolerate β blockers and oesophageal endoscopic band ligation (EBL) was subsequently undertaken. He underwent six further upper GI endoscopies with repeated EBL of his oesophageal varices; however, the grade III varices with red signs persisted. Contrast-enhanced arterial phase imaging was performed and the reason for him failing to respond to...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Sinn, D. H., Kang, D., Chang, Y., Ryu, S., Gu, S., Kim, H., Seong, D., Cho, S. J., Yi, B.-K., Park, H.-D., Paik, S. W., Song, Y. B., Lazo, M., Lima, J. A. C., Guallar, E., Cho, J., Gwak, G.-Y.
    Non-alcoholic fatty liver disease and progression of coronary artery calcium score: a retrospective cohort study
    Background and aim

    Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, was associated with subclinical atherosclerosis in many cross-sectional studies, but the prospective association between NAFLD and the progression of atherosclerosis has not been evaluated. This study was conducted to evaluate the association between NAFLD and the progression of coronary atherosclerosis.

    Methods

    This retrospective cohort study included 4731 adult men and women with no history of cardiovascular disease (CVD), liver disease or cancer at baseline who participated in a repeated regular health screening examination between 2004 and 2013. Fatty liver was diagnosed by ultrasound based on standard criteria, including parenchymal brightness, liver-to-kidney contrast, deep beam attenuation and bright vessel walls. Progression of coronary artery calcium (CAC) scores was measured using multidetector CT scanners.

    Results

    The average duration of follow-up was 3.9 years. During follow-up, the annual rate of CAC progression in participants with and without NAFLD were 22% (95% CI 20% to 23%) and 17% (16% to 18%), respectively (p<0.001). The multivariable ratio of progression rates comparing participants with NAFLD with those without NAFLD was 1.04 (1.02 to 1.05; p<0.001). The association between NAFLD and CAC progression was similar in most subgroups analysed, including in participants with CAC 0 and in those with CAC >0 at baseline.

    Conclusions

    In this large cohort study of adult men and women with no history of CVD, NAFLD was significantly associated with the development of CAC independent of cardiovascular and metabolic risk factors. NAFLD may play a pathophysiological role in atherosclerosis development and may be useful to identify subjects with a higher risk of subclinical disease progression.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Nahon, P., Lescat, M., Layese, R., Bourcier, V., Talmat, N., Allam, S., Marcellin, P., Guyader, D., Pol, S., Larrey, D., De Ledinghen, V., Ouzan, D., Zoulim, F., Roulot, D., Tran, A., Bronowicki, J.-P., Zarski, J.-P., Goria, O., Cales, P., Peron, J.-M., Alric, L., Bourliere, M., Mathurin, P., Blanc, J.-F., Abergel, A., Serfaty, L., Mallat, A., Grange, J.-D., Attali, P., Bacq, Y., Wartelle, C., Dao, T., Benhamou, Y., Pilette, C., Silvain, C., Christidis, C., Capron, D., Bernard-Chabert, B., Hillaire, S., Di Martino, V., Trinchet, J.-C., Moreau, R., Roudot-Thoraval, F., for the ANRS CO12 CirVir and Microcir Groups, Kempf, Bert, Doloy, Poilane, Peuchant, Carbonnelle, Picard, Burucoa, Cattoir, Decre, Degand, Dortet, Kayal, Vernet-Garnier, Lozniewski, Tuaillon, Vimont, Bessede, Patry, Lemaitre, Pachetii
    Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort)
    Objective

    To assess incidence and prognostic significance of bacterial infections (BIs) occurring in compensated viral cirrhosis.

    Design

    This prospective study involved 35 French centres. Inclusion criteria were biopsy-proven HCV or HBV cirrhosis, Child–Pugh A and no previous hepatic complications. Cumulative incidence (CumI) of events was estimated in a competing risks framework.

    Results

    1672 patients were enrolled (HCV 1323, HBV 318, HCV-HBV 31). During a median follow-up of 43 months, 234 BIs occurred in 171 patients (5 year CumI: 12.9%), among whom 14.6% had septic shock. Main localisations included the urinary tract (27.4%), lung (25.2%) and peritoneum (10.7%) (other, 86 (36.7%)). Most BIs occurred as a first event prior to liver decompensation (n=140, 81.8%) and were community-acquired (CA, 84.2%). The risk of BI was higher in patients with HCV than in patients with HBV (5 year CumI: 15.2% vs 5.5%, p=0.0008). Digestive localisation, concomitant interferon-based treatment, isolation of resistant bacteria and non-CA BIs were associated with lowest probability of resolution. The occurrence of a first BI impaired survival in patients infected with HCV (5 year survival: 60.2% vs 90.4%, p<0.001) and patients infected with HBV (5 year survival: 69.2% vs 97.6%, p<0.001). BIs represented the third cause of death (14.1%) after liver failure and liver cancer. BI risk factors comprised older age, lower albumin, proton pump inhibitor intake and absence of virological eradication/control.

    Conclusion

    BI mostly occurs as a first complication and represents a turning point in the course of compensated viral cirrhosis. Its occurrence impacts long-term prognosis and may define a subgroup of patients in whom adaptation of management is warranted.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Garnelo, M., Tan, A., Her, Z., Yeong, J., Lim, C. J., Chen, J., Lim, K. H., Weber, A., Chow, P., Chung, A., Ooi, L. L. P., Toh, H. C., Heikenwalder, M., Ng, I. O. L., Nardin, A., Chen, Q., Abastado, J.-P., Chew, V.
    Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma
    Objective

    The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis.

    Design

    Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study.

    Results

    Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells.

    Conclusions

    The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Jamil, K. M., Hydes, T. J., Cheent, K. S., Cassidy, S. A., Traherne, J. A., Jayaraman, J., Trowsdale, J., Alexander, G. J., Little, A.-M., McFarlane, H., Heneghan, M. A., Purbhoo, M. A., Khakoo, S. I.
    STAT4-associated natural killer cell tolerance following liver transplantation
    Objective

    Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype.

    Design

    Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using gene expression analysis and donor:recipient HLA typing.

    Results

    NK cells from non-HCV LT recipients were hypofunctional, with reduced expression of NKp46 (p<0.05) and NKp30 (p<0.001), reduced cytotoxicity (p<0.001) and interferon (IFN)- secretion (p<0.025). There was no segregation of this effect with HLA-C, and these functional changes were not observed in individuals with HCV. Microarray and RT-qPCR analysis demonstrated downregulation of STAT4 in NK cells from LT recipients (p<0.0001). Changes in the expression levels of the transcription factors Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFN expression, respectively, were also detected. Hypofunctionality of NK cells was associated with impaired STAT4 phosphorylation and downregulation of the STAT4 target microRNA-155. Conversely in HCV-LT NK cell tolerance was reversed, consistent with the more aggressive outcome of LT for HCV.

    Conclusions

    LT is associated with transcriptional and functional changes in NK cells, resulting in reduced activation. NK cell tolerance occurs upstream of major histocompatibility complex (MHC) class I mediated education, and is associated with deficient STAT4 phosphorylation. STAT4 therefore represents a potential therapeutic target to induce NK cell tolerance in liver disease.


    Date de mise en ligne : Vendredi 06 janvier 2017
    Subramanian, S., Ekbom, A., Rhodes, J. M.
    Recent advances in clinical practice: a systematic review of isolated colonic Crohn's disease: the third IBD?

    The genetics of isolated colonic Crohn's disease place it approximately midway between Crohn's disease with small intestinal involvement and UC, making a case for considering it as a separate condition. We have therefore systematically reviewed its epidemiology, pathophysiology and treatment. Key findings include a higher incidence in females (65%) and older average age at presentation than Crohn's disease at other sites, a mucosa-associated microbiota between that found in ileal Crohn's disease and UC, no response to mesalazine, but possibly better response to antitumour necrosis factor than Crohn's disease at other sites. Diagnostic distinction from UC is often difficult and also needs to exclude other conditions including ischaemic colitis, segmental colitis associated with diverticular disease and tuberculosis. Future studies, particularly clinical trials, but also historical cohorts, should assess isolated colonic Crohn's disease separately.


    Date de mise en ligne : Vendredi 06 janvier 2017
    McLean, M. H.
    GI highlights from the literature
    Basic scienceMLKL-mediated hepatocyte necrosis in immune liver disease—not all hepatocyte death is the same

    Gunther C, He GW, Kremer AE, et al. The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis. J Clin Invest 2016;126:4346–60.

    Hepatocellular death has long been associated with both acute and chronic liver injury. Mechanisms of cell death can extend beyond apoptosis and necrosis and vary greatly, with pathways such as necroptosis (programmed cell necrosis) now well described. A more detailed dissection of the pathways involved in hepatocellular death in different modes of liver injury may yield new insights into disease pathogenesis. In this article, the authors describe a novel mixed lineage kinase domain-like protein (MLKL)-dependent programmed hepatocyte necrosis pathway, which may have relevance for the pathogenesis of immune-mediated liver diseases. In the context of necroptosis, receptor interacting protein kinase 3 (RIPK3) results in the activation of MLKL, which...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Murugesan, S. V. M., Hendrickse, M. T.
    Colonic stenting in patients on P2Y12 receptor antagonists and direct oral anticoagulants: are current BSG/ESGE guidelines practical?

    We thank the British Society of Gastroenterology and the European Society of Gastrointestinal Endoscopy for updating guidelines relating to endoscopy in patients on antiplatelets or anticoagulation therapy.1 However, we wish to raise two important issues. First, this guideline recommends deferring colonic stent placement in patients on P2Y12 receptor antagonists until it is discontinued for at least 5 days. However, malignant colonic obstruction (unlike oesophageal or pyloric obstruction) is an emergency, which if not dealt with immediately could potentially result in serious adverse events. Self-expanding mesh stent (SEMS) insertion is a feasible alternative to emergency surgery in selected patients with malignant colonic obstruction. The risks of bleeding secondary to an appropriately placed colonic SEMS are low and this is referred to within the guidelines. It would be unsafe to delay colonic SEMS insertion in patients who are on P2Y12 receptor antagonist. Second, there remains the potential to use idarucizumab...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Graham, D. Y.
    Vonoprazan Helicobacter pylori eradication therapy: ethical and interpretation issues

    We read with interest the important study on vonoprazan in Helicobacter pylori eradication therapy.1 Vonoprazan likely represents a significant advance in antisecretory and H. pylori eradication therapy. Despite being technically well done, several issues related to study conduct and interpretation remain. Their sample size was based on 90% success with lansoprazole, which has not been achieved in Japan for several decades. When the cure rates proved to be lower, the sample size was increased to ‘maintain the statistical power of the study’. We question whether this was ethical. It is generally considered unethical to randomise against a regimen that provides unacceptably low cure rates; many journals reject papers that do this.2 3 We believe the ethical response would be to stop the study.

    The study concluded that vonoprazan eradication therapy was superior. However, the cure rates of clarithromycin-susceptible infections with vonoprazan and lansoprazole...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Dickson, R. P., Cox, M. J.
    Gut microbiota and protection from pneumococcal pneumonia

    Dear Editor,

    We read with interest the work by Schuijt et al1 reporting that sustained treatment with broad-spectrum antibiotics increases the susceptibility of mice to pneumococcal pneumonia, an effect that is reversed via faecal microbiota transplantation (FMT). Yet we question the authors' confidence that this effect is entirely attributable to alterations in gut microbiota.

    Antibiotic therapy, as used by the authors, alters the microbiota of the upper and lower respiratory tract.2 3 The authors used FMT to determine that the protective effect was due to gut microbiota, yet their protocol for FMT—oral gavage with faecal material—is also a direct manipulation of the microbiota of the upper respiratory tract. Differences in respiratory microbiota correlate strongly with alterations in the abundance and behaviour of alveolar inflammatory cells.4 5

    We thus wonder why the authors conclude that the effects of antibiotics and...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Quraishi, M. N., Sergeant, M., Kay, G., Iqbal, T., Chan, J., Constantinidou, C., Trivedi, P., Ferguson, J., Adams, D. H., Pallen, M., Hirschfield, G. M.
    The gut-adherent microbiota of PSC-IBD is distinct to that of IBD

    Primary sclerosing cholangitis–IBD (PSC–IBD) is an inflammatory autoimmune hepato–biliary–enteric disease in which it is predicted that gut microbiota have potential pathophysiological effects, relevant to disease initiation and outcome. The recent article by Kummen et al1 who reported that the gut microbiota in PSC is distinct compared with those from healthy controls and patients with UC without liver disease, is therefore of interest. However, it remains unclear if these alterations in the gut microbiota are a cause or an effect of liver disease, and there remains a challenging task to link dysbiosis with disease pathogenesis, as well as clarify whether faecal microbiota are entirely representative of communities of mucosa-associated bacteria, which might uniquely interact with immune and epithelial cells.

    Nevertheless Kummen et al notably demonstrated that the Veillonella genus showed a marked increase in PSC–IBD, in comparison with both healthy controls and patients with UC alone. Given interest...


    Date de mise en ligne : Vendredi 06 janvier 2017
    Murakami, K., Sakurai, Y., Shiino, M., Funao, N., Nishimura, A., Asaka, M.
    Reply to the letter by Dr Graham concerning ethical and interpretation issues with vonoprazan-containing H. pylori eradication therapy

    We thank Dr Graham for his interest in our article.1 2 In Japan, 7 days administration of PPI+amoxicillin+clarithromycin is standard treatment for Helicobacter pylori eradication3 and is the only approved treatment as first-line therapy in Japan. Therefore, there is no ethical issue in increasing sample size to match the current eradication rate. In a blinded interim analysis, the overall eradication rate was 81.6%, which was a lower rate than 90% that we used in the initial sample size estimation. However, at the time, it was difficult to determine whether this was due to a difference between a high eradication rate of vonoprazan-based triple therapy and a low eradication rate of lansoprazole-based triple therapy or due to the eradication rates for both treatment regimens being identical. Once again, given that we used the approved first-line treatment for H. pylori eradication in Japan as our comparator...