Degraded Carrageenan Causing Colitis in Rats Induces TNF Secretion and ICAM-1 Upregulation in Monocytes through NF-κB Activation

Carrageenan (CGN) is a high molecular weight sulphated polysaccharide derived from red seaweeds. In rodents, its degraded forms (dCGN) can induce intestinal inflammation associated with macrophage recruitment and activation. The aim of this study was: 1) to analyze the size-dependent effects of dCGN on colon inflammation in vivo, and 2) to correlate these effects with monocyte/macrophage proliferation, cytokine production and expression of various cell surface antigens including ICAM-1 adhesion molecule. Peripheral blood monocytes (PBM) and THP-1 monocytic cells were cultured in the presence of either 10 or 40 kDa, dCGN. The 40 kDa, but not the 10 kDa dCGN, induced colitis in in vivo. Degraded CGN inhibited THP-1 cell proliferation in vitro, arresting the cells in G1 phase. In addition, dCGN increased ICAM-1 expression in both PBM and THP-1 cells with a major effect seen after 40 kDa dCGN exposure. Also, dCGN stimulated monocyte aggregation in vitro that was prevented by incubation with anti-ICAM-1 antibody. Finally, dCGN stimulated TNF-α expression and secretion by both PBM and THP-1 cells. All these effects were linked to NF-κB activation. These data strongly suggest that the degraded forms of CGN have a pronounced effect on monocytes, characteristic of an inflammatory phenotype

Definition and diagnostic methods for Barrett’s esophagus

L’oesophage de Barrett ou endobrachyoesophage (EBO) est le remplacement de la muqueuse malpighienne de l’oesophage par une métaplasie glandulaire. Son diagnostic repose sur la combinaison d’une suspicion endoscopique et d’une confirmation histologique. L’EBO est un facteur de risque reconnu de l’adénocarcinome oesophagien, et il est considéré comme une condition pré-cancéreuse pouvant évoluer chez certains patients selon une séquence métaplasie – dysplasie – cancer. Du fait de son potentiel dégénératif, une surveillance endoscopique est souvent préconisée en l’absence de contre-indication à un traitement éventuel du fait du terrain. Cette surveillance vise à dépister des lésions pré-cancéreuses ou cancéreuses précoces à un stade curable. Dans cette revue générale, nous rappelons la définition de Montréal, la classification endoscopique de Prague, ainsi que les nouvelles modalités endoscopiques de dépistage et de surveillance de l’EBO.Barrett’s esophagus (BE) is a metaplastic change of the lining of the esophagus characterized by the replacement of normal squamous epithelium by a glandular epithelium. The diagnosis of BE requires both an endoscopic suspicion of esophageal metaplasia (ESEM) and a histological proof of gastric or intestinal metaplasia. BE is an established risk factor for esophageal adenocarcinoma, according to a metaplasia – low dysplasia – adenocarcinoma sequence. Therefore, an endoscopic surveillance is frequently recommended in patients without any contra-indication for potential treatment (e.g. associated life-threatening disorders). This surveillance aims at diagnosing early cancerous lesions at a curable stage. In this review, we focus on the Montreal definition, the Prague endoscopic classification and new endoscopic modalities for screening and surveillance of BE

Pathological lesions in colonic biopsies during Parkinson's disease.

International audiencePas de résum

Real-Time Increased Detection of Neoplastic Tissue in Barrett’s Esophagus with Probe-Based Confocal Laser Endomicroscopy: Final Results of an International Multicenter, Prospective, Randomized, Controlled Trial

BACKGROUND: Probe-based confocal laser endomicroscopy (pCLE) allows real-time detection of neoplastic Barrett's esophagus (BE) tissue. However, the accuracy of pCLE in real time has not yet been extensively evaluated. OBJECTIVE: To compare the sensitivity and specificity of pCLE in addition to high-definition white-light endoscopy (HD-WLE) with HD-WLE alone for the detection of high-grade dysplasia (HGD) and early carcinoma (EC) in BE. DESIGN: International, prospective, multicenter, randomized, controlled trial. SETTING: Five tertiary referral centers. PATIENTS: A total of 101 consecutive BE patients presenting for surveillance or endoscopic treatment of HGD/EC. INTERVENTIONS: All patients were examined by HD-WLE, narrow-band imaging (NBI), and pCLE, and the findings were recorded before biopsy samples were obtained. The order of HD-WLE and NBI was randomized and performed by 2 independent, blinded endoscopists. All suspicious lesions on HD-WLE or NBI and 4-quadrant random locations were documented. These locations were examined by pCLE, and a presumptive diagnosis of benign or neoplastic (HGD/EC) tissue was made in real time. Finally, biopsies were taken from all locations and were reviewed by a central pathologist, blinded to endoscopic and pCLE data. MAIN OUTCOME MEASUREMENTS: Diagnostic characteristics of pCLE. RESULTS: The sensitivity and specificity for HD-WLE were 34.2% and 92.7%, respectively, compared with 68.3% and 87.8%, respectively, for HD-WLE or pCLE (P = .002 and P < .001, respectively). The sensitivity and specificity for HD-WLE or NBI were 45.0% and 88.2%, respectively, compared with 75.8% and 84.2%, respectively, for HD-WLE, NBI, or pCLE (P = .01 and P = .02, respectively). Use of pCLE in conjunction with HD-WLE and NBI enabled the identification of 2 and 1 additional HGD/EC patients compared with HD-WLE and HD-WLE or NBI, respectively, resulting in detection of all HGD/EC patients, although not statistically significant. LIMITATIONS: Academic centers with enriched population. CONCLUSIONS: pCLE combined with HD-WLE significantly improved the ability to detect neoplasia in BE patients compared with HD-WLE. This may allow better informed decisions to be made for the management and subsequent treatment of BE patients. (Clinical trial registration number: NCT00795184.)

Second-generation colon capsule endoscopy compared with colonoscopy

Colon capsule endoscopy (CCE) represents a noninvasive technology that allows visualization of the colon without requiring sedation and air insufflation. A second-generation colon capsule endoscopy system (PillCam Colon 2) (CCE-2) was developed to increase sensitivity for colorectal polyp detection compared with the first-generation system. OBJECTIVE: To assess the feasibility, accuracy, and safety of CCE-2 in a head-to-head comparison with colonoscopy. DESIGN AND SETTING: Prospective, multicenter trial including 8 European sites. PATIENTS: This study involved 117 patients (mean age 60 years). Data from 109 patients were analyzed. INTERVENTION: CCE-2 was prospectively compared with conventional colonoscopy as the criterion standard for the detection of colorectal polyps that are >/=6 mm or masses in a cohort of patients at average or increased risk of colorectal neoplasia. Colonoscopy was independently performed within 10 hours after capsule ingestion or on the next day. MAIN OUTCOME MEASUREMENTS: CCE-2 sensitivity and specificity for detecting patients with polyps >/=6 mm and >/=10 mm were assessed. Capsule-positive but colonoscopy-negative cases were counted as false positive. Capsule excretion rate, level of bowel preparation, and rate of adverse events also were assessed. RESULTS: Per-patient CCE-2 sensitivity for polyps >/=6 mm and >/=10 mm was 84% and 88%, with specificities of 64% and 95%, respectively. All 3 invasive carcinomas were detected by CCE-2. The capsule excretion rate was 88% within 10 hours. Overall colon cleanliness for CCE-2 was adequate in 81% of patients. LIMITATIONS: Not unblinding the CCE-2 results at colonoscopy; heterogenous patient population; nonconsecutive patients. CONCLUSION: In this European, multicenter study, CCE-2 appeared to have a high sensitivity for the detection of clinically relevant polypoid lesions, and it might be considered an adequate tool for colorectal imaging

Colonic Biopsies to Assess the Neuropathology of Parkinson's Disease and Its Relationship with Symptoms

The presence of Lewy bodies and Lewy neurites (LN) has been demonstrated in the enteric nervous system (ENS) of Parkinson's disease (PD) patients. The aims of the present research were to use routine colonoscopy biopsies (1) to analyze, in depth, enteric pathology throughout the colonic submucosal plexus (SMP), and (2) to correlate the pathological burden with neurological and gastrointestinal (GI) symptoms.A total of 10 control and 29 PD patients divided into 3 groups according to disease duration were included. PD and GI symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively. Four biopsies were taken from the ascending and descending colon during the course of a total colonoscopy. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha-synuclein, neurofilaments NF 220 kDa (NF) and tyrosine hydroxylase (TH). The density of LN, labeled by anti-phosphorylated alpha-synuclein antibodies, was evaluated using a quantitative rating score. Lewy pathology was apparent in the colonic biopsies from 21 patients and in none of the controls. A decreased number of NF-immunoreactive neurons per ganglion was observed in the SMP of PD patients compared to controls. The amount of LN in the ENS was inversely correlated with neuronal count and positively correlated with levodopa-unresponsive features and constipation.Analysis of the ENS by routine colonoscopy biopsies is a useful tool for pre-mortem neuropathological diagnosis of PD, and also provides insight into the progression of motor and non-motor symptoms

LEPTINE ET TISSU ADIPEUX MESENTERIQUE DANS L'INFLAMMATION INTESTINALE

LA LEPTINE, HORMONE PRINCIPALEMENT SECRETEE PAR L'ADIPOCYTE, DIMINUE LA PRISE ALIMENTAIRE ET AUGMENTE LA DEPENSE ENERGETIQUE. ELLE INTERAGIT AVEC LE SYSTEME IMMUNITAIRE. ANOREXIE, AUGMENTATION DE LA DEPENSE ENERGETIQUE, ET PERTE DE POIDS CONSTITUENT DES ARGUMENTS CLINIQUES EN FAVEUR D'UN ROLE DE LA LEPTINE DANS LES MALADIES INFLAMMATOIRES CHRONIQUES DE L'INTESTIN (MICI). L'HYPERTROPHIE DE LA GRAISSE MESENTERIQUE EST CARACTERISTIQUE DE LA MALADIE DE CROHN (MC). UNE DYSREGULATION DE L'EXPRESSION DE PPAR, RECEPTEUR HORMONAL NUCLEAIRE MEDIATEUR-CLE FAVORISANT L'ADIPOGENESE, POURRAIT PARTICIPER A L'HYPERTROPHIE DU MESENTERE, CE DERNIER REPRESENTANT UNE NOUVELLE SOURCE TISSULAIRE DE TNF. L'OBJECTIF DE CETTE THESE ETAIT D'IDENTIFIER L'IMPLICATION DE LA LEPTINE ET DU MESENTERE DANS L'INFLAMMATION INTESTINALE. LES OBJECTIFS SPECIFIQUES DES TRAVAUX ONT ETE 1) DE DETERMINER LA CINETIQUE DE LA LEPTINEMIE DANS DES MODELES D'INFLAMMATION INTESTINALE CHEZ LE RAT, 2) D'IDENTIFIER UNE IMPLICATION POTENTIELLE DE LA LEPTINE DANS LA PATHOGENIE D'UNE COLITE EXPERIMENTALE, 3) DE QUANTIFIER L'EXPRESSION DES MESSAGERS DE LA LEPTINE DANS LA GRAISSE MESENTERIQUE DE PATIENTS AVEC MICI, 4) D'EVALUER LA CAPACITE DES CELLULES MESENTERIQUES A SYNTHETISER DU TNF ET DU PPAR DANS DES MODELES MURINS D'ILEITE. NOS TRAVAUX 1) METTENT EN EVIDENCE UNE HYPERLEPTINEMIE LORS DU STADE PRECOCE D'UNE INFLAMMATION INTESTINALE CHEZ LE RAT ; 2) MONTRENT QUE LA LEPTINE JOUE UN ROLE PRO-INFLAMMATOIRE DANS LA PATHOGENIE DE L'INFLAMMATION INTESTINALE CHEZ LE RAT ; 3) METTENT EN EVIDENCE UNE SUREXPRESSION MESENTERIQUE DES ARNM DE LA LEPTINE CHEZ LES PATIENTS AVEC MICI, QUI POURRAIT PARTICIPER AU PROCESSUS INFLAMMATOIRE, CONDUIRE A UNE HYPERLEPTINEMIE RESPONSABLE A SON TOUR DE L'ANOREXIE OBSERVEE LORS DES POUSSEES DES MICI ; 4) MONTRENT QUE LE MESENTERE CONSTITUE UNE SOURCE QUALITATIVEMENT ET QUANTITATIVEMENT IMPORTANTE DE TNF DANS L'ILEITE CHEZ LE RAT, QUI POURRAIT PARTICIPER AU MAINTIEN DU PROCESSUS INFLAMMATOIRE.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Neuropathies entériques (méthodes d'exploration et caractérisation dans un modèle expérimental humain de shigellose)

Le système nerveux entérique (SNE), constitué de neurones et de cellules gliales entériques, est un régulateur clef des fonctions digestives. Néanmoins, la nature des lésions du SNE au cours des principales pathologies digestives ainsi que le rôle de l'inflammation restent mal connus. Ce travail de thèse visait : 1) à développer une méthode permettant d'étudier les neuropathies du SNE chez l homme, et 2) à caractériser ex vivo les atteintes du SNE dans le colon humain dans un modèle d'inflammation aiguë induite par Shigella flexneri (S. flexneri) afin d'identifier les mécanismes physiopathologiques mis en cause. Dans un premier temps, nous avons montré la possibilité d'étudier le SNE sur des biopsies coliques humaines en combinant des approches immunohistochimiques et de Western blot du plexus sous-muqueux interne. Parallèlement, nous avons développé un modèle de culture organotypique afin de caractériser les interactions précoces entre le SNE et S. flexneri. Nous avons ainsi montré que S. flexneri induisait une plasticité neuronale bloquée par un inhibiteur de la NOS (L-Name), ainsi qu'une dégénérescence neuronale et gliale inhibée par un antagoniste des récepteurs NMDA au glutamate. Outre les lésions du SNE, nous avons montré que S. flexneri induisait des altérations majeures de la BEI et identifié le rôle clef de la sérine protéase SepA dans l'induction de ces lésions.The enteric nervous system (ENS) is composed of neurons and enteric glial cells. It plays a major role in the regulation of digestive functions. However, the nature of ENS lesions during the majority of digestive disease, as well as the role of inflammation, is poorly understood. The aims of this study were : 1) to develop a routine method allowing characterisation of enteric neuropathies in humans, and 2) to characterise the ENS alterations ex vivo in a human colonic model of shigella infection and identify the mechanisms involved. Firstly, we demonstrated the accuracy of human colonic biopsies to study the ENS, by combining immunohistochemical and Western blot methods. Secondly, we developed an organotypic culture model to study early interactions between the ENS and Shigella flexneri (S. flexneri), and showed that S. flexneri induced a neuronal plasticity that was bloked by NOS inhibitor (L-Name), as well as neuronal and glial damages that were prevented by NMDA receptors to glutamate. Beyond ENS alterations, we also noted a major disruption of the intestinal epithelial barrier and identified the key role of the SepA serine protease in these alterations.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Influence des fermentations coliques sur la motricité du SIO (mise en évidence et mécanismes en physiologie et au cours du reflux gastro-oesophagien)

Les relaxations transitoires du sphincter inférieur de l'œsophage (RT SIO) sont à l'origine de la majorité des épisodes de reflux chez l'homme. Leur modulation repose sur des réflexes vago-vagaux initiés par des stimuli pharyngés et/ou gastriques et l'intervention de plusieurs neuropeptides. Des travaux récents indiquent que les acides gras à chaîne courte (AGCC), peuvent moduler à distance la motricité de l'estomac proximal. Chez des sujets sains nous avons montré que l'instillation colique de lactose augmentait l'incidence postprandiale des RT SIO et que cet effet était reproduit par la perfusion colique d'AGCC. Chez des malades atteints de reflux gastro-œsophagien, nous avons montré qu'une alimentation enrichie en fructooligosaccharides, des glucides indigestibles, augmentait l'incidence des RT SIO, les épisodes et les symptômes de reflux. Enfin, l'administration du SR48692, un antagoniste spécifique des récepteurs NT 1 n'a pas d'effet sur la motricité du SIO chez l'homme.Transient lower esophageal sphincter relaxations are the main mechanism of reflux in man. TLESRs are triggered by pharyngeal and/or gastric stimuli involving the vagus nerve and several neuropetides. Recent findings indicate that short chain fatty acid (SCFAs), the main end products of colonic fermentation, may influence gastric motility. In healthy volunteers, we showed that colonic instillation of lactose increased the number of TLESRs stimulated by a meal and that this effect was reproduced by colonic instillation of SCFAs. In patients with gastroesophageal reflux (GERD), we also showed that colonic fermentation induced by oral administration of fructooligosaccharides (FOS) increased the rate of TLESRs, the number of reflux episodes and the symptoms of GERD. In a third trial, we found that SR 48692, a specific neurotensin 1 receptor antagonist, had no effect on LOS motilty in man.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

L'endoscopie digestive haute couplée à la coloscopie (indications et pertinence)

L'endoscopie oesogastroduodénale (EOGD) couplée à la coloscopie dans le même temps anesthésique est une pratique de plus en plus fréquente mais non évaluée, en terme d'indications et de pertinence. Trois cohortes de patients inclus successivement ont été comparées : 150 patients ayant une EOGD seule sans anesthésie ; 152 patients ayant une coloscopie seule sous anesthésie ; 142 patients ayant une EOGD couplée à la coloscopie. Nous avons analysé les indications et vérifié leur caractère plus ou moins approprié selon les critères EPAGE. Nous avons ensuite déterminé le nombre de lésions pertinentes dans chacune des cohortes et recherché les facteurs prédictifs de découverte de lésions pertinentes en analyse uni et multivariée. Plus de 80% des indications de l'EOGD étaient appropriées selon EPAGE mais il existait significativement plus de lésions pertinentes dans la cohorte EOGD seule. La proportion de coloscopies appropriées atteignait respectivement, 54 et 57% des indications selon les critères EPAGE dans la cohorte coloscopie seule et la cohorte EOGD-coloscopie couplées. Le caractère approprié de EPAGE n'était pas prédictif de la découverte de lésions pertinentes, contrairement à l'âge (p=0,001) et au sexe masculin (p=0,011). Ces résultats confirment la validité des indications lorsque l'EOGD est couplée à la coloscopie. L'absence de valeur prédictive des critères EPAGE incite à prendre en compte d'autres critères comme l'âge et le sexe afin d'optimiser le rendement diagnostique de l'endoscopie.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF