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SummaryBackground Whether aminosalicylates or thiopurines reduce the risk of colorectal cancer (CRC) in inflammatory bowel (IBD) disease is controversial. Aim To assess simultaneously the chemopreventive effect of aminosalicylates or thiopurines in a case–control study nested in the CESAME observational cohort that enrolled consecutive patients with IBD between May 2004 and June 2005. Patients were followed up to December 2007. Methods Study population comprised 144 case patients who developed CRC from the diagnosis of IBD (65 and 79 cases diagnosed, respectively, before and from 2004, starting year of the prospective observational period of CESAME) and 286 controls matched for gender, age, IBD subtype and year of diagnosis, and cumulative extent of colitis. Exposure to aminosalicylates or thiopurines was defined by an exposure to the treatment during the year of the diagnosis of cancer. The propensity of receiving 5-ASA and thiopurines was quantified by a composite score taking into account patient and IBD characteristics. The role of aminosalicylates or thiopurines was assessed by multivariate analysis. Propensity scores and the history of primary sclerosing cholangitis were entered into the multivariate model for adjustment. Results By multivariate analysis adjusted for propensity, a significant protective effect of exposure to drugs during the year of cancer was found for aminosalicylates (OR = 0.587, 95% CI: 0.367–0.937, P = 0.0257), but not for thiopurines (OR = 0.762, 95% CI: 0.432–1.343, P = 0.3468). Conclusion In a case–control study nested in the CESAME cohort, a significant decrease in the risk of colorectal cancer in IBD was associated with exposure to aminosalicylates, not to thiopurines.

Crohn’s disease (CD) is a progressive inflammatory disease affecting the entire gastrointestinal tract. The need for a definitive stoma (DS) is considered as the ultimate phase of damage. It is often believed that the risk of further disease progression is small when a DS has been performed. The goals of the study were to establish the rate of CD recurrence above the DS and to identify predictive factors of CD recurrence at the time of DS. We retrospectively reviewed all medical records of consecutive CD patients having undergone DS between 1973 and 2010. We collected clinical data at diagnosis, CD phenotype, treatment, and surgery after DS and mortality. Stoma was considered as definitive when restoration of continuity was not possible due to proctectomy, rectitis, anoperineal lesions (APL), or fecal incontinence. Clinical recurrence (CR) was defined as the need for re-introduction or intensification of medical therapy, and surgical recurrence (SR) was defined as a need for a new intestinal resection. Eighty-three patients (20 males, 63 females) with a median age of 34 years at CD diagnosis were included. The median time between diagnosis and DS was 9 years. The median follow-up after DS was 10 years. Thirty-five patients (42%) presented a CR after a median time of 28 months (2–211) and 32 patients (38%) presented a SR after a median time of 29 months (4–212). In a multivariate analysis, APL (HR = 5.1 (1.2–21.1), p = 0.03) and colostomy at time of DS (HR = 3.8 (1.9–7.3), p = 0.0001) were associated factors with the CR. After DS for CD, the risk of clinical recurrence was high and synonymous with surgical recurrence, especially for patients with APL and colostomy.

International audience; Background and Aims:Data on extra-intestinal manifestations [EIM] and their impact on the disease course of ulcerative colitis [UC] in population-based cohorts are scarce, particularly in paediatric- and elderly-onset UC patients. The aims of this population-based study were to assess: 1] the occurrence of EIM in paediatric- and elderly-onset UC; 2] the factors associated with EIM; and 3] their impact on long-term disease outcome.Methods:Paediatric-onset [< 17 years at diagnosis] and elderly-onset UC patients [> 60 years at diagnosis] from a French prospective population-based registry [EPIMAD] were included. Data on EIM and other clinical factors at diagnosis and at maximal follow-up were collected.Results:In all, 158 paediatric- and 470 elderly-onset patients were included [median age at diagnosis 14.5 and 68.8 years, median follow-up 11.2 and 6.2 years, respectively]. EIM occurred in 8.9% of childhood- and 3% of elderly-onset patients at diagnosis and in 16.7% and 2.2% of individuals during follow-up [p < 0.01], respectively. The most frequent EIM was joint involvement [15.8% of paediatric onset and 2.6% of elderly-onset]. Presence of EIM at diagnosis was associated with more severe disease course [need for immunosuppressants or biologic therapy or colectomy] in both paediatric- and elderly-onset UC (hazard ratio [HR] = 2.0, 95% confidence interval [CI]: 1.0-4.2; and HR = 2.8, 0.9-7.9, respectively). Extensive colitis was another independent risk factor in both age groups.Conclusions:Elderly-onset UC patients had lower risk of EIM either at diagnosis or during follow-up than paediatric-onset individuals. EIM at diagnosis predicted more severe disease outcome, including need for immunosuppressive or biologic therapy or surgery, in both paediatric- and elderly-onset UC.

International audience; Objective Natural history of paediatric-onset ulcerative proctitis (UP) is poorly described. Our aim was to describe the phenotype and disease course of incident UP in a population-based study of paediatric-onset UC.Patients and methods All patients with UC diagnosed 2 years have been extracted from a population-based registry. UC location was defined according to the Paris classification. Cumulative risks for use of immunosuppressants (IS), anti-tumour necrosis factor alpha (TNF-α) therapy, colonic extension and colectomy were described using Kaplan-Meier method. Risk factors for colonic extension were assessed using Cox proportional hazards models.Results 158 patients with paediatric-onset UC (91 females) with a median age at diagnosis of 14.5 years (Q1: 11.4–Q3: 16.1) have been identified and followed during a median of 11.4 years (8.2–15.8). Among them, 25% had UP (E1) at diagnosis and 49% of them presented a colonic extension at maximal follow-up. In these children, the cumulative risk for colonic extension was 10% at 1 year, 45% at 5 years and 52% at 10 years. No parameter at diagnosis was associated with colonic extension in the UP (E1 group). IS use was significantly lower in patients with UP than in those with E2, E3 or E4 location (p=0.049). For the UP cohort, the cumulative risk for colectomy was 3% at 1 year, 10% at 5 years, 13% at 10 years and 13% at 15 years. Risks for colonic extension, treatment with anti-TNF-α and colectomy did not differ between the E1 group and the E2–E3–E4 group.Conclusions UP is frequent in paediatric-onset UC and should not be considered as a minor disease. Compared with more extensive UC locations, risks for colonic extension, anti-TNF-α therapy and colectomy were similar in UP, whereas the risk for use of IM was lower.

International audience; Background and Aims: Infliximab and adalimumab are increasingly used to prevent postoperative recurrence in Crohn's disease patients. The impact of previous exposure to one or more anti-tumour necrosis factor [TNF] agents before surgery on the efficacy of anti-TNF therapy on postoperative recurrence is unknown. Methods: We performed a retrospective analysis of Crohn's disease patients who underwent surgical bowel resection with anastomosis and prophylactic treatment with anti-TNF therapy between January 2005 and June 2013. Results: A total of 57 consecutive Crohn's disease patients with bowel resection and anastomosis followed by prophylactic treatment with anti-TNF were included; 21 [37%] and 24 [42%] patients had a previous exposure to one and more than one anti-TNF agents, respectively; 39 patients [68%] had a surveillance colonoscopy. Cumulative rates of postoperative endoscopic recurrence at 2 years were 45.5% [26.6-69.6%] in patients exposed to two or more anti-TNFα as compared with 29.1% [11.5-48.1%] in patients exposed to one or to zero anti-TNFα before surgery [p = 0.07]. Cumulative rates of clinical recurrence at 1 year were 21.6% [9.6-44.4%] in patients exposed to two or more anti-TNFα as compared with 6.9% [1.8-25.1%] in patients exposed to zero or one anti-TNFα before surgery [p = 0.02]. Multivariable analysis identified smoking and previous exposure to two or more anti-TNFα as risk factors for Crohn's disease clinical or endoscopic postoperative recurrence (hazard ratio [HR] = 3.17; 95% confidence interval [CI]: 1.3-7.8, p = 0.01 and HR = 4.2; 95% CI: 1.8-10.2, p = 0.001, respectively). Conclusions: Previous exposure to two or more anti-TNF agents was associated with a higher risk of postoperative recurrence in Crohn's disease patients.

Ileoanal anastomoses (J-pouches) are an alternative to permanent ostomy. The functional outcomes associated with the use of J-pouches are usually good, but continence disorders persist in a significant number of cases and have a negative impact on quality of life. The aim of this study was to assess the efficacy of sacral nerve stimulation (SNS) for poor functional results after J-pouch ileoanal anastomosis.Patients suffering from severe fecal incontinence (FI) following coloproctectomy underwent a staged implant SNS procedure. Demographic data and functional results for FI episodes, urgencies per week, frequency of stools, ability to defer defecation, and Wexner scores were obtained at specified intervals. Patients also completed quality-of-life assessments.Four female patients were included in this analysis. All 4 experienced active and passive FI at baseline and subsequently underwent test stimulation with a 75 % success rate. Three received definitive implants. These 3 patients experienced improvement in functional outcomes at 1, 3, and 6 month assessments. Improvements in quality of life were also noted.Our preliminary study suggests that SNS is effective for the treatment of poor functional results following J-pouch ileoanal anastomosis; however, larger studies with long-term follow-up are needed for confirmation of our findings.

Epidemiological evidences suggested that 5-aminosalicylic acid (5-ASA) therapy may prevent the development of colorectal cancer in inflammatory bowel disease patients. Our aim is to investigate whether peroxisome proliferator-activated receptor-γ (PPARγ) mediates the antineoplastic effects of 5-ASA. HT-29 and Caco-2 cells were treated by 5-ASA, rosiglitazone (PPARγ ligand) or etoposide (anticarcinogenic drug). Epithelial cell growth, proliferation and apoptosis were assessed by cell count, Ki-67 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. The antineoplastic effect of 5-ASA was evaluated in a xenograft tumor model in SCID mice and in azoxymethane (AOM)-induced colon carcinogenesis in A/JOlaHsd mice. The role of PPARγ was examined by administration of PPARγ antagonist, GW9662 and in PPAR knockdown cells. Compared with untreated cells, treatment of HT-29 cells by 5-ASA inhibited significantly cell growth and cell proliferation (respectively, 60% and 63%) and induced apoptosis in 75% of cells. These effects were abolished by co-treatment with GW9662 and blunted in PPAR knockdown cells. Contrarily to etoposide, similar inhibitory effects of GW9662 were obtained in HT-29 cells treated with rosiglitazone. In the xenograft model, GW9662 abolished the therapeutic effect of 5-ASA, which decreased tumor weight and volume by 80% in SCID mice compared with untreated mice. In A/JOlaHsd mice, 5-ASA suppressed colon carcinogenesis by decreasing the number of aberrant crypt foci (75%) and aberrant crypts (22%) induced by AOM treatment with an absence of 5-ASA response after GW9662 administration. In conclusion, 5-ASA exerts potent antineoplastic effects that are mediated through PPARγ. These data provide new rational for designing more effective and safe antineoplastic PPARγ ligands with topical effects.

Background & Aims Some women with inflammatory bowel disease require therapy with tumor necrosis factor (TNF) antagonists during pregnancy. It is not clear whether these drugs are transferred to the fetus via the placenta and then cleared, or whether structurally different TNF antagonists have different rates of transfer. Methods We studied 31 pregnant women with inflammatory bowel disease receiving infliximab (IFX, n=11), adalimumab (ADA, n=10), or certolizumab (CZP, n=10). Serum concentrations of the drugs were measured at birth in the mother, infant, and in cord blood, and then monthly in the infant until the drugs were undetectable. Drug concentrations in the cord and the infant at birth were compared with those of the mother. Results Concentrations of IFX and ADA, but not CZP, were higher in infants at birth and their cords than in their mothers. The levels of CZP in infants and their cords were less than 2 μg/mL. The median level of IFX in the cord was 160% that of the mother, the median level of ADA in the cord was 153% that of the mother, and the median level of CZP in the cord was 3.9% that of the mother. IFX and ADA could be detected in the infants for as long as 6 months. No congenital anomalies or serious complications were reported. Conclusions The TNF antagonists IFX and ADA are transferred across the placenta and can be detected in infants at birth; the drugs were detected in infants up to 6 months after birth. CZP has the lowest level of placental transfer, based on levels measured in cords and infants at birth, of the drugs tested.

Resume Introduction Un troisieme Plan Alzheimer et maladies apparentees (PA) comprenant un volet Recherche detaille a ete mis en œuvre de 2008 a 2013. Le but de ce travail a ete d’evaluer l’impact du PA sur la production d’articles originaux concernant la maladie d’Alzheimer et maladies apparentees (MA) avant (2004–2008) et apres (2009–2013) sa mise en place. Methodes Le nombre et le classement base sur le facteur d’impact (FI) des articles originaux produits par les 27 centres hospitalo-universitaires (CHU) de Metropole ont ete evalues grâce aux donnees du Systeme d’interrogation, de gestion et d’analyse des publications scientifiques (SIGAPS) utilise pour attribuer une partie des credits de Missions d’enseignement, de recherche, de reference et d’innovation (MERRI). La production scientifique relative a la MA a ete comparee a celle concernant 4 pathologies controles, 2 neurologiques (accidents vasculaires cerebraux, et maladie de Parkinson) et 2 autres (diabete et sida). La production a ete mesuree par centre hospitalo-universitaire (CHU) et par inter-regions selon 7 Groupements interregionaux de recherche clinique et d’innovation (GIRCI) en calculant leurs indices de specialisation (IS). Resultats Le nombre d’articles sur la MA a augmente de 1277 a 1972 (+ 54,4 %), le score SIGAPS de 18 038 a 29 309 (+ 62,5 %) et le nombre d’articles classes A et B (correspondant aux 25 % des meilleures revues de la specialite) de 430 a 846 (+ 114,1 %). Ces indicateurs ont augmente de la meme maniere pour la MA et les AVC, alors que pour les 3 autres pathologies, l’evolution a ete variable : stagnation a un haut niveau pour la maladie de Parkinson et le sida et augmentation pour le diabete (+ 15,5 %). Les IS etaient > 1 pour les 3 pathologies neurologiques dont la MA dans le Nord-Ouest et le Sud-Ouest outre-mer (SOOM). Les IS des CHU sur la MA variaient peu entre les 2 periodes, 4 etablissements ayant a la fois une production et un IS eleves : Toulouse, Bordeaux, Montpellier et Lille. Conclusion La production et la qualite des articles originaux sur la MA par les CHU ont augmente apres la mise en place du PA en 2008. Determiner si cette augmentation est en rapport avec l’application du volet recherche du PA reste a confirmer. La production sur la MA etait inegalement repartie sur le territoire francais et les etablissements qui avaient deja une recherche active avant la mise en place d’un PA renforcaient celle-ci apres. Enfin, ce travail illustre l’utilisation strategique qui peut etre faite de SIGAPS au-dela de son utilisation comme outil de financement.

Introduction Les patients atteints d’un cancer du poumon, en traitement therapeutique actif par chimiotherapie et/ou par chirurgie d’exerese tumorale, sont a risque eleve de denutrition. Nous avons mis en place une evaluation nutritionnelle a la prise en charge (PEC) initiale et un suivi nutritionnel tout au long du parcours de soins en cancerologie. Cette etude a pour objectif d’evaluer la PEC nutritionnelle des patients ( Fig. 1 ). Methodes Sur la periode de janvier 2009 a decembre 2012, ont ete etudies les patients ayant necessite d’une PEC dietetique dans les services de chirurgie thoracique et pneumologie oncothoracique (chirurgie d’exerese et chimiotherapie). Apres evaluation initiale systematique, cette PEC etait assuree a chaque sejour du patient et tout au long de son parcours de soins. Resultats Parmi les 51 patients etudies, 15 ont beneficie d’une chimiotherapie neoadjuvante suivie d’une chirurgie d’exerese et 36 etaient traites par chirurgie d’exerese puis chimiotherapie adjuvante. La proportion du type de chirurgie recu est la suivante, lobectomie (37 %) vs pleurectomie (33 %) vs segmentectomie (13 %) vs pneumonectomie (8,5 %) vs pleuropneumonectomie (8,5 %). Pour la population etudiee, l’âge moyen est de 59 ans, poids moyen est de 71 kg, avec majoritairement des hommes (73 %). La duree du suivi dietetique etait de 422 jours (28–1341) avec une moyenne de 7 cycles de chimiotherapie (1–27). La duree du traitement (chirurgie/chimiotherapie) etait de 125 jours (28–821). Tous les patients ont beneficies d’un conseil dietetique personnalise. Les PEC proposees dependaient du bilan nutritionnel realise. L’acceptation du patient au support nutritionnel variait entre le debut et la fin du parcours de soins, passant de 96 % a 84 % pour la complementation orale (CO) et de 33 % a 64 % pour la nutrition enterale (NE). La mise en place de la CO diminuait de 55 % a 49 % et la NE augmentait de 12 % a 22 % entre le debut et la fin du parcours de soins. Conclusion La coordination dietetique en cancerologie pulmonaire permet d’assurer un suivi optimal du patient tout au long de son parcours de soins. Au terme d’une PEC lourdes associant chirurgie et chimiotherapie, tous les parametres nutritionnels anthropometriques, biologiques et fonctionnels restent stables. Il semble que l’acceptation de la CO diminue au cours du temps tandis que celle de la NE s’ameliore. L’organisation de la PEC dietetique a contribue a l’implication des acteurs medicaux et paramedicaux dans la PEC nutritionnelle du patient.

Aliment Pharmacol Ther 2011; 33: 1133–1142 Summary Background Crohn’s disease incidence rates have stabilised in industrialised countries since the 1980s. Conversely, a continuing increase in childhood-onset Crohn’s disease incidence has been reported. Aim To confirm trends in inflammatory bowel disease (IBD) incidence in northern France over an extended time period (1988–2007) with a focus on childhood-onset Crohn’s disease. Methods The IBD patients recorded in the EPIMAD registry between 1988 and 2007 were included. Standardised incidence rates were calculated for Crohn’s disease and ulcerative colitis in the entire population, and separately according to age. Evolution of phenotypes at diagnosis was also studied. Results A total of 12 084 incident IBD cases (7428 Crohn’s disease and 4656 ulcerative colitis) were recorded. Crohn’s disease incidence rates increased from 5.2 cases/100 000 persons in 1988–1990 to 6.7 in 2006–2007 (+29%), stabilising after a peak at 7.1 in 1997–1999. Crohn’s disease incidence rates in the 10–19-year age category increased by 71%, from 6.5 (1988–1990) to 11.1 (2006–2007). The frequency of initial ileo-colonic localisation increased from 52.9% in 1988–1990 to 68.6% in 2006–2007 (P

Background. Although diosmectite has demonstrated efficacy in the treatment of acute watery diarrhoea in children, its efficacy in adults still needs to be assessed. The objective of this study was therefore to assess the efficacy of diosmectite on the time to recovery in adults with acute diarrhoea.Methods. A total of 346 adults with at least three watery stools per day over a period of less than 48 hours were prospectively randomized to diosmectite (6 g tid) or placebo during four days. The primary endpoint was time to diarrhoea recovery.Results. In the intention-to-treat population, median time to recovery was 53.8 hours (range [3.7–167.3]) with diosmectite (n=166) versus 69.0 hours [2.2–165.2] with placebo, (n=163;P=.029), which corresponds to a difference of 15.2 hours. Diosmectite was well tolerated.Conclusion. Diosmectite at 6 g tid was well tolerated and reduced the time to recovery of acute watery diarrhoea episode in a clinically relevant manner.

Background & Aims Little is known about the magnitude of the risk of anal and rectal cancer in patients with anal and/or perineal Crohn's disease. We aimed to assess the risk of anal and rectal cancer in patients with Crohn's perianal disease followed up in the Cancers Et Surrisque Associe aux Maladies Inflammatoires Intestinales En France (CESAME) cohort. Methods We collected data from 19,486 patients with inflammatory bowel disease (IBD) enrolled in the observational CESAME study in France, from May 2004 through June 2005; 14.9% of participants had past or current anal and/or perianal Crohn's disease. Subjects were followed up for a median time of 35 months (interquartile range, 29–40 mo). To identify risk factors for anal cancer in the total CESAME population, we performed a case-control study in which participants were matched for age and sex. Results Among the total IBD population, 8 patients developed anal cancer and 14 patients developed rectal cancer. In the subgroup of 2911 patients with past or current anal and/or perianal Crohn's lesions at cohort entry, 2 developed anal squamous-cell carcinoma, 3 developed perianal fistula–related adenocarcinoma, and 6 developed rectal cancer. The corresponding incidence rates were 0.26 per 1000 patient-years for anal squamous-cell carcinoma, 0.38 per 1000 patient-years for perianal fistula–related adenocarcinoma, and 0.77 per 1000 patient-years for rectal cancer. Among the 16,575 patients with ulcerative colitis or Crohn's disease without anal or perianal lesions, the incidence rate of anal cancer was 0.08 per 1000 patient-years and of rectal cancer was 0.21 per 1000 patient-years. Among factors tested by univariate conditional regression (IBD subtype, disease duration, exposure to immune-suppressive therapy, presence of past or current anal and/or perianal lesions), the presence of past or current anal and/or perianal lesions at cohort entry was the only factor significantly associated with development of anal cancer (odds ratio, 11.2; 95% CI, 1.18-551.51; P = .03). Conclusions In an analysis of data from the CESAME cohort in France, patients with anal and/or perianal Crohn's disease have a high risk of anal cancer, including perianal fistula–related cancer, and a high risk of rectal cancer.

Resume La gastroenterite a eosinophiles est une maladie rare d’etiologie inconnue, caracterisee par une infiltration primitive du tube digestif par des polynucleaires eosinophiles. L’origine allergique de la gastroenterite a eosinophiles reste controversee, un terrain allergique avec antecedents personnels ou familiaux n’etant present que dans la moitie des cas. Elle est responsable de symptomes digestifs varies qui dependent de la profondeur de l’infiltration dans la paroi digestive et du segment intestinal atteint. Son diagnostic est difficile necessitant l’elimination d’autres causes d’eosinophilie digestive secondaire telles que les parasitoses intestinales, le syndrome hypereosinophilique essentiel, certains medicaments et les neoplasies. Son traitement repose essentiellement sur les corticoides utilises par voie orale en cure courte. Son evolution est benigne avec une absence de recidive apres l’episode initial dans la majorite des cas. Cependant un certains nombre de malades presentent un profil evolutif plus complexe marque par des recidives imprevisibles, sensibles aux corticoides ou par une maladie chronique corticodependante pouvant necessiter un traitement de fond par antihistaminiques ou immunosuppresseurs.

Background: Tumor necrosis factor is an adipocytokine possessing a well-established lipolytic effect. In Crohn’s disease (CD) patients, infliximab therapy may thus result in visceral fat accumulation, which is associated with an increased risk of metabolic syndrome. Methods: A total of 132 CD patients were investigated. In a first prospective study, magnetic resonance imaging (MRI) quantification of subcutaneous and visceral abdominal fat was performed before and 8 weeks after initiation of infliximab induction therapy (5 mg/kg at weeks 0, 2, and 6) in 21 responding patients treated for perianal disease. In a second prospective study, fasting glycemia, glycated hemoglobin (HbA1c), HDL, LDL, and total cholesterol and triglyceride levels were assessed in 111 responding patients receiving infliximab infusions every 8 weeks, with a mean follow-up of 41 weeks. Results: A significant homogeneous 18% increase in total abdominal fat was observed in the 21 CD patients after infliximab induction therapy (P ¼ 0.027), independently of body mass index evolution. Infliximab maintenance therapy was associated with a decrease in glycemia (P < 0.0001) and HbA1c (P ¼ 0.0005) concentrations, together with an increase in both total cholesterol (P ¼ 0.02) and HDL cholesterol (P ¼ 0.008) concentrations. All glycemic and lipid parameters remained within the normal range throughout the study. Conclusions: Infliximab induction therapy is associated with a significant increase in abdominal fat tissue in CD patients. Infliximab maintenance therapy has no deleterious effects on lipid profile and is accompanied by a decrease in glycemia and HbA1c concentrations, probably by reversing the impairment of tumor necrosis factor-induced insulin-mediated glucose uptake. (Inflamm Bowel Dis 2009;15:1476–1484)

Pathophysiology of inflammatory bowel diseases depends on the interaction between genetic susceptibility and environmental factors leading to a deregulated immune intestinal response resulting in bowel lesions. Epidemiologic variations of inflammatory bowel diseases with time (incidence, prevalence) and space suggest a role for risk environmental factors, but so far only smoking habits and appendectomy have been identified as influencing the risk of occurrence and the course of the diseases. Studies of monozygotic and dizygotic twins and the existence of familial aggregation are strong evidence for an important, but not exclusive, role for genetic susceptibility. Since the discovery of NOD2/CARD15 mutations, numerous genes have been associated with inflammatory bowel diseases, some of them involved in the regulation of innate immunity and cellular clearance of infectious agents (autophagy). Thus, new hypothesis include a key role of mucosal human microbiota which could be partly influenced by environmental factors generated by modern life. The improvement of life hygiene, the change of food composition and habits, the industrial pollution in developed countries, may influence, directly or by the way of modifying intestinal human microbiota, inflammatory bowel diseases risk occurrence.

Background & Aims: The natural history of pediatric Crohn's disease and risk factors necessitating surgery have not been thoroughly described. Methods: In a geographically derived incidence cohort diagnosed from 1988 to 2002, we identified 404 Crohn's disease patients (ages, 0–17 years at diagnosis) with a follow-up time ≥2 years. Results: Median follow-up time was 84 months (range, 52–124 months). The most frequent disease location at diagnosis was the terminal ileum/colon (63%). Follow-up was characterized by disease extension in 31% of children. Complicated behavior was observed in 29% of children at diagnosis and 59% at follow-up. Kaplan–Meier survival estimates of the cumulative incidence of surgery were 20% at 3 years and 34% at 5 years from diagnosis. Multivariate Cox models showed that both structuring behavior at diagnosis (hazard ratio [HR], 2.54; 95% confidence interval [CI]: 1.58–4.01) and treatment with corticosteroids (HR, 2.98; 95% CI: 1.64–5.41) were associated with increased risk for surgery, whereas treatment with azathioprine (HR, 0.51; 95% CI: 0.33–0.78) was associated with decreased risk. Azathioprine was introduced earlier in the course of disease in patients not undergoing surgery than in patients requiring surgery. Conclusions: Pediatric Crohn's disease was characterized by frequent occurrence, with time, of a severe phenotype with extensive, complicated disease. Immunosuppressive therapy may improve the natural history of this disease and decrease the need for performing surgery.

To determine in a noninferiority study whether mesalamine foam is as effective as mesalamine liquid enema for inducing clinical remission in patients with active left-sided ulcerative colitis (UC). In a multicenter investigator-blind trial, 375 patients with mild-to-moderate UC were randomized to receive mesalamine foam 1 g/80 mL/day or mesalamine liquid enema 1 g/100 mL/day for 4 wk (W). Inclusion criteria were: disease extension at least 5 cm from anorectal junction and not above splenic flexure and Clinical Activity Index (CAI) 1-4 > or = 4. Primary end point was clinical remission at W4 defined as a CAI 1-4

Background: Recently we published an analysis of environmental factors in familial Crohn's disease (CD) in Belgium. The aim of the current study was to assess pedigrees and sibships, temporal relationships among cases, and family circumstances relevant to the frequency or onset of CD. Study: Twenty-one families with 3 or more affected first-degree relatives were studied. Seventy-four patients with CD and 84 unaffected family members were interviewed together at the parental home, with the aid of a 176 item questionnaire. Pedigrees were constructed establishing which family members had the disease and their relationships within sibships. Dates of onset of disease, validation of first symptoms and circumstances potentially relevant to the onset and distribution of disease within families were among the data documented during the interviews. Sequence of disease within families, consecutive versus nonconsecutive sequence of disease within sibships, and temporal relationships among cases were tabulated. Results: In 12 of the 21 families CD occurred in a parent before CD in any children. Five affected fathers preceded 9 affected children; 7 affected mothers preceded 10 affected children. First borns were affected more frequently. Within sibships there were 21 instances (36%) when an affected sibling was consecutive in birth order with an affected sibling. When a parent had CD before the birth of the first child the "exposure interval" to CD in the children was longer (mean 22.4 y) than when the parent developed CD after the child was born (mean 11.8 y). Conclusions: The clusterings of CD within sibships and in time suggest that there is a contagious element in the etiology of CD.

Inflammatory bowel diseases (IBD) are a public health problem in industrialized countries, where 1 in 1000 people are affected Most patients are young adults. The incidence of IBD has increased considerably in western countries since the second world war but is beginning to level off. On the other hand, the incidence is still rising in low-incidence areas such as Eastern Europe, Asia and developing countries. Differences in incidence rates across age, time, and geographic areas suggest that environmental factors are involved in IBD, but only cigarette smoking and appendectomy have consistently been identified as risk factors. An important role of genetic factors in IBD was first suggested by epidemiological studies showing familial aggregation of IBD and by twin studies. In 2001, the first CD susceptibility gene, NOD2/CARD15 on chromosome 16, was characterized. Other susceptibility genes have since been located. Their identification should help to understand the complex interaction between the environment and the intestinal immune system.

The 24-hour intragastric pH of 12 patients with an acute duodenal ulcer was recorded with the aim of comparing the effects of two different times of administration of 300 mg ranitidine: post evening meal, or bedtime. This double-blind crossover trial involved 3 centres. Twenty-four-hour gastric pH was measured under standard conditions (meals, time schedule) at the middle of each 14-day treatment period. The analysis was performed on the percentage of times spent at pH levels below 1.5, 2, 3 and 4 for different periods and for the total 24 hours. During the whole day and night combined, as well as during the afternoon (12.00 hours-19.00 hours), there was no difference between the 2 regimens regardless of the pH profile studied. During the morning (07.30 hours-12.00 hours), the time spent below pH 1.5 and 2 was less when the drug was taken at bedtime (P less than 0.05). In contrast, during the whole night (19.00 hours-07.30 hours) the percentage of time spent below pH 1.5, 2 and 3 was significantly less when the drug was taken at post evening meal (P less than 0.05). These results show that in patients with acute duodenal ulcer, 300 mg ranitidine administered at the end of the evening meal provides better control of nocturnal acidity than administration at bedtime and hence is suggested for optimization of therapeutic efficacy.

A third Alzheimer and related diseases plan (AP), including a detailed research part has been implemented from 2008 to 2013. The aim of this study was to assess the AP impact on the original articles production concerning Alzheimer and related disease (AD) before (2004-2008) and after its implementation (2009-2013).Number and impact factor (IF) based ranking of original articles coming from French University Hospitals (CHU) have been assessed using the data provided by the SIGAPS bibliometric software used so far for calculating allocation of the governmental medical research funding (MERRI). Scientific production on AD has been compared to four other control pathologies: 2 neurologic (stroke and Parkinson disease) and 2 non-neurologic (diabetes and AIDS). Publication trends of the 27 CHU and of the 7 Interregional grouping of clinical research and innovation (GIRCI) have been analyzed using specialization indices (SI).The number of AD articles increased from 1277 to 1972 (+54.4 %) as well as SIGAPS score from 18,038 to 29,309 (+62.5 %). Meanwhile number of articles rated A and B (published in the 25 % best journals of the specialty) increased from 430 to 846 (+114.1 %). The figures for these indicators evolved similarly for AD and stroke while quite differently for the 3 other diseases: plateauing at a high level for Parkinson disease and AIDS and modestly increasing for diabetes. SI was1 for the 3 neurologic diseases, including AD in North-Western and South-West GIRCI. SI of CHU on AD did not vary before and after AP implementation, 4 CHU having both a production and an SI at a high level: Toulouse, Bordeaux, Montpellier and Lille.The number and "quality" of original articles on AD production by the CHU increased after the AP starting of AP initiation in 2008. Whether or not this was directly due to the financial support provided by the AP remains to be determined. The scientific production on AD was unequally distributed throughout the country, the CHU being already strongly involved in AD research before the AP reinforced their commitment after. This work illustrates the potential implication of SIGAPS as a strategic tool for research policy.

This article has an accompanying continuing medical education activity on page e130 (https://www.sciencedirect.com/science/article/pii/S1542356515008320). Learning Objective–Upon completion of this activity, successful learners will be able to discuss the implication of vaccination and environmental factors in the development of inflammatory bowel disease.; International audience; BACKGROUND & AIMS:Environmental factors may play a key role in the pathogenesis of inflammatory bowel disease (IBD). Whether vaccination is associated causally with IBD is controversial. We performed a meta-analysis of case-control and cohort studies on the association between vaccination and the risk for IBD.METHODS:Studies and abstracts investigating the relationship between vaccination and subsequent risk for developing IBD were reviewed. Childhood or adult immunizations with any vaccine type, at any dose, and with any vaccine schedule were used as inclusion criteria.RESULTS:Eleven studies were included in the systematic review and meta-analysis: 8 case-control studies and 3 cohort studies. Studied vaccines were bacille Calmette-Guérin), vaccines against diphtheria, tetanus, smallpox, poliomyelitis, pertussis, H1N1, measles, rubella, mumps, and the combined measles, mumps, and rubella vaccine. Only a few details about vaccine type or route of administration were found in studies. Overall, there was no association between childhood immunization and risk for developing IBD: bacille Calmette-Guérin, relative risk (RR) of 1.04 (95% confidence interval [CI], 0.78-1.38), diphtheria, RR of 1.24 (95% CI, 0.80-1.94), tetanus, RR of 1.27 (95% CI, 0.77-2.08), smallpox, RR of 1.08 (95% CI, 0.70-1.67), poliomyelitis, RR of 1.79 (95% CI, 0.88-3.66), an measles containing vaccines, RR of 1.33 (95% CI, 0.31-5.80) in cohort studies, and RR of 0.85 (95% CI, 0.60-1.20) in case-control studies. Subgroup analysis for Crohn's disease (CD) and ulcerative colitis (UC) found an association between the poliomyelitis vaccine and risk for developing CD (RR, 2.28; 95% CI, 1.12-4.63) or UC (RR, 3.48; 95% CI, 1.2-9.71). The RR of developing IBD after H1N1 vaccination was 1.13 (95% CI, 0.97-1.32).CONCLUSIONS:Results of this meta-analysis show no evidence supporting an association between childhood immunization or H1N1 vaccination in adults and risk of developing IBD. The association between the poliomyelitis vaccine and the risk for CD or UC should be analyzed with caution because of study heterogeneity.

Background: Environmental exposures in early life have been implicated in the aetiology of inflammatory bowel disease. Objective: To examine environmental risk factors prior to the development of inflammatory bowel disease in a paediatric population based case control study. Methods: A total of 222 incident cases of Crohn’s disease and 60 incident cases of ulcerative colitis occurring before 17 years of age between January 1988 and December 1997 were matched with one control subject by sex, age, and geographical location. We recorded 140 study variables in a questionnaire that covered familial history of inflammatory bowel disease, events during the perinatal period, infant and child diet, vaccinations and childhood diseases, household amenities, and the family’s socioeconomic status. Results: In a multivariate model, familial history of inflammatory bowel disease (odds ratio (OR) 4.3 (95% confidence interval 2.3–8)), breast feeding (OR 2.1 (1.3–3.4)), bacille Calmette-Guerin vaccination (OR 3.6 (1.1–11.9)), and history of eczema (OR 2.1 (1–4.5)) were significant risk factors for Crohn’s disease whereas regular drinking of tap water was a protective factor (OR 0.56 (0.3–1)). Familial history of inflammatory bowel disease (OR 12.5 (2.2–71.4)), disease during pregnancy (OR 8.9 (1.5–52)), and bedroom sharing (OR 7.1 (1.9–27.4)) were risk factors for ulcerative colitis whereas appendicectomy was a protective factor (OR 0.06 (0.01–0.36)). Conclusions: While family history and appendicectomy are known risk factors, changes in risk based on domestic promiscuity, certain vaccinations, and dietary factors may provide new aetiological clues.

Background: Environmental factors are believed to trigger the onset of Crohn's disease (CD) in genetically susceptible individuals. The aim of this study was to assess environmental and familial factors that might be etiologically related to CD. Methods: Twenty-one families with 3 or more affected first-degree relatives were studied, together with 10 matched control families. There were 74 patients with CD, 84 unaffected family members, and 59 controls. Family members were interviewed together at the parental home. A 176-item questionnaire delved into first symptoms, childhood vaccinations and diseases, food items, potable water supplies, social activities, travel, pets, and home and surrounding environment. Questions were directed specifically for 2 time-frames, childhood until age 20 and a 10-year epoch before the onset of first symptoms within a family. The possible factors linked to disease were evaluated using univariate and multivariate logistic regression. Results: There were significantly more smokers in the patients and their relatives than in controls. Patients had more appendicitis during adolescence, ate less oats, rye, and bran than controls, and consumed more unpasteurized cheese. Patients drank significantly less tap water and more well water than controls. Clustering of cases in time occurred in 13 of the 21 affected families. Conclusions: The less frequent consumption of oats, rye, and bran and the more frequent eating of unpasteurized cheeses imitate potential dietary influences on gastrointestinal flora. More importantly, our data suggest that the drinking of well water represents an important risk factor for CD.

Summary Background: Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases. Aims : To evaluate the tolerance and efficacy of TG in patients with Crohn's disease, intolerant or resistant to AZA/MP. Methods : An open prospective study was made on Crohn's disease patients treated with TG. Intolerance to AZA/MP was defined as a reaction occurring within 1 month after introduction of AZA/MP, including pancreatitis, abdominal pain, fever, arthralgia, myalgia, cutaneous rash, fatigue, alopecia, hepatitis and digestive intolerance. Resistance to AZA/MP was defined as the persistence of activity after at least 3 months of AZA/MP therapy. Results : Forty-nine Crohn's disease patients (36 women, 13 men; intolerance: n = 39; resistance: n= 10) were treated with TG (20 mg/day). Clinical pancreatitis did not recur under TG. Five patients (10%) had to stop TG due to intolerant reactions observed 13–21 days after TG was started. No haematological side-effects were observed under TG. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79%, respectively, in the 40 patients with active disease at baseline. The probability of clinical relapse during maintenance TG therapy at 6 and 12 months was 29% and 53%, respectively, in the 28 patients in remission at baseline or who had achieved remission on TG. Conclusions : TG is a possible alternative treatment in Crohn's disease patients, intolerant (especially for pancreatitis) or resistant to AZA/MP.

Controlled ileal release budesonide and slow release mesalazine are both used to treat mild to moderate active Crohn's disease, although data show that budesonide is more effective in inducing remission. When comparing different treatment options, the effects of agents on health-related quality of life must be considered as well as efficacy. In this study, we sought to compare the effects of budesonide and mesalazine on the health-related quality of life of patients with active Crohn's disease.The study included 182 patients with Crohn's Disease Activity Index scores between 200 and 400. Patients were randomized in a double blind, double dummy, multicenter study to receive 9 mg of budesonide, once daily (n = 93), or 2 g of mesalazine, b.i.d. (n = 89), for 16 wk. Quality of life was assessed at baseline and after 2, 4, 8, 12, and 16 wk of treatment using the Psychological General Well-Being index. In addition, a physician's global evaluation was used to assess how symptoms affected patients' normal activities.Patients treated with budesonide experienced significantly greater improvement in Psychological General Well-Being scores than the group treated with mesalazine after 2, 8, 12, and 16 wk. All components of this index showed greater improvements in the budesonide-treated group than in the mesalazine group at 12 and 16 wk. The physician's global evaluation showed significantly greater improvements in the budesonide group than in the mesalazine group at all visits.Budesonide (9 mg once daily) improves health-related quality of life to a greater extent than mesalazine (2 g b.i.d.) in patients with mild to moderate active Crohn's disease.

BACKGROUND Benefits of recombinant human growth hormone (rhGH) alone or combined with glutamine in patients with intestinal failure because of short-bowel syndrome remain controversial. OBJECTIVE We explored effects of rhGH on whole-body protein metabolism in patients with short-bowel syndrome with intestinal failure (SBS-IF) to gain insight into its mechanism of action. DESIGN Eight stable hyperphagic patients with severe SBS-IF received, in a double-blind, randomized crossover study, low-dose rhGH (0.05 mg · kg⁻¹ · d⁻¹) and a placebo for two 3-wk periods. Leucine and glutamine kinetics under fasting and fed conditions, fat-free mass (FFM), and serum insulin were determined on the final day of each treatment. RESULTS rhGH increased FFM and nonoxidative leucine disposal (NOLD; an index of protein synthesis) (P < 0.02), whereas FFM and NOLD were correlated in the fed state (r = 0.81, P = 0.015). With rhGH administration, leucine release from protein breakdown (an index of proteolysis) decreased in the fed compared with fasting states (P = 0.012), which was not observed with the placebo. However, the fast-to-fed difference in leucine release from protein breakdown was not significantly different between rhGH and placebo (P = 0.093). With rhGH, the intestinal absorption of leucine and glutamine increased (P = 0.036) and correlated with serum insulin (r = 0.91, P = 0.002). rhGH increased glutamine de novo synthesis (P < 0.02) and plasma concentrations (P < 0.03) in both fasting and fed states. CONCLUSIONS In SBS-IF patients, feeding fails to decrease proteolysis in contrast to what is physiologically observed in healthy subjects. rhGH enhances FFM through the stimulation of protein synthesis and might decrease proteolysis in response to feeding. Improvements in de novo synthesis and intestinal absorption increase glutamine availability over the physiologic range, suggesting that beneficial effects of rhGH in hyperphagic patients might be achieved without glutamine supplementation.

The glucagon-like peptide 2 (GLP-2) is an intestinotrophic hormone with growth promoting and anti-inflammatory actions. However, the full biological functions of GLP-2 and the localization of its receptor (GLP-2R) remain controversial. Among cell lines tested, the expression of GLP-2R transcript was detected in human colonic myofibroblasts (CCD-18Co) and in primary culture of rat enteric nervous system but not in intestinal epithelial cell lines, lymphocytes, monocytes, or endothelial cells. Surprisingly, GLP-2R was expressed in murine (GLUTag), but not human (NCI-H716) enteroendocrine cells. The screening of GLP-2R mRNA in mice organs revealed an increasing gradient of GLP-2R toward the distal gut. An unexpected expression was detected in the mesenteric fat, mesenteric lymph nodes, bladder, spleen, and liver, particularly in hepatocytes. In two mice models of trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis, the colonic expression of GLP-2R mRNA was decreased by 60% compared with control mice. Also, GLP-2R mRNA was significantly downregulated in intestinal tissues of inflammatory bowel disease patients. Therapeutically, GLP-2 showed a weak restorative effect on intestinal inflammation during TNBS-induced colitis as assessed by macroscopic score and inflammatory markers. Finally, GLP-2 treatment accelerated mouse liver regeneration following partial hepatectomy as assessed by histological and molecular analyses. In conclusion, the limited therapeutic effect of GLP-2 on colonic inflammation dampens its utility in the management of severe inflammatory intestinal disorders. However, the role of GLP-2 in liver regeneration is a novelty that might introduce GLP-2 into the management of liver diseases and emphasizes on the importance of elucidating other extraintestinal functions of GLP-2.

International audience; Data on the natural history of elderly-onset inflammatory bowel disease (IBD) are scarce.METHODS:In a French population-based cohort we identified 841 IBD patients >60 years of age at diagnosis from 1988 to 2006, including 367 Crohn's disease (CD) and 472 ulcerative colitis (UC).RESULTS:Median age at diagnosis was similar for CD (70 years (IQR: 65-76)) and UC (69 years (64-74)). Median follow-up was 6 years (2-11) for both diseases. At diagnosis, in CD, pure colonic disease (65%) and inflammatory behaviour (78%) were the most frequent phenotype. At maximal follow-up digestive extension and complicated behaviour occurred in 8% and 9%, respectively. In UC, 29% of patients had proctitis, 45% left-sided and 26% extensive colitis without extension during follow-up in 84%. In CD cumulative probabilities of receiving corticosteroids (CSs), immunosuppressants (ISs) and anti tumor necrosis factor therapy were respectively 47%, 27% and 9% at 10 years. In UC cumulative probabilities of receiving CS and IS were 40% and 15%, respectively at 10 years. Cumulative probabilities of surgery at 1 year and 10 years were 18% and 32%, respectively in CD and 4% and 8%, respectively in UC. In CD complicated behaviour at diagnosis (HR: 2.6; 95% CI 1.5 to 4.6) was associated with an increased risk for surgery while CS was associated with a decreased risk (HR: 0.5; 0.3 to 0.8). In UC CS was associated with an increased risk (HR: 2.2; 1.1 to 4.6) for colectomy.CONCLUSIONS:Clinical course is mild in elderly-onset IBD patients. This information would need to be taken into account by physicians when therapeutic strategies are established.

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.

Une vascularite localisee pourrait rendre compte des lesions initiales de recidive de la maladie de Crohn apres chirurgie. Cette etude avait pour but d'etudier par endoscopie de fluorescence la microcirculation muqueuse de l'ileon pre-anastomotique, chez des malades ayant eu une resection ileocolique droite pour une maladie de Crohn, relativement a la recidive endoscopique. Dix malades ont ete inclus dans un protocole prospectif de suivi endoscopique un an apres chirurgie. L'ileon preanastomotique etait examine en endoscopie standard et en fluorescence. Des biopsies etaient realisees en zones fluorescentes et nonfluorescentes pour rechercher des lesions inflammatoires et vasculaires en microscopie optique et en immunohistochimie. Une recidive endoscopique a ete observee chez huit malades. En fluorescence, la muqueuse prenait un aspect heterogene avec a) des zones fluorescentes correspondant aux lesions aphtoides, b) des anneaux fluorescents centrant des zones sombres correspondant a des ulceres plus profonds « en carte de geographie » et c) des petits spots brillants disperses sur la muqueuse normale en endoscopie standard. L'examen histologique des biopsies des spots fluorescents a revele sur 79% d'entre elles des alterations inflammatoires interessant les vaisseaux. La recidive endoscopique de la maladie de Crohn est associee a des aspects fluorescents qui peuvent rendre compte soit d'une vasodilatation associee a une inflammation soit d'une authentique atteinte de la microvascularisation. L'etude histologique suggere que les lesions vasculaires sont plutot secondaires a l'atteinte inflammatoire.

OBJECTIVE: A 16-wk, placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn’s disease. The long-term efficacy and safety of this antimetabolite drug, however, are not yet well established and are assessed in this study. METHODS: A total of 49 patients with Crohn’s disease who were treated with methotrexate for ≥6 months were studied. All patients had been chronically treated with steroids; but at the time of initiation, only 27 were still on steroids. Of the 49 patients, 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure. Clinical remission was defined as a Harvey-Bradshaw index of RESULTS: In all, 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months (range, 7–59 months). In these patients the probabilities of relapse were 29%, 41%, and 48% at 1, 2, and 3 yr, respectively. A higher rate of relapse was observed in women and in patients with ileocolitis. Adverse reactions were recorded in 24 patients, requiring discontinuation of methotrexate in five. A liver biopsy was performed in 11 patients; a mild steatosis was found in five, a slight dilation of the sinusoids in one, a granulomatous hepatitis with a mild portal fibrosis in one, and a slight periportal fibrosis in one patient. CONCLUSIONS: This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn’s disease, with side effects that are usually only moderate.

Since its definition in 1932, it has been recognized that Crohn’s disease contains elements that might be the result of microbial processes in the gut [I-41. These include evidence of onset in the Peyer’s patches and in lymphoid aggregates of the colon, ulcerations, microabscesses, fissures, fistulas, granulomas and lymphangitis. Aphthous ulcers in the intestine represent the earliest lesions, and we know that these occur in viral and bacterial infections. Crohn’s lesions occur in segments that suggest the distribution of Peyer’s patches. Ulcerations in colonic Crohn’s disease originate in the follicle-associated epithelium of colonic lymphoid nodules. Recent studies in animal models have led to the widespread belief that microbial constituents provide the antigenic stimulus in Crohn’s disease, and the most common hypothesis is that chronic inflammation results from an abnormal host immune response to normal luminal flora. Although present data do not convincingly incriminate a single, persistent pathogen as a universal cause of Crohn’s disease, this hypothesis should not be abandoned. Our current understanding of the complexity of the intestinal flora is very limited, and it is quite possible that one or more etiologic agents for Crohn’s disease exist but have not been detected. We will review in this note the infectious agents which have been implicated in the etiology of Crohn’s disease within the last few years. Mycobacteria The etiologic role of mycobacteria in Crohn’s disease has been a controversial issue for some time. In 1984, Chiodini et al recovered slow-growing Mycobacteriurn paratuberculosis from tissues of three patients with Crohn’s disease 151, and it was encouraging that other laboratories also recovered this organism, albeit rarely. However

Our goal was to determine the effect of transdermal nicotine on cytokine and mucin gene transcription in ulcerative colitis (UC). Sixty-four nonsmoking patients with active UC were randomly assigned to transdermal nicotine (maximum dose 22 mg/day) or placebo for 4 weeks. Clinical assessment and colonic mucosal biopsies were obtained at entry and after 4 weeks. Inflammatory and immunoregulatory cytokines were assessed by qualitative reverse transcriptase-polymerase chain reaction (RT-PCR). Based on this initial screen. IL-8 mRNA levels were measured by RT-competitive PCR. MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, and MUC6 mRNA concentrations were measured by quantitative dot blot analysis. Cytokine mRNA expression, except for IL-8, was similar in all patients. IL-8 mRNA levels were significantly decreased in the colonic mucosa of nicotine-treated patients who improved (p = 0.04). IL-8 mRNA values were similar before and after treatment in nonresponding nicotine-treated patients and in all placebo-treated patients. Mucin gene expression was similar in all patient groups. Beneficial effects of transdermal nicotine in active UC may result from decrease of IL-8 expression at the transcriptional level. Transdermal nicotine has no effect on mucin gene transcription.

Background & Aims: Abnormalities of fat in the mesentery including adipose tissue hypertrophy and fat wrapping have been long recognized on surgical specimens as characteristic features of Crohn's disease. However, the importance, origin, and significance of the mesenteric fat hypertrophy in this chronic inflammatory disease are unknown. Peroxisome proliferator–activated receptor γ (PPARγ) is a crucial factor involved in the homeostasis of adipose tissue, a major source of biologically active mediators. Methods: Intra-abdominal fat accumulation was quantified using a magnetic resonance imaging method in patients with Crohn's disease and controls. PPARγ and inflammatory cytokines synthesized by mesenteric adipose tissues were assessed by quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. Results: In vivo, patients with Crohn's disease have an important accumulation of intra-abdominal fat. This mesenteric obesity, present from the onset of the disease, is associated with overexpression of PPARγ and tumor necrosis factor (TNF)-α, synthesized, at least in part, by adipocytes. Conclusions: These results suggest that confined increased PPARγ mesenteric concentrations could lead to the mesenteric fat hypertrophy, which could actively participate through the synthesis of TNF-α in the inflammatory response. GASTROENTEROLOGY 1999;117:73-81

Background & Aims: Prevention of postoperative recurrence after resection for Crohn's disease (CD) would be of great clinical benefit. The efficacy of oral budesonide for prevention of endoscopic recurrence was evaluated in patients undergoing resection for ileal or ileocecal CD. Methods: Sixty-three patients received budesonide and 66 received placebo in a double-blind, randomized trial with parallel groups. Ileocolonoscopy, including biopsy, was performed after 3 and 12 months. Indications for surgery were fibrostenosis (78 patients), disease activity (41), and other reasons (10). Results: The frequency of endoscopic recurrence did not differ between the groups at 3 and 12 months. In patients with disease activity as indication for surgery, the endoscopic recurrence rate at the anastomosis was lower in the budesonide group at 3 months, although not significantly (21% vs. 47%; P = 0.11), and at 12 months (32% vs. 65%; P = 0.047). There was no such difference with respect to fibrostenosis as indication for surgery. No differences in adverse event patterns were found between the two groups. Conclusions: Oral budesonide, 6 mg daily, offered no benefit in prevention of endoscopic recurrence after surgery for ileal/ileocecal fibrostenotic CD but decreased the recurrence rate in patients who had undergone surgery for disease activity. GASTROENTEROLOGY 1999;116:294-300

Background Crohn's disease is often treated with glucocorticoids or mesalamine. We compared the efficacy and safety of controlled-ileal-release budesonide capsules and slow-release mesalamine tablets in patients with active Crohn's disease affecting the ileum, the ascending colon, or both. Methods In a double-blind, multicenter trial, we enrolled 182 patients with scores of 200 to 400 on the Crohn's Disease Activity Index (with higher scores indicating greater disease activity) and randomly assigned 93 to receive 9 mg of budesonide once daily and 89 to receive 2 g of mesalamine twice daily for 16 weeks. The primary efficacy variable was clinical remission, defined as a score of 150 or less on the Crohn's Disease Activity Index. Results In the analysis of all patients who received at least one dose of study drug, the rates of remission after 8 weeks of treatment were 69 percent in the budesonide group and 45 percent in the mesalamine group (P=0.001); the respective rates after 16 weeks of treatment were 62...

Anti-Saccharomyces cerevisiae mannan antibodies (ASCA) are associated with Crohn's disease. The aim of this study was to determine the prevalence of ASCA in families in which at least two members were affected with Crohn's disease.A total of 20 families including two (n=15) or more (n=5) patients with Crohn's disease were tested for ASCA with use of an ELISA method. Overall, 51 affected members, 66 healthy first degree relatives, and 163 healthy control subjects were studied.ASCA were detected in 35 of 51 (69%) patients with Crohn's disease and in 13 of 66 (20%) healthy relatives versus one of 163 healthy control subjects (p0.0001 and p0.001). ASCA-positive relatives were distributed in 12 of 20 families. ASCA were present in eight healthy parents and four healthy siblings. The prevalence of ASCA in relatives did not depend on the ASCA status of affected members.ASCA in 20% of healthy first degree relatives of patients with Crohn's disease suggest that these antibodies might be a subclinical marker for Crohn's disease in families. Whether ASCA reflect environmental or genetic factors or a combination of both is unknown.

Celiac disease (CD) and dermatitis herpetiformis (DH) are gluten-sensitive diseases with different clinical features that can initiate similar intestinal changes. The flat-destructive stage corresponds to severe lesions involving activated T-cells. However, other inflammatory cells such as eosinophils are also abundant. The mechanisms for the intestinal recruitment of eosinophils in patients with CD and DH remain unknown. Eosinophil recruitment and activation are induced in vitro by three main cytokines: interleukin-3 (IL-3), interleukin-5 (IL-5), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In this study, IL-3, IL-5, and GM-CSF were detected by immunohistochemistry in all patients with CD and DH but not in the control group. By ultrastructural immunogold staining, these three cytokines had the same subcellular localization in the granule matrix of eosinophils. This result suggests that eosinophils may be involved in the immune response at the flat-destructive stage of both CD and DH.

Digestive bacterial microflora play a major rolein the pathogenesis of Crohn's disease (CD). Bacterialenzyme activities, especially β-D-galactosidase,are decreased in fecal extracts from CD patients. We hypothesized that an alteration of thecolonic flora might be responsible for this decrease.Indeed, we demonstrate that β-D-galactosidaseproduction in supernates of anaerobic cultures wassignificantly (P < 0.01) reduced in feces from patientswith active Crohn's disease (N = 7), when compared tohealthy controls (N = 8). Therefore using X-gal andselective media, we enumerated bacteria able to releaseβ-D-galactosidase in feces from patients with active (N = 16) orquiescent disease (N = 5) and healthy controls (N = 14).Bifidobacteria numbers were significantly reduced inpatients (P < 0.01 for active; P < 0.02 forquiescent disease) whereas Bacteroides and Lactobacilli countsremained unchanged. β-D-Galactosidase activity andBifidobacteria counts were significantly correlated (P< 0.03). Bifidobacteria are regarded as beneficial for the host. The reduction in Bifidobacteriais responsible for decreased β-D-galactosidaseactivity. Thus oral administration of prebiotics thatpromote their growth might have potential therapeutic interest.

International audience; OBJECTIVE: To explore the risk of new or recurrent cancer among patients with IBD and previous cancer, exposed or not to immunosuppressants. DESIGN: Among the 17 047 patients of the CESAME prospective observational cohort who were enrolled from May 2004 to June 2005, and followed-up until December 2007, we identified 405 patients with cancer diagnosed previous to study entry. We calculated the rates of incident cancer in patients with or without previous cancer, and we assessed by survival analysis and nested case-control study the impact of immunosuppressants on the risk of incident new or recurrent cancer in patients with previous cancer. RESULTS: The rate of incident cancer was 21.1/1000 patient-years (PY) and 6.1/1000 PY in patients with and without previous cancer, respectively. The multivariate-adjusted HR of incident cancer between patients with and without previous cancer was 1.9 (95% CI 1.2 to 3.0, p=0.003). Among patients with previous cancer, the rates of new and recurrent cancers were, respectively, 13.2/1000 PY and 6.0/1000 PY in the 312 patients who were not taking immunosuppressant at the time of study entry, and 23.1/1000 PY and 3.9/1000 PY in the 93 patients treated with immunosuppressants at study entry. There was no significant association between the exposure to immunosuppressants and the risk of new or recurrent cancer. CONCLUSIONS: Patients with IBD with a history of cancer are at increased risk of developing any (new or recurrent) cancer, with a predominant incidence of new cancers. Treatment with immunosuppressants has no overall major impact per se on this risk.

The increasing incidence of inflammatory bowel diseases (IBDs) in developing countries has highlighted the critical role of environmental pollutants as causative factors in their pathophysiology. Despite its ubiquity and immune toxicity, the impact of aluminum in the gut is not known. This study aimed to evaluate the effects of environmentally relevant intoxication with aluminum in murine models of colitis and to explore the underlying mechanisms. Oral administration of aluminum worsened intestinal inflammation in mice with 2,4,6-trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis and chronic colitis in interleukin 10-negative (IL10(-/-)) mice. Aluminum increased the intensity and duration of macroscopic and histologic inflammation, colonic myeloperoxidase activity, inflammatory cytokines expression, and decreased the epithelial cell renewal compared with control animals. Under basal conditions, aluminum impaired intestinal barrier function. In vitro, aluminum induced granuloma formation and synergized with lipopolysaccharide to stimulate inflammatory cytokines expression by epithelial cells. Deleterious effects of aluminum on intestinal inflammation and mucosal repair strongly suggest that aluminum might be an environmental IBD risk factor.