No description available.

Les Maladies Inflammatoires Chroniques de l’Intestin (MICI) comprennent la maladie de Crohn (MC) et la rectocolite hémorragique (RCH). Ce sont des inflammations chroniques du tube digestif dont les causes sont inconnues. Une meilleure connaissance de leur épidémiologie pourrait orienter vers des pistes étiologiques. Jusqu’à la création du Registre EPIMAD en 1988, il n’existait en France aucune donnée d’incidence. Nous avons créé en 1988 une étude prospective d’incidence des MICI, reconnu «Registre» par l’Inserm et l’InVS en 1992. Le territoire couvert par Epimad comporte le Nord, le Pas-de-Calais, la Somme et la Seine-Maritime avec près de 6 millions d’habitants soit 9,3% de la population française. La collection des cas repose sur une collaboration multidisciplinaire incluant les gastroentérologues (GE) (libéraux, hospitaliers, adultes et pédiatres; n=262), les services d’Epidémiologie de Lille et Rouen, la plateforme d’aide méthodologique en Biostatistiques du CHRU de Lille et les Centres Hospitalo-Universitaires de Lille, Amiens et Rouen. Neuf enquêteurs se déplacent sur les lieux de consultation des GE et recueillent les informations nécessaires à la validation des diagnostics. Deux GE experts revoient chaque dossier indépendamment et posent le diagnostic final de MC ou RCH certaine, probable ou possible, de colite indéterminée, de colite aiguë ou de colite inclassée. Pour les cas atypiques et non classés, un suivi systématique est effectué pour le classement définitif (MICI ou non MICI). Un croisement des bases du Registre et des bases hospitalières est effectué une fois par an pour mesurer l’exhaustivité. 80% des cas incidents sont diagnostiqués par les GE libéraux, 13% par les GE des hôpitaux généraux et 7% par les GE universitaires. Entre 1988 et 2008, l’incidence moyenne des MICI était de 11,3/105 habitants (6,4 pour la MC, 4,4 pour la RCH et 0,5 pour IBDU). Pendant cette période, l’incidence de la MC a augmenté de 30% (100% chez l’adolescent) alors que celle de la RCH est restée stable. Le délai diagnostique médian était de 3 mois dans la MC et de 2 mois dans la RCH. Le pourcentage de patients ayant un diagnostic posé plus de 9 mois après l’apparition des symptômes a diminué avec le temps. La validité diagnostique dans les cas non classant d’emblée a été assurée par un suivi de 2 ans et a montré que seul l’âge < 40 ans était prédictif d’une évolution vers une MICI chez un patient présentant une colite aiguë. Nous avons aussi mis en évidence des présentations cliniques différentes en fonction de l’âge. Ainsi, chez l’adulte jeune, la MC est plus étendue que chez les sujets > 60 ans au diagnostic. Grâce à un nombre élevé de cas incidents, une hétérogénéité spatiale de l’incidence des MICI a été montrée dans les zones agricoles et suburbaines sans lien avec le niveau social des populations. En utilisant la méthode des statistiques de scan rajoutant la dimension temporelle à l’analyse spatiale, nous avons trouvé plusieurs clusters de sur et sous incidence constants dans le temps. Nos perspectives sont: 1) Poursuivre l’enregistrement des cas incidents et établir des données de prévalence; 2) Etudier les facteurs de risque environnementaux par des études d’épidémiologie analytique (corrélations écologiques, études cas témoins, études exposés-non exposés); 3) Etudier les facteurs de risque génétiques (fréquence des variants NOD2) dans la population du Registre; 4) Créer une étude prospective sur les paramètres prédictifs (profil génétique, profil métagénomique du microbiote intestinal, profil sérologique) de développer une MC dans une population de sujets à haut risque (sujets indemnes de MC âgés de 10 à 35 ans et appartenant à une famille multiplexe, à la descendance de formes conjugales ou à une paire de jumeaux discordants). Conclusions: EPIMAD est le plus gros Registre mondial sur les MICI en population générale, reconnu pour la qualité de ses travaux, rendu possible par la création d’un réseau-ville-hôpital unique. / Inflammatory Bowel Disease (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) are among the most serious and perplexing of digestive diseases. Their pathophysiology remains poorly understood. Geographic variations in the incidence of IBD could offer new clues about environmental risk factors. There were no data concerning the incidence of IBD in France. We created the first French prospective study on IBD incidence in 1988. This study became “Registre” recognized by Inserm and InVS in 1992. This prospective study was performed through all gastroenterologists (GE) (n=262) of the region of Nord, Pas-de-Calais, Somme and Seine-Maritime including near of 6 million of inhabitants corresponding to 9.3% of the whole French population. Collection of new cases is based on a close multidisciplinary collaboration including GE (whatever their practice), Epidemiology Unit of Hospital and University of Lille and Rouen, Biostatistics Unit of Lille Hospital and University and Academic Hospitals of Amiens, Lille and Rouen. Each GE referred patients consulting for the first time with clinical symptoms compatible with IBD. Data are collected by 9 interviewer practitioners present at the GE’s consulting room. Two independent experts GE assessed each case independently and made a final diagnosis of definite, probable, possible CD, UC or ulcerative proctitis (UP); Inflammatory Bowel Disease unclassifiable (IBDU); acute colitis or unspecified colitis. Possible cases of IBD, acute colitis and unspecified colitis are systematically followed-up and when a new event is recorded the chart is reviewed by the experts and a new final diagnosis is made. A control of the completeness collection is made each year by crossing data from Hospital Health databases. 80% of incident cases have been reported by private GE, 13% by general hospitals and 7% by academic centres. From 1988 to 2008 the mean annual incidence was 11.3/105 inhabitants for IBD including 6.4 for CD, 4.4 for UC and 0.5 for IBDU with a ratio CD/UC of 1.45. During this period CD incidence increased by 30% (100% in young adults) while that of UC remained stable. Valuable clinical information has been obtained; median time between onset of symptoms and diagnosis was 3 months in CD and 2 months in UC. The number of patients with a diagnosis delay > 9 months decreased over time. Age < 40 years at diagnosis was the only clinical predictor for subsequent IBD in patients with an initial diagnosis of acute colitis. Clinical presentation according to age at diagnosis may influence clinical course of IBD. In younger patients IBD had a more disabling course than in the elderly-onset IBD patients. Thanks to the large number of incident cases, we assessed spatial IBD incidence variation at the canton level and analyzed its association with a deprivation index. A spatial heterogeneity was found with a noteworthy predominance of CD in agricultural areas but no significant link with deprivation. We completed the spatial analysis using spatial scan statistics methods allowing revealing several time-constant (since 1988) clusters and other time-varying clusters. Perspectives: 1) To continue to record incident cases and establish prevalence data of IBD; 2) To study environmental risk factors using epidemiological analytic studies; 3) To study genetic risk factors establishing a geographic map of NOD2 variants in the EPIMAD’s area and 4) To assess the predictiveness of patient microbiota and host factors in a prospective, longitudinal study enrolling yet-healthy subjects at risk to develop CD (healthy patients aged 10-35 years and belonging to discordant twins, to offspring of IBD affected couples and to IBD multiplex families). In conclusion, since 1988, the EPIMAD registry has been recognized as a valuable tool for studies on genetic and environmental risk factors. It has also made it possible to reinforce networking between private practices, general and university hospitals at a regional level.

BACKGROUND: Inflammatory bowel disease (IBD) is a group of conditions characterized by chronic inflammation of the gastrointestinal (GI) tract. A new diagnosis of IBD in children and adolescents can have significant psychosocial effects on both the patient and the family. Child and parental coping strategies play a crucial role in the adjustment to IBD, especially within the first year of the diagnosis. AIMS: The primary aim of the study was to assess the stability of coping measures over time in children and parents following a new pediatric IBD diagnosis. The study also aimed to assess the impact of parental coping on parental healthcare resource utilization for children with newly diagnosed IBD, as well as the impact of parental coping on anxiety, depression, and quality of life in children with newly diagnosed IBD. METHODS: This was a prospective, longitudinal cohort study at Boston Children’s Hospital (BCH) that focused on children and adolescents with newly diagnosed IBD, as well as their parents. Patients and their parents were approached at the time they enrolled in the study and then again about 12 months later as part of a one-year follow-up. At both time points, they were asked to fill out various questionnaires about psychological functioning and answer other questions about medical care. RESULTS: The study identified and encountered 465 IBD patients, of which 126 were eligible for recruitment. There were 70 patients and families who signed a consent form for enrollment, 55 who fully or partially completed the questionnaires at baseline, and only 5 who also completed the questionnaires at follow-up. Due to the limited number of participants who completed the questionnaires at follow-up, no definitive conclusions could be drawn about the stability of coping measures over time. Parental anxiety, parental depression, frequent parental stress, and difficult parental stress were all found to be positively correlated with healthcare utilization and negatively correlated with the child’s quality of life. Parental anxiety, frequent parental stress, and difficult parental stress were all found to be positively correlated with the child’s anxiety. Parental depression, frequent parental stress, and difficult parental stress were all found to be positively correlated with the child’s depression. CONCLUSION: Preliminary findings suggest that poor parental coping leads to decreased child quality of life and increased healthcare utilization, child anxiety, and child depression. A larger sample size is needed to accurately evaluate the stability of coping measures over time. The next steps for this study involve further examination of the impact of parental coping and enrollment of more patients and families.

Murine small intestinal CD103+ dendritic cells (DCs) produce retinoic acid (RA) through retinaldehyde dehydrogenase (RALDH) activity, thereby inducing ‘gut-homing’ α4β7 and CCR9 on T cells they activate, enhancing TGF-β-mediated induction of Foxp3+ regulatory T cells and suppressing induction of pro-inflammatory TH17 cells. RALDH activity of CD103+ DCs is reduced in mouse models of inflammatory bowel disease (IBD) but the role of RALDH activity in human intestinal DCs in the pathogenesis of IBD is undefined. This project aimed to determine the influence of inflammation on RALDH activity of antigen presenting cell (APC) subsets including CD103+ DCs within human distal intestinal mucosa. RALDH activity was identified by Aldefluor assay in intestinal DCs (CD103+ and CD103- subsets) alongside ALDH1A2 expression in healthy controls. In contrast with mouse models, RALDH activity was not reduced in CD103+ DCs from IBD patients. An increased frequency of CD14+ macrophages (MФ) of IBD patients displayed ALDH1A1-associated RALDH activity compared with healthy controls. Blood CD14+ monocytes, putative precursors of intestinal CD14+ MФ, of healthy controls and IBD patients displayed ALDH1A1-associated RALDH activity indicating RALDH is systemically acquired by monocytes and upregulated within the mucosa of IBD patients, or alternatively that RALDH+ monocytes are selectively recruited in IBD. In vitro, inhibition of RA receptor-α signalling blocked GM-CSF-mediated differentiation of TNFα-producing pro-inflammatory RALDH+ CD14+ MФ from monocytes, consistent with enhanced RALDH activity of intestinal CD14+ MФ in IBD supporting a pro-inflammatory phenotype. Soluble intestinal mediators including prostaglandin E2 suppressed RALDH activity of MoDCs in vitro, whilst mediators from inflamed IBD mucosa conditioned MoDCs to imprint enhanced levels of α4β7 expression on naive CD4+ T cells independent of RALDH activity. This study provides the first systematic analysis of RALDH activity in human intestinal APCs and indicates important distinctions between mouse models and human IBD.

The purpose of this study was to describe how adolescents aged 12-18 years with inflammatory bowel disease experience their illness and what coping strategies they use to manage their illness and improve their wellbeing. The method used was a descriptive literature study, and the result of the study included 15 scientific articles. Our results showed that IBD affected the adolescent’s everyday life and social life with friends, family and activities. The adolescents also reported that they experienced a feeling of vulnerability, altered body image and that they saw themselves as different from healthy subjects. Adolescents with IBD have been shown to use the same coping strategies that healthy adolescents are using, that is, confrontational, evasive, independent and optimistic coping. The avoidance coping is more prevalent in adolescents with IBD, as the use of such strategies is specific for IBD because of illness symptoms. There is a need for more research directed at young people with IBD, since previous research is based mostly on adults' experiences of illness.

No description available.

This thesis explores aspects pertinent to the phenotypic classification of paediatric patients with inflammatory bowel disease (IBD). In the current era it has never been more important to have rigourous phenotypic classification to facilitate genotype-phenotype correlation studies as well as to optimize design of clinical trials of emerging therapies, where frequently response may differ according to phenotype of disease. The first study examined the reliability of the Montreal Classification for classifying paediatric IBD patients. This is the first study exploring the reliability of phenotypic classification in a paediatric population. The reliability of assigning an overall diagnosis of type of IBD was good, but not excellent. Amongst Crohn’s disease patients, reliability of assigning disease behaviour was excellent, while the reliability of assigning disease location categories varied from fair to good. The percentage agreement when describing disease extent for ulcerative colitis was high. The second study described the evolution of disease phenotype in a cohort of paediatric IBD patients. Similar to observations in adult-onset IBD, disease location was found to be relatively stable, while Crohn’s disease behaviour evolves from an inflammatory to a stricturing and/or penetrating phenotype in 20% of patients by 5 years of follow-up. The final study explored the association between 2 polymorphisms in the NOD2 gene with the requirement for intestinal resection (a surrogate marker of complicated disease) in models that included and excluded disease duration. Although no difference was found, this may have been influenced by data quality, which was suboptimal. In conclusion, this thesis has demonstrated that imprecision exists in the phenotyping of paediatric IBD patients, in whom phenotypic characteristics evolve over time. It is pertinent that disease duration be considered in any study attempting to make phenotypic correlations.

This thesis explores aspects pertinent to the phenotypic classification of paediatric patients with inflammatory bowel disease (IBD). In the current era it has never been more important to have rigourous phenotypic classification to facilitate genotype-phenotype correlation studies as well as to optimize design of clinical trials of emerging therapies, where frequently response may differ according to phenotype of disease. The first study examined the reliability of the Montreal Classification for classifying paediatric IBD patients. This is the first study exploring the reliability of phenotypic classification in a paediatric population. The reliability of assigning an overall diagnosis of type of IBD was good, but not excellent. Amongst Crohn’s disease patients, reliability of assigning disease behaviour was excellent, while the reliability of assigning disease location categories varied from fair to good. The percentage agreement when describing disease extent for ulcerative colitis was high. The second study described the evolution of disease phenotype in a cohort of paediatric IBD patients. Similar to observations in adult-onset IBD, disease location was found to be relatively stable, while Crohn’s disease behaviour evolves from an inflammatory to a stricturing and/or penetrating phenotype in 20% of patients by 5 years of follow-up. The final study explored the association between 2 polymorphisms in the NOD2 gene with the requirement for intestinal resection (a surrogate marker of complicated disease) in models that included and excluded disease duration. Although no difference was found, this may have been influenced by data quality, which was suboptimal. In conclusion, this thesis has demonstrated that imprecision exists in the phenotyping of paediatric IBD patients, in whom phenotypic characteristics evolve over time. It is pertinent that disease duration be considered in any study attempting to make phenotypic correlations.

The gastrointestinal (GI) tract is subject to regulation by several neuronal networks, one of which is the sympathetic nervous system (SNS). Inflammatory bowel diseases (IBD), most importantly Crohn’s disease and ulcerative colitis, are chronic diseases of the GI tract that result in such functional symptoms as abdominal pain and diarrhea. These symptoms suggest an important role for dysregulation of the SNS in IBD, since this branch of the autonomic nervous system aids in regulation of blood flow, secretion and motility. Inflammatory cytokines that are elevated in the serum and tissue of IBD patients can have wide-ranging effects on neuronal function in vitro, and may be responsible for the functional alterations observed in vivo. With these neuronal alterations in mind, we hypothesized that interleukin-17, a novel cytokine with a central role in the pathogenesis of IBD, modulates the properties of sympathetic neurons innervating the gastrointestinal tract. Using electrophysiological techniques and Ca2+ imaging, we examined the effect of IL-17 on currents passing through voltage-gated Ca2+ channels in neurons from the superior mesenteric ganglion, which innervates the gut, and found that IL-17 inhibited these currents. In parallel, we found that IL-17 enhances the growth of sympathetic neurites in vitro. These effects depend upon activation of the nuclear factor κB (NF-κB) pathway, and do not appear to require glial cells. Therefore, dysregulated neural function during IBD may be due to direct effects of IL-17 on sympathetic neurons. / Thesis (Master, Physiology) -- Queen's University, 2009-09-03 11:33:53.63

No description available.