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Crohn Disease: HELP
Articles from Quebec
Based on 131 articles published since 2008

These are the 131 published articles about Crohn Disease that originated from Quebec during 2008-2019.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
76 Article Rasmussen encephalitis and comorbid autoimmune diseases: A window into disease mechanism? 2014

Amrom, Dina / Kinay, Demet / Hart, Yvonne / Berkovic, Samuel F / Laxer, Ken / Andermann, Frederick / Andermann, Eva / Bar-Or, Amit. ·From the Neurogenetics Unit (D.A., E.A.), Epilepsy Clinic (F.A.), and Neuroimmunology Unit (A.B.-O.), Montreal Neurological Hospital and Institute, Quebec, Canada · Departments of Neurology & Neurosurgery (D.A., F.A., E.A., A.B.-O.), Pediatrics (F.A.), and Human Genetics (E.A.), McGill University, Montreal, Quebec, Canada · Okmeydani Education and Research Hospital (D.K.), Istanbul, Turkey · Royal Victoria Infirmary (Y.H.), Newcastle-upon-Tyne, UK · Epilepsy Research Center (S.F.B.), Department of Medicine (Neurology), University of Melbourne, Australia · and Department of Neurology (K.L.), University of California at San Francisco. ·Neurology · Pubmed #25142901.

ABSTRACT: OBJECTIVE: To describe a potential association between comorbid autoimmune disease and Rasmussen encephalitis (RE) and discuss potential insights into underlying RE pathogenesis. METHODS: We report a case series of 4 patients with RE in whom a comorbid autoimmune disease was subsequently diagnosed and review the literature on possible common susceptibility factors. RESULTS: In 4 patients who presented with typical clinical features of RE, a comorbid autoimmune disease was subsequently diagnosed: Hashimoto thyroiditis, ulcerative colitis, Crohn disease, and systemic lupus erythematosus. We discuss the possible common predisposing factors. CONCLUSIONS: The association of RE, a rare entity, with a comorbid autoimmune disease raises the possibility of shared mechanisms of susceptibility, including common immunogenetic and/or environmental risk factors.

77 Article Timing, frequency and type of physician-diagnosed infections in childhood and risk for Crohn's disease in children and young adults. 2014

Springmann, Vicky / Brassard, Paul / Krupoves, Alfreda / Amre, Devendra. ·*Department of Gastroenterology & Hepatology, Ste-Justine Hospital Research Centre, Montreal, QC, Canada; †Department of Social and Preventive Medicine, University of Montreal, Montreal, QC, Canada; ‡Department of Clinical Epidemiology and Community Studies, Jewish General Hospital, Montreal, QC, Canada; §Division of Occupational & Environmental Health, Institut national de santé publique du Québec, Montreal, QC, Canada; and ‖Department of Pediatrics, University of Montreal, Montreal, QC, Canada. ·Inflamm Bowel Dis · Pubmed #25046007.

ABSTRACT: BACKGROUND: Recent experimental data show that exposure to microbes during early childhood can confer immunological tolerance and protect against Crohn's disease (CD). Epidemiological evidence for this link, however, remains controversial. Using prospective data, we examined the link between this hypothesis and risk for CD in children and young adults. METHODS: A case-control study design was used. CD cases (diagnosed before age 20 years) were recruited from a tertiary-care pediatric hospital in Montreal, and population-based controls matched for age, gender and, geographical location were selected. Infection data were ascertained from physician-billing records. These records, which use International Classification of Diseases, Ninth Revision diagnostic codes, were consulted retrospectively but provide prospectively collected diagnostic information. Conditional logistic regression analysis was used to study potential associations. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated. RESULTS: Four hundred nine cases and 1621 controls were included. Regression analysis adjusting for potential confounding variables suggested that any recorded infection before the diagnosis of CD was associated with reduced risk of CD (OR, 0.67; 95% CI, 0.48-0.93). The protective effect was restricted to infections occurring mainly before 5 years of age, with increasing number of infections resulting in greater protection (1-5 infections: OR, 0.74; ≥6 infections: OR, 0.61; P value for trend = 0.039). Infections affecting the oral and upper respiratory tracts, cellulitis, and, enteric infections seemed most protective. CONCLUSIONS: Our study provides support for the hygiene hypothesis, whereby exposure to infections in early childhood could potentially reduce risks of CD.

78 Article Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease--the McGill experience. 2014

Kopylov, U / Afif, W / Cohen, A / Bitton, A / Wild, G / Bessissow, T / Wyse, J / Al-Taweel, T / Szilagyi, A / Seidman, E. ·Division of Gastroenterology, McGill University Health Center, Montreal, Quebec, Canada. Electronic address: ukopylov@gmail.com. · Division of Gastroenterology, McGill University Health Center, Montreal, Quebec, Canada. · Division of Gastroenterology, Jewish General Hospital, Montreal, Quebec, Canada. ·J Crohns Colitis · Pubmed #24996483.

ABSTRACT: BACKGROUND: Ustekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohn's disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients. METHODS: A retrospective observational open-label study. Clinical response was defined by physician's global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up. RESULTS: Thirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them. SUMMARY: In this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

79 Article Basophils increase in Crohn disease and ulcerative colitis and favor mesenteric lymph node memory TH17/TH1 response. 2014

Chapuy, Laurence / Bsat, Marwa / Mehta, Heena / Rubio, Manuel / Wakahara, Keiko / Van, Vu Quang / Baba, Nobuyasu / Cheong, Cheolho / Yun, Tae Jin / Panzini, Benoît / Wassef, Ramses / Richard, Carole / Tamaz, Raja / Soucy, Geneviève / Delespesse, Guy / Sarfati, Marika. ·Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada. · Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Center for Innovative and Translational Medicine, Kochi University Medical School, Kochi, Japan. · Cellular Physiology and Immunology Research Unit, Institut de recherches cliniques de Montréal, Montreal, Quebec, Canada. · Department of Gastroenterology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada. · Department of Digestive Tract Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada. · Department of Pathology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada. · Allergy Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada. · Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada. Electronic address: m.sarfati@umontreal.ca. ·J Allergy Clin Immunol · Pubmed #24996262.

ABSTRACT: -- No abstract --

80 Article Thiopurine metabolite ratios for monitoring therapy in pediatric Crohn disease. 2014

Kopylov, U / Amre, D / Theoret, Y / Deslandres, C / Seidman, E G. ·*Division of Gastroenterology, McGill University Health Center †Department of Pediatrics, Research Center, Sainte Justine Hospital, University of Montreal, Quebec, Canada. ·J Pediatr Gastroenterol Nutr · Pubmed #24918978.

ABSTRACT: OBJECTIVES: Thiopurines (azathioprine, 6-mercaptopurine) are a mainstay of treatment in Crohn disease (CD). Monitoring intracellular metabolite (6-thioguanine nucleotides [6-TGN] and 6-methylmercaptopurine [6-MMP]) levels can help optimize therapeutic efficacy and minimize potential toxicity. Determination of 6-MMP/6-TGN ratios may provide additional useful information, such as the identification of individuals with excessive thiopurine methyltransferase activity and disadvantageous 6-MMP overproduction. These patients are at increased risk of therapeutic failure and hepatotoxicity. The aim of the study was to evaluate the correlation of 6-MMP/6-TGN ratios with therapeutic efficacy and risk of hepatotoxicity in CD. METHODS: The present study was a single-center cross-sectional study including pediatric patients with CD studied prospectively with clinical and laboratory assessments along with serial measurements of 6-MMP and 6-TGN. Clinical response was determined using established clinical indices. RESULTS: The study included 238 pediatric patients with CD with a total of 1648 evaluation points. The patients were in steroid-free remission at 59.1% of the evaluation points. 6-MMP/6-TGN ratios of 4 to 24 were protective against relapse (odds ratio [OR] 0.52, 95% confidence interval [CI] -0.39 to 0.69, P = 0.001). Hepatotoxicity was associated with high 6-MMP levels (>3919  pmol/8 × 10 red blood cell count: OR 7.65, 95% CI 3.7-15.9, P = 0.001) and high 6-MMP/6-TGN ratios (>24: OR 5.35, 95% CI -3.43 to 8.43, P = 0.001). CONCLUSIONS: We observed significant associations between 6-MMP/6-TGN ratios and clinical response, and risk of hepatotoxicity. Our results suggest that determination of thiopurine metabolite ratios is a valuable tool for identification of patients at increased risk of therapeutic failure and hepatotoxicity.

81 Article Host defense peptide resistance contributes to colonization and maximal intestinal pathology by Crohn's disease-associated adherent-invasive Escherichia coli. 2014

McPhee, Joseph B / Small, Cherrie L / Reid-Yu, Sarah A / Brannon, John R / Le Moual, Hervé / Coombes, Brian K. ·Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. · Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada. · Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada coombes@mcmaster.ca. ·Infect Immun · Pubmed #24866805.

ABSTRACT: Host defense peptides secreted by colonocytes and Paneth cells play a key role in innate host defenses in the gut. In Crohn's disease, the burden of tissue-associated Escherichia coli commonly increases at epithelial surfaces where host defense peptides concentrate, suggesting that this bacterial population might actively resist this mechanism of bacterial killing. Adherent-invasive E. coli (AIEC) is associated with Crohn's disease; however, the colonization determinants of AIEC in the inflamed gut are undefined. Here, we establish that host defense peptide resistance contributes to host colonization by Crohn's-associated AIEC. We identified a plasmid-encoded genomic island (called PI-6) in AIEC strain NRG857c that confers high-level resistance to α-helical cationic peptides and α- and β-defensins. Deletion of PI-6 sensitized strain NRG857c to these host defense molecules, reduced its competitive fitness in a mouse model of infection, and attenuated its ability to induce cecal pathology. This phenotype is due to two genes in PI-6, arlA, which encodes a Mig-14 family protein implicated in defensin resistance, and arlC, an OmpT family outer membrane protease. Implicit in these findings are new bacterial targets whose inhibition might limit AIEC burden and disease in the gut.

82 Article Differential effect of vitamin D on NOD2- and TLR-induced cytokines in Crohn's disease. 2014

Dionne, S / Calderon, M R / White, J H / Memari, B / Elimrani, I / Adelson, B / Piccirillo, C / Seidman, E G. ·McGill Center for IBD Research, Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada. · Department of Physiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. ·Mucosal Immunol · Pubmed #24781050.

ABSTRACT: Accumulating evidence implicates defective innate immunity in the pathogenesis of Crohn's disease (CD). Ineffectual NOD2 (nucleotide-binding oligomerization domain 2) is the most common susceptibility gene contributing to CD. Vitamin D (vD), a potent modulator of innate and adaptive immunity, induces NOD2 gene expression and its downstream function. We hypothesized that the hormonal form of vD (1,25D) could beneficially modulate innate immune function in CD. Using peripheral mononuclear cells and monocyte-derived dendritic cells (Mo-DCs) from CD, it was found that 1,25D decreased Toll-like receptor (TLR)-induced cytokine production and enhanced cytokine levels induced by muramyl dipeptide (MDP), the NOD2 ligand. 1,25D increased the synergistic effect provided by NOD2 and TLR co-activation on interleukin (IL)-10, IL-23, and tumor necrosis factor-alpha (TNF-α). Whereas 1,25D inhibits Mo-DC TLR-induced cytokines, co-stimulation of NOD2 results in increased IL-10 and IL-23. IL-12p70 was completely abrogated by 1,25D. 1,25D similarly modulated cytokine production by immune cells in ulcerative colitis patients and healthy controls. Mo-DCs from CD patients heterozygous for NOD2 mutations had a response similar to those from patients without NOD2 mutations. Immune cells from patients homozygous for the 1007 fs mutation were unresponsive to MDP and 1,25D. Our in vitro data support 1,25D as a potential modulator of immunity. However, these results cannot be extrapolated to CD patients without further controlled studies.

83 Article 25-Hydroxyvitamin D concentrations in children with Crohn's disease supplemented with either 2000 or 400 IU daily for 6 months: a randomized controlled study. 2014

Wingate, Kirstin E / Jacobson, Kevan / Issenman, Robert / Carroll, Matthew / Barker, Collin / Israel, David / Brill, Herbert / Weiler, Hope / Barr, Susan I / Li, Wangyang / Lyon, Michael R / Green, Timothy J. ·Food, Nutrition, and Health, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada. · Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada. · Canadian Center for Functional Medicine, Coquitlam, British Columbia, Canada. · Food, Nutrition, and Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: tim.green@ubc.ca. ·J Pediatr · Pubmed #24423431.

ABSTRACT: OBJECTIVES: To assess vitamin D status of pediatric patients with Crohn's disease (CD) and to compare their serum 25-hydroxyvitamin D (s-25OHD) with established cutoffs and assess whether 6 months of supplementation with 2000 IU/d, vs 400 IU/d, would reduce the group prevalence of vitamin D below these cutoffs. STUDY DESIGN: Subjects 8-18 years (n = 83) with quiescent CD were randomized to either 400 or 2000 IU vitamin D3/d for 6 months. RESULTS: Baseline mean ± SD s-25OHD was 24 ± 8 ng/mL; 13 subjects (16%) had an s-25OHD <16 ng/mL, 27 (33%) < 20 ng/mL, and 65 (79%) < 30 ng/mL. There was no significant difference between groups in achieving the cutoffs of 16 ng/mL or 20 ng/mL at 6 months; however, only 35% of the 400 IU group achieved the greater cutoff of 30 ng/mL compared with 74% in the 2000 IU group (P < .001). Baseline adjusted mean s-25OHD concentrations at 6 months were 9.6 ng/mL (95% CI 6.0-13.2, P < .001) greater in the 2000 IU than the 400 IU group. Disease activity was not affected by supplement dose. Few subjects exceeded safety marker cutoffs, and this did not differ by dose. CONCLUSIONS: At baseline, a high proportion of patients had a mean s-25OHD >20 ng/mL. 2000 IU vitamin D3/d is more effective in raising s-25OHD concentrations to > 30 ng/mL in children with CD than 400 IU/d, but both treatments were equally effective at achieving 16 or 20 ng/mL.

84 Article Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease. 2014

Costea, Irina / Mack, David R / Lemaitre, Rozenn N / Israel, David / Marcil, Valerie / Ahmad, Ali / Amre, Devendra K. ·Public Health Agency of Canada, Montreal, Canada. · Division of Gastroenterology, Children's Hospital of Eastern Ontario, Ottawa, Canada. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington. · Division of Gastroenterology, Hepatology and Nutrition, British Columbia's Children's Hospital, Vancouver, Canada. · Research Institute, McGill University, Montreal, Quebec, Canada. · Department of Microbiology and Immunology, University of Montreal, Quebec, Canada; Research Centre, Le Centre Hospitalier Universitaire-Ste-Justine, Montreal, Canada. · Research Centre, Le Centre Hospitalier Universitaire-Ste-Justine, Montreal, Canada; Department of Pediatrics, University of Montreal, Quebec, Canada. Electronic address: devendra.amre@gmail.com. ·Gastroenterology · Pubmed #24406470.

ABSTRACT: Increased dietary ratios of ω6/ω3 polyunsaturated fatty acids have been implicated in the pathogenesis of Crohn's disease (CD), but epidemiologic data are limited. We investigated whether variants of genes that control polyunsaturated fatty acid metabolism (CYP4F3, FADS1, and FADS2), along with the dietary ratio of ω6/ω3, confers susceptibility to CD. Based on data from 182 children newly diagnosed with CD and 250 controls, we found that children who consumed a higher dietary ratio of ω6/ω3 were susceptible for CD if they were also carriers of specific variants of CYP4F3 and FADS2 genes. Our findings implicate diet-gene interactions in the pathogenesis of CD.

85 Article Crohn's disease susceptibility variants in Colombian tuberculosis patients. 2014

Sánchez, D / Lefebvre, C / García, L F / Rioux, J / Barrera, L F. ·Grupo de Inmunología Celular e Inmunogenética, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia; Centro Colombiano de Investigación en Tuberculosis, Medellin, Colombia; Health Sciences Center, Louisiana Cancer Research Center, Louisiana State University, New Orleans, Louisiana, USA. · Laboratory in Genetics and Genomic Medicine of Inflammation, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; ECOGENE-21 Clinical Trial Center, Centre de Médecine Génique Communautaire de l'Université de Montréal, Centre Hospitalier Affilié Universitaire Régional de Chicoutimi, Chicoutimi, Québec, Canada. · Grupo de Inmunología Celular e Inmunogenética, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia; Centro Colombiano de Investigación en Tuberculosis, Medellin, Colombia. · Laboratory in Genetics and Genomic Medicine of Inflammation, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada. ·Int J Tuberc Lung Dis · Pubmed #24365559.

ABSTRACT: BACKGROUND: The molecular basis of genetic predisposition to pulmonary tuberculosis (PTB) in adults remains largely elusive. A chronic granulomatous inflammatory reaction is one of the main characteristics of the immune response to TB; however, a similar reaction is observed in other diseases, such as Crohn's disease. OBJECTIVE: To assess the association of genetic polymorphisms previously associated with Crohn's disease and PTB in a Colombian population of PTB patients and controls. DESIGN: A case-control study was performed among 500 newly diagnosed PTB patients and 320 healthy control subjects. Thirty-one single nucleotide polymorphisms (SNPs) identified in a previous meta-analysis of genome-wide association studies of Crohn's disease were used for genotyping using MassARRAY technology. RESULTS: In this study, we identified an association with borderline significance (P = 0.0009433 and P = 0.029 after multiple testing by Bonferroni's correction) of SNP rs10995271 with PTB. SNP rs10995271 is in linkage disequilibrium with SNPs belonging to the zinc finger protein (ZNF365) gene. CONCLUSIONS: Our results suggest that human PTB shares a genetic basis with Crohn's disease, and that SNPs in the ZNF365 gene would have a role in the occurrence of chronic granulomatous inflammatory reaction in TB as well as Crohn's disease.

86 Article Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease. 2014

Feagan, Brian G / McDonald, John W D / Panaccione, Remo / Enns, Robert A / Bernstein, Charles N / Ponich, Terry P / Bourdages, Raymond / Macintosh, Donald G / Dallaire, Chrystian / Cohen, Albert / Fedorak, Richard N / Paré, Pierre / Bitton, Alain / Saibil, Fred / Anderson, Frank / Donner, Allan / Wong, Cindy J / Zou, Guangyong / Vandervoort, Margaret K / Hopkins, Marybeth / Greenberg, Gordon R. ·Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. Electronic address: brian.feagan@robartsinc.com. · Robarts Clinical Trials, Western University, London, Ontario, Canada. · Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Alberta, Canada. · St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. · Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada. · Department of Medicine, Western University, London, Ontario, Canada; London Health Sciences Centre, South Street Hospital, London, Ontario, Canada. · Hôtel-Dieu de Lévis, Lévis, Quebec, Canada. · Dalhousie University, Halifax, Nova Scotia, Canada. · Centre Hospitalier Universitaire de Québec-Pavillon St. François d'Assise, Quebec City, Quebec, Canada. · Jewish General Hospital, Montreal, Quebec, Canada. · University of Alberta, Edmonton, Alberta, Canada. · Hôpital St. Sacrement, Quebec City, Quebec, Canada. · McGill University Health Centre, Montreal, Quebec, Canada. · Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. · The Liver and Intestinal Research Centre, Vancouver, British Columbia, Canada. · Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. · Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. ·Gastroenterology · Pubmed #24269926.

ABSTRACT: BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

87 Article High residential sun exposure is associated with a low risk of incident Crohn's disease in the prospective E3N cohort. 2014

Jantchou, Prévost / Clavel-Chapelon, Francoise / Racine, Antoine / Kvaskoff, Marina / Carbonnel, Franck / Boutron-Ruault, Marie-Christine. ·*Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, Villejuif, France; †Univ Paris Sud, UMRS 1018, Villejuif, France; ‡Inserm U1018, Institut Gustave Roussy, Villejuif, France; §Sainte Justine University Hospital, Montréal, Canada; and ‖Service de Gastroentérologie, Hôpitaux Universitaires Paris Sud, CHU de Bicêtre, APHP, Le Kremlin Bicêtre, France. ·Inflamm Bowel Dis · Pubmed #24247650.

ABSTRACT: BACKGROUND: Vitamin D insufficiency has been suggested to be associated with high risk of Crohn's disease (CD). In France, where food fortification is limited, the major source of vitamin D is through sun exposure. The aim of this work was to analyze the relationship between residential sun exposure and the risk of incident CD or ulcerative colitis (UC). METHODS: The E3N cohort consists of women living in France, aged 40 to 65 years and free of major diseases at inclusion in 1990. Among the 91,870 women included in the study, we identified 123 incident cases (45 CD, 71 UC, and 7 indeterminate colitis). To assess residential sun exposure, we used a database containing mean daily ultraviolet radiation (UVR) dose for each French county. The relationship between residential sun exposure and risk of incident inflammatory bowel diseases was explored using Cox models. RESULTS: Higher levels of residential sun exposure were associated with a significant decreased risk of CD (hazard ratio [HR] for the third versus the first tertile of UVR dose, 0.49; 95% confidence interval (CI), 0.23-1.01; P for trend = 0.04), but not of UC (HR, 1.21; CI, 0.61-2.11). In women with available data on dietary vitamin D intake, we observed a lower risk of CD with higher residential UVR (HR, 0.29; 95% CI, 0.11-0.80; P for trend = 0.01). Dietary vitamin D intake was neither associated with the risk of CD (HR, 0.41; 95% CI, 0.14-1.24; P for trend = 0.14) nor UC (HR, 1.61; CI, 0.61-4.23). CONCLUSIONS: In this prospective cohort of women, high residential sunlight exposure was associated with decreased incidence of CD, but not UC.

88 Article Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn's disease. 2014

Leighton, Jonathan A / Gralnek, Ian M / Cohen, Stanley A / Toth, Ervin / Cave, David R / Wolf, Douglas C / Mullin, Gerard E / Ketover, Scott R / Legnani, Peter E / Seidman, Ernest G / Crowell, Michael D / Bergwerk, Ari J / Peled, Ravit / Eliakim, Rami. ·Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona. Electronic address: leighton.jonathan@mayo.edu. · Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel. · Children Center for Digestive Health Care, Children Healthcare of Atlanta, Atlanta, Georgia. · Department of Gastroenterology, Skane University Hospital, Malmö, Sweden. · University of Massachusetts Medical School, Worcester, Massachusetts. · Atlanta Gastroenterology Associates, Atlanta, Georgia. · Johns Hopkins Hospital, Baltimore, Maryland. · Minnesota Gastroenterology PA, Minneapolis, Minnesota. · Mount Sinai School of Medicine, New York, New York. · Research Institute of McGill University Health Center, Montreal General Hospital, Montreal, Quebec, Canada. · Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona. · Shaare Zedek Medical Center, Jerusalem, Israel. · Given Imaging Ltd, Yoqneam, Israel. · Department of Gastroenterology, Sheba Medical Center, Tel-Aviv, Israel. ·Clin Gastroenterol Hepatol · Pubmed #24075891.

ABSTRACT: BACKGROUND & AIMS: Evaluation of the small intestine for inflammation has traditionally relied on small-bowel follow-through (SBFT), but multiple studies have demonstrated its low diagnostic accuracy. Capsule endoscopy (CE) transmits high-quality images of the small intestinal mucosa; it can be used to visualize the entire length of the small bowel and much of the mucosa. We compared the diagnostic yields of CE vs SBFT in a prospective study of patients with suspected small-bowel Crohn's disease. METHODS: Eighty patients with signs and/or symptoms of small-bowel Crohn's disease (age, 10-65 years) underwent CE, followed by SBFT and ileocolonoscopy. Readers were blinded to other test results. The primary outcome was the diagnostic yield for inflammatory lesions found with CE before ileocolonoscopy compared with SBFT and ileocolonoscopy. A secondary outcome was the incremental diagnostic yield of CE compared with ileocolonoscopy and CE compared with SBFT. RESULTS: The combination of CE and ileocolonoscopy detected 107 of 110 inflammatory lesions (97.3%), whereas the combination of SBFT and ileocolonoscopy detected only 63 lesions (57.3%) (P < .001). The diagnostic yield of CE compared with ileocolonoscopy was not different (P = .09). The diagnostic yield was higher for CE than for SBFT (P < .001). Of the 80 patients with suspected Crohn's disease, 25 (31.3%) had the diagnosis confirmed. Eleven were diagnosed by CE findings alone and 5 by ileocolonoscopy findings alone. In the remaining 9 patients, diagnostic findings were identified by at least 2 of the 3 modalities. No diagnoses were made on the basis of SBFT findings alone. CONCLUSIONS: CE was better than SBFT and equivalent to ileocolonoscopy in detecting small-bowel inflammation. Although ileocolonoscopy remains the initial diagnostic test of choice, CE is safe and can establish the diagnosis of Crohn's disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated. ClinicalTrials.gov Number: NCT00487396.

89 Article Characterization of PTPN2 and its use as a biomarker. 2014

Bussières-Marmen, Stéphanie / Hutchins, Andrew P / Schirbel, Anja / Rebert, Nancy / Tiganis, Tony / Fiocchi, Claudio / Miranda-Saavedra, Diego / Tremblay, Michel L. ·Goodman Cancer Research Center, McGill University, Montreal, QC, Canada; Department of Biochemistry, McGill University, Montreal, QC, Canada. · Bioinformatics and Genomics Laboratory, World Premier International (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan. · Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin, Berlin, Germany. · Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. · Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. · Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. · Goodman Cancer Research Center, McGill University, Montreal, QC, Canada; Department of Biochemistry, McGill University, Montreal, QC, Canada. Electronic address: Michel.tremblay@mcgill.ca. ·Methods · Pubmed #23994241.

ABSTRACT: For years, the two main isoforms of PTPN2 have been an interesting yet academic topic of debate for researchers working on this phosphatase. In recent years, several studies were published in which these isoforms were attributed specific functions. Most importantly, differences in their stoichiometry have been reported to be associated with certain diseases such as inflammatory bowel diseases (IBDs). Hence, understanding the evolutionary ontogeny of the main transcripts and the physiological consequences of their expression have now become clinically relevant issues. Herein we describe the genomic controls placed upon PTPN2, the identified splice variants, the encoded PTPN2 proteins, and both the known and putative post-translational modifications that have been reported. Moreover, we examine the expression of PTPN2 isoforms in specific tissues as well as in a disease setting. PTPN2 is an important negative regulator of inflammation. Therefore, the following protocols are effective approaches for its adequate monitoring in inflammatory diseases' progression and outcome.

90 Article Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. 2013

Beaudoin, Mélissa / Goyette, Philippe / Boucher, Gabrielle / Lo, Ken Sin / Rivas, Manuel A / Stevens, Christine / Alikashani, Azadeh / Ladouceur, Martin / Ellinghaus, David / Törkvist, Leif / Goel, Gautam / Lagacé, Caroline / Annese, Vito / Bitton, Alain / Begun, Jakob / Brant, Steve R / Bresso, Francesca / Cho, Judy H / Duerr, Richard H / Halfvarson, Jonas / McGovern, Dermot P B / Radford-Smith, Graham / Schreiber, Stefan / Schumm, Philip L / Sharma, Yashoda / Silverberg, Mark S / Weersma, Rinse K / Anonymous4700770 / Anonymous4710770 / Anonymous4720770 / D'Amato, Mauro / Vermeire, Severine / Franke, Andre / Lettre, Guillaume / Xavier, Ramnik J / Daly, Mark J / Rioux, John D. ·Montreal Heart Institute, Research Center, Montreal, Quebec, Canada. ·PLoS Genet · Pubmed #24068945.

ABSTRACT: Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

91 Article CD47 fusion protein targets CD172a+ cells in Crohn's disease and dampens the production of IL-1β and TNF. 2013

Baba, Nobuyasu / Van, Vu Quang / Wakahara, Keiko / Rubio, Manuel / Fortin, Geneviève / Panzini, Benoît / Soucy, Geneviève / Wassef, Ramses / Richard, Carole / Tamaz, Raja / Lahaie, Raymond / Bernard, Edmond-Jean / Caussignac, Yves / Leduc, Raymond / Lougnarath, Rasmy / Bergeron, Carole / Racicot, Marc-André / Bergeron, Fanny / Panzini, Marie-Andrée / Demetter, Pieter / Franchimont, Denis / Schäkel, Knut / Weckbecker, Gisbert / Kolbinger, Frank / Heusser, Christoph / Huber, Thomas / Welzenbach, Karl / Sarfati, Marika. ·Immunoregulation Laboratory, The Research Center of the Centre Hospitalier de L'Université de Montréal (CRCHUM), Montreal, Canada. ·J Exp Med · Pubmed #23669395.

ABSTRACT: In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell-driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn's disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX3CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(-)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD.

92 Article Genome-wide association study signal at the 12q12 locus for Crohn's disease may represent associations with the MUC19 gene. 2013

Kumar, Vijay / Mack, David R / Marcil, Valerie / Israel, David / Krupoves, Alfreda / Costea, Irina / Lambrette, Philippe / Grimard, Guy / Dong, Jinsong / Seidman, Ernest G / Amre, Devendra K / Levy, Emile. ·Division of Gastroenterology, Hepatology & Nutrition, Research Centre, CHU-Ste-Justine, Montreal, Canada. ·Inflamm Bowel Dis · Pubmed #23619718.

ABSTRACT: BACKGROUND: Genome-wide association studies (GWAS) in Crohn's disease (CD) have identified associations with single-nucleotide polymorphism (SNP) rs11175593 at chromosome 12q12. The MUC19 and LRRK2 genes reside close to the GWAS signal, but it is as yet unclear which of the 2 genes represent the CD susceptibility genes. METHODS: We studied associations between nonsynonymous coding variants in the MUC19 (5) and LRRK2 (3) genes in a case-control sample comprising CD cases aged <18 years at diagnosis. The GWAS lead SNP rs11175593 was also investigated. Allelic, genotype, and haplotype associations were examined assuming different models of inheritance. RESULTS: A total of 530 cases and 600 controls were studied. The mean (±SD) age at diagnosis was 12.4 (±3.3). Most cases were male (57.4%). Most patients had ileocolonic disease location (48.8%) and inflammatory behavior at diagnosis (87.0%). Three MUC19 SNPs were nominally significantly associated with CD (rs11564245, Asp→His: P = 0.02; rs4768261, Ser→Phe: P = 0.0008; and rs2933353, Glu→Ala: P = 0.01). Associations with rs4768261 were maintained after corrections for multiple comparisons (permuted, P = 0.007). None of the LRRK2 SNPs were associated with CD. Haplotype analysis supported the single SNP associations noted with the MUC19 gene. CONCLUSIONS: GWAS signal at chromosome 12q12 for CD may represent associations with the MUC19 gene.

93 Article Association between the PTPN2 gene and Crohn's disease: dissection of potential causal variants. 2013

Marcil, Valerie / Mack, David R / Kumar, Vijay / Faure, Christophe / Carlson, Christopher S / Beaulieu, Patrick / Israel, David / Krupoves, Alfreda / Costea, Irina / Lambrette, Philippe / Grimard, Guy / Dong, Jinsong / Seidman, Ernest G / Amre, Devendra K / Levy, Emile. ·Research Institute, McGill University, Montreal, Quebec, Canada. ·Inflamm Bowel Dis · Pubmed #23518806.

ABSTRACT: BACKGROUND: Although genome-wide association studies (GWAS) and subsequent meta-analyses have confirmed associations between the PTPN2 (protein tyrosine phosphatase, nonreceptor type 2) gene and Crohn's disease (CD), the potential causal variants remain unidentified. We aimed to dissect potential causal CD-associated PTPN2 variants, assess their functional significance, and relate PTPN2 protein expression with inflammation in CD. METHODS: A 3-stage study was carried out. In stage 1, we genotyped tagging single nucleotide polymorphisms (tag-SNPs) in the PTPN2 gene in a sample of patients with CD (<20 years, n = 556) and controls (n = 602). In stage 2, we resequenced the putative promoter, target exons and introns in the PTPN2 gene, and examined associations with high-frequency variants with CD in the stage 1 cohort. In stage 3 we studied the relationship between PTPN2 protein expression and mucosal inflammation and carried out in silico analyses to study the functional characteristics of the PTPN2 CD-associated SNPs. RESULTS: In stage 1, we observed associations between 5 intronic SNPs and CD including rs1893217 (P = 2 × 10⁻⁴), the SNP that is in perfect linkage disequilibrium with the lead genome-wide association studies SNP rs2542151. Resequencing revealed 2 known promoter polymorphisms. No associations between these promoter SNPs and CD were evident. In silico analyses revealed that the 5 associated intronic SNPs influenced PTPN2 expression and binding to important transcription factors. PTPN2 protein was overexpressed in inflamed intestinal tissues of patients with CD. CONCLUSIONS: Our findings suggest that noncoding variation in the PTPN2 gene may represent the causal variations influencing susceptibility for CD.

94 Article Association between genetic variants in the HNF4A gene and childhood-onset Crohn's disease. 2012

Marcil, V / Sinnett, D / Seidman, E / Boudreau, F / Gendron, F-P / Beaulieu, J-F / Menard, D / Lambert, M / Bitton, A / Sanchez, R / Amre, D / Levy, E. ·Departments of Medicine and Pediatrics, Research Institute, McGill University, Montreal, Quebec, Canada. ·Genes Immun · Pubmed #22914433.

ABSTRACT: Hepatocyte nuclear 4 alpha (HNF4α), involved in glucose and lipid metabolism, has been linked to intestinal inflammation and abnormal mucosal permeability. Moreover, in a genome-wide association study, the HNF4A locus has been associated with ulcerative colitis. The objective of our study was to evaluate the association between HNF4α genetic variants and Crohn's disease (CD) in two distinct Canadian pediatric cohorts. The sequencing of the HNF4A gene in 40 French Canadian patients led to the identification of 27 single nucleotide polymorphism (SNP)s with a minor allele frequency >5%. To assess the impact of these SNPs on disease susceptibility, we first conducted a case-control discovery study on 358 subjects with CD and 542 controls. We then carried out a replication study in a separate cohort of 416 cases and 1208 controls. In the discovery cohort, the genotyping of the identified SNPs revealed that six were significantly associated with CD. Among them, rs1884613 was replicated in the second CD cohort (odds ratio (OR): 1.33; P<0.012) and this association remained significant when both cohorts were combined and after correction for multiple testing (OR: 1.39; P<0.004). An 8-marker P2 promoter haplotype containing rs1884613 was also found associated with CD (P<2.09 × 10(-4) for combined cohorts). This is the first report showing that the HNF4A locus may be a common genetic determinant of childhood-onset CD. These findings highlight the importance of the intestinal epithelium and oxidative protection in the pathogenesis of CD.

95 Article Herpes simplex virus-1 infection of colonic explants as a model of viral-induced activation of Crohn's disease. 2012

Silva, Manuel A / Menezes, José / Dionne, Serge / Levy, Emile / Amre, Devendra K / Seidman, Ernest G. ·Sainte-Justine Hospital Research Center, Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada. ·J Crohns Colitis · Pubmed #22398063.

ABSTRACT: The exogenous triggers responsible for Crohn's disease (CD) relapses are not often identified. Cytomegalovirus and other members of the herpesvirus family have been implicated in precipitating relapses. However, the role of viral infections in the immunopathogenesis of CD remains poorly understood. We describe an ex-vivo model of primary viral infection of CD tissue with Herpes Simplex Virus type I (HSV-1). IL-6 and CD68 served as markers for CD inflammation, type I IFNs for viral infection. Colonic explants obtained from CD resections were infected via the luminal or the submucosal compartments with HSV-1 or mock virus solution, at varying concentrations for up to 20 h. Serial tissue sections were assayed for expression of HSV-1 specific antigens, CD-68, IL-6 and DC-SIGN. Culture supernatants were tested for IL-6 and type I IFN production. Positive immunostaining for HSV-1 specific antigens was consistently detectable using 11×10(6)PFU from 13 h onwards, mainly on cells located in the submucosa, and in the perivascular area. CD68 was up-regulated in lamina propria macrophages from mildly and non-inflamed CD tissue after HSV-1 infection. IL-6+ cells in the infected tissues were mainly submucosal DC-SIGN+ dendritic cells. IL-6 and IFN-β levels were higher in the supernatants from HSV-1-infected explants compared to controls after 20 h of culture (p<0.01). These data show increased expression of inflammatory markers during the initial stages of HSV-1 primary infection using CD colonic explants. This in vitro model appears promising to study the immunoregulatory changes induced by microbial infection in reactivation of CD.

96 Article Expression and functional analysis of intestinal organic cation/L-carnitine transporter (OCTN) in Crohn's disease. 2012

Girardin, Marc / Dionne, Serge / Goyette, Philippe / Rioux, John / Bitton, Alain / Elimrani, Ihsan / Charlebois, Patrick / Qureshi, Ijaz / Levy, Emile / Seidman, Ernest G. ·DigestiveLab, Research Institute, McGill University Health Centre, Montreal, QC, Canada. marcgirardin@gmail.com ·J Crohns Colitis · Pubmed #22325173.

ABSTRACT: BACKGROUND: The IBD5 locus is a genetic risk factor for IBD, particularly Crohn's Disease, coding for the organic cation/carnitine transporters (OCTN1 and 2). Two variants of OCTN are associated with susceptibility to Crohn's Disease. Modified transport of carnitine in vitro has been reported for a polymorphism of OCTN1. The aim was to investigate the function of intestinal OCTNs in IBD in relation to genetic polymorphisms. METHODS: Intestinal tissue was obtained from endoscopic biopsies and surgical resections from IBD patients (n=33 and 14, resp.) and controls (n=22 and 14, resp.). OCTN protein levels were measured in intestinal biopsies and carnitine transport was quantified in intestinal resections. RESULTS: OCTN1 protein levels were significantly higher in ileal versus colonic tissue (2.95% ± 0.4 vs 0.66% ± 0.2, resp.; p<0.0002). OCTN1 expression was higher in Crohn's disease patients with mutant homozygous or heterozygous genotypes (0.6% ± 0.1 vs 3% ± 0.8, resp., p<0.02). Carnitine transport was very rapid and Na+ dependent (10s). It was not different comparing Crohn's Disease and control groups (0.45 ± 0.12 vs 0.51 ± 0.12 nM carnitine/mg prot/min, resp.). Carnitine transport tended to be higher in subjects with mutant homozygous and heterozygous OCTN1 and OCTN2 genotypes (0.19 vs 0.59 and 0.25 vs 0.6, respectively). CONCLUSIONS: The present data reveal that OCTN protein levels appear to be similar in intestinal tissue from Crohn's Disease patients and controls. Overall, ileal carnitine transport appears to as well equal in Crohn's Disease and control groups. However, there was a trend towards higher carnitine transport in subjects with OCTN1 and OCTN2 mutations.

97 Article Matriptase protects against experimental colitis and promotes intestinal barrier recovery. 2012

Netzel-Arnett, Sarah / Buzza, Marguerite S / Shea-Donohue, Terez / Désilets, Antoine / Leduc, Richard / Fasano, Alessio / Bugge, Thomas H / Antalis, Toni M. ·Center for Vascular and Inflammatory Diseases and Department of Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada. ·Inflamm Bowel Dis · Pubmed #22081509.

ABSTRACT: BACKGROUND: Matriptase is a membrane-anchored serine protease encoded by suppression of tumorigenicity-14 (ST14) that is required for epithelial barrier homeostasis. However, its functional role in inflammatory bowel disease (IBD) is unexplored. METHODS: Matriptase expression in control, Crohn's disease, and ulcerative colitis tissue specimens was studied by quantitative polymerase chain reaction (qPCR) and immunostaining. Matriptase function was investigated by subjecting St14 hypomorphic and control littermates to dextran sodium sulfate (DSS)-induced colitis and by siRNA silencing in cultured monolayers. Mice were analyzed for clinical, histological, molecular, and cellular effects. RESULTS: Matriptase protein and ST14 mRNA levels are significantly downregulated in inflamed colonic tissues from Crohn's disease and ulcerative colitis patients. Matriptase-deficient St14 hypomorphic mice administered DSS for 7 days followed by water without DSS for 3 days develop a severe colitis, with only 30% of the St14 hypomorphic mice surviving to day 14, compared with 100% of control littermates. Persistent colitis in surviving St14 hypomorphic mice was associated with sustained cytokine production, an inability to recover barrier integrity, and enhanced claudin-2 expression. Cytokines implicated in barrier disruption during IBD suppress matriptase expression in T84 epithelial monolayers and restoration of matriptase improves barrier integrity in the cytokine-perturbed monolayers. CONCLUSIONS: These data demonstrate a critical role for matriptase in restoring barrier function to injured intestinal mucosa during colitis, which is suppressed by excessive activation of the immune system. Strategies to enhance matriptase-mediated barrier recovery could be important for intervening in the cycle of inflammation associated with IBD.

98 Article Clinical and pathological analysis of colonic Crohn's disease, including a subgroup with ulcerative colitis-like features. 2012

Soucy, Genevieve / Wang, Helen H / Farraye, Francis A / Schmidt, Jason F / Farris, Alton B / Lauwers, Gregory Y / Cerda, Sandra R / Dendrinos, Kleanthis G / Odze, Robert D. ·Department of Pathology, Centre Hospitalier Universitaire de Montreal, Montreal, Quebec, Canada. ·Mod Pathol · Pubmed #21841769.

ABSTRACT: Little is known regarding the clinical and, in particular, pathological manifestations of patients with isolated colonic Crohn's disease. The purpose of this study was to evaluate the clinical and pathological features of patients with Crohn's disease limited to the colon at initial presentation, and to determine whether there are any histological features that are predictive of outcome after surgery. The clinical features, outcome after surgery, and pathological features of colonic resection specimens of 73 patients who presented initially with isolated colonic Crohn's disease were evaluated and compared with 45 Crohn's disease patients who presented initially with both ileal and colonic involvement. Clinically, patients with isolated colonic Crohn's disease presented at a significantly older age at the time of diagnosis, and had a significantly shorter duration of colitis before surgical resection, than did patients with ileocolonic Crohn's disease at disease onset. Pathologically, patients with isolated colonic Crohn's disease showed a significantly higher proportion of cases with subtotal, total, or left-sided colitis, and significantly fewer strictures/stenosis, pericolonic adhesions, pyloric metaplasia, and cases with proximal worse than distal colonic disease. Overall, patients with isolated colonic Crohn's disease showed a trend toward a lower number of major microscopic Crohn's disease features. A small proportion of patients from both Crohn's disease groups (14% and 13%, respectively) showed inflammatory disease limited to the mucosa, without mural involvement, reminiscent of ulcerative colitis, and these were termed 'ulcerative colitis-like Crohn's disease'. These patients were significantly younger than those with mural involvement. Overall, 44% of patients from both Crohn's disease groups developed at least one adverse outcome, and neither the number nor the type of major Crohn's disease features correlated with adverse outcome. Patients with isolated colonic involvement have distinctive clinical and pathological features. A small subgroup of Crohn's patients shows only mucosal involvement reminiscent of ulcerative colitis.

99 Article NELL1, NCF4, and FAM92B genes are not major susceptibility genes for Crohn's disease in Canadian children and young adults. 2012

Amre, Devendra K / Mack, David R / Israel, David / Krupoves, Alfreda / Costea, Irina / Lambrette, Philippe / Grimard, Guy / Dong, Jinsong / Levy, Emile. ·Department of Pediatrics, University of Montreal, Montreal, Canada; Research Centre, Sainte-Justine Hospital, Montreal, Canada. devendra.amre@umontreal.ca ·Inflamm Bowel Dis · Pubmed #21472827.

ABSTRACT: BACKGROUND: Genome-wide association studies (GWAS) and replication studies have shown conflicting associations between the NELL1, NCF4, and FAM92B genes and susceptibility for Crohn's disease (CD). We sought to examine whether these genes were associated with CD in Canadian children and young adults. METHODS: A case-control study was carried out at three pediatric gastroenterology clinics across Canada. Patients, ≤20 years at diagnosis, along with controls representative of the general population were selected. Study subjects were genotyped for 22 single nucleotide polymorphisms (SNPs) across the target genes. Allelic and haplotype associations were examined. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated. RESULTS: In all, 566 CD cases and 602 controls were investigated. The mean (±SD) age of the patients was 12.3 (±3.3) years. Most patients were male (57.8%), of Caucasian ancestry (98.2%), and had ileocolonic disease location (48.8%). Barring nominal associations with one FAM92B SNP, none of the other 21 SNPs analyzed were associated with CD either at the allelic or haplotype level. Separate analysis for ileal CD (L1 plus L3) also did not reveal significant associations with any of the SNPs. Similarly, a pooled analysis using data from two recent studies did not demonstrate associations between the NCF4 (OR = 1.10, 95% CI = 0.91-1.32, P = 0.32) and FAM92B (OR = 1.05, 95% CI = 0.95-1.17, P = 0.36) GWAS lead SNPs and ileal CD. CONCLUSIONS: GWAS-reported associations in the NELL1, NCF4, and FAM92B genes could not be replicated in Canadian children and young adults. Further investigation in other populations will be required to confirm the presence/absence of associations, if any.

100 Article Associations between variants in the ABCB1 (MDR1) gene and corticosteroid dependence in children with Crohn's disease. 2011

Krupoves, Alfreda / Mack, David / Seidman, Ernest / Deslandres, Colette / Amre, Devendra. ·Research Centre, Ste-Justine Hospital, Montreal, Quebec, Canada. ·Inflamm Bowel Dis · Pubmed #21987299.

ABSTRACT: BACKGROUND: Corticosteroids (CS) effectively induce remission in patients with moderate to severe Crohn's disease (CD). However, CS dependence in children is a significant clinical problem associated with numerous side effects. Identification of molecular markers of CS dependence is of paramount importance. The ABCB1 gene codes for P-glycoprotein, a transporter involved in the metabolism of CS. We examined whether DNA variation in the ABCB1 gene was associated with CS dependency in children with CD. METHODS: A retrospective study was carried out in two Canadian tertiary pediatric gastroenterology centers. Clinical information was abstracted from medical charts of CD patients (N = 260) diagnosed with CD prior to age 18 and administered a first course of CS during the 1 year since diagnosis. Patients were classified as CS-dependent if they relapsed during drug tapering or after the end of therapy. DNA was extracted from blood or saliva. Thirteen tagging single nucleotide polymorphisms (tag-SNPs) and a synonymous variation (C3435T) in the ABCB1 gene were genotyped. Allelic, genotype, and haplotype associations were examined using logistic regression and Haploview. RESULTS: Tag-SNP rs2032583 was statistically significantly associated with CS dependency. The rare C allele of this SNP (odds ratio [OR] = 0.56, 95% confidence interval [CI]: 0.34-0.95, P = 0.029) and heterozygous genotype TC (OR = 0.52, 95% CI: 0.28-0.95, P = 0.035) conferred protection from CS dependency. A three-marker haplotype was significantly associated with CS dependence (multiple comparison corrected P-value = 0.004). CONCLUSIONS: Our results suggest that the ABCB1 gene may be associated with CS dependence in pediatric CD patients.

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