Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3.

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.

Response to medical treatment in patients with Crohn's disease: the role of NOD2/CRAD15, disease phenotype, and age of diagnosis.

PURPOSE: Factors influencing response to medications in Crohn's disease (CD) patients are not fully understood. We aimed to evaluate the relationships between NOD2/CARD15 mutations, disease phenotype and age of CD diagnosis and response to medical treatment with systemic steroids, azathioprine (AZA) or 6-mercaptopurine (6-MP), and infliximab. METHODS: A retrospective medical records analysis was made of patients previously tested for the CD-associated NOD2/CARD15 mutations. Harvey- Bradshaw score was used to assess remission or response to therapy. RESULTS: CD-associated NOD2/CARD15 mutations were not related to the rate of steroids dependency or clinical response to AZA/6-MP and infliximab. Steroid dependency was associated with colonic involvement. Thirty-three of 127 (26%) patients with colonic disease were steroid dependent, compared with 7/72 (9.7%) patients with isolated small bowel disease (ISBD), (p = 0.009). ISBD was mildly associated with a better remission/response to AZA/6-MP treatment. Disease behavior and age of diagnosis were not related to response to therapy. CONCLUSIONS: Response to treatment with systemic steroids, AZA/6-MP and infliximab are not related to NOD2/CARD15 mutations, age of diagnosis and disease behavior. Patients with colonic disease have higher rates of steroid dependency.

Effect of smoking on inflammatory bowel disease: Is it disease or organ specific?

Smoking is an important environmental factor in inflammatory bowel disease (IBD) with differing effects in ulcerative colitis (UC) and Crohn's disease (CD). Never smoking and formerly smoking increase the risk of UC, whereas smoking exacerbates the course of CD. The potential mechanisms involved in this dual relationship are yet unknown. A reasonable assumption is that smoking has different effects on the small and large intestine. This assumption is based on animal and human studies that show that the effects of smoking/nicotine on CD and UC depend on the site of inflammation and not on the type of disease.

Outcome and early complications of ERCP: a prospective single center study.

BACKGROUND/AIMS: ERCP has been used since 1968 both as a diagnostic and as a therapeutic procedure. In the last ten years several less invasive imaging methods have developed which allow visualization of bile ducts and pancreatic ducts; therefore ERCP has become mainly a therapeutic tool. The aim of the study was to prospectively evaluate the early outcome of ERCP when used essentially as a therapeutic tool. METHODOLOGY: All patients referred to our unit between April 1 1998 and March 31 2000 were included in the study. The indication for the procedure, number of cannulations, duration of procedure, performance of endoscopic sphinterotomy or pre-cut, insertion of stent and the final outcome were recorded. All patients were visited (in-patients) or contacted by phone (outpatients) 24 hours and one week after the procedure. If a complication occurred the patient was followed until it was resolved. RESULTS: 722 ERCP procedures were performed on 534 patients (59% females), mean age 63.4 years (range 3 to 98 years). The procedure was performed with a therapeutic intention in 95% of cases because of suspicion of: cholelithiasis (58%), tumor of pancreas/bile ducts (30%), post-cholecystectomy bile leak or bile duct stenosis (6%) or treatment of chronic pancreatitis (1%). The overall success rate of selective duct cannulation was 92%. Endoscopic sphincterotomy was performed in 375 procedures (52%), pre-cut in 152 (21%) and stent inserted in 180 (25%). Among the 701 procedures with complete information 76 complications occurred in 73 patients (10.8%): pancreatitis 4.3%, perforation 1.3%, sepsis 3.7%, bleeding 1.4%. Most of the complications (63/701, 9%) were mild to moderate. Procedure-related mortality was 0.6% due to perforation (1 patient), and sepsis (3 patients). The main factors influencing the complication rate were the difficulty of the examination, performance of an invasive procedure or the operator. CONCLUSIONS: In the era of therapeutic ERCP, the risk of severe complication from the procedure is low--1.8% (including a mortality rate of 0.6%) when using the appropriate technique in experienced and skilled hands.

[National survey of antibiotic use after abdominal surgery].

A postal survey of 283 members of the Israeli Association of Surgeons was conducted to determine their current practices as to duration of antibiotic therapy following emergency abdominal operations (response rate 26.5%). The maximal acceptable length of antibiotic administration after various emergency operations was based on recommendations in the recent literature. By these criteria, about half those responding were using excessive courses of post-operative antibiotics. We conclude that failure to distinguish between contamination, which requires either minimal post-operative administration of antibiotics or none at all, and infection which requires a proper postoperative course, is the main reason for unnecessarily prolonged postoperative use of antibiotics.

Outcome and complications of colonoscopy: a prospective multicenter study in northern Israel.

Background. Colonoscopy for screening the population at an average risk of colorectal cancer (CRC) is recommended by many leading gastrointestinal associations. Objectives. The objective was to assess the quality, complications and acceptance rate of colonoscopy by patients. Methods. We prospectively gathered data from colonoscopies which were performed between October 2003 and September 2006. Patients were asked to return a follow-up form seven days after the procedure. Those who failed to do so were contacted by phone. Results. 6584 patients were included (50.4% males). The average age of subjects was 57.73 (SD 15.22). CRC screening was the main indication in 12.8%. Cecal intubation was achieved in 92% of patients and bowel preparation was good to excellent in 76.2%. The immediate outcome after colonoscopy was good in 99.4%. Perforations occurred in 3 cases-1 in every 2200 colonoscopies. Significant bleeding occurred in 3 cases (treated conservatively). 94.2% of patients agreed to undergo repeat colonoscopy in the future if indicated. Conclusions. The good quality of examinations, coupled with the low risk for complications and the good acceptance by the patients, encourages us to recommend colonoscopy as a primary screening test for CRC in Israel.

Lack of association of the 3'-UTR polymorphism in the NFKBIA gene with Crohn's disease in an Israeli cohort.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract associated with dysregulation of the immune response. It is caused by a combination of environmental and genetic factors. Patients with CD have a TH1-type inflammatory response characterized by nuclear factor kappa B (NFkappaB) activation. Mutations in the bacterial pattern recognition receptors NOD2/CARD15 and Toll-like receptor 4 (TLR4) genes, which lead to activation of NFkappaB under normal circumstances, have been associated with increased susceptibility for CD. NFkappaB plays a critical role in the immune response and is down-regulated by NFkappaB inhibitor alpha (NFKBIA). NFKBIA was found to be a susceptibility gene for German CD patients lacking NOD2/CARD15 mutations. MATERIALS AND METHODS: A cohort of 231 Israeli CD patients previously genotyped for the single nucleotide polymorphisms (SNPs) in the CARD15, TLR4 susceptibility genes for CD, was analyzed for the 3'-untranslated region (UTR) SNP of the NFKBIA gene in comparison to 100 healthy ethnically matched controls. We evaluated the contribution of the 3'-UTR SNP in NFKBIA in patients with or without other SNPs in CARD15 to age of onset, disease location, and disease behavior (Vienna classification). RESULTS: We did not identify a significant difference in allele and genotype frequencies between either groups or an effect on phenotype. No interactions were found between NFKBIA and any NOD2. CONCLUSIONS: The contribution of population diversity to susceptibility genes for CD plays an important role in disease-associated variants and is important for better understanding of the pathologic mechanisms of the polymorphism.

Comparison of capsule endoscopy with ileocolonoscopy for detecting small-bowel lesions in patients with seronegative spondyloarthropathies.

BACKGROUND AND STUDY AIMS: Patients with spondyloarthropathies are often found to have signs of small-bowel inflammation when examined by ileocolonoscopy. Because capsule endoscopy has been found to be superior to other endoscopic and radiological modalities in the detection of small-bowel inflammation, we aimed to compare the diagnostic yield of capsule endoscopy with that of ileocolonoscopy in the detection of small-bowel lesions in patients with spondyloarthropathies. PATIENTS AND METHODS: Twenty patients with documented seronegative peripheral arthritis, ankylosing spondylitis, or sacroiliitis, who had not taken nonsteroidal anti-inflammatory drugs (NSAIDs) in the preceding 2 months, participated in the study. The patients underwent capsule endoscopy, followed by ileocolonoscopy within 7 days, with blinded assessment of both examinations. Biopsies were taken when indicated and adverse events were monitored. Patients completed a questionnaire on their satisfaction with the two procedures. RESULTS: A total of 20 patients (11 men, 9 women; mean age 41+/-13 years) with seronegative inflammatory spondyloarthropathies but without abdominal complaints completed the study. No adverse effects were reported and all the capsules were excreted. Of these 20 patients, 11 (55%) had a normal small bowel on both examinations. Significant small-bowel findings (erythema, mucosal breaks, aphthous or linear ulcers, erosions) were detected by capsule endoscopy in six patients (30%) and by ileocolonoscopy in only one patient. In addition, capsule endoscopy detected significant upper gastrointestinal pathology in 40% of patients. The patients preferred capsule endoscopy to ileocolonoscopy. CONCLUSIONS: Capsule endoscopy detected more small-bowel lesions than ileocolonoscopy, and provided additional potentially relevant information on upper gastrointestinal pathology in patients with spondyloarthropathies.

Prevalence and significance of mutations in the familial Mediterranean fever gene in patients with Crohn's disease.

The concurrence of Crohn's disease (CD) and familial Mediterranean fever was repeatedly reported. In this study we determined the distribution and contribution of MEFV gene mutations to CD susceptibility and clinical heterogeneity. An Israeli cohort of 209 CD patients (120 men and 89 women) was investigated for mutations in the MEFV gene. A detailed chart review, interview and physical examination were used to determine sociodemographic and clinical characteristics. MEFV and NOD2/CARD15 genotypes were analyzed in all patients and a genotype-phenotype correlation analysis was undertaken. The results of this study do not implicate MEFV mutations as major modifiers in CD. However, the E148Q MEFV variant was associated with susceptibility to perianal disease. More specifically, 19% (9/47) of CD patients with perianal disease carried the E148Q mutation compared to 6.7% (11/162) of CD patients without perianal involvement (OR 3.26, 95% CI 1.2-8.8, P=0.02). Although, for all mutations taken together, the prevalence of MEFV gene mutations among CD patients and controls was similar, the hypothesis that E148Q mutation modulates the phenotypic expression of CD is corroborated by the results of this study and needs to be further evaluated.

Natural beta-carotene for the prevention of post-ERCP pancreatitis.

OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) is a commonly used procedure. Pancreatitis is its most common complication. As the injury may be mediated by oxidative stress, it could be ameliorated by antioxidants. METHODS: We conducted a double-blind trial, giving the patients a single dose of natural beta-carotene or placebo, 12 hours prior to procedure, and monitoring them for 24 hours post-procedure for procedure complications, antioxidant levels, and plasma oxidation. RESULTS: The overall incidence of acute pancreatitis according to our definition was 9.6%. The incidence of pancreatitis was not significantly different between the beta-carotene group (10%) and the placebo group (9.4%). Four patients in the placebo group had severe pancreatitis (2.22%), but none in the beta-carotene group. This difference is statistically significant. CONCLUSION: We did not see a reduction in the incidence of post-ERCP pancreatitis, but there may be some protective effect of treatment with beta-carotene regarding the severity of disease.

Cytokine profile in coeliac disease.

Coeliac disease (CD), an inflammatory enteropathy, is believed to be caused by immune sensitivity to ingested gluten. T-cell activation appears to be implicated in the disease although little is known regarding the role of T-cell subsets, Th1/Th2, and the cytokines they secrete. Reverse transcription-polymerase chain reaction was used to examine the mRNA expression of a wide profile of cytokines in intestinal and peripheral samples taken from active and inactive CD paediatric patients. Differential mRNA expression was observed for cytokines, between CD patients and controls, in both compartments. The percentage of samples expressing interleukin (IL)-2, interferon (IFN)-gamma, tumor necrosis factor (TNF)-beta, IL-10, IL-1beta, TNF-alpha and transforming growth factor (TGF)-beta mRNA from active CD patients was higher than from controls. A prominent finding was the expression of both Th1 (IFN-gamma, IL-2) and Th2 (IL-4, IL-10)-associated cytokine transcripts in the same biopsies and peripheral blood cells from patients with active CD implying activation of Th0 cells. The expression of IL-2 and IL-4 mRNA was not observed in peripheral blood samples from inactive CD patients associating them with disease activity. These results are important to the understanding of the inflammatory process in CD while cytokine levels may prove to be relevant markers of disease activity.