AIMS:: Pediatric onset of Crohn disease (CD) is characterized by male sex predominance while adult-onset disease demonstrates female sex predominance. It has been postulated that this phenomenon may be genetically determined or due to an effect of estrogen on age of onset. Interleukin (IL)-6 modulates the TH17 pathway, and the IL-6 promoter is modulated by estrogen, possibly linking genetically determined inflammation and the presence of estrogen. The aim of our study was to investigate whether differences in IL-6 promoter genotype could explain male sex in earlier disease onset. PATIENTS AND METHODS:: We genotyped 333 patients with CD and 100 controls, 162 pediatric-onset patients (age of onset 18 years and younger) for the IL-6-174 polymorphic site. Genotype, sex, and age of onset were compared. RESULTS:: Males with IL-6-174GG genotype (the wild-type allele) had an increased risk for a younger age of onset compared to males with IL-6-174GC or CC genotype (G --> C genotype), hazard ratio (HR) 1.49, P = 0.02, 95% confidence interval (CI) 1.07-2.09. Females with GG genotype were not found to have an increased risk for a younger age of onset compared with females with G --> C genotype, HR 1.01, P = 0.96, 95% CI 0.72-1.41. CONCLUSIONS:: Males with IL-6-174GG genotype are prone to develop CD at a younger age than males with the IL-6-174G --> C genotype. Our study suggests that age of onset may be modified by the IL-6-174GG genotype and this modification is sex dependent. This may be due to increased transcription of IL-6, an effect that may be repressed by estrogen in females.

Abstract Objective. Recently, several publications in adults have shown an increased incidence of non-Helicobacter pylori (HP), non-non-steroidal anti-inflammatory drug (NSAID) peptic disease (PD). There are only a few case reports linking celiac disease (CD) to PD. We therefore aimed to review our experience of CD presenting with PD. Material and methods. We retrospectively reviewed all the endoscopies performed for children and young adults diagnosed with CD between 1 January, 2004 and 31 October, 2008. The diagnosis of CD was based on accepted guidelines. Patients with a doubtful diagnosis of CD were excluded. Results. We had 240 patients with the diagnosis of CD. We had 29 (12.0%) patients [15 males (52%), 14 females (48%)] for whom the diagnosis of PD was ascertained. The age range was 1-50 years (mean 16.9 +/- 12.1 years). Twenty-three of the 29 patients (79%) were HP-negative. Duodenal PD was noted in 22 patients (76%) and 16 (73%) were HP-negative. Gastric PD was noted in eight patients (28%) and 7 (87%) were HP-negative. The PD group was significantly older at diagnosis (p < 0.001) compared to the whole CD group. Conclusions. PD is not uncommon in the presentation of CD. It is more likely to be found in the second decade of life. CD should be included in the differential diagnosis of patients with non-HP PD and we suggest routine CD serology and small bowel biopsy in patients with unexplained PD.

OBJECTIVE: To assess the safety and prebiotic effects of lactulose in preterm infants. STUDY DESIGN: This was a prospective, double-blinded, placebo-controlled, single-center study in 23- to 34-weeks premature infants. The study group received 1% lactulose, and control infants received 1% dextrose in all feeds (human milk or formula). RESULTS: Twenty-eight infants participated (15 lactulose, 13 placebo). Small doses of lactulose appeared to be safe and did not cause diarrhea. Premature infants on lactulose had more Lactobacilli-positive stool cultures that appeared earlier with larger number of colonies. The lactulose group tended to have less intolerance to enteral feedings, to reach full oral feeds earlier, and to be discharged home earlier. They also tended to have fewer episodes of late-onset sepsis, lower Bell stage necrotizing enterocolitis, and their nutritional laboratory indices were better, especially calcium and total protein. CONCLUSIONS: This pilot study supports the safety of supplementing preterm infants' feeds with low doses of lactulose. It also demonstrated trends that may suggest positive prebiotic effects.

BACKGROUND: Pleiotropic (lipid lowering-independent) effects of statins are attributed to their antiinflammatory, antioxidant, and/or vascular actions. Extensive studies in various experimental models have established that pretreatment with simvastatin significantly protects heart and kidney injured by ischemia-reperfusion (IR). The purpose of the present study was to examine the effect of simvastatin on intestinal recovery and enterocyte turnover after intestinal IR injury in rats. METHODS: Male Sprague-Dawley rats were divided into three experimental groups:(1) sham rats underwent laparotomy,(2) IR-rats underwent occlusion of both superior mesenteric artery and portal vein for 30 min followed by 48 h of reperfusion, and (3) IR-SIM rats underwent IR and were treated with oral simvastatin (10 mg/kg) given by gavage immediately before and 24 h after operation. Intestinal structural changes, Park's injury score, enterocyte proliferation and enterocyte apoptosis were determined 24 h following IR. A non-parametric Kruskal-Wallis ANOVA test was used for statistical analysis with P less than 0.05 considered statistically significant. RESULTS: Treatment with simvastatin resulted in a significant increase in bowel and mucosal weight in ileum, villus height and crypt depth in jejunum and ileum compared to IR animals. IR-SIM rats had also a significantly lower intestinal injury score as well as lower apoptotic index in jejunum and ileum compared to IR animals. CONCLUSIONS: Treatment with simvastatin prevents gut mucosal damage and inhibits programmed cell death following intestinal IR in a rat.

PURPOSE: It has been reported that oral insulin (OI) has a trophic effect on intestinal mucosa. In the present study, we evaluated the effect of OI on enterocyte turnover and correlated it with insulin-receptor expression along the villus-crypt axis in a rat model of short bowel syndrome (SBS). METHODS: Male rats were divided into three groups: Sham rats underwent bowel transection, SBS rats underwent a 75% bowel resection, and SBS-OI rats underwent bowel resection and were treated with OI given in drinking water (1 U/ml) from the fourth postoperative day. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined on day 15. Real-time PCR was used to determine the level of insulin receptor-beta (IRB) mRNA. Insulin-receptor expression along the villus-crypt axis (villus tips, lateral villi and crypts) was assessed by immunohistochemistry. The effect of OI on cell turnover for each compartment was evaluated in correlation with the receptor expression. Statistical analysis was performed using the one-way ANOVA test, with P < 0.05 considered statistically significant. RESULTS: Treatment with OI resulted in a significant increase in all parameters of intestinal adaptation. Insulin-receptor expression in crypts significantly increased in SBS rats (vs. Sham rats) and was accompanied by a significant increase in enterocyte proliferation following OI administration. A significant increase in insulin-receptor expression at the tip of the villous and in the lateral villous in SBS rats (vs. Sham) was accompanied by decreased cell apoptosis in these compartments following treatment with OI. CONCLUSIONS: In a rat model of SBS, OI enhances enterocyte turnover and stimulates intestinal adaptation. The stimulating effect of insulin on enterocyte turnover correlates with insulin-receptor expression along the villus-crypt axis.

In the present study, we examine the responsiveness of intestinal epithelial cell turnover to leptin (LEP) in correlation with leptin receptor (LEPr) expression along the villus-crypt axis in a rat with short bowel syndrome (SBS). Adult rats underwent either a 75% intestinal resection or a transection. SBS-LEP rats underwent bowel resection and were treated with leptin starting from the 4th postoperative day. Parameters of intestinal adaptation, enterocyte proliferation and enterocyte apoptosis were determined at sacrifice. RT-PCR technique was used to determine bax and bcl-2 gene expression in ileal mucosa. Villus tips, lateral villi, and crypts were separated using laser capture microdissection. LEPr expression for each compartment was assessed by quantitative real-time PCR (Taqman). Treatment with leptin significantly stimulated all parameters of adaptation. LEPr expression in crypts significantly increased in SBS rats (vs. Sham rats) and was accompanied by a significant increase in enterocyte proliferation and decreased apoptosis following leptin administration. A significant increase in LEPr expression at the tip of the villus in SBS rats was accompanied by decreased cell apoptosis. In conclusion: leptin accelerated enterocyte turnover and stimulated intestinal adaptation. The effect of leptin on enterocyte proliferation and enterocyte apoptosis correlated with receptor expression along the villus-crypt axis.

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.