Joram Wardi

A polymorphism in the TNF-alpha promoter gene is associated with pediatric onset and colonic location of Crohn's disease.

OBJECTIVES:Studies suggest that pediatric onset of Crohns disease (CD) may demonstrate more frequent upper intestinal and colonic location and in male gender, in comparison to adults. Variability in age of onset (AOO) and location of disease have not been adequately explained to date. NOD2/CARD15 is highly expressed in the ileum, while TNF-α expression is distributed throughout the gastrointestinal tract. We hypothesized that polymorphisms that affect TNF-α function may influence variability of disease location and AOO of CD.METHODS:We evaluated two CD cohorts based on AOO (pediatric and adult onset) and 100 ethnically matched healthy controls. Patients were evaluated for AOO, disease location, and genotyped for the presence of polymorphisms in NOD2/CARD15 and in the TNF-α promoter region.RESULTS:Early AOO was associated with male gender, upper intestinal involvement, and a polymorphism in the binding site for NF-κB (TNF-863A polymorphism). NOD2 mutations and TNF-863A polymorphism had equivalent but opposite effects on disease location, with a strong combined effect (p = 0.004 corrected for multiple testing). NOD2/CARD15 was associated with ileal involvement, while presence of TNF-863A was inversely associated with ileal disease (OR = 0.42, p = 0.008) and positively associated with isolated colitis (OR = 2.16, p = 0.008, OR = 2.12, p = 0.03 corrected) and familial disease (p = 0.004).CONCLUSIONS:Pediatric onset of CD in our population was associated with a frequent polymorphism in the binding site for NF-κB in TNF-α promoter but not to defined NOD2/CARD15 disease-associated mutations. This polymorphism is associated with colitis and familial disease. NOD2/CARD15 mutations and the TNF-863C/A polymorphism have equivalent but opposite effects on disease location. These findings may help explain differences in CD phenotype.

Glycine modulates cytokine secretion, inhibits hepatic damage and improves survival in a model of endotoxemia in mice.

Background and aim: There is substantial experimental evidence that the amino acid glycine may have a role in protecting tissues against insults such as ischemia, hypoxia and reperfusion. Our aim was to investigate the ability of the amino acid glycine to prevent hepatic damage induced by injection of lipopolysaccharide and d‐galactosamine (d‐Gal), to modulate pro‐ and anti‐inflammatory cytokine levels, and to improve survival.

NOD2/CARD15 mutations and presence of granulomas in pediatric and adult Crohn's disease

Objectives:The etiology and mechanism leading to granuloma formation in patients with Crohn’s disease (CD) are presently unknown. The first susceptibility gene to be identified as a risk factor for CD is the NOD2/CARD15 gene on Chromosome 16. Mutations in NOD2 could affect the intracellular response to bacterial products and may eventually lead to granuloma formation. The association between NOD2 and granulomas has not been previously explored. We evaluated a possible association between NOD2 mutations and granuloma formation, and compared the prevalence of granulomas in both pediatric and adult cohorts. Methods:Patients were consecutively recruited through pediatric gastroenterology and adult gastroenterology programs. Patients were eligible if CD was confirmed, and they had undergone full colonoscopy with biopsy and/or surgical resection. Patients underwent genotyping for NOD2 disease-associated mutations. Results:A total of 230 patients were enrolled into the study, of whom 169 patients met all inclusion/exclusion criteria (Group 1, 77 patients [age range 1–16 years]; Group 2, 92 patients [age range 17–68 years]). Surgical resection was performed more often in adults (P < 0.005), and gastroscopy was performed more frequently in children (P < 0.001). Granulomas were found in 34% of the patients studied. The prevalence of granulomas did not differ by age, age group, or gender. A disease-associated NOD2 mutation was found in 37.8% of patients. Granulomas were found in 39% of patients with NOD2 mutations compared with 31% of those without NOD 2 mutations (difference was not significant). In addition, no difference was noted for the specific mutations. Conclusions:We did not find any correlation between NOD2 mutations and granuloma formation. The cause of granulomas in CD remains elusive.

Chronic Cholestasis Associated with Turner’s Syndrome: 12 Years of Clinical and Histopathological Follow-Up

Clinically significant liver disease is probably a rare condition in Turner’s syndrome and only a few cases of severe liver disease have been described. The natural history of patients with Turner’s syndrome and elevated cholestatic liver enzymes is unclear. We report a case with a long history of intrahepatic cholestasis and without clinical or histopathological progression in 12 years of follow-up. Like some other reports our case suggests, also histologically, that the liver disease in these patients runs a benign course.

A rapid continuous-real-time 13C-urea breath test for the detection of Helicobacter pylori in patients after partial gastrectomy.

Introduction: Before the development of efficient medications for peptic ulcer disease many patients were treated surgically by partial gastrectomy. The pathogenetic role of Helicobacter pylori was also not known yet. Some of these patients may therefore still harbor H. pylori in their remnant stomach as a carcinogenic agent for gastric cancer. This could be even more relevant for patients who were operated for tumors in the stomach. The efficacy of the urea breath test (UBT) is not clear in this population. Aims: To study the prevalence of H. pylori and to evaluate the sensitivity and specificity of the continuous UBT (BreathID) in postgastrectomized patients in Israel. In this system, the pH of the stomach is lowered by the addition of citric acid that may be beneficial in the smaller and more alkalic stomach. Methods: We compared retrospectively the results of our continous UBT with a rapid urease test (RUT) and the histology in all our patients who underwent gastroscopy for any clinical indication, and had a history of partial gastrectomy during the years 2002 to 2010. Only patients in whom H. pylori was tested by all the 3 methods during the same day were included in the study. We identified 76 such patients older than 18 years and performed a statistical analysis of all possibly related clinical data. The 3 methods were compared with each other. Results: H. pylori was positive in 14/76 (18.4%) patients when histology was considered as the gold standard method. The positive predictive value of the continuous UBT and the RUT was 0.64 and 0.35, respectively. The negative predictive value was high by both the methods, 0.92 and 0.95, respectively. Weight loss was correlated with positivity for H. pylori (P=0.032) and a longer gastric stump was marginally related to H. pylori (P=0.071). There was no difference for H. pylori positivity between patients with Billroth I or Billroth II operations. Prevalence of H. pylori was not lower in patients who had partial gastrectomy several years earlier. Conclusions: The prevalence of H. pylori is considerable even several years after partial gastrectomy. The BreathID is reliable to exclude H. pylori after partial gastrectomy. The positive predictive value of the UBT is not very high but better than the RUT. We suggest that all positive patients found by the breath test should be treated. Our results support the view that alternative noninvasive methods, such as the stool antigen test should be further studied and compared with the BreathID in larger populations.

Unusual cause of upper gastrointestinal bleeding

We report a case of recurrent severe upper gastrointestinal bleeding where the bleeding source was difficult to find during recurrent hospitalizations. Eventually videocapsule endoscopy was the modality that finally diagnosed an ulcerated lipoma within an area of intussuscepted jejunum. Segmental resection of small bowel was performed and no further bleeding episodes have occurred. Our case illustrates the value of capsule endoscopy and the rare potential of lipomas to cause serious gastrointestinal bleeding.

3-Aminobenzamide Prevents Concanavalin A-Induced Acute Hepatitis by an Anti-inflammatory and Anti-oxidative Mechanism

Background and AimsConcanavalin A is known to activate T cells and to cause liver injury and hepatitis, mediated in part by secretion of TNFα from macrophages. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been shown to prevent tissue damage in various animal models of inflammation. The objectives of this study were to evaluate the efficacy and mechanism of the PARP-1 inhibitor 3-aminobenzamide (3-AB) in preventing concanavalin A-induced liver damage.MethodsWe tested the in vivo effects of 3-AB on concanavalin A-treated mice, its effects on lipopolysaccharide (LPS)-stimulated macrophages in culture, and its ability to act as a scavenger in in vitro assays.Results3-AB markedly reduced inflammation, oxidative stress, and liver tissue damage in concanavalin A-treated mice. In LPS-stimulated RAW264.7 macrophages, 3-AB inhibited NFκB transcriptional activity and subsequent expression of TNFα and iNOS and blocked NO production. In vitro, 3-AB acted as a hydrogen peroxide scavenger. The ROS scavenger N-acetylcysteine (NAC) and the ROS formation inhibitor diphenyleneiodonium (DPI) also inhibited TNFα expression in stimulated macrophages, but unlike 3-AB, NAC and DPI were unable to abolish NFκB activity. PARP-1 knockout failed to affect NFκB and TNFα suppression by 3-AB in stimulated macrophages.ConclusionsOur results suggest that 3-AB has a therapeutic effect on concanavalin A-induced liver injury by inhibiting expression of the key pro-inflammatory cytokine TNFα, via PARP-1-independent NFκB suppression and via an NFκB-independent anti-oxidative mechanism.