Eran Israeli

Anti- Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease

Background and aims: Several antibodies have been reported in the sera of patients with Crohn’s disease (CD) and ulcerative colitis (UC). The most commonly described are anti-Saccharomyces cerevisiae mannan antibodies (ASCA) in CD and perinuclear antineutrophil cytoplasm antibodies (pANCA) in UC. Familial clustering of these antibodies has been described, suggesting they might be genetic markers. Our aim was to investigate the presence of these antibodies before the emergence of overt clinical manifestations. Methods: Since 1980, the Israeli Defense Force (IDF) Medical Corps Serum Repository has stored serum samples obtained systematically from 5% of all recruits on enlistment, and from the same population on discharge from compulsory military service. We evaluated serum samples obtained from 32 subjects with CD and eight with UC before they were clinically diagnosed, along with samples from matched controls. Results: ASCA were present in 10/32 (31.3%) CD patients before clinical diagnosis compared with 0/95 (0%) controls (p<0.001). None of the eight patients with serum samples available before diagnosis of UC were ASCA positive. ASCA was positive in 54.5% of patients after diagnosis of CD. The mean interval between ASCA detection and diagnosis was 38 months. In 90% of patients, antibodies were detected in the first available serum sample; therefore, measurements of the average time from the presence of ASCA to diagnosis may be even longer. pANCA were present in 2/8 (25%) patients with available sera before the diagnosis of UC. None of their 24 matched controls were positive (p = 0.014). Conclusions: ASCA and pANCA may predict development of inflammatory bowel disease years before the disease is clinically diagnosed.

Treatment of chronic hepatitis C virus infection via antioxidants : Results of a phase I clinical trial

Background: The pathogenesis of chronic hepatitis C virus (HCV) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress. Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation (steatosis) that leads to necro-inflammation and necrosis of hepatic cells. Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection. Aims: To determine the safety and efficacy of treatment of chronic HCV patients via a combination of antioxidants. Methods: Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol), along with four different intravenous preparations (glycyrrhizin, ascorbic acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Patients were monitored for HCV-RNA levels, liver enzymes, and liver histology. Assessment of quality of life was performed using the SF-36 questionnaire. Results: In one of the tested parameters (eg, liver enzymes, HCV RNA levels, or liver biopsy score), a combination of antioxidants induced a favorable response in 48% of the patients (24). Normalization of liver enzymes occurred in 44% of patients who had elevated pretreatment ALT levels (15 of 34). ALT levels remained normal throughout follow-up period in 72.7% (8 of 11). A decrease in viral load (one log or more) was observed in 25% of the patients (12). Histologic improvement (2-point reduction in the HAI score) was noted in 36.1% of the patients. The SF-36 score improved in 26 of 45 patients throughout the course of the trial (58% of the patients). Treatment was well tolerated by all patients. No major adverse reactions were noted. Conclusions: These data suggest that multi antioxidative treatment in chronic HCV patients is well tolerated and may have a beneficial effect on necro-inflammatory variables. A combination of antiviral and antioxidative therapies may enhance the overall response rate of these patients.

Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease

BACKGROUND & AIMS Osteoporosis frequently occurs in Crohns disease, often because of corticosteroids. Budesonide as controlled release capsules is a locally acting corticosteroid with low systemic bioavailability. We investigated its effects on bone compared with prednisolone. METHODS In 34 international centers, 272 patients with Crohns disease involving ileum and/or colon ascendens were randomized to once daily treatment with budesonide or prednisolone for 2 years at doses adapted to disease activity. One hundred eighty-one corticosteroid-free patients had active disease (98 had never received corticosteroids, corticosteroid naive; 83 had received corticosteroids previously, corticosteroid exposed), and 90 had quiescent disease, receiving long-term low doses of corticosteroids, corticosteroid-dependent; in 1 patient, no efficacy data were obtained. Bone mineral density and fractures were assessed in a double-blinded fashion; disease activity, side effects, and quality of life were monitored. RESULTS Neither the corticosteroid-free nor the corticosteroid-dependent patients treated with budesonide differed significantly in bone mineral density from those receiving prednisolone. However, corticosteroid-naive patients receiving budesonide had smaller reductions in bone mineral density than those on prednisolone (mean, -1.04% vs -3.84%; P = .0084). Treatment-emergent corticosteroid side effects were less frequent with budesonide. Efficacy was similar in both groups. CONCLUSIONS Treatment with budesonide is associated with better preserved bone mass compared with prednisolone in only the corticosteroid-naive patients with active ileocecal Crohns disease. In both the corticosteroid-free and corticosteroid-dependent groups, budesonide and prednisolone were equally effective for up to 2 years, but budesonide caused fewer corticosteroid side effects.

Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response

Background: Intensifying infliximab therapy is often practiced in Crohns disease (CD) patients losing response to the drug but there are no data if halving the interval is superior to doubling the dose. We aimed to assess the efficacy of infliximab dose intensification by interval‐halving compared with dose‐doubling. Methods: A multicenter retrospective study of CD patients losing response to infliximab was undertaken. The clinical outcome of patients whose infusion intervals were halved (5 mg/kg/4 weeks) was compared with patients treated by dose‐doubling (10 mg/kg/8 weeks). Results: In all, 168 patients were included from 18 centers in Europe, USA, and Israel. Of these, 112 were intensified by dose‐doubling and 56 received interval‐halving strategy. Early response to dose‐escalation was experienced by 86/112 (77%) patients in the dose‐doubling group compared with 37/56 patients (66%) in the interval‐halving group (odds ratio [OR] 1.7, 95% confidence interval [CI] 0.8–3.4, P = 0.14). Sustained clinical response at 12 months postescalation was maintained in 50% of patients in the dose‐doubling group compared with 39% in the interval‐halving group (OR 1.5, 95% CI 0.8–2.9, P = 0.2). On multivariate analysis, predictors of long‐term response to escalation were a nonsmoking status, CD diagnosis between 16–40 years of age, and normal C‐reactive protein (CRP). Conclusions: Dose intensification leads to a sustained regained response in 47% of CD patients who lost response to standard infliximab dose, but halving the infusion intervals is probably not superior to dose‐doubling. Given the costs and patient inconvenience incurred by an additional infusion visit, the dose‐doubling strategy may be preferable to the interval‐halving strategy. (Inflamm Bowel Dis 2012;)

Discordance between the degree of osteopenia and the prevalence of spontaneous vertebral fractures in Crohn's disease.

Background : A high prevalence of osteoporosis has been noted in Crohns disease, but data about fractures are scarce.

The efficacy of shortening the dosing interval to once every six weeks in Crohn's patients losing response to maintenance dose of infliximab.

Aliment Pharmacol Ther 2011; 33: 349–357

Childhood hygiene is associated with the risk for inflammatory bowel disease: a population-based study.

OBJECTIVES:The “hygiene hypothesis” postulates that individuals raised in a sanitary environment are more likely to develop inflammatory bowel disease (IBD). Several studies previously demonstrated contradictory results in this regard. We performed for the first time a population-based study on the association of surrogate markers of childhood hygiene with the risk for IBD.METHODS:A cross-sectional population-based study was undertaken. Information on number of siblings, birth order, and living in an urban versus rural environment was obtained for 399,251 Jewish adolescents at the age of 17 yr from 1998 to 2004. The study population included only subjects born in Israel. In order to control for genetic confounding, subjects were also divided according to their ethnic group as being Ashkenazi, Sephardic, or Israeli in origin.RESULTS:In total, 768 cases of inflammatory bowel disease (IBD) were diagnosed (0.19%), with 53.8% of the cases being of Ashkenazi origin. On multivariate analysis, variables significantly associated with IBD were male gender (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.24–1.67), Ashkenazi origin (OR 1.91, 95% CI 1.63–2.22), living in an urban environment (OR 1.38, 95% CI 1.02–1.78), small number of siblings in the family (for 1 sibling vs 5 or more, OR 2.63, 95% CI 1.49–4.62), and higher birth order (for birth order of 5 or higher vs 1, OR 2.35, 95% CI 1.47–3.77), showing for both variables an almost strictly highly significant monotonic association (P value for trend <0.001).CONCLUSIONS:Surrogate markers of childhood hygiene are associated with the risk for IBD, thus reinforcing the “hygiene hypothesis.”

The prevalence of chronic diarrhea among diabetic patients.

OBJECTIVE:The prevalence of chronic diarrhea in patients with type I and type II diabetes is uncertain, most data being available from tertiary referral centers. We report the prevalence and etiology of chronic diarrhea in 861 heterogeneous diabetic patients attending a primary care diabetic outpatient clinic.METHODS:All patients attending the clinic were asked to fill in a questionnaire relating to their bowel habits. Patients who fulfilled the criteria for chronic diarrhea underwent a comprehensive workup to define the cause of the diarrhea. Additional parameters were the mean duration of diabetes, hemoglobin-A1c levels, and the presence of autonomic neuropathy.RESULTS:Chronic diarrhea was diagnosed in 32 patients (overall prevalence of 3.7%). The prevalence of nondiabetic diarrhea was higher among type I diabetic patients than among type II patients (3.29%vs 2.3%), although it did not reach statistical significance. Diabetic diarrhea was more common among type I than type II diabetic patients (5.2%vs 0.4%, respectively, p < 0.01). The most common cause of nondiabetic diarrhea was medication induced (metformin).CONCLUSIONS:Chronic diarrhea is more frequent in type I diabetic patients. The higher prevalence of diarrhea in this population can be attributed to diabetic diarrhea (which is quite rare in type II patients). The most common cause of nondiabetic diarrhea is drug therapy with metformin.

Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice

Endocannabinoids function as neurotransmitters and neuromodulators in the central nervous system via specific receptors and apparently have a neuroprotective role. We assumed that the endocannabinoid system could be involved in the pathogenesis of hepatic encephalopathy (HE), a neuropsychiatric syndrome due to liver disease. We used a mouse model of a thioacetamide induced fulminant hepatic failure. We found that the levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) were elevated in the brain. Treatment with either 2-AG or with the CB1 receptor antagonist, SR141716A, improved a neurological score, activity and cognitive function. Activation of the CB2 receptor by a selective agonist, HU308, also improved the neurological score. 2-AG activity could be blocked with the specific CB2 receptor antagonist SR144528A. The CB1 receptor agonist noladin ether was inactive. We conclude that the endocannabinoid system may play an important role in the pathogenesis of HE. Modulation of this system either by exogenous agonists specific for the CB2 receptors or possibly also by antagonists to the CB1 receptors may have therapeutic potential.

Effects of a 4-Month Recruit Training Program on Markers of Bone Metabolism

UNLABELLED Stress fracture susceptibility results from accelerated bone remodeling after onset of novel exercise and may be reflected in bone turnover changes. It is unknown if the bone turnover response to exercise is different between sexes. PURPOSE To assess disparity between sexes in bone metabolism markers during military recruit training and to evaluate relationships between bone turnover markers and factors that may affect bone metabolism. METHODS Volunteers were age-matched men (n = 58) and women (n = 199), 19 yr old, entering gender-integrated combat training. Blood was collected at 0, 2, and 4 months and anthropometric and fitness measures at 0 and 4 months. Serum was analyzed for biomarkers reflecting bone formation (bone alkaline phosphatase and procollagen I N-terminal peptide), bone resorption (C-telopeptide cross-links of type I collagen and tartrate-resistant acid phosphatase), endocrine regulation (parathyroid hormone, calcium, and 25(OH)D), and inflammation (interleukin 1B, interleukin 6, and tumor necrosis factor alpha). Data were analyzed using ANOVA, correlation, and regression analyses. RESULTS Bone turnover markers were higher in men (P < 0.01) and increased similarly for both sexes from 0 to 2 months (P < 0.01). Independent of gender, VO2max (R = 0.477) and serum calcium (R = 0.252) predicted bone formation activity (bone alkaline phosphatase) at baseline (P < 0.01). Serum calcium and parathyroid hormone decreased (2.0 and 6.4%, respectively) from 0 to 2 months (P < 0.001), returning to baseline at 4 months for both sexes. Men exhibited a decrease in 25(OH)D from 0 to 4 months (P = 0.007). Changes in endocrine regulators were significantly correlated with changes in bone turnover markers. Inflammatory markers did not differ between sexes and did not increase. CONCLUSION Military training increased bone formation and resorption markers in 2 months, suggesting rapid onset of strenuous exercise accelerates bone turnover similarly in men and women. Although bone turnover markers were higher in men than women, bone formation status may be related to aerobic fitness and serum calcium independent of gender and may be affected by small changes in endocrine regulators related to nutrition.