Publications by authors named "Alon Lang"

26 Publications

  • Page 1 of 1

A Rare Nonrecognized Cause of Dysphagia.

Gastroenterology 2021 03 16;160(4):e8-e9. Epub 2020 Sep 16.

Department of Gastroenterology.

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http://dx.doi.org/10.1053/j.gastro.2020.08.059DOI Listing
March 2021

Prospective Observational Evaluation of Time-Dependency of Adalimumab Immunogenicity and Drug Concentrations: The POETIC Study.

Am J Gastroenterol 2018 06 5;113(6):890-898. Epub 2018 Jun 5.

Department of Gastroenterology, Sheba Medical Center Tel Hashomer, Ramat Gan, Israel. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Rambam Health Care Campus and Bruce Rappaport School of Medicine, Haifa, Israel. Technion Israel Institute of Technology, Haifa, Israel. Department of Gastroenterology, Meir Medical Center, Kfar Saba, Israel. The Kamila Gonczarowski Institute of Gastroenterology, Assaf Harofeh Medical Center, Zerifin, Israel.

Objectives: Adalimumab is usually self-injected at home, making prospective serial-sampling studies challenging and scarce. This has led to a gap in knowledge about evolution of anti-adalimumab antibodies (AAAs) over time and its correlation with clinical and inflammatory outcomes.

Methods: A program for home visits by physicians at induction, every 3 months and at event of relapse, was established prospectively for Crohn's disease (CD) patients. At each visit, patients' clinical scores were determined and sera were obtained for C-reactive protein, drug, and AAA levels. This cohort was compared to a parallel prospective cohort of infliximab-treated CD patients. In a subgroup of 29 patients, trough and in-between-trough levels were compared, to elucidate the importance of timing of sampling during the injection cycle.

Results: Ninety-eight CD patients starting adalimumab were prospectively followed (median follow-up 44 weeks) and 621 serum samples were analyzed. Thirty-three patients (32%) developed AAA; 18/33 (55%) of them as early as week 2, and 26/33 (79%) by week 14. Induction period AAAs were strongly associated with primary non-response (odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6-17.8, p = 0.005). As compared to antibodies-to-infliximab (ATI), AAA formation rate over time was significantly lower (p = 0.01) and AAA were much more specific-85% of AAA events were associated with loss-of-response compared with 58% rate for ATI (p = 0.01). In 29 patients sampled serially during an injection cycle, levels of drug and AAA seemed comparable between four time-points during a single cycle both in patients with or without AAA (n = 8, n = 21, respectively).

Conclusions: When followed prospectively and serially, AAAs are found to arise earlier than previously appreciated and their impact may be more pronounced for primary rather than secondary, non-response. Drug and AAA levels were similar both at trough and in-between injections, enabling to simplify therapeutic drug monitoring of adalimumab.
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http://dx.doi.org/10.1038/s41395-018-0073-0DOI Listing
June 2018

Percutaneous Needle Aspiration of a Partially Deflated Intragastric Balloon: a Forgotten Modality? Review of the Literature.

Obes Surg 2018 06;28(6):1781-1784

Sheba Hospital, Department of Gastroenterology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

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http://dx.doi.org/10.1007/s11695-018-3205-0DOI Listing
June 2018

Reply.

Clin Gastroenterol Hepatol 2016 06 3;14(6):913-913.e2. Epub 2016 Mar 3.

Gastroenterology Department, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer, Israel.

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http://dx.doi.org/10.1016/j.cgh.2016.02.025DOI Listing
June 2016

Reply.

Clin Gastroenterol Hepatol 2016 Jan 17;14(1):168. Epub 2015 Oct 17.

Gastroenterology Department, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer, Israel.

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http://dx.doi.org/10.1016/j.cgh.2015.09.020DOI Listing
January 2016

Stenting in malignant colonic obstruction--is it a real therapeutic option?

Int J Colorectal Dis 2016 Jan 28;31(1):131-5. Epub 2015 Aug 28.

Department of Surgery, Sheba Medical Center, Tel-Hashomer, and Faculty of Medicine, Tel-Aviv University, 52621, Tel-Aviv, Israel.

Background: Malignant colonic obstruction is commonly treated surgically. Colonic stents are a therapeutic option for palliation or used as a bridge to surgery or chemotherapy.

Objective: The aim of the study was to evaluate the clinical success rate of stenting as a bridge to one-step surgery, chemotherapy, or as a palliative measure.

Design: This was a retrospective observational study.

Settings: The study was conducted at a university-affiliated tertiary referral center.

Patients And Interventions: From 2007 to 2014, 45 patients with malignant colonic obstruction were referred for stent insertion.

Main Outcome Measures: Patients were grouped according to three pre-defined treatment goals: group 1: restorative one-step procedure without an ostomy, group 2: completion of scheduled chemotherapy before surgery, and group 3: palliation without surgical intervention.

Results: Group 1 included 11 patients. Three patients (27.3 %) met the treatment goal of one-step surgery. Eight patients (72.7 %) did not reach the primary goal due to stent insertion failure (four patients), stent-related complications (two patients), and failure to perform a one-step surgery after successful stent insertion (two patients). Group 2 included 12 patients. Chemotherapy was successfully completed prior to surgery in six patients (50 %). Six patients (50 %) did not achieve treatment goal due to stent insertion failure (two patients), stent migration (two patients), stent-related perforation (one patient), and mortality (one patient). Group 3 included 20 patients. Long-term palliation without surgical intervention was achieved in eight patients (40 %). Stent insertion failed in seven patients (35 %). Five patients (25 %) needed urgent surgery due to stent complications (three migrations and two perforations).

Limitations: The study was limited by its retrospective nature and small sample size.

Conclusions: This study demonstrates only a modest success rate of colonic stents in the treatment of malignant colonic obstruction. Although colonic stenting seems to be an effective method of relieving colonic obstruction, high failure rates limits its applicability.
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http://dx.doi.org/10.1007/s00384-015-2375-7DOI Listing
January 2016

Ashkenazi Jewish origin protects against formation of antibodies to infliximab and therapy failure.

Medicine (Baltimore) 2015 May;94(18):e673

From the Department of Gastroenterology, Sheba Medical Center Tel Hashomer (BU, OH-N, UK, MY, EF, OP, AL, YM, BA, AL, RE, SB-H); Institute of Clinical Pharmacology, Sheba Medical Center Tel Hashomer (RL); Pediatric Gastroenterology Unit, Edmond & Lily Safra Children's Hospital Tel Hashomer (BW); Sackler School of Medicine, Tel-Aviv University (BU, OH-N, UK, MY, EF, OP, RL, AL, YM, BA, AL, BW, RE, SB-H); and Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel (YC).

Infliximab is an anti-tumor necrosis factor (TNF) used for treatment of inflammatory bowel disease (IBD) as well as rheumatoid arthritis, psoriasis, and other inflammatory conditions. Antibodies to infliximab (ATI) develop in approximately 45% of infliximab-treated IBD patients and are correlated with loss of clinical response. Scarce data exist as to factors which predict infliximab immunogenicity.To investigate factors that may predict formation of antibodies to infliximab (ATI) and infliximab therapy failure an observational study of consecutive IBD patients treated with infliximab between 2009 and 2013 was performed. Trough levels of ATI were measured. Patients were monitored for disease activity using clinical activity indexes and were classified according to ATI formation and clinical response. All clinical and demographic parameters were analyzed for association with the designated outcomes.One hundred fifty-nine patients were included and 1505 sera were tested. On multivariate analysis, Jewish Ashkenazi ethnicity was protective against both development of ATI (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.17-0.7, P = 0.005) and treatment failure (OR 0.29, 95% CI 0.13-0.66, P = 0.003). Concomitant immunomodulator therapy was also negatively associated with immunogenicity and infliximab therapy failure (OR 0.31, 95% CI 0.15-0.65, P = 0.002; OR 0.42 95% CI 0.18-0.99, p = 0.04, respectively), whereas episodic therapy was positively associated with both outcomes (OR 4.2 95% CI 1.07-16.1, p = 0.04, OR 4.45 95% CI 1.2-16.6, p = 0.026 respectively). All other variables, including IBD type, gender, weight, age, smoking status and disease duration, were not predictive of ATI formation or clinical failure. However, among Crohn's disease patients, a non-stricturing non-penetrating phenotype was protective against ATI formation (OR 0.4, 95% CI 0.14-0.96, p = 0.04). P = 0.04, respectively), whereas episodic/interrupted therapy was positively associated with both outcomes (OR 4.2, 95% CI 1.07-16.1, P = 0.04; OR 4.45, 95% CI 1.2-16.6, P = 0.026, respectively). All other variables, including IBD type, sex, weight, age, smoking status, and disease duration, were not predictive of ATI formation or clinical failure. However, among Crohn disease patients, a nonstricturing nonpenetrating phenotype was protective against ATI formation (OR 0.4, 95% CI 0.14-0.96, P = 0.04).Jewish Ashkenazi ethnicity is protective of ATI formation and infliximab therapy failure. These findings suggest a role for ethnicity, and implicitly for genetic predisposition, in modulating the risk of anti-TNF immunogenicity and treatment unresponsiveness.
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http://dx.doi.org/10.1097/MD.0000000000000673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602524PMC
May 2015

[Curcumin add-on therapy for ulcerative colitis].

Harefuah 2015 Jan;154(1):56-8, 66

Ulcerative Colitis (UC) is a chronic inflammatory disease of colon mucosa, which results from inappropriate inflammatory response. Pharmacological treatments that are used to manage UC are usually targeted to moderate the inflammatory response, however, they are associated with significant adverse effects, which call for finding additional treatment options. Curcumin is a polyphenol that is extracted from turmeric (Curcuma longa). This medicinal plant has been traditionally used in India and in China since ancient times. Recently curcumin has been demonstrated to possess anti-inflammatory, anti-proliferative and antibacterial properties. Based on these reports, our article describes a case report of a patient treated with curcumin in addition to 5-Aminosalicylic acid (5ASA) and presents an integrative approach for the treatment of ulcerative colitis.
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January 2015

Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial.

Clin Gastroenterol Hepatol 2015 Aug 24;13(8):1444-9.e1. Epub 2015 Feb 24.

Gastroenterology Department, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer, Israel.

Background & Aims: The phytochemical compound curcumin was reported to be effective in maintaining remission in patients with ulcerative colitis (UC). We investigated curcumin's efficacy in inducing remission in patients with active mild-to-moderate UC.

Methods: We performed a multicenter randomized, placebo-controlled, double-blind study of 50 mesalamine-treated patients with active mild-to-moderate UC (defined by the Simple Clinical Colitis Activity Index [SCCAI]) who did not respond to an additional 2 weeks of the maximum dose of mesalamine oral and topical therapy. Patients were randomly assigned to groups who were given curcumin capsules (3 g/day, n = 26) or an identical placebo (n = 24) for 1 month, with continued mesalamine. The primary outcome was the rate of clinical remission (SCCAI ≤2) at week 4. Clinical and endoscopic responses were also recorded.

Results: In the intention-to-treat analysis, 14 patients (53.8%) receiving curcumin achieved clinical remission at week 4, compared with none of the patients receiving placebo (P = .01; odds ratio [OR], 42; 95% confidence interval [CI], 2.3-760). Clinical response (reduction of ≥3 points in SCCAI) was achieved by 17 patients (65.3%) in the curcumin group vs. 3 patients (12.5%) in the placebo group (P < .001; OR, 13.2; 95% CI, 3.1-56.6). Endoscopic remission (partial Mayo score ≤1) was observed in 8 of the 22 patients evaluated in the curcumin group (38%), compared with none of 16 patients evaluated in the placebo group (P = .043; OR, 20.7; 95% CI, 1.1-393). Adverse events were rare and comparable between the 2 groups.

Conclusions: Addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects. Curcumin may be a safe and promising agent for treatment of UC. Clinicaltrials.gov number: NCT01320436.
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http://dx.doi.org/10.1016/j.cgh.2015.02.019DOI Listing
August 2015

Severe and morbid obesity in Crohn's disease patients: prevalence and disease associations.

Digestion 2013 25;88(1):26-32. Epub 2013 Jun 25.

Department of Internal Medicine D, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: Crohn's disease (CD) is frequently associated with weight loss and malnutrition. However, as the prevalence of obesity increases worldwide, it may become a clinical problem even in CD.

Aim: To assess the prevalence of severe/morbid obesity in CD patients and to compare their disease characteristics to nonobese CD patients.

Methods: A retrospective analysis of a computerized CD patient database was performed to identify severely/morbidly obese patients (BMI >35). Prevalence was compared to data of the general population. Severely/morbidly obese CD patients were then compared to randomly selected nonobese CD patients (BMI <30) in a 1:3 ratio.

Results: Thirteen severely/morbidly obese patients out of 560 CD patients were found (2.3%), which is significantly lower than the prevalence in the general population (5.6%, p = 0.001). When compared to 39 nonobese CD patients, colonic disease was significantly more common among severely/morbidly obese CD patients (odds ratio: 6, 95% CI: 1.35-26.3, p = 0.02), while there was no difference in other disease parameters. Interestingly, 4 morbidly obese CD patients had undergone laparoscopic sleeve gastrectomy for treatment of morbid obesity with a favorable surgical course.

Conclusion: CD in severely/morbidly obese patients is more often colonic, but otherwise no different than CD in nonobese patients. Sleeve gastrectomy is a viable therapeutic option for morbidly obese CD patients.
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http://dx.doi.org/10.1159/000351529DOI Listing
March 2014

Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease.

J Crohns Colitis 2011 Dec;5(6):555-8

Dept. of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel.

Introduction: Limited data suggest the absence of infliximab in breast milk, thereby implying the safety of this drug during breast-feeding. We aimed to re-evaluate the presence of infliximab in breast milk of nursing IBD patients.

Methods: Serum and breast milk were obtained post-partum from 3 breast-feeding patients with Crohn's disease before and after re-initiation of infliximab. ELISA assay was employed to measure infliximab level in maternal serum and in breast milk. The level of infliximab was also measured in breast milk of a control group of 8 nursing healthy mothers.

Results: Infliximab was undetectable in breast milk prior to the first infusion and was also not measurable in 8 lactating women not exposed to infliximab. Infliximab levels in breast milk rose up to 101ng/ml within 2-3days of the infusion. These levels of infliximab in breast milk were roughly 1/200th of the level in blood.

Conclusions: In contrast with prior reports, infliximab can be detected in the breast milk of nursing mothers. The miniscule amounts of infliximab transferred in breast milk are unlikely to result in systemic immune-suppression of the infant. Nonetheless, local effects of this exposure on the neonates' intestine and potential immune sensitization or tolerization towards the drug can not be excluded and merit further investigations.
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http://dx.doi.org/10.1016/j.crohns.2011.05.006DOI Listing
December 2011

Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study.

Digestion 2012 17;85(1):1-8. Epub 2011 Nov 17.

Department of Gastroenterology, Chaim Sheba Medical Center affiliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background And Aims: Inflammatory bowel disease (IBD) patients suffer from significant morbidity and diminished life quality. The plant cannabis is beneficial in various gastrointestinal diseases, stimulating appetite and causing weight gain. Our aims were to assess whether treatment with inhaled cannabis improves quality of life, disease activity and promotes weight gain in these patients.

Methods: Patients with long-standing IBD who were prescribed cannabis treatment were included. Two quality of life questionnaires and disease activity indexes were performed, and patient's body weight was measured before cannabis initiation and after 3 months' treatment.

Results: Thirteen patients were included. After 3 months' treatment, patients reported improvement in general health perception (p = 0.001), social functioning (p = 0.0002), ability to work (p = 0.0005), physical pain (p = 0.004) and depression (p = 0.007). A schematic scale of health perception showed an improved score from 4.1 ± 1.43 to 7 ± 1.42 (p = 0.0002). Patients had a weight gain of 4.3 ± 2 kg during treatment (range 2-8; p = 0.0002) and an average rise in BMI of 1.4 ± 0.61 (range 0.8-2.7; p = 0.002). The average Harvey-Bradshaw index was reduced from 11.36 ± 3.17 to 5.72 ± 2.68 (p = 0.001).

Conclusions: Three months' treatment with inhaled cannabis improves quality of life measurements, disease activity index, and causes weight gain and rise in BMI in long-standing IBD patients.
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http://dx.doi.org/10.1159/000332079DOI Listing
May 2012

Travel-associated health risks for patients with inflammatory bowel disease.

Clin Gastroenterol Hepatol 2012 Feb 2;10(2):160-5, 165.e1. Epub 2011 Nov 2.

Gastroenterology Department, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Hashomer, Israel.

Background & Aims: There are few data on risk of travel for patients with inflammatory bowel disease (IBD). We assessed rates of illness while traveling among patients with IBD.

Methods: We performed a retrospective, case-controlled study of illnesses among 222 patients with IBD and 224 healthy individuals (controls) during 1099 total trips. Data were retrieved by structured questionnaires, personal interviews, and chart review.

Results: Participants had 142 episodes of illness during the trips; 92% were enteric disease. An episode of illness occurred during 79/523 (15.1%) trips made by patients with IBD compared with 63/576 (10.9%) trips made by controls (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.01-2.0; P = .04). However, this difference was mostly attributable to the increased incidence of illness among IBD patients traveling in industrialized countries. In contrast, the rate of illness among travelers to developing countries was similar among patients with IBD and controls (34/200, 17% vs 52/243, 21% of trips, respectively; P = .24). Moreover, numerically more controls that traveled to the tropics developed illness than travelers with IBD (43/135 vs 23/97, respectively; P = .18). In multivariate analysis, factors that increased risk for travel illness included frequent flares of IBD (OR, 1.9; 95% CI, 1.1-3.4; P = .02) and prior IBD-related hospitalizations (OR, 3.5; 95% CI, 1.3-9.3; P = .01); remission within 3 months before traveling reduced the risk for illness (OR, 0.3; 95% CI, 0.16-0.5; P < .001). Use of immunomodulatory drugs was not independently associated with risk of illness during travel.

Conclusions: Patients with IBD have a higher rate of illness compared with controls during trips to industrialized countries, but not to developing or tropical regions. These findings indicate that most travel-associated illnesses stem from sporadic IBD flares rather than increased susceptibility to enteric infections.
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http://dx.doi.org/10.1016/j.cgh.2011.10.025DOI Listing
February 2012

Familial ulcerative colitis in Israeli Jews: its prevalence and clinical severity compared to sporadic disease.

Ann Gastroenterol 2011 ;24(4):285-289

Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa (Yehuda Chowers).

Background: A family history of inflammatory bowel disease (IBD) is present in some ulcerative colitis (UC) patients. We aimed to investigate the familial occurrence of UC and its impact on disease severity.

Methods: A structured questionnaire was distributed to patients with UC. Parameters pertaining to disease severity were compared for patients with or without positive family history of IBD.

Results: The study group consisted of 168 UC patients with a total of 952 first degree relatives. Positive family history for IBD in a first degree relative was reported in 24 patients (14%). Six of the 336 parents (1.8%) had IBD (all with UC). There were 13 siblings with IBD (4 CD, 9 UC) out of 249 (5.4%). Seven of 376 (1.9%) offsprings had IBD (4 CD, 3 UC). Familial patients were more commonly females and have reported significantly more disease exacerbations than the sporadic group (17.7±15 versus 6.8±11, respectively, p=0.006). On multivariate analysis, familial disease was significantly and independently associated with both female sex (OR 4.1, 95% CI 1.1-14.9, p=0.04) and more exacerbations per year (annual OR 1.05, 95% CI 1.01-1.1, p=0.02). However, similar proportions of sporadic and familial patients wherever hospitalized, underwent colectomy or were treated by immune-suppressors.

Conclusions: Familial occurrence of UC is not uncommon among Jewish patients in Israel. The familial-genetic component may preferentially influence disease occurrence among females, and is possibly associated with more disease flares although other parameters of disease severity do not seem to be impacted.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959319PMC
January 2011

Lidocaine inhibits epithelial chemokine secretion via inhibition of nuclear factor kappa B activation.

Immunobiology 2010 Apr 26;215(4):304-13. Epub 2009 Jun 26.

Department of Gastroenterology, Chaim Sheba Medical Center, Tel-Aviv University, Tel-Hashomer 52621, Israel.

Aim: To study the antiinflammatory effect of lidocaine in intestinal epithelial cells.

Methods: HT-29 and T-84 cells were grown in culture with and without TNF-alpha, lidocaine, aconitine and veratridine. The secretion of IL-8 and IP-10 was measured by ELISA. A cDNA microarray was used to assess gene expression. Real-time PCR was used to confirm the results. Western blots and a modified electromobility shift assay (EMSA) were used to assess NFkappaB activation.

Results: Lidocaine inhibited spontaneous and TNF-alpha induced secretion of IL-8 and IP-10. The combination of veratridine or aconitine, voltage-gated sodium channels (VGSC) agonists that open VGSCs, with lidocaine did not alter the effect of lidocaine on cytokine secretion. Gene array analysis revealed that IkappaB transcription was induced by TNF-alpha and inhibited by lidocaine. IkappaB real-time PCR confirmed this observation. A Western blot analysis demonstrated that the degradation of IkappaB following TNF-alpha treatment was markedly inhibited by lidocaine. Lidocaine treatment resulted in decreased generation of phosphorylated IkappaB. A modified EMSA was complementary and demonstrated marked inhibition of NFkappaB nuclear binding.

Conclusion: Lidocaine inhibits IL-8 and IP-10 secretion from intestinal cells. This effect is mediated by inhibition of NFkappaB activation via decreased IkappaB phosphorylation and is not mediated by lidocaine's effect on VGSC.
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http://dx.doi.org/10.1016/j.imbio.2009.05.006DOI Listing
April 2010

Familial clustering of Crohn's disease in Israel: prevalence and association with disease severity.

Inflamm Bowel Dis 2009 Feb;15(2):171-5

Gastroenterology Division, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Israel.

Background: There is limited data addressing the severity of Crohn's disease (CD) in patients with a family history of inflammatory bowel disease (IBD) compared to sporadic cases.

Methods: We investigated the familial occurrence of IBD and its correlation with disease behavior in CD patients attending the Israeli IBD Foundation meeting using a structured questionnaire.

Results: The study group consisted of 181 CD patients with a total of 825 1(st) degree relatives. Positive family history for IBD in a 1(st) degree relative was reported in 30 patients (16%). Nine out of the 360 parents (2.5%) had IBD (4 CD, 5 UC). There were 17 siblings with IBD (15 CD, 2 UC) out of 351 (4.8%). Ten out of 114 (8.8%) offsprings had IBD (6 CD, 4 UC). When two siblings were affected, their respective age of disease onset was strikingly concordant (r = 0.76, p = 0.008). There was no difference between sporadic and familial CD patients in the age of disease onset, the location of disease, proportion of smokers or percentage of Ashkenazi origin. Furthermore, similar proportions of sporadic and familial patients underwent intestinal surgery, had penetrating or obstructive complications or were treated by immunomodulators and/or biologics. There was also no difference in the reported percentage of time with active disease or the number of flare-ups.

Conclusions: The prevalence of familial disease among Jewish CD patients in Israel is at the high range of the rate found in other ethnicities. Having a positive family history of IBD has no impact on the severity of the disease.
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http://dx.doi.org/10.1002/ibd.20740DOI Listing
February 2009

Functional voltage-gated sodium channels are expressed in human intestinal epithelial cells.

Digestion 2008 7;77(2):108-17. Epub 2008 Apr 7.

Department of Pathology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Background And Aim: Local anesthetics which preferentially interact with voltage-gated sodium channels (VGSCs) were shown to have a clinical beneficial effect in ulcerative colitis and to regulate the secretion of inflammatory mediators from intestinal epithelial cells. However, expression of VGSCs in epithelial cells was not demonstrated. Herein we assessed whether intestinal epithelial cells express VGSCs.

Methods: The expression of VGSCs in normal human colonic tissue and in the TNFalpha-treated or untreated intestinal epithelial cell line HT-29 was studied by immunofluorescence staining and FACS analysis, Western blot, immunohistochemistry, and RT-PCR using primers specific for several VGSC alpha subunits. The function of VGSCs was assessed by measuring changes in the membrane potential of the intestinal epithelial cells following incubation with lidocaine, veratridine, or both.

Results: HT-29 cells were shown to express the VGSC alpha protein. mRNA analysis revealed the expression of nine of ten VGSC alpha isoforms. Immunohistochemical staining of normal colonic tissue confirmed the expression of VGSCs in colonic epithelial cells, smooth muscle cells, and nerves. Lidocaine induced membrane depolarization of HT-29 cells and its effect was blocked by veratridine.

Conclusion: Malignant and normal intestinal epithelial cells express functional VGSCs. These molecules may play a role in the regulation of inflammation in gut physiology and pathology.
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http://dx.doi.org/10.1159/000123840DOI Listing
June 2008

Endoscopic ultrasound (EUS) before gastric polyp resection: is it mandatory?

J Clin Gastroenterol 2007 Apr;41(4):371-4

Department of Gastroenterology, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel.

Introduction: Gastric polypectomy is associated with increased risk of bleeding. The use of endoscopic ultrasound (EUS) before polypectomy to decrease the rate of bleeding in such patients has not been studied.

Methods: All gastric polyps excised by snare polypectomy were evaluated. The primary outcome was the occurrence of immediate or delayed bleeding episodes. Postpolypectomy bleeding was correlated with the presence of blood vessels at the base of the polyp on EUS examination. Characteristics of both patients and polyps were analyzed as risk factors for postpolypectomy bleeding.

Results: One-hundred and two snare polypectomies were performed. Fifty-seven polyps (56%) had been evaluated by prior EUS. Bleeding occurred in 7 (7%) patients. Of these, 4 had not undergone EUS evaluation, whereas in 3 patients who had had a prepolypectomy EUS evaluation, none were found to harbor a visible blood vessel. Bleeding did not occur in any of the 8 patients in whom EUS suggested the presence of blood vessel. The size, location, type, and histology did not show any significance in predicting postpolypectomy bleeding.

Conclusions: The risk of bleeding after endoscopic resection of gastric polyps was 7%. EUS evaluation before gastric polypectomy does not seem to contribute to the safety of such a procedure.
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http://dx.doi.org/10.1097/01.mcg.0000225578.58138.56DOI Listing
April 2007

[Clinical and communication simulation workshop for fellows in gastroenterology: the trainees' perspective].

Harefuah 2006 Nov;145(11):798-802, 863

Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Israel.

Background: The continuing development in computer-based medical simulators provides an ideal platform for simulator-assisted training programs for medical trainees. Computer-based endoscopic simulators provide a virtual reality environment for training endoscopic procedures. This study illustrates the use of a comprehensive training model combining the use of endoscopic simulators with simulated (actor) patients (SP).

Aim: To evaluate the effectiveness of a comprehensive simulation workshop from the trainee perspective.

Methods: Four case studies were developed with emphasis on communication skills. Three workshops with 10 fellows in each were conducted. During each workshop the trainees spent half of the time in SP case studies and the remaining half working with computerized endoscopic simulators with continuous guidance by an expert endoscopist. Questionnaires were completed by the fellows at the end of the workshop.

Results: Seventy percent of the fellows felt that the endoscopic simulator was close or very close to reality for gastroscopy and 63% for colonoscopy. Eighty eight percent thought the close guidance was important for the learning process with the simulator. Eighty percent felt that the case studies were an important learning experience for risk management.

Conclusion: Further evaluation of multi-modality simulation workshops in gastroenterologist training is needed to identify how best to incorporate this form of instruction into training for gastroenterologists.
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November 2006

Increasing the infliximab dose is beneficial in Crohn's disease patients who responded to a lower dose and relapsed.

Digestion 2005 16;72(2-3):124-8. Epub 2005 Sep 16.

Department of Gastroenterology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Background: Relapse after an initial response to infliximab therapy poses a problem for maintenance treatment.

Aim: To assess the effects of increasing the infliximab dosage in Crohn's disease (CD) patients who initially responded but flared during maintenance therapy.

Methods: This was an observational study. Twelve CD patients with both inflammatory and fistulizing manifestations were included. All patients initially responded to 5 mg/kg of infliximab, relapsed during maintenance therapy, and were treated with 10 mg/kg. The Harvey-Bradshaw index, the fistula activity, and steroid use were assessed before and after treatment with the increased dose of infliximab.

Results: The mean Harvey-Bradshaw index score after flare-up during treatment with 5 mg/kg of infliximab was 13.5+/-3.7. Treatment with 10 mg/kg, in a mean of 3.3 infusions, decreased the activity score to a mean of 8.8+/-2.5. Two patients were weaned off prednisone, and a reduced dose was possible in the other steroid-treated patients.

Conclusions: Increasing the infliximab dose may be beneficial in CD patients who initially responded to therapy, but relapsed during maintenance with the lower dosage.
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http://dx.doi.org/10.1159/000088367DOI Listing
January 2006

Somatostatin inhibits pro-inflammatory cytokine secretion from rat hepatic stellate cells.

Liver Int 2005 Aug;25(4):808-16

Department of Gastroenterology and Liver Diseases, Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Background/aims: Activated hepatic stellate cells (HSCs) have been implicated in hepatic fibrosis. Somatostatin (SOM) has an immunomodulatory role. The aim of this study was to assess the secretion of pro-inflammatory cytokines by HSCs and to determine the effect of SOM on the secretion of these mediators.

Methods: Activated rat HSCs were evaluated for their secretion of IL-1beta, IL-8, and TNF-alpha using ELISA. RNA protection assay was used to determine cytokine mRNA levels. The expression of chemokine and cytokine mRNA and the secretion of these mediators were assessed following incubation with SOM or octreotide.

Results: HSCs spontaneously secreted IL-1beta, IL-8, and TNF-alpha. This secretion was augmented following stimulation by IL-1beta and TNF-alpha. SOM inhibited the spontaneous and TNF-alpha-induced secretion of IL-1beta, IL-8, and TNF-alpha and suppressed the expression of IL-1beta and TNF-alpha mRNA. Octreotide suppressed the secretion of IL-1beta and IL-8.

Conclusions: These observations indicate that SOM exerts an inhibitory immunomodulatory effect on HSCs.
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http://dx.doi.org/10.1111/j.1478-3231.2005.01057.xDOI Listing
August 2005

Allicin inhibits spontaneous and TNF-alpha induced secretion of proinflammatory cytokines and chemokines from intestinal epithelial cells.

Clin Nutr 2004 Oct;23(5):1199-208

Department of Gastroenterology, Chaim Sheba Medical Center, Affiliaated to the Tel-Aviv University, Tel-Hashomer 5261, Israel.

Background & Aims: Allicin, the active substance of fresh crushed garlic has different biological activities and was implicated as an anti-inflammatory agent. Epithelial cells have an important role in intestinal inflammation. The aim of this study was to assess the immunomodulatory effect of allicin on intestinal epithelial cells.

Methods: The spontaneous and TNF-alpha-stimulated secretion of IL-1beta, IL-8, IP-10 and MIG from HT-29 and Caco-2 cells was tested with, or without pretreatment with allicin. Cytokine secretion was assessed using ELISA and expression of mRNA was determined by an RNA protection assay.

Results: Allicin markedly inhibited the spontaneous and TNF-alpha -induced secretion of IL-1beta, IL-8, IP-10 and MIG from the two different cell lines in a dose-dependent manner and suppressed the expression of IL-8 and IL-1beta mRNA levels. In addition, allicin suppressed the degradation of IkappaB. No effect on cell viability was noted.

Conclusions: These observations indicate that allicin exerts an inhibitory immunomodulatory effect on intestinal epithelial cells and suggest that allicin may have the potential to attenuate intestinal inflammation.
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http://dx.doi.org/10.1016/j.clnu.2004.03.011DOI Listing
October 2004

Colorectal cancer screening in patients presenting with an inguinal hernia: is it necessary?

Gastrointest Endosc 2004 Mar;59(3):369-73

Department of Gastroenterology, Chaim Sheba Medical Center, Tel-Hashomer, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: It has been suggested that patients presenting with an inguinal hernia have an increased risk for colorectal cancer. Therefore, surgeons frequently request screening for colorectal cancer before surgery. The aim of this study was to assess the frequency of premalignant and malignant colonic lesions in a group of patients with an inguinal hernia, and to compare this with a control group of subjects undergoing screening colonoscopy.

Methods: In a case-control study, 243 patients with an inguinal hernia and no history of colonic neoplasia or symptoms suggestive of colorectal cancer underwent perioperative colonoscopy. The patients were stratified into two age groups: less than 50 years old (Group I) and more than 50 years old (Group II). The colonoscopic findings were compared with findings in 534 asymptomatic control patients who underwent screening colonoscopy.

Results: The mean age of patients (n=64) and control subjects (n=200) in Group I was similar, at 44 (3) years. The mean age of the patients (n=179) and control subjects (n=334) in Group II was, respectively, 70 (9) years and 64 (7) years (p<0.001). In Group I, no colorectal cancer was found in patients with inguinal hernia, and only one colorectal cancer was found among control subjects (p=0.571). In Group II, a diagnosis of colorectal cancer was made in 7 patients (4%) with inguinal hernia as compared with 10 patients (3%) among the control subjects (p=0.769). In both groups, the size and the histopathologic type of the polyps were not significantly different.

Conclusions: In otherwise asymptomatic patients, the presence of inguinal hernia is not associated with an increased risk for colorectal cancer. Therefore, the presence of an inguinal hernia alone does not justify screening colonoscopy before herniorrhaphy.
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http://dx.doi.org/10.1016/s0016-5107(03)02715-9DOI Listing
March 2004

Association between mutations in the CARD15 (NOD2) gene and Crohn's disease in Israeli Jewish patients.

Am J Med Genet A 2003 Sep;121A(3):240-4

Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Israel.

Ulcerative colitis (UC) and Crohn's disease (CD) are heterogeneous disorders characterized by chronic intestinal inflammation. Genetic predisposition is a major risk factor in both diseases. The CARD15 (NOD2) gene has been implied as a candidate gene in the pathogenesis CD. Our aim was to delineate the frequency of three missense and one frameshift variant of CARD15 in Israeli Jewish CD and UC patients. DNA was extracted from blood samples from 238 unrelated inflammatory bowel disease (IBD) patients, 68 with UC and 170 with CD. The DNA was genotyped for two missense mutations, R675W and G881R, and one frameshift mutation, 980FS981X. Mutations in CARD15 were observed with significantly greater frequency in CD patients (46/170, 27%) than in UC patients (7/68, 10%) (P = 0.005). Homozygous and compound heterozygous carriers were restricted to seven (4%) patients with CD as compared to none of the UC patients (P = 0.01). Similar rates in Ashkenazi and non-Ashkenazi Jewish patients were observed. Age-of-onset of disease was lower in Ashkenazi mutation carriers as compared to non-carriers of Ashkenazi origin (18.7 +/- 8.6 years vs. 25.8 +/- 13.4 years, respectively, P = 0.03). No other phenotypic characteristics could distinguish mutation carriers from non-carriers. We conclude that germline mutations in the CARD15 gene are more frequently found in CD than UC patients and appear to predict an earlier age-of-onset in Ashkenazi Jewish patients. No association could be demonstrated between CARD15 mutations and specific disease course or behavior.
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http://dx.doi.org/10.1002/ajmg.a.20209DOI Listing
September 2003

The role of focal adhesion kinase-phosphatidylinositol 3-kinase-akt signaling in hepatic stellate cell proliferation and type I collagen expression.

J Biol Chem 2003 Mar 26;278(10):8083-90. Epub 2002 Dec 26.

Division of Digestive Diseases, Department of Medicine, University of North Carolina, Chapel Hill 27599, USA.

Following a fibrogenic stimulus, the hepatic stellate cell (HSC) undergoes a complex activation process associated with increased cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, cell attachment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-beta, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-beta mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and alpha1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, cell attachment, and PDGF-induced cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.
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http://dx.doi.org/10.1074/jbc.M212927200DOI Listing
March 2003
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