A double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant IBS.

BACKGROUND: Micro-inflammation is considered an element in the pathogenesis of irritable bowel syndrome (IBS). High-sensitivity C reactive protein (hs-CRP) was previously shown to be higher in IBS compared to healthy controls, albeit within the normal range. Since probiotics may suppress micro-inflammation in the gut, we tested if they reduce symptoms and inflammatory markers (hs-CRP and fecal calprotectin (FC) in diarrhea-predominant IBS (IBS-D). The aim of this study was to assess the clinical and laboratory effects of BIO-25, a multispecies probiotic, in women with IBS-D. METHODS: A double-blind, placebo-controlled study. Following a 2-week run-in, eligible women were assigned at random to a probiotic capsule or an indistinguishable placebo, twice daily for 8 weeks. IBS symptoms and stool consistency were rated daily by Visual Analogue Scales (VAS) and the Bristol Stool Scale (BSS). High-sensitivity C reactive protein was tested at baseline, 4 and 8 weeks. FC was tested at baseline and 8 weeks. KEY RESULTS: One hundred and seventy-two IBS-D patients were recruited and 107 eligible patients were allocated to the intervention (n=54) or placebo (n=53) group. All symptoms improved in both groups with no significant difference between them in symptom improvement, hs-CRP or FC levels. CONCLUSIONS & INFERENCES: An 8-week treatment with BIO-25 improved symptoms in women with IBS-D, but was not superior to placebo. This rigorously designed and executed study supports the findings of other studies that did not demonstrate superiority of probiotics over placebo in IBS. High quality clinical studies are necessary to examine the efficacy of other specific probiotics in IBS-D patients since data are still conflicting.

Safety and efficacy of the vibrating capsule, an innovative non-pharmacological treatment modality for chronic constipation.

BACKGROUND: Constipation is a common disorder. Because the prevalence is high and the satisfaction level with currently available treatment is low, there is an unmet need for innovative treatment. We assessed the safety and efficacy of the Vibrant Capsule, a non-pharmacological device that is assumed to induce a normal peristaltic wave in the large intestine to alleviate constipation. METHODS: Two animal safety studies and a safety study on healthy volunteers were conducted, followed by a prospective, non-randomized, open-label, single group assignment, safety and efficacy study. The latter was conducted among 26 patients who ingested the capsule twice weekly for a study period of 7.5 weeks, after a run-in period of 2 weeks without usual treatment for constipation. KEY RESULTS: In the studies on animals and healthy volunteers, there were no adverse events. Twenty-eight patients began the clinical trial and 26 completed it (25 women). The mean age was 47.0 ± 12.6 years (range: 19-65). The two dropouts, who completed the safety phase, and the 26 who completed the entire study expelled the capsule without difficulty. Twelve participants reported 27 adverse events, none serious, and all transient. There was a significant increase of 1.60 ± 1.09 in the mean number of bowel movements/week from 2.19 ± 0.67 to 3.79 ± 1.31 (p < 0.001). This increase was seen in 23 of the 26 patients (88.5%). The mean number of spontaneous bowel movements for the study group increased in each treatment week compared to baseline. CONCLUSIONS & INFERENCES: The Vibrant Capsule is safe and potentially effective in the treatment of constipation, justifying randomized controlled studies.

Elevated alanine aminotransferase independently predicts new onset of depression in employees undergoing health screening examinations.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of elevated alanine aminotransferase (ALT). NAFLD is associated with insulin resistance and hepatic inflammation. Similarly, patients with depression exhibit insulin resistance and increased inflammatory markers. However, no study has shown a clear association between elevated ALT and the development of depression. The aim of the study was to test whether elevated ALT, a surrogate marker for NAFLD, predicts the development of depression. METHOD: The present prospective cohort study investigated 12 180 employed adults referred for health examinations that included fasting blood tests and anthropometric measurements between 2003 and 2010. Exclusion criteria were: baseline minor/major depression, excessive alcohol consumption and other causes for ALT elevation. Depression was evaluated by the eight-item Patient Health Questionnaire (PHQ-8) score. RESULTS: The final cohort included 5984 subjects [69.4% men, aged 45.0 (s.d. = 10.24) years]. The incidence rate of minor and major depression was 3.8% and 1.4%, respectively. Elevated ALT was a significant independent predictor for the occurrence of minor [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.40-2.92] and major (OR 3.132, 95% CI 1.81-5.40) depression after adjusting for age, gender, body mass index, education level, serum levels of lipids, glucose, smoking and physical activity. Adding subjective health and affective state parameters (sleep disturbances, self-rated health, anxiety and burnout) as potential mediators only slightly ameliorated the association. Persistently elevated ALT was associated with the greatest risk for minor or major depression as compared with elevation only at baseline or follow-up (p for trend < 0.001). CONCLUSIONS: Elevated ALT was associated with developing depressive symptoms, thus suggesting that NAFLD may represent an independent modifiable risk factor for depression.

Restorative proctocolectomy impairs fertility and pregnancy outcomes in women with ulcerative colitis.

AIM: The effect of restorative proctocolectomy (RPC) on fertility and pregnancy in women with ulcerative colitis (UC) was evaluated. METHOD: Post-RPC female patients with UC who were attempting to become pregnant filled out questionnaires on fertility and pregnancy. Demographic and pouch data of pregnancies ending with delivery were collected from a prospective database. RESULTS: Forty-one women, 44 ± 10 years of age, completed the questionnaires. The median follow-up period post-RPC was 167 (range, 20-352) months. Before RPC, 26 women had 70 pregnancies and 62 deliveries. After RPC, 17 women had 32 pregnancies and 26 deliveries (P = 0.0035). Post-RPC, 10 (37%) of 27 patients failed to conceive compared with 26/26 successful attempts before RPC (P = 0.0006). The number of offspring per patient was 2.38 ± 1.27 before, and 0.68 ± 0.93 after, RPC (P < 0.0001). A higher number of spontaneous pregnancies occurred before (56/62; 90%) than after (15/25; 60%) RPC (P = 0.0004). The time to conception was longer (5.0 ± 11.6 vs 16.3 ± 25.1 months; P = 0.039) and there were more in-vitro fertilization procedures (three vs six) post-RPC. The gestation period was similar, but after RPC more deliveries were by Caesarean section (12.9% vs 46.2%; P = 0.0007). Babies born before RPC weighed more than those born after RPC (3.16 ± 0.61 kg vs 2.79 ± 0.68 kg, respectively; P = 0.0327). CONCLUSION: RPC is associated with an increased risk of infertility, similar duration of gestation and lower birthweight. Female candidates for RPC who have not finished family planning should be counselled accordingly.

Serum bile acid levels as a predictor for the severity of liver fibrosis in patients with chronic hepatitis C.

Serum bile acids (SBAs) are commonly elevated in cholestatic liver diseases, but it is unclear if SBA levels are also elevated in noncholestatic chronic liver diseases and whether those levels correlate with disease severity. We analysed SBA levels of 135 consecutive patients with chronic hepatitis C virus infection and correlated these levels with the degree of liver fibrosis as determined by liver biopsy. In addition, we assessed the accuracy of SBA levels as a noninvasive predictor for liver fibrosis by its comparison to the patients' FibroTest scores. Two-thirds (90/135 patients, 67%) of the study patients had nonsevere liver fibrosis (Metavir F0-F2), and the others (45/135, 33%) had severe fibrosis or cirrhosis (Metavir F3-F4). The SBA levels were significantly higher in patients with severe fibrosis as compared to nonsevere fibrosis (11.46 ± 10.01 vs 6.37 ± 4.69, P < 0.0001). Furthermore, a receiver operator characteristics curve based on a model that included serum bile acids, age, body mass index, serum AST, glucose and cholesterol levels suggested that this combination reliably predicts the degree of liver fibrosis and is not inferior to the current noninvasive FibroTest score (areas under the curve of 0.837 vs 0.83, respectively, P = 0.87). We conclude that measurement of SBA levels may have a clinical role as a simple noninvasive tool to assess the severity of HCV-induced liver disease. Combined with widely available laboratory parameters, SBA levels can predict disease severity with a high degree of accuracy.

The metabolic regulator PGC-1α links anti-cancer cytotoxic chemotherapy to reactivation of hepatitis B virus.

Patients with chronic hepatitis B virus (HBV) infection are at an increased risk for a severe and a potentially fatal viral reactivation following anti-cancer therapy. The molecular mechanism for this induction of HBV expression is still unclear. Here, we show that treating hepatoma cell line expressing HBV with various anti-cancer cytotoxic agents results in a significant up-regulation of HBV expression. This HBV induction is at the transcriptional level and is time dependent. Interestingly, treating hepatoma cells with anti-cancer cytotoxic agents results in a robust induction of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a metabolic and energy regulator that is normally induced in the liver under starvation conditions and that has been previously shown to strongly coactivate HBV transcription. Most importantly, HBV up-regulation following anti-cancer therapy depends on PGC-1α induction, because PGC-1α knock-down abolishes HBV induction. Finally, pretreatment of HBV-expressing cells with the antioxidant agent N-acetylcysteine attenuates the induction of both PGC-1α and HBV in response to anti-cancer treatment, suggesting that chemotherapy-associated PGC-1α induction is mediated by cellular oxidative stress that ultimately leads to HBV up-regulation. We conclude that cytotoxic anti-cancer chemotherapy has a direct and an immune system-independent effect on HBV gene expression, which is mediated by PGC-1α. Our results attribute to this metabolic regulator an unexpected role in linking anti-cancer treatment to HBV reactivation and make PGC-1α a potential target for future anti-HBV therapy, especially under conditions in which it is robustly induced, such as following anti-cancer treatment.

MedJet--a new CO2-based disposable cleaning device allows safe and effective bowel cleansing during colonoscopy: a pilot study.

BACKGROUND AND STUDY AIMS: Complete bowel cleansing is mandatory for effective colon cancer screening and surveillance. The aim of the current pilot study, which was conducted in humans, was to test the safety and efficiency of a newly developed disposable cleaning device, the MedJet, for intraprocedural bowel cleansing. PATIENTS AND METHODS: Patients with screening or surveillance colonoscopy after previous polypectomy were included. The colonoscope was first inserted to the cecum and the overall cleansing was assessed according to the Ottawa scale. The MedJet device was used if colon cleansing had been incomplete. The MedJet catheter was passed over the working channel of the colonoscope and the colon was cleaned during withdrawal. The MedJet device delivered controlled jets comprising compressed CO2 and minimal amounts of sterile water, which allowed disintegration and removal of residual stool. The efficiency of cleaning was assessed according to the Boston scale. RESULTS: A total of 32 patients (16 female; mean age 61 years) were treated with the device. No device-related adverse or serious adverse events were noted. MedJet application during withdrawal provided effective and significant improvement in bowel cleansing (P = 0.005). Furthermore, 18 adenomas and 1 colon cancer, which were hidden behind stool remnants, could be identified in 11 patients following use of the MedJet device. However, the withdrawal times were prolonged (11.4±6.0 minutes) due to the additional cleaning procedure. All patients tolerated the procedure well. CONCLUSIONS: The new MedJet device enabled highly effective and safe bowel cleansing during colonoscopy. The catheter-based system was easy to use and CO2 was applied for cleansing. The procedure was well tolerated by patients.

Risk factors for chronic pouchitis after ileal pouch-anal anastomosis: a prospective cohort study.

AIM: The association between various demographic, clinical and pathological parameters and the evolution of chronic pouchitis was evaluated. METHOD: All ulcerative colitis patients who underwent ileal pouch anal anastomosis (1981-2009) were followed prospectively in a comprehensive pouch clinic. We examined risk factors including the presence of appendiceal inflammation and backwash ileitis in the colonic specimen, gender, ethnicity, age at disease onset, disease duration, extent of colitis, presence of extraintestinal manifestations (e.g. primary sclerosing cholangitis), family history of inflammatory bowel disease, indication for surgery, medical treatment, age at operation, staged procedure, diverting ileostomy and length of follow-up. Univariate analysis was performed on all risk factors followed by logistic regression analysis. RESULTS: The 201 enrolled patients (106 women, age at surgery 35 ± 15 years) were followed for a mean of 108 months. One hundred and thirty-eight (69%) had either a normal pouch or episodes of acute pouchitis and 63 (31%) developed chronic pouchitis. On univariate analysis the presence of an ileostomy (P = 0.017), pancolitis (P = 0.008), shorter disease duration (P = 0.04) and longer follow-up (P = 0.01) were identified as risk factors for chronic pouchitis. Multivariate analysis showed that patients with pancolitis (OR 3.26, 95% CI 1.20-8.85) and longer follow-up (OR 1.09, 95% CI 1.01-1.18) were more likely to develop chronic pouchitis. There was also an association to disease duration but this did not reach a level of significance. CONCLUSIONS: Pancolitis and longer follow-up are directly related to the development of chronic pouchitis.

Assessment of high-sensitivity CRP as a marker of micro-inflammation in irritable bowel syndrome.

BACKGROUND: The diagnosis of irritable bowel syndrome (IBS) is symptom-based. Although considered a functional disease, accumulating evidence supports a low-grade gut inflammation as an element of its pathophysiology. Thus, high-sensitivity C-reactive protein (hs-CRP), a marker of micro inflammation, may be elevated in IBS. Our aim was to assess whether hs-CRP is higher in IBS patients compared to healthy controls (HC) and does it differ among the IBS clinical subgroups and correlate with disease severity. METHODS: A diagnostic case control study was conducted in two gastroenterology departments. Eighty-eight IBS patients who were recruited prospectively answered the Rome III diagnostic questionnaire. They all completed the Functional Bowel Disorder Severity Index (FBDSI), dietary, and general health questionnaires. All patients underwent blood sampling for hs-CRP levels. Each IBS patient was matched to four HC by age, gender, and BMI. Blood samples were obtained from the HC at a periodic health survey. KEY RESULTS: The mean hs-CRP level in the IBS group was significantly higher than in HC (1.17±1.26mg L(-1) vs 0.72±0.91mg L(-1) respectively, P=0.001). Hs-CRP levels were highest in patients with diarrhea-predominant IBS and in patients with greater disease severity. A cut-off value of 1.08mg L(-1) had a sensitivity of 60.2% and a specificity of 68% for differentiating IBS from HC. CONCLUSIONS & INFERENCES: Hs-CRP levels are higher in IBS patients than HC, but still in the normal laboratory range. This may reflect the low-grade gut inflammation believed to occur in IBS and support its existence.

Mifepristone (RU486), a pure antiprogesterone drug, in combination with vinblastine for the treatment of progesterone receptor-positive desmoid tumor.

We report the case of a patient who developed a desmoid tumor following total proctocolectomy and J-pouch reconstruction that was unresponsive to any medical treatment. Based on estrogen receptor alpha (ERalpha) and progesterone receptor (PR) evaluation (ERalpha-negative, but PR-positive), treatment with mifepristone, a pure antiprogesterone drug, was initiated, and partial tumor regression was achieved.

Halitosis and gastroesophageal reflux disease: a possible association.

OBJECTIVE: Previous reports have suggested that gastrointestinal (GI) diseases may cause halitosis. The aim of this study was to evaluate the relationship between upper GI conditions, especially gastroesophageal reflux disease (GERD), and halitosis. PATIENTS AND METHODS: One hundred and thirty two consecutive patients complaining of upper GI symptoms were included in the study. All the patients completed a validated questionnaire that was designed to characterize and measure the severity of their symptoms. The questionnaire also contained questions about awareness and severity of oral bad breath. Following the filling of the questionnaire, the patients were physically examined and subjected to an upper GI endoscopy. RESULTS: The final diagnosis among the 132 patients (M/F = 70/62, mean age 45.2 years, range 20-87 years) was GERD in 72 patients (55%), Functional dyspepsia in 52 (39%), Peptic ulcer in seven patients (5%) and gastric cancer in one patient (1%). Halitosis was significantly associated with the occurrence and severity of heartburn (P = 0.027), regurgitation (P = 0.002) sour taste (P < 0.001), belching (P = 0.001) and burburigmus (P = 0.006). Halitosis was not associated with upper abdominal pain, bloating, early satiety and chest pain. In relation to the final diagnosis, halitosis was significantly associated only with GERD (P = 0.002) but not with functional dyspepsia (P = 0.855) and peptic ulcer disease (0.765). No correlation was found between Helicobacter pylori infection status and halitosis occurrence and severity (analysis of variance F = 0.001, P = 0.977). CONCLUSIONS: Halitosis is a frequent symptom of GERD and may be considered as an extra-esophageal manifestation of GERD. On the other hand, we did not find an association between functional dyspepsia, peptic ulcer disease and H. pylori infection with halitosis occurrence or severity.

Clinical trial: evaluation of a clinical decision-support model for upper abdominal complaints in primary-care practice.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) and dyspepsia affect 25-40% of the general population. In the absence of alarm symptoms, the current recommended policy in young dyspeptic patients is a 'test and treat' strategy for Helicobacter pylori; in GERD patients, a therapeutic trial with proton pump inhibitors is the treatment of choice. AIM: To create a short and simple clinical algorithm, for the diagnosis and treatment of patients with upper gastrointestinal complaints. METHODS: The clinical usefulness and cost-effectiveness of the new algorithm were evaluated in a controlled clinical trial, held in primary-care clinics in Israel. Clinical and economical treatment outcomes were evaluated after 1, 3 and 6 months comparing doctors who used the algorithm (cases) vs. those who did not (controls). RESULTS: 78 cases and 54 controls completed the 6 months of follow up. The improvement in symptom severity and quality of life was greater in the cases than in the controls (P < 0.05). General practitioner clinics visits (P = 0.04), gastroenterology clinics visits (P = 0.02) and medication costs (P = 0.004) were all significantly reduced among cases. Controls underwent also more imaging tests (computerized tomography, ultrasound and X-ray) and endoscopies. The average cost for 6 months' treatment and follow-up was $US 199 for cases compared with an average of $US 336 in the control group. CONCLUSION: The use of a clinical decision-support tool can facilitate and promote the implementation of management guidelines by general practitioners. The short algorithm presented in the study was found to be useful and easy to apply in clinical practice. Its effectiveness can be further increased by implementing it in computerized medical systems.

Acute hepatitis B in the era of immunisation: pitfalls in the identification of high risk patients.

BACKGROUND: Since the adoption of a universal hepatitis B immunisation strategy, the reported incidence of acute hepatitis B has declined dramatically worldwide including in Israel. However, new cases of acute hepatitis B still occur. The aim of this study was to describe the incidence of acute hepatitis B in a referral area, routes of transmission, and outcome. METHODS: The charts of all new hepatitis B patients, who visited the clinic in the years 2002 and 2003 (January 2002 to December 2003), were reviewed. The main criteria for a diagnosis of acute hepatitis B were transient increase of alanine transaminase activity, and hepatitis B surface antigen seroconversion. RESULTS: Twenty nine men and seven women were diagnosed with acute hepatitis B infection during the study period. Two patients were previously vaccinated with hepatitis B vaccine. One case of hepatitis D coinfection was reported. The incidence of acute hepatitis B in the referral area was estimated as 2.25 per 100,000 adult population. Mean age was 36 years (17-75). Twenty one patients (18 men and 3 women) acquired the virus through unprotected sexual contact, and seven patients through iatrogenic exposure. Thirty three patients underwent spontaneous seroconversion while three patients became chronic carriers. CONCLUSIONS: Despite a universal immunisation policy, frequent cases of acute hepatitis B in Israel are still seen. High risk heterosexual activity and iatrogenic exposure seem to be the commonest routes of transmission. Further recommendations regarding vaccination policy are discussed.

The Aer-O-Scope: proof of the concept of a pneumatic, skill-independent, self-propelling, self-navigating colonoscope in a pig model.

BACKGROUND AND STUDY AIMS: Considerable training is needed to enable endoscopists to use the currently available commercial colonoscopes and sigmoidoscopes effectively and safely. The aim of this study was to evaluate the safety and efficacy of the propulsion mechanism incorporated into the Aer-O-Scope (GI View Ltd., Ramat Gan, Israel)--a novel self-propelled, self-navigating colonic endoscope for diagnostic purposes. MATERIALS AND METHODS: Twenty young female pigs underwent complete bowel preparation followed by a sedated examination using the new device. Ten pigs underwent two consecutive procedures, with a wash-out period of 7 days between each procedure. The total number of procedures was 30. Two prototypes of the Aer-O-Scope, with different cable lengths and vehicle balloon sizes (n = 20 and n = 10 for prototypes I and II, respectively) were used. Each examination was followed by a standard colonoscopy for safety evaluation. The insertion length of the Aer-O-Scope was determined by fluoroscopy images. RESULTS: The colon was adequately clean in 25 procedures. Maximum insertion was achieved in 21 procedures (84%)--80% with prototype I (n = 15) and 90% with prototype II (n = 10). The time to maximum insertion averaged 8.9 +/- 4.4 min (10 +/- 4.6 and 6.6 +/- 2.9 min for prototypes I and II; P < 0.05), and the withdrawal time averaged 3.4 +/- 2.1 and 4.2 +/- 3.4 min, respectively. The driving pressures for prototypes I and II averaged 46.3 and 34.5 mbar, respectively. The follow-up conventional colonoscopy identified no mucosal tears or perforations. Minor mucosal petechiae were noted in 43% of the cases. No adverse events were noted up to 7 days after the procedure. CONCLUSIONS: The propulsion mechanism used in this novel self-propelled, self-navigating colonoscope was effective and safe in pigs.

Rofecoxib reduces polyp recurrence in familial polyposis.

The long-term (mean of 16.4 +/- 4.2 months) efficacy and safety of rofecoxib (a specific COX-2 inhibitor) in maintaining the colon free of polyps in familial polyposis patients was assessed. Eight patients were treated with rofecoxib 25 mg every day. Sigmoidoscopy/colonoscopy was performed at study entry and every six months. At each endoscopy the number, size, and histological grade of all polyps were assessed, and the polyps were removed. The drug was well tolerated with no significant adverse events throughout the study. A highly significant reduction in the rate of polyp formation (70-100%) was observed in all patients from a mean number of 15.1 +/- 11.7 at baseline to 6.0 +/- 5.8 at one year and 1.6 +/- 1.6 at the end of follow-up (P = 0.016 and 0.008, respectively). No patient developed cancer or high-grade adenoma. In conclusion, Long-term use of rofecoxib is well tolerated and effective in inhibiting polyp formation in polyposis patients.

Triiodothyronine and interleukin-6 (IL-6) induce expression of HGF in an immortalized rat hepatic stellate cell line.

BACKGROUND/AIMS: Despite its being considered a primary mitogen for hepatocytes, triiodothyronine (T3) has no effect on the proliferation of hepatocytes in vitro, and in our studies, induces significant in vivo hepatocyte proliferation only during liver injury. We hypothesized that T3 may affect hepatocytes proliferation indirectly, by inducing other cells in the liver to secrete hepatic mitogens. METHODS: In vivo studies: Lipopolysaccharide, T3 and a combination of the two were injected into rats, and hepatocyte proliferation was determined by PCNA staining and mitotic index. IN VITRO STUDIES: a rat hepatic stellate cell line (HSC-6T) was cultured with T3, IL-6 and a combination of the two, and we assessed the effect of these cytokine/hormone combinations on the cell proliferation and on secretion of IL-6 and HGF, measured by ELISA. Expression of thyroid hormone receptors was assessed by RT-PCR. RESULTS: In vivo: T3, together with lipopolysaccharide, enhances PCNA staining and the mitotic index of hepatocytes in the treated rats. In vitro: the hepatic stellate cell line expresses thyroid hormone receptor alpha 1, but not beta 1. Proliferation of stellate cells is not affected by T3, with or without IL-6. T3 has no effect on secreted levels of IL-6 in the stellate cell line. Hepatic stellate cells cultured with T3 and IL-6 show significantly increased amounts of secreted HGF after 48 h in culture. CONCLUSION: T3 may induce hepatocyte proliferation in vivo during injury by turning on expression of HGF in stellate cells and acting together with IL-6.

Prospective assessment of microsatellite instability in gastrointestinal neoplasia in Ashkenazi and non-Ashkenazi Jews.

BACKGROUND: Microsatellite instability (MSI) is a useful marker of replication errors in neoplasia, resulting from mutations in the mismatch repair (MMR) genes. Nearly all hereditary non-polyposis colorectal cancer (HNPCC) and about 15% of sporadic colorectal cancers (CRC) exhibit high MSI (MSI-H). The use of the Amsterdam criteria for HNPCC diagnosis may fail to identify many HNPCC cases. Genetic screening of mutations in the MMR genes is laborious, time-consuming, expensive and limited by a low detection rate. Hence, MSI testing is a feasible and cost-effective method to select suspected HNPCC patients for genetic analysis. MSI has not been used routinely or prospectively in the assessment of newly diagnosed CRC. AIMS: To prospectively evaluate MSI status in a cohort of patients seen at the Gastrointestinal Oncology Unit of the Tel Aviv Medical Center. METHODS: Ninety-eight consecutive patients with colonic or gastric neoplasia were included. Samples from neoplastic and normal mucosa were obtained at the time of diagnostic endoscopy. MSI was determined based on five Bethesda markers using standard polymerase chain reaction procedures. RESULTS: The overall incidence of MSI was 20.4%. MSI-H was detected in 22.2% of CRC, 20% of colonic adenomas and 18.2% of gastric neoplasia. MSI-positive neoplasia tended to display multiple colonic sites, moderate-well differentiated tumors, and a higher rate of familial gastrointestinal neoplasia. CONCLUSIONS: MSI may be involved in the early stages of some colorectal tumorigenesis pathways since it may be detected in adenomas. MSI may serve as a cost-effective, reliable and important tool in the selection of HNPCC-suspected families for genetic testing. A small study population, referral bias or ethnic variation might explain the higher MSI rate. It is suggested that, similar to familial adenomatous polyposis, a state of attenuated HNPCC may exist. Hence, the clinical approach in positive patients, and their family members, should be conducted as for families with genetically proven HNPCC.

Fighting colorectal cancer: molecular epidemiology differences among Ashkenazi and Sephardic Jews and Palestinians.

BACKGROUND: To evaluate and compare differences in the molecular genetics among high-risk (Ashkenazi Jews), intermediate-risk (Sephardic Jews) and low-risk (Palestinians) groups for colorectal cancer who live in the same geographical region. PATIENTS AND METHODS: The 1995-1996 records from the Tel Aviv Medical Center and Muqased hospital (East Jerusalem) randomly identified patients with colorectal cancer. There were 25 patients from each ethnic group. Epidemiological data were obtained from interviews with the patients and from their hospital charts. The levels of cyclin D1, beta-catenine, p27, p53, Ki-67 and Her-2/neu proteins were determined by immunohistochemistry. The main outcome measures were the association between gene expression and colorectal incidence in the different ethnic groups. RESULTS: Ashkenazi Jews have the highest rate of colorectal cancer, and are diagnosed at an early stage compared with Palestinians (72% and 33% of the cases are in Dukes' A and B, respectively), and, hence, this may explain the better 5-year survival rate among this group. Sephardic Jews are diagnosed at a more advanced stage, the tumors are poorly differentiated and they lack p27. Palestinians have significantly higher cyclin D1 levels. There was a statistically significant inverse correlation between the expression of beta-catenine and cyclin D1, as well as p53 and p27 (P <0.05). CONCLUSIONS: Increased expression of cyclin D1, p53, Ki-67, beta-catenine and Her-2/neu, and decreased expression of p27 may be important events in the three ethnic groups with colorectal cancer. The lower mortality rate among Ashkenazi Jews may be partially explained by their better molecular biology profile.

Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus.

Neoplastic progression in Barrett's esophagus is a multi-step process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasia-carcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barrett's esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-fixed, paraffin-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27(kip1) protein, but did not display appreciable nuclear staining for p16(kip4), p21(cip1) or cyclins D1 and E. Barrett's metaplastic specimens displayed increased expression levels of p16(kip4) (74%), p21(cip1) (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a significant correlation between the expression of p16(kip4) and cyclin E, and p21(cip1) and p27(kip4) with cyclin D1. DNA analysis did not reveal any amplification or deletion of these genes. Acid suppression, however, was associated with significantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barrett's esophagus. Treatment with proton pump inhibitors appears to alter this increased expression.

Botulinum toxin type-A in therapy of patients with anismus.

INTRODUCTION: Anismus is a common cause of constipation and outlet obstruction. Standard therapy with laxatives or biofeedback has conflicting results. Surgical treatment gives poor results and has practically been abandoned. PURPOSE: This study was designed to evaluate the efficacy of botulinum toxin type-A (Botox) injection to the puborectalis muscle in patients with anismus. METHODS: Twenty-five patients (15 females; mean age, 23.2) with history of constipation and symptoms of outlet obstruction underwent anorectal perfusion manometry and video-proctography. All patients were found to have a nonrelaxing puborectalis muscle on both modalities. All have been unable to expel a rectal balloon. Each patient who participated in the study was randomly assigned to undergo local injection of Botox--10 units to each side of the puborectalis or 20 units to the posterior aspect of this muscle. Eight patients underwent further injections1-5 every 3 months in accordance with previous results. Follow-up was conducted 1, 4, 12, and 24 weeks after injection. Straining, anorectal pain, and overall satisfaction were assessed on a visual analog scale. Weekly evacuation, fecal incontinence, and complications were recorded. At the weekly meeting, each patient underwent anorectal manometry with a balloon expulsion test. RESULTS: Manometric relaxation was achieved after the first injection in 18 patients (75 percent). Once relaxation was achieved, it lasted throughout the follow-up. Nine patients (37.5 percent) expelled the rectal balloon after the first injection. Seven of 16 patients who failed the first injection had an additional one. In 2 patients it was successful (28.6 percent). Symptom improvement of 29.2 percent in straining index was recorded during follow-up. In 3 patients (12.5 percent) pain developed after injection. No other complications were observed. Overall satisfaction with Botox injection results was observed in 58.3 percent. CONCLUSIONS: Botox injection to the puborectalis muscle has been found to have a limited therapeutic effect on patients suffering from anismus. Our results justify the need for further double-blind placebo-controlled trials to determine the exact role of botulinum toxin type-A in anismus.