Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study.

OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring. RESULTS: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3)). CONCLUSIONS: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

Penta-carbon-yl{3-[(2S)-1-methyl-pyrrolidin-2-yl]pyridine}tungsten(0).

The title compound, [W(C(10)H(14)N(2))(CO)(5)], contains five carbonyl ligands and a nicotine ligand in an octa-hedral arrangement around the tungsten atom. The metal atom shows cis angles in the range 87.30 (16)-94.2 (2)°, and trans angles between 175.2 (2) and 178.1 (4)°. The W-CO bond trans to the pyridine N atom [1.987 (6) Å] is noticeably shorter than the others, which range between 2.036 (3) and 2.064 (3) Å, possibly due to the well-known trans effect. The distance between the W atom and the pyridine N atom is 2.278 (4) Å.

Nonspecific esophageal motility disorders may be an early stage of a specific disorder, particularly achalasia.

The clinical significance of nonspecific esophageal motility disorder (NEMD) is unclear. Our aim was to investigate the natural history of NEMD. All manometries performed at Meir Hospital from 1997 to 2004 and diagnosed as NEMD were reviewed. Manometric criteria for NEMD included either low-amplitude peristalsis, nonprogression of peristalsis, prolonged retrograde or triple-peaked waves, or incomplete relaxation of the lower sphincter. Patients determined to have NEMD were contacted and asked to complete a questionnaire and undergo a second manometry. NEMD had been diagnosed in 137 patients. Upon review of manometry results, 65 patients were eligible for the study (36 men and 29 women). The other 72 patients did not have NEMD when we reviewed their manometry tracing, applying strict criteria as specified in Table 1. The average age was 64 +/- 16 years (range 24-83 years). The average follow-up period was 7 +/- 2 years. All 65 patients were symptomatic at their initial prestudy visit. By the second visit, symptoms had resolved in 33 (51%) patients and improved in 13 (19%). Dysphagia, chest pain, and food regurgitation had improved, whereas heartburn and respiratory symptoms had not. Of 37 patients with triple-peaked waves, only 11 (30%) had improved clinically. Of the 65 study patients, 17 (26%) had a second manometry during the study, which was normal in 2 (12%), unchanged in 11 (69%), and revealed achalasia in 4 (23%), representing 6% of all study patients. NEMD is generally a benign disorder that improves clinically in most cases. Nevertheless, in about 6% of patients, NEMD may evolve into achalasia.

Randomized clinical study: Partially hydrolyzed guar gum (PHGG) versus placebo in the treatment of patients with irritable bowel syndrome.

BACKGROUND: The treatment of Irritable bowel syndrome (IBS) is still challenging. Partially hydrolyzed guar gum (PHGG) is a known prebiotic fiber. To assess the effects of PHGG on clinical symptoms of IBS patients in a prospective randomized double blind placebo-controlled study. METHODS: Suitable IBS patients were recruited into an 18-week-long study (2 weeks of run-in, 12 weeks of treatment and 4 weeks of follow-up). They were blindly randomized to receive 6 gr of PHGG or placebo. Treatment efficacy was evaluated by the Francis Severity IBS score, the IBS quality-of-life scores and scored parameters of weekly journal of symptoms. Deltas of changes between the final and baseline scores were compared between two groups. RESULTS: Of 121 patients who underwent randomization, 108 patients (49 in the PHGG group and 59 in the placebo group) had all the data needed for intention-to-treat analysis. A 12-week administration of PHGG led to a significant improvement of journal bloating score in the PHGG group versus placebo (-4.1±13.4 versus -1.2±11.9, P=0.03), as well as in bloating+gasses score (-4.3±10.4 versus -1.12±10.5, P = 0.035). The effect lasted for at least 4 weeks after the last PHGG administration. PHGG had no effect on other journal reported IBS symptoms or on Severity and Quality of life scores. There were no significant side effects associated with PHGG ingestion. The rate of dropouts was significantly higher among patients in the placebo group compared with the PHGG group (49.15% versus 22.45%, respectively, P = 0.01). CONCLUSIONS: The results of this study support the administration of 6 g/day PHGG for IBS patients with bloating. TRIAL REGISTRATION: NCT01779765.

Electrogastrography in patients with Parkinson's disease.

BACKGROUND: Impaired gastrointestinal motility in Parkinson's disease may affect absorption of levodopa and contribute to the disabling response fluctuations (RF). In this study gastric myoelectric activity was recorded with electrogastrography in patients with PD and correlated with the duration, severity and the presence of RF. METHOD: Electrogastrography (EGG) was performed in 36 patients with PD of which 22 were men. The mean age was 67 years (48-81), mean duration of disease was 7.07 years (1-20), and mean duration of treatment with levodopa was 5.07 years (1-20). Gastric dysrhythmia was diagnosed when either preprandial or postprandial dysrhythmia for more than 30% of the recording period was detected. RESULTS: The EGG was abnormal in 24 of 36 patients. Significant association was found between preprandial dysrhythmia and duration of disease (P=0.002); duration of levodopa treatment (P=0.003), severity of 86RF (P=0.001), but not with age (P=0.076). Out of 18 patients with RF, 17 had at least one pattern of dysrhythmia. In 11 out of the 18 patients without RF, the EGG was normal while the remaining seven had at least one pattern of dysrhythmia. CONCLUSION: Abnormal EGG was quite common in this group of patients with PD, particularly in those with RF. The most common pattern of abnormality was preprandial dysrhythmia, which was positively associated with disease duration and length of levodopa treatment. Although frequently asymptomatic, preprandial dysrhythmia leading to impaired gastric emptying may contribute to irregular absorption of levodopa from the small intestine and contribute to disabling response fluctuations.

The effect of sildenafil on gastric emptying in patients with end-stage renal failure and symptoms of gastroparesis.

BACKGROUND: Delayed gastric emptying is a common disorder among patients with end-stage renal failure (ESRF). Pyloric relaxation, a major determinant of gastric emptying, is a nitric oxide (NO)-mediated process. NO-induced smooth muscle relaxation is mediated through its second messenger cyclic guanosine monophosphate, which is broken by tissue phosphodiesterases (PDEs). Thus the inhibition of cyclic guanosine monophosphate breakdown by PDE inhibitors can potentiate NO-mediated responses and facilitate pyloric relaxation. In an animal model of diabetes mellitus, treatment with sildenafil (a PDE-5 inhibitor) restored NO-mediated pyloric relaxation and improved gastric emptying. The aim of our study was to examine the hypothesis that sildenafil may improve gastric emptying in patients with ESRF and symptoms of gastric paresis. METHODS: We studied 12 patients with ESRF (6 men; age range, 54-80 years; 5 with diabetic nephropathy; 4 +/- 1 years receiving long-term renal replacement therapy) after either placebo or a 25-mg tablet of sildenafil (Viagra; Pfizer Inc). Gastric emptying of a solid meal (one medium-sized fried egg mixed with 37 MBq [1 mCi] technetium Tc 99m phytate plus 1 slice of bread and 150 mL of water at the end of the meal) was assessed 1 hour after dosing by use of a single-headed camera. Images were acquired every 30 seconds for 90 minutes immediately after patients ate. RESULTS: The gastric emptying rate was decreased at baseline (after placebo), to 33% +/- 6% (normal, > or =50%). Treatment with sildenafil had no effect on gastric emptying rates after 90 minutes (from 33% +/- 6% after placebo to 30% +/- 6% after sildenafil, P =.9). CONCLUSIONS: Sildenafil did not improve gastric emptying in patients with ESRF and gastric paresis. Sildenafil may have opposing effects on gastric peristalsis (causing gastric relaxation) compared with its effects on pyloric relaxation. Studies combining sildenafil with prokinetic drugs are of interest.

Cyclosporin for severe ulcerative colitis.

BACKGROUND: About one-third of patients with severe ulcerative colitis do not respond to conventional therapy and require urgent colectomy. It was recently shown that cyclosporin is effective in some of these patients. OBJECTIVES: To review the current experience of six hospitals in central Israel that used cyclosporin in patients with severe ulcerative colitis. METHODS: The files of all 32 patients treated with cyclosporin for corticosteroid-resistant ulcerative colitis were reviewed. Activity of disease was measured by a clinical activity, index colonoscopy and laboratory tests. RESULTS: The average duration of treatment with intravenous cyclosporin was 12.7 days (range 9-28) after which the disease activity index dropped from an average of 14.22 to 4.74. The mean time for response was 7.5 days (4-14). Twelve patients (40%) required surgery within 6 months and another 6 patients (18.8%) were operated on after more than 6 months. Twelve patients (37%) maintained remission for at least 6 months and did not require surgery. In one patient treatment was stopped because of non-compliance and one was lost to follow-up. There were numerous side effects, but in only one case with neurotoxicity was treatment withdrawn. CONCLUSIONS: Cyclosporin is a relatively safe and effective treatment for severe ulcerative colitis. It induced long-term remission in 37% of the patients, and in those who required surgery the treatment resulted in an improved clinical condition before the operation.

Toilet reading habits in Israeli adults.

Although toilet reading (TR) is a common habit, the effect of TR on bowel movements is neglected in the medical literature. Our hypothesis was that TR provides a distraction and acts as an unconscious relaxation technique and allows an easier defecation process. The aim of this study was to assess how common is TR and to map the reading/playing toilet habits in the Israeli adult population. In addition, we aimed to explore a possible connection between TR and the nature of bowel habits in general and constipation and haemorrhoids in particular. Five hundred adults who represent the diverse demographic backgrounds have been asked to fill an anonymous short questionnaire. The subjects were questioned regarding their demographic details, their TR and playing habits, their bowel habits, whether they suffer from haemorrhoids and whether they use some sort of faecal softener. We found that TR is common and involves 52.7% of the population. Males, younger age, secular population, higher education level and white collar workers compose the TR profile. Although toilet readers spent significantly more time in the toilets, no differences were noted for the type or frequency of stools. Nevertheless, the TR group considered themselves to be less constipated (8.0%vs 13.7%) and had more haemorrhoids (23.6%vs 18.2%). These differences, however, were not significant. Toilet reading is a common and benign habit. It is involved with a longer time spent in the toilet. It seems to be more for fun and not necessarily to solve or due to medical problems.

High levels of glucocorticoid receptors in patients with active Crohn's disease may predict steroid resistance.

Up to 20% of Crohn's disease (CD) patients respond poorly to glucocorticoids (GC). A product of an alternative splicing of the glucocorticoid receptor (GR) premRNA, GRbeta, may play a role as a dominant inhibitor of the glucocorticoid response. Increasing evidence suggests that inflammatory cytokines such as interleukin (IL)-18 alternate the splicing of the primary transcript between the two isoforms GRbeta and GRalpha in hGR gene of CD patients. The aim of this study is to assess the expression of GRalpha and GRbeta in patients with CD and to look for a possible correlation between these receptors and the response to glucocorticoid treatment. Forty-two CD patients and 17 healthy volunteers were studied. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed using real-time PCR techniques. Serum IL-18 protein levels were measured by enzyme-linked immunosorbent assay (ELISA). The amount of hGRalpha-mRNA in patients in remission was significantly lower than in controls (P < 0.05). The amount of hGRbeta-mRNA was significantly higher in GC-resistant patients in the active stage of disease compared with all other groups (P < 0.05). Patients in the active stage of the disease had higher levels of IL-18 than patients in remission and both had higher levels than controls (P < 0.05). The amounts of IL-18 were directly correlated with the amount of hGRbeta mRNA in GC-resistant patients with an active disease. High levels of hGRbeta might be connected to GC resistance. IL-18 might participate in the alternative splicing of the hGR preliminary mRNA of CD patients. The results support the theory that augmented hGRbeta mRNA expression level in PBMC is connected with GC-resistance of CD patients.

Helicobacter pylori: the Middle East scenario.

A review of Helicobacter pylori in the Middle East is presented. Prevalence studies have been performed in asymptomatic population groups from Algeria, Israel, Saudi Arabia and Turkey. These showed that the prevalence of H. pylori is similar to that of the developing countries of the world with a high level of infection in childhood (40 to 70 percent), which increases with age to 85 to 90 percent. Israel, however, has a low prevalence in children (10 percent), but there is a rapid rise in the second decade of life to 39 percent, reaching 79 percent in those over 60 years old. The prevalence rates were higher in those living in communal settlements (72 percent) than in urban dwellers (65 percent). The infection rates were higher in persons of Mediterranean and Asian origin (89 percent) compared to those of Western European/North American origin (57 percent). The prevalence rate of H. pylori infection in patients undergoing endoscopy for upper gastrointestinal symptoms has now been reported from many Middle Eastern countries, including Egypt, Iran, Israel, Oman, Saudi Arabia, the United Arab Emirates and Yemen. These studies showed that patients with gastritis and peptic ulcer disease had similar rates of infection as reported from Europe, United States and Africa (71 to 92 percent). However, patients with non-ulcer dyspepsia had higher rates of infection (61 to 89 percent). The H. pylori scenario from the prevalence rates, treatment protocols and responses to treatment does not differ very much from other developing areas of the world.

Expression of bcl-2 in autoimmune and Helicobacter pylori-associated atrophic gastritis.

Chronic atrophic gastritis can be induced either by H. pylori or by an autoimmune process. The protein product of bcl-2, which is a protooncogene, blocks apoptosis. Aberrant bcl-2 expression has been found in 68% of atrophic gastritis patients. The aim of this study was to compare bcl-2 expression in 20 autoimmune atrophic gastritis patients to that in 20 H. pylori-associated atrophic gastritis patients. Twenty patients with H. pylori antral gastritis but without atrophy served as controls. The bcl-2 expression was assessed by immunohistochemical staining of gastric biopsies, using mouse anti-human bcl-2 monoclonal antibodies. Autoimmune atrophic gastritis patients were younger, mainly females, with a significantly higher serum gastrin level than the H. pylori-associated atrophic gastritis group (P < 0.001). The bcl-2 was expressed in 10/20 (50%) of autoimmune atrophic gastritis patients, in 9/20 (45%) of H. pylori-associated atrophic gastritis patients (P = 0.73), and in 2/20 (10%) of controls. There was no correlation between bcl-2 expression and the presence of intestinal metaplasia (P = 0.35). Our findings confirm that H. pylori-associated atrophic gastritis and autoimmune atrophic gastritis are two different conditions, but with equal expression of bcl-2. Excessive expression of bcl-2 is found only in atrophic gastritis, but not in H. pylori antral gastritis without atrophy.