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BACKGROUND & AIMS: We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD). METHODS: We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1-0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05-6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period. RESULTS: Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P = .01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07-0.31) was significantly associated with a lower risk of major adverse outcome. CONCLUSIONS: In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy. ispartof: GASTROENTEROLOGY vol:159 issue:1 pages:139-147 ispartof: location:United States status: published

Background & Aims: Despite treatment with corticosteroids, severe to moderately severe attacks of ulcerative colitis have a high colectomy rate. We intended to find a rescue therapy other than cyclosporin A, which imposes a high risk of side effects and cyclosporine-related mortality. Methods: This was a randomized double-blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment. Patients were randomized to infliximab/placebo either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on day 3 or on day 6–8 if they fulfilled index criteria on day 5–7 for a severe or moderately severe acute attack of ulcerative colitis. Results were analyzed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomization. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation. Results: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy ( P = .017; odds ratio, 4.9; 95% confidence interval, 1.4–17) within 3 months after randomization. No serious side effects occurred. Three patients in the placebo group required operation for septic complications. Conclusions: Infliximab 4–5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment.

Background: Glucagon-like peptide-1 (GLP-1) is secreted from L-cells after nutrient ingestion, inhibiting motility. Aims: To clarify whether infused GLP-1 inhibits in vivo prandial motility respons ...

Neurokinin A (NKA)-immunoreactivities and substance P (SP)-immunoreactivities were found in picomolar amounts in colonic tissues and almost an order of magnitude higher amounts in vagal, pelvic, splanchnic, and lumbar colonic nerves of the cat. Continuous electric stimulation of the pelvic nerve at 4 Hz or intermittent electric burst stimulation of the pelvic nerve at 40 Hz during 1 second with 10-second rest periods produced a marked release of NKA-like immunoreactivity (NKA-LI) and SP-LI from the colon to blood (P less than 0.001). Reflex activation of the pelvic nerve by mechanical stimulation of the anus or rectal distension produced a less pronounced release of NKA-LI and SP-LI from the colon to blood (P less than 0.01). There was a simultaneous colonic contraction and vasodilation during each nerve stimulation. Reverse-phase high performance liquid chromatography showed presence of NKA, NKA oxide, NKA (3-10)/NKA (4-10), and neuropeptide K (NPK) in colonic tissues and release of all these molecular forms except NPK on nerve stimulation. Substance P and SP oxide were present both in colonic tissue extracts and in released material. Close intraarterial infusions of NKA, neurokinin B, SP, NPK, eledoisin, and physalaemin at doses of 0.1-100 pmol/min induced dose-dependent contractions of the proximal and distal colon (P less than 0.001) and vasodilatation (P less than 0.001), NKA being the most potent. The effects of the tachykinins were reduced after tetrodotoxin (P less than 0.05) and atropine (P less than 0.05) but unchanged after treatment with hexamethonium. Our findings indicate that tachykinins are released from the pelvic nerve to induce a nonadrenergic noncholinergic contraction and vasodilatation of the colon in the cat.

Background: Nitric oxide (NO) is known to be up-regulated by the induction of induciblenitric oxide synthase (iNOS) in inflammatory conditions. NO gas can be used as a markerof inflammatory activit ...

Background: Neuropeptide S (NPS) is expressed by gastrointestinal (GI) enteroendocrine cells and macrophages in rat and man. Polymorphisms of the NPS receptor are linked to increased risk of inflammatory bowel disease as well as motor and sensory disturbances of the gut, suggesting a role for NPS in GI disorders. Further knowledge of NPS effects on motility and inflammation is needed. Methods: Studies of motility were carried out in rats with electrodes implanted in the small bowel. NPS was infused IV for 60 min and effects on myoelectrical activity were recorded. Motility effects of NPS were further studied as luminal pressure changes in anaesthetized rats where the proximal small intestine with intact blood supply was perfused with saline for motility recordings. Tissue samples were obtained from rats for evaluation of gene expression and protein elaboration of inflammatory biomarkers. Muscle strips of the human stomach, small intestine and colon were used for pharmacological analysis in organ baths of motility responses to NPS. Localization of the NPS receptor was done with fluorescent-protein tagging using Cy3-NPS. Plasma levels of NPS were measured using ELISA in 5 healthy and 14 IBD patients before and after meal. Results: In conscious rats, NPS 1 nmol kg-1min-1 increased irregular spiking, 4 nmol kg-1min-1 reduced spiking and increased the MMC cycle length (P=0.005). In anesthetized rats, NPS 0.01-1 nmol kg-1min-1 dose-dependently reduced small bowel motility (P

INTRODUCTION: Atrophic gastritis (AG) with concomitant acid-free or hypochlorhydric stomach and Helicobacter pylori infection are the two most important risk factors for gastric cancer. Gastric mucosa, many microbes colonizing acid-free stomach and H. pylori strains possess alcohol dehydrogenase activity capable of locally producing acetaldehyde (ACH) from ethanol. ACH produced from ethanol in oral cavity contributes to gastric ACH exposure via saliva. Limited capacity of mucosal cells and microbes to eliminate ACH, results in enhanced exposure of gastric mucosa to the carcinogenic actions of ACH. ACH associated with alcoholic beverages has been classified as carcinogenic (Group 1) to humans by IARC/ WHO. Capsule that slowly releases L-cysteine in the stomach converting ACH to inactive 4-methyltiazolidine-2-carboxylic acid (MTCA) has been recently implicated in prevention of gastric carcinogenesis among patients with AG. AIMS: To assess the production of ACH and MTCA in the stomach of AG patients following an exposure to 15% ethanol, with or without administration of L-cysteine. METHODS: Seven H.pylori positive patients, selected among 42 subjects with biopsy-confirmed AG, and fasting serum levels of pepsinogen (PG) I 10 pmol/L participated in the study. In a single-blinded fashion and on two separate days, patients were intubated with a nasogastric tube and exposed to15 % ethanol (0.3g/kg) and randomly 200 mg of L-cysteine or placebo. Gastric juice samples (5mL) were drawn every 20 min over a period of 4 hours and analyzed for pH and ACH-, ethanol-, L-cysteineand MTCA-concentrations. ACH and ethanol were analyzed by headspace gas chromatography and L-cysteineand MTCA-levels by liquid chromatography coupled to a triple-quadropole mass spectrometer. RESULTS: After intake of L-cysteine, free ACH levels in gastric juice decreased by a mean of 76% for 20 to 100min (p=0.0023

Gastrin Receptor Antagonist YF476 : Effects on Gastric Acid Secretion, Regulatory Peptides and Receptor Gene Expression in Rats

* Percentage of patients with a score ≥ 1 **Where 0=none,1=very mild, 2=mild, 3=moderate, 4=severe, and 5=very severe for individual symptoms. TZP-102, Ghrelin Agonist, Phase 2 Data: The Improvement in Symptoms of Gastroparesis (Nausea, Early Satiety, Bloating and Abdominal Pain) Significantly Correlated with Patient Rating of Overall Treatment Effect R McCallum1, J Wo2, R Venuti3, T Esfandyari4, M Jamal5, G Dimcevski6, L Tarnow7, R Malik8, PM Hellstom9, L Shaughnessy3, P Charlton3, G Kosutic3, N Ejskjaer10 1Texas Tech Univ Health Sci Ctr El Paso TX, 2Univ Louisville, Louisville KY, 3Tranzyme, Inc., Durham NC, 4Univ Kansas Med Ctr, Kansas City KS; 5Long Beach VA Med Ctr, Long Beach CA, 6Haukeland Univ Hosp, Bergen NO, 7Steno Diabetes Ctr, Gentofte DK, 8Univ Manchester, Manchester UK, 9Uppsala Univ Hosp, Uppsala SE, 10Aarhus Univ Hosp, Aarhus DK