. Rectoceles are commonly investigated by barium proctography This is a qualitaive investigation and does not provide data on rectcele enptying. We have used a quantitative method [isotope defaccography (ID)] with the aim of differentiating between significant (SR) and non-significant rectoceles (NSR). We studied 95 patients with a clinical diagnosis of rectocele. ID was performed using 100 Mbq of "Tc mixed with 100 mls of oat porridge. 71 of the 95 patients wer found to have a rectocele. The percentage and rate of evauation (%Isec) and also the percentage of isotope retained in the rectocele were calculated. Patients with 15% or more retention in the rectocele were defined as having a significant rectocele. Results: 34 of 71 had a significant rectocele. The SR group had a significantly higher retention of the isotope than NSR [22.3 (1.4) vs 9.6 (0.4), p<0.0005). Similarly the retention of the iotope as percentage of final rectal content was significantly higher in the SR than NSR group [52.6 (2.4) vs 33.1 (1.8)J, p<0.0001]. The rate of evacuation in the two groups was similar [0.97 (0.1) vs 1.3 (0.1), p> 0.05. There was no significant difference in the total percent evacuation between the no rectocele and NSR groups. There was a significant correlation between the presence of a significant rectocele and total percentage evacuation (r=0.61, p<0.0001). There was no significant correlation between the presence of a SR or NSR and the rate of evacuation. These data suggest that retention of 15% or more of the rectal

Background: Inflammatory bowel disease (IBD) is characterised by intense mucosal recruitment of activated leukocytes. Chemokines determine inflammatory leukocyte recruitment and retention.Aim: To compare expression of the entire chemokine family within colonic mucosa from IBD patients and uninflamed controls.Methods: A microarray of cDNAs, representing every member of this superfamily and their cognate receptors, was hybridised with probes derived from colonoscopic biopsies.Results: A distinct subset of chemokines, consisting of CXCLs 1-3 and 8 and CCL20, was upregulated in active colonic IBD, compared with uninflamed areas or tissue from controls. Increased expression of their cognate receptors, CXCR1, CXCR2 and CCR6, was confirmed by quantitative PCR and immunohistochemistry. An identical chemokine response was induced in Caco-2 cells by stimulation with interleukin (IL)-1beta, but not tumour necrosis factor-alpha (TNF-alpha). By contrast, IL-1beta and TNF-alpha were synergistic in an HT29 cell line and primary keratinocytes.Conclusions: IL-1beta and TNF-alpha appear to be the pivotal mediators of a previously unidentified coordinated epithelial chemokine response that dominates the mucosal chemokine environment in inflamed IBD tissue.

Background: Few studies have investigated the prevalence of multiple gastrointestinal diseases in the general British population.Aim: To examine the prevalence of Crohn's disease (CD), ulcerative colitis (UC), irritable bowel syndrome (IBS), gall stones (GS), and peptic ulcer disease (PUD).Subjects: The 1970 British Cohort Study (BCS70) and the National Child Development Study (NCDS) are two one week national birth cohorts born in 1970 and 1958, respectively. All cohort members living in Great Britain were interviewed in 1999/2000.Methods: The prevalence rates of the five diseases were calculated, and associations with sex and childhood social class were investigated using logistic regression.Results: At age 30 years, the prevalence rates per 10 000 (95% confidence interval (CI)) in the 1970 and 1958 cohorts, respectively, were: CD 38 (26-49), 21 (13-30); UC 30 (20-41), 27 (18-37); IBS 826 (775-877), 290 (267-330); GS 88 (71-106), 78 (62-94); and PUD 244 (214-273), 229 (201-256). There was a significantly higher proportion with CD (p=0.023) and IBS (p=0.000) in the 1970 cohort compared with the 1958 cohort at age 30 years. Comparing the cohorts in the 1999/2000 sweep, UC, GS, and PUD were significantly (p=0.001, p=0.000, p=0.000) more common in the 1958 cohort. There was a statistically significant trend for a higher risk of GS with lower social class in both cohorts combined (p=0.027).Conclusion: The study indicates an increasing temporal trend in the prevalence of CD and suggests a period effect in IBS, possibly due to adult life exposures or variation in recognition and diagnosis of IBS.

Background: The eradication of Helicobacter pylori decreases the antisecretory activity of omeprazole and lansoprazole. Rabeprazole is a potent proton pump inhibitor that may not be affected as greatly by H. pylori status.Aim: To compare the effect of H. pylori eradication on intragastric acidity and plasma gastrin during dosing with lansoprazole, omeprazole, rabeprazole and placebo.Methods: Twenty-four healthy H. pylori -infected volunteers were studied on day 7 of dosing with placebo, lansoprazole 30 mg, omeprazole 20 mg and rabeprazole 20 mg, before and at least 5 weeks after H. pylori eradication. On each occasion, the 24-h intragastric acidity was measured by gastric aspiration. Plasma gastrin concentrations were measured hourly from 08.00 to 13.00 h.Results: Sixteen subjects completed the study. For all three drugs and placebo, H. pylori eradication increased intragastric acidity, particularly nocturnal acidity, and decreased plasma gastrin. There were no differences between the three drugs with respect to 24-h acidity, percentage of time pH > 4 or 5-h plasma gastrin, either before or after H. pylori eradication. Before eradication, the percentage nocturnal time at pH > 3 was significantly greater during rabeprazole than during lanso-prazole dosing.Conclusions: The increase in intragastric acidity seen after H. pylori eradication during dosing with proton pump inhibitors is a drug-class effect, particularly affecting nocturnal acid control. This is related to increased spontaneous intragastric acidity after H. pylori eradication.

PURPOSE:The prognosis for advanced pancreatic cancer remains poor. Gastrin acts as a growth factor for pancreatic cancer. We describe the first study of the antigastrin immunogen G17DT in pancreatic cancer. Our aims were to determine the antibody response, safety, tolerability, and preliminary evidence of efficacy of G17DT in advanced pancreatic cancer.PATIENTS AND METHODS:Thirty patients with advanced pancreatic cancer were immunized with three doses of either 100 micro g or 250 micro g of G17DT.RESULTS:In the whole group, 20 (67%) of 30 patients produced an antibody response. The 250- micro g dose resulted in a significantly greater response rate of 82% compared with 46% for the 100- micro g group (P =.018). The most significant side effects, seen in three patients, were local abscess and/or fever. The median survival for the whole group from the date of the first immunization was 187 days; median survival was 217 days for the antibody responders and 121 days for the antibody nonresponders. The difference in survival between the antibody responders and nonresponders was significant (P =.0023).CONCLUSION:Patients with advanced pancreatic cancer are able to mount an adequate antibody response to G17DT. The 250- micro g dose is superior to the 100- micro g dose, and it appears to be generally well tolerated. Antibody responders demonstrate significantly greater survival than antibody nonresponders. Phase III studies are currently underway in order to determine efficacy.

Background: Environmental exposures in early life have been implicated in the aetiology of inflammatory bowel disease (IBD). Siblings are used as proxy markers to characterize patterns of exposure relevant to the risk of IBD. Methods: Some 15,823 patients with ulcerative colitis and 12,668 with Crohn disease from the Swedish In-patient Register were compared with 79,546 and 63,035 controls, respectively, in a case-control study. Multiple logistic regression was used to investigate associations with older and younger siblings, and adjustment was made for sex, year of birth, mother's age, region and, additionally, father's social class. Results: Older siblings are associated with a graded increased risk for ulcerative colitis ( P for trend <0.001) and an adjusted odds ratio of 1.15 (95% CI 1.07-1.24) for three or more older siblings. Younger siblings are associated with a graded decreased risk for Crohn disease ( P for trend <0.001) with an adjusted odds ratio of 0.83 (0.76-0.90) for three or more younger siblings. The greatest protective association with Crohn disease was seen for younger siblings born within 2 years of the subject. Older maternal age is independently associated with a decreased risk of Crohn disease, with P for trend <0.001. Additional adjustment for social class did not substantially alter the results. Conclusions: Having siblings is associated with the risk and phenotype of developing IBD, possibly through their influence on patterns of antigenic exposure in early life. The association of maternal age with Crohn disease may reflect age-related changes in maternal immune profile.

BACKGROUNDLeft handedness has been associated with inflammatory bowel disease (IBD) and autoimmune diseases.AIMSTo determine whether left handedness is associated with IBD in two prospective national birth cohorts.METHODSSubjects with Crohn's disease (CD) and ulcerative colitis (UC) were identified from two national longitudinal birth cohorts at age 26 years (1970 British Cohort Study (BCS70), born in 1970) and age 33 years (National Child Development Study (NCDS), born in 1958). Laterality was determined at age 10 (BCS70) or seven (NCDS) years, based on hand preference for writing and foot preference for kicking a ball (BCS70 only). Multiple logistic regression was used to assess the relationship of handedness with CD, UC, and IBD in the cohorts combined and adjusted for sex.RESULTSBoth cohorts combined showed increased adjusted relative odds of 2.13 (95% confidence interval (CI) 0.97–4.65; p=0.059), 2.13 (95% CI 0.92–4.91; p=0. 077), and 2.13 (95% CI 1.20–3.78; p=0.010) for CD, UC, and IBD, respectively in left handers.CONCLUSIONSThe study suggests a link between IBD and left handedness which may be genetic and/or environmental in origin.

BACKGROUND:Histamine H2-receptor antagonists are available over the counter for the treatment of heartburn.AIM:To compare the effects of low doses of ranitidine and famotidine on intragastric acidity in a three-way crossover study.METHODS:Healthy subjects (12 male, 12 female) were dosed on three occasions with single oral doses of placebo, ranitidine, 75 mg, and famotidine, 10 mg, 1 h after lunch. The pH of gastric aspirates was then measured for 20 h. Subjects ate standard meals and snacks. Analysis of variance was used to determine the statistical significance of differences in acidity (mmol/L) during the day (12.30-22.30 hours) and night (22.30-08.30 hours).RESULTS:Ranitidine and famotidine were superior (P < 0.05) to placebo in decreasing acidity for daytime and night-time intervals. There were no significant differences in mean gastric acidity between ranitidine and famotidine during the daytime (11.37 mmol/L vs. 13.42 mmol/L, respectively) and night-time (23.57 mmol/L vs. 24.74 mmol/L, respectively). Intragastric acidity after ranitidine was significantly lower than that after famotidine in the first 2.5-h period following dosing (4.32 mmol/L vs. 9.28 mmol/L; P < 0.05).CONCLUSIONS:Lunchtime doses of ranitidine and famotidine decreased acidity during day- and night-time periods. The effect of ranitidine was significantly greater for the first 2.5 h after dosing.

BACKGROUND & AIMS:alpha4 integrins are important mediators of leukocyte migration across vascular endothelium. This pilot placebo-controlled study aimed to assess the safety and efficacy of natalizumab, a recombinant humanized monoclonal antibody to alpha4 integrin, in patients with mild to moderately active Crohn's disease.METHODS:Thirty patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =151 and < or =450) received a 3-mg/kg infusion of natalizumab (n = 18) or placebo (n = 12) by double-blind randomization. The study's primary endpoint was change in CDAI at week 2.RESULTS:At week 2, the CDAI decreased significantly from baseline after infusion of natalizumab (mean 45 points) but not placebo (mean 11 points). Seven (39%) natalizumab-treated patients achieved remission at week 2, compared with 1 (8%) treated with placebo. In contrast, 4 (33%) of the placebo-treated patients required rescue medication by week 2, compared with 2 (11%) natalizumab-treated patients. Significant increases in circulating B and T lymphocytes were detected only after natalizumab administration. The frequency of commonly reported adverse events did not differ significantly between groups.CONCLUSIONS:A single 3-mg/kg natalizumab infusion was well tolerated by Crohn's disease patients, although the dose used may have been suboptimal. Elevated circulating lymphocyte levels after natalizumab suggest interrupted lymphocyte trafficking. Natalizumab therapy in active Crohn's disease merits further investigation.

Background: Indomethacin has been shown to damage the villous microvasculature concomitant with alterations in villous blood flow in the rat.Aim: To test the hypothesis that alterations in blood flow result from ultrastructural damage to microvasculature endothelium.Methods: In anaesthetized rats, jejunal villi were exteriorized in a chamber and blood flow in surface capillaries visualized by fluorescence microscopy. Villi were exposed both luminally and systemically to indomethacin (100 μg/mL) for 10 min or until blood slowing or stasis had occurred in superficial capillaries (n=3 per group). Control animals received both a luminal and intravenous vehicle for 45 min (n=3). The small intestines were vascular perfusion‐fixed with 1.5% glutaraldehyde and studied by transmission electron microscopy.Results: All controls appeared to be ultrastructurally normal. A 10 min exposure to indomethacin had no effect upon the epithelium but resulted in mild endothelial vacuolization and the development of small finger‐like projections into the lumen of villus surface microvasculature. At the point of blood slowing, villus tip epithelium was again normal but the endothelial vacuolization and finger‐like projections became more obvious. The endothelial projections and vacuolization became severe at the point of blood stasis; this also coincided with epithelial degeneration.Conclusion: This study shows that villus surface microvasculature is the earliest site of morphological damage after indomethacin exposure.

BACKGROUND:We previously localized beta3-adrenergic receptors immunohistochemically in human gastrointestinal smooth muscle and incidently found a population of human pancreatic islet cells and duodenal epithelial neuroendocrine cells that also expressed beta3-adrenergic receptors.AIM:To identify the nature of the islet and duodenal cells that stained positive for beta3-adrenergic receptors.METHODS:Paraffin sections of human pancreas and duodenum and Chinese hamster ovary cells transfected with the human beta3-adrenergic receptor were immuno-stained for beta3-adrenergic receptors using an affinity-purified rabbit polyclonal antibody (anti-P12) raised against a 15 amino acid sequence (P12) of the human receptor. Immunohistochemical staining for the receptor was carried out in the presence and absence of P12 peptide and both somatostatin 14 and 18 peptides. beta3-adrenergic receptor-stained sections were also double-immunostained with anti-insulin, -glucagon, -somatostatin and -pancreatic polypeptide antibodies.RESULTS:A subpopulation of human pancreatic islet cells and duodenal epithelial cells expressed positive cytoplasmic beta3-adrenergic receptor immunostaining. Using distribution and double-staining techniques, these cells were found to be somatostatin-positive D cells but not A or B cells. The positive staining of D cells with anti-P12 antibody was inhibited by prior incubation of the antibody with P12 peptide but not somatostatin-14 or -28 peptides. Pancreatic vascular smooth muscle and duodenal vascular and non-vascular smooth muscle also stained with anti-P12 antibody. Transfected Chinese hamster ovary cells showed positive membrane staining.CONCLUSION:We have identified a population of neuroendocrine cells in the human pancreas and duodenum that express beta3-adrenergic receptors. These cells appear to be somatostatin D cells.