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SUMMARY The importance of leucocyte–endothelial cell interactions in the inflammatory process is now recognized. In Crohn's disease, we have proposed that these interactions mediate not only the development of the parenchymal cell infiltrate, but also initiate a process (multifocal gastrointestinal infarction) that leads to ischaemic damage to the bowel wall. We review data on the actions of drugs in the treatment of Crohn's disease and, where known, we highlight their effects on leucocyte adhesion to the endothelium. Corticosteroids inhibit adhesion by inhibiting production of interleukin-1, tumour necrosis factor, interferon gamma, leukotrienes and platelet activating factor. Drugs liberating 5-aminosalicylate inhibit leukotriene production. Cyclosporin inhibits T-cell activation, and amplification of the immune response. Inhibition of leucocyte–endothelial cell interactions probably accounts for some of the beneficial effects of these drugs in Crohn's disease.

In a double-blind, placebo-controlled study of SKF 94482 (BMY-25368) (400-mg, post-evening meal, for 7 days in 11 healthy subjects), there was a significant 75% decrease in median integrated 24-h intragastric acidity during dosing with the drug (218 mmol h/L) compared with placebo (883 mmol h/L; P = 0.003). The single daily dose of 400 mg SKF 94482 decreased median hourly intragastric acidity until the time of the next dose 24 h later. There was also a sustained and significant 80% rise in median 24-h integrated plasma-gastrin concentration during dosing with SKF 94482 (364 pmol h/L) when compared with placebo (202 pmol h/L; P = 0.003). The study demonstrates a significant inverse correlation between 24-h integrated intragastric acidity and 24-h plasma gastrin concentration (rs = -0.484; P less than 0.001). The study shows that a single oral daily dose of an H2-antagonist can provide control of intragastric acidity throughout the day and night, decreased acidity being associated with statistically significantly, but modestly elevated plasma-gastrin levels.

SUMMARY Plasma alcohol concentration following oral ingestion of 0.3 g/kg of alcohol (ethyl alcohol), one hour after an evening meal, was measured in four groups of 12 healthy subjects. Each group had a control study and a repeat study after 7 days dosing with either placebo or an H2-receptor antagonist (300 mg ranitidine nocte, 800 mg cimetidine nocte, or 40 mg famotidine nocte). There was no significant difference between the control and post-dosing studies in the integrated 4-h plasma alcohol concentration, peak plasma alcohol concentration, or time to reach peak alcohol concentration. This study shows that post-prandial alcohol absorption after 0.3 g/kg of alcohol is not affected by ranitidine, cimetidine or famotidine.

SUMMARY Fourteen patients with chronic diarrhoea, but no evidence of active organic disease, completed a double-blind crossover comparison of the anti-diarrhoeal effects of loperamide, placebo and the clonidine analogue, lidamidine. Failure of diarrhoea control led to early withdrawals from seven placebo- and six lidamidine-treatment periods, but there was only one early withdrawal during treatment with loperamide. Loperamide was found to be superior to lidamidine or placebo for the control of stool consistency in patients with chronic diarrhoea.

Twenty-four-hour plasma pepsinogen I and II concentrations were determined in 8 healthy subjects with antibody to Helicobacter pylori, before and after treatment with tripotassium dicitrato bismuthate, amoxycillin and metronidazole, Therapy was successful in the 5 subjects with active H. pylori infection. In these subjects, median integrated 24-h plasma pepsinogen I and II concentrations significantly decreased from 2288 and 357 micrograms.h/L before treatment, respectively, to 1811 and 171 micrograms.h/L at 4-6 weeks after treatment, and 1643 and 150 micrograms.h/L at 20-24 weeks. By contrast, in the 3 subjects without evidence of active H. pylori infection, pre-treatment plasma pepsinogen I and II concentrations were similar to values found in the H. pylori-infected subjects after successful therapy, and they did not change significantly in response to therapy. H. pylori infection is associated with reversible hyperpepsinogenaemia.

The effects of bedtime 70 micrograms and twice daily 35 micrograms doses of enprostil on 24-hour intragastric acidity were investigated in nine duodenal ulcer patients in remission. Median nocturnal acidity decreased significantly by 30% with 35 micrograms twice daily, and by 48% with 70 micrograms at bedtime. In a clinical trial using bedtime dosing, 102 duodenal ulcer patients randomly received either ranitidine 300 mg or enprostil 70 micrograms. More ulcers healed after 4 and 8 weeks treatment with ranitidine than with enprostil (76% ranitidine vs 52% enprostil, at 4 weeks p = 0.0065 and 94% vs 68%, respectively at 8 weeks, P = 0.0007). However, 6 months after cessation of treatment there was no material difference in overall outcome. Despite combining mucosal protection with acid inhibition enprostil treatment conferred no advantage over simple acid inhibition.

Ten dyspeptic patients were treated with 1 g sucralfate q.d.s. for six weeks. The plasma aluminium concentration and 24-h urinary aluminium excretion were measured at 3-weekly intervals before, during and after treatment with sucralfate. Compared with before treatment, there were significant rises in the median plasma aluminium concentration at 3 and 6 weeks during treatment with sucralfate (6 micrograms/L to 13 and 12 micrograms/L). The median 24-h urinary aluminium excretion rose significantly from a pretreatment level of 20 micrograms to 71 and 78 micrograms after 3 and 6 weeks of treatment; the significant increase of urinary aluminium excretion persisted for three weeks after cessation of treatment (52 micrograms/24 hours), but thereafter urinary excretion was not significantly different from pretreatment. The results are consistent with significant absorption and tissue accumulation of aluminium during standard treatment with sucralfate in individuals with normal renal function.

SUMMARY Eight patients with active uncomplicated Crohn's disease, who were resistant to or intolerant of conventional treatment, were treated for 6 weeks with oral cyclosporin (mean dose 8.2 mg kg−1 day−1). Seven of the eight patients responded to treatment with cyclosporin by symptomatic improvement, weight gain and a return of serum C-reactive protein concentration towards normal. All patients relapsed on stopping cyclosporin. No serious side-effects were encountered. This favourable early experience justifies further trials using cyclosporin for active Crohn's disease.

Background: Helicobacter pylori is associated with B-type gastritis, duodenal ulcer disease, and possibly gastric carcinoma. The object of this study was to assess the effect of eradication of H. pylori infection on gastric epithelial cell proliferation.Methods: Gastric epithelial cell proliferation was assessed in 22 H. pylori-positive duodenal ulcer patients before and 6 weeks after 'triple therapy' with bismuth, tetracycline and metronidazole. Cell proliferation was studied either by immunostaining for the proliferating cell nuclear antigen (PCNA) or by a microdissection technique.Results: Eradication was successful in 10 of the 22 H. pylori-positive patients. Treatment with 'triple therapy' resulted in a significant fall in the rate of gastric epithelial cell proliferation; this effect was seen in both the gastric body and antrum. There was a significant correlation between the number of PCNA-labelled cells and the histological grade of activity (neutrophil inflammation) (r = 0.49, P = 0.02);the same correlation was found for the number of mitoses per gland (r = 0.5, P = 0.02). There was no significant difference in the treatment effect for eradicated or non-eradicated patients or either the body or antrum. Six patients, who had at least one antral biopsy that showed evidence of focal intestinal metaplasia, had a higher rate of cell proliferation.Conclusions: The reduction in epithelial cell proliferation in the body and antrum after triple therapy is independent of successful eradication of H. pylori, and it may be due to an anti-inflammatory effect of triple therapy.

SUMMARY In a double-blind placebo-controlled study in nine healthy volunteers, the effects of single doses of oral enprostil (8.75, 17.5, 35 and 70 μg), taken before a standard breakfast, were assessed on the post-prandial release of gastrin into the plasma. All doses of enprostil caused a significant dose-related decrease in median post-prandial plasma gastrin concentration (range from — 29 to — 44%). In the same subjects, two doses of 25 mg indomethacin caused a significant (38%) increase in median post-prandial plasma gastrin concentration.

Aim: We investigated the effect of dexamethasone on indomethacin-induced ulceration in the rat.Methods: Groups of four rats received oral indomethacin (15 mg/kg) and the jejunal mucosa was examined 24 h later for mucosal ulceration, Three of the groups received oral dexamethasone (1, 3 and 6 mg/kg) 0.5 h prior to indomethacin, while the fourth received vehicle. Haematological evaluation was performed and ulcers were assessed both histologically and immunohistochemically.Results: Indomethacin caused multifocal jejunal ulceration that was reduced only by the highest dose of dexamethasone (6 mg/kg), Indomethacin caused a significant fall in the blood haemoglobin concentration that was prevented by dexamethasone at all doses, The ulcers induced by indomethacin alone were deep, punched-out and haemorrhagic while the ulcers arising in rats pre-treated with dexamethasone (all doses) were ''plugged'' by a white fibrino-purulent exudate. Histologically, the dexamethasone ulcer exudate was composed of bacteria, fibrin, mucus and a significant increase in the numbers of neutrophils. Dexamethasone alone had no significant pathological effect on the small intestine.Conclusions: We report the observation that dexamethasone at high doses inhibits indomethacin-induced jejunal ulceration in the rat while at low doses it promotes ''plugging'' of ulcers with bacteria, fibrin, mucus and neutrophils that probably reduces haemorrhage from the ulcer base.

SUMMARY Background: Patients on nonsteroidal antiinflammatory drugs can develop curious intestinal fibrotic diaphragms. Methods: Groups of rats received indomethacin mixed into a powdered diet at 3 mg.kg/day for 6 and 12 weeks and 6 mg. kg/day for up to 6 weeks. In an attempt to reproduce a human dosing regimen, another group of rats, for a total of 30 weeks, received consecutive periods of indomethacin at 3 mg. kg/day for 12 weeks, 4.5 mg.kg/day for 1 week, 6 mg.kg/day for 1 week, control diet for 6 weeks, 4.5 mg.kg/day for 2 weeks and finally, a control diet for a healing period of 8 weeks. Control rats received powdered diet alone. At termination, the small and large intestines were examined macroscopically and histologically. Results: Indomethacin caused microcytic anaemia, hypoalbuminaemia, small intestinal ulceration, caecal ulceration and inconspicuous raised mucosal lesions in the caecum that histologically showed submucosal fibrosis with disruption and thickening of the apical muscularis mucosae. No control rats showed any abnormality. Conclusion: These fibrotic lesions of the rat caecum resemble human diaphragms and may arise from healed caecal ulcers.

SUMMARY Background: In indomethacin-induced jejunal ulceration in the rat, villi undergo both early microvascular injury and shortening that may involve activation of villous smooth muscle. Aim: This study sought to substantiate light microscopic observations using three-dimensional imaging of early villous architectural changes in response to indomethacin. Methods: At both 2 and 6 h after oral indomethacin 15 mg/kg or vehicle to groups of rats, the vasculature of the small intestine was visualised by both carbon-ink perfusion/confocal microscopy and injection casting. The mucosa was also examined for lesions by dissection microscopy and scanning electron microscopy. Results: In indomethacin-dosed rats examined by scanning electron microscopy and histology, the mucosa at 2 h showed villous shortening and wrinkling of the surface epithelium without epithelial loss: at 6 h, the mucosa was flattened, often with epithelial loss to expose a ‘contracted’ villous core. Examination of the vasculature in carbon-injected tissues indicated significant reductions of both mucosal height and inter-capillary distance at both 2 and 6 h post-indomethacin. Scanning electron microscopy of injection casts at 2 and 6 h indicated similar changes. These changes were not seen in control tissues. Conclusion: Histology, confocal microscopy and scanning electron microscopy support the proposal that villous shortening with disruption of surface capillary architecture are early changes in the ulcerative enteropathy induced by nonsteroidal anti-inflammatory drugs.

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

Background: Alpha-4 integrins facilitate leucocyte migration across vascular endothelium.Aim: To assess the safety and efficacy of natalizumab (Antegren), a humanized antibody to alpha-4 integrin, in patients with active ulcerative colitis.Methods: Ten patients with active ulcerative colitis, defined by a Powell-Tuck activity score > 4, received a single 3 mg/kg natalizumab infusion. The primary end-point was the change in Powell-Tuck score at 2 weeks post-infusion.Results: Significant decreases in the median Powell-Tuck score were observed at 2 and 4 weeks post-infusion (7.5 and 6, respectively) compared to the median baseline score (10). Five of 10 patients achieved a good clinical response at 2 weeks and one more patient by 4 weeks, defined by a Powell-Tuck score of less than or equal to 5. Significant improvements in quality of life scores were found at week 4. Rescue medication was required by two (20%). three (30%) and eight (80%) patients by weeks 2, 4 and 8. respectively (median, 34 days; range, 8-43 days). One patient remained in remission at 12 weeks. The median C-reactive protein at 2 weeks (6 mg/L) was lower than that pre-treatment (16 mg/L).Conclusions: A single 3 mg/kg infusion of natalizumab was well tolerated by ulcerative colitis patients. The positive efficacy demonstrated in this study merits further investigation by randomized, placebo-controlled trials.

This study assessed the duration of action of single doses of ranitidine (75 mg), cimetidine (200 mg), or placebo on intragastric acidity in healthy subjects. When dosed with placebo, mean daytime intragastric acidity (0-10 hr after dose) was 37.62 mmol/liter, decreasing to 17.21 mmol/liter (mean decrease 59%; P < 0.001 vs placebo) and 25.06 mmol/liter (mean decrease 35%; P < 0.001 vs placebo) when treated with ranitidine and cimetidine, respectively. Ranitidine inhibited intragastric acidity to a greater degree than cimetidine (P < 0.001). Mean nighttime (10-20 hr after-dose) intragastric acidity when dosed with placebo was 34.37 mmol/liter, decreasing to 29.06 mmol/liter (mean decrease 18%; P = 0.027 vs placebo) when dosed with ranitidine and remaining virtually unchanged at 33.85 mmol/liter (mean decrease 2%; NS vs. placebo) when dosed with cimetidine. Ranitidine inhibited acidity to a greater degree than cimetidine (P = 0.043). The inhibitory effect of ranitidine, 75 mg, on intragastric acidity can be detected from 0-15 hr after an oral dose. Cimetidine 200 mg has little inhibitory effect beyond 10 hr.

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.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.Older siblings are associated with a graded increased risk for ulcerative colitis (P for trend0.001) 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 trend0.001) 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 trend0.001. Additional adjustment for social class did not substantially alter the results.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.

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

Background & Aims: α4 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 α4 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] ≥151 and ≤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. GASTROENTEROLOGY 2001;121:268-274

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: Patterns of neonatal exposure to microorganisms have changed substantially over the last 100 years, and it has been suggested that this has influenced the risk of immune-mediated disease. Using a proxy measure, we tested the hypothesis that the initial handling of newborn infants, which is known to affect the pattern of exposure to microorganisms, may alter the risk of developing subsequent atopy, as indicated by hay fever. Methods: Analysis was performed on 5519 members of the 1970 British Cohort Study, a nationally representative birth cohort. Cohort members with hay fever were identified at intervals up to the age of 26 years. Details of neonatal care and childhood circumstances were recorded prospectively. Those who had spent their first night away from their mother in the communal infant nursery were selected as likely to have experienced atypical exposure compared with infants who remained with their mother. Adjustment was made for potential confounding factors in infancy and childhood by multiple logistic regression analysis. Results: Unadjusted relative odds (with 95% CI) for developing hay fever among those spending the first night in the communal nursery, when compared with other infants who remained with the mother, were 1.48 (1.23–1.77), P

Aim: To compare the effects of rabeprazole 10, 20 and 40 mg o.d. on 24-h intragastric acidity and plasma gastrin concentration in a randomized, double-blind placebo-controlled trial. Methods: Twenty-four healthy male volunteers were studied on the 7th day of morning dosing with either placebo or rabeprazole 10, 20 or 40 mg in a crossover fashion. On day 7, hourly intragastric acidity was measured for 24 h from 08.00 hours by gastric aspiration. Plasma gastrin concentrations were also measured hourly from 08.00 to 24.00 hours, and 2-hourly thereafter. Results: Compared with placebo, rabeprazole 10, 20 and 40 mg produced significant dose-related decreases in intragastric acidity (median 24-h integrated acidity=697, 186, 129 and 82 mmol h/L, respectively). This was associated with significant elevation of plasma gastrin concentration (median 24-h integrated gastrin=141, 1184, 1484 and 1763 pmol.h/L, respectively). Rabeprazole 40 mg resulted in significantly decreased acidity compared with both 10 and 20 mg, and in longer times for which intragastric pH was maintained at > 3 (19.2 h vs. 17.3 h and 17.5 h) and > 4 (17 h vs. 14.2 h and 15.2 h), but was accompanied by significantly increased plasma gastrin. There was a consistent trend for greater antisecretory activity for 20 mg compared with 10 mg, but these differences did not reach statistical significance. The interindividual variability in antisecretory response was greatest with 10 mg. Conclusions: Rabeprazole 10, 20 and 40 mg produce significant, profound dose-related inhibition of gastric acid secretion. Taking into account reciprocal increases in plasma gastrin and the interindividual variation in antisecretory response, 20 mg appears to be the preferred dose for routine clinical use.

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 : Both Crohn’s disease ileal ulcers and indomethacin-induced jejunal ulcers in the rat have a predilection for the mesenteric margin of the bowel wall. Unlike the anti-mesenteric margin, the mesenteric margin is supplied by small end-arteries that might render it more sensitive to ischaemic injury. Aim : To examine, in both situations, the histological relationship between the precise localization of small bowel ulcers and the mesenteric margin. Methods : Ileal Crohn’s disease ulcers identified in surgical resection specimens (n=5) and indomethacin-induced lesions in the rat jejunum (n=6) were examined macroscopically and histologically. Results : In both the human ileum and the rat jejunum, ulcers occurred consistently along the mesenteric margin, with the most extensive mucosal injury occurring at two adjacent sites on either side of the midline of this margin. At these two sites, feeding arteries entered the muscularis propria. Conclusions : For anatomical reasons apparently related to the vasculature of the human and rodent small bowel, specific sites along the mesenteric margin are susceptible to Crohn’s disease ulceration and NSAID damage, respectively.

OBJECTIVE: To examine previously cited early risk factors for inflammatory bowel disease. DESIGN: The 1946 National Survey of Health & Development (NSHD) and the 1958 National Child Development Study (NCDS) are on-going, longitudinal birth cohort studies. A nested case- control design was used combining data from both cohorts; eight controls per case, matched for gender and social class, were selected randomly. METHODS: Data concerning maternal infection in pregnancy (NCDS only), childhood infection (measles, mumps and whooping cough), birth order, appendicectomy, breast-feeding and measures of poor housing conditions in childhood were analysed. In both cohorts, the member's hospital physician or medical records were used to confirm the diagnosis. RESULTS: Twenty-six cases of Crohn's disease and 29 cases of ulcerative colitis were identified. No significant association was found between the development of Crohn's disease or ulcerative colitis and any of the studied factors. There was a trend that those with Crohn's disease were more likely not to have been breast-fed (OR 0.4, 95% CI 0.15-1.03) and not to have had an appendicectomy (OR < 1.00). The opposite was true of those with ulcerative colitis (OR 2.76, 95% CI 0.86-9.81 and OR 2.34, 95% CI 0.69-7.46, respectively). The prevalence of inflammatory bowel disease was 5.12/1000 by the age of 43 years in NSHD and 2.02-2.54/1000 by the age of 33 years in NCDS. CONCLUSIONS: The prevalence of inflammatory bowel disease in these cohorts is among the highest recorded in Europe. Childhood factors may be different for those with Crohn's disease and ulcerative colitis. These cohorts will be increasingly valuable data sources

Half of the world's population is infected with Helicobacter pylori, making it a pathogen of potentially great significance. Although in the majority of cases, infection is harmless, many infected individuals develop peptic ulcer disease or gastric cancer. In developed countries, the prevalence of infection has decreased along with the incidences of duodenal and gastric ulcer and distal gastric cancer. In developing countries, H. pylori infection rates remain high, and, as life expectancy increases, the incidence of gastric cancer will increase. Recently, a working party of the World Health Organization designated H. pylori a class I carcinogen. This designation, along with the description of an H. pylori-infected animal model of gastric cancer, has strengthened the case for H. pylori eradication to prevent gastric cancer. However, concerns are growing that H. pylori eradication itself may cause harm. And, in developed countries, an increase in the rate of cancers arising near the gastroesophageal junction might be linked to the disappearance of H. pylori. Therefore, we are faced with a dilemma: Should we eradicate H. pylori to prevent cancer of the distal stomach, or should we leave it and hence avoid cancer of the proximal stomach or distal esophagus? The need for more reliable treatments further complicates the issue. So far, we cannot assume that current treatment regimens provide adequate eradication rates to justify widespread screening. Further research is needed to determine in whom, when, and how to eradicate H. pylori infection.

Background : Novel technology based on laser optogalvanic spectroscopy called the LARA (Laser Assisted Ratio Analyser) system was developed to measure 12C/13C ratios in breath samples using stable 13C isotopes, to detect Helicobacter pylori infection. Aim : To determine the sensitivity and specificity of the 13C-LARA-urea breath test in the detection of H. pylori infection in a prospective European multicentre trial; FDA-and EMEA-approved. Methods : Consecutive dyspeptic patients underwent diagnostic gastroscopy with biopsies for culture and histopathology, to detect H. pylori infection (gold standard). Subsequently, the LARA-urea breath test was performed using either a system without a cold trap (part I) or a system with a cold trap (part II). In both instances baseline, 30-min and 60-min breath samples were collected. The optimum cut-off level for 12C/13C ratios was determined by Receiver Operator Characteristics analysis. Results : In part I, 544 out of 604 patients were evaluable (low CO2: 47; withdrawn: 13). 284 out of 544 patients (52%) were H. pylori-positive according to the gold standard. The sensitivity of the LARA-urea breath test was 95% and the specificity 94%. In part II, 257 out of 272 were evaluable (low CO2: 14; withdrawn: 1). Sensitivity and specificity were 93% and 96%, respectively. Conclusion : The LARA-technology represents an accurate and non-invasive testing system for the detection of H. pylori infection. Its major advantages are the use of stable 13C isotope, the high throughput of samples and the easy means of collecting, storing and transporting the samples, thus making the system convenient to both patient and clinician.

Rabeprazole sodium is a new substituted benzimidazole proton pump inhibitor with several differences compared with existing proton pump inhibitors. In vitro and animal studies have demonstrated that rabeprazole is a more potent inhibitor of H+,K(+)-ATPase and acid secretion than omeprazole, and is a more rapid inhibitor of proton pumps than omeprazole, lansoprazole, or pantoprazole. This probably reflects rabeprazole's faster activation in the parietal cell canaliculus. In human studies, once-daily doses of 5-40 mg of rabeprazole inhibit gastric acid secretion in a dose-dependent fashion. A once-daily dose of 20 mg has consistently achieved profound decreases in 24-h intragastric acidity in single and repeat dosing studies, in healthy volunteers and patients with either peptic ulcer disease or gastro-oesophageal reflux disease. Significantly greater decreases in intragastric acidity are achieved on day 1 of dosing with rabeprazole 20 mg than with omeprazole 20 mg. As with other proton pump inhibitors, rabeprazole has in vitro antibacterial activity against Helicobacter pylori, with greater activity against this organism than either lansoprazole or omeprazole. In addition to inhibiting bacterial urease activity, rabeprazole binds to several molecules on H. pylori. Clinical trials are needed to assess the clinical importance of these findings, as well as to assess whether the potential advantages of rabeprazole result in clinical benefit for patients with acid-related diseases.

Background: Crohn's disease ileal ulcers and indomethacin-induced jejunal ulceration in the rat tend to occur in the mucosa nearest to the mesentery (mesenteric margin), an area of the bowel wall that has a critical blood supply. Mercuric chloride induces caecal and colonic ulceration in the Brown Norway rat.Aim: To examine whether the mesenteric margin is more sensitive to injury by a substance known to be vasculotoxic in the caecum and colon.Methods: Brown Norway rats received a single subcutaneous dose of either mercuric chloride 1 mg/kg or saline. The gastrointestinal tract was examined macro- and microscopically for lesions 48 h later. The vascular anatomy of the normal rat colon and caecum was also examined using the carbon ink perfusion technique.Results: Mercuric chloride induced caecal and colonic ulceration preferentially along the mesenteric margin of the bowel wall, Histologically, the lesions showed mucosal necrosis and neutrophil infiltration. There was also extensive vascular degeneration/necrosis with microaneurysm formation and extensive submucosal haemorrhage, Cellular infiltration of the vasculature was not a feature. The caecal and colonic mesenteric margins in control rats were supplied by small end arteries.Conclusions: The colonic and caecal mesenteric margins are susceptible to injury by mercuric chloride, a chemical known to induce haemorrhagic vasculopathy in the rat gastrointestinal tract. The large bowel mesenteric margin may be susceptible to injury by mercuric chloride because of the critical blood supply to that side of the bowel wall.

Background/Aims: Gastrin is a trophic factor within the normal gastrointestinal tract and is also a mitogen for a number of gastrointestinal and non-gastrointestinal tumours. Precursor forms of gastrin including progastrin (proG) and glycine-extended gastrin (G-gly) as well as the fully processed amidated gastrin (G-NH2) are expressed by tumours. There has been little study of the role of gastrin in either normal liver or liver tumours. The aim of this study was to identify the expression of CCK-B/gastrin receptor (CCK-BR), proG, G-gly and G-NH2 in normal liver and liver tumours. Methods: Tissue sections from patients with hepatocellular carcinoma, fibrolamellar carcinoma, cholangiocarcinoma as well as normal liver biopsies were assessed for expression of CCK-BR and gastrin isoforms. Results: Most liver tumours express CCK-BR and are able to process gastrin as far as proG and G-gly, although not as far as the amidated form. There appears to be little expression of the receptor and no expression of precursor forms of gastrin in normal liver. Conclusions: Liver tumours express the CCK-BR and precursor forms of gastrin. This expression may be associated with tumour proliferation.

Background: In the rat, indomethacin causes jejunal villous shortening, microvascular distortion, and blood stasis prior to ulceration, The beta(3)-adrenoceptor agonist CL316,243 (CL) prevents both the early histological changes and ulceration,Aim: To test the hypothesis that the beta(3)-adrenoceptor agonist CL316,243 exerts its protective effect by prevention and/or reversal of blood flow changes in the rat jejunum exposed to indomethacin,Methods: In anaesthetized rats, jejunal villous blood flow was measured in surface capillaries using fluorescence microscopy, Stasis of superficial capillary blood flow was induced by combined topical and i.v. indomethacin (100 mu g/mL, 2.8 x 10(-4) M). To examine the effect of CL on blood stasis, CL was applied either i.v. (1 mg/kg) or luminally (100 mu g/mL, 2.5 x 10(-5) M) at the onset of stasis. Prophylactic protection was assessed by giving i.v. CL simultaneously with indomethacin, Results were compared with controls which received luminal saline applied at blood stasis, The effect of i.v. CL (1 mg/kg) alone, or luminal CL (100 mu g/mL) alone on basal villous blood flow was also examined. The small intestines were perfusion-fixed with 10% formol saline, and removed for histology, n = 5 for all groups.Results: Luminal CL given at stasis reversed indomethacin-induced stasis within 10 min, whereas i.v. CL did not. Pretreatment with i.v. CL prevented the onset of stasis, Basal blood flow was raised slightly only by luminal CL,Conclusion: The beta(3)-adrenoceptor agonist CL316,243 can protect against indomethacin-induced blood stasis in rat jejunal villi.

Background—The appropriate medical treatment of patients with ulcerative colitis is determined largely by the severity of symptoms. Hospital assessment of the severity of disease activity includes investigation of laboratory indices and sigmoidoscopic assessment of mucosal inflammation.Aims—To develop a simplified clinical colitis activity index to aid in the initial evaluation of exacerbations of colitis.Methods—The information for development of the simple index was initially evaluated in 63 assessments of disease activity in patients with ulcerative colitis where disease activity was evaluated using the Powell-Tuck Index (which includes symptoms, physical signs, and sigmoidoscopic appearance). The new index was then further evaluated in 113 assessments in a different group of patients, by comparison with a complex index utilising clinical and laboratory data, as well as five haematological and biochemical markers of disease severity.Results—The newly devised Simple Clinical Colitis Activity Index, consisting of scores for five clinical criteria, showed a highly significant correlation with the Powell-Tuck Index (r=0.959, pr=0.924, pConclusions—This new Simple Colitis Activity Index shows good correlation with existing more complex scoring systems and therefore could be useful in the initial assessment of patients with ulcerative colitis.

Background: H2-receptor antagonists are becoming widely available as over-the-counter medications for the treatment of heartburn and excess gastric acidity. Aim: To determine the effects of single low doses of ranitidine on intragastric acidity. Methods: Intragastric pH was measured for 9 h after lunch in five studies involving 24 healthy male volunteers. Antacid was given to all subjects on day 1. They then received single oral doses of a study drug 45 min after lunch on four separate occasions: placebo and either ranitidine 25 mg, 75 mg or 125 mg were given double-blind according to a predetermined randomization schedule. Results: During both of the post-dosing time periods (0–5 h and 5–9 h) there were significant decreases in integrated intragastric acidity for each ranitidine dose compared with placebo (P 3 was significantly greater for ranitidine 75 mg and 125 mg (P

The end-point of Helicobacter pylori eradication trials in peptic ulcer disease should be the presence or absence of continuing H. pylori infection, and not ulcer healing or recurrence. This is not to suggest that ulcer healing or prevention of recurrence is not the desired clinical end-point. It is to allow large trials to be conducted in a 'patient-friendly' manner and in a shorter time-scale, both of which reduce patient withdrawals, protocol violations and cost. For the same reasons, diagnosis of cure should be made by noninvasive means whenever possible. It is currently impossible to make anything other than generalisations regarding the relative efficacies of modern eradication regiments. As it seems unlikely that definitive head-to-head studies will be performed, the conduct and reporting of current trials needs to be improved and standardised, to allow meaningful comparisons. In particular, the course of each and every patient through the trial should be fully and clearly reported, especially withdrawals and dropouts. The primary efficacy analysis should be the intention-to-treat analysis, with per protocol and modified intention-to-treat analyses also reported, where appropriate.

BACKGROUND: Ileal ulcers in Crohn's disease tend to lie along the same side of the bowel wall as the mesenteric attachment; the mesenteric and antimesenteric borders are supplied by short and long arteries, respectively. AIM: To examine the localisation of ileal Crohn's ulcers and to test the hypothesis that predilection of Crohn's ulcers for the ileal mesenteric margin is explained by the existence of end arteries that supply the mesenteric margin. METHODS: The localisation of ulcers in the bowel wall was examined in eight resection specimens of Crohn's disease of the terminal ileum. The vascular anatomy of normal terminal ileum (n = 8) and proximal jejunum (n = 8) postmortem specimens was studied; isolated long and short vessels were ligated before perfusion in four of these specimens. RESULTS: All eight specimens of Crohn's disease of the terminal ileum showed longitudinal ulceration along the mesenteric margin. In the postmortem study, the submucosal vascular plexus derived from ileal, but not jejunal short vessels, comprised end arteries with little or no communication with the submucosal plexus arising from long vessels. Prior ligation of ileal, but not jejunal, short vessels resulted in a filling defect of the submucosal plexus along the mesenteric margin in three of the four specimens. Ligation of ileal and jejunal long vessels did not affect carbon ink perfusion of the bowel wall. CONCLUSIONS: In the human terminal ileum, the short vessels supplying the mesenteric margin are end arteries, and their pathological occlusion might cause ischaemia of this region. These findings support a vascular hypothesis for Crohn's disease and may explain, in part, both the ileal and mesenteric distribution of Crohn's disease ulcers.

The aim of this study was to identify and eradicate H. pylori infection in patients with haemophilia. Patients were screened for IgG antibodies against H. pylori; active infection was determined using a (13) C-urea breath test and infected patients were given combination therapy with antibiotics to eradicate infection. Seventy-eight of 219 (36%) patients with haemophilia were found to have an elevated serum antibody titre against H. pylori; of 36 antibody-positive patients with confirmatory testing, 14 were found to have active H. pylori infection. H. pylori infection was successfully eradicated in every infectedpatient using acombination of ranitidine plus two antibiotics (usually amoxycillin and metronidazole). It is concluded that eradication of H. pylori infection is likely to be a cost-effective screening strategy in patients with haemophilia, to prevent complications of peptic ulcer disease.

The implied aetiological association of measles virus with Crohn's disease would be supported by detection of an immune response to infected cells in affected tissues. This study sought to detect and characterise in situ immune responses to measles virus in both acutely and persistently infected tissues, and in particular, Crohn's granulomata. Tissue sections from patients with Crohn's disease (n = 17), tuberculosis (n = 9), acute intestinal ischaemia (n = 5), acute measles pneumonitis (n = 2), acute measles appendicitis (n = 1), subacute sclerosing panencephalitis (SSPE; n = 1), and measles inclusion body encephalitis (MIBE; n = 1), were examined. Single and double immunohistochemical labelling was performed to identify both cytotoxic lymphocytes (CD8, TIA, perforin, Leu 7, CD45RO, CD45RA) and macrophages (KP1). The relationship of these cells to measles infected cells was examined by double immunolabelling with anti-measles virus nucleoprotein antibody. In both acute measles appendicitis and SSPE, CD8+/TIA+ cytotoxic lymphocytes · (CTL) targeted infected cells. In the cases of Crohn's disease (13/17), MIBE, fatal pneumonitis, and one tuberculous granuloma, that were positive for measles virus, infected cells appeared to be targeted by macrophages rather than CTL. CTL in both tuberculous and Crohn's granulomata were similar in their peripheral distribution, number, and phenotype. The data suggest that measles-specific CTL responses may be attenuated in Crohn's disease compared with acute measles appendicitis and SSPE, and secondly, that an abnormal macrophage response to persistent measles virus infection of the intestine may result in granulomatous inflammation. J Med Virol 51:90–100, 1997. © 1997 Wiley-Liss, Inc.

BACKGROUND: Bactericidal/permeability-increasing protein (BPI), a constituent of primary neutrophil granules, is a potent natural antibiotic and an antineutrophil cytoplasm antibody (ANCA) antigen in cases of vasculitis in which the target antigen is neither myeloperoxidase (MPO) nor proteinase-3 (PR3). AIM: To investigate BPI as a possible target antigen for ANCAs in inflammatory bowel disease. METHODS: ANCAs were detected by routine immunofluorescence (IIF) and solid phase enzyme linked immunosorbent assay (ELISA) performed for antibodies to the purified neutrophil granule proteins; MPO, PR3, cathepsin-G, lactoferrin, and BPI in serum samples from 88 patients with inflammatory bowel disease (36 with Crohn's disease, 52 with ulcerative colitis). Thirty patients with bacterial enteritis acted as controls. RESULTS: Significantly more patients with ulcerative colitis were ANCA positive by IIF (60%) than patients with Crohn's disease (28%) or infectious enteritis (23%) (p < 0.001). IgG anti-BPI antibodies were present in 29% of patients with ulcerative colitis, 14% of patients with Crohn's disease, and 23% of patients with infectious enteritis, occurring in 44% of those patients with inflammatory bowel disease who were ANCA positive by IIF. Antibodies to other ANCA antigens were rare. The presence of ANCAs was not related to either disease activity or extent; presence of anti-BPI antibodies was significantly related to both a lower serum albumin concentration (p = 0.001) and a higher erythrocyte sedimentation rate (p = 0.02) in patients with ulcerative colitis, and to colonic involvement in patients with Crohn's disease (p = 0.01). CONCLUSION: BPI is a significant minority target antigen for ANCAs in inflammatory bowel disease that seems related to colonic Crohn's disease and disease activity in ulcerative colitis. Anti-BPI antibodies occur in infectious enteritis.

BACKGROUND: In contrast with earlier reports that neutrophils play a primary part in non-steroidal anti-inflammatory drug (NSAID) injury to the stomach, recent evidence suggests only a secondary role for these cells. AIM: To examine whether early microscopic changes induced by indomethacin in the gastric corpus of fasted rats and the antrum of fasted-refed rats involve neutrophil infiltration. METHODS: Oral indomethacin 30 mg/kg or vehicle was given to six groups of fasted rats that were killed five, 15, and 30 minutes after dosing. Subcutaneous indomethacin 30 mg/kg was also given to six groups of fasted-refed rats that were killed one, two, and four hours later. Haematoxylin and eosin and reticulin stained sections were examined to identify mucosal architectural changes. The gastric mucosa was also examined immunohistochemically for actin, fibrin, and neutrophils. RESULTS: In both the corpus and antrum, indomethacin caused an early phase of mucosal injury that occurred prior to mucosal neutrophil infiltration. Within the superficial corpus mucosa, this phase preceded coagulative necrosis and included surface epithelial expulsion, mucosal contraction with capillary aggregation and distortion, intravascular vascular fibrin deposition, and capillary congestion. The antrum showed similar early changes except that full thickness mucosal coagulative necrosis was a predominant early finding. CONCLUSIONS: In two experimental models of NSAID gastric ulceration the mucosa undergoes early contraction, vascular fibrin deposition, and necrosis prior to neutrophil infiltration. These findings support a primary, neutrophil independent, ischaemic pathogenesis for NSAID gastric ulceration.

Jejunal villi undergo early histological shortening and vascular injury in indomethacin-induced ulcerative enteropathy in the rat. The protective effects of the beta 3-adrenoceptor agonist CL316243 on this rat model and the mechanism of action were examined using histological techniques. Groups of rats received oral indomethacin (15 mg/kg) and oral CL316243 (0, 0.01-10 mg/kg) 0.5 h beforehand. Jejunal ulceration was assessed 48 h after indomethacin. Other groups received CL316243 either 6 h before or 3 or 6 h after indomethacin. Plasma indomethacin and jejunal prostaglandin E2 levels were determined in groups of rats with and without prior CL316243. CL316243 was a potent dose-dependent inhibitor of jejunal ulceration (> 98 percent inhibition at doses > or = 0.1 mg/kg; ED50 = 0.025 mg/kg) but was not protective when given 6 h after indomethacin. CL316243, 1 mg/kg, reversed early villous shortening and vascular injury. CL316243 did not affect either indomethacin bioavailability or the inhibition of prostaglandin E2. To conclude, the beta 3-adrenoceptor agonist CL316243 is a potent inhibitor of indomethacin-induced jejunal ulceration and the mechanism of protection involves reversal of both villous shortening and vascular injury, which are usefully assessed by histomorphological techniques.

BACKGROUND--Thrombosis may be an important effector mechanism in the pathogenesis of Crohn's disease. METHODS--This study therefore investigated the prevalence of independent thrombotic risk factors (factor VII coagulant activity, lipoprotein (a), fibrinogen, plasma triglycerides, and smoking) in patients with Crohn's disease, ulcerative colitis, and normal controls. RESULTS--In Crohn's disease (n = 75), the mean plasma VII:C, lipoprotein (a) and fibrinogen concentrations were significantly greater than in the normal population (n = 85). In ulcerative colitis (n = 35), only the mean factor VII:C concentration was significantly higher than normal. Ninety three per cent of patients with Crohn's disease and 86% of those with ulcerative colitis had at least one risk factor for thrombotic vascular disease, compared with 61% of the normal population (p < 0.001). CONCLUSIONS--In many young patients with inflammatory bowel disease, plasma concentrations of these prothrombotic factors were in excess of the limits that are regarded as posing an increased risk for the development of occlusive vascular disease.

Background: Ranitidine bismuth citrate is a novel salt of ranitidine and a bismuth citrate complex. It has intrinsic antisecretory and anti-Helicobacter pylori activity, but monotherapy rarely eradicates H. pylori infection in man. Aim: A pilot study to investigate rates of H. pylori eradication achieved by co-prescription of ranitidine bismuth citrate with antibiotics, and to identify several regimens which would merit further investigation. Method: One hundred dyspeptic patients infected with H. pylori were randomly allocated to treatment with ranitidine bismuth citrate 800 mg b.d. plus either amoxycillin, metronidazole, clarithromycin, cefuroxime axetil, tetracycline, tetracycline plus metronidazole or clarithromycin plus tetracycline for 14 days. Eradication of infection was assessed using the 13C-urea breath test 4 weeks after the end of treatment. Results: In a per protocol analysis eradication of H. pylori ranged between 22 and 100%; the intention-to-treat eradication rates ranged between 15 and 92%. No adverse events were specifically attributed to ranitidine bismuth citrate. Conclusion: Co-prescription therapy, using ranitidine bismuth citrate and one or more antibiotics, is suitable for further investigation in large-scale clinical trials in patients infected with H. pylori.

Crohn's disease and ulcerative colitis seem to be rarely associated with inherited diseases of coagulation. Histological and hematologic studies suggest that thrombotic mesenteric microvascular occlusion is involved in the pathogenesis of inflammatory bowel disease. The aim of this study was to perform a national survey to determine the prevalence of inflammatory bowel disease among patients with inherited disorders of coagulation.Using a postal and telephone questionnaire survey sent to directors of all 129 hemophilia centers in the United Kingdom, the number of patients with inflammatory bowel disease and either hemophilia or von Willebrand's disease was determined. The expected number of cases of inflammatory bowel disease in this population was estimated using published data.Of 6433 patients with hemophilia and 3129 patients with von Willebrand's disease, 4 cases of Crohn's disease were reported compared with expected 11.97-16.58 cases (standardized morbidity ratio, 0.33-0.24; 95% confidence interval, 0.90-0.01; P0.05). Ulcerative colitis also occurred significantly less frequently than expected: 9 observed cases in comparison with expected 19.43-31.35 cases (standardized morbidity ratio, 0.46-0.29; 95% confidence interval, 0.91-0.01; P0.025).This epidemiological study provides further evidence that thrombosis and vascular occlusion may be important in the pathogenesis of inflammatory bowel disease.

Measles virus may persist in intestinal tissue, particularly that affected by Crohn's disease, and early exposure to measles may be a risk factor for the development of Crohn's disease. Crohn's disease and ulcerative colitis occur in the same families and may share a common aetiology. In view of the rising incidence of inflammatory bowel disease (Crohn's disease and ulcerative colitis), we examined the impact of measles vaccination upon these conditions. Prevalences of Crohn's disease, ulcerative colitis, coeliac disease, and peptic ulceration were determined in 3545 people who had received live measles vaccine in 1964 as part of a measles vaccine trial. A longitudinal birth cohort of 11407 subjects was one unvaccinated comparison cohort, and 2541 partners of those vaccinated was another. Compared with the birth cohort, the relative risk of developing Crohn's disease in the vaccinated group was 3·01 (95% Cl 1·45-6·23) and of developing ulcerative colitis was 2·53 (1·15-5·58). There was no significant difference between these two groups in coeliac disease prevalence. Increased prevalence of inflammatory bowel disease, but not coeliac disease or peptic ulceration, was found in the vaccinated cohort compared with their partners. These findings suggest that measles virus may play a part in the development not only of Crohn's disease but also of ulcerative colitis.

The Inflammatory Bowel Disease Study Group at the Royal Free Hospital School of Medicine has tested the hypothesis that the primary pathological abnormality in Crohn's disease is in the mesenteric blood supply. Early morphological studies involved arterial perfusion-fixation and either resin casting and scanning electron microscopy or vascular immunostaining of resected intestine affected by Crohn's disease. Granulomatous and lymphocytic damage to intramural blood vessels, even in macroscopically normal areas, was observed. We put forward possible mechanisms by which a chronic ischemic process might account for many of the idiosyncracies of Crohn's disease. It was proposed that persistent viral infection of the mesenteric microvascular endothelium might underly this vasculitic process; based on certain behavioral characteristics of measles virus, including its tropism for the submucosal endothelium of the intestine, this agent was investigated further. This report reviews the preliminary evidence from both epidemiological and basic scientific data for persistent measles virus in the intestine of patients with Crohn's disease. Possible mechanisms for virus persistence and subsequent reactivation are discussed. In conclusion, we believe that Crohn's disease may be a chronic granulomatous vasculitis in reaction to a persistent infection with measles virus within the vascular endothelium. This granulomatous inflammation, perhaps aggravated by either a hypercoagulable state or mechanical stress, results in the clinical features of Crohn's disease.

In view of the association between non-steroidal anti-inflammatory drugs (NSAIDs) and microvascular injury in the intestine, this study investigated the procoagulant changes in cultured human umbilical vein endothelial cells (HUVEC) when exposed to indomethacin either alone or in the presence of bacterial lipopolysaccharide (LPS).Confluent HUVEC cultures were cultured for 1, 6, 12, and 24 h in the presence of LPS (10 micrograms/ml) with or without indomethacin (1-100 microM). After incubation, supernatants were analysed for 6-keto-prostaglandin (PG) F1 alpha and PGE2 content, whereas cells were freeze-fractured and assayed in a one-stage clotting assay for the expression of procoagulant activity (PCA).LPS induced a significant expression of PCA at 6, 12, and 24 h, with a significantly increased production of 6-keto-PGF1 alpha, whereas the increased PGE2 production was much less pronounced. Indomethacin alone induced a time-dependent PCA response; when coincubated with LPS the PCA response was greater than that produced by either indomethacin or LPS alone. Indomethacin totally abolished the synthesis of antithrombotic eicosanoids.Indomethacin induces PCA in HUVEC and augments LPS-induced PCA, while it abolishes the antithrombotic prostanoid response in these cells. These observations may be relevant to the microvascular injury and thrombosis observed in NSAID enteropathy.

Aphthoid ulceration has been regarded as an early macroscopic feature of Crohn's disease, yet the cause of this mucosal lesion is unknown. Examination of areas of apparently normal and non-inflamed bowel in Crohn's disease has allowed the identification of mucosal changes which occur before macroscopic and microscopic ulceration. Thirty five resection specimens from patients with Crohn's disease were compared with 12 specimens from patients with ulcerative colitis and 13 controls. Specimens were fixed either by immersion in formalin in the routine way or by perfusion fixation with formalin at mean arterial pressure. Immunostaining for macrophages, vessel wall, and blood constituents allowed identification of small mucosal capillaries which were not apparent otherwise. In Crohn's disease damage and rupture of these small capillaries occurred before infiltration of the lamina propria by inflammatory cells. Loss of the overlying epithelium seemed to follow this vascular damage.

Microvascular injury and ischaemia may be factors in anastomotic recurrence after resection for Crohn's disease. This hypothesis was explored in a ferret model of multifocal intestinal infarction. At laparotomy, isolated loops of small intestine were injected intraarterially with styrene microspheres (test loop) or saline (control). At a second laparotomy 72 h later, test and control loops were divided and an end-to-end anastomosis performed between test loops (n = 2), test and control loops (n = 9) or control loops (n = 2). Abnormalities including chronic transmural inflammation, ulceration and granuloma formation were identified 2 weeks after the second operation in ten of the 11 surviving animals; changes were confined to the test loops and were most prominent adjacent to the anastomosis. No abnormalities were seen in control loops. The combination of two self-limiting ischaemic insults can produce a pattern of intestinal inflammation similar to that seen in anastomotic recurrence in Crohn's disease.

Factor XIIIA is the active subunit of plasma factor XIII that is responsible for cross linking fibrin into a stable clot. Sixteen patients with Crohn's disease were studied prospectively from relapse (Crohn's disease activity index > 150) into remission. Plasma factor XIIIA concentrations were significantly lower in active disease (median 63 (95% CI 46-72) U/dl) than remission (median 90 (95% CI 60-112) U/dl; p = 0.002). Plasma factor XIIIA concentrations correlated positively with the activity index (p = 0.005) and platelet count (p = 0.003), and negatively with serum albumin (p = 0.006). In five patients with persistent aggressive disease, the factor XIIIA concentration remained below the lower range of normal despite apparent clinical improvement in response to medical treatment. Tissues from three patients who underwent surgical resection during the study were immunostained for factor XIIIA. Gut mucosal and submucosal macrophages stained strongly for factor XIIIA. In one patient, capillary thrombi near superficial mucosal erosions immunostained for factor XIIIA in macroscopically normal mucosa. Similar changes were identified in more severely inflamed sections of intestine from the other two patients. The demonstration of significantly low plasma factor XIIIA concentrations in active Crohn's disease, and the immunostaining of factor XIIIA in capillary thrombi in the bowel wall, suggest that activation of coagulation may be involved in the pathogenesis of Crohn's disease. The plasma factor XIIIA concentration may prove a useful laboratory marker of disease activity.