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Forty-seven healthy male subjects were studied twice using a randomized, placebo-controlled design. Each subject took an 8-day course of two of the following four regimens; 300 mg ranitidine, 800 mg cimetidine, 40 mg famotidine or placebo (identical either to 300 mg ranitidine or 800 mg cimetidine). The systemic bioavailability of ethanol (integrated 6-h plasma ethanol concentration, peak plasma ethanol concentration, and the time to peak plasma ethanol concentration) was measured after the oral ingestion of 0.8 g of ethanol per kg body weight, given one hour after an evening meal on Day 8 of each regimen. There was no significant difference of integrated 6-h plasma ethanol concentration, peak ethanol concentration, or time to reach peak ethanol concentration after dosing with either ranitidine, cimetidine or famotidine or placebo.

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.

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 & 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

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

Background & Aims: Specific regions of the cag pathogenicity island (PAI) believed to enhance the virulence of Helicobacter pylori, as well as vacuolating cytotoxin gene alleles and IS 605 inserts, were investigated to define diversity within infecting strain populations from patients with peptic ulcer disease and from healthy individuals. Methods: The H. pylori studied comprised 67 isolates from 26 subjects and 14 reference strains. Specific polymerase chain reaction assays were used to test for cag A and pic B in the cag I region, the vir D4 homologue in the cag II region, IS 605 in the genome and in the cag PAI, the "empty site" indicating absence of the cag PAI, and different vac A gene alleles. Results: Most (89%) subjects were infected by H. pylori with a contiguous cag PAI. No intermediate forms were found. IS 605 was not detected within the cag PAI of any strain but was present elsewhere in the genomes of strains from 62% of subjects. Twenty individuals were infected with genotypically conserved populations of H. pylori . Six subjects had mixed infections, and in 3 of these cag + / cag − variants were present. Conclusions: The cag PAI–positive H. pylori was a feature of most infected individuals, irrespective of severity of associated disease. Combined genotyping showed that 8 individuals (31%) had mixed infections, which suggests that strain population structure may be an additional contributing factor in disease development. GASTROENTEROLOGY 1999;117:1308-1315

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.

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/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: Escherichia coli, listeria, and streptococcal antigens have been found in Crohn's disease tissues. Antibodies to Klebsiella pneumoniae have been found in patients with inflammatory bowel disease and ankylosing spondylitis. The presence of these bacterial antigens in Crohn's granulomas would be of aetiological interest, while their presence in ulcers alone would be more likely to indicate secondary infection. AIM: To investigate inflammatory bowel disease tissues for the presence of these bacteria. METHODS: Formalin fixed, paraffin processed sections from 53 patients (19 ulcerative colitis, 23 Crohn's disease; 11 normal tissues from cancer resections) were studied by immunohistochemistry. Control tissue consisted of normal human small bowel injected submucosally with either E coli, Listeria monocytogenes, Proteus mirabilis, or Klebsiella pneumoniae serotypes K2, 3, 17, 21, 26, 36, and 50, and colonic biopsies from a child with E coli 0114 infection. Tissues were stained by Gram-Twort, and with specific antibodies for E coli (Dako B357), L monocytogenes (Difco 2302-50), and K pneumoniae (Biogenesis 5580-5208) using an immunoperoxidase technique. RESULTS: Positive staining for E coli was observed on the luminal surface epithelium and in ulcers in 35% of Crohn's disease patients, 26% of ulcerative colitis patients, and no normal controls. Superficial staining for L monocytogenes was observed in one case of ulcerative colitis only. Staining for K pneumoniae was observed in one case of ulcerative colitis and one of Crohn's disease. No granulomas, giant cells, or germinal centres stained positively for any of the three bacterial antigens. CONCLUSIONS: These data do not support a primary role for E coli, L monocytogenes, and K pneumoniae in inflammatory bowel disease. The presence of E coli antigens in ulcers suggests secondary infection in these lesions.

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.

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.

The aim of this study was to compare measles RNA amplification methods and to develop and select the most rapid, sensitive and robust procedure. The use of hybrid capture for measles RNA isolation was evaluated, and three RNA amplification detection techniques were compared. These were: (a) reverse transcription followed by nested polymerase chain reaction (RT-PCR) with MMLV reverse transcriptase and Taq polymerase; (b) a combined RT-PCR reaction using rTth polymerase; and (c) NASBA. An internal positive control was also developed. The sensitivities of the detection methods were quantified by using a dilution series of a known amount of total RNA from measles-infected Vero cells or by calculation of the number of transcript molecules (produced from a recombinant plasmid containing an insert measles nucleoprotein DNA) present in each amplification reaction, respectively. The results indicated that hybrid capture followed by combined RT-PCR with rTth polymerase was the most reproducibly robust and sensitive protocol and could detect as few as 10(4) synthetic measles RNA transcripts added to tissue homogenates. However, NASBA proved to be the most sensitive method for measles RNA detection in water.

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.

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--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.

The indirect intracellular polymerase chain reaction (in situ PCR) combines the potential sensitivity of the polymerase chain reaction (PCR) with the high specificity and morphological preservation of in situ hybridization (ISH). This study describes a method for the amplification of small, specific cytomegalovirus (CMV) genomic sequences [100 base pairs (bp)] within large formalin-fixed, paraffin-embedded tissue sections. A heat-resistant glue surrounds the section, creating a well which contains a relatively large volume of isotonic reaction solution without a covering mineral oil layer; this optimizes morphological preservation, permits the evaluation of large sections, and allows both denaturation steps and up to 40 cycles of in situ PCR to be performed, whilst progressively concentrating the reaction solution by evaporation during thermal cycling. ISH was performed using a non-isotopic DNA probe with specificity for CMV, with or without prior in situ PCR amplification, both for samples on slides (fibroblasts and lung) and in suspension (fibroblasts). Samples on slides were evaluated by both blinded studies and image analysis, comparing the intensity of signal (P < 0.003) and the numbers of positive cells detected (P < 0.007), with or without intracellular amplification. Cells in suspension were analysed by blinded studies on cytospins and by gel electrophoresis of cell lysates. Successful intracellular amplification was achieved in this high copy model.

1. The magnitude of the variability of ethanol absorption is an important factor for studies that seek to determine the significance of potential interactions between ethanol and drugs. The aim of this study was to determine the extent of inter- and intra-individual variability of ethanol concentration-time profiles in fasted and fed subjects. 2. Twenty-four healthy male subjects were randomized to receive ethanol 0.3 g kg-1 before an evening meal on two study days and ethanol 0.3 g kg-1 after an evening meal on two study days. Plasma ethanol concentrations were measured at intervals from 0-240 min. 3. There were significant differences in the mean area under the ethanol concentration-time curve (AUC), the mean peak ethanol concentration (Cmax), the mean ethanol elimination slope and the time to peak ethanol concentration between the fed and fasted subjects. There were no significant differences between the first and second study days for either fed or fasting subjects for all parameters. 4. There was no statistically significant difference in inter- or intra-subject variance between fed and fasted studies although the coefficients of variation (standard deviation expressed as a percentage of the mean) for the differences between the first and second study day were higher for fed studies. 5. The large inter- and intra-individual variability of alcohol absorption for both fasted and fed subjects must be considered in the design of alcohol-drug interaction studies.

This study sought to investigate persistent measles virus infection of the intestine: a novel protocol for immunogold electron microscopy was developed using a polyclonal anti-measles nucleoprotein antibody on reprocessed, formalin fixed paraffin wax embedded tissue sections. Antibody binding was detected using both immunoperoxidase and light microscopy on tissue sections, and 10 nm gold conjugated secondary antibody and electron microscopy on ultrathin sections. The techniques were validated using both measles infected vero cells and human tissues with established measles infection: these included brain affected by subacute sclerosing panencephalitis and acute measles appendicitis. The technique was applied subsequently to six untreated cases of granulomatous Crohn's disease, and two cases of ileocaecal tuberculosis, a granulomatous control. Mumps primary antibody--applied to both mumps infected vero cells, and measles infected vero cells and tissues studied by immunoperoxidase, and measles antibody on mumps infected cells studied by immunoperoxidase and immunogold--were used as specificity controls: the primary antibodies identified their respective target antigen and there was no antibody cross reactivity. Measles virus nucleocapsids labelled with gold conjugated antibody in both infected cells and tissues, including foci of granulomatous inflammation in five of six cases of Crohn's disease: in the fifth case, the granuloma could not be identified in ultrathin section. In one of the tuberculosis cases, a low level of signal was noted while the second case was negative. Labelling adopted a characteristic pattern in all infected tissues, strengthening the specificity of these findings. This study provides the first direct confirmation of persistent measles virus infection of the intestine.

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.

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.

Transmission electron microscopy was used to examine the microvasculature of perfusion-fixed tissues from Crohn's disease and control patients. Paramyxovirus-like particles, and inclusions consisting of condensations of nucleocapsid, in giant cells and endothelium at foci of vascular injury were identified in all 9 Crohn's disease patients. Tissues from patients with Crohn's disease were also examined by either in situ hybridisation (n = 10) or immunohistochemistry (n = 15), and compared to inflammatory and noninflammatory controls (n = 22). Hybridisation for measles virus N-protein genomic RNA was positive in all cases of Crohn's disease localising to foci of granulomatous vasculitis and lymphoid follicles. Positive immunohistochemical staining for measles virus nucleocapsid protein was positive in 13 of 15 patients with Crohn's disease, localising to foci of granulomatous inflammation. Hybridisation for measles virus RNA was positive in a minority of control intestinal tissues; viral inclusions were not seen ultrastructurally. Immunostaining was negative in control cases of intestinal tuberculosis. These observations suggest that measles virus is capable of causing persistent infection of the intestine and that Crohn's disease may be caused by a granulomatous vasculitis in response to this virus.

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.

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.

Stomach function and secretions are altered significantly in patients with cirrhosis, both with or without portal hypertension. This review covers the abnormalities of gastric acid and pepsin secretion, and gastrin release. Histological and endoscopic changes, and the impaired cytoprotection associated with cirrhosis, are discussed in the context of abnormal gastric secretion. In addition, the symptomatology and association of H. pylori, and treatment of duodenal ulceration in cirrhosis are discussed. It is clear from this review that additional studies are needed to further understand gastric function in cirrhotic patients.

Haemostatic changes in 16 patients with Crohn's disease were studied from active disease into clinical remission and beyond. Elevated concentrations of fibrinopeptide A (FpA) and prothrombin fragments F1 + 2 (F1 + 2) were found at times of both active (FpA median 3.2, range [0.3–40] ng/ml and F1 + 2 median 2.3, range [0.3–18] nm/1) and inactive disease (FpA median 2, range [0.4–40] ng/ml and F1 + 2 median 1.3, range [0.2–20) nm/1]. We also measured the physiological inhibitors of coagulation and fibrinolysis; there was no significant difference in the levels of antithrombin III, protein C or the Exner ratio between active and inactive disease. Free protein S levels were significantly lower in active disease (median 34, range 9–54 U/dl) than in remission (median 40, range 12–65 U/dl). Plasminogen activator inhibitor type 1 (PAI-1) was significantly raised in remission (median 11, range 3–32 ng/ml) when compared to active disease (median 7, range 3–42 ng/ml). The D-dimer correlated significantly with fibrinopeptide A (P < 0.001), suggesting reactive fibrinolysis in some patients. Most (35/52, 67%) samples showed evidence of persistent haemostatic activation (elevated FpA and/or F1 + 2) during phases of apparent clinical remission in Crohn's disease, a factor that is not reflected by clinical activity scores. This study supports the hypothesis that coagulation is activated in the mesenteric vasculature of patients with Crohn's disease.

The prevalence of herpesvirus DNA was examined in inflammatory bowel disease tissue. DNA was extracted from resection and biopsy specimens of the large intestine from patients with ulcerative colitis (n = 21), patients with Crohn's disease (n = 29), and patients with noninflammatory bowel disease (controls) (n = 21). The nested polymerase chain reaction was used to detect viral DNA using primer pairs specific for either cytomegalovirus (CMV), herpes simplex virus 1 (HSV1), human herpesvirus 6 (HHV6), varicella zoster virus (VZV), or Epstein Barr virus (EBV). HSV1 and VZV DNA were not detected in any of tissue samples. There was a high prevalence of CMV (81%), HHV6 (76%), and EBV (76%) DNA in ulcerative colitis tissue compared to Crohn's disease tissues (CMV 66%, HHV6 45%, EBV 55%). Control tissue had a relatively low frequency of CMV (29%) and EBV (19%) DNA but a prevalence of HHV6 DNA similar to that of ulcerative colitis (86%). However, the simultaneous presence of HHV6 and CMV and/or EBV DNA in ulcerative colitis tissue (76%) was much greater than in either Crohn's disease tissues (38%) or control tissue (29%) (P < 0.05). There was a low prevalence of CMV, HHV6, and EBV DNA in peripheral blood mononuclear cells from all patient groups. CMV and EBV are capable of reactivating HHV6: the high prevalence of coexistent HHV6 infection with either or both of these two viruses in ulcerative colitis tissue suggests that they may play a synergistic role in the pathogenesis of this disease.

We studied the initial rectal biopsy from 46 patients in whom subsequent follow-up established the diagnosis of either self-limited colitis or inflammatory bowel disease. An additional 12 non-inflamed rectal biopsies were also studied. There was between 2 and 8 years of follow-up in each of these cases. Staining for fibrin (MSB, fibrinogen), platelets (factor XIIIA, Y2/51), and capillary basement membrane (reticulin, collagen 4) was performed to identify thrombotic material within capillaries. Mucosal capillary thrombi were best identified by staining for factor XIIIA; thrombi were observed in 8/13 cases of ulcerative colitis, 4/10 cases of Crohn's disease, 1/3 cases of unspecified inflammatory bowel disease and 5/20 cases of self-limited colitis. The presence of capillary thrombi was not related to the severity of inflammation, but none of the control biopsies showed capillary thrombi. Their presence seems of little diagnostic value in distinguishing inflammatory bowel disease from self-limited colitis. The pathogenetic significance of these mucosal capillary thrombi is uncertain.

Biopsy specimens for culture of Helicobacter pylori were obtained from two different sites in the antrum, gastric body, and duodenal cap in 20 patients during endoscopic investigation of dyspepsia. H. pylori was identified in 64 isolates obtained from 15 of the 20 patients. Analysis of chromosomal DNA from these isolates of H. pylori showed that 13 of 15 patients harbored a single strain of H. pylori throughout their stomach and duodenum. Two differing H. pylori types were found in two patients. Unique DNA patterns were shown in each of the 15 patients. The genetic heterogeneity of H. pylori is unexplained but it could be of considerable value for epidemiological studies.

Repeated dosing with an H2-receptor antagonist results in a modest decrease in antisecretory potency termed "tolerance." The object of this prospective study was to determine whether tolerance is a progressive phenomenon or whether it levels off during prolonged dosing with a standard maintenance dose of an H2-antagonist. The effect of continuous dosing with ranitidine, 150 mg nightly, was compared with intermittent dosing (27 days of placebo each month) with active ranitidine, 150 mg nightly, only on the night of each experiment. Simultaneous 24-hour intragastric acidity and plasma gastrin concentration were measured monthly for 5 months in 17 healthy subjects (7 continuous and 10 intermittent dosing). In the intermittent-dosing group, the antisecretory response to ranitidine, 150 mg nightly, was preserved throughout the 141-day trial period; the median nocturnal integrated acidity decreased from 557 mmol.h/L (day 0) to 38 mmol.h/L on day 1 of dosing, and it ranged between 32 and 55 (median, 45) mmol.h/L during days 29-141. In the continuous-dosing group, there was a significant return of nocturnal intragastric acidity on days 29 and 85 compared with day 1 of dosing. The median nocturnal integrated acidity decreased in the continuous-dosing group from 554 mmol.h/L (day 0) to 87 mmol.h/L on the first day of dosing, and it ranged between 145 and 287 (median, 170) mmol.h/L during days 29-141. Either intermittent or continuous dosing with ranitidine was associated with an elevation of plasma gastrin concentration, which remained constant throughout the 5-month study. Tolerance does develop in healthy subjects during the first month of dosing with ranitidine, 150 mg nightly, but it is not a progressive phenomenon, and it is probably not of clinical relevance.

Both cigarette smoking and the oral contraceptive pill have been implicated as aggravating factors in Crohn's disease. Based upon the recent demonstration of multifocal gastrointestinal infarction in Crohn's disease, a possible pathogenic mechanism for this condition, we propose how smoking and the oral contraceptive pill may potentiate a tendency for focal thrombosis and hence exacerbate the activity of Crohn's disease.Both cigarette smoking and oral contraceptives (OCs) have been shown to exacerbate Crohn's disease. The pathogenic mechanism for Crohn's disease proposed by the authors--multifocal gastrointestinal infarction, mediated by a chronic mesenteric vasculitis--provides a framework for understanding these effects. Smoking induces morphologic injury to endothelial cells, inhibits aortic endothelial prostacyclin synthesis, and leads to elevated levels of plasma fibrinogen and decreased levels of plasminogen and tissue plasminogen activator activity. OCs that contain more than 50 mcg of ethinyl estradiol increase levels of procoagulant substrates and produce decreases in both anticoagulant and fibrinolytic activity. Enhanced expression of both monocyte and vascular endothelial cell procoagulant activity is the initiating event in the fibrin formation that initially characterizes Crohn's disease. Although microvascular changes have been observed in Crohn's disease patients who neither smoke nor use OCs, it appears likely that when further prothrombic stimuli such as OCs and nicotine are superimposed on Crohn's disease, the result is an exacerbation of disease activity.

The magnitude and duration of changes in nocturnal intragastric acidity caused by 25 days of dosing with the antisecretory drugs ranitidine and omeprazole were investigated in a double-blind study of 22 healthy subjects. Nocturnal intragastric acidity was studied before (twice), during (on day 25), and after (every 3 days for 21 days) dosing with either 300 mg ranitidine at night or 40 mg omeprazole every morning. Three and six days after withdrawal of dosing with ranitidine, median integrated nocturnal intragastric acidity was increased significantly (17% and 14%, P = 0.01 and P = 0.05, respectively) compared with before dosing. Three days after withdrawal of dosing with omeprazole, median integrated nocturnal intragastric acidity was decreased significantly (-23%, P = 0.003). Compared with before dosing, no significant differences were seen in the ranitidine group between days 9 and 21 or the omeprazole group between days 6 and 21 after cessation of dosing. Fasting plasma gastrin concentration was measured on the morning of each study; compared with before treatment, the only significant elevations occurred on the last day of dosing with omeprazole (before, 4 pmol/L; during, 7 pmol/L). It is concluded that rebound intragastric hyperacidity after dosing with 300 mg ranitidine at night or sustained hypoacidity after dosing with 40 mg omeprazole every morning reflect transient disturbances of gastric function that are unlikely to be of clinical importance.

The Royal Free Hospital protocol for simultaneous measurement of 24-hour intragastric acidity and plasma gastrin concentration is described in detail. The methods of analysing such data are discussed, with recommendations for a standard four-way analysis: median hourly 24-hour intragastric acidity or pH, or plasma gastrin concentration; integrated 24-hour intragastric acidity, or plasma gastrin concentration; analysis of integrated values according to meal-related intervals; and quantification of the percentage of time in a 24-hour period that intragastric pH is greater than 3.

The European working time directive may put doctors' and patients' lives at risk T he European working time directive was implemented for doctors in training in the UK NHS and elsewhere in Europe in August 2004. Junior doctors' working hours are now limited to a shift of no more than 13 hours followed by a break of at least 11 hours.1 As a result, the work pattern out of hours for most junior doctors at the front line of acute medicine has changed completely from providing on-call cover to working in shifts.2 The directive aims to reduce working hours in order to improve workers' health and safety, but the current NHS shift system could threaten doctors' and, moreover, patients' safety. More than three quarters of medical senior house officers and nearly half of specialist registrars in NHS trusts were working seven consecutive night shifts when surveyed in December 2004 by the …

Summary 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)-1β, but not tumour necrosis factor-alpha (TNF-α). By contrast, IL-1β and TNF-α were synergistic in an HT29 cell line and primary keratinocytes. Conclusions : IL-1β and TNF-α 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.

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%; P0.001 vs placebo) and 25.06 mmol/liter (mean decrease 35%; P0.001 vs placebo) when treated with ranitidine and cimetidine, respectively. Ranitidine inhibited intragastric acidity to a greater degree than cimetidine (P0.001). 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.