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Objective: To assess intermittent treatment over 12 months in patients with symptomatic gastro-oesophageal reflux disease. Design: Randomised, multicentre, double blind, controlled study. Patients with heartburn and normal endoscopy results or mild erosive changes received omeprazole 10 mg or 20 mg daily or ranitidine 150 mg twice daily for 2 weeks. Patients remaining symptomatic had omeprazole 10 mg or ranitidine dose doubled for another 2 weeks while omeprazole 20 mg was continued for 2 weeks. Patients who were symptomatic or mildly symptomatic were followed up for 12 months. Recurrences of moderate or severe heartburn during follow up were treated with the dose which was successful for initial symptom control. Setting: Hospitals and primary care practices between 1994 and 1996. Subjects: 677 patients with gastro-oesophageal reflux disease. Main outcome measures: Total time off active treatment, time to failure of intermittent treatment, and outcomes ranked from best to worst. Results: 704 patients were randomised, 677 were eligible for analyses; 318 reached the end of the study with intermittent treatment without recourse to maintenance antisecretory drugs. The median number of days off active treatment during follow up was 142 for the entire study (281 for the 526 patients who reached a treatment related end point). Thus, about half the patients did not require treatment for at least 6 months, and this was similar in all three treatment groups. According to outcome, 378 (72%) patients were in the best outcome ranks (no relapse or one (or more) relapse but in remission until 12 months); 630 (93%) had three or fewer relapses in the intermittent treatment phase. Omeprazole 20 mg provided faster relief of heartburn. The results were similar in patients with erosive and non-erosive disease. Conclusions: Intermittent treatment is effective in managing symptoms of heartburn in half of patients with uncomplicated gastro-oesophageal reflux disease. It is simple and applicable in general practice, where most patients are seen.

It has previously been shown that microalbuminuria is a useful disease activity marker for inflammatory bowel disease (IBD). Microalbuminuria correlates strongly with the markers of clinical and laboratory disease activity such as erythrocyte sedimentation rate (ESR), and C reactive protein (CRP). The aim of this study was to discover if microalbuminuria accurately reflects the intestinal inflammation by correlating it with intestinal inflammation using a standard histopathological grading system in patients with ulcerative colitis and Crohn's colitis. Forty two patients with IBD who had undergone endoscopic examination of the entire colon for the assessment of severity and extent of the disease (Crohn's colitis (n = 21), ulcerative colitis (n = 21)) were recruited to the study. Patients with small bowel Crohn's disease were not studied. Twenty four patients had left sided colonic disease and 18 patients had extensive colonic disease. Each patient's colonic biopsy specimens were scored blindly by a histopathologist and a composite score was compiled on the basis of the severity of changes in the enterocytes and crypts and the cellularity of the lamina propria. A clinical disease activity was obtained using the simple index of Harvey and Bradshaw. Microalbuminuria was measured in all patients by an immunoturbiditimetric method. ESR and CRP were also measured, as indicators of acute phase response in the same patients. It was found that patients with active IBD had higher concentrations of microalbuminuria compared with those patients in remission (median 222 micrograms/min (range 40-686 micrograms/min) v median 96 micrograms/min (range 30-376 micrograms/min); p < 0.001)). Significantly higher concentrations of microalbuminuria were also detected in patients with extensive colonic IBD compared with those patients with left sided disease (median 297 micrograms/min (range 132-686 micrograms/min) v median 101 micrograms/min (range 30-433 micrograms/min); p < 0.001)). A strong positive correlation was seen between microalbuminuria and intestinal histopathological score in IBD patient groups with left sided colitis (r = 0.77; p < 0.001) and extensive disease (r = 0.71; p < 0.01). The standard histopathological grading system correlated with the clinical disease activity (r = 0.64; p < 0.005) and CRP (r = 0.62; p < 0.02), however, it did not correlate with ESR. In conclusion, the strong correlation of microalbuminuria with a standard intestinal histopathological grading system suggests that microalbuminuria accurately reflects the severity of colonic inflammation in patients with Crohn's colitis and ulcerative colitis.

Methyltertbutyl ether (MTBE) administered by percutaneous transhepatic catheter rapidly dissolves radiolucent cholesterol gall bladder stones. However, complete dissolution and clearance of non-cholesterol debris is essential to prevent recurrence. In this study we analysed 25 consecutive patients with reference to efficacy and recurrence based on the presence or absence of non-cholesterol stone fragments after dissolution. Placement of the catheter was successful in 24 patients, one patient requiring cholecystectomy for bile peritonitis. MTBE was infused and aspirated continuously, four to six cycles per minute, resulting in rapid stone dissolution (median six hours; range 4-23 hours for solitary stones and median seven hours, range 4-30 hours for multiple stones). In 18 patients who had complete dissolution, four (22%) had recurrent stones within six to 18 months. Five patients had residual debris which failed to clear completely despite bile acid treatment. One patient with an incomplete rim of calcium in a large stone did not respond to MTBE treatment. A further patient required cholecystectomy for symptomatic recurrence. There were no serious side effects observed. MTBE treatment is a rapid, safe, and effective treatment for patients who refuse surgery or who for medical reasons cannot undergo cholecystectomy. The results of this study confirm that complete dissolution of all fragments is essential and may prevent recurrence.

Fifty two strains of anaerobic bacteria isolated from the upper gut of patients with small intestinal bacterial overgrowth were screened for phospholipase activity. Bacteroides melaninogenicus spp intermedius had the greatest activity. The effects of culture supernatants of this organism and deoxycholate on intestinal calcium absorption and disaccharidase activity were studied using a rat closed loop model. The supernatant decreased the in vitro uptake of calcium by 15% (p less than 0.001). Deoxycholate reduced calcium uptake by 16% (p less than 0.001). Combined culture supernatant and deoxycholate reduced calcium uptake by 39% (p less than 0.001) suggesting a potentiation of supernatant activity by deoxycholate. Culture supernatant and deoxycholate, both alone and combined, significantly reduced lactase, sucrase, and maltase activity. Electron microscopic evidence showed degeneration of microvilli, disruption of mitochondrial structure, and swelling of the endoplasmic reticulum after exposure of the intestinal loops to the supernatant or deoxycholate.

PUBLISHED, BACKGROUND: There is concern that the incidence of non-Hodgkin's lymphoma (NHL) will rise with increasing use of immunosuppressive therapy. AIMS: Our aim was to determine the risk of NHL in a large cohort of patients with inflammatory bowel disease (IBD), and to study the association between IBD, NHL, and immunosuppressive therapy. METHODS: We studied 782 IBD patients (238 of whom received immunosuppressive therapy) who attended our medical centre between 1990 and 1999 (median follow up 8.0 years). Standardised incidence ratios (SIRs) and 95% confidence intervals (CI) were calculated. Expected cases were derived from 1995 age and sex specific incidence rates recorded by the National Cancer Registry of Ireland. RESULTS: There were four cases of NHL in our IBD cohort (SIR 31.2; 95% CI 2.0-85; p=0.0001), all of whom had received immunosuppressive therapy: azathioprine (n=2), methotrexate (n=1), and methotrexate and cyclosporin (n=1). Our immunosuppressive group had a significantly (59 times) higher risk of NHL compared with that expected in the general population (p=0.0001). Three cases were intestinal NHL and one was mesenteric. Mean age at NHL diagnosis was 49 years, mean duration of IBD at the time of NHL diagnosis was 3.1 years, and mean duration between initiation of immunosuppressive therapy and diagnosis of NHL was 20 months. CONCLUSIONS: Although underlying IBD may be a causal factor in the development of intestinal NHL, our experience suggests that immunosuppressive drugs can significantly increase the risk of NHL in IBD. This must be weighed against the improved quality of life and clinical benefit immunosuppressive therapy provides for IBD patients.

The treatment with streptozotocin of a patient with metastatic gastrinoma is described. Two courses of intravenous streptozotocin were without effect. However, three months after two doses of 4 g streptozotocin were given into the coeliac axis, there was a marked reduction in hepatic size and a fall in fasting plasma gastrin levels from 1430 pmol/l to 240 pmol/l. Seven months after treatment fasting plasma gastrin levels were 125 pmol/l.

The diagnostic value in coeliac disease of circulating antibodies to casein, crude gliadin, and alpha gliadin was assessed using an adaption of the enzyme linked immunosorbent assay system. alpha Gliadin was the only antigen which consistently separated 26 patients with untreated coeliac disease from 26 normal controls and 13 patients with chronic inflammatory bowel disease. The mean assay index for the 26 patients was 3.1 (SD 1.2) compared with 1.05 (0.5) for the normal controls and 1.1 (0.6) for patients with chronic inflammatory bowel disease. The alpha gliadin antibody levels of six patients with coeliac disease who had maintained a gluten free diet for at least two years were not significantly higher than normal (1.0 (0.4)). The validity of the test was determined in 90 consecutive patients who were being investigated for the presence of coeliac disease. Levels of alpha gliadin antibody were raised in 36 out of 44 patients found to have histologically proved coeliac disease and in six out of 46 subjects whose jejunal mucosa was normal. Serial alpha gliadin concentrations were measured in 12 patients with coeliac disease who had repeat jejunal biopsies performed six months after starting a gluten free diet. The levels of antibody fell in seven of the eight patients whose jejunal mucosa improved on maintaining the diet. They remained raised in four patients who did not adhere to the diet and whose mucosa did not improve. Although a test measuring alpha gliadin antibodies is unlikely to replace jejunal biopsy in the diagnosis of coeliac disease it may be useful in screening for the disease among outpatients.

PUBLISHED, T helper and suppressor cell control of autologous immunoglobulin production was measured in 14 patients with Crohn's disease (CD) using autologous B cells or monocytes to stimulate regulatory T-cell activity. A pronounced defect in suppressor cell function was observed in the patient group but not in matched controls irrespective of whether B cells or monocytes were used as the stimulus. This defect was observed for IgG, A and M. This defect was seen both in patients with active disease and with inactive CD suggesting the possibility that a primary regulatory defect might exist in this disease. The patient group displayed normal helper cell function.

A group of teenage coeliac patients has been followed at three monthly intervals in the Outpatient Department to assess their progress and also to monitor their ability to maintain a gluten-free diet. After a follow-up period of four to six years a detailed reassessment was carried out in hospital on 10 patients, only five of whom had persevered with a gluten-free diet. The jejunal mucosal histology of those patients who did not persist with a gluten-free diet remained `flat' although these patients appeared to have remitted clinically. Those subjects who did persist with a gluten-free regime had a normal or near normal mucosal histology. It was difficult on the basis of clinical, haematological, or biochemical criteria to separate the two groups. The best single assessment of whether these patients were maintaining a gluten-free diet was serial serum folate estimations. It is often extremely difficult to say whether teenage coeliac patients are keeping to their diet unless repeated jejunal biopsies are obtained, and this study suggests that serial serum folate estimations can act as a reasonable criterion of whether subjects are maintaining a gluten-free regime.

Complement activation may play an important role in the pathogenesis of coeliac disease. In the present study immunohistochemical localisation of C3 and of a neoantigen exposed only on the terminal C5b-9 complement complex has been performed on small intestinal biopsy sections from newly diagnosed untreated coeliac patients, from coeliac patients on long-term gluten-free diet and from disease controls. Levels of C3 were markedly increased in treated coeliac patients compared with controls. Staining of C3 was concentrated subepithelially and within the centre of the lamina propria. No staining was detected at these sites using antibody to the neoantigen, however, strongly suggesting that the increased levels of C3 seen in the coeliac patients was the result of increased extravasation of serum proteins rather than complement activation. Surprisingly, complement activation was detected within the glands of Brunner. Positive staining using anti-C5b-9 neoantigen was found in all coeliac patients, both treated and untreated. Three of the 13 disease controls also showed reactivity with this antibody. This novel finding suggests that Brunner's glands, hitherto largely neglected structures, may play an important role in the development of coeliac disease.

Twenty three cases of pseudomembranous colitis (PMC) occurred in three hospitals in 10 months. Retrospective analysis shows that they represented a single epidemic with a readily traceable chain of person-to-person contact within and between hospitals. Most patients had severe pre-existing illness and all had broad spectrum antibiotics, including either ampicillin/amoxycillin, a broad spectrum cephalosporin (particularly cefotaxime), or both. All patients had severe diarrhoea and all responded to vancomycin, but relapse occurred in five. Ten patients eventually died, principally because of underlying disease rather than from PMC. Failure to find fibrin thrombi in blood vessels in biopsies and the scanty distribution of non-invasive bacteria supports the concept of mucosal damage by bacterial toxin, rather than by direct infection, or ischaemia. Although environmental colonisation cannot be excluded, the observed pattern of spread suggests a major role for direct person-to-person crossinfection in the spread of disease in this outbreak.

An improved technique for the detection of alpha-gliadin sensitised mononuclear cells in the peripheral blood of untreated coeliac patients is described. This method is a modification of the direct LMIF assay, and involves exposure of lymphocytes to alpha-gliadin and the assay of the resultant lymphokine produced using normal leucocytes as indicator cells. All untreated coeliac patients, 14 of 15 treated patients, and two of 28 controls responded to alpha-gliadin. The direct LMIF assay in comparison is less sensitive, and detected sensitivity to alpha-gliadin in only four out of eight patients with untreated coeliac disease. Use of the indirect LMIF technique demonstrates that in untreated as well as treated coeliac patients there are cells sensitised to alpha-gliadin circulating in the peripheral blood. These findings may have pathogenic and diagnostic significance.

Investigations into the standardization and reproducibility of the urinary excretion method for determining the absorption of tritiated folic acid were carried out. By proper timing of tissue-loading doses of folic acid a clear difference between the percentage excretion ranges of normal and coeliac subjects was obtained. In addition conditions were found whereby the procedure could be repeated on an individual up to four times with reproducible results. Methotrexate in pharmacological amounts was found to have no inhibitory effect on the human intestinal absorption of a small oral dose (300 mug) of folic acid as determined by this method. This indicates that reduction of folic acid is not necessary for its absorption in man.

Serial measurements in alcoholic subjects showed a profound fall of serum iron for three days after withdrawal of alcohol and a reversion of abnormal accumulation of erythroblastic haemosiderin to normal. These findings suggest an interference in normal haem synthesis, most probably by a direct effect.

A retrospective study was conducted to assess the association of alpha-gliadin antibodies with intraepithelial lymphocyte counts. Twelve subjects with apparently normal small intestinal histology and raised alpha-gliadin antibody titres had significantly increased intraepithelial lymphocyte counts (42 (SEM) 5.9) when compared with 16 subjects with normal alpha-gliadin antibody titres (17 (3.2); p less than 0.001). These findings show that in the absence of gross pathology raised alpha-gliadin antibody titres are associated with increased numbers of intraepithelial lymphocytes and may reflect continuous immunological processes in the small intestine.

The standard double-isotope Schilling test was used to study vitamin B12 absorption in seven patients with obstructive jaundice and 10 with T-tube bile duct drainage after cholecystectomy and bile duct exploration. In three and five of these patients respectively absorption was impaired. In the second group six patients were restudied after removal of the T tube, and in each case absorption was improved. Similar results were obtained after bile duct ligation in rats. Bile exclusion produced a 50-60% reduction in renal and hepatic uptake of vitamin B12 from the intestinal lumen. The malabsorption was corrected by replacing bile. These studies suggest that bile plays a part in the normal absorption of vitamin B12.

The purpose of this study was to determine if pirenzepine and cimetidine given together was superior to cimetidine alone in inducing healing of refractory duodenal ulcers which remained unhealed after treatment with cimetidine or ranitidine for at least eight weeks. One hundred and thirty one patients from six centres were randomised to receive either cimetidine (C) 800 mg daily or cimetidine 800 mg plus pirenzepine (C + P) 100 mg daily under double blind conditions for six weeks. The healing rate was similar in both groups, irrespective of the method of calculation. On an intent-to-treat analysis, healing was: C 66%, C + P 57%, and amongst the patients who completed treatment, healing was 70% in both groups. Patients on C and on C + P experienced a similar decrease in daytime and in night time pain. Side effects of treatment, notably dry mouth and blurred vision, were reported more often by patients on combination therapy. Combined treatment with cimetidine plus pirenzepine in patients with refractory duodenal ulcer is unlikely to be beneficial.