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A prevalence study of primary biliary cirrhosis was carried out in the state of Victoria, Australia, by means of a mail survey of specialist physicians and a review of hospital records. Eighty four cases were identified, giving a prevalence of 19.1 per million population (95% confidence limits (CI) 15.3, 23.7), which is among the lowest in published reports. The prevalence in the Australian born, at risk population (women over the age of 24) was 51 per million (95% CI 37.5, 67.9). Both these figures are considerably lower than those in populations of similar age distribution in the UK and northern Europe. Since most Victorians are descended from British or European settlers, the low prevalence of primary biliary cirrhosis in this study supports the hypothesis that local environmental factors may be important in the pathogenesis of this disease.

We investigated, using the single-pass isolated perfused rat liver preparation, whether the centrilobular location of hepatic oxidative drug metabolism could be a contributing factor to the marked sensitivity of drug oxidation to hypoxia. Livers (N = 7) were each perfused for 130 min with 2 micrograms/mL (+)-propranolol, a drug metabolized almost entirely by oxidation in the rat. The direction of flow was reversed after 60 min, the order of flow direction being randomized. Normal oxygenation was used during the first 30 min of antegrade and of retrograde perfusion, but in the second 30 min perfusate was equilibrated with a N2/O2 mixture designed to reduce hepatic oxygen delivery by half. During normal oxygenation there was no significant difference between antegrade and retrograde perfusion in hepatic oxygen delivery and physiological parameters such as oxygen consumption and extraction, perfusion pressure and bile flow. During hypoxia, mean oxygen delivery was slightly lower with retrograde perfusion (retrograde: mean = 2.37 mumol/min/g liver, range = 1.56-3.17; antegrade: mean = 2.90 mumol/min/g liver, range = 1.96-4.08; P = 0.04), but there was no significant difference in physiological parameters within each liver (P > 0.05). Propranolol clearance during normal oxygenation was similar to the perfusion rate (10 mL/min) and was the same for both directions of perfusion (antegrade 9.88 +/- 0.07 mL/min, retrograde 9.88 +/- 0.13 mL/min, P > 0.05). Hypoxia reduced propranolol clearance substantially, but the decrease was significantly greater with antegrade perfusion (5.65 +/- 1.89 mL/min) than with retrograde perfusion (6.76 +/- 1.95 mL/min, P = 0.014). Oxidative drug metabolism is located primarily in the centrilobular zone and sinusoidal oxygen concentration is lowest in the "downstream" zone with both antegrade and retrograde perfusion. These findings suggest that the centrilobular location of propranolol metabolism may influence the effect of hypoxia on propranolol elimination, but is not a major contributor to the marked sensitivity of propranolol elimination to hypoxia antegrade perfusion.

Coeliac disease (CD) is associated with a wide spectrum of clinical presentation and may be overlooked as a diagnosis. There is some evidence that untreated CD is associated with a doubling of mortality, largely due to an increase in the incidence of malignancy and small intestinal lymphoma, which is decreased by a strict gluten-free diet. We studied the clinical features of screening-detected coeliacs compared to age- and sex-matched controls as a 3-year follow-up to a population screening survey, and followed-up subjects who had had CD-associated serology 11 years previously to determine whether they have CD or an increased mortality rate compared to the general population. Samples of the general population (MONICA 1991 and 1983) were screened for CD-associated serology and followed-up after 3 and 11 years, respectively, and assessed by a clinical questionnaire, screening blood tests and jejunal biopsy. Mortality rates for 'all deaths' and 'cancer deaths' were compared in subjects with positive serology in 1983 with reference to the general population. Thirteen coeliacs were diagnosed by villous atrophy following screening, compared to two patients with clinically detected CD, giving a prevalence of 1:122. Clinical features or laboratory parameters were not indicative of CD compared to controls. Subjects with positive serology followed up after 11 years did not have an excess mortality for either cancer deaths or all causes of death. Screening-detected CD is rarely silent and may be associated with significant symptoms and morbidity. In this limited study with small numbers, there does not appear to be an increased mortality from screening-detected CD, although the follow-up may be too short to detect any difference.

To find out if the in vitro responses of neutrophils (PMN) and monocytes preoperatively can predict their activation postoperatively.Prospective open study.Teaching hospital, Ireland.46 Patients (32 men, 14 women, mean age 65 years, range 33-85) who were to undergo elective major vascular or gastrointestinal operations for benign (n = 18) or malignant (n = 28) diseases.Measurement by flow cytometry of functional (PMN and monocyte respiratory burst activity) and phenotypic (expression of PMN CD 11b adhesion receptors and monocyte CD14 receptors) markers of activation.Correlation between mean channel fluorescence (MCF) preoperatively and postoperatively.In 24 patients PMN respiratory burst activity was increased before operation and had decreased significantly (p0.01) on postoperative day 1 (high responders group). In the remaining 22 patients (low responders group) respiratory burst activity was low before operation and had increased significantly (p0.05) on postoperative day 1. PMN CD 11b activity followed a similar trend. Monocyte activity responded similarly (in the high group mean (SEM) MCF preoperatively was 69.14 (13.15) compared with 58.23 (10.8) on day 1, and in the low group the corresponding figures were 38.5 (7.01) and 8.43 (5.2). Expression of CD14 did not differ between the groups and was less postoperatively than preoperatively. The groups did not differ in age, sex, APACHE 11 scores, smoking habits or types of disease and there was no major infective complications in either group.There are two distinct patterns of PMN and monocyte responses to injury that are independant of age, sex and severity of operation. These may be associated with the degree of stress preoperatively or with genetic factors.

This study compared high dose ranitidine versus low dose omeprazole with antibiotics for the eradication of H pylori. 80 patients (mean age 48 years, range 18-75) who had H pylori infection were randomised in an investigator-blind manner to either a two-week regime of omeprazole 20 mg daily, amoxycillin 500 mg tid and metronidazole 400 mg tid (OAM), or ranitidine 600 mg bd, amoxycillin 500 mg tid and metronidazole 400 mg tid (RAM), or omeprazole 20 mg daily and clarithromycin 500 mg tid (OC), or omeprazole 20 mg daily and placebo (OP). H pylori was eradicated in 6 of 19 patients in the OAM group (32%); 8 of 18 in the RAM group (44%), 4 of 15 in the OC group (27%); none of 18 in the OP group (0%). [< P0.005 for OAM, RAM, OC vs OP; P = N.S. between OAM, RAM, OC]. Overall metronidazole resistance was unexpectedly high at 58%. Eradication rates in metronidazole sensitive patients were 71% (5/7) and 100% (3/3) for OAM and RAM respectively. In conclusion, H pylori eradication rates using high dose ranitidine plus amoxycillin and metronidazole may be similar to that of low dose omeprazole in combination with the same antibiotics for omeprazole with clarithromycin. Overall eradication rates were low due to a high incidence of metronidazole resistance but were higher in metronidazole-sensitive patients. Even high dose ranitidine with two antibiotics achieves a relatively low eradication rate. These metronidazole-based regimens cannot be recommended in areas with a high incidence of metronidazole resistance.

UNLABELLED Coeliac disease is often under-diagnosed, particularly in cases which are atypical or asymptomatic. OBJECTIVE The aim of this study was to comprehensively assess the prevalence and clinical profile of adult coeliac disease in our community. METHODS One-hundred-and-thirteen subjects from the most recent MONICA (multinational MONItoring of trends and determinants in CArdiovascular disease)1991/2 survey with positive serology were followed up 3 years after initial screening and assessed by means of (i) a clinical questionnaire, (ii) screening blood tests, and (iii) jejunal biopsy. RESULTS Forty-six subjects (21 male, mean age 51 years) have been followed up to date. Prior to follow-up, two of these subjects were diagnosed as having coeliac disease. Ten (3 male, mean age 51 years) of 44 subjects had enteropathy. Three of these 10 subjects were relatively asymptomatic, 3 had folate deficiency and 3 had iron deficiency. Thus 12 of the 1823 initially screened had enteropathy consistent with coeliac disease. CONCLUSIONS Coeliac disease is more prevalent than previous estimations and was found to be at least 1 in 152.

We prospectively measured serum alkaline phosphatase (ALP), aspartate and alanine transaminase (AST/ALT), and tested sera for antinuclear, smooth-muscle, and antimitochondrial antibodies (ANA, SMA, AMA) in our patients with celiac sprue to determine the prevalence of associated liver abnormalities and its relevance to clinical management. Of 129 patients, ALP was the only elevated enzyme in 12 (9%) and in most cases was not thought to reflect significant liver disease. Seventeen (13%) had elevated AST and/or ALT with normal ALP. Levels normalized in 15 patients after dietary gluten exclusion and remained elevated in 2 noncompliers. Two patients (2%) with elevated AST, ALT, and ALP underwent further investigation: one had negative autoantibodies, liver biopsy, and endoscopic retrograde cholangiography and the other had ANA-positive chronic active hepatitis; enzymes in both cases improved with a gluten-free diet. There was no significant association between elevated AST/ALT and positive ANA/SMA; no patient had AMA. Abnormalities in liver enzymes are common in celiac sprue, but usually respond to dietary gluten exclusion. We propose that there is no need for invasive liver investigation in these patients unless there is more specific evidence of primary liver disease or failure of dietary response.

We report the case of a patent urachus presenting as an umbilical discharge. The urachus was visualised laparoscopically, divided at either extremity, and successfully removed with subsequent abrogation of symptoms.

Eighteen patients with a variety of non-gastrointestinal symptoms were incidentally found to have circulating antireticulin antibody and on subsequent testing were also positive for antigliadin antibody. They prospectively underwent jejunal biopsy to determine whether or not they had coeliac disease. Their age range was 21-79 years (mean 42 years). Enteropathy was present in 13 (72 per cent) and was always associated with circulating IgA antigliadin antibody. Enteropathy was not present in the five cases who had only IgG antibody. Clinical improvement occurred in eight of 11 patients who complied with a gluten-free diet and was paralleled by an improvement in the mucosal histology in seven of eight who were re-biopsied. The most remarkable cases were two patients who presented with severe debility and no apparent haematological or biochemical abnormalities, and who subsequently made a dramatic recovery on a gluten-free diet. It is concluded that antireticulin antibody detected by routine autoantibody screening and confirmed to have IgA antigliadin antibody specificity is a useful indicator of an otherwise undiagnosed enteropathy. This serves to emphasize that the condition can sometimes be associated with atypical features and significant morbidity.

e14502 Background: Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Previous work has shown that thymidylate synthase (TYMS) copy gains were associated with significantly shorter survival, while increased expression of thymidine phosphorylase (TP) led to greater sensitivity to 5-FU in vitro. We assessed TYMS and TP copy number in colorectal liver metastases from untreated patients and patients treated with 5-FU in an effort to elucidate the underlying molecular mechanisms for 5-FU resistance. Methods: Liver metastases were procured from 59 patients who had received 5-FU within 6 months preceding liver resection (treated samples) and from 46 patients who had received no 5-FU treatment in the 6 months prior to their liver resections (untreated samples). DNA copy number of TYMS and TP was evaluated in frozen colorectal liver metastases using quantitative real time PCR. Results: For TYMS, 8.9% of the treated samples showed copy number gain, as compared to 4.8% of the untreated samples. Loss of TYMS was rare, with only 1 and 2 occurrences seen in the treated and untreated samples, respectively. For TP, both groups exhibited similar copy number gains (25% for treated, 29% for untreated); however, a greater proportion of the treated samples exhibited loss of TP (20% vs. 10%). Collectively, the treated samples have a much higher incidence of genetic alterations potentially associated with resistance (TYMS gain or TP loss) than untreated samples (30% vs. 10%, p = 0.03 Fisher exact test). Conclusions: Colorectal liver metastases treated with 5-FU exhibit DNA copy variants that may reduce 5- FU's efficacy. Our data suggest that these genetic alterations may have important implications for the management of advanced colorectal cancer patients with recurrent disease. No significant financial relationships to disclose.

A chemical investigation of a large purple sponge, Spongia sp., from the Great Australian Bight, resulted in the isolation of a new sesquiterpene/quinone (8), together with the known compounds dehydrocyclospongiaquinone-1 (4) and spongiaquinone (2). The last compound was also isolated as the potassium salt (9), this being the first recorded account of a naturally occurring marine sesquiterpene/quinone salt. The structure for (8) was assigned by detailed spectroscopic analysis. A re-investigation into the stereostructure of spongiaquinone (2) resulted in the first unambiguous assignment of absolute stereochemistry, and uncovered the peculiar chiroptical properties of spongiaquinone (2) and its potassium salt (9).

Atoms are chiral due to the parity‐violating weak neutral current interaction between the nucleus and the electrons. A simple pictorial representation of the chirality of an atom is obtained by mapping the electron probability current density in the atom. Results are shown for a hydrogenic 2p1/2 stationary state.

One hundred patients with biochemically proved primary hyperparathyroidism had serum amylase estimations before and after cervical or mediastinal exploration. After operation the patients were monitored for the development of abdominal symptoms suggestive of pancreatitis. Although hyperamylasemia occurred in four patients after operation, clinical acute pancreatitis did not arise. Amylase fractionation confirmed the presence of excessive salivary isoamylase in all four patients. Operation on patients with marginally elevated serum creatinine concentrations, those receiving furosemide, and those undergoing concomitant thyroid operation appeared to increase the likelihood of salivary-based hyperamylasemia; this finding suggested an altered renal handling of amylase in the immediate postoperative period. The results of this prospective study and reviewed reports of additional patients undergoing parathyroidectomy indicate that this operation is unlikely to be complicated by postoperative pancreatitis. The probable risk of both pancreatitis and hyperamylasemia would appear to be no more than that with other nonabdominal surgical procedures.

Circulating antigliadin antibody has been described in patients with gluten enteropathy although the prevalence varies in different studies. It has been suggested that the investigation for antigliadin antibody might be useful as a screening test. The object of the present study was to evaluate two different techniques for assaying these antibodies — an indirect immunofluorescent method and an enzyme-linked immunosorbent assay (ELISA). Antibodies were assayed in the sera of 102 patients in whom jejunal biopsies were also obtained. The specificity of both tests was greater than 95%, and the correlation between the presence of antibody and histology was significant (p < 0.005), though the sensitivity of each test was less than 70%.

Ligation of the common bile duct in pigs causes esophagogastric ulceration in 100 per cent of instances within seven days postoperatively. The results of previous studies have suggested a peptic cause for these ulcers. The possible role of lysosomal acid hydrolases in the primary pathogenesis was investigated herein. The total activities of two lysosomal acid hydrolases in mucosal specimens taken at biopsy from ulcerated pars esophagea and one in ulcerated gastric cardia were significantly lower in pigs undergoing ligation of the bile duct postoperatively, than in comparable pigs undergoing sham operations while there was evidence of increased extracellular activity. Mucosal deoxythymidine kinase activity was increased in gastric cardia suggesting attempted repair. Pigs with parakeratosis of the pars esophagea and edema of the gastric cardia, consistent with the preulcerative state also showed lowered enzyme activity. These results in intact pigs suggest that release of lysosomal acid hydrolases occurs with and may precede peptic ulceration.

The reported incidence of gastrointestinal endocrine tumours is variable. In Northern Ireland circumstances allowing such an assessment are favourable with a central diagnostic laboratory and register established to collect data on tumours from a well-defined population of 1.5 million people. From 1970 to 1985, 368 cases were recorded of which 85 per cent were carcinoid tumours. The annual incidence of carcinoid tumours was 1.3 per 100,000 of the population and the majority occurred in the appendix (61 per cent). No patients presented with the carcinoid syndrome. The annual incidence for other tumours was 0.12 per 100,000 for insulinomas; islet cell tumours of unknown type 0.07; Zollinger-Ellison syndrome 0.05; and multiple endocrine neoplasia (MEN) 0.05. There were two cases of VIPoma, one glucagonoma, one neurotensinoma and one tumour producing ACTH. It is possible that some tumours are more uncommon than others because of difficulty in diagnosis.

A comparison was made in pigs of the tensile strength of the bile duct anastomosis after simple dochotomy and after hepatic autograft or allograft. It appears that tensile strength returned to normal levels within 15 days of simple dochotomy and indeed rose past normal at 50 days, but that after either form of hepatic grafting, tensile strength did not reach normal levels even by 50 days postoperation.

A retrospective survey was made of all 189 patients admitted with acute upper gastrointestinal haemorrhage to the Belfast City Hospital in one year. The commonest single reason for admission was peptic ulcer disease, but this was lower than in other published series from the United Kingdom. Overall mortality was 4.8%. The majority of patients did not require either blood transfusion or surgery. There may be potential benefits of endoscopic haemostatic techniques to deal with this condition.

The reported incidence of gastrointestinal endocrine tumours is variable. In Northern Ireland circumstances allowing such an assessment are favourable with a central diagnostic laboratory and register established to collect data on tumours from a well-defined population of 1.5 million people. From 1970 to 1985, 368 cases were recorded of which 85 per cent were carcinoid tumours. The annual incidence of carcinoid tumours was 1.3 per 100,000 of the population and the majority occurred in the appendix (61 per cent). No patients presented with the carcinoid syndrome. The annual incidence for other tumours was 0.12 per 100,000 for insulinomas; islet cell tumours of unknown type 0.07; Zollinger-Ellison syndrome 0.05; and multiple endocrine neoplasia (MEN) 0.05. There were two cases of VIPoma, one glucagonoma, one neurotensinoma and one tumour producing ACTH. It is possible that some tumours are more uncommon than others because of difficulty in diagnosis.

Pigs develop gastric ulceration spontaneously and after bile duct ligation. Despite increased basal acid secretion, serum gastrin levels are not elevated, and a possible 'protective' role of gastrin was proposed. Continuous intravenous infusion of synthetic human gastrin did not protect from gastric ulceration, but was associated with simultaneous duodenal ulceration. Another ulcerogenic mechanism must be invoked.

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