Showing papers in "Gut in 1995"

A controlled double blind study of azathioprine in the management of Crohn's disease.

Abstract: While immunosuppressive agents are used widely in the management of Crohn's disease, their efficacy has not been well established in randomised controlled trials. This study was designed to examine whether azathioprine increases remission rate when used in conjunction with a diminishing dose regimen of prednisolone over a period of 12 weeks. It further examined whether azathioprine offers any therapeutic advantage over placebo in the maintenance of remission in Crohn's disease over a period of 15 months. Sixty three patients with active Crohn's disease were treated with a 12 weeks diminishing dose of prednisolone and at the same time entered into a randomised, double blind 15 month trial of either azathioprine (2.5 mg/kg) or placebo. Remission rates between the two groups were compared at 12 weeks and at 15 months. There was no significant difference in the proportion of patients who had achieved and maintained remission by week 12 but at 15 months there was a highly significant difference in the proportion of patients in remission (42% receiving azathioprine v 7% receiving placebo), p = 0.001. Using life tables this beneficial effect was reflected as the difference in the median number of days on the trial (p = 0.02). There were significantly greater decreases over the trial period in the median erythrocyte sedimentation rate, C reactive protein, and leucocyte count in the azathioprine group. There were no cases of severe bone marrow suppression or clinical pancreatitis. In conclusion, azathioprine offers a therapeutic advantage over placebo in the maintenance of remission in Crohn's disease.

Indications, methods, and outcomes of percutaneous liver biopsy in England and Wales: an audit by the British Society of Gastroenterology and the Royal College of Physicians of London.

Abstract: The liver section of the British Society of Gastroenterology and the research unit of the Royal College of Physicians collaborated to set up a nationwide audit to investigate the practice of percutaneous liver biopsy in England and Wales. Each of 189 health districts in England and Wales was approached to provide a list of 10 consecutive percutaneous biopsies performed during 1991, and details of demographic data, indications, suspected diagnosis, investigations, biopsy technique, outcome, and influence on patient management were collected. Data were retrieved on 1500 (79%). The age distribution showed 6% of biopsies were done in those over 80 years of age and as many over 90 as under 10 years of age. Suspected malignancy and chronic liver disease each contributed one third of the indications. In 34% the procedure was carried out by radiologists under ultrasound image control. The remainder were done by general physicians and gastroenterologists, with the operator in the second group being more senior and experienced. The Trucut biopsy needle accounted for two thirds of biopsies, the remainder being the Menghini type. For both needles the samples were recorded as excellent or satisfactory in 83% and inadequate in only 5%. Bleeding complicated 26 procedures (1.7%), requiring transfusion in 11, and was commoner when clotting was impaired or serum bilirubin raised. There were two definite and three possible procedure related, given an overall mortality of 0.13-0.33%. The diagnosis made before biopsy was confirmed in 63% of patients, and the clinician found the biopsy helpful in treatment in 75%. Day case biopsy and techniques to reduce the risk of bleeding were surprisingly rare in this series, which has given a unique opportunity to examine everyday practice across a wide range of hospitals.

Prospective audit of upper gastrointestinal endoscopy in two regions of England: safety, staffing, and sedation methods.

Abstract: A prospective audit of upper gastrointestinal endoscopy in 36 hospitals across two regions provided data from 14,149 gastroscopies of which 1113 procedures were therapeutic and 13,036 were diagnostic. Most patients received gastroscopy under intravenous sedation; midazolam was the preferred agent in the North West and diazepam was preferred in East Anglia. Mean doses of each agent used were 5.7 mg and 13.8 mg respectively, although there was a wide distribution of doses reported. Only half of the patients endoscoped had some form of intravenous access in situ and few were supplied with supplementary oxygen. The death rate from this study for diagnostic endoscopy was 1 in 2000 and the morbidity rate was 1 in 200; cardiorespiratory complications were the most prominent in this group and there was a strong relation between the lack of monitoring and use of high dose benzodiazepines and the occurrence of adverse outcomes. In particular there was a link between the use of local anaesthetic sprays and the development of pneumonia after gastroscopy (p < 0.001). Twenty perforations occurred out of a total of 774 dilatations of which eight patients died (death rate 1 in 100). A number of units were found to have staffing problems, to be lacking in basic facilities, and to have poor or virtually non-existent recovery areas. In addition, a number of junior endoscopists were performing endoscopy unsupervised and with minimal training.

Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease.

Abstract: Recent studies have suggested that nitric oxide (NO.), the product of nitric oxide synthase in inflammatory cells, may play a part in tissue injury and inflammation through its oxidative metabolism. In this study the colonic generation of oxides of nitrogen (NOx) and nitric oxide synthase activity was determined in ulcerative colitis and Crohn's disease. Colonic biopsy specimens were obtained from inflammatory bowel disease patients and from normal controls. Mucosal explants were cultured in vitro for 24 hours and NOx generation was determined. Nitric oxide synthase activity was monitored by the conversion of [3H]-L-arginine to citrulline. Median NOx generation by inflamed colonic mucosa of patients with active ulcerative colitis and Crohn's colitis was 4.2- and 8.1-fold respectively higher than that by normal human colonic mucosa. In ulcerative colitis and Crohn's colitis nitric oxide synthase activity was 10.0- and 3.8-fold respectively higher than in normal subjects. Colonic NOx generation is significantly decreased by methylprednisolone and ketotifen. The decrease in NOx generation by cultured colonic mucosa induced by methylprednisolone suggests that NO synthase activity is induced during the culture and the steroid effect may contribute to its therapeutic effect. Enhanced colonic NOx generation by stimulated nitric oxide synthase activity in ulcerative colitis and Crohn's disease may contribute to tissue injury.

Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma.

Abstract: Coeliac disease is precipitated in susceptible subjects by ingestion of wheat gluten or gluten related prolamins from some other cereals. The disease is strongly associated with certain HLA-DQ heterodimers, for example, DQ2 (DQ alpha 1*0501, beta 1*0201) in most patients and apparently DQ8 (DQ alpha 1*0301, beta 1*0302) in a small subset. Gluten specific T cell clones (TCC) from coeliac intestinal lesions were recently established and found to be mainly restricted by HLA-DQ2 or HLA-DQ8. Antigen induced production of cytokines was studied in 15 TCC from three patients, 10 being DQ2 and five DQ8 restricted. Cell culture supernatants were prepared by stimulation with gluten peptides in the presence of DQ2+ or DQ8+ Epstein-Barr virus transformed B cells as antigen presenting cells (APC). Supernatants were analysed for cytokines by bioassays, ELISA, and CELISA. Cellular cytokine mRNA was analysed semi-quantitatively by slot blotting and polymerase chain reaction (PCR). All TCC were found to secrete interferon (IFN) gamma, often at high concentrations (> 2000 U/ml); some secreted in addition interleukin (IL) 4, IL 5, IL 6, IL 10, tumour necrosis factor (TNF), and transforming growth factor (TGF) beta. The last TCC thus displayed a Th0-like cytokine pattern. However, other TCC produced IFN gamma and TNF but no IL 4, or IL 5, compatible with a Th1-like pattern. In conclusion, most DQ8 restricted TCC seemed to fit with a Th0 profile whereas the DQ2 restricted TCC secreted cytokines more compatible with a Th1 pattern. The TCC supernatants induced upregulation of HLA-DR and secretory component (poly-Ig receptor) in the colonic adenocarcinoma cell line HT-29.E10, most probably reflecting mainly the high IFN gamma concentrations. This cytokine, particularly in combination with TNF alpha, might be involved in several pathological features of the coeliac lesion. The characterised cytokine profiles thus support the notion that mucosal T cells activated in situ by gluten in a DQ restricted fashion play a central part in the pathogenesis of coeliac disease.

Photosensitisation and photodynamic therapy of oesophageal, duodenal, and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX--a pilot study

Abstract: The first study of photodynamic therapy in the human gastrointestinal tract using 5 aminolaevulinic acid (ALA) induced protoporphyrin IX as the photosensitising agent is described. Eighteen patients with colorectal, duodenal, and oesophageal tumours were studied. After 30-60 mg/kg of ALA given orally, biopsy specimens of tumour and adjacent normal mucosa were taken 1-72 hours later. These specimens were examined by quantitative fluorescence microscopy for assessment of sensitisation with protoporphyrin IX. Ten patients were given a second dose of ALA a few weeks later and their tumours were treated with red laser light (628 nm). With 30 mg/kg ALA, the highest fluorescence values were detected in the duodenum and oesophagus, and the lowest in the large bowel. Doubling the ALA dose in patients with colorectal tumours gave protoporphyrin IX fluorescence intensities similar to those in patients with upper gastrointestinal lesions and improved the tumour:normal mucosa protoporphyrin IX sensitisation ratio. The treated patients showed superficial mucosal necrosis in the areas exposed to laser light. Six patients had transient rises in serum aspartate aminotransferases, two mild skin photosensitivity reactions, and five mild nausea and vomiting. In conclusion, photodynamic therapy with systemically administered ALA may be a promising technique for the treatment of small tumours and areas of dysplasia such as in Barrett's oesophagus.

Changes in the intragastric distribution of Helicobacter pylori during treatment with omeprazole.

Abstract: Omeprazole is a powerful inhibitor of gastric acid and may suppress Helicobacter pylori by effecting the pKa of H pylori urease, by altering the pattern of infection, or by promoting overgrowth of other bacteria. At routine endoscopy H pylori was detected by histology and culture before and after four weeks' treatment with omeprazole, 40 mg each morning. A 13C-urea breath test was also done at t = 0, 2, 4, and 6 weeks. Thirty nine patients with duodenal ulcer (n = 25) or reflux oesophagitis (n = 14) were studied, of whom 29 of 39 had H pylori infection. During omeprazole treatment, 13C-urea breath test values fell significantly--mean (SEM) values before treatment and at four weeks were 23.0 (2.1) and 15.5 (2.7) per mil respectively, p < 0.001. Before treatment H pylori was seen in 28 of 29 antral, 29 of 29 corpus, and 28 of 29 fundic biopsy specimens. After four weeks of omeprazole treatment, the histological density of H pylori in the antrum and corpus was reduced (p < 0.001), while that in the fundus was increased. The migration of H pylori from the antrum to the fundus was associated with a corresponding decrease in the activity of antral gastritis. H pylori was not seen in antral biopsy specimens from 12 of 29 patients whose median excess delta 13CO2 excretion fell from 23.0 to 9.9 per mil. In the body mucosa, 26 of 29 specimens were still positive for H pylori and there was no significant change in the gastritis type. Two weeks after finishing treatment, the mean (SEM) excess delta 13CO2 excretion returned to levels before treatment. Omeprazole decreases antral H pylori colonisation but increases that in the fundus. The changes in the intragastric distribution of the organism are associated with concomitant changes in the activity of gastritis and are matched by a progressive fall in the excretion of delta 13CO2.

Factors influencing morbidity and mortality in acute pancreatitis; an analysis of 279 cases.

Abstract: Of 279 patients admitted to a specialist unit with acute pancreatitis, 210 were admitted directly and 69 were transferred for treatment of local or systemic complications. Outcome was assessed in terms of mortality and morbidity and in relation to aetiology, predicted severity of disease (modified Glasgow score), organ failure (modified Goris multiple organ failure score), and need for surgical intervention. The death rate was 1.9% in patients admitted directly but was 18.8% in those transferred from other units. Mortality in gall stone related pancreatitis was 3% compared with 15% (p = 0.03) in pancreatitis of unknown aetiology and 27% (p = 0.01) in post-endoscopic retrograde cholangiopancreatography pancreatitis. Mortality was related to age (mortality > 55 years old 11% v 2%; p = 0.003) and Goris score (score 0, mortality 0% v score 5-9, mortality 67%; p = 0.001). In patients transferred from other units, mortality was 11% in those transferred within a week of diagnosis and 35% when transfer was delayed (p = 0.04). Thirty six patients had pancreatic necrosis on dynamic computed tomography of whom 29 underwent pancreatic necrosectomy with a 34% mortality. Mortality was related to the modified Goris score (median score 2 in survivors v 6 in non-survivors; p = 0.005) and was higher when necrosectomy was performed within the first two weeks of admission (100% vs 21%; p = 0.004). In conclusion, mortality in acute pancreatitis is influenced by age, aetiology of the disease, and presence of organ failure. Patients transferred for specialist care have a 10-fold greater mortality than those admitted directly and mortality is greatest when transfer is delayed. Early necrosectomy carries a prohibitively high mortality.

Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD.

Abstract: Some patients undergoing ambulatory oesophageal pH monitoring to investigate symptoms suggestive of gastro-oesophageal reflux disease (GORD) are found to have oesophageal acid exposure within the physiological range but show a close correlation between their symptoms and individual reflux episodes. It is suggested that these patients might exhibit enhanced oesophageal sensation, akin to the heightened perception of both physiological and provocative stimuli in the gut that has been described in patients with functional gastrointestinal disorders. This study tested the hypothesis by measuring the sensory thresholds for oesophageal balloon distension and discomfort in 20 patients with symptoms of GORD, in whom ambulatory pH monitoring had shown normal acid exposure times, but in whom the symptom index for reflux events was 50% or greater, and compared these with 15 healthy volunteer controls, and with control groups with confirmed excess reflux. The study group showed lower thresholds both for initial perception of oesophageal distension, and for discomfort, compared with healthy controls (median ml (range)); 7.5 (2-19) v 12 (6-30) (p = 0.002) and 10 (5-20) v 16 (8-30) (p < 0.0001), respectively. Sensory thresholds in the study group were also significantly lower than in patients with excess reflux, and than patients with Barrett's oesophagus, who also exhibited significantly higher sensory thresholds than healthy controls. No differences in sensory thresholds for somatic nerve stimulation were found between the study group and health controls. The results show a spectrum of visceral sensitivity in GORD, with enhanced oesophageal sensation in patients with symptomatic but not excess gastro-oesophageal reflux, suggesting that their symptoms result from a heightened perception of normal reflux events.

Interferon gamma and interleukin 4 secreting cells in the gastric antrum in Helicobacter pylori positive and negative gastritis.

Abstract: Little is known of the function of the T cells in the inflammatory infiltrate in Helicobacter pylori associated gastritis. This study thus measured T cell in vivo activation by enumerating the frequency of interferon gamma (IFN gamma) and interleukin 4 (IL 4) secreting cells isolated from the gastric antral mucosa in patients with or without gastritis and in H pylori positive and negative gastritis. Fifty four samples were examined for cytokine secretion. Four antral biopsy specimens from each patient (n = 51) were taken during diagnostic endoscopy. One was used to estimate histological gastritis and the presence of H pylori, and three of the samples were used to isolate T cells by enzymatic digestion. IFN gamma and IL 4 secreting cells were enumerated by ELISPOT. Thirty four samples had gastritis and 79% of those were H pylori positive. None of the samples from non-inflamed mucosa had H pylori. The numbers of IFN gamma secreting cells per 10(5) T cells were higher in gastritis than in normal mucosa (145 v 20 IFN gamma spots, p < 0.01), and higher in H pylori negative than H pylori positive gastritis (371 v 110 IFN gamma spots, p < 0.05). The frequencies of IL 4 secreting cells did not differ between gastritis and non-inflamed mucosa. In conclusion, there is an increase in IFN gamma secreting cells but not in IL 4 secreting cells in H pylori positive and negative gastritis. It is not known if this TH1 type reaction has a pathogenetic or protective role.

Drug induced acute pancreatitis: incidence and severity.

Abstract: To determine the incidence and severity of drug induced acute pancreatitis, data from 45 German centres of gastroenterology were evaluated. Among 1613 patients treated for acute pancreatitis in 1993, drug induced acute pancreatitis was diagnosed in 22 patients (incidence 1.4%). Drugs held responsible were azathioprine, mesalazine/sulfasalazine, 2',3'-dideoxyinosine (ddI), oestrogens, frusemide, hydrochlorothiazide, and rifampicin. Pancreatic necrosis not exceeding 33% of the organ was found on ultrasonography or computed tomography, or both, in three patients (14%). Pancreatic pseudocysts did not occur. A decrease of arterial PO2 reflecting respiratory insufficiency, and an increase of serum creatinine, reflecting renal insufficiency as complications of acute pancreatitis were seen in two (9%) and four (18%) patients, respectively. Artificial ventilation was not needed, and dialysis was necessary in only one (5%) case. Two patients (9%) died of AIDS and tuberculosis, respectively; pancreatitis did not seem to have contributed materially to their death. In conclusion, drugs rarely cause acute pancreatitis, and drug induced acute pancreatitis usually runs a benign course.

Reflux related symptoms in patients with normal oesophageal exposure to acid.

Abstract: Several studies, using pH monitoring with event markers, have identified patients with normal oesophageal exposure to acid despite an apparent relation between symptoms and reflux episodes. In this series of 771 consecutive patients referred for 24 hour oesophageal pH monitoring, a probability calculation was used to evaluate the relation between symptoms and reflux episodes. Oesophageal exposure to acid was normal in 462 of 771 recordings (59.9%); despite this, 70.8% (327 of 462) of these patients used at least once the event marker. In 96 patients (12.5% of total patients) with normal oesophageal exposure to acid, there was a statistically significant association between symptoms and reflux episodes. The symptom cluster of such patients was similar to that usually seen in patients with gastro-oesophageal reflux disease, but symptoms like belching, bloating, and nausea were common thus overlapping with the symptom pattern of functional dyspepsia. In these patients both the duration and the minimum pH of reflux episodes (either symptom related or asymptomatic) were significantly shorter and higher, respectively, when compared with those of patients with gastro-oesophageal reflux disease. These results are consistent with the idea that oesophageal hypersensitivity to acid is the underlying pathophysiological feature of this syndrome.

A controlled study of bone mineral density in patients with inflammatory bowel disease.

Abstract: To assess the prevalence of and risk factors for low bone mineral density in inflammatory bowel disease (IBD), 152 IBD patients and 73 healthy controls were studied. Sixty seven patients had ulcerative colitis, 78 had Crohn's disease (52 of them (66.7%) had ileal disease), and seven had indeterminate colitis. Bone mineral density values (g/cm2) measured by dual energy x ray absorbtiometry at the spine (L2-L4), the femoral neck, Ward's triangle, and the trochanter were 1.177, 0.948, 0.850, and 0.838 in the patients and 1.228 (p = 0.034), 1.001 (p = 0.009), 0.889 (NS), and 0.888 (p = 0.012) in the control group, respectively. The type or extent of the disease or previous small bowel resection did not have any significant effect on the bone mineral density values. There was a weak, but statistically significant negative correlation between bone mineral density and the total lifetime corticosteroid dose (in the lumbar spine r = -0.164, p = 0.04, the femoral neck r = -0.185, p = 0.02, Ward's triangle r = -0.167, p = 0.04, and the trochanter r = -0.237, p = 0.003). The patients whose lifetime corticosteroid dose (prednisone/prednisolone) was more than 10 g had especially low bone mineral density (p < 0.05 compared with the groups with no or less than 5 g of corticosteroid). The patients who had never taken peroral corticosteroids did not have decreased bone mineral density. In conclusion, IBD patients have significantly lower bone mineral density values than healthy controls, but the difference is not so great as has been reported previously. Low bone mineral density values in these patients are related to high lifetime corticosteroid doses.

Significance of systemic endotoxaemia in inflammatory bowel disease.

Abstract: Quantitative and qualitative disturbances in faecal flora suggest a role for enteric bacteria and their products in the pathogenesis of inflammatory bowel disease (IBD). This study investigated the hypothesis that systemically circulating endotoxins are of pathogenic significance in IBD by measuring antibody, cytokine, and acute phase protein responses. Systemic endotoxaemia was found in 88% patients with ulcerative colitis (n = 25) and 94% with Crohn's disease (n = 31) during clinical relapse. Systemic endotoxaemia correlated positively with anatomic extent and clinical activity of ulcerative colitis. Circulating tumour necrosis factor (TNF) was detected in 40% of patients with ulcerative colitis and 45% with Crohn's disease. Plasma TNF concentrations correlated with clinical and laboratory measures of disease activity and were associated with a surgical outcome to the disease episode. Plasma soluble TNF receptor p55 concentration correlated positively with disease activity and endotoxin core antibody concentrations. Plasma IgG endotoxin core antibody concentrations were significantly increased in patients with Crohn's disease and correlated with systemic endotoxaemia. The presence of systemic endotoxaemia, its correlation with disease activity, disease extent, and endotoxin core antibody concentration and the detection of circulating TNF and soluble TNF receptors all support a pathogenic role for endotoxins in IBD.

Adhesion molecules in inflammatory bowel disease.

Abstract: The ability of leucocytes to adhere to endothelium is essential for leucocyte migration into inflammatory sites. Some of these adhesion molecules are released from the cell surface and can be detected in serum. The soluble adhesion molecules intercellular adhesion molecule 1 (ICAM-1), E selectin, and vascular cell adhesion molecule 1 (VCAM-1) were studied in the serum of patients with Crohn's disease, ulcerative colitis, and healthy controls. A second blood sample was taken from patients with active disease after one month of treatment and a third two months after remission was achieved. Tissue expression of the same adhesion molecules was studied by immunohistology. Circulating VCAM-1 concentrations were significantly higher in patients with active ulcerative colitis (n = 11, median = 165 U/ml) compared with patients with inactive ulcerative colitis (n = 10, median = 117 U/ml, p < 0.005), active Crohn's disease (n = 12, median = 124 U/ml, p < 0.02), and controls (n = 90, median = 50 U/ml, p < 0.0001). Within each disease group there were no significant differences in E selectin or ICAM-1 concentrations between the active and inactive states, however, patients with active Crohn's disease had significantly higher ICAM-1 concentrations (n = 12, median = 273 ng/ml) than controls (n = 28, median = 168, p < 0.003). VCAM-1 concentrations fell significantly from pretreatment values to remission in active ulcerative colitis (p < 0.01). In Crohn's disease there was a significant fall in ICAM-1 both during treatment (p < 0.01) and two months after remission (p < 0.02). Vascular expression of ICAM-1 occurred more often and was more intense in inflamed tissue sections from patients with ulcerative colitis and Crohn's disease than from controls. Vascular labelling with antibody to E selectin also occurred more often in patients with active inflammatory bowel disease. In conclusion, increased circulating concentrations of selected adhesion molecules are associated with inflammatory bowel disease. There is also evidence of local upregulation, particularly of ICAM-1. Differential expression of adhesion molecules in tissue may play a part in the initiation of leucocyte migration and local inflammation; the function of circulating adhesion molecules is unknown, but may play a physiological part in blocking adhesion.

Loss of CD4 T lymphocytes in patients infected with human immunodeficiency virus type 1 is more pronounced in the duodenal mucosa than in the peripheral blood. Berlin Diarrhea/Wasting Syndrome Study Group.

Abstract: Although changes in T lymphocyte subset distribution in the peripheral blood of patients infected with human immunodeficiency virus (HIV) are well defined it is not known whether these changes reflect changes in lymphoid compartments clearly involved in HIV related disease like the intestinal mucosa. This study analysed lymphocytes isolated simultaneously from the peripheral blood and duodenal biopsy specimens by three colour flow cytometry in eight asymptomatic HIV infected patients, 26 AIDS patients, and 23 controls. The proportion of CD4, CD8, CD4-CD8-, or gamma delta T cells did not correlate between circulating and duodenal T cells. CD4 T cells were reduced in the peripheral blood (7.5% (25th-75th percentile, 2-16%) v 52% (41-63%), p < 0.0005) and even more reduced in the duodenum (1% (1-2%) v 36% (23-57%), p < 0.0005) of AIDS patients compared with controls. Patients with asymptomatic HIV infection had intermediate CD4 T cells in the peripheral blood (24% (22-35%); p < 0.002 v controls; p < 0.01 v AIDS) but like AIDS patients very low CD4 T cells in the duodenum (3% (1-6%); p < 0.002 v controls). The ratio of duodenal to circulating CD4+ T cells was significantly reduced to 0.2 (0-1) in AIDS patients (p < 0.001) and even to 0.1 (0.04-0.5) in asymptomatic HIV infected patients (p < 0.002) compared with 0.72 (0.44-0.95) in controls. These findings show an early and preferential loss of duodenal CD4 T cells in HIV infection. Immunological abnormalities in HIV infection are distinct between lymphoid compartments, and profound immunodeficiency may occur in the intestinal immune system although circulating T cells are largely preserved.

Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole.

Abstract: To test the hypothesis that Helicobacter pylori infection is associated with a decreased intragastric acidity during omeprazole therapy, ambulatory 24 hour dual point gastric pH recordings were performed in 18 H pylori positive and 14 H pylori negative subjects. There was a four to six week washout period between the two pH recordings made in each subject after one week courses of placebo or omeprazole, 20 mg daily. During placebo, median 24 hour pH values were not different in the corpus (H pylori positive = 1.5, negative = 1.4; p = 0.9) or antrum (H pylori positive = 1.3, negative = 1.2; p = 0.1). However, during omeprazole treatment, median 24 hour pH values were higher in H pylori positive subjects, both in the corpus (H pylori positive = 5.5, negative = 4.0; p = 0.001) and antrum (H pylori positive = 5.5, negative = 3.5; p = 0.0004). During placebo treatment, the only difference between the two groups was a higher later nocturnal pH in the antrum in the H pylori positive group. During omeprazole treatment, gastric pH was higher both in the corpus and in the antrum in the H pylori positive group for all periods, except for mealtime in the corpus. These data indicate that omeprazole produces a greater decrease in gastric acidity in subjects with H pylori infection than in those who are H pylori negative. It is not, however, known whether there is a causal relationship between H pylori infection and increased omeprazole efficacy.

Colonic mucin synthesis is increased by sodium butyrate.

Abstract: The effects of sodium butyrate and sodium bromo-octanoate (an inhibitor of beta oxidation) on colonic mucus glycoprotein (mucin) synthesis have been assessed using tissue from colonic resection samples. Epithelial biopsy specimens were incubated for 16 hours in RPMI 1640 with glutamine, supplemented with 10% fetal calf serum and N-acetyl-[3H]-glucosamine ([3H]-Glc NAc), and differing concentrations of sodium butyrate. Incorporation of [3H] Glc NAc into mucin by normal epithelium at least 10 cm distant from colonic cancer was increased in the presence of sodium butyrate in a dose dependent manner, with maximum effect (476%) at a concentration of 0.1 mM (number of specimens = 24 from six patients, p < 0.001). The increase in response to butyrate was not seen when specimens were incubated in the presence of the beta oxidation inhibitor sodium bromo-octanoate 0.05 M. The striking increase in mucin synthesis that results when butyrate is added to standard nutrient medium suggests that this may be an important mechanism affecting the rate of mucin synthesis in vivo and may also explain the therapeutic effect of butyrate in colitis.

Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity.

Abstract: Enhanced nitric oxide (NO) generation by stimulated NO synthase (NOS) activity may, through its oxidative metabolism contribute to tissue injury in experimental colitis. In this study the possible amelioration of experimental colitis by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS activity, was evaluated. Colitis was induced in rats by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB) dissolved in 0.25 ml 50% ethanol or by flushing the colon of capsaicin pretreated rats with 2 ml of 5% acetic acid. In several experiments, L-NAME 0.1 mg/ml was added to the drinking water at the time of colitis induction with TNB or seven days before acetic acid treatment. Rats were killed at various time intervals after induction of colitis. A 10 cm distal colonic segment was isolated, weighed, lesion area measured, and explants organ cultured for 24 hours for determination of NO generation by the Greiss reaction. The rest of the mucosa was scraped for determination of myeloperoxidase and NOS activities and leukotriene generation. In TNB treated rats mean arterial pressure was also determined up to 72 hours after damage induction, with or without cotreatment with nitroprusside. L-NAME significantly decreased the extent of tissue injury in TNB treated rats. Seven days after TNB treatment lesion area was reduced by 55%, colonic weight by 37%, and myeloperoxidase and NOS activity by 59% and 42%, respectively. Acetic acid induced colitis in capsaicin pretreated rats was also significantly decreased by L-NAME. Twenty four hours after acetic acid treatment lesion area was reduced by 61%, colonic weight by 21% and NOS activity by 39%. Mean (SEM) arterial blood pressure in TNB+L-NAME treated rats was 37.6 (8.1) mm Hg higher than in TNB treated rats, an effect that was only partially abolished by nitroprusside. These results show that inhibition of NO synthesis by an L-arginine analogue significantly ameliorates the extent of tissue injury in two models of experimental colitis, an effect that is not due only to its vasoconstrictor properties. Modulation of NO generation may be a novel therapeutic approach in inflammatory bowel disease.

Efficacy and safety of hydrostatic balloon dilatation of ileocolonic Crohn's strictures: a prospective longterm analysis.

Abstract: Preliminary reports have suggested that dilatation using hydrostatic through the scope balloons may be useful for the treatment of Crohn's strictures, A prospective longterm follow up (mean (SD) 33.6 (11.2) months) was carried out in 55 Crohn's patients with 59 ileocolonic strictures submitted to 78 dilatation procedures. Hydrostatic balloons were used (Rigiflator, Microvasive) with a diameter of 18 mm on inflation. As soon as the balloons became available dilatation up to a diameter of 20 and 25 mm was attempted. The dilatations were performed under general anaesthesia using propofol (Diprivan). The patients were kept for one night in the hospital after dilatation. Seventy (90%) procedures were technically successful and passage of the stricture with a 13.6 mm diameter colonoscope was possible after 73% of the dilatations. Complications occurred in six patients (11%; 8% of procedures), including sealed perforations (n = 2), retroperitoneal perforations (n = 2), and intraperitoneal perforations (n = 2). Two of the patients were treated surgically with a one stage resection of the stricture and recovered uneventfully. Four patients were treated conservatively with intravenous fluids and antibiotics. There was no mortality. Dilatation completely relieved obstructive symptoms in 20 patients after one procedure, in another 14 patients after two (n = 13) or three (n = 1) dilatations. Total longterm success rate was 34 of 55 patients (62%). Nineteen patients (38%) were operated on because of persistent obstructive symptoms. The data show that endoscopic dilatation using the through the scope hydrostatic balloon system relieves obstructive symptoms resulting from ileocolonic Crohn's strictures. The procedure, however, carries a definite risk of perforation.

Cross linking of collagen is increased in colonic diverticulosis.

Abstract: Development of colonic diverticulosis is a function of age and declining colonic wall mechanical strength. The latter is partly a consequence of changes in the collagen structure. Collagen from unaffected human colons (n = 20, age range 20-80 years) and those with colonic diverticulosis (n = 5, age range 67-80 years) were obtained at necropsy. The total collagen content was measured as the hydroxyproline content and cross linkage by collagen solubility in weak acid was studied. The colonic total collagen content was constant with age (mean (SD) 15.8 (0.3) mg/100 mg wet weight of tissue). The acid solubility of the collagen, however, increased after the age of 40 years: at over 60 years, colonic diverticulosis was associated with an increased acid solubility ratio compared with values in unaffected colons (15.3 (0.2); compared with 9.2 (0.2), p < 0.001). The cross linking of colonic collagen increases with age. These changes seem to be a factor in the aetiology of colonic diverticulosis.

Cell proliferation in Helicobacter pylori associated gastritis and the effect of eradication therapy.

Abstract: Helicobacter pylori causes chronic (type B) gastritis. The 'intestinal' form of gastric cancer arises against a background of chronic gastritis, and prospective epidemiological studies have shown that H pylori is a major risk factor for this. An increase in mucosal cell proliferation increases the likelihood of a neoplastic clone of epithelial cells emerging where there is chronic epithelial cell injury associated with H pylori gastritis. In vitro bromodeoxyuridine labelling of endoscopic antral biopsy specimens was used to measure mucosal cell proliferation in H pylori associated gastritis before and after therapy for H pylori triple infection. Cell proliferation was increased in H pylori associated gastritis patients compared with normal controls and patients with H pylori negative chronic gastritis (p = 0.0001; Tukey's Studentised range). There was no difference in antral epithelial cell proliferation between duodenal ulcer and non-ulcer subjects infected with H pylori (p = 0.62; Student's t test). Antral mucosal cell proliferation fell four weeks after completing triple therapy, irrespective of whether or not H pylori had been eradicated (p = 0.0001). At retesting six to 18 months later (mean = 12 months), however, those in whom H pylori had not been successfully eradicated showed increased mucosal proliferation compared with both H pylori negative subjects at a similar follow up interval and all cases (whether H pylori positive or negative) four weeks after completion of triple therapy (p = 0.024). These findings suggest that H pylori infection causes increased gastric cell proliferation and in this way may play a part in gastric carcinogenesis.

Pelvic and perineal complications of Crohn's disease: assessment using magnetic resonance imaging.

Abstract: This study evaluated the role of magnetic resonance imaging (MRI) in the demonstration of the pelvic and perianal complications of Crohn's disease. Twenty five patients with active Crohn's disease were studied (12 male; mean age 41.1 years). MRI examinations were performed using a 1.5 Tesla system, within 14 days after clinical assessment. T1 and T2 weighted fast spin echo sequences in two or three orthogonal planes were performed, with fat suppression in some cases. The MRI results were correlated with surgical and clinical findings. In 16 patients, cutaneous, deep perineal or enterovesical fistulas or abscesses were diagnosed at MRI which showed close correlation with findings at examination under anaesthetic. In eight patients no fistulas or abscesses were seen at MRI nor was there any evidence of complications on clinical examination and flexible sigmoidoscopy. There was one false negative examination in a patient who had a colovesical fistula. In conclusion, MRI can accurately show the pelvic and perineal complications of Crohn's disease and may render examination under anaesthetic unnecessary.

Diagnosis of pancreatic cancer by 2[18F]-fluoro-2-deoxy-D-glucose positron emission tomography.

Abstract: The detection of pancreatic cancer or the discrimination between pancreatic cancer and chronic pancreatitis remains an important diagnostic problem. The increased glucose metabolism in malignant tumours formed the basis for this investigation, which focused on the role of positron emission tomography (PET) with 2[18F]-fluoro-2-deoxy-D-glucose (FDG) in the detection of pancreatic cancer and its differentiation from chronic pancreatitis. Eighty patients admitted for elective pancreatic surgery received preoperatively 250-350 mBq FDG intravenously and emission scans were recorded 45 minutes later. Intense focal activity in the pancreatic region was taken at the time of scanning as showing the presence of pancreatic cancer. The presence of cancer was later confirmed by histological examination of the surgical specimens and histological findings were compared with the preoperative PET results. Forty one patients with pancreatic cancer (group I: n = 42) had a focally increased FDG uptake in the pancreatic region. Two patients with a periampullary carcinoma (group II: n = 6) failed to develop FDG accumulation. In 28 patients with chronic pancreatitis (group III: n = 32) no FDG accumulation occurred. Overall sensitivity and specificity of PET for malignancy (group I + II) were 94% (45 of 48) and 88% (28 of 32), respectively. The standard uptake value of the patients with pancreatic carcinoma was significantly higher than in patients with chronic pancreatitis (3.09 (2.18) v 0.87 (0.56); p < 0.001; median (interquartile range)). These findings show that FDG-PET represents a new and non-invasive diagnostic procedure for the diagnosis of pancreatic cancer and to differentiate pancreatic cancer from chronic pancreatitis. However, the diagnostic potential of this technique requires further evaluation.

Prospective study of physical activity and the risk of symptomatic diverticular disease in men.

Abstract: The relationship between physical activity and risk of symptomatic diverticular disease has not been investigated directly. This association was examined in a prospective cohort of 47,678 American men, 40 to 75 years of age, and free of diagnosed diverticular disease, colon or rectal polyp, ulcerative colitis, and cancer before 1988. During four years of follow up, 382 newly diagnosed cases of symptomatic diverticular disease were documented. After adjustment for age, energy adjusted dietary fibre, and energy adjusted total fat, overall physical activity was inversely associated with the risk of symptomatic diverticular disease (for highest versus lowest extremes, relative risk (RR) = 0.63 (95% confidence interval (CI) 0.45, 0.88). Most of the inverse association was attributable to vigorous activity, for extreme categories RR = 0.60 (95% CI 0.41, 0.87). For activity that was not vigorous the RR was 0.93 (95% CI 0.67, 1.69). Several specific activities were inversely associated with the risk of diverticular disease, but jogging and running combined was the only individual activity that was statistically significant (p for trend = 0.03). For men in the lowest quintile for dietary fibre intake and total physical activity (compared with those in the opposite extreme), the RR was 2.56 (95% CI 1.36, 4.82). Physical activity, along with a high fibre diet, may be an important factor in the prevention of symptomatic diverticular disease.

Satiety effects of a physiological dose of cholecystokinin in humans.

Abstract: Cholecystokinin 33 (CCK) was infused intravenously to eight healthy obese women and 10 healthy lean women of the same age, in doses that elicited plasma cholecystokinin concentrations in the physiological range. The effect of these infusions after a standardised banana 'shake' (preload) on food intake and satiety signals was compared with the effect of saline infusions in the same subjects. For the whole group food intake (mean (SEM)) (282 (29 g)) was significantly less during CCK than during saline (346 (31) g, p < 0.05). Hunger feelings tended to be less during CCK infusions. Examination of the separate subgroups showed no differences between lean and obese subjects in the satiety effects of CCK. In conclusion, under the conditions of this study, CCK significantly decreases food intake in humans, and this effect is similar for lean and obese subjects.

Osteoporosis in treated adult coeliac disease

Abstract: Forty five women and 10 men with coeliac disease diagnosed in adult life, who were already on a gluten free diet, had serial bone mineral density measurements at the lumbar spine and femoral neck over 12 months. Osteoporosis, defined as a bone mineral density (BMD) < or = 2 SD below the normal peak bone mass was found in 50% of male and 47% of female coeliac patients. Patients with a BMD < or = 2 SD below age and sex matched normal subjects, had a significantly lower body mass index (21.3 kg.m-2 compared with 25.2 kg.m-2, p < 0.02 Wilcoxon rank sum test) and lower average daily calcium intake (860 mg/day compared with 1054 mg/day, p < 0.05 Wilcoxon rank sum test) than patients with normal bone mineral density. In postmenopausal women with coeliac disease there was a strong correlation between the age at menopause and BMD at both the lumbar spine (r = 0.681, p < 0.01, Spearman's rank correlation) and femoral neck (r = 0.632, p < 0.01). No overall loss of bone was shown over the 12 months of follow up, and relative to the reference population there was a significant improvement in BMD at the lumbar spine in women (p < 0.025, paired t test) and at the femoral neck in men (p < 0.05, paired t test). There was a significant negative correlation between the annual percentage change in BMD at the lumbar spine and the duration of gluten free diet (r = -0.429, p<0.01, Spearman's rank correlation), with the largest gain in BMD in patients with most recently diagnosed coeliac disease. Osteoporosis was shown in 47% of patients with treated adult coeliac disease. Recognised risk factors for osteoporosis in the general population including low body mass index, dietary calcium intake, and early menopause are particularly important in coeliac disease. Treatment of coeliac disease with a gluten free diet probably protects against further bone loss, and in the early stages is associated with a gain in bone mineral density.

Collagenous colitis in Orebro, Sweden, an epidemiological study 1984-1993.

Abstract: The incidence and prevalence of collagenous colitis are unknown. An epidemiological study was undertaken between 1984-93. All patients living in the immediate catchment area of Orebro Medical Center Hospital with the diagnosis collagenous colitis were identified. Biopsy specimens classified as unspecific intestinal fibrosis were re-examined to identify cases not correctly diagnosed at first. Medical records were scrutinised and colorectal biopsy specimens re-evaluated. Thirty patients with collagenous colitis were diagnosed during the study period. The female:male ratio was 9:1. The median age at diagnosis was 64 (28-78) years. The prevalence at 31 December 1993, was 15.7/10(5) inhabitants (95% CI; 9.8 to 21.6/10(5)). The mean annual incidence during the period 1984-93 was 1.8/10(5) inhabitants (95% CI; 1.2 to 2.4/10(5)). A peak incidence was found in women 70-79 years old. Collagenous colitis occurs mainly in middle aged women, and the frequency is higher than earlier anticipated. The prevalence and incidence is similar to primary biliary cirrhosis. In women 70-79 years of age, the incidence for collagenous colitis approaches the incidence for ulcerative colitis.

Kinetic studies on colonocyte metabolism of short chain fatty acids and glucose in ulcerative colitis.

Abstract: Short chain fatty acids (SCFAs) are potentially valuable as a topical therapy for distal ulcerative colitis. The mechanism of action is unknown but may involve improved intracellular energy production as previous evidence indicates that colonocyte oxidation of butyrate is impaired in ulcerative colitis. No information is, however, available on human mucosal metabolism of acetate and propionate in either health or disease or the Vmax and Km values of butyrate oxidation. The aim of the study was to assess the kinetic parameters, Vmax and Km, of the complete oxidation of short chain fatty acids and glucose by human colonocytes and to explore whether a metabolic abnormality could be confirmed in patients with ulcerative colitis. Colonocytes were isolated from surgical specimens obtained from 14 patients with ulcerative colitis and eight control subjects. Incubations were performed in the presence of a concentration range of 14C-labelled acetate, propionate butyrate, and glucose. Oxidation rates were obtained by quantifying the production of 14CO2. Vmax and Km were calculated by computer fitting of the data to a Michaelis-Menten plot. No significant differences were shown in either Vmax or Km values of any of the SCFAs or glucose comparing controls and patients with ulcerative colitis. Comparing the results obtained regarding the individual SCFAs, the most striking difference was the considerably lower Km value of butyrate. The apparent Vmax of acetate tended to be higher than Vmax of propionate and butyrate. Vmax of glucose oxidation was significantly lower compared with the Vmax values of SCFA oxidation. The study shows the ability of isolated human colonocytes to utilise each of the three major SCFAs, but does not support a pathogenic role for defective metabolism of butyrate in ulcerative colitis. The considerably lower Km of butyrate oxidation supports a specific role of butyrate as an energy source for the colonic mucosa in both health and ulcerative colitis.