[Infliximab--practical guidelines for the treatment of Crohn's disease]. / Infliximab--recommandations pratiques pour te traitement de la maladie de Crohn.

Infliximab is a monoclonal chimeric antibody, with high affinity and specificity for tumour necrosis factor alpha (TNFalpha) that plays a central role in the pathogenesis of immune mediated inflammatory disorders including Crohn's disease and ulcerative colitis. Globally over 600000 patients have been treated with infliximab to date. This global experience led to a better definition of the overall safety and efficacy profile of this medication. The goal of the present recommendations is to provide practical information to physicians involved in the care of patients with inflammatory bowel disease.

[Patients with inflammatory bowel disease in specialist gastroenterology practice: a prospective survey]. / Patienten mit chronisch-entzündlichen Darmkrankheiten in der gastroenterologischen Praxis: Eine prospektive Beobachtungsstudie.

PRINCIPLES: Ulcerative colitis (UC) and Crohn's disease (CD) are chronic relapsing disorders with significant implications for health care. The latest epidemiological data for Switzerland were prospectively collected in 1971. METHODS: A prospective nationwide survey over a period of five weeks was initiated by IBDNet.ch and a questionnaire sent to all gastroenterologists in hospital or private practice. RESULTS: The response rate was 42% (85/204). 930 patients were recorded, 505 (54.3%) had CD, 425 (44.9%) UC, male/female ratio was 47 vs. 53%, mean age 44 +/- 15.8 years (standard deviation, SD). Median duration of disease was 84 months (mean 101 +/- 3.15 SEM). In CD, intestinal involvement was colitis in 135 (26.7%), ileitis in 142 (28.1%) and ileocolitis in 228 (45.2%) patients. In UC, (n = 425) pancolitis was present in 182 (43.5%), left-sided colitis in 140 (33.6%) and proctitis in 95 (22.9%) cases. Diarrhea was the main symptom (52.8%; CD/UC: 47.5% vs. 59.2%; p < 0.001), as well as abdominal pain 35.8% (CD/UC: 48.5% vs. 20.1%; p < 0.001), rectal bleeding 27.8% (CD/UC: 8.4% vs. 51.8%; p < 0.001). Weight loss was reported in 12.2% (CD/UC: 14% vs. 9.8%), anemia in 15.1% ( CD/UC: 14.8% vs. 15.3%). The mean number of medications per patient was 2.1 (+/- 1.2SD), CD/UC 2.4 vs. 1.9 (p < 0.001). 5-ASA preparations per os were used in 74%, topical treatment in 18% in both groups. Corticosteroids CD/UC 56.5%/54%, oral or topical budesonide (CD/UC: 19% vs. 16%; CD/UC: 1.9% vs. 2.1%). Antibiotics (18%) or immunomodulatory therapy, as well as infliximab, was similar in both groups. Inflammatory bowel disease related surgery was performed in 233 (25.4%): resection of stenosis or in fistula 132 (14.2%), colectomy (total and subtotal) in 70 (7.5%), colostomy in situ in 21 patients (2.3%). Extraintestinal manifestations occurred in 36.6%, significantly more in patients with CD vs. UC: 25% vs. 16% (p < 0.001). Arthritis 18.6% (CD/UC: 22.6 vs. 13.7%, p < 0.001) and osteoporosis were recorded in 9.7% (CD/UC: 13.65 vs. 4.8%, p < 0.001). Skin and eye involvement was seen in 6.3% and 2% respectively (CD/UC: 7.8 vs. 4.5% and 3.1 vs. 1%, p = n.s.). CONCLUSION: In conclusion, we attempted to characterise the patients with IBD seen by specialist gastroenterologists in Switzerland. The ultimate goal would be to set up a national cohort study to collect long-term data, which could be useful for epidemiological studies in patient and health care management, as well as for therapeutic intervention studies and basic research.

Regulation of gastric function by endogenous gastrin releasing peptide in humans: studies with a specific gastrin releasing peptide receptor antagonist.

BACKGROUND AND AIMS: The main goal of our study was to characterise the activity of BIM26226 as a peripheral gastrin releasing peptide (GRP) receptor antagonist in healthy human subjects and to determine if endogenous GRP is a physiological regulator of gastric acid secretion and gastrin release. METHODS: Our study consisted of three parts. In part I, subjects received saline or BIM26226 followed by graded doses of intravenous human GRP in a four period crossover design. In part II, subjects received BIM26226 or saline during oral meal ingestion or modified sham feeding. In part III, subjects received an acidified meal in the presence and absence of BIM26226 in a two period crossover design. In addition, gastrin and somatostatin mRNA were measured in biopsy specimens during saline and BIM26226 infusion. RESULTS: BIM26226 dose dependently inhibited GRP induced acid output. Acid secretion after oral liquid meal intake and sham feeding was significantly inhibited by BIM26226 (p<0.01) whereas plasma gastrin release remained unchanged. Gastrin and somatostatin mRNAs were not significantly different after saline or BIM26226. CONCLUSIONS: BIM26226 is a potent GRP antagonist in humans. Endogenous GRP may be a physiological regulator of gastric acid secretion. Gastrin release does not seem to be under the control of GRP.

Screening of patients with acute infectious diarrhoea: evaluation of clinical features, faecal microscopy, and faecal occult blood testing.

BACKGROUND: For optimal management of acute infectious diarrhoeal diseases, it is necessary to utilize a screening process to distinguish between invasive and non-invasive diarrhoeas. The aim of this study was to compare the diagnostic utilities of clinical features, faecal microscopy (FM), and faecal occult blood testing (FOBT) in distinguishing invasive diarrhoeas from non-invasive ones. METHODS: A total of 1008 patients with acute diarrhoea were evaluated. Rectal swabs were cultured for Salmonella, Shigella, and Vibrio species; rectal swabs from 109 of these patients were also examined for Campylobacter, enterotoxigenic Escherichia coli, and rotavirus species. Isolation of faecal enteropathogens served as the gold standard. FOBT was performed with a commercial modified guaiac test. Specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and likelihood ratio were compared. RESULTS: Among the 1008 patients 402 with a single identified enteropathogen were available for analysis. Invasive and non-invasive enteropathogens were isolated from 262 (65.2%) and 140 (34.8%) cases, respectively. The presence of visible blood in faeces was almost a pathognomonic sign of invasive diarrhoea but had poor sensitivity. Clinical features were useful but inadequate in differentiating patients with non-bloody diarrhoea (74% of patients) into invasive and non-invasive categories. The sensitivities, specificities, PPVs, and NPVs of FM and FOBT were 75%, 77%, 58%, 88%, and 85%, 68%, 53%, and 91%, respectively. CONCLUSION: The presence of visible blood in faeces is a highly specific clinical feature of invasive diarrhoea but suffers from low sensitivity. In non-bloody diarrhoea FOBT is a valuable screening test and is comparable to FM, particularly when interpreted in the clinical context.

Human colonic subepithelial myofibroblasts modulate transepithelial resistance and secretory response.

The epithelium of the gastrointestinal tract transports ions and water but excludes luminal microorganisms and toxic molecules. The factors regulating these important functions are not fully understood. Intestinal myofibroblasts lie subjacent to the basement membrane, at the basal surface of epithelial cells. We recently showed that primary cultures of adult human colonic subepithelial myofibroblasts express cyclooxygenase (COX)-1 and COX-2 enzymes and release bioactive transforming growth factor-beta (TGF-beta). In this study we have investigated the role of normal human colonic subepithelial myofibroblasts in the regulation of transepithelial resistance and secretory response in HCA-7 and T84 colonic epithelial cell lines. Cocultures of epithelial cells-myofibroblasts and medium conditioned by myofibroblasts enhanced transepithelial resistance and delayed mannitol flux. A panspecific antibody to TGF-beta (but not piroxicam) antagonized this effect. In HCA-7 cells, myofibroblasts downregulated secretagogue-induced change in short-circuit current, and this effect was reversed by pretreatment of myofibroblasts with piroxicam. In contrast to HCA-7 cells, myofibroblasts upregulated the agonist-induced secretory response in T84 cells. This study shows that intestinal subepithelial myofibroblasts enhance barrier function and modulate electrogenic chloride secretion in epithelial cells. The enhancement of barrier function was mediated by TGF-beta. In contrast, the modulation of agonist-induced change in short-circuit current was mediated by cyclooxygenase products. These findings suggest that colonic myofibroblasts regulate important functions of epithelial cells via distinct secretory products.

TGF-alpha reduces bradykinin-stimulated ion transport and prostaglandin release in human colonic epithelial cells.

The effect of chronic exposure to transforming growth factor-alpha (TGF-alpha) on bradykinin-stimulated acute prostanoid production and ion secretion in monolayers of HCA-7 colony 29 colonic epithelial cells has been studied. Monolayers synthesized prostaglandin E2 (PGE2) at a basal rate of 2.10 +/- 0.31 pg. monolayer-1. min-1 over 24 h. Bradykinin (10(-8)-10(-5) M) dose dependently increased acute PGE2 release by three orders of magnitude. This was associated with a rise in cAMP from 1.60 +/- 0.14 to 2.90 +/- 0.1 pmol/monolayer (P < 0.02) and a dose-dependent increase in short-circuit current (SCC). When monolayers were primed by a 24-h exposure to TGF-alpha, basal PGE2 release rose to 6.31 +/- 0.38 pg. monolayer-1. min-1 (TGF-alpha concn 10 ng/ml; P = 0.001). However, the stimulation of acute prostaglandin release, intracellular cAMP, and increased SCC by bradykinin was significantly reduced by preincubation with TGF-alpha. Priming with PGE2 (10(-8)-10(-6) M) over 24 h mimicked the effect of TGF-alpha on bradykinin-induced changes in cAMP and SCC. These data suggest that enhanced chronic release of prostaglandins in response to stimulation with TGF-alpha may downregulate acute responses to bradykinin. In vivo, TGF-alpha could have an important modulatory function in regulating secretion under inflammatory conditions.

Effects of spiroglumide, a gastrin receptor antagonist, on acid secretion in humans.

BACKGROUND: A gastrin receptor antagonist, CR2194 (spiroglumide), was used to explore the physiological role of gastrin in regulating gastric acid secretion in humans. MATERIALS AND METHODS: The effect of CR2194 on inhibition of gastrin-stimulated acid output was evaluated in a four-period crossover study. Each subject received intravenous doses of 1, 2.5 or 7.5 mg kg-1 h-1 CR2194 or saline (control) followed by graded increasing doses of gastrin (6.4-800 pmol kg-1 h-1). Secondly, the effect of CR2194 on meal-stimulated intragastric acidity was evaluated by infusing either saline (control) or CR2194 (7.5 mg kg-1 h-1) before and after food ingestion. RESULTS: Acid secretion was dose-dependently inhibited by CR2194. With CR2194, acidity was significantly reduced in the pre-meal and post-prandial period (P < 0.01 and 0.002 respectively), and the integrated gastrin response was augmented to 8.0 +/- 1.4 ng mL-1 240 min compared with 1.5 +/- 0.8 ng mL-1 240 min in the control experiment (P < 0.01). Finally, acid secretion in response to sham feeding was significantly reduced: 15.9 +/- 0.9 mmol 90 min-1 in the control experiment compared with 2.8 +/- 0.9 mmol 90 min-1 during CR2194 infusion (P < 0.05). CONCLUSION: Gastrin receptor blockade with CR2194 alters gastric acid secretion in response to food ingestion or to sham feeding. The results support a physiological role for gastrin in regulating acid secretion in humans.

Immunological testing for occult blood in patients with acute infectious diarrhea. Can it improve the specificity of the guaiac test?

Microscopic stool examination can distinguish inflammatory from noninflammatory diarrheas. The modified guaiac test was shown to have good correlation to stool microscopy. In a prospective study we evaluated the diagnostic accuracy of a modified guaiac test (Colo-Rectal-Test, Roche) and of an immunological test for fecal haemoglobin (Colo-Immun-Test, Roche) in relation to the diarrheal pathogens identified and compared it with the stool microscopy. In 304 patients, clinical presentation, stool microscopy, stool culture, and modified guaiac test were recorded. Sensitivity of the guaiac test was 69% as compared to 63-67% for the stool microscopy. Specificity could be improved by 10-15% using an immunological test to exclude false-positive guaiac reactions. A modified guaiac test can replace microscopic stool examination to distinguish between inflammatory and non-inflammatory diarrhea. Immunological testing for occult blood can improve the specificity of the guaiac test, but is too elaborate to serve as a screening test. The modified guaiac test can easily be handled by community health workers and could be important in the diagnostic work-up for acute infectious diarrhea.

Adult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and -2.

Interactions between epithelial cells and subepithelial myofibroblasts are increasingly recognized as important in the regulation of epithelial cell function. We have established primary cultures of subepithelial myofibroblasts from adult human colonic mucosal samples denuded of epithelial cells and maintained in culture. During culture of mucosal tissue, subepithelial myofibroblasts migrated out via basement membrane pores before establishment in culture. Despite prolonged culture and passage, the myofibroblasts maintained their phenotype, as demonstrated by expression of alpha-smooth muscle actin and vimentin. The cells expressed transcripts and protein for cyclooxygenase (COX)-1 and -2 enzymes, and their release of prostaglandin E2 (PGE2) was inhibited by selective COX-1 and -2 inhibitors. The myofibroblasts also expressed the extracellular matrix (ECM) proteins collagen type IV, laminin-beta 1 and -gamma 1, and fibronectin. Adult human colonic subepithelial myofibroblasts may influence epithelial cell function via products of COX-1 and -2 enzymes, such as PGE2 and secreted ECM proteins.

[Upper influx distension in a patient with HIV; unusual localization of an HIV-associated lymphoma]. / Obere Einflussstauung bei einem HIV-Patienten: ungewöhnliche Lokalisation eines HIV-assoziierten Lymphoms.

A 33 year old patient was admitted to the hospital because of deteriorated general condition, upper abdominal pain and progressive dyspnea. He had a positive HIV-serology associated with i.v. drug abuse. The CDC classification on admission was B1. There was no history of opportunistic infections, the patient had refused all prophylactic treatment. The physical examination showed an elevated central venous pressure, decreased breath-sound and percussible dullness, the liver was enlarged and a tumor was palpable on chest. The x-ray of the thorax confirmed a pleural effusion. Cytology of the effusion revealed blasts of malignant non-Hodgkin's lymphoma of B-cell type. A CT-scan of the thorax and abdomen showed a tumor mass in the right ventricle and superior vena cava, a pleural effusion and multiple lesions in the liver. The patient refused a palliative chemotherapy with vincristine and prednisone and died few days after admission.