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Notes: Background:  The ligation of CD40 by CD154 is a critical step in the interaction between APC and T cells. In animals, antagonizing CD40L-CD40 has been shown to reduce the severity of several autoimmune and inflammatory disorders, including experimental colitis.Aim:  To investigate tolerability and safety of an antagonist chimeric monoclonal anti-human CD40 antibody (ch5D12) for treatment of Crohn's disease.Method:  ch5D12 was administrated to 18 patients with moderate to severe Crohn's disease in a single dose, open-label dose-escalation phase I/IIa study.Results:  ch5D12 plasma concentrations increased dose-dependently after infusion. Two patients developed an anti-ch5D12 antibody response. Overall response and remission rates were 72 and 22%, respectively with no evidence for a dose–response effect. Treatment with ch5D12 reduced microscopic disease activity and intensity of the lamina propria cell infiltrate, but did not alter percentages of circulating T and B cells. ch5D12 was well tolerated, although some patients experienced headache, muscle aches, or joint pains, which may have been related to the study drug.Conclusions:  Antagonizing CD154–CD40 interactions with ch5D12 is a promising therapeutic approach for remission induction in Crohn's disease.

Notes: Aim:  To evaluate, using isotope techniques, the in vivo effectiveness of a pH-dependent colonic delivery system.Methods:  In order to dispose of differently labelled substrates for measurement of orocaecal transit time, inulin-14C-carboxylic acid was evaluated as an alternative substrate to inulin and lactose-13C-ureide. Secondly, the time of release of 13C- and 15N-urea from the colonic delivery system was compared with the orocaecal transit time, measured using inulin and inulin-14C-carboxylic acid. This study was repeated after a 2-week lactulose intake period.Results:  The orocaecal transit time determined using inulin-14C-carboxylic acid (398 min) was not significantly different from the orocaecal transit time determined using inulin (420 min) or lactose-13C-ureide (396 min). Before lactulose intake, the 13CO2 excretion time was 358 min and the orocaecal transit times determined with the inulin-14C-carboxylic acid and inulin breath test were 376 and 375 min respectively. After lactulose, the 13CO2 excretion time was 383 min and orocaecal transit times were 354 min for inulin-14C-carboxylic acid and 392 min for inulin. A highly significant correlation was found. Good agreement was found between the urinary 15N excretion and the appearance of 13CO2 in breath.Conclusion:  Isotope techniques provide an excellent non-invasive tool for the in vivo evaluation of a colonic delivery system.

Notes: Background : A better substrate is needed for a hydrogen breath test to measure the orocaecal transit time. The currently used substrate, lactulose, accelerates the orocaecal transit time by increasing the osmolality of the gut contents. The recently developed lactose 13C-ureide breath test is reliable, but a hydrogen breath test is preferred, as it allows the simultaneous investigation of the digestion and absorption of nutrients by means of 13C-labelled compounds.Methods : The usefulness of different types of inulin as a substrate for a hydrogen breath test was studied. Raftilin HP (〉 99% inulin with a degree of polymerization of between 5 and 60 and 〈 0.5% glucose, fructose and sucrose) was further evaluated and compared with lactulose with regard to its effects on gastric emptying and the digestion of protein and lipids.Results : A good correlation was found between the orocaecal transit times using Raftilin HP (338 min; interquartile range, 300–383 min) and lactose 13C-ureide (353 min; interquartile range, 285–375 min) (r = 0.85; P 〈 0.001). The administration of 5 or 10 g Raftilin HP had no influence on the orocaecal transit time, whereas lactulose significantly shortened the orocaecal transit time. Neither inulin nor lactulose had a significant influence on gastric emptying or protein or lipid assimilation.Conclusion : Raftilin HP is an ideal substrate for a hydrogen breath test to measure the orocaecal transit time.

Notes: The administration of indometacin to rats increases intestinal permeability and induces inflammatory pathology of the small bowel. This represents a potential model for Crohn’s disease.〈section xml:id="abs1-2"〉〈title type="main"〉Aims:To analyse the pathogenic role of T cells, tumour necrosis factor and bacterial flora in indometacin-induced changes in small bowel permeability and inflammation.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Rats were given indometacin, 13 mg/kg, on day 1 and day 2. The effects of antibiotic (metronidazole, aztreonam and amoxicillin/clavulanic acid), anti- tumour necrosis factor and interleukin-10 therapy were evaluated. The parameters used were weight change, serum haemoglobin, chromium-51 ethylenediaminetetra-acetate permeability and macro-and microscopic score on day 5. Results in conventionally harboured rats were compared with those in T-cell-free rats. Additional in vitro experiments were carried out to test the effect of metronidazole on tumour necrosis factor production.〈section xml:id="abs1-4"〉〈title type="main"〉Results:Indometacin administration resulted in small bowel ulcers and inflammation, independently of T cells. Metronidazole was more potent than amoxicillin/clavulanic acid and anti-tumour necrosis factor in improving the indometacin-induced small bowel inflammation. Only part of the efficacy was through improvement of increased intestinal permeability. Aztreonam and interleukin-10 had no effect. Metronidazole also suppressed in vitro lipopolysaccharide-induced tumour necrosis factor production, suggesting a therapeutic effect of this drug through the inhibition of tumour necrosis factor.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:These data implicate anaerobic bacteria and tumour necrosis factor production, but not T cells, as essential elements of the pathogenesis of indometacin-induced small bowel inflammation. Tumour necrosis factor is also involved in the change in intestinal permeability. Metronidazole was the most efficacious drug in this model, probably because it suppressed anaerobic bacteria and directly inhibited tumour necrosis factor production.

Notes: Long-term acid suppression is believed to accelerate atrophic gastritis in Helicobacter pylori-positive patients. The influence of long-term therapy with lansoprazole has not been examined.〈section xml:id="abs1-2"〉〈title type="main"〉Aim:To study the clinical and endoscopic efficacy and histological evolution of gastric mucosa during 5 years of maintenance treatment with lansoprazole, 30 mg.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Seventy-eight patients with endoscopically proven oesophagitis were followed for 5 years. Biopsies taken at the start of the study, during follow-up and after 5 years were available for 73 patients.〈section xml:id="abs1-4"〉〈title type="main"〉Results:The total endoscopic relapse rate was 14.1%. At the start of the study, 34 patients were Helicobacter pylori negative and 39 were Helicobacter pylori positive (two atrophy, 25 antral gastritis, 12 pangastritis). At 5 years, no histological changes had occurred in Helicobacter pylori-negative patients. In the Helicobacter pylori-positive group, 20 patients developed pangastritis, six had normal histology and one had antral gastritis. Ten of the 12 patients with pangastritis had reduced antral activity. There was no increase in intestinal metaplasia, but there was a tendency towards regression of atrophy in the antrum and towards increased atrophy in the body of the stomach.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:Maintenance treatment with lansoprazole, 30 mg, is efficacious. The development of glandular atrophy and intestinal metaplasia was not accelerated in Helicobacter pylori-positive patients. Helicobacter pylori eradication must be considered only because of the higher cancer risk associated with chronic Helicobacter pylori-related gastritis.

Notes: Background : Adalimumab, a fully human monoclonal antibody to tumour necrosis factor, was recently introduced for therapy of Crohn's disease.Aim : Since induction of apoptosis of inflammatory cells is thought to be an important mechanism of action of the antitumour necrosis factor monoclonal antibody infliximab, we studied the induction of apoptosis of activated peripheral blood monocytes by adalimumab.Method : Apoptosis was analysed at the levels of the cell membrane, mitochondria and DNA by flow cytometry.Results: We found that both adalimumab and infliximab induced apoptosis in cultured monocytes, while etanercept did not. Apoptosis induction was caspase-dependent and detectable already after 2 h. The production of interleukin-10 and interleukin-12 by monocytes was down-regulated significantly by adalimumab and infliximab but not by etanercept, while levels of soluble tumour necrosis factor in monocyte cultures were down-regulated by all three reagents.Conclusions : These data show that both adalimumab and infliximab affect monocyte cytokine production and induce apoptosis of activated monocytes. Our findings will have to be further correlated to therapeutic efficacy of these antitumour necrosis factor reagents.

Notes: Background : An inverse relationship has been established between serum magnesium and serum lipid levels. By means of breath tests, we tested the hypothesis that magnesium inhibits intraluminal lipid digestion and subsequently causes changes in lipid metabolism. We also investigated the influence of the administration of magnesium chloride on protein digestion and gastric emptying.Methods : Five healthy volunteers performed simultaneous breath tests for gastric emptying and intraluminal lipid digestion, and six others for gastric emptying and protein digestion. Each test was performed in basal conditions and after the intake of 800 mg of magnesium chloride dissolved in water. Breath samples were taken at regular time intervals and analysed for 13CO2 and 14CO2 enrichment in order to calculate gastric emptying and lipid and protein digestion rates.Results : The oral administration of a single dose of magnesium chloride resulted in a diminished rate of intraluminal lipid and protein digestion. The most pronounced effect of magnesium chloride, however, was a decreased gastric emptying rate of both test meals. After correction for gastric emptying, no differences were noted in intraluminal lipid or protein digestion. Therefore, the lower lipid levels noted after magnesium supplementation are unlikely to be the result of altered lipid assimilation.Conclusion : Magnesium chloride slows gastric emptying but does not influence lipid digestion.

Notes: Whipple's disease is a multisystem disorder with protean manifestations and with poorly understood aetiopathogenesis. It is unclear how the immune system reacts, whether it functions normally or not, whether it protects the organism or is defeated in one way or another by the ‘Whipple bacillus’. The purpose of our study was to assess humoral and cellular immunity at the level of the intestinal mucosa. This histochemical, immunocytochemical and electronmicroscopic study, based on 16 cases, has shown that the changes in components of the mucosal immune system in Whipple's disease are quite different from normal. The phagocytic capacity of the macrophages, assessed microscopically, is abnormal, the number of intra-epithelial lymphocytes is increased, the CD 4/CD 8 cell ratio is decreased and the IgM positive cells in the lamina propria outnumber the IgA positive cells. These changes may be inter-dependent.

Notes: An immunoperoxidase technique with monoclonal antibodies for the identification of lymphocyte subsets and MHC Class II antigens was applied to oesophageal biopsies from two patients with herpetic oesophagitis. Oesophageal epithelial cells were found to express the MHC Class II antigen. The inflammatory infiltrate of the lamina propria was composed of both B lymphocytes and T lymphocytes.

Notes: Alpha-I-antitrypsin immunoreactivity was demonstrated by immunofluorescence in epithelial cells of the normal human small intestine. Its presence was also confirmed in biopsies of patients with Crohn's disease. Specific fluorescence was observed in only four out of 14 adult patients with coeliac disease. These results implicate the human small intestinal epithelium as a possible source of alpha-I-antitrypsin. The absence of positive cells may have implications in the aetiology of coeliac disease.