Gastroduodenal permeability in Crohns disease.
Puspok A. Oberhuber G. Wyatt J. Maier-Dobersberger T. Hammer J. Pfeffel F. Wrba F. Potzi R. Vogelsang H.
Department of Gastroenterology and Hepatology, University of Vienna, Austria. firstname.lastname@example.org
BACKGROUND: Gastric permeability was prospectively investigated by determination of sucrose excretion in 100 patients with Crohn's disease. Results were compared with histological findings and the lactulose-mannitol ratio as a measure of intestinal permeability. METHODS: All subjects underwent oesophagogastroduodenoscopy with biopsies of all investigated parts. Thirty-two Helicobacter pylori-positive patients were excluded from further analyses. RESULTS: Gastroduodenal permeability was significantly higher in patients with Crohn's disease than in control subjects (P < 0.00001). Sucrose excretion alone did not predict microscopic inflammation of the upper gastrointestinal tract. Increased gastroduodenal permeability with a concomitant rise in intestinal permeability predicted histological upper gastrointestinal involvement of Crohn's disease with a likelihood of 86%. The negative predictive value was 43%. CONCLUSION: In parallel with findings in the small intestine, gastroduodenal permeability is increased in a high proportion of patients with Crohn's disease. In patients with an increased lactulose-mannitol ratio, elevated sucrose excretion is highly predictive of histological gastroduodenal involvement.
Endogenous dopaminergic activity in Child-Pugh A cirrhosis: potential role in renal sodium handling and in the maintenance of clinical compensation.
Sansoe G. Ferrari A. Baraldi E. Grisolia C. De Santis MC. Villa E. Manenti F.
University of Modena, Italy.
BACKGROUND: We studied the main determinants of aldosterone secretion in a group of 20 patients with biopsy-proven Child-Pugh A cirrhosis without previous ascites or diuretic consumption. METHODS: We evaluated the plasma levels of adrenocorticotrophic hormone (ACTH), active renin and aldosterone (both supine at 07.00 h and after 30 min of upright posture),and active renin and aldosterone responses 30 min and 60 min after the administration of metoclopramide, a dopamine DA2 antagonist (10 mg e.v.). Nine normal subjects were also submitted to the metoclopramide stimulation test. RESULTS: Compared with control subjects, the patients showed significantly greater incremental aldosterone responses both 30 min and 60 min after metoclopramide (+30 min: 157.5+/-73.3 vs. 83.5+/-32.2 pg mL(-1), P< 0003; +60 min: 142.1+/-87.2 vs. 36.8+/-39.0 pg mL(-1), P < 0-001). We found significant positive correlations between amplitude of aldosterone response 30 min after metoclopramide and 24-h urinary fractional excretion of sodium (r=0.61, P < 0.01) and basal morning aldosterone levels (r=0.69, P < 0.001). CONCLUSIONS: The higher incremental aldosterone responses observed after metoclopramide in cirrhotic patients are expressions of increased dopaminergic activity in these patients compared with control subjects. Moreover, the correlation we found between the degree of dopaminergic activity and 24-h urinary fractional excretion of sodium suggests a role for endogenous dopamine as a relevant mediator of natriuresis in cirrhosis, at least in patients with compensated disease.
Antioxidants inhibit the in vitro production of inflammatory cytokines in Crohns disease and ulcerative colitis.
Reimund JM. Allison AC. Muller CD. Dumont S. Kenney JS. Baumann R. Duclos B. Poindron P.
Centre de Recherches Pharmacologiques, Illkirch-Graffenstaden, France.
BACKGROUND: Modulation of cytokine secretion may be of interest in the treatment of Crohn's disease or ulcerative colitis. METHODS: The effect of three antioxidants - butylated hydroxyanisol, tetrahydropapaveroline and nordihydroguaiaretic acid - on the production of tumour necrosis factor (TNF), interleukin (IL) 1, IL-6 and IL-8 (measured by enzyme-linked immunosorbent assay) by peripheral mononuclear cells and biopsies of inflamed colonic mucosa from inflammatory bowel disease patients were studied. RESULTS: We observed a decrease in IL-1 and IL-6 production by peripheral mononuclear cells from inflammatory bowel disease patients (approximately 50% of control). The three drugs did not decrease IL-6 and IL-8 secretion by colonic biopsies, whereas they did inhibit IL-1 and, to some degree, TNF production. The cytokine-inhibitory effect of antioxidants seems to be more pronounced in ulcerative colitis than in Crohn's disease. CONCLUSION: Our results suggest that the studied antioxidants, or related compounds, may be of interest in inflammatory bowel disease treatment.
Bezafibrate down-regulates fibrinogen biosynthesis in human hepatoma HepG2 cells.
Binsack R. Stegmeier K. Dorge L. Volkl A.
Boehringer Mannheim, Germany.
BACKGROUND: Bezafibrate reportedly lowers serum lipids and plasma fibrinogen in humans and rats, but the mechanism of this process has still to be clarified. We have addressed this problem by investigating the effects of bezafibrate on fibrinogen in the human hepatoma HepG2 cell line. METHODS: In cells cultured with and without bezafibrate, intra- and extracellular fibrinogen was quantified using an enzyme-linked immunosorbent assay (ELISA), and changes in the biosynthesis and secretion of bezafibrate were monitored by [35S]-methionine labelling. In addition, expression of the corresponding mRNA was investigated by Northern blotting. As fibrinogen is an acute-phase protein, HepG2 cells exposed to interleukin 6 were also analysed. RESULTS: Bezafibrate decreased fibrinogen biosynthesis by about 25%, regardless of whether or not the cultures were also exposed to interleukin 6. mRNA was reduced in proportion to the concentration of interleukin 6 to which the cells were exposed, but intracellular transport and release of the protein were not affected. CONCLUSION: Apparently, bezafibrate interferes with the biosynthesis of fibrinogen at the pretranslational level but does not affect the export of the protein.
Gastric emptying of the liquid, solid and oil phase of a meal in normal volunteers and patients with Billroth II gastrojejunostomy.
Maes BD. Hiele MI. Geypens BJ. Ghoos YF. Rutgeerts PJ.
Department of Medicine, University Hospital Gasthuisberg, Leuven, Belgium.
BACKGROUND: The relationship between gastric emptying of different phases of a meal in humans has only been partly studied in normal subjects and in patients with previous gastric surgery. METHODS: In the present study, gastric emptying of the liquid, solid and oil phase and the relationship between the phases was evaluated in 10 normal control subjects and in seven patients with Billroth II gastrojejunostomy using breath test technology. RESULTS: Gastric emptying in normal subjects showed a clear separation between the emptying of the liquid, solid and oil phase. In healthy volunteers, the liquid phase emptied in the same manner in the presence of a solid phase as in the presence of an oil phase. In contrast, the oil phase emptied more slowly with liquids than with solids. The emptying rate of the oil phase was not only inversely related to the amount administered but was also dependent on its chemical composition. Gastric emptying in patients with Billroth II gastroenterostomy was characterized by a complete loss of discrimination between the different phases of the meal, with an extremely fast emptying of the oil phase compared with normal control subjects. CONCLUSION: In normal subjects, the liquid, solid and oil phase of a meal are emptied differently. In patients with Billroth II gastrojejunostomy, dumping of the oil phase is the most pronounced difference from the normal physiology of gastric emptying. This could be one of the reasons why Billroth II gastrectomy may be associated with fat malabsorption.
Inflammatory bowel disease: no association between allele combinations of the interleukin (IL) I beta and IL-I receptor antagonist gene polymorphisms.
Hacker UT. Bidlingmaier C. Gomolka M. Keller E. Eigler A. Hartmann G. Folwaczny C. Fricke H. Albert E. Loeschke K. Endres S.
Medizinische Klinik, Klinikum Innenstadt, University of Munich, Germany.
BACKGROUND: Interleukin 1 (IL-1) and its physiological antagonist interleukin-1 receptor antagonist (IL-1 ra) play a crucial role in the pathogenesis of inflammatory bowel disease. Polymorphisms in the genes coding for these cytokines, the restriction enzyme TaqI polymorphism for IL-1 beta and the variable number of tandem repeats (VNTR) polymorphism for IL-1 ra, have been shown to influence cytokine synthesis in vitro. Recently, an association has been described for distinct allele combinations of these two polymorphisms in patients with ulcerative colitis and with Crohn's disease but not in healthy control subjects. METHODS: We studied 56 patients with ulcerative colitis, 64 patients with Crohn's disease and 196 healthy control subjects. All were unrelated Caucasians of European ancestry. After polymerase chain reaction (PCR) the amplification products were analysed on agarose gels. For the IL-1 beta polymorphism the PCR product was additionally digested using the restriction enzyme TaqI. RESULTS: The allele and genotype frequencies as well as the carriage rates of the IL-1 beta TaqI polymorphism in healthy control subjects were in agreement with previous findings in other populations. Allele and genotype frequencies of the IL-1 beta polymorphism were not different in inflammatory bowel disease patients compared with healthy control subjects. Comparing allele combinations of both polymorphisms no association could be identified either within healthy control subjects or in the groups of patients with ulcerative colitis or Crohn's disease. CONCLUSION: Thus, we could not confirm the results of a previous study reporting an association between the IL-1ra and IL-1 beta gene polymorphisms in patients with inflammatory bowel disease.
Association of copper to metallothionein in hepatic lysosomes of Long-Evans cinnamon (LEC) rats during the development of hepatitis [se e comments]
Klein D. Lichtmannegger J. Heinzmann U. Muller-Hocker J. Michaelsen S. Summer KH.
Institute of Toxicology and Environmental Hygiene, Technical University Munich, Germany.
BACKGROUND: The Long-Evans cinnamon (LEC) rat has a mutation homologous to the human Wilson's disease gene, leading to copper-induced hepatotoxicity. The mechanism of how excess copper damages the liver or what chemical form of copper is toxic is still unclear. RESULTS: In liver cytosol, copper levels were highest just before the onset of hepatitis and declined thereafter. In cytosol, total copper was bound to metallothionein (MT). Considerable amounts of both copper and iron accumulated in lysosomes with increasing age and development of liver damage. Lysosomal levels of presumably reactive non-MT-bound copper were increased. In severely affected livers, large amounts of copper were associated with insoluble material of high density which, upon ultrastructural information, was found to be derived from the lysosomes of Kupffer cells. This copper-rich material is considered to consist of polymeric degradation products of copper-MT. CONCLUSION: We suggest that chronic copper toxicity in LEC rats involves the uptake of copper-loaded MT into lysosomes, where it is incompletely degraded and polymerizes to an insoluble material containing reactive copper. This copper, together with iron, initiates lysosomal lipid peroxidation, leading to hepatocyte necrosis. Subsequent to phagocytosis by Kupffer cells, the reactive copper may amplify liver damage either directly or through stimulation of these cells.
Effects of short-term treatment with pravastatin on the hepatic synthesis of cholesterol and bile acids in gallstone patients.
Hillebrant CG. Axelson M. Bjorkhem I. Wang FH. Nyberg B. Einarsson C.
Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
BACKGROUND: HMG-CoA reductase inhibitors are now the therapy of choice in the treatment of hypercholesterolaemia. The effects of long-term treatment with these substances on plasma lipoproteins, cholesterol metabolism and biliary secretion of lipids have been extensively studied in humans. Much less is known about the effects of short-term treatment. The aim of this study was to determine the time course of the effects of HMG-CoA reductase inhibitors on plasma lipoprotein levels as well as cholesterol and bile acid synthesis in gallstone patients. METHODS: Thirty-six patients undergoing elective cholecystectomy were included in the study. Except for the gallstone disease, these patients were otherwise healthy. Four groups of subjects were treated with the HMG-CoA reductase inhibitor pravastatin (Pravachol), 20 mg twice daily for 12, 24, 48 and 72 h preoperatively. Plasma lipoproteins and plasma levels of lathosterol and 7 alpha-hydroxy-4-cholesten-3-one were determined before initiation of pravastatin treatment and on the morning of the day of the operation, lathosterol reflecting hepatic HMG-CoA reductase activity and 7 alpha-hydroxy-4-cholesten-3-one the activity of cholesterol 7 alpha-hydroxylase, the rate-determining enzyme in bile acid synthesis. RESULTS: All treatment groups displayed a significant decrease in total cholesterol and low-density lipoprotein (LDL)-cholesterol, by about 12% and 17% respectively. Lathosterol was reduced by about 50% in all treatment groups. Of great interest was the finding that 7 alpha-hydroxy-4-cholesten-3-one was unaffected in all treatment groups. CONCLUSION: The results show that short-term pravastatin treatment in gallstone patients rapidly inhibits cholesterol synthesis and lowers plasma LDL-cholesterol levels without effects on bile acid synthesis.