[Defensins: endogenous antibiotics as a central part of innate immunity].
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Bacterial Infections↗
Biomedical subjects
E F Stange
Publications and source records attributed to E F Stange.
Biliary lipids, cholesterol and bile synthesis: different adaptive mechanisms to dietary cholesterol in lean and obese subjects.
BACKGROUND: Increased biliary cholesterol secretion together with elevated cholesterol synthesis may predispose obese subjects to cholesterol gallstone formation. AIM: To investigate whether processing of dietary cholesterol is altered in obesity, we enrolled eight lean and seven obese subjects in a double-blind crossover study. METHODS: Cholesterol consumption was 300 mg/day on low and 1300 mg/day on high cholesterol diet. After 3 weeks on either diet, hepatic bile was collected to determine biliary lipid secretion, and bile salt composition by high-performance liquid chromatography and cholesterol saturation index was calculated. Cholesterol synthesis was measured employing mass isotopomer distribution analysis. Bile acid synthesis via neutral and acidic pathway was assessed by serum levels of 7alpha-hydroxy-4-cholesten-3-one and 27-hydroxycholesterol. RESULTS: Cholesterol synthesis was increased in obese compared with lean and feedback inhibited only in obese. On low cholesterol diet, cholesterol secretion was doubled in obese but bile acid composition and synthesis was similar between the two groups. After high cholesterol diet, cholesterol saturation index and bile secretion were unchanged. In contrast to obese, lean increased bile acid synthesis only via the acidic pathway. CONCLUSIONS: Dietary cholesterol appears to preferentially induce bile acid synthesis via the acidic pathway in lean, whereas cholesterol synthesis was inhibited in obese. Thus, stable cholesterol saturation index may be achieved by different mechanisms.
Adult↗
[Disturbances in volume and electrolytes with intestinal and kidney diseases].
The intestines and kidney are the most important excretion organs. Both organ systems are key players in keeping the homeostatic balance regarding hydration and electrolytes. Disturbances of function can lead to enormous and sometimes life-threatening complications. Intestinal diseases lead often to diarrhoea, which can be associated with fluid loss of up to 20 l per day. The accompanying electrolyte disturbances can be hypo- or hypernatremia in combination with hypokalemia. The therapy is substitution guided by knowledge of the pathophysiology. Kidney diseases lead to excessive volume and electrolyte balances, depending on the underlying molecular or pathological defect, but deficiencies can also be found. In case of kidney impairment with 30-50% total loss of function, calcium and phosphate metabolism is impaired.
Humans↗
Urinary excretion of polyethylene glycol 3350 during colonoscopy preparation.
BACKGROUND: Whole gut lavage with a polyethylene glycol electrolyte solution (PEG) is a common bowel cleansing method for diagnostic and therapeutic colon interventions. Absorption of orally administered PEG from the gastrointestinal tract in healthy human beings is generally considered to be poor. In patients with inflammatory bowel disease (IBD), intestinal permeability and PEG absorption were previously reported to be higher than in normal subjects. In the current study, we investigated the absorption of PEG 3350 in patients undergoing routine gut lavage. METHODS AND RESULTS: Urine specimens were collected for 8 hours in 24 patients undergoing bowel cleansing with PEG 3350 for colonoscopy. The urinary excretion of PEG 3350, measured by size exclusion chromatography, ranged between 0.01 and 0.51 % of the ingested amount, corresponding to 5.8 and 896 mg in absolute amounts, respectively. Mean PEG excretion in patients with impaired mucosa such as inflammation or ulceration of the intestine (0.24 % +/- 0.19, n = 11) was not significantly higher (p = 0.173) compared to that in subjects with macroscopically normal intestinal mucosa (0.13 % +/- 0.13, n = 13). CONCLUSION: The results indicate that intestinal absorption of PEG 3350 is higher than previously assumed and underlies a strong inter-individual variation. Inflammatory changes of the intestine do not necessarily lead to a significantly higher permeability of PEG.
Administration, Oral↗
Review article: the effect of aminosalicylates and immunomodulation on cancer risk in inflammatory bowel disease.
Ulcerative colitis and, maybe to a similar extent, Crohn's disease are associated with an increased risk of colorectal carcinoma. As a consequence of this increased risk, surveillance strategies have been proposed to prevent colorectal carcinoma through early detection of dysplasia, which may herald malignant disease. These surveillance strategies are controversial for several reasons discussed in this review. It may be concluded from the relevant studies that regular use of at least 1.2 g of mesalazine per day may effectively prevent about two out of three colon cancers in ulcerative colitis. In contrast, there seems to be no role for either mercaptopurine or folic acid in protection from colon cancer.
Aminosalicylic Acids↗
European evidence based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis.
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Biopsy↗
European evidence based consensus on the diagnosis and management of Crohn's disease: current management.
This second section of the European Crohn's and Colitis Organisation (ECCO) Consensus on the management of Crohn's disease concerns treatment of active disease, maintenance of medically induced remission, and surgery. The first section on definitions and diagnosis includes the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn's disease. The third section on special situations in Crohn's disease includes postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy for Crohn's disease.
Adrenal Cortex Hormones↗
Tacrolimus--finally!
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Administration, Oral↗
[Chronic inflammatory bowel diseases (IBD): novel pathophysiological concepts and their clinical relevance].
Despite many years of intensive research the pathogenesis of inflammatory bowel diseases is still enigmatic. All efforts to identify the cause of Crohn's disease and ulcerative colitis in a dysregulation of specific immune mechanisms have failed. This review presents a novel pathogenetic concept, based on the expression of natural mucosal antibiotic peptides. These so called defensins are part of innate immunity and defend the mucosa as antimicrobial peptides against intraluminal potentially pathogenic and invasive bacteria. In contrast to ulcerative colitis, Crohn's disease is characterised by a diminished defensin expression. This defect may represent the molecular pathogenesis of this disease.
Bacterial Translocation↗
Cyclosporine for induction of remission in Crohn's disease.
BACKGROUND: Cyclosporine was first found to be an effective and well-tolerated immunosuppressive agent in organ transplant recipients, and subsequently in several autoimmune diseases. It was reported in open studies that cyclosporine is effective for induction of remission in Crohn's disease. Four randomized controlled trials have been performed to determine whether the results observed in these open studies were valid. This systematic review summarizes the evidence on the use of oral cyclosporine for the induction of remission in Crohn's disease. OBJECTIVES: To evaluate the effectiveness of oral cyclosporine for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. Secondary objectives were to evaluate clinical response rates and adverse events associated with cyclosporine. SEARCH STRATEGY: Computer-assisted searches of the on-line bibliographic databases MEDLINE and EMBASE were performed to identify potentially relevant publications between 1980 and July 2004. The MeSH terms "Crohn Disease" or "Inflammatory Bowel disease" and "Cyclosporin" (exploded) were used to perform key word searches of the databases. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed. Abstracts from major gastroenterological meetings, The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched for relevant studies. Appropriate officials at Sandoz Corporation were contacted to seek information on any unpublished trials. SELECTION CRITERIA: Prospective, randomized, double-blinded, placebo-controlled trials of parallel design with treatment duration of a minimum 12 weeks comparing oral cyclosporine therapy with placebo for treatment of patients with active Crohn's disease were eligible for inclusion. DATA COLLECTION AND ANALYSIS: All data were analyzed on an intention-to-treat basis. Data were extracted from the original research articles and converted into 2x2 tables (cyclosporine vs. placebo). Where available, individual 2x2 tables for strata within studies were also used. Heterogeneity was assessed using the chi-square test (p < 0.10 was regarded as statistically significant). For non-pooled data, p-values were derived using the chi-square test. For pooled data, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. A fixed effects model was used for pooling of data. For continuous data, summary test statistics were derived using the weighted mean difference and 95% confidence intervals. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar. MAIN RESULTS: Brynskov 1989a found that patients receiving high dose cyclosporine (median 7.6 mg/kg/day) had statistically significant clinical improvement at 12 weeks compared to placebo patients. None of the other studies found any statistically significant benefit for clinical improvement or induction of remission for low dose cyclosporine treatment (5 mg/kg/day) used by itself or in combination with corticosteroids compared to placebo. Cyclosporine was associated with a significantly higher proportion of adverse events and withdrawals due to adverse events relative to placebo. AUTHORS' CONCLUSIONS: Brynskov 1989a enrolled a small number of patients and the modified clinical grading scale used in the study has not been validated in other studies. Furthermore, statistically significant clinical improvement does not imply induction of clinical remission. Indeed, Brynskov 1989a found no statistically significant differences in the mean Crohn's Disease Activity Index score at 12 weeks indicating that cyclosporine was no more effective than placebo for induction of remission in Crohn's disease. The results of this review demonstrate that low dose (5 mg/kg/day) oral cyclosporine is not effective for the induction of remission in Crohn's disease. Patients treated with low dose oral cyclosporine are more likely than placebo treated patients to experience adverse events including renal dysfunction. The use of low dose oral cyclosporine for the treatment of chronic active Crohn's disease does not appear to be justified. Oral dosing at higher levels or parenteral administration of cyclosporine have not been adequately evaluated in controlled clinical trials. Higher doses of cyclosporine are not likely to be useful for the long-term management of Crohn's disease because of the risk of nephrotoxicity and the availability of other proven interventions.
Crohn Disease↗
Enhanced human beta-defensin-2 (hBD-2) expression by corticosteroids is independent of NF-kappaB in colonic epithelial cells (CaCo2).
Beta-defensins are small cationic peptides with antimicrobial properties that contribute to innate host defense. Unlike human beta-defensin-1 (hBD-1), which is produced constitutively, human beta-defensin-2 (hBD-2) is expressed after adequate stimulation by cytokines and/or bacterial endotoxins in epithelial tissue and mononuclear phagocytes but may be deficient in patients with Crohn's disease. To further elucidate the role of the intestinal epithelium in antimicrobial host defense, gene regulation of hBD-2 and the interaction with NF-kappaB were analyzed in a cell culture model. Human colonic epithelial cells (CaCo2) were stimulated by pro-inflammatory cytokines (IL-1beta, TNF-alpha, IF-gamma) to induce hBD-2 mRNA transcription. Interactions with NF-kappaB were analyzed using specific inhibitors (sulfasalazine, gliotoxine, dexamethasone) at different concentrations. Defensin mRNA expression was quantified by competitive RT-PCR and antibacterial capacity of supernatants was determined by an antimicrobial assay. HBD-2 mRNA transcription and antimicrobial activity of CaCo2 cells were induced by stimulation with pro-inflammatory cytokines. Induction was not inhibited by sulfasalazine or gliotoxine, whereas dexamethasone further enhanced both gene transcription and antimicrobial capacity. The lack of inhibition of induced hBD-2 expression by specific NF-kappaB antagonists suggests an additional pathway of activation, independent of NF-kappaB. The induction of hBD-2 expression in cytokine-stimulated CaCo2 cells by corticosteroids indicates further immunomodulatory ability of steroid hormones not yet understood.
Adrenal Cortex Hormones↗
[Chronic inflammatory bowel diseases].
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Adrenal Cortex Hormones↗
Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease.
BACKGROUND: 6-Thioguanine-nucleotides seem to be the active metabolites of thiopurine therapy, and their monitoring has been considered a useful tool for optimizing response in inflammatory bowel diseases. Tioguanine (thioguanine) therapy results in much higher levels of 6-thioguanine-nucleotide levels when compared with azathioprine or mercaptopurine. AIM: To elucidate the influence of 6-thioguanine-nucleotide and methylated 6-thioguanine-nucleotide levels under tioguanine on efficacy and toxicity in Crohn's disease. METHODS: 6-Thioguanine-nucleotide and methylated 6-tioguanine-nucleotide levels were measured regularly in 26 Crohn's disease patients treated with tioguanine. Nucleotide levels were related to efficacy and toxicity. RESULTS: 6-Thioguanine-nucleotide levels rose very high [median 1241 pmol/8 x 10(8) red blood cells (range 313-1853)]. Methylated 6-thioguanine-nucleotide levels were detected in all patients [491 pmol/8 x 10(8) red blood cells (154-1775)]. 6-Thioguanine-nucleotide and methylated 6-thioguanine-nucleotide concentrations correlated significantly (r = 0.7, P < 0.0001). Nucleotide levels from patients achieving remission (n = 14) did not differ significantly from non-remitters (n = 12) [6-thioguanine-nucleotide: 1077 (599-2160) vs. 1210 (534-4665); methylated 6-thioguanine-nucleotide: 510 (214-1222) vs. 421 (145-1284)]. One patient with intermediate thiopurine S-methyltransferase activity experienced bone marrow toxicity upon dose escalation parallel with excessively high thioguanine-nucleotide levels. CONCLUSIONS: 6-Thioguanine-nucleotide as well as methylated 6-thioguanine-nucleotide levels under tioguanine therapy were not related to efficacy. This suggests that monitoring of 6-thioguanine-nucleotide levels is not a useful tool to predict response to thiopurines.
Adult↗
[Another paradigm shift: defective innate--not specific--immune system in Crohn's disease?].
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Crohn Disease↗
[The role of defensins in the pathogenesis of chronic-inflammatory bowel disease].
Defensins are endogenous antimicrobial peptides with a broad activity spectrum. Even at micromolar concentrations gramnegative and grampositive bacteria, but also mycobacteria, as well as fungi (candida), viruses (herpes) and protozoa (giardia lamblia) are destroyed. As part of the innate immune system defensins are expressed by the intestinal epithelium and contribute to the maintenance of the mucosal barrier. This barrier appears to be defective in inflammatory bowel diseases since on one hand, the immune response is directed against the "normal" luminal bacterial flora and on the other hand, mucosal adherent and invasive bacteria have been observed in these diseases. A defective defensin expression may well explain these phenomena. Indeed, Crohn's disease of the terminal ileum, especially if associated with a NOD2 mutation, is characterised by a diminished alpha-defensin (human defensin 5 and 6) expression, and in inflamed Crohn's colitis, in contrast to ulcerative colitis, the beta-defensin (human beta-defensins 2 and 3) response is reduced. Through a deficient chemical mucosal barrier this defect could lead to increased bacterial invasion into the intestinal mucosa and might well explain an adequate inflammatory response. Although the final proof that this deficient defensin response leads to a reduced antibacterial activity of the intestinal mucosa is still lacking, the most plausible concept of pathogenesis of Crohn's disease is a defensin deficiency syndrome.
Animals↗
[Diagnosis and therapy of ulcerative colitis: results of an evidence based consensus conference by the German society of Digestive and Metabolic Diseases and the competence network on inflammatory bowel disease].
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Adolescent↗
NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression.
BACKGROUND: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human alpha defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. METHODS: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor alpha, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. RESULTS: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. CONCLUSION: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.
Adolescent↗