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C Stettler

Publications and source records attributed to C Stettler.

10 recordsLinked to original sources
PubMed1998

Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats.

1. In the stomach, prostaglandins protect the gastric mucosa against injuries. One rate-limiting step in prostaglandin synthesis is mediated by prostaglandin endoperoxide synthase (PGHS), the target enzyme of non-steroidal anti-inflammatory drugs (NSAIDs). Two isoforms of PGHS exist: a constitutive (PGHS-1) and an inducible (PGHS-2) enzyme. PGHS-1 is the major source of gastric prostaglandins under physiological conditions. Inhibition of prostaglandin synthesis by traditional NSAIDs such as indomethacin and diclofenac which non-selectively inhibit both PGHS-1 and PGHS-2, causes gastric and intestinal ulceration and delays gastric ulcer healing in chronic models. It has been shown that selective PGHS-2 inhibitors such as L-745,337 (5-methanesulphonamide-6-(2,4-difluorothio-phenyl)-1-inda none) are not ulcerogenic and do not inhibit gastro-intestinal prostaglandin synthesis. However, minimal information is available on the long-term effects of PGHS-2 inhibitors on the healing of previously established gastric injuries. We assessed the cellular localization and expression of PGHS-1 and PGHS-2 during gastric ulcer healing and assessed the effects of L-745,337 on previously established cryoulcers in the rat gastric stomach. 2. PGHS-1 and PGHS-2 were located and quantified by immunohistochemistry during experimental gastric ulcer healing. PGHS-2 immunoreactivity was only negligible in the normal gastric wall, but after gastric ulcerations, it was strongly detected in monocytes, macrophages, fibroblasts and endothelial cells below and between the regenerative glands. PGHS-1 immunoreactivity detected in normal gastric mucosa, disappeared after gastric ulceration in the mucosa adjacent to the ulcer crater. However, it reappeared in the regenerative glands from day 5 onwards. Thus, PGHS-1 and PGHS-2 were located at different sites and their maximal expression followed a different time-sequence. 3. We assessed the effects of L-745,337, indomethacin and diclofenac on gastric ulcer healing and histological healing parameters in rats. L-745,337, indomethacin and diclofenac dose-dependently decreased the healing of gastric ulcers. L-745,337, indomethacin and diclofenac decreased epithelial cell proliferation in the ulcer margin and microvessel density in the ulcer bed on day 8 and increased the thickness of the granulation tissue below the ulcer crater and the gap between both edges of the muscularis mucosae on day 15. Indomethacin and diclofenac, but not L-745,337, decreased synthesis of 6-keto-PGF1alpha and PGE2 in tissue fragments from the stomach and terminal ileum and decreased platelet thromboxane B2 synthesis in clotting whole blood. 4. Dose-response curves for the inhibition of chronic gastric ulcer healing by L-745,337 (administered twice daily intragastrically) showed an ID50 value of 1.7 mg (4.3 micromol) kg(-1). Dose-response curves for the inhibition of PGE2 synthesis in inflammatory exudates in the acute carrageenin sponge rat model, showed ID50 values of 1.1 mg (3.1 micromol) kg(-1) and 1.3 (3.3 micromol) mg kg(-1) for indomethacin and L-745,337, respectively. Thus, inhibition of chronic gastric ulcer healing by L-745,337 occurs within a potentially therapeutic dose-range. 5. In summary, PGHS-2 is markedly accumulated after gastric ulceration in monocytes, macrophages, fibroblasts and endothelial cells in regions of maximal repair activity. Selective inhibition of PGHS-2 by L-745,337 delayed gastric ulcer healing though interference with epithelial cell proliferation, angiogenesis and maturation of granulation tissue in a potentially therapeutic dose range. PGHS-2-derived prostaglandins seem to have an important role in gastric ulcer healing.

Animals↗
PubMed1997

Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis.

While the benefits of intensified insulin treatment in insulin-dependent (Type 1) diabetes mellitus (IDDM) are well recognized, the risks have not been comprehensively characterized. We examined the risk of severe hypoglycaemia, ketoacidosis, and death in a meta-analysis of randomized controlled trials. The MEDLINE database, reference lists, and specialist journals were searched electronically or by hand to identify relevant studies with at least 6 months of follow-up and the monitoring of glycaemia by glycosylated haemoglobin measurements. Logistic regression was used for calculation of combined odds ratios and 95% confidence intervals (95% CI). The influence of covariates was examined by including covariate-by-treatment interaction terms. Methodological study quality was assessed and sensitivity analyses were performed. Fourteen trials were identified. These contributed 16 comparisons with 1028 patients allocated to intensified and 1039 allocated to conventional treatment. A total of 846 patients suffered at least one episode of severe hypoglycaemia, 175 patients experienced ketoacidosis and 26 patients died. The combined odds ratio (95% CI) for hypoglycaemia was 2.99 (2.45-3.64), for ketoacidosis 1.74 (1.27-2.38) and for death from all causes 1.40 (0.65-3.01). The risk of severe hypoglycaemia was determined by the degree of normalization of glycaemia achieved (p=0.005 for interaction term), with the results from the Diabetes Control and Complications Trial (DCCT) in line with the other trials. Ketoacidosis risk depended on the type of intensified treatment used. Odds ratios (95% CI) were 7.20 (2.95-17.58) for exclusive use of pumps, 1.13 (0.15-8.35) for multiple daily injections and 1.28 (0.90-1.83) for trials offering a choice between the two (p = 0.004 for interaction). Mortality was significantly (p = 0.007) increased for causes potentially associated with acute complications (7 vs 0 deaths, 5 deaths attributed to ketoacidosis, and 2 sudden deaths), and non-significantly (p = 0.16) decreased for macrovascular causes (3 vs 8 deaths). We conclude that there is a substantial risk of severe adverse effects associated with intensified insulin treatment. Mortality from acute metabolic causes is increased; however, this is largely counterbalanced by a reduction in cardiovascular mortality. The excess of severe hypoglycemia in the DCCT is not exceptional. Multiple daily injection schemes may be safer than treatment with insulin pumps.

Blood Glucose↗
PubMed1997

Roles of hepatocyte growth factor and its receptor Met during gastric ulcer healing in rats.

BACKGROUND & AIMS: It is unclear which growth factors are primarily responsible for stimulating gastric ulcer healing. The roles of hepatocyte growth factor (HGF) and Met/HGF receptor during gastric ulcer healing were studied in rats. METHODS: HGF and Met/HGF receptor were located and quantified by in situ hybridization and immunohistochemistry during experimental gastric ulcer healing. The in vivo effects of exogenous recombinant human HGF on cell proliferation and ulcer healing were assessed and compared with those of placebo and omeprazole treatment. RESULTS: Compared with intact oxyntic mucosa, messenger RNA (mRNA) of HGF and met was substantially greater in the ulcerated region on days 3 and 15. HGF mRNA was located in stromal cells between the regenerative glands and in the arterial vessels of submucosal tissue, whereas met mRNA was located in the epithelial cells of the regenerative glands. After cryoinjury, immunoreactivity for the Met/HGF receptor was absent on day 3, reappeared on day 8, and was overexpressed on day 15. Exogenous recombinant human HGF had no effect on the ulcer healing parameters over days 3-8, but it did increase epithelial cell proliferation in the ulcer margin over days 8-15. CONCLUSIONS: These data suggest that HGF mediates specific tissue interactions between mesenchyme and epithelia during gastric ulcer healing.

Actins↗
PubMed1997

Localization of cholecystokinin A and cholecystokinin B-gastrin receptors in the human stomach.

BACKGROUND & AIMS: Gastrin and cholecystokinin (CCK) are gut-brain peptides, with multiple functions in the gastrointestinal tract mediated through CCK-B-gastrin and CCK-A receptors. The receptor localization is, however, not well established in humans. The aim of this study was to investigate the distribution and pharmacological characteristics of CCK-A and CCK-B receptors in the human upper gastrointestinal tract and compare them with those in the rat and dog. METHODS: CCK receptors were localized by in vitro receptor autoradiography with 125I-[Leu15]gastrin-I and 125I-[D-Tyr-Gly, Nle(28,31)]-CCK 26-33 in stomach and gallbladder. RESULTS: High concentrations of CCK-B-gastrin receptors were detected in the midglandular region of the human fundic mucosa. CCK-A receptors were found in the basal region of the antral and fundic mucosa. CCK-A receptors were also located in the muscularis propria of antrum, fundus, and gallbladder, whereas CCK-B-gastrin receptors were only detected in gastric fundic circular muscle. Two nonpeptide CCK receptor antagonists distinguish both receptor subtypes. Comparisons among humans, dogs, and rats suggest that localization and density of CCK receptor subtypes in the upper gastrointestinal tract are species-dependent. CONCLUSIONS: Localization of CCK receptor subtypes in human upper gastrointestinal tract provides a biochemical and morphological basis for the separate regulatory roles of gastrin and CCK.

Animals↗
PubMed1995

Pouchitis--a poorly understood entity.

Pouchitis is an increasing drawback to patients who undergo ileal pouch-anal anastomosis for ulcerative colitis; complication overshadows the overall good functional results of this sphincter-saving operation. There is a need for cooperative, multicenter, and longitudinal studies of patients undergoing ileal pouch-anal anastomosis, to unravel the etiology and pathophysiology of pouchitis. Because of the absence of a mucosal inflammation before pouch construction, patients operated on for familial adenomatous polyposis are the perfect control group. Thus, it may be possible to elucidate and define the sequence that leads to pouchitis, including overgrowth of a colonic type flora, transformation of the histology to an epithelium with colonic features, an altered biochemical milieu in the lumen (volatile fatty acids, secondary bile acids), and changes in mucosal defense mechanisms.

Anal Canal↗
PubMed1995

Assessment of dysplasia, mucosal mucins, p53 protein expression, and DNA content in ulcerative colitis patients with colectomy and ileorectal anastomosis.

BACKGROUND: Patients with ileorectal anastomosis after colectomy for ulcerative colitis remain at risk of developing rectal malignancy. Detection of mucosal dysplasia has been used for regular screening but is difficult in inflammatory mucosa, prompting the search for complementary markers. METHODS: This prospective study aimed to assess the prevalence of dysplasia, the predominance of sialomucin, DNA aneuploidy, and p53 overexpression as possible predictors of colorectal tumourigenesis, in the rectal mucosa of an unselected group of 27 patients with ileorectal anastomosis performed for ulcerative colitis. Patients had neither neoplastic nor dysplastic lesions on the colectomy specimen and the retained rectum at the time of surgery. One biopsy specimen of each lateral rectal wall was studied, using routine histology, mucin histochemistry, DNA flow cytometry, and the streptavidin-biotin complex method with D07 monoclonal antibodies directed towards the p53 protein. RESULTS: Seventeen, seven, and three patients showed inflammatory lesions of inactive, moderate, and severe active colitis, respectively. Dysplasia, sialomucin predominance, DNA aneuploidy, and p53 overexpression were not detected. CONCLUSIONS: The risk of malignant transformation of the rectal mucosa after ileorectal anastomosis seemed to be low in this ulcerative colitis group without high-grade dysplasia or carcinoma in the previous colectomy specimen, carefully followed up endoscopically and histologically. It remains to be evaluated which of the methods studied above will optimize the histopathologic surveillance of the rectal mucosa of ulcerative colitis patients with ileorectal anastomosis.

Adult↗
PubMed1993

[Ileo-anal "pouchitis": a still misunderstood pathology].

Chronic and/or acute inflammation of the ileal reservoir, so-called "pouchitis", is a frequently observed long-term complication of the ileo-anal "pouch" anastomosis. In ulcerative colitis patients, the prevalence of "pouchitis" varies from less than 10% to higher than 40%. These large variations reflect differences in diagnostic criteria and length of follow-up. The definition of "pouchitis" should include clinical symptoms, macroscopic inflammatory lesions at endoscopy and histological evidence of intense acute inflammation of the reservoir mucosa. Local bacterial overgrowth, lack of short chain fatty acids, increased secondary biliary acids, decreased intraepithelial T-lymphocytes and oxygen derived free-radicals could be implicated in the pathogenesis of pouchitis. In the absence of definite aetiology for pouchitis, its treatment is purely empirical: metronidazole, corticosteroids and 5-aminosalicylic acids are the most used drugs. The long-term consequences of the partial colic metaplasia of the pouch mucosa remain to be elucidated by regular clinical, endoscopical and histological longitudinal.

Adrenal Cortex Hormones↗
PubMed1993

[Is ileorectal anastomosis still a valid therapeutic alternative in the surgical treatment of hemorrhagic rectocolitis? Analysis of the functional, endoscopic and histologic result of 74 cases].

The objectives of this study were to determine the functional results of ileorectal anastomosis (IRA) and the endoscopical and histological outcome of the rectal stump in 74 patients operated on for ulcerative colitis. Median follow-up was 7.5 years (range 1 to 35). Functional results, as defined by the usual accepted criteria, were good in 80% of patients. The mean daily number of bowel movements was 4.2 +/- 1.6 (SD). Long term endoscopical and histological features improved in most of cases and only 13.3% of rectal biopsies showed the persistence of acute inflammatory changes; 28.4% of the patients had one or more episodes of acute proctitis during the follow-up period, but none of the patients required proctectomy. One case of severe dysplasia was disclosed, leading to proctectomy. A second case of proctectomy was performed in a patient with microrectum. Biopsies performed preoperatively in this case showed the only case of moderate dysplasia found in our population. Provided that the usual contraindications to this surgical procedure are observed, IRA is still a valid option in the surgical treatment of ulcerative colitis.

Adolescent↗