Amidino-substituted aromatic heterocycles as probes of the specificity pocket of trypsin-like proteases.
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Biomedical subjects
Publications and source records attributed to F M Stevens.
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A series, consisting of 52 benzamidine derivatives, was evaluated for inhibitory activity against homogeneous boar sperm acrosin. All of the compounds in the series proved to be more potent than benzamidine (Ki = 4.0 x 10(-6) M), with one of the derivatives, alpha-(4-amidino-2,6-diiodophenoxy)-3-nitrotoluene (compound 16), showing outstanding potency with a Ki value of 4.5 X 10(-8) M. Although all of the derivatives were effective acrosin inhibitors, structural specificity was observed within homologous groups of compounds. The information gained from this preliminary study should prove extremely beneficial in the design and synthesis of future acrosin inhibitors.
The results of endoscopic examination, biopsy taken at endoscopy and cytology of brush smears and/or gastric lavage specimens in 100 patients with proven malignant gastric lesions are described. Overall, a correct pre-operative diagnosis was achieved in 98 cases. Endoscopic appearance was a more accurate criterion in cases of exophytic advanced carcinoma, malignant ulcer and lymphoma than in diffuse infiltrative carcinoma or in early carcinoma, where biopsy and cytology were more accurate. Nine per cent of neoplasms were malignant lymphomas, which is much higher than the usual reported incidence. Early carcinoma was found in 5% of cases. In spite of readily available facilities for endoscopic diagnosis, most cases of gastric neoplasm were already advanced at the time of examination.
A correlation was sought between changes in enzymes involved in gastric acid secretion (Mg-, NaK-, K- and HCO3-stimulated ATPases) and histological changes in gastric biopsies. Alkaline phosphatase was also studied. Mg- and NaK-stimulated ATPase activities increased significantly in biopsies from the pylorus and antrum which showed moderate or severe gastritis. NaK ATPase levels increased and HCO3 ATPase decreased in incisural, body and fundic mucosa which had intestinal metaplasia and atrophic gastritis. No K+ ATPase was found in normal mucosa. The total activity of alkaline phosphatase did not vary with histological changes in the gastric mucosa. Results indicate that the ATPase enzyme systems are sensitive indicators of gastric mucosal disease.
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To test the hypothesis of an association between schizophrenia and coeliac disease, the sera of 380 chronic schizophrenic in-patients in two mental hospitals in the West of Ireland have been screened for the presence of reticulin antibodies. Antibodies were found in 26 patients. Twenty-one of these patients were further studied by proximal duodenal mucosal biopsy. None of the biopsies showed the morphological and histological features found in untreated coeliac disease. The incidence of reticulin antibodies in schizophrenic patients and controls is similar. The findings of this study lead to the rejection of the hypothesis of a positive genetic relationship between schizophrenia and coeliac disease.
1. Gliadin from which carbohydrate was removed by treatment with carbohydrase from Aspergillus niger was fed to three coeliac patients in remission. 2. Xylose absorption, mucosal morphology and brush-border enzymes were used to assess the toxicity of the carbohydrase-treated gliadin. 3. Gliadin treated with carbohydrases did not damage the intestinal mucosa of the coeliac patients. 4. The primary structure of the gliadin proteins was not altered by the enzyme treatment.
The absorption of xylose following an oral load of 15 g D-xylose has been studied by serial blood levels in 17 untreated adult coeliac patients, 21 treated coeliac patients, and 30 non-coeliac patients. A statistically significant difference in xylose blood levels was found between untreated coeliac and non-coeliac patients at all the times studied, but a complete separation between these two groups occurred only at the 75 minute stage. The reproducibility of absorption was assessed by repeating the test in 16 subjects. The 95% confidence limits of the standard error of estimate are narrowest at 75 and 90 minutes.
The first part of the duodenum has been studied endoscopically in treated and untreated coeliac patients. Biopsies taken from the duodenal cap during endoscopic examination, show villous atrophy similar to that found in the distal duodenum and jejunum. Using the indigocarmine scattering method, severe atrophy of the mucosal surface can be demonstrated throughout the duodenal cap, in vivo, in untreated coeliac disease.
The sera of 69 index coeliac patients, 121 of their first-degree relatives, and 104 controls were screened for the presence of reticulin antibodies. Among the untreated coeliac patients 75% of adults and 93% of children had reticulin antibody in their serum. Reticulin antibody was not present in any adequately treated coeliac patient. Of the first-degree relatives, 21 were reticulin antibody positive; 17 of these were biopsied and 12 were shown to have coeliac disease. Sixty-five of the coeliac relatives who did not have reticulin antibodies in their sera were biopsied and two had coeliac disease. Of the 68 relatives and 63 controls with normal biopsies, five of the relatives and four of the controls were reticulin antibody positive.
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