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Syntheses of several tripeptide analogues of leupeptin containing C-terminal argininal, lysinal, or ornithinal units are presented. The synthetic analogues were tested as inhibitors of trypsin, plasmin, and kallikrein. (Benzyloxycarbonyl)-L-leucyl-L-leucyl-L-argininal (2a) was significantly less effective as an inhibitor of trypsin and plasmin activity than leupeptin. (Benzyloxycarbonyl)-L-leucyl-L-leucyl-L-lysinal (2e) and (benzyloxycarbonyl)-L-leucyl-L-leucyl-L-ornithinal (2i) display different inhibition characteristics than (benzyloxycarbonyl)-L-leucyl-L-leucyl-L-argininal (2a). While (benzyloxycarbonyl)-L-leucyl-L-leucyl-L-argininal (2a) showed moderate inhibition of all three enzymes tested, (benzyloxycarbonyl)-L-leucyl-L-leucyl-L-lysinal (2e) was less effective as an inhibitor of trypsin and plasmin activity. Of the three enzymes tested, (benzyloxycarbonyl)-L-leucyl-L-leucyl-L-ornithinal (2i) showed significant inhibition of kallikrein activity only. Modifications made in the composition and sequence of the P2 and P3 amino acids also resulted in variations in the inhibitory activity of the analogues. In general, plasmin showed a strong preference for inhibitors which contain an L-phenylalanyl-L-leucyl or an L-leucyl-L-valyl unit in the P2 and P3 positions. 相似文献
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The techniques specific to peroperative fluorocholangiography are discussed based on an experience of 632 cholangiograms and an estimation has been made of the associated radiation doses to staff and patients. Rapid and accurate information can be obtained during fluorocholangiography using appropriate techniques with acceptably low radiation hazards. 相似文献
5.
Paul J Limburg Rachael Z Stolzenberg-Solomon Robert A Vierkant Katherine Roberts Thomas A Sellers Philip R Taylor Jarmo Virtamo James R Cerhan Demetrius Albanes 《Clinical gastroenterology and hepatology》2006,4(12):1514-1521
BACKGROUND & AIMS: Hyperinsulinemia is a putative colorectal cancer (CRC) risk factor. Insulin resistance (IR) commonly precedes hyperinsulinemia and can be quantitatively measured by using the homeostasis model assessment-insulin resistance (HOMA-IR) index. To date, few studies have directly examined serum insulin as an indicator of CRC risk, and none have reported associations on the basis of HOMA-IR. METHODS: We performed a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (n=29,133). Baseline exposure and fasting serum biomarker data were available for 134 incident CRC case and 399 non-case subjects. HOMA-IR was derived as fasting insulin x fasting glucose/22.5. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by using age-adjusted and multivariable-adjusted Cox proportional hazards regression models. RESULTS: Median (interquartile range) values for serum insulin, glucose, and HOMA-IR were 4.1 (2.9-7.2) mIU/L, 101 (94-108) mg/dL, and 0.99 (0.69-1.98) for case subjects and 4.1 (2.7-6.1) mIU/L, 99 (93-107) mg/dL, and 1.02 (0.69-1.53) for non-case subjects, respectively. On the basis of comparison of the highest versus lowest quartiles for each biomarker, insulin (HR, 1.84; 95% CI, 1.03-3.30) and HOMA-IR (HR, 1.85; 95% CI, 1.06-3.24) were significantly associated with incident CRC, whereas glucose was marginally associated with incident CRC (HR, 1.70; 95% CI, 0.92-3.13) in age-adjusted risk models. However, trends across biomarker quartiles were somewhat inconsistent (P trend=.12, .04, and .12, respectively), and multivariable adjustment generally attenuated the observed risk estimates. CONCLUSIONS: Data from this prospective study of male smokers provide limited support for hyperinsulinemia, hyperglycemia, and/or insulin resistance as CRC risk factors. 相似文献
6.
Valery L Feigin Craig S Anderson Anthony Rodgers Neil E Anderson Alistair J Gunn 《Journal of clinical neuroscience》2002,9(5):502-507
Current treatment of acute stroke remains unsatisfactory. This review presents experimental and clinical data which suggest that mild induced hypothermia could be a potent and practicable neuroprotective treatment of acute ischaemic stroke and intracerebral haemorrhage. Hypothermia, if proven to be safe, effective and widely practicable in patients with acute stroke, could have an enormous positive impact on reducing the burden of stroke worldwide. Critical issues that will need to be considered in a well designed randomised controlled trial of induced hypothermia in acute stroke patients are discussed. 相似文献
7.
Esa-Pekka P?lvim?ki Hannu Majasuo Erkka Syv?lahti Jarmo Hietala 《Pharmacological research》2005,51(5):419-425
Selective serotonin reuptake inhibitors (SSRIs) bind directly to various neurotransmitter receptors. The clinical effects of SSRIs appear gradually during weeks of treatment, suggesting a role for adaptive changes in neurotransmitter receptors. Most clinically used antidepressants, e.g. fluoxetine, bind to 5-HT2C receptors. When administered chronically, many antidepressants elicit adaptive regulation of 5-HT2C receptors. The present study was conducted in order to determine the effects of acute and chronic fluoxetine and citalopram treatments on the density and function of 5-HT2C receptors in the rat choroid plexus. Acute and chronic treatments followed by phosphoinositide (PI) hydrolysis assays and quantitative receptor autoradiography were performed. Acute (single-dose) treatment with neither drug significantly affected basal or 5-HT-stimulated PI hydrolysis, but acute citalopram (20 mg/kg) treatment increased both agonist and antagonist binding to 5-HT(2C) receptors. Chronic (14 days) citalopram treatment (20 mg/kg) increased the maximal PI hydrolysis response by 40%, but fluoxetine lacked this effect. The present data suggest that sensitisation of 5-HT2C receptor-mediated intracellular signal transduction may play a role in the effects of citalopram. In contrast, fluoxetine treatment does not functionally sensitise 5-HT2C receptors. Thus, functional 5-HT2C receptor sensitisation is not a common effect of antidepressants, but the differential effects may explain some of the pharmacodynamic differences seen with these drugs, especially upon repeated administration. 相似文献
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Prediction of choledocholithiasis using a pocket microcomputer 总被引:4,自引:0,他引:4
T V Taylor C P Armstrong S Rimmer S B Lucas J Jeacock A A Gunn 《The British journal of surgery》1988,75(2):138-140
A computerized method, using a small pocket computer, has been used to predict the presence of choledocholithiasis in a prospective series of 239 patients undergoing cholecystectomy. From an initial data base of 424 patients 36 factors were evaluated and the most important 2 of these were determined by multivariate analysis for use in the prospective analysis. Satisfactory operative cholangiograms were a prerequisite to evaluation of the statistical method and were obtained in 90.4 per cent of cases. Using the computerized method a common bile duct stone would have been overlooked in only 1 patient but 17 unnecessary explorations would have been carried out. The overall accuracy of the computerized method was 92.5 per cent. When the method was applied to a further study of 97 patients from a separate centre the overall accuracy was 85.6 per cent. If the method was used to aid selective use of operative cholangiography, cholangiograms would be performed in 20 per cent and stones would be overlooked in less than 1 per cent. 相似文献
10.
The management of patients with asymptomatic hyperparathyroidism remains controversial. This study examined the extent to which the presence of prospect of bone disease should influence treatment. Bone mineral content (BMC) of the distal forearm was measured by single photon absorptiometry in 67 patients with mild hyperparathyroidism. Twenty-six patients treated surgically and 17 managed conservatively were reviewed regularly for up to 4 years. Eighty per cent of patients had a baseline fat-corrected BMC within the local reference interval for age and sex, but about 75 per cent of values fell below the mean. BMC at the 'distal' site of the surgically treated patients improved or stabilized, but a continuing decline was seen in the patients managed conservatively (P less than 0.01). Differences were small and concern about future osteoporotic fracture should seldom be a major factor in making decisions about surgical correction of mild hyperparathyroidism. 相似文献