基于受体结构的药物分子设计系统:维甲类分子与其结合蛋白之间相互作用的研究

大分子解剖程序,配体分子契合适配和DOCK程序,以及计算化学的其它程序等,已集成为基于受体结构和分子间相互作用的进行分子设计的软件系统,定名为BIOS(Biomolecularinteractionsandorientationsimulator)。BIOS软件可在普通的微机上运行。使用BIOS分别剥离了细胞浆维甲结合蛋白(CRBP)和副睾维甲酸结合蛋白(E-RABP)两种蛋白的配体结合腔,剥离是围绕配体以同样的分子距离进行的。从而得到了芳香性残基分布相似的两个结合腔,其结合位点的几何排布却有相当差别。揭示出的结合腔已用于一系列的维甲类化合物的DOCK研究。E-RABP的结合腔可做为设计新维甲类分子的模板。     

A case of buprenorphine abuse

Buprenorphine is a powerful new analgesic agent with agonist and antagonist opiate receptor activity. Its withdrawal symptoms have been reported as being mild; however, its potential for abuse is not known. A case of buprenorphine abuse is reported, in which the patient's history and his response to naloxone suggest that important underlying factors were physical tolerance and dependence.     

Administration of dexamethasone induces proteinuria of glomerular origin in mice

The administration of glucocorticoids has been reported to exacerbate proteinuria in a few patients with glomerulonephritis. This effect has not been well recognized, and the pathogenetic mechanism responsible for this phenomenon remains to be clarified. In this study, we observed that a high daily oral dose (0.5 mg/kg body weight) of dexamethasone was capable of inducing overt proteinuria in mice, beginning on day 5 and persisting for a 19-day duration. One fourth of mice also intermittently presented with slight hematuria beginning on day 12. Renal lesions in the dexamethasone-treated mice, which were killed on day 23, were characterized by mild mesangial expansion, segmental or global hyalinosis/sclerosis in deep cortical glomeruli, and focal tubular changes. No glomerular inflammatory cell infiltration or proliferative lesion was noted in any of the mice. Ultrastructural features of glomeruli included mesangial widening characterized by either an increase of mesangial matrix, dilated mesangial channels filled with slightly electron-dense material or mesangial lysis-like appearance showing intracytoplasmic microcysts filled with electron-lucent material, and evidence to support injury of endothelial cells, erythrocytes, and podocytes. An immunofluorescence study revealed enhanced glomerular deposition of IgG, IgA, IgM, and fibrinogen (P < 0.001, compared with normal control mice), but no glomerular C3 deposition was identified in any of the dexamethasone-treated mice. Charge analysis showed no impairment in anionic property of glomerular tufts in the dexamethasone-treated mice. In addition, the dexamethasone-induced proteinuria was greatly attenuated by treatment with a low molecular weight heparin, although it was not reduced by an angiotensin-converting enzyme inhibitor. Data from these experiments suggest that a large dose of glucocorticoids is potentially nephrotoxic. Alteration of a size-dependent permeability may predominantly contribute to the dexamethasone-induced proteinuria. However, the effect of glomerular hyperfiltration may be only partially involved in the pathogenesis of this dexamethasone-induced glomerulopathy in mice.     

The prevalence of furcation foramina in primary molars

Accessory canals in the furcation region of primary molars provide pulpal-periodontal communications which have important clinical implications. This study of 75 extracted primary molars using dye penetration under vacuum suction showed that 42.7% have foramina located within the furcation region. There were no significant differences in the prevalence between the first and second primary molars. However, in the second primary molar series most of these foramina were located on the root surfaces within the furcation region, rather than in the immediate area of root division. The high prevalence of accessory canals in the furcation region of primary teeth indicates the need for greater clinical consideration during endodontic and periodontal management.     

A longitudinal controlled study of factors associated with mutans streptococci infection and caries lesion initiation in children 21 to 72 months old

PURPOSE: The purpose of this longitudinal study was to determine factors associated with mutans streptococci (MS) infection and development of caries lesions in a group of children 21 to 72 months old. METHODS: The 63 caries-free children, recruited since birth, were divided into: (1) a study group of 24 children who were colonized with MS; and (2) a control group of 39 children without MS. The children were recalled every 3 months for approximately 24 months, and their social, medical, and dental histories were updated. At each recall, the teeth were checked for presence or absence of plaque, enamel hypoplasia, and caries lesions, and their MS status was assessed using a commercial test kit. RESULTS: MS infection was associated with: (1) visible plaque (P < .01); (2) enamel hypoplasia (P < .05); (3) commencement of tooth-brushing after 12 months of age (P < .05); (4) lack of parental assistance with tooth-brushing (P < .025); and (5) increased hours of child care/school (P < .05). Four children (20%) were colonized at an age range of 21 to 36 months, 9 (45%) at 37 to 48 months, and 7 (35%) at 49 to 72 months (P < .001). Eight children who developed caries lesions: (1) had more hypoplastic teeth (P < .001); (2) ate sugar-containing snacks (P < .05); and (3) did not brush regularly with chlorhexidine gel (P < .01) compared to those who remained free of caries lesions. CONCLUSIONS: Lack of oral hygiene, consumption of sugar-containing snacks, and enamel hypoplasia are significant factors for both MS infection and caries lesion initiation.     

Opposing trends in incidence of esophageal squamous cell carcinoma and adenocarcinoma in a multi-ethnic Asian country

OBJECTIVES: To describe the incidence trends in esophageal squamous cell carcinoma (SCC) and adenocarcinoma among the three major ethnic groups in Singapore from 1968 to 2002. METHODS: Esophageal cancer cases in Singapore citizens and permanent residents obtained from the Singapore Cancer Registry and population data derived from the national census were used to calculate the incidence rates from 1968 to 2002. RESULTS: The age-standardized incidence rates (ASRs) for SCC decreased progressively from 8.31 to 3.85 per 100,000 men (p = 0.017) and from 3.43 to 0.81 per 100,000 women (p = 0.027). The rates fell for all three ethnic groups. The ASR for adenocarcinoma rose from 0 to 0.54 per 100,000 men and from 0.03 to 0.13 per 100,000 women, although these time trends did not achieve statistical significance. The frequency of regular smoking in the population decreased from 23% in 1966/1977 to 12.6% in 2004. The percentage of obesity in adults rose from 4.3% in 1982-1985 to 6.9% in 2004. The frequency of esophagitis in Singapore based on endoscopic findings increased from 3.9% in 1992 to 9.8% in 2001. CONCLUSIONS: The decline in the incidence of SCC is likely to be associated with the known decrease in the frequency of smoking among Singaporeans. In contrast, there appears to be a trend toward an increase in the incidence of adenocarcinoma in Singapore, although the absolute incidence remains relatively low. This may be due to the associated rise in the frequency of reflux esophagitis and obesity in Singapore.     

Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents

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