二氢吡啶类钙拮抗剂对钙调素依赖性环核苷酸磷酸二酯酶的抑制机理

用单克隆抗体纯化的60kd为亚基的牛脑钙调素依赖性环核苷酸磷酸二酯酶的动力学研究表明,二氢吡啶类钙拮抗剂Nicardipine和Felodipine是该酶的“部分”竞争性抑制剂。因为近饱和浓度的药物抑制该酶活性仅能达到某限定值,且Dixon作图法不呈直线关系。该酶被一定浓度Felo-dipine抑制时,增加Nicardipine浓度可逆转酶的抑制而达到Nicardipine的最大抑制水平,Nicardipine不影响典型的竞争性抑制剂甲基异丁基黄嘌呤对该酶的抑制作用,说明该酶活性中心以外存在和二氢吡啶结合的部位。     

A Thirty-year Review of Vulvar Cancer in Jamaica, 1978 to 2007

Objective

To evaluate the trends in vulvar cancer between 1978 and 2007 in Kingston and St Andrew, Jamaica, with respect to age-standardized rates and histologic types.

Methods

All cases of vulvar cancer recorded in the Jamaica Cancer Registry from 1978 to 2007 were extracted and analysed for age distribution and histologic type.

Results

There were 78 cases (one person of unknown age) of vulvar cancer recorded over the 30-year period. Sixty per cent of the affected patients were between 50 and 80 years old. The most common histologic type of vulvar malignancy was squamous cell carcinoma (82%). There was a decline in age-standardized incidence rates of both vulvar cancers overall and vulvar squamous cell carcinoma over the 30-year period.

Conclusion

Squamous cell carcinoma is the most common vulvar malignancy in the Jamaican population, and affects primarily older women. Despite high prevalence rates of high-risk human papillomavirus infection, no increase in the age-standardized incidence of vulvar squamous cell carcinoma was identified.     

Novel pyrazole compounds for pharmacological discrimination between receptor-operated and store-operated Ca2+ entry pathways

Background and purpose

Pyrazole derivatives have recently been suggested as selective blockers of transient receptor potential cation (TRPC) channels but their ability to distinguish between the TRPC and Orai pore complexes is ill-defined. This study was designed to characterize a series of pyrazole derivatives in terms of TRPC/Orai selectivity and to delineate consequences of selective suppression of these pathways for mast cell activation.

Experimental approach

Pyrazoles were generated by microwave-assisted synthesis and tested for effects on Ca²⁺ entry by Fura-2 imaging and membrane currents by patch-clamp recording. Experiments were performed in HEK293 cells overexpressing TRPC3 and in RBL-2H3 mast cells, which express classical store-operated Ca²⁺ entry mediated by Orai channels. The consequences of inhibitory effects on Ca²⁺ signalling in RBL-2H3 cells were investigated at the level of both degranulation and nuclear factor of activated T-cells activation.

Key Results

Pyr3, a previously suggested selective inhibitor of TRPC3, inhibited Orai1- and TRPC3-mediated Ca²⁺ entry and currents as well as mast cell activation with similar potency. By contrast, Pyr6 exhibited a 37-fold higher potency to inhibit Orai1-mediated Ca²⁺ entry as compared with TRPC3-mediated Ca²⁺ entry and potently suppressed mast cell activation. The novel pyrazole Pyr10 displayed substantial selectivity for TRPC3-mediated responses (18-fold) and the selective block of TRPC3 channels by Pyr10 barely affected mast cell activation.

Conclusions and Implications

The pyrazole derivatives Pyr6 and Pyr10 are able to distinguish between TRPC and Orai-mediated Ca²⁺ entry and may serve as useful tools for the analysis of cellular functions of the underlying Ca²⁺ channels.     

Economic status and survivorship in digestive system cancers

This study investigates economic differentials in cancer survival in a sample of 1180 white men, focusing in particular on the relationship between income level and survivorship in the various subsites comprising the digestive system cancer category. Using the Cox proportional hazards model to control for confounding variables, the economic status-survivorship relationship is estimated for several subgroupings of primary malignancies. The results show significant variation in this relationship across different cancer sites, with a pronounced effect observed in carcinomas of the small intestine, peritoneum and, especially, colon and rectum. High-income patients with these malignancies had a significantly lower risk of dying from the disease (P less than 0.05) than either their middle- or lower-income counterparts, controlling for age, stage, and initial course of treatment. Differences in immunologic status, tumor characteristics, and follow-up treatment may account for these economic effects.     

Survivorship differences in geographical comparisons of cancer mortality: an urban-rural analysis

Epidemiologists have traditionally used geographical comparisons of cancer site-specific mortality rates to draw aetiological inferences about neoplasms. This approach is based on the unproven assumption that cancer mortality and incidence rates are highly correlated within geographical areas. Since mortality is a function of both incidence and survival rates, geographical differences in cancer survivorship may confound area comparison of cancer mortality rates. To test this possibility, the survival experience of white male cancer patients residing in rural and urban areas is examined using cancer registry data. A multi-variable proportional hazards model is specified to determine the unique effect of geographical residence on survival. Only for cancers of the gastro-intestinal (GI) tract are there statistically significant differences in survivorship by geographical residence. This suggests that for most cancers, survival differences are not likely to play a confounding role in geographical comparisons of cancer mortality rates. However for GI cancers, survival differences should probably be considered in geographical-oriented analyses and their interpretation.     

Efficacy and cost-effectiveness of a minimal intervention to prevent smoking relapse: dismantling the effects of amount of content versus contact

Relapse prevention remains a major challenge to smoking cessation efforts. T. H. Brandon, B. N. Collins, L. M. Juliano, and A. B. Lazev (2000) found that a series of 8 empirically based relapse-prevention booklets mailed to ex-smokers over 1 year significantly reduced relapse. This study dismantled 2 components of that intervention: the amount of content (number of booklets) and the frequency of contact. Content and contact were crossed in a 2 X 2 factorial design. The criteria of at least 1 week of abstinence at baseline was met by 431 participants, 75%-85% of whom returned 12-, 18-, and 24-month follow-up questionnaires. Eight booklets produced consistently higher point-prevalence abstinence rates than did a single booklet, but frequency of contact did not affect outcome. Moreover, the high-content interventions were highly cost-effective.     

State health manpower policy

The health manpower policies of state governments are discussed on the basis of an appraisal of a set of recently completed health manpower studies. Examination suggests that both state health manpower policy processes and outcomes may be limited in fundamental ways. Resolution depends upon changes in the ways in which we perceive health manpower problems and in the institutional mechanisms used to deal with them.Dr. Chirikos is Associate Professor, Department of Preventive Medicine and Faculty of Labor & Human Resources, The Ohio State University, 410 West 10th Avenue, Columbus, Ohio 43210. This article draws, in part, on research supported by an award from the National Science Foundation. The views expressed here are those of the author and should not be attributed to the National Science Foundation.