Androgenic Activity of Antiandrogens Predicted by Fit into DNA

Computer modeling including graphics and energy calculations were employed for the first time to examine the stereochemical fit of antiandrogens into double-stranded DNA. In this study, we assessed the relative fit of antiandrogens in the cavity between base pairs known to accommodate androgens. When compared to testosterone which was given a normalized value of 100%, the antiandrogens manifested the following order of fit: RU23908 (88%) > hydroxyflutamide (71%) > cyproterone acetate (41%). A correlation was observed between the relative fit of the antiandrogens and reported agonistic properties as assessed by the ability to increase nuclear androgen receptor levels in the rat ventral prostate. These findings may be useful in the design and development of androgen antagonists without agonistic activity.     

Spatio-temporal progression of the AEP P300 component using the cortical imaging technique

Summary The cortical imaging technique (CIT), a mathematical method for simulating the potential fields on the surface of the brain, was used to analyze the spatio-temporal progression of the AEP P300 component (as well as the preceding and subsequent N2a and N3 components) from thirty normal adult subjects recorded in a standard oddball paradigm. Comparisons were made between the progressions of the endogenous event-related cognitive potentials and the exogenous stimulus-dependent potentials (Nl component). Cortical imaging results suggest that different and multiple generator sites are involved in the production of exogenous and endogenous evoked responses. We particularly note the asymmetric development of the P300 component and the apparent anterior generator sites for the N2a component. This last result is interesting because the N2a precedes the P300 component and supports an earlier frontal contribution.     

Reliability of level of care decisions in a Long-Term Care program

This paper addresses the question of the degree of agreement between experienced assessors making level-of-care placement decisions for the same client, given a comparable opportunity to obtain and record client information in a community-based Long-Term Care program.A systematic sample of 246 cases was selected, consisting of 47 preadmission assessments and 199 reviews. The resulting data were subjected to analysis using the statistic Kappa and the degree of agreement categories suggested by Fleiss.¹ It was found that at the level-of-care extremes— Extended Care and Personal Care—the agreement between two nurse assessors for reviews could be considered excellent. In the Intermediate Care range, however, the reliability of the level-of-care decision can only be considered fair. Agreement for initial assessments was less, withK=0.469 indicating, overall, only fair agreement. While there was most often only a one-care-level difference between assessors, the program assessor tended to recommend a higher level than the study or check assessor. This has implications for funding agencies and/or facility planners who must assess the likely care requirements of an increasing number of disabled elderly. From a program management perspective, the preceding analyses allow an objective judgement of the extent of the placement decision problem, if any, and further provide a definition of areas most in need of revision. The value of collaboration between practitioner and researcher is evident in these analyses.Dr. Stark is Director, Division of Health Services Research and Development and Assistant Professor, Department of Health Care and Epidemiology, The University of British Columbia. Dr. Gutman is Director, Gerontology Centre and Associate Professor, Faculty of Interdisciplinary Studies, Simon Fraser University. Dr. Brothers is Research Associate, Division of Health Systems, The University of British Columbia. Address enquiries to Dr. A. Stark, Director, Division of Health Services Research and Development, Office of the Coordinator of Health Sciences, The John F. McCreary Health Sciences Centre, 2194 Health Sciences Mall, The University of British Columbia, Vancouver, B.C., V6T 1Z6.The research described in this paper, as well as the larger study of which it is a part, is supported by a grant from the B.C. Health Care Research Foundation. In addition, the cooperation and support of the Ministry of Health, Province of British Columbia is gratefully acknowledged.     

Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway.

PURPOSE: Overexpression of eIF4E in surgical margins of head and neck cancer patients is an independent risk factor for recurrence. We hypothesize that overexpressed eIF4E is functionally active in tumor margins through activation of the Akt/mammalian target of rapamycin (mTOR) pathway EXPERIMENTAL DESIGN: Western blots and/or immunohistochemistry were performed to determine whether phosphorylation of mTOR and activation of its downstream molecules eIF4E-binding protein-1 (4E-BP1) and p70 S6 kinase and the upstream modulator of mTOR, Akt, were expressed in margins overexpressing eIF4E. RESULTS: There was a significant association between phospho-4E-BP1 and eIF4E expression of a margin or a significant difference in phospho-4E-BP1 expression between the eIF4E-positive and -negative margins (P < 0.01). A significant association between eIF4E and phospho-p70 S6 kinase as well as eIF4E and phospho-mTOR was also noted (P < 0.05). Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins. A total of 89% of the 4E-BP1-expressing margins expressed more of the phosphorylated (beta, gamma, and delta) isoforms, whereas 81% of the 4E-BP1-expressing tumors expressed more of the unphosphorylated alpha isoform. A similar difference in Akt activation was noted between eIF4E-positive margins and tumors (P < 0.05). CONCLUSIONS: Overexpression of eIF4E is functionally active in tumor margins through activation of the Akt/mTOR signaling pathway. The greater degree of expression of downstream targets and upstream regulators of mTOR in margins compared with the tumors indicates preferential activation of the Akt/mTOR signaling pathway in margins overexpressing eIF4E. Rapamycin analogs can potentially be used as adjuvant therapy for patients with eIF4E-positive margins.     

Peripheral progesterone (P) levels and endometrial response to various dosages of vaginally administered P in estrogen-primed women

Objective: To compare the pharmacokinetics and pharmacodynamics of 100 mg/d, 200 mg/d, and 400 mg/d (200 mg two times per day) of P administered vaginally for 14 days to estrogen-primed postmenopausal women.Design: Randomized, open-label, three-way crossover study.Setting: Two university-based investigative sites.Patient(s): Twenty healthy postmenopausal women with histologically normal endometria.Intervention(s): Oral 17,β-E₂ was given each day of a 28-day cycle; a P vaginal suppository was inserted daily according to the randomization schedule during days 15–28 of each cycle; blood samples were collected; an endometrial biopsy was obtained on day 25; and patients were crossed over to the next treatment cycle after a washout period of at least 30 days.Main Outcome Measure(s): Mean P blood levels, endometrial dating/conversion.Result(s): There was good vaginal absorption of P for all dosages. Endometrial conversion occurred in all 200- and 400-mg/d P-dosed cycles, whereas the 100-mg/d dosage failed to convert primed endometria consistently. There also was a significantly increased tendency for earlier bleeding and spotting with the 100-mg/d dosage.Conclusion(s): Both the 200- and 400-mg/d dosage regimens consistently convert an estrogen-primed endometrium, and yield appropriate endometrial dating and bleeding patterns. However, the 400-mg/d dosage attains the highest sustained blood levels and may be the best dosage regimen for further study.     

治疗糖尿病及糖尿病足的疼痛

病史:T.N.,男性,55岁,两年前确诊患有糖尿病。近来他的糖化血红蛋白(GHbA1c)达到11.8%,他的医生在他服用格列甲嗪XL20mg/d及吡格列酮(Actos,武田/礼来)15mg/d的基础上,又增加了晚间最小剂量的中效胰岛素。T.N.同时每天还服用阿托伐他汀(Lipitor,辉瑞)10mg和雷米普利(Altace,安万特)10mg。另外,医生给T.N.处方卡马西平治疗其糖尿病足。对此,你有什么想法,能给出一些建议吗?点评一综合各方面因素制订治疗方案,以下是一些需要考虑的问题。首先是CYPT2C8/9酶诱导剂卡马西平与该酶的底物格列甲嗪及吡格列酮之间的药物相互作用问题。治疗…     

Magnesium sulfate effectively reduces blood pressure in an animal model of preeclampsia.

OBJECTIVE: We tested the ability of magnesium sulfate to reduce hypertension and neonatal growth retardation in an animal model of preeclampsia. STUDY DESIGN: On day 17 of pregnancy, osmotic minipumps were inserted subcutaneously to continuously deliver either vehicle (saline control group), or N-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg/day), or L-NAME (50 mg/kg/day) in combination with magnesium sulfate (60 mg/kg/day). Prior to insertion, blood pressure and heart rate were monitored with a pneumatic tail cuff device. Blood pressure measurements were repeated on days 18, 20, and 21 of pregnancy. Blood was obtained on days 17 and 21, along with urine, to assess magnesium levels and degree of proteinuria. Pups were weighed and measured at 48 hours postpartum. RESULTS: Rats receiving L-NAME developed hypertension within 24 hours of implantation (108 +/- 3.9 vs. 123 +/- 3.4 mmHg, p < 0.05). Magnesium sulfate, given along with L-NAME did not prevent mean blood pressure from increasing, but reduced it by day 21 compared to L-NAME given alone (107 +/- 3.4 vs. 122 +/- 8.7 mmHg, respectively, p < 0.05). Magnesium sulfate reduced neonatal growth retardation by improving the weight of the pups compared to pups from maternal rats given L-NAME alone (6.1 +/- 0.1 vs. 5.2 +/- 0.3 grams, respectively, p < 0.05). CONCLUSION: Maternal magnesium sulfate reduces blood pressure and increases neonatal size compared to L-NAME without magnesium. These findings support a beneficial effect of magnesium in preeclampsia.