Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate

Background: We and others have identified the aldo-keto reductase AKR1C3 as a potential drug target in prostate cancer, breast cancer and leukaemia. As a consequence, significant effort is being invested in the development of AKR1C3-selective inhibitors. Methods: We report the screening of an in-house drug library to identify known drugs that selectively inhibit AKR1C3 over the closely related isoforms AKR1C1, 1C2 and 1C4. This screen initially identified tetracycline as a potential AKR1C3-selective inhibitor. However, mass spectrometry and nuclear magnetic resonance studies identified that the active agent was a novel breakdown product (4-methyl(de-dimethylamine)-tetracycline (4-MDDT)). Results: We demonstrate that, although 4-MDDT enters AML cells and inhibits their AKR1C3 activity, it does not recapitulate the anti-leukaemic actions of the pan-AKR1C inhibitor medroxyprogesterone acetate (MPA). Screens of the NCI diversity set and an independently curated small-molecule library identified several additional AKR1C3-selective inhibitors, none of which had the expected anti-leukaemic activity. However, a pan AKR1C, also identified in the NCI diversity set faithfully recapitulated the actions of MPA. Conclusions: In summary, we have identified a novel tetracycline-derived product that provides an excellent lead structure with proven drug-like qualities for the development of AKR1C3 inhibitors. However, our findings suggest that, at least in leukaemia, selective inhibition of AKR1C3 is insufficient to elicit an anticancer effect and that multiple AKR1C inhibition may be required

Women's Education Level, Maternal Health Facilities, Abortion Legislation and Maternal Deaths: A Natural Experiment in Chile from 1957 to 2007

The aim of this study was to assess the main factors related to maternal mortality reduction in large time series available in Chile in context of the United Nations' Millennium Development Goals (MDGs).Time series of maternal mortality ratio (MMR) from official data (National Institute of Statistics, 1957-2007) along with parallel time series of education years, income per capita, fertility rate (TFR), birth order, clean water, sanitary sewer, and delivery by skilled attendants were analysed using autoregressive models (ARIMA). Historical changes on the mortality trend including the effect of different educational and maternal health policies implemented in 1965, and legislation that prohibited abortion in 1989 were assessed utilizing segmented regression techniques.During the 50-year study period, the MMR decreased from 293.7 to 18.2/100,000 live births, a decrease of 93.8%. Women's education level modulated the effects of TFR, birth order, delivery by skilled attendants, clean water, and sanitary sewer access. In the fully adjusted model, for every additional year of maternal education there was a corresponding decrease in the MMR of 29.3/100,000 live births. A rapid phase of decline between 1965 and 1981 (-13.29/100,000 live births each year) and a slow phase between 1981 and 2007 (-1.59/100,000 live births each year) were identified. After abortion was prohibited, the MMR decreased from 41.3 to 12.7 per 100,000 live births (-69.2%). The slope of the MMR did not appear to be altered by the change in abortion law.Increasing education level appears to favourably impact the downward trend in the MMR, modulating other key factors such as access and utilization of maternal health facilities, changes in women's reproductive behaviour and improvements of the sanitary system. Consequently, different MDGs can act synergistically to improve maternal health. The reduction in the MMR is not related to the legal status of abortion

Effects of Aqueous Extract of Garlic (Allium Sativum) on Testicular Functions in the Rat

There are several beneficial effects of garlic (Allium sativum) in scientific literature, coupled with its nutritional uses as tenderizer and spices. Folklore medicine also refers to its use in the treatment of some diseases. To the best of our knowledge, the impact of the A. sativum extract on male reproductive system has not been duly reported. The effect of aqueous extract of A. sativum on male reproductive system was therefore investigated in albino rats. Fifteen male rats divided into three groups were treated with distilled water (control), 50mg/kgBW/day (low dose), 100mg/kgBW/day (high dose) of the extract respectively. Administration of the vehicle and extract was done orally for 30 days before the animals were sacrificed 24 hours after the last dose. There was a significant decrease in the weight of the epididymis but the testis, seminal vesicles and prostate were not affected. Alanine aminotransferase [ALT] and Aspartate aminotransferase [AST] activities were significantly reduced by the crude extract in the treated rats. A significant decrease in sperm count, motility, percentage normal morphology and epididymal volume were observed. However, the percentage live sperm was not affected. Serum testosterone levels were significantly decreased. The result suggests that the crude extract has deleterious effect on the sperm functions without systemic toxicity Keywords: Allium sativum, nitric oxide, sperm, ALT, AST and testosterone Nigerian Journal of Health and Biomedical Sciences Vol. 7 (2) 2008: pp. 26-3

Relationship Between Spasticity and Health Related Quality of Life in Individuals with Cerebral Palsy

Background: There is growing awareness of health related quality of life in cerebral palsy patients, though there is paucity of data in determining its relationship with spasticity in cerebral palsy patients.Objective: The purpose of this study was to determine the relationship between spasticity and health related quality of life in cerebral palsy patients.Method: A cross-sectional survey design was employed in this study. A total of fifty individuals with cerebral palsy, males (54%) and females (46%) within the age range of 5 years and 18 years (9.06+ 3.38 years) participated in the study. Measurement of spasticity was done by the researcher using the Modified Ashworth Scale (MAS) and the parents or primary caregivers of the participants were required to complete the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire, which is a 37-item questionnaire that collects information on the health related quality of life. Data was analysed separately for each of the six domains of the questionnaire using the Pearson Product-Moment Correlation coefficient on SPSS version 17 and the level of significance was set at p= 0.05.Results: According to the results, the domains of comfort and emotions with communication and social interaction do not have an influence on spasticity. The results also revealed that there was a significant relationship between spasticity and health related quality of life in cerebral palsy patients (p = 0.01).Conclusion: Personal care and mobility which are aspects of the health related quality of life should be paid more attention to, as they are negatively affected by spasticity in patients with cerebral palsy.Key words: Cerebral palsy, Spasticity. Health related quality of life