Using Basic Science to Design a Clinical Trial: Baseline Characteristics of Women Enrolled in the Kronos Early Estrogen Prevention Study (KEEPS)

Observational and epidemiological studies suggest that menopausal hormone therapy (MHT) reduces cardiovascular disease (CVD) risk. However, results from prospective trials showed neutral or adverse effects most likely due to differences in participant demographics, such as age, timing of initiation of treatment, and preexisting cardiovascular disease, which reflected in part the lack of basic science information on mechanisms of action of hormones on the vasculature at the time clinical trials were designed. The Kronos Early Estrogen Replacement Study (KEEPS) is a prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women’s Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD

Active, but not passive cigarette smoking was inversely associated with mammographic density

The opposing carcinogenic and antiestrogenic properties of tobacco smoke may explain why epidemiologic studies have not consistently reported positive associations for active smoking and breast cancer risk. A negative relation between mammographic density, a strong breast cancer risk factor, and active smoking would lend support for an antiestrogenic mechanism. We used multivariable linear regression to assess the associations of active smoking and secondhand smoke (SHS) exposure with mammographic density in 799 pre- and early perimenopausal women in the Study of Women’s Health Across the Nation (SWAN). We observed that current active smoking was associated with 7.2% lower mammographic density, compared to never active smoking and no SHS exposure (p = 0.02). Starting to smoke before 18 years of age and having smoked ≥20 cigarettes/day were also associated with statistically significantly lower percent densities. Among nulliparous women having smoked ≥20 cigarettes/day was associated with 23.8% lower density, compared to having smoked ≤9 cigarettes/day (p < 0.001). Our findings support the hypothesis that tobacco smoke exerts an antiestrogenic effect on breast tissue, but counters the known increased risk of breast cancer with smoking prior to first full-term birth. Thus, our data suggest that the antiestrogenic but not the carcinogenic effects of smoking may be reflected by breast density

Association between CYP19 gene SNP rs2414096 Polymorphism and polycystic ovary syndrome in Chinese women

<p>Abstract</p> <p>Background</p> <p>Several studies have reported the association of the SNP rs2414096 in the CYP19 gene with hyperandrogenism, which is one of the clinical manifestations of polycystic ovary syndrome (PCOS). These studies suggest that SNP rs2414096 may be involved in the etiopathogenisis of PCOS. To investigate whetherthe CYP19 gene SNP rs2414096 polymorphism is associated with the susceptibility to PCOS, we designed a case-controlled association study including 684 individuals.</p> <p>Methods</p> <p>A case-controlled association study including 684 individuals (386 PCOS patients and 298 controls) was performed to assess the association of SNP rs2414096 with PCOS. Genotyping of SNP rs2414096 was conducted by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method that was performed on genomic DNA isolated from blood leucocytes. Results were analyzed in respect to clinical test results.</p> <p>Results</p> <p>The genotypic distributions of rs2414096 (GG, AG, AA) in the CYP19 gene (GG, AG, AA) in women with PCOS (0.363, 0.474, 0.163, respectively) were significantly different from that in controls (0.242, 0.500, 0.258, respectively) (<it>P </it>= 0.001). E2/T was different between the AA and GG genotypes. Age at menarche (AAM) and FSH were also significantly different among the GG, AG, and AA genotypes in women with PCOS (P = 0.0391 and 0.0118, respectively). No differences were observed in body mass index (BMI) and other serum hormone concentrations among the three genotypes, either in the PCOS patients or controls.</p> <p>Conclusions</p> <p>Our data suggest that SNP rs2414096 in the CYP19 gene is associated with susceptibility to PCOS.</p

The relationship between fertility and lifespan in humans

Evolutionary theories of aging predict a trade-off between fertility and lifespan, where increased lifespan comes at the cost of reduced fertility. Support for this prediction has been obtained from various sources. However, which genes underlie this relationship is unknown. To assess it, we first analyzed the association of fertility with age at menarche and menopause, and with mortality in 3,575 married female participants of the Rotterdam Study. In addition, we conducted a candidate gene study where 1,664 single nucleotide polymorphisms (SNPs) in 25 candidate genes were analyzed in relation to number of children as a measure of fertility. SNPs that associated with fertility were analyzed for association with mortality. We observed no associations between fertility and age at menarche (p = 0.38) and menopause (p = 0.07). In contrast, fertility was associated with mortality. Women with two to three children had significantly lower mortality (hazard ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69–0.97) compared to women with no children. No such benefit was observed for women with four or more children, who had a similar mortality risk (HR, 0.93; 95% CI, 0.76–1.13) as women with no children. The analysis of candidate genes revealed four genes that influence fertility after correction for multiple testing: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHBA (p = 0.021). However, none of the independent SNPs in these genes predicted mortality. In conclusion, women who bear two to three children live longer than those who bear none or many children, but this relationship was not mediated by the candidate genes analyzed in this study

Linkage analysis of obesity phenotypes in pre- and post-menopausal women from a United States mid-western population

<p>Abstract</p> <p>Background</p> <p>Obesity has a strong genetic influence, with some variants showing stronger associations among women than men. Women are also more likely to distribute weight in the abdomen following menopause. We investigated whether genetic loci link with obesity-related phenotypes differently by menopausal status.</p> <p>Methods</p> <p>We performed univariate and bivariate linkage analysis for the phenotypes of body mass index (BMI), waist (W) and hip (H) circumferences (WC, HC), and WH ratio (WHR) separately among 172 pre-menopausal and 405 post-menopausal women from 90 multigenerational families using a genome scan with 403 microsatellite markers. Bivariate analysis used pair-wise combinations of obesity phenotypes to detect linkage at loci with pleiotropic effects for genetically correlated traits. BMI was adjusted in models of WC, HC and WHR.</p> <p>Results</p> <p>Pre-menopausal women, compared to post-menopausal women, had higher heritability for BMI (<it>h</it>²= 94% versus <it>h</it>²= 39%, respectively) and for HC (<it>h</it>²= 99% versus <it>h</it>²= 43%, respectively), and lower heritability for WC (<it>h</it>²= 29% versus <it>h</it>²= 61%, respectively) and for WHR (<it>h</it>²= 39% versus <it>h</it>²= 57%, respectively). Among pre-menopausal women, the strongest evidence for linkage was for the combination of BMI and HC traits at 3p26 (bivariate LOD = 3.65) and at 13q13-q14 (bivariate LOD = 3.59). Among post-menopausal women, the highest level of evidence for genetic linkage was for HC at 4p15.3 (univariate LOD = 2.70) and 14q13 (univariate LOD = 2.51). WC was not clearly linked to any locus.</p> <p>Conclusions</p> <p>These results support a genetic basis for fat deposition that differs by menopausal status, and suggest that the same loci encode genes that influence general obesity (BMI) and HC, specifically, among pre-menopausal women. However, lower heritability among pre-menopausal women for WC and WHR suggests that pre-menopausal waist girth may be influenced to a greater extent by controllable environmental factors than post-menopausal waist girth. Possibly, targeted interventions for weight control among pre-menopausal women may prevent or attenuate post-menopausal abdominal weight deposition.</p

Bone mass in schizophrenia and normal populations across different decades of life

<p>Abstract</p> <p>Background</p> <p>Chronic schizophrenic patients have been reported as having higher osteoporosis prevalence. Survey the bone mass among schizophrenic patients and compare with that of the local community population and reported data of the same country to figure out the distribution of bone mass among schizophrenic patients.</p> <p>Methods</p> <p>965 schizophrenic patients aged 20 years and over in Yuli Veterans Hospital and 405 members aged 20 and over of the community living in the same town as the institute received bone mass examination by a heel qualitative ultrasound (QUS) device. Bone mass distribution was stratified to analyzed and compared with community population.</p> <p>Results</p> <p>Schizophrenic patients have lower bone mass while they are young. But aging effect on bone mass cannot be seen. Accelerated bone mass loss during menopausal transition was not observed in the female schizophrenic patients as in the subjects of the community female population.</p> <p>Conclusion</p> <p>Schizophrenic patients have lower bone mass than community population since they are young. Further study to investigate the pathophysiological process is necessary to delay or avoid the lower bone mass in schizophrenia patients.</p

Kidney function, endothelial activation and atherosclerosis in black and white Africans with rheumatoid arthritis

OBJECTIVE: To determine whether kidney function independently relates to endothelial activation and ultrasound determined carotid atherosclerosis in black and white Africans with rheumatoid arthritis (RA). METHODS: We calculated the Jelliffe, 5 Cockcroft-Gault equations, Salazar-Corcoran, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (EGFR) equations in 233 (112 black) RA patients. RESULTS: The CKD-EPI eGFR was 0.1 for comparisons of AUC (SE)) for the other 8 equations. Based on optimal eGFR cutoff values with sensitivities and specificities ranging from 42 to 60% and 70 to 91% respectively, as determined in ROC curve analysis, a low eGFR increased the odds ratio for plaque 2.2 to 4.0 fold. CONCLUSION: Reduced kidney function is independently associated with atherosclerosis and endothelial activation in black and white Africans with RA, respectively. CKD is highly prevalent in black Africans with RA. Apart from the MDRD, eGFR equations are useful in predicting carotid plaque presence, a coronary heart disease equivalent, amongst black African RA patients

In vitro inhibitory activities of selected Australian medicinal plant extracts against protein glycation, angiotensin converting enzyme (ACE) and digestive enzymes linked to type II diabetes

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background There is a need to develop potential new therapies for the management of diabetes and hypertension. Australian medicinal plants collected from the Kuuku I’yu (Northern Kaanju) homelands, Cape York Peninsula, Queensland, Australia were investigated to determine their therapeutic potential. Extracts were tested for inhibition of protein glycation and key enzymes relevant to the management of hyperglycaemia and hypertension. The inhibitory activities were further correlated with the antioxidant activities. Methods Extracts of five selected plant species were investigated: Petalostigma pubescens, Petalostigma banksii, Memecylon pauciflorum, Millettia pinnata and Grewia mesomischa. Enzyme inhibitory activity of the plant extracts was assessed against α-amylase, α-glucosidase and angiotensin converting enzyme (ACE). Antiglycation activity was determined using glucose-induced protein glycation models and formation of protein-bound fluorescent advanced glycation endproducts (AGEs). Antioxidant activity was determined by measuring the scavenging effect of plant extracts against 1, 1-diphenyl-2-picryl hydrazyl (DPPH) and using the ferric reducing anti-oxidant potential assay (FRAP). Total phenolic and flavonoid contents were also determined. Results Extracts of the leaves of Petalostigma banksii and P. pubescens showed the strongest inhibition of α-amylase with IC50 values of 166.50 ± 5.50 μg/mL and 160.20 ± 27.92 μg/mL, respectively. The P. pubescens leaf extract was also the strongest inhibitor of α-glucosidase with an IC50 of 167.83 ± 23.82 μg/mL. Testing for the antiglycation potential of the extracts, measured as inhibition of formation of protein-bound fluorescent AGEs, showed that P. banksii root and fruit extracts had IC50 values of 34.49 ± 4.31 μg/mL and 47.72 ± 1.65 μg/mL, respectively, which were significantly lower (p < 0.05) than other extracts. The inhibitory effect on α-amylase, α-glucosidase and the antiglycation potential of the extracts did not correlate with the total phenolic, total flavonoid, FRAP or DPPH. For ACE inhibition, IC50 values ranged between 266.27 ± 6.91 to 695.17 ± 15.38 μg/mL. Conclusions The tested Australian medicinal plant extracts inhibit glucose-induced fluorescent AGEs, α-amylase, α-glucosidase and ACE with extracts of Petalostigma species showing the most promising activity. These medicinal plants could potentially be further developed as therapeutic agents in the treatment of hyperglycaemia and hypertension