Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.

Microphysiological modeling of the reproductive tract: A fertile endeavor

Preclinical toxicity testing in animal models is a cornerstone of the drug development process, yet it is often unable to predict adverse effects and tolerability issues in human subjects. Species-specific responses to investigational drugs have led researchers to utilize human tissues and cells to better estimate human toxicity. Unfortunately, human cell-derived models are imperfect because toxicity is assessed in isolation, removed from the normal physiologic microenvironment. Microphysiological modeling often referred to as 'organ-on-a-chip' or 'human-on-a-chip' places human tissue into a microfluidic system that mimics the complexity of human in vivo physiology, thereby allowing for toxicity testing on several cell types, tissues, and organs within a more biologically relevant environment. Here we describe important concepts when developing a repro-on-a-chip model. The development of female and male reproductive microfluidic systems is critical to sex-based in vitro toxicity and drug testing. This review addresses the biological and physiological aspects of the male and female reproductive systems in vivo and what should be considered when designing a microphysiological human-on-a-chip model. Additionally, interactions between the reproductive tract and other systems are explored, focusing on the impact of factors and hormones produced by the reproductive tract and disease pathophysiology.

Interspecific comparison of estrogen and testosterone concentrations in three species of amphipods (Gammarus duebeni celticus, G. pseudolimnaeus, and G. pulex)

The presence and biological significance of vertebrate-related steroid sex hormones in aquatic invertebrates are poorly understood. We compared the concentrations of estrogen (17β-estradiol) and testosterone between amplexing male and female freshwater amphipods of three species from two continents: Gammarus duebeni celticusLiljeborg, 1852 and G. pulex(L., 1758) from Europe, and G. pseudolimnaeusBousfield, 1958 from North America. All three species were found to have measureable concentrations of both hormones in whole body lysate samples but the concentrations differed between species, with testosterone differing significantly between species only for male amphipods and estradiol differing significantly between species only for female amphipods. Concentrations of both testosterone and estrogen differed between males and females in two of the three species ( G. duebeni celticusand G. pseudolimnaeus). Females had the highest concentration of both hormones in G. duebeni celticusand the lowest concentration of both hormones in G. pseudolimnaeus. These results contribute to a growing body of evidence that these hormones are endogenously produced and biologically relevant in amphipods. Such evidence is particularly important in light of increasing prevalence of endocrine-disrupting compounds in the environment and the central role played by amphipods in aquatic ecosystems.

A rapid dot-blot assay to assess chimerism following sex-mismatched bone marrow transplantation

Mixed chimerism may occur more frequently than previously thought following allogeneic bone marrow transplantation and may have implications in terms of relapse, graft-versus-host disease and immune reconstitution. DNA analysis using single or multilocus polymorphic probes cannot reliably discriminate between donor and recipient cells below a level of 10%. We used probe pHY2.1, a cloned segment of tandemly repeated DNA (2000 copies) on the long arm of chromosome Y. A dot blot procedure allowed us to immobilize DNA directly from 50 microliter of peripheral blood or bone marrow. Cross-reactivity was eliminated by hybridization at conditions of extreme stringency (65 degrees C, 50% formamide). Mixing experiments detected male DNA at a level of 0.1% after 10 h exposure. Five patients were studied serially post-bone marrow transplantation. One patient showed mixed chimerism for 12 months, one had complete autologous recovery and the remaining three showed complete engraftment. All results were verified by standard karyotyping on bone marrow cells. This technique is a simple, rapid and sensitive assay for chimerism following sex mismatched bone marrow transplantation.

Gendered Violence and International Human Rights: Thinking Non-Discrimination Beyond the Sex Binary

The concept of non-discrimination has been central in the feminist challenge to gendered violence within international human rights law. This article critically explores non-discrimination and the challenge it seeks to pose to gendered violence through the work of Judith Butler. Drawing upon Butler’s critique of heteronormative sex/gender, the article utilises an understanding of gendered violence as effected by the restrictive scripts of sex/gender within heteronormativity to illustrate how the development of non-discrimination within international human rights law renders it ineffective to challenge gendered violence due to its own commitments to binarised and asymmetrical sex/gender. However, the article also seeks to encourage a reworking of non-discrimination beyond the heteronormative sex binary through employing Butler’s concept of cultural translation. Analysis via the lens of cultural translation reveals the fluidity of non-discrimination as a universal concept and offers new possibilities for feminist engagement with universal human rights.

Molecular pathways: Estrogen pathway in colorectal cancer.

Worldwide, colorectal cancer has a higher incidence rate in men than in women, suggesting a protective role for sex hormones in the development of the disease. Preclinical data support a role for estrogen and its receptors in the initiation and progression of colorectal cancer and establishes that protective effects of estrogen are exerted through ERβ. Hormone replacement therapy (HRT) in postmenopausal women as well as consumption of soy reduces the incidence of colorectal cancer. In the Women's Health Initiative trial, use of HRT in postmenopausal women reduced the risk of colon cancer by 56% [95% confidence interval (CI), 0.38-0.81; P = 0.003]. A recent meta-analysis showed that in women, consumption of soy reduced the risk of colon cancer by 21% (95% CI, 0.03-0.35; P = 0.026). In this review, using the preclinical data, we translate the findings in the clinical trials and observational studies to define the role of estrogen in the prevention of colorectal cancer. We hypothesize that sometime during the tumorigenesis process ERβ expression in colonocytes is lost and the estrogen ligand, HRT, or soy products, exerts its effects through preventing this loss. Thus, in the adenoma-to-carcinoma continuum, timing of HRT is a significant determinant of the observed benefit from this intervention. We further argue that the protective effects of estrogen are limited to certain molecular subtypes. Successful development of estrogen modulators for prevention of colorectal cancer depends on identification of susceptible colorectal cancer population(s). Thus, research to better understand the estrogen pathway is fundamental for clinical delivery of these agents.

Biometric gonioscopy and the effects of age, race, and sex on the anterior chamber angle.

AIM:

To utilise a novel method for making measurements in the anterior chamber in order to compare the anterior chamber angles of people of European, African, and east Asian descent aged 40 years and over.

METHODS:

A cross sectional study on 15 people of each sex from each decade from the 40s to the 70s, from each of three racial groups-black, white, and Chinese Singaporeans. Biometric gonioscopy (BG) utilises a slit lamp mounted reticule to make measurements from the apparent iris insertion to Schwalbe's line through a Goldmann one mirror goniolens. The main outcome measures were BG measurements of the anterior chamber angle as detailed above.

RESULTS:

There was no significant difference in angle measurement between black, white, and Chinese races in this study. However, at younger ages people of Chinese race appeared to have deeper angles than white or black people, whereas the angles of older Chinese were significantly narrower (p = 0.004 for the difference in slope of BG by age between Chinese and both black and white people).

CONCLUSION:

The failure to detect a difference in angle measurements between these groups was surprising, given the much higher prevalence of angle closure among Chinese. It appears that the overall apparent similarity of BG means between Chinese and Western populations may mask very different trends with age. The apparently more rapid decline in angle width measurements with age among Chinese may be due to the higher prevalence of cataract or "creeping angle closure." However, longitudinal inferences from cross sectional data are problematic, and this may represent a cohort phenomenon caused by the increasing prevalence of myopia in the younger Singaporean population.

Spatial variation in adult sex ratio across multiple scales in the invasive golden apple snail, Pomacea canaliculata

Adult sex ratio (ASR) has critical effects on behavior and life history and has implications for population demography, including the invasiveness of introduced species. ASR exhibits immense variation in nature, yet the scale dependence of this variation is rarely analyzed. In this study, using the generalized multilevel models, we investigated the variation in ASR across multiple nested spatial scales and analyzed the underlying causes for an invasive species, the golden apple snail Pomacea canaliculata. We partitioned the variance in ASR to describe the variations at different scales and then included the explanatory variables at the individual and group levels to analyze the potential causes driving the variation in ASR. We firstly determined there is a significant female-biased ASR for this species when accounting for the spatial and temporal autocorrelations of sampling. We found that, counter to nearly equal distributed variation at plot, habitat and region levels, ASR showed little variation at the town level. Temperature and precipitation at the region level were significantly positively associated with ASR, whereas the individual weight, the density characteristic, and sampling time were not significant factors influencing ASR. Our study suggests that offspring sex ratio of this species may shape the general pattern of ASR in the population level while the environmental variables at the region level translate the unbiased offspring sex ratio to the female-biased ASR. Future research should consider the implications of climate warming on the female-biased ASR of this invasive species and thus on invasion pattern.