The estrogen-injected female mouse: new insight into the etiology of PCOS

<p>Abstract</p> <p>Background</p> <p>Female mice and rats injected with estrogen perinatally become anovulatory and develop follicular cysts. The current consensus is that this adverse response to estrogen involves the hypothalamus and occurs because of an estrogen-induced alteration in the GnRH delivery system. Whether or not this is true has yet to be firmly established. The present study examined an alternate possibility in which anovulation and cyst development occurs through an estrogen-induced disruption in the immune system, achieved through the intermediation of the thymus gland.</p> <p>Methods, Results and Conclusion</p> <p>A putative role for the thymus in estrogen-induced anovulation and follicular cyst formation (a model of PCOS) was examined in female mice by removing the gland prior to estrogen injection. Whereas all intact, female mice injected with 20 ug estrogen at 5–7 days of age had ovaries with follicular cysts, no cysts were observed in animals in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. Thus, when estrogen is unable to act on the thymus, ovulation occurs and follicular cysts do not develop. This implicates the thymus in the cysts' genesis and discounts the role of the hypothalamus. Subsequent research established that the disease is transferable by lymphocyte infusion. Transfer took place between 100-day-old estrogen-injected and 15-day-old naïve mice only when recipients were thymectomized at 3 days of age. Thus, a prerequisite for cyst formation is the absence of regulatory T cells. Their absence in donor mice was judged to be the result of an estrogen-induced increase in the thymus' vascular permeability, causing de facto circumvention of the final stages of regulatory T cell development. The human thymus has a similar vulnerability to steroid action during the fetal stage. We propose that in utero exposure to excessive levels of steroids such as estrogen has a long-term effect on the ability of the thymus to produce regulatory T cells. In female offspring this can lead to PCOS.</p

All Our Babies Cohort Study: recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment

<p>Abstract</p> <p>Background</p> <p>Preterm birth is the leading cause of perinatal morbidity and mortality. Risk factors for preterm birth include a personal or familial history of preterm delivery, ethnicity and low socioeconomic status yet the ability to predict preterm delivery before the onset of preterm labour evades clinical practice. Evidence suggests that genetics may play a role in the multi-factorial pathophysiology of preterm birth. The All Our Babies Study is an on-going community based longitudinal cohort study that was designed to establish a cohort of women to investigate how a women's genetics and environment contribute to the pathophysiology of preterm birth. Specifically this study will examine the predictive potential of maternal leukocytes for predicting preterm birth in non-labouring women through the examination of gene expression profiles and gene-environment interactions.</p> <p>Methods/Design</p> <p>Collaborations have been established between clinical lab services, the provincial health service provider and researchers to create an interdisciplinary study design for the All Our Babies Study. A birth cohort of 2000 women has been established to address this research question. Women provide informed consent for blood sample collection, linkage to medical records and complete questionnaires related to prenatal health, service utilization, social support, emotional and physical health, demographics, and breast and infant feeding. Maternal blood samples are collected in PAXgene™ RNA tubes between 18-22 and 28-32 weeks gestation for transcriptomic analyses.</p> <p>Discussion</p> <p>The All Our Babies Study is an example of how investment in clinical-academic-community partnerships can improve research efficiency and accelerate the recruitment and data collection phases of a study. Establishing these partnerships during the study design phase and maintaining these relationships through the duration of the study provides the unique opportunity to investigate the multi-causal factors of preterm birth. The overall All Our Babies Study results can potentially lead to healthier pregnancies, mothers, infants and children.</p

The role of chemotherapeutic drugs in the evaluation of breast tumour response to chemotherapy using serial FDG-PET

INTRODUCTION: The aims of this study were to investigate whether drug sequence (docetaxel followed by anthracyclines or the drugs in reverse order) affects changes in the maximal standard uptake volume (SUVmax) on [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) during neoadjuvant chemotherapy in women with locally advanced breast cancer. METHODS: Women were randomly assigned to receive either drug sequence, and FDG-PET scans were taken at baseline, after four cycles and after eight cycles of chemotherapy. Tumour response to chemotherapy was evaluated based on histology from a surgical specimen collected upon completion of chemotherapy. RESULTS: Sixty women were enrolled into the study. Thirty-one received docetaxel followed by anthracyclines (Arm A) and 29 received drugs in the reverse order (Arm B). Most women (83%) had ductal carcinoma and 10 women (17%) had lobular or lobular/ductal carcinoma. All but one tumour were downstaged during therapy. Overall, there was no significant difference in response between the two drug regimens. However, women in Arm B who achieved complete pathological response had mean FDG-PET SUVmax reduction of 87.7% after four cycles, in contrast to those who had no or minor pathological response. These women recorded mean SUVmax reductions of only 27% (P < 0.01). Women in Arm A showed no significant difference in SUVmax response according to pathological response. Sensitivity, specificity, accuracy and positive and negative predictive values were highest in women in Arm B. CONCLUSIONS: Our results show that SUVmax uptake by breast tumours during chemotherapy can be dependent on the drugs used. Care must be taken when interpreting FDG-PET in settings where patients receive varied drug protocols

Conflicting Views on Chemical Carcinogenesis Arising from the Design and Evaluation of Rodent Carcinogenicity Studies

Conflicting views have been expressed frequently on assessments of human cancer risk of environmental agents based on animal carcinogenicity data; this is primarily because of uncertainties associated with extrapolations of toxicologic findings from studies in experimental animals to human circumstances. Underlying these uncertainties are issues related to how experiments are designed, how rigorously hypotheses are tested, and to what extent assertions extend beyond actual findings. National and international health agencies regard carcinogenicity findings in well-conducted experimental animal studies as evidence of potential carcinogenic risk to humans. Controversies arise when both positive and negative carcinogenicity data exist for a specific agent or when incomplete mechanistic data suggest a possible species difference in response. Issues of experimental design and evaluation that might contribute to disparate results are addressed in this article. To serve as reliable sources of data for the evaluation of the carcinogenic potential of environmental agents, experimental studies must include a) animal models that are sensitive to the end points under investigation; b) detailed characterization of the agent and the administered doses; c) challenging doses and durations of exposure (at least 2 years for rats and mice); d) sufficient numbers of animals per dose group to be capable of detecting a true effect; e) multiple dose groups to allow characterization of dose–response relationships, f) complete and peer-reviewed histopathologic evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted tumor incidence. Pharmacokinetic models and mechanistic hypotheses may provide insights into the biological behavior of the agent; however, they must be adequately tested before being used to evaluate human cancer risk

Population uptake of antiretroviral treatment through primary care in rural South Africa

<p>Abstract</p> <p>Background</p> <p>KwaZulu-Natal is the South African province worst affected by HIV and the focus of early modeling studies investigating strategies of antiretroviral treatment (ART) delivery. The reality of antiretroviral roll-out through primary care has differed from that anticipated and real world data are needed to inform the planning of further scaling up of services. We investigated the factors associated with uptake of antiretroviral treatment through a primary healthcare system in rural South Africa.</p> <p>Methods</p> <p>Detailed demographic, HIV surveillance and geographic information system (GIS) data were used to estimate the proportion of HIV positive adults accessing antiretroviral treatment within northern KwaZulu-Natal, South Africa in the period from initiation of antiretroviral roll-out until the end of 2008. Demographic, spatial and socioeconomic factors influencing the likelihood of individuals accessing antiretroviral treatment were explored using multivariable analysis.</p> <p>Results</p> <p>Mean uptake of ART among HIV positive resident adults was 21.0% (95%CI 20.1-21.9). Uptake among HIV positive men (19.2%) was slightly lower than women (21.8%, P = 0.011). An individual's likelihood of accessing ART was not associated with level of education, household assets or urban/rural locale. ART uptake was strongly negatively associated with distance from the nearest primary healthcare facility (aOR = 0.728 per square-root transformed km, 95%CI 0.658-0.963, <it>P </it>= 0.002).</p> <p>Conclusions</p> <p>Despite concerns about the equitable nature of antiretroviral treatment rollout, we find very few differences in ART uptake across a range of socio-demographic variables in a rural South African population. However, even when socio-demographic factors were taken into account, individuals living further away from primary healthcare clinics were still significantly less likely to be accessing ART</p

How Attractive Is the Girl Next Door? An Assessment of Spatial Mate Acquisition and Paternity in the Solitary Cape Dune Mole-Rat, Bathyergus suillus

Behavioural observations of reproduction and mate choice in wild fossorial rodents are extremely limited and consequently indirect methods are typically used to infer mating strategies. We use a combination of morphological, reproductive, spatial, and genetic data to investigate the reproductive strategy of a solitary endemic species, the Cape dune mole-rat Bathyergus suillus. These data provide the first account on the population dynamics of this species. Marked sexual dimorphism was apparent with males being both significantly larger and heavier than females. Of all females sampled 36% had previously reproduced and 12% were pregnant at the time of capture. Post-partum sex ratio was found to be significantly skewed in favour of females. The paternity of fifteen litters (n = 37) was calculated, with sires assigned to progeny using both categorical and full probability methods, and including a distance function. The maximum distance between progeny and a putative sire was determined as 2149 m with males moving between sub-populations. We suggest that above-ground movement should not be ignored in the consideration of mate acquisition behaviour of subterranean mammals. Estimated levels of multiple paternity were shown to be potentially as high as 26%, as determined using sibship and sire assignment methods. Such high levels of multiple paternity have not been found in other solitary mole-rat species. The data therefore suggest polyandry with no evidence as yet for polygyny

High-levels of acquired drug resistance in adult patients failing first-line antiretroviral therapy in a rural HIV treatment programme in KwaZulu-Natal, South Africa.

OBJECTIVE: To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa. DESIGN: Cross-sectional study nested within HIV treatment programme. METHODS: Adult (≥ 18 years) HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART) regimen and with evidence of virological failure (one viral load >1000 copies/ml) were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms. RESULTS: A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%); and stavudine, lamivudine and nevirapine (24%). Median duration of ART was 42 months (interquartile range (IQR) 32-53) and median duration of antiretroviral failure was 27 months (IQR 17-40). One hundred and ninety one (86%) had at least one drug resistance mutation. For 34 individuals (15%), the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI) substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR) 5.70, 95% confidence interval (CI) 2.60-12.49). CONCLUSIONS: There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved

Choice-Disability and HIV Infection: A Cross Sectional Study of HIV Status in Botswana, Namibia and Swaziland

Interpersonal power gradients may prevent people implementing HIV prevention decisions. Among 7,464 youth aged 15–29 years in Botswana, Namibia and Swaziland we documented indicators of choice-disability (low education, educational disparity with partner, experience of sexual violence, experience of intimate partner violence (IPV), poverty, partner income disparity, willingness to have sex without a condom despite believing partner at risk of HIV), and risk behaviours like inconsistent use of condoms and multiple partners. In Botswana, Namibia and Swaziland, 22.9, 9.1, and 26.1% women, and 8.3, 2.8, and 9.3% men, were HIV positive. Among both women and men, experience of IPV, IPV interacted with age, and partner income disparity interacted with age were associated with HIV positivity in multivariate analysis. Additional factors were low education (for women) and poverty (for men). Choice disability may be an important driver of the AIDS epidemic. New strategies are needed that favour the choice-disabled