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Roberts J.M.,Magee Womens Research Institute | Roberts J.M.,University of Pittsburgh
Seminars in Perinatology | Year: 2014

The pregnancy disorders associated with placental ischemia share many similar pathological and pathophysiological features and are associated with the failure to deliver adequate nutrients and oxygen to the placenta. The origins of this deficiency are a subject of intense study. In this article, I review the genesis and consequences of this pathology addressing the similarities and the differences with the different disorders and addressing current gaps in our knowledge. © 2014 Elsevier Inc.

Burgener A.,Public Health Agency of Canada | Burgener A.,University of Manitoba | Burgener A.,Karolinska Institutet | McGowan I.,University of Pittsburgh | And 3 more authors.
Current Opinion in Immunology | Year: 2015

The mucosal barrier plays an integral function in human health as it is the primary defense against pathogens, and provides a critical transition between the external environment and the human internal body. In the context of HIV infection, the most relevant mucosal surfaces include those of the gastrointestinal (GI) and genital tract compartments. Several components help maintain the effectiveness of this mucosal surface, including the physical anatomy of the barrier, cellular immunity, soluble factors, and interactions between the epithelial barrier and the local microenvironment, including mucus and host microbiota. Any defects in barrier integrity or function can rapidly lead to an increase in acquisition risk, or with established infection may result in increased pathogenesis, morbidities, or mortality. Indeed, a key feature to all aspects of HIV infection from transmission to pathogenesis is disruption and/or dysfunction of mucosal barriers. Herein, we will detail the host-pathogen relationship of HIV and mucosal barriers in both of these scenarios. © 2015.

Majumdar S.S.,National Institute of Immunology | Sarda K.,National Institute of Immunology | Bhattacharya I.,National Institute of Immunology | Plant T.M.,Magee Womens Research Institute
Human Reproduction | Year: 2012

background: In humans, as well as in other higher primates, the infantile testis is exposed to an adult-like hormonal milieu, but spermatogenesis is not initiated at this stage of primate development. In the present study, we examined the molecular basis of this intriguing infertile state of the primate testis. methods: The integrity of androgen receptor (AR) and FSH receptor (FSHR) signaling pathways in primary cultures of Sertoli cells (Scs) harvested from azoospermic infant and spermatogenic pubertal monkey testes were investigated under identical in vitro hormonal conditions. In order to synchronously harvest Scs from early pubertal testis, the activation of testicular puberty was timed experimentally by prematurely initiating gonadotrophin secretion in juvenile animals with an intermittent infusion of gonadotrophin-releasing hormone. results: While qRT-PCR demonstrated that AR and FSHR mRNA expression in Scs from infant and pubertal testes were comparable, androgen-binding and FSH-mediated cAMP production by infant Scs was extremely low. Compromised AR and FSHR signaling in infant Scs was further supported by the finding that testosterone (T) and FSH failed to augment the expression of the T responsive gene, claudin 11, and the FSH responsive genes, inhibin-bB, stem cell factor (SCF) and glial cell line-derived neurotrophic factor (GDNF) in Scs harvested at this stage of development. conclusion: These results indicate that compromised AR and FSHR signaling pathways in Scs underlie the inability of the infant primate testis to respond to an endogenous hormonal milieu that later in development, at the time puberty, stimulates the initiation of spermatogenesis. This finding may have relevance to some forms of idiopathic infertility in men. © The Author 2012.

Lash T.L.,Emory University | Abrams B.,University of California at Berkeley | Bodnar L.M.,University of Pittsburgh | Bodnar L.M.,Magee Womens Research Institute
Epidemiology | Year: 2014

BACKGROUND: Epidemiologic data sets continue to grow larger. Probabilistic-bias analyses, which simulate hundreds of thousands of replications of the original data set, may challenge desktop computational resources. METHODS: We implemented a probabilistic-bias analysis to evaluate the direction, magnitude, and uncertainty of the bias arising from misclassification of prepregnancy body mass index when studying its association with early preterm birth in a cohort of 773,625 singleton births. We compared 3 bias analysis strategies: (1) using the full cohort, (2) using a case-cohort design, and (3) weighting records by their frequency in the full cohort. RESULTS: Underweight and overweight mothers were more likely to deliver early preterm. A validation substudy demonstrated misclassification of prepregnancy body mass index derived from birth certificates. Probabilistic-bias analyses suggested that the association between underweight and early preterm birth was overestimated by the conventional approach, whereas the associations between overweight categories and early preterm birth were underestimated. The 3 bias analyses yielded equivalent results and challenged our typical desktop computing environment. Analyses applied to the full cohort, case cohort, and weighted full cohort required 7.75 days and 4 terabytes, 15.8 hours and 287 gigabytes, and 8.5 hours and 202 gigabytes, respectively. CONCLUSIONS: Large epidemiologic data sets often include variables that are imperfectly measured, often because data were collected for other purposes. Probabilistic-bias analysis allows quantification of errors but may be difficult in a desktop computing environment. Solutions that allow these analyses in this environment can be achieved without new hardware and within reasonable computational time frames. Copyright © 2014 by Lippincott Williams & Wilkins.

Weissgerber T.L.,Magee Womens Research Institute | Davies G.A.L.,Queens University | Tschakovsky M.E.,Queens University
Journal of Applied Physiology | Year: 2010

Radial artery diameter decreases when a wrist cuff is inflated to stop blood flow to distal tissue. This phenomenon, referred to as low flow-mediated vasoconstriction (L-FMC), was proposed as a vascular function test. Recommendations that L-FMC be measured concurrently with flow-mediated dilation (FMD) were based on radial artery data. However, cardiovascular disease prediction studies traditionally measure brachial artery FMD. Therefore, studies should determine whether L-FMC occurs in the brachial artery. The hypothesis that reduced shear causes L-FMC has not been tested. Brachial and radial artery L-FMC and FMD were assessed in active nonpregnant (n = 17), inactive nonpregnant (n = 10), active pregnant (n = 15, 34.1 ± 1.2 wk gestation), and inactive pregnant (n = 8, 34.2 ± 2.2 wk gestation) women. Radial artery diameter decreased significantly during occlusion in all groups (nonpregnant, -4.4 ± 4.2%; pregnant, -6.4 ± 3.2%). Brachial artery diameter did not change in active and inactive nonpregnant, and inactive pregnant women; however, the small decrease in active pregnant women was significant. Occlusion decreased shear rate in both arteries, yet L-FMC only occurred in the radial artery. Radial artery L-FMC was not correlated with the reduction in shear rate. L-FMC occurs in the radial but not the brachial artery and is not related to changes in shear rate. Positive correlations between L-FMC (negative values) and FMD (positive values) suggest that radial artery FMD may be reduced among women who experience greater L-FMC. Studies should clarify the underlying stimulus and mechanisms regulating L-FMC, and test the hypothesis that endothelial dysfunction is manifested as enhanced brachial artery L-FMC, but attenuated radial artery L-FMC. Copyright © 2010 the American Physiological Society.

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