Flutamide-induced hypospadias in rats: A critical assessment.

This paper provides the first detailed description of flutamide-induced hypospadias in the rat based upon wholemount, histologic, three-dimensional reconstruction, scanning electron microscopic, and immunocytochemical analysis. The penile malformations elicited by this potent anti-androgen include a substantial proximal shift in the urethral meatus that clearly conforms to the definition of hypospadias based upon specific morphological criteria for this malformation. Through examination of the normal penile development and flutamide-induced abnormal penile development observed in prenatally oil- and flutamide-treated rats, our analysis provides insights into the morphogenetic mechanism of development of hypospadias. In this regard, a common theme in normal penile development is midline fusion of epithelia followed by removal of the epithelial seam and establishment of midline mesenchymal confluence during development of the penile urethra and prepuce, processes which are impaired as a result of prenatal flutamide treatment. The developmental processes occurring in normal penile development, through comparison with development of female external genitalia and those impaired due to prenatal flutamide treatment, are consistent with critical role of androgen receptors in normal penile development in the rat, and the specific penile abnormalities embodied in flutamide-induced rat hypospadias

Integrating Statistical Evidence and Legal Theory to Challenge the Selection of Grand and Petit Jurors

The increasing allergy prevalence in affluent countries may be caused by reduced microbial stimulation and a decreased dietary ω-3/ω-6 long-chain polyunsaturated fatty acid (LCPUFA) ratio, resulting in an abnormal postnatal immune maturation. The timing of allergy-preventive probiotic and ω-3 LCPUFA interventions is critical, as early-life events occurring during critical windows of immune vulnerability can have long-term impact on immune development. The maternal dietary and microbial environment during pregnancy may programme the immune development of the child. Prenatal environmental exposures may alter gene expression via epigenetic mechanisms, aiming to induce physiological adaptations to the anticipated postnatal environment, but potentially also increasing disease susceptibility in the offspring if exposures are mismatched. Although the importance of fetal programming mostly has been studied in cardiovascular and metabolic disease, this hypothesis is also very attractive in the context of environmentally influenced immune-mediated diseases. This review focuses on how prenatal, perinatal or postnatal ω-3 LCPUFA interventions regulate childhood immune and allergy development, and if synergistic effects may be obtained by simultaneous probiotic supplementation. We propose that combined pre- and postnatal preventive measures may be most efficacious. Increasing knowledge on the immunomodulatory effects of prenatal, perinatal and postnatal interventions will help to direct future strategies to combat the allergy epidemic.Funding Agencies|Swedish Research Council||Ekhaga Foundation||Research Council for the South-East Sweden||Swedish Asthma and Allergy Association||Olle Engkvist Foundation||Vardal Foundation - for Health Care Sciences and Allergy Research||</p

Severe congenital microcephaly with AP4M1 mutation, a case report

Background: Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset. Case presentation: We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly. Conclusions: Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly

Neonatal abstinence syndrome: Pharmacologic strategies for the mother and infant.

Opioid use in pregnancy has increased dramatically over the past decade. Since prenatal opioid use is associated with numerous obstetrical and neonatal complications, this now has become a major public health problem. In particular, in utero opioid exposure can result in neonatal abstinence syndrome (NAS) which is a serious condition characterized by central nervous system hyperirritability and autonomic nervous system dysfunction. The present review seeks to define current practices regarding the approach to the pregnant mother and neonate with prenatal opiate exposure. Although the cornerstone of prenatal management of opioid dependence is opioid maintenance therapy, the ideal agent has yet to be definitively established. Pharmacologic management of NAS is also highly variable and may include an opioid, barbiturate, and/or α-agonist. Genetic factors appear to be associated with the incidence and severity of NAS. Establishing pharmacogenetic risk factors for the development of NAS has the potential for creating opportunities for personalized genomic medicine and novel, individualized therapeutic interventions

Influence of prenatal maternal stress, maternal plasma cortisol and cortisol in the amniotic fluid on birth outcomes and child temperament at 3 months

This prospective, longitudinal study aimed to investigate relationships between indicators of maternal prenatal stress, infant birth outcomes and early temperament. We examined the pattern of associations and postulated pathways between physiological (cortisol plasma concentrations) and self-report indices (stress, anxiety) of maternal prenatal stress, cortisol in the amniotic fluid, birth outcomes and infant temperament at 3 months. The sample consisted of 158 women undergoing amniocentesis in the 2nd trimester of pregnancy. Questionnaire measures of maternal stress and anxiety were found to be unrelated to cortisol in plasma or amniotic fluid. Maternal cortisol was related to amniotic cortisol, which in turn was associated with lower birth weight. Birth weight predicted infant fear and distress to limitation at 3 months old. We found trend-like indirect effects of amniotic fluid on infant distress to limitation and fear via birth weight. This is one of the few studies to simultaneously assess the role of maternal and amniotic fluid cortisol on birth outcomes and infant emotional development. The results suggest that foetal cortisol may be an important predictor of infant outcomes and shed light on the mechanisms through which prenatal maternal stress affects infant psychological health

Integrating Economic Analysis with a Randomized Controlled Trial: Willingness-to-Pay for a New Maternal Nutrient Supplement

Maternal nutrition during pregnancy can have significant implications for a child’s prenatal growth and development, and undernutrition experienced during the prenatal period increases the risk of early childhood morbidity and mortality and can permanently impair a child’s physical growth and cognitive development. We use new data from Ghana generated using contingent valuation and experimental auction techniques to estimate willingness-to-pay (WTP) for LNS, a new nutrient supplement aimed at preventing maternal undernutrition during pregnancy. We also explore the relative importance of individual and household characteristics as well as information about the long-term benefits of preventing undernutrition on WTP. We find that WTP is positive for a large majority of individuals in our samples, and the level of WTP varies significantly with individual and household characteristics including gender, household food insecurity, and household expenditures. These findings suggest important policy implications for the development of delivery options and pricing mechanisms for LNS.Economic Development, Nutrition, Willingness-to-Pay, Food Consumption/Nutrition/Food Safety, Health Economics and Policy, International Development,

Identification of side population cells in mouse primordial germ cells and prenatal testis

In mammals, the stem cells of spermatogenesis are derived from an embryonic cell population called primordial germ cells (PGCs). Spermatogonial stem cells displaying the "side population" (SP) phenotype have been identified in the immature and adult mouse testis, but noting is known about the expression of the SP phenotype during prenatal development of germ cells. The SP phenotype, defined as the ability of cells to efflux fluorescent dyes such as Hoechst, is common to several stem/progenitor cell types. In the present study, we analyzed and characterized the Hoechst SP via cytofluorimetric analysis of disaggregated gonads at different time points during embryonic development in mice. To directly test the hypothesis that the SP phenotype is a feature of germ cell lineage, experiments were performed on transgenic animals expressing enhanced green fluorescent protein (EGFP) under the control of the Oct4 promoter, to identify early germ cells up to PGCs. We found that prenatal gonads contain a fraction of SP cells at each stage analyzed, and the percentage of cells in the SP fraction decreases as development proceeds. Surprisingly, more than 50% of the PGCs displayed the SP phenotype at 11.5 dpc (days post coitum). The percentage of germ cells with the SP phenotype decreased steadily with development, to less than 1% at 18.5 dpc. Cytofluorimetric analysis along with immunocytochemistry performed on sorted cells indicated that the SP fraction of prenatal gonads, as in the adult testis, was heterogeneous, being composed of both somatic and germ cells. Both cell types expressed the ABC transporters Abcg2, Abcb1a, Abcb1b and Abcc1. These findings provide evidence that the SP phenotype is a common feature of PGCs and identifies a subpopulation of fetal testis cells including prospermatogonia whose differentiation fate remains to be investigated. © 2011 UBC Press

New regression formula to estimate the prenatal crown formation time of human deciduous central incisors derived from a Roman imperial sample (Velia, Salerno, Italy, I-II cent. CE)

The characterization and quantification of human dental enamel microstructure, in both permanent and deciduous teeth, allows us to document crucial growth parameters and to identify stressful events, thus contributing to the reconstruction of the past life history of an individual. Most studies to date have focused on the more accessible post-natal portion of the deciduous dental enamel, even though the analysis of prenatal enamel is pivotal in understanding fetal growth, and reveals information about the mother's health status during pregnancy. This contribution reports new data describing the prenatal enamel development of 18 central deciduous incisors from the Imperial Roman necropolis of Velia (I-II century CE, Salerno, Italy). Histomorphometrical analysis was performed to collect data on prenatal crown formation times, daily secretion rates and enamel extension rates. Results for the Velia sample allowed us to derive a new regression formula, using a robust statistical approach, that describes the average rates of deciduous enamel formation. This can now be used as a reference for pre-industrial populations. The same regression formula, even when daily incremental markings are difficult to visualize, may provide a clue to predicting the proportion of infants born full term and pre-term in an archaeological series

Testosterone and grasp-reflex differences in human neonates

According to the Geschwind-Behan-Galaburda (GBG) hypothesis, prenatal testosterone (T) causes a slowing in the development of the left brain with a consequent compensatory growth in the right brain, creating a reverse organisation of the cerebral lateralisation. That is, left- and right-handedness might be associated with high and low prenatal T levels, respectively. To test this hypothesis, the relations of T levels (umbilical cord blood) to grasp-reflex strengths were studied in human neonates. Handedness was assessed by measuring the grasp-reflex strengths from the right and left hands in 10 trials from each hand alternatively. There were two handedness groups: right-handers (R-L significantly greater than zero) and left-handers (significantly smaller than zero). Contrary to the GBG model, the mean free T concentration was found to be significantly higher in right-handers than left-handers for males and females. There was no significant difference in the total T levels between right- and left-handers. Free T concentrations positively correlated with R-L grasp-reflex strengths, i.e. right-handedness increased as T increased, and left-handedness increased as T decreased. Contrary to these positive correlations, T negatively correlated with the grasp-reflex strengths from the right and left hands. These results partly supported the GBG hypothesis for this spinal-motor-asymmetry model. Total T did not significantly correlate with grasp-reflex strengths. The results suggest that prenatal T may at least play a role in prenatal determination of spinal motor lateralisation, with a possible consequent upward regulation of cerebral lateralisation

Ghana’s National Health Insurance Scheme in the Context of the Health MDGs – An Empirical Evaluation Using Propensity Score Matching

In 2003 the Government of Ghana established a National Health Insurance Scheme (NHIS) to improve health care access for Ghanaians and eventually replace the cashand- carry system. This study evaluates the NHIS to determine whether it is fulfi lling its purpose in the context of the Millennium Development Goals #4 and #5 which deal with the health of women and children. We use Propensity Score Matching techniques to balance the relevant background characteristics in our survey data and compare health outcomes of recent mothers who are enrolled in the NHIS with those who are not. Our fi ndings suggest that NHIS women are more likely to receive prenatal care, deliver at a hospital, have their deliveries attended by trained health professionals, and experience less birth complications. We conclude that NHIS is an eff ective tool for increasing health care access, and improving health outcomes.Health insurance, prenatal care, Millennium Development Goals, Propensity Score Matching