Louis J Muglia

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

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Publications (194)1237.97 Total impact

  • Gloria Laryea, Melinda Arnett, Louis J Muglia
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    ABSTRACT: Glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN) are important regulators of negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previous evaluation of endogenous PVN GR function in adult mice demonstrated that mice with loss of GR exon 3 in the PVN (Sim1Cre-GRe3Δ) have a hyperactive HPA axis, growth impairment and metabolic disruptions. Here, we hypothesized that lack of negative feedback inhibition of the HPA axis through PVN GR, as demonstrated through loss of PVN GR early in life, will have developmental-stage-specific consequences. Immunofluorescence revealed that Sim1Cre-GRe3Δ mice display PVN GR loss as early as post-natal day 2 compared to control mice. Sim1Cre-GRe3Δ mice compared to controls also displayed increased corticotropin-releasing hormone (CRH) mRNA in the PVN at post-natal day 10, as shown by in situ hybridization. Corticosterone radioimmunoassay revealed that the disruptions in PVN GR and CRH expression led to elevated basal corticosterone secretion in male Sim1Cre-GRe3Δ mice by early adolescence and increased stress-induced (restraint) corticosterone secretion in late adolescence into adulthood. In comparison, female Sim1Cre-GRe3Δ mice did not display corticosterone disruption until adulthood. Circadian rhythmicity of corticosterone secretion was normal for male and female mice at all age groups regardless of genotype with one exception. In late adolescence, female Sim1Cre-GRe3Δ mice had disrupted circadian corticosterone secretion due to significantly elevated circulating levels at nadir. We conclude that PVN GR function matures at an earlier developmental time point in male than in female mice and thus leads to later differential stress responsiveness between sexes.
    Stress (Amsterdam, Netherlands) 06/2015; DOI:10.3109/10253890.2015.1046832 · 3.46 Impact Factor
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    ABSTRACT: Early-life stress (ELS) leads to sustained changes in gene expression and behavior, increasing the likelihood of developing a psychiatric disorder in adulthood. The neurobiological basis for the later-in-life psychopathology is relatively unknown. The current study used a mouse model of ELS, achieved by daily maternal separations during the first 2 weeks of postnatal life, to test the role of amygdalar glucocorticoid receptor (GR) function in mediating the persistent increase in risk-taking behaviors. ELS produced a decrease in GR mRNA in the brain, with a notable reduction in the amygdala that was associated with sustained alterations in anxiety, fear and sociability-like behaviors. Lentiviral-mediated restoration of the GR mRNA deficit, specifically within the adult central nucleus of the amygdala (CeA), reversed the enduring changes in anxiety and social behavior after ELS. These results provide evidence of lasting changes in CeA GR neural circuitry following ELS and suggest a mechanistic role for GR-regulated processes in the CeA in mediating the lifelong maladaptive behaviors of ELS. We demonstrate that the long-lasting behavioral effects of ELS are reversible later in life and implicate the involvement of CeA GR-dependent activity in the sustained dysregulation of emotion following ELS.
    Translational Psychiatry 04/2015; 5(4):e542. DOI:10.1038/tp.2015.35 · 4.36 Impact Factor
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    ABSTRACT: OBJECTIVE: To test the hypothesis that exposure to fine particulate air pollution (PM2.5) is associated with stillbirth. STUDY DESIGN: Geo-spatial population-based cohort study using Ohio birth records (2006-2010) and local measures of PM2.5, recorded by the EPA (2005-2010) via 57 monitoring stations across Ohio. Geographic coordinates of the mother's residence for each birth were linked to the nearest PM2.5 monitoring station and monthly exposure averages calculated. The association between stillbirth and increased PM2.5 levels was estimated, with adjustment for maternal age, race, education level, quantity of prenatal care, smoking, and season of conception. RESULTS: There were 349,188 live births and 1,848 stillbirths of non-anomalous singletons (20-42 weeks) with residence </=10 km of a monitor station in Ohio during the study period. The mean PM2.5 level in Ohio was 13.3 mug/m3 [+/-1.8 SD, IQR(Q1: 12.1, Q3: 14.4, IQR: 2.3)], higher than the current EPA standard of 12 mug/m3. High average PM2.5 exposure through pregnancy was not associated with a significant increase in stillbirth risk, adjOR 1.21(95% CI 0.96,1.53), nor was it increased with high exposure in the 1st or 2nd trimester. However, exposure to high levels of PM2.5 in the third trimester of pregnancy was associated with 42% increased stillbirth risk, adjOR 1.42(1.06,1.91). CONCLUSIONS: Exposure to high levels of fine particulate air pollution in the third trimester of pregnancy is associated with increased stillbirth risk. Although the risk increase associated with high PM2.5 levels is modest, the potential impact on overall stillbirth rates could be robust as all pregnant women are potentially at risk.
    PLoS ONE 03/2015; 10(3-3):e0120594. DOI:10.1371/journal.pone.0120594 · 3.53 Impact Factor
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    ABSTRACT: Transposable elements (TEs) comprise approximately half of the human genome, and several independent lines of investigation have demonstrated their role in rewiring gene expression during development, evolution, and oncogenesis. The identification of their regulatory effects has largely been idiosyncratic, by linking activity with isolated genes. Their distribution throughout the genome raises critical questions - do these elements contribute to broad tissue-and lineage-specific regulation? If so, in what manner, as enhancers, promoters, RNAs? Here, we devise a novel approach to systematically dissect the genome-wide consequences of TE insertion on gene expression, and test the hypothesis that classes of endogenous retrovirus long terminal repeats (LTRs) exert tissue-specific regulation of adjacent genes. Using correlation of expression patterns across 18 tissue types, we reveal the tissue-specific uncoupling of gene expression due to 62 different LTR classes. These patterns are specific to the retroviral insertion, as the same genes in species without the LTRs do not exhibit the same effect. While the LTRs can be transcribed themselves, the most highly transcribed TEs do not have the largest effects on adjacent regulation of coding genes, suggesting they function predominantly as enhancers. Moreover, the tissue-specific patterns of gene expression that are detected by our method arise from a limited number of genes, rather than as a general consequence of LTR integration. These findings identify basic principles of co-opting LTRs for genome evolution, and support the utility of our method for the analysis of TE, or other specific gene sets, in relation to the rest of the genome. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
    Genome Biology and Evolution 03/2015; 7(4). DOI:10.1093/gbe/evv049 · 4.53 Impact Factor
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    ABSTRACT: The molecular mechanisms controlling human birth timing at term, or resulting in preterm birth, have been the focus of considerable investigation, but limited insights have been gained over the past 50 years. In part, these processes have remained elusive because of divergence in reproductive strategies and physiology shown by model organisms, making extrapolation to humans uncertain. Here, we summarize the evolution of progesterone signaling and variation in pregnancy maintenance and termination. We use this comparative physiology to support the hypothesis that selective pressure on genomic loci involved in the timing of parturition have shaped human birth timing, and that these loci can be identified with comparative genomic strategies. Previous limitations imposed by divergence of mechanisms provide an important new opportunity to elucidate fundamental pathways of parturition control through increasing availability of sequenced genomes and associated reproductive physiology characteristics across diverse organisms. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor Perspectives in Medicine 02/2015; 5(2). DOI:10.1101/cshperspect.a023127 · 7.56 Impact Factor
  • James M. Greenberg, Louis J. Muglia
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    ABSTRACT: To assess the influence of birth spacing on neonatal morbidity, stratified by gestational age at birth.Study DesignPopulation-based retrospective cohort study using Ohio birth records, 2006-2011. We compared various interpregnancy interval (IPI) lengths in multiparous mothers with the rate and risk of adverse newborn outcomes. The frequency of neonatal intensive care unit (NICU) admission or neonatal transport to a tertiary care facility was calculated for births occurring after IPI lengths: <6, 6 to <12, 12 to <24, 24 to <60 and ≥60 months, and stratified by week of gestational age. Neonatal morbidity risk was calculated for each IPI compared to 12 to <24 months (referent), and adjusted for the concomitant influences gestational age at birth, maternal race, age and prior preterm birth.ResultsWe analyzed 395,146 birth outcomes of singleton non-anomalous neonates born to multiparous mothers. The frequency and adjusted odds of neonatal morbidity were lowest following IPI of 12 to <24 months (4.1%) compared to short IPIs of <6 months (5.7%, adjOR 1.40, 95% CI 1.32,1.49), 6 to <12 months (4.7%, adjOR 1.19, CI 1.13-1.25), and long IPIs 24 to <60 months (4.6%, adjOR 1.12, CI 1.08-1.17) and ≥60 months (5.8%, adjOR 1.34, CI 1.28-1.40), despite adjustment for important confounding factors including gestational age at birth. The lowest frequency of adverse neonatal outcomes occurred at 40-41 weeks for all IPI groups.The frequency of other individual immediate newborn morbidities were also increased following short and long IPIs compared to birth following a 12 to <24 month IPI.Conclusions Interpregnancy interval length is a significant contributor to neonatal morbidity, independent of gestational age at birth. Counseling women to plan an optimal amount of time between pregnancies is important for newborn health.
    American Journal of Obstetrics and Gynecology 11/2014; 212(3). DOI:10.1016/j.ajog.2014.11.017 · 3.97 Impact Factor
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    ABSTRACT: Preterm birth is a leading cause of infant morbidity and mortality worldwide, but current interventions to prevent prematurity are largely ineffective. Preterm birth is increasingly recognized as an outcome that can result from a variety of pathological processes. Despite current research efforts, the mechanisms underlying these processes remain poorly understood and are influenced by a range of biological and environmental factors. Research with modern techniques is needed to understand the mechanisms responsible for preterm labor and birth and identify targets for diagnostic and therapeutic solutions. This review evaluates the state of reproductive science relevant to understanding the causes of preterm birth, identifies potential targets for prevention, and outlines challenges and opportunities for translating research findings into effective interventions.
    Science translational medicine 11/2014; 6(262):262sr5. DOI:10.1126/scitranslmed.3009871 · 14.41 Impact Factor
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    ABSTRACT: Negative feedback regulation of glucocorticoid (GC) synthesis and secretion occurs through the function of glucocorticoid receptor (GR) at sites in the hypothalamic–pituitary–adrenal (HPA) axis, as well as in brain regions such as the hippocampus, prefrontal cortex, and sympathetic nervous system. This function of GRs in negative feedback coordinates basal glucocorticoid secretion and stress-induced increases in secretion that integrate GC production with the magnitude and duration of the stressor. This review describes the effects of GR loss along major sites of negative feedback including the entire brain, the paraventricular nucleus of the hypothalamus (PVN), and the pituitary. In genetic mouse models, we evaluate circadian regulation of the HPA axis, stress-stimulated neuroendocrine response and behavioral activity, as well as the integrated response of organism metabolism. Our analysis provides information on contributions of region-specific GR-mediated negative feedback to provide insight in understanding HPA axis dysregulation and the pathogenesis of psychiatric and metabolic disorders.
    Frontiers in Neuroendocrinology 09/2014; 36. DOI:10.1016/j.yfrne.2014.09.002 · 7.58 Impact Factor
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    ABSTRACT: Insulin signaling in the central nervous system (CNS) regulates energy balance and peripheral glucose homeostasis. Rictor is a key regulatory/structural subunit of the mTORC2 complex and is required for hydrophobic motif site phosphorylation of Akt at serine 473. To examine the contribution of neuronal Rictor/mTORC2 signaling to CNS regulation of energy and glucose homeostasis, we utilized Cre-LoxP technology to generate mice lacking Rictor in all neurons, or in either POMC or AgRP expressing neurons. Rictor deletion in all neurons led to increased fat mass and adiposity, glucose intolerance and behavioral leptin resistance. Disrupting Rictor in POMC neurons also caused obesity and hyperphagia, fasting hyperglycemia and pronounced glucose intolerance. AgRP neuron specific deletion did not impact energy balance but led to mild glucose intolerance. Collectively, we show that Rictor/mTORC2 signaling, especially in POMC-expressing neurons, is important for central regulation of energy and glucose homeostasis.
    07/2014; 3(4). DOI:10.1016/j.molmet.2014.01.014
  • The Lancet 05/2014; 383(9929):1611-3. DOI:10.1016/S0140-6736(14)60583-3 · 45.22 Impact Factor
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    ABSTRACT: OBJECTIVE: Test the hypothesis that exposure to fine particles in the air (PM2.5) is associated with increased risk of preterm birth (PTB). STUDY DESIGN: Geo-spatial population-based cohort study using live birth records from Ohio(2007-2010) linked to average daily measures of PM2.5, recorded by 57 EPA network monitoring stations across the state. Geographic coordinates of the home residence for births were linked to the nearest monitoring station using ArcGIS. Association between PTB and high PM2.5 levels (above the EPA annual standard of 15ug/m3) was estimated using GEE, with adjustment for age, race, education, parity, insurance, tobacco, birth season and year, and baby gender. An exchangeable correlation matrix for the monitor stations was used in the models. Analyses limited to singleton births at 20-42 wks with no known chromosome abnormality occurring within 10km of a monitor station. RESULTS: The frequency of PTB was 8.5% and small for gestational age (SGA, BW < 2500 gm) was 6.9% in the study cohort, n= 224,921. High PM2.5 exposure > EPA recommended max occurred frequently during the study period, with 24,662 women (11%) having high exposure in all three trimesters. Pregnancies with high PM2.5 exposure through pregnancy had increased PTB risk even after adjustment for coexisting risk factors, aOR1.15(1.06-1.25). Assessed per trimester, high 3rd trimester PM2.5 had the highest PTB risk, aOR1.25(1.18-1.33). High exposure in 3rd trimester and through pregnancy also increased SGA risk, aOR1.16(1.09-1.24) and1.24(1.16-1.32) respectively. CONCLUSION: Exposure to high levels of fine particulate air pollution, PM2.5, in pregnancy is associated with increased risk of PTB and SGA. Although the risk increase associated with high PM2.5 levels is modest, the potential impact on overall PTB rates is robust as all pregnant women are potentially at risk. This may in part contribute to the higher preterm birth rates in Ohio compared to other states in the US, especially in urban areas.
    American Journal of Obstetrics and Gynecology 01/2014; 210(1-1):S346. DOI:10.1016/j.ajog.2013.10.736 · 3.97 Impact Factor
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    ABSTRACT: Reproduction in eutherian mammals is characterized by extended intrauterine retention of the fetus after implantation. We summarize evolutionary innovations that enable this form of vivipary, including early maternal recognition of pregnancy, invasive placentation, and emergence of the decidual cell type. We first review the structure of the marsupial endometrium and its relationship to that of eutherian mammals. While the tissue components of endometrium are the same in marsupials and eutherians, an important difference is the amount of stromal cells, which are much more abundant in eutherians. Moreover, the nature of the invasive placentation differs in marsupials and eutherians. In the opossum, it consists of cytoplasmatic extensions of trophoblast cells that penetrate between the luminal epithelial cells to contact maternal capillaries. In bandicoots, the trophoblast and luminal epithelial cells fuse, and the maternal epithelium is replaced by a layer of multinucleated cells. In no case has there been evidence of a direct interaction between trophoblast and stromal cells. The direct interface between the trophoblast and maternal stroma is a derived feature of eutherian mammals, coincidental with the origin of decidual cells. Gene expression studies are suggestive of “categorical reprograming” of endometrial fibroblasts during decidualization. This reprogramming suggests that the decidual cell is a distinct cell type rather than a modulation of endometrial fibroblasts. Further support for this hypothesis is the origin of derived transcription factor interactions that are necessary for the regulation of decidual gene expression, in particular the interactions between HOXA11 and CEBPB with FOXO1A.
    The International Journal of Developmental Biology 01/2014; 58(2-3-4):117-126. DOI:10.1387/ijdb.130335gw · 2.57 Impact Factor
  • American Journal of Obstetrics and Gynecology 01/2014; 210(1):S346. DOI:10.1016/j.ajog.2013.10.737 · 3.97 Impact Factor
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    ABSTRACT: Administration of a single low dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been demonstrated to elicit long-lasting antidepressant effects in humans with depression, as well as in rodent models of depression. Although pharmacological studies have implicated the GluN2B subunit of the NMDA receptor in these effects, drugs targeting this subunit have off-target actions, and systemic administration of these compounds does not allow for delineation of specific brain regions involved. In this study, we assessed the role of GluN2B in the bed nucleus of the stria terminalis (BNST) in novelty-induced hypophagia (NIH) in mice. First, we verified that ketamine, as well as the GluN2B antagonist Ro25-6981, decreased the latency to consume food in a novel environment in a version of the NIH test. We then hypothesized that GluN2B-containing receptors within the BNST may be a target of systemic ketamine and contribute to behavioral effects. Through the combination of a GluN2B-floxed mouse line and stereotaxic delivery of lentiviral Cre recombinase, we found that targeted knockdown of this subunit within the BNST mimicked the reduction in affective behavior observed with systemic ketamine or Ro25-6981 in the NIH test. These data suggest a role for GluN2B-containing NMDARs within the BNST in the affective effects of systemic ketamine.
    Translational Psychiatry 12/2013; 3(12):e331. DOI:10.1038/tp.2013.103 · 4.36 Impact Factor
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    Louis J. Muglia, Dhavendra Kumar
    12/2013; 2. DOI:10.1016/j.atg.2013.10.003
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    ABSTRACT: It has recently been hypothesized that polygenic adaptation, resulting in modest allele frequency changes at many loci, could be a major mechanism behind the adaptation of complex phenotypes in human populations. Here we leverage the large number of variants that have been identified through genome-wide association (GWA) studies to comprehensively study signatures of natural selection on genetic variants associated with complex traits. Using population differentiation based methods, such as FST and phylogenetic branch length analyses, we systematically examined nearly 1300 SNPs associated with 38 complex phenotypes. Instead of detecting selection signatures at individual variants, we aimed to identify combined evidence of natural selection by aggregating signals across many trait associated SNPs. Our results have revealed some general features of polygenic selection on complex traits associated variants. First, natural selection acting on standing variants associated with complex traits is a common phenomenon. Second, characteristics of selection for different polygenic traits vary both temporarily and geographically. Third, some studied traits (e.g. height and urate level) could have been the primary targets of selection, as indicated by the significant correlation between the effect sizes and the estimated strength of selection in the trait associated variants; however, for most traits, the allele frequency changes in trait associated variants might have been driven by the selection on other correlated phenotypes. Fourth, the changes in allele frequencies as a result of selection can be highly stochastic, such that, polygenic adaptation may accelerate differentiation in allele frequencies among populations, but generally does not produce predictable directional changes. Fifth, multiple mechanisms (pleiotropy, hitchhiking, etc) may act together to govern the changes in allele frequencies of genetic variants associated with complex traits.
    12/2013; 2. DOI:10.1016/j.atg.2013.10.002
  • The Lancet Global Health 12/2013; 1(6):e328-e330. DOI:10.1016/S2214-109X(13)70120-7 · 10.04 Impact Factor
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    ABSTRACT: Preterm birth is a complex disorder defined by gestations of less than 37 weeks. While preterm birth is estimated to have a significant genetic component, relative few genes have been associated with preterm birth. Polymorphism in one such gene, follicle-stimulating hormone receptor (FSHR), has been associated with preterm birth in Finnish and African American mothers but not other populations. To refine the genetic association of FSHR with preterm birth we conducted a fine-mapping study at the FSHR locus in a Finnish cohort. We sequenced a total of 44 kb, including protein-coding and conserved non-coding regions, in 127 preterm and 135 term mothers. Overall, we identified 288 single nucleotide variants and 65 insertion/deletions of 1-2 bp across all subjects. While no common SNPs in protein-coding regions were associated with preterm birth, including one previously associated with timing of fertilization, multiple SNPs spanning the first and second intron showed the strongest associations. Analysis of the associated SNPs revealed that they form both a protective (OR = 0.50, 95% CI = 0.25-0.93) as well as a risk (OR = 1.89, 95% CI = 1.08-3.39) haplotype with independent effects. In these haplotypes, two SNPs, rs12052281 and rs72822025, were predicted to disrupt ZEB1 and ELF3 transcription factor binding sites, respectively. Our results show that multiple haplotypes at FSHR are associated with preterm birth and we discuss the frequency and structure of these haplotypes outside of the Finnish population as a potential explanation for the absence of FSHR associations in some populations.
    PLoS ONE 10/2013; 8(10):e78032. DOI:10.1371/journal.pone.0078032 · 3.53 Impact Factor
  • Gloria Laryea, Günther Schütz, Louis J Muglia
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    ABSTRACT: The glucocorticoid receptor (GR) regulates hypothalamic-pituitary-adrenal (HPA) axis activity during the stress response. The paraventricular nucleus (PVN) is a major site of negative feedback to coordinate the degree of the HPA axis activity with the magnitude of the exposed stressor. To define the function of endogenous PVN GR, we used Cre-loxP technology to disrupt different GR exons in Sim1-expressing neurons of the hypothalamus. GR exon 2 deleted mice (Sim1Cre-GRe2Δ) demonstrated 50% loss of PVN GR compared to an 80% GR loss in exon 3 deleted mice (Sim1Cre-GRe3Δ). Sim1Cre-GRe3Δ mice display stunted growth at birth but develop obesity in adulthood, and display impaired stress-induced glucose release. We observed elevated basal and stress-induced corticosterone levels in Sim1Cre-GRe3Δ mice, compared to control and Sim1Cre-GRe2Δ mice, and impaired dexamethasone suppression, indicating an inability to negatively regulate corticosterone secretion. Sim1Cre-GRe3Δ mice also showed increased corticotropin-releasing hormone mRNA in the PVN, increased basal plasma ACTH levels, and reduced locomotor behavior. We observed no differences in Sim1Cre-GRe2Δmice compared to control mice in any measure. Our behavioral data suggest that GR deletion in Sim1-expressing neurons has no effect on anxiety or despair-like behavior under basal conditions. We conclude that loss of PVN GR results in severe HPA axis hyperactivity and Cushing's syndrome-like phenotype, but does not affect anxiety and despair-like behaviors.
    Molecular Endocrinology 08/2013; 27(10). DOI:10.1210/me.2013-1187 · 4.20 Impact Factor

Publication Stats

7k Citations
1,237.97 Total Impact Points

Institutions

  • 2012–2015
    • Cincinnati Children's Hospital Medical Center
      • • Department of Pediatrics
      • • Perinatal Institute
      Cincinnati, Ohio, United States
  • 2012–2014
    • University of Cincinnati
      • • College of Medicine
      • • Department of Pediatrics
      Cincinnati, Ohio, United States
  • 2013
    • University of Iowa
      • Department of Pediatrics
      Iowa City, Iowa, United States
  • 2010–2012
    • Vanderbilt University
      • Department of Pediatrics
      Нашвилл, Michigan, United States
  • 1999–2012
    • Washington University in St. Louis
      • • Department of Pediatrics
      • • Department of Obstetrics and Gynecology
      • • Department of Pathology and Immunology
      San Luis, Missouri, United States
  • 2007
    • Yale University
      • Department of Obstetrics, Gynecology and Reproductive Sciences
      New Haven, Connecticut, United States
    • The University of Manchester
      Manchester, England, United Kingdom
    • Duke University
      Durham, North Carolina, United States
  • 2006
    • VU University Amsterdam
      • Department of Biological Psychology
      Amsterdamo, North Holland, Netherlands
  • 2002
    • University of Kentucky
      Lexington, Kentucky, United States
  • 2000
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 1995–2000
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1994–1999
    • Boston Children's Hospital
      • Division of Endocrinology
      Boston, MA, United States
  • 1997
    • Rady Children's Hospital
      San Diego, California, United States