Childrens Health Research Institute

London, Canada

Childrens Health Research Institute

London, Canada

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Brown H.K.,University of Western Ontario | Brown H.K.,Childrens Health Research Institute | Speechley K.N.,University of Western Ontario | Speechley K.N.,Childrens Health Research Institute | And 4 more authors.
International Journal of Epidemiology | Year: 2014

Background: The aim of this study was to elucidate the role of gestational age in determining the risk of neonatal morbidity among infants born late preterm (34-36 weeks) and early term (37-38 weeks) compared with those born full term (39-41 weeks) by examining the contribution of gestational age within the context of biological determinants of preterm birth.Methods: This was a retrospective cohort study. The sample included singleton live births with no major congenital anomalies, delivered at 34-41 weeks of gestation to London-Middlesex (Canada) mothers in 2002-11. Data from a city-wide perinatal database were linked with discharge abstract data. Multivariable models used modified Poisson regression to directly estimate adjusted relative risks (aRRs). The roles of gestational age and biological determinants of preterm birth were further examined using mediation and moderation analyses.Results: Compared with infants born full term, infants born late preterm and early term were at increased risk for neonatal intensive care unit triage/admission [late preterm aRR = 6.14, 95% confidence interval (CI) 5.63, 6.71; early term aRR = 1.54, 95% CI 1.41, 1.68] and neonatal respiratory morbidity (late preterm aRR = 6.16, 95% CI 5.39, 7.03; early term aRR = 1.46, 95% CI 1.29, 1.65). The effect of gestational age was partially explained by biological determinants of preterm birth acting through gestational age. Moreover, placental ischaemia and other hypoxia exacerbated the effect of gestational age on poor outcomes.Conclusions: Poor outcomes among infants born late preterm and early term are not only due to physiological immaturity but also to biological determinants of preterm birth acting through and with gestational age to produce poor outcomes. © The Author 2013; all rights reserved.


Russell E.,University of Western Ontario | Koren G.,University of Western Ontario | Koren G.,Hospital for Sick Children | Rieder M.,University of Western Ontario | And 2 more authors.
Psychoneuroendocrinology | Year: 2012

The detrimental effects of stress on human health are being increasingly recognized. There is a critical need for the establishment of a biomarker that accurately measures its intensity and course over time. Such a biomarker would allow monitoring of stress, increase understanding of its pathophysiology and may help identify appropriate and successful management strategies. Whereas saliva and urine cortisol capture real-time levels, hair cortisol analysis presents a complementary means of monitoring stress, capturing systemic cortisol exposure over longer periods of time. This novel approach for cortisol quantification is being increasingly used to identify the effects of stress in a variety of pathological situations, from chronic pain to acute myocardial infarctions. Because of its ability to provide a long-term, month-by-month measure of systemic cortisol exposure, hair cortisol analysis is becoming a useful tool, capable of answering clinical questions that could previously not be answered by other tests. In this paper we review the development, current status, limitations and outstanding questions regarding the use of hair cortisol as a biomarker of chronic stress. © 2011 Elsevier Ltd.


Market-Velker B.A.,University of Western Ontario | Market-Velker B.A.,Childrens Health Research Institute | Fernandes A.D.,University of Western Ontario | Mann M.R.W.,University of Western Ontario | Mann M.R.W.,Childrens Health Research Institute
Biology of Reproduction | Year: 2010

Assisted reproductive technologies (ARTs) are becoming increasingly prevalent and are generally considered to be safe medical procedures. However, evidence indicates that embryo culture may adversely affect the developmental potential and overall health of the embryo. One of the least studied but most important areas in this regard is the effects of embryo culture on epigenetic phenomena, and on genomic imprinting in particular, because assisted reproduction has been linked to development of the human imprinting disorders Angelman and Beckwith-Wiedemann syndromes. In this study, we performed side-by-side comparisons of five commercial embryo culture systems (KSO-Maa, Global, Human Tubal Fluid, Preimplantation 1/Multiblast, and G1v5PLUS/G2v5PLUS) in relation to a best-case (in vivo-derived embryos) and a worst-case (Whitten culture) scenario. Imprinted DNA methylation and expression were examined at three well-studied loci, H19, Peg3, and Snrpn, in mouse embryos cultured from the 2-cell to the blastocyst stage. We show that embryo culture in all commercial media systems resulted in imprinted methylation loss compared to in vivo-derived embryos, although some media systems were able to maintain imprinted methylation levelsmore similar to those of in vivo-derivedembryos in comparison to embryos cultured inWhitten medium. However, all media systems exhibited loss of imprinted H19 expression comparable to that usingWhitten medium. Combined treatment of superovulation and embryo culture resulted in increased perturbation of genomic imprinting, above that from culture alone, indicating that multiple ART procedures further disrupt genomic imprinting. These results suggest that timein culture and number of ART procedures should be minimized to ensure fidelity of genomic imprinting during preimplantation development. © 2010 by the Society for the Study of Reproduction, Inc.


Denomme M.M.,University of Western Ontario | Denomme M.M.,Childrens Health Research Institute | Mann M.R.W.,University of Western Ontario | Mann M.R.W.,Childrens Health Research Institute
Reproduction | Year: 2012

Gamete and early embryo development are important stages when genome-scale epigenetic transitions are orchestrated. The apparent lack of remodeling of differential imprinted DNA methylation during preimplantation development has lead to the argument that epigenetic disruption by assisted reproductive technologies (ARTs) is restricted to imprinted genes. We contend that aberrant imprinted methylation arising from assisted reproduction or infertility may be an indicator of more global epigenetic instability. Here, we review the current literature on the effects of ARTs, including ovarian stimulation, in vitro oocyte maturation, oocyte cryopreservation, IVF, ICSI, embryo culture, and infertility on genomic imprinting as a model for evaluating epigenetic stability. Undoubtedly, the relationship between impaired fertility, ARTs, and epigenetic stability is unquestionably complex. What is clear is that future studies need to be directed at determining the molecular and cellular mechanisms giving rise to epigenetic errors. © 2012 Society for Reproduction and Fertility.


Mudd L.M.,Michigan State University | Owe K.M.,Norwegian School of Sport Sciences | Mottola M.F.,Childrens Health Research Institute | Pivarnik J.M.,Michigan State University
Medicine and Science in Sports and Exercise | Year: 2013

Health Benefits of Physical Activity during Pregnancy: An International Perspective. Med. Sci. Sports Exerc., Vol. 45, No. 2, pp. 268-277, 2013. While early studies on the effects of leisure time physical activity (LTPA) during pregnancy were concerned about possible harm to the mother or fetus, these fears have not been substantiated. Instead, a growing body of literature has documented several health benefits related to pregnancy LTPA. The purpose of this article was to synthesize evidence from epidemiological studies conducted in the United States, Canada, and Scandinavia on the benefits of LTPA and exercise during pregnancy with regard to maternal health, pregnancy outcomes, and child health. We focused on studies evaluating relations between pregnancy LTPA and gestational diabetes, hypertensive disorders, excessive gestational weight gain, birth weight, timing of delivery, and child body composition. The bulk of evidence supports beneficial effects of pregnancy LTPA on each outcome; however, most previous studies have been observational and used self-reported LTPA at only one or two time points in pregnancy. Limitations of the current knowledge base and suggestions for future research on the health benefits of LTPA during pregnancy are provided. © 2012 by the American College of Sports Medicine.


Moon P.M.,University of Western Ontario | Beier F.,University of Western Ontario | Beier F.,Childrens Health Research Institute
Current Rheumatology Reports | Year: 2015

Osteoarthritis causes tremendous individual suffering and staggering societal costs, but due to our limited understanding of the underlying molecular and cellular mechanisms, our avenues for treating this disease are very restricted. Recent years have seen a drastic increase in the use of genetically modified mice to characterize the pathophysiology of osteoarthritis. Many new players and mechanisms driving osteoarthritis pathogenesis have been elucidated, some of which might be strong candidates as therapeutic targets for the human disease. The current review summarizes key findings (selected subjectively by the authors) from mouse osteoarthritis studies over recent years. © 2015, Springer Science+Business Media New York.


Turnbull K.,University of Western Ontario | Reid G.J.,University of Western Ontario | Reid G.J.,Childrens Health Research Institute | Morton J.B.,University of Western Ontario
Sleep | Year: 2013

Bedtime resistance and night waking are common sleep problems throughout childhood, especially in the early years. These sleep problems may lead to difficulties in neurobehavioral functioning, but most research into childhood sleep problems has not emphasized the importance of the developmental context in which disruptions in neurobehavioral and daytime functioning occur. We review the development of sleep as well as executive functioning (EF) in childhood and suggest that EF may be particularly vulnerable to the effects of these common childhood sleep problems because of its prolonged course of maturation. Behavioral problems associated with common sleep problems suggest poor self-regulation in the context of sleep loss, and developing EF skills play important roles in self-regulation. A research agenda that considers a developmental approach to sleep and sleep problems in the context of childhood EF performance is outlined to promote future research in this area.


Kernohan K.D.,University of Western Ontario | Kernohan K.D.,Childrens Health Research Institute | Vernimmen D.,Weatherall Institute of Molecular Medicine | Vernimmen D.,Roslin Institute | And 3 more authors.
Nucleic Acids Research | Year: 2014

ATRX and MeCP2 belong to an expanding group of chromatin-associated proteins implicated in human neurodevelopmental disorders, although their gene-regulatory activities are not fully resolved. Loss of ATRX prevents full repression of an imprinted gene network in the postnatal brain and in this study we address the mechanistic aspects of this regulation. We show that ATRX binds many imprinted domains individually but that transient co-localization between imprinted domains in the nuclei of neurons does not require ATRX. We demonstrate that MeCP2 is required for ATRX recruitment and that deficiency of either ATRX or MeCP2 causes decreased frequency of long-range chromatin interactions associated with altered nucleosome density at CTCF-binding sites and reduced CTCF occupancy. These findings indicate that MeCP2 and ATRX regulate gene expression at a subset of imprinted domains by maintaining a nucleosome configuration conducive to CTCF binding and to the maintenance of higher order chromatin structure. © 2014 The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.


Macdonald W.A.,University of Western Ontario | Macdonald W.A.,Childrens Health Research Institute | Mann M.R.W.,University of Western Ontario | Mann M.R.W.,Childrens Health Research Institute
Molecular Reproduction and Development | Year: 2014

Genomic imprinting is an epigenetic process that distinguishes parental alleles, resulting in parent-specific expression of a gene or cluster of genes. Imprints are acquired during gametogenesis when genome-wide epigenetic remodeling occurs. These imprints must then be maintained during preimplantation development, when another wave of genome-wide epigenetic remodeling takes place. Thus, for imprints to persist as parent-specific epigenetic marks, coordinated factors and processes must be involved to both recognize an imprint and protect it from genome-wide remodeling. Parent-specific DNA methylation has long been recognized as a primary epigenetic mark demarcating a genomic imprint. Recent work has advanced our understanding of how and when parent-specific DNA methylation is erased and acquired in the germ line as well as maintained during preimplantation development. Epigenetic factors have also been identified that are recruited to imprinted regions to protect them from genome-wide DNA demethylation during preimplantation development. Intriguingly, asynchrony in epigenetic reprogramming appears to be a recurrent theme with asynchronous acquisition between male and female germ lines, between different imprinted genes, and between the two parental alleles of a gene. Here, we review recent advancements and discuss how they impact our current understanding of the epigenetic regulation of genomic imprinting. © 2013 Wiley Periodicals, Inc.


Denomme M.M.,University of Western Ontario | Denomme M.M.,Childrens Health Research Institute | Mann M.R.W.,University of Western Ontario | Mann M.R.W.,Childrens Health Research Institute
Reproductive BioMedicine Online | Year: 2013

Genomic imprinting is a specialized transcriptional phenomenon that employs epigenetic mechanisms to facilitate parental-specific expression. Perturbations in parental epigenetic asymmetry can lead to the development of imprinting disorders, such as Beckwith-Wiedemann syndrome and Angelman syndrome. DNA methylation is one of the most widely studied epigenetic marks that characterizes imprinted regions. During gametogenesis and early embryogenesis, imprinted methylation undergoes a cycle of erasure, acquisition and maintenance. Gamete and embryo manipulations for the purpose of assisted reproduction are performed during these reprogramming events and may lead to their disruption. Recent studies point to the role of maternal-effect proteins in imprinted gene regulation. Studies are now required to increase understanding of how these factors regulate genomic imprinting as well as how assisted reproduction technologies may alter their function. Assisted reproductive technologies have been linked to the development of Beckwith-Wiedemann syndrome and Angelman syndrome. This may relate to the fact that the use of assisted reproduction technology coincides with crucial events that establish and maintain gene expression during egg and early embryo development. Recent studies have identified several proteins that are found in the egg that may play a role in gene expression in the early embryo. Studies are now required to increase understanding of how these factors work as well as how assisted reproductive technologies may alter their function. © 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

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