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Hanson M.A.,University of Southampton | Gluckman P.D.,University of Auckland | Gluckman P.D.,Singapore Institute for Clinical science
Best Practice and Research: Clinical Obstetrics and Gynaecology | Year: 2015

The rapidly rising prevalence of non-communicable diseases (NCDs) represents a major challenge to public health and clinical medicine globally. NCDs are increasing rapidly in high-income countries, but even more rapidly in some low-middle-income countries with insufficient resources to meet the challenge. Whilst not identified in the Millennium Development Goals, there is much attention paid to NCDs in the discussions at many levels on the Sustainable Development Goals, as they underpin economic, social and environmental development in the post-2015 era. In this article, we discuss how a life-course approach to health, commencing of necessity in early development, can provide new opportunities for addressing this challenge. The approach can leverage human health capital throughout life and across generations. New insights into mechanisms, especially those processes by which the developmental environment affects epigenetic processes in the developing offspring, offer the prospect of identifying biomarkers of future risks. New interventions to promote health literacy, lifestyle and physical fitness in adolescents, young adults and their children hold great promise. In this respect, health-care professionals concerned with preconceptional, pregnancy and newborn care will have a vital role to play. © 2014 Elsevier Ltd. All rights reserved.

Rifkin-Graboi A.,Singapore Institute for Clinical science
Biological psychiatry | Year: 2013

Antenatal maternal cortisol levels associate with alterations in the amygdala, a structure associated with emotion regulation, in the offspring. However, because offspring brain and behavior are commonly assessed years after birth, the timing of such maternal influences is unclear. This study aimed to examine the association between antenatal maternal depressive symptomatology and neonatal amygdala volume and microstructure and thus establish evidence for the transgenerational transmission of vulnerability for affective disorders during prenatal development. Our study recruited Asian mothers at 10 to 13 weeks pregnancy and assessed maternal depression at 26 weeks gestation using the Edinburgh Postnatal Depression Scale. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 157 nonsedated, 6- to 14-day-old newborns and then analyzed to extract the volume, fractional anisotropy, and axial diffusivity values of the amygdala. Adjusting for household income, maternal age, and smoking exposure, postconceptual age at magnetic resonance imaging, and birth weight, we found significantly lower fractional anisotropy (p = .009) and axial diffusivity (p = .028), but not volume (p = .993), in the right amygdala in the infants of mothers with high compared with those with low-normal Edinburgh Postnatal Depression Scale scores. The results reveal a significant relation between antenatal maternal depression and the neonatal microstructure of the right amygdala, a brain region closely associated with stress reactivity and vulnerability for mood anxiety disorders. These findings suggest the prenatal transmission of vulnerability for depression from mother to child and that interventions targeting maternal depression should begin early in pregnancy. © 2013 Society of Biological Psychiatry.

Bertoletti A.,National University of Singapore | Bertoletti A.,Singapore Institute for Clinical science | Bertoletti A.,University of Birmingham | Rivino L.,National University of Singapore
Current Opinion in Infectious Diseases | Year: 2014

Purpose of review Hepatitis B virus (HBV) causes a large proportion of chronic liver disease worldwide, The limited efficiency of current treatments based on the use of nucleotide/nucleoside analogues or interferon-alpha requires the development of new therapeutic tools for the treatment of chronic HBV, We summarize the most recent therapeutic strategies designed to directly target HBV-infected hepatocytes or to restore antiviral immunity during chronic HBV infection, Recent findings Novel therapies directly target HBV-infected hepatocytes by inducing covalently closed circular DNA degradation or by inhibiting HBV entry or the expression of viral proteins, In addition, immunotherapeutic approaches may boost HBV-specific T-cell responses or stimulate the intrahepatic innate response, Summary These new therapeutic approaches have mainly been tested in animal models, In humans, therapeutic strategies could be tailored to different chronic HBV patients in relation to their clinical and virological disease profile. Copyright © 2014 Lippincott Williams & Wilkins.

Rehermann B.,U.S. National Institutes of Health | Bertoletti A.,National University of Singapore | Bertoletti A.,Singapore Institute for Clinical science
Hepatology | Year: 2015

Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause a large proportion of acute and chronic liver disease worldwide. Over the past decades many immunological studies defined host immune responses that mediate spontaneous clearance of acute HBV and HCV infection. However, host immune responses are also relevant in the context of treatment-induced clearance of chronic HBV and HCV infection. First, the pretreatment level of interferon-stimulated genes as well as genetic determinants of innate immune responses, such as single nucleotide polymorphisms near the IFNL3 gene, are strong predictors of the response to interferon-alpha (IFN-α)-based therapy. Second, IFN-α, which has been a mainstay of HBV and HCV therapy over decades, and ribavirin, which has also been included in interferon-free direct antiviral therapy for HCV, modulate host immune responses. Third, both IFN-α-based and IFN-α-free treatment regimens of HBV and HCV infection alter the short-term and long-term adaptive immune response against these viruses. Finally, treatment studies have not just improved the clinical outcomes, but also provided opportunities to study virus-host interaction. This review summarizes our current knowledge on how a patient's immune response affects the treatment outcome of HBV and HCV infection and how innate and adaptive immune responses themselves are altered by the different treatment regimens. © 2014 by the American Association for the Study of Liver Diseases.

Zhang T.Y.,McGill University | Labonte B.,McGill University | Wen X.L.,McGill University | Turecki G.,McGill University | And 2 more authors.
Neuropsychopharmacology | Year: 2013

Parental care influences development across mammals. In humans such influences include effects on phenotypes, such as stress reactivity, which determine individual differences in the vulnerability for affective disorders. Thus, the adult offspring of rat mothers that show an increased frequency of pup licking/grooming (ie, high LG mothers) show increased hippocampal glucocorticoid receptor (GR) expression and more modest hypothalamicpituitaryadrenal responses to stress compared with the offspring of low LG mothers. In humans, childhood maltreatment associates decreased hippocampal GR expression and increased stress responses in adulthood. We review the evidence suggesting that such effects are mediated by epigenetic mechanisms, including DNA methylation and hydroxymethylation across GR promoter regions. We also present new findings revealing associated histone post-translational modifications of a critical GR promoter in rat hippocampus. Taken together these existing evidences are consistent with the idea that parental influences establish stable phenotypic variation in the offspring through effects on intracellular signaling pathways that regulate the epigenetic state and function of specific regions of the genome. © 2013 American College of Neuropsychopharmacology. All rights reserved.

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