Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are ...unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944-45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.
For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Early theories about psychic conflict and toxic parenting have been replaced by more ...recent formulations of complex interactions of genes and environment. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. The mechanisms for these effects remain almost as much a mystery today as they were a century ago. Recent studies suggest that maternal diet can program offspring growth and metabolic pathways, altering lifelong susceptibility to diabetes and obesity. If maternal psychosocial experience has similar programming effects on the developing offspring, one might expect a comparable contribution to neurodevelopmental disorders, including affective disorders, schizophrenia, autism, and eating disorders. Due to their early onset, prevalence, and chronicity, some of these disorders, such as depression and schizophrenia, are among the highest causes of disability worldwide according to the World Health Organization 2002 report. Consideration of the early life programming and transcriptional regulation in adult exposures supports a critical need to understand epigenetic mechanisms as a critical determinant in disease predisposition. Incorporating the latest insight gained from clinical and epidemiological studies with potential epigenetic mechanisms from basic research, the following review summarizes findings from a workshop on Early Life Programming and Neurodevelopmental Disorders held at the University of Pennsylvania in 2009.
Abstract
We investigated the relationships between syndromic manifestations of defective placentation and the incidence of intellectual disability (ID) in offspring by conducting a population-based ...cohort study of 1,581,200 nonmalformed, live singleton infants born in Sweden between 1998 and 2014. Exposures were: 1) placental abruption, 2) preterm preeclampsia (<34 weeks of gestation), 3) preeclampsia combined with infant being small for gestational age (SGA) at birth, and 4) spontaneous preterm birth. The outcome was an ID diagnosis after 3 years of age. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for each syndrome using Cox regression and robust variances. There were 9,451 children with ID (5.5 per 10,000 child-years). ID incidence rates increased with placental abruption (HR = 2.8, 95% CI: 2.3, 3.5), preterm preeclampsia (HR = 3.7, 95% CI: 2.9, 4.7), preeclampsia combined with SGA (HR = 3.3, 95% CI: 2.6, 4.1), and spontaneous preterm birth (for 32–36 and 22–31 weeks, respectively, HR = 1.6 (95% CI: 1.4, 1.8) and 5.2 (95% CI: 4.3, 6.2)). The same pattern of results was evident in sibling-controlled analyses among 1,043,158 full siblings. The strength of associations increased with ID severity. Preterm birth only partly explained the associations of placental abruption, preeclampsia, or SGA with ID. We conclude that defective placentation is related to increased incidence of ID in the offspring.
Multidimensional progressive declines in the absence of standard biomarkers for neurodegeneration are observed commonly in the development of schizophrenia, and are accepted as consistent with ...neurodevelopmental etiological hypotheses to explain the origins of the disorder. Far less accepted is the possibility that neurodegenerative processes are involved as well, or even that key dimensions of function, such as cognition and aspects of biological integrity, such as white matter function, decline in chronic schizophrenia beyond levels associated with normal aging. We propose that recent research germane to these issues warrants a current look at the question of neurodegeneration. We propose the view that a neurodegenerative hypothesis provides a better explanation of some features of chronic schizophrenia, including accelerated aging, than is provided by neurodevelopmental hypotheses. Moreover, we suggest that neurodevelopmental influences in early life, including those that may extend to later life, do not preclude the development of neurodegenerative processes in later life, including some declines in cognitive and biological integrity. We evaluate these views by integrating recent findings in representative domains such as cognition and white and gray matter integrity with results from studies on accelerated aging, together with functional implications of neurodegeneration for our understanding of chronic schizophrenia.
Little is known about the economic impact of disability grants for people living with schizophrenia in low- and middle- income countries. In this brief report, we show that receipt of disability ...benefits is significantly associated (
β
= 0.105,
p
< 0.0001) with increased household and personal wealth in large sample of people living with schizophrenia in South Africa (
n
= 1154). This study provides further support for the use of disability grants as a mechanism to protect people living with schizophrenia and their families against the economic costs associated with schizophrenia.
In adults, leukocyte telomere length (LTL) is variable, familial, and longer in women and in offspring conceived by older fathers. Although short LTL is associated with atherosclerotic cardiovascular ...disease, long LTL is associated with major cancers. The prevailing notion is that LTL is a "telomeric clock," whose movement (expressed in LTL attrition) reflects the pace of aging. Accordingly, individuals with short LTL are considered to be biologically older than their peers. Recent studies suggest that LTL is largely determined before adulthood. We examined whether factors that largely characterize LTL in adults also influence LTL in newborns.
LTL was measured in blood samples from 490 newborns and their parents.
LTL (mean ± SD) was longer (9.50 ± 0.70 kb) in newborns than in their mothers (7.92 ± 0.67 kb) and fathers (7.70 ± 0.71 kb) (both P < .0001); there was no difference in the variance of LTL among the 3 groups. Newborn LTL correlated more strongly with age-adjusted LTL in mothers (r = 0.47; P < .01) than in fathers (r = 0.36; P < .01) (P for interaction = .02). Newborn LTL was longer by 0.144 kb in girls than in boys (P = .02), and LTL was longer by 0.175 kb in mothers than in fathers (P < .0001). For each 1-year increase in father's age, newborn LTL increased by 0.016 kb (95% confidence interval: 0.04 to 0.28) (P = .0086).
The large LTL variation across newborns challenges the telomeric clock model. Having inherently short or long LTL may be largely determined at birth, anteceding by decades disease manifestation in adults.
The World Health Organization recommends that treatment of depression in low and middle-income countries with a scarcity of psychiatrists could be done in primary care and should include prescription ...of antidepressant medications for moderate and severe depression. Little is known, however, about the actual practices of antidepressant prescription by primary care physicians in low and middle-income countries, nor about adherence by people receiving such prescriptions. In a large study of primary care clinics in Goa, India, we examined the relationship of actual to recommended prescribing practices for depression, among all patients who screened positive for common mental disorder. We also examined other patient and clinic characteristics associated with antidepressant prescription, and self-reported adherence over a one-month period.
Patients attending 24 primary care clinics were screened for common mental disorders. Those who screened positive were eligible to enroll in a trial to assess the effectiveness of a collaborative stepped care (CSC) intervention for mental disorders. Physicians in the 12 intervention and 12 control clinics (usual care) were free to prescribe antidepressants and follow-up interviews were conducted at 2, 6 and 12 months. Screening results were shared with the physician, but they were blinded to the diagnosis generated later using a standardized diagnostic interview administered by a health counsellor. We categorized these later diagnoses as "moderate/severe depression", "mild depression or non-depression diagnosis", and "no diagnosis". We used a two-level hierarchical logistic regression model to examine diagnostic and other factors associated with antidepressant prescription and one-month adherence.
Overall, about 47% of screened positive patients (n = 1320) received an antidepressant prescription: 60% of those with moderate/severe depression, 48% of those with mild depression or non-depression diagnosis, and 31% with no diagnosis. Women (OR 1.29; 95%CI 1.04-1.60) and older adults (OR 1.80; 95%CI 1.32-2.47) were more likely to receive an antidepressant prescription. While the overall rate of antidepressant prescription was similar in clinics with and without CSC, patients without any diagnosis were more likely to receive a prescription (OR 2.20 95% CI 1.03-4.70) in the usual care clinics. About 47% of patients adhered to antidepressant treatment for one month or more and adherence was significantly better among older adults (OR 3.92; 95% CI 1.70-8.93) and those who received antidepressant as part of the CSC treatment model (OR 6.10 95% CI 3.67-10.14) compared with those attending the usual care clinic.
Antidepressants were widely prescribed following screening in primary care, but prescription patterns were in poor accord with WHO recommendations. The data suggest under-prescription for people with moderate/severe depression; over-prescription for people with mild depression or non-depression diagnoses; and over-prescription for people with no disorders. For all diagnoses adherence was low, especially in usual care clinics. To address these concerns, there is an urgent need to study and develop strategies in primary care practices to limit unnecessary antidepressant prescriptions, target prescription for those patients who clearly benefit, and to improve adherence to antidepressant treatment. ClinicalTrials.gov Identifier: NCT00446407.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Converging evidence suggests that a neurodevelopmental disruption plays a role in the vulnerability to schizophrenia. The authors review evidence supporting in utero exposure to nutritional ...deficiency as a determinant of schizophrenia. We first describe studies demonstrating that early gestational exposure to the Dutch Hunger Winter of 1944-1945 and to a severe famine in China are each associated with an increased risk of schizophrenia in offspring. The plausibility of several candidate micronutrients as potential risk factors for schizophrenia and the biological mechanisms that may underlie these associations are then reviewed. These nutrients include folate, essential fatty acids, retinoids, vitamin D, and iron. Following this discussion, we describe the methodology and results of an epidemiologic study based on a large birth cohort that has tested the association between prenatal homocysteine, an indicator of serum folate, and schizophrenia risk. The study capitalized on the use of archived prenatal serum specimens that make it possible to obtain direct, prospective biomarkers of prenatal insults, including levels of various nutrients during pregnancy. Finally, we discuss several strategies for subjecting the prenatal nutritional hypothesis of schizophrenia to further testing. These approaches include direct assessment of additional prenatal nutritional biomarkers in relation to schizophrenia in large birth cohorts, studies of epigenetic effects of prenatal starvation, association studies of genes relevant to folate and other micronutrient deficiencies, and animal models. Given the relatively high prevalence of nutritional deficiencies during pregnancy, this work has the potential to offer substantial benefits for the prevention of schizophrenia in the population.
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