Abstract Children who experience chronic stressors are vulnerable to emotional and physical health problems across the lifespan. This phenomenon raises questions for scientists and clinicians alike. ...How does adversity get under the skin of the developing child? Through what mechanisms does it confer vulnerability to a heterogeneous set of mental and physical illnesses? And how does it instantiate risk across different life stages, engendering vulnerability to conditions that develop shortly after stressor exposure—like depression—and conditions that manifest decades later, like heart disease? Although answers to these questions have started to emerge, research has typically focused on single diseases or organ systems. To understand the plethora of health problems associated with childhood adversity, we argue that the field needs a second generation of research that recognizes multidirectional transactions among biological systems. To help facilitate this process, we propose a neuroimmune network hypothesis as a heuristic framework for organizing knowledge from disparate literatures and as a springboard for generating integrative research. Drawing on existing data, we argue that early-life adversity amplifies crosstalk between peripheral inflammation and neural circuitries subserving threat-related, reward-related, and executive control-related processes. This crosstalk results in chronic low-grade inflammation, thereby contributing to adiposity, insulin resistance, and other predisease states. In the brain, inflammatory mediators act on cortico-amygdala threat and cortico-basal ganglia reward, circuitries in a manner that predisposes individuals to self-medicating behaviors like smoking, drug use, and consumption of high-fat diets. Acting in concert with inflammation, these behaviors accelerate the pathogenesis of emotional and physical health problems.
As next-generation sequencing projects generate massive genome-wide sequence variation data, bioinformatics tools are being developed to provide computational predictions on the functional effects of ...sequence variations and narrow down the search of casual variants for disease phenotypes. Different classes of sequence variations at the nucleotide level are involved in human diseases, including substitutions, insertions, deletions, frameshifts, and non-sense mutations. Frameshifts and non-sense mutations are likely to cause a negative effect on protein function. Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to insertions or deletions. Here, we introduce a versatile alignment-based score as a new metric to predict the damaging effects of variations not limited to single amino acid substitutions but also in-frame insertions, deletions, and multiple amino acid substitutions. This alignment-based score measures the change in sequence similarity of a query sequence to a protein sequence homolog before and after the introduction of an amino acid variation to the query sequence. Our results showed that the scoring scheme performs well in separating disease-associated variants (n = 21,662) from common polymorphisms (n = 37,022) for UniProt human protein variations, and also in separating deleterious variants (n = 15,179) from neutral variants (n = 17,891) for UniProt non-human protein variations. In our approach, the area under the receiver operating characteristic curve (AUC) for the human and non-human protein variation datasets is ∼0.85. We also observed that the alignment-based score correlates with the deleteriousness of a sequence variation. In summary, we have developed a new algorithm, PROVEAN (Protein Variation Effect Analyzer), which provides a generalized approach to predict the functional effects of protein sequence variations including single or multiple amino acid substitutions, and in-frame insertions and deletions. The PROVEAN tool is available online at http://provean.jcvi.org.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To summarize quantitatively the literature comparing hypothalamic-pituitary-adrenal (HPA) axis function between depressed and nondepressed individuals and to describe the important sources of ...variability in this literature. These sources include methodological differences between studies, as well as demographic or clinical differences between depressed samples.
The current study used meta-analytic techniques to compare 671 effect sizes (cortisol, adrenocorticotropic hormone, or corticotropin-releasing hormone) across 361 studies, including 18,454 individuals.
Although depressed individuals tended to display increased cortisol (d = 0.60; 95% confidence interval CI, 0.54-0.66) and adrenocorticotropic hormone levels (d = 0.28; 95% CI, 0.16-0.41), they did not display elevations in corticotropin-releasing hormone (d = 0.02; 95% CI, -0.47-0.51). The magnitude of the cortisol effect was reduced by almost half (d = 0.33; 95% CI, 0.21-0.45) when analyses were limited to studies that met minimal methodological standards. Gender did not significantly modify any HPA outcome. Studies that included older hospitalized individuals reported significantly greater cortisol differences between depressed and nondepressed groups compared with studies with younger outpatient samples. Important cortisol differences also emerged for atypical, endogenous, melancholic, and psychotic forms of depression.
The current study suggests that the degree of HPA hyperactivity can vary considerably across patient groups. Results are consistent with HPA hyperactivity as a link between depression and increased risk for conditions, such as diabetes, dementia, coronary heart disease, and osteoporosis. Such a link is strongest among older inpatients who display melancholic or psychotic features of depression.
Health disparities (differences in health by socioeconomic groups) are a pressing issue in our society. This article provides an overview of a multilevel approach that seeks to understand the ...mechanisms underlying health disparities by considering factors at the individual, family, and neighborhood levels. In addition, we describe an approach to connecting these factors to various levels of biological processes (systemic inflammation, cellular processes, and genomic pathways) that drive disease pathophysiology. In the second half of the article, we address the question of why some low-socioeconomic-status (low-SES) individuals manage to maintain good physical health. We identify naturally occurring psychosocial factors that help buffer these individuals from adverse physiological responses and pathogenic processes leading to chronic disease. What is protective for low-SES individuals is not the same as what is protective for high-SES individuals, and this needs to be taken into account in interventions aimed at reducing health disparities.
A growing body of evidence indicates that children reared in harsh families are prone to chronic diseases and premature death later in life. To shed light on the mechanisms potentially underlying ...this phenomenon, we evaluated the hypothesis that harsh families engender a proinflammatory phenotype in children that is marked by exaggerated cytokine responses to bacterial stimuli and resistance to the anti-inflammatory properties of cortisol. We repeatedly measured psychological stress and inflammatory activity in 135 female adolescents on four occasions over 1.5 years. To the extent that they were reared in harsh families, participants displayed an increasingly proinflammatory phenotype during the follow-up analyses. This phenotype was marked by increasingly pronounced cytokine responses to in vitro bacterial challenge and a progressive desensitization of the glucocorticoid receptor, which hampered cortisol's ability to properly regulate inflammatory responses. If sustained, these tendencies may place children from harsh families on a developmental trajectory toward the chronic diseases of aging.
Among people exposed to major psychological stressors in early life, there are elevated rates of morbidity and mortality from chronic diseases of aging. The most compelling data come from studies of ...children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality. These findings raise challenging theoretical questions. How does childhood stress get under the skin, at the molecular level, to affect risk for later diseases? And how does it incubate there, giving rise to diseases several decades later? Here we present a biological embedding model, which attempts to address these questions by synthesizing knowledge across several behavioral and biomedical literatures. This model maintains that childhood stress gets "programmed" into macrophages through epigenetic markings, posttranslational modifications, and tissue remodeling. As a consequence these cells are endowed with proinflammatory tendencies, manifest in exaggerated cytokine responses to challenge and decreased sensitivity to inhibitory hormonal signals. The model goes on to propose that over the life course, these proinflammatory tendencies are exacerbated by behavioral proclivities and hormonal dysregulation, themselves the products of exposure to early stress. Behaviorally, the model posits that childhood stress gives rise to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices. Hormonally, early stress confers altered patterns of endocrine and autonomic discharge. This milieu amplifies the proinflammatory environment already instantiated by macrophages. Acting in concert with other exposures and genetic liabilities, the resulting inflammation drives forward pathogenic mechanisms that ultimately foster chronic disease.
Background There is mounting interest in the hypothesis that inflammation contributes to the pathogenesis of depression and underlies depressed patients' vulnerability to comorbid medical conditions. ...However, research on depression and inflammation has yielded conflicting findings, fostering speculation that these conditions associate only in certain subgroups, such as patients exposed to childhood adversity. Methods We studied 147 female adolescents. All were in good health at baseline but at high risk for depression because of family history or cognitive vulnerability. Subjects were assessed every 6 months for 2.5 years, undergoing diagnostic interviews and venipuncture for measurement of two inflammatory biomarkers, C-reactive protein (CRP) and interleukin-6 (IL-6). Childhood adversity was indexed by parental separation, low socioeconomic status, and familial psychopathology. Results Multilevel models indicated that childhood adversity promotes clustering of depression and inflammation. Among subjects exposed to high childhood adversity, the transition to depression was accompanied by increases in both CRP and IL-6. Higher CRP remained evident 6 months later, even after depressive symptoms had abated. These lingering effects were bidirectional, such that among subjects with childhood adversity, high IL-6 forecasted depression 6 months later, even after concurrent inflammation was considered. This coupling of depression and inflammation was not apparent in subjects without childhood adversity. Conclusions These findings suggest that childhood adversity promotes the formation of a neuroimmune pipeline in which inflammatory signaling between the brain and periphery is amplified. Once established, this pipeline leads to a coupling of depression and inflammation, which may contribute to later affective difficulties and biomedical complications.
There are persistent socioeconomic disparities in many aspects of child development in America. Relative to their affluent peers, children of low socioeconomic status (SES) complete fewer years of ...education, have a higher prevalence of health problems, and are convicted of more criminal offenses. Based on research indicating that low self-control underlies some of these disparities, policymakers have begun incorporating character-skills training into school curricula and social services. However, emerging data suggest that for low-SES youth, self-control may act as a “double-edged sword,” facilitating academic success and psychosocial adjustment, while at the same time undermining physical health. Here, we examine this hypothesis in a five-wave study of 292 African American teenagers from rural Georgia. From ages 17 to 20 y, we assessed SES and self-control annually, along with depressive symptoms, substance use, aggressive behavior, and internalizing problems. At age 22 y, we obtained DNA methylation profiles of subjects’ peripheral blood mononuclear cells. These data were used to measure epigenetic aging, a methylation-derived biomarker reflecting the disparity between biological and chronological aging. Among high-SES youth, better mid-adolescent self-control presaged favorable psychological and methylation outcomes. However, among low-SES youth, self-control had divergent associations with these outcomes. Self-control forecasted lower rates of depressive symptoms, substance use, aggressive behavior, and internalizing problems but faster epigenetic aging. These patterns suggest that for low-SES youth, resilience is a “skin-deep” phenomenon, wherein outward indicators of success can mask emerging problems with health. These findings have conceptual implications for models of resilience, and practical implications for interventions aimed at ameliorating social and racial disparities.
Abstract Purpose Low-grade inflammation, measured by circulating levels of cytokines, is a pathogenic mechanism for several chronic diseases of aging. Identifying factors related to inflammation ...among African-American youths may yield insights into mechanisms underlying racial disparities in health. The purpose of the study was to determine whether (1) reported racial discrimination from ages 17–19 years forecasts heightened cytokine levels at the age of 22 years and (2) this association is lower for youths with positive racial identities. Methods A longitudinal research design was used with a community sample of 160 African-Americans who were aged 17 years at the beginning of the study. Discrimination and racial identity were measured with questionnaires, and blood was drawn to measure basal cytokine levels. Ordinary least squares regression analyses were used to examine the hypotheses. Results After controlling for socioeconomic risk, life stress, depressive symptoms, and body mass index, racial discrimination (β = .307; p < .01), racial identity (β = −.179; p < .05), and their interaction (β = −.180; p < .05) forecast cytokine levels. Youths exposed to high levels of racial discrimination evinced elevated cytokine levels 3 years later. This association was not significant for young adults with positive racial identities. Conclusions High levels of interpersonal racial discrimination and the development of a positive racial identity operate jointly to determine low-grade inflammation levels that have been found to forecast chronic diseases of aging, such as coronary disease and stroke.
Children of low socioeconomic status (SES) are at elevated risk for health problems across the lifespan. Observational studies suggest that nurturant parenting might offset some of these health ...risks, but their design precludes inferences about causal direction and clinical utility. Here we ask whether a psychosocial intervention, focused improving parenting, strengthening family relationships, and building youth competencies, can reduce inflammation in low-SES, African Americans from the rural South. The trial involved 272 mothers and their 11-y-old children from rural Georgia, half of whose annual household incomes were below the federal poverty line. Families were randomly assigned to a 7-wk psychosocial intervention or to a control condition. When youth reached age 19, peripheral blood was collected to quantify six cytokines that orchestrate inflammation, the dysregulation of which contributes to many of the health problems known to pattern by SES. Youth who participated in the intervention had significantly less inflammation on all six indicators relative to controls (all P values < 0.001; effect sizes in Cohen’s d units ranged from −0.69 to −0.91). Mediation analyses suggested that improved parenting was partially responsible for the intervention’s benefits. Inflammation was lowest among youth who received more nurturant-involved parenting, and less harsh-inconsistent parenting, as a consequence of the intervention. These findings have theoretical implications for research on resilience to adversity and the early origins of disease. If substantiated, they may also highlight a strategy for practitioners and policymakers to use in ameliorating social and racial health disparities.
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