Aberrant Epigenomic Modulation of Glucocorticoid Receptor Gene (NR3C1) in Early Life Stress and Major Depressive Disorder Correlation: Systematic Review and Quantitative Evidence Synthesis

Early life stress (ELS) induced by psychological trauma, child maltreatment, maternal separation, and domestic violence predisposes to psycho-behavioral pathologies during adulthood, namely major depressive disorder (MDD), anxiety, and bipolar affective disorder. While environmental data are available in illustrating this association, data remain to be established on the epigenomic underpinning of the nexus between ELS and MDD predisposition. Specifically, despite the observed aberrant epigenomic modulation of the NR3C1, a glucocorticoid receptor gene, in early social adversity and social threats in animal and human models, reliable scientific data for intervention mapping in reducing social adversity and improving human health is required. We sought to synthesize the findings of studies evaluating (a) epigenomic modulations, mainly DNA methylation resulting in MDDfollowing ELS, (b) epigenomic modifications associated with ELS, and (c) epigenomic alterations associated with MDD. A systematic review and quantitative evidence synthesis (QES) were utilized with the random effect meta-analytic procedure. The search strategy involved both the PubMed and hand search of relevant references. Of the 1534 studies identified through electronic search, 592 studies were screened, 11 met the eligibility criteria for inclusion in the QES, and 5 examined ELS and MDD; 4 studies assessed epigenomic modulation and ELS, while 2 studies examined epigenomic modulations and MDD. The dense DNA methylation of the 1F exon of the NR3C1, implying the hypermethylated region of the glucocorticoid receptor gene, was observed in the nexus between ELS andMDD,common effect size (CES) = 14.96, 95%CI, 10.06–19.85. With respect to epigenomic modulation associated with child ELS, hypermethylation was observed, CES = 23.2%, 95%CI, 8.00–38.48. In addition, marginal epigenomic alteration was indicated in MDD, where hypermethylation was associated with increased risk of MDD, CES = 2.12%, 95%CI, −0.63–4.86. Substantial evidence supports the implication of NR3C1 and environmental interaction, mainly DNA methylation, in the predisposition to MDD following ELS. This QES further supports aberrant epigenomic modulation identified in ELS as well as major depressive episodes involving dysfunctional glucocorticoid-mediated negative feedback as a result of allostatic overload. These findings recommend prospective investigation of social adversity and its predisposition to the MDD epidemic via aberrant epigenomic modulation. Such data will facilitate early intervention mapping in reducing MDD in the United States population

Prophylactic methylprednisolone to reduce inflammation and improve outcomes from one lung ventilation in children: a randomized clinical trial.

BACKGROUND: One lung ventilation (OLV) results in inflammatory and mechanical injury, leading to intraoperative and postoperative complications in children. No interventions have been studied in children to minimize such injury. OBJECTIVE: We hypothesized that a single 2-mg·kg(-1) dose of methylprednisolone given 45-60 min prior to lung collapse would minimize injury from OLV and improve physiological stability. METHODS: Twenty-eight children scheduled to undergo OLV were randomly assigned to receive 2 mg·kg(-1) methylprednisolone (MP) or normal saline (placebo group) prior to OLV. Anesthetic management was standardized, and data were collected for physiological stability (bronchospasm, respiratory resistance, and compliance). Plasma was assayed for inflammatory markers related to lung injury at timed intervals related to administration of methylprednisolone. RESULTS: Three children in the placebo group experienced clinically significant intraoperative and postoperative respiratory complications. Respiratory resistance was lower (P = 0.04) in the methylprednisolone group. Pro-inflammatory cytokine IL-6 was lower (P = 0.01), and anti-inflammatory cytokine IL-10 was higher (P = 0.001) in the methylprednisolone group. Tryptase, measured before and after OLV, was lower (P = 0.03) in the methylprednisolone group while increased levels of tryptase were seen in placebo group after OLV (did not achieve significance). There were no side effects observed that could be attributed to methylprednisolone in this study. CONCLUSIONS: Methylprednisolone at 2 mg·kg(-1) given as a single dose prior to OLV provides physiological stability to children undergoing OLV. In addition, methylprednisolone results in lower pro-inflammatory markers and higher anti-inflammatory markers in the children\u27s plasma

Black-White Risk Differentials in COVID-19 (SARS-COV2) Transmission, Mortality and Case Fatality in the United States: Translational Epidemiologic Perspective and Challenges

Background: Social and health inequities predispose vulnerable populations to adverse morbidity and mortality outcomes of epidemics and pandemics. While racial disparities in cumulative incidence (CmI) and mortality from the influenza pandemics of 1918 and 2009 implicated Blacks with survival disadvantage relative to Whites in the United States, COVID-19 currently indicates comparable disparities. We aimed to: (a) assess COVID-19 CmI by race, (b) determine the Black-White case fatality (CF) and risk differentials, and (c) apply explanatory model for mortality risk differentials. Methods: COVID-19 data on confirmed cases and deaths by selective states health departments were assessed using a cross-sectional ecologic design. Chi-square was used for CF independence, while binomial regression model for the Black-White risk differentials. Results: The COVID-19 mortality CmI indicated Blacks/AA with 34% of the total mortality in the United States, albeit their 13% population size. The COVID-19 CF was higher among Blacks/AA relative to Whites; Maryland, (2.7% vs. 2.5%), Wisconsin (7.4% vs. 4.8%), Illinois (4.8% vs. 4.2%), Chicago (5.9% vs. 3.2%), Detroit (Michigan), 7.2% and St. John the Baptist Parish (Louisiana), 7.9%. Blacks/AA compared to Whites in Michigan were 15% more likely to die, CmI risk ratio (CmIRR) = 1.15, 95% CI, 1.01-1.32. Blacks/AA relative to Whites in Illinois were 13% more likely to die, CmIRR = 1.13, 95% CI, 0.93-1.39, while Blacks/AA compared to Whites in Wisconsin were 51% more likely to die, CmIRR = 1.51, 95% CI, 1.10-2.10. In Chicago, Blacks/AA were more than twice as likely to die, CmIRR = 2.24, 95% CI, 1.36-3.88. Conclusion: Substantial racial/ethnic disparities are observed in COVID-19 CF and mortality with Blacks/AA disproportionately affected across the United States

DNA Methylation of Candidate Genes (ACE II, IFN-γ, AGTR 1, CKG, ADD1, SCNN1B and TLR2) in Essential Hypertension: A Systematic Review and Quantitative Evidence Synthesis

Physical, chemical, and social environments adversely affect the molecular process and results in cell signal transduction and the subsequent transcription factor dysregulation, leading to impaired gene expression and abnormal protein synthesis. Stressful environments such as social adversity, isolation, sustained social threats, physical inactivity, and highly methylated diets predispose individuals to molecular level alterations such as aberrant epigenomic modulations that affect homeostasis and hemodynamics. With cardiovascular disease as the leading cause of mortality in the US and blacks/African Americans being disproportionately affected by hypertension (HTN) which contributes substantially to these deaths, reflecting the excess mortality and survival disadvantage of this sub-population relative to whites, understanding the molecular events, including epigenomic and socio-epigenomic modulations, is relevant to narrowing the black-white mortality risk differences. We aimed to synthesize epigenomic findings in HTN namely (a) angiotensin-converting enzyme 2 (ACE II) gene, (b) Toll-like receptor 2 (TLR2) gene, (c) interferon γ (IFN-γ) gene, and (d) Capping Actin Protein, Gelosin-Like (CAPG) gene, adducin 1(ADD1) gene, (e) Tissue inhibitor of metalloproteinase 3 (TIMP3), (f) mesoderm specific transcript (MEST) loci, (g) sodium channel epithelial 1 alpha subunit 2 (SCNN1B), (h) glucokinase (CKG) gene (i) angiotensin II receptor, type1 (AGTR1), and DNA methylation (mDNA). A systematic review and quantitative evidence synthesis (QES) was conducted using Google Scholar and PubMed with relevant search terms. Data were extracted from studies on: (a) Epigenomic modulations in HTN based on ACE II (b) TLR2, (c) IFN-γ gene, (d) CAPG, ADD1, TIMP3, MEST loci, and mDNA. The random-effect meta-analysis method was used for a pooled estimate of the common effect size, while z statistic and I^2 were used for the homogeneity of the common effect size and between studies on heterogeneity respectively. Of the 642 studies identified, five examined hypermethylation while seven studies assessed hypomethylation in association with HTN. The hypermethylation of ACE II, SCNN1B, CKG, IFN-γ gene, and miR-510 promoter were associated with hypertension, the common effect size (CES) = 6.0%, 95% CI, −0.002–11.26. In addition, the hypomethylation of TLR2, IFN-γ gene, ADD1, AGTR1, and GCK correlated with hypertension, the CES = 2.3%, 95% CI, −2.51–7.07. The aberrant epigenomic modulation of ACE II, TLR2, IFN-γ, AGTR1, and GCK correlated with essential HTN. Transforming the environments resulting from these epigenomic lesions will facilitate early intervention mapping in reducing HTN in the US population, especially among socially disadvantaged individuals, particularly racial/ethnic minorities

Aberrant Epigenomic Modulation of Glucocorticoid Receptor Gene (NR3C1) in Early Life Stress and Major Depressive Disorder Correlation: Systematic Review and Quantitative Evidence Synthesis

Early life stress (ELS) induced by psychological trauma, child maltreatment, maternal separation, and domestic violence predisposes to psycho-behavioral pathologies during adulthood, namely major depressive disorder (MDD), anxiety, and bipolar affective disorder. While environmental data are available in illustrating this association, data remain to be established on the epigenomic underpinning of the nexus between ELS and MDD predisposition. Specifically, despite the observed aberrant epigenomic modulation of the NR3C1, a glucocorticoid receptor gene, in early social adversity and social threats in animal and human models, reliable scientific data for intervention mapping in reducing social adversity and improving human health is required. We sought to synthesize the findings of studies evaluating (a) epigenomic modulations, mainly DNA methylation resulting in MDD following ELS, (b) epigenomic modifications associated with ELS, and (c) epigenomic alterations associated with MDD. A systematic review and quantitative evidence synthesis (QES) were utilized with the random effect meta-analytic procedure. The search strategy involved both the PubMed and hand search of relevant references. Of the 1534 studies identified through electronic search, 592 studies were screened, 11 met the eligibility criteria for inclusion in the QES, and 5 examined ELS and MDD; 4 studies assessed epigenomic modulation and ELS, while 2 studies examined epigenomic modulations and MDD. The dense DNA methylation of the 1F exon of the NR3C1, implying the hypermethylated region of the glucocorticoid receptor gene, was observed in the nexus between ELS and MDD, common effect size (CES) = 14.96, 95%CI, 10.06–19.85. With respect to epigenomic modulation associated with child ELS, hypermethylation was observed, CES = 23.2%, 95%CI, 8.00–38.48. In addition, marginal epigenomic alteration was indicated in MDD, where hypermethylation was associated with increased risk of MDD, CES = 2.12%, 95%CI, −0.63–4.86. Substantial evidence supports the implication of NR3C1 and environmental interaction, mainly DNA methylation, in the predisposition to MDD following ELS. This QES further supports aberrant epigenomic modulation identified in ELS as well as major depressive episodes involving dysfunctional glucocorticoid-mediated negative feedback as a result of allostatic overload. These findings recommend prospective investigation of social adversity and its predisposition to the MDD epidemic via aberrant epigenomic modulation. Such data will facilitate early intervention mapping in reducing MDD in the United States population

Implication of Vaginal and Cesarean Section Delivery Method in Black–White Differentials in Infant Mortality in the United States: Linked Birth/Infant Death Records, 2007–2016

Racial/ethnic disparities in infant mortality (IM) continue to persist in the United States, with Black/African Americans (AA) being disproportionally affected with a three-fold increase in mortality compared to Whites. Epidemiological data have identified maternal characteristics in IM risk such as preeclampsia, eclampsia, maternal education, smoking, maternal weight, maternal socioeconomic status (SES), and family structure. Understanding the social gradient in health including implicit bias, as inherent in the method of labor and delivery and the racial heterogeneity, may facilitate intervention mapping in narrowing the Black–White IM risk differences. We aimed to assess the temporal/racial trends and the methods of delivery, mainly vaginal vs. cesarean section (C-section) as an exposure function of IM. The United States linked birth/infant death records (2007–2016) were used with a cross-sectional ecological design. The analysis involved chi squared statistic, incidence rate estimation by binomial regression model, and period percent change. Of the 40,445,070 births between 2007 and 2016, cumulative mortality incidence was 249,135 (1.16 per 1000). The IM rate was highest among Black/AA (11.41 per 1000), intermediate among Whites (5.19 per 1000), and lowest among Asian /Pacific Islanders (4.24 per 1000). The cumulative incidence rate difference, comparing vaginal to cesarean procedure was 1.73 per 1000 infants, implying excess IM with C-section. Compared to C-section, there was a 31% decreased risk of IM among mothers with vaginal delivery, rate ratio (RR) = 0.69, 95% confidence interval (CI): 0.64–0.74. Racial disparities were observed in the method of delivery associated with IM. Black/AA mothers with vaginal delivery had a 6% decreased risk of IM compared to C-section, RR = 0.94, 95% CI: 0.92–0.95, while Whites with vaginal delivery had a 38% decrease risk of IM relative to C-section, RR= 0.68, 95% CI: 0.67–0.69, p < 0.001. Infant mortality varied by race, with Black/AA disproportionally affected, which is explained in part by labor and delivery procedures, suggestive of reliable and equitable intrapartum assessment of Black/AA mothers during labor, as well as implicit bias marginalization in the healthcare system

Disruption of Basal Lamina Components in Neuromotor Synapses of Children with Spastic Quadriplegic Cerebral Palsy

<div><p>Cerebral palsy (CP) is a static encephalopathy occurring when a lesion to the developing brain results in disordered movement and posture. Patients present with sometimes overlapping spastic, athetoid/dyskinetic, and ataxic symptoms. Spastic CP, which is characterized by stiff muscles, weakness, and poor motor control, accounts for ∼80% of cases. The detailed mechanisms leading to disordered movement in spastic CP are not completely understood, but clinical experience and recent studies suggest involvement of peripheral motor synapses. For example, it is recognized that CP patients have altered sensitivities to drugs that target neuromuscular junctions (NMJs), and protein localization studies suggest that NMJ microanatomy is disrupted in CP. Since CP originates during maturation, we hypothesized that NMJ disruption in spastic CP is associated with retention of an immature neuromotor phenotype later in life. Scoliosis patients with spastic CP or idiopathic disease were enrolled in a prospective, partially-blinded study to evaluate NMJ organization and neuromotor maturation. The localization of synaptic acetylcholine esterase (AChE) relative to postsynaptic acetylcholine receptor (AChR), synaptic laminin β2, and presynaptic vesicle protein 2 (SV2) appeared mismatched in the CP samples; whereas, no significant disruption was found between AChR and SV2. These data suggest that pre- and postsynaptic NMJ components in CP children were appropriately distributed even though AChE and laminin β2 within the synaptic basal lamina appeared disrupted. Follow up electron microscopy indicated that NMJs from CP patients appeared generally mature and similar to controls with some differences present, including deeper postsynaptic folds and reduced presynaptic mitochondria. Analysis of maturational markers, including myosin, syntrophin, myogenin, and AChR subunit expression, and telomere lengths, all indicated similar levels of motor maturation in the two groups. Thus, NMJ disruption in CP was found to principally involve components of the synaptic basal lamina and subtle ultra-structural modifications but appeared unrelated to neuromotor maturational status.</p></div