The serotonin 1A receptor (5-HT1A), a critical regulator of the brain serotonergic tone, is implicated in major depressive disorder (MDD) where it is often found to be dys-regulated. However, the extent to which stress and antidepressant treatment impact 5-HT1A expression in adults remains unclear. To address this issue, we subjected adult male BALB/c mice to unpredictable chronic mild stress (UCMS) to induce a depression-like phenotype that was reversed by chronic treatment with the antidepressant imipramine. In prefrontal cortex (PFC) and midbrain tissue, UCMS increased 5-HT1A RNA and protein levels, changes that are expected to decrease the brain serotonergic activity. The stress-induced increase in 5-HT1A expression was paralleled by a specific increase in DNA methylation of the conserved -681 CpG promoter site, located within a Sp1-like element. We show that the -681 CpG site is recognized and repressed by Sp4, the predominant neuronal Sp1-like factor and that Sp4-induced repression is attenuated by DNA methylation, despite a stress-induced increase in PFC Sp4 levels. These results indicate that adult life stress induces DNA methylation of a conserved promoter site, antagonizing Sp4 repression to increase 5-HT1A expression. Chronic imipramine treatment fully reversed the UCMS-induced increase in methylation of the -681 CpG site in the PFC but not midbrain of stressed animals and also increased 5-HT1A expression in the PFC of control animals. Incomplete reversal by imipramine of stress-induced changes in 5-HT1A methylation and expression indicates a persistence of stress vulnerability, and that sustained reversal of behavioral impairments may require additional pathways.

Background: Optimizing outcomes in Respiratory Syncytial Virus (RSV) pneumonia requires accurate diagnosis and determination of severity that, in resource-limited settings, is often based on clinical assessment alone. We describe host inflammatory biomarkers and clinical outcomes among children hospitalized with RSV lower respiratory tract infection (LRTI) in Uganda and controls with rhinovirus and pneumococcal pneumonia. Methods: 58 children hospitalized with LRTI were included. We compared 37 patients with RSV, 10 control patients with rhinovirus, and 11 control patients with suspected pneumococcal pneumonia. Results: Patients in the RSV group had significantly lower levels of C-Reactive Protein (CRP) and Chitinase-3-Like Protein 1 (CHI3L1) than the pneumococcal pneumonia group (p<0.05 for both). Among children with RSV, higher admission levels of CRP predicted prolonged time to resolution of tachypnea, tachycardia, and fever. Higher levels of CHI3L1 were associated with higher composite clinical severity scores and predicted prolonged time to resolution of tachypnea and tachycardia, time to wean oxygen, and time to sit. Higher levels of Lipocalin-2 (LCN2) predicted prolonged time to resolution of tachypnea, tachycardia and time to feed. Higher admission levels of all three biomarkers were predictive of a higher total volume of oxygen administered during hospitalization (p<0.05 for all comparisons). Of note, CHI3L1 and LCN2 appeared to predict clinical outcomes more accurately than CRP, the inflammatory biomarker most widely used in clinical practice. Conclusions: Our findings suggest that CHI3L1 and LCN2 may be clinically informative biomarkers in childhood RSV LRTI in low-resource settings.

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Background: Systemic inflammation, platelet dysfunction, and endothelial activation persist in people living with HIV despite sustained virologic suppression (SVS) with combined antiretroviral therapy (cART) and may lead to complications such as atherosclerosis and cardiovascular disease. Angiopoietin-1 (Ang-1) is a key regulator of angiogenesis and endothelial activation and has been studied as an objective biomarker in disease states such as atherosclerosis, sepsis, and severe malaria. Setting: Eight pediatric HIV care centers across Canada. Methods: Cross-sectional study of 61 children living with vertically acquired HIV on cART with undetectable RNA viral load. Plasma levels of Ang-1 were measured by ELISA and analyzed in relation to clinical characteristics abstracted from medical records. Results: Ang-1 levels were directly correlated with clinical indices of virologic control: cumulative proportion of life on effective cART (ρ = +0.35, P = 0.0078) and cumulative proportion of life with SVS (ρ = +0.36, P = 0.0049). Furthermore, higher Ang-1 levels were associated with younger age at SVS (ρ = −0.56, P < 0.0001). These associations remained statistically significant in multivariable linear regression models adjusting for potential confounders (P < 0.05 for all associations). Conclusions: Early effective cART and SVS were associated with higher Ang-1 levels in children living with vertically acquired HIV-1.