Neuroprotective tissue adaptation induced by IL-12 attenuates CNS inflammation

IL-12 is a well-established driver of type 1 immune responses. Paradoxically, in several autoimmune conditions including neuroinflammation, IL-12 reduces pathology and exhibits regulatory properties. Yet, the mechanism and the involved cellular players behind this immune regulation remain elusive. To identify the IL-12-responsive elements which prevent immunopathology, we generated mouse models lacking a functional IL-12 receptor either in all cells or in specific populations within the immune or central nervous system (CNS) compartments, and induced experimental autoimmune encephalomyelitis (EAE), which models human Multiple Sclerosis (MS). This revealed that the CNS tissue-protective features of IL-12 are mediated by cells of the neuroectoderm, and not immune cells. Importantly, sections of brain from patients with MS show comparable patterns of expression, indicating parallel mechanisms in humans. By combining spectral flow cytometry, bulk and single-nucleus RNA sequencing, we uncovered an IL-12-induced neuroprotective adaption of the neuroectoderm critically involved in maintaining CNS tissue integrity during inflammation

IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice

“I was a full time proper smoker”: A qualitative exploration of smoking in the home after childbirth among women who relapse postpartum

Background: Many women stop smoking during pregnancy but relapse shortly afterwards, potentially putting their infants at risk of secondhand smoke (SHS) exposure. Women who were able to stop during pregnancy may be a motivated group, receptive to making behaviour changes postpartum to protect their infant from SHS exposure. Understanding more about their experiences of relapse, and if this influences home smoking behaviours and children’s exposure to SHS in the home may help to inform intervention development to prevent infant SHS exposure. Methods: Guided by interpretative phenomenological methodology we conducted and analysed nine semi-structured interviews with women who quit smoking during pregnancy, but relapsed ≤3 months postpartum. Findings: Central to mothers’ accounts of their smoking behaviours during pregnancy and postpartum was their desire to be a ‘responsible mother’. Mothers described using strategies to protect their infant from SHS exposure, and held strong negative attitudes towards other smoking parents. After relapsing, mothers appeared to reposition themselves as ‘social’ or ‘occasional’ smokers rather than ‘regular’ smokers Conclusions: Findings suggest that interventions to prevent/reduce infants' home SHS exposure should build on mothers' intentions to be responsible parents. As mothers who relapse principally view themselves as ‘social’ or ‘occasional’ smokers, interventions that are highlighted as relevant for women with these types of smoking patterns may be more likely to be responded to, and, ultimately, be effective

A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex

We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer’s disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-β and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease

Female veterans of the OEF/OIF conflict: Concordance of PTSD symptoms and substance misuse

This study examined the post-deployment rates of comorbid PTSD and substance abuse in a cohort of female veterans who served in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF). Female OEF/ OIF veterans and reservists (N=36) completed a battery of assessments as part of a larger study. Of the 36 participants, 11 (31%) screened positive for posttraumatic stress disorder (PTSD), 17 (47%) screened positive for high-risk drinking and 2 (6%) screened positive for drug abuse. Higher scores on measures of alcohol and drug use predicted positive PTSD status (p≤0.01) and alcohol misuse was significant in explaining unique variance of PTSD status (p≤0.05). Our findings suggest a trend toward increased problematic drinking among female OEF/OIF veterans and reservists and a relationship between substance misuse and PTSD. Future research should investigate needs for gender-specific PTSD and substance-abuse treatment needs

HRSA's evidence-based tele-emergency network grant program: Multi-site prospective cohort analysis across six rural emergency department telemedicine networks.

BackgroundThe Health Resources and Services Administration (HRSA), Federal Office of Rural Health Policy (FORHP) funded the Evidence-Based Tele-Emergency Network Grant Program (EB TNGP) to serve the dual purpose of providing telehealth services in rural emergency departments (teleED) and systematically collecting data to inform the telehealth evidence base. This provided a unique opportunity to examine trends across multiple teleED networks and examine heterogeneity in processes and outcomes.Method and findingsSix health systems received funding from HRSA under the EB TNGP to implement teleED services and they did so to 65 hospitals (91% rural) in 11 states. Three of the grantees provided teleED services to a general patient population while the remaining three grantees provided teleED services to specialized patient populations (i.e., stroke, behavioral health, critically ill children). Over a 26-month period (November 1, 2015 -December 31, 2017), each grantee submitted patient-level data for all their teleED encounters on a uniform set of measures to the data coordinating center. The six grantees reported a total of 4,324 teleED visits and 99.86% were technically successful. The teleED patients were predominantly adult, White, not Latinx, and covered by Medicare or private insurance. Across grantees, 7% of teleED patients needed resuscitation services, 58% were rated as emergent, and 30% were rated as urgent. Across grantees, 44.2% of teleED patients were transferred to another inpatient facility, 26.0% had a routine discharge, and 24.5% were admitted to the local inpatient facility. For the three grantees who served a general patient population, the most frequent presenting complaints for which teleED was activated were chest pain (25.7%), injury or trauma (17.1%), stroke symptoms (9.9%), mental/behavioral health (9.8%), and cardiac arrest (9.5%). The teleED consultation began before the local clinician exam in 37.8% of patients for the grantees who served a general patient population, but in only 1.9% of patients for the grantees who provided specialized services.ConclusionsGrantees used teleED services for a representative rural population with urgent or emergent symptoms largely resulting in transfer to a distant hospital or inpatient admission locally. TeleED was often available as the first point of contact before a local provider examination. This finding points to the important role of teleED in improving access for rural ED patients

The association of posttraumatic stress disorder and metabolic syndrome: a study of increased health risk in veterans

<p>Abstract</p> <p>Background</p> <p>There is accumulating evidence for a link between trauma exposure, posttraumatic stress disorder (PTSD) and diminished health status. To assess PTSD-related biological burden, we measured biological factors that comprise metabolic syndrome, an important established predictor of morbidity and mortality, as a correlate of long-term health risk in PTSD.</p> <p>Methods</p> <p>We analyzed clinical data from 253 male and female veterans, corresponding to five factors linked to metabolic syndrome (systolic and diastolic blood pressure, waist-to-hip ratio and fasting measures of high-density lipoprotein (HDL) cholesterol, serum triglycerides and plasma glucose concentration). Clinical cut-offs were defined for each biological parameter based on recommendations from the World Health Organization and the National Cholesterol Education Program. Controlling for relevant variables including sociodemographic variables, alcohol/substance/nicotine use and depression, we examined the impact of PTSD on metabolic syndrome using a logistic regression model.</p> <p>Results</p> <p>Two-fifths (40%) of the sample met criteria for metabolic syndrome. Of those with PTSD (<it>n </it>= 139), 43% met criteria for metabolic syndrome. The model predicted metabolic syndrome well (-2 log likelihood = 316.650, chi-squared = 23.731, <it>p </it>= 0.005). Veterans with higher severity of PTSD were more likely to meet diagnostic criteria for metabolic syndrome (Wald = 4.76, <it>p </it>= 0.03).</p> <p>Conclusion</p> <p>These findings provide preliminary evidence linking higher severity of PTSD with risk factors for diminished health and increased morbidity, as represented by metabolic syndrome.</p

Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like Peptide-1 receptor signaling

We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)-deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1r(-/-) mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance