Public Health
Abstract
BACKGROUND Suboptimal fetal growth (SFG), being born small for gestational age (SGA), and catch-up (CU) growth are, individually and together, linked to cardiometabolic risks. However, not all develop adverse outcomes. This study aimed to validate a transcriptomic signature to identify individuals at greatest cardiometabolic risk.METHODS Using National Heart, Lung and Blood Institute (NHLBI) criteria to define cardiometabolic risk, healthy and prehypertensive 17-year-olds were identified in the Avon Longitudinal Study of Parents and Children (ALSPAC) (UK) childhood cohort. Epigenomic and transcriptomic differences were analyzed. A hypergraph identified functionally related genes, which were used in random forest classification to predict prehypertensive phenotypes. The BabyGRO (UK) cohort included 80 children aged 3–7 years, born at term following pregnancies with SFG risks. Anthropometric and cardiometabolic markers and transcriptomic profiles were collected, fetal and childhood weight trajectories and their relationship to cardiometabolic markers were assessed, and transcriptome was used for prediction.RESULTS Individuals with CU-SGA in ALSPAC were 1.6 times more likely than all others to be prehypertensive at 17 years (P < 1 × 10–5). A 42-gene hypergraph cluster was highly predictive of prehypertension (AUC 0.984, error rate 5.4%). In BabyGRO, 20 of these genes accurately predicted higher systolic blood pressure (AUC 0.971, error rate 3.6%). This transcriptomic signature could help identify children with adverse pre- and postnatal growth who may develop prehypertension.CONCLUSION A blood transcriptomic signature exists in childhood which distinguishes those at risk of adult cardiometabolic disease among children with adverse pre- and postnatal growth.TRIAL REGISTRATION Regional ethics committee reference 17/NW/0153, IRAS project ID 187679.FUNDING Centre grant to the Maternal and Fetal Health Research Centre by Tommy’s The Pregnancy and Baby Charity, Child Growth Foundation, European Research Council funding as part of the Health and Environment-wide Associations based on Large Population Surveys (HEALS) study
Authors
Reena Perchard, Terence Garner, Philip G. Murray, Amirul Roslan, Lucy E. Higgins, Edward D. Johnstone, Adam Stevens, Peter E. Clayton
Abstract
Empirical data from survivors of Lassa fever and experimental disease modelling efforts, particularly those using mouse models, are at odds with respect to T cell-mediated pathogenesis. In mice, T cells have been shown to be imperative in disease progression and lethality, whereas in humans, an early and robust T cell responses has been associated with survival. Here, we assessed the role of CD4+ and CD8+ T cells on disease progression and severity of Lassa virus infection in a non-human primate model. Using an antibody-mediated T cell depletion strategy prior to and post-inoculation, we were able to examine Lassa virus infection in the absence of specific T cell responses. In animals depleted for either CD4+ or CD8+ T cells, Lassa virus infection remained uniformly lethal, with only a slight delay in disease progression observed in the CD4-depleted group when compared to non-depleted controls. Milder pulmonary pathology was noticed in the absence of CD4+ or CD8+ T cells. Overall, our findings suggest that T cells have a limited impact on the development of Lassa fever in non-human primates.
Authors
Jérémie Prévost, Nikesh Tailor, Geoff Soule, Jonathan Audet, Yvon Deschambault, Robert Vendramelli, Jessica Prado-Smith, Kevin Tierney, Kimberly Azaransky, Darwyn Kobasa, Chad S. Clancy, Heinz Feldmann, Kyle Rosenke, David Safronetz
Abstract
The FDA-approved phosphodiesterase type 4 (PDE4) inhibitor, apremilast, has been recently investigated as a pharmacotherapy for alcohol use disorder (AUD) with promising efficacy in rodent models and humans. However, apremilast’s effects on mechanical allodynia associated with AUD as well as distinct responses of this drug between males and females are understudied. The present study examined the behavioral and electrophysiological effects of apremilast in Marchigian Sardinian alcohol-preferring (msP) rats and their Wistar counterparts. We used a 2–bottle choice (2-BC) alcohol drinking procedure and tested mechanical sensitivity across our drinking regimen. Spontaneous inhibitory GABA-mediated postsynaptic currents from the central nucleus of the amygdala (CeA) following apremilast application were tested in a subset of rats using ex vivo electrophysiology. Transcript levels for Pde4a or -4b subtypes were assessed for their modulation by alcohol. Apremilast reduced alcohol drinking in both strains of rats. Apremilast reduced mechanical allodynia immediately after drinking, persisting into early and late abstinence. Apremilast increased GABAergic transmission in CeA slices of alcohol-exposed Wistars but not msP rats, suggesting neuroadaptations in msPs by excessive drinking and mechanical allodynia. Pde4 subtype transcript levels were increased in CeA by alcohol. These results suggest that apremilast alleviates co-occurring excessive drinking and pain sensitivity, and they further confirm PDE4’s role in pain-associated AUD.
Authors
Valentina Vozella, Vittoria Borgonetti, Bryan Cruz, Celsey M. St. Onge, Ryan Bullard, Roman Vlkolinsky, Diego Gomez Ceballos, Angela R. Ozburn, Amanda J. Roberts, Roberto Ciccocioppo, Michal Bajo, Marisa Roberto
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