Citations

Background: Amino acid metabolism is crucial for inflammatory processes during atherogenesis. The endogenous amino acid homoarginine is a robust biomarker for cardiovascular outcome and mortality with high levels being protective. However, the underlying mechanisms remain elusive. We investigated the effect of homoarginine supplementation on atherosclerotic plaque development with a particular focus on inflammation. Methods: Female ApoE-deficient mice were supplemented with homoarginine (14 mg/L) in drinking water starting 2 weeks before and continuing throughout a 6-week period of Western-type diet feeding. Control mice received normal drinking water. Immunohistochemistry and flow cytometry were used for plaque- and immunological phenotyping. T cells were characterized using mass spectrometry–based proteomics, by functional in vitro approaches, for example, proliferation and migration/chemotaxis assays as well as by super-resolution microscopy. Results: Homoarginine supplementation led to a 2-fold increase in circulating homoarginine concentrations. Homoarginine-treated mice exhibited reduced atherosclerosis in the aortic root and brachiocephalic trunk. A substantial decrease in CD3 + T cells in the atherosclerotic lesions suggested a T-cell–related effect of homoarginine supplementation, which was mainly attributed to CD4 + T cells. Macrophages, dendritic cells, and B cells were not affected. CD4 + T-cell proteomics and subsequent pathway analysis together with in vitro studies demonstrated that homoarginine profoundly modulated the spatial organization of the T-cell actin cytoskeleton and increased filopodia formation via inhibition of Myh9 (myosin heavy chain 9). Further mechanistic studies revealed an inhibition of T-cell proliferation as well as a striking impairment of the migratory capacities of T cells in response to relevant chemokines by homoarginine, all of which likely contribute to its atheroprotective effects. Conclusions: Our study unravels a novel mechanism by which the amino acid homoarginine reduces atherosclerosis, establishing that homoarginine modulates the T-cell cytoskeleton and thereby mitigates T-cell functions important during atherogenesis. These findings provide a molecular explanation for the beneficial effects of homoarginine in atherosclerotic cardiovascular disease.

Abstract We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints.

AbstractObjectiveYouth with chronic orthostatic intolerance (OI) can experience significant physical, social, and academic functional debilitation. Previous studies have indicated associations among symptom severity, psychosocial factors, and functional disability. However, empirically tested models explaining how different medical and psychosocial factors may contribute to functional disability are lacking. The current cross-sectional study aimed to evaluate mediation, moderation, and additive models of the effect of physical symptoms and psychological distress on functional disability.MethodsOne hundred and sixty-five youth (13–22 years old) undergoing medical evaluation of chronic OI symptoms completed measures of autonomic dysfunction symptom severity, depressive and anxiety symptoms, and functional disability. Models were evaluated using tests of indirect effects and linear and logistic regression analyses.ResultsResults supported the mediation and additive effects models for depressive symptoms. Mediation, moderation, and additive models for hypothesized effects of anxiety symptoms were not supported.ConclusionsResults provide preliminary support for models in which OI symptoms affect functional debility via their effects on mood and in which depressive symptoms have unique and additive effects on functioning. Findings lay the foundation for longitudinal and experimental evaluation of biopsychosocial models of functional disability in youth with chronic OI and related conditions. Implications include the importance of a biopsychosocial conceptualization of OI symptoms and debility as a complex interplay of factors rather than as a purely physiological or psychological process.

AbstractBackground and ObjectiveIntensive interdisciplinary pain treatment (IIPT) for youth with high impact chronic pain has been found to be effective in improving child symptoms and functioning. However, it remains unclear how these interventions impact the parents' own well‐being, as well as cognitions and behaviours which are known to influence child pain and functioning. Thus, the current study sought to determine the effect of IIPT on parent mental health, cognitions and behaviours in parents of youth attending IIPT with their child.Databases and Data TreatmentA search of the electronic databases CINAHL, Ovid EBM Reviews, Embase, Medline, APA PsychINFO, Scopus and web of Science was conducted. Studies were included if they comprised at least 10 parents of patients aged 9–22 with nonmalignant chronic pain attending an IIPT and were written in English.ResultsA random‐effects model was used to pool the standardized mean change (SMC) across seven prepost studies. At discharge, IIPT participation was associated with small to moderate improvements in direct parental outcomes (general mental health, anxiety, depression and parenting stress), a moderate improvement in pain catastrophizing and large improvements in psychological flexibility and parenting behaviours. Most improvements were maintained at follow‐up. The risk of bias of all studies was rated as serious and the certainty of the evidence as low, suggesting limited confidence in the estimates.ConclusionsAlthough parents appear to benefit from attending an IIPT with their child, RCTs are needed to substantiate the effect of these interventions on important aspects of parent well‐being and functioning.

Abstract Aims CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. Method and Results Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe−/− background were generated (CD40wt and CD40mac−/−, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac−/− compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac−/− atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b− macrophages in the atherosclerotic aorta of CD40mac−/− compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac−/− mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1). Conclusions We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.

Among adolescents with fatigue and postural dizziness, it is unclear how health behaviors and emotional distress relate to the presence of excessive postural tachycardia. We prospectively evaluated adolescents aged 13-22 years presenting with symptoms suggestive of autonomic dysfunction between September 2017 and December 2018. Patients underwent standard 10-minute, 70-degree head-up tilt testing. Clinician diagnoses and recommendations were recorded from the medical record. Patients completed validated self-report measures of lifestyle factors, autonomic symptoms, depression, anxiety, and functional disability. Of 179 patients, 58 were diagnosed with postural orthostatic tachycardia syndrome and 59 had excessive postural tachycardia, with 90.5% concordance between the 2 groups. Presence of excessive postural tachycardia was associated with greater baseline fluid intake and likelihood of medication prescription in their treatment plan. Medication findings were replicated for postural orthostatic tachycardia syndrome diagnosis. Presence of excessive postural tachycardia or postural orthostatic tachycardia syndrome did not differentiate patients on perceived symptom severity, emotional distress, disability, or health behaviors but did appear to determine treatment recommendations.