Showing items related by title, author, creator and subject.

• Cardiac Biomarkers and Risk of Incident Heart Failure in Chronic Kidney Disease: The CRIC (Chronic Renal Insufficiency Cohort) Study

  Christenson, R.; Seliger, S.; CRIC Study Investigators (American Heart Association, 2019)

  Background Cardiac biomarkers may signal mechanistic pathways involved in heart failure (HF), a leading complication in chronic kidney disease. We tested the associations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor-15 (GDF-15), and soluble ST2 (sST2) with incident HF in chronic kidney disease. Methods and Results We examined adults with chronic kidney disease enrolled in a prospective, multicenter study. All biomarkers were measured at baseline. The primary outcome was incident HF. Secondary outcomes included HF with preserved ejection fraction (EF?50%) and reduced ejection fraction (EF<50%). Cox models were used to test the association of each cardiac biomarker with HF, adjusting for demographics, kidney function, cardiovascular risk factors, and medication use. Among 3314 participants, all biomarkers, with the exception of galectin-3, were significantly associated with increased risk of incident HF (hazard ratio per SD higher concentration of log-transformed biomarker): NT-proBNP (hazard ratio, 2.07; 95% CI, 1.79-2.39); hsTnT (hazard ratio, 1.38; 95% CI, 1.21-1.56); GDF-15 (hazard ratio, 1.44; 95% CI, 1.26-1.66) and sST2 (hazard ratio, 1.19; 95% CI, 1.05-1.35). Higher NT-proBNP, hsTnT, and GDF-15 were also associated with a greater risk of HF with reduced EF; while higher NT-proBNP GDF-15 and sST2 were associated with HF with preserved EF. Galectin-3 was not associated with either HF with reduced EF or HF with preserved EF. Conclusions In chronic kidney disease, elevations of NT-proBNP, hsTnT, GDF-15, sST2 were associated with incident HF. There was a borderline association of galectin-3 with incident HF. NT-proBNP and hsTnT were more strongly associated with HF with reduced EF, while the associations of the newer biomarkers GDF-15 and sST2 were stronger for HF with preserved EF.
• An in vitro model yields ‘importin’ new insights into chronic traumatic encephalopathy: damaged astrocytes stop ‘thrombospondin’ to the injury An Editorial Highlight for ‘Defective synthesis and release of astrocytic thrombospondin‐1 mediates the neuronal TDP‐43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies’

  Jaber, S.M.; Polster, B.M. (Blackwell Publishing Ltd, 2017)

  This Editorial highlights a study by Jayakumar and colleagues (2016) in the current issue of Journal of Neurochemistry. The authors introduce an in vitro model of chronic traumatic encephalopathy (CTE) to explore the mechanistic underpinnings of CTE pathogenesis, including investigation of how traumatized astrocytes affect traumatized neurons through the release of secreted factors. The model recapitulates two key features of the human post-mortem CTE brain: neuronal tauopathy and TDP-43 proteinopathy—the respective accretion of hyperphosphorylated tau and cytoplasmic hyperphosphorylated and ubiquitinated TDP-43. Oxidative stress and casein kinase 1 episilon (CK1ε) are identified as key upstream regulators of cytoplasmic TDP-43 phosphorylation, and this phosphorylation is found to correlate with decreased importin-β protein level and a decline in synaptic integrity. RNA silencing of importin-β is sufficient to mimic both the phospho-TDP-43 accumulation and synaptic injury observed after mild in vitro trauma. Strikingly, Jayakumar et al. find that thrombospondin-1 (TSP-1), a protein secreted by traumatized astrocytes at elevated levels during the initial 5 days after damage, can attenuate CK1ε phosphorylation of TDP-43 and synaptic injury. However, TSP-1 secretion by astrocytes is lost at 10–15 days post-injury, and neurons succumb to unchecked TDP-43 pathogenesis.
• Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis

  Gerzanich, V.; Makar, T.K.; Guda, P.R. (BioMed Central Ltd., 2017)

  Background: In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), inflammation is perpetuated by both infiltrating leukocytes and astrocytes. Recent work implicated SUR1-TRPM4 channels, expressed mostly by astrocytes, in murine EAE. We tested the hypothesis that pharmacological inhibition of SUR1 during the chronic phase of EAE would be beneficial. Methods: EAE was induced in mice using myelin oligodendrocyte glycoprotein (MOG) 35-55. Glibenclamide (10 ?g/day) was administered beginning 12 or 24 days later. The effects of treatment were determined by clinical scoring and tissue examination. Drug within EAE lesions was identified using bodipy-glibenclamide. The role of SUR1-TRPM4 in primary astrocytes was characterized using patch clamp and qPCR. Demyelinating lesions from MS patients were studied by immunolabeling and immunoFRET. Results: Administering glibenclamide beginning 24 days after MOG 35-55 immunization, well after clinical symptoms had plateaued, improved clinical scores, reduced myelin loss, inflammation (CD45, CD20, CD3, p65), and reactive astrocytosis, improved macrophage phenotype (CD163), and decreased expression of tumor necrosis factor (TNF), B-cell activating factor (BAFF), chemokine (C-C motif) ligand 2 (CCL2) and nitric oxide synthase 2 (NOS2) in lumbar spinal cord white matter. Glibenclamide accumulated within EAE lesions, and had no effect on leukocyte sequestration. In primary astrocyte cultures, activation by TNF plus IFN? induced de novo expression of SUR1-TRPM4 channels and upregulated Tnf, Baff, Ccl2, and Nos2 mRNA, with glibenclamide blockade of SUR1-TRPM4 reducing these mRNA increases. In demyelinating lesions from MS patients, astrocytes co-expressed SUR1-TRPM4 and BAFF, CCL2, and NOS2. Conclusions: SUR1-TRPM4 may be a druggable target for disease modification in MS. Copyright 2017 The Author(s).