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.
• Role of the muscarinic acetylcholine receptor in parathion toxicity: Chronic acetylcholinesterase inhibition and direct effects

  Jett, David Alan; Eldefrawi, A. T. (Amira T.) (1992)

  Certain muscarinic acetylcholine receptors (mAChRs) have high affinity for organophosphate (OP) anticholinesterases, and their density is reduced by chronic exposure to OPs. The effects of acute in vitro and chronic in vivo exposures to the OP insecticide, parathion, and its more toxic metabolite paraoxon, were studied on mAChRs in the brains and submaxillary gland (SMG) of rats and white-footed mice. Binding of subtype-nonselective and -selective radioligands, receptor functional assays as well as mRNA expression measurements were utilized. In addition to its binding and inhibition of acetyl-cholinesterase (AChE), paraoxon bound directly with even higher affinities to mAChRs. It bound to mAChRs in rat striatum (possibly an M{dollar}\sb4{dollar} subtype) and acted as an agonist, producing atropine-sensitive inhibition of forskolin-activated ({dollar}\sp3{dollar}H) cAMP synthesis. Paraoxon also bound to M{dollar}\sb3{dollar} mAChRs in rat SMG cells, but to a noncompetitive site. Although paraoxon at submicromolar concentration inhibited forskolin-activated ({dollar}\sp3{dollar}H) cAMP synthesis, this was not reversed by atropine. It suggested that paraoxon had two binding sites: an allosteric one on the mAChR, and the other on the G{dollar}\sb{lcub}\rm i{rcub}{dollar} protein-adenylyl cyclase system. The direct high-affinity reversible actions of paraoxon on mAChRs would contribute significantly to its toxicity, especially early on before most AChE is phosphorylated. The majority of mAChRs in the brains of white-footed mice were found to be of the M{dollar}\sb3{dollar} subtype. Adults exposed chronically for 14 days to dietary sublethal doses of parathion had reduced brain AChE activity, and densities of total mAChRs as well as the M{dollar}\sb3{dollar} subtype by {dollar}\approx{dollar}50% without significant change in their affinities. The reduction in mAChRs increased with higher AChE inhibition, which reflected paraoxon concentrations in the brain. The data provide the first evidence for down-regulation of mAChRs in a wild rodent species after dietary exposure to parathion, which would affect their adaptation to environmental exposure to OP insecticides. Furthermore, the changes in mAChRs may provide a molecular basis for certain chronic toxicities of OPs in humans and other mammals.