Metabolomics Fingerprint Predicts Risk of Death in Dilated Cardiomyopathy and Heart Failure

BACKGROUND: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Metabolomics may help refine risk assessment and potentially guide HF management, but dedicated studies are few. This study aims at stratifying the long-term risk of death in a cohort of patients affected by HF due to dilated cardiomyopathy (DCM) using serum metabolomics via nuclear magnetic resonance (NMR) spectroscopy. METHODS: A cohort of 106 patients with HF due to DCM, diagnosed and monitored between 1982 and 2011, were consecutively enrolled between 2010 and 2012, and a serum sample was collected from each participant. Each patient underwent half-yearly clinical assessments, and survival status at the last follow-up visit in 2019 was recorded. The NMR serum metabolomic profiles were retrospectively analyzed to evaluate the patient's risk of death. Overall, 26 patients died during the 8-years of the study. RESULTS: The metabolomic fingerprint at enrollment was powerful in discriminating patients who died (HR 5.71, p = 0.00002), even when adjusted for potential covariates. The outcome prediction of metabolomics surpassed that of N-terminal pro b-type natriuretic peptide (NT-proBNP) (HR 2.97, p = 0.005). Metabolomic fingerprinting was able to sub-stratify the risk of death in patients with both preserved/mid-range and reduced ejection fraction [hazard ratio (HR) 3.46, p = 0.03; HR 6.01, p = 0.004, respectively]. Metabolomics and left ventricular ejection fraction (LVEF), combined in a score, proved to be synergistic in predicting survival (HR 8.09, p = 0.0000004). CONCLUSIONS: Metabolomic analysis via NMR enables fast and reproducible characterization of the serum metabolic fingerprint associated with poor prognosis in the HF setting. Our data suggest the importance of integrating several risk parameters to early identify HF patients at high-risk of poor outcomes

A Reciprocal Cell–Cell Interaction Mediated by NT-3 and Neuregulins Controls the Early Survival and Development of Sympathetic Neuroblasts

Neurotrophin 3 (NT-3) can support the survival of some embryonic sympathetic neuroblasts before they become nerve growth factor dependent. We show that NT-3 is produced in vivo by nonneuronal cells neighboring embryonic sympathetic ganglia. NT-3 mRNA is produced by these nonneuronal cells in vitro and is up-regulated by platelet-derived growth factor, ciliary neurotrophic factor, and glial growth factor 2 (a neuregulin). Nonneuronal cell–conditioned medium promotes survival and induces TrkA expression in isolated sympathetic neuroblasts, and this activity is blocked by anti-NT-3 antibody. Neuroblasts also enhance NT-3 production by nonneuronal cells. Neuroblasts synthesize several forms of neuregulin, and antibodies to neuregulin attenuate the effect of the neuroblasts on the nonneuronal cells. These data suggest a reciprocal cell–cell interaction, in which neuroblast-derived neuregulins promote NT-3 production by neighboring nonneuronal cells, which in turn promotes neuroblast survival and further differentiation

The PRRT2 knockout mouse recapitulates the neurological diseases associated with PRRT2 mutations.

Heterozygous and rare homozygous mutations in PRoline-Rich Transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders including epilepsy, kinesigenic dyskinesia episodic ataxia and migraine. Most of the mutations lead to impaired PRRT2 expression and/or function. Recently, an important role for PRTT2 in the neurotransmitter release machinery, brain development and synapse formation has been uncovered. In this work, we have characterized the phenotype of a mouse in which the PRRT2 gene has been constitutively inactivated (PRRT2 KO)beta-galactosidase staining allowed to map the regional expression of PRRT2 that was more intense in the cerebellum, hindbrain and spinal cord, while it was localized to restricted areas in the fore-brain. PRRT2 KO mice are normal at birth, but display paroxysmal movements at the onset of locomotion that persist in the adulthood. In addition, adult PRRT2 KO mice present abnormal motor behaviors characterized by wild running and jumping in response to audiogenic stimuli that are ineffective in wild type mice and an increased sensitivity to the convulsive effects of pentylentetrazol. Patch-clamp electrophysiology in hippocampal and cerebellar slices revealed specific effects in the cerebellum, where PRRT2 is highly expressed, consisting in a higher excitatory strength at parallel fiber-Purkinje cell synapses during high frequency stimulation. The results show that the PRRT2 KO mouse reproduces the motor paroxysms present in the human PRRT2-linked pathology and can be proposed as an experimental model for the study of the pathogenesis of the disease as well as for testing personalized therapeutic approaches

Electro-oxidation of ethylene glycol and glycerol at palladium-decorated FeCo@Fe core-shell nanocatalysts for alkaline direct alcohol fuel cells : functionalized MWCNT supports and impact on product selectivity

Half-cell reactions and alkaline direct ethylene glycol and glycerol fuel cells (DEGFC and DGFC) have been studied on Pd-based ternary core–shell (FeCo@Fe@Pd) nanocatalyst using multi-walled carbon nanotubes bearing carboxylic (MWCNT-COOH) and sulfonic acid (MWCNT-SO3H) as supporting platforms. The core–shell–shell nature of this nanocatalyst, obtained via the “microwave-induced top-down nanostructuring and decoration”, was clearly proven from atomic resolution transmission electron microscopy (ARTEM). The functional groups of the MWCNTs show a huge impact on the physicochemical properties of the FeCo@Fe@Pd nanocatalyst towards the electrocatalytic oxidation of EG and GLY in alkaline media. The FeCo@Fe@Pd on –COOH-treated MWCNTs showed the small particle size of ca. 7.4 nm, uniform loading of the catalyst on the support, large electrochemically-active surface area and enhanced electrocatalytic activity compared to the FeCo@Fe@Pd on –SO3H-bearing MWCNTs. As a preliminary test, FeCo@Fe@Pd/MWCNT-COOH was used for passive, air-breathing anion-exchange membrane based fuel cells (AEM-DEGFC and AEM-DGFC). The analysis of the exhaust products, established using NMR spectroscopy, revealed a high selectivity towards the complete oxidation of both EG and GLY under benign experimental conditions.This work was funded by the CSIR, the University of Pretoria as well as the South Africa's Department of Science and Technology (DST) and National Research Foundation (NRF) under the “Nanotechnology Flagship Programme” (supercapacitors and fuel cell project, Grant no. 69849). OOF thanks the DST/NRF for doctoral bursary under this project.http://www.rsc.org/journals-books-databases/about-journals/journal-of-materials-chemistry-ahb2016Chemistr