A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS-FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS-FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS-FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials

Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal

INTRODUCTION: Prothrombin complex concentrate (PCC) and recombinant Factor VIIa (rFVIIa) have been used for emergent reversal of warfarin anticoagulation. Few clinical studies have compared these agents in warfarin reversal. We compared warfarin reversal in patients who received either 3 factor PCC (PCC3) or low-dose rFVIIa (LDrFVIIa) for reversal of warfarin anticoagulation. METHODS: Data were collected from medical charts of patients who received at least one dose of PCC3 (20 units/kg) or LDrFVIIa (1000 or 1200 mcg) for emergent warfarin reversal from August 2007 to October 2011. The primary end-points were achievement of an INR 1.5 or less for efficacy and thromboembolic events for safety. RESULTS: Seventy-four PCC3 and 32 LDrFVIIa patients were analyzed. Baseline demographics, reason for warfarin reversal, and initial INR were equivalent. There was no difference in the use of vitamin K or fresh frozen plasma. More LDrFVIIa patients achieved an INR of 1.5 or less (71.9% vs. 33.8%, p =0.001). The follow-up INR was lower after LDrFVIIa (1.25 vs. 1.75, p < 0.05) and the percent change in INR was larger after LDrFVIIa (54.1% vs. 38.8%, p = 0.002). There was no difference in the number of thromboembolic events (2 LDrFVIIa vs. 5 PCC3, p = 1.00), mortality, length of hospital stay, or cost. CONCLUSIONS: Based on achieving a goal INR of 1.5 or less, LDrFVIIa was more likely than PCC3 to reverse warfarin anticoagulation. Thromboembolic events were equivalent in patients receiving PCC3 and LDrFVIIa

The effect of DPP-4 inhibitors on asthma control : an administrative database study to evaluate a potential pathophysiological relationship

Acknowledgments The authors acknowledge Koustubh Ranade (MedImmune, Gaithersburg, MD, USA) and Stephen Johnston, a member of the steering committee who was employed by Truven Health Analytics at the time the study was conducted, for their contributions to this study . Truven Health Analytics, an IBM Company, received funding from AstraZeneca in relation to this study. This work was previously presented as a poster at the annual international conference of the American Thoracic Society, May 19–24, 2017, Washington, DC (Colice G, et al. The Effect of Dipeptidyl-Peptidase-4 Inhibitors on Asthma Control: An Administrative Database Study to Evaluate a Potential Pathophysiological Relationship. Am J Respir Crit Care Med. 2017;195:A3050).Peer reviewedPublisher PD

A new globular cluster black hole in NGC 4472

We discuss CXOU~1229410+075744, a new black hole candidate in a globular cluster in the elliptical galaxy NGC~4472. By comparing two Chandra observations of the galaxy, we find a source that varies by at least a factor of 4, and has a peak luminosity of at least $2\times10^{39}$ ergs/sec. As such, the source varies by significantly more than the Eddington luminosity for a single neutron star, and is a strong candidate for being a globular cluster black hole. The source's X-ray spectrum also evolves in a manner consistent with what would be expected from a single accreting stellar mass black hole. We consider the properties of the host cluster of this source and the six other strong black hole X-ray binary candidates, and find that there is suggestive evidence that black hole X-ray binary formation is favored in bright and metal rich clusters, just as is the case for bright X-ray sources in general.Comment: 6 pages, one 2-panel figure, 2 tables; accepted to MNRA

Proper Motion Study of the Magellanic Clouds using SPM material

Absolute proper motions are determined for stars and galaxies to V=17.5 over a 450 square-degree area that encloses both Magellanic Clouds. The proper motions are based on photographic and CCD observations of the Yale/San Juan Southern Proper Motion program, which span over a baseline of 40 years. Multiple, local relative proper motion measures are combined in an overlap solution using photometrically selected Galactic Disk stars to define a global relative system that is then transformed to absolute using external galaxies and Hipparcos stars to tie into the ICRS. The resulting catalog of 1.4 million objects is used to derive the mean absolute proper motions of the Large Magellanic Cloud and the Small Magellanic Cloud; (\mu_\alpha\cos\delta,\mu_\delta)_{LMC}=(1.89,+0.39)\pm (0.27,0.27)\;\;\{mas yr}^{-1} and (\mu_\alpha\cos\delta,\mu_\delta)_{SMC}=(0.98,-1.01)\pm (0.30,0.29)\;\;\{mas yr}^{-1}. These mean motions are based on best-measured samples of 3822 LMC stars and 964 SMC stars. A dominant portion (0.25 mas yr$^{-1}$) of the formal errors is due to the estimated uncertainty in the inertial system of the Hipparcos Catalog stars used to anchor the bright end of our proper motion measures. A more precise determination can be made for the proper motion of the SMC {\it relative} to the LMC; (\mu_{\alpha\cos\delta},\mu_\delta)_{SMC-LMC} = (-0.91,-1.49) \pm (0.16,0.15)\;\;\{mas yr}^{-1}. This differential value is combined with measurements of the proper motion of the LMC taken from the literature to produce new absolute proper-motion determinations for the SMC, as well as an estimate of the total velocity difference of the two clouds to within $\pm$54 kms$^{-1}$.Comment: 50 pages (referee format), 13 figures. Accepted for publication in A

Lewy Body Dementia Association\u27s Research Centers of Excellence Program: Inaugural Meeting Proceedings.

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator\u27s meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson\u27s disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics

Development of a Training Knowledge Management System for the SERVIR Global Network

No abstract availabl

Lewy Body Dementia Association\u27s Research Centers of Excellence Program: Inaugural Meeting Proceedings

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator\u27s meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson\u27s disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics