Simulation of prompt emission from GRBs with a photospheric component and its detectability by GLAST

The prompt emission from gamma-ray bursts (GRBs) still requires a physical explanation. Studies of time-resolved GRB spectra, observed in the keV-MeV range, show that a hybrid model consisting of two components, a photospheric and a non-thermal component, in many cases fits bright, single-pulsed bursts as well as, and in some instances even better than, the Band function. With an energy coverage from 8 keV up to 300 GeV, GLAST will give us an unprecedented opportunity to further investigate the nature of the prompt emission. In particular, it will give us the possibility to determine whether a photospheric component is the determining feature of the spectrum or not. Here we present a short study of the ability of GLAST to detect such a photospheric component in the sub-MeV range for typical bursts, using simulation tools developed within the GLAST science collaboration.Comment: 12 pages, 5 figures; submitted proceeding for GRB Symposium in Stockholm, Sweden : "Gamma-Ray Bursts: Prospects for GLAST

The fundamental relation between supermassive black holes and their host galaxies

We study the correlations between supermassive black holes (BHs) and their host galaxies, using a sample of 83 BH masses collected from the most recent and reliable spatially resolved estimates available from the literature. We confirm the mono- and bivariate correlations between SMBHs and the bulges of their host galaxies, confirming that the correlation with the effective velocity dispersion is not significantly improved by higher dimensionality. Instead, pseudo-bulges do not seem to correlate with their SMBHs, probably because their secular evolution is often unable to trigger accretion onto the central BH. We then present a novel approach aimed at finding the fundamental relation between SMBHs and their host galaxies. For the first time, we analytically combine BH masses with the Fundamental Plane (FP), showing that M_(BH)–σ_e appears to be the fundamental relation rather than a putative ‘BH Fundamental Plane’ of the kind M_(BH)–σ_e–R_e. These results can be explained by a picture which sees the M_(BH)–σ_e relation as a natural outcome of the change in AGN feedback from momentum-driven to energy-driven. The other scaling relations are then established through the FP

The Fundamental Relation between Supermassive Black Holes and Their Host Galaxies

We study the correlations between Supermassive Black Holes (BH) and their host galaxies, using a sample of 83 BH masses collected from the most recent and reliable spatially resolved estimates available from the literature. We confirm the mono- and bivariate correlations between SMBHs and the bulges of their host galaxies, confirming that the correlation with the effective velocity dispersion is not significantly improved by higher dimensionality. Instead, pseudobulges do not seem to correlate with their SMBHs, probably because their secular evolution is often unable to trigger accretion onto the central BH. We then present a novel approach aimed at finding the fundamental relation between SMBHs and their host galaxies. For the first time, we analytically combine BH masses with the Fundamental Plane (FP), showing that Mbh-sigma_e appears to be the fundamental relation rather than a putative "BH Fundamental Plane" of the kind Mbh-sigma_e-R_e. These results can be explained by a picture which sees the Mbh-sigma_e relation as a natural outcome of the change in AGN feedback from momentum- to energy-driven. The other scaling relations are then established through the FP.Comment: 15 pages, 11 figures, accepted by MNRA

An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy.

BackgroundFollowing a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naïve children with Fabry disease.MethodsIn an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged ≥7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life.ResultsAmong five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=-0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (-3.3, 3.7) g/m(2.7); midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m(2); urine protein, -1.8 (-6.0, 2.4) mg/dL; urine microalbumin, 0.6 (-0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), -5.71 (-10.8, -0.6) nmol/mL; urinary Gb3, -1,403.3 (-3,714.0, 907.4) nmol/g creatinine, or clinical quality-of-life outcomes.ConclusionFifty-five weeks' agalsidase alfa ERT at 0.2 mg/kg every other week was well tolerated. Disease progression may be slowed when ERT is started prior to major organ dysfunction.Trial registrationhttps://ClinicalTrials.gov identifier NCT01363492

Mesenchymal Stem Cell for Prevention and Management of Intervertebral Disc Degeneration

Intervertebral disc degeneration (IVD) is a frequent pathological condition. Conservative management often fails, and patients with IVD degeneration may require surgical intervention. Several treatment strategies have been proposed, although only surgical discectomy and arthrodesis have been proved to be predictably effective. The aim of biological strategies is to prevent and manage IVD degeneration, improve the function, the anabolic and reparative capabilities of the nucleus pulposus and annulus fibrosus cells, and inhibit matrix degradation. At present, clinical applications are still in their infancy. Further studies are required to clarify the role of mesenchymal stem cells and gene therapy for the prevention and treatment of IVD degeneration

Biomarkers for Drug Development in Propionic and Methylmalonic Acidemias

There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of 13C-propionate (exhaled 13CO2), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias

Exploratory study of the effect of one week of orally administered CNSA-001 (sepiapterin) on CNS levels of tetrahydrobiopterin, dihydrobiopterin and monoamine neurotransmitter metabolites in healthy volunteers

Tetrahydrobiopterin (BH4) is a cofactor for the enzymes tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes in the production of the neurotransmitters, dopamine and serotonin, respectively, in the central nervous system (CNS). Administration of BH4 is used clinically within the management of persons with genetic BH4 deficiencies, but the BH4 molecule does not cross the blood-brain barrier sufficiently. CNSA-001 is a pharmaceutical preparation of sepiapterin, a natural precursor of BH4 that induced larger increases in plasma BH4 compared with administration of the same doses of BH4 itself in healthy volunteers in a randomized trial. Here, we report the effects of 7days of once-daily treatment with CNSA-001 60mg/kg (n=6) or placebo (n=2) on metabolites of the BH4 synthetic pathway and on biomarkers of the serotonin (5-hydroxyindoleacetic acid [5-HIAA]) and dopamine (homovanillic acid [HVA]) pathways in cerebrospinal fluid (CSF) in subjects from this trial. There were no notable changes in any metabolite in placebo-treated subjects. Administration of CNSA-001 increased mean BH4 from 18.1 (SD 3.0) to 35.1 (10.0) nmol/L, and of dihydrobiopterin (BH2) from 2.1 (0.3) to 7.9 (1.5) nmol/L. Overall, administration of CNSA-001 had little effect on mean levels (pre- vs. post-treatment) of 5-HIAA (76.1 [SD 29.8] vs. 70.1 [23.1] nmol/L) or HVA (177.2 [66.5] vs. 184.8 [35.3]) nmol/L. One subject with low 5-HIAA and HVA at baseline responded with approximately three-fold increases in CNS levels of these metabolites after CNSA-001 treatment, with post-treatment levels within the range of those seen in other subjects. Administration of CNSA-001 60mg/kg markedly increased levels of BH4 in the CNS of healthy volunteers, with apparently little overall effect in CNS levels of already normal key neurotransmitter metabolites