A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare, progressive, neurodegenerative disease characterized by ataxia, spasticity and polyneuropathy. First described in the French-Canadian population of Quebec in 1978, ARSACS has since been identified in multiple patients worldwide. In this clinical case report, we describe the evaluation of an 11-years-old African-American male who presented to neuromuscular clinic for assessment of a gait abnormality. He had a history of gross motor delay since early childhood, frequent falls and a below average IQ. Chromosomal microarray revealed a 1.422 megabase loss in the 13q12.12 region, which includes the SACS gene. Next Generation Sequencing then showed a novel, predicted to be pathogenic missense mutation (c.11824dup) of this gene. His clinical presentation and neurological imaging further confirmed the diagnosis of ARSACS. To our knowledge, this is the first reported case of this disease in the African-American population of the United States. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide

Isosorbide dinitrate, with or without hydralazine, does not reduce wave reflections, left ventricular hypertrophy, or myocardial fibrosis in patients with heart failure with preserved ejection fraction

Background-Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. Methods and Results-We randomized 44 patients with heart failure with preserved ejection fraction in a double-blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6-minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14-0.17], 3 months=0.11 [95% CI, 0.10-0.13], 6 months=0.10 [95% CI, 0.08-0.12] mmHg/mL per second; P=0.003) and forward wave amplitude (P-f, mean baseline=54.8 [95% CI, 47.6-62.0], 3 months=42.2 [95% CI, 33.2-51.3]; 6 months=37.0 [95% CI, 27.2-46.8] mmHg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35-0.43]; 3 months=0.31 [95% CI, 0.25-0.36]; 6 months=0.44 [95% CI, 0.37-0.51], P=0.03), reduced 6-minute walk distance (mean baseline=343.3 [95% CI, 319.2-367.4]; 6 months=277.0 [95% CI, 242.7-311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7-1029.7]; 6 months=1054.5 [95% CI, 1036.5-1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007). Conclusions-ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction

A Multi-Season Study of the Effects of MODIS Sea-Surface Temperatures on Operational WRF Forecasts at NWS Miami, FL

Studies at the Short-term Prediction Research and Transition (SPORT) Center have suggested that the use of Moderate Resolution Imaging Spectroradiometer (MODIS) sea-surface temperature (SST) composites in regional weather forecast models can have a significant positive impact on short-term numerical weather prediction in coastal regions. Recent work by LaCasse et al (2007, Monthly Weather Review) highlights lower atmospheric differences in regional numerical simulations over the Florida offshore waters using 2-km SST composites derived from the MODIS instrument aboard the polar-orbiting Aqua and Terra Earth Observing System satellites. To help quantify the value of this impact on NWS Weather Forecast Offices (WFOs), the SPORT Center and the NWS WFO at Miami, FL (MIA) are collaborating on a project to investigate the impact of using the high-resolution MODIS SST fields within the Weather Research and Forecasting (WRF) prediction system. The project's goal is to determine whether more accurate specification of the lower-boundary forcing within WRF will result in improved land/sea fluxes and hence, more accurate evolution of coastal mesoscale circulations and the associated sensible weather elements. The NWS MIA is currently running WRF in real-time to support daily forecast operations, using the National Centers for Environmental Prediction Nonhydrostatic Mesoscale Model dynamical core within the NWS Science and Training Resource Center's Environmental Modeling System (EMS) software. Twenty-seven hour forecasts are run dally initialized at 0300, 0900, 1500, and 2100 UTC on a domain with 4-km grid spacing covering the southern half of Florida and adjacent waters of the Gulf of Mexico and Atlantic Ocean. Each model run is initialized using the Local Analysis and Prediction System (LAPS) analyses available in AWIPS. The SSTs are initialized with the NCEP Real-Time Global (RTG) analyses at 1/12deg resolution (approx.9 km); however, the RTG product does not exhibit fine-scale details consistent with its grid resolution. SPORT is conducting parallel WRF EMS runs identical to the operational runs at NWS MIA except for the use of MODIS SST composites in place of the RTG product as the initial and boundary conditions over water, The MODIS SST composites for initializing the SPORT WRF runs are generated on a 2-km grid four times daily at 0400, 0700, 1600, and 1900 UTC, based on the times of the overhead passes of the Aqua and Terra satellites. The incorporation of the MODIS SST data into the SPORT WRF runs is staggered such that SSTs are updated with a new composite every six hours in each of the WRF runs. From mid-February to July 2007, over 500 parallel WRF simulations have been collected for analysis and verification. This paper will present verification results comparing the NWS MIA operational WRF runs to the SPORT experimental runs, and highlight any substantial differences noted in the predicted mesoscale phenomena for specific cases

Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12

BACKGROUND: Age-related macular degeneration (AMD) is a complex disorder that is responsible for the majority of central vision loss in older adults living in developed countries. Phenotypic and genetic heterogeneity complicate the analysis of genome-wide scans for AMD susceptibility loci. The ordered subset analysis (OSA) method is an approach for reducing heterogeneity, increasing statistical power for detecting linkage, and helping to define the most informative data set for follow-up analysis. OSA assesses the linkage evidence in subsets of potentially more homogeneous families by rank-ordering family-specific lod scores with respect to trait-associated covariates or phenotypic features. Here, we present results of incorporating five continuous covariates into our genome-wide linkage analysis of 389 microsatellite markers in 62 multiplex families: Body mass index (BMI), systolic (SBP) and diastolic (DBP) blood pressure, intraocular pressure (IOP), and pack-years of cigarette smoking. Chromosome-wide significance of increases in nonparametric multipoint lod scores in covariate-defined subsets relative to the overall sample was assessed by permutation. RESULTS: Using a correction for testing multiple covariates, statistically significant lod score increases were observed for two chromosomal regions: 14q13 with a lod score of 3.2 in 28 families with average IOP ≤ 15.5 (p = 0.002), and 6q14 with a lod score of 1.6 in eight families with average BMI ≥ 30.1 (p = 0.0004). On chromosome 16p12, nominally significant lod score increases (p ≤ 0.05), up to a lod score of 2.9 in 32 families, were observed with several covariate orderings. While less significant, this was the only region where linkage evidence was associated with multiple clinically meaningful covariates and the only nominally significant finding when analysis was restricted to advanced forms of AMD. Families with linkage to 16p12 had higher averages of SBP, IOP and BMI and were primarily affected with neovascular AMD. For all three regions, linkage signals at or very near the peak marker have previously been reported. CONCLUSION: Our results suggest that a susceptibility gene on chromosome 16p12 may predispose to AMD, particularly to the neovascular form, and that further research into the previously suggested association of neovascular AMD and systemic hypertension is warranted

Author Correction: A population-specific reference panel empowers genetic studies of Anabaptist populations.

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A new conceptual framework for revenge firesetting

Revenge has frequently been acknowledged to account for a relatively large proportion of motives in deliberate firesetting. However, very little is actually known about the aetiology of revenge firesetting. Theoretical approaches to revenge-seeking behaviour are discussed. A brief review of how revenge is accounted for in existing theoretical explanations of deliberate firesetting and the known characteristics of revenge firesetters are provided. On this basis, the authors suggest, as a motive, revenge firesetting has to date been misconceptualised. A new conceptual framework is thus proposed, paying particular attention to the contextual, affective, cognitive, volitional and behavioural factors which may influence and generate a single episode of revenge firesetting. Treatment implications and suggestions for future research are also provided

The XMM Cluster Survey: Active Galactic Nuclei and Starburst Galaxies in XMMXCS J2215.9-1738 at z=1.46

We use Chandra X-ray and Spitzer infrared observations to explore the AGN and starburst populations of XMMXCS J2215.9-1738 at z=1.46, one of the most distant spectroscopically confirmed galaxy clusters known. The high resolution X-ray imaging reveals that the cluster emission is contaminated by point sources that were not resolved in XMM observations of the system, and have the effect of hardening the spectrum, leading to the previously reported temperature for this system being overestimated. From a joint spectroscopic analysis of the Chandra and XMM data, the cluster is found to have temperature T=4.1_-0.9^+0.6 keV and luminosity L_X=(2.92_-0.35^+0.24)x10^44 erg/s extrapolated to a radius of 2 Mpc. As a result of this revised analysis, the cluster is found to lie on the sigma_v-T relation, but the cluster remains less luminous than would be expected from self-similar evolution of the local L_X-T relation. Two of the newly discovered X-ray AGN are cluster members, while a third object, which is also a prominent 24 micron source, is found to have properties consistent with it being a high redshift, highly obscured object in the background. We find a total of eight >5 sigma 24 micron sources associated with cluster members (four spectroscopically confirmed, and four selected using photometric redshifts), and one additional 24 micron source with two possible optical/near-IR counterparts that may be associated with the cluster. Examining the IRAC colors of these sources, we find one object is likely to be an AGN. Assuming that the other 24 micron sources are powered by star formation, their infrared luminosities imply star formation rates ~100 M_sun/yr. We find that three of these sources are located at projected distances of <250 kpc from the cluster center, suggesting that a large amount of star formation may be taking place in the cluster core, in contrast to clusters at low redshift.Comment: Accepted for publication in ApJ, 16 pages, 10 figure

Relative energetics and structural properties of zirconia using a self-consistent tight-binding model

We describe an empirical, self-consistent, orthogonal tight-binding model for zirconia, which allows for the polarizability of the anions at dipole and quadrupole levels and for crystal field splitting of the cation d orbitals. This is achieved by mixing the orbitals of different symmetry on a site with coupling coefficients driven by the Coulomb potentials up to octapole level. The additional forces on atoms due to the self-consistency and polarizabilities are exactly obtained by straightforward electrostatics, by analogy with the Hellmann-Feynman theorem as applied in first-principles calculations. The model correctly orders the zero temperature energies of all zirconia polymorphs. The Zr-O matrix elements of the Hamiltonian, which measure covalency, make a greater contribution than the polarizability to the energy differences between phases. Results for elastic constants of the cubic and tetragonal phases and phonon frequencies of the cubic phase are also presented and compared with some experimental data and first-principles calculations. We suggest that the model will be useful for studying finite temperature effects by means of molecular dynamics.Comment: to be published in Physical Review B (1 march 2000