Treatment of Fabry Disease: Outcome of a Comparative Trial with Agalsidase Alfa or Beta at a Dose of 0.2 mg/kg

Two different enzyme preparations, agalsidase alfa (Replagal(TM), Shire) and beta (Fabrazyme(TM), Genzyme), are registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a randomized controlled open label trial.Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both agalsidase alfa). The occurrence of treatment failures did not differ between the two treatment groups; chi(2) = 0.38 p = 0.54.Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly. Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease.International Standard Randomized Clinical Trial ISRCTN45178534 [http://www.controlled-trials.com/ISRCTN45178534]

Type 2 Diabetes Susceptibility Gene Expression in Normal or Diabetic Sorted Human Alpha and Beta Cells: Correlations with Age or BMI of Islet Donors

BACKGROUND: Genome-wide association studies have identified susceptibility genes for development of type 2 diabetes. We aimed to examine whether a subset of these (comprising FTO, IDE, KCNJ11, PPARG and TCF7L2) were transcriptionally restricted to or enriched in human beta cells by sorting islet cells into alpha and beta - specific fractions. We also aimed to correlate expression of these transcripts in both alpha and beta cell types with phenotypic traits of the islet donors and to compare diabetic and non-diabetic cells. METHODOLOGY/PRINCIPAL FINDINGS: Islet cells were sorted using a previously published method and RNA was extracted, reverse transcribed and used as the template for quantitative PCR. Sorted cells were also analysed for insulin and glucagon immunostaining and insulin secretion from the beta cells as well as insulin, glucagon and GLP-1 content. All five genes were expressed in both alpha and beta cells, with significant enrichment of KCNJ11 in the beta cells and of TCF7L2 in the alpha cells. The ratio of KCNJ11 in beta to alpha cells was negatively correlated with BMI, while KCNJ11 expression in alpha cells was negatively correlated with age but not associated with BMI. Beta cell expression of glucagon, TCF7L2 and IDE was increased in cells from islets that had spent more time in culture prior to cell sorting. In beta cells, KCNJ11, FTO and insulin were positively correlated with each other. Diabetic alpha and beta cells had decreased expression of insulin, glucagon and FTO. CONCLUSIONS/SIGNIFICANCE: This study has identified novel patterns of expression of type 2 diabetes susceptibility genes within sorted islet cells and suggested interactions of gene expression with age or BMI of the islet donors. However, expression of these genes in islets is less associated with BMI than has been found for other tissues

Computational AeroAcoustics of Realistic Co-Axial Engines

The present work is devoted to the numerical simulation of acoustic emissions characterizing turbojet engines, a subject that is relevant of the more general purpose of aircraft noise prevision and reduction. More precisely, we explore here the ability of a structured CAA (Computational AeroAcoustics) method/solver to handle complicated industrial problems of engine noise prediction. With that end, and by using the ONERA's CAA solver sAbrinA.v0, we compute a realistic aft fan noise emission/radiation problem, which involves both a full-3D exhaust geometry (with its pylon / internal bifurcations) and a typical fan noise modal content (high azimuthal order / frequency). The results highlight how far acoustic installation effects induced by the full-3D nature of a particular engine can affect its fan noise emission. Results also tend to demonstrate that both the here used CAA method and solver are mature enough to face out real industrial-like problems. Copyright © 2008 by ONERA

Numerical and Experimental Characterization of Aft-Fan Noise for Isolated and Installed Configurations

The main objective of this paper is the characterization of the fan noise radiated in the aft direction for a coaxial turbofan installed in RFN (Rear Fuselage Nacelle) position. The challenge is to validate a numerical hybrid methodology, which has been developed for several years by Onera and Airbus, to provide the acoustic far field in the presence of the aircraft. This activity refers to the NACRE European project, in which a dedicated isolated/installed fan noise experiment was conducted with an aircraft model and a Turbine Powered Simulator (TPS). The numerical approach combines near field CAA computations, achieved by Onera with the sAbrinA-V0 solver, and farfield BEM computations achieved either by Airbus with the ACTIPOLE solver or by Onera with the BEMUSE solver. The fan noise source consists in azimuthal/radial modes of an infinite annular duct with uniform mean flow. All "cut-on" modes are computed individually, and then the un-correlated mode contributions are summed with amplitudes derived from measurements performed inside the by-pass duct with a circular array of pressure sensors. It is shown that the simulation of the internal propagation must take into account the three-dimensional geometry of the bypass duct, including the bifurcation, to explain the strong azimuthal oscillations of the RMS pressure inside and outside the TPS. Onera and Airbus's BEM solvers are used to compute the installation effects generated by the rear part of the aircraft equipped with an H-tail plane. The agreement between both solvers is excellent, and the comparison with the experiments is satisfying. © 2010 by the American Institute of Aeronautics and Astronautics, Inc

Towards numerical simulation of engine installation effects for rear fan noise

Future large transport aircraft will increasingly rely on installation effects for global noise reduction. One promising application is to use airframe elements to mask the main aircraft noise sources, and especially the rear fan noise. The simulation of such effects must include (i) the propagation/radiation of acoustic modes through the bypass duct, the engine exhaust and the jet non uniform flow and (ii) the acoustic scattering on near rigid surfaces. This two-step process could typically rely on hybrid methods combining (i) a high-order finite difference solver based on full Euler's equation in perturbation form and (ii) a Boundary Element Method solver. This paper presents some aspects of the first step : ONERA's solver sAbrinA is used to compute the nearfield propagation/radiation of a mode with high azimuthal order. A 3D grid limited to an azimuthal sector is used, with an aperture related to the mode order. First computations are performed without mean flow, and compared to axi-symmetrical BEM results. Then final computations are performed over the actual jet mean flow previously computed using elsA, ONERA's RANS solver. In further works, these sAbrinA results will be used as entry data for further installation effects simulations using BEM

Computational AeroAcoustics of a Realistic Co-Axial Engine, possibly Equipped with Acoustic Liners

The present work is devoted to the numerical simulation of acoustic emissions characterizing turbojet engines, a subject that is relevant of the more general purpose of aircraft noise prevision and reduction. More precisely, we explore here the ability of a structured / time-domain CAA (Computational AeroAcoustics) method/solver to address complicated problems of engine noise prediction. With that end, and by using the ONERA's CAA solver sAbrinA.v0, we conduct realistic calculations of aft fan noise emissions, such computations involving a full-3D exhaust geometry (with its pylon / internal bifurcations) to be possibly equipped with noise absorbing materials (acoustic liner). Being conducted for a representative fan noise modal content (high azimuthal order / frequency) and within realistic flight conditions (take-off), such calculations deliver insights of both phenomenological / physical and methodological / numerical natures; firstly, it is here shown how far aft fan noise emissions can be reduced by a proper use of absorbing materials. Secondly, it is further demonstrated how 'industrial-like' engine noise problems can be handled via numerical simulations based on a structured / time-domain CAA approach. © 2010 by ONERA. Published by the American Institute of Aeronautics and Astronautics, Inc