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 Assessment of Acoustic Installation Effects Characterizing NASA/LaRC Quiet Flow Facility using Computational AeroAcoustics

This paper presents a numerical assessment of acoustic installation effects characterizing the NASA Langley Quiet Flow Facility (QFF), an open-jet, anechoic wind tunnel. Several Computational Aeroacoustics (CAA) calculations based on equivalent simplistic sources are conducted, enabling the estimation of the installation effects possibly induced by the QFF environment on the measured acoustic signatures during typical airframe noise experiments. First, the conclusions that had been previously made by the present author in an earlier assessment of QFF installation effects onto the so-called Tandem Cylinder experiments are reproduced. Then, these conclusions are extended to various situations which are more representative of the usual airframe noise tests that are typically conducted in the QFF. In particular, this provides an opportunity to compare the refraction/convection effects of the QFF jet flow to the reflection/diffraction induced by the experimental apparatus. All this further aids in the identification of acoustic installation effects that may be important in the type of testing typically done in the NASA/LARC QFF facility