Adjunctive albuterol enhances the response to enzyme replacement therapy in late-onset Pompe disease.

Effective dosages for enzyme replacement therapy (ERT) in Pompe disease are much higher than for other lysosomal storage disorders, which has been attributed to low cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle. We have previously demonstrated the benefit of increased CI-MPR-mediated uptake of recombinant human acid-α-glucosidase during ERT in mice with Pompe disease following addition of albuterol therapy. Currently we have completed a pilot study of albuterol in patients with late-onset Pompe disease already on ERT for >2 yr, who were not improving further. The 6-min walk test (6MWT) distance increased in all 7 subjects at wk 6 (30±13 m; P=0.002), wk 12 (34±14 m; P=0.004), and wk 24 (42±37 m; P=0.02), in comparison with baseline. Grip strength was improved significantly for both hands at wk 12. Furthermore, individual subjects reported benefits; e.g., a female patient could stand up from sitting on the floor much more easily (time for supine to standing position decreased from 30 to 11 s), and a male patient could readily swing his legs out of his van seat (hip abduction increased from 1 to 2+ on manual muscle testing). Finally, analysis of the quadriceps biopsies suggested increased CI-MPR at wk 12 (P=0.08), compared with baseline. With the exception of 1 patient who succumbed to respiratory complications of Pompe disease in the first week, only mild adverse events have been reported, including tremor, transient difficulty falling asleep, and mild urinary retention (requiring early morning voiding). Therefore, this pilot study revealed initial safety and efficacy in an open label study of adjunctive albuterol therapy in patients with late-onset Pompe disease who had been stable on ERT with no improvements noted over the previous several years.

Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease.

Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.

Clinical utility of a Web-enabled risk-assessment and clinical decision support program.

PURPOSE: Risk-stratified guidelines can improve quality of care and cost-effectiveness, but their uptake in primary care has been limited. MeTree, a Web-based, patient-facing risk-assessment and clinical decision support tool, is designed to facilitate uptake of risk-stratified guidelines. METHODS: A hybrid implementation-effectiveness trial of three clinics (two intervention, one control). PARTICIPANTS: consentable nonadopted adults with upcoming appointments. PRIMARY OUTCOME: agreement between patient risk level and risk management for those meeting evidence-based criteria for increased-risk risk-management strategies (increased risk) and those who do not (average risk) before MeTree and after. MEASURES: chart abstraction was used to identify risk management related to colon, breast, and ovarian cancer, hereditary cancer, and thrombosis. RESULTS: Participants = 488, female = 284 (58.2%), white = 411 (85.7%), mean age = 58.7 (SD = 12.3). Agreement between risk management and risk level for all conditions for each participant, except for colon cancer, which was limited to those <50 years of age, was (i) 1.1% (N = 2/174) for the increased-risk group before MeTree and 16.1% (N = 28/174) after and (ii) 99.2% (N = 2,125/2,142) for the average-risk group before MeTree and 99.5% (N = 2,131/2,142) after. Of those receiving increased-risk risk-management strategies at baseline, 10.5% (N = 2/19) met criteria for increased risk. After MeTree, 80.7% (N = 46/57) met criteria. CONCLUSION: MeTree integration into primary care can improve uptake of risk-stratified guidelines and potentially reduce "overuse" and "underuse" of increased-risk services.Genet Med 18 10, 1020-1028.

Thyroid volumes and urinary iodine in Swiss school children, 17 years after improved prophylaxis of iodine deficiency

Salt iodine content in Switzerland was raised from 7.5 to 15 mg per kg in 1980, and since then dietary iodine intake has been considered to be sufficient, even though a slight decrease due to imported food has recently been reported. The aim of this study was to establish normal values for thyroid volumes of school children who can be assumed to have had a sufficient iodine intake all their lifetime. Moreover, the present investigation was undertaken to verify that iodine sufficiency had been achieved equally in two regions each served by one of the two Swiss salt producers. Mean iodine concentration in urine spot samples from school children was 16.1 μg/dl, and it was identical in both the city of Lausanne (n=215) and the city of Solothurn (n=208). Thus it can be stated that in both cities (served by two different salt producers) iodine intake is equal and sufficient. Accordingly, thyroid volumes measured by ultrasound in school children aged 6 to 16 years were the same in both Lausanne (n=202) and Solothurn (n=207). Moreover, the age-adjusted median volumes at the 97th percentiles closely agree with and validate provisional international reference values recently proposed by the World Health Organisation and by the International Council for Control of Iodine Deficiency Disease.

A general approach to validating evacuation models with an application to EXODUS

Too often, validation of computer models is considered as a "once and forget" task. In this paper a systematic and graduated approach to evacua tion model validation is suggested.

A finite volume unstructured mesh approach to dynamic fluid–structure interaction: an assessment of the challenge of predicting the onset of flutter

Computational modelling of dynamic fluid–structure interaction (DFSI) is a considerable challenge. Our approach to this class of problems involves the use of a single software framework for all the phenomena involved, employing finite volume methods on unstructured meshes in three dimensions. This method enables time and space accurate calculations in a consistent manner. One key application of DFSI simulation is the analysis of the onset of flutter in aircraft wings, where the work of Yates et al. [Measured and Calculated Subsonic and Transonic Flutter Characteristics of a 45° degree Sweptback Wing Planform in Air and Freon-12 in the Langley Transonic Dynamic Tunnel. NASA Technical Note D-1616, 1963] on the AGARD 445.6 wing planform still provides the most comprehensive benchmark data available. This paper presents the results of a significant effort to model the onset of flutter for the AGARD 445.6 wing planform geometry. A series of key issues needs to be addressed for this computational approach. • The advantage of using a single mesh, in order to eliminate numerical problems when applying boundary conditions at the fluid-structure interface, is counteracted by the challenge of generating a suitably high quality mesh in both the fluid and structural domains. • The computational effort for this DFSI procedure, in terms of run time and memory requirements, is very significant. Practical simulations require even finer meshes and shorter time steps, requiring parallel implementation for operation on large, high performance parallel systems. • The consistency and completeness of the AGARD data in the public domain is inadequate for use in the validation of DFSI codes when predicting the onset of flutter.

Parallel implementation of the recurrence method for computing the power-spectral density of thin avalanche photodiodes

A simulation program has been developed to calculate the power-spectral density of thin avalanche photodiodes, which are used in optical networks. The program extends the time-domain analysis of the dead-space multiplication model to compute the autocorrelation function of the APD impulse response. However, the computation requires a large amount of memory space and is very time consuming. We describe our experiences in parallelizing the code using both MPI and OpenMP. Several array partitioning schemes and scheduling policies are implemented and tested Our results show that the OpenMP code is scalable up to 64 processors on an SGI Origin 2000 machine and has small average errors.

A fast, streaming SIMD extensions 2, logistic squashing function

Schraudolph proposed an excellent exponential approximation providing increased performance particularly suited to the logistic squashing function used within many neural networking applications. This note applies Intel's streaming SIMD Extensions 2 (SSE2), where SIMD is single instruction multiple data, of the Pentum IV class processor to Schraudolph's technique, further increasing the performance of the logistic squashing function. It was found that the calculation of the new 32-bit SSE2 logistic squashing function described here was up to 38 times faster than the conventional exponential function and up to 16 times faster than a Schraudolph-style 32-bit method on an Intel Pentum D 3.6 GHz CPU.

Modeling the structural breakdown of solder paste using the structural kinetic model

Solder paste is the most important strategic bonding material used in the assembly of surface mount devices in electronic industries. It is known to exhibit a thixotropic behavior, which is recognized by the decrease in apparent viscosity of paste material with time when subjected to a constant shear rate. The proper characterization of this time-dependent rheological behavior of solder pastes is crucial for establishing the relationships between the pastes structure and flow behavior; and for correlating the physical parameters with paste printing performance. In this article, we present a novel method which has been developed for characterizing the time-dependent and non-Newtonian rheological behavior of solder pastes and flux mediums as a function of shear rates. We also present results of the study of the rheology of the solder pastes and flux mediums using the structural kinetic modeling approach, which postulates that the network structure of solder pastes breaks down irreversibly under shear, leading to time and shear-dependent changes in the flow properties. Our results show that for the solder pastes used in the study, the rate and extent of thixotropy was generally found to increase with increasing shear rate. The technique demonstrated in this study has wide utility for R&D personnel involved in new paste formulation, for implementing quality control procedures used in solder-paste manufacture and packaging; and for qualifying new flip-chip assembly lines.