Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study.

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain

Multiscale Random-Walk Algorithm for Simulating Interfacial Pattern Formation

We present a novel computational method to simulate accurately a wide range of interfacial patterns whose growth is limited by a large scale diffusion field. To illustrate the computational power of this method, we demonstrate that it can be used to simulate three-dimensional dendritic growth in a previously unreachable range of low undercoolings that is of direct experimental relevance.Comment: 4 pages RevTex, 6 eps figures; substantial changes in presentation, but results and conclusions remain the sam

Homogeneous nucleation of a non-critical phase near a continuous phase transition

Homogeneous nucleation of a new phase near a second, continuous, transition, is considered. The continuous transition is in the metastable region associated with the first-order phase transition, one of whose coexisting phases is nucleating. Mean-field calculations show that as the continuous transition is approached, the size of the nucleus varies as the response function of the order parameter of the continuous transition. This response function diverges at the continuous transition, as does the temperature derivative of the free energy barrier to nucleation. This rapid drop of the barrier as the continuous transition is approached means that the continuous transition acts to reduce the barrier to nucleation at the first-order transition. This may be useful in the crystallisation of globular proteins.Comment: 6 pages, 1 figur

Enzyme replacement therapy in mice lacking arylsulfatase B targets bone-remodeling cells, but not chondrocytes

Mucopolysaccharidosis type VI (MPS-VI), caused by mutational inactivation of the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), is a lysosomal storage disorder primarily affecting the skeleton. We have previously reported that Arsb-deficient mice display high trabecular bone mass and impaired skeletal growth. In the present study, we treated them by weekly injection of recombinant human ARSB (rhARSB) to analyze the impact of enzyme replacement therapy (ERT) on skeletal growth and bone remodeling. We found that all bone-remodeling abnormalities of Arsb-deficient mice were prevented by ERT, whereas chondrocyte defects were not. Likewise, histologic analysis of the surgically removed femoral head from an ERT-treated MPS-VI patient revealed that only chondrocytes were pathologically affected. Remarkably, a side-by-side comparison with other cell types demonstrated that chondrocytes have substantially reduced capacity to endocytose rhARSB, together with low expression of the mannose receptor. We finally took advantage of Arsb-deficient mice to establish quantification of chondroitin sulfation for treatment monitoring. Our data demonstrate that bone-remodeling cell types are accessible to systemically delivered rhARSB, whereas the uptake into chondrocytes is inefficient

Crossover Scaling in Dendritic Evolution at Low Undercooling

We examine scaling in two-dimensional simulations of dendritic growth at low undercooling, as well as in three-dimensional pivalic acid dendrites grown on NASA's USMP-4 Isothermal Dendritic Growth Experiment. We report new results on self-similar evolution in both the experiments and simulations. We find that the time dependent scaling of our low undercooling simulations displays a cross-over scaling from a regime different than that characterizing Laplacian growth to steady-state growth

Simulation study of Non-ergodicity Transitions: Gelation in Colloidal Systems with Short Range Attractions

Computer simulations were used to study the gel transition occurring in colloidal systems with short range attractions. A colloid-polymer mixture was modelled and the results were compared with mode coupling theory expectations and with the results for other systems (hard spheres and Lennard Jones). The self-intermediate scattering function and the mean squared displacement were used as the main dynamical quantities. Two different colloid packing fractions have been studied. For the lower packing fraction, $\alpha$-scaling holds and the wave-vector analysis of the correlation function shows that gelation is a regular non-ergodicity transition within MCT. The leading mechanism for this novel non-ergodicity transition is identified as bond formation caused by the short range attraction. The time scale and diffusion coefficient also show qualitatively the expected behaviour, although different exponents are found for the power-law divergences of these two quantities. The non-Gaussian parameter was also studied and very large correction to Gaussian behaviour found. The system with higher colloid packing fraction shows indications of a nearby high-order singularity, causing $\alpha$-scaling to fail, but the general expectations for non-ergodicity transitions still hold.Comment: 13 pages, 15 figure

The low temperature interface between the gas and solid phases of hard spheres with a short-ranged attraction

At low temperature, spheres with a very short-ranged attraction exist as a close-packed solid coexisting with an infinitely dilute gas. We find that the ratio of the interfacial tension between these two phases to the thermal energy diverges as the range of the attraction goes to zero. The large tensions when the interparticle attractions are short-ranged may be why globular proteins only crystallise over a narrow range of conditions.Comment: 6 pages, no figures (v2 has change of notation to agree with that of Stell

Nonergodicity transitions in colloidal suspensions with attractive interactions

The colloidal gel and glass transitions are investigated using the idealized mode coupling theory (MCT) for model systems characterized by short-range attractive interactions. Results are presented for the adhesive hard sphere and hard core attractive Yukawa systems. According to MCT, the former system shows a critical glass transition concentration that increases significantly with introduction of a weak attraction. For the latter attractive Yukawa system, MCT predicts low temperature nonergodic states that extend to the critical and subcritical region. Several features of the MCT nonergodicity transition in this system agree qualitatively with experimental observations on the colloidal gel transition, suggesting that the gel transition is caused by a low temperature extension of the glass transition. The range of the attraction is shown to govern the way the glass transition line traverses the phase diagram relative to the critical point, analogous to findings for the fluid-solid freezing transition.Comment: 11 pages, 7 figures; to be published in Phys. Rev. E (1 May 1999

A good practice guide to managing human resource s in regional SMEs.

This publication is intended not only for small and medium-sized enterprises, but also for those who are in charge of human resources and are looking for inspiration on how to acquire and retain them or wish to educate themselves in this field further. The publication focuses on practice; it details the crucial challenges of HR in terms of literature, as well as practical case studies. And it is this focus - this lead in human resource management - that can give many companies a competitive edge and advance of others which have not yet gained that knowledge

Spatial Extent of Charge Repulsion Regulates Assembly Pathways for Lysozyme Amyloid Fibrils

Formation of large protein fibrils with a characteristic cross β-sheet architecture is the key indicator for a wide variety of systemic and neurodegenerative amyloid diseases. Recent experiments have strongly implicated oligomeric intermediates, transiently formed during fibril assembly, as critical contributors to cellular toxicity in amyloid diseases. At the same time, amyloid fibril assembly can proceed along different assembly pathways that might or might not involve such oligomeric intermediates. Elucidating the mechanisms that determine whether fibril formation proceeds along non-oligomeric or oligomeric pathways, therefore, is important not just for understanding amyloid fibril assembly at the molecular level but also for developing new targets for intervening with fibril formation. We have investigated fibril formation by hen egg white lysozyme, an enzyme for which human variants underlie non-neuropathic amyloidosis. Using a combination of static and dynamic light scattering, atomic force microscopy and circular dichroism, we find that amyloidogenic lysozyme monomers switch between three different assembly pathways: from monomeric to oligomeric fibril assembly and, eventually, disordered precipitation as the ionic strength of the solution increases. Fibril assembly only occurred under conditions of net repulsion among the amyloidogenic monomers while net attraction caused precipitation. The transition from monomeric to oligomeric fibril assembly, in turn, occurred as salt-mediated charge screening reduced repulsion among individual charged residues on the same monomer. We suggest a model of amyloid fibril formation in which repulsive charge interactions are a prerequisite for ordered fibril assembly. Furthermore, the spatial extent of non-specific charge screening selects between monomeric and oligomeric assembly pathways by affecting which subset of denatured states can form suitable intermolecular bonds and by altering the energetic and entropic requirements for the initial intermediates emerging along the monomeric vs. oligomeric assembly path