101 research outputs found
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
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
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
Non-monotonic variation with salt concentration of the second virial coefficient in protein solutions
The osmotic virial coefficient of globular protein solutions is
calculated as a function of added salt concentration at fixed pH by computer
simulations of the ``primitive model''. The salt and counter-ions as well as a
discrete charge pattern on the protein surface are explicitly incorporated. For
parameters roughly corresponding to lysozyme, we find that first
decreases with added salt concentration up to a threshold concentration, then
increases to a maximum, and then decreases again upon further raising the ionic
strength. Our studies demonstrate that the existence of a discrete charge
pattern on the protein surface profoundly influences the effective interactions
and that non-linear Poisson Boltzmann and Derjaguin-Landau-Verwey-Overbeek
(DLVO) theory fail for large ionic strength. The observed non-monotonicity of
is compared to experiments. Implications for protein crystallization are
discussed.Comment: 43 pages, including 17 figure
Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis
Introduction Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such
data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM).
Methods Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were
integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II
or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a
comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and
the 3-minute stair climb test (3MSCT).
Results Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the
overall population at 12 months (mean change: –72.7%, P < 0.001) and remained statistically significant at last observation
(−62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained
statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric
subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation.
Conclusions Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were
maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and
well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of
treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints
Analysis of the caregiver burden associated with Sanfilippo syndrome type B: Panel recommendations based on qualitative and quantitative data
PubMedID: 31287005Background: Sanfilippo syndrome type B (Sanfilippo B) belongs to a group of rare lysosomal storage diseases characterized by progressive cognitive decline from an early age, acute hyperactivity, and concomitant somatic symptoms. Caregivers face a unique set of challenges related to the complex nature of Sanfilippo B, but the burden and impact on quality of life (QoL) of caregivers is poorly defined and best practice guidance for clinicians is lacking. Methods: An international clinical advisors meeting was convened to discuss key aspects of caregiver burden associated with Sanfilippo B based on findings from qualitative and quantitative research undertaken to identify and quantify the nature and impact of the disease on patients and caregivers. Results: Providing care for patients with Sanfilippo B impinges on all aspects of family life, evolving as the patient ages and the disease progresses. Important factors contributing toward caregiver burden include sleep disturbances, impulsive and hyperactive behavior, and communication difficulties. Caregiver burden remained high throughout the life of the patient and, coupled with the physical burden of daily care, had a cumulative impact that generated significant psychological stress. Conclusion: A Sanfilippo-specific QoL questionnaire is needed that is directed at caregiver needs and burden and best practice management of these domains. © 2019 The Author(s).Shire Alexion Pharmaceuticals Sanofi Genzyme Swedish Orphan Biovitrum Genzyme Genzyme ShireWe thank the participants for their cooperation in this research. The research and analysis into caregiver burden was conducted by Earlene Biggs at MediMedia Managed Markets (Yardley, PA), an ICON Group company, and funded by BioMarin Pharmaceuticals Inc. Editorial support for development of this manuscript was provided by Alan Storey, PhD, and Maryann T. Travaglini, PharmD at Complete Healthcare Communications, LLC (North Wales, PA), an ICON Group company, and funded by BioMarin Pharmaceuticals Inc.ES reports consulting fees from Shapiro Neuropsychology Consulting, LLC. CML has received honoraria for speakers’ fees from Actelion, Genzyme, and Shire HGT; all fees are donated to the CML Medical Foundation for Research and Genetic Diagnosis Support for families with unknown genetic disorders. NM is a consultant for BioMarin, Shire, Genzyme Sanofi, Lysogene, and SOBI; has received grants/research support from BioMarin, Shire, and Genzyme Sanofi; and has received honoraria and travel grants from BioMarin, Shire, Genzyme Sanofi, Actelion, and Amicus. CO’N and NOM declare they have no competing interests. SV has received research support from Alexion Pharmaceuticals; has received travel grants from Actelion, BioMarin, Genzyme, and Shire; and has served as an advisory board member for Vtesse
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