In vitro dissolution methods for hydrophilic and hydrophobic porous silicon microparticles

Porous silicon (PSi) is an innovative inorganic material that has been recently developed for various drug delivery systems. For example, hydrophilic and hydrophobic PSi microparticles have been utilized to improve the dissolution rate of poorly soluble drugs and to sustain peptide delivery. Previously, the well-plate method has been demonstrated to be a suitable in vitro dissolution method for hydrophilic PSi particles but it was not applicable to poorly wetting hydrophobic thermally hydrocarbonized PSi (THCPSi) particles. In this work, three different in vitro dissolution techniques, namely centrifuge, USP Apparatus 1 (basket) and well-plate methods were compared by using hydrophilic thermally carbonized PSi (TCPSi) microparticles loaded with poorly soluble ibuprofen or freely soluble antipyrine. All the methods showed a fast and complete or nearly complete release of both model compounds from the TCPSi microparticles indicating that all methods described in vitro dissolution equally. Based on these results, the centrifuge method was chosen to study the release of a peptide (ghrelin antagonist) from the THCPSi microparticles since it requires small sample amounts and achieves good particle suspendability. Sustained peptide release from the THCPSi microparticles was observed, which is in agreement with an earlier in vivo study. In conclusion, the centrifuge method was demonstrated to be a suitable tool for the evaluation of drug release from hydrophobic THCPSi particles, and the sustained peptide release from THCPSi microparticles was detected

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Genetic influences on human brain morphology

Structural magnetic resonance imaging (MRI) studies have started to address the contributions of genetic and environmental factors to brain morphology in healthy individuals. These studies have largely been limited to assessing heritability for single and mostly gross anatomical structures. To avoid this limitation, we developed a method using high-dimensional 3D nonlinear registration to apply an elastic deformation vector field in the cortical parameter space and assess regional cortical gray matter density on the entire cortical surface in healthy monozygotic (MZ) and dizygotic (DZ) twins. Once aligned across subjects, surface maps of gray matter density were subjected to variance component analyses. By fitting structural equation models, we generated cortical surface maps to reflect the regional percent variance explained by genetic, shared and unique environmental factors. Initial analyses suggest that cortical structure in primary motor and sensory areas is highly heritable with variance components for additive genetic influences reaching as high as 70%. ©2004 IEEE