Visualization of interindividual differences in spinal dynamics in the presence of intraindividual variabilities

Surface topography systems enable the capture of spinal dynamic movement. A visualization of possible unique movement patterns appears to be difficult due to large intraclass and small inter-class variabilities. Therefore, we investigated a visualization approach using Siamese neural networks (SNN) and checked, if the identification of individuals is possible based on dynamic spinal data. The presented visualization approach seems promising in visualizing subjects in the presence of intraindividual variability between different gait cycles as well as day-to-day variability. Overall, the results indicate a possible existence of a personal spinal ‘fingerprint’. The work forms the basis for an objective comparison of subjects and the transfer of the method to clinical use cases

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Effect of crospovidone and hydroxypropyl cellulose on carbamazepine in high-dose tablet formulation

The aim of this study was to develop a high-dose tablet formulation of the poorly soluble carbamazepine (CBZ) with sufficient tablet hardness and immediate drug release. A further aim was to investigate the influence of various commercial CBZ raw materials on the optimized tablet formulation. Materials and methods: Hydroxypropyl cellulose (HPC-SL) was selected as a dry binder and crospovidone (CrosPVP) as a superdisintegrant. A direct compacted tablet formulation of 70% CBZ was optimized by a 3(2) full factorial design with two input variables, HPC (0-10%) and CrosPVP (0-5%). Response variables included disintegration time, amount of drug released at 15 and 60?min, and tablet hardness, all analyzed according to USP 31. Results and discussion: Increasing HPC-SL together with CrosPVP not only increased tablet hardness but also reduced disintegration time. Optimal condition was achieved in the range of 5-9% HPC and 3-5% CrosPVP, where tablet properties were at least 70 N tablet hardness, less than 1?min disintegration, and within the USP requirements for drug release. Testing the optimized formulation with four different commercial CBZ samples, their variability was still observed. Nonetheless, all formulations conformed to the USP specifications. Conclusions: With the excipients CrosPVP and HPC-SL an immediate release tablet formulation was successfully formulated for high-dose CBZ of various commercial sources

Radial die-wall pressure as a reliable tool for studying the effect of powder water activity on high speed tableting

The effect of moisture as a function of water activity (Aw) on the compaction process is important to understand particle/water interaction and deformation. Studying powder/moisture interaction under pressure with radial die-wall pressure (RDWP) tool was never done. The aim of our study was to use this tool to study this interaction at high compression pressure and speed. Moreover, the effect of changing ejection cam angle (EA) of the machine on ejection force (EF) was investigated. Also, a new tool for prediction of tablet sticking was proposed. Materials with different deformation behaviors stored at low and high moisture conditions were used. Compaction simulation guided by modeling was applied. High Aw resulted in a low residual die-wall pressure (RDP) for all materials, and a high maximum die-wall pressure (MDP) for plastic materials, p>0.05. This was due to the lubricating and plasticizing effects of water, respectively. However, microcrystalline cellulose showed capping at high Aw and compaction pressure. By increasing compression pressure at high Aw for all materials, effective fall time (EFT) was increased, p>0.05, showing tendency for sticking. Increasing EA caused an increase of friction and EF for powders, p>0.05. RDWP was a useful tool to understand particle/moisture interaction under pressure

A novel tool for the prediction of tablet sticking during high speed compaction

During tableting, capping is a problem of cohesion while sticking is a problem of adhesion. Sticking is a multi-composite problem; causes are either material or machine related. Nowadays, detecting such a problem is a pre-requisite in the early stages of development. The aim of our study was to investigate sticking by radial die-wall pressure monitoring guided by compaction simulation. This was done by using the highly sticking drug; Mefenamic acid (MA) at different drug loadings with different fillers compacted at different pressures and speeds. By increasing MA loading, we found that viscoelastic fillers showed high residual radial pressure after compaction while plastic/brittle fillers showed high radial pressure during compaction, p > 0.05. Visually, plastic/brittle fillers showed greater tendencies for adhesion to punches than viscoelastic fillers while the later showed higher tendencies for adhesion to the die-wall. This was confirmed by higher values of axial stress transmission for plastic/brittle than viscoelastic fillers (higher punch surface/powder interaction), and higher residual die-wall and ejection forces for viscoelastic than plastic/brittle fillers, p > 0.05. Take-off force was not a useful tool to estimate sticking due to cohesive failure of the compacts. Radial die-wall pressure monitoring is suggested as a robust tool to predict sticking

Study of radial die-wall pressure changes during pharmaceutical powder compaction

In tablet manufacturing, less attention is paid to the measurement of die-wall pressure than to force-displacement diagrams.; Therefore, the aim of this study was to investigate radial stress change during pharmaceutical compaction.; The Presster(TM), a tablet-press replicator, was used to characterize compaction behavior of microcrystalline cellulose (viscoelastic), calcium hydrogen phosphate dihydrate (brittle), direct compressible mannitol (plastic), pre-gelatinized starch (plastic/elastic), and spray dried lactose monohydrate (plastic/brittle) by measuring radial die-wall pressure; therefore powders were compacted at different (pre) compaction pressures as well as different speeds. Residual die-wall pressure (RDP) and maximum die-wall pressure (MDP) were measured. Various tablet physical properties were correlated to radial die-wall pressure.; With increasing compaction pressure, RDP and MDP (P > 0.0001) increased for all materials, with increasing precompaction RDP decreased for plastic materials (P > 0.05), whereas with increasing speed MDP decreased for all materials (P > 0.05). During decompression, microcrystalline cellulose and pre-gelatinized starch showed higher axial relaxation, whereas mannitol and lactose showed higher radial relaxation, calcium hydrogen phosphate showed high axial and radial relaxations. Plastic and brittle materials showed increased tendencies for friction because of high radial relaxation.; Die-wall monitoring is suggested as a valuable tool for characterizing compaction behavior of materials and detecting friction phenomena in the early stage of development

Compressibility of binary powder formulations : investigation and evaluation with compaction equations

The purpose of this work was to investigate and evaluate the powder compressibility of binary mixtures containing a well-compressible compound (microcrystalline cellulose) and a brittle active drug (paracetamol and mefenamic acid) and its progression after a drug load increase. Drug concentration range was 0%-100% (m/m) with 10% intervals. The powder formulations were compacted to several relative densities with the Zwick material tester. The compaction force and tensile strength were fitted to several mathematical models that give representative factors for the powder compressibility. The factors k and C (Heckel and modified Heckel equation) showed mostly a nonlinear correlation with increasing drug load. The biggest drop in both factors occurred at far regions and drug load ranges. This outcome is crucial because in binary mixtures the drug load regions with higher changeover of plotted factors could be a hint for an existing percolation threshold. The susceptibility value (Leuenberger equation) showed varying values for each formulation without the expected trend of decrease for higher drug loads. The outcomes of this study showed the main challenges for good formulation design. Thus, we conclude that such mathematical plots are mandatory for a scientific evaluation and prediction of the powder compaction process. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:777-793, 2012

Investigating the effect of punch geometry on high speed tableting through radial die-wall pressure monitoring

Dwell time mainly depends on punch geometry, so some tableting problems such as capping and lamination could occur at high speed compaction. Robust tools are required to monitor the interaction of punch tip and powder bed at these high speeds. Our aim was to investigate the effect of punch geometry (flat and standard concave) on powder compaction at high speed using radial die-wall pressure (RDWP) as a monitoring tool. Instrumented die guided by compaction simulation was applied for five materials with different compaction behaviors. Flat-faced punch showed higher residual, maximum die-wall pressures, and axial stress transmission than concave punches, p > 0.003. Moreover, flat-faced punches showed less friction upon ejection, p > 0.003. Flat compacts showed higher elastic recovery, tensile strength, and required less work of compaction than convex compacts, p > 0.05. RDWP monitoring was a useful tool to prove that flat-faced punch induced higher radial stresses and particle/particle interactions in comparison to concave punch