Aggregation and neurotoxicity of alpha-synuclein and related peptides

Fibrillar deposits of alpha-synuclein occur in several neurodegenerative diseases. Two mutant forms of alpha-synuclein have been associated with early-onset Parkinson's disease, and a fragment has been identified as the non-amyloid-beta peptide component of Alzheimer's disease amyloid (NAC). Upon aging, solutions of alpha-synuclein and NAC change conformation to beta-sheet, detectable by CD spectroscopy, and form oligomers that deposit as amyloid-like fibrils, detectable by electron microscopy. These aged peptides are also neurotoxic. Experiments on fragments of NAC have enabled the region of NAC responsible for its aggregation and toxicity to be identified. NAC(8-18) is the smallest fragment that aggregates, as indicated by the concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. Fragments NAC(8-18) and NAC(8-16) are toxic, whereas NAC(12-18), NAC(9-16) and NAC(8-15) are not. Hence residues 8-16 of NAC comprise the region crucial for toxicity. Toxicity induced by alpha-synuclein, NAC and NAC(1-18) oligomers occurs via an apoptotic mechanism, possibly initiated by oxidative damage, since these peptides liberate hydroxyl radicals in the presence of iron. Molecules with anti-aggregational and/or antioxidant properties may therefore be potential therapeutic agents.

Numerical and Experimental Study of the Performance Effects of Varying Vaneless Space and Vane Solidity in Radial Inflow Turbine Stators.

An extensive experimental program has been carried out on a 135?mm tip diameter radial turbine using a variety of stator designs, in order to facilitate direct performance comparisons of varying stator vane solidity and the effect of varying the vaneless space. A baseline vaned stator was designed using commercial blade design software, having 15 vanes and a vane trailing edge to rotor leading edge radius ratio (Rte/rle) of 1.13. Two additional series of stator vanes were designed and manufactured; one series having varying vane numbers of 12, 18, 24, and 30, and a further series with Rte/rle ratios of 1.05, 1.175, 1.20, and 1.25. As part of the design process a series of CFD simulations were carried out in order to guide design iterations towards achieving a matched flow capacity for each stator. In this way the variations in the measured stage efficiency could be attributed to the stator passages only, thus allowing direct comparisons to be made. Interstage measurements were taken to capture the static pressure distribution at the rotor inlet and these measurements were then used to validate subsequent numerical models. The overall losses for different stators have been quantified and the variations in the measured and computed efficiency were used to recommend optimum values of vane solidity and Rte/rle.

A short synthesis of (+) and (−)-falcarinol

A short, practical synthesis of the bis-acetylenic natural product falcarinol 1 is reported. This method relies on the alternate functionalisation of bis-trimethylsilylbutadiyne 10. This may be achieved in one-pot, however, better yields were obtained more conventionally. Lipase mediated enzymatic kinetic resolution of the racemic adduct in an organic solvent afforded (+)-1 in 97% enantiomeric excess. The analogous process performed with racemic 3-acetoxy falcarinol 11 under aqueous conditions gave (-)-1. Oxidation of 1 with Dess–Martin periodinane gave falcarinone 2.

Mitomycin-C supplemented trabeculectomy, phacoemulsification, and foldable lens implantation

Purpose: To evaluate the outcome of combined mitomycin-C filtering surgery, phacoemulsification, and foldable intraocular lens (IOL) implantation. Setting: Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Methods: This retrospective study evaluated 182 eyes of 174 patients who had combined mitomycin-C trabeculectomy, phacoemulsification, and insertion of a foldable IOL through a 3.5 mm incision. Success of the combined procedure was defined as intraocular pressure (IOP) below 21 mm Hg, with or without medications, and no serious complication. Success rates were calculated using the Kaplan-Meier actuarial method. Results: Mean follow-up was 16.7 months ± 5.4 (SD). The probability of success at 6, 12, 18, and 24 months was 98.3, 95.6, 90.6, and 88.0%, respectively. When compared with preoperativety, visual acuity improved one or more lines in 148 eyes (81.3%) and worsened one or more lines in 15 (8.2%); 111 eyes (61.0%) achieved visual acuity of 20/40 or better. The most frequent complication was posterior capsule opacification requiring capsulotomy, which occurred in 22 cases (12.0%). Conclusion: The 1 year and 2 year IOP control rate of combined mitomycin-C filtering procedures and phacoemulsification in glaucoma patients was high.

Control of intraocular pressure after deep sclerectomy

Aim: To study the long-term outcome of deep sclerectomy in patients with open angle glaucoma. Methods: Prospective consecutive series of 43 eyes (38 patients) with medically uncontrolled open-angle glaucoma undergoing deep sclerectomy. All patients underwent clinical assessment before and after surgery at day 7 and at months 1, 3, 6, 12, 18, 24, 36. Surgical success was considered if the patient's intraocular pressure (IOP)>22 mmHg and the IOP was lowered by more than 20% without the use of any medication. Kaplan-Meier survival curves were used to evaluate the success rate. Results: The mean follow-up time was 28.1±8.2 months. Mean IOP decreased significantly from a preoperative value of 24.6±5.5 mmHg to a postoperative value of 18.5±4.6 mmHg at 36 months (P>0.001). Microperforation of TDM occurred in three cases (7.0%) and ciliary body prolapse in one case (2.3%) but did not prevent completion of the operation. Postoperatively, hyphaema was detected in one case and shallow anterior chamber in another case and both were treated conservatively. Bleb encapsulation with elevation of IOP occurred in two cases (4.7%) and was treated with 5-fluorouracil subconjunctival injection. Goniopuncture with neodymium : YAG laser was performed in two cases (4.7%). There were no other late complications with the exception of failure of the operation. On the life-table analysis the success rate at 12, 24, and 30 months were 61.4, 36.6, and 18.9%, respectively. Conclusion: Deep sclerectomy reduced the IOP temporarily while minimising the risk of postoperative complications commonly encountered with standard trabeculectomy. However, after long-term follow-up surgery failed to maintain a low IOP. © 2006 Nature Publishing Group. All rights reserved.

Longitudinal relations between sectarian and nonsectarian community violence and child adjustment in Northern Ireland

Although relations between political violence and child adjustment are well documented, longitudinal research is needed to adequately address the many questions remaining about the contexts and developmental trajectories underlying the effects on children in areas of political violence. The study examined the relations between sectarian and nonsectarian community violence and adolescent adjustment problems over 4 consecutive years. Participants included 999 mother-child dyads (482 boys, 517 girls), M ages = 12.18 (SD = 1.82), 13.24 (SD = 1.83), 13.61 (SD = 1.99), and 14.66 (SD = 1.96) years, respectively, living in socially deprived neighborhoods in Belfast, Northern Ireland, a context of historical and ongoing political violence. In examining trajectories of adjustment problems, including youth experience with both sectarian and nonsectarian antisocial behaviors, sectarian antisocial behavior significantly predicted more adjustment problems across the 4 years of the study. Experiencing sectarian antisocial behavior was related to increased adolescent adjustment problems, and this relationship was accentuated in neighborhoods characterized by higher crime rates. The discussion considers the implications for further validating the distinction between sectarian and nonsectarian violence, including consideration of neighborhood crime levels, from the child's perspective in a setting of political violence. Copyright © Cambridge University Press 2013.

Meta-Theoretical Paradigms Underpinning Risk in Child Welfare: Towards a Position of Methodological Pragmatism

The aim of this paper is to explore the ‘natural attitude’ underpinning risk practices in child welfare. This refers to various taken-for-granted approaches to risk that social workers and other human service professionals draw upon in their everyday practice. The approach proceeds by identifying and critically examining three key, meta-theoretical paradigms on risk which typically shape the natural attitude. They are labelled ‘objectivist’, ‘subjectivist’ and ‘critical’. The ontological, epistemological, axiological and methodological premises supporting each paradigm, and how they shape risk practices, are then reviewed leading to a composite, meta-theoretical position on risk termed ‘methodological pragmatism’. This position draws on the strengths of each paradigm and is formulated into ten propositions which consider how risk should be approached in child welfare. Within this corpus of thought salient themes are endorsed such as the need for method triangulation, an examination of ‘deep causality’, and the promotion of emancipatory perspectives. By critically reflecting on meta-theory, the paper contributes to the development of substantive theories of risk assessment and management in child welfare.

Microneedles for intradermal and transdermal drug delivery

The formidable barrier properties of the uppermost layer of the skin, the stratum corneum, impose significant limitations for successful systemic delivery of broad range of therapeutic molecules particularly macromolecules and genetic material. Microneedle (MN) has been proposed as a strategy to breach the stratum corneum barrier function in order to facilitate effective transport of molecules across the skin. This strategy involves use of micron sized needles fabricated of different materials and geometries to create transient aqueous conduits across the skin. MN, alone or with other enhancing strategies, has been demonstrated to dramatically enhance the skin permeability of numerous therapeutic molecules including biopharmaceuticals either in vitro, ex vivo or in vivo experiments. This suggested the promising use of MN technology for various possible clinical applications such as insulin delivery, transcutaneous immunisations and cutaneous gene delivery. MN has been proved as minimally invasive and painless in human subjects. This review article focuses on recent and future developments for MN technology including the latest type of MN design, challenges and strategies in MNs development as well as potential safety aspects based on comprehensive literature review pertaining to MN studies to date. (C) 2013 Elsevier B.V. All rights reserved.