Evaluating the potential neurotoxicity of hexanedione isomers:an in vitro approach

2,5-hexanedione (2,5HD) is the neurotoxic metabolite of the aliphatic hydrocarbon n-Hexane. The isomers, 2,3-hexanedione (2,3HD) and 3,4-hexanedione (3,4HD) are used as food additives. Although the neurotoxicity of 2,5HD is well established, there are no human data of the possible toxicity of the 2,3- and 3,4- isomers. MTT and flow cytometry were utilised to determine the cytotoxicity of hexanedione isomers in neuroblastoma cells. The neuroblastoma cell lines SK-N-SH and SH-SY5Y are sufficiently neuron-like to provide preliminary assessment of the neurotoxic potential of these isomers, in comparison with toxicity towards human non-neuronal cells. Initial studies showed that 2,5HD was the least toxic in all cell lines at all times (4, 24 and 48h). Although considerably lower than for 2,5HD, in general the IC50s for the α isomers were not significantly different from each other and, besides 4h exposure, the SH-SY5Y cells were significantly more sensitive to 2,3HD and 3,4HD than the SK-N-SH cells. All three isomers caused varying degrees of apoptosis in the neuroblastoma lines, with 3,4HD more potent than 2,3HD. Flow cytometry highlighted cell cycle arrest indicative of DNA damage with 2,3- and 3,4HD. The toxicity of the isomers towards 3 non-neuronal cell lines (MCF7, HepG2 and CaCo-2) was assessed by MTT assay. All 3 hexanedione isomers proved to be cytotoxic in all non-neuronal cell lines at all time points. These data suggest cytotoxicity of 2,3- and 3,4HD (mM range), but it is difficult to define this as specific neurotoxicity in the absence of specific neurotoxic endpoints. However, the neuroblastomas were significantly more susceptible to the cytotoxic effects of the α hexanedione isomers at exposures of 4 and 24 hours, compared to non-neuronal lines. Finally, a mechanism of toxicity is suggested for the α HD isomers whereby inhibition of the oxoglutarate carrier (OGC) releases apoptosis inducing factor (AIF), causing apoptosis-like cell death.

Evaluation of biodegradable polymer microspheres and an anionic dendrimer for the potential delivery of antisense oligonucleotides

Antisense oligonucleotides (AODNs) can selectively inhibit individual gene expression by binding specifically to rnRNA. The over-expression of the epidermal growth factor receptor (EGFR) has been observed in human breast and glioblastoma tumours and therefore AODNs designed to target the EGFR would be a logical approach to treat such tumours. However, poor pharmacokinetic/pharmacodynamic and cellular uptake properties of AODNs have limited their potential to become successful therapeutic agents. Biodegradable polymeric poly (lactide-co-glycolide) (P(LA-GA)) and dendrimer delivery systems may allow us to overcome these problems. The use of combination therapy of AODNs and cytotoxic agents such as 5-fluorouracil (5-FU) in biodegradable polymeric formulations may further improve therapeutic efficacy. AODN and 5-FU were either co-entrapped in a single microsphere formulation or individually entrapped in two separate microsphere formulations (double emulsion method) and release profiles determined in vitro. The release rates (biphasic) of the two agents were significantly slower when co-entrapped as a single microsphere formulation compared to those obtained with the separate formulations. Sustained release over 35 days was observed in both types of formulation. Naked and microsphere-loaded AODN and 5-FU (in separate formulations) were tested on an A431 vulval carcinoma cell line. Combining naked or encapsulated drugs produced a greater reduction in viable cell number as compared with either agent alone. However, controls and Western blotting indicated that non-sequence specific cytotoxic effects were responsible for the differences in viable cell number. The uptake properties of an anionic dendrimer based on a pentaerythritol structure covalently linked to AODNs (targeting the EGFR) have been characterised. The cellular uptake of AODN linked to the dendrimer was up to 3.5-fold higher in A431 cells as compared to naked AODN. Mechanistic studies suggested that receptor-mediated and adsorptive (binding protein-mediated) endocytosis were the predominant uptake mechanisms for the dendrimer-AODN. RNase H cleavage assay suggested that the dendrimer-AODN was able to bind and cleave the target site. A reduction of 20%, 28% and 45% in EGFR expression was observed with 0.05μM, 0.1μM and 0.5μM dendrimer-AODN treatments respectively with a reduction in viable cell number. These results indicated that the dendrimer delivery system may reduce viable cell number by an antisense specific mechanism.

Thin film bearings with phase change of lubricant

The possible evaporation of lubricant in fluid film bearings has been investigated theoretically and by experiment using a radial flow hydrostatic bearing supplied with liquid refrigerant R114. Good correlation between measured and theoretical values was obtained using a bespoke computational fluid dynamic model in which the flow was assumed to be laminar and adiabatic. The effects of viscous dissipation and vapour generation within the fluid film are fully accounted for by applying a fourth order Runge-Kutta routine to satisfy the radial and filmwise transverse constraints of momentum, energy and mass conservation. The results indicate that the radial velocity profile remains parabolic while the flow remains in the liquid phase and that the radial rate of enthalpy generation is then constant across the film at a given radius. The results also show that evaporation will commence at a radial location determined by geometry and flow conditions and in fluid layers adjacent to the solid boundaries. Evaporation is shown to progress in the radial direction and the load carrying capacity of such a bearing is reduced significantly. Expressions for the viscosity of the liquid/vapour mixture found in the literature survey have not been tested against experimental data. A new formulation is proposed in which the suitable choice of a characteristic constant yields close representation to any of these expressions. Operating constraints imposed by the design of the experimental apparatus limited the extent of the surface over which evaporation could be obtained, and prevented clear identification of the most suitable relationship for the viscosity of the liquid/vapour mixture. The theoretical model was extended to examine the development of two phase flow in a rotating shaft face seal of uniform thickness. Previous theoretical analyses have been based on the assumption that the radial velocity profile of the flow is always parabolic, and that the tangential component of velocity varies linearly from the value at the rotating surface, to zero at the stationary surface. The computational fluid dynamic analysis shows that viscous shear and dissipation in the fluid adjacent to the rotating surface leads to developing evaporation with a consequent reduction in tangential shear forces. The tangential velocity profile is predicted to decay rapidly through the film, exhibiting a profile entirely different to that assumed by previous investigators. Progressive evaporation takes place close to the moving wall and does not occur completely at a single radial location, as has been claimed in earlier work.

An investigation of production workers' performance variations and the potential impact of attitudes

In most manufacturing systems the contribution of human labour remains a vital element that affects overall performance and output. Workers’ individual performance is known to be a product of personal attitudes towards work. However, in current system design processes, worker performance variability is assumed to be largely insignificant and the potential impact of worker attitudes is ignored. This paper describes a field study that investigated the extent to which workers’ production task cycle times vary and the degree to which such variations are associated with attitude differences. Results show that worker performance varies significantly, much more than is assumed by contemporary manufacturing system designers and that this appears to be due to production task characteristics. The findings of this research and their implications are discussed.

The impact of Islamic banking on the cost efficiency and productivity change of Malaysian commercial banks

This study employs Stochastic Frontier Analysis (SFA) to analyse Malaysian commercial banks during 1996–2002, and particularly focuses on determining the impact of Islamic banking on performance. We derive both net and gross efficiency estimates, thereby demonstrating that differences in operating characteristics explain much of the difference in costs between Malaysian banks. We also decompose productivity change into efficiency, technical, and scale change using a generalized Malmquist productivity index. On average, Malaysian banks experience moderate scale economies and annual productivity change of 2.68%, with the latter driven primarily by Technical Change (TC), which has declined over time. Our gross efficiency estimates suggest that Islamic banking is associated with higher input requirements. However, our productivity estimates indicate that full-fledged Islamic banks have overcome some of these cost disadvantages with rapid TC, although this is not the case for conventional banks operating Islamic windows. Merged banks are found to have higher input usage and lower productivity change, suggesting that bank mergers have not contributed positively to bank performance. Finally, our results suggest that while the East Asian financial crisis had a short-term costreducing effect in 1998, the crisis triggered a long-lasting negative impact by increasing the volume of nonperforming loans.

Marine Le Pen and the 'New' FN:a change of style or of substance?

The electoral challenge of the far right is an enduringly problematic feature of contemporary French politics. In the first rounds of the 2012 presidential and parliamentary elections, the Front National (FN) under new leader Marine Le Pen attracted a combined total of ten million votes, bringing its ultra-nationalist policies to the centre of national political debate. This article examines the FN's impact on these elections and its implications for French politics. Drawing on official FN programmes, detailed election results and a range of opinion polling data, it assesses the strength of support for Le Pen and her party and seeks to explain their electoral appeal. In particular, it subjects to analysis the claim that the new leader has ‘de-demonised’ the FN, transforming it from perennial outsider to normal participant in mainstream French politics; and it reflects on the strategic dilemma posed for the centre-right by this newly invigorated far-right challenge.

Pilot study reviewing the receptivity for change of the business improvement department and the core leadership programme

Consultancy report for the Deputy Chief Constable, Warwickshire Police

Method of detecting a significant change of scene

A significant change of scene in a gradually changing scene is detected with the aid of a least one camera means for capturing digital images of the scene. A current image of the scene is formed together with a present weighted reference image which is formed from a plurality of previous images of the scene. Cell data is established based on the current image and the present weighted reference image. The cell data is statistically analysed so as to be able to identify at least one difference corresponding to a significant change of scene. When identified, an indication of such significant change of scene is provided.

Study of the potential role of the community pharmacist in health promotion

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A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer

The mammalian retromer is a multimeric protein complex involved in mediating endosome-to-trans-Golgi-network retrograde transport of the cation-independent mannose-6-phosphate receptor. The retromer is composed of two subcomplexes, one containing SNX1 and forming a membrane-bound coat, the other comprising VPS26, VPS29 and VPS35 and being cargo-selective. In yeast, an additional sorting nexin--Vps17p--is a component of the membrane bound coat. It remains unclear whether the mammalian retromer requires a functional equivalent of Vps17p. Here, we have used an RNAi loss-of-function screen to examine whether any of the other 30 mammalian sorting nexins are required for retromer-mediated endosome-to-trans-Golgi-network retrieval of the cation-independent mannose-6-phosphate receptor. Using this screen, we identified two proteins, SNX5 and SNX6, that, when suppressed, induced a phenotype similar to that observed upon suppression of known retromer components. Whereas SNX5 and SNX6 colocalised with SNX1 on early endosomes, in immunoprecipitation experiments only SNX6 appeared to exist in a complex with SNX1. Interestingly, suppression of SNX5 and/or SNX6 resulted in a significant loss of SNX1, an effect that seemed to result from post-translational regulation of the SNX1 level. Such data suggest that SNX1 and SNX6 exist in a stable, endosomally associated complex that is required for retromer-mediated retrieval of the cation-independent mannose-6-phosphate receptor. SNX5 and SNX6 may therefore constitute functional equivalents of Vps17p in mammals.

Investigating mental health risk assessment in primary care and the potential role of a structured decision support tool, GRiST

Aim: To explore current risk assessment processes in general practice and Improving Access to Psychological Therapies (IAPT) services, and to consider whether the Galatean Risk and Safety Tool (GRiST) can help support improved patient care. Background: Much has been written about risk assessment practice in secondary mental health care, but little is known about how it is undertaken at the beginning of patients' care pathways, within general practice and IAPT services. Methods: Interviews with eight general practice and eight IAPT clinicians from two primary care trusts in the West Midlands, UK, and eight service users from the same region. Interviews explored current practice and participants' views and experiences of mental health risk assessment. Two focus groups were also carried out, one with general practice and one with IAPT clinicians, to review interview findings and to elicit views about GRiST from a demonstration of its functionality. Data were analysed using thematic analysis. Findings Variable approaches to mental health risk assessment were observed. Clinicians were anxious that important risk information was being missed, and risk communication was undermined. Patients felt uninvolved in the process, and both clinicians and patients expressed anxiety about risk assessment skills. Clinicians were positive about the potential for GRiST to provide solutions to these problems. Conclusions: A more structured and systematic approach to risk assessment in general practice and IAPT services is needed, to ensure important risk information is captured and communicated across the care pathway. GRiST has the functionality to support this aspect of practice.