Formulation of immunomodulatory agents

Reversed-phase high-performance liquid chromatography procedures were developed for the analysis of pyrimidine-based drugs bropirimine and its derivatives (2-N-acetyl- and 2-N-propanoyl-) and for pyrimethamine and its 2/4- substituted derivatives (2, N-propanoyl and 2,4-N, N-dipropanoyl-) and its 6- substituted (methyl-, ethyl-, propyl- and isopropyl- carboxylates) analogues. Stability studies indicated that these derivatives were not sufficiently labile to act as potential prodrugs. Solubility-pH profiles were constructed from which the dissociation constants were calculated. The physicochemical properties of these compounds were studied and attempts were made to increase the poor aqueous solubility of bropirimine (35μg/mL) by prodrug synthesis, solvate formation (acetic acid, N, N-dimethylformamide and N-methylformamide) and the use of co-solvents and additives. The first two methods proved to be fruitless whereas the latter method resulted in an intravenous formulation incorporating 32mg/mL of bropirimine. An in-vitro method for the detection of precipitation was developed and the results suggested that by using low injection rates (< 0.24mL/min) and high mobile phase flow rates (> 500mL/hr) precipitation could be minimised. Differential scanning calorimetry showed that bropirimine debrominates in the presence of a number of additives commonly used in formulation work but the temperature at which this occurred were usually > 200oC. In-vitro work gave encouraging results for the possibility of rectal delivery of bropirimine but in-vivo work on rabbits showed considerable variations in the resulting plasma levels and pharmacokinetic parameters.

The effectiveness of an innovative intervention aimed at reducing binge drinking among young people:results from a pilot study

Aims: To assess the effectiveness of a digital-story intervention (short videos made by young people) seeking to reduce the prevalence of young people's binge drinking in Caerphilly. Method: A quasi-experimental design was adopted with three intervention sites and one control site providing the sample (mainly aged 1415 years). Three rounds of self-completion questionnaires, completed prior (T1), immediately after (T2) and 6 months after the intervention (T3). Findings: A total of 1031 questionnaires completed across the three time-points. Two-factor ANOVAs revealed a positive effect on knowledge for the intervention sample. The intervention group results showed stable attitudes towards drinking at the three time-points whilst the control group showed increasing positive attitudes towards drunkenness over the same time period. Intentions towards drunkenness were higher in the control group than the intervention group at T2 (ControlT1 Mean 3.37, T2 Mean 3.90; interventionT1 Mean 3.26, T2 Mean 3.29). Intervention participants got drunk on fewer occasions in the last week (mean occasions last week 1.57) compared to control participants (mean occasions last week 2.00), with the difference approaching statistical significance (F 1.90, p 0.07). Conclusions: Promoting negative attitudes towards drunkenness, alongside a greater sense of control and potential regret about drunkenness are likely to be important factors when considering how to change people's intentions to drink. The study shows the potential to reduce the frequency of drinking behaviour when intentions are changed, and provides recommendations for future interventions of this nature. © 2010 Informa UK Ltd.

Adaptive congestion control of DSRC vehicle networks for collaborative road safety applications

Congestion control is critical for the provisioning of quality of services (QoS) over dedicated short range communications (DSRC) vehicle networks for road safety applications. In this paper we propose a congestion control method for DSRC vehicle networks at road intersection, with the aims of providing high availability and low latency channels for high priority emergency safety applications while maximizing channel utilization for low priority routine safety applications. In this method a offline simulation based approach is used to find out the best possible configurations of message rate and MAC layer backoff exponent (BE) for a given number of vehicles equipped with DSRC radios. The identified best configurations are then used online by an roadside access point (AP) for system operation. Simulation results demonstrated that this adaptive method significantly outperforms the fixed control method under varying number of vehicles. The impact of estimation error on the number of vehicles in the network on system level performance is also investigated.

QoS guarantee with adaptive transmit power and message rate control for DSRC vehicle network based road safety applications

Quality of services (QoS) support is critical for dedicated short range communications (DSRC) vehicle networks based collaborative road safety applications. In this paper we propose an adaptive power and message rate control method for DSRC vehicle networks at road intersections. The design objective is to provide high availability and low latency channels for high priority emergency safety applications while maximizing channel utilization for low priority routine safety applications. In this method an offline simulation based approach is used to find out the best possible configurations of transmit power and message rate for given numbers of vehicles in the network. The identified best configurations are then used online by roadside access points (AP) according to estimated number of vehicles. Simulation results show that this adaptive method significantly outperforms a fixed control method. © 2011 Springer-Verlag.

Selectivity and timing performance of UK investment trusts

This study examines the selectivity and timing performance of 218 UK investment trusts over the period July 1981 to June 2009. We estimate the Treynor and Mazuy (1966) and Henriksson and Merton (1981) models augmented with the size, value, and momentum factors, either under the OLS method adjusted with the Newey-West procedure or under the GARCH(1,1)-in-mean method following the specification of Glosten et al. (1993; hereafter GJR-GARCH-M). We find that the OLS method provides little evidence in favour of the selectivity and timing ability, consistent with previous studies. Interestingly, the GJR-GARCH-M method reverses this result, showing some relatively strong evidence on favourable selectivity ability, particularly for international funds, as well as favourable timing ability, particularly for domestic funds. We conclude that the GJR-GARCH-M method performs better in evaluating fund performance compared with the OLS method and the non-parametric approach, as it essentially accounts for the time-varying characteristics of factor loadings and hence obtains more reliable results, in particular, when the high frequency data, such as the daily returns, are used in the analysis. Our results are robust to various in-sample and out-of-sample tests and have valuable implications for practitioners in making their asset allocation decisions across different fund styles. © 2012 Elsevier B.V.

An alternative formulation for the fuzzy assignment problem

The existing assignment problems for assigning n jobs to n individuals are limited to the considerations of cost or profit measured as crisp. However, in many real applications, costs are not deterministic numbers. This paper develops a procedure based on Data Envelopment Analysis method to solve the assignment problems with fuzzy costs or fuzzy profits for each possible assignment. It aims to obtain the points with maximum membership values for the fuzzy parameters while maximizing the profit or minimizing the assignment cost. In this method, a discrete approach is presented to rank the fuzzy numbers first. Then, corresponding to each fuzzy number, we introduce a crisp number using the efficiency concept. A numerical example is used to illustrate the usefulness of this new method. © 2012 Operational Research Society Ltd. All rights reserved.

Results of the IEA round robin on viscosity and stability of fast pyrolysis bio-oils

An international round robin study of the stability of fast pyrolysis bio-oil was undertaken. Fifteen laboratories in five different countries contributed. Two bio-oil samples were distributed to the laboratories for stability testing and further analysis. The stability test was defined in a method provided with the bio-oil samples. Viscosity measurement was a key input. The change in viscosity of a sealed sample of bio-oil held for 24 h at 80 °C was the defining element of stability. Subsequent analyses included ultimate analysis, density, moisture, ash, filterable solids, and TAN/pH determination, and gel permeation chromatography. The results showed that kinematic viscosity measurement was more generally conducted and more reproducibly performed versus dynamic viscosity measurement. The variation in the results of the stability test was great and a number of reasons for the variation were identified. The subsequent analyses proved to be at the level of reproducibility, as found in earlier round robins on bio-oil analysis. Clearly, the analyses were more straightforward and reproducible with a bio-oil sample low in filterable solids (0.2%), compared to one with a higher (2%) solids loading. These results can be helpful in setting standards for use of bio-oil, which is just coming into the marketplace. © 2012 American Chemical Society.

Quasi-pilot aided phase noise estimation for coherent optical OFDM systems

In this letter, a novel phase noise estimation scheme has been proposed for coherent optical orthogonal frequency division multiplexing systems, the quasi-pilot-aided method. In this method, the phases of transmitted pilot subcarriers are deliberately correlated to the phases of data subcarriers. Accounting for this correlation in the receiver allows the required number of pilots needed for a sufficient estimation and compensation of phase noise to be reduced by a factor of 2 in comparison with the traditional pilot-aided phase noise estimation method. We carried out numerical simulation of a 40 Gb/s single polarization transmission system, and the outcome of the investigation indicates that by applying quasi-pilot-aided phase estimation, only four pilot subcarriers are needed for effective phase noise compensation. © 2014 IEEE.

Nanotechnology and microfluidics:formulation design and on-chip manufacture of nanoparticles

Nanoparticles offer an ideal platform for the delivery of small molecule drugs, subunit vaccines and genetic constructs. Besides the necessity of a homogenous size distribution, defined loading efficiencies and reasonable production and development costs, one of the major bottlenecks in translating nanoparticles into clinical application is the need for rapid, robust and reproducible development techniques. Within this thesis, microfluidic methods were investigated for the manufacturing, drug or protein loading and purification of pharmaceutically relevant nanoparticles. Initially, methods to prepare small liposomes were evaluated and compared to a microfluidics-directed nanoprecipitation method. To support the implementation of statistical process control, design of experiment models aided the process robustness and validation for the methods investigated and gave an initial overview of the size ranges obtainable in each method whilst evaluating advantages and disadvantages of each method. The lab-on-a-chip system resulted in a high-throughput vesicle manufacturing, enabling a rapid process and a high degree of process control. To further investigate this method, cationic low transition temperature lipids, cationic bola-amphiphiles with delocalized charge centers, neutral lipids and polymers were used in the microfluidics-directed nanoprecipitation method to formulate vesicles. Whereas the total flow rate (TFR) and the ratio of solvent to aqueous stream (flow rate ratio, FRR) was shown to be influential for controlling the vesicle size in high transition temperature lipids, the factor FRR was found the most influential factor controlling the size of vesicles consisting of low transition temperature lipids and polymer-based nanoparticles. The biological activity of the resulting constructs was confirmed by an invitro transfection of pDNA constructs using cationic nanoprecipitated vesicles. Design of experiments and multivariate data analysis revealed the mathematical relationship and significance of the factors TFR and FRR in the microfluidics process to the liposome size, polydispersity and transfection efficiency. Multivariate tools were used to cluster and predict specific in-vivo immune responses dependent on key liposome adjuvant characteristics upon delivery a tuberculosis antigen in a vaccine candidate. The addition of a low solubility model drug (propofol) in the nanoprecipitation method resulted in a significantly higher solubilisation of the drug within the liposomal bilayer, compared to the control method. The microfluidics method underwent scale-up work by increasing the channel diameter and parallelisation of the mixers in a planar way, resulting in an overall 40-fold increase in throughput. Furthermore, microfluidic tools were developed based on a microfluidics-directed tangential flow filtration, which allowed for a continuous manufacturing, purification and concentration of liposomal drug products.

Differences in the density and spatial distribution of florid and diffuse plaques in variant Creutzfeldt-Jakob disease (vCJD)

Objective: To determine whether in cases of variant Creutzfeldt-Jakob disease (vCJD), the florid-type plaques are derived from the diffuse plaques or whether the 2 plaque types develop independently. Material: Blocks of frontal, parietal, occipital and temporal neocortex and cerebellar cortex from 11 cases of vCJD. Method: The density, distribution and spatial pattern of the florid and diffuse plaques were determined in each brain region using spatial pattern analysis. Results: The density of the diffuse plaques was significantly greater than that of the florid plaques in most areas. The ratio of the diffuse to florid plaques varied between brain regions and was maximal in the molecular layer of the cerebellum. The densities of the florid and diffuse plaques were positively correlated in the parietal cortex, occipital cortex, the inferior temporal gyrus and the dentate gyrus. Plaque densities were not related to disease duration. In the cerebral cortex, the diffuse plaques were more commonly evenly distributed or occurred in large clusters along the cortex parallel to the pia mater compared with the florid plaques which occurred more frequently in regularly distributed clusters. Conclusion: The florid plaques may not be derived from the diffuse plaques, the 2 plaque types appearing to develop independently with unique factors involved in their pathogenesis.

Species-specific differences in the expression of the HNF1A, HNF1B and HNF4A genes

Background: The HNF1A, HNF1B and HNF4A genes are part of an autoregulatory network in mammalian pancreas, liver, kidney and gut. The layout of this network appears to be similar in rodents and humans, but inactivation of HNF1A, HNF1B or HNF4A genes in animal models cause divergent phenotypes to those seen in man. We hypothesised that some differences may arise from variation in the expression profile of alternatively processed isoforms between species. Methodology/Principal Findings: We measured the expression of the major isoforms of the HNF1A, HNF1B and HNF4A genes in human and rodent pancreas, islet, liver and kidney by isoform-specific quantitative real-time PCR and compared their expression by the comparative Ct (??Ct) method. We found major changes in the expression profiles of the HNF genes between humans and rodents. The principal difference lies in the expression of the HNF1A gene, which exists as three isoforms in man, but as a single isoform only in rodents. More subtle changes were to the balance of HNF1B and HNF4A isoforms between species; the repressor isoform HNF1B(C) comprised only 6% in human islets compared with 24–26% in rodents (p = 0.006) whereas HNF4A9 comprised 22% of HNF4A expression in human pancreas but only 11% in rodents (p = 0.001). Conclusions/Significance: The differences we note in the isoform-specific expression of the human and rodent HNF1A, HNF1B and HNF4A genes may impact on the absolute activity of these genes, and therefore on the activity of the pancreatic transcription factor network as a whole. We conclude that alterations to expression of HNF isoforms may underlie some of the phenotypic variation caused by mutations in these genes.

Gender differences in the relationships between bullying at school and unhealthy eating and shape-related attitudes and behaviours

Background. Previous research has found links between being a victim of bullying and reporting more unhealthy eating behaviours and cognitions, particularly in girls. However, little is known about the factors that might mediate these relationships. Aim. The present study compared the relationships between bullying, emotional adjustment, restrained eating, and body dissatisfaction in adolescent boys and girls. Sample/method. Self-report data were collected from a sample of 11- to 14-year-olds (N= 376) on experiences of bullying, emotional symptoms, and unhealthy eating and shape-related attitudes and behaviours. Results. Bullying, emotional symptoms, restrained eating, and body dissatisfaction were all correlated. Emotional symptoms were found to significantly mediate the relationships between verbal bullying with body dissatisfaction in girls but not in boys. Conclusions. Findings suggest that the experience of being verbally bullied places adolescent girls at risk of developing emotional problems which can then lead to body dissatisfaction. Longitudinal research is necessary to disentangle these pathways in more detail to facilitate the development of informed interventions to support children who are being bullied.

Gender differences in the sensitivity to negative stimuli:cross-modal affective priming study

Background: There is evidence showing that men and women differ with regard to the processing of emotional information. However, the mechanisms behind these differences are not fully understood. Method: The sample comprised of 275 (167 female) right-handed, healthy participants, recruited from the community. We employed a customized affective priming task, which consisted of three subtests, differing in the modality of the prime (face, written word, and sound). The targets were always written words of either positive or negative valence. The priming effect was measured as reaction time facilitation in conditions where both prime and target were emotional (of the same positive or negative valence) compared with conditions where the emotional targets were preceded by neutral primes. Results: The priming effect was observed across all three modalities, with an interaction of gender by valence: the priming effect in the emotionally negative condition in male participants was stronger compared with females. This was accounted for by the differential priming effect within the female group where priming was significantly smaller in the emotionally negative conditions compared with the positive conditions. The male participants revealed a comparable priming effect across both the emotionally negative and positive conditions. Conclusion: Reduced priming in negative conditions in women may reflect interference processes due to greater sensitivity to negative valence of stimuli. This in turn could underlie the gender-related differences in susceptibility to emotional disorders.

Uncovering the root cause of ethnic difference in ability testing:differential test functioning, test familiarity and trait optimism as explanations of ethnic group differences

The present research represents a coherent approach to understanding the root causes of ethnic group differences in ability test performance. Two studies were conducted, each of which was designed to address a key knowledge gap in the ethnic bias literature. In Study 1, both the LR Method of Differential Item Functioning (DIF) detection and Mixture Latent Variable Modelling were used to investigate the degree to which Differential Test Functioning (DTF) could explain ethnic group test performance differences in a large, previously unpublished dataset. Though mean test score differences were observed between a number of ethnic groups, neither technique was able to identify ethnic DTF. This calls into question the practical application of DTF to understanding these group differences. Study 2 investigated whether a number of non-cognitive factors might explain ethnic group test performance differences on a variety of ability tests. Two factors – test familiarity and trait optimism – were able to explain a large proportion of ethnic group test score differences. Furthermore, test familiarity was found to mediate the relationship between socio-economic factors – particularly participant educational level and familial social status – and test performance, suggesting that test familiarity develops over time through the mechanism of exposure to ability testing in other contexts. These findings represent a substantial contribution to the field’s understanding of two key issues surrounding ethnic test performance differences. The author calls for a new line of research into these performance facilitating and debilitating factors, before recommendations are offered for practitioners to ensure fairer deployment of ability testing in high-stakes selection processes.