The spatial pattern of senile plaques, neurofibrillary tangles and A4 deposits in Alzheimer's disease

The spatial patterns of senile plaques (SP) and neurofibrillary tangles (NFT) as visualised using the Gallyas stain and of discrete A4 protein deposits were determined in coronal serial sections from a variety of brain regions in six elderly patients with Alzheimer's disease (AD). These lesions showed clustering in virtually all tissues examined with many of the clusters being regularly spaced. These spatial patterns were compared with the clustering observed for SP and NFT stained by the Glees and Marsland method in the same tissues. The data suggest that on average, while the regular clusters of A4 deposits and NFT were of approximately the same mean diameter (3600 microns), clusters of both Glees and Gallyas SP were approximately half this diameter (1800 - 2000 microns). If SP develop in local areas of the brain where both A4 deposition and neurofibrillary changes have occurred, the data suggest that the SP clusters would represent the region of overlap of the A4 deposits and neurofibrillary changes. Various hypothese are advocated to explain the regular clsuetring of the A4 deposits.

Inference and optimization of real edges on sparse graphs:A statistical physics perspective

Inference and optimization of real-value edge variables in sparse graphs are studied using the Bethe approximation and replica method of statistical physics. Equilibrium states of general energy functions involving a large set of real edge variables that interact at the network nodes are obtained in various cases. When applied to the representative problem of network resource allocation, efficient distributed algorithms are also devised. Scaling properties with respect to the network connectivity and the resource availability are found, and links to probabilistic Bayesian approximation methods are established. Different cost measures are considered and algorithmic solutions in the various cases are devised and examined numerically. Simulation results are in full agreement with the theory. © 2007 The American Physical Society.

An evaluation of pharmacy education and pre-registration training

This thesis covers two major aspects of pharmacy education; undergraduate education and pre-registration training. A cohort of pharmacy graduates were surveyed over a period of four years, on issues related to undergraduate education, pre-registration training and continuing education. These graduates were the first-ever to sit the pre-registration examination. In addition, the opinions of pre-registration tutors were obtained on pre-registration training, during the year that competence-based assessment was introduced. It was concluded that although the undergraduate course provided a broad base of knowledge suitable for graduates in all branches of pharmacy, several issues were identified which would require attention in future developments of the course. These were: 1. the strong support for the expansion of clinical, social and practice-based teaching. 2. the strong support to retain the scientific content to the same extent as in the three-year course. 3. a greater use of problem-based learning methods. The graduates supported the provision of a pre-registration continuing education course to help prepare for the examination and in areas inadequately covered in the undergraduate course. There was also support for the introduction of some form of split branch training. There was no strong evidence to suggest that the training had been an application of undergraduate education. In general, competence-based training was well regarded by tutors as an appropriate and effective method of skill assessment. However, community tutors felt it was difficult to carry out effectively due to day-to-day time constraints. The assistant tutors in hospital pharmacy were found to have a very important role in provision of training, and should be adequately trained and supported. The study recommends the introduction of uniform training and a quality assurance mechanism for all tutors and assistants undertaking this role.

The analysis and prediction of the quantity and composition of household refuse

This thesis describes the development of a simple and accurate method for estimating the quantity and composition of household waste arisings. The method is based on the fundamental tenet that waste arisings can be predicted from information on the demographic and socio-economic characteristics of households, thus reducing the need for the direct measurement of waste arisings to that necessary for the calibration of a prediction model. The aim of the research is twofold: firstly to investigate the generation of waste arisings at the household level, and secondly to devise a method for supplying information on waste arisings to meet the needs of waste collection and disposal authorities, policy makers at both national and European level and the manufacturers of plant and equipment for waste sorting and treatment. The research was carried out in three phases: theoretical, empirical and analytical. In the theoretical phase specific testable hypotheses were formulated concerning the process of waste generation at the household level. The empirical phase of the research involved an initial questionnaire survey of 1277 households to obtain data on their socio-economic characteristics, and the subsequent sorting of waste arisings from each of the households surveyed. The analytical phase was divided between (a) the testing of the research hypotheses by matching each household's waste against its demographic/socioeconomic characteristics (b) the development of statistical models capable of predicting the waste arisings from an individual household and (c) the development of a practical method for obtaining area-based estimates of waste arisings using readily available data from the national census. The latter method was found to represent a substantial improvement over conventional methods of waste estimation in terms of both accuracy and spatial flexibility. The research therefore represents a substantial contribution both to scientific knowledge of the process of household waste generation, and to the practical management of waste arisings.

Study of the deposition, properties and applications of electroless deposits containing particles

The deposition efficiencies of a number of electroless nickel and cobalt plating solutions were studied and in the case of nickel compared with a commercial plating solution Nifoss 80. At the optimum plating conditions (92ºC and pH 4.5) Nifoss 80 produced nickel layers most efficiently, the alkaline cobalt solution operated most efficiently at 90ºC and pH 9. The methods of producing compostte layers containing 2-3 µm carbide particles and chromium powder is described. Nickel and cobalt layers containing approximately 27% carbide particles, or 40% (Ni) and 30% (Co) chromium particles by volume were obtained. This value is independent of the particle concentration in the plating solution within the range (20~200 g/l). Hardness of the nickel. as deposited was 515 Hv, this was increased to a maximum of 1155 Hv by heat treatment at 200ºC for 5 hours in vacuum. Incorporation. of .chromium carbide particles resulted in a maximum hardness of 1225 Hv after heating at 500ºC for 5 hours in vacuum and chromium particles resulted in a maximum hardness of 16S0 Hv after heat treatment at 400ºC for 2 hours in vacuum. Similarly the hardness of cobalt as deposited was 600 Hv, this was increased to a maximum of 1300 Hv after heat treatment at 400ºC for 1 hour. Incorporation of chromium carbide particles resulted jn a maximum hardness of 1405 Hv after heating at 400ºC for 5 hours in vacuum and chromium particles resulted in a maximum hardness of 1440 Hv after. heat treating for 2 hours at 400ºC in vacuum. The structure of the deposits was studied by optical and scanning electron microscopy. The wear rate and coefficient of friction was determined by a pin and disc method. Wear rate and coefficient of friction decreased with increase in hardness. The wear resistance of the materials was also determined using a simulated forging test. Dies made of standard die steel were coated and the wear rates of the layers as deposited and after heat treatment were compared with those of uncoated tools. The wear resistance generally increased with hardness, it was 50-75% more than the uncoated die steel. Acetic acid salt spray test and outdoor exposure for six months was used to study the corrosion behaviour of the deposits and potentiodynamic curves plotted to find their corrosion potential. Nickel deposit exhibited less staining than carbide composite deposits and nickel-chromium deposits had the most noble corrosion potential.

Immuno-potentiating activity of surfactant vesicles in DNA and subunit vaccination

Enhanced immune responses for DNA and subunit vaccines potentiated by surfactant vesicle based delivery systems outlined in the present study, provides proof of principle for the beneficial aspects of vesicle mediated vaccination. The dehydration-rehydration technique was used to entrap plasmid DNA or subunit antigens into lipid-based (liposomes) or non-ionic surfactant-based (niosomes) dehydration-rehydration vesicles (DRV). Using this procedure, it was shown that both these types of antigens can be effectively entrapped in DRV liposomes and DRV niosomes. The vesicle size of DRV niosomes was shown to be twice the diameter (~2µm) of that of their liposome counterparts. Incorporation of cryoprotectants such as sucrose in the DRV procedure resulted in reduced vesicle sizes while retaining high DNA incorporation efficiency (~95%). Transfection studies in COS 7 cells demonstrated that the choice of cationic lipid, the helper lipid, and the method of preparation, all influenced transfection efficiency indicating a strong interdependency of these factors. This phenomenon has been further reinforced when 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE): cholesteryl 3b- [N-(N’ ,N’ -dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol)/DNA complexes were supplemented with non-ionic surfactants. Morphological analysis of these complexes using transmission electron microscopy and environmental scanning electron microscopy (ESEM) revealed the presence of heterogeneous structures which may be essential for an efficient transfection in addition to the fusogenic properties of DOPE. In vivo evaluation of these DNA incorporated vesicle systems in BALB/c mice showed weak antibody and cell-mediated immune (CMI) responses. Subsequent mock challenge with hepatitis B antigen demonstrated that, 1-monopalmitoyl glycerol (MP) based DRV, is a more promising DNA vaccine adjuvant. Studying these DRV systems as adjuvants for the Hepatitis B subunit antigen (HBsAg) revealed a balanced antibody/CMI response profile on the basis of the HBsAg specific antibody and cytokine responses which were higher than unadjuvated antigen. The effect of addition of MP, cholesterol and trehalose 6,6’-dibehenate (TDB) on the stability and immuno-efficacy of dimethyldioctadecylammonium bromide (DDA) vesicles was investigated. Differential scanning calorimetry showed a reduction in transition temperature of DDA vesicles by ~12°C when incorporated with surfactants. ESEM of MP based DRV system indicated an increased vesicle stability upon incorporation of antigen. Adjuvant activity of these systems tested in C57BL/6j mice against three subunit antigens i.e., mycobacterial fusion protein- Ag85B-ESAT-6, and two malarial antigens - merozoite surface protein-1, (MSP1), and glutamate rich protein, (GLURP) revealed that while MP and DDA based systems induced comparable antibody responses, DDA based systems induced powerful CMI responses.

Evaluation and development of drainage and pipeline construction processes

In 1974 Dr D M Bramwell published his research work at the University of Aston a part of which was the establishment of an elemental work study data base covering drainage construction. The Transport and Road Research Laboratory decided to, extend that work as part of their continuing research programme into the design and construction of buried pipelines by placing a research contract with Bryant Construction. This research may be considered under two broad categories. In the first, site studies were undertaken to validate and extend the data base. The studies showed good agreement with the existing data with the exception of the excavation trench shoring and pipelaying data which was amended to incorporate new construction plant and methods. An inter-active on-line computer system for drainage estimating was developed. This system stores the elemental data, synthesizes the standard time of each drainage operation and is used to determine the required resources and construction method of the total drainage activity. The remainder of the research was into the general topic of construction efficiency. An on-line command driven computer system was produced. This system uses a stochastic simulation technique, based on distributions of site efficiency measurements to evaluate the effects of varying performance levels. The analysis of this performance data quantities the variability inherent in construction and demonstrates how some of this variability can be reconciled by considering the characteristics of a contract. A long term trend of decreasing efficiency with contract duration was also identified. The results obtained from the simulation suite were compared to site records collected from current contracts. This showed that this approach will give comparable answers, but these are greatly affected by the site performance parameters.

Efficacy and toxicity of biocides used in handling sterile pharmaceuticals

This thesis has sought to investigate disinfection agents and procedures which may provide sanitisation against bacterial spores. A hard-surface disinfection test method was designed to ascertain which combinations of biocide and application method were most effective against bacterial spores. A combination of spraying and wiping was the most effective method of disinfection against Bacillus spores, with wiping found to play a key role in spore removal. The most efficacious of the biocides investigated was the 6% hydrogen peroxide. Vaporised Hydrogen Peroxide (VHP) gassing was more effective than traditional disinfection. In addition to efficacy, the toxic potential of the biocides to human airway epithelial cells in vitro was evaluated. Toxicity against human bronchial and nasal epithelial cells was assessed by determining cell viability, inflammatory status, protein oxidation and epithelial cell layer integrity. In addition the cell death mechanism following biocide exposure was investigated. There was a decrease in viable cells following exposure to all biocides when applied at practical concentrations. Almost all of the biocides tested elicited a pro-inflammatory response from the cells as measured by IL-8 production. All biocides increased protein oxidation as measured by thiol and carbonyl levels. Measurement of transepithelial electrical resistance and paracellular permeability indicated biocide-dependent decrease in epithelial cell barrier function. The cellular response was biased towards necrotic rather than apoptotic death. The use of biocides, although efficacious to some effects against Bacillus spores, will require careful monitoring for adverse health effects on personnel.

A quantitative analysis of optic nerve axons in elderly control subjects and patients with Alzheimer's disease

Objective: To study the density and cross-sectional area of axons in the optic nerve in elderly control subjects and in cases of Alzheimer's disease (AD) using an image analysis system. Methods: Sections of optic nerves from control and AD patients were stained with toluidine blue to reveal axon profiles. Results: The density of axons was reduced in both the center and peripheral portions of the optic nerve in AD compared with control patients. Analysis of axons with different cross-sectional areas suggested a specific loss of the smaller sized axons in AD, i.e., those with areas less that 1.99 μm2. An analysis of axons >11 μm2 in cross-sectional area suggested no specific loss of the larger axons in this group of patients. Conclusions: The data suggest that image analysis provides an accurate and reproducible method of quantifying axons in the optic nerve. In addition, the data suggest that axons are lost throughout the optic nerve with a specific loss of the smaller-sized axons. Loss of the smaller axons may explain the deficits in color vision observed in a significant proportion of patients with AD.

A method of fundamental solutions for transient heat conduction

In this paper we investigate an application of the method of fundamental solutions (MFS) to transient heat conduction. In almost all of the previously proposed MFS for time-dependent heat conduction the fictitious sources are located outside the time-interval of interest. In our case, however, these sources are instead placed outside the space domain of interest in the same manner as is done for stationary heat conduction. A denseness result for this method is discussed and the method is numerically tested showing that accurate numerical results can be obtained. Furthermore, a test example with boundary singularities shows that it is advisable to remove such singularities before applying the MFS.

Radiolabelling of antigen and liposomes for vaccine biodistribution studies

A relatively simple and effective method to follow the movement of pharmaceutical preparations such as vaccines in biodistribution studies is to radiolabel the components. Whilst single radiolabelling is common practice, in vaccine systems containing adjuvants the ability to follow both the adjuvant and the antigen is favourable. To this end, we have devised a dual-radiolabelling method whereby the adjuvant (liposomes) is labelled with 3H and the antigen (a subunit protein) with 125I. This model is stable and reproducible; we have shown release of the radiolabels to be negligible over periods of up to 1 week in foetal calf serum at 37° C. In this paper we describe the techniques which enable the radiolabelling of various components, assessing stability and processing of samples which all for their application in biodistribution studies. Furthermore we provide examples derived from our studies using this model in tuberculosis vaccine biodistribution studies. © 2010 by the authors.

Expanding the evidence within evidence-based healthcare:thinking about the context, acceptability and feasibility of interventions

Evidence-based medicine is crucial to contemporary healthcare. It is dependent on systematic review methodology modelled on an arguably inadequate hierarchy of evidence. There has been a significant increase in medical and health research using qualitative and mixed method designs. The perspective taken in this article is that we need to broaden our evidence base if we are to fully take account of issues of context, acceptability and feasibility in the development and implementation of healthcare interventions. One way of doing this is to use a range of methods that better fit the different aspects of intervention development and implementation. Methods for the systematic review of evidence, other than randomised-controlled trials, are available and there is a readiness to incorporate these other types of evidence into good-practice guidance, but we need a clear methodology to translate these advances in research into the world of policy.

Spillovers from foreign direct investment in Central and Eastern Europe:an index for measuring a country’s potential to benefit from technology spillovers

In the paper, we construct a composite indicator to estimate the potential of four Central and Eastern European countries (the Czech Republic, Hungary, Poland and Slovakia) to benefit from productivity spillovers from foreign direct investment (FDI) in the manufacturing sector. Such transfers of technology are one of the main benefits of FDI for the host country, and should also be one of the main determinants of FDI incentives offered to investing multinationals by governments, but they are difficult to assess ex ante. For our composite index, we use six components to proxy the main channels and determinants of these spillovers. We have tried several weighting and aggregation methods, and we consider our results robust. According to the analysis of our results, between 2003 and 2007 all four countries were able to increase their potential to benefit from such spillovers, although there are large differences between them. The Czech Republic clearly has the most potential to benefit from productivity spillovers, while Poland has the least. The relative positions of Hungary and Slovakia depend to some extent on the exact weighting and aggregation method of the individual components of the index, but the differences are not large. These conclusions have important implications both the investment strategies of multinationals and government FDI policies.

Method of Elimination Data Sources Conflicts in Information System

Use of modern object-oriented methods of designing of information systems (IS) both descriptions of interrelations IS and automated with its help business-processes of the enterprises leads to necessity of construction uniform complete IS on the basis of set of local models of such system. As a result of use of such approach there are the contradictions caused by inconsistency of actions of separate developers IS with each other and that is much more important, inconsistency of the points of view of separate users IS. Besides similar contradictions arise while in service IS at the enterprise because of constant change separate business- processes of the enterprise. It is necessary to note also, that now overwhelming majority IS is developed and maintained as set of separate functional modules. Each of such modules can function as independent IS. However the problem of integration of separate functional modules in uniform system can lead to a lot of problems. Among these problems it is possible to specify, for example, presence in modules of functions which are not used by the enterprise to destination, to complexity of information and program integration of modules of various manufacturers, etc. In most cases these contradictions and the reasons, their caused, are consequence of primary representation IS as equilibrium steady system. In work [1] representation IS as dynamic multistable system which is capable to carry out following actions has been considered:

An analysis of police interview discourse and its role(s) in the judicial process

This study analyses the current role of police-suspect interview discourse in the England & Wales criminal justice system, with a focus on its use as evidence. A central premise is that the interview should be viewed not as an isolated and self-contained discursive event, but as one link in a chain of events which together constitute the criminal justice process. It examines: (1) the format changes undergone by interview data after the interview has taken place, and (2) how the other links in the chain – both before and after the interview – affect the interview-room interaction itself. It thus examines the police interview as a multi-format, multi-purpose and multi-audience mode of discourse. An interdisciplinary and multi-method discourse-analytic approach is taken, combining elements of conversation analysis, pragmatics, sociolinguistics and critical discourse analysis. Data from a new corpus of recent police-suspect interviews, collected for this study, are used to illustrate previously unaddressed problems with the current process, mainly in the form of two detailed case studies. Additional data are taken from the case of Dr. Harold Shipman. The analysis reveals several causes for concern, both in aspects of the interaction in the interview room, and in the subsequent treatment of interview material as evidence, especially in the light of s.34 of the Criminal Justice and Public Order Act 1994. The implications of the findings for criminal justice are considered, along with some practical recommendations for improvements. Overall, this study demonstrates the need for increased awareness within the criminal justice system of the many linguistic factors affecting interview evidence.