A critical analysis of the 'amyloid cascade hypothesis'

The 'amyloid cascade hypothesis' (ACH) is the most influential model of the pathogenesis of Alzheimer's disease (AD). The hypothesis proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD, leading to the formation of extracellular senile plaques (SP), tau-immunoreactive neurofibrillary tangles (NFT), neuronal loss, and ultimately, clinical dementia. Ever since the formulation of the ACH, however, there have been questions regarding whether it completely describes AD pathogenesis. This review critically examines various aspects of the ACH including its origin and development, the role of amyloid precursor protein (APP), whether SP and NFT are related to the development of clinical dementia, whether Aβ and tau are 'reactive' proteins, and whether there is a pathogenic relationship between SP and NFT. The results of transgenic experiments and treatments for AD designed on the basis of the ACH are also reviewed. It was concluded: (1) Aβ and tau could be the products rather than the cause of neuro-degeneration in AD, (2) it is doubtful whether there is a direct causal link between Aβ and tau, and (3) SP and NFT may not be directly related to the development of dementia, (4) transgenic models involving APP alone do not completely replicate AD pathology, and (5) treatments based on the ACH have been unsuccessful. Hence, a modification of the ACH is proposed which may provide a more complete explanation of the pathogenesis of AD.

The value of risk reporting:a critical analysis of value-at-risk disclosures in the banking sector

This paper critically reviews the evolution of financial reporting in the banking sector with specific reference to the reporting of market risk and the growing use of the measure known as Value at Risk (VaR). The paper investigates the process by which VaR became 'institutionalised'. The analysis highlights a number of inherent limitations of VaR as a risk measure and questions the usefulness of published VaR disclosures, concluding that risk 'disclosure' might be more apparent than real. It also looks at some of the implications for risk reporting practice and the accounting profession more generally.

A critical assessment of the finite element method for calculating electric and magnetic fields

The present dissertation is concerned with the determination of the magnetic field distribution in ma[.rnetic electron lenses by means of the finite element method. In the differential form of this method a Poisson type equation is solved by numerical methods over a finite boundary. Previous methods of adapting this procedure to the requirements of digital computers have restricted its use to computers of extremely large core size. It is shown that by reformulating the boundary conditions, a considerable reduction in core store can be achieved for a given accuracy of field distribution. The magnetic field distribution of a lens may also be calculated by the integral form of the finite element rnethod. This eliminates boundary problems mentioned but introduces other difficulties. After a careful analysis of both methods it has proved possible to combine the advantages of both in a .new approach to the problem which may be called the 'differential-integral' finite element method. The application of this method to the determination of the magnetic field distribution of some new types of magnetic lenses is described. In the course of the work considerable re-programming of standard programs was necessary in order to reduce the core store requirements to a minimum.

An analysis of the effect of process parameters on the formability of sheet metal

This investigation is in two parts, theory and experimental verification. (1) Theoretical Study In this study it is, for obvious reasons, necessary to analyse the concept of formability first. For the purpose of the present investigation it is sufficient to define the four aspects of formability as follows: (a) the formability of the material at a critical section, (b) the formability of the material in general, (c) process efficiency, (d) proportional increase in surface area. A method of quantitative assessment is proposed for each of the four aspects of formability. The theoretical study also includes the distinction between coaxial and non-coaxial strains which occur, respectively, in axisymmetrical and unsymmetrical forming processes and the inadequacy of the circular grid system for the assessment of formability is explained in the light of this distinction. (2) Experimental Study As one of the bases of the experimental work, the determination of the end point of a forming process, which sets the limit to the formability of the work material, is discussed. The effects of three process parameters on draw-in are shown graphically. Then the delay of fracture in sheet metal forming resulting from draw-in is analysed in kinematical terms, namely, through the radial displacements, the radial and the circumferential strains, and the projected thickness of the workpiece. Through the equilibrium equation of the membrane stresses, the effect on the shape of the unsupported region of the workpiece, and hence the position of the critical section is explained. Then, the effect of draw-in on the four aspects of formability is discussed throughout this investigation. The triangular coordinate system is used to present and analyse the triaxial strains involved. This coordinate system has the advantage of showing all the three principal strains in a material simultaneously, as well as representing clearly the many types of strains involved in sheet metal work.

An analysis of the role of soft systems methodology in the change process and the contribution of the facilitator within this process

This research aims to examine the effectiveness of Soft Systems Methodology (SSM) to enable systemic change within local goverment and local NHS environments and to examine the role of the facilitator within this process. Checkland's Mode 2 variant of Soft Systems Methodology was applied on an experimental basis in two environments, Herefordshire Health Authority and Sand well Health Authority. The Herefordshire application used SSM in the design of an Integrated Care Pathway for stroke patients. In Sandwell, SSM was deployed to assist in the design of an Infonnation Management and Technology (IM&T) Strategy for the boundary-spanning Sandwell Partnership. Both of these environments were experiencing significant organisational change as the experiments unfurled. The explicit objectives of the research were: To examine the evolution and development of SSM and to contribute to its further development. To apply the Soft Systems Methodology to change processes within the NHS. To evaluate the potential role of SSM in this wider process of change. To assess the role of the researcher as a facilitator within this process. To develop a critical framework through which the impact of SSM on change might be understood and assessed. In developing these objectives, it became apparent that there was a gap in knowledge relating to SSM. This gap concerns the evaluation of the role of the approach in the change process. The case studies highlighted issues in stakeholder selection and management; the communicative assumptions in SSM; the ambiguous role of the facilitator; and the impact of highly politicised problem environments on the effectiveness of the methodology in the process of change. An augmented variant on SSM that integrates an appropriate (social constructivist) evaluation method is outlined, together with a series of hypotheses about the operationalisation of this proposed method.

The single-phase induction motor:a critical appraisal of the rotating-field and cross-field theories with particular reference to skin effect

The purpose of this thesis is twofold: to examine the validity of the rotating-field and cross-field theories of the single-phase induction motor when applied to a cage rotor machine; and to examine the extent to which skin effect is likely to modify the characteristics of a cage rotor machine. A mathematical analysis is presented for a single-phase induction motor in which the rotor parameters are modified by skin effect. Although this is based on the usual type of ideal machine, a new form of model rotor allows approximations for skin effect phenomena to be included as an integral part of the analysis. Performance equations appropriate to the rotating-field and cross-field theories are deduced, and the corresponding explanations for the steady-state mode of operation are critically examined. The evaluation of the winding currents and developed torque is simplified by the introduction of new dimensionless factors which are functions of the resistance/reactance ratios of the rotor and the speed. Tables of the factors are included for selected numerical values of the parameter ratios, and these are used to deduce typical operating characteristics for both cage and wound rotor machines. It is shown that a qualitative explanation of the mode of operation of a cage rotor machine is obtained from either theory; but the operating characteristics must be deduced from the performance equations of the rotating-field theory, because of the restrictions on the values of the rotor parameters imposed by skin effect.

A critical evaluation of the volume, relevance and quality of evidence submitted by the tobacco industry to oppose standardised packaging of tobacco products

OBJECTIVES: To examine the volume, relevance and quality of transnational tobacco corporations' (TTCs) evidence that standardised packaging of tobacco products 'won't work', following the UK government's decision to 'wait and see' until further evidence is available. DESIGN: Content analysis. SETTING: We analysed the evidence cited in submissions by the UK's four largest TTCs to the UK Department of Health consultation on standardised packaging in 2012. OUTCOME MEASURES: The volume, relevance (subject matter) and quality (as measured by independence from industry and peer-review) of evidence cited by TTCs was compared with evidence from a systematic review of standardised packaging . Fisher's exact test was used to assess differences in the quality of TTC and systematic review evidence. 100% of the data were second-coded to validate the findings: 94.7% intercoder reliability; all differences were resolved. RESULTS: 77/143 pieces of TTC-cited evidence were used to promote their claim that standardised packaging 'won't work'. Of these, just 17/77 addressed standardised packaging: 14 were industry connected and none were published in peer-reviewed journals. Comparison of TTC and systematic review evidence on standardised packaging showed that the industry evidence was of significantly lower quality in terms of tobacco industry connections and peer-review (p<0.0001). The most relevant TTC evidence (on standardised packaging or packaging generally, n=26) was of significantly lower quality (p<0.0001) than the least relevant (on other topics, n=51). Across the dataset, TTC-connected evidence was significantly less likely to be published in a peer-reviewed journal (p=0.0045). CONCLUSIONS: With few exceptions, evidence cited by TTCs to promote their claim that standardised packaging 'won't work' lacks either policy relevance or key indicators of quality. Policymakers could use these three criteria-subject matter, independence and peer-review status-to critically assess evidence submitted to them by corporate interests via Better Regulation processes.