Hypothesis: is Alzheimer's disease a metal-induced immune disorder?

A hypothesis that a metal-induced immune disorder may be involved in the pathogenesis of some forms of Alzheimer's disease (AD) is presented. The classical complement pathway is activated in AD and T cells and reactive microglia appear in the brain. Studies of metal induced autoimmunity and the use of compounds containing aluminium as vaccine adjuvants suggest that metals can activate complement and can be taken up by antigen presenting cells. The consequent immune response could contribute to neuronal damage, beta-amyloid deposition and cell death. The strengths and weaknesses of this hypothesis are discussed and tests of some aspects are proposed.

The reponse of lichen growth to transplantation to rock surfaces of different aspect

Thalli of four saxicolous lichens on slate rock fragments were transplanted from rock surafces to horizontal boards and then to south-east-facing and north-west-facing rock surfaces. The radial growth rate of Physcia orbicularis and Parmelia conspersa thalli declined after transplatation to north-west-facing rock surfaces and was unchanged after transplantation to south-east-facing rock surfaces cmpared with growth rates on the boards. The radial growth rate of P. glabratula ssp. fuliginosa thalli declined after transplantation to south-east-facing rock surfaces and was unchanged after transplantation to north-west-facing rock surfaces compared with grwoth rate on the boards. The radial growth rate of P. saxatilis thalli was similar on the horizontal boards, south-east-facing and north-west-facing rock surfaces. These results are dsicussed in relation to the aspect distribution of the four lichens in South Gwynedd, Wales.

The influence of aspect on the pattern of saesonal growth in the lichen Parmelia glabratula ssp. fuliginosa (Fr. ex Duby) Laund

The radial growth of samples of thalli of Parmelia glabratula ssp. fuliginosa were measured in situ on a south-facing and a northwest-facing rock surface each month from August 1973 to July 1974. In the periods August to October 1973 and March to July 1974 the radial growth of thalli in the northwest population was greater than in the south population. In the period November 1973 to February 1974 the radial growth of thalli in the south population was greater than in the northwest population. A physiological basis for the differences in seasonal growth in the two populations was suggested. The mean annual radial growth rate (in units of mm/year) was not significantly different in the two populations. However, the variability in radial growth rate between thalli was signifiacntly larger in the northwest than in the south population. These results may be explained by genetic difference between the populations and environmental differences between the rock surfaces.

Data analysis methods in optometry Part 7: multiple linear regression

Multiple regression analysis is a complex statistical method with many potential uses. It has also become one of the most abused of all statistical procedures since anyone with a data base and suitable software can carry it out. An investigator should always have a clear hypothesis in mind before carrying out such a procedure and knowledge of the limitations of each aspect of the analysis. In addition, multiple regression is probably best used in an exploratory context, identifying variables that might profitably be examined by more detailed studies. Where there are many variables potentially influencing Y, they are likely to be intercorrelated and to account for relatively small amounts of the variance. Any analysis in which R squared is less than 50% should be suspect as probably not indicating the presence of significant variables. A further problem relates to sample size. It is often stated that the number of subjects or patients must be at least 5-10 times the number of variables included in the study.5 This advice should be taken only as a rough guide but it does indicate that the variables included should be selected with great care as inclusion of an obviously unimportant variable may have a significant impact on the sample size required.

The 'hard problem' and the quantum physicists. Part 2: modern times

This is the second part of a review of the work of quantum physicists on the ‘hard part’ of the problem of mind. After an introduction which sets the scene and a brief review of contemporary work on the neural correlates of consciousness (NCC) the work of four prominent modern investigators is examined: J.C. Eccles/Friedrich Beck; Henry Stapp; Stuart Hameroff/Roger Penrose; David Bohm. With the exception of David Bohm, all attempt to show where in the brain’s microstructure quantum affects could make themselves felt. It is reluctantly concluded that none have neurobiological plausibility. They are all instances, to paraphrase T.H. Huxley, of a beautiful hypothesis destroyed by ugly facts. David Bohm does not attempt to fit his new quantum physics to contemporary neurobiology but instead asks for a radical rethink of our conventional scientific paradigm. He suggests that we should look towards developing a ‘pan-experientialism’ or ‘dual-aspect monism’ where consciousness goes ‘all the way down’ and that the ‘hard problem’ is not soluble within the framework of ideas provided by ‘classical’ natural science.

Interlanguage variability in verb tense/aspect

This thesis presents a study of interlanguage variability in the use of three tense/aspect forms: the simple present, simple past, and the present perfect. The need for research in this area comes from the problems encountered in the classroom. Language performance in one task sometimes does not reflect that in another. How and why this ocurrs is what this thesis aims to discover. A preliminary study explores the viability of using the Labovian variable model to elicit and explain variability. Difficulties highlight problems which help refine the methodology used in the main study. A review of past research point the direction in which this study should go. Armed with a sample of 17 Chinese Singaporean university students, whose first language is Chinese or a dialect of Chinese, the investigation began with the elicitation of variability to be found in four tasks. Using the attention-to-speech framework, these four tasks are designed to reflect varying degrees of required attention to language form. The results show that there is variability in the use of tense/aspect in all the tasks. However, the framework on which the tasks are based cannot explain the variability pattern. Further analyses of contextual factors, primarily pragmatic ones, point to a complex interplay of factors affecting the variability found in the results.

The pathogenesis of Alzheimer's disease: a reevaluation of the "amyloid cascade hypothesis"

The most influential theory to explain the pathogenesis of Alzheimer's disease (AD) has been the "Amyloid Cascade Hypothesis" (ACH) first formulated in 1992. The ACH proposes that the deposition of ß-amyloid (Aß) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs) death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1) is there a relationship between the pathogenesis of SPs and NFTs, and (2) what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.

Self-assembly of trehalose molecules on a lysozyme surface: the broken glass hypothesis

To help understand how sugar interactions with proteins stabilise biomolecular structures, we compare the three main hypotheses for the phenomenon with the results of long molecular dynamics simulations on lysozyme in aqueous trehalose solution (0.75 M). We show that the water replacement and water entrapment hypotheses need not be mutually exclusive, because the trehalose molecules assemble in distinctive clusters on the surface of the protein. The flexibility of the protein backbone is reduced under the sugar patches supporting earlier findings that link reduced flexibility of the protein with its higher stability. The results explain the apparent contradiction between different experimental and theoretical results for trehalose effects on proteins.

Fabrication of high aspect ratio microfluidic devices using direct FS ablation

We present a single stage direct fs ablation results which show that it is possible to make high quality and high aspect ratio devices in a single stage process using a CAD optimised approach.

Further studies on the patterns of senile plaques in senile dementia of the Alzheimer type (SDAT) with a hypothesis on the colonization of the cortex

The pattern of senile plaques was investigated in various brain regions of six SDAT brains. In 91 pattern analyses, the regularly spaced clump was the most common pattern found in 64.8% of analyses. Clumping due to large aggregations of uncored plaques in sulci was also common. Regularly spaced clumps were equally common in the hippocampus and neocortex. The pattern of plaques varied in different tissue sections from the same brain region. Cored and uncored plaques presented a similar range of patterns but their pattern varied when they were both present in the same tissue section. Both clump diameter and the intensity of clumping were positively correlated with cored but unrelated to uncored plaque density. Plaques may develop in regular clumps on subcortical afferents and during development of the disease the clumps may spread laterally and ultimately coalesce.

The spatial patterns of plaques and tangles in Alzheimer's disease do not support the 'cascade hypothesis'

In Alzheimer's disease (AD), the 'Cascade hypothesis' proposes that the formation of paired helical filaments (PHF) may be casually linked to the deposition of beta/A4 protein. Hence, there should be a close spatial relationship between senile plaques and cellular neurofibrillary tangles in a local region of the brain. In tissue from 6 AD patients, plaques and tangles occurred in clusters and individual clusters were often regularly spaced along the cortical strip. However, the clusters of plaques and tangles were in phase in only 4/32 cortical tissues examined. Hence, the data were not consistent with the 'Cascade hypothesis' that beta/A4 and PHF are directly linked in AD.

Effect of aspect ratio on thermal convection in open and closed systems

Internally heated fluids are found across the nuclear fuel cycle. In certain situations the motion of the fluid is driven by the decay heat (i.e. corium melt pools in severe accidents, the shutdown of liquid metal reactors, molten salt and the passive control of light water reactors) as well as normal operation (i.e. intermediate waste storage and generation IV reactor designs). This can in the long-term affect reactor vessel integrity or lead to localized hot spots and accumulation of solid wastes that may prompt local increases in activity. Two approaches to the modeling of internally heated convection are presented here. These are based on numerical analysis using codes developed in-house and simulations using widely available computational fluid dynamics solvers. Open and closed fluid layers at around the transition between conduction and convection of various aspect ratios are considered. We determine optimum domain aspect ratio (1:7:7 up to 1:24:24 for open systems and 5:5:1, 1:10:10 and 1:20:20 for closed systems), mesh resolutions and turbulence models required to accurately and efficiently capture the convection structures that evolve when perturbing the conductive state of the fluid layer. Note that the open and closed fluid layers we study here are bounded by a conducting surface over an insulating surface. Conclusions will be drawn on the influence of the periodic boundary conditions on the flow patterns observed. We have also examined the stability of the nonlinear solutions that we found with the aim of identifying the bifurcation sequence of these solutions en route to turbulence.