Is there a spatial association between senile plaques and neurofibrillary tangles in Alzheimer's disease?

Objective: To test the hypothesis that the clusters of senile plaques (SP) and neurofibrillary tangles (NFT) in patients with Alzheimer's disease (AD) are spatially associated as predicted by the 'Amyloid Cascade Hypothesis'. Methods: The spatial association between the SP and NFT was studied in the cerebral cortex and hippocampus in six cases of sporadic Alzheimer's disease (AD) using contingency tables. The coefficient C7 was used as an index of spatial association while chi-square with correction for continuity was used as a test of significance. Results: In the brain regions analysed, values of C7 were in the range -0.31 to +0.32 but a statistically significant spatial association between SP and NFT was present in only 8/39 (21%) regions. The degree of spatial association between the SP and NFT was similar in dfferent brain regions and did not vary with apolipoprotein ε genotype of the patient. However, the magnitude of C7 in a region was positively correlated with the density of the NFT and with the total density of SP and NFT but not with the density of SP alone. Conclusion: There was little evidence that SP and NFT were spatially associated except in brain areas with high densities of lesions. The data support the hypothesis that SP and NFT are distributed relatively independently in the cerebral cortex and hippocampus and therefore, could be distinct phenomena in AD.

An online assessment and development tool for business incubators:optimising business-incubation management practice, performance and impact, Project Report

This project is focused on exchanging knowledge between ABS, UKBI and managers of business incubators in the UK. The project relates to exploitation of extant knowledge-base on assessing and improving business incubation management practice and performance and builds on two earlier studies. It addresses a pressing need for assessing and benchmarking business incubation input, process and outcome performance and highlighting best practice. The overarching aim of this project was to obtain proof-of-concept for a business incubation performance assessment and benchmarking online tool, fine-tune it and put it in use by nurturing a community of business incubation management practice, aligned by the resultant tool. The purpose was to offer an appropriate set of measures, in areas identified by relevant research on business incubation performance management and impact as critical, against which: 1.The input and process performance of business incubation management practice can be assessed and benchmarked within the auspices of a community of incubator managers concerned with best practice 2.The outcome performance and impact of business incubators can be assessed longitudinally. As such, the developed online assessment framework is geared towards the needs of researchers, policy makers and practitioners concerned with business incubation performance, added value and impact.

Autochthonous heritage languages and social media:writing and bilingual practices in Low German on Facebook

This article analyses how speakers of an autochthonous heritage language (AHL) make use of digital media, through the example of Low German, a regional language used by a decreasing number of speakers mainly in northern Germany. The focus of the analysis is on Web 2.0 and its interactive potential for individual speakers. The study therefore examines linguistic practices on the social network site Facebook, with special emphasis on language choice, bilingual practices and writing in the autochthonous heritage language. The findings suggest that social network sites such as Facebook have the potential to provide new mediatized spaces for speakers of an AHL that can instigate sociolinguistic change.

Low spatial frequencies are suppressively masked across spatial scale, orientation, field position, and eye of origin

Masking is said to occur when a mask stimulus interferes with the visibility of a target (test) stimulus. One widely held view of this process supposes interactions between mask and test mechanisms (cross-channel masking), and explicit models (e.g., J. M. Foley, 1994) have proposed that the interactions are inhibitory. Unlike a within-channel model, where masking involves the combination of mask and test stimulus within a single mechanism, this cross-channel inhibitory model predicts that the mask should attenuate the perceived contrast of a test stimulus. Another possibility is that masking is due to an increase in noise, in which case, perception of contrast should be unaffected once the signal exceeds detection threshold. We use circular patches and annuli of sine-wave grating in contrast detection and contrast matching experiments to test these hypotheses and investigate interactions across spatial frequency, orientation, field position, and eye of origin. In both types of experiments we found substantial effects of masking that can occur over a factor of 3 in spatial frequency, 45° in orientation, across different field positions and between different eyes. We found the effects to be greatest at the lowest test spatial frequency we used (0.46 c/deg), and when the mask and test differed in all four dimensions simultaneously. This is surprising in light of previous work where it was concluded that suppression from the surround was strictly monocular (C. Chubb, G. Sperling, & J. A. Solomon, 1989). The results confirm that above detection threshold, cross-channel masking involves contrast suppression and not (purely) mask-induced noise. We conclude that cross-channel masking can be a powerful phenomenon, particularly at low test spatial frequencies and when mask and test are presented to different eyes. © 2004 ARVO.

Spatial distribution of diffuse, primitive, and classic amyloid-beta deposits and blood vessels in the upper laminae of the frontal cortex in Alzheimer disease

The spatial distribution of the diffuse, primitive, and classic amyloid-beta deposits was studied in the upper laminae of the superior frontal gyrus in cases of sporadic Alzheimer disease (AD). Amyloid-beta-stained tissue was counterstained with collagen IV to determine whether the spatial distribution of the amyloid-beta deposits along the cortex was related to blood vessels. In all patients, amyloid-beta deposits and blood vessels were aggregated into distinct clusters and in many patients, the clusters were distributed with a regular periodicity along the cortex. The clusters of diffuse and primitive deposits did not coincide with the clusters of blood vessels in most patients. However, the clusters of classic amyloid-beta deposits coincided with those of the large diameter (>10 microm) blood vessels in all patients and with clusters of small-diameter (< 10 microm) blood vessels in four patients. The data suggest that, of the amyloid-beta subtypes, the clusters of classic amyloid-beta deposits appear to be the most closely related to blood vessels and especially to the larger-diameter, vertically penetrating arterioles in the upper cortical laminae.

The relationship between the spatial pattern of senile plaques and neurofibrillary tangles in Alzheimer's disease

The topographic pattern of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in silver stained coronal sections of neocortex and hippocampus in ten cases of Alzheimer's disease (AD). Both lesions showed evidence of clustering in the tissue with many of the clusters being regularly spaced. The patterns of SP and NFT were compared 1) in the same cortical zone, 2) between upper and lower zones of the cortex and 3) in regions connected by either association fibres or the perforant path. Correlations between the lesions in the same cortical zone were found in 20% of the layers examined while correlations between upper and lower zones occurred in 64% of cortical regions examined. There was evidence that NFT in upper and lower cortex may be in register in some tissues. In addition, positive correlations were found between upper NFT and lower SP and negative correlations between upper SP and lower NFT in some tissues. Regular clustering of lesions was also observed in brain regions connected to one another suggesting that they develop on functinally related sets of neurons.

The effect of blending on selected physical properties of crude oils and their products

A study was made of the effect of blending practice upon selected physical properties of crude oils, and of various base oils and petroleum products, using a range of binary mixtures. The crudes comprised light, medium and heavy Kuwait crude oils. The properties included kinematic viscosity, pour point, boiling point and Reid vapour pressure. The literature related to the prediction of these properties, and the changes reported to occur on blending, was critically reviewed as a preliminary to the study. The kinematic viscosity of petroleum oils in general exhibited non-ideal behaviour upon blending. A mechanism was proposed for this behaviour which took into account the effect of asphaltenes content. A correlation was developed, as a modification of Grunberg's equation, to predict the viscosities of binary mixtures of petroleum oils. A correlation was also developed to predict the viscosities of ternary mixtures. This correlation showed better agreement with experimental data (< 6% deviation for crude oils and 2.0% for base oils) than currently-used methods, i.e. ASTM and Refutas methods. An investigation was made of the effect of temperature on the viscosities of crude oils and petroleum products at atmospheric pressure. The effect of pressure on the viscosity of crude oil was also studied. A correlation was developed to predict the viscosity at high pressures (up to 8000 psi), which gave significantly better agreement with the experimental data than the current method due to Kouzel (5.2% and 6.0% deviation for the binary and ternary mixtures respectively). Eyring's theory of viscous flow was critically investigated, and a modification was proposed which extends its application to petroleum oils. The effect of blending on the pour points of selected petroleum oils was studied together with the effect of wax formation and asphaltenes content. Depression of the pour point was always obtained with crude oil binary mixtures. A mechanism was proposed to explain the pour point behaviour of the different binary mixtures. The effects of blending on the boiling point ranges and Reid vapour pressures of binary mixtures of petroleum oils were investigated. The boiling point range exhibited ideal behaviour but the R.V.P. showed negative deviations from it in all cases. Molecular weights of these mixtures were ideal, but the densities and molar volumes were not. The stability of the various crude oil binary mixtures, in terms of viscosity, was studied over a temperature range of 1oC - 30oC for up to 12 weeks. Good stability was found in most cases.

The chemical structure and mechanical properties of phenolic resins and related polymers

Paper-based phenolic laminates are used extensively in the electrical industry. Many small components are fabricated from these materials by the process known as punching. Recently an investigation was carried out to study the effect of processing variables on the punching properties. It was concluded that further work would be justified and that this should include a critical examination of the resin properties in a more controlled and systematic manner. In this investigation an attempt has been made to assess certain features of the resin structure in terms of thermomechanical properties. The number of crosslinks in the system was controlled using resins based on phenol and para-cresol formulations. Intramolecular hydrogen bonding effects were examined using substituted resins and a synthetically derived phenol based on 1,3-di-(o-hydroxyphenyl) propane.. A resin system was developed using the Friedel Crafts reaction to examine inter-molecular hydrogen bonding at the resin-paper interface. The punching properties of certain selected resins were assessed on a qualitative basis. In addition flexural and dynamic mechanical properties were determined in a general study of the structure-property relationships of these materials. It has been shown that certain features of the resin structure significantly influenced mechanical properties. :F'urther, it was noted that there is a close relationship between punching properties, mechanical damping and flexural strain. This work includes a critical examination of the curing mechanism and views are postulated in an attempt to extend knowledge in this area of the work. Finally, it is argued that future work should be based on a synthetic approach and that dynamic mechanical testing would provide a powerful tool In developing a deeper understanding of the resin fine structure.

Evaluating and developing project-based learning:an empirical approach to evaluating CDIO

As a global profession, engineering is integral to the maintenance and further development of society. Indeed, contemporary social problems requiring engineering solutions are not only a consequence of natural and ‘manmade’ disasters (such as the Japanese earthquake or the oil leakage in the Gulf of Mexico) but also encapsulate 21st Century dilemmas around sustainability, poverty and pollution [2,6,7]. Given the complexity of such problems and the constant need for innovation, the demand for engineering education to provide a ready supply of suitably qualified engineering graduates, able to make innovative decisions has never been higher [3,5]. Bearing this in mind, and taking account problems of attrition in engineering education [1,6,4] innovation in the way in which the curriculum is developed and delivered is crucial. CDIO [Conceive, Design, Implement, Operate] provides a potentially ground-breaking solution to such dilemmas. Aimed at equipping students with practical engineering skills supported by the necessary theoretical background, CDIO could potentially change the way engineering is perceived and experienced within higher education. Aston University introduced CDIO into its Mechanical Engineering and Design programmes in October 2011. From its induction, engineering education researchers have ‘shadowed’ the staff responsible for developing and teaching the programme. Utilising an Action Research Design, and adopting a mixed methodological research design, the researchers have worked closely with the teaching team to critically reflect on the processes involved in introducing CDIO into the curriculum. Concurrently, research has been conducted to capture students’ perspectives of CDIO. In evaluating the introduction of CDIO at Aston, the researchers have developed a distinctive research strategy with which to evaluate CDIO. It is the emergent findings from this research that form the basis of this paper. Although early-on in its development CDIO is making a significant difference to engineering education at the University. The paper draws attention to pedagogical, practical and professional issues – discussing each one in turn and in doing so critically analysing the value of CDIO from academic, student and industrial perspectives. The paper concludes by noting that whilst CDIO represents a forwardthinking approach to engineering education, the need for constant innovation in learning and teaching should not be forgotten. Indeed, engineering education needs to put itself at the forefront of pedagogic practice. Providing all-rounded engineers, ready to take on the challenges of the 21st Century!

A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems

The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine whether a relevant in vitro model may aid the identification of anticholinergic responses to drugs and the prediction of anticholinergic risk during polypharmacy. In this preliminary study we employed a co-culture of human-derived neurons and astrocytes (NT2.N/A) derived from the NT2 cell line. NT2.N/A cells possess much of the functionality of mature neurons and astrocytes, key cholinergic phenotypic markers and muscarinic acetylcholine receptors (mAChRs). The cholinergic response of NT2 astrocytes to the mAChR agonist oxotremorine was examined using the fluorescent dye fluo-4 to quantitate increases in intracellular calcium [Ca2+]i. Inhibition of this response by drugs classified as severe (dicycloverine, amitriptyline), moderate (cyclobenzaprine) and possible (cimetidine) on the Anticholinergic Cognitive Burden (ACB) scale, was examined after exposure to individual and pairs of compounds. Individually, dicycloverine had the most significant effect regarding inhibition of the astrocytic cholinergic response to oxotremorine, followed by amitriptyline then cyclobenzaprine and cimetidine, in agreement with the ACB scale. In combination, dicycloverine with cyclobenzaprine had the most significant effect, followed by dicycloverine with amitriptyline. The order of potency of the drugs in combination frequently disagreed with predicted ACB scores derived from summation of the individual drug scores, suggesting current scales may underestimate the effect of polypharmacy. Overall, this NT2.N/A model may be appropriate for further investigation of adverse anticholinergic effects of multiple medications, in order to inform clinical choices of suitable drug use in the elderly.

A comparison of two distributed large-volume measurement systems:the mobile spatial co-ordinate measuring system and the indoor global positioning system

Advances in the area of industrial metrology have generated new technologies that are capable of measuring components with complex geometry and large dimensions. However, no standard or best-practice guides are available for the majority of such systems. Therefore, these new systems require appropriate testing and verification in order for the users to understand their full potential prior to their deployment in a real manufacturing environment. This is a crucial stage, especially when more than one system can be used for a specific measurement task. In this paper, two relatively new large-volume measurement systems, the mobile spatial co-ordinate measuring system (MScMS) and the indoor global positioning system (iGPS), are reviewed. These two systems utilize different technologies: the MScMS is based on ultrasound and radiofrequency signal transmission and the iGPS uses laser technology. Both systems have components with small dimensions that are distributed around the measuring area to form a network of sensors allowing rapid dimensional measurements to be performed in relation to large-size objects, with typical dimensions of several decametres. The portability, reconfigurability, and ease of installation make these systems attractive for many industries that manufacture large-scale products. In this paper, the major technical aspects of the two systems are briefly described and compared. Initial results of the tests performed to establish the repeatability and reproducibility of these systems are also presented. © IMechE 2009.

Across-formant integration and speech intelligibility:effects of acoustic source properties in the presence and absence of a contralateral interferer

The role of source properties in across-formant integration was explored using three-formant (F1+F2+F3) analogues of natural sentences (targets). In experiment 1, F1+F3 were harmonic analogues (H1+H3) generated using a monotonous buzz source and second-order resonators; in experiment 2, F1+F3 were tonal analogues (T1+T3). F2 could take either form (H2 or T2). Target formants were always presented monaurally; the receiving ear was assigned randomly on each trial. In some conditions, only the target was present; in others, a competitor for F2 (F2C) was presented contralaterally. Buzz-excited or tonal competitors were created using the time-reversed frequency and amplitude contours of F2. Listeners must reject F2C to optimize keyword recognition. Whether or not a competitor was present, there was no effect of source mismatch between F1+F3 and F2. The impact of adding F2C was modest when it was tonal but large when it was harmonic, irrespective of whether F2C matched F1+F3. This pattern was maintained when harmonic and tonal counterparts were loudness-matched (experiment 3). Source type and competition, rather than acoustic similarity, governed the phonetic contribution of a formant. Contrary to earlier research using dichotic targets, requiring across-ear integration to optimize intelligibility, H2C was an equally effective informational masker for H2 as for T2.

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.

The spatial patterns of beta-amyloid (Abeta) deposits in dementia with Lewy bodies and Alzheimer’s disease

The spatial patterns of diffuse, primitive and classic beta-amyloid (Abeta) deposits were studied in regions of the temporal lobe in cases of ‘pure’ Dementai with Lewy bodies (DLB), cases of DLB with associated Alzheimer’s disease (AD) (DLB/AD) and cases of ‘pure’ AD. Abeta deposits occurred in clusters in all patient groups. In the majority of brain areas studied, either a single large (=6400 micron) cluster of Abeta deposits was present or Abeta deposits occurred in smaller clusters which were regularly distributed parallel to the tissue boundary. No significant differences in the spatial patterns of Abeta deposits were observed in ‘pure’ DLB compared with DLB/AD. The spatial patterns of Abeta deposits in DLB/AD cases were generally similar to those observed in AD. However, in DLB/AD the primitive deposits occurred less often in a single large cluster and more often in smaller, regularly spaced clusters than in ‘pure’ AD. The data suggest a more specific pattern of degeneration associated with Abeta deposition in DLB/AD cases compared with ‘pure’ AD.