Investigating white matter fibre density and morphology using fixel-based analysis

Voxel-based analysis of diffusion MRI data is increasingly popular. However, most white matter voxels contain contributions from multiple fibre populations (often referred to as crossing fibres), and therefore voxel-averaged quantitative measures (e.g. fractional anisotropy) are not fibre-specific and have poor interpretability. Using higher-order diffusion models, parameters related to fibre density can be extracted for individual fibre populations within each voxel (‘fixels’), and recent advances in statistics enable the multi-subject analysis of such data. However, investigating within-voxel microscopic fibre density alone does not account for macroscopic differences in the white matter morphology (e.g. the calibre of a fibre bundle). In this work, we introduce a novel method to investigate the latter, which we call fixel-based morphometry (FBM). To obtain a more complete measure related to the total number of white matter axons, information from both within-voxel microscopic fibre density and macroscopic morphology must be combined. We therefore present the FBM method as an integral piece within a comprehensive fixel-based analysis framework to investigate measures of fibre density, fibre-bundle morphology (cross-section), and a combined measure of fibre density and cross-section. We performed simulations to demonstrate the proposed measures using various transformations of a numerical fibre bundle phantom. Finally, we provide an example of such an analysis by comparing a clinical patient group to a healthy control group, which demonstrates that all three measures provide distinct and complementary information. By capturing information from both sources, the combined fibre density and cross-section measure is likely to be more sensitive to certain pathologies and more directly interpretable

Insulin-mediated changes in tau hyperphosphorylation and autophagy in a drosophila model of tauopathy and neuroblastoma cells

Almost 50 million people in the world are affected by dementia; the most prevalent form of which is Alzheimer’s disease (AD). Although aging is considered to be the main risk factor for AD, growing evidence from epidemiological studies suggests that type 2 diabetes mellitus (T2DM) increases the risk of dementia including AD. Defective brain insulin signaling has been suggested as an early event in AD and other tauopathies but the mechanisms that link these diseases are largely unknown. Tau hyperphosphorylation is a hallmark of neurofibrillary pathology and insulin resistance increases the number of neuritic plaques particularly in AD. Utilizing a combination of our Drosophila models of tauopathy (expressing the 2N4R-Tau) and neuroblastoma cells, we have attempted to decipher the pathways downstream of the insulin signaling cascade that lead to tau hyperphosphorylation, aggregation and autophagic defects. Using cell-based, genetic, and biochemical approaches we have demonstrated that tau phosphorylation at AT8 and PHF1 residues is enhanced in an insulin-resistant environment. We also show that insulin-induced changes in total and phospho-tau are mediated by the crosstalk of AKT, glycogen synthase kinase-3β, and extracellular regulating kinase located downstream of the insulin receptor pathway. Finally, we demonstrate a significant change in the levels of the key proteins in the mammalian target of rapamycin/autophagy pathway, implying an increased impairment of aggregated protein clearance in our transgenic Drosophila models and cultured neuroblastoma cells

Frame dragging with optical vortices

General Relativistic calculations in the linear regime have been made for electromagnetic beams of radiation known as optical vortices. These exotic beams of light carry a physical quantity known as optical orbital angular momentum (OAM). It is found that when a massive spinning neutral particle is placed along the optical axis, a phenomenon known as inertial frame dragging occurs. Our results are compared with those found previously for a ring laser and an order of magnitude estimate of the laser intensity needed for a precession frequency of 1 Hz is given for these "steady" beams of light.Comment: 13 pages, 2 figure

Construction contingency determination : a review of processes and techniques

Abstract

Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo

This work was funded by grants from the Biotechnology and Biological Sciences Research Council Experimental Research on Aging Initiative, Research Into Aging, The Sir Jules Thorne Research Trust, and The Hayward Foundation and Dermatrust

A short-duration dark adaptation protocol for assessment of age-related maculopathy

Dark adaptometry may be a useful diagnostic test and clinical trial endpoint for age-related maculopathy (ARM) because impaired night vision is a hallmark of early ARM. A novel dark adaptometer, the AdaptDx, was evaluated for the detection of ARM. The AdaptDx incorporates a 20-minute protocol optimized for the detection of ARM. ARM patients (N = 17) exhibited substantial dark adaptation impairment compared with normal adults (N = 17). The diagnostic sensitivity was 88% and the specificity was 100%. The diagnostic test characteristics of the AdaptDx are similar to previously reported studies using 60- to 120-minute protocols

A governance model for integrated primary/ secondary care for the health-reforming first world: results of a systematic review

Internationally, key health care reform elements rely on improved integration of care between the primary and secondary sectors. The objective of this systematic review is to synthesise the existing published literature on elements of current integrated primary/secondary health care. These elements and how they have supported integrated healthcare governance are presented.A systematic review of peer-reviewed literature from PubMed, MEDLINE, CINAHL, the Cochrane Library, Informit Health Collection, the Primary Health Care Research and Information Service, the Canadian Health Services Research Foundation, European Foundation for Primary Care, European Forum for Primary Care, and Europa Sinapse was undertaken for the years 2006-2012. Relevant websites were also searched for grey literature. Papers were assessed by two assessors according to agreed inclusion criteria which were published in English, between 2006-2012, studies describing an integrated primary/secondary care model, and had reported outcomes in care quality, efficiency and/or satisfaction.Twenty-one studies met the inclusion criteria. All studies evaluated the process of integrated governance and service delivery structures, rather than the effectiveness of services. They included case reports and qualitative data analyses addressing policy change, business issues and issues of clinical integration. A thematic synthesis approach organising data according to themes identified ten elements needed for integrated primary/secondary health care governance across a regional setting including: joint planning; integrated information communication technology; change management; shared clinical priorities; incentives; population focus; measurement - using data as a quality improvement tool; continuing professional development supporting joint working; patient/community engagement; and, innovation.All examples of successful primary/secondary care integration reported in the literature have focused on a combination of some, if not all, of the ten elements described in this paper, and there appears to be agreement that multiple elements are required to ensure successful and sustained integration efforts. Whilst no one model fits all systems these elements provide a focus for setting up integration initiatives which need to be flexible for adapting to local conditions and settings

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Elevated c-Src protein expression has been shown in breast cancer and <i>in vitro</i> evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan–Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (<i>P</i>=0.047) and lower recurrence rates on tamoxifen (<i>P</i>=0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (<i>P</i><0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (<i>P</i>=0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in <i>de novo</i> endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome