Convective infux/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways

Tracers injected into CSF pass into the brain alongside arteries and out again. This has been recently termed the "glymphatic system" that proposes tracers enter the brain along periarterial "spaces" and leave the brain along the walls of veins. The object of the present study is to test the hypothesis that: (1) tracers from the CSF enter the cerebral cortex along pial-glial basement membranes as there are no perivascular "spaces" around cortical arteries, (2) tracers leave the brain along smooth muscle cell basement membranes that form the Intramural Peri-Arterial Drainage (IPAD) pathways for the elimination of interstitial fluid and solutes from the brain. 2 μL of 100 μM soluble, fluorescent fixable amyloid β (Aβ) were injected into the CSF of the cisterna magna of 6-10 and 24-30 month-old male mice and their brains were examined 5 and 30 min later. At 5 min, immunocytochemistry and confocal microscopy revealed Aβ on the outer aspects of cortical arteries colocalized with α-2 laminin in the pial-glial basement membranes. At 30 min, Aβ was colocalised with collagen IV in smooth muscle cell basement membranes in the walls of cortical arteries corresponding to the IPAD pathways. No evidence for drainage along the walls of veins was found. Measurements of the depth of penetration of tracer were taken from 11 regions of the brain. Maximum depths of penetration of tracer into the brain were achieved in the pons and caudoputamen. Conclusions drawn from the present study are that tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. The exit route is along IPAD pathways in which Aβ accumulates in cerebral amyloid angiopathy (CAA) in Alzheimer's disease. Results from this study suggest that CSF may be a suitable route for delivery of therapies for neurological diseases, including CAA

Phasing for medical sequencing using rare variants and large haplotype reference panels.

Motivation: There is growing recognition that estimating haplotypes from high coverage sequencing of single samples in clinical settings is an important problem. At the same time very large datasets consisting of tens and hundreds of thousands of high-coverage sequenced samples will soon be available. We describe a method that takes advantage of these huge human genetic variation resources and rare variant sharing patterns to estimate haplotypes on single sequenced samples. Sharing rare variants between two individuals is more likely to arise from a recent common ancestor and, hence, also more likely to indicate similar shared haplotypes over a substantial flanking region of sequence.Results: Our method exploits this idea to select a small set of highly informative copying states within a Hidden Markov Model (HMM) phasing algorithm. Using rare variants in this way allows us to avoid iterative MCMC methods to infer haplotypes. Compared to other approaches that do not explicitly use rare variants we obtain significant gains in phasing accuracy, less variation over phasing runs and improvements in speed. For example, using a reference panel of 7420 haplotypes from the UK10K project, we are able to reduce switch error rates by up to 50% when phasing samples sequenced at high-coverage. In addition, a single step rephasing of the UK10K panel, using rare variant information, has a downstream impact on phasing performance. These results represent a proof of concept that rare variant sharing patterns can be utilized to phase large high-coverage sequencing studies such as the 100 000 Genomes Project dataset.</br

Observational Intensity Bias Associated with Illness Adjustment: Cross Sectional Analysis of Insurance Claims

Objective: To determine the bias associated with frequency of visits by physicians in adjusting for illness, using diagnoses recorded in administrative databases. Setting: Claims data from the US Medicare program for services provided in 2007 among 306 US hospital referral regions. Design: Cross sectional analysis. Participants 20% sample of fee for service Medicare beneficiaries residing in the United States in 2007 (n=5 153 877)

Challenging empowerment: AIDS-affected southern African children and the need for a multi-level relational approach

Critics of empowerment have highlighted the concept's mutability, focus on individual transformation, one-dimensionality and challenges of operationalisation. Relating these critiques to children's empowerment raises new challenges. Drawing on scholarship on children's subjecthood and exercise of power, alongside empirical research with children affected by AIDS, I argue that empowerment envisaged as individual self-transformation and increased capacity to act independently offers little basis for progressive change. Rather it is essential to adopt a relational approach that recognises the need to transform power relationships at multiple levels. This analysis has implications for our wider understanding of empowerment in the 21st century. © The Author(s) 2013.This research was funded by DFID

Forty-seven Years of Research on the Devon Island Ice Cap, Arctic Canada

The Devon Island ice cap has been the subject of scientific study for almost half a century, beginning with the first mass balance measurements in 1961. Research on the ice cap was the first to investigate (1) the role of meltwater in seasonal ice-velocity variations on a polythermal Arctic ice cap, (2) the use of air temperature rather than net radiation as a proxy for the energy driving surface melt, and (3) the influence of the changing frequency of specific synoptic weather configurations on glacier melt and mass balance. Other research has included investigations of ice cap geometry, flow dynamics, and mass balance; ice core analyses for records of past climate and contaminant deposition; and studies of changes in ice cap area and volume and their relationship to surface mass balance and ice dynamics. Current research includes ground studies connected to efforts to calibrate and validate the radar altimeter that will be carried by the European Space Agency’s (ESA) CryoSat2 satellite, and a major collaborative Canadian International Polar Year (IPY) project focused on the Belcher Glacier, on the northeast side of the ice cap, that examines hydrodynamics of large tidewater glaciers. This paper summarizes our current knowledge of the Devon Island ice cap and identifies some of the outstanding questions that continue to limit our understanding of climate-ice cap interactions in Arctic regions.La calotte glaciaire de l’île Devon fait l’objet d’une étude scientifique depuis près d’un demi-siècle, les premières mesures du bilan massique remontant à 1961. C’est la première fois que des travaux de recherche sur la calotte glaciaire permettent de faire enquête sur 1) le rôle de l’eau de fonte dans les variations caractérisant la vélocité de la glace d’une calotte glaciaire polytherme de l’Arctique; 2) l’utilisation de la température de l’air au lieu du bilan radiatif en surface en guise d’approximation pour la fonte superficielle conductrice d’énergie, et 3) l’influence exercée par la fréquence changeante de configurations climatiques synoptiques spécifiques sur la fonte du glacier et le bilan massique. Parmi les autres travaux de recherche, notons des enquêtes sur la géométrie de la calotte glaciaire, la dynamique des débits d’écoulement et le bilan massique; l’analyse des enregistrements relatifs aux carottes glaciaires en ce qui a trait à d’anciens dépôts climatiques et dépôts de contaminants; et l’étude des changements caractérisant l’aire et le volume de la calotte glaciaire de même que leur relation par rapport au bilan massique en surface et à la dynamique des glaces. Par ailleurs, les travaux de recherche actuels prennent la forme d’études sur le terrain se rapportant aux efforts visant à calibrer et à valider l’altimètre radar, études qui seront effectuées par le satellite CryoSat2 de l’Agence spatiale européenne (ASE), et un projet d’envergure en collaboration avec l’Année polaire internationale (API) au Canada portant sur le glacier Belcher, du côté nord-est de la carotte glaciaire, projet qui examine l’hydrodynamique des gros glaciers de marée. La présente communication résume nos connaissances actuelles de la calotte glaciaire de l’île Devon de même que certaines des questions en suspens qui continuent de restreindre la façon dont nous comprenons les interactions entre le climat et la calotte glaciaire dans les régions arctiques

Northwest Africa 10658, a Uniquely Shocked Eucrite with a Range of Deformation, Transformation and Recrystallization Effects

Impacts are a fundamental geologic process that has influenced the formation and modification of asteroids and planets throughout time. An important part of the impact history of the solar system is recorded in shocked meteorites. The asteroid Vesta has experienced large impacts, evidenced by two ~400-500 km impact structures that overprint the south pole region. While a range of shock-induced effects such as brecciation, melting and the formation of maskelynite has been reported in howardite-eucrite-diogenite (HED) meteorites originating from Vesta, high-pressure minerals have previously only been described in two eucrites [1-2]. Here, we present results on an inventory of shock effects and high-pressure minerals preserved in the polymict eucrite NWA 10658

Enhanced cerebral blood volume under normobaric hyperoxia in the J20-hAPP mouse model of Alzheimer’s disease

Early impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer’s disease (AD). Studies have shown impaired neurovascular function in several mouse models of AD, including the J20-hAPP mouse. In this study, we aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. A thinned cranial window was prepared to allow access to cortical vasculature and imaged using 2D-optical imaging spectroscopy (2D-OIS). After chronic imaging sessions where the skull was intact, a terminal acute imaging session was performed where an electrode was inserted into the brain to record simultaneous neural activity. We found that cerebral haemodynamic changes were significantly enhanced in J20-hAPP mice compared with controls in response to physiological stimulations, potentially due to the significantly higher neural activity (hyperexcitability) seen in the J20-hAPP mice. Thus, neurovascular coupling remained preserved under a chronic imaging preparation. Further, under hyperoxia, the baseline blood volume and saturation of all vascular compartments in the brains of J20-hAPP mice were substantially enhanced compared to WT controls, but this effect disappeared under normoxic conditions. This study highlights novel findings not previously seen in the J20-hAPP mouse model, and may point towards a potential therapeutic strategy

Our Sun. IV. The Standard Model and Helioseismology: Consequences of Uncertainties in Input Physics and in Observed Solar Parameters

Helioseismology provides a powerful tool to explore the deep interior of the Sun: for example, the adiabatic sound speed can be inferred with an accuracy of a few parts in 10,000. This has become a serious challenge to theoretical models of the Sun. Therefore, we have undertaken a self-consistent, systematic study of sources of uncertainties in the standard solar model, which must be understood before the helioseismic observations can be used as constraints on theory. We find that the largest uncertainty in the sound speed in the solar interior, namely, 3 parts in 1000, arises from uncertainties in the observed photospheric abundances of the elements; uncertainties of 1 part in 1000 arise from (1) the 4% uncertainty in the OPAL opacities, (2) the 5% uncertainty in the basic pp nuclear reaction rate, (3) the 15% uncertainty in the diffusion constants for the gravitational settling of helium, and (4) the 50% uncertainties in diffusion constants for the heavier elements. (Other investigators have shown that similar uncertainties arise from uncertainties in the interior equation of state and in rotation-induced turbulent mixing.) The predicted pre-main-sequence solar lithium depletion is a factor of order 20 (an order of magnitude larger than that predicted by earlier models that neglected gravitational settling and used older opacities), and is uncertain by a factor of 2. The predicted neutrino capture rate is uncertain by 30% for the Cl-37 experiment and by 3% for the Ga-71 experiments (not including uncertainties in the capture cross sections), while the B-8 neutrino flux is uncertain by 30%.Comment: LaTeX, 38 pages (including 8 figures); ApJ, in press. Added figures/color figurea available at http://www.cita.utoronto.ca/~boothroy/sun4.htm

Using alternatives to the car and risk of all-cause, cardiovascular and cancer mortality

Abstract: Objective: To investigate the associations between using alternatives to the car which are more active for commuting and non-commuting purposes and morbidity and mortality Methods: We conducted a prospective study using 358799 participants aged 37-73 from UK Biobank. Commute and non-commute travel were assessed at baseline in 2006-2010. We classified participants according to whether they relied exclusively on the car, or used alternative modes of transport that were more active at least some of the time. Main outcome measures were incident CVD and cancer, and CVD, cancer and all-cause mortality. We excluded events in the first two years and conducted analyses separately for those who regularly commuted and those who did not. Results: In maximally-adjusted models, regular commuters with more active patterns of travel on the commute had a lower risk of incident (HR 0.89, 95% CI 0.79 to 1.00) and fatal CVD (HR 0.70, 95% CI 0.51 to 0.95). Those regular commuters who also had more active patterns of non-commute travel had an even lower risk of fatal CVD (HR 0.57, 95% CI 0.39 to 0.85). Among those who were not regular commuters, more active patterns of travel were associated with a lower risk of all-cause mortality (HR 0.92, 95% CI 0.86 to 0.99). Conclusions: More active patterns of travel are associated with a reduced risk of incident and fatal CVD and all-cause mortality in adults. This is an important message for clinicians advising people about how to be physically active and reduce their risk of disease.JP, DO, SB and SS are supported by the Medical Research Council (Unit Programme Nos MC_UU_12015/1, MC_UU_12015/3 and MC_UU_12015/6) and KW is also supported by the British Heart Foundation (Intermediate Basic Science Research Fellowship grant No FS/12/58/29709). AAL is funded by the NIHR (RP 014-04-032), and the Public Health Policy Evaluation Unit are grateful for the support of the NIHR School of Public Health Research. This research was conducted using the UK Biobank resource (application No 20684). The work was also supported under the auspices of the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence at the University of Cambridge, for which funding from the British Heart Foundation, Economic and Social Research Council, Medical Research Council, National Institute for Health Research and the Wellcome Trust, under the auspices of the United Kingdom Clinical Research Collaboration, is gratefully acknowledged