Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology

Light-intensity physical activity and cardiometabolic biomarkers in US adolescents

BackgroundThe minimal physical activity intensity that would confer health benefits among adolescents is unknown. The purpose of this study was to examine the associations of accelerometer-derived light-intensity (split into low and high) physical activity, and moderate- to vigorous-intensity physical activity with cardiometabolic biomarkers in a large population-based sample.MethodsThe study is based on 1,731 adolescents, aged 12&ndash;19 years from the 2003/04 and 2005/06 National Health and Nutrition Examination Survey. Low light-intensity activity (100&ndash;799 counts/min), high light-intensity activity (800 counts/min to &lt;4 METs) and moderate- to vigorous-intensity activity (&ge;4 METs, Freedson age-specific equation) were accelerometer-derived. Cardiometabolic biomarkers, including waist circumference, systolic blood pressure, diastolic blood pressure, HDL-cholesterol, and C-reactive protein were measured. Triglycerides, LDL- cholesterol, insulin, glucose, and homeostatic model assessments of &beta;-cell function (HOMA-%B) and insulin sensitivity (HOMA-%S) were also measured in a fasting sub-sample (n=807).ResultsAdjusted for confounders, each additional hour/day of low light-intensity activity was associated with 0.59 (95% CI: 1.18&ndash;0.01) mmHG lower diastolic blood pressure. Each additional hour/day of high light-intensity activity was associated with 1.67 (2.94&ndash;0.39) mmHG lower diastolic blood pressure and 0.04 (0.001&ndash;0.07) mmol/L higher HDL-cholesterol. Each additional hour/day of moderate- to vigorous-intensity activity was associated with 3.54 (5.73&ndash;1.35) mmHG lower systolic blood pressure, 5.49 (1.11&ndash;9.77)% lower waist circumference, 25.87 (6.08&ndash;49.34)% lower insulin, and 16.18 (4.92&ndash;28.53)% higher HOMA-%S.ConclusionsTime spent in low light-intensity physical activity and high light-intensity physical activity had some favorable associations with biomarkers. Consistent with current physical activity recommendations for adolescents, moderate- to vigorous-intensity activity had favorable associations with many cardiometabolic biomarkers. While increasing MVPA should still be a public health priority, further studies are needed to identify dose-response relationships for light-intensity activity thresholds to inform future recommendations and interventions for adolescents.</div

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Actigraph Accelerometer-Defined Boundaries for Sedentary Behaviour and Physical Activity Intensities in 7 Year Old Children

Background: Accurate objective assessment of sedentary and physical activity behaviours during childhood is integral to the understanding of their relation to later health outcomes, as well as to documenting the frequency and distribution of physical activity within a population.Purpose: To calibrate the Actigraph GT1M accelerometer, using energy expenditure (EE) as the criterion measure, to define thresholds for sedentary behaviour and physical activity categories suitable for use in a large scale epidemiological study in young children.Methods: Accelerometer-based assessments of physical activity (counts per minute) were calibrated against EE measures (kcal.kg(-1).hr(-1)) obtained over a range of exercise intensities using a COSMED K4b(2) portable metabolic unit in 53 seven-year-old children. Children performed seven activities: lying down viewing television, sitting upright playing a computer game, slow walking, brisk walking, jogging, hopscotch and basketball. Threshold count values were established to identify sedentary behaviour and light, moderate and vigorous physical activity using linear discriminant analysis (LDA) and evaluated using receiver operating characteristic (ROC) curve analysis.Results: EE was significantly associated with counts for all non-sedentary activities with the exception of jogging. Threshold values for accelerometer counts (counts. minute(-1)) were = 3841 for light, moderate and vigorous physical activity respectively. The area under the ROC curves for discrimination of sedentary behaviour and vigorous activity were 0.98. Boundaries for light and moderate physical activity were less well defined (0.61 and 0.60 respectively). Sensitivity and specificity were higher for sedentary (99% and 97%) and vigorous (95% and 91%) than for light (60% and 83%) and moderate (61% and 76%) thresholds.Conclusion: The accelerometer cut points established in this study can be used to classify sedentary behaviour and to distinguish between light, moderate and vigorous physical activity in children of this age

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

Background: reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN. Methods: to test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. Results: correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan-caspase inhibited cells. Conclusions: in summary, reovirus is potently oncolytic in a broad panel of SCCHN cell lines. Attempts to define sensitivity/resistance by analysis of the EGFR/Ras/MAPK pathway have failed to provide a clear predictive biomarker of response. Further analysis of material from in vitro and clinical studies is ongoing in an attempt to shed further light on this issue

Research on information systems failures and successes: Status update and future directions

The final publication is available at Springer via http://dx.doi.org/10.1007/s10796-014-9500-yInformation systems success and failure are among the most prominent streams in IS research. Explanations of why some IS fulfill their expectations, whereas others fail, are complex and multi-factorial. Despite the efforts to understand the underlying factors, the IS failure rate remains stubbornly high. A Panel session was held at the IFIP Working Group 8.6 conference in Bangalore in 2013 which forms the subject of this Special Issue. Its aim was to reflect on the need for new perspectives and research directions, to provide insights and further guidance for managers on factors enabling IS success and avoiding IS failure. Several key issues emerged, such as the need to study problems from multiple perspectives, to move beyond narrow considerations of the IT artifact, and to venture into underexplored organizational contexts, such as the public sector. © 2014 Springer Science+Business Media New York

Characterization of a fluvial aquifer at a range of depths and scales: the Triassic St Bees Sandstone Formation, Cumbria, UK

Fluvial sedimentary successions represent porous media that host groundwater and geothermal resources. Additionally, they overlie crystalline rocks hosting nuclear waste repositories in rift settings. The permeability characteristics of an arenaceous fluvial succession, the Triassic St Bees Sandstone Formation in England (UK), are described, from core-plug to well-test scale up to ~1 km depth. Within such lithified successions, dissolution associated with the circulation of meteoric water results in increased permeability (K~10−1–100 m/day) to depths of at least 150 m below ground level (BGL) in aquifer systems that are subject to rapid groundwater circulation. Thus, contaminant transport is likely to occur at relatively high rates. In a deeper investigation (> 150 m depth), where the aquifer has not been subjected to rapid groundwater circulation, well-test-scale hydraulic conductivity is lower, decreasing from K~10−2 m/day at 150–400 m BGL to 10−3 m/day down-dip at ~1 km BGL, where the pore fluid is hypersaline. Here, pore-scale permeability becomes progressively dominant with increasing lithostatic load. Notably, this work investigates a sandstone aquifer of fluvial origin at investigation depths consistent with highly enthalpy geothermal reservoirs (~0.7–1.1 km). At such depths, intergranular flow dominates in unfaulted areas with only minor contribution by bedding plane fractures. However, extensional faults represent preferential flow pathways, due to presence of high connective open fractures. Therefore, such faults may (1) drive nuclear waste contaminants towards the highly permeable shallow (< 150 m BGL) zone of the aquifer, and (2) influence fluid recovery in geothermal fields

Recombinant HIV Envelope Proteins Fail to Engage Germline Versions of Anti-CD4bs bNAbs

Vaccine candidates for HIV-1 so far have not been able to elicit broadly neutralizing antibodies (bNAbs) although they express the epitopes recognized by bNAbs to the HIV envelope glycoprotein (Env). To understand whether and how Env immunogens interact with the predicted germline versions of known bNAbs, we screened a large panel (N:56) of recombinant Envs (from clades A, B and C) for binding to the germline predecessors of the broadly neutralizing anti-CD4 binding site antibodies b12, NIH45-46 and 3BNC60. Although the mature antibodies reacted with diverse Envs, the corresponding germline antibodies did not display Env-reactivity. Experiments conducted with engineered chimeric antibodies combining the mature and germline heavy and light chains, respectively and vice-versa, revealed that both antibody chains are important for the known cross-reactivity of these antibodies. Our results also indicate that in order for b12 to display its broad cross-reactivity, multiple somatic mutations within its VH region are required. A consequence of the failure of the germline b12 to bind recombinant soluble Env is that Env-induced B-cell activation through the germline b12 BCR does not take place. Our study provides a new explanation for the difficulties in eliciting bNAbs with recombinant soluble Env immunogens. Our study also highlights the need for intense efforts to identify rare naturally occurring or engineered Envs that may engage the germline BCR versions of bNAbs

A systematic review of intervention effects on potential mediators of children\u27s physical activity

Background : Many interventions aiming to increase children&rsquo;s physical activity have been developed and implemented in a variety of settings, and these interventions have previously been reviewed; however the focus of these reviews tends to be on the intervention effects on physical activity outcomes without consideration of the reasons and pathways leading to intervention success or otherwise. To systematically review the efficacy of physical activity interventions targeting 5-12 year old children on potential mediators and, where possible, to calculate the size of the intervention effect on the potential mediator. Methods : A systematic search identified intervention studies that reported outcomes on potential mediators of physical activity among 5-12 year old children. Original research articles published between 1985 and April 2012 were reviewed. Results : Eighteen potential mediators were identified from 31 studies. Positive effects on cognitive/psychological potential mediators were reported in 15 out of 31 studies. Positive effects on social environmental potential mediators were reported in three out of seven studies, and no effects on the physical environment were reported. Although no studies were identified that performed a mediating analysis, 33 positive intervention effects were found on targeted potential mediators (with effect sizes ranging from small to large) and 73% of the time a positive effect on the physical activity outcome was reported. Conclusions : Many studies have reported null intervention effects on potential mediators of children&rsquo;s physical activity; however, it is important that intervention studies statistically examine the mediating effects of interventions so the most effective strategies can be implemented in future programs