The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain

Fabry disease is an X-linked lysosomal storage disorder characterised by accumulation of glycosphingolipids, and accompanied by clinical manifestations, such as cardiac disorders, renal failure, pain and peripheral neuropathy. Globotriaosylsphingosine (lyso-Gb3), a deacylated form of globotriaosylceramide (Gb3), has emerged as a marker of Fabry disease. We investigated the link between Gb3, lyso-Gb3 and pain. Plantar administration of lyso-Gb3 or Gb3 caused mechanical allodynia in healthy mice. In vitro application of 100nM lyso-Gb3 caused uptake of extracellular calcium in 10% of sensory neurons expressing nociceptor markers, rising to 40% of neurons at 1μM, a concentration that may occur in Fabry disease patients. Peak current densities of voltage-dependent Ca(2+) channels were substantially enhanced by application of 1μM lyso-Gb3. These studies suggest a direct role for lyso-Gb3 in the sensitisation of peripheral nociceptive neurons that may provide an opportunity for therapeutic intervention in the treatment of Fabry disease-associated pain

Education associated with a delayed onset of terminal decline

Background: the terminal decline hypothesis suggests an acceleration in the rate of loss of cognitive function before death. Evidence about the association of educational attainment and the onset of terminal decline is scarce. Objective: to investigate the association of education with the onset of terminal decline in global cognitive function measured by Mini Mental State Exam (MMSE) scores. Subjects: deceased participants of the Cambridge City over 75 Cohort Study who were interviewed at about 2, 7, 9, 13, 17 and 21 years after baseline. Methods: regular and Tobit random change point growth models were fitted to MMSE scores to identify the onset of terminal decline and assess the effect of education on this onset. Results: people who left school at an older age had a delayed onset of terminal decline. Thus better educated individuals experience a slightly shorter period of faster decline before death. Conclusion: an important finding emerging from our work is that education does appear to delay the onset of terminal decline, although only by a limited amount

Internal and external cooling methods and their effect on body temperature, thermal perception and dexterity

© 2018 The Authors. Published by PLOS. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1371/journal.pone.0191416© 2018 Maley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective The present study aimed to compare a range of cooling methods possibly utilised by occupational workers, focusing on their effect on body temperature, perception and manual dexterity. Methods Ten male participants completed eight trials involving 30 min of seated rest followed by 30 min of cooling or control of no cooling (CON) (34C, 58% relative humidity). The cooling methods utilised were: ice cooling vest (CV0), phase change cooling vest melting at 14C (CV14), evaporative cooling vest (CVEV), arm immersion in 10C water (AI), portable water-perfused suit (WPS), heliox inhalation (HE) and ice slushy ingestion (SL). Immediately before and after cooling, participants were assessed for fine (Purdue pegboard task) and gross (grip and pinch strength) manual dexterity. Rectal and skin temperature, as well as thermal sensation and comfort, were monitored throughout. Results Compared with CON, SL was the only method to reduce rectal temperature (P = 0.012). All externally applied cooling methods reduced skin temperature (P0.05). Conclusion The present study observed that ice ingestion or ice applied to the skin produced the greatest effect on rectal and skin temperature, respectively. AI should not be utilised if workers require subsequent fine manual dexterity. These results will help inform future studies investigating appropriate pre-cooling methods for the occupational worker.This project is financially supported by the US Government through the Technical Support Working Group within the Combating Terrorism Technical Support Office.Published versio

Metaflammasome components in the human brain: a role in dementia with alzheimer's pathology?

Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimer's disease (AD). Evidence in obesity and type-2 diabetes suggests a role for a metabolic inflammasome (“metaflammasome”) in mediating chronic inflammation in peripheral organs implicating IKKβ (inhibitor of nuclear factor kappa-B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c-jun N-terminal kinase), and PKR (double-stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKKβ [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analyzed to investigate whether the proteins were expressed together and in relation with metabolic disorders, dementia, Alzheimer's pathology and APOE genotype. We observed a change from a positive to a negative association between the proteins and hypertension according to the dementia status. Type-2 diabetes was negatively related with the proteins among participants without dementia; whereas participants with dementia and AD pathology showed a positive association with JNK. A significant association between IKKβ and JNK in participants with dementia and AD pathology was observed, but not in those without dementia. Otherwise, weak to moderate associations were observed among the protein loads. The presence of dementia was significantly associated with JNK and negatively associated with IKKβ and IRS1. Cognitive scores showed a significant positive relationship with IKKβ and a negative with IRS1, JNK and PKR. The proteins were significantly associated with pathology in Alzheimer's participants with the relationship being inverse or not significant in participants without dementia. Expression of the proteins was not related to APOE genotype. These findings highlight a role for these proteins in AD pathophysiology but not necessarily as a complex

Microinfarcts in an older population-representative brain donor cohort (MRC CFAS): Prevalence, relation to dementia and mobility, and implications for the evaluation of cerebral Small Vessel Disease.

INTRODUCTION: Microinfarcts, small ischaemic foci common in ageing brain, are associated with dementia and gait dysfunction. We determined their relationship with dementia, mobility and cerebrovascular disease in an older population-representative brain donor cohort. These data on microinfarcts were evaluated in relation to pathological assessments of clinically significant cerebral small vessel disease (SVD). METHODS: Microinfarcts were assessed in the MRC Cognitive Function and Ageing Study (n = 331). Nine brain areas were staged according to the number of areas affected. RESULTS: 36% of brains showed at least 1 microinfarct. Higher cortical microinfarct stage was associated with dementia at death (OR 1.41, 95% CI 1.02; 1.96, P = 0.038), whilst cortical and subcortical microinfarct stages were associated with impaired mobility (OR 1.36, 95% CI 1.05-1.74; P 0.018) and falls (OR 1.96, 95% CI 1.11-3.43; P = 0.02). Adding data on microinfarcts to a definition of SVD, based on white matter lesions (WMLs), lacunes and significant arteriosclerosis, were assessed by comparing area under ROC curve (AUC) with and without microinfarcts. SVD was significantly related to dementia status with or without inclusion of microinfarcts. Modelling potential pathological definitions of SVD to predict dementia or impaired mobility indicated optimal prediction using combined assessment of WMLs, lacunes and microinfarcts. CONCLUSION: Cortical (dementia) and subcortical microinfarcts (impaired mobility) are related to diverse clinical outcomes. Optimal pathological assessment of significant SVD in brain ageing is achieved based on WMLs, lacunes and microinfarcts and may not require subjective assessment of the extent and severity of arteriosclerosis

Neuropsychological profiles of vascular disease and risk of dementia: implications for defining vascular cognitive impairment no dementia (VCI-ND)

$\textbf{Background}$ vascular cognitive impairment no dementia (VCI-ND) defines a preclinical phase of cognitive decline associated with vascular disorders. The neuropsychological profile of VCI-ND may vary according to different vascular conditions. $\textbf{Objective}$ to determine the neuropsychological profile of individuals with no dementia and vascular disorders, including hypertension, peripheral vascular disease (PVD), coronary heart disease (CHD), diabetes and stroke. Risk of 2-year incident dementia in individuals with disease and cognitive impairment was also tested. $\textbf{Methods}$ participants were from the Cognitive Function and Ageing Study. At baseline, 13,004 individuals aged ≥65 years were enrolled into the study. Individuals were grouped by baseline disorder status (present, absent) for each condition. Cognitive performance was assessed using the Mini Mental State Examination (MMSE) and the Cambridge Cognitive Examination (CAMCOG). Dementia was assessed at 2 years. $\textbf{Results}$ in the cross-sectional analysis, hypertension, PVD and CHD were not associated with cognitive impairment. Stroke was associated with impaired global (MMSE) and CAMCOG sub-scale (including memory and non-memory) scores. Diabetes was associated with impairments in global cognitive function (MMSE) and abstract thinking. In the longitudinal analysis, cognitive impairments were associated with incident dementia in all groups. $\textbf{Conclusion}$ the neuropsychological profile in individuals with vascular disorders depends on the specific condition investigated. In all conditions cognitive impairment is a risk factor for dementia. A better understanding of which cognitive domains are affected in different disease groups could help improve operationalisation of the neuropsychological criteria for VCI-ND and could also aid with the development of dementia risk prediction models in persons with vascular disease.MRC CFAS has been funded by the Medical Research Council (G9901400) and Department of Health

The impact of environmental temperature deception on perceived exertion during fixed-intensity exercise in the heat in trained-cyclists

Purpose This study examined the effect of environmental temperature deception on the rating of perceived exertion (RPE) during 30 min of fixed-intensity cycling in the heat. Methods Eleven trained male cyclists completed an incremental cycling test and four experimental trials. Trials consisted of 30 min cycling at 50% Pmax, once in 24 °C (CON) and three times in 33 °C. In the hot trials, participants were provided with accurate temperature feedback (HOT), or were deceived to believe the temperature was 28 °C (DECLOW) or 38 °C (DECHIGH). During cycling, RPE was recorded every 5 min. Rectal and skin temperature, heart rate and oxygen uptake were continuously measured. Data were analysed using linear mixed model methods in a Bayesian framework, magnitude-based inferences (Cohens d), and the probability that d exceeded the smallest worthwhile change. Results RPE was higher in the heat compared to CON, but not statistically different between the hot conditions (mean [95% credible interval]; DECLOW: 13.0 [11.9, 14.1]; HOT: 13.0 [11.9, 14.1]; DECHIGH: 13.1 [12.0, 14.2]). Heart rate was significantly higher in DECHIGH (141 b·min−1 [132, 149]) compared to all other conditions (DECLOW: 138 b·min−1 [129, 146]; HOT: 138 b·min−1 [129, 145]) after 10 min; however, this did not alter RPE. All other physiological variables did not differ between the hot conditions. Conclusion Participants were under the impression they were cycling in different environments; however, this did not influence RPE. These data suggest that for trained cyclists, an awareness of environmental temperature does not contribute to the generation of RPE when exercising at a fixed intensity in the heat

An Actuarial Analysis of Calibration of Crop Insurance Premiums to Heterogeneous Risks

This paper examines whether the loadings on the crop insurance premium rates for risks such as moral hazard and adverse selection are adequate. From the discrete choice (tobit) analysis conducted, we discover that the premium loadings for 75% coverage level are not adequate, resulting in losses for the Risk Management Agency

Addressing the welfare needs of farmed lumpfish: knowledge gaps, challenges and solutions

Lumpfish (Cyclopterus lumpus L.) are increasingly being used as cleaner fish to control parasitic sea lice, one of the most important threats to salmon farming. However, lumpfish cannot survive feeding solely on sea lice, and their mortality in salmon net pens can be high, which has welfare, ethical and economic implications. The industry is under increasing pressure to improve the welfare of lumpfish, but little guidance exists on how this can be achieved. We undertook a knowledge gap and prioritisa tion exercise using a Delphi approach with participants from the fish farming sector, animal welfare, academia and regulators to assess consensus on the main challenges and potential solutions for improving lumpfish welfare. Consensus among participants on the utility of 5 behavioural and 12 physical welfare indicators was high (87–89%), reliable (Cronbach's alpha = 0.79, 95CI = 0.69–0.92) and independent of participant background. Participants highlighted fin erosion and body damage as the most use ful and practical operational welfare indicators, and blood parameters and behav ioural indicators as the least practical. Species profiling revealed profound differences between Atlantic salmon and lumpfish in relation to behaviour, habitat preferences, nutritional needs and response to stress, suggesting that applying a common set of welfare standards to both species cohabiting in salmon net-pens may not work well for lumpfish. Our study offers 16 practical solutions for improving the welfare of lumpfish and illustrates the merits of the Delphi approach for achieving consensus among stakeholders on welfare needs, targeting research where is most needed and generating workable solutions.info:eu-repo/semantics/publishedVersio

Consensus and ordering in language dynamics

We consider two social consensus models, the AB-model and the Naming Game restricted to two conventions, which describe a population of interacting agents that can be in either of two equivalent states (A or B) or in a third mixed (AB) state. Proposed in the context of language competition and emergence, the AB state was associated with bilingualism and synonymy respectively. We show that the two models are equivalent in the mean field approximation, though the differences at the microscopic level have non-trivial consequences. To point them out, we investigate an extension of these dynamics in which confidence/trust is considered, focusing on the case of an underlying fully connected graph, and we show that the consensus-polarization phase transition taking place in the Naming Game is not observed in the AB model. We then consider the interface motion in regular lattices. Qualitatively, both models show the same behavior: a diffusive interface motion in a one-dimensional lattice, and a curvature driven dynamics with diffusing stripe-like metastable states in a two-dimensional one. However, in comparison to the Naming Game, the AB-model dynamics is shown to slow down the diffusion of such configurations.Comment: 7 pages, 6 figure